Inlay

VH4524184 (VH-184) is an emerging third-generation integrase strand transfer inhibitor (INSTI) with an enhanced in vitro resistance profile compared with second-generation INSTIs being developed as a long-acting antiretroviral therapy (ART) for HIV-1. We present data from a proof-of-concept phase 2a trial of VH-184 in people with HIV-1.MethodsThis randomized, double-blind, placebo-controlled trial evaluated oral VH-184 monotherapy in adults naive to ART with HIV-1 RNA ≥3000 copies/mL. Participants received oral VH-184 10, 50, or 300 mg or placebo on Days 1 (baseline), 4, and 7. On Day 10, participants initiated standard-of-care ART. The primary endpoint was maximum change from baseline in plasma HIV-1 RNA through Day 10. Secondary endpoints included safety, tolerability, exposure-response relationship, CD4+ cell effects, and treatment-emergent resistance.ResultsOf 22 participants enrolled (VH-184, n=19; placebo, n=3), 86% were male, 68% were White, and median age was 32 years. Mean maximum change from baseline through Day 10 in HIV-1 RNA was −1.17, −2.15, and −2.31 log10 copies/mL for VH-184 10, 50, and 300 mg, respectively. No adverse events (AEs) leading to withdrawal, treatment-emergent serious AEs, or deaths occurred. There were no clinically relevant changes in safety laboratory parameters, electrocardiograms, or vital signs. No VH-184 genotypic or phenotypic resistance was detected through Day 10.ConclusionsVH-184 monotherapy demonstrated rapid and potent antiviral activity and a favorable safety and tolerability profile. The established exposure-response model and efficacy and safety results support further development of VH-184 as the core agent in complete ART regimens for HIV-1 (ClinicalTrials.gov, NCT06214052).

AbstractThis review combines historical reports and surveillance data to contextualize Clostridioides difficile infection (CDI) in the U.S. as a phased epidemic, currently in the deceleration phase. C. difficile was first isolated in 1935. During a prolonged emergence phase, the organism attracted limited clinical attention. In 1978, C. difficile was established as the cause of antibiotic-associated pseudomembranous colitis and from 1978 to a peak in 2010, CDI was in an acceleration phase characterized by fluoroquinolone-resistant, toxin-overproducing strains, large hospital outbreaks, and incidence rates over 150 per 100,000 population. Beginning around 2010, CDI incidence decreased, with a shift from healthcare-associated to community-acquired CDI. Changes in diagnostics complicate incidence comparison between phases; only recently is it apparent that CDI has entered a deceleration phase characterized by infectious reservoirs and possible increases in immunity. It may behoove us to prepare for a different kind of CDI: community-based and insidious rather than hospital-predominant and explosive.

Fecal microbiota transplantation (FMT) is the cost-effective strategy for managing recurrent Clostridioides difficile infection (rCDI). Prior costing models assumed FMT administration via colonoscopy. With the commercialization of microbiota therapeutics for rCDI, this study sought to determine the impact of commercial, Food and Drug Administration (FDA) approved microbiota-based therapeutics relative to traditional FMT on the cost-effectiveness for rCDI.MethodsWe used a Markov model to simulate a cohort of patients with rCDI to evaluate the cost-effectiveness of varied methods of FMT administration for rCDI. The model includes estimates of cure, recurrence, and mortality. Data sources were taken from national guidelines and published literature on treatment outcomes. Outcome measures were quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs).ResultsFMT by colonoscopy is the cost-effective strategy for preventing second or subsequent rCDI with an incremental cost-effectiveness ratio (ICER) of $44 158. Assuming a willingness-to-pay threshold of $100 000 per quality adjusted life years (QALY) gained, FMT by colonoscopy was optimal in the majority (70%) of simulations. At a willingness-to-pay threshold of $100 000 per quality adjusted life year (QALY), commercial, FDA approved microbiota therapeutics were not cost effective under any circumstance when donor-derived FMT products are available.ConclusionsTraditional FMT administered by colonoscopy is the optimal cost-effective strategy for preventing second or subsequent episodes of rCDI. If FMT is not available, then microbiota therapeutics are not a cost-effective option for rCDI at current pricing.

AbstractPost-tuberculosis disability impairs quality-of-life, yet chronic functional outcomes for tuberculosis survivors remain under-characterized. This cross-sectional sub-study (2022–2024) estimated Fried frailty phenotype prevalence among adults aged ≥40 years with self-reported prior tuberculosis in South Africa and Zimbabwe, compared to those with no tuberculosis history. Survivor bias was evaluated using historic WHO data. After adjusting for age, sex, education, and HIV, prior tuberculosis was associated with twice the odds of frailty (OR=2.06, 95%CI 1.38–3.03, p=0.001), and worse survival into older age. As longevity increases in Southern Africa, healthy-ageing interventions for tuberculosis survivors could improve function and survival into older age.

