Editorial

Preventing Mother-to-Child Transmission of HIV — Protecting This Generation and the Next

Marc Lallemant, M.D., and Gonzague Jourdain, M.D.

N Engl J Med 2010; 363:1570-1572October 14, 2010

Approximately half of the 33.4 million persons living with the human immunodeficiency virus (HIV) worldwide are women of reproductive age, and among the 2.1 million HIV-infected children, virtually all were infected during pregnancy, delivery, or breast-feeding.1 Since 2002, the number of newly infected children has declined, probably owing to increased implementation of interventions for the prevention of mother-to-child transmission of HIV and the global stabilization of HIV prevalence among women.2 With these advances, new challenges have surfaced.

In 2008, almost half of HIV-infected pregnant women received antiretroviral medications for the prevention of mother-to-child transmission.1 In most cases, the simplest intervention, single-dose nevirapine, was given to the mother during labor and to the infant after birth. Nevirapine halves the risk of peripartum transmission3 but persists at clinically significant levels for days, potentially selecting HIV resistance mutations that may negatively affect the efficacy of nevirapine-based therapies when mothers and infected children subsequently require treatment for their own health. This poses an important public health challenge, since nevirapine-based therapies are the most widely available and affordable treatments in resource-limited countries, where more than 95% of infections in infants and children occur.

Because resistance mutations may fade away over time, there has been considerable uncertainty regarding treatment outcomes with regimens based on non-nucleoside reverse-transcriptase inhibitors (NNRTIs) as compared with outcomes with NNRTI-sparing regimens, when therapy is initiated more than 6 months after exposure to single-dose nevirapine. Two articles in this issue of the Journal 4,5 provide some of the most clear, concrete, and consistent evidence to address this question.

Lockman and colleagues report the results of the Optimal Combination Therapy after Nevirapine Exposure (OCTANE) A5208 trial,4 in which 241 HIV-infected mothers who had been exposed to single-dose nevirapine 6 months or more before randomization were assigned to receive ritonavir-boosted lopinavir–based therapy or nevirapine-based therapy. After 2 years, 8% of the women in the ritonavir-boosted lopinavir group had virologic failure (or died), as compared with 26% in the nevirapine group. In the nevirapine group, the proportion of women with resistance mutations detectable at the time of the initiation of treatment was small (13%), but these women had the highest failure rate, 73%, as compared with 19% among women in the nevirapine group without resistance mutations. In a companion trial involving women who had not been exposed to single-dose nevirapine, failure rates were 14% in both the ritonavir-boosted lopinavir group and the nevirapine group.

Palumbo and colleagues5 report similar findings among children. In the P1060 trial, 164 HIV-infected children were randomly assigned to ritonavir-boosted lopinavir–based therapy or nevirapine-based therapy more than 6 months after exposure to single-dose nevirapine. After 24 weeks, 40% of the children in the nevirapine group, as compared with 22% in the ritonavir-boosted lopinavir group, had treatment failure or discontinued the study treatment (the corresponding rates for treatment failure were 27% and 10%). Again, resistance mutations, detectable at initiation in 9.3% of children in the nevirapine group who were tested, predicted treatment failure: 83% with resistance mutations had treatment failure, as compared with 36% without resistance mutations. No unexpected toxic effects were observed, and deaths in both studies were unlikely to have been attributable to the study treatments.

The OCTANE and P1060 studies confirm that women and children in whom therapy is initiated 6 months or more after exposure to single-dose nevirapine have diminished response to nevirapine-based therapy, as compared with ritonavir-boosted lopinavir–based therapy, and the difference in failure rates is largest among those with detectable resistance mutations at initiation. One important point — although it is to be interpreted with caution — is that the differential response between nevirapine-based therapy and ritonavir-boosted lopinavir–based therapy tended to decrease as the interval between exposure to single-dose nevirapine and initiation of therapy increased; however, there is no clear cutoff time for equivalence. Furthermore, the bulk sequencing performed in these studies to determine the presence of HIV-resistant clones at baseline is a relatively insensitive technique (detecting variants that are present more than 20% of the time); however, a more sensitive test may improve the prediction.

