COMMENTARY

Cardiovascular Care for the Patient Living With HIV: What You Need to Know

Merle Myerson, MD, EdD

Disclosures

July 07, 2016

Antiretroviral therapy (ART) has changed the course of HIV to where it is now a chronic disease. Patients are now less likely to succumb to HIV-related illness than to comorbidities, in particular cardiovascular disease (CVD). Patients infected with HIV have been shown to have an increased risk for CVD compared with the general population.[1] It is anticipated that CVD will become the leading cause of morbidity and mortality in this patient population, making the diagnosis, management, and prevention of CVD essential to patient care.

HIV and Risk for Cardiovascular Disease

The etiology of this increased risk is multifactorial. The virus itself produces metabolic changes including insulin resistance, lipodistrophy (fat maldistribution including increased abdominal visceral fat), and abnormal lipids (elevated triglycerides and low HDL cholesterol [HDL-C]). Therapy with ART, in particular protease inhibitors (PI), exacerbate these abnormalities, although newer drugs (nonnucleoside reverse transcriptase inhibitors [NNRTI]) that are less cardiotoxic have been replacing PI.[2,3,4]

The role of inflammation in the pathogenesis of atherosclerosis is well-known in the general population[5] and is believed to play a significant and unique role in the development of cardiovascular disease in patients infected with HIV.[6,7] Recent research has suggested that the development of atherosclerosis and formation of plaque may be different in patients with HIV. Data from the all-male Multicenter AIDS Cohort (MACS) and other studies show a greater prevalence and extent of noncalcified plaque (vs calcified plaque).[8,9,10]

Patients with HIV tend to have greater prevalence of CVD risk factors, in particular smoking, than the general population.[11,12] Finally, patients are now living to an age where CVD is more prevalent.

Guidelines for Cardiovascular Care of Patients Living with HIV

At present there are no comprehensive guidelines for the cardiovascular care of patients infected with HIV, nor are there risk-prediction schemes that have been validated in this population. Standard guidelines for general cardiac care (ie, coronary artery disease, valve disease, heart failure) are used. Expert opinion and recommendations have been developed for diagnosis and management of CVD risk factors, in particular risk stratification for dyslipidemia management. Management of other risk factors such as hypertension, weight loss, smoking, diabetes, and physical activity tend to follow guidelines for the general population.

Risk Stratification

Risk scores and algorithms are used to determine intensity of treatment for CVD risk factors, most notably LDL-cholesterol (LDL-C) lowering.

The 2013 HIV Medical Association (HIVMA) of the Infectious Disease Society of American Primary Care Guidelines[13] recommend using the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III)[14,15] risk-stratification scheme, which is a Framingham-based algorithm.

The Data Collection on Adverse Effects of Anti-HIV Drugs (D:A:D) Study Group developed a risk calculator that includes both traditional risk factors and exposure to individual ART.[16] The Veterans Aging Cohort Study (VACS) was used to develop the VACS Index to predict overall mortality. The index includes age, CD4 count, viral load, hemoglobin, aspartate and alanine transaminase, platelets, creatinine, and hepatitis-C status.[17] It has been used in studies predicting coronary heart disease but has not been validated for this use.[18,19]

In 2015, the National Lipid Association (NLA) published "Recommendations for Patient-Centered Management of Dyslipidemia: Part 2" that included a section on risk prediction for patients infected with HIV[20] written by HIV and cardiovascular-disease experts. The panelists acknowledge that existing risk scores do not accurately assess risk in HIV patients[16,21] and the lack of validated scores specific to this patient population. In the interim, they recommend that initial risk stratification be based on the number of major atherosclerotic cardiovascular risk factors and use of risk-prediction tools, such as the ATP III, Framingham Risk Score, or the American College of Cardiology/American Heart Association (ACC/AHA) Pooled Cohort Equations if two risk factors are present, as well as the use of clinical indicators, to help inform clinical judgment, if needed. Furthermore, the presence of HIV infection may be counted as an additional risk factor. For example, if an HIV-infected patient has one major CV risk factor and would be considered low risk by traditional risk schemes, the practitioner can consider increasing to intermediate risk based on HIV-positive status.

