Background:We analysed the association between host genetic risk scores (GRSs) predicting efavirenz (EFV) plasma levels and exposure and suicidal behaviours in participants in one of several global antiretroviral therapy (ART) clinical trials linked to the International Network for Strategic Initiatives in Global HIV Trials (INSIGHT). Methods:We conducted a matched case-control study (two controls per case) on suicide or grade-4 suicidal ideation/attempts or depression. Cases and controls were matched by EFV initiation strategy, study, and follow-up time. CYP2B6-based GRS classified participants as extensive, intermediate, or slow metabolisers. EFV and its metabolites (8-hydroxy-EFV and 7-hydroxy-EFV) were measured in plasma. Conditional logistic regression was used to analyse the associations between GRS categories, EFV levels, and suicidal behaviour. Results:Among 74 cases and 146 controls, 128 (58.2%) started EFV-containing first-line treatment. Of the treatment-experienced participants, 35% were on EFV at entry. Pre-existing psychiatric conditions and recreational drug-use were more common in cases (16.2%, 25.7%) than in controls (0.7%, 9.6%). On comparing cases to controls, more cases were extensive metabolisers (52% vs. 45%), but there were fewer slow metabolisers (8% vs. 13%). The unadjusted odds ratio (OR) for suicidal behaviour per one more minor allele was 0.76 (95% CI: 0.49-1.18). The OR for being a case vs. a control was 0.57 (95% CI: 0.38-0.86) per doubling of the EFV plasma level. Conclusion:CYP2B6-based GRS for cytochrome P450 enzymatic activity appeared not to be associated with suicidal behaviour in individuals living with HIV treated with EFV-containing ART combinations. CYP2B6-based GRS effectively predicted EFV exposure, but suicidal behaviour appeared more likely in extensive (normal) metabolisers.

Purpose Ebola virus disease (EVD) is associated with vision-threatening ophthalmic sequelae, yet outcomes in young survivors remain poorly characterized. We sought to distinguish ophthalmic pathology in pediatric EVD survivors relative to close contacts and adult EVD survivors. Design and Participants Cross-sectional baseline analysis of 88 pediatric EVD survivors, 203 close contacts aged 6–17 years, and 463 adult EVD survivors (≥18 years) enrolled in the Partnership for Research on Ebola Virus in Liberia (PREVAIL) III longitudinal cohort study.Testing:Visual function testing, slit-lamp biomicroscopy, indirect ophthalmoscopy, and optical coherence tomography (OCT).Main Outcome Measures:Prevalence of ocular symptoms, functional vision measures, and evidence of inflammation on examination and imaging. Results Compared with close contacts, pediatric EVD survivors at their baseline visit experienced significantly higher rates of light sensitivity (43.2% vs. 31.2%, p<0.05), best-corrected visual acuity less than 20/40 (6.8% vs. 0.5%, p=0.013), impaired color discrimination with at least three incorrect Ishihara color plates (10.2% vs. 1.5%, p=0.003), further accommodative near point (16.8cm vs. 16cm, p=0.015), and lower intraocular pressure (13.0 vs. 14.3 mmHg, p=0.001). Slit-lamp biomicroscopy revealed higher rates of anterior chamber cells (8% vs. 2.5%, p=0.036), cataract (8% vs. 0.5%, p=0.0078), vitreous cell (6.8% vs. 0.5%, p=0.018), and peripheral retinal scars (9.1% vs. 3%, p=0.03) in pediatric EVD survivors relative to pediatric close contacts. Relative to adult EVD survivors, pediatric EVD survivors experienced higher rates of anterior chamber cells (8% vs. 3.2%, p=0.04), but were less likely to experience posterior uveitis (5.7% vs. 13.8% p=0.04), and less likely to demonstrate mild or greater vitreous opacities on OCT (20.9% vs. 34.1%, p=0.017). Conclusions Pediatric EVD survivors exhibit a distinct profile of ocular sequelae compared with both close contacts and adult survivors, characterized by higher rates of anterior segment inflammation. These findings highlight the importance of considering the unique needs of children in the setting of emerging infectious diseases.

