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Antiretroviral Therapy: From Heart Risk Factor to Heart Protector?

Summer 2013

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Table of Contents


Introduction

Abstract

Multiple studies indicate that certain antiretrovirals raise chances of cardiovascular morbidity and mortality. At the same time, diverse research indicates that combination antiretroviral therapy lowers cardiovascular risk. Studies addressing this question have been pooled in several systematic reviews and meta-analyses. One meta-analysis of recent observational studies determined that recent abacavir or protease inhibitor use approximately doubled chances of myocardial infarction. Every additional year of lopinavir or indinavir therapy also independently raised MI risk. A second meta-analysis determined that HIV-positive antiretroviral-naive people had a 60% higher risk of cardiovascular disease than did HIV-negative people, while antiretroviral-treated people had a doubled risk compared with the HIV-negative group. Antiretroviral-treated people had about a 50% higher cardiovascular disease risk than did treatment-naive HIV-positive people. This analysis could not factor in other cardiovascular risks, such as smoking, which may be more prevalent in people with HIV and have nothing to do with cART. In this second meta-analysis, each year of treatment with protease inhibitors, nucleoside reverse transcriptase inhibitors, or nonnucleoside reverse transcriptase inhibitors added to cardiovascular disease risk. Studies are divided on whether a lower viral load or higher CD4 count cuts cardiovascular risk.


In 2010 EuroSIDA investigators found that a lower CD4 count inflated chances of every non-AIDS event analyzed, except one -- cardiovascular disease.1 Bolstering their finding with results of two other studies,2,3 the EuroSIDA team noted "there is, to date, no strong evidence linking cardiovascular disease with immunodeficiency." But even as the EuroSIDA team steered their paper into print, a small army of other researchers was amassing data pointing in the opposite direction.

If a low CD4 count tips the scales toward cardiovascular disease, one would expect combination antiretroviral therapy (cART) to ease cardiovascular risk by boosting CD4 tallies -- and maybe via other mechanisms. Yet studies from the United States,4 France,5 and the international Data Collection on Adverse Events of Anti-HIV Drugs (DAD) Study Group2 from the early 2000s all implicated cART -- and specifically protease inhibitor (PI)-based cART -- in surging cardiovascular rates seen in people with HIV. Other research tied certain nucleoside reverse transcriptase inhibitors (NRTIs) to heart disease. Ten years later, however, the French team found evidence that a viral load above 50 copies/mL hiked the risk of myocardial infarction 50%.6

A stockpot of other data simmered throughout these years, as researchers refined their multivariate recipes. Sometimes data implicating cART in heart matters bubbled to the top; sometimes cART emerged as an essential ingredient of a heart-healthy recipe. So where are we today, in 2013? Does antiretroviral therapy inflate chances of cardiovascular morbidity and mortality? Or does cART help HIV-positive people trim their coronary risk? The answers to those two questions would be yes and yes.

The Department of Health and Human Services (DHHS) Panel on Antiretroviral Guidelines for Adults and Adolescents believes stavudine, zidovudine, abacavir, efavirenz, and all ritonavir-boosted PIs can send lipids awry and so pose a cardiovascular threat to people taking those drugs (see Table 2 in the first review article in this issue).7 Franck Boccara, an HIV cardiology expert at Saint Antoine University Hospital in Paris, and colleagues suggest "the 2 most important and recent observational cohorts8,9 with a sufficient duration of exposure to PIs showed that the duration of exposure was associated with an increased risk for MI."10

Yet suspending cART in the SMART treatment interruption trial hoisted hazards of cardiovascular events more than 50% compared with taking steady cART.3 And when AIDS Clinical Trials Group (ACTG) investigators randomized antiretroviral-naive people to NRTIs plus efavirenz, NRTIs plus lopinavir/ritonavir, or efavirenz plus lopinavir/ritonavir, they found that all three regimens rapidly improved endothelial function (measured as brachial artery flow-mediated dilation), and that improvement persisted through 24 weeks of follow-up.11 Only one factor appraised predicted improved arterial function -- viral suppression. (For details of this study, see below under the subhead "Low viral load: low cardiovascular risk (usually).")