The US Food and Drug Administration (FDA) approved the first treatment for chronic hepatitis delta virus infection, a liver disease that only occurs in people who have hepatitis B virus infection. Once-daily injections with bulevirtide-gmod, marketed as Hepcludex, demonstrated efficacy in a phase 3 randomized clinical trial. Participants were assigned to either begin immediate treatment with 8.5 mg of bulevirtide-gmod or to wait about 1 year before starting to take the medicine. After about 3 years, participants who had taken the treatment the entire time had a combined response rate—determined by a decline in hepatitis delta virus RNA and aminotransferase normalization—of 48%, compared with 2% in delayed treatment group. Rates of undetectable RNA in the initial treatment group increased over time, from 20% after 1 year to 50% after 3 years. “For individuals living with this chronic viral infection, this new treatment option offers hope in managing a disease that can rapidly progress to serious liver complications,” Wendy Carter, DO, acting director of the Office of Infectious Diseases in the FDA’s Center for Drug Evaluation and Research, said in a press release. Back to top Article Information Published Online: June 12, 2026. doi:10.1001/jama.2026.8292

Importance Ebola virus disease (EVD) causes multiorgan damage and is highly fatal. EVD’s neurological impact among survivors remains poorly characterized due to limited neurological assessment capabilities in the remote regions where most outbreaks occur.Objective To characterize neurological sequelae in EVD survivors over more than 7 years’ longitudinal follow-up.Design, Setting, and Participants Under the Ebola Natural History Study (PREVAIL III; PIII), the Neurology Study of PIII was a prospective longitudinal cohort study in Liberia of adult Ebola survivors and control individuals conducted from September 2015 to March 2023 at the Partnership for Research on Vaccines and Infectious Diseases in Liberia (PREVAIL) site at John F. Kennedy Medical Center in Monrovia, Liberia. Data were analyzed from April 2023 to September 2025.Exposures Neurological evaluations were performed by trained neurologists biannually. Questionnaire and neurological examination data were collected on case report forms.Main Outcomes and Measures Neurological symptom prevalence and neurological examination scores were compared to those of control individuals. Tests for differences between survivors and control individuals were conducted using generalized linear mixed-effects models controlling for age and sex. Overdispersed Poisson models were used to test for computed neurological examination score differences. Neurological examination scores were developed for this study, representing the cumulative abnormalities on neurological examinations, denoted on standardized case report forms, with the general neurological examination score representing all examination abnormalities and the central nervous system score representing the central nervous system–specific abnormalities on examination.Results Analysis after serologic testing included 148 Ebola antibody-positive survivors (mean [SD] age, 34.8 [10.5] years; 74 [50%] female) and 81 antibody-negative contacts (mean [SD] age, 35.8 [12.6] years; 41 [51%] female). During acute infection, survivors reported headaches, altered mental status, and strokelike symptoms or meningoencephalitis (rarely). Survivors had significant neurological sequelae involving the entire neuraxis: cognitive dysfunction (83 [56.1%]), persistent headaches (98 [66.2%]), sleep abnormalities (40 [27.0%]), depression (73 [49.3%]), sexual dysfunction (48 [32.4%]), tremor (18 [20.3%]), fatigue (71 [51.1%]), cranial nerve abnormalities (60 [40.5%]), and sensory abnormalities (45 [30.4%]). Over 7 years’ follow-up, most survivors demonstrated improvement in neurological status. The final visit included 115 survivors (77.7%) and 61 close contacts (75.3%). Persistent symptoms at final evaluation in survivors compared to contacts were memory loss (66 [57.4%] vs 16 [26.2%], respectively; P < .001), irritability (42 [36.5%] vs 9 [14.8%], respectively; P = .006), and trouble concentrating (34 [29.6%] vs 6 [9.8%], respectively; P = .002).Conclusions and Relevance The findings indicate that Ebola virus infection is associated with neurological complications in survivors, with increased health care burden and socioeconomic consequences. These neurological issues generally improved with time, but some persisted long-term. Close neurological follow-up of EVD survivors may be warranted.

