Web Annex 3.1. Adult hepatitis C virus treatment systematic review

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1 Web Annex 3.. Adult hepatitis C virus treatment systematic review Michael Zoratti, Hamilton, Canada In: Guidelines for the care and treatment of persons diagnosed with chronic hepatitis C virus infection July 208 i

2 WHO/CDS/HIV/8.36 World Health Organization 208 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial- ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. In any use of this work, there should be no suggestion that WHO endorses any specific organization, products or services. The use of the WHO logo is not permitted. If you adapt the work, then you must license your work under the same or equivalent Creative Commons licence. If you create a translation of this work, you should add the following disclaimer along with the suggested citation: This translation was not created by the World Health Organization (WHO). WHO is not responsible for the content or accuracy of this translation. The original English edition shall be the binding and authentic edition. Any mediation relating to disputes arising under the licence shall be conducted in accordance with the mediation rules of the World Intellectual Property Organization. Suggested citation. Zoratti M. Web Annex 3.. Adult hepatitis C virus treatment systematic review. In: Guidelines for the care and treatment of persons diagnosed with chronic hepatitis C virus infection. Geneva: World Health Organization; 208 (WHO/CDS/HIV/8.36). Licence: CC BY-NC-SA 3.0 IGO. Cataloguing-in-Publication (CIP) data. CIP data are available at Sales, rights and licensing. To purchase WHO publications, see To submit requests for commercial use and queries on rights and licensing, see Third-party materials. If you wish to reuse material from this work that is attributed to a third party, such as tables, figures or images, it is your responsibility to determine whether permission is needed for that reuse and to obtain permission from the copyright holder. The risk of claims resulting from infringement of any third-party-owned component in the work rests solely with the user. General disclaimers. 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 WHO 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 WHO 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. The named author alone is responsible for the views expressed in this publication. This publication forms part of the WHO guideline entitled Guidelines for the care and treatment of persons diagnosed with chronic hepatitis C virus infection. It is being made publicly available as supplied by those responsible for its development for transparency purposes and information, as required by WHO (see the WHO handbook for guideline development, 2nd edition (204) ii

3 Contents Tables... 3 Figures... 6 Acronyms... 7 Administrative structure... Error! Bookmark not defined. Version history... 9 Executive summary... 0 Objective... 2 Methods... 3 Systematic literature review... 3 Eligibility criteria... 3 Literature searches... 4 Study selection... 4 Data extraction... 5 Data analysis... 5 Software... 5 Quality assessments... 5 For randomized controlled trials... 6 For non-randomized studies... 6 GRADE... 7 Results... 9 Evidence base... 9 Efficacy outcomes (SVR2) comers... 2 Daclatasvir + Asunaprevir... 2 Daclatasvir + Sofosbuvir Elbasvir + Grazoprevir Glecaprevir + Pibrentasvir Ledipasvir + Sofosbuvir Paritaprevir/ritonavir + Ombitasvir + Dasabuvir Sofosbuvir + Velpatasvir Sofosbuvir + Velpatasvir + Voxilaprevir Efficacy outcomes (SVR2) Patients with cirrhosis Daclatasvir + Asunaprevir... 36

4 Daclatasvir + Sofosbuvir Elbasvir + Grazoprevir Glecaprevir + Pibrentasvir... 4 Ledipasvir + Sofosbuvir Paritaprevir/ritonavir + Ombitasvir + Dasabuvir Sofosbuvir + Velpatasvir Sofosbuvir + Velpatasvir + Voxilaprevir Daclatasvir + Sofosbuvir + Ribavirin Sofosbuvir + Ribavirin Efficacy outcomes (SVR2) Patients with HIV co-infection Daclatasvir + Asunaprevir Daclatasvir + Sofosbuvir Elbasvir + Grazoprevir Glecaprevir + Pibrentasvir Ledipasvir + Sofosbuvir Paritaprevir/ritonavir + Ombitasvir + Dasabuvir Sofosbuvir + Velpatasvir Sofosbuvir + Velpatasvir + Voxilaprevir Safety outcomes Discontinuations due to adverse events Serious adverse events Mortality Summary of findings Strengths and limitations... 6 Appendices Appendix A: Search strategies Appendix B: Publication eligibility assessment process Appendix C: Included studies Appendix D: GRADE profiles References

5 TABLES Table : Population, Interventions, Comparisons, Outcomes, and Study design (PICOS) criteria... 3 Table 2: SVR2 in all patients treated with daclatasvir + asunaprevir, arranged by genotype... 2 Table 3: SVR2 in treatment-naïve patients treated with daclatasvir + asunaprevir, arranged by genotype... 2 Table 4: SVR2 in treatment-experienced patients treated with daclatasvir + asunaprevir, arranged by genotype Table 5: SVR2 in all patients treated with daclatasvir + sofosbuvir, arranged by genotype Table 6: SVR2 in treatment-naive patients treated with daclatasvir + sofosbuvir, arranged by genotype 23 Table 7: SVR2 in treatment-experienced patients treated with daclatasvir + sofosbuvir, arranged by genotype Table 8: SVR2 in all patients treated with elbasvir + grazoprevir, arranged by genotype Table 9: SVR2 in treatment-naive patients treated with elbasvir + grazoprevir, arranged by genotype.. 25 Table 0: SVR2 in treatment-experienced treated with elbasvir + grazoprevir, arranged by genotype Table : SVR2 in all patients treated with glecaprevir + pibrentasvir, arranged by genotype Table 2: SVR2 in treatment-naïve patients treated with glecaprevir + pibrentasvir, arranged by genotype Table 3: SVR2 in treatment-experienced patients treated with glecaprevir + pibrentasvir, arranged by genotype Table 4: SVR2 in all patients treated with ledipasvir + sofosbuvir, arranged by genotype Table 5: SVR2 in treatment-naive patients treated with ledipasvir + sofosbuvir, arranged by genotype 29 Table 6: SVR2 in treatment-experienced patients treated with ledipasvir + sofosbuvir, arranged by genotype Table 7: SVR2 in all patients treated with paritaprevir/ritonavir + ombitasvir + dasabuvir, arranged by genotype Table 8: SVR2 in treatment-naive patients treated with paritaprevir/ritonavir + ombitasvir + dasabuvir, arranged by genotype... 3 Table 9: SVR2 in treatment-experienced patients treated with paritaprevir/ritonavir + ombitasvir + dasabuvir, arranged by genotype... 3 Table 20: SVR2 in all patients treated with sofosbuvir + velpatasvir, arranged by genotype Table 2: SVR2 in treatment-naïve patients treated with sofosbuvir + velpatasvir, arranged by genotype Table 22: SVR2 in treatment-experienced patients treated with sofosbuvir + velpatasvir, arranged by genotype Table 23: SVR2 in all patients treated with sofosbuvir + velpatasvir + voxilaprevir, arranged by genotype Table 24: SVR2 in treatment-naïve patients treated with sofosbuvir + velpatasvir + voxilaprevir, arranged by genotype Table 25: SVR2 in treatment-experienced patients treated with sofosbuvir + velpatasvir + voxilaprevir, arranged by genotype Table 26: SVR2 in patients with cirrhosis treated with daclatasvir + asunaprevir, arranged by genotype36 Table 27: SVR2 in treatment-naïve patients with cirrhosis treated with daclatasvir + asunaprevir, arranged by genotype Table 28: SVR2 in treatment-experienced patients with cirrhosis treated with daclatasvir + asunaprevir, arranged by genotype Table 29: SVR2 in patients with cirrhosis treated with daclatasvir + sofosbuvir, arranged by genotype. 38 Table 30: SVR2 in treatment-naïve patients with cirrhosis treated with daclatasvir + asunaprevir, arranged by genotype

6 Table 3: SVR2 in treatment-experienced patients with cirrhosis treated with daclatasvir + sofosbuvir, arranged by genotype Table 32: SVR2 in patients with cirrhosis treated with elbasvir + grazoprevir, arranged by genotype Table 33: SVR2 in treatment-naïve patients with cirrhosis treated with elbasvir + grazoprevir, arranged by genotype Table 34: SVR2 in treatment-experienced patients with cirrhosis treated with elbasvir + grazoprevir, arranged by genotype... 4 Table 35: SVR2 in patients with cirrhosis treated with glecaprevir + pibrentasvir, arranged by genotype Table 36: SVR2 in patients with cirrhosis treated with ledipasvir + sofosbuvir, arranged by genotype Table 37: SVR2 in treatment-naïve patients with cirrhosis treated with ledipasvir + sofosbuvir, arranged by genotype Table 38: SVR2 in treatment-experienced patients with cirrhosis treated with ledipasvir + sofosbuvir, arranged by genotype Table 39: SVR2 in patients with cirrhosis treated with paritaprevir/ritonavir + ombitasvir + dasabuvir, arranged by genotype Table 40: SVR2 in patients with cirrhosis treated with sofosbuvir + velpatasvir, arranged by genotype. 45 Table 4: SVR2 in treatment-naïve patients with cirrhosis treated with sofosbuvir + velpatasvir, arranged by genotype Table 42: SVR2 in treatment-experienced patients with cirrhosis treated with sofosbuvir + velpatasvir, arranged by genotype Table 43: SVR2 in patients with cirrhosis treated with sofosbuvir + velpatasvir + voxilaprevir, arranged by genotype Table 44: SVR2 in treatment-naïve patients with cirrhosis treated with sofosbuvir + velpatasvir + voxilaprevir, arranged by genotype Table 45: SVR2 in treatment-experienced patients with cirrhosis treated with sofosbuvir + velpatasvir + voxilaprevir, arranged by genotype Table 46: SVR2 in genotype 2 or 3 patients with cirrhosis treated with daclatasvir + sofosbuvir + ribavirin, arranged by genotype Table 47: SVR2 in treatment-naïve genotype 2 or 3 patients with cirrhosis treated with daclatasvir + sofosbuvir + ribavirin, arranged by genotype Table 48: SVR2 in treatment-experienced genotype 2 or 3 patients with cirrhosis treated with daclatasvir + sofosbuvir + ribavirin, arranged by genotype Table 49: SVR2 in genotype 2 or 3 patients with cirrhosis treated with sofosbuvir + ribavirin, arranged by genotype Table 50: SVR2 in treatment-naïve genotype 2 or 3 patients with cirrhosis treated with sofosbuvir + ribavirin, arranged by genotype... 5 Table 5: SVR2 in treatment-experienced genotype 2 or 3 patients with cirrhosis treated with sofosbuvir + ribavirin, arranged by genotype... 5 Table 52: SVR2 in HIV co-infected patients treated with daclatasvir + sofosbuvir, arranged by genotype Table 53: SVR2 in HIV co-infected patients treated with elbasvir + grazoprevir, arranged by genotype. 53 Table 54: SVR2 in HIV co-infected patients treated with glecaprevir + pibrentasvir, arranged by genotype Table 55: SVR2 in HIV co-infected patients treated with ledipasvir + sofosbuvir, arranged by genotype 54 Table 56: SVR2 in HIV co-infected patients treated with paritaprevir/ritonavir + ombitasvir + dasabuvir, arranged by genotype Table 57: SVR2 in HIV co-infected patients treated with ledipasvir + sofosbuvir, arranged by genotype 55 Table 58: Discontinuations due to adverse events, arranged by treatment

7 Table 59: Serious adverse events, arranged by treatment Table 60: Mortality, arranged by treatment Table A6: Search strategy for EMBASE Table A62: Search strategy for MEDLINE Table A63: Search strategy for CENTRAL

8 FIGURES Figure : Flow of information

9 ACRONYMS AASLD CENTRAL CI DAA DAC + ASV DAC + SOF DAC + SOF + RBV DAE DDW EASL EMBASE ESV + GZR GCR + PBV GRADE HCV ITT LDV + SOF MEDLINE PTV/r + OMV + DBV RBV RCT SAE SOF + RBV SOF + VEL SOF + VEL + VOX SVR2 American Association for the Study of Liver Diseases Cochrane Register of Controlled s Confidence interval Direct acting anti-viral Daclatasvir + asunaprevir Daclatasvir + sofosbuvir Daclatasvir + sofosbuvir + ribavirin Discontinuation due to adverse event Digestive Diseases Week European Association for the Study of the Liver Excerpta Medica database Elbasvir + grazoprevir Glecaprevir + pibrentasvir Grading Recommendations of Assessment, Development and Evaluation Hepatitis C Virus Intention to treat Ledipasvir + sofosbuvir Medical Literature Analysis and Retrieval System Online Paritaprevir/ritonavir + ombitasvir + dasabuvir Ribavirin Randomized controlled trial Serious adverse event Sofosbuvir + ribavirin Sofosbuvir + velpatasvir Sofosbuvir + velpatasvir + voxilaprevir Sustained virological response 2 weeks post-treatment 7

10 Sponsor Dr. Marc Bulterys World Health Organization Geneva, Switzerland Operator Michael Zoratti; Zoratti HEOR Consulting Inc. 244 Greenwich Drive Unit 80 Oakville, Ontario, Canada L6M 0S3 8

11 VERSION HISTORY V V2 V3 Preliminary summary of the literature review and analyses Complete summary of the literature review and analyses Revised GRADE methodology Addition of GRADE Evidence Profile tables (Appendix D) 9

12 EXECUTIVE SUMMARY Objective: To identify and synthesize the on treatment options for chronic hepatitis C virus (HCV), with emphasis on direct acting antivirals, for genotypes through 6. Methodology: A systematic literature review was conducted to identify prospective studies, including randomized controlled trials, non-randomized comparative trials, single-arm trials, and observational studies. The interventions of interest include: daclatasvir + asunaprevir; daclatasvir + sofosbuvir; elbasvir + grazoprevir; glecaprevir + pibrentasvir; ledipasvir + sofosbuvir; paritaprevir/ritonavir + ombitasvir + dasabuvir; sofosbuvir + velpatasvir; sofosbuvir + velpatasvir + voxilaprevir; daclatasvir + sofosbuvir + ribavirin (only patients with cirrhosis and genotype 2 or 3 infection); and sofosbuvir + ribavirin (only patients with cirrhosis and genotype 2 or 3 infection). No restrictions were applied to doses or treatment durations. The primary outcomes of interest include: sustained virologic response at 2-weeks post-treatment (SVR2); discontinuations due to adverse events (DAEs); serious adverse events (SAEs); and mortality. Outcomes was gathered, as available, separately by: genotype (HCV, 2, 3, 4, 5, 6, mixed genotype population); treatment-experience (treatment-naïve; treatment-experienced; mixed treatment experience population); and patient subgroup (all comers; patients with cirrhosis only; patients with HCV/HIV co-infection). The systematic search was conducted in three major medical literature databases (EMBASE, MEDLINE, and CENTRAL) as well as select conference proceedings from the last 2 years (Digestive Diseases Week; the American Association for the Study of Liver Diseases; and the European Association for the Study of the Liver). For this review, the time period of interest was publication from January, 205. A previously commissioned systematic review was searched for eligible studies and cross-referenced with the current review to identify publications reporting updated outcome data. Evidence was synthesized by pooling untransformed proportions of SVR2, DAEs, SAEs, and mortality for each treatment by population stratification to generate a point estimate with 95% confidence interval. Treatments, including generics, were pooled for all doses and treatment durations. Separate analyses were conducted for collected from clinical trials (trial-only : RCTs, non-randomized comparative trials; single-arm trials) and collected from clinical trials as well as observational studies (all ). As a consequence of the non-comparative analytical approach, naïve comparisons, where relative effects are inferred without distinguishing study effects from treatment effects, should be avoided. Results: From the systematic literature search, 238 publications describing 42 studies were identified. Evidence was identified for all treatments of interest in the all-comer population, which includes patients irrespective of cirrhosis status, HCV/HIV co-infection status, or other comorbidities. However, the availability of varied by genotype and previous HCV treatment experience, with some pooled proportions based on a single studies or very small sample sizes. The proportions of patients achieving SVR2 was high across stratifications in the all-comer population, though with mixed for patients with genotypes 2 or 3 infection. The availability of was similarly high in the subgroup analysis of patients with cirrhosis, with lower SVR2 rates in patients with genotypes 2 or 3 infection. Limited was identified for patients with HCV/HIV co-infection, though SVR2 rates were generally high. Safety outcomes were available for all treatments and genotype stratifications. The proportion of patients with DAEs, SAEs, and mortality was consistently very low. 0

13 Conclusions: The findings of this systematic literature review indicate high SVR2 efficacy rates across most treatments and patient stratifications. Mixed was found for patients with cirrhosis, particularly those with genotype 2 or 3 infection. While limited was identified, SVR2 rates were generally high in patients with HCV/HIV co-infection. Inferences on relative treatment effects should be avoided as the analytical approach adopted for this review was non-comparative.

14 OBJECTIVE The objective of this review was to identify and synthesize the for the efficacy and safety of antiviral therapies for chronic hepatitis C virus infection genotypes -6. Specifically, we sought to describe efficacy with respect to sustained virologic response at 2 weeks post-treatment (SVR2) and safety with respect to discontinuations due to adverse events (DAEs), serious adverse events (SAEs), and mortality. 2

15 METHODS Systematic literature review Eligibility criteria Refer to Table for the original Population, Interventions, Comparisons, Outcomes, and Study design (PICOS) statement which was used to guide the SLR process. A secondary set of criteria, described below, was developed to refine the scope of the review. Table : Population, Interventions, Comparisons, Outcomes, and Study design (PICOS) criteria Criteria Population Interventions Comparators Definition Adults with chronic hepatitis C infection genotype -6 infection Subgroups include: Persons with cirrhosis HCV/HIV co-infection HBV/HCV co-infection TB/HCV co-infection Chronic kidney disease Duration of treatment Prior treatment experience Sofosbuvir + Velpatasvir Sofosbuvir + Velpatasvir + Voxilaprevir Ledipasvir + Sofosbuvir Paritaprevir/ritonavir + Ombitasvir + Dasabuvir Daclatasvir + Asunaprevir Daclatasvir + Sofosbuvir Sofosbuvir + Ribavirin Elbasvir + Grazoprevir Glecaprevir + Pibrentasvir Daclatasvir + Sofosbuvir + Ribavirin Any active intervention for chronic hepatitis C infection Placebo* Standard of care No treatment Efficacy: Sustained virological response (SVR) (2 or 24 weeks post end of treatment) Outcomes Safety: Discontinuations due to adverse events (DAEs) Serious adverse events (SAEs) Mortality (during randomized period) Randomized clinical trials and controlled clinical trials with at least one arm assessing an intervention of interest Study design Non-randomized clinical trials, including single-arm prospective clinical trials assessing an intervention of interest Prospective and retrospective observational studies Language Published in English Time Published since January, 205 *Outcomes are not extracted for patients assigned to a deferred treatment (e.g. placebo) arm 3

16 A set of secondary eligibility criteria was developed and applied to each publication and/or study arm within publications which were included based on the original PICOS table: Studies with a retrospective design are to be excluded; Study arms which include post-transplant patients, where outcomes are presented without stratification of outcomes by transplant status, are to be excluded; Study arms with less than 20 patients are to be excluded, with exception for pan-genotypic regimens (sofosbuvir + velpatasvir; daclatasvir + sofosbuvir; glecaprevir + pibrentasvir; and sofosbuvir + velpatasvir + voxilaprevir); Study arms with the addition of RBV to an intervention of interest are to be excluded; Studies in SOF + RBV and DAC + SOF + RBV are only to be included for patients who are genotype 2 or 3 and who also have cirrhosis; and Studies where outcomes are not reported by intervention are to be excluded. Using the complete eligibility criteria, it is possible that select trial arms or subgroups may be extracted from a study, where the broader enrolled patient population does not meet the eligibility criteria specified here. Literature searches Sources queried Three clinical literature databases were queried: Medical Literature Analysis and Retrieval System Online (MEDLINE); Excerpta Medica database (EMBASE); and Cochrane Central Register of Controlled s (CENTRAL). Conferences proceedings from Digestive Diseases Week (DDW), the American Association for the Study of Liver Diseases (AASLD), and the European Association for the Study of the Liver (EASL) were reviewed from last 2 years. Select meetings (DDW 206, AASLD 205, AASLD 206, EASL 206) had been indexed in EMBASE at the time of database searching and were not hand searched. Search strategies Separate literature search strategies were developed for MEDLINE, EMBASE, and CENTRAL (via Ovid). Refer to Appendix A for complete search strategies. Study selection Two investigators, working independently and in duplicate, reviewed all abstracts identified from the database searches against the complete PICOS criteria. The full text publication of each included abstract was retrieved. The same two investigators assessed the eligibility of all full text publications. Discrepancies between investigators was resolved by discussion. Refer to Appendix B for details on the publication eligibility assessment process. The abstract books of conferences not indexed in EMBASE were hand-searched independently by two investigators to identify eligible publications. When available, posters and/or presentation slide decks were also retrieved. 4

17 A previous SLR, commissioned by the World Health Organization and performed by Global Health Sciences (August 20, 205), was also reviewed for studies meeting the eligibility criteria of the current review. The literature search for the original review was executed on March 20, 205 and thus the review was considered current up until this date. From the final list of included publications, a mapping exercise was performed to match publications reporting on the same study. This process uses a combination of various publication characteristics, including registration numbers, study authors, and sample sizes, and is a means of preventing double counting of outcomes in the final data set. Study mapping was adapted to complement the reporting style of the included studies. Thus, while studies identified as unique in this review may be related, the patients included in each are distinct. Data extraction Data extraction of included studies was performed by four investigators, with study characteristics and outcomes extracted independently and in duplicate by a minimum of two investigators. Discrepancies between investigators were resolved either through discussion or by arbitration provided by a third reviewer. Patient characteristics were extracted by a single reviewer. Data analysis Evidence was synthesized by pooling the proportion of patients with the outcome of interest for SVR2, DAEs, SAEs, and mortality. Untransformed proportions were pooled to generate a point estimate with 95% confidence interval using the DerSimonian-Laird method (binary random effects model). A correction was applied to zero-count cells. Analyses were stratified by treatment experience, with separate analyses to present on treatment-experienced only and treatment-naïve only patients. Patients were considered treatmentexperienced if they had received any prior HCV intervention, including interferon-based regimens and/or DAAs, and/or were classified as non-responders or patients who had relapsed. The all-treatment experience analyses included mixed or unclear treatment-experience populations, as well as completely treatment-naïve or treatment-experienced patient sets. Further stratifications included patients with cirrhosis and patients with HCV/HIV co-infection. The primary set of analyses included only coming from trials, including RCTs, non-rct comparative trials, and uncontrolled single-arm trials (trial-only ). A secondary set of analyses was performed to include all, including that coming from observational studies (all ). No formal statistical tests were performed to compare outcomes across any stratification. Software data was maintained in Microsoft Excel 206 workbooks. analyses were performed using OpenMeta[analyst], an open-source software funded by the Agency for Healthcare Research and Quality (AHRQ). Analyses were based on the Metafor package (R).,2 Quality assessments The traditional approaches of quality assessment were adopted to the clinical and methodological context of both HCV research and of the current review, including the statistical approach to synthesis. The clinical efficacy of HCV treatments is high, and this has been demonstrated across multiple treatments in the era of DAAs. Thus, RCTs comparing two different active treatment interventions, rather than variations in dose or treatment duration, are rare. This observation guided the statistical approach for 5

