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HIV & Aging Clinical Recommendations
Cardiovascular disease (CVD) is the leading cause of death in the United States and world-wide (Mathers 2006). Since the main predictor of heart disease is age, and since PLWH are living longer and growing older as a result of effective antiretroviral therapy (ART), the prevalence of CVD will increase (Freiberg 2013; Sackoff 2006). We already observe that 6 to 15% of AIDS-related mortality is attributable to cardiovascular disease, higher than in uninfected individuals and at a younger age (Escarcega 2014; Eyawo 2017).
Several population-based studies have investigated the association between HIV, ART, and CVD. Triant summarized data from the past ten years and indicated that the CVD risk among PLWH is nearly two times higher than in non-infected population (Triant 2014).
Besides aging, the major Framingham risk factors for heart disease include high blood pressure, hyperlipidemia, diabetes mellitus, and cigarette smoking. These are widely prevalent among PLWH. The attributable contribution of these major risk factors to CVD-associated death is well over 90%, and more than 80% of that risk is attributable to lifestyle-modifiable factors, including high blood pressure, hyperlipidemia, diabetes mellitus, and smoking.
It appears that aging PLWH have increased exposure to traditional risk factors. The rate of smoking, for example, is two to three times higher among PLWH (40-60%) than in the general population, and it has been suggested that the impact of smoking-related morbidity is greater among PLWH (Nahvi 2009). Insulin resistance and diabetes are also more prevalent in PLWH. Visceral fat accumulation, a poorly understood complication of HIV or ART, may also contribute to CVD risk in certain patients.
Although the reduction in major CVD risks will continue to be an important prevention modality, studies have shown that these risk factors by themselves do not account for all of the observed increased CVD in PLWH. An analysis of the Veterans Aging Cohort Study (VACS) of more than 27,000 primarily male PLWH reported that HIV-positive veterans had almost 50% increased relative risk of acute myocardial infarction (MI) compared with those without HIV, even after adjustment for traditional Framingham risk factors (Freiberg 2013). This association may be due to a complex interaction between HIV infection and ART that results in increased cardiac events.
The role of ART in promoting atherosclerosis and CVD has been extensively debated; both alterations of lipid metabolism and direct detrimental effect of specific drugs have been described. The D:A:D (Data Collection in Adverse Effects of Anti-HIV Drugs) observational cohort study investigated the association of ART and CVD in PLWH and identified a significant increase in MI risk with ART, especially with the use of older protease inhibitors (PI). Most of this effect may be due to metabolic effects of protease inhibitors (Friis-Møller 2007). Furthermore, specific evaluation of individual PIs suggests that the increased risk of CVD may not be a class effect. More commonly used PIs (atazanavir and darunavir, each combined with low-dose ritonavir) may not have the increased CVD risk associated with older agents from this class such as such as lopinavir-ritonavir and indinavir (Marra 2009).
Other studies have identified non-PI-based ART as also contributing to CVD risk. Among the non-PI-based ART options, nucleoside reverse transcriptase inhibitors (NRTIs), such as abacavir (Young 2015) and didanosine, have been associated with increased MI risk in some but not all studies. The mechanism of this potentially increased risk has not been determined. Although a meta-analysis by the U.S. Food and Drug administration has suggested that there is no association between abacavir use and MI (Ding 2012), other observational studies imply a CVD risk from abacavir (Young 2015). Taken together, these studies suggest that some of the increased CVD risk in the setting of HIV is independent of patient demographics or traditional CVD risk factors, and may be due to direct and indirect effects of certain ART regimens.
In addition to the role of ART in CVD risk, many studies now suggest that uncontrolled HIV infection and greater immunosuppression (low CD4 cell counts) are associated with MI and stroke. The SMART (Strategies for Management of Antiretroviral Therapy) study was the first to identify an increase in cardiovascular events with interruption in ART (El-Sadr 2006). Treatment interruption was associated with a 2.6-fold increase in risk of HIV disease progression or death and a 57% increase in risk for the composite endpoint of MI, percutaneous coronary intervention/coronary artery bypass grafting, or cardiovascular death (P=.05) (Phillips 2008a).
