AIDS INFORMATION NEWSLETTER Michael Howe, MSLS, Editor AIDS Information Center VA Medical Center, San Francisco (415) 221-4810 ext 3305 November 18, 1994 Women and HIV Infection (Part XIII) Zidovudine for the Prevention of HIV Transmission from Mother to Infant Worldwide, perinatal (i.e., mother to infant) transmission accounts for most human immunodeficiency virus (HIV) infections among children; in the United States, of the approximately 7000 infants born to HIV-infected mothers each year, 1000-2000 are HIV-infected (1). Strategies for reducing perinatally acquired HIV infection have included preventing HIV infection among women and, for HIV-infected women, avoiding pregnancy or refraining from breastfeeding their infants (2). On February 21, 1994, the National Institutes of Health's National Institute of Allergy and Infectious Diseases (NIAID) and National Institute of Child Health and Human Development (NICHD) announced preliminary results from a randomized, multicenter, double-blinded clinical trial of zidovudine (ZDV) to prevent HIV transmission from mothers to their infants (AIDS Clinical Trials Group [ACTG] protocol 076). This report summarizes the interim results of that trial, which indicate effectiveness of ZDV for prevention of perinatal transmission. The study was initiated in April 1991 by the Pediatric ACTG of NIAID in collaboration with NICHD and the National Institute of Health and Medical Research (INSERM) and the National Agency of Research on AIDS (ANRS), France. Eligible participants were HIV-infected pregnant women who had received no antiretroviral treatment during their current pregnancy, had no clinical indications for maternal antepartum antiretroviral therapy in the judgment of their health-care provider, and who had a CD4+ T-lymphocyte count greater than 200/uL at time of entry into the study. Enrolled women were randomized to receive either a ZDV or placebo regimen. The ZDV regimen included antepartum ZDV (100 mg given orally five times daily) initiated at 14-34 weeks' gestation and continued for the remainder of the pregnancy; intravenous ZDV during labor (administered intravenously as a loading dose of 2 mg per kg body weight given over 1 hour, followed by continuous infusion of 1 mg per kg body weight per hour until delivery); and oral administration of ZDV to the newborn (ZDV syrup at 2 mg per kg body weight per dose given every 6 hours) for the first 6 weeks of life, beginning 8-12 hours after birth (see box). The placebo regimen was given on the same schedule. Blood specimens were obtained for HIV culture from all infants at birth and at ages 12, 24, and 78 weeks. A positive viral culture was considered indicative of HIV infection. Infants also were tested for HIV antibody at ages 15 and 18 months. ---------------------------------------------------------------- Eligibility Criteria and Zidovudine Regimen for HIV-Infected Pregnant Women and Their Infants Participating in AIDS Clinical Trials Group Protocol 076 Patient Eligibility: * Has not received antiretroviral treatment during current pregnancy * Has no clinical indications for maternal antepartum antiretroviral therapy in the judgment of her health-care provider * Has a CD4+ T-lymphocyte count greater than 200/uL at initial assessment Zidovudine Regimen: * Oral administration of 100 mg zidovudine (ZDV) five times daily, initiated at 14-34 weeks' gestation and continued for the remainder of the pregnancy * During labor, intravenous administration of ZDV in a loading dose of 2 mg per kg body weight given over 1 hour, followed by continuous infusion of 1 mg per kg body weight per hour until delivery * Oral administration of ZDV to the newborn (ZDV syrup at 2 mg per kg body weight per dose given every 6 hours) for the first 6 weeks of life, beginning 8-12 hours after birth ---------------------------------------------------------------- Based on analysis of data for 364 births through December 1993, ZDV therapy was associated with a 67.5% reduction in the risk for HIV transmission; the estimated rates of transmission were 25.5% (95% confidence interval [CI]=18.3%-33.7%) among the 184 children in the group receiving the placebo regimen compared with 8.3% (95% CI=3.8%-13.8%) among the 180 children in the group receiving ZDV (Kaplan-Meier estimate at age 18 months; p=0.00006). Although the ZDV regimen was well tolerated by mothers and infants, hemoglobin levels were lower for infants in the ZDV group (mean decrease in hemoglobin was less than 1 g/dL); however, this problem resolved without therapy following completion of ZDV treatment. The incidence of reported side effects was similar among mothers and infants between the two randomized groups. Based on these interim findings, NIAID accepted the recommendation of an independent data and safety monitoring board to terminate enrollment into the trial and to offer ZDV to women in the group who had received the placebo but had not yet delivered and to their infants aged less than 6 weeks. An NIAID Clinical Trials Alert summarizing the trial is available by calling (800) 874-2572. REPORTED BY: Div of AIDS, National Institute of Allergy and Infectious Diseases; Center for Research for Mothers and Children, National Institute of Child Health and Human Development; National Institutes of Health. EDITORIAL