[Electronic distribution for GENA by GENA/aegis (714.248.2836) Volume 8 no. 7 - August 1994 Gay Men's Health Crisis: Treatment Issues ^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^^ > Acyclovir Therapy for HIV Infection > Pregnancy Hormone Studied for KS > AIDS Drug Interactions: Part II > Safe Travel with HIV > Commentary: Studying Protease Inhibitors > Treatment Briefs >> No Boost for AIDS Research Budget >> Promising Lymphoma Treatment >> Oral Ganciclovir for CMV Prophylaxis >> Barley Green Company Refuses to Fund Trial >> Nevaripine Toxicity report >> New Clinical Trials >> TAG Issues KS Report >> From Our Files ============================== ============================== Acyclovir Therapy for HIV Infection by Dave Gilden The quest to prolong survival in people with AIDS through the use of anti-HIV drugs has been a disappointing one so far. The best such HIV drugs modern medicine has to offer, AZT and the other nucleoside analogs, have benefits that are temporary at best and hard to document precisely. One physician, Marcus Conant, M.D., of San Francisco, has long been a proponent of administering a succession of nucleoside analogs (AZT, ddI and ddC) once a patient's CD4 count starts falling below 500. Now, he says, "The anti-HIV drugs only work for eighteen to 24 months. People should only go on them when signs of immune deterioration arise." Dr. Conant recommends that his patients start acyclovir as soon as they know that they are HIV-positive, a regimen he says he first tried in 1987. He thinks that acyclovir helps slow disease progression by suppressing herpes viruses, which perhaps act as a co-factor in producing AIDS. The dose he recommends is 400 mg twice a day, the standard one used to prevent recurrent herpes attacks. Dr. Conant's recommendation is really based on his intuitive feeling; he has little data to back him up. Other community physicians may have different ideas. In New York, for example, Craig Metroka, M.D., prescribes high dose acyclovir in an effort to prevent infections with CMV (cytomegalovirus), which is a member of the herpes family that can cause blindness and death. However, studies, as of yet, have failed to confirm that acyclovir prevents CMV. Dr. Metroka says, "Generally I start people with less than 100 T- cells on 800 mg five times a day. Before I started acyclovir there was much more CMV in my patients." Previous Acyclovir Studies Two recently published trial reports do give some guidance about using acyclovir but these two studies raise many questions. The first paper[1] described a ten-year-old study in people with ARC or AIDS. The 265 trial participants received high doses of both AZT (250 mg four times daily) and acyclovir (4,800 mg per day). During the one year of follow-up, the death rate among the participants with AIDS was 41 percent in the AZT only arm and 21 percent in the AZT plus acyclovir arm. In the group with ARC, the death rate in the combination arm was a quarter of those in the monotherapy arm, but because of the small number of deaths, this reduction was only barely statistically significant. Adding acyclovir seemed to have no influence on CD4 counts or blood levels of HIV p24 antigen, although there was a profound decrease in herpes episodes. Unfortunately, this trial was marred by the fact that nearly half the participants dropped out of the study before its termination, indicating a high level of dissatisfaction with the conditions of the trial. One of the problems was that participants were not allowed to receive prophylaxis for pneumocystis carinii pneumonia (PCP), which since then has become standard practice. The survival benefits of PCP prophylaxis are now well established and might overwhelm any benefit acyclovir confers when the two are used together. The second paper described a trial in people with ARC or AIDS who were using acyclovir to prevent infections with cytomegalovirus (CMV).[2] Acyclovir failed to reduce the incidence of CMV despite the use of very high doses (800 mg four times a day). Herpes outbreaks were significantly reduced, though, and death rates decreased by more than 40 percent over the course of a year. These two studies are highly suggestive, but neither is definitive about how and when to gain the most advantage from acyclovir. One important issue is the proper dosage to take. Another is the duration of acyclovir's benefit. The MACS Study Now, statisticians have analyzed data obtained from the Multicenter AIDS Cohort Study (MACS), which follows the experiences of over 2,600 HIV-positive men in four U.S. cities.[3] The new analysis looked back at what happened to 786 men who began AZT prior to an AIDS diagnosis, including 515 who subsequently also received acyclovir for any reason. The authors found that the use of acyclovir was not associated with a lower rate of progression to AIDS. But once one had AIDS, it reduced the risk of death in any given time period, again, by more than 40 percent. The median dose of acyclovir used by MAC participants was in the 600 to 800 mg per day range. Survival benefits conferred by the drug did not seem related to the dose, although they did correlate with greater duration of use. Neil Graham, M.D., of Johns Hopkins University and one of the report's authors, says, "Given the limited nucleoside analogs available, taking acyclovir now makes sense. It's well tolerated. There's now enough data to indicate that people with both AIDS and herpes virus should take it. This is the first evidence that combination therapy works." Lead author Daniel Stein, M.D., of the Albany [New York] Medical Center, is more circumspect, however. He commented, "Before we can say whether people should take acyclovir, we have to look at the unanswered questions. There were certain things we couldn't answer: Exactly who do you treat? At what dose? When do you start?" More Clinical Data An observational data base like the MACS can indicate the unsuspected value of available therapies since it studies the outcome of using various medications in real clinical practice. Yet many of the details remain obscured because of the large differences in the way medicines are used and the range of individual differences between patients. There is also the problem of "confounding variables." Use of acyclovir may be associated with other factors, such as higher quality overall health care, higher income levels, and greater access to current treatment information and experimental therapies, which may be responsible for the decrease in death rate. Data on the way from several clinical trials should help clarify the issues surrounding acyclovir's significance in prolonging survival. ZDV/ACV Collaborative Study: Two years ago, researchers released preliminary results from a three-year, 677-person study comparing AZT (also known as ZDV) to AZT plus high dose acyclovir (4,800 mg per day) in early symptomatic HIV infection were released.