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Treatment Direct Acting Antiviral Therapy Versus Pegylated WHO/HIV/2014.33 © World Health Organization 2014 Global Hepatitis Programme Guideline development for Hepatitis C virus Screening, Care and Treatment in low- and middle-income countries PICO 7: Treatment Direct acting antiviral therapy versus pegylated interferon and ribavirin treatment for chronic hepatitis C infection: a meta-analytical systematic review Conducted by the Burnet Institute, Melbourne and Health Protection Scotland, Glasgow 23 June 2013 Review Members Dr Joseph Doyle Burnet Institute, Melbourne Dr Alexander Thompson St Vincent’s Hospital, University of Melbourne, and Victorian Infectious Diseases Reference Laboratory, Melbourne Dr Esther Aspinall Health Protection Scotland, Glasgow Prof Sharon Hutchinson Caledonian University, Glasgow Prof Margaret Hellard Burnet Institute, Melbourne Review Advisory Group Dr Mark Stoove Burnet Institute, Melbourne Prof David Goldberg Health Protection Scotland Prof Stanley Luchters Burnet Institute, Melbourne Dr Stefan Wiktor WHO Global Hepatitis Program Mr Tim Nguyen WHO Global Hepatitis Program Dr Bryce Smith Centre for Disease Control and Prevention, Atlanta Dr Yngve Falck-Ytter Case Western Reserve University, Ms Rebecca Morgan Centre for Disease Control and Prevention, Atlanta PICO 7 (Treatment): DAA+PR versus PR for chronic HCV © World Health Organization 2014 All rights reserved. Publications of the World Health Organization are available on the WHO website (www.who.int) or can be purchased from WHO Press, World Health Organization, 20 Avenue Appia, 1211 Geneva 27, Switzerland (tel.: +41 22 791 3264; fax: +41 22 791 4857; E-mail: [email protected]). Requests for permission to reproduce or translate WHO publications –whether for sale or for non- commercial distribution– should be addressed to WHO Press through the WHO website (www.who.int/about/licensing/copyright_form/en/index.html). The designations employed and the presentation of the material in this publication do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted and dashed lines on maps represent approximate border lines for which there may not yet be full agreement. The mention of specific companies or of certain manufacturers’ products does not imply that they are endorsed or recommended by the World Health Organization in preference to others of a similar nature that are not mentioned. Errors and omissions excepted, the names of proprietary products are distinguished by initial capital letters. All reasonable precautions have been taken by the World Health Organization to verify the information contained in this publication. However, the published material is being distributed without warranty of any kind, either expressed or implied. The responsibility for the interpretation and use of the material lies with the reader. In no event shall the World Health Organization be liable for damages arising from its use. Page 2 PICO 7 (Treatment): DAA+PR versus PR for chronic HCV Contents BACKGROUND ..................................................................................................................................... 4 METHODS ............................................................................................................................................ 4 RESULTS .............................................................................................................................................. 7 CONCLUSIONS ..................................................................................................................................... 9 FIGURES ............................................................................................................................................. 10 Figure 1: Flow chart describing selection of included studies ...................................................... 10 Figure 2: Failure to achieve SVR using DAA+PR versus PR treatment for chronic HCV ................ 11 Figure 3a: Failure to achieve SVR using DAA+PR versus PR for chronic HCV, among treatment naïve individuals ............................................................................................................................ 12 Figure 3b: Failure to achieve SVR using DAA+PR versus PR for chronic HCV, among treatment experience individuals .................................................................................................................. 13 Figure 4a: Failure to achieve SVR using DAA+PR versus PR for chronic HCV, with mild fibrosis (F0-2) ............................................................................................................................................. 14 Figure 4b: Failure to achieve SVR using DAA+PR versus PR for chronic HCV, with advanced fibrosis (F3-4) ................................................................................................................................ 15 Figure 5: Adverse Events (Grade 3/4 anaemia) using DAA+PR versus PR for chronic HCV .......... 16 Figure 6: Adverse Events (Grade 3/4 neutropenia) using DAA+PR versus PR for chronic HCV .... 17 Figure 7: Adverse Events (Treatment discontinuation) using DAA+PR versus PR for chronic HCV ...................................................................................................................................................... 18 Figure 8: Mortality (to 72 weeks) using DAA+PR versus PR for chronic HCV ............................... 20 TABLES ............................................................................................................................................... 21 Table 1: Characteristics of included studies.................................................................................. 21 Table 2: Evidence Profile – DAA+PR versus PR in chronic HCV infection ..................................... 23 REFERENCES ...................................................................................................................................... 25 APPENDICIES ..................................................................................................................................... 27 Appendix 1: Search Syntax ............................................................................................................ 27 Appendix 2: Cochrane Collaboration’s tool for assessing risk of bias........................................... 29 Appendix 3: GRADE approach to assessing the quality of evidence across studies ..................... 30 Page 3 PICO 7 (Treatment): DAA+PR versus PR for chronic HCV BACKGROUND The World Health Organization (WHO) estimates that between 130 and 150 million people are chronically infected with hepatitis C (HCV) virus worldwide (World Health Organization 2012). People with untreated HCV are at increased risk of liver cirrhosis, hepatocellular carcinoma, and liver- related mortality (Grebely and Dore 2011). The combination of pegylated interferon and ribavirin, where available, has been the standard of care for treating individuals with chronic HCV for many years (European Association for the Study of the Liver 2011). However newer direct acting antiviral agents in development and approved for therapeutic use promise to further improve virological response to treatment, but may add to treatment complexity, adverse effects, monitoring requirements and cost. This review will assess the available evidence in an effort to determine whether the addition of regimens containing direct acting antiviral agents are more effective at treating HCV compared to pegylated interferon/ribavirin therapy with respect to virological response, morbidity, mortality and adverse effects. METHODS Narrative review question Among people with chronic HCV, is treatment containing direct acting antiviral agents (DAA) more effective than treatment with pegylated interferon and ribavirin (PR) alone? PICO Question Population: Adults and children with chronic HCV infection Intervention: Direct-acting antiviral (DAA) therapy in addition to pegylated interferon (PEG) and ribavirin (RBV) therapy Comparison: Pegylated interferon and ribavirin therapy alone Outcomes: Number achieving sustained virological response; number of cases of decompensated liver disease/hepatocellular carcinoma/all-cause mortality; treatment-related serious adverse events leading to discontinuation of therapy; and quality of life. Cost outcomes will require economic modelling which will be conducted separately from this protocol. Study type/limits: Experimental studies (human) published between 1994 and the present; limited to published phase 3 studies of licensed anti-HCV drugs Page 4 PICO 7 (Treatment): DAA+PR versus PR for chronic HCV Search strategy A systematic review was carried out using the following electronic databases and information sources: - OVID MEDLINE, OVID EMBASE, and the Cochrane Library (CENTRAL and DARE) (without language restrictions); - Reference lists of all relevant articles and reviews; - Recommendations from Guideline Development Group (GDG) members and other experts in the field; - Relevant articles identified during the conduct of the other systematic reviews. Search terms included combinations of free text and medical subject heading terms (MeSH, Emtree), briefly summarized as: Hepatitis C AND Direct Acting Antiviral Agents. Conduct of the review The review process followed the Cochrane methodology for conducting a
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