New perinatal HIV infections in resource-rich countries have nearly been eliminated with the combination of universal, opt-out antenatal HIV testing, antiretroviral prophylaxis of the mother and infant, elective cesarean delivery, and avoidance of breastfeeding.1 Although effective interventions are also available to reduce in utero and intrapartum transmission in resource-limited settings, postnatal transmission of HIV through breastfeeding has remained a significant problem.2 Acquisition of HIV through breast milk accounts for an estimated 40% of new infections in sub-Saharan Africa, where more than 90% of perinatal infection occurs.3,4 Replacement feeding from birth is not feasible or safe in many resource-limited countries due to cost, lack of a safe water supply, the stigma of being associated with HIV infection, and the high risk of mortality and morbidity from diarrhea, pneumonia, and malnutrition in infants who are not breastfed, which can outweigh the risks associated with HIV itself.5-7 HIV-infected mothers in these settings have faced a difficult if not impossible choice-to breastfeed but risk transmitting HIV to their infant or to not breastfeed and risk their infant dying of other infectious diseases or malnutrition. Exclusive breastfeeding has been shown to lower the risk of postnatal HIV transmission compared with mixed feeding, but does not to eliminate risk.8,9
In the past year, exciting new results from observational studies and randomized clinical trials have become available that provide potential solutions to this difficult dilemma. In this issue of JAIDS, Kilewo et al10 present results of the observational Mitra-Plus study. In this study, highly active combination antiretroviral therapy (HAART) was provided to HIV-infected pregnant women starting at 34 weeks gestation and continued through up to 6 months of breastfeeding. The cumulative risk of HIV infection was 5% at 6 months and 6% at 18 months of age; the risk of postnatal infection between 6 weeks and 6 months was only 1%. This risk is significantly lower than observed in breastfeeding infants in the Petra trial arm A, in which zidovudine (AZT)/lamivudine (3TC) was provided starting at 36 weeks gestation, intrapartum, and for 1-week postpartum, with no further postnatal prophylaxis11; in this study, the risk of postnatal HIV infection between 6 weeks and 6 months was 6.5%, with cumulative transmission of 16.4% at 6 months and 17.7% at 18 months of age. Several other observational studies have also suggested that maternal HAART during breastfeeding reduces postnatal HIV transmission.12-14
An alternative intervention that has been evaluated to reduce postnatal infection is antiretroviral prophylaxis given to the infant. The Mitra study was an earlier observational study conducted by Kilewo et al in the same clinics in which they subsequently conducted Mitra-Plus. In Mitra, mothers were given AZT/3TC from 36 weeks gestation to 1-week postpartum, combined with 1-week AZT/3TC to the infant, followed by administration of daily 3TC to the infant during breastfeeding for a maximum of 6 months.15 The cumulative infection rate was 3.8% at 6 weeks and 4.9% at 6 months of age, with the risk of postnatal HIV infection between 6 weeks and 6 months 1.1%, remarkably similar to what is reported in the current study with maternal HAART prophylaxis.
Two randomized, controlled clinical trials were published last year that also demonstrated that infant prophylaxis with daily nevirapine (NVP) or NVP/AZT significantly reduced postnatal infection compared with short regimens without extended infant prophylaxis. The Six Week Extended Nevirapine (SWEN) study, a combined analysis of similar studies in Ethiopia, Uganda, and India, compared single-dose maternal/infant NVP alone to single-dose NVP plus extended daily infant NVP through age 6 weeks.16 The Post-Exposure Prophylaxis to the Infant (PEPI) trial in Malawi evaluated a somewhat longer regimen of infant prophylaxis, comparing a control regimen of single-dose maternal/infant NVP combined with 1 week of infant AZT to combining the control regimen with 14 weeks of extended daily infant NVP or 14 weeks of extended NVP/AZT.17 In both studies, a significant decrease in postnatal HIV infection compared with the control group was observed during the period of infant prophylaxis-in SWEN, there was a 46% decrease in postnatal HIV infection at age 6 weeks in infants uninfected at birth with extended NVP compared with the control arm, and in PEPI-Malawi there was a 66% decrease in postnatal infection at age 14 weeks with infant NVP compared with the control arm. In both studies, after discontinuation of prophylaxis, there was a continued risk of postnatal HIV transmission in infants who continued to be breastfed, which was seen at similar rates between study arms.
