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Lipid impact on HIV heart disease, and antiretroviral impact on lipids.

Strong evidence linking abnormal lipids to cardiovascular disease and mortality in the general population dates to the 1970s (1) and grew deeper and wider in succeeding decades. (2-4) Research also shows that lowering cholesterol has a clinical impact: Analysis of 10 prospective cohorts, three international studies, and 28 randomized trials figured that cutting total cholesterol about 10% lowered the risk of incident ischemic heart disease approximately 54% in men 40 years old. (5) The impact on women was similar though based on slimmer data.

Impact of lipids on cardiovascular disease with HIV

Smaller studies in HIV populations also tie unruly lipids to heart disease. Three studies found links between incident cardiovascular disease and high total cholesterol, high triglycerides, small dense low-density lipoprotein cholesterol (LDL-C), or apolipoprotein B. (6-8)

A case-control study matched 52 HIV-positive people who had incident cardiovascular disease from 1995 through 2009 to 104 HIV-positive people with no cardiovascular disease.6 Prevalence of dyslipidemia (use of lipid-lowering drugs or any abnormal lipid) was significantly higher in cases than controls (87% versus 72%, P = 0.05), and cases had significantly higher levels of total cholesterol (212 versus 188 mg/dL, P = 0.002) and LDL-C (130 versus 116 mg/dL, P = 0.04) in the 4 months before the cardiovascular event. Multivariable analysis identified high total cholesterol 4 months before the event as an independent predictor of the cardiovascular diagnosis (P = 0.0005).

In another case-control analysis, Swiss HIV Cohort Study (SHCS) investigators evaluated the impact of two highly atherogenic particles on coronary event risk from April 2000 through July 2008: small dense LDL-C and apolipoprotein B, which is the main protein in LDL-C. (7) This study involved 98 antiretroviral-treated cases who had a first coronary event and 393 antiretroviral-treated controls matched for age, gender, and smoking status. Logistic regression models determined that every 1 mg/ dL higher small dense LDL-C level raised the odds of a coronary event 7% (adjusted odds ratio [aOR] 1.07, 95% confidence interval [CI] 1.01 to 1.12), while every 10 mg/dL higher apolipoprotein B level upped the odds 17% (aOR 1.17, 95% CI 1.06 to 1.28). In both the LDL-C model and the apolipoprotein B model, longer duration of protease inhibitor (PI) therapy did not affect coronary event chances, but higher viral load and lower nadir CD4 count did.

A study of HIV-positive people in DAD cohorts isolated high triglycerides as an independent predictor of myocardial infarction (MI). (8) The analysis involved 33,308 DAD participants who had 580 MIs from 1999 to 2008. An unadjusted analysis determined that every doubling of triglyceride level boosted the MI risk by two thirds (relative risk [RR] 1.67, 95% CI 1.54 to 1.80). After adjustment for latest total cholesterol and high-density lipoprotein cholesterol (HDL-C), every twice higher triglyceride tally raised MI risk by one third (aRR 1.33, 95% CI 1.21 to 1.45), meaning total cholesterol and HDL-C also contributed to MI risk. Even after additional adjustment for other cardiovascular risk factors, HIV factors, and treatment factors, every twice-higher triglyceride level independently boosted MI risk 11% (aRR 1.11, 95% CI 1.01 to 1.23).

Researchers studying 29,515 HIV-positive people in 7 US/Canadian NA-ACCORD cohorts determined that avoiding high total cholesterol would prevent 43% of MIs in this group. (9) The NA-ACCORD team figured population-attributable fractions (PAFs) for various risk factors, defining those fractions as "the proportion of MIs that could be avoided in HIV-infected adults if all were unexposed to the modifiable risk factor of interest" and other risk factors remained unchanged. PAFs combine two metrics, prevalence of the risk factor in cohort members who had an MI and the adjusted hazard ratio for that risk factor. Elevated total cholesterol (>240 mg/ dL) had the highest PAF, 43%, meaning this group would avoid 43% of MIs if no one ever had high total cholesterol (Figure 1). Avoiding hypertension would prevent 41% of MIs, according to this analysis, and never smoking would prevent 38%. But avoiding a CD4 below 200 cells/ [mm.sup.3] would avert only 10% of MIs, and avoiding a viral load at or above 400 copies/mL would avert only 6%.

