So what's the bottom line? No one suggests stopping or delaying or interrupting cART to trim the risk of heart disease, even in people with an otherwise foreboding risk profile. When US antiretroviral guideline writers began recommending cART for everyone with HIV, regardless of CD4 count, the first reason they listed is the higher risk of AIDS, cardiovascular disease, and other non-AIDS diseases with untreated infection or uncontrolled viremia.7
But what about avoiding or switching from PIs or abacavir in people with an otherwise high risk? Certainly one would not want to avoid all PIs when considering cardiovascular risk. A big DAD analysis sniffed out not a whiff of evidence that cumulative atazanavir treatment boosts MI or stroke risk.28
A comparable analysis has not weighed the impact of darunavir/ritonavir on cardiovascular risk. But a review of trials involving two NRTIs plus a ritonavir/boosted PI as first-line therapy found darunavir/ritonavir comparable to atazanavir/ritonavir in 48-week lipid readings, and superior to lopinavir/ritonavir or amprenavir/ritonavir in triglyceride or total cholesterol results.29 A 13-person study tracked lipids and cystatin C in people who switched from lopinavir/ritonavir or amprenavir/ritonavir to darunavir/ritonavir.30 Total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides all improved through 12 months of follow-up, as did cystatin C. (High levels of cystatin C have been linked to cardiovascular disease, kidney disease, and death.)
What about abacavir in people with a high background cardiovascular risk? US antiretroviral advisors demoted abacavir/lamivudine from a "preferred" to an "alternative" NRTI backbone7 because of some evidence indicating worse virologic outcomes with abacavir/lamivudine than with tenofovir/emtricitabine.31,32 But after reviewing studies of cardiovascular risk with abacavir, these experts concluded that "to date [in February 2013], no consensus on the association between abacavir use and MI risk or the mechanism for such an association has been reached."7
The DAD Study Group, whose two big analyses first turned the spotlight on abacavir as a possible MI risk factor,9,16 stressed in their later report that the overall MI rate in this population was low -- 3.2 events per 1000 person-years.9 In other words, 3 of 1000 people in the DAD cohort (0.3%) died of an MI every year. And "any toxicities of antiretroviral drugs must always be interpreted in the context of the benefits that these drugs provide," the DADmasters added.9
A team of top-drawer HIV researchers distilled HIV-related cardiovascular risk variables into a list of seven -- three that raise risk and four that lower risk (Figure 3).33 Antiretroviral therapy figures in most of these risk factors in one way or another. On the increased-risk side of the equation, cART can contribute to dyslipidemia, insulin resistance, and body shape changes. And because cART prolongs survival with HIV, it paradoxically favors the higher risk of cardiovascular death that comes with older age. On the decreased-risk side of the equation, all four factors involve cART.
Top HIV clinicians, cardiologists, and epidemiologists proposed this scheme summarizing the balance between decreased and increased cardiovascular risk in people with HIV.33 Most factors on both sides of the equation involve cART.
In an interview in this issue, the University of Wisconsin's James Stein stresses that viral suppression remains the overriding principle of antiretroviral. "As a cardiologist," he says, "I would never tell an HIV treater or a patient with HIV infection that they can't start an antiretroviral because it raises their heart disease risk so much that it will overshadow the risk of uncontrolled HIV infection." But if two drugs are good candidates for viral control and one carries some cardiovascular disease risk, he would opt for the antiretroviral with a cleaner cardiovascular risk profile in someone with an already high risk of cardiovascular disease.
Current US antiretroviral guidelines lean toward favoring cART-induced viral control as one way to cut cardiovascular risk, citing multiple lines of evidence suggesting "that early control of HIV replication with ART can be used as a strategy to reduce risk of CVD, particularly if drugs with potential cardiovascular toxicity are avoided."7 But no study demonstrates that cART prevents heart disease, these experts caution. And "for HIV-infected individuals with a significant risk of CVD, as assessed by medical history and established estimated risk calculations, risk of CVD should be taken into consideration when selecting a specific ART regimen."7
A well-planned cART regimen usually boosts CD4 tallies and curbs HIV replication. Abundant research addresses whether those responses directly affect cardiovascular risk. By and large the answer seems to be yes, though several key studies say no. Sorting out the reasons for these divergent results is tough, but close analysis offers some clues.
