Printer Friendly

Screening for and managing dyslipidemia in people with HIV.

HIV care guidelines recommend close lipid monitoring in people with HIV. Department of Health and Human Services (DHHS) HIV treatment guidelines for adults and adolescents recommend regular fasting lipid measures: (1)

* First patient visit

* When starting or changing antiretroviral therapy (ART)

* Every 6 months if the last measures had an abnormal result

* Every 12 months if the last measures were normal

Other HIV guidelines suggest some wrinkles to this plan. IDSA/HIVMA experts advise retesting lipids 1 to 3 months after starting ART. (2) HRSA HIV guidelines suggest monitoring as often as every 4 to 6 weeks in people with dyslipidemia, until the low-density lipoprotein cholesterol (LDL-C) goal is met, then every 4 to 6 months. (3) However, dyslipidemia in many people with HIV entails high triglycerides and low high-density lipoprotein cholesterol (HDL-C) rather than high LDL-C. And a portion of HIV-positive people who do have high LDL-C never reach their target with therapy.

Managing dyslipidemia with HIV: where to start

When planning how to treat dyslipidemia in people with HIV, DHHS guidelines (1) recommend consulting current National Lipid Association (NLA) advice. (4) That's a logical place to start--and a logical place to continue, now that part 2 of the NLA tract offers a special section on people with HIV. (5)

NLA guidance on starting antilipid drug therapy in the general population combines two variables: (1) level of LDL-C or non-HDL-C, and (2) an atherosclerotic cardiovascular disease (ASCVD) risk score. (4) (See Table 1 footnote for ASCVD risk factors.) Based on this detailed advice, HRSA HIV guidelines offer a simplified scheme suggesting when to start lifestyle interventions and when to consider drug therapy (Table 1). (3) In people with high triglycerides--a frequent lipid problem in people with HIV--HRSA recommends drug therapy to get triglycerides below 500 mg/dL to prevent pancreatitis, then focusing on LDL-C (Table 2).

So much has been written--and continues to be written--about managing dyslipidemia in people with HIV that one could easily fill several issues of RITA dissecting it. Rather than attempting such a feat, this review will offer selected insights into lifestyle changes and treatment with statins and other medications, while pointing readers to current worthy reviews (see "Some worthy HIV lipid management reviews").

Changing lifestyles to change lives

More than a few clinicians cringe at entreaties to start lipid management with lifestyle modifications. It's so much easier to start a statin--but also much riskier to put a patient on a potentially lifelong therapy that carries its own risks and interacts with antiretrovirals and many other drugs. Getting people to exercise, adopt a healthy diet, and quit smoking can be tough, but statistics show it can be done.

* Quitting smoking has a huge HIV cardio impact.

Smoking lowers HDL-C6 and heightens the cardio vascular risk conferred by dyslipidemia. Analysis of 29,515 HIV-positive North Americans determined that if these people never smoked, they would avert 38% of lifetime myocardial infarctions. (7) (See page 26 of this issue for details.)

* Many smokers quit for good.

In the United States smokers make up 42% of the HIV population but only 21% of the general population. (8) Yet this 419,945-person analysis counted lots of quitters in the HIV contingent: 1 in 5 had stopped smoking. And the general US population now has more former smokers than current smokers. (9)

Impact of dietary factors on cardiometabolic death

* Effective online quitting tool for HIV smokers.

An 8-session online interactive program designed for people with HIV, Positively Smoke Free, (10) is already helping HIV-positive people quit. (11)

* Quick-and-easy dietary do-list.

For clinicians who work with a good dietician, referring HIV-positive people with bad diets or poor weight control makes lots of sense. But for providers without a savvy diet planner at their elbow, quick-and-easy eating pointers could help. And a bounty of such tips just arrived from a big analysis by the US National Health and Nutrition Examination Surveys (NHANES) (Figure 1). (12) A comparative risk assessment model incorporating data on population demographics and dietary habits figured that the biggest fractions of diet-related cardiometabolic deaths could be traced to too much sodium, too few nuts/ seeds, too many processed meats, not enough seafood omega-3 fats, too few vegetables, too few fruits, and too many sugar-sweetened drinks.

