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  21st Conference on Retroviruses and
Opportunistic Infections
Boston, MA March 3 - 6, 2014
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Low CD4/CD8 Ratio Predicts non-AIDS Illness in Large Italian Cohort
  CROI 2014, March 3-6, 2014, Boston
Mark Mascolini
Fewer than 15% of a 3000-person Italian cohort attained a normal CD4/CD8 ratio after reaching an undetectable viral load with antiretroviral therapy (ART) [1]. A low CD4/CD8 ratio predicted a serious non-AIDS event or death independently of CD4 count in this Icona cohort analysis.
The Icona investigators noted that CD4 count remains the most important predictor of clinical progression in people with HIV infection, but it does not consistently predict immune activation and non-AIDS illnesses [2]. In people without HIV, the Icona team observed, a CD4/CD8 ratio below 1 predicts immune senescence and all-cause mortality. In people with HIV, the CD4/CD8 ratio has been linked to T-cell activation, carotid intima-media thickness, arterial stiffness, estimated glomerular filtration rate, and muscle wasting. Previous research in antiretroviral-naive people with a CD4 count above 200 found that low CD4 percent and low CD4/CD8 ratio predict clinical progression [3].
To learn more about the predictive value of the CD4/CD8 ratio in people with HIV, the Icona investigators undertook this study. They aimed specifically to determine how many antiretroviral-treated people reached a normal ratio and whether the ratio affected risk of non-AIDS conditions or death from any cause.
Icona recruits antiretroviral-naive people and checks clinical and lab data every 4 months on average. This analysis included everyone who started their first ART combination after January 1, 1997, reached a confirmed viral load below 80 copies, and had a CD4/CD8 ratio at or below 0.8 when they had an undetectable viral load. The investigators defined progression as a serious non-AIDS event or death from any cause. Follow-up continued until a person had a confirmed normal CD4/CD8 ratio, had consecutive viral loads above 80 copies, died, or dropped out of care. Serious non-AIDS events included non-AIDS malignancy, severe non-AIDS infection, cardiovascular events, hepatic events, and acute kidney injury or failure.
The analysis included 3236 people who attained viral suppression with ART and had a CD4/CD8 ratio at or below 0.8. Three quarters of study participants were men, and median age stood at 39 years (interquartile range [IQR] 34 to 46). The largest proportion of people (41.4%) acquired HIV heterosexually, while 31.9% became infected during sex between men and 20.7% while injecting drugs. The group had HIV infection for a median of 2.6 years (IQR 0.7 to 7.4).
During 7305 person-years of follow-up, 458 people (14%) reached a CD4/CD8 ratio at or above 1 for an overall incidence of 6.3 per 100 person-years. Chances of attaining a normal ratio were 4.4% at 1 year, 11.5% at 2 years, and 29.4% at 5 years. Median time to a normal ratio was 10.1 years.
A multivariable Poisson regression model to identify factors associated with reaching a normal CD4/CD8 ratio adjusted for age, gender, HIV transmission mode, type of antiretroviral regimen, nucleoside pairs, HCV and HBV status, and an array of other factors. Every additional 10 years of age lowered chance of reaching a normal ratio 13% (adjusted rate ratio [aRR] 0.87, 95% confidence interval [CI] 0.78 to 0.98, P = 0.017). HIV transmission between men cut chances of reaching a normal ratio 25% compared with heterosexual transmission (aRR 0.75, 95% CI 0.58 to 0.98, P = 0.034). And having a nadir CD4 count below versus above 200 tapered chances 28% (aRR 0.72, 95% CI 0.56 to 0.94, P = 0.014).
During 14,926 person-years of follow-up, 93 cohort members (3%) died and 278 (9%) had a serious non-AIDS event. Incidence of a non-AIDS diagnosis or death was 4.8 per 100 person-years among people with a CD4/CD8 ratio below 0.30, 2.4 among those with a ratio between 0.30 and 0.45, and 2.0 among those with a ratio above 0.45.
Multivariable Poisson regression determined that every 100-cell higher current CD4 lowered chances of a serious non-AIDS diagnosis or death 6% (aRR 0.94, 95% CI 0.89 to 0.99, P < 0.013). When the regression model included both current CD4 count and current CD4/CD8 ratio, a ratio below 0.30 raised chances of a new non-AIDS diagnosis or death 64% when compared with a ratio above 0.45 (aRR 1.64, 95% CI 1.20 to 2.24, P = 0.002). A CD4/CD8 ratio between 0.30 and 0.45, compared with above 0.45, did not affect chances of progression in this analysis. Both models controlled for gender, HIV transmission mode, white race, and baseline age, HCV status, CDC stage, and HIV load.
The Icona team concluded that a low CD4/CD8 ratio despite viral suppression predicts serious non-AIDS events or death independently of CD4 count.].
1. Mussini C, Lorenzini P, Cozzi-Lepri A, et al. Incidence of CD4/CD8 ratio normalization and its role in the onset of non-AIDS-related events. CROI 2014. Conference on Retroviruses and Opportunistic Infections. March 3-6, 2014. Boston. Abstract 753.
2. Lucero T, Torres B, Leon A, et al. Rate and predictors of non-AIDS events in a cohort of HIV-infected patients with a CD4 T cell count above 500 cells/mm3. AIDS Res Hum Retroviruses. 2013;29:993-999.
3. Guiguet M, Kendjo E, Carcelain G, et al. CD4+ T-cell percentage is an independent predictor of clinical progression in AIDS-free antiretroviral-naive patients with CD4+ T-cell count >200 cells/mm3. Antivir Ther. 2009;14:451-457.