Inclusion of women in clinical trials of antiretroviral agents for HIV/AIDS during pregnancy
Authors: Julie E Mangino, Robert J Fass
Journal: The Lancet (1997)

In the past, women of child-bearing age were excluded from clinical trials of new drugs for fear of pregnancy and subsequent fetal damage. Inclusion of women in such trials is now regarded as essential for the promotion of women's health; doctrine is to avoid pregnancy, with withdrawal should it occur. Between 1990 and 1994, an NIAID-sponsored trial, ACTG 076, was targeted at antiretroviral naive, HIV-infected pregnant women. Zidovudine or placebo was given during the later trimesters and intrapartum, and to infants post-partum. Transmission rates were 8·3% and 25·5%, respectively—a 67·5% risk reduction with zidovudine.1Connor EM Sperling RS Gelber RG et al.Reduction of maternal-infant transmission of HIV with zidovudine treatment.N Engl J Med. 1994; 331: 1173-1180Crossref PubMed Scopus (3404) Google Scholar Reported cases of perinatally acquired AIDS in the USA have subsequently declined strikingly since the peak in 1992,2AIDS among children—United StatesMMWR Morb Mortal Wkly Rep. 1996; 45: 1005-1010PubMed Google Scholar despite an increasing incidence of HIV infection among women of child-bearing age. On Jan 14, 1997, an NIH panel reaffirmed the USPHS recommendation to treat HIV-infected pregnant women with zidovudine. Currently, this drug, which lowers viral load two-fold to ten-fold in antiretroviral naive patients, is regarded as suboptimum treatment compared with combinations of newer agents which lower viral load by 100-fold to 1000-fold, often to undetectable levels, with appreciable clinical benefit.3Carpenter CC Fischl MA Hammer SM et al.Antiretroviral therapy for HIV infection in 1996.JAMA. 1996; 276: 146-154Crossref PubMed Google Scholar A recent analysis of the ACTG 076 data revealed the transmission rates were lower among mothers with a lower viral load.4Sperling RS Shapiro DE Coombs RW et al.Maternal viral load, zidovudine treatment, and the risk of transmission of human immunodeficiency virus type 1 from mother to infant.N Engl J Med. 1996; 335: 1621-1629Crossref PubMed Scopus (707) Google Scholar We can only hope that more potent regimens will further reduce perinatal transmission rates without adverse effects on the fetus. The Antiretroviral Pregnancy Registry5A collaborative project managed by:Bristol-Myers Squibb Co, Glaxo Wellcome, Hoffman-La Roche Inc, and Merck and Co, Inc. Antiretroviral pregnancy registry for didanosine, indinavir, lamivudine, saquinavir, stavudine, zalcitabine, and zidovudine. Interim report—Jan 1, 1989, to Dec 31, 1996.Google Scholar was initiated in 1989 to provide an early signal of teratogenicity associated with prenatal use of antiretroviral agents. Initially for zidovudine, it has been expanded to include voluntarily reported outcomes of pregnancies among patients receiving zalcitabine, didanosine, stavudine, lamivudine, saquinavir, and most recently indinavir. So far, there has been no increase in the number of birth defects among the prospective reports of first-trimester zidovudine exposures when compared with that expected in the general population. Zidovudine use in any trimester led to a risk of 3·8% birth defects with no uniqueness of pattern to suggest a common cause. Although data for other drugs are limited, there have been no birth defects reported from exposure to them, either alone or in combinations, among prospectively reported pregnancies. Although insufficient data exist to conclude that antiretroviral drugs are not teratogenic,5A collaborative project managed by:Bristol-Myers Squibb Co, Glaxo Wellcome, Hoffman-La Roche Inc, and Merck and Co, Inc. Antiretroviral pregnancy registry for didanosine, indinavir, lamivudine, saquinavir, stavudine, zalcitabine, and zidovudine. Interim report—Jan 1, 1989, to Dec 31, 1996.Google Scholar we believe that the benefit/risk ratio favours allowing HIV-infected pregnant women enrolled in clinical trials with potent antiretrovirals to continue participation, if they choose to do so. Those who were withdrawn would probably seek treatment with the same or similar agents, without the advantages of careful observation and the accumulation of important information. Supported in part by NIAID Grant No. A125924.