NOTE: This clinical trial demonstrated efficacy of ZDV in reducing perinatal HIV transmission when administered to HIV-infected women meeting the study's eligibility criteria (see box). However, these findings are subject to at least four limitations. First, the study did not assess the efficacy of ZDV among women with CD4+ T-lymphocyte counts less than or equal to 200 cells/uL or among women who had previously used ZDV for extended periods and who may be infected with ZDV-resistant strains of HIV. Second, this trial could not assess the relative or independent contributions of the antepartum treatment, intrapartum treatment, or treatment of the infant; therefore, the efficacy and side effects of ZDV regimens restricted to only one or two of these treatment periods is unknown. Third, the study did not evaluate the risk or benefit of ZDV use in the first trimester. Finally, the study has not yet provided information about long-term side effects for infants and mothers treated with ZDV, including infants who did not become infected with HIV; however, long-term follow-up of infants and mothers is being conducted to monitor for possible late side effects. Based on the findings of ACTG protocol 076, the Public Health Service (PHS) provides the following interim recommendations*: 1) all health-care workers providing care to pregnant women and women of childbearing age should be informed of the results of ACTG protocol 076; 2) HIV-infected pregnant women meeting the protocol eligibility criteria should be informed of the potential benefits but unknown long-term risks of ZDV therapy as administered in ACTG protocol 076, and decisions to use ZDV for prevention of perinatal transmission should be made in consultation with their health-care providers (see box); 3) health-care providers should inform their patients that this ZDV regimen substantially reduced, but did not eliminate, the risk for HIV infection among the infants; and 4) until the potential risk for teratogenicity and other complications from ZDV therapy given in the first trimester can be assessed, ZDV therapy only for the purpose of reducing the risk for perinatal transmission should not be instituted earlier than the 14th week of gestation. PHS is developing further recommendations for the uses of ZDV for HIV-infected pregnant women whose clinical indications differ from the ACTG protocol 076 eligibility criteria and for counseling and HIV-antibody testing for women of childbearing age. The international Antiretroviral Pregnancy Registry, sponsored by Burroughs Wellcome Co. (Research Triangle Park, North Carolina)** and Hoffmann-LaRoche Foundation, Inc. (Nutley, New Jersey)**, is collecting observational, nonexperimental data on exposure to ZDV and dideoxycytidine (ddC) during pregnancy. Women who have been treated with either of these drugs at any time during pregnancy for any duration are eligible for registry enrollment. Patients can be enrolled by contacting the registry, telephone (800) 722-9292, extension 8465; fax (919) 315-8981. REFERENCES 1. CDC. National HIV serosurveillance summary: results through 1991. Vol 3. Atlanta: US Department of Health and Human Services, Public Health Service, 1994. 2. CDC. Recommendations for assisting in the prevention of perinatal transmission of human T-lymphotropic virus type III/lymphadenopathy-associated virus and acquired immunodeficiency syndrome. MMWR 1985;34:721-6,731-2. * These recommendations do not reflect current Food and Drug Administration-approved labeling for ZDV. ** Use of trade names and commercial sources is for identification only and does not imply endorsement by the Public Health Service or the U.S. Department of Health and Human Services. (Centers for Disease Control and Prevention. Morbidity and Mortality Weekly Report. 1994;43(16):285-87.) Task Force to Study Implications of AZT in Pregnancy The U.S. Public Health Service has established a task force to explore the medical and policy implications of the recently announced findings of a National Institutes of Health clinical trial that tested the effectiveness of AZT in preventing transmission of the human immunodeficiency virus (HIV) from pregnant women to their babies. Preliminary findings from randomized, blind clinical trials showed a 67.5 percent effectiveness rate in blocking HIV transmission to newborn infants through the use of AZT, with little apparent adverse effect on the women or on the progression of their disease. Perinatal transmission is responsible for the majority of HIV infections in children in the United States and throughout the world. "The challenge of the task force will be to develop a rational approach in translating the results of this clinical trial into appropriate policy and practices," said Dr. Philip R. Lee, HHS assistant secretary for health and director of the U.S. Public Health Service. "Under the leadership of the National Institutes of Health, the efforts of the task force will address critical questions regarding treatment, testing, monitoring and resource needs, which are raised as a result of this study. The task force has begun moving expeditiously because of the urgency of these issues for the community and for the health care providers." The task force members are: Chairwoman Lynne Mofenson, M.D., associate chief of the