[4] Investigators reported at the time that "preliminary analysis suggests the combination of [AZT and high dose acyclovir] is safe and may enhance CD4+ cell response." The final analysis is now being prepared for publication, and, according to a Treatment Issues source, will not indicate any survival advantage to using high dose of acyclovir with AZT in this HIV-positive group. The slightly greater CD4 count in the group taking AZT plus acyclovir was not considered statistically significant. ACTG 204: After two years, enrollment in another acyclovir study, the government-funded ACTG 204, has just filled up. This 1,000 person, one-year study compares high-dose acyclovir (800 mg four times a day) versus low-dose acyclovir (400 mg twice a day) versus high-dose valaciclovir (2,000 mg four times a day). (Valaciclovir is a new acyclovir "prodrug" that breaks down into acyclovir in the body and, reportedly, is much better absorbed. Like both acyclovir and AZT, it is manufactured by Burroughs Wellcome.) Unfortunately, the main purpose of ACTG 204 is to test the two drugs as CMV preventives in people with AIDS. The previous trials mentioned above do not hold out any hope that they will delay CMV in people with HIV, although the massive quantities of drug delivered by the valaciclovir prodrug form have not been tried before. The survival data collected in ACTG 204 will provide some further evidence as to whether people with AIDS live longer on high or low dose acyclovir. But since everyone in ACTG 204 will be on some regimen of acyclovir or valaciclovir, the trial cannot say whether some acyclovir is better than no acyclovir in prolonging survival. ACTG 063: One study that could definitively answer many of the questions surrounding acyclovir's role in treating AIDS is ACTG 063, which has been languishing in the hands of the statisticians for over a year. ACTG 063 is a two-year trial comparing AZT to AZT plus acyclovir (400 mg twice daily) in 400 persons with CD4 counts of less than 200. Data collected included survival rates, the incidence of opportunistic infections, and the effect of treatment on human herpes virus-6 (HHV-6) and Epstein-Barr virus (EBV). Both of these viruses are herpes viruses related to the herpes simplex (HSV) and varicella zoster (VZV) viruses that cause cutaneous herpes outbreaks and shingles, respectively. Results from ACTG 063 Languish One of ACTG 063's principle investigators, Anne Collier, M.D., of the University of Washington, said, "I am extremely frustrated. I more than anyone want to know what the data say and fought to keep the trial going." Dr. Collier at this point would not hazard a guess as to when the analysis of 063 will be finished. Dr. Collier lists in-fighting within the government's ACTG network and manufacturer Burroughs Wellcome's wavering financial support as two of the major obstacles to ACTG 063's completion. AIDS-related acyclovir trials have not been accorded priority by either private or public researchers. According to noted AIDS researcher Michael Saag, M.D., of the University of Alabama, "People don't stand up and endorse acyclovir because no one understands why it should work." (Dr. Saag was one of the investigators in the acyclovir plus AZT for early HIV infection trial mentioned above. He now says that he is beginning to suggest that advanced patients take acyclovir, but "not with the same enthusiasm as I recommend prophylaxis for pneumocystis.") Unknown Mode of Action Acyclovir, although it is a nucleoside analog like AZT, has no established effect on HIV levels. Its proponents therefore wonder whether it works by preventing the effects of one or more herpes viruses. The value of preventing a devastating, life-threatening opportunistic infection like PCP is obvious and the life-extension benefits have been documented in clinical practice.[5] But herpes virus infections most often do not have extreme, debilitating effects (except for CMV, which acyclovir apparently does not prevent). It may be that the long-term immune stimulation provoked by a chronic unsuppressed herpes infection promotes an increase in HIV replication. Another possibility is that the specific type of immune response elicited by herpes viruses creates conditions favorable to HIV or that reinforces the disease process leading to AIDS. Altered levels of some specific cytokine (intercellular messenger molecule), say, could increase cell death, reinforcing the effect of HIV. Finally, herpes viruses may force the cells they infect to produce some substance that is helpful to HIV. A report published last winter described an enormous increase in both HSV and HIV replication in cell cultures in co-infected individuals.[6] The report's chief author, Madalene Heng, M.D., of the University of California Los Angeles, told Treatment Issues, "We think that herpes simplex virus makes the difference between ARC and advanced disease. HIV and herpes simplex activate each other's promoter sequence and exchange DNA. Normally HIV infects only CD4 cells, but there are HSV-HIV hybrids that can enter most other cells." Burroughs Wellcome's Role Unless acyclovir's anti-AIDS mechanism is definitively elucidated, Burroughs Wellcome is unlikely to incur the substantial cost of a full-scale human testing program when the drug does not work well against HIV in the laboratory. But perhaps the major reason such a trial is unlikely is the fact that acyclovir's U.S. patent will expire in three years. One financial analyst noted, "The market for end-stage HIV is small compared to herpes. Wellcome's strategy seems to be to make acyclovir an over-the-counter drug (OTC) while shifting the prescription market to the new prodrug, valaciclovir." For HIV and AIDS therapy, Burroughs' new drugs include the nucleoside analog 3TC and a protease inhibitor - both bought from other companies and likely to be tested in combination with AZT. There will be a small revolution in the cost of treatment should