Needle and syringe sharing among people who have recently injected drugs in Australia: The ETHOS Engage Study.

INTRODUCTION: Understanding needle/syringe sharing is crucial for reducing hepatitis C virus (HCV) infection and reinfection. This study aimed to assess the prevalence and factors associated with needle/syringe sharing among people who inject drugs in Australia, including those previously receiving HCV treatment. METHODS: The ETHOS Engage study was an observational cohort study which collected self-reported survey data on demographic and drug use information from people who inject drugs attending drug treatment clinics and needle and syringe programs over two waves between May 2018 and June 2021. Logistic regression was used to identify factors associated with needle/syringe sharing. RESULTS: Overall, 1555/2395 people enrolled in ETHOS Engage (65%) injected drugs in the past month. Among these, 432 (28%) reported needle/syringe sharing in the past month and 276 (18%) reported receptive sharing. Factors associated with receptive sharing included younger age (adjusted odds ratio [aOR] 1.72; 95% confidence interval [CI] 1.28-2.30), recent incarceration (aOR 2.04; 95% CI 1.40-2.94), more frequent injecting (≥daily vs. less than weekly; aOR 2.59; 95% CI 1.75-3.84) and unstable housing (aOR 1.78; 95% CI 1.26-2.52). Among 560 participants with prior HCV treatment, 87 (16%) reported receptive sharing with younger age (aOR 2.42; 95% CI 1.45-4.05) and daily or greater injection frequency (aOR 2.51; 95% CI 1.31-4.83) associated with receptive sharing. DISCUSSION AND CONCLUSIONS: Needle/syringe sharing was common among this population accessing harm reduction services. This study identifies high-risk populations with needle/syringe sharing. Research is needed to optimise HCV treatment to ensure people with ongoing risk behaviours receive adequate harm reduction following treatment to prevent reinfection.

Factors associated with hepatitis C testing, treatment, and current hepatitis C infection among men and women who inject drugs: The ETHOS engage study.

BACKGROUND: Evaluating gender-specific trends in hepatitis C virus (HCV) treatment uptake among men and women who inject drugs is crucial for ensuring equitable progress towards HCV elimination. This study aimed to quantify differences in testing, treatment, and current HCV infection between men and women who inject drugs. METHOD: ETHOS Engage is an observational cohort study of people who inject drugs attending drug treatment clinics and needle and syringe programs in Australia recruited from May 2018-September 2019 (wave 1) and November 2019-April 2021 (wave 2). Participants completed a questionnaire including self-reported HCV testing and treatment history and underwent point-of-care HCV RNA testing (Xpert® HCV Viral Load Fingerstick). Logistic regression was used to compare the factors associated with self-reported HCV testing and treatment and current HCV infection for men and women who inject drugs. RESULTS: Among 2,395 participants enrolled in ETHOS Engage, 66% (n = 1,591) were men, 33% (n = 786) women, and <1% (n = 18) did not identify as a man or woman. HCV testing history and current infection were similar among men and women. Among men or women ever eligible for HCV treatment (ever chronic HCV) (n = 1,242), women were less likely to report a history of HCV treatment compared to men (227/352, 64% vs. 631/890, 71%; p = 0.03). Among women, those aged <45 were less likely to report HCV testing (aOR: 0.57, 95%CI: 0.36, 0.90), treatment (aOR: 0.47, 95%CI: 0.29, 0.77), and more likely to have HCV infection (aOR: 1.48, 95%CI: 1.00, 2.20) CONCLUSION: Among women, those of childbearing age (<45) were less likely to report testing and treatment and were more likely to have current HCV infection. Women <45 years old should be a priority population for HCV care. Services that interface with these women should be optimised to enhance HCV testing and treatment.

Corrigendum to "Trends in decompensated cirrhosis and hepatocellular carcinoma among people with a hepatitis B notification in New South Wales" [JHEP Reports 4 (2022)].

[This corrects the article DOI: 10.1016/j.jhepr.2022.100552.].

Patient and healthcare provider perceptions of acceptability of fingerstick point-of-care hepatitis C testing at Aboriginal Community Controlled Health Services in Australia.

