BETA (Bulletin of Experiment Treatments for AIDS) Online - No. 21 Published by the San Francisco AIDS Foundation - June 1994 ----------------------------------------------------------------- Electronically distributed for the Global Electronic Network for AIDS (GENA) by AEGIS/San Juan Capistrano * 714.248.2836 * 8N1 ----------------------------------------------------------------- Table of Contents The Use of Alternative Medicine in the Treatment of HIV Infection and AIDS Jason Heyman Aggressive Intervention in HIV Disease: An Interview with 4 San Francisco Physicians Mark Bowers Human Herpesvirus Type 6 (HHV-6): Cofactor or Opportunistic Infection in AIDS? Ronald A. Baker, PhD Recommended Reading Ronald A. Baker, PhD Vitamin and Nutritional Supplements in HIV Disease 1994 BETA Readership Survey: Readers' Comments Acyclovir Increases Survival! ù FDA Approval of d4T ù Alternative Therapies: Hope and Hype Ronald A. Baker,PhD Mycobacteria and HIV Infection Leslie Hanna Mycobacterium avium Complex (MAC): An Interview with Stephen D. Nightingale, MD Leslie Hanna A Master Protocol to Evaluate the Safety and Efficacy of Triple Combination Antiretroviral Therapy for HIV Infection David Barry, MD, Research Notes Ronald A. Baker, PhD ********* The Use of Alternative Medicine in the Treatment of HIV Infection and AIDS Jason Heyman Jason Heyman is a free-lance medical writer. A walk down the aisles of any health-food store will reveal a large number of popular alternative treatments from the past and present. In fact, some treatments that have been studied in multi-million dollar clinical trials were originally found on these shelves. In an effort to find effective treatments for HIV and related illnesses, the AIDS community has spent the past 12 years exploring many possible treatments. Before allopathic treatments such as AZT, ddI and ddC were available, people with AIDS sought help from healers of all types. Although more widely available today than ever before, reliable information on alternative treatments is still difficult to find. This article will explore both the history of alternative treatments for HIV infection and AIDS, and current research on a variety of alternative and holistic therapies. Since there is such an abundance of alternative treatments, this article will focus on the most popular herbal remedies and holistic approaches. The use of vitamins and nutritional supplements, and the off-label use of pharmaceutical drugs for HIV/AIDS will not be covered here. Terminology The terminology used to describe this field of medicine can be confusing since many terms are used interchangeably. Alternative medicine generally refers to all healing modalities that are not considered part of orthodox western medicine. The field of alternative medicine can be separated into 2 categories: alternative treatments, which are usually individual herbs or therapeutic activities such as massage, and holistic approaches, which are systems of healing that incorporate the body, mind and spirit. Holistic approaches such as traditional Chinese medicine usually derive from the healing traditions of indigenous cultures. Western medicine relies upon allopathy as an approach to healing. In the allopathic school of thought, treatments are designed to produce a condition antagonistic to the primary condition being treated. For example, if a patient is suffering from inflammation, a treatment is applied that reduces inflammation. The pervasiveness of this approach to medicine may make it hard to conceptualize any other. In contrast to allopathy, homeopathy attempts to treat conditions with therapies that mimic the condition being treated. Homeopathy will be discussed in more detail later. There are a variety of terms currently in use that describe alternative treatments. The term complementary applies to treatments that are used in conjunction with allopathic treatment, and is used in Europe in place of "alternative." Experimental refers to all treatments that have not been studied in controlled clinical trials and have not been approved for use by the U.S. Food and Drug Administration (FDA). Sometimes alternative treatments are referred to as natural treatments even though they do not have an organic basis (Smith, 1993). History and Politics The precise beginning of the alternative HIV/AIDS treatment movement is hard to establish, since at one time all treatments were considered experimental. Donald Abrams, MD, of San Francisco General Hospital, watched many of his patients try alternative treatments over the years, and observed their rise in popularity: "Born into the generation when smallpox and polio had been conquered with vaccines and the mysteries of Legionnaire's disease and toxic shock syndrome had been rapidly unraveled, many of the young adults threatened by HIV were surprised at the doggedly slow velocity of medical research....It was from within this community that the seeds were planted from which would grow an increasingly vocal and assertive alternative therapy movement" (Abrams, 1990). The popularity of alternative medicine among people with HIV/AIDS has fluctuated greatly over the years, particularly when AZT and other antiretroviral drugs became available. Recently, with disappointing results from clinical trials of antiretroviral drugs (such as the Concorde AZT study), many people have turned once again to alternative treatments. The research establishment has been slow to acknowledge the significance of alternative treatments and their widespread usage, but some changes have been made. At the 1992 VIII International Conference on AIDS in Amsterdam, for the first time in its history and under pressure from AIDS activists, alternative medicine was officially included among the oral presentations. That same year the Office of Alternative Medicine (OAM) was founded at the National Institutes of Health (NIH) to study the use of alternative medicine in the U.S. This includes treatments for both AIDS-related and non-AIDS-related conditions. The OAM has a relatively small budget of 2 million dollars, but its creation was a milestone in the history of alternative medicine. A survey published in the New England Journal of Medicine in January 1993 estimated that 34% of all Americans had used at least one form of alternative medicine in the previous year (Eisenberg, 1993). Although the survey was not limited to HIV and AIDS, the current popularity of alternative medicine is due in part to the increased attention it has received from people with AIDS. Most herbs and plant extracts that have been used to treat HIV and its related conditions, such as bitter melon, licorice root and aloe vera, have long been used in various indigenous medical systems. These systems usually combine a variety of herbs into a single treatment, in an effort to diminish side effects. Currently, however, and in keeping with the approach of allopathic medicine, herbs are being taken like pharmaceutical drugs_alone and in high doses. Used in this manner, herbs can have side effects that are just as dangerous as potent drugs. For example, licorice root has been known to cause high blood pressure, and mistletoe can cause liver toxicity (Kassler, 1991). The anecdotal experiences of individuals offer important insights into which treatments may be effective, but many people with HIV and AIDS have put themselves at risk by trying unproven or dangerous treatments. Anecdotal reports about the effectiveness of a treatment often spread by word-of-mouth and may create intense interest in a treatment. Information is also spread through AIDS treatment newsletters, and by buyers' clubs that specialize in selling alternative treatments. Despite little or no notice from the mainstream medical establishment or media, a treatment can become popular in the HIV/AIDS community within a short period of time. The impact of the use of alternative treatments on people with HIV and AIDS is often downplayed, but there can be serious repercussions. Other than the possibility of toxic side effects, alternative treatments can also drain financial resources. The costs of these treatments are almost never covered by health insurance, and some may be very expensive even though they come from inexpensive sources. A one-month supply of both bitter melon capsules and curcumin tablets costs approximately $60 per month (Healing Alternatives Foundation, 1994). A recent survey of health-food stores in New Orleans found that most stores recommend a combination of products that costs an average of $35 per month (Phillips, 1994). The difficulty of finding reliable information and reliable (i.e., non-fraudulent) alternative treatments provokes skepticism about their use. A debate has raged within the AIDS community for years about how to stay open to new, potentially helpful treatments without putting people's health and financial security at risk. In 1987 John James described the dilemma that still faces us today: "With so much unknown about AIDS, and with existing treatments so unsatisfactory, it will be hard to find consensus on how to distinguish legitimate, unproven and unconventional treatment attempts from unconscionable schemes to exploit people's desperation" (James, 1987). There is also an ongoing debate about the roles of government and business in the development of alternative treatments. Some people believe that the use of effective alternative treatments has been actively repressed by the research establishment; others believe that a self-selecting process is at work, whereby effective treatments become popular through their own successes in the community. Since alternative treatments by definition cannot be patented, money is an important element that is lacking in the development of these treatments. Since alternative treatments are of little interest to pharmaceutical companies, they are not pushed through the multi-million dollar development process the way that commercially viable pharmaceutical products are. In a few rare cases, drugs developed from alternative treatments have been patented, but these efforts have largely failed. An example of this is pseudohypericin, a form of hypericin, which showed disappointing results in a recent clinical trial. Of the millions of dollars that have been spent studying potential AIDS treatments, only a fraction of the money has gone into studying alternative treatments that do not have pharmaceutical backing. The few treatments studied with government funding include Compound Q (GLQ223), pseudohypericin, N-acetylcysteine (NAC) and marijuana (Marinol). Currently, there are plans for a small number of studies through the OAM, including a study of traditional Chinese medicine for the treatment of HIV-related sinusitis. For years, AIDS activists have demanded well-conducted clinical trials of treatments that are widely used in the AIDS community. One activist, Jon Greenberg, who died of AIDS in 1993, was intent on having alternative treatments undergo the same scrutiny as other drugs: "When questioned, most honest alternative practitioners will confess that their prescriptions of a specific dose of an herbal compound are based more on intuition than science. Although this may be acceptable in the hands of a gifted practitioner, too often these same treatments are sold over-the-counter with no more information than can be found on a jar of instant coffee" (Greenberg, 1992). A Review of Popular Alternative Treatments Acemannan Acemannan is a polysaccharide, or complex sugar, extracted from the aloe vera plant, Aloe barbardensis Miller. Aloe vera has been long noted for its healing properties, and is used in many cultures as a treatment for burns. Acemannan, which comes in an injectable form, was patented by Carrington Laboratories under the brand name Carrisyn. It has been FDA-approved for the treatment of fibrosarcoma, a form of cancer, in cats and dogs. People with HIV and AIDS sometimes use the raw form of aloe vera juice, but the concentrations of the active proteins may not be high enough to be effective (Korsia, 1991). Laboratory studies have shown that Carrisyn is active against HIV and enhances the efficacy of AZT (Kahlon, 1991). Carrisyn is also thought to stimulate the immune system, and has been promoted for use in combination with dinitrochlorobenzene (DNCB). There is much controversy about how these 2 treatments work, but perhaps as they become more widely used, better clinical studies will reveal more information (Andriote, 1993). Clinical studies of Carrisyn have generated contradictory results. In a trial conducted for Carrington Labs, half of the participants taking 250 mg four times a day had a 10% increase in CD4 cell counts (McDaniel, 1990). In contrast, a clinical trial conducted more recently by the Canadian HIV Clinical Trials group did not have similar findings. This placebo-controlled trial, which enrolled 62 patients with CD4 counts between 50 and 300, looked at whether Carrisyn was synergistic with AZT or ddI. The results showed that the CD4 counts of people taking Carrisyn declined more slowly than those on placebo but, by the end of the 48-week study, both groups had similar losses in CD4 cells. No difference was noted for p24 antigen, and no synergistic interaction with the antiretroviral drugs was observed (Singer, 1993). Bitter Melon Bitter melon, Momordica charantia, was first used for treating HIV by a Filipino man who was familiar with its traditional use as a treatment for leukemia in the Philippines. By 1992 bitter melon had become extremely popular, and support groups for people using it formed in many major cities around the country. Juice and/or tea made from the leaves and vines are used as a retention enema. Coated capsules of a freeze-dried powder are also available through buyers' clubs. Recently, the popularity of bitter melon has declined, even though there have been anecdotal reports of patients experiencing large increases in CD4 cells (Zhang, 1992). However, these findings have not been duplicated in a well-designed clinical trial. A protein from bitter melon, MAP 30, has been shown in laboratory tests to effectively kill HIV-infected cells and to inhibit a common herpesvirus (HSV-1) without causing cellular toxicity. It also stops cell-to-cell infection and inhibits viral replication (Lee-Huang, 1990). No clinical studies of MAP 30 have been implemented. Two other proteins isolated from the bitter melon plant have been found to have immunological effects. Although their modes of action are unclear, these proteins may work synergistically (Leung, 1987). Curcumin In 1993 reports began to circulate throughout the AIDS community about the alleged anti-HIV properties of curcumin, a compound found in the food spice turmeric. Interest was fueled by anecdotal experiences and laboratory studies that seemed to show that curcumin was a relatively safe and effective anti-HIV agent. A mainstay of traditional Indian and Chinese medicine, turmeric is now under study for its possible anti-cancer, anti-inflammatory and antioxidant properties. Due to its wide availability, turmeric could be important for the treatment of HIV infection in developing countries. Search Alliance in Los Angeles has recently completed the first study of curcumin in people with AIDS. No results have been released. DNCB Recently, there has been a resurgence in the popularity of DNCB (dinitrochlorobenzene), an alternative treatment that first became popular in the AIDS community in 1986. In fact, DNCB is now the most popular treatment sold at the Healing Alternatives Foundation buyers' club in San Francisco. This renewed interest can mostly be attributed to a group of zealous supporters in San Francisco. In recent years there have been anecdotal reports of individuals having good results with DNCB, particularly for the treatment of Kaposi's sarcoma lesions, but scientific research on the drug has shown negative results. In a recent study of 24 HIV positive gay men, CD4 cells dropped from a mean of 353 to 251, after 12 months of treatment with DNCB (Stricker, 1993). Using an unconventional theory to explain AIDS pathogenesis, supporters look at this same study and declare it a success. While most alternative treatments are derived from natural sources, DNCB is a chemical that was first used in photographic development. It was later used as a treatment for warts. Painted onto a patch of skin, DNCB causes an immune response known as delayed-type hypersensitivity. This is believed to cause a type of immune suppression that is desirable when fighting an autoimmune disease (Stricker, 1991). DNCB supporters argue that all treatments for HIV/AIDS except for PCP prophylaxis should be discontinued. Considering the many questions regarding the therapeutic effectiveness of DNCB, it may be dangerous to stop using other treatments that have shown beneficial effects (Gilden, 1993). Glycyrrhizin Glycyrrhizin is an extract from the root of the licorice plant Glycyrrhiza radix, which is sometimes referred to by the brand name Stronger Neo-Minophagen C (SNMC). Licorice root is a common ingredient in traditional Chinese herbal remedies, recommended for its anti-inflammatory properties. Currently, glycyrryzin is used in Japan as a treatment for hepatitis (Berger, 1990). Laboratory studies have found that it is also has a strong anti-HIV effect, and clinical studies have shown similar results (Ito, 1987; Hattori, 1989). Glycyrrhizin is administered intravenously, which is one reason why the treatment has not become very popular in the United States. Glycyrrhizin may cause serious side effects, including high blood pressure and heart complications (Kassler, 1991). A number of clinical studies of glycyrrhizin conducted in Japan have shown promising results, but a more recent study was less convincing. In 1993, researchers from 9 different Japanese universities followed 42 hemophilia patients with HIV. They found that glycyrrhizin at high doses (over 400 ml per day) caused increases in CD4 counts and improvements in clinical symptoms, but these changes were not statistically significant. More encouragingly, researchers observed improvement in liver function, which is damaged in many HIV positive hemophilia patients (Mori, 1993). Homeopathy Homeopathy, created in Germany in the nineteenth century by Dr. Samuel Hahnemann, remains popular in Europe to this day. It is believed that up to 25% of European doctors prescribe homeopathic remedies in their practice (Horvilleur, 1986). The scientific rationale behind homeopathy causes confusion because it is in direct opposition to the standard allopathic medical model prevalent in the U.S. Homeopathy ascribes to "the 'law of similars'-_that is, a substance which creates in overdose a specific set of symptoms in a healthy person will cure these similar symptoms in a sick person when given in very small doses" (Homeopathic Education Services, 1993). Apparently, homeopathy depends upon the ability of the immune system to mount a response. In people with advanced HIV disease such an immune response may not be possible. Homeopathic treatments, which usually come from herbs or flowers, were discovered by Hahnemann through trial and error. Oddly, he found that using less of an antigen provoked a proportionally stronger reaction. Therefore, the resulting remedy is usually a small sugar pill that no longer contains any of the actual antigen, since it has been extracted thousands of times. Therefore, these remedies are generally considered safe. Although there is no standardized training for homeopathic practitioners, it may be helpful to consult someone knowledgeable before beginning treatment (Horvilleur, 1986). Hypericin Extracted from the plant St. John's Wort (Hypericum perforatum), hypericin was used in Europe in the 1940s as a treatment for depression (Scott-Hartland, 1993-94). In laboratory studies, hypericin inhibits HIV replication in infected cells, protects laboratory animals from infection with some retroviruses, and is not toxic to cells. Hypericin has also been found to be effective against cytomegalovirus (CMV) and human papillomavirus (HPV), suggesting a wide range of uses in the treatment of people with HIV and AIDS (Meruelo, 1988; Schinazi, 1990). Compared to other alternative treatments, hypericin was on a drug development fast-track. Pharmaceutical backing eventually led to a government- funded clinical trial of pseudohypericin, an intravenous formulation made by VIMRx Pharmaceuticals. Unfortunately, this study showed that pseudohypericin caused phototoxicity (abnormal sensitivity to sunlight or other strong light) in patients taking 2 mg twice a week. The trial was stopped and restarted with lower doses (0.25 mg/kg, 2 or 3 times weekly.) This dose also caused light sensitivity, and the study was generally regarded as a failure (James, 1992). A new study of an orally administered version of pseudohypericin is currently underway at New York University (call 212-263-8724 for more information). These side effects were not reported in anecdotal use of the natural form of hypericin. It is possible that the natural form contains some important element that is lacking in the synthetic version. Plant extracts sold in health-food stores are rarely pure enough to contain only the desired chemical components; the more primitive form of a product may actually contain a synergistic combination of active agents. However, it is difficult to standardize the doses of natural hypericin, which lacks the financial backing of pseudohypericin. Iscador Iscador is an extract of the mistletoe plant, Viscum album. Animal studies of Iscador indicate that it has anti-tumor properties, and is active against lung cancer (Hajto, 1989; Khwaja, 1983). There also have been claims that Iscador has anti-HIV and immune-stimulatory properties (Gorter, 1992). Iscador is the first and only whole plant substance to be given Investigational New Drug (IND) status by the FDA for a clinical trial in people with AIDS. This means that the chemical components of this plant extract do not have to be analyzed separately, which could save millions of dollars and years of research. The IND has not been followed by a clinical trial, and research in the United States has stalled. Research has continued in Europe, where Iscador has been a popular alternative cancer therapy since the 1960s. The brand name Iscador is applied to the fermented and unfermented extracts of both European and Korean mistletoe. Mistletoe, a parasitic plant that lives on trees, can also be classified by the type of tree on which it grows. These different varieties of mistletoe may have different medicinal properties. According to one researcher, patients are not receiving the same type of mistletoe used in the laboratory research (Khwaja, 1992). In one laboratory study, researchers found that a lectin from mistletoe promotes the expression of tumor necrosis factor (TNF), a cytokine that has been associated with increased HIV replication and wasting syndrome in people with AIDS. These contradictory findings may be partially explained by the complex nature of plant extracts (Mannel, 1991). Iscador is administered by intramuscular injection, which may cause welts at the site of injection and fevers. At the IX International Conference on AIDS researchers released data on 40 patients who gave themselves injections of 0.01 to 10 mg of Iscador twice a week for 18 weeks. They reported that 77% of the patients had CD4 cell increases of greater than 20%. This unblinded study has not been published, leaving these results questionable. Shark Cartilage Kaposi's sarcoma (KS) involves a proliferation of blood vessels (angiogenesis) that is similar to the network of blood vessels that grow around cancerous tumors. Although pharmaceutical companies have been testing angiogenesis inhibitors for some time, they still are not available for general use. In the meantime, a natural angiogenesis inhibitor has been found in shark cartilage, a discovery made partially on the basis of scientists' observation that sharks rarely get cancer. In one study, tumors introduced into the eyes of rabbits failed to grow in the presence of shark cartilage (Oikawa, 1991). Anecdotal reports of the use of shark cartilage in humans generally have been positive (Callen, 1992), but one study showed mixed results. Search Alliance in Los Angeles conducted a study of shark cartilage for the treatment of KS. Since oral administration had not been shown to produce effective blood levels, they compared an oral formulation to retention enemas. Upon completion of the study, all the participants switched to oral administration, and half dropped out of the study because they couldn't tolerate the treatment's foul taste or because they experienced intense nausea. The study results showed that patients did not improve by taking shark cartilage alone, but using it in combination with radiation therapy had a synergistic anti-tumor effect. Much less radiation was needed when used in combination with the shark cartilage (Fleischman, 1993). Soybean Recently there has been some discussion about the possible anti-angiogenetic qualities of a protein found in soybeans called genistein. In a laboratory study, genistein was found to inhibit angiogenesis, the abnormal growth of blood vessels seen in Kaposi's sarcoma and other cancerous tumors. Genistein occurs naturally in the body as a result of eating soy products. Researchers found that patients on a traditional Japanese vegetarian diet have 30 times more genistein in their urine than patients on a typical western diet. According to the laboratory study results, this concentration would be high enough to have activity against angiogenesis. But conclusions cannot be drawn until the effects of genistein in patients with KS have been studied. Unlike the other treatments discussed in this article, genistein does not have a history of use in the AIDS community. Nutritional approaches to the treatment of AIDS have been explored, but diet is a difficult area to study, and so far little research has been done (James, 1994; Fotsis, 1993). Therapeutic Activities (exercise, massage) In his book Immune Power: A Comprehensive Treatment Program for HIV, Jon Kaiser, MD, discusses the importance of combining alternative approaches with standard allopathic treatment regimens. He also emphasizes the importance of a holistic approach that goes beyond the medicinal herbs that are usually associated with alternative medicine: "It is important to realize that these herbs should comprise one component of an overall treatment program that includes a healthful diet, vitamins, exercise, stress reduction, and, when indicated, standard pharmaceutical medications. This type of overall approach will enable your herbal program to work much more effectively_The immune strengthening value of each of the individual therapies potentiates the other therapies. This enables the overall program to more effectively keep HIV dormant" (Kaiser, 1993). Clinical trials to evaluate the therapeutic benefit of activities such as exercise, massage and meditation are difficult to conduct. Recently, however, the Office of Alternative Medicine (OAM) made 2 grants for the study of the possible immune-enhancing effects of massage. One study will be in preterm newborns of HIV-infected mothers and the other will be in patients with advanced AIDS (Burroughs, 1993-94). If done carefully, therapeutic activities have neither contraindications with drug treatments nor noticeable toxicities, indicating they can be an effective complement to an HIV treatment strategy. Holism and Indigenous Medicines One aspect shared by most non-western healing traditions is a belief in holism_the idea that the physical body is inseparable from the mind, emotions and spirit. In this thought system, all beings possess an essential healthy balance that in illness is somehow lost. Treatments usually focus on restoring that balance so that the body can then heal itself with its own natural abilities (Chopra, 1991). Unlike allopathic medicine, traditional medical systems usually focus on resolving symptoms of illness instead of attacking a specific pathogen. This difference highlights a complementary relationship that can develop between holistic treatments and western medicine that, when used together, addresses all aspects of the patient (Kaiser, 1993). In a sense, traditional medical systems focus on "who you are," while western medicine focuses on "what you have" (Ryan, 1994). Allopathic medicine tends to view the body as a war zone where battles against invading organisms are fought, and won or lost. From this foundation, therapeutic approaches are usually based on our intellectual ability to understand the nature of the battle being fought and to employ an effective arsenal of weapons. For some HIV-related opportunistic infections, allopathic treatments such as the use of antibiotics for fighting Pneumocystis carinii pneumonia (PCP) are effective. But with other conditions the allopathic approach has been less successful. Perceptions of mortality also influence a culture's medical traditions. For instance, a given culture may use medicine to fight off death, or to make a limited lifespan as comfortable as possible. The prognosis of a disease is affected by these different philosophical approaches, as are the eventual course and outcome of a disease. African Herbal Medicine With the onset of illness, almost all Africans with HIV go to traditional healers before they visit western-trained doctors. With their direct access to the general population, traditional practitioners could play important roles in education, prevention and treatment. Unfortunately, this potentially invaluable resource is not being put to efficient use (brochure, VII International Conference on AIDS in Africa, 1992). Traditional African medicine uses a variety of different healing techniques, including spiritual and mystical practices, dance and herbal medicines (International Organization of Traditional and Medical Practitioners and Researchers, 1991). Fokoundang Adam Usumanu, a traditional healer from Cameroon, uses the bark of the Corynanthe johimbe tree for treating impotence in men (Usumanu, 1992). In the United States, yohimbine, an extract from this same tree, is a prescription drug used for the same purpose. There have been reports of people with HIV who have had positive results using yohimbine for the treatment of HIV-related fatigue (James, 1992). This coincidence supports the idea that traditional healers have knowledge of useful treatments that may be unknown to western pharmacists. In Tanzania, research has been conducted on the effects of herbal remedies in Africans with HIV infection and AIDS. In 2 cases, traditional African healers teamed up with western-trained doctors to study African herbal remedies (the ingredients of which were not described). They conducted preliminary, uncontrolled clinical studies with over 100 participants. In both studies, over 75% of the patients showed improvement. Unfortunately, these studies are too vague to permit the drawing of conclusions other than the need for more studies (Lugakingira, 1992; Scheinman, 1992). Ayurveda The indigenous healing tradition of India, Ayurvedic medicine, is said to be over 5,000 years old. Like other forms of traditional medicine, Ayurveda is based on a holistic model. The goal of Ayurveda is to return the body to a state of balance and health by emphasizing the body's natural healing abilities. Treatment may include herbal remedies and teas, nutrition, exercise (yoga), meditation, aromatherapy, music therapy, massage and detoxification through the use of enemas or other cleansing techniques (Ayurveda Health and Education Resources of San Francisco, 1993). Ayurveda has received a lot of attention recently with the popularity of books by Deepak Chopra, a medical doctor and traditional Ayurvedic practitioner, who has attempted to combine the 2 approaches into a single, comprehensive view of health: "The guiding principle of Ayurveda is that the mind exerts the deepest influence on the body, and freedom from sickness depends upon contacting our own awareness, bringing it into balance, and then extending that balance to the body. This state of balanced awareness, more than any kind of physical immunity, creates a higher state of health" (Chopra, 1991). Traditional Chinese Medicine When the first cases of AIDS were diagnosed, western medicine had little to offer people who were suffering from a disease that seemed to come from nowhere, i.e., had no readily identifiable cause. In contrast, practitioners of traditional Chinese medicine (TCM) then and now focus on the symptoms of AIDS, fitting it into their models of disease as best they can (Cohen, 1990). In TCM, health is understood to be a balance between a variety of constantly changing variables. "TCM emphasizes treatments which enhance the body's natural immunities so that it may more effectively resist disease. Specifically, the fundamental principles of TCM for the treatment of infectious diseases are: fu zheng (supporting the body's natural order, i.e., enhancing immunity), and quxie (eliminating external evil, i.e., reducing the potency of the pathogen)" (Zhang, 1990). Treatment with TCM generally consists of drinking brewed medicinal herbs (similar to a very strong tea), and acupuncture, but may include breathing exercises (qigong) and massage. Acupuncture is used to control pain or, in combination with qigong, to increase the circulation of qi (life energy). There is some confusion about the effects of the medicinal herbs on the immune systems of people with HIV and AIDS. "Some of the herbs which are used to treat depressed immunity also appear to successfully treat autoimmune diseases (which in western medicine are treated by inhibiting rather than enhancing immune function). This suggests that the complex herbal ingredients effectively modulate or regulate the immune functions instead of simply stimulating them" (Dharmananda, 1989). Some of the herbs most commonly used in Chinese medicine for the treatment of immune disorders are Astragalus membranaceous and different forms of ginseng (Eleutherococcus senticosus and Panax notoginseng) (Sun, 1983; Liu, 1992). Some Chinese herbs have been found to be active against HIV in laboratory studies, including Viola Yedoensis, Arctium lappa and Andrographis paniculata (Chang, 1988). The precise mode of action of these herbs in unknown, but they are very potent-_and therefore as dangerous as some pharmaceutical drugs with severe toxic side effects. Anyone considering using Chinese herbal medicine should see a qualified Chinese herbalist. A few clinical studies of TCM in the treatment of HIV-specific disorders have been conducted. A study of acupuncture for the treatment of HIV-related peripheral neuropathy showed a small improvement in "quantitative sensory testing" (a test of sensitivity to applied stimulation in the hands and feet). TCM also caused self-reported improvement in quality of life. Although preliminary, these findings attempt to systematically study the effects of a treatment that is difficult to measure by western medical standards (Tosches, 1993). Over the years a number of observational studies have been done on the effects of Chinese herbal formulas on patients with HIV and AIDS. These studies show improvements in symptoms, but because they are generally unblinded and without control groups, the results have to be viewed with skepticism (Young, 1993; James, 1987; Hawkins, 1993). San Francisco General Hospital recently concluded the first double-blinded, controlled clinical trial at a major research institution of a Chinese herbal compound for the treatment of AIDS. Misha Cohen, director of Quan Yin Chinese Herbal Clinic in San Francisco, formulated the compound and collaborated with western-trained researchers in this ground-breaking study (Burack, 1993). This placebo-controlled study had 30 symptomatic subjects whose CD4 counts were between 200-500, but who did not have an AIDS diagnosis. For 12 weeks participants took 28 pills per day of a Chinese herbal formula similar to Enhance, a popular Chinese herbal compound. The pilot study showed that there was a statistically significant improvement in the areas of "life satisfaction," fatigue, gastrointestinal symptoms and neurological symptoms, all of which were measured by standardized questionnaires. The small sample size limits the scope of these findings, but these 4 outcome variables are all areas that western medicine has been particularly unsuccessful in treating. If future research, undertaken on a larger scale, can reproduce these results, it would have a serious impact on the standard of care in AIDS treatment. According to a new book entitled, Treating AIDS with Chinese Medicine, "Western science has yet to arrive at a satisfactory or complete explanation of TCM. Although acupuncture and Chinese herbs are understood to have measurable, biochemical effects, these effects do not fully, or often adequately, explain the therapeutic efficacy of the system. In addition, acupuncture and Chinese herbs can be very difficult to test via standard western methods because the treatment approach is based on entirely different concepts. The result has been that TCM has been ignored, underestimated as nothing more than a pain-reliever, and under-utilized" (Ryan, 1994). One of the studies approved this year by the OAM is a study of TCM for the treatment of HIV sinusitis. This will be a blinded study with 40 participants receiving either the standard pharmaceutical treatment (augmentin) for 28 days, or a Chinese herbal formula and weekly acupuncture for 12 weeks. This study will be conducted by Tom Sinclair at the Immune Enhancement Program in San Francisco (415-252-8711). Psychoneuroimmunology Another positive aspect of alternative treatments, which may not be discernible in clinical trials, is the placebo effect, which occurs because one believes that a treatment being used will be helpful. Similarly, the process of taking an active role in one's own health care may play an important role in the success of alternative treatments. In fact, emotional status and general state of mind both seem to have an effect on physical well-being. Both of these effects are being studied in a new field of science called psychoneuroimmunology (PNI), which examines the relationships between psychology, neurology and immunology. PNI seems to be western science's attempt to understand and integrate the concept of holism. The word psychoneuroimmunology can itself be understood as a reflection of the 3 aspects of holism: spirit (psyche), mind (neuro) and body (immuno). The results of a well-known study of women with breast cancer at Stanford University depict the impact that emotions have on health. In this study, women who were involved in a support group with other patients benefitted from the emotional support of the other women and had an increased lifespan of 2 years (Spiegel, 1989). This approach is also being used by people with HIV and AIDS. At UCLA, Margaret Kemeny, PhD, found that chronically depressed people with HIV had much steeper declines in their immune systems over a 5-year period than those who were not depressed (Kemeny, 1991). It will be some time before the research techniques used to study PNI are standardized. Until then, studies will have to be scrutinized with extra care. A general review of research in the area shows that while results are often contradictory, there is enough evidence of a positive correlation between emotional health and immune status to support further study (Solomon, 1990; Antoni, 1992). The relationship between depression and immune function has come under question after the results of 2 major studies were recently published. The Journal of the American Medical Association reports that while a study completed at the University of California at San Francisco showed a positive correlation between depression and immune system decline, a more thorough study conducted at John Hopkins University showed the opposite, i.e., no correlation (Lyketsos, 1993; Burack, 1993). Conclusion In many ways the alternative treatment movement has been in reaction to perceived limitations of western medicine. This has caused re-examination of some of the basic elements of clinical research and treatment, and created some changes. One result is that many people with AIDS have taken their healthcare decisions into their own hands, using themselves as guinea pigs to try out new and unproven treatments. Patients also are educating themselves, and becoming more involved in planning their treatment strategy. In another divergence from standard medicine, alternative treatments are being employed as preventive measures, to support and prolong health. Political changes have also occurred, such as the creation of the Office of Alternative Medicine at the NIH, which bodes well for the integration of alternative treatments into the standard western model. But it is unlikely that indigenous medical systems can be integrated as easily since they are based on different philosophical approaches to healing. Perhaps new fields of medicine, such as psychoneuroimmunology, will begin to bridge the gaps between allopathic medicine and holistic approaches. Sources Abrams DI. Alternative therapies in HIV infection. AIDS 4: 1179-1187. December 1990. Andriote J. Acemannan: a quiet alternative. Medical Alert: a publication of the National Association of People With AIDS 1(5): 1,6. September/October 1993. 