Background Antivirals remain an important treatment strategy for persons who experience severe and life-threatening COVID-19. Ensitrelvir is an oral 3CL protease inhibitor with potent antiviral activity. Methods We conducted an international randomized, placebo-controlled trial of ensitrelvir with standard of care (SOC) among adults hospitalized for COVID-19. The primary outcome was clinical recovery assessed by the days to recovery scale through day 60 (DRS-60), analyzed using a Van Elteren test. Results From 2023 to 2025, 589 participants received blinded study treatment (293 ensitrelvir and 296 placebo). Median age was 69 years, 49% were female, 68% were White, and SOC commonly included corticosteroids (61% and 54%) and remdesivir (62% and 60%) in ensitrelvir and placebo groups, respectively. Median DRS-60 category was 6 (IQR: 3-15) in the ensitrelvir and 5.5 (IQR: 3-12) in the placebo group (P = .19), and the OR was 0.82 (95% CI: 0.62-1.09) for a better DRS-60 category with ensitrelvir. Ensitrelvir participants had lower detectable viral antigen in plasma at Day 5 (13.4% vs 25.1%; P < .001). There was no difference in secondary clinical outcomes or prespecified safety outcomes, though the mortality rate was 6.1% vs 4.4% and the frequency of hemorrhagic events was 3.4% vs 0.3% among ensitrelvir and placebo groups, respectively. Conclusions Ensitrelvir treatment did not improve clinical recovery in addition to SOC for adults hospitalized for COVID-19. The lower illness severity in the Omicron era compared with earlier periods in the COVID-19 pandemic and high use of remdesivir and corticosteroids, may have contributed to the lack of clinical benefit.

Background:Cardiovascular disease (CVD) prediction models for persons living with HIV (PLWH) depend on traditional CVD risk factors, but these underestimate true risk. We aimed to identify proteins and genetic variants and create proteo-genomic risk scores for CVD in PLWH. Methods:We analyzed genetic and protein data from participants involved in trials for PLWH. We used state-of-the-art statistical methods for data integration, identified correlated signatures, and developed a protein score (PS) and a genetic score (GS) to predict CVD. We conducted functional enrichment analysis to explore biological functions of signatures identified in relation to CVD. Results:A panel of 14 proteins and a set of 15 genetic variants were found to be better at distinguishing between CVD cases and controls than individual proteins or genetic variants. The PS or GS was each independently associated with a higher risk of CVD (OR for PS: 2.36, CI: 1.78-3.19; OR for GS: 4.59, CI: 3.21-6.80). Combining CVD-, HIV-related factors, genetics, and protein scores resulted in the most powerful discrimination with an AUC of 0.86 (CI: 0.82-0.90). Having a PS in the top 25% compared to the bottom 75% resulted in a 3.9 times higher risk of CVD. Having a GS in the top 25% compared to the bottom 75% resulted in a 7.3 times higher risk of CVD. For individuals with both PS and GS in the top 25% compared to others, the risk of CVD was 7.9 times higher. Functional enrichment analysis showed an upregulation of the cytokine tumor necrosis factor (TNF) and strong enrichment for inflammation related pathways such as the pathogen induced cytokine storm. Conclusions:A panel of protein biomarkers, some new (IGFBP7, HGF) and some previously known in PLWH (CLEC6A), could help identify PLWH at higher risk of developing CVD. If confirmed, these scores could be used with CVD and HIV-related factors to identify PLWH at risk for CVD who would benefit from proactive risk reduction strategies.

BACKGROUND:Individuals with HIV remain at higher risk of non-communicable diseases associated with interleukin-6-specific (IL-6) inflammation compared to the background population. Despite antiretroviral therapy, some individuals exhibit persistent hyperinflammation. We characterise these understudied longitudinal profiles and distinguish the predictors of chronic versus acute inflammation. METHODS:A subset from the Strategic Timing of Antiretroviral Treatment (START) trial with up to seven years of biomarker follow-up was included. Inflammatory states were defined based on plasma IL-6 levels, measured at randomisation, months eight, 12, and annually until 84. Hyperinflammation was defined as IL-6>1.8 pg/mL; ≥2 consecutive elevated measurements defined persistent hyperinflammation and a single elevated bracketed by non-elevated measurements defined IL-6 blips. Variables associated with these outcomes were analysed by generalized estimating equations. RESULTS:Among 2,102 individuals with a median of 5 (IQR: 4-6) measurements, 861 (41%) had persistent hyperinflammation whereas 575 (27%) had blips. Participants with BMI≥40 versus 18.5 to <25 (OR: 5.49, 95%CI: 4.18-7.20) and females with black ethnicity versus white males (2.58, 2.17-3.06) had increased risk of persistent hyperinflammation but not blips. Other persistent hyperinflammation predictors included higher white blood cell (WBC) counts, HIV-1 RNA, total cholesterol to high-density lipoprotein ratio >5, older age, smoking and diabetes. Of these only higher WBCs were also associated with blips. CONCLUSIONS:Persistent hyperinflammation is strongly associated with demographic characteristics, comorbidities, and HIV-1 RNA, whereas blips were associated with markers of immune activation. Longitudinal IL-6 measurements are needed to distinguish persistent hyperinflammation from blips, which can lead to establishing a "high-risk phenotype" to target for clinical intervention.

