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

Published:September 21, 2022DOI:


      • Seven percent of people treated for HCV in Australia were retreated.
      • Machine learning was used to classify retreatments based on national administrative data.
      • Overall, 52% of retreatment was for reinfection and 48% was for treatment failure.
      • Retreatment for reinfection increased over time, reflecting increasing numbers of people at-risk for reinfection following cure.
      • Retreatment for treatment failure increased when salvage DAAs became available.

      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.


      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).


      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.


      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.

      Graphical abstract


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        • Falade-Nwulia O.
        • Suarez-Cuervo C.
        • Nelson D.R.
        • Fried M.W.
        • Segal J.B.
        • Sulkowski M.S.
        Oral direct-acting agent therapy for hepatitis C virus infection: a systematic review.
        Ann Intern Med. 2017 May 2; 166: 637-648
        • Hajarizadeh B.
        • Cunningham E.B.
        • Valerio H.
        • Martinello M.
        • Law M.
        • Janjua N.Z.
        • et al.
        Hepatitis C reinfection after successful antiviral treatment among people who inject drugs: a meta-analysis.
        J Hepatol. 2020; : 1-15
        • World Health Organization
        Combating hepatitis B and C to reach elimination by 2030. World Health Organization, 2016;(May):1-16
        • Backus L.I.
        • Belperio P.S.
        • Shahoumian T.A.
        • Mole L.A.
        Direct-acting antiviral sustained virologic response: impact on mortality in patients without advanced liver disease.
        Hepatology. 2018; 68: 827-838
        • Martinello M.
        • Dore G.J.
        • Matthews G.v.
        • Grebely J.
        Strategies to reduce hepatitis C virus reinfection in people who inject drugs.
        Infect Dis Clin North America. 2018; 32: 371-393
        • Hepatitis C Virus Infection Consensus Statement Working Group
        Australian recommendations for the management of hepatitis C virus infection: a consensus statement (September 2018).
        ([Internet]. Melbourne, Australia)2018 (Available from)
        • Hajarizadeh B.
        • Grebely J.
        • Matthews G.V.
        • Martinello M.
        • Dore G.J.
        Uptake of direct-acting antiviral treatment for chronic hepatitis C in Australia.
        J Viral Hepat. 2018; 25: 640-648
        • Yee J.
        • Carson J.
        • Hanson J.
        • O’Beirne J.
        • Iser D.
        • Read P.
        • et al.
        High efficacy of DAA therapy for chronic HCV in an Australian real-world cohort : the REACH-C study.
        in: Australasian viral hepatitis elimination conference. The Kirby Institute, UNSW Sydney, Australia, Sydney, Australia2019
        • Carson J.M.
        • Hajarizadeh B.
        • Hanson J.
        • Beirne J.O.
        • Iser D.
        • Read P.
        • et al.
        Effectiveness of treatment for hepatitis C virus reinfection following direct acting antiviral therapy in the REACH-C cohort.
        Int J Drug Pol. 2021; 96103422
        • Breiman L.
        Random forests.
        Machine Learn. 2001; 45: 5-32
        • Friedman J.H.
        Greedy function approximation: a gradient boosting machine.
        Ann Stat. 2001; 29: 1189-1232
        • Geisser S.
        The predictive sample reuse method with applications.
        J Am Stat Assoc. 1975; 70: 320-328
        • DiCiccio T.J.
        • Efron B.
        Bootstrap confidence intervals.
        Stat Sci. 1996; 11: 189-228
        • Kwon J.A.
        • Dore G.J.
        • Hajarizadeh B.
        • Alavi M.
        • Valerio H.
        • Grebely J.
        • et al.
        Australia could miss the WHO hepatitis C virus elimination targets due to declining treatment uptake and ongoing burden of advanced liver disease complications.
        PLoS ONE. 2021 Sep 1; : 16
