Obesity at antiretroviral therapy initiation and long-term risk of cardiovascular disease, cancer, or death in people with HIV in Italy: a prospective cohort study

Background Altered adipose tissue biology plays a key role in the development of cardiovascular disease (CVD) and cancer and contributes to mortality. We assessed the association between obesity in people with HIV (PWH) at antiretroviral therapy (ART) initiation and the risk of clinical events. Methods In this prospective cohort study, we included ART-na & iuml;ve adults PWH enrolled in the Italian Cohort Naive Antiretrovirals (Icona) Foundation study cohort in Italy across 96 sites between January 1997 and July 2025. Participants were included if they initiated ART, had body mass index (BMI) > 18.5 kg/m(2), and were free from AIDS, CVD, and cancer at ART initiation. Participants were classified as having obesity, defined as BMI >= 30 kg/m(2), or not having obesity, defined as BMI 18.5-29.9 kg/m(2), at ART initiation. The primary outcome was the first occurrence of CVD, cancer, or death. We performed a standard survival analysis with time-fixed covariates at baseline with a composite outcome of CVD/cancer/death. We hypothesized that age may be an effect measure modifier: results are presented after stratification by age (young [18-30], middle aged [31-60] and older [>60 years]). Findings A total of 11,652 PWH (20.7% females, median age 38 years [Inter Quartile Range (IQR): 31, 46]) were included: 11,005 (94.4%) were people without obesity and 647 (5.6%) people with obesity. A total of 837 events were recorded: 122 CVD, 374 cancers and 341 deaths. By 15 years from ART initiation, the risk of CVD/cancer/death was 19.1% in people with obesity (95% Confidence Interval [CI]: 14.1-24.9%) vs. 12.4% in people without obesity (95% CI:11.3-13.4%, log-rank p = 0.0029). After controlling for confounding, the difference was attenuated (adjusted hazard ratio [aHR] 1.28 [95% CI:0.98-1.67], p = 0.073). Although we did not find evidence for interaction (p-value = 0.758) there was a trend for a larger effect among younger PWH: young (aHR 1.83 [95% CI 0.74, 4.56]), middle aged (aHR 1.49 [95% CI 1.11, 2.00]) and older (aHR 1.20 [95% CI 0.60, 2.41]). Interpretation Obesity at ART initiation may be associated with a clinically meaningful increase in the risk of CVD, cancer, and death. We found weak evidence of a possible age-related gradient, with larger effect size in PWH under 60 years of age, which warrants further investigation.