AIDS Clinical Trials Group Protocol Research Articles

Pharmacokinetics of zidovudine in infants: a population analysis across studies.

Although the use of zidovudine in newborns and infants has become standard therapy for prophylaxis and therapy of human immunodeficiency virus infection, the developmental pharmacology of zidovudine in the first months of life has not been fully described. We used population analysis to estimate zidovudine pharmacokinetic parameters in newborns and infants who either participated in one of five Pediatric AIDS Clinical Trials Group (PACTG) protocols or were premature infants who had zidovudine concentrations drawn for therapeutic drug monitoring. The data set consisted of 698 serum samples from 83 infants with a mean gestational age at birth of 37.5 weeks (range, 26.0 to 41.5 weeks), mean postnatal age at sampling of 19.3 days (range, 0 to 144 days), and a mean weight at sampling of 3.1 kg (range, 0.71 to 6.0 kg). With use of the program NONMEM and a two-compartment open model, the influences of demographic and clinical factors on the elimination rate constant (k10), volume of distribution of the central compartment (Vc) and bioavailability (F1) were examined. Zidovudine elimination was slow immediately after birth but increased rapidly in term infants during the first weeks of life, reaching a plateau by 4 to 8 weeks of age. In premature infants, zidovudine elimination increased at a much slower rate than in the term infants. Gender, race, and exposure to didanosine or nevirapine had no impact on zidovudine elimination. Bioavailability was increased in infants less than 14 days old. Zidovudine elimination kinetics undergo large increases during the first months of life, and the pattern of maturation is different in term and preterm infants. Higher bioavailability in younger infants is consistent with decreased first-pass metabolism associated with reduced clearance.

Rapid testing and zidovudine treatment to prevent vertical transmission of human immunodeficiency virus in unregistered parturients: a cost-effectiveness analysis

Objective: To assess the potential effectiveness and costs of a program to prevent vertical transmission of human immunodeficiency virus (HIV) in parturients without prenatal care. Methods: A decision-analysis model was constructed to compare three management strategies for unregistered women presenting in labor: 1) the current standard of treating no one; 2) HIV testing with a rapid antibody assay, followed by zidovudine treatment according to AIDS Clinical Trial Group Protocol 076 if seropositive; and 3) treating all women without rapid testing. Cost and probability data were obtained from a literature review and local estimates. Sensitivity analyses were performed for pertinent uncertainties. Results: Under baseline assumptions (5% HIV prevalence, treatment efficacy of an 18% reduction in transmission rate, and lifetime cost of pediatric HIV $103,708), giving no treatment resulted in 1275 infected infants per 100,000 mother-infant pairs. The rapid-test strategy prevented 183 cases of infant HIV infection and resulted in a net savings to the medical system of $57,997 per case averted. The treat-all strategy prevented an additional 46 cases per 100,000 mother-infant pairs, but at a cost of $342,068 per additional case averted. With other estimates at baseline, rapid testing was cost-saving when the HIV prevalence exceeded 0.97%, the treatment efficacy exceeded a 5.8% reduction in the transmission rate, and the lifetime cost of pediatric HIV infection exceeded $33,625. Conclusion: Rapid HIV testing of unregistered parturients followed by zidovudine treatment if seropositive would be cost saving to the medical system.

Translating clinical trial results into practice: the effect of an AIDS clinical trial on prescribed antiretroviral therapy for HIV-infected pregnant women.

The success of Pediatric AIDS Clinical Trials Group (PACTG) Protocol 076 in preventing vertical HIV transmission prompted intensive efforts to inform lay-persons and professionals about the trial's results. To explore community responsiveness to these efforts by assessing temporal, maternal, and health care factors associated with prescribed antiretroviral therapy before and after PACTG Protocol 076. Retrospective cohort study. New York State Medicaid program. 2607 HIV-infected women who delivered a living child between January 1993 and September 1996. Adjusted odds of being prescribed antiretroviral treatment in the second or third trimester for women who delivered in period 1 (during the trial [January 1993 to February 1994]), period 2 (after the trial's end and announcement of the results to publication of the results [March 1994 to November 1994]), and period 3 (after publication of the trial results [December 1994 to September 1996]). The adjusted odds of being prescribed antiretroviral therapy increased 21% per month in period 2 and decreased to 3% per month in period 3. In all time periods, the adjusted odds of being prescribed antiretroviral therapy were at least 60% greater (P < 0.05) for women who were treated at an institution that performed HIV clinical trials, received HIV-focused ambulatory care, or had adequate prenatal care visits. After the trial, women receiving methadone treatment had at least twofold (95% CI, 1.5- to 4.3-fold) greater adjusted odds of being prescribed antiretroviral therapy than women who did not take any illicit drugs. Latin-American women, older women, and women born in the United States had greater adjusted odds (P < 0.05) of being prescribed treatment in period 3. Community practice responded rapidly to efforts to disseminate the results of PACTG Protocol 076; however, the absolute increase in prescribed therapy was greatest for women who had adequate prenatal visits or were receiving HIV-focused care, care at a site that performed clinical trials, or methadone therapy.

