The COVID-19 pandemic has contributed to more than 7 million deaths globally and has triggered a variety of postacute sequelae, now commonly referred to as long COVID, in millions more. Early efforts during the pandemic resulted in several therapies to mitigate the severity and mortality of acute COVID-19. However, despite effective therapies and accumulated immunity through vaccination and natural infection reducing disease severity, COVID-19 continues to contribute to hospitalizations and mortality. Long COVID encompasses several distinct yet overlapping clinical syndromes, and evidence suggests that these manifestations are mediated by numerous underlying mechanisms. There are currently no approved therapies for the treatment of long COVID, driven in part by its heterogeneity in presentation and etiology. This review will outline the current guidelines for treating acute COVID-19 and summarize information on the mechanistic rationale behind various published and ongoing clinical trials investigating potential long COVID therapeutic agents.
Islatravir (ISL; MK-8591; 4'-ethynyl-2-fluoro-2'-deoxyadenosine; EFdA) is the first antiviral drug that acts as a nucleoside reverse transcriptase translocation inhibitor (NRTTI). Unlike classic nucleoside and nucleotide analogue reverse transcriptase inhibitors (nRTIs) that terminate viral DNA chain extension upon incorporation because they lack the 3'-hydroxyl group, ISL primarily interferes with reverse transcriptase (RT) translocation. After ISL-triphosphate (ISL-TP) is incorporated into viral DNA, RT has a reduced ability to shift along the template to effectively position the subsequent nucleotide for incorporation, thereby inhibiting further DNA synthesis. In addition, ISL is frequently misincorporated by RT, leading to mismatched primer termini that further reduces productive DNA elongation. ISL has highly potent antiviral activity against both wildtype HIV-1 (50% effective concentration [EC₅₀], ∼0.07-0.20 nM) and a broad panel of nRTI-resistant clinical isolates in vitro. It is also active against HIV-2, with an EC50 on average 4.8-fold more potent than observed for HIV-1. In late 2025, a fixed-dose combination of the nonnucleoside reverse transcriptase inhibitor (NNRTI) doravirine (DOR) and ISL (DOR/ISL 100/0.25 mg once daily) was filed with the US Food and Drug Administration for therapy in adults with HIV who are virologically suppressed on their antiretroviral (ARV) regimens and have no known resistance to either drug. In parallel, a once-weekly oral regimen combining ISL with the capsid inhibitor lenacapavir is currently undergoing phase III clinical investigation as maintenance therapy for people with HIV-1 who are virologically suppressed. People with HIV who are expected to be eligible for combinations with ISL may have been previously exposed to ARV therapy or preexposure prophylaxis, during which resistance mutations may have emerged. In addition, some individuals may have acquired virus containing resistance mutations through the transmission of a resistant strain.
Antiretroviral therapy has transformed HIV into a chronic condition, resulting in a growing population of older people with HIV (PWH). This shift has been accompanied by an increased burden of age-related conditions, including frailty and sarcopenia, that compromise physical function and quality of life. Frailty and sarcopenia arise from complex biologic processes, many of which may be amplified in PWH. Recent conceptual advances emphasize intrinsic capacity (the composite of physical and mental capacities that determine functional ability) as a framework for understanding aging-related vulnerability. Emerging evidence suggests that social and structural determinants influence trajectories of intrinsic capacity and contribute to disparities in frailty risk. Geriatric-informed care models, including comprehensive geriatric assessment and the Integrated Care for Older People framework set forth by the World Health Organization, offer structured approaches to identify early declines in intrinsic capacity and guide individualized interventions. Exercise, nutrition optimization, and multidisciplinary care remain foundational strategies to mitigate frailty and sarcopenia, and emerging pharmacologic approaches targeting inflammation and metabolic dysfunction may influence aging trajectories. Integrating intrinsic capacity into HIV care may improve risk stratification and support interventions aimed at preserving function and healthy aging among PWH.
Obesity is a chronic, relapsing disease that is defended by complex biologic regulatory mechanisms, and is defined by excessive or abnormal adipose tissue that impairs health. Among people with HIV (PWH), the epidemiology of body weight has shifted dramatically in the modern antiretroviral therapy (ART) era, with obesity now replacing wasting and lipodystrophy as dominant body-composition phenotypes. Excess adiposity in PWH arises from overlapping influences: persistent immune activation, ART-specific effects on adipose tissue, and the same environmental factors driving the global obesity epidemic. The consequences include insulin resistance, dyslipidemia, cardiovascular disease, and fatty liver disease, which now constitute the leading causes of morbidity and mortality in this population. This review summarizes the pathophysiology, epidemiology, and management of obesity in PWH, emphasizing mechanisms that link ART exposure to altered adipose biology and metabolic risk. Effective care requires an integrated approach combining behavioral, pharmacologic, and procedural strategies within multidisciplinary HIV programs. Recognizing obesity as a chronic, treatable disease reframes management away from lifestyle blame toward durable metabolic control. In contemporary HIV care, the goal extends beyond viral suppression to encompass the prevention of cardiometabolic disease and preservation of long-term health.