BACKGROUND: Hepatitis C (HCV) is highly prevalent in First Nations communities globally. Barriers in the uptake of testing and treatment create challenges to realise elimination of HCV in these communities. In efforts to reduce barriers to testing and treatment, the SCALE-C study implemented an HCV test-and-treat intervention integrating point-of-care HCV testing and FibroScan®. SCALE-C was carried out at four Aboriginal Community Controlled Health Services (ACCHS; renowned for providing culturally safe care) in four regional towns in Australia. This qualitative analysis sought to understand healthcare provider and patient perceptions of acceptability of a community-based HCV test-and-treat intervention within ACCHS. METHODS: Semi-structured interviews were undertaken with 23 patient participants and 14 healthcare personnel (including Aboriginal Health Workers/Practitioners, nurses, general practitioners, and practice managers) from across the four ACCHS involved in SCALE-C. A coding framework was developed among study authors and informed by Sekhon's Theoretical Framework of Acceptability. RESULTS: The SCALE-C intervention enabled opportunities for healthcare providers to listen to patients, and for patients to feel heard (affective attitude). HCV testing was opportunistic and often occurred outside of the allocated SCALE-C clinical hours (burden). For patients, HCV testing within SCALE-C was viewed as a moral responsibility and ensured protection of self and others (ethicality). For personnel, SCALE-C (including following up visits) was regarded as an opportunity to engage with patients especially those with complex health needs which may be unrelated to HCV risk factors (ethicality). Patients and personnel widely regarded the SCALE-C intervention to be effective, and the test-and-treat model was preferable for both patients and personnel. CONCLUSION: The SCALE-C intervention was broadly perceived to be acceptable among both healthcare providers and patients within ACCHS. Whilst the prioritisation of HCV was viewed as increasing patient engagement, it was also regarded as an opportunity for addressing other healthcare needs within Aboriginal communities. HCV test-and-treat models of care delivered by ACCHS simplify the HCV care pathway and ensure all HCV care is provided in a culturally safe setting (e.g., patients did not need to attend external services such as pathology).

Incidence of hepatitis C virus infection in the prison setting: The SToP-C study.

People in prison are at high risk of HCV given high injecting drug use prevalence. This study evaluated HCV incidence and associated injecting drug use characteristics in prison. The SToP-C study enrolled people incarcerated in four Australian prisons. Participants were tested for HCV at enrolment and then every 3-6 months (October-2014 to November-2019). Participants eligible for this analysis included those at-risk of HCV primary infection (anti-HCV negative) or re-infection (anti-HCV positive, HCV RNA negative) with follow-up assessment. A total of 1643 eligible participants were included in analyses (82% male; median age 33 years; 30% injected drugs in prison; 1818 person-years of follow-up). Overall HCV incidence was 6.11/100 person-years (95%CI: 5.07-7.35), with higher rate of re-infection (9.34/100 person-years; 95%CI: 7.15-12.19) than primary infection (4.60/100 person-years; 95%CI: 3.56-5.96). In total population (n = 1643), HCV risk was significantly higher among participants injecting drugs in prison [vs. no injecting; adjusted hazard ratio (aHR): 10.55, 95%CI: 5.88-18.92), and those who were released and re-incarcerated during follow-up (vs. remained incarcerated; aHR: 1.60, 95%CI: 1.03-2.49). Among participants who injected recently (during past month, n = 321), HCV risk was reduced among those receiving high-dosage opioid agonist therapy (OAT), i.e. methadone ≥60 mg/day or buprenorphine ≥16 mg/day, (vs. no OAT, aHR: 0.11, 95%CI: 0.02-0.80) and increased among those sharing needles/syringes without consistent use of disinfectant to clean injecting equipment (vs. no sharing, HR: 4.60, 95%CI: 1.35-15.66). This study demonstrated high HCV transmission risk in prison, particularly among people injecting drugs. High-dosage OAT was protective, but improved OAT coverage and needle/syringe programmes to reduce sharing injecting equipment are required.

The APPRISE Virtual Biobank for Infectious Diseases.

The Australian Partnership for Preparedness Research on InfectiouS disease Emergencies (APPRISE) has developed a virtual biobank to support infectious disease research in Australia. The virtual biobank (https://apprise.biogrid.org.au) integrates access to existing distributed infectious disease biospecimen collections comprising multiple specimen types, including plasma, serum, and peripheral blood mononuclear cells. Through the development of a common data model, multiple collections can be searched simultaneously via a secure web portal. The portal enhances the visibility and searchability of existing collections within their current governance and custodianship arrangements. The portal is easily scalable for integration of additional collections.

