Immunological dysfunction persists for 8 months following initial mild-to-moderate SARS-CoV-2 infection.

A proportion of patients surviving acute coronavirus disease 2019 (COVID-19) infection develop post-acute COVID syndrome (long COVID (LC)) lasting longer than 12 weeks. Here, we studied individuals with LC compared to age- and gender-matched recovered individuals without LC, unexposed donors and individuals infected with other coronaviruses. Patients with LC had highly activated innate immune cells, lacked naive T and B cells and showed elevated expression of type I IFN (IFN-ß) and type III IFN (IFN-λ1) that remained persistently high at 8 months after infection. Using a log-linear classification model, we defined an optimal set of analytes that had the strongest association with LC among the 28 analytes measured. Combinations of the inflammatory mediators IFN-ß, PTX3, IFN-γ, IFN-λ2/3 and IL-6 associated with LC with 78.5-81.6% accuracy. This work defines immunological parameters associated with LC and suggests future opportunities for prevention and treatment.

Associations between antiretroviral regimen and changes in blood pressure: results from the D2EFT study.

In this randomised, controlled study in 14 low- and middle-income countries, individuals taking dolutegravir with darunavir/ritonavir for 48 weeks had a greater increase in systolic and diastolic blood pressure than individuals taking two nucleoside reverse transcriptase with darunavir/ritonavir. The difference remained significant after controlling for confounding factors including weight gain.

Hepatitis C virus reinfection incidence among gay and bisexual men with HIV in Australia from 2016 to 2020.

BACKGROUND: There is some concern that hepatitis C virus (HCV) reinfection might impact HCV micro-elimination efforts among gay and bisexual men (GBM) with HIV. However, there is a limited understanding of reinfection incidence in the context of unrestricted government-funded HCV treatment. We aimed to estimate HCV reinfection incidence among GBM with HIV in Australia from 2016 to 2020. METHODS: Data were from 39 clinics participating in ACCESS, a sentinel surveillance network for blood borne viruses and sexually transmissible infections across Australia. GBM with HIV who had evidence of treatment or spontaneous clearance with at least one positive HCV RNA test, a subsequent negative HCV RNA test, and at least one additional HCV RNA test between 1st January 2016 and 31st December 2020 were eligible for inclusion. A new HCV RNA positive test and/or detectable viral load was defined as a reinfection. Generalised linear modelling was used to examine trends in reinfection. RESULTS: Among 12 213 GBM with HIV who had at least one HCV test, 540 were included in the reinfection incidence analysis, of whom 38 (7%) had evidence of reinfection during the observation period. Over 1124 person-years of follow-up, the overall rate of reinfection was 3.4/100PY (95% CI 2.5-4.6). HCV reinfection incidence declined on average 30% per calendar year (Incidence Rate Ratio 0.70, 95% CI 0.54-0.91). CONCLUSION: HCV reinfection incidence has declined among GBM with HIV in Australia since government-funded unrestricted DAAs were made available. Ongoing HCV RNA testing following cure and prompt treatment for anyone newly diagnosed is warranted to sustain this.

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.

National trends in retreatment of HCV due to reinfection or treatment failure in Australia.

