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Read Now: News and Research From IDWeek 2014

Cardiovascular Risk Factors With HIV Infection: A Long and Motley List

Summer 2013

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Whether and When to Treat Lofty Lipids

Like heart disease itself, aberrant lipids trouble a high fraction of all US residents, not just people with HIV. CDC head counters figure that one third of American adults have high LDL ("bad") cholesterol.26 That rate tops the 27% prevalence of high non-HDL cholesterol charted by HIV Outpatient Study (HOPS) investigators among US men in a survey of 3166 cART-treated men and women in care in 2006-2010.27 But 81% of these men had some sort of dyslipidemia, 41% had low HDL cholesterol, 32% had high triglycerides, and their median age was only 47. Among women in this study group, 67% had dyslipidemia of some sort, including 27% with low HDL cholesterol. More than half of these women had hypertension, 32% were obese, and their median age was only 45.

The HOPS study group had taken cART for a median of 6.8 years, and treatment almost certainly contributed to their bad lipid numbers. Current US antiretroviral guidelines list all ritonavir-boosted PIs, efavirenz, and abacavir (but not integrase inhibitors or the CCR5 antagonist maraviroc) as lipid mischief-makers (Table 2).17 But HIV itself, in antiretroviral-naive people, can send lipids off on wayward paths, boosting triglycerides and cutting HDL cholesterol.28 And studies comparing HIV-positive and negative groups consistently find worse lipid scores in people with HIV.2


Table 2. Antiretrovirals Linked to Abnormal Lipids
Nucleoside AnalogsNonnucleosidesProtease Inhibitors
Stavudine > zidovudine > abacavirEfavirenzAll ritonavir-boosted PIsLPV/r > DRV/r > ATV/r
↑ LDL and TG↑ TG, LDL, and HDL↑ LDL, HDL, and TG↑ TG

Source: Panel on Antiretroviral Guidelines for Adults and Adolescents.17

ATV, atazanavir; DRV, darunavir; HDL, high-density lipoprotein cholesterol; LDL, low-density lipoprotein cholesterol;

LPV, lopinavir; r, ritonavir; TG, triglycerides


Lofty triglycerides do heighten myocardial infarction risk in people with HIV, according to a 33,308-person DAD Study analysis.29 The DAD team figured that the overall impact of high triglycerides on MI risk is small -- though still independent of other factors -- when the analysis included those other factors.

This DAD analysis followed people enrolled in this European-American-Australian cohort at some point from 1999 through 2008. During 178,835 person-years of follow-up, the investigators recorded 580 MIs. Every triglyceride doubling upped the MI risk 67% in an unadjusted analysis. Layering on one statistical adjustment after another, the DAD team found that relative risk fell with each adjustment but remained independent of other risk factors:


MI risk per triglyceride doubling with HIV:

  • Unadjusted relative risk (RR): 1.67, 95% CI 1.54 to 1.80
  • Plus adjustment for latest total and HDL cholesterol: RR 1.33, 95% CI 1.21 to 1.45
  • Plus adjustment for other cardiovascular risk factors: RR 1.17, 95% CI 1.06 to 1.29
  • Plus adjustment for HIV and treatment risk factors: RR 1.11, 95% CI 1.01 to 1.23


Because the relative MI risk dwindled when the analysis considered other risk factors, the DAD team questions whether drugs that cut triglyceride levels would make a dent in MI incidence among people with HIV.29 These investigators note that European AIDS Clinical Society Guidelines do not recommend niacin or fibrates to treat high triglycerides in people with HIV.30 In a review of cardiovascular risk and capricious lipids in people with HIV, US cardiologist James Stein suggests high triglycerides should become a target of lipid-lowering therapy only if levels exceed 500 mg/dL, when pancreatitis poses a threat.31 (Stein's review, accessible online, is loaded with advice on managing dyslipidemia in people with HIV. He also addresses lipid control in the interview in this issue.)

Of course lipid values other than triglycerides sway MI risk. In the DAD analysis considering triglycerides, total cholesterol, and HDL cholesterol at the same time (second bullet above), every mmol/L (39 mg/dL) higher total cholesterol boosted MI risk 26% (RR 1.26, 95% CI 1.20 to 1.32, P < 0.001) and HDL cholesterol below 0.9 mmol/L (35 mg/dL) doubled the risk (RR 2.02, 95% CI 1.39 to 2.95, P < 0.001).29

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US HIV/heart guidelines from the HIV Medicine Association and allied groups are a decade old, but little has changed to affect bedrock management principles: measure fasting lipids before people start cART and within 3 to 6 months after starting a new combo.28 If changing diet, exercise, and smoking habits doesn't control lipids, start statins (that don't interact with prescribed antiretrovirals) for high LDL or non-HDL cholesterol and fibrates for lofty triglycerides. These guidelines are linked at reference 28 below.

