Kumwenda NI, Hoover DR, Mofenson LM, et al. Extended antiretroviral prophylaxis to reduce breast-milk HIV-1 transmission. N Engl J Med 2008 Jul 10;359(2):119-29.
The aim of the Post-Exposure Prophylaxis of Infants (PEPI) trial was to determine the degree to which extended prophylaxis of infants with nevirapine (NVP) or with NVP plus zidovudine (AZT) administered until the age of 14 weeks would decrease the rate of HIV-1 infection, compared with single-dose nevirapine (sd-NVP) combined with 1 week of AZT.
Six hospitals in Blantyre, Malawi
Inclusion criteria for mothers were HIV-1 infection, at least 18 years of age if no guardian permission, pregnancy or delivery within the previous 24 hours at one of the study clinics, residence in the study area, willingness to return for postnatal follow-up visits for 2 years, and intention to breastfeed. Infants with life-threatening conditions were excluded. Women who underwent screening for HIV-infection totaled 46,186, of whom 3,216 women met inclusion criteria and were enrolled.
Randomized, controlled, open-label phase III trial
At birth, infants were randomized to one of three antiretroviral regimens: 1) the control regimen consisting of single dose NVP (2 mg/kg plus oral AZT [4 mg/kg] twice daily for 1 week; 2) the extended-NVP regimen consisting of the control regimen plus daily extended prophylaxis with NVP (2 mg/kg once daily during week 2; 4 mg per kg once daily during weeks 3 through 14) until the age of 14 weeks; or 3) the extended dual prophylaxis regimen consisting of the control regimen plus daily extended prophylaxis with NVP (as described above) and AZT (4 mg/kg twice daily during weeks 2 through 5; 4 mg/kg three times daily during weeks 6 through 8; 6 mg/kg three times daily during weeks 9 through 14) until the age of 14 weeks. Women were counseled at each visit to exclusively breastfeed for 6 months and to consider complete cessation thereafter. A small percentage of women (2.6% in the control group, 2.8% in the extended-NVP group, and 3.2% in the extended dual prophylaxis group) received antiretroviral therapy (ART) before 14 weeks postpartum (P=0.77 for all comparisons). Maternal rates of receiving ART were slightly higher after the 14-week study period (11.8% in the control group, 12.2% in the extended-NVP group, and 11.4% in the extended dual prophylaxis group). All infants received trimethoprim-sulfamethoxazole prophylaxis. Antiretroviral prophylaxis was discontinued for infants in the extended-prophylaxis arms who were found to have HIV-1 infection, and the infants were referred for ART.
Primary outcomes were the rate of HIV-1 infection by 9 months of age among live-born infants who were HIV-1 negative per DNA PCR assay (Roche Amplicor) within 48 hours of birth; survival free of HIV-1 infection during follow-up; and safety of the experimental regimens. Infants were evaluated for HIV-1 infection at 6, 9, and 14 weeks and at 6, 12, 18, and 24 months. The study stopped enrollment at the second interim analysis per a data and safety monitoring board recommendation.
Of the 3,276 infants enrolled, 3,016 were included in the analysis: 1,088 infants were randomized to the control arm, 1,099 to the extended NVP arm, and 1,089 to the extended dual-prophylaxis arm. A total of 260 infants were excluded because they either were found to have HIV-1 infection or their HIV-1 status at birth was unknown (14 infants in the control group, 5 in the extended NVP group, and 15 in the extended dual prophylaxis group). Loss to follow up rates at 9 months were similar among study groups (136 in the control group, 131 in the extended NVP group, and 109 in the extended dual prophylaxis group). Baseline demographic and laboratory characteristics were similar in the three study groups.
All infants received sd-NVP at birth, and of the 2,427 infants who returned for their first week visit, 99% received AZT. Adherence at 14 weeks (defined as the proportion of infants who received treatment each month and those who returned for the visit) was determined to be 97.3% among infants randomized to the extended-NVP arm and 97.8% among those randomized to the dual-prophylaxis arm (P=0.60). Among the 3,016 infants included in the analysis, those in the control arm had consistently higher rates of HIV-1 infection from age 6 weeks through 18 months. At 9 months of age, the estimated rate of HIV-1 infection was 10.6% in the control arm (95% confidence interval [CI]: 8.7-12.8), compared with 5.2% in the extended-NVP arm (95% CI: 3.9-7.0; P<0.001) and 6.4% in the extended-dual prophylaxis arm (95% CI: 4.9-8.3; P=0.002).
