1. A systematic review of hepatitis C clinical practice guidelines: Benefits, limitations and harms Lim, D., Siegel, E., Hepworth, J., Bain, T., and van Driel, M. c113.lim@qut.edu.au

2. Hepatitis C Virus imaged with an electron microscope. Image : http://hedgeclippers.org/hedgepapers-no-13-hepatitis-c-and-hedge-fund-profiteers/

3. Hepatitis C treatment Interferon alfa 1998: ribavirin and interferon alfa 2001: pegylated interferon 2011: boceprevir, telaprevir (triple therapy) 2013: simeprevir, sofosbuvir – 2013: pegylated interferon and ribavirin listed on WHO Essential Medicines List 2014: ledipasvir-sofosbuvir combination, Viekira Pak® (ombitasvir, paritaprevir, ritonavir and dasabuvir), daclatasvir – 2015: sofosbuvir, simeprevir, daclatasvir, dasabuvir, ledipasvir + sofosbuvir combination, and the combination of ombitasvir + paritaprevir + ritonavir added to WHO Essential Medicines List

4. systematically and comparatively appraise the consistency of national and international clinical practice guidelines for the therapeutic management of HCV Purpose:

5. Methods Definition of ‘clinical practice guidelines’ – statements that include recommendations intended to optimise patient care. They are informed by a systematic review of evidence and an assessment of the benefits and harms of alternative care options [Institute of Medicine] Databases: – PubMed, Embase, Cochrane, Trip Clinical Evidence Database, National Health and Medicine Research Council Guideline Portal, National Guideline Clearinghouse and Guidelines International Network – Snowball – Terms: hepatitis C [MeSH] and practice guideline [MeSH] Inclusion: – Full text available in English; – Published after January 2002; – Fulfilled the Institute of Medicine’s definition of ‘clinical practice guideline’; – On hepatitis C management and or treatment; and – Latest version from the same author/s or agency. Exclusion criteria used were: – the guidelines were for managing HCV exposure rather than management of the disease state itself; and – HCV management was secondary to other primary morbidities such as hepatitis B, HIV/AIDS, and in vitro fertilisation University of York PROSPERO database (registration number CRD42014014694)

7. Results – Acute hepatitis C Standard interferon or pegylated interferon monotherapy [68, 71, 77]; Pegylated interferon monotherapy [55, 57, 59, 70, 78, 79]; Combination of pegylated interferon and weight-based ribavirin therapy [65, 66] – C.f. not to use ribavirin [70, 79] o Oral direct acting antivirals can “theoretically be used” [59]

8. Results – naïve, chronic hepatitis C HCV-1HCV-2HCV-3HCV-4HCV-5HCV-6 Pegylated interferon monotherapy [25, 64, 84][78] Standard interferon with ribavirin [81, 87][81, 84, 87][81, 87] Pegylated interferon and ribavirin [22, 25, 55-57, 60, 66, 68, 70, 71, 75, 78, 80, 83, 85, 104] [22, 25, 55-58, 64, 67, 68, 70, 71, 75, 77, 78, 80, 83, 104] [22, 25, 55-58, 61, 64, 68, 70, 71, 75, 77, 78, 80, 83, 101, 104] [22, 55, 56, 58, 64, 66, 68, 71, 75, 77, 78, 104][22, 55, 57, 58, 68, 71, 77, 104] Pegylated interferon, ribavirin and boceprevir [22, 42, 57, 58, 60, 62, 64, 65, 71, 74, 77, 85, 86] Pegylated interferon, ribavirin and telaprevir [22, 42, 57, 58, 60, 62, 64, 65, 71, 77, 84-86] Pegylated interferon, ribavirin and sofosbuvir [59, 61, 65, 67, 76, 101][59, 67, 76][22, 59, 61, 69, 76, 101][59, 61, 69, 76, 101][59, 61, 65, 67, 69, 75, 76, 101] Pegylated interferon, ribavirin and simeprevir [22, 65, 101] [59, 101][101] Pegylated interferon, ribavirin and daclatasvir [59] Pegylated interferon, ribavirin and faldaprevir [101] Ribavirin monotherapy [66] Ribavirin and sofosbuvir [59, 76][22, 59, 61, 65, 67, 69, 76, 101][22, 61, 65, 67, 69, 76, 101][59, 65, 69, 76][59, 76] Ribavirin, sofosbuvir and simeprevir [59, 69] Ribavirin, sofosbuvir and daclatasvir [59] Ribavirin, paritaprevir + ritonavir + ombitasvir [67, 69] Ribavirin, paritaprevir + ritonavir + ombitasvir and dasabuvir [67, 69] Simeprevir monotherapy [67] Sofosbuvir monotherapy [67] [22] Sofosbuvir and simeprevir [59, 69] Sofosbuvir and ledipasvir [67, 69] [69][67, 69] Sofosbuvir and daclatasvir [59] Sofosbuvir and ledipasvir [67] Paritaprevir + ritonavir + ombitasvir and dasabuvir [67]

9. Benefits Guidance – Clinicians – Peer-reviewed – Philosophy of EBM to restrain practice variations in effective and efficient patient care – 3 international, 6 from North America, 2 from South America, 22 from Europe, 5 from Asia and 2 from Australia Some consistency – E.g. when to treat – Based on same primary studies and have reference to one another Practice context: resource-constrained c.f. resource-rich countries

10. Limitations Difference in weightage of evidence and recommendations Inconsistency in the details – E.g. “stopping rule”: 48 weeks [55] c.f. 24 weeks [22, 64, 68, 83] – E.g. liver biopsy and or transient liver elastography, qualitative vs. quantitative HCV Quality of reporting – iCAHE: local maximums 9 and 11 (out of 14) – chi-square test did not demonstrate a statistically significant association between the year of clinical practice guideline publication and the iCAHE score (x 2 = 12.997, p = 0.224). Review date – Mode 2012, SD 2.8 years, range 2004-2015 – 2015: Canadian Association for the Study of the Liver American Association for the Study of the Liver Disease and Infectious Diseases Society of America National Institute for Health and Care Excellence (UK)

11. Potential harms Newer, oral, direct acting antivirals – WHO listing of direct acting antivirals on Essential Medicines List (April 2015) C.f. most commonly listed treatment agents: pegylated interferon and ribavirin Pressure on States to make pharmaceuticals available – USD$60,000 to USD$90,000 per patient – Boceprevir patent’s until 2029  International consensus