INTRODUCTION:Since its global reemergence in 2022, monkeypox (mpox) has demonstrated increased incidence and severity among people with human immunodeficiency virus (HIV [PWH]). Predictors of mpox diagnosis, vaccination, and outcomes among PWH are limited. METHODS:We included PWH with primary care visits after 1 January 2022 at 9 US sites participating in the Centers for AIDS Research Network of Integrated Clinic Systems Network. We identified mpox diagnosed between 1 June 2022 and 31 May 2023, through a combination of polymerase chain reaction result, diagnosis code, and/or tecovirimat receipt. We examined validated clinical diagnoses, laboratory results, vaccine data, and patient reported outcomes. We evaluated relative risks (RR) of mpox diagnosis, hospitalization, tecovirimat treatment, and vaccine receipt. FINDINGS:Among 19 777 PWH in care, 413 mpox cases (all male sex at birth) occurred (2.2 cases/100 person-years). Age <40 years, geographic region, Hispanic/Latine ethnicity, lack of antiretroviral therapy, detectable HIV viral load, and recent bacterial sexually transmitted infection predicted mpox diagnosis. PWH with CD4 200-349 cells/mm3 were most likely to be hospitalized (adjusted RR, 3.20; 95% confidence interval: 1.44-7.09) compared to CD4 ≥500, but half as likely as those with CD4 <200 to receive tecovirimat. Overall, smallpox/mpox vaccine effectiveness of ≥1 vaccine was 71% (adjusted RR, 0.29; 95% confidence interval: .14-.47) at preventing mpox, and 86% or better with CD4 ≥350 or HIV viral suppression. Non-Hispanic Black PWH were less likely to be vaccinated than other racial/ethnic identities. INTERPRETATION:PWH not on antiretroviral therapy or with unsuppressed HIV were more likely to be diagnosed with, and hospitalized for, mpox. Mpox/smallpox vaccine effectiveness was high, inclusive of those with low CD4 count and HIV viremia.

Background:Molecular amplification of tongue swab samples is a non-sputum-based investigational approach to diagnose pulmonary tuberculosis (pTB). An improved manual qPCR method for tongue swabs recently achieved >90% sensitivity overall in diagnosing TB, compared to a sputum microbiologic reference standard. Performance characteristics in persons with low-positive results on sputum molecular tests are unknown. Methods:Adults in South Africa and Uganda with sputum Xpert MTB/RIF Ultra Trace (TR+) results were recruited for confirmatory evaluation and follow-up. They underwent symptom evaluation, examination, chest X-ray, further sputum testing (repeat Xpert Ultra and two solid and liquid mycobacterial cultures), and two tongue swabs. Tongue swabs were tested using qPCR amplification of the IS6110 gene. A single copy detected on >=1 swab was considered TB-positive. TR+ persons not diagnosed with TB at baseline were re-evaluated at 1 and 3 months. We determined the sensitivity and specificity of tongue swabs against TB culture alone, a microbiologic reference standard (MRS: any positive result from Xpert Ultra or TB culture) and a composite reference standard (CRS: a clinical recommendation for TB treatment or any positive culture) at baseline. Results:225 enrolled TR+ participants (115 (51%) women, median age 38 [IQR 30-47], 130 (58%) people living with HIV (PWH)) provided at least 1 tongue swab at baseline. With a culture reference standard, 45 (20%) were positive for TB at baseline testing; 58 (26%) were positive for TB by MRS and 83 (37%) by CRS. Sensitivity and specificity of tongue swabs against culture were 25% [95% CI 13-40%] and 94% [90-97%], vs. MRS were 25% [95% CI 14-38%] and 96% [91-98%], and vs. CRS were 16% [9-26%] and 94% [89-98%]. Conclusion:Tongue swabs had low sensitivity and moderately high specificity for TB in persons with a Trace Xpert Ultra result. Tongue swabs have limited value for diagnosing people with low-positive molecular test results of uncertain clinical significance.