Screening for Hepatitis C Virus Reinfection Using a Behaviour-Based Risk Score among Men Who Have Sex with Men with HIV: Results from a Case-Control Diagnostic Validation Study.

We assessed the predictive capacity of the HCV-MOSAIC risk score, originally developed for primary early HCV infection, as a screening tool for HCV reinfection in 103 men who have sex with men (MSM) with HIV using data from the MOSAIC cohort, including MSM with HIV/HCV-coinfection who became reinfected (cases, n = 27) or not (controls, n = 76) during follow-up. The overall predictive capacity of the score was assessed using the area under the receiver operating characteristic (AUROC) curve. The effects of covariates on the receiver operating characteristic (ROC) curve were assessed using parametric ROC regression. The score cut-off validated for primary early infection (≥2.0) was used, from which the sensitivity and specificity were calculated. The AUROC was 0.74 (95% confidence interval (CI) = 0.63-0.84). Group sex significantly increased the predictive capacity. Using the validated cut-off, sensitivity was 70.4% (95%CI = 49.8-86.2%) and specificity was 59.2% (95%CI: 47.3-70.4%). External validation from a cohort of 25 cases and 111 controls, all MSM with HIV, resulted in a sensitivity of 44.0% (95%CI = 24.4-65.1) and specificity of 71.2% (95%CI = 61.8-79.4). The HCV-MOSAIC risk score may be useful for identifying individuals at risk of HCV reinfection. In sexual health or HIV-care settings, this score could help guide HCV-RNA testing in MSM with a prior HCV infection.

Sexual and drug use risk behaviour trajectories among people treated for recent HCV infection: the REACT study.

INTRODUCTION: Exploration of sexual and drug use behaviours following treatment for recent hepatitis C virus (HCV) is limited. This analysis modelled behavioural trajectories following treatment for recent HCV and assessed reinfection. METHODS: Participants treated for recent HCV in an international trial (enrolled 2017-2019) were followed at 3-monthly intervals for up to 2 years to assess longitudinal behaviours. Population-averaged changes were assessed using generalized estimating equations. Distinct behavioural trajectories were identified using group-based trajectory modelling. HCV reinfection incidence was calculated using person-years (PY) of observation. RESULTS: During the follow-up of 212 participants (84% gay and bisexual men [GBM]; 69% HIV; 26% current injecting drug use [IDU]), behavioural trajectories for IDU and stimulant use (past month) did not change. However, population-averaged decreases in the likelihood of daily IDU (adjusted odds ratio [AOR] 0.83; 95% CI 0.72, 0.95) and opioid use (AOR 0.84; 95% CI 0.75, 0.93) were observed. Among GBM, behavioural trajectories for chemsex did not change. Population-averaged decreases in condomless anal intercourse with casual male partners (CAI-CMP) (AOR 0.95; 95% CI 0.90, 0.99) and group-sex (AOR 0.86; 95% CI 0.80, 0.93) were observed, but masked distinct trajectories. While a proportion had a decreased probability of CAI-CMP (23%) and group-sex (59%) post-treatment, a substantial proportion retained a high probability of these behaviours. High HCV reinfection incidence was observed for the sustained high probability IDU (33.0/100 PY; 95% CI 17.7, 61.3) and chemsex (23.3/100 PY; 95% CI 14.5, 37.5) trajectories. CONCLUSIONS: Limited sexual and drug use behavioural change was observed following treatment for recent HCV, supporting access to surveillance and (re)treatment.

Glecaprevir-pibrentasvir for 4 weeks among people with recent HCV infection: The TARGET3D study.

