Web Annex 3.1. Adult Hepatitis C Virus Treatment Systematic Review

Web Annex 3.1. 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 2018

WHO/CDS/HIV/18.36

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Suggested citation. Zoratti M. Web Annex 3.1. 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; 2018 (WHO/CDS/HIV/18.36). Licence: CC BY-NC-SA 3.0 IGO.

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Contents

Tables ...... 3 Figures ...... 6 Acronyms ...... 7 Administrative structure ...... Error! Bookmark not defined. Version history ...... 9 Executive summary ...... 10 Objective ...... 12 Methods...... 13 Systematic literature review ...... 13 Eligibility criteria ...... 13 Literature searches ...... 14 Study selection ...... 14 Data extraction ...... 15 Data analysis ...... 15 Software ...... 15 Quality assessments ...... 15 For randomized controlled trials ...... 16 For non-randomized studies ...... 16 GRADE ...... 17 Results ...... 19 Evidence base ...... 19 Efficacy outcomes (SVR12) – All comers ...... 21 Daclatasvir + Asunaprevir ...... 21 Daclatasvir + Sofosbuvir ...... 23 Elbasvir + Grazoprevir ...... 24 Glecaprevir + Pibrentasvir ...... 26 Ledipasvir + Sofosbuvir ...... 28 Paritaprevir/ritonavir + Ombitasvir + Dasabuvir ...... 30 Sofosbuvir + Velpatasvir ...... 32 Sofosbuvir + Velpatasvir + Voxilaprevir ...... 33 Efficacy outcomes (SVR12) – Patients with cirrhosis ...... 36 Daclatasvir + Asunaprevir ...... 36

Daclatasvir + Sofosbuvir ...... 38 Elbasvir + Grazoprevir ...... 40 Glecaprevir + Pibrentasvir ...... 41 Ledipasvir + Sofosbuvir ...... 42 Paritaprevir/ritonavir + Ombitasvir + Dasabuvir ...... 44 Sofosbuvir + Velpatasvir ...... 45 Sofosbuvir + Velpatasvir + Voxilaprevir ...... 47 Daclatasvir + Sofosbuvir + Ribavirin ...... 49 Sofosbuvir + Ribavirin ...... 50 Efficacy outcomes (SVR12) – Patients with HIV co-infection ...... 52 Daclatasvir + Asunaprevir ...... 52 Daclatasvir + Sofosbuvir ...... 52 Elbasvir + Grazoprevir ...... 53 Glecaprevir + Pibrentasvir ...... 53 Ledipasvir + Sofosbuvir ...... 54 Paritaprevir/ritonavir + Ombitasvir + Dasabuvir ...... 54 Sofosbuvir + Velpatasvir ...... 55 Sofosbuvir + Velpatasvir + Voxilaprevir ...... 56 Safety outcomes ...... 57 Discontinuations due to adverse events ...... 57 Serious adverse events ...... 57 Mortality ...... 58 Summary of findings ...... 60 Strengths and limitations ...... 61 Appendices ...... 62 Appendix A: Search strategies ...... 62 Appendix B: Publication eligibility assessment process ...... 67 Appendix C: Included studies...... 68 Appendix D: GRADE evidence profiles ...... 78 References ...... 178

TABLES

Table 1: Population, Interventions, Comparisons, Outcomes, and Study design (PICOS) criteria ...... 13 Table 2: SVR12 in all patients treated with daclatasvir + asunaprevir, arranged by genotype ...... 21 Table 3: SVR12 in treatment-naïve patients treated with daclatasvir + asunaprevir, arranged by genotype ...... 21 Table 4: SVR12 in treatment-experienced patients treated with daclatasvir + asunaprevir, arranged by genotype...... 22 Table 5: SVR12 in all patients treated with daclatasvir + sofosbuvir, arranged by genotype ...... 23 Table 6: SVR12 in treatment-naive patients treated with daclatasvir + sofosbuvir, arranged by genotype 23 Table 7: SVR12 in treatment-experienced patients treated with daclatasvir + sofosbuvir, arranged by genotype...... 24 Table 8: SVR12 in all patients treated with elbasvir + grazoprevir, arranged by genotype ...... 25 Table 9: SVR12 in treatment-naive patients treated with elbasvir + grazoprevir, arranged by genotype .. 25 Table 10: SVR12 in treatment-experienced treated with elbasvir + grazoprevir, arranged by genotype ... 26 Table 11: SVR12 in all patients treated with glecaprevir + pibrentasvir, arranged by genotype ...... 26 Table 12: SVR12 in treatment-naïve patients treated with glecaprevir + pibrentasvir, arranged by genotype...... 27 Table 13: SVR12 in treatment-experienced patients treated with glecaprevir + pibrentasvir, arranged by genotype...... 28 Table 14: SVR12 in all patients treated with ledipasvir + sofosbuvir, arranged by genotype ...... 28 Table 15: SVR12 in treatment-naive patients treated with ledipasvir + sofosbuvir, arranged by genotype 29 Table 16: SVR12 in treatment-experienced patients treated with ledipasvir + sofosbuvir, arranged by genotype...... 29 Table 17: SVR12 in all patients treated with paritaprevir/ritonavir + ombitasvir + dasabuvir, arranged by genotype...... 30 Table 18: SVR12 in treatment-naive patients treated with paritaprevir/ritonavir + ombitasvir + dasabuvir, arranged by genotype ...... 31 Table 19: SVR12 in treatment-experienced patients treated with paritaprevir/ritonavir + ombitasvir + dasabuvir, arranged by genotype ...... 31 Table 20: SVR12 in all patients treated with sofosbuvir + velpatasvir, arranged by genotype ...... 32 Table 21: SVR12 in treatment-naïve patients treated with sofosbuvir + velpatasvir, arranged by genotype ...... 32 Table 22: SVR12 in treatment-experienced patients treated with sofosbuvir + velpatasvir, arranged by genotype...... 33 Table 23: SVR12 in all patients treated with sofosbuvir + velpatasvir + voxilaprevir, arranged by genotype ...... 34 Table 24: SVR12 in treatment-naïve patients treated with sofosbuvir + velpatasvir + voxilaprevir, arranged by genotype ...... 34 Table 25: SVR12 in treatment-experienced patients treated with sofosbuvir + velpatasvir + voxilaprevir, arranged by genotype ...... 35 Table 26: SVR12 in patients with cirrhosis treated with daclatasvir + asunaprevir, arranged by genotype36 Table 27: SVR12 in treatment-naïve patients with cirrhosis treated with daclatasvir + asunaprevir, arranged by genotype ...... 37 Table 28: SVR12 in treatment-experienced patients with cirrhosis treated with daclatasvir + asunaprevir, arranged by genotype ...... 37 Table 29: SVR12 in patients with cirrhosis treated with daclatasvir + sofosbuvir, arranged by genotype . 38 Table 30: SVR12 in treatment-naïve patients with cirrhosis treated with daclatasvir + asunaprevir, arranged by genotype ...... 39

Table 31: SVR12 in treatment-experienced patients with cirrhosis treated with daclatasvir + sofosbuvir, arranged by genotype ...... 39 Table 32: SVR12 in patients with cirrhosis treated with elbasvir + grazoprevir, arranged by genotype ..... 40 Table 33: SVR12 in treatment-naïve patients with cirrhosis treated with elbasvir + grazoprevir, arranged by genotype ...... 40 Table 34: SVR12 in treatment-experienced patients with cirrhosis treated with elbasvir + grazoprevir, arranged by genotype ...... 41 Table 35: SVR12 in patients with cirrhosis treated with glecaprevir + pibrentasvir, arranged by genotype ...... 42 Table 36: SVR12 in patients with cirrhosis treated with ledipasvir + sofosbuvir, arranged by genotype ... 42 Table 37: SVR12 in treatment-naïve patients with cirrhosis treated with ledipasvir + sofosbuvir, arranged by genotype ...... 43 Table 38: SVR12 in treatment-experienced patients with cirrhosis treated with ledipasvir + sofosbuvir, arranged by genotype ...... 44 Table 39: SVR12 in patients with cirrhosis treated with paritaprevir/ritonavir + ombitasvir + dasabuvir, arranged by genotype ...... 44 Table 40: SVR12 in patients with cirrhosis treated with sofosbuvir + velpatasvir, arranged by genotype . 45 Table 41: SVR12 in treatment-naïve patients with cirrhosis treated with sofosbuvir + velpatasvir, arranged by genotype ...... 46 Table 42: SVR12 in treatment-experienced patients with cirrhosis treated with sofosbuvir + velpatasvir, arranged by genotype ...... 47 Table 43: SVR12 in patients with cirrhosis treated with sofosbuvir + velpatasvir + voxilaprevir, arranged by genotype ...... 47 Table 44: SVR12 in treatment-naïve patients with cirrhosis treated with sofosbuvir + velpatasvir + voxilaprevir, arranged by genotype ...... 48 Table 45: SVR12 in treatment-experienced patients with cirrhosis treated with sofosbuvir + velpatasvir + voxilaprevir, arranged by genotype ...... 49 Table 46: SVR12 in genotype 2 or 3 patients with cirrhosis treated with daclatasvir + sofosbuvir + ribavirin, arranged by genotype ...... 49 Table 47: SVR12 in treatment-naïve genotype 2 or 3 patients with cirrhosis treated with daclatasvir + sofosbuvir + ribavirin, arranged by genotype ...... 50 Table 48: SVR12 in treatment-experienced genotype 2 or 3 patients with cirrhosis treated with daclatasvir + sofosbuvir + ribavirin, arranged by genotype ...... 50 Table 49: SVR12 in genotype 2 or 3 patients with cirrhosis treated with sofosbuvir + ribavirin, arranged by genotype...... 50 Table 50: SVR12 in treatment-naïve genotype 2 or 3 patients with cirrhosis treated with sofosbuvir + ribavirin, arranged by genotype ...... 51 Table 51: SVR12 in treatment-experienced genotype 2 or 3 patients with cirrhosis treated with sofosbuvir + ribavirin, arranged by genotype ...... 51 Table 52: SVR12 in HIV co-infected patients treated with daclatasvir + sofosbuvir, arranged by genotype ...... 52 Table 53: SVR12 in HIV co-infected patients treated with elbasvir + grazoprevir, arranged by genotype . 53 Table 54: SVR12 in HIV co-infected patients treated with glecaprevir + pibrentasvir, arranged by genotype ...... 53 Table 55: SVR12 in HIV co-infected patients treated with ledipasvir + sofosbuvir, arranged by genotype 54 Table 56: SVR12 in HIV co-infected patients treated with paritaprevir/ritonavir + ombitasvir + dasabuvir, arranged by genotype ...... 55 Table 57: SVR12 in HIV co-infected patients treated with ledipasvir + sofosbuvir, arranged by genotype 55 Table 58: Discontinuations due to adverse events, arranged by treatment ...... 57

Table 59: Serious adverse events, arranged by treatment ...... 58 Table 60: Mortality, arranged by treatment ...... 58 Table A61: Search strategy for EMBASE ...... 62 Table A62: Search strategy for MEDLINE ...... 64 Table A63: Search strategy for CENTRAL ...... 66

FIGURES

Figure 1: Flow of information...... 20

ACRONYMS

AASLD American Association for the Study of Liver Diseases CENTRAL Cochrane Register of Controlled Trials CI Confidence interval DAA Direct acting anti-viral DAC + ASV Daclatasvir + asunaprevir DAC + SOF Daclatasvir + sofosbuvir DAC + SOF + RBV Daclatasvir + sofosbuvir + ribavirin DAE Discontinuation due to adverse event DDW Digestive Diseases Week EASL European Association for the Study of the Liver EMBASE Excerpta Medica dataBASE ESV + GZR Elbasvir + grazoprevir GCR + PBV Glecaprevir + pibrentasvir GRADE Grading Recommendations of Assessment, Development and Evaluation HCV Hepatitis C Virus ITT Intention to treat LDV + SOF Ledipasvir + sofosbuvir MEDLINE Medical Literature Analysis and Retrieval System Online PTV/r + OMV + DBV Paritaprevir/ritonavir + ombitasvir + dasabuvir RBV Ribavirin RCT Randomized controlled trial SAE Serious adverse event SOF + RBV Sofosbuvir + ribavirin SOF + VEL Sofosbuvir + velpatasvir SOF + VEL + VOX Sofosbuvir + velpatasvir + voxilaprevir SVR12 Sustained virological response 12 weeks post-treatment

Sponsor Dr. Marc Bulterys

World Health Organization

Geneva, Switzerland

Operator Michael Zoratti; [email protected]

Zoratti HEOR Consulting Inc.

