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      Australia could miss the WHO hepatitis C virus elimination targets due to declining treatment uptake and ongoing burden of advanced liver disease complications

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          Abstract

          Australia was one of the first countries to introduce government-funded unrestricted access to direct-acting antiviral (DAA) therapy, with 88,790 treated since March 2016. However, treatment uptake is declining which could potentially undermine Australia’s progress towards the WHO HCV elimination targets. Using mathematical modelling, we updated estimates for those living with chronic HCV in Australia, new cases of decompensated cirrhosis (DC), hepatocellular carcinoma (HCC), and liver-related mortality among the HCV-cured and viraemic populations from 2015 to 2030. We considered various DAA treatment scenarios incorporating annual treatment numbers to 2020, and subsequent uptake per year of 6,790 (pessimistic), 8,100 (intermediate), and 11,310 (optimistic). We incorporated the effects of excess alcohol consumption and reduction in progression to DC and HCC among cirrhosis-cured versus viraemic individuals. At the end of 2020, we estimated 117,810 Australians were living with chronic HCV. New cases per year of DC, HCC, and liver-related mortality among the HCV viraemic population decreased rapidly from 2015 (almost eliminated by 2030). In contrast, the growing population size of those cured with advanced liver disease meant DC, HCC, and liver-related mortality declined slowly. The estimated reduction in liver-related mortality from 2015 to 2030 in the combined HCV viraemic and cured population is 25% in the intermediate scenario. With declining HCV treatment uptake and ongoing individual-level risk of advanced liver disease complications, including among cirrhosis-cured individuals, Australia is unlikely to achieve all WHO HCV elimination targets by 2030.

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          Global prevalence and genotype distribution of hepatitis C virus infection in 2015: a modelling study

          The 69th World Health Assembly approved the Global Health Sector Strategy to eliminate hepatitis C virus (HCV) infection by 2030, which can become a reality with the recent launch of direct acting antiviral therapies. Reliable disease burden estimates are required for national strategies. This analysis estimates the global prevalence of viraemic HCV at the end of 2015, an update of-and expansion on-the 2014 analysis, which reported 80 million (95% CI 64-103) viraemic infections in 2013.
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            Sofosbuvir and ledipasvir fixed-dose combination with and without ribavirin in treatment-naive and previously treated patients with genotype 1 hepatitis C virus infection (LONESTAR): an open-label, randomised, phase 2 trial.

            Interferon-based treatment is not suitable for many patients with hepatitis C virus (HCV) infection because of contraindications such as psychiatric illness, and a high burden of adverse events. We assessed the efficacy and safety of an interferon-free regimen--a fixed-dose combination of the nucleotide polymerase inhibitor sofosbuvir (400 mg) and the HCV NS5A inhibitor ledipasvir (90 mg), with and without ribavirin--in patients with genotype-1 hepatitis C infection who were treatment-naive or previously treated with a protease-inhibitor regimen. For this open-label study, we enrolled 100 adult patients (>18 years) with HCV infection at a centre in the USA between Nov 2, 2012, and Dec 21, 2012. In cohort A, we used a computer-generated sequence to randomly assign (1:1:1; stratified by HCV genotype [1a vs 1b]) 60 non-cirrhotic, treatment-naive patients to receive sofosbuvir plus ledipasvir for 8 weeks (group 1), sofosbuvir plus ledipasvir and ribavirin for 8 weeks (group 2), or sofosbuvir plus ledipasvir for 12 weeks (group 3). In cohort B, we randomly allocated (1:1; stratified by genotype and presence or absence of cirrhosis) 40 patients who previously had virological failure after receiving a protease inhibitor regimen to receive sofosbuvir plus ledipasvir for 12 weeks (group 4) or sofosbuvir plus ledipasvir and ribavirin for 12 weeks (group 5). 22 (55%) of 40 patients in cohort B had compensated cirrhosis. The primary endpoint was sustained virological response 12 weeks after treatment (SVR12), analysed by intention to treat. This study is registered with ClinicalTrials.gov, number NCT01329978. In cohort A, SVR12 was achieved by 19 (95%) of 20 patients (95% CI 75-100) in group 1, by 21 (100%) of 21 patients (84-100) in group 2, and by 18 (95%) of 19 patients (74-100) in group 3. In cohort B, SVR12 was achieved by 18 (95%) of 19 patients (74-100) in group 4 and by all 21 (100%) of 21 patients (84-100) in group 5. Two patients had viral relapse; one patient was lost to follow-up after achieving sustained virological response 8 weeks after treatment. The most common adverse events were nausea, anaemia, upper respiratory tract infection, and headache. One patient in group five had a serious adverse event of anaemia, thought to be related to ribavirin treatment. These findings suggest that the fixed-dose combination of sofosbuvir-ledipasvir alone or with ribavirin has the potential to cure most patients with genotype-1 HCV, irrespective of treatment history or the presence of compensated cirrhosis. Further clinical trials are needed to establish the best treatment duration and to further assess the contribution of ribavirin. Gilead Sciences. Copyright © 2014 Elsevier Ltd. All rights reserved.
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              Changing hepatocellular carcinoma incidence and liver cancer mortality rates in the United States.