BACKGROUND & AIMS: Population-level uptake of direct-acting antiviral (DAA) treatment for hepatitis C virus (HCV) infection, including retreatment, can be estimated through administrative pharmaceutical dispensation data. However, the reasons for retreatment are not captured in these data. We developed a machine learning model to classify retreatments as reinfection or treatment failure at a national level. METHODS: Retreatment data from the REACH-C cohort (n = 10,843 treated with DAAs; n = 320 retreatments with known reason), were used to train a random forest model. Nested cross validation was undertaken to assess model performance and to optimise hyperparameters. The model was applied to data on DAA retreatment dispensed during 2016-2021 in Australia, to identify the reason for retreatment (treatment failure or reinfection). RESULTS: Average predictive accuracy, precision, sensitivity, specificity and F1-score for the model were 96.3%, 96.5%, 96.3%, 96.3% and 96.3%, respectively. Nationally, 95,272 individuals initiated DAAs, with treatment uptake declining from 32,454 in 2016 to 6,566 in 2021. Of those treated, 6,980 (7%) were retreated. Our model classified 51.8% (95% CI 46.7-53.6%; n = 3,614) of cases as reinfection and 48.2% (95% CI 46.4-53.3%; n = 3,366) as treatment failure. Retreatment for reinfection increased steadily over the study period from 14 in 2016 to 1,092 in 2020, stabilising in 2021. Retreatment for treatment failure increased from 73 in 2016 to 1,077 in 2019, then declined to 515 in 2021. Among individuals retreated for treatment failure, 50% had discontinued initial treatment. CONCLUSIONS: We used a novel methodology with high classification accuracy to evaluate DAA retreatment patterns at a national level. Increases in retreatment uptake for treatment failure corresponded to the availability of pangenotypic and salvage regimens. Increasing retreatment uptake for reinfection likely reflects increasing reinfection incidence. IMPACT AND IMPLICATIONS: This study used machine learning methodologies to analyse national administrative data and characterise trends in HCV retreatment due to reinfection and treatment failure. Retreatment for reinfection increased over time, reflecting increasing numbers of people at risk for reinfection following HCV cure. Increased retreatment for treatment failure corresponded to the availability of pangenotypic and salvage DAA regimens. The findings of this study can be used by public health agencies and policy makers to guide and assess HCV elimination strategies, while the novel methodology for monitoring trends in HCV retreatment has the potential to be used in other settings, and health conditions.

Hepatitis C virus-specific immune responses following direct-acting antivirals administered during recent hepatitis C virus infection.

Individuals who spontaneously clear hepatitis C virus (HCV) infection have demonstrated evidence of partial protective immunity, whereas treatment-induced clearance provides little or no protection against reinfection. We aimed to investigate whether treatment of acute HCV infection with direct-acting antivirals (DAA) prevents establishment of, or reverses, T-cell exhaustion, leading to a virus-specific T-cell immune profile more similar to that seen in spontaneous clearance. The magnitude and breadth of HCV-specific T-cell responses before and after DAA or interferon-based therapy in acute or chronic HCV were compared to those of participants with spontaneous clearance of infection, using Enzyme-linked Immunospot (ELISPOT). PBMCs were available for 55 patients comprising 4 groups: spontaneous clearance (n = 17), acute interferon (n = 14), acute DAA (n = 13) and chronic DAA (n = 11). After controlling for sex, the magnitude of post-treatment HCV-specific responses after acute DAA treatment was greater than after chronic DAA or acute IFN treatment and similar to those found in spontaneous clearers. However, spontaneous clearers responded to more HCV peptide pools indicating greater breadth of response. In conclusion, early treatment with DAAs may prevent or reverse some degree of immune exhaustion and result in stronger HCV-specific responses post-treatment. However, individuals with spontaneous clearance had broader HCV-specific responses.

Hepatitis C Virus Reinfection Following Direct-Acting Antiviral Treatment in the Prison Setting: The SToP-C Study.