        • Valerio H.
        • Alavi M.
        • Law M.
        • Tillakeratne S.
        • Amin J.
        • Janjua N.Z.
        • et al.
        High hepatitis C treatment uptake among people with recent drug dependence in New South Wales, Australia.
        J Hepatol. 2021; 74: 293-302
        • Heard S.
        • Iverson J.
        • Geddes L.
        • Maher L.
        Australian needle and syringe program survey 25 year national data report 1995-2019. Sydney, Australia.
        • Read P.
        • Gilliver R.
        • Kearley J.
        • Lothian R.
        • Cunningham E.B.
        • Chronister K.J.
        • et al.
        Treatment adherence and support for people who inject drugs taking direct-acting antiviral therapy for hepatitis C infection.
        J Viral Hepat. 2019; 26: 1301-1310
        • Norton B.L.
        • Akiyama M.J.
        • Arnsten J.H.
        • Agyemang L.
        • Heo M.
        • Litwin A.H.
        High HCV cure rates among people who inject drugs and have suboptimal adherence: a patient-centered approach to HCV models of care.
        Int J Drug Pol. 2021 Jul 1; 93103135
        • Amin J.
        • Vaccher S.
        • Templeton D.J.
        • Bavinton B.
        • Jin F.
        • Zablotska I.
        • et al.
        Low prior exposure and incidence of hepatitis C in human immunodeficiency virus–negative gay and bisexual men taking preexposure prophylaxis (PrEP): findings from the expanded PrEP implementation in communities–New South Wales prospective implementation study.
        Clin Infect Dis. 2022 Oct 29; 75: 1497-1502
        • Hosseini-Hooshyar S.
        • Martinello M.
        • Yee J.
        • Read P.
        • Baker D.
        • Post J.J.
        • et al.
        Low hepatitis C virus reinfection rate despite ongoing risk following universal access to direct-acting antiviral therapy among people living with HIV.
        AIDS. 2020; 34: 1347-1358
        • Carson J.M.
        • Dore G.J.
        • Lloyd A.R.
        • Grebely J.
        • Byrne M.
        • Cunningham E.
        • et al.
        Hepatitis C virus reinfection following direct-acting antiviral treatment in the prison setting: the SToP-C study.
        Clin Infect Dis. 2022 Apr 1; : ciac246
        • Cunningham E.B.
        • Hajarizadeh B.
        • Amin J.
        • Hellard M.
        • Bruneau J.
        • Feld J.J.
        • et al.
        Reinfection following successful direct-acting antiviral therapy for hepatitis C virus infection among people who inject drugs.
        Clin Infect Dis. 2020; 1–9
        • Australian Institute of Health and Welfare
        Australia’s welfare 2021 data insights.
        2021 (Canberra)
        • MacLachlan J.H.
        • Stewart S.
        • Cowie B.C.
        Viral hepatitis mapping project.
        (National Report 2020 [Internet]. Sydney)2020 (Available from:)
        • Carson J.M.
        • Hajarizadeh B.
        • Hanson J.
        • O’Beirne J.
        • Iser D.
        Phillip |, et al. Retreatment for hepatitis C virus direct-acting antiviral therapy virological failure in primary and tertiary settings: the REACH-C cohort.
        J Viral Hepat. 2022; 29: 11
        • Tatara E.
        • Gutfraind A.
        • Collier N.T.
        • Cotler S.J.
        • Major M.
        • Ozik J.
        • et al.
        Modeling hepatitis C micro-elimination among people who inject drugs with direct-acting antivirals in metropolitan Chicago.
        bioRxiv. 2021; 1–33
        • Campos Fernández de Sevilla M.Á.
        • Gallego Úbeda M.
        • Tovar Pozo M.
        • García-Cabrera E.
        • Monje García B.
        • Tutau Gómez F.
        • et al.
        Measure of adherence to direct-acting antivirals as a predictor of the effectiveness of hepatitis C treatment.
        Int J Clin Pharm. 2019; 41: 1545-1554
        • Spinelli M.A.
        • Haberer J.E.
        • Chai P.R.
        • Castillo-Mancilla J.
        • Anderson P.L.
        • Gandhi M.
        Approaches to Objectively Measure Antiretroviral Medication Adherence and Drive Adherence Interventions.
        in: Current HIV/AIDS reports. 17. Springer, 2020: 301-314