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Management of cardiovascular risk (including dyslipidemia) in patients with HIV

Management of cardiovascular risk (including dyslipidemia) in patients with HIV
Literature review current through: May 2024.
This topic last updated: Mar 22, 2024.

INTRODUCTION — Lipid abnormalities are common in people with human immunodeficiency virus (HIV) infection who are receiving antiretroviral therapy [1]. Although the implications of dyslipidemia in this patient population are not fully understood, mounting evidence suggests that lipid abnormalities are associated with cardiovascular morbidity and mortality. One systematic review indicated that one in five people with HIV have moderate to high cardiovascular risk [2]. These epidemiologic observations have prompted increased awareness of the need for risk assessment and modification for cardiovascular disease as an integral part of routine HIV care.

Approximately one-half of all patients with a coronary heart disease event have no established risk factors other than age and sex. Due to this observation, concepts of optimal blood pressure, blood glucose, and lipid values have been revised downward in the past 20 years. Accumulating evidence indicates that HIV infection itself is also a risk factor for coronary heart disease. (See "Overview of established risk factors for cardiovascular disease" and "Epidemiology of cardiovascular disease and risk factors in patients with HIV".)

The evaluation and management of cardiovascular risk factors, including lipid-lowering therapy, in patients with HIV infection is discussed here. The epidemiology, morbidity, and mortality associated with dyslipidemia in patients with HIV infection and issues related to HIV-associated lipodystrophy are discussed elsewhere. (See "Epidemiology of cardiovascular disease and risk factors in patients with HIV" and "Epidemiology, clinical manifestations, and diagnosis of HIV-associated lipodystrophy" and "Treatment of HIV-associated lipodystrophy".)

ASSESSING CARDIOVASCULAR RISK — Mounting data suggest that HIV infection is associated with an excess risk of cardiovascular disease. It is of paramount importance that clinicians identify and initiate preventive interventions since most patients eventually do warrant treatment of modifiable risk factors. (See "Epidemiology of cardiovascular disease and risk factors in patients with HIV", section on 'Traditional risk factors'.)

Evaluating for risk factors — Clinicians should assess a patient's individual risk factors as part of the initial medical visit. This includes assessment for [3]:

Fasting lipid levels (see 'Screening for dyslipidemia' below)

Presence of diabetes mellitus using glycated hemoglobin (A1C) and/or fasting blood glucose (see "Screening for type 2 diabetes mellitus", section on 'Screening tests')

Smoking habits

Diet

Level of exercise activity

Family history of coronary artery or vascular disease, hypertension, or diabetes mellitus

Baseline blood pressure

Waist circumference

Body mass index

The presence of these risk factors should be assessed over time. In particular, because antiretroviral therapy (ART) has been associated with changes in lipid levels and glucose control, these should also be evaluated subsequent to ART initiation. As an example, the HIV Medicine Association of the Infectious Disease Society of America recommends that fasting lipid levels and A1C and/or fasting blood glucose be checked prior to and one to three months after starting ART, and routinely thereafter [3]; A1C should not be used for diagnosis of diabetes mellitus in patients on ART. (See 'Screening for dyslipidemia' below and 'Recognizing and managing diabetes mellitus' below.)

Cardiovascular risk calculation — Results of the risk factor assessments described above can be used to estimate an individual's risk for the development of coronary heart disease using established multivariate risk models [4-6]. Various models exist, including the Framingham risk score (calculator 1 and calculator 2), the American Heart Association/American College of Cardiology (AHA/ACC) Pooled Cohort Equations CV Risk Calculator (PCE), and the Data Collection on the Adverse Effects of Anti-HIV Drugs (DAD) cohort risk calculator that includes measure of HIV disease [7,8]. (See "Atherosclerotic cardiovascular disease risk assessment for primary prevention in adults: Our approach", section on 'Estimate ASCVD risk using a risk calculator'.)

Although the utility of these calculators in the population with HIV may not be optimal, as discussed below, they are a likely a reasonable starting point for assessing risk [6]. We typically use the AHA/ACC PCE model.

Interpretation of the results of the risk calculation should be informed by other risk factors not accounted for. Additional factors that may increase the cardiovascular risk above the calculated risk include hepatitis C virus coinfection; metabolic syndrome, lipodystrophy, or fatty liver disease; HIV treatment failure or nonadherence; low CD4 cell count (less than 350 cells/microL); or a history of prolonged HIV viremia or delayed initiation of ART [9]. (See "Epidemiology of cardiovascular disease and risk factors in patients with HIV", section on 'Risk modifiers' and "Epidemiology of cardiovascular disease and risk factors in patients with HIV", section on 'Effects of CD4 cell count and viral load'.)

Standard risk assessment methods may underestimate the actual cardiac risk in patients with HIV infection because they may not account for some of the pathophysiological mechanisms that confer increased risk in patients with HIV infection [10]. As an example, in a large cohort study of almost 30,000 veterans with HIV, current smoking, low high-density lipoprotein (HDL) levels, and elevated triglyceride levels were more common compared with an age- and race-matched cohort of over 50,000 veterans without HIV, but the median Framingham risk score was the same and intermediate in both groups [11]. Nevertheless, the incidence of acute myocardial infarction was higher among the patients with HIV infection, even after adjusting for Framingham risk factors and other potential contributors (adjusted hazard ratio 1.48, 95% CI 1.27-1.72).

The cardiac risk model based upon data from the large international Data Collection on the Adverse Effects of Anti-HIV Drugs (DAD) cohort, which consisted of patients with HIV infection who were followed longitudinally for cardiac events, performed better than the Framingham risk score among patients in that cohort [7].

