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Screening for and Managing Dyslipidemia in People With HIV

April 20, 2017

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Key Statin Advice and Findings in People With HIV

Research confirms lowered atherosclerotic cardiovascular event risk with statins,5 which remain the first drug choice to control dyslipidemia in people with HIV.5 As in the general population, the U.S. National Lipid Association (NLA) recommends starting with lifestyle changes in people with HIV, then proceeding to statin therapy.5 People with triglycerides over 500 mg/dL are an exception; they may need to start a fibrate to control the high triglycerides before addressing other lipid abnormalities (Table 3). The NLA and others offer the following advice on antilipid therapy in general -- and statin therapy in particular -- for people with HIV:

  • Setting lipid goals for people with HIV.
    "HIV-infected patients should be treated similarly to the general population," the National Lipid Association says, "with atherogenic cholesterol goals according to the NLA Part 1 Recommendations4 with the caveat of considering the presence of HIV infection an additional major ASCVD risk factor."5 Whether treatment goals should be more aggressive in people with HIV, as in people with other high-risk features (Table 1), remains unknown.5
  • Which HIV patients should start statins?
    According to the European AIDS Clinical Society (EACS), "statins should be used by all those with established vascular disease and among those with type 2 diabetes or at high risk of cardiovascular disease, irrespective of lipid levels."16 HRSA HIV guidelines offer cutoffs for starting antilipid drug therapy in general (Tables 1 and 2) and advice on using statins or other antilipid agents for specific lipid abnormalities (Table 3).3
  • Which statin to try.
    The National Lipid Association recommends atorvastatin, rosuvastatin, or pitavastatin as "generally preferred agents" for people with HIV.5 Pitavastatin is the only statin that does not interact with antiretrovirals and requires no dose adjustments, whereas atorvastatin and rosuvastatin may require dose adjustments.5 But the ACC/AHA considers higher doses of atorvastatin and rosuvastatin as "high-intensity statins,"17 and HIV cardiologist Christopher Longenecker underlines the need for high-intensity statins in people with HIV. Despite pitavastatin's clean interaction profile, the ACC/AHA ranks it as a low-intensity statin.


Table 3. Which Antilipid Drug for Which Abnormality?
Lipid AbnormalityFirst ChoiceSecond Choice
Isolated high LDL-C or non-HDL-CStatinFibrate
Isolated high TG*FibrateStatin, omega-3 fatty acids
High LDL-C and TG 200-500 mg/dLStatinFibrate
High LDL-C and TG >500 mg/dL*FibrateOmega-3 fatty acids, niacin, statin

HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TG, triglycerides.

Source: U.S. Department of Health and Human Services.3

*For triglycerides at or above 500 mg/dL that do not respond to lifestyle modification, the National Lipid Association recommends a fibrate (preferably fenofibrate) or prescription omega-3 fatty acids.5


Pravastatin has limited interactions with antiretrovirals but trails atorvastatin and rosuvastatin in potency.5 Lovastatin and simvastatin are contraindicated with all protease inhibitors and with cobicistat.5 Statins do not have significant interactions with nucleosides or integrase inhibitors (except when boosted by cobicistat).5

In studies involving people with HIV, rosuvastatin lowered LDL-C and triglycerides more than atorvastatin or pravastatin in two small randomized trials,18,19 while in a 700-person retrospective analysis, rosuvastatin and atorvastatin lowered total cholesterol, LDL-C and non-HDL-C more than pravastatin.20 After 52 weeks in a 252-person double-blind U.S. trial, pitavastatin lowered LDL-C (but not triglycerides) significantly more than pravastatin, with similar rates of treatment-emergent adverse events.21 Though 96 weeks in a double-blind placebo-controlled trial enrolling 147 antiretroviral-treated people with HIV, rosuvastatin significantly slowed intima-media thickness progression.22 Through 12 months in a double-blind placebo-controlled trial involving 37 HIV-positive people with subclinical coronary atherosclerosis and LDL-C below 130 mg/dL, atorvastatin significantly reduced noncalcified coronary plaque volume and number of high-risk plaques.23

A 2015 systematic review of 18 clinical trials of statins in people with HIV concluded that (1) atorvastatin, pravastatin, and rosuvastatin are safe, well-tolerated, and efficacious in lowering LDL-C, (2) atorvastatin and rosuvastatin are more potent than pravastatin and "decrease the burden of subclinical cardiovascular disease," and (3) pitavastatin has "a particularly favorable pharmacokinetic profile" even with protease inhibitors.24 In people with HIV, a large U.S. trial summarized above21 and a small Thai trial25 recorded significant reductions in LDL-C with pitavastatin.

