Clinical Scorecard: Genetic Variants of the Melanocortin-4 Receptor and Weight Changes After Transitioning to Integrase Inhibitor-Based Antiretroviral Treatment
At a Glance
Category
Detail
Condition
Weight gain associated with integrase strand transfer inhibitor (INSTI)-based antiretroviral therapy in persons with HIV
Key Mechanisms
Variants in the melanocortin-4 receptor (MC4R) gene influence appetite and body weight regulation, potentially contributing to neuroendocrine-mediated weight changes after INSTI switch
Target Population
Persons with HIV (PWH) switching from non-INSTI to INSTI-based ART
Care Setting
HIV clinical care and antiretroviral therapy management
Key Highlights
INSTI-based ART is associated with greater weight gain compared to other ART regimens, with wide interindividual variability suggesting genetic influences.
MC4R gene variants, known to regulate appetite and obesity risk, are associated with weight changes following switch to INSTI-based ART.
DTG (dolutegravir), an INSTI, inhibits melanocortin-stimulating hormone binding to MC4R, supporting a pharmacogenetic mechanism for weight gain.
Guideline-Based Recommendations
Diagnosis
Assess weight and BMI before and after switching to INSTI-based ART.
Consider genetic testing for MC4R variants in research or specialized settings to understand individual risk of weight gain.
Management
Monitor weight changes closely after switching to INSTI-based ART, especially in patients with known risk factors for obesity.
Incorporate lifestyle interventions targeting diet and physical activity to mitigate weight gain.
Monitoring & Follow-up
Regular weight and metabolic parameter monitoring up to 2 years post INSTI switch.
Evaluate CD4+ T cell counts and viral load to ensure ART efficacy alongside metabolic monitoring.
Risks
Weight gain associated with INSTI use may increase risk of obesity-related complications.
Genetic predisposition via MC4R variants may exacerbate weight gain risk.
Patient & Prescribing Data
529 persons with HIV, median age 50 years, 29% non-Hispanic Black, 22% female, majority overweight or obese at INSTI switch
62% switched to raltegravir; weight changes post-switch correlated with specific MC4R gene variants, suggesting genetic influence on treatment-related weight gain
Clinical Best Practices
Use patient-specific factors including genetic background to anticipate weight changes when switching ART regimens.
Educate patients on potential weight gain risks associated with INSTI-based ART and engage in shared decision-making.
Incorporate multidisciplinary approaches including nutrition and behavioral counseling to manage weight.
Consider ongoing research findings on pharmacogenetics to personalize ART selection and management.
by Todd Hulgan, Kristine M Erlandson, Yuki Bradford, Katherine Tassiopoulos, Kunling Wu, Sara H Bares, Todd T Brown, Jordan E Lake, Michael Leonard, Grace A McComsey, Marylyn D Ritchie, Paul E Sax, John R Koethe, David W Haas
