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Single-Dose Nevirapine + Short-Course AZT: Great for the Baby, but What About Mom?

In a Thai cohort, single-dose nevirapine + short course AZT reduced the rate of perinatal transmission to <3%; however, a related study shows reduced efficacy of nevirapine-based therapy in women treated with this intrapartum regimen.

UNAIDS estimates that 630,000 children were newly infected with HIV in 2003 alone, the overwhelming majority through perinatal HIV transmission. Perinatal transmission rates have been reduced from approximately 25% to 1% or 2% among nonbreastfeeding women with access to interventions such as combination antiretroviral therapy and cesarean section. Previous research found that AZT given to the mother starting at 28 weeks' gestation and to the infant until age 6 weeks reduced the transmission rate to 6.5%, and HIVNET 012 found that an even shorter intervention, single doses of nevirapine given to breastfeeding mothers during delivery and their newborns within 72 hours of birth reduced the transmission rates from 26% to 16%. Researchers in Thailand now address two key questions about these interventions: Is there any benefit to adding single-dose nevirapine to a short-course AZT regimen? And what are the effects of single-dose nevirapine on future treatment for the mothers?

Lallemant and colleagues report on a double-blind, placebo-controlled trial among mothers and infants who were receiving the short-course AZT regimen. The women were randomized to one of three arms: single-dose nevirapine to the mother at onset of labor and to the infant at 48 to 72 hours of life; single-dose nevirapine to mother and placebo to infant; or placebo to both mother and infant.

Overall, 1807 women were followed through delivery. A planned interim analysis in May 2002 found that the perinatal transmission rate at six months of age was 6.3% in the mother-infant pairs who both received placebo and 1.1% in the pairs that both received nevirapine; the researchers stopped enrollment in the double-placebo group. In the final analysis, the transmission rate in the nevirapine + placebo group (2.8%) was not statistically inferior to the rate in the mothers and infants who both received nevirapine (2.0%). Compared with the effects of no nevirapine treatment, the beneficial effect of single-dose nevirapine to both mother and child was greater among women with CD4 counts <200 cells/mm³, viral load at least 25,000 copies/mL, and shorter AZT treatment (no more than 8.5 weeks). However, single-dose nevirapine was superior to AZT alone across all of these risk-factor strata.

Despite such encouraging data, the frequent emergence of nevirapine resistance after single-dose nevirapine exposure and the uncertain implications of this resistance for response to NNRTI-containing therapy have somewhat dampened enthusiasm for this intervention. Jourdain and colleagues describe the virologic outcomes of women in the same Thai cohort who later started nevirapine-containing therapy with CD4 counts <250 cells/mm³. Baseline characteristics were similar between women who received nevirapine during delivery and those who did not, apart from a significant difference in the interval between delivery and initiation of later treatment (6.1 months among intrapartum nevirapine recipients vs. 14.9 months among intrapartum placebo recipients; P<0.001), which was due to the fact that the placebo arm stopped enrolling in May 2002 and nevirapine-based therapy became available starting in June 2002.

Genotypic resistance to nevirapine at approximately 12 days postpartum was detectable in 32% of the subset of women who had received single-dose nevirapine intrapartum and subsequently started nevirapine-containing therapy. Six months after starting nevirapine-containing therapy, 92 of 188 women who had received intrapartum nevirapine (49%) and 28 of 41 women who had received placebo (68%) had viral loads <50 copies/mL (P= 0.03). When the analysis was restricted to those women who were enrolled in the nevirapine arms before cessation of the placebo arm in May 2002, the difference in virologic suppression was no longer significant (P=0.12), although the proportions with virologic suppression were similar. In a multivariate analysis, baseline viral load above the median and prior exposure to single-dose nevirapine were both associated with virologic failure at 6 months. Clinical events and CD4-cell count increase on antiretroviral therapy did not differ by intrapartum nevirapine exposure.

Comment: Where combination antiretroviral therapy is unavailable to pregnant women, short-course AZT plus single-dose nevirapine to mother and infant provide a very effective perinatal prevention intervention, particularly in nonbreastfeeding populations. Although single-dose nevirapine exposure was associated with a lower rate of viral suppression to <50 copies/mL in this cohort, these results alone should not prompt the discontinuation of prevention programs based on this intervention, for several reasons. The placebo group receiving antiretroviral therapy was small; if only 2 more placebo recipients had failed therapy, the difference in virologic failure would not have been significant. Because initial placebo recipients had similar surrogate markers at treatment initiation despite enrollment much later postpartum, they may have been less likely to experience HIV progression and more likely to respond to therapy than the single-dose intrapartum nevirapine recipients. It remains uncertain whether women are more likely to fail if they start therapy shortly after intrapartum single-dose nevirapine exposure versus many months later. Finally, the longer-term clinical significance of these findings in women previously exposed to single-dose nevirapine remains unknown, particularly given the similar clinical and CD4-cell count benefit seen in this study regardless of intrapartum nevirapine exposure. Pregnant women who are at highest risk of transmitting HIV to their infants (high viral load, low CD4-cell count) also have the greatest risk of developing nevirapine-resistance mutations after single-dose nevirapine and, whenever possible, should receive potent combination antiretrovirals during pregnancy.

— Shahin Lockman, MD, MSc

Published in Journal Watch HIV/AIDS Clinical Care August 1, 2004

Citation(s):

Lallemant M et al. Single-dose perinatal nevirapine plus standard zidovudine to prevent mother-to-child transmission of HIV-1 in Thailand. N Engl J Med 2004 Jul 15; 351:217-28.

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• Medline abstract (Free)

Jourdain G et al. Intrapartum exposure to nevirapine and subsequent maternal responses to nevirapine-based antiretroviral therapy. N Engl J Med 2004 Jul 15; 351:229-40.

• Original article (Subscription may be required)
• Medline abstract (Free)