Background & Aims: Short duration treatment may aid HCV elimination among key populations. This study evaluated the efficacy of glecaprevir-pibrentasvir for 4 weeks among people with recent HCV infection. Methods: In this single-arm multicentre international trial, adults with recent HCV (duration of infection <12 months) received glecaprevir-pibrentasvir 300 mg-120 mg daily for 4 weeks. Primary infection was defined as a first positive anti-HCV antibody and/or HCV RNA measurement within 6 months of enrolment and either acute clinical hepatitis within 12 months (symptomatic illness or alanine aminotransferase >10x the upper limit of normal) or antibody seroconversion within 18 months. Reinfection was defined as new positive HCV RNA within 6 months and prior clearance (spontaneous or treatment). The primary endpoint was sustained virological response at 12 weeks post-treatment (SVR12) in the intention-to-treat (ITT) and per-protocol (PP) populations. Results: Twenty-three participants (96% men, 70% HIV, 57% ever injected drugs) received treatment, of whom 74% had genotype 1a infection and 35% recent reinfection. At baseline, median duration of infection was 17 weeks (IQR 11-29) and HCV RNA was 5.8 log10IU/ml (IQR 5.2-6.9). SVR12 was achieved by 78% (18/23; 95% CI 56-93%) and 82% (18/22; 95% CI 60-95%) of the ITT and PP populations, respectively, and in 100% (12/12; 95% CI 74-100%) of participants with baseline HCV RNA ≤6 log10. There were four cases of virological failure (relapse); three received retreatment with 12 weeks sofosbuvir-velpatasvir or grazoprevir-elbasvir (SVR, n = 2; loss to follow-up, n = 1). No serious adverse events were reported. Conclusion: While most achieved SVR, the efficacy of a 4-week regimen of glecaprevir-pibrentasvir was lower than observed with longer treatment durations (≥6 weeks) among people with recent HCV. Trial Registration: Clinicaltrials.gov Identifier: NCT02634008. Impact and implications: Short duration treatment may aid HCV elimination among key populations. This investigator-initiated single-arm multicentre international pilot trial demonstrated that efficacy of glecaprevir-pibrentasvir for 4 weeks among people with recent HCV infection was sub-optimal (SVR12 78% ITT, 82% PP). Baseline HCV RNA appeared to impact response, with higher efficacy among participants with lower baseline HCV RNA (≤6 log10; SVR12 100% ITT, 12/12). While most achieved SVR, the efficacy of 4 weeks of glecaprevir-pibrentasvir was below that seen with longer treatment durations (≥6 weeks).

Hepatitis C.

Hepatitis C virus (HCV) is a hepatotropic RNA virus that can cause acute and chronic hepatitis, with progressive liver damage resulting in cirrhosis, decompensated liver disease, and hepatocellular carcinoma. In 2016, WHO called for the elimination of HCV infection as a public health threat by 2030. Despite some progress, an estimated 57 million people were living with HCV infection in 2020, and 300 000 HCV-related deaths occur per year. The development of direct-acting antiviral therapy has revolutionised clinical care and generated impetus for elimination, but simplified and broadened HCV screening, enhanced linkage to care, and higher coverage of treatment and primary prevention strategies are urgently required.

A unique cytotoxic CD4+ T cell-signature defines critical COVID-19.

Objectives: SARS-CoV-2 infection causes a spectrum of clinical disease presentation, ranging from asymptomatic to fatal. While neutralising antibody (NAb) responses correlate with protection against symptomatic and severe infection, the contribution of the T-cell response to disease resolution or progression is still unclear. As newly emerging variants of concern have the capacity to partially escape NAb responses, defining the contribution of individual T-cell subsets to disease outcome is imperative to inform the development of next-generation COVID-19 vaccines. Methods: Immunophenotyping of T-cell responses in unvaccinated individuals was performed, representing the full spectrum of COVID-19 clinical presentation. Computational and manual analyses were used to identify T-cell populations associated with distinct disease states. Results: Critical SARS-CoV-2 infection was characterised by an increase in activated and cytotoxic CD4+ lymphocytes (CTL). These CD4+ CTLs were largely absent in asymptomatic to severe disease states. In contrast, non-critical COVID-19 was associated with high frequencies of naïve T cells and lack of activation marker expression. Conclusion: Highly activated and cytotoxic CD4+ T-cell responses may contribute to cell-mediated host tissue damage and progression of COVID-19. Induction of these potentially detrimental T-cell responses should be considered when developing and implementing effective COVID-19 control strategies.

Direct-Acting Antiviral Therapy for Treatment of Acute and Recent Hepatitis C Virus Infection: A Narrative Review.

Following the discovery of hepatitis C virus (HCV) in 1989, 3 decades of basic, translational, and clinical research culminated in the development of direct-acting antiviral (DAA) therapy-curative oral treatment for HCV infection. The availability of DAA therapy revolutionized HCV clinical management, including acute (duration of infection <6 mo) and recent (duration of infection <12 mo) infection. Several DAA regimens, including the contemporary pan-genotypic combinations of sofosbuvir-velpatasvir and glecaprevir-pibrentasvir, have been shown to be safe and effective among people with acute and recent HCV infection, highlighting their potential in an HCV controlled human infection model. This article describes the natural history and management of acute and recent HCV infection in the era of DAA therapy and outlines a strategy for use of DAA therapies in the setting of an HCV controlled human infection model.