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September 3, 1993. Gorter R and others. Anti-HIV and immunomodulating activities of Viscum album (mistletoe). VIII International Conference on AIDS. Amsterdam, 1992. PuB 7214. Greenberg J. Research for Alternative AIDS Treatments. NYQ. February 6, 1992. Hajto T and others. Modulatory potency of the beta-galactoside-specific lectin from mistletoe extract (Iscador) on the host defense system in vivo in rabbits and patients. Cancer Research 49(17): 4803-4808. September 1, 1989. Hattori T and others. Preliminary evidence for inhibitory effect of glycyrrhizin on HIV replication in patients with AIDS. Antiviral Research 11(5,6): 255-262. June/July 1989. Hawkins M and others. Use of a Chinese herbal composition for the treatment of human immunodeficiency virus_a descriptive study. First International Conference on HIV, AIDS and Chinese Medicine. San Francisco, June 1993. Healing Alternatives Foundation. Product Price List. March 15, 1994. Homeopathic Education Services, Berkeley, CA. 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Experimental basis for the use of iscador in cancer treatment. The 13th International Congress of Chemotherapy. Vienna, August/September 1983. Khwaja T. Personal Communication. April 1992. Korsia S. Aloe vera: the plot thickens, but does the concentrate. I Heard It Through The Grapevine 5: 3-4. December 1991. Lee-Huang S and others. MAP30: a new inhibitor of HIV-1 infection and replication. Federation of European Biochemical Societies Letters 272: 12-18. October 15, 1990. Leung SO and others. The immunosuppressive activities of two abortifacient proteins isolated from the seeds of bitter melon (Momordica charantia). Immunopharmacology 13(3): 159-171. June 1987. Li CJ and others. Three inhibitors of type-1 human immunodeficiency virus long terminal repeat-directed gene expression and virus replication. Proceedings of the National Academy of Sciences USA 90: 1839-1842. March 1993. Liu CX and Xiao PG. Recent advances in ginseng research in China. Journal of Ethnopharmacology 36(1): 27-38. February 1992. Lugakingira E and Borongo L. Traditional Medicines Unit, Nansio, Tanzania. VIII International Conference on AIDS. Amsterdam, 1992. PoB 3396. Lyketsos CG and others. Depressive symptoms as predictors of medical outcomes in HIV infection. The Journal of the American Medical Association 270(21) 2563-2567. December 1, 1993. Mannel DN and others. Induction of tumor necrosis factor expression by a lectin from Viscum album. Cancer Immunology & Immunotherapy 33(3): 177-182. May 1991. McDaniel HR and others. HIV-1-infected patients respond favorably to oral acemannan. VI International Conference on AIDS. San Francisco, 1990. SB-493. Meruelo D and others. Therapeutic agents with dramatic antiretroviral activity and little toxicity at effective doses: aromatic polycyclic diones hypericin and pseudohypericin. Proceedings of the National Academy of Sciences USA 85: 5230-5234. July 1988. Mori K and others. Effects of glycyrrhizin (SNMC) in hemophilia patients with HIV-1 infection. Journal of Naturopathic Medicine 4(1): 2-9. 1993. Oikawa T and others. A novel angiogenic inhibitor derived from Japanese shark cartilage. Cancer Letters 51(3): 181-186. June 15, 1991. Padma 1(2). Spring 1993. Newsletter of Ayurveda Health and Education Resources of San Francisco, 347 Dolores St. #221, San Francisco, CA, 94110. Phillips L and others. Herbs and HIV: The Health Food Industry's Answer. AIDS Weekly. February 7, 1994. Ryan MK and Shattuck AD. Treating AIDS with Chinese Medicine. Pacific View Press, Berkeley, CA. 1994. Schinazi RF and others. Anthraquinones as a new class of antiviral agents against HIV. Antiviral Research 13(5): 265-272. May 1990. Scott-Hartland B. Common alternative therapies. Treatment Issues 7(11/12): 4-12. Winter 1993-94. Singer J and others. A randomized placebo-controlled trial of oral acemannan as an adjunctive to anti-retroviral therapy in advanced HIV disease. IX International Conference on AIDS. Berlin, 1993. PoB 28-2153. Smith D. The ongoing role of alternative and off-label therapies. New Treatment News #8, St. Mary's Hospital and Medical Center, San Francisco, CA. November 30, 1993. Solomon GF and others. Psychoneuroimmunologic aspects of human immunodeficiency virus infection. Psychoneuroimmunology II. Academic Press, Orlando. 1990. Spiegel D and others. Effect of psychosocial treatment on survival of patients with metastatic breast cancer. The Lancet 2(8668): 888-891. October 14, 1989. Stricker RB and others. Dendritic cells and dinitrochlorobenzene (DNCB): a new treatment approach to AIDS. Immunology Letters 29: 191-196. 1991. Stricker RB. Analysis of lymphocyte subsets in HIV-infected patients treated with topical dinitrochlorobenzene (DNCB). IX International Conference on AIDS. Berlin, 1993. POB 282140. Sun Y and others. Immune restoration and/or augmentation of local graft versus host reaction by traditional Chinese medicinal herbs. Cancer 52: 70-73. July 1, 1983. Tosches W and others. A pilot study of acupuncture for the symptomatic treatment of HIV-associated peripheral neuropathy. First International Conference on HIV, AIDS and Chinese Medicine. San Francisco, CA. June 1993. Treatment Issues of the Gay Men's Health Crisis (GMHC), New York City. Write to: Medical Information, 129 W. 20th St., New York, NY, 10011, and ask for the special winter 1993/1994 edition on alternative treatments. Usumanu FA. Personal communication. December 10, 1992. Young M. Chinese herbal therapies and HIV infection, a clinical report. First International Conference on HIV, AIDS and Chinese Medicine. San Francisco, June 1993. Zhang QC and Hsu H. AIDS and Chinese medicine: applications of the oldest medicine to the newest disease. OHAI Press. 1990. Zhang QC. Preliminary report on the use of Momordica charantia extract by HIV patients. Journal of Naturopathic Medicine 4(1): 65-69. 1993. Ed. note: this is a publication of the Journal Management Group in Norwalk, CT; call 203-866-7664. Guidelines for Using Alternative Treatments ù Research the treatment that you are interested in, including information on dosing amount, dosing regimen and side effects. Local buyers' clubs, AIDS organization libraries and treatment newsletters may have useful information. Be skeptical about what you read since the author may be biased in some way. Also, the media has a tendency to focus on or create a "drug-of-the-month," which can be dangerous because little is usually known about treatments that become big news this way. Peer-reviewed journals are the best source for medical information, because articles in these publications have to pass a qualified board of knowledgeable individuals. ù Seek out people who have had both good and bad experiences with the treatment you are interested in. It is always a good idea to investigate possible negative side effects of a treatment. AIDS organizations in some cities have support groups for people using alternative treatments. ù Consult your doctor before you begin an alternative treatment to make sure that it is not contraindicated with any medication that you are currently using. Contrary to popular opinion, herbs and vitamins can have very serious side effects and can be dangerous in combination with other drugs. People often mistakenly believe that a "natural" substance cannot do them any harm. ù Be cautious of "secret formulas." Anyone unwilling to say what is in their product, thereby avoiding public discussion about their treatment, could be hiding something. Be wary of questionable scientific explanations for the way a treatment is supposed to work. In some cases it is appropriate for someone not to disclose the ingredients of their treatment. For example, some traditional healers do not like to give out their formulas because that is how they make a living. ù Shop around to get the best price, particularly since the cost of alternative treatments is not reimbursed by insurance or government programs. Supposed AIDS "cures," sold in the U.S. and abroad for huge amounts of money, often turn out to be frauds. Before making a large financial investment, consider lower-priced alternative treatments that are available locally. San Francisco currently has programs for free or low-cost traditional Chinese medicine and acupuncture for people with HIV/AIDS (see resource list, page 8). Some health food stores give a discount to people with HIV/AIDS, but buyers' clubs, which are usually run as nonprofit organizations, generally have the lowest prices around. ù Buyer beware. The manufacturers of alternative treatments have no watchdog agency to monitor the accuracy of product contents and labels. Products may be contaminated with other, possibly dangerous, substances. ù Take an organized approach. Try one treatment at a time, for a set period of time, so that you can monitor yourself to see if it is working. Starting multiple treatments at once can make it hard to determine the effect of a particular treatment. Since many alternative treatments are expensive, careful monitoring of your health can save you money by allowing you to weed out those that do not work. Keeping a journal of how you feel and fluctuations in your weight can be helpful. Having your blood work done before and after using a treatment can also be useful, but the length of time it takes a treatment to work often varies. Some community organizations are doing their own studies of alternative treatments. (A survey of alternative treatments is being conducted currently by a community research group in Toronto. For more information contact the Toronto Community Research Initiative, 416-324-9505 (phone), or 416-324-9921 (fax).) ù Use common sense about what feels right for your body. You are the only judge of how something makes you feel. Discontinue a treatment if you develop an unexpected rash or if you have difficulty breathing_these could be signs of a dangerous allergic reaction. Resources For More Information On Alternative Treatments American College of Traditional Chinese Medicine Community Clinic, San Francisco, CA, 415-282-9603. Carl Vogel Center, buyers' club, Washington, DC, 202-289-4898. Center for Natural and Traditional Medicines/The NATC Caucus of the International AIDS Society, 1601 Connecticut Ave. Suite 201C, Washington, DC, 20009, 202-234-9632. This group works mainly on political issues and on organizing conferences, particularly the International Conferences on AIDS. Direct AIDS Alternative Information Resources (DAAIR), buyers' club, New York, NY, 212-689-8140. Healing Alternatives Foundation, buyers' club, 1748 Market Street #204, San Francisco, CA, 94102, 415-626-4053. (Contact local AIDS organizations to find out about local buyers' clubs.) Immune Enhancement Program, Chinese medical clinic, San Francisco, CA, 415-252-8711. PWA Health Group, buyers' club, New York, NY, 212-255-0520. Quan Yin Chinese Herbal Clinic, San Francisco, CA, 415-861-4964. San Francisco Center for Living, 4054 18th St., San Francisco, CA, 415-252-1666. This nonprofit institution assists people with life-challenging illnesses (and their families and friends) by offering support groups, individual counseling, healing circles, meditation classes and bodywork (massage). Also, in New York City at 212-533-3550 and Los Angeles at 213-655-4802. ********** Aggressive Intervention in HIV Disease: An Interview with 4 San Francisco Physicians Mark Bowers Mark Bowers is a medical writer and AIDS treatment activist. BETA asked 4 San Francisco physicians who treat adult patients with HIV disease to provide a template for aggressive early intervention to slow disease progression and possibly extend life. We also asked for their views on other treatment issues: which vaccines are recommended for HIV positive people? What measures of disease progression are most reliable? What opportunistic infections warrant prophylaxis? Paul Volberding, MD, is Director of the AIDS Activities Division at San Francisco General Hospital. Mary Romeyn, MD, an internist with an HIV practice in San Francisco, is the author of a forthcoming book entitled Nutrition and AIDS: a New Model for Treatment. Gifford Leoung, MD, is Medical Director of HIVCare at Saint Francis Memorial Hospital. Stephen Follansbee, MD, is Medical Director of the Institute of HIV Treatment and Research at Davies Medical Center in San Francisco. Drs. Volberding and Romeyn see many patients in the early stage of HIV disease, and both have strong views about the value of early intervention and aggressive treatment for HIV infection. Drs. Leoung and Follansbee specialize in infectious diseases; most of their patients are symptomatic. BETA: What are the most aggressive early strategies that you offer to your HIV positive patients? VOLBERDING: What do we mean by early intervention? I think one of the big changes in the past year and a half is the sense that our definition of early treatment has broadened. Early intervention used to be offered to all asymptomatics with CD4 counts below 500. We now know from research on the pathogenesis of HIV disease that true early intervention is therapy applied as soon as possible after HIV infection occurs, before the virus damages the lymph nodes. In fact, the breakdown of the lymphoid system and the resultant release of virus [into the bloodstream] occurs at a count of about 500 CD4 cells. There are many health-promoting activities that can be started before antiretroviral drug therapy is considered. One issue that keeps coming up is the realization that physicians should discuss lifestyle issues with HIV positive individuals. The provider can work with each patient in a one-on-one, confidential manner to ensure that the individual understands how the virus is transmitted and is not engaging in behaviors that will put other people at risk for becoming HIV positive. So one important aspect of early intervention is prevention of HIV transmission. In terms of preventing disease progression, there are ways to empower patients to decrease their risk of progression. We talk about stress reduction, appropriate diet and the necessity of avoiding excessive use of recreational drugs, including alcohol. These are important parts of a program of early HIV care. Optimal drug treatment for people with HIV infection continues to be a source of controversy. Although a substantial amount of new data on the safety and efficacy of the nucleoside analogs [AZT, ddI, ddC, d4T] has been released during the past year, it is difficult to develop specific treatment algorithms that represent a consensus of most treating physicians. Increasingly, patients are prescribed combinations of nucleoside analogs as initial and, more commonly, secondary treatments. Because AZT plus ddC is [FDA-] approved for such an indication, there is more clinical experience with this combination. In both clinical trials and clinical practice, this combination apparently has not increased the toxicity anticipated from each drug given separately. AZT is the drug of first choice for patients beginning antiretroviral therapy. If patients are absolutely unable to tolerate AZT, then the decision to initiate a second antiviral, either ddI or ddC, is straightforward. If the patient tolerates AZT easily, there is the option of adding a second agent in continuous combination. On the other hand, if the patient experiences toxicity after beginning combination antiretroviral therapy, it is possible to initiate intermittent therapy. The patient could be continuously treated with the better-tolerated drug and the more toxic agent could be added, for example, on alternating months. Problems of drug toxicity require individualized treatment. ROMEYN: I discuss 7 basic principles with all my HIV positive patients. First, based on the results from new studies, we strongly recommend not smoking and not drinking alcohol. These activities create an environment of oxidative stress that encourages HIV replication. The in vitro data on alcohol and HIV is impressive. Social drugs that expend an individual's energy also are discouraged: we have all seen how quickly speed (methamphetamine) and cocaine can bring the immune system to its knees. Second, we inquire about the patient's work situation. If and when there is disease progression, we address chronic stress in the workplace. We work with the patient on an individual basis to minimize work-related stressors. Third, we ask whether the patient is having sex, and what kind of sex he or she is having. We strongly discourage unprotected oral sex and unprotected insertive sex, especially receptive anal sex. There is another dimension to this line of questioning: we want to know something about the emotional health and the support systems of our patients. We work especially hard on behavior modification with bipolar couples (one positive and one negative partner). We are currently treating one couple where the negative partner recently caught hepatitis B from the positive partner but, thankfully, did not seroconvert for HIV. We always test the negative partner at least yearly for HIV antibodies. Fourth, we test HIV positive patients and their partners for hepatitis B antibodies. If either person tests negative, we give a recombinant vaccine course as soon as possible. It would be irresponsible to do otherwise. Fifth, for all male gay patients, we test 3 times at intake for intestinal ova and parasites, even if they do not acknowledge having receptive anal intercourse. Sometimes a patient will not immediately feel comfortable telling me that. We look for cryptosporidium in patients with fewer than 500 T-cells. Perhaps we should look even sooner. When we find a pathogen, we treat for eradication if we can. In late-stage HIV disease, eradication of Giardia or Entamoeba histolytica is very difficult; it is more prudent to eliminate these problems early, if possible. Sixth, an important part of our approach to HIV management is through close monitoring of nutritional status and prevention of the wasting syndrome. We attempt to preserve or increase lean body mass. To do this, we need to be aggressive in the early identification and treatment of secondary infections that induce the endocrine and metabolic changes characteristic of HIV disease. Lean body mass is estimated by caliper measurements, although we hope to use an impedance monitor soon. A nutritional consultation is arranged for each HIV positive patient at intake. Triglycerides are monitored regularly, as a screen for increasing metabolic abnormalities. One of the earliest changes that we see in the gut of HIV positive patients is lactose deficiency. Therefore, we do not rely on milk products for nutritional value, although we support their use as comfort foods for pleasure. In contrast with dietary recommendations for other conditions, we recommend eggs and meat (excellent sources of protein) for patients in early-stage HIV disease. Also, we check vitamin B-12 and folate levels in every patient. When there are deficiencies, we supplement them. All of our patients are urged to take 2 multivitamins per day, as supplementation is shown in the literature to be of benefit. We also recommend a trace element supplement, because zinc and selenium levels may be reduced. AZT also lowers zinc levels. We are careful about not over-recommending beta carotene, because of the dangers of hypervitaminosis. Our conservative recommendation on antioxidants is to start with 1,000 mg of vitamin C and 800 units of vitamin E. Many of our patients take more. Seventh, we aggressively promote progressive resistance exercise for the early asymptomatic patient. Some patients have personal trainers; others join gyms; for those who cannot afford either, there are plans underway to connect them with trainers who offer free services to HIV positive clients. Aerobics are good early on, but not all of the results are in; we do know that there can be a drop in the immune status of marathon runners. We want to avoid continued stress from aerobic exercise, especially if and when there is disease progression. We are interested in the new attention being paid to the role of testosterone supplementation, and look forward to studies of its use in late-stage HIV disease. BETA: Setting aside candidate vaccines for HIV, which vaccines do you offer to your HIV positive patients? LEOUNG: All patients, if possible, should try to complete the usual childhood series of vaccines, if they haven't already. The only concern is the attenuated vaccines, like polio. These are not recommended, particularly for people who are symptomatic. Otherwise, people should try to complete the normal series. An annual influenza vaccine may be useful, although it's not clear how useful, particularly in people who have advanced HIV disease. But there is no evidence that it is clinically harmful. Other things worth considering are the pneumococcal and hemophilus vaccines. It is very clear that people with HIV at some stage have more and more problems clearing these organisms. They are both encapsulated organisms. We have good data to show that there is an increase in pneumococcal bacteremia and probably invasive pneumococcal disease, and we have data to show that there is an increase in hemophilus sinusitis and bronchitis/pneumonia. I think that it's worth it to offer those 2 vaccines to patients even if they have not had any significant problem with these organisms before. FOLLANSBEE: We avoid live vaccines like BCG [a tuberculosis vaccine invented by the French researcher Calmette-Guerin_ Ed.], for example. We are using killed vaccines or subtype vaccines. The problem in adult HIV disease has been to assess the risks and consequences of some of these other bacterial infections, or of influenza. There is very little known about the consequences of viral influenza in someone with HIV disease. The literature has been contradictory. The official recommendation has been to vaccinate all HIV positive people for influenza on a yearly basis. I follow that recommendation, but there are a lot of unanswered questions. The pilot study done by the Gladstone Institute in conjunction with the Community Consortium looked at the possibility that vaccination with influenza vaccine may lead to a burst of HIV production. We looked at 30 HIV positive individuals divided into 3 cohorts and 10 HIV negative controls. One cohort of 10 had more than 500 CD4 cells, one cohort had between 200 and 500 CD4 cells, and one cohort had fewer than 200. By using the current investigative methods for assessing HIV viral load, Chiron's branched DNA assay and QC-PCR, it appears that there is a short burst of virus activity in response to the influenza vaccination. This burst was detectable in all 3 cohorts; it appeared generally within 7 days and maxed out at 14 days. This effect had been predicted, but not documented before. The increased replication began to diminish at 28 days. The study was initially a 28-day study, so we brought almost everyone back for a repeat analysis at 13 weeks. Most individuals had returned to baseline. No fevers, sweats, chills or swollen lymph nodes were reported. There was no symptomatic change during the period of the study. No one came down with influenza, but there was no true epidemic in the Bay Area. Influenza itself, or any external challenge, may produce a similar viral burst or one that is logarithmically worse and prolonged. If a relatively weak vaccine of killed virus can do this, who knows what other challenges do. Most people were on antiretroviral therapy at the same time, except for the ones with more than 500 CD4 cells. The pilot study was so small that we can't really make any hard and fast conclusions. ROMEYN: We are giving the Pneumovax vaccination to any HIV positive patient as early as possible. We give tetanus and annual influenza vaccines. At this point in time we are not giving hemophilus influenza vaccination, although there is some interest in doing that with kids. We haven't seen a lot of hemophilus influenza in adults. We do a yearly PPD test for tuberculosis, and controls for comparison. Many physicians forget to do the controls and do not discover anergy until it is too late. BETA: Do you consider markers of progression other than CD4 counts? If so, how do you evaluate them when you are deciding to offer therapeutic interventions to your patients? VOLBERDING: This is probably the most interesting question in the field of AIDS research right now. However, it is a little premature to give a complete answer. At San Francisco General Hospital, we are investigating methods of viral quantitation. In our laboratory we have been evaluating both the Chiron branched DNA assay (bDNA) and qualitative competitive polymerase chain reaction (QC-PCR) from Genelabs. There is now absolutely no doubt that we can reproducibly measure how much virus most of our patients are carrying in their blood. My belief is that the information that these 2 new assays provide will prove to be extremely useful, both in estimating the risk of disease progression and in following the response to therapy. We do not yet know whether tracking the amount of HIV will improve the way that we use current antiretrovirals, because the drugs we have may not be potent enough to have much impact on the quantity of virus in the blood. However, we are designing clinical trials to answer that question. At San Francisco General Hospital, we plan to do these quantitation tests on a large population of patients in order to gain some experience with the assays. My hope is that these new tools will help us to manage our patients more effectively. FOLLANSBEE: I try not to rely on any one test: p24 alone, CD4 cell counts alone, a single CD4 cell count, or simply molluscum in the absence of anything else. I look at CD4 cell counts, but I also look at the CD4 percentage, as well as suppressor counts and the ratio. And I still follow p24 antigens. They're not perfect markers, but changes from undetectable to detectable levels of virus cannot be a good sign. I'm impressed that p24 levels are relatively constant from blood draw to blood draw in any given individual, without changing interventions. The main problem with respect to treatment is what can we really do about some of these endpoints. Some individuals are very cognizant of soft endpoints like the appearance of molluscum, for example, and will become quite concerned_and there may be reason for concern. The appearance of oral candidiasis or hairy leukoplakia also triggers my attention. In contrast, the resolution of chronic lymphadenopathy may not be good news. Resolution of lymphadenopathy may herald further seeding of the virus to other parts of the body. Those may seem like "soft endpoints" but, in fact, if they are changing at the same time that laboratory parameters are changing, then I think it's time to change therapy. LEOUNG: HIV positive people have always been concerned about weight loss, thrush and prolonged fevers. I think these symptoms are an indication that there is something going on. There can be considerable disagreement about whether or not to start someone on antivirals who has some of these findings intermittently but who has good T-cell counts. I am more concerned about people who have good T-cell counts with other infections such as Neisseria meningitis. We can treat the meningitis, and the patient recovers completely. Even though he had very good T-cell counts, to my mind, this person has an AIDS diagnosis. A person with a T-cell count of 500 or 600 who has significant illness deserves antiretroviral therapy much more than someone with a high T-cell count who has no additional illness. ROMEYN: Certainly, an abrupt drop in CD4 count or an abrupt change in ratio would catch my attention, but I don't check CD4 counts on sick people. If patients are in an acute state, we know their counts are going to be low, and we don't need to give people reasons to think that they are even sicker. I treat them, and then I check their CD4 counts. Under these circumstances, drops in CD4 counts are more meaningful. The last thing people need to hear when they are sick with pharyngitis or diarrhea, or some perfectly normal garden-variety bug, is that their CD4 count is now 300 when it was 585 two months ago. I want to be very aggressive up front. I always start by telling people what the basic recommendations are, and then I explain how essentially proactive we are. We start by looking for things. I get almost every test in the world the first time. When I initiate treatment, I often recommend initiating double [combination] treatment. I tend to do double treatment with AZT and ddI. There's a new study that maybe makes ddC look a little better. I have patients with very high CD4 counts who are on combinations of regimens, because they can afford it and they want it. These tend to be very proactive people. We monitor triglycerides very closely. We've seen that triglycerides are elevated as a result of the activation of an acute phase response to infection. For that reason, if triglycerides are up, I want to know why. I look for an underlying pathogen. I don't mind seeing people with hairy leukoplakia, because it gives me an excuse to put them on acyclovir to suppress Epstein-Barr virus (EBV). Acyclovir is shown to increase survival, whether or not people have herpes [herpes simplex]. But no managed care company will let me give a patient acyclovir if they don't have herpes simplex or Epstein-Barr. So, if I find hairy leukoplakia, I can write a script for acyclovir. BETA: Do you prescribe drugs for prophylaxis against opportunistic infections? LEOUNG: It has been clearly established that prophylaxis against Pneumocystis [PCP] is good. I participated in the first study that demonstrated that aerosolized pentamidine was useful. Since then there have been a number of studies that look at other agents, including trimethoprim-sulfamethoxazole, or TMP-SMX (Bactrim, Septra), and dapsone. It is clear that TMP-SMX works better than anything else that we have now for PCP prophylaxis. Because Pneumocystis only rarely occurs at CD4 counts above 200 in adults, I usually start prophylaxis at that point. Whether you use TMP-SMX or dapsone may not make any difference, although some evidence suggests Septra has greater efficacy against Pneumocystis, and it's cheaper. Therefore, if patients can tolerate Septra, there is no reason why they should not be on it. My personal feeling is that we should direct our antifungal therapies against Candida (thrush) because that is most common. I prefer to treat thrush with agents such as clotrimazole (Mycelex) or ketoconazole (Nizoral). I think you can get good therapy with those without having to go to fluconazole (Diflucan). I don't use fluconazole as prophylaxis against Cryptococcus. I feel that I can monitor patients for fungal diseases, catch them early when they occur, and treat them with a variety of means, including intravenous amphotericin plus or minus 5-flucytosine, oral fluconazole plus or minus 5-flucytosine, and even itraconazole (Sporanox). And if I monitor my patients closely enough, then I can treat them early and effectively when they get fevers, which is one of the hallmarks of cryptococcal disease. Last year rifabutin (Mycobutin) was approved by the FDA for prophylaxis against MAC [in individuals with fewer than 100 CD4 cells]. In the interim months, there has been a lot of concern from physicians, particularly infectious disease physicians, regarding the use of rifabutin for MAC prophylaxis, for a variety of reasons. One reason is that the studies do not actually show a change in survival [for those using prophylaxis]. They basically show that there was some decrease in some of the symptoms among some patients treated with rifabutin, compared with those who did not take rifabutin. There also appeared to be a delay in the onset of MAC-positive blood cultures in people receiving rifabutin, but this delay was temporary. My concern is that widespread use of rifabutin may cause resistance that will cross over to rifampin. If we lose rifampin as a useful agent against TB, we are going to be in big trouble. FOLLANSBEE: In the last year, despite the prevalence of fluconazole usage, we saw more cryptococcal disease. Fluconazole may in fact prophylax against cryptococcal disease. I believe it was [the results of] ACTG 098 that suggested there was some prophylactic value with fluconazole for Cryptococcus as well as for endemic mycoses, such as histoplasmosis or coccidioidomycosis. But I'm still relatively conservative, because I'm concerned about the other side of the coin with fluconazole, which is basically drug resistance, as well as drug interactions. I think that as we increasingly get into polypharmacy, particularly with many of the new antiretroviral drugs such as protease inhibitors, and some of the non-nucleoside reverse transcriptase inhibitors that are metabolized through the same hepatic enzyme system as fluconazole, itraconazole and ketoconazole, we're going to see more and more drug interactions. We need to be aware of this up front. I tend to use fluconazole in more of a pulse for the treatment of oral candidiasis or indicated diseases, and not on a regular prophylactic schedule. I'm involved in the CMV prophylaxis studies with oral ganciclovir (Cytovene). I think oral ganciclovir has a role in the maintenance of people with CMV retinitis. Studies are emerging that suggest efficacy. Whether the drug will have a prophylactic advantage is not clear to me at this point, but there is no other prophylaxis. I'm quite clear that acyclovir does not prophylax against CMV disease. ROMEYN: We offer PCP prophylaxis to anyone with under 500 CD4 cells. I know that's high, but I've seen PCP in people who have 400 CD4 cells. Usually, I prophylax with Bactrim 3 times a week. If and/or when someone develops a reaction to Bactrim, I switch them over to dapsone. I don't treat through a rash. Unfortunately, we don't yet have the answers on atovaquone (Mepron) prophylaxis. The other thing that is important about starting Bactrim early is that you see less of an allergic response to a continuous regimen than you see to a start-and-stop regimen. I let my patients choose a regimen and then keep them on it. I have them on Bactrim 3, 5 or 7 times a week. I think Bactrim 3 times a week is enough. Another technique that we use here is borrowed from my large geriatric practice: I make an effort not to change more than one medication at a time. If you add 2 medicines and you see a rash reaction, you don't know where it came from. Wherever possible, I make only one change in a regimen at a time. We can often do this by phone. The other strategy we use to build tolerance is to start people on half-doses of AZT, 100 mg 3 times a day. Side effects, if they occur, usually resolve within a few weeks. Then you can up the dose. If people are interested in combination antiretroviral prophylaxis, I start the second drug a month later. I don't start both at once. I also prophylax against the ongoing adrenal response to this illness. With HIV infection, the body is in a chronically stressed state. This stress activates the immune system in ways that are harmful and allow for progression of the virus. I'm quick to write a prescription for the treatment of depression or anxiety. I'm slow to do this for patients who are not HIV positive. I don't think people with HIV can afford to be crazy; they have to maintain their sanity. BETA: What are the major changes you have made in your HIV practice in the last year? FOLLANSBEE: I am becoming increasingly convinced that acyclovir does play a role in HIV treatment. There are now 2 prospective studies that unfortunately haven't made it to press, which were designed to look at the role of acyclovir for CMV prophylaxis and in fact showed no such role. But both studies did show a survival benefit in those people who received acyclovir. I understand that a retrospective analysis of patients in the Multicenter AIDS Cohort Study (MACS) has now been completed that shows the same survival benefit. There does not appear to be a dose response, and there is no proposed mechanism to explain why acyclovir may improve longevity. From discussions that I've had with some of the investigators, it does not appear that this is related to a specific antiretroviral regimen. It seems to be an independent survival advantage. It may be through a cofactor role. Acyclovir probably will not be an early treatment, because most of these studies are done with people who are at risk for CMV disease. So it is probably a strategy to reserve for later on, unless of course the patients have recurrent herpes. I am now putting patients on acyclovir, which is a change for me. VOLBERDING: We have a unique situation at San Francisco General Hospital. About 20 providers work in the HIV/AIDS clinic. Each clinician has a personal style and approach. We have come to appreciate that therapy has to be individualized. What is appropriate for one person might very well be inappropriate for another. Some patients prefer to follow a more aggressive course, and feel less reluctant to use drugs to treat their HIV infection. Those who are concerned about the limitations and side effects of the drugs tend not to use drug therapy. It is important for each provider to learn each patient's attitude about the wide spectrum of treatment options. We need to find ways to work with patients without compromising our own professional standards. We all agree that PCP prophylaxis is necessary, and strongly recommend it. It is much more difficult to come to consensus regarding antiretroviral therapy. From what we know about the biology of HIV, I still believe that asymptomatics should be treated. The perceptions of other providers in our clinic have been swayed by the Concorde data; they tend to recommend later initiation of antiretroviral therapy. Most importantly, providers need to work with patients and allow them a central role in discussions about treatment. If they are going to be in this field, providers need to know the data well enough to actually make recommendations. It is a confusing time, but I hope that professionals will not run away from this important responsibility to their patients. ROMEYN: In researching and writing my book, Nutrition and AIDS, I looked at growth hormone, cytokine blockers and progressive resistance exercise, as well as vitamins and antioxidants. In the last year we've also begun to recognize that progressive resistance exercise is a means to build lean body mass in early asymptomatic patients. Not only can they build lean body mass early on, so that you have a higher mountain to slide down, but it also gives your highly motivated, highly anxious, newly diagnosed, healthy HIV patients something to do for themselves. We strongly recommend weightlifting. I hope to get my own impedance monitor so I can measure lean body mass. I'd like to get one for me and one for Project Open Hand. Then we can appropriately measure lean body mass instead of weight, and monitor how people are really doing. The Kotler studies show statistically that at 54% or 66% of lean body mass, people die. We say that they died of MAC or lymphoma, but they really die because they only have 54% of lean body mass. If you can build up lean body mass early and reduce the episodes of acute drop-off of lean body mass by getting a head start on infection, and if you can replete lean body mass by watching for malabsorption and aggressively attending to calories during a period of secondary infection, then you may greatly lengthen the time between diagnosis and death. LEOUNG: Over the last year the likelihood has become greater that we will come up with new, more effective antiretroviral drugs. A number of agents of different types and with different mechanisms of action are being investigated simultaneously in several places in this country. With the promise of these new modalities, I think that we are drawing closer to truly controlling HIV. What is different this year is that we have more reason to be hopeful about that. ********* Human Herpesvirus Type 6 (HHV-6): Cofactor or Opportunistic Infection in AIDS? Ronald A. Baker, PhD Ronald Baker is editor of BETA. A recent post-mortem study of lung, lymph node, spleen, liver and kidney tissues of 9 people with AIDS revealed that every tissue examined (34 of 34) was positive for active HHV-6 infection (Knox and Carrigan, 1994). Based on these and other results from their study, a research team at the Medical College of Wisconsin concludes that HHV-6 is an important disease-causing agent in people with AIDS. The HHV-6 infection rate was significantly higher in the tissues examined