Long-term psychosocial sequelae of Ebola virus disease (EVD) survivors are poorly understood. We conducted a cross-sectional study of a cohort of EVD survivors and their uninfected contacts in Liberia. Beginning in November 2019, we consecutively sampled eligible participants until the end of the parent study follow up. Enrolled participants completed a questionnaire administered by trained study staff. Outcome measurements were symptoms of depression (PHQ-8) and anxiety (GAD-7) as well as experiences of trauma (PC-PTSD-5), food insecurity (HFIAS), and social support (Duke-UNC SSQ). Excess prevalence was defined as the difference in prevalence between survivors and contacts. We performed adjusted analyses with logistic regression models and restricted to the survivor population for assessment of risk factors. Our analysis cohort included 1,144 participants among whom 363 were Ebola survivors and 781 were contacts. Participants were sampled a median of 55 months (IQR: 51, 60) after enrollment in the parent study. Excess prevalence was as follows: 7.9% had severe food insecurity by HFIAS (18.5% EVD survivors vs. 10.6% contacts), 6.2% had any anxiety symptoms by GAD-7 (11.6% EVD survivors vs. 5.4% contacts), 3.7% had any depression symptoms by PHQ-8 (8.3% EVD survivors vs. 4.6% contacts), and 3.2% had probable PTSD by PC-PTSD-5 (4.5% EVD survivors vs. 1.3% contacts). Levels of support were similar between survivors and contacts. EVD survivors had a higher adjusted odds of scoring in a more severe category on the GAD-7 scale (adjusted odds ratio [AOR]: 3.60; 95% CI: 1.42, 9.16), PC-PTSD-5 scale (AOR: 3.26; 95% CI: 1.40, 7.58), and HFIAS scale (AOR: 1.84; 95% CI: 1.29, 2.61). Age, history of post-acute symptoms, and non-Ebola related trauma were risk factors for multiple psychosocial outcomes among survivors. We found significant but modest evidence of psychosocial sequelae among EVD survivors compared with contacts between four to five years after the acute illness.

ABSTRACT Background Knowledge of the human genetic contribution to the risk of complications from influenza is limited. This study assessed the association between human single‐nucleotide polymorphisms (SNPs) and disease progression in individuals with influenza. Methods A targeted analysis of 10 SNPs with prior evidence in COVID‐19 and a genome‐wide association study (GWAS) were used to assess associations between SNPs and disease progression in two multinational cohorts with suspected or laboratory‐confirmed influenza: a hospitalized cohort (n = 1634) and a pooled cohort of hospitalized and outpatients (n = 3469). Disease progression was defined as prolonged hospitalization (> 28 days), progression to mechanical ventilation, admittance to intensive care unit, or death (for hospitalized individuals) or progression to hospitalization or death (for outpatients). Results Disease progression was observed in 9.1% of hospitalized patients and 2.2% of outpatients. Age was a significant risk factor for disease progression, with 20% increased odds of disease progression per 10‐year increase in age (OR: 1.20, 95%CI: 1.08–1.33, p < 0.001). Disease progression rates also differed by continent (p < 0.0001). Targeted SNP analyses did not identify significant associations with disease progression; however, the strength of associations was most pronounced in sensitivity analyses for the pooled cohort in individuals < 65 years old. GWAS analyses did not identify significant common SNP associations in either the hospitalized or pooled cohorts, nor in sensitivity analysis of (1) individuals with laboratory‐confirmed influenza and (2) those aged < 65 years. Conclusion In a geographically diverse cohort of individuals with influenza, the genetic links to disease progression only started to become evident in the sensitivity analyses, mainly when looking at younger individuals. The power to detect associations was limited by the rate of disease progression and heterogeneity in phenotypes of the individuals studied, and therefore, additional studies focused on the role of genetics in influenza disease progression are needed.

