Beyond Viral Suppression: Navigating Structural Barriers, Aging and Frailty, Drug Resistance, Therapeutic Innovations, and Reproductive Health Challenges in the Global HIV/AIDS Epidemic

HIV programs worldwide have achieved remarkable gains toward viral suppression, transforming HIV from a fatal illness into a chronic condition for many. Despite these successes, a substantial proportion of people living with HIV (PLWH) continue to face poor health outcomes that extend well beyond viral control. Persistent social determinants of health and structural barriers, including poverty, stigma, discrimination, and disrupted health systems, limit access to prevention, treatment, and retention in care. At the same time, demographic shifts have created new challenges, with more than half of PLWH in high-income countries now aged ≥50 years, facing accelerated aging, multi-morbidity, and neurocognitive decline. Emerging drug resistance, both pretreatment and transmitted, threatens the durability of existing regimens, particularly in low- and middle-income countries where routine resistance testing remains limited. In reproductive health, women of childbearing age remain disproportionately affected, with ongoing complexities around antiretroviral selection, adverse pregnancy outcomes, and the long-term health of HIV-exposed but uninfected (HEU) infants. This narrative review synthesizes evidence from peer-reviewed studies, global guidelines, and major clinical trials published up until September 2025 to explore these converging issues. By highlighting gaps and opportunities across aging, structural barriers to care, social determinants of health, therapeutic innovation, and reproductive health, we underscore the need for inclusive, multidisciplinary, and evidence-based HIV care models for the next decade.