HIV-infected patients are at increased risk of myocardial infarction and stroke due to the accelerated atherosclerosis that often complicates HIV disease, even among patients who have been virologically suppressed on antiretroviral therapy (ART) for many years. Thus, a high priority in medical management of HIV disease is to eliminate or mitigate any reversible risk factors for cardiovascular disease (CVD) such as smoking, hyperlipidemia, diabetes mellitus, and hypertension.
We recommend all HIV patients have fasting serum lipids tested yearly and 3 months after initiating any antiretroviral drug that can cause hyperlipidemia as an adverse effect (ie, regimens containing efavirenz or protease inhibitors [PIs]). The lipid test should include low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides.
HIV-infected patients should be assessed using American Heart Association and American College of Cardiology (AHA/ACC) guidelines for statin therapy. Risk of atherosclerotic cardiovascular disease (ASCVD) can be estimated with the ACC calculator, and if the estimated 10-year risk is >7.5%, statin therapy should be considered.
Numerous trials have demonstrated that statin therapy can reduce the relative risk of a CVD event by 20-30% in patients with LDL levels >100 mg/dL. Because the benefit of statin treatment is proportional to the underlying risk of having such an event, recent guidelines have focused on determining a patient's underlying CVD event risk, rather than targeting a specific LDL threshold, as a trigger for initiating statin therapy. In November 2013, the AHA/ACC recommended that statins be administered when a patient's 10-year risk of a CVD event can be estimated to be >7.5% and that statins be considered when the predicted 10-year risk is 5-7.5%.(4) However, subsequent analyses have reported that the risk calculator recommended by the AHA/ACC systematically overestimates risk by 75-150%. An additional concern with the AHA/ACC guidelines is that none of the large, randomized, controlled trials of statin therapy that demonstrated efficacy of statin primary prevention used risk prediction scores for trial entry. Finally, trials of primary prevention of cardiovascular disease in general populations do not include HIV disease as a risk factor for atherosclerosis. Despite these caveats, the general practice of statin management has shifted toward broad adoption of the risk calculator as a primary point of analysis in decision-making regarding a patient's therapy options. We encourage providers to evaluate every patient on an individual basis and to discuss with them the pros and cons of statin therapy.
It is recommended that statin therapy be initiated for patients (who are not already taking it) with any of three key criteria: 1) documented ASCVD, 2) an LDL level >190 mg/dL, or 3) diabetes, regardless of calculated ASCVD risk. Refer to the guidelines for considerations on moderate-intensity vs high-intensity statins.
ASCVD includes myocardial infarction, stroke, symptomatic peripheral vascular disease, and evidence of clinically significant coronary artery stenosis.
Patients without any of the three key criteria listed above (documented ASCVD, LDL level >190 mg/dL, diabetes) should have their 10-year ASCVD risk assessed using the ACC calculator. When 10-year risk is >7.5%, statin therapy generally is recommended. When 10-year risk is 5.0-7.5%, a discussion should be had about potential pros and cons of statin therapy. At any time during the management of hyperlipidemia in HIV-positive patients, the ART regimen should be examined for possible optimization (to a less-lipogenic regimen). This typically means first considering whether a patient can be on an unboosted integrase inhibitor-based therapy. Patients taking efavirenz, nivaripine, a PI, or cobicistat-boosted elvitegravir (ie, Genvoya or Stribild) should be evaluated for the possibility of switching to a regimen that does not include these agents, such as one consisting of 2 nucleoside reverse transcriptase inhibitors + an unboosted integrase inhibitor (eg, dolutegravir + tenofovir disoproxil/emtricitabine [TDF/FTC], dolutegravir + tenofovir alafenamide [TAF]/FTC, dolutegravir/abacavir/lamivudine, or raltegravir-based therapy). Of note, TAF may mildly increase total cholesterol, which is one of the factors used in estimating ASCVD risk in this calculator. Since TAF has less overall toxicity than TDF, we do not recommend switching from TAF to TDF, but rather favor a bit more vigilant lipid monitoring.
Statin choice and dosage: Interactions between statins and PIs, as well as between statins and certain nonnucleoside reverse transcription inhibitors (NNRTIs), can inhibit or induce statin metabolism, thus raising or lowering plasma levels of statins. Elevated levels of statins can be toxic, particularly by causing rhabdomyolysis. Thus, statin therapy always should be initiated at a low dosage with subsequent LDL monitoring and dosage titration (see example below for atorvastatin) in individuals receiving an ART regimen containing a PI or the pharmacokinetic boosters ritonavir and cobicistat.