18 the current review, where the primary analyses were based on the pooled proportion of patients achieving SVR2 irrespective of treatment characteristics such as dose or treatment duration. Moreover, this review was designed to include from all prospective study designs, including non-randomized trials, single-arm trials, and observational studies. Assessments of study quality and validity were conducted as a means of guiding GRADE assessments. For randomized controlled trials The Risk of Bias instrument, endorsed by the Cochrane Collaboration, was used to evaluate the validity of all included RCTs. 3 This instrument evaluates 7 domains: sequence generation; allocation concealment; blinding of participants and personnel; blinding of outcome assessors; incomplete outcome data; selective outcome reporting; and other sources of bias. For each domain, investigators rate the risk of bias as either low, high, or unclear. In the clinical context of this review, where most outcomes are considered to be well-established (e.g. SVR2) and objective, and where most studies were expected to be of an open-label design, blinding of participants and personnel and blinding of outcome assessors was not considered to pose a significant risk of bias. As it was expected that few RCTs would evaluate different active treatments, sequence generation and allocation concealment were also not considered to pose significant risk to bias as the non-comparative statistical approach adopted for this review involved pooling outcomes by treatment, irrespective of duration or dose. For non-randomized studies The validity of non-randomized studies, including single-arm trials, cohort studies, and observational study studies, were evaluated using the Tool to Assess the Risk of Bias in Cohort Studies, developed by the Clinical Advances through Research and Information Translation (CLARITY) group at McMaster University (Hamilton, Canada). For each question, respondents select a response varying from Definitely yes to Definitely no, indicative of a low risk of bias and a high risk of bias, respectively. Questions that were not applicable, such as in the context of a single-arm trial, were marked with NA. The instrument consists of 8 questions: ) Was the selection of exposed and non-exposed cohorts drawn from the same population? 2) Can we be confident in the assessment of exposure? 3) Can we be confident that the outcome of interest was not present at the start of the study? 4) Did the study match exposed and unexposed for all variables that are associated with the outcome of interest or did the statistical analysis adjust for these prognostic variables? 5) Can we be confident in the assessment of the presence or absence of prognostic factors? 6) Can we be confident in the assessment of outcome? 7) Was the follow-up of cohorts adequate? 8) Were the co-interventions similar between groups? 6

19 GRADE The Grading Recommendations of Assessment, Development and Evaluation (GRADE) approach was used to assess the strength of for all outcomes. 4-9 In the GRADE framework, outcomes based on RCTs begin as high-quality. The outcome is then evaluated across five categories: risk of bias; consistency; directness; imprecision; and publication bias. A final GRADE score is then applied to each outcome, representing one of four levels: (High): We are confident that the true effect is likely close to the estimate of the effect. (Moderate): We are moderately confident that the true effect is likely close to the estimate of the effect. (Low): We have limited confidence in the estimate of the effect and that the true effect may be substantially different. (Very low): We have very little confidence in the estimate of the effect and that the true effect is likely to be substantially different. The traditional GRADE approach was adopted to suit the unique clinical and methodological characteristics of HCV research in the context of the current review. Evidence was pooled from trials, including both RCTs and non-rcts, as well as observational studies. While the traditional GRADE approach evaluates from RCTs and non-rcts separately, the rationale for this decision is as follows: Spontaneous SVR rates are very low; SVR rates from non-daa regimens are low; Available demonstrates similar SVR rates from DAA regimens in placebo-controlled randomized trials (RCTs) and head-to-head trials of DAA regimens, as well as in observational studies and single-arm trials; There is limited coming from head-to-head RCTs of different DAA regimens; and The primary outcome of interest is SVR, which we interpret to be an objective outcome. In light of this consideration, we will downgrade the quality of : By one level if: More than 50% of patients in the pooled SVR outcome, which is a pooled proportion of patients across all studies, come from non-trials; or By two levels if: More than 75% of patients in the pooled SVR outcome, which is a pooled proportion of patients across all studies, come from non-trials. The quality of may be further downgraded based on other considerations in the GRADE assessment. The following are guidelines as, per the GRADE Handbook, a mechanistic approach to grading the quality of should be avoided. Additional considerations may lead to further downgrading or re-evaluating a factor in context (e.g. when substantial correlation is observed between pooled from trials and from a primarily observational study-based analysis, the latter analysis will not be downgraded). The 5 GRADE domains (risk of bias; consistency of results; directness of ; imprecision; and publication bias) will be evaluated according to the following criteria: 7

20 ) Risk of Bias Risk of bias will be evaluated according to limitations in study methodology (e.g. blinding, allocation concealment, sampling methods) and execution (e.g. high attrition) relevant to the respective randomized and non-randomized study designs. For the purpose of this review, studies will not be considered at high risk of bias for non-blinded designs with exception of the discontinuations due to adverse event outcome. The quality of will be downgraded by one level if 50% of patients come from studies determined to have a high risk of bias. The quality of will be downgraded by two levels if 75% of patients come from studies determined to have a high risk of bias. 2) Consistency of results Consistency will be evaluated by considering the variation in SVR rates across the studies included in the pooled analysis. With the sample size of each contributing study considered, as proportions are sensitive in small samples, we will downgrade by one level if the spread is greater than 25% across the included studies. Where an outcome was informed by only a single study, consistency will not be evaluated. 3) Directness of The quality of will not be downgraded for directness (i.e. indirectness) for any outcome in this systematic literature review. There is demonstrating an association between SVR and improved clinical outcomes. Furthermore, there is no anticipated indirectness based on population, setting, or treatment as these criteria were specified a prior in the PICOS statement. 4) Imprecision Imprecision will be evaluated according to the pooled SVR outcome, considering the width of the 95% confidence interval (CI) where multiple studies have been pooled. Specifically: Where a pooled outcome is available (i.e. comes from multiple studies), quality of will be downgraded by one level if the spread of the 95% CI exceeds 0% (±5%); or Where no pooled outcome is available (i.e. comes from a single study), quality of will be downgraded by one level if the sample size is approximately less than 50 (N<50) or by two levels if the sample size is approximately less than 25 (N<25). 5) Publication bias The quality of will not be downgraded for publication bias. This systematic literature review was not designed to evaluate publication bias in the HCV DAA literature. Moreover, the review methodology included a search of both published and unpublished literature supplemented by direct contact with industry bodies. 8

21 RESULTS Evidence base From the search of the clinical literature databases, 4,200 publications were identified (July 20/2, 207). A total of 3,553 publications were excluded at the abstract-screening phase:,696 publications published prior to 205; 994 duplicate publications; 458 for ineligible study design; 47 for assessing a population not of interest; 338 for assessing an intervention not of interest; and 20 for other reasons. For the full-text screening phase, 647 publications were retrieved. The full texts could not be retrieved for 7 records. From the primary eligibility criteria, 272 publications were excluded: 8 for ineligible study design; 7 for assessing a population not of interest; 9 for assessing an intervention not of interest; 47 for not reporting an outcome of interest; and 7 for other reasons. Based on the secondary eligibility criteria, which added additional restrictions on study design (i.e. prospective), sample size (i.e. N 20 for most interventions), and interventions (i.e. absence of RBV for most interventions), an additional 79 publications were excluded. Thus, 89 publications were included from the clinical literature databases. From the review of conference proceedings and additional supplementary hand searching, 28 publications were identified. An additional 2 publications were identified from the previous review conducted by Global Health Sciences. Thus, the identified base consisted of 238 publications describing unique 42 studies The flow of information diagram is presented in Figure. Study characteristics are presented in Appendix C. Complete GRADE profiles, including reasons downgrading the, are presented in Appendix D: GRADE profiles. Complete data extraction, including complete trial characteristics, patient characteristics, outcomes, and quality/validity evaluations, as well as detailed analysis summaries, are available in the accompany Microsoft Excel file (WHO2070 HCV SLR Data and Analyses v2). 9

22 Figure : Flow of information 20

23 Efficacy outcomes (SVR2) comers For each treatment in the all-comer population, the pooled proportions of patients achieving SVR2 are presented by genotype and treatment-experience. The number of treatment arms may represent subgroups of treatment arms in a single study, such as where outcomes are reported separately by prior treatment experience. The all-treatment experience analysis pools outcomes from patients who are treatment-naïve, treatment-experienced, and where previous treatment status was unclear. refers to coming from RCTs and other non-randomized or single-arm trials. This analysis is supplemented with an all analysis, which also incorporates outcomes from observational studies. Comparative is not available and inferences on relative treatment effect should be avoided. Daclatasvir + Asunaprevir -treatment experience In the all-treatment experience analysis of patients treated with daclatasvir + asunaprevir, was available for patients with genotype infection, as well as an unknown or mixed genotype population. The percentage of patients achieving SVR2 varied from 89% to 92%. GRADE assessments varied from low to high across outcomes. A summary of the analyses is presented in Table 2. Table 2: SVR2 in all patients treated with daclatasvir + asunaprevir, arranged by genotype Genotype Genotype 2 Genotype 3 Genotype 4 Genotype 5 Genotype 6 Mixed genotype Number Number Pooled proportion Total N of studies of arms (95% CI) GRADE (0.87, 0.92) (0.87, 0.9) (0.89, 0.94) Treatment-naïve patients only In the analysis of treatment-naïve only patients treated with daclatasvir + asunaprevir, was available only for patients with genotype infection (N=552). The pooled percentage of patients achieving SVR2 was 90%, with a GRADE assessment of high. A summary of the analyses is presented in Table 3. Table 3: SVR2 in treatment-naïve patients treated with daclatasvir + asunaprevir, arranged by genotype 2

24 Genotype Genotype 2 Genotype 3 Genotype 4 Genotype 5 Genotype 6 Mixed genotype Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) (0.88, 0.93) Treatment-experienced patients only In the analysis of treatment-experienced only patients treated with daclatasvir + asunaprevir, was available only for patients with genotype infection (N=484). The pooled percentage of patients achieving SVR2 was 85%, with a GRADE assessment of moderate. A summary of the analyses is presented in Table 4. Table 4: SVR2 in treatment-experienced patients treated with daclatasvir + asunaprevir, arranged by genotype Genotype Genotype 2 Genotype 3 Genotype 4 Genotype 5 Genotype 6 Mixed genotype Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) (0.76, 0.94) 22

25 Daclatasvir + Sofosbuvir -treatment experience In the all-treatment experience analysis of patients treated with daclatasvir + sofosbuvir, was available for patients across all genotypes. The percentage of patients achieving SVR2 varied from 88% to 98%. Across outcomes, GRADE assessments varied from very low to high. A summary of the analyses is presented in Table 5. Table 5: SVR2 in all patients treated with daclatasvir + sofosbuvir, arranged by genotype Genotype Genotype 2 Genotype 3 Genotype 4 Genotype 5 Genotype 6 Mixed genotype Number Number Pooled proportion Total N of studies of arms (95% CI) GRADE (0.96, 0.98) (0.94, 0.98) (0.86,.00) (0.88, 0.97) (0.85, 0.94) (0.95,.00) (0.95,.00) (0.70,.00) (0.90, 0.98) (0.88, 0.99) (0.88, 0.97) Treatment-naïve patients only In the analysis of treatment-naïve only patients treated with daclatasvir + sofosbuvir, was available for patients with genotypes -5 infection, as well as an unknown or mixed genotype population. The percentage of patients achieving SVR2 varied from 75% to 98%. Across outcomes, GRADE assessments varied from very low to high. A summary of the analyses is presented in Table 6. Table 6: SVR2 in treatment-naive patients treated with daclatasvir + sofosbuvir, arranged by genotype Genotype Genotype 2 Genotype 3 Genotype 4 Number Number Pooled proportion Total N of studies of arms (95% CI) GRADE (0.96,.00) (0.90, 0.99) 0.75 (0.5,.00) (0.89, 0.98) (0.88, 0.98) (0.87,.00) (0.87, 0.99) 23

26 Genotype 5 Genotype 6 Mixed genotype Number Number Pooled proportion Total N of studies of arms (95% CI) GRADE (0.4,.00) (0.82,.00) Treatment-experienced patients only In the analysis of treatment-experienced only patients treated with daclatasvir + sofosbuvir, was available for patients with genotypes -4 infection, as well as an unknown or mixed genotype population. The percentage of patients achieving SVR2 varied from 75% to 98%. Across outcomes, GRADE assessments varied from very low to moderate. A summary of the analyses is presented in Table 7. Table 7: SVR2 in treatment-experienced patients treated with daclatasvir + sofosbuvir, arranged by genotype Genotype Genotype 2 Genotype 3 Genotype 4 Genotype 5 Genotype 6 Mixed genotype Number Number Pooled proportion Total N of studies of arms (95% CI) GRADE (0.92,.00) (0.95, 0.98) 0.75 (0.5,.00) (0.77, 0.96) (0.78, 0.92) (0.4,.00) (0.94,.00) Elbasvir + Grazoprevir -treatment experience In the all-treatment experience analysis of patients treated with elbasvir + grazoprevir, was available for patients with genotypes, 4, and 6 infection, as well as an unknown or mixed genotype population. The percentage of patients achieving SVR2 varied from 62% to 97%. Across outcomes, GRADE assessments varied from moderate to high. A summary of the analyses is presented in Table 8. 24

27 Table 8: SVR2 in all patients treated with elbasvir + grazoprevir, arranged by genotype Genotype Genotype 2 Genotype 3 Genotype 4 Genotype 5 Genotype 6 Mixed genotype Number Number Pooled proportion Total N of studies of arms (95% CI) GRADE (0.96, 0.98) (0.96, 0.98) (0.92,.00) (0.39, 0.85) (0.88, 0.99) Treatment-naïve patients only In the analysis of treatment-naïve only patients treated with elbasvir + grazoprevir, was available for patients with genotypes, 4, and 6 infection, as well as an unknown or mixed genotype population. The percentage of patients achieving SVR2 varied from 62% to 96%. Across outcomes, GRADE assessments varied from moderate to high. A summary of the analyses is presented in Table 9. Table 9: SVR2 in treatment-naive patients treated with elbasvir + grazoprevir, arranged by genotype Genotype Genotype 2 Genotype 3 Genotype 4 Genotype 5 Genotype 6 Mixed genotype Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) (0.95, 0.97) (0.92,.00) (0.39, 0.85) (0.78, 0.96) 25

28 Treatment-experienced patients only In the analysis of treatment-experienced only patients treated with elbasvir + grazoprevir, was available for patients with genotype infection, as well as an unknown or mixed genotype population. The percentage of patients achieving SVR2 was 95% in both genotype subgroups, with GRADE assessments varying from low to high. A summary of the analyses is presented in Table 0. Table 0: SVR2 in treatment-experienced treated with elbasvir + grazoprevir, arranged by genotype Genotype Genotype 2 Genotype 3 Genotype 4 Genotype 5 Genotype 6 Mixed genotype Number Number Pooled proportion Total N of studies of arms (95% CI) GRADE (0.90,.00) (0.90,.00) Glecaprevir + Pibrentasvir -treatment experience In the all-treatment experience analysis of patients treated with glecaprevir + pibrentasvir, was available for patients across all genotypes. The percentage of patients achieving SVR2 varied from 83% to 98%. Across outcomes, GRADE assessments varied from very low to high. A summary of the analyses is presented in Table. Table : SVR2 in all patients treated with glecaprevir + pibrentasvir, arranged by genotype Genotype Genotype 2 Genotype 3 Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) (0.97,.00) (0.96,.00) (0.93, 0.97) 26

29 Genotype 4 Genotype 5 Genotype 6 Mixed genotype Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) (0.89,.00) (0.4,.00) (0.77,.00) (0.93,.00) Treatment-naïve patients only In the analysis of treatment-naïve only patients treated with glecaprevir + pibrentasvir, was available only for patients with genotype 3 infection (N=49). The percentage of patients achieving SVR2 was 95%, with a GRADE assessment of high. A summary of the analyses is presented in Table 2. Table 2: SVR2 in treatment-naïve patients treated with glecaprevir + pibrentasvir, arranged by genotype Genotype Genotype 2 Genotype 3 Genotype 4 Genotype 5 Genotype 6 Mixed genotype Number Number Pooled proportion Total N of studies of arms (95% CI) GRADE (0.93, 0.97) Treatment-experienced patients only In the analysis of treatment-experienced only patients treated with glecaprevir + pibrentasvir, was available only for patients with genotype 3 infection (N=24). The percentage of patients achieving SVR2 was 92%, with a GRADE assessment of very low. A summary of the analyses is presented in Table 3. 27

30 Table 3: SVR2 in treatment-experienced patients treated with glecaprevir + pibrentasvir, arranged by genotype Genotype Genotype 2 Genotype 3 Genotype 4 Genotype 5 Genotype 6 Mixed genotype Number Number Pooled proportion Total N of studies of arms (95% CI) GRADE (0.8,.00) Ledipasvir + Sofosbuvir -treatment experience In the all-treatment experience analysis of patients treated with ledipasvir + sofosbuvir, was available for patients across all genotypes. The percentage of patients achieving SVR2 varied from 64% to 98%. GRADE assessments varied from very low to high across outcomes. A summary of the analyses is presented in Table 4. Table 4: SVR2 in all patients treated with ledipasvir + sofosbuvir, arranged by genotype Genotype Genotype 2 Genotype 3 Genotype 4 Genotype 5 Genotype 6 Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) (0.98, 0.99) (0.96, 0.98) (0.65,.00) (0.45, 0.83) (0.5, 0.79) (0.93, 0.99) (0.93, 0.98) (0.89,.00) (0.93,.00) (0.8, 0.99) Mixed genotype (0.92, 0.99) 28

31 Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) (0.92, 0.97) Treatment-naïve patients only In the analysis of treatment-naïve only patients treated with ledipasvir + sofosbuvir, was available for patients with genotypes, 3-5 infection, as well as an unknown or mixed genotype population. The percentage of patients achieving SVR2 varied from 64% to 98%. GRADE assessments varied from very low to high across outcomes. A summary of the analyses is presented in Table 5. Table 5: SVR2 in treatment-naive patients treated with ledipasvir + sofosbuvir, arranged by genotype Genotype Genotype 2 Genotype 3 Genotype 4 Genotype 5 Genotype 6 Mixed genotype Number Number Pooled proportion Total N of studies of arms (95% CI) GRADE (0.97, 0.99) (0.95, 0.99) (0.45, 0.83) (0.93,.00) (0.86,.00) (0.93,.00) (0.93, 0.98) Treatment-experienced patients only In the analysis of treatment-experienced only patients treated with ledipasvir + sofosbuvir, was available for patients with genotypes, 4-6 infection, as well as an unknown or mixed genotype population. The percentage of patients achieving SVR2 varied from 87% to 97%. GRADE assessments varied from very low to high across outcomes. A summary of the analyses is presented in Table 6. Table 6: SVR2 in treatment-experienced patients treated with ledipasvir + sofosbuvir, arranged by genotype Genotype Genotype 2 Number Number Pooled proportion Total N of studies of arms (95% CI) GRADE (0.94, 0.99) (0.94, 0.98) 29

32 Genotype 3 Genotype 4 Genotype 5 Genotype 6 Mixed genotype Number Number Pooled proportion Total N of studies of arms (95% CI) GRADE (0.87,.00) (0.85,.00) (0.70,.00) (0.95,.00) Paritaprevir/ritonavir + Ombitasvir + Dasabuvir -treatment experience In the all-treatment experience analysis of patients treated with paritaprevir/ritonavir + ombitasvir + dasabuvir, was available only for patients with genotype infection. The percentage of patients achieving SVR2 varied from 98% to 99% across the trial-only and all analyses. GRADE was assessed as high for both analyses. A summary of the analyses is presented in Table 7. Table 7: SVR2 in all patients treated with paritaprevir/ritonavir + ombitasvir + dasabuvir, arranged by genotype Genotype Genotype 2 Genotype 3 Genotype 4 Genotype 5 Genotype 6 Mixed genotype Number Number Pooled proportion Total N of studies of arms (95% CI) GRADE (0.98,.00) (0.97, 0.99) Treatment-naïve patients only In the analysis of treatment-naïve only patients treated with paritaprevir/ritonavir + ombitasvir + dasabuvir, was available only for patients with genotype infection. The percentage of patients achieving 30

33 SVR2 varied from 97% to 98% across the trial-only and all analyses. GRADE was assessed as high for both analyses. A summary of the analyses is presented in Table 8. Table 8: SVR2 in treatment-naive patients treated with paritaprevir/ritonavir + ombitasvir + dasabuvir, arranged by genotype Genotype Genotype 2 Genotype 3 Genotype 4 Genotype 5 Genotype 6 Mixed genotype Number Number Pooled proportion Total N of studies of arms (95% CI) GRADE (0.96,.00) (0.95, 0.99) Treatment-experienced patients only In the analysis of treatment-experienced only patients treated with paritaprevir/ritonavir + ombitasvir + dasabuvir, was available only for patients with genotype infection. The percentage of patients achieving SVR2 varied from 99% to 00% across the trial-only and all analyses. GRADE was assessed as high for both analyses. A summary of the analyses is presented in Table 9. Table 9: SVR2 in treatment-experienced patients treated with paritaprevir/ritonavir + ombitasvir + dasabuvir, arranged by genotype Genotype Genotype 2 Genotype 3 Genotype 4 Genotype 5 Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) (0.99,.00) (0.98,.00) Genotype 6 3

34 Mixed genotype Number Number Pooled proportion Total N of studies of arms (95% CI) GRADE Sofosbuvir + Velpatasvir -treatment experience In the all-treatment experience analysis of patients treated with sofosbuvir + velpatasvir, was available for patients across all genotypes. The percentage of patients achieving SVR2 varied from 89% to 99%. GRADE assessments varied from low to high across outcomes. A summary of the analyses is presented in Table 20. Table 20: SVR2 in all patients treated with sofosbuvir + velpatasvir, arranged by genotype Genotype Genotype 2 Genotype 3 Genotype 4 Genotype 5 Genotype 6 Mixed genotype Number Number Pooled proportion Total N of studies of arms (95% CI) GRADE (0.95, 0.98) (0.97,.00) (0.85, 0.93) (0.98,.00) (0.92,.00) (0.95,.00) (0.97,.00) (0.97,.00) Treatment-naïve patients only In the analysis of treatment-naïve only patients treated with sofosbuvir + velpatasvir, was available for patients with genotypes -3 infection, as well as an unknown or mixed genotype population. The percentage of patients achieving SVR2 varied from 84% to 98%. GRADE assessments varied from very low to high across outcomes. A summary of the analyses is presented in Table 2. Table 2: SVR2 in treatment-naïve patients treated with sofosbuvir + velpatasvir, arranged by genotype Genotype Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) (0.90,.00) 32