Purpose:Ebola virus disease (EVD) is associated with vision-threatening ophthalmic sequelae, yet outcomes in young survivors remain poorly characterized. We sought to distinguish ophthalmic pathology in pediatric EVD survivors relative to close contacts and adult EVD survivors. Design:Cross-sectional baseline analysis of participants enrolled in the Partnership for Research on Ebola Virus in Liberia (PREVAIL) III longitudinal cohort study. Participants:Eighty-eight pediatric EVD survivors (ages 6-17 years), 203 pediatric close contacts (ages 6-17 years), and 463 adult EVD survivors (ages ≥18 years). Testing:Visual function testing, slit-lamp biomicroscopy, indirect ophthalmoscopy, and OCT. Main Outcome Measures:Prevalence of ocular symptoms, functional vision measures, and evidence of inflammation on examination and imaging. Results:Compared with close contacts, pediatric EVD survivors at their baseline visit experienced significantly higher rates of light sensitivity (43.2% vs. 31.2%, P < 0.05), best-corrected visual acuity less than 20/40 (6.8% vs. 0.5%, P = 0.013), impaired color discrimination with ≥3 incorrect Ishihara color plates (10.2% vs. 1.5%, P = 0.003), further accommodative near point (16.8 cm vs. 16 cm, P = 0.015), and lower intraocular pressure (13.0 vs. 14.3 mmHg, P = 0.001). Slit-lamp biomicroscopy revealed higher rates of anterior chamber cells (8% vs. 2.5%, P = 0.036), cataract (8% vs. 0.5%, P = 0.0078), vitreous cell (6.8% vs. 0.5%, P = 0.018), and peripheral retinal scars (9.1% vs. 3%, P = 0.03) in pediatric EVD survivors relative to pediatric close contacts. Relative to adult EVD survivors, pediatric EVD survivors experienced higher rates of anterior chamber cells (8% vs. 3.2%, P = 0.04), but were less likely to experience posterior uveitis (5.7% vs. 13.8%, P = 0.04), and less likely to demonstrate mild or greater vitreous opacities on OCT (20.9% vs. 34.1%, P = 0.017). Conclusions:Pediatric EVD survivors exhibit a distinct profile of ocular sequelae compared with both close contacts and adult survivors, characterized by higher rates of anterior segment inflammation. These findings highlight the importance of considering the unique needs of children in the setting of emerging infectious diseases. Financial Disclosures:Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

The accurate measurement of Ebola virus (EBOV)-specific antibody responses is crucial to assessing immunity induced by EBOV infection or vaccination. For this purpose, the Filovirus Animal Nonclinical Group (FANG) anti-EBOV glycoprotein (GP1,2) ELISA is considered the "gold-standard". However, it has limitations such as high repeat-rates and variability, and low throughput. Here, we describe two new alternative assays: a Single-Molecule Assay Planar EBOV GP1,2 ELISA and a multiplexed EBOV GP1,2, EBOV nucleoprotein, and EBOV Viral Protein 40 Luminex assay, and compare these with two versions of the FANG ELISA. Samples were selected from participants receiving vaccine or placebo in a randomized, placebo-controlled, double-blinded study of two EBOV vaccines (PREVAIL 1), and a longitudinal cohort study of Ebola virus disease (EVD) survivors and their close contacts (PREVAIL 3). All four assays were concordant in their measurements of anti-EBOV GP1,2-specific immunoglobulin G responses, allowing for the determination of conversion equations for antibody measurements across assays. In addition, all four showed a similar ability to distinguish vaccine recipients from placebo recipients and EVD survivors from their close contacts. Compared to the FANG assays, the Quanterix and Luminex assays had lower variability, lower repeat rates, and higher throughput, making them good alternatives for future studies.

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.

Numerous neurologic symptoms were reported more commonly in EVD cases than in controls, suggesting that EVD may have a lasting effect on the nervous system. Limitations included small sample size and reliance on participant self-report. Our findings highlight the importance of long-term clinical monitoring of pediatric EVD survivors, given the potential impact on childhood development.