Introduction Tuberculosis (TB) remains the leading cause of infectious disease deaths, particularly among people living with HIV (PWH). Despite being preventable, TB preventive therapy (TPT) uptake is low in high-burden regions like South Africa, where new guidelines have expanded TPT eligibility and introduced shorter, more effective regimens like 3 months of weekly rifapentine and isoniazid (3HP). As differentiated service delivery models for HIV care have proven effective, there is increasing recognition that decentralising TPT delivery may improve coverage and completion. This study explores whether a community-based TPT delivery strategy can enhance uptake and completion of TPT compared with traditional clinic-based services.Method and analysis We will conduct a household-randomised, non-blinded, controlled trial. Persons eligible for TPT will be recruited from the TB TRIAGE+Trial study, a community-based household TB screening study. Households containing at least one person eligible for TPT will be randomised 1:1 to either community-based TPT or standard-of-care clinic referral for TPT. At enrolment, all participants will be provided with a 2-week supply of TPT in the community. Participants randomised to the community arm will receive the entire course of TPT in a single dispense (12 weeks of 3HP or 6 months of isoniazid, if 3HP is contraindicated). Clinic-arm participants will be referred to their local clinic for the remainder of their course of TPT and will collect TPT refills on the clinic-determined schedule. Our primary outcome is the proportion of participants who complete a course of TPT. Secondary outcomes include overall adherence to TPT, predictors of adherence with TPT, participant satisfaction with the assigned TPT delivery method and adverse events.Ethics and dissemination The study and its tools were approved by the Human Sciences Research Councils Research Ethics Committee (approval number: 2/25/10/23), based in Pretoria, Gauteng, South Africa, as well as the University of Washington Institutional Review Board (Study 00018448). Study findings will be shared through the community advisory group and local stakeholder meetings, relevant international and local meetings/conferences and peer-reviewed publications.Trial registration number NCT06214910. Date and version: 3.0, 30 July 2024.

A leading HIV vaccine strategy requires a priming immunogen to induce broadly neutralizing antibody (bnAb) precursors, followed by a series of heterologous boosters to elicit somatic hypermutation (SHM) and produce bnAbs. In two randomized, open-label phase 1 human clinical trials, IAVI G002 in the United States and IAVI G003 in Rwanda and South Africa (IAVI, International Aids Vaccine Initiative), we evaluated the safety and immunogenicity of mRNA-encoded nanoparticles as priming immunogens (both trials) and first-boosting immunogens (IAVI G002). The vaccines were generally safe and well tolerated, except that 18% of IAVI G002 participants experienced skin reactions. Priming induced bnAb precursors with substantial frequencies and SHM; heterologous boosting elicited increased SHM, affinity, and neutralization activity toward bnAb development; and elicited antibodies exhibited precise bnAb structural mimicry. The results establish clinical proof of concept that heterologous boosting can advance bnAb precursor maturation and demonstrate bnAb priming in Africa, where the HIV burden is highest.

Background: On the basis of recent clinical trial data for the treatment of drug-susceptible and drug-resistant tuberculosis (TB), the American Thoracic Society, U.S. Centers for Disease Control and Prevention, European Respiratory Society, and Infectious Diseases Society of America have updated clinical practice guidelines for TB treatment in children and adults in settings in which mycobacterial cultures, molecular and phenotypic drug susceptibility tests, and radiographic studies, among other diagnostic tools, are available on a routine basis. Methods: A Joint Panel representing multiple interdisciplinary perspectives convened with American Thoracic Society methodologists to review evidence and make recommendations using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) and GRADE-ADOLOPMENT (adoption, adaptation, and, as needed, de novo development of recommendations) methodology. Results: New drug-susceptible TB recommendations include the use of a novel 4-month regimen for people with pulmonary TB and a shortened 4-month regimen for children with nonsevere TB. Drug-resistant TB recommendation updates include the use of novel regimens containing bedaquiline, pretomanid, and linezolid with or without moxifloxacin. Conclusions: All-oral, shorter treatment regimens for TB are now recommended for use in eligible individuals

