Microbial translocation predicts disease progression of HIV-infected antiretroviral-naive patients with high CD4+ cell count

Objectives: We investigated the significance of microbial translocation measured on average 3 years after HIV seroconversion in driving disease progression in HIV(+) untreated patients with high CD4(+) cell count. Design: We included ICONA patients with documented last HIV-negative and first HIV-positive test, at least one plasma sample stored while antiretroviral therapy (ART)-naive and CD4(+) cell count greater than 200 cells/mu l. Methods: Microbial translocation [lipopolysaccharide (LPS), sCD14 and EndoCAb] and immune activation (IL-6 and TNF-alpha) were measured. Correlation between immune activation, microbial translocation, CD4(+) and plasma HIV-RNA was evaluated by linear regression and nonparametric Spearman's rho. The independent predictive value of these markers on time to progression to the combined endpoint of AIDS, death, CD4(+) cell count less than 200 cells/mu l or start of antiretroviral therapy (ART) was assessed using survival analysis. Results: We analysed 1488 biomarker measures from 379 patients. A median of 3.1 years after the estimated seroconversion date [interquartile range (IQR) 1.6-5.4], median (IQR) markers values were LPS, 110 pg/ml (IQR 75-215), sCD14, 3.3 mu g/ml (2.2-4.8), IL-6, 1.1 pg/ml (0.6-1.9) and TNF-alpha, 2.4 pg/ml (1.8-3.4). Two hundred and sixty progression events were recorded over a median of 1.6 years from the first sample (2% AIDS, 84% ART initiation, 12% CD4(+) cell count less than 200 cells/mu l and 2% death). LPS was the only biomarker associated with this primary composite outcome independently of age, HIV-RNA and CD4(+) (relative hazard = 1.40 per log(e) higher, 95% confidence interval 1.18-1.66, P<0.001). Conclusion: Circulating LPS in the first years of chronic HIV infection is a strong predictor of disease progression independent of CD4(+) cell count and HIV viraemia and may be considered a candidate biomarker for HIV monitoring and evaluation in clinical trials.