a major AIDS drug become available over-the-counter, without prescription. (As a prescription drug, acyclovir at present costs about $2.00 per 400 mg tablet.) But at the Food and Drug Administration, deliberations on changing acyclovir's status have been postponed until the end of the year. The major issue holding up the change concerns the development of resistant viruses. Inappropriate or intermittent use of acyclovir creates environmental pressures favoring herpes viruses containing mutations that render the drug ineffectual. Resistant viruses are particularly likely to evolve in people with immune deficiencies, and these are just the people most in need of the active drug. (Infection with acyclovir-resistant herpes usually requires intravenous foscarnet therapy, which has serious toxicities.) Assistance Programs for Acyclovir One of the questions about making acyclovir an OTC medication is whether insurance companies and state programs will continue to reimburse patients who take it. Right now both Medicaid and the AIDS drug assistance programs in some states, including New York, cover acyclovir. In response to pressure from activists who pointed out that acyclovir was originally priced for intermittent, and not continual use, Burroughs Wellcome has instituted a very limited price cap for unreimbursed HIV-infected individuals. Under the program, patients who use in excess of 730 grams of acyclovir per year are entitled to an additional 730 grams of acyclovir free for the remainder of the year. For more information on Patient Assistance Programs at Burroughs Wellcome, call 800/722-9294. For Those Considering Acyclovir At this point, most of those who recommend acyclovir as a therapy for HIV-infection suggest it only in advanced disease. There is no hard data, as of yet, which supports using the drug before an AIDS diagnosis. In addition, no studies support using more than 600 to 800 mg per day, the standard herpes simplex suppressive dose. Whatever dose and point in time is best, though, acyclovir should be continued without a pause after it is started to reduce the chance of resistant virus. It remains to be seen whether acyclovir is useful in HIV-infected people without any evidence of herpes simplex infection, but this question may not be as important as it might seem. In the MACS study, nearly everyone who tested HIV-positive also was positive for herpes simplex. (The MACS group includes only gay men, though. Trials in other populations are needed to find out how universally helpful acyclovir could be.) One Final Question One last question is whether acyclovir increases survival in people who are not taking AZT. As one observer wryly noted, though, "One thing you'll never find out from Burroughs Wellcome is whether acyclovir is useful without AZT." 1 Cooper DA, et al. AIDS. Feb 1993; 7(2):197-207. 2 Youle MS, et al. AIDS. May 1994; 8(5):641-9. 3 Stein DS, et al. Annals of Internal Medicine. Jul 15 1994; 121(2):100-8. 4 Lavelle J, et al. Eighth International Conference on AIDS. Jul 19-24 1992; abstract PoB 3585. 5 Osmond D et al., Journal of the American Medical Association. Apr 13 1994; 271(14):1083-7. 6 Heng MC, et al. The Lancet. Jan 29 1994; 343():255-8. ============================== ============================== Pregnancy Hormone Studied for KS by David Gold Based on data in animal studies, a pregnancy hormone, Human Chorionic Gonadotropin (HCG), may show promise as a treatment for Kaposi's sarcoma (KS). HCG is produced in the placenta during pregnancy and inhibits the mother's immune system from rejecting the fetus as "foreign tissue." It is an approved therapy for treating infertility in women and cryptorchidism (failure of the testicles to descend) in boys. Reports circulated last year that two European women with KS had a "spontaneous resolution" of their lesions after becoming pregnant. [See Treatment Issues, September 1993.] Dr. Robert Gallo's lab at the National Cancer Institute duplicated this phenomenon in mice and proposed that HCG may be a useful treatment for KS. Initially, according to Dr. Yanto Linardi-Eskandar of Dr. Gallo's lab, a KS cell line was put into six mice. In the two males, the KS lesions grew and the mice died. But in the four females, all of whom became pregnant, tumors did not develop, even after delivery. The researchers then tried to isolate the time during pregnancy in which the greatest protection against KS tumors occurs. KS cells were put into pregnant mice during early pregnancy, when high levels of the "beta sub-unit" of HCG are found, and no tumors developed. However, when the cells were put into mice during late pregnancy when the "alpha sub-unit" levels are predominant, very small tumors developed. This suggests to the researchers that the "beta sub-unit" of HCG has the greatest anti-KS properties. Dr. Linardi-Eskandar now reports that HCG has been tested in "more than 500 mice" with KS lesions, using both intralesional (directly into the lesion) and intramuscular (systemic) injections of 50 to 100 International Units (IU) per ten grams of mouse weight, three times per week. The results have been "very encouraging," he said. In addition, there are unconfirmed accounts that HCG has been given to three people with AIDS-related KS. One individual from the West Coast told Treatment Issues that he began treatment with HCG for his KS in July of this year. He is receiving HCG therapy with the support of his physician, who gave him a prescription for the drug. This indivual consulted with researchers who suggested that a regimen of one IU per ten grams of body weight (100 IU per kilogram) may be an appropriate dose to consider (this is 50 to 100 times less than the dosing regimen given to mice). At this rate, a 73 kilogram man would be given 7,300 IU. However, since HCG is sold in doses of 5,000 IU per vial, this individual is starting at the 5,000 IU dose three times per week. After three weeks of administering HCG, this individual reports that he has yet to see an effect on his KS lesions. A clinical study of HCG in individuals with KS is planned at the University of Southern California (Parkash Gill, M.D., 213/224-6668). Dr. Gill, a leading KS researcher, says that his study will evaluate HCG as both an intralesional and intramuscular injection. A number of companies have approval to market HCG, including Wyeth Ayerst (brand name "APL"). There is, at this point, no definitive information about what