Intravenous fluid resuscitation is a cornerstone of early sepsis management, yet the optimal fluid volume and target population for early resuscitation remain controversial. The Surviving Sepsis Campaign (SSC) guidelines have long recommended administration of at least 30 mL/kg of intravenous crystalloids within the first 3 hours for patients with sepsis-induced hypoperfusion.1 However, since the early goal-directed therapy era, increasing recognition of potential harms associated with overresuscitation has led some clinicians to adopt a more cautious approach, particularly in patients at risk for fluid overload. Randomized trials comparing restrictive and liberal fluid strategies, including CLASSIC and CLOVERS, enrolled patients after initial resuscitation and therefore did not directly address optimal fluid volume in the earliest phase of care.2,3 Accordingly, the 30 mL/kg threshold is largely derived from observational studies suggesting benefit and from indirect evidence from randomized trials of resuscitation in septic shock in which patients had typically already received this amount of fluid prior to enrollment. Reflecting the limited certainty of this evidence base, the strength of this 30 mL/kg recommendation has been downgraded in recent guideline iterations and is now classified as a conditional recommendation.1 Uncertainty also persists regarding the appropriate target population for early fluid resuscitation. Current definitions of sepsis-induced hypoperfusion, typically hypotension or lactate level of 36 mg/dL or above (≥4 mmol/L), are embedded in clinical guidelines and reinforced in the US by the Centers for Medicare & Medicaid Services’ Severe Sepsis and Septic Shock Management Bundle (SEP-1) measure, which uses these criteria to define the population targeted for administration of at least 30 mL/kg of intravenous fluid. However, this framework excludes a large group of patients with intermediate lactate elevation (18-36 mg/dL [2-4 mmol/L]), in whom early resuscitation could potentially prevent progression to overt hypoperfusion. Prior observational studies have suggested that these patients may benefit from early fluid administration, but they remain outside the scope of most guidelines and quality initiatives.4,5 Munroe and colleagues6 provide timely data to inform these controversies through a large, multicenter cohort study using the Michigan Hospital Medicine Safety Consortium Sepsis Registry. Among more than 25 000 patients with community-onset sepsis and an indication for fluid resuscitation (which the investigators defined as hypotension or lactate level of ≥18 mg/dL [≥2 mmol/L]), the study evaluated outcomes of administering at least 30 mL/kg of fluid vs less than 30 mL/kg by comorbidity status and clinical indication, distinguishing between overt hypoperfusion (hypotension or lactate level >36 mg/dL [>4 mmol/L]) and intermediate lactate elevation (18-36 mg/dL [2-4 mmol/L]). Using inverse probability weighting and complementary modeling approaches to account for confounding, the authors found that receipt of at least 30 mL/kg vs less than 30 mL/kg of intravenous fluid within 6 hours was associated with lower adjusted mortality rates among patients with hypoperfusion (26.0% vs 30.4%) and patients with intermediate lactate elevation without severe comorbidities (12.0% vs 13.9%). Among patients with hypoperfusion and severe comorbidities, associations were not statistically significant in primary analyses, but spline models suggested decreasing mortality with increasing fluid volumes. The study by Munroe et al6 has several notable strengths that enhance confidence in its findings. It leveraged a large, multicenter registry with detailed data abstracted by trained clinical reviewers, supported by ongoing quality assurance, feedback, and auditing processes. This approach allowed for more accurate identification of community-onset sepsis as well as comorbidities. Importantly, the investigators also made substantial efforts to ensure accurate quantification of fluid administration, a notoriously challenging aspect of retrospective electronic health record–based analyses. Their findings were consistent across analytic approaches and robust in the many thoughtful sensitivity analyses performed, which provides reassurance that early fluid resuscitation is likely beneficial for most patients with hypoperfusion. Beyond these strengths, Munroe and colleagues’6 study provides important insights into opportunities to improve care at a population level. Patients with hypoperfusion without severe cardiac or kidney comorbidities constituted the largest subgroup (12 943 patients [51%]), yet only approximately 60% of those patients received at least 30 mL/kg of fluid, highlighting a substantial gap in adherence to existing recommendations. Equally important is the study’s clarification of a large and often underrecognized group of patients with intermediate lactate elevation who fall outside traditional definitions of hypoperfusion. Nearly 10 000 patients had intermediate lactate elevation without severe comorbidities, representing nearly one-quarter of all patients with community-onset sepsis and 40% of those with an indication for fluid resuscitation; fewer than half of these patients received at least 30 mL/kg of fluid. While prior studies have suggested benefit in this population, Munroe and colleagues’6 findings better define