Cardiovascular disease (CVD) in HIV-infected patients is increasing.¹ As rates of virologic suppression rise and numbers of older HIV patients increase,² more HIV-infected patients are suffering complications from CVD.³ Therefore, greater clinical attention to CVD prevention in this population is needed.

HIV is an independent risk factor for CVD and the development of coronary artery calcium. Implicated mechanisms include immune dysregulation and systemic inflammation.⁴ Since CVD risk is increased even in HIV-infected individuals who demonstrate virologic suppression, it is thought that antiretroviral therapies (ART), including older generations of protease inhibitors, may contribute to CVD risk.⁵ Furthermore, dyslipidemia is a well-known complication of HIV infection and ART. Typically, HIV-infected patients have a lipid profile characterized by elevated levels of triglycerides, low-density lipoprotein cholesterol (LDL-C), total cholesterol and reduced levels of high-density lipoprotein cholesterol (HDL-C).⁶

The 2013 American College of Cardiology/American Heart Association guidelines and ASCVD risk estimator, based on the Pooled Cohort Equations, do not specifically address HIV-infected individuals, and likely underestimate CVD risk in HIV patients.⁷ In this population with elevated but unclearly delineated higher CVD risks, which individuals warrant discussion about initiating a statin?

Statins remain key to primary and secondary CVD prevention; they improve endothelial function, slow the progression of atherosclerosis and stabilize atherosclerotic plaque.⁸ Improved lipid profiles and lower mortality have been seen in observational studies of patients with HIV on statin therapies.^9,10 Statins may also have anti-inflammatory properties with particular benefit in HIV-infected individuals.^10,11 Nevertheless, the strongest evidence for statins is the Cholesterol Treatment Trialists' Collaboration meta-analyses of statin trials showing consistent net benefit across a wide range of populations; there is no reason to believe that at-risk HIV individuals would not benefit too.

In fact, since atherosclerosis risk accumulates over time, lipid-lowering therapies may be beneficial at an earlier age in patients with HIV compared to the general population. A notable tool that may be used in HIV-infected patients who fall short of standard thresholds for primary prevention statin therapy is coronary artery calcium scoring for further risk stratification.^12,13

The potency of lipid-lowering therapies must be considered in HIV patients as well, since lowering LDL-C levels have demonstrated CVD risk reduction that is proportional to the absolute reduction in LDL-C.¹⁴ The LDL-C- lowering potency of statins is variable; rosuvastatin produces much greater LDL-C lowering effect than pravastatin in HIV patients.¹⁵ Furthermore, statin effects are dose-dependent, suggesting that dosage be increased to maximum tolerable doses to maximize the reduction of CVD risk.

Statins have greater LDL-C lowering potency compared to ezetimibe, bile acid sequestrants and niacin within the general population.¹⁶ Recent data have demonstrated benefit of PSCK9 inhibitors, as well as a favorable risk profile in HIV-infected patients.^17,18 However, more data are warranted and the EPIC-HIV (Effect of PCSK9 Inhibition on Cardiovascular Risk in Treated HIV Infection) trial will examine the effect of PCSK9 inhibition on arterial inflammation as assessed by FDG-PET/CT in 140 individuals with HIV and known CVD or CVD risk factors.¹⁹

Drug-drug interactions can present a challenging barrier in patients on ART. Lipophilic statins (e.g., simvastatin and lovastatin) are metabolized through the CYP3A4 pathway of the cytochrome P (CYP)-450 system, whereas hydrophilic statins (e.g., pravastatin) are not significantly metabolized by CYP enzymes.^6,8 Interactions arise since protease inhibitors inhibit CYP3A4 and the majority of NNRTIs induce CYP3A4.^8,20 Drug interactions may be further complicated in patients who are receiving antifungal therapy with azoles or non-dihydropyridine calcium channel blockers.

Statins that have demonstrated the greatest safety profile at low doses include atorvastatin, pitavastatin, pravastatin and rosuvastatin, whereas statins that should be avoided include simvastatin and lovastatin.⁸ Although pravastatin and pitavastatin demonstrate a favorable safety profile especially if additional medications such as azoles or amiodarone are being utilized, atorvastatin and rosuvastatin demonstrate greater LDL-C lowering potency compared to pravastatin.^6,11,20 Ezetimibe has weaker ability to lower LDL-C levels and should be considered in HIV-infected patients who are unable to tolerate statins or who still have relatively high LDL-C levels on maximally tolerated statin therapy.²¹ PCSK9 inhibitor trials in HIV populations are currently underway and may have a favorable safety profile in HIV patients on ART.¹⁹

Results of one study suggests that addition of statin to an existing antiretroviral regimen may be more beneficial than changing ART for the purpose of statin therapy.²² Protease inhibitors and non-nucleotide reverse transcriptase inhibitors have the greatest potential for statin interactions, but dose adjustments are not always necessary.^6,8,11

The US Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents and the International Antiviral Society are a helpful resource for understanding drug interactions between ART therapies and statins and for identifying safe statin dosages.²⁰ Since ART regimens vary widely, individualized assessment of statin effects in context of a patient's ART medications and with assistance of these guidelines is helpful.