Several studies suggest that higher CD4 cell counts and lower HIV RNA levels are associated with decreased MI risk (Lang 2012). AIDS Clinical Trials Group (ACTG) researchers studied the impact of ART on endothelial function in a randomized study (ACTG 5152) of various ART regimens, and showed that there was improvement in arterial endothelial function with viral suppression regardless of ART regimen (Torriani 2008). The greater the reduction in HIV RNA level, the greater the improvement in endothelial function, despite substantial differences among the groups in lipid level changes and irrespective of ART regimen. If there is any increase in CVD risk associated with ART, it appears to be counterbalanced by the potentially beneficial effects (possibly anti-inflammatory) of ART on blood vessels. In fact, treating HIV with ART clearly has beneficial effects on MI risk.
CVD mortality trends in women living with HIV parallel those of the general HIV population, with decreasing AIDS-related mortality accompanied by increasing CVD-related mortality. Nevertheless, HIV may have a greater impact on the CVD risk of women compared with men (Lang 2010). In the Partners cohort study, the adjusted RR for MI comparing PLWH with non-PLWH was 3.0 for women versus 1.4 for men (Triant 2007). This underscores the need for greater effort to identify CVD risk and promote primary prevention in women.
The proposed pathogenesis of atherosclerosis and arterial disease in HIV infection is a multifactorial and complex process that is incompletely understood (see Figure 1). Dyslipidemia is a well-described independent risk factor for CVD, and it occurs in a high proportion of PLWH. This dyslipidemia is caused by a combination of factors associated with HIV disease, ART regimens, and individual patient characteristics. It has been known since the 1980s that HIV infection is associated with lipid abnormalities, particularly in persons with more advanced disease who are not on ART. They often have elevations in triglyceride (TG) levels and decreases in high-density lipoprotein (HDL) as well as in low-density lipoprotein (LDL) cholesterol and total cholesterol (TC).
In the 1990s we observed that dyslipidemia may be caused by certain ART. More recently, we have recognized that persistent inflammation associated with both untreated and well-controlled HIV may contribute to the observed increased CVD risk (Hsue 2012). PLWH with elevated C-reactive protein had an odds ratio for acute MI four times higher than that of patients without HIV who had normal C-reactive protein (Stein 2014).
This may represent a similar mechanism of increased risk that can be seen in patients with other chronic inflammatory conditions, such as rheumatoid arthritis, systemic lupus erythematosus, and inflammatory bowel disease. Numerous studies show increases in soluble makers of inflammation such as C-reactive protein, cytokine IL-6, D-dimer, and monocyte activation among HIV patients (Borges 2016). The effects of persistent HIV infection and its associated immune activation and inflammation, reduce the ability of blood vessels to dilate and generate an anticoagulant surface. This facilitates a higher incidence of friable and unstable plaques which easily erode and rupture leading to acute coronary syndromes (D’Ascenzo 2015).
In summary, the observed increased CVD risk in HIV is a consequence of increased traditional risk factors, as well as immune activation, inflammation, and a possible predisposition to coronary plaque rupture and thrombosis from uncontrolled HIV viremia.
Assessing risk and preventing CVD in PLWH remains challenging, as traditional risk models tend to underestimate the risk. The Framingham Risk Score was not designed for use in HIV populations, and a recalibration may be needed to adjust for under- or over-prediction (D’Agostino 2012). Although new risk assessment algorithms have been proposed, they have not been validated.
Investigators have used data from the D:A:D study to develop a risk calculator and have compared it to the Framingham risk calculator (Friis-Moller 2010). They included some ART variables in their models in addition to the traditional Framingham risk factors and found that the D:A:D models performed reasonably well in terms of discriminating risks and performed better in terms of predicted-to-observed number of CVD events (Markowicz 2014).
