Changing Burden of Opportunistic Infections in the New ART Era

Human immunodeficiency virus (HIV) remains a major global health challenge, characterized by progressive CD4⁺ T-cell depletion leading to opportunistic infections (OIs) and acquired immunodeficiency syndrome (AIDS). Despite widespread antiretroviral therapy (ART) coverage, significant disparities persist, particularly in resource-limited settings. This review critically appraises the evolving burden and spectrum of OIs in the pre- and post-ART eras.

A comprehensive literature search for this narrative review was conducted in PubMed, Embase, Web of Science, and Google Scholar using the most relevant keywords focused on epidemiological trends, clinical manifestations, and outcomes of OIs across ART eras, combined with the Boolean operator "AND". Studies published in English from inception through April 5, 2026, were included.

The pre-ART era was marked by a high incidence of severe, disseminated OIs. The advent of combination ART, particularly highly active ART (HAART), led to substantial immune restoration and a marked decline in the incidence and severity of most OIs. Notably, CMV disease, Kaposi's sarcoma, tuberculosis, and Pneumocystis pneumonia have significantly decreased in PLWH in the post-ART period. However, OIs persist in individuals with delayed diagnosis, poor adherence, or treatment failure. Additionally, the post-ART era has seen emerging challenges, including immune reconstitution inflammatory syndrome (IRIS), antimicrobial resistance, chronic viral co-infections, and a rising burden of non-AIDS-defining malignancies.

ART has transformed HIV into a chronic, manageable condition for most patients. Most studies show an ART-associated decline in the epidemiology of OIs in HIV, shifting the pattern from acute, life-threatening infections to a manageable chronic infectious condition, with or without immune-mediated complications such as IRIS. However, persistent inequities in ART access, late presentation, and incomplete immune recovery sustain the global burden of OIs.

Although ART has dramatically reduced OI-related morbidity and mortality, these infections remain a significant concern. Strengthening early diagnosis, ensuring universal ART access, and improving adherence are essential to further reduce the burden of HIV-associated OIs.