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).

Connecting patients notified with hepatitis C to treatment (CONNECT Study): A randomized controlled trial of active case management by a health department to support primary care practitioners.

BACKGROUND: Despite subsidised access to direct-acting antivirals (DAAs), hepatitis C (HCV) treatment uptake in Australia is declining. Interventions are needed to link people living with HCV to care and treatment. We implemented and measured effectiveness of a state-wide, health department-led, enhanced case management through the primary care practitioner for all HCV notifications, aiming to encourage and support treatment commencement. METHODS: A randomised controlled trial compared enhanced case management, delivered by the health department to diagnosing clinicians, with standard of care using notifiable disease systems in Tasmania, Australia (2020-21). The intervention involved a nurse specialist contacting and providing support by telephone to primary care practitioners making an HCV notification. The primary outcome was the proportion of cases notified with chronic hepatitis C who commenced treatment within 12 weeks of notification. We allowed a 12-week extended follow-up period at the end of the study for participants with no outcomes. RESULTS: Eighty-five primary care practitioners randomised to the intervention and 86 to standard of care arms notified 111 and 115 HCV cases, respectively. The proportion of cases notified with chronic hepatitis (HCV RNA detected) commencing treatment within 12 weeks was similar between study arms (41% vs 33%; p=0·51) and after extended study follow-up (65% vs 48%; p=0·18). RNA test completion was higher in the intervention than in standard of care arm (89% vs. 78%; p=0·03), while completing pre-treatment workup for chronic patients (65% vs. 64%; p=0·93) was similar. CONCLUSION: This was the first prospective randomised study of the utility of immediate HCV notification follow-up of primary care practitioners to enhance treatment uptake using disease notification surveillance data. We demonstrated improvement in HCV RNA testing and trend toward better engagement in care, but no significant increase in treatment uptake.

Health-related quality of life in people receiving opioid agonist treatment and treatment for hepatitis C virus infection.

BACKGROUND: In people with chronic hepatitis C virus (HCV) infection, viral eradication is associated with improved health-related quality of life (HRQOL). OBJECTIVE: To assess changes in HRQOL among participants receiving opioid agonist therapy undergoing treatment for HCV infection. METHODS: COSTAR (NCT02251990) was a randomized, double-blind, placebo-controlled study. Adults with HCV infection on opioid agonist therapy received elbasvir (50 mg)/grazoprevir (100 mg) or placebo for 12 weeks. HRQOL was evaluated using the Medical Outcomes Study 36-Item Short Form Health Survey version 2 (SF-36v2) Acute Form. Participants remained blinded until 4 weeks after end of treatment. RESULTS: Overall, 201 participants received elbasvir/grazoprevir and 100 participants received placebo. Treatment difference mean change from baseline scores (elbasvir/grazoprevir minus placebo) indicated an improvement in HRQOL at 4 weeks after end of treatment in participants receiving elbasvir/grazoprevir versus those receiving placebo, driven by declining HRQOL in those receiving placebo and improved HRQOL in certain domains among participants receiving elbasvir/grazoprevir. Notable differences in SF-36v2 scores were evident in the general health (mean treatment difference [MTD], 6.00; 95% CI, 1.37-10.63), vitality (MTD, 6.81; 95% CI, 1.88-11.75), and mental health (MTD, 5.17; 95% CI, 0.52-9.82) domains and in the mental component summary score (mean, 2.83; 95% CI, 0.29-5.37). No notable between-treatment differences were evident at treatment weeks 4 or 12. CONCLUSION: HRQOL in patients receiving medication for opioid dependence was improved following treatment for HCV infection with elbasvir/grazoprevir, suggesting that eradication of HCV infection with direct-acting antivirals is associated with improved HRQOL. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov, NCT02251990.

Care Navigation Increases Initiation of Hepatitis C Treatment After Release From Prison in a Prospective Randomized Controlled Trial: The C-LINK Study.

