HIV Cardiovascular Disease CVD Coronary Heart Disease Angina Myocardial Infarction Heart Attack Stroke Heart Failure HF

By C. Michael White, PharmD, FCP, FCCP; Nissen D. Weisman, BS Pharmacy Studies; and Joseph D. Dalo, BS Pharmacy Studies

The risk for cardiovascular disease (CVD), including coronary artery disease manifestations such as angina, myocardial infarction, stroke, heart failure (HF), and sudden cardiac death, is 1.5- to 2-fold greater in patients with HIV infections than the general population.^1-3 When patients with HIV also have other viral infections, such as hepatitis C or herpes simplex virus-2, the risk (measured by CVD events or intracellular calcium scores) is increased up to 4-fold.¹

This is not out of alignment with the increase in risk caused by inflammatory diseases, such as rheumatoid arthritis and psoriasis, but the American Heart Association/American College of Cardiology (AHA/ACC) atherosclerotic CVD (ASCVD) scoring tool does not account for HIV or these diseases and how it should affect cardiovascular risk reduction strategies.^4,5 Since an estimated 50% of global patients with known HIV are older than 50 years of age, understanding the implications for cardiovascular risk in patients with HIV who are treated or not treated with antiretroviral therapy (ART) is important.⁶

This article reviews why HIV infections increase cardiovascular risk, how antiretroviral therapy (ART) affect lipid parameters, whether the infectious disease implications of using ART is greater than their long-term cardiovascular risk, and to what extent statin therapy is effective for modifying the cardiovascular risk of patients with HIV infection.

Why Does HIV Exacerbate Cardiovascular Risk?

HIV increases the risk for ASCVD events through several overlapping mechanisms, but the most common include myocardial and vascular inflammation, hyperlipidemia, and immune and autonomic dysregulation.^7,8 The vascular inflammation—driven by heightened levels of CD163, CD14, and interleukin-6—could be a driver of other negative surrogate end points for cardiovascular health including the pro- coagulant effect, vascular stiffness, myocardial fibrosis, and myo-/pericardial fat deposition that people living with HIV exhibit, which is then exacerbated by the hyperlipidemic and hypertensive effects that HIV drives as well.^7,8 While HIV can cause HF with reduced ejection fraction as a result of cell death induced by myocardial infarction (MI), it also causes HF with preserved left ventricular function. Hypertension from autonomic dysfunction coupled with vascular and myocardial stiffness and fibrosis likely drive HF with preserved left ventricular function. Valvular disease is more common in patients who have HIV, which can cause or contribute to HF with reduced ejection fraction (mitral valve or aortic regurgitation) or preserved ejection fraction (aortic stenosis).^7,8

How Do Antiretroviral Treatments Affect Cardiovascular Risk Factors?

The Table presents the relative impact of ART on serum total cholesterol and serum triglyceride concentrations.^9-27 Unfortunately, the impact on low-density lipoprotein (LDL) was not presented across ART and could not be used. Generally, changes in the 2 factors mirror each other, with total cholesterol values always exceeding LDL values because the total cholesterol value is the sum of LDL, high-density lipoprotein, and very LDLs (VLDLs). Trying to present exact values is very difficult because many of the length of the studies were different, they used complex regimens, and the results were frequently reported as the percentage of people exceeding a threshold, such as total cholesterol of more than 500 mg/dL or triglycerides greater than 750 mg/dL, rather than increases from the baseline. With these caveats in mind, protease inhibitors (PIs) increase total cholesterol and triglycerides more than other ART.^9-27 In one study, a total of 679 eligible patients were dispensed PIs at the initiation of therapy. Twelve months after treatment initiation of PIs, there was a 20% (95% CI, 17%-24%) increase in total cholesterol and 22% (95% CI, 12%-33%) increase in triglycerides.²⁸

Protease inhibitors	Total cholesterol	Triglycerides
Table. Relative Impact of ART on Serum Lipids
Amprenavir	++++	+++
Indinavir-ritonavir	++++	+++
Lopinavir-ritonavir	++++	+++
Saquinavir-ritonavir	++++	+++
Tipranavir-ritonavir	++++	+++
Darunavir-ritonavir	+++	+++
Nelfinavir	+++	++
Atazanavir ± ritonavir	++	++
Integrase strand transfer inhibitors
Dolutegravir	++	++
Elvitegravir	++	++
Raltegravir	++	++
Nucleoside reverse transcription inhibitors
Abacavir	+	++
Lamivudine	+	++
Zidovudine	+	++
Emtricitabine	+	+
Tenofovir alafenamide	0	+
Tenofovir disoproxil fumarate	–	–
Non-nucleoside reverse transcription inhibitors
Efavirenz	+++	++
Delavirdine	++	++
Etravirine	++	++
Nevirapine	++	++
Rilpivirine	+	+
Legend: “–“ denotes value goes down (reduced total cholesterol or triglycerides); “0” denotes no appreciable change in total cholesterol or triglycerides; “+, ++, +++, ++++” denote minimal (2%-5% increases), modest (6%-10%), large (11%-19%), and very large increases (=20%) in total cholesterol or triglycerides, respectively.

Approximately 20% of circulating triglycerides in patients without severe hypertriglyceridemia appear in the form of atherogenic VLDLs. Hence, the combination of greater LDL and triglyceride effects are worse for ASCVD risk than elevations in 1 or the other. In the PI class, atazanavir may have a lower lipid impact than the others and be more aligned with integrase strand transfer inhibitor and non-nucleoside reverse transcription inhibitor (NNRTI) therapy but still above that seen with nucleoside reverse transcription inhibitor therapy.^9-27 The only ART that has been shown to reduce total cholesterol and triglycerides is tenofovir disoproxil fumarate, with the tenofovir alafenamide form having no impact on total cholesterol and minimal increases in triglycerides. Among the NNRTIs, efavirenz causes greater increases in total cholesterol than others in the class, with rilpivirine having the least impact on total cholesterol and triglycerides.^9-27

Are the Benefits of ART Worth Their Adverse Impact on Cardiovascular Risk?