Kenya faces a persistent shortage in the supply of blood for transfusion, collecting only half its estimated annual need. This shortage critically affects care for patients with conditions relying on timely and adequate blood availability, such as postpartum hemorrhage, severe anemia, or trauma. Factors contributing to persistent blood shortages include limited community awareness of the role of blood in healthcare, reliance on family replacement donors, low rates of voluntary donation, and fragmented governance and coordination across the blood system continuum from donor mobilization to point of care transfusion. The CoBAnK study evaluated whether Community-Facility Transfusion Committees (CFTCs), a novel, shared governance model designed to improve linkages between communities and healthcare facilities, can improve blood availability at the point of care. The study assessed the impact of CFTCs on blood request fulfillment, time to transfusion, and patient outcomes, as well as their feasibility, acceptability, fidelity, and sustainability across diverse health system settings. This was a hybrid effectiveness-implementation cluster-randomized trial across nine sites (transfusing hospitals without an on-site blood bank, and the communities they serve) in three Kenyan counties. Sites were randomized to intervention and control arms. At intervention sites, CFTCs were established with representation from three local blood transfusion stakeholder groups: clinical or laboratory health facility staff, community leaders, and community health workers. Committees received technical and financial support to design and implement initiatives for improving local blood availability. Facilities assigned to the control arm continued their usual blood management and transfusion practices in accordance with current local blood availability conditions, without implementing the CFTC model. The primary effectiveness outcome is the met blood need by crossmatch in transfusing hospitals; secondary effectiveness outcomes are time to transfusion and 14-day patient outcomes. Effectiveness analyses will use regression models for blood requests that account for clustering at the facility level. Co-primary implementation outcomes include acceptability, feasibility, fidelity, and sustainability of the CFTC model. These will be assessed using validated measures guided by the RE-AIM, CFIR and PSE frameworks. Data collected includes structured meeting observations, stakeholder surveys, interviews, and data on individual blood requests. Recruitment and data collection are complete. This study evaluates a novel approach to community-engaged governance of health systems to address persistent blood shortages. By linking communities where blood resides with facilities where blood is needed, this intervention aims to enable sustainable, context-specific solutions to chronic blood shortages that affect healthcare systems globally. Findings from this study will inform local, regional, national and global strategies for strengthening blood systems. ClinicalTrials.gov NCT06142825; https://clinicaltrials.gov/study/NCT06142825

OBJECTIVES:Deferring antiretroviral therapy (ART) until a CD4 count below cells/mm3 or other clinical indication in people with HIV (PWH) carries an increased risk of severe bacterial infections and tuberculosis (TB). It is not known if this increased risk is reversed after ART initiation. METHODS:We analyzed 4684 adult PWH with CD4 cell counts above 500 cells/mm3 who were randomized to immediate or deferred ART in the Strategic Timing of AntiRetrovial Treatment trial. In May 2015, the deferred group was offered ART and follow-up continued until December 2021. Cox proportional hazards models were used to compare the risks of severe bacterial infections including TB in the immediate and deferred groups before and after ART initiation in the deferred group. RESULTS:A total of 217 (4.6%) participants experienced a severe bacterial infection during the entire follow-up period. Pre-2016, the immediate group had a lower rate of severe bacterial infections compared to the deferred group (hazard ratio [HR] 0.38; 95% CI 0.26, 0.55). During 2016-2021, there was no longer a statistically significant difference (HR 0.75; 95% CI 0.49, 1.16). No differences were observed between clinical or demographic subgroups. CONCLUSION:The increased risk of severe bacterial infections seen after deferring ART is reversed once ART is initiated.

The impact on immunogenicity and efficacy of SARS-CoV-2 vaccination in people with prior COVID-19 could differ depending on timing of vaccination and number of doses. The VATICO study randomized 66 hospitalized recovered COVID-19 individuals to receive either immediate or deferred vaccination, with one or two doses of mRNA SARS-CoV-2 vaccines. We measured binding and neutralizing antibodies against SARS-CoV-2 at enrollment and longitudinally. Median (IQR) time from SARS-CoV-2 infection to first vaccination was 68 (53-75) days in the immediate group, and 151 (137-173) days in the deferred group. At week 48, timing or number of vaccine doses did not influence the change in antibody levels relative to baseline. Adherence to the assigned vaccine regimen was lower in the deferred group, particularly in participants receiving two doses. Although the study ultimately lacked adequate power to draw firm conclusions, these results suggest possible benefits of prompt vaccination after recovery from COVID-19.

