Increased Prevalence of Cardiovascular Disease in Adults with HIV

Despite advancements in the treatment of human immunodeficiency virus (HIV) with combination antiretroviral therapy (ART), non-infectious causes of morbidity and mortality have had an increasingly negative impact on morbidity and mortality in affected patients.¹ More specifically, cardiovascular disease (CVD) appears to significantly impact this morbidity as evidenced by a rise in CVD hospitalization rates among HIV-infected patients.² Additionally, the World Health Organization predicts that by 2030, HIV and ischemic heart disease will be among the three leading causes of disease burden globally. This suggests a strong interdependency between these two disease processes, which poses a major public health challenge.³

The increased incidence of CVD in HIV patients may relate to an interplay of traditional CVD risk factors manifesting in an aging population, higher incidence of traditional risk factors such as smoking, higher incidence of related co-morbidities such as Hepatitis C (HCV), toxicities including dyslipidemia and lipodystrophy related to ART, and the inherent inflammatory response and immune activation related to the virus.¹ Data indicate an approximately two-fold higher rate of acute myocardial infarction (AMI) compared to a non-HIV population. Among HIV-infected patients, dyslipidemia was the cardiac risk factor most predictive of AMI.⁴ Moreover, independent of traditional risk factors, HIV infection was associated with an increased risk of CVD.

HIV is an Independent Risk Factor for CVD Events

In the Strategies for Management of Antiretroviral Therapy (SMART) randomized controlled trial comparing treatment with episodic use of ART guided by CD4+ count versus continuous antiretroviral therapy, participants with a higher viral load had a higher incidence of fatal and non-fatal CVD (HR 1.6, 95% CI 1.0-2.5).⁵ However, the specific inflammatory and immunologic mechanism in CVD development among HIV-affected individuals is incompletely understood.

Hanna et al. recently investigated associations between macrophage-associated inflammatory markers and carotid artery plaque development in the Multicenter AIDS Cohort Study (MACS) and Women's Interagency HIV Study (WIHS) cohorts;⁶ the authors found that of the four markers of macrophage activation associated with HIV seropositivity, soluble CD14 and soluble CD163 were prospectively associated with carotid plaque formation. Other work has implicated IL-6, hsCRP, and D-dimer in CVD.⁷ In addition to further elucidating the pathogenesis of HIV and CVD, these findings may have implications for improving precision in risk-prediction models of CVD in HIV patients.

HCV co-infection is common in HIV patients, and synergism may increase CVD risk.⁸ Current HIV treatment guidelines recommend the initiation of ART regardless of CD4+ count; however, there are not yet randomized controlled trials confirming that earlier initiation of therapy lowers the incidence of CVD. In fact, ART may have an unfavorable impact on risk of CVD due to lipid abnormalities induced by the pharmacologic treatment. Given the increasing prevalence of an aging HIV population and the burden of CVD, it is critical to consider how to optimally manage dyslipidemia in HIV-infected patients and if our current guidelines adequately address this.

Risk Stratification in HIV patients: Should the Presence of HIV be Considered a CHD Risk Equivalent?

Management of HIV and prevention of CVD centers largely on adequate risk prediction within this patient population. The Data Collection on Adverse events of Anti-HIV Drugs (D:A:D) study was a prospective, multi-cohort observational study performed in 2012 to develop cardiovascular risk prediction tailored to HIV patients. In comparison to the Framingham Risk Score, the risk predictor included exposure to ART drug therapy and more accurately estimated the risk of CVD outcomes, specifically noting that the Framingham equation under-predicted CVD event rates in patients on ART.⁹ The patient population included was predominantly white, and race or ethnicity were not incorporated into the risk prediction.

In 2013, the American College of Cardiology/American Heart Association (ACC/AHA) released cholesterol treatment guidelines based on the Pooled Cohort Equations (PCEs) for 10- year ASCVD risk prediction to assist with decision making about lipid lowering therapy. Currently, treatment guidelines are designed for the general population and do not take into account the presence of HIV or other inflammatory disorders. Similar to the strategy of selectively using cardiac CT to assess the presence and extent of coronary artery calcium in order to improve risk prediction, Zanni et al. used contrast-enhanced computed tomographic angiography (CTA) for additional risk stratification in subjects with HIV. Patients with high-risk morphology (HRM) plaques on CTA were deemed at increased risk for CVD and presumed to have more benefit from initiation of statin therapy. The prevalence of HRM in this population was an alarming 36%.

