Therapeutic strategies for recent hepatitis C virus infection in the era of direct-acting antiviral therapy Marianne Martinello A thesis in fulfilment of the requirements for the degree of Doctor of Philosophy The Kirby Institute Faculty of Medicine May 2017 Page 1 of 309 Thesis/Dissertation Sheet THE UNIVERSITY OF NEW SOUTH WALES Thesis/Dissertation Sheet Surname or Family name: Martinello First name: Marianne Abbreviation for degree as given in the University calendar: PhD School: Kirby Institute Faculty: Medicine Title: Therapeutic strategies for recent hepatitis C virus infection in the era of direct-acting antiviral therapy Abstract: Background: The management of recent hepatitis C virus (HCV) infection is uncertain, as the therapeutic landscape evolves with the advent of direct-acting antiviral (DAA) therapy. Aims: The broad aim of this research was to examine novel therapeutic strategies in recent HCV following the availability of DAA therapy. Specific aims included assessing the feasibility, efficacy and safety of response-guided interferon (IFN) -containing and ultra-short IFN-free therapy; calculating reinfection incidence following treatment; and determining the clinical significance of drug-drug interactions in HIV/HCV co-infection. Methods: In Chapters Two and Three, the efficacy and safety of short and/or response-guided treatment among individuals with recent HCV was examined in three open-label trials: ATAHC II (n=52; pegylated-IFN +/- ribavirin), DARE-C I (n=14; pegylated-IFN, ribavirin + telaprevir) and DARE-C II (n=19; sofosbuvir + ribavirin). In Chapter Four, reinfection incidence following treatment for recent HCV was calculated among those who achieved an end-of-treatment response in ATAHC I and II, DARE-C I and II (n=120). In Chapter Five, a simulation of potential drug-drug interactions between combination antiretroviral therapy and DAAs was performed in those with HIV/HCV enrolled in CEASE-D (n=257). Page 2 of 309 Key Findings: A total of 85 individuals (73% HIV) with recent HCV commenced short and/or response-guided treatment between 2010 and 2015; none of the strategies trialled was optimal. Given toxicity, the applicability of an IFN-containing strategy is limited. Conversely, six weeks of sofosbuvir and ribavirin was safe and well tolerated, but efficacy was poor. High reinfection incidence, particularly in individuals reporting injection drug use following treatment, was seen. These trials confirmed the feasibility of short duration therapy in recent HCV and informed contemporary trial design. Optimal DAA regimen choice for future research will be crucial; the combination of a nucleotide analogue and an NS5A inhibitor appears appropriate given potency and little potential for drug-drug interactions in HIV/HCV co-infection. Conclusion: The role and efficacy of ultra-short duration therapy in recent HCV requires further evaluation with potent DAA regimens. The significant risk for HCV reinfection following treatment in individuals with ongoing behaviour facilitating transmission emphasises the need for post-treatment surveillance, harm reduction strategies and education. Declaration relating to disposition of project thesis/dissertation I hereby grant to the University of New South Wales or its agents the right to archive and to make available my thesis or dissertation in whole or in part in the University libraries in all forms of media, now or here after known, subject to the provisions of the Copyright Act 1968. I retain all property rights, such as patent rights. I also retain the right to use in future works (such as articles or books) all or part of this thesis or dissertation. I also authorise University Microfilms to use the 350 word abstract of my thesis in Dissertation Abstracts International (this is applicable to doctoral theses only). 14 Dec 2016 Signature Witness Date The University recognises that there may be exceptional circumstances requiring restrictions on copying or conditions on use. Requests for restriction for a period of up to 2 years must be made in writing. Requests for a longer period of restriction may be considered in exceptional circumstances and require the approval of the Dean of Graduate Research. FOR OFFICE USE ONLY Date of completion of requirements for Award: Page 3 of 309 Contents Thesis/Dissertation Sheet .............................................................................................................. 2 Supervisor Statement .................................................................................................................... 8 Originality Statement .................................................................................................................... 9 Copyright Statement ................................................................................................................... 10 Authenticity Statement ................................................................................................................ 11 Acknowledgements ..................................................................................................................... 12 List of publications and presentations ......................................................................................... 14 Publications ............................................................................................................................. 14 Conference presentations ........................................................................................................ 15 Abbreviations .............................................................................................................................. 17 Chapter 1 Introduction and Literature Review............................................................................ 19 Epidemiology of recent HCV infection .................................................................................. 19 HCV incidence and risk factors for acquisition .................................................................. 20 Detection of acute HCV infection ....................................................................................... 27 Management of acute and recent HCV infection .................................................................... 29 Natural history and spontaneous clearance ......................................................................... 29 Timing of HCV treatment initiation .................................................................................... 30 Interferon-based treatment of acute HCV mono-infection ................................................. 30 Interferon-based treatment of recent HCV infection in PWID ........................................... 32 Interferon-based treatment of recent HCV infection in HIV co-infection .......................... 32 Duration of interferon-based treatment in recent HCV infection ....................................... 33 Evidence gaps related to the treatment of acute and recent HCV infection ........................ 33 Overview of Protease, Polymerase and Assembly Inhibitors for the Treatment of HCV....... 35 Mechanism of drug action................................................................................................... 38 Mode of drug administration and dosage ............................................................................ 42 Adverse reactions and toxicity ............................................................................................ 46 Direct-acting antiviral efficacy in chronic HCV infection among PWID and people with HIV/HCV coinfection ............................................................................................................. 52 Evidence from clinical trials ............................................................................................... 52 Evidence from “real world” cohorts ................................................................................... 57 Reinfection following HCV treatment .................................................................................... 58 Who is at “high-risk” of reinfection? Defining the population of interest .......................... 58 HCV reinfection among people who inject drugs ............................................................... 61 HCV reinfection among HIV-positive MSM ...................................................................... 62 Mathematical modelling: Treatment-as-Prevention and the impact of reinfection ............. 63 Thesis rationale and objectives ............................................................................................... 65 Chapter 2 The efficacy, safety and feasibility of response-guided interferon-based therapy in recent HCV infection .................................................................................................................. 67 Chapter Introduction and Objectives ...................................................................................... 67 Page 4 of 309 Declaration .............................................................................................................................. 69 Co-authorship Acknowledgement........................................................................................... 70 Short duration response-guided treatment is effective for most individuals with recent hepatitis C infection: the ATAHC II and DARE-C I studies .................................................. 71 Abstract ..................................................................................................................................