both the population’s size and the gap between evidence and practice. Together, their results highlight complementary avenues to improve sepsis outcomes through both better implementation of existing recommendations and broader identification of patients who may benefit from early resuscitation. Beyond identifying these opportunity gaps, the study by Munroe et al6 also provides important reassurance regarding other areas of clinical uncertainty. Among patients with sepsis-associated hypoperfusion and coexisting severe cardiac or kidney disease—groups in whom clinicians are often hesitant to administer large fluid volumes7—the findings consistently suggested that underresuscitation may be more harmful than previously assumed. While point estimates of mortality rate differences in this subgroup did not always reach statistical significance, the overall pattern across analyses, including spline models, supported a benefit, or at least absence of harm, with guideline-concordant fluid resuscitation. In contrast, estimates were less precise among patients with intermediate lactate elevation and severe cardiac or kidney comorbidities, where sample sizes were smaller and findings more uncertain. In addition, the consistency of Munroe and colleagues’6 results across approaches to calculating weight-based fluid doses suggests that the exact method used to operationalize the 30 mL/kg target may be less important than delivering a sufficiently large initial fluid volume in a timely manner. This supports prioritizing a reasonable target range over strict adherence to a single dosing convention. These findings should be interpreted in the context of several important limitations. As with all observational analyses, residual confounding remains a concern, particularly given that decisions regarding early fluid resuscitation are highly susceptible to confounding by indication and are influenced by clinical factors that may not be fully captured in structured data. In addition, some subgroups, particularly patients with intermediate lactate elevation and severe comorbidities, were relatively small, resulting in imprecise estimates and limiting confidence in the findings. Furthermore, although Munroe et al6 appropriately used more specific cardiac phenotypes, such as left ventricular ejection fraction less than 40%, this category still encompassed a heterogenous population, and the sickest patients with advanced cardiomyopathy or combined cardiac and kidney dysfunction may have been underrepresented. Caution is therefore warranted in extrapolating these results to the highest-risk patients. In summary, the large, methodologically rigorous study by Munroe and colleagues6 highlights 2 complementary opportunities to improve sepsis outcomes: more consistent implementation of early fluid resuscitation for patients with overt hypoperfusion, including many with cardiac or kidney comorbidities, and expansion of early resuscitation strategies to a large, undertargeted group of patients with intermediate lactate elevation. Although these findings, being observational, cannot definitively resolve ongoing debate regarding optimal fluid strategies, the study represents one of the most rigorous analyses to date addressing initial resuscitation and provides a compelling and clinically actionable signal. Pending prospective randomized studies, Munroe and colleagues’6 data support efforts to address gaps in implementation and targeting of early fluid resuscitation as a means to improve sepsis outcomes at scale. Back to top Article Information Published: June 12, 2026. doi:10.1001/jamanetworkopen.2026.18245Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2026 Shappell CN et al. JAMA Network Open.Corresponding Author: Chanu Rhee, MD, MPH, Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, 401 Park Dr, Ste 401, Boston, MA 02215 ([email protected]).Conflict of Interest Disclosures: Dr Shappell reported receiving grants from the Agency for Healthcare Research and Quality (AHRQ) outside the submitted work. Dr Rhee reported receiving grants from the Centers for Disease Control and Prevention and AHRQ and personal fees from UpToDate, Inc, and DynaMed outside the submitted work. References 1.Prescott HC, Antonelli M, Alhazzani W, et al. Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock 2026. Crit Care Med. 2026;54(4):725-812. doi:10.1097/CCM.0000000000007089 PubMedGoogle ScholarCrossref2.Meyhoff TS, Hjortrup PB, Wetterslev J, et al; CLASSIC Trial Group. Restriction of intravenous fluid in ICU patients with septic shock. N Engl J Med. 2022;386(26):2459-2470. doi:10.1056/NEJMoa2202707 PubMedGoogle ScholarCrossref3.Shapiro NI, Douglas IS, Brower RG, et al; National Heart, Lung, and Blood Institute Prevention and Early Treatment of Acute Lung Injury Clinical Trials Network. Early restrictive or liberal fluid management for sepsis-induced hypotension. N Engl J Med. 2023;388(6):499-510. doi:10.1056/NEJMoa2212663 PubMedGoogle ScholarCrossref4.Liu VX, Morehouse JW, Marelich GP, et al. Multicenter implementation of a treatment bundle for patients with sepsis and intermediate lactate values. Am J Respir Crit Care Med. 2016;193(11):1264-1270. doi:10.1164/rccm.201507-1489OC PubMedGoogle ScholarCrossref5.Liu V, Morehouse JW, Soule J, Whippy A, Escobar GJ. Fluid volume, lactate values, and mortality in sepsis patients with intermediate lactate values. Ann Am Thorac Soc. 2013;10(5):466-473. doi:10.1513/AnnalsATS.201304-099OC PubMedGoogle ScholarCrossref6.Munroe ES, Walzl E, Seelye S, et al. Comorbidities, weight-based initial fluid resuscitation, and mortality in patients with sepsis. JAMA Netw Open. 2026;9(6):e2618232. doi:10.1001/jamanetworkopen.2026.18232ArticleGoogle Scholar7.Powell RE, Kennedy JN, Senussi MH, Barbash IJ, Seymour CW. Association between preexisting heart failure with reduced ejection fraction and fluid administration among patients with sepsis. JAMA Netw Open. 2022;5(10):e2235331. doi:10.1001/jamanetworkopen.2022.35331 ArticlePubMedGoogle ScholarCrossref