2441 Greenwich Drive

Unit 80

Oakville, Ontario, Canada

L6M 0S3

VERSION HISTORY

V1 Preliminary summary of the literature review and analyses

V2 Complete summary of the literature review and analyses

V3 Revised GRADE methodology Addition of GRADE Evidence Profile tables (Appendix D)

EXECUTIVE SUMMARY

Objective: To identify and synthesize the evidence on treatment options for chronic hepatitis C virus (HCV), with emphasis on direct acting antivirals, for genotypes 1 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 12-weeks post-treatment (SVR12); discontinuations due to adverse events (DAEs); serious adverse events (SAEs); and mortality. Outcomes evidence was gathered, as available, separately by: genotype (HCV 1, 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 1, 2015. 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 SVR12, 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 evidence collected from clinical trials (trial-only evidence: RCTs, non-randomized comparative trials; single-arm trials) and evidence collected from clinical trials as well as observational studies (all evidence). 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 142 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 evidence 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 SVR12 was high across stratifications in the all-comer population, though with mixed evidence for patients with genotypes 2 or 3 infection. The availability of evidence was similarly high in the subgroup analysis of patients with cirrhosis, with lower SVR12 rates in patients with genotypes 2 or 3 infection. Limited evidence was identified for patients with HCV/HIV co-infection, though SVR12 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.

Conclusions: The findings of this systematic literature review indicate high SVR12 efficacy rates across most treatments and patient stratifications. Mixed evidence was found for patients with cirrhosis, particularly those with genotype 2 or 3 infection. While limited evidence was identified, SVR12 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.

OBJECTIVE

The objective of this review was to identify and synthesize the evidence for the efficacy and safety of antiviral therapies for chronic hepatitis C virus infection genotypes 1-6. Specifically, we sought to describe efficacy with respect to sustained virologic response at 12 weeks post-treatment (SVR12) and safety with respect to discontinuations due to adverse events (DAEs), serious adverse events (SAEs), and mortality.

METHODS

Systematic literature review

Eligibility criteria Refer to Table 1 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 1: Population, Interventions, Comparisons, Outcomes, and Study design (PICOS) criteria

Criteria Definition Adults with chronic hepatitis C infection genotype 1-6 infection

Subgroups include:  Persons with cirrhosis  HCV/HIV co-infection Population  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 Interventions  Daclatasvir + Sofosbuvir  Sofosbuvir + Ribavirin  Elbasvir + Grazoprevir  Glecaprevir + Pibrentasvir  Daclatasvir + Sofosbuvir + Ribavirin  Any active intervention for chronic hepatitis C infection  Placebo* Comparators  Standard of care  No treatment Efficacy:  Sustained virological response (SVR) (12 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 1, 2015 *Outcomes are not extracted for patients assigned to a deferred treatment (e.g. placebo) arm

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 Trials (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 2016, AASLD 2015, AASLD 2016, EASL 2016) 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.

A previous SLR, commissioned by the World Health Organization and performed by Global Health Sciences (August 20, 2015), 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, 2015 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 SVR12, 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 evidence on treatment-experienced only and treatment-naïve only patients. Patients were considered treatment- experienced 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 evidence coming from trials, including RCTs, non-RCT comparative trials, and uncontrolled single-arm trials (trial-only evidence). A secondary set of analyses was performed to include all evidence, including that coming from observational studies (all evidence).

No formal statistical tests were performed to compare outcomes across any stratification.

Software All data was maintained in Microsoft Excel 2016 workbooks. All 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).1,2

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 evidence 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

15 the current review, where the primary analyses were based on the pooled proportion of patients achieving SVR12 irrespective of treatment characteristics such as dose or treatment duration. Moreover, this review was designed to include evidence 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. SVR12) 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:

1) 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?

GRADE The Grading Recommendations of Assessment, Development and Evaluation (GRADE) approach was used to assess the strength of evidence for all outcomes.4-9 In the GRADE framework, outcomes based on RCTs begin as high-quality evidence. 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 evidence 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 evidence 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 evidence 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 evidence:

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 evidence 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 evidence 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 evidence 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 evidence; imprecision; and publication bias) will be evaluated according to the following criteria:

1) 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 evidence will be downgraded by one level if ≥50% of patients come from studies determined to have a high risk of bias.

The quality of evidence 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 evidence The quality of evidence will not be downgraded for directness (i.e. indirectness) for any outcome in this systematic literature review. There is evidence 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. evidence comes from multiple studies), quality of evidence will be downgraded by one level if the spread of the 95% CI exceeds 10% (±5%); or

 Where no pooled outcome is available (i.e. evidence comes from a single study), quality of evidence 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 evidence 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.

RESULTS

Evidence base

From the search of the clinical literature databases, 4,200 publications were identified (July 20/21, 2017). A total of 3,553 publications were excluded at the abstract-screening phase: 1,696 publications published prior to 2015; 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: 18 for ineligible study design; 71 for assessing a population not of interest; 19 for assessing an intervention not of interest; 147 for not reporting an outcome of interest; and 17 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 179 publications were excluded. Thus, 189 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 21 publications were identified from the previous review conducted by Global Health Sciences.

Thus, the identified evidence base consisted of 238 publications describing unique 142 studies.10-247 The flow of information diagram is presented in Figure 1. Study characteristics are presented in Appendix C. Complete GRADE evidence profiles, including reasons downgrading the evidence, are presented in Appendix D: GRADE evidence 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 (WHO201701 HCV SLR Data and Analyses v2).

Figure 1: Flow of information

Efficacy outcomes (SVR12) – All comers

For each treatment in the all-comer population, the pooled proportions of patients achieving SVR12 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.

Trial evidence refers to evidence coming from RCTs and other non-randomized or single-arm trials. This analysis is supplemented with an all evidence analysis, which also incorporates outcomes from observational studies.

Comparative evidence is not available and inferences on relative treatment effect should be avoided.

Daclatasvir + Asunaprevir All-treatment experience

In the all-treatment experience analysis of patients treated with daclatasvir + asunaprevir, evidence was available for patients with genotype 1 infection, as well as an unknown or mixed genotype population. The percentage of patients achieving SVR12 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: SVR12 in all patients treated with daclatasvir + asunaprevir, arranged by genotype

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Trial evidence 15 18 3642 0.89 (0.87, 0.92) ⨁⨁⨁⨁ Genotype 1 All evidence 21 24 6341 0.89 (0.87, 0.91) ⨁⨁⨁⨁ Trial evidence – – – – – Genotype 2 All evidence – – – – – Trial evidence – – – – – Genotype 3 All evidence – – – – – Trial evidence – – – – – Genotype 4 All evidence – – – – – Trial evidence – – – – – Genotype 5 All evidence – – – – – Trial evidence – – – – – Genotype 6 All evidence – – – – – Trial evidence – – – – – Mixed genotype All evidence 2 2 405 0.92 (0.89, 0.94) ⨁⨁

Treatment-naïve patients only

In the analysis of treatment-naïve only patients treated with daclatasvir + asunaprevir, evidence was available only for patients with genotype 1 infection (N=552). The pooled percentage of patients achieving SVR12 was 90%, with a GRADE assessment of high. A summary of the analyses is presented in Table 3.

Table 3: SVR12 in treatment-naïve patients treated with daclatasvir + asunaprevir, arranged by genotype

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI)

Trial evidence 4 4 552 0.90 (0.88, 0.93) ⨁⨁⨁⨁ Genotype 1 All evidence Same as trial-only evidence Trial evidence – – – – – Genotype 2 All evidence – – – – – Trial evidence – – – – – Genotype 3 All evidence – – – – – Trial evidence – – – – – Genotype 4 All evidence – – – – – Trial evidence – – – – – Genotype 5 All evidence – – – – – Trial evidence – – – – – Genotype 6 All evidence – – – – – Trial evidence – – – – – Mixed genotype All evidence – – – – –

Treatment-experienced patients only

In the analysis of treatment-experienced only patients treated with daclatasvir + asunaprevir, evidence was available only for patients with genotype 1 infection (N=484). The pooled percentage of patients achieving SVR12 was 85%, with a GRADE assessment of moderate. A summary of the analyses is presented in Table 4.

Table 4: SVR12 in treatment-experienced patients treated with daclatasvir + asunaprevir, arranged by genotype

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI)

Trial evidence 4 5 484 0.85 (0.76, 0.94) ⨁⨁⨁ Genotype 1 All evidence Same as trial-only evidence Trial evidence – – – – – Genotype 2 All evidence – – – – – Trial evidence – – – – – Genotype 3 All evidence – – – – – Trial evidence – – – – – Genotype 4 All evidence – – – – – Trial evidence – – – – – Genotype 5 All evidence – – – – – Trial evidence – – – – – Genotype 6 All evidence – – – – – Trial evidence – – – – – Mixed genotype All evidence – – – – –

Daclatasvir + Sofosbuvir All-treatment experience

In the all-treatment experience analysis of patients treated with daclatasvir + sofosbuvir, evidence was available for patients across all genotypes. The percentage of patients achieving SVR12 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: SVR12 in all patients treated with daclatasvir + sofosbuvir, arranged by genotype

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Trial evidence 1 4 91 0.98 (0.96, 0.98) ⨁⨁⨁⨁ Genotype 1 All evidence 6 19 773 0.96 (0.94, 0.98) ⨁⨁⨁⨁ Trial evidence – – – – – Genotype 2 All evidence 2 4 21 0.94 (0.86, 1.00) ⨁ Trial evidence 3 4 293 0.92 (0.88, 0.97) ⨁⨁⨁⨁ Genotype 3 All evidence 9 16 895 0.89 (0.85, 0.94) ⨁⨁⨁ Trial evidence 2 3 180 0.97 (0.95, 1.00) ⨁⨁⨁⨁ Genotype 4 All evidence 3 5 183 0.97 (0.95, 1.00) ⨁⨁⨁⨁ Trial evidence – – – – – Genotype 5 All evidence 2 3 8 0.88 (0.70, 1.00) ⨁ Trial evidence – – – – – Genotype 6 All evidence 1 4 123 0.94 (0.90, 0.98) ⨁⨁ Trial evidence 2 5 233 0.94 (0.88, 0.99) ⨁⨁⨁ Mixed genotype All evidence 5 9 591 0.92 (0.88, 0.97) ⨁⨁