The effects of zidovudine in the subset of infants infected with human immunodeficiency virus type-1 (Pediatric AIDS Clinical Trials Group Protocol 076)

Objective: To describe the effect of zidovudine on human immunodeficiency virus type 1 (HIV-1) and on the course of disease in infants who became infected while they and their mothers received zidovudine preventive therapy or placebo in Pediatric AIDS Clinical Trials Group Protocol 076. Study design: Observational substudy of a multicenter, randomized, double-blind, placebo-controlled trial. Methods: We compared the progression of disease, timing of HIV-1 transmission, and the plasma HIV-1 RNA level in infected infants of mother-infant pairs who were randomly assigned to receive zidovudine (n = 14) or placebo (n = 43). The development of genotypic zidovudine resistance was assessed among infected infants in the zidovudine treatment group. Results: In this limited study, zidovudine therapy during pregnancy and labor and in the neonatal period for 6 weeks failed to have a major effect on rapid progression of disease, timing of transmission, and viral replication in HIV-infected infants. When the zidovudine treatment regimen failed to prevent maternal-infant transmission of HIV-1, resistance to zidovudine did not develop during study treatment. Conclusions: Our study supports the safety of zidovudine use in pregnancy and in the newborn period but demonstrates the continued need for more potent antiretroviral treatment of the infected infant. (J Pediatr 1999;134:717-24)

Abbreviated Regimens of Zidovudine Prophylaxis and Perinatal Transmission of the Human Immunodeficiency Virus

Background The Pediatric AIDS Clinical Trials Group Protocol 076 reported a reduction in the rate of perinatal transmission of the human immunodeficiency virus (HIV) from 25.5 percent to 8.3 percent with a three-part regimen of zidovudine given ante partum, intra partum, and to the newborn. We examined the effects of abbreviated zidovudine regimens on perinatal HIV transmission using data from the HIV polymerase-chain-reaction (PCR) testing service of the New York State Department of Health. Pregnant women who received abbreviated regimens rather than the recommended regimens did so because of limited prenatal care or by choice. Methods The requisition form used by the PCR testing service included information on the demographic characteristics of the infants and the timing of any perinatal treatment with zidovudine. We also analyzed data on the timing of zidovudine prophylaxis collected by chart review in a subgroup of 454 infants as a means of validating the results in the entire cohort. Results From Aug...

Lack of tumors in infants with perinatal HIV-1 exposure and fetal/neonatal exposure to zidovudine.

Zidovudine (ZDV) therapy during pregnancy and to the neonate reduced perinatal HIV transmission by nearly 70% in Pediatric AIDS Clinical Trials Group (PACTG) protocol 076. ZDV has been reported as positive in several in vitro carcinogenicity screening tests. We evaluated the short-term risk for tumors in 727 children with known ZDV exposure enrolled into the PACTG 076/219 and the Women and Infants Transmission Study (WITS). ZDV exposure in utero (antepartum) occurred in 97% and 99% of infants in PACTG 076/219 or WITS, respectively. Mean follow-up was 38.3 months with 366.9 person years follow-up for PACTG 076/219 and 14.5 months with 743.7 person years follow-up for WITS. No tumors of any nature were observed; relative risk was 0 (95% confidence interval [CI], 0-17.6). These data are reassuring regarding the short-term lack of tumors for ZDV-exposed infants observed to date. Longitudinal, standardized follow-up for infants with in utero antiretroviral exposure is necessary to assess long-term carcinogenicity.

Predictive value of CD19 measurements for bacterial infections in children infected with human immunodeficiency virus.

