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.
Clinical pharmacology plays a crucial role in the successful treatment and prevention of HIV and other viral infections. Information from the field of clinical pharmacology leads to the development of novel antiviral treatments, supports the evaluation of efficacy and safety of antiviral therapies, informs the management of drug-drug interactions, and defines the optimal dosing and drug selection for special populations. The International Workshop on Clinical Pharmacology of HIV, Hepatitis, and Other Antiviral Drugs recently held its 26th meeting. This review focuses on selected abstracts presented at the 2025 workshop and provides insights to assist clinicians in applying this new knowledge to clinical practice.
Neurodivergence, including autism spectrum disorder (ASD) and attention-deficit/hyperactivity disorder (ADHD), is increasingly recognized as an important factor influencing health across the lifespan. Although ASD and ADHD are diagnosed categorically using standardized criteria based on the Diagnostic and Statistical Manual of Mental Disorders, the traits that define these conditions exist dimensionally across the population and are expressed with wide variability in support needs. Global ASD prevalence is approximately 1% to 2%, and emerging data suggest higher rates of autistic traits among some populations affected by HIV; however, estimates vary substantially based on methodology and diagnostic approach. ADHD affects approximately 2.5% of adults worldwide, although adult prevalence in people with HIV is not well characterized and likely underrecognized. Neurodevelopmental differences in executive function, reward processing, sensory regulation, and social communication may influence HIV acquisition risk, engagement in care, and long-term outcomes. Health care systems designed primarily for neurotypical individuals may inadvertently create barriers for neurodivergent patients. This review outlines a conceptual framework for understanding neurodivergence in the context of HIV, summarizes available epidemiologic and outcomes data, and provides practical strategies for delivering neurodiversity- affirming, accessible care.
The primary care clinician can play a substantial role in the management and prevention of viral hepatitis infections, which cause a substantial burden of hepatocellular carcinoma and cirrhosis worldwide and in the US. One-time hepatitis B and C virus testing is now recommended as part of universal adult screening measures, and more frequently based on risk factors. Immunization strategies for hepatitis A and B have also been updated, with a new adjuvanted, conjugated hepatitis B vaccine (HepB-CpG) that provides greater efficacy than older vaccines. Management of hepatitis B and C has been streamlined based on current tolerable, effective oral regimens that can reduce the individual's risks of liver fibrosis and cancer and interrupt the cycles of community transmission. The epidemiology and natural history of these viral infections are summarized and concise updates of screening, diagnosis, treatment, and prevention strategies are provided.
The National Clinician Consultation Center (NCCC) has operated for the past 30 years as a federally supported educational resource for US clinicians, addressing a wide range of questions regarding HIV and viral hepatitis care. Changes in practice spurred on by scientific breakthroughs and new research have led to new questions and challenges for HIV practitioners. These include optimal clinical and laboratory monitoring for people receiving postexposure prophylaxis, preexposure prophylaxis, or long-acting injectable antiretroviral therapy; evolving approaches to maternal and infant antiretroviral therapy for prevention of perinatal HIV transmission; and management of comorbidities such as hepatitis C and substance use disorders. Prevalent questions received by NCCC consultants over the last 5 years are described, high-lighting key areas of HIV medicine that clinicians and clinical educators commonly face in practice, as well as opportunities for future research to address areas of ongoing clinical uncertainty.
There has been a substantial increase in the prevalence of sexually transmitted infections (STIs) and a widening gap in health care disparities over the past decade. New technologies, emerging public health research, and growing antimicrobial resistance have changed how practitioners counsel patients and diagnose and manage common STIs. Updating practitioners' understanding of best care practices for patients with STIs is crucial in averting preventable morbidity and mortality. This review covers important changes in the screening, diagnosis, treatment, and prevention of common STIs over the past 5 years.