Background: Prison-based hepatitis C treatment is safe and effective; however, many individuals are released untreated due to time or resource constraints. On community re-entry, individuals face a number of immediate competing priorities, and in this context, linkage to hepatitis C care is low. Interventions targeted at improving healthcare continuity after prison release have yielded positive outcomes for other health diagnoses; however, data regarding hepatitis C transitional care are limited. Methods: We conducted a prospective randomized controlled trial comparing a hepatitis C care navigator intervention with standard of care for individuals released from prison with untreated hepatitis C infection. The primary outcome was prescription of hepatitis C direct-acting antivirals (DAA) within 6 months of release. Results: Forty-six participants were randomized. The median age was 36 years and 59% were male. Ninety percent (n = 36 of 40) had injected drugs within 6 months before incarceration. Twenty-two were randomized to care navigation and 24 were randomized to standard of care. Individuals randomized to the intervention were more likely to commence hepatitis C DAAs within 6 months of release (73%, n = 16 of 22 vs 33% n = 8 of 24, P < .01), and the median time between re-entry and DAA prescription was significantly shorter (21 days [interquartile range {IQR}, 11-42] vs 82 days [IQR, 44-99], P = .049). Conclusions: Care navigation increased hepatitis C treatment uptake among untreated individuals released from prison. Public policy should support similar models of care to promote treatment in this high-risk population. Such an approach will help achieve hepatitis C elimination as a public health threat.

Reinfection and Risk Behaviors After Treatment of Hepatitis C Virus Infection in Persons Receiving Opioid Agonist Therapy : A Cohort Study.

BACKGROUND: Hepatitis C virus (HCV) reinfection after successful treatment may reduce the benefits of cure among people who inject drugs. OBJECTIVE: To evaluate the rate of HCV reinfection for 3 years after successful treatment among people receiving opioid agonist therapy (OAT). DESIGN: A 3-year, long-term, extension study of persons enrolled in the CO-STAR (Hepatitis C Patients on Opioid Substitution Therapy Antiviral Response) study (ClinicalTrials.gov: NCT02105688). SETTING: 55 clinical trial sites in 13 countries. PATIENTS: Aged 18 years and older with chronic HCV infection with genotypes 1, 4, or 6 receiving stable OAT. INTERVENTION: No treatments were administered. MEASUREMENTS: Serum samples were assessed for HCV reinfection. Urine drug screening was performed. RESULTS: Among 296 participants who received treatment, 286 were evaluable for reinfection and 199 were enrolled in the long-term extension study. The rate of HCV reinfection was 1.7 [95% CI, 0.8 to 3.0] per 100 person-years; 604 person-years of follow-up). A higher rate of reinfection was seen among people with recent injecting drug use (1.9 [95% CI, 0.5 to 4.8] per 100 person-years; 212 person-years). Ongoing drug use and injecting drug use were reported by 59% and 21% of participants, respectively, at the 6-month follow-up visit and remained stable during 3 years of follow-up. LIMITATIONS: Participants were required to be 80% adherent to OAT at baseline and may represent a population with higher stability and lower risk for HCV reinfection. Rate of reinfection may be underestimated because all participants did not continue in the long-term extension study; whether participants who discontinued were at higher risk for reinfection is unknown. CONCLUSION: Reinfection with HCV was low but was highest in the first 24 weeks after treatment completion and among people with ongoing injecting drug use and needle-syringe sharing. PRIMARY FUNDING SOURCE: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.

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.

Randomised controlled trial of active case management to link hepatitis C notifications to treatment in Tasmania, Australia: a study protocol.