than that for cytomegalovirus (CMV), which was present in only 9 of the 34 tissues. HHV-6 infection of the lung of one individual was extensive enough to account for his fatal pneumonitis, according to the investigators. Background HHV-6 is a commonly found virus that infects at least 90% of the general population in the U.S. by age 2, and is widely and highly prevalent in many parts of the world. HHV-6 was first discovered in 1986 at the Tumor Cell Biology Laboratory of the National Cancer Institute (Bethesda, Maryland) by Dr. Zaki Salahuddin and colleagues (Salahuddin, 1986). The potential pathogenic role of HHV-6 is not yet clearly understood, but there is suggestive evidence that the virus may play a significant role in several diseases. Researchers have conclusively linked the virus to only one disease_exanthem subitum (roseola), a benign illness of early childhood associated with primary HHV-6 infection. As with other herpesviruses, available serologic tests have limited value in differentiating between latent (inactive) and active infection with HHV-6. Only recently have researchers developed and employed special techniques that can detect HHV-6 replication in vivo (immunohistochemical staining with a specific polyclonal antiserum). Dr. Robert Gallo and colleagues at the National Cancer Institute (NCI) suggested 5 years ago that HHV-6 might contribute to the depletion of CD4 cells (T-helper cells) in people with AIDS. These government researchers found that, like HIV (but unlike CMV), HHV-6 selectively infects CD4 cells. They also discovered that, in laboratory tests of HIV and HHV-6 coinfected cells, HHV-6 stimulates the release of cytokines that activate HIV replication. Thus, HHV-6 and HIV can coinfect individual lymphocytes and cause increased cytopathic changes in these immune system white blood cells, when compared to lymphocytes infected only with HIV. HHV-6 also induces CD8 cells and natural killer (NK) cells to express the CD4 receptor (the major receptor of HIV), thus increasing the number of cells susceptible to infection with HIV. Natural Killer Cellsand HHV-6 Natural killer cells provide the body with an important mechanism of primary defense against infection with viruses. When natural killer cell functioning is significantly compromised or reduced (as in AIDS), the natural immunity of the individual is seriously impaired. For example, multiple herpesvirus infections occur in individuals who congenitally lack natural killer cells. [Ed. note: a reduced natural killer cell function has been documented not only in AIDS but also in chronic fatigue syndrome (CFS), a disorder of unknown cause that often presents with signs of active HHV-6 infection.] In laboratory tests, HHV-6 can directly target and kill natural killer cells. In humans, this could result in the suppression of the individual's natural antiviral immunity. HHV-6 is the only virus known that efficently infects and kills natural killer cells, according to NCI researchers. Disseminated, Active HHV-6 Infection Researchers in the Department of Pathology at the Medical College of Wisconsin evaluated the frequency of active HHV-6 infection in 9 people who died of AIDS. The demographic data of these individuals closely resembled that of the general population of HIV positive individuals in Wisconsin. As mentioned above, every tissue examined was positive for active HHV-6 infection, while CMV infection was found in only 9 of the 34 tissues examined. The investigators conclude that HHV-6 was probably the cause of one individual's fatal pneumonitis. They point out that respiratory failure is the main cause of death in AIDS patients, with pneumonitis of unknown cause being the primary cause of death in 5-10% of people with AIDS. They suggest that HHV-6 infection may be the cause of the fatal pneumonitis in some of these individuals. Most of the HHV-6-infected cells in tissues of AIDS patients examined were lymphocytes. HHV-6-infected lymphocytes located within areas of inflammation, suggest the researchers, could transfer the infection to other lymphocytes, thereby perpetuating the inflammation and causing a significant systemic destruction of lymphocytes. The lymphoid organs are important reservoirs of HIV infection, and recent studies have demonstrated that HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of HIV disease. The Wisconsin pathologists note that HHV-6-infected lymphocytes account for the increased density of HHV-6 infection found in the lymphoid organs. HHV-6 can infect and destroy CD4 cells, and when HHV-6 and HIV infect the same CD4 cells, the destruction of these cells is enhanced by mechanisms not yet understood. Other Evidence of the Interaction between HHV-6 and HIV-1 Many isolates of HHV-6 have been drawn from the lymphocytes of people with an AIDS diagnosis. Because the primary cellular target of both HHV-6 and HIV is CD4 cells, it has been suggested that HHV-6 may be a cofactor in progression to AIDS. The manifestations of such a role might include the following criteria: (1) changes in HHV-6 antibody levels as AIDS progresses; (2) changes in levels of HHV-6 in tissues or bodily fluids; and (3) evidence for interactions between the viruses at the cellular or molecular levels (Pellet, 1992). The study of HHV-6 in people with HIV disease has yielded uncertain results. Published reports include evidence of a high seroprevalence of HHV-6 and/or increased antibody titers in people with AIDS (Levy, 1990); no differences in immune profiles (Balachandran, 1991); no significant differences in HHV-6 antibody titer between HIV positive and random male blood donors (Brown, 1988); lower prevalence of HHV-6 in AIDS patients; and no difference between antibody titers of HIV positive lymphadenopathy patients who did or did not progress to AIDS (Spira, 1990). In laboratory tests of cell cultures coinfected with HIV and HHV-6, a wide range of effects have been found. Individual CD4 cells can be simultaneously infected with both viruses, with the coinfected cells demonstrating increased HIV activity, increased reverse transcriptase levels and earlier cell death (Lusso, 1989). Lusso and colleagues found that HHV-6 induced the expression of the CD4 receptor in lymphocytes, making these cells more susceptible to infection with HIV (Lusso, 1991). Other experiments have shown suppression of HIV replication in cells coinfected with HHV-6 and HIV (Carrigan, 1990). HHV-6 replication in these cells was unaffected or only slightly enhanced. It was even suggested that HHV-6 may slow the progression of disease in some HIV positive individuals. Chronic Fatigue Syndrome Several studies have noted higher HHV-6 antibody titers or seroprevalence in people diagnosed with chronic fatigue syndrome (Krueger, 1987; Read, 1988; Balachandran, 1991). In a controlled study, HHV-6 antibodies were detected in 69% of the cases and in only 12.5% of the controls (Dale, 1989). In contrast, one study found no difference in seroprevalence between cases and controls (Wakefield, 1988), and another noted no correlation between HHV-6 seroprevalence or antibody titers and chronic fatigue syndrome (Gold, 1990). Immune Response HHV-6 induces the increased expression of several cytokines, including interferon alpha, interleukin-1B and tumor necrosis factor (Kikuta, 1990; Flamand, 1991). HHV-6 may produce an immunomodulatory effect by stimulating the production of these cytokines, which, in turn, may result in disease progression (Carrigan, 1991), viral avoidance of immune surveillance (Flammand, 1991) or stimulation of viral activity (Folks, 1989). Other Disease Associations As mentioned above, HHV-6 infection occurs early in life, and has been shown to be the cause of a mild disease in children, exanthem subitum (roseola or sixth disease). In addition, significant increases in anti-HHV-6 titers have been found in several types of transplant recipients whose immune systems were suppressed by chemotherapy: cardiac (Irving, 1988), bone marrow (Asano, 1991), liver (Ward, 1989) and renal (Asano, 1989). In a study of 15 bone marrow recipients, only one participant was culture-positive for HHV-6, suggesting that active HHV-6 infection is not common among this patient population. HHV-6-infected lymphocytes were detected in the lungs of 2 bone marrow transplant recipients who developed pneumonitis, but the lung tissue cells had no evidence of HHV-6 infection, suggesting that disease resulted from HHV-6-associated inflammation rather than cell destruction by the virus. It is clear that HHV-6 can become active due to post-transplant immunosuppression, but its role in causing complications following transplantation is unclear. There is evidence suggesting a role for HHV-6 in some adult cases of hepatitis (Dubedat and Kappagoda, 1989). Researchers also have reported an association of HHV-6 with cases of mononucleosis-like illnesses that did not appear to result from infection with Epstein-Barr virus (EBV) or CMV (Irving and Cunningham, 1990). HHV-6 was cultured from the blood of a patient with a severe mononucleosis-like illness, elevated numbers of activated B cells, depressed numbers of T-cells, extremely high titers of anti-HHV-6 antibodies, and who met the case definition of chronic fatigue syndrome (Buchwald and others, 1991). Immune Disorders and Lymphoproliferative Diseases The first 6 isolates of HHV-6 were taken from individuals with lymphoproliferative disorders (Salahuddin, 1986), but the role of HHV-6 in immune disorders and lymphoproliferative diseases is uncertain. Individuals with autoimmune diseases (e.g., sarcoidosis, Sjogren's syndrome and systemic lupus erythematosis) reportedly have higher than normal HHV-6 antibody titers (Ablashi, 1988). Researchers found that patients with leukemia and lymphoma had higher anti-HHV-6 titers than controls, with the highest titers among those with acute myeloid leukemia, Hodgkin's disease and non-Hodgkin's lymphoma (Clark, 1990). Others have also noted higher HHV-6 antibody titers in people with Hodgkin's disease (Balachandran, 1991). It is possible that, even if HHV-6 does not play a direct causative role, the virus may be a cofactor in the progression of these diseases. Some researchers have suggested that HHV-6 may stimulate the production and activation of B-cells, thus expanding the population of cells targeted by another pathogen or event that gives rise to malignant lymphomas. Treatment Implications The possible involvement of HHV-6 in serious illnesses has motivated a search for antivirals to inhibit its replication. The results of HHV-6 susceptibility to antivirals is summarized in Table I. Although it is difficult to compare the results due to the variety of assays, viral strains and culture conditions, some conclusions can be drawn. Ganciclovir (GCV), foscarnet (PFA) and phosphonoacetic acid clearly inhibit almost all HHV-6 replication, indicating that the virus is susceptible to similar antivirals as cytomegalovirus. HHV-6 is also sensitive to acyclovir (ACV), although somewhat less than to the other antivirals shown. It is possible that acyclovir (Zovirax) at doses adequate to suppress herpes simplex virus infection (oral and genital herpes) also might have an inhibitory effect on the reactivation of HHV-6. The effect of the new acyclovir prodrug valacyclovir (Valtrex) in HHV-6 has not yet been studied. Because Valtrex produces significantly higher blood levels of acyclovir than Zovirax, it may effectively suppress the activity of HHV-6. Commentary If the destruction of CD4 cells caused by coinfection with HHV-6 and HIV seen in laboratory tests also occurs in vivo, the result of this coinfection in the lymphoid organs could be the synergistic destruction of CD4 lymphocyte cells. This process, in turn, would eventually result in the progressive disintegration of the immune system. Conclusive evidence demonstrating an immunosuppressive role for HHV-6 in AIDS is not yet available. It is possible that the widespread reactivation of HHV-6 infection shown by Knox and Carrigan may result from the immunodeficiency caused by HIV infection, but in his commentary on the Wisconsin post-mortem study, Dr. Gallo suggests that the reactivation of HHV-6 over the course of HIV infection may significantly increase disease progression: "...the unique biological properties of HHV-6, especially its 'immunotropic' nature and its positive interactions with HIV, strongly suggest that, once reactivated in the course of HIV infection, it may have detrimental effects on the immune system and expedite progression of the disease." "How can we solve this puzzle that may have critical implications for the prophylaxis and management of AIDS? Longitudinal studies of HHV-6 replication in HIV-infected people are essential to establish a solid association with disease progression. Nevertheless, valuable information can be expected from other approaches_for example, coinfection studies in animal model systems...and therapeutic trials of drugs with selective activity against HHV-6" (Gallo and Lusso, 1994). Conclusion Although a good deal has been learned about HHV-6 in a short period of time, much significant information remains unclear or unknown. Researchers have presented data suggesting HHV-6 involvement in a number of diseases, but it is unlikely that the virus plays a causative or cofactor role in all of them. The evidence for a cofactor role for HHV-6 in HIV disease progression is suggestive, but inconclusive. HHV-6 may be an opportunistic infection, like so many others in AIDS. Controlled clinical trials will be necessary to clarify further what role, if any, HHV-6 plays in HIV-associated immune dysfunction. Sources Asano Y and others. Human herpesvirus 6 harbouring in kidney. The Lancet ii: 1391. 1989. Asano Y and others. Reactivation of herpesvirus type 6 in children receiving bone marrow transplants for leukemia. New England Journal of Medicine 324: 634-635. 1991. Balachandrian N and others. Electrophoretic analysis of human herpesvirus 6 polypeptides immunoprecipitated from infected cells with human sera. Journal of Infectious Diseases 163: 29-34. 1991. Brown NA and others. Prevalence of antibody to human herpesvirus 6 among blood donors infected with HIV. The Lancet ii: 1146. 1988. Carrigan DR and others. Suppression of human immunodeficiency virus type-1 replication by human herpesvirus-6. Journal of Infectious Diseases 162: 844-851. 1990. Carrigan DR and others. Interstitial pneumonitis associated with human herpesvirus-6 infection after marrow transplantation. The Lancet 338: 147-149. 1991. Corbellino M and others. Disseminated human herpesvirus 6 infection in AIDS. The Lancet 342: 1242. 1993. Dale JK and others. The Inoue-Melnick virus, human herpesvirus type 6, and the chronic fatigue syndrome. Annals of Internal Medicine 110: 92-93. 1989. Drobyski WRR and others. Human herpesvirus 6 (HHV-6) infection in allogeneic bone marrow transplant recipients I: evidence for a marrow-suppressive role for HHV-6 in vivo. Journal of Infectious Diseases 167: 735-739. 1993. Dubedat S and Kappagoda N. Hepatitis due to human herpesvirus-6. The Lancet ii: 1463-1464. Flamand L. Human herpesvirus 6 induces interleukin-1B and tumor necrosis factor alpha, but not interleukin-6, in peripheral blood mononuclear cell cultures. Journal of Virology 65: 5105-5110. 1991. Folks TM and others. Tumor necrosis factor alpha induces expression of human immunodeficiency virus in a chronically infected T-cell clone. Proceedings of the National Academy of Sciences USA 86: 2365-2368. 1989. Gallo RC and Lusso P. Human herpesvirus 6 in AIDS (commentary). The Lancet 343: 555-556. March 5, 1994. Gold D and others. Chronic fatigue. A prospective clinical and virologic study. American Medical Association 264: 48-53. 1990. Knox KK and Carrigan DR. Disseminated active HHV-6 infections in patients with AIDS. The Lancet 343: 577-578. March 5, 1994. Krueger GRF. Persistent fatigue and depression in a patient with antibody to human B-lymphotropic virus. The Lancet ii: 36. 1987. Levy JA and others. Frequent isolation of HHV-6 from saliva and high seroprevalence of the virus in the population. The Lancet 335: 1047-1050. 1990. Lusso P and others. Productive dual infection of human CD4 T lymphocytes by HIV-1 and HHV-6. Nature (London) 337: 370-373. 1989. Lusso P and others. Induction of CD4 and susceptibility to HIV-1 infection in human CD8+ T lymphocytes by human herpesvirus 6. Nature (London) 349: 533-555. 1991. Lusso P and others. Infection of natural killer cells by human herpesvirus 6. Nature 362: 458-462. April 1, 1993. Lusso P and Gallo RC. Human herpesvirus 6 in AIDS. The Lancet 343: 555-556. March 5, 1994. Lusso P. Interactions between HHV-6 and HIV: HHV-6 as a potential cofactor in AIDS. In: Interactions between retroviruses and herpesviruses. Kung HJ, Wood C, eds. River Edge, New Jersey. World Scientific Publishing (in press). Pellet PE and others. Human herpesvirus 6: the virus and the search for its role as a human pathogen. Advances in Viral Research 41: 1-51. 1992. Salahuddin SZ and others. Isolation of a new virus, HBLV, in patients with lymphoproliferative disorders. Science 234: 596-601. 1986. Wakefield D. Human herpesvirus 6 and myalgic encephalomyelitis. The Lancet i: 1059. 1988. Ward KN and others. Brief report: primary human herpesvirus 6 infection in a patient following liver transplantation from a seropositive donor. Journal of Medical Virology 28: 69-72. 1989. --------- Inhibition of HHV-6 Growth by Antiviral Drugs Inhibitory Drug Virus strain Cells dose (æM) Inhibition (%) PFAa African PBL 83 100 HBLV HSB-2 104 100 PAAb Z29 PBL 2141 88 Z29 CBL 714 100 Roseola CBL 357 100 Z29 CBL 200 100 ACVc Z29 PBL 400 85 OK CBL 444 100 Z29 CBL 50 88 KF PBL 128 90 African PBL 100 100 HBLV HSB-2e 0.4 80 GCVd African PBL 10 100 KF PBL 6 100 Z29 CBL 25 94 HBLV HSB-2 0.6 0 a Phosphonoformate c Acyclovir e Drug was cytotoxic b Phosphonoacetic acid d Ganciclovir ********** Recommended Reading Ronald A. Baker, PhD Treating AIDS with Chinese Medicine. Mary Kay Ryan and Arthur D. Shattuck. Published by Pacific View Press (1994). 364 pages. Paperback. $29.95. This easy-to-read book offers an excellent introduction to the use of Traditional Chinese Medicine (TCM) in the treatment of HIV infection and AIDS. The book opens with a description of the differences between western and Chinese medicine and a synopsis of how TCM understands the human body. Basic TCM concepts are discussed, including Qi ("vital energy"), Channels ("internal and external routes"), Yin and Yang ("types of bodily activities, developments, processes and outcomes"), Xue (blood) Jin and Ye (fluids). The authors, cofounders and codirectors of the North Side HIV Treatment Center in Chicago, combine both western and Chinese medical treatment. In their view, both systems have value, and they use them in tandem. At the Chicago clinic, patients are evaluated by a team of providers that includes a physican, but also an acupuncturist, a message specialist and an expert in the use of Chinese herbal treatments. Sometimes western medicine is the therapy of choice, for example, in the treatment of AIDS-associated opportunistic infections. As a result of western medications, however, adverse side effects often occur that, in their view, are best helped by TCM. The book contains a lengthy chapter on the appropriate TCM treatments to accompany western drug treatment for opportunistic infections, as well as a detailed section on the management of symptoms associated with HIV disease (diarrhea, fatigue, fever, headaches, night sweats), using both TCM and western treatments. The authors also address the special problems of certain groups coping with AIDS_women, hemophilics and IV drug users_and then propose specific TCM approaches to treating problems unique to these groups. The use of dietary supplements is also discussed, including many now familiar to the HIV/AIDS community: beta carotene, egg lecithin, selenium, vitamins A, B and C, zinc and germanium. Less familiar herbs and plants are also outlined, such as bitter melon, chaparral, comfrey root, hops, mistletoe, licorice root, Siberian ginseng and turmeric. In the chapter entitled "Addressing the Crisis of AIDS," Ryan and Shattuck write, "There are long-term survivors of AIDS. There are people who have beaten other usually terminal illnesses. How can we know any given patient won't be among these miracles? The work of medicine is to support the quality of life in the living and to help and support patients through death_" "Patients' lives are often prolonged by their involvement in fighting for their rights. If, as many people think, there will come a time when AIDS, like diabetes, is debilitating and serious, but not consistently terminal, then any prolonging of life may get a patient to that time. We hope they are right. In the meantime, we see our job as supporting quality of life, prolonging life when possible, and respecting death when it comes." ********* Vitamin and Nutritional Supplements in HIV Disease The following text is an edited transcript of 3 BETA LIVE! teleconferences held April 5, 7 and 12, 1994. BAKER: Good evening, everyone, and welcome to the first BETA LIVE! teleconference. Thanks to the miracle of the information super-highway, there are about 200 of us online together from cities and towns across the U.S., and from Canada, Puerto Rico and Spain. I'm Ronald Baker, editor of BETA and the moderator of this evening's program. I'm speaking to you from the offices of BETA at the San Francisco AIDS Foundation. We have online with us this evening 3 distinguished guest panelists who will take your questions about the main subject of our teleconference: "Vitamin and Nutritional Supplements in HIV Disease." The format of tonight's teleconference is this: I'll start with some questions for the panelists, and after about 20 minutes we'll take questions from callers. Later I'll report briefly on recent drug developments and review important drug studies that are now open to enrollment. We'll close the program with a preview of upcoming BETA LIVE! teleconferences. Let me introduce you now to our guest panelists. Dr. Jon Kaiser is a San Francisco physician who specializes in treating people with immune disorders. He is also the author of a new book entitled Immune Power: A Comprehensive Treatment Program for HIV. Dr. Kaiser joins us tonight from his office in San Francisco. Cade Fields is a registered dietician who specializes in nutrition and AIDS. She joins us from her home in Cary, Illinois. Dr. Howard Greenspan is a researcher and expert on oxidative stress. Last November he chaired a conference on oxidative stress in AIDS that was sponsored by the National Institutes of Health [NIH]. Dr. Greenspan joins us tonight from his home in Clinton, New Jersey. Dr. Kaiser, let's begin with a question for you. Why do you believe that vitamins and nutritional supplements can make a significant difference in the treatment of HIV infection in AIDS? KAISER: Well, Ron, I think that whenever we're talking about supporting the immune system, we have to understand that its strength is connected to, and dependent on, the nutritional status of the individual. We knew even before HIV came on the scene that nutrient deficiencies were responsible for promoting a weakened immune state and more frequent infections. And Pneumocystis pneumonia, which we attribute to the effects of HIV, is often found in profoundly malnourished children. So there's a direct link between T-cell function, T-cell numbers, antibody production and the amount of nutrients_vitamins, minerals, protein and calories_that are available to the body. We also know that the stress of infection creates a need for higher levels of the nutrients that I just mentioned. When we take a look at people who have chronic infections, or who have sepsis, we see that those with a higher nutritional state do much better than those that are in a weakened nutritional state. Separate studies by Marianna Baum and by Richard Beech, both at the University of Miami, showed that there was a high prevalence of these nutritional deficiencies in HIV positive patients who were asymptomatic, well-nourished, taking nutritional supplements of 3 to 5 times the RDA, and with as high as over 500 T-cells. They found that 67% of this population of patients had at least one nutrient deficiency, and a third had several nutrient deficiencies in the bloodstream. We also see that some of the drug therapies that are used in HIV, namely AZT, can also precipitate deficiencies of copper and zinc. So we are starting to get evidence that relative deficiencies exist in HIV positive people despite their high levels of intake. The deficiency is due either to poor absorption or to greater utilization of nutrients because of higher metabolism. We're also starting to find out that there are systems of the body that are designed to keep the immune system healthy_such as the antioxidant pathways_and that they are inordinately sensitive to deficiencies of some of the compounds we're going to be talking about, such as vitamins C and E, zinc, selenium and the amino acid glutathione. So we need further research into this area to find out whether high-dose nutrient supplementation of these antioxidant vitamins and minerals_either alone or in combination with antivirals_can have a significant therapeutic effect, can slow the trend of decreasing immune function, and can help support the immune system. Another issue is whether or not lower drug dosages can be utilized in combination with these vitamins for better overall results, fewer toxic side effects and resistance. Evidence from published studies and from my clinical practice, in which I use a lot of nutrient supplementation, has proven to me that a lot of potential exists in this area. Except for a couple of nutrients that I'm sure we'll talk about today, we really haven't found the upper limit of what benefits HIV positive individuals. All of these studies reveal that there are deficiencies, and that higher intakes of many of these supplements seems to decrease the immune system deterioration over time. With much more information and emphasis on nutrition and nutrient therapy, we will be able to lessen the dosages of some of the more toxic antiviral medications and prevent some undesirable side effects of the drugs by keeping people stronger and healthier through good nutrition. This will make a significant impact on helping people live long and healthy lives while being HIV positive. So I would like to say to the listeners that this is a real fertile area for you to gather as much information as possible. As much as your resources allow, work with a nutritionist to look into the possibilities of vitamin supplementation and to make decisions that hopefully will make a big impact in keeping you healthy for as long as possible. BAKER: Thank you, Dr. Kaiser. Dr. Greenspan, will you explain, in layman's terms, what antioxidants are and tell us about their possible role in the treatment of HIV infection? GREENSPAN: There's so much information flying around these days about antioxidants, and the good and bad aspects of their use, that it has become quite confusing. The use of antioxidants has been promoted to help fight against the excess production of what we call "free radicals," or reactive forms of oxygen. They are formed in the body as natural by-products of oxygen metabolism and are essential components of our immune system. The problem with free radicals arises when the natural balance between their production and the buffering, protective mechanism of antioxidants is lost. Then damage can occur. This is commonly seen in cardiovascular disease and cancer, and may even be the main component of aging. So some people may say antioxidants are very important, while others say that they may compromise our ability to utilize our immune system. In the HIV-infected individual, the virus compromises the delicate balance between free radicals and antioxidants in a number of ways. The virus may change the absorption level of certain nutrients from the bowel, including antioxidant vitamins and amino acids essential in the body's production of antioxidants. In fact, the virus can effectively inhibit the cellular production of essential antioxidant enzymes. The result in the HIV-infected patient is this excess activity of free radicals, a condition that we call "oxidative stress." The research published in the last 2 years shows that oxidative stress can increase the rate of replication of the HIV virus. Perhaps more importantly, oxidative stress can also initiate a cascade of events that results in the destruction or premature death of immune cells, particularly T-lymphocytes. So if you are able to bring this oxidative activity under control, you may be able to slow viral replication and preserve the T-cell population. In fact, evidence that was presented at the NIH conference last November supported both of these premises: that using certain types of antioxidants can decrease viral replication and can help to maintain, and even raise, T-cell levels. BAKER: What antioxidants do you recommend, Dr. Greenspan, and could you give us some examples of dosages? GREENSPAN: I can give you some recommendations that I would use for myself if I was an infected individual, but I caution that every individual is different, and that dietary intake and stage of illness may govern what type of supplemental therapy would be recommended. Generally, with beta carotene I would probably stay with a dosage somewhere around 50,000 units/day; with vitamin E, I would try to work up to 1,200 units/day. I normally go to bowel tolerance on oral vitamin C; flavonoids usually come in combination with the vitamin C, and 300 to 600 mg/day of flavonoids is probably adequate. Certain individual flavonoids, such as quercetin, may be prescribed on an individual dosage basis. BAKER: What about NAC [N-acetylcysteine] which is very commonly used in the HIV community now? What dose would you recommend for most individuals? GREENSPAN: I happen to be one of those who feel that NAC, which is a precursor to glutathione, has very limited toxicity. I use it in fairly high doses, between 3 and 5 grams/day, although certain of my colleagues will dose twice that amount. Most of the studies that have been done_and there have been quite a few_have shown very little, if any, toxicity at reasonably high levels. I know that there is controversy in this area and that's why there are so many researchers doing work on N-acetylcysteine here at NIH, at Stanford University, the Pasteur Institute and Heidelburg University. It's quite an open subject for debate but I myself don't hesitate to use it. BAKER: Thank you, Dr. Greenspan. I know there will be more questions from our callers about antioxidants. Miss Fields, as a specialist in nutrition in AIDS, what's the most important nutritional advice you have for people living with HIV infection and AIDS? FIELDS: First I would like to stress that nutritional supplements are just that, supplements. So the most important advice I can give a person who is HIV positive is to make sure to have the necessary nutritional foundation before starting with supplements, which unfortunately won't work without this foundation. Building the foundation requires knowing your nutritional priorities and making the commitment to fulfill them. The most important priority is fluids, which doesn't have to mean water and which can contain calories. The amounts that people need are anywhere from 16 to 17 cc per pound of body weight, which works out to about 1 cup of fluids for every 15 pounds, or 32-35 cc per kg of body weight. Calories are your second priority. Men need approximately 16 calories per pound and women need between 13 and 14 calories for every pound of body weight. The third priority is protein. You need at least 0.6 grams of protein per pound of body weight. Your fourth priority is micronutrients and making sure, before looking into nutrient supplements, that you get an adequate amount of them. Natural and traditional medicine is not nontoxic, and I think it's important to remember that. Also there are a number of antioxidants in food which may work synergistically with a supplement program. Certainly there are more specific recommendations that a clinician can make for you after assessment. The second piece of advice is that it is important to monitor trends in your status. It is important to get baselines on basic things like albumin, prealbumin, creatinine and others that you can get tested on a regular visit to a physician. Since every person has different baseline values, knowing your own numbers is more useful than comparing yourself to a range. Weight, height and body composition measurements are very important. Don't guess. Get a baseline on your nutrient intake and compare it to your estimated needs. Get a body composition done by means of caliper measurements or mid-arm circumference measurements. Make sure that the person is trained in the area and knows what he or she is doing because measurements taken by different people can vary greatly. Also get a baseline on your daily activity. When you have all these baseline values, take a look at any symptoms, or interactions of drugs you may be taking, and see how they affect your nutritional status. The third piece of advice I'd have is to develop a plan together with your healthcare professional for intake and supplementation, and to follow it wisely. Know what your options are for the future in terms of specialized nutrition support, things like tube-feeding and TPN [total parenteral nutrition], which during rough times can help you get back to your normal regimen. Include exercise in this regimen because it could play one of the most important roles in your body functioning normally and in controlling all of the related events in HIV seropositivity. BAKER: Thank you, Miss Fields. Jennifer, I'll turn the program over to you to take questions from our audience. JENNIFER: Thank you, Dr. Baker. Our first caller is from Los Angeles. LOS ANGELES: This question is for Dr. Greenspan. Hi, Howard, we've spoken in the past. My name is Steve Franco. As an HIV positive individual aware of vitamin deficiencies and possible oxidative stress damage, my question to you is whether there is a test, other than the standard T-cell test, that can be done regularly to monitor specific vitamin deficiencies or to test for the state or rate of oxidative stress? GREENSPAN: Well, there's quite a number of tests that are available, but not necessarily all physicians know about them. They certainly can be ascertained by some investigation. The tests measure vitamin levels, levels of amino acids, levels of superoxide dismutase, catalase and peroxidase. You can check actual levels of free radicals such as hydroxyl free radicals. You can check for products of oxidation fairly easily. In fact, now there's a new method of determining the degree of oxidative damage to DNA, which may be a very significant site of the oxidative damage in T-cells. So those types of tests are readily available if you know who to speak to and where to go. LOS ANGELES: So individuals need to approach a medical practitioner who has that capability or is willing to do those tests. GREENSPAN: Right. And as I've said, if they can't be found, you could probably check with BETA or come directly to me. And I can certainly give BETA a list of where these tests can be done. HOUSTON: Hi, this question could go to any of the panelists. This is Clint Stevens. I'm a dietician working with HIV positive patients in Houston, and I get a lot of questions on how to structure a supplement program. Like Cade, I prefer to emphasize food sources. With some of the recent studies suggesting zinc may speed progression of HIV disease, I'd like some comments about maximum levels of zinc and selenium that could be recommended with some comfort for supplementation. KAISER: Zinc is a double-edged sword. There are a fair number of studies which show that inordinately high levels cause depressed lymphocyte function and, like the caller suggested, can decrease the time before symptoms and immune suppression is evident. On the other hand, in Dr. Beech's study, 50% of the participants were found to be zinc-deficient, and zinc deficiency is also associated with impaired phagocytic function, as well as cellular and humoral immune dysfunction. So what we need to do is to find a dosage that will give individuals the optimum level of the nutrient. It might need to be individualized based on a person's diet and exercise level, and whether or not he or she is taking antiviral medications (which can decrease absorption). What I usually recommend is somewhere between 50-75 mg/day, and I caution my patients not to exceed 100 mg/day in supplement form. The zinc level in the bloodstream is easily tested, and anybody who questions whether they're getting too much or too little should have their level tested by a reputable laboratory. FIELDS: I'd like to add that the level of some nutrients is very dependent on other components in the blood. A person with a low zinc level also should have a very low albumin level, which will be associated with an acute phase of infection as well as with low zinc. It may have little to do with the actual true level of zinc itself. There have also been some studies that have tried to establish whether or not blood levels of nutrients, especially for individuals with some degree of infection, are really accurate. So it's just a note of caution for the interpretation of those laboratory values. KAISER: Yes, I would agree with that. As far as selenium goes, 200 micrograms (mcg)/day is the usual upper limit of dietary tolerance, and the dose we often use. However, there have been some research studies published in which subjects have supplemented selenium up to 400 mcg and have increased immune function without any incidence of toxic side effects. Again, it depends on your diet, and on what part of the country you live in because, for example, some rural areas already have a lot of selenium in the ground water, and supplementing may cause toxicity. As a moderate dosage, I recommend no more than 200 mcg in supplemental form per day. PHOENIX: My question is for anyone on the panel. I became HIV positive in 1989 and started taking just about all the vitamins and supplements that you've mentioned. However, I have another complication. I have hepatitis B and I also took an experimental drug at the NIH, the FIAU drug. So I'm interested in where the test in Dr. Greenspan's area would be since I am only temporarily here in Phoenix. Also, what vitamins I should be extremely careful of since I have hepatitis B? GREENSPAN: As far as where the various tests can be done, I will furnish that to BETA rather than go through a whole list on the phone. As far as knowing what level of vitamins you can tolerate, it's determined by the extent of liver damage that you may have experienced either from the hepatitis or from drug therapy. Taken in reasonable dosages, most of the antioxidant vitamins really work to decrease inflammatory processes, and hepatitis is an inflammatory-type process. Yours is a very individual case, though, and someone would have to look at your blood and liver function to really give you aa appropriate answer. But in general, most of these substances have no known toxicity, taken at reasonable levels. NEW YORK CITY: My question is for Dr. Kaiser. It's about NAC. I was wondering, is there any difference between NAC bought in the underground and the NAC vitamin supplement? I read that if you have gastrointestinal problems or if you have a tendency to get ulcers or gastritis, that you should stay away from NAC. Is that true? KAISER: I'll take the second part of your question first. Probably the most common, though not extremely common, side effect from taking high doses of NAC is gastric irritation. It does have a thinning effect on the mucous. We call it a mucolytic effect. If you have problems with gastric or esophageal reflux or ulcers, be cautious of the NAC dosage that you take, especially because it's meant to be taken on an empty stomach. Take it at a low dosage first and then gradually increase the dosage to make sure that it doesn't exacerbate a previous condition. As far as the different formulations, antioxidants, and especially NAC, by their very nature are very reactive with the oxygen in the air. Make sure that the source you get it from keeps it very fresh and that the bottle is well sealed. I know that there are some companies that put it out in a foil packet so that it is protected from the light and air. I'll defer to Dr. Greenspan to find out more on particular formulations, but I would advise that you keep it tightly closed and protected from the light and air as much as possible, and that you obtain it as fresh as possible. GREENSPAN: I might add that when taking supplements, and especially something like NAC, which has become quite popular, you should stay with companies that have longer-term experience in producing these types of substances, rather