Metabolic Complications Among Persons with HIV in Nigeria

About This Grant

Weight gain following initiation of integrase strand transfer inhibitor (INSTI)-based antiretroviral therapy (ART) is a major emerging public health threat, significantly increasing risks for dyslipidemia, systemic inflammation, hypertension, diabetes, and cardiovascular disease among people with HIV (PWH) in both the United States (U.S.) and globally. Addressing this challenge is a priority for U.S. health, as identifying why some individuals experience "excessive" weight gain (well beyond “return to health” weight gain) will enable earlier, targeted interventions in at-risk U.S. populations. This research environment cannot be replicated in the U.S. due to extreme clinical heterogeneity: the U.S. Food and Drug Administration (FDA) has approved 26+ individual ARV medications across 7 mechanistic classes, leading to diverse prescribing patterns in which only ~52% of patients follow recommended initial regimens. Furthermore, the median U.S. ART treatment duration is 9.8 years, creating a complex history of prior drug exposures that act as significant confounders in metabolic studies. In contrast, Nigeria uniquely offers a high volume of new HIV diagnoses and a near-uniform use of TLD (tenofovir/lamivudine/dolutegravir). This uniformity provides a unique "natural laboratory" that yields faster, more direct answers about metabolomic and lipidomic signatures by eliminating the noise introduced by varied drug histories. Consequently, these findings can be scaled and adapted globally, directly benefiting the U.S. by informing next-generation diagnostic tools, treatment strategies, and prevention modalities. We hypothesize that substantial early weight gain on TLD is driven by distinct alterations in metabolic and lipid pathways. To test this, we will: 1) Determine the effect of substantial early weight gain on TLD on insulin resistance, blood pressure, dyslipidemia, and inflammation. We will enroll previously ART-naïve patients who initiated TLD regimens (n=200 total) in northern Nigeria and gained <3% body weight (n=100) versus >10% body weight (n=100) over their first 12–24 months of therapy. 2) Determine the metabolic and lipid pathways associated with weight gain during the first 12 months of TLD exposure using metabolomic and lipidomic profiling. We will enroll 60 ART-naïve patients initiating TLD and collect longitudinal sociodemographic, behavioral, clinical, metabolomic, and lipidomic data, along with abdominal CT imaging, to characterize visceral adiposity, hepatic density, and alterations in carbohydrate and lipid metabolism among participants with differing weight trajectories.