However, other observational studies evaluating the relative accuracies of these three risk scores have varying results, possibly because of differences in race/ethnicity and other characteristics of the cohorts with HIV that were studied [8,12-16]. In one analysis of the HIV Outpatient Study cohort, all three scores were able to distinguish high- from low-risk patients with moderate discriminatory function, but the AHA/ACC PCE and DAD models underestimated the risk by 12 and 20 percent, respectively [13]. In a separate study that used data from the Centers for acquired immunodeficiency syndrome (AIDS) Research Network of Integrated Clinical Systems (CNICS) cohort, the AHA/ACC PCE had acceptable discrimination for myocardial infarction risk, with less robust performance for Black individuals [14]. The mismatch between observed and predicted events occurred around the 10 percent risk threshold (near the threshold for statin initiation), with individuals with 5 to 10 percent predicted risk having a higher event rate and those with higher predicted risk having fewer events. Models that included HIV disease variables did not improve risk prediction. In another report, applying the ACC/AHA PCE model increased the number of patients in whom statin therapy was recommended as compared with the Adult Treatment Panel III guidelines (which is based on the Framingham risk score); however, in the majority of adults with HIV and evidence of subclinical atherosclerosis (carotid artery intima-media thickening), statins were not recommended based on either approach [12].

These results suggest that, while none of the available risk assessment tools are optimal for patients with HIV infection, the PCE is a reasonable starting place for clinical use until more data are available.

MINIMIZING THE RISK OF CARDIOVASCULAR DISEASE — The optimal approach to cardiovascular risk reduction in patients with HIV infection is not precisely defined, but it is widely accepted that, in addition to suppression of HIV viremia, the same risk reduction techniques that are used in the general population should apply [17]. The findings that traditional risk factors do appear to predict risk in individuals with HIV further support this point. These strategies include, statin therapy, blood pressure control, and management of diabetes [18]. Additionally, counseling about lifestyle interventions should address potentially modifiable risk factors, such as smoking, weight control, excessive alcohol use, diet, and lack of physical activity. (See 'Assessing cardiovascular risk' above and "Overview of primary prevention of cardiovascular disease".)

Despite the growing importance of cardiovascular morbidity in patients with HIV infection, strategies to minimize cardiovascular disease are often not optimally implemented. As an example, in a study of nearly 14,000 male veterans with HIV, of whom 51 percent had an indication for statin therapy, nearly one-quarter of those with indications were not receiving a statin [19]. This finding highlights the importance of improving awareness of cardiovascular disease risk reduction interventions in the primary care of patients with HIV infection.

Exercise and diet modification — Exercise and weight reduction should be given emphasis in any preventive cardiovascular program and as part of a healthy lifestyle for all patients with HIV infection [20,21]. These interventions can improve other risk factors that contribute to cardiovascular disease [22].

One study compared the dietary intake of 362 individuals with and 164 individuals without HIV [23]. Compared with participants without HIV, a significantly greater number of patients with HIV infection had a dietary history above the United States recommended allowances for total fat, saturated fat, and cholesterol intake. The investigators postulated that the increased intake of saturated fat and cholesterol contributed to the elevated triglycerides that were also noted in this patient population. These data suggest the potential benefit of dietary counseling in individuals with HIV.

The benefit of intensive dietary guidance is further supported by the results of a trial of 83 patients with HIV infection newly initiating antiretroviral therapy (ART), in which all subjects received individually tailored nutritional counseling and then were randomly assigned to quarterly nutritional guidance or no further counseling [24]. An equivalent majority of patients in both groups were started on a regimen of zidovudine, emtricitabine, and efavirenz. The study reported the following findings at 12 months:

Patients in the intervention group had lower intake of total calories, total cholesterol, and percentage of calories from fat and had higher intake of carbohydrate and fiber compared with their own baseline and to the control group.

The intervention group had a decrease in triglycerides and no change in total cholesterol, low-density lipoprotein (LDL) cholesterol, and body mass index (BMI) compared with baseline. By contrast, the control group experienced increases in total cholesterol, triglycerides, and LDL cholesterol as well as BMI compared with baseline. Compared with the control group, the intervention group had lower levels of total cholesterol, triglycerides, and LDL cholesterol and lower BMI.

There were fewer patients with total cholesterol >200 mg/dL, triglycerides >150 mg/dL, and LDL cholesterol >130 mg/dL in the intervention group than in the control group (7, 16, and 2 versus 39, 51, and 18 percent).

Other small case series and studies also demonstrate an improvement in dyslipidemia as well as improvements in waist circumference, systolic blood pressure, hemoglobin A1C levels, and health-related quality of life with dietary or exercise interventions [22,25-28].

The role of healthy diet and increased physical activity in the reduction of cardiovascular risk in the general population are discussed elsewhere. (See "Healthy diet in adults" and "Exercise and fitness in the prevention of atherosclerotic cardiovascular disease" and "Obesity: Association with cardiovascular disease".)

While some patients substantially improve their dyslipidemia from dietary interventions and exercise, many patients warrant the addition of a statin to reduce cardiovascular risk [29]. (See 'Other lipid-lowering agents' below.)

Smoking cessation — All patients with HIV infection who smoke should be advised of the benefits of quitting. In the United States, smoking accounts for nearly one in five deaths [30]. In the general population, the benefits of smoking cessation with regards to cardiovascular risk are well established (see "Cardiovascular risk of smoking and benefits of smoking cessation"). Despite the higher prevalence of smoking observed among individuals with HIV compared with those without [10,31], there are few studies evaluating smoking cessation in those infected with HIV [32]. (See "Epidemiology of cardiovascular disease and risk factors in patients with HIV", section on 'Cigarette smoking'.)

The efficacy of two smoking cessation approaches was evaluated in 95 economically disadvantaged patients with HIV infection [33]. All study participants received nicotine patches for 10 weeks, self-help pamphlets, and initial counseling by their clinician. Forty-eight study patients were randomly assigned to receive an additional intervention of eight counseling phone calls over the initial two-month cessation period. Three months after completion of treatment, individuals who received the counseling intervention were significantly more likely to be abstinent than the control group (mean 30.4 days versus 18.5 days). Interventions that integrate treatment for anxiety and depression with smoking cessation have been associated with improved outcomes compared with smoking cessation alone [34].