At the 5th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention held in Capetown, South Africa, in July 2009, results from several randomized clinical trials became available that confirmed the efficacy of both maternal HAART and infant antiretroviral prophylaxis in reducing postnatal infection. The Kesho Bora trial randomized HIV-infected pregnant women with CD4 counts 200-500 cells/μL to maternal HAART starting at 28-36 weeks gestation through 6-months postpartum compared with antepartum AZT starting at 28-36 weeks, with single-dose NVP at the onset of labor combined with 1 week of postnatal AZT/3TC to prevent NVP resistance (which will subsequently be referred to as “short-course AZT”).18 All infants received single-dose NVP and 1 week of AZT. The rates of HIV infection at birth (reflecting the comparative efficacy of antepartum maternal HAART to short-course AZT in preventing in utero infection) were similar between study arms, 1.8% in the maternal HAART arm, and 2.2% in the short-course AZT arm. However, at age 6 months, cumulative HIV infection rates were 4.9% in the maternal HAART arm compared with 8.5% in the short-course arm, demonstrating that a maternal HAART regimen with extended maternal postnatal prophylaxis was significantly better than a short-course AZT regimen without an extended postnatal component in reducing breast milk infection. Between 6 weeks and 6 months of age, the postnatal infection rate was 1.6% in the maternal HAART arm compared with 3.7% in the short-course AZT arm without extended postnatal prophylaxis. Of note, as in the SWEN and PEPI-Malawi studies, the rate of infection after prophylaxis was discontinued, between 6 months and 12 months of age, was similar in the 2 arms, 0.6% in the maternal HAART arm, and 1.0% in the short-course AZT arm.
The Mma Bana trial randomized HIV-infected pregnant women with CD4 counts >200 cells/μL to 2 different HAART regimens, a triple nucleoside regimen or a protease inhibitor-containing regimen, initiated between 26 and 34 weeks gestation and given through 6 months of breastfeeding; infants received single-dose NVP and 4 weeks of AZT.19 The rates of viral suppression at delivery and during breastfeeding were >90% and similar between the 2 HAART regimens. The cumulative rate of infant HIV infection at age 6 months was 1.0% (95% CI, 0.5%-2.0%), with only 2 infections (0.4% transmission) observed in 553 infants during breastfeeding, without significant differences between the 2 HAART regimens.
Finally, the Breastfeeding, Antiretroviral and Nutrition (BAN) trial enrolled HIV-infected pregnant women with CD4 counts >250 cells/μL at the time of delivery (no antepartum antiretroviral drugs were received) and compared a control arm of maternal intrapartum single-dose NVP plus 1 week of AZT/3TC (all infants also received single-dose NVP and 1 week of AZT/3TC) with either the control arm regimen plus maternal HAART given from 1 week to 6 months postpartum or the control arm regimen plus daily infant NVP given from 1 week to 6 months of age.20 The cumulative probability of HIV infection at age 6 months in infants who were uninfected at birth was 6.4% in the control arm, 3.0% in the maternal HAART arm (P = 0.0032 vs control), and 1.8% in the infant NVP arm (P < 0.0001 vs control). Although the trial was not powered to detect differences between the 2 experimental arms, the rates were not statistically different between maternal HAART and infant NVP prophylaxis (P = 0.12).
There are major difficulties in comparing HIV transmission rates between the various maternal and infant postnatal prophylaxis studies. For example, antepartum antiretroviral drug administration and duration (if given) differs between studies, yet is clearly important in terms of prevention of in utero infection and for comparisons of cumulative infection risk; the duration of postnatal prophylaxis differs between studies; CD4 count at entry into the studies differs; rates of exclusive breastfeeding differ; the duration of breastfeeding, and hence the time at risk for postnatal infection, is not specified in several studies; some studies do not provide birth infection rates, making it difficult to compare incremental benefit of interventions during the breastfeeding period because the proportion of transmission occurring in utero cannot be determined. For example, in the Mma Bana trial, which reported the lowest rate of infant HIV transmission of all studies to date (cumulative HIV transmission 1% at age 6 months), median maternal CD4 at enrollment was 398-403 cells/μL, the median duration of antepartum HAART was 11 weeks, 93% of infants exclusively breastfed through age 6 months, and reported adherence to HAART was 93%. In contrast, in the maternal HAART arm in the Kesho Bora study, where 6-month cumulative HIV transmission was 4.9%, the median maternal CD4 at enrollment was 335 cell/μL, the median duration of antepartum HAART was 6 weeks, only 48% of infants exclusively breastfed through age 3 months, and adherence to HAART was not specified but was 89% in a Kesho Bora observational cohort of women on HAART with CD4 count <200 cells/μL.18,21
Given these caveats, the currently available data suggest that provision of antiretroviral drugs to the breastfeeding infant may have comparable efficacy to provision of HAART to the lactating mother. The Mitra study of infant prophylaxis and Mitra-Plus study of maternal prophylaxis were conducted sequentially in the same clinics, both provided some maternal antepartum antiretroviral prophylaxis, and both provided the same duration (6 months) of postnatal prophylaxis; the cumulative HIV transmission rates at 6 months were similar (4.9% with infant prophylaxis in MITRA and 5.0% with maternal prophylaxis in Mitra-Plus), and the risk of late transmission between 6 weeks and 6 months was similar (1.1% and 1.0%, respectively).10,15 Similarly, data from the randomized comparison of extended maternal and infant postnatal prophylaxis interventions in the BAN study showed similar efficacy between the 2 intervention (with a 72% decrease in postnatal HIV infection between birth and age 6 months compared with the control group with extended infant NVP and 53% decrease with maternal HAART).20
Thus, observational studies confirmed by randomized clinical trials have now identified 2 interventions that can significantly reduce postnatal HIV infection. One key issue in decisions related to what antiretroviral regimens to choose for an HIV-infected pregnant woman is whether the antiretroviral drugs are being provided for treatment (in which case HAART should be provided) or for solely for prevention of mother-to-child transmission (in which case shorter, less intensive regimens may be equally as effective). Women who require treatment for their own health (eg, clinical symptoms or CD4 count <350 cells/μL) are those at greatest risk of maternal morbidity and mortality and are also at greatest risk of postnatal transmission to their infant22; these women should clearly receive HAART for their own health starting as soon as possible during pregnancy and continuing after cessation of breastfeeding; this will both preserve maternal health and increase survival and also decrease postnatal HIV transmission. In both Mitra-Plus and Mma Bana, the duration of antepartum HAART therapy was significantly associated with the risk of transmission,10,19 demonstrating the importance of early identification HIV infection and rapid determination of the need for treatment to allow prompt initiation of HAART for HIV-infected pregnant women with clinical symptoms or CD4 count <350 cells/μL.