* Saturated fat intake is triglyceride culprit in HIV group.

A comparison of 356 people with HIV and metabolic problems (55% men, 44% nonwhite) and 162 HIVnegative community-dwelling individuals found significantly greater intake of total fat, saturated fat, cholesterol, and calories from saturated fat and trans fat in the HIV group. (13) Saturated fat intake correlated positively with triglycerides, which were 8.7 mg/dL higher with every additional gram of saturated fat. Total fat intake was inversely associated with triglyceride level.

* Quarterly dietary follow-up prevents dyslipidemia with ART.

A National Cholesterol Education Program diet with follow-up every 3 months maintained total cholesterol and LDL-C while lowering triglycerides in a small open-label randomized trial of people starting ART in Brazil. (14) After 1 year of follow-up, 21% of people in the diet group compared with 68% in the control group, which got general dietary counseling without follow-up, (15) had a lipid profile indicating dyslipidemia (P < 0.001). Fat intake fell in the diet group but not in the control group.

* How much exercise has a lipid impact?

The National Lipid Association recommends 150 minutes of moderate to higher intensity aerobic activity weekly to lower triglycerides and sometimes raise HDL-C. (5) Boosting that level to 200 to 300 minutes per week can improve triglycerides, HDL-C, and LDL-C while trimming body fat and weight.

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 US 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 Recommendations (4) 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 (see Table 1 on page 21). Despite pitavastatin's clean interaction profile, the ACC/AHA ranks it as a low-intensity statin.

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 US 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 US trial summarized above (21) and a small Thai trial (25) 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 (http://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 US 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 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 US 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)

* 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/statin (40) or fibrate/niacin (41) 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) Metaanalysis 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 starting on page 16, research shows that HIV-positive people have higher levels of PCSK9 in blood (57) 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)

Some worthy HIV lipid management reviews

* General population

Jacobson TA, Ito MK, Maki KC, et al. National Lipid Association recommendations for patient-centered management of dyslipidemia: part 1--full report. J Clin Lipidol. 2015; 9:129-169. http://www.lipidjournal.com/article/S1933-2874(15)00059-8/pdf

Jacobson TA, Maki KC, Orringer CE, et al. National Lipid Association recommendations for patientcentered management of dyslipidemia: part 2. J Clin Lipidol. 2015; 9(6 Suppl):S1-122. http://www.lipidjournal.com/article/S1933-2874(15)00380-3/pdf Includes section on HIV infection.

* HIV-specific

Myerson M, Malvestutto C, Aberg JA. Management of lipid disorders in patients living with HIV. J Clin Pharmacol. 2015; 55:957-974. http://onlinelibrary.wiley.com/doi/10.1002/jcph.473/epdf

Eckard AR, McComsey GA. The role of statins in the setting of HIV infection. Curr HIV/AIDS Rep. 2015; 12:305-312. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4860807/pdf/nihms780235.pdf

da Cunha J, Maselli LM, Stern AC, Spada C, Bydlowski SP. Impact of antiretroviral therapy on lipid metabolism of human immunodeficiency virus-infected patients: Old and new drugs. World J Virol. 2015; 4:56-77. http://www.wjgnet.com/2220-3249/full/v4/i2/56.htm

References

(1.) Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. July 2016. https://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf

(2.) Aberg JA, Gallant JE, Ghanem KG, Emmanuel P, Zingman BS, Horberg MA; Infectious Diseases Society of America. Primary care guidelines for the management of persons infected with HIV: 2013 update by the HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis. 2014; 58:1-10. https://oup.silverchair-cdn.com/oup/backfile/Content_public/Journal/cid/58/1/10.1093/cid/cit757/2/cit757.pdf

(3.) US Department of Health and Human Services. Health Resources and Services Administration. Guide for HIV/AIDS clinical care. April 2014. https://hab.hrsa.gov/sites/default/files/hab/clinical-quality-management/2014guide.pdf

(4.) Jacobson TA, Ito MK, Maki KC, et al. National Lipid Association recommendations for patient-centered management of dyslipidemia: part 1--full report. J Clin Lipidol. 2015; 9:129-169. http://www.lipidjournal.com/article/S1933-2874(15)00059-8/pdf

(5.) Jacobson TA, Maki KC, Orringer CE, et al. National Lipid Association recommendations for patient-centered management of dyslipidemia: part 2. J Clin Lipidol. 2015; 9(6 Suppl):S1-122. http://www.lipidjournal.com/article/S1933-2874(15)00380-3/pdf

(6.) He BM, Zhao SP, Peng ZY. Effects of cigarette smoking on HDL quantity and function: implications for atherosclerosis. J Cell Biochem. 2013; 114:2431-2436.