Treatment-naïve patients only

In the analysis of treatment-naïve only patients treated with daclatasvir + sofosbuvir, evidence was available for patients with genotypes 1-5 infection, as well as an unknown or mixed genotype population. The percentage of patients achieving SVR12 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: SVR12 in treatment-naive patients treated with daclatasvir + sofosbuvir, arranged by genotype

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Trial evidence 1 3 70 0.98 (0.96, 1.00) ⨁⨁⨁⨁ Genotype 1 All evidence 4 8 196 0.94 (0.90, 0.99) ⨁⨁⨁ Trial evidence – – – – – Genotype 2 All evidence 1 1 1 0.75 (0.15, 1.00) ⨁ Trial evidence 3 3 242 0.94 (0.89, 0.98) ⨁⨁⨁⨁ Genotype 3 All evidence 6 7 470 0.93 (0.88, 0.98) ⨁⨁⨁⨁ Trial evidence 1 1 60 0.93 (0.87, 1.00) ⨁⨁⨁ Genotype 4 All evidence 2 2 61 0.93 (0.87, 0.99) ⨁⨁⨁

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Trial evidence – – – – – Genotype 5 All evidence 1 1 2 0.83 (0.41, 1.00) ⨁ Trial evidence – – – – – Genotype 6 All evidence – – – – – Trial evidence 2 4 181 0.91 (0.82, 1.00) ⨁⨁⨁ Mixed genotype All evidence Same as trial-only evidence

Treatment-experienced patients only

In the analysis of treatment-experienced only patients treated with daclatasvir + sofosbuvir, evidence was available for patients with genotypes 1-4 infection, as well as an unknown or mixed genotype population. The percentage of patients achieving SVR12 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: SVR12 in treatment-experienced patients treated with daclatasvir + sofosbuvir, arranged by genotype

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Trial evidence 1 1 21 0.98 (0.92, 1.00) ⨁⨁ Genotype 1 All evidence 5 10 573 0.97 (0.95, 0.98) ⨁⨁⨁ Trial evidence – – – – – Genotype 2 All evidence 1 1 1 0.75 (0.15, 1.00) ⨁ Trial evidence 1 1 51 0.86 (0.77, 0.96) ⨁⨁⨁ Genotype 3 All evidence 3 5 110 0.85 (0.78, 0.92) ⨁⨁⨁ Trial evidence – – – – – Genotype 4 All evidence 1 1 2 0.83 (0.41, 1.00) ⨁ Trial evidence – – – – – Genotype 5 All evidence – – – – – Trial evidence – – – – – Genotype 6 All evidence – – – – – Trial evidence 1 1 52 0.98 (0.94, 1.00) ⨁⨁⨁ Mixed genotype All evidence Same as trial-only evidence

Elbasvir + Grazoprevir All-treatment experience

In the all-treatment experience analysis of patients treated with elbasvir + grazoprevir, evidence was available for patients with genotypes 1, 4, and 6 infection, as well as an unknown or mixed genotype population. The percentage of patients achieving SVR12 varied from 62% to 97%. Across outcomes, GRADE assessments varied from moderate to high. A summary of the analyses is presented in Table 8.

Table 8: SVR12 in all patients treated with elbasvir + grazoprevir, arranged by genotype

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Trial evidence 10 20 1975 0.97 (0.96, 0.98) ⨁⨁⨁⨁ Genotype 1 All evidence 11 21 1996 0.97 (0.96, 0.98) ⨁⨁⨁⨁ Trial evidence – – – – – Genotype 2 All evidence – – – – – Trial evidence – – – – – Genotype 3 All evidence – – – – – Trial evidence 5 5 66 0.96 (0.92, 1.00) ⨁⨁⨁⨁ Genotype 4 All evidence Same as trial-only evidence Trial evidence – – – – – Genotype 5 All evidence – – – – – Trial evidence 4 4 52 0.62 (0.39, 0.85) ⨁⨁⨁ Genotype 6 All evidence Same as trial-only evidence Trial evidence 2 4 317 0.94 (0.88, 0.99) ⨁⨁⨁ Mixed genotype Same as trial-only evidence All evidence

Treatment-naïve patients only

In the analysis of treatment-naïve only patients treated with elbasvir + grazoprevir, evidence was available for patients with genotypes 1, 4, and 6 infection, as well as an unknown or mixed genotype population. The percentage of patients achieving SVR12 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: SVR12 in treatment-naive patients treated with elbasvir + grazoprevir, arranged by genotype

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Trial evidence 6 11 1112 0.96 (0.95, 0.97) ⨁⨁⨁⨁ Genotype 1 All evidence Same as trial-only evidence Trial evidence – – – – – Genotype 2 All evidence – – – – – Trial evidence – – – – – Genotype 3 All evidence – – – – – Trial evidence 4 4 60 0.96 (0.92, 1.00) ⨁⨁⨁⨁ Genotype 4 All evidence Same as trial-only evidence Trial evidence – – – – – Genotype 5 All evidence – – – – – Trial evidence 4 4 52 0.62 (0.39, 0.85) ⨁⨁⨁ Genotype 6 All evidence Same as trial-only evidence Trial evidence 1 1 53 0.87 (0.78, 0.96) ⨁⨁ Mixed genotype All evidence Same as trial-only evidence

Treatment-experienced patients only

In the analysis of treatment-experienced only patients treated with elbasvir + grazoprevir, evidence was available for patients with genotype 1 infection, as well as an unknown or mixed genotype population. The percentage of patients achieving SVR12 was 95% in both genotype subgroups, with GRADE assessments varying from low to high. A summary of the analyses is presented in Table 10.

Table 10: SVR12 in treatment-experienced treated with elbasvir + grazoprevir, arranged by genotype

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Trial evidence 1 2 65 0.95 (0.90, 1.00) ⨁⨁ Genotype 1 All evidence Same as trial-only evidence Trial evidence – – – – – Genotype 2 All evidence – – – – – Trial evidence – – – – – Genotype 3 All evidence – – – – – Trial evidence – – – – – Genotype 4 All evidence – – – – – Trial evidence – – – – – Genotype 5 All evidence – – – – – Trial evidence – – – – – Genotype 6 All evidence – – – – – Trial evidence 2 3 264 0.95 (0.90, 1.00) ⨁⨁⨁⨁ Mixed genotype All evidence Same as trial-only evidence

Glecaprevir + Pibrentasvir All-treatment experience

In the all-treatment experience analysis of patients treated with glecaprevir + pibrentasvir, evidence was available for patients across all genotypes. The percentage of patients achieving SVR12 varied from 83% to 98%. Across outcomes, GRADE assessments varied from very low to high. A summary of the analyses is presented in Table 11.

Table 11: SVR12 in all patients treated with glecaprevir + pibrentasvir, arranged by genotype

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Trial evidence 3 6 231 0.98 (0.97, 1.00) ⨁⨁⨁⨁ Genotype 1 All evidence Same as trial-only evidence Trial evidence 4 6 242 0.98 (0.96, 1.00) ⨁⨁⨁⨁ Genotype 2 All evidence Same as trial-only evidence Trial evidence 2 7 533 0.95 (0.93, 0.97) ⨁⨁⨁⨁ Genotype 3 All evidence Same as trial-only evidence

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Trial evidence 1 1 16 0.97 (0.89, 1.00) ⨁ Genotype 4 All evidence Same as trial-only evidence Trial evidence 1 1 2 0.83 (0.41, 1.00) ⨁ Genotype 5 All evidence Same as trial-only evidence Trial evidence 1 1 7 0.94 (0.77, 1.00) ⨁ Genotype 6 All evidence Same as trial-only evidence Trial evidence 3 5 276 0.97 (0.93, 1.00) ⨁⨁⨁⨁ Mixed genotype All evidence Same as trial-only evidence

Treatment-naïve patients only

In the analysis of treatment-naïve only patients treated with glecaprevir + pibrentasvir, evidence was available only for patients with genotype 3 infection (N=419). The percentage of patients achieving SVR12 was 95%, with a GRADE assessment of high. A summary of the analyses is presented in Table 12.

Table 12: SVR12 in treatment-naïve patients treated with glecaprevir + pibrentasvir, arranged by genotype

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Trial evidence – – – – – Genotype 1 All evidence – – – – – Trial evidence – – – – – Genotype 2 All evidence – – – – – Trial evidence 2 3 419 0.95 (0.93, 0.97) ⨁⨁⨁⨁ Genotype 3 All evidence Same as trial-only evidence Trial evidence – – – – – Genotype 4 All evidence – – – – – Trial evidence – – – – – Genotype 5 All evidence – – – – – Trial evidence – – – – – Genotype 6 All evidence – – – – – Trial evidence – – – – – Mixed genotype All evidence – – – – –

Treatment-experienced patients only

In the analysis of treatment-experienced only patients treated with glecaprevir + pibrentasvir, evidence was available only for patients with genotype 3 infection (N=24). The percentage of patients achieving SVR12 was 92%, with a GRADE assessment of very low. A summary of the analyses is presented in Table 13.

Table 13: SVR12 in treatment-experienced patients treated with glecaprevir + pibrentasvir, arranged by genotype

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Trial evidence – – – – – Genotype 1 All evidence – – – – – Trial evidence – – – – – Genotype 2 All evidence – – – – – Trial evidence 1 1 24 0.92 (0.81, 1.00) ⨁ Genotype 3 All evidence Same as trial-only evidence Trial evidence – – – – – Genotype 4 All evidence – – – – – Trial evidence – – – – – Genotype 5 All evidence – – – – – Trial evidence – – – – – Genotype 6 All evidence – – – – – Trial evidence – – – – – Mixed genotype All evidence – – – – –

Ledipasvir + Sofosbuvir All-treatment experience

In the all-treatment experience analysis of patients treated with ledipasvir + sofosbuvir, evidence was available for patients across all genotypes. The percentage of patients achieving SVR12 varied from 64% to 98%. GRADE assessments varied from very low to high across outcomes. A summary of the analyses is presented in Table 14.

Table 14: SVR12 in all patients treated with ledipasvir + sofosbuvir, arranged by genotype

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Trial evidence 18 27 3032 0.98 (0.98, 0.99) ⨁⨁⨁⨁ Genotype 1 All evidence 30 47 13327 0.97 (0.96, 0.98) ⨁⨁⨁⨁ Trial evidence 1 2 53 0.86 (0.65, 1.00) ⨁⨁ Genotype 2 All evidence Same as trial-only evidence Trial evidence 1 1 25 0.64 (0.45, 0.83) ⨁ Genotype 3 All evidence 3 3 42 0.65 (0.51, 0.79) ⨁⨁ Trial evidence 4 7 188 0.96 (0.93, 0.99) ⨁⨁⨁⨁ Genotype 4 All evidence 5 20 458 0.96 (0.93, 0.98) ⨁⨁⨁⨁ Trial evidence 1 2 41 0.95 (0.89, 1.00) ⨁⨁⨁ Genotype 5 All evidence Same as trial-only evidence Trial evidence 2 4 85 0.97 (0.93, 1.00) ⨁⨁⨁⨁ Genotype 6 All evidence 3 5 124 0.90 (0.81, 0.99) ⨁⨁ Mixed genotype Trial evidence 7 9 1228 0.95 (0.92, 0.99) ⨁⨁⨁⨁

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) All evidence 10 14 1421 0.95 (0.92, 0.97) ⨁⨁⨁⨁

Treatment-naïve patients only

In the analysis of treatment-naïve only patients treated with ledipasvir + sofosbuvir, evidence was available for patients with genotypes 1, 3-5 infection, as well as an unknown or mixed genotype population. The percentage of patients achieving SVR12 varied from 64% to 98%. GRADE assessments varied from very low to high across outcomes. A summary of the analyses is presented in Table 15.