These results support the updated World Health Organization (WHO) recommendations that a regimen based on ritonavir-boosted lopinavir should be used for women and for children younger than 24 months of age if they have had previous exposure to single-dose nevirapine.6 The results of these studies also pose additional important questions. First, what are the differences in long-term response (at 5 or 10 years) to the two treatments, after allowing for discontinuation of treatment owing to toxic effects and response to second-line therapies? Treatment options are severely limited in developing countries. Longer follow-up of these cohorts and broader end points than those in these studies are essential for informing long-term policy and practice. It is possible that nonsignificant differences between the nevirapine group and the ritonavir-boosted lopinavir group that were seen over the short term in the P1060 study, such as increases in the percentage of CD4+ lymphocytes and in z scores for height and weight, could translate into more important differences over the long term.

Second, are there safe and feasible strategies for the preservation (or recycling) of nevirapine-based therapy? The Pediatric Nevirapine Resistance Study (ClinicalTrials.gov number, NCT00117728) involving children exposed to single-dose nevirapine proposed an innovative approach of switching to nevirapine after 3 months of virologic suppression with the use of ritonavir-boosted lopinavir–based therapy.7 Although preliminary results suggest that virologic replication is not as well controlled with nevirapine as it is with continued ritonavir-boosted lopinavir, this strategy could be considered after a longer induction with ritonavir-boosted lopinavir–based therapy to allow for further decay of resistance mutations or could be used in older children, for whom a longer time has elapsed since exposure to single-dose nevirapine.

Third, since the cost of ritonavir-boosted lopinavir is considerably higher than that of nevirapine, is there a role for resistance screening to identify those who require ritonavir-boosted lopinavir–based therapy? Furthermore, when genotyping is not available, is it feasible (albeit controversial) to initiate a nevirapine-based therapy under close laboratory monitoring, with swift provision of second-line therapy in the event of failure? This would preserve the potent, low-cost, well-tolerated nevirapine-based therapy for those — the majority — who would respond to it. Cost-effectiveness analyses are needed alongside these important trials before large-scale implementation is considered.

The results of the OCTANE and P1060 trials are highly relevant despite the paradigm shift away from interventions incorporating single-dose nevirapine to interventions comprising highly active antiretroviral drugs for the prevention of mother-to-child transmission. In resource-limited settings, where many women still present late for antenatal care and too few are screened for CD4+ cell count, single-dose nevirapine will most likely remain an important component of the toolkit for the prevention of mother-to-child transmission. Nonetheless, these studies highlight the weaknesses in the current implementation of strategies for the prevention of mother-to-child transmission. Early and effective antenatal and postnatal HIV care are needed, including the provision of efficacious antiretroviral regimens, or “tails,” for both mothers and children who are being exposed to single-dose nevirapine, in order to avert resistance mutations in the first place.8,9 With provision of an efficacious tail, the response to nevirapine-based therapy in women and infected children would probably be considerably better than it was in the two studies in this issue of the Journal. However, we do not yet know how to effectively avoid resistance mutations in children with long-term exposure to nevirapine prophylaxis during breast-feeding.

These studies help equip us with strategies to deal with the current imperfections in our scale-up efforts. With the new WHO guidelines calling for increased access to therapy and prophylaxis for both immunocompromised and nonimmunocompromised pregnant women and timely provision of maternal and infant antiretroviral prophylaxis throughout pregnancy, delivery, and breast-feeding, the goal of eradication of pediatric HIV is within sight.2,6 Reaching that goal will require long-term investment in health systems, integration of strategies for the prevention of mother-to-child transmission into maternal and child health programs and national HIV treatment programs, access to laboratory monitoring, and second-line and third-line regimens. It is remarkable that despite the economic downturn, major international agencies and nongovernmental organizations have committed themselves to this ambitious goal.10

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

Source Information

From Institut de Recherche pour le Développement, Marseille, France; Harvard School of Public Health, Boston; and Chiang Mai University, Chiang Mai, Thailand.