Studies Look at Association between CD4 Cell Count and Cardiovascular Risk in People with HIV

By Liz Highleyman

Cardiovascular disease is a growing concern as HIV positive people live longer thanks to effective antiretroviral therapy. In addition to traditional risk factors such as advancing age, various studies have shown a link between increased heart disease risk and HIV infection or its treatment, but the mechanisms underlying these associations are not well understood.

Some observational studies have linked certain antiretroviral agents -- especially protease inhibitors (PIs) -- to coronary artery disease, in part attributable to the drugs' effect on blood lipids (cholesterol and triglycerides). Some experts once thought delaying or interrupting therapy might reduce this risk, but the large SMART study found that people who undertook CD4-guided treatment breaks and spent more time at lower CD4 cell counts had a higher rate not only of classic opportunistic infections, but also serious heart, liver, and kidney disease.

Two recent studies shed further light on the relationship between CD4 cell count and cardiovascular disease.

Study 1

In the first study, presented at the XVII International AIDS Conference this month in Mexico City, Kenneth Lichtenstein and colleagues evaluated 1697 participants in the HIV Outpatient Study (HOPS) who were actively followed after December 31 2001, had at least 2 visits, at least 2 blood pressure measurements, and at least 1 fasting lipid panel. Patients were followed until June 2007, death, or their last office visit.

The researchers calculated rates of incident (new) cardiovascular events, including myocardial infarction (heart attack), coronary artery disease, peripheral vascular disease, transient ischemic attack (temporary loss of blood flow to the brain), angina (chest pains), aortic aneurysm, coronary artery bypass surgery, or angioplasty.

Using Infectious Diseases Society of America (IDSA)/ACTG guidelines based on the National Cholesterol Education Program (NCEP), they categorized patients into 4 cardiovascular risk categories from low risk to highest risk, based on traditional risk factors such as age, family history, smoking, abnormal blood lipid levels, and high blood pressure.

They then looked at associations between cardiovascular risk group, injection drug use, baseline CD4 cell count, viral load, use of antiretroviral agents, and incident cardiovascular disease in a Cox proportional hazard model. With regard to antiretroviral therapy, they considered PIs; the "d-drugs" stavudine (d4T; Zerit), didanosine (ddI; Videx), and zalcitabine (ddC; Hivid - now discontinued); zidovudine (AZT; Retrovir); abacavir (Ziagen, also in the Epzicom and Trizivir combination pills); and HAART overall.

Results

• Of the 1697 HOPS participants analyzed, 557 (32.8%) had 0 or 1 risk factor (low risk).

• In patients with more than 2 risk factors:

• 470 (27.7%) had a 10-year cardiovascular risk < 10% (moderate risk);

• 322 (19.0%) had a risk of 10%-20% (borderline high risk);

• 348 (20.5%) had a risk > 20% (high risk).

• Cardiovascular disease incidence was 0.4 per 100 person-years in the low-risk group, rising to 1.0, 2.2, and 3.7, respectively, in the 3 higher-risk groups.

• The median number of years on nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), NNRTIs, PIs, zidovudine, abacavir, d-drugs, and HAART overall were not significantly different within each risk category.

• In a multivariate analysis, cardiovascular risk group and baseline CD4 cell count < 350 cells/mm3 were independently associated with incident cardiovascular disease (P < 0.05).

• Collectively, traditional risk factors were strongly linked to cardiovascular disease:

• Moderate risk group: hazard ratio (HR) 2.58 compared with low-risk group;

• Borderline high risk group: HR 6.01;

• High risk group: HR 10.20.

• Individual risk factors were also independently associated with cardiovascular disease, with 3 factors more than doubling the risk:

• Age over 42 years: HR 2.78;

• Male sex: HR 2.18;

• Smoking: HR 2.04.

• CD4 count < 350 cells/mm3 remained independently associated with incident cardiovascular disease after adjusting for individual traditional risk factors (HR 1.83).

National Jewish Health, Denver, CO; Cerner Corporation, Vienna, VA; Temple University, Philadelphia, PA; Northwestern University, Chicago, IL; Centers for Disease Control and Prevention, Atlanta, GA.