Table 15: SVR12 in treatment-naive patients treated with ledipasvir + sofosbuvir, arranged by genotype

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Trial evidence 9 12 1263 0.98 (0.97, 0.99) ⨁⨁⨁⨁ Genotype 1 All evidence 13 16 5457 0.97 (0.95, 0.99) ⨁⨁⨁ Trial evidence – – – – – Genotype 2 All evidence – – – – – Trial evidence 1 1 25 0.64 (0.45, 0.83) ⨁ Genotype 3 All evidence Same as trial-only evidence Trial evidence 2 3 108 0.97 (0.93, 1.00) ⨁⨁⨁⨁ Genotype 4 All evidence Same as trial-only evidence Trial evidence 1 1 21 0.95 (0.86, 1.00) ⨁ Genotype 5 All evidence Same as trial-only evidence Trial evidence 2 3 70 0.97 (0.93, 1.00) ⨁⨁⨁⨁ Genotype 6 All evidence Same as trial-only evidence Trial evidence 3 3 223 0.96 (0.93, 0.98) ⨁⨁⨁⨁ Mixed genotype All evidence Same as trial-only evidence

Treatment-experienced patients only

In the analysis of treatment-experienced only patients treated with ledipasvir + sofosbuvir, evidence was available for patients with genotypes 1, 4-6 infection, as well as an unknown or mixed genotype population. The percentage of patients achieving SVR12 varied from 87% to 97%. GRADE assessments varied from very low to high across outcomes. A summary of the analyses is presented in Table 16.

Table 16: SVR12 in treatment-experienced patients treated with ledipasvir + sofosbuvir, arranged by genotype

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Trial evidence 9 10 561 0.97 (0.94, 0.99) ⨁⨁⨁⨁ Genotype 1 All evidence 13 18 1620 0.96 (0.94, 0.98) ⨁⨁⨁⨁ Trial evidence – – – – – Genotype 2 All evidence – – – – –

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Trial evidence – – – – – Genotype 3 All evidence – – – – – Trial evidence 2 2 58 0.94 (0.87, 1.00) ⨁⨁⨁ Genotype 4 All evidence Same as trial-only evidence Trial evidence 1 1 20 0.95 (0.85, 1.00) ⨁ Genotype 5 All evidence Same as trial-only evidence Trial evidence 1 1 15 0.87 (0.70, 1.00) ⨁ Genotype 6 All evidence Same as trial-only evidence Trial evidence 2 2 222 0.97 (0.95, 1.00) ⨁⨁⨁⨁ Mixed genotype All evidence Same as trial-only evidence

Paritaprevir/ritonavir + Ombitasvir + Dasabuvir All-treatment experience

In the all-treatment experience analysis of patients treated with paritaprevir/ritonavir + ombitasvir + dasabuvir, evidence was available only for patients with genotype 1 infection. The percentage of patients achieving SVR12 varied from 98% to 99% across the trial-only and all evidence analyses. GRADE was assessed as high for both analyses. A summary of the analyses is presented in Table 17.

Table 17: SVR12 in all patients treated with paritaprevir/ritonavir + ombitasvir + dasabuvir, arranged by genotype

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Trial evidence 7 8 1139 0.99 (0.98, 1.00) ⨁⨁⨁⨁ Genotype 1 All evidence 9 13 1457 0.98 (0.97, 0.99) ⨁⨁⨁⨁ Trial evidence – – – – – Genotype 2 All evidence – – – – – Trial evidence – – – – – Genotype 3 All evidence – – – – – Trial evidence – – – – – Genotype 4 All evidence – – – – – Trial evidence – – – – – Genotype 5 All evidence – – – – – Trial evidence – – – – – Genotype 6 All evidence – – – – – Trial evidence – – – – – Mixed genotype All evidence – – – – –

Treatment-naïve patients only

In the analysis of treatment-naïve only patients treated with paritaprevir/ritonavir + ombitasvir + dasabuvir, evidence was available only for patients with genotype 1 infection. The percentage of patients achieving

SVR12 varied from 97% to 98% across the trial-only and all evidence analyses. GRADE was assessed as high for both analyses. A summary of the analyses is presented in Table 18.

Table 18: SVR12 in treatment-naive patients treated with paritaprevir/ritonavir + ombitasvir + dasabuvir, arranged by genotype

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Trial evidence 5 5 847 0.98 (0.96, 1.00) ⨁⨁⨁⨁ Genotype 1 All evidence 7 7 1090 0.97 (0.95, 0.99) ⨁⨁⨁⨁ Trial evidence – – – – – Genotype 2 All evidence – – – – – Trial evidence – – – – – Genotype 3 All evidence – – – – – Trial evidence – – – – – Genotype 4 All evidence – – – – – Trial evidence – – – – – Genotype 5 All evidence – – – – – Trial evidence – – – – – Genotype 6 All evidence – – – – – Trial evidence – – – – – Mixed genotype All evidence – – – – –

Treatment-experienced patients only

In the analysis of treatment-experienced only patients treated with paritaprevir/ritonavir + ombitasvir + dasabuvir, evidence was available only for patients with genotype 1 infection. The percentage of patients achieving SVR12 varied from 99% to 100% across the trial-only and all evidence analyses. GRADE was assessed as high for both analyses. A summary of the analyses is presented in Table 19.

Table 19: SVR12 in treatment-experienced patients treated with paritaprevir/ritonavir + ombitasvir + dasabuvir, arranged by genotype

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Trial evidence 2 2 232 1.00 (0.99, 1.00) ⨁⨁⨁⨁ Genotype 1 All evidence 4 5 307 0.99 (0.98, 1.00) ⨁⨁⨁⨁ Trial evidence – – – – – Genotype 2 All evidence – – – – – Trial evidence – – – – – Genotype 3 All evidence – – – – – Trial evidence – – – – – Genotype 4 All evidence – – – – – Trial evidence – – – – – Genotype 5 All evidence – – – – – Genotype 6 Trial evidence – – – – –

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) All evidence – – – – – Trial evidence – – – – – Mixed genotype All evidence – – – – –

Sofosbuvir + Velpatasvir All-treatment experience

In the all-treatment experience analysis of patients treated with sofosbuvir + velpatasvir, evidence was available for patients across all genotypes. The percentage of patients achieving SVR12 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: SVR12 in all patients treated with sofosbuvir + velpatasvir, arranged by genotype

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Trial evidence 7 12 1011 0.96 (0.95, 0.98) ⨁⨁⨁⨁ Genotype 1 All evidence Same as trial-only evidence Trial evidence 7 9 395 0.99 (0.97, 1.00) ⨁⨁⨁⨁ Genotype 2 All evidence Same as trial-only evidence Trial evidence 8 15 776 0.89 (0.85, 0.93) ⨁⨁⨁ Genotype 3 All evidence Same as trial-only evidence Trial evidence 4 5 184 0.99 (0.98, 1.00) ⨁⨁⨁⨁ Genotype 4 All evidence Same as trial-only evidence Trial evidence 1 1 35 0.97 (0.92, 1.00) ⨁⨁ Genotype 5 All evidence Same as trial-only evidence Trial evidence 3 3 51 0.99 (0.95, 1.00) ⨁⨁⨁⨁ Genotype 6 All evidence Same as trial-only evidence Trial evidence 2 4 485 0.99 (0.97, 1.00) ⨁⨁⨁⨁ Mixed genotype All evidence 3 5 489 0.99 (0.97, 1.00) ⨁⨁⨁⨁

Treatment-naïve patients only

In the analysis of treatment-naïve only patients treated with sofosbuvir + velpatasvir, evidence was available for patients with genotypes 1-3 infection, as well as an unknown or mixed genotype population. The percentage of patients achieving SVR12 varied from 84% to 98%. GRADE assessments varied from very low to high across outcomes. A summary of the analyses is presented in Table 21.

Table 21: SVR12 in treatment-naïve patients treated with sofosbuvir + velpatasvir, arranged by genotype

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Trial evidence 1 4 114 0.95 (0.90, 1.00) ⨁⨁ Genotype 1 All evidence Same as trial-only evidence

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Trial evidence 1 2 52 0.84 (0.73, 0.95) ⨁ Genotype 2 All evidence Same as trial-only evidence Trial evidence 3 4 337 0.98 (0.96, 0.99) ⨁⨁⨁⨁ Genotype 3 All evidence Same as trial-only evidence Trial evidence – – – – – Genotype 4 All evidence – – – – – Trial evidence – – – – – Genotype 5 All evidence – – – – – Trial evidence – – – – – Genotype 6 All evidence – – – – – Trial evidence 1 2 45 0.96 (0.90, 1.00) ⨁ Mixed genotype All evidence Same as trial-only evidence

Treatment-experienced patients only

In the analysis of treatment-experienced only patients treated with sofosbuvir + velpatasvir, evidence was available for patients with genotypes 1-3 infection. The percentage of patients achieving SVR12 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: SVR12 in treatment-experienced patients treated with sofosbuvir + velpatasvir, arranged by genotype

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Trial evidence 2 3 120 0.96 (0.92, 1.00) ⨁⨁⨁⨁ Genotype 1 All evidence Same as trial-only evidence Trial evidence 1 1 33 0.97 (0.91, 1.00) ⨁⨁ Genotype 2 All evidence Same as trial-only evidence Trial evidence 4 7 312 0.85 (0.78, 0.92) ⨁⨁⨁ Genotype 3 All evidence Same as trial-only evidence Trial evidence – – – – – Genotype 4 All evidence – – – – – Trial evidence – – – – – Genotype 5 All evidence – – – – – Trial evidence – – – – – Genotype 6 All evidence – – – – – Trial evidence – – – – – Mixed genotype All evidence – – – – –

Sofosbuvir + Velpatasvir + Voxilaprevir All-treatment experience

In the all-treatment experience analysis of patients treated with sofosbuvir + velpatasvir + voxilaprevir, evidence was available for patients across all genotypes. The percentage of patients achieving SVR12 varied from 81% to 98%. GRADE assessments varied from very low to high across outcomes. A summary of the analyses is presented in Table 23.

Table 23: SVR12 in all patients treated with sofosbuvir + velpatasvir + voxilaprevir, arranged by genotype

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Trial evidence 4 4 485 0.96 (0.94, 0.99) ⨁⨁⨁⨁ Genotype 1 All evidence Same as trial-only evidence Trial evidence 3 3 99 0.98 (0.95, 1.00) ⨁⨁⨁⨁ Genotype 2 All evidence Same as trial-only evidence Trial evidence 4 5 334 0.98 (0.96, 0.99) ⨁⨁⨁⨁ Genotype 3 All evidence Same as trial-only evidence Trial evidence 3 3 104 0.94 (0.90, 0.99) ⨁⨁⨁⨁ Genotype 4 All evidence Same as trial-only evidence Trial evidence 2 1 19 0.94 (0.83, 1.00) ⨁⨁⨁ Genotype 5 All evidence Same as trial-only evidence Trial evidence 2 2 36 0.98 (0.94, 1.00) ⨁⨁⨁ Genotype 6 All evidence Same as trial-only evidence Trial evidence 2 2 3 0.81 (0.46, 1.00) ⨁ Mixed genotype All evidence Same as trial-only evidence

Treatment-naïve patients only

In the analysis of treatment-naïve only patients treated with sofosbuvir + velpatasvir + voxilaprevir, evidence was available only for patients with genotype 3 infection. The percentage of patients achieving SVR12 was 96%, with a GRADE assessment of high. A summary of the analyses is presented in Table 24.