Introduction Long-acting injectable antiretroviral therapy (LA-ART) represents a major advance in HIV treatment, offering sustained viral suppression without daily pill adherence dosing since its approval by the Food and Drug Administration in 2021.1,2 However, empirical uptake in the Medicare population with HIV, including among individuals from minoritized racial and ethnic groups and across diverse regions in the country, remains poorly understood. This knowledge gap is particularly salient given that many Medicare beneficiaries are older,3 have complex multimorbidity with increased susceptibility to bone and kidney complications from certain oral ART regimens, and may face cost-related and access barriers. We quantify use of LA-ART among Medicare beneficiaries with HIV and characterize the differences between people receiving oral ART vs LA-ART. Methods This cross-sectional study was approved by the Harvard institutional review board, which waived informed consent given the deidentified data. We followed the STROBE guidelines for cross-sectional studies. We used 100% Medicare data to identify people with HIV (PWH) enrolled in Medicare Parts B and D between 2021 to 2023. Prior to the year of assessing ART regimens, we applied the Chronic Conditions Warehouse algorithm with a 2-year look-back period (2019-2022) to identify HIV and other chronic conditions, such as heart failure, mental health disorders (defined as major depressive disorder, schizophrenia or related psychotic disorders, and bipolar disease), and dementia. We used Part D outpatient and carrier files to determine oral ART vs LA-ART (cabotegravir or rilpivirine). Demographics included age, sex, race and ethnicity (determined using the RTI Race Variable, which applies an algorithm on self-reported data, and classified as American Indian or Alaska Native, Asian, Black, Hispanic, White, unknown, or any other race), Medicaid dual eligibility, enrollment in Traditional Medicare vs Medicare Advantage, rurality, and state. Data on race and ethnicity are included in this study given known racial disparities in ART use.4 Next, we determined the number and proportion of PWH taking oral ART vs LA-ART yearly. For 2023, we reported patient demographics and calculated adjusted odds ratios (aORs) of receiving LA-ART using logistic regressions. Statistical significance was defined as 2-sided P < .05. Variables used in our model for adjustment included demographics, chronic conditions, rurality, and region. Data were analyzed using SAS version 8.5 (SAS Institute, Inc) from October 2025 to April 2026. Results The sample included 638 PWH (0.4%) taking LA-ART vs 162 495 (99.6%) taking oral ART in 2021, 3202 (1.9%) taking LA-ART vs 165 059 (98.1%) taking oral ART in 2022, and 5162 (3.0%) taking LA-ART vs 167 836 (97.0%) taking oral ART in 2023. PWH taking LA-ART were younger (aged <55 years, 1719 PWH [33.3%] vs 30 499 PWH [18.2%]; standardized mean difference [SMD] = 0.351), more likely to be dual eligible for Medicaid (3828 PWH [74.2%] vs 110 964 PWH [66.0%]; SMD = 0.180), and less likely to live in the South (2070 PWH [41.1%] vs 76 480 PWH [45.6%]; SMD = 0.111) vs those taking oral ART (Table 1). In adjusted analyses (Table 2), older PWH were less likely to receive LA-ART (aged, 55-64 years, aOR, 0.60 [95% CI, 0.56-0.65]; aged ≥65 years, aOR, 0.40 [95% CI, 0.37-0.43) than PWH younger than 55 years. American Indian or Alaska Native individuals were also less likely to receive LA-ART than White PWH (aOR, 0.52; 95% CI, 0.29-0.92); there were no significant differences for other racial and ethnic groups or by sex. PWH in rural areas and the South were significantly less likely than their counterparts to receive LA-ART. Dual-eligible individuals (aOR, 1.12; 95% CI, 1.04-1.20) and Medicare Advantage beneficiaries (aOR, 1.07; 95% CI, 1.00-1.13) were more likely to receive LA-ART than their respective counterparts. Notably, PWH with Alzheimer disease and related dementias, stroke disorders, heart failure, and chronic kidney disease or kidney failure were less likely to receive LA-ART, whereas people with mental health disorders were more likely to receive LA-ART. Table 1. Characteristics of Medicare Beneficiaries With HIV Receiving Oral ART vs LA-ART View LargeDownload (opens in new tab)Go to Figure in ArticleCharacteristicTotal No. of patientsPatients, No. (%)SMDaOral ARTLA-ARTYearb 2021163 133162 495 (99.6)638 (0.4)NA 2022168 261165 059 (98.1)3202 (1.9)NA 2023172 998167 836 (97.0)5162 (3.0)NACharacteristics of patients in 2023c Age, y <5532 21830 499 (18.2)1719 (33.3)0.351 55-6452 40350 709 (30.2)1694 (32.8)0.056 ≥6588 37786 628 (51.6)1749 (33.9)0.364 Sex Female47 52846 095 (27.5)1433 (27.8)0.007 Male125 470121 741 (72.5)3729 (72.3) Race and ethnicityd American Indian or Alaska Native637625 (0.4)12 (0.2)0.025 