Subject: Treatment Issues Vol. 5 No. 6 Date: Aug 30 1991 (726 lines) &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& TREATMENT ISSUES -- The GMHC Newsletter of Experimental AIDS Therapies &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& Treatment Issues 56 Volume 5 Number 6 -- Aug. 30, 1991 Contents: [items are separated by "*****" for this display] Antiviral Combinations Vaccine Update ddI Recommended for Approval Pregnancy & HIV In Brief ***** News from Florence: Combination Antiviral Therapy by Kevin Armington Predictably, no new antiviral dethroned AZT as the most effective AIDS drug at the Seventh International Conference on AIDS in Florence, Italy. AZT -- with all its well-known limitations -- is still outperforming other experimental antivirals. Countless studies have led to strategies that minimize the drug's toxicities and enhance its antiviral potential. Several studies presented in Italy clearly show that the bet approach currently available to inhibit HIV is combining AZT with other antivirals. This article will focus on three of the most popular antiviral "cocktails": AZT combined with ddC, alpha interferon, or ddI. AZT With ddC The most promising antiviral data from Florence in the opinion of this observer, emerged from studies of AZT and ddC. Oddly enough, these data were not prominently presented as part of the regular conference program. Dr. Margaret Fischl, a researcher at the University of Miami, is the principal investigator of the study on ddC that was recently completed. This trial compares five different combinations of AZT and ddC. Rumor has it that the results will soon be published in a prestigious medial journal. In any event, the data are quite impressive. Fifty-six patients with AIDS or ARC, with average T4 counts between 60 and 70, received different doses of this combination and were observed for 40 weeks. Patients on lower doses (150 mg AZT and .015 mg/kg ddC daily) experienced only small, transient rises in T4 counts. However, at higher does of drug (300 or 600 mg AZT with 0.03 mg/ kg ddC daily), patients saw increases in T4 counts of up to 120 cells. At this dose the T4 counts remained above baseline values for as long as a year. No other treatment option has produced and maintained similar increases in T4 counts for so long in persons with such low T4 counts. There was also some evidence that 600 mg AZT daily wa more effective than 300 mg AZT daily. In general the combination was well-tolerated. Two patients experienced peripheral neuropathies, which resolved when ddC was discontinued. Two other patients had to withdraw from the study because of low white cell counts. At least one case of drug- related liver toxicity was observed. A larger efficacy trial is now under way to gather more data on this promising combination. AIDS Clinical Trials Group (ACTG) trial #155 is employing 600 mg AZT with 0.03 mg/kg ddC. The study is open to persons whose T4 counts are below 300 and who have taken at least 500 mg of AZT daily for six months. Many sites nationwide are recruiting. For a complete list offering more information on clinical trials call 1-800-TRIALS-A. AZT with Alpha Interferon Theoretically, it makes good sense to target HIV with AZT and alpha interferon, since each drug interferes at a different point in the virus' "life cycle." However, results in people so far have not shown the same positive effects as test tube studies. Three small studies, presented in Florence, examined the effects of this combination in mildly symptomatic patients with evidence of increased HIV reproduction in their blood (i.e., p24 antigen positive). The most optimistic results were reported by Dr. Donna Mildvan, who is conducting a study (trial #068) supported by the ACTG at Beth Israel Medical Center. This ongoing trial is also offered at a number of centers around the country: for a complete list, call 1-800-TRIALS-A. Twenty three patients with T4 counts over 200 and p24 antigen levels over 70 received AZT alone or AZT with alpha interferon for at least six months. The bottom line result of this subtle and complicated trial was that the combination had a greater suppressive effect on viral replication than AZT therapy alone. Dr. Mildvan went so far as to claim that AZT plus alpha interferon had a synergistic effect on p24 antigen levels. This means that the two drugs together had a greater effect than the combined effects of each drug taken alone (i.e., 2+2=5). One the negative side, 12 out of 28 participants needed to cut their doses by 50% due to toxicity. Dr. Mildvan also noted that the combination was better tolerated when d at the same time, rather than adding one drug after a period of monotherapy. Due to strict eligibility criteria, it is extraordinary difficult to recruit patients for this rial. Therefore, it may be some time before these very preliminary and encouraging results are verified. A somewhat larger study conducted int he Netherlands yielded conflicting results. This study compared 1000 mg AZT daily to 600 mg AZT daily augmented with three million units (MU) of alpha interferon three times a week. This dose of interferon is less than the amount administered in ACTG trial #068 (described above) which calls for