The predictive ability of the 2013 ACC/AHA guidelines as compared to the 2004 update of the ATP III guidelines in recommending statin therapy for more HIV-infected patients without CTA assessment was deemed superior.¹⁰ However, without CTA assessment the 2013 guidelines considerably underestimated CV risk and statin therapy would not have been recommended for the majority of HIV patients with HRM plaque based on the 2013 ACC/AHA pooled cohort equation (PCE) alone.¹⁰ Given the high prevalence of HRM plaques in HIV patients, the cost-effectiveness of a strategy of selective use of noninvasive imaging in addition to the ACC/AHA PCE should be investigated.

Recently, Feinstein et al. evaluated the ACC/AHA PCEs in a large HIV cohort to evaluate the performance of risk prediction and to create HIV-specific MI risk estimation models.¹¹ Although the PCEs predicted ASCVD risk adequately (C statistic 0.75, 0.71-0.78), observed MI rates consistently exceeded predicted rates in patients with <10% estimated 10-year ASCVD risk. This under-prediction was most apparent in black men and women. This finding may have been due in part to a significantly smaller sample size in these populations. An additional limitation to this study was that the definition of MI included Type 2 non-ACS MI. Thus, as risk estimation models emerge incorporating specific HIV factors and biomarkers, model calibration may be particularly important for patients who are low-to-moderate risk and facing a decision threshold to start statin therapy. However, based on the adequate prediction of the PCEs on the population as a whole, traditional CVD risk factors remain essential for risk estimation and are reasonable to use as a baseline gauge of lowest predicted risk.¹¹

Interaction of Statin Therapy with Concomitant ART for HIV

The potential for drug interactions with ART complicates the selection of statin therapy in HIV patients. Protease inhibitors (PIs) and cobicistat are cytochrome 3A4 inhibitors (CYP3A) and can increase toxicity of statins by inhibiting their metabolism. For this reason, lovastatin and simvastatin, which have extensive first-pass metabolism by CYP3A, should not be used with PIs. Atorvastatin, fluvastatin, pravastatin, and pitavastatin are metabolized less by CYP3A and the potential for drug interactions are reduced. Rosuvastatin is mainly metabolized by CYP2C9; however, due to a small contribution of CYP3A4 metabolism and non-CYP mechanisms that can cause significant drug interaction, it must be used with caution.¹⁸

Non-nucleoside reverse transcriptase inhibitors (NNRTIs) ART in combination with statins cause less dyslipidemia in comparison to ART with protease inhibitors. However, the impact of NNRTIs and statin in reducing CV risk is unknown and the impact on HIV viral load management and survival is beyond the scope of this discussion. Some statins also interact with non-nucleoside reverse transcriptase inhibitors as well. Efavirenz in particular decreases the efficacy of simvastatin, atorvastatin, and pravastatin; thus, higher doses of these statins may be needed to achieve target lipid levels. Potential toxicities of statins to consider are similar to the general population and may include liver or muscle injury. Though insulin resistance is more common in HIV patients, it is not known if statin use poses a greater risk of development of diabetes. However, the INTREPID (HIV-infected patieNts and TREatment with PItavastatin vs pravastatin for Dyslipidemia) trial did not show a significant effect of pitavastatin on glucose homeostasis.¹⁹

Consideration for Empiric Statin Therapy

Given heightened risk of ASCVD in patients with HIV, there may be a role of empiric statin therapy in the absence of a contraindication.²⁰ Though prior studies have shown that statin therapy in HIV patients improves lipids and reduces markers of inflammation, only recently was statin therapy prospectively studied in this patient population with CT angiography.

In 2015, Lo and colleagues reported a small randomized clinical trial of 40 HIV patients without vascular disease or an existing indication for statin therapy to receive either atorvastatin or placebo.¹⁴ The primary endpoint assessed was arterial inflammation by FDG-PET of the aorta with other endpoints including coronary plaque assessed by coronary CT angiography. The study did not show a reduction in arterial inflammation, but it did show that statin therapy slowed coronary plaque progression and in some cases promoted regression, mainly of non-calcified plaque volume. In the placebo group, plaque volume increased and a small subset of patients demonstrated progression of clinically significant coronary stenosis. This was the first study to investigate the effects of statin therapy on coronary arteriosclerosis exclusively in patients with HIV and provides encouraging results while awaiting an outcomes trial.

