Clinical Drug Experience Knowledgebase

BACKGROUND:

The HIV epidemic in the United States has changed its course in the past few years. The main risk group of the past, homosexual males, has reduced numbers of new infections because of education and prevention. Other groups, including intravenous drug abusers, disadvantaged urban socioeconomic classes and adolescents, continue to be infected and to transmit HIV by needle sharing and/or unprotected heterosexual activity. Many of these newly infected individuals are women of child-bearing age. These women in turn infect their children. The Centers for Disease Control estimates that there will be 2,000 infected infants born to 6,000 HIV-positive mothers annually in the United States.

Over the past few years, several studies have identified the risk of maternal-fetal transmission of HIV by seropositive mothers. The risk is close to 30 percent. However, for reasons not yet understood, the risk appears to be higher in Africa, approaching 40 percent, and lower in Europe, approaching 16 percent. Factors influencing maternal-fetal transmission of HIV are not well defined but may include the clinical state of the mother, plasma p24 antigen positivity of the mother, viral load, prior pregnancy associated with maternal-fetal HIV transmission, absence of maternal epitope specific and/or high affinity gp120 antibodies, or prematurity.

The results of a Phase III, multicenter, double-blind, randomized, placebo-controlled clinical trial to evaluate the efficacy, safety, and tolerance of zidovudine for the prevention of HIV transmission from infected pregnant women to their infants (ACTG protocol 076) provided for the first time proof of the concept that a preventive intervention can reduce vertical HIV transmission (47). Based on analysis of data for 364 evaluable births, zidovudine (ZDV or AZT) treatment according to the regimen employed in ACTG 076 appeared to reduce the risk of HIV transmission by two thirds, from 25.5 percent to 8.3 percent. Eligible subjects were HIV-infected pregnant women who had received no antiretroviral therapy during their current pregnancy, who had no maternal clinical indications for antiretroviral therapy, and who had CD4+ T-lymphocyte counts above 200 per microliter at study entry.

Efficacy of ZDV for reduction of vertical HIV transmission in women with advanced HIV disease who are already receiving antiretroviral treatment according to current clinical indications for their own health, or with CD4+ T-lymphocyte counts of 200 per microliter or below, or both was not evaluated in ACTG 076.

Administration of an antiretroviral agent to a pregnant woman in theory could reduce the risk of neonatal infection by reducing the exposure of the fetus to maternal virus, or by prophylaxis of the fetus prior to exposure. Because it is postulated that intense exposure of a potentially uninfected fetus to HIV present in maternal blood and genital tract secretions occurs during parturition, the design of this study includes intrapartum administration of ZDV followed by six weeks of oral ZDV to the infant.

An identical regimen for ZDV administration was employed in ACTG Protocol 076.

Pediatric ACTG Protocol 185 evaluated the hypothesis that in HIV-infected pregnant women receiving oral ZDV for medical indications, HIVIG administered monthly beginning at 20-30 weeks gestation in combination with intravenous ZDV intrapartum, together with a single newborn dose of HIVIG within 12 hours after birth in combination with six weeks of newborn oral ZDV, would reduce vertical HIV transmission compared with IVIG administered identically as a control agent.

DESIGN NARRATIVE:

Randomized, double-blind, controlled. Approximately half of the women were given intravenous HIVIG every four weeks until delivery. The other half received standard intravenous immunoglobulin (IVIG) without anti-HIV antibody. Both groups received AZT. A similar dose of HIVIG or IVIG was given to the newborn infant within 12 hours of birth. Each infant of a multiple birth received the mother's randomized study drug. Infant blood samples were taken at birth and at several intervals during the first 24 months of life to determine the infants' HIV status by p24 antigen assays, plasma viremia, or HIV co-culture assays. An existing NICHD contract with Westat, Inc. was used to conduct the trial. Westat, the study coordinating center subcontracted to 25 NICHD clinical trial units. An approximately similar number of NIAID clinical trial units also participated in the trial. As of February 1, 1996, there were 51 clinical trial units participating. Data analysis was performed by Westat. In 1993, NHLBI contracted with North American Biologics to supply HIVIG. The trial ended in December, 1996.