The American Heart Association and American College of Cardiology (AHA/ACC) Pooled Cohort Equations CV Risk Calculator is one of the newer global risk calculators. In an analysis that used data from the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) cohort, the AHA/ACC Pooled calculator had acceptable discrimination for myocardial infarction risk, with less robust performance for black men and women (Feinstein 2017). Although the utility of these calculators in the HIV-infected population may not be optimal, they are a reasonable starting point for assessing risk and should be utilized.
The IDSA/HIVMA HIV primary care guidelines recommend obtaining a baseline fasting blood glucose and/or hemoglobin A1C and a fasting lipid profile prior to and within three months after starting ART to screen for metabolic syndrome, diabetes mellitus, and dyslipidemia (Aberg 2014). The fasting lipid profile should be obtained three to six months after initiating or switching ART and then every twelve months thereafter. Blood pressure, weight with body mass index (BMI) and waist circumference calculation should be performed at least annually.
Care of the older adult living with HIV includes proper management of blood pressure, diabetes risk reduction, smoking cessation, and treatment of dyslipidemia to reduce the cardiovascular risk. All the available guidelines emphasize the importance of adherence to a heart-healthy lifestyle that includes regular exercise, following a low-glycemic-index diet, maintaining BMI <25 kg/m2, and smoking cessation. Smoking cessation might be the single most important factor in reducing CVD risk.
The guiding principle of CVD risk management is that a patient’s absolute CVD risk determines the intensity of interventions. Aspirin use is an important component in the primary prevention of CVD. Although the decision to recommend aspirin for the prevention of CVD in the HIV-infected patient is the same as that for the general population, it has been underutilized in HIV. The 2013 American College of Cardiology/American Heart Association (ACC/AHA) guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults has been a major shift from prior cholesterol management guidelines. The ACC/AHA guidelines address the broader outcome of clinical atherosclerotic CVD (ASCVD), which includes CVD, MI, stroke, and peripheral arterial disease, not just MI or CV death.
The ACC/AHA guidelines do not emphasize treatment-specific goals based on LDL targets (Stone 2014a). These guidelines take a different approach to many aspects of lipid management, including the evaluation of patients for lipid-lowering therapy, the use and monitoring of lipid-lowering agents, and the use of treatment targets. The ACC/AHA guidelines focus on treatment of LDL-C that is based on risk and not on LDL-C level. Risk assessment is used to identify patients to treat, and the intensity of treatment is based on clinical trials evidence; without LDL targets. To estimate ten-year ASCVD risk, the ACC/AHA guidelines employ a simplified global risk-assessment tool with pooled cohort risk equations adapted for different genders and race (non-Hispanic whites and African-Americans in the U.S.). The Pooled Cohort Equations CV Risk Calculator is relatively easy to employ and can be found at http://www.cvriskcalculator.com/. It is also available as an app for mobile devices.
The ACC/AHA guidelines have not been validated in PLWH. There is concern that most CVD prevention guidelines for the general population will underestimate the CVD risk of people living with HIV. Zanni (Zanni 2014) and others compared the ACC/AHA and NCEP/ATP III recommendations among 108 PLWH without known CVD and obtained contrast-enhanced cardiac computed tomography angiography to evaluate the cohort for high-risk morphology (HRM) plaque formation (Zanni 2014). The study found by applying 2013 ACC/AHA guidelines, a higher percentage (26% vs 10%) of subjects with and without HRM coronary plaque would receive statin therapy relative to applying the recommendations from NCEP guidelines.
Statins represent the primary ASCVD prevention intervention. Numerous studies among HIV-uninfected individuals without evidence of coronary heart disease have demonstrated substantial relative reductions in cardiovascular events with the use of statins. Statins are an attractive option in HIV because, in addition to their cholesterol-lowering properties, they have anti-inflammatory effects that may further reduce CVD and all-cause mortality.
A previously published cohort study has identified a significant survival benefit for HIV-positive statin users who were virologically controlled on ART.
