CROI 2024 Abstract eBook

Abstract eBook

Poster Abstracts

804

Weight Gain After Initiating ART Close to HIV Seroconversion: Is There a Return to Health Effect? Nikos Pantazis 1 , Sophie Grabar 2 , Marc Van der Valk 3 , Caroline Sabin 4 , Inma Jarrin 5 , Laurence Meyer 6 , Christina Carlander 7 , John Gill 8 , Shema Tariq 4 , Alain Volny Anne 9 , Fiona Burns 4 , Elisa Ruiz-Burga 4 , Giota Touloumi 1 , Kholoud Porter 4 , for the CASCADE Collaboration 1 National and Kapodistrian University of Athens, Athens, Greece, 2 Institut National de la Santé et de la Recherche Médicale, Paris, France, 3 Stichting HIV Monitoring Foundation, Amsterdam, Netherlands, 4 University College London, London, United Kingdom, 5 Institute of Health Carlos III, Madrid, Spain, 6 Université Paris-Saclay, Paris, France, 7 Karolinska University Hospital, Stockholm, Sweden, 8 Southern Alberta Clinic, Calgary, Canada, 9 Paris, France Background: Findings from seroprevalent cohorts suggest that weight gain after ART initiation is greater with regimens containing Integrase Strand Transfer Inhibitors (INSTI) than with other antiretrovirals. We investigate weight trends among individuals initiating ART within one year of seroconversion (SC). Methods: Included individuals from the CASCADE Collaboration seroconverted 1997-2022, were ≥16 years, had HIV- to HIV+ test interval ≤1 year or other laboratory evidence of SC, and initiated ART ≤12 months from SC. Weight changes from baseline (censored after switching ART class) were analyzed with piecewise linear mixed models. Results: 6482 (22.7%) of 28556 individuals were included (2814, 1999 and 1669 with INSTI, boosted PI or NNRTI regimens, respectively). Most acquired HIV through sex between men (79.3%), and 8.3% men and 8.9% women through heterosexual contact. Median (IQR) age at SC was 34 (27, 43) years, CD4 at ART initiation 451 (320, 620) cells/μl and follow-up time 1.4 (0.3, 3.6) years. Weight changes differed significantly (p<0.001) by ART class and baseline BMI. In the first 6 months, weight gains were generally most pronounced among those on INSTIs, regardless of baseline weight. This trend remained by 3 years for BMI categories <30, although those receiving boosted PIs also experienced weight gain. "Typical individuals" (Figure) had significant weight gains with all three ART classes after 3 years except for baseline BMI ≥30. Individuals with BMI 18.5-29.9 gained weight significantly faster with INSTIs compared to other ART classes. Overall, 16% with BMI 18.5-24.9 and 11% with BMI 25-29.9 on INSTIs gained >10% of their baseline weight after 3 years (9% and 8% for boosted PIs; 7% and 6% for NNRTIs). Significant differences in initial (0-6 months) rate of weight gain were observed between INSTI regimens (p<0.001). Bictegravir or Elvitegravir + TAF backbone were associated with the fastest rates. Dolutegravir without TAF/TDF, and Elvitegravir + TDF were associated with the slowest. Estimated (95% CI) weight gains after 3 years among "typical individuals" with BMI 18.5-24.9 were 5.6 (4.5, 6.6), 4.4 (3.5, 5.4), 3.6 (2.8, 4.4), and 3.4 (2.5, 4.2) kgs, respectively. Conclusion: As reported in seroprevalent cohorts, Bictegravir and Elvitegravir combined with TAF were associated with the fastest increases in weight. Given that ART was initiated soon after SC, it is unlikely that this is a return to health phenomenon, although the effect of unmeasured confounders can't be disregarded.

803

Dolutegravir Targets the Hypothalamus to Suppress Energy Expenditure via Estrogen Receptor Ikrak Jung 1 , Sunghee Jin 1 , Woosub Yang 2 , Yoonmi Cho 2 , Becky Tu-Sekine 1 , Frederick Anokye-Danso 1 , In-Hyun Park 2 , Todd T. Brown 1 , Sangwon F Kim 1 1 The Johns Hopkins University School of Medicine, Baltimore, MD, USA, 2 Yale University, New Haven, CT, USA Background: Antiretroviral therapy (ART) containing integrase strand transfer inhibitors (INSTI) has been associated with weight gain in both ART-initiation and switch studies, especially in women, but the underlying mechanisms are unclear. Estrogen promotes energy expenditure via suppressing AMP dependent kinase (AMPK) in the hypothalamus and yet very few studies are available examining the central effects of INSTI on weight gain. Hence, we hypothesized that dolutegravir (DTG) may inhibit thermogenesis via estrogen receptors in the hypothalamus. Methods: We examined the effects of DTG (10mg/kg for 5 days) on food intake, energy expenditure, oxygen consumption in female mice using the Comprehensive Laboratory Animal Monitoring System. Adipose and brain tissues were analyzed using qRT-PCR and immunoblotting for appetite and thermogenesis. Primary hypothalamic neurons and inducible human pluripotent stem cells-driven hypothalamic organoids were treated with DTG and estradiol and examined for changes in cellular signaling associated with the regulation of energy homeostasis. Computational analysis was performed to evaluate the potential interaction between DTG and estrogen receptors. Results: We found that DTG administration to female mice reduced oxygen consumption and energy expenditure by 16% without affecting food consumption. Gene expression analyses in adipose tissues confirmed that thermogenic marker expression (UCP1, DIO2 and CIDEA) was reduced. Moreover, DTG administration activated the AMPK signaling cascade in the hypothalamus. Murine primary hypothalamic neurons treated with estrogen led to inactivation of AMPK while DTG attenuated estrogen-mediated suppression of AMPK activity. We further confirmed the DTG activates AMPK and inhibits estrogen effect on human hypothalamic organoids, which retain the heterogeneity and neural circuity of the brain. Finally, molecular docking analysis showed that DTG can physically bind to estrogen receptors. Conclusion: DTG administration increased body weight by suppressing energy expenditure without affecting food intake. Tissue analyses revealed that DTG activates the hypothalamic AMPK pathway, which suppresses thermogenesis. In vitro study using murine primary hypothalamic neurons and human hypothalamic organoids showed that DTG inhibits estrogen-mediated hypothalamic regulation of thermogenesis. These findings suggest a novel mechanism by which INSTIs may lead to weight gain, especially in women. The figure, table, or graphic for this abstract has been removed.

Poster Abstracts

CROI 2024 243