No randomized trials or long-term epidemiologic studies show that lowering harmful LDL-C, total cholesterol, or triglycerides with antilipid drugs prevents cardiovascular disease in people with HIV. In the general population, according to the National Lipid Association, evidence abounds that "reducing elevated levels of atherogenic cholesterol will lower atherosclerotic cardiovascular disease risk in proportion to the extent that atherogenic cholesterol is reduced." (10) A Cholesterol Treatment Trialists' meta-analysis found that every 1 mmol/L (38.7 mg/dL) lower LDL-C achieved with statin therapy yielded a 22% drop in relative risk of cardiovascular events. (11) A large trial in people with HIV is under way to confirm that this correlation holds true in people with HIV (see page 43).

Lipids, kidneys, cognition, neuropathy, and sex

Other research in people with HIV ties out-of-line lipids to falling renal function, cognitive decline, sensory neuropathy, and even erectile dysfunction (Figure 2).

Two recent studies linked dyslipidemia to waning kidney function in people with HIV. A Multicenter AIDS Cohort Study (MACS) analysis involved 365 gay/bisexual men who started antiretroviral therapy (ART) between the end of 1995 and September 30, 2011. (12) In adjusted models 3 years after ART began, men who gained more than 50 mg/dL in total cholesterol averaged a 2.6-mL/min yearly drop in estimated glomerular filtration rate (eGFR) (P < 0.001). In contrast, men whose total cholesterol changed less than 50 mg/dL had an average 1.4-mL/min yearly drop in eGFR (P < 0.001). Five years after ART began, the group that gained more than 50 mg/dL in total cholesterol had an average 2.4-mL/min yearly drop in eGFR (P = 0.008), compared with an average 0.1-mL/ min yearly decline in men with a smaller total cholesterol change (P = 0.594).

A retrospective study in Japan tracked eGFR over 6 years in 661 people with HIV. (13) The group averaged an annual eGFR decline of 2.01 mL/min, more than 6 times higher than the drop in age-matched controls without HIV. Dividing non-HDL-C levels into quartiles, the researchers used multivariate logistic regression to determine that the distribution of eGFR declines increased significantly across non-HDL-C quartiles (P = 0.0359). A non-HDL-C level above the cohort's median value boosted the odds of decreased eGFR more than 75% (aOR 1.77, 95% CI 1.07 to 3.00).

The MACS investigators suggest "dyslipidemia may promote renal injury through damage to glomerular capillary endothelial and mesangial cells as well as podocytes, resulting in glomerulosclerosis and interstitial fibrosis." (12,14) At the same time, chronic kidney disease is an acknowledged risk factor for dyslipidemia, (10) so causality can run in both directions.

MACS researchers published two recent studies linking dyslipidemia to cognitive decline in men with HIV. (15,16) A 1996-2010 analysis compared 273 HIV-positive men with 516 sociodemographically matched HIV-negative men, 81% of them white and 89% with more than a high-school education. (15) Median age stood at 51 years, and all HIV-positive men had a baseline viral load below 400 copies/mL. Mixed-effects models tied higher total cholesterol and LDL-C to faster cognitive decline (P < 0.01), while higher HDL-C and statin use slowed that decline (P = 0.02 for both).

A study of 364 MACS men with HIV found that severity of HIV-associated neurocognitive disorder (HAND) remained stable through 4 years of follow-up in 77% of men, deteriorated in 13%, and improved in 10%.16 Logistic regression determined that a self-reported hypercholesterolemia diagnosis nearly tripled the odds of HAND progression (aOR 2.8, 95% CI 1.3 to 5.9, P = 0.01). That finding led the MACS team to suggest that lipid-mediated cerebrovascular disease could contribute to cognitive impairment in people with HIV.

