BETA (Bulletin of Experimental Therapies for AIDS) Online No. 23-- December 1994; Electronically Distributed for GENA/aegis, your online global freeway to a world of people, knowledge and resources. 714.248.2836 * 8N1/Full Duplex * v.fc/v.34 ************************************************************* TI Cryptosporidium & Other Environmental Pathogens DT 9412 AU Leslie Hanna; associate editor of BETA. SO BETA (Bulletin of Experimental Therapies for AIDS) Online - No. 23; Published by the San Francisco AIDS Foundation - December 1994 TX Cryptosporidiosis A recent Dateline television special and articles in the mainstream press have brought Cryptosporidium parvum to the attention of the general public. Cryptosporidium is an extremely tiny parasite found in animal and human feces. It can be transmitted by fecal-oral contact, or ingestion of contaminated soil or unpeeled fruits or vegetables grown in contaminated soil. Another vector of transmission for the parasite is water. In 1993 there was a well-documented outbreak of cryptosporidiosis in Milwaukee, Wisconsin, in which filtration system problems led to contamination of the water supply. Like many environmental pathogens, such as the mycobacteria that cause Mycobacterium avium complex (MAC), Cryptosporidium is ubiquitous. Based on antibody testing in small sample groups, it is estimated that 40-80% of people are exposed to Cryptosporidium at some time in their lives. Infection, Clinical Symptoms and Treatment In humans, infection with Cryptosporidium is usually localized in the gastrointestinal tract, but may occasionally involve the biliary tract and/or lungs. Cryptosporidiosis commonly manifests as diarrhea, accompanied by abdominal pain and cramping, vomiting and anorexia. Immunocompetent individuals who acquire the parasite are generally able to self-limit any resulting infection: after a few days, gastrointestinal symptoms resolve and the infection clears. During the symptomatic phase, even an immunocompetent person will shed infectious oocysts in the stool. Oocysts may be excreted up to 1-2 weeks after clinical improvement. Oocysts are environmentally protected "egg-cyst" capsules formed during the dormant stage of the parasitic life cycle. Inert and not growing, they nevertheless may be infectious. Very resistant to damage, oocysts can survive being soaked in chlorine bleach. Immunocompromised persons, such as people with AIDS, are more susceptible to infection. Severely immunocompromised persons may develop fulminant infection, or extremely severe infection that develops rapidly. Cryptosporidiosis may cause abdominal pain, severe diarrhea and extreme debilitation, and can interfere with the absorption of medications taken for other infections. Chronic cryptosporidiosis in a person with HIV infection is an AIDS-defining condition. It is theoretically possible that immunocompromised persons achieve self-limiting infection but are unable to clear the parasite, i.e., their immune system defenses may succeed in reducing levels of the parasite so that symptoms resolve, but without eliminating the parasite. This raises the theoretical possibilities of asymptomatic shedding and reactivation. It is not yet known if asymptomatic or latent cryptosporidial infection occurs, or if an infected asymptomatic person might shed the parasite in their feces and thus infect others. It is also unknown whether cryptosporidial infection in people with AIDS is due to new infection or to reactivation of latent infection. Unfortunately, there is no effective treatment for cryptosporidiosis. Paromomycin (Humatin), not widely available in the U.S., and azithromycin (Zithromax) are most commonly used to treat the disease, but these agents cannot eradicate the parasite in people with AIDS. The San Francisco Bay Area Picture It is somewhat difficult to prescribe reasonable measures that an individual can take to prevent acquisition of Cryptosporidium, beyond avoiding water known to be contaminated and contact with animals and people known to be infected. BETA spoke with several San Francisco Bay Area authorities who work in the areas of water quality control, epidemiology, public health and healthcare about Cryptosporidium and related issues. The current public focus is on water as a potential source of Cryptosporidium, so the quality of the local water supply was the first line of inquiry. Is water regularly tested and monitored? Are there guidelines about water contaminants? What can one do on an individual basis to minimize chances of exposure? Would using only distilled, bottled or boiled water be protective? What kinds of home filtration systems are effective? Water quality varies greatly from one area to another. BETA surveys the municipal water situation in the San Francisco Bay Area as an example of what may be happening in other large urban settings in the U.S. For details about the risk of Cryptosporidium in other areas, consult local health authorities. San Francisco Department of Public Health AIDS Office The water in San Francisco is supplied by the Hetch Hetchy and local reservoirs (San Andreas, Crystal Springs, Calaveras and San Antonio). Water obtained from Hetch Hetchy is unfiltered because it is collected at high altitudes in Yosemite National Park and is well protected from sediment, debris and sanitary problems. Water from local supplies, on the other hand, is filtered before delivery to San Francisco because local watersheds have higher sediment levels. Although owned and protected by the San Francisco Water Department (SFWD), these watersheds do not match the quality of Hetch Hetchy. The unfiltered water serves 80% of all San Francisco customers. For the past 2 years, the San Francisco Department of Public Health has been looking for an association of Cryptosporidium with filtered or unfiltered water. Water Quality Testing and Assurance Andy Moran, General Manager of the San Francisco Public Utilities Commission (PUC), says that public water suppliers operate under a host of regulatory controls including various Environmental Protection Agency (EPA) guidelines, the Clean Water Act and the Safe Drinking Water Act. The PUC works with the State Department of Health Services, the City Health Department and, specifically in the case of Cryptosporidium, with the medical community. Locally, the PUC has worked for several years in collaboration with providers of healthcare for immunocompromised people to determine which organisms are risky. Cryptosporidium was identified as a pathogen in the mid-1980s. The SFWD is vigilant about testing, partially out of concern for immunocompromised residents. About 3 years ago the SFWD voluntarily implemented a method for detecting Cryptosporidium. The test involves running a high volume of water through a filter. The particulate materials caught by the filter are pulverized, centrifuged and examined under a microscope to identify oocysts. This data is then shared with the Department of Health Services. Most local samples are free of Cryptosporidium, with an average occurrence rate of 0.2 oocysts/100 liters of water, or 1 oocyst in 500 gallons. The SFWD has never found any level that would be actionable under any regulatory criteria. While the quality of raw water is a factor--it can, for various reasons, become badly degraded with parasites--most cryptosporidial outbreaks have been associated with filtered water and failures in the water treatment process (and associated contamination of the raw water). Water treatment process failures have been caused both by error and improper maintenance and by inherent problems with the filtration systems. To clear or maintain filters in municipal water districts, regular servicing involves running water backward through the filter to flush it out. Some of this backwash water may be returned to the system before the filter is replaced, giving spores multiple opportunities to pass through. After the filter has been flushed and put back into regular operation, a "ripening process" takes place in which fine sediments lodge back into the filter, increasing its effectiveness. However, before the sediments have re-lodged, some particles may escape through the filter. Mechanical problems with the filters may pose occasional problems as well. Finally, water treatment facilities may experience Cryptosporidium problems by design, since most use a chlorination disinfection process that is ineffective against Cryptosporidium. Ozone, a powerful oxidant that works against many pathogens, appears effective against Cryptosporidium. Locally, 1 of the 2 filtering plants uses an ozone disinfection system, implemented specifically for its anti-Cryptosporidium action. According to Mr. Moran, the primary way the SFWD provides water quality protection is by "compulsively protecting" the watershed. "It is much easier to keep bad things out than to remove them," especially Cryptosporidium, which is difficult to remove from water supplies. Filtration does not guarantee protection against Cryptosporidium. Its extremely small size makes it difficult to remove, and Cryptosporidium is resistant to chlorination methods of disinfection (e.g., sodium hypochlorite disinfection) which are commonly used and which work well against other waterborne pathogens like cholera, Giardia, E. coli and viruses. The main watershed for San Francisco waters, in the High Sierras, is very pure; the watershed on the peninsula is restricted from contamination (e.g., no domestic animals pasture on this land, nor is it open to general public use). Levels of concern regarding Cryptosproidium may differ by region according to the nature of the watershed--e.g., if dairy cattle pasture on watershed areas. Currently, there is no regulatory framework to depend upon regarding Cryptosporidium, except what local authorities have elected to do. Although the EPA has been criticized for a lack of regulatory guidelines regarding Cryptosporidium, they generally have been informed that it does not pose a large public health risk. San Francisco Water Department Water Quality Control Philip Caskey, an assistant water quality manager with the SFWD, said that the Department routinely tests water supplies (such as storage reservoirs) on a variable weekly to monthly basis. Results of testing indicate an average presence of Cryptosporidium in Bay Area water supplies ranging from 0.1-0.3 oocysts/100 liters of water. Interestingly, tests of the unfiltered water derived from the Hetch Hetchy reservoir reveal about 0.14 oocysts/100 liters. There are strict criteria for unfiltered waters that supply municipal water districts. Mr. Caskey also said that the local philosophy is to prevent parasites from entering the water in the first place, removing the need for filtering which, evidence indicates, can in itself involve additional, potentially quite serious problems. Many waterborne Cryptosporidium and Giardia problems have been caused by filtration treatment failures (e.g., mechanical problems) that permit breakthroughs. In the absence of established, standardized definitions for "acceptable" levels of Cryptosporidium, Mr. Caskey said that "academic wisdom is zeroing in on 0.5-1.0 oocysts/100 liters as equal to a 10-4 risk." A 10-4 risk is a factor used by the EPA to establish an upper limit for essentially safe levels of contamination. (The EPA uses this risk threshold as a maximum contamination limit for waterborne substances such as chloroform or asbestos.) Since levels of Cryptosporidium in local water fall well below 0.5 oocysts/100 liters, risk is negligible. At present, answers to questions about tap water must be couched in qualified terms, in the absence of data that associates water levels with risk levels. The number of oocysts a person would need to ingest to become infected is unknown, and it is unclear what water levels can be correlated with actual risk of infection. Although the actual number of oocysts required to cause infection is unknown, it may be very small. There are other opportunistic pathogens of potentially greater concern for immunocompromised people, both known and as yet unidentified, Mr. Caskey added. Most of these are ubiquitous, existing in air, soil and water. Gastrointestinal distress in response to contact with various opportunistic pathogens is extremely common; often, the organism responsible is unidentified and likely unknown. Similarly, extremely common, ubiquitous bacteria frequently cause common infections--bacteria found on household and workplace surfaces and on animals, including humans. Research is being conducted to better understand routes of transmission and to quantify risks. San Francisco Department of Public Health According to Dr. Frances Taylor, head of Communicable Disease Control at the San Francisco Department of Public Health, there is currently no great concern about water as a source of infection with cryptosporidiosis for people in San Francisco. The available evidence suggests that more cases of cryptosporidiosis occurred among those receiving filtered water. Dr. Taylor is working to secure funding for a case-control study of Cryptosporidium, which would provide important information on local sources of infection. The overall incidence of reported cryptosporidiosis in San Francisco is low (138 cases reported for the 1993 calendar year). Nearly all identified cases are among immunocompromised persons. In fact, 83% of those with cryptosporidiosis in the study of filtered and unfiltered water have AIDS, and 95% of them are male. The remaining 17% are likely to be immunocompromised as well. One question raised by combining findings from small studies with epidemiologic data is, what other modes of transmission are relevant in San Francisco? A significant proportion of the cryptosporidiosis seen in San Francisco may be sexually transmitted (by fecal-oral contact, "rimming" or the use of sex toys). Many of the enteric infections common elsewhere, e.g., in daycare settings, in San Francisco are seen in adults and are known to be sexually transmitted (amebiasis, shigella, hepatitis A and possibly even giardiasis, as well as cryptosporidiosis). There is a strong likelihood that sexual transmission is a risk for cryptosporidiosis. Nonsexual, person-to-person contact in household settings may be a factor in cryptosporidiosis in the severely immunocompromised. There have been several reports in the medical literature of nonsexual transmission of cryptosporidiosis between family members. The greater than 100 annual cases of cryptosporidiosis in San Francisco, mostly in people with AIDS, arguably defines a public health problem. However, because the overall incidence is low and water quality is high, there currently are no specific local recommendations for action. Anti-Cryptosporidium Measures in the Home Although at present there are no data to indicate that Bay Area municipal water is a significant source of infection, there are a few things that can be done at home. The preventive measures and guidelines that follow apply to people living in other regions of the U.S., as well as the San Francisco Bay Area. Given the risks outlined above, some people have decided to boil water before drinking or toothbrushing. The organism is heat-sensitive; bringing water to a rolling boil for 1 minute will destroy it. There are a couple of problems with boiling water, however. First, boiling water can cause burns. Second, people often object to the taste of boiled water; lemon or other flavorings may be added to boiled water to improve its taste. People interested in taking these precautions should be careful not to ingest non-boiled or nondisinfected waters in other places and ways, including fountain beverages (mixed with tap water in fast-food establishments), reconstituted or non-pasteurized, bottled juices, and shower water. The other thing someone can do at home is to install a water filtration system. The consumer must research the product carefully to make sure it filters out particles smaller than 1-2 microns, the size of Cryptosporidium. Some filters only remove larger chemicals and minerals, like chlorine, that simply affect taste. A prospective buyer should carefully read all the product information before purchasing a system. If it says that it filters out viruses, it probably would filter out Cryptosporidium. Specifications on a good filter will include particle size on the apparatus; some filters mention specific organisms. The National Sanitation Foundation (NSF International) provides a listing of NSF-certified water filters that conform to public health safety standards for drinking water. Certification is based on consensus standards, or combined federal, state, local, user and industry standards. Filters indicated for the reduction of Cryptosporidium oocysts are certified against American National Standards Institute (ANSI)/NSF standard 53. Founded in 1944, NSF is a not-for-profit, nongovernmental consumer protection agency. Their telephone number is 313-769-8010 and their fax number is 313-769-0109. An equal if not greater concern is proper maintenance of the filters themselves--an improperly maintained filter can cause more problems than no filter at all. Improperly operated filters may grow bacteria that are pathogenic, especially for immunocompromised persons. Theoretically, oocysts might accumulate to high concentrations in the filter, precipitating a risk of household contamination when the filter at some point is flushed (a problem very similar, albeit on a smaller scale, to that which has occurred at large municipal filtration plants). Drinking bottled water is no assurance of avoiding Cryptosporidium. In California, bottled water is not regulated by special standards, thus there is no way to tell if there is mineral, chemical or bacterial contamination. While the bottled water may be safe, there is no way for the consumer to determine this. In general, bottled water standards are the same as those for public drinking water. (An estimated 25% of bottled waters on the market are derived from the same supplies as tap water.) NSF also provides consumer health information on bottled water. Distilled water is boiled, and commercially bottled sodas are probably filtered adequately for Cryptosporidium protection. Other bottled beverages such as juices are safe if pasteurized and non-reconstituted, and if they do not require refrigeration before opening. Other Environmental Pathogens Waterborne Pathogens Regarding waterborne pathogens in general, Legionella is the most likely to be a problem for immunocompromised persons. Legionella, which causes Legionaire's disease, is a ubiquitous inhabitant of water. It is found in tap water in every part of the country. More commonly, it is transmitted by humidified air, e.g., air ventilation systems and air conditioners. It does not constitute a concern for immunocompetent people except for the elderly. Legionella infections are not commonly seen in San Francisco (approximately 5 reported cases per year), but are of concern for severely immunosuppressed persons including organ transplant recipients and people with AIDS. Hospitals have tried hyperchlorination, ozone treatment and ultraviolet radiation of water to remove Legionella. Although Legionella is an important pathogen, recommendations about prevention of infection are difficult because it is so ubiquitous. Legionella is treatable with available antibiotics. See the June issue of BETA for an article on hospital and municipal water sources of Mycobacterium avium complex in the eastern U.S. Non-Waterborne Environmental Pathogens Of likely greater concern to immunocompromised persons are non-waterborne bacterial hazards, the most prominent of which are Salmonella and, possibly, Listeria. Salmonella is of particular concern for people with AIDS. Although HIV-related Salmonella is treatable with antibiotics, this may be an inadequate; prevention is critical. According to Dr. Taylor, all raw chicken must be assumed to be heavily contaminated with Salmonella. This translates into both making sure that chicken is well-cooked and paying scrupulous attention to handling and preparation. It is essential to sterilize surfaces such as cutting boards and instruments that come into contact with uncooked or undercooked chicken. It is also prudent to assume that eggs are contaminated (prior to being laid by the hen). There have recently been a series of Salmonella outbreaks associated with whole-shell eggs in southern California. There have been many in the past in the Northeast. Therefore, uncooked and undercooked eggs by themselves or as components of other foods must be avoided altogether, including: raw cookie dough (or batter for cakes, etc.), egg nog made with raw eggs, Hollandaise sauce and Caesar's salad dressing. Although some gourmet cooks protest that use of pasteurized eggs results in lower-quality dishes, Hollandaise and Caesar's salad dressing may be prepared with pasteurized eggs. (The San Francisco Department of Health is working to convince restaurateurs to use pasteurized eggs.) Other guidelines: * Always purchase eggs that are refrigerated. While it is impossible to tell whether the eggs were constantly refrigerated during transport, the consumer can at least avoid buying eggs that are left unrefrigerated, such as those sitting on the floor in certain shops. A small bit of Salmonella present in eggs is likely multiply to much larger numbers in the more nurturing conditions created by room temperature. * Be sure eggs are refrigerated at home and leave them in the refrigerator until ready to use. * Be sure eggs are cooked properly, because thorough cooking kills any Salmonella present. Avoid runny yolks: no eggs over easy, soft-boiled eggs, etc. Listeria, a bacteria, is another opportunistic pathogen of concern for people with AIDS. It appears that contaminated foods play an important role in listeriosis transmission. A 1992 study implicated certain foods as risk factors for listeriosis, which can cause encephalitis, meningitis and death (23% of listeriosis patients died). A case-control study that compared 165 listeriosis patients to 376 healthy controls found that those with listeriosis were more likely to have eaten soft cheeses (feta and Mexican-style cheeses) or foods from delicatessens (pate, cole slaw, hot dogs, sliced meats and block cheeses). In a related investigation, 79 of 123 listeriosis patients (64%) had at least one food item in their refrigerator that contained Listeria. Of men and nonpregnant women patients studied, 69% were immunosuppressed due to cancer, HIV/AIDS, a recent transplant or corticosteroid treatment. Pregnant women and the elderly also are at increased risk for listeriosis. Researchers recommend that people in listeriosis risk groups "avoid eating raw or undercooked foods of animal origin; avoid cross-contamination between raw and cooked foods during food preparation and storage [as might occur in store delicatessen counters]; reheat leftovers until too hot to touch; avoid soft cheeses such as feta and Mexican-style cheeses [versus hard cheeses, cottage cheese and cream cheese, which pose little risk]; raw vegetables should be thoroughly washed before eating." Products that may have been prepared from unpasteurized milk should also be avoided. Thus, despite recent publicity, cryptosporidiosis is only 1 of the threats from infectious organisms in the environment and, in San Francisco, actually poses a lesser threat than some others. Again, according to San Francisco Bay Area public health experts, people with HIV/AIDS who wish to take active precautions against environmental pathogens would be advised to first attend to avoiding Salmonella (chicken, eggs) and Listeria. Following are a number of enteric (food, water, fecal-born) illnesses of proven or theoretical concern to HIV-infected persons and the respective numbers of cases reported to the San Francisco Department of Public Health for 1993: amebiasis, 259; cryptosporidiosis, 138; giardiasis, 347; hepatitis A, 220; listeriosis, 4; salmonellosis, 200; shigellosis, 245. Conclusion The weight of the evidence suggests that, at least in the San Francisco Bay Area, water is not a significant source of cryptosporidial infection. There are a few measures that concerned individuals can implement. A home water filtration system, capable of filtering particles smaller than 1 micron (slightly smaller than the size of Cryptosporidium) may be effective. However, proper maintenance of the filters is necessary--failure to do so may result in greatly increased risk of infection from bacterial and other overgrowth, and potentially infection from parasites such as Cryptosporidium. The ubiquitous nature of Cryptosporidium and other pathogens makes tracing the source of infection difficult. In addition to persons with HIV/AIDS, other groups are also at risk, e.g., the elderly in nursing homes, cancer patients receiving chemotherapy, and children and workers in daycare centers. A multifaceted approach to modifying behaviors that may put one at risk may be most appropriate for the avoidance of Cryptosporidium as well as other potentially damaging pathogens (Giardia, Mycobacterium). Such behaviors include: (1) practicing good hygiene, i.e., washing hands often and especially before eating; (2) avoiding drinking from springs, lakes or streams; (3) wearing gloves and a mask when changing pet litter boxes; (4) avoiding contact with fecal material, pet/animal or human, and; (5) practicing safer sex behaviors to avoid fecal-oral contact (rimming, anal contact with sex toys or fingers and subsequent oral contact). Dr. Jack Colford of the UCSF Division of Infectious Disease and the UC Berkeley School of Public Health advises the severely immunocomprised patients in his practice not to swim in lakes or rivers. Risk of acquiring cryptosporidiosis from swimming in public pools is undefined (chlorine is effective against many pathogens in pools, but not Cryptosporidium). However, because the risks are theoretical and unproven, and there are no indications of actual risk, Dr. Colford does not advise his HIV positive patients to avoid swimming in public pools--in fact, he encourages swimming as an excellent form of exercise. Finally, sexual transmission of Cryptosporidium is likely to be of greater concern than transmission by water. References AmFAR AIDS/HIV Treatment Directory 7(3): 82-84. June 10, 1994. Colford J, MD, MPH, UCSF Division of Infectious Diseases/UC Berkeley School of Public Health. Personal Communication. November 4, 9, 1994. Caskey P, Assistant Water Quality Manager, San Francisco Water Department. Personal Communication. November 3, 1994. Leonard, S, Program Manager, Hetch Hetchy Water Treatment Program. Personal Communication. November 7, 1994. McKinney K, Field Unit AIDS Surveillance Coordinator, San Francisco Department of Public Health/AIDS Office. Personal Communication. October 28, 1994. Moran, A, General Manager, San Francisco Public Utilites Commission. Personal Communication. November 4, 1994. Pinner RW and others. Role of foods in sporadic listeriosis: II. microbiologic and epidemiologic investigations. The Journal of the American Medical Association 267: 2046-2045. April 15, 1992. Schuchat A and others. Role of foods in sporadic listeriosis: I. case-control study of dietary risk factors. The Journal of the American Medical Association 267: 2041-2045. April 15, 1992. Taylor F, San Francisco Department of Public Health/Epidemiology and Disease Control. Personal Communication. November 1, 1994. TI Women & HIV/AIDS: Nutritional Considerations for Women with HIV AU Leslie Hanna; associate editor of BETA. TX Nutritional interventions continue to gain prominence in the healthcare of persons with HIV, and knowledge about the interplay between nutritional status and HIV infection is slowly increasing. Little is currently known about the gender-specific needs of HIV-infected persons. While all women, HIV positive and negative, are likely to have certain nutritional needs that differ from those of men, most of the nutritional studies relating to HIV conducted thus far have been among men. Given an overall lack of research into nutrition and HIV, it is not surprising that there is little gender-specific nutritional data for women with HIV and their providers to rely upon or even to refer to. Despite the uncertainties, there are some general guidelines that HIV positive women can follow. HIV Infection Metabolism and nutrient needs change with the onset of HIV infection. Certain nutrients, including some known to play immune-supportive roles, are routinely deficient in HIV-infected persons (see "Vitamins, Minerals & Supplemention" below). As people with HIV live longer, due in part to advances in successful prophylaxis of opportunistic infections, appropriate nutritional interventions become even more important. Nutritional care may help avoid or counteract HIV-related depletion of nutrient stores, malnutrition, weight loss and wasting, which can be life-threatening. Optimizing nutritional status and lean body mass provide a foundation for maintaining health and weight, as well as for optimal absorption of any medications a person may be taking. Although different sorts of interventions may be needed at different stages of HIV disease, early, aggressive intervention is a key strategy. Nutritional Concerns of Women with HIV Many women with HIV are at least borderline malnourished, whether due to HIV or to secondary causes like suboptimal dietary patterns or eating disorders or drug use, according to Lisa Ploss, RD, MPH. Malnutrition itself depresses immunity, increasing susceptiblity to opportunistic infections that may lead to hospitalization, prolonged recovery and secondary complications. Malnutrition also adversely affects one's ability to absorb medications as well as his/her quality of life. Wasting may begin early in HIV disease, while CD4 cell counts are relatively high. Since women, whose early symptoms of HIV disease often go undetected, tend to present for healthcare later than men with HIV disease, one possibly gender-related challenge is to begin nutritional intervention with women as soon as possible, to protect against wasting and other conditions that may occur at any disease stage. A woman's nutritional status and needs are affected by her age, hormonal state (premenstrual, menstrual, pregnant, menopausal) and overall health (HIV and other conditions). Psychosocial and environmental factors are also influential, e.g., body image, caretaking and access to food. Women with HIV, especially those who care for children and/or other family members, may require special encouragement to take the initiative to care for their bodies. Nutrition is one of the relatively few areas in which the individual can exert a great deal of influence and control, says Kristen Weaver, RN, MSN, CNSN; doing so has immediate and long-term benefits both physically and psychologically. A dietitian familiar with and knowledgable about HIV disease can help HIV positive women of all ages and health statuses design and implement appropriate, individualized programs. Minimally, it is important for women with HIV and their providers to follow calorie intake, weight and, if possible, lean body mass. Age The nutritional needs of a woman with HIV will vary somewhat depending on her age, although, relative to HIV negative women, calorie requirements even for post-menopausal women remain high. The chronic inflammatory state that HIV causes means that calorie requirements remain high for women with HIV of all ages, according to Mary Romeyn, MD. Consistent with levels of growth and activity, the nutrient needs of HIV positive teenagers are high. During these years, a woman achieves 50% of her adult body weight and 15-20% of her height. Dietitians suggest that teenagers eat nutrient-dense snacks that are easy to make and similar to what their peers may be eating, such as blenderized drinks made with ice cream or yogurt, quesadillas and macaroni and cheese. Dairy products may be difficult to digest for HIV positive people of any age. Because lactose intolerance is common in persons with HIV, non-dairy substitutes may be preferable. For example, tofu, which is made from soybeans and may be used in e.g., place of cheese, is high in protein, easily digested and tastes good (because it easily absorbs the flavors of other cooking ingredients). Regardless of serostatus, pregnant women experience some degree of immunosuppression. HIV positive pregnant women may be at increased risk for developing various infections. Nutritional interventions are aimed at optimizing immune system strength. Ms. Ploss recommends adding 300 calories and 10 grams of protein daily to estimated pre-pregnancy needs, and taking prenatal vitamins. A recent study suggested that vitamin A repletion in pregnant HIV positive women with vitamin A deficiencies decreased the likelihood of perinatal HIV transmission (see "Women and HIV/AIDS" in the September 1994 issue of BETA, p.74). Some increased nutrient needs can be met by adding extra servings of foods from the basic food pyramid (see graphic where). Pregnant women should discuss the use of nutrient supplements with their physicians. Consultation with a dietitian who can assess individual needs and variables may be particularly valuable for an HIV positive woman during pregnancy. Premature menopause may occur more frequently in HIV positive women, according to Ms. Weaver. In all menopausal women, decreased production of estrogen causes the release of calcium from bones. Since HIV infection elevates calcium needs, it is even more important for HIV positive menopausal women to receive adequate amounts of calcium. Calcium supplements may be taken in the form of calcium citrate (easier to digest than other forms) or, most simply, calcium-enriched antacids such as Tums. Weight-bearing exercise has been recommended to maintain bone strength as well as lean body mass. Women with HIV may experience more severe hot flashes, sometimes mistaken for night sweats, which may depress appetite and food intake as well as disrupt sleep. Current research efforts are evaluating the use of vitamin C and E supplements to alleviate hot flashes. Metabolism usually slows with age, loss of lean body mass and muscle tone, and increases in fat storage. However, because HIV infection elevates metabolic rates, and to guard against the removal of protein from muscles, older women with HIV need to continue to receive adequate amounts of protein as well as vitamins and minerals. Studies of eating patterns in older adults suggest that their diets often are relatively low in important nutrients (and high in sugars, fats and alcohol). It is important for older women with HIV to eat nutrient-dense foods to prevent weight loss and age-related nutrient deficiencies and immune system deterioration. Dr. Romeyn suggests that, while high levels of dietary fats are generally to be avoided by HIV-infected persons (fats are difficult to metabolize and often cause the individual to feel ill), sugar in fact may be helpful. Sugar is easily absorbed, spares protein from being broken down to provide energy and gives pleasure, which is important for quality of life. Eating enough carbohydrates, i.e., sugar, reduces the need for the body to break down protein stores, i.e., muscle, as a source of fuel. Impaired taste bud function and taste alteration, which may be caused by drugs taken for the treatment of HIV or other infections, may result in further decreased food intake. Because compromised taste buds still detect sugar, the pleasure derived from eating it may encourage further eating. Hormones Women of childbearing age experience extreme fluctuations in hormones and hormonal levels, which affect metabolic rate, appetite, eating habits, food intake, glucose tolerance, mood and behavior. Thus, Ms. Weaver recommends incorporating hormonal factors into nutritional interventions and strategies for HIV positive women. Many women with HIV experience menstrual abnormalities including heavier or lighter menstrual flows. Heavy periods may lead to anemia, which in a woman with HIV may be further exacerbated by the use of AZT and/or other drugs. HIV positive women, particularly those experiencing heavy periods, are advised to choose iron-rich foods. Some women report experiencing more intense episodes of premenstrual syndrome (PMS): breast swelling and pain, bloating, fatigue, head and body aches, irritability, mood shifts and cramping. These symptoms can occur before and during menstruation. The physiological effects of HIV and PMS may be additive, according to Ms. Weaver. Some basic guidelines for relief of PMS are to eat the right amounts of foods from all food groups, exercise and take supplements that include the B vitamins, magnesium and vitamin E. Fatty acids are integrally involved in the rise and fall of hormone levels throughout the menstrual cycle; taking supplements may help maintain hormonal balance. Ms. Weaver suggests taking supplements of evening primrose oil, an essential fatty acid that can be found in capsule form in health-food stores. Some people feel that avoiding salt and drinks with caffeine, such as coffee, tea and colas, helps to reduce or eliminate the symptoms of PMS. Related Concerns of Women with HIV Lisa Ploss discussed with BETA various lifestyle, psychosocial and physiological influences that bear on an HIV positive woman's dietary patterns and nutritional strategies. Is she responsible for caring for and feeding others, such as children, parents or other family members? The added financial burdens of childcare may force an HIV-infected woman to neglect her own healthcare. Does she live with others, or alone, or in a recovery house or a single room occupancy hotel? Does she have access to equipment for preparing and storing food, and to food itself? For women who become too fatigued or ill to care for others, alterations in roles can be very difficult. Body image, which changes greatly with weight loss and illness in general, may be a particular concern for women. Eating disorders such as anorexia nervosa and bulemia, common among women, can be extremely damaging in women with HIV, and present great challenges to creating an effective intervention for optimizing nutritional status. Fatigue, depression and lack of appetite are common complaints among women with HIV and may be related to hormonal shifts, psychosocial influences (e.g., caretaking), opportunistic infections and the use of medications. Food Eating well provides a foundation for any nutritional strategy. While use of a daily high-potency multivitamin is recommended, food contains calories, fiber and other important (and incompletely understood) substances that vitamins and supplements do not contain. General Nutritional Guidelines for HIV Positive Women The following was compiled from an interview with Lisa Ploss, RD, MPH, the HIV Services Nutritionist at Lyon-Martin Women's Health Services in San Francisco, CA, and excerpts from an article she previously wrote. Consult with a physician or registered dietitian before making any drastic dietary changes and to help bring weight within a healthy range. Choose a variety of foods from each food group every day. (See the "Food Pyramid.") Emphasize grains, grain products, fruits and vegetables, which contain high amounts of vitamins and minerals. Eat small, frequent meals or snacks at least 3 times a day--4 or 5 times if possible. Drink 6-8 glasses of fluids every day. Avoid fluids that increase urination such as alcohol, coffee or tea. Take a balanced high-potency multivitamin supplement at least once a day. Prenatal vitamins have more of the necessary micronutrients. Remember that a vitamin or mineral supplement cannot substitute for a well-balanced diet or for a food group. Maintain weight at your usual weight range or 5-10% higher, unless overweight. If weight is below ideal body weight range, increase intake of carbohydrates and protein-rich foods. If you feel that your weight needs to change, seek the assistance of a physician or dietitian. Establish a regular exercise program to build and maintain muscle tissue. Overly strenuous exercise is neither necessary nor recommended. Exercise that involves muscle resistance is important for stimulating muscle tissue. Increasing or at least maintaining muscle tissue, or lean body mass, appears both to help someone stay healthy longer and to recover faster and better, if s/he becomes ill. Dietary Items to Include in Daily Diet: 2-3 servings of dairy and calcium alternatives (Milk, yogurt, cheese and ice cream. Other high-calcium foods include bok choy, spinach and other dark green, leafy vegetables, broccoli, sardines with bones, calcium-fortified tofu or soy milk and calcium-fortified orange juice. Yogurt contains different types of bacteria such as Lactobacillus acidophilus that may prevent or ameliorate Candida albicans infections and diarrhea by restoring normal bacteria. Again, lactose intolerance may make digesting dairy products problematic. A dietitian may recommend suitable substitutes or lactase supplements to offset the symptoms of lactose intolerance.) 