We investigated the predictive value of CD19 cell percentages (CD19%) for times to bacterial infections, using data from six pediatric AIDS Clinical Trials Group protocols and adjusting for other potentially prognostic variables, such as CD4%, CD8%, immunoglobulin (IgA) level, lymphocyte count, prior infections, prior zidovudine treatment, and age. In addition, we explored the combined effects of CD19% and IgG level in predicting time to infection. We found that a low CD19% is associated with a nonsignificant 1.2-fold increase in hazard of bacterial infection (95% confidence interval: 0.97, 1.49). In contrast, a high IgG level is associated with a nonsignificant 0.87-fold decrease in hazard of infection (95% confidence interval: 0.68, 1.12). CD4% was more prognostic of time to bacterial infection than CD19% or IgG level. Low CD19% and high IgG levels together lead to a significant (P < 0. 01) 0.50-fold decrease in hazard (95% confidence interval: 0.35, 0. 73) relative to low CD19% and low IgG levels. Similarly, in a model involving assay result changes (from baseline to 6 months) as well as baseline values, the effect of CD19% by itself is reversed from its effect in conjunction with IgG. In this model, CD19% that are increasing and high are associated with decreases in hazard of infection (P < 0.01), while increasing CD19% and increasing IgG levels are associated with significant (at the P = 0.01 level) fourfold increases in hazard of infection relative to stable CD19% and decreasing, stable, or increasing IgG levels. Our data suggest that CD19%, in conjunction with IgG level, provides a useful prognostic tool for bacterial infections. It is highly likely that T-helper function impacts on B-cell function; thus, inclusion of CD4% in such analyses may greatly enhance the assessment of risk for bacterial infection.

Short-course zidovudine for prevention of perinatal infection

In 1994, the Pediatric AIDS Clinical Trials Group (PACTG) protocol 076 showed that a 6-week course of zidovudine, given to the mother during pregnancy and labor, and then to the neonate for 6 weeks, reduced HIV transmission rates by almost 70%. The adoption of this regimen in the US and Europe has caused perinatal HIV transmission rates to decline to 6% or less, while transmission rates of 2% have been reported when zidovudine prophylaxis is combined with elective cesarean delivery. However, in absolute terms, the impact of perinatal HIV transmission prevention measures will be greater in developing than in industrialized countries, in part because the overall level of HIV infection among pregnant women in developing countries is far higher than the overall level in industrialized countries. While trials must continue to identify simpler and more cost-effective HIV prevention measures, effort must still be given to implementing the already proven effective regimens in developing countries. To implement short-course HIV prophylactic regimens requires available and accessible antenatal care, HIV testing and follow-up for pregnant women, available and affordable zidovudine, and patient compliance with the drug regimen. To ensure intrapartum zidovudine administration, deliveries must be attended by professional birth attendants. Then, to prevent postpartum HIV transmission, there must be a safe and effective strategy for reducing the risk of HIV-1 transmission through breast milk.

Codon 215 Mutations in Human Immunodeficiency Virus–Infected Pregnant Women

In 1994, the Pediatric AIDS Clinical Trials Group (PACTG) Protocol 076 demonstrated a two-thirds reduction of perinatal human immunodeficiency virus (HIV) type 1 transmission with zidovudine chemoprophylaxis. However, zidovudine alone does not fully suppress HIV replication, and chemoprophylaxis with zidovudine alone might select for zidovudine-resistant viral variants, decreasing the efficacy of zidovudine prophylaxis and affecting future responses to combined antiretroviral regimens. Sixty-two HIV-infected pregnant women consecutively enrolled in the ongoing Swiss HIV and Pregnancy Study were prospectively evaluated for the presence or development of zidovudine resistance by analysis of codon 215 of the reverse transcriptase gene. Six women (9.6%) harbored a codon T215Y/F mutation, which is associated with high-level resistance to zidovudine. Postnatal evaluation was completed in all children of mothers harboring the mutation. None was HIV-infected. The observed prevalence of codon 215 mutations of 9.6% raises important concerns regarding the future use of the PACTG 076 regimen.