(7.) Althoff KN, Palella FJ, Gebo K, et al. Impact of smoking, hypertension and cholesterol on myocardial infarction in HIV+ adults. Conference on Retroviruses and Opportunistic Infections (CROI), February 13-16, 2017, Seattle. Abstract 130.

(8.) Mdodo R, Frazier EL, Dube SR, et al. Cigarette smoking prevalence among adults with HIV compared with the general adult population in the United States: cross-sectional surveys. Ann Intern Med. 2015; 162:335-344.

(9.) US Department of Health and Human Services, Centers for Disease Control and Prevention, National Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health. The Health Consequences of Smoking--50 Years of Progress: A Report of the Surgeon General. 2014.

(10.) Positively Smoke Free. Created by experts, refined by real users like you. https://www.positivelysmokefree.com/

(11.) Shuter J, Morales DA, Considine-Dunn SE, An LC, Stanton CA. Feasibility and preliminary efficacy of a web-based smoking cessation intervention for HIV-infected smokers: a randomized controlled trial. J Acquir Immune Defic Syndr. 2014; 67:59-66.

(12.) Micha R, Penalvo JL, Cudhea F, et al. Association between dietary factors and mortality from heart disease, stroke, and type 2 diabetes in the United States. JAMA. 2017; 317:912-924.

(13.) Joy T, Keogh HM, Hadigan C, et al. Dietary fat intake and relationship to serum lipid levels in HIV-infected patients with metabolic abnormalities in the HAART era. AIDS. 2007; 21:1591-1600.

(14.) Lazzaretti RK, Kuhmmer R, Sprinz E, Polanczyk CA, Ribeiro JP. Dietary intervention prevents dyslipidemia associated with highly active antiretroviral therapy in human immunodeficiency virus type 1-infected individuals: a randomized trial. J Am Coll Cardiol. 2012; 59:979-988.

(15.) ClinicalTrials.gov. Effect of nutritional intervention on the lipid profile of HIV-positive patients who start HAART: a randomized trial. ClinicalTrials.gov identifier NCT00429845.

(16.) EACS European AIDS Clinical Society. Guidelines. Version 8.0. October 2015. http://www. eacsociety. org/files/guidelines_8_0-english_web.pdf

(17.) 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; 129(suppl 2):S1-S45. http://circ.ahajournals.org/content/129/25_suppl_2/S1.long

(18.) Calza L, Manfredi R, Colangeli V, Pocaterra D, Pavoni M, Chiodo F. Rosuvastatin, pravastatin, and atorvastatin for the treatment of hypercholesterolaemia in HIV-infected patients receiving protease inhibitors. Curr HIV Res. 2008; 6:572-578.

(19.) Aslangul E, Assoumou L, Bittar R, et al. Rosuvastatin versus pravastatin in dyslipidemic HIV-1-infected patients receiving protease inhibitors: a randomized trial. AIDS. 2010; 24:77-83.

(20.) Singh S, Willig JH, Mugavero MJ, et al. Comparative effectiveness and toxicity of statins among HIV-infected patients. Clin Infect Dis. 2011; 52:387-395.

(21.) Sponseller CA, Aberg J, INTREPID Team. After 52 weeks pitavastatin is superior to pravastatin for LDL-C lowering in patients with HIV. Conference on Retroviruses and Opportunistic Infections. March 3-6, 2014. Boston. Abstract 751LB.

(22.) Longenecker CT, Sattar A, Gilkeson R, McComsey GA. Rosuvastatin slows progression of subclinical atherosclerosis in patients with treated HIV infection. AIDS. 2016; 30:2195-2203.

