Frenkel, Lisa M.Boyce, Ceejay2023-01-212023-01-212022Boyce_washington_0250E_24987.pdfhttp://hdl.handle.net/1773/49738Thesis (Ph.D.)--University of Washington, 2022HIV pretreatment drug resistance – defined as resistance detected prior to the initiation of antiretroviral therapy (ART) – has increased in prevalence over time in parallel with the increased global utilization of ART. The prevalence of pretreatment drug resistance has surpassed 10% to non-nucleoside reverse transcriptase inhibitors (NNRTI) in multiple countries, potentially threatening the efficacy of NNRTI-containing regimens which have been recommended for first-line ART in resource-limited settings for nearly two decades. In 2019, the WHO updated the recommended first-line regimen to integrase inhibitor-based ART to address the high levels of NNRTI pretreatment resistance; however, NNRTIs are still recommended in the alternative first-line regimen and for postnatal prophylaxis in infants to prevent vertical HIV transmission. The work presented in this dissertation sought to better understand the impact of HIV drug resistance on maternal treatment outcome and vertical transmission. We performed a series of clinical trial sub-studies that investigated genotypic HIV drug resistance – using Sanger and/or next-generation sequencing assays – among women living with HIV in resource-limited settings. Salient observations from the three studies include that (1) NNRTI resistance was prevalent among women prior to efavirenz-based ART initiation, but NNRTI resistance alone was not associated with virologic failure by 12 months of treatment; (2) maternal drug resistance was a risk factor for vertical transmission during breastfeeding, and drug resistance was prevalent among infants and accumulated during breastfeeding; and (3) pretreatment drug resistance among pregnant women living with HIV did not significantly contribute to virologic non-suppression at term; however, higher pretreatment HIV RNA load, randomization to efavirenz- versus integrase inhibitor-based ART, and shorter duration of ART were associated with non-suppression. Taken together, these results support WHO recommendations of early prenatal care engagement and initiation of integrase inhibitor-based ART for pregnant women living with HIV for optimal maternal outcomes and to prevent vertical transmission. However, for individuals who are unable to take integrase inhibitor-based ART, our data and others suggest the utility of TLE could be extended despite the high prevalence of NNRTI pretreatment resistance in resource-limited settings. Lastly, our findings suggest that NNRTI infant prophylaxis may be insufficient against drug-resistant variants in maternal breast milk and support the recommendation to replace NNRTI infant prophylaxis with regimens that have a greater barrier to drug resistance to prevent vertical transmission and retain NNRTI susceptibility in infected infants.application/pdfen-USnoneAntiretroviral therapyDrug resistanceHIVVertical transmissionMolecular biologyVirologyPathobiologyThesis