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CROI 2015: Cardiovascular Risk Factors for HIV-Positive People

Consistent with past research, an analysis from New York City has shown that people with HIV are at higher risk for death due to cardiovascular disease, although this risk is declining, according to a report at the recent 2015 Conference on Retroviruses and Opportunistic Infections (CROI). Several other studies looked at cardiovascular risk factors in this population, including inflammatory biomarkers, chronic kidney disease, gut bacteria, and use of abacavir.

Cardiovascular Mortality

Several previous observational studies have found that cardiovascular disease (CVD) and associated events such as heart attacks and strokes are more common among HIV-positive people compared to the HIV-negative general population. But the relationship between heart disease and HIV infection itself, inflammation and metabolic abnormalities, antiretroviral drug toxicities, and traditional risk factors such as smoking is not fully understood.

David Hanna from Albert Einstein College of Medicine and colleagues assessed changing CVD mortality rates among people with HIV in New Your City (abstract 729). The analysis included all HIV-positive people age 13 or older between 2001 and 2012, as reported to the New York City HIV Surveillance Registry. Surveillance data were linked with the city's Vital Statistics Registry and National Death Index to determine how many people with HIV died due to major CVD-related events.

The study included 145,009 HIV-positive people, who contributed nearly 1,227,000 total person-years of data; 71% were men and the median age was 49 years. Between 2001 and 2012, a total of 29,326 deaths occurred. Overall mortality declined over time, mostly due to fewer HIV/AIDS-related deaths.

During this period, about one-tenth of all deaths among people with HIV were attributed to major CVD events, including ischemic heart disease events such as myocardial infarction (42% of CVD deaths), hypertensive or high blood pressure disease (27%), and cerebrovascular events such as stroke (10%).

However, while the proportion of deaths due to CVD rose during this period from 7% to 13% -- because fewer people were dying of AIDS and other causes -- the actual cardiovascular mortality rate for people with HIV fell over time. Cardiovascular mortality in the general population declined as well, from 47% to 39%.

Overall, after adjusting for other factors including sex, race/ethnicity, and year, people with HIV had a 54% higher CVD death rate than HIV-negative people. CVD mortality was significantly higher for people with HIV in all age groups through age 65. Among older people, CVD mortality was similar or higher in the general population. While HIV-positive people with both detectable viral load and those with viral suppression had higher CVD death rates than HIV-negatives, those whose latest HIV RNA measurement was <400 copies/mL had a significantly lower rate than those with higher viral load (3.9 vs 7.7 per 1000 person-year, respectively).

"CVD deaths constitute an increasing share of deaths among HIV-diagnosed persons," the researchers concluded. "HIV care providers should emphasize preventive measures to reduce CVD risk such as smoking cessation, blood pressure control, and lipid management."

Inflammation and Gut Flora

In recent years there has been a growing emphasis on the detrimental effects of chronic inflammation and immune activation in people with HIV, even those with sustained viral suppression. As previously reported, this was the theme of a CROI plenary talk by Steven Grinspoon of Massachsuetts General Hospital and Harvard Medical School (abstract 134).

Inflammation and immune activation may result from low-level residual viral replication even in people with undetectable plasma viral load using standard clinical tests.

In an analysis of the large NA-ACCORD trial, Daniel Drozd from the University of Washington and colleagues (abstract 748) found that detectable HIV viral load, a history of AIDS-defining illness, and lower CD4 T-cell count were independent predictors of myocardial infarction, or heart attack. Similarly, Jorge Salinas from Emory University and colleagues (abstract 746) showed that cumulative HIV viremia and CD4 count over time -- not just at a single time-point -- predicted risk of myocardial infarction in the Veterans Aging Cohort Study.

Another potential trigger of inflammation is microbial translocation, or leakage of bacteria from the gut resulting from damage to the intestinal lining. Research has shown that this damage happens soon after HIV infection and may not be fully reversed even after starting effective antiretroviral therapy (ART).

Suman Srinivasa, a member of Grinspoon's team at Massachusetts General, and colleagues (abstract 138) prospectively compared therelationship between gut microbes and their metabolites in 155 HIV-positive and 67 HIV-negative people without known CVD at baseline. HIV-positive participants were relatively young (mean age 47 years), had been infected for 14 years and on ART for 8 years on average, and most had undetectable viral load.

HIV-positive people weresignificantly more likely than their HIV-negative counterparts to have coronary plaque (53% vs 35%), as well as higher plaque volume. Among people with HIV, but not those without, higher levels of serum trimethylamine (TMA) -- a microbe-derived precursor of trimethylamine N-oxide (TMAO), which plays a role in cholesterol metabolism -- were associated with more plaque and higher levels of lipopolysaccharide (a bacterial toxin). TMAO has previously been linked to CVD in the HIV-negative population.

Based on these findings, the researchers concluded, "Our data demonstrate that serum, not serum TMAO, is associated with the presence of calcified and total coronary plaque burden in HIV-infected patients," an association largely independent of traditional CVD risk factors.