BACKGROUND:Increasingly, persons with HIV in Liberia are receiving antiretroviral therapy containing the integrase strand-transfer inhibitor (InSTI) dolutegravir (DTG), but the prevalence of and factors associated with virologic failure and HIV drug resistance (HIVDR) remain unknown. METHODS:Cross-sectional analysis of 2019-2022 enrolment data from 1276 persons with HIV in the HONOR cohort included sociodemographic information, plasma viral loads (pVL), CD4 counts, and HIVDR testing by next generation sequencing in participants with virologic failure (pVL≥1000 copies/mL). RESULTS:Of the 1201 participants with pVL results, 72% are female and median age is 42 (interquartile range [IQR] 35-50) years. All are on ART (median 6.1 [2.1-11] years): 74% on DTG-based and 23% on non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens. Ninety (7.5%) had virologic failure; 970 (81%) are suppressed (<40 copies/mL). Virologic failure is less prevalent with DTG- versus NNRTI-based regimens (5.3% vs. 14%, adjusted prevalence ratio [aPR]=0.3, 95% confidence interval [CI] 0.2-0.5) and is associated with age <50 years, CD4 count <200 cells/µL, and hemoglobin <11 g/dL. In 70 participants with virologic failure and successful sequencing, HIVDR prevalence is 81% for any ARV, 5.7% for InSTIs, 79% for NNRTIs, and 61% for nucleos(t)ide reverse transcriptase inhibitors (NRTIs). Intermediate-to-high resistance to ≥1 NRTI in current ART is less prevalent with DTG+2NRTIs than NNRTI+2NRTIs regimens (aPR = 0.5, 95%CI 0.3-0.8). CONCLUSIONS:Most participants in the cohort are virologically-suppressed. Among those with virologic failure, HIVDR prevalence is high to NRTIs and NNRTIs, but low to InSTIs. Ongoing evaluation is necessary to determine the durability of DTG-based ART.

BACKGROUND AND OBJECTIVES:The West Africa Ebola virus disease (EVD) outbreak resulted in over 28,000 individuals infected, primarily in Liberia, Guinea, and Sierra Leone. Data from previous outbreaks indicate lasting health problems in survivors. The long-term neurologic impact of EVD remains largely unknown. The aim of this study was to characterize the neurologic and neurocognitive sequelae of EVD in pediatric survivors of the 2015 outbreak in Liberia. METHODS:In this cross-sectional observational study conducted in Monrovia, Liberia, pediatric survivors of acute EVD aged younger than 18 years at the time of infection and older than 2 years at the time of the visit, along with their asymptomatic close contacts as controls, were seen at a median of 18 months after EVD. The single clinic visit included a neurologic history and symptom questionnaire, neurologic examination, and neurocognitive testing. Seropositive survivors and seronegative controls were included in analyses, with the t test used for continuous variables and the χ2 or Fisher exact test used for categorical variables. RESULTS:The cohort included 31 EVD cases and 41 controls, with a median age of 11 years (44% female). Neurologic symptoms that were reported significantly more frequently in cases than in controls included arm/leg weakness (67.7% vs 4.9%, p < 0.0001); problems with sitting, standing, or walking (22.6% vs 4.9%, p = 0.031); difficulty seeing (38.7% vs 9.8%, p = 0.003); difficulty understanding speech (32.3% vs 0%, p < 0.0001); fecal incontinence (19.4% vs 0%, p = 0.0051); and lack of motivation (22.2% vs 0%, p = 0.0052). EVD cases more often demonstrated disability than controls on the modified Rankin Scale. EVD cases "either sometimes or often" faced consequences for poor behavior, became upset for unknown reasons, and had difficulty completing tasks independently more often than controls on executive function assessment. There was no significant difference between groups in individual neurologic examination components, frequency of uveitis, or cognitive test scores. DISCUSSION:Numerous neurologic symptoms were reported more commonly in EVD cases than in controls, suggesting that EVD may have a lasting effect on the nervous system. Limitations included small sample size and reliance on participant self-report. Our findings highlight the importance of long-term clinical monitoring of pediatric EVD survivors, given the potential impact on childhood development.

