Inflammation and micronutrient biomarkers predict clinical HIV treatment failure and incident active TB in HIV-infected adults: a case-control study

Rupak Shivakoti, Nikhil Gupte, Srikanth Tripathy, Selvamuthu Poongulali, Cecilia Kanyama, Sima Berendes, Sandra W. Cardoso, Breno R. Santos, Alberto La Rosa, Noluthando Mwelase, Sandy Pillay, Wadzanai Samaneka, Cynthia Riviere, Patcharaphan Sugandhavesa, Robert C. Bollinger, Ashwin Balagopal, Richard D. Semba, Parul Christian, Thomas B. Campbell, Amita Gupta, for the NWCS 319 and PEARLS Study Team

Various individual biomarkers of inflammation and micronutrient status, often correlated with each other, are associated with adverse treatment outcomes in human immunodeficiency virus (HIV)-infected adults. The objective of this study was to conduct exploratory factor analysis (EFA) on multiple inflammation and micronutrient biomarkers to identify biomarker groupings (factors) and determine their association with HIV clinical treatment failure (CTF) and incident active tuberculosis (TB). Within a multicountry randomized trial of antiretroviral therapy (ART) efficacy (PEARLS) among HIV-infected adults, we nested a case-control study (n = 290; 124 cases, 166 controls) to identify underlying factors, based on EFA of 23 baseline (pre-ART) biomarkers of inflammation and micronutrient status. The EFA biomarker groupings results were used in Cox proportional hazards models to study the association with CTF (primary analysis where cases were incident World Health Organization stage 3, 4 or death by 96 weeks of ART) or incident active TB (secondary analysis). In the primary analysis, based on eigenvalues> 1 in the EFA, three factors were extracted: (1) carotenoids), (2) other nutrients, and (3) inflammation. In multivariable-adjusted models, there was an increased hazard of CTF (adjusted hazard ratio (aHR) 1.47, 95% confidence interval (CI)1.17-1.84) per unit increase of inflammation factor score. In the secondary incident active TB case-control analysis, higher scores of the high carotenoids and low interleukin-18 factor was protective against incident active TB (aHR 0.48, 95% CI 0.26-0.87). Factors identified through EFA were associated with adverse outcomes in HIV-infected individuals. Strategies focused on reducing adverse HIV outcomes through therapeutic interventions that target the underlying factor (e.g., inflammation) rather than focusing on an individual observed biomarker might be more effective and warrant further investigation.