Table 1: Summary of key recommendations from the 2013 ACC/AHA cholesterol guideline
|Groups most likely to benefit from statin therapy||Recommended statin intensity|
|Secondary prevention for patients with clinical ASCVD||High intensity|
|Primary prevention for LDL-C>190 mg/dL||High intensity|
|Primary prevention for diabetics aged 40–75 years with LDL-C 70–189 mg/dL and without clinical ASCVD||≥7.5% 10-year risk—high intensity
<7.5% 10-year risk—moderate intensity
|Primary prevention for non-diabetics aged 40–75 years with an estimated 10-year ASCVD risk <7.5%||Moderate to high intensity if appropriate after clinician‒patient discussion|
Thresholds for initiating statin therapy were derived from large randomized controlled trials. The choice of statin and dose was recommended based on estimated level of risk for a patient (Table 1). If the patient had major cardiovascular risk factors such as clinical ASCVD, LDL-C >190 mg/dL, or age 40 to 75 years with diabetes mellitus, or if the calculated ten-year risk of ASCVD was >7.5%, then the guidelines recommended moderate- to high-intensity statin therapy. The definition of high-intensity statin therapy is LDL-C reduction of >50% and that of moderate-intensity therapy is a reduction of 30% to 50%.
The efﬁcacy of statins in HIV is not completely proven, because of small sample-size and the observational nature of many studies (Gili 2016). As a result, a large, multicenter, randomized, placebo-controlled trial, the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE clinicaltrials.gov: NCT02344290) was initiated in March 2015. The REPRIEVE clinical trial will randomize 6500 PLWH to pitavastatin—not metabolized via CYP3A4, or placebo. Results should provide a better understanding of the real impact of statins on CV events including effects on plaque and immune function.
Table 2: Choice of Statin and Dose Intensity Options
|Statin||Dose and Expected LDL-C % lowering|
|atorvastatin (Lipitor)||10 mg||20 mg||40 mg||80 mg|
|pravastatin (Pravacol)||10 mg||20 mg||40 mg||80 mg|
|rosuvastatin (Crestor)||5 mg||10 mg||20 mg||40 mg|
|fluvastatin (Lescol)||20 mg||40 mg||80 mg|
|simvastatin (Zocor)||5 mg||10 mg||20 mg||40 mg|
|pitavastatin (Livalo)||1 mg||2 mg||4 mg|
|lovastatin (Mevacor)||10 mg||20 mg||40 mg||80 mg|
Choice of statin and dose intensity are listed in Table 2. Statin doses that have been used in clinical trials of primary prevention include low- to moderate-intensity (pravastatin 40 mg; lovastatin 20 to 40 mg; atorvastatin 10 mg) and high-intensity (atorvastatin 40 mg; rosuvastatin 20 mg) therapy. No trials have directly compared the effects of low- to moderate-intensity with high-intensity statin therapy for primary prevention.
In PLWH, the selection of statins should take into account the relative efficacy of the statin as well as any potential drug-drug interactions and side effects. There are few head-to-head studies of statin drugs in patients with HIV to help guide decision-making. Because simvastatin and lovastatin interact with cytochrome P450 3A4 (CYP3A4) inhibitors, as is the case with most PIs, these statins are contraindicated with PIs or cobicistat that inhibit CYP3A4. Dose modification may be needed for most statins and PIs, NNRTIs, and the pharmacokinetic enhancer cobicistat because potential drug interactions increase the risk of severe statin adverse events such as rhabdomyolysis. Atorvastatin, if used, should be initiated at low dosage (10 mg) and titrated slowly upward. Other available statins include rosuvastatin, pitavastatin, and fluvastatin. These may be used with most PIs started at low dosage and increased incrementally, if indicated; in general, maximum dosages should not be used.
Pitavastin has some advantages for patients on a boosted PI regimen, since it minimally interacts with these antiretrovirals. It is also an effective agent with a favorable adverse effect profile. For patients not using a boosted PI, consider atorvastatin given its potent efficacy and the greater clinical experience with its use in this population. Rosuvastatin is a potent reducer of total LDL cholesterol, decreases certain markers of inflammation, improves bone density, and is not expected to have substantial interactions with antiretroviral agents. However, it has the potential for exacerbation of insulin resistance. Fluvastatin is not metabolized by the CYP3A4 system and thus may theoretically be started at usual doses. However, there are few clinical data concerning the concurrent use of fluvastatin with PIs. Although pravastatin is an acceptable alternative to these agents due to its lack of metabolism via CYP3A4, it is not as potent as these other statins in reducing LDL cholesterol.