Asian19911941 (1.2)50 (1.0)0.018 Black73 01970 803 (42.2)2216 (42.9)0.015 Hispanic24 47223 718 (14.1)754 (14.6)0.014 White69 65367 617 (40.3)2036 (39.5)0.017 Any other race or unknown32263132 (1.9)94 (1.8)0.003 Medicare insurance typee Medicare Advantage111 932108 514 (64.7)3418 (66.2)0.033 Traditional Medicare61 06659 322 (35.3)1744 (33.8) Dual eligibility for Medicaid Yes114 522110 964 (66.0)3828 (74.2)0.180 No58 47657 142 (34.0)1334 (25.8) Region Midwest21 14620 326 (12.1)820 (15.9)0.109 Northeast39 89238 735 (23.1)1157 (22.4)0.016 South78 55076 480 (45.6)2070 (41.1)0.111 West33 41032 295 (19.2)1115 (21.6)0.059 Ruralityf Rural16 79616 408 (9.8)388 (7.5)0.080 Urban156 202151 428 (90.2)4774 (92.5) Chronic conditionsg Acute myocardial infarction or ischemic heart disease36 74035 779 (21.3)961 (18.6)0.066 Asthma or chronic obstructive pulmonary disease54 59252 826 (31.5)1766 (34.2)0.061 Alzheimer dementia and related disorders87298572 (5.1)157 (3.0)0.104 Cancer16 22315 810 (9.4)413 (8.0)0.049 Chronic kidney disease or kidney failure55 23853 850 (32.1)1388 (26.9)0.112 Diabetes57 87656 301 (33.5)1575 (30.5)0.063 Heart failure or nonischemic heart disease24 12623 528 (14.0)598 (11.6)0.072 Mental health disorders73 21670 798 (42.0)2718 (52.7)0.215 Stroke disorders12 30512 013 (7.2)292 (5.7)0.061 Substance use disorders38 80737 399 (22.3)1408 (27.3)0.116 Table 2. Likelihood of Receiving Long-Acting Antiretroviral Therapy by Patient Characteristics, 2023 View LargeDownload (opens in new tab)Go to Figure in ArticleCharacteristicUnadjusted OR (95% CI)aP valueAdjusted OR (95% CI)bP valueAge, y <551 [Reference]NA1 [Reference]NA 55-640.59 (0.55-0.63)<.0010.60 (0.56-0.65)<.001 ≥650.36 (0.33-0.38)<.0010.40 (0.37-0.43)<.001Sex Female1.01 (0.95-1.08).640.96 (0.90-1.03).28 Male1 [Reference]NA1 [Reference]NARace and ethnicity American Indian or Alaska Native0.64 (0.36-1.13).120.52 (0.29-0.92).03 Asian0.86 (0.64-1.14).280.82 (0.62-1.10).19 Black1.04 (0.98-1.10).221.03 (0.96-1.10).47 Hispanic1.06 (0.97-1.15).211.00 (0.92-1.10).92 White1 [Reference]NA1 [Reference]NA Any other race or unknown1.00 (0.81-1.23).981.04 (0.84-1.29).71Medicare insurance type Medicare Advantage1.07 (1.01-1.14).021.07 (1.00-1.13).04 Traditional Medicare1 [Reference]NA1 [Reference]NADual-eligible for Medicaid Yes1.48 (1.39-1.58)<.0011.12 (1.04-1.20).002 No1 [Reference]NA1 [Reference]NARegion Midwest1.49 (1.37-1.62)<.0011.42 (1.30-1.54)<.001 Northeast1.10 (1.03-1.19).0081.18 (1.10-1.27)<.001 West1.28 (1.18-1.37)<.0011.41 (1.30-1.52)<.001 South1 [Reference]NA1 [Reference]NARurality Rural0.75 (0.68-0.83)<.0010.73 (0.66-0.82)<.001 Urban1 [Reference]NA1 [Reference]NAChronic conditionsc Acute myocardial infarction or ischemic heart disease0.85 (0.79-0.91)<.0011.05 (0.97-1.14).23 Asthma or chronic obstructive pulmonary disease1.14 (1.07-1.21)<.0011.09 (1.02-1.16).007 Alzheimer dementia or Alzheimer dementia related disorder0.58 (0.50-0.69).0010.64 (0.54-0.75)<.001 Cancer0.84 (0.76-0.93)<.0011.01 (0.91-1.12).89 Chronic kidney disease or kidney failure0.78 (0.73-0.83)<.0010.93 (0.87-0.99).03 Diabetes0.87 (0.82-0.93)<.0010.98 (0.92-1.05).62 Heart failure or nonischemic heart disease0.81 (0.74-0.88)<.0010.85 (0.78-0.94).002 Mental health disorders1.54 (1.45-1.62)<.0011.32 (1.25-1.41)<.001 Stroke0.78 (0.69-0.88)<.0010.87 (0.77-0.99).03 Substance use disorders1.31 (1.23-1.39)<.0011.05 (0.99-1.13).12 Discussion In this national cross-sectional study, uptake of LA-ART among Medicare PWH was low, reaching only 3.0% by 2023. Early diffusion appeared uneven, with lower use among American Indian or Alaska Native beneficiaries and people living in rural areas or the South—patterns that mirror longstanding disparities in HIV care delivery and access to specialty services.4-7 In addition, despite potentially greater benefit from reduced daily adherence burden and lower risk of potential adverse effects of oral tenofovir–based regimens, older beneficiaries and people with complex chronic conditions, including Alzheimer disease and related dementias and chronic kidney disease or kidney failure, were less likely to receive LA-ART, possibly reflecting clinician concerns about drug-drug interactions.7,8 Conversely, dual-eligible beneficiaries, who automatically qualify for subsidized drug coverage under the Part D Low-Income Subsidy,9 and people enrolled in Medicare Advantage, who receive financial protections through out-of-pocket maximum caps and reduced cost-sharing, were more likely to receive LA-ART, suggesting that differences in structural access, system-level factors, and affordability may be barriers to LA-ART. Finally, higher use among beneficiaries with mental health disorders is encouraging, given LA-ART’s potential to mitigate adherence challenges in this population,7 and additional consideration for those with substance use disorders remains critical. This study has limitations. This descriptive study cannot establish causal reasons for different ART prescription patterns, including from logistical challenges, patient selection, and access to physicians. Other limitations included lack of clinical detail in data, inability to capture patient or physician-level factors associated with treatment choice (including affordability), limited generalizability to people enrolled in Medicaid and commercial insurance, and lack of data from 2024 and beyond. We could not quantify lenacapavir use because its billing