(23.) Lo J, Lu MT, Ihenachor EJ, et al. Effects of statin therapy on coronary artery plaque volume and high-risk plaque morphology in HIV-infected patients with subclinical atherosclerosis: a randomised, double-blind, placebo-controlled trial. Lancet HIV. 2015; 2:e52-e63.

(24.) Feinstein MJ, Achenbach CJ, Stone NJ, Lloyd-Jones DM. A systematic review of the usefulness of statin therapy in HIV-infected patients. Am J Cardiol. 2015; 115:1760-1766.

(25.) Wongprikorn A, Sukasem C, Puangpetch A, Numthavej P, Thakkinstian A, Kiertiburanakul S. Effects of pitavastatin on lipid profiles in HIV-infected patients with dyslipidemia and receiving atazanavir/ritonavir: a randomized, double-blind, crossover study. PLoS One. 2016; 11:e0157531.

(26.) Food and Drug Administration. FDA drug safety communication: interactions between certain HIV or hepatitis C drugs and cholesterollowering statin drugs can increase the risk of muscle injury. 2012. http://www.fda.gov/Drugs/DrugSafety/ucm293877.htm

(27.) Willig JH, Jackson DA, Westfall AO, et al. Clinical inertia in the management of low-density lipoprotein abnormalities in an HIV clinic. Clin Infect Dis. 2008; 46:1315-1318.

(28.) Freiberg MS, Chang CC, Kuller LH, et al. HIV infection and the risk of acute myocardial infarction. JAMA Intern Med. 2013; 173:614-622.

(29.) Clement ME, Park LP, Navar AM, et al. Statin utilization and recommendations among HIV- and HCV-infected veterans: a cohort study. Clin Infect Dis. 2016; 63:407-413.

(30.) Althoff KN, Horberg MA, Eron JJ, et al. The large gap between statin eligibility and prescription among HIV+ in North America. Conference on Retroviruses and Opportunistic Infections (CROI), February 13-16, 2017, Seattle. Abstract 619.

(31.) Monroe AK, Fu W, Zikusoka MN, et al. Low-density lipoprotein cholesterol levels and statin treatment by HIV status among Multicenter AIDS Cohort Study men. AIDS Res Hum Retroviruses. 2015; 31:593-602.

(32.) Glass TR, Weber R, Vernazza PL, et al. Ecological study of the predictors of successful management of dyslipidemia in HIV-infected patients on ART: the Swiss HIV Cohort Study. HIV Clin Trials. 2007; 8:77-85.

(33.) ClinicalTrials.gov. Evaluating the use of pitavastatin to reduce the risk of cardiovascular disease in HIV-infected adults (REPRIEVE). Clinical Trial Identifier NCT02344290. https://www.clinicaltria1s.gov/ct2/show/NCT02344290

(34.) Oliver NT, Hartman CM, Kramer JR, Chiao EY. Statin drugs decrease progression to cirrhosis in HIV/hepatitis C virus coinfected individuals. AIDS. 2016; 30:2469-2476.

(35.) FDA Drug Safety Communication: Important safety label changes to cholesterol-lowering statin drugs. February 28, 2012. https://www.fda.gov/Drugs/DrugSafety/ucm293101.htm

(36.) Myerson M, Malvestutto C, Aberg JA. Management of lipid disorders in patients living with HIV. J Clin Pharmacol. 2015; 55:957-974. http://onlinelibrary.wiley.com/doi/10.1002/jcph.473/epdf

(37.) Boekholdt SM, Hovingh GK, Mora S, et al. Very low levels of atherogenic lipoproteins and the risk for cardiovascular events: a metaanalysis of statin trials. J Am Coll Cardiol. 2014; 64:485-494.

(38.) Dube MP, Wu JW, Aberg JA, et al; AIDS Clinical Trials Group A5148 Study Team. Safety and efficacy of extended-release niacin for the treatment of dyslipidaemia in patients with HIV infection: AIDS Clinical Trials Group Study A5148. Antivir Ther. 2006; 11:1081-1089.