Table 24: SVR12 in treatment-naïve patients treated with sofosbuvir + velpatasvir + voxilaprevir, arranged by genotype

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Trial evidence – – – – Genotype 1 All evidence – – – –

Trial evidence – – – – Genotype 2 All evidence – – – –

Trial evidence 1 1 75 0.96 (0.92, 1.00) ⨁⨁⨁⨁ Genotype 3 All evidence Same as trial-only evidence Trial evidence – – – – Genotype 4 All evidence – – – –

Trial evidence – – – – Genotype 5 All evidence – – – –

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Trial evidence – – – – Genotype 6 All evidence – – – –

Trial evidence – – – – Mixed genotype All evidence – – – –

Treatment-experienced patients only

In the analysis of treatment-experienced patients treated with sofosbuvir + velpatasvir + voxilaprevir, evidence was available for patients across all genotypes. The percentage of patients achieving SVR12 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: SVR12 in treatment-experienced patients treated with sofosbuvir + velpatasvir + voxilaprevir, arranged by genotype

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Trial evidence 3 3 252 0.97 (0.96, 0.99) ⨁⨁⨁⨁ Genotype 1 All evidence Same as trial-only evidence Trial evidence 2 2 36 0.98 (0.94, 1.00) ⨁⨁⨁⨁ Genotype 2 All evidence Same as trial-only evidence Trial evidence 3 3 167 0.96 (0.92, 0.99) ⨁⨁⨁⨁ Genotype 3 All evidence Same as trial-only evidence Trial evidence 2 2 41 0.96 (0.90, 1.00) ⨁⨁⨁ Genotype 4 All evidence Same as trial-only evidence Trial evidence 1 1 1 0.75 (0.15, 1.00) ⨁ Genotype 5 All evidence Same as trial-only evidence Trial evidence 1 1 6 0.93 (0.74, 1.00) ⨁ Genotype 6 All evidence Same as trial-only evidence Trial evidence 1 1 1 0.75 (0.15, 1.00) ⨁ Mixed genotype All evidence Same as trial-only evidence

Efficacy outcomes (SVR12) – Patients with cirrhosis

For each treatment in the patients with cirrhosis subset, the pooled proportions of patients achieving SVR12 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.

Trial evidence refers to evidence coming from RCTs and other non-randomized or single-arm trials. This analysis is supplemented with an all-evidence analysis, which also incorporates outcomes from observational studies.

Comparative evidence is not available and inferences on relative treatment effect should be avoided.

Daclatasvir + Asunaprevir All-treatment experience

In the all-treatment experience analysis of patients with cirrhosis treated with daclatasvir + asunaprevir, evidence was available for patients with genotype 1 infection, as well as an unknown or mixed genotype population. The percentage of patients achieving SVR12 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: SVR12 in patients with cirrhosis treated with daclatasvir + asunaprevir, arranged by genotype

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Trial evidence 5 7 388 0.89 (0.85, 0.93) ⨁⨁⨁⨁ Genotype 1 All evidence 7 9 919 0.89 (0.86, 0.91) ⨁⨁⨁⨁ Trial evidence – – – – – Genotype 2 All evidence – – – – – Trial evidence – – – – – Genotype 3 All evidence – – – – – Trial evidence – – – – – Genotype 4 All evidence – – – – – Trial evidence – – – – – Genotype 5 All evidence – – – – – Trial evidence – – – – – Genotype 6 All evidence – – – – – Trial evidence – – – – – Mixed genotype All evidence 1 1 4 0.90 (0.64, 1.00) ⨁

Treatment-naïve patients only

In the analysis of treatment-naïve only patients with cirrhosis treated with daclatasvir + asunaprevir, evidence was available only for patients with genotype 1 infection. The pooled percentage of patients achieving SVR12 was 91%, with a GRADE assessment of moderate. A summary of the analyses is presented in Table 27.

Table 27: SVR12 in treatment-naïve patients with cirrhosis treated with daclatasvir + asunaprevir, arranged by genotype

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Trial evidence 3 3 65 0.91 (0.84, 0.98) ⨁⨁⨁ Genotype 1 All evidence Same as trial-only evidence Trial evidence – – – – – Genotype 2 All evidence – – – – – Trial evidence – – – – – Genotype 3 All evidence – – – – – Trial evidence – – – – – Genotype 4 All evidence – – – – – Trial evidence – – – – – Genotype 5 All evidence – – – – – Trial evidence – – – – – Genotype 6 All evidence – – – – – Trial evidence – – – – – Mixed genotype All evidence – – – – –

Treatment-experienced patients only

In the analysis of treatment-experienced only patients with cirrhosis treated with daclatasvir + asunaprevir, evidence was available only for patients with genotype 1 infection. The pooled percentage of patients achieving SVR12 was 83%, with a GRADE assessment of moderate. A summary of the analyses is presented in Table 28.

Table 28: SVR12 in treatment-experienced patients with cirrhosis treated with daclatasvir + asunaprevir, arranged by genotype

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Trial evidence 1 2 174 0.83 (0.75, 0.91) ⨁⨁⨁⨁ Genotype 1 All evidence Same as trial-only evidence Trial evidence – – – – – Genotype 2 All evidence – – – – – Trial evidence – – – – – Genotype 3 All evidence – – – – – Trial evidence – – – – – Genotype 4 All evidence – – – – –

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Trial evidence – – – – – Genotype 5 All evidence – – – – – Trial evidence – – – – – Genotype 6 All evidence – – – – – Trial evidence – – – – – Mixed genotype All evidence – – – – –

Daclatasvir + Sofosbuvir All-treatment experience

In the all-treatment experience analysis of patients with cirrhosis treated with daclatasvir + sofosbuvir, evidence was available for patients with genotypes 1-3, 5, and 6 infection, as well as an unknown or mixed genotype population. The percentage of patients achieving SVR12 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: SVR12 in patients with cirrhosis treated with daclatasvir + sofosbuvir, arranged by genotype

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Trial evidence – – – – – Genotype 1 All evidence 3 4 467 0.93 (0.88, 0.99) ⨁⨁ Trial evidence – – – – – Genotype 2 All evidence 1 1 11 0.96 (0.85, 1.00) ⨁ Trial evidence 1 2 32 0.63 (0.46, 0.80) ⨁⨁ Genotype 3 All evidence 4 7 85 0.79 (0.68, 0.89) ⨁⨁ Trial evidence – – – – – Genotype 4 All evidence – – – – – Trial evidence – – – – – Genotype 5 All evidence 1 1 1 0.75 (0.15, 1.00) ⨁ Trial evidence – – – – – Genotype 6 All evidence 1 3 63 0.93 (0.87, 0.99) ⨁⨁ Trial evidence – – – – – Mixed genotype All evidence 2 3 244 0.83 (0.62, 1.00) ⨁

Treatment-naïve patients only

In the analysis of treatment-naïve only patients with cirrhosis treated with daclatasvir + sofosbuvir, evidence was available only for patients with genotype 3 infection. The percentage of patients achieving SVR12 varied from 58% to 65% across the trial-only and all-evidence analyses. GRADE was assessed as very low in both cases. A summary of the analyses is presented in Table 30.

Table 30: SVR12 in treatment-naïve patients with cirrhosis treated with daclatasvir + asunaprevir, arranged by genotype

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Trial evidence – – – – – Genotype 1 All evidence – – – – – Trial evidence – – – – – Genotype 2 All evidence – – – – – Trial evidence 1 1 19 0.58 (0.36, 0.80) ⨁ Genotype 3 All evidence 2 2 24 0.65 (0.45, 0.85) ⨁ Trial evidence – – – – – Genotype 4 All evidence – – – – – Trial evidence – – – – – Genotype 5 All evidence – – – – – Trial evidence – – – – – Genotype 6 All evidence – – – – – Trial evidence – – – – – Mixed genotype All evidence – – – – –

Treatment-experienced patients only

In the analysis of treatment-experienced only patients with cirrhosis treated with daclatasvir + sofosbuvir, evidence was available for patients with genotypes 1 and 3 infection. The percentage of patients achieving SVR12 varied from 69% to 98%. GRADE assessments varied from very low to low. A summary of the analyses is presented in Table 31.

Table 31: SVR12 in treatment-experienced patients with cirrhosis treated with daclatasvir + sofosbuvir, arranged by genotype

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Trial evidence – – – – – Genotype 1 All evidence 1 1 27 0.98 (0.93, 1.00) ⨁⨁ Trial evidence – – – – – Genotype 2 All evidence – – – – – Trial evidence 1 1 13 0.69 (0.44, 0.94) ⨁ Genotype 3 All evidence 2 2 24 0.82 (0.61, 1.00) ⨁ Trial evidence – – – – – Genotype 4 All evidence – – – – – Trial evidence – – – – – Genotype 5 All evidence – – – – – Trial evidence – – – – – Genotype 6 All evidence – – – – – Mixed genotype Trial evidence – – – – –

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) All evidence – – – – –

Elbasvir + Grazoprevir All-treatment experience

In the all-treatment experience analysis of patients with cirrhosis treated with elbasvir + grazoprevir, evidence was available for patients with genotype 1 infection, as well as an unknown or mixed genotype population. The percentage of patients achieving SVR12 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: SVR12 in patients with cirrhosis treated with elbasvir + grazoprevir, arranged by genotype

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Trial evidence 2 3 95 0.96 (0.92, 1.00) ⨁⨁⨁ Genotype 1 All evidence Same as trial-only evidence Trial evidence – – – – – Genotype 2 All evidence – – – – – Trial evidence – – – – – Genotype 3 All evidence – – – – – Trial evidence – – – – – Genotype 4 All evidence – – – – – Trial evidence – – – – – Genotype 5 All evidence – – – – – Trial evidence – – – – – Genotype 6 All evidence – – – – – Trial evidence 4 5 157 0.97 (0.95, 1.00) ⨁⨁⨁⨁ Mixed genotype All evidence Same as trial-only evidence

Treatment-naïve patients only

In the analysis of treatment-naïve only patients with cirrhosis treated with elbasvir + grazoprevir, evidence was available for patients with genotype 1 infection, as well as an unknown or mixed genotype population. The percentage of patients achieving SVR12 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: SVR12 in treatment-naïve patients with cirrhosis treated with elbasvir + grazoprevir, arranged by genotype

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Trial evidence 1 2 60 0.95 (0.90, 1.00) ⨁⨁ Genotype 1 All evidence Same as trial-only evidence Trial evidence – – – – – Genotype 2 All evidence – – – – –

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Trial evidence – – – – – Genotype 3 All evidence – – – – – Trial evidence – – – – – Genotype 4 All evidence – – – – – Trial evidence – – – – – Genotype 5 All evidence – – – – – Trial evidence – – – – – Genotype 6 All evidence – – – – – Trial evidence 2 2 105 0.98 (0.95, 1.00) ⨁⨁⨁⨁ Mixed genotype All evidence Same as trial-only evidence

Treatment-experienced patients only

In the analysis of treatment-experienced only patients with cirrhosis treated with elbasvir + grazoprevir, evidence was available only for patients in the unknown or mixed genotype population. The percentage of patients achieving SVR12 was 92%, with a GRADE assessment of high. A summary of the analyses is presented in Table 34.