a range of 7 to 42 MU/week. Forty patients with T4 counts above 150 were treated for a t least six months. Patients on the combination had a greater drop in HIV reproduction and higher T4 increases after three months. However, there were no longer any significant differences in these parameters between the two groups after six months of treatment. Also, the incidence of opportunistic infections (OIs), Kaposi's Sarcoma, and neuropathy was the same for both groups. In addition, the author is reported that the combination resulted in more toxicity, more need for dose reduction, and more fatigue than with single therapy. On the other hand, the authors also concluded that the combination is worth further investigation because the use of AZT and alpha interferon may delay the development of resistance to AZT. Researchers at the Center for Special Immunology in Ft. Lauderdale tried adding alpha interferon to AZT in fifteen patients who had high p24 levels despite six months of AZT alone (600-1200 mg/day). Trial participants received huge amounts of alpha interferon: three MU/day for the first week, five MU/day for the second week, and 10 MU/day thereafter. The dose of AZT was 600-800 mg/day. Four patients withdrew: three due to toxicity. Five of the remaining eleven "responded," and had reduced HIV reproduction. Those who responded had higher T4 cell count percentages and fewer clinical events. In other words, people who were healthier had more benefit from the combination therapy. The authorities also reported that responding patients could be identified in the first month of treatment. The implication may be that combination AZT and alpha interferon is worth trying for one month to see if results are desirable. Asymptomatic persons with T4 counts between 300-600 were the focus of a six month trail of AZT plus alpha interferon at Laennee Hospital in Paris. Seventeen participants received 500 mg AZT/day and eleven participants received 500 mg AZT/day plus 3 MU alpha interferon three times a week. During the trial only one patient, who was taking AZT alone, progressed to AIDS. Researchers noted a more pronounced drop in p24 antigen levels for patients receiving the combination. While p24 antigen levels were on the rise again at six months, those on the combination showed a more gradual rise. No information on toxicity was reported Traditionally, alpha interferon has produced better results in treating Kaposi's sarcoma in people with T4 counts above 200. So there is perhaps a greater hope for the drug's antiviral effect in people with counts in that range. It does not necessarily follow, however, that alpha interferon will not be useful to people with counts below 200. In fact, one study showed that alpha interferon and AZT produced improvements in some KS patients with T4 counts below 200. AZT with ddI Two small studies in adults and children of combination AZT/ddI are still ongoing. Very early data from both trials were presented in Florence. Dr. Ann Collier presented data from a small study of 37 adults who have received varying doses of AZT with ddI or AZT alone. The group consisted of asymptomatic persons with T4 counts below 400 and positive p24 antigen levels. None had received AZT for more than three months before the trial began. Dr. Collier found that T4 counts rose more impressively in people taking the combination therapy versus people taking AZT alone. However, after six months of treatment, T4 counts declined in both groups. There was some evidence that T4 counts stayed elevated longer in people on higher doses of AZT (600 mg/day as opposed to 300 mg or 150 mg combined with ddI). The two drugs were not antagonistic and caused little serious toxicity. While nine participants needed to reduce their doses, only one person withdrew altogether from the trial due to toxicity. combination AZT and ddI is also being given to children in a small trial at L.A. Children's Hospital. Many different dose levels are being tried. Nine children had been accrued by the time the abstract was published and the drugs had been well- tolerated for an average of six weeks. No efficacy data is yet available. CONCLUSION Current evidence strongly suggests that combination therapy may very well be the way of the future for antiviral therapy. larger human trials are needed to compare the many combination possibilities and to determine which options and dosings are the most effective. Trial designs will inevitably become more complicated. Such research raises the stakes for efficiency and smooth functioning of clinical trials. Treatment Issues looks forward to creative and effective designs from researchers with input from AIDS activists. ***** UPDATE ON VACCINE DEVELOPMENT Significant advances in vaccine development were reported by European and American researchers at the seventh International Conference on AIDS in Florence, Italy. Vaccine research over the past few years has focused on the prevention of HIV infection in animals and the testing of potential vaccines for safety and tolerance in HIV-infected humans. These approaches attempt to stimulate an immune response against the virus and retard progression of disease. Most vaccine experiments are first conducted in animal