Comparative Metabolic Safety of Efavirenz-, Dolutegravir-, and Bictegravir-based antiretroviral regimens in HIV-Infected Adults: Evidence for Weight-Dependent Lipid Deterioration

Background The second-generation integrase strand transfer inhibitors (INSTIs) are gradually replacing efavirenz (EFV) in antiretroviral therapy due to their superior efficacy and tolerability. However, there are still concerns about their long-term metabolic safety, particularly weight gain and dyslipidemia. In real-world settings, comparative evidence on the longitudinal metabolic effects of EFV, dolutegravir (DTG), and bictegravir (BIC) in the Asian population is still limited. This study evaluated the metabolic trajectories of these regimens and explored the mediating role of weight gain in hypertriglyceridemia(HTG). Methods HIV-infected adults initiating EFV-, DTG-, or BIC-based regimens were included. Linear mixed-effects models assessed longitudinal changes in metabolic parameters. Growth mixture modeling(GMM) identified distinct BMI trajectories, and mediation analysis evaluated weight gain's role in incident HTG.The mediation analysis for incident HTG was performed in a sub-cohort of 492 participants with normal baseline triglyceride(TG) levels. Results In the study population, the baseline characteristics, including education, WHO clinical stage and viral load, differed significantly. Both the DTG and BIC groups exhibited significantly faster increases in BMI and FBG over time than the EFV group (P interaction < 0.05). Regarding lipids, the DTG regimen demonstrated a generalized effect of increasing TG, whereas the BIC regimen significantly accelerated TG elevation, specifically in individuals with normal baseline levels. GMM identified a distinct "BMI increasing" trajectory (17.7% of participants). Crucially, mediation analysis revealed that the risk of incident HTG associated with INSTI-based regimens was fully mediated by weight gain (indirect effects, P < 0.05), with no significant direct drug effects. Conclusion Compared to EFV-based regimen, DTG- and BIC-based regimens are associated with time-dependent weight gain and hyperglycemia. The risk of incident HTG associated with these regimens is primarily driven by progressive weight gain rather than by direct drug toxicity. Monitoring dynamic BMI trajectories is essential for early identification of metabolic risk.