The results of the REPRIEVE (Randomized Trial to Prevent Vascular Events in HIV) trial (see section below) will provide further insight into the clinical applicability of the hypothesis that Lo and colleagues investigated. To date, however, data are lacking to support the full extent that statins can modify cardiovascular risk in all HIV patients. Additionally, though Lo and colleagues did not find that there were significant toxicities of statin therapy over twelve months, better definition of the full spectrum of toxicities of statins in HIV patients and longer follow-up are needed due to the high prevalence of comorbid liver disease and metabolic syndrome features.²¹ Lastly, adherence rates were lower in the statin group compared to the non-statin group, and there is concern for possible polypharmacy adversely affecting ART adherence.

Management of Dyslipidemia and CV Risk Reduction in HIV-Positive Adults

Optimal management of CVD prevention in HIV patients, as in those without HIV, begins with lifestyle modification and treatment of traditional risk factors. However, a key question is whether traditional risk factor modification is sufficient since the increased prevalence of traditional risk factors does not fully account for the substantial increase in CVD in HIV patients.⁴

Among HIV patients, small studies have begun to assess the utility and timing of initiating statin therapy. In 2009, Silverberg and colleagues performed a retrospective review measuring the percent change in lipids in HIV patients compared to non-HIV patients beginning lipid lowering therapy.¹² Patients with HIV beginning statin therapy had a 26% reduction in low-density lipoprotein-cholesterol (LDL-C), which was less than non-HIV-infected individuals.

Additionally, in HIV-infected individuals, statin therapy appears to improve key indices of immune activation in HIV individuals, with the suggestion that statin therapy improves high risk plaque morphology.^13,14 However, to date, studies have not addressed if these effects translate to a reduction in clinical CVD.

The REPRIEVE trial, launched in April 2015, aims to more definitively assess the efficacy of statins as primary prevention for clinical CVD as the largest clinical trial of HIV-related CVD to date.¹⁵ The REPRIEVE trial, funded by the NHLBI/NIH, is targeting enrollment of 6500 HIV patients at approximately 100 sites in the AIDS Clinical Trials Group network. Eligible participants are those at low-to-moderate risk for ASCVD between the ages of 40 to 75 years old on ART for at least six months prior to study entry with no known clinical history or symptoms of CVD and not on statin therapy.

Patients will be randomized to receive pitavastatin 4 mg/day or placebo for ~4 years. Pitavastatin was chosen due to fewer interactions with ARTs compared to other statins. Additionally, in the INTREPID study, pitavastatin showed a greater reduction in select markers of immune activation on arterial inflammation and in LDL lowering among HIV patients compared to the more commonly used drug, pravastatin.^16,17

The primary composite endpoint of REPRIEVE includes CVD-related mortality, myocardial infarction, stroke, unstable angina, peripheral artery disease, and cardiac revascularization. REPRIEVE differs from previously published studies on HIV and statin efficacy by examining hard endpoints over long-term follow-up. In addition, there will be a substudy of 800 participants investigating the mechanism of action of pitavastatin in reducing immune activation and inflammation. REPRIEVE is currently in the enrollment phase and results should become available in the next 3 to 5 years with the potential to significantly influence future guidelines on lipid lowering therapy in the HIV population.

Tailored Risk Assessment and Statin Therapy in HIV

Though a more definitive link needs to be established between statin therapy and a clinical benefit in HIV patients, the increased risk of CVD inherent to the virus and ART use not currently incorporated into the PCEs should be considered in treatment decisions. The compelling evidence of increased prevalence of CVD in HIV patients not fully captured by the current means of risk stratification with PCEs supports at the very least a clinician patient risk discussion for patients when the risk based treatment decision is uncertain including those who have a low 10-year risk of ASCVD but additional factors such as family history of premature ASCVD, elevated lifetime risk, elevated CAC (>75th percentile), hsCRP ≥ 2.0 mg/l, or ankle-brachial index <0.9.²⁴ HIV is not commonly cited as an ASCVD risk factor that warrants clinician patient risk discussion, though incorporating it as one should be strongly considered.