Pharmacologic interventions may be of benefit to individuals who want to stop smoking. Clinicians should be aware that bupropion, which is commonly used as a smoking cessation agent, is metabolized by the cytochrome P450 enzyme system and may cause interactions with certain less-commonly used antiretroviral drugs (but not with commonly used first-line ART regimens containing integrase inhibitors). Other commonly employed smoking cessation agents are not metabolized by this system and theoretically should not interact with a patient's antiretroviral regimen.

Detailed discussions on smoking cessation strategies in the general population, including behavioral approaches and pharmacologic interventions are found elsewhere. (See "Overview of smoking cessation management in adults" and "Behavioral approaches to smoking cessation" and "Pharmacotherapy for smoking cessation in adults".)

Recognizing and managing dyslipidemia

Screening for dyslipidemia — Because of the association of HIV infection and ART with dyslipidemia, patients with HIV should undergo lipid testing routinely throughout care. The approach to screening for patients with HIV is generally the same as for the general population, which is discussed in detail elsewhere. (See "Screening for lipid disorders in adults", section on 'Choice of tests'.)

Some expert groups in the United States recommend screening for dyslipidemia prior to initiating ART and within one to three months after starting a new regimen [3,4,17]. However, we typically check lipids annually since the commonly used integrase strand transfer inhibitor-based regimens (eg, bictegravir-tenofovir alafenamide-emtricitabine) are less likely to affect lipids. (See 'Role of antiretroviral therapy' below.)

Indications for statins — The decision about whether to lower LDL with pharmacotherapy incorporates both LDL level and a patient's estimated 10-year atherosclerotic cardiovascular disease (ASCVD) risk [35]. (See 'Cardiovascular risk calculation' above.)

These factors help guide shared decision-making (ie, risk and benefit) discussions between patients and their providers. Regimen selection for statins is discussed below. (See 'Statin use' below.)

When discussing the use of statins, we discuss the absolute benefit of the intervention. Although studies suggest lipid-lowering therapy with statins reduces the relative CVD risk by approximately 20 to 30 percent, regardless of baseline LDL-C, the absolute benefit of treatment is proportional to the patient's underlying absolute risk of CVD. (See "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease", section on 'Rationale for our approach and treatment goals'.)

The following recommendations are in accordance with the United States Department of Health and Human Services (HHS) clinical HIV guidelines [35].

Patients between 40 to 75 years of age

LDL ≥190 mg/dL or ASCVD score ≥5 percent – For such patients, we recommend lipid lowering therapy with a statin [35]. For patients with LDL ≥190 mg/dL or ASCVD score ≥20 percent, we prefer a high-intensity statin dose. For patients with ASCVD score 7.5 to 19.9 percent, we prefer a moderate-intensity statin dose.

Within this patient population, the higher the ASCVD score, the higher the risk of serious cardiac events and the greater the absolute benefit of statin therapy. A lower ASCVD risk threshold is used to recommend statin therapy in patients with HIV compared with patients without HIV because the available risk scores may underestimate ASCVD risk in those with HIV. The lower the ASCVD score, the lower the risk of serious cardiac events and the lower the absolute benefit. While the absolute benefit is small in patients with ASCVD scores near the threshold of 5 percent, the treatment is generally safe and well-tolerated.

There is moderate to high-quality evidence in persons with and without HIV supporting the benefits of statin use in reducing major cardiac events [36,37]. The efficacy of statin use in persons without HIV is presented separately. (See "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease", section on 'Indications for statin therapy'.)

LDL <190 mg/dL and ASCVD score <5 percent – For patients with ASCVD score lower than 5 percent, we discuss the evidence that statin use reduces the likelihood of major cardiovascular events [35,37]. However, because of the even lower baseline risk, the number needed to treat to prevent cardiac events is greater than in patients at higher risk. For these patients, statins may be most beneficial in those with other HIV and non-HIV-related CV risk factors, such as prolonged duration of HIV viremia, current or nadir CD4 count <350 cells/mL, history of non-adherence to or failure of ART, or presence of lipodystrophy/lipoatrophy, metabolic syndrome, fatty liver disease, or coinfection with hepatitis C.  

The best evidence supporting the use of statins in patients with HIV comes from a randomized trial that compared pitavastatin versus placebo in 7700 persons with HIV aged 40 to 75 years who were receiving antiretroviral therapy and had a 10-year ASCVD risk score <15 percent [37]. The median 10-year ASCVD of the participants was 4.5 percent. The study was stopped early after a median 5.1 years of follow-up because the statin group had a 35 percent lower rate of major cardiovascular events compared with the placebo group (4.81 versus 7.32/1000 person-years; hazard ratio, 0.65; 95% CI, 0.48 to 0.90). The primary outcome was a composite which included cardiovascular events of varying severity. The statin group had a lower incidence of first cardiac ischemia or myocardial infarction and appeared to have a lower incidence of other components of the composite endpoint. Mortality rates were similar in both groups (6.2 versus 6.8 per 1000 person years). Overall, the number needed to treat for five years to prevent one major cardiovascular event was 106, which is comparable to other primary prevention interventions, like treating hypertension.

In this trial, the rate of nonfatal serious adverse events was similar between the groups. However, there was a higher incidence of diabetes mellitus (5.3 versus 4.0 percent; incidence rate ratio 1.35 [95% CI, 1.09 to 1.66]) and muscle related symptoms (2.3 versus 1.4 percent; incidence rate ratio 1.74 [95% CI, 1.24 to 2.45]) in those receiving pitavastatin. Additional information on the adverse effects of statins is presented below. (See 'Adverse effects' below.)

The efficacy of statin use in persons without HIV is presented separately. (See "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease", section on 'Indications for statin therapy'.)

Patients less than 40 or older than 75 years of age – For patients with HIV who are less than 40 or older than 75 years of age, we use the same approach as for those without HIV since we don’t have data evaluating the impact of statins in these age groups [35]. (See "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease", section on 'Indications for statin therapy' and "Atherosclerotic cardiovascular disease risk assessment for primary prevention in adults: Our approach", section on 'Patients under 40 years of age'.)