Modern antiretroviral therapy has led to a dramatic reduction in HIV-associated opportunistic infections and mortality, but late diagnosis of HIV and poor linkage to care persist and lead to a worse prognosis. HIV care is now focused on early therapy initiation and virologic control, and new practitioners may have less experience and fewer educational resources for diagnosis and management of opportunistic infections. In this special issue, we outline the clinical presentation, diagnosis, and management of opportunistic infections in the modern antiretroviral therapy era alongside clinical photography, radiographic findings, and microbiologic, endoscopic, pathologic, and retinal images.
Important new data were presented at the 2025 Conference on Retroviruses and Opportunistic Infections. Mathematic models predicted a reversal of progress toward Ending the HIV Epidemic metrics if funding is discontinued. Interventions that improved HIV care outcomes included a clinic-based, person-centered care intervention and a low-barrier care clinic service delivery model. Several studies demonstrated varying trends in hepatitis B and C incidence and outcomes, and data from one trial showed the seroprotective durability of the adjuvanted hepatitis B vaccine in people with HIV. Focus continued on long-acting antiretroviral therapy (ART) including data on promising new agents and formulations. Integrase strand transfer inhibitors (InSTIs) may be effective in the real world despite baseline reverse transcriptase resistance, although 2 studies highlighted the emergence of mutations outside the integrase genome that contribute to InSTI resistance. The data on HIV and maternal and pediatric health included studies aimed at HIV testing and counseling. It also covered drug interactions between implant and injectable hormonal contraceptives and dolutegravir-based ART, along with selected pharmacokinetics and safety data for ART in infants and children. Various abstracts addressed weight gain and cardiometabolic dysfunction in youth with perinatally acquired HIV and in women with HIV, as well as health outcomes for children exposed to HIV and ART in utero.
New research on acute and postacute COVID-19 was presented at the 2025 Conference on Retroviruses and Opportunistic Infections (CROI). Results of the SCORPIO-PEP (Stopping COVID-19 Progression With Early Protease Inhibitor Treatment-Postexposure Prophylaxis) study indicated that the protease inhibitor ensitrelvir is effective for postexposure prophylaxis. Results from the second phaseof the Ubuntu study suggested that monovalent or bivalent booster doses of mRNA vaccines are equally protective in people with or without HIV. A phase II study of an inhaled broad-spectrum antiviral small interfering RNA showed faster clearance of virus and more rapid resolution of symptoms with its use. In addition, numerous studies improved our understanding of the long-term consequences of SARS-CoV-2 infection, including immunologic, metabolic, cardiovascular, neurologic, and other clinical sequelae. The application of new and more specific case definitions in research studies of long COVID provided new insights into the epidemiology and pathogenesis of this condition, although data on therapeutics from randomized clinical trials are still lacking.
Aging-related comorbid conditions have major effects on health, quality of life, and survival in people with HIV (PWH). The 2025 Conference on Retroviruses and Opportunistic Infections (CROI) featured numerous studies about comorbid diseases in PWH. Cardiovascular diseases, including atherosclerosis and heart failure were important topics at the CROI, with ancillary analyses from REPRIEVE (the Randomized Trial to Prevent Vascular Events in HIV) and studies from lower- and middle-income countries. Numerous studies examined epigenetic markers of biologic aging in PWH and the effects of treatments, including glucagon-like peptide-1 receptor agonists. In a clinical trial, cytomegalovirus suppression was shown to decrease immune activation and systemic inflammation, as well as improve physical function. Large epidemiologic studies examining the effect of switching to integrase strand transfer inhibitors showed an increased risk of diabetes and hypertension, which was independent of weight gain. This review focuses on the abstracts presented at CROI 2025 in these areas, highlighting those with the most clinical impact.