BACKGROUND:Xpert MTB/RIF Ultra (Xpert Ultra) is a molecular World Health Organization (WHO)-recommended rapid diagnostic test that simultaneously detects tuberculosis and rifampicin resistance. This review updates a comparative accuracy Cochrane review of Xpert MTB/RIF and Xpert Ultra as Xpert Ultra has replaced Xpert MTB/RIF. OBJECTIVES:To determine the diagnostic accuracy of Xpert MTB/RIF Ultra (Xpert Ultra) for detecting pulmonary tuberculosis and rifampicin resistance in adults and adolescents with presumptive tuberculosis based on signs or symptoms or with an abnormal chest x-ray suggestive of tuberculosis. SEARCH METHODS:We searched seven databases including CENTRAL, MEDLINE, and Embase, plus two trial registers (ClinicalTrials.gov and the WHO ICTRP) to 16 October 2023 without language restrictions. A WHO Public Call for ongoing and unpublished studies was made between 30 November 2023 and 15 February 2024. SELECTION CRITERIA:We included cross-sectional studies, cohort studies, and randomised controlled trials that provided data on the diagnostic accuracy of Xpert Ultra using respiratory specimens in adolescents (aged 10 to 14 years) and adults (aged 15 years and older) with presumptive pulmonary tuberculosis. For pulmonary tuberculosis detection, the reference standards were culture and a composite reference standard. For rifampicin resistance, the reference standards were culture-based phenotypic drug susceptibility testing with or without whole genome sequencing. DATA COLLECTION AND ANALYSIS:Two review authors independently extracted data using a standardised form. We assessed risk of bias using QUADAS-2. We performed meta-analyses using a bivariate model to produce summary sensitivities and specificities, separately for pulmonary tuberculosis detection and rifampicin resistance detection. We performed subgroup analyses by smear status, HIV status, and history of tuberculosis. We summarised Xpert Ultra trace-positive results. MAIN RESULTS:Pulmonary tuberculosis detection For detection of pulmonary tuberculosis, Xpert Ultra summary sensitivity and specificity against culture were 90.7% (95% confidence interval (CI) 88.2 to 92.7) and 94.8% (95% CI 92.8 to 96.3) (32 studies, 12,529 participants; high-certainty evidence). Most studies had low risk of bias in all QUADAS-2 domains. If the point estimates for Xpert Ultra are applied to a hypothetical cohort of 1000 people, where 100 of those presenting with symptoms have pulmonary tuberculosis, Xpert Ultra will miss nine cases. The number of people wrongly diagnosed with pulmonary tuberculosis would be 47. In people living with HIV, Xpert Ultra summary sensitivity and specificity were 87.7% (82.0 to 91.7) and 95.3% (92.2 to 97.2) (11 studies, 1164 participants). Amongst people with smear-negative, culture-positive pulmonary tuberculosis, Xpert Ultra summary sensitivity and specificity were 80.7% (75.4 to 85.0) and 94.0% (91.3 to 95.9) (16 studies, 6460 participants). In people with a history of tuberculosis, Xpert Ultra summary sensitivity and specificity were 84.8% (78.2 to 89.7) and 86.2% (78.9 to 91.3) (9 studies, 809 participants). The proportion of Ultra trace-positive results that were true positives compared to the microbiological reference standard was 38.8%. Reclassifying trace-positive results as Xpert Ultra-negative led to a reduction in sensitivity and modest increase in specificity. Rifampicin resistance detection For detection of rifampicin resistance, Xpert Ultra summary sensitivity and specificity were 95.8% (93.2 to 97.4) and 98.3% (97.0 to 99.0) (10 studies, 1644 participants; high-certainty evidence). Most studies had low risk of bias in all QUADAS-2 domains. If the point estimates for Xpert Ultra are applied to a hypothetical cohort of 1000 people, where 100 of those presenting with symptoms have rifampicin resistance, Xpert Ultra will miss four cases. The number of people wrongly diagnosed with rifampicin resistance would be 16 out of the 900 who do not have rifampicin resistance. Xpert Ultra performed similarly, for rifampicin resistance, in people with smear-positive and smear-negative tuberculosis. AUTHORS' CONCLUSIONS:Xpert Ultra has high sensitivity and specificity for detection of pulmonary tuberculosis rifampicin resistance. Xpert Ultra for the detection of pulmonary tuberculosis has lower sensitivity in people with smear-negative/culture-positive tuberculosis and lower sensitivity and specificity in people with a history of tuberculosis. Xpert Ultra trace-positive results were common. Strengths of this review include the approach to identifying relevant studies, the number of studies and participants included in this systematic review, and that most studies were at low risk of bias. The small number of studies (six) and participants who were adolescents is a limitation to our accuracy estimates in this age group. Xpert Ultra testing provides accurate results and can allow rapid initiation of treatment for rifampicin-resistant and multiple-drug-resistant tuberculosis. FUNDING:The WHO supported this systematic review. Liverpool School of Tropical Medicine hosted the Cochrane Infectious Diseases Group (CIDG) editorial base, which supported the authors in the development of this review update. The Foreign, Commonwealth and Development Office funded the CIDG. REGISTRATION:Generic protocol available on Open Science Framework via https://osf.io/26wg7/wiki/home/. Previous protocol and review versions available via DOI 10.1002/14651858.CD009593 and DOI 10.1002/14651858.CD009593.pub5.