Table 34: SVR12 in treatment-experienced patients with cirrhosis treated with elbasvir + grazoprevir, arranged by genotype

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Trial evidence – – – – – Genotype 1 All evidence – – – – – Trial evidence – – – – – Genotype 2 All evidence – – – – – Trial evidence – – – – – Genotype 3 All evidence – – – – – Trial evidence – – – – – Genotype 4 All evidence – – – – – Trial evidence – – – – – Genotype 5 All evidence – – – – – Trial evidence – – – – – Genotype 6 All evidence – – – – – Trial evidence 1 2 74 0.92 (0.86, 0.98) ⨁⨁⨁⨁ Mixed genotype All evidence Same as trial-only evidence

Glecaprevir + Pibrentasvir All-treatment experience

In the all-treatment experience analysis of patients treated with glecaprevir + pibrentasvir, evidence was available for patients with genotypes 1, 2, and 4-6 infection, as well as an unknown or mixed genotype

population. The percentage of patients achieving SVR12 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: SVR12 in patients with cirrhosis treated with glecaprevir + pibrentasvir, arranged by genotype

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Trial evidence 1 1 90 0.99 (0.97, 1.00) ⨁⨁⨁⨁ Genotype 1 All evidence Same as trial-only evidence Trial evidence 2 2 49 0.98 (0.95, 1.00) ⨁⨁⨁ Genotype 2 All evidence Same as trial-only evidence Trial evidence – – – – – Genotype 3 All evidence – – – – – Trial evidence 1 1 16 0.97 (0.89, 1.00) ⨁ Genotype 4 All evidence Same as trial-only evidence Trial evidence 1 1 2 0.83 (0.41, 1.00) ⨁ Genotype 5 All evidence Same as trial-only evidence Trial evidence 1 1 7 0.94 (0.77, 1.00) ⨁ Genotype 6 All evidence Same as trial-only evidence Trial evidence 1 1 15 0.93 (0.81, 1.00) ⨁ Mixed genotype All evidence Same as trial-only evidence

Treatment-naïve patients only

No evidence was available for the treatment-naive population treated with glecaprevir + pibrentasvir.

Treatment-experienced patients only

No evidence was available for the treatment-experienced population treated with glecaprevir + pibrentasvir.

Ledipasvir + Sofosbuvir All-treatment experience

In the all-treatment experience analysis of patients with cirrhosis treated with ledipasvir + sofosbuvir, evidence was available for patients with genotypes 1, 3, 4, and 6 infection, as well as an unknown or mixed genotype population. The percentage of patients achieving SVR12 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: SVR12 in patients with cirrhosis treated with ledipasvir + sofosbuvir, arranged by genotype

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Trial evidence 7 10 404 0.97 (0.95, 0.98) ⨁⨁⨁⨁ Genotype 1 All evidence 11 14 744 0.96 (0.95, 0.98) ⨁⨁⨁⨁

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Trial evidence – – – – – Genotype 2 All evidence – – – – – Trial evidence – – – – – Genotype 3 All evidence 2 2 14 0.58 (0.33, 0.83) ⨁ Trial evidence 1 2 26 0.94 (0.84, 1.00) ⨁ Genotype 4 All evidence Same as trial-only evidence Trial evidence – – – – – Genotype 5 All evidence – – – – – Trial evidence 1 2 27 0.97 (0.91, 1.00) ⨁⨁ Genotype 6 All evidence 2 3 44 0.75 (0.38, 1.00) ⨁⨁ Trial evidence 2 3 83 0.97 (0.92, 1.00) ⨁⨁⨁⨁ Mixed genotype All evidence 4 6 118 0.94 (0.88, 0.99) ⨁⨁⨁

Treatment-naïve patients only

In the analysis of treatment-naïve only patients with cirrhosis treated with ledipasvir + sofosbuvir, evidence was available for patients with genotypes 1, 4 and 6 infection, as well as an unknown or mixed genotype population. The percentage of patients achieving SVR12 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: SVR12 in treatment-naïve patients with cirrhosis treated with ledipasvir + sofosbuvir, arranged by genotype

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Trial evidence 2 3 78 0.97 (0.93, 1.00) ⨁⨁⨁⨁ Genotype 1 All evidence Same as trial-only evidence Trial evidence – – – – – Genotype 2 All evidence – – – – – Trial evidence – – – – – Genotype 3 All evidence – – – – – Trial evidence 1 1 7 0.86 (0.60, 1.00) ⨁ Genotype 4 All evidence Same as trial-only evidence Trial evidence – – – – – Genotype 5 All evidence – – – – – Trial evidence 1 1 21 0.98 (0.92, 1.00) ⨁ Genotype 6 All evidence Same as trial-only evidence Trial evidence 1 1 20 0.85 (0.69, 1.00) ⨁ Mixed genotype All evidence 2 2 33 0.85 (0.73, 0.93) ⨁⨁

Treatment-experienced patients only

In the analysis of treatment-experienced only patients with cirrhosis treated with ledipasvir + sofosbuvir, evidence was available for patients with genotypes 1 and 6 infection, as well as an unknown or mixed genotype population. The percentage of patients achieving SVR12 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: SVR12 in treatment-experienced patients with cirrhosis treated with ledipasvir + sofosbuvir, arranged by genotype

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Trial evidence 3 4 148 0.97 (0.95, 1.00) ⨁⨁⨁⨁ Genotype 1 All evidence 4 5 175 0.97 (0.95, 1.00) ⨁⨁⨁⨁ Trial evidence – – – – – Genotype 2 All evidence – – – – – Trial evidence – – – – – Genotype 3 All evidence – – – – – Trial evidence – – – – – Genotype 4 All evidence – – – – – Trial evidence – – – – – Genotype 5 All evidence – – – – – Trial evidence 1 1 6 0.83 (0.54, 1.00) ⨁ Genotype 6 All evidence Same as trial-only evidence Trial evidence 1 1 47 0.98 (0.94, 1.00) ⨁⨁ Mixed genotype All evidence 2 2 60 0.95 (0.84, 1.00) ⨁⨁⨁

Paritaprevir/ritonavir + Ombitasvir + Dasabuvir All-treatment experience

In the all-treatment experience analysis of patients with cirrhosis treated with paritaprevir/ritonavir + ombitasvir + dasabuvir, evidence was available only for patients with genotype 1 infection. The percentage of patients achieving SVR12 was 99% in both the trial-only and all evidence analyses. GRADE was assessed as high for both analyses. A summary of the analyses is presented in Table 39.

Table 39: SVR12 in patients with cirrhosis treated with paritaprevir/ritonavir + ombitasvir + dasabuvir, arranged by genotype

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Trial evidence 1 1 60 0.99 (0.97, 1.00) ⨁⨁⨁⨁ Genotype 1 All evidence 3 3 73 0.99 (0.97, 1.00) ⨁⨁⨁⨁ Trial evidence – – – – – Genotype 2 All evidence – – – – – Trial evidence – – – – – Genotype 3 All evidence – – – – –

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Trial evidence – – – – – Genotype 4 All evidence – – – – – Trial evidence – – – – – Genotype 5 All evidence – – – – – Trial evidence – – – – – Genotype 6 All evidence – – – – – Trial evidence – – – – – Mixed genotype All evidence – – – – –

Treatment-naïve patients only

No evidence was available for the treatment-naive population with cirrhosis treated with paritaprevir/ritonavir + ombitasvir + dasabuvir.

Treatment-experienced patients only

No evidence was available for the treatment-experienced population with cirrhosis treated with paritaprevir/ritonavir + ombitasvir + dasabuvir.

Sofosbuvir + Velpatasvir All-treatment experience

In the all-treatment experience analysis of patients with cirrhosis treated with sofosbuvir + velpatasvir, evidence was available for patients with genotypes 1-4 and 6 infection, as well as an unknown or mixed genotype population. The percentage of patients achieving SVR12 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: SVR12 in patients with cirrhosis treated with sofosbuvir + velpatasvir, arranged by genotype

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Trial evidence 1 2 139 0.90 (0.85, 0.95) ⨁⨁⨁⨁ Genotype 1 All evidence Same as trial-only evidence Trial evidence 1 2 8 0.86 (0.64, 1.00) ⨁ Genotype 2 All evidence Same as trial-only evidence Trial evidence 3 6 215 0.86 (0.77, 0.96) ⨁⨁ Genotype 3 All evidence Same as trial-only evidence Trial evidence 1 2 6 0.88 (0.66, 1.00) ⨁ Genotype 4 All evidence Same as trial-only evidence Genotype 5 Trial evidence – – – –

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) All evidence – – – –

Trial evidence 1 1 1 0.75 (0.15, 1.00) ⨁ Genotype 6 All evidence Same as trial-only evidence Trial evidence 4 4 293 0.97 (0.94, 1.00) ⨁⨁⨁⨁ Mixed genotype All evidence Same as trial-only evidence

Treatment-naïve patients only

In the analysis of treatment-naïve only patients with cirrhosis treated with sofosbuvir + velpatasvir, evidence was available only for patients with genotype 3 infection. The percentage of patients achieving SVR12 was 97%, with evidence 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 41.

Table 41: SVR12 in treatment-naïve patients with cirrhosis treated with sofosbuvir + velpatasvir, arranged by genotype

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Trial evidence – – – – – Genotype 1 All evidence – – – – – Trial evidence – – – – – Genotype 2 All evidence – – – – – Trial evidence 2 2 120 0.97 (0.92, 1.00) ⨁⨁⨁⨁ Genotype 3 All evidence Same as trial-only evidence Trial evidence – – – – – Genotype 4 All evidence – – – – – Trial evidence – – – – – Genotype 5 All evidence – – – – – Trial evidence – – – – – Genotype 6 All evidence – – – – – Trial evidence – – – – – Mixed genotype All evidence – – – – –

Treatment-experienced patients only

In the analysis of treatment-experienced only patients with cirrhosis treated with sofosbuvir + velpatasvir, evidence was available for patients with genotype 2 infection as well as an unknown or mixed genotype population. The percentage of patients achieving SVR12 varied from 86% to 90%. GRADE was assessed as moderate in both analyses. A summary of the analyses is presented in Table 42.