code was introduced mid-2023. Nonetheless, these early patterns suggest the need for strategies that ensure equitable access to LA-ART through affordability protections, outreach to marginalized populations, and an improved understanding of treatment decisions for older PWH with complex multimorbidity. Back to top Article Information Accepted for Publication: April 21, 2026.Published: June 12, 2026. doi:10.1001/jamanetworkopen.2026.18029Open Access: This is an open access article distributed under the terms of the CC-BY-NC-ND License, which does not permit alteration or commercial use, including those for text and data mining, AI training, and similar technologies. © 2026 Figueroa JF et al. JAMA Network Open.Corresponding Author: Jose F. Figueroa, MD, MPH, Department of Health Policy & Management, Harvard T.H. Chan School of Public Health, 677 Huntington Ave, Kresge Room 402, Boston, MA 02115 ([email protected]).Author Contributions: Ms Stein had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.Concept and design: Figueroa, Stein, Hyle.Acquisition, analysis, or interpretation of data: All authors.Drafting of the manuscript: Figueroa, Hyle.Critical review of the manuscript for important intellectual content: All authors.Statistical analysis: Stein, Phelan, Orav.Obtained funding: Figueroa, Hyle.Administrative, technical, or material support: Figueroa, Luu.Supervision: Figueroa, Mukerji, Hyle.Conflict of Interest Disclosures: Dr Figueroa reported receiving grants from Commonwealth Fund, Laura and John Arnold Foundation, Robert Wood Johnson Foundation, SCAN Foundation, and Department of Veterans of Affairs and personal fees from Project Hope for editorial services outside the submitted work. Dr Mukerji reported receiving grants from Massachusetts General Hospital during the conduct of the study. Dr Hyle reported receiving grants from Massachusetts General Hospital during the conduct of the study and personal fees from UpToDate outside the submitted work. No other disclosures were reported.Funding/Support: This publication was supported by grants R01AG081151 (to Drs Figueroa, Orav, Mukerji, and Hyle), R01AG069575 (to Drs Figueroa and Hyle) and RF1AG088640 (to Drs Figueroa and Orav) from the National Institute on Aging.Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.Data Sharing Statement: See the Supplement. References 1.Orkin C, Arasteh K, Górgolas Hernández-Mora M, et al; FLAIR Study Group. Long-acting cabotegravir and rilpivirine after oral induction for HIV-1 infection. N Engl J Med. 2020;382(12):1124-1135. doi:10.1056/NEJMoa1909512PubMedGoogle ScholarCrossref2.DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents. HHS Adults and Adolescents Antiretroviral Guidelines Panel recommendation for the long-acting injectable antiretroviral regimen of cabotegravir and rilpivirine. February 18, 2021. Accessed December 20, 2025. https://clinicalinfo.hiv.gov/sites/default/files/guidelines/archive/adult-arv-cabotegravir-rilpivirine-2021-02-18.pdf3.Figueroa JF, Katz IT, Hyle EP, et al. The association of HIV with health care spending and use among Medicare beneficiaries. Health Aff (Millwood). 2022;41(4):581-588. doi:10.1377/hlthaff.2021.01793PubMedGoogle ScholarCrossref4.Figueroa JF, Duggan C, Phelan J, et al. Antiretroviral therapy use and disparities among Medicare beneficiaries with HIV. J Gen Intern Med. 2024;39(12):2196-2205. doi:10.1007/s11606-024-08847-yPubMedGoogle ScholarCrossref5.Haser GC, Balter L, Gurley S, et al. Early implementation and outcomes among people with HIV who accessed long-acting injectable cabotegravir/rilpivirine at two Ryan White Clinics in the U.S. South. AIDS Res Hum Retroviruses. 2024;40(12):690-700. doi:10.1089/AID.2024.0007PubMedGoogle ScholarCrossref6.Centers for Disease Control and Prevention. Estimated HIV incidence and prevalence in the United States. September 5, 2024. Accessed December 20, 2025. https://www.cdc.gov/hiv-data/nhss/estimated-hiv-incidence-and-prevalence.html#:~:text=At%20a%20glance,fell%2016%25%20in%20the%20South7.Nachega JB, Scarsi KK, Gandhi M, et al. Long-acting antiretrovirals and HIV treatment adherence. Lancet HIV. 2023;10(5):e332-e342. doi:10.1016/S2352-3018(23)00051-6PubMedGoogle ScholarCrossref8.O’Shea JG, Cholli P, Heil EL, Buchacz K. Considerations for long-acting antiretroviral therapy in older persons with HIV. AIDS. 2023;37(15):2271-2286. doi:10.1097/QAD.0000000000003704PubMedGoogle ScholarCrossref9.Roberts ET, Phelan J, Schwartz AL, et al. Loss of subsidized drug coverage and mortality among Medicare beneficiaries. N Engl J Med. 2025;392(20):2025-2034. doi:10.1056/NEJMsa2414435PubMedGoogle ScholarCrossref