(39.) Dube MP, Komarow L, Fichtenbaum CJ, et al; AIDS Clinical Trials Group A5293 Study Team. Extended-release niacin versus fenofibrate in HIV-infected participants with low high-density lipoprotein cholesterol: effects on endothelial function, lipoproteins, and inflammation. Clin Infect Dis. 2015; 61:840-849.

(40.) Aberg JA, Zackin RA, Brobst SW, et al; ACTG 5087 Study Team. A randomized trial of the efficacy and safety of fenofibrate versus pravastatin in HIV-infected subjects with lipid abnormalities: AIDS Clinical Trials Group Study 5087. AIDS Res Hum Retroviruses. 2005; 21:757-767.

(41.) Balasubramanyam A, Coraza I, Smith EO, et al. Combination of niacin and fenofibrate with lifestyle changes improves dyslipidemia and hypoadiponectinemia in HIV patients on antiretroviral therapy: results of "heart positive," a randomized, controlled trial. J Clin Endocrinol Metab. 2011; 96:2236-2247.

(42.) Wohl DA, Waters D, Simpson RJ Jr, et al. Ezetimibe alone reduces low-density lipoprotein cholesterol in HIV-infected patients receiving combination antiretroviral therapy. Clin Infect Dis. 2008; 47:1105-1108.

(43.) Chow D, Chen H, Glesby MJ, et al. Short-term ezetimibe is well tolerated and effective in combination with statin therapy to treat elevated LDL cholesterol in HIV-infected patients. AIDS. 2009; 23:2133-2141.

(44.) Saeedi R, Johns K, Frohlich J, Bennett MT, Bondy G. Lipid lowering efficacy and safety of ezetimibe combined with rosuvastatin compared with titrating rosuvastatin monotherapy in HIV-positive patients. Lipids Health Dis. 2015; 14:57.

(45.) Wohl DA, Tien HC, Busby M, et al. Randomized study of the safety and efficacy of fish oil (omega-3 fatty acid) supplementation with dietary and exercise counseling for the treatment of antiretroviral therapy-associated hypertriglyceridemia. Clin Infect Dis. 2005; 41:1498-1504.

(46.) Gerber JG, Kitch DW, Fichtenbaum CJ, et al. Fish oil and fenofibrate for the treatment of hypertriglyceridemia in HIV-infected subjects on antiretroviral therapy: results of ACTG A5186. J Acquir Immune Defic Syndr. 2008; 47:459-466. Erratum in J Acquir Immune Defic Syndr. 2009; 50:343.

(47.) Peters BS, Wierzbicki AS, Moyle G, Nair D, Brockmeyer N. The effect of a 12-week course of omega-3 polyunsaturated fatty acids on lipid parameters in hypertriglyceridemic adult HIV-infected patients undergoing HAART: a randomized, placebo-controlled pilot trial. Clin Ther. 2012; 34:67-76.

(48.) Metkus TS, Timpone J, Leaf D, Bidwell Goetz M, Harris WS, Brown TT. Omega-3 fatty acid therapy reduces triglycerides and interleukin-6 in hypertriglyeridemic HIV patients. HIV Med. 2013; 14:530-539.

(49.) Paranandi A, Asztalos BF, Mangili A, et al. Effects of omega-3 fatty acids on triglycerides and high-density lipoprotein subprofiles in HIV-infected persons with hypertriglyceridemia. AIDS Res Hum Retroviruses. 2014; 30:800-805.

(50.) Volpe G. Long-term effects of omega-3 fatty acids in HIV: a RCT. ID Week. October 26-30, 2016. New Orleans. http://www.natap.org/2016/IDSA/IDSA_48.htm

(51.) Oliveira JM, Rondo PH. Omega-3 fatty acids and hypertriglyceridemia in HIV-infected subjects on antiretroviral therapy: systematic review and meta-analysis. HIV Clin Trials. 2011; 12:268-274.

(52.) Stradling C, Chen YF, Russell T, Connock M, Thomas GN, Taheri S. The effects of dietary intervention on HIV dyslipidaemia: a systematic review and meta-analysis. PLoS One. 2012; 7:e38121.

