Can Biomarkers Advance HIV Research and Care in the Antiretroviral Therapy Era?

Abstract

Despite achieving human immunodeficiency virus type 1 (HIV-1) RNA suppression below levels of detection and, for most, improved CD4+ T-cell counts, those aging with HIV experience excess low-level inflammation, hypercoagulability, and immune dysfunction (chronic inflammation), compared with demographically and behaviorally similar uninfected individuals. A host of biomarkers that are linked to chronic inflammation are also associated with HIV-associated non-AIDS-defining events, including cardiovascular disease, many forms of cancer, liver disease, renal disease, neurocognitive decline, and osteoporosis. Furthermore, chronic HIV infection may interact with long-term treatment toxicity and weight gain after ART initiation. These observations suggest that future biomarker-guided discovery and treatment may require attention to multiple biomarkers and, possibly, weighted indices. We are clinical trialists, epidemiologists, pragmatic trialists, and translational scientists. Together, we offer an operational definition of a biomarker and consider how biomarkers might facilitate progress along the translational pathway from therapeutic discovery to intervention trials and clinical management among people aging with or without HIV infection.

Keywords: Biomarker; HIV; index; inflammation; therapeutic discovery.

Figure 1.

Can we find the tree trunk? One might liken the optimal process for identifying therapeutic targets to cutting down a tree. One could attempt to identify targets in a piecemeal fashion by cutting off each individual “root” driver of the inflammatory state (eg, human immunodeficiency virus [HIV]–associated microbial translocation) or by cutting off each “branch” (eg, hypercoagulability). However, piecemeal approaches may fail to reverse pathology if all important “root” causes are not blunted and/or downstream pathways reversed. Identifying the “trunk”—a central pathway activated by all major drivers and giving rise to all parallel pathways—would be optimal. Applying systems biology and assessing multiple parallel inflammatory pathways in the context of trials of immune-based interventions may help identify promising central pathways. CMV, cytomegalovirus; IL-1β, interleukin 1β; IL-6, interleukin 6; sCD14, soluble CD14; sCD163, soluble CD163.