BACKGROUND: Injection drug use (IDU) following treatment for hepatitis C virus (HCV) infection may lead to reinfection, particularly if access to harm reduction services is suboptimal. This study assessed HCV reinfection risk following direct-acting antiviral therapy within Australian prisons that had opioid agonist therapy (OAT) programs but did not have needle and syringe programs (NSPs). METHODS: The Surveillance and Treatment of Prisoners With Hepatitis C (SToP-C) study enrolled people incarcerated in 4 prisons between 2014 and 2019. Participants treated for HCV were followed every 3-6 months to identify reinfection (confirmed by sequencing). Reinfection incidence and associated factors were evaluated. RESULTS: Among 388 participants receiving treatment, 161 had available posttreatment follow-up and were included in analysis (92% male; median age, 33 years; 67% IDU in prison; median follow-up 9 months). Among those with recent (in the past month) IDU (n = 71), 90% had receptive needle/syringe sharing. During 145 person-years (PY) of follow-up, 18 cases of reinfection were identified. Reinfection incidence was 12.5/100 PY (95% confidence interval [CI]: 7.9-19.8) overall, increasing to 28.7/100 PY (95% CI: 16.3-50.6) among those with recent IDU and needle/syringe sharing. In adjusted analysis, recent IDU with needle/syringe sharing was associated with increased reinfection risk (adjusted hazard ratio [aHR], 4.74 [95% CI: 1.33-16.80]; P = .016) and longer HCV testing interval with decreased risk (ie, chance of detection; aHR, 0.41 per each month increase [95% CI: .26-.64]; P < .001). CONCLUSIONS: A high rate of HCV reinfection was observed within prison. Posttreatment surveillance and retreatment are -essential to limit the impact of reinfection. High-coverage OAT and NSPs should be considered within prisons. CLINICAL TRIALS REGISTRATION: NCT02064049.

Preferences of Persons With or at Risk for Hepatitis C for Long-Acting Treatments.

BACKGROUND: Whereas safe, curative treatments for hepatitis C virus (HCV) have been available since 2015, there are still 58 million infected persons worldwide, and global elimination may require new paradigms. We sought to understand the acceptability of approaches to long-acting HCV treatment. METHODS: A cross-sectional, 43-question survey was administered to 1457 individuals with or at risk of HCV at 28 sites in 9 countries to assess comparative interest in a variety of long-acting strategies in comparison with oral pills. RESULTS: Among HCV-positive participants, 37.7% most preferred an injection, 5.6% an implant, and 6% a gastric residence device, as compared with 50.8% who stated they would most prefer taking 1-3 pills per day. When compared directly to taking pills, differences were observed in the relative preference for an injection based on age (P<.001), location (P<.001), and prior receipt of HCV treatment (P=.005) but not sex. When an implant was compared with pills, greater preference was represented by women (P=.01) and adults of younger ages (P=.01 per 5 years). Among participants without HCV, 49.5% believed that injections are stronger than pills and 34.7% preferred taking injections to pills. Among those at-risk participants who had received injectable medications in the past, 123 of 137 (89.8%) expressed willingness to receive one in the future. CONCLUSIONS: These data point to high acceptability of long-acting treatments, which for a substantial minority might even be preferred to pills for the treatment of HCV infection. Long-acting treatments for HCV infection might contribute to global efforts to eliminate hepatitis C.

Evaluation of the hepatitis C cascade of care among people living with HIV in New South Wales, Australia: A data linkage study.

People living with HIV (PLHIV) are a priority population to receive hepatitis C virus (HCV) screening and treatment. We aimed to characterize the HCV care cascade among PLHIV between 2010 and 2018 and to compare HCV testing and treatment uptake pre- and post-availability of direct-acting antivirals (DAAs) in New South Wales (NSW), Australia. Records of all HCV notifications (1993-2017) were linked to HIV notifications, deaths, hospitalizations, incarcerations, opioid agonist therapy, HCV RNA testing and treatment databases. Numbers and proportions were calculated for all stages of the care cascade and factors associated with HCV testing, and DAA treatment uptake were evaluated using logistic regression. From 383 individuals with HCV notification (2009-2017), 349 (91%) were ever HCV RNA tested, 285 (74%) had an indicator of chronic HCV infection, and from those eligible for treatment, 210 (74%) received HCV treatment. HCV testing was recorded for 85% pre-DAA era and reached a cumulative proportion of 90% post-DAA while treatment uptake had a 10-fold increase from 7% pre- to 73% post-DAA era. Younger age (adjusted odds ratio [aOR] 0.98; 95% CI 0.96-0.99), female gender (aOR 1.87; 95% CI 1.10-3.19), and rural region residence at notification (aOR 1.56; 95% CI 1.03-2.36) were associated with not receiving HCV testing. No identified factor was associated with not receiving treatment post-DAA era. Removing barriers to HCV testing, expanding treatment to a variety of settings and continuous education and harm reduction are essential to achieve HCV elimination among PLHIV in Australia.