BACKGROUND:A high proportion of survivors of Ebola virus disease (EVD) have post-acute sequelae of EVD (PASE), but the relationship between inflammation and PASE pathogenesis is poorly understood. This study tests the hypothesis that inflammation is associated with PASE among survivors with and without viral RNA shedding in the semen. METHODS:This was a case-control study nested in a longitudinal cohort that recruited confirmed survivors of EVD and their uninfected contacts from the 2013-16 EVD epidemic in Liberia, starting on June 1, 2015. We included participants aged at least 18 years with clinical data and plasma available at cohort baseline for analysis. A semen donation substudy tested male survivors for Ebola virus RNA shedding in the semen. A sex-stratified and survivor-stratified random sample of cases (survivors) and controls (contacts) was obtained to select stored baseline plasma samples for cytokine testing of markers of inflammation, immune regulation, and antiviral responses. Serostatus of cases and controls was confirmed by Filovirus Animal Nonclinical Group assay. We identified inflammatory markers (adjusted p≤0·05) elevated in cases compared with controls and then used these biomarkers in analyses comparing survivors with and without pre-specified PASE-associated clinical findings (self-reported symptoms and abnormal examination findings). Survivors with viral RNA shedding in the semen formed subgroup analyses. FINDINGS:Our analysis cohort consisted of 1044 participants (594 survivors of EVD and 450 uninfected contacts); 515 (49·3%) were female and 529 (50·7%) were male. The subcohort of 243 male survivors with data on viral shedding included 81 (33%) participants with viral shedding in semen. Median time from acute EVD to baseline was 317 days (IQR 271-366). Survivors of EVD showed a pattern of elevated inflammatory markers indicative of macrophage (MCP-1, IL-1β, and M-CSF) and angiogenic factor activation (VEGF-A) compared with controls (adjusted p<0·05). In survivors with viral shedding in the semen compared with controls, VEGF-A was the only inflammatory marker that was significantly higher (adjusted p<0·001). After restricting the analysis to survivors, each inflammatory marker had a specific pattern of clinical findings. Higher levels of IL-1β were associated with higher odds of urinary frequency (p=0·002), musculoskeletal abnormalities (p=0·003), and abdominal abnormalities (p=0·03). By contrast, higher levels of MCP-1 were associated with lower odds of the same clinical findings. M-CSF was the only inflammatory marker associated with lower odds of joint pain (p=0·04). Higher levels of VEGF-A were associated with higher odds of abnormal chest findings in the overall survivor group (p=0·02) and in the subgroup with viral shedding in the semen (p=0·02). INTERPRETATION:We found evidence of distinct biological pathways for PASE. Although viral RNA shedding in the semen could be associated with angiogenic activation, it did not explain many of the PASE symptoms and exam findings associated with the elevated macrophage markers, suggesting the pathobiology of some clinical manifestations might be autoimmunity, immune dysregulation, or another biological mechanism. These findings could inform shared biological pathways with other infection-associated chronic conditions, including post-acute sequelae of SARS-CoV-2 infection. FUNDING:National Cancer Institute and National Institute of Allergy and Infectious Diseases at the US National Institutes of Health.

Background:Clonal hematopoiesis of indeterminate potential (CHIP) has been associated with older age, inflammation and with risk of coronary artery disease (CAD). We aimed to characterize the burden of CHIP, and to explore the association between CHIP, inflammatory markers, and CAD in older persons with HIV (PWH).Methods:From the Copenhagen Comorbidity in HIV Infection (COCOMO) study, we included 190 individuals older than 55 years of age. We defined CHIP as variant allele fraction at least 2%. CAD was categorized according to the most severe coronary artery lesion on coronary computed tomography (CT) angiography as no coronary atherosclerosis; any atherosclerosis defined as at least 1% stenosis and obstructive CAD defined as at least 50% stenosis.Results:In the entire population (median age 66 years, 87% men), we identified a total of 62 mutations distributed among 49 (26%) participants. The three most mutated genes were DNMT3A, TET2, and ASXL1, accounting for 49, 25, and 16% of mutations, respectively. Age and sex were the only variables associated with CHIP. IL-1 beta, IL-1Ra, IL-2, IL-6, IL-10, soluble CD14, soluble CD163 and TNF-alpha were not associated with CHIP, and CHIP was not associated with any atherosclerosis or with obstructive CAD in adjusted analyses.Conclusion:In older, well treated, Scandinavian PWH, more than one in four had at least one CHIP mutation. We did not find evidence of an association between CHIP and inflammatory markers or between CHIP and CAD. CHIP is an unlikely underlying mechanism to explain the association between inflammation and CAD in treated HIV disease.