models, such as cats, rhesus monkeys, macaques and chimpanzees. Researchers hope that vaccines in animals will work similarly in the human body. BACKGROUND Vaccines are designed to stimulate the production of antibodies and cellular responses which protect against infection. Antibodies are substances produced by plasma cells (a type of white blood cell) whose function is to recognize certain proteins found on the surface of viruses or bacteria which have entered the body. Antibodies bind to these viral proteins and neutralize them. Such an action can be difficult to achieve with HIV because the original virus is able to change the proteins on its outer coat. Neutralizing antibodies, therefore, may not be enough to stop viral reproduction or the destruction of certain important immune cells. Therefore, another major challenge in HIV vaccines is to trigger a cellular response, or to activate white blood cells (i.e., T-cells, phagocytes, macrophages, and natural killer cells). These cells kill the virus and the ells infected with the virus. VACCINE APPROACHES An antibody and cellular response can be achieved in a variety of ways with the use of vaccines. Whole live virus and whole inactivated virus injected into the body may create such a response but also carry the risk of causing HIV infection. The safest vaccine is one produced by technology. A genetically engineered vaccine is referred to as recombinant. Only part of the virus is incorporated into the recombinant vaccine, called a subunit. Researchers have identified specific regions in the HIV virus which trigger an inhibiting immune response. One such region is the focus of a vaccine being tested in both animal and human experiments. It works as follows: A Specific HIV outer- coat protein, pg120, contains a specific region called the V3 loop. The V3 loop does not change and so provides a stable target against which to develop a vaccine. Antibodies directed at the V3 loop bind to HIV, neutralizing the virus, and prevent it from infecting target cells. Unfortunately, during natural infection, neutralizing antibodies alone do not protect the infected person from developing disease, since the structure of HIV is so complex. Other vaccine approaches consist of inserting pieces of the HIV outer envelope into another virus, such as vaccinia (the smallpox virus), in order to trigger an immune response. This type of vaccine is called a recombinant vector vaccine because the live vaccinia virus serves as a vector, or transport vehicle for the HIV protein. Finally, other researchers have used synthetic peptides (small pieces of an HIV-derived protein) to induce an immune response. ANIMAL EXPERIMENTS Several animal studies presented in Florence generated considerable controversy. For instance, the simian immunodeficiency virus (SIV) -- the long-considered monkey equivalent of HIV in humans -- was challenged as not being suitable for testing vaccines directed against the V3 loop. One American study found marked differences between HIV and SIV in the way each virus stimulates production of neutralizing antibodies. Additionally, most SIV experiments introduce the virus by an artificial means, such as an intravenous challenge (the virus is injected directly into the bloodstream). Protection against the virus which is acquired across mucous membranes (through the vagina or anus) has not been achieved in the SIV model. U.S. vaccine expert, Dr. Dani Bolognesi however, defended the SIV model, despite the differences noted above. Bolognesi contends that crude vaccines made from killed whole virus, or from killed infected cells have been successful in preventing infection of SIV in macaque monkeys. Another focus in florence was the use of monoclonal antibody vaccine, which is highly specific against the V3 loop. A monoclonal antibody is a protein manufactured in the laboratory which targets a single region in HIV. Protection against disease obtained by injecting monoclonal antibodies into an animal or human is referred to as passive immunization. The vaccine, developed by Merck, Sharp and Dohme Corporation, was found to block infection the same strain of HIV used to produce the monoclonal antibody. Three chimpanzee experiments using different types of monoclonal vaccines targeting the V3 loop achieved protective immunity in animals challenged with the virus. Another study reported that a recombinant gp 160 subunit vaccine, called rgp160, made by Immuno, Inc., protected a chimpanzee from HIV infection for two and a half years. Another chimp, injected with the same vaccine, has remained HIV-negative for three and a half years, the longest period of protection of any HIV vaccine to date. Based on the response of the first chimps studied, a similar vaccine was granted approval by the FDA in November, 1990, for phase I testing in human beings. These trials are currently underway at five AIDS Vaccine Evaluation Units (AVEU) in the United States. HUMAN EXPERIMENTS The results of some early safety trials in humans with various recombinant vaccines were presented in Florence. There is much hope that these trials will pave the way for large-scale efficacy trials within the next three years. A study from Vanderbilt University reported