2-3 servings of protein (Including all types of meat, fish, poultry, eggs, beans, cheese, nuts and tofu) 5 or more servings of fruits and vegetables (Including dark green and orange fruits and vegetables) 6 or more servings of breads, cereals, tortillas, rice and pastas (Preferably whole grain-enriched) Adequate amounts of iron, vitamin B12 and folate in an HIV positive woman's diet can help prevent or reduce the seriousness of anemia, which more women experience than men. Good dietary sources of iron include liver, poultry, meat, fish, iron-fortified cereals, dried apricots, soybeans, spinach and other dark green, leafy vegetables. Cooking in cast iron pots and skillets may also increase the iron in your diet. Dietary sources of vitamin B12 include meat, fish, poultry, shellfish, milk, yogurt, cheese and eggs. Nutrient-Dense Snacks Bagels and tuna Macaroni and cheese Whole-grain toaster waffles and fruit Burritos Whole grain cereal with milk Blender drinks made with fruit, ice cream or yogurt Bean soup topped with toast cubes and shredded cheese Powerbars Vitamins, Minerals & Supplementation According to Dr. Romeyn, the altered metabolic state of a person with HIV virtually necessitates the use of nutrient supplements in order to ensure that all necessary nutrients are being received. Since many people with HIV have reduced food intake as well as impaired abilities to absorb nutrients, supplements are especially important. Several nutrients are believed to be involved in immune system health: vitamins A, B6, C and E; beta carotene; and minerals including copper, iodine, iron, magnesium, manganese, selenium and zinc. Several nutrients are routinely deficient in persons with HIV disease, especially B6, B12, copper and zinc. Other nutrients that may be deficient in HIV-infected persons are folate and vitamins B1 and B2. Deficiencies of B12 and magnesium in people with HIV have been associated with peripheral neuropathy. One study examined HIV positive persons with decreased levels of B6 and B12 who reported slight cognitive abnormalities. Restoring levels of B6 and B12 alleviated the cognitive symptoms. Low levels of these B vitamins may indicate problems with gastrointestinal absorptive abilities; a person with low levels should be evaluated to determine the cause(s) and the corrective action that should be implemented (e.g., intramuscular administration of B vitamins). Ms. Weaver and Ms. Ploss recommend that malnutrition or deficiencies of certain micronutrients and megadosing should be explored routinely as part of the work-up of a person with HIV who presents with nonspecific symptoms. Supplemental use of some nutrients is considered safe, regardless of dose. For example, excess amounts of vitamins B1 and B2 are excreted; B12 is considered nontoxic (albeit poorly absorbed). According to Dr. Romeyn, magnesium, required for the metabolism of other minerals, is an important mineral that is almost impossible to get too much of (except for someone with kidney failure)--it is hard to get enough from foods, to absorb and to retain. However, iron, zinc and copper supplementation must be approached cautiously, says Dr. Romeyn. Even for women, whose iron needs tend to be higher than those of men, high levels of iron supplementation are not recommended--adverse effects of overly high daily doses of iron range from constipation to iron storage and metabolism abnormalities that damage tissues and organs. There are blood tests that can determine iron needs and appropriate doses for the individual. Taking high daily levels of zinc has been associated with decreased survival in people with HIV disease. Megadosing, or taking high amounts of vitamin and mineral supplements (in doses larger than 10 times the Recommended Daily Allowance, or RDA), is common yet controversial in HIV disease. Megadosing may enhance immune status and protect against micronutrient deficiencies common in HIV disease. A placebo effect can increase energy levels, appetite and overall sense of well being, Ms. Weaver adds. However, concerns exist about megadosing-related toxicities and nutrient/drug interactions, about which there are little data. Megadosing-related toxicity may present as diarrhea (e.g., associated with vitamin C). Ms. Weaver recommends that women who present with diarrhea and/or anemia, which may result from large doses of zinc, should be questioned about megadosing or use of multivitamins, because these may be side effects that could cloud diagnosis. Excessive doses of all the fat-soluble vitamins (A, D, E and K) can cause toxicities. Megadoses of vitamin A may be hepatotoxic. Excessive amounts of vitamin C (>10g/day) may cause diarrhea and also, if abruptly discontinued, may cause scurvy. Extended use of high levels of zinc (> 100mg/day) interferes with the body's ability to utilize another important mineral, copper, and may actually increase disease progression. Some people experiment with megadosing because they mistrust conventional therapies, which they may inappropriately discontinue. Megadosing also may be expensive. Optimal megadoses have yet to be established for persons with HIV disease. Although the RDA were not created for, and are inadequate for, persons with HIV, suggested guidelines regarding the use of high doses of supplements by persons with HIV are both preliminary and non-gender-specific. A physician's and/or dietitian's help should be enlisted to assess an individual's particular nutritional profile, i.e., micronutrient status, etc. This information may be used to create a specific, individualized supplementation program that goes beyond taking the recommended daily multivitamin. Perhaps the most fundamental principle in nutritional care is individualization. Universal recommendations are probably an appropriate place to begin, but may be of limited utility. Again, if nutritional problems are attacked early and aggressively, weight loss may be prevented, physiological and mechanical gut function improved (by utilizing the gut to its full extent), susceptibility to opportunistic infections reduced, response to medical therapies enhanced and, most importantly, overall quality of life and sense of well-being improved. Much research remains to be conducted, particularly with regard to the distinct needs of women with HIV. Alternative therapies such as megadosing need more investigation in order to establish when they are appropriate and what dosing regimens to use for appropriate effect, for men and women. [DAVID--please sidebar/screen] Guidelines for Selecting a Dietitian In an interview with BETA, Lisa Ploss, RD, MPH, offered the following guidelines for finding a dietitian with whom to work. Either a dietitian or a nutritionist may help design an individualized nutritional strategy. A registered dietitian must complete an undergraduate program, supervised internship and training, and pass a national examination. Continuing education units also are required for continued registration. Nutritionists, however, at least in California, are not required to undergo any formal training. When meeting a dietitian or nutritionist for the first time, be sure that s/he discusses certain things: lifestyle (good recommendations are those that are practical); laboratory work and values; 24-hour or 3-day food records for use in baseline nutrient analysis; individualized recommendations. She suggests being cautious of someone who looks at certain isolated samples, e.g., hair, or who makes blanket recommendations without testing or taking into account individual variables. Hospital clinics can perform tests of lean body mass, as well. Statewide, the California Dietetic Association at 1-800-234-7348 provides dietitian referrals. Ask for a dietitian with experience working with people with HIV. Nationwide, individuals may call the National Center for Nutrition and Dietetics at 1-800-366-1655 to speak directly with a dietitian as well as to obtain referrals for a particular state. References Beach RS and others. Plasma vitamin B12 level as a potential cofactor in studies of human immunodeficiency virus infection.: association with neurological dysfunction. Archives of Neurology 49(5): 501-506. May 1992. Gilden D. Nutritional intervention in HIV disease. BETA: 3-11. March 1994. Ploss L, RD, MPH. Nutrition guidance for positive women. Positive Nutrition 4: 6-8. Winter 1994. Ploss L, RD, MPH. Personal Communication. November 2, 1994. Romeyn M, MD. Internal Medicine. Personal Communication. November 29, 1994. Weaver K, RN, MSN, CNSN. Nutritional concerns for the HIV-infected woman. Third Annual Women and HIV Update. San Francisco, October 14, 1994. Weaver K. Personal Communication. November 11, 1994. TI Nutrition and Wasting AU Brenda Lein; Director of the Information and Advocacy Departments at Project Inform, an AIDS treatment information and advocacy organization in San Francisco. TX The following article was originally published in the PI Perspective, a free biannual publication of Project Inform. For more information, contact the PI Treatment hotline at 415-558-9051 or 1-800-822-7422. Weight loss and malnutrition are common problems associated with HIV. Weight loss can begin and become severe anywhere across the spectrum of CD4 counts. Wasting is defined as an unexplained loss of 10% or more of normal lean body mass. There are people who report wasting despite very high levels of CD4 cells, but the risk of wasting and serious malnutrition increases dramatically when CD4 cell counts fall below 100. The body's ability to absorb nutrients and maintain lean body mass is associated with general good health and the ability to fight disease. There are many approaches to managing nutrition and wasting. A comprehensive treatment strategy for managing HIV/AIDS should include a component on nutrition. Weight should be monitored with the same watchful eye as CD4 counts and other laboratory parameters. Early intervention in weight loss is critical. Specialists note that the difference between successful treatment of an opportunistic infection and treatment failure often depends on a few pounds of weight. There are many options for prevention and treatment of weight loss; different approaches may be needed across the spectrum of disease. Someone who is healthy with no overt signs of weight loss will probably develop a very different kind of nutritional strategy than someone experiencing significant weight loss. Similarly, weight loss due to gastrointestinal distress, diarrhea or other HIV-related conditions may require different interventions than weight loss that is due to chemotherapy or drug interactions. Finding a nutrition and weight stabilization program that adapts to both lifestyle and nutritional needs is critical for success. The following are a few points to consider: + Evaluate nutrition and exercise as part of a comprehensive, early intervention treatment strategy for HIV. + Follow reasonable guidelines for "safer" food preparation. + Employ rigorous diagnosis and appropriate treatment for causes of weight loss. + When necessary, consider using nutritional and vitamin supplements to replenish deficiencies. + Learn the potential advantages and disadvantages of various intervention options. Evaluate Nutrition and Exercise as Part of a Comprehensive, Early Intervention Strategy for HIV The importance of nutrition and maintaining lean body mass cannot be overstated. Good nutrition, combined with exercise, not only relieves stress, which is immunosuppressive, but also provides a solid foundation to optimize the potential benefits of HIV therapeutic regimens. Most physicians and people living with HIV do not recognize early signs of weight loss. Careful monitoring of weight, periodic laboratory evaluations looking for vitamin and hormone deficiencies, and an aggressive nutritional and exercise program can help prevent wasting and malnutrition. While complex solutions like total parenteral nutrition (TPN) can sometimes correct severe wasting, the cost is often unacceptably high, both in dollars and risks of side effects or risks associated with treatment. Whenever possible, it is far better to take action to correct nutritional problems before they become severe. This may mean intervening with improved diet, appetite stimulants or weight gain supplements before weight loss becomes unmanageable. A nutritional handout is available through the Project Inform Hotline. This handout includes dietary and alternative interventions for dealing with symptoms associated with HIV and HIV-related conditions such as diarrhea, candidiasis, hair loss, peripheral neuropathy, skin problems and appetite loss. Like any basic program, an individual's strategy for coping with nutritional and exercise needs should be re-evaluated periodically, adapting strategies to the body's changing needs. Two people at the same stage of wasting may use completely different approaches depending on their willingness to exercise and work at a nutritional program. Someone willing to follow a workout regimen and careful diet may rebound from wasting by simply adopting better eating habits. Someone who is less inclined to invest in an exercise regimen and finds it more difficult to follow a careful dietary plan may require more invasive intervention, ranging from the use of appetite stimulants and supplements to total parenteral nutrition (TPN). Both individuals might successfully rebound from wasting, but each intervention regimen reflects individual lifestyle factors and choices. There are advantages and disadvantages to each option. Weigh the risks and benefits and develop a realistic plan to prevent or reverse wasting. Many people who experience weight loss feel frail and avoid strenuous activity. People who are experiencing weight loss and malnutrition may also experience depression, a condition linked to malnutrition. Depression may get in the way of maintaining a regimen of good nutrition and exercise. This perpetuates a cycle. It is important for individuals to remember that the body is resilient, even when feeling frail. Employ Rigorous Diagnosis and Treatment for Causes of Weight Loss HIV itself and many HIV-related conditions can cause weight loss, fatigue, loss of muscle mass and chronic diarrhea. The gastrointestinal tract is a major site of early HIV infection. It is also a prime site for many bacterial, viral, fungal and parasitic infections that can independently contribute to weight loss once a damaged immune system permits such organisms to proliferate. Some health professionals conduct repeated tests to identify the causes of diarrhea and weight loss. Others treat symptoms without attempting to identify the cause. It is important to do both. Aggressive diagnosis should be accompanied by aggressive treatment. Diagnosing and treating unexplained weight loss and diarrhea can be difficult as there are often multiple causes. An infectious agent, like a parasite, might be identified but treatment may only reduce and not resolve the problem. This might be because the parasite was "masking" another infection and additional diagnostic and treatment procedures may be required to deal with the underlying problem. Similarly, some instances of wasting are due to malabsorption, a condition in which damage to the cells and tissues lining the intestinal tract have lost the ability to properly transfer nutrients. Finding the cause or causes of weight loss or diarrhea is critical to finding the proper treatment. An article from AIDS Treatment News outlining the diagnosis and treatment of gastrointestinal manifestations of HIV is available through the hotline. Consider Nutritional and Vitamin Supplements to Replenish Deficiencies Studies have shown that 2 phenomena are present at all stages of HIV disease, even when CD4 counts are high and there are no apparent signs or symptoms of disease: (1) the virus is always actively replicating, and (2) there is some evidence of nutritional deficiency. Many people attempt to give the body an edge over the virus by complementing their diet with vitamins and nutritional supplements. This may not only help correct minor nutritional deficiencies, but may also strengthen the body's natural immune defenses. Much research still needs to be done to fully document vitamin and nutritional deficiencies across the spectrum of HIV disease and the degree to which supplements may correct these problems. Nonetheless, a reasonable level of vitamin and nutritional supplementation to replenish deficiencies seems sensible. Gay Men's Health Crisis' Treatment Issues did a special edition on alternative medicine and vitamins that is available through the Project Inform hotline. This article gives an overview of research on vitamins, outlines potential side effects and lists foods which may be rich in certain vitamins. Vitamin and nutritional supplements should not be used to replace food. Whenever possible, increasing vitamin intake through improved eating habits is preferable. For people on strict budgets, living on disability or other assistance programs, vitamins and other supplements are often too expensive. Some people spend hundreds of dollars per month on such products. This may be unwarranted in many situations, as there is little data to support the use of "megadoses" of vitamins and supplements in AIDS. Some states, such as New York, provide vitamins free through AIDS Drug Assistance Programs. Some counties have programs that help cover the cost of alternative therapies and supplements. To find out if such programs exist in your area, call your local health department. Vitamin supplementation, like nutrition and exercise regimens, should be periodically re-evaluated. In the course of HIV disease, there appears to be a decrease in the body's abilities to absorb nutrients and to incorporate amino acids and enzymes that promote the digestion of food. With malabsorption, it is unclear whether taking ever-larger doses of supplements produces any added benefit. Some physicians who specialize in the use of vitamins and supplements recommend intravenous administration when absorption is a problem. Conventional TPN formulas include vitamin supplements in the mix. Similarly, some hospitals include intravenous vitamin supplements when patients are restricted from oral food intake. A "brown-bag medical checkup" is an important part of health monitoring. Each time you visit your healthcare provider, throw all the medications you take, intermittently and regularly, into a bag. Include vitamins, herbs, nutritional supplements and prescribed medications. Ask your doctor to have a pharmacist conduct a personalized review of your therapies for safety, appropriateness, compatibility and instructions for use. This will help avoid drug interactions and may help diagnose symptoms caused by drug side effects. Just because something is available over the counter or perceived as "alternative" does not mean it is nontoxic or safe to take with other therapies. Also, be sure to see the Project Inform Drug Interaction Chart, published in PI Perspective #14 and available from the hotline. Learn the Advantages and Disadvantages of Various Intervention Options Like all other aspects of HIV/AIDS treatment, there is no free lunch when it comes to the intervention options for nutrition and wasting. There are a number of products and approaches that may be helpful for many people, but there are no guaranteed solutions for every possible situation. Likewise, there is a fair amount of hype and misinformation about various approaches. Nutritional supplements and vitamins are often promoted aggressively, whether or not there are adequate data to support the claims made for them. There are varying degrees of effectiveness and varying side effects. A good rule is to remember that what works for one person in one situation may not work for the next person. The best solution is to form your own opinions after collecting as much information as possible. Weight Gain Supplements Many weight gain and protein supplements are available through pharmacies and health-food stores. These are not recommended as a sole source of nutrition. Protein supplements, such as those used by bodybuilders, are sometimes used by people living with HIV to prevent or help treat weight loss. Products that are high in protein and low in sugars and fats have been recommended. Some protein supplements claim to be better for metabolic weight gain, promoting the development of protein. Weight gain protein drinks, including Ensure, Advera, Nutren and Resource, are also commonly used by people with HIV. Advera has the lowest fat content and is highest in predigested protein. It is also the most costly. Ensure is less expensive, but higher in fat and sugars, containing both sucrose and corn syrup. Both Nutren and Resource are less expensive, but have high fat content. Again, these products should not replace solid food. Combining protein and weight gain supplements with exercise is critical for optimal success. Even if exercise is limited to stretching, anything that helps build lean body mass is important. Appetite Stimulants In addition to adjusting eating habits and diet, taking appetite stimulants may help to maintain weight and good nutrition. Many people believe that marijuana stimulates appetite and calms the stomach. Smoking marijuana can be hard on the lungs so some people prefer baking it into brownies or truffles. The chemical agent in marijuana, THC, has been synthesized and is the active agent in Marinol, which is FDA-approved as an appetite stimulant for people with HIV. Absorption of Marinol is problematic. Sometimes it works well, sometimes not at all and still other times it works a little too well, leaving people too euphoric or "stoned" to carry on with planned activities. These appetite stimulants may not be appropriate for people in recovery from alcohol or substance abuse. Megace, a synthetic progesterone, has been shown in a number of studies to increase appetite and weight. A recent report in the September 1994 Annals of Internal Medicine suggests that most, if not all, weight gain associated with Megace is in the form of body fat. These studies, however, show that people on Megace reported increases in weight and general well being. While side effects associated with Megace are rare, a few people in studies reported blood clotting and breast enlargement in males. Growth Hormone Therapy and Steroids One piece of exciting news from the 1994 International Conference on AIDS in Yokohama was new data on a trial of recombinant human growth hormone (rHGH) for AIDS wasting. In a multicenter, double-blind, placebo-controlled study of rHGH, 178 volunteers were randomized to receive either rHGH or placebo for 12 weeks. People in the rHGH treated group demonstrated a decrease in body fat and an increase in lean body mass. This may indicate that rHGH helps to correct a metabolic abnormality and addresses one of the underlying causes of AIDS wasting. People receiving rHGH had an average of 1.7 kilograms lean body mass increase over the placebo group and demonstrated increases in treadmill endurance. Side effects associated with rHGH included joint stiffness, edema, elevated glucose and triglycerides and nausea. These were usually mild and resolved with dose reductions. Anabolic steroids, such as testosterone, may be useful to treat or prevent wasting. Anabolism refers to building protein. There have been few studies examining the use of anabolic steroids in HIV, but clinicians routinely correct testosterone deficiencies with replacement therapy. A broader and largely unanswered question is whether wider use of anabolic compounds is useful in preventing or treating wasting syndrome. There is no information currently available on the effect of anabolic steroids on viral replication, but many people are experimenting to see if using steroids can help maintain or increase lean body mass. Cytokine Manipulation Increases in certain cytokines (chemical messengers that are produced by immune system cells) have been associated with increases in HIV replication, KS tumor progression, HIV disease progression and wasting syndrome. These cytokines, which include tumor necrosis factor (TNF) and interleukin-1 and -6 (IL-I and IL-6), are called pro-inflammatory cytokines because they are associated with inflammatory responses. Several studies are ongoing to see if down-regulating these cytokines will impact wasting. Pentoxifylline (PTX), also known as Trental, is FDA-approved for use in blood-clotting disorders in the elderly and is therefore available "off-label" by prescription. Small studies demonstrate that PTX lowers TNF levels in people with HIV who have elevated TNF. Because TNF is an important cytokine for controlling mycobacteria and other HIV-associated pathogens, lowering TNF to, but not below, normal levels may be the most beneficial approach. Studies of PTX have been small and results have been mixed. Some studies show trends toward weight stabilization while others show no impact. Studies of PTX with AZT show that the drugs can be taken safely together. Side effects of PTX are apparently rare, but include nausea and headache. An older drug, thalidomide, inhibits TNF and reduces viral replication in test tubes. Several studies of thalidomide are ongoing in HIV, one to examine its benefits in treating HIV-related aphthous ulcers, one in HIV-related wasting syndrome and another to examine its anti-HIV effects. Other approaches to lowering TNF levels, including synthetic antibodies against TNF and soluble TNF receptors, are being tested at the National Cancer Institute and in Canada. Total and Partial Parenteral Nutrition (TPN and PPN) TPN and PPN are liquid nutrients which are delivered intravenously, through a line surgically implanted in a major vein. Some providers use PPN, in combination with solid food nutrients, to treat moderate to severe wasting. When wasting becomes severe, TPN is used. Often, due to expense (up to $13,000 per month), TPN is utilized too late to help restore body mass. As wasting increases in severity, it becomes more and more difficult to treat. Intervening early, even with TPN, is important. An IV diet is hard on the body; intestines are not "exercised," and the longer TPN is continued the more difficult it is to readjust to solid foods. TPN is very high in fatty proteins, and weight gain associated with TPN is primarily fat and water weight. While this is clearly not optimal, it may help someone with severe wasting. TPN should only be used when the intestines have stopped working and other oral interventions are not being absorbed. Finally, good nutrition and maintaining lean body mass are core components of a comprehensive HIV treatment strategy. Evaluate the advantages and disadvantages of available options and develop a nutrition and weight maintenance strategy that fits your lifestyle. Interventions are available if wasting becomes a problem, but as with almost every aspect of HIV, preventing the problem is the best solution. TI Immune-Based Therapies AU Mark Bowers; medical writer and AIDS treatment activist. TX Research has established that HIV is the primary cause of AIDS. The immune system itself is the target of HIV, and most people who succumb to AIDS die from infections or cancers that take advantage of a weakened immune system. Immune-based therapies (IBT) are designed to address this problem by preserving or replacing damaged immune cells. The scope of immune-based therapies is already quite wide, and growing continually. Some immune-based therapies are treatments intended to modify or manipulate the responses of the immune system against HIV or HIV-related diseases. Other therapies, such as vaccines, are designed to increase beneficial or protective immune responses, while still other therapies are designed to decrease harmful immune responses, such as the overproduction of tumor necrosis factor (TNF) in HIV-associated wasting. Yet other experimental therapies, such as thymic tissue transplants, provide for the replacement of cells destroyed by HIV. The rationale for employing IBT is found in the very difference between IBT and traditional antiviral drug therapies. Antivirals are designed to be active against viral pathogens that invade the body and as such cannot directly correct immune imbalances or deficiencies. Immune-based therapies employ strategies that boost or replace the immune system's natural defenses, or act to decrease the harmful effects that accompany immune dysregulation, deregulation or dysfunction. Areas that are currently receiving the attention of immunologists are nutrition, vitamin supplementation, antioxidants, cytokine manipulation, active immunization (therapeutic and prophylactic vaccines), passive immunization (pooled antibodies), gene therapy, hormone manipulation and psycho-neuro-immunology. This article is intended as a broad overview of immune-based therapies for HIV disease. More detailed information about specific immune-based therapies can be found in previous issues of BETA and other journals. Diet, Nutritional Supplements and Antioxidants Please refer to previously published information in BETA on the benefits to the immune system of adequate diet, and the potential benefits of nutritional supplementation and the use of antioxidants (Gilden, 1994; Baker and others, 1994; Bihari 1993). Malnutrition is a common cause of immunodeficiency. Lymph nodes, thymus and lymphoid organs become smaller, and increased susceptibility to infections of all types occurs. Protein deficiency results in decreased skin delayed type hypersensitivity, reduced T-cells in general, and CD4 subsets specifically, and attenuated T-cell response to antigen stimulation. Vitamin A deficiency can cause atrophy of the spleen and thymus, reduced T-cell and B-cell responsiveness, and high infection rates. Similar effects accompany vitamin B6 and vitamin B12 deficiencies, plus pernicious anemia accompanies abnormally low levels of B12. Trace elements, particularly iron, copper, zinc and selenium, are known to result in impaired immune status when they are deficient. Most of the immune deficiencies are reversible with nutritional supplementation. Cytokine Manipulation Cytokines are chemical messenger proteins that provide essential communication between cells of the immune system, and between the immune system and other cells in the body. Dozens of cytokines have been identified and sequenced. Many, but not all, of their effects are known. An increase of certain cytokines and a decrease in others may be associated with a given disease state. Researchers believe that cytokines can be manipulated to restore the balance of cytokines characteristically found in healthy individuals and thereby restore some immune system function (Baker, 1994). Interleukin 2 (IL-2 or T-cell growth factor) is a cytokine that is produced by T-cells. The release of IL-2 sends a message to natural killer and cytotoxic (cell-killing) cells to divide rapidly and enhances their cytolytic capabilities. As such, IL-2 is critical for cell-mediated immune responses. IL-2 has been approved by the FDA as a cancer therapy, and it is available commercially. Some physicians offer their patients IL-2 infusions in their offices; these infusions represent "off-label" usage (use of a drug for an indication that is not approved by the FDA) that are not routinely reimbursed by insurance carriers. Several clinical studies have examined the effects of IL-2 in HIV disease. Patients enrolled in the National Institutes of Health (NIH) study received 18 million IU of IL-2 intravenously administered on an 8-week cycle, consisting of 5 days of infusion followed by 7 weeks of rest. Some of these patients showed sustained increases in CD4 cell counts. Most reported substantial toxic side effects including chronic fatigue, nausea, vomiting, fever and chills. A Stanford study of polyethylene glycolated IL-2 involved infusions of smaller doses (3-5 million IU) once a week for 3 weeks, then one infusion every other week; there were also sustained CD4 cell counts for these 19 patients. Trends which have emerged indicate that IL-2 may be useful in people whose CD4 counts are between 100-300 and declining. IL-2 may not be of enough benefit to people whose counts are below 100 to justify the associated toxicities. Interleukin 12 (IL-12) is also a potent growth factor for natural killer and cytotoxic T-cells. Interest in IL-12 arises from some immunologists' belief that TH1 and TH2 balance can be favorably influenced by the administration of IL-12 (Baker, 1994). Recombinant human IL-12 is under investigation in a Phase I study for people with 100-500 CD4 cells/mm3. Study sites are the University of California at Los Angeles and the University of California at San Francisco. The study objective is to determine the safety of IL-12 in humans. Future studies will determine whether the administration of IL-12 increases cellular immune function and provides any advantage in HIV disease. Interleukin 4 (IL-4) is a cytokine that increases the B-cell (or humoral) immune response. IL-4 is a growth and differentiation factor for B-cells, for some T-cells and for mast cells, immune cells with variable functions found in tissue throughout the body, particularly in lungs and intestines. IL-4 also is a macrophage-activating factor, although it is less powerful than gamma interferon in this regard. In addition, some recent evidence indicates that IL-4 may play a role in cell-mediated immunity. The AIDS Clinical Trials Group is currently sponsoring a study of IL-4 for the treatment of Kaposi's sarcoma (ACTG 224). The study objective is to determine the most effective and least toxic dose of IL-4. This cytokine is only available through participation in a clinical study. Increased levels of tumor necrosis factor alpha (TNF-a) have been associated with wasting in AIDS. TNF-a also brings about the activation of HIV expression in test-tube studies. TNF-a inhibition is a strategy that seeks to manipulate some of the body's basic metabolic processes in an attempt to reverse wasting. Thalidomide (Synovir) is under study by the Food and Drug Administration (FDA 230A) for both its antiviral and TNF-a inhibiting properties. Thalidomide is also being studied for its anti-mycobacterial properties and to determine its efficacy in treating aphthous ulcers. Another drug that inhibits the synthesis and activity of TNF is pentoxifylline (Trental). Some researchers believe that pentoxifylline also indirectly inhibits HIV expression through inhibition of a binding protein (NF-kB). Yet another immune based strategy to decrease TNF levels is the administration of anti-TNF monoclonal antibodies. At present, all of these strategies are considered experimental, but promising. Gamma interferon (also called immune interferon) is produced by IL-2 secreting CD4 T-cells and all CD8 cells. Natural killer cells may also produce small amounts of gamma interferon. Levels of gamma interferon are low in HIV disease. Interferon gamma can signal macrophages to kill cells that are infected with parasites, bacteria or viruses. This macrophage activation brings about an increase in MHC II molecules on the cell surface of macrophages, and allows them to display more antigens to more CD4 cells. This in turn allows more effective CD4 T-cell activation. Gamma interferon as well inhibits proliferation of TH2 T-cells that participate in the B-cell response. Clinical research on gamma interferon has so far only allowed the participation of HIV negative individuals. Mycobacterial infections respond particularly well to treatment with gamma interferon, and successful research in HIV positive individuals would represent a real clinical advance. A recombinant form of gamma interferon (Actimmune) is commercially available. Colony stimulating factors (CSF) have been identified for many red and white blood cells. All blood cells that are generated in adults arise from a common hematopoietic stem cell in the bone marrow that becomes committed to differentiate into various lineages in the presence of certain CSF. Interleukin 3 (IL-3 or multi-CSF) acts on all stem cells. Granulocyte-macrophage-CSF (GM-CSF) stimulates stem cells specifically to produce all of the non-lymphoid cells--monocytes, neutrophils, eosinophils, basophils and megakaryocytes. Other CSF are specific for granulocytes (G-CSF) or monocytes (M-CSF). Stem cell factor (SCF or Steel factor) is essential in forming red blood cells, and thought to act on stem cells and B-cell progenitors. Researchers are still studying these factors to determine if they are necessary and sufficient to produce white or red blood cells that may be deficient as a direct consequence of HIV infection. Current research on Steel factor includes expansion of CD4 and CD8 cells outside the body for eventual replacement and stimulation of mast cell production. Investigation in these areas should increase, since Steel factor is easily isolated from umbilical cord blood, and there are no current restrictions on such research. Erythropoietin (EPO, Procrit, Epogen) is a growth factor that has been cloned and purified and is FDA approved for the treatment of AZT-induced anemia. EPO stimulates the production of new erythrocytes, or red blood cells. The success of EPO has encouraged researchers to test other growth factors, such as the ones described above. Active Immunization Prophylactic and therapeutic vaccines are examples of active immunization in HIV disease. There are important differences between the expected immune responses to the 2 modalities. Preventive vaccines are expected to provide widely protective immune responses in HIV negative individuals. The exact nature of this immunity remains unclear to date, and wide-scale studies of current vaccine candidates have been voted down by the National Institutes of Health (for an in-depth discussion of vaccines for HIV, see BETA, March 1993, pp. 1-9, and BETA, December 1993, pp. 7-10). Active immunization generally results in the production of antibodies to the infecting virus; it may also initiate protective cellular immune responses. To satisfy the NIH that wide-scale testing in the US may safely proceed, more promising vaccine candidates need to be found. Therapeutic vaccines for HIV are purely immunomodulatory in their intent. While some current vaccine candidates continue to focus on the production of neutralizing antibodies to catch and disarm HIV as it travels between cells, other candidates are pursuing enhanced T-cell cytotoxicity. It is not yet clear whether the immunogen, the part of the virus that is thought to trigger the most nearly protective response, or the adjuvant (additive) is responsible for increased T-cell function, as seen in data from the Salk vaccine and the Immuno AG (Austrian) vaccine candidates. Passive Immunization Passive immunization may be accomplished by transferring either preformed serum or cells. Immunoglobulins, or antibodies primarily of the IgG isotype, can be transferred from one individual to another. These antibodies may provide immediate benefit for antibody-deficient individuals because they help neutralize HIV and because they likely reduce the severity and occurrence of opportunistic infections. Results from a year-long study of passive hyperimmune plasma therapy were recently reported in the journal Blood. HemaCare Corporation of California collected and processed plasma from asymptomatic donors with high titers of HIV p24 antibody, reasoning that high titers correlated with an improved prognosis. 