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Cardio Meta-Analyses With (Slightly) Different Outcomes

When matters get this messy, who can resist a meta-analysis? But meta-analyses can get murky, too: Because they ask different questions, use different methods, and examine different studies, they can reach different conclusions. The earliest such effort -- already a decade old -- focused on 30 randomized double-blind trials involving the first four PIs: indinavir, ritonavir, saquinavir, and nelfinavir.12 Comparing trial participants who took a PI with those who took only NRTIs, these researchers found no higher MI risk with PIs (relative risk [RR] versus NRTIs 1.69, 95% confidence interval [CI] 0.54 to 7.48). The absolute difference in MI risk in PI takers was +0.77 per 1000 person-years, meaning an excess MI rate below 1 MI per 1000 people each year.

Three meta-analyses focused solely on abacavir,13-15 the NRTI famously yoked to higher MI risk in a DAD study.9,16 These three studies came from the FDA,13 the ACTG,14 and abacavir's maker, GlaxoSmith-Kline.15 None of them turned up any evidence that abacavir predisposes people to heart attacks.

A team from Stanford University offered the latest meta-analysis of cardiovascular risk with cART17 and compared their findings with those of the most comprehensive abacavir analysis13 and the early PI analysis.12 The Stanford group criticized both of these meta-analyses, noting they did not assess study quality or the likelihood of publication bias. These investigators winnowed a field of 1458 articles to 27 studies published through June 2011, only one of them a randomized controlled trial.

The Stanford researchers could combine data from only a handful of these studies for each of the risk profiles they explored.17 Two studies of cumulative exposure to NRTIs reached opposite conclusions on whether abacavir or didanosine magnifies MI risk, DAD saying those NRTIs did,9 the French national team saying they did not.8 Pooled analysis of two studies16,18 determined that abacavir use within the last 6 months almost doubled MI risk (RR 1.91, 95% CI 1.50 to 2.42) (Figure 1). Three studies of recent didanosine use8,16,19 could not be combined by meta-analysis, but together they indicated a "harmful association" between didanosine and MI risk. No studies yielded evidence that other NRTIs imperil heart health.


Figure 1. Meta-Analysis of PI and Abacavir Impact on MI Risk

Meta-Analysis of PI and Abacavir Impact on MI Risk

Meta-analysis of recent observational studies determined that recent abacavir or protease inhibitor (PI) use approximately doubled chances of myocardial infarction (MI).17 Every additional year of lopinavir or indinavir therapy also independently raised MI risk. (Risks for abacavir, lopinavir, and indinavir calculated as relative risk (RR); risk for recent PI use calculated as odds ratio (OR). See text for 95% confidence intervals.)


The Stanford team melded data from a DAD study9 and a French study8 to determine that every additional year of lopinavir use boosted MI chances more than 20% (RR 1.22, 95% CI 1.01 to 1.47) (Figure 1). Every additional year of indinavir use inflated MI chances a little more than 10% (RR 1.11, 95% 1.05 to 1.17). Another DAD analysis figured that every additional year of exposure to PIs as a class significantly raised MI risk.20 Combining three studies21-23 that calculated odds ratios for recent PI use, the Stanford statisticians reckoned a doubled MI risk with recent PI use (OR 2.13, 95% CI 1.06 to 4.28). Combining 6 studies21-26 by a different method, they confirmed a significantly higher MI risk with recent PI use (P = 0.003).

The Stanford group does a good job not only sifting through these hazards, odds, and oddities, but also explaining what they mean:17

  • Evidence from observational studies implicated both PIs and abacavir in myocardial infarction risk.
  • Evidence from randomized trials did not.
  • Randomized trials offer the least biased approach to reckoning cardiovascular risk.
  • But none of the clinical trials analyzed was designed for that purpose, and none lasted very long.
  • Observational studies include a much larger and more representative patient sample than clinical trials.
  • But observational studies are fraught with confounders that cannot be adjusted away by savvy statisticians.
  • Also, combining evidence from several studies is hard because the studies differ in design and analytical plan.