HCG may do in immune- compromised individuals or how it may interact with other HIV therapies. According to the Physicians Desk Reference, injectable HCG may cause significant side effects. Among them are headache, irritability, aggressive behavior, and phallic or testicular enlargement. ============================== ============================== AIDS Drug Interactions: Part II by Gabriel Torres, M.D. People with HIV commonly take several medications at the same time to fight both HIV and its related conditions. These drugs can interact with each other, leading to more toxic side effects and reduced effectiveness. Last month's Treatment Issues (July 1992; volume 8, no. 6) presented the first part of this article, surveying antiretroviral drugs, drugs for pneumocystis pneumonia and antifungal drugs. We conclude this month with drugs for mycobacteria (TB and MAC), cytomegalovirus and toxoplasmosis. TB and MAC Drugs 1. INH (Isoniazid): INH is the mainstay in the treatment and prevention of tuberculosis. Its main toxicities are hepatitis and peripheral neuropathy. Liver damage seems to be more common in persons over the age of 35, those who consume a lot of alcohol and those who also are taking rifampin for TB. Liver enzyme levels in the blood must be monitored when INH is taken along with rifampin and/or pyrazinamide, a combination used for treating active TB. INH is usually discontinued when liver enzyme test results are five times the upper limit of normal, signaling severe liver inflammation. Peripheral neuropathy is also common with INH, but can be avoided if it is taken along with vitamin B6 (pyridoxine). Aluminum-containing antacids can decrease the absorption of INH and reduce the compound's effect. INH on the other hand can inhibit liver enzymes that metabolize certain drugs, leading to increased blood levels of such medications as Dilantin, Tegretol, Coumadin, theophylline and the benzodiazepines (Valium, Ativan). Skin flushes due to inhibition of histamine metabolism by INH occur in some patients who eat certain fishes or cheeses while receiving the drug. Finally, the body metabolizes INH more quickly in the presence of alcohol and steroid medications (prednisone). This could result in decreased effectiveness. 2. Rifampin and rifabutin: These anti-TB and anti-MAC drugs are fraught with potential drug- drug interactions. Physicians must administer them extremely carefully in order to achieve their therapeutic effects and avoid interfering with other, concurrent therapies. Several studies have found rifampin to have a greater incidence of side effects among HIV-positive patients as compared to HIV-negative controls.[1] Rifampin decreases the blood levels of such common drugs as ketoconazole, dapsone, atovaquone, fluconazole, corticosteroids, oral contraceptives, cyclosporine, Coumadin, methadone, theophylline, levothyroxine, digoxin, quinidine and propanolol. If possible, these drugs' blood concentrations should be monitored when patients take them along with rifampin. Dosages require upward adjustment in most cases in order to maintain effectiveness. Rifabutin seems to have fewer drug-drug interactions than rifampin, yet like INH can change liver enzyme production and thus alter the metabolism of the drugs mentioned in the previous section. In addition, lowered blood levels of AZT have been observed in rifabutin trials for MAC prophylaxis.[2] 3. Ciprofloxacin: This drug is used for the treatment of MAC and multi-drug resistant TB. Concomitant administration of antacids that contain aluminum or magnesium hydroxide (Mylanta or Amphogel) can lead to the formation of insoluble chelates that prevent the drug's absorption, reducing its level in the blood. Another drug that decreases the absorption of ciprofloxacin is sucralfate, a stomach ulcer remedy that should not be taken along with ciprofloxacin. Ciprofloxacin in contrast can increase the absorption and blood levels of theophylline (an asthma remedy). Theophylline blood levels should be monitored, and its dosage may require reduction to prevent toxicity. 4. Clarithromycin: Decreased AZT blood levels have occurred with this MAC drug, but the clinical significance of this reduction are unknown. Clarithromycin can increase theophylline and Tegretol blood levels, resulting in added toxicity form these drugs. Another MAC drug, rifabutin has recently been shown to lower clarithromycin levels.[3] 4. Clofazimine: This is another drug for MAC. It can decrease the rate of rifampin absorption and thus reduce its effects. In addition, it lowers Dilantin levels, which has led to breakthrough seizures.[4] Anti-CMV Drugs 1. Ganciclovir (Cytovene): Ganciclovir's main toxicity is bone marrow suppression leading to low neutrophil and platelet counts. Drugs with similar effects on the bone marrow should not in general be prescribed at the same time unless the benefits are felt to outweigh the risks. These include AZT, amphotericin, pyrimethamine, amphotericin, dapsone, flucytosine, imipenem-cilastatin, pentamidine, Bactrim, vinblastine, vincristine and adriamycin. Fortunately, the advent of agents like G-CSF (Neupogen) that help increase white blood cell production has made it possible to administer ganciclovir together with many of these drugs without running the risk of bone marrow suppression. G-CSF is usually started when the total neutrophil count is at 750 or below and continued until the count is near or above the normal range. Another drug-drug interaction seen with ganciclovir and imipenem- cilastatin, an antibiotic used to treat severe bacterial infections, is seizures.[5] Oral ganciclovir has been reported to be associated with an increased risk of pancreatitis if administered in association with ddI. 2. Foscarnet: Foscarnet can cause kidney dysfunction, reduced blood levels of calcium and phosphorus, anemia and nausea. The necessity of avoiding other kidney-damaging drugs, pentamidine, aminoglycoside antibiotics and amphotericin B, needs to be underscored. If these drugs are prescribed concomitantly with foscarnet, then patients must undergo hydration with intravenous fluid (usually saline). Hydration may also prevent the formation of the penile ulcers occasionally noted with foscarnet, which are due to the local irritant effect of the drug in the urine. Another observed interaction is that of foscarnet and pentamidine together can lower blood calcium levels, a condition that can lead to seizures and spasms.