Several other studies at CROI looked at biomarkers of inflammation and immune activation and their association with CVD in people with HIV.

Álvaro Borges and fellow investigators with the INSIGHT SMART and ESPRIT study groups (abstract 761) found that the pro-inflammatory cytokine interleukin 6 (IL-6) was a strong predictor of non-AIDS-related clinical events and deaths, and also of CVD, among HIV-positive participants in these 2 trials -- stronger, in fact, than C-reactive protein and D-dimer were in the earlier SMART study.

A related study by Denise Hsu fromthe National Institute of Allergy and Infectious Diseases and colleagues (abstract 752), looking at 149 HIV-positive patients on suppressive ART in the SCOPE cohort, saw a link between elevated IL-6 and carotid intimal thickness, indicating buildup of plaque in the arteries supplying the brain. Likewise, Dominic Chow from the University of Hawaii and colleagues (abstract 754) found that HIV-positive people on suppressive ART had elevated levels of non-classical monocytes (characterized by unusual CD cell-surface markers) and of the pro-inflammatory cytokine MCP-1, which were associated with progression of carotid intima-media thickening. 


Researchers from the National Institutes of Health (abstract 928) reported that artery plaque build-up was greater even in adolescents and young adults (age 15-29) infected with HIV early in life compared with age-matched HIV-negative people, and was associated with CD8 T-cell activation and elevated levels of the cell adhesion molecule E-selectin.

Chronic Kidney Disease

Two research groups reported findings from studies looking at the association between CVD and kidney disease in people with HIV -- a link that is well-established in the HIV-negative general population.

Lene Ryom from the University of Copenhagen and fellow investigators with theD:A:D study group (abstract 742) assessed nearly 35,000 HIV-positive D:A:D participants  who had at least 2 estimated glomerular filtration rate (eGFR) measurements, a marker of kidney function. Over a median follow-up period of 6 years, 1033 people experienced CVD events (myocardial infarction, stroke, or related surgical procedures) during follow-up, for a rate of 5.1 events per 1000 person-years.

They found a "clear relationship" between confirmed eGFR at baseline and incidence of CVD events. While just 1.7% of people with eGFR >90 mL/min/1.73m² progressed to CVD within 5 years, this rose to 23.4% of those with eGFR <30. While this was largely explained by age -- as older people are at higher risk for both kidney and heart disease -- a "strong trend" remained after adjusting for age, largely driven by a high CVD rate among people with eGFR <30.

"In a large contemporary cohort of HIV-positive individuals we observed a strong relationship between baseline and current confirmed impaired renal function and incident CVD," the researchers concluded. "These findings highlight the need for an intensified monitoring for all types of emerging CVD, in particular in older individuals with continuously low eGFR levels, and calls for an increased focus on applying different renal and cardiovascular preventive measures in HIV-positive individuals." 


Drozd and colleagues' analysis of more than 25,000 NA-ACCORD participants also saw a significant association between advanced chronic kidney disease (eGFR <30) and primary myocardial infarction.

What About Abacavir?

Frank Palella from Northwestern University and colleagues (abstract 749LB) presented findings another NA-ACCORD analysis looking at the association between heart attacks and use of abacavir (Ziagen, also in the Epzicom coformulation) -- a topic of ongoing debate as prior studies have produced conflicting results.

Looking at 16,733 HIV-positive adults in 7 U.S. cohorts, a total of 301 new myocardial infarctions occurred over more than 64,600 person-years of follow-up. Focusing on a subgroup of 6485 treatment-naive people starting ART that mirrored a previous D:A:D analysis, recent use of abacavir (within the past 6 months) was associated with a 71% adjusted increased risk of myocardial infarction -- approaching the nearly 2-fold risk seen in D:A:D.

However, a significant association was no longer apparent in an adjusted analysis of the full study population. Further, people who started an abacavir-containing ART regimen were more likely to have traditional and HIV-associated CVD risk factors, and the link between abacavir and myocardial infarction was diminished after taking these into account.

Traditional Risk Factors

Finally, traditional cardiovascular risk factors such as older age, smoking, abnormal blood lipid levels, diabetes, and obesity also play a role in people with HIV.

Perhaps stating the obvious, Drozd's NA-ACCORD analysis found that tobacco smoking was an independent risk factor for atherosclerosis, or build-up of plaque in arteries that can rupture and cause blockages in the heart (causing myocardial infarction) or brain (causing stroke).

A study by Sean Kelly and fellow investigators with the Multicenter AIDS Cohort Study (abstract 743) reported that cigarette smoking was the major independent risk factor for atherosclerosis. This analysis also found that HIV-positive gay and bisexual men in MACS were more likely to smoke than a group of similar at-risk HIV-negative men (31% vs 22%). Use of other substances, including alcohol and marijuana, had an inconsistent relationship with atherosclerosis.