Retreatment for hepatitis C virus direct acting antiviral therapy virological failure in primary and tertiary settings: the REACH-C cohort.

Virological failure occurs in a small proportion of people treated for hepatitis C virus (HCV) with direct-acting antiviral (DAA) therapies. This study assessed retreatment for virological failure in a large real-world cohort. REACH-C is an Australian observational study (n=10843) evaluating treatment outcomes of sequential DAA initiations across 33 health services between March 2016 to June 2019. Virological failure retreatment data were collected until October 2020. Of 408 people with virological failure (81% male; median age 53; 38% cirrhosis; 56% genotype 3), 213 (54%) were retreated once; 15 were retreated twice. A range of genotype specific and pangenotypic DAAs were used to retreat virological failure in primary (n=56) and tertiary (n=157) settings. Following sofosbuvir/velpatasvir/voxilaprevir availability in 2019, the proportion retreated in primary care increased from 21% to 40% and median time to retreatment initiation declined from 294 to 152 days. Per-protocol (PP) sustained virological response (SVR12) was similar for people retreated in primary and tertiary settings (80% vs 81%; p=1.000). In regression analysis, sofosbuvir/velpatasvir/voxilaprevir (vs. other regimens) significantly decreased likelihood of second virological failure (PP SVR12 88% vs. 77%; adjusted odds ratio [AOR] 0.29; 95%CI 0.11-0.81); cirrhosis increased likelihood (PP SVR12 69% vs. 91%; AOR 4.26; 95%CI 1.64-11.09). Indigenous Australians had lower likelihood of retreatment initiation (AOR 0.36; 95%CI 0.15-0.81). Treatment setting and prescriber type were not associated with retreatment initiation or outcome. Virological failure can be effectively retreated in primary care. Expanded access to simplified retreatment regimens through decentralised models may increase retreatment uptake and reduce HCV-related mortality.

Australian consensus recommendations for the management of hepatitis B.

INTRODUCTION: The prevalence of hepatitis B virus (HBV) infection in Australia is nearly 1%. In certain well defined groups the prevalence is far greater, yet an estimated 27% of people living with HBV infection remain undiagnosed. Appropriate screening improves detection, increases opportunity for treatment, and ultimately reduces the significant morbidity and mortality associated with the development of liver fibrosis and hepatocellular carcinoma (HCC). MAIN RECOMMENDATIONS: This statement highlights important aspects of HBV infection management in Australia. There have been recent changes in nomenclature and understanding of natural history, as well as a newly defined upper limit of normal for liver tests that determine phase classification and threshold for antiviral treatment. As the main burden of hepatitis B in Australia is within migrant and Indigenous communities, early identification and management of people living with hepatitis B is essential to prevent adverse outcomes including liver cancer and cirrhosis. CHANGE IN MANAGEMENT AS A RESULT OF THIS GUIDELINE: These recommendations aim to raise awareness of the current management of hepatitis B in Australia. Critically, the timely identification of individuals living with hepatitis B, and where appropriate, commencement of antiviral therapy, can prevent the development of cirrhosis, HCC and mother-to-child transmission as well as hepatitis B reactivation in immunocompromised individuals. Recognising patient and viral factors that predispose to the development of cirrhosis and HCC will enable clinicians to risk-stratify and appropriately implement surveillance strategies to prevent these complications of hepatitis B.

Characteristics Associated with Monitoring and Treatment of Chronic Hepatitis B in a Large Cohort of Australian Adults.