The 2025 Conference on Retroviruses and Opportunistic Infections (CROI) in San Francisco maintained its existing format with a combination of plenary lectures, workshops, oral and poster abstract sessions, themed discussions, and interactive symposia to deliver the latest advances in HIV/AIDS research to the approximately 4000 delegates in attendance. The conference featured a comprehensive collection of presentations addressing the molecular biology of HIV-1, with the basic virology track offering mechanistic insights into viral replication, immune evasion, and host-pathogen interactions. CROI showcased a range of innovative approaches to decipher and target the latent reservoir. From high-resolution lineage tracking in nonhuman primates to dissection of chromatin landscapes and latency regulatory circuits, studies presented at this year's meeting underscored the complexity of HIV persistence and the need for multidimensional intervention strategies. Selected abstracts are high-lighted, emphasizing mechanistic insights, methodologic innovations, and therapeutic implications. As with prior renditions of the conference, CROI continues to set the standard for engagement of early career investigators. Sessions such as the Scott M. Hammer Workshop for New Investigators and Trainees provide an effective forum for orientation to the various thematic areas covered at CROI.
At the 2025 Conference on Retroviruses and Opportunistic Infections (CROI), investigators presented updates on the global HIV epidemic. Although new HIV infections have been declining globally, new infections are expanding in Eastern Europe and central Asia, the Middle East and North Africa, and Latin America. HIV incidence remains high among key populations and their partners. Initiation of oral preexposure prophylaxis (PrEP) is increasing globally, with 91% of PrEP starts funded by the US President's Emergency Plan for AIDS Relief, and large rises in new HIV infections are predicted to occur due to international funding cuts. Several presentations focused on strategies to increase HIV testing, including home HIV self-testing, couples HIV testing, and use of digital strategies. Substance use continues to be a driver of new HIV infections. Implementation of harm reduction and opiate agonist therapy significantly reduced new infections among people who inject drugs in Malaysia, and other person-centered approaches tailored for people who use drugs are being investigated. The uptake of PrEP has been increasing in a number of priority populations; however, persistence on oral PrEP remains sub-optimal. Although the use of long-acting injectable cabotegravir (CAB-LA) remains low in the US, several programs have demonstrated high persistence. When provided choice, many individuals choose CAB-LA over other available options, and adherence to follow-up injections has been high. Several interventions to increase PrEP uptake and adherence show promise, including pharmacy-based refills and incentives, point-of-care urine tenofovir testing with counseling, and use of mobile health tools. PrEP with emtricitabine/tenofovir alafenamide was shown to reduce HIV infections in cisgender women adherent to PrEP. A single once-yearly injection with lenacapavir showed promising pharmacokinetic results and a phase III trial is planned. Interest in doxycycline postexposure prophylaxis is high, and real-world implementation has been associated with significant declines in bacterial sexually transmitted infections.
The 2025 Conference on Retroviruses and Opportunistic Infections (CROI) showcased advances in understanding neuropsychiatric complications among people with HIV (PWH). This review synthesizes key findings related to central nervous system (CNS) reservoirs, neuropathogenesis, and biomarkers of brain health. Emerging data underscore the persistence of HIV in brain tissues despite antiretroviral therapy (ART), with compartmentalization occasionally observed in the spinal cord and brain, and evidence suggesting that HIV-infected cells may contribute to chronic inflammation in the CNS. Single-cell and epigenetic profiling of cerebrospinal fluid cells revealed immune dysregulation in myeloid and B cells, suggesting ongoing CNS dysfunction during suppressive ART. Longitudinal neuroimaging and cognitive studies reinforced that incomplete or unstable HIV suppression correlates with worse brain outcomes. Notably, higher blood phosphorylated tau 217 and systemic inflammation predicted cognitive decline in aging PWH. Promising therapeutic avenues included observations that glucagon-like peptide-1 receptor agonists, such as semaglutide, improve visuospatial performance in PWH and cannabinoid receptor 2 agonists reduced neuroinflammatory pathways in preclinical models. Additionally, early initiation of ART was associated with normalization of brain volumes and attenuation of neuronal injury markers. Together, these findings highlight the complexity of neuro-HIV interactions and underscore the need for targeted interventions to protect brain health in PWH.