Comparative Longitudinal Serological Study of Anti-SARS-CoV-2 Antibody Profiles in People with COVID-19.

Serological diagnostic assays are essential tools for determining an individual's protection against viruses like SARS-CoV-2, tracking the spread of the virus in the community, and evaluating population immunity. To assess the diversity and quality of the anti-SARS-CoV-2 antibody response, we have compared the antibody profiles of people with mild, moderate, and severe COVID-19 using a dot blot assay. The test targeted the four major structural proteins of SARS-CoV-2, namely the nucleocapsid (N), spike (S) protein domains S1 and S2, and receptor-binding domain (RBD). Serum samples were collected from 63 participants at various time points for up to 300 days after disease onset. The dot blot assay revealed patient-specific differences in the anti-SARS-CoV-2 antibody profiles. Out of the 63 participants with confirmed SARS-CoV-2 infections and clinical COVID-19, 35/63 participants exhibited diverse and robust responses against the tested antigens, while 14/63 participants displayed either limited responses to a subset of antigens or no detectable antibody response to any of the antigens. Anti-N-specific antibody levels decreased within 300 days after disease onset, whereas anti-S-specific antibodies persisted. The dynamics of the antibody response did not change during the test period, indicating stable antibody profiles. Among the participants, 28/63 patients with restricted anti-S antibody profiles or undetectable anti-S antibody levels in the dot blot assay also exhibited weak neutralization activity, as measured by a surrogate virus neutralization test (sVNT) and a microneutralization test. These results indicate that in some cases, natural infections do not lead to the production of neutralizing antibodies. Furthermore, the study revealed significant serological variability among patients, regardless of the severity of their COVID-19 illness. These differences need to be carefully considered when evaluating the protective antibody status of individuals who have experienced primary SARS-CoV-2 infections.

Evaluating the prevalence of current hepatitis C infection and treatment among Aboriginal and Torres Strait Islander peoples who inject drugs in Australia: The ETHOS engage study.

INTRODUCTION: Evaluating progress towards hepatitis C virus (HCV) elimination among Aboriginal and Torres Strait Islander peoples is critical given the disproportionate burden of infection. We examined factors associated with current HCV infection and self-reported treatment among Aboriginal and Torres Strait Islander (hereafter referred to as Aboriginal peoples) and non-Aboriginal peoples who inject drugs (PWID) in Australia. METHODS: ETHOS Engage is an observational cohort study of PWID attending drug treatment and needle and syringe programs in Australia. Participants underwent point-of-care HCV RNA testing (Xpert HCV RNA Viral Load Fingerstick) and completed a questionnaire including self-reported history of HCV treatment. RESULTS: Between May 2018 and June 2021, 2395 participants were enrolled and 555 (23%) identified as Aboriginal (median age 42 years, 58% were men, 63% injected drugs in last month, 76% ever incarcerated). HCV RNA prevalence was 23% among Aboriginal PWID (24% in 2018-2019 and 21% in 2019-2021; p = 0.44), and 21% among non-Aboriginal PWID (24% in 2018-2019 and 16% in 2019-2021; p < 0.001). Self-reported HCV treatment was 65% among Aboriginal PWID (63% in 2018-2019 and 69% in 2019-2021; p = 0.30), and 70% among non-Aboriginal PWID (67% in 2018-2019 and 75% in 2019-2021; p < 0.001). Among Aboriginal PWID, current HCV infection was associated with recently injecting drugs and receiving opioid agonist treatment, and self-reported HCV treatment was negatively associated with younger age, homelessness and recently injecting drugs. DISCUSSION AND CONCLUSIONS: Equitable access to HCV care and prevention is needed to ensure Australia meets its elimination targets among Aboriginal PWID.

Reinfection incidence and risk among people treated for recent hepatitis C virus infection.

