Hepatitis B (HBV) coinfection in HIV is common in resource-limited settings and is a leading cause of mortality. Infant immunoprophylaxis to prevent perinatal HBV transmission is often unavailable in resource- limited settings endemic for HIV and HBV, including those in Africa. As in HIV, antiviral therapy can be effective in the prevention of mother to child transmission (PMTCT) of HBV. However, there are potentially unintended consequences of single agent antiviral drug exposure for PMTCT. In HIV, when single agent nevirapine is used for PMTCT, HIV resistance commonly occurs and is associated with HIV treatment failure in infants and mothers. Similarly, the use of single agent lamivudine, an antiviral with both HIV and HBV activity, results in high rates of HBV resistance and a vaccine escape phenotype. Despite the widespread use of lamivudine in WHO-recommended HIV PMTCT regimens in areas endemic for HBV, it is unknown how lamivudine will impact HBV perinatal transmission and HBV drug resistance in HIV coinfection. The long-term goal of this research program is to identify the optimal prevention of mother to child transmission (PMTCT) regimen in HIV/HBV coinfected pregnant women. The objective here is to determine how lamivudine-containing PMTCT regimens impact HBV transmission. The central hypothesis is that lamivudine will reduce HBV perinatal transmission but result in maternal and infant HBV drug resistance and HBV vaccine escape mutations. Maternal minor populations of drug resistance may also be important in the transmission of resistance. The rationale is that if HBV drug resistance is common after lamivudine- containing PMTCT therapies, then regimens with higher HBV potency will be required. This central hypothesis will be tested using the serum repository of HPTN 046, an HIV PMTCT trial of extended infant nevirapine prophylaxis in 1522 mother-infant pairs in Africa. We will pursue three specific aims: 1) Determine the impact of lamivudine in the prevention of HBV perinatal transmission in HIV/HBV coinfected pregnant women, 2) Identify the predictors of perinatal HBV transmission and 3) Determine the impact of lamivudine on maternal and infant HBV drug resistance and vaccine escape phenotypes. Under the first two aims, the incidence and predictors of perinatal HBV transmission in HIV coinfection, including the role of antepartum lamivudine, will be determined. Under the third aim, the impact of lamivudine exposure on maternal and infant drug resistance will be examined. Using a novel minority variant assay developed by the applicant, the role of HBV minority variants as predictors of transmission will also be examined. The approach is innovative because it will change how HBV PMTCT regimens are selected and because it will utilize a novel minority variant detection assay that has several advantages over currently available techniques. The proposed research is significant because it will be the first step in defining the optimal PMTCT regimen in HIV/HBV coinfected women. Ultimately, such knowledge will inform global HBV public health prevention strategies.
The proposed research is relevant to public health, as it will inform global strategies in the prevention of HBV perinatal transmission, applicable to both HIV coinfection and HBV monoinfection. Thus, the proposed research is relevant to NIH's mission, particularly to the Division of AIDS (DAIDS), which has identified viral hepatitis an emerging critical research priority.