  • Start a statin, a fibrate, or something else?
    HRSA guidelines offer clear direction on which type of antilipid drug to start for which type of lipid abnormality (Table 3).3
  • How can statin drug interactions be tracked?
    In 2012 the FDA summarized statin-antiretroviral interactions and outlined statin dose limitations.26 The National Lipid Associations offers a statin-by-statin guide to interactions with protease inhibitors, cobicistat, and nonnucleosides in Table 23 at the link provided at reference 5 below. DHHS antiretroviral guidelines provide detailed tables on interactions and dose adjustments with statins and protease inhibitors (Table 19a), nonnucleosides (Table 19b), and integrase inhibitors (Table 19d) at the link provided at reference 1 below. The University of Liverpool HIV Drug Interaction Checker (www.hiv-druginteractions.org) is a regularly updated tool that allows users to check interactions between individual antiretrovirals and other major drugs, including statins.
  • Statins remain underprescribed in people with HIV.
    Several studies have reached this conclusion,27-30 most recently an 86,535-person analysis of 13 U.S. and 2 Canadian HIV cohorts,30 which found that more than half of these people were eligible for statins but not getting them. National Lipid Association experts suggest the big gap between eligibility and prescription reflects relatively low prevalence of high LDL-C in HIV populations, potential statin side effects, and drug-drug interactions.5 The National Lipid Association and this review cite numerous studies showing statins are safe and effective in people with HIV and have the added potential benefit of reducing chronic inflammation.
  • Smoking and diabetes tied to LDL-C target failure with statins.
    A study of 434 HIV-positive or negative men in the Multicenter AIDS Cohort Study (MACS) found that 31 of 230 with HIV and 29 of 204 without HIV and receiving statin therapy had not achieved the LDL-C target at a MACS visit between October 2011 and March 2012 (13.5% versus 14.2%, P = 0.82).31 Factors independently associated with not hitting the LDL-C target were current smoking (odds ratio [OR] 2.72, 95% confidence interval [CI] 1.30 to 5.67) and diabetes (OR 5.31, 95% CI 2.47 to 11.42). A 958-person Swiss HIV Cohort Study analysis confirmed the link between diabetes and failure to reach a total cholesterol target.32 Other factors predicting treatment-resistant total cholesterol in the Swiss study were older age, history of coronary heart disease, higher initial total cholesterol, and longer time taking a protease inhibitor and/or a nonnucleoside.
  • Do statins help HIV-positive people not eligible by lipid criteria?
    Two placebo-controlled trials in HIV-positive people with low LDL-C found that rosuvastatin or atorvastatin slowed intima-media thickness progression or reduced noncalcified coronary plaque volume.22,23 But the National Lipid Associations maintains "it is not clear whether statins should be used more aggressively in persons with HIV infection" to prevent cardiovascular disease.5 A large randomized trial to address that question, REPRIEVE, began in 2015 and has a target completion date of April 2020.33 REPRIEVE is still recruiting HIV-positive 40- to 75-year-olds on ART but not eligible for statins by lipid criteria and randomizing them to once-daily pitavastatin or placebo.
  • More statin use with HIV/HCV means less cirrhosis.
    A study of 5985 HIV/HCV-coinfected U.S. veterans used Cox proportional hazards analysis to determine that in people with alanine aminotransferase at 40 IU/L or lower, every 30% longer time on statins cut risk of incident cirrhosis 32% (hazard ratio 0.68, 95% CI 0.47 to 0.98).34
  • What about the higher risk of diabetes with statins?
    For the general population, the FDA concluded that the cardiovascular benefits of statins outweigh any diabetes risk.35 In the INTREPID trial pitavastatin had no significant impact on glucose homeostasis in people with HIV.21 Experts recommend assessing HIV patients for diabetes risk before starting a statin and monitoring them during statin use for changes in blood glucose and HbA1c.36
  • Where do niacin, fibrates, ezetimibe, and fish oils fit in?
    A 2014 meta-analysis of statin trials in the general population found wide interindividual variations in LDL-C and non-HDL-C responses.37 The National Lipid Association says findings like these demonstrate "that statin therapy alone may be insufficient for some individuals to reach goal and [support] the recommendation to consider combination drug therapy."4 Also, statins may be inappropriate for people with isolated high triglycerides (Table 3).