(53.) Alexander DD, Miller PE, Van Elswyk ME, Kuratko CN, Bylsma LC. A meta-analysis of randomized controlled trials and prospective cohort studies of eicosapentaenoic and docosahexaenoic long-chain omega-3 fatty acids and coronary heart disease risk. Mayo Clin Proc. 2017; 92:15-29.

(54.) Lloyd-Jones DM, Hong Y, Labarthe D, et al, American Association Strategic Planning Task Force and Statistics Committee. Defining and setting national goals for cardiovascular health promotion and disease reduction: the American Heart Association's strategic impact goal through 2020 and beyond. Circulation. 2010; 121:586-613.

(55.) Everett BM, Smith RJ, Hiatt WR. Reducing LDL with PCSK9 inhibitors--the clinical benefit of lipid drugs. N Engl J Med. 2015; 373: 1588-1591. http://www.nejm.org/doi/full/10.1056/NEJMp1508120#t=article

(56.) Kazi DS, Moran AE, Coxson PG, et al. Cost-effectiveness of PCSK9 inhibitor therapy in patients with heterozygous familial hypercholesterolemia or atherosclerotic cardiovascular disease. JAMA. 2016; 316:743-753.

(57.) Kohli P, Ganz P, Ma Y, et al. HIV and hepatitis C-coinfected patients have lower low-density lipoprotein cholesterol despite higher proprotein convertase subtilisin kexin 9 (PCSK9): an apparent "PCSK9-lipid paradox." J Am Heart Assoc. 2016; 5:pii:e002683.

(58.) Cholesterol Treatment Trialists' (CTT) Collaboration, Baigent C, Blackwell L, Emberson J, et al. Efficacy and safety of more intensive lowering of LDL cholesterol: a meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet. 2010; 376:1670-1681.
Table 1. HRSA guidelines on managing high LDL-C with HIV (3)

Risk category               LDL-C goal

Lower risk: No CHD or CHD   <160 mg/dL (<4.1 mmol/L)
risk equivalents * and
0-1 risk factors
([dagger])

Moderate risk: No CHD or    <130 mg/dL (<3.4 mmol/L)
CHD risk equivalents and
[greater than or equal
to] 2 risk factors and
10-y estimated risk <10%

Moderately high risk: No    <130 mg/dL (<3.4 mmol/L)
CHD or CHD risk             Optional goal <100 mg/dL
equivalents and [greater
than or equal to] 2 risk
factors and 10-y
estimated risk 10-20%

High risk: CHD or CHD       <100 mg/dL (<2.6 mmol/L)
risk equivalent             Optional goal <70 mg/
                            dL ([double dagger]))

Risk category               Start therapeutic
                            lifestyle changes

Lower risk: No CHD or CHD   LDL-C [greater than or
risk equivalents * and      equal to] 160 mg/dL (>4.1
0-1 risk factors            mmol/L)
([dagger])

Moderate risk: No CHD or    LDL-C [greater than or
CHD risk equivalents and    equal to]130 mg/dL
[greater than or equal      ([greater than or equal
to] 2 risk factors and      to] 3.4 mmol/L)
10-y estimated risk <10%

Moderately high risk: No    LDL-C [greater than or
CHD or CHD risk             equal to] 130 mg/dL
equivalents and [greater    ([greater than or equal
than or equal to] 2 risk    to] 3.4 mmol/L)
factors and 10-y
estimated risk 10-20%

High risk: CHD or CHD       LDL-C [greater than or
risk equivalent             equal to] 100 mg/dL
                            ([greater than or equal
                            to] 2.6 mmol/L)

Risk category               Consider drug therapy

Lower risk: No CHD or CHD   LDL-C [greater than or
risk equivalents * and      equal to] 190 mg/dL
0-1 risk factors            ([greater than or equal
([dagger])                  to] 4.9 mmol/L); drug
                            therapy optional at
                            160-189 mg/dL

Moderate risk: No CHD or    LDL-C [greater than or
CHD risk equivalents and    equal to] 160 mg/dL
[greater than or equal      ([greater than or equal
to] 2 risk factors and      to] 4.1 mmol/L)
10-y estimated risk <10%

Moderately high risk: No    LDL-C [greater than or
CHD or CHD risk             equal to] 130 mg/dL
equivalents and [greater    ([greater than or equal
than or equal to] 2 risk    to] 3.4 mmol/L)
factors and 10-y
estimated risk 10-20%

High risk: CHD or CHD       LDL-C [greater than or
risk equivalent             equal to] 100 mg/dL
                            ([greater than or equal
                            to] 2.6 mmol/L)

CHD, coronary heart disease; LDL-C, low-density lipoprotein
cholesterol.