"Our findings underscore the value of effective smoking cessation strategies targeting HIV+ persons to decrease cardiovascular disease burden," the researchers concluded.

Turning to management of elevated CVD risk, Sahera Dirajlal-Fargo from Case Western Reserve University School of Medicine and colleagues (abstract 745) looked at the relationship between physical activity and markers of cardiovascular and metabolic health and inflammation among people with HIV.

This analysis included 147 participants on ART (80% men, median age 46 years) in SATURN-HIV, a trial of rosuvastatin (Crestor) for people with HIV.They found that physical activity was significantly associated with several markers of cardio-metabolic health and inflammation. After adjusting for other factors, exercise remained independently associated with markers of cardiovascular disease including carotid intima-media thickness and endothelial function, as well as insulin resistance.

"[O]ver the 96 week study period, exercise was associated with multiple measures of subclinical vascular disease, suggesting that exercise in HIV-infected patients may improve vascular structure as well as function," the researchers concluded. "This association was evident even when accounting for statin use."

A large multicenter trial known as REPRIEVE is now underway to learn more about cardiovascular disease, its predictors and outcomes, and the benefits of statins for people with HIV.

SEE ALSO:

Predicting Cardiovascular Disease in People with HIV -- Can We Do Better?

Statins May Reduce Risk of Heart Disease in People with HIV

4/22/15

References

DB Hanna, C Ramaswamy, CP Kaplan, et al. Cardiovascular Disease Mortality Among HIV-Infected Persons, New York City, 2001-2012. 2015 Conference on Retroviruses and Opportunistic Infections. Seattle, February 23-24, 2015. Abstract 729.

SGrinspoon. Cardiovascular Disease in HIV Patients: An Emerging Paradigm and Call to Action. 2015 Conference on Retroviruses and Opportunistic Infections. Seattle, February 23-24, 2015. Abstract 134.

D Drozd, M Kitahata, S Heckbert, et al. Incidence and Risk of Myocardial Infarction (MI) by Type in the NA-ACCORD. 2015 Conference on Retroviruses and Opportunistic Infections. Seattle, February 23-24, 2015. Abstract 748.

J Salinas, V Marconi, D Rimland, et al. Cumulative HIV Care Measures Highly Associated With Acute Myocardial Infarction. 2015 Conference on Retroviruses and Opportunistic Infections. Seattle, February 23-24, 2015. Abstract 746.

S Srinivasa, V Fitch, J Lo, et al. Calcified Plaque Burden Is Associated With Serum Gut Microbiota-Generated TMA in HIV. 2015 Conference on Retroviruses and Opportunistic Infections. Seattle, February 23-24, 2015. Abstract 138.

AH Borges, JL O'Connor, AN Phillips, et al (INSIGHT SMART and ESPRIT Study Groups). IL-6 Is a Stronger Predictor of Clinical Events Than hsCRP or D-Dimer in HIV Disease. 2015 Conference on Retroviruses and Opportunistic Infections. Seattle, February 23-24, 2015. Abstract 761.

D Hsu, Z Hu, I Sereti, et al. IL-6 and CD8 Senescence Independently Associate With Atherosclerosis in Treated HIV. 2015 Conference on Retroviruses and Opportunistic Infections. Seattle, February 23-24, 2015. Abstract 752.

DC Chow, JM Kagihara, GG Zhang, et al. Non-Classical Monocytes Predict Progression of Carotid Intima-Media Thickness. 2015 Conference on Retroviruses and Opportunistic Infections. Seattle, February 23-24, 2015. Abstract 754.

JB Purdy, A Unsal, S Abd-Elmoniem, et al. T-Cell Activation and E-Selectin Associated With Coronary Plaque in HIV-Infected Youth. 2015 Conference on Retroviruses and Opportunistic Infections. Seattle, February 23-24, 2015. Abstract 928.

L Ryom, JD Lundgren, P Reiss, et al. (D:A:D Study Group). Relationship Between Confirmed eGFR and Cardiovascular Disease in HIV-Positive Persons. 2015 Conference on Retroviruses and Opportunistic Infections. Seattle, February 23-24, 2015. Abstract 742.

FJ Palella, KN Althoff, R Moore, et al. Abacavir Use and Risk for Myocardial Infarction in the NA-ACCORD. 2015 Conference on Retroviruses and Opportunistic Infections. Seattle, February 23-24, 2015. Abstract 749LB.

SG Kelly, M Plankey, W Post, FJ Palella, et al. Smoking, Other Substance Use and Coronary Atherosclerosis Among HIV-Infected and Uninfected Men. 2015 Conference on Retroviruses and Opportunistic Infections. Seattle, February 23-24, 2015. Abstract 743.

S Dirajlal-Fargo, AR Webel, B Kinley, et al. The Effect of Physical Activity on Cardiometabolic Health and Inflammation in HIV. 2015 Conference on Retroviruses and Opportunistic Infections. Seattle, February 23-24, 2015. Abstract 745.