INTRODUCTION: By subsidising access to direct acting antivirals (DAAs) for all people living with hepatitis C (HCV) in 2016, Australia is positioned to eliminate HCV as a public health threat. However, uptake of DAAs has declined over recent years and new initiatives are needed to engage people living with HCV in care. Active follow-up of HCV notifications by the health department to the notifying general practitioner (GP) may increase treatment uptake. In this study, we explore the impact of using hepatitis C notifications systems to engage diagnosing GPs and improve patient access to treatment. METHODS AND ANALYSIS: This study is a randomised controlled trial comparing enhanced case management of HCV notifications with standard of care. The intervention includes phone calls from a department of health (DoH) specialist HCV nurse to notifying GPs and offering HCV management support. The level of support requested by the GP was graded in complexity: level 1: HCV information only; level 2: follow-up testing advice; level 3: prescription support including linkage to specialist clinicians and level 4: direct patient contact. The study population includes all GPs in Tasmania who notified HCV diagnosis to the DoH between September 2020 and December 2021. The primary outcome is proportion of HCV cases who initiate DAAs after 12 weeks of HCV notification to the health department. Secondary outcomes are proportion of HCV notifications that complete HCV RNA testing, treatment workup and treatment completion. Multiple logistic regression modelling will explore factors associated with the primary and secondary outcomes. The sample size required to detect a significant difference for the primary outcome is 85 GPs in each arm with a two-sided alpha of 0.05% and 80% power. ETHICS AND DISSEMINATION: The study was approved by University of Tasmania's Human Research Ethics Committee (Protocol ID: 18418) on 17 December 2019. Results of the project will be presented in scientific meetings and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: NCT04510246. TRIAL PROGRESSION: The study commenced recruitment in September 2020 and end of study expected December 2021.

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.

High Effectiveness of Broad Access Direct-Acting Antiviral Therapy for Hepatitis C in an Australian Real-World Cohort: The REACH-C Study.

Australia was one of the first countries with unrestricted access to government subsidized direct-acting antiviral (DAA) therapy for adults with chronic hepatitis C virus. This study assessed real-world DAA treatment outcomes across a diverse range of Australian clinical services and evaluated factors associated with successful treatment and loss to follow-up. Real-world Effectiveness of Antiviral therapy in Chronic Hepatitis C (REACH-C) consisted a national observational cohort of 96 clinical services including specialist clinics and less traditional settings such as general practice. Data were obtained on consecutive individuals who commenced DAAs from March 2016 to June 2019. Effectiveness was assessed by sustained virological response ≥12 weeks following treatment (SVR) using intention-to-treat (ITT) and per-protocol (PP) analyses. Within REACH-C, 10,843 individuals initiated DAAs (male 69%; ≥50 years 52%; cirrhosis 22%). SVR data were available in 85% (9,174 of 10,843). SVR was 81% (8,750 of 10,843) by ITT and 95% (8,750 of 9,174) by PP. High SVR (≥92%) was observed across all service types and participant characteristics. Male gender (adjusted odds ratio [aOR] 0.56, 95% confidence interval [CI] 0.43-0.72), cirrhosis (aOR 0.52, 95% CI 0.41-0.64), recent injecting drug use (IDU; aOR 0.64, 95% CI 0.46-0.91) and previous DAA treatment (aOR 0.50, 95% CI 0.28-0.90) decreased the likelihood of achieving SVR. Multiple factors modified the likelihood of loss to follow-up including IDU ± opioid agonist therapy (OAT; IDU only: aOR 1.75, 95% CI 1.44-2.11; IDU + OAT: aOR 1.39, 95% CI 1.11-1.74; OAT only, aOR 1.36; 95% CI 1.13-1.68) and age (aOR 0.97, 95% CI 0.97-0.98). Conclusion: Treatment response was high in a diverse population and through a broad range of services following universal access to DAA therapy. Loss to follow-up presents a real-world challenge. Younger people who inject drugs were more likely to disengage from care, requiring innovative strategies to retain them in follow-up.

A multi-site, nurse-coordinated hepatitis C model of care in primary care and community services in Melbourne, Australia.