Background:Highly sensitive molecular tests, like Xpert Ultra, are reshaping TB diagnosis-detecting paucibacillary TB but sometimes creating uncertainty when they detect DNA in extremely low quantities that may not signal disease. This ambiguity also complicates the evaluation of novel diagnostic strategies. We sought to monitor adults with a 'Trace' result on an Xpert Ultra test to estimate the risk of tuberculosis disease up to 24 months later. Methods:We conducted a multi-site clinical observational study in South Africa and Uganda, where we enrolled ambulatory participants aged >=15 years with a sputum Xpert Ultra Trace result who had not yet initiated TB treatment. All participants underwent comprehensive clinical evaluation and repeated, standard sputum TB testing. Clinicians deferred treatment recommendations if TB status remained uncertain after evaluation. Untreated participants were followed regularly until TB diagnosis and/or treatment initiation. We estimated cumulative incidence of TB disease, defined by three reference standards. Results:Of 311 participants with Trace results (50% male, 57% PLHIV, 37% treated for TB within the last 5 years), 24% were positive for TB within 12 months by culture, 37% by sputum Xpert or culture, and 54% by culture or clinical diagnosis. After excluding those diagnosed with TB at baseline, patients identified at baseline as having recent TB history, abnormal chest x-ray, or positive tongue swab, had higher risk of TB diagnosis (hazard ratios: 2.6, 2.4, 4.5, respectively) during follow-up. This hazard was highest in the first three months after the negative baseline evaluation (0.22 [95% CI: 0.19-0.26] per person-month) and decreased to 0.01 [95% CI: 0-0.02] per person-month in both the 3-6 and 6-12-month intervals. Conclusion:Approximately half of adults and adolescents with a sputum Trace result were diagnosed with TB disease within twelve months. Although most TB diagnoses were made within 3 months, risk remained higher than estimated population incidence rates through the follow-up period. Individuals with sputum Trace results should receive close clinical monitoring, despite initial clinical treatment decision.

