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Lower CD4 Count Before ART Tied to Higher Risk of Three Non-AIDS Diseases
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18th Conference on Retroviruses and Opportunistic Infections, February 27-March 2, 2011, Boston
Mark Mascolini
A lower CD4 count before combination antiretroviral therapy (ART) began in the Dutch ATHENA cohort correlated with a higher risk of major cardiovascular disease, renal failure, and liver disease [1]. The link between CD4 count and these non-AIDS diagnoses was not as strong after therapy began, and viral load before or during treatment was not associated with non-AIDS disease risk.
Earlier research found that lower CD4 counts--and often the lowest-ever CD4 count--raise the risk of certain major non-AIDS diseases. Because antiretroviral side effects can confound such associations, ATHENA investigators set out to determine whether the association between CD4 counts, viral load, and heart, kidney, and liver disease before ART remains the same after therapy begins.
This analysis focused on 9777 people diagnosed with HIV after 1997 who had at least one CD4 count and viral load measured before starting ART. The ATHENA team considered new diagnoses of three non-AIDS diseases and a combined endpoint including all three diseases: cardiovascular disease (myocardial infarction, stroke, invasive coronary procedures), chronic renal failure (confirmed estimated glomerular filtration rate at or below 60 mL/min/1.73m(2) or a confirmed glomerular filtration rate drop of at least 25% if at or below 60 mL/min/1.73m(2) at baseline), and liver disease (cirrhosis, fibrosis, hepatocellular carcinoma).
Most study participants (79.1%) were men and more came from the Netherlands than from sub-Saharan Africa (56.1% versus 18.5%). While 32% never smoked, 43.7% were current or former smokers, and 24.4% had an unknown smoking status. Rates of HBV, HCV, diabetes, and alcohol abuse were all below 6%, and fewer than 10% had an AIDS diagnosis.
Median age at study entry stood at 37.1 (interquartile range [IQR] 30.2 to 44.3) and at 38.6 (IQR 31.8 to 45.9) when ART began. Median CD4 count at study entry was 350 (IQR 170 to 55) and median viral load 4.8 log (about 65,000 copies, IQR 4.1 to 5.2). Median CD4 count when ART began measured 215 (IQR 101 to 310) and median viral load 5.0 log (100,000 copies). Median follow-up before ART began was only 0.4 year (IQR 0.1 to 2.1), while median follow-up on ART was 3.5 years (IQR 1.5 to 6.6).
Partly because of the shorter follow-up before ART, incidence of non-AIDS diagnoses was lower then (0.52 per 100 person-years) than overall (1.12 per 100 person-years). Pre-ART incidence was especially low for cardiovascular disease (0.18 before ART versus 0.45 during) and renal failure (0.05 before ART versus 0.43 during).
Statistical analysis controlling for age, gender, diabetes, HBV or HCV coinfection, CDC stage of HIV infection, smoking, alcohol abuse, and hypertension found a significant association between a lower CD4 count and adjusted relative risk (ARR) of cardiovascular disease, liver disease, kidney failure, and overall non-AIDS diseases before ART began. These associations were weaker but still usually significant after ART began. (When the 95% confidence interval [CI] crosses 1.0, the association is not significant.)
Cardiovascular disease: ARR 0.53 (95% CI 0.35 to 0.80) before ART, 0.80 (95% CI 0.64 to 0.99) after ART
Liver disease: ARR 0.62 (95% CI 0.42 to 0.92) before ART, 0.85 (95% CI 0.64 to 1.12) after ART
Kidney failure: ARR 0.33 (95% CI 0.27 to 0.40) before ART, 0.42 (95% CI 0.36 to 0.50) after ART
Overall endpoint: ARR 0.40 (95% CI 0.35 to 0.47) before ART, 0.60 (95% CI 0.53 to 0.68) after ART
Compared with a viral load between 1000 and 100,000, a load above 100,000 or below 1000 did not affect relative risk of any of the non-AIDS conditions or of the combined conditions before or after ART began.
The ATHENA investigators concluded that lower CD4 counts are more strongly associated with a higher risk of these three non-AIDS diseases before ART begins than afterwards. "Despite more variation in [viral load] before combination ART," they noted, "there was no significant association with incidence of non-AIDS events," probably partly because of the low number of non-AIDS diagnoses before ART in this study group. The findings add to mounting evidence that low CD4 counts heighten the risk not only of AIDS diseases, but of serious non-AIDS complications.
Reference
1. Zhang S, van Sighem A, Gras I, et al. Initiation of cART for HIV infection and the risk of non-AIDS diseases. 18th Conference on Retroviruses and Opportunistic Infections. February 27-March 2, 2011. Boston. Abstract 791.
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