* Risk equivalents are diabetes, peripheral vascular disease,
symptomatic carotid artery disease, abdominal aortic aneurysm,
transient ischemic attack, and [greater than or equal to] 2 CHD risk
factors with a 10-year CHD risk >20%.

([dagger]) Risk factors are male sex; age [greater than or equal to]
45 in men, [greater than or equal to]55 in women; current cigarette
smoking; family history of CHD <55 years of age in male first-degree
relative, <65 in female first-degree relative; blood pressure
[greater than or equal to] 140/90 mm Hg or blood pressure medication;
HDL-C <40 mg/dL in men, <50 mg/dL in women.

([double dagger]) Goal preferred by many cardiologists for people
with CHD or CHD risk equivalents.

Table 2. HRSA guidelines on managing high triglycerides with HIV (3)

Risk category              Triglyceride      Begin therapy
                           level

Normal triglycerides       <150 mg/dL

Borderline high            150-199 mg/dL *
triglycerides

High triglycerides         200-499 mg/dL     Start therapeutic
                                             lifestyle changes;
                                             consider drug therapy
                                             for people with CHD, CHD
                                             equivalents, ([dagger])
                                             or high risk

Very high triglycerides    [greater than     Start therapeutic
                           or equal to]      lifestyle changes;
                           500 mg/dL         consider drug therapy

CHD, coronary heart disease.

* Some experts recommend lifestyle intervention in this range. See
Myerson et al. in "Some worthy HIV lipid management reviews."

([dagger]) Risk equivalents are diabetes, peripheral vascular
disease, symptomatic carotid artery disease, abdominal aortic
aneurysm, transient ischemic attack, and [greater than or equal to] 2
CHD risk factors with a 10-year CHD risk >20%.

Table 3. Which antilipid drug for which abnormality?

Lipid abnormality                  First     Second choice
                                   choice

Isolated high LDL-C or non-HDL-C   Statin    Fibrate

Isolated high TG *                 Fibrate   Statin, omega-3
                                             fatty acids

High LDL-C and TG 200-500 mg/dL    Statin    Fibrate

High LDL-C and TG >500 mg/dL *     Fibrate   Omega-3 fatty acids,
                                             niacin, statin

HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density
lipoprotein cholesterol; TG, triglycerides. Source: US 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)

Table 4. Selected trials of niacin and/or fibrate for dyslipidemia
in people with HIV

Author, year      Study design *                   n *

Dube, (38) 2006   Nondiabetic men with TG          33
                  [greater than or equal to] 200
                  mg/dL and non-HDL-C [greater
                  than or equal to] 180 mg/dL
                  took escalating doses of
                  extended-release niacin up to
                  2000 mg nightly for 44 wk
                  (ACTG A5148)

Dube, (39) 2015   Patients with low HDL-C (men     74
                  <40 mg/dL, women <50 mg/dL)
                  and TG >150 mg/dL randomized
                  open-label to extended-release

                  niacin plus aspirin or to
                  fenofibrate for 24 wk (ACTG
                  A5293)

Aberg, (40) 2005  Patients with LDL-C              174
                  [greater than or
                  equal to] 130 mg-dL
                  and TG [greater than
                  or equal to] 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)

Balasubramanyam,  Patients with TG >150 mg/ dL     191
(41) 2011         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/N

                  For fenofibrate and/or fish
                  oil trial, see Gerber in Table
                  6

Author, year      Main results

Dube, (38) 2006   At 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

Dube, (39) 2015   In 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) 2005  Composite 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,  D/E + F improved TG, total
(41) 2011         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 ratic
                  -24.5%

* All participants adults on stable antiretroviral therapy.