High triglycerides are linked to sensory neuropathy in people with diabetes, and a study in 436 people with HIV made the same association. (17) Among these people with a median age of 52 years, 75% were taking ART and 27% had clinically defined sensory neuropathy. Multivariable logistic regression figured that triglycerides in the highest group tertile versus the lowest (>244 versus <142 mg/dL) nearly tripled the odds of neuropathy (aOR 2.7, 95% CI 1.4 to 5.5).

Finally, HIV clinicians may want to tell men who complain of erectile dysfunction that abnormal lipids could contribute to this problem. (18) The study involved 109 HIV-positive men who completed the International Index of Erectile Function (IIEF) survey at a Mexico City HIV clinic. The group averaged 39.9 years in age, had been diagnosed with HIV for an average 92.7 months, and had taking ART for an average 56.4 months. Almost two thirds, 65%, had IIEF-determined erectile dysfunction, and 33% had dyslipidemia (triglycerides >200 mg/dL, total cholesterol >240 mg/dL, or both). Dyslipidemia emerged as the sole variable linked to erectile dysfunction in univariate or multivariate analysis (adjusted hazard ratio [aHR] 3.75, 95% CI 1.25 to 11.28, P = 0.02). The authors note that dyslipidemia alters vascular relaxation, which can compromise blood flow and thus lead to erectile dysfunction.

Keeping up with antiretroviral-lipid interactions

A 2015 systematic review and meta-analysis embracing 51 observational studies offers broad insight into how ART affects lipid levels. (19) The analysis focused on 37,110 HIV-positive adults, comparing lipid readings in those still naive to antiretrovirals with levels in treatment-experienced people. Compared with the naive group, ART-exposed people averaged 29 mg/dL higher total cholesterol, 15 mg/dL higher LDL-C, and 47 mg/dL higher triglycerides. Pooled odds ratios indicated that antiretroviral-experienced people had almost quadrupled chances of high total cholesterol (OR 3.8, 95% CI 3.1 to 4.7) and more than doubled chances of high triglycerides (OR 2.2, 95% CI 1.7 to 2.9).

Comparing PI-based regimens with non-PI regimens, the meta-analysis found significantly higher ART-associated changes in total cholesterol (pooled estimate 33 versus 25 mg/dL, P = 0.024) and triglycerides (pooled estimate 70 versus 26 mg/dL, P = 0.006) with PIs. (19) But pooled odds ratios for hypercholesterolemia or hypertriglyceridemia were not significantly greater with PI combinations than non-PI regimens. These investigators also found higher ART-associated jumps in total cholesterol in studies published between 2000 and 2009 than in studies published more recently (mean difference 35 versus 25 mg/dL, P = 0.005). (19) The same held true for ART-associated gains in LDL-C in studies before versus after 2009 (mean difference 20 versus 12 mg/dL, P = 0.03). Those findings suggest newer antiretrovirals have a milder impact on total cholesterol and LDL-C.

But the meta-analysis (19) did not attempt to compare dyslipidemia risk between individual antiretrovirals. Such drug-versus-drug breakdowns can get tricky. For example, some PIs rile lipids more than others, and nucleosides taken with PIs can promote dyslipidemia. Older nonnucleosides also affect lipids, while newer nonnucleosides and integrase inhibitors generally do not. But current Department of Health and Human Services (DHHS) antiretroviral guidelines take a crack at summarizing the lipid effects of currently favored antiretrovirals, and 2014 Department of Health and Human Services HIV care guidelines weigh in on the lipid impact of certain antiretrovirals (Table 1).