Use of fibrates — In patients who have severely elevated triglycerides, early initiation of a fibrate, in addition to nonpharmacologic therapy, is warranted to reduce the risk of pancreatitis [4]. (See "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease" and "Atherosclerotic cardiovascular disease risk assessment for primary prevention in adults: Our approach" and "Hypertriglyceridemia in adults: Management".)

Recognizing and managing diabetes mellitus — A higher risk of insulin resistance and diabetes mellitus has been described in patients with HIV infection on ART compared with the general population (see "Epidemiology of cardiovascular disease and risk factors in patients with HIV", section on 'Insulin resistance and diabetes mellitus'). Thus, patients with HIV infection should be screened for diabetes at baseline and after initiation of ART. As an example, several expert groups in the United States recommend checking glycated hemoglobin (A1C) and a random blood glucose at baseline prior to initiating ART [3,35]. If the random blood glucose is abnormal, a fasting blood glucose is recommended. On subsequent visits, one of the expert groups recommends checking a random blood glucose annually and one to three months after starting or changing ART regimens [3].

Of note, the A1C level may underestimate fasting glucose in patients with HIV infection. In a study of almost 3000 men in the Multicenter AIDS Cohort Study, at a given fasting glucose level ≥125 mg/dL, the corresponding A1C was lower in men with HIV compared with men without [38]. Lower CD4 cell counts and ART use were independently associated with a lower A1C level than expected for the fasting glucose level. Research on the utility of hemoglobin A1C for screening for diabetes in people with HIV in low- and middle-income countries where conditions that predispose to higher rates of red cell turnover (such as malaria and hemoglobinopathies) may be more prevalent is emerging. A study of 1659 Ugandan people with HIV (PWH) demonstrated that A1C performed similarly to fasting plasma glucose (FPG) although A1C had lower specificity compared with FPG [39].

Strategies for glycemic control in patients with HIV infection with diabetes are generally the same as for the general population. (See "Overview of general medical care in nonpregnant adults with diabetes mellitus", section on 'Glycemic management'.)

Hypertension control — Hypertension is a well-established risk factor for cardiovascular disease. Patients with HIV infection may have higher rates of hypertension compared with the general population [40,41]. Definition and management of hypertension in the patient with HIV are the same as those for the general population. These issues are discussed in detail elsewhere. (See "Overview of hypertension in adults" and "Epidemiology of cardiovascular disease and risk factors in patients with HIV", section on 'Hypertension'.)

Aspirin use — The decision on whether to recommend aspirin for the prevention of cardiovascular disease in the patient with HIV is the same as that for the general population. (See "Aspirin in the primary prevention of cardiovascular disease and cancer".)

The clinical impact of aspirin has not been extensively studied in patients with HIV. A randomized trial of two doses of aspirin (100 and 300 mg) over 12 weeks in adults with HIV on ART failed to demonstrate an impact on endothelial function or immune activation [42].

ROLE OF ANTIRETROVIRAL THERAPY — Globally, HIV treatment guidelines recommend the initiation of antiretroviral therapy (ART) in all patients with HIV regardless of CD4 cell count [35,43,44]. (See "When to initiate antiretroviral therapy in persons with HIV".)

Certain antiretroviral agents have been associated with greater risk of cardiovascular events than others, namely older-generation protease inhibitors (eg, lopinavir-ritonavir) and abacavir, although the data on some of these agents are conflicting. However, these agents are no longer recommended for first-line therapy and are only used in specific situations for individual patients. (See "Epidemiology of cardiovascular disease and risk factors in patients with HIV", section on 'Effect of antiretroviral therapy' and "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach".)

Treatment-naïve patients — When initiating ART in the patient with abnormal lipids or other cardiovascular risk factors, consideration should be given to initiating medications with more favorable lipid profiles. All recommended first-line regimens have minimal lipid effects [44]. (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach".)

Associations between specific antiretrovirals and cardiovascular risk or lipid aberrations are discussed in detail elsewhere. (See "Epidemiology of cardiovascular disease and risk factors in patients with HIV", section on 'Effect of antiretroviral therapy' and "Epidemiology of cardiovascular disease and risk factors in patients with HIV", section on 'Effect of antiretroviral therapy on lipid levels'.)

Treatment-experienced patients — For patients who are already on ART, especially with older agents, and have abnormal lipids, there may be a modest benefit to the lipid profile in switching to a regimen that is associated with better lipid effects. Potential drawbacks to this strategy include the risk of loss of virologic control and new adverse effects or intolerance [45-52]. Also, the assumption that this would result in improved cardiovascular outcomes has not been proven.

For patients with dyslipidemia who have an undetectable viral load (and no prior history of virologic failure or drug resistance) while on a regimen that contains lopinavir/ritonavir or other protease inhibitors associated with lipid abnormalities, we suggest a switch to an integrase inhibitor-based regimen [53,54]. Alternatively, a protease inhibitor can be switched to a non-nucleoside reverse transcriptase inhibitor (NNRTI), such as rilpivirine or doravirine. Past HIV genotype information and the prior ART history should be examined to evaluate for potential underlying drug resistance that may increase the risk of virological failure with a switch in antiretroviral regimen. (See "Switching antiretroviral therapy for adults with HIV-1 and a suppressed viral load", section on 'Hyperlipidemia'.)

Several trials have highlighted the potential benefits and risks of such switch strategies. In randomized controlled trials of patients with stable virologic suppression on a boosted-protease inhibitor-based regimen, switching to an integrase inhibitor-based regimen resulted in more favorable lipid levels compared with remaining on the original regimen, and virologic outcomes were largely the same with high rates of suppression maintained [55-59]. However, in one trial, some patients with pre-existing nucleoside reverse transcriptase resistance who were switched to raltegravir experienced virologic breakthrough [56].