pediatric, adolescent and maternal AIDS branch, Center for Research for Mothers and Children, National Institute of Child Health and Human Development, NIH. James Balsley, M.D., Ph.D., chief of the pediatric medicine branch of the Division of AIDS, National Institute of Allergy and Infectious Diseases, NIH. Martha Rogers, M.D., chief of the epidemiology branch of the Division of AIDS, Centers for Disease Control and Prevention. Helene D. Gayle, M.D., Ph.D., chief of the HIV/AIDS division, CDC. David Feigal, M.D., director of the anti-viral drug product division, Food and Drug Administration. Patricia S. Fleming, special assistant to the secretary, HHS. Frances Page, RN, MN, public health adviser, Office of National AIDS Policy. Patricia Salomon, M.D., associate director for clinical affairs, Bureau of Primary Health Care, Health Resources and Services Administration. David Lanier, M.D., health policy analyst, Agency for Health Care Policy and Research. The task force will also make use of outside experts, including academic researchers, clinicians, HIV-infected women, representatives of professional societies, state and local public health officials and ethicists. (Press Release. Public Health Service. National Institutes of Health. May 10, 1994.) Ethical Challenges Posed by Zidovudine Treatment to Reduce Vertical Transmission of HIV Despite the prospect of great benefits from the study showing that the use of zidovudine (AZT) can help reduce maternal-infant transmission of HIV, many ethical questions remain unanswered. The most important issue is whether AZT will put at risk the 70 to 80 percent of children who, though born to infected women, would not have been infected themselves. Many clinicians argue that the case for testing pregnant women for HIV is now stronger than ever, but many AIDS and women's rights advocates are skeptical about the claims on behalf of AZT treatment during pregnancy. The underlying fear is that the new findings would be used to undermine the privacy rights of pregnant women at risk for HIV--the majority of whom are poor, black, or Hispanic women. Mandatory screening of children could be justifiable if therapeutic interventions could significantly extend the lives of infected children because treatment would be necessary, despite parental objections. Mandatory screening of pregnant women, however, is problematic because mandatory treatment of competent adults is rarely acceptable. Also, no recommendation for HIV testing would be ethical if access to the necessary therapy and counseling were not guaranteed. The daily five-dose AZT regimen would be too difficult and too expensive to enforce. (Bayer R. New England Journal of Medicine. 1994 Nov 3;331(18):1223.) Mother and Child and AZT by Elizabeth B. Cooper In February 1994, a federal Data Safety and Monitoring Committee announced that, based on preliminary data, it would halt enrollment in clinical trial ACTG 076, a study designed to examine whether mother-to-child (vertical) transmission of HIV could be reduced if the mother and newborn were given AZT. To the surprise of many observers, initial data projections indicated that there was a 67 percent reduction in maternal HIV transmission among trial participants given AZT. ACTG 076 was a double-blind, placebo-controlled trial in which women were given AZT or a placebo beginning in the second or third trimester and intravenously during labor, with infants receiving AZT syrup for the first six weeks of life. The women enrolled had CD4 counts above 200, no other need for AZT treatment, and no prior experience with the drug. Additional preliminary investigation indicated similarly low levels of birth defects and mortality in the newborns given AZT and those given the placebo. It is not yet possible to know the long-term effects of AZT on children (e.g., with regard to growths, cancers, or other medical complications) or mother (e.g., with regard to AZT resistance). ACTG 076 was begun under the cloud of significant community concern that adequate protections for the women enrolled were not established and that the trial was not well-designed. For example, it was only after much community agitation that researchers recently agreed to examine the long-term impact of AZT use during pregnancy among women; initially, follow-up studies were to focus solely on the newborns. While the results of this trial bring hope to HIV-positive women who wish to bear children, they spark a host of questions as well. Many have raised concerns about the lessons to be gleaned from this study. Because the trial involved women in good health with CD4 counts averaging above 500, it is not known whether the protocol will be effective for women with more advanced HIV disease, previous use of AZT, or AZT-resistant virus. The protocol involved the intake of AZT at three different points: gestation, delivery, and after birth. Yet we remain unsure of the point at which AZT was most effective in helping to reduce transmission. It is likely that the significantly reduced transmission rates experienced in the controlled environment of the ACTG 076 trial may not be achieved in the "real world" of limited access to health care. The Public Health Service has issued guidelines on the counseling of HIV-positive women on the use of AZT during pregnancy yet many