Virologic and pharmacologic determinants of dolutegravir failure in East Africa

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PROJECT SUMMARY Background: In response to rising rates of pre-treatment drug resistance (PDR) and risk of increasing rates of virologic failure in much of sub-Saharan Africa (SSA), a new affordable first-line antiretroviral therapy (ART) regimen of tenofovir (TFV), lamivudine (3TC), and dolutegravir, known as TLD, will be implemented widely throughout the region. Beginning in 2018, TLD will be the preferred first-line regimen both for individuals who are newly initiating ART and those currently on non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens. Given the scope of this policy, there is a critical responsibility to assess potential threats to the effectiveness of TLD in this population, such as pre-existing drug resistance to TFV and 3TC. Candidate: I am an Infectious Diseases specialist and clinical investigator engaged in international HIV research with 1.5 years of experience living and working as a clinical researcher in southwestern Uganda. I have also completed introductory didactics in clinical study design and analysis and have studied HIV epidemiology in SSA, leading to four related publications. My overarching career goal is to become an independent, NIH-funded clinician scientist with expertise in development and implementation of strategies to optimize the management of HIV treatment failure and drug resistance in SSA. Training: To achieve research independence, I will require targeted mentoring and additional training in 1) advanced biostatistical methods for large observational datasets, 2) HIV genomics and antiretroviral resistance interpretation and analysis, and 3) ART clinical pharmacology and pharmacologic adherence monitoring. Mentors: My training and research plans will be overseen by my primary mentor Dr. Mark Siedner, who has extensive mentoring and research experience conducting clinical studies in Uganda. Drs. Bethany Hedt-Gauthier (biostatistics), Daniel Kuritzkes (HIV drug resistance), and Jose Castillo-Mancilla (pharmacologic adherence monitoring) will serve as co-mentors to provide additional focused expertise. I will also receive annual feedback from my Scientific Advisory Board, which includes Drs. Mwebesa Bwana, Vincent Marconi, Jessica Haberer, and Rochelle Walensky. Research: With guidance from my team of mentors, I will evaluate the rate and determinants of HIV treatment failure following the planned implementation of TLD in East Africa through the following specific aims: 1) Compare the effect of TLD versus efavirenz-based first-line ART on viral suppression in a large cohort from East Africa. 2) Determine the contributions of pre-existing drug resistance to risk of treatment failure both for people newly initiating ART with TLD as well as for people switching to TLD from an NNRTI-based regimen. 3) Explore pharmacologic measures of adherence to distinguish virologic failure on TLD with versus without resistance using urine TFV levels and TFV-diphosphate in dried blood spots. Through this period of training and research, I will be well positioned to achieve research independence and plan to submit an NIH R01 application to study an innovative clinic-based ART adherence measure to guide management of virologic failure on TLD in SSA.