The HRSA HIV care guide offers advice on whether to start with a statin, a fibrate, niacin, or omega-3 fatty acids (fish oils) for specific lipid abnormalities (Table 3).3 All of these agents, plus ezetimibe (which inhibits intestinal absorption of cholesterol), have also been studied in people with HIV. Tables 4-6 summarize selected trials of these agents in HIV populations. HRSA guidelines make these general points:

  • "Fibrates may be considered as an alternative or adjunct to statins ... When given concomitantly, statins and fibrates increase the risk of rhabdomyolysis and must be used cautiously and with careful monitoring."3
  • "Niacin may be effective as adjunctive therapy, but it has not been shown to decrease CHD events. It may worsen insulin resistance and may cause hepatotoxicity. It also causes uncomfortable flushing in some patients; the sustained-release formulations are better tolerated."3
  • "Ezetimibe (Zetia) appears to be effective in combination with statins for patients whose cholesterol is not controlled adequately with a statin alone, but it also has not been shown to decrease CHD events."3
  • "Bile acid sequestrants generally should be avoided because they may interfere with the absorption of other drugs and may increase triglyceride levels."3


Table 4. Selected Trials of Niacin and/or Fibrate for Dyslipidemia in People With HIV
Author, YearStudy Design*n*Main Results
Dubé,38 2006Nondiabetic men with TG ≥200 mg/dL and non-HDL-C ≥180 mg/dL took escalating doses of extendedrelease niacin up to 2000 mg nightly for 44 wk (ACTG A5148)33At week 48 median total cholesterol (-8.1 mg/dL), non-HDL-C (-18.9 mg/dL), and TG (-153.2 mg/dL) declined; no persistent hyperglycemia
Dubé,39 2015Patients with low HDL-C (men <40 mg/dL, women <50 mg/dL) and TG >150 mg/dL randomized openlabel to extended-release niacin plus aspirin or to fenofibrate for 24 wk (ACTG A5293)74In men HDL-C rose 3 mg/dL with niacin and 6.5 mg/dL with fenofibrate (P < 0.001 for both); in women HDL-C rose 16 mg/dL with niacin and 8 mg/dL with fenofibrate (P = 0.08 for both); brachial artery flow-mediated dilation did not change significantly in either arm
Aberg,40 2005Patients with LDL-C ≥130 mg/dL and TG ≥200 mg/dL randomized open-label to daily fenofibrate or pravastatin; if composite lipid goal not reached in 12 wk, agents combined in wk 12-48 (ACTG 5087)174Composite goal reached at 12 wk by 1% on fenofibrate (F), 5% on pravastatin (P); at week 48, 7% on F+P and 3% on P+F achieved goal; median LDL-C decrease at 48 wk -8 mg/dL with F+P, -14 mg/dL with P+F
Balasubramanyam,41 2011Patients with TG >150 mg/dL randomized for 24 wk to (1) usual care, (2) diet plus exercise (D/E), (3) D/E + fenofibrate, (4) D/E + niacin, (5) D/E + F/N191D/E + F improved TG, total cholesterol, non-HDL-C; D/E + N improved HDL-C; D/E + F/N had maximum impact vs usual care: TG -52%, non-HDL-C -18.5%, HDL-C +12%, T-to-HDL-C ratio -24.5%
 For fenofibrate and/or fish oil trial, see Gerber in Table 6  

* All participants adults on stable antiretroviral therapy.


Table 5. Selected Trials of Ezetimibe for Dyslipidemia in People With HIV
Author, YearStudy Design*n*Main Results
Wohl,42 2008Patients with LDL-C ≥75 mg/dL, TG ≤800 mg/dL randomized double-blind to crossover of daily ezetimibe vs placebo for 6 w with 2-w washout between48LDL-C -5.3% with ezetimibe vs + 5.5% with placebo (P = 0.04)
Chow,43 2009Patients with LDL-C >130 mg/dL with stable statin randomized double-blind to crossover of ezetimibe vs placebo for 12 w with 4-w washout between44Median difference in absolute LDL-C between ezetimibe and placebo -32 mg/dL (P < 0.0001)
Saeedi,44 2015Patients short of lipid goal on 10-mg rosuvastatin randomized open-label to add ezetimibe or raise statin to 20 mg for 12 wk43With ezetimibe significantly greater declines in total cholesterol, non-HDL-C, and triglycerides

* All participants adults on stable antiretroviral therapy.


Table 6. Selected Trials of Fish Oils for Dyslipidemia in People With HIV
Author, YearStudy Design*n*Main Results
Wohl,45 2005Patients with TG >200 mg/ dL randomized open-label to dietary + exercise counseling or to D/E counseling plus fish oils for 16 wk52Fish oils group had mean 16-wk TG decline of 19.5% vs 5.7% with counseling alone (not significant at P = 0.12); LDL-C rose 22.4% at wk 16 with fish oils but did not change with counseling
Gerber,46/sup> 2009Patients with TG ≥400 mg/dL randomized open-label to fish oils or fenofibrate for 8 wk; if TG >200 mg/dL at week 8, fish oils and fenofibrate combined for wk 10-18 (ACTG A5186)100Median TG dropped 46% with fish oils alone, 58% with fenofibrate alone, 65.5% with combination; TG ≤200 mg/dL in 22.7% with combination
Peters,47/sup> 2012Patients with TG 300-1000 mg/dL randomized double-blind to fish oils or placebo for 12 wk48TG fell by median 154.9 mg/dL with fish oils but rose 36.3 mg/dL with placebo (P = 0.019)
Metkus,48/sup> 2013Patients with TG ≥200 mg/dL randomized double-blind to fish oils or placebo for 8 wk48TG decreased by median 34 mg/dL with fish oils but rose 46.5 mg/dL with placebo (P = 0.01)
Paranandi,49/sup> 2014Patients with TG ≥150 mg/dL randomized double-blind to crossover of fish oils vs placebo for 12 wk followed by 4-wk washout41Mean TG decreased significantly with fish oils (-63.2 mg/dL, P
Volpe,50/sup> 2016Patients with TG 150-2500 mg/dL randomized to fish oils or placebo for 24 months117Median TG decreased significantly more with fish oils than placebo (-68 vs -22 mg/dL, P = 0.041); no significant difference in HDL-C

