Pitavastatin to Prevent Cardiovascular Disease in HIV Infection

Abstract

Background: The risk of cardiovascular disease is increased among persons with human immunodeficiency virus (HIV) infection, so data regarding primary prevention strategies in this population are needed.

Methods: In this phase 3 trial, we randomly assigned 7769 participants with HIV infection with a low-to-moderate risk of cardiovascular disease who were receiving antiretroviral therapy to receive daily pitavastatin calcium (at a dose of 4 mg) or placebo. The primary outcome was the occurrence of a major adverse cardiovascular event, which was defined as a composite of cardiovascular death, myocardial infarction, hospitalization for unstable angina, stroke, transient ischemic attack, peripheral arterial ischemia, revascularization, or death from an undetermined cause.

Results: The median age of the participants was 50 years (interquartile range, 45 to 55); the median CD4 count was 621 cells per cubic millimeter (interquartile range, 448 to 827), and the HIV RNA value was below quantification in 5250 of 5997 participants (87.5%) with available data. The trial was stopped early for efficacy after a median follow-up of 5.1 years (interquartile range, 4.3 to 5.9). The incidence of a major adverse cardiovascular event was 4.81 per 1000 person-years in the pitavastatin group and 7.32 per 1000 person-years in the placebo group (hazard ratio, 0.65; 95% confidence interval [CI], 0.48 to 0.90; P = 0.002). Muscle-related symptoms occurred in 91 participants (2.3%) in the pitavastatin group and in 53 (1.4%) in the placebo group; diabetes mellitus occurred in 206 participants (5.3%) and in 155 (4.0%), respectively.

Conclusions: Participants with HIV infection who received pitavastatin had a lower risk of a major adverse cardiovascular event than those who received placebo over a median follow-up of 5.1 years. (Funded by the National Institutes of Health and others; REPRIEVE ClinicalTrials.gov number, NCT02344290.).

Figure 1.. Treatment Effect of Pitavastatin on Major Adverse Cardiovascular Events.

Shown is the incidence rate of a major adverse cardiovascular event (MACE) among trial participants with human immunodeficiency virus (HIV) infection in the pitavastatin group and the placebo group and the estimated treatment effect, according to stratified Cox proportional-hazards analysis (Panel A). Also shown are the cumulative incidence of the primary outcome (first MACE) (Panel B) and a key secondary outcome (first MACE or death from any cause) (Panel C). In Panels B and C, the insets show the data on an expanded y axis. At the top of Panel A, the primary outcome of the trial is shown in bold text. Panel A also shows the treatment effect for secondary and supportive analyses. Cox proportional-hazards models were stratified according to sex at birth and the CD4 cell count at screening. Aside from the primary result, the widths of the confidence intervals have not been adjusted for multiplicity and therefore may not be used in place of hypothesis testing. TIA denotes transient ischemic attack.

Figure 2.. Treatment Effect on First MACE in Predefined Subgroups.

Each subgroup factor was included individually in a cause-specific Cox proportional-hazards model that was stratified according to sex at birth and the CD4 count at screening. For reference, the overall treatment effect in the primary analysis is shown at the top of the graph. The widths of the confidence intervals have not been adjusted for multiplicity and therefore may not be used in place of hypothesis testing. The 95% confidence intervals in subgroups with small numbers of events have been truncated, as indicated by arrows. To convert the values for cholesterol to millimoles per liter, multiply by 0.02586. ART denotes antiretroviral therapy, ASCVD atherosclerotic cardiovascular disease, GBD global burden of disease, LDL low-density lipoprotein, and LLOQ lower limit of quantification.

Figure 3.. Fasting Cholesterol Levels.

Shown are violin plots of data regarding LDL cholesterol (Panel A) and non–high-density lipoprotein (HDL) cholesterol (Panel B) in the pitavastatin group and the placebo group. In each plot, the mean value is indicated by a circle, the median by a horizontal line, and the interquartile range (Q1–Q3) by the top and bottom of a box; whiskers indicate the 5th and 95th percentiles, and the tapering points reflect the shape of the distribution. For reference, the shaded area indicates the matching interquartile ranges in the pitavastatin and placebo groups at trial entry. To convert the values for cholesterol to millimoles per liter, multiply by 0.02586.