than go with someone who is new on the market and trying to mimic an existing product. I don't want to endorse one product or another, but most of the good underground organizations, certainly the ones I'm familiar with in New York City, like DAAIR, are very well versed on which products are good. I would go along with their advice. DISCUSSION GROUP: This is a question for Dr. Greenspan. I'm curious whether he sees any role for the use of BHT as an antioxidant. GREENSPAN: Certainly BHT has been used for many years as a preservative in foods and in early antioxidant therapies. In the mid-70's it was a very popular antioxidant. Much of the work that we are seeing now has been moving somewhat away from use of BHT and towards some of the more updated forms such as the flavonoids and quinones that I've mentioned. I'm not saying that BHT is necessarily bad, but there are not many research groups now establishing clinical data on its use in HIV patients. SITE #17: Dr. Fields, would you address the nutritional value of lecithin, sugar and sunlight? As for protein supplements, how much additional protein powder might be necessary to take as a supplement? FIELDS: First, let me recommend that you check the type of protein that you use, see whether it's complete or not, and whether it complements what you have in your current diet. Protein has a nasty habit of dehydrating, so make sure that you get adequate amounts of fluid in at the same time. Overdoses of protein have shown no particular benefit, but just end up as extra adipose tissue [fat]. Your body has to tear apart the protein in order to store it as adipose, which creates a bit of a load on nitrogen. If you want to build body protein, one way to do that is through exercise. You have to have an adequate amount of calories, fluids and protein in order to do the type of exercise that you would need to build mass. Without activity you would see that providing protein to your body won't necessarily improve your lean body mass. As far as sunlight, I'm assuming you're talking about vitamin D and its production, which requires sunlight. Perhaps one of the other speakers has more information on this. Regarding sugar, there are some interesting relations between sugar and immune toxicity. Once again, I would recommend you prioritize in terms of getting an adequate amount of nutrition before concerning yourself with micromodulation. To my knowledge, there is not a sound basis for sugar being a problem, or at least not a high-risk problem, with toxicity to the immune system. In terms of lecithin, I'm not sure what particular aspect the caller is interested in. In the past lecithin has been used to alter the permeability of cells, and it has sort of waxed and waned in popularity. BARCELONA, SPAIN: I have 2 questions. Dr. Greenspan, what is the best way to take vitamin E? I understand that the epitope form might not be as useful as an antioxidant. And one question for Dr. Kaiser: you mentioned that in high doses vitamin A and zinc have adverse effects. What would be safe doses? GREENSPAN: Basically, we recommend that people try to get the alpha-tocopherol form. Succinate seems to be an adequate format to use, as well, depending upon the individual. The dosages that I gave before are what I would use for myself, but there are some potential risks for certain individuals in using high-dose vitamin E. KAISER: Overdosage of zinc and vitamin A can cause significant toxicities. If an individual consumes beta carotene, which the body uses to form vitamin A, there is very little chance of toxicity from as high as 100,000 or 200,000 units/day. The reported toxicity at that level has been the skin turning an orange color, which resolves when the person cuts back on it. Now I'm certainly not suggesting that most individuals take dosages that high. I'm more comfortable in general with what Dr. Greenspan recommended, which is from 25,000 to 50,000 units/day. As far as zinc goes, there's a significant body of research that has shown that both elevations in dosage above 100 mg/day as well as deficiencies can have immunosuppressive effects. So take a look at what's in the multiple vitamin and at what you're getting from your diet, and shoot for between 50 and 75 mg of zinc per day. ST. PETERSBURG, FL: Yes, my question is for Ms. Fields, who was discussing the use of TPN [total parenteral nutrition]. Who could we address to lobby to get TPN into earlier usage for HIV-infected persons? I don't know if it would be the companies that make the TPN or someone else. FIELDS: There are 2 key players to address, and one is the physician. It's important to talk with the physician to find out when, in fact, TPN should be used. This means that close self-monitoring will be important. Based on studies, we recommend that people keep in close touch with their physicians, and, if 2 days go by where intake is very difficult, to go in and address the problem. The other key player is the insurance case manager. As much as we would like to think that insurance is not a factor, case management has had a lot to do with the medical decisions that are made for individual patients. So I think that educating insurance case managers as well as physicians about the use of TPN and when it's most appropriate will be helpful. We've talked with a number of insurance groups that have said we are not going to be reducing the cost of care with nutrition therapies, and my answer to them at this point is, "you're right, we're not. We're going to increase the cost of care because we haven't agreed on where it is appropriate to provide that particular care." So, anyway, those are the 2 groups to educate about valuable and not-so-valuable use of TPN and TPN dollars. DISCUSSION GROUP: I would like to address a question to whichever member of the panel is best able to answer it. It concerns the level of cholesterol. It is noticed that people who are in advanced stages of AIDS or HIV infection have very low levels, if not zero, of cholesterol. Has any study been done to determine the benefit of supplemental intake of cholesterol, if any? FIELDS: Cholesterol laboratory levels in your blood have very little to do with the intake of dietary cholesterol. Though my gut feeling about that is that there wouldn't be any significant benefit from dietary cholesterol intake. DISCUSSION GROUP: I've been told that getting infusions or injections of certain vitamins is superior to taking them orally. I would like to know which vitamins you would recommend taking orally and which you would recommend taking intravenously. And also I would like to know, is there a certain time you should take certain vitamins_should you take certain ones in the morning and certain ones in the evening? Should you mix them together? Should you take all the vitamins at once, along with the minerals? GREENSPAN: There are only certain types of vitamins that are available in an injectable form, such as vitamin C and the B complex vitamins. Taking those on an injectable basis would give you higher doses than you normally could tolerate orally, especially vitamin C. Other substances such as beta carotene, vitamin E, flavonoids and quinones are only available in an oral form. As far as combinations of vitamins, I tend to advise patients to take their vitamins all together, although they may want to take the vitamin E in the evening. That's one of the only substances that may interact with other antioxidants. I always advise people to take vitamins on a stomach with food already in it so that there is a decrease in the potential for gastric upset. The only substance that we advise taking on an empty stomach is NAC. KAISER: I agree with Dr. Greenspan's comments on when to take the vitamins. As far as the choice of intravenous or intramuscular, there really haven't been any studies which have looked at the type of administration of high dosages of B vitamins, vitamin C and some of the antioxidant minerals. I am currently preparing a protocol for a Phase I-II study here in San Francisco to look at a 2-month course of twice-a-week IV administration of higher than normal dosages of vitamin C, B vitamins and some of the antioxidant minerals. The study is intended to answer the question that I think you are asking, and that is whether nutrients in dosages this high become drugs, and whether they have the potential to cause side effects. That's why I really think before anybody takes them that they need to be looked at in a controlled, scientific manner. The theory is that if you provide the antioxidant system of the body with nutrient compounds, you may in fact be able to tip the balance back from a high level of oxidative stress, increased HIV activity and cell death, to a more balanced situation where the body has the ability to hold its own against this infection. I think it's an interesting direction for research to go and hopefully we'll have at least some preliminary information over the next 6 months. FIELDS: I'd like to mention one thing. I recently was talking with a patient who told me that one of his clinicians recommended injections of B12 twice a day. The only concern I really have about that is every time you puncture your skin, you are putting yourself at a little more risk of infection. That should be taken into consideration. DISCUSSION GROUP: Regarding the fluid status in the body composition, you said there was a test to look at how much total body water there was. Would you talk about that some more? And for the people who have to get rehydrated at the hospital, would you discuss what they need to do to better maintain hydration? FIELDS: There are a number of ways to test body composition and the one I think you're interested in involves an electronic sort of "mini-jolt" to test total body water. A machine shoots a single frequency through the body and measures the water level inside and outside the cell. It doesn't tell you specifically how much is either inside or outside the cell. What you're concerned with is how much is inside the cell because that is more likely to be associated with protein stores. So in order to differentiate between the total body water and the amount that's inside the cells, a number of people have turned to multifrequency meters. However, they're not good clinical tools at this time because they're not transportable and they're difficult to use. If you have to go into the hospital for rehydration, there's a serious problem. Maintaining hydration is always important, but especially so during times of fever, for example. To get something that is tailored to your needs, you would need to see a clinician to make sure that the amount of fluid that you get meets the amount that you need. Taking in about 2 to 2 1/2 quarts of fluid a day, not necessarily water but some fluid, is a good baseline. OMAHA, NEBRASKA: Glad to talk to everyone on the teleconference. The question I want to ask is about the importance of massive dosages of vitamin C, such as 40,000 to 80,000 mg, and high dosages of vitamin E to keep the immune system functioning well. And secondly, I'd like to know what resources are available to help people with the cost of vitamins. Vitamins are not cheap, as you all know, and some people can barely afford them. Is there some kind of a program to help? My last question is, what are the foods that naturally contain antioxidants? KAISER: Well, I think the person on the other end brought up some excellent points, and I think we could probably talk about the answers for the rest of the hour. But just to address a few things that he brought up_first of all, I think that if I had to pick one category of food that contains the most antioxidants_and I hope Cade will say more about this_it would be fruits and vegetables. There was an article in the newspaper today about a component of broccoli that had been shown in an animal study to significantly block the occurrence of cancer in rats, compared to a control group, when both groups were exposed to heavy doses of carcinogens. So getting at least 5 large servings of fruits and vegetables each day would be, I think, your best food source for antioxidants. As far as the cost of vitamins, with continued research hopefully we will get some recommendations that nutrient and vitamin supplementation is a valid, even at times an indicated, form of medical therapy, and it will be covered by insurance. Unfortunately that's not the case right now, so if your finances are stretched, what I would recommend is finding the least expensive source of many of these. They come in generic forms. You can get a generic multivitamin. You can get generic vitamin C. Seek out the least expensive forms of these individual nutrients, and try to balance whatever dollars you have both on food and these nutrient supplements. FIELDS: Before we go on, I'm thrilled that the subject of food sources of certain vitamins and minerals was mentioned. I'd like to add a couple of things that may be helpful. One medium baked sweet potato has about 14-15,000 IUs of beta carotene; one large carrot has 11,000 IUs. So you can see that food can be a real good source of this. Vitamin C in a medium orange is about 80 mg. A less common fruit source is an acerola [a cherry-like fruit produced by various West Indian shrubs] which in 3 1/2 ounces has 1,300 mg of vitamin C, but I don't think too many people will find that in their stores. A large green pepper can have 128 mg of vitamin C. KAISER: These food sources may actually have better bioavailability than supplement forms, so you don't have to take as high doses. FIELDS: They may have some items that synergistically work along with, say, beta carotene, for instance. Carrots have canthaxanthin [an orange pigment] in them, which actually may prove to be a little more powerful than beta carotene alone, and which may not be found in the beta carotene supplement. GREENSPAN: There are citrus bioflavonoids which are very prevalent in some citrus fruits. They have been studied by the National Cancer Institute and shown to be very effective anticancer substances, and are known to be among the substances with the highest antioxidant activity. NEW YORK CITY: This is addressed to all 3 parties. Regarding various extracts, vitamins and even drugs like Bactrim, if the body can't absorb them, or develops toxicities, what can you do to try to get them into the system? KAISER: In my holistic medical practice I do everything as naturally as possible before resorting to drugs. In about 3 1/2 years' experience of people taking 1 Bactrim double-strength tablet 3 times a week to prevent Pneumocystis, the only people in my practice who have come down with Pneumocystis have been those who either refused to take Bactrim or who decided that, due to allergic reactions, they needed to use an alternative. The other thing is that, as expected, if a person wasn't allergic but refused Bactrim, there was a higher incidence of fungal infections, viral infections and gastrointestinal distress. As it turns out, 1 Bactrim tablet 3 times a week has been associated with very, very few of these long-term side effects that I was concerned about when I started. So my experience has been that it's very safe and effective, and I recommend it highly. FIELDS: People often look for a single answer but really, because HIV affects so many different systems and mechanisms in the body, there's probably not going to be a single answer. Antioxidant supplements are not the answer to everything that happens in HIV infection. Since there is no good single answer, it's going to be multifactorial approach that includes a lot of the available medications, some nutritional interventions, exercise and a number of other things. Looking to solve everything with one answer will probably be more risky than beneficial. GREENSPAN: I support Cade on that point. Although much of my work now concentrates on antioxidants, I have to say that in my 18 years of clinical practice, regardless of the disease situation, good nutrition, proper care of the body, just an overall good program is really the answer. No one nutrient or set of nutrients is going to be the answer. As every day goes by we find new pieces of the puzzle, and new answers. KAISER: Ron, I have one more comment for people who are taking antibiotics over the long term for prophylaxis. It's very important that the quality of the diet be extremely high, and that people consider supplementing with acidophilus preparations. If you have these things, you'll have a much lower chance of developing side effects from chronic antibiotic use. BAKER: Excellent comments. Thank you. Jennifer, let's take a question from one of the discussion groups. WASHINGTON, DC: My question is regarding the juicing of vegetables and fruits, which makes it easier to get 6 servings per day. Does juicing affect the nutrients in those fruits and vegetables? FIELDS: There are 2 ways to think about that. One is that in juicing you can get a lot of stuff in a good amount of fluid, and it may be easier for some people to deal with. The other thing is that, juicing things does allow for an oxidative reaction in a number of the nutrients. For instance, if you were to juice an orange and leave it sitting for a while, you would lose a great deal of the activity of vitamin C, which is why most of the commercial orange juices add vitamin C back. I would say if you're going to drink juice, consume it very shortly after you juice for optimal nutritional value. The fact that you're using juice to get a number of the nutrients at once is an excellent idea. Juice can also help if you have problems digesting more solid food. NEW YORK CITY: I've been associated with the Gay Men's Health Crisis in New York, as a staff nutritionist. I just wanted to say that, with beta carotene in particular, the nutrition is mostly in the pulp. If you figure that a cup of carrot juice contains roughly the juice of five carrots, you're still only getting the beta carotene of about one carrot since about 4/5 of the beta carotene stays in the pulp. So, unfortunately, it isn't an efficient way of getting beta carotene. GREENSPAN: Likewise for most of the citrus fruits. Much of the nutrient value is in the fibrous material. NEW HAVEN, CT: Dr. Kaiser mentioned that patients taking 3 to 5 times the RDA still showed nutritional deficiencies in things like zinc. I'm interested to know what's really causing these nutritional deficiencies. KAISER: I have 3 quick comments on that. One is, I think that RDA requirements for most of the nutrients are woefully inadequate when you're talking about people who are under the stress of HIV infection. The RDA are effective at keeping people just above the level where an individual who doesn't have a health problem, who is not overly stressed, will not come down with a disease related to nutrient deficiencies. But for someone with HIV infection RDA are woefully inadequate, due to increased metabolic requirements, due to increased stress. The second point is that HIV itself tends to cause changes in the bowel that may influence the absorption. In different individuals the absorption will be affected to different degrees. Without doing very expensive and sometimes inaccurate tests, we need to shoot for a level that in most HIV positive people will provide sufficient levels of absorption and that help with the deficiencies that the condition causes. There are people who are bypassing the absorptive mechanism of the gut and who are taking nutrients in intravenous form. I really don't think we have enough data on whether or not that is effective or whether it's safe. It's a personal decision, but I think one should try to take as much as possible orally and naturally. WHARTON, NEW JERSEY: What sort of supplementation would you recommend to a diabetic, HIV-infected person on a restricted diet? FIELDS: A diabetic diet allows a person to get an adequate amount of nutrients, including micronutrients, without requiring additional supplementation. If you're having a problem getting an adequate amount of nutrients with a diabetic diet, then you probably need to talk with a diabetic educator on an individual basis. SAN FRANCISCO: I'm a physician's assistant for Marcus Conant's Medical Group in San Francisco. This question is for any of the panelists who would like to answer. We see, almost universally, increased triglycerides in our HIV patients, and we were wondering whether the amino acid carnitine has been shown to be effective in reducing these levels. We really haven't found much else that has worked for some of these patients. GREENSPAN: Certainly carnitine has been used in that capacity, although I've not seen any studies that verify its activity. We do know that one of the primary causes of the elevations in triglycerides has to do with the production of TNF [tumor necrosis factor] from macrophages and monocytes, which are prevalent in HIV infection. More progressive infection has higher levels of TNF. And one of the things we are looking at are mechanisms of reducing the levels of tumor necrosis factor production. BAKER: There have been several studies suggesting that use of the drug Trental (pentoxifylline) reduces levels of tumor necrosis factor in people with AIDS. Patients might want to discuss use of the drug with their doctors. Trental has shown no significant adverse side effects. Thank you all for your excellent questions. Now I'm going to report briefly on recent AIDS drug developments and also tell you about some important clinical studies which are open for enrollment. D4T Although there haven't been any new antiviral drugs approved by the Food and Drug Administration for a long time now, there is one anti-HIV drug called D4T that is currently awaiting FDA approval. Bristol-Myers Squibb, the manufacturer of D4T has asked the FDA to approve this drug for HIV positive adults who have previously taken AZT. The FDA Antiviral Advisory Committee, which makes recommendations on drug approvals, will meet in May to make a recommendation for or against approval of this drug. Right now D4T is only available to people who have failed or are intolerant to both AZT and ddI. If you fall into that category, you should speak with your doctor about the possibility of getting the drug. Acyclovir There's quite a bit recently to report about the anti-herpes drug acyclovir, especially its use in HIV. Government health officials in Australia have approved acyclovir as a treatment for people with symptomatic HIV infection who have fewer than 150 T-helper (CD4+) cells. Several studies, as many of you know, have shown a significant survival benefit for people with AIDS who take acyclovir daily. This survival benefit may not be related to the use of high doses of acyclovir, as was previously thought, but rather to the drug's use for a longer time without interruption and at doses between 600 and 800 mg/day. One study found that acyclovir produces an increased survival rate in people with AIDS taking it in combination with AZT, compared to people taking AZT by itself. Another study concluded that acyclovir increases survival when it's started after the individual receives an AIDS diagnosis, but not in people who started before they received an AIDS diagnosis. There's more news on acyclovir. In May the FDA will consider a request to make acyclovir an over-the-counter drug in the U.S. If granted, this would mean that no prescription would be necessary to buy acyclovir. AZT The most important news recently regarding AZT, as I'm sure many of you read, is that a recent government-sponsored trial has demonstrated that AZT significantly reduces the transmission of the virus from HIV positive pregnant women to their newborn infants. Because of this study result, the manufacturer, Burroughs Wellcome, has asked the FDA to approve AZT to treat HIV positive pregnant women. This is a controversial area, and the NIH will probably soon convene a national conference to come up with recommendations regarding AZT use for pregnant women who are HIV positive. HIV and HSV Researchers have long suspected that there may be an interaction between HIV and the herpes simplex virus. Now a new study has shown that when these 2 viruses are present together, they can infect many more cells then when either is present alone. HIV positive individuals may benefit from daily use of acyclovir. HHV-6 Another herpesvirus, which was discovered just a few years ago, is also in the news. It is called human herpes virus type 6, or HHV-6 for short. More than 90% of the population of the U.S. has become infected with HHV-6 by the time they are 2 years old. Like other herpesviruses such as herpes simplex and varicella zoster, HHV-6 can remain inactive for many years and then reactivate, causing disease in people with weakened immune systems such as people with HIV disease and AIDS. Researchers in Wisconsin say they have found a significant link between HHV-6 and AIDS. Most of the cells in the individuals infected with HHV-6 were T-helper cells, which are the same cells that HIV infects and destroys. These researchers concluded that HHV-6 may be an important disease-causing agent in people with AIDS. In an editorial on this subject, Dr. Robert Gallo, the co-discoverer of HIV, pointed out that HHV-6 is the only virus known that can effectively infect and destroy the body's natural killer cells. Losing the protective effect of natural killer cells is one of the hallmarks of HIV disease progression. In the June issue, BETA will examine the question of whether HHV-6 is a significant contributor to HIV disease progression or whether it is an opportunistic infection that may cause disease in people with AIDS. Interleukin-12 I want to mention a new development in the area of immunotherapy for HIV infection. Immunotherapy is treatment to help restore normal immune function. In June of this year the first human study of the immunomodulating drug interleukin-12 will begin. The results of animal studies using this drug have made some researchers optimistic about the ability of interleukin-12 to stop the growth of cancerous tumors in humans without causing severe toxicity. AIDS researchers are excited about the potential of this drug to restore normal immune function in people with HIV. If the drug can do this without causing severe toxicity, it may help to slow disease progression. One of the manufacturers of interleukin-12, Genetics Institute in Cambridge, Massachusetts, has announced that a Phase I study of interleukin-12 in people with HIV will start by June of this year. Hoffman-La Roche also will begin a Phase I study of interleukin-12 as a treatment for cancer some time this year. Roche scientists have said that interleukin-12 is active against a widespread group of cancers, including the dangerous skin cancer, melanoma, and 14 other malignancy types. BETA will continue to follow the development of this drug very closely. Septra One of the callers tonight mentioned the anti-Pneumocystis drug Bactrim, also commonly called by the brand name Septra. Researchers have found that HIV positive people using the drug to prevent Pneumocystis also avoided toxoplasmosis, a life-threatening infection in people with AIDS. We summarized the results of this study in the March issue of BETA and we wanted to stress that Septra or Bactrim is very clearly the best drug to prevent these dangerous infections. It's important for people with HIV who are at risk for these diseases to seriously consider using the drug. Because Septra often causes serious side effects in people with HIV, it's best for a patient and physician to discuss using a "desensitization protocol" for Septra before starting preventive treatment. This involves taking very small doses of the drug at the beginning of therapy and gradually increasing the dose until the full-strength dose for prophylaxis is reached. By using such a desensitization procedure, many people who otherwise cannot tolerate Septra may be able to do so. We know of 2 successful desensitization protocols, one from Dr. Marcus Conant in San Francisco. For more information on this protocol you may call 415-923-1333. The other was developed by Dr. Brian Lipson in Redwood City, California; his number is 415-365-6300. Peptide T Researchers have concluded from a Phase II trial recently that peptide T, which is a widely used experimental drug sold by AIDS buyers' clubs, is not effective in reducing the pain and discomfort caused by HIV-related peripheral neuropathy. A 12-week study of about 100 people in Miami showed that there was no significant difference between peptide T and a placebo in treating the pain caused by peripheral neuropathy. Although peptide T is nontoxic, a month's supply costs about $250 when purchased from an AIDS buyers' club, so buyer beware! Protease Drugs I want to mention briefly a couple of important drug studies that are currently open to enrollment for people with HIV infection and AIDS. As many of you may have heard or read recently, the most promising anti-HIV drugs that are likely to be approved in the near future are called protease inhibitors. These drugs attack HIV in an entirely different way than currently available anti-HIV drugs do. Their most effective use may be in combination with AZT and/or ddI and ddC, or with each other. The protease inhibitor that is farthest along in development is the Roche protease, which has been given the name saquinavir. The results of a government-sponsored study of saquinavir used in a triple combination with AZT and ddC will be released in the near future. This significant study will give us the first information on whether the combination of a protease inhibiting drug with currently available anti-HIV drugs produces more benefit than taking the drugs alone. Another interesting aspect of the study is that researchers are measuring the effect of the combination treatment on viral load in people taking the drug. It will be important to know how effectively and for how long this combination treatment may reduce the amount of HIV in the body. Saquinavir Saquinavir is just now entering Phase III trials in North America. About 40 medical centers are currently recruiting for 1,200 HIV positive individuals with T-helper cell counts between 50 and 300, who have previously used AZT but no other anti-HIV drug. In this study, saquinavir will be evaluated as single-agent therapy and in combination with ddC and compared to results with ddC alone. Study sites are open for enrollment in the following states: California (in the San Francisco Bay Area and in Southern California), Illinois, the District of Columbia, Florida, Georgia, Massachusetts, Missouri, New York (including New York City), Oregon, Pennsylvania (Philadelphia) and Texas. The toll-free number to call for more information about this study is 800-526-6367. An international trial of saquinavir, scheduled to begin this month, has been postponed. That trial will eventually recruit about 1,800 people who have never taken AZT or any other anti-HIV drug. About 600 people will be recruited in the U.S. and about 1,200 in Europe. Again, the number to call for more information is 800-526-6367. Interleukin-4 for KS For the first time people with Kaposi's sarcoma (KS) are now being treated with an experimental therapy that may allow them to avoid chemotherapy and its adverse side effects. The therapy involves interleukin-4. Laboratory tests show that this drug interferes with the growth of KS. For more information about this study in the Southern California area, call (310) 206-6414; in the Boston area, call (617) 632-8528. Marijuana and Weight Gain The last study I'll mention involves the use of marijuana against weight loss in people with AIDS who are suffering from wasting syndrome. An FDA-approved pilot study will compare use of inhaled marijuana to the synthetic THC oral drug called Marinol which is already FDA-approved for weight loss in people with AIDS. For information about this trial in the San Francisco Bay Area, call 415-476-9554. We hope that you can participate in future BETA LIVE! teleconferences. We've tentatively scheduled another teleconference for July. The subject will be "Aggressive Treatment for HIV Infection." Please call the 800-707-BETA number anytime after May 1st to find out dates, times and panelists. We've also tentatively planned a third teleconference in August to report on treatment updates from the International AIDS Conference in Yokohoma, Japan. Ms. Fields, Dr. Greenspan and Dr. Kaiser, thank you so much for your participation. Thanks to Hoffmann-La Roche for providing the educational grant that supports the BETA LIVE! teleconferences, and thanks to you, our audience, for joining us this evening. We hope to talk with you again in July. Good-bye for now, and stay well. ********** Nutrition for HIV-Associated Wasting Syndrome Serono Laboratories soon will produce the following text as a free educational brochure. If you are HIV positive and losing weight, you are not alone. HIV-associated weight loss, known as wasting syndrome, is a common manifestation of HIV infection. Although much needs to be learned about wasting syndrome, there are certain nutrition and fitness strategies from which all people with HIV-associated weight loss can benefit. Why is wasting important? The key to understanding wasting is to recognize that HIV-associated weight loss differs from ordinary weight loss. With ordinary weight loss, fat is initially depleted more than muscle. In wasting syndrome, however, muscle and other protein stores are significantly affected. Without these essential protein stores, the body cannot function at optimal levels. In fact, when more than 45% of lean tissue, such as muscle, is depleted, wasting can become life-threatening. If you are HIV positive, you may be losing vital muscle mass for several reasons. You may have lost your appetite due to such factors as infection or depression. You may have metabolic disorders that cause changes in the way the body transforms food into energy. Or, you may not be able to absorb the nutrients in the food you eat due to an infection that affects the function of your gastrointestinal tract, including vomiting and/or diarrhea. What's the best nutrition plan? The importance of proper nutrition cannot be emphasized enough. When the body is malnourished, as is the case with wasting, immune system function is impaired. Because HIV infection itself jeopardizes the immune system, it is especially important for people who are HIV positive to maintain proper nutrition. What foods are recommended? You should eat a balanced diet that includes foods from a variety of food groups, being sure to include adequate protein. Protein is essential to help build up muscle mass that is lost because of wasting. To reach the proper balance of fat, protein and other foods, it is helpful to eat foods from a variety of categories. If you are HIV positive, however, you need more calories than people who are HIV negative. Therefore, you should not restrict your diet to limited servings, but eat as much as you can when you are hungry. Select foods from the following categories, which are recommended for all people by the American Dietetic Association: Bread, Cereal, Rice, Pasta: These foods, like potatoes and corn, are high in carbohydrates and low in fat, which means that you will derive significant energy from starches without gaining undesirable weight from fat. For this reason, these foods, along with protein-containing foods, should form a large part of your diet. Dairy: Milk, eggs, yogurt and ice cream are just some of the foods that comprise the dairy group. It is not uncommon for people who are HIV positive to have problems digesting dairy products because of lactose intolerance. Lactose-free dairy products are available for this problem. Even if you tolerate dairy products well, you should always drink pasteurized milk and milk products, and you should not eat raw eggs (often present in Caesar salad dressing and uncooked cookie dough). People who are lactose-intolerant may take Lactaid, an oral, over-the-counter product, to aid in lactose digestion. Protein: Meat, poultry, fish, nuts, beans, eggs and peanut butter provide protein, which is essential for building muscle. Meat provides more complete proteins than nuts and beans, but there are ways to form complete proteins by combining foods such as rice and beans. Your physician or a nutritionist can help you plan meals that meet protein requirements if you do not want to eat meat. Vegetables: Thoroughly washed fresh and frozen vegetables are rich sources of vitamins. All vitamins are essential to your diet, but because those who are HIV positive are often deficient in vitamins C and A, these vitamins are especially important for people who are HIV positive. Vitamin C is provided by such vegetables as tomatoes, potatoes, broccoli, green pepper and cabbage. Vitamin A is provided by such foods as carrots, broccoli, spinach, yams and pumpkins. Some methods of food preparation, such as boiling, can deplete the vitamins in vegetables. Fruit: Fruit also is an important source of vitamins. Vitamin C is provided by such fruits as oranges, tangerines and grapefruits. Apricots are an excellent source of Vitamin A. Thorough washing is as important for fruit as for vegetables. Fats, Oils, Sweets: Although some fat is necessary in your diet, you should eat very limited quantities. Fat is present in great amounts in foods such as butter, cream, ice cream, mayonnaise, avocado, salad dressing and fried foods. How can I make my food safe to eat? HIV infection weakens the immune system, making people who are HIV positive more vulnerable to infection than those who are not. For this reason, the common bacteria found on food presents a significant risk to people who are HIV positive. Therefore, you should take certain precautions when you select and prepare food. With the proper steps, you can greatly increase your chances of eating safely: ù Be sure all foods that require refrigeration are properly stored. ù Wash your hands in hot, soapy water before handling food. ù Avoid tap water because it may contain bacteria that may adversely affect people with HIV; buy bottled water or purify water from the tap. ù Use only pasteurized milk and milk products. ù Never consume any product after the "sell-by" date has passed. ù Cook foods as soon as they thaw, and never thaw them at room temperature. Use a microwave oven set on the defrost setting, or place frozen food in the refrigerator to thaw. ù Do not eat raw vegetables and salads at restaurants. ù If you eat raw vegetables and fruits, the safest method to use is to wash and peel them at home before eating. Let vegetables or fruit stand in a disinfected mixture 10 minutes before rinsing. A mixture of one gallon water to 20 drops of 2% iodine tincture solution is recommended. The mixture may turn blue, but the food is still safe to eat. Discard the mixture after each use. ù Use paper or cloth towels only once before discarding. ù Cook all meats, poultry, fish and eggs thoroughly. ù Heat leftovers to an internal temperature of 165øF and do not leave any cooked food in the refrigerator longer than 3 days. ù Place meats, poultry and seafood in double plastic bags before refrigeration. Keep them out of contact with other foods. ù Clean all reusable items (cutting board, utensils, plates, pots, countertops, etc.) that come into contact with your food after each use with hot water and soap or diluted bleach (2 tablespoons/gallon of water). Follow the same process when preparing food. For example, a knife that has been used to clean chicken should be thoroughly cleaned before using the same utensil on other food. ù Do not drink or eat directly from a storage container (milk carton, peanut butter jar). What if eating is painful? If you have an infection that makes eating painful, there are steps you can take to make food easier to swallow. Eating soft foods, such as yogurt and bananas, can minimize discomfort. Additionally, you or your caregiver can chop or puree food in a blender. It may also help to chill blended foods, such as fruit shakes, because the cool temperature is soothing. There are also medicinal approaches to decreasing painful chewing or swallowing. Of course, be sure to talk with your doctor about any unexplained pain during eating. Exercise: an Important Part of Your Regimen Although exercise is frequently seen as a way to lose weight, you should view exercise as an opportunity to increase muscle mass. The foremost objective of exercise is to use and build muscle, which can be achieved by including walking, performing resistance exercises and stretching, among other activities. Strenuous aerobic exercise is not recommended because it burns a great deal of calories. No matter what activity you enjoy, the key to a successful program is consistency. On days that you feel stronger, increase the level of difficulty and duration of exercise. Even when you feel fatigued, mild exercise may help to give you more energy while maintaining and building muscle. Exercise often has the added benefit of decreasing stress, improving sleep and increasing your appetite. Before you begin an exercise regimen, talk to your physician. He or she will be able to help you select appropriate exercises and compensate for additional calorie use by adding foods to your diet. Managing problems that contribute to weight loss Problems such as diarrhea or taste changes can make it difficult to consume or enjoy food. There are ways to alleviate or lessen the severity of these problems and encourage weight maintenance or gain. If you feel so fatigued that it is impossible to prepare your own food, you may want to utilize food delivery services in your community or have a caregiver assist you in meal preparation. Following are some guidelines for dealing with several common problems associated with HIV infection that can interfere with optimal food intake. Diarrhea Do: Drink plenty of fluids. Apple, grape, peach and nectar drinks are recommended. However, fruit juices can cause diarrhea. Non-citrus juices may be diluted with water to help alleviate this problem. Eat foods high in soluble fiber. Oatmeal, potatoes, apples/applesauce, bananas, peaches, pears and apricots are recommended. Eat small, frequent meals served at room temperature. Consult with your physician if the diarrhea lasts for more than 2 days. Do not: Consume high fat foods, such as cream, bacon, sausage, cheese, oil, avocados and salad dressing. Consume lactose-containing foods such as milk, ice cream and dairy products. Eat foods high in insoluble fiber, such as granola, whole grain breads/cereals and wheat germ. Eat citrus fruits or drink citrus juices such as orange, lemon or grapefruit. Drink alcohol. Drink caffeinated drinks. Loss of appetite Do: Choose high-calorie and protein foods. Keep track of what and how much you eat. Eat small meals frequently. Keep easy-to-prepare foods on hand. Plan meals with friends. Eat a lot on days you feel like eating. Ventilate the area in which you prepare food_stale odors can decrease appetite. Do not: Drink liquids just before or during meals because they can be filling and can result in a bloated feeling. Eat high-fat foods, which empty out of your stomach more slowly than other foods. Mouth sores/Difficulty swallowing Do: Keep your mouth clean by rinsing often with a dilute solution of hydrogen peroxide and water or other solution recommended by your dentist or physician. Eat soft foods such as pudding, custard and mashed potatoes. Use a straw. Do not: Eat steaming hot foods. Eat deep fried, salty, sticky and sour foods. Use commercial mouthwash. Taste changes Do: Eat a variety of foods. Keep your mouth clean. Try increasing aroma in foods by using spices, lemon and vinegar. Nausea/Vomiting Do: Eat dry and liquid foods separately. Eat smaller portions, more often. Eat saltine crackers, pretzels or dry toast. Consult with your physician if symptoms persist. Do not: Eat high-fat foods. Eat very sweet or spicy foods. Eat foods with strong aromas. Lie down after eating. Creating Your Own Strategy Eating a proper diet, maximizing food safety and engaging in a regular exercise program are important steps in managing wasting syndrome. These suggestions are intended to help you in this regard. Your physician can help you create a plan that meets your individual needs. This information is provided as an educational service by Serono Laboratories, Inc., a subsidiary of the Ares-Serono Group. We gratefully acknowledge the assistance of Donald P. Kotler and Viva Tai. Sources Jensen J. Controlling wasting and tasting. Being Alive: 5. September 1993. Kotler DP and others. Magnitude of body-cell-mass depletion and the timing of death from wasting in AIDS. American Journal of Clinical Nutrition 50: 444-447. September 1989. Kraak V. You are what you eat. The Body Positive. October 1993. Weber J. Gastrointestinal disease in AIDS. Clinics in Immunology and Allergy 6: 519-541. 