220 participants with symptomatic HIV were randomized to receive monthly infusions of 500 ml hyperimmune plasma, 250 ml hyperimmune plasma diluted in 250ml of 5% human serum albumin, or 500ml of placebo. Results were stratified for CD4 level, with those individuals below 50 cells/mm3 and those between 50-200 cells/mm3 analyzed separately. All were on nucleoside analog antivirals and took Pneumocystis carinii pneumonia prophylaxis. The only group to show benefit defined by negative p24 antigenemia and increased CD4 cell counts, were participants who received full doses (500 ml of hyperimmune plasma) and whose CD4 counts were between 50-200 cells/mm3. The average rise in CD4 counts was 37 cells/mm3. Further study is needed to better establish when this intervention might best be used. The AIDS Clinical Trials Group (ACTG 185) is sponsoring a study of HIV Ig (HIV-specific immunoglobulin) plus AZT versus IVIG (non-specific immunoglobulins) plus AZT for pregnant women. IVIG is a standard treatment for severe humoral immune deficiencies, and may increase suppressor T-cell activities. The 2 main questions to be resolved are:  Is there a reason to administer preformed antibody along with AZT to pregnant women, and to their newborns?  Is non-specific immunoglobulin as effective as HIV Ig for this purpose? There are many sites across the nation open for participation (call 1-800-TRIALS-A). Gene Therapy One rapidly developing area of genetic therapeutics concentrates on developing genetic antivirals. Like other currently approved and experimental antivirals, genetic antivirals can be categorized by their mode of action. The products of gene therapy, like more conventional pharmacologic agents, include therapeutic strategies to inhibit reverse transcriptase, prevent viral entry into CD4 cells and to inhibit intracellular protease. Gene therapy targets HIV at the molecular level by selecting parts of RNA or DNA and moving them into cells. Genetic antivirals currently being researched include antisense molecules, ribozymes, decoys, transdominant mutants, toxins and immunogens. Antisense molecules are genetically tailored to bind directly to viral RNA and prevent its translation into protein building blocks for more virus particles. They can be delivered by viral vectors, engineered viruses that introduce genetic material to cells without harming them. Once inside the desired cell, they are either expressed (produced) constitutively (continuously) or induced by specific events in the HIV life cycle. Ribozymes are catalytic antisense molecules that cleave certain viral RNAs. Both antisense oligonucleotides and ribozymes can be designed to be useful even after HIV integrates into cellular DNA. There must be much higher concentrations of antisense or ribozyme to prevent RNA translation once HIV is already integrated in the genetic material of the infected cell than would be necessary to prevent HIV integration in the first place. Such high levels of expression raise serious concerns about toxic side effects. This problem is one reason why the 2 clinical studies that have been approved so far by the Recombinant DNA Advisory Committee (RAC) target integration mechanisms. The study of the effects of a "hairpin" ribozyme on HIV replication targets HIV RNA before it is integrated. This study is ongoing at the University of California at San Diego. The other gene therapy study, a Phase I evaluation of the safety of HIV-IT TAF (IT: immunotherapy, TAF: transduced, autologous fibroblasts), attempts to stimulate the immune system, particularly CD8+ cytotoxic lymphocytes, more broadly and to a more vigorous level than is allowed by the natural virus infection. The study recruits participants as early as possible after infection with HIV, and thus is limited to asymptomatic individuals with more than 200 CD4 T-lymphocytes (call 1-800-TRIALS-A for enrollment information). RNA decoys are another proposed genetic antiviral strategy that target specific HIV genes. The 2 proposed targets so far are rev and tat, genes that are responsible for regulatory functions. RNA decoys bind to the same proteins as HIV-produced rev and tat gene products, but do not initiate further activity. The decoys thus sabotage production of proteins needed to make new HIV. Unfortunately, the effectiveness of the decoys depends upon how much rev and tat are expressed in a given cell. The decoys may also bind to essential human cellular co-factors, and thus result in unwanted toxic effects. Decoys are not yet in human testing. Transdominant proteins are genetically engineered, non-functional copies of HIV viral proteins. They are designed to competitively decrease the ability of HIV to contact effector molecules needed in the HIV life cycle. Transdominant proteins face some of the same challenges as decoys; large numbers need to be manufactured and they must not interfere with normal cell functions. Furthermore, transdominant proteins expressed on the cell surface may initiate unwanted cytotoxic T-cell responses, and destroy the cell they were designed to protect. Also, use of transdominant proteins theoretically could place selective evolutionary pressure on HIV, resulting in a survival advantage for slower replicating but more pathogenic HIV. Immunoendocrinology The hybrid field called immunoendocrinology has been receiving notable interest from the HIV-infected community and their physicians in recent years. HIV disease results in consistent patterns of hormonal increases and decreases that are beginning to be confirmed and further defined by experimental research on the effects of recombinant human growth hormone, recombinant anabolic steroids, human chorionic gonadotropin, corticosteroids and dehydroepiandrosterone, among others. The following is a synopsis of some recent and planned studies of immunoendrocrinologic agents in the treatment of HIV disease. Human growth hormone received considerable attention at the X International AIDS Conference in Yokohama, Japan. A San Francisco-based study of 178 patients with AIDS-related wasting syndrome showed that daily treatment with recombinant human growth hormone resulted in significant increases in lean body mass and decreases in body fat (Bartnof, 1994). Increased lean body mass is associated with a survival advantage for people with HIV. The resulting clamor for access to the Serono growth hormone, which is available commercially in Canada and Mexico, although not in the United States, has resulted in negotiations between Serono, FDA and treatment activists to set up a Treatment IND program that would provide broad access to the drug for people with AIDS-related wasting. It is worth noting that Genentech also bioengineers a human growth hormone, but this product, while valuable in the treatment of growth abnormalities, is not useful in adding lean body mass for people who are experiencing wasting. Testosterone replacement is a hormonal strategy to correct a common deficiency in HIV disease, and at the same time potentially increase lean body mass. A survey of physicians in San Francisco discovered that many physicians are measuring the free-testosterone levels of their male HIV positive patients and supplementing testosterone on a variety of replacement schedules if they are found to be low or out-of-range, a condition known as hypogonadism. The choice of replacement is complicated by uncertainty about the frequency and amount of testosterone to offer. A clinical study of the treatment of HIV-hypogonadism with either weekly intramuscular injections of testosterone or a continuous-release sub-scrotal patch developed by Alza Pharmaceuticals is under development at the Community Consortium in San Francisco. Exact dosing schedules and degree of hypogonadism for study entry are still not determined. Michael Dullnig, MD, may have been responsible for the cross-over of anabolic and anti-catabolic steroid use from the bodybuilding subculture to the community of individuals affected by HIV wasting syndrome. In a column in the magazine Muscle Media 2000, Dr. Dullnig chronicled the results of his personal experimentation with a variety of anabolic steroids to treat his own wasting and osteomyelitis. He attempted to manipulate dysregulation in his hypothalamic-pituitary-gonadal axis (HPGA) through the use of anti-estrogen drugs like Nolvadex (tamoxifen) and Teslac (testolactone), gonadotropin Synarel (nafarelin acetate), oral testosterone such as Anadrol (testosterone undecenoate) and anabolics including Dianabol and Deca-Durabolin (nandrolone decanoate). After more than a year of experimentation, Dr. Dullnig contracted CMV retinitis, for which he refused treatment. On June 1, 1994, he took his own life. Dr. Dullnig raised more questions about the legitimate use of steroids in AIDS than he was able to answer, and researchers at the University of California at San Francisco are designing a study to answer one of those questions. The study will compare the use of nandrolone decanoate to placebo in HIV-wasting disease. Current FDA distrust of medical research on anabolic steroids has slowed progress on this to some extent. The design of the study is expected to finalize by 1995, and recruitment of participants should begin shortly thereafter. Two years ago, at the Laboratory of Tumor Cell Biology meeting in Washington, DC, there was a presentation of the case of a woman whose Kaposi's sarcoma lesions resolved completely during her pregnancy but returned after she gave birth. It was concluded that human chorionic gonadotropin (HCG), a hormone that increases in concentration in pregnant women, was responsible for the remission. Further investigation suggests that it is a single subunit of HCG that has anti-tumor properties. The National Cancer Institute is developing a pure source of the subunit of HCG for clinical testing in KS. Studies of an adrenal cortical hormone, dehydroepiandrosterone (DHEA), which is reported to inhibit viral expression in animals and has been associated with decreased risk of cancer, have been completed in San Francisco, New Orleans, Paris and Amsterdam. It had been repeatedly observed in the medical literature that increased levels of glucocorticoids and decreased levels of DHEA are found in persons with advanced HIV disease. These observations led to the hypothesis that DHEA deficiency may worsen immune status. Laboratory studies at Temple University in Philadelphia found that DHEA supplementation resulted in modest down-regulation of HIV replication and reduced syncytia (giant cell) formation. The researchers conclude that treatment with DHEA down-regulates latency reactivation--or maintains the clinical latency state. They speculate that reduced levels of the cellular transactivator NF-kB may contribute to latency, and that DHEA may help maintain low levels of intracellular NF-kB activation. San Francisco researchers did not find any CD4 cell count rises with DHEA oral administration, but did see encouraging changes in the marker neopterin. A final note on hormonal strategies to combat HIV disease involves the reappearance of a neurotransmitter precursor called gamma hydroxy butyrate (GHB). GHB is a precursor and a breakdown product of gamma aminobutyric acid (GABA), a chemical in the brain that has been implicated in the pathogenesis of Huntington's disease, Parkinsonism, epilepsy, schizophrenia and senile dementia. GHB was originally developed as an anesthetic, but was found to have unacceptable central nervous system depressant and hallucinogenic effects. It then passed through a period of use in veterinary medicine for large animals. GHB appeared simultaneously in the recreational drug world and in the bodybuilding subculture, where its minimal growth hormone stimulating properties were valued. It has reappeared in the activist "underground" because of purported immune-enhancing effects, none of which are documented in the medical literature. Serious seizures, coma and death have been reported following ingestion of GHB. The FDA has been investigating and prosecuting manufacturers of the drug for several years. It is highly unlikely that GHB will find a place in the anti-HIV drug armamentarium. Psycho-neuro-immunology Psycho-neuro-immunology (PNI) is a 30-year-old medical specialty that studies the interactions among psychological issues, neurological and hormonal factors, and the immune system. PNI is a well-established branch of medical science, with both developed theoretical models and published experimental research studies that number in the thousands. Accumulated research evidence demonstrates that psychological issues (especially intense and sustained emotional experiences), and performance on healthcare behaviors (sleep, nutrition, toxin intake and others) can impact significantly the functioning of the immune system. The psychophysiological mechanisms whereby mind can impact brain and thus immunity are understood and well delineated. One significant pathway is the cortico-hypothalamic-pituitary-adrenal axis (CHPA). Sustained activation and arousal of the axis is intimately tied with depressed immune system functioning, especially T-cells. Adrenal, produced by the body during intense emotional states such as fear, panic and rage, is known to suppress T-cell functioning. The following psychosocial and health behavior cofactors have been identified as impacting the immune systems of HIV-infected individuals: grief, depression, cognitive belief that HIV equals death, trusted support, self-assertiveness, coping style and body care performance (nutrition, sleep, toxins and physical exercise). Based on this research, mental health professionals recently have begun to craft psychological interventions that teach HIV-infected individuals about how positive cofactor management can directly boost the immune system. Experimental studies on the efficacy of psychosocial interventions as immune-boosting treatment for HIV infection must be launched to fully evaluate the potential of this strategy. Adoptive Immune Transfer Bone marrow transfer (BMT) has been in clinical use in the U.S. since 1968 for marrow deficiency states associated with certain cancers and their treatments. Most bone marrow transfers have involved identical twins (syngeneic transfer) or genotypically human leukocyte antigen (HLA)-identical individuals (allogeneic). HLA is the genetic locus that codes for the immune system's mixed histocompatibility complex (MHC) cell surface molecules, including class I and class II antigen presentation molecules. Five diseases have been treated with BMT, including AIDS. This may be a valuable strategy to pursue, since HIV seems to decrease the number of stem cells that are responsible for making all types of blood cells. Variations on BMT, including partially matched allogeneic cell transfers of undifferentiated peripheral blood white cells, have now been performed. At least one individual in San Francisco has received repeated transfers from his siblings, and a protocol for other such transfers has received the approval of the Project Inform Institutional Review Board. A small clinical study of partially HLA-matched individuals awaits funding at HIVCare in San Francisco, and another study is underway at Case Western Reserve Institute in Cleveland, OH. Anecdotal evidence indicates that some engraftment of stem cells from the uninfected donor is possible, so the recipient may make new, uninfected T-cells, and other previously lost immune functions are restored. The transferred cells, if genetically unaltered, are still at risk of becoming HIV-infected. Thymic transplants are the next logical step in transplant technology in HIV disease. The thymus, which is responsible for the maturation of virtually all T-cells in adults, is a gland found under the sternum that continually shrinks as a function of both age and stress. The engraftment of transplanted thymic tissue from one mouse to another shows that thymic tissue homes for the thymus and immediately begins conditioning new T-cells. Thymic transplants in AIDS may help to restore lost CD4 function. Research is set to begin on fetal thymic transplants. Some researchers intend to alter the transplant tissue in such a way that it will be resistant to HIV infection, and thereby will enjoy an advantage over simply transferring CD4 cells that can immediately become HIV-infected. Meanwhile, 6 thymic factors that have been derived from thymic tissue have been investigated in HIV disease and variable results have been reported. Three factors are natural thymic extracts--thymodulin, thym-uvo-cal and thymostimulin. The other 3 are patented, synthetic molecules--thymosin-a-1, thymic humoral factor and thymopentin. Thymulin, thymosin-b and thymopoietin are also synthesized in the human thymus, but have not been clinically evaluated for use in HIV disease. Thymodulin is available commercially in Italy, and has been used extensively in Europe to treat conditions with associated immune dysfunctions. (See AIDS Treatment News, Issue 202, July 8, 1994 for a complete history and bibliography of thymodulin.) Thymopentin is available through participation in clinical studies in the US. One large multisite study is recruiting asymptomatic HIV positive volunteers with CD4 counts from 100-400 and 6 months prior AZT use; a smaller study, looking intensively at viral load and lymphoproliferative responses, recruits volunteers with CD4 counts less than 400. Intramuscularly injected thymic humoral factor is available in double-blinded, placebo-controlled clinical studies sponsored by Abbott Pharmaceuticals at sites around the U.S. (Call 1-800-TRIALS-A for open sites and enrollment information.) Six new gene therapy grants were approved by the National Institute of Allergy and Infectious Diseases in September 1994. Most involve removing cells from persons with HIV or their siblings, changing and expanding the cells, and returning them to the patient. These experimental approaches are a hybrid of gene therapy and adoptive immune transfer. In each case, human studies are expected to begin within the next 4 years. SOURCES Baker RA. Immune Modulation Therapy: Interleukin-2 and interleukin-12. BETA (Bulletin of Experimental Treatments for AIDS): 12-19. March 1994. Baker RA and others. Vitamins and Nutritional Supplements in HIV Disease: A Transcript of BETA LIVE! teleconferences held April 5, 7 and 12, 1994. BETA (Bulletin of Experimental Treatments for AIDS): 22-32. June 1994. Bartnof HS. Treatment updates from the X international conference on AIDS in Yokohama, Japan. BETA (Bulletin of Experimental Treatments for AIDS): 10-17. September 1994. Bihari B. The role of free radicals and antioxidants in HIV disease. BETA (Bulletin of Experimental Treatments for AIDS): 5-6. December 1993. Bowers M. Vaccines for HIV. BETA (Bulletin of Experimental Treatments for AIDS): 1-9. March 1993. Bowers M. Vaccines Revisited. BETA (Bulletin of Experimental Therapies for AIDS): 7-11. December 1993. Coodley GO and others. Endocrine function in the HIV wasting syndrome. Journal of Acquired Immune Deficiency Syndromes 7(1): 46-51. 1994. Cooper JR and others. Amino acid transmitters. In The Biochemical Basis of Neuropharmacology: 133-189. Oxford University Press, 1991. Dropulic B and others. Gene therapy for human immunodeficiency virus infection: genetic antiviral strategies and targets for intervention. Human Gene Therapy 5: 927-939. August 1994. Dullnig M. X-cerpts. Muscle Media 2000 36: 66-71. February 1994. Dyner TS and others. An open-label dose-escalation trial of oral dehydroepiandrosterone tolerance and pharmacokinetics in patients with HIV disease. Journal of Acquired Immune Deficiency Syndromes 6: 459-465. 1993. Galpin JE and others. A phase I clinical trial to evaluate the safety and biological activity of HIV-IT (TAF) (HIV-1IIIB env-transduced, autologous fibroblasts) in asymptomatic HIV-1 infected subjects. Human Gene Therapy 5: 997-1017. August 1994. Gilden D. Oxidative Stress and AIDS. BETA (Bulletin of Experimental Treatments for AIDS): 3-4. December 1993. Gilden D. Nutritional Intervention in HIV Disease. BETA (Bulletin of Experimental Treatments for AIDS): 3-11. March 1994. James J and others. Thymodulin. AIDS Treatment News 202: 1-7. July 8, 1994. Johnson HM and others. How interferons fight disease. Scientific American 270(5): 68-75. May 1994. Levy J and others. Passive hyperimmune plasma therapy in the treatment of acquired immunodeficiency syndrome: results of a 12-month multicenter double-blind controlled trial. Blood 84(7): 2130-2135. October 1994. Levy J. Passive hyperimmune therapy in the treatment of AIDS and ARC. Journal of Clinical Apheresis 6: 122-123. 1991. Mosmann, TR. Cytokine patterns during the progression to AIDS. Science 265: 193-194. July 8, 1994. Visser JW and others. The expression of cytokine receptors by purified hemopoietic stem cells. Stem Cells. Suppl 2: 49-55. July 1993. Wisniewski TD and others. The relationship of serum DHEA-S and cortisol levels to measures of immune function in human immunodeficiency virus-related illness. American Journal of the Medical Sciences 305(2): 79-83. Yang JY. Inhibition of HIV-1 latency reactivation by dehydroepiandrosterone (DHEA) and an analog of DHEA. AIDS Research and Human Retroviruses 9(8): 747-754. August 1993. TI RESEARCH NOTES AU Leslie Hanna; associate editor of BETA, Mark Mascolini; freelance writer who specializes in HIV infection. TX Clarithromycin for Prevention of MAC Interim results of a U.S./European study comparing clarithromycin (Biaxin) with placebo in people with CD4 counts at or below 100 cells/mm3 showed that the antibiotic reduced the risk of disseminated Mycobacterium avium Complex (MAC) infection by 68% and prolonged survival. Principal investigator Mark Pierce, MD, of Vanderbilt University in Nashville, reported that 343 people taking 500 mg of clarithromycin twice daily for a median 8.7 months had only a 4.5% rate of MAC detectable in blood compared with a 12.6% rate among 341 people taking placebo. People taking clarithromycin also had a 30% lower risk of death from any cause than people taking placebo. Although those in the clarithromycin group had more gastrointestinal complaints and altered taste sensation than people who took placebo, the overall incidence of side effects was similar in the 2 groups. Only 6% stopped taking clarithromycin because of adverse side effects compared with 4% who stopped taking placebo. [MM] Pierce M and others. A placebo-controlled trial of clarithromycin prophylaxis against MAC infection in AIDS patients. 34th Interscience Conference on Antimicrobial Agents and Chemotherapyerapy. Orlando, Florida. October 1994. Abstract A/2. HIV Replication Rate Faster Than Suspected The notion that HIV rests languidly inside cells for years after it first infects the body has gradually given way to the belief that the virus is constantly multiplying and being cleared from the body by immune defenses. But just how fast that HIV "turnover" rate might be was not appreciated until recent reports by David Ho, MD, of the Aaron Diamond AIDS Research Center in New York, and George M. Shaw, MD, PhD, of the University of Alabama at Birmingham. Ho studied an investigational protease inhibitor to determine the rate of HIV replication before and during therapy. He calculated that the body of an infected person produces and clears anywhere from 60 million to 1.7 billion HIV particles daily. The rapidity of this turnover does not depend on how compromised the immune system is. Even during the first 5 years of HIV infection when CD4 counts are usually high, Ho estimates that newly-infected cells are producing billions of new HIV particles. Shaw used a different approach to estimate the rate of viral turnover. Studying the antiretroviral drug nevirapine in combination with AZT and ddI, he calculated the proportion of virus that mutated into nevirapine-resistant strains over the course of the study. Within 28 days after nevirapine was added to the AZT/ddI regimen, 100% of the virus isolated in plasma had a key mutation signifying resistance to nevirapine. The finding that "wild" or nonresistant strains of HIV were completely replaced by a resistant strain in 4 weeks, Shaw explained, indicates that the entire viral population "turned over" in that time. The implication of this furious replication rate, according to Shaw's colleague Michael Saag, MD, is that clinicians should "keep the viral burden as low as possible for as long as possible." Ho said his findings bolster the rationale for beginning antiretroviral therapy as soon as HIV infection is detected. But such a strategy will be practical, he added, only when more potent anti-HIV agents are available. [MM] Ho DD. Long-term non-progressors with HIV-1 infection. 34th Interscience Conference on Antimicrobial Agents and Chemotherapy. Opening session. Orlando, Florida. October 1994. Shaw G and others. Rapid HIV-1 turnover in patients receiving combination nevirapine therapy. 34th Interscience Conference on Antimicrobial Agents and Chemotherapy. Orlando, Florida. October 1994. Abstract I64. More AZT-resistant HIV Found in Newly-Infected People The rate at which AZT-resistant strains of HIV are found in recently infected people has been growing steadily in the developed world since 1988. A joint U.S./Swiss/Australian study reported by Douglas L. Mayers, MD, of the Walter Reed Army Institute of Research, found that 3% of 38 people newly-infected in 1988 to 1990 harbored the resistant virus, 8% of 39 people were infected with the AZT-resistant strain in 1992 and 19% of 86 people showed evidence of the resistant virus soon after infection in 1993 and 1994. The prevalence of infection with AZT-resistant HIV did not vary greatly from country to country in the study. If people infected with AZT-resistant virus are not treated with AZT immediately after infection, strains of the virus that are sensitive to AZT will quickly outnumber the resistant virus, according to Mayers. But as soon as such people are given AZT, the resistant virus will reemerge. As a result, Mayers said, it may eventually become necessary to determine whether a person harbors the resistant strain before starting therapy with AZT. [MM] Mayers DL and others. Prevalence of AZT-resistant HIV-1 in persons seroconverting in Switzerland, Australia, and the United States between 1988 and 1994. 34th Interscience Conference on Antimicrobial Agents and Chemotherapy. Orlando, Florida. October 1 1994. Abstract A11. Oral Ganciclovir Delays Progression to CMV Prophylaxis with oral ganciclovir significantly delays the onset of cytomegalovirus (CMV) disease in people with low CD4 cell counts, according to the results of a placebo-controlled trial headed by Stephen A. Spector, MD, of the University of California, San Diego. Spector said that the oral formulation of this antiherpes agent may also prolong survival for people with more advanced HIV disease. AIDS expert Clyde Crumpacker, MD, of Beth Israel Hospital in Boston, hailed the findings as strong evidence that oral ganciclovir could soon become a standard prophylactic regimen for people approaching the latter stages of HIV disease. The incidence of 2 serious blood disorders, neutropenia and anemia, was substantially higher among people taking oral ganciclovir than in those who took placebo, Spector reported. As a result of these problems, those receiving ganciclovir used G-CSF and erythropoietin, which stimulate growth of new blood cells, more often than study participants who got placebo. See page ___ for more information on the implications of this study. [MM] Spector SA and others. A randomized, double-blind study of the efficacy and safety of oral ganciclovir for the prevention of cytomegalovirus disease in HIV-infected persons. 34th Interscience Conference on Antimicrobial Agents and Chemotherapy. Orlando, Florida. October 1994. Abstract A9. Wolf DG and Spector SA. Central nervous system infection with ganciclovir-resistant human cytomegalovirus in AIDS patients determined by analysis of the UL97 gene in cerebrospinal fluid. 34th Interscience Conference on Antimicrobial Agents and Chemotherapy. Orlando, Florida. October 1994. Abstract H27. Viral Load Is Better Than CD4 as a Marker of Nonprogression Viral load, an estimate of the total amount of virus in the body, can distinguish between people destined to progress to AIDS within a few years and those whose immune systems will stay healthy for at least 5 years. A low viral load can distinguish a "long-term nonprogressor" from a more rapid progressor even if both have high CD4 cell counts when their viral loads are measured. Updating a recently published report in which viral load was calculated by counting copies of HIV messenger RNA (mRNA), David Baltimore, PhD, of the Massachusetts Institute of Technology in Cambridge, said his group assayed 150 blood samples collected from HIV positive people in 1984 and 1985 and stored by the New York Blood Bank. The 150 clinical nonprogressors were chosen at random, stratified by CD4 counts and followed to progression to AIDS. Based on this retrospective study, it appears that viral mRNA may be a strong predictor of disease progression even when CD4 counts are stable or normal. Disease progression was slower in people who had fewer than 2,000 mRNA copies per microgram of blood than in those with more than 2,000 copies. The 2,000-copy dividing line separated progressors from nonprogressors even when both had between 500 and 750 CD4 cells/mm3 at the time their blood was sampled. The predictive power of CD4 counts is limited, Baltimore speculated, because as many as 90% of CD4 cells in tissues may be destroyed before CD4 counts in the blood begin to decrease. As a result, viral load measures may be a much better way to predict progression and to guide antiretroviral therapy. [MM] Baltimore D. HIV research in crisis. Annual Meeting of the Laboratory of Tumor Cell Biology. Rockville, Maryland. September 1994. Abstract 2. Saksela K and others. Human immunodeficiency virus type-1 mRNA expression in peripheral blood cells predicts disease progression independently of the number of CD4+ lymphocytes. Proceedings of the National Academy of Sciences USA. 91: 1104-1108. 1994. New Strategies Against KS Work by Barbara Ensoli, MD, and Yanto Lunardi-Iskandar, MD, in the National Cancer Institute laboratory of Robert C. Gallo, MD, is giving scientists a better idea of how HIV triggers the development of Kaposi's sarcoma (KS). Research is suggesting new therapeutic approaches for these malignant lesions. Gallo believes that HIV has only an indirect role in promoting the development of KS. First, it triggers an outpouring of inflammatory cytokines, immune system proteins that eventually lead to the swellings typically seen in late-stage KS. Levels of these cytokines are often already high in gay men, even those not infected with HIV, due to other chronic viral and/or intestinal infections. Second, an HIV protein called tat probably contributes to the growth of KS tumor cells. Ensoli reported that tat released by T cells that are acutely infected with HIV can be taken up by KS cells. There, tat works together with a substance called basic fibroblast growth factor (bFGF) to promote the continued growth of the spindle-shaped KS tumor cells. This action of tat may explain why KS is more common and aggressive in people with HIV infection than in HIV negative individuals. However, the only tat inhibitor tested to date in patients with KS, the same Hoffmann-La Roche drug studied for its effect against HIV, proved as ineffective against the cancer as it did against HIV. Another possibly more potent tat inhibitor is now being developed by Allelix Biopharmaceuticals in Mississauga, Ontario. Lunardi-Iskandar found that sera from pregnant women block the growth of KS in a laboratory "cell line" of the tumor that he developed. He then showed that the active factor in the sera is the alpha chain of a pregnancy hormone called human chorionic gonadotropin (alpha-hCG). In immunodeficient mice, alpha-hCG stifled the growth and spread of KS tumor cells. In one HIV-positive woman with extensive KS, the lesions cleared during pregnancy, then returned after she gave birth. The implication of a pregnancy hormone in the suppression of KS could explain why KS is so much more prevalent in HIV-infected men than in women. Gallo said that alpha-hCG is a good candidate for clinical trials of KS since biopsy specimens from KS tumors of patients show evidence of cell surface molecules that can link with alpha-hCG, and since alpha-hCG is not toxic at concentrations studied so far in his lab. In a survey of the state of KS drug research presented at the meeting, leading researchers including Susan E. Krown, MD, of New York University, and Steven A. Miles, MD, of UCLA, decried the tendency of many clinicians to delay therapy until the later stages of progression. They urged community oncologists, dermatologists and primary care physicians to enroll KS patients in one of many trials of promising experimental therapies. [MM] Gallo RC. Kaposi's sarcoma. Annual Meeting of the Laboratory of Tumor Cell Biology. Rockville, Maryland. September 1994. Ensoli B and others. In vitro and in vivo evidence that basic fibroblast growth factor (bFGF) and HIV-1 tat protein synergize in inducing Kaposi's sarcoma development. Annual Meeting of the Laboratory of Tumor Cell Biology. Rockville, Maryland. September 1994. Abstract 54. Lunardi-Iskandar Y and others. A pregnancy hormone human chorionic gonadotropin (hCG) blocks tumorigenesis and metastasis of KS cells (KS Y-1) in immunodeficient mice. Annual Meeting of the Laboratory of Tumor Cell Biology. Rockville, Maryland. September 1994. Abstract 55. Marco M and others. KS project report. Part 1 of the oncology project. Annual Meeting of the Laboratory of Tumor Cell Biology. Rockville, Maryland. September 1994. Abstract 51. ddI Linked to 80% Survival After 4 Years A 5-year follow-up of a 77-person ddI trial that began at the National Cancer Institute (NCI) in 1988 indicates that ddI, alone or in combination with AZT, is often well tolerated for up to 4 years and probably prolongs survival in a large majority of people with CD4 counts between 100 and 300 cells/mm3. All patients who entered the study had a CD4 count below 400 cells/mm3, and the median survival for all was 28 months after therapy began. But among those with counts between 100 and 300, 80% survived for 4 years. Therapy-induced increases in CD4 counts 3 months to 1 year after the trial began were significant predictors of survival. The principal drug-related toxicity was pancreatitis in 8%. Robert Yarchoan, MD, the study's principal investigator, concluded that "HIV-infected patients with moderate infection can have reasonable survival with current therapies." He stressed, though, that the results would not lead him to recommend ddI as single-drug therapy for people in the 100 to 300 CD4 cell/mm3 range. [MM] Yarchoan R and others. Five-year follow-up of a phase-I study of didanosine (ddI) used alone and with zidovudine (AZT) in patients with advanced HIV infection. Annual Meeting of the Laboratory of Tumor Cell Biology. Rockville, Maryland. September 1994. Abstract 351. Delayed Progression of HIV Disease In an "Editorial Comment" in a recent issue of the journal AIDS, Philippa Easterbrook provided a summary of studies of delayed HIV disease progression. She noted a shift in focus of natural history studies of HIV disease, which now tend to examine factors that contribute to slow rates of disease progression or even stabilization and non-progression. There are several ongoing studies of people with HIV who remain healthy and asymptomatic for 10 years or more after seroconversion. Commonly called "long-term healthy seropositives" or "non-progressors," such people are often defined for study purposes as individuals who lack clinical symptoms of HIV disease, have CD4 cell counts greater than 500, and experience no "net loss" of CD4 cells over a specific time interval that qualifies as "course of infection." From study to study, approximately 5-15% of people with HIV can thus be defined as non-progressors. Non-progressors cannot be characterized by race, age, sex or transmission category. (No large studies of women or injection drug users have been conducted.) However, studies have revealed certain patterns in the immune responses of these individuals. In the months immediately following infection, the CD4 cell responses of non-progressors differ from those in people whose disease develops more rapidly. This may be attributable to the virulence of the particular strain of HIV with which the non-progressors were infected and/or to their unique immune response to infection with HIV. Researchers are continuing to learn more about the specific anti-HIV immune responses that may encourage non-progression. For example, non-progressors appear to have high levels of CD8 cells and strong, continuing CD8 responses that target specific proteins of HIV. There is insufficient evidence to suggest that high levels of certain micronutrients (e.g., vitamins C and B1, niacin) can slow HIV disease progression. The possible influence on disease progression of lifestyle factors such as exercise, stress reduction, sleep and psychological state have not been well studied. Generally, studies have failed to find evidence to support the notion that "healthy" lifestyle changes (e.g., reducing recreational drug use) after seroconversion can significantly influence the course of HIV disease. Instead, baseline health status and early immune responses to HIV infection may be more relevant to long-term prognosis. Laboratory marker characteristics early in HIV infection, such as beta-2 microglobulin, neopterin and p24 antigen, may be predictive of disease course, as well as reflective of the viral strain. Further research is needed to better understand how an individual's particular biologic and behavioral factors impact disease progression. See also "Treatment Updates from Yokohama" in the September 1994 issue of BETA. [LH] Easterbrook PJ. Non-progression in HIV infection. AIDS 8(8): 1179-1182. August 1994. bDNA Test Proves Useful in Clinical Research Setting Researchers from the National Institute of Allergy and Infectious Diseases (NIAID) have tested the clinical utility of the branched DNA (bDNA) assay, a new and relatively simple test for determining in vivo levels of HIV RNA in the blood. Unlike CD4 cell count results, which may vary signficiantly, the bDNA test results are more consistent. Until recently the test was available only in research settings; now it