Attempting to Enhance the Enrollment of Adolescents into AIDS Clinical Trials: The Design of ACTG Protocol 220

The epidemic of HIV infection continues to grow in adolescents and young adults. Unfortunately, because treatment regimens have been developed based on data derived from clinical trials, little data are available on adolescents because they are infrequently included in these trials. In an effort to facilitate the enrollment of more adolescents into AIDS Clinical Trials Group (ACTG) clinical trials, we designed a nontreatment protocol to familiarize adolescents with clinical trials requirements. Two hundred fifty-six adolescents (150 females, 106 males) between the ages of 13 and 21 years were enrolled at 43 different clinical trials sites throughout the United States. The majority of patients (50%) were enrolled at sites that had specific programs for adolescents. Most of the young women (85%) had acquired their infection via heterosexual transmission, whereas the largest transmission categories in men were blood or factor transfusions (43%) or same-sex contact (34%). Admission CD4 counts were lower in males (mean = 396 cells/mm3) than in females (mean = 513 cells/mm3) (p = 0.01). Psychosocial profiles revealed a variety of ongoing risk behaviors in HIV-infected adolescents. Two years into the study, 223 patients are still being observed. We conclude that adolescents can be enrolled in an observational protocol. The success of this trial will be determined by how many ACTG Protocol 220 participants are ultimately enrolled in therapeutic trials.

Construction of a Continuous Stopping Boundary from an Alpha Spending Function

Lan and DeMets (1983, Biometrika 70, 659-663) proposed a flexible method for monitoring accumulating data that does not require the number and times of analyses to be specified in advance yet maintains an overall Type I error, alpha. Their method amounts to discretizing a preselected continuous boundary by clumping the density of the boundary crossing time at discrete analysis times and calculating the resultant discrete-time boundary values. In this framework, the cumulative distribution function of the continuous-time stopping rule is used as an alpha spending function. A key assumption that underlies this method is that future analysis times are not chosen on the basis of the current value of the statistic. However, clinical trials may be monitored more frequently when they are close to crossing the boundary. In this situation, the corresponding continuous-time boundary should be used. Here we demonstrate how to construct a continuous stopping boundary from an alpha spending function. This capability is useful in the design of clinical trials. We use the Beta-Blocker Heart Attack Trial (BHAT) and AIDS Clinical Trials Group protocol 021 for illustration.

CCR5/delta(ccr5) heterozygosity: a selective pressure for the syncytium-inducing human immunodeficiency virus type 1 phenotype. NIAID AIDS Clinical Trials Group Protocol 241 Virology Team.

Mechanisms underlying the delay in dominance of syncytium-inducing (SI) phenotype HIV-1 (human immunodeficiency virus type 1) in vivo are unknown. Both random mutational events and selective pressures operative only late in the disease process have been suggested to underlie the shift from CCR5 to alternative coreceptor usage. Among the moderately advanced patients who entered AIDS Clinical Trials Group protocol 241, SI viral phenotype was more common among CCRS/delta(ccr5) heterozygotes (7/7, 100%) than among CCR5/CCR5 homozygotes (29/88, 33%; P < .001, Fisher's exact test). Other characteristics did not differ at study entry by CCR5 genotype, including median CD4 cell counts, plasma RNA levels, and infectious HIV-1 titers in circulating cells. These data indicate that CCR5/delta(ccr5) heterozygosity, which decreases cell-surface levels of CCR5 available to serve as an HIV-1 entry coreceptor, is a selective pressure for evolution of T cell line-tropic viruses that use an alternative coreceptor.

ANTIRETROVIRAL THERAPY AND INTERRUPTION OF HIV PERINATAL TRANSMISSION

Mother-to-child transmission is the primary mode of HIV acquisition in children worldwide. Thus, the HIV epidemic in children mirrors the HIV epidemic in women of childbearing age. In the United States, the number of women diagnosed with AIDS increased by 63% between 1991 and 1995, the largest increase in any group of persons at risk of HIV infection.64 Globally, the World Health Organization estimates that 22 million adults are currently living with HIV infection, approximately 42% of whom are women.50, 63 This proportion continues to grow, with the predominant mode of acquisition being heterosexual intercourse. In the United States, approximately 7000 HIV-infected women give birth annually; without any intervention to reduce transmission, 1750 newly infected babies would be born every year.21 On a global basis, approximately 2.2 million children have been infected with HIV, 1.4 million of whom have already died secondary to HIV-associated disease. The vast majority of these children live in the developing world, and it is estimated that an additional 1000 infants with HIV infection are born daily.63 Thus, prevention of HIV infection in women and of transmission of HIV to their infants is a significant public health priority. In the United States, prevention of perinatal transmission became a reality in 1994, when the results of Pediatric AIDS Clinical Trials Group (PACTG) Protocol 076 demonstrated that a regimen of zidovudine (ZDV) administered during pregnancy, labor, and to the newborn for the first 6 weeks of life could reduce the risk of transmission from mother to infant by two thirds.15 Implementation of this regimen into general clinical practice has been associated with dramatic declines in perinatal transmission in the United States and other industrialized countries.6, 18, 26 However, the complexity and cost of the ZDV regimen limits its applicability in many developing countries, where the majority of perinatal transmission occurs. The success of PACTG 076 has stimulated the development of clinical trials of modified antiretroviral and other interventions to identify preventive regimens more applicable to the developing world and to further reduce transmission risk in the United States and other industrialized countries.

