Dyslipidemia and statin therapy in patients with HIV

Human immunodeficiency virus (HIV) infection is now essentially a chronic medical condition owing to the effectiveness of contemporary antiretroviral (ARV) therapy. Patients are now rarely dying of Kaposi sarcoma and opportunistic infections, but rather atherosclerotic cardiovascular disease (ASCVD) and other non-HIV-related causes.HIV and atherosclerotic cardiovascular diseaseThe risk of ASCVD among HIV-positive persons is higher than in the general population.1,2 The risk of myocardial infarction (MI) in patients with HIV may be up to two-fold higher compared to those without HIV.3 The exact mechanism of this increased risk is unknown, but is thought to be a combination of chronic inflammation and immune activation (though independent of viral load, as it is still observed in patients who have achieved viral suppression), as well as traditional cardiovascular risk factors.1 Most ASCVD risk algorithms do not include HIV infection as a variable, although it is considered to be a “risk-enhancing factor,” which may be used to guide decisions around the use or intensification of statin therapy.4HIV and dyslipidemia Most patients with HIV have concurrent dyslipidemia.5 Despite that, ARV-induced hyperlipidemia is much less of an issue nowadays due to advances in therapy. Commonly used nucleoside reverse transcriptase inhibitors, such as emtricitabine and tenofovir, have been associated with hypertriglyceridemia and hypercholesterolemia. However, many of the ARV agents known to cause hyperlipidemia are rarely used in practice anymore, such as efavirenz and early-phase protease inhibitors (e.g., lopinavir, ritonavir). Second-generation protease inhibitors (e.g., atazanavir, darunavir) and integrase inhibitors (e.g., bictegravir, dolutegravir) have more favourable effects on lipid parameters. The often-used combination tablet of bictegravir/emtricitabine/tenofovir has a relatively minor impact on lipid values other than a possible increase in low-density lipoprotein cholesterol (LDL-C). Currently, the most controversial issue regarding ARV-induced dyslipidemia involves the salt form of tenofovir. Tenofovir disoproxil fumarate has now been replaced by tenofovir alafenamide in newer formulations; it has more advantageous pharmacokinetic properties but has been associated with increased levels of total cholesterol, LDL-C and triglycerides.6 The 2021 Canadian Cardiovascular Society dyslipidemia guidelines recommend screening patients with HIV for dyslipidemia regardless of age, but do not make any specific treatment recommendations.7HIV and statin therapyDue to the increased risk of ASCVD in patients with HIV, aggressive treatment with lifestyle modifications and lipid-lowering therapy are generally recommended. Historically, many patients may have been not treated or were undertreated due to drug–drug interactions between ARV and statin therapy. However, newer ARV agents have fewer interactions with statins. For example, the interaction between CYP3A4 statins (e.g., atorvastatin) and protease inhibitors is now basically irrelevant with the introduction of integrase inhibitors.8 Randomized trial to prevent vascular events in HIV The international, multicentre REPRIVE trial, published in August 2023, was designed to ascertain whether statin therapy reduces cardiovascular events in HIV-positive patients without a history of ASCVD.9 It is the first, and only, outcome-driven trial of lipid-lowering therapy in patients with HIV. Included were persons aged 40–75 years with HIV on stable ARV therapy who had no established ASCVD (i.e., primary prevention). Participants needed to be low-to-intermediate risk (10-year risk of ASCVD up to 15% based on the American Pooled Cohort Equations). Patients were randomized to pitavastatin 4 mg daily (moderate-intensity) or identical placebo. Pitavastatin (not available in Canada, but available in other countries) was chosen because of its lack of drug interactions with ARV therapy.8 The primary outcome was an extensive composite endpoint that included cardiovascular death, MI, unstable angina, stroke/transient ischemic attack, peripheral arterial ischemia, revascularization, and death from an undetermined cause. The study was primarily funded by the US National Institutes