35 Genotype 2 Genotype 3 Genotype 4 Genotype 5 Genotype 6 Mixed genotype Number Number Pooled proportion Total N of studies of arms (95% CI) GRADE (0.73, 0.95) (0.96, 0.99) (0.90,.00) Treatment-experienced patients only In the analysis of treatment-experienced only patients treated with sofosbuvir + velpatasvir, was available for patients with genotypes -3 infection. The percentage of patients achieving SVR2 varied from 85% to 97%. GRADE assessments varied from low to high across outcomes. A summary of the analyses is presented in Table 22. Table 22: SVR2 in treatment-experienced patients treated with sofosbuvir + velpatasvir, arranged by genotype Genotype Genotype 2 Genotype 3 Genotype 4 Genotype 5 Genotype 6 Mixed genotype Number Number Pooled proportion Total N of studies of arms (95% CI) GRADE (0.92,.00) (0.9,.00) (0.78, 0.92) Sofosbuvir + Velpatasvir + Voxilaprevir -treatment experience 33

36 In the all-treatment experience analysis of patients treated with sofosbuvir + velpatasvir + voxilaprevir, was available for patients across all genotypes. The percentage of patients achieving SVR2 varied from 8% to 98%. GRADE assessments varied from very low to high across outcomes. A summary of the analyses is presented in Table 23. Table 23: SVR2 in all patients treated with sofosbuvir + velpatasvir + voxilaprevir, arranged by genotype Genotype Genotype 2 Genotype 3 Genotype 4 Genotype 5 Genotype 6 Mixed genotype Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) (0.94, 0.99) (0.95,.00) (0.96, 0.99) (0.90, 0.99) (0.83,.00) (0.94,.00) (0.46,.00) Treatment-naïve patients only In the analysis of treatment-naïve only patients treated with sofosbuvir + velpatasvir + voxilaprevir, was available only for patients with genotype 3 infection. The percentage of patients achieving SVR2 was 96%, with a GRADE assessment of high. A summary of the analyses is presented in Table 24. Table 24: SVR2 in treatment-naïve patients treated with sofosbuvir + velpatasvir + voxilaprevir, arranged by genotype Genotype Genotype 2 Genotype 3 Genotype 4 Genotype 5 Number Number Pooled proportion Total N of studies of arms (95% CI) GRADE (0.92,.00) 34

37 Genotype 6 Mixed genotype Number Number Pooled proportion Total N of studies of arms (95% CI) GRADE Treatment-experienced patients only In the analysis of treatment-experienced patients treated with sofosbuvir + velpatasvir + voxilaprevir, was available for patients across all genotypes. The percentage of patients achieving SVR2 varied from 75% to 98%. GRADE assessments varied from very low to high across outcomes. A summary of the analyses is presented in Table 25. Table 25: SVR2 in treatment-experienced patients treated with sofosbuvir + velpatasvir + voxilaprevir, arranged by genotype Genotype Genotype 2 Genotype 3 Genotype 4 Genotype 5 Genotype 6 Mixed genotype Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) (0.96, 0.99) (0.94,.00) (0.92, 0.99) (0.90,.00) 0.75 (0.5,.00) (0.74,.00) 0.75 (0.5,.00) 35

38 Efficacy outcomes (SVR2) Patients with cirrhosis For each treatment in the patients with cirrhosis subset, the pooled proportions of patients achieving SVR2 are presented by genotype and treatment-experience. Outcomes for patients treated with sofosbuvir + ribavirin or with sofosbuvir + daclatasvir + ribavirin are available only for patients with genotype 2 or 3 infection. The number of treatment arms may represent subgroups of treatment arms in a single study, where outcomes are reported separately by prior treatment experience. The all-treatment experience analysis pools outcomes from patients who are treatment-naïve, treatment-experienced, and where previous treatment status was unclear. refers to coming from RCTs and other non-randomized or single-arm trials. This analysis is supplemented with an all- analysis, which also incorporates outcomes from observational studies. Comparative is not available and inferences on relative treatment effect should be avoided. Daclatasvir + Asunaprevir -treatment experience In the all-treatment experience analysis of patients with cirrhosis treated with daclatasvir + asunaprevir, was available for patients with genotype infection, as well as an unknown or mixed genotype population. The percentage of patients achieving SVR2 varied from 89% to 90%. GRADE assessments varied from very low to high. A summary of the analyses is presented in Table 26. Table 26: SVR2 in patients with cirrhosis treated with daclatasvir + asunaprevir, arranged by genotype Genotype Genotype 2 Genotype 3 Genotype 4 Genotype 5 Genotype 6 Mixed genotype Number Number Pooled proportion Total N of studies of arms (95% CI) GRADE (0.85, 0.93) (0.86, 0.9) (0.64,.00) 36

39 Treatment-naïve patients only In the analysis of treatment-naïve only patients with cirrhosis treated with daclatasvir + asunaprevir, was available only for patients with genotype infection. The pooled percentage of patients achieving SVR2 was 9%, with a GRADE assessment of moderate. A summary of the analyses is presented in Table 27. Table 27: SVR2 in treatment-naïve patients with cirrhosis treated with daclatasvir + asunaprevir, arranged by genotype Genotype Genotype 2 Genotype 3 Genotype 4 Genotype 5 Genotype 6 Mixed genotype Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) (0.84, 0.98) Treatment-experienced patients only In the analysis of treatment-experienced only patients with cirrhosis treated with daclatasvir + asunaprevir, was available only for patients with genotype infection. The pooled percentage of patients achieving SVR2 was 83%, with a GRADE assessment of moderate. A summary of the analyses is presented in Table 28. Table 28: SVR2 in treatment-experienced patients with cirrhosis treated with daclatasvir + asunaprevir, arranged by genotype Genotype Genotype 2 Genotype 3 Genotype 4 Number Number Pooled proportion Total N of studies of arms (95% CI) GRADE (0.75, 0.9) 37

40 Genotype 5 Genotype 6 Mixed genotype Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Daclatasvir + Sofosbuvir -treatment experience In the all-treatment experience analysis of patients with cirrhosis treated with daclatasvir + sofosbuvir, was available for patients with genotypes -3, 5, and 6 infection, as well as an unknown or mixed genotype population. The percentage of patients achieving SVR2 varied from 63% to 96%. GRADE assessments varied from very low to low. A summary of the analyses is presented in Table 29. Table 29: SVR2 in patients with cirrhosis treated with daclatasvir + sofosbuvir, arranged by genotype Genotype Genotype 2 Genotype 3 Genotype 4 Genotype 5 Genotype 6 Mixed genotype Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) (0.88, 0.99) 0.96 (0.85,.00) (0.46, 0.80) (0.68, 0.89) 0.75 (0.5,.00) (0.87, 0.99) (0.62,.00) Treatment-naïve patients only In the analysis of treatment-naïve only patients with cirrhosis treated with daclatasvir + sofosbuvir, was available only for patients with genotype 3 infection. The percentage of patients achieving SVR2 varied from 58% to 65% across the trial-only and all- analyses. GRADE was assessed as very low in both cases. A summary of the analyses is presented in Table

41 Table 30: SVR2 in treatment-naïve patients with cirrhosis treated with daclatasvir + asunaprevir, arranged by genotype Genotype Genotype 2 Genotype 3 Genotype 4 Genotype 5 Genotype 6 Mixed genotype Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) (0.36, 0.80) (0.45, 0.85) Treatment-experienced patients only In the analysis of treatment-experienced only patients with cirrhosis treated with daclatasvir + sofosbuvir, was available for patients with genotypes and 3 infection. The percentage of patients achieving SVR2 varied from 69% to 98%. GRADE assessments varied from very low to low. A summary of the analyses is presented in Table 3. Table 3: SVR2 in treatment-experienced patients with cirrhosis treated with daclatasvir + sofosbuvir, arranged by genotype Genotype Genotype 2 Genotype 3 Genotype 4 Genotype 5 Genotype 6 Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) (0.93,.00) (0.44, 0.94) (0.6,.00) Mixed genotype 39

42 Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Elbasvir + Grazoprevir -treatment experience In the all-treatment experience analysis of patients with cirrhosis treated with elbasvir + grazoprevir, was available for patients with genotype infection, as well as an unknown or mixed genotype population. The percentage of patients achieving SVR2 varied from 96% to 97%. GRADE assessments varied from moderate to high across outcomes. A summary of the analyses is presented in Table 32. Table 32: SVR2 in patients with cirrhosis treated with elbasvir + grazoprevir, arranged by genotype Genotype Genotype 2 Genotype 3 Genotype 4 Genotype 5 Genotype 6 Mixed genotype Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) (0.92,.00) (0.95,.00) Treatment-naïve patients only In the analysis of treatment-naïve only patients with cirrhosis treated with elbasvir + grazoprevir, was available for patients with genotype infection, as well as an unknown or mixed genotype population. The percentage of patients achieving SVR2 varied from 95% to 98%. GRADE assessments varied from low to high across outcomes. A summary of the analyses is presented in Table 33. Table 33: SVR2 in treatment-naïve patients with cirrhosis treated with elbasvir + grazoprevir, arranged by genotype Genotype Genotype 2 Number Number Pooled proportion Total N of studies of arms (95% CI) GRADE (0.90,.00) 40

43 Genotype 3 Genotype 4 Genotype 5 Genotype 6 Mixed genotype Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) (0.95,.00) Treatment-experienced patients only In the analysis of treatment-experienced only patients with cirrhosis treated with elbasvir + grazoprevir, was available only for patients in the unknown or mixed genotype population. The percentage of patients achieving SVR2 was 92%, with a GRADE assessment of high. A summary of the analyses is presented in Table 34. Table 34: SVR2 in treatment-experienced patients with cirrhosis treated with elbasvir + grazoprevir, arranged by genotype Genotype Genotype 2 Genotype 3 Genotype 4 Genotype 5 Genotype 6 Mixed genotype Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) (0.86, 0.98) Glecaprevir + Pibrentasvir -treatment experience In the all-treatment experience analysis of patients treated with glecaprevir + pibrentasvir, was available for patients with genotypes, 2, and 4-6 infection, as well as an unknown or mixed genotype 4

44 population. The percentage of patients achieving SVR2 varied from 83% to 99%. GRADE assessments varied from very low to high across all outcomes. A summary of the analyses is presented in Table 35. Table 35: SVR2 in patients with cirrhosis treated with glecaprevir + pibrentasvir, arranged by genotype Genotype Genotype 2 Genotype 3 Genotype 4 Genotype 5 Genotype 6 Mixed genotype Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) (0.97,.00) (0.95,.00) (0.89,.00) (0.4,.00) (0.77,.00) (0.8,.00) Treatment-naïve patients only No was available for the treatment-naive population treated with glecaprevir + pibrentasvir. Treatment-experienced patients only No was available for the treatment-experienced population treated with glecaprevir + pibrentasvir. Ledipasvir + Sofosbuvir -treatment experience In the all-treatment experience analysis of patients with cirrhosis treated with ledipasvir + sofosbuvir, was available for patients with genotypes, 3, 4, and 6 infection, as well as an unknown or mixed genotype population. The percentage of patients achieving SVR2 varied from 58% to 97%. GRADE assessments varied from very low to high across outcomes. A summary of the analyses is presented in Table 36. Table 36: SVR2 in patients with cirrhosis treated with ledipasvir + sofosbuvir, arranged by genotype Genotype Number Number Pooled proportion Total N of studies of arms (95% CI) GRADE (0.95, 0.98) (0.95, 0.98) 42

45 Genotype 2 Genotype 3 Genotype 4 Genotype 5 Genotype 6 Mixed genotype Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) (0.33, 0.83) (0.84,.00) (0.9,.00) (0.38,.00) (0.92,.00) (0.88, 0.99) Treatment-naïve patients only In the analysis of treatment-naïve only patients with cirrhosis treated with ledipasvir + sofosbuvir, was available for patients with genotypes, 4 and 6 infection, as well as an unknown or mixed genotype population. The percentage of patients achieving SVR2 varied from 85% to 98%. GRADE assessments varied from very low to high across outcomes. A summary of the analyses is presented in Table 37. Table 37: SVR2 in treatment-naïve patients with cirrhosis treated with ledipasvir + sofosbuvir, arranged by genotype Genotype Genotype 2 Genotype 3 Genotype 4 Genotype 5 Genotype 6 Mixed genotype Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) (0.93,.00) (0.60,.00) (0.92,.00) (0.69,.00) (0.73, 0.93) 43

46 Treatment-experienced patients only In the analysis of treatment-experienced only patients with cirrhosis treated with ledipasvir + sofosbuvir, was available for patients with genotypes and 6 infection, as well as an unknown or mixed genotype population. The percentage of patients achieving SVR2 varied from 83% to 98%. GRADE assessments varied from very low to high across outcomes. A summary of the analyses is presented in Table 38. Table 38: SVR2 in treatment-experienced patients with cirrhosis treated with ledipasvir + sofosbuvir, arranged by genotype Genotype Genotype 2 Genotype 3 Genotype 4 Genotype 5 Genotype 6 Mixed genotype Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) (0.95,.00) (0.95,.00) (0.54,.00) (0.94,.00) (0.84,.00) Paritaprevir/ritonavir + Ombitasvir + Dasabuvir -treatment experience In the all-treatment experience analysis of patients with cirrhosis treated with paritaprevir/ritonavir + ombitasvir + dasabuvir, was available only for patients with genotype infection. The percentage of patients achieving SVR2 was 99% in both the trial-only and all analyses. GRADE was assessed as high for both analyses. A summary of the analyses is presented in Table 39. Table 39: SVR2 in patients with cirrhosis treated with paritaprevir/ritonavir + ombitasvir + dasabuvir, arranged by genotype Genotype Genotype 2 Genotype 3 Number Number Pooled proportion Total N of studies of arms (95% CI) GRADE (0.97,.00) (0.97,.00) 44

47 Genotype 4 Genotype 5 Genotype 6 Mixed genotype Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Treatment-naïve patients only No was available for the treatment-naive population with cirrhosis treated with paritaprevir/ritonavir + ombitasvir + dasabuvir. Treatment-experienced patients only No was available for the treatment-experienced population with cirrhosis treated with paritaprevir/ritonavir + ombitasvir + dasabuvir. Sofosbuvir + Velpatasvir -treatment experience In the all-treatment experience analysis of patients with cirrhosis treated with sofosbuvir + velpatasvir, was available for patients with genotypes -4 and 6 infection, as well as an unknown or mixed genotype population. The percentage of patients achieving SVR2 varied from 75% to 97%. GRADE assessments varied from very low to high across outcomes. A summary of the analyses is presented in Table 40. Table 40: SVR2 in patients with cirrhosis treated with sofosbuvir + velpatasvir, arranged by genotype Genotype Genotype 2 Genotype 3 Genotype 4 Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) (0.85, 0.95) (0.64,.00) (0.77, 0.96) (0.66,.00) Genotype 5 45

48 Genotype 6 Mixed genotype Number Number Pooled proportion Total N of studies of arms (95% CI) 0.75 (0.5,.00) GRADE (0.94,.00) Treatment-naïve patients only In the analysis of treatment-naïve only patients with cirrhosis treated with sofosbuvir + velpatasvir, was available only for patients with genotype 3 infection. The percentage of patients achieving SVR2 was 97%, with only coming from clinical trials (i.e. no observational studies were identified). GRADE was assessed as high. A summary of the analyses is presented in Table 4. Table 4: SVR2 in treatment-naïve patients with cirrhosis treated with sofosbuvir + velpatasvir, arranged by genotype Genotype Genotype 2 Genotype 3 Genotype 4 Genotype 5 Genotype 6 Mixed genotype Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) (0.92,.00) Treatment-experienced patients only In the analysis of treatment-experienced only patients with cirrhosis treated with sofosbuvir + velpatasvir, was available for patients with genotype 2 infection as well as an unknown or mixed genotype population. The percentage of patients achieving SVR2 varied from 86% to 90%. GRADE was assessed as moderate in both analyses. A summary of the analyses is presented in Table

49 Table 42: SVR2 in treatment-experienced patients with cirrhosis treated with sofosbuvir + velpatasvir, arranged by genotype Genotype Genotype 2 Genotype 3 Genotype 4 Genotype 5 Genotype 6 Mixed genotype Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) (0.83, 0.97) (0.77, 0.94) Sofosbuvir + Velpatasvir + Voxilaprevir -treatment experience In the all-treatment experience analysis of patients with cirrhosis treated with sofosbuvir + velpatasvir + voxilaprevir, was available for patients with genotypes and 3, as well as an unknown or mixed genotype population. The percentage of patients achieving SVR2 varied from 95% to 96%. GRADE assessments varied from very low to high across outcomes. A summary of the analyses is presented in Table 43. Table 43: SVR2 in patients with cirrhosis treated with sofosbuvir + velpatasvir + voxilaprevir, arranged by genotype Genotype Genotype 2 Genotype 3 Genotype 4 Genotype 5 Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) 0.96 (0.85,.00) (0.93,.00) Genotype 6 47

50 Mixed genotype Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) (0.9, 0.98) Treatment-naïve patients only In the analysis of treatment-naïve only patients with cirrhosis treated with sofosbuvir + velpatasvir + voxilaprevir, was available only for patients with genotype 3 infection. The percentage of patients achieving SVR2 was 96%, with only coming from clinical trials (i.e. no observational studies were identified). GRADE was assessed as moderate. A summary of the analyses is presented in Table 44. Table 44: SVR2 in treatment-naïve patients with cirrhosis treated with sofosbuvir + velpatasvir + voxilaprevir, arranged by genotype Genotype Genotype 2 Genotype 3 Genotype 4 Genotype 5 Genotype 6 Mixed genotype Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) (0.92,.00) Treatment-experienced patients only In the analysis of treatment-experienced only patients with cirrhosis treated with sofosbuvir + velpatasvir + voxilaprevir, was available for patients with genotypes and 3 infection, as well as an unknown or mixed genotype population. The percentage of patients achieving SVR2 varied from 96% to 97%, with only coming from clinical trials (i.e. no observational studies were identified). GRADE was assessed as very low to high across outcomes. A summary of the analyses is presented in Table

51 Table 45: SVR2 in treatment-experienced patients with cirrhosis treated with sofosbuvir + velpatasvir + voxilaprevir, arranged by genotype Genotype Genotype 2 Genotype 3 Genotype 4 Genotype 5 Genotype 6 Mixed genotype Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) 0.96 (0.85,.00) (0.92,.00) (0.92,.00) Daclatasvir + Sofosbuvir + Ribavirin -treatment experience The literature review for daclatasvir + sofosbuvir + ribavirin was restricted to patients with cirrhosis and genotype 2 or 3 infection. No was identified for patients with genotype 2 infection. From the alltreatment experience analysis of patients with genotype 3 infection, the pooled percentage of patients achieving SVR2 varied from 86% to 9%, with GRADE assessed as low. A summary of the analyses is presented in Table 46. Table 46: SVR2 in genotype 2 or 3 patients with cirrhosis treated with daclatasvir + sofosbuvir + ribavirin, arranged by genotype Genotype 2 Genotype 3 Number Number Pooled proportion Total N of studies of arms (95% CI) GRADE (0.76, 0.97) (0.86, 0.97) Treatment-naïve patients only In the analysis of treatment-naïve only patients with cirrhosis treated daclatasvir + sofosbuvir + ribavirin, was only available for patients with genotype 3 infection. The pooled percentage of patients achieving SVR2 varied from 83% and 98% across the trial-only and all- analyses, respectively. GRADE was assessed as very low both cases. A summary of the analyses is presented in Table

52 Table 47: SVR2 in treatment-naïve genotype 2 or 3 patients with cirrhosis treated with daclatasvir + sofosbuvir + ribavirin, arranged by genotype Genotype 2 Genotype 3 Number Number Pooled proportion Total N of studies of arms (95% CI) GRADE (0.54,.00) (0.95,.00) Treatment-experienced patients only In the analysis of treatment-experienced only patients with cirrhosis treated daclatasvir + sofosbuvir + ribavirin, was only available for patients with genotype 3 infection. From a single clinical trial (N=30), the percentage of patients achieving SVR2 was 87%. The GRADE assessment was low. No observational studies were identified to support this analysis. A summary of the analyses is presented in Table 48. Table 48: SVR2 in treatment-experienced genotype 2 or 3 patients with cirrhosis treated with daclatasvir + sofosbuvir + ribavirin, arranged by genotype Genotype 2 Genotype 3 Number Number Pooled proportion Total N of studies of arms (95% CI) GRADE (0.75, 0.99) Sofosbuvir + Ribavirin -treatment experience The literature review for sofosbuvir + ribavirin was restricted to patients with cirrhosis and genotype 2 or 3 infection. Evidence was available for patients with genotypes 2 and 3 infection, as well as a single study where these patient groups were reported together. The pooled percentage of patients achieving SVR2 varied from 6% to 86%, with GRADE assessed as low in all cases. A summary of the analyses is presented in Table 49. Table 49: SVR2 in genotype 2 or 3 patients with cirrhosis treated with sofosbuvir + ribavirin, arranged by genotype Genotype 2 Genotype 3 Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) (0.72, 0.87) (0.8, 0.90) (0.58, 0.80) (0.58, 0.76) Mixed genotype (0.44, 0.77) 50

53 Number Number Total N of studies of arms 2 & 3 Pooled proportion (95% CI) GRADE Treatment-naïve patients only In the analysis of treatment-naïve only patients with cirrhosis treated sofosbuvir + ribavirin, was available for patients with genotypes 2 and 3 infection, as well as a single study where these patient groups were reported together. The pooled percentage of patients achieving SVR2 varied from 6% to 85%, with GRADE assessed as low in all cases. A summary of the analyses is presented in Table 50. Table 50: SVR2 in treatment-naïve genotype 2 or 3 patients with cirrhosis treated with sofosbuvir + ribavirin, arranged by genotype Genotype 2 Genotype 3 Mixed genotype 2 & 3 Number Number Pooled proportion Total N of studies of arms (95% CI) GRADE (0.65, 0.88) (0.73, 0.97) (0.69, 0.89) (0.64, 0.84) (0.44, 0.77) Treatment-experienced patients only In the analysis of treatment-experienced only patients with cirrhosis treated sofosbuvir + ribavirin, was available for patients with genotypes 2 and 3 infection. The pooled percentage of patients achieving SVR2 varied from 57% to 82%, with GRADE assessments varying from low to moderate. A summary of the analyses is presented in Table 5. Table 5: SVR2 in treatment-experienced genotype 2 or 3 patients with cirrhosis treated with sofosbuvir + ribavirin, arranged by genotype Genotype 2 Genotype 3 Number Number Pooled proportion Total N of studies of arms (95% CI) GRADE (0.67, 0.9) (0.76, 0.88) (0.38, 0.75) (0.4, 0.70) 5

