CVD in HIV patients

There was a recent Am Heart Assn scientific statement on the prevention/management of cardiovascular disease in people living with HIV (PLWH), see cad hiv controlled AHA statement circ2019 in dropbox, or DOI: 10.1161/CIR.0000000000000695).

Overview:

 -- those with HIV infection are at increased risk for a variety of non-infectious cardiovascular complications, including myocardial infarction, heart failure, stroke, and coronary artery disease, as well as pulmonary hypertension and sudden cardiac death.

-- This increase in cardiovascular diseases continues even in those with HIV viral suppression and high CD4 counts, controlling for the standard cardiovascular risk factors; however there is more cardiovascular disease in those with lower CD4 counts or unsuppressed HIV viral loads

-- the clinical issue here is that PLWH are living longer as HIV has become a chronic disease, but even though the incidence of cardiovascular complications is lower in PLWH who have suppressed viral loads, their absolute burden of cardiovascular disease related to HIV is still increased because of their anticipated longer lifespans

    -- a meta-analysis of 800,000 individuals with total 3.5 million person-years of follow-up found that the global burden of HIV-associated cardiovascular diseases tripled over the past 2 decades, accounting for 2.6 million disability-adjusted life-years annually

-- the relative risk of various cardiovascular diseases are typically in the 1.5 to 2-fold greater in PLWH

--Risk Factors

-- there is a complex interplay between the traditional cardiovascular risk factors, HIV-specific risk factors (chronic immune activation/inflammation), HIV therapy-related metabolic comorbidities, behavioral factors, and disparities in access to or receipt of care

    -- cardiovascular risk factors: PLWH have higher rates of dyslipidemia, metabolic disease, smoking, hypertension, and substance use

        -- of these risk factors, smoking is probably the most important modifiable one overall: smoking prevalence in PLWH from a 2009 assessment of a representative US sample was that 42% were current smokers and 20% former smokers. The population attributable fraction of MI associated with ever-smoking was 72% for PLWH vs 24% for the general population

    -- chronic immune activation/inflammation: many markers are abnormal in the setting of effectively treated HIV infection and do predict mortality, non-AIDS events, and CVD

        --e.g., IL-6 and soluble tumor necrosis factor receptors alpha-1 and alpha-2 may be associated with coronary atherosclerosis in HIV, as are elevated levels of inflammatory monocyte activation markers.

        --even elite controllers, those lucky ones who have undetectable viral loads without taking medications, have increased clinical cardiovascular events, as found in the multicenter AIDS cohort study

        -- switching HIV regimens from a PI-based one to an integrase inhibitor-based one does not reduce inflammatory markers

    -- metabolic disease: there are increased levels of insulin resistance and diabetes in those with HIV. PLWH with diabetes have a 2.4-fold increased risk of CHD events, though this study was in 2005 and a majority were on protease inhibitors, which may produce more dyslipidemia

        --the D:A:D study found that each year of cumulative PI use was associated with a 10% greater risk of MI, after adjusting for changes in cholesterol, including with ritovavir-boosted darunavir (which is perhaps the most frequently used PI now, with studies suggesting efficacy as dual therapy with dolutegravir)

        --and abacavir has been associated with MI in observational studies (abacavir is associated with endothelial dysfunction, vascular inflammation and platelet hyperactivity)

-- MI/stroke

    -- stroke: more than one third of strokes are related to intracranial ischemic arterial disease, and this may be related to the fact that HIV infection distorts the blood brain barrier, and HIV enters the brain early during infection

    -- there are limited data about long-term cardiovascular outcomes, given the relatively recent timeframe of HIV morphing into a controllable chronic disease. There are upcoming larger studies which should supply more rigorous information

    -- coronary CT angiography has revealed a greater prevalence of extensive noncalcified coronary plaques and coronary artery modeling, both of which predispose a plaque to rupture and leading to an acute coronary syndrome. Statins do seem to reduce this plaque volume. This means that CAC (coronary artery calcium scoring) measured by noncontrast CT scans will not detect these noncalcified plaques and may not therefore be as accurate a CAD predictor in PLWH as in the general population

--those PLWH people who achieve viral suppression and have low cardiovasc factor burden still have higher risk of MIs than people without HIV, particularly in women

-- Heart failure: there is >1.5 fold increased risk independent of having had a prior MI, both with preserved and reduced ejection fractions. This risk for heart failure is worse in those with HIV viremia and immune dysfunction, however even in those with controlled virus,  high CD4 counts and without other risk factors, there still is more heart failure than in uninfected individuals. Heart failure hospitalization and mortality seems to be higher in women. Abacavir in some studies, but not all, may be associated with increased heart failure risk; tenofovir has been associated with a lower heart failure risk. Of note, there have not been any specific studies on the efficacy of accepted heart failure treatment regimens in PLWH.

