In the PEPI-Malawi trial, a substantial proportion of the HIV-infected breastfeeding infants whose mothers started HAART postpartum developed MCR. Although the NNRTI resistance mutations in these HIV-infected infants may have arisen due to infant receipt of sdNVP (in the control study arm) or extended NVP (in the extended NVP and extended NVP plus ZDV study arms), four lines of evidence suggest that acquisition of NRTI resistance in the infants resulted from maternal HAART use and not from exposure to ZDV in the infant regimens used for pMTCT. First, in a previous study, we analyzed resistance in infants in the PEPI-Malawi trial whose mothers did not initiate HAART by 14 weeks; none of the 85 infants in that study had virus with ZDV resistance mutations or any other NRTI mutations at 14 weeks of age (the maximum length of prophylaxis) [16
]. Second, in this report, we did not detect NRTI resistant virus in any infant prior to the mother's first report of HAART use; among the 11 infants who subsequently developed MCR, none of the 6 infants with pre-HAART samples had NRTI resistance before the mother's first report of HAART use, and 2 of the remaining infants did not have NRTI resistance, at the time the mother first reported HAART use. Third, in this report, acquisition of MCR was not associated with the type or duration of the regimen used for pMTCT (eg, MCR virus was not more frequent among infants in the extended NVP plus ZDV arm than among infants in the control or extended NVP study arms). Finally, the NRTI mutations detected in infants with MCR virus were typical of those selected by drugs in the maternal HAART regimen (3TC and d4T). We did not detect any mutations that are typically associated with ZDV resistance.
In contrast to our findings related to NRTI resistance, infants in the PEPI-Malawi trial frequently acquired NNRTI resistance as a result of exposure to the infant regimens used for pMTCT. Therefore, exposure to both infant NVP used for pMTCT and NVP in the mother's HAART regimen may have contributed to acquisition of NNRTI resistance in the infants. This study did not find an association between acquisition of MCR and maternal sdNVP administration but was not powered to detect small associations. We also did not find an association between acquisition of MCR and the type of regimen that the infant received for pMTCT, the duration of prophylaxis, or detection of NNRTI resistance in the infant at the study visit prior to the mother's first report of HAART use.
Two factors were statistically associated with acquisition of MCR in these infants: (1) earlier initiation of maternal HAART, and (2) exclusive breastfeeding. Mothers of all 11 infants who developed MCR first reported HAART use by 6 months post-partum (8 of 11 mothers reported HAART use by 14 weeks), and all 11 were providing exclusive breastfeeding when they first reported HAART use. We recognize that the small number of infants in this sub-study may have limited the power to detect associations between MCR and other variables examined. Also, because we did not have information on maternal HAART adherence, we were not able to assess the association between maternal HAART adherence and acquisition of MCR in the infants. Acquisition of MCR occurred soon after maternal HAART initiation. Two infants had MCR detected at the visit where the mother first reported HAART use (note that the mother initiated HAART at some point between that visit and the prior study visit), 8 infants developed MCR within 3 months after the mother first reported HAART use, and 1 developed MCR within 6 months after that visit.
We are currently investigating the mechanism(s) responsible for acquisition of MCR in this setting, which include direct transmission of resistant strains to the infant through breast milk and/or transfer of antiretroviral drugs through breast milk that result in sub-therapeutic infant plasma concentrations and selection of MCR virus after infant HIV infection. Women in the PEPI-Malawi trial who received HAART postpartum received the first-line treatment regimen of NVP-3TC-d4T. NVP and 3TC are transferred into breast milk and breastfeeding infants when women receive HAART [21
], but less is known about the transfer of d4T into breast milk and breastfeeding infants.
The results of this study should also be considered in the context of the availability of treatment programs for HIV-infected infants. A recent study demonstrated dramatic improvement in the survival of HIV-infected infants who started HAART by 3 months postpartum [23
]. As antiretroviral treatment for HIV-infected infants becomes more widely available, more infants may initiate HAART near the time of birth. Current WHO recommendations for infants who are HIV infected despite exposure to NVP prophylaxis are to initiate therapy with protease inhibitor–based regimens [24
]. Our data suggest that the choice of antiretroviral drugs for treatment may be limited in HIV-infected infants whose mothers initiate HAART postpartum while they are still breastfeeding. It is not known whether concurrent use of HAART in women and their breastfeeding HIV-infected infants reduces the infants’ risk of MCR or whether concurrent antiretroviral treatment of women and their breastfeeding infants exposes the infants to levels of antiretroviral drugs that may be associated with toxicity. Exposure to maternal HAART in utero and during breastfeeding has been found to increase the risk of neutropenia in infants who are not receiving any antiretroviral drugs [25
]. These issues are likely to become increasingly important as treatment programs for HIV-infected women and infants are scaled up around the world.
As antiretroviral drug availability continues to improve in resource-limited settings, the issues surrounding use of antiretroviral drugs for pMTCT and for treatment of HIV-infected women and their infants are becoming increasingly complex. Although significant advances have been made in pMTCT, there is still an urgent need to address issues associated with effective antiretroviral interventions, such as acquisition of MCR, that could compromise the safety and scale-up of these programs.
To optimally preserve maternal health and reduce mother-to-child transmission of HIV, women who need antiretroviral treatment for their own health need to be identified and to initiate HAART early in pregnancy; this will significantly reduce the risk of in utero as well as intrapartum HIV transmission, compared with initiation of antiretroviral drugs late in pregnancy or postpartum. By reducing the number of infants who become infected, the problem of MCR will also be reduced. The WHO recommendations for pMTCT include use of extended maternal triple-drug regimens when treatment is not required for maternal health; this approach is being used with increasing frequency [26
]. Our data, along with other reports [18
], indicate that maternal triple-drug use, either for treatment or solely for prophylaxis, particularly when first initiated postpartum, may be associated with development of MCR in the infants who are infected with HIV despite prophylaxis for pMTCT. These data emphasize the importance of prompt identification of HIV infection in pregnant women, initiation of antiretroviral treatment early in pregnancy when needed for maternal health, and initiation of effective prophylaxis regimens beginning in pregnancy when treatment is not needed, to reduce the risk of mother-to-child transmission of HIV. Finally, when initiating antiretroviral therapy in infants who have HIV infection despite maternal HAART or triple-drug prophylaxis, the risk of MCR infection in infants should be taken into account when choosing an appropriate treatment regimen.