Trials have also reported reductions in total cholesterol, triglycerides, and LDL with switching from a ritonavir-boosted protease inhibitor to an NNRTI-based regimen [60,61].

A detailed discussion of the various antiretroviral medications and their effects on lipids is discussed elsewhere. (See "Epidemiology of cardiovascular disease and risk factors in patients with HIV".)

STATIN USE — This section will review statin selection and dosing. Indications for statin use in persons with HIV are discussed above. (See 'Indications for statins' above.)

Statin selection and dosing — When choosing a statin, regimen selection should take into account the relative efficacy of the statin as well as any potential drug interactions and side effects. There are few head-to-head studies of statin drugs in patients with HIV to help guide decision making. Specific details on statin efficacy, interactions and contraindications with antiretrovirals, and adverse effects are discussed below. (See 'Efficacy' below and 'Use and interactions with antiretrovirals' below and 'Adverse effects' below.)

Approach for most patients — For patients receiving ART, most of the statins can be used. In general, we prefer pitavastatin (starting dose 4 mg daily). Among statins, this agent is least likely to interact with ART, and in clinical trials, it has been associated with a reduction in major cardiovascular events (eg, myocardial infarction, stroke) [37]. (See 'Indications for statins' above.)

If pitavastatin is not available, atorvastatin and rosuvastatin are reasonable options [9]. In general, we favor atorvastatin given its potent efficacy and the greater clinical experience with its use in this population. We use a starting dose of 10 mg daily. If rosuvastatin is used, we start at 10 mg daily. In patients who are not receiving cobicistat or protease inhibitors, we use statin doses that are the same as in people without HIV. Special considerations for persons receiving a protease inhibitor or cobicistat are discussed below. (See 'Patients receiving a PI or cobicistat' below.)

Pravastatin (20 daily starting dose) is also an acceptable alternative, but it is not as potent as these other three statins in reducing LDL cholesterol. (See "Statins: Actions, side effects, and administration".)

Patients receiving a PI or cobicistat — For patients on a ritonavir-boosted protease inhibitor regimen or on a regimen including cobicistat, we suggest pitavastatin because of its minimal interactions with these antiretrovirals. It is also an effective agent with a favorable adverse effect profile. We use a starting dose of 4 mg daily.

If this agent is not available, most other alternatives can be used (eg, atorvastatin, rosuvastatin, pravastatin). However, simvastatin and lovastatin should be avoided with protease inhibitors, cobicistat, or ritonavir containing ART.

Because of the potential for drug interactions with PIs and cobicistat, statins are generally initiated at a low dose and increased with caution as needed to achieve a target statin dose. The maximum dose of atorvastatin and rosuvastatin is 20 mg daily. (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease" and "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease".)

Efficacy — Several trials have demonstrated reduction in cardiovascular events and lipid levels with statins that are comparable to those seen in the general population [37,62-67]. Emerging evidence also suggests that statins can decrease certain markers of inflammation that have been associated with cardiovascular disease in individuals with HIV.

Lipid lowering — As in the general population, certain statins may be more effective at LDL cholesterol reduction than others (table 1).

Rosuvastatin and atorvastatin appear to have greater lipid-lowering potency than pravastatin in patients with HIV infection [62,65,68]. As an example, in a meta-analysis of 18 studies evaluating statin therapy (with atorvastatin, fluvastatin, pravastatin, or simvastatin) among over 700 patients with HIV infection on stable ART, rosuvastatin and atorvastatin were associated with the largest reductions in total cholesterol (mean reductions of 65 mg/dL [1.7 mmol/L] and 56 mg/dL [1.4 mmol/L], respectively) [67]. Rosuvastatin, high-dose atorvastatin, and simvastatin produced the largest reductions in LDL cholesterol (mean reductions of 54 mg/dL [1.12 mmol/L], 81 mg/dL [2.1 mmol/L], and 61 mg/dL [2.7 mmol/L], respectively) and triglyceride levels.

Pitavastatin also appears to be superior to pravastatin in individuals with HIV. In a trial of 242 patients with HIV infection on stable ART who had LDL cholesterol levels 130 to 220 mg/dL and were randomly assigned to take pitavastatin (4 mg) or pravastatin (40 mg) for 52 weeks, pitavastatin resulted in greater decreases in LDL (30 versus 21 percent reduction) and total cholesterol reductions (20 versus 14 percent reduction, respectively) [69].

The lipid-lowering effect of statins has been associated with improvements in other markers of cardiovascular risk in patients with HIV infection. As an example, in a study of 36 individuals with HIV on stable ART with moderately high cardiovascular risk (mean 18.5 percent 10-year myocardial infarction risk by the Framingham equation) who were given rosuvastatin 10 mg daily, mean total and LDL cholesterol values decreased by a mean of 25 and 29 percent, respectively, after two years [63]. Additionally, the intima-media thickness of the internal carotid artery (a measurement of subclinical atherosclerosis) decreased by a mean of approximately 25 percent.

The efficacy of pitavastatin on major cardiovascular events is described above [37]. (See 'Indications for statins' above.)

Inflammatory markers — Data on the effect of statins on measures of inflammation are emerging. Observational studies had suggested that statins were associated with decreases in inflammatory markers, such as high-sensitivity C-reactive protein (hsCRP), tumor necrosis factor (TNF)-alpha, and interleukin (IL)-6 [70,71]. However, this was not supported by the SATURN trial of 147 patients with HIV infection on stable ART who also had LDL cholesterol ≤130 mg/dL and indirect evidence of heightened inflammation (eg, hsCRP ≥2 mg/L or 0.2 mg/dL) [65]. Those randomly assigned to rosuvastatin (10 mg) had a greater reduction in LDL cholesterol compared with those who received placebo (28 percent reduction versus 4 percent increase) after 24 weeks, but changes in the majority of markers of systemic inflammation (including hsCRP, IL-6) were not significantly different between groups. Nevertheless, there were significant decreases in other cellular markers of monocyte activation, such as the soluble CD14, which has been associated with the development of atherosclerosis in HIV [72]. Subsequent analyses of this trial after 48 weeks of rosuvastatin or placebo use further demonstrated statin-induced reductions in other inflammatory and cellular activation markers [73]. (See "Pathogenesis and biomarkers of cardiovascular disease in patients with HIV".)