BACKGROUND: Regular monitoring and treatment of chronic hepatitis B (CHB) are known to reduce the risk of hepatocellular carcinoma. We sought to describe patterns of monitoring and treatment among adults diagnosed with CHB in Australia. METHODS: Population-based prospective cohort study of Australian adults aged 45 + years followed by record-linkage to hepatitis B notifications, monitoring and treatment. Proportions of those with CHB who: had viral load test; were dispensed antiviral treatment; and had ultrasound surveillance were estimated. The characteristics associated with viral load test and ultrasound surveillance were examined using logistic regression. RESULTS: A total of 576 adults with CHB were identified. From 2008 to 2015, 14.8% (85/576) had at least one viral load test recorded every 2 years and 19.1% (110/576) had at least one antiviral treatment recorded, 19.9% (58/292) had at least one ultrasound recorded every year among those eligible for ultrasound surveillance. A record of having at least one viral load test every 2 years was more likely among adults born in Asia compared to Australian-born (21.4% vs 8.6%), those notified in more recent years compared to earlier years, and those on antiviral treatment compared to not on treatment. Increasing proportions of cases had records of at least one viral load test over time (2008: 10.5%, 2015: 27.2%) and at least one antiviral treatment (2008: 3.0%, 2015: 18.5%). CONCLUSIONS: In Australian adults, estimates of care interventions for CHB management have increased over time but still fall short of targets recommended in the National Hepatitis B Strategy.

Concomitant Marked Decline in Prevalence of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) and Other Respiratory Viruses Among Symptomatic Patients Following Public Health Interventions in Australia: Data from St Vincent's Hospital and Associated Screening Clinics, Sydney, NSW.

Our Australian hospital tested almost 22 000 symptomatic people over 11 weeks for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in a multiplex polymerase chain reaction (PCR) assay. Following travel bans and physical distancing, SARS-CoV-2 and other respiratory viruses diagnoses fell dramatically. Increasing rhinovirus diagnoses as social control measures were relaxed may indirectly indicate an elevated risk of coronavirus disease 2019 (COVID-19) resurgence.

Opportunities to Enhance Linkage to Hepatitis C Care Among Hospitalized People With Recent Drug Dependence in New South Wales, Australia: A Population-based Linkage Study.

BACKGROUND: People who inject drugs are at greater risk of hepatitis C virus (HCV) infection and hospitalization, yet admissions are not utilized for HCV treatment initiation. We aimed to assess the extent to which people with HCV notification, including those with evidence of recent drug dependence, are hospitalized while eligible for direct-acting antiviral (DAA) therapy, and treatment uptake according to hospitalization in the DAA era. METHODS: We conducted a longitudinal, population-based cohort study of people living with HCV in the DAA era (March 2016-December 2018) through analysis of linked databases in New South Wales, Australia. Kaplan-Meier estimates were used to report HCV treatment uptake by frequency, length, and cause-specific hospitalization. RESULTS: Among 57 467 people, 14 938 (26%) had evidence of recent drug dependence, 50% (n = 7506) of whom were hospitalized while DAA eligible. Incidence of selected cause-specific hospitalization was highest for mental health-related (15.84 per 100 person-years [PY]), drug-related (15.20 per 100 PY), and injection-related infectious disease (9.15 per 100 PY) hospitalizations, and lowest for alcohol use disorder (4.58 per 100 PY) and liver-related (3.13 per 100 PY). In total, 65% (n = 4898) of those who were hospitalized had been admitted ≥2 times, and 46% (n = 3437) were hospitalized ≥7 days. By the end of 2018, DAA therapy was lowest for those hospitalized ≥2 times, for ≥7 days, and those whose first admission was for injection-related infectious disease, mental health disorders, and drug-related complications. CONCLUSIONS: Among people who have evidence of recent drug dependence, frequent hospitalization-particularly mental health, drug, and alcohol admissions-presents an opportunity for engagement in HCV care.

Reinfection Following Successful Direct-acting Antiviral Therapy for Hepatitis C Virus Infection Among People Who Inject Drugs.