OBJECTIVE: Reinfection poses a challenge to hepatitis C virus (HCV) elimination. This analysis assessed incidence of, and factors associated with reinfection among people treated for recent HCV (duration of infection <12 months). METHODS: Participants treated for recent HCV (primary infection or reinfection) in an international randomized trial were followed at 3-monthly intervals for up to 2 years to assess for reinfection. Reinfection incidence was calculated using person-time of observation. Factors associated with HCV reinfection were assessed using Cox proportional hazards regression analysis. RESULTS: Of 222 participants treated for recent HCV, 196 (62% primary infection, 38% reinfection) were included in the cohort at risk for reinfection, of whom 87% identified as gay or bisexual men, 71% had HIV and 20% injected drugs in the month prior to enrolment. During 198 person-years of follow-up, 28 cases of HCV reinfection were identified among 27 participants, for an incidence of 14.2 per 100 person-years [95% confidence interval (CI) 9.8-20.5]. Reinfection was associated with prior HCV reinfection [adjusted hazards ratio (aHR) 2.42; 95% CI 1.08-5.38], injection drug use posttreatment (aHR 2.53; 95% CI 1.14-5.59), condomless anal intercourse with casual male partners (aHR 3.32; 95% CI 1.14-9.65) and geographic region (United Kingdom, aHR 0.21; 95% CI 0.06-0.75). Among gay and bisexual men (GBM), reinfection was also associated with sexualized drug use involving injecting posttreatment (aHR 2.97; 95% CI 1.10-8.02). CONCLUSION: High reinfection incidence following treatment for recent HCV among people with ongoing sexual and drug use risk behaviour highlights the need for posttreatment surveillance, rapid retreatment of reinfection and targeted harm reduction strategies.

Hepatitis C virus transmission between eight high-income countries among men who have sex with men: a whole-genome analysis.

BACKGROUND: Microelimination of the hepatitis C virus (HCV) among men who have sex with men (MSM) could be complicated by continuous external introductions and the emergence of phylogenetic clusters harbouring clinically significant resistance-associated substitutions (RAS). To investigate international clustering and the prevalence and transmission of RAS, we aimed to analyse whole-genome HCV sequences from MSM with a recently acquired infection who participated in a large, international HCV treatment trial. METHODS: For this whole-genome analysis, we obtained HCV sequences from 128 MSM who had acquired HCV within the past 12 months and were participating in the REACT trial. The participants from whom sequences were obtained were recruited at 24 sites in eight countries. We inferred maximum-likelihood phylogenies and identified transmission clusters for HCV genotypes separately. We constructed time-scaled phylogenies to estimate cluster introduction dates and used a Bayesian Skygrid approach to estimate the effective population size over the past 50 years. We calculated the prevalence of RAS and the extent of RAS transmission in the study population. FINDINGS: The majority of recent HCV infections were part of international networks that arose in the late 1990s and early 2000s. Sequences obtained in the same country clustered frequently, and in 36% of subclusters since 2015 we found evidence of international transmission. European MSM were more likely than non-European MSM to be in a cluster (odds ratio 11·9 [95% CI 3·6-43·4], p<0·0001). The effective population size decreased rapidly since around 2015 in Europe. RAS associated with substantially diminished cure rates were infrequently detected and transmission of highly resistant viruses was not observed. INTERPRETATION: Despite antiviral treatment becoming widely available, international transmission of HCV among MSM has still occurred over the past 8 years, which could complicate microelimination of the virus in this population. RAS-enriched clusters and widespread RAS transmission are currently not a threat to elimination goals. These findings support an international approach for HCV microelimination among MSM. FUNDING: National Institutes of Health and Dr. C.J. Vaillant Fonds.

Highly Networked SARS-CoV-2 Peptides Elicit T Cell Responses with Enhanced Specificity.

Identifying SARS-CoV-2-specific T cell epitope-derived peptides is critical for the development of effective vaccines and measuring the duration of specific SARS-CoV-2 cellular immunity. In this regard, we previously identified T cell epitope-derived peptides within topologically and structurally essential regions of SARS-CoV-2 spike and nucleocapsid proteins by applying an immunoinformatics pipeline. In this study, we selected 30 spike- and nucleocapsid-derived peptides and assessed whether these peptides induce T cell responses and avoid major mutations found in SARS-CoV-2 variants of concern. Our peptide pool was highly specific, with only a single peptide driving cross-reactivity in people unexposed to SARS-COV-2, and immunogenic, inducing a polyfunctional response in CD4+ and CD8+ T cells from COVID-19 recovered individuals. All peptides were immunogenic and individuals recognized broad and diverse peptide repertoires. Moreover, our peptides avoided most mutations/deletions associated with all four SARS-CoV-2 variants of concern while retaining their physicochemical properties even when genetic changes are introduced. This study contributes to an evolving definition of individual CD4+ and CD8+ T cell epitopes that can be used for specific diagnostic tools for SARS-CoV-2 T cell responses and is relevant to the development of variant-resistant and durable T cell-stimulating vaccines.