Lifestyle Modification

Therapeutic lifestyle modification is advised for all patients regardless of risk category. Implementing these changes for patients living with HIV has many unique and challenging aspects. Access to healthy food choices and options for exercise may be limited by availability, knowledge, or finances. Prevalence of smoking is higher than the general population, as is alcohol and illicit drug use. Lifestyle changes include diet, weight loss (if indicated), physical activity, and cessation of smoking. Smoking cessation was associated with a lower risk for CVD events in the D:A:D HIV cohort;[22] small studies have shown that exercise and diet can improve CV risk profile in people with HIV.[23,24]

Dyslipidemia

Dyslipidemia refers to any abnormal serum lipid level. Although there are many different lipid particles, the cornerstone of lipid therapy has focused on LDL-C as a target for therapy with lower targets for those at greater risk.

The 2013 ACC/AHA Guidelines[25] introduced a new risk calculator, "Pooled Cohort Risk Assessment Equations" that, along with four defined groups of patients, is used to determine who should be treated with a statin drug. Targets for LDL-C were eliminated. Existing guidelines in Europe and Canada, the International Atherosclerosis Society (IAS),[26] and the NCEP ATP III continue to have LDL-C targets based on risk scores such as Framingham. In 2014, The NLA issued a statement recommending continued use of a Framingham-based risk stratification and outlining targets for both LDL-C and non–HDL-C (total cholesterol minus HDL-C).[27]

Existing recommendations for patients infected with HIV include guidelines from the European AIDS Clinical Society (EACS), where a goal of < 155 mg/dL (4.0 mmol/L) for total cholesterol and < 80 mg/dL (2.0 mmol/L) for LDL-C is identified for those at highest risk (>20% 10-year risk).[28] The EACS recommendations were published in 2008; more recently, the HIVMA guidelines for primary care of patients with HIV recommend that a fasting lipid profile be obtained upon initiation of care and that lipid testing and targets should be based on the NCEP ATP III guidelines with consideration for more stringent targets.[13] The NCEP ATP III guidelines include metabolic syndrome as a CV risk factor; clinicians should assess patients for this constellation of risk factors because they appear to be prevalent in patients infected with HIV.[29,30] If the metabolic syndrome is present, it should be factored into patient risk stratification and identification of target for LDL-C.[31]

Standard targets for lipids according to the NLA Recommendations are applicable to patients with HIV.

Table 1. Targets for LDL-C, Non-HDL-C, ApoB per NLA Guidelines

Risk Category LDL-C mg/dL Non-HDL-C mg/dL Apolipoprotein B mg/dL
Very high <70 <100 <80
High <100 <130 <90
Moderate <100 <130 <90
Low <100 <130 <90
Abbreviations: ApoB = apolipoprotein B; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; NLA = National Lipid Association
Approx mg/dL to mmol/L: 70 = 1.8 mmol/L; 80 = 2.0 mmol/L; 90 = 2.3 mmol/L; 100 = 2.6 mmol/L; 130 = 3.4 mmol/L

Since patients infected with HIV are at higher risk, assessing for residual risk after treating and achieving LDL-C goals may be considered. LDL cholesterol is highly associated with CVD but does not reflect the total amount of atherosclerotic particles,[32,33,34] meaning all particles that have apolipoprotein B (apoB), which includes very low-density lipoprotein, intermediate-density lipoprotein, LDL, and lipoprotein(a). Measures of residual risk including non–HDL-C (total cholesterol minus HDL-C), apoB, or LDL-particle (LDL-P) number better predict risk for CVD than LDL-C, with apoB and LDL-P performing better than non–HDL-C.[32,33] Certain populations, including patients infected with HIV, may have a discordance between measures of LDL-C and LDL-P and apoB. Relying solely on LDL-C may underestimate risk and treatment targets.[35,36] Although measures of residual risk are increasingly incorporated into diagnosis and management plans, LDL-C continues to be the primary focus of treatment in the general population and for patients infected with HIV.