54 Efficacy outcomes (SVR2) Patients with HIV co-infection For each treatment in the patients with HIV co-infection subset, the pooled proportions of patients achieving SVR2 are presented by genotype in an all-treatment experience population only. The number of treatment arms may represent subgroups of treatment arms in a single study, where outcomes are reported separately by prior treatment experience. The all-treatment experience analysis pools outcomes from patients who are treatment-naïve, treatment-experienced, and where previous treatment status was unclear. refers to coming from RCTs and other non-randomized or single-arm trials. This analysis is supplemented with an all- analysis, which also incorporates outcomes from observational studies. Daclatasvir + Asunaprevir No was available for the treatment-naive population with HIV co-infection treated with daclatasvir + asunaprevir. Daclatasvir + Sofosbuvir -treatment experience In patients with HIV co-infection treated with daclatasvir + sofosbuvir, on the percentage of patients achieving SVR2 was available only in a mixed or unknown genotype population across two observational studies (N=347). The pooled percentage of patients achieving SVR2 was 87%. The GRADE assessment was very low. A summary of the analyses is presented in Table 52. Table 52: SVR2 in HIV co-infected patients treated with daclatasvir + sofosbuvir, arranged by genotype Genotype Genotype 2 Genotype 3 Genotype 4 Genotype 5 Genotype 6 Mixed genotype Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) (0.69,.00) 52

55 Elbasvir + Grazoprevir -treatment experience In patients with HIV co-infection treated with elbasvir + grazoprevir, was available for patients with genotypes, 4, and 6 infection, as well as an unknown or mixed genotype population. The pooled percentage of patients achieving SVR2 was varied from 83% to 96%. The GRADE assessments varied from very low to moderate. A summary of the analyses is presented in Table 53. Table 53: SVR2 in HIV co-infected patients treated with elbasvir + grazoprevir, arranged by genotype Genotype Genotype 2 Genotype 3 Genotype 4 Genotype 5 Genotype 6 Mixed genotype Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) (0.85, 0.99) (0.90,.00) (0.4,.00) (0.54,.00) Glecaprevir + Pibrentasvir -treatment experience In patients with HIV co-infection treated with glecaprevir + pibrentasvir, on the percentage of patients achieving SVR2 was available only for patients in an unknown or mixed genotype population coming from a single observational study. The percentage of patients achieving SVR2 was 00%. The GRADE assessment was high. A summary of the analyses is presented in Table 54. Table 54: SVR2 in HIV co-infected patients treated with glecaprevir + pibrentasvir, arranged by genotype Genotype Genotype 2 Genotype 3 Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Genotype 4 53

56 Genotype 5 Genotype 6 Mixed genotype Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) (0.99,.00) Ledipasvir + Sofosbuvir -treatment experience In patients with HIV co-infection treated with ledipasvir + sofosbuvir, was available for patients with genotypes and 4, as well as an unknown or mixed genotype population. The pooled percentage of patients achieving SVR2 was varied from 75% to 98%. The GRADE assessments varied from very low to high. A summary of the analyses is presented in Table 55. Table 55: SVR2 in HIV co-infected patients treated with ledipasvir + sofosbuvir, arranged by genotype Genotype Genotype 2 Genotype 3 Genotype 4 Genotype 5 Genotype 6 Mixed genotype Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) (0.95,.00) (0.93, 0.98) 0.75 (0.5,.00) (0.94, 0.98) (0.94, 0.98) Paritaprevir/ritonavir + Ombitasvir + Dasabuvir -treatment experience In patients with HIV co-infection treated with paritaprevir/ritonavir + ombitasvir + dasabuvir, on the percentage of patients achieving SVR2 was available only for patients with genotype infection in an observational study. The percentage of patients achieving SVR2 was 86%. The GRADE assessment was very low, largely attributed to the very small analysis sample size (N=7). A summary of the analyses is presented in Table

57 Table 56: SVR2 in HIV co-infected patients treated with paritaprevir/ritonavir + ombitasvir + dasabuvir, arranged by genotype Genotype Genotype 2 Genotype 3 Genotype 4 Genotype 5 Genotype 6 Mixed genotype Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) (0.60,.00) Sofosbuvir + Velpatasvir -treatment experience In patients with HIV co-infection treated with ledipasvir + sofosbuvir, was available for patients with genotypes -4 infection. The pooled percentage of patients achieving SVR2 was varied from 92% to 96%. The GRADE assessments varied from very low to low. A summary of the analyses is presented in Table 57. Table 57: SVR2 in HIV co-infected patients treated with ledipasvir + sofosbuvir, arranged by genotype Genotype Genotype 2 Genotype 3 Genotype 4 Genotype 5 Genotype 6 Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) (0.90,.00) 0.96 (0.85,.00) (0.76,.00) (0.70,.00) Mixed genotype 55

58 Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Sofosbuvir + Velpatasvir + Voxilaprevir No was available for the treatment-naive population with HIV co-infection treated with sofosbuvir + velpatasvir + voxilaprevir. 56

59 Safety outcomes The number of patients experiencing each adverse event outcome category was pooled across studies, arranged by treatment. When possible, outcomes were extracted from each study based on the safety analysis set (i.e. number of patients who received dose). Comparative is not available and inferences on relative treatment effect should be avoided. Discontinuations due to adverse events Evidence on the number of patients who experienced a DAE was available for every treatment. The analyses for daclatasvir + sofosbuvir + ribavirin and sofosbuvir + ribavirin was restricted to patients with cirrhosis and genotype 2 or 3 infection. Across treatments and studies, the number of DAEs was very low, with the pooled percentages varying from 0% to 0.04%. GRADE was assessed as moderate in all cases. As very few studies blinded patients or outcome assessors, GRADE was lowered by one level due to the perceived subjectivity of labelling a discontinuation as a DAE (Risk of Bias). A summary of the analyses is presented in Table 58. Table 58: Discontinuations due to adverse events, arranged by treatment Daclatasvir + asunaprevir Daclatasvir + sofosbuvir Elbasvir + grazoprevir Glecaprevir + pibrentasvir Ledipasvir + sofosbuvir Paritaprevir/ritonavir + ombitasvir + dasabuvir Sofosbuvir + velpatasvir Sofosbuvir + velpatasvir + voxilaprevir Daclatasvir + sofosbuvir + ribavirin* Sofosbuvir + ribavirin* Number Number Pooled proportion Total N of studies of arms (95% CI) GRADE (0.02, 0.05) (0.03, 0.05) (0.00, 0.0) (0.0, 0.0) (0.00, 0.0) (0.00, 0.0) (0.00, 0.0) (0.00, 0.0) (0.00, 0.0) (0.00, 0.0) (0.00, 0.0) (0.00, 0.0) (0.00, 0.00) (0.00, 0.07) (0.00, 0.04) (0.0, 0.03) (0.0, 0.03) Serious adverse events Evidence on the number of patients who experienced a SAE was available for every treatment with the exception of daclatasvir + sofosbuvir + ribavirin, where inclusion in this review was restricted to patients 57

60 with cirrhosis and genotype 2 or 3 infection. Across treatments and studies, the number of SAEs was very low, with the pooled percentage varying % to 5% and GRADE assessments varying from moderate to high. A summary of the analyses is presented in Table 59. Table 59: Serious adverse events, arranged by treatment Daclatasvir + asunaprevir Daclatasvir + sofosbuvir Elbasvir + grazoprevir Glecaprevir + pibrentasvir Ledipasvir + sofosbuvir Paritaprevir/ritonavir + ombitasvir + dasabuvir Sofosbuvir + velpatasvir Sofosbuvir + velpatasvir + voxilaprevir Daclatasvir + sofosbuvir + ribavirin* Sofosbuvir + ribavirin* Number Number Pooled proportion Total N of studies of arms (95% CI) GRADE (0.03, 0.07) (0.02, 0.04) (0.00, 0.02) (0.0, 0.05) (0.0, 0.02) (0.0, 0.02) (0.0, 0.03) (0.0, 0.03) (0.0, 0.02) (0.02, 0.04) (0.02, 0.03) (0.03, 0.07) Mortality Evidence on mortality was available for every treatment. Incidence was very low across treatments, with the pooled morality percentage varying from 0% to 4%. GRADE assessments were high for all treatments and types. A summary of the analyses is presented in Table 60. Table 60: Mortality, arranged by treatment Daclatasvir + asunaprevir Daclatasvir + sofosbuvir Elbasvir + grazoprevir Number Number Pooled proportion Total N of studies of arms (95% CI) GRADE (0.00, 0.0) (0.00, 0.00) (0.00, 0.0) (0.00, 0.0) (0.00, 0.0) (0.00, 0.0) 58

61 Glecaprevir + pibrentasvir Ledipasvir + sofosbuvir Paritaprevir/ritonavir + ombitasvir + dasabuvir Sofosbuvir + velpatasvir Sofosbuvir + velpatasvir + voxilaprevir Daclatasvir + sofosbuvir + ribavirin* Sofosbuvir + ribavirin* Number Number Pooled proportion Total N of studies of arms (95% CI) GRADE (0.00, 0.02) (0.00, 0.0) (0.00, 0.00) (0.00, 0.0) (0.00, 0.0) (0.00, 0.00) (0.00, 0.00) (0.00, 0.09) (0.00, 0.07) (0.00, 0.0) (0.00, 0.0) 59

62 SUMMARY OF FINDINGS Evidence was available for all treatments in the all-comer patient population, though the number of studies or patient samples included in each analysis set varied substantially by genotype and treatmentexperience. Treatments typically yielded high SVR2 rates, and GRADE assessments were often rated as high or moderate. However, there was mixed for patients with genotype 2 and 3 HCV infection in the all-comer population, likely attributable to the inclusion of patients with cirrhosis. Indeed, in this corresponding sub-analysis, efficacy was mixed for patients with a genotype 2 or 3 infection. However, analyses in patients with cirrhosis were often limited by small sample sizes. While relatively few studies reported on patients with HIV co-infection, the SVR2 rates in these patients were generally high. Safety outcome, specifically DAEs, SAEs, and mortality, was available for every intervention with the exception of daclatasvir + sofosbuvir + ribavirin. Across all treatments and genotypes, the pooled percentage of patients experiencing an adverse event was very low ( 5%) Given the analytical approach taken to synthesis in this review, it is not possible to infer the relative treatment effects between competing interventions as study effects and treatment effects cannot be disentangled (i.e. naïve comparison). Rather, each outcome should be considered independently. Across most interventions, analyses for select stratifications were informed by few studies and small sample sizes. In these cases, the estimated SVR2 rates should be interpreted with caution. 60

63 STRENGTHS AND LIMITATIONS This review was built upon a rigorous literature search. In addition to searching expansive medical literature databases, namely EMBASE, MEDLINE, and CENTRAL, a hand search of relevant conferences was conducted. This was supplemented by cross-referencing with previously published SLRs and the inclusion of publications identified by the project sponsor (the World Health Organization), including publications made available by pharmaceutical companies. The scope of the review was significant, with the base not restricted to only RCTs but also including non-randomized comparative trials, single-arm trials, and prospective observational studies. The analytical approach included stratifications by study design, genotype and previous HCV treatment experience, as well as separate analyses for patients with cirrhosis and HIV co-infection. A modified GRADE assessment was conducted to evaluate the strength of for every outcome in the clinical and methodological context of HCV research. The findings presented in this report should be interpreted in light of several limitations. Analyses were based on the pooling of proportions from single arms, rather than based on comparative. Thus, it is not possible to draw inferences on relative treatment effects. Such comparisons are described as naïve comparisons, where it not possible to disentangle study effects from treatment effects. The statistical analyses were conducted despite this limitation given the clinical context and the few RCTs comparing two or more active treatments that were identified in the literature. Despite the stratification of analyses across multiple factors, heterogeneity may have been introduced. A formal assessment of the heterogeneity of the pooled patient samples beyond the stratification factors was not conducted, such as patient age, country, and comorbidities. Similarly, no comparisons were made across study inclusion and exclusion criteria, nor the definitions of HCV infection and outcome. Additionally, generic drugs, treatment doses, and treatment durations were collapsed by drug name. The present analyses were based only on the proportion of patients achieving SVR2, though some studies only reported SVR24 data. Thus, there are opportunities to explore additional stratifications and through future analyses. Separate analyses were conducted for trial-only and all available, which included outcomes coming from observational studies. As the study design was difficult to establish in some publications, such as conference abstracts, both sets of analyses should be considered when evaluating the for a given outcome. Moreover, many analyses were based on patients coming from a single study. Thus, future research may change the effect estimates for some patient stratifications. 6

64 APPENDICES Appendix A: Search strategies Table A6: Search strategy for EMBASE No. Query exp hepatitis C/ or exp hepatitis C virus/ or exp hepatitis C, chronic/ (hepatitis C virus or hepacivirus or hep c virus or hep-c virus or hepacvirus or hepatitis c 2 infection or HCV or HVC or chronic hepatitis C or chronic hepatitis C infection or (hepatitis c adj3 (infection* or virus))).ti,ab. 3 or/-2 4 exp grazoprevir/ or exp elbasvir/ or exp elbasvir plus grazoprevir/ or exp ruzasvir/ or exp uprifosbuvir/ 5 (grazoprevir or mk572 or (mk adj2 "572")).ti,ab. 6 (elbasvir or mk8742 or (mk adj2 "8742")).ti,ab. 7 (ruzasvir or mk8408 or (mk adj2 "8408")).ti,ab. 8 (uprifosbuvir or mk3682 or (mk adj2 "3682")).ti,ab. 9 exp glecaprevir/ or exp pibrentasvir/ 0 (glecaprevir or abt493 or (abt adj2 "493")).ti,ab. (pibrentasvir or abt530 or (abt adj2 "530")).ti,ab. 2 exp sofosbuvir/ or exp ledipasvir/ or exp ledipasvir plus sofosbuvir/ or exp velpatasvir/ or exp sofosbuvir plus velpatasvir/ or exp voxilaprevir/ 3 (sofosbuvir or gs7977 or (gs adj2 "7977")).ti,ab. 4 (ledipasvir or gs5885 or (gs adj2 "5885")).ti,ab. 5 (velpatasvir or gs586 or (gs adj2 "586")).ti,ab. 6 (voxilaprevir or gs9857 or (gs adj2 "9857")).ti,ab. 7 exp daclatasvir/ or daclatasvir plus sofosbuvir/ or exp asunaprevir/ 8 (daclatasvir or bms or (bms adj2 "790052")).ti,ab. 9 (asunaprevir or bms or (bms adj2 "650032")).ti,ab. 20 exp simeprevir/ or simeprevir plus sofosbuvir/ or exp odalasvir/ 2 (simeprevir or tmc435 or (tmc adj2 "435")).ti,ab. 22 (odalasvir or ach302 or (ach adj2 "302")).ti,ab. 23 (al335 or (al adj2 "335")).ti,ab. 24 exp ombitasvir/ or exp paritaprevir/ or exp dasabuvir/ 25 (ombitasvir or abt267 or (abt adj2 "267")).ti,ab. 26 (paritaprevir or abt450 or (abt adj2 "450")).ti,ab. 27 (dasabuvir or abt333 or (abt adj2 "333")).ti,ab. 28 exp boceprevir/ or exp telaprevir/ 29 (boceprevir or bocepravir or sch or (sch adj2 "503034")).ti,ab. 30 (telaprevir or teleprevir or telepravir or vx950 or (vx adj2 "950")).ti,ab. (Incivek or Incivo or Victrelis or Olysio or Galexos or Sovriad or Valdi or Virunon or Harvoni or 3 Epclusa or Sofosvel or Velpanat or Daklinza or Sunvepra or Technivie or Viekira or Holkira or Exviera).ti,ab. 32 or/ clinical trial/ 34 randomized controlled trial/ 35 controlled clinical trial/ 36 multicenter study/ 62

65 37 phase 2 clinical trial/ 38 phase 3 clinical trial/ 39 phase 4 clinical trial/ 40 exp randomization/ 4 single blind procedure/ 42 double blind procedure/ 43 crossover procedure/ 44 placebo/ 45 randomi?ed controlled trial$.tw. 46 rct.tw. 47 (random$ adj2 allocat$).tw. 48 single blind$.tw. 49 double blind$.tw. 50 ((treble or triple) adj blind$).tw. 5 placebo$.tw. 52 prospective study/ 53 or/ clinical study/ 55 case control study/ 56 family study/ 57 longitudinal study/ 58 retrospective study/ 59 prospective study/ 60 cohort analysis/ 6 (cohort adj (study or studies)).mp. 62 (case control adj (study or studies)).tw. 63 (follow up adj (study or studies)).tw. 64 (observational adj (study or studies)).tw. 65 (epidemiologic$ adj (study or studies)).tw. 66 (cross sectional adj (study or studies)).tw. 67 or/ or case study/ 70 case report.tw. 7 abstract report/ or letter/ 72 conference proceeding.pt. 73 conference abstract.pt. 74 editorial.pt. 75 letter.pt. 76 note.pt. 77 or/ not and 32 and limit 79 to english language 63

66 Table A62: Search strategy for MEDLINE No. Query exp hepatitis C/ or exp hepatitis C virus/ or exp hepatitis C, chronic/ 2 3 or/-2 (hepatitis C virus or hepacivirus or hep c virus or hep-c virus or hepacvirus or hepatitis c infection or HCV or HVC or chronic hepatitis C or chronic hepatitis C infection or (hepatitis c adj3 (infection* or virus))).ti,ab. 4 (grazoprevir or mk572 or (mk adj2 "572")).mp. 5 (elbasvir or mk8742 or (mk adj2 "8742")).mp. 6 (ruzasvir or mk8408 or (mk adj2 "8408")).mp. 7 (uprifosbuvir or mk3682 or (mk adj2 "3682")).mp. 8 (glecaprevir or abt493 or (abt adj2 "493")).mp. 9 (pibrentasvir or abt530 or (abt adj2 "530")).mp. 0 exp sofosbuvir/ (sofosbuvir or gs7977 or (gs adj2 "7977")).mp. 2 (ledipasvir or gs5885 or (gs adj2 "5885")).mp. 3 (velpatasvir or gs586 or (gs adj2 "586")).mp. 4 (voxilaprevir or gs9857 or (gs adj2 "9857")).mp. 5 (daclatasvir or bms or (bms adj2 "790052")).mp. 6 (asunaprevir or bms or (bms adj2 "650032")).mp. 7 exp simeprevir/ 8 (simeprevir or tmc435 or (tmc adj2 "435")).mp. 9 (odalasvir or ach302 or (ach adj2 "302")).mp. 20 (al335 or (al adj2 "335")).mp. 2 (ombitasvir or abt267 or (abt adj2 "267")).mp. 22 (paritaprevir or abt450 or (abt adj2 "450")).mp. 23 (dasabuvir or abt333 or (abt adj2 "333")).mp. 24 (boceprevir or bocepravir or sch or (sch adj2 "503034")).mp. 25 (telaprevir or teleprevir or telepravir or vx950 or (vx adj2 "950")).mp or/4-26 (Incivek or Incivo or Victrelis or Olysio or Galexos or Sovriad or Valdi or Virunon or Harvoni or Epclusa or Sofosvel or Velpanat or Daklinza or Sunvepra or Technivie or Viekira or Holkira or Exviera).mp. 28 randomized controlled trials as topic/ 29 randomized controlled trial/ 30 random allocation/ 3 double blind method/ 32 single blind method/ 33 clinical trial/ 34 clinical trial, phase i.pt. 35 clinical trial, phase ii.pt. 36 clinical trial, phase iii.pt. 64

67 37 clinical trial, phase iv.pt. 38 controlled clinical trial.pt. 39 randomized controlled trial.pt. 40 multicenter study.pt. 4 clinical trial.pt. 42 exp clinical trials as topic/ 43 (clinical adj trial$).tw. 44 ((singl$ or doubl$ or treb$ or tripl$) adj (blind$3 or mask$3)).tw. 45 placebos/ 46 placebo$.tw. 47 randomly allocated.tw. 48 (allocated adj2 random$).tw. 49 or/ epidemiologic studies/ 5 exp case control studies/ 52 exp cohort studies/ 53 case control.tw. 54 (cohort adj (study or studies)).tw. 55 cohort analy$.tw. 56 (follow up adj (study or studies)).tw. 57 (observational adj (study or studies)).tw. 58 longitudinal.tw. 59 retrospective.tw. 60 cross sectional.tw. 6 cross-sectional studies/ 62 or/ or case report.tw. 65 letter/ 66 historical article/ 67 or/ not and 27 and limit 69 to english language 65

68 Table A63: Search strategy for CENTRAL No. Query exp hepatitis C/ or exp hepatitis C virus/ or exp hepatitis C, chronic/ 2 3 or/-2 (hepatitis C virus or hepacivirus or hep c virus or hep-c virus or hepacvirus or hepatitis c infection or HCV or HVC or chronic hepatitis C or chronic hepatitis C infection or (hepatitis c adj3 (infection* or virus))).ti,ab. 4 (grazoprevir or mk572 or (mk adj2 "572")).mp. 5 (elbasvir or mk8742 or (mk adj2 "8742")).mp. 6 (ruzasvir or mk8408 or (mk adj2 "8408")).mp. 7 (uprifosbuvir or mk3682 or (mk adj2 "3682")).mp. 8 (glecaprevir or abt493 or (abt adj2 "493")).mp. 9 (pibrentasvir or abt530 or (abt adj2 "530")).mp. 0 exp sofosbuvir/ (sofosbuvir or gs7977 or (gs adj2 "7977")).mp. 2 (ledipasvir or gs5885 or (gs adj2 "5885")).mp. 3 (velpatasvir or gs586 or (gs adj2 "586")).mp. 4 (voxilaprevir or gs9857 or (gs adj2 "9857")).mp. 5 (daclatasvir or bms or (bms adj2 "790052")).mp. 6 (asunaprevir or bms or (bms adj2 "650032")).mp. 7 exp simeprevir/ 8 (simeprevir or tmc435 or (tmc adj2 "435")).mp. 9 (odalasvir or ach302 or (ach adj2 "302")).mp. 20 (al335 or (al adj2 "335")).mp. 2 (ombitasvir or abt267 or (abt adj2 "267")).mp. 22 (paritaprevir or abt450 or (abt adj2 "450")).mp. 23 (dasabuvir or abt333 or (abt adj2 "333")).mp. 24 (boceprevir or bocepravir or sch or (sch adj2 "503034")).mp. 25 (telaprevir or teleprevir or telepravir or vx950 or (vx adj2 "950")).mp or/4-26 (Incivek or Incivo or Victrelis or Olysio or Galexos or Sovriad or Valdi or Virunon or Harvoni or Epclusa or Sofosvel or Velpanat or Daklinza or Sunvepra or Technivie or Viekira or Holkira or Exviera).mp and limit 28 to english language 66