Recent French and US studies appraised the impact of viral replication on a clinical endpoint -- myocardial infarction,6,34 and a European-Canadian-Australian cohort study gauged the impact of viral load on cardiovascular death.35 A case-control study within the French Hospital Database on HIV determined that a viral load above 50 copies/mL upped chances of incident myocardial infarction 50%.6 This study involved 289 people with a new MI between January 2000 and December 2006, matched by age, sex, and clinical center to 884 HIV-positive people with no MI history.
Median age was 47 in people with an MI and 46 in those without an MI. A higher proportion of control patients had a body mass index in the overweight range, but otherwise classic cardiovascular risk factors were more prevalent in the case group, including current smoking (64% versus 40%, P = 0.028), family history of premature coronary artery disease (18% versus 7%, P < 0.001), hypertension (20% versus 12%, P = 0.001), current cocaine or injection drug use (13% versus 9%, P = 0.041), and diabetes (16% versus 10%, P = 0.036). Fasting glucose and lipid measurements were significantly worse in people who had an MI.
Statistical analysis that considered antiretroviral exposure, CD4 and CD8 counts, and a mélange of classic risk factors determined that a current viral load above 50 copies/mL (versus below) independently raised the odds of a new MI 51% (adjusted odds ratio 1.51, 95% CI 1.09 to 2.10). Cumulative exposure to PIs more than doubled MI odds in this analysis (adjusted odds ratio 2.23 per 10 years, 95% CI 1.17 to 4.24), but abacavir exposure did not.
A study of 6517 HIV-positive people in two tertiary-care Boston hospitals found links between higher viral load and incident MI in statistical models that did not include CD4 count, but not in the models that did factor in CD4 tallies.34 The Boston team checked records of HIV-positive people in care sometime between December 1998 and February 2008 to see how many suffered an acute MI. Age averaged 53.7 years in the 273 people who had an MI and 45.7 in the 6244 who did not. Women made up almost one third of the study group; 55% were white, 24% black, and 18% Hispanic. Half of these people smoked (55% with an MI and 50% without an MI). Classic cardiovascular risk factors were consistently more prevalent in the MI group.
Statistical analysis accounting for classic risk factors, antiretrovirals, CD4 count, and viral load determined that a load above 100,000 copies/mL predicted acute MI, but not significantly (adjusted odds ratio [aOR] 1.63, 95% CI 0.91 to 2.93, P = 0.10). In statistical models not including CD4 count, a higher viral load invariably altered odds of acute MI:
More HIV RNA may also inflate prospects of cardiovascular death, according to a 23-cohort European-Canadian-Australian CASCADE collaboration analysis involving 9858 people with an estimated date of HIV seroconversion.35 Compared with people whose viral load lay below 100,000 copies/mL while not on cART, those with a load above that level while not on cART had almost a 6 times higher risk of death from cardiovascular disease (adjusted hazard ratio 5.81, 95% CI 1.59 to 21.24) and those with a viral load above 100,000 copies/mL while on cART had almost a 5 times higher risk (adjusted hazard ratio 4.70, 95% CI 1.25 to 17.73). However, the study group included only 36 people who died from heart disease. And this analysis uncovered no link between CD4 count and death from cardiovascular disease.
Not all big studies tie viral load to cardiovascular disease or death. Two notable exceptions are the SMART study3 and a big DAD analysis.20 SMART randomized 5472 adults with a CD4 count above 350 cells/mm3 to continuous cART or to CD4 count-guided interruptions. During follow-up a major cardiovascular condition developed in 79 people, with more than a 50% higher risk in the interruption arm (hazard ratio 1.57, 95% CI 1.00 to 2.46, P = 0.05). With an expanded definition of major cardiovascular events, that risk reached statistical significance (hazard ratio 1.58, 95% CI 1.12 to 2.22, P = 0.009). But statistical analysis considering age, gender, use of anti-hypertensives, smoking, and total cholesterol found no evidence that being off cART at the time of the cardiovascular event or in the past 6 months made the event more likely. Every 10-fold higher most recent viral load also failed to implicate viral replication in incident cardiovascular events in several analyses.