BACKGROUND: The aim of this analysis was to calculate the incidence of hepatitis C virus (HCV) reinfection and associated factors among 2 clinical trials of HCV direct-acting antiviral treatment in people with recent injecting drug use or currently receiving opioid agonist therapy (OAT). METHODS: Participants who achieved an end-of-treatment response in 2 clinical trials of people with recent injecting drug use or currently receiving OAT (SIMPLIFY and D3FEAT) enrolled between March 2016 and February 2017 in 8 countries were assessed for HCV reinfection, confirmed by viral sequencing. Incidence was calculated using person-time of observation and associated factors were assessed using Cox proportional hazard models. RESULTS: Seventy-three percent of the population at risk of reinfection (n = 177; median age, 48 years; 73% male) reported ongoing injecting drug use. Total follow-up time at risk was 254 person-years (median, 1.8 years; range, 0.2-2.8 years). Eight cases of reinfection were confirmed for an incidence of 3.1/100 person-years (95% confidence interval [CI], 1.6-6.3) overall and 17.9/100 person-years (95% CI, 5.8-55.6) among those who reported sharing needles/syringes. Younger age and needle/syringe sharing were associated with HCV reinfection. CONCLUSIONS: These data demonstrate the need for ongoing monitoring and improved strategies to prevent HCV reinfection following successful treatment among people with ongoing injecting drug use to achieve HCV elimination. CLINICAL TRIALS REGISTRATION: NCT02336139 and NCT02498015.

Microelimination of Hepatitis C Among People With Human Immunodeficiency Virus Coinfection: Declining Incidence and Prevalence Accompanying a Multicenter Treatment Scale-up Trial.

BACKGROUND: Gay and bisexual men (GBM) are a key population affected by human immunodeficiency virus (HIV) and hepatitis C virus (HCV) coinfection. We aimed to measure HCV treatment effectiveness and to determine the population impact of treatment scale-up on HCV prevalence and incidence longitudinally among GBM. METHODS: The co-EC Study (Enhancing Care and Treatment Among HCV/HIV Coinfected Individuals to Eliminate Hepatitis C Transmission) was an implementation trial providing HCV direct-acting antiviral treatment in Melbourne, Australia, during 2016-2018. Individuals with HCV/HIV coinfection were prospectively enrolled from primary and tertiary care services. HCV viremic prevalence and HCV antibody/viremic incidence were measured using a statewide, linked, surveillance system. RESULTS: Among 200 participants recruited, 186 initiated treatment during the study period. Sustained virological response in primary care (98% [95% confidence interval {CI}, 93%-100%]) was not different to tertiary care (98% [95% CI, 86%-100%]). From 2012 to 2019, between 2434 and 3476 GBM with HIV infection attended our primary care sites annually, providing 13 801 person-years of follow-up; 50%-60% received an HCV test annually, and 10%-14% were anti-HCV positive. Among those anti-HCV positive, viremic prevalence declined 83% during the study (54% in 2016 to 9% in 2019). HCV incidence decreased 25% annually from 1.7/100 person-years in 2012 to 0.5/100 person-years in 2019 (incidence rate ratio, 0.75 [95% CI, .68-.83]; P < .001). CONCLUSIONS: High treatment effectiveness by nonspecialists demonstrates the feasibility of treatment scale-up in this population. Substantial declines in HCV incidence and prevalence among GBM provides proof-of-concept for HCV microelimination. CLINICAL TRIALS REGISTRATION: NCT02786758.

SARS-CoV-2 neutralizing antibodies: Longevity, breadth, and evasion by emerging viral variants.

The Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) antibody neutralization response and its evasion by emerging viral variants and variant of concern (VOC) are unknown, but critical to understand reinfection risk and breakthrough infection following vaccination. Antibody immunoreactivity against SARS-CoV-2 antigens and Spike variants, inhibition of Spike-driven virus-cell fusion, and infectious SARS-CoV-2 neutralization were characterized in 807 serial samples from 233 reverse transcription polymerase chain reaction (RT-PCR)-confirmed Coronavirus Disease 2019 (COVID-19) individuals with detailed demographics and followed up to 7 months. A broad and sustained polyantigenic immunoreactivity against SARS-CoV-2 Spike, Membrane, and Nucleocapsid proteins, along with high viral neutralization, was associated with COVID-19 severity. A subgroup of "high responders" maintained high neutralizing responses over time, representing ideal convalescent plasma donors. Antibodies generated against SARS-CoV-2 during the first COVID-19 wave had reduced immunoreactivity and neutralization potency to emerging Spike variants and VOC. Accurate monitoring of SARS-CoV-2 antibody responses would be essential for selection of optimal responders and vaccine monitoring and design.

High hepatitis C treatment uptake among people with recent drug dependence in New South Wales, Australia.

BACKGROUND & AIMS: High HCV treatment uptake among people at most risk of transmission is essential to achieve elimination. We aimed to characterise subpopulations of people with HCV based on drug dependence, to estimate direct-acting antiviral (DAA) uptake in an unrestricted treatment era, and to evaluate factors associated with treatment uptake among people with recent drug dependence. METHODS: HCV notifications in New South Wales, Australia (1995-2017) were linked to opioid agonist therapy (OAT), hospitalisations, incarcerations, HIV notifications, deaths, and prescription databases. Drug dependence was defined as hospitalisation due to injectable drugs or receipt of OAT, with indicators in 2016-2018 considered recent. Records were weighted to account for spontaneous clearance. Logistic regression was used to analyse factors associated with treatment uptake among those with recent drug dependence. RESULTS: 57,467 people were estimated to have chronic HCV throughout the DAA era. Treatment uptake was highest among those with recent (47%), compared to those with distant (38%), and no (33%) drug dependence. Among those with recent drug dependence, treatment was more likely among those with HIV (adjusted odds ratio [aOR] 1.71; 95% CI 1.24-2.36), recent incarceration (aOR 1.10; 95% CI 1.01-1.19), and history of alcohol use disorder (aOR 1.22; 95% CI 1.13-1.31). Treatment was less likely among women (aOR 0.78; 95% CI 0.72-0.84), patients of Indigenous ethnicity (aOR 0.75; 95% CI 0.69-0.81), foreign-born individuals (aOR 0.86; 95% CI 0.78-0.96), those with outer-metropolitan notifications (aOR 0.90; 95% CI 0.82-0.98), HBV coinfection (aOR 0.69; 95% CI 0.59-0.80), and >1 recent hospitalisation (aOR: 0.91; 95% CI 0.84-0.98). CONCLUSIONS: These data provide evidence of high DAA uptake among people with recent drug dependence, including those who are incarcerated. Enhancing this encouraging initial uptake among high-risk populations will be essential to achieve HCV elimination. LAY SUMMARY: To facilitate HCV elimination, those at highest risk of infection and transmission are a treatment priority. This study shows the successes of Australia's universal provision of DAA therapy in reducing the barriers to treatment which have historically persisted among people who inject drugs. Despite higher DAA therapy uptake among those with recent drug dependence, gaps remain. Strategies which aim to reduce marginalisation and increase treatment uptake to ensure equitable HCV elimination must be advanced.

Sofosbuvir/velpatasvir for 12 vs. 6 weeks for the treatment of recently acquired hepatitis C infection.