Atorvastatin: This is the most commonly prescribed statin. We recommend starting with a dosage of 10 mg PO daily in most patients. Recheck lipid profile every 3 months, increasing statin dosage until ASCVD risk is acceptably reduced (ie, to a serum LDL level of <100 mg/dL for those with ASCVD risk factors other than HIV and to <130 mg/dL for those without additional risk factors), up to a maximum dosage of 80 mg daily (no more than 10-20 mg for patients receiving ritonavir or cobicistat) or until clinical evidence of toxicity occurs. Of note, statin levels can rise particularly high with lopinavir/ritonavir (Kaletra) or tipranavir/ritonavir (400-800% increase in statin area-under-the-curve [AUC]) compared with other PIs (150% compared with non-PI regimens). Thus, extra caution should be used with lopinavir/ritonavir and statin coadministration, and tipranavir coadministration with statins should be avoided. Serum creatin kinase (CK) also can be monitored as a marker for early rhabdomyolysis. Such toxicity monitoring should be done in patients on concomitant PIs. Among the NNRTI antiretrovirals, concomitant nevirapine, efavirenz, or etravirine may lower statin levels and thus may require increasing the statin dosage, though 80 mg is still the maximum dosage, especially with etravirine, which may increase active metabolite levels of atorvastatin, thus increasing the risk of toxicity. Rilpivirine, conversely, increases atorvastatin exposure (AUC plus AUC of metabolites) mildly, by about 21%. Thus, monitoring for rhabdomyolysis is also recommended for patients receiving NNRTI antiretrovirals.
Pravastatin: We recommend beginning with a dosage of 20-40 mg PO daily (10 mg for patients receiving ritonavir or cobicistat); recheck lipid profile every 3 months, increasing statin dosage until ASCVD risk is acceptably reduced, up to a maximum dosage of 80 mg daily. Efavirenz is the only NNRTI that has been reported to lower serum pravastatin levels.
Rosuvastatin: Begin with a dosage of 5-10 mg PO daily (5 mg for patients receiving ritonavir or cobicistat); recheck lipid profile every 3 months, increasing statin dosage (up to a maximum of 40 mg daily) until ASCVD risk is acceptably reduced. No drug interactions with NNRTIs have been reported.
Pitavastatin: This statin does not have significant drug interactions with PIs or NNRTIs and appears to be safe and effective for use with HIV-infected patients.(5) Begin with dosage of 2 mg PO daily, 1 mg daily if renal impairment is present.
Patients receiving a PI or efavirenz who have a serum triglyceride level of >500 mg/dL despite dietary modifications should, if possible, be switched to an alternative ART regimen that eliminates PIs and efavirenz or should be treated with a fibrate agent (fenofibrate or gemfibrozil).
A growing body of evidence links severe hypertriglyceridemia (>500 mg/dL) with elevated risk of cardiovascular disease. As noted above, there are less-lipogenic HIV antiretroviral drugs that can be used in place of PIs, including integrase inhibitors and the NNRTIs etravirine and rilpivirine.
Fibrate choice and dosage: We prefer fenofibrate (145-160 mg micronized fenofibrate PO daily) over gemfibrozil because of its lower rate of muscle toxicity. Patients receiving combined fibrate and statin therapy are at greater risk of muscle toxicity and should have serum CK checked at baseline and at least every 6 months during follow-up. Of note, the fenofibrate dosage needs to be adjusted for patients with renal insufficiency if the estimated glomerular filtration rate (eGFR) is <30 mL/min or <60 mL/min, depending on the specific fenofibrate product prescribed.
Althoff KN, McGinnis KA, Wyatt CM, et al; Veterans Aging Cohort Study. Comparison of risk and age at diagnosis of myocardial infarction, end-stage renal disease, and non-AIDS-defining cancer in HIV-infected vs uninfected adults. Clin Infect Dis. 2014 Oct 30.
Hsue PY, Scherzer R, Hunt PW, et al. Carotid intima-media thickness progression in HIV-infected adults occurs preferentially at the carotid bifurcation and is predicted by inflammation. J Am Heart Assoc. 2012 Apr;1(2). pii: jah3-e000422.
Grunfeld C, Delaney JA, Wanke C, et al. Preclinical atherosclerosis due to HIV infection: carotid intima-medial thickness measurements from the FRAM study. AIDS. 2009 Sep 10;23(14):1841-9.
Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. 2014 Jun 24;129(25 Suppl 2):S1-45.
Aberg JA, Sponseller CA, Ward DJ, et al.Pitavastatin versus pravastatin in adults with HIV-1 infection and dyslipidaemia (INTREPID): 12 week and 52 week results of a phase 4, multicentre, randomised, double-blind, superiority trial. Lancet HIV. 2017 Jul;4(7):e284-e294.