Rosuvastatin was shown to reduce LDL cholesterol and measures of monocyte immune activation in patients with HIV in the SATURN-HIV trial [72]. Additional data from this trial also demonstrated a decline in oxidative LDL with rosuvastatin; however, this did not correlate with the reductions in other markers of inflammation [74].

Other effects — As in the general population, statins have potential non-cardiovascular benefits in individuals with HIV. In the SATURN trial of 147 individuals with HIV randomly assigned to rosuvastatin or placebo, statin therapy resulted in an increase in total hip bone mineral density at 48 weeks, in contrast to a decrease with placebo [75]. The majority of the participants were men.

Use and interactions with antiretrovirals

Use with protease inhibitors — All statins are metabolized to some degree by CYP3A4 (table 1), and all protease inhibitors and the pharmacologic booster cobicistat downregulate the activity of CYP3A4. Thus, coadministration of a statin and a protease inhibitor or cobicistat may lead to an increased serum concentration of the statin and the potential for severe adverse reactions, including rhabdomyolysis.

For this reason, coadministration of statins that are highly metabolized by CYP3A4 with protease inhibitors and cobicistat is contraindicated [4]. These include simvastatin and lovastatin.

Other statins can be used with protease inhibitors cautiously and in some cases at lower doses than may be used in the general population.

Atorvastatin is partially metabolized by the CYP3A4 system, and two- to sixfold elevations in atorvastatin levels (area under the curve) have been observed with coadministration of various protease inhibitors [76]. Thus, a low dose (10 mg) is suggested for initial therapy, along with close monitoring for dose-related adverse effects, including myositis and hepatitis [4].

Rosuvastatin is not metabolized by the CYP3A4 system, and several studies have not demonstrated substantial increases in rosuvastatin levels with concomitant protease inhibitors [62,77,78]. However, clinical pharmacokinetic studies performed by the manufacturer suggested five- and sevenfold increases in rosuvastatin steady-state Cmax levels when coadministered to healthy volunteers with lopinavir-ritonavir or ritonavir-boosted atazanavir, respectively [79]. Thus, a low dose (5 to 10 mg) is suggested for concomitant therapy, along with close monitoring for dose-related adverse effects.

Pitavastatin is not metabolized by the CYP3A4 system. In a trial of pitavastatin in individuals with HIV on various ART regimens, there were no safety concerns after 52 weeks of therapy [69]. Studies in healthy volunteers have suggested that there are no substantial increases in drug levels with lopinavir-ritonavir or ritonavir-boosted darunavir [80-82].

Pravastatin is not metabolized by CYP3A4, and concomitant use of protease inhibitors does not appear to affect drug levels [62]. Its suboptimal potency in reducing LDL cholesterol in both individuals with HIV and those without may be a greater limitation to its use. (See 'Efficacy' above and "Statins: Actions, side effects, and administration".)

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 protease inhibitors [83,84]. Theoretically, fluvastatin may be started at usual doses since it is not metabolized by the CYP3A4 system.

Use with NNRTIs — In general, most statins can be used with non-nucleoside reverse transcriptase inhibitors (NNRTIs) as long as appropriate dosing and monitoring are employed. Pharmacokinetics with the NNRTIs can be difficult to predict, as they can have varying and, in some cases, opposing effects on the cytochrome systems that metabolize statins. As an example, efavirenz is a mixed inducer and inhibitor of CYP3A4 [4], whereas etravirine is a substrate and a weak inducer of CYP3A4.

Overall, efavirenz use is associated with decreased levels of various statins. As an example, a study of 52 adults without HIV who were administered efavirenz and three different statins (pravastatin, simvastatin, and atorvastatin) demonstrated that efavirenz leads to significant induction of statin metabolism [85]. By contrast, there was no evidence for alteration of efavirenz metabolism by coadministration of the statins.

Etravirine has also been associated with decreased levels of atorvastatin [86]. Similar effects are predicted for simvastatin and lovastatin. By contrast, fluvastatin levels are expected to increase with etravirine, and no substantial change is expected for rosuvastatin, pitavastatin, or pravastatin.

Rilpivirine is not expected to have significant drug interactions with statins. Doravirine is a CYP3A4 substrate and had no clinically relevant effect on atorvastatin pharmacokinetics in healthy adults [87]. No drug interactions are expected between doravirine and other statins [88].

The potential for induction of statin metabolism with NNRTIs suggests that an increased dosing of certain statins may be needed in patients who are taking both agents. If such an approach is considered, it must be also accompanied by increased surveillance for drug toxicity (eg, quarterly creatine phosphokinase and liver function tests). We suggest starting with the lowest usual dose of the chosen statin and carefully titrating upward to maximize LDL cholesterol reduction while avoiding toxicity.

Use with integrase inhibitors — In general, interactions between integrase inhibitors and statins are not expected and have not been described.

However, the integrase inhibitor, elvitegravir, is available only as a component of a fixed-dose formulation that also includes cobicistat, tenofovir, and emtricitabine. Cobicistat is an inhibitor of CYP3A4, and thus coadministration of statins that are highly metabolized by CYP3A would result in increased levels of those statins. Thus, lovastatin and simvastatin are contraindicated in patients receiving cobicistat. Similar caution with other statins, as is taken with protease inhibitors, is reasonable. (See 'Use with protease inhibitors' above.)

Coadministration studies have not been done for all statins; however, based on the metabolism and clearance, clinically significant drug interactions are not expected between statin drugs (ie, atorvastatin, pitavastatin, rosuvastatin, or simvastatin) and bictegravir-emtricitabine-tenofovir alafenamide [89].

Adverse effects — Hepatic and muscle toxicity have been the most concerning side effects of statin therapy.