Table 42: SVR12 in treatment-experienced patients with cirrhosis treated with sofosbuvir + velpatasvir, arranged by genotype

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Trial evidence – – – – – Genotype 1 All evidence – – – – – Trial evidence – – – – – Genotype 2 All evidence – – – – – Trial evidence 2 2 69 0.90 (0.83, 0.97) ⨁⨁⨁ Genotype 3 All evidence Same as trial-only evidence Trial evidence – – – – – Genotype 4 All evidence – – – – – Trial evidence – – – – – Genotype 5 All evidence – – – – – Trial evidence – – – – – Genotype 6 All evidence – – – – – Trial evidence 1 1 69 0.86 (0.77, 0.94) ⨁⨁⨁ Mixed genotype All evidence Same as trial-only evidence

Sofosbuvir + Velpatasvir + Voxilaprevir All-treatment experience

In the all-treatment experience analysis of patients with cirrhosis treated with sofosbuvir + velpatasvir + voxilaprevir, evidence was available for patients with genotypes 1 and 3, as well as an unknown or mixed genotype population. The percentage of patients achieving SVR12 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: SVR12 in patients with cirrhosis treated with sofosbuvir + velpatasvir + voxilaprevir, arranged by genotype

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Trial evidence 1 1 11 0.96 (0.85, 1.00) ⨁ Genotype 1 All evidence Same as trial-only evidence Trial evidence – – – – – Genotype 2 All evidence – – – – – Trial evidence 1 2 110 0.96 (0.93, 1.00) ⨁⨁⨁⨁ Genotype 3 All evidence Same as trial-only evidence Trial evidence – – – – – Genotype 4 All evidence – – – – – Trial evidence – – – – – Genotype 5 All evidence – – – – – Genotype 6 Trial evidence – – – – –

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) All evidence – – – – – Trial evidence 3 3 295 0.95 (0.91, 0.98) ⨁⨁⨁⨁ Mixed genotype All evidence Same as trial-only evidence

Treatment-naïve patients only

In the analysis of treatment-naïve only patients with cirrhosis treated with sofosbuvir + velpatasvir + voxilaprevir, evidence was available only for patients with genotype 3 infection. The percentage of patients achieving SVR12 was 96%, with evidence 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: SVR12 in treatment-naïve patients with cirrhosis treated with sofosbuvir + velpatasvir + voxilaprevir, arranged by genotype

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Trial evidence – – – – – Genotype 1 All evidence – – – – – Trial evidence – – – – – Genotype 2 All evidence – – – – – Trial evidence 1 1 75 0.96 (0.92, 1.00) ⨁⨁⨁ Genotype 3 All evidence Same as trial-only evidence Trial evidence – – – – – Genotype 4 All evidence – – – – – Trial evidence – – – – – Genotype 5 All evidence – – – – – Trial evidence – – – – – Genotype 6 All evidence – – – – – Trial evidence – – – – – Mixed genotype All evidence – – – – –

Treatment-experienced patients only

In the analysis of treatment-experienced only patients with cirrhosis treated with sofosbuvir + velpatasvir + voxilaprevir, evidence was available for patients with genotypes 1 and 3 infection, as well as an unknown or mixed genotype population. The percentage of patients achieving SVR12 varied from 96% to 97%, with evidence 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 45.

Table 45: SVR12 in treatment-experienced patients with cirrhosis treated with sofosbuvir + velpatasvir + voxilaprevir, arranged by genotype

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Trial evidence 1 1 11 0.96 (0.85, 1.00) ⨁ Genotype 1 All evidence Same as trial-only evidence Trial evidence – – – – – Genotype 2 All evidence – – – – – Trial evidence 1 1 35 0.97 (0.92, 1.00) ⨁⨁ Genotype 3 All evidence Same as trial-only evidence Trial evidence – – – – – Genotype 4 All evidence – – – – – Trial evidence – – – – – Genotype 5 All evidence – – – – – Trial evidence – – – – – Genotype 6 All evidence – – – – – Trial evidence 2 2 205 0.96 (0.92, 1.00) ⨁⨁⨁⨁ Mixed genotype All evidence Same as trial-only evidence

Daclatasvir + Sofosbuvir + Ribavirin All-treatment experience

The literature review for daclatasvir + sofosbuvir + ribavirin was restricted to patients with cirrhosis and genotype 2 or 3 infection. No evidence was identified for patients with genotype 2 infection. From the all- treatment experience analysis of patients with genotype 3 infection, the pooled percentage of patients achieving SVR12 varied from 86% to 91%, with GRADE assessed as low. A summary of the analyses is presented in Table 46.

Table 46: SVR12 in genotype 2 or 3 patients with cirrhosis treated with daclatasvir + sofosbuvir + ribavirin, arranged by genotype

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Trial evidence – – – – – Genotype 2 All evidence – – – – – Trial evidence 1 4 36 0.86 (0.76, 0.97) ⨁⨁ Genotype 3 All evidence 6 11 361 0.91 (0.86, 0.97) ⨁⨁

Treatment-naïve patients only

In the analysis of treatment-naïve only patients with cirrhosis treated daclatasvir + sofosbuvir + ribavirin, evidence was only available for patients with genotype 3 infection. The pooled percentage of patients achieving SVR12 varied from 83% and 98% across the trial-only and all-evidence analyses, respectively. GRADE was assessed as very low both cases. A summary of the analyses is presented in Table 47.

Table 47: SVR12 in treatment-naïve genotype 2 or 3 patients with cirrhosis treated with daclatasvir + sofosbuvir + ribavirin, arranged by genotype

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Trial evidence – – – – – Genotype 2 All evidence – – – – – Trial evidence 1 2 6 0.83 (0.54, 1.00) ⨁ Genotype 3 All evidence 2 4 80 0.98 (0.95, 1.00) ⨁

Treatment-experienced patients only

In the analysis of treatment-experienced only patients with cirrhosis treated daclatasvir + sofosbuvir + ribavirin, evidence was only available for patients with genotype 3 infection. From a single clinical trial (N=30), the percentage of patients achieving SVR12 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: SVR12 in treatment-experienced genotype 2 or 3 patients with cirrhosis treated with daclatasvir + sofosbuvir + ribavirin, arranged by genotype

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Trial evidence – – – – – Genotype 2 All evidence – – – – – Trial evidence 1 2 30 0.87 (0.75, 0.99) ⨁⨁ Genotype 3 All evidence Same as trial-only evidence

Sofosbuvir + Ribavirin All-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 SVR12 varied from 61% to 86%, with GRADE assessed as low in all cases. A summary of the analyses is presented in Table 49.

Table 49: SVR12 in genotype 2 or 3 patients with cirrhosis treated with sofosbuvir + ribavirin, arranged by genotype

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Trial evidence 5 8 107 0.79 (0.72, 0.87) ⨁⨁ Genotype 2 All evidence 10 18 486 0.86 (0.81, 0.90) ⨁⨁ Trial evidence 7 14 369 0.69 (0.58, 0.80) ⨁⨁ Genotype 3 All evidence 12 20 603 0.67 (0.58, 0.76) ⨁⨁ Mixed genotype Trial evidence 1 1 33 0.61 (0.44, 0.77) ⨁⨁

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) 2 & 3 All evidence Same as trial-only evidence

Treatment-naïve patients only

In the analysis of treatment-naïve only patients with cirrhosis treated sofosbuvir + ribavirin, 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 SVR12 varied from 61% to 85%, with GRADE assessed as low in all cases. A summary of the analyses is presented in Table 50.

Table 50: SVR12 in treatment-naïve genotype 2 or 3 patients with cirrhosis treated with sofosbuvir + ribavirin, arranged by genotype

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Trial evidence 2 2 48 0.77 (0.65, 0.88) ⨁⨁ Genotype 2 All evidence 4 5 132 0.85 (0.73, 0.97) ⨁⨁ Trial evidence 4 6 105 0.79 (0.69, 0.89) ⨁⨁ Genotype 3 All evidence 6 8 198 0.74 (0.64, 0.84) ⨁⨁ Mixed genotype Trial evidence 1 1 33 0.61 (0.44, 0.77) ⨁⨁ 2 & 3 All evidence Same as trial-only evidence

Treatment-experienced patients only

In the analysis of treatment-experienced only patients with cirrhosis treated sofosbuvir + ribavirin, evidence was available for patients with genotypes 2 and 3 infection. The pooled percentage of patients achieving SVR12 varied from 57% to 82%, with GRADE assessments varying from low to moderate. A summary of the analyses is presented in Table 51.

Table 51: SVR12 in treatment-experienced genotype 2 or 3 patients with cirrhosis treated with sofosbuvir + ribavirin, arranged by genotype

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Trial evidence 3 4 40 0.79 (0.67, 0.91) ⨁⨁ Genotype 2 All evidence 5 7 132 0.82 (0.76, 0.88) ⨁⨁⨁ Trial evidence 4 6 180 0.57 (0.38, 0.75) ⨁⨁ Genotype 3 All evidence 7 8 260 0.55 (0.41, 0.70) ⨁⨁

Efficacy outcomes (SVR12) – Patients with HIV co-infection

For each treatment in the patients with HIV co-infection subset, the pooled proportions of patients achieving SVR12 are presented by genotype in an all-treatment experience population only.

Daclatasvir + Asunaprevir No evidence was available for the treatment-naive population with HIV co-infection treated with daclatasvir + asunaprevir.

Daclatasvir + Sofosbuvir All-treatment experience

In patients with HIV co-infection treated with daclatasvir + sofosbuvir, evidence on the percentage of patients achieving SVR12 was available only in a mixed or unknown genotype population across two observational studies (N=347). The pooled percentage of patients achieving SVR12 was 87%. The GRADE assessment was very low. A summary of the analyses is presented in Table 52.

Table 52: SVR12 in HIV co-infected patients treated with daclatasvir + sofosbuvir, arranged by genotype

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Trial evidence – – – – – Genotype 1 All evidence – – – – – Trial evidence – – – – – Genotype 2 All evidence – – – – – Trial evidence – – – – – Genotype 3 All evidence – – – – – Trial evidence – – – – – Genotype 4 All evidence – – – – – Trial evidence – – – – – Genotype 5 All evidence – – – – – Trial evidence – – – – – Genotype 6 All evidence – – – – – Trial evidence – – – – – Mixed genotype All evidence 2 2 347 0.87 (0.69, 1.00) ⨁

Elbasvir + Grazoprevir All-treatment experience

In patients with HIV co-infection treated with elbasvir + grazoprevir, evidence was available for patients with genotypes 1, 4, and 6 infection, as well as an unknown or mixed genotype population. The pooled percentage of patients achieving SVR12 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: SVR12 in HIV co-infected patients treated with elbasvir + grazoprevir, arranged by genotype

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Trial evidence 2 4 248 0.92 (0.85, 0.99) ⨁⨁⨁ Genotype 1 All evidence Same as trial-only evidence Trial evidence – – – – – Genotype 2 All evidence – – – – – Trial evidence – – – – – Genotype 3 All evidence – – – – – Trial evidence 1 1 28 0.96 (0.90, 1.00) ⨁⨁ Genotype 4 All evidence Same as trial-only evidence Trial evidence – – – – – Genotype 5 All evidence – – – – – Trial evidence 1 1 2 0.83 (0.41, 1.00) ⨁ Genotype 6 All evidence Same as trial-only evidence Trial evidence 1 1 6 0.83 (0.54, 1.00) ⨁ Mixed genotype All evidence Same as trial-only evidence

Glecaprevir + Pibrentasvir All-treatment experience

In patients with HIV co-infection treated with glecaprevir + pibrentasvir, evidence on the percentage of patients achieving SVR12 was available only for patients in an unknown or mixed genotype population coming from a single observational study. The percentage of patients achieving SVR12 was 100%. The GRADE assessment was high. A summary of the analyses is presented in Table 54.