1986. ********* 1994 BETA Readership Survey: Readers' Comments The marketing research firm Communications Technologies is now analyzing the surveys returned by over 1,500 BETA readers. Their report will be published in the September issue of BETA. The comments below were drawn from the hundreds of handwritten notes returned by readers with their completed surveys. "I am grateful for your publication. I share the information in it with HIV positive females in recovery from alcohol and drugs_it has been most helpful. I also do inservices on HIV at work and I use your magazine for that as well. I believe it is critical that accurate information is passed along to all people, positive or negative." Alameda, California "Living in Indiana makes it very difficult to obtain information on alternative treatments. Because I have just started ddI I would greatly appreciate as much information on herbs, massage, acupuncture_and contact numbers. BETA has helped me over the past 2 years to make informed decisions about my treatment. Thanks." Evansville, Indiana "I enjoy reading BETA very much! I wish it was published monthly, but your quarterly published volumes still provide much information. I read it faithfully and feel that I have survived this long due to experimenting with therapies that you have written about. Thank you very much." Las Cruces, New Mexico "I greatly appreciate that BETA is provided to me by scholarship. The information is extremely helpful. I have advanced AIDS and used to work as an AIDS educator and substance abuse counselor. I also started and facilitated an HIV support group for addicts. I have found BETA to be helpful both personally and professionally in my life and work. I would like to see some articles about drug use and HIV." Van Nuys, California "Keep on keeping on_I know there must be some days you feel like it's hopeless, not worth the effort_but it is! Particularly you help us out here in small towns and rural areas. We have to educate the physicians here, not the other way around. You are our lifeline and all the latest news." Fayetteville, Arkansas "In the year that I've been receiving BETA, I have been able to make several significant suggestions to my doctor. Quite often what I offered was new to them as well. Thanks for the good work_please keep it up." Baton Rouge, Louisiana "We could benefit from a computerized research/retrieval, archive and current information system." San Quentin, California "I am the Executive Director of an AIDS support organization that focuses on mental health and education. Over the seven years I have been involved with this organization, your publication has been among the best we have ever received. Keep up the excellent work. You are helping so many. Thank you!" Orlando, Florida "Your publication helps to keep me informed of new treatments and to ask more intelligent questions of my physicians. I believe my continued participation in my treatment has helped me retain my status as a longtime survivor. Please continue to keep up the good work." Richmond, Virginia "Would greatly appreciate more information on pediatric AIDS. This last BETA was very helpful! Thanks, a concerned mom." West Palm Beach, Florida "More information on women, please!" Nevada City, California "Thank you for providing an invaluable information source for AIDS patients, especially for those of us who do not live in big cities. Many doctors in smaller cities and public health clinics do not have much information on treating AIDS and related illnesses." Reno, Nevada "I live in a city which is behind in most of their alternative therapy information. BETA has not only enabled me to learn what else is being used, but to show this valuable information [to others]. You're doing a great job! Keep it up!" Buffalo, New York "Rural America is about to suffer a big loss as people ignore the fact that AIDS does not discriminate. We need to educate rural teenagers immediately." Trinidad, Colorado "BETA is the first thing we show HIV positive people who come to our health education center to ask for information." South San Francisco, California "My interest in HIV/AIDS is because my son died in January 1993 of Kaposi's sarcoma in his lungs. We (he and I) read every issue and were informed and aware. We thought that being educated would put off his ultimate death. Perhaps it did. He lived 3 years after his AIDS diagnosis. He had no skin lesions so doctors didn't know he had KS. Keep informing people_every day an AIDS sufferer lives is a gift to those who love him." Tucson, Arizona "I find your journal an excellent source of information that prepares me for my doctor's visits by supplying ideas and questions." New Hyde Park, New York "Excellent publication overall. I used to live on Maui, and BETA was a lifeline for me. One criticism: I'd like to see more explanation and discussion of alternative treatments/theories." Albany, California "I've only been reading BETA for 2 months and look forward to each issue. My husband and I are both HIV positive." Sacramento, California "People must be made aware of how important nutrition and lifestyles are. My doctor just gave me drugs (AZT, ddI) and didn't even mention smoking and drinking! That's not right. Please print as much as possible about taking care of ourselves. It's really all we've got." Phoenix, Arizona "More on women, also more alternative therapies, great publication. Thank you all!" Lakeland, Florida "By far, BETA is my best information source. It is more technical than most, but I feel this is necessary to fully explain a bodily process or experiment. Please keep up the good work. I look forward to each issue and modify my health program based on your reports. I would particularly like to see more articles on Chinese medicine, herbs, acupuncture and nutritional supplements." Chicago, Illinois "This publication is invaluable for me living in northern New England. A physician recommended this publication. Medical books become outdated soon so keep up the good work. It helps a great deal to stay informed." Manchester, New Hampshire "Excellent publication! I look forward to every issue and often use articles in current and past issues to council recently symptomatic HIV individuals and even AIDS patients dealing with new complications." San Diego, California "Excellent, highly useful publication The technical orientation is hard to understand for a layperson, but I prefer to make the effort because the result is so precise and unambiguous. BETA is my primary source for authoritative AIDS information." San Francisco, California "The information has proven invaluable in managing the course of my health care. Understandably, your publishing costs and overhead are significant but subscriptions to BETA for myself and friends on limited incomes are simply not possible. Fortunately, I live in the Bay Area and most times can obtain my quarterly issues without incidence. However, I do not hesitate to photocopy and forward to others. Still, I cannot help but sympathize with the countless individuals on all levels who could benefit as I have. Please increase your circulation. And first and foremost, thank you!" San Francisco, California "I wait for your issue of BETA every month from the AIDS Assistance Association. When they come and see me here in jail it is basically all I have to look forward to. I've written a lot of agencies and have not had a response except for 2 or 3 out of 50. So what you put in BETA is my lifeline. Thank you!" Anchorage, Alaska "The information you provide in BETA I cannot get anywhere else. You have a very complete and wide range of information and test studies. Thank you for making it available to those of us who are financially strapped and could use any extra help in our everyday lives." Medford, Oregon "I truly believe I've lived so long because BETA helped me decide my own treatment. I've tried everything I could use in BETA. I still learn. BETA keeps up my hope with knowledge." Fort Smith, Arizona ********** Acyclovir Increases Survival! ù FDA Approval of d4T ù Alternative Therapies: Hope and Hype Ronald A. Baker,PhD Ronald Baker is editor of BETA. Acyclovir Increases Survival! There is a growing consensus among clinicians that, in addition to anti-HIV therapy, acyclovir (Zovirax) should be offered to all individuals with advanced HIV disease to increase their survival time. Several studies have concluded that daily use of acyclovir significantly increases the lifespan of people with AIDS who are also on antiretroviral treatment (Cooper, 1993; Stein, 1993; Youle, 1994). No one knows why acyclovir confers a survival benefit; it may be related to the ability of the drug to suppress reactivation of one or more of the herpesviruses. It is also possible that the drug interferes with the activity of an as yet unidentified cofactor for HIV disease progression. The optimal dose of acyclovir for increasing lifespan is unclear. One recent study suggests that 600-800 mg/day is sufficent (Stein, 1993). Other studies showing a survival advantage from acyclovir plus AZT used 3,200 mg/day acyclovir (Cooper, 1993; Youle, 1994). Stein and colleagues conclude that longer, uninterrupted periods of acyclovir use are associated with longer survival. In their study group, acyclovir conferred significantly increased survival time when used following an AIDS diagnosis, but not pre-AIDS. An important unanswered question is whether HIV positive individuals at earlier stages of infection will also experience a survival benefit from acyclovir use, even if they do not have recurrent genital or oral herpes simplex. The Australian government has approved acyclovir use for all HIV positive individuals with fewer than 150 CD4 cells. Based on the weight of the available evidence, Marcus Conant, MD, now recommends lifetime treatment with oral acyclovir (400 mg twice daily) to all his HIV positive patients, regardless of CD4 count or disease stage (Conant, 1994). Dr. Conant is an AIDS researcher and community physician with a large HIV practice in San Francisco, CA. "It is important for physicans to discuss with their HIV positive patients the potential benefits and risks of lifelong treatment with acyclovir as soon as possible." Because acyclovir appears to significantly increase survival time, it is important for physicans to discuss with their HIV positive patients the potential benefits and risks of lifelong treatment with acyclovir as soon as possible. Conant MA. Director of the Conant Medical Group, San Francisco, CA. Personal Communication. May 25, 1994. Cooper DA and others. The efficacy and safety of zidovudine alone or as co-therapy with acyclovir for the treatment of patients with AIDS and AIDS-related complex: a double-blind, randomized trial. AIDS 7(2): 197-207. 1993. Stein DS and the MACS. The interaction of acyclovir (ACV) with zidovudine (ZDV) on survival in HIV infection. The First National Conference on Human Retroviruses and Related Infections, December 12-16, 1993. Abstract #527. Youle MS and others. Effects of high-dose oral acyclovir on herpesvirus disease and survival in patients with advanced HIV disease: a double-blind, placebo-controlled study. AIDS 8(5): 641-649. May 1994. FDA Approval of d4T On May 20 the Antiviral Advisory Committee of the U.S. Food and Drug Administration (FDA) recommended that the government grant accelerated approval of the anti-HIV drug d4T (see Research Notes, page 50 of this issue). Although d4T is not a breakthrough treatment, its approval definitely will benefit many people living with HIV infection and AIDS. HIV positive individuals desperately need access to new treatment options. Currently d4T is available only to people with AIDS who have failed or are intolerant to all 3 licensed anti-HIV drugs: AZT, ddC and ddI. Although d4T likely will be licensed with this same restriction, following FDA approval, physicians will be able to prescribe the drug to patients at all stages of HIV disease. Community groups that spoke to the FDA panel raised legitimate concerns about the safety and effectiveness of d4T, citing a lack of knowledge about how to use the drug and questions about its adverse side effects. Although these concerns deserve attention, d4T appears to be reasonably safe and has demonstrated some promise of efficacy. With so few treatment options, d4T is a welcome addition to the short list of anti-HIV agents now available by prescription. Preliminary data suggest that d4T is about as effective as AZT (the first-line treatment for HIV infection), yet causes less severe side effects. For these reasons alone, d4T should be made available by prescription as soon as possible. Several activists and advisory panel members strongly criticized a new FDA policy that allows AIDS drugs to be evaluated using CD4 counts as a marker for HIV disease progression. The best evidence presented for approval of d4T was its ability to raise CD4 counts by 20-30 cells among former AZT users, compared to a decline in CD4 cells among people who continued on AZT. Although changes in CD4 counts are not the ideal method for evaluating anti-HIV drug effectiveness, their use is both appropriate and necessary until more reliable markers (such as PCR measurement of HIV load) become widely available. The potential for benefit in making d4T available by prescription far outweighs the potential for harm from the drug, particularly if physicians and patients closely monitor for the drug's most serious side effect, peripheral neuropathy. The risk of experiencing this adverse side effect from d4T is no greater nor more harmful that the risk of bone marrow toxicity from AZT, pancreatitis from ddI or peripheral neuropathy from ddC. While making d4T available by prescription is not a major treatment development, it is a step forward from the current restriction that limits access to the drug only to those who have already failed on AZT, ddI and ddC. These are the least likely people to benefit from d4T. The drug may prove far more useful to asymptomatic or mildly symptomatic individuals and to people with AIDS who have not yet exhausted all other anti-HIV treatment options. Alternative Therapies:Hope and Hype The term "alternative treatment" has 2 distinctly different meanings. For some individuals, the term literally means an alternative that excludes the use of orthodox therapies. For others, it implies "complementary" treatment, i.e., used in addition to standard therapies. The distinction is important, since strict adherence to the first definition could be life-threatening to people with advanced HIV disease. A recent survey of HIV positive individuals who regularly visit a London medical clinic revealed that 44% were using one or more alternative therapies (Barton, 1994). Of these people, 27% were also participants in a clinical trial of some standard therapy. As this report indicates, the use of alternative treatments appears to be increasing among HIV positive individuals, probably due to widespread disappointment and pessimism about the limited benefits of available standard treatments. "DNCB is reportedly the current 'best-seller' in U.S. AIDS buyers' clubs, despite the lack of scientificevidence for its efficacy." Given the renewed popularity of alternative treatments, it is important for HIV positive individuals and their caregivers to educate themselves about these agents. One or more of these therapies may prove useful in HIV disease. Official acknowledgement of their potential importance occurred in 1992, when the National Institutes of Health founded the Office of Alternative Medicine to study the use of alternative treatments for both AIDS-related and non-AIDS-related illnesses. A few alternative therapies, once considered unorthodox and "underground," have entered FDA-sanctioned clinical studies: Compound Q (GLQ223), hypericin and acupuncture are prominent examples. Recent research results suggest a benefit to HIV positive individuals from daily use of high-dose nutrients such as beta carotene (provitamin A), vitamin E, L-carnitine and the antioxidant agent N-acetylcysteine (NAC). A study in San Francisco will evaluate whether inhaled marijuana stimulates appetite and promotes weight gain among individuals with HIV-related wasting syndrome. A number of AIDS "buyers' clubs" in the U.S. sell and distribute dozens of alternative compounds that supporters claim will work effectively against HIV and/or AIDS-related illnesses. The number and variety of substances sold is extensive. Some of these products, such as vitamin C and Chinese herbs, have been used for decades as alternative therapies for certain cancers and other incurable diseases. Others, like DNCB (dinitrochlorobenzene), have become popular only since the advent of the HIV pandemic. DNCB is reportedly the current "best-seller" in U.S. AIDS buyers' clubs, despite the lack of scientific evidence for its efficacy (Gilden, 1993). Although DNCB is inexpensive and relatively nontoxic, its more zealous supporters have advocated a dangerous policy, namely that DNCB users abandon all standard HIV/AIDS treatments except PCP prophylaxis. Individuals using DNCB are urged to discuss with an AIDS-knowledgeable physician the potential for harm of this action. ACT-UP/San Francisco reportedly will meet with officials of the National Institutes of Health (NIH) to present study findings and anecdotal information from current DNCB users. The history of the AIDS alternative therapies movement is strewn with examples of treatments once considered promising, now discredited: AL-721, ribavirin, dextran sulfate, isoprinosine, oral alpha interferon and DTC (diethyl-dithiocarbamate), to name only a few. Despite the failed promise of these products, a commercial market for alternative therapies likely will continue to flourish so long as HIV disease remains incurable. Abrams DA. Dealing with alternative therapies for HIV. In: The Medical Management of AIDS, 3rd edition. Sande and Volberding, editors. W.B. Saunders Company. 1992. Barton SE and others. Complementary therapies used by people with HIV infection (letter). AIDS 8(4): 561. April 1994. Gilden D. DNCB treatment today. AIDS Treatment News 182: 3-8. September 3, 1993. Ryan MK and Shattuck AD. Treating AIDS with Chinese Medicine. Pacific View Press, Berkeley. 1994. ********* Mycobacteria and HIV Infection Leslie Hanna Leslie Hanna is associate editor of BETA. BETA spoke about AIDS-related mycobacterial infections with researcher Stephen Nightingale, MD. This introduction to the subject precedes the interview. General Characteristics of Mycobacteria Mycobacteria are a major cause of human diseases. This category of bacteria includes normal human flora as well as the microorganisms that cause the diseases tuberculosis, leprosy and Mycobacterium avium complex, or MAC. Mycobacteria are rod-shaped, aerobic, "acid-fast" bacteria, i.e., they hold onto particular laboratory stains, once stained, despite acid or alcohol rinsing. This staining technique is used for identification purposes. Mycobacteria contain large amounts of lipids, or fats. Their waxy, hydrophobic cell surfaces cause them to form masses or clumps that help them to resist chemical attack. Mycobacteria are generally slow-growing, and the diseases they cause typically develop slowly as well. Disease results from the ability of the microorganisms to take up residence inside the cells of the host organism. This intracellular location affords them protection from chemical agents and encourages their persistence. They most frequently reside inside monocytes or macrophages (white blood cells). Once established inside the cell, mycobacteria interfere with normal cell function and immune response. Mycobacterial diseases are generally chronic and often involve the formation of characteristic infectious granulomas (lesions). These lesions may appear externally, on the skin, or internally, affecting various tissues and organs. Atypical Mycobacteria Mycobacterium tuberculosis and Mycobacterium leprae, the organisms that cause tuberculosis and leprosy, respectively, have been the 2 species of mycobacteria of greatest historic concern for humans, who are considered the "natural" hosts for both organisms. Mycobacterium tuberculosis has caused severe epidemics probably for thousands of years. In contrast, the so-called atypical mycobacteria are species of mycobacteria that do not reside in humans as natural hosts but which can adapt to cause disease in humans. Although infections due to atypical mycobacteria have long been known to occur in immunosuppressed individuals, they were previously rare and aroused little scientific interest. Now, however, atypical mycobacteria are of increasing medical concern because of their ability to infect and cause disease in people with HIV. Most of the so-called atypical mycobacteria are found in the environment: in soil, dust and water. They are not easily transmitted from one person to another. Atypical mycobacteria include Mycobacterium avium and Mycobacterium intracellulare, the organisms responsible for causing MAC, the mycobacterial infection of greatest HIV-related concern. Birds and swine also carry these organisms. Other atypical species continue to emerge as pathogens, as the numbers of HIV infections rise and as survival time among individuals infected with HIV increases. The Centers for Disease Control and Prevention (CDC) reports that M. kansasii, M. gordonae, M. fortuitum and M. chelonei, in that order of frequency, are all known to cause infection in people with HIV. Mycobacterium haemophilum is another emerging pathogen in people with AIDS. Infections caused by a recently appearing species, M. xenopi, occur more commonly in the Northeast (compared to infections caused by M. kansasii, which occur more frequently in the Midwest). Diagnosis of and differentiation between mycobacterial infections can be difficult. Some species of atypical mycobacteria are cross-reactive with M. tuberculosis, making accurate diagnosis as challenging as it is critical. Another species of atypical bacteria, Mycobacterium genavense, has been noted to cause infection closely resembling MAC in people with HIV. An article about M. genavense in American Journal of Clinical Pathology (AJCP) concludes that "scrupulous microbiologic investigations, including molecular biologic techniques, are necessary in cases with mycobacterial infections." Mycobacterium avium Complex (MAC) At this time, the organisms that cause MAC, M. avium and M. intracellulare, remain of greatest practical concern for people with HIV. It is estimated that up to nearly one-half of people with AIDS will develop MAC at some point. The U.S. Public Health Service recommends MAC prophylaxis and therapy (summarized in the next section) for people with fewer than 100 CD4 (T-helper) cells. While many experts feel that the actual risks of developing MAC develop at CD4 counts lower than 100, what is certain is that the risk of MAC increases with worsening immunosuppression. MAC can occur in a specific organ or become disseminated throughout the body, indicating a more severe infection. The symptoms of MAC include fever, night sweats, weight loss, weakness and gastrointestinal disturbances and, occasionally, chest pain. Diagnosis is usually made on the basis of cultures taken from sterile sites such as the blood or bone marrow. The clinical significance of the presence of MAC in sputum or stool cultures is unclear. U.S. Public Health Service Recommendations In 1993, a U.S. Public Health Service Task Force on MAC published recommendations on prophylaxis and therapy for disseminated MAC, based on 2 clinical trials that found that therapy with rifabutin reduced by 50% the number of MAC organisms in blood. The following is a summary of the recommendations: Prophylaxis should be given to people with HIV and fewer than 100 T-helper cells. Three hundred (300) mg of rifabutin per day is recommended (after screening for tuberculosis with chest x-ray and PPD skin test). Before beginning a prophylactic regimen, the individual should be evaluated to eliminate the possibility of active mycobacterial disease (MAC, tuberculosis, etc.). Prophylaxis continues for the individual's lifetime unless MAC disease develops, which would necessitate the use of multiple drugs. Diagnosis of active, disseminated MAC disease is best made on the basis of one positive blood culture. Blood cultures are indicated in people who have clinical or laboratory abnormalities suggestive of mycobacterial infection. Treatment (for disseminated MAC) should include at least 2 agents, one of which should be clarithromycin or azithromycin. Effective treatment should continue for life. The recommendations note that many clinicians use ethambutol as the second drug, and that other candidate second, third or fourth drug(s) include: clofazimine, rifabutin, rifampin, ciprofloxacin and amikacin. The recommendations do not support the use of isoniazid (INH) or pyrazinamide for MAC therapy. Uveitis Uveitis, an unanticipated side effect associated with the use of rifabutin in multidrug regimens, recently emerged in the context of a clinical trial of MAC prevention strategies. Uveitis is an inflammation of portions of the eye, including the iris. Symptoms of uveitis include blurred vision, eye pain, redness and sensitivity to light. Fortunately, uveitis is reversible. Uveitis seems to occur when blood levels of rifabutin become very high, which may be caused by combining rifabutin with other drugs such as clarithromycin (Biaxin) or fluconazole. So far, only 12 cases have been reported, but anyone taking rifabutin should report any changes in vision to his/her doctor. Since the release of these guidelines, the FDA has approved clarithromycin for the treatment of disseminated MAC; questions remain unanswered about which drug or drugs to pair with clarithromycin for treatment. Recent reports of uveitis in connection with clarithromycin plus rifabutin point out some of the complications that may arise as experimental treatments are used. Still more general concerns and questions about MAC, such as the optimal time to begin prophylaxis, the significance of various diagnostic tests, resistance, whether treatment prolongs life, and more, remain to be elucidated. Selected Sources Georgii A and others. Mycobacterium genavense: autopsy findings in three patiets. American Journal of Clinical Pathology 101(1): 95-99. January 1994. MAC (Mycobacterium avium Complex). AmFAR AIDS/HIV Treatment Directory 7(1): 90-92. Mycobacterium. In Fundamentals of Medical Bacteriology & Mycology, 2d ed. Myrvik QN and Weiser RS, editors. Philadelphia. Lea & Febiger. 1988. Recommendations on prophylaxis and therapy for disseminated Mycobacterium avium complex for adults and adolescents infected with human immunodeficiency virus. Morbidity and Mortality Weekly Report 42(RR-9): 17-19. June 25, 1993. Review of Medical Microbiology, 17th ed. Jawetz E, Melnick JL and Adelberg EA, editors. Appleton & Lange. 1987. Strauss and others. Clinical and epidemiological characteristics of Mycobacterium haemophilum, an emerging pathogen in immunocompromised patients. Annals of Internal Medicine 120(1): 118-125. January 1, 1994. Young LS. Atypical mycobacteria. In Textbook of AIDS Medicines. Broder S, Merigan TC and Bolognesi D, editors. Baltimore. Williams & Wilkins. 1994. ********* Mycobacterium avium Complex (MAC): An Interview with Stephen D. Nightingale, MD Leslie Hanna Leslie Hanna is associate editor of BETA. Stephen D. Nightingale, MD, teaches at the University of Texas Southwestern Medical Center, where he was director of its HIV clinic from 1988 to 1992. He now directs the North Texas and Oklahoma AIDS Education and Training Center, where he is researching prophylaxis and treatment for AIDS-related opportunistic illnesses. BETA recently spoke with Dr. Nightingale about prophylaxis and treatment for Mycobacterium avium complex (MAC). Treatment for MAC BETA: What do you consider to be the first-line treatment for established MAC infection? Stephen D. Nightingale: The first-line treatment for established MAC infection is clarithromycin (Biaxin). However, we're not yet sure of the correct dose. Some people feel that 1,000 milligrams (mg) twice a day clears the blood faster than 1,000 mg once a day. Others stress that 1,000 mg twice a day is more toxic than 1,000 mg once a day. In my experience the 2 grams/day dose is a little harder on the gastrointestinal tract, so I use 1 gram/day as initial therapy. I combine clarithromycin with at least one other drug and what I use is ethambutol (Myambutol). I use 400 mg of ethambutol 3 times a day for all patients who have MAC that I've cultured from an ordinarily sterile site like blood or bone marrow. BETA: Is ethambutol the drug most often used in combination with clarithromycin? SDN: Yes, I think that is standard practice right now. Some people are using azithromycin (Zithromax) for treatment as a first drug instead of clarithromycin. In fact, the U.S. Public Health Service expert panel said that azithromycin could be an alternative to clarithromycin. At the moment I only use azithromycin for the rare patient who cannot tolerate clarithromycin. I wouldn't recommend azithromycin as the first drug until more information about it comes out. BETA: The FDA recently approved clarithromycin for the treatment of disseminated MAC but recommend using it in combination with at least 1 other drug. Since the other drug hasn't been specified, what does the FDA's approval mean? SDN: The FDA has said, "You've got to use clarithromycin plus something else," but they don't know what else. In other words, the FDA in its approval of clarithromycin explicitly told doctors to use some other drug that they had not yet approved in combination with clarithromycin. That doesn't mean that the FDA is stupid. What it actually means is that the FDA recognizes that medicine is changing faster than the regulatory apparatus can keep up with it, and that people have a strong interest in getting good medicine. FDA has a strong interest in being good regulators but they're also being much more responsive to the needs of the public than they might have been, or have been in the past. So I like the approval. I think it's objective proof that the FDA is trying to respond to AIDS. BETA: You said you use at least one drug in addition to clarithromycin to treat disseminated MAC. Do you ever use more than one? The recommendations are tentative, suggesting merely that a "minimum of 2 drugs" be used for treatment. SDN: At the moment I don't know whether or not a third drug is necessary for all patients, but I generally do prescribe a third drug for treatment. There are several drugs you can use, but I use rifabutin (Mycobutin). I only use rifabutin at a dose of 300 mg/day, although some doctors use up to 600 mg/day. The reason I use the lower dose of rifabutin is to avoid the possibility of uveitis, inflammation of the eye. Uveitis has occurred only at 600 and 900 mg doses of rifabutin, and only in association with clarithromycin or fluconazole (Diflucan). [SN: Since this statement was made, uveitis has been reported in patients taking only 300 mg rifabutin a day.] Over the next year there likely will be a lot of new evidence or at least new experience with combination drugs. BETA: Has anyone considered using more than 3 drugs? SDN: Well, 4 might be better than 3 but we don't know. With 4 drugs you have even more toxicity. Uveitis is an important example of what can happen with additional drugs. Fluconazole, clarithromycin and rifabutin by themselves are safe. Compared to AZT, their safety profiles are phenomenal. But when you start mixing these drugs together, bang! This serious and unanticipated side effect [uveitis] appeared. BETA: Leaving side effects and toxicity aside for the moment, is it correct to say that you feel that 3 drugs are the optimal number to use for treating MAC? SDN: I'm still using 3 drugs (clarithromycin, ethambutol and rifabutin) but I can certainly understand why other physicians might now choose 2. Prophylaxis vs Treatment BETA: Clinical trials have shown that the development of MAC bacteremia is highly associated with disseminated MAC. What is the difference between MAC bacteremia and disseminated MAC? SDN: MAC bacteremia is a sign of disseminated MAC disease, but you can have MAC bacteremia before you have all the symptoms of disseminated MAC. The MAC organisms seem to get into the bloodstream relatively early in infection. Organ damage appears to occur 2, 3 or even 4 months after the organisms can be isolated from the blood. BETA: The mortality associated with MAC would seem to support aggressive, early intervention. How do you decide exactly when to start prophylaxis against or treatment for dMAC? SDN: There are a couple of ways to go: (1) start prophylaxis at 100 T-cells [CD4 cells] before anyone gets it, which is what the U.S. Public Health Service Task Force recommends; (2) start at 50 T-cells before just about anyone gets it, which is what I currently recommend; (3) at 100 T-cells, do lots of tests, or (4) wait and then treat active infection. Decisions about when to treat are based on several considerations_including financial ones since these are expensive drugs_and opinions vary. We all know that as the T-cell count goes down towards zero, the incidence of disseminated MAC increases. The lower the T-cell count, the more likely the person is to develop infection. Of course, people want to start prophylaxis before subclinical infection starts. The question is, how long can an infection be subclinical? One hypothesis is that patients have a prolonged period during which they are colonized with a large number of the organisms that cause MAC, but are not infected. In this view, as T-cells go down, the individual becomes colonized with more and more organisms until active infection breaks through, something that takes months to happen. The numbers of organisms present and the length of time they're in the body before getting into the blood are important points if you are worried about resistance. BETA: What concerns are there about resistance and MAC? SDN: If there are hundreds of millions of organisms in the sputum or in the stool before they get into the blood, and you give somebody prophylaxis that doesn't kill all of those organisms, the organisms that survive are likely to be the ones that are resistant to that prophylactic agent. If, on the other hand, there are only a few organisms in the stool or in the blood, when those organisms get into the blood the chance that one or more of them will be resistant to the prophylactic agent is very small. However, we don't see resistance during asymptomatic infection. I believe this is because people don't have a large number of organisms in their body when they are asymptomatic. There will be a few hundred or maybe a few thousand but not a few hundred million organisms. And the fewer organisms there are the less likely you are to develop resistance. (You also need less drug.) BETA: Why do you favor beginning prophylaxis later, at 50 T-cells, particularly if resistance is less of a concern when the numbers of organisms in the body are fewer? SDN: There are 2 important published studies right now, one from Atlanta and the other from San Francisco General Hospital (Havlik and others, Journal of Infectious Diseases, October 1993; Chin and others, Journal of Infectious Diseases, February 1994). Both studies tried to follow patients prospectively to see if they had organisms in their sputum or organisms in their stool before they developed organisms in their blood. Neither study was able to find that. I personally no longer believe that people with AIDS have long periods of latent MAC infection, although I'm not sure how many other people would agree with me. People with 50 T-cells cannot suppress MAC infection very well. Based on the work of Chin and Havlik, and based on the failure to detect resistance in prophylaxis trials, I feel that the period from when colonization begins to active infection is brief, a matter of days or a few weeks, rather than weeks to months. This is one of the best explanations for why, so far, prophylaxis has not appeared to promote the development of resistant organisms. However, these are relatively new conditions and areas of research, and the information changes rapidly. Treatment decisions should be made on the basis of all currently available information, which is subject to change without notice. BETA: How would you proceed with someone whose sputum or stool cultures come back positive for MAC? SDN: I think if you detect MAC on [a diagnostic test] smear, until you have it cultured, the big question actually is "Is it MAC or is it tuberculosis?" While there are many pathologists who believe they can differentiate between MAC and tuberculosis, nobody has published how to do so yet. This is something that you want to be real sure about, not just a little sure. If I find acid-fast organisms that might be MAC or might be Tb then, frankly, I treat for Tb not MAC. If I find acid-fast organisms in the sputum, I order a blood culture. If I were the patient I would have a bone marrow exam done, even if the chest x-ray was normal. If the bone marrow was negative and the blood was negative I would not continue Tb