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Low CD4/CD8 Ratio Predicts Non-AIDS Morbidity, Mortality in ART Responders
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7th IAS Conference on HIV Pathogenesis, Treatment and Prevention, June 30-July 3, 2013, Kuala Lumpur
Mark Mascolini
A low CD4/CD8 ratio, indicating an unbalanced immune system, independently predicted non-AIDS morbidity and mortality in a case-control study involving more than 400 people responding well to antiretroviral therapy [1]. The association held true for each of the non-AIDS illnesses explored--ischemic heart disease, stroke, and non-AIDS cancer.
CD4/CD8 ratios sometimes fail to return to normal (about 2) despite rising CD4 counts during suppressive antiretroviral therapy. Persistently high levels of CD8 cells, which keep the ratio low, signal ongoing immune activation despite long-term viral suppression, as these investigators at Madrid's University Hospital Ramon y Cajal recently demonstrated [2]. Because chronic immune activation can drive potentially fatal non-AIDS conditions, they hypothesized that a low CD4/CD8 ratio can predict risk of serious non-AIDS illnesses and non-AIDS mortality in people with HIV.
To address that possibility, the Madrid team planned a case-control study in which cases were patients who took a suppressive antiretroviral regimen for at least 1 year and had a well-documented serious non-AIDS event--ischemic heart disease, stroke, or non-AIDS cancer. For each case the investigators selected three controls who were also good antiretroviral responders but did not have one of these non-AIDS diagnoses. The researchers used multivariate logistic regression analysis to probe for an association between non-AIDS events and CD4/CD8 ratio.
About 80% of study participants were men and about three quarters were former injection drug users. Case patients had taken ART for 10.5 years, versus 3.3 years in controls (P < 0.0001). Yet current CD4 count was significantly lower in cases than controls (368 versus 532, P = 0.005).
Median CD4/CD8 ratio was significantly lower in cases than controls for any non-AIDS event (0.44 versus 0.70, P < 0.0001) and for non-AIDS cancer (0.44, P = 0.016), Hodgkin lymphoma (0.41, P = 0.051), ischemic heart disease (0.48, P = 0.002), stroke (0.47, P = 0.045), and non-AIDS death (0.45, P = 0.021). Univariate analysis determined that people with a low CD4/CD8 ratio had more than 5 times higher odds of a non-AIDS diagnosis (odds ratio [OR] 5.4, 95% confidence interval [CI] 3.2 to 8.9).
To explore the power of the CD4/CD8 ratio, CD4 count, CD8 count, and nadir CD4 count to predict non-AIDS events, the researchers calculated the area under the curve (AUC) for each variable. The CD4/CD8 ratio had the highest AUC (0.720, 95% CI 0.662 to 0.777), significantly higher than AUCs for CD4 count, CD8 count, or nadir CD4 count (P < 0.001). A CD4/CD8 ratio of 0.4 proved the most accurate cutoff for predicting non-AIDS events.
Logistic regression analysis determined that a CD4/CD8 ratio below 0.4 raised the odds of non-AIDS morbidity 10 times (OR 10.3, 95% CI 5.0 to 21.1, P , 0.0001) and raised chances of non-AIDS mortality almost 13 times (OR 12.8, 95% CI 3.6 to 45.1, P < 0.0001). The association between low CD4/CD8 ratio and non-AIDS morbidity held true for people with a nadir CD4 count below 200 (OR 10.4, 95% CI 4.6 to 23.5, P < 0.0001), for those with a current CD4 count above 350 (OR 17.5, 95% CI 5.7 to 53.3, P < 0.0001), and for those with a current CD4 count above 500 (OR 14.5, 95% CI 2.8 to 73.9, P = 0.001).
The investigators concluded that "the CD4/CD8 ratio is a strong predictor of non-AIDS associated morbidity and mortality in treated HIV-infected patients" and that "this association is robust and maintained across subjects with low CD4 nadir or those with high CD4 counts."
A recent study of 78 middle-aged HIV-positive men with no history of coronary artery disease linked a lower CD4/CD8 ratio to number of plaque-bearing coronary artery segments and to plaque volume detected by computed tomography coronary angiography [3]. In this Boston study the relationship between CD4/CD8 ratio and plaque volume proved stronger than the association seen with CD4 count or viral load and plaque volume.
References
1. Serrano-Villar S, Perez-Elias MJ, Dronda F, et al. The CD4/CD8 ratio identifies treated HIV-infected subjects at increased risk of cardiovascular events and non-AIDS neoplasias. 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention, June 30-July 3, 2013, Kuala Lumpur. Abstract TUPE266.
2. Serrano-Villar S, Gutierrez C, Vallejo A, et al. The CD4/CD8 ratio in HIV-infected subjects is independently associated with T-cell activation despite long-term viral suppression. J Infect. 2013;66:57-66.
3. Lo J, Abbara S, Shturman L, et al. Increased prevalence of subclinical coronary atherosclerosis detected by coronary computed tomography angiography in HIV-infected men. AIDS. 2010;24:243-253.
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