Non–HDL-C is calculated from the basic lipid panel and is also recommended as a measure of residual risk for patients infected with HIV. Not all labs are equipped to measure other lipid parameters, and insurance coverage for these measurements is not universal.

Lipid Medications

Many issues regarding use of HMG-CoA reductase inhibitors, known as statins, in patients infected with HIV are still unclear, including metabolism and efficacy, not only for LDL-C lowering but also regarding their effect on CVD events and mortality.

Care should be taken when prescribing statins with ART; Tables 2 and 3 show significant interactions and contraindications. The Food and Drug Administration (FDA) no longer recommends routine monitoring of liver-function tests in patients taking statins unless indicated. Patients infected with HIV often have concurrent liver disease, or they may be taking several medications that can influence liver function; thus, monitoring may be considered.

In addition to the statin drugs, there are several nonstatin LDL-C–lowering medications. Intestine-absorption inhibitors (ezetimibe [Zetia, Merck)[37] and niacin[38,39] have been tested in patients infected with HIV. Of note, niacin in higher doses can help to lower both LDL-C and triglycerides but is often poorly tolerated due to side effects (flushing, itching). Research has questioned the overall benefit of niacin for reducing cardiovascular events[40] and the FDA recently withdrew approvals for use of niacin and fenofibric acid with statins to treat high cholesterol. Bile-acid sequestrants (colesevelam [Welchol, Daiichi-Sankyo) moderately reduce LDL-C levels but have not been evaluated in patients infected with HIV. These drugs may interfere with absorption of other medications and may also raise triglycerides. The new proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors, which are approved for the treatment of people with familial hyperlipidemia and others at high risk who are not at goal on standard therapy, have not been tested in the HIV population.

Treatment of high triglycerides should include both lifestyle and medication if indicated. Triglycerides are very responsive to weight loss and dietary intervention. Medications include fibrates (gemfibrozil and fenofibrate) as well as prescription omega-3-fatty acids. Both have been tested in patients with HIV.[41]

Table 2. Statin Drugs and Protease Inhibitors

Drug Notes
Atorvastatin (Lipitor, Pfizer) generic Use lowest starting dose and titrate carefully

Do not exceed 20 mg/day with boosted darunavir (Prezista, Janssen), fosamprenavir (Lexiva, GlaxoSmithKline), or saquinavir (Invirase, Genentech)

Do not use with boosted tipranavir (Aptivus, Boehringer-Ingelheim)

Do not exceed 40 mg with nelfinavir (Viracept, Viiv Healthcare)
Fluvastatin (Lescol, Novartis) generic Not recommended with nelfinavir
Lovastatin (Mevacor, Merck) generic Contraindicated
Pitavastatin (Livalo, Kowa Pharmaceuticals America) No restrictions
Pravastatin (Pravachol, Bristol-Myers Squibb) generic No restrictions
Rosuvastatin (Crestor, AstraZeneca) generic Max 10 mg with boosted atazanavir (Reyataz, Bristol-Myers Squibb) or boosted lopinavir (Kaletra, Abbvie); cautious use with tipranaivir (use lower doses 5, 10 mg daily)
Simvastatin (Zocor, Merck) generic Contraindicated
Adapted from Myerson M et al. J Clin Pharmacol. 2015;55:957-974.

Table 3. Statin Drugs and Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Drug Notes
Atorvastatin Efavirenz (Sustiva, Bristol-Myers Squibb) and etravirine (Intelence, Janssen Therapeutics) decrease AUC (may need higher starting dose); no data for nevirapine (Viramune, Boehringer Ingelheim); no dose adjustments for rilpivirine (Edurant, Janssen Therapeutics)
Fluvastatin Etravirine may increase AUC (may need lower starting dose)
Lovastatin Efavirenz and etravirine decrease AUC (may need higher starting dose); no dose adjustments for rilpivirine
Pitavastatin No dose adjustment for efavirenz or rilpivirine
Pravastatin Efavirenz decreases AUC (may need higher starting dose); no dose adjustment for etravirine, no data for nevirapine and rilpivirine
Rosuvastatin No reported interactions
Simvastatin Efavirenz and etravirine decrease AUC (may need higher starting dose); no data for nevirapine
Abbreviation: AUC = area under the concentration-time curve
Adapted from Aberg JA et al . Clin Infect Dis. 2014;58:e1-34, and Myerson.