treatment for the rest of my life. I might go on prophylaxis, however, for the rest of my life. I'm giving you a complicated recommendation right now that is really patient-specific because I don't think there's enough data to give a simple answer for all patients. I make decisions about MAC found in sputum on a case-to-case basis. Until I'm sure it's MAC and not Tb I treat for Tb. Meanwhile I do lots of cultures of the patient and, if all the bone marrow and blood cultures are negative and the patient's feeling O.K., then I think I'd do prophylaxis with 1 drug rather than treatment with 3. Prophylaxis BETA: The current approved prophylactic strategy for MAC is monotherapy with rifabutin [in people with equal to or less than 100 T-cells]. When or to whom do you recommend prophylaxis? SDN: I would recommend prophylaxis to someone who has had an AIDS-defining OI and less than 200 T-cells, especially to someone who's had PCP. Those were the people we had in the rifabutin prophylaxis trials. That's different than saying everybody with less than 200 T-cells, though. I emphatically don't recommend it to someone with 200 T-cells who hasn't had an OI. If you haven't had an OI, my own recommendation is to consider prophylaxis at 50 T-cells, because it's at 50 T-cells that it seems to me that the benefits exceed the risks and justify the cost [of the drug] for such patients. Again, the recommendations of the Public Health Service are different from mine. They recommend prophylaxis at 100 T-cells, AIDS or no AIDS. I respectfully disagree_neither the investigative evidence nor any economic rationale supports that recommendation, to my way of thinking. This drug costs a lot of money. When I look at the evidence of the studies to date, what I see is if you've had an AIDS-defining event, then you've got a 20% chance of getting it in a year. If you have less than 50 T-cells you have a 16% chance of getting it in a year. These are risks that justify MAC prophylaxis for me. If my own patients get MAC between 50 and 100 T-cells, which they hardly ever do, then I treat them. I suspect that somebody with 70 T-cells is much more likely to respond to therapy for MAC than somebody with 7 T-cells. To me somebody with no prior OI and more than 50 T-cells who shows up with MAC in their blood or in their sputum is probably someone you're better off treating than preventing. But once you get under 50 T-cells, you have less immune function, and MAC becomes more inevitable. As far as I can tell, clarithromycin will be about as effective as rifabutin for prophylaxis. The difference between clarithromycin and rifabutin is that clarithromycin is not effective against tuberculosis, and rifabutin is, or seems to be. Although it remains to be proven, the available evidence suggests that rifabutin will protect against tuberculosis as well as protect against MAC. For that reason more than the lack of FDA approval, I still favor rifabutin over clarithromycin. But for anyone who can't take rifabutin then I think clarithromycin is a definite second choice. I personally do not recommend the combination. BETA: What doses would you use for prophylaxis with clarithromycin? SDN: The trials are being done with 500 mg twice a day, which is what I would go with. I suspect that a lower dose of clarithromycin, 500 mg once a day, would be effective, but I don't know that for a fact. If clarithromycin at 1 gram/day works, I'd like to see a trial of 1 gram/day versus 500 mg/day. I'd like to see the AIDS Clinical Trials Group (ACTG) focus more on getting down to the minimum dose, seeing how low the dose can be pushed, rather than seeing how high it can be pushed. BETA: You did say that you would not advocate using clarithromycin and rifabutin together as prophylaxis at any doses? SDN: Yes, in any combination. There are studies of the combination going on, and if those studies show that the combination is a lot better, then I would revise what I say. But at the moment I see no evidence to recommend giving 2 drugs when 1 is effective. I think it's much more important to push compliance with 1 drug. In my experience, if you take this drug it usually works. And if it doesn't work, you just treat them with a combination of drugs that often includes the drug that "failed" as a prophylaxis agent. There's a point at which prophylaxis is more trouble than its worth. Lots of people are using clarithromycin and are having good luck with it. When there's more data on rifabutin my guess is that it will be shown to be equivalent to clarithromycin. The issue is going to revolve around whether clarithromycin is good for tuberculosis, which it isn't, or what kind of resistance to normal flora clarithromycin induces. But that's a year down the road. BETA: Is anyone considering combinations for prophylaxis? SDN: Combinations are being tried right now. I myself don't think that combinations will prove preferable to monotherapy for prophylaxis. I think the reason that most prophylaxis regimens fail is that people don't take them right. I'm not sure that giving 2 drugs instead of 1 will increase compliance. I think increasing patient understanding of the benefits as well as the risk of the study is what will increase compliance. The breakthrough cases in the rifabutin prophylaxis study were not with resistant organisms. The breakthrough cases broke through with sensitive organisms and the only explanation that I can come up with for that is that people who broke through weren't taking it or didn't absorb it. BETA: Isn't it difficult to say then what the real risk of breakthrough MAC with rifabutin prophylaxis is? SDN: It's difficult to answer. The first risk is that you don't take it, the second risk is that if you take it, you don't absorb it, and the third is that in any population someone is going to be less responsive. BETA: One study suggests that rifabutin has the potential to decrease the blood concentration of AZT. SDN: I am the second author on that abstract, and that abstract has a problem: the conclusion was based on only 6 patients, which makes the clinical significance of the study highly questionable. For example, our study suggests that rifabutin drops AZT levels, but a bigger and better study showed that rifabutin didn't do anything to ddI levels. There was no difference in the outcome of our patients in the rifabutin prophylaxis trials who were on AZT or on ddI_if the rifabutin effect on AZT had been clinically significant you would have expected to see a difference between those on ddI and AZT, but it wasn't there. That conclusion was included in the paper because Adria Pharmaceuticals has tried hard to be honest and accurate in their presentation of the data, but more work needs to be done before it's widely accepted. MAC Treatment and the Side Effect of Uveitis BETA: When was uveitis first observed? SDN: Late October 1993. The Adria Data Safety Committee met on December 3, 1993, and the letter by Steven Shafran was published in the February 7, 1994 New England Journal of Medicine. We're still collecting cases. BETA: How was uveitis first detected? Or, with what drug combinations did or does the condition occur? SDN: The first reports were with rifabutin and clarithromycin. One of my cases, and some other cases, were of rifabutin and fluconazole. Both clarithromycin and fluconazole raise rifabutin levels. The common denominator in most people who developed uveitis is rifabutin plus some other drug or rifabutin at high levels, like 600 or 900 mg/day. But I have to emphasize to you that this is very preliminary. This isn't going to be at a scientific meeting until the fall. Adria has been exceptionally good at getting out information. They have a list of every doctor in the U.S. who has prescribed AZT, and they have sent to each of those doctors a letter saying, "This is the possibility, and here's the data_" If more companies understood that doctors really appreciate this, maybe they would be a little more forthcoming about side effects. BETA: Side effects that no one is aware of until after marketing? SDN: More than 6,000 people have received rifabutin before it was out on the market but the condition only appeared after we started doing combination therapy. This is a dangerous business. Right now there are 30,000 people out there who got rifabutin and it looks like 30 or 40 of those 30,000 people have gotten uveitis. I'm projecting up from some cases that haven't been reported yet. That's not a high percentage, but 30 eyes are a lot of eyes. Studies are being redesigned right now because of the uveitis. I think there are 5 studies currently in progress just for MAC treatment that use rifabutin and other drugs. Uveitis and the redesigns will set back the results by a year, probably. BETA: What is the second-line choice for treatment for someone who develops uveitis? SDN: For uveitis the prudent thing to do is to discontinue rifabutin. If I had to discontinue rifabutin, I would try to continue clarithromycin and continue ethambutol. Ethambutol is a drug that probably works by making other drugs more effective. Ethambutol is a really neat compound but there's a lot that we don't know about it. We know that ethambutol in very high doses can induce blindness (called optic neuritis). For this reason I am very careful to keep the dose of ethambutol below 20 mg/kilogram (kg). So if you weigh 132 pounds or about 60 kg, then you get 1200 mg/day of ethambutol. If you weigh 70 kg I might give you a little more, but if you weigh 50 kg or are under 130 pounds, then I'd give only 800 mg/day. Alternative drugs include clofazimine. I use 100 mg/day; some people may use more, but it has a lot of gastrointestinal toxicity. Some people have found success with ciprofloxacin (Cipro)_I have not. I think ciprofloxacin is a good drug for tuberculosis but not for MAC. Liposomal gentamicin was not as successful as I had hoped it would be, at least as a single agent. Sparfloxacin is another quinalone like ciprofloxacin. Dr. Lowell Young has studied sparfloxacin. The development of sparfloxacin is going slowly. Amikacin has been around a long time. Some people feel that it works. I am neutral on the subject of amikacin; I don't usually use it. Rifampin is not effective against MAC in the test tube. When I treated MAC with anti-TB drugs, I did not find rifampin successful. Rifabutin is a second-generation rifampin; it's like rifampin in its activity against tuberculosis. Unlike rifampin, rifabutin is active against MAC as well. Next Steps: Multiple Opportunistic Infection (OI) Prophylaxis and Treatment for HIV Infection BETA: What do you see in terms of next steps? SDN: For the treatment of OI, the next step to take is to look for lower rather than higher doses. For prophylaxis, now that ACTG 981 has been presented, which shows that fluconazole works [for fungal infections], and now that the rifabutin trials show that it works [for MAC], the next step is to get the ganciclovir prophylaxis trials done to see if ganciclovir works [for CMV]. Then, we can start thinking about a combo trial of all 3 to look for other side effects. Beyond that, the next step is to find the role played by the Epstein-Barr virus (EBV) in lymphomas and in HIV disease overall. The ideal OI prophylaxis regimen right now, it seems to me, would include: (1) a sulfa drug like Bactrim, which as far as I can tell prevents toxoplasmosis as well as PCP; (2) fluconazole at some dose to prevent esophagitis and systemic fungal infections (the dose is uncertain but 100 mg rather than 200 mg is probably right; (3) rifabutin for mycobacterial infections; and (4) hopefully a third-generation oral acyclovir/ganciclovir to help prevent all the herpes infections (including herpes simplex 1 and 2, CMV, EBV and all the other herpesviruses). I think that people who are on that kind of combo prophylaxis, with that 4-level moat, are the ideal candidates in which to test better anti-HIV strategies. Preparations are under way for a 10,000-person trial, natural history, kind of off-the-street. I understand the reasons for this study and intellectually applaud it, but I also have reservations about it. I think that a 10,000-patient study is going to be complicated by people who get CMV, and that the effect the investigators are looking for is going to be overridden by CMV and other opportunistic infections. It seems to me that progress in defining which antiretroviral therapies work best will be a lot easier to achieve in people who you can put in a "chemical coat" so that your treatment effect doesn't get washed away by CMV, EBV [the virus that causes hairy leukoplakia and mononucleosis], cryptococcal meningitis or MAC infection. You're going to have to take care of OI before you can design the ideal antiretroviral trial, particularly for people with less than 50 T-cells. For people with 500 T-cells that's not the case because they rarely get OI, but if you want to find out if AZT alone or nevirapine alone works in people with 50 T-cells, you've got to have good prophylaxis regimens, or the OI are going to wash out your AZT effects. Furthermore, there is evidence that OI stimulate HIV replication, and this would even further counteract the effects of antivirals and make them look worse than they actually are. That may not be the only reason why we are in such a quandary about antivirals, but I think it's one of them. ********* A Master Protocol to Evaluate the Safety and Efficacy of Triple Combination Antiretroviral Therapy for HIV Infection David Barry, MD, Director of Research, Development and Medical Affairs, Wellcome plc and the Clinical Trials Subcommittee of the Inter-Company Collaboration for AIDS Drug Development The Inter-Company Collaboration for AIDS Drug Development, a consortium of 15 pharmaceutical companies, was established in April 1993. It will begin an unprecedented program this fall to test for the efficacy of various triple anti-HIV drug combinations. The regimens will be tested among HIV positive, asymptomatic individuals who have never used anti-HIV medication. This program is the result of an agreement among the 15 member pharmaceutical companies in the Collaboration to accelerate research into anti-HIV drugs by sharing information and compounds, and conducting joint research. The major objective of these studies is to identify triple drug combinations that demonstrate strong activity against HIV. Regimens that show promise will be tested further in traditional trials. Below is an introduction to the master protocol for these triple combination studies. The participating pharmaceutical companies are (in alphabetical order) AB Astra (Sweden), Aji Pharma USA (New Jersey and Japan), Boehringer Ingelheim (Connecticut and Germany), Bristol-Myers Squibb (New York), Burroughs Wellcome (North Carolina and Great Britain), DuPont Merck (Delaware), Glaxo (North Carolina and Great Britain), Hoechst AG (Germany), Hoffmann-La Roche (New Jersey and Switzerland), Miles Pharmaceuticals (Connecticut), Pfizer (New York), Sigma Tau (Italy), SmithKline Beecham (Great Britain) and Syntex (California). Study Rationale The effective treatment of serious, chronic, immunosuppressive, infectious or malignant diseases has generally required the administration of 3 or more chemotherapeutic agents. In some instances, such as tuberculosis or leprosy, this requirement is based primarily on the need to obviate the generation and eventual overgrowth of resistant organisms. The number of agents required to accomplish this is proportional to the number of organisms present in the body and to the probability of these organisms developing resistant mutations to each of the agents employed. In other instances, such as childhood acute lymphoblastic leukemia or Hodgkin's lymphoma, the explanations for the success of multiple-drug regimens are not as clear. Here, efficacy may depend upon synergistic effectiveness and/or differential sensitivity of a heterogeneous, transformed cell population, as well as the prevention of resistance development. The principles underlying successful multidrug approaches are straightforward and based on 2 determinative elements. First, the mechanism of action (and thus the presumed mechanism of resistance) of the various agents should be different, leading to independent probabilities of resistance development. Second, the toxicities of the drugs used should be different so that they may be used in combination without additive, specific end-organ toxicities. Even though the sum total of toxicities within a given patient may be greater when polytherapy rather than monotherapy is used, the number and dosages of the drugs can usually be adjusted so that the function of the patient is not seriously compromised. Viral Resistance In the case of HIV infection, it is clear that monotherapy in most stages of disease will lead to the development of viral resistance, and that this viral resistance may seriously compromise or even negate the effectiveness of the drug. Resistance may occur in weeks or years, depending on the virus numbers in the body and on the drug in question. The hypervariability of HIV and the lack of any DNA repair mechanism makes it highly likely that resistance will develop at some point with any single agent, no matter what its mechanism of action. Resistance has most commonly been described with RETROVIR (zidovudine) [AZT], Videx (ddI), 3TC and various non-nucleoside reverse transcriptase inhibitors (NNRTI). Furthermore, because antiviral agents are, by definition, "virustatic" rather than "virucidal," complete or near complete suppression of replication will need to occur in order for resistance development to be prevented. Double Combination Therapy For reasons that are not entirely clear, many proven anti-HIV agents in combination are either additive, superadditive or synergistic in their in vitro activity against the virus. Pilot studies in humans with the combinations of AZT and several other agents indicate that the in vitro promise of synergy may be fulfilled at least partially in vivo. Whether these combinations also inhibit the development of resistance is currently under study. Such inhibition is likely to be observed to some degree because the molecular basis of resistance for these agents appears to be different even though their general mechanism of action may be the same. These drugs generally have different toxicities and thus are likely to be useful clinical combinations, leading to the next significant advance in the treatment of HIV infection. In spite of the apparent early successes of duotherapy, the difficulties with relying on only 2 agents for the complete control of HIV infection, unfortunately, are manifold. The virus is extremely unstable. Mutation rates within genome segments controlling drug-sensitive functions may be as high as 104. In addition, the virus load in patients, particularly those with advanced disease, may be extraordinarily high. In fully advanced disease (AIDS), for example, the cell-free (serum) virus titer may average 6 X 102 per ml but can be as high as 108 per ml. If one assumes a patient's total blood volume to be approximately 5 liters, then there would be 3 X 106 to 5 x 1011 infectious virus particles in the serum of an AIDS patient, in addition to an undetermined but large number of intracellular viruses in lymphocytes, macrophages and other mononuclear cells. Most mutations are unlikely to lead to resistance, and the rate of resistance development to single agents is not known with precision. Nevertheless, it is likely, given these numbers, to observe resistance development to agents over some period of time in patients who have high viral loads at the time therapy is begun. By analogy, this in fact was observed in mycobacterial infections in clinical conditions where organism counts were high, such as cavitary tuberculosis or lepromatous leprosy. In addition, because of prior exposure to single agents, partial or complete (high-level) resistance may already be present at the time of the addition of the second agent. The interactive effect of chemotherapeutic agents on HIV is extremely complex. Rapid mutation of the virus leads to the development of resistance to single and even 2-drug combinations. In vitro evidence points to the distinct possibility that development of resistance can be circumvented with the proper combination of agents. First, resistant strains exposed to additional agents have shown increased sensitivity to the initial agent. For example, AZT-resistant virus exposed to ddI or ddC has shown increasing sensitivity to AZT. Viral sensitivity to AZT was reportedly restored when AZT-resistant virus mutated to develop resistance to 3TC or FTC. Likewise, increased sensitivity to nevirapine was reported when mutation of HIV was induced in response to exposure and subsequent development of resistance to NNRTI. Triple Combination Therapy Additionally, development of resistance by HIV to certain nonnucleoside reverse transcriptase inhibitors resulted in the suppressed resistance to nucleoside analog reverse transcriptase inhibitors. Second, several in vitro studies with 3-drug combinations have shown complete suppression of all virus replication. Such combinations may not be able to induce a series of mutations inconsistent with continuous virus replications, as had been originally postulated. Still, the ability of these combinations to suppress all viral replication for as long as they are present in the culture could provide a clear clinical advantage over existing therapies. The complex interaction of chemotherapeutic agents and the replicative enzyme systems of HIV could hold the key to successful chemotherapeutic treatment for HIV infection. The rapid identification of the best combinations of antiretroviral agents which can completely suppress viral replication and development of resistance over an extended period is therefore not only possible but urgently needed. Only a limited number of clinical 2- and 3-drug combination studies have been performed. In general they support additional and continued benefit with the addition of the second or third drug. Unfortunately, the interpretation of the results of prior and ongoing 2- and 3- drug regimens are clouded by the fact that many of the patients in these studies harbored virus which was already resistant, to some degree, to 1 or more of the agents used. Study Population Our knowledge of the in vitro details and clinical consequences of antiretroviral combination therapy is still in its infancy. However, it is not unreasonable to deduce that the potential advantages of such therapy with regard to additive or synergistic effectiveness are likely to be minimized or obviated if the viruses are already poorly sensitive to 1 or more of the agents employed. The ideal patient population to study the maximum benefits of combination therapy would be one without advanced disease or prior antiretroviral therapy. Rapid antiviral sensitivity assays are difficult to perform and would pose major logistical difficulties were they to be used as criteria for study entry. Fortunately, we know that virtually all wild-type HIV isolates are sensitive to most antiretroviral agents prior to exposure to these agents. Thus, appropriate patient selection with only post hoc analysis of sensitivity will be sufficient to conduct a study that can fairly evaluate the maximum benefit of multidrug therapy. These patients will necessarily have less advanced disease and will be exposed to the potential toxicities of 3 drugs. In such patients, however, these toxicities are expected to be minimal when appropriate dosages are chosen. In addition, because 3-drug combinations can suppress 93-100% of virus replication in in vitro assays as opposed to the 63-77% suppression seen in assays of 1- and 2-drug combinations, these patients may experience a return to normal of their immune function with 3-drug therapy. Available Triple Combinations There are currently 6 FDA-approved drugs with known in vitro anti-HIV activity: AZT, ddI, ddC, interferon, foscarnet and ribavirin, and an additional 2 (d4T and 3TC) with parallel-track status. Altogether, there are now 56 possible 3-drug combinations that could be tested. Even allowing for the elimination of several potential combinations because of antiviral antagonism (e.g., those combinations containing both AZT and ribavirin) or additive toxicity (e.g., those combinations containing both ddI and ddC), the number of remaining possible combinations exceeds the clinical research capacity of the U.S. and Western Europe (if any significant number were studied by statistically rigorous comparative methodology and used clinical endpoints). In addition, the emergence of other compounds, including protease inhibitors, NNRT inhibitors and therapeutic vaccines from Phase II studies in the coming year will raise the number of potential combinations to several thousand. Because antiviral resistance will occur to any new single drug, it is unlikely that any such agent could provide greater benefit for periods longer than existing 2-drug regimens. Thus a streamlined system of clinical research is required if 3-drug combinations are to provide immediate and long-term benefit to those currently infected with HIV. The Master Protocol We have therefore designed a Continuous Cohort Variable Regimen (CCVR) study to rapidly evaluate current 3-drug combinations and to allow the addition of new agents as they become available. This design will provide information which could be implemented quickly into clinical practice. In this study, patients will be assigned to various 3-drug combination protocols and followed until the relative efficacy of the treatment combination is determined. Although these protocols are designed as pilot Phase II studies, it is conceivable that they could become the basis for widespread use within the parallel-track system if the results are sufficiently impressive. Likewise, a sufficiently negative outcome would lead to rapid elimination of that combination from the options available to patients. Intermediate responses would obviously require Phase III studies to fully define the comparative therapeutic index of that combination. Significant and prolonged suppression of virus is likely to have extremely positive impacts on horizontal and vertical transmission rates and thus on the progress of the epidemic. Therefore, some regimens may be accepted as appropriate therapy if they lead only to virological and not immunologic benefit and if adverse reactions are minimal. Each 3-drug regimen will be chosen on the basis of the best scientific knowledge available from laboratory and Phase I studies. Factors to be considered when choosing a triple combination to be included in a treatment cohort include but are not limited to: ù in vitro evidence of synergy ù in vitro evidence of prevention of resistance patterns ù lack of expected additive toxicity The protocols in this series of studies will evaluate 3-drug combinations. The first 4 combinations to be tested have been selected; they are (1) AZT, ddC and saquinavir (the Hoffman La-Roche protease inhibitor), (2) AZT, ddI and nevirapine, (3) AZT, ddI and 3TC, and (4) AZT, ddC and nevirapine. These combinations were chosen because they show in vitro evidence of synergistic anti-HIV activity as well as no evidence of overlapping toxicity. Testing these first 4 regimens will also allow investigators to evaluate the mechanisms of the study protocol. If you would like the source references for Dr. Barry's article, please write to BETA: P.O. Box 426182, San Francisco, CA, 94142, ATTN: Master Protocol. ********* Research Notes Ronald A. Baker, PhD Ronald Baker is editor of BETA. This issue of Research Notes is organized under 7 categories: (1) Basic Science, (2) Treatment for HIV Infection, (3) Treatment for Opportunistic Infections, (4) Nutrition, (5) Immunotherapy, (6) Laboratory Markers and (7) Miscellaneous. Basic Science The 10th International Conference on AIDSin Yokohama, Japan The 10th International Conference on AIDS and Sexually Transmitted Diseases (STD) will be held in Yokohama, Japan, from August 7-12, 1994. For the first time in its 10-year history the International Conference will take place in Asia. Although a relatively new health problem in Asia, HIV infection represents a serious threat to a number of Asian countries. By the year 2000 Asia is expected to have the world's highest rate of HIV infection. The World Health Organization (WHO) estimates there may be more new HIV infections in Asia than in either Africa or Latin America. In Thailand, between 400,000 and 600,000 individuals are HIV positive, and 2 to 4 million infections are expected by 2000. In India, approximately 1.5 million people are already HIV positive. Cambodia, Vietnam and Indonesia are all expected to have an enormous increase in new HIV infections in the coming 5 years. In Japan, 2,900 individuals are officially diagnosed with HIV infection, and 700 people have been officially diagnosed with AIDS. The Japanese Ministry of Health and Welfare predicts that 26,000 Japanese citizens will be HIV positive by 1997. The conference organizers are attaching great importance to the participation of Asian and other developing countries, increased involvement of women and a strong focus on community activities. The Conference will of course include the latest findings in basic science and clinical medicine. Various groups and individuals have expressed concern about Japanese immigration policy toward foreigners living with HIV infection and AIDS entering Japan. No one will be denied a Japanese visa or entry into Japan because of their HIV positive serostatus, according to Naoko Yamamoto, MD, Deputy Director of the Infectious Diseases Control Division of the Japanese Ministry of Health and Welfare. Dr. Yamamoto added that Japanese officials do not ask visa applicants about their HIV status, and do not require them to take an HIV antibody test. "The policy applies regardless of length of stay, and it applies not only during the Yokohama conference, but at all times," said Dr. Yamamoto. For further information about the Yokohama Conference, contact: Secretariat for the Tenth International Conference on AIDS/STD, Congress Corporation Namiki Building, 5-3 Kamiyama-cho Shibuya-ku, Tokyo 150, Japan Tel: 81-(3)-3466-5812 Fax: 81-(3)-3466-5929 Triple Combination Study with Hoffmann-La Roche Protease Drug Yields Promising Results Preliminary results of a study (ACTG 229) show that using the triple combination of saquinavir (a protease inhibitor), AZT and ddC reduces HIV load significantly and produces a transient, but significant increase in CD4 (T-helper) counts. The study compared the safety and activity of the 3-drug combination to 2 double combinations: ddC plus AZT and saquinavir plus AZT. The triple combination was significantly better than the 2 double combinations in reducing viral load and in increasing CD4 counts. With 302 participants, ACTG 229 is the largest study of an HIV protease inhibitor yet completed. All study participants had 50-300 CD4 cells and had used AZT for at least 4 months before enrollment. Participants took 600 mg saquinavir 3 times a day, 200 mg AZT 3 times a day and/or 0.750 mg ddC 3 times a day for 24 weeks. Reduced HIV Load and CD4 Increases Viral load is the amount of HIV in circulating blood. The 3-drug combination decreased viral load as measured by quantitative cell culture significantly better than the 2 double combinations. CD4 counts rose during the first 8 weeks of study but then gradually declined in all 3 treatment arms. The increase in CD4 cells was greatest in the 3-drug combination group: 60 of 96 people (63%) maintained a 25 CD4 cell increase or a 25% rise from baseline CD4 count. Increases in the 2-drug combinations were significantly smaller: 52 of 98 (53%) using saquinavir plus AZT and 33 of 100 (33%) using ddC plus AZT maintained this same CD4 increase. In addition, a greater proportion of patients using the triple combination sustained increases of 50 CD4 cells or 50% from baseline CD4 count. Adverse Side Effects The type, severity and frequency of adverse side effects were the same in all 3 treatment groups. Eleven individuals experienced a major clinical event (an AIDS-defining opportunistic infection or death). One of these individuals was on the triple combination, 6 were on saquinavir plus AZT and 4 were on ddC plus AZT. There were 2 deaths during the 24-week study, both of which were attributed to HIV-related events and not associated with drug therapy. Implications These study results, although promising, do not demonstrate a clinical benefit from use of the combinations studied. The study was not designed to evaluate the clinical effectiveness of the treatment regimens. The endpoints used in the study were laboratory values ("surrogate markers") such as CD4 count, viral load, and p24 antigen, and not clinical endpoints, such as opportunistic infections or death. It remains unknown if the favorable effect of the 3-drug combination on laboratory markers is associated with a delay in disease progression or improved survival (clinical endpoints). The Phase III trials of saquinavir now open to enrollment (see Open Clinical Trials on page 62) are designed to evaluate the clinical effectiveness of the drug. Despite the limitations of ACTG 229, the study results are encouraging, particularly the fact that the 3-drug combination suppressed HIV load significantly better than either of the 2 double combination regimens. In addition, this suppressive effect continued for the duration of the 24-week study. The results of the upcoming Phase III studies of saquinavir will provide important information about how long the triple combination can suppress viral load. Bassett R and others. ACTG 229: Executive Summary. May 26, 1994. ACTG 229: Antiviral Trial of Combination Therapy. Press Release from the National Institute of Allegy and Infectious Diseases. HIV Can Cause Cancer Scientists have known for some time that HIV can cause cancer indirectly by weakening the immune systems of infected individuals, leaving them susceptible to many opportunistic infections and cancers. A new study from the University of California at San Francisco (UCSF) now shows that HIV can cause cancer directly, by "turning on" the cancer genes in some of the cells it invades. "This is the first direct evidence that we have [of] a human virus causing cancer through some mechanism_not just indirectly by immunosuppression," said lead investigator Michael McGrath, MD. The UCSF research team reviewed 30 lymphoma cases and discovered that, in 4, HIV had inserted itself into the same location in the DNA of the infected cell. Dr. McGrath estimates that HIV may directly cause over 30% of all B-cell lymphomas in people with AIDS. These findings probably will lead researchers to search for a possible role for other viruses in causing cancer. Scientists currently do not know what causes Hodgkin's disease or lymphomas. Although the UCSF study appears to have important implications, many questions remain about the role of HIV in causing cancer, such as (1) what is the exact mechanism by which HIV activates the cancer genes in infected cells? (2) how often does HIV cause cancer? (3) how long does it take for cancer to develop in HIV-infected cells? Some scientists say the UCSF study results raise concerns about using retroviruses such as HIV for vaccines or gene therapy. "Hooking up a gene to a retrovirus and then infecting human cells might risk cancer [in the treated individual]," said Dr. McGrath. Shiramizu B and others. Identification of a common clonal human immunodeficiency virus integration site in human immunodeficiency virus-associated lymphomas. Cancer Research 54(8): 2079-2072. April 15, 1994. TREATMENT FOR HIV INFECTION Advisory Panel Recommends Approval for d4T The FDA Antiviral Advisory Committee on May 20 recommended accelerated approval for for the anti-HIV drug d4T (stavudine). The FDA is not required to follow the recommendations of the advisory committee, but usually does so. The advisory panel concluded there was "an unmet need for d4T," and found that the drug probably offers some benefit over AZT, ddI and ddC, but also noted that it was unclear who would benefit most from the drug and how safe it is. In asking for acclerated approval for d4T, Bristol-Myers Squibb told the FDA panel that the drug appears to improve immune function among people with AIDS and causes less serious toxic effects than existing FDA-approved anti-HIV drugs. The most serious adverse side effect of d4T is a painful peripheral neuropathy that has occurred in about 21% of those using the drug. Because HIV itself can cause peripheral neuropathy, it is difficult to know whether this side effect is due to the virus or to the drug among those taking it. d4T versus AZT Preliminary results of an ongoing study of 359 people presented to the FDA panel suggest that d4T is beneficial for individuals who switch to the drug after using AZT for about 6 months. In the study, half the participants switched to d4T after 6 months of AZT treatment while the other half continued with AZT. Those who changed to d4T experienced a CD4 cell increase of 20-30. The participants on AZT had decreases in their CD4 cell counts. The d4T group also gained weight, while those on AZT lost weight, according to Susan Yarin, Director of Communications for Bristol-Myers Squibb. Data from Expanded Access Program Bristol-Myers Squibb also presented data from the ongoing expanded access program that has enrolled about 12,000 people with AIDS taking either 20 or 40 mg d4T twice daily. There appears to be no significant difference in effectiveness between the low and high dose, but those on the higher dose experienced a higher incidence of peripheral neuropathy. As a result of these findings, the recommended d4T dose likely will be 20 mg twice daily. Access to d4T The advisory panel has recommended that use of d4T be restricted to people with AIDS who have failed or are intolerant to AZT, ddI and ddC. However, if the FDA approves d4T, it will become available by prescription, and physicians may then prescribe the drug to HIV positive patients at all stages of HIV disease and with or without previous use of AZT, ddI and ddC. Associated Press. FDA committee recommends new AIDS drug. Los Angeles Times. A-21. May 21, 1994. Yarin, S. Director of Communications, Bristol-Myers Squibb. Personal Communication. May 23, 1994. ddI versus ddC ddI and ddC are equally safe and effective for people with AIDS who have failed or are intolerant to AZT, according to the results of a national study of 467 volunteers published in the New England Journal of Medicine. "Although neither of these drugs are very effective in this population of patients with advanced disease, this study suggests that ddC alone is as good as ddI [alone], and both should be available as single-agent therapies," said lead investigator Donald Abrams, MD, assistant director of the AIDS Program at UCSF-affiliated San Francisco General Hospital. Dr. Abrams noted that there was no significant difference between ddI and ddC in the number of patients who had progression of disease or who died. Among those taking ddI (230), 157 had disease progression and 100 died. Among those taking ddC (237), 152 progressed and 88 died. These results suggest a slight survival advantage for those using ddC. About 66% of all participants experienced some significant adverse side effect (e.g., peripheral neuropathy among ddC users; abdominal pain and diarrhea among ddI users). Abrams DI and others. A comparative trial of didanosine or zalcitabine after treatment with zidovudine in patients with human immunodeficiency virus infection. New England Journal of Medicine 330(10): 657-662. March 10, 1994. Merck Protease Drug Suffers Setback The following information appeared in the March 15, 1994 edition of BETA BULLETIN. The protease inhibitors are regarded by many AIDS treatment activists as the most promising class of anti-HIV drugs currently in the research pipeline. In a small study last summer, Merck's lead protease drug, L-735,524, demonstrated promising results, exhibiting an anti-HIV effect roughly comparable to AZT. Unfortunately, study results obtained 6 months later have proven disappointing. Merck announced on February 25, 1994, that L-524 failed to effectively suppress HIV in volunteers receiving the experimental compound for about 6 months. Merck researchers learned from PCR testing of stored plasma samples that the study volunteers' plasma HIV RNA levels began to rise after about 12 weeks of treatment. After 24 weeks of L-524 use, these levels rose to almost pretreatment levels. Merck scientists said they are not yet certain why the drug's initial promise faded so quickly, but they suspect that HIV developed resistance to L-524 at the doses tested. Researchers are examining blood samples from the study volunteers for the presence of resistant strains. As a result of these disappointing study results, Merck has canceled plans to test L-524 in several hundred HIV positive volunteers. Instead, researchers will modify an ongoing study (protocol 006) comparing L-524 at low and high doses to AZT monotherapy in 60 asymptomatic, p24-positive volunteers. Dr. Linda Distlerath, Director of Public Policy at Merck, told BETA that 006 participants who were on the L-524 arms now will take a higher dose of L-524 (600 mg 4 times a day). A separate study will test the safety and effectiveness of L-524 plus AZT. The investigators are hoping that higher doses of L-524 monotherapy, or L-524 in combination with AZT or other nucleoside analogs will effectively suppress viral activity. Emilio Emini, Executive Director of Virology at the Merck Research Laboratories, told the Wall Street Journal that the company has other protease inhibitors in preclinical development that may show stronger activity against HIV than L-524. Distlerath L. Director of Public Policy, Merck and Company. Personal Communication. March 2, 1994. Other Protease Drugs Hoffmann-La Roche A number of pharmaceutical companies are developing oral protease drugs for use in HIV infection. Hoffmann-La Roche's saquinavir (formerly called Ro 31-8959), now entering Phase III trials, is the farthest along in the drug development process. The international trial of saquinavir is now recruiting for 1,800 study volunteers (600 in the U.S.) with no previous use of any anti-HIV drug. In the North American trial of saquinavir, 40 medical centers will enroll a total of 1,200 HIV people with CD4 cell counts between 50 and 300 who have previously used AZT (but no other anti-HIV drug). For more information about the international and North American trials of saquinavir, call 1-800-526-6367. Abbott Abbott has experienced considerable difficulties with its protease drug development program. Two Abbott protease candidates have failed, but a third, A-84538, is now entering Phase I safety studies in New York City, St. Louis, and at sites in Alabama and in Europe. Call 1-800-TRIALS-A for enrollment information. Monsanto Searle Searle has started Phase I testing of its protease drug, SC-52151, in Berlin. The bioavailability of this compound reportedly is high, a definite advantage in the ongoing race to bring a safe and effective protease drug to market. Burroughs Wellcome Burroughs Wellcome has made an agreement with Vertex, a small biotechnology company in Cambridge, Massachusetts, to develop and market that company's experimental protease drug, VX-478. A Phase I study of VX-478 sponsored by Burroughs Wellcome is expected to begin this year. The results of laboratory testing suggest that VX-478 may be a powerful inhibitor of HIV activity. Other Protease Developers Other companies developing protease inhibitors include Agouron, Ciba-Geigy, DuPont Merck, Hoechst-Bayer, Nippon Mining, Parke-Davis and Upjohn. AZT Reduces Spread of HIV to Newborns The following information appeared in the March 15, 1994 edition of BETA BULLETIN. Preliminary results of a U.S. government-sponsored study (ACTG 076) indicate that AZT reduces by two-thirds the risk of transmission of HIV from infected pregnant women to their newborn infants. The finding is considered so important that a monitoring board halted the study before its scheduled completion date. Based on these results, Burroughs Wellcome, manufacturer of AZT, has asked the U.S. Food and Drug Administration (FDA) to approve AZT for the treatment of HIV positive pregnant women. The National Institute of Allergy and Infectious Diseases (NIAID) has released a summary of the data as a "Clinical Alert" so that physicians and healthcare professionals worldwide are aware of the findings. These documents are available in the U.S. on request from the AIDS Clinical Trials Information Service (call 1-800-TRIALS-A). Background The large majority of HIV positive children become infected through maternal-infant transmission, either in the womb, during birth or after birth, from breastfeeding. The ACTG 076 study was designed to test the hypothesis that treatment with AZT could reduce the risk of maternal-infant transmission. Study Results The 477 HIV positive pregnant volunteers in the study took either AZT or a placebo during pregnancy and labor. After birth, the babies received a syrup containing either AZT or placebo for 6 weeks. Of the 364 infants delivered for whom at least 1 HIV culture test was available, 53 were HIV positive. Thirteen (8%) of these babies were born to women taking AZT and 40 (26%) to mothers taking the placebo. The researchers reported that both mothers and infants experienced no significant short-term adverse side effects except for a mild, reversible anemia. They also have found no differences in the quantity or type of birth defects in infants whose mothers took AZT or the placebo. Researchers will continue to monitor the growth and development of the infants and watch for any unusual illnesses. Government health officials are expected to convene a panel of medical experts this summer to consider new recommendations on the testing and treatment of pregnant women. AZT reduces rate of maternal transmission of HIV. NIAID NEWS. February 21, 1994. The Concorde AZT Trial Revisited Results of the largest study ever conducted on AZT (1,749 participants) were published in April 1994, a year after release of the study's preliminary findings in a letter to The Lancet (April 3, 1993). The data prompted many physicians and patients to reevaluate AZT use in early (asymptomatic) HIV infection. In their published report, the Concorde researchers reaffirm their preliminary conclusions that asymptomatic HIV positive individuals do not benefit more from starting AZT early than from delaying AZT treatment until symptoms appear. The investigators found no significant differences in clinical outcome between the 2 treatment strategies of early versus deferred treatment, irrespective of the participants' initial CD4 T-cell count. They also report no significant differences in rates of progression of HIV disease between the 2 groups, and no differences in survival rates. CD4 T-cell counts were significantly higher for the early therapy group after 3 months (a 29 cell increase), a difference that continued for up to 3 years, although the researchers note no clinical benefit from the CD4 cell increase. They also state that the Concorde trial results cast doubt on the value of using changes over time in CD4 counts as a predictive measure for the effects of antiviral therapy on disease progression and survival. The results of the Concorde trial do not encourage the early use of AZT as monotherapy nor in combination with other antivirals among asymptomatic HIV positive individuals. In fact, the Concorde findings prompted a significant change in the "official" U.S. government recommendations on AZT use by asymptomatic individuals. Prior to release of the Concorde preliminary findings, AZT was recommended to all asymptomatic HIV positive individuals with fewer than 500 CD4 cells. Current U.S. government recommendations for this group support either "continued observation" (no AZT use) or initiation of AZT treatment. Commentary BETA spoke with Michael Saag, MD, Associate Professor of Medicine, University of Alabama at Birmingham, about the Concorde results. In response to the question of whether AZT should still be considered a viable treatment among asymptomatics, given the Concorde findings, Dr. Saag replied: "Absolutely. Concorde basically confirmed what we already knew about AZT. Specifically, AZT is an effective antiretroviral that has a limited durability of effect when used as monotherapy. The benefit of AZT appears to be of longer duration when used earlier in treatment, rather than when initiated later." "On a theoretical level and in all likelihood on a practical level, it makes good sense to add antiretroviral therapy as early as possible to help the immune system in its battle against the virus. This is especially true if we believe that better therapies will be available in the next 3-5 years." On the subject of AZT use in combination therapy, Dr. Saag added: "AZT has an integral role to play in combination therapy and is, in my view, the cornerstone of combination therapy at the present time." In response to publication of the Concorde trial results, Burroughs Wellcome Company, the manufacturer of AZT, released a statement defending the use of the drug among asymptomatics, pointing out that several clinical studies in the U.S. and abroad have shown that AZT delays HIV disease progression and slows viral replication in asymptomatic individuals: "In the final analysis, while Burroughs Wellcome believes early therapy with Retrovir [AZT] is an appropriate and effective strategy for managing HIV infection in asymptomatic patients, physicians and patients will need to weigh all available data and make the choices that are most appropriate for each individual." Seligmann M and others. Concorde: MRC/ANRS randomized double-blind controlled trial of immediate and deferred zidovudine [AZT] in symptom-free HIV infection. The Lancet 343: 871-867. April 9, 1994. Twice Daily AZT in Asymptomatics AZT appears to delay disease progression among asymptomatics for at least a year, according to results of a study of volunteers using twice daily AZT (500 mg 2 times/day) or placebo for 104 weeks. The study enrolled 329 asymptomatic individuals from 5 European countries and Australia. With 200-400 CD4 cells, this study population was considered at high risk for progression to AIDS. The primary endpoint of the study was the development of AIDS or severe AIDS-related complex (ARC). Study Results Progression to AIDS or severe ARC occurred in 17 people in the placebo group and 12 in the AZT-treated group. After 2 years, no statistically significant difference in progression to AIDS or severe ARC was found between the 2 groups. However, after 1 year of follow-up, significantly more placebo than AZT users had progressed to AIDS or severe ARC. Commentary The researchers emphasize that while AZT confers a clear benefit over placebo in the first year of treatment, it fails to do so in the second year. They suggest that the steady increase in the probability of progression in the second year for the AZT group may be related to the development of viral resistance to the drug. In conclusion, they write: "Phase I/II studies with combination treatment have shown more substantial and prolonged rises in CD4 cell counts than observed with monotherapy. It is likely that more aggressive initial treatment regimens than AZT monotherapy will be necessary." Mulder JW, Cooper DA and others. Zidovudine [AZT] twice daily in asymptomatic subjects with HIV infection and a high risk of progression to AIDS: a randomized, double-blind placebo-controlled study. AIDS 8: 313-321. March 1994. AZT and Quality of Life The benefits to asymptomatics of taking AZT may be outweighed by the drug's adverse side effects, according to the results of a study of 1,338 asymptomatic HIV positive individuals with fewer than 500 CD4 cells. After 18 months, the AZT group taking 500 mg/day gained an average of 0.5 months without disease progression, as compared to the placebo group. However, the AZT group experienced severe adverse events an average of 0.6 month sooner than the placebo group. The research team concluded that, for asymptomatic patients treated with 500 mg/day AZT, a reduction in the quality of life due to severe side effects of therapy approximately equals the increase in the quality of life associated with a delay in the progression of HIV disease. Burroughs Wellcome has criticized the methodology of the study and its conclusions, noting that the authors did not measure overall patient quality of life, but focused only on the adverse side effects of AZT. Lenderking WR and others. Evaluation of the quality of life associated with zidovudine [AZT] treatment in asymptomatic human immunodeficiency virus infection. The New England Journal of Medicine 330: 738-743. March 17, 1994. How AZT Affects Progression to AIDS and Survival in People with ARC AZT may benefit people with ARC by significantly postponing the development of AIDS, but AZT use by these individuals does not appear to extend their survival after they develop AIDS, according to the results of a 3-year study of 235 Australian gay and bisexual men with ARC. The benefit of AZT appears to be greater in those who do not develop intolerance to the drug. The investigators suggest that people with ARC who develop clinical intolerance to AZT, or who develop AIDS while using AZT should immediately consider another anti-HIV regimen (e.g., adding ddI or ddC to AZT or switching to ddI or ddC monotherapy). At the time of study entry, participants had a mean CD4 cell count of 117 and a mean age of 38.1 years. The daily dose of AZT used was 1,200 mg/day. Eighty-two individuals (35%) were taking some prophylactic treatment: dapsone (33%), pyrimethamine-sulfadoxine (26%), acyclovir (26%) and ketaconazole (15%). Only one participant was taking trimethoprim-sulfamethoxazole. Swanson CE and others. Efficacy of zidovudine treatment in homosexual men with AIDS-related complex: factors influencing development of AIDS, survival and drug intolerance. AIDS 8(5): 625-634. May 1994. Switching from AZT to ddI The duration of response to treatment with AZT has been quite variable: some individuals experience a slow decrease in CD4 cells despite treatment, while others maintain a stable CD4 cell count for up to 3 years. This variation in response may be due, at least in part, to the development of HIV resistance to AZT. Laboratory studies have shown that viral resistance to AZT and ddI develops at different genetic locations, and AZT-resistant strains of HIV remain sensitive to ddI. A recent study of 312 individuals at 19 study sites was designed to examine the benefits of switching to ddI compared to continuing AZT among people who have used AZT for 6 or more months and who have signs of progressive disease. The study volunteers took either ddI tablets (600 mg/day adjusted for weight) or AZT (600 mg/day). The study results show that individuals who continued to receive AZT had a 50% greater risk for disease progression than those who switched to ddI. Patients with either a diagnosis of AIDS or AIDS-related complex (ARC) appeared to benefit from changing to ddI treatment. The beneficial effect of switching was greater in individuals with a CD4 cell count at study entry of 100 or greater. This is the first study to show a benefit for switching from AZT to ddI among people with AIDS or ARC, and the first to prove the clinical effectiveness of the tablet formulation of ddI and to validate the practice of using clinical signs or a decrease in the CD4 count as an indication for changing drug treatment. Spruance SL and others. Didanosine [ddI] compared with continuation of zidovudine [AZT] in HIV-infected patients with signs of clinical deterioration while receiving zidovudine. Annals of Internal Medicine 120: 360-368. March 1, 1994. Alternating vs Simultaneous AZT and ddI Treatment Although both simultaneous and alternating regimens of anti-HIV drugs have been studied, there is little information available directly comparing these 2 approaches. A randomized pilot study comparing alternating and simultaneous regimens of AZT and ddI was conducted at the National Cancer Institute (NCI) in 41 individuals with AIDS or symptomatic HIV disease. Individuals on each regimen took the same overall amounts of AZT and ddI over the course of the one-year study. Volunteers taking the simultaneous regimen had significantly better responses in terms of CD4 cell count increase and weight gain over a year than those taking the alternating regimen. Those taking the simultaneous regimen also had an overall greater decrease in p24 antigen levels and fewer opportunistic infections, although these trends were not statistically significant. Two relatively low-dose regimens of AZT and ddI were used in this small study. Results of a 1992 study of combination treatment with AZT plus ddI suggest that CD4 cell increases are optimal from use of relatively high doses of each drug. However, this study shows that sustained CD4 cell increases can be attained with half the usual daily dose of AZT and ddI. In addition, recent laboratory experiments suggest that AZT resistance is less likely to occur when a combination of AZT and ddI is used. Prevention or the delay of the generation of AZT-resistant strains may be responsible in part for the clinical benefits and the CD4 increases observed in this NCI pilot study. Antonelli G and others. Drug combination of AZT and ddI_synergism of action and prevention of appearance of AZT resistance. Antiviral Chemistry and Chemotherapy 5: 51-55. January 1994. Yarchoan R and others. A randomized pilot study of alternating or simultaneous zidovudine [AZT] and didanosine [ddI] therapy in patients with symptomatic human immunodeficiency virus infection. The Journal of Infectious Diseases 169: 9-17. January 1994. Combination ddI plus AZT Beneficial in Children HIV positive, previously untreated children who took full-dose AZT in combination with ddI gained weight, had increased numbers of CD4 cells and showed decreases in HIV load, according to the results of a 24-week study at the National Cancer Institute. After 24 weeks on the combination, children in both the previously AZT-treated and untreated groups experienced significant CD4 cell count increases: the median CD4 cell count for all the children increased from 331 to 556 cells. For the previously untreated group, the median increase in CD4 counts was from 386 to 726 cells. This study of 68 children, the first to evaluate the effects of the combination of AZT and ddI in children, showed the combination did not enhance toxic side effects. The low incidence of pancreatitis or any other serious toxicity suggests that full doses of ddI can be used in combination with AZT among children. The researchers conclude that the doses used in combination treatment for children could be the same as those currently used in monotherapy, i.e., AZT at 90-180 mg/m2 every 6 hours combined with ddI at doses between 90-135 mg/m2 every 12 hours. Husson RN and others. Zidovudine [AZT] and didanosine [ddI] combination therapy in children with human immunodeficiency virus infection. Pediatrics 93: 316-322. February 1994. AZT plus 3TC Glaxo and Burroughs Wellcome (manufacturers of 3TC and AZT, respectively) have made an agreement whereby Burroughs holds the option to develop and market 3TC for the treatment of HIV infection. 3TC is currently in Phase II/III studies, with one arm evaluating the safety and effectiveness of combination treatment with 3TC and AZT. Pending the results of that study, Burroughs may ask the FDA to approve AZT in combination with 3TC for the treatment of HIV infection in adults. AZT Resistance Correlates with Treatment Failure A study by Spanish researchers confirms the results of other laboratory tests suggesting that development of HIV resistance to AZT at codon 215 of the reverse transcriptase enzyme correlates with declining responsiveness to treatment with the drug. The investigators conclude that "the zidovudine [AZT] resistance mutation at codon 215 of reverse transcriptase was associated with a worse response to therapy. Absence of antiviral response and resistance mutations were more frequent in patients with lower CD4 cell counts and higher provirus loads. These findings support a more beneficial effect of early than late therapy." Luque F and others. Provirus load changes in untreated and zidovudine-treated HIV-1 infected patients. Journal of Infectious Diseases 169(2): 267-273. February 1994. TREATMENT FOR OPPORTUNISTIC INFECTIONS Oral Ganciclovir: Effective Maintenance Therapy for CMV Retinitis This information is reprinted from the March 15, 1994 BETA BULLETIN. Many individuals with CMV retinitis become understandably upset when they learn that the standard treatment for their condition involves the permanent installation of a catheter for intravenous access to ganciclovir (Cytovene) or foscarnet. Fortunately, new data indicate that the oral formulation of ganciclovir is both safe and effective as maintenance therapy for CMV retinitis. Two studies (at the University of Alabama and Beth Israel Hospital in Boston) showed no statistically significant difference in effectiveness between intravenous (IV) and oral ganciclovir, when the assessment of progression was based on retinal photographs. However, a significant difference in the 2 approaches did emerge when the assessment of progression was based on examination by onsite ophthalmologists. In the latter case, the IV ganciclovir appeared more effective than the oral formulation. It has been suggested that there may be ophthalmologist bias against the oral drug. One of the studies also showed more adverse side effects (fever, neutropenia and sepsis) in individuals receiving IV ganciclovir. Based on the data from these 2 studies, Syntex, manufacturer of ganciclovir, will file a New Drug Application (NDA) with the FDA seeking approval of oral ganciclovir as maintenance therapy for CMV retinitis. Two ongoing studies are testing the hypothesis that oral ganciclovir may prevent first-episode CMV retinitis in HIV positive individuals with fewer than 100 CD4 cells. Japour AJ. Update on oral ganciclovir for CMV retinitis. AIDS Clinical Care 6(3): 23. March 1994. Spector SA. A randomized, controlled study of intravenous ganciclovir therapy for cytomegalovirus peripheral retinitis in patients with AIDS. AIDS Clinical Trials Group and Cytomegalovirus Cooperative Study Group. Journal of Infectious Diseases 168: 557-563. 1993. Interferon Gamma for Disseminated Mycobacterial Infection A study published in the New England Journal of Medicine (May 12, 1994) suggests that treatment with interferon gamma dramatically benefits individuals with disseminated mycobacterial infection that is resistant to therapy. The study involved 7 HIV negative individuals with mycobacterial infection that had spread to involve at least 2 organs or types of body tissues. Six had disseminated Mycobacterium avium complex (MAC), which is difficult to treat in people with AIDS. At the beginning of the study all 7 participants were either unresponsive to, or experiencing disease progression despite standard anti-mycobacterial therapy. Interferons are a class of proteins naturally produced by the body to help fight infection. Previous studies had led researchers to believe that gamma interferon, secreted by immune system T cells, plays a particular role in controlling mycobacterial infection, possibly through cytokine-mediated signaling of T-cells and macrophages. All participants received subcutaneous injections of gamma interferon 3 times weekly in doses that varied according to body weight (50 micrograms/meter2). While there were no striking changes in CD4 cell counts or characteristics, all had dramatically improved clinical responses, which began within 8 weeks and continued for several months. Side effects were minimal_fever, malaise and myalgia (muscle ache or pain)_and resolved with dose reduction. Researchers conclude that interferon gamma in combination with standard therapy may be beneficial for treating disseminated refractory mycobacterial infection. Holland SM and others. Treatment of refractory disseminated nontuberculous mycobacterial infection with interferon gamma. The New England Journal of Medicine 330(19): 1348-1355. May 12, 1994. PWA Living 29 Months Longer than in 1986 The lifespan of people with AIDS (PWA) has increased on average to 40 months since 1986, according to a recent report in the Journal of the American Medical Association by a team of University of California at San Francisco researchers. Survival time was defined as the time the study participants' CD4 cells dropped below 200 until their death. Changes in survival time were studied through an examination of the medical records of 761 HIV positive men enrolled in the San Francisco Men's Health Study (1984 to 1993) and the San Francisco General Hospital Cohort Study (1983 to 1993). The median survival time following an AIDS diagnosis in the first 500 people diagnosed with AIDS in San Francisco was 11 months, according to lead investigator Dennis Osmond, PhD. Since that time, studies have reported an increase in survival time ranging from 14.4 months to about 2 years. This increase in lifespan following an AIDS diagnosis generally had been attributed to the beneficial effects of treatment with anti-HIV drugs. PWA who took AZT or other anti-HIV drugs alone did not have a statistically significant increase in survival, said Dr. Osmond: "The most important finding in our study was that the major contributor to improved survival during the past 10 years has been in HIV-infected individuals diagnosed with PCP, suggesting that prophylaxis and treatment for PCP, rather than antiretroviral therapy, were responsible for most of the improvement." The study showed that people treated for PCP who also took anti-HIV treatment did best, but that the role of anti-HIV drug treatment was less significant to the survival benefit than the anti-PCP therapy. The UCSF study results suggest that people with lower CD4 counts are living longer now because more of them have used prophylaxis and treatment for PCP than was the case earlier in the epidemic. "Now patients are diagnosed more frequently with opportunistic infections other than PCP as their CD4 counts drop over time. They tend to die of other infections or cancer, rather than PCP," according to Dr. Osmond. Osmond D and others. Changes in AIDS survival time in 2 San Francisco cohorts of homosexual men, 1983 to 1993. Journal of the American Medical Association 271(14): 1083-1087. April 13, 1994. Trinkl A. Survival time in some HIV-infected men has increased by approximately one year since beginning of the AIDS epidemic, UCSF study finds. News from SFGH/UC-San Francisco. April 12, 1994. The Effects of High-Dose Acyclovir on Survival and Herpesvirus Disease High-dose acyclovir (3,200 mg/day) does not reduce the incidence of cytomegalovirus disease (CMV), but does significantly reduce the probability of dying after 1 year of therapy, according to results of a double-blind, placebo-controlled trial of 304 men and women with AIDS in 16 hospitals in Europe and Australia. There were 43 deaths in the placebo group compared to 27 deaths in the acyclovir group. As expected, acyclovir also significantly reduced the incidence and frequency of herpes simplex virus disease. Trial participants were seropositive for CMV and had fewer than 150 CD4 cells at study entry. There was a steady decline in CD4 counts in both the acyclovir and placebo groups. The data showed that anti-HIV treatment significantly improved survival in both the acyclovir- and placebo-treated groups. Participants used AZT monotherapy, AZT plus ddC or ddI monotherapy. Ninety-six percent (96%) of individuals in both the acyclovir and placebo groups were on PCP prophylaxis. Taking this into account, the investigators still found that acyclovir therapy had an independent and significant beneficial effect on survival. Researchers chose to use a high dose of acyclovir in this trial in an effort to achieve drug blood levels sufficent to produce an anti-CMV effect similar to that reported in organ transplant patients. They note that if the survival benefit from acyclovir is due to the drug's ability to suppress acyclovir-sensitive herpesviruses, then lower doses of the drug might be as effective as the high dose used in this trial (3,200 mg/day). On the other hand, use of the experimental drug valacyclovir may provide even greater benefit, since it produces significantly higher blood levels of acyclovir than acyclovir (Zovirax). An international study (ACTG 204) is now addressing these possibilities. Youle MS and others. Effects of high-dose oral acyclovir on herpesvirus disease and survival in patients with advanced HIV disease: a double-blind, placebo-controlled study. AIDS 8(5): 641-649. May 1994. Over-the-Counter Acyclovir On May 19, 1994, a public hearing was held by the FDA to create a forum for the expression of various perspectives on the proposed granting of over-the-counter (OTC) availability of acyclovir (Zovirax) 200 mg for the management of recurrent genital herpes. Burroughs Wellcome Company, manufacturer of acyclovir, presented their case for approval of OTC status, citing the desirability of wider access and the increased opportunity approval would create for early treatment, as well as their intention to launch a major program to educate the public about genital herpes. The FDA heard passionate objections to allowing OTC sales of acyclovir from both AIDS activists and some medical experts. Their major concern is that people will overuse the drug and thereby increase the odds that the herpes simplex virus will develop resistance to it. "If acyclovir is used casually on and off again, the likelihood of resistance developing may increase and the likelihood of the disease [genital and oral herpes simplex] spreading may increase," according to Stephen Straus, a virologist at the National Institute of Allergy and Infectious Diseases. In addition to concerns about OTC acyclovir contributing to the risk of acyclovir-resistant herpes simplex, activists cited economic reasons for their opposition to the Burroughs Wellcome proposal. "Over-the-counter drugs are not reimbursed by insurance carriers nor are they included in government assistance programs," a spokesperson for San Francisco's ACT-UP/ Golden Gate told BETA. According to Kathy Bartlett of Burroughs Wellcome, the advisory panel expects to reconvene for continued discussion of the acyclovir OTC issue at the end of July. Bartlett K. Manager of Corporate Media Relations, Burroughs Wellcome Company. Personal Communication. May 24, 1994. Bowers M. Medical Writer.Personal Communication. May 27, 1994. FDA Approves Septra Brand TMP-SMX to Prevent PCP The FDA has made it official: Septra brand trimethoprim-sulfamethoxazole (TMP-SMX) is indicated for treatment to prevent Pneumocystis carinii pneumonia (PCP) in people with HIV infection and other immunocompromising conditions. TMP-SMX is the most effective prophylaxis for PCP as well as for toxoplasmosis in individuals who can tolerate the drug. Septra is the brand name for TMP-SMX manufactured by Burroughs Wellcome Company. Bactrim, manufactured by Hoffmann-La Roche, is another brand of TMP-SMX. There are also generic TMP-SMX products. The FDA action on Septra, applied for by Burroughs Wellcome Company, validates common clinical practice already in use. Desensitization Protocols Because TMP-SMX may cause adverse side effects in people with HIV infection (often severe enough to necessitate discontinuation of the drug), it may be most beneficial for these individuals to start TMP-SMX using a desensitization protocol. Two California physicians have reported success using desensitization protocols. For more information, call the offices of Dr. Marcus Conant in San Francisco (415-923-1333) and Dr. Brian Lipson in Redwood City, CA (415-365-6300). Steroid Therapy: a Role in the Management of MAC? A report in the January 1994 issue of the journal AIDS describes beneficial effects from adjunctive corticosteroid therapy in the management of 2 individuals with AIDS and disseminated MAC. The 2 patients were adult men who both previously had an AIDS-defining illness. When diagnosed with MAC, both had fewer than 40 CD4 cells and presented with fever, night sweats and weight loss. They were treated first with rifampin, isoniazid and pyrazinamide, and later with azithromycin and clofazimine. One patient also took ciprofloxacin. In both cases only a partial response was achieved during the first 2 weeks of treatment. However, the introduction of 20 mg prednisolone daily produced a resolution of fever and sweats and a feeling of well-being, according to physicians at the Heartland Hospital in Birmingham, U.K. During follow-up, both patients gained weight and one who was anemic did not require transfusion after starting prednisolone treatment. Both patients have continued to take azithromycin (with clofazimine in one case and ciprofloxacin in the other). One has continued to be free of fever and has maintained his weight gain for 5 months. His prednisolone dose has been halved, in an attempt to control resistant oral candidiasis. The second has maintained his improvement in symptoms and is back at work 8 months after starting prednisolone. The attending physicians speculate that the anti-inflammatory actions of prednisolone may inhibit the production of cytokines such as tumor necrosis factor (TNF). Excessive production of TNF, they say, is one cause of fever and weight loss in advanced AIDS. They also point out that prednisolone is commonly used in the treatment of immunocompetent individuals with tuberculosis to reduce their symptoms of prolonged fever. TNF also has been shown to stimulate HIV replication. Immunosuppressive treatment with prednisolone may both reduce the symptoms of MAC and slow disease progression in people with AIDS, suggest the British physicians. There has been concern among researchers and clinicians that use of corticosteroid therapy in HIV positive individuals might accelerate disease progression, due to the immunosuppressive action of these drugs. In the 2 individuals described here, prednisolone did not seem to promote disease progression (although one has resistant oral candidiasis). It would be useful to conduct a controlled study of prednisolone use in the treatment of MAC, and to monitor cytokine levels in study participants with MAC before treatment, especially for levels of tumor necrosis factor. Elliott AM and others. Use of prednisolone in the treatment of HIV positive tuberculosis patients. Quarterly Journal of Medicine 85: 855-860. 1992. Steven N and others. Corticosteroid therapy for AIDS patients with Mycobacterium avium/intracellulare infection. AIDS 8(1): 136-137. January 1994. Hospital and Municipal Water Systems May Be a Primary Source of MAC Infection Mycobacterium avium complex (MAC) organisms were found in 10 (30%) of 33 water samples collected from environmental and municipal water sources in Boston and New Hampshire between March 1990 and February 1992, according to results of a study by researchers at Dartmouth-Hitchcock Medical Center and Boston City Hospital. This is the first documented report of a water system that may be persistently colonized with a particular strain of Mycobacterium avium. Background Disseminated infection with MAC organisms occurs in up to 40% of people with advanced AIDS in the U.S. These environmental mycobacteria are found in water, soil and animals, but the specific source of human infection is not known. It is also unknown whether people with AIDS develop MAC disease from recent infection with the MAC organisms or through a reactivation of previous infection. The investigators of the study reported here believe it is likely that MAC organisms are acquired from an environmental source to which most people are exposed. The researchers collected and analyzed water samples from environmental sources (e.g., lakes, rivers) and water supply systems (e.g., home municipal water, hospital water) in New Hampshire and Boston. They then compared the MAC strains isolated from these sources to the M. avium strains of 28 individuals in New Hampshire and Boston with disseminated MAC infection. Four groups of strains infecting these patients were also isolated from 2 or more epidemiologically related sources. "For 3 of these [M. avium] strains, the epidemiological data implicate water as the source of infection, including 2 strains associated with nosocomial [hospital-asociated] acquisition [from hot water]." The authors implicate "recirculating hot water systems which are used in large institutions, including hospitals, hotels and apartment buildings." They also note that investigators "have not found MAC in single-family residential water supplies." The researchers report that the results of recent M. avium skin test studies suggest that previous infection with M. avium is not sufficently common in healthy populations to explain the high incidence of disseminated M. avium in AIDS solely on the basis of reactivation of an existing infection. "The identification of water as the source of infection for 5 patients confirms that infection was acquired recently and was not the result of reactivation of latent infection." Implications for Prevention of MAC? The investigators believe that their findings suggest another approach to the prevention of disseminated MAC in AIDS than the use of rifabutin in patients with fewer than 100 CD4 cells. They propose an aggressive program to identify (and then avoid) environmental sources of M. avium infection: "Patients might be advised to avoid institutional showers and exposure to non-sterile drinking water; colonised institutional water systems might be sterilised, as recommended in the prevention of nosocomial legionella infection." These proposed risk-reduction strategies may be a useful supplement to the use of rifabutin in HIV positive individuals at risk for developing disseminated MAC infection. du Moulin GC and others. Concentration of Mycobacterium avium by hospital hot water systems. Journal of the American Medical Association 260: 1599-1601. 1988. Singh N and Yu VI. Potable water and Mycobacterium avium complex in HIV patients: is prevention possible? (commentary). The Lancet 343: 1110-1111. May 7, 1994. von Reyn and others. Persistent colonisation of potable water as a source of Mycobacterium avium infection in AIDS. The Lancet 343: 1137-1141. May 7, 1994. von Reyn CF and others. Isolation of Mycobacterium avium complex from water in the United States, Finland, Zaire, and Kenya. Journal of Clinical Microbiology 32: 27-30. 1993. ISIS 2922: Promising New Drug for CMV Retinitis Isis Pharmaceuticals' experimental antisense drug, ISIS 2922, has shown promising results in a small Phase I/II study of people with CMV retinitis. Preliminary results suggest that ISIS 2922 halted disease progression (eye lesion progression) in most study participants who received the middle and high doses of the drug. All 10 individuals in the study had failed or were intolerant to either ganciclovir or foscarnet (or both), the standard treatments for CMV retinitis. As of late April, none of the participants have shown progression, according to the company. Two out of 3 individuals in the middle-dose group and all in the high-dose groups showed positive clinical responses. In addition, the participants experienced no significant, dose-related side effects from ISIS 2922. The drug is administered by intravitreal injection into the globe of the eye. CMV retinitis, a sight-threatening disease that damages the retina of the eye, affects up to 40% of people with AIDS. Treatment with ganciclovir and/or foscarnet may produce little benefit and also may cause severe toxicities. Individuals receiving ganciclovir frequently must cease taking AZT due to the synergistic toxicities of the 2 drugs. ISIS 2922 may be compatible in combination with anti-HIV drugs and with the anti-CMV drugs ganciclovir and foscarnet. ISIS 2922 is the first antisense drug to show activity against a disease-causing agent in humans. Antisense drugs are a new and unique class of pharmaceuticals designed to work more selectively than traditional drugs and to act against pathogens at a different or earlier stage in the disease process. The design of antisense drugs is "rational," i.e., based on information about the targeted pathogen. This "rational" approach allows for a relatively rapid and more efficient drug design. Based on the results of the initial human study, 2 randomized, placebo- controlled Phase II/III trials of ISIS 2922 in individuals with CMV retinitis are planned to begin this summer at 10 to 15 clinical centers in the U.S. Other ISIS Drugs Isis Pharmaceuticals is considering developing ISIS 2922 as a treatment for CMV pneumonia and CMV gastroenteritis. The company is also exploring the potential of antisense treatments for HIV infection. In addition, a new ISIS anti-HIV drug, ISIS 5320, is in preclinical development. In laboratory testing, this drug inhibits HIV from infecting immune cells, blocks cell-to-cell transmission of the virus and is active against AZT-resistant strains of HIV. Isis Pharmaceuticals announces clinical activity of antisense drug. Phase I/II Preliminary Data from annual meeting of the Federation of American Societies for Experimental Biology (FASEB) in Anaheim, CA. April 28, 1994. NUTRITION High-Dose Oral L-Carnitine in PWA Supplementation with high-dose oral carnitine (6 g/day) may have a role as a complementary therapy among people with HIV infection, according to the results of a small Italian study. Carnitine is a naturally occuring substance in the body that stimulates the oxidation and synthesis of fatty acids. In people with HIV infection, it may reduce wasting and improve immune cell production. Carnitine concentrations in the sera of people with AIDS are usually lower in those taking AZT (De Simone, 1992), and carnitine deficiency has been found in the skeletal muscle of people with AZT-related myopathy (Dalakas, 1994). In addition, people with AIDS taking L-carnitine supplements have demonstrated enhanced peripheral blood mononuclear cell (PBMC) responses to mitogens and a decrease in triglycerides and beta-2 microglobulin levels (De Simone, 1993). Study Results The investigators enrolled 20 men with advanced AIDS (22-109 CD4 cells) who had normal serum levels of carnitines. The participants were randomly assigned to receive either L-carnitine (6 g/day) or placebo for 2 weeks. At study entry and at the end of the study, the researchers measured carnitines in both sera and in PBMC, serum triglycerides, CD4 counts and the effects of mitogen stimulation. Despite having normal concentrations of carnitines as measured by serum levels, these patients had lower concentrations of total carnitine in PBMC than healthy, HIV negative controls. In those participants treated with high-dose L-carnitine, appropriate levels of carnitine were restored. In addition, the immune function of the treated individuals also improved, as measured by an improved lymphocyte response to mitogen stimulation. At the end of the study, the researchers also found a significant reduction in serum triglyceride levels in the L-carnitine group compared with baseline levels. Increased serum levels of triglycerides are common in people with AIDS, and appear to result from the unregulated production of cytokines, particularly tumor necrosis factor (TNF). The Italian investigators believe that the effect of L-carnitine on serum triglyceride levels is probably mediated via the modulation of TNF. L-carnitine has previously been shown to modulate the production of TNF both in vitro and in vivo (Delogu, 1993; Ruggiero, 1992). The researchers believe their study findings suggest a significant relationship between carnitine status in PBMC and immune function in people with AIDS. They recommend that L-carnitine supplementation be considered as a complementary therapy for HIV positive individuals. "Further studies are currently in progress to address the important question of whether the encouraging results obtained by administering high-dose L-carnitine supplements for a short timespan persists, or whether prolonged treatment is required. No adverse side effects were noted in those receiving high-dose L-carnitine. Six patients (30%) on L-carnitine reported psychological well-being, weight gain, increased energy and feeling healthy. The investigators note that reduced serum carnitine levels have been associated with AZT treatment, and they conclude that supplementation with high-dose L-carnitine may be useful to prevent or treat AZT-related myopathy. Dalakas MC and others. The AZT-induced mitochondrial myopathy is associated with muscle carnitine deficiency and lipid storage. Annals of Neurology. 