are concerned that health care workers may attempt to coerce women into taking AZT. In addition, as a result of ACTG 076, calls for the mandatory HIV-antibody testing of pregnant women and newborns have increased. Legislation to this effect has been introduced, but thus far tabled or defeated, in New York, Michigan, Pennsylvania, Florida and the U.S. Congress. Because the women primarily affected by this issue are likely to be low-income women of color, the political landscape of the study and its ramifications must be examined. While it is important that women have the option of learning their serostatus during pregnancy and delivery (if not before), we must carefully consider the methods by which this option is presented. First, many more women may already know their status than health care providers are aware; others may choose not to know of their status. The reasons for ignorance of HIV status and non- disclosure are ongoing: fears of breaches of confidentiality, a perception of insufficient access to care and services for those who test positive, and continuing discrimination against people (and families) with HIV. As we have seen throughout the epidemic, mandatory testing programs consistently frighten people away from services. For example, when New York City required newborns to be screened for drug metabolites there was a significant increase in the number of babies not taken home from the hospital; many women either feared prosecution or assumed that their children would be taken from them regardless. Furthermore, legal experts conclude that such a mandatory testing program--whether focusing on pregnant women, women who have just delivered, or newborns--would likely be found to violate many of a woman's constitutional and statutory rights, including her right to privacy (with regard to consent to testing as well as privacy of personal medical information), equal protection, informed consent, and the right to make medical decisions on behalf of her children. It would be highly unethical--and illegal--to force a woman to take AZT without her full voluntary and informed consent. Absent extraordinary circumstances, not present in this context, a woman cannot legally be forced to accept medical intervention she does not wish to have. In addition, she must be counseled with regard to the possible risks and benefits of this potentially toxic treatment. It would be inappropriate to yield to the expectations of some that every HIV-infected pregnant women should take AZT regardless of her own treatment decisions. Early identification of HIV infection is important, but it is not enough. We must shift the focus of the debate to the need for accessible, comprehensive health care. What has worked--quite effectively--is access to HIV-related counseling that provides links to confidential pre-natal care and well-baby services. A woman's consent for HIV testing and treatment decisions is dependent on this education and counseling, which must be universally incorporated into pre-natal and pre-pregnancy care. Although it is useful for a woman to learn her serostatus following delivery, learning it before she becomes pregnant or during pregnancy will give her a wider range of prevention, treatment and reproductive options. As important, decent quality of care should not be tied to a woman's decision to be tested or not tested. In reality, neither mandatory testing nor "mandatory treatment" will accomplish what their adherents claim: access to care for the child or mother. Rather, such programs are likely to drive a wedge between the woman and health care provider, undermining this critical relationship and, in turn, undermining the care that must be provided. If we devote our attention solely to the child--at the expense of providing care to both mother and child--a woman's role as the critical component of her baby's health is reduced to that of carrier and deliverer. By building policy on the assumption that a pregnant woman, including an HIV-positive pregnant women, is interested in giving birth to a health baby, we foster, rather than undermine, the essential parent-child loving bond and the critical provider- patient trust relationship. Notably, this conclusion also has been reached by divisions of the American Medical Association, the American Academy of Pediatrics, the American Public Health Association, the National Academy of Science/Institute of Medicine, and the American College of Obstetricians and Gynecologists (NY). This more comprehensive approach both respects the individual and protects the public health--thereby benefitting both mother and child--which, indeed, is our goal. Editor's Note The article above is reprinted from The Active Voice (Autumn 1994, pp. 1,5), a publication of The National Association of People with AIDS Public Policy and Education Department (NAPWA, 1413 K Street, N.W., Washington DC 20005. Phone: 202-898-0414 or fax: 202- 898-0435). Information contained in this publication is for educational purposes only and does not constitute an endorsement. Permission to duplicate is granted and encouraged; please acknowledge the source. The author of the article, Elizabeth B. Cooper, is a clinical instructor at the Brooklyn School of Law in New York City and Co- Chair of the New York Task Force on Women and AIDS.