In summary, CVD risk lowering via statin therapy should be considered in all HIV-infected patients, especially those with at least an estimated 5% risk of an ASCVD event over the next decade. Risk assessment by the ASCVD estimator should be performed with the knowledge that this calculator likely underestimates CVD risk in HIV-infected individuals. Achievement of lower LDL-C provides greater benefit with regard to CVD event reduction; therefore, potency of chosen lipid-lowering therapies must be considered.

Careful attention must be given to drug-drug interactions with individual-specific ART regimens. While pitavastatin and fluvastatin do not have significant interactions with protease inhibitors, for other statins, start at lowest dose, titrate carefully and monitor for side effects. In general, it is prudent not to exceed 10 mg/day of rosuvastatin or 20 mg/day of atorvastatin. In the future, CVD risk assessment in HIV-infected patients may include calculators that incorporate HIV status, coronary artery calcium scoring may be used in decision-making algorithms for HIV-infected individuals with borderline ASCVD risk estimates and PCSK9 inhibitors may demonstrate a greater role in therapy.

Table 1: Key Points in Primary Prevention of CVD in Patients With HIV Infection

Mechanisms of increased CVD risk in HIV-infected patients	- Immune dysregulation - Systemic inflammation - Antiretroviral therapy - Dyslipidemia
Estimating ASCVD risk in HIV-infected patients	- Traditional risk-prediction tools underestimate risk in HIV-infected patients - HIV seropositivity is not included in risk-prediction tools.
Lifestyle interventions for reducing ASCVD risk	- Given the elevated ASCVD risk in HIV-infected patients, clinicians should highlight the importance of lifestyle changes to reduce CVD risk, particularly smoking cessation and risk factors for insulin resistance (diet, exercise, weight management).
Statins for primary prevention in HIV-infected patients	- Use validated risk-prediction tools and advise statins in patients who meet standard guideline indications. - Consider starting statin therapy at lower thresholds in HIV-infected patients, such as an estimated 10-year ASCVD risk ≥5%. - Consider coronary artery calcium scoring for further risk stratification in intermediate-risk groups.
General principles of statin metabolism and DDI	- Lipophilic statins (e.g., lovastatin, simvastatin, atorvastatin) are substrates for CYP450, particularly CYP3A4 - Hydrophilic statins (e.g., pravastatin and rosuvastatin) are not significantly metabolized by CYP450 - DDI are not easily predictable; variability in organ function, co-morbidities, and genetic variability play a significant role in DDI - Clinicians should follow the dosing recommendations provided by the US Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents and the International Antiviral Society—USA Panel
General principles of DDI between statins with protease inhibitors and pharmacokinetic boosters	- Protease inhibitors and pharmacokinetic boosters (e.g., atazanavir, darunavir, lopinavir, ritonavir, cobicistat) interact with several CYP450 enzymes, such as CYP3A4, and transporters (e.g., P-glycoprotein); they carry the greatest risk of DDI with statins. - Simvastatin and lovastatin should be avoided in patients taking protease inhibitors and pharmacokinetic boosters; pitavastatin and fluvastatin do not have significant DDI with protease inhibitors; for other statins, start at lowest dose, titrate carefully and monitor for side effects
General principles of DDI between statins with other anti-retroviral therapy	- There are no clinically significant DDI between statins and chemokine receptor-5 inhibitors (e.g., maraviroc), fusion inhibitors (e.g., enfurvitide), integrase inhibitors (e.g., dolutegravir, raltegravir), and nucleoside reverse-transcriptase inhibitors (e.g., abacavir, emtricitabine, lamivudine) - Non-nuclease reverse transcriptase inhibitors (e.g., efavirenz, nevirapine) require CYP metabolism and can have statin DDI.  Consider avoiding lipophilic statins; close monitoring for side effects is warranted