Importance Guidelines suggest administering at least 30 mL/kg of initial fluid to patients with sepsis-induced hypoperfusion. However, there is uncertainty regarding the benefits of fluid resuscitation in patients with severe cardiac or kidney comorbidities or intermediate elevation of lactate level (18.0-36.0 mg/dL).Objective To evaluate the association of 30 mL/kg or more of fluid administered within 6 hours of hospital arrival with 30-day mortality across key target populations with community-onset sepsis.Design, Setting, and Participants This cohort study included adults hospitalized for community-onset sepsis in 67 hospitals in the Michigan Hospital Medicine Safety Consortium (discharge dates from December 2021 to January 2025) who had an indication for fluid resuscitation (ie, hypotension or lactate level of 18.0 mg/dL or greater) within 3 hours of hospital arrival. Data were analyzed from November 26, 2024, to November 16, 2025.Exposure Receipt of at least 30 mL/kg vs less than 30 mL/kg fluid in the first 6 hours after hospital arrival. Fluid volume included all crystalloid fluid and blood products.Main Outcomes and Measures Association between administration of 30 mL/kg or more of fluid within 6 hours of hospital arrival and 30-day mortality using weighted regression models adjusted for patient characteristics. Target populations were defined by (1) fluid indication: hypoperfusion (hypotension or lactate level >36.0 mg/dL) vs intermediate lactate elevation (18.0-36.0 mg/dL) and (2) presence of severe comorbidities that might increase risk of fluid overload (left ventricular ejection fraction <40%, severe-to-critical aortic stenosis, or end-stage kidney disease). Secondary analyses used adjusted logistic regression models with restricted cubic spline terms to evaluate associations of fluid volume administered with mortality.Results Among 43 321 patients hospitalized for community-onset sepsis, 25 481 (58.8%) had an indication for fluid resuscitation and were included in the study (median age, 71 years [IQR, 61-80 years]; 50.5% male; 37.0% with body mass index >30.0, calculated as weight in kilograms divided by height in meters squared). A total of 12 943 (50.8%) had hypoperfusion without severe comorbidities; 1741 (6.8%), hypoperfusion with severe comorbidities; 9974 (39.1%), intermediate lactate elevation without severe comorbidities; and 823 (3.2%), intermediate lactate elevation with severe comorbidities. Administration of 30 mL/kg or more of fluid vs less than 30 mL/kg was associated with lower adjusted 30-day mortality rates in patients with hypoperfusion without severe comorbidities (26.0% [95% CI, 24.9%-27.2%] vs 30.4% [95% CI, 28.8%-32.0%]; adjusted absolute difference [diff], −4.4 percentage points [pp] [95% CI, −6.1 to −2.7 pp]) and intermediate lactate elevation without severe comorbidities (12.0% [95% CI, 10.6%-13.5%] vs 13.9% [95% CI, 12.9%-14.8%]; diff, −1.8 pp [95% CI, −3.6 to −0.1 pp]). For patients with hypoperfusion and severe cardiac or kidney comorbidities, the association between 30-day adjusted mortality and receiving 30 mL/kg or more of fluid vs less than 30 mL/kg was not statistically significant (34.7% [95% CI, 30.8%-38.6%] vs 38.8% [95% CI, 35.8%-41.8%]; diff, −4.1 pp [95% CI, −9.0 to 0.8 pp]), although spline models indicated decreasing mortality with fluid resuscitation of 30 mL/kg or more of fluid.Conclusions and Relevance In this cohort study of patients with community-onset sepsis, initial administration of 30 mL/kg or more of fluid was associated with lower 30-day mortality among patients who had either hypoperfusion or intermediate lactate elevation without severe cardiac or kidney comorbidities. The findings suggest that broader application of at least 30 mL/kg of initial fluid resuscitation for sepsis in patients with hypoperfusion and cardiac or kidney comorbidities or intermediate lactate elevation may reduce sepsis-related mortality.

and objectivesAntimicrobial resistance (AMR) is a growing threat to child health in low- and middle-income countries (LMICs), where inadequate antibiotic access frequently causes morbidity and mortality. We sought to identify effective interventions to optimize antibiotic use in children with suspected infections in LMIC ambulatory healthcare settings.MethodsMEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), Cochrane Infectious Disease Group Specialized Register, Web of Science, PsycInfo, WHO library database (WHOLIS) and regional databases (inception until 16 December 2024) were searched to identify studies of interventions to optimize antibiotic use in children in LMIC peripheral healthcare settings.ResultsOur search identified 7154 articles post de-duplication; 23 studies met the inclusion and Integrated quality Criteria for the Review of Multiple Study designs (ICROMS) assessment criteria. Seventeen were randomized trials, conducted in five LMICs, four upper-middle income countries (UMICs) and two low-income countries (LICs). Single-intervention studies investigated electronic algorithms (n = 3) and point-of-care tests (POCTs) (n = 4). Electronic algorithms and enhanced POCTs reduced antibiotic prescriptions for children with acute illness at primary care facilities in Tanzania. C-reactive protein POCTs achieved modest reductions in antibiotic prescribing for children in Vietnam and Uganda but not for those with febrile illness in Myanmar and Thailand. A diagnostic tool algorithm showed reduction of antibiotic prescriptions in Ghana and Burkina Faso, but not in Uganda.ConclusionsInitial evidence suggests that algorithmic decision-support tools combined with point-of-care diagnostics and provider education can reduce antibiotic prescribing in children attending ambulatory healthcare settings in LMICs, with most studies demonstrating no compromise of clinical outcomes. However, few studies assessed prescription appropriateness or microbiological outcomes, limiting conclusions about long-term impact. Future interventions should prioritize context-adaptable strategies that incorporate rapid diagnostics, evaluate clinical and appropriateness outcomes, and consider implementation feasibility across diverse LMIC settings.