Exploring low-level HIV viremia among individuals on dolutegravir in sub-Saharan Africa (Low-V Africa Study)

About This Grant

PROJECT SUMMARY Significance: Low-level viremia (LLV) is considered a category of clinical concern by health agencies due to the potential for adverse individual and public health consequences. As such, there is a need to better understand the downstream effects of LLV, particularly for individuals on tenofovir, lamivudine, dolutegravir (TLD), which is now the most common regimen in sub-Saharan Africa, where the global burden of HIV is highest. Innovation: We propose to enroll a comprehensive, longitudinal cohort specifically for the study of people living with HIV experiencing persistent LLV (pLLV) while on TLD in South Africa (Low-V Africa). This proposal also incorporates cutting-edge plasma and proviral sequencing and integration site studies to explore a novel mechanism of clonal expansion of the HIV-1 reservoir as a contributor to outcomes of pLLV. Investigators: Our expert team of clinical epidemiologists (Suzanne McCluskey, Richard Lessells, Mark Siedner), virologists (Jonathan Li, Nokukhanya Msomi), clinical HIV experts (Mahomed Yunus Moosa), and biostatisticians (Musie Ghebremichael) is well-suited to address these important public health questions. We will build upon well-established collaborations and clinical research infrastructure in South Africa to promote an in-depth examination of LLV in the setting of TLD use through completion of the following specific aims: Specific Aims: Aim 1) The Low-V Africa Study will prospectively enroll and follow a cohort of adults with at least two consecutive HIV-1 RNA viral loads between 50-1,000 copies/mL while on TLD. We will then determine longitudinal outcomes at 96 weeks after enrollment. Specifically, we will determine the cumulative incidence of virologic failure, as well as viral suppression and ongoing persistence of LLV (Aim 1a). We will also determine the cumulative incidence of emergent HIV drug resistance and a hyperactive viral reservoir during pLLV (Aim 1b). Aim 2) We will elucidate pharmacologic, viral, and host factor determinants of the progression to virologic failure among participants in the Low-V Africa Cohort. We will evaluate adherence patterns, as determined by tenofovir-diphosphate concentrations from dried blood spots (Aim 2a), HIV drug resistance (Aim 2b), and the HIV reservoir (Aim 2c) as determinants of progression to virologic failure. We will then define the relative contributions of adherence, resistance, and reservoir to virologic failure following pLLV (Aim 2d). Impact: Aligned with NIH HIV research priorities, knowledge gained from this study will improve our understanding of the outcomes of LLV in the dolutegravir era, paving the way for future studies to determine optimal management for this population in sub-Saharan Africa.