Although some ART agents negatively affect lipids, national guidelines for the treatment of patients living with HIV from the Infectious Diseases Society of America and the HIV Medicine Association state that therapy should not be delayed or withheld because the benefits are greater than the risk for CVD.²⁹

In the INSIGHT Start trial, patients diagnosed with HIV were treated immediately or therapy was delayed until they developed a CD4 count of 350 cells/mm³, developed an AIDS-related event, or developed another condition that dictated the use of ART.³⁰ They randomly assigned 4,685 patients to receive immediate or deferred ART at sites in 35 countries with 60 months of follow-up. The occurrence of AIDS-related events and non–AIDS-related events, including cardiovascular, renal, liver, or non-AIDS oncologic events, were determined in the 2 groups. Patients in the immediate-initiation group received ART for 94% of the total follow-up period, but only 28% of the same period in the deferred-initiation group (median delay to start therapy, 3 years). Tenofovir (89% in the 2 groups), emtricitabine (89% and 88%, respectively), and efavirenz (73% and 51%, respectively) were the most common ART used in the immediate and delayed groups, respectively. The estimated hazard ratio was 0.28 (95% CI, 0.15-0.50; P<0.001) for a serious AIDS-related event, 0.61 (95% CI, 0.38-0.97; P=0.04) for a serious non–AIDS-related event, and 0.58 (95% CI, 0.28-1.17; P=0.13) for death from any cause in the immediate versus delayed treatment group. When ASCVD events were evaluated separately, total ASCVD (12 vs 14), acute MI (6 vs 5), revascularization (8 vs 5), stroke (1 vs 4), and ASCVD death (3 vs 1) were similar between the groups. This large trial demonstrates that ART is blocking the direct negative impact of HIV on CVD events, which is counterbalanced by the negative lipid effects of the drugs being employed.³⁰

To What Extent Do Statins Reduce Cardiovascular Risk in Patients With HIV?

Statin therapy is commonly employed in the adult population, with LDL goals linked to the patient’s AHA/ACC predicted 10-year risk for ASCVD. Statins can lower LDL, triglycerides (which include the atherogenic VLDLs), and high-sensitivity C-reactive protein concentrations, which reduce the risk for ASCVD events in those without CVD and both overall mortality and ASCVD events in those with current CVD.³¹ While VLDLs are atherogenic, the national lipid guidelines do not specifically factor them into treatment decisions unless a patient’s triglycerides are high enough of a risk to cause pancreatitis.³¹

In the HIV population, lovastatin and simvastatin are usually avoided because cytochrome P450 3A4 (CYP3A4) inhibitors can dramatically increase their concentrations and thus the risk for rhabdomyolysis.³¹ However, pitavastatin, pravastatin, and rosuvastatin are alternate statins that are not CYP3A4 substrates. Eighty-three HIV-infected patients on a boosted PI regimen were randomly selected to 8 weeks of rosuvastatin 10 mg daily or pravastatin 40 mg daily with greater reductions in LDL (–37% vs 19%; P<0.001) and triglycerides (–19% vs 7%; P=0.035).³¹ These LDL reductions are lower than the expected 45% and 37% reductions seen in non-HIV populations.^32,33

The extent to which statins can specifically reduce ASCVD events in HIV patients is unknown. In the SATURN-HIV trials, a population of HIV-infected patients on ART with an LDL lower than 130 mg/dL was given rosuvastatin or placebo for 96 weeks. Those receiving rosuvastatin had no further progression of carotid intima-media thickness (narrowing of the arteries), and an effect was also observed in non-HIV patients receiving statins. We await the results of the REPRIEVE trial, in which 6,500 participants with HIV were randomized to pitavastatin versus placebo to assess primary prevention of ASCVD events.³⁴ This is the largest trial of its kind ever to be conducted and the first study to date directly assessing ASCVD events. Randomization has been completed, but the 72 months of follow-up continue with an anticipated end date of March 2023.³⁴

Conclusion

ART for HIV is a powerful tool in reducing total body risk, but the cardiovascular risk by itself is not reduced very much, if it all. This is likely because the beneficial impact of blocking HIV is counterbalanced by increases in serum lipids. Statins are attractive options for reducing the cardiovascular risk but have not been studied in robust trials to prove reductions in ASCVD or HF events. Due to the risk for drug interactions, statins such as rosuvastatin and pravastatin are good initial options, with rosuvastatin being much more effective at higher doses. The REPRIEVE trial is ongoing and designed and powered to determine the role of statins in patients with HIV.

About the authors:

C. Michael White, PharmD, FCP, FCCP, is the Distinguished Professor and Chair of the Department of Pharmacy Practice at the University of Connecticut School of Pharmacy, in Storrs, Connecticut.

Nissen D. Weisman, BS Pharmacy Studies, is a PharmD candidate at the UConn School of Pharmacy, PharmD class of 2024.

Joseph D. Dalo, BS Pharmacy Studies, is a PharmD candidate at the UConn School of Pharmacy, PharmD class of 2024.

Download to read this article in PDF document:
Don’t Go Breakin’ My Heart: Caring for Cardiovascular Issues in Patients With HIV

This article is in PDF format and it requires Abobe Reader. If you do not have Adobe Reader installed on your computer then please download and install from the link below.

Download Adobe Reader

Review Articles

Don’t Go Breakin’ My Heart: Caring for Cardiovascular Issues in Patients With HIV

Related Content

About the authors: