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INTRODUCTION — Lipid abnormalities are common in HIV-infected patients who are receiving antiretroviral therapy (ART) . Although the implications of dyslipidemia in this patient population are not fully understood, an increasing amount of data suggests that lipid abnormalities are associated with cardiovascular morbidity and mortality. 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 (CHD) event have no established risk factors other than age and gender. Due to this observation, concepts of optimal blood pressure, blood glucose, and lipid values have been revised downward in the past 20 years. Whether HIV infection is itself a risk factor for CHD is unclear. (See "Overview of the risk equivalents and established risk factors for cardiovascular disease" and "Epidemiology of cardiovascular disease and risk factors in HIV-infected patients".)
The evaluation and management of cardiovascular risk factors, including lipid-lowering therapy, in HIV-infected patients is discussed below. The epidemiology, morbidity, and mortality associated with dyslipidemia in HIV-infected patients and issues related to HIV-associated lipodystrophy are discussed elsewhere. (See "Epidemiology of cardiovascular disease and risk factors in HIV-infected patients" and "Epidemiology, clinical manifestations, and diagnosis of HIV-associated lipodystrophy" and "Treatment of HIV-associated lipodystrophy".)
ASSESSING CARDIOVASCULAR RISK — Mounting data suggests 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 HIV-infected patients", section on 'Prevalence of traditional cardiovascular 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:
●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')
●Level of exercise activity
●Family history of coronary artery or vascular disease, hypertension, or diabetes mellitus
●Baseline blood pressure
●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 . In addition, the guidelines on antiretroviral management of HIV-infected patients from the US Department of Health and Human Services suggest checking lipids every 6 to 12 months and glucose levels every 3 to 6 months during ART use . (See 'Screening for dyslipidemia' below and 'Recognizing and managing diabetes mellitus' below.)
Cardiovascular risk calculation — Results of these risk factor assessments can then be used to predict an individual's risk for the development of CHD using established multivariate risk models [4,5]. Various models exist, including the older Framingham risk score (calculator 1 and calculator 2) and the more recent American Heart Association/American College of Cardiology (AHA/ACC) Pooled Cohort Equations CV Risk Calculator. Although the utility of these calculators in the HIV-infected population may not be optimal, as discussed below, they are a likely a reasonable starting point for assessing risk. (See "Estimation of cardiovascular risk in an individual patient without known cardiovascular disease".)
The pathophysiological mechanisms that confer increased risk in HIV-infected patients may not be accounted for in standard risk assessment methods, which may thus underestimate the actual cardiac risk in HIV-infected patients . As an example, in a large cohort study of almost 30,000 HIV-infected veterans, 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 HIV-uninfected veterans, but the median Framingham risk score was the same and intermediate in both groups . Nevertheless, the incidence of acute myocardial infarction was higher among the HIV-infected patients, even after adjusting for Framingham risk factors and other potential contributors (adjusted hazard ratio (HR) 1.48; 95% CI 1.27-1.72). The Framingham risk score for stroke was also demonstrated to underestimate the risk of stroke among HIV-infected men in a separate study . The accuracy of the AHA/ACC calculator among HIV-infected patients is unknown.
A different cardiac risk model was created based upon data from the large international Data Collection on the Adverse Effects of Anti-HIV Drugs (DAD) cohort of HIV-infected patients who were followed longitudinally for cardiac events and performed better than the Framingham risk score among patients in that cohort . However, the model has not been extensively or consistently validated outside of the cohort population.
MINIMIZING THE RISK OF CARDIOVASCULAR DISEASE — The optimal approach to cardiovascular risk reduction in HIV-infected patients is not precisely defined, but it is widely accepted that the same risk reduction techniques that are used in HIV-uninfected individuals 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 'Assessing cardiovascular risk' above and "Overview of primary prevention of coronary heart disease and stroke".)
Despite the growing importance of cardiovascular morbidity in HIV-infected patients, strategies to minimize cardiovascular disease are often not optimally implemented. As an example, in a study of 397 HIV-infected individuals who were established patients of an HIV clinic and met criteria for aspirin for primary prevention of cardiovascular disease based on their Framingham risk scores, only 66 (17 percent) were prescribed the medication . This finding highlights the importance of improving awareness of cardiovascular disease risk reduction interventions in the primary care of HIV-infected patients.
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 HIV-infected patients . These interventions can improve other risk factors that contribute to cardiovascular disease.
One study compared the dietary intake of 362 HIV-infected and 164 uninfected individuals . Compared to the HIV-uninfected participants, a significantly greater number of HIV-infected patients had a dietary history above the US 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 HIV-infected individuals.
The benefit of intensive dietary guidance is further supported by the results of a trial of 83 HIV-infected patients newly initiating antiretroviral therapy, in which all subjects received individually tailored nutritional counseling and then were randomly assigned to quarterly nutritional guidance or no further counseling . 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, LDL cholesterol, and body mass index compared with baseline. In contrast, the control group experienced increases in total cholesterol, triglycerides, and LDL cholesterol, as well as body mass index compared with baseline. Compared with the control group, the intervention group had lower levels of total cholesterol, triglycerides, and LDL cholesterol and lower body mass index.
●There were fewer patients with total cholesterol >200, triglycerides >150, and LDL cholesterol >130 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, and hemoglobin A1C levels with dietary or exercise interventions [16-18].
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 cardiovascular disease" and "Obesity, weight reduction, and 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 . (See 'Other lipid-lowering agents' below.)
Smoking cessation — All HIV-infected patients who smoke should be advised of the benefits of quitting. In the United States, smoking accounts for nearly one in five deaths . 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 HIV-infected compared with HIV-uninfected individuals [6,21], there are few studies evaluating smoking cessation in those infected with HIV . (See "Epidemiology of cardiovascular disease and risk factors in HIV-infected patients", section on 'Smoking'.)
The efficacy of two smoking cessation approaches was evaluated in 95 economically disadvantaged HIV-infected patients . 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).
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 antiretroviral drugs. 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:
Recognizing and managing dyslipidemia
Screening for dyslipidemia — Because of the association of HIV infection and antiretroviral treatment (ART) with dyslipidemia, HIV-infected patients should undergo lipid testing routinely throughout care. As an example, several expert groups in the United States recommend screening for dyslipidemia at baseline, prior to initiating ART, within one to three months after starting a new regimen, and every 6 to 12 months thereafter [2,4,10]. The approach to screening is no different than screening an HIV-uninfected patient and includes an overnight fasting lipid profile for triglycerides, high density lipoprotein (HDL) cholesterol, and total cholesterol. Low density lipoprotein (LDL) cholesterol (in mg/dL) is then calculated using Friedewald's equation :
●LDL cholesterol = total cholesterol - HDL cholesterol - triglycerides/5
When the triglyceride level is greater than 400 mg/dL, the calculated LDL fraction is unreliable and a direct measurement of LDL cholesterol should be obtained . Other exacerbating factors should also be considered such as alcohol use, hypothyroidism, hypogonadism, or use of drugs known to interfere with glucose or lipid metabolism (eg, growth hormone) .
The World Health Organization (WHO) does not recommend routine lipid monitoring during first-line ART regimens in resource-limited settings . One study from Uganda of 987 treatment-naïve patients taking an NNRTI-containing regimen supported the safety of this approach; over a period of 24 months of follow-up, increases in HDL-c were substantial and proportionally greater than increases in total cholesterol or triglycerides .
Indications for lipid lowering therapy — Indications for the use of lipid-lowering therapy in primary prevention of coronary heart disease among HIV-infected patients are the same as those for HIV-uninfected patients. Briefly, statin therapy, specifically, is an intervention that reduces the relative cardiovascular risk by approximately 20 to 30 percent. Thus, the absolute benefit of statin therapy becomes greater with higher cardiovascular risk, and so cardiovascular risk assessment is an essential component of the decision to initiate a statin. Patients and providers can then decide whether the individual absolute risk reduction is large enough to be worth the cost, burdens, and potential side effects of statin therapy. The decision on whether to initiate statins is discussed in detail elsewhere. (See "Treatment of lipids (including hypercholesterolemia) in primary prevention", section on 'Deciding whom to treat'.)
Statin use in HIV-infected patients warrants specific consideration, in part because of the potential for drug interactions with antiretroviral agents. These are discussed below. (See 'Statin use' below.)
For patients who have severely elevated triglycerides, early initiation of a fibrate, in addition to nonpharmacologic therapy, is warranted to reduce the risk of pancreatitis . (See "Treatment of lipids (including hypercholesterolemia) in primary prevention" and "Estimation of cardiovascular risk in an individual patient without known cardiovascular disease" and "Hypertriglyceridemia".)
Recognizing and managing diabetes mellitus — A higher risk of insulin resistance and diabetes mellitus has been described in HIV-infected patients on ART compared with HIV-uninfected patients (see "Epidemiology of cardiovascular disease and risk factors in HIV-infected patients", section on 'Insulin resistance and diabetes'). Thus, HIV-infected patients 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/or fasting blood glucose at baseline, prior to initiating ART, within one to three months after starting a new regimen, and every three to six months thereafter while on ART [2,3].
Of note, the A1C level may underestimate fasting glucose in HIV-infected patients. 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 HIV-infected compared with uninfected men . Lower CD4 cell counts and ART use were independently associated with a lower A1C level than expected for the fasting glucose level.
Strategies for glycemic control in HIV-infected patients with diabetes are generally the same as for the general population. (See "Overview of medical care in adults with diabetes mellitus", section on 'Glycemic control'.)
Hypertension control — Hypertension is a well-established risk factor for cardiovascular disease. HIV-infected patients may have higher rates of hypertension compared with uninfected patients [27,28]. Definition and management of hypertension in the HIV-infected patient 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 HIV-infected patients", section on 'Hypertension'.)
Aspirin use — The benefits of aspirin in decreasing the risk of cardiovascular events must be balanced against the risk of bleeding with its use. The decision on whether to recommend aspirin for the prevention of cardiovascular disease in the HIV-infected patient is the same as that for the general population. (See "Aspirin in the primary prevention of cardiovascular disease and cancer".)
ROLE OF ANTIRETROVIRAL THERAPY — Globally, HIV treatment guidelines recommend the initiation of antiretroviral therapy (ART) in all HIV-infected patients regardless of CD4 cell count, in part because of the risk of non-AIDS-associated complications, including cardiovascular morbidity, with uncontrolled HIV infection [3,29]. (See "When to initiate antiretroviral therapy in HIV-infected patients".)
To date, however, data from randomized clinical trials do not confirm that earlier initiation of antiretroviral therapy (ART) actively lowers the incidence of cardiovascular disease. Although the START trial demonstrated an overall clinical benefit of early versus delayed ART, there was no difference in the rates of cardiovascular events with the two strategies . Rather, the beneficial cardiovascular effect of ART is supported by the SMART trial, in which ART discontinuation resulted in a greater incidence of cardiac events compared to continuation of ART , and some studies that suggest an improvement in cardiovascular biomarker (such as C-reactive protein) profiles with ART [32-34]. It has been suggested that the benefits of ART in reducing cardiovascular risk are greatest at lower CD4 cell counts and only modest prior to significant immunodeficiency . (See "Epidemiology of cardiovascular disease and risk factors in HIV-infected patients", section on 'Effect of ART interruption' and "Pathogenesis and biomarkers of cardiovascular disease in HIV-infected patients".)
Of note, certain antiretroviral agents have been associated with greater risk of cardiovascular events than others, namely older generation protease inhibitors (such as indinavir and lopinavir-ritonavir) and abacavir, although the data on some of these agents are conflicting. Thus, we only use these agents, if otherwise indicated, with caution among patients with significant risk factors for coronary artery disease. (See "Epidemiology of cardiovascular disease and risk factors in HIV-infected patients", section on 'Effect of antiretroviral therapy' and "Selecting antiretroviral regimens for the treatment-naïve HIV-infected patient".)
Additionally, certain agents are associated with unfavorable changes to the lipid profile and avoiding their use in certain high-risk patients may be warranted.
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. Although there are limited data to suggest that this approach improves cardiovascular outcomes, this is a logical and reasonable practice, provided that other considerations (such as the patient’s viral load and expected toxicity) are also accounted for in regimen selection. (See "Selecting antiretroviral regimens for the treatment-naïve HIV-infected patient".)
As an example, integrase inhibitors are an attractive option for such patients because of their neutral effects on lipids [36,37]. Of non-nucleoside reverse transcriptase inhibitors, rilpivirine is associated with more favorable lipid effects than efavirenz. Although atazanavir and darunavir, each boosted with ritonavir, have less negative lipid effects than other protease inhibitors, they may not be as lipid neutral as raltegravir , and potential for drug interactions should also be taken into account for patients who may also warrant statin therapy. (See 'Statin use' below.)
Some [38-44], but not all [45-49], studies have demonstrated an association between abacavir use and risk of myocardial infarction. In treatment-naïve patients with significant cardiovascular risk and no evidence of drug resistance or renal disease, tenofovir-emtricitabine may be a preferred nucleoside analog backbone.
Associations between specific antiretrovirals and cardiovascular risk or lipid aberrations are discussed in detail elsewhere. (See "Epidemiology of cardiovascular disease and risk factors in HIV-infected patients", section on 'Effect of antiretroviral therapy' and "Epidemiology of cardiovascular disease and risk factors in HIV-infected patients", section on 'Effects of antiretroviral therapy on lipid levels'.)
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. 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. Alternatively, a protease inhibitor can be switched to a non-nucleoside reverse transcriptase inhibitor, such as rilpivirine. 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.
Several studies have evaluated whether certain switch strategies may be beneficial in lowering lipids:
●Several randomized studies suggest that switching from a lopinavir-containing regimen to an atazanavir-containing regimen has a beneficial effect on lipid profiles while maintaining virologic suppression [50-52]; however, one study, which also evaluated endothelial function (as measured by brachial artery flow mediated dilation) did not show any improvement after switching to atazanavir . Nevertheless, atazanavir-containing regimens are still associated with less favorable lipid profiles compared with raltegravir-containing regimens .
●Several randomized controlled trials have evaluated the impact of a switch from a boosted protease inhibitor to an integrase inhibitor-based regimen [53-55]. This approach has been associated with a favorable impact on lipids; however, some patients who were switched to raltegravir experienced virologic breakthrough.
●Trials have also reported reductions in total cholesterol, triglycerides, and low-density lipoprotein (LDL) with switching from a ritonavir-boosted protease inhibitor to a non-nucleoside reverse transcriptase inhibitor-based regimens [56,57].
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 HIV-infected patients".)
STATIN USE — When pharmacologic lipid lowering therapy is warranted for primary prevention, statins are the drug of choice. 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. However, efficacy data of statins among HIV-infected individuals is limited. An additional consideration with the use of statins in the setting of HIV infection is the potential for interactions with antiretroviral agents; thus the selection of statin should take into account the patient’s antiretroviral treatment (ART) regimen.
Indications for statin use in HIV-infected patients are the same as those for the general population and are discussed elsewhere. (See 'Indications for lipid lowering therapy' above and "Treatment of lipids (including hypercholesterolemia) in primary prevention", section on 'Deciding whom to treat'.)
Statin selection and dosing — In HIV-infected patients, the selection of statins should take into account the relative efficacy of the statin as well as any potential drug interactions and side effects. There are currently few head to head studies of statin drugs in patients with HIV to help guide decision making. Atorvastatin, pitavastatin, and rosuvastatin are all reasonable options [58,59].
For patients on a ritonavir-boosted protease inhibitor regimen, we favor pitavastatin for 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.
For patients not using a ritonavir-boosted protease inhibitor, 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.
Rosuvastatin is a potent reducer of total LDL cholesterol, decreases certain markers of inflammation, has been associated with other favorable metabolic effects (eg, improvement in bone mineral density), and is not expected to have substantial interactions with antiretroviral agents. However, its potential for exacerbation of insulin resistance slightly dampens enthusiasm for this agent . When used, we start at a 10 mg daily dose and monitor routinely for diabetes.
Although pravastatin (20 daily starting dose) is an acceptable alternative to these agents due to its lack of metabolism through the CYP3A4 system, it is not as efficacious as these other three statins in reducing LDL cholesterol. (See "Statins: Actions, side effects, and administration".)
Because of the potential for drug interactions with antiretrovirals, statins are generally initiated at a low dose in HIV-infected patients and increased with caution as needed to achieve a target statin dose. (See "Treatment of lipids (including hypercholesterolemia) in primary prevention", section on 'Dose' and "Intensity of lipid lowering therapy in secondary prevention of cardiovascular disease", section on 'Medication choice versus goal LDL'.)
Certain statin-antiretroviral combinations are not recommended and others may warrant additional dose modification. 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.)
Efficacy — Although trials that demonstrate reduction in actual cardiovascular endpoints with statin use among HIV-infected patients are pending, several trials have demonstrated reduction in lipid levels with statins that are comparable to those seen in the general population [61-66]. Emerging evidence also suggests that statins can decrease certain markers of inflammation that have been associated with cardiovascular disease in HIV-infected individuals.
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 HIV-infected patients [61,64,67]. Specifically, in a trial of 88 HIV-infected patients on stable ART with dyslipidemia (LDL cholesterol >160 mg/dL) who were randomly assigned to rosuvastatin 10 mg daily or pravastatin 40 mg daily, rosuvastatin resulted in greater reductions in the LDL cholesterol (39 versus 19 percent reduction) and triglycerides (19 versus 7 percent reduction) after 45 days . Similarly, in another study of 94 HIV-infected patients with hyperlipidemia (total cholesterol >250 mg/dL), rosuvastatin (10 mg) was associated with a greater decrease in total cholesterol than pravastatin (20 mg) or atorvastatin (10 mg) . Rosuvastatin (10 mg) has also been shown to reduce LDL cholesterol by 30 percent even in HIV-infected patients with normal baseline LDL cholesterol levels (≤130 mg/dL) .
Pitavastatin also appears to be superior to pravastatin in HIV-infected individuals. In a trial of 242 HIV-infected patients 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) .
Although trials that demonstrate reduction in actual cardiovascular endpoints with statin use among HIV-infected patients are pending, the lipid-lowering effect of statins has been associated with improvements in other markers of cardiovascular risk in HIV-infected patients. As an example, in a study of 36 HIV-infected individuals 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 . Additionally, the intima media thickness of the internal carotid artery (a measurement of subclinical atherosclerosis) decreased by a mean of approximately 25 percent.
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 alpha (TNFa), and interleukin-6 (IL-6) [69,70]. However, this was not supported by the SATURN trial of 147 HIV-infected patients on stable ART who also had LDL cholesterol ≤130 mg/dL and indirect evidence of heightened inflammation (eg, hsCRP ≥2 mg/L) . Those randomly assigned to rosuvastatin (10 mg) had a greater reduction in LDL cholesterol compared to 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, interleukin-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 . 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 . (See "Pathogenesis and biomarkers of cardiovascular disease in HIV-infected patients".)
Rosuvastatin was shown to reduce LDL cholesterol and measures of monocyte immune activation in patients with HIV in the SATURN-HIV trial . More recent 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 .
Other effects — As in the uninfected population, statins have potential non-cardiovascular benefits in HIV-infected individuals. In the SATURN trial of 147 HIV-infected individuals 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 . The majority of the participants were men.
Other potential benefits of statins are discussed elsewhere. (See "Statins: Possible noncardiovascular benefits".)
Use and interactions with antiretrovirals
Use with protease inhibitors — All statins are metabolized to some degree by cytochrome P450 3A4 (CYP3A4) (table 1) and all protease inhibitors down regulate the activity of CYP3A4. Thus, coadministration of a statin and a protease inhibitor 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 is contraindicated . These include:
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 six-fold elevations in atorvastatin levels (area-under-the curve) have been observed with coadministration of various protease inhibitors . Thus, a low dose (10 mg) is suggested for initial therapy along with close monitoring for dose-related adverse effects, including myositis and hepatitis .
●Rosuvastatin is not metabolized by the CYP3A4 system, and several studies have not demonstrated substantial increases in rosuvastatin levels with concomitant protease inhibitors [61,74,75]. However, clinical pharmacokinetic studies performed by the manufacturer suggested five- and seven-fold increases in rosuvastatin steady-state Cmax levels when coadministered to healthy volunteers with lopinavir-ritonavir or ritonavir-boosted atazanavir, respectively . Thus, a low dose (10 mg) is suggested for initial therapy along with close monitoring for dose-related adverse effects.
●Pitavastatin is not metabolized by the CYP3A4 system. In a trial of pitavastatin in HIV-infected individuals on various ART regimens, there were no safety concerns after 52 weeks of therapy . Studies in healthy volunteers have suggested that there are no substantial increases in drug levels with lopinavir-ritonavir or ritonavir-boosted darunavir [77-79].
●Pravastatin is not metabolized by CYP3A4, and concomitant use of protease inhibitors does not appear to affect drug levels . Its suboptimal potency in reducing LDL cholesterol in both HIV-infected and uninfected individuals 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 [80,81]. 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 , 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 HIV-uninfected adults who were administered efavirenz and three different statins (pravastatin, simvastatin, and atorvastatin) demonstrated that efavirenz leads to significant induction of statin metabolism . In 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 . Similar effects are predicted for simvastatin and lovastatin. In 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.
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 CYP3A, 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.)
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 HIV-infected patients. A retrospective study of 80 HIV-infected patients who were taking statins, including 38 patients with underlying chronic viral hepatitis, demonstrated that statin therapy did not lead to drug-induced liver injury . 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.
As among HIV-uninfected patients, there appears to be an association between statins and the development of diabetes mellitus among HIV-infected adults. In a cohort of over 4500 HIV-infected patients among whom 590 initiated a statin and 355 developed diabetes mellitus, incident diabetes mellitus was associated with statin use (adjusted HR 1.14 per year of use) . Similarly, in the SATURN trial of 147 HIV-infected individuals randomly assigned to rosuvastatin or placebo, markers of insulin resistance in those who received rosuvastatin worsened from baseline compared to those taking placebo; one individual on rosuvastatin developed diabetes . 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 "Treatment of lipids (including hypercholesterolemia) in primary prevention", section on 'Failure to achieve goal LDL'.)
LDL cholesterol goals for secondary prevention are also discussed in detail elsewhere. (See "Treatment of lipids (including hypercholesterolemia) in secondary prevention".)
Although baseline levels for liver biochemical tests and creatinine 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 myopathy", 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 HIV-infected patients is the same as that in the general population. (See "Hypertriglyceridemia".)
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/d. In contrast to the statins, these agents are metabolized by CYP4a and are unlikely to have significant drug interactions with antiretroviral medications. Options include gemfibrozil (600 mg twice daily given 30 minutes before morning and evening meals) and fenofibrate (54 to 160 mg daily).
If the patient is considered at risk of pancreatitis due to severe elevations of triglycerides, attention should also be paid to any other modifiable risk factors for pancreatitis (eg, alcohol use).
Fibrates can also be used in conjunction with statins if the patient’s global cardiovascular risk warrants statin treatment [86,87]. When employing the two different classes together, the patient should be monitored closely for development of myositis.
The mechanism of action and adverse events associated with fibrates are discussed elsewhere. (See "Lipid lowering with fibric acid derivatives".)
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 HIV-infected patients.
Fibrates — 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 discussed elsewhere. (See 'Management of hypertriglyceridemia' above and "Lipid lowering with fibric acid derivatives".)
Niacin — Niacin can be used to decrease LDL cholesterol and triglycerides, as well as increase HDL cholesterol, in HIV-uninfected individuals. However, very little data exists evaluating this agent in HIV-infected patients.
In very small studies, niacin use in HIV-infected patients was associated with reductions in total cholesterol and triglycerides [88-90]. As an example, in one small study, 14 HIV-infected patients on ART were prescribed extended release (ER) niacin for dyslipidemia . ER niacin was titrated up as high as 2000 mg per day for 14 weeks resulting in a 34 percent decline in median triglyceride levels and a 14 percent decline in median total cholesterol levels. No significant change was noted in LDL cholesterol or HDL cholesterol. In addition, although none of the patients developed diabetes during the course of the study, fasting insulin sensitivity was significantly reduced after treatment with ER niacin. Treatment was well tolerated; preadministration of aspirin (325 mg 30 minutes before niacin) minimized niacin-associated cutaneous flushing. Despite lipid improvements, niacin has not been associated with endothelial function improvements, as measured by brachial artery Niacin and fenofibrate each improved lipids in HIV patients with low HDL and TG >150 but failed to demonstrate any improvement in endothelial function as measured by brachial artery flow mediated dilation .
Although uncommon, niacin can also cause hepatotoxicity. The mechanism of action and adverse events associated with niacin are discussed elsewhere. (See "Low density lipoprotein cholesterol lowering with drugs other than statins and PCSK9 inhibitors".)
Fish oil — Fish oil contains two medically relevant long-chain polyunsaturated fatty acids: eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), collectively known as omega-3 fatty acids. Omega-3 fatty acids are successfully employed to treat hypertriglyceridemia in HIV-uninfected individuals . They are dosed at 4 grams per day either singly or in a divided dose.
Fish oils have demonstrated a positive effect on triglyceride levels in HIV-infected patients [92,93]. One study randomly assigned 52 HIV-infected patients with hypertriglyceridemia to receive lifestyle modification counseling with or without fish oil supplementation for 16 weeks . After four weeks, mean triglyceride levels significantly declined from 461 to 306 mg/dL in the supplementation group and remained low. Omega-3 fatty acid supplementation was well tolerated when taken daily with food. However, one retrospective study suggested that fish oil was associated with more modest reductions in triglycerides than fibrates .
Since fish oil has antiplatelet effects, patients concomitantly using drugs that affect bleeding time should be monitored for adverse effects. Potential side effects of fish oil are discussed elsewhere. (See "Lipid lowering with diet or dietary supplements", section on 'Fish oil and omega-3 fatty acids'.)
Ezetimibe — Ezetimibe reduces the absorption of cholesterol from the gastrointestinal tract and is indicated as an adjunctive therapy to diet and/or statins for the reduction of LDL cholesterol in patients with primary hypercholesterolemia. Although studies in HIV-uninfected patients demonstrate that ezetimibe reduces LDL cholesterol, including when used in combination with a statin, there is as yet no convincing evidence that it improves clinical outcomes beyond treatment with a statin alone. (See "Low density lipoprotein cholesterol lowering with drugs other than statins and PCSK9 inhibitors", section on 'Ezetimibe'.)
In HIV-infected patients, ezetimibe may have a role in lipid reduction among patients who cannot tolerate statins or use them because of drug interactions, as ezetimibe does not have any P450 interactions, which decreases the risk of potential drug interactions with other antiretroviral agents. However, there are limited data on the use of ezetimibe in HIV-infected patients:
●The safety and efficacy of ezetimibe was evaluated in randomized, double-blind cross over trial in 48 HIV-infected individuals with LDL cholesterol ≥ 75 mg/dL . All patients were using ART and none were receiving lipid lowering agents on study admission. Individuals were randomized to ezetimibe 10 mg daily or placebo for a six week period, followed by a two week wash out period and finally a six week cross over. During the six weeks of use, ezetimibe was well tolerated and resulted in a significant decline in LDL cholesterol (median 12 percent decrease compared to placebo). No changes in HDL cholesterol or total were observed.
●In a multicenter, double-blind, placebo-controlled crossover trial, 44 patients were randomly assigned to ezetimibe (10 mg daily) or placebo for 12 weeks followed by 4 weeks of washout and then 12 weeks with the alternative study assignment . All patients were already taking a statin for an abnormal lipid profile. The addition of ezetimibe was associated with significant declines in LDL cholesterol, total cholesterol, non-HDL cholesterol and apolipoprotein. No significant changes in triglycerides were seen.
Bile-sequestering resins — Bile-sequestering resins (eg, cholestyramine) are not recommended in HIV-infected individuals 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 or at high risk".)
Considerations for HIV-infected individuals, specifically, should include selection and dosing of statins that are appropriate for use with the patient’s antiretroviral regimen. (See 'Statin use' above.)
SUMMARY AND RECOMMENDATIONS
●Mounting data suggests that HIV infection leads to an excess risk of developing cardiovascular disease. Risk factors for cardiovascular disease should be evaluated at the initial visit and continually assessed over time. This evaluation can then be used to predict an individual's overall cardiovascular risk using established multivariate risk models, such as the Framingham risk score (calculator 1 and calculator 2) or The American Heart Association/American College of Cardiology (AHA/ACC) Pooled Cohort Equations CV Risk Calculator. Although the utility of these calculators in the HIV-infected population may not be optimal and may underestimate the true risk, they are likely a reasonable starting point. (See 'Assessing cardiovascular risk' above.)
●The optimal approach to cardiovascular risk reduction in HIV-infected patients is not precisely defined, but it is widely accepted that the same risk reduction strategies that are used in HIV-uninfected individuals 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.)
●We screen for diabetes mellitus with hemoglobin A1c and/or fasting glucose at baseline, prior to initiating ART, within 1 to 3 months after starting a new regimen, and every 3 to 6 months thereafter, in agreement with expert groups in the United States. Strategies for glycemic control in HIV-infected patients with diabetes are generally the same as for the general population. (See 'Recognizing and managing diabetes mellitus' above and "Overview of medical care in adults with diabetes mellitus".)
●We screen for dyslipidemia at baseline, prior to initiating ART, within 1 to 3 months after starting a new regimen, and every 6 to 12 months thereafter, in agreement with expert groups in the United States. Indications for the use of lipid-lowering therapy in primary prevention of cardiovascular disease among HIV-infected patients are the same as those for HIV-uninfected patients. Briefly, this decision involves determining if the expected absolute reduction in an individual’s cardiovascular risk with statin therapy outweighs its cost, burdens, and potential side effects. (See 'Recognizing and managing dyslipidemia' above and "Treatment of lipids (including hypercholesterolemia) in primary prevention", section on 'Deciding whom to treat'.)
●Certain antiretroviral agents have been associated with greater risk of cardiovascular events and dyslipidemia than others. When initiating ART in the treatment-naïve patient with abnormal lipids or other cardiovascular risk factors, consideration should be given to initiating medications with more favorable lipid profiles, if appropriate based on other patient and viral characteristics. Such agents include integrase inhibitors. 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.)
●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 lopinavir/ritonavir or other 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, such as rilpivirine. (See 'Treatment-experienced patients' above.)
●When pharmacologic lipid lowering therapy is warranted for primary prevention, statins are the drug of choice. In HIV-infected patients, 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. For patients taking a ritonavir-boosted protease inhibitor for whom statin therapy is indicated, we suggest pitavastatin (Grade 2B). For other HIV-infected patients for whom statin therapy is indicated, we suggest atorvastatin (Grade 2B). Statins are generally initiated at a low dose in HIV-infected patients (pitavastatin 4 mg daily, atorvastatin 10 mg daily, and rosuvastatin 10 mg daily). (See 'Statin use' above.)
●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 of subsequent cardiovascular events in HIV-infected patients who have known cardiovascular disease is similar to that for the general population. (See "Prevention of cardiovascular disease events in those with established disease or at high risk".)
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