BACKGROUND: Hepatitis C virus (HCV) treatment through primary care and community-based services will be a critical component of HCV elimination. We evaluated a nurse-coordinated programme providing care across eight sites and analysed progression through the HCV care cascade. METHODS: People-accessing services from six primary care clinics, a homeless crisis accommodation provider and a mental health service were directly referred to nurses or engaged by nurses during regular clinic visits. Nurses supported HCV testing, treatment and follow-up. The prescription was provided by affiliated clinicians. Logistic regression was used to examine factors associated with treatment commencement and sustained virological response (SVR) testing. RESULTS: Of 640 people referred to and/or engaged by the nurses from January 2017 to July 2019, 518 had an HCV RNA test of whom 381 (74%) were HCV RNA positive. Treatment was commenced by 281 (74%) people of whom 161 had an SVR test, 157 (97.5%) were cured. Opioid agonist therapy was associated with treatment commencement (aOR 2.68, 95% CI 1.48-4.88). People who were homeless/unstably housed were less likely to commence treatment (aOR 0.45, 95% CI 0.23-0.87). Treatment prescription from a specialist (aOR 2.39, 95% CI 1.20-4.74) and recent injection drug use (<6 months) (aOR 2.15, 95% CI 1.07-4.31) was associated with SVR testing. CONCLUSION: A nurse-coordinated model of care led to high levels of HCV treatment uptake and cure amongst people attending primary care and community services. More tailored models of care may be beneficial for people who are homeless or have unstable housing. These results support primary care and community-based hepatitis C treatment.

Effectiveness of treatment for hepatitis C virus reinfection following direct acting antiviral therapy in the REACH-C cohort.

BACKGROUND: Direct acting antiviral (DAA) therapy is highly effective for hepatitis C virus (HCV) infection, but reinfection following treatment may compromise benefits of cure. This study assessed the real-world effectiveness of treatment for reinfection. METHODS: Real-world effectiveness of antiviral therapy in chronic hepatitis C (REACH-C) is an observational study evaluating treatment outcomes following sequential DAA initiations across 33 health services in Australia between March 2016-June 2019. Reinfection was defined by post-treatment genotype switch or HCV viraemia after sustained virologic response (SVR12). RESULTS: Of the 10,843 individuals initiating DAA therapy post-treatment viraemia was reported in 526 of whom 99 were reinfections. Treatment for reinfection occurred in 88 individuals. In those with available treatment outcomes, SVR12 was similar to initial treatment in the overall REACH-C cohort (95% vs 95%; p = 0.745) and comparable across primary, tertiary, and prison settings. Classifying unknown treatment outcomes as failures, SVR12 for treatment of reinfection was lower than initial treatment in REACH-C (67% vs 81%; p = 0.002), due to higher lost to follow-up. CONCLUSIONS: Treatment of reinfection is highly effective and can be delivered in non-specialist settings. Access to treatment for reinfection in high-risk populations is crucial to HCV elimination.

A qualitative exploration of enablers for hepatitis B clinical management among ethnic Chinese in Australia.

An estimated 18% of people living with chronic hepatitis B (CHB) in Australia were born in China. While guideline-based care, including regular clinical monitoring and timely treatment, prevent CHB-related cirrhosis, cancer and deaths, over three-quarters of people with CHB do not receive guideline-based care in Australia. This qualitative study aimed to identify enablers to engagement in CHB clinical management among ethnic Chinese people attending specialist care. Participants self-identified as of Chinese ethnicity and who attended specialist care for CHB clinical management were interviewed in Melbourne in 2019 (n = 30). Semi-structured interviews covered experiences of diagnosis and engagement in clinical management services, and advice for people living with CHB. Interviews were recorded with consent; data were transcribed verbatim and thematically analysed. Receiving clear information about the availability of treatment and/or the necessity of long-term clinical management were the main enablers for participants to engage in CHB clinical management. Additional enablers identified to maintain regular clinical monitoring included understanding CHB increases risks of cirrhosis and liver cancer, using viral load indicators to visualize disease status in patient-doctor communication; expectations from family, peer group and medical professionals; use of a patient recall system; availability of interpreters or multilingual doctors; and largely subsidized healthcare services. In conclusion, to support people attending clinical management for CHB, a holistic response from community, healthcare providers and the public health sector is required. There are needs for public health programmes directed to communicate (i) CHB-related complications; (ii) availability of effective and cheap treatment; and that (iii) long-term engagement with clinical management and its benefits.