* All participants adults on stable antiretroviral therapy.


  • How well do niacin, fibrates, ezetimibe, and fish oils work in people with HIV?
    In single-arm and randomized trials over the past decade (Tables 4-6), these agents always improved certain measures of abnormal lipids in people with HIV but often met standard lipid treatment goals only in small proportions of participants. Combined fibrate/statin40 or fibrate/niacin41 therapy worked better than single-agent therapy in two trials. Ezetimibe successfully lowered LDL-C or non-HDL-C,42-44 and fish oils (omega-3 fatty acids) cut high triglycerides;45-50 neither ezetimibe nor fish oils interact with antiretrovirals. Throughout these studies,38-50 antilipid agents were usually safe but often failed to meet secondary goals, such as improving flow-mediated dilation.39,50 The drugs had mixed impacts on markers of inflammation.39,42,46,48,50
  • Meta-analyses find fish oils cuts TG 80 to 100 mg/dL with HIV.
    Two meta-analyses of fish oil (omega-3 fatty acid) trials in people with HIV found similar short-term impacts on triglycerides. An analysis of four studies of 900 to 3360 mg of fish oils daily for 8 to 16 weeks yielded a weighted mean triglyceride reduction of 80.34 mg/dL.51 Meta-analysis of seven randomized trials of fish oils for 12 to 24 weeks figured an average triglyceride drop of 99.2 mg/dL with fish oils.52
  • Meta-analysis suggests fish oils lower heart disease risk.
    A general-population meta-analysis of 18 randomized controlled trials found a nonsignificant reduction in coronary heart disease risk with fish oils from food or supplements (summary relative risk estimate [SRRE] 0.94, 95% CI 0.85 to 1.05).53 The coronary heart disease risk reduction with fish oils became significant in people with high triglycerides (SRRE 0.84, 95% CI 0.72 to 0.98) or high LDL-C (SRRE 0.86, 95% CI 0.76 to 0.98). Meta-analysis of 16 prospective cohort studies found almost a 20% lower risk of coronary heart disease with fish oils (SRRE 0.82, 95% CI 0.74 to 0.92). To improve cardiovascular health, the American Heart Association calls for at least two 3.5-oz servings of fish weekly -- preferably oily fish.54
  • Will PCSK9 inhibitors have a role in HIV dyslipidemia?
    The PCSK9 inhibitors alirocumab (Praluent) and evolocumab (Repatha) increase LDL-receptor expression on hepatocytes and thus promote elimination of LDL-C reflected by lower levels in blood.55 Statins exploit the same mechanism by inhibiting HMG-CoA reductase. Fully humanized monoclonal antibodies delivered by injection every 2 or 4 weeks, PCSK9 inhibitors are licensed as an adjunct to diet and maximally tolerated statins in people with heterozygous familial hypercholesterolemia or clinical atherosclerotic cardiovascular disease. At a hefty cost exceeding $14,000 yearly (wholesale), PCSK9 inhibitors are not cost-effective by standard criteria.56

    As Christopher Longenecker points out in the interview in this issue, research shows that HIV-positive people have higher levels of PCSK9 in blood57 and thus could be candidates for PCSK9 inhibitors when other treatments fail. Longenecker observes that the safety of PCSK9 inhibitors in people with HIV remains to be determined, as does their clinical impact in people with or without HIV.
  • What to do when no treatment strategy achieves lipid targets.
    In its advice on dyslipidemia in people with HIV, the National Lipid Association reminds clinicians that "atherogenic cholesterol goals may not be attainable in all patients, but there is incremental benefit to lowering non-HDL-C and LDL-C to approach these goal levels."5 For example, one general-population analysis figured that every 38.7 mg/dL reduction in LDL-C with statin therapy lowered chances of major cardiovascular events 22% after about 5 years of statin therapy, compared with placebo or less intensive statin therapy.58
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This article was provided by The Center for AIDS Information & Advocacy. It is a part of the publication Research Initiative/Treatment Action!. Visit CFA's website to find out more about their activities and publications.
 

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