[6] Anti-toxoplasmosis Drugs 1. Pyrimethamine: Pyrimethamine in combination with sulfadiazine is the mainstay for the treatment of toxoplasmosis. Unfortunately its most important toxicity is bone marrow suppression (causing neutropenia and thrombocytopenia), and it can interact with other drugs that also harm the bone marrow. In order to save the bone marrow from the toxic effects of the drug, which are predominantly from depression of the normal metabolism of folate caused by the combined action of pyrimethamine and sulfa drugs, folinic acid (or calcium leucovorin) is given along with pyrimethamine. 2. Atovaquone and Clindamycin: See the section on PCP in part one. Conclusion Drug-drug interactions are a complex system of effects that arise when patients receive several drugs concurrently. Individuals with HIV disease often require multiple drugs to combat different opportunistic infections, to treat the underlying HIV infection or for treatment of symptoms (antacids, pain medications etc.). This puts them at high risk of using drugs which interact with each other with the end result being a less than desired effect or increased toxicity and adverse effects. Ways of coping with these interactions include more frequent blood tests of drug concentrations, adjusting the dosage of the drug if it is known to have a lower blood level in the presence of the second drug, or avoiding combinations that interact, which last can be achieved by substituting drugs with similar therapeutic activity but lacking the interaction. For example, substituting fluconazole for ketoconazole when a patient is also receiving ddI will sidestep the issue of ketoconazole malabsorption induced by the buffer in the ddI formulation. Fluconazole does not require acidity for its absorption. Sometimes no alternatives are available, and interacting substances must be administered together. Repeated blood tests may then be the only way to detect early signs of compound drug effects on organs like the bone marrow and the kidney. Alternatively, the dosages of the interacting drugs may be adjusted, and physicians can add drugs such as G-CSF to avoid the combined toxicities. 1 Soriano E, et al. AIDS. 1988; 2(6):429-32. 2 Narang P, et al. Eighth International Conference on AIDS. Amsterdam, 1992; abstract PoB 3888. 3 Hafner R. personal communication. 4 Cone LA, et al. Clinical Infectious Diseases. 1992; 15(6):1066-8. 5 Lee BL, et al. Clinical Infectious Diseases. 1992; 14(3):773-9. 6 Youle MS, et al. The Lancet. 1988; 1(8600):1455-6. ============================== ============================== Safe Travel with HIV by William Mandell, M.D., Jay Ward Kislak, M.D. and Dennis Karter, M.D. Travel to developing nations can be enjoyable and enriching. Persons infected with HIV need not deny themselves this experience. It is true that they may encounter germs that are uncommon or unknown in the United States, but their specific risk of acquiring infections may not be greater than for HIV-negative travelers. Infections frequently are more severe or persistent in persons with HIV, however. HIV-positive travelers should exercise a little extra care to keep themselves safe, healthy and happy. The following are some of the major precautions. Immunization The immunizations necessary for travelers with HIV vary according to the destination. All travelers must have a tetanus-diphtheria booster within the past ten years. Those who have never had hepatitis A require gamma globulin shots. Most destinations still have polio, some have typhoid fever and a few have epidemics of meningitis. Vaccinations to prevent these illnesses are available. The live oral polio and typhoid vaccines are not appropriate for patients with HIV, though, so the injectable inactivated forms must be given. The only available yellow fever vaccine is a live virus vaccine. To our knowledge, there are no reported cases of illness from this vaccine in persons with HIV, but it still is not generally recommended for HIV-infected individuals. Since the yellow fever risk varies greatly from locale to locale in South America and Africa, take into account your individual travel itinerary when deciding about this vaccine. Other immunizations, such as those for measles, cholera, rabies, influenza, pneumococcus and hepatitis B, are safe and may be administered when circumstances warrant. Food and Drink Traveler's diarrhea is very common. It can be caused by viruses, bacteria or parasites. Some of these organisms may be difficult to treat and result in chronic illness. Just a tiny amount of tainted water or food can result in severe diarrhea. Strict safety measures are highly advised. Avoid ice cubes, raw or undercooked meats, fish, seafood, vegetables, salads and unpeeled fruits, even on the flight home. Dairy products are acceptable only if cold and fresh. Some authorities recommended against all shellfish. Water can be purified by boiling or with water purification tablets containing iodine. Bottled carbonated water also is safe. Unopened bottled still water is safe only if you are certain that the original seal is intact. Brush your teeth with bottled water and make sure water does not enter your mouth when taking showers. If three or more loose stools occur during a 24-hour interval, or a single loose stool is associated with fever or severe cramps, then initiate treatment with an antidiarrheal agent (such as Immodium, Pepto-Bismol or Kaopectate) plus an antibiotic. If severe diarrhea continues for more than 72 hours, examination by a physician is in order. Insects and Sex Malaria is common throughout the tropical world. Since the medications that prevent malaria do not interact with medications commonly prescribed for HIV-related indications, they are acceptable for people with HIV. Malaria prevention, with either chloroquine or mefloquine, must begin two weeks before departure and continue until four weeks after return. Despite prophylaxis, certain forms of malaria can occur weeks to months after leaving a malaria-infested area. Fever is the prominent symptom, and a simple blood test determines the diagnosis. Numerous other infections also are spread by mosquitoes, as well as by sandflies, ticks and fleas. Preventing insect bites is essential. Apply insecticides containing permethrin to your clothing and netting, and repellents containing DEET to your skin. Repellents last only up to four hours and need renewal after