on a phase I trial using two recombinant vaccines in ten uninfected volunteers. The first vaccine was genetically engineered and was produced by inserting the gp160 gene into a vaccinia virus. It was produced by Bristol-Myers Squibb. A booster vaccine, consisting of a subunit of purified gp160 (VaxSyn), made by MicroGene Sys Inc., was then given to the same ten volunteers 11 to 27 months after the initial vaccinia-derived vaccine was administered. After they received the booster, the vaccinated volunteers developed immune responses, including neutralizing antibodies, determined to be strong enough to protect them against HIV infection. Another researcher who has used the vaccinia virus vaccine in humans is Dr. Daniel Zagury of the Pierre and Marie Curie University in France. He was ordered by his government, however, to stop testing the vaccine after three AIDS patients receiving the vaccine on a compassionate basis, died. Their deaths were due to improper inactivation of the vaccinia virus. In Florence, Dr. Zagury also presented data on a new vaccine therapy which may have restored immune function in six other AIDS patients. This vaccine -- a combination of alpha-interferon, HIV proteins, and an inactivated HIV pseudo-virus -- has been referred to as a vaccine "cocktail." Zagury reported marked clinical improvement in the six AIDS patients treated with the vaccine cocktail, including increases in T4 cell counts to near normal values. A press release from the conference news office was highly critical of the presentation, and called Zagury an "enfant terrible" and his vaccine cocktail, "the dubious concoction of a witch." GP 160 VACCINE (VAXSYN) A more rigorous and widely-publicized vaccine trial was reported in the New England Journal of Medicine just a week before the conference. The trial tested recombinant gp160 (VaxSyn), produced by genetic engineering by MicroGeneSys, Inc. in Connecticut. The trial was conducted at the Walter Reed Army Institute of Research, Rockville, Maryland. Thirty HIV positive volunteers who had asymptomatic infection and T4 cell counts over 400 were injected with the vaccine, given either as three or six injections over 4-6 months. In 19 of the 30 participants (63%) both antibody and cellular immunity to HIV proteins increased in response to the vaccine. After ten months of follow-up, the mean T4 cell counts had not decreased in the 19 subjects who responded to the vaccine. Counts decreased by 7.3% in the 11 patients who did not respond. The best responses in the trial were seen in those subjects who received six injections and those who had over 600 T4 upon entry of the trial. There was no increase in HIV replication or viral activity in any of the subjects as a consequence of vaccination. This study, though very promising, must be interpreted cautiously since it is still unclear whether T cell responses to gp160 and neutralizing antibodies will translate into clinical benefits for patients with HIV. A larger placebo-controlled phase II trial involving 140 subjects is fully enrolled at the Walter Reed Research Center. The first analysis of the data should be available in early 1992. CONCLUSION Significant progress has been made in the design and testing of vaccines that have the potential for protecting both HIV- uninfected and HIV-infected persons. Because of he large variability in HIV strains and because of the ability of the virus to mutate, vaccines directed at conserved regions, such as the V3 loop, have the greatest potential for success. The potential for vaccines to serve as immunotherapies in persons already infected seems to be real. The years to come await much larger efficacy trials to determine if the preliminary results of phase I trials will be reproduced in large populations of persons at risk for HIV or with asymptomatic infection. The World Health Organization and the vaccine researchers will be convening to decide on the specific populations to have used in the large vaccine trials. Unfortunately, the potential for significant benefit from a vaccine in persons with advanced diseases is very low. ***** ddI Recommended for Approval by David Barr In July, ddI was recommended for approval by the FDA's AntiViral Advisory Committee for symptomatic HIV-infected individuals who are resistant or intolerant to AZT. The recommendation for approval was based solely on data that shows that ddI is effective in raising T4 cell counts of individuals who are already taking AZT. It is unknown what effect, if any ddI c infections or death. Bristol-Myers Squibb, maker of the drug, has made ddI available to patients through an expanded access program developed by the company, the FDA, and AIDS activists. Through this program, the drug has reached over 20,000 people during the past two years. FDA approval will make ddI available to many more people who might benefit from it and will allow doctors to prescribe the drug in combination with AZT. There is, however, no conclusive evidence so far showing that AZT in combination with ddI is better than either drug alone. The most prevalent side effects of ddI are pancreatitis, peripheral neuropathy and gastrointestinal (GI) problems. The GI difficulties are most probably related to