An (almost) up-to-date antiretroviral-lipid interaction review by researchers in Brazil offers another reasonable overview of how individual antiretrovirals affect lipids. (20) This University of Sao Paulo group gives the second-generation PIs--ritonavir-boosted lopinavir, amprenavir, fosamprenavir, and tipranavir--the worst dyslipidemia marks in their Table 2 summary: three up-arrows indicating the greatest likelihood of spawning dyslipidemia. In contrast, the two currently favored ritonavir-boosted PIs--darunavir and atazanavir--get only one up-arrow, reflecting only modest or no short-term lipid gains with each of these two PIs plus ritonavir. (21-25)

The Sao Paulo team (20) does not address lipid changes when the nonantiviral cobicistat boosts darunavir or atazanavir. Data reported so far indicate "lipid disturbances ... in a small percentage of patients" (26) taking darunavir/cobicistat (Prezcobix). Preclinical studies of cobicistat show that the booster does not foster lipid accumulation in adipocytes and alters lipid metabolism less than ritonavir. (27) Prezcobix prescribing information does not mention lipids, lipoproteins, or cholesterol. (28) Clinical trials of atazanavir/cobicistat (Evotaz) show on-treatment changes in total cholesterol, LDL-C, HDL-C, and triglycerides within the normal range through 144 weeks and largely similar to changes with atazanavir/ ritonavir. (29) But DHHS guidelines note lipid elevations with elvitegravir/cobicistat. (1) Also, cobicistat boosting can make creatinine readings harder to interpret. Prescribing information for both cobicistat-boosted PIs notes that "cobicistat decreases estimated creatinine clearance due to inhibition of tubular secretion of creatinine without affecting actual renal glomerular function." (29)

Among the three licensed integrase inhibitors, elvitegravir requires a cobicistat boost, but raltegravir and atazanavir do not. Studies show good lipid profiles with dolutegravir, (30,31) elvitegravir, (32) and raltegravir, (30,32) and the Sao Paulo reviewers rate their effect on lipids as "neutral." (20) DHHS guidelines, however, caution the elvitegravir/cobicistat may boost lipids (Table 1). Among nonnucleosides, both efavirenz and nevirapine pump up "good" HDL-C, (33) but efavirenz is tied to dyslipidemia (20,32) and nevirapine can boost "bad" LDL-C. (20,34) The newer nonnucleosides etravirine and rilpivirine have better lipid profiles. (20,32) The Sao Paulo team says currently used nucleosides abacavir, emtricitabine, and lamivudine modestly promote dyslipidemia. (20) Tenofovir disoproxil fumarate (TDF), discussed in the next section, lowers lipids, but tenofovir alafenamide (TAF) does not have this effect.

Nonlipid drugs that boost or lower lipids

Besides antiretrovirals, a bagful of medications can pump lipids into the danger zone--and a handful of nonlipid drugs can cut cholesterol (Table 2). (10,35) In the second category, the antihypertensive angiotensin receptor blockers and the antiobesity agent orlistat may be taken by people with HIV. But for HIV clinicians, the best-known drug among unintended lipid trimmers is tenofovir disoproxil fumarate (TDF).

When several studies found improving lipid profiles in people who switched to a TDF regimen, AIDS Clinical Trials Group (ACTG) investigators formally assessed TDF's lipid impact in a double-blind placebo-controlled crossover trial. (36) ACTG A5206 recruited adults with a viral load below 400 copies/mL while taking a stable antiretroviral regimen. Everyone had dyslipidemia, defined as triglycerides between 150 and 1000 mg/dL or non-HDL-C between 100 and 250 mg/dL. No one had a history of coronary heart disease and no one could change or add lipid-lowering drugs during the trial. Participants randomly added TDF or placebo for 12 weeks in a blinded order with a 4-week drug washout between each dosing. In the 13 participants with complete data, non-HDL-C, LDL-C, and total cholesterol all improved significantly more through 12 weeks of TDF than through 12 weeks of placebo. Triglycerides fell with TDF then rebounded in the 4-week washout, a bounce suggesting that stopping TDF inflates triglycerides. The ACTG team concluded that TDF independently lowers lipids. The study offered no hints at a mechanism, though it appeared to exclude viremia as a cause since participants maintained virologic suppression throughout the study.