The total number of infants with positive HIV-1 DNA PCR at 9 months was 98 in the control groups, 51 in the extended NVP group, and 61 in the extended dual-prophylaxis group. The estimated protective efficacy of the extended NVP regimen was 67% (95% CI: 43-81) at 6 weeks, 67% (95% CI: 49-79) at 14 weeks, 60% (95% CI: 42-73) at 6 months, and 51% (95% CI, 30-66) at 9 months. The estimated protective efficacy of the extended dual prophylaxis regimen was 69% (95% CI: 45-83) at 6 weeks, 66% (95% CI: 48-78) at 14 weeks, 49% (95% CI: 27-64) at 6 months, and 40% (95% CI: 16-57) at 9 months. There were no significant differences between the two extended-prophylaxis groups at any time point.
By 9 months, 71 infants in the control group (8.9%; 95% CI: 7.1-11.1), 55 in the extended NVP group (6.8%; 95% CI: 5.2-8.7), and 51 in the extended dual prophylaxis group (6.3%; 95% CI: 4.8-8.2) had died. Although there were no significant differences in mortality among the three arms, the control group had greater mortality after age 6 months than either of the extended prophylaxis arms. Overall, 1,283 serious adverse events (SAE) were reported in 887 infants, with no significant differences between the three study arms. The most frequently reported SAEs in all three groups were respiratory (329 events), gastrointestinal (227 events), and hematologic (191 events). Of all SAEs, 12.7% were possibly related to a study drug and were more frequent in the extended dual-prophylaxis arm (P=0.02); the most common SAE in this group was neutropenia. The frequency of breastfeeding did not differ significantly between the three arms, ranging from close to 100% at 1 week to approximately 90% at age 6 months for all three arms. At 9 and 15 months, breastfeeding decreased to 32.0% in the control group, 26.9% in the extended NVP group, and 29.3% in the extended dual-prophylaxis group.
The authors concluded that extended infant prophylaxis with NVP or NVP plus AZT significantly reduced the risk of postnatal HIV-1 transmission at 14 weeks, with a protective efficacy of more than 60%.
This randomized controlled trial was of good quality. Although details on how randomization was conducted were not provided, the authors clearly described recruitment, attrition, and loss to follow-up, and all analyses were performed on an intent-to-treat basis. Additionally, sample size calculations were performed before the start of the study based on an assumed rate of mother-to-child HIV-1 transmission. The authors did not, however, indicate if outcomes differed in small percentages of women who were receiving ART during the breastfeeding period, nor did they comment on any effects of exclusive versus mixed breastfeeding practices.
In sub-Saharan Africa, where breastfeeding is critical for infant survival, postnatal transmission of HIV-1 occurs in up to 16% of untreated infants when breastfeeding continues into the second year of life.(1) The control regimen used in this randomized trial has been shown to be effective in Malawi(2) and is recommended by the World Health Organization for use in resource-limited settings.(3) Data from the MITRA and MITRA-PLUS studies conducted in Tanzania suggest that infant antiretroviral prophylaxis and maternal highly active antiretroviral therapy (HAART) may result in similar postnatal HIV-1 transmission rates.(4.5)
The authors asserted that infant-only prophylaxis is practical and effective in reducing mother-to-child transmission of HIV-1 in settings where breastfeeding is common. The 14-week time period for this study was based on completion of immunization schedules in Malawi at that time. Given the reduced rates of infant HIV-1 infection in this study, continuation of antiretroviral prophylaxis for the entire duration of breastfeeding deserves consideration and further study. Benefits must be weighed with potential toxicity to the child, although this study showed low overall rates of SAEs. Moreover, the similar efficacy in the two extended prophylaxis regimens argues against the need for AZT, thus removing the potential for SAEs associated with that drug. This study does not address possible resistance to ART in the children who do seroconvert, which should be assessed in future studies. Another approach to prevention of mother-to-child transmission is maternal HAART, regardless of other indications in the mother. Trials are ongoing to determine the efficacy and long-term safety of this approach for both mother and child.
- World Health Organization. Antiretroviral drugs for treating pregnant women and preventing HIV infection in infants: towards universal access: recommendations for a public health approach. Geneva, 2006. Abstract not available.
- Kilewo C, Karlsson K, Massawe A, et al. Prevention of mother-to-child transmission of HIV-1 through breast-feeding by treating infants prophylactically with lamivudine in Dar es Salaam, Tanzania: the Mitra Study. J Acquir Immune Defic Syndr 2008 Jul 1;48(3):237-40.
- Kilewo C, Karlsson K, Ngarina M, et al. Prevention of mother-to-child transmission of HIV-1 through breastfeeding by treating mothers prophylactically with triple antiretroviral therapy in Dar es Salaam, Tanzania - the MITRA PLUS study. In: Proceedings of the International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, Sydney, July 20-25, 2007:96. No abstract available.