Interpreting treatment differences when patients drop out of a clinical trial.

Clinical trials are the standard for identifying new drugs for the treatment of disease, but results are dependent on patient compliance. The success of treatments for HIV disease in particular may be judged in part by their effect on immunologic, virologic, or clinical measures collected on patients at regular predefined intervals. If patients drop out of a trial before study completion, the analysis of the repeatedly collected parameters needs to be undertaken and interpreted with care. The authors recommend using graphic techniques to assess the impact of the missing data on the profiles of the parameters over time. To assess treatment differences, a variety of simple tests are proposed that allow different assumptions to be made regarding the reasons for the incomplete data. A case study is presented providing an analysis of CD4 data from the Pediatric Aids Clinical Trials Group (PACTG) Protocol 051, in which only 52% of the patients completed the study while remaining on treatment; younger patients with lower CD4 counts were more likely to stop treatment earlier. This type of systematic missing data can lead to incorrect conclusions regarding different treatment effects on CD4 counts. With the data of PACTG 051, however, regardless of the methodology used, no treatment differences were found. Inconsistent conclusions would have indicated the need for more sophisticated statistical techniques to adequately test for treatment differences.

Multiple Imputation for Early Stopping of a Complex Clinical Trial

It is desirable to have procedures available for stopping a clinical trial early if there appears to be no treatment effect. Conditional power procedures allow for early stopping in favor of the null hypothesis if the probability of rejecting H0 at the planned end of the trial given the current data and a value of the parameter of interest is below some threshold level. Lan, Simon, and Halperin (1982, Communications in Statistics C1, 207-219) proposed a stochastic curtailment procedure that calculates the conditional power under the alternative hypothesis. Alternatively, predictive power procedures incorporate information from the observed data by averaging the conditional power over the posterior distribution of the parameter. For complex problems in which explicit evaluation of conditional power is not possible, we propose treating the problem of projecting the outcome of a trial given the current data as a missing data problem. We then complete the data using multiple imputation and thus eliminate the need for explicit calculation of conditional power. We apply this method to AIDS Clinical Trials Group (ACTG) protocol 118 and to several simulated clinical trials.

The use of simulation and bootstrap in information-based group sequential studies.

In this paper, we present an information-based design and monitoring procedure which applies to any type of model for any type of group sequential study provided there is a unique parameter of interest one can estimate efficiently. Simulation techniques are described to handle the design phase of this procedure. Since designs depend on potentially unreliable guesses of nuisance parameters, we propose a bootstrap method that uses the information available at the interim analysis times to generate projections and prediction intervals for the time at which the study will be fully powered. A monitoring board can use this information to decide whether a redesign of the trial is warranted. We also show how to use simulation to redesign studies in progress. We illustrate all of these techniques with data from AIDS Clinical Trial Group Protocol 021.

Pharmacokinetics of saquinavir, zidovudine, and zalcitabine in combination therapy