Study 2

In the second study, described in the August 20, 2008 issue of AIDS, investigators assessed the association between HIV infection, disease parameters (including CD4 cell count, HIV viral load, and AIDS diagnosis), and use of antiretroviral therapy with sub-clinical carotid artery atherosclerosis ("hardening" of the arteries due to build-up of plaque, inflammation, and loss of elasticity).

This cross-sectional sub-study involved participants in 2 large cohorts:

• Women's Interagency HIV Study (WIHS): 1331 HIV positive and 534 at-risk HIV negative women.

• Multicenter AIDS Cohort Study (MACS): 600 HIV positive and 325 HIV negative men.

The investigators used ultrasound to measure sub-clinical lesions of the carotid arteries in the neck that supply blood to the brain and common carotid artery intima-media thickness (a measure of the interior width of blood vessels). They then estimated adjusted mean carotid intima-media thickness differences and prevalence (hazard) ratios for carotid lesions associated with HIV-related disease and antiretroviral therapy, using multivariate analysis to control for confounding variables.

Results

• There were no significant differences between HIV positive and HIV negative individuals with regard to frequency of carotid lesions or intima-media thickness.

• Among HIV positive individuals, low CD4 cell count was independently associated with an increased prevalence of carotid lesions.

• Compared with HIV negative individuals, the adjusted hazard ratio for carotid lesions among HIV positive patients with a CD4 count < 200 cells/mm3 was 2.00 for women and 1.74 for men.

• In a multivariate analysis, the prevalence of carotid lesions increased by 70%-100% among HIV positive individuals with fewer than 200 cells/mm3 compared with HIV negative individuals.

• Carotid lesions and atherosclerosis were also associated with traditional risk factors such as older age, smoking, and elevated blood lipids.

• No consistent significant association was observed between antiretroviral therapy and carotid atherosclerosis.

• There was a borderline significant association between PI use and carotid lesions among men, but not among women.

• History of clinical AIDS and HIV viral load were not significantly associated with carotid atherosclerosis.

Based on these findings, the authors concluded, "Beyond traditional cardiovascular disease risk factors, low CD4+ T-cell count is the most robust risk factor for increased sub-clinical carotid atherosclerosis in HIV-infected women and men."

"These findings are consistent with prior evidence that low CD4+ T-cell count may increase the risk of cardiovascular diseases in HIV-infected populations," they wrote in their discussion.

However, they added, "Our data, based on a surrogate marker for cardiovascular diseases, provide little support for the conclusion that increased atherosclerotic vascular disease is associated with longer duration of protease inhibitor therapy."

Taken together, these studies provide further support for the recent shift toward earlier treatment before significant immune dysfunction develops, suggesting that the benefits of maintaining a high CD4 cell count and low viral load may extend well beyond avoidance of traditionally defined AIDS-related opportunistic illnesses.

Albert Einstein College of Medicine, New York, NY; University of Pittsburgh, Pittsburgh, PA; Johns Hopkins Bloomberg School of Public Health, Baltimore, MD; State University of New York Downstate Medical Center, Brooklyn, NY; University of California, San Francisco, CA; San Francisco Veterans Affairs Medical Center, San Francisco, CA; Keck School of Medicine, University of Southern California, Los Angeles, CA.

8/22/08

References

KA Lichtenstein, K Buckner, C Armon, and others. Low CD4 count is an important risk factor for cardiovascular disease in the HIV outpatient study (HOPS) in the U.S. XVII International AIDS Conference (AIDS 2008). Mexico City. August 3-8, 2008. Abstract THPE0236.

RC Kaplan, LA Kingsley, SJ Gange, and others. Low CD4+ T-cell count as a major atherosclerosis risk factor in HIV-infected women and men. AIDS 22(13): 1615-1624. August 20, 2008.

R Murphy and D Costagliola. Increased cardiovascular risk in HIV infection: drugs, virus and immunity. AIDS 22(13): 1625-1627. August 20, 2008.