of Health.A total of 7,769 patients were enrolled. Median age was 50 years, median CD4 count was 621 cells/mm3, 31% were women and 65% were non-white. Only 2% had substance use disorder or chronic active hepatitis C. At baseline, median 10-year cardiovascular risk was 4.5% (low-risk) and median LDL-C was 2.8 mmol/L, which decreased to 1.9 mmol/L in the pitavastatin group. Over 5.1 years, the primary outcome was significantly lower with pitavastatin (4.8 vs 7.3 events per 1,000 patient-years, hazard ratio 0.65, 95% confidence interval 0.48–0.90, estimated 5-year number needed to treat of 106). Pitavastatin also significantly reduced MI/cardiac ischemia, but there was no significant difference in cardiovascular or all-cause death. Significantly higher rates of incident diabetes (5.3% vs 4.0%) and myalgias/myopathy (2.3% vs 1.4%) were seen with pitavastatin, but only 2% of patients discontinued pitavastatin due to adverse events.Pharmacist’s role A first step in addressing ASCVD risk in HIV-positive persons is educating other clinicians about the REPRIVE trial and recommending statin therapy to appropriate patients with HIV (aged 40–75 years without ASCVD at low-to-intermediate cardiovascular risk). Some patients, particularly younger patients with no other cardiovascular risk factors, may be reluctant to start a statin. Pill burden, which used to contribute to ARV therapy nonadherence, is presently less of an issue. For instance, the combination tablet of bictegravir/emtricitabine/tenofovir is just one tablet daily. It is vital, however, to check for drug–drug interactions between statins and a patient’s ARV regimen, as older ARV agents are still used occasionally. Of note, statin therapy should be recommended for all patients with HIV who have experienced a cardiovascular event (i.e., secondary prevention). Finally, it is essential to educate all HIV-positive patients about modifiable cardiovascular risk factors, such as smoking, sedentary lifestyle and poor dietary habits.SummaryThe REPRIEVE trial demonstrated that moderate-intensity statin therapy reduced cardiovascular events, mostly coronary and cerebrovascular events, in patients with HIV at low-risk of ASCVD. As pitavastatin is unavailable in Canada, a reasonable alternative would be fixed-dose rosuvastatin 5–10 mg daily or atorvastatin 10–20 mg daily. Arden Barry is a clinical pharmacy and research specialist in ambulatory cardiology at the Jim Pattison Outpatient Care and Surgery Centre in Surrey, BC, and associate professor (partner) at the Faculty of Pharmaceutical Sciences, University of British Columbia in Vancouver, BC. References:So-Armah K, Benjamin LA, Bloomfield GS, et al. HIV and cardiovascular disease. Lancet HIV 2020;7:e279-e293.Bernelli C, Danzi GB, Cerrato E, et al. Cardiovascular events recurrence and coronary artery disease in HIV patients: the price we have to pay for the chronicization of the disease. Can J Cardiol 2020;36:127-34.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;138:1100-12.Arnett DK, Blumenthal RS, Albert MA, et al. 2019 ACC/AHA guideline on the primary prevention of cardiovascular disease: a report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol 2019;74:e177-e232.Waters DD, Hsue PY. Lipid abnormalities in persons living with HIV infection. Can J Cardiol 2019;35:249-59.Surial B, Mugglin C, Calmy A, et al. Weight and metabolic changes after switching from tenofovir disoproxil fumarate to tenofovir alafenamide in people living with HIV: a cohort study. Ann Intern Med 2021;174:758-67.Pearson GJ, Thanassoulis G, Anderson TJ, et al. 2021 Canadian Cardiovascular Society guidelines for the management of dyslipidemia for the prevention of cardiovascular disease in adults. Can J Cardiol 2021;37:1129-50.Giguère P, Nhean S, Tseng AL, et al. Getting to the heart of the matter: a review of drug interactions between HIV antiretrovirals and cardiology medications. Can J Cardiol 2019;35:326-40.Grinspoon SK, Fitch KV, Zanni MV, et al. Pitavastatin to prevent cardiovascular disease in HIV infection. N Engl J Med 2023;389:687-99.

Dyslipidemia and statin therapy in patients with HIV

Register for free access or login.

More Blog Posts in This Series

High-dose NSAID + PPI + colchicine? It’s probably pericarditis

Blog Author

Arden Barry

Related Topics