Enteropathogen detection and early mortality among people with advanced HIV disease in sub-Saharan Africa

One-third of people with HIV in sub-Saharan Africa initiate treatment with advanced HIV disease, with high associated mortality. Whether enteropathogens and intestinal inflammation contribute to mortality remains unclear. We leveraged participant samples from the Reduction of Early Mortality in HIV-infected Adults and Children Starting Antiretroviral Therapy (REALITY) trial (ISRCTN43622374) to investigate associations between enteropathogens (assayed by multiplex nucleic acid detection), immune biomarkers (assayed by ELISA and Luminex) and mortality, and to explore the mechanism by which an enhanced prophylaxis bundle (containing albendazole, azithromycin, fluconazole, and isoniazid/pyridoxine) significantly reduced mortality. Cox models were adjusted for age, sex, CD4, WHO stage, viral load, BMI, site, and biomarkers. In 265 participants initiating treatment with median CD4 36 cells/ml, we found extensive sub-clinical enteropathogen carriage and frequent co-infection. Enteropathogens had differential associations with gut biomarkers and mortality. Clostridium difficile was associated with elevated faecal neopterin and higher mortality (adjusted hazard ratio (aHR)=3.78, 95%CI 1.31-10.93; P=0.014) while Giardia was associated with lower faecal myeloperoxidase and reduced mortality (aHR=0.20, 95%CI 0.07-0.60; P=0.004). Enhanced antimicrobial prophylaxis reduced Shigella . Our findings highlight the interactions between sub-clinical pathogens, enteropathy and immunosuppression. The effects of azithromycin on the intestinal milieu may confer mortality benefits in people with advanced HIV disease.