As in the general population, hepatotoxicity with statins is not particularly common in patients with HIV infection. A retrospective study of 80 patients with HIV infection who were taking statins, including 38 patients with underlying chronic viral hepatitis, demonstrated that statin therapy did not lead to drug-induced liver injury [90]. In fact, many patients with abnormal baseline aminotransferase levels had improvement in these parameters. Although the reason for the decline in liver function tests was not readily apparent, statins have led to similar declines in patients with steatohepatitis.

Similar to the general population, there appears to be an association between statins and the development of diabetes mellitus among adults with HIV infection. In a cohort of over 4500 patients with HIV infection among whom 590 initiated a statin and 355 developed diabetes mellitus, incident diabetes mellitus was associated with statin use (adjusted hazard ratio [HR] 1.14 per year of use) [91]. Similarly, in the SATURN trial of 147 individuals with HIV infection randomly assigned to rosuvastatin or placebo, markers of insulin resistance in those who received rosuvastatin worsened from baseline compared with those taking placebo; one individual on rosuvastatin developed diabetes [92]. This association should not prevent administration of a statin when indicated, but it is reasonable to monitor glucose during statin use.

The adverse events associated with statins in general are discussed in detail elsewhere. (See "Statins: Actions, side effects, and administration".)

Monitoring on statin therapy — Once an intervention is selected, we generally check a fasting lipid profile within the next three to four months to assess the therapeutic response, which can reflect patient adherence to therapy.

Discussion of the rationale not to target an LDL cholesterol goal for primary prevention is found elsewhere. (See "Low-density lipoprotein cholesterol-lowering therapy in the primary prevention of cardiovascular disease".)

LDL cholesterol goals for secondary prevention are also discussed in detail elsewhere. (See "Management of low density lipoprotein cholesterol (LDL-C) in the secondary prevention of cardiovascular disease".)

Although baseline levels for liver biochemical tests and creatine phosphokinase are helpful to have if there is subsequent concern for hepatotoxicity or myopathy with statin use, there is generally no indication for routine monitoring of these parameters in the absence of suggestive symptoms. (See "Statins: Actions, side effects, and administration", section on 'Hepatic dysfunction' and "Statin muscle-related adverse events", section on 'Monitoring'.)

MANAGEMENT OF HYPERTRIGLYCERIDEMIA — Elevated triglyceride levels are independently associated with cardiovascular risk, particularly coronary artery disease risk. In addition, patients with very elevated triglyceride levels are at increased risk of pancreatitis, and for such patients one goal of lipid-lowering therapy is to reduce the risk of pancreatitis. The management of hypertriglyceridemia in patients with HIV infection is the same as that in the general population. (See "Hypertriglyceridemia in adults: Management".)

Briefly, fibrates may be used initially to lower triglycerides before statin use in patients who warrant pharmacologic management of cardiovascular risk and have triglyceride levels >500 mg/dL. These agents are metabolized by CYP3A4. In healthy volunteer studies, decreased gemfibrozil levels have been noted when coadministered with lopinavir-ritonavir; however, neither lopinavir-ritonavir nor ritonavir alone altered the pharmacokinetics of fenofibric acid [93,94].

The mechanism of action and adverse events associated with fibrates are discussed elsewhere. (See "Low-density lipoprotein cholesterol lowering with drugs other than statins and PCSK9 inhibitors", section on 'Fibrates'.)

OTHER LIPID-LOWERING AGENTS — Although statins are the preferred therapy for most patients requiring treatment of dyslipidemia, a number of other agents are available with varying levels of evidence for clinical benefits in the general population. Data on these agents are overall limited among patients with HIV infection. Indications for use, dosing and side effects for most other lipid-lowering agents follow the same recommendations as for the general population and are discussed elsewhere:

Ezetimibe (see "Low-density lipoprotein cholesterol lowering with drugs other than statins and PCSK9 inhibitors", section on 'Ezetimibe')

PCSK9 inhibitors (see "PCSK9 inhibitors: Pharmacology, adverse effects, and use")

Fish oil

Niacin (see "Low-density lipoprotein cholesterol lowering with drugs other than statins and PCSK9 inhibitors", section on 'Nicotinic acid (niacin)')

In a randomized controlled trial of 467 patients with HIV, the evolocumab (a PCSK9 inhibitor) treatment group had a significant reduction in LDL cholesterol (57 percent reduction) and triglycerides (12 percent reduction) as well as an increase in HDL cholesterol (11 percent increase) at 52 weeks compared with the placebo group; adverse events were similar in both groups [95].

The use of fibrates in patients with HIV is also the same as in the general population, although drug interactions are a potential consideration. (See 'Management of hypertriglyceridemia' above and "Low-density lipoprotein cholesterol lowering with drugs other than statins and PCSK9 inhibitors", section on 'Fibrates'.)

Bile-sequestering resins (eg, cholestyramine) are not recommended in patients with HIV due to concerns about possible effects on absorption of antiretroviral agents.

SECONDARY PREVENTION OF CARDIOVASCULAR DISEASE — Prevention of subsequent cardiovascular events in patients who have known cardiovascular disease is similar to that for the general population. This includes therapeutic lifestyle changes to address dyslipidemia, hypertension, smoking, obesity, physical inactivity, and diabetes as well as pharmacologic intervention with agents such as aspirin, statins, beta blockers, and angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk".)

Considerations for individuals with HIV, specifically, should include selection and dosing of statins that are appropriate for use with the patient’s antiretroviral regimen. (See 'Statin use' above.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Primary care of adults with HIV".)

SUMMARY AND RECOMMENDATIONS

Assessing cardiovascular risk – We evaluate risk factors for cardiovascular disease at the initial and subsequent visits to use in an established multivariate risk model to predict the individual's overall cardiovascular risk. We typically use the American Heart Association/American College of Cardiology (AHA/ACC) Pooled Cohort Equations CV Risk Calculator; the Framingham risk score (calculator 1 and calculator 2) is an alternative.