swimming. Long sleeve shirts, long pants and socks provide further barriers against bites. Make sure to sleep in screened areas or under netting. Since many insects are attracted by perfumes, colognes, after-shave lotions and scented soaps, it is wise to remain fragrance-free. Finally, sexually transmitted diseases are much more common in developing nations than in the United States. Safer sex is imperative. You need not lead a chaste life, but bear in mind that even kissing can result in syphilis, gonorrhea, herpes or Epstein- Barr virus infection. A prompt visit to the doctor is essential if any sign of an STD appears, and that may not always be possible in developing countries. Have fun this summer, but do not let this summer's fun interfere with the possibilities for the rest of the year! ============================== ============================== Commentary: Studying Protease Inhibitors by Gabriel Torres, M.D. and Dave Gilden Protease inhibitors, a new class of anti-retrovirals, are about to enter the second phase of clinical development. It is hoped that these drugs will provide a more effective and less toxic alternative to the nucleoside analogs currently in use. There is widespread disappointment in the nucleosides (AZT, ddI, ddC and d4T), and clinical research has failed to produce meaningful information about how to get the most out of this minimally effective group of therapies. In the study of protease inhibitors, can we find a more useful approach of clinical investigation? The "accelerated approval" policy of the Food and Drug Administration has resulted in the marketing of nucleoside analogues based primarily on short-term, modest influence on CD4 counts. Information as to how well these drugs work in clinical practice is rarely published despite FDA requirements that companies conduct post-marketing studies. Protease inhibitors will not be a cure for AIDS or HIV. Like nucleoside analogues, they present physicians and persons with HIV with a great conundrum. How are we to determine when and how well they work? How easily can HIV evolve to overcome this new therapeutic challenge? A Large Simple Trial To answer such questions, New York's Treatment Action Group (TAG) is proposing a large two-year clinical efficacy trial comparing various protease inhibitors to a placebo in a sample of approximately 18,000 people with HIV. This "large simple trial" (LST) would go beyond previous parallel track or expanded access programs that have allowed people failing standard therapies to receive experimental drugs even before FDA approval. The phase II/III LST efficacy trial could commence immediately after the preliminary Phase I safety trials were completed. The trial would be open to nearly anyone with HIV, and participants could take any drugs they desired in addition to the protease inhibitor. While the proposed trial would offer access to the experimental protease inhibitor to thousands of people, one-third of the trial participants would receive placebo rather than protease inhibitor in blinded fashion, i.e. neither doctors nor participants would know who was in the placebo arm. But TAG also proposes a non-placebo trial comparing different doses of the protease inhibitors for people who have CD4 counts of less than 50, who cannot tolerate any of the nucleoside analogues, or who have reached advanced disease in the large simple trial. The data collected in the LST would be much more extensive than that previously gathered from expanded access participants. This information on clinical outcome (incidence of opportunistic infections, death, etc.) would be recorded by people's usual physicians and would reflect the effects that protease inhibitor have during actual use by the public. The trial furthermore would lend itself to subset analysis, in which particular subgroups would be monitored for the predictive power of laboratory tests (such as for HIV levels in the blood (see below) and improvements in immune response), drug-drug interactions, and specific toxic reactions that might normally go unobserved. By TAG's own admission, the LST proposal is a work-in-progress that needs further development and analysis. The group felt it had to act fast. The proposal's initial impetus was reports that Hoffmann- La Roche was considering seeking accelerated approval for its protease inhibitor, saquinavir, on the basis of the data from the government-funded trial ACTG 229 - a trial with somewhat ambiguous results. [See Treatment Issues, June 1994.] The Drawbacks Although the LST concept has a number of attractive features, there are also a number of immediate drawbacks. Conducting a large trial would consume huge amounts of resources in terms of research dollars, human bodies exposed to an experimental drug, and attention diverted from other potential therapies inching their way through the pipeline. No one has ever organized large simple trials among HIV positive patients in the U.S., nor has anyone ever analyzed the costs in detail. A more "traditional" expanded access program would also be very costly. The diverse, volatile factors influencing recruitment of volunteers for such a study are also unknown: A smaller LST evaluating immediate versus delayed AZT therapy in San Francisco is presently having difficulty enrolling patients. A large simple trial of protease inhibitors risks becoming similarly out-dated before enough people sign up for it. Protease inhibitors are enormously expensive to produce, and the resource question has loomed large in TAG's discussions with drug companies over its proposal. Hoffmann-La Roche postponed a meeting with community representatives on the East Coast. The company has long claimed that the difficulty and expense in producing its saquinavir product limits its ability to expand supply. Roche is conducting two large multi-center trials, however, involving a total of 4,200 participants. These trials will collect data on disease progression and survival, although TAG questions whether their size will be large enough to really document saquinavir's benefits given the drug's medium level of effect on HIV. (Saquinavir may be more effective at higher doses, according to initial observations of a high-dose saquinavir trial being conducted at Stanford University.) Merck & Co., whose protease inhibitor (L-524) is the next furthest along in development, did meet with TAG recently, but Merck officials plan on following their previously