Elsevier

The Lancet

Volume 372, Issue 9635, 26 July–1 August 2008, Pages 300-313
The Lancet

Articles
Extended-dose nevirapine to 6 weeks of age for infants to prevent HIV transmission via breastfeeding in Ethiopia, India, and Uganda: an analysis of three randomised controlled trials

https://doi.org/10.1016/S0140-6736(08)61114-9Get rights and content

Summary

Background

UNICEF/WHO recommends that infants born to HIV-infected mothers who do not have access to acceptable, feasible, affordable, sustainable, and safe replacement feeding should be exclusively breastfed for at least 6 months. The aim of three trials in Ethiopia, India, and Uganda was to assess whether daily nevirapine given to breastfed infants through 6 weeks of age can decrease HIV transmission via breastfeeding.

Methods

HIV-infected women breastfeeding their infants were eligible for participation. Participants were randomly assigned to receive either single-dose nevirapine (nevirapine 200 mg to women in labour and nevirapine 2 mg/kg to newborns after birth) or 6 week extended-dose nevirapine (nevirapine 200 mg to women in labour and nevirapine 2 mg/kg to newborn babies after birth plus nevirapine 5 mg daily from days 8–42 for the infant). The randomisation sequences were generated by computer at a central data coordinating centre. The primary endpoint was HIV infection at 6 months of age in infants who were HIV PCR negative at birth. Analyses were by modified intention to treat, excluding infants with missing specimens and those with indeterminate or confirmed HIV infection at birth. These studies are registered with ClinicalTrials.gov, numbers NCT00074399, NCT00061321, and NCT00639938.

Findings

2024 liveborn infants randomised in the study had at least one specimen tested before 6 months of age (1047 infants in the single-dose group and 977 infants in the extended-dose group). The modified intention-to-treat population included 986 infants in the single-dose group and 901 in the extended-dose group. At 6 months, 87 children in the single-dose group and 62 in the extended-dose group were infected with HIV (relative risk 0·80, 95% CI 0·58–1·10; p=0·16). At 6 weeks of age, 54 children in the single-dose group and 25 in the extended-dose group were HIV positive (0·54, 0·34–0·85; p=0·009). 393 infants in the single-dose group and 346 in the extended-dose group experienced grade 3 or 4 serious adverse events during the study (p=0·54).

Interpretation

Although a 6-week regimen of daily nevirapine might be associated with a reduction in the risk of HIV transmission at 6 weeks of age, the lack of a significant reduction in the primary endpoint—risk of HIV transmission at 6 months—suggests that a longer course of daily infant nevirapine to prevent HIV transmission via breast milk might be more effective where access to affordable and safe replacement feeding is not yet available and where the risks of replacement feeding are high.

Funding

US National Institutes of Health; US National Institute of Allergy and Infectious Diseases; Fogarty International Center.

Introduction

Prevention of mother-to-child transmission of HIV can be achieved through administration of highly active antiretroviral therapy (HAART) to pregnant HIV-infected women.1 In settings where access to HAART is limited, other effective strategies have been developed, including administration of single-dose nevirapine to HIV-infected mothers in labour and to their infants within 72 hours of birth.2, 3 However, breastfeeding continues to pose a significant risk of HIV transmission to infants born to HIV-infected mothers, accounting for about 150 000 infant infections per year, mainly in low-income settings.4 HIV-infected mothers in communities where safe and affordable infant feeding alternatives are available are advised not to breastfeed their infants.5 In resource-limited settings, infants of HIV-infected mothers who are not breastfed are at very high risk for mortality and morbidity, which can exceed the risk associated with HIV infection itself.6, 7 As a result, UNICEF/WHO recommendations advise that infants born to HIV-infected mothers who do not have access to acceptable, feasible, affordable, sustainable, and safe replacement feeding should be exclusively breastfed for at least 6 months.5 Since more than 80% of all HIV-infected mothers are in sub-Saharan Africa and Asia,4 where access to safe and nutritionally adequate alternatives to breast milk are limited, there is a critical need to identify strategies to prevent HIV transmission by breastfeeding. Provision of antiretroviral medications to infants exposed to HIV by breastfeeding is one potential prevention strategy in these settings. A significant risk for breast milk transmission of HIV occurs within the first 6 weeks post partum.8, 9 Therefore, targeting interventions to this early breastfeeding period could be particularly important.

This combined analysis of data from three separate, but coordinated, randomised clinical trials in Ethiopia, India, and Uganda provides an opportunity to determine whether giving low-dose nevirapine to breastfed infants born to HIV-infected mothers in the first 6 weeks of life could prevent more early post-partum HIV transmission than the standard single-dose nevirapine regimen given to mothers and infants alone.

Section snippets

Participants

Pregnant women who presented to antenatal and delivery facilities in Addis Ababa, Ethiopia, Pune, India, and Kampala, Uganda, who were identified as HIV-infected, were offered the local standard of care for prevention of mother-to-child transmission of HIV and provided infant feeding counselling, consistent with WHO/UNICEF guidelines. Women who indicated an intention to breastfeed their infants and provided informed consent were eligible for study enrolment. Written consent was obtained where

Results

Figure 1 shows the trial profile. 2024 liveborn infants with at least one specimen tested before 6 months of age were randomised (1047 infants in the single-dose group and 977 infants in the extended-dose group). 137 infants were excluded from the modified intention-to-treat population: 36 did not have birth specimens available for testing, eight were of indeterminate HIV infection status at birth or 6 months, and 93 were found to be infected at birth. Inverse variance-weighted HIV infection

Discussion

The results of this study indicate that, among breastfeeding infants who were HIV uninfected at birth, extended use of oral nevirapine 5 mg/day did not significantly reduce the risk of infection with HIV at 6 months compared with single-dose nevirapine. This lack of significance could have been due to a loss of statistical power from underlying HIV transmission rates that were lower than those used for our sample size calculation, particularly in the control group (estimated rate of 18·0% vs

References (32)

  • PG Miotti et al.

    HIV transmission through breastfeeding: a study in Malawi

    JAMA

    (1999)
  • R Nduati et al.

    Effect of breastfeeding and formula feeding on transmission of HIV-1: a randomized clinical trial

    JAMA

    (2000)
  • P Musoke et al.

    A phase I/II study of the safety and pharmacokinetics of nevirapine in HIV-1 infected pregnant Ugandan women and their neonates (HIVNET 006)

    AIDS

    (1999)
  • JS Read

    Diagnosis of HIV-1 infection in children younger than 18 months in the United States

    Pediatrics

    (2007)
  • JM Nam

    Sample size determination for case-control studies and the comparison of stratified and unstratified analyses

    Biometrics

    (1992)
  • KJ Rothman

    Modern epidemiology

    (1986)
  • Cited by (229)

    • Role of pyridines as enzyme inhibitors in medicinal chemistry

      2022, Recent Developments in the Synthesis and Applications of Pyridines
    • Epidemiology and Prevention of HIV Infection in Children and Adolescents

      2018, Principles and Practice of Pediatric Infectious Diseases
    View all citing articles on Scopus

    Members listed at end of paper

    View full text