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Background  In people living with HIV (PLWH), statins may be disproportionately effective but remain underutilized. A large prospective trial in patients with low to moderate cardiovascular (ASCVD) risk will reveal whether they should be considered in all PLWH. But its effect size may not apply to real-world PLWH with higher ASCVD and mortality risk. Also, the clinical role of non-statin lipid-lowering therapy (LLT) and LLT adherence in this population is unknown.    Methods  Comparative multi-level marginal structural model for all-cause mortality examining four time-updated exposure levels to LLT, antihypertensives, and aspirin in a virtual cohort of older PLWH. Incident coronary, cerebrovascular, and overall ASCVD events, serious infections, and new cancer diagnoses served as explanatory outcomes.    Results  In 23,276 HIV-infected US-veterans who were followed for a median of 5.2 years after virologic suppression overall mortality was 33/1000 patient years: > 3 times higher than in the US population. Use of antihypertensives or aspirin was associated with increased mortality. Past LLT use (> 1 year ago) had no effect on mortality. LLT exposure in the past year was associated with a reduced hazard ratio (HR) of death: 0.59, 95% confidence interval (CI) 0.51–0.69,  p  < 0.0001 for statin containing LLT and 0.71 (CI: 0.54–0.93),  p  = 0.03 for statin-free LLT. For consistent LLT use (> 11/12 past months) the HR of death was 0.48 (CI: 0.35–0.66) for statin-only LLT, 0.34 (CI: 0.23–0.52) for combination LLT, and 0.27 (CI: 0.15–0.48) for statin-free LLT (p < 0.0001 for all). The ASCVD risk in these patients was reduced in similar fashion. Use of statin containing LLT was also associated with reduced infection and cancer risk. Multiple contrasting subgroup analyses yielded comparable results. Confounding is unlikely to be a major contributor to our findings.    Conclusions  In PLWH, ongoing LLT use may lead to substantially lower mortality, but consistent long-term adherence may be required to reduce ASCVD risk. Consistent non-statin LLT may be highly effective and should be studied prospectively.    Supplementary Information  The online version contains supplementary material available at 10.1186/s12879-021-05787-4.

Consistent use of lipid lowering therapy in HIV infection is associated with low mortality