69 Appendix B: Publication eligibility assessment process Table B: Exclusion hierarchy for abstract screening Hierarchy Reason Exclude if: Duplicate publications Multiple entries for same publication 2 Other Published prior to Study design Review/editorial/letter/comment/meta-analysis Pre-clinical/In-vitro studies 4 Populations Not chronically infected with HCV Not adult population (<8 years of age) 5 Interventions Not specified treatment Table B2: Exclusion hierarchy for full text screening Hierarchy Reason Exclude if: Other Published prior to 205* 2 Study design Review/editorial/letter/comment/meta-analysis Pre-clinical/In-vitro studies 3 Populations Not chronically infected with HCV Not adult population (<8 years of age) 4 Interventions Not specified treatment 5 Outcomes At least outcome of interest is not reported *If not evaluable at abstract screening phase 67

70 Appendix C: Included studies Table C: List of included studies, with treatments and study design categorization Study name Registration Treatment arms Study design Abdel-Aziz DAC 60 mg qd 2 weeks + SOF 400 mg qd 2 weeks Yes AI NCT DAC 60 mg 24 weeks + SOF 400 mg 24 weeks DAC 60 mg 2 weeks + SOF 400 mg 2 weeks Yes AI ,9,225 NCT00544 DAC 60 mg 24 weeks + ASV 200 mg bid 24 weeks Yes AI NCT07845 DAC 60 mg qd 24 weeks + ASV 00 mg bid 24 weeks Yes ALLY 3+ 26,37 ALLY-2 24,3,37, NCT NCT DAC 60 mg qd 2 weeks + SOF 400 mg qd 2 weeks + RBV 000 mg/day (<75 kg) or 200 mg/day ( 75 kg), 2 weeks DAC 60 mg qd 6 weeks + SOF 400 mg qd 6 weeks + RBV 000 mg/day (<75 kg) or 200 mg/day ( 75 kg), 6 weeks DAC 60 mg qd 8 weeks + SOF 400 mg qd 8 weeks DAC 60 mg qd 2 weeks + SOF 400 mg qd 2 weeks Yes Yes ALLY-3 25,,37,48,49 NCT DAC 60 mg 2 weeks + SOF 400 mg 2 weeks Yes ANRS CO22 HEPATHER 55,64 NCT DAC 60 mg qd 2 weeks + SOF 400 mg qd 2 weeks DAC 60 mg qd 24 weeks + SOF 400 mg qd 24 weeks Yes ASCEND 03 LDV 2, 3, or 6 months + SOF 2, 3, or 6 months Yes Yes Yes Yes Yes ASTRAL- 49,7,73,94,46,29,229 NCT SOF 400 mg qd 2 weeks + VEL 00 mg qd 2 weeks PBO SOF 400 mg qd 2 weeks + VEL 00 mg qd 2 weeks ASTRAL- 2 59,7,73,94,46,85,29,23 NCT SOF 400 mg qd 2 weeks + RBV bid 2 weeks for 000 mg daily (body weight <75 kg) or 200 mg daily (body weight 75 kg) SOF 400 mg qd 2 weeks + VEL 00 mg qd 2 weeks ASTRAL- 3 59,7,73,94,46,29,23 NCT SOF 400 mg qd 24 weeks + RBV bid 24 weeks for 000 mg daily (body weight <75 kg) or 200 mg daily (body weight 75 kg) ASTRAL- 4 29,37,38,46,57,228 NCT SOF 400 mg qd 2 weeks + VEL 00 mg qd 2 weeks SOF 400 mg qd 24 weeks + VEL 00 mg qd 24 weeks ASTRAL- 09,46,28,29,232 NCT SOF 400 mg qd 2 weeks + VEL 00 mg qd 2 weeks Yes 5 Observational study 68

71 Study name Registration Treatment arms Autorisation Temporaire d Utilisation (ATU) Program 20 Backus Bansal BOSON 62,63 C-CORAL 72,205,22 DAC 30/60/90 qd 2 weeks + SOF 400 mg qd 2 weeks DAC 30/60/90 qd 24 weeks + SOF 400 mg qd 24 weeks LDV 2 weeks + SOF 2 weeks PTV/r 2 weeks + OMV 2 weeks + DBV 2 weeks DAC 60 mg 2 weeks + SOF 400 mg 2 weeks DAC 60 mg 2 weeks + SOF 400 mg 2 weeks + RBV 000 mg/day (<75 kg) or 200 mg/day ( 75 kg), twice per day 2 weeks DAC 60 mg 24 weeks + SOF 400 mg 24 weeks + RBV 000 mg/day (<75 kg) or 200 mg/day ( 75 kg), twice per day 24 weeks SOF 400 mg qd 6 weeks + RBV 000 mg/day (<75 kg) or 200 mg/day ( 75 kg), twice per day 6 weeks SOF 400 mg qd 24 weeks + RBV 000 mg/day (<75 kg) or 200 mg/day ( 75 kg), twice per day 24 weeks ESV 50 mg qd 2 weeks + GZR 00 mg qd 2 weeks PBO 2 weeks Study design Yes Yes Yes Yes Yes C-EDGE 72 NCT ESV 50 mg qd 2 weeks + GZR 00 mg qd 2 weeks Yes CO-INFECTION C-EDGE CO-STAR 45,46 NCT ESV 50 mg qd 2 weeks + GZR 00 mg qd 2 weeks PBO Yes C-EDGE 79,80 NCT ESV 50 mg qd 2 weeks + GZR 00 mg qd 2 weeks Yes HEAD-2-HEAD C-EDGE IBLD 75-78,8 C-EDGE Treatment- Experienced 5-7 C-EDGE Treatment- Naïve 52,224, NCT NCT NCT ESV 50 mg qd 2 weeks + GZR 00 mg qd 2 weeks PBO ESV 50 mg qd 2 weeks + GZR 00 mg qd 2 weeks ESV 50 mg qd 6 weeks + GZR 00 mg qd 6 weeks ESV 50 mg qd 2 weeks + GZR 00 mg qd 2 weeks PBO Yes Yes Yes CERTAIN-, 30,3,98 NCT GCR 300 mg qd 2 weeks + PBV 20 mg qd 2 weeks Yes Sub-study 2 CERTAIN-2 3,98 NCT GCR 300 mg qd 8 weeks + PBV 20 mg qd 8 weeks Yes Chamorro-de-Vega PTV/r 50/00 mg qd 2 weeks + OMV 25 mg qd 2 weeks + DBV 250 mg bid 2 weeks Yes Observational study 69

72 Study name Registration Treatment arms Chen DAC 60 mg/day 2 or 24 weeks + SOF 400 mg/day 2 or 24 weeks LDV 90 mg/day 2 or 24 weeks + SOF 400 mg/day 2 or 24 weeks Study design Yes Chuang ,27,86 Korea NCT LDV 90 mg qd 2 weeks + SOF 400 mg qd 2 weeks Yes Chuang ,27,86 Taiwan NCT LDV 90 mg qd 2 weeks + SOF 400 mg qd 2 weeks Yes C-WORTHY 70,2,84,224 NCT ESV 50 mg qd 2 weeks + GZR 00 mg qd 2 weeks ESV 50 mg qd 8 weeks + GZR 00 mg qd 8 weeks Yes Dashtseren ,40 LDV 80 mg qd 2 weeks + SOF 400 mg qd 2 weeks Yes Desnoyer DAC 60 mg qd 2 weeks + SOF 400 mg qd or tiw 2 weeks DAC 60 mg qd 24 weeks + SOF 400 mg qd or tiw 24 weeks Yes Deterding ,83 SOF + RBV Yes ELECTRON 69 NCT SOF 400 mg 2 weeks + LDV 90 mg 2 weeks Yes ELECTRON-2 64,66,67,25 NCT SOF 400 mg 2 weeks + LDV 90 mg 2 weeks Yes ENDURANCE-3 60 NCT GCR 300 mg qd 2 weeks + PBV 20 mg qd 2 weeks DAC 60 mg qd 2 weeks + SOF 400 mg qd 2 weeks GCR 300 mg qd 8 weeks + PBV 20 mg qd 8 weeks Yes ERADICATE 58,59,96,9 7 NCT SOF 400 mg 2 weeks + LDV 90 mg 2 weeks Yes Everson NCT SOF 400 mg qd 2 weeks + VEL 25 mg qd 2 weeks SOF 400 mg qd 2 weeks + VEL 00 mg qd 2 weeks SOF 400 mg qd 8 weeks + VEL 25 mg qd 8 weeks SOF 400 mg qd 8 weeks + VEL 00 mg qd 8 weeks Yes EXPEDITION NCT GCR 300 mg qd 2 weeks + PBV 20 mg qd 2 weeks Yes EXPEDITION-2 7 NCT GCR 300 mg qd 8 weeks + PBV 20 mg qd 8 weeks GCR 300 mg qd 2 weeks + PBV 20 mg qd 2 weeks Yes Fierer LDV 8 weeks + SOF 8 weeks Yes Foster DAC 60 mg qd 2 weeks + SOF 400 mg qd 2 weeks LDV 90 mg qd 2 weeks + SOF 400 mg qd 2 weeks Yes Observational study 70

73 Study name Registration Treatment arms FUSION 26,52,47,234 Gane GARNET 23,24 NCT NCT NCT DAC 60 mg qd 2 weeks + SOF 400 mg qd 2 weeks + RBV Clinician discretion SOF 400 mg qd 2 weeks + RBV mg/day 2 weeks SOF 400 mg qd 6 weeks + RBV mg/day 6 weeks LDV 90 mg qd 2 weeks + SOF 400 mg qd 2 weeks LDV 90 mg qd 8 weeks + SOF 400 mg qd 8 weeks PTV/r 50 mg/00 mg qd 8 weeks + OMV 25 mg qd 8 weeks + DBV 250 mg bid 8 weeks Study design Yes Yes Yes GECCO-0 89 LDV 8 weeks + SOF 8 weeks Yes German Hepatitis C- LDV 2 weeks + SOF 2 weeks Registry Yes (GT patients) 202 LDV 8 weeks + SOF 8 weeks German Hepatitis C- Registry (GT2 patients) 36,92 SOF 2 weeks + RBV 2 weeks Yes German Hepatitis C- Registry (GT3 patients) 36 SOF 24 weeks + RBV 24 weeks DAC 2 weeks + SOF 2 weeks DAC 2 weeks + SOF 2 weeks + RBV 2 weeks DAC 24 weeks + SOF 24 weeks DAC 24 weeks + SOF 24 weeks + RBV 24 weeks Yes GS-US / GS-US LDV 2 weeks + SOF 2 weeks Yes (Pooled) 230,239 GS-US ,66 [Genotype 4] NCT LDV 90 mg qd 2 weeks + SOF 400 mg qd 2 weeks Yes GS-US-337-9,66 [Genotype 5] NCT LDV 90 mg qd 2 weeks + SOF 400 mg qd 2 weeks Yes HALLMARK DUAL 00,0,35 NCT DAC 60 mg qd 24 weeks + ASV 00 mg bid 24 weeks PBO Yes HCV Research UK 33 DAC 2 weeks + SOF 2 weeks Yes (HCVRUK) HCV- TARGET 50,6,69,94,25,2 27 NCT04748 SOF 400 mg qd 2 weeks + RBV Clinician discretion 2 weeks SOF 400 mg qd 6 weeks + RBV Clinician discretion 6 weeks SOF 24 weeks + RBV Clinician discretion 24 weeks Yes Observational study 7

74 Study name Registration Treatment arms LDV 90 mg qd 8, 2, or 24 weeks + SOF 400 mg qd 8, 2, or 24 weeks ESV + GZR SOF + VEL + VEL Study design HepNet Acute HCV IV 43,44 NCT LDV 90 mg qd 6 weeks + SOF 400 mg qd 6 weeks Yes Study Hezode ,80 DAC 60 mg qd 8 weeks + SOF 400 mg qd 8 weeks Yes Hlaing Ide 206a 84 SOF 400 mg qd 24 weeks + RBV 5 mg/kg/day 24 weeks LDV 90 mg qd 2 weeks + SOF 400 mg qd 2 weeks DAC 60 mg qd 2 weeks + SOF 400 mg qd 2 weeks + RBV 5 mg/kg/day 2 weeks DAC 24 weeks + ASV 24 weeks LDV 2 weeks + SOF 2 weeks Yes Yes Ide 206b 85 DAC 60 mg qd 24 weeks + ASV 00 mg bid 24 weeks Yes Iio 207a 86 DAC 60 mg qd 24 weeks + ASV 00 mg bid 24 weeks Yes Iio 207b 87 LDV 90 mg qd 2 weeks + SOF 400 mg qd 2 weeks Yes Ikeda DAC 60 mg qd 24 weeks + ASV 00 mg bid 24 weeks Yes ION- 4-6,74,26,233,235 ION-2 3,5,6,74,26,233,235 ION-3 5,6,74,0,26,233,235 NCT07040 NCT NCT LDV 90 mg 2 weeks + SOF 400 mg 2 weeks LDV 90 mg 24 weeks + SOF 400 mg 24 weeks LDV 90 mg 2 weeks + SOF 400 mg 2 weeks LDV 90 mg 24 weeks + SOF 400 mg 24 weeks LDV 90 mg 2 weeks + SOF 400 mg 2 weeks LDV 90 mg 8 weeks + SOF 400 mg 8 weeks Yes Yes Yes ION-4 44,45,236 NCT SOF 400 mg 2 weeks + LDV 90 mg 2 weeks Yes Isakov ,247 LDV 90 mg qd 8 weeks + SOF 400 mg qd 8 weeks Yes Ishigami DAC + ASV Yes Itoh ESV qd 2 weeks + GZR qd 2 weeks Yes Iwamoto DAC 2 weeks + SOF 2 weeks DAC 24 weeks + SOF 24 weeks Yes Observational study 72

75 Study name Registration Treatment arms Study design Jargalsaikhan LDV 2 weeks + SOF 2 weeks Yes Ji Johnson Kawada DAC 60 mg/day 2 weeks + SOF 400 mg/day 2 weeks LDV 90 mg qd 2 weeks + SOF 400 mg qd 2 weeks LDV 8 weeks + SOF 8 weeks LDV 2 weeks + SOF 2 weeks LDV 24 weeks + SOF 24 weeks ESV 50 mg qd 2 weeks + GZR 50 mg qd 2 weeks ESV 50 mg qd 2 weeks + GZR 00 mg qd 2 weeks Yes Yes Yes Kawakami UMIN DAC 60 mg qd 24 weeks + ASV 00 mg bid 24 weeks Yes Korenaga LDV 2 weeks + SOF 2 weeks Yes Kumada 204 3,39,225 NCT DAC 60 mg 24 weeks + ASV 00 mg bid 24 weeks Yes Kumada 206a 2 NCT07845 DAC 60 mg qd 24 weeks + ASV 00 mg bid 24 weeks Yes Kumada 206b 4,90 NCT ESV 50 mg qd 2 weeks + GZR 50 mg qd 2 weeks ESV 50 mg qd 2 weeks + GZR 00 mg qd 2 weeks Yes Kwo GCR 300 mg qd 2 weeks + PBV 20 mg qd 2 weeks Yes Lawitz ,24 NCT SOF 400 mg qd 2 weeks + VEL 00 mg qd 2 weeks + VOX 00 mg qd 2 weeks Yes Lionetti DAC 24 weeks + SOF 24 weeks + RBV 922 ± 200 mg/day 24 weeks DAC 24 weeks + SOF 24 weeks Yes Liu LDV 90 mg qd 2 weeks + SOF 400 mg qd 2 weeks Yes Lok NCT DAC 60 mg 24 weeks + ASV 600 mg bid 24 weeks Yes LONESTAR 23 NCT LDV 90 mg 2 weeks + SOF 400 mg 2 weeks LDV 90 mg 8 weeks + SOF 400 mg 8 weeks MAGELLAN-, Part 65,66 NCT GCR 200 mg qd 2 weeks + PBV 80 mg qd 2 weeks GCR 300 mg qd 2 weeks + PBV 20 mg qd 2 weeks MAGELLAN-, Part 2 67,68 NCT GCR 300 mg qd 2 weeks + PBV 20 mg qd 2 weeks GCR 300 mg qd 6 weeks + PBV 20 mg qd 6 weeks Yes Yes Yes Observational study 73

76 Study name Registration Treatment arms MALACHITE-I 35,47 Mangia 206a 32 Mangia 207a 33 Mangia 207b 34 Mehta NCT EUDRACT PTV/r 50 mg/00 mg qd 2 weeks + OMV 25 mg qd 2 weeks + DBV 250 mg bid 2 weeks DAC 60 mg qd 2 weeks + SOF 400 mg qd 2 weeks DAC 60 mg qd 24 weeks + SOF 400 mg qd 24 weeks Study design Yes Yes LDV 90 mg qd 2 weeks + SOF 400 mg qd 2 weeks Yes SOF 400 mg qd 6 weeks + RBV 000 or 200 mg/day 6 weeks SOF 400 mg qd 20 weeks + RBV 000 or 200 mg/day 20 weeks LDV 90 mg qd 2 weeks + SOF 400 mg qd 2 weeks DAC 60 mg qd 2 weeks + SOF 400 mg qd 2 weeks DAC 60 mg qd 24 weeks + SOF 400 mg qd 24 weeks DAC 60 mg qd 24 weeks + SOF 400 mg qd 24 weeks + RBV 000 mg/day (<75 kg) or 200 mg/day (>75 kg), divided doses 24 weeks Yes Yes Mizokami NCT LDV 90 mg qd 2 weeks + SOF 400 mg qd 2 weeks Yes Nagao LDV 90 mg qd 2 weeks + SOF 400 mg qd 2 weeks Yes Nguyen ,5 LDV 90 mg qd 8 weeks + SOF 400 mg qd 8 weeks LDV 90 mg qd 2 weeks + SOF 400 mg qd 2 weeks Yes Ogawa SOF 400 mg qd 2 weeks + RBV Weight-adjusted ( mg/day) 2 weeks Yes Ogawa 207a 56 UMIN DAC 60 mg qd 24 weeks + ASV 00 mg bid 24 weeks Yes Ogawa 207b 53,54 UMIN LDV 90 mg qd 2 weeks + SOF 400 mg qd 2 weeks Yes ONYX-I 206,207 PTV/r 2 weeks + OMV 2 weeks + DBV 2 weeks PBO 2 weeks Yes PEARL-II 7,208 NCT PTV/r 50/00 mg 2 weeks + OMV 25 mg 2 weeks + DBV 250 mg bid 2 weeks Yes PEARL-III 53,208 NCT07676 PTV/r 50/00 mg 2 weeks + OMV 25 mg 2 weeks + DBV 250 mg bid 2 weeks Yes PEARL-IV 53 NCT PTV/r 50/00 mg 2 weeks + OMV 25 mg 2 weeks + DBV 250 mg bid 2 weeks Yes Persico LDV 90 mg qd 2 weeks + SOF 400 mg qd 2 weeks Yes PHOTON-2 4,42,234 NCT SOF 400 mg qd 24 weeks + RBV 000 mg/day (<75 kg) or 200 mg/day ( 75 kg), twice per day 24 weeks SOF 400 mg qd 2 weeks + RBV 000 mg/day (<75 kg) or 200 mg/day ( 75 kg), twice per day 2 weeks Yes Observational study 74

77 Study name Registration Treatment arms Pianko POLARIS- 2,22 POLARIS-2 96 POLARIS-3 96 POLARIS-4 2,242 NCT NCT NCT NCT NCT SOF 400 mg qd 2 weeks + VEL 25 mg qd 2 weeks SOF 400 mg qd 2 weeks + VEL 00 mg qd 2 weeks SOF 400 mg qd 2 weeks + VEL 00 mg qd 2 weeks + VOX 00 mg qd 2 weeks PBO SOF 400 mg qd 8 weeks + VEL 00 mg qd 8 weeks + VOX 00 mg qd 8 weeks SOF 400 mg qd 2 weeks + VEL 00 mg qd 2 weeks SOF 400 mg qd 8 weeks + VEL 00 mg qd 8 weeks + VOX 00 mg qd 8 weeks SOF 400 mg qd 2 weeks + VEL 00 mg qd 2 weeks SOF 400 mg qd 2 weeks + VEL 00 mg qd 2 weeks + VOX 00 mg qd 2 weeks SOF 400 mg qd 2 weeks + VEL 00 mg qd 2 weeks Study design Yes Yes Yes Yes Yes POSITRON 26,95 NCT SOF 400 mg qd 2 weeks + RBV mg/day 2 weeks Yes Reddy DAC + ASV Yes Sezaki DAC 60 mg qd 24 weeks + ASV 00 mg bid 24 weeks Yes Shah Shiha NCT SOF 400 mg qd 6 weeks + RBV 000 mg/day (<75 kg) or 200 mg/day ( 75 kg), twice per day 6 weeks SOF 400 mg qd 24 weeks + RBV 000 mg/day (<75 kg) or 200 mg/day ( 75 kg), twice per day 24 weeks LDV 8 weeks + SOF 8 weeks LDV 2 weeks + SOF 2 weeks Yes Yes SIRIUS 20,23,27,203,237,238 NCT SOF 400 mg 24 weeks + LDV 90 mg qd 24 weeks Yes Slash C 60 LDV 90 mg qd 2 weeks + SOF 400 mg qd 2 weeks Yes Suda UMIN DAC 60 mg qd 24 weeks + ASV 00 mg bid 24 weeks Yes Suda UMIN DAC 60 mg qd 24 weeks + ASV 00 mg bid 24 weeks Yes Sung DAC 60 mg qd 24 weeks + ASV 00 mg bid 24 weeks Yes SURVEYOR-I 65,8 NCT GCR 200 mg qd 2 weeks + PBV 20 mg qd 2 weeks GCR 200 mg qd 2 weeks + PBV 40 mg qd 2 weeks GCR 300 mg qd 8 weeks + PBV 20 mg qd 8 weeks GCR 300 mg qd 2 weeks + PBV 20 mg qd 2 weeks Yes Observational study 75

