Intrapartum and neonatal single-dose nevirapine compared with zidovudine for prevention of mother-to-child transmission of HIV-1 in Kampala, Uganda: 18-month follow-up of the HIVNET 012 randomised trial

Summary

Background

In 1999, we reported safety and efficacy data for short-course nevirapine from a Ugandan perinatal HIV-1 prevention trial when 496 babies were followed up to age 14–16 weeks. Safety and efficacy data are now presented for all babies followed up to 18 months of age.

Methods

From November, 1997, to April, 1999, HIV-1 infected pregnant women in Kampala, Uganda, were randomly assigned nevirapine (200 mg at labour onset and 2 mg/kg for babies within 72 h of birth; regimen A) or zidovudine (600 mg orally at labour onset and 300 mg every 3 h until delivery, and 4 mg/kg orally twice daily for babies for 7 days, regimen B). Infant HIV-1 testing was done at birth, age 6–8 and 14–16 weeks, and age 12 months by HIV-1 RNA PCR, and by HIV-1 antibody at 18 months. HIV-1 transmission and HIV-1-free survival were assessed using Kaplan-Meier analysis. We recorded adverse experiences through 6–8 weeks postpartum for mothers, and 18 months for babies. Efficacy analyses were by intention to treat.

Findings

We enrolled 645 mothers to the study: 313 were assigned regimen A, 313 regimen B, and 19 placebo. Eight mothers were lost to follow-up before delivery. 99% of babies were breastfed (median duration 9 months). Estimated risks of HIV-1 transmission in the zidovudine and nevirapine groups were 10·3% and 8·1% at birth (p=0·35); 20·0% and 11·8% by age 6–8 weeks (p=0·0063); 22·1% and 13·5% by age 14–16 weeks (p=0·0064); and 25·8% and 15·7% by age 18 months (p=0·0023). Nevirapine was associated with a 41% (95% CI 16–59) reduction in relative risk of transmission through to age 18 months. Both regimens were well-tolerated with few serious side-effects.

Interpretation

Intrapartum/neonatal nevirapine significantly lowered HIV-1 transmission risk in a breastfeeding population in Uganda compared with a short intrapartum/neonatal zidovudine regimen. The absolute 8·2% reduction in transmission at 6–8 weeks was sustained at age 18 months (10·1% [95% CI 3·5–16·6]). This simple, inexpensive, well-tolerated regimen has the potential to significantly decrease HIV-1 perinatal transmission in less-developed countries.

Introduction

In 2002, an estimated 800 000 children became infected with HIV-1 through mother-to-child transmission,¹ with more than 90% residing in resource-poor countries. In more-developed countries, mother-to-child transmission has been dramatically lowered through use of the Paediatric AIDS Clinical Trials Group (PACTG) 076 zidovudine regimen, given to the mother during pregnancy and labour and to the infant for 6 weeks after birth.² However, this regimen is too complex and expensive for use in resource-poor countries.

The knowledge that most mother-to-child transmission occurs late in pregnancy or during labour and delivery3, 4 led to shorter zidovudine regimens being given to women a few weeks before and during labour as prophylaxis. This strategy was shown to decrease mother-to-child HIV-1 transmission by 37–38% in breastfeeding populations and by 50% in non-breastfeeding populations.5, 6, 7 However, these regimens, while simpler and less expensive, still remain problematic for implementation in some resource-poor countries, and transmission of HIV-1 postnatally via breast milk remains a problem.8, 9, 10

Because antiretroviral prophylaxis of the neonate during HIV-1 exposure at birth is thought to be an important mechanism for prophylaxis efficacy,¹¹ provision of antiretroviral therapy to the woman at onset of labour and for a short period postnatally to the infant was thought to be sufficient to decrease vertical transmission during the intrapartum and early breastfeeding period. This might offer a less complex and more affordable prophylaxis regimen for HIV-1 infected pregnant women in less-developed countries. The HIVNET 012 study team reported in 1999¹² that a single-dose intrapartum and neonatal nevirapine regimen significantly decreased the risk of transmission of HIV-1 from mother to child by 47% compared with a short intrapartum/neonatal zidovudine regimen when 87% of babies in the trial had reached age 14–16 weeks. We report on the safety and efficacy of the nevirapine regimen in all study mothers through 6 weeks postpartum and all babies through to 18 months of age.