Background: Higher levels of inflammatory markers are often observed in HIV-positive individuals despite antiretroviral therapy (ART)-induced viral suppression, while some are strongly associated with mortality. We aimed to evaluate the association between markers of inflammation or immune activation and overall mortality in the ANRS Temprano trial conducted in Côte d''Ivoire. As the risk of mortality is increased in HIV-hepatitis B virus (HBV) co-infected patients, we also determined whether inflammatory markers mediate this association.
Methods: HIV-1-positive individuals enrolled in the trial and randomized to receive ART according to concomitant World Health Organization recommendations were included. Soluble markers of inflammation (sVCAM-1, sCD14, IP-10, IL-6, IL-1, fibrogen, CRP, CD163, albumin, D-dimer) were quantified at inclusion. Hepatitis B surface antigen (HBsAg) and HBV-DNA viral loads were also determined at inclusion. Cox proportional hazards models were used to assess the association between baseline marker levels and overall mortality.
Results: Of 1023 included patients, median age was 35 years (IQR=30-42) and 77% were female. At inclusion, median CD4+ T cell count was 459/mm3 (IQR=362-567) and HIV-RNA viral load 4.63 log10 copies/mL (IQR=3.96-5.21). 91 (9%) patients were HBsAg-positive. During a median follow-up of 58 months (IQR=40-69), 801 (78%) patients initiated ART and 49 deaths occurred. The only markers associated with mortality were higher CD163 (aHR=1.96, 95%CI=1.06-3.62) and lower albumin levels (aHR=0.51, 95%CI=0.29-0.90) after adjusting for age, gender, CD4+ cell count and HIV-RNA viral load. Median CD163 and albumin levels, respectively, were significantly different in HIV-HBV co-infected participants with HBV-DNA >10,000 copies/mL (1856 ng/mL, IQR=1399-2427 and 34.0 mg/L, IQR=30.0-40.0) compared to those with HIV-HBV co-infection and HBV-DNA ≤10,000 copies/mL (1552 ng/mL, IQR=1225-2096 and 36.6 mg/L, IQR=32.8-41.0) or HIV mono-infection (1518 ng/mL, IQR=1073-2129, and 36.9 mg/mL, IQR=32.5-41.7) (overall p=0.05 and p< 0.001). Of note, the significant association between HIV-HBV co-infected individuals with HBV-DNA >10,000 copies/mL and mortality (aHR=2.86, 95%CI=1.02-8.01) was attenuated when additionally adjusting for baseline CD163 and albumin levels (aHR=2.25, 95%CI=0.79-6.37).
Conclusions: CD163 and albumin levels are associated with overall mortality in HIV-infected individuals and appear to mediate the association between HIV-HBV co-infection with high HBV-DNA viral loads and mortality. The reasons for increased CD163, in particular, warrant further study.

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