Tenofovir alafenamide (TAF), now replacing TDF in many antiretroviral regimens, upsets kidney and bone markers less than TDF, but it does not carry TDF's lipid silver lining. A placebo-controlled trial comparing single-tablet regimens including TAF or TDF in antiretroviral-naive people found higher 48-week rates of grade 3 or 4 LDL-C with TAF than TDF (9% versus 3%). (37) Although median LDL-C rose more with the elvitegravir/TAF pill than with the elvitegravir/TDF pill (17 versus 11 mg/dL), the difference did not reach statistical significance (P = 0.11), while HDL-C rose significantly more in the TAF group (7 versus 3 mg/dL, P = 0.023). The researchers observe that the important total-to-HDL-C ratio barely changed in either study arm through 48 weeks (median increase 0.2 versus 0.1, P = 0.34), and triglyceride changes did not differ significantly between the two groups. The investigators suggest that markedly lower tenofovir plasma levels with TAF than TDF could explain the differing lipid impact of the two drugs.

Another placebo-controlled trial comparing continued TDF with a switch to TAF in single-tablet regimens with rilpivirine/emtricitabine charted similar lipid results:38 Total cholesterol, LDL-C, HDL-C, and triglycerides all rose through 48 weeks with TAF but stayed flat with continued TDF. Total-to-HDL-C ratio changed only slightly in both arms, with no significant difference between arms (P = 0.18). But in 48 weeks 13 of 316 people in the TAF arm versus 2 of 314 in the TDF arm started antilipid therapy, a significant difference (4% versus 1%, P = 0.0067).

At the end of the day, HIV cardiologist Christopher Longenecker says in the interview on page 18, the lipid difference between TDF and TAF lies "on the margins of clinically relevant," except perhaps for people with familial hypercholesterolemia or a very bad initial lipid profile.

Among the many non-HIV drugs that elevate lipids, about a half-dozen may figure frequently in treating conditions common in people with HIV (Table 2). (10,35 Notably, the antidiabetic glitazones, especially rosiglitazone, can boost LDL-C or triglycerides. Two groups of antihypertensives--thiazide diuretics and betablockers--can drive up lipids. Two lipid-controlling agents may paradoxically raise LDL-C (omega-3 fatty acids containing docosahexaenoic acid) or triglycerides (bile acid sequestrants). Inflammation-fighting glucocorticoids may raise triglycerides.

References

(1.) Pooling Project Research Group. Relationship of blood pressure, serum cholesterol, smoking habit, relative weight and ECG abnormalities to incidence of major coronary events: final report of the Pooling Project. J Chronic Dis. 1978; 31:201-306.

(2.) Stamler J, Wentworth D, Neaton JD. Is the relationship between serum cholesterol and risk of premature death from coronary heart disease continuous and graded? Findings in 356,222 primary screenees of the Multiple Risk Factor Intervention Trial (MRFIT). JAMA. 1986; 256:2823-2828.

(3.) Anderson KM, Castelli WP, Levy D. Cholesterol and mortality: 30 years of follow-up from the Framingham Study. JAMA. 1987; 257: 2176-2180.

(4.) Anderson KM, Wilson PW, Garrison RJ, Castelli WP. Longitudinal and secular trends in lipoprotein cholesterol measurements in a general population sample. The Framingham Offspring Study. Atherosclerosis. 1987; 68:59-66.

(5.) Law MR, Wald NJ, Thompson SG. By how much and how quickly does reduction in serum cholesterol concentration lower risk of ischaemic heart disease? BMJ. 1994; 308:367-372.

(6.) Ford ES, Greenwald JH, Richterman AG, et al. Traditional risk factors and D-dimer predict incident cardiovascular disease events in chronic HIV infection. AIDS. 2010; 24:1509-1517.

(7.) Bucher HC, Richter W, Glass TR, et al. Small dense lipoproteins, apolipoprotein B, and risk of coronary events in HIV-infected patients on antiretroviral therapy: the Swiss HIV Cohort Study. J Acquir Immune Defic Syndr. 2012; 60:135-142.

(8.) Worm SW, Kamara DA, Reiss P, et al. Elevated triglycerides and risk of myocardial infarction in HIV-positive persons. AIDS. 2011; 25:1497-1504.

(9.) 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.

(10.) 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.

(11.) 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.

(12.) Abraham AG, Li X, Jacobson LP, et al. Antiretroviral therapy-induced changes in plasma lipids and the risk of kidney dysfunction in HIV-infected men. AIDS Res Hum Retroviruses. 2013; 29:1346-1352.