Switching ART

Many ART influence lipids levels; however, changing an ART regimen to drugs with fewer interactions may also present problems. By the time of evaluation for dyslipidemia, many patients have already undergone genotype and phenotype evaluation for ART and have been stable on a virologic-effective regimen that is tolerated. Because virologic suppression is a priority, it is reasonable to treat the lipid abnormalities on an established ART regimen. Switching regimens may not significantly improve lipids and may also result in virologic failure. Switching can be considered for patients with marked lipid abnormalities, who are at very high risk, or who are unable to attain reasonable response with therapy. This change should be done in consultation with the provider who is managing the patient's ART.[42,43]

Hypertension

Estimates of hypertension prevalence in patients infected with HIV vary. An analysis that I was involved in found that 43% of more than 4000 patients in an urban HIV clinic were hypertensive.[11] In a multicenter Italian study, hypertension prevalence was 29% with an additional 12% having high-normal blood pressure.[44]

The HIVMA guidelines recommend an annual blood-pressure assessment as part of the routine healthcare check in patients with HIV. At present there are no specific guidelines or recommendations for managing hypertension in patients infected with HIV in terms of goals or medications. There has been debate about blood-pressure guidelines (the Eighth Joint National Committee (JNC8) issued in 2014 called for a goal of < 140/90 mm Hg for most and < 150/90 mm Hg for those over age 60 years).[45]

Updated guidelines are anticipated in light of the SPRINT trial[46] showing a benefit for an even lower target (120/80 mm Hg) in patients with hypertension and CV risk factors. In the Swiss HIV Cohort Study poor blood-pressure control was associated with a higher risk for cardiovascular events in HIV patients with hypertension (SBP > 139 or DBP > 89 mm Hg at baseline).[47]

Antiplatelets

A proposed mechanism for the increased CVD risk in patients infected with HIV is platelet and immune activation leading to a prothrombotic state. In a small pilot study, 1 week of aspirin therapy attenuated platelet and immune activation in HIV patients compared with control subjects.[48] There are data suggesting underutilization of aspirin for primary prevention of CVD in eligible patients with HIV.[49] It is unclear if ART interacts with clopidogrel.[50] One review concluded that it does not appear to have clinically significant interactions with protease inhibitors,[51] despite reported interactions between ritonavir (a potent CYP3A inhibitor) and clopidogrel.[52] Clopidogrel may decrease the elimination of efavirenz by blocking CYP2B6, a major enzyme responsible for metabolizing efavirenz. This effect may be exacerbated in patients with the CYP2B6*6 genotype.[53]

Diabetes

The HIVMA 2013 Primary Care Guidelines recommend a fasting blood glucose and/or hemoglobin A1c test prior to and within 1 to 3 months of starting ART.

These guidelines note that a cutoff of HbA1c ≥ 5.8% improves the sensitivity for diagnosis for patients on ART, citing data that suggest that ART may have a variable influence on the relationship between HbA1c and fasting blood glucose.[54] Patients with diabetes mellitus should have an HbA1c goal of < 7% in accordance with the American Diabetes Association for the general public.[13]

In the D:A:D trial, the incidence of diabetes increased with cumulative exposure to ART, a finding that remained significant after adjustment for potential diabetes risk factors.[55] It is not known whether patients with HIV where insulin resistance is more prevalent have greater risk for developing manifest diabetes due to statin use. Data from the INTREPID trial showed no significant effects on fasting serum glucose and HbA1c levels for pitavastatin 4 mg and pravastatin 40 mg over 12 weeks in patients with HIV.