is widely available for clinical use. In the NIAID study, researchers (1) compared 3 tests of viremia (bDNA, end-point dilution culture and immune complex- dissociated, or ICD, p24 antigen) and (2) used bDNA to determine changes in viral load. The study group was composed of HIV-1 positive people who were outpatients at the NIAID HIV Clinic. The sensitivity of HIV-1 RNA and ICD serum p24 assays, reproducibility of the bDNA assay and association between viremia and CD4 count were evaluated by testing plasma and serum sample from 102 people with HIV who were being screened for enrollment into clinical trials. Virologic data from 30 people was used by researchers to gauge the utility of the tests for creating therapeutic interventions by monitoring viremia. Twenty-three (23) had 100-300 CD4 cells/mm3 and were participants in a clinical trial of combination therapy (AZT, ddI and U-90). Seven (7) had less than 200 CD4 cells/mm3 and were enrolled in a trial of interleukin-2 (IL-2). Researchers determined that the bDNA was the most sensitive and reproducible test of the 3 for monitoring viral load across all disease stages. They note that plasma cultures represent a better measurement for HIV infectivity, and may still have clinical utility. Although ICD serum p24 antigen testing is fairly reproducible, not only is it not as sensitive as bDNA testing, but it does not always measure virus. Moreover, it seems to be incapable of detecting antigen in people with high levels of antibodies. Among the 23 people in the combination therapy trial, bDNA detected significant decreases in viral load in 13 after 1 week; plasma culture and ICD p24 antigen tests detected decreases in only 7. In the 7 interleukin-2 trial participants, plasma viremia was seen to increase in all 7 immediately after infusions; levels returned to baseline (preinfusion) within 1 month. The p24 antigen test detected changes in virus level in 3 of the 7 patients. The investigators conclude that "the bDNA assay yields reproducible results, is relatively easy, and should be useful in measuring HIV-1 RNA in patients in clinical trials." In addition to its sensitivity and reliability in determining viral load, bDNA promises to be a valuable tool to help evaluate the efficacy of treatments, when to change therapy and to elucidate the association between viral load and HIV disease progression. (See related report on the bDNA and other assays in "Individualized Therapy" in the September 1994 BETA.) [LH] Dewar RL and others. Application of branched DNA signal amplification to monitor human immunodeficiency virus type 1 burden in human plasma. Journal of Infectious Diseases 170: 1,172-1,179. November 1994. Cohort Study of Healthy Long-Term HIV Positives Findings from the San Francisco City Clinic Cohort Study (SFCCC), led by Susan Buchbinder, MD, appear in the August 1994 issue of AIDS. Participants were gay and bisexual men who took part in a STD clinic study of hepatitis B in 1978-1980. Blood samples drawn at that time were frozen, and testing of the samples for HIV began in 1983, when recruitment started for prospective studies of people with HIV/AIDS. This study sought to identify and describe a subgroup of men infected with HIV for 10-15 years who were healthy and asymptomatic. Researchers also looked for associations between HIV disease stage and either sexually transmitted diseases (STD) or recreational drug use. Upon written consent from the participants, samples were tested for HIV, and positive results were confirmed by immunofluorescence or Western blot. Behavioral data, which had been gathered for the purposes of the original hepatitis study, was used for the HIV/AIDS (SFCCC) study. From the time of entry, participants were evaluated every 6-12 months. Evaluations consisted of a physical examination, medical history reporting and a full battery of blood tests (complete blood, CD4 and CD8 counts; beta 2-microglobulin and p24 antigen). The same laboratory performed the blood work from 1988-1992. AIDS diagnoses (according to the 1987 CDC definition) and deaths were recorded through 1992. Data was available for analysis for 588 men with determinable dates of HIV seroconversion and 197 HIV negative controls. Of the HIV positive men, 539 were estimated to have seroconverted before 1983. Researchers determined, compared and analyzed characteristics of the men who seroconverted before 1983, or who had been infected for 10-15 years. Of them, 42 men (8%) had been classified as healthy long-term HIV positives (HLP). The operational definition of HLP was "men without AIDS with CD4+ cell counts greater than 500mm3 at their most recent visit, 10 years or more after seroconversion." Those men with AIDS or fewer than 200 CD4 cells/mm3 at their most recent visit were characterized as progressors and represent a comparison group to the HLP. There were 382 men with AIDS or less than 200 CD4 cells/mm3. Of these, 177 were alive in 1990, 102 of whom were available for follow-up in 1992. Compared to progressors, HLP had more stable CD4 counts, higher CD8 counts and fewer immunologic, blood and clinical abnormalities. HLP were less likely to have used AZT than progressors (38% vs 94%). Also, HLP were less likely to have had enteric infections or to have used tranquilizers. The incidence of STD and recreational drug use was roughly the same for HLP and progressors. Compared to the HIV negative controls, HLP had lower CD4 counts and white blood cells. HLP had higher levels of CD8 cell than controls or progressors. Researchers conclude that HLP "represent a distinct subgroup within the cohort. Compared to other men with long-term HIV infection, these men have more stable CD4+ cell counts, less abnormal immunologic and hematologic parameters and fewer significant HIV-related signs or symptoms." After experiencing an initial drop in CD4 cells, cell counts stabilize and disease progression appears to decrease or even stop among these men. The distinctive elevated levels of CD8 cells seen in HLP suggest that these immune cells play an important role in delaying disease progression. Other studies have noted that people with asymptomatic HIV disease as well as HLP tend to have relatively high levels of CD8 cytotoxic lymphocyte (CTL) activity. The delayed disease progression seen in HLP has not yet been fully characterized. The investigators concluded that "it does not appear that slower [disease] progression is due to decreased exposure to behavioral or sexual risk factors. The possibility exists that HLP have slowed or arrested HIV disease progression through effective immunologic responses, host genetic factors, viral factors, or as yet unidentified biologic or behavioral cofactors. The role of these mechanisms...deserves further investigation." (See the Yokohama Treatment Updates report in the September 1994 issue of BETA.) [LH] Buchbinder SP and others. Long-term HIV-1 infection without immunologic progression. AIDS 8(8): 1,123-1,128. August 1994. Malaria as AIDS Therapy? Henry Heimlich, MD, renowned inventor of the Heimlich maneuver, is currently promulgating another unique medical strategy. A treatment for AIDS, his experimental Induced Malaria Therapy (IMT) is at best unusual; many are calling it scientifically highly questionable. IMT involves injecting blood that is infected with the parasites that cause malaria into people with AIDS. Dr. Heimlich theorizes that the resulting malarial infection prompts a strong anti-HIV immune response. The therapy requires hospitalization and causes high fevers. Three to four weeks after infection with malaria, the patient receives treatment for this parasitic disease. Human studies of Dr. Heimlich's unusual regimen have already begun in China. Detractors, including Anthony Fauci, MD, director of the National Institutes of Allergy and Infectious Diseases (NIAID), assert that IMT is not only unorthodox but unsound, exploitative and dangerous. A coalition of American AIDS specialists have petitioned U.S. officials to investigate Dr. Heimlich's fundraising and research. In his defense, Dr. Heimlich cites the prior use of a similar (pre-penicillin) therapy for treating syphilis, and refers to the medical establishment as reactionary. He asserts that his inoculations are prepared with a mild strain of malaria (Plasmodium vivax), and that other pathogens are carefully screened out. He says that the people who have received IMT have recovered from malaria and are feeling better. [LH] Warrick P. Famed doctor's treatment for AIDS: malaria. San Francisco Examiner p. A-1, A-13. October 30, 1994. New Burroughs Wellcome Drug 1592U89 (159), an investigational anti-HIV drug manufactured by Burroughs Wellcome, is a nucleoside analogue. Laboratory tests show that it is active against HIV and synergistic with AZT. In vitro studies indicate that HIV develops resistance to 159 extremely slowly. In addition, strains of HIV resistant to AZT are sensitive to 159. Animal studies show that 159, like AZT, crosses the blood-brain barrier without causing detectible central nervous system side effects. Currently in a Phase I dose-escalating study, Phase I/II studies are expected to begin in late 1994 or early 1995. New Wellcome antiviral compound shows promise as anti-HIV agent. Burroughs Wellcome Co. News Release. October 5, 1994. MAC Treatment Increases Survival in People with AIDS To date, there has been no consensus among scientists and clinicians about the benefits of treating people with advanced AIDS for Mycobacterium avium complex (MAC). A report published in the September 1994 issue of the Journal of Infectious Diseases offers evidence of an association between survival and antimycobacterial treatment in people with advanced HIV disease. The authors of the report examined data from a prospective observational study. Although the U.S. Public Health Service Task Force now recommends using multiple antimycobacterial agents to treat disseminated MAC, this study concluded before that recommendation was issued. Since participants in this study were not routinely offered such treatment, the study represents an opportunity to study the natural history of MAC in severely immunodepressed persons, according to the authors. The study involved 367 people with 50 or fewer CD4 cells/mm3 and MAC bacteremia, or disseminated MAC. MAC bacteremia was independently associated with an increased risk of death; 23% died within 28 days of diagnosis. (The authors note that few of these people received treatment.) People who were treated survived longer than those who did not (263 vs 139 days); treatment was independently associated with increased survival. One problem with this type of analysis is an inability to detect cause and effect. The authors also hypothesize that because people with AIDS sometimes quit taking their medications when they become very sick, use of medications may actually be a marker for less severe illness. Although they found only an association--not a cause-and-effect relationship--between anti-MAC treatment and survival, this finding at the very least supports the recommendation to treat people with MAC bacteremia. Finally, because some people "will not survive long enough to benefit from drug treatment...our results underscore the importance of chemoprophylaxis against disseminated MAC infection and also the early diagnosis of this infection." [LH] Chin DP and others. The impact of Mycobacterium avium complex bacteremia and its treatment on survival of AIDS patients--a prospective study. The Journal of Infectious Diseases 170: 578-584. September 1994. Trimethoprim-Sulfamethoxazole (TMP-SMX) Desensitization Researchers from Harbor-UCLA Medical Center in Torrance, CA, recently published a study of their TMP-SMX desensitization protocol. TMP-SMX (Bactrim, Septra, others) is an effective and inexpensive antibiotic for preventing Pneumocystis carinii pneumonia (PCP) as well as toxoplasmosis. It is also the first-line treatment for isosporiasis, a severe AIDS-defining diarrhea. Some evidence suggests that TMP-SMX also may play a partial role in protecting against Mycobacterium avium complex. However, many people are forced to discontinue using the drug due to adverse reactions such as high fevers, rash, itchiness and muscle aches and pains. For these individuals, one option is to switch to another agent. A more compelling option is to try TMP-SMX desensitization. Desensitization allows one to begin taking a low, tolerable dose of the agent and to gradually increase the tolerated amount until an effective level is reached. Twenty-three (23) of the original 28 participants, or 82%, experienced no difficulty with the protocol and continued to take TMP-SMX. Four people failed on the protocol. Within the first 20 days of the study, they developed severe skin reactions that were not alleviated with antihistamine treatment. One person dropped out of the study for personal reasons. All but 2 were desensitized on an outpatient basis; 2 required hospitalization for severe diarrhea. During the 10-day protocol, patients were seen 4 times. Four patients used antihistamines for itchiness. See figure 1 for the study protocol. [david--please insert figure 1] Six of the 23 participants considered successfully desensitized subsequently stopped taking TMP-SMX. Four developed rashes 12-33 weeks after completing the protocol. Of these 4 with rashes, one already had significant eosinophilia before developing the rash, and another developed the rash when treated with sulfadiazine for another OI. Although the other 2 of the 6 who discontinued only had mild itchiness, rather than rash, they stopped taking the drug on the advice of their primary physicians at weeks 4 and 12 of follow-up. Another 6 who were successfully desensitized were lost to follow-up. Of the remaining 11, one died of Kaposi's sarcoma; the other 10 continue to take TMP-SMX without difficulty. For information about another TMP-SMX desensitization protocol, developed by the Conant Medical Group in San Francisco, see Research Notes in the September 1994 issue of BETA, p. 54. [LH] Absar N and others. Desensitization to trimethoprim/sulfamethoxazole in HIV-infected patients. The Journal of Allergy and Clinical Immunology 93(6): 1001-1005. June 1994. Approval Sought for Kaposi's Sarcoma (KS) Treatment Liposome Technology, Inc. filed a new drug application (NDA) with the Food and Drug Administration (FDA) on September 7, 1994, seeking approval of their stealth liposome formulation of the anti-cancer agent doxorubicin hydrochloride (DOX-SL) for the treatment of KS. DOX-SL is indicated for treating AIDS-related KS in people who cannot tolerate or have failed standard treatment. Efficacy data gathered in a large European/Australian Phase II/III study of DOX-SL were presented at the X International AIDS Conference in Yokohama, Japan. In this study, 247 people with moderate to severe KS received 1 of 3 intravenous doses of DOX-SL every 2 weeks. Of 133 participants for whom complete data was available, 63% had positive responses, 29% experienced disease stabilization and 8% experienced disease progression. The DOX-SL formulation of the chemotherapeutic agent doxorubicin is designed to deliver the active agent as efficiently as possible to the KS tumor. The "stealth" liposomal covering permits the drug to evade the immune system and to remain circulating through the blood plasma for 48 hours or more, thereby reaching more tumorous growths than the standard formulation, which is eliminated from the plasma in a matter of hours (standard liposomal formulation) or minutes (free drug). KS lesions begin to form when blood vessels grow abnormally, and blood cells leak from impaired vessels, creating reddish lesions. DOX-SL moves from the plasma through flawed portions of blood vessels into tumorous growth areas. Studies indicate that 5-11 times as much drug reaches the tumor site with this formulation, compared to free drug. Phase III trials of DOX-SL are ongoing in the U.S. and Europe. Liposome Technologies also plans to study the drug as a treatment for various other cancers, including lung, liver, breast and ovarian cancer. [LH] Liposome Technology, Inc. seeks U.S. marketing approval for novel anticancer product. Liposome Technology, Inc. News Release. September 7, 1994. Liposome Technology, Inc. seeks U.S. marketing for DOX-SL. AIDS Weekly 12-14. September 12, 1994. Regular Acyclovir Use Reduces Herpesviral Shedding Asymptomatic shedding occurs when an infected individual shows no outward symptoms of herpes simplex virus infection but still has live virus in genital fluids. For herpesvirus infections this means that, although lesions are absent, infectious virus is released through secretions or is present on the skin. Although genital herpes transmission within the population is very likely to occur when an individual has an active outbreak, a significant amount of transmission occurs during asymptomatic shedding, especially if the individual has been recently infected. A recent study in women found that daily use of prophylactic acyclovir reduced the period of asymptomatic viral shedding in vulvar, cervico-vaginal and rectal sites. The randomized, placebo-controlled study of 34 women with recently acquired genital herpes found that 25 of 34 taking placebo shed virus during asymptomatic intervals, while only 5 of 34 did so when taking acyclovir. The asymptomatic shedding period was reduced from 6.9% of days on placebo to 0.3% of days on acyclovir, a reduction rate of 95%. Investigators note that it is still important for people with herpes to use latex condoms to help prevent transmission to sexual partners. [LH] Wald A and others. Acyclovir suppresses asymptomatic shedding of HSV-2 in the genital tract. 34th Interscience Conference on Antimicrobial Agents and Chemotherapy. Orlando, Florida. October 1994. Abstract H5. Passive Hyperimmune Therapy In early October, the results of several clinical trials of passive hyperimmune therapy (PHT) were presented at the First International Symposium on the Effects of Passive Immunetherapy in AIDS in London, England. PHT is the removal of plasma from HIV-infected, healthy individuals, with subsequent sterilization and transfusion into people with more advanced HIV disease. This technique essentially transfers active, HIV-neutralizing antibodies, found in significant numbers in the plasma of healthy individuals. The procedure generally is conducted once or twice monthly. A U.S. team presented results of a 12-month, multicenter, double-blind controlled Phase I/II trial among 220 people with AIDS, none of whom suffered any adverse effects or toxicity. Participants with 50-200 CD4 cells/mm3 who received "full-dose plasma" registered "a five-fold reduction in the mortality rate...compared to the placebo group." One out of 21 people receiving active treatment (500 ml PHT monthly) died compared to 6 of 30 who received monthly placebo (albumin). There were 3 deaths among 21 people who received half-dose treatments (250 ml of PHT monthly). Use of PHT was associated with increased CD4 cell counts as well as levels of circulating antibodies; 95% of those receiving PHT experienced no decline in CD4 levels after 12 months. A French research team found that people with AIDS who received PHT twice monthly developed far fewer opportunistic infections than those receiving placebo. New opportunistic infections occurred 3 times as much in the placebo group, compared to the PHT group. PHT may be an effective treatment for AIDS since it appears: (1) to cause no detectible adverse side effects, (2) to delay progression to AIDS and death, and (3) to be non-harmful to donors. (See also article by Mark Bowers on immunotherapy in this issue of BETA.) [LH] Transfusion may retard AIDS, 2 new trials show. The San Francisco Examiner A2. October 2, 1994. Testing and Treatment of Tuberculosis Health officials have been challenged by steadily rising rates of tuberculosis (Tb) since the mid-1980s. In the search for effective ways to prevent the further spread of Tb, various strategies have been researched and tried, but successful prophylaxis remains key. The diagnostic test most commonly used is the PPD skin test. PPD, or purified protein derivative of tuberculin, is an extract made from cultures of M. tuberculosis, the bacteria that causes Tb. A positive response to this test, which indicates that an individual has been exposed to and infected by Tb bacteria, can be used to identify persons at risk for developing active disease and who are candidates for prophylaxis. A positive response generally has been defined as an induration, or observable skin tissue hardness, of a diameter greater than or equal to 10mm. Among HIV positive persons, one of the groups at high risk for developing Tb, anergy can be a complicating factor. Anergy is a lack of immune response to the injection of a foreign substance, or antigen (PPD), that would otherwise produce a marked, observable reaction in a person with normal immunity, and who is infected with Tb. An anergic reaction to PPD testing is typically defined as less than 3mm induration of PPD, in addition to less than 3mm induration to control panel antigens (e.g., mumps, candida and/or tetanus). Obviously, anergy makes Tb risk determination and diagnosis problematic among HIV positive persons. Anergy testing can be time-consuming and/or costly. For example, the CMI Multitest test panel for anergy consists of 8 individual antigens at an approximate cost of $18-20/panel. The pressing task for researchers and public health officials has been to design the most simple, efficient and cost-effective way to determine who to put on isoniazid (INH, a Tb antibiotic) prophylaxis without anergy testing, which may be unreliable even in people without HIV. To obviate the need for anergy testing, researchers have recommended lowering the induration cutoff point for people with HIV. Dr. Neil Graham, a researcher from the Johns Hopkins School of Hygiene and Public Health, was an original proponent of a significantly lower induration cutoff point (e.g., 2-3 mm) for HIV positive persons. However, Dr. Graham now considers a cutoff point of 5mm for HIV seropositive persons (and 10mm for seronegative persons) to be adequate. In his Baltimore cohort of drug users, use of the 5mm induration cutoff point for INH prophylaxis recipients has dramatically reduced the Tb rate and appears to be appropriate. He added that anergy testing probably should be restricted to people with less than 500 CD4 cells/mm3 and should be repeated at least once. The incidence of Tb among anergic individuals seems to be low in Baltimore and other cities with a low incidence of Tb. However, in high incidence cities such as New York, Tb incidence in anergics is higher and anergy testing may be appropriate for HIV-infected individuals in these settings. Recommendations also have been made by the Centers for Disease Control and Prevention (CDC) and other research teams. The CDC now recommends giving INH to HIV-infected people with equal to or greater than 5 mm induration; if anergic (defined as less than 3mm response to the PPD test plus a Mantoux test that returns negative for all allergens), clinicians are advised to consider giving INH. (For example, a clinician who treats drug users in an area with high rates of Tb might opt to give INH to his/her anergic patients.) Another consideration has been to give INH to all HIV-infected patients in high-risk areas for Tb, e.g., East Coast cities with high rates of HIV and Tb. Problems associated with this method would be high cost; medication side effects; difficulty in tracking patients; a likelihood of losing patients to follow-up, with the consequent risk(s) of the development of INH-resistant strains; and attendant public health problems. Finally, consideration has been given to simply lowering the cutoff point for people with HIV from 5 to 2 mm, and giving INH to anyone PPD-reactive (within those parameters). Yet, according to an Italian study presented in Yokohama, current evidence seems to indicate that HIV positive persons with 2-4 mm reactions are not at significantly increased risk of developing Tb. The researchers concluded that "5mm appears to be an adequate cutpoint for PPD positivity among HIV positive persons...Further lowering of PPD cutpoint does not appear indicated." Thus, lowering the induration cutoff point below 5mm may not be particularly useful for the identification of candidates for INH prophylaxis. Recommendations and guidelines for testing and prophylaxis used will most likely entail some regional adjustment, based on local risks and patterns. [LH] Girardi E and others. Prospective evaluation of risk of tuberculosis in HIV-infected persons by tuberculin reaction size. X International Conference on AIDS. Yokohama, Japan. August 1994. Abstract 405B. Graham NMH, MD, MBBS, MPH, Johns Hopkins School of Hygiene and Public Health. Personal communication. November 3, 1994. Graham NMH and others. Prevalence of tuberculin positivity and skin test anergy in HIV-1 seropositive and seronegative intravenous drug users. The Journal of the American Medical Association 267: 369-373. 1992. Megace Study Findings The final results of 2 large clinical trials of megestrol acetate (Megace) that led to FDA approval of the drug for treatment of HIV-related wasting appear in the September issue of Annals of Internal Medicine. Both were Phase III multicenter trials. One trial (Von Roenn) compared 3 doses of Megace (100, 400 or 800 mg/day) to placebo in 271 people with AIDS and significant weight loss and anorexia. Over a 12-week period, participants receiving high-dose Megace were approximately 3 times as likely to gain weight as those on placebo; 64.2% taking 800 mg/day gained 5 pounds. In this group, increased food intake and appetite were associated with an increased sense of well-being. In the other published trial (Oster), 800 mg/day Megace or placebo were taken by 100 people with AIDS and weight loss equal to or greater than 10% of ideal body weight. Those taking Megace gained about 3.86 kg by week 8 (of 12 total weeks), whereas the placebo group lost 0.46 kg during the same time interval. Researchers note that the weight gain was mainly a gain in fat body mass. The Megace group increased their caloric intake, and reported increased sense of well-being. While Megace appears to benefit people with AIDS-related wasting, a concern is that the weight gains are mainly from fat increases. Megace is available in an oral suspension formulation, and is FDA-approved for people with AIDS and cachexia, anorexia and/or significant, unexplained weight loss. Thus far, it appears that people with relatively higher CD4 cell counts experience greater benefits than those with more advanced HIV disease. It is not yet clear if people with earlier-stage disease will benefit from Megace treatment. A typical course of therapy is expected to last for about 4 months. Individuals take 800 mg/day for 1 month, then 400 mg/day for the remaining 3. The daily cost has been estimated at about $3.50-$4.00/day, or just under $500 for a 4-month course. Bristol-Myers Squibb has expanded their Reimbursement Assistance Program and has said that they will provide drug free of charge to those in need. [LH] New options for treatment of AIDS cachexia. AIDS Weekly: 2-4. October 3, 1994. Oster MH and others. Megestrol acetate in patients with AIDS and cachexia. Annals of Internal Medicine 121(6): 400-408. September 15, 1994. Vonroenn JH and others. Megestrol acetate in patients with AIDS-related cachexia. Annals of Internal Medicine 121(6): 393-399. September 15, 1994. Strategic Program for Innovative Research on AIDS Treatment (SPIRAT) The National Institute of Allergy and Infectious Diseases (NIAID) announced a new program of AIDS research on September 1, 1994. The purpose of the program is to support innovative research in humans in such areas as gene therapy and immune restoration. Under SPIRAT, 6 separate research teams were awarded a total of $25 million for 4 years. Each team is composed of at least 3 researchers, from different U.S. institutions or companies. Award recipients are groups that have already demonstrated dedication and expertise in AIDS research and may be in good positions to move into testing in humans. While the program is designed to expedite innovative research efforts, it is also being touted as a much-needed return to basic research. Because many anti-HIV drugs have limited effectiveness, the hope is that a more creative approach to basic science will uncover new ways to boost the host immune response against HIV. The 6 recipients are the New England Medical Center in Boston, MA; the University of Pennsylvania in Philadelphia, PA; the University of Michigan, Ann Arbor, MI; the Fred Hutchinson Cancer Research Center in Seattle, WA; Stanford University, Palo Alto, CA, and the University of California, San Diego. Each team is charged with a different primary mission. In Boston, the team will explore ways to augment the immune system's capacity to destroy HIV-infected cells, an approach referred to as "adoptive immunotherapy," wherein immune cells are combined with enhancing cytokines (protein messengers). University of Pennsylvania researchers are working on therapeutic vaccines against HIV made from HIV genetic material, or DNA. The Michigan team is exploring pediatric gene therapy that seeks to diminish or halt CD4 cell depletion. In Seattle, researchers are removing immune system cells from people with HIV, genetically altering them to elicit extremely strong, specific, anti-HIV qualities, and reinfusing them. The Stanford team is working on the transfer of healthy immune system cells from an HIV negative identical twin to his/her HIV positive sibling. Finally, the San Diego group is exploring a type of gene therapy uniquely designed to thwart HIV in the body. In this technique, immune cells are removed from the body and equipped with an antiviral gene. Once reinfused, these cells are designed to slice up and inactivate the HIV in the body. [LH] NIAID mobilizes team of scientists to advance novel AIDS therapies. NIAID News. September 1, 1994. Terry Beirn Community Programs for Clinical Research on AIDS (CPCRA) Adds New Sites CPCRA, a community-based clinical trials network supported by the National Institute of Allergy and Infectious Diseases (NIAID), was founded in 1989. A recent "recompetition" for awards resulted in the creation of 4 new sites and renewed support of 12 established sites. The CPCRA now has units in 15 cities in the U.S.: Camden, NJ, Philadelphia, PA, Baltimore, MD, Albuquerque, NM, Atlanta, GA, Chicago, IL, New York, NY, Denver, CO, Detroit, MI, Portland, OR, Newark, NJ, New Orleans, LA, San Francisco, CA, Richmond, VA and Washington, DC. An ongoing CPCRA priority is the provision of services to ethnically and demographically diverse HIV-affected communities, including those in which the incidence of HIV/AIDS is increasing most rapidly. Of the more than 15,000 people who have participated in the 23 CPCRA trials to date, representation has been 39% African American, 18% Latino, 43% Caucasian, 20% women and 35% injection drug users. A current scientific focus of the CPCRA is finding new and effective treatments for HIV-related opportunistic infections (OI). Trials are underway to evaluate strategies to prevent multiple, late-stage OI including Pneumocystis carinii pneumonia (PCP), cytomegalovirus (CMV) disease and fungal infections that affect women with HIV. Other CPCRA trials are evaluating antiviral treatments. [LH] Sites awarded, renewed for community-based AIDS trials. NIAID News. September 1, 1994. Off-Label Drug Use and Payment Problems Many drugs approved before the AIDS pandemic are used to successfully prevent HIV-related opportunistic infections (e.g., trimethoprim-sulfamethoxazole [Bactrim, Septra] for Pneumocystis carinii pneumonia). Others, like cimetidine (Tagament) and acyclovir (Zovirax), are used by some physicians in the management of AIDS. While Bactrim/Septra recently received official FDA approval for use in preventing PCP, many drugs on the market that are commonly used in the treatment of HIV and related conditions are not FDA-approved for HIV-related use. A study at the Community Consortium in San Francisco affirms that the vast majority of people with HIV use at least 1 off-label drug. Of 1,148 HIV-infected patients, 81% reported using 1 or more off-label drugs and 46% use 2 or more. Twelve drugs comprised 2/3 of those being used in off-label fashion, including Bactrim or Septra (approved since the study), dapsone, acyclovir, megestrol acetate (Megace), cimetidine and amitripylline (Elavil). Sixty-eight percent (68%) of the 387 healthcare providers surveyed in the study stated that they had difficulty staying current with reimbursement policies of third-party payers, and 50% had difficulty securing reimbursement for off-label drug use. A full 33% reported that they had hospitalized a patient in order to receive reimbursement for the delivery of off-label drugs, since reimbursement by the insurance company was not covered for outpatients. Dr. Carol Brosgart, a clinical instructor at the University of California at San Francisco and principal investigator of the study, said that "it really is a shame...that there is so much difficulty getting reimbursement for the drugs that work. They are the standard of care, with general consensus among practitioners that they are the most effective, and yet most of them are off-label." [LH] UC San Francisco study finds that most HIV-infected patients take "off-label" drugs for opportunistic infections. News from SFGH/UC-San Francisco. October 6, 1994. New Research Consultation Clinic Opens at San Francisco General Hospital A new clinic, designed to help people with HIV ascertain if joining a clinical research trial is appropriate for them, has opened at San Francisco General Hospital (SFGH). Part of the University of California, San Francisco AIDS Program, the HIV Research Consultation Clinic is located on Ward 86 and is free for people with HIV. Clients meet for approximately one half hour with a specialist to discuss HIV disease, experimental treatments and local trials. The details of specific trials are discussed to inform and assist a client's decision to enroll or not. For more information or to make an appointment, call 415-476-0828. [LH] UCSF AIDS program opens research consultation clinic at San Francisco General Hospital. News from SFGH/UC-San Francisco. October 21, 1994. Can One Opportunistic Infection Predict Another? A retrospective analysis of 2 large trials comparing ddI with AZT indicates that patterns in the sequence in which opportunistic infections occur may help clinicians and people with AIDS plan preventive therapies more precisely. Deborah Cotton, MD, of Harvard Medical School, reported that cytomegalovirus (CMV) and Pneumocystis carinii pneumonia (PCP) were strong predictors of subsequent Mycobacterium avium complex infection, and that PCP also heralded a higher risk of subsequent CMV. These results held true regardless of a person's CD4 count. But PCP and mycotic infections (esophageal candidiasis, cryptococcosis and histoplasmosis) could only be predicted by the CD4 counts of people in the studies. Cotton said the results of the analysis, if confirmed by similar studies, could give physicians a useful tool to guide prophylactic therapy during the course of infection. As more prophylactic agents become available, it is unlikely that an individual will be able to tolerate all of them simultaneously, so deciding which might have the greatest impact will be critical. Cotton cautioned, however, that the results of the study cannot be applied to all people infected with HIV because nearly all of the participants in the 2 trials were gay white men and because the analysis did not factor in some common AIDS-related conditions, such as Kaposi's sarcoma. [MM] Cotton D and others. The occurrence of certain AIDS-related opportunistic infections is associated with an increased likelihood of occurrence of subsequent OIs independent of CD4 count. 34th Interscience Conference on Antimicrobial Agents and Chemotherapy. Orlando, Florida. October 1994. Abstract I245. TI Treatment Updates from the X International AIDS Conference in Yokohama, Japan TX The following is an edited transcript of 3 BETA LIVE! conference calls held August 19, 23 and 25, 1994. Susan Buchbinder, MD, is Chief of the Research Branch of the AIDS Office at the San Francisco Department of Public Health. She directs a long-term study of a unique group of gay and bisexual men in San Francisco. Testing blood specimens collected from these men as far back as 1979 has helped Dr. Buchbinder and her colleagues to estimate that the median time from initial HIV infection to the development of AIDS is about 10 years. Dr. Buchbinder has closely followed a subset of these men who have been HIV positive for over 12 years with stable, high CD4 counts and no symptoms of HIV disease. Marcus Conant, MD, Professor of Dermatology at the University of California, is an AIDS researcher and a clinician with an HIV practice that involves over 3,000 patients in San Francisco. He has a special interest in the diagnosis and treatment of Kaposi's sarcoma (KS) and other dermatological manifestations of HIV disease. His group is currently conducting studies on several new anti-HIV drugs including thymopentin-5, the Merck protease inhibitor, gene therapy and the gp120 treatment vaccine. Anthony Fauci, MD, is an internationally renowned scientist and researcher who serves as the Director of the National Institute of Allergy and Infectious Diseases (NIAID). As director of the NIAID, Dr. Fauci is responsible for administrating the federally funded national AIDS treatment and vaccine research program. NIAID also is responsible for government-funded research efforts on other illnesses such as tuberculosis, asthma and allergy. Ronald Mitsuyasu, MD, is Director of the University of California at Los Angelesž Center for Clinical AIDS Research and Education, known in Los Angeles as the Care Center. He also heads the UCLA AIDS Clinical Trial Unit. Dr. Mitsuyasu's research interests include AIDS-related malignancies, immune-based therapies and novel anti-HIV drugs. Paul Volberding, MD, is an AIDS researcher and clinician who serves as Director of the AIDS Program at San Francisco General Hospital (SFGH). SFGH was recently named for the second year in a row as providing the best AIDS care of any hospital in the United States. Dr. Volberding is internationally known for his research on AZT. Ronald Baker, PhD, is editor of BETA and producer and moderator of BETA LIVE! BAKER: The most recent estimates of the global spread of HIV infection are astonishing and alarming. Every day, 6,000 people around the world are newly infected with HIV. Today there are a total of 4 million people in the world with an AIDS diagnosis. This represents a 60% increase over last year's figure. In the last 12 months alone, 3 million people have become infected with HIV. This brings the total estimated number of HIV-infected individuals to the staggering figure of 17 million. One million of these are children. In Latin America, 1.3 million people are infected. In North America, the figure is now an estimated 1.1 million. Sub-Saharan Africa currently has the largest number of infected people in the world: 15.5 million men, women and children. Two and half million of these people have AIDS diagnoses. Over 75% percent of those newly infected in Africa are under the age of 20. Africa now faces a tragic explosion of sickness and death from AIDS, with 90% of deaths occurring in adults between the ages of 27 and 44. As incredible as these African statistics are, Asia is now experiencing the largest expansion of the HIV pandemic. In the last year, over 1 million people in Southeast Asia have become infected. The total number infected in this region is now 3 million, with women constituting 40% of this number. By the year 2000, Asia is expected to have the largest number of HIV-infected inhabitants in the world, a staggering 12 million people. BAKER: Dr. Fauci, you and your colleagues at the NIAID have conducted extensive research on the pathogenesis of HIV disease. Could you tell us more about your work in this area and also something about the information presented by Dr. Haase in Yokohama on the early and rather extensive infection of the lymph nodes by the virus? FAUCI: Our work focuses on the infected individual rather than on the various components of the virus. In our quest to understand what we call pathogenic mechanisms--how the body's immune system is destroyed by the virus--we have looked at a variety of patients, and with particular interest at their lymphoid tissue, which we obtain from biopsies of lymph nodes at various stages of disease. At Yokohama I presented a study of long-term non-progressors, individuals who have been infected from 10-15 years who not only are surviving but whose immune systems are bascially intact. Their CD4 cell counts essentially remain constant. These long-term non-progressors don't have the insidious decrease in CD4 cells that we see in so many other individuals. We study these people intensively by doing lymph node biopsies, examining their viral burden and viral expression, and looking at the virus itself. From the lymph node biopsies we learned that these long-term non-progressors had perfectly normal lymph nodes, with intact architecture of the lymphoid tissue. The nodes were normal, but they were also activated, although not in the exuberant way that lymph nodes are typically activated in the early phases of HIV infection in individuals who ultimately progress. Viral burden in the lymphoid tissue and viral expression are low in non-progressors, sometimes 10 or more times as low as they are in progressors. Interestingly, often we were unable to isolate virus from the lymph nodes of non-progressors. The virus didn't appear to be defective; we were able to isolate it from infected cells in culture. This suggests to us that these individuals were able to contain the virus well. Although levels of plasma viremia or virions (virus particles in the blood) were considerably lower in non-progressors than in those who had progressed, there was still a persistent presence of circulating virus. This means that these individuals were able to handle the virus either immunologically or by not having a flagrant activation response to the virus. Non-progressors had excellent neutralizing antibodies and good cytotoxic T-lymphocytes (CTL), a type of cell that can ultimately kill HIV-infected cells. Hopefully we'll be able to use the secrets we unlock from individuals who are able to contain the virus as a more intelligent basis for the design of therapeutic and vaccine strategies. Dr. Ashley Haase used a very sensitive in vitro technique to assay the number of infected cells in lymphoid tissue. She found that even people early in the disease course have a much larger number of infected cells in the lymphoid tissue than most people realize. This indicates, along with other data, that when we talk about clinical latency, we really cannot assume disease latency, because the virus is present. Except in the small percentage of about 5-8% who are non-progressors, it generally destroys the immune system. BAKER: Dr. Conant, what did you learn in Yokohama that you feel will be of the most practical benefit to your patients with HIV infection and AIDS? CONANT: In terms of educational messages, clearly one of the most important was that women can be empowered to prevent getting infected through the use of condoms and nonoxynol-9. That's the good news. The bad news is that with the rapid spread of this disease worldwide, the people who need condoms don't have them available. Prevention messages tragically cannot be utilized in areas where the disease is spreading most rapidly if there is a lack of resources. The most important message I heard in terms of prevention was information we already knew: we can prevent the infection of a fetus from its infected mother by treating the mother with AZT. AZT is an effective antiviral that reduces the transmission rate from 25% in those who received placebo down to 8% in those who received AZT. There was a 66% reduction in the number of children infected, which tells us that AZT is an effective antiviral. The bad news, again, is that where we need these interventions--e.g., in Africa and in Asia--AZT is not affordable. When I chaired the California AIDS Leadership Committee, we found that half of the women in Los Angeles who were giving birth to HIV positive babies had no identifiable risk factor. This means that they did not know that they had slept with either a bisexual male or an intravenous drug user or someone who had received a transfusion. Of course this also means that these people don't sense that they're at risk, so they're not being tested for HIV. Even in the United States, while we may now have effective therapy to prevent maternal-to-fetal transmission, these interventions are not going to be as widely used as possible because people are not being tested. I think the most important message in terms of treatment was that we should be combining therapies as early as possible. Yablonga summed it up the best when he said that if we had approached tuberculosis the way we're approaching AIDS, we still wouldn't have a treatment. The problem with our treatment strategy is that we are sequentially testing drugs in people who have generally low CD4 counts. We're looking for disease progression, AIDS-defining diagnoses or death to tell us if these drugs are effective. Those kinds of outcome markers clearly need to be measured. Yet we should also be measuring viral load both in the blood and in the lymph nodes to see if we can reduce the viral burden earlier. The take-home message in terms of treatment is that patients should be treated earlier, with combination therapy, and that we should be using markers such as PCR and branched chain DNA (bDNA) to measure viral load as surrogate markers in clinical trials. The work that Dr. Fauci mentioned and that Dr. Haase reported on clearly shows that the virus is responsible for AIDS. This is an infectious disease that may work through a variety of mechanisms such as apoptosis, superantigens, immune responses and cytokine release, but basically, if we can reduce viral load the patient will survive longer. In terms of vaccine development, Dr. Denny Paglasi reported that we're not going to see vaccine trials in the U.S. for at least 3 years. I feel that's short-sighted. While the vaccines we have at present are marginally effective, we do have very high-risk populations in which those vaccines should be tested: young gay and bisexual men who are still having unprotected sex; people who are in serodiscordant relationships (one partner is positive and one is negative); street prostitutes in India; and people in Northern Thailand, where the seroconversion rate is very high. We could be testing even marginally effective vaccines in these populations today. We want to test vaccines (1) to try to find something that's effective as quickly as possible, and (2) to provide incentives to encourage the private sector to enter this market and begin to develop vaccines. In terms of research, the most important work is on viral burden, which Dr. Fauci summarized. HIV disease behaves like other infectious diseases. This confused us for a while because although many cells can be infected, only the viral DNA is present and we don't see active viral replication. This led to people like Peter Duesberg saying that HIV isn't the cause of AIDS. I think these new findings confirm that HIV is clearly the cause of AIDS. We can now see the virus replicating in the lymph nodes. We now know that what we see in the blood is only a minor reflection of what's going on in the lymph nodes. Whatever we can do to suppress that viral load, whether it's through treatment or immune stimulation, is what we should be doing in infected patients. My biggest disappointment in Yokohama was that we don't see the international leadership and vision needed to confront AIDS as a disease that is capable of threatening the entire planet. Each year we find that the number of cases worldwide has increased exponentially but we don't see the leaders of the world coming together and saying, "Our vision for what we need to do for the next 5 years is as follows..." This is an international problem that should be approached on an international level. We need full cooperation from the countries involved and true vision on the part of the leaders to give us a plan to attack this disease. BAKER: Dr. Mitsuyasu, as an expert in immune-based therapies and in the treatment of AIDS-related malignancies, what useful new information did you learn in Yokohama? MITSUYASU: There were a number of papers presented on immune-based therapies that may help us understand some viral factors that may be critical in HIV disease progression and how we may be able to intervene to prevent this process from occurring. There were a number of papers presented on lymph node biopsies in patients with HIV infection. These researchers found not only a high level of viral replication within the lymph node but, unfortunately, very little effect of nucleoside analogs in reducing the substantial amount of virus replication within that tissue. What we see in the peripheral blood may be just a small reflection of the total amount of viral replication in the host. This indicates that we need better treatment for HIV infection. Nonetheless, the fact that we see a reduction in viral load indicates that by slowing viral replication we may slow disease. We need multiple drugs and better drugs that will slow viral activity and replication even further. Jay Levy and others looked at HIV-specific cytotoxic T-lymphocytes (CTL), which are a group of CD8 cells which may be important in a patient's immune response to viral replication. These cells seem to be critical in slowing HIV replication early in the disease. Patients who are long-term non-progressors have high levels of these CTL. If there are ways of enhancing their function or increasing their numbers, we may have another way of slowing down the progression of HIV. Unfortunately, some of the therapeutic recombinant vaccine studies have not matured sufficiently to tell us whether they're effective in slowing the course of HIV disease. There is some suggestion that patients with higher CD4 cell counts generate neutralizing antibodies to the specific vaccine protein, and that cellular function in terms of their ability to proliferate seems to be enhanced. This may translate into a meaningful slowing of the progression of HIV disease, but it's still too early to tell whether these vaccines will be efficient or not. In the cytokine arena, there were reports on a couple of preliminary Phase I studies of agents such as interleukin-1 (IL-1) receptor antagonists and tumor necrosis factor (TNF) receptor antagonists. There was one paper from the NIH and another from UCLA on this topic. IL-1 and TNF are cytokines that are important for viral replication, and antagonists of their receptors may slow viral replication. These agents may be useful as adjunctive, antiviral therapy in slowing HIV replication. Finally, there was some preliminary information about the potential role of gene therapy in HIV infection. One paper discussed an HIV envelope chain gene that can be inserted into a patient's skin cells in culture. These cells are then reintroduced into the patient in an attempt to elicit an immune response against the virus. This generates specific CTL against various viral proteins that hopefully will translate into controlling HIV replication. Longer-term studies have not yet been done. A number of very hopeful leads regarding immune-based therapies are coming out of the basic science laboratories. Some early clinical studies suggest new approaches to inhibiting the virus that hopefully will be more effective. NEW YORK, NY: Dr. Conant mentioned combination therapy. What kind of indicators will you use in order to decide when to start therapy or when to change therapy? Would you use a combination of CD4 cell count and viral load? Also, do you think antioxidants such as NAC [N-acetylcysteine] play a role in therapy? CONANT: If a cheap and perfectly safe drug existed, to which HIV never developed resistance, we would probably start every patient on that drug the day we found that they were infected, just as we might do with tuberculosis or leprosy or some other chronic disease. We would treat until there was good evidence that the virus had been completely suppressed, and with HIV that might require lifetime therapy. The trouble is that none of the treatments that we currently have available as monotherapy work in this fashion, and there's no evidence that they would be successful even as part of a combination therapy. In my clinic in San Francisco, when someone falls below a CD4 count of 500 cells/mm3 , and certainly if they're below 500 and symptomatic, we put them on AZT in combination with either ddI or ddC. We keep them on that regimen until either they show a dramatic decrease in their CD4 count or they show clinical evidence of disease progression. BAKER: There is a rather unusual program that will start this fall called the Intercompany Collaboration. It consists of a group of 15 pharmaceutical firms that are collaborating and sharing AIDS drug research results. They will begin a series of 1-year studies of triple combination antiretroviral drugs to determine as quickly as possible whether any of these combinations show a strong promise of efficacy. They'll be looking at combinations such as AZT plus ddI plus nevirapine. They'll be looking at AZT plus ddI plus saquinavir and several others combinations. VOLBERDING: I left the conference in Yokohama feeling more positive than I did after the preceding couple of international conferences. This was in part due to the demonstrated value of combination therapy and our clearer sense of how to use antiviral drugs. The fact that people are collaborating and are realizing that rapid progress is necessary is also encouraging. At the same time we appreciate that barriers are still there in terms of developing truly exciting new classes of drugs. We have accepted the limitations of our current therapies. We need to move into more aggressive combination therapies, but we don't have anything other than the reverse transcriptase inhibitors and the protease inhibitors. We need a broader array of treatments. The intercompany consortium is an important first step in that direction. Finally, this process might be accelerated by the development of new tests for viral load. BAKER: Paul, regarding antiretroviral therapy, you presented some new information on AZT treatment among your ACTG 019 study participants. VOLBERDING: We presented for the first time the results from the ACTG 019 trial in people who started with CD4 cells above 500 cells/mm3. While we found a significant effect on the CD4 counts themselves, especially in people with higher initial CD4 cell counts, we also found a longer time to CD4 decreases below 500. Still, when we stopped the study after an average treatment duration of 5 years, there wasn't any benefit in terms of slowing the progression to AIDS or prolonging survival. However, AZT clearly does work. If someone is sick enough when starting the drug, it works for a couple of years. The reason the Concorde study didn't show any positive effect is that they mixed the populations of people with CD4 cell levels above and below 500 cells/mm3. In terms of those patients who were at highest risk of progressing, it was obviously a much smaller study. I am much more confident now than I was before in recommending zidovudine therapy for people with CD4 counts at 500 or below. BAKER: What do you think about combination therapy, adding ddI or ddC to AZT? VOLBERDING: One of the central themes of this conference was the growing consensus regarding the benefit of combination therapy, whether it's 2 drugs in a similar family like AZT and ddI, or drugs that might include the non-nucleoside analogs like nevirapine or the protease inhibitors. There's a growing belief that multiple therapies are going to be necessary with this virus, and that they will help prolong and increase the benefit. I wouldn't routinely recommend combination therapy for people with CD4 cell levels above 500 cells/mm3. Now, I might very well recommend that those persons enter clinical trials, and I might in various individual situations recommend combination therapy. For example, I might do so if the patient really wanted a very aggressive approach and the viral load was high or the CD4 cell count was were dropping more rapidly. I think we should appreciate that 500 CD4 cells/mm3 is not a magic number. There are people with lower CD4 counts who are quite healthy and people with higher CD4 counts who are quite ill. VERONA, WI: I've been on AZT since October 1991. I started on 5 tablets, but because I had nausea, they reduced the dose to 4 tablets. Now I'm back to the point where I'm often feeling sick again. Would you recommend combination therapy or adding something to AZT in situations like mine? VOLBERDING: Physicians talk about AZT in kind of either/or words, as though it's either toxic or nontoxic. People--certainly this was true in the 019 trial--are able to tolerate AZT even at very high dosages for years. On the other hand, some people can't tolerate it at all. So the choice of drugs is going to depend on what fits your quality of life. I don't think a clinician should urge you to continue taking a drug if it makes you feel chronically sick. Fortunately, there are more and more choices. In terms of combinations, there's a growing interest in the possibility that drugs like D4T and ddI might prove to be useful in combination with AZT. So I think there are going to be increasing options as we get more of these drugs in larger-scale use. VOLBERDING: Ideally we want people to be able to take combination therapy. We believe that approach is going to be more successful at slowing the virus. On the other hand, another option is using 1 drug at a time and switching from 1 drug, in this case, from the one you're not tolerating very well, to another that you might tolerate much better. Your options now would be ddI, ddC or D4T. So there are a number of choices that you should discuss with your physician. SAN FRANCISCO, CA: Can anyone give me some information, either from the conference or from personal experience, about protease inhibitors? CONANT: There were 20 different companies presenting information on protease inhibitors in Yokohama. This is clearly the most exciting area of antiviral research. It's not another drug of the same family [nucleoside analogs] and it appears safe. Unfortunately, resistance develops pretty rapidly with these drugs. All of us are waiting anxiously to see the protease inhibitors used in combination with nucleoside analogs such as AZT and non-nucleoside reverse transcriptase inhibitors like nevirapine. VOLBERDING: I would point out that there are increasing options for protease inhibitor therapy. We have trials at SFGH and there are others around the United States. As these companies begin to test their drugs, I think you'll find it increasingly possible to enroll in one of the clinical trials. BAKER: I might mention that Phase III trials of the Roche protease inhibitor saquinavir are now enrolling up to 1,800 people in the United States. For more information about where these studies will be held and what the entry requirements are, call toll-free 1-800-526-6367. CLEVELAND, OH: You were discussing using AZT in combination. While I was in Japan, I talked to many other people with AIDS (PWA). Our doctors are prescribing primarily either AZT or ddI, and we're not getting the combination therapies. CONANT: The pressure needs to be on the doctors. As a doctor who's cared for AIDS patients since 1981, I'm not too arrogant to admit that most of what I've learned about AIDS has been from my patients. That's one of the roles these meetings play--the dissemination of information not only to physicians and scientists but to patients as well. Patients like you can go home and say, "Doctor, what you're doing was the state-of-the-art 2 years ago, but people managing this disease on the cutting edge feel that combination therapy is the way to go. I'd like to do AZT with, rather than instead of, ddI." COLUMBIA, SC: I'd like to ask a question about patients who have been on anti-HIV nucleoside analogs for long periods of time, particularly patients whose CD4 cell counts have fallen below 100 or even below 50 cells/mm3. Is there any evidence that we're helping these people? Are we prolonging their lives? Are we improving the quality of their lives by continuing the nucleoside analogs after the count gets very low? CONANT: That's a great question but unfortunately there's not a great answer. The studies show that combination therapy, when the CD4 count gets very low, is not that beneficial. And yet clinically, some patients appear to benefit from combination antiretroviral therapy even with low CD4 counts. Hopefully this is going to be answered more quickly than we've been able to in the past, due to improvements like PCR technology. I'm not suggesting that you can order that tomorrow and have it available. But from the data presented, one would hope that we would have available in the next 6-18 months either branched chain DNA or quantitative competitive PCR that we can use on a fairly cost-efficient basis to measure viral load. That will really answer the question for us. In our clinic in San Francisco we start combination therapy in anyone with a CD4 cell count below 350 cells/mm3. Often we will consider starting combination therapy in symptomatic people with fewer than 500 cells/mm3. As you know, Paul Volberding presented data from the 019 study in Yokohama showing no clear benefit from intervention when the CD4 count is above 500 cells/mm3. That doesn't mean that it would not be beneficial if we had a drug that had no side effects, that was cost-effective and to which resistance did not develop. If we had such a drug, we would start every patient on it the day they were diagnosed. The problem is that patients with more than 500 CD4 cells/mm3 don't get sick. By the time their CD4 cell counts drop low enough for illness to develop, they're already resistant to the agents they started using early. In our clinic in San Francisco we start patients on combination AZT and ddI or AZT and ddC when we begin therapy; if they tolerate those drugs well, we leave them on those. If they show rapid CD4 cell drops, we may change to a different agent. We're now using 3TC in expanded access. If I had a patient who had less than 50 CD4 cells/mm3 who was tolerating the drugs well, I would probably leave him or her on the drugs. On the other hand, if they were experiencing severe fatigue or GI upset or neurological problems from the drugs at that level, I would probably stop them. BAKER: What about the notion of initiating combination therapy in patients with greater than 500 CD4 cells/mm3? CONANT: I would like to see a study tomorrow combining 2 nucleoside analogs, say AZT and ddI or ddC with a non-nucleoside reverse transcriptase inhibitor, in combination with a protease inhibitor. I would combine all 4 drugs. I would look at the safety of that combination and I would measure viral burden, both in the plasma and in the lymph nodes in of a small group of patients. If we saw a significant decrease in viral burden, I would then follow an increasingly large cohort for disease progression and survival. But we can't wait 3-5 years because the patients I'm caring for in San Francisco--where we have an aging epidemic--won't be alive in 3-5 years. If we're going to really have an impact on this disease, we need bold leadership that moves ahead with combinations we think make sense, acknowledging up front that it may not work but it's clearly better than what we're doing now. PHILADELPHIA, PA: Would the same resistance develop to a combination of drugs as to a single drug? CONANT: Research shows that the resistance pattern, or the mutations necessary for resistance, are different for the different drugs. Theoretically, you are increasing your probability of efficacy and decreasing the chance that the virus can mutate by combining drugs. The problem is that these drugs work at essentially the same place. There is some hope that the resistance patterns you see with AZT and 3TC and combinations may cancel each other out. This happens in the test tube. In patients, who are much bigger than test tubes, my guess is that it's not going to be effective. However, if you're trying to buy time until we get combination therapies using protease inhibitors and other agents, then I would consider the combination, regardless of the potential for resistance in the long run. Part of the question is academic. Are we talking about a long-term answer or are we talking about buying time until more effective therapies come along? All we've been doing for the last 14 years of this epidemic is buying time while we find strategies to prolong the lives of our patients. FAUCI: I agree with that. You're always going to wind up getting resistance. The question is will resistance develop in the combinations that we have available right now. We're using them in the hope that by the time we extend the disease-free state in individuals, we'll have other combinations to overcome the original resistance that developed with the first combination. The objective is to delay the onset of disease indefinitely. BAKER: Given your talk about the pathogenesis of HIV disease, Dr. Fauci, it would appear that the earlier we intervene, the better our chances of keeping the viral load as low as possible. FAUCI: Viral burden and expression are so low, even in the lymph nodes, that it's difficult to show differences from treatment early in infection. We looked at a period of 8 weeks, which isn't long, so perhaps we need to look longer. Philosophically, I agree completely with Dr. Conant. If we had safe and effective drugs, there is scientific rationale right now to go ahead and start the moment we find out somebody's HIV-infected. Unfortunately, we don't have those drugs right now, but we need to continue to look for therapeutic strategies and protocols that get us closer to that paradigm. NEW JERSEY: Dr. Mitsuyasu, you mentioned that some cytotoxic treatments are most effective as early intervention. Did I get that right? MITSUYASU: It's difficult to say exactly where in the course of HIV infection normal host immunity would be most effective. We don't know whether it's best to use methods to enhance immunity earlier or later in the disease. We know, however, from studies in patients with high counts of CD4 cells who have been HIV positive for long periods of time without opportunistic infections that these patients have high levels of CTL cells. They also may have high levels of neutralizing antibodies. This would suggest that the immune response of the host may be very critical in controlling viral replication early in the course of the disease. If there are ways of enhancing someone's immunity, then clearly that would be a good time to try to do so. NEW JERSEY: Our son was tested in 1989, but it's possible he was infected much earlier, maybe 5 years before. Can one still use early intervention treatment for something that may have progressed further? MITSUYASU: Maybe I didn't make myself clear. The approach I'm suggesting entails enhancing immunity, and is still under investigation. We clearly don't have methods that can consistently improve people's host immunity against the virus. There are a number of approaches being evaluated in clinical research settings and also a number of things being tested in the laboratory. But we don't yet have a drug or a particular approach that we can say with certainty will enhance people's immunity enough to prevent or slow the spread of HIV. Clearly, the current medications we have available, the nucleoside analogs--AZT, ddI and ddC--dramatically reduce the amount of virus present in the patient, by 2- or 3-log reductions. Immunomodulatory approaches can reduce the amount of virus in the patient as well, but the degree of the reduction is actually less and it varies from individual to individual. So we're talking about something we would like to have available, but that is not on the immediate horizon as far as what we can do to enhance your son's ability to fend off infections. NORFOLK, VA: I'd like to know what kind of experience the doctor has had with cytokines, IL-2 and IL-12, used to boost the immune system. Also, how can I get a protocol done in my city? FAUCI: We're doing an IL-2 protocol at the NIH hospital in Bethesda. We're trying various doses of IL-2. The patient takes IL-2 for 5 days, then is off the therapy for 8 weeks, then starts another cycle of 5 days of therapy and 8 weeks without therapy. We started with 10 patients, and now we have a randomized study with 60 patients. The enhancements of CD4 cell counts are substantial, better than we have seen with any antiretroviral agent. One of the difficulties, and it isn't an insurmountable difficulty, is that at the higher concentrations, IL-2 is temporarily toxic. It makes you sick for 5 days, but after that you return to baseline. Although the CD4 cells in some people go up dramatically, the unanswered question is whether or not there will be an ultimate effect on the course of the disease. Answering this will require a considerable amount of time. That's why we're being very circumspect before claiming that this is a major new modality of therapy. There are a number of sites throughout the country that will be using IL-2 in protocol-fashion. BAKER: Dr. Fauci, is it possible for patients not enrolled in a study to obtain IL-2? FAUCI: I wouldn't recommend that until it was clear just what the benefit is. There's always concern about making a drug accessible to people before a clinical trial really shows efficacy. It's the dilemma we face all the time with HIV. When something looks promising, when do you let it out? Since IL-2 can be toxic, particularly in the doses required to have an effect, it's really recommended that it be used in a study led by someone who has considerable experience with it. CONANT: The caller asks a very reasonable question: How can I get a protocol done in my city? One of the difficulties I face as a clinician is trying to counsel patients. There are times when you want to get involved in a trial and times when you may want to wait to see the results of the trial. The difficulty is that while all of us want some investigational treatment that really works, there are trials in which patients can enroll in which the drug may be only marginally beneficial. The downside is that the patient may then not qualify for other trials that come along that may be far more efficacious. For example, I have reservations about gene therapy and whether what we're doing is going to be beneficial. I don't think it will hurt anybody, but I think it may not be beneficial because we may not get enough immune response. The question is, if you have 400 CD4 cells/mm3, do you want to do gene therapy or do you want to wait to get into a Merck protease inhibitor trial in a few months? Just having a clinical trial available is not enough. As a patient, you want to be certain that the trial you're getting into is the best trial available to prolong your life. MITSUYASU: There were no new data presented at the conference with regard to the use of IL-2 in HIV positive individuals. However, Dr. Clifford Lane did review some of the data from his previously reported studies of IL-2. In a group of patients with early HIV infection and CD4 counts above 200 cells/mm3, roughly 70% of them had a sustained rise in CD4 count from using a moderate dose of IL-2 (12-18 million units per day for 5 days and repeated every 8 weeks). The downside of treatment with IL-2 are the side effects, which are fairly substantial. Patients will develop fairly significant flu-like symptoms including fevers, muscle aches and fatigue that can last for varying periods of time. Second, there is a transient rise in HIV viral load as measured in the peripheral blood by branched chain DNA (bDNA) assay. However, this returns to baseline levels through the use of antiretroviral drugs. So the net effect appears to be a gradual rise in CD4 counts, which tends to occur preferentially in people with higher CD4 counts. This suggests that in order for the drug to be effective, the patient needs to have a certain degree of normal immune restorative capability. If you do have that capability and have adequate antiretroviral therapy, the use of IL-2 will give you some about a 70% likelihood of having your CD4 cell numbers increase. Dr. Lane also presented data to show that these cells are functional and proliferate in response to a variety of challenges in the laboratory. They don't seem to be clonal [a group of cells developing from only one cell]. One of the concerns is that maybe we're stimulating just one population of T-cells that might have a greater likelihood of becoming malignant at some point, although that does not appear to be the case. These cells appear to be functional and appear to be polyclonal T-cells. This is very positive. There are additional controlled studies around the United States with larger numbers of patients to determine whether this treatment will ultimately be useful and for what population, i.e., down to what CD4 cell numbers can one go and still get a rise in their CD4 counts with therapy? BAKER: Dr. Fauci mentioned that it was around the 150 cells/mm3 level that there did not seem to be an increase in CD4 cells. VOLBERDING: More like around 500 cells/mm3. Lane actually presented this data at one of the workshops on Thursday at the conference. I was concerned because real increases in CD4 counts were not seen in the patients with CD4 counts below 500 cells/mm3. CONANT: That's why Dr. Lane stressed that with lower CD4 cell levels you should use antiretroviral therapy, and hopefully get cell counts up high enough that you might see benefit. I think others are seeing the same thing. BROOKLYN, NY: Was there mention at the conference of any side effects of the human growth hormone treatment for wasting syndrome? If there are side effects, can we live with them or will they force people to seek other therapies? Second, does anybody know of something called soluble TNF receptors as a marker for HIV infection? VOLBERDING: I can answer the last question. One paper by Dr. Steven Miles of UCLA indicated that soluble TNF receptor antagonists will be entering clinical trials shortly for KS treatment. The rationale here is that KS can be stimulated by a variety of cytokines, including tumor necrosis factor (TNF). Using a receptor antagonist may block TNF from binding to its receptors on KS cells, which may cause the tumors to shrink. Those studies are in progress. Dr. Lane also reported on a different soluble receptor antagonist, the IL-1 receptor antagonist, that has been tested in patients with HIV infection. In that situation there is a reduction in HIV replication. The theory is that since we know that IL-1 is a potent cytokine that stimulates HIV replication, inhibiting the binding of IL-1 to its receptor may inhibit HIV replication. This seems to be the case, at least from the results of the early Phase I studies. With regard to the human growth hormone situation, my understanding was that it was extremely well tolerated and there were really no major side effects. MITSUYASU: Human growth hormone treatment is very expensive and has to be given by injection. Treatment requires a close working relationship with a sophisticated healthcare system. FAUCI: I didn't see the presentation concerning human growth hormone, but it's clear from a number of groups over a period of time that you can get a beneficial effect. We have to be careful because if we give something as potent as a growth hormone for a considerable period of time, we could wind up with a whole variety of different toxicities that might outweigh the anti-cachectic [anti-wasting] effects. So I would be concerned that people would hear the results and think, "Wow, this is a great idea. Why don't we just go ahead and use it." We need to learn more about it from the controlled studies that are taking place rather than from anecdotal reports. CONANT: I would agree with Tony. The take-home message was that while we can do things to increase people's appetite, such as prescribing Marinol, that may not necessarily lead to them gaining the weight they want to gain. What we want to gain is lean body mass, or muscle. If you're just eating and getting fat, even if the weight is going up, that's not giving you what you need. So the message here is yes, growth hormone can give you lean body mass. Exercise will give you that as well. I think we need to start combining things that increase appetite with strategies that give us the kind of weight gain we want, which is muscle. VOLBERDING: There has been a growing interest in the use of anabolic steroids and testosterone. If a person can maintain an active exercise program, some of those treatments also may be useful in maintaining more lean body mass. CONANT: People should couple their increased dietary intake with exercise, if possible. Our patients who are going to the gym are doing the right thing. VOLBERDING: Right. And if you're not able to do that, if you're so fatigued or your disease is relatively advanced, apparently testosterone and anabolic steroids don't add anything. You should probably question your physician if they're being recommended routinely. BAKER: It also seems that resistance exercise like weight training is more helpful than aerobic exercise. BAKER: Dr. Mitsuyasu, you mentioned tumor necrosis factor (TNF). I wondered if anyone had heard results of the studies of pentoxifylline, which has both an anti-TNF effect and an anti-HIV effect? Was there any information in Yokohama on that drug? MITSUYASU: There were a couple of posters presented from a variety of sites around the world, including Dr. Sonnabend's site in New York City. They suggested that the use of pentoxifylline, particularly at higher doses than we would typically use for claudication [lack of blood flow, the indication for which the drug is currently approved], does appear to have some effect in reducing the level of TNF in the plasma of patients with HIV infection. It does not appear to translate into a decrease in viral load. In Dr. Sonnabend's study, as in other studies, there did appear to be some improvement in quality of life. Patients felt better; they were less fatigued and had fewer fevers. It would appear, therefore, that the drug does inhibit TNF. However, in and of itself, pentoxifylline is not potent enough to reduce viral load, at least not according to our standard measures. BAKER: Was it being used in combination with an antiretroviral drug? MITSUYASU: I believe that in most cases pentoxifylline is being used with antiretroviral drugs, which are not altered during the course of treatment. Still, pentoxifylline taken in combination with currently available drugs does not appear to decrease viral load significantly. That doesn't mean it's not a useful agent. It may be useful in reducing some symptoms such as fever, fatigue and wasting. BAKER: I think it's worth mentioning that this is a prescription drug that's readily available and does not appear to have any serious toxicities. Individuals might want to discuss possible use of the drug with their physician. CLEVELAND, OH: Was there any information on thalidomide and its anti-HIV properties at the conference? VOLBERDING: Thalidomide, like pentoxifylline, inhibits TNF. Interest started with the observation that thalidomide may help decrease some of the ulcers we find in the mouths of patients with HIV. At the same time, people observed that thalidomide also blocked TNF. Small trials have already been conducted, and some larger ones are now being organized. They want to see if thalidomide blocks TNF and is perhaps useful in preventing wasting. So far I haven't heard any results. BAKER: I read a report on a paper given by Dr. Robert Gallo in which he mentioned a compound called hydroxyurea. I understand that this is an inexpensive oral drug. CONANT: I've used it for years in patients with psoriasis and cancer. Hydroxyurea is an anti-metabolite like methatrexate; it's a cell poison. The argument Gallo's people made suggested that the mechanism by which hydroxyurea worked might be a fruitful area of AIDS research. What they were pointing out was that hydroxyurea, by poisoning some of the cellular enzymes, slowed down the replication of the virus. If you could slow down various parts of the cell, you might also be able to block the virus. VOLBERDING: Hydroxyurea made the cells more susceptible to the effects of AZT, which was intriguing. There were some French researchers who suggested that there might be some related compounds, perhaps less toxic, that might do the same thing. Hydroxyurea, for those of us who use chemotherapy, is an interesting option. CONANT: You're on a tightrope with hydroxyurea. If you use too little, it's not going to do anything. If you use too much, you may suppress the immune system even more and hasten the patient's death. A similar example would be cortisone. The use of cortisone in certain AIDS patients has benefit. The problem is that it's immunosuppressive and can lead to the development of Pneumocystis carinii pneumonia (PCP). I went up after the presentation and said to Bob Gallo, "With you now having mentioned this twice, certainly someone has tried it. What are the results?" And he said, "No, we don't know of anyone who has in fact tried it in the clinic." So I think the message should be that it's an interesting area of research, but don't run out and take hydroxyurea today because it is potentially a very dangerous drug. NEW BEDFORD, MA: I'd like for you to discuss the new antiretroviral D4T. Also, I'd like recommendations for the prophylactic medication regimen for an individual with a CD4 count of less than 50 cells/mm3 who is basically asymptomatic. CONANT: D4T is part of the nucleoside analog drug family which includes AZT, ddI, ddC and 3TC. Each of them is slightly different from the others. All of them block the reverse transcriptase stage of HIV replication, but different ones have different side effects. D4T is less toxic than some of the others and thus is better tolerated. However, because studies have not been done, it is not yet clear whether it is as good as or better than AZT or ddI or ddC. The initial studies showd significant reductions in viral load that persisted for a long period of time. Unfortunately, in almost all of the patients they treated with D4T at doses that caused significant reductions in viral load, they saw a significant degree of neuropathy. So neurological problems were seen when the dose level was high enough to get a marked viral reduction. That dose was about 4 times higher than what is currently used in patients. At the doses currently used we saw side effects in up to 50% of the patients, including neuropathy, sleep disturbances, panic reactions and anxiety attacks. Since this drug has significant side effects, some patients can take it and some patients can't. This also significantly limits the amount of drug we can use in an effort to reduce the viral load. The good news is that the more of these drugs we have, the more opportunities there are for those of us treating patients. For example, you may not be able to use D4T, but you may be able to use 3TC or ddI or ddC. This gives us the opportunity to find the drug that the patient will hopefully be able to tolerate for a period of time. BAKER: The second part of the question was about prophylaxis regimens. MITSUYASU: Someone who has a CD4 count under 50 cells/mm3 clearly needs to be on prophylaxis for a number of opportunistic infections. Something for PCP, preferably something systemic such as TMP-SMX (Septra or Bactrim) or dapsone. If a person can't tolerate these, then try aerosolized pentamidine. There are also studies looking at whether atovaquone, an anti-PCP medication, is effective. This hasn't yet been clearly demonstrated. In addition, fungal infections can occur at that stage of the disease, so fluconazole, an anti-fungal drug, would be indicated. Mycobacterium avium complex (MAC), a bacterial infection that can cause serious complications in a patient with AIDS, can also be prevented with medications such as rifabutin and/or clarithromycin [Biaxin]. There is data that suggests that perhaps even oral ganciclovir may have some effect in preventing cytomegalovirus (CMV) infection, a virus that can cause serious problems including retinitis in patients with AIDS. Though a large number of medications may be needed, hopefully by preventing these infections we can prolong life and increase the quality of life for patients. We also hope to prevent further rapid destruction of immunity as sometimes occurs after opportunistic infections. BAKER: I think one part of the question was that the individual was asymptomatic. He wanted to know if that would have any effect on any of your recommendations regarding prophylaxis? CONANT: No. We base our decisions about prophylaxis on the CD4 cell count and CD4 percentage, not on whether the patient is symptomatic. This is important. Tragically, there are still people out there who know they were at risk for exposure to HIV back in the early 1980s who have not been tested. They don't know they're HIV positive, they just suspect they might be. They choose to ignore this disease hoping they weren't infected. The tragedy is that we see them turn up in emergency rooms dying of PCP. They already have a CD4 count of 180 cells/mm3 when they arrive in the emergency room. This does not need to happen. If we had been following that person, we might have started AZT when the CD4 count got down around 300-350 cells/mm3, and we certainly would have started Septra when the CD4 count went below 200. That patient would have been spared an episode of PCP. The denial which has kept him from being tested has altered his quality of life and perhaps even his prognosis. VIRGINIA: I have a question about AZT. When I saw my first blood count, the MCV [mean corpuscular volume] was elevated. I gave myself a vitamin B12 shot every day because it's got a short half-life. I continue to take AZT and have no infections and my question is, are we sure that AZT wears out, or does the bone marrow wear out? MITSUYASU: The question is very interesting. Many of us who treat patients have seen patients who do seem to have an increase in their MCV, which is a measure of the size of red blood cells. Many of those patients actually do get a good response to the antiviral effect of AZT. It's a clinical observation; it hasn't really been proven in prospective studies. If you're getting adequate absorption of the medication it affects your bone marrow, causing the red blood cells to get a little bigger (a normal effect of the medication). Those patients getting adequate absorption of the drug are probably also getting the good antiviral effect. So the fact your MCV went up and you had a good response is not particularly surprising. The adverse, long-term effect of AZT on inhibiting bone marrow is clearly well recognized. As your disease progresses, the sensitivity of your bone marrow to AZT may become greater, so your blood counts may go down. But that's not the reason why the effect of AZT wears off with time. There's a large body of data now suggesting that, as a result of long-term exposure to AZT, your virus may mutate and become resistant to the effects of that drug. As a result, you get more virus in the blood. As you get more virus in the blood, the virus replicates faster and you get more mutations, and ultimately it causes more damage to your CD4 cells. So that, more than the effects on the bone marrow, is why the effects of the drug wear off. CHICAGO, IL: First, what is the place of Zovirax [acyclovir, an anti-herpes drug] in addition to conventional antiretrovirals for the treatment of HIV infection? Second, does routine vaccination of HIV-infected patients with the flu or tetanus vaccine or any other immunization make the situation worse? You may be stimulating the cells that contain the virus and therefore increasing the viral burden. CONANT: There have now been a variety of studies on acyclovir. At least 5 are published studies and Dr. Graham reviewed the data from the MACS cohort at Yokohama. These 5 studies and the MACS study show that acyclovir given for any reason, once the patient has an AIDS diagnosis, increases survival somewhere between 26% and 36%. Now in my mind as a clinician, that's important news. When I treat a patient with AZT, I can cut down on progression from asymptomatic to ARC and from ARC to AIDS, but I can't increase that patient's survival beyond 3 years. That was the message of the Concorde study. Tony Fauci presented data years ago from test-tube studies showing that a cell infected with both HIV and herpes simplex virus (HSV) exhibit increased HIV replication. We have routinely been putting all patients on acyclovir in doses ranging from 400 mg twice a day to 400 mg 3 times a day, and we are going to continue because we think it has a number of benefits. We believe it increases survival and this data confirms that. We think it cuts down on the incidence of herpes zoster. It cuts down on the incidence of recurrent herpes outbreaks. We do not see the emergence of resistant herpes or oral hairy leukoplakia in those patients taking acyclovir. BAKER: Dr. Fauci, would you like to take the second part of the question? FAUCI: It's very clear that if you antigenically stimulate someone with a vaccine of any sort you will get a transient increase in viremia, or the amount of virus that you can measure in the peripheral blood. In studies done in a number of groups, either with immunizations with proteins or with cytokines, that increase returns to baseline. Although there's no evidence at this point that the total viral burden increases, this doesn't mean one should be cavalier about it. When you think in terms of immunizations, it really is a delicate balance. We get stimulated with environmental antigens all the time, which gives the same increase in viremia as in those people who have measurable viremia. It seems to go back down to baseline. The trade-off of not immunizing people against microbes is that the little blip you get with the vaccination might really be insignificant compared to the induction of substantial viremia you might get if you actually get infected. In other words, if the vaccination protects you against an infection, you may have done yourself a lot more good than if you skipped the vaccine, ultimately got infected and had 3 or 4 days of stimulation with that other microbe. BEDFORD, MA: I wondered if Dr. Conant could tell us the comparative effectiveness of aerosolized pentamidine treatment for people who are allergic to Bactrim [TMP-SMX]. CONANT: From studies it appears that TMP-SMX given orally is 4 times more effective than aerosolized pentamidine. So while aerosolized pentamidine was a major advance at one time, we can do 4 times better with a cheap and easily administered drug. The problem is that about half the people who try to take TMP-SMX, which is sold as either Septra or Bactrim, are allergic to it. That's why clinicians managing these patients need to be prepared to desensitize patients if they are allergic to it. In our clinic the patients we cannot effectively desensitize are those who are getting PCP and, unfortunately, dying. We now put those patients on dapsone if they can take that drug, at 100 mg every day, and we add 300 mg of aerosolized pentamidine every 3-4 weeks. BAKER: What did you hear about prophylaxis or treatments for opportunistic infections? I'm thinking specifically of some information about oral ganciclovir as primary prophylaxis for CMV disease? CONANT: There was not a formal presentation from Syntex. However, the data discussed among the investigators points to the conclusion that oral ganciclovir is effective in terms of prophylaxis against CMV retinitis. This is good news because the face of AIDS keeps changing as we keep prophylaxing against the diseases that make our patients sick. Early in the epidemic, 60% of AIDS patients got PCP. Now in my clinic in San Francisco we hardly ever see a case of PCP. When I opened our AIDS clinic 5 years ago, the most common cause of death was Mycobacterium avium complex (MAC). We haven't seen a death from MAC in over a year because we're prophylaxing all patients with clarithromycin. The major cause of morbidity in our patients is CMV retinitis. If we could have an effective oral drug to prevent that disease, it would be a major advance. It looks as is that will come within a matter of 4-6 months. The bad news is trials of an oral form of foscarnet, the other agent effective against CMV, were stopped because it was not effective. So we had one bit of good news, that oral ganciclovir appears effective, and the bad news that foscarnet cannot be given orally. BAKER: You could ask your physician to call the manufacturer of oral ganciclovir, Syntex Corporation, in the San Francisco Bay Area, and ask whether the drug is available. Also ask whether there are open studies and where they're located. STATE COLLEGE, PA: In Pittsburgh, a company called Novum is still enrolling a Phase III trial of oral ganciclovir. My question is, what are the current recommendations for prophylaxis for individuals who may be at risk for exposure to multidrug-resistant tuberculosis (MDR-TB) but not necessarily showing infection? VOLBERDING: MDR-TB is fortunately not proving to be as widespread as it looked like it might become a year and a half ago. In terms of prophylaxis, I think most people are still recommending standard prophylaxis for hospital workers whose skin tests convert. BAKER: Isn't there a new 3-drug pill--combining 3 individual drugs into 1 pill--that has been approved? As of last month it was not yet available in pharmacies. This was supposed to be something of a breakthrough because since they are contained in 1 pill, compliance is much better. CONANT: I haven't heard that. It wouldn't surprise me if that's the case because that is the problem--compliance. MONTANA: Was any new information about KS presented at the conference? MITSUYASU: There weren't as many things in the KS arena as there have been in previous conferences. There were a couple of papers presented on treatment of KS. The major study was by Dr. Jim Warrens in New York on 42 patients treated with a liposomal daunorubicin compound called Daunoxome. That paper is one of several presented over the last few years that demonstrates that this agent is effective in controlling KS, particularly in patients with more advanced disease. There are side effects from the medication, including those typical with chemotherapy such as nausea and hair loss. But by and large the drug seems to be effective and is very well-tolerated. There was also some work presented by Dr. Robert Gallo at the National Cancer Institute (NCI) about the potential benefits of a female hormone called human chorionic gonadotropin (HCG). In some in vitro studies he was able to demonstrate that HCG affected KS cell growth. This is interesting because we and others who have looked at this in the laboratory find that there are a number of hormones, both corticosteroids and male sex steroids, that can increase HIV replication. It's interesting to speculate that perhaps female sex hormones may have the opposite effect, that they may inhibit KS cell growth. Clearly Gallo's preliminary results need to be validated in other laboratories before one begins using this agent in patients. Those were really the only 2 major presentations on KS. There were a number of clinical papers presented from different countries outlining the presentation of KS. It seems to be increasing in severity in many parts of the world. Patients who get KS end up coming in with more advanced tumors. Perhaps by inhibiting some of the cytokines that stimulate KS cell growth, we may be able to control KS proliferation in patients. However, these things will need to be tested in the clinic in patients. There are some Phase I studies currently underway. BAKER: Dr. Conant, did anything on KS strike your attention? CONANT: Yes, liposomal doxorubicin [a treatment that puts chemotherapeutic agents into a liposome, or lipid capsule] looks as if it's going to be a major new weapon in our armamentarium. We've been working with Al Newman in San Francisco who has a number of patients now treated with this new technology. These liposomes are engineered to specifically target KS lesions without poisoning all the cells in the body. Due to the specificity of this therapy, higher doses can be used with fewer side effects. We look forward to FDA approval in the near future. Except for that, I didn't see any new and promising therapies for KS at this meeting. BAKER: What about the theory that KS is caused by an as yet unidentified infectious agent? Is that still current thinking? CONANT: Very much so. I think the evidence is pretty overwhelming that there must have been some agent transmitted in the gay community, prior to the AIDS epidemic, that causes KS. That agent would have remained dormant in gay men for years, but when their immune systems were damaged by HIV infection, the disease then manifested itself. The evidence for this is that KS is seen almost exclusively in homosexual, HIV positive men. If you acquire HIV from a transfusion or from IV drug use, the incidence of KS is less than 2%. The incidence in gay men early in the epidemic was 40%. Over time, probably because of safe sex practices, that's dropped to 12% in San Francisco. I think the evidence is fairly overwhelming that there must be some other agent, probably sexually transmitted. We've not isolated or identified the agent yet. BAKER: I think an important and perhaps "revolutionary" development in management of HIV disease is that the new quantitative PCR tests and the branched chain DNA tests can be used to help quickly evaluate new therapies. I think the current problem is that these tests have not yet been standardized. There still needs to be definitive data from trials showing that there is a direct correlation with the results from these tests in terms of a clinical benefit or the lack of clinical benefit. VOLBERDING: I agree, and I think it is too early to tell a clinician or a patient how to use this in day-to-day practice. It is possible to say that this new technology will permit us to more rapidly test new drugs. There is without doubt a relationship between the antiviral effect of the drug and the effect on these markers. As opposed to CD4 counts, which are important for patient management but which haven't been very successful in terms of drug testing, we'll finally have a test that can be used to make the clinical trials shorter. BAKER: It would also seem to be very important for individualizing therapy. These tests could allow therapy that is much more closely tailored to the needs of an individual patient. VOLBERDING: There is the hope that this will be the case. I have to say there's still some anxiety from the data I've seen regarding the response to therapy in terms of these RNA viral markers. It may be quite comparable to the effect these drugs have on CD4 counts. We know CD4 counts have not proven to be a very useful marker of drug benefit. I admit it's intriguing and certainly tempting to think that we can individualize therapy, but we're in the process within the ACTG now of developing some clinical trials that will actually put that to the test. I hope it proves to be the case, but I do think we need to prove it first. HARRISBURG, PA: My question is about the PCR test. When you see DNA or copies of DNA, does that mean the virus is replicating actively or is it the reverse? When you see RNA, is the virus replicating actively? FAUCI: It's the other way around. DNA means that the virus has gotten into the cell. It reverse-transcribes its RNA into DNA, which we call a pro-virus state. This viral DNA then integrates itself into the gene of the host cell. The characteristic of a cell in the latency period is that it's not expressing any RNA. So if you do a standard DNA PCR and all you see is the DNA in the cell, that cell is more likely in the quiescent stage. When you do an RNA PCR and start to see a lot of viral messenger RNA, that's a tip-off that the virus is starting to replicate. ATLANTA, GA: Among the non-progressors Dr. Fauci talked about, was the virus strain tested to see if there were any significant genetic deletions, such as the nef section? FAUCI: We are in the process of doing what's called heteroduplex analysis, which looks for any deleted genes. Other laboratories that have looked at the virus, like Mark Feinberg's lab in San Francisco and David Ho's lab in New York, indicate that there are no obvious abnormalities in the viruses themselves that one could detect by a gross deletion of a segment such as nef. If you put all the data together from different laboratories, most of the time the virus that caused low burden and low replication was what we call a replication-competent virus. Yet that doesn't mean you're not going to find an occasional person with a defective virus. NEW YORK, NY: This is regarding the validation of viral load information with a clinical endpoint. My concern is that it will take a long time to do this. I wonder if in the case of HIV care there is information about viral load in other circumstances, like in CMV infection, where we can expect to see clinical manifestations sooner. If you have to wait for HIV viral load to be validated by clinical endpoints, it may take several years to actually do so. CONANT: I agree with Paul. I think it's too early for clinicians to start widely using PCR or branched chain DNA to decide on treatments, but I also share Paul's optimism that these technologies will allow small, quick studies to look at viral load. If we find something that really works, we can get that to patients sooner. Let's say you're going to measure how many people get sick with AIDS or die, and that's going to be your endpoint. The ACTG 019 study showed seven [out of 100] people would die, and they had all sorts of CD4 counts. You woulud need to enroll 200 or 300 patients in a trial to begin to get some kind of answer, because you must have enough people who will progress to actually see the difference. To enroll 300 people in a study sometimes takes up to 2 years; if you enroll 1 person a day, it will take a year. You then have to wait another year to get results, so it takes at least 2 years, and probably 3 or 4, to get an answer. If you could do a study on 30 patients that could be enrolled very quickly, and show with PCR technology a substantial reduction in viral load, then clinicians would use those treatments much sooner. That's the promise of Ashley Haase's data and the various ways of measuring viral load--we're going to see new treatments hopefully in a year to a year and a half, not 2 or 3 years as before. MIAMI, FL: Are markers such as beta-2 microglobulin and p24 antigen considered the best markers? CONANT: Well, they're probably the best we have today. The CD4 count is probably still the best, albeit not the gold standard. Beta-2 microglobulin, neopterin levels, p24 antibody and p24 antigen are all useful at times. But some newer markers such as branched chain DNA PCR will be useful in clinical trials and probably in the clinic in the not-too-distant future. We'll be able to use more reliable markers that give us a better fix on viral load. GEORGIA: I wondered if there was any information from the conference about the minority of people with HIV who have a fairly high CD4 cell percentage. Doctors here seem not to know when to start putting you on prophylactic therapy. Let's say you have 500 CD4 cells/mm3 and a CD4 percentage of 12%. Would the use of any viral load tests such as PCR be helpful in making some of those determinations? CONANT: In terms of using a percentage, the absolute number of cells like 500 or 400 or 300 cells/mm3 is actually calculated by multiplying the percentage of CD4 cells against your total white blood cell count. So really the percentage is more important than the absolute number. If anything happens to get your white blood cell count up--for example, an infection or exercise--and your percentage is 20, your absolute number is going to be high that day. If the percentage is 20 and your white cell count has gone down for any reason, your absolute number is going to be low that day. The percentage is the most important number even though by convention we normally recite them in absolute numbers, such as a CD4 count of 500 cells/mm3 rather than saying a CD4 count of 27%. In our clinic we get concerned when the CD4 percentage drops below about 20%. If I saw a percentage down to 12%, even if the patient had 500 CD4 cells/mm3, I would first ask why is this patient's white blood count so high--because it must be--and then look at the various treatment options available, including antiretroviral therapy and prophylaxis. I would also look at the patient's clinical symptoms. Is there evidence of fatigue, fever, night sweats, weight loss, cough, diarrhea or some of the cutaneous markers such as hairy leukoplakia or molluscum contagiosum that indicate disease progression? Physicians on the West Coast would couple your percentage with your clinical symptoms to try to help you decide where you should be in terms of therapy. MITSUYASU: Clearly the CD4 cell percentage is the most critical measurement, and tends to vary less than the absolute number on a day-to-day basis. Transient CD4 percentages are what we use to make therapeutic decisions. To answer the question of whether viral load would be helpful in terms of major decisions as to when to initiate antiviral therapy and when to initiate prophylactic antibiotics, it will not add much additional information. While there was a lot of information presented at the conference in regard to the potential utility of viral load measures and assessing response to antiviral therapy, and perhaps also with regard to survival, they are still only investigational. Results have not been validated in large numbers of patients. On an individual patient basis, it is still somewhat questionable. Given the expense of the test and some of the concerns about how it's processed--it has to be processed in a very specific way to prevent contamination--it may not be worth doing at this point. IDAHO: In regard to prenatal transmission, the studies I've seen suggest very strongly that good prenatal care and good prenatal nutrition (specifically one study in Africa regarding vitamin A) dramatically reduced mother-to-infant transmission of the virus. Given the problems of the availability of AZT, are we well-advised to continue along that route as a primary method of preventing transmission, or should we work on prenatal care? CONANT: There are a lot of issues there. Certainly good prenatal care is something one would want in any area of the world, and the prenatal care given in the United States is not nearly as exemplary as that offered in many other developed countries. But if we can reduce the transmission rate by two-thirds using monotherapy in HIV-infected women, many of us think we can do even better with combination therapy. The problem I see is social. AIDS has been so stigmatized and people have been so marginalized by the disease that women are not coming forward to be tested to find out if they're infected. They're afraid they'll be in some way discriminated against or their children will be taken from them. IDAHO: I have 2 basic levels of concern now. First, of course, is the cost of AZT. Second is that if we emphasize nutrition in prenatal care, we don't have to worry about the stigmatization--we don't even have to identify whether or not people are infected. CONANT: Even if you had excellent prenatal care, you would still, if it was your wife, want her on a drug to prevent transmission or reduce transmission to the lowest possible level, would you not? IDAHO: Well, I'm concerned about the possible long-term effects on both the mother and the child. We don't know a lot about that yet. CONANT: In the study that was done, there was no evidence of adverse short-term effects either in the mother or the child. VOLBERDING: There have been a number of babies born to women who have been taking zidovudine [AZT] for long periods of time, sometimes during the entire pregnancy. There's no case I'm aware of where there have been any long-term adverse effects on the baby. In the study we've been talking about, the babies did have slightly lower hemoglobin at birth, but that reversed very quickly. They showed no signs of any side effects. Of course, we have a lot of experience with giving this drug for a number of years to people with HIV infection with no evidence of surprising long-term toxicity, so I think there's probably no strong argument against it. SAN FRANCISCO, CA: Are women who are pregnant given the alternative to abort if they know they are HIV positive? BUCHBINDER: It really depends on the kind of counseling women who are HIV positive and pregnant receive. Obviously, it is our hope that women are given a full range of options--information about the likelihood of transmission to the newborn child, and the relative risks and benefits to the woman of continuing to carry the pregnancy. A number of studies in both the United States and Europe indicate that the risk of transmission to a newborn child from an HIV-infected woman is between 20-25%. It may be lower in certain groups and higher in others. Some studies in developing countries indicate somewhat higher rates of infection of newborns. It's still not entirely clear how much that has to do with the role of breast-feeding--which can transmit HIV--and how much has to do with the woman's own health status when she is pregnant and gives birth. There are certainly some things that can affect the likelihood that a woman will transmit HIV to a child, including the woman's health status, her CD4 count and the amount of virus circulating in her blood. There's some evidence that suggests Cesarean section may decrease the risk of infection to the newborn. There have been twin studies that indicate that the first-born twin is more likely to become infected than the second-born twin, suggesting that contact with maternal blood and tissues during the process of labor and delivery may expose the child to HIV. A large proportion of the transmission may be occurring either late in pregnancy, or perhaps during labor and delivery. It's important that women receive as much information as possible so that they can make their own decisions about whether to complete or terminate a pregnancy. Obviously the kind of counseling a woman receives is dependent on where she receives the counseling, but she should be given all of the information to make an informed decision with her provider and her family. DALLAS, TX: An HIV positive participant has been with his girlfriend for at least 3 years. She's repeatedly tested negative. The physicians have said she probably no longer needs testing. Would you all agree? CONANT: No, I don't agree with that. I take care of HIV positive patients every day. I try not to stick myself with needles and I try to have the people around me not stick themselves. I know I'm at risk of contracting this disease, because I'm coming into contact with it daily. It woulud be negligent to the people I'm intimate with if I did not regularly test myself. While this woman is at low risk, and depending on what level of safe sex practices the couple is using, hopefully they've diminished that risk to almost zero. I think it would be prudent for her to test every 4 to 6 months, as part of her routine health care. If that condom breaks and she gets infected, she wants to know it rather than waiting until she becomes ill. Instead of the healthcare provider saying, as we often do to people, "you're being careful aren't you?," the provider needs to propose that all 3 of them have a candid discussion about what the couple really does. I have often found that my patients are mistaken as to what safe sex practices are. I can remember someone who was HIV negative and his boyfriend was HIV positive. He said, "Of course he uses a condom when he's the insertive partner, but I know I don't have to when I'm the insertive partner." And I said, "What! You're out of your mind." You realize people are mistaken about what are safe-sex practices, and they also get into denial. They need a frank discussion with their provider as to what they are doing when they are with their partners. DALLAS, TX: Do either of you have any comments on the use of transfer factor? FAUCI: There's no evidence that transfer factor provides any lasting immunological enhancement. Transfer factor has an anecdotal history that goes back decades of its supposed ability to enhance immune response, but there really is no solid evidence that it does. HOUSTON, TX: Can you give us an update on gene therapy and suggest a realistic time line for when something useful might be put into widespread use? CONANT: We are engineering novel viruses incable of replication that can code for the HIV proteins env and rev. We then inject this virus into humans, and the virus will present proteins on the surface of muscles cells of the buttocks [the injection site] that look like the viral HIV envelope and rev proteins, as well as MHC receptors. One of the mysterious things about HIV is that it down-regulates the MHC signal, which signals killer CD8 cells to come in and kill the infected cell. This method of gene therapy up-regulates the expression of the MHC signal. The patient theoretically will now mount a cytotoxic response to these muscle cells. The recently infected muscle cells are eliminated, but theoretically extra killer cells will remain available to recognize and kill HIV-infected cells elsewhere in the body, which have very low expression of MHC receptors. My concern is that the degree of CTL response that we will be able to stimulate with this vaccine--which has to be given repeatedly and intermittently--will not be high enough to do the job. It makes sense theoretically and will probably work, but whether it will work to a degree that will be efficacious I don't know. We have screened 100 patients for this trial in San Francisco. We've already inserted the genes into about 6 patients. We will continue until something in the range of 60 patients have been injected. We will measure viral load and the number of CTL produced as an initial endpoint. FAUCI: The description Marcus gave is 1 type of gene therapy designed to induce an immune response that ultimately eliminates virally infected cells. There are also other forms of gene therapy. In its purest form, gene therapy replaces a defective or malfunctioning gene. We have experience with diseases like cystic fibrosis and severe combined immunodeficiency disease (SCID) where the malfunctioning gene is extracted from the cells of the individual. We insert a new functional gene into those cells and infuse the cells back into the patient's body. Whatever enzyme was missing can now be made. The standard gene therapy approach for HIV disease is different from what Dr. Conant described, because his is a straight-forward intellectual response. Others are working on ways to "decoy" the virus. Researchers are working on ways to protect cells even after infection by replacing some immune system cells with cells that have a gene inserted into them in order to prevent the virus from replicating. The logistics of engineering such cells are extremely difficult. If something like what Dr. Conant mentioned works, that approach would be more feasible for use in large numbers of individuals than replacing an immune system with cells that contain a viral decoy. That's a scientifically elegant concept, but not a feasible approach for 17 million infected people. SAN FRANCISCO, CA: Given a choice between delavirdine [a non-nucleoside analog reverse transcriptase inhibitor] or a protease inhibitor in a clinical study--since you can either do one or the other--which would you recommend? CONANT: The problem is that if you're using those agents as monotherapy, resistance develops pretty rapidly. I have seen data from a European group that combined AZT, 3TC and a non-nucleoside reverse transcriptase inhibitor. At least as measured by serum p24 antigen level, which is a very poor marker, those 3 drugs in combination were superior to AZT or 3TC alone. At this point we don't know which combination is the best. If it were me, I would probably go with a protease inhibitor and a nucleoside analog like AZT or ddI, but that's purely a hunch with no experimental data to back it up. SAN FRANCISCO, CA: I'm entering a trial for RO31 [the Roche protease inhibitor] in combination with ddC. I know the side effects of ddC, and I know it's hard to tell what the protease inhibitor is going to do. Could I withdraw from the study if I decide to do so? CONANT: While no one thinks protease drugs in the combination they are using are going to be injurious, we don't know whether they are using the best protease inhibitor or the best combination. That's why we've got to do clinical trials. If that trial is available to you, it's a reasonable strategy to consider. I'm sure you've talked about it with your provider and they talked to you about the other options you have. We would all rather see a trial using a couple of nucleoside analogs with a non-nucleoside reverse transcriptase inhibitor and a protease inhibitor. In other words, we'd like to see even more extensive combinations than the one you're using. The problem is that the one you're using is the only one available. Whether you should go into the trial depends on a number of questions you should discuss with your physician. How far advanced is your disease? Are you symptomatic? Are other things not working? Those would be the things you and your provider should discuss, rather than just entering a trial because it's there. BAKER: Dr. Buchbinder, you've been involved with one of the most fascinating studies in the whole history of this epidemic, following long-term non-progressors who have been healthy for about 10-15 years now. Could you talk about this study? What are the characteristics of long-term non-progressors? How do they differ from long-term survivors? BUCHBINDER: The term "long-term survivors" has been used to describe a variety of individuals who are living with HIV. At times it's even been used to describe a group of people who