-- Pulmonary artery hypertension: increased risk despite effective HIV treatment

--atrial fib: there are some studies finding increased incidence of atrial fib in PLWH, there may be increased cardiac deaths, and atrial fib may be more prevalent in those with low CD4 count (though unclear what the relation is with viral load). But, as with many cardiovascular events, there have not been specific trials on cardiovascular therapies in PLWH, anticoagulation in atrial fibrillation (esp direct acting oral anticoagulants), or even the accuracy of the CHA2DS2-VASc and HAS-BLED scores; thrombolysis, etc

Commentary:

-- one study i came across (see hiv cad outcomes JAHA2014 in dropbox or doi: 10.1161/JAHA.114.000844), assessed 9764 PLWH (mean CD4 460, 77% with HIV RNA<500) with no history of CVD, 288 of whom developed a CVD event over 5 years; these 288 patients had biomarkers assessed on average 2.6 years before the CV event, finding:

    -- those with fatal vs nonfatal CVD, comparing highest vs lowest tertile of values:

        --IL-6: adjusted OR 2.62 (1.26-5.46)

        --D-dimer: aOR 2.70 (1.27-5.75)

        --hsCRP: aOR 1.55 (0.78-3.10), not statistically significant

    --all-cause mortality after a nonfatal CVD, associated with a doubling of the biomarker:

        --IL-6: adjusted OR1.85(1.25-2.72)

        --D-dimer: aOR 1.76 (1.17-2.66)

        --hsCRP: aOR 1.39 (1.08-1.78)

    --so, the odds of a fatal MI or a fatal outcome after a non-fatal MI increase as the inflammatory markers increase in PLWH (esp IL-6 and D-dimer)

-- in terms of other, non-cardiovasc outcomes with increased risk in PLWH with well-controlled HIV:

    -- a veterans study including 42K veterans found a decreased likelihood of cancer in those who had HIV viral suppression, but this was still significantly elevated compared to non-HIV infected veterans. And this included both the typical AIDS-defining cancers as well as non-AIDS-defining ones (see http://gmodestmedblogs.blogspot.com/2018/06/hiv-treatment-decreases-cancer-but.html )

    --other studies have found increases in AIDS, CVD, non-AIDS cancers and Grade 4 events (potentially life-threatening events), though in the latter case, only increased in those who had Grade 4 events that are considered to be related to chronic inflammation, and these events tracked with increased IL-6 and D-dimer levels in those with HIV and suppressed viral loads (see hiv other mortality JAIDS2018 in dropbox, or doi:10.1097/QAI.0000000000001554)

--one significant concern is that the standard cardiovasc risk prediction models in PLWH are not so accurate: the paper notes “CVD risk prediction models performed similarly overall, with apparent underestimation of CVD risk among PLWH”

 -- and, it seems that PLWH may not be getting full standard-of-care medicine:

    --as compared to uninfected people, secondary prevention in PLWH was associated with less high-intensity statin prescribing (15% vs 45%), with less LDL reduction 6 months after an acute CAD event

    --another study found lower rates of guideline-directed statin use (23.6% vs 35.8%)

    --also, in a 2017 Dutch study, 57% of PLWH did not meet guideline-recommended BP targets

    --aspirin use in those with CAD was similarly lower in PLWH: 52% vs 65%

So, there are a few important lessons from the above:

-- with the availability of our current highly effective HIV suppressive medications, increasing numbers of people are living longer and susceptible to the myriad of typical comorbidities associated with aging

-- optimizing therapy for HIV is important for decreasing cardiovascular morbidity and mortality

-- but there still is a residual increased risk of cardiovasc disease (as well as cancers, overall mortality)

-- therefore, we should work especially hard with PLWH in helping them correct their modifiable risk factors

-- and, though there are not studies so far showing the efficacy of statins in HIV-infected persons, it is reasonable to assume that statins are beneficial pending these studies (eg the ongoing REPRIEVE study), with the following notes:

    --as with all meds, it is important to make sure that the statin is free from significant drug-drug interactions with the HIV meds. The statins with typically the least interaction are pravastatin and pitavastatin, moderate interactions are with atorvastatin and rosuvastatin, and the most interactions with simvastatin and lovastatin

    --the residual increased cardiac risk is significant enough to me to be incorporated into our decision-analysis of when to start a statin and what the lipid goal should be, especially since, as noted by the above AHA document, all of the CV risk calculators underestimate the risk in PLWH. And, the increased risk of HIV, even if controlled, is in the ballpark of the increased risk from prediabetes and even diabetes itself in some studies (ie, I think we should be more vigorous in working with PLWH around the accepted lifestyle changes of weight loss/diet/exercise, and have a much lower threshold for starting statins).

--and, it is really important to decrease disparities in access to care, given that HIV infection itself, as well as the cohorts of people more often infected with it, may be stigmatized and face both structural and socioeconomic barriers to receiving optimal health care

geoff​

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