laid-out development strategy. The company, which has had, to its credit, extensive and open discussions with community representatives, does not want to go the accelerated approval route with the FDA. Merck wants to thoroughly test its drug, including completing small trials that document L-524's effect on physical symptoms, before seeking marketing approval. It will therefore probably be two or three years before L-524 is for sale, and in the meantime, Merck is planning no expanded access program. L-524 may be a very useful tool against HIV, but it will not be a cure or "home-run" drug. The company's position is that, at this time, L-524's potential does not appear great enough to merit what it claims is the substantial investment in rapidly expanding production at this time. TAG representatives came away from the Merck meeting very disappointed. "We wanted both access and answers [as to how the drug works], and we're getting neither," one said. Access and Information Are there other methods of screening protease inhibitors and other promising medications in a more efficient and rapid manner? One option might be to conduct a smaller placebo-controlled trial in people with advanced AIDS. Data collection for this trial would center on the ordinarily high incidence of opportunistic infections and deaths in the group. The results might provide a "quick-and- dirty" answer as to whether protease inhibitors provide any clinical benefit to this population. However, there are serious practical and ethical questions about a placebo study in such seriously-ill patients. If the trial ends with positive data, it would encourage both drug developers and trial participants since both would have benefited, at least temporarily. But the study population in this case has high initial HIV levels and rates of replication. If not completely suppressed, the virus could rapidly rebound as it develops drug- resistant mutations and spreads into the fresh crop of uninfected CD4 cells. One fears a replay of the AZT story, in which rapid FDA approval, widespread use outside of the populations in which the drug had been tested, and the absence of long-term data, led to eventual disappointment. New technology may help avoid the disappointments of the past. Tests such as "quantitative polymerase chain reaction" and "branched chain DNA" measure HIV levels in the blood and can be used to correlate changes in viral burden with antiretroviral therapy. These tests offer the possibility of continuously and directly monitoring the effect of protease inhibitors (and other experimental drugs) on HIV activity from the beginning of a clinical trial. Yet it remains to be seen how closely levels of HIV correlate with disease state, and more importantly, whether short term reductions in HIV viral load can provide real benefits in terms of disease progression and survival. HIV viral burden will have to be evaluated within the context of other variables, including immune system parameters (such as CD4 count) and, most importantly, clinical outcome. Still, the final, definitive trials - that demonstrate under real- world conditions, whether protease inhibitors work, when is the best time to initiate therapy, and how to combine these compounds with existing therapies - will necessarily follow the large simple trial concept. Such trials need not be conducted prior to a drug's approval by the FDA, but they should already be underway and their continuation assured. Cooperation between industry, government agencies, patients from diverse communities and primary care providers will be essential in completing these trials. One of the best contributions of the TAG proposal is the debate it has sparked over expanded access and accelerated approval. There are no easy ways to balance the different demands for quick access to drugs and more information about their use. Once a treatment is available in the community, it is difficult to organize the studies needed to document its effect. The time to thrash out this issue is now, not when protease inhibitors start coming before FDA Antiviral Drugs Advisory committee for approval. ============================== ============================== Treatment Briefs by David Gold No Boost for AIDS Research Budget A Senate appropriations subcommittee failed to increase the NIH's AIDS research budget. [See Treatment Issues, July 1994.] The subcommittee left research funding at the same level as the House ($38.5 million below President Clinton's request). It also reduced the House's appropriation for AIDS prevention by $37.7 million and increased care money under the Ryan White Act by $8 million. Richard Ford, of Senator Patrick A. Moynihan's (D-NY) staff, contacted Treatment Issues proudly reporting that Senator Moynihan had written to Senator Harkin, (chair of the appropriations subcommittee) requesting that Ryan White funds not be reduced in the 1995 budget. Ford, who is Senator Moynihan's chief staffperson on AIDS, expressed both surprise and skepticism when it was pointed out to him that the AIDS research budget was part of the NIH authorization and not part of Ryan White funding for AIDS care. Promising Lymphoma Treatment MGBG, a product developed by Sterling Winthrop, may show promise as a treatment for AIDS-lymphoma, according to a report at the Thirteenth Annual Meeting of the American Society of Clinical Oncology held in Dallas from May 14 to 17, 1994 (abstract 11). In the study, led by Alexandra Levine, M.D., of the University of Southern California, MGBG was given intravenously (600 mg) on day one, day eight, and then every other week to fifteen patients with relapsed and refractory AIDS lymphoma. A median of five doses of MGBG was given. Two complete responses and three partial responses were reported. Thus five of fourteen patients (36 percent) saw some response to the drug. The average CD4 count was 90 at the trial's start, and median survival was 4.3 months. MGBG also was associated with some weight gain. Toxicites were "very mild" according to Dr. Levine and included skin flushes during infusions, nausea and vomiting (three cases), and euphoria. Standard chemotherapy for lymphoma is often difficult to tolerate, particularly for those with advanced HIV disease. This small study suggests that MGBG may be of some benefit in treating AIDS-related lymphoma. Larger trials should be started without delay. These studies should consider an arm with a higher