People who interrupted cART during SMART had a worse total-to-high-density lipoprotein (HDL) cholesterol ratio than steadily treated people.3 That difference, the SMART team suggested, "could offer a partial explanation" for the higher cardiovascular event rate in the interruption arm. The researchers also acknowledged the hypothesis that inflammation kicked off by a "sudden burst of high level HIV replication" when a drug break began could trigger an MI or a stroke. Perhaps, the authors surmised, the trial did not measure viral load often enough to capture these viremic flares. Or maybe viral load simply is not a good way to measure inflammation and immune activation. The SMART team also suggested their analysis may have suffered from low statistical power because of the scant cardiovascular events recorded (79).
DAD investigators focused only on MIs,20 as the French6 and Boston34 studies did. The DAD team counted 345 MIs in 23,437 HIV-positive people monitored through February 2005 for an incidence of 3.65 per 1000 person-years. Median age at last follow-up was 43 years overall and 49 in people who had an MI. Three quarters of cohort members (78%) were white, and almost everyone (94%) had taken antiretrovirals. The DAD team found no link between peak viral load and MI risk (relative rate for each 10-fold higher peak viral load 1.06, 95% CI 0.95 to 1.18) or between CD4 count and MI risk (relative rate for each 50-cell higher count 0.98, 95% CI 0.95 to 1.01). But the investigators did not reckon the impact of other viral load measures on MI risk -- such as latest viral load or viral load at MI.
Why would a low viral load cut chances of cardiovascular disease or death? Uncontrolled viral replication means prodigious inflammation and immune activation, both of which threaten the heart and its vascular tributaries. But a subgroup analysis of an ACTG antiretroviral trial suggests another reason: endothelial function improves when cART curbs viral replication.11 ACTG investigators found that starting either a standard PI or NNRTI regimen -- or lopinavir plus efavirenz without NRTIs -- swiftly improved endothelial function reckoned as brachial artery flow-mediated dilation. This 82-person analysis charted significant improvements in flow-mediated dilation with all three regimens (Figure 4).
Combination antiretroviral therapy (cART) may lower the risk of cardiovascular disease by improving arterial endothelial function, measured as flow-mediated dilation, according to results of an ACTG trial substudy.11 Arteries must be able to dilate readily to generate an anticoagulant surface.36 (Illustration from Servier Medical Art.)
Study participants were young (median 35 years, interquartile range 30 to 40), and 91% were men.11 As in many HIV populations, a high percentage, 44%, smoked. Median body mass index just crossed the overweight threshold (25.1 kg/m2), but group blood pressure was good (119/74 mm Hg). Except for low HDL cholesterol, other lipid, glucose, and insulin values were within the normal range. The group had a median pre-cART CD4 count of 245 cells/mm3 and a median viral load around 66,000 copies/mL.
After 24 weeks of treatment, 67% of study participants had a viral load below 50 copies/mL and another 18% had between 50 and 100 copies/mL. After only 4 weeks of treatment, flow-mediated dilation rose (improved) 0.74% overall (IQR (-0.62% to +2.74%, P = 0.003), with no difference between study arms.
After 24 weeks of treatment flow-mediated dilation continued to improve in every study arm, increasing by 1.48% overall (IQR -0.20% to +4.30%, P < 0.001). Change in flow-mediated dilation from baseline to week 24 correlated with only two factors -- adiponectin and change in viral load. (Adiponectin is an adipocyte-specific protein that may play a role in insulin resistance and atherosclerosis.) The correlation with viral load was inverse (-0.30, P = 0.017), meaning the bigger the drop in viral load, the greater the improvement in endothelial function. The ACTG team suggests their findings support the hypothesis that controlling HIV replication improves endothelial function, but they note that follow-up was short and the study group young.
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