Statin Therapy Could Reduce Cardiovascular Events in People with HIV

Results of a phase 3 trial in patients with human immunodeficiency virus (HIV) infection suggests use of statin therapy could help prevent cardiovascular disease events among this patient population.

Named the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) trial, results suggest use of daily pitavastatin calcium was associated with a 35% relative reduction in risk of major adverse cardiovascular events compared with placebo therapy among patients with HIV who were receiving antiretroviral therapy.

“We enrolled a representative global sample of such participants at low-to-moderate cardiovascular risk for whom the benefits of statin therapy for primary prevention are unknown in order to determine whether the receipt of statins would reduce the incidence of major adverse cardiovascular events,” wrote investigators.¹ “The trial was stopped early after we found that participants in the pitavastatin group had a lower incidence of major adverse cardiovascular events than those in the placebo group.”

In the last 50 years, few public health crises had captivated the public consciousness in the same way as the HIV epidemic and the fight against cardiovascular disease. However, what has often gone overlooked is the persistent risk of cardiovascular disease events associated with a diagnosis of HIV. Presented at the 12th International AIDS Society (IAS) Conference on HIV Science, the trial, which was supported by grants from the National Institutes of Health, Kowa Pharmaceuticals America, Gilead Sciences, and ViiV Healthcare, the REPRIEVE trial was launched with the intent of assessing whether the use of statin therapy might reduce cardiovascular risk among patients with HIV using antiretroviral therapy.¹

With this in mind, the phase 3 trial, which was led by Steven Grinspoon, MD, of Massachusetts General Hospital, was designed to randomize patients in a 1:1 ratio to receive oral pitavastatin calcium at a dose of 4 mg per day or identical placebo therapy. The primary outcome of interest was the occurrence of a major adverse cardiovascular event, which investigators defined as a composite of cardiovascular death, myocardial infarction, hospitalization for unstable angina, stroke, transient ischemic attack, peripheral arterial ischemia, revascularization of a coronary, carotid, or peripheral artery, or death from an undetermined cause, as measured in a time-to-event analysis.¹

For inclusion in the trial, patients were required to have a diagnosis of HIV infection, be 40-75 years of age, and be on stable antiretroviral therapy. Investigators pointed out all participants had low-to-moderate risk of atherosclerotic cardiovascular disease, which was determined using the American Heart Association and American College of Cardiology 2013 Pooled Cohort Equation risk calculator.¹

Overall, 10,865 participants underwent screening at 145 in 12 countries from March 26, 2015, to July 31, 2019. Of these, 7769 participants underwent randomization, with 3888 randomized to pitavastatin and 3881 randomized to placebo therapy. Participants undergoing randomization had a median age of 50 (Interquartile range [IQR], 45-55) years, 65.2% were non-White, and 31.1% were women.¹

At baseline screening, the median LDL-C level among the study cohort was 108 (IQR, 87-128) mg/dL, the median CD4 count was 621 (448-827) cells per cubic millimeter, and the median 10-year ASCVD risk score was 4.5% (IQR, 2.1-7.0). Investigators also pointed out HIV viral load was below the lower limit of quantification in 87.5% of the cohort and, among 747 participants with quantifiable viremia, the median viral load was 62 (IQR, 34-199) copies per millimeter.¹

As mentioned above, the trial was discontinued early for efficacy after a median follow-up of 5.1 years (IQR, 4.3-5.9). Upon analysis, results indicated rate of major adverse cardiovascular events was 4.81 per 1000 person-years with use of pitavastatin compared to 7.32 per 1000 person-years in the placebo group (Hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.48-0.90; P = .002). Further analysis suggested the effect of pitavastatin was generally consistent among subgroups, with some apparent differences according to hypertension status.¹

Analysis of secondary outcomes of interest revealed incidence of a major adverse cardiovascular event or death from any cause was 9.18 per 1000 person-years in the pitavastatin group and 11.63 per 1000 person-years in the placebo group (HR, 0.79; 95% CI, 0.65-0.96). Additionally, analysis of change in LDL-C from screening indicated LDL-C levels decreased from a median of 107 to 74 mg/dL in the pitavastatin group and from a median of 106 to 105 mg/dL in the placebo group at 12 months.¹

When assessing safety of use, results demonstrated muscle-related symptoms were observed in 2.3% of the pitavastatin group and in 1.4% of the placebo group while a new diagnosis of diabetes mellitus was observed in 5.3% of the pitavastatin and in 4.0% of the placebo group.¹

In an editorial, Matthew Freiberg, MD, a cardiovascular epidemiologist and director of the Vanderbilt Center for Clinical Cardiovascular Outcomes Research and Trials Evaluation at the Vanderbilt University Medical Center, commended the REPRIEVE investigators for their efforts and implications of their findings, which Freiberg suggests underlines the importance of addressing other risk factors such as obesity, smoking, diabetes, and alcohol use.²

“This trial underscores the importance of cardiovascular disease prevention measures. Although pitavastatin targets one and perhaps two important risk factors for atherosclerotic cardiovascular disease (i.e., LDL cholesterol and systemic inflammation), other risk factors merit attention for this preventive approach to be transformative,” Freiberg wrote.²

References:

1. Grinspoon SK, Fitch KV, Zanni MV, et al. Pitavastatin to prevent cardiovascular disease in HIV infection. New England Journal of Medicine. Published online July 23, 2023. doi:10.1056/nejmoa2304146
2. Freiberg MS. HIV and cardiovascular disease — an ounce of prevention. New England Journal of Medicine. Published online 2023. doi:10.1056/nejme2306782