Table 5. Selected trials of ezetimibe for dyslipidemia in people
with HIV

Author, year        Study design *               n *

Wohl, (42) 2008     Patients with LDL-C          48
                    [greater than or equal
                    to] 75 mg/dL, TG [less
                    than or equal to] 800
                    mg/dL randomized
                    double-blind to crossover
                    of daily ezetimibe vs
                    placebo for 6 w with 2-w
                    washout between

Chow, (43) 2009     Patients with LDL-C >130     44
                    mg/dL with stable statin
                    randomized double-blind
                    to crossover of ezetimibe
                    vs placebo for 12 w with
                    4-w washout between

Saeedi, (44) 2015   Patients short of lipid      43
                    goal on 10-mg
                    rosuvastatin randomized
                    open-label to add
                    ezetimibe or raise statin
                    to 20 mg for 12 wk

Author, year        Main results

Wohl, (42) 2008     LDL-C -5.3% with
                    ezetimibe vs + 5.5% with
                    placebo (P = 0.04)

Chow, (43) 2009     Median difference in
                    absolute LDL-C between
                    ezetimibe and placebo -32
                    mg/dL (P < 0.0001)

Saeedi, (44) 2015   With 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, year           Study design *              n *

Wohl, (45) 2005        Patients with TG >200 mg/   52
                       dL randomized open-label
                       to dietary + exercise
                       counseling or to D/E
                       counseling plus fish oils
                       for 16 wk

Gerber, (46) 2009      Patients with TG [greater   100
                       than or equal to] 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)

Peters, (47) 2012      Patients with TG 300-1000   48
                       mg/ dL randomized
                       double-blind to fish oils
                       or placebo for 12 wk

Metkus, (48) 2013      Patients with TG [greater   48
                       than or equal to] 200
                       mg/dL randomized
                       double-blind to fish oils
                       or placebo for 8 wk

Paranandi, (49) 2014   Patients with TG [greater   41
                       than or equal to] 150
                       mg/dL randomized
                       double-blind to crossover
                       of fish oils vs placebo
                       for 12 wk followed by
                       4-wk washout

Volpe, (50) 2016       Patients with TG 150-2500   117
                       mg/ dL randomized to fish
                       oils or placebo for 24
                       months

Author, year           Main results

Wohl, (45) 2005        Fish 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) 2009      Median 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) 2012      TG fell by median 154.9
                       mg/dL with fish oils but
                       rose 36.3 mg/dL with
                       placebo (P = 0.019)

Metkus, (48) 2013      TG decreased by median 34
                       mg/dL with fish oils but
                       rose 46.5 mg/dL with
                       placebo (P = 0.01)

Paranandi, (49) 2014   Mean TG decreased
                       significantly with fish
                       oils (-63.2 mg/dL, P <
                       0.001); total
                       cholesterol, LDL-C, or
                       HDL-C did not change

Volpe, (50) 2016       Median 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.

Figure 1. Analysis of the National Health and Nutrition Examination
Surveys (NHANES) determined that seven dietary factors accounted
for similar proportions of all cardiometabolic deaths in the
general US population. (12)

Impact of dietary factors on cardiometabolic death

Percent of all cardiomet deaths

Excess sodium             9.5%
Too few nuts/needs        8.5%
Excess processed meats    8.2%
Too little fish oil       7.8%
Too few vegetables        7.6%
Too few fruits            7.5%
Excess sugary drinks      7.4%

Note: Table made from bar graph.
COPYRIGHT 2017 The Center for AIDS: Hope & Remembrance Project
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 2017 Gale, Cengage Learning. All rights reserved.

Article Details
Printer friendly Cite/link Email Feedback
Title Annotation:Perspectives
Author:Mascolini, Mark
Publication:Research Initiative/Treatment Action!
Article Type:Report
Date:Mar 22, 2017
Words:7001
Previous Article:Lipid impact on HIV heart disease, and antiretroviral impact on lipids.
Next Article:High depression rates with HIV--and its scathing clinical impact.
Topics:

Terms of use | Privacy policy | Copyright © 2019 Farlex, Inc. | Feedback | For webmasters