INTRODUCTION:As differentiated HIV services provided outside of clinics are scaled up, clients may have fewer interactions with ancillary services for non-communicable disease (NCD) prevention and management traditionally offered within facilities. This study was embedded in the DO ART randomised trial (2016-2019), which demonstrated that community-based differentiated service delivery (DSD) improved HIV viral suppression compared with facility-based care. We assessed NCD risk among men and women living with HIV accessing community-based DSD versus facility-based care in KwaZulu-Natal, South Africa. METHODS:First, we described lifestyle and clinical NCD risk among DO ART participants in rural and semi-rural KwaZulu-Natal. Next, we compared clinical NCD risk at 12 months by randomisation arm (community-based DSD vs. facility-based care). Finally, we explored the relationship between 12-month viral suppression and clinical NCD risk, overall and stratified by randomisation arm (i.e. service delivery type). RESULTS:Among 1010 participants, the median age was 32 years, 245 (24%) smoked, 229 (23%) had hypertension and 502 (50%) were overweight or obese (body mass index [BMI] ≥ 25). Smoking was more common among men than women (43% vs. 6%, p ≤ 0.001), while overweight/obesity was more common among women than men (65% vs. 34%, p ≤ 0.001). We found no statistically significant association between service delivery type and clinical NCD risk factors at 1 year. We also found no significant associations between viral suppression at 12 months and blood pressure, haemoglobin A1c or smoking. However, virally suppressed clients had higher mean BMI (+0.93 kg/m2, p = 0.004) and higher mean cholesterol (+5.79 mg/dl, p = 0.001). These associations were greater in effect size and statistically significant among clients receiving community-based DSD (BMI: p = 0.003; cholesterol: p = 0.001), but smaller and not significant for facility-based care (BMI: p = 0.299; cholesterol: p = 0.448). CONCLUSIONS:Relatively younger adults accessing HIV treatment in South Africa had substantial NCD risk, which differed by gender and may increase with age. Among clients receiving community-based DSD, viral suppression was associated with modestly higher BMI and cholesterol levels. Community-based DSD programmes should consider integrating NCD risk screening and management that addresses gender-specific needs to prevent premature mortality among people living with HIV. CLINICAL TRIAL NUMBER:NCT0292999.

INTRODUCTION:Differentiated service delivery (DSD) models for HIV and tuberculosis (TB) care prioritize efficient resource allocation and targeted interventions, and benefit from accurate assessment of patients' antiretroviral therapy (ART) pill-taking status. Accurate ART use identification is essential for ensuring proper care transition services rather than unnecessary initiation. A point-of-care urine tenofovir (TFV) assay may identify undisclosed ART use in settings with high rates of TB and HIV coinfection. METHODS:A cohort of people living with HIV (PWH) presenting for routine care, including newly diagnosed and those returning to care, and reporting no ART use within 90 days, was enrolled in a clinic-based cross-sectional study of TB prevalence which tested for TB using sputum and urine-based TB tests in two clinics in KwaZulu-Natal, South Africa. CD4 counts were determined at the time of ART initiation, per national guidelines. A novel urine-based lateral flow assay (LFA) which detects TFV ingested within the past 4-7 days was used to assess ART use from thawed urine samples, which were collected concurrently with the self-report assessment. Conditional logistic regression models assessed predictors of ART non-disclosure. RESULTS:Between 12/2021 and 5/2024, 404 PWH (40% male) reporting no recent ART use presented for ART initiation. TB testing identified 14 (3%) PWH with undiagnosed TB. Seventy-nine (20%) had detectable TFV in urine indicating undisclosed ART use, with a median CD4 count of 466 cells/mm3 (IQR 277-625) compared to 322 cells/mm3 (IQR 175-490, p = 0.001) in those without undisclosed ART use. In a multivariable model, undisclosed ART use was associated with older age, rural clinic site, higher CD4 count and having active TB, but not with gender, education or employment. CONCLUSIONS:Among people presenting for HIV treatment initiation, 20% had evidence of ART use within 4-7 days by TFV urine LFA testing. Integration of point-of-care urine TFV assays into DSD models of HIV care may support providers to engage PWH about treatment challenges, address potential barriers to disclosure and facilitate seamless transfers between clinics. If successful, this strategy may reduce duplicative care entries and promote more efficient use of resources.