78 Study name Registration Treatment arms SURVEYOR-II 65,8 NCT GCR 300 mg qd 2 weeks + PBV 20 mg qd 2 weeks GCR 200 mg qd 2 weeks + PBV 20 mg qd 2 weeks GCR 200 mg qd 2 weeks + PBV 40 mg qd 2 weeks GCR 300 mg qd 8 weeks + PBV 20 mg qd 8 weeks Study design Yes Suzuki DAC 60 mg qd 24 weeks + ASV 00 mg bid 24 weeks Yes SYNERGY 66,06,07,78,9 7,27 NCT LDV 90 mg qd 2 weeks + SOF 400 mg qd 2 weeks Yes Terashita DAC + ASV Yes Torres LDV + SOF SOF + VEL DAC + SOF Yes Toyoda UMIN DAC 60 mg qd 24 weeks + ASV 00 mg bid 24 weeks Yes Toyoda UMIN DAC 60 mg qd 24 weeks + ASV 00 mg bid 24 weeks Yes TURQUOISE-III 5 NCT PTV/r 50/00 mg qd 2 weeks + OMV 25 mg qd 2 weeks + DBV 250 mg bid 2 weeks Yes UNITY-3 20 NCT DAC 60 mg qd 24 weeks + ASV 00 mg bid 24 weeks Yes VALENCE 25,234,24,246 VALOR-HCV 82 VASCUVALDIC 2 73,74 NCT NCT NCT SOF 400 mg qd 2 weeks + RBV 000 mg/day (<75 kg) or 200 mg/day ( 75 kg), twice per day 2 weeks SOF 400 mg qd 24 weeks + RBV 000 mg/day (<75 kg) or 200 mg/day ( 75 kg), twice per day 24 weeks PBO SOF 400 mg qd 2 weeks + RBV Weight-adjusted ( mg/day divided doses) 2 weeks DAC 60 mg qd 2 weeks + SOF 400 mg qd 2 weeks DAC 60 mg qd 24 weeks + SOF 400 mg qd 24 weeks Yes Yes Yes Vierling ESV 50 mg 8 weeks + GZR 00 mg 8 weeks Yes Wei NCT DAC 60 mg qd 24 weeks + ASV 00 mg bid 24 weeks Yes Wei 207a 20 SOF 400 mg 2 weeks + RBV mg divided daily dose 2 weeks SOF 400 mg 24 weeks + RBV mg divided daily dose 24 weeks Yes Wei 207b 209 DAC 60 mg qd 24 weeks + ASV 00 mg bid 24 weeks Yes Observational study 76

79 Study name Registration Treatment arms Yakoot ACTRN PBO DAC (generic) 60 mg/day 2 weeks + SOF (generic) 400 mg/day 2 weeks DAC (generic) 60 mg/day response-tailored duration + SOF (generic) 400 mg/day response-tailored duration Study design Yes Younossi LDV 2 weeks + SOF 2 weeks Yes Zeng LDV (generic) 90 mg qd 8 weeks + SOF (generic) 400 mg qd 8 weeks Yes Observational study 77

80 Appendix D: GRADE profiles Table D: GRADE profile for patients treated with daclatasvir + asunaprevir, all-comer analysis, arranged by genotype Quality assessment Risk of Design Inconsistency Indirectness Imprecision studies bias Genotype, -treatment experience population SVR2 5 2 Genotype 2, -treatment experience population SVR2 Genotype 3, -treatment experience population SVR2 Genotype 4, -treatment experience population SVR2 Genotype 5, -treatment experience population SVR2 Other considerations patients Effect Quality Importance 0.89 (0.87, 0.92) 0.89 (0.87, 0.9) 78

81 Quality assessment Risk of Other Design Inconsistency Indirectness Imprecision patients studies bias considerations Effect Quality Importance Genotype 6, -treatment experience population SVR2 Mixed genotype group, -treatment experience population SVR2 2 Genotype, Treatment-naïve population SVR h (0.89, 0.94) 0.90 (0.88, 0.93) 4 Genotype 2, Treatment-naïve population SVR2 Genotype 3, Treatment-naïve population SVR2 Genotype 4, Treatment-naïve population SVR2 79

82 Quality assessment Risk of Design Inconsistency Indirectness Imprecision studies bias Genotype 5, Treatment-naïve population SVR2 Genotype 6, Treatment-naïve population SVR2 Mixed genotype group, Treatment-naïve population SVR2 Genotype, Treatment-experienced population SVR2 4 Other considerations patients Effect Quality Importance d Genotype 2, Treatment-experienced population SVR2 Genotype 3, Treatment-experienced population SVR (0.76, 0.94) 80

83 Design studies Risk of bias Genotype 4, Treatment-experienced population SVR2 Quality assessment Genotype 5, Treatment-experienced population n SVR2 Genotype 6, Treatment-experienced population SVR2 Inconsistency Indirectness Imprecision Other considerations patients Effect Quality Importance Mixed genotype group, Treatment-experienced population SVR2 Discontinuations due to adverse events a (0.02, 0.05) 8 - a Serious adverse events (0.03, 0.05) 8

84 studies 2 Mortality 7 Quality assessment Risk of Other Design Inconsistency Indirectness Imprecision patients bias considerations Effect Quality Importance (0.03, 0.07) (0.02, 0.04) (0, 0.0) (0, 0) Legend for GRADE: Very low; Low; Moderate; High. a Rated down as 50% of patients contributing to the pooled estimate comes from studies determined to pose a high risk of bias b Rated down as 75% of patients contributing to the pooled estimate comes from studies determined to pose a high risk of bias c Rated down for consistency as differences in the proportion of patients with the outcome of interest in the pooled studies exceeds 25% d Rated down for imprecision as the width of the 95% CI exceeds 0% (±5%) e Rated down for imprecision as the sample size from the single study informing the analysis is less than 50 (N<50) f Rated down for imprecision as the sample size from the single study informing the analysis is less than 25 (N<25); May also be applied when pooling outcomes from multiple studies with very small sample sizes g Rated down as 50% of patients contributing to the pooled estimate come from observational studies h Rated down as 75% of patients contributing to the pooled estimate come from observational studies i Rated down as the estimate of effect is based on a very small sample size or the estimate is based on a single, small study Table D2: GRADE profile for patients treated with daclatasvir + sofosbuvir, all-comer analysis, arranged by genotype Quality assessment Risk of Design Inconsistency Indirectness Imprecision studies bias Genotype, -treatment experience population SVR2 6 Other considerations patients Effect Quality Importance 0.98 (0.96,.00) 0.96 (0.94, 82

85 studies Design Risk of bias Quality assessment Inconsistency Indirectness Imprecision Other considerations patients Effect Quality Importance 0.98) Genotype 2, -treatment experience population SVR d -2 h 2 (0.86,.00) Genotype 3, -treatment experience population SVR2 3 9 Genotype 4, -treatment experience population SVR g (0.88, 0.97) 0.89 (0.85, 0.94) 0.97 (0.95,.00) 0.97 (0.95,.00) Genotype 5, -treatment experience population SVR f -2 h 8 (0.70,.00) Genotype 6, -treatment experience population SVR h

86 Quality assessment Risk of Other Design Inconsistency Indirectness Imprecision patients studies bias considerations Effect Quality Importance (0.90, 0.98) Mixed genotype group, -treatment experience population SVR2 2 5 Genotype, Treatment-naïve population SVR d a g g (0.88, 0.99) 0.92 (0.88, 0.97) 0.98 (0.96,.00) 0.94 (0.90, 0.99) Genotype 2, Treatment-naïve population SVR f -2 h (0.5,.00) Genotype 3, Treatment-naïve population SVR (0.89, 0.98) 0.93 (0.88, 0.98) Genotype 4, Treatment-naïve population SVR e

87 studies 2 Quality assessment Risk of Other Design Inconsistency Indirectness Imprecision patients bias considerations Effect Quality Importance (0.87,.00) d 0 6 (0.87, 0.99) Genotype 5, Treatment-naïve population SVR f -2 h 2 Genotype 6, Treatment-naïve population SVR2 Mixed genotype group, Treatment-naïve population SVR d Genotype, Treatment-experienced population SVR f g (0.4,.00) 0.9 (0.82,.00) 0.98 (0.92,.00) Genotype 2, Treatment-experienced population SVR (0.95, 0.98) 85

88 studies Design Risk of bias Genotype 3, Treatment-experienced population SVR2 3 Quality assessment Inconsistency Indirectness Imprecision Other considerations f -2 h e d 0 0 patients Effect Quality Importance 0.75 (0.5,.00) 0.86 (0.77, 0.96) 0.85 (0.78, 0.92) Genotype 4, Treatment-experienced population SVR f -2 h 2 (0.4,.00) Genotype 5, Treatment-experienced population n SVR2 Genotype 6, Treatment-experienced population SVR2 Mixed genotype group, Treatment-experienced population SVR e (0.94,.00) 86

89 studies Design Risk of bias Quality assessment Discontinuations due to adverse events 5 2 Serious adverse events 5 0 Mortality Inconsistency Indirectness Imprecision Other considerations - a patients - a g 875 Effect Quality Importance 0.0 (0, 0.0) 0.0 (0.0, 0.0) 0.0 (0, 0.02) 0.03 (0.0, 0.05) 0.0 (0, ) 0.0 (0, ) Legend for GRADE: Very low; Low; Moderate; High. a Rated down as 50% of patients contributing to the pooled estimate comes from studies determined to pose a high risk of bias b Rated down as 75% of patients contributing to the pooled estimate comes from studies determined to pose a high risk of bias c Rated down for consistency as differences in the proportion of patients with the outcome of interest in the pooled studies exceeds 25% d Rated down for imprecision as the width of the 95% CI exceeds 0% (±5%) e Rated down for imprecision as the sample size from the single study informing the analysis is less than 50 (N<50) f Rated down for imprecision as the sample size from the single study informing the analysis is less than 25 (N<25); May also be applied when pooling outcomes from multiple studies with very small sample sizes g Rated down as 50% of patients contributing to the pooled estimate come from observational studies h Rated down as 75% of patients contributing to the pooled estimate come from observational studies i Rated down as the estimate of effect is based on a very small sample size or the estimate is based on a single, small study Table D3: GRADE profile for patients treated with elbasvir + grazoprevir, all-comer analysis, arranged by genotype Quality assessment Risk of Design Inconsistency Indirectness Imprecision studies bias Genotype, -treatment experience population SVR2 Other considerations patients Effect Quality Importance 87

90 studies 0 Design Risk of bias Quality assessment Inconsistency Indirectness Imprecision Other considerations patients Effect Quality Importance 0.97 (0.96, 0.98) 0.97 (0.96, 0.98) Genotype 2, -treatment experience population SVR2 Genotype 3, -treatment experience population SVR2 Genotype 4, -treatment experience population SVR (0.92,.00) 5 Genotype 5, -treatment experience population SVR2 Genotype 6, -treatment experience population SVR d (0.39, 0.85) 88

91 studies Design Risk of bias Quality assessment 4 Mixed genotype group, -treatment experience population SVR2 2 Inconsistency Indirectness Imprecision Other considerations d Genotype, Treatment-naïve population SVR2 6 patients Effect Quality Importance 0.94 (0.88, 0.99) 0.96 (0.95, 0.97) 6 Genotype 2, Treatment-naïve population SVR2 Genotype 3, Treatment-naïve population SVR2 Genotype 4, Treatment-naïve population SVR Genotype 5, Treatment-naïve population 0.96 (0.92,.00) 89

92 Quality assessment Risk of Design studies bias Inconsistency Indirectness Imprecision SVR2 Genotype 6, Treatment-naïve population SVR2 4 Other considerations patients Effect Quality Importance d Mixed genotype group, Treatment-naïve population SVR e - i 53 Genotype, Treatment-experienced population SVR2 - a i 65 Genotype 2, Treatment-experienced population SVR2 Genotype 3, Treatment-experienced population SVR (0.39, 0.85) 0.87 (0.78, 0.96) 0.95 (0.90,.00) 90

93 Quality assessment Risk of Design Inconsistency Indirectness Imprecision studies bias Genotype 4, Treatment-experienced population SVR2 Genotype 5, Treatment-experienced population n SVR2 Genotype 6, Treatment-experienced population SVR2 Mixed genotype group, Treatment-experienced population SVR2 2 Other considerations patients Effect Quality Importance Discontinuations due to adverse events - a a Serious adverse events (0.90,.00) 0.0 (0, 0.0) 0.0 (0, 0.0) 0.02 (0.0, 0.02) 9

94 studies 0 Mortality Design Risk of bias Quality assessment Inconsistency Indirectness Imprecision Other considerations patients Effect Quality Importance 0 (0, ) 0 (0, ) Legend for GRADE: Very low; Low; Moderate; High. a Rated down as 50% of patients contributing to the pooled estimate comes from studies determined to pose a high risk of bias b Rated down as 75% of patients contributing to the pooled estimate comes from studies determined to pose a high risk of bias c Rated down for consistency as differences in the proportion of patients with the outcome of interest in the pooled studies exceeds 25% d Rated down for imprecision as the width of the 95% CI exceeds 0% (±5%) e Rated down for imprecision as the sample size from the single study informing the analysis is less than 50 (N<50) f Rated down for imprecision as the sample size from the single study informing the analysis is less than 25 (N<25); May also be applied when pooling outcomes from multiple studies with very small sample sizes g Rated down as 50% of patients contributing to the pooled estimate come from observational studies h Rated down as 75% of patients contributing to the pooled estimate come from observational studies i Rated down as the estimate of effect is based on a very small sample size or the estimate is based on a single, small study 92

95 Table D4: GRADE profile for patients treated with glecaprevir + pibrentasvir, all-comer analysis, arranged by genotype Quality assessment Risk of Design Inconsistency Indirectness Imprecision studies bias Genotype, -treatment experience population SVR2 3 Other considerations Genotype 2, -treatment experience population SVR Genotype 3, -treatment experience population SVR Genotype 4, -treatment experience population SVR f - i 6 Genotype 5, -treatment experience population SVR f - i 2 patients Effect Quality Importance 0.98 (0.97,.00) 0.98 (0.96,.00) 0.95 (0.93, 0.97) 0.97 (0.89,.00) 0.83 (0.4,.00) 93

96 Quality assessment Risk of Design Inconsistency Indirectness Imprecision studies bias Genotype 6, -treatment experience population SVR2 Other considerations f - i 7 Mixed genotype group, -treatment experience population SVR patients Effect Quality Importance 0.94 (0.77,.00) 0.97 (0.93,.00) 3 Genotype, Treatment-naïve population SVR2 Genotype 2, Treatment-naïve population SVR2 Genotype 3, Treatment-naïve population SVR (0.93, 0.97) 2 Genotype 4, Treatment-naïve population SVR2 94

97 Design studies Risk of bias Genotype 5, Treatment-naïve population SVR2 Genotype 6, Treatment-naïve population SVR2 Quality assessment Mixed genotype group, Treatment-naïve population SVR2 Genotype, Treatment-experienced population SVR2 Genotype 2, Treatment-experienced population SVR2 Inconsistency Indirectness Imprecision Other considerations patients Effect Quality Importance Genotype 3, Treatment-experienced population SVR f - i

98 Quality assessment Risk of Other Design Inconsistency Indirectness Imprecision patients studies bias considerations Effect Quality Importance (0.8,.00) Genotype 4, Treatment-experienced population SVR2 Genotype 5, Treatment-experienced population n SVR2 Genotype 6, Treatment-experienced population SVR2 Mixed genotype group, Treatment-experienced population SVR2 Discontinuations due to adverse events a (0, 0.0) 0 Serious adverse events

99 studies 9 Mortality 3 Quality assessment Risk of Other Design Inconsistency Indirectness Imprecision patients bias considerations Effect Quality Importance (0.0, 0.02) (0, 0.02) 3 Legend for GRADE: Very low; Low; Moderate; High. a Rated down as 50% of patients contributing to the pooled estimate comes from studies determined to pose a high risk of bias b Rated down as 75% of patients contributing to the pooled estimate comes from studies determined to pose a high risk of bias c Rated down for consistency as differences in the proportion of patients with the outcome of interest in the pooled studies exceeds 25% d Rated down for imprecision as the width of the 95% CI exceeds 0% (±5%) e Rated down for imprecision as the sample size from the single study informing the analysis is less than 50 (N<50) f Rated down for imprecision as the sample size from the single study informing the analysis is less than 25 (N<25); May also be applied when pooling outcomes from multiple studies with very small sample sizes g Rated down as 50% of patients contributing to the pooled estimate come from observational studies h Rated down as 75% of patients contributing to the pooled estimate come from observational studies i Rated down as the estimate of effect is based on a very small sample size or the estimate is based on a single, small study 97

100 Table D5: GRADE profile for patients treated with ledipasvir + sofosbuvir, all-comer analysis, arranged by genotype Quality assessment Risk of Design Inconsistency Indirectness Imprecision studies bias Genotype, -treatment experience population SVR Genotype 2, -treatment experience population SVR2 Other considerations patients e - i 53 Genotype 3, -treatment experience population SVR2 3 Genotype 4, -treatment experience population SVR f - i c 0 - d Genotype 5, -treatment experience population SVR e 0 4 Effect Quality Importance 0.98 (0.98, 0.99) 0.97 (0.96, 0.98) 0.86 (0.65,.00) 0.64 (0.45, 0.83) 0.65 (0.5, 0.79) 0.96 (0.93, 0.99) 0.96 (0.93, 0.98) 0.95 (0.89, 98

101 studies Design Risk of bias Quality assessment Genotype 6, -treatment experience population SVR2 2 3 Inconsistency Indirectness Imprecision Other considerations c 0 - d 0 24 Mixed genotype group, -treatment experience population SVR2 7 0 Genotype, Treatment-naïve population SVR2 9 3 patients a Effect Quality Importance.00) 0.97 (0.93,.00) 0.90 (0.8, 0.99) 0.95 (0.92, 0.99) 0.95 (0.92, 0.97) 0.98 (0.97, 0.99) 0.97 (0.95, 0.99) Genotype 2, Treatment-naïve population SVR2 Genotype 3, Treatment-naïve population SVR f - i

102 studies Quality assessment Risk of Other Design Inconsistency Indirectness Imprecision patients bias considerations Effect Quality Importance (0.45, 0.83) Genotype 4, Treatment-naïve population SVR Genotype 5, Treatment-naïve population SVR f - i 2 Genotype 6, Treatment-naïve population SVR Mixed genotype group, Treatment-naïve population SVR Genotype, Treatment-experienced population SVR (0.93,.00) 0.95 (0.86,.00) 0.97 (0.93,.00) 0.96 (0.93, 0.98) 0.97 (0.94, 00

103 studies Design Risk of bias Quality assessment Inconsistency Indirectness Imprecision Other considerations patients Effect Quality Importance 0.99) (0.94, 0.98) Genotype 2, Treatment-experienced population SVR2 Genotype 3, Treatment-experienced population SVR2 Genotype 4, Treatment-experienced population SVR d Genotype 5, Treatment-experienced population n SVR f - i 20 Genotype 6, Treatment-experienced population SVR f - i (0.87,.00) 0.95 (0.85,.00) 0.87 (0.70,.00) 0

104 studies Design Risk of bias Quality assessment Mixed genotype group, Treatment-experienced population SVR2 2 Inconsistency Indirectness Imprecision Other considerations patients 2 Discontinuations due to adverse events 20 - a a Serious adverse events 9 23 Mortality Effect Quality Importance 0.97 (0.95,.00) 0 (0, 0.0) 0 (0, 0.0) 0.02 (0.0, 0.03) 0.02 (0.0, 0.03) 0.0 (0, ) (0, 0) Legend for GRADE: Very low; Low; Moderate; High. a Rated down as 50% of patients contributing to the pooled estimate comes from studies determined to pose a high risk of bias b Rated down as 75% of patients contributing to the pooled estimate comes from studies determined to pose a high risk of bias c Rated down for consistency as differences in the proportion of patients with the outcome of interest in the pooled studies exceeds 25% d Rated down for imprecision as the width of the 95% CI exceeds 0% (±5%) e Rated down for imprecision as the sample size from the single study informing the analysis is less than 50 (N<50) f Rated down for imprecision as the sample size from the single study informing the analysis is less than 25 (N<25); May also be applied when pooling outcomes from multiple studies with very small sample sizes g Rated down as 50% of patients contributing to the pooled estimate come from observational studies h Rated down as 75% of patients contributing to the pooled estimate come from observational studies i Rated down as the estimate of effect is based on a very small sample size or the estimate is based on a single, small study 02

105 03

106 Table D6: GRADE profile for patients treated with paritaprevir/ritonavir + ombitasvir + dasabuvir, all-comer analysis, arranged by genotype Quality assessment Risk of Design Inconsistency Indirectness Imprecision studies bias Genotype, -treatment experience population SVR2 7 9 Other considerations patients Effect Quality Importance 0.99 (0.98,.00) 0.98 (0.97, 0.99) Genotype 2, -treatment experience population SVR2 Genotype 3, -treatment experience population SVR2 Genotype 4, -treatment experience population SVR2 Genotype 5, -treatment experience population SVR2 Genotype 6, -treatment experience population SVR2 04

107 studies Design Risk of bias Quality assessment Inconsistency Indirectness Imprecision Other considerations patients Effect Quality Importance Mixed genotype group, -treatment experience population SVR2 Genotype, Treatment-naïve population SVR (0.96,.00) 0.97 (0.95, 0.99) Genotype 2, Treatment-naïve population SVR2 Genotype 3, Treatment-naïve population SVR2 Genotype 4, Treatment-naïve population SVR2 05

108 Quality assessment Risk of Other Design Inconsistency Indirectness Imprecision patients studies bias considerations Effect Quality Importance Genotype 5, Treatment-naïve population SVR2 Genotype 6, Treatment-naïve population SVR2 Mixed genotype group, Treatment-naïve population SVR2 Genotype, Treatment-experienced population SVR (0.99,.00) 0.99 (0.98,.00) Genotype 2, Treatment-experienced population SVR2 Genotype 3, Treatment-experienced population SVR2 06

109 studies Design Risk of bias Quality assessment Inconsistency Indirectness Imprecision Other considerations patients Effect Quality Importance Genotype 4, Treatment-experienced population SVR2 Genotype 5, Treatment-experienced population n SVR2 Genotype 6, Treatment-experienced population SVR2 Mixed genotype group, Treatment-experienced population SVR2 Discontinuations due to adverse events 6 - a 0 (0, ) 7 - a 0 (0, ) Serious adverse events (0.0, 0.02) 6 07

110 studies Design Risk of bias Quality assessment Inconsistency Indirectness Imprecision Other considerations patients Effect Quality Importance Mortality 0 (0, ) 0 (0, ) Legend for GRADE: Very low; Low; Moderate; High. a Rated down as 50% of patients contributing to the pooled estimate comes from studies determined to pose a high risk of bias b Rated down as 75% of patients contributing to the pooled estimate comes from studies determined to pose a high risk of bias c Rated down for consistency as differences in the proportion of patients with the outcome of interest in the pooled studies exceeds 25% d Rated down for imprecision as the width of the 95% CI exceeds 0% (±5%) e Rated down for imprecision as the sample size from the single study informing the analysis is less than 50 (N<50) f Rated down for imprecision as the sample size from the single study informing the analysis is less than 25 (N<25); May also be applied when pooling outcomes from multiple studies with very small sample sizes g Rated down as 50% of patients contributing to the pooled estimate come from observational studies h Rated down as 75% of patients contributing to the pooled estimate come from observational studies i Rated down as the estimate of effect is based on a very small sample size or the estimate is based on a single, small study 08

