Extend Infant PrEP for HIV to 12 Months in Breast-fed Babies

Veronica Hackethal, MD

November 20, 2015

Infant preexposure prophylaxis (PrEP) for HIV using a pediatric liquid formulation should extend for 12 months in breast-fed babies of HIV-positive mothers, according to a study conducted in Africa and published online November 18 in the Lancet.

"Our study showed that two infant PreP regimens, using lopinavir–ritonavir or lamivudine, were equally well tolerated and effective to reduce postnatal HIV-1 transmission incidence to lower than 1.5%," write Philippe Van de Perre, MD, from the Université Montpellier in France, and colleagues.

The study represents the first assessment beyond 6 months of ways to prevent mother-to-child transmission of HIV-1 while breast-feeding. It included the 6- to 12-month period when breast-feeding decreases and babies are introduced to new foods, and suggests that mothers should be told about continued risk for HIV transmission during this time.

"The trial is unique in that it assessed a postnatal [prevention of mother-to-child transmission programmes] strategy (infant PreP) for the recommended 12 months duration of breastfeeding and that it compared head-to-head two antiretroviral drugs for infant PreP," the study authors write.

Breast-feeding is recommended up to 12 months after birth, especially in developing countries with poor sanitation and high rates of child death resulting from infection. However, breast-feeding can increase the risk for mother-to-child transmission of HIV. Two strategies can reduce this risk: give the mother antiretroviral therapy (ART) to decrease infectiousness, or provide direct protection to the infant, using child formulations of PrEP.

The randomized controlled trial took place at four sites in Africa: Burkina Faso, South Africa, Uganda, and Zambia. It included children born to mothers with HIV-1 and CD4 counts higher than 350/μL, making them ineligible for ART according to guidelines at that time. (Subsequently, the World Health Organization in 2013 recommended lifelong ART during pregnancy and beyond for women diagnosed with HIV, regardless of CD4 count.)

Researchers randomly assigned HIV-1 negative breast-fed infants aged 7 days to twice-daily pediatric liquid formulations of lopinavir-ritonavir (n = 615) or lamivudine (n = 621). Infants were to receive PrEP up to 1 week after mothers completely stopped breast-feeding, or at their final clinic visit at week 50. Participants, clinical staff, and research staff remained masked to treatment group throughout the study.

Researchers counseled mothers to breast-feed exclusively for 6 months, then to gradually introduce complementary feeds, and then to completely stop breast-feeding by 49 weeks.

During the study period (November 2009 - May 2012), infants had a high overall mean drug adherence, which was slightly better with lamivudine (93% [standard deviation, 15%]) than with lopinavir-ritonavir (90% [standard deviation, 14%]; P < .0001). Eighty-eight percent (n = 1112) of infants attended the final clinic visit.

HIV transmission occurred in 17 children (eight in the lopinavir ritonavir group and nine in the lamivudine group). Both groups had similar infection rates, with a cumulative HIV-1 infection of 1.4% (95% confidence interval [CI], 0.4 - 2.5) and 1.5% (95% CI, 0.7 - 2.5), respectively (hazard ratio [HR] of lopinavir-ritonavir vs lamivudine, 0.90; 95% CI, 0.35 - 2.34; P = .83).

Both groups also had similar rates of grade 3 to 4 adverse events: 251 (51%) with lopinavir-ritonavir vs 246 (50%) with lamivudine.

Three percent (n = 33) of children died, with similar rates found in the lopinavir-ritonavir group (3.0%; n = 18; 95% CI, 1.9 - 4.8) and the lamivudine group (2.5%; n = 15; 95% CI, 1.5 - 4.1; HR, 1.22; 95% CI, 0.61 - 2·42; P = .57). All infants who died were HIV negative; and no deaths were thought to be a result of the study drugs.

About half of HIV infections in infants occurred after 6 months, when breast-feeding decreased and infants were introduced to complementary foods. Five infections occurred before 50 weeks in babies of mothers who had reportedly stopping breast-feeding.

The authors note that most infections resulted from adherence issues, instead of lack of efficacy in the study drugs. In a subanalysis of infants with very high adherence, the lopinavir-ritonavir group had a rate of transmission of 0.2% (95% CI, 0.0% - 1.6), and the lamivudine group had a rate of 0.8% (95% CI, 0.3% - 2.5%). No statistically significant difference existed between the two groups (HR, 0.28; 95% CI, 0.03 - 2.46; P = .25).

"Infant PreP proved an effective and safe alternative to prevent postnatal HIV-1 transmission for mothers who are not ready or prepared to embark on long-term ART," the authors conclude. "At the population level, in countries where universal maternal ART cannot be implemented as recommended by [the World Health Organization], infant PreP with either lopinavir–ritonavir, lamivudine, or nevirapine for the whole duration of breastfeeding is also advisable."

Writing in a linked comment, Hoosen Coovadia, MD, from the University of the Witwatersrand, Durban, South Africa, and Dhayendre Moodley, PhD, from the University of KwaZulu Natal, Durban, South Africa, say the study represents a "high point in 20 years of progress to reduce risk of HIV transmission and make breastfeeding safe."

Several questions remain, however, including whether infant PrEP can be used in other settings, as well as issues surrounding the use of maternal ART to decrease the risk for mother-to-child transmission of HIV, they add.

"Given the opportunities for infant PREP in optimising prevention of breastfeeding transmission, and faced with the challenges of maternal ART use, further research is now needed to evaluate the feasibility, cost-effectiveness, and safety of a multipronged prevention of mother-to-child transmission programme to eliminate mother to child transmission of HIV while promoting a long duration of breastfeeding and equally maintaining maternal and child survival," they conclude.

The authors and commentators have disclosed no relevant financial relationships.

Lancet. Published online November 18, 2015. Article abstract, Comment extract

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