In his 2012 lipid review, James Stein opines, "if there is a single take-home message about treating dyslipidemia to reduce [coronary heart disease] risk [in people with HIV], it is to put patients on statin therapy."31 Simply stated, Stein observes, statins saves lives: A meta-analysis of statins versus no statins in 160,000 people in the general population found that every 39-mg/dL (1 mmol/L) drop in LDL cholesterol with statins over 5 years trimmed all-cause mortality 10%, coronary heart disease (CHD) mortality 20%, MI and CHD mortality 26%, and major cardiovascular events 21%.32

Recent research links statin therapy to a higher risk of diabetes in the general population33,34 and in people with HIV.35 In all these studies the statin-related diabetes risk was small and apparently outweighed by the cardiovascular benefits of these drugs. Another recent study tied statin use to lower all-cause mortality in 25,884 people with cART-induced virologic suppression.36

How well do US clinicians follow lipid therapy guidelines in people with HIV? The report card features some high marks and some low marks, at least for clinicians seeing people in the HIV Outpatient Study cohort from 2002 through 2009.37 Among more than 1300 cohort members who had their 10-year cardiovascular risk figured, 28% had less than a 10% 10-year risk, 18% had a 10% to 20% risk, and 20% had a 10-year risk above 20%. Using National Cholesterol Education Program Adult Treatment Panel III (NCEP) guidelines as the standard, the HOPS team found that 81% to 87% of eligible patients got treated for high LDL/non-HDL cholesterol and 56% to 91% got prescriptions for high triglycerides. But only 2% to 11% took lipid drugs for low HDL cholesterol, and only 46% to 69% who needed anti-hypertensives got them. The investigators concluded that "a large percentage of at-risk patients who were eligible for pharmacologic treatment did not receive recommended interventions and did not reach recommended treatment goals."37


Rates and Impact of Hypertension and Diabetes

Abnormal lipids -- and what to do about them -- have preoccupied HIV clinicians and researchers since the first report of coronary artery disease in cART-treated people.1 But early on it became clear that flaring lipids are hardly the only heart worry in people with HIV -- and hardly the only trigger for vascular "events." Among classic cardiovascular risk factors, hypertension and diabetes represent two of the most treatable conditions.

The CDC estimates that one third of Americans have high blood pressure.38 An HIV Outpatient Study analysis logged even higher rates in US men and women with HIV.27 The 3166 people studied had a median age of 47 years and had taken cART for a median of 6.8 years; 21% were women and more than half smoked or used to smoke. Similar high proportions of women (57.4%) and men (54.4%) had hypertension. Almost one third of these women were obese.

Untreated or inadequately treated hypertension has a profound impact on morbidity and mortality (and not only cardiovascular mortality) in people with HIV. A DAD Study analysis of 33,308 HIV-positive cohort members figured that current hypertension doubled the risk of cardiovascular death (adjusted relative rate [aRR] 2.04, 95% CI 1.57 to 2.66) and more than doubled the risk of liver death (aRR 2.34, 95% CI 1.83 to 2.99).5 Hypertension also independently hoisted chances of all-cause mortality and AIDS mortality.

Meta-analysis of 2242 HIV-positive people in 11 studies determined that hypertension independently magnified the odds of left ventricular dysfunction almost as much as 10 years of age.39 The adjusted odds ratio for hypertension stood at 2.3 (95% CI 1.2 to 4.5), compared with 2.5 (95% CI 1.70 to 3.6) for every decade of age.

A Swiss HIV Cohort Study analysis of 2595 people with HIV and confirmed hypertension calculated that every 10 mm Hg higher systolic blood pressure boosted the risk of cardiovascular disease 18% (hazard ratio 1.18, 95% CI 1.06 to 1.32).40 "Insufficient control of hypertension was associated with increased risk for cardiovascular events," the Swiss team noted, "indicating the need for improved management of hypertension in HIV-infected individuals."

Diabetes affects 11.3% of US residents 20 years old or order, according to a 2011 CDC estimate.41 In contrast, big HIV cohort studies in Europe record much lower diabetes prevalence: 2.5% of 17,852 DAD Study members (from Europe, Australia, and Israel),42 2.7% of 8033 Swiss HIV Cohort Study participants,43 and 3% of 394 HIV-positive people at a London hospital.44

Compared with these European cohorts, US studies tabulate much higher diabetes prevalence in HIV-positive people -- perhaps reflecting the older age in these US groups than the European groups (Figure 4) and the high diabetes rate in the US population at large.41 A Multicenter AIDS Cohort Study (MACS) comparison of 534 men with HIV and 322 at-risk men without HIV charted an 11.4% diabetes prevalence in the HIV group and an 8.0% rate in the HIV-negative group, a nonsignificant difference (P = 0.16).45 But average age was significantly younger in the HIV group (48.9 versus 52.6, P < 0.0001).