Clinical variation in the early assessment and management of suspected community-acquired meningitis: a multicentre retrospective study.

BACKGROUND: Bacterial meningitis is a medical emergency and timely management has been shown to improve outcomes. The aim of this study was to compare the early assessment and management of adults with suspected community-onset meningitis between hospitals and identify opportunities for clinical practice improvement. METHODS: This retrospective cohort study was conducted at three principal referral hospitals in Sydney, Australia. Adult patients with suspected meningitis undergoing cerebrospinal fluid sampling between 1 July 2018 and 31 June 2019 were included. Relevant clinical and laboratory data were extracted from the medical record. Differences between sites were analysed and factors associated with time to antimicrobial therapy were assessed by Cox regression. RESULTS: In 260 patients, the median time from triage to antibiotic administration was 332 min with a difference of up to 147 min between hospitals. Median time from triage to lumbar puncture (LP) was 366 min with an inter-hospital difference of up to 198 min. Seventy per cent of patients had neuroimaging prior to LP, and this group had a significantly longer median time to antibiotic administration (367 vs 231 min; P = 0.001). Guideline concordant antibiotics were administered in 84% of patients, with only 39% of those administered adjunctive corticosteroids. Seven (3%) patients had confirmed bacterial meningitis. Modifiable factors associated with earlier antimicrobial administration included infectious diseases involvement (adjusted hazard ratio [aHR], 1.50 [95% confidence interval (CI), 1.01-2.24]) and computed tomography (CT) scanning (aHR, 0.67 [95% CI, 0.46-0.98]). CONCLUSION: Opportunities for improvement include reducing the time to LP and antibiotic administration, improving coadministration of corticosteroids and avoiding potentially unnecessary CT scanning.

Reasons for not commencing direct-acting antiviral treatment despite unrestricted access for individuals with HIV and hepatitis C virus: a multinational, prospective cohort study.

BACKGROUND: Individuals with HIV and hepatitis C virus (HCV) who remain untreated with direct-acting antivirals can contribute to HCV transmission and HCV-related mortality. We aimed to compare rates of uptake of direct-acting antivirals following unrestricted access to this treatment in high-income countries and examine factors associated with remaining untreated. METHODS: This multinational, prospective cohort study used data from the International Collaboration on Hepatitis C Elimination in HIV Cohorts (InCHEHC). We analysed data from nine observational cohorts participating in the InCHEHC, including data from six high-income countries (Australia, Canada, France, the Netherlands, Spain, and Switzerland). We included individuals aged 18 years and older, with HIV and HCV (ie, HCV-RNA positive without evidence of spontaneous clearance) during unrestricted access to interferon-free direct-acting antiviral treatment in each country. We calculated the cumulative proportion of participants who remained untreated with direct-acting antivirals, with follow-up starting after the date of unrestricted access or cohort inclusion, whichever occurred most recently. Factors associated with the commencement rate of direct-acting antiviral treatment were assessed using competing-risks regression with the Fine-Gray method. FINDINGS: The date of unrestricted access to direct-acting antiviral treatment for people with HIV ranged from Nov 1, 2014, in France to Nov 1, 2017, in Switzerland. We included 4552 individuals with HIV-HCV, mainly men who have sex with men (MSM; n=2156 [47%]) and people who inject or have injected drugs (n=1453 [32%]). 1365 (30%) of 4552 participants remained untreated with direct-acting antivirals. For individuals treated with direct-acting antivirals, median time from start of follow-up to treatment was 5 months (IQR 2-12). For individuals who were not treated with direct-acting antivirals, median follow-up was 22 months (8-30). Being linked to care in Australia, France, or the Netherlands, on antiretroviral therapy, having undetectable HIV RNA, and shorter duration since first positive HCV test were independently associated with higher commencement rate of direct-acting antiviral treatment. Compared with MSM, male heterosexuals and females with unknown or other routes of HIV transmission (ie, neither injection drug use nor heterosexual transmission) had lower rates of commencement. INTERPRETATION: Despite unrestricted access, almost a third of individuals with HIV-HCV remained untreated with direct-acting antivirals during follow-up, with variation in commencement rate of HCV treatment between countries and key populations. Increased efforts are required to reach the remaining individuals with HIV who are HCV-viraemic to achieve HIV-HCV micro-elimination. FUNDING: None.