the buffer used and should be resolved when Bristol releases the new formulation of the drug. This is the first time that an AIDS treatment for approval based solely on the improvement of T4 counts. Most of the data presented to the committee were from phase I trials and from the expanded access program. Therefore, the amount of data was not sufficient to reach a standard worthy of drug approval. However, supplementary data were presented from an interim analysis of ACTG trial #117, a phase Ii study comparing ddI with AZT in patients on long-term AZT. These data showed a higher sustained T4 cell rise in ddI patients as compared to patients taking AZT, and proved instrumental to the committee's decision. The continuing ACTG ddI trials will eventually offer a better picture about the drug's effectiveness and clinical outcomes. Participants in the committee meeting were uncomfortable with the small amount of useful data presented. However, the importance of ddI's approval was apparent to those involved. While we would all like more and better data to help in making our treatment decisions, the reality is that patients and physicians have had to use insufficient data to make every single treatment decision since the first day of the epidemic. Unfortunately, we do not have time to wait until better data are available. The drugs that look most promising must be made available as soon as possible in order to provide patients and doctors with choices. At the same time, we must ensure that researchers continue to collect solid data, in ways which meet both the immediate and future needs of people with AIDS. The development of ddI should be seen as the model for all AIDS drugs in the future. Expanded access programs, the use of surrogate markers for approval and an expeditious approval process must be the status quo in developing treatments for life- threatening illnesses. Further, community involvement is important at every step to facilitate a drug development process that best meets the needs of patients. Some aspects of the approval process for ddI went well, and others did not. We must learn from our mistakes and move on. FDA should approve ddI soon. There is still no word on the price of the drug. ***** Pregnancy and HIV As of March, 1991, 18,181 women have been diagnosed with AIDS in the United States. Women are the population currently being diagnosed at the fastest rate, even though the Center for Disease Control (CDC) definition for AIDS by many accounts does not adequately reflect the way the disease manifests itself in women. One study found that 65% of HIV-positive women die without fitting the official government definition for AIDS. Because of this incomplete definition, the umber of women with AIDS is underrepresented. Estimating HIV seroprevalence in women is further complicated by the lack of research, attention, and understanding about how HIV illness progresses in women. Where women's health is concerned, there is often an intense focus on the well-being of the fetus or the potential fetus. This is also true where health care for HIV is concerned. the potential for pregnancy in all women of childbearing age has been the foremost reason given for withholding experimental drugs, as well as for coercive and directive counselling regarding contraception, abortion, and sterilization. In 1985, the CDC published recommendations which, in effect, advised clinicians to discourage HIV-positive women from carrying pregnancies, as a means of avoiding transmission to their infants. These recommendations were endorsed by the American College of Obstetrics and Gynecologists (ACOG). But many women with HIV, 73% of whom are women of color, their community leaders, and feminist AIDS activists view these recommendations as an infringement on reproductive rights. While HIV serostatus is considered an important factor in the informed decision of an HIV- infected woman to carry a pregnancy to term or not, the decision must ultimately remain hers. One study found no difference in the frequency of voluntary abortions in methadone clinics between women who were HIV-positive and women who were HIV- negative. This indicates that other factors, not accounted for by the CDC and ACOG, are involved in a woman's decision regarding her pregnancy. STUDIES SHOW . . . OR DO THEY? In the U.S., perinatal transmission accounts for over 80% of all cases of pediatric AIDS. Despite the fact that the epidemiology for women and HIV infected is skewed, we have a fairly precise figure for the number of HIV-positive babies born each year. It has been estimated that every year approximately 5,000 women give birth to HIV-positive infants. Early studies indicated that 40%-60% of infants born to HIV-positive women became infected with HIV. But more recent studies, with longer follow-up periods, suggest that transmission rates from HIV- infected mother to child range from 25%-40%. And one of the most recent European studies indicates that the rate of transmission may be as low as 13%. While the exact transmission rate is hard to predict based on different populations studied, many professionals in the U.S. commonly accept that 30% of children born to HIV-positive mothers may be infected. At 12-18 