1994 (in press). Delogu G and others. Anaesthetics modulate tumour necrosis factor alpha: effects of L-carnitine supplementation in surgical patients. Preliminary results. Medical Inflammation 2(supp): S33-S36. 1993. De Simone C and others. Carnitine depletion in peripheral blood mononuclear cells from patients with AIDS: effect of oral L-carnitine. AIDS 8(5): 655-660. May 1994. De Simone C and others. L-carnitine deficiency in AIDS patients. AIDS 6: 203-205. 1992. De Simone C and others. High-dose L-carnitine improves immunologic and metabolic parameters. Immunopharmacologic Immunotoxicology 15: 1-12. 1993. Ruggiero V and others. LPS-induced serum TNF production and lethality in mice: effect of L-carnitine and some acyl-derivatives. Medical Inflammation 2(supp): S43-S50. Vitamin E and Beta Carotene Have No Beneficial Effect on the Incidence of Lung Cancer and Other Cancers in Male Smokers The results of several studies over the last 10 years have suggested that high intake of antioxidant vitamins such as vitamin E (alpha-tocopherol) and beta carotene (provitamin A), either through diet or vitamin supplementation, might help to prevent cancer or cardiovascular disease (Peto, 1981; Packer, 1991). In 1993, a large clinical trial of 15,000 inhabitants of Linxian County in China found that a combination of beta carotene, vitamin E and selenium reduced the number of deaths from stomach cancer by 21%. More recently, several studies have suggested a beneficial role in the treatment of HIV infection for a high intake of nutrients and antioxidant vitamins (Abrams, 1993; Beach, 1992). Many epidemiologic studies have linked the intake of vegetables rich in beta carotene with a lower risk of cancer, especially lung cancer, and have suggested that certain micronutrients are inhibitors of cancer (Peto, 1981). Some observers have pointed out that the limitation of these observational studies is that the demonstrated benefits are not large and might be due to other, unmeasured differences in lifestyle. In April 1994 the New England Journal of Medicine published the first randomized, double-blind, placebo-controlled trial of supplementation with antioxidant vitamins in a large, well-nourished population (The Alpha Tocopherol, Beta Carotene Cancer Prevention Study Group [ATBC], 1994). This study enrolled more than 29,000 middle-aged male smokers in Finland who were treated for 6 years. The purpose of the study was to determine if supplementation with vitamin E, beta carotene or both would reduce the incidence of lung cancer in male smokers. A secondary purpose was to see if the incidence of other cancers would be affected by this supplementation. Study Results The trial failed to detect any significant protective effect of either of the 2 vitamins on lung cancer. On the contrary, among those treated with beta carotene (20 mg/day), there were significantly more new cases of lung cancer. In regard to the incidence of other cancers, there was no statistically significant difference with either vitamin. Neither vitamin significantly affected death rates due to heart disease or stroke. When adjustments were made for multiple comparisons, neither vitamin was associated with greater increases or decreases in any particular cause of death than could be due to chance. The researchers concluded that "these supplements may actually have harmful as well as beneficial effects." Commentary The results of the ATBC trial should not be viewed as proving that these vitamins are ineffective or even hazardous. The development of lung cancer may require many years, possibly decades, and treatment with vitamin supplements sufficient to significantly affect the middle or late stages of the disease may require substantially longer than the median 6 years of the ATBC trial. In addition, although the 20 mg daily dose of beta carotene appeared adequate and had high bioavailability, increasing blood levels 10-fold, the 50 mg daily vitamin E supplement was a synthetic form of the vitamin that does not have a high bioavailability, and increased blood levels of vitamin E in study participants by only one third. It may be necessary to at least double blood levels of vitamin E to show whether it produces a significant benefit. Ongoing Trials of Antioxidant Vitamins Three ongoing large trials are assessing the benefit of beta carotene: the Carotene and Retinoid Efficacy Trial (CARET), the Women's Health Study (Harvard) and the Physicians' Health Study (Harvard). The safety monitoring committee for the CARET trial may decide to notify participants' of the Finnish study finding that 20 mg/day beta carotene could increase the risk for lung cancer among cigarette smokers. The 2 Harvard trials are scheduled to continue without notification of the participants. Dr. Charles Hennekens, lead investigator of the Physicians' Health study, told Science magazine "[The Finnish trial] does not disprove the value of antioxidant vitamins, nor does it incriminate them as harmful. But it does provide support for skepticism, and a moratorium on unsubstantiated claims [about beta carotene and other antioxidants]." Abrams B and others. A prospective study of dietary intake and acquired immune deficiency syndrome in HIV-seropositive homosexual men. Journal of Acquired Immune Deficiency Syndromes 6(8): 949-958. August 1993. Baum MK and others. Interim dietary recommendations to maintain adequate blood nutrient levels in early HIV-1 infection. VII International Conference on AIDS. Amsterdam, 1992. PoB 3657. Beach RS and others. Specific nutrient abnormalities in asymptomatic HIV-1 infection. AIDS 6(7): 701-708. July 1992. Gilden D. Nutritional intervention in HIV disease. BETA: 3-11. 1994. Nowak R. Beta-carotene: helpful or harmful? Science 264: 500-501. April 22, 1994. Packer L. Protective role of vitamin E in biological systems. American Journal of Clinical Nutrition 53 (supp): S1050-S1055. 1991. Peto R and others. Can dietary beta carotene materially reduce human cancer rates? Nature 290: 201-208. 1981. IMMUNOTHERAPY Impaired Response to Hepatitis B Vaccine in Asymptomatics Hepatitis B virus (HBV) is commonly found in HIV positive individuals because the 2 viruses share the same modes of transmission: parenteral (via shared contaminated needles), sexual and vertical (from mother to child during pregnancy, childbirth or from breastfeeding). HIV infection is associated with a high degree of HBV replication, which increases the potential of transmitting this often life-threatening viral infection. Prevention of HBV infection through use of the hepatitis B vaccine among previously unexposed HIV positive individuals is highly desirable. Researchers at the General Hospital in Newcastle, United Kingdom, studied the immune response (especially in relation to CD4 counts) to hepatitis B vaccine among asymptomatic, HIV positive gay and heterosexual individuals (Tayal and Saukar, 1994). A 20 microgram (mcg) dose of recombinant hepatitis B vaccine (Engerix B) was given to 20 asymptomatic, HIV positive individuals intramuscularly in the deltoid muscle region at 0, 1 and 6 months. An additional dose of vaccine was given to those who did not respond or had poor response to the standard regimen. Of the 20 individuals vaccinated, anti-HBV level was checked in 12 of 13 who completed 3 doses of vaccination. The remaining 7 patients had either 1 or 2 doses of vaccine and were not available for follow-up. Of the 12 patients, 2 (16.6%) had a fully protective response, 2 (16.6 %) had a poor response and 8 (66.7 %) had no response. A fourth dose of vaccine was given to 5 patients. Of these, one had a poor response to the initial 3 doses but showed a fully protective response to the fourth. Of the 4 patients with no response to the 3 initial doses, one (33.3%) had a poor response to the fourth dose of vaccine and 2 no response. A response was not determined in the fourth patient. The mean pre- and post-vaccination CD4 counts of 435 and 367, respectively, among the responders was not significantly higher than the corresponding CD4 counts of 377 and 332 among nonresponders. Two of the nonresponders progressed to AIDS within 3 years of diagnosis of their HIV infection. The researchers found a positive response to vaccination in 4 of 12 patients (33.3%) with fewer than 660 CD4 cells. Hepatitis B vaccination results in a much higher response rate of 80-90% among HIV negative individuals who are immunocompetent. The response rates among immunocompromised individuals show a marked difference according to the type of vaccine used. The response rate to plasma-derived vaccine is 50-56% compared with a lower response range of 20-40% following the use of recombinant hepatitis vaccine in asymptomatic HIV positive individuals (Loke, 1990). In the study reviewed here, the response rate from the Engerix B recombinant vaccine was 33.3%. Additional doses and/or higher doses of hepatitis B vaccine may be required to overcome the relative unresponsiveness to hepatitis B vaccine among HIV positive individuals, according to Drs. Tayal and Sankar. An optimal dose in this population might include a higher dose (e.g., 40 mcg/dose) or a higher number of doses (e.g., at 0, 1, 6 and 9 or 0, 1, 2 and 12 months). Further studies are needed to determine the optimal regimen for hepatitis B vaccination of HIV positive individuals. Carne CA and others. Impaired response of homosexual men with HIV antibodies to plasma derived hepatitis B vaccine. British Medical Journal 294: 866-868. 1987. Loke RHT and others. Diminished response to recombinant hepatitis B vaccine in homosexual men with HIV antibody: an indicator of poor prognosis. Journal of Medical Virology 31: 109-111. 1990. Tayal SC and Sankar KN. Impaired response to recombinant hepatitis B vaccine in asymptomatic HIV infected individuals. AIDS 8(4): 558-559. April 1994. LABORATORY MARKERS Triglyceride Levels in Asymptomatics A 1993 report described elevated triglyceride levels (hypertriglyceridemia) in association with lower survival rates in 58 people with AIDS and suggested that hypertriglyceridemia might be a useful marker for HIV disease progression (Gonz_lez-Clemente, 1993). In contrast, a recent study of 94 HIV positive individuals concludes that mean levels of triglyceride among asymptomatics are not significantly different from those of healthy, HIV negative controls (Baum and Shor-Posner, 1994). Drs. Baum and Shor-Posner also conclude that serum triglyceride levels do not appear to be associated with indicators of immune function during early HIV infection. They found no significant correlation between triglyceride levels and CD4 count, CD8 count, CD4/CD8 ratio or B2-microglobulin level. Further, an analysis conducted over 18 months indicated that triglyceride levels were not associated with survival or stage of disease progression. Baum MK and Shor-Posner G. Normal triglyceride levels in early HIV-1 infection (letter). AIDS 8: 131-132. January 1994. Gonz_lez-Clemente IM and others. High triglyceride levels as a predictor of mortality in AIDS patients. AIDS 7: 1022-1023. 1993. Lowered Cholesterol in Early HIV Infection A 1993 study demonstrated that lowered cholesterol levels (hypocholesterolemia) are prevalent in early HIV infection (Shor-Posner, 1993). Disturbances in cholesterol metabolism appear to precede the development of hypertriglyceridemia (elevated triglyceride levels) in HIV infection (Grunfeld, 1992). Researchers also have shown that low values of total, high-density and low-density cholesterol are significantly associated with elevated B2-microglobulin levels (Rubsamen-Waigmann, 1991). This finding suggests that hypocholesterolemia may contribute significantly to immune dysfunction in early HIV infection and therefore may be a reliable marker for disease progression, according to the authors. Grunfeld C and others. Lipids, lipoproteins, triglyceride clearance and cytokines in human immunodeficiency virus infection and the acquired immunodeficiency syndrome. Journal of Clinical Endocrinologic Metabolism 74: 1045-1052. 1992. Rubsamen-Waigmann H and others. Markers for HIV disease progression in untreated patients and patients receiving AZT: evaluation of viral activity, AZT resistance, serum cholesterol, B2-microglobulin, CD4+ cell counts, and HIV antigen. Infection 19 (supp): S77-S82. 1992. Shor-Posner G and others. Hypocholesterolemia is associated with immune dysfunction in early human immunodeficiency virus-1 infection. American Journal of Medicine 94: 515-519. 1993. MISCELLANEOUS HSV-1 and HIV Enhance Each Other's Replication Coinfection of tissues by HIV and HSV-1 particles in non-genital herpes simplex lesions among people with AIDS significantly enhances the replication of both viruses, resulting in the production of increased numbers of both HIV and HSV-1 virions, according to study results published in a recent issue of The Lancet. This new finding suggests that HSV-1 may be a significant cofactor in HIV disease progression, and supports the use of suppressive therapy with acyclovir for herpes simplex infection among people with HIV infection. In the abstract of their article the authors state: "HIV uses the CD4 molecule_as a receptor for entry into host cells. In tissues co-infected with herpes simplex type 1 (HSV-1), HIV virions were observed to infect keratinocytes, which, because they lack the CD4 molecule, are normally incapable of being infected by HIV." "Although a number of other viruses have been reported to enhance HIV viral transcription in vitro, this is the first in-vivo report to our knowledge of reciprocal enhancement of viral replication associated with co-infection of keratinocytes and macrophages by HIV and HSV-1 in patients with AIDS and non-genital herpes simplex lesions." Heng MCY and others. Co-infection and synergy of human immunodeficiency virus-1 and herpes simplex virus-1. The Lancet 343: 255-258. January 29, 1994. ********** Selected Open Clinical Trials for HIV/AIDS Treatments Leslie Hanna The following studies are actively recruiting for participants. For further information, call the number provided with the individual listing or call the AIDS Clinical Trials Information Service (ACTIS) toll-free at 1-800-874-2572 (1-800-TRIALS-A). This government-sponsored service can provide information about many of the following trials, but can only provide information about privately sponsored trials when the sponsor has elected to give ACTIS that information. Treatment for HIV Infection L-735,524 (protease inhibitor) This Phase II clinical trial will look at the safety and tolerability of a higher dose of the Merck protease inhibitor than previously studied, alone and in combination with other anti-HIV agents. Specifically, participants will be randomized to 1 of 3 treatment arms: (1) 600 mg L-524 plus AZT plus ddI, (2) 600 mg L-524 or (3) AZT plus ddI. The study lasts for 6 months. Entrance requirements include less than 500 CD4 (T-helper) cells and no greater than 2 weeks of prior use of AZT and/or ddI. Individuals must discontinue using ddC 2 weeks prior to treatment, and d4T, 3TC or another experimental agent 30 days prior to treatment. There are multiple sites. In San Francisco, call the Conant Medical Group at 415-923-0222. saquinavir (protease inhibitor) high-dose study This study will randomize 40 people to 2 treatment arms, and will take place at Stanford University in Palo Alto, CA. Participants in arm 1 will take 600 mg of Hoffman La-Roche's protease inhibitor, saquinavir, 6 times daily; those in arm 2 will take 1,200 mg 6 times daily. Entrance requirements include 200-500 CD4 cells, less than 3 months prior use of AZT and less than 2 weeks prior use of ddC or ddI. Participants may be p24 antigen positive or -negative. Call Jane Norris, PA, at 415-723-2805. saquinavir (protease inhibitor) and ddC This 40-center Phase III study will involve 1,200 participants. The trial is open to people with HIV with 50-300 CD4 cells who have failed on AZT. Prior use of ddC, ddI or d4T must not be greater than 2 weeks. There are 4 treatment arms: (1) saquinavir monotherapy, (2) ddC monotherapy, (3) ddC plus low-dose saquinavir and (4) ddC plus high-dose saquinavir. For more information about the international and North American trials of saquinavir, call 1-800-526-6367. saquinavir (protease inhibitor) and AZT This study compares saquinavir to AZT. Partipcipants will be randomized to take protease alone, AZT alone, or protease inhibitor in one of 2 doses with AZT. Some sites are still open. Call 1-800-526-6367. A-84538 (protease inhibitor) A protease inhibitor manufactured by Abbott, called A-84538, is now entering Phase I safety studies in New York City, St. Louis, and at sites in Alabama and in Europe. HIVIG plus AZT vs IVIG plus AZT for pregnant women HIVIG, a solution of concentrated antibodies, is a type of passive immunotherapy. ACTG 185 is a Phase III trial that compares HIVIG to IVIG for efficacy in preventing transmission of HIV from mother to infant. Participants are randomized to take either HIVIG or IVIG; all participants take AZT. Mothers are given AZT intravenously during labor. Infants receive the same treatment as mothers. Newborns also receive either intravenous HIVIG or IVIG, within 12 hours of birth, and a syrup formulation of AZT for 6 weeks. There are numerous sites nationwide. nevirapine, AZT, ddI and ddC ACTG 193A is a Phase II/III, double-blind, placebo-controlled trial that compares various combinations of antiretrovirals. Participants are randomized into 4 treatment arms: (1) nevirapine, AZT and ddI, (2) AZT and ddC, (3) AZT and ddI, or (4) AZT and ddI taken in 1-month, alternating cycles. Participants have less than 50 CD4s, and do not have acute or chronic pancreatitis. HIV gene mutation and antiretroviral treatments ACTG 244 is a nationwide, multicenter study that compares the effectiveness of various antiviral regimens in people with HIV. Using a special test, the study will determine whether or not participants have developed a specific viral mutation, at codon 215 of the HIV genome, which is associated with the development of resistance to AZT. Thus, the study also will explore issues involved in determining when to switch from AZT to another anti-HIV drug. Participants will take one or more of the following drugs: AZT, ddI and nevirapine. The trial is open to people with 300-600 CD4 cells who have taken AZT for more than 1 month but less than 2 years. SC-49483 vs AZT for inhibition of syncytia formation ACTG 259 is a study of SC-49483, a new drug that may help prevent the formation of syncytia, which are clumps of infected and healthy immune cells that are targeted for elimination from the bloodstream. Syncytia formation is an event associated with disease progression. Entrance requirements include 50-350 CD4 cells and less than 6 months prior use of AZT. GS-840 A Phase I study of an oral drug known as GS-840 (also called BIS-PON PMEA) is underway. Manufactured by Gilead Sciences, GS-840 is a prodrug of another Gilead Sciences product, GS-393, or PMEA, which is in ongoing Phase I/II clinical trials. GS-840 is designed to be efficiently converted in the body into GS 393 and to achieve the highest possible bioavailability. Ongoing trials of GS 393 or PMEA demonstrated an association between taking the drug and decreased levels of p24 as well as increases in CD4 cell counts. Call Dr. Paul Leitman at Johns Hopkins University at 410-955-9707. thalidomide Thalidomide (Synovir) inhibits tumor necrosis factor (TNF), a cytokine associated with HIV-related wasting syndrome and increased HIV replication. There are 2 open-label Phase I trials underway that look at the anti-HIV effects of thalidomide; one focuses on whether thalidomide is an effective treatment for HIV-related weight loss. Two other trials independently evaluate the drug for the treatment of apthous ulcers and of tuberculosis. Celgene, the manufacturer, and NIAID/ACTG will cosponsor an upcoming Phase II trial of thalidomide for the treatment of cachexia (HIV-related wasting), with weight gain as the primary clinical endpoint. GEM 91 This Phase I study of an antisense therapy made by Massachussetts-based Hybridon called GEM 91 will evaluate its pharmacokinetic and safety profiles. Antisense is a new type of therapy. In preliminary studies in Europe, GEM 91 has shown a strong ability to inhibit HIV replication by disrupting the process at its genetic base. The initial U.S. studies will take place at the University of Alabama in Birmingham. 935U83 This Phase I study of 935U83 (a nucleoside analog) will evaluate the safety, tolerance and pharmacokinetics of various oral doses of the drug. The study is open to people with 200-500 CD4 cells, not more than 1 month's prior use of nucleoside analogs (AZT, ddI, ddC, d4T) and no prior use of non-nucleoside reverse transcriptase inhibitors. delavirdine (DLV) and AZT A Phase II/III randomized, double-blind study of the BHAP compound delavirdine (DLV), a non-nucleoside reverse transcriptase inhibitor, will look at 3 fixed doses of DLV plus AZT vs AZT alone to examine safety, tolerance and preliminary efficacy of the combination. This 6-month study will enroll asymptomatic, HIV positive individuals with 200-500 CD4 cells. Exclusion criteria include prior use of AZT for longer than 4 months, AZT intolerance and prior use of ddI, ddC, d4T or 3TC. In San Francisco, call Mark Bowers at St. Francis Memorial Hospital at 415-353-6215. For information on other study sites, call the Upjohn AIDS Hotline at 1-800-432-4702. delavirdine (DLV) and ddI This Phase II/III randomized, comparative trial will evaluate the safety, tolerance and efficacy of DLV in combination with ddI vs ddI alone. Participants have 300 or fewer CD4 cells and less than 4 months prior ddI experience (unlimited AZT experience is permitted). One arm will receive ddI and 400 mg DLV; the other arm will receive ddI and placebo. For study sites and more information, call 1-800-432-4702. Note: participants in both DLV studies described here who do not respond to the study treatment will be eligible for open-label, triple-drug therapy containing DLV. atevirdine Atevirdine, another BHAP compound manufactured by Upjohn, is synergistic with AZT. This one-year, multicenter Phase II trial randomizes participants to one of 3 arms: (1) atevirdine 600 mg/day plus AZT, (2) atevirdine 200 mg/day plus AZT, or (3) placebo plus AZT. Participants will have 50-350 CD4 cells, have had 1 or more opportunistic infection(s), and have been taking AZT for at least 3 months. For information about trial locations, call 1-800-432-4702. PMEA The National Cancer Institute (NCI) is conducting a Phase I/II dose-ranging study of the safety and efficacy of the combination of AZT and PMEA, a nucleoside analog like AZT, known to be active against herpesviruses and HIV. PMEA is given in IV form 3 times a week. Participants have less than 500 CD4 cells. Call Sergio Bauzo of NCI at 301-496-8959. thymopentin Thymopentin, derived from a natural hormone, stimulates the immune system. This Phase III double-blind, placebo-controlled trial will evaluate the safety and efficacy of thymopentin (Timunox) in HIV positive individuals taking an anti-HIV drug(s). Specifically, participants are randomized to receive thymopentin with AZT or ddI, or AZT combined with ddI, or AZT combined with ddC. A previous study indicated that the combination of thymopentin and AZT was more effective than AZT alone in slowing HIV disease progression. A related Phase II placebo-controlled trial will look at the impact of various doses of thymopentin on viral load; the study is open to people with less than 400 CD4 cells. oral hypericin (VIMRxyn) The NIH is sponsoring a trial of oral hypericin, an antiviral compound made by VIMrx. The Phase I/II trial will evaluate the efficacy of a daily oral regimen. Eligibility requirements include being p24-positive and having less than 350 CD4 cells. Efficacy will be evaluated by measuring p24 antigen levels and viremia using cultures and PCR. Study sites are New York University Medical Center/Bellevue Hospital, Beth Israel Hospital in Boston, MA, and Johns Hopkins University in Baltimore, MD. short-term AZT for primary infection This NIAID trial, DATRI 002, will evaluate the effect of short-term daily doses of AZT in people recently infected by HIV. The p24 antigen test will be used to determine eligibility. Participants will be randomized to receive either 1,000 mg/day AZT or placebo for 24 weeks. CD4 cell counts will be measured during and after the 24-week period to determine whether or not taking AZT produced an increase in CD4 cells. ViRx gene therapy screening and treatment (San Francisco Bay Area) Two sequential studies will first screen and then provide a new treatment to people with at least 350 CD4 cells. In the screening phase, blood tests will determine participants' human leukocyte antigen (HLA) type, the type of genetic marker found on white blood cells, which has predictive value about certain immune system characteristics. Lab work and clinical evaluations are free. People who meet the HLA and CTL requirements, and who have never used HIV immunotherapy or vaccine therapy, will be eligible for the treatment study. (The treatment study will evaluate the ability of injected treatments derived from mouse virus to enhance the immune system's ability to destroy HIV-infected cells.) Call ViRx at 415-474-2233. The Conant Medical Group in San Francisco is conducting a similar screening study of 100-200 people to identify about 50 candidates for a future study of "gene transfer technology" for the treatment of HIV disease; call 415-923-0555. BuCast in San Francisco BuCast is a compound closely related to a chemical (castanospermine) that is naturally found in a particular variety of chestnut trees. Laboratory studies have shown that castanospermine prevents HIV replication, and prevents HIV from binding to host cells. HIVCare is conducting a Phase I study to establish a maximum tolerated single dose and to evaluate the safety and pharmacokinetics involved in using the agent over a period of 2 weeks. Participants have at least 500 CD4 cells. For more information call Mark Bowers at 415-353-6215. N-acetylcysteine (NAC) trial in San Francisco Sponsored by the National Cancer Institute, this 8-week study will look at the effects of oral NAC on glutathione levels inside T-cells in people with HIV. The reduced levels of glutathione in many people with HIV may promote an increased rate of viral replication. NAC is a prodrug that is converted in the body to cysteine and then to glutathione. Participants will receive either NAC or placebo. Inclusion criteria include reduced glutathione levels and a CD4 cell count equal to or less than 500. Concurrent use of AZT, ddI, ddC or d4T is permitted as long as therapy began at least 4 months prior to the beginning of the study. Exclusion criteria include current use of NAC, OTC, cysteine or glutathione; use of Trental; B-cell lymphoma; and any acute opportunistic infection requiring treatment. For more information, call David Hook, RN, Laura Goldbaum, RN, or Greg Dubs at 415-863-8090. Children non-Hodgkin's lymphoma The National Cancer Institute (NCI) is conducting a pilot study of 2 drugs, systemic cyclophosphamide and methotrexate, for the treatment of HIV-related non-Hodgkin's lymphoma in children. The drugs under study are considered the 2 most effective drugs for treating childhood lymphomas. During the study, participants will continue to use antitretroviral therapy as well as IV gamma globulin, acyclovir and PCP prophylaxis to minimize the risk of complicating infection. The treatment period is 2 1/2 months. The age range is 3 months to 18 years. For more information, call the NCI at 301-496-2321. nevirapine, AZT and ddI This 3-drug combination pilot study is open to children already taking AZT and ddI. Nevirapine will be added to the participant's ongoing regimen, which will continue at the same dose level. Participants must have been using AZT and ddI for at least 12 weeks before entering the study. CD4 cell requirements are: children 1-11 months, greater than 1,750; children 12-23 months, greater than 1,000; children 24 months-5 years, greater than 750; and children 6-18 years, greater than 500. Lymph node biopsies will be performed the week before adding nevirapine, and at 24 weeks. Call Susan Sandelli, RN, at the NCI at 310-402-1391. AZT, ddI and 3TC This Phase I/II study will evaluate the safety and tolerability of different combinations of all 3 agents. Participants will be assigned to treatment arms according to previous experience with antiretroviral therapy. Children with less than 6 weeks of (or no) prior therapy will be assigned to arm A; children with prior therapy will be assigned to arm B. Participants in arm A will receive combination therapy with all 3 drugs, but will be assigned to 2 different doses of AZT. Those in arm B will be assigned to a treatment regimen and dose level based on their medical histories and prior use of antiretrovirals. Specifically, those with prior toxicity to ddI will take AZT and 3TC; those with prior toxicity to AZT will take ddI and 3TC; those with prior toxicity to both AZT and ddI or with progressive HIV will take all 3 drugs but a reduced dose of AZT. Call 301-496-4256. Immune Modulators interleukin-12 (IL-12) The first Phase I studies of recombinant (genetically engineered in the laboratory) human interleukin-12, a protein that stimulates the cell-mediated immune response, will take place in San Francisco and Los Angeles. About 40 people with HIV and 100-500 CD4 cells who are on stable antiretroviral therapy will be enrolled at each site. Investigators will evaluate the safety of a single dose of IL-12; about 75% of the participants will receive IL-12 and about 25%, placebo. In Los Angeles, call Dr. Hardy, Suzette Chafey or Rob Noga of the UCLA Center for AIDS Research and Education at 310-206-6414. In San Francisco, call Anna Martinson of the UCSF AIDS Program at 415-476-9296. interleukin-2, CD8+ cell infusion and antiretroviral therapies This Phase II trial will compare the safety and efficacy of 5 different combinations of recombinant IL-2, CD8+ cell infusion and standard antiretroviral therapy (AZT, ddI, ddC or d4T, singly or in combation). Participants will be randomized to 1 of 5 arms: (1) antiretroviral therapy alone, (2) antiretroviral therapy plus low-dose IL-2, (3) antiretroviral therapy plus high-dose IL-2, (4) antiretroviral therapy plus low-dose IL-2 plus CD8+ infusions, or (5) antiretroviral therapy plus high-dose IL-2 plus CD8+ cell infusions. There is no placebo. Eligibility requirements include more than 250 CD4 cells and 800 CD8+ cells, and current, stable anti-HIV therapy (at least 12 weeks before beginning the study). Contact Brian Camp, RN, at the AIDS Community Research Consortium at 415-364-6563, or call ViRx at 415-474-2233. Treatment for Opportunistic Infections oral ganciclovir for maintenance treatment of CMV retinitis Syntex Research is sponsoring an open-label safety study of oral ganciclovir for maintenance treatment for CMV retinitis. Enrollment may be made through any licensed physician in the U.S. and Canada. Participants have stable CMV retinitis; treatment with IV gancicvlovir or foscarnet during at least 18 of the last 21 days prior to study enrollment; known difficulty with tolerating the IV catheter; no known sensitivity to acyclovir or ganciclovir. oral ganciclovir to prevent CMV infection NIAID CPCRA 023 will evaluate the effectiveness of oral ganciclovir in preventing CMV infections of the retina and gastrointestinal tract, the most common sites of CMV infection. Oral ganciclovir is easier and safer to take than IV ganciclovir. Participants have CD4 counts less than 100 and will receive either 3 grams ganciclovir per day or placebo. The 12-month monitoring period will be followed up with 12-24 months of follow-up. azithromycin for the prevention of MAC disease This study evaluates the safety and effectiveness of weekly azithromycin for the prevention of MAC disease in people with fewer than 100 CD4 cells. Participants take azithromycin or placebo. Criteria include not having had a positive MAC culture within 1 month of beginning the study, and no treatment with any anti-MAC drugs within the last 4 weeks. amphotericin B, fluconazole and itraconazole to treat cryptococcal meningitis ACTG 159 is a multicenter, Phase I/II comparative trial. For the first 2 weeks of the study, participants will receive either amphotericin B alone or in combination with flucytosine. Then, for 8 weeks afterward, half will take fluconazole and half will take itraconazole. Treatment for Malignancies and Cancers 5-FU for cervical dysplasia 5-FU is a cream applied intravaginally for preventing and treating cervical cancer. ACTG 200, a Phase II/III trial of safety and efficacy, compares the use of intravaginal 5-FU to observation for maintenance treatment of cervical dysplasia. After standard treatment for high-grade cervical dysplasia, women participants are randomized to receive treatment (topical intravaginal administration of 5-FU) or to be observed. There are numerous sites nationwide. interleukin-4 (IL-4) for Kaposi's sarcoma (KS) ACTG 224 is a Phase I/II open-label, dose-ranging study of IL-4 for treating KS. In Boston call Dr. Scadden at 617-632-8528 and in Los Angeles call Dr. Miles at 310-206-6414. For more information about another Phase II open-label trial of IL-4 for KS, call Dr. Gill in Los Angeles at 213-343-8275. photodynamic therapy for KS: Tin Ethyl Etopurpin and lasers This Phase I/II trial looks at the safety and effectiveness of photodynamic therapy for cutaneous KS. The drug Tin Ethyl Etopurpin is injected directly into lesions, followed by irradiation of the lesions with a laser. All participants receive treatment for a period of only a few days. Participants must have at least 3 measurable KS lesions that have been not been treated within the last 30 days. Contact Margot Whitfield at UCSF/SFGH Dermatology Department at 415-206-6099. implants of 5-FU and MPI 5003 for KS This open-label, Phase II study looks at the safety and efficacy of intralesional drug implants for treating cutaneous lesions of Kaposi's sarcoma. Participants will receive implants of either of 5-FU or MPI 5003, or of the 2 combined, or placebo, into 4 lesions. Entrance requirements include greater than 4, but fewer than 52 red-to-purple colored KS skin lesions, and no prior treatment for KS. At the UCSF/SFGH Dermatology Department, contact Timothy Berger at 415-206-8680 or Margot Whitfeld at 415-206-6099. Treatment for Wasting Syndrome and Myopathy human growth hormone Serono Laboratories is sponsoring a trial to evaluate the efficacy of their recombinant human growth hormone, Saizen, in promoting weight gain in people with HIV infection. Saizen stimulates lean tissue production. Twenty-five (25) centers nationwide will enroll 180 individuals. Eligibility requirements include documented unintentional weight loss and use of an antiretroviral drug (AZT, ddI, ddC or d4T). For the first 3 months, one group will receive human growth hormone; the other, placebo. After that, all participants will receive growth hormone for an indefinite period of time. For information about nationwide sites, call Gina Cella of Serono Laboratories at 800-283-8088, extension 5251. inhaled marijuana vs Marinol An FDA-approved pilot study will compare inhaled marijuana to the synthetic THC drug, Marinol, for use in promoting weight gain in people with HIV-related wasting syndrome. For information about this San Francisco Bay Area trial, call 415-476-9554. L-carnitine for myopathy (muscle weakness/degeneration) L-carnitine is a natural biochemical that stimulates the oxidation and synthesis of fatty acids. The NIH is conducting a Phase II placebo-controlled trial to evaluate L-carnitine as a treatment for myopathy, which in some cases is a side effect associated with use of AZT. Call Dr. Cupler at the National Institute of Neurological Disorders and Stroke (NIND), a division of NIH, at 301-402-4479. Clinical Trials Information by Region SAN FRANCISCO BAY AREA 415-476-9554 SOUTHERN CALIFORNIA HIV TREATMENT DIRECTORY 213-469-5888 AIDS/HIV TREATMENT DIRECTORY FOR NEW ENGLAND 617-424-1524 NEW YORK, CONNECTICUT, NEW JERSEY AND PHILADELPHIA 212-268-4196 AIDS Institute Experimental Treatment Infoline in New York state: 800-MEDS-4-HIV outside New York: 212-239-5523 DIRECTORY OF WISCONSIN HIV/AIDS CLINICAL TRIALS in Wisconsin: 800-359-9272 outside Wisconsin: 414-291-2799 NORTHERN GEORGIA & ALABAMA 404-874-7926 GULF COAST REGION 504-584-3605 HOUSTON CLINICAL TRIAL NETWORK 713-520-2083 CANADIAN HIV TRIAL NETWORK 604-631-5327 ACTIVELY RECRUITING U.S. TRIALS AmFAR Treatment Directory 212-682-7440 Drug information and Clinical Trial Hotline 1-800-874-2572 English and Spanish Monday through Friday, 9 am _ 7pm EST Free Up-to-date information and customized searches of the National Clinical Trials Database. ------------------------------------------------------------ CORRECTIONS It is a policy of BETA to correct factual errors. We regret these errors and any misunderstanding they may have caused. In the March 1994 issue of BETA, the dosage units for the B vitamins in the chart on page 5 entitled "Therapeutic Use of Nutrients in HIV Infection" were mistakenly reversed. The RDA for vitamin B6 is 2 milligrams (mg) and the therapeutic doses in use are 20-100 mg/day (not micrograms). The text in the Possible Toxicities column should read "greater than 300 mg/day can lead to peripheral neuropathy." The RDA for Vitamin B12, on the other hand, is 2 micrograms (mcg), not milligrams, and the therapeutic uses in dose are 50-500 micrograms. Copyright 1994. Bulletin of Experimental Treatments for AIDS (BETA) is a quarterly publication of the San Francisco AIDS Foundation (SFAF). Reproduced with permission. Reproduction of this article (other than one copy for personal reference) requires written consent from the SFAF. For subscription information, please contact the BETA Subscription Office at 1.800.959.1059. To contact BETA via the Internet, the E-mail address in: beta@sfsuvax1.sfsu.edu. Please note that subscriptions are not available via the Internet.