111 Table D7: GRADE profile for patients treated with sofosbuvir + velpatasvir, all-comer analysis, arranged by genotype Quality assessment Risk of Design Inconsistency Indirectness Imprecision studies bias Genotype, -treatment experience population SVR2 7 Other considerations patients Genotype 2, -treatment experience population SVR Genotype 3, -treatment experience population SVR c Genotype 4, -treatment experience population SVR Genotype 5, -treatment experience population SVR e - i 35 Effect Quality Importance 0.96 (0.95, 0.98) 0.99 (0.97,.00) 0.89 (0.85, 0.93) 0.99 (0.98,.00) 0.97 (0.92,.00) 09

112 Quality assessment Risk of Design Inconsistency Indirectness Imprecision studies bias Genotype 6, -treatment experience population SVR2 3 Other considerations Mixed genotype group, -treatment experience population SVR2 2 3 Genotype, Treatment-naïve population SVR b Genotype 2, Treatment-naïve population SVR2-2 b e - i 52 Genotype 3, Treatment-naïve population SVR patients Effect Quality Importance 0.99 (0.95,.00) 0.99 (0.97,.00) 0.99 (0.97,.00) 0.95 (0.90,.00) 0.84 (0.73, 0.95) 0.98 (0.96, 0.99) 0

113 Quality assessment Risk of Other Design Inconsistency Indirectness Imprecision patients studies bias considerations Effect Quality Importance Genotype 4, Treatment-naïve population SVR2 Genotype 5, Treatment-naïve population SVR2 Genotype 6, Treatment-naïve population SVR2 Mixed genotype group, Treatment-naïve population SVR2-2 b e - i 45 Genotype, Treatment-experienced population SVR Genotype 2, Treatment-experienced population SVR e - i (0.90,.00) 0.96 (0.92,.00) 0.97 (0.9,

114 studies Design Risk of bias Quality assessment Genotype 3, Treatment-experienced population SVR2 4 Inconsistency Indirectness Imprecision Other considerations d 0 32 patients Effect Quality Importance 4 Genotype 4, Treatment-experienced population SVR2 Genotype 5, Treatment-experienced population n SVR2 Genotype 6, Treatment-experienced population SVR2 Mixed genotype group, Treatment-experienced population SVR2 Discontinuations due to adverse events 0 - a (0,.00) 0.85 (0.78, 0.92) 2

115 Quality assessment Risk of Other Design Inconsistency Indirectness Imprecision patients studies bias considerations Effect Quality Importance 0.0) 0 Serious adverse events (0.02, 0.04) 0 Mortality (0, 0) 0 Legend for GRADE: Very low; Low; Moderate; High. a Rated down as 50% of patients contributing to the pooled estimate comes from studies determined to pose a high risk of bias b Rated down as 75% of patients contributing to the pooled estimate comes from studies determined to pose a high risk of bias c Rated down for consistency as differences in the proportion of patients with the outcome of interest in the pooled studies exceeds 25% d Rated down for imprecision as the width of the 95% CI exceeds 0% (±5%) e Rated down for imprecision as the sample size from the single study informing the analysis is less than 50 (N<50) f Rated down for imprecision as the sample size from the single study informing the analysis is less than 25 (N<25); May also be applied when pooling outcomes from multiple studies with very small sample sizes g Rated down as 50% of patients contributing to the pooled estimate come from observational studies h Rated down as 75% of patients contributing to the pooled estimate come from observational studies i Rated down as the estimate of effect is based on a very small sample size or the estimate is based on a single, small study 3

116 Table D8: GRADE profile for patients treated with sofosbuvir + velpatasvir + voxilaprevir, all-comer analysis, arranged by genotype Quality assessment Risk of Design Inconsistency Indirectness Imprecision studies bias Genotype, -treatment experience population SVR2 4 Other considerations Genotype 2, -treatment experience population SVR Genotype 3, -treatment experience population SVR Genotype 4, -treatment experience population SVR Genotype 5, -treatment experience population SVR d 0 9 patients Effect Quality Importance 0.96 (0.94, 0.99) 0.98 (0.95,.00) 0.98 (0.96, 0.99) 0.94 (0.90, 0.99) 0.94 (0.83,.00) 4

117 Quality assessment Risk of Design Inconsistency Indirectness Imprecision studies bias Genotype 6, -treatment experience population SVR2 2 Other considerations d Mixed genotype group, -treatment experience population SVR f - i 3 patients Effect Quality Importance 2 Genotype, Treatment-naïve population SVR2 Genotype 2, Treatment-naïve population SVR2 Genotype 3, Treatment-naïve population SVR (0.94,.00) 0.8 (0.46,.00) 0.96 (0.92,.00) Genotype 4, Treatment-naïve population SVR2 5

118 studies Design Risk of bias Quality assessment Inconsistency Indirectness Imprecision Other considerations patients Effect Quality Importance Genotype 5, Treatment-naïve population SVR2 Genotype 6, Treatment-naïve population SVR2 Mixed genotype group, Treatment-naïve population SVR2 Genotype, Treatment-experienced population SVR Genotype 2, Treatment-experienced population SVR Genotype 3, Treatment-experienced population 0.97 (0.96, 0.99) 0.98 (0.94,.00) 6

119 studies SVR2 3 Design Risk of bias Quality assessment Inconsistency Indirectness Imprecision Other considerations Genotype 4, Treatment-experienced population SVR i 4 2 Genotype 5, Treatment-experienced population n SVR f - i Genotype 6, Treatment-experienced population SVR f - i 6 Mixed genotype group, Treatment-experienced population SVR f - i patients Effect Quality Importance 0.96 (0.92, 0.99) 0.96 (0.90,.00) 0.75 (0.5,.00) 0.93 (0.74,.00) Discontinuations due to adverse events 5 - a (0, 0) 0.75 (0.5,.00) 7

120 Design studies 5 Serious adverse events 5 5 Risk of bias Quality assessment Inconsistency Indirectness Imprecision Other considerations patients Effect Quality Importance 0.02 (0.02, 0.03) Mortality (0, 0) 5 Legend for GRADE: Very low; Low; Moderate; High. a Rated down as 50% of patients contributing to the pooled estimate comes from studies determined to pose a high risk of bias b Rated down as 75% of patients contributing to the pooled estimate comes from studies determined to pose a high risk of bias c Rated down for consistency as differences in the proportion of patients with the outcome of interest in the pooled studies exceeds 25% d Rated down for imprecision as the width of the 95% CI exceeds 0% (±5%) e Rated down for imprecision as the sample size from the single study informing the analysis is less than 50 (N<50) f Rated down for imprecision as the sample size from the single study informing the analysis is less than 25 (N<25); May also be applied when pooling outcomes from multiple studies with very small sample sizes g Rated down as 50% of patients contributing to the pooled estimate come from observational studies h Rated down as 75% of patients contributing to the pooled estimate come from observational studies i Rated down as the estimate of effect is based on a very small sample size or the estimate is based on a single, small study 8

121 Table D9: GRADE profile for patients treated with daclatasvir + asunaprevir, patients with cirrhosis analysis, arranged by genotype Quality assessment Risk of Design Inconsistency Indirectness Imprecision studies bias Genotype, -treatment experience population SVR2 5 7 Other considerations patients Effect Quality Importance 0.89 (0.85, 0.93) 0.89 (0.86, 0.9) Genotype 2, -treatment experience population SVR2 Genotype 3, -treatment experience population SVR2 Genotype 4, -treatment experience population SVR2 Genotype 5, -treatment experience population SVR2 Genotype 6, -treatment experience population SVR2 9

122 studies Design Risk of bias Quality assessment Inconsistency Indirectness Imprecision Other considerations patients Effect Quality Importance Mixed genotype group, -treatment experience population SVR2 Genotype, Treatment-naïve population SVR2 3-2 b f -2 h d Genotype 2, Treatment-naïve population SVR2 Genotype 3, Treatment-naïve population SVR2 Genotype 4, Treatment-naïve population SVR (0.64,.00) 0.9 (0.84, 0.98) 20

123 Quality assessment Risk of Other Design Inconsistency Indirectness Imprecision patients studies bias considerations Effect Quality Importance Genotype 5, Treatment-naïve population SVR2 Genotype 6, Treatment-naïve population SVR2 Mixed genotype group, Treatment-naïve population SVR2 Genotype, Treatment-experienced population SVR (0.75, 0.9) Genotype 2, Treatment-experienced population SVR2 Genotype 3, Treatment-experienced population SVR2 2

124 studies Design Risk of bias Genotype 4, Treatment-experienced population SVR2 Quality assessment Inconsistency Indirectness Imprecision Other considerations patients Effect Quality Importance Genotype 5, Treatment-experienced population n SVR2 Genotype 6, Treatment-experienced population SVR2 Mixed genotype group, Treatment-experienced population SVR2 Legend for GRADE: Very low; Low; Moderate; High. a Rated down as 50% of patients contributing to the pooled estimate comes from studies determined to pose a high risk of bias b Rated down as 75% of patients contributing to the pooled estimate comes from studies determined to pose a high risk of bias c Rated down for consistency as differences in the proportion of patients with the outcome of interest in the pooled studies exceeds 25% d Rated down for imprecision as the width of the 95% CI exceeds 0% (±5%) e Rated down for imprecision as the sample size from the single study informing the analysis is less than 50 (N<50) f Rated down for imprecision as the sample size from the single study informing the analysis is less than 25 (N<25); May also be applied when pooling outcomes from multiple studies with very small sample sizes g Rated down as 50% of patients contributing to the pooled estimate come from observational studies h Rated down as 75% of patients contributing to the pooled estimate come from observational studies i Rated down as the estimate of effect is based on a very small sample size or the estimate is based on a single, small study 22

125 23

126 Table D0: GRADE profile for patients treated with daclatasvir + sofosbuvir, patients with cirrhosis analysis, arranged by genotype Quality assessment Risk of Other Design Inconsistency Indirectness Imprecision patients studies bias considerations Effect Quality Importance Genotype, -treatment experience population SVR h 467 (0.88, 0.99) Genotype 2, -treatment experience population SVR2 2 Genotype 3, -treatment experience population SVR f -2 h e - i c 0 - d (0.85,.00) 0.63 (0.46, 0.80) 0.79 (0.68, 0.89) Genotype 4, -treatment experience population SVR2 Genotype 5, -treatment experience population SVR f -2 h 0.75 (0.5,.00) 24

127 Quality assessment Risk of Other Design Inconsistency Indirectness Imprecision patients studies bias considerations Effect Quality Importance Genotype 6, -treatment experience population SVR h 63 (0.87, 0.99) Mixed genotype group, -treatment experience population SVR2 2-2 b - c 0 - d -2 h 244 Genotype, Treatment-naïve population SVR2 Genotype 2, Treatment-naïve population SVR2 Genotype 3, Treatment-naïve population SVR2 2 Genotype 4, Treatment-naïve population SVR f - i f - i (0.62,.00) 0.58 (0.36, 0.80) 0.65 (0.45, 0.85) 25

128 studies Design Risk of bias Quality assessment Inconsistency Indirectness Imprecision Other considerations patients Effect Quality Importance Genotype 5, Treatment-naïve population SVR2 Genotype 6, Treatment-naïve population SVR2 Mixed genotype group, Treatment-naïve population SVR2 Genotype, Treatment-experienced population SVR h 27 Genotype 2, Treatment-experienced population SVR2 Genotype 3, Treatment-experienced population 0.98 (0.93,.00) 26

129 studies SVR2 2 Design Risk of bias Quality assessment Inconsistency Indirectness Imprecision Other considerations f - i d -2 f 24 patients Effect Quality Importance 0.69 (0.44, 0.94) 0.82 (0.6,.00) Genotype 4, Treatment-experienced population SVR2 Genotype 5, Treatment-experienced population n SVR2 Genotype 6, Treatment-experienced population SVR2 Mixed genotype group, Treatment-experienced population SVR2 Legend for GRADE: Very low; Low; Moderate; High. a Rated down as 50% of patients contributing to the pooled estimate comes from studies determined to pose a high risk of bias b Rated down as 75% of patients contributing to the pooled estimate comes from studies determined to pose a high risk of bias c Rated down for consistency as differences in the proportion of patients with the outcome of interest in the pooled studies exceeds 25% d Rated down for imprecision as the width of the 95% CI exceeds 0% (±5%) 27

130 e Rated down for imprecision as the sample size from the single study informing the analysis is less than 50 (N<50) f Rated down for imprecision as the sample size from the single study informing the analysis is less than 25 (N<25); May also be applied when pooling outcomes from multiple studies with very small sample sizes g Rated down as 50% of patients contributing to the pooled estimate come from observational studies h Rated down as 75% of patients contributing to the pooled estimate come from observational studies i Rated down as the estimate of effect is based on a very small sample size or the estimate is based on a single, small study 28

131 Table D: GRADE profile for patients treated with elbasvir + grazoprevir, patients with cirrhosis analysis, arranged by genotype Quality assessment Risk of Design Inconsistency Indirectness Imprecision studies bias Genotype, -treatment experience population SVR2 2 Other considerations - a patients Effect Quality Importance 2 Genotype 2, -treatment experience population SVR2 Genotype 3, -treatment experience population SVR2 Genotype 4, -treatment experience population SVR2 Genotype 5, -treatment experience population SVR2 Genotype 6, -treatment experience population SVR (0.92,.00) 29

132 studies Design Risk of bias Quality assessment Mixed genotype group, -treatment experience population SVR2 4 Inconsistency Indirectness Imprecision Other considerations patients Effect Quality Importance Genotype, Treatment-naïve population SVR2-2 b (0.95,.00) 0.95 (0.90,.00) Genotype 2, Treatment-naïve population SVR2 Genotype 3, Treatment-naïve population SVR2 Genotype 4, Treatment-naïve population SVR2 Genotype 5, Treatment-naïve population 30

133 Quality assessment Risk of Other Design Inconsistency Indirectness Imprecision patients studies bias considerations Effect Quality Importance SVR2 Genotype 6, Treatment-naïve population SVR2 Mixed genotype group, Treatment-naïve population SVR (0.95,.00) 2 Genotype, Treatment-experienced population SVR2 Genotype 2, Treatment-experienced population SVR2 Genotype 3, Treatment-experienced population SVR2 3

134 Quality assessment Risk of Other Design Inconsistency Indirectness Imprecision patients studies bias considerations Effect Quality Importance Genotype 4, Treatment-experienced population SVR2 Genotype 5, Treatment-experienced population n SVR2 Genotype 6, Treatment-experienced population SVR2 Mixed genotype group, Treatment-experienced population SVR (0.86, 0.98) Legend for GRADE: Very low; Low; Moderate; High. a Rated down as 50% of patients contributing to the pooled estimate comes from studies determined to pose a high risk of bias b Rated down as 75% of patients contributing to the pooled estimate comes from studies determined to pose a high risk of bias c Rated down for consistency as differences in the proportion of patients with the outcome of interest in the pooled studies exceeds 25% d Rated down for imprecision as the width of the 95% CI exceeds 0% (±5%) e Rated down for imprecision as the sample size from the single study informing the analysis is less than 50 (N<50) f Rated down for imprecision as the sample size from the single study informing the analysis is less than 25 (N<25); May also be applied when pooling outcomes from multiple studies with very small sample sizes g Rated down as 50% of patients contributing to the pooled estimate come from observational studies h Rated down as 75% of patients contributing to the pooled estimate come from observational studies i Rated down as the estimate of effect is based on a very small sample size or the estimate is based on a single, small study 32

135 33

136 Table D2: GRADE profile for patients treated with glecaprevir + pibrentasvir, patients with cirrhosis analysis, arranged by genotype Quality assessment Risk of Design Inconsistency Indirectness Imprecision studies bias Genotype, -treatment experience population SVR2 Other considerations Genotype 2, -treatment experience population SVR i 49 patients Effect Quality Importance 0.99 (0.97,.00) 0.98 (0.95,.00) 2 Genotype 3, -treatment experience population SVR2 Genotype 4, -treatment experience population SVR f - i 6 Genotype 5, -treatment experience population SVR f - i 2 Genotype 6, -treatment experience population 0.97 (0.89,.00) 0.83 (0.4,.00) 34

137 studies SVR2 Design Risk of bias Quality assessment Inconsistency Indirectness Imprecision Other considerations f - i 7 Mixed genotype group, -treatment experience population SVR f - i 5 patients Effect Quality Importance Genotype, Treatment-naïve population SVR2 Genotype 2, Treatment-naïve population SVR2 Genotype 3, Treatment-naïve population SVR2 Genotype 4, Treatment-naïve population SVR (0.77,.00) 0.93 (0.8,.00) 35

138 studies Design Risk of bias Genotype 5, Treatment-naïve population SVR2 Quality assessment Inconsistency Indirectness Imprecision Other considerations patients Effect Quality Importance Genotype 6, Treatment-naïve population SVR2 Mixed genotype group, Treatment-naïve population SVR2 Genotype, Treatment-experienced population SVR2 Genotype 2, Treatment-experienced population SVR2 Genotype 3, Treatment-experienced population SVR2 36

139 studies Design Risk of bias Genotype 4, Treatment-experienced population SVR2 Quality assessment Inconsistency Indirectness Imprecision Other considerations patients Effect Quality Importance Genotype 5, Treatment-experienced population n SVR2 Genotype 6, Treatment-experienced population SVR2 Mixed genotype group, Treatment-experienced population SVR2 Legend for GRADE: Very low; Low; Moderate; High. a Rated down as 50% of patients contributing to the pooled estimate comes from studies determined to pose a high risk of bias b Rated down as 75% of patients contributing to the pooled estimate comes from studies determined to pose a high risk of bias c Rated down for consistency as differences in the proportion of patients with the outcome of interest in the pooled studies exceeds 25% d Rated down for imprecision as the width of the 95% CI exceeds 0% (±5%) e Rated down for imprecision as the sample size from the single study informing the analysis is less than 50 (N<50) f Rated down for imprecision as the sample size from the single study informing the analysis is less than 25 (N<25); May also be applied when pooling outcomes from multiple studies with very small sample sizes g Rated down as 50% of patients contributing to the pooled estimate come from observational studies h Rated down as 75% of patients contributing to the pooled estimate come from observational studies i Rated down as the estimate of effect is based on a very small sample size or the estimate is based on a single, small study 37

140 38

141 Table D3: GRADE profile for patients treated with ledipasvir + sofosbuvir, patients with cirrhosis analysis, arranged by genotype Quality assessment Risk of Design Inconsistency Indirectness Imprecision studies bias Genotype, -treatment experience population SVR2 7 Other considerations patients Effect Quality Importance 0.97 (0.95, 0.98) 0.96 (0.95, 0.98) Genotype 2, -treatment experience population SVR2 Genotype 3, -treatment experience population SVR2 2 Genotype 4, -treatment experience population SVR2 - a - c 0 - d -2 h f - i 26 Genotype 5, -treatment experience population SVR2 Genotype 6, -treatment experience population 0.58 (0.33, 0.83) 0.94 (0.84,.00) 39

142 studies SVR2 2 Design Risk of bias Quality assessment Inconsistency Indirectness Imprecision Other considerations e - i c 0 - d 0 44 Mixed genotype group, -treatment experience population SVR2 2 4 Genotype, Treatment-naïve population SVR d patients Effect Quality Importance 0.97 (0.9,.00) 0.75 (0.38,.00) 0.97 (0.92,.00) 0.94 (0.88, 0.99) 0.97 (0.93,.00) 2 Genotype 2, Treatment-naïve population SVR2 Genotype 3, Treatment-naïve population SVR2 Genotype 4, Treatment-naïve population SVR2 40

143 studies Design Risk of bias Quality assessment Inconsistency Indirectness Imprecision Other considerations f - i 7 patients Effect Quality Importance Genotype 5, Treatment-naïve population SVR2 Genotype 6, Treatment-naïve population SVR f - i 2 Mixed genotype group, Treatment-naïve population SVR2 2 Genotype, Treatment-experienced population SVR2 3 4 Genotype 2, Treatment-experienced population SVR f - i d - i (0.60,.00) 0.98 (0.92,.00) 0.85 (0.69,.00) 0.85 (0.73, 0.97) 0.97 (0.95,.00) 0.98 (0.95,.00) 4

144 studies Design Risk of bias Quality assessment Inconsistency Indirectness Imprecision Other considerations patients Effect Quality Importance Genotype 3, Treatment-experienced population SVR2 Genotype 4, Treatment-experienced population SVR2 Genotype 5, Treatment-experienced population n SVR2 Genotype 6, Treatment-experienced population SVR f - i 6 Mixed genotype group, Treatment-experienced population SVR e - i d (0.54,.00) 0.98 (0.94,.00) 0.95 (0.84, 42

145 studies Design Risk of bias Quality assessment Inconsistency Indirectness Imprecision Other considerations patients Effect Quality Importance.00) Legend for GRADE: Very low; Low; Moderate; High. a Rated down as 50% of patients contributing to the pooled estimate comes from studies determined to pose a high risk of bias b Rated down as 75% of patients contributing to the pooled estimate comes from studies determined to pose a high risk of bias c Rated down for consistency as differences in the proportion of patients with the outcome of interest in the pooled studies exceeds 25% d Rated down for imprecision as the width of the 95% CI exceeds 0% (±5%) e Rated down for imprecision as the sample size from the single study informing the analysis is less than 50 (N<50) f Rated down for imprecision as the sample size from the single study informing the analysis is less than 25 (N<25); May also be applied when pooling outcomes from multiple studies with very small sample sizes g Rated down as 50% of patients contributing to the pooled estimate come from observational studies h Rated down as 75% of patients contributing to the pooled estimate come from observational studies i Rated down as the estimate of effect is based on a very small sample size or the estimate is based on a single, small study 43

146 Table D4: GRADE profile for patients treated with paritaprevir/ritonavir + ombitasvir + dasabuvir, patients with cirrhosis analysis, arranged by genotype Quality assessment Risk of Design Inconsistency Indirectness Imprecision studies bias Genotype, -treatment experience population SVR2 3 Other considerations patients Effect Quality Importance 0.99 (0.97,.00) 0.99 (0.97,.00) Genotype 2, -treatment experience population SVR2 Genotype 3, -treatment experience population SVR2 Genotype 4, -treatment experience population SVR2 Genotype 5, -treatment experience population SVR2 Genotype 6, -treatment experience population SVR2 44

147 studies Design Risk of bias Quality assessment Inconsistency Indirectness Imprecision Other considerations patients Effect Quality Importance Mixed genotype group, -treatment experience population SVR2 Genotype, Treatment-naïve population SVR2 Genotype 2, Treatment-naïve population SVR2 Genotype 3, Treatment-naïve population SVR2 Genotype 4, Treatment-naïve population SVR2 Genotype 5, Treatment-naïve population SVR2 45