Non-traditional risk factors that may increase risk over and above a calculated risk score include: hepatitis C coinfection; metabolic syndrome, lipodystrophy, or fatty liver disease; HIV treatment failure or nonadherence; low CD4 count (less than 350 cells/microL); or a history of prolonged HIV viremia or delayed initiation of antiretroviral therapy (ART). (See 'Assessing cardiovascular risk' above.)

Minimizing risk of cardiovascular disease – The optimal approach to cardiovascular risk reduction in patients with HIV infection is not precisely defined, but it is widely accepted that the same risk reduction strategies that are used in the general population should apply. These strategies include, if indicated, aspirin use, statin therapy, blood pressure control, and management of diabetes. Additionally, counseling about lifestyle interventions should address potentially modifiable risk factors, such as smoking, obesity, excessive alcohol use, diet, and lack of physical activity. (See 'Minimizing the risk of cardiovascular disease' above.)

Screening for diabetes – We screen for diabetes mellitus with hemoglobin A1c and a random glucose at baseline and prior to initiating ART. Then we screen with a random glucose level within one to three months after starting a new regimen, and every 12 months thereafter, in agreement with expert groups in the United States. Diagnosis of diabetes should be made by measuring fasting glucose levels rather than A1C. Strategies for glycemic control in patients with HIV and diabetes are generally the same as for the general population. (See 'Recognizing and managing diabetes mellitus' above and "Overview of general medical care in nonpregnant adults with diabetes mellitus".)

Recognizing and managing dyslipidemia – We screen for dyslipidemia at baseline and every 12 months thereafter. (See 'Screening for dyslipidemia' above.)

For persons between 40 and 75 years of age, our approach to statin use depends upon the LDL level and the 10-year atherosclerotic cardiovascular disease (ASCVD) score. (See 'Indications for statins' above and 'Cardiovascular risk calculation' above.)

For persons with HIV and an LDL ≥190 or a 10-year ASCVD score ≥5 percent, we recommend a statin (Grade 1B). For patients with LDL ≥190 mg/dL or ASCVD score ≥20 percent, we choose a high-intensity statin dose. For patients with ASCVD score 7.5 to 19.9 percent, we choose a moderate-intensity statin dose.

Clinical trials in persons with and without HIV have consistently shown that statin use reduces the risk of major cardiovascular events. The higher the ASCVD score, the higher the risk of serious cardiovascular events and the greater the absolute benefit of statin therapy. While the absolute benefit is small in patients with ASCVD scores near the threshold of 5 percent, the treatment is generally safe and well-tolerated.

For patients with ASCVD score lower than 5 percent, we discuss the evidence that statin use reduces the likelihood of major cardiovascular events. However, because of the lower baseline risk, the number needed to treat to prevent cardiac events is greater than in patients at higher risk. For these patients, statins may be most beneficial in those with other HIV and non-HIV-related CV risk factors, such as prolonged duration of HIV viremia, current or nadir CD4 count <350 cells/mL, history of non-adherence to or failure of ART, or presence of lipodystrophy/lipoatrophy, metabolic syndrome, fatty liver disease, or coinfection with hepatitis C.  

For persons younger than 40 or older than 75 years of age, our approach continues to be the same as in persons without HIV. (See 'Indications for statins' above.)

Role of antiretroviral therapy

Treatment-naïve patients – Certain antiretroviral agents have been associated with greater risk of cardiovascular events and dyslipidemia than others. All of the preferred ART regimens have minimal effects on lipids. For treatment-naïve patients who have significant cardiovascular risk and other therapeutic options, we suggest avoiding the use of an abacavir-containing backbone (Grade 2C). (See 'Treatment-naïve patients' above.)

Treatment-experienced patients – For patients who are already on ART and have abnormal lipids, there may be a modest benefit to the lipid profile in switching to a regimen that is associated with better lipid effects. Potential drawbacks to this strategy include the risk of loss of virologic control and new adverse effects or intolerance. For patients with dyslipidemia who have an undetectable viral load (and no prior history of virologic failure or drug resistance) while on a regimen containing a protease inhibitor associated with lipid abnormalities, we suggest a switch to an integrase-inhibitor based regimen (Grade 2C). Alternatively, a protease inhibitor can be switched to a non-nucleoside reverse transcriptase inhibitor (NNRTI), such as doravirine. (See 'Treatment-experienced patients' above.)

Statin use – When pharmacologic lipid-lowering therapy is warranted for primary prevention, statins are the drug of choice. In patients with HIV infection, the selection of statins should take into account the relative efficacy of the statin as well as any potential drug interactions and side effects. Atorvastatin, pitavastatin, and rosuvastatin are all appropriate options. (See 'Statin selection and dosing' above.)

For patients taking a ritonavir-boosted protease inhibitor, we suggest pitavastatin (Grade 2B). For other patients with HIV, we also prefer pitavastatin since this agent has few drug interactions with ART agents and has been associated with a reduction in major cardiac events in a large clinical trial.

However, if pitavastatin is not available, atorvastatin and rosuvastatin are reasonable alternatives. For patients receiving a protease inhibitor or cobicistat, statins should be initiated at a low dose and increased with caution; the maximum dose of atorvastatin and rosuvastatin is 20 mg daily.

Management of hypertriglyceridemia – Elevated triglyceride levels are independently associated with cardiovascular risk. Fibrates may be used initially to lower triglycerides before statin use in patients who warrant pharmacologic management of cardiovascular risk and have triglyceride levels >500 mg/d. These agents are unlikely to have significant drug interactions with antiretroviral medications. (See 'Management of hypertriglyceridemia' above.)

Prevention – Prevention of subsequent cardiovascular events in patients with HIV infection who have known cardiovascular disease is similar to that for the general population. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk".)

ACKNOWLEDGMENT — UpToDate gratefully acknowledges John G Bartlett, MD, who contributed as Section Editor on earlier versions of this topic and was a founding Editor-in-Chief for UpToDate in Infectious Diseases.

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Topic 3739 Version 64.0

References

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