dose to see if the response rate can be improved. An expanded access program for those who have failed standard therapy may also be appropriate. Oral Ganciclovir for CMV Prophylaxis An initial look at data from an ongoing study of an oral version of ganciclovir reportedly suggests that the drug may help prevent the onset of CMV disease. The study, which enrolled over 700 HIV-positive individuals with less than 50 CD4 cells and a positive CMV viral titer, randomized patients to either 1,000 mg of ganciclovir taken by mouth three times daily or placebo. According to Linda Thomas, a spokesperson for ganciclovir's developer, Syntex Laboratories, the trial's Data Safety and Monitoring Board did its first regular review in July and determined that the data showed "highly significant evidence of efficacy plus a trend towards improved survival which reached near statistical significance." The Board recommended that the placebo portion of the trial be eliminated and that all trial participants receive the drug. Before this new data was available, Syntex had already submitted a new drug application requesting that the FDA approve oral ganciclovir as a maintenance therapy in people who had already experienced one instance of CMV retinitis. The company is likely to amend its application to add CMV prophylaxis before any symptoms appear to the proposed indication. While the FDA has this under consideration, it is hoped that some expanded access program for CMV prophylaxis can be initiated. Barley Green Company Refuses to Fund Trial Barley green extracts and other "green juices" are used by many HIV-positive individuals as nutritional supplements. A few reports from Japan suggest that barley green extract may have some beneficial impact on the immune system. [See Treatment Issues, January 1994.] These reports led researchers Mike Barr and Gabriel Torres, M.D., of St. Vincent's Hospital in New York City to propose a trial of barley green in HIV-infected individuals. The twelve-week study would examine virological and immunological markers and would cost approximately $30,000. The two leading barley green products "Barley Green" and "Green Magma" are manufactured by Japan Pharmaceutical Development, Ltd., a large, worldwide company which, by its own claim, sells more barley green worldwide than all other grass juice powders combined. The company's own literature boasts of the fact that ten percent of all sales go to research on barley green extract. Earlier this year, Barr, Torres and colleagues met with JPD president Hideaki Hagiwara at the company's Trump Tower apartment. During the meeting, Hagiwara voiced strong interest in helping fund a study. However, Barr recently received a correspondence from the company stating that they will be unable to fund such a trial. The company's refusal to fund this small and inexpensive trial is extremely disappointing. Readers may want to call Pakahiko Amano, executive vice-president of the company's U.S. subsidiary, Green Foods Corp. of Oxnard, CA, at 805/983-1130 to encourage the company to help pay for this useful study. Nevaripine Toxicity report The FDA temporarily halted enrollment in clinical studies of nevirapine, a non-nucleoside reverse transcriptase inhibitor, after results of an early study measuring safety and how the drug was absorbed in the body revealed that three of four HIV-negative women had substantial increases in liver functions tests (LFTs). The increases occurred in the first three weeks of taking the drug and resolved after discontinuation of the drug. The most common side effect previously seen with nevirapine had been skin rashes. Enrollment was resumed two weeks later, though, after a look at data from a much larger nevirapine study, ACTG 241, reported no significant differences in toxicities. New Clinical Trials SUNY at Stony Brook is now enrolling participants for three studies involving the new Merck protease inhibitor. One is a dose escalation study for which previous AZT experience is irrelevant. The other two involve combinations of the Merck drug and either AZT or AZT plus ddI and require participants to have had little past experience with AZT. Call 516/444-1658. An eight-week study of a soluble Interleukin-1 (IL-1) receptor in HIV-positive individuals with less than 300 CD4 cells is underway at Memorial Sloan Kettering in New York City. IL-1, a cytokine, is overproduced in people with HIV and is believed to increase HIV replication and possibly stimulate KS cell growth. The receptor, it is hoped, will bind to circulating IL-1. Call 212/639-7161. A study of acitretin, a retinoid, in the treatment of psoriasis in HIV- positive individuals is underway at Beth Israel Hospital in New York. Call Leslie Borow at 212/420-3000. Rockefeller University is studying interleukin-2 (IL-2) as a treatment for HIV. Participants must have 300 to 500 CD4 cells and be on AZT, ddI or ddC. Call Dr. Tang at 212/327-7795. The UCLA Center for AIDS Research is studying the safety of a single dose of recombinant human IL-12 in HIV-positive individuals with CD4 counts between 100 and 500. Call 310/206-6414. TAG Issues KS Report The Treatment Action Group (TAG) has issued "The KS Project Report: Current Issues in Research & Treatment of Kaposi Sarcoma." The 85-page document, written by Michael Marco with Martin Majchrowicz, is extremely informative and an impressive example of effective and targeted treatment activism. Copies of the report can be obtained by sending ten dollars to TAG, KS Report, 147 Second Avenue, Suite 601, New York, NY 10003. From Our Files A summer cleaning turned up the following: From the "We'll Pass It On to Our Readers File": a subscriber from New York City writes "Noting your commenting (sic) on yet another pharmaceutical drug for toe-nail fungal infections, I'd suggest you look into Australian Tea Tree Oil. Available in nutrition and herb shops it is one of the most powerful anti-fungals known." From the "Gee, Why Does American Health Care Cost So Much File": one 100 mg capsule of itraconazole, a major new anti-fungal medication manufactured by Janssen Pharmaceuticals, costs $6.00 in the U.S. but less than $1.00 in Mexico. From the "Let's Go Out on a Limb File": the headline of a press statement distributed by AIDS Action Council, a Washington DC- based lobbying group, boldly proclaims "AIDS Action Council Urges President Clinton to Listen to the AIDS Communities" (dated June 22, 1994).