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.

Non-invasive fibrosis algorithms are clinically useful for excluding cirrhosis in prisoners living with hepatitis C.

BACKGROUND AND AIMS: Prison-based HCV treatment rates remain low due to multiple barriers, including accessing transient elastography for cirrhosis determination. The AST-to-platelet ratio index (APRI) and FIB-4 scores have excellent negative predictive value (NPV) in hospital cohorts to exclude cirrhosis. We investigated their performance in a large cohort of prisoners with HCV infection. METHODS: This was a retrospective cohort study of participants assessed by a prison-based hepatitis program. The sensitivity, specificity, NPV and positive predictive value (PPV) of APRI and FIB-4 for cirrhosis were then analysed, with transient elastography as the reference standard. The utility of age thresholds as a trigger for transient elastography was also explored. RESULTS: Data from 1007 prisoners were included. The median age was 41, 89% were male, and 12% had cirrhosis. An APRI cut-off of 1.0 and FIB-4 cut-off of 1.45 had NPVs for cirrhosis of 96.1% and 96.6%, respectively, and if used to triage prisoners for transient elastography, could reduce the need for this investigation by 71%. The PPVs of APRI and FIB-4 for cirrhosis at these cut-offs were low. Age ≤35 years alone had a NPV for cirrhosis of 96.5%. In those >35 years, the APRI cut-off of 1.0 alone had a high NPV >95%. CONCLUSION: APRI and FIB-4 scores can reliably exclude cirrhosis in prisoners and reduce requirement for transient elastography. This finding will simplify the cascade of care for prisoners living with hepatitis C.

The Impact of Markers of HIV Infection on Change in Liver Stiffness in People With HIV and Hepatitis C Virus Co-infection After Treatment and Cure of Hepatitis C.

BACKGROUND: Markers of HIV disease severity are associated with increased liver fibrosis in HIV/Hepatitis C virus (HCV) co-infected individuals. HCV treatment may reverse liver fibrosis, but evidence among HIV/HCV-co-infected populations and the impact of HIV parameters on fibrosis regression is limited. We aimed to assess the influence of surrogate markers of HIV-infection and other determinants of liver stiffness before HCV treatment and changes after HCV cure in people living with HIV. METHODS: We used data from an HCV treatment implementation study aiming for HCV micro-elimination among gay and bisexual men with HIV in Melbourne, Australia (co-EC Study). We obtained liver stiffness measurements (LSM) before and after direct-acting antiviral treatment using transient elastography (FibroScan). Linear mixed models were used to evaluate determinants of pretreatment LSM and changes in LSM following cure with duration in years between pre- and post-LSM assessment as main exposure variable. RESULTS: At least one LSM was available in 173 participants, and 98 participants had 2 LSMs. Median pre- and post-treatment LSMs were 5.7 and 5.1 kPa, respectively. Median time between transient elastography measurements was 1.3 years (interquartile range = 0.9-2.1). In multivariable analysis, longer duration of known HIV infection, a lower CD4 and CD8 T-cell count and hazardous alcohol consumption were associated with higher LSM values before treatment initiation. Successfully treated patients had a 6% (95% confidence interval = -10% to -2%) annual decrease (0.34 kPa predicted decrease) in LSM following cure. Changes in LSM values did not depend on any of the pretreatment HIV markers or other factors. CONCLUSION: Low levels of liver stiffness were observed before treatment initiation and a small decrease (6%) in LSM following HCV cure in people living with HIV. No clear predictors affecting change in LSM following cure were found in this study, including markers of HIV infection. However, markers of advanced HIV immunodeficiency and hazardous alcohol consumption remained associated with higher LSM values even after HCV cure.