Keeping all those caveats in mind, the Stanford investigators "believe there is still uncertainty whether ART leads to increased cardiovascular risk, and if so, the magnitude of that risk."17 But the observational studies analyzed yield enough good data "to warrant further study in prospective studies designed to assess cardiovascular risk from ART."

People dissatisfied with "uncertainty" after all these numbers get crunched down to bite-sized portions can consult yet another meta-analysis of studies weighing cardiovascular risk with cART.27 Of course this second meta-analysis, by researchers at the University of New South Wales, catechizes mostly the same studies as the first meta-analysis,17 so the findings are largely concordant. But the Australian team asked some different questions and used somewhat different methods, so their findings do not perfectly mirror those of the Stanford team.

The Australian meta-analysis focused on 23 studies, including 2 randomized trials, published before August 2010.27 Unlike the Stanford group,17 the Australian investigators combined studies with different risk metrics (odds ratios, relative risks, or hazard ratios). While myocardial infarction was the outcome in the Stanford study, the main Australian outcome was "cardiovascular disease," meaning coronary artery atherosclerosis. Whereas both groups assessed the impact of individual antiretrovirals and antiretroviral classes, the Australians also compared outcomes in antiretroviral-naive people, antiretroviral-treated people, and HIV-negative people. In that analysis, the antiretroviral-naive group had about a 60% higher cardiovascular disease risk than people without HIV (RR 1.61, 95% CI 1.42 to 1.83) and antiretroviral-treated people had a doubled risk (RR 2.00, 95% CI 1.70 to 2.37). cART-treated people had about a 50% higher cardiovascular disease risk than treatment-naive HIV-positive people (RR 1.52, 95% CI 1.35 to 1.70). Notably, though, this analysis could not factor in other cardiovascular risks, such as smoking, which may be more prevalent in people with HIV and have nothing to do with cART.

In the Australian meta-analysis, every added year of PI therapy upped the cardiovascular disease risk 11% (RR 1.11, 95% CI 1.05 to 1.17)27 (Figure 2), about the same as each year of lopinavir therapy jacked MI risk in the Stanford inquest17 (Figure 1). Each year of NRTI therapy boosted cardiovascular disease risk 4%, a relative risk just beyond the confines of statistical significance (RR 1.04, 95% CI 0.99 to 1.09). Each year of nonnucleoside therapy budged cardiovascular risk 5%, a statistically significant impact (RR 1.05, 95% CI 1.01 to 1.10). DAD saw the same per-year MI risk with NNRTIs, but the association stopped short of statistical significance: relative rate 1.05, 95% CI 0.98 to 1.33.)20


Figure 2. Meta-Analysis of CVD Risk With Each Year of Treatment

Meta-Analysis of CVD Risk With Each Year of Treatment

Meta-analysis of studies assessing cardiovascular disease (CVD) risk in antiretroviral-treated people found that each year of treatment with a protease inhibitor (PI), lopinavir (LPV), a nucleoside reverse transcriptase inhibitor (NRTI), abacavir (ABC), or a nonnucleoside reverse transcriptase inhibitor (NNRTI) raised that risk.27 The association with NRTIs fell just short of statistical significance. See text for 95% confidence intervals.


Every year taking lopinavir inflated chances of cardiovascular disease 19% (RR 1.19, 95% CI 1.03 to 1.39), and each year of abacavir boosted chances 5% (RR 1.05, 95% CI 1.02 to 1.16).27 The lopinavir and abacavir risks of cardiovascular disease diverge from the lopinavir- and abacavir-linked MI risks in the Stanford study17 (Figure 1). In the Australian analysis, people who took a PI regimen ran about a 40% higher risk of cardiovascular disease than people taking a non-PI combo (RR 1.41, 95% CI 1.21 to 1.65).

The Australian team stresses that cART has improved the "quality and length of life" in people with HIV.27 And "it is possible," they caution, "that the use of ART increases life expectancy and hence increases the average age of those taking ART in comparison to the reference group, which may lead to confounding of results."

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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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