Within the general population, mounting evidence supports the selective use of coronary artery calcium (CAC) scoring to personalize risk assessment in intermediate risk patients (5-15% or 5-20% ASCVD risk group). Specifically, the absence of CAC can reclassify an individual to a lower risk category and allow for flexibility in treatment decisions with statin therapy. Specifically in HIV patients, CAC was associated with traditional atherosclerotic risk factors and nearly half of individuals had accelerated aging by CAC.²² In the MACS cohort, there was a marginally significant increased prevalence of having any CAC in HIV patients compared to non-HIV patients after adjustment for age, race, study center, cohort, and CAD risk factors.²³

Furthermore, CT angiography identified a higher non-calcified plaque prevalence in HIV patients. Though this particular study was limited to only men and the clinical event rate was low, HIV patients seem to have an increased prevalence and extent of non-calcified coronary artery plaque even after adjustment for CAD risk factors. CAC may provide better assessment of the risk of ASCVD in HIV patients as the additive value of CAC in addition to traditional risk factors has been well validated.²⁵

Conclusions

The optimal approach to lipid management in HIV patients will be shaped by the results of the REPRIEVE trial. However, in the decision to treat hyperlipidemia, we propose use of the PCEs to first estimate risk of HIV in ASCVD. In patients who are low or intermediate risk (5-15% ASCVD estimated 10-year risk), a further clinician patient risk discussion to weigh the untreated risk of ASCVD against potential risks of therapy should take place. Lastly, a CAC scan is certainly reasonable to help make a decision about necessity of statin therapy and possibly about its intensity.

In addition, the increasing longevity of an aging HIV population is encouraging. However, further strides should be made to refine cardiovascular risk assessment and management based on the somewhat unquantifiable risk inherent to the virus and ART use. The PCEs may underestimate true risk of ASCVD, especially in women and black men. Provider patient discussion is critical to the care of HIV patients who are low or intermediate risk in deciding about statin therapy. There may be a role for selective use of CAC or perhaps CTA (in the future if radiation and contrast exposure can be decreased further) to better risk stratify HIV patients to aid in the decision regarding lifestyle versus lifestyle plus lipid lowering pharmacotherapy. Continued investigation is needed to further evaluate if CAC and the current risk prediction model better estimates ASCVD in HIV patient specifically. Additionally, we suspect that the underappreciation of CVD may extend to other inflammatory disorders such as SLE, rheumatoid arthritis, and related conditions. We are hopeful that ongoing studies such as the REPREIEVE trial will provide further insight into the true clinical benefit of statin therapy in HIV patients.

References

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Keywords: Acquired Immunodeficiency Syndrome, Adenosine Triphosphate, Angina, Unstable, Angiography, Ankle Brachial Index, Anti-HIV Agents, Aorta, Arteritis, Arthritis, Rheumatoid, Benzoxazines, Biomarkers, CD4 Lymphocyte Count, Calcium, Calibration, Cardiovascular Diseases, Carotid Stenosis, Cholesterol, LDL, Cohort Studies, Coinfection, Coronary Artery Disease, Coronary Stenosis, Cost-Benefit Analysis, Cytochrome P-450 CYP3A, Decision Making, Diabetes Mellitus, Drug Interactions, Dyslipidemias, Fatty Acids, Monounsaturated, Fibrin Fibrinogen Degradation Products, Glucose, HIV Infections, HIV Seropositivity, Hepatitis C, Homeostasis, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Hyperlipidemias, Indoles, Inflammation, Insulin Resistance, Interleukin-6, Life Style, Lipids, Lipodystrophy, Liver Diseases, Longevity, Lovastatin, Macrophage Activation, Macrophages, Metabolic Syndrome, Myocardial Infarction, Peripheral Arterial Disease, Polypharmacy, Pravastatin, Prevalence, Primary Prevention, Prospective Studies, Protease Inhibitors, Public Health, Quinolines, Retrospective Studies, Reverse Transcriptase Inhibitors, Risk Assessment, Risk Factors, Risk Reduction Behavior, Simvastatin, Smoking, Stroke, Viral Load

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