Immunologic Biomarkers, Morbidity, and Mortality in Treated HIV Infection

Abstract

Despite marked improvements in the modern treatment era, human immunodeficiency virus (HIV)-infected individuals, particularly those who initiated antiretroviral therapy (ART) at advanced disease stages, continue to have increased age-related morbidity and mortality, compared with the general population. Immune activation and inflammation persist despite suppressive ART and predict many of these morbidities. The goal of this review is to examine the evidence suggesting a link between the persistent inflammatory state and morbidity and mortality in this setting, to describe the impact of early ART initiation on these factors, and to highlight important unanswered questions for the field. We also advance a hypothesis to explain why some morbidities-and their root inflammatory drivers-may be prevented more than others by early ART initiation.

Keywords: HIV-1 infection; antiretroviral therapy; biomarkers; immune activation; inflammation; morbidity; mortality.

Figure 1.

The incidence of opportunistic infections (A) and cardiovascular events (B) from published Strategies for Management of Antiretroviral Therapy (SMART) and Strategic Timing of Antiretroviral Treatment (START) trials, according to the median pretherapy nadir CD4⁺ T-cell counts reported in each of the randomized groups from SMART and START Trials [, 51]. Abbreviation: ART, antiretroviral therapy.

Figure 2.

A theoretical model for the impact of nadir CD4⁺ T-cell count on the root drivers of immune activation in treated human immunodeficiency virus (HIV) infection and their disease manifestations is shown. While several putative drivers of persistent immune activation despite antiretroviral therapy (ART)–mediated viral suppression have been described (ie, HIV reservoirs in T cells and macrophages, microbial translocation, and cytomegalovirus [CMV] coinfection), not all of them are likely to be active in individuals who initiate ART at high nadir CD4⁺ T-cell counts (ie, very early disease stages), and many of them preferentially drive inflammation in distinct anatomic compartments. Consequently, both the root drivers of inflammation reflected by systemic biomarker measurements and the disease manifestations induced by inflammation are likely to vary on the basis of nadir CD4⁺ T-cell count.