              The objectives were to describe Surveillance, Epidemiology and End Results (SEER) hepatocellular carcinoma (HCC) incidence trends and the US liver cancer mortality trends by geography, age, race/ethnicity, and gender. HCC incidence data from SEER 18 registries and liver cancer mortality data from the National Center for Health Statistics were analyzed. Rates and joinpoint trends were calculated by demographic subgroup. State-level liver cancer mortality rates and trends were mapped. HCC incidence rates in SEER registries did not significantly increase during 2007-2010; however, the US liver cancer mortality rates did increase. HCC incidence and liver cancer mortality rates increased among black, Hispanic, and white men aged 50+ years and decreased among 35-49-year-old men in all racial/ethnic groups including Asians/Pacific Islanders. Significantly increasing incidence and mortality rates among women were restricted to blacks, Hispanics, and whites aged 50+ years. Asian/Pacific Islander liver cancer mortality rates decreased during 2000-2010 with decreasing rates among women aged 50-64 years and men aged 35-49 years and stable rates in other groups. During 2006-2010, among individuals 50-64 years of age, blacks and Hispanics had higher incidence and mortality rates than Asians/Pacific Islanders. Liver cancer mortality rates were highest in Louisiana, Mississippi, Texas, and Washington, DC. Decreasing HCC incidence and liver cancer mortality rates among Asians/Pacific Islanders, men aged 35-49 years, and the nonsignificant increase in overall HCC incidence rates suggest that the peak of the epidemic may be near or have passed. Findings of geographic variation in mortality rates can inform control efforts.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: MethodologyRole: Writing – original draft
                Role: ConceptualizationRole: MethodologyRole: Writing – original draft
                Role: Data curationRole: Writing – review & editing
                Role: Data curationRole: MethodologyRole: Writing – review & editing
                Role: Data curationRole: Writing – review & editing
                Role: ConceptualizationRole: Writing – review & editing
                Role: ConceptualizationRole: VisualizationRole: Writing – review & editing
                Role: ConceptualizationRole: InvestigationRole: MethodologyRole: Writing – original draft
                Role: Editor
                Journal
                PLoS One
                PLoS One
                plos
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                16 September 2021
                2021
                : 16
                : 9
                Affiliations
                [001] Kirby Institute, UNSW Sydney, Sydney, New South Wales, Australia
                Centers for Disease Control and Prevention, UNITED STATES
                Author notes

                Competing Interests: RTG and JAK have provided project advice for Gilead. There are no patents, products in development, or marketed products associated with this research to declare. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

                Article
                PONE-D-21-13026
                10.1371/journal.pone.0257369
                8445464
                9ac8cc70-6d71-4f1a-a5ee-d1d01724a585
                © 2021 Kwon et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                Page count
                Figures: 4, Tables: 2, Pages: 15
                Product
                Funding
                Funded by: Australian Government Department of Health
                Award Recipient :
                The Kirby Institute is funded by the Australian Government Department of Health and is affiliated with the Faculty of Medicine, UNSW Sydney. The views expressed in this publication do not necessarily represent the position of the Australian Government. GJD has received research grant funding from Gilead, Merck, and Abbvie. JG has received research grant funding from Camurus, Cepheid, Gilead, Hologic, Indivior, Merck, and Abbvie unrelated to this work. JG is supported by an Australian National Health and Medical Research Council (NHMRC) Investigator Grant (#1176131). Funders did not have any additional role in the study design, data collection, and analysis, decision to publish, or preparation of the manuscript. The specific roles of each author are articulated in the ‘author contributions’ section.
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