(13.) Hara M, Yanagisawa N, Ohta A, et al. Increased non-HDL-C level linked with a rapid rate of renal function decline in HIV-infected patients. Clin Exp Nephrol. 2016 May 18. Epub ahead of print.

(14.) Abrass CK. Cellular lipid metabolism and the role of lipids in progressive renal disease. Am J Nephrol. 2004; 24:46-53.

(15.) Mukerji SS, Locascio JJ, Misra V, et al. Lipid profiles and APOE4 allele impact midlife cognitive decline in HIV-infected men on antiretroviral therapy. Clin Infect Dis. 2016; Jul 22.pii:ciw495.

(16.) Sacktor N, Skolasky RL, Seaberg E, et al. Prevalence of HIV-associated neurocognitive disorders in the Multicenter AIDS Cohort Study. Neurology. 2016; 86:334-340.

(17.) Banerjee S, McCutchan JA, Ances BM, et al. Hypertriglyceridemia in combination antiretroviral-treated HIV-positive individuals: potential impact on HIV sensory polyneuropathy. AIDS. 2011; 25:F1-F6.

(18.) Romero-Velez G, Lisker-Cervantes A, Villeda-Sandoval CI, et al. Erectile dysfunction among HIV patients undergoing highly active antiretroviral therapy: dyslipidemia as a main risk factor. Sex Med. 2014; 2:24-30.

(19.) Nduka C, Sarki A, Uthman O, Stranges S. Impact of antiretroviral therapy on serum lipoprotein levels and dyslipidemias: a systematic review and meta-analysis. Int J Cardiol. 2015; 199:307-318.

(20.) 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

(21.) Ucciferri C, Falasca K, Vignale F, Di Nicola M, Pizzigallo E, Vecchiet J. Improved metabolic profile after switch to darunavir/ritonavir in HIV positive patients previously on protease inhibitor therapy. J Med Virol. 2013; 85:755-759.

(22.) Overton ET, Arathoon E, Baraldi E, Tomaka F. Effect of darunavir on lipid profile in HIV-infected patients. HIV Clin Trials. 2012; 13: 256-270.

(23.) Vrouenraets SM, Wit FW, Fernandez Garcia E, et al. Randomized comparison of metabolic and renal effects of saquinavir/r or atazanavir/r plus tenofovir/emtricitabine in treatment-naive HIV-1-infected patients. HIV Med. 2011; 12:620-631.

(24.) Young J, Weber R, Rickenbach M, et al. Lipid profiles for antiretroviral-naive patients starting PI- and NNRTI-based therapy in the Swiss HIV Cohort Study. Antivir Ther 2005; 10:585-591.

(25.) Cahn PE, Gatell JM, Squires K, et al. Atazanavir--a once-daily HIV protease inhibitor that does not cause dyslipidemia in newly treated patients: results from two randomized clinical trials. JInt Assoc Physicians AIDS Care. 2004; 3:92-98.

(26.) Navarro J, Curran A. Profile of once-daily darunavir/cobicistat fixed-dose combination for the treatment of HIV/AIDS. HIV AIDS (Auckl). 2016; 8:175-182.

(27.) Xu L, Liu H, Murray BP, et al. Cobicistat (GS-9350): a potent and selective inhibitor of human CYP3A as a novel pharmacoenhancer. ACS Med Chem Lett. 2010; 1:209-213.

(28.) Janssen. Prezcobix prescribing information. https://www.prezcobixhcp.com/sites/www.prezcobix.com-hcp/files/prescribing-information-prezcobix.pdf

(29.) Bristol-Myers Squibb. Evotaz prescribing information. http://packageinserts.bms.com/pi/pi_evotaz.pdf

(30.) Quercia R, Roberts J, Martin-Carpenter L, Zala C. Comparative changes of lipid levels in treatment-naive, HIV-1-infected adults treated with dolutegravir vs. efavirenz, raltegravir, and ritonavir-boosted darunavir-based regimens over 48 weeks. Clin Drug Investig. 2015; 35:211-219.