Abstract Background Human genetic contribution to HIV progression remains inadequately explained. The type 1 interferon (IFN) pathway is important for host control of HIV and variation in type 1 IFN genes may contribute to disease progression. This study assessed the impact of variations at the gene and pathway level of type 1 IFN on HIV-1 viral load (VL). Methods Two cohorts of antiretroviral (ART) naïve participants living with HIV (PLWH) with either early (START) or advanced infection (FIRST) were analysed separately. Type 1 IFN genes (n = 17) and receptor subunits (IFNAR1, IFNAR2) were examined for both cumulated type 1 IFN pathway analysis and individual gene analysis. SKAT-O was applied to detect associations between the genotype and HIV-1 study entry viral load (log10 transformed) as a proxy for set point VL; P-values were corrected using Bonferroni (P < 0.0025). Results The analyses among those with early infection included 2429 individuals from five continents. The median study entry HIV VL was 14,623 (IQR 3460–45100) copies/mL. Across 673 SNPs within 19 type 1 IFN genes, no significant association with study entry VL was detected. Conversely, examining individual genes in START showed a borderline significant association between IFNW1, and study entry VL (P = 0.0025). This significance remained after separate adjustments for age, CD4+ T-cell count, CD4+/CD8+ T-cell ratio and recent infection. When controlling for population structure using linear mixed effects models (LME), in addition to principal components used in the main model, this was no longer significant (p = 0.0244). In subgroup analyses stratified by geographical region, the association between IFNW1 and study entry VL was only observed among African participants, although, the association was not significant when controlling for population structure using LME. Of the 17 SNPs within the IFNW1 region, only rs79876898 (A > G) was associated with study entry VL (p = 0.0020, beta = 0.32; G associated with higher study entry VL than A) in single SNP association analyses. The findings were not reproduced in FIRST participants. Conclusion Across 19 type 1 IFN genes, only IFNW1 was associated with HIV-1 study entry VL in a cohort of ART-naïve individuals in early stages of their infection, however, this was no longer significant in sensitivity analyses that controlled for population structures using LME.

Background. Persistent mortality in adults hospitalized due to acute COVID-19 justifies pursuit of disease mechanisms and potential therapies. The aim was to evaluate which virus and host response factors were associated with mortality risk among participants in Therapeutics for Inpatients with COVID-19 (TICO/ACTIV-3) trials. Methods. A secondary analysis of 2625 adults hospitalized for acute SARS-CoV-2 infection randomized to 1 of 5 antiviral products or matched placebo in 114 centers on 4 continents. Uniform, site-level collection of participant baseline clinical variables was performed. Research laboratories assayed baseline upper respiratory swabs for SARS-CoV-2 viral RNA and plasma for anti-SARS-CoV-2 antibodies, SARS-CoV-2 nucleocapsid antigen (viral Ag), and interleukin-6 (IL-6). Associations between factors and time to mortality by 90 days were assessed using univariate and multivariable Cox proportional hazards models. Results. Viral Ag >= 4500 ng/L (vs <200 ng/L; adjusted hazard ratio [aHR], 2.07; 1.29-3.34), viral RNA (<35 000 copies/mL [aHR, 2.42; 1.09-5.34], >= 35 000 copies/mL [aHR, 2.84; 1.29-6.28], vs below detection), respiratory support (<4 L O2 [aHR, 1.84; 1.06-3.22]; >= 4 L O2 [aHR, 4.41; 2.63-7.39], or noninvasive ventilation/high-flow nasal cannula [aHR, 11.30; 6.46-19.75] vs no oxygen), renal impairment (aHR, 1.77; 1.29-2.42), and IL-6 >5.8 ng/L (aHR, 2.54 [1.74-3.70] vs <= 5.8 ng/L) were significantly associated with mortality risk in final adjusted analyses. Viral Ag, viral RNA, and IL-6 were not measured in real-time. Conclusions. Baseline virus-specific, clinical, and biological variables are strongly associated with mortality risk within 90 days, revealing potential pathogen and host-response therapeutic targets for acute COVID-19 disease.