Liver disease remains a key contributor to morbidity and mortality among people with HIV. Although substantial progress has been made in terms of a cure for hepatitis C, increased life expectancy is associated with emerging issues associated with steatotic liver disease. Hepatitis B and D are still prevalent and often underrecognized as a cause of indolent liver injury leading to inflammation and fibrosis. Barriers to care exist in many subpopulations that reduce the use of potentially lifesaving therapies. Hepatocellular carcinoma continues to be a factor in advanced hepatic fibrosis.
Updated strategies and new insights into tuberculosis and mpox treatment were a major focus at the 2025 Conference on Retroviruses and Opportunistic Infections, headlined by findings that high-dose rifampicin plus levofloxacin increased early mortality in hospitalized people with HIV with disseminated tuberculosis, whereas tecovirimat demonstrated no efficacy for clade II mpox. Herein, we summarize clinically relevant updates related to tuberculosis, mpox, Kaposi sarcoma, human papillomavirus, and other HIV-associated infectious complications presented at the conference.
Certain mutations in HIV-1 that emerge during exposure to antiretroviral drugs may have varied impact on the effectiveness of current and subsequent treatments for HIV. This 2025 edition of the International Antiviral Society-USA (IAS-USA) drug resistance mutations list updates the Figure last published in November 2022 based on new data that have become available. The mutations listed are those that have been identified by specific criteria to contribute to a reduced virologic response to currently available antiretroviral drugs. The Figure is designed to assist practitioners in identifying key mutations associated with resistance to antiretroviral drugs, and therefore, to consider when making clinical decisions regarding the components of an initial antiretroviral regimen and changing a regimen in the settings of avoiding toxicity, regimen simplification, or previous or current virologic failure.
Weight gain among persons with HIV PWH) on contemporary antiretroviral therapy (ART) can extend beyond an initial return-to-health phenomenon and lead to overweight/obesity in the first 1 to 2 years, resulting in enhanced cardiometabolic risk. Factors that may contribute to increased weight gain include specific ART regimens (those initiating dolutegravir and tenofovir alafenamide or withdrawing tenofovir disoproxil and efavirenz), women with HIV, and certain virologic factors including lower baseline CD4 count and higher HIV viral load. Weight reduction starting at 5% body weight confers metabolic protection, such as improved hypertension and dysglycemia. Even greater metabolic impact has been shown with weight reduction in the approximate range of 15% body weight, as evidenced by decreases in cardiovascular disease mortality. Effective weight management is essential to reducing cardiometabolic risk, may not be achieved with lifestyle changes alone, and requires other therapeutic strategies. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are well recognized to provide potent weight reduction among persons with overweight/obesity; in addition, studies have shown cardiovascular benefit among those with established cardiovascular disease. Recent studies have permitted us to begin to understand the potential role of GLP-1 RAs among PWH and overweight/obesity. This review highlights weight gain specific to PWH and discusses current evidence and key clinical considerations for GLP-1 RA use among PWH.
People with HIV (PWH) are living longer and experiencing a greater burden of morbidity from non-AIDS-defining conditions. Chronically treated HIV disease is associated with ongoing systemic inflammation that contributes to the development of chronic conditions (eg, cardiovascular disease) and geriatric syndromes (eg, frailty). Apart from HIV disease, a progressive increase in systemic inflammation is a characteristic feature of biologic aging, a process described as "inflammaging." Inflamm-aging is driven by persistent antigen stimulation and stress, leading to an immune profile characterized by elevated levels of blood inflammatory markers and cellular activation and senescence. Chronic HIV disease is hypothesized to accentuate the immune profile of inflamm-aging, in part through viral persistence in lymphatic tissues, permanent injury impairing immune recovery, the presence of copathogens, gut dysbiosis and microbial translocation, and chromosomal and genetic alterations associated with immune activation. Few strategies exist for safe and effective modulation of systemic inflammation among older PWH. The strongest current evidence supports aggressive management of modifiable risk factors such as lipids, blood pressure, and levels of physical activity. Future inflamm-aging research should be directed toward advancing the implementation of proven approaches, such as physical activity, as well as studying novel mechanisms of, and treatments for, inflamm-aging among PWH.