For women with CD4 count >350 cells/μL, either maternal HAART or infant prophylaxis seem acceptable interventions for prevention of postnatal infection. The Kesho Bora trial results suggest that for women with higher CD4 count, antepartum maternal HAART and antepartum short-course AZT/plus single-dose NVP have similar efficacy for preventing in utero infection,18 and the Mitra-Plus/Mitra studies and the BAN trial results suggest similar efficacy of maternal HAART and infant prophylaxis for preventing postnatal infection.10,15,20 In the trials reported to date, both interventions seem to be safe in the short-term for the mother and the infant. Both interventions are associated with the potential for the risk of drug resistance in infants who become infected despite maternal or infant prophylaxis.23,24
The maternal and infant antiretroviral prophylaxis interventions evaluated to date provide prophylaxis for a maximum of 6 months, counseling infant weaning at that time. However, increasing data suggest that shortening the duration of breastfeeding may be associated with increased risk of malnutrition and infant mortality due to infectious diseases.2,5-7,25-28 In the Zambia Exclusive Breastfeeding Study, early cessation of breastfeeding was particularly harmful for infants of women with higher CD4 cell count.28 In the PEPI-Malawi infant prophylaxis study, where weaning at 6 months of age was recommended, there was a higher incidence of gastroenteritis and infant mortality in the period immediately after breastfeeding cessation when compared with a historical control with continued breastfeeding.25 In the Mashi study, discontinuation of breastfeeding was the primary risk factor for infant morbidity.27
The choice of intervention for prevention of perinatal and postnatal HIV transmission in women who do not require treatment for their own health will involve weighing a number of considerations including the relative costs, feasibility, risks, and benefits of the interventions. The World Health Organization is having a meeting in the fall to review the available data and to modify their current guidelines for prevention of mother-to-child HIV transmission.
A number of important issues still remain to be addressed. The effect of prolonged HAART administration in women who do not require it for their own health followed by discontinuation after weaning needs further evaluation, as do the long-term effects of in utero exposure to multiple antiretroviral drugs during pregnancy. Given that the effects of prophylaxis are limited to the period prophylaxis is provided and that early weaning of infants even at age 6 months is associated with increased morbidity and mortality, the risks and benefits of using these strategies used long term for the duration of breastfeeding (without early weaning) needs to be directly compared in a rigorous scientific fashion. A number of studies are planned to address these questions.
It is important to note that although we have new tools added to our armamentarium for prevention of mother-to-child HIV transmission, implementation of the existing proven effective interventions has been slow in resource-limited countries. Low rates of HIV testing among pregnant women, lack of availability and access to antenatal and prevention of mother-to-child transmission services, and difficulties integrating perinatal prevention interventions within existing antiretroviral treatment and maternal and child health services, compounded by human resource constraints, have contributed to the slow pace of expansion of prevention coverage. Additionally, prevention of mother-to-child HIV transmission cannot be viewed in isolation from optimization of maternal health and survival. Maternal and infant health are inextricably linked; uninfected infants born to HIV-infected women have higher rates of mortality than infants born to uninfected women and infant mortality is associated with advanced maternal disease. Assuring HAART for HIV-infected pregnant and postpartum women who require treatment for HIV disease (CD4 count <350 cells/μL or clinical symptoms) is essential to optimize maternal and child health and survival.
Implementation of postnatal antiretroviral prophylaxis, whether for infants or women, will be challenging, as it has been for implementation of perinatal prophylaxis. However, the cost of indecision and delay in program implementation is high. Each pediatric HIV infection that is not prevented increases the ultimate economic and social cost to each family, community, and country. We have proven interventions to prevent perinatal and breast milk HIV transmission in resource-limited countries-now we need to implement them.
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