Biomarkers of mortality in adults and adolescents with advanced HIV in sub-Saharan Africa

Victor Riitho, Roisin Connon, Agnes Gwela, Josephine Namusanje, Ruth Nhema, Abraham Siika, Mutsa Bwakura-Dangarembizi, Victor Musiime, James A. Berkley, Alex J. Szubert, Diana M. Gibb, A. Sarah Walker, Nigel Klein and Andrew J. Prendergast ()
Additional contact information
Victor Riitho: Queen Mary University of London
Roisin Connon: MRC Clinical Trials Unit at UCL
Agnes Gwela: KEMRI-Wellcome Trust Research Programme
Josephine Namusanje: Joint Clinical Research Centre
Ruth Nhema: University of Zimbabwe
Abraham Siika: Moi University
Mutsa Bwakura-Dangarembizi: University of Zimbabwe
Victor Musiime: Joint Clinical Research Centre
James A. Berkley: KEMRI-Wellcome Trust Research Programme
Alex J. Szubert: MRC Clinical Trials Unit at UCL
Diana M. Gibb: MRC Clinical Trials Unit at UCL
A. Sarah Walker: MRC Clinical Trials Unit at UCL
Nigel Klein: University of Zimbabwe
Andrew J. Prendergast: Queen Mary University of London

Nature Communications, 2024, vol. 15, issue 1, 1-11

Abstract: Abstract One-third of people with HIV in sub-Saharan Africa start antiretroviral therapy (ART) with advanced disease. We investigated associations between immune biomarkers and mortality in participants with advanced HIV randomised to cotrimoxazole or enhanced antimicrobial prophylaxis in the Reduction of Early Mortality in HIV-Infected Adults and Children Starting Antiretroviral Therapy (REALITY) trial (ISRCTN43622374). Biomarkers were assayed using ELISA and Luminex. Associations between baseline values and all-cause 24-week mortality were analysed using Cox models, and for cause-specific mortality used Fine & Gray models, including prophylaxis randomisation, viral load, CD4, WHO stage, age, BMI, and site as covariates; and weighted according to inverse probability of selection into the substudy. Higher baseline CRP, IFN-γ, IL-6 and IP-10 were associated with higher all-cause mortality; and higher IL-23, IL-2 and RANTES with lower all-cause mortality. Associations varied by cause of death: tuberculosis-associated mortality was most strongly associated with higher CRP and sST2, and cryptococcosis-associated mortality with higher IL-4 and lower IL-8. Changes in I-FABP (p = 0.002), faecal alpha-1 antitrypsin (p = 0.01) and faecal myeloperoxidase (p = 0.005) between baseline and 4 weeks post-ART were greater in those receiving enhanced versus cotrimoxazole prophylaxis. Our findings highlight how the immune milieu shapes outcomes following ART initiation, and how adjunctive antimicrobials can modulate the gut environment in advanced HIV.

Date: 2024
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DOI: 10.1038/s41467-024-49317-7

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