References

1. Chastain DB, Henderson H, Stover KR. Epidemiology and management of antiretroviral-associated cardiovascular disease. Open AIDS J 2015;9:23-37.
2. Sepkowitz KA. AIDS—the first 20 years. N Engl J Med 2001;344:1764-72.
3. Trickey A, May MT, Vehreschild J, et al. Cause-specific mortality in HIV-positive patients who survived ten years after starting antiretroviral therapy. PLoS One 2016;11:e0160460.
4. Freiberg MS, Chang CC, Kuller LH, et al. HIV infection and the risk of acute myocardial infarction. JAMA Intern Med 2013;173:614-22.
5. Islam FM, Wu J, Jansson J, Wilson DP. Relative risk of cardiovascular disease among people living with HIV: a systematic review and meta-analysis. HIV Med 2012;13:453-68.
6. Wiggins BS, Lamprecht DG, Page RL, Saseen JJ. Recommendations for managing drug-drug interactions with statins and HIV medications. Am J Cardiovasc Drugs 2017;17:375-89.
7. Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association task force on practice guidelines. J Am Coll Cardiol 2014;63:2889-934.
8. Chastain DB, Stover KR, Riche DM. Evidence-based review of statin use in patients with HIV on antiretroviral therapy. J Clin Transl Endocrinol 2017;8:6-14.
9. Moore RD, Bartlett JG, Gallant JE. Association between use of HMG CoA reductase inhibitors and mortality in HIV-infected patients. PLoS One 2011;6:e21843.
10. Overton ET, Kitch D, Benson CA, et al. Effect of statin therapy in reducing the risk of serious non-AIDS-defining events and nonaccidental death. Clin Infect Dis 2013;56:1471-9.
11. Eckard AR, McComsey GA. The role of statins in the setting of HIV infection. Curr HIV/AIDS Rep 2015;12:305-12.
12. Chow D, Young R, Valcour N, et al. HIV and coronary artery calcium score: comparison of the Hawaii Aging with HIV Cardiovascular Study and Multi-Ethnic Study of Atherosclerosis (MESA) cohorts. HIV Clin Trials 2015;16:130-8.
13. Kingsley LA, Deal J, Jacobson L, et al. Incidence and progression of coronary artery calcium in HIV-infected and HIV-uninfected men. AIDS 2015;29:2427-34.
14. Collins R, Reith C, Emberson J, et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet 2016;388:2532-61.
15. Aslangul E, Assoumou L, Bittar R, et al. Rosuvastatin versus pravastatin in dyslipidemic HIV-1-infected pateitns receiving protease inhibitors: a randomized trial. AIDS 2010;24:77-83.
16. Lee S, Cannon CP. Combination lipid-lowering therapies for the prevention of recurrent cardiovascular events. Curr Cardiol Rep 2018;20:55.
17. Kohli P, Ganz P, Ma Y, et al. HIV and hepatitis c-coinfected patients have lower low-density lipoprotein cholesterol despite higher proprotein convertase subtilisin kexin 9 (PCSK9): an apparently "PCSK9-lipid paradox." J Am Heart Assoc 2016;5:e002683.
18. Kohli M, Patel K, MacMahon Z, et al. Pro-protein subtilisin kexin-9 (PCSK9) inhibition in practice: lipid clinic experience in 2 contrasting UK centres. Int J Clin Pract 2017;71. [Epub ahead of print]
19. Hsue, P. Effect of PCSK9 Inhibition on Cardiovascular Risk in Treated HIV Infection (EPIC-HIV). Identification No. NCT03207945. 2017. https://clinicaltrials.gov/ct2/show/NCT03207945
20. US Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV. https://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf. Accessed 25 July 2018.
21. Wohl DA, Waters D, Simpson RJ, et al. Ezetimibe alone reduces low-density lipoprotein cholesterol in HIV-infected patients receiving combination antiretroviral therapy. Clin Infect Dis 2008;47:1105-8.
22. Calza L, Manfredi R, Colangeli V, et al. Substitution of nevirapine or efavirenz for protease inhibitor versus lipid-lowering therapy for the management of dyslipidaemia. AIDS 2005;19:1051-8.

Clinical Topics: Cardiovascular Care Team, Diabetes and Cardiometabolic Disease, Dyslipidemia, Noninvasive Imaging, Prevention, Vascular Medicine, Hypertriglyceridemia, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Computed Tomography, Nuclear Imaging

Keywords: Dyslipidemias, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Pravastatin, Cholesterol, LDL, Cholesterol, HDL, Risk Factors, Reverse Transcriptase Inhibitors, Simvastatin, Niacin, HIV Infections, Cytochrome P-450 CYP3A, Lovastatin, Amiodarone, Calcium Channel Blockers, Fluorodeoxyglucose F18, American Heart Association, Cardiovascular Diseases, Triglycerides, Protease Inhibitors, Plaque, Atherosclerotic, Azoles, Positron-Emission Tomography, Coronary Vessels, Fatty Acids, Monounsaturated, Atherosclerosis, Risk Assessment, Primary Prevention, Drug Interactions, Risk Reduction Behavior, Inflammation, Arteritis, Algorithms, Bile Acids and Salts, Cohort Studies

< Back to Listings