months after birth, infants lose their maternal antibodies, and, if actually infected with the virus, start to make their own. Many officials have suggested antibody testing of all newborns, a procedure which indicates only the serostatus of the mother, an may conflict directly with her right to confidentiality. Notably, studies do not suggest that HIV disease is accelerated by pregnancy in women who are asymptomatic. Some of the early studies indicated an adverse impact of pregnancy on the course of disease; however, preliminary data from more recent studies indicate that if there is an adverse effect it is uncommon. Women do have lower T4 cell counts during pregnancy and in HIV- positive women these lowered counts may be more sever and may persist after pregnancy. However, this depletion of T4 cells due to pregnancy has not been correlated with disease progression. Ideally, care for the HIV-positive pregnant woman should be provided in the same setting where the woman goes for general primary care. However, if a women is a patient in an obstetrical clinic, consultation with a primary care provider experienced in HIV infection must be readily available. Medical care for the child should be arranged in a way that considers the mother's needs as well. A well coordinated, team-approach to care is often needed. Drug detoxification and treatment is difficult to procure for pregnant women. Nevertheless, it is essential for women actively using alcohol, crack, heroine, speed, or cocaine. the use of prescription and street drugs, alcohol, and tobacco are all known to affect the outcome of pregnancy for both mother and baby. It is important to note that pregnant women are at risk for the same opportunistic infections (Ois) as other people with HIV, and should be treated accordingly. Respiratory infections during pregnancy should be identified early and treated aggressively. The medical literature reports incidents of pregnant women dying of PCP and high rates of bacterial pneumonia, asthma, and bronchitis. Tuberculosis (TB) should be ruled out by aggressive screening with skin tests, chest x-rays (using appropriate shields), and sputum analysis. For women with active TB, medication regimens against his infection must be continued during pregnancy, with careful monitoring of liver function tests. SCREENING More rigorous screening for sexually transmitted diseases (STDs) in HIV-positive women is recommended. STDs have increased dramatically in the past decade and alone account for a significant number of complications and deaths in pregnant women. One study conducted at prenatal clinics found a 10% rate of syphilis in HIV- infected female patients versus a 4% rate in all female patients visiting the clinic. Routine prenatal screening for pneumonia, TB, hepatitis, CMV, toxoplasmosis and herpes simplex virus (HSV) is recommended. To avoid transmission of HSV, which is particularly damaging to newborns, a Caesarian section (surgical removal of the fetus) may be necessary if active lesions are present in the cervix or vagina. It is notable, though, that while Caesarian sections may assist in the avoidance of transmission of herpes from mother to infant, there have been no data to suggest that the procedure avoids HIV transmission. THERAPIES The CDC has provided little guidance regarding the use of antivirals and prophylaxis for Ois in pregnant women. One CDC guide stated that the use of aerosolized pentamidine (AP) is "inadvisable" for treatment of PCP in pregnancy, but AP results in little systemic absorption, making it a good potential regimen in pregnancy. Bactrim (Septra), another treatment for PCP, may cause some problems in the third trimester, such as jaundice in newborns. Prophylaxis for PCP must be initiated when T4 counts drop to 200 in all patients, including pregnant women. No findings have been reported regarding the use of acyclovir for herpes simplex virus during pregnancy, but its use in the gird trimester calls for further investigation. Urinary tract infections and vaginitis should be treated with full 7-14 day antibiotic regimens during pregnancy, and not with abbreviate antibiotic therapy. Vaginal thrush may be especially troublesome during pregnancy in women who are HIV-positive. Such a condition may require continuous suppression with Nystatin vaginal suppositories daily or every other day. Oral antifungals such as ketaconazole or fluconazole must be considered in the second or third trimester of pregnancy if the infection is refractory. AZT therapy has been studied for safety in HIV-positive pregnant women in a federally-funded trial, which enrolled 20 participants. Outside of trials, 41 other pregnant women have been observed. Experience with the drug in human pregnancies is very limited. In animal models it is worth noting that, according to Burroughs Wellcome studies reported in 1989, a significant incidence of vaginal cancers in female rats and mice treated with high-dose AZT was observed. However, preliminary analysis of the data on AZT in pregnant women suggests that AZT is safe in this population, as long as frequent blood monitoring and dose reduction or drug withdrawal is provided. Of the 61 HIV-positive pregnant women who took AZT, two