BACKGROUND:Development of a non-sputum test using readily-obtainable biospecimens remains a global priority for tuberculosis (TB) control. We quantified lipoarabinomannan (LAM) concentrations, a pathogen biomarker for Mycobacterium tuberculosis, in urine, plasma and serum for real-world diagnostic accuracy of pulmonary TB among people living with and without HIV. METHODS:We conducted a prospective diagnostic study among adults with TB symptoms in South Africa. We measured LAM concentrations in time-matched urine, plasma and serum with an electrochemiluminescence immunoassay using two capture antibodies (FIND 28 and S4-20). From the completed cohort, we randomly selected 210 participants (2 cases: 1 control) based on sensitivity estimates, and we compared diagnostic accuracy of LAM measurements against the microbiological reference standard. FINDINGS:Urine and blood specimens from 210 of 684 adults enrolled were tested for LAM. Among 138 TB-positive adults (41% female), median urine LAM was 137 pg/mL and 52 pg/mL by FIND 28 and S4-20, respectively. Average LAM concentrations were highest in HIV-positive participants with CD4+ T cells <200 cells/mm3. Urine LAM by S4-20 achieved diagnostic sensitivity of 62% (95% CI: 53%-70%) and specificity of 99% (95% CI: 96%-100%). Plasma and serum LAM by FIND 28 showed similar sensitivity (70%, 95% CI: 62%-78%) and comparable specificities (90%, 95% CI: 82%-97%; 94%, 95% CI: 88%-99%). Diagnostic sensitivity of urine LAM by S4-20 was higher among participants without HIV (41%, 95% CI: 24%-61%) compared to HIV-positive participants with CD4 ≥200 cells/mm3 (20%, 95% CI: 8%-39%). INTERPRETATION:Detection of LAM was achievable in non-sputum specimens for pulmonary TB, but additional analyte concentration or signal amplification may be required to achieve diagnostic accuracy targets. FUNDING:Bill and Melinda Gates Foundation.

Alcohol use was associated with elevated COVID-19 risk in the general population. People with HIV (PWH) have high prevalences of alcohol use. To evaluate the effect of alcohol use on COVID-19 risks among PWH, we estimated the risk of COVID-19 diagnosis and COVID-19-related hospitalization among PWH in routine care at 8 HIV primary care centers that contributed data to the Centers for AIDS Research Network of Integrated Clinical Systems (CNICS) cohort according to their alcohol use just prior to the COVID-19 pandemic. The CNICS data repository includes demographic characteristics, clinical diagnoses, and laboratory test results from electronic medical records and other sources. Alcohol use, substance use, and mental health symptoms were self-reported on tablet-based standardized surveys. Alcohol use was categorized according to standard, sex-specific Alcohol Use Disorder Identification Test-Consumption instrument cut-offs. We followed 5,496 PWH (79% male, 48% Black race, median age = 53 years) from March 1, 2020 to December 31, 2020. Relative to PWH with no baseline alcohol use, the adjusted hazard ratio (aHR) of COVID-19 diagnosis was 1.09 (95% confidence interval [CI]: 0.78, 1.51) for lower-risk drinking and 1.19 (95%CI: 0.81, 1.73) for unhealthy drinking. The aHR of COVID-19-related hospitalization was 0.82 (95%CI: 0.33, 1.99) for lower-risk drinking and 1.25 (95%CI: 0.50, 3.09) for unhealthy drinking. Results were not modified by recent cocaine or non-prescribed opioid use, depressive symptoms, or diagnoses of alcohol use disorder. The study suggested a slightly increased, but not statistically significant risk of COVID-19 diagnosis and hospitalization associated with unhealthy alcohol use.

We examined changes in the proportion of people with human immunodeficiency virus (PWH) with virologic suppression (VS) in a multisite US cohort before and since the coronavirus disease 2019 (COVID-19) pandemic. Overall, prior gains in VS slowed during COVID-19, with disproportionate impacts on Black PWH and PWH who inject drugs.

