P-465. Melanocortin-4 Receptor Gene Variants and Weight Change Following Switch to Integrase Inhibitor-containing Antiretroviral Therapy
Authors: Hulgan Todd , Erlandson Kristine M , Bradford Yuki , Tassiopoulos Katherine , Wu Kunling , Bares Sara H , Brown Todd T , Lake Jordan , Leonard Michael A , McComsey Grace A , Ritchie Marylyn , Sax Paul E , Koethe John R , Haas David 
Published: January 2025

Abstract

Background
Weight gain among persons with HIV (PWH) on integrase strand transfer inhibitors (INSTIs) is highly variable. Given the importance of the melanocortin-4 receptor (MC4R) in obesity, we examined associations between MC4R gene variants and weight gain following switch to INSTI-containing antiretroviral therapy (ART) among PWH in ACTG observational cohort studies A5001 and A5322.

Methods
Eligible participants switched to their first INSTI-containing ART from 2005-2018 and had available genetic and weight data. Imputed genotypes were from genome-wide data. Linear models assessed associations between MC4R variants and weight change, including 20 variants previously associated with weight/obesity in populations without HIV. Analyses adjusted for age, sex at birth, genetic principal components, time after switch, and body mass index, CD4 count and virologic control at switch; separate models were stratified by race/ethnicity, sex and baseline BMI category.

Results
Among 530 PWH, median age was 50 (IQR 42, 57) years, 29% were non-Hispanic Black, 22% were cis-gender female, 62% were overweight or obese at INSTI switch, and 73% switched from a protease inhibitor. INSTIs were raltegravir (62%), dolutegravir (21%), elvitegravir (17%), and bictegravir (1%). The switch regimen included tenofovir alafenamide (TAF) in 9%. Overall median weight gain after switch was 1.25 kg (IQR -1.2, 4.0). Of 20 MC4R variants previously associated with weight/obesity, three were nominally associated (p&lt; 0.05) with weight change after switch in all participants or in subgroups. One (rs11873305) was associated with weight gain in all participants (p=0.01), and male (p=0.004) and White (p=0.02) subgroups. Of 507 additional MC4R variants, the lowest p-value among all participants was for rs56758444 (p=0.001). After Bonferroni correction, no variant was significant in MC4R or in exploratory genome-wide analysis.

Conclusion
Among PWH, MC4R variants were nominally associated with weight change after switch to INSTI-based ART. These findings are consistent with the known importance of melanocortins in appetite and weight, and suggest a neuroendocrine contribution to INSTI-related weight gain. Additional studies with newer INSTIs and TAF are needed.

Disclosures
Kristine M. Erlandson, MD MS, Gilead: Advisor/Consultant|Gilead: Grant/Research Support|ViiV: Advisor/Consultant Sara H. Bares, MD, Gilead Sciences: Expert Testimony|Janssen: Grant/Research Support|ViiV Healthcare: Grant/Research Support Todd T. Brown, MD, PhD, EMD Serono: Advisor/Consultant|Janssen: Advisor/Consultant|Merck: Advisor/Consultant|ViiV Healthcare: Advisor/Consultant|ViiV Healthcare: Honoraria Jordan Lake, MD, Merck: Advisor/Consultant|Theratechnologies: Advisor/Consultant Grace A. McComsey, MD, Gilead, Merck, GSK: Advisor/Consultant John R. Koethe, MD, Gilead Sciences: Advisor/Consultant|Gilead Sciences: Grant/Research Support|Merck & Co.: Advisor/Consultant|Merck & Co.: Grant/Research Support