may have been exposed to HIV but have not been infected with the virus. There's been increasing interest in how people infected with HIV stay healthy. Research on these individuals can help us to understand some natural protective mechanisms against HIV and may give us clues about new kinds of treatments and vaccines. We've been studying a subgroup of the long-term survivors who we call long-term non-progressors. Basically, they're at one end of the spectrum of HIV disease progression. We know on average that the time from infection to the time AIDS develops is about 10 years. Some people develop AIDS quite quickly after HIV infection; others develop AIDS more slowly. We've been studying a group of individuals who've been infected for up to 16 years. They are not only healthy and without an AIDS diagnosis, but they have high CD4 counts, in the range of 500-1500 cells/mm3. Is it just a random event that some people happen to develop AIDS quickly and others develop AIDS slowly or perhaps not at all, or is there something that's actually helping to keep the non-progressors healthy? Five to ten percent of individuals with long-term HIV infection have been infected for over 10 years. We've been exploring different areas of explanation for why these people have stayed healthy for so long. We divide them into behavioral, exposure or cofactor categories. Viral factors may be keeping non-progressors healthy. Immune factors or genetics may be keeping them healthy. In terms of the behavioral, lifestyle or cofactor issues, one of the questions is, are non-progressors living particularly healthy lifestyles? Is there something that they are doing that's keeping them healthy or not doing that's keeping them from getting sick? Many people living with HIV are living healthy lifestyles, and some of them seem to progress despite this. We can't say that living a healthy lifestyle doesn't make any difference; it certainly may improve the quality of life and it may be contributing to some people staying healthy for so long, but it doesn't seem to be the sole answer. We've been looking at the virus non-progressors have been infected with to see if they have a weakened strain. We've been able to isolate HIV from all of the individuals, so we know they're truly infected; it's not a question of a mistaken diagnosis. Some of them, however, have very little circulating virus. That's now been replicated by other groups and is also being evaluated by Fauci and Penolayo at NIH. They've been finding that non-progressors have very little virus even in their lymph nodes. There does seem to be something unusual going on with some of these individuals, but others who we've been studying have much higher levels of circulating virus. Why, despite more virus in their bloodstream, are some people not getting sick? Is it that they have a weakened strain of HIV? Is it something about their cells that keeps them from becoming infected or suffering harmful effects, or is it some combination of both? There's a group from Australia that presented some data this year. A group of individuals received transfusions from a single HIV-infected donor. The donor has been healthy, and 5 of the 6 individuals who received transfusions from that donor have also remained healthy 7 to 10 years after infection. This seems to be a situation in which either a weakened strain of virus or something else about that particular strain may be responsible for why people are staying healthy. It certainly would be helpful to know if there is such a thing as a weakened strain of HIV--that could be used to develop treatments. We've been looking at the immune system, in particular, at the cellular immune response and CD8 cells. Two different kinds of CD8 cells have been described. One is the CTL, which are white blood cells that kill cells infected with virus. We think that's a good immune response, and may be part of what's keeping people healthy. In fact, in our particular group the men who have the broadest range of CTL seem to have the least amount of virus present. It may be that these individuals have strong immune responses. These CD8 CTL are killing off virally infected cells and keeping the virus from causing disease. Dr. Levy has also been studying a group of individuals who have a kind of CD8 cell that seems not to kill cells infected with the virus but rather suppresses the virus inside those cells. He thinks they are secreting some kind of substance which is protecting the cell and keeping HIV from replicating in those cells. There may be multiple kinds of immune functions keeping HIV from replicating. In addition, Dr. David Ho at the Aaron Diamond Center in New York presented data on some neutralizing antibodies in the long-term non-progressors indicating that perhaps there are also antibodies keeping the virus in check. All of these are promising areas of research that may help us understand what kinds of immune responses help protect against HIV disease. Finally, we've been looking at the genetics of the individuals who have stayed healthy. There seem to be genes associated with long-term non-progression. There's a lot more work to be done in that area because it's very complex. We need to look not just at single genes but also at the interactions of one gene with another. There was a very preliminary presentation at one of the sessions by Dr. Deedles of UCLA that looked at the role of genetics in protecting against infection. The genes that may protect against infection may be different than the ones that protect against disease. The more we can understand about how people can live for long periods of time with HIV infection, the more successful we'll be in trying to make everybody a long-term non-progressor. SAN FRANCISCO, CA: I read a study that said that there was no difference in mortality rates for people with CMV colitis. They used an induction period of 40 days, whereas I've been on a daily maintenance regimen for a number of years. Do you think it's proper to do an induction period of 40 days and then see what happens? Or do you think it's better to do maintenance infusion daily? CONANT: The general wisdom is that if a patient is doing well on maintenance therapy, whether for CMV colitis or retinitis, you keep them on maintenance therapy. If there is a relapse of retinitis, which we have the most information about, we generally reinduce the patient and then go back to maintenance therapy. So the answer to your question really requires more information about your clinical status. If the maintenance therapy is controlling the disease, you should stay where you are. If you did well for a long period of time and then it flared up, you should be reinduced. ORANGEBURG, SC: Are there any alternative treatments for cryptococcal meningitis? My friend is presently on amphotericin B. CONANT: Cryptococcal meningitis has been successfully treated with amphotericin B (still the best drug), fluconazole and ketoconazole. The latter 2 drugs are better for suppressive treatment after the patient has initially been treated with amphotericin. Amphotericin has been around longer than I have, and that's 30 years. It's a very effective antifungal agent, but it has serious toxicity. Most of us hospitalize patients with cryptococcal meningitis, treat them aggressively with amphotericin, and then usually switch them to fluconazole once the disease is under control. On a few occasions ketoconazole has been used. MITSUYASU: That's exactly how we tend to treat people. However, there is some data from the California Collaborative Treatment Group that indicates that higher doses of fluconazole might be effective as a first-line treatment. Still, for cryptococcal meningitis, amphotericin is clearly the gold standard, if one can tolerate the side effects. NEW JERSEY: Were alternative therapies presented or are they being investigated? What about carnivora, which is a derivative of the venus flytrap that's being used by a doctor in Germany? CONANT: There were a number of papers, especially posters, on alternative therapies. The definition depends on where you draw the line for alternative, because at the moment if something shows efficacy it becomes part of conventional therapy. Posters were presented on everything from vitamins and nutrition to fermented foods to red algae to DNCB. Many of the individuals investigating these therapies are clearly motivated by the right instincts; they're looking for something that works and they have observed that a therapy seems beneficial to a group of people. However, they need to talk with people accustomed to doing clinical trials--like the various investigators who present formal papers--so they can design a trial acceptable to the scientific community. For example, someone might say, "I've had 8 patients who ate this food, and they look healthier." That's an interesting observation, but it's not scientifically valid. So, yes, there was material presented, but no, I didn't see anything that looked worthy of intensive investigation or trials in my patient population. I would urge the people looking at alternative therapies to use the same types of measurements we use with conventional therapies to ascertain if the therapies are beneficial. FLORIDA: I saw in the news last night that development of artificial blood is coming closer. Would these be any use in HIV-related treatment for fortifying or replacing a person's blood? VOLBERDING: The use of artificial blood is important for several reasons. Around the world its potential for decreasing the need for the very cumbersome collection and distribution of human blood is critical. Yet as a treatment for HIV, I don't see much possibility. Marcus really noted one of the central problems, also pointed out by the work of Ashley Haase and others at the conference: the virus is present in huge numbers of cells in the body, not just in the blood. Even if you completely replaced the blood you would not make much of a dent in the amount of virus that's present in cells throughout the body. NEW YORK, NY: I was wondering if somebody could explain the decision to switch from an annual conference to a biennial conference? It seems to be another sign not enough is being done here to even merit having a conference every year. Is that a valid interpretation? CONANT: The decision to go to a conference every other year was actually made during the Florence conference 3 years ago. The feeling by that time was that the amount of data coming in does not justify an international meeting every year. Like you, I think that was a terrible decision. Many of my friends participated in making that decision, and I have had the opportunity of telling them directly that I think it was misguided and stupid. As someone who goes to conferences, one of the advantages is that it sets a deadline for me. If you want to present your new data, you have to have it ready for submission by February for presentation in August. This deadline forces us to clarify our thoughts, to distill our work into brief vignettes as we're doing in this conversation. This requires articulating it in a format communicable to colleagues. So I see advantages to international conferences that extend far beyond the data actually being presented. While I was one of the people lamenting the fact that there was very little coming out of this conference, I think it's due to the fact that we never planted the seeds from which we could reap a harvest of information. During the Reagan years, we didn't do the research. We're not seeing much today because of that. But I certainly am one of the people who feel that conferences should be held annually until we have a vaccine and until we have a cure. BUCHBINDER: It is certainly vital to have international conferences at which people can get together from around the world to discuss different solutions to common problems. With the wealth of information and research that's been going on in a variety of areas concerning HIV and AIDS, there have been a number of smaller national and international conferences that allow people to get together, yet save some resources. We put those resources into actual research and share information with smaller groups of people. The smaller conferences focus on issues such as resistance to antiretrovirals, new developments in vaccine research, psychosocial issues or home care. That's part of the reason people felt that having one large conference could go to an every-other-year format. One of the problems with frequent conferences is that you must travel frequently. Going to meetings can sometimes take you away from the very research you're trying to report on. So part of it is an efficiency issue, involving both cost and time. MITSUYASU: I have mixed feelings about having an international conference every 2 years. I agree with Dr. Buchbinder that it's important to have smaller, more focused meetings in which reseachers doing work in similar targeted areas can share information. That may be a more efficient way of getting information across. However, an international forum focused on AIDS is important to make people aware of the problem of HIV. If AIDS-related issues aren't embedded in the media, people tend to forget about it. We need to keep the pressure on the politicians and others to continue to sponsor research and treatment for patients with AIDS. PENNSYLVANIA: What happens to the released viral particles after the infected cell is lysed by CD8 cells or after apoptosis? MITSUYASU: Clearly if there are fully formed viral particles that are replication-competent, they can infect other cells. However, nucleoside analogs can inhibit the initial replication of the virus even before it integrates within the host DNA. If you're going to use the treatment to destroy HIV-infected cells, those infected cells could potentially be released into the circulation. You want to have medications such as AZT, ddI, ddC and other nucleoside analogs in the body to try to minimize the number of cells that could potentially be infected. There are other viral particles that are obviously not able to infect other cells. They lack the necessary molecular makeup to allow that to occur. These viral particles will ultimately be destroyed in the normal process of metabolism. The relative proportion of competent viruses and incompetent viruses varies a great deal. We want a treatment that minimizes the likelihood of competent viruses infecting the cells. SAN FRANCISCO, CA: What is your opinion on passports for infusion? Is there a greater chance of infection with a passport, as opposed to other infusion techniques? CONANT: In my clinic we commonly use passports because of patient preference. Patients generally prefer something other people won't see when they undress to the waist. They seem to work as well as other methods. We have had patients who have had passports for over a year and a half now with pretty good results. BAKER: Thank you all for your excellent questions. I wanted to take just a few minutes to report on some recent treatment-related developments. As many of you know, the FDA has granted accelerated approval to the anti-HIV drug D4T. The brand name is Zerit, and it is available from pharmacies with a prescription from your physician. You might want to speak with your doctor about whether Zerit could be of benefit of you. As many of you have read in BETA and elsewhere, and as has been discussed here today, the most promising anti-HIV drugs likely to be approved in the near future are called the protease inhibitors. The protease drug that is furthest along in development is called saquinavir. Its brand name is Invirase. This drug is now entering Phase III trials in the United States and Europe, and about 4,000 people will eventually be enrolled in these studies. The toll-free number to call for more information about study sites and entry requirements for Inverase is 1-800-526-6367. The toll-free number to call for information about all AIDS drug studies in the United States that are currently enrolling participants is 1-800-874-2572. Because Invirase appears to be quite safe with no serious toxicities, and because early study results have suggested that it can provide a clinical benefit to patients, many clinicians, researchers and activists such as myself believe that the drug should be granted accelerated approval by the FDA as soon as possible. Accelerated approval means that physicians could write a prescription for the drug for their patients sooner. Without accelerated approval, this drug may not be available by prescription for several years. If you support accelerated approval for this promising new AIDS drug, write or fax the commissioner of the FDA, Dr. David Kessler (his office address is 5600 Fishers Lane, Rockville, Maryland, 20857; fax number 301-443-3100). Simply let Dr. Kessler know that you support accelerated approval for Inverase as soon as possible because people with AIDS need and have a right to speedy access to promising new drugs. TI Therapuetic Vaccines Update AU Mark Bowers; medical writer and AIDS treatment activist. TX The search continues for an effective treatment vaccine for use after an individual has become infected with HIV. The goal of a therapeutic vaccine is to halt disease progression, and perhaps to reverse immune system damage. A therapeutic vaccine is not a drug. It works by encouraging the bodyžs own immune system to more efficiently combat HIV infection. Currently, however, hard facts about what constitutes žprotectionž against progressive infection remain elusive. Some vaccine researchers hypothesize that inducing humoral immunity will slow disease progression. Humoral immune cells destroy pathogens before they infect cells. Other researchers point to evidence suggesting that the induction of cell-mediated immunity is key. The cell-mediated immune response is responsible for identifying and destroying infected cells. Six vaccine candidates are being assessed for use in HIV-infected individuals. All have demonstrated safety thus far. The recent performance of at least one vaccine candidate has many researchers confident that treatment vaccines will play an important role in a strategy that will combine drug therapies and immunotherapies in the treatment of HIV disease. Does an Ounce of Prevention Equal a Pound of Cure? A recent news report that 5 people who received 1, 2 or 3 inoculations of different vaccines in small preventive trials have become infected with HIV has raised serious questions about the effectiveness of those vaccine candidates. Further research reveals that at least 10 people who have received various vaccines in clinical trials, as well as 2 who have received placebo, have seroconverted. Six of the 10 became infected before getting the minimum 3 inoculations usually needed for a vaccine to work. What may be deduced is that these vaccine candidates are not 100% effective in preventing HIV infection. Other bad news was released last December: none of the vaccine candidates was effective against HIV in the serum taken from infected individuals. These 2 news events have seriously affected the future of preventive vaccine trials in general. The AIDS Research Advisory Committee decided on June 17 to recommend that testing of preventive vaccines be maintained at present levels, rather than enlarged. Dr. Anthony Fauci, director of the National Institutes of Allergy and Infectious Diseases (NIAID), agreed to the recommendation to maintain but not increase the scale of testing. The greatest effect that this may have on the future of treatment vaccines may be one of public perception: if a vaccine cannot prevent HIV infection, how can it affect the course of an already established infection? Part of the answer may come from experience with treatment vaccines for viruses other than HIV. Researchers have been assessing the effects of new treatment vaccines for herpes simplex, varicella zoster (chickenpox and shingles), leishmaniasis, tuberculosis and hepatitis B. Preliminary findings indicate that, after innoculation with herpes simplex vaccine, outbreaks of herpes simplex may be much milder and less frequent. It is not yet clear whether treatment vaccines for herpes will compare favorably to the success of the drug acyclovir, but the prospect of synergy between a vaccine and drug therapy intrigues researchers. Another clear advantage of vaccine over drug therapy would be less frequent administrationžvaccines are administered monthly, while drugs often are taken daily. One treatment vaccine, Human Diploid Cell Vaccine (HDCV) for rabies, has been in use for post-exposure prophylaxis for many years. An important distinction needs to be drawn between this rabies vaccine and potential vaccines for HIV or other viruses, however. The rabies vaccine is given after exposure to rabies, but before the virus reaches the central nervous system (CNS), which can be fatal. In this sense, the vaccine is prophylactic and not therapeutic. The vaccine is frequently given with immunoglobulins, which provide an immediate humoral response to neutralize the rabies virus before its reaches the CNS. Could a similar strategy be employed with HIV? The use of vaccines in the treatment of persistent or chronic viral infections clearly warrants further study. A study of combined vaccine and traditional drug treatment of leprosy showed that previously dampened cell-mediated immune responses could be restored in many patients with chronic severe disease. These individualsž immune systems were bolstered to the extent that relapse and reinfection were prevented. The enhancement of cell-mediated immunity is also a goal of many HIV treatment vaccine researchers. The approaches to the development of an HIV treatment vaccine have so far been empirical; hit-or-miss strategies have characterized much of the drug discovery and development process. However, some interesting patterns are now beginning to emerge. New tools have allowed researchers to evaluate the many functions of the immune system, and now allow for rational design of vaccine candidates. The Moving Target Stands Still The principal neutralizing epitope (the part of the HIV envelope that elicits strong antibody responses that may be protective) has been identified as the V3 loop, and the 3-dimensional structure of the V3 loop has just been mapped. The shape unexpectedly turns out to be a large, 3-dimensional žS.ž Now, using computer simulations, researchers can compare their vaccine candidates directly with the model, making adjustments where necessary. Some candidates may require some modification; others may remain the same, but require different adjuvants. Sequencing studies will clarify what part of a vaccine candidate needs to be changed. Humoral or Cell-Mediated Immunity? The immune system possesses specialized cells that recognize and repel pathogenic invaders (antigens) of every kind. During the humoral response, antibodies are released when B-cells come into contact with a recognizable antigen and a helper T-cell or a macrophage. The B-lymphocyte then matures into a plasma cell, which can secrete antibodies. Antibodies effectively bind either the pathogen itself (frequently bacteria or parasites) or the toxins released by the pathogen. This system is particularly effective at combatting diseases that do not take up residence inside human cells (a strategy that is always employed by viruses). However, a B-cell may recognize a virus when it is released into the blood to seek out another cell to infect. New studies of antibodies from HIV-infected individuals suggest that the humoral immune system is continually playing catch-up with HIV as the virus mutates. Studies show that many HIV-infected individuals progress to AIDS despite high levels of neutralizing antibodies in their blood. It may well be that, by the time the immune system has had time to gear up production of antibodies to HIV, the virus has mutated, and evades the masses of presumed now-obsolete antibodies. Cell-mediated immunity involves complex communication between several different cells of the immune system, primarily various subpopulations of T-cells. There are 2 kinds of cell-mediated immune responses that involve the cooperation of different sets of immune cells. Cytotoxic T-lymphocytes (CTL) recognize antigens (invaders) that appear on the outside of cell membranes. Proper recognition leads to a proliferative response, causing one CTL to expand into many thousands of CTL. Thereby, virally infected human cells are targeted for destruction. The destruction is accomplished through the release of chemicals that bore holes in the target cell, causing it to leak and die. The second type of cell-mediated immunity is called delayed-type hypersensitivity. It occurs generally 1-2 weeks after first contact with an antigen, the time it takes for T-helper cells to expand and recruit macrophages. There is also a combined defense that involves the interaction of both the cell-mediated and humoral immune reponses. Antibody-dependent cell-mediated cytotoxicity (ADCC) is the subject of much recent discussion in the vaccine literature. ADCC is a process whereby antibodies recruit natural killer (NK) cells and macrophages (both of which are non-specific immune cells that hunt and kill cells infected by parasites or other foreign organisms) and link them with foreign cells. In the process the immune system destroys and eliminates infected cells. ADCC is likely to be an important factor in mounting a successful immune response to HIV. The main target for ADCC in humans with HIV is gp120, either on infected cells or on the outside of all T-cells. It has been recently reported that in HIV-infected chimpanzees, the pattern of ADCC is entirely different from the pattern in humans. Chimpanzees can be infected with HIV, but they do not get AIDS. Could this response be the vital first line of defense that protects the chimps from progressive immune deficiency? A better understanding of the workings of T-cells, the principle targets of HIV infection, is leading to new insights on how to best construct a treatment vaccine for HIV. The demonstration of TH1 and TH2 patterns of cytokine release (chemical messengers that carry information over short distances from one immune cell to another) in response to different infections has been documented in humans after months of intensive research and heated debate. TH1 involves the release of interleukin-2, tumor necrosis factor beta and inferferon gamma, the main ingredients in a cell-mediated immune response. TH2 involves release of interleukins -4, -5, -10 and -13, characteristic of the humoral response. There is evidence that one kind of response precludes the other, but certain outside forces can cause a shift from one predominant pattern to the other. This understanding leads to the theoretical conclusion that a failure to successfully fight off infection might be because the immune system is mounting not an insufficient response, but an inappropriate one. There are heated arguments over the relative importance of humoral responses and cell-mediated responses. However, most researchers feel that both components will be necessary to successfully neutralize HIV; their theoretical recipes for success include varying proportions of each kind of immunity in the mix. Add the issue of timing the responses, and the job of vaccine makers becomes increasingly difficult. Now that there are models for appropriate immune responses, what remains is to test the models in people. New Adjuvants Tailor Immune Responses In mid-1993, the NIAID initiated studies of 2 gp120 vaccine candidates with novel adjuvants alongside the same vaccine candidates with an alum adjuvant. Alum is the only licensed adjuvant in the United States, and brings about modest increases in humoral immunity. It does not, however, appreciably increase cell-mediated immunity. The side-by-side trials could provide some partial answers to questions about the appropriate type of immune responses to control or harness in established HIV infection. In this new area of inquiry, the smart money is on new adjuvants known to provoke cell-mediated immunity. Vaccines are becoming more common in cancer research. Unusual adjuvants are also being tested. One such adjuvant is di-nitro fluorobenzene (DNFB), cousin to DNCB, sometimes promoted as a topical immune stimulant. In clinical trials, DNFB is attached to a vaccine that is prepared from an affected individual's own melanoma cells. The DNFB provokes a vigorous immune response that is targeted against melanoma cells, which are then destroyed. Could such an approach yield benefit when combined with personalized HIV vaccines drawn from each individual's own viral isolates? The technology exists, but there are no clinical trials in progress or planned for this strategy at this time. The Candidates Face Off More preliminary results of the safety of the MicroGeneSys VaxSyn, a gp160 recombinant vaccine, were recently published in the Journal of Acquired Immune Deficiency Syndrome. Arguing that cell-mediated responses are the most important because a few high-risk gays with frequent exposure to HIV have been shown to mount such responses without seroconverting (i.e., remain HIV antibody negative), Swedish researchers investigated the responses of 40 asymptomatic HIV positive volunteers to 6 vaccinations with gp160, with and without AZT. Responses to several non-HIV recall antigens, including cytomegalovirus (CMV), tetanus, influenza and measles, were measured in an effort to find T-cell proliferative responses. The vaccine candidate was able to bring about HIV-specific cellular responses and low levels of non-HIV cellular responses. These new responses to vaccination, if given early during HIV infection, might be a way to delay disease progression. Again, clinical experience is lacking. This study was a Phase I human safety trial, and the only relevant conclusion is that (so far), VaxSyn is safe and free of side effects for 40 asymptomatic HIV-infected individuals. The therapeutic vaccine candidate produced by the collaboration between Immune Response Corporation and Rhone-Poulenc Rhorer, Inc., is an inactivated form of HIV. It was tested in a 1-year, double-blind, placebo-controlled study in 103 HIV positive people. One measure that was collected during this study, HIV DNA, reflects viral load in the blood. Vaccinated participants showed an average increase of 14% in viral load while those on placebo increased 56%. This measure, which depends on the technology called polymerase chain reaction (PCR), was initially criticized, but now increasing numbers of researchers accept that it is more valid than surrogate markers, such as CD4 counts or p24 antigenemia, as a measure of disease progression. Standardization for PCR testing does not exist in the U.S. because it is not FDA-approved and is used for research purposes only at this time. The question that remains to be answered about the vaccine is whether the lower viral load is associated with a delay in AIDS symptoms and extended survival. Further studies, clearly warranted, are underway. The Outlook: Some Advances, and More Questions Recent advances have made it possible for researchers to have increasing confidence in their approach towards treatment vaccine trials. Several findings have advanced therapeutic vaccine research in clear ways and deserve further investigation: * We are now able to compare molecules from individual vaccine candidates directly with their binding sites on the V3 loop of the virus. We can look directly at the different areas of the loop that bind antibodies and T-cells. The areas are not the same. In order to tweak the immune response, vaccine molecules need to target single or multiple binding areas. Which areas should be targeted by researchers in order to maximize appropriate immune responses? * Antibodies to HIV are naturally produced in abundance, but may be too late to be of use to the infected individual at the time of an AIDS diagnosis. Can we predict the evolution of HIV in an individual, for example the onset of the codon 215 mutation in response to lengthy AZT therapy, and stand ready to administer the appropriate antibodies when they are most needed, instead of when it is already too late? * A few high-risk, multiply exposed gay men mount primarily cell-mediated responses to HIV, and no detectable antibody response. Are CMI responses protective with respect to initial HIV infection? * The pattern of ADCC in HIV-infected chimpanzees differs from that of infected humans. Is the timing of the ADCC response critical in preventing AIDS in chimps? * TH1 and TH2 patterns of cytokine release are now observed in humans. How can we apply our new understanding to the development of new immunotherapies and vaccines? * New adjuvants can tilt the immune response toward either humoral or cell-mediated immunity. Which should be used, and when? * Cancer vaccine studies employ cells taken from the affected individual, conjugated to immunogens, and reinfused. Can this personal strategy help solve the problem of rapid mutation in HIV? The answers to these and other questions await the initiation of wide-scale testing of therapeutic HIV candidate vaccines. The rationale for widescale testing continues to be the hypothesis that the immune system can be prodded to better control HIV infection by vaccination. While the evidence seems to indicate that todayžs preventive vaccine candidates are less than optimal, there is cautious optimism about some of the same products for therapeutic effects. Although there is currently a chill on the world of preventive vaccine research, there is no reason for that chill to spill over into treatment vaccine research. There are good reasons to believe that treatment vaccines will be an important element in combined strategies to combat the progressive immunosuppression that most often accompanies HIV infection. Sources Bolognesi DP. Prospects for an HIV vaccine. Science and Medicine 1: 44-53. January/February 1994. Clerici M and others. Cell-mediated immune response without humoral response in non-seroconverters. Journal of Infectious Diseases 165: 1012-1019. June 1992. Cohen J. Vaccines get a new twist. Science 264: 503-505. April 22, 1994. Cohen J. Immune response corp.žtake two. Science 264: 1402. June 7, 1994. Cohen J. Will media reports KO upcoming real-life trials? Science 264: 1660. June 17, 1994. Doepel LK. New vaccines stimulate research on adjuvants. Dateline: NIAID February 1994. Liegler TJ and Stites DP. HIV-1 gp120 and anti-gp120 induce reversible unresponsiveness in peripheral CD4 T-lymphocytes. Journal of Acquired Immune Deficiency Syndrome 7: 340-348. April 1994. Romagnani S. TH1 and TH2 subsets of CD4+ T-lymphocytes. Science and Medicine 2: 68-77. March/April 1994. Schwartz DH and others. Lack of correlation between the number of circulating B-cells and the concentration of serum antibodies reactive with the HIV-1 envelope glycoprotein. Journal of Acquired Immune Deficiency Syndrome 7: 447-453. May 1994. Walker BD. The rationale for immunotherapy in HIV-1 infection. Journal of Acquired Immune Deficiency Syndrome 7(1): S6-S13. May 1994. Wahren B and others. Improved cell-mediated immune responses in HIV-1-infected asymptomatic individuals after immunization with envelope glycoprotein gp160. Journal of Acquired Immune Deficiency Syndrome 7: 220-229. March 1994. TI Oral Ganciclovir: A Breakthrough Drug To Prevent AIDS-Related Blindness? AU Ronald Baker, PhD; editor of BETA. TX The following is an update of a BETA Treatment Alert mailed to subscribers in October 1994. Preventive treatment with oral ganciclovir (Cytovene) reduces the incidence of cytomegalovirus (CMV) disease, including sight-threatening CMV retinitis, by about 50% among people with AIDS, according to preliminary results of a trial sponsored by Syntex Corporation among 725 people with AIDS at 19 medical centers across the U.S. This dramatic new finding may represent a major breakthrough for the medical management of people with AIDS who are at high risk for developing CMV retinitis and other manifestations of CMV disease. Syntex is expected to ask FDA to approve oral ganciclovir for primary prophylaxis of CMV disease in the spring of 1995. In the meantime, to provide access to the drug for primary prophylaxis, Syntex is setting up a Treatment Investigational New Drug (IND) program. This program will be in place by late January 1995 to provide oral ganciclovir to patients at high risk for developing CMV disease at no cost until FDA approves the drug for this specific indication. For more information about enrollment in the Treatment IND protocol, physicians and patients may call the Syntex Study Center at 1-800-569-4630. Background CMV is a herpesvirus that may cause blindness and other, life-threatening illnesses in individuals with severe immunosuppressive conditions, such as AIDS. A high percentage of HIV positive individuals are coinfected with CMV, reaching almost 100% among gay and bisexual men and 75% in other HIV risk groups. Up to 40% of people with AIDS develop CMV in a particular organ. CMV infection of the eye (retinitis), esophagus and colon are most common, but diseases of the lung, liver, biliary system, adrenal glands and central nervous system also occur. The Syntex multicenter trial of oral ganciclovir was designed to evaluate the safety and efficacy of the drug for the prevention of CMV disease in HIV and CMV positive individuals with fewer than 50 CD4 cells/mm3 and in individuals with a previous AIDS-defining opportunistic infection and fewer than 100 CD4 cells/mm3. An interim analysis of the data showed that after approximately 10 months, 30% of those on placebo developed some form of CMV disease compared to only 16% of those taking 3,000 mg/day oral ganciclovir. Because of the significant benefit experienced by the group treated with oral ganciclovir compared to those in the placebo arm, an independent Data and Safety Monitoring Board (DSMB) halted the Syntex study and all participants on placebo were offered the drug. Toxicity Participants using oral ganciclovir in the Syntex trial generally tolerated the drug well, according to principal investigator Stephen Spector, MD, who presented the study results at the 34th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) in Orlando, Florida, on October 5, 1994. The most frequently occurring adverse side effects associated with ganciclovir are leukopenia, anemia and thrombocytopenia (abnormally low numbers of white blood cells, red blood cells and platelets, respectively). In recent studies that compared oral to intravenous (IV) ganciclovir, the IV formulation was associated with more leukopenia (41%) and anemia (25%) than the oral drug (29% and 19%, respectively). Thrombocytopenia occurred in 6% of both groups. Twenty-nine percent (29%) of those taking placebo died during the study, compared to 22% of those using oral ganciclovir, with a trend (just short of statistical significance) toward longer survival in the treatment group. FDA Action On November 17, 1994, the FDA Antiviral Advisory Committee recommended approval of oral ganciclovir as an alternative to IV ganciclovir for the maintenance treatment of CMV retinitis in immunocompromised individuals whose retinitis has been stabilized by IV induction therapy. Maintenance therapy refers to drug treatment to prevent recurrence of disease among patients who have been treated successfully for the initial episode of an illness. FDA is expected to accept the recommendation of its advisory committee, and to approve oral ganciclovir for maintenance treatment of CMV retinitis by January 1995. Once FDA approves the drug for maintenance treatment, physicians can prescribe it for primary prophylaxis, although some insurers may not reimburse use of the drug for this purpose. However, The Treatment IND program that will be in place by late January 1995 assures access to the drug for primary prophylaxis. Sources Baker R. Oral ganciclovir delays onset of CMV disease. BETA Treatment Alert. October 21, 1994. Spector SA and others. A randomized, double-blind study of the efficacy and safety of oral ganciclovir for the prevention of cytomegalovirus disease in HIV-infected persons. 