By Jake Scott, MD
Clinical Assistant Professor, Infectious Diseases and Geographic Medicine, Stanford University School of Medicine; Antimicrobial Stewardship Program Medical Director, Stanford Health Care Tri-Valley
SYNOPSIS: A large randomized, controlled trial (REPRIEVE) conducted by Grinspoon and colleagues showed that in participants living with human immunodeficiency virus (HIV) who are at low-to-moderate risk for cardiovascular disease, those who received pitavastatin had a 35% lower risk of experiencing a major adverse cardiovascular event over a follow-up of approximately five years than those who received placebo.
SOURCE: Grinspoon SK, Fitch KV, Zanni MV, et al. Pitavastatin to prevent cardiovascular disease in HIV infection. N Engl J Med 2023; Jul 23. doi: 10.1056/NEJMoa2304146. [Online ahead of print].
Grinspoon and colleagues conducted the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE), a double-blind, randomized, placebo-controlled, Phase III trial that evaluated whether pitavastatin use prevents atherosclerotic cardiovascular events in people living with human immunodeficiency virus (HIV) (PLWH) who are at low-to-moderate risk for cardiovascular events.1 Participants were recruited from 12 countries around the world who had a diagnosis of HIV infection and were on stable antiretroviral therapy (ART), and were between the ages of 40 and 75 years with a low-to-moderate risk of atherosclerotic cardiovascular disease, as estimated by the American Heart Association and American College of Cardiology 2013 Pooled Cohort Equation risk calculator.2 Patients were randomized in a 1:1 ratio to receive either 4 mg of oral pitavastatin calcium per day or placebo. The primary outcome was the occurrence of a major adverse cardiovascular event, 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. Secondary outcomes included a composite of a major adverse cardiovascular event or death from any cause, changes in low-density lipoprotein (LDL) and non-high-density lipoprotein (non-HDL), and various adverse events.
The study screened 10,865 participants between 2015 and 2019 and enrolled a total of 7,769 participants. Roughly half (52.7%) of participants were enrolled in high-income countries, 18.3% in Latin American or Caribbean, 7.6% in Southeast or East Asian, 6.5% in South Asian, and 14.9% in Sub-Saharan African countries. The median age was 50 years (interquartile range [IQR], 45-55), 68.9% were male, 94.8% identified as cisgender, 41.3% were Black, 34.8% were white, 14.6% were Asian, and 9.3% were characterized as other. The median screening LDL cholesterol level was 108 mg/dL, and the median atherosclerotic cardiovascular disease risk score was 4.5% for both groups. The HIV viral load was below the lower limit of quantification in 87.8% and 87.3% of participants in the pitavastatin and placebo groups, respectively. The majority of participants in both groups (67.7%) had CD4 counts greater than 500 cells/mm3. The baseline median CD4 count was 621 cells/mm3 [IQR, 448 to 827]) and the distribution of nadir CD4 counts was similar. Follow-up was completed over a median duration of 5.1 years (IQR, 4.3 to 5.9). Treatment was discontinued because of adverse events in 82 participants (2.1%) in the pitavastatin group and in 46 (1.2%) in the placebo group.
The incidence of the primary outcome of major adverse cardiovascular events was 4.81 per 1,000 person-years in the pitavastatin group as compared with 7.32 per 1,000 person-years in the placebo group (hazard ratio, 0.65; 95% confidence interval [CI], 0.48 to 0.90; P = 0.002). The treatment effect was consistent among subgroups with the exception of those with hypertension. LDL cholesterol levels were similar between the two groups at the time of study enrollment but decreased from a median of 107 mg/dL to 74 mg/dL in the pitavastatin group and from a median of 106 mg/dL to 105 mg/dL in the placebo group at 12 months. The incidence of nonfatal serious adverse events was similar between groups; 695 events (4.16 per 100 person-years) occurred in the pitavastatin group vs. 694 events (4.13 per 100 person-years) in the placebo group, with an incidence rate ratio of 1.01 (95% CI, 0.91 to 1.12). There was a higher incidence of diabetes mellitus among those in the pitavastatin group (incidence rate ratio, 1.35 [95% CI, 1.09 to 1.66]) and of myalgia, muscle weakness, or treatment-limiting myopathy of grade 3 or higher (incidence rate ratio, 1.74 [95% CI, 1.24 to 2.45]). Forty-four participants (1.1%) in the pitavastatin group discontinued treatment because of muscle-related symptoms, as compared with 21 participants (0.5%) who discontinued treatment in the placebo group.
