Nevirapine resistance in HIV-infected women and infants after exposure to nevirapine-based prophylaxis.

摘要

Over 300,000 infants are HIV-infected each year, and the majority of HIV-infected pregnant women do not have access to any antiretroviral prophylaxis. The simplest option for prevention of vertical HIV transmission is the HIVNET012 regimen of a single-dose of nevirapine (SD NVP) to the mother in labor and SD NVP to the infant shortly after birth. This regimen drastically reduces the risk of mother-to-child transmission of HIV (MTCT), is easy to implement, and is more affordable than other regimens. One of the main disadvantages to the regimen is the emergence of NVP resistant variants in mothers and in infants who are HIV-infected despite prophylaxis.;A variety of assays are available for detection of NVP resistance. Work in this dissertation shows that if the risk of resistance is expected to be high, then population genotyping methods should be used. Alternative assays (i.e. point mutation assays, phenotypic assays) should be considered for special circumstances (i.e. low-levels of resistance mutations, complex resistance mutation patterns).;One of the major risk factors for detection of resistance in HIV-infected women who were exposed to SD NVP is HIV subtype. I have shown that the difference in risk of resistance in subtype D versus subtype A HIV is not explained by pre-existing levels of resistance mutations or differences in the types of amino acid changes that occur after exposure to SD NVP. Several factors affect emergence of NVP resistance in HIV-infected infants. As described in this dissertation, the most important determinant of resistance in HIV-infected infants who are SD NVP exposed is in utero infection. Infants who are HIV-infected despite receiving extended NVP prophylaxis are at a high risk of resistance regardless of time of infection, and these infants also have a higher risk of persistence of resistance compared to SD NVP infants. Prior maternal exposure to SD NVP does not increase the overall risk of resistance in infants. Infants who do have multiple resistance mutations occur can have complex patterns of mutations, which may lead to treatment failure with NNRTIs. Further clinical trials should be designed to reduce the risk of resistance in infants.