had babies born with extra digits. No other abnormalities in maternal or fetal health were noted on AZT, with the possible exception of increased risk for anemia. Many clinicians withdraw AZT therapy during the first trimester in the HIV-positive patient because the concern for fetal harm is concerned greater early in pregnancy. The pregnant woman then often starts taking AZT again in the second or third trimester when the antiviral benefits to her may outweigh harm to the fetus. A study to evaluate the safety and efficacy of AZT as a means of preventing vertical transmission (from mother to fetus) in pregnant mice was recently reported in The Journal of Infectious Diseases. Evidence exists that AZT is nontoxic for mice during mid-gestation pregnancy, but this study was designed to determine the effectiveness of chronic use of AZT before and during gestation. The resulting data indicate that AZT had a direct toxic effect on the developing mouse embryo, and led to considerable pregnancy failure. The data indicate that early pregnancy failure, rather than fetal malformation, is the primary result from AZT exposure during gestation. The prepartum effects of AZT were recently studies in 15 pregnant women. Six of the participants conceived while taking AZT, and four of these six elected to terminate the pregnancy within the first trimester. The other nine patients began taking AZT during the second or third trimester of pregnancy because T4 counts dropped to below 500. These patients gave birth to live, full-term infants, after an average of almost 13 weeks of AZT exposure. The infants had normal birth weights, and no abnormalities were observed. During the eight months of follow- up two of the nine infants have developed clinical symptoms of HIV infection, including lymphadenopathy, oral thrush, and failure to thrive. The AIDS Clinical Trial Group (ACTG) is planning a phase II, randomized, placebo-controlled trial to evaluate the efficacy, safety and tolerance of AZT in pregnant HIV-infected women and their infants. The trial, called 076, plans to enroll 748 HIV- positive women in the second or third trimester of pregnancy with T4 counts between 200-500. The trial is primarily designed to see if AZT can prevent transmission of HIV from mother to child. Much controversy has been raised over the ethics of this trial. Since most animal models indicate that AZT does not stop transmission of the virus from mother to fetus, many feel that the purpose of the study is misguided. The informed consent, a paper which explains the pros and cons of the study, does not include some of the negative effects of AZT on female rats and mice. Others think that the data from the 61 pregnant HIV- positive women who have been on AZT, ought to be further evaluated before the start of this trial. Additionally, the study results of 076 will not be available until 1995, at which time other antivirals, such as ddC or ddI may be more widely used. Neither NIAID nor Burroughs Wellcome is paying for any of the long-term medical care that may be required due to the effects of the trial. Lastly, many activists feel that since no studies have been designed specifically to observe HIV in women, more complete studies might make better use of research money. CONCLUSION It is important to note that this article reflects the artificial nature of isolating pregnancy as a single issue, or as the only issue concerning women and HIV. It is difficult and often misleading to do so. More research is desperately needed to understand HIV in women, and such research will also shed more light on HIV in all aspects of women's health and lives, including pregnancy. ***** IN BRIEF IMUTHIOL PULLED FROM TRIALS In a shocking move, the French drug company Institute Merieux has summarily halted trials of their experimental drug Imuthiol. According to Dr. Jean Caraux, a Merieux representative, preliminary analysis of a large French trial underway since 1987 has raised serious questions about Imuthiol's efficacy. The double-blind, placebo-controlled trial enrolled 1,550 mostly asymptomatic patients. The mean T4 count of participants was 450. Patients who progressed were offered AZT. Merieux claims that no benefit was seen for participants receiving drug, and, indeed, those on Imuthiol may have progressed faster than patients taking placebo. Dr. Caraux did emphasize that more analyses of data would be performed and that these were preliminary data. But, the company did pull the drug from all ongoing trials, and seems to posture that Imuthiol has no future as a treatment for HIV. The PWA Health Group, an underground buyers' club, has reported that sales are brisk as people are trying to stock up on the drug. Merieux stated they will encourage regulatory authorities in New Zealand, the only country where the drug has been approved for AIDS, to stop selling the drug for that indication. However, Merieux cannot force the drug off the market. If authorities in New Zealand decide to discontinue Imuthiol, the underground in other countries will have to find another source for the drug. Treatment Issues will report any further developments as they occur. &&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&&& End of display