BACKGROUND & AIMS: Shortened duration therapy for acute and recent HCV infection has been shown to be highly effective in several small non-randomised studies with direct-acting antiviral regimens; however, large randomised studies are lacking. METHODS: REACT was an NIH-funded multicentre international, open-label, randomised, phase IV non-inferiority trial examining the efficacy of short course (6-week) vs. standard course (12-week) therapy with sofosbuvir-velpatasvir for recent HCV infection (estimated duration of infection ≤12 months). Randomisation occurred at week 6. The primary endpoint was sustained virological response 12 weeks after treatment end (SVR12) in the intention-to treat (ITT) population. A total of 250 participants were due to be enrolled, but on advice of the data safety and monitoring board the study was halted early. RESULTS: The primary analysis population consisted of 188 randomised participants at termination of study enrolment; short arm (n = 93), standard arm (n = 95). Ninety-seven percent were male and 69% HIV positive. ITT SVR12 was 76/93, 81.7% (95% CI 72.4-89.0) in the short arm and 86/95, 90.5% (95% CI 82.7-95.6) in the standard arm. The difference between the arms was -8.8 (95% CI -18.6 to 1.0). In modified ITT analysis, wherein non-virological reasons for failure were excluded (death, reinfection, loss to follow-up), SVR12 was 76/85, 89.4% (95% CI 80.8-95.0) in the short arm and 86/88, 97.7% in the standard arm (95% CI 92.0-99.7; difference -8.3%, p = 0.025). CONCLUSIONS: In this randomised study in recent HCV infection, a 6-week course of sofosbuvir-velpatasvir did not meet the criteria for non-inferiority to standard 12-week therapy. LAY SUMMARY: In this randomised trial, 188 people with recently acquired hepatitis C infection were randomly assigned to treatment using either a short 6-week course (93 people) or standard 12-week course (95 people) of the hepatitis C treatment sofosbuvir/velpatasvir. There were 9 cases of relapse after treatment with the short course and 2 following the standard course. A shortened course of 6-week therapy for hepatitis C infection appeared to be less effective than a standard 12-week course in people with recently acquired hepatitis C infection. CLINICALTRIALS. GOV IDENTIFIER: NCT02625909.

Short-Duration Pan-Genotypic Therapy With Glecaprevir/Pibrentasvir for 6 Weeks Among People With Recent Hepatitis C Viral Infection.

BACKGROUND AND AIMS: Among treatment-naive individuals with chronic hepatitis C viral (HCV) infection and without cirrhosis, glecaprevir/pibrentasvir for 8 weeks is recommended. The aim of this analysis was to evaluate the efficacy of glecaprevir/pibrentasvir for 6 weeks in people with acute and recent HCV infection. APPROACH AND RESULTS: In this open-label, single-arm, multicenter, international pilot study, adults with recent HCV (duration of infection < 12 months) received glecaprevir/pibrentasvir 300/120 mg daily for 6 weeks. Primary infection was defined by first positive anti-HCV antibody and/or HCV RNA within 6 months of enrollment and either acute clinical hepatitis within the past 12 months (symptomatic seroconversion illness or alanine aminotransferase > 10 × upper limit of normal) or anti-HCV antibody seroconversion within 18 months. Reinfection was defined as new positive HCV RNA within 6 months of enrollment and evidence of prior spontaneous or treatment-induced clearance. The primary endpoint was sustained virologic response at 12 weeks posttreatment (SVR12). Thirty men (median age 43 years, 90% men who have sex with men) received treatment, of whom 77% (n = 23) were human immunodeficiency virus-positive, 47% (n = 14) had ever injected drugs, and 13% (n = 4) had HCV reinfection. The majority had HCV genotype 1 (83%, n = 25), followed by genotype 4 (10%, n = 3) and genotype 3 (7%, n = 2). At baseline, median estimated duration of infection was 29 weeks (range 13, 52) and median HCV RNA was 6.2 log10 IU/mL (range 0.9, 7.7). SVR12 in the intention-to-treat and per-protocol populations was achieved in 90% (27/30) and 96% (27/28), respectively. There was one case of relapse, and there were two cases of nonvirological failure (death, n = 1; loss to follow-up, n = 1). No treatment-related serious adverse events were seen. CONCLUSIONS: Glecaprevir/pibrentasvir for 6 weeks was highly effective among people with acute and recent HCV infection, supporting further evaluation of shortened-duration pan-genotypic therapy in this setting.