We investigated the pharmacokinetics of zidovudine, zalcitabine, and saquinavir in AIDS Clinical Trial Group protocol 229. Patients received either saquinavir, zalcitabine, or a combination of both, together with zidovudine three times a day. Approximately 100 patients were enrolled in each treatment arm, and intensive pharmacokinetic studies were performed on about 25 patients per arm at weeks 1 and 12. We estimated the pharmacokinetic parameters of all three drugs by using parametric and nonparametric methods. The mean values of the pharmacokinetic parameters of zidovudine (clearance [CL]/bioavailability [F], 168 liters/h; volume of distribution [V]/F, 185 liters; half-life, 0.76 h) and zalcitabine (CL/F, 25 liters/h; V/F, 92.2 liters; half-life, 2.7 h) were similar to those reported previously. For saquinavir, the mean pharmacokinetic parameter estimates using parametric methods were as follows: maximum concentration of drug in serum [Cmax], 70.8 ng/ml; time to Cmax, 3.11 h; area under the curve, 809 ng x h/ml; CL/F, 989 liters/h; V/F, 1,503 liters; half-life, 1.38 h. For all three drugs, clearance decreased with age. Weight did not influence the clearance of zidovudine, but the clearance of zalcitabine and saquinavir increased with weight. There were no differences in pharmacokinetic parameters between study weeks and arms, suggesting that there is no change in kinetics with chronic administration and that there are no significant pharmacokinetic interactions among these three drugs.

Ethical complexities of conducting research in developing countries.

Ethical challenges are posed by attempts to conduct clinical trials in developing countries. Such trials must seek interventions that could realistically benefit the population involved. An inadequate understanding of the complexity of such trials has led to unfair charges that developing country trials of interventions to prevent maternal-infant transmission of HIV are comparable with the infamous Tuskegee study where subjects were deprived of available treatment for syphilis. The system of ethical protection developed after the Tuskegee scandal called for respect for persons, beneficence, and justice in research trials. To apply these principles to research in developing countries requires the support and involvement of the host country as well as an understanding of how conditions in the host country may differ from conditions in the partner country and, thus, may require different types of clinical trials. The current debate hinges on the morality of using a placebo control when the AIDS Clinical Trials Group protocol 076 is being effectively used in other parts of the world. The 076 protocol, however, has not been proved effective in developing country settings, and its per person treatment cost exceeds that which can be assumed by developing countries. The most compelling response to criticisms of the placebo-control test designs is that it provides definitive answers to safety and effectiveness questions in the study setting. Debate on this issue is healthy but should be informed by adequate knowledge of local factors that influence research.

Predictors of survival in HIV-infected persons with 50 or fewer CD4 cells/mm3.

The objective of this study was to identify prognostic factors for survival in patients with pretreatment CD4 < or =50 cells/mm3 treated with nucleoside analogs, and to develop and validate a mortality risk model based on these factors. The design of the study consisted of retrospective analysis of AIDS Clinical Trials Group (ACTG) protocols 116a, 116b/117, 155, and 118. The setting was the multicenter AIDS Clinical Trials Group. The patients were HIV-infected with pretreatment CD4 < or =50 cells/mm3 and various degrees of prior zidovudine (ZDV) use. Double-blind, three-arm randomized control trials ACTG 116a and ACTG 116b/117 compared ZDV with didanosine (ddI). ACTG 155 compared ZDV with zalcitabine or combination therapy. Our validation study, ACTG 118, compared the effects of three different doses of ddI on survival. The main outcome measures were survival and mortality. The three studies combined enrolled 699 patients with entry CD4 T-lymphocyte counts of < or =50 cells/mm3. Forty percent of patients died during follow-up, with a median survival of 19.7 months. Multivariate analysis showed shorter survival at p < 0.0001 with lower CD4 count (relative hazard [RH] = 0.98) and lower hemoglobin level (RH = 0.81). Other factors included older age (RH = 1.03), male gender (RH = 1.70), Hispanic ethnicity (RH = 1.68), and symptomatic disease stage (RH = 2.06). Our predictive mortality risk model differentiated well patients with differing risks of mortality. When the risk model was applied to ACTG 118, the validation data set, the identified prognostic factors could distinguish patients with varying risks of death (p < 0.001, stratified log-rank test). These results demonstrate that CD4 T-lymphocytes counts < or =50 cells/mm3 should not be considered a precursor of imminent death; considerable variability in survival exists in severely immunocompromised patients. Our identification of prognostic indicators for survival can aid clinicians and patients in management of their disease and researchers in design of future clinical trials.

Reducing the risk of perinatal HIV‐1 transmission with zidovudine: results and implications of AIDS Clinical Trials Group protocol 076

This paper reviews the rationale for the AIDS Clinical Trials Group (ACTG) protocol 076 design, the study results and the implications of these results, including discussion of the US Public Health Service Task Force recommendations on the use of zidovudine to reduce perinatal transmission and for prenatal human immunodeficiency virus (HIV) counseling and testing.