148 studies Design Risk of bias Quality assessment Inconsistency Indirectness Imprecision Other considerations patients Effect Quality Importance Genotype 6, Treatment-naïve population SVR2 Mixed genotype group, Treatment-naïve population SVR2 Genotype, Treatment-experienced population SVR2 Genotype 2, Treatment-experienced population SVR2 Genotype 3, Treatment-experienced population SVR2 Genotype 4, Treatment-experienced population SVR2 46

149 studies Design Risk of bias Quality assessment Inconsistency Indirectness Imprecision Other considerations patients Effect Quality Importance Genotype 5, Treatment-experienced population n SVR2 Genotype 6, Treatment-experienced population SVR2 Mixed genotype group, Treatment-experienced population SVR2 Legend for GRADE: Very low; Low; Moderate; High. a Rated down as 50% of patients contributing to the pooled estimate comes from studies determined to pose a high risk of bias b Rated down as 75% of patients contributing to the pooled estimate comes from studies determined to pose a high risk of bias c Rated down for consistency as differences in the proportion of patients with the outcome of interest in the pooled studies exceeds 25% d Rated down for imprecision as the width of the 95% CI exceeds 0% (±5%) e Rated down for imprecision as the sample size from the single study informing the analysis is less than 50 (N<50) f Rated down for imprecision as the sample size from the single study informing the analysis is less than 25 (N<25); May also be applied when pooling outcomes from multiple studies with very small sample sizes g Rated down as 50% of patients contributing to the pooled estimate come from observational studies h Rated down as 75% of patients contributing to the pooled estimate come from observational studies i Rated down as the estimate of effect is based on a very small sample size or the estimate is based on a single, small study 47

150 Table D5: GRADE profile for patients treated with sofosbuvir + velpatasvir, patients with cirrhosis analysis, arranged by genotype Quality assessment Risk of Design Inconsistency Indirectness Imprecision studies bias Genotype, -treatment experience population SVR2 Other considerations Genotype 2, -treatment experience population SVR f - i 8 Genotype 3, -treatment experience population SVR c 0 - d Genotype 4, -treatment experience population SVR f - i 6 patients Effect Quality Importance 0.90 (0.85, 0.95) 0.86 (0.64,.00) 0.86 (0.77, 0.96) 0.88 (0.66,.00) Genotype 5, -treatment experience population SVR2 Genotype 6, -treatment experience population 48

151 studies SVR2 Design Risk of bias Quality assessment Inconsistency Indirectness Imprecision Other considerations f - i Mixed genotype group, -treatment experience population SVR patients Effect Quality Importance 0.75 (0.5,.00) 0.97 (0.94,.00) 4 Genotype, Treatment-naïve population SVR2 Genotype 2, Treatment-naïve population SVR2 Genotype 3, Treatment-naïve population SVR (0.92,.00) 2 Genotype 4, Treatment-naïve population SVR2 49

152 studies Design Risk of bias Quality assessment Inconsistency Indirectness Imprecision Other considerations patients Effect Quality Importance Genotype 5, Treatment-naïve population SVR2 Genotype 6, Treatment-naïve population SVR2 Mixed genotype group, Treatment-naïve population SVR2 Genotype, Treatment-experienced population SVR2 Genotype 2, Treatment-experienced population SVR2 Genotype 3, Treatment-experienced population SVR d (0.83, 50

153 studies Design Risk of bias Quality assessment Inconsistency Indirectness Imprecision Other considerations patients Effect Quality Importance 0.97) 2 Genotype 4, Treatment-experienced population SVR2 Genotype 5, Treatment-experienced population n SVR2 Genotype 6, Treatment-experienced population SVR2 Mixed genotype group, Treatment-experienced population SVR i 69 Legend for GRADE: Very low; Low; Moderate; High. a Rated down as 50% of patients contributing to the pooled estimate comes from studies determined to pose a high risk of bias b Rated down as 75% of patients contributing to the pooled estimate comes from studies determined to pose a high risk of bias c Rated down for consistency as differences in the proportion of patients with the outcome of interest in the pooled studies exceeds 25% d Rated down for imprecision as the width of the 95% CI exceeds 0% (±5%) e Rated down for imprecision as the sample size from the single study informing the analysis is less than 50 (N<50) f Rated down for imprecision as the sample size from the single study informing the analysis is less than 25 (N<25); May also be applied when pooling outcomes from multiple studies with very small sample sizes 0.86 (0.77, 0.94) 5

154 g Rated down as 50% of patients contributing to the pooled estimate come from observational studies h Rated down as 75% of patients contributing to the pooled estimate come from observational studies i Rated down as the estimate of effect is based on a very small sample size or the estimate is based on a single, small study 52

155 Table D6: GRADE profile for patients treated with sofosbuvir + velpatasvir + voxilaprevir, patients with cirrhosis analysis, arranged by genotype Quality assessment Risk of Design Inconsistency Indirectness Imprecision studies bias Genotype, -treatment experience population SVR2 Other considerations f - i patients Effect Quality Importance Genotype 2, -treatment experience population SVR2 Genotype 3, -treatment experience population SVR (0.85,.00) 0.96 (0.93,.00) Genotype 4, -treatment experience population SVR2 Genotype 5, -treatment experience population SVR2 Genotype 6, -treatment experience population SVR2 53

156 studies Design Risk of bias Quality assessment Mixed genotype group, -treatment experience population SVR2 3 Inconsistency Indirectness Imprecision Other considerations patients Effect Quality Importance (0.9, 0.98) 3 Genotype, Treatment-naïve population SVR2 Genotype 2, Treatment-naïve population SVR2 Genotype 3, Treatment-naïve population SVR i 75 Genotype 4, Treatment-naïve population SVR (0.92,.00) 54

157 Quality assessment Risk of Other Design Inconsistency Indirectness Imprecision patients studies bias considerations Effect Quality Importance Genotype 5, Treatment-naïve population SVR2 Genotype 6, Treatment-naïve population SVR2 Mixed genotype group, Treatment-naïve population SVR2 Genotype, Treatment-experienced population SVR f - i Genotype 2, Treatment-experienced population SVR2 Genotype 3, Treatment-experienced population SVR e - i (0.85,.00) 0.97 (0.92,.00) 55

158 studies Design Risk of bias Quality assessment Inconsistency Indirectness Imprecision Other considerations patients Effect Quality Importance Genotype 4, Treatment-experienced population SVR2 Genotype 5, Treatment-experienced population n SVR2 Genotype 6, Treatment-experienced population SVR2 Mixed genotype group, Treatment-experienced population SVR (0.92,.00) 2 Legend for GRADE: Very low; Low; Moderate; High. a Rated down as 50% of patients contributing to the pooled estimate comes from studies determined to pose a high risk of bias b Rated down as 75% of patients contributing to the pooled estimate comes from studies determined to pose a high risk of bias c Rated down for consistency as differences in the proportion of patients with the outcome of interest in the pooled studies exceeds 25% d Rated down for imprecision as the width of the 95% CI exceeds 0% (±5%) e Rated down for imprecision as the sample size from the single study informing the analysis is less than 50 (N<50) f Rated down for imprecision as the sample size from the single study informing the analysis is less than 25 (N<25); May also be applied when pooling outcomes from multiple studies with very small sample sizes g Rated down as 50% of patients contributing to the pooled estimate come from observational studies 56

159 h Rated down as 75% of patients contributing to the pooled estimate come from observational studies i Rated down as the estimate of effect is based on a very small sample size or the estimate is based on a single, small study 57

160 Table D7: GRADE profile for patients treated with daclatasvir + sofosbuvir + ribavirin, patients with cirrhosis analysis, arranged by genotype Quality assessment Risk of Other Design Inconsistency Indirectness Imprecision patients studies bias considerations Effect Quality Importance Genotype 2, -treatment experience population SVR2 Genotype 3, -treatment experience population SVR e - i c h (0.76, 0.97) Genotype 2, Treatment-naïve population SVR2 Genotype 3, Treatment-naïve population SVR f - i c h (0.86, 0.97) 0.83 (0.54,.00) Genotype 2, Treatment-experienced population SVR (0.95,.00) 58

161 Quality assessment Risk of Design Inconsistency Indirectness Imprecision studies bias Genotype 3, Treatment-experienced population SVR2 Other considerations e - i 30 Discontinuations due to adverse events Genotypes 2 and 3 only 2 Serious adverse events Genotypes 2 and 3 only Mortality Genotypes 2 and 3 only 2 - a a patients Effect Quality Importance 0.87 (0.75, 0.99) 0.03 (0, 0.07) 0.02 (0, 0.04) (0, 0.09) 0.04 (0, 0.07) Legend for GRADE: Very low; Low; Moderate; High. a Rated down as 50% of patients contributing to the pooled estimate comes from studies determined to pose a high risk of bias b Rated down as 75% of patients contributing to the pooled estimate comes from studies determined to pose a high risk of bias c Rated down for consistency as differences in the proportion of patients with the outcome of interest in the pooled studies exceeds 25% d Rated down for imprecision as the width of the 95% CI exceeds 0% (±5%) e Rated down for imprecision as the sample size from the single study informing the analysis is less than 50 (N<50) f Rated down for imprecision as the sample size from the single study informing the analysis is less than 25 (N<25); May also be applied when pooling outcomes from multiple studies with very small sample sizes 59

162 g Rated down as 50% of patients contributing to the pooled estimate come from observational studies h Rated down as 75% of patients contributing to the pooled estimate come from observational studies i Rated down as the estimate of effect is based on a very small sample size or the estimate is based on a single, small study 60

163 Table D8: GRADE profile for patients treated with sofosbuvir + ribavirin, patients with cirrhosis analysis, arranged by genotype Quality assessment Risk of Design Inconsistency Indirectness Imprecision studies bias Genotype 2, -treatment experience population SVR2 5 0 Genotype 3, -treatment experience population SVR2 7 2 Other considerations 0 - c 0 - d c h c 0 - d c 0 - d Genotype 2 or 3 (mixed), -treatment experience population SVR e - i 33 Genotype 2, Treatment-naïve population SVR d - i c 0 - d 0 32 Genotype 3, Treatment-naïve population SVR c 0 - d 0 05 patients Effect Quality Importance 0.79 (0.72, 0.87) 0.86 (0.8, 0.90) 0.69 (0.58, 0.80) 0.67 (0.58, 0.76) 0.6 (0.44, 0.77) 0.77 (0.65, 0.88) 0.85 (0.73, 0.97) 0.79 (0.69, 6

164 studies 6 Design Risk of bias Quality assessment Inconsistency Indirectness Imprecision Other considerations 0 - c 0 - d 0 98 Genotype 2 or 3 (mixed), -treatment experience population SVR e - i 33 Genotype 2, Treatment-experienced population SVR2 2 4 Genotype 3, Treatment-experienced population SVR2 4 6 Discontinuations due to adverse events Genotypes 2 and 3 only 3 4 Serious adverse events 0 - c 0 - d d c 0 - d c 0 - d a a patients Effect Quality Importance 0.89) 0.74 (0.64, 0.84) 0.6 (0.44, 0.77) 0.79 (0.67, 0.9) 0.82 (0.76, 0.88) 0.57 (0.38, 0.75) 0.55 (0.4, 0.70) 0.02 (0.0, 0.03) 0.02 (0.0, 0.03) 62

165 Design studies Genotypes 2 and 3 only 3 3 Mortality Genotypes 2 and 3 only 3 6 Risk of bias Quality assessment Inconsistency Indirectness Imprecision Other considerations patients Effect Quality Importance 0.05 (0.03, 0.07) 0 (0, 0.0) 0.0 (0, 0.0) Legend for GRADE: Very low; Low; Moderate; High. a Rated down as 50% of patients contributing to the pooled estimate comes from studies determined to pose a high risk of bias b Rated down as 75% of patients contributing to the pooled estimate comes from studies determined to pose a high risk of bias c Rated down for consistency as differences in the proportion of patients with the outcome of interest in the pooled studies exceeds 25% d Rated down for imprecision as the width of the 95% CI exceeds 0% (±5%) e Rated down for imprecision as the sample size from the single study informing the analysis is less than 50 (N<50) f Rated down for imprecision as the sample size from the single study informing the analysis is less than 25 (N<25); May also be applied when pooling outcomes from multiple studies with very small sample sizes g Rated down as 50% of patients contributing to the pooled estimate come from observational studies h Rated down as 75% of patients contributing to the pooled estimate come from observational studies i Rated down as the estimate of effect is based on a very small sample size or the estimate is based on a single, small study 63

166 Table D9: GRADE profile for patients treated with daclatasvir + asunaprevir, patients with HIV co-infection analysis, arranged by genotype No available 64

167 Table D20: GRADE profile for patients treated with daclatasvir + sofosbuvir, patients with HIV co-infection analysis, arranged by genotype Quality assessment Risk of Other Design Inconsistency Indirectness Imprecision patients studies bias considerations Effect Quality Importance Genotype, -treatment experience population SVR2 Genotype 2, -treatment experience population SVR2 Genotype 3, -treatment experience population SVR2 Genotype 4, -treatment experience population SVR2 Genotype 5, -treatment experience population SVR2 Genotype 6, -treatment experience population SVR2 65

168 studies Design Risk of bias Quality assessment Inconsistency Indirectness Imprecision Other considerations patients Effect Quality Importance Mixed genotype group, -treatment experience population SVR2 2-2 b h 347 Legend for GRADE: Very low; Low; Moderate; High. a Rated down as 50% of patients contributing to the pooled estimate comes from studies determined to pose a high risk of bias b Rated down as 75% of patients contributing to the pooled estimate comes from studies determined to pose a high risk of bias c Rated down for consistency as differences in the proportion of patients with the outcome of interest in the pooled studies exceeds 25% d Rated down for imprecision as the width of the 95% CI exceeds 0% (±5%) e Rated down for imprecision as the sample size from the single study informing the analysis is less than 50 (N<50) f Rated down for imprecision as the sample size from the single study informing the analysis is less than 25 (N<25); May also be applied when 0.87 (0.69,.00) pooling outcomes from multiple studies with very small sample sizes g Rated down as 50% of patients contributing to the pooled estimate come from observational studies h Rated down as 75% of patients contributing to the pooled estimate come from observational studies i Rated down as the estimate of effect is based on a very small sample size or the estimate is based on a single, small study 66

169 Table D2: GRADE profile for patients treated with elbasvir + grazoprevir, patients with HIV co-infection analysis, arranged by genotype Quality assessment Risk of Design Inconsistency Indirectness Imprecision studies bias Genotype, -treatment experience population SVR2 2 Other considerations d patients Effect Quality Importance 2 Genotype 2, -treatment experience population SVR2 Genotype 3, -treatment experience population SVR2 Genotype 4, -treatment experience population SVR e - i 28 Genotype 5, -treatment experience population SVR2 Genotype 6, -treatment experience population SVR (0.85, 0.99) 0.96 (0.90,.00) 67

170 studies Design Risk of bias Quality assessment Inconsistency Indirectness Imprecision Other considerations f - i 2 Mixed genotype group, -treatment experience population SVR f - i 6 patients Effect Quality Importance Legend for GRADE: Very low; Low; Moderate; High. a Rated down as 50% of patients contributing to the pooled estimate comes from studies determined to pose a high risk of bias b Rated down as 75% of patients contributing to the pooled estimate comes from studies determined to pose a high risk of bias c Rated down for consistency as differences in the proportion of patients with the outcome of interest in the pooled studies exceeds 25% d Rated down for imprecision as the width of the 95% CI exceeds 0% (±5%) e Rated down for imprecision as the sample size from the single study informing the analysis is less than 50 (N<50) f Rated down for imprecision as the sample size from the single study informing the analysis is less than 25 (N<25); May also be applied when pooling outcomes from multiple studies with very small sample sizes g Rated down as 50% of patients contributing to the pooled estimate come from observational studies h Rated down as 75% of patients contributing to the pooled estimate come from observational studies i Rated down as the estimate of effect is based on a very small sample size or the estimate is based on a single, small study 0.83 (0.4,.00) 0.83 (0.54,.00) 68

171 Table D22: GRADE profile for patients treated with glecaprevir + pibrentasvir, patients with HIV co-infection analysis, arranged by genotype Quality assessment Risk of Other Design Inconsistency Indirectness Imprecision patients studies bias considerations Effect Quality Importance Genotype, -treatment experience population SVR2 Genotype 2, -treatment experience population SVR2 Genotype 3, -treatment experience population SVR2 Genotype 4, -treatment experience population SVR2 Genotype 5, -treatment experience population SVR2 Genotype 6, -treatment experience population SVR2 69

172 studies Design Risk of bias Quality assessment Inconsistency Indirectness Imprecision Mixed genotype group, -treatment experience population SVR2 Other considerations patients Effect Quality Importance (0.99,.00) Legend for GRADE: Very low; Low; Moderate; High. a Rated down as 50% of patients contributing to the pooled estimate comes from studies determined to pose a high risk of bias b Rated down as 75% of patients contributing to the pooled estimate comes from studies determined to pose a high risk of bias c Rated down for consistency as differences in the proportion of patients with the outcome of interest in the pooled studies exceeds 25% d Rated down for imprecision as the width of the 95% CI exceeds 0% (±5%) e Rated down for imprecision as the sample size from the single study informing the analysis is less than 50 (N<50) f Rated down for imprecision as the sample size from the single study informing the analysis is less than 25 (N<25); May also be applied when pooling outcomes from multiple studies with very small sample sizes g Rated down as 50% of patients contributing to the pooled estimate come from observational studies h Rated down as 75% of patients contributing to the pooled estimate come from observational studies i Rated down as the estimate of effect is based on a very small sample size or the estimate is based on a single, small study 70

173 Table D23: GRADE profile for patients treated with ledipasvir + sofosbuvir, patients with HIV co-infection analysis, arranged by genotype Quality assessment Risk of Design Inconsistency Indirectness Imprecision studies bias Genotype, -treatment experience population SVR2 3 5 Other considerations a patients Effect Quality Importance 0.98 (0.95,.00) 0.96 (0.93, 0.98) Genotype 2, -treatment experience population SVR2 Genotype 3, -treatment experience population SVR2 Genotype 4, -treatment experience population SVR f - i Genotype 5, -treatment experience population SVR2 Genotype 6, -treatment experience population SVR (0.5,.00) 7

174 studies Design Risk of bias Quality assessment Mixed genotype group, -treatment experience population SVR2 3 Inconsistency Indirectness Imprecision Other considerations patients Effect Quality Importance (0.94, 0.98) 0.96 (0.94, 0.98) Legend for GRADE: Very low; Low; Moderate; High. a Rated down as 50% of patients contributing to the pooled estimate comes from studies determined to pose a high risk of bias b Rated down as 75% of patients contributing to the pooled estimate comes from studies determined to pose a high risk of bias c Rated down for consistency as differences in the proportion of patients with the outcome of interest in the pooled studies exceeds 25% d Rated down for imprecision as the width of the 95% CI exceeds 0% (±5%) e Rated down for imprecision as the sample size from the single study informing the analysis is less than 50 (N<50) f Rated down for imprecision as the sample size from the single study informing the analysis is less than 25 (N<25); May also be applied when pooling outcomes from multiple studies with very small sample sizes g Rated down as 50% of patients contributing to the pooled estimate come from observational studies h Rated down as 75% of patients contributing to the pooled estimate come from observational studies i Rated down as the estimate of effect is based on a very small sample size or the estimate is based on a single, small study 72

175 Table D24: GRADE profile for patients treated with paritaprevir/ritonavir + ombitasvir + dasabuvir, patients with HIV co-infection analysis, arranged by genotype Quality assessment Risk of Other Design Inconsistency Indirectness Imprecision patients studies bias considerations Effect Quality Importance Genotype, -treatment experience population SVR b f -2 h 7 (0.60,.00) Genotype 2, -treatment experience population SVR2 Genotype 3, -treatment experience population SVR2 Genotype 4, -treatment experience population SVR2 Genotype 5, -treatment experience population SVR2 Genotype 6, -treatment experience population SVR2 73

176 studies Design Risk of bias Quality assessment Inconsistency Indirectness Imprecision Other considerations patients Effect Quality Importance Mixed genotype group, -treatment experience population SVR2 Legend for GRADE: Very low; Low; Moderate; High. a Rated down as 50% of patients contributing to the pooled estimate comes from studies determined to pose a high risk of bias b Rated down as 75% of patients contributing to the pooled estimate comes from studies determined to pose a high risk of bias c Rated down for consistency as differences in the proportion of patients with the outcome of interest in the pooled studies exceeds 25% d Rated down for imprecision as the width of the 95% CI exceeds 0% (±5%) e Rated down for imprecision as the sample size from the single study informing the analysis is less than 50 (N<50) f Rated down for imprecision as the sample size from the single study informing the analysis is less than 25 (N<25); May also be applied when pooling outcomes from multiple studies with very small sample sizes g Rated down as 50% of patients contributing to the pooled estimate come from observational studies h Rated down as 75% of patients contributing to the pooled estimate come from observational studies i Rated down as the estimate of effect is based on a very small sample size or the estimate is based on a single, small study 74

177 Table D25: GRADE profile for patients treated with sofosbuvir + velpatasvir, patients with HIV co-infection analysis, arranged by genotype Quality assessment Risk of Design Inconsistency Indirectness Imprecision studies bias Genotype, -treatment experience population SVR2 Other considerations -2 b Genotype 2, -treatment experience population SVR2-2 b f - i Genotype 3, -treatment experience population SVR2-2 b f - i 2 Genotype 4, -treatment experience population SVR2-2 b f - i 5 patients Effect Quality Importance Genotype 5, -treatment experience population SVR (0.90,.00) 0.96 (0.85,.00) 0.92 (0.76,.00) 0.92 (0.70,.00) 75

178 Quality assessment Risk of Other Design Inconsistency Indirectness Imprecision patients studies bias considerations Effect Quality Importance Genotype 6, -treatment experience population SVR2 Mixed genotype group, -treatment experience population SVR2 Legend for GRADE: Very low; Low; Moderate; High. a Rated down as 50% of patients contributing to the pooled estimate comes from studies determined to pose a high risk of bias b Rated down as 75% of patients contributing to the pooled estimate comes from studies determined to pose a high risk of bias c Rated down for consistency as differences in the proportion of patients with the outcome of interest in the pooled studies exceeds 25% d Rated down for imprecision as the width of the 95% CI exceeds 0% (±5%) e Rated down for imprecision as the sample size from the single study informing the analysis is less than 50 (N<50) f Rated down for imprecision as the sample size from the single study informing the analysis is less than 25 (N<25); May also be applied when pooling outcomes from multiple studies with very small sample sizes g Rated down as 50% of patients contributing to the pooled estimate come from observational studies h Rated down as 75% of patients contributing to the pooled estimate come from observational studies i Rated down as the estimate of effect is based on a very small sample size or the estimate is based on a single, small study 76

179 Table D26: GRADE profile for patients treated with sofosbuvir + velpatasvir + voxilaprevir, patients with HIV co-infection analysis, arranged by genotype No available 77

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