Outcomes of Treatment for Hepatitis C in Primary Care, Compared to Hospital-based Care: A Randomized, Controlled Trial in People Who Inject Drugs.

BACKGROUND: To achieve the World Health Organization hepatitis C virus (HCV) elimination targets, it is essential to increase access to direct-acting antivirals (DAAs), especially among people who inject drugs (PWID). We aimed to determine the effectiveness of providing DAAs in primary care, compared with hospital-based specialist care. METHODS: We randomized PWID with HCV attending primary care sites in Australia or New Zealand to receive DAAs at their primary care site or local hospital (standard of care [SOC]). The primary outcome was to determine whether people treated in primary care had a noninferior rate of sustained virologic response at Week 12 (SVR12), compared to historical controls (consistent with DAA trials at the time of the study design); secondary outcomes included comparisons of treatment initiation, SVR12 rates, and the care cascade by study arm. RESULTS: We recruited 140 participants and randomized 136: 70 to the primary care arm and 66 to the SOC arm. The SVR12 rate (100%, 95% confidence interval [CI] 87.7-100) of people treated in primary care was noninferior when compared to historical controls (85% assumed). An intention-to-treat analysis revealed that the proportion of participants commencing treatment in the primary care arm (75%, 43/57) was significantly higher than in the SOC arm (34%, 18/53; P < .001; relative risk [RR] 2.48, 95% CI 1.54-3.95), and the proportion of participants with SVR12 was significantly higher in the primary care arm, compared to in the SOC arm (49% [28/57] and 30% [16/53], respectively; P = .043; RR 1.63, 95% CI 1.0-2.65). CONCLUSIONS: Providing HCV treatment in primary care increases treatment uptake and cure rates. Approaches that increase treatment uptake among PWID will accelerate elimination strategies. CLINICAL TRIALS REGISTRATION: NCT02555475.

Retreatment with elbasvir, grazoprevir, sofosbuvir ± ribavirin is effective for GT3 and GT1/4/6 HCV infection after relapse.

INTRODUCTION: Despite highly effective direct-acting antiviral (DAA) therapies for chronic hepatitis C virus (HCV) infection, some patients experience virological relapse. Salvage regimens should include multiple agents to suppress emergence of resistance-associated substitutions (RAS) and minimise treatment failure. The combination of sofosbuvir (SOF) and elbasvir/grazoprevir (ELB/GZR) ±ribavirin (RBV) is an effective retreatment strategy for HCV genotype (GT)1 and 4 infection. We hypothesised that SOF and ELB/GZR (±RBV) would also be an effective salvage regimen for DAA-experienced GT3 patients. METHODS: We evaluated the efficacy and safety of SOF/ELB/GZR ± RBV in DAA-experienced participants with chronic HCV infection who had prior relapse. Participants were treated at four hospitals between December 2016 and March 2018 for either 12- or 16-weeks. The primary endpoint was sustained virological response at week 12 post-treatment (SVR12) using intention-to-treat analysis. RESULTS: There were 40 participants included in the analysis. The mean age was 53 years, 53% had GT3, 33% had GT1 infection and 63% had cirrhosis. Fifty-eight percent were treated for 12 weeks, 42% were treated for 16 weeks and 90% received RBV. The SVR12 rate was 98% overall, 100% in non-GT3 participants and 95% in GT3 participants. One GT3 cirrhotic participant relapsed. ELB/GZR was stopped at week 6 in one GT3 cirrhotic participant who switched to SOF/velpatasvir/RBV for a further 12 weeks and achieved SVR12. RBV dose reduction was required in two participants. Treatment was otherwise well tolerated. DISCUSSION: The combination of SOF/ELB/GZR ± RBV is effective and safe for difficult-to-cure patients who relapse after first-line DAA, including those with cirrhosis and GT3 infection.