34th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). Orlando, Florida. October 1994. Abstract A/9. TI Oral Manifestations of HIV Disease AU Caroline L. Dodd, BDS and Deborah Greenspan, BDS, DSc, FDS RCSEd TX Caroline Dodd received her dental education at the Royal Dental School, University of London, graduating with the B.D.S. degree in 1984. She is now at the University of Edinburgh, Scotland, where she is completing her MS in Epidemiology. Deborah Greenspan received her dental education at the Royal Dental School, University of London, graduating with the B.D.S. degree in 1964. She received a DSc from the University of London in 1991. Dr. Greenspan is the discoverer of a new type of lesion, oral hairy leukoplakia. She has published over 100 papers and is a principal author of the book, "AIDS and the Mouth." Dr. Greenspan is currently Clinical Professor of Oral Medicine in the Department of Stomatology at UCSF, Chair of the Task Force on Infection Control for the School of Dentistry and Clinical Director of the Oral AIDS Center. Oral lesions related to HIV infection may appear at any stage of HIV disease. Lesions in the mouth may be the first indication that a person is infected with HIV, or may reflect more advanced systemic disease resulting from immunosuppression. They occur more frequently as CD4 counts drop and are seen in men, women and children. Therefore, regular oral examinations and the diagnosis of any lesions present are important in recognizing both early HIV-related disease and advanced systemic disease. Oral lesions seen in HIV infection may reflect the degree of immunosuppression caused by HIV. These lesions include fungal, bacterial and viral infections, neoplasms (cancers), aphthous ulcers (commonly known as canker sores), complaints of dry mouth and salivary gland enlargement. Early diagnosis and treatment of oral lesions improves the quality of life for an HIV-infected person. Fungal Infections The most common oral fungal infection is candidiasis, usually caused by Candida albicans. Most people normally have Candida albicans living in their bodies. However, the organism may become pathogenic and infections of the skin, nails or mucous membranes, including those of the mouth, may occur. Oral candidiasis may cause a variety of symptoms. Often patients complain of a burning sensation and an inability to tolerate some foods. Occasionally they may notice a metallic or "odd" taste. Inside the mouth candidal infections can present different appearances. In pseudomembranous candidiasis (thrush), removable white plaques may be present throughout the mouth, but most commonly on the tongue and the palate. Erythematous candidiasis commonly occurs as red patches on the hard and soft palate and also as smooth, shiny areas on the dorsal surface of the tongue. Sometimes candidal infection causes cracking and soreness at the corners of the mouth, a condition known as angular cheilitis. Oral candidiasis may be treated, and further episodes possibly controlled, with the use of topical antifungal medications such as nystatin (Mycostatin) or clotrimazole (Mycelex). Nystatin vaginal tablets taken orally are a useful form of this medication because they do not contain sucrose. The tablets may be more palatable if used at the same time as sugarless candy. Mycelex troches contain a sweetening agent which may cause tooth decay. Frequent use of Mycelex should be accompanied by the daily use of a topical fluoride rinse which can be bought without a prescription. Systemic antifungals such as ketoconazole (Nizoral), fluconazole (Diflucan) and itraconazole (Sporanox) are available. The use of these medications will depend upon preference, other medical problems such as abnormal liver function, and the concurrent use of other medications. Recently, fluconazole-resistant oral candidiasis has been seen. This appears most commonly in people with CD4 counts of less than 100 cells/mm3. Occasionally oral lesions due to histoplasmosis occur in the mouth. These lesions may be ulcers or swellings and may appear anywhere in the mouth. Oral ulcers due to coccidiodomycosis are seen very rarely. These 2 fungal infections often respond to systemic antifungal therapies (see above). Bacterial Infections Gingivitis and periodontal disease are very common in the general population, increasing in incidence with age and with poor oral hygiene. HIV-associated gingivitis and periodontal disease tend to be much more aggressive. Patients often complain of a nasty taste or bad breath, along with painful, red gums that bleed spontaneously. They may notice rapid loss of tissue around the teeth. This rapid gum loss may lead to exposure and destruction of the underlying bone supporting the teeth, causing the teeth to become very mobile. Acute infections should be evaluated by a dentist, and treatment will include thorough scaling of the teeth (scraping away tartar buildup) and irrigation with topical antiseptic agents such as chlorhexidine (Peridex) and povidone iodine. Sometimes the use of antibiotics such as metronidazole or clindamycin may be indicated. It should be emphasized that antibiotic therapy alone does not "cure" gingivitis or periodontal disease. Recurrent episodes of acute gingivitis and periodontal disease resulting in further bone loss may be prevented with the attention received during regular dental hygiene appointments, the use of antiseptic mouthwashes such as chlorhexidine and povidone iodine, and an improvement of oral hygiene at home. Regular dental examinations are helpful in the early treatment and prevention of these infections. Occasionally ulcers in the mouth result from other bacterial infections, including gonorrhea and syphilis. Mycobacterium avium complex (MAC) and tuberculosis may cause granulomatous nodular lesions. These lesions should be identified so that patients can be treated appropriately. Viral Infections The most common oral lesions caused by viruses are oral warts, lesions of primary and recurrent herpes simplex, lesions of herpes zoster and hairy leukoplakia. Skin, oral and genital warts are caused by human papillomaviruses (HPV). There are many types of HPV, each tending to produce lesions at different sites on the body. Oral warts seen in patients with HIV disease may be due to reactivation of a latent HPV infection rather than direct transmission. Warts may occur anywhere in the mouth as single or multiple, white or mucosa-colored lesions; they may be flat or slightly elevated with a spiky or a cauliflower-like appearance. They are rarely painful, but may be bothersome to the patient and can be surgically removed. However, all warts have a tendency to recur, and repeated treatment may be necessary. Herpes simplex virus can cause primary and recurrent infections in the mouth. Oral lesions are usually caused by herpes simplex virus type-I, but herpes simplex virus type-II (normally associated with genital lesions) may occasionally cause oral lesions. A primary herpes infection may appear as groups of small, very painful ulcers on the gingiva or palate and may be accompanied by fever. Recurrent lesions due to reactivation of the latent virus may occur as painful, crusting areas on the lips (often called cold sores), or as groups of extremely painful ulcers on the gingiva or palate. Many patients do not recall having had a primary infection with herpes, possibly because the infection caused no signs or symptoms or occurred early in childhood. Recurrences may be triggered by trauma, dental treatment, stress, sunlight or cold weather. The lesions usually heal in about 10 days. If they do not heal, treatment with oral acyclovir may be indicated. Some oral and anogenital herpes lesions are resistant to acyclovir, and other antiviral drugs such as foscarnet have been used in their treatment. Another herpesvirus, the varicella-zoster virus, causes chickenpox on initial infection. Like herpes simplex, the virus becomes latent; if reactivated, it causes an infection called shingles. Painful oral ulcers are seen in both chickenpox and shingles. In shingles, facial or oral pain may precede the appearance of raised, crusting lesions erupting on one side of the face, in the mouth, or both. These lesions usually last 2-3 weeks. Treatment with high doses of acyclovir should be started as soon as a diagnosis is made. During 1981 a few patients came to the Oral Medicine clinic at UCSF with a white thickening of the mucosa on the sides of the tongue. The cause of this lesion was not known, and the lesion was termed "hairy leukoplakia." These patients were later found to be immunosuppressed and infected with HIV. Patients may complain of a "furry" feeling of the tongue or a bad taste. A definitive diagnosis requires biopsy of the lesion. The Epstein-Barr virus (EBV), which has been identified in biopsy tissue, is considered to be the cause of the lesions. Hairy leukoplakia has been seen, although rarely, in other immunosuppressed patients such as kidney transplant patients. It is theorized that, in the immunosuppressed patient, the virus is reactivated in the cells of the oral mucous membranes causing a thickening and whitening of the tissue. Treatment of hairy leukoplakia may not be necessary. Lesions may occur, disappear and recur. High doses of acyclovir can eliminate the lesions, but when treatment ceases the lesions usually return. Some patients taking zidovudine (AZT) have reported resolution of hairy leukoplakia lesions, but studies have not substantiated these reports. Hairy leukoplakia may sometimes be eliminated with the use of topically applied Retin A or podophyllin. However, hairy leukoplakia usually returns. Neoplastic Disease (Cancer) Oral Kaposi's sarcoma (KS) is seen in 44-50% of people with AIDS who have KS and may be the first manifestation of AIDS. Occasionally it is the only indication of infection with HIV. In the mouth KS occurs as flat or nodular, red or purple lesions on the oral mucous membranes, most commonly on the palate. The lesions may be single or multiple, may appear only in the mouth, or may occur together with skin or internal lesions. The cause of KS is as yet unknown, but the observation of KS in homosexual men not infected with HIV has led to the suggestion that KS may be due to an agent other than HIV, perhaps a sexually transmitted agent. The treatment of oral lesions of KS depends on their size, location and symptoms. Small or single lesions may be excised, either surgically or with the carbon dioxide laser, or may be treated with intralesional injection of chemotherapeutic agents such as vinblastine (Velban). More extensive lesions may be treated with radiation therapy or with systemic chemotherapy. Another neoplasm, non-Hodgkin's lymphoma, has been reported to occur in the mouth in more than 4% of people with AIDS who have lymphoma. Oral lymphomas appear as ill-defined swellings and non-healing ulcers on the palate and gums. Lymphoma can only be diagnosed by a biopsy. Once diagnosed, patients need a work-up to identify any systemic disease present before appropriate treatment with radiation therapy or chemotherapy may be started. Recurrent Aphthous Ulcers Many people have a history of recurrent aphthous ulcers (RAU), commonly called canker sores, starting in childhood. In HIV positive people episodes of RAU may occur more frequently and be more persistent, with larger and more painful ulcers. The ulcers may occur on the surface of the throat, the floor of the mouth, the cheek, the soft palate and the tongue. They may be very painful and interfere with speaking and eating. The use of topical steroids such as fluocinonide in orabase or dexamethasone elixir will help to reduce pain and aid healing. The effectiveness of thalidomide in the treatment of aphthous ulcers is currently being assessed in clinical trials. A recent study that we presented at the X International Conference on AIDS in Yokohama described an increased risk of oral ulcers with ddC use. The presence of oral ulcers peaked between 3-6 months of ddC use, and were more common in those who did not smoke. HIV-Associated Salivary Gland Disease Some HIV-infected individuals have symptoms of dry mouth, which may be associated with medications the patient is taking. Occasionally, however, a patient's symptoms cannot be attributed to medication, and in some of these patients swelling of the salivary glands on the side of the face or under the chin has been noticed. We hypothesize that this may be due to CD8 cells in the salivary glands and may indicate a slightly longer time to the development of AIDS, due to CD8-mediated anti-HIV effects. The cause of these symptoms has not yet been determined, and diagnosis of these patients at this time includes exclusion of other diseases. It is interesting that some of these patients report a reduction of salivary gland swelling and dryness following treatment with zidovudine (AZT). Early Care It is important that any individual infected or at risk of infection with HIV have regular oral examinations of both the soft tissues and the teeth. Oral lesions may warrant therapy, and early therapeutic intervention and maintenance can aid in improving the quality of life in persons with HIV disease. More about the Authors: Caroline Dodd: After training posts in oral surgery and hospital dentistry in the United Kingdom she came to the University of California, San Francisco (UCSF) as a General Practice Resident in 1986. Dr. Dodd then went on to train in Oral Medicine at UCSF. Dr. Dodd's research interests include oral Kaposižs sarcoma, HIV-associated salivary gland disease (HIV-SGD) and oral lymphoma. She is actively involved in several clinical and epidemiological studies relating to the oral manifestations of AIDS. Deborah Greenspan: After training posts in general practice she became the principal of practices in London for over 10 years. On emigrating to California in 1976, she trained in oral medicine at UCSF, specializing in the diagnosis and care of oral malignancy and sequelae of treatment. More recently she has focused on the oral manifestations of AIDS. Dr. Greenspan is involved as the principal investigator or coinvestigator in a number or clinical, laboratory and epidemiologic studies relating to the oral manifestations of AIDS, and is a member of the UCSF AIDS investigators group. She received the Assistant Secretary for Health Certificate of Commendation in 1989. She has also written chapters for several books and has spoken extensively on oral cancer, AIDS, the oral manifestations of HIV infection and infection control. TI Management of Herpesvirus Infection in HIV Disease DT 9412 TX Reprinted with permission from World Health Communications, Inc. This article presents selected highlights of 2 conferences held in San Francisco November 10-15, 1994: the Fourth Triennial Symposium on New Directions in Antiviral Chemotherapy, sponsored by the Division of Infectious Diseases, San Francisco General Hospital and the Department of Medicine, University of California San Francisco School of Medicine; and the Second Annual Meeting of the International Herpes Management Forum. Both conferences were devoted to reviews of current management of herpesvirus infections, with updates on new and anticipated management options. Viral Shedding in Genital Herpes Simplex Infections Lawrence Corey, MD, of the University of Washington and Pacific Medical Center, Seattle, Washington, observed that only 20% of seropositive persons recognize their herpes symptoms; 60% have unrecognized symptomatic disease; and 20% have subclinical, asymptomatic shedding of virus. Viral shedding in all 3 patient groups may play a significant role in transmitting genital herpes. Samples from female patients who obtain their own viral cultures from genital and perirectal sites reveal a higher incidence of positive viral cultures than samples obtained by the provider during clinic visits, probably because patients obtain early-morning samples at home that represent an overnight pool of vaginal secretions. Subclinical episodes of viral shedding tend to occur on clusters of days, particularly during the weeks prior to and after symptomatic outbreaks. This pattern appears to be the same in males and females. The spectrum of subclinical and clinical viral shedding appears to be different from what was previously thought based on older surveillance trials. Many episodes of shedding associated with symptoms are shorter and subclinical episodes are longer than had been believed, so that their mean combined durations are approximately the same. The cohort of women in the research study conducted by Dr. Corey and colleagues experienced approximately 10 virologic recurrences (i.e., shedding) per year; 66% of episodes were clinical (symptomatic) and 33% were subclinical (asymptomatic). Subclinical shedding is more likely to occur in recently acquired infection and in patients having more frequent symptomatic recurrences. The suggestion has been made that shedding that is apparently asymptomatic may really be taking place via microlesions on the epithelial surface. As determined by polymerase chain reaction (PCR) testing, a more sensitive detector of viral shedding than viral culture, viral DNA could be detected via swabs of mucocutaneous surfaces in untreated women with genital herpes on an average of 21% of days. A large double-blind study reported at the Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) showed that chemosuppression with acyclovir significantly decreased the frequency of asymptomatic viral shedding in women with frequent symptomatic recurrences (see Herpes Management Forum Fax Newsletter, October 6, 1994). Whether transmissibility of virus to sexual partners and neonates is decreased by suppressive therapy requires further study. Acyclovir-Resistant Herpes Simplex Virus and Varicella-Zoster Virus Drug-resistant herpes simplex virus (HSV) infection was comprehensively covered by Sharon Safrin, MD, of the University of California, San Francisco, and San Francisco General Hospital. This problem is rare and is usually of major clinical significance only in immunosuppressed persons such as people with AIDS. In a single reported case, acyclovir resistance was manifested by an increased frequency of recurrences in an immunocompetent person despite use of acyclovir. Infection in immunocompromised patients most often is localized rather than disseminated, and most often involves HSV-2. Lesions tend to be large and painful, and can be disfiguring. Resistance arises spontaneously and is not dependent on exposure to the drug; selection pressure exerted by drug use, however, may facilitate emergence of resistance. Prior exposure to acyclovir is the rule, but there are exceptions. Drug-resistance varicella-zoster virus (VZV) is less common than resistant HSV. To date, it has been reported only in persons with AIDS. Involvement is usually cutaneous. Lesions are few in number and widely scattered (i.e., disseminated rather than dermatomal in distribution), and raised and hyperkeratotic, interspersed with more typical lesions. Prior exposure to acyclovir is common but not invariable and may be related to suboptimal exposure to the drug (i.e., use of less than 10 mg/kg intravenously every 8 hours or 800 mg 5 times daily). Three mechanisms have been identified as being responsible for drug resistance in HSV and VZV: (1) deficient or absent activity of the viral enzyme thymidine kinase (TK), which catalyzes activation of acyclovir by intracellular phosphorylation (addition of phosphate); (2) altered substrate affinity for viral TK; and (3) altered DNA polymerase. TK mutants are far more common than DNA polymerase mutants in isolates recovered from clinical lesions. Thus, the drugs that have a greater likelihood of efficacy against resistant strains of herpesviruses are those that do not depend on TK for their activity. Trials aimed at treatment of acyclovir-resistant HSV infection include ACTG 095, a comparison of foscarnet and vidaribine. In this study, foscarnet was found superior to vidarabine in acyclovir-resistant HSV infections as measured by time to healing (P=0.01) and time to virologic cure (P=0.006). Time to resolution of pain was shorter for the foscarnet group but did not reach statistical significance (P=0.12). Other studies suggest that a foscarnet dose of 60 mg/kg every 12 hours may be as effective as 40 mg/kg every 8 hours for this indication. However, foscarnet-resistant HSV infection has been described recently in patients with AIDS. Both foscarnet and vidarabine have many potentially serious toxicities. Topical trifluridine has also been evaluated in the treatment of acyclovir-resistant HSV infection. In ACTG 172, 7 of 24 patients with AIDS experienced complete healing at a median of 7.1 weeks, and 14 had at least a 50% reduction in lesion size at a median of 2.4 weeks. There was a 50% decrease in pain score in 17 patients at a median of 1.6 weeks. One third of patients developed new lesions while on therapy. Other trials have used continuous-infusion acyclovir, which required difficult-to-obtain serum level determinations to titrate dosage, and which has not been validated in large series of patients; and 2 additional investigational topical agents, BV348U87 and SP-303, neither of which appeared to yield significant or prolonged benefit. Other new or investigational agents include cidofovir (HPMPC), topical foscarnet, sorivudine (BVaraU), valacyclovir, famciclovir and lobucavir (cyclobut-G). Data on treatment of resistant VZV are scant, but foscarnet seems likely to be effective, as may trifluridine in some clinical situations. New and Investigational Therapies Famciclovir for Herpes Zoster: Ron Boon, MD, of SmithKline Beecham Pharmaceuticals, discussed the effects of the recently approved antiherpetic agent famciclovir on herpes zoster rash and pain. For most patients the latter is the most significant problem in herpes zoster outbreaks. Results of famciclovir taken 3 times daily were comparable to those achieved with acyclovir 5 times daily for uncomplicated herpes zoster. Famciclovir treatment of patients over 18 years of age who entered the trial within 72 hours of onset of an outbreak was significantly better than placebo. As with acyclovir, differences between drug and placebo in healing time were small, on the order of a few days. In one study, famciclovir and acyclovir were acknowledged to probably be equivalent in preventing postherpetic neuralgia. Time to cutaneous healing was comparable for the 2 drugs. More direct "head-to-head" comparisons between the 2 agents must be undertaken. Sorivudine for Herpes Zoster Richard J. Whitley, MD, Department of Pediatrics, University of Alabama at Birmingham, described this agent, also called BVaraU, which has been used in Japan for management of herpes zoster. Fatalities recently reported in Japan among immunocompromised patients who took sorivudine concomitantly with 5-fluorouracil resulted from severe bone marrow depression. U.S. trials are underway or have been completed for chickenpox among naval recruits; in 2 comparative studies vs acyclovir in treating herpes zoster within 72 hours of onset; and in another comparative trial vs acyclovir in immunocompromised hosts with localized herpes zoster. Sorivudine has been evaluated at dosages of 10 mg or 40 mg once daily. Its oral bioavailability is greater than 50%. In a double-blind study of sorivudine 40 mg once daily for 7 days in 137 evaluable HIV-infected persons over 18 years of age with confirmed herpes zoster of less than 72 hours duration, the major improvements over standard therapy were earlier cessation of new lesion formation and earlier time to total crusting. There were no statistically significant differences between the study groups in incidence of clinical adverse events or laboratory abnormalities. According to Dr. Whitley, the most significant question left unanswered, given its greater in vitro potency against VZV, was why did sorivudine not accomplish more? More studies should help provide answers. In rodent models, sorivudine has been shown to be carcinogenic, but not teratogenic or mutagenic; the significance of this finding in humans is not yet determined. Valacyclovir for Herpes Zoster M. Lynn Smiley, MD, of Burroughs Wellcome Company, reviewed experience to date with valacyclovir, a valyl ester prodrug of acyclovir that is converted to acyclovir in the body. Acyclovir accelerates healing and decreases the duration of pain in herpes zoster. Valacyclovir was developed to have greater bioavailability than acyclovir with the same confirmed safety profile. In a double-blind study 1,141 immunocompetent patients at least 40 years of age with active herpes zoster of under 72 hours duration were randomized into 3 groups, receiving acyclovir 800 mg 5 times daily for 7 days, or valacyclovir 1,000 mg 3 times daily for either 7 or 14 days. Patients were followed for 24 weeks. Primary efficacy endpoints included duration of pain, cessation of new lesion formation, and lesion crusting/healing. Secondary efficacy endpoints included assessment of intensity of pain, viral shedding, analgesic use and lesion staging. The 1-week course of valacyclovir proved to be as effective as the 2-week course. Both valacylovir regimens provided a 25% reduction, compared with acyclovir, with regard to median duration of pain and time taken for 70% of patients to become pain-free. The number of patients who were pain-free at 24 weeks was 23% higher with valacyclovir than with acyclovir. Resolution of abnormal sensations, e.g., numbness and paresthesias, was more rapid with valacyclovir, and the need for help at home and days lost from normal activities were both reduced. Such adverse events as nausea, vomiting, headache and diarrhea were generally mild, did not interfere with treatment and were similar in all 3 treatment groups. TI BETA NEWS BRIEFS Oral Ganciclovir to Prevent CMV Disease Oral ganciclovir (Cytovene) is effective in preventing CMV disease, including sight-threatening CMV retinitis, according to preliminary results of a trial of the drug for primary prophylaxis. Physicians and patients may call the Syntex Study Center at 1-800-569-4630 for information on enrollment in a Treatment Investigational New Drug (IND) protocol that will provide oral ganciclovir for primary prophylaxis free to qualified patients, beginning in late January 1995. FDA is expected to approve the drug for maintenance treatment of CMV retinitis by the end of 1994 (see page ?). AZT Plus 3TC Preliminary results of 2 studies reported at the Glasgow AIDS Conference in November suggest that the double combination of AZT plus 3TC produces the most pronounced and sustained anti-HIV effect of any drug regimen yet studied. Participants in a French study who took the combination for 48 weeks experienced a 49 CD4 cell/mm3 increase over baseline. Viral load reduction for those on the combination was 91% below baseline by week 48 (see page ?). Growth Hormone for AIDS-Related Wasting After extensive negotiations between FDA, Serono Laboratories and treatment activists, FDA has approved a Treatment Investigational New Drug (IND) protocol that will provide access to Serono's recombinant human growth hormone (Serostim) to people with AIDS-related wasting in early 1995. Patients and physicians may call Serono at 1-800-714-AIDS for information on enrollment and reimbursement. Results of a Phase III study presented at the X International AIDS Conference in Yokohama by Morris Schambelan, MD, of San Francisco General Hospital show that Serostim is safe, well-tolerated and produces significant weight gain as measured by lean body (muscle) mass (see BETA. September 1994. p. 10). Although the study did not show that Serostim impacts disease progression or survival compared to placebo, the drug does appear to provide a quality-of-life benefit. Serono expects to file for FDA approval of Serostim in the spring of 1995. In the meantime, the Treatment IND program will provide broad access to the drug for people with AIDS-related wasting. Baboon Bone Marrow Transplant for AIDS Will it be possible to treat people with advanced AIDS successfully by grafting the immune cells of a baboon onto their immune systems? Suzanne Ildstad, MD, of the University of Pittsburg and Paul Volberding, MD, of the University of California in San Francisco (UCSF) have petitioned the ethics review board at UCSF for permission to transplant baboon bone marrow into 4 people with late-stage AIDS. The rationale for this operation stems from the fact that baboons are resistant to infection with HIV-1. However, some researchers, such as Mark Feinberg, MD, of the Gladstone Institute in San Francisco, oppose the procedure for AIDS patients at this time, saying that the outcome is too uncertain. The proposed UCSF baboon transplant into people with AIDS and the controversy surrounding xenotransplants, the transplantation of organs from one species into another, is discussed in the November 18, 1994 issue of Science. Protease Inhibitor Drugs Abbott Laboratories released encouraging preliminary data on Phase I studies of its protease inhibitor drug ABT-538 at the Glasgow AIDS Conference. Participants were required to be p24 antigenemic at study entry. After 4 weeks of monotherapy with ABT-538, CD4 count increases ranged from 75 to 150 cells/mm3 above baseline in all 4 dose groups (300 mg, 400 mg, 500 mg and 600 mg twice daily). Reductions in p24 antigen of 80%-90% also occurred in all 4 groups. Viral load, measured by the branched DNA assay, decreased by 0.8 log to 1.2 logs below baseline, and these decreases were sustained throughout the 4-week study. Participants taking 500 mg and 600 mg twice daily experienced sustained increases in CD4 counts of 300 to 400 cells/mm3 above baseline through 12 weeks of treatment. Some patients had increases as high as 600 CD4 cells/mm3 above baseline, and sustained p24 antigen decreases of 100%. Reductions in viral load among participants on the highest doses (500 and 600 mg twice daily) were as high as 2.75 logs below baseline after 12 weeks of study, according to Sven Danner, MD, of the Academic Medical Center in Amsterdam, Holland. Danner noted that the remaining important questions about ABT-538 include how long the antiviral effect of ABT-538 will last, at what point viral resistance will emerge, whether resistance will be low- or high-level and what the clinical effects of the drug will be. Phase II/III trials of ABT-538 are expected to begin enrollment in early 1995. Protease Inhibitor Drugs In November, Merck told AIDS treatment activists once again that the company will not sponsor an expanded access program for its protease inhibitor drug L-524 in 1995, because all of the L-524 produced will be needed for clinical trials of the drug. However, Merck said the company will consider filing an accelerated approval application for L-524 in the spring of 1996. Merck also asked activists for input on a draft protocol for Phase III studies of L-524, and expressed a willingness to meet with an expert process chemist, to be chosen by community representatives, who could help assess the production challenges faced by Merck in manufacturing sufficent quantities of L-524. Roche Protease In public testimony at the September 12, 1994 meeting of the FDA Antivirals Advisory Committee, Ronald Baker of the San Francisco AIDS Foundation called on FDA to grant accelerated approval "as soon as possible" to saquinavir (Invirase), the protease inhibitor drug from Hoffmann-La Roche (Roche). Saquinavir is now in Phase III testing at medical centers throughout the U.S. and Europe. A petition released at the October meeting of the National Task Force calls on Roche, FDA and NIH "to implement without delay" an expanded access program for saquinavir. Roche announced in September that the company would sponsor an expanded access program for saquinavir by mid-1995, when Roche also expects to file for accelerated approval of the drug. Roche is meeting with treatment activists to get community input and recommendations on the design of a "limited" expanded access program for saquinavir. Under expanded access, drug is provided to qualified patients through their physicians at the expense of the drug's manufacturer. Under accelerated approval, the cost to patients for drug therapy is reimbursable by third-party insurers. Searle has halted development of its protease inhibitor drug SC-52151. The encouraging data from laboratory studies of the drug were not confirmed in 2 human studies. SC-52151 failed to show any evidence of anti-HIV activity in HIV positive study participants as measured by CD4 cell counts, p24 antigen levels and quantitative PCR HIV RNA testing. Protease Drug Meeting FDA Commissioner David Kessler, MD, has announced a special meeting of the National Task Force on AIDS Drug Development on February 23-24, 1995 in Washington, D.C., to focus on issues related to the development of the protease inhibitor drugs. FDA and Accelerated Approval FDA convened a meeting of the Antiviral Advisory Committee on September 12-13, 1994 in Washington D.C., to hear public testimony on the agency's regulations regarding accelerated approval of drugs for AIDS and other life-threatening conditions. Under the accelerated approval regulations adopted by FDA in 1991, the effectiveness of AIDS drugs are evaluated preliminarily by laboratory markers (such as CD4 counts) rather than by clinical endpoints (such as disease progression or death). At the September FDA meeting and in interviews with the mainstream media, the New York-based Treatment Activist Group (TAG) advocated strongly in favor of changing the existing rules governing accelerated approval, especially in regard to early approval of the protease inhibitor drugs. TAG urged FDA not to accept laboratory ("surrogate marker") data for accelerated approval of this new class of drugs, and proposed Large Simple Trials for assessing their efficacy. TAG specifically opposes accelerated approval for saquinavir (Invirase), the protease inhibitor drug from Hoffmann-La Roche. They were joined in their criticism of FDA's existing accelerated approval mechanism by Advisory Committee member Deborah Cotton, MD. The overwhelming majority of AIDS community groups represented at the meeting spoke against making any significant changes in the FDA regulations governing accelerated approval of AIDS drugs, including the San Francisco AIDS Foundation, Project Inform and ACT-UP Golden Gate. At the close of the meeting, FDA Commissioner David Kessler, MD, reaffirmed his support for accelerated approval as a means for making promising new AIDS drugs available more quickly. In a press interview Kessler said, "The riskiest thing we can do when we're dealing with life-threatening and serious diseases is to be unwilling to take any risks." AZT plus ddI plus Nevirapine ACTG 241, a clinical trial begun in 1993, was designed to compare the use of a 3-drug combination (AZT plus ddI plus nevirapine) to a 2-drug combination (AZT plus ddI) among 398 people with 350 or fewer CD4 cells/mm3. The trial ran for 48 weeks, and preliminary results were released in November 1994. The principal findings are: (1) the triple combination produced a 40% increase in CD4 counts over baseline, which persisted through 40 weeks of study; (2) the double combination produced a 25% increase in CD4 cells/mm3, which lasted for only 10 weeks; (3) patients on the 3-drug regimen experienced a 1-log drop in HIV RNA compared to a 0.5-log drop with the 2-drug combination, but the decline was not statistically significant between the 2 regimens; (4) patients taking the triple combination experienced more adverse side effects than those taking the double combination. A severe skin rash (possibly due to nevirapine) affected 8% of those taking the triple combination; (5) there were no differences between the 2 groups in terms of disease progression or survival. Herpesviruses in AIDS The management of herpesviruses in AIDS received considerable attention at 2 conferences held in San Francisco in November (see page ? ). At the International Herpes Management Forum, Lawrence Corey, MD, of the University of Washington gave a keynote presentation on the interaction between HIV and herpesviruses. In HIV infection, the herpesviruses may act as opportunistic pathogens or they may interact with HIV as cofactors to affect HIV pathogenesis and progression to AIDS and death, according to Corey. The herpesviruses include herpes simplex type-1 (oral herpes) and type-2 (genital herpes), cytomegalovirus (CMV), Epstein Barr virus (EBV), human herpes type-6 (HHV-6) and varicella-zoster virus (VZV, aka herpes zoster). Ron Boon, MD, of SmithKlein Beecham, discussed the use of the recently approved antiherpetic agent famciclovir on herpes zoster rash and pain. Boon reported that famciclovir taken 3 times daily produces results comparable to those achieved with acyclovir dosed 5 times daily for uncomplicated zoster (see page ?). M. Lynn Smiley, MD, of Burroughs Wellcome reviewed experience to date with valacyclovir, a prodrug of acyclovir. Valacyclovir was developed to have greater bioavailability than acyclovir with the latter drug's safety profile. "The number of patients [with herpes zoster] who were pain-free at 24 weeks was 23% higher with valacyclovir than with acyclovir," said Smiley (see page ?). Early Treatment For the best results in slowing disease progression, treatment for HIV should be started as soon as possible following initial infection with the virus, according to David Ho, MD, of the Aaron Diamond AIDS Research Center. Ho presented his model of HIV replication over the course of HIV disease at the 34th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC), held October 4-7 in Orlando, Florida. Also speaking at ICAAC, Michael Saag, MD, of the University of Alabama endorsed early treatment for HIV infection with as many anti-HIV drugs as can be tolerated. Combination Treatment and Survival At the Glasgow AIDS Conference in November, Melanie Thompson, MD, of the AIDS Research Consortium of Atlanta emphasized that combination therapy with AZT plus ddI or ddC achieves longer survival than AZT alone. Analysing data from the U.S. Multicenter AIDS Cohort Study, Neil Graham, MD, reported in Glasgow that combination therapy offers a survival advantage of about 33% over sequential therapy (See BETA. September 1994. p. 12). Cancer Drug has Anti-HIV Effect Hydroxyurea, a widely used cancer treatment, also inhibits HIV replication in laboratory studies. Robert Gallo, MD, and colleagues at the National Cancer Institute have found that, in vitro, the combination of hydroxyurea and ddI produces a synergistic anti-HIV effect without increasing toxicity. In some instances, inhibition of HIV by hydroxyurea was maintained for several weeks after drug treatment was stopped. These and other findings about the drug's potential as an AIDS therapy appear in an article in the November 4, 1994 issue of Science. 801-805). DISTRIBUTED FOR GENA by AEGIS/San Juan Capistrano - 714.248.2836: Copyright (c) 1994 - Bulletin of Experimental Treatments for AIDS (BETA), 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 contact the BETA Subscription Office at 1.800.959.1059 or 1.510.549.4300, or via the internet at beta@sfsuvax1.sfsu.edu.