The fact that the ACC/AHA guidelines do not recommend LDL-C targets does not mean that lipid panels should not be measured. Lipid panels should be checked at least annually to see if the prescribed statin therapy has put the patient in a reasonable range for ASCVD risk. Likewise, if LDL-C <40 mg/dL, it may be too low, and the patient’s statin dosage should be lowered. Finally, if the patient’s LDL-C is not low enough for moderate to high ASCVD risk, then clinicians should emphasize lifestyle modifications.
Some patients are unable to take statin medications because of side effects—most commonly myalgias and other muscular symptoms. Clinicians may consider multiple interventions to control statin myopathy (e.g., switching statin, dose reduction, alternative dosing schedules, Coenzyme Q10 supplementation). In general, clinicians should discontinue statin therapy until symptoms are evaluated. They should consider other conditions that might increase the risk for muscle symptoms, such as hypothyroidism, kidney/liver disease, rheumatologic disorders, steroid myopathy, low Vitamin D status, or primary muscle diseases. If, after two months without statin therapy, muscle symptoms or elevated creatinine kinase levels do not resolve completely, clinicians should consider other causes of muscle symptoms.
Based on current data, there is not enough evidence to suggest that PLWH need a more aggressive approach to the management of CVD risk compared with that recommended for uninfected people. But efforts to apply the newer 2013 ACC/AHA guidelines broadly would raise the level and intensity of CVD preventive management for aging PLWH compared with the NCEP/ATP III guidelines. Before initiating statin therapy, clinicians should engage in a patient discussion of the potential for ASCVD risk, potential benefits of statin therapy, potential for adverse effects, medication interactions, and patient preferences.
Non-statin lipid-lowering agents such as niacin, fibrates, fish oil, and ezetimibe have not shown enough benefit in randomized trials to merit recommendation in the 2013 ACC/AHA guidelines. The triglyceride level is a primary target of lipid-lowering therapy only when the triglyceride level exceeds 500 mg/dL, because of the associated risk of pancreatitis. Although high triglyceride levels may be a modest independent risk factor, triglycerides are most associated with other cardiovascular risk factors (e.g., low HDL-C level, hypertension, obesity, inflammation, and insulin resistance).
For triglyceride levels below 500 mg/dL, LDL-C should be targeted to reduce CVD risk. For higher triglyceride levels, where the primary goal of treatment is to prevent pancreatitis, fibrates are the preferred initial therapy. Dietary intervention can also have a dramatic effect on triglyceride levels. Patients should restrict saturated fats and trans-fats, emphasize intake of omega-3 fatty acids and monounsaturated fats, limit simple carbohydrates and calories, and reduce alcohol intake. Fish oil in a dose of 3 grams per day can lower triglyceride levels by up to 25%.
The prevalence of cardiovascular disease is increasing as PLWH live longer, age, and acquire traditional cardiovascular disease risk factors. The ACC/AHA guidelines introduce several major paradigm shifts. These include aiming for ASCVD risk reduction as opposed to targeting
LDL-C levels, promoting the use of evidence-based doses of statins as first-line therapy, and utilizing a simplified risk calculator and risk cut point to guide initiation of statin therapy. Although lowering cardiovascular risk is focused on statin therapy and lifestyle modification, controlling virus levels is crucial as well.
El-Sadr WM, Lundgren J, Neaton JD, et al. CD4+ count-guided interruption of antiretroviral treatment. Strategies for Management of Antiretroviral Therapy (SMART) Study Group. N Engl J Med 355.22 (2006):2283.
Aberg JA, Gallant JE, Ghanem KG, et al. Primary care guidelines for the management of persons infected with HIV: 2013 update by the HIV medicine association of the Infectious Diseases Society of America. Clin Infect Dis. 2014;58:1-34.