Background Tuberculosis is a leading cause of infectious disease mortality worldwide, but diagnosis of pulmonary tuberculosis remains challenging. Oral swabs are a promising non-sputum alternative sample type for the diagnosis of pulmonary tuberculosis. We aimed to assess the diagnostic accuracy of oral swabs to detect pulmonary tuberculosis in adults and children and suggest research implications. Methods In this systematic review, we searched published and preprint studies from Jan 1, 2000, to July 5, 2022, from eight databases (MEDLINE, Embase, Scopus, Science Citation Index, medRxiv, bioRxiv, Global Index Medicus, and Google Scholar). We included diagnostic accuracy studies including cross-sectional, cohort, and case-control studies in adults and children from which we could extract or derive sensitivity and specificity of oral swabs as a sample type for the diagnosis of pulmonary tuberculosis against a sputum microbiological (nucleic acid amplification test [NAAT] on sputum or culture) or composite reference standard. Findings Of 550 reports identified by the search, we included 16 eligible reports (including 20 studies and 3083 participants) that reported diagnostic accuracy estimates on oral swabs for pulmonary tuberculosis. Sensitivity on oral swabs ranged from 36% (95% CI 26-48) to 91% (80-98) in adults and 5% (1-14) to 42% (23-63) in children. Across all studies, specificity ranged from 66% (95% CI 52-78) to 100% (97-100), with most studies reporting specificity of more than 90%. Meta-analysis was not performed because of sampling and testing heterogeneity. Interpretation Sensitivity varies in both adults and children when diverse methods are used. Variability in sampling location, swab type, and type of NAAT used in accuracy studies limits comparison. Although data are suggestive that high accuracy is achievable using oral swabs with molecular testing, more research is needed to define optimal methods for using oral swabs as a specimen for tuberculosis detection. The current data suggest that tongue swabs and swab types that collect increased biomass might have increased sensitivity. We would recommend that future studies use these established methods to continue to refine sample processing to maximise sensitivity.

Aim: Sotrovimab, an engineered human monoclonal antibody, targets a conserved region of the SARS-CoV-2 spike protein. The phase III COMET-TAIL study evaluated noninferiority of intravenous versus intramuscular sotrovimab for early treatment of high-risk COVID-19 in 973 participants. Materials & methods: We investigated prevalence of variants of concern/interest (VOC/VOI) and characterized baseline, postbaseline and treatment-emergent sotrovimab epitope amino acid substitutions. Results: The Delta variant was predominant; the Alpha, Delta or Mu variants were detected in participants meeting the primary clinical endpoint for progression. Of 82 participants with sotrovimab epitope substitutions, two participants with baseline epitope substitutions met the primary endpoint for progression. Conclusion: Overall, there was no evidence that specific VOC/VOI, or postbaseline and treatment-emergent epitope substitutions, impacted clinical progression.

Lipoarabinomannan (LAM) is a cell wall component of Mycobacterium tuberculosis that is excreted in the urine of persons with active tuberculosis (TB). Limited diagnostic sensitivity of LAM immunoassays has been due to selecting antibodies against LAM derived from in vitro cultured M. tuberculosis, rather than LAM purified from in vivo clinical urine specimens. Urinary LAM (uLAM) is critical to enable the development of and/or screening of novel uLAM-specific antibodies but is typically dilute and in heterogeneous mixtures with other urine components. We used physical, enzymatic, and chemical processes for the scaled isolation and purification of uLAM. The purified material may then be used to develop more sensitive uLAM diagnostic tests for active TB disease.