(31.) Patel DA, Snedecor SJ, Tang WY, et al. 48-Week efficacy and safety of dolutegravir relative to commonly used third agents in treatmentnaive HIV-1-infected patients: a systematic review and network meta-analysis. PLoS One. 2014; 9:e105653.

(32.) Sension M, Deckx H. Lipid metabolism and lipodystrophy in HIV-1-infected patients: the role played by nonnucleoside reverse transcriptase inhibitors. AIDS Rev. 2015; 17:21-36.

(33.) Fisac C, Fumero E, Crespo M, et al. Metabolic benefits 24 months after replacing a protease inhibitor with abacavir, efavirenz or nevirapine. AIDS. 2005; 19:917-925.

(34.) Podzamczer D, Andrade-Villanueva J, Clotet B, et al. Lipid profiles for nevirapine vs. atazanavir/ritonavir, both combined with tenofovir disoproxil fumarate and emtricitabine over 48 weeks, in treatment-naive HIV-1-infected patients (the ARTEN study). HIV Med. 2011; 12:374-382.

(35.) Whayne TF, Mukherjee D. Medications not intended for treatment of dyslipidemias and with a variable effect on lipids. Curr Pharm Des. 2014; 20:6325-6338.

(36.) Tungsiripat M, Kitch D, Glesby MJ, et al. A pilot study to determine the impact on dyslipidemia of adding tenofovir to stable background antiretroviral therapy: ACTG 5206. AIDS. 2010; 24:1781-1784.

(37.) Sax PE, Zolopa A, Brar I, et al. Tenofovir alafenamide vs. tenofovir disoproxil fumarate in single tablet regimens for initial HIV-1 therapy: a randomized phase 2 study. J Acquir Immune Defic Syndr. 2014; 67:52-58.

(38.) Orkin C, DeJesus E, Ramgopal M, et al. Switching from tenofovir disoproxil fumarate to tenofovir alafenamide coformulated with rilpivirine and emtricitabine in virally suppressed adults with HIV-1 infection: a randomised, double-blind, multicentre, phase 3b, non-inferiority study. Lancet HIV. 2017; Mar 1; pii:S2352-3018(17)30031-0.

Caption: Figure 2. Research in people with HIV links abnormal lipids to cardiovascular disease, falling renal function, cognitive decline, sensory neuropathy, and perhaps erectile dysfunction. (Illustrations from Servier PowerPoint Image Bank, http://servier.com/ Powerpoint-image-bank.)
Table 1. Impact of currently favored antiretrovirals on lipids *

DHHS first-line status *          Lipid and CVD impact ([dagger])

Integrase inhibitors

Dolutegravir     Recommended      Few lipid effects (DHHS) (1)

Elvitegravir/c   Recommended      [up arrow] TG, [up arrow] LDL-C,
                                  [up arrow] HDL-C (DHHS)

Raltegravir      Recommended      Few lipid effects (DHHS)

Protease inhibitors

Atazanavir/r     Alternatiave     Fewer metabolic side effects than
or                                most other PIs (DHHS); rarely
atazanavir/c                      linked to dyslipidemia (HRSA)2

Darunavir/r      Recommended      Lipid changes similar to ATV/r in
                                  ACTG A5257 (DHHS); rarely linked
                                  to dyslipidemia (HRSA)

Lopinavir/r      Other            TTG vs ATV/r and DRV/r (DHHS)

Nonnucleosides

Efavirenz        Alternative      [up arrow] TG, [up arrow] LDL-C,
                                  [up arrow] HDL-C (DHHS)

Rilpivirine      Alternative      Linked to less dyslipidemia than
                                  EFV in randomized trials (DHHS)

Etravirine       Not              Product information lists
                 recommended      myocardial infarction,
                                  dyslipidemia as "less common
                                  adverse reactions"; grade 3 to 4
                                  lipid elevations reported in 10%
                                  or fewer ART-experienced patients

Nevirapine       Not              Better lipid profile than EFV. (3)
                 recommended