Heart Failure

The epidemiology of HIV-associated cardiomyopathy has changed since it was first reported in 1986.[56] In the past, this was often a severe, dilated cardiomyopathy, but now a milder form with slightly reduced left ventricular systolic function is common.

The etiology and prevalence of heart failure is not fully understood. Causes include myocarditis, toxicity from medications, opportunistic infections, substance abuse (alcohol, illicit drugs), and coronary artery disease.[57] Treatment is the same as that recommended for the general population. More patients with HIV and heart failure are receiving advanced therapies, including defibrillators, resynchronization therapy, and in some institutions, heart transplants.[58]

Pulmonary arterial hypertension (PAH) incidence is approximately 0.5% in the HIV-infected population and has not declined over time.[59] Causes are believed to be multifactorial, and clinical presentation and diagnosis are similar to other forms of pulmonary hypertension.[60]

Heart-Valve Disease

Few data exist regarding prevalence of valvular heart disease in patients infected with HIV. The German HIV HEART study found an association between the onset of valvular heart disease and clinical stage of HIV infection (per CDC classification).[61] A history of intravenous drug use may be more common, as is rheumatic fever for those who have lived in countries where this remains a medical problem. In the absence of specific guidelines, treatment is the same as for the general population.

Electrocardiographic Abnormalities

Treatment with ART has been associated with changes in the electrocardiogram, in particular prolongation of the QT segment. In addition, patients may also be on methadone and psychiatric medications that also can prolong the QT segment. In the HIV HEART study, QTc prolongation was seen in nearly 20% of the 802 patients assessed but was not linked to a specific antiviral.[62] The INSIGHT SMART study group[63] found that different PI-based regimens have a similar, small effect on the QT segment compared with NNRTI-based regimens. All protease inhibitor–based regimens were associated with prolongation of the PR interval, and interruption reduced PR duration. However, the authors cautioned that the clinical relevance of these findings was unclear. Routine use of baseline ECG and surveillance have not been practiced for these patients.

Assessment/Referral

Primary-Care Provider

Primary-care providers for patients infected with HIV should discuss with patients that they are at increased risk for CVD due to their HIV status. Initial testing and assessment should include:

  1. Height and weight with calculation of BMI, blood pressure.

  2. Waist circumference and identification of metabolic syndrome.

  3. Fasting lipid profile, glucose, HbA1c.

  4. History and cardiovascular exam.

  5. Review of all CVD risk factors.

  6. Lifestyle counseling and plan for management of CVD risk factors.

When to Refer

Many primary-care providers, especially those trained in infectious diseases, may not have training and experience in diagnosis and treatment of CVD risk factors and cardiac issues. In addition, the limited time that can be spent with patients may preclude a more in-depth CVD evaluation and discussion.

For complex or hard-to-treat hypertension or dyslipidemia, referral should be sought by a cardiologist, hypertension specialist, or lipidologist. For overt or suspect cardiac disease (coronary artery disease, valve disease, heart failure, arrhythmia) a referral should be made for cardiology consultation.

Conclusion

This review has provided background on HIV and how both the virus and the therapy affect cardiovascular disease and risk factors, in particular dyslipidemia. As patients infected with HIV are living longer, prevention efforts focusing on diagnosis and treatment of CVD risk factors will be an increasing need.

Epidemiologic studies and clinical trials are needed to establish specific and comprehensive guidelines for this patient population. In 2008, the NHLBI established the 5-year HIV CVD Collaborative, which supports research on various aspects of HIV-related CAD. The National Institutes of Health–sponsored Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) trial is ongoing. This multicenter, randomized placebo-controlled trial for the primary prevention of CVD will enroll over 6000 HIV-infected participants at low CV risk (by ACC/AHA risk stratification), with low LDL-C (ie, not candidates for treatment) and assign them to placebo or pitavastatin. Outcomes will be major cardiac events, and there will be substudies using CT angiography and biomarker assessment. Results should be available in approximately 2020.

Until we have the results of such studies conducted in persons with HIV infection, we must extrapolate from guidelines for non-HIV patients to help us manage patients who are living with HIV.

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