Early HIV Treatment and Cardiovascular Health: Insights from the START Study

Highlight

• Early initiation of antiretroviral therapy (ART) in HIV-positive adults with high CD4+ counts does not significantly reduce cardiovascular disease (CVD) risk overall compared to deferred therapy.
• Women receiving immediate ART may experience a notable reduction in CVD events, while men do not show the same benefit.
• The study observed differing cardiovascular event patterns: strokes were more frequent in women, whereas coronary revascularizations were more common in men.
• The findings highlight the need for further research on sex-specific cardiovascular outcomes related to ART timing.

Study Background

Cardiovascular disease remains a significant cause of morbidity and mortality among people living with HIV (PLWH). With the advent of antiretroviral therapy (ART), life expectancy for PLWH has improved markedly; however, concerns persist regarding the long-term cardiovascular consequences of ART initiation timing. High CD4+ counts typically indicate preserved immune function, and whether initiating ART early—despite low baseline cardiovascular risk—confers cardiovascular advantages or risks remains uncertain. Understanding these dynamics is crucial for optimizing clinical decision-making and minimizing non-infectious comorbidities in HIV care.

Study Design

Researchers performed an extended follow-up of the Strategic Timing of Antiretroviral Treatment (START) trial to evaluate cardiovascular outcomes associated with early versus deferred ART initiation. The study enrolled 4684 ART-naive adults living with HIV, median age 36 years, including 27% women. Inclusion criteria mandated CD4+ counts above 500 cells/μL and low baseline CVD risk.

Participants were randomized into two groups: immediate ART initiation within 7 days, or deferred ART initiation triggered by CD4+ decline below 350 cells/μL or clinical disease progression. The median delay to ART start in the deferred arm was approximately 2.5 years. The composite cardiovascular outcome encompassed myocardial infarction, stroke, coronary revascularization, and cardiovascular-related death.

Key Findings

Over the entire study duration, the primary composite cardiovascular event rate was similar between immediate and deferred ART groups — 0.16–0.18 vs. 0.17 per 100 person-years, respectively (hazard ratio [HR] 0.98, 95% confidence interval [CI] 0.61-1.56). This lack of statistical significance indicates that early ART initiation does not broadly impact cardiovascular risk in individuals with intact immunity and low baseline risk profiles.

However, subgroup analysis revealed that women allocated to immediate ART experienced fewer composite cardiovascular events than those in the deferred group (HR 0.19, 95% CI 0.04-0.86). Notably, men did not demonstrate this benefit and had a HR of 1.33 (95% CI, 0.79-2.24), with a significant interaction between sex and treatment effect (interaction P = .014). The small number of cardiovascular events in women warrants cautious interpretation but raises important hypotheses about gender-specific cardiovascular effects.

Event pattern differences by sex were also observed. Coronary revascularization procedures were more frequent in men, suggesting a higher burden of ischemic coronary disease, whereas strokes occurred more commonly among women. These findings may reflect underlying biological or behavioral influences or differential ART effects on cardiovascular pathophysiology across sexes.

Expert Commentary

This study challenges assumptions that early ART universally reduces cardiovascular risk among PLWH with preserved immune function. The overall neutral effect aligns with prior evidence suggesting ART’s cardiovascular impact is complex and influenced by individual patient factors such as immune status and comorbidities.

The observed cardiovascular benefit in women initiating ART early is intriguing but limited by small event numbers. Potential mechanisms could include sex differences in immune activation, inflammation, and ART pharmacodynamics. The disparity in event types also underscores the need for sex-specific cardiovascular risk assessment in HIV care.

Limitations include the relatively young, low-risk population studied and limited power to detect definitive subgroup effects. Additionally, the trial’s extended follow-up remains important to understand late cardiovascular consequences.

Conclusion

In adults with HIV infection and high CD4+ counts, early ART initiation does not significantly decrease overall cardiovascular events compared with deferred therapy. However, women may derive cardiovascular protective benefits from immediate ART, warranting further targeted investigation. Clinicians should continue to individualize ART timing decisions considering immunological status and cardiovascular risk profiles.

Future research should clarify biological mechanisms behind sex-specific differences in cardiovascular outcomes post-ART and explore strategies to mitigate cardiovascular risk across diverse patient populations living with HIV.

Reference

Dharan NJ, Sharma S, Arenas-Pinto A, Duprez D, Estrada V, Ha K, Angelica Kundro M, Mngqibisa R, Mugerwa H, Munroe D, Nasreddine R, Peterson TE, Sereti I, Trevillyan JM, Baker JV, Matthews GV, Phillips AN. Early versus deferred antiretroviral therapy initiation and long-term cardiovascular disease outcomes in people with HIV: The START study. Open Forum Infect Dis. 2025 Sep 15;12(9):ofaf561. doi: 10.1093/ofid/ofaf561. PMID: 41018697; PMCID: PMC12461870.