Figure 4. Diabetes Prevalence in 3 European and 3 US HIV Cohorts

Diabetes Prevalence in 3 European and 3 US HIV Cohorts

Diabetes prevalence was much lower in three European HIV cohorts42-44 than in three US HIV cohorts45-47 or the US population at large.41 Younger age in the European groups than the US groups could partly explain the difference between cohorts, but US national data41 indicate that diabetes is highly prevalent throughout the US, at a rate of 11.3%. In comparison, Diabetes UK estimates that 2.5 million people in England had diabetes in 2012, or 4.7% of the 53 million people in England.48 (DAD data from Europe, Israel, Australia; SHCS, Swiss HIV Cohort Study; London, Chelsea and Westminster Hospital; MACS, Multicenter AIDS Cohort Study; VACS, Veterans Aging Cohort Study; WIHS, Women's Interagency HIV Study. Ages are medians, mean, or range [for USA]. USA national estimate from CDC.41)


A Veterans Aging Cohort Study of 3227 vets with HIV and 3240 without HIV found a significantly lower diabetes prevalence in the HIV group (14.9% versus 21.4%, P < 0.0001),46 though prevalence in this largely male HIV-positive contingent was higher than among HIV-positive men in the MACS analysis.45 Ages averaged 49.6 in the veterans HIV group and 50.8 in the HIV-negative group (P < 0.001). A recent Women's Interagency HIV Study (WIHS) survey logged a diabetes prevalence of 12.3% in 1797 women with HIV and 14.0% in 679 without HIV.47 These HIV-positive and negative women had median ages of only 39 and 35 and a collective body mass index in the overweight range.

Whether HIV and cART confer a higher diabetes risk remains open to question -- at least for men. MACS and WIHS studies from the mid-2000s differed in determining the impact of HIV on diabetes risk -- MACS findings a higher diabetes risk with HIV in men49 and WIHS finding no higher diabetes risk with HIV in women.50 The Veterans Aging Cohort Study discerned a lower diabetes prevalence with HIV than without HIV in a mostly male population.46

At least two factors contribute to these seemingly contradictory results -- what antiretrovirals people are taking and how the researchers define diabetes. For example, a nationwide French study of 1046 HIV-positive people charted a diabetes incidence of 14.1 per 1000 person-years.51 Incidence peaked in 1999-2000 at 23.2 and fell afterwards, a turnaround at least partly reflecting abandonment of indinavir, stavudine, and didanosine, all of which heightened diabetes risk in this analysis. CD4 count, CD4/CD8 ratio, and viral load did not affect diabetes risk, but traditional risk factors did (older age, overweight, and waist-to-hip ratio).

The French team defined diabetes by a confirmed high blood glucose and/or starting anti-diabetic medication.51 The two US studies that found a higher diabetes risk with than without HIV in men49 but not in women50 relied on a single blood glucose level (or anti-diabetic medication or a clinical diagnosis). The 97.5% male veterans study that discerned a lower diabetes risk with HIV relied on a confirmed high blood glucose (or other dual clinical criteria).46 And a Swiss HIV Cohort Study analysis, which used confirmed fasting glucose to define diabetes, observed similar age- and gender-specific diabetes incidence in HIV-positive cohort members and in a population-based cohort of HIV-negative people.52

When WIHS researchers updated their diabetes incidence analysis using multiple confirmed diagnostic criteria, they found an independently higher incident diabetes risk in HIV-positive women when diagnosis depended on a confirmed high blood glucose.47 HIV doubled the diabetes risk in these women after statistical adjustment for age, body mass index, and other variables. The WIHS investigators cautioned that relying on an unconfirmed blood glucose can result in an overestimate of diabetes incidence.

The Swiss study buttressed earlier work linking incident diabetes to nucleosides with or without protease inhibitors -- but not to nucleosides plus nonnucleosides.52 Among protease inhibitors the association held true for the first-generation protease inhibitor indinavir, but not for atazanavir or lopinavir. Three nucleoside combinations -- none used routinely today -- upped the risk of incident diabetes: didanosine/stavudine, stavudine/lamivudine, and didanosine/tenofovir. Reviewing all recent antiretroviral data, US guidelines list diabetes or insulin resistance as a side effect of three nucleosides (zidovudine, stavudine, and didanosine) and two protease inhibitors (indinavir and lopinavir/ritonavir).17

Regardless of whether HIV makes diabetes more likely in women, men, or both, no one doubts the potentially deadly impact of this chronic and often poorly controlled disease. The 33,308-person DAD study analysis that linked current hypertension to higher death rates from cardiovascular disease, liver disease, AIDS, and all causes also found that current diabetes independently raised the risk of death in those four categories.5

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This article was provided by The Center for AIDS. 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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