Nucleosides/nucleotides

Abacavir         Recommended      Tied to CVD and CV events in some
                 (with DTG/3TC)   but not all observational studies
                                  (DHHS); may [up arrow] TC, [up
                                  arrow] TG (HRSA)

Tenofovir        Recommended      Worse lipid profiles than TDF in
alafenamide                       randomized trials, but similar
(TAF)                             total-to-HDL-C ratio (DHHS)

Tenofovir        Recommended      Better lipid profiles than TAF in
disoproxil                        randomized trials (DHHS)
fumarate (TDF)

ART, antiretroviral therapy; ATV, atazanavir; c, cobicistat-boosted;
CV, cardiovascular; CVD, cardiovascular disease; DHHS, US Department
of Health and Human Services; DRV, darunavir; DTG, dolutegravir;
HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density
lipoprotein cholesterol; PI, protease inhibitor; r,
ritonavir-boosted; TC, total cholesterol; 3TC, lamivudine; TG,
triglycerides.

* Includes currently DHHS-favored first-line antiretrovirals (1) with
important lipid impacts.

([dagger]) Indicates advice from DHHS1 or HRSA. (2)

References for Table 1

(1.) DHHS Panel on Antiretroviral Guidelines for Adults and
Adolescents. Guidelines for the use of antiretroviral agents in
HIV-1-infected adults and adolescents. July 14, 2016.
https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent
-treatment-guidelines/0

(2.) HRSA: 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

(3.) van Leth F, Phanuphak P, Stroes E, et al. Nevirapine and
efavirenz elicit different changes in lipid profiles in
antiretroviral-therapynaive patients infected with HIV-1. PLoS Med.
2004; 1:e19.

http://journals.plos.org/plosmedicine/article/file?id=10.1371/
journal.pmed.0010019&type=printable

Table 2. Nonlipid drugs that elevate or lower lipids

Raise LDL-C

Frequently taken by people with HIV

* Glitazones
* Glucocorticoids
* Omega-3 fatty acids
(if containing docosahexaenoic acid)
* Thiazide diuretics

Others

* Amiodarone
* Anabolic steroids
* Danazol
* Fibric acids
* Immunosuppressive drugs (cyclosporine)
* Isotretinoin
* Some progestins

Raise triglycerides

Frequently taken by people with HIV

* Beta-blockers (especially non-beta 1 selective)
* Bile acid sequestrants
* Glucocorticoids
* Rosiglitazone

Others

* Atypical antipsychotic drugs
(fluperlapine, clozapine, olanzapine)
* Capecitabine
* Cyclophosphamide
* Estrogens, oral
* Immunosuppressive drugs
(cyclosporine, sirolimus)
* Interferon
* L-asparaginease
* Propofol
* Raloxifene
* Retinoids
* Rexinoids
* Tamoxifen
* Thiazide diuretics

Nonlipid drugs with lipid-lowering effects

* Angiotensin receptor blockers
* Doxazosin
* Orlistat
* Tenofovir disoproxil fumarate (TDF) but not tenofovir alafenamide
(TAF)

Sources: National Lipid Association, (10) Whayne TF,
Mukherjee D. (35)

Figure 1. Classic cardiovascular risk factors
had a bigger impact in preventing myocardial
infarction (MI) than did HIV-related
risk factors in an analysis of population-attributable
fraction (PAF) in a large HIV
population. PAF is the "proportion of MIs
that could be avoided in HIV-infected adults
if all were unexposed to the modifiable risk
factor of interest," if all other variables are
held constant. (9) (TC, total cholesterol; HTN;
hypertension; CD4 count <200 cells/[mm.sup.3];
HIV RNA >400 copies/mL.)

MIs averted by avoiding key risk factors

Classic risk factors

High TC    43%
HTN        41%
Smoking    38%

HIV risk factors

CD4 <200   10%
RNA >400   6%

Note: Table made from bar graph.
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Title Annotation:Perspectives
Author:Mascolini, Mark
Publication:Research Initiative/Treatment Action!
Article Type:Report
Date:Mar 22, 2017
Words:4718
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