Community-based delivery and monitoring of antiretroviral therapy (ART) for HIV has the potential to increase viral suppression for individual- and population-level health benefits. However, the cost-effectiveness and budget impact are needed for public health policy. We used a mathematical model of HIV transmission in KwaZulu-Natal, South Africa, to estimate population prevalence, incidence, mortality, and disability-adjusted life-years (DALYs) from 2020 to 2060 for two scenarios: 1) standard clinic-based HIV care and 2) five-yearly home testing campaigns with community ART for people not reached by clinic-based care. We parameterised model scenarios using observed community-based ART efficacy. Using a health system perspective, we evaluated incremental cost-effectiveness and net health benefits using a threshold of $750/DALY averted. In a sensitivity analysis, we varied the discount rate; time horizon; costs for clinic and community ART, hospitalisation, and testing; and the proportion of the population receiving community ART. Uncertainty ranges (URs) were estimated across 25 best-fitting parameter sets. By 2060, community ART following home testing averted 27.9% (UR: 24.3–31.5) of incident HIV infections, 27.8% (26.8–28.8) of HIV-related deaths, and 18.7% (17.9–19.7) of DALYs compared to standard of care. Adolescent girls and young women aged 15–24 years experienced the greatest reduction in incident HIV (30.7%, 27.1–34.7). In the first five years (2020–2024), community ART required an additional $44.9 million (35.8–50.1) annually, representing 14.3% (11.4–16.0) of the annual HIV budget. The cost per DALY averted was $102 (85–117) for community ART compared with standard of care. Providing six-monthly refills instead of quarterly refills further increased cost-effectiveness to $78.5 per DALY averted (62.9–92.8). Cost-effectiveness was robust to sensitivity analyses. In a high-prevalence setting, scale-up of decentralised ART dispensing and monitoring can provide large population health benefits and is cost-effective in preventing death and disability due to HIV.

Abstract Background The COMET-ICE trial demonstrated that sotrovimab clinically and statistically significantly reduces the risk of all-cause > 24-h hospitalization or death due to any cause among patients with COVID-19 at high risk of disease progression. Patient-reported outcomes are important to capture symptom burden of COVID-19 and assess treatment effectiveness. This study investigated symptoms and their impact over the acute phase of COVID-19 infection among patients on sotrovimab versus placebo. Methods Randomized (1:1), double-blind, multicenter, placebo-controlled, phase 2/3 study in 57 centers across five countries. Participants were non-hospitalized patients with symptomatic, mild-to-moderate COVID-19 and ≥ 1 baseline risk factor for disease progression (aged ≥ 55 years or ≥ 1 of the following: diabetes requiring medication, obesity, chronic kidney disease, congestive heart failure, chronic obstructive pulmonary disease, or moderate-to-severe asthma). An intravenous infusion of sotrovimab 500 mg or placebo was administered on Day 1. The FLU-PRO Plus questionnaire was administered once-daily with 24-h recall from Day 1–21, and at Day 29. Intensity and duration of COVID-19 symptoms were determined from area under the curve (AUC) and mean change in total and individual domain scores through Days 7, 14, and 21. Time to symptom alleviation was assessed. Results In total, 1057 patients were randomized to sotrovimab (n = 528) or placebo (n = 529). At Day 7, mean decrease in FLU-PRO Plus total score (measured by AUC) was statistically significantly greater for patients on sotrovimab (–3.05 [95% confidence interval (CI) –3.27 to –2.83]) than placebo (–1.98 [95% CI –2.20 to –1.76]; difference –1.07 [95% CI –1.38 to –0.76]; p < 0.001). Significant differences were also observed at Days 14 and 21. A more rapid decline in symptom severity was observed with sotrovimab versus placebo through Week 1 and the first 21 days post-treatment. By Day 21, 41% of patients on sotrovimab and 34% on placebo reported symptom resolution. In a post-hoc analysis, median time to symptom alleviation was 4 and 6 days, respectively. Conclusions Sotrovimab provides significant and rapid improvements in patient-reported COVID-19 symptoms, as measured by the FLU-PRO Plus. These results further show the benefits of sotrovimab in alleviating symptoms among high-risk patients with COVID-19. Trial registration ClinicalTrials.Gov: NCT04545060 ( https://clinicaltrials.gov/ct2/show/NCT04545060 ). Date of registration: September 10, 2020 (retrospectively registered).