COMMENTARY
This study showed that in participants traditionally considered to be at a relatively low risk for cardiovascular disease, who typically would not be prescribed a statin for primary prevention, pitavastatin use was associated with a 35% lower risk of major cardiovascular events. The treatment effect translated to a five-year number needed to treat (NNT) of 106 (95% CI, 64 to 303), which is comparable to the estimated five-year NNT for the treatment of hypertension (80 to 160) to prevent one major adverse cardiovascular event,3,4 and lower than the estimated five-year NNT for aspirin (values exceeding 300).5 The study was stopped early after the pitavastatin-associated risk reduction was found.
HIV infection is associated with an excess risk of cardiovascular disease, even with effective HIV viral suppression, potentially due to chronic inflammation and immune activation.6,7 In a systematic review and meta-analysis that used data from around the world, Shah and colleagues estimated that PLWH are twice as likely to develop cardiovascular disease as compared with individuals without HIV (risk ratio 2.16 [95% CI, 1.68 to 2.77]). The authors also found that the global burden of HIV-attributable cardiovascular disease was increasing, with the highest burden seen in sub-Saharan Africa and the Asia Pacific regions.8 The results of this study by Grinspoon and colleagues, and of other studies, indicate that the effects of statins on cardiovascular risk in PLWH may be related to more than simply lowering LDL cholesterol and also may be related to their effects on inflammatory and immune pathways.9,10
Although pitavastatin is not widely available since it is not generic, it was chosen because it is one of the statins that is least likely to interact with ART. It is important that potential drug interactions be reviewed carefully before prescribing statins to patients on ART; the coadministration of simvastatin or lovastatin with protease inhibitors and cobicistat or ritonavir, for instance, is contraindicated, since they are highly metabolized by the cytochrome P450 3A4 system.
In summary, the REPRIEVE trial demonstrated that pitavastatin use in PLWH significantly reduced the risk of major adverse cardiovascular events in an otherwise low-to-moderate risk population. While the absolute risk reduction is relatively low, it is important for HIV providers to consider the excess risk of cardiovascular disease among PLWH. Further research into the mechanisms for this excess risk and whether other statins that are more widely available can similarly reduce the risk of cardiovascular events is needed.
REFERENCES
- Grinspoon SK, Fitch KV, Zanni MV, et al. Pitavastatin to prevent cardiovascular disease in HIV infection. N Engl J Med 2023; July 23: doi:10.1056/NEJMoa2304146. [Online ahead of print].
- Goff DC, Lloyd-Jones DM, Bennett G, et al. 2013 ACC/AHA guideline on the assessment of cardiovascular risk: A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation 2014;129(25 Suppl 2):S49-S73.
- Pearce KA, Furberg CD, Psaty BM, Kirk J. Cost-minimization and the number needed to treat in uncomplicated hypertension. Am J Hypertens 1998;11:618-629.
- Wiysonge CS, Bradley H, Mayosi BM, et al. Beta-blockers for hypertension. Cochrane Database Syst Rev 2007;(1):CD002003.
- Ridker PM, Danielson E, Fonseca FAH, et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008;359:2195-2207.
- Longenecker CT, Sullivan C, Baker JV. Immune activation and cardiovascular disease in chronic HIV infection. Curr Opin HIV AIDS 2016;11:216-225.
- Feinstein MJ, Hsue PY, Benjamin LA, et al. Characteristics, prevention, and management of cardiovascular disease in people living with HIV: A scientific statement from the American Heart Association. Circulation 2019;140:e98-e124.
- Shah ASV, Stelzle D, Lee KK, et al. Global burden of atherosclerotic cardiovascular disease in people living with HIV: Systematic review and meta-analysis. Circulation 2018;138:1100-1112.
- Toribio M, Fitch KV, Sanchez L, et al. Effects of pitavastatin and pravastatin on markers of immune activation and arterial inflammation in HIV. AIDS 2017;31:797-806.
- Eckard AR, Jiang Y, Debanne SM, et al. Effect of 24 weeks of statin therapy on systemic and vascular inflammation in HIV-infected subjects receiving antiretroviral therapy. J Infect Dis 2014;209:1156-1164.