Table 54: SVR12 in HIV co-infected patients treated with glecaprevir + pibrentasvir, arranged by genotype

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) All evidence – – – – – Trial evidence – – – – – Genotype 5 All evidence – – – – – Trial evidence – – – – – Genotype 6 All evidence – – – – – Trial evidence 1 2 151 1.00 (0.99, 1.00) ⨁⨁⨁⨁ Mixed genotype All evidence Same as trial-only evidence

Ledipasvir + Sofosbuvir All-treatment experience

In patients with HIV co-infection treated with ledipasvir + sofosbuvir, evidence was available for patients with genotypes 1 and 4, as well as an unknown or mixed genotype population. The pooled percentage of patients achieving SVR12 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: SVR12 in HIV co-infected patients treated with ledipasvir + sofosbuvir, arranged by genotype

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Trial evidence 3 3 129 0.98 (0.95, 1.00) ⨁⨁⨁⨁ Genotype 1 All evidence 5 5 383 0.96 (0.93, 0.98) ⨁⨁⨁ Trial evidence – – – – – Genotype 2 All evidence – – – – – Trial evidence – – – – – Genotype 3 All evidence – – – – – Trial evidence 1 1 1 0.75 (0.15, 1.00) ⨁ Genotype 4 All evidence Same as trial-only evidence Trial evidence – – – – – Genotype 5 All evidence – – – – – Trial evidence – – – – – Genotype 6 All evidence – – – – – Trial evidence 1 2 335 0.96 (0.94, 0.98) ⨁⨁⨁⨁ Mixed genotype All evidence 3 4 364 0.96 (0.94, 0.98) ⨁⨁⨁⨁

Paritaprevir/ritonavir + Ombitasvir + Dasabuvir All-treatment experience

In patients with HIV co-infection treated with paritaprevir/ritonavir + ombitasvir + dasabuvir, evidence on the percentage of patients achieving SVR12 was available only for patients with genotype 1 infection in an observational study. The percentage of patients achieving SVR12 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 56.

Table 56: SVR12 in HIV co-infected patients treated with paritaprevir/ritonavir + ombitasvir + dasabuvir, arranged by genotype

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Trial evidence – – – – – Genotype 1 All evidence 1 1 7 0.86 (0.60, 1.00) ⨁ Trial evidence – – – – – Genotype 2 All evidence – – – – – Trial evidence – – – – – Genotype 3 All evidence – – – – – Trial evidence – – – – – Genotype 4 All evidence – – – – – Trial evidence – – – – – Genotype 5 All evidence – – – – – Trial evidence – – – – – Genotype 6 All evidence – – – – – Trial evidence – – – – – Mixed genotype All evidence – – – – –

Sofosbuvir + Velpatasvir All-treatment experience

In patients with HIV co-infection treated with ledipasvir + sofosbuvir, evidence was available for patients with genotypes 1-4 infection. The pooled percentage of patients achieving SVR12 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: SVR12 in HIV co-infected patients treated with ledipasvir + sofosbuvir, arranged by genotype

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Trial evidence 1 1 78 0.95 (0.90, 1.00) ⨁⨁ Genotype 1 All evidence Same as trial-only evidence Trial evidence 1 1 11 0.96 (0.85, 1.00) ⨁ Genotype 2 All evidence Same as trial-only evidence Trial evidence 1 1 12 0.92 (0.76, 1.00) ⨁ Genotype 3 All evidence Same as trial-only evidence Trial evidence 1 1 5 0.92 (0.70, 1.00) ⨁ Genotype 4 All evidence Same as trial-only evidence Trial evidence – – – – – Genotype 5 All evidence – – – – – Trial evidence – – – – – Genotype 6 All evidence – – – – – Mixed genotype Trial evidence – – – – –

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) All evidence – – – – –

Sofosbuvir + Velpatasvir + Voxilaprevir No evidence was available for the treatment-naive population with HIV co-infection treated with sofosbuvir + velpatasvir + voxilaprevir.

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 ≥1 dose). Comparative evidence 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

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Daclatasvir + Trial evidence 12 15 3496 0.04 (0.02, 0.05) ⨁⨁⨁ asunaprevir All evidence 18 21 7186 0.04 (0.03, 0.05) ⨁⨁⨁ Daclatasvir + Trial evidence 5 8 650 0.01 (0.00, 0.01) ⨁⨁⨁ sofosbuvir All evidence 12 20 1955 0.01 (0.01, 0.01) ⨁⨁⨁ Elbasvir + Trial evidence 11 22 2084 0.01 (0.00, 0.01) ⨁⨁⨁ grazoprevir All evidence 12 23 2105 0.01 (0.00, 0.01) ⨁⨁⨁ Glecaprevir + Trial evidence 10 14 1333 0.01 (0.00, 0.01) ⨁⨁⨁ pibrentasvir All evidence Same as trial-only evidence Ledipasvir + Trial evidence 20 27 3102 0.00 (0.00, 0.01) ⨁⨁⨁ sofosbuvir All evidence 29 36 4678 0.00 (0.00, 0.01) ⨁⨁⨁ Paritaprevir/ritonavir Trial evidence 6 6 938 0.00 (0.00, 0.01) ⨁⨁⨁ + ombitasvir + dasabuvir All evidence 7 7 973 0.00 (0.00, 0.01) ⨁⨁⨁ Sofosbuvir + Trial evidence 10 15 2445 0.00 (0.00, 0.01) ⨁⨁⨁ velpatasvir All evidence Same as trial-only evidence Sofosbuvir + Trial evidence 5 5 1080 0.00 (0.00, 0.00) ⨁⨁⨁ velpatasvir + voxilaprevir All evidence Same as trial-only evidence Daclatasvir + Trial evidence 1 6 72 0.03 (0.00, 0.07) ⨁⨁⨁ sofosbuvir + ribavirin* All evidence 2 7 126 0.02 (0.00, 0.04) ⨁⨁⨁ Sofosbuvir + Trial evidence 3 4 736 0.02 (0.01, 0.03) ⨁⨁⨁ ribavirin* All evidence 4 6 908 0.02 (0.01, 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 with cirrhosis and genotype 2 or 3 infection. Across treatments and studies, the number of SAEs was very low, with the pooled percentage varying 1% 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

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Daclatasvir + Trial evidence 9 12 1940 0.05 (0.03, 0.07) ⨁⨁⨁⨁ asunaprevir All evidence 12 15 2422 0.03 (0.02, 0.04) ⨁⨁⨁⨁ Daclatasvir + Trial evidence 5 8 650 0.01 (0.00, 0.02) ⨁⨁⨁⨁ sofosbuvir All evidence 10 19 1875 0.03 (0.01, 0.05) ⨁⨁⨁ Elbasvir + Trial evidence 10 20 2022 0.02 (0.01, 0.02) ⨁⨁⨁⨁ grazoprevir All evidence Same as trial-only evidence Glecaprevir + Trial evidence 9 14 1309 0.02 (0.01, 0.02) ⨁⨁⨁⨁ pibrentasvir All evidence Same as trial-only evidence Ledipasvir + Trial evidence 19 26 2572 0.02 (0.01, 0.03) ⨁⨁⨁⨁ sofosbuvir All evidence 23 30 2747 0.02 (0.01, 0.03) ⨁⨁⨁⨁ Paritaprevir/ritonavir Trial evidence 6 6 938 0.02 (0.01, 0.02) ⨁⨁⨁⨁ + ombitasvir + dasabuvir All evidence Same as trial-only evidence Sofosbuvir + Trial evidence 10 15 2445 0.03 (0.02, 0.04) ⨁⨁⨁⨁ velpatasvir All evidence Same as trial-only evidence Sofosbuvir + Trial evidence 5 5 1080 0.02 (0.02, 0.03) ⨁⨁⨁⨁ velpatasvir + voxilaprevir All evidence Same as trial-only evidence Daclatasvir + Trial evidence ------sofosbuvir + All evidence ------ribavirin* Sofosbuvir + Trial evidence 3 4 736 0.05 (0.03, 0.07) ⨁⨁⨁⨁ ribavirin* All evidence Same as trial-only evidence

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 evidence types. A summary of the analyses is presented in Table 60.

Table 60: Mortality, arranged by treatment

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Daclatasvir + Trial evidence 7 9 1863 0.00 (0.00, 0.01) ⨁⨁⨁⨁ asunaprevir All evidence 11 14 4832 0.00 (0.00, 0.00) ⨁⨁⨁⨁ Daclatasvir + Trial evidence 4 7 535 0.01 (0.00, 0.01) ⨁⨁⨁⨁ sofosbuvir All evidence 11 22 2156 0.01 (0.00, 0.01) ⨁⨁⨁⨁ Elbasvir + Trial evidence 8 18 1741 0.00 (0.00, 0.01) ⨁⨁⨁⨁ grazoprevir All evidence 9 19 1762 0.00 (0.00, 0.01) ⨁⨁⨁⨁

Number Number Pooled proportion Total N GRADE of studies of arms (95% CI) Glecaprevir + Trial evidence 3 4 539 0.01 (0.00, 0.02) ⨁⨁⨁⨁ pibrentasvir All evidence Same as trial-only evidence Ledipasvir + Trial evidence 13 17 1177 0.01 (0.00, 0.01) ⨁⨁⨁⨁ sofosbuvir All evidence 20 24 2317 0.00 (0.00, 0.00) ⨁⨁⨁⨁ Paritaprevir/ritonavir Trial evidence 5 5 878 0.00 (0.00, 0.01) ⨁⨁⨁⨁ + ombitasvir + dasabuvir All evidence 6 6 913 0.00 (0.00, 0.01) ⨁⨁⨁⨁ Sofosbuvir + Trial evidence 10 15 2445 0.00 (0.00, 0.00) ⨁⨁⨁⨁ velpatasvir All evidence Same as trial-only evidence Sofosbuvir + Trial evidence 5 5 1080 0.00 (0.00, 0.00) ⨁⨁⨁⨁ velpatasvir + voxilaprevir All evidence Same as trial-only evidence Daclatasvir + Trial evidence 1 6 72 0.04 (0.00, 0.09) ⨁⨁⨁⨁ sofosbuvir + ribavirin* All evidence 2 7 93 0.04 (0.00, 0.07) ⨁⨁⨁⨁ Sofosbuvir + Trial evidence 3 4 736 0.00 (0.00, 0.01) ⨁⨁⨁⨁ ribavirin* All evidence 6 8 939 0.01 (0.00, 0.01) ⨁⨁⨁⨁

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 treatment- experience. Treatments typically yielded high SVR12 rates, and GRADE assessments were often rated as high or moderate. However, there was mixed evidence 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 evidence 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 SVR12 rates in these patients were generally high. Safety outcome evidence, 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 evidence 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 SVR12 rates should be interpreted with caution.

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 evidence 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 evidence 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 evidence. 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 SVR12, though some studies only reported SVR24 data. Thus, there are opportunities to explore additional stratifications and evidence through future analyses.

Separate analyses were conducted for trial-only evidence and all available evidence, 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 evidence 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.

APPENDICES

Appendix A: Search strategies

Table A61: Search strategy for EMBASE

No. Query 1 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/1-2 exp grazoprevir/ or exp elbasvir/ or exp elbasvir plus grazoprevir/ or exp ruzasvir/ or exp 4 uprifosbuvir/ 5 (grazoprevir or mk5172 or (mk adj2 "5172")).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/ 10 (glecaprevir or abt493 or (abt adj2 "493")).ti,ab. 11 (pibrentasvir or abt530 or (abt adj2 "530")).ti,ab. exp sofosbuvir/ or exp ledipasvir/ or exp ledipasvir plus sofosbuvir/ or exp velpatasvir/ or exp 12 sofosbuvir plus velpatasvir/ or exp voxilaprevir/ 13 (sofosbuvir or gs7977 or (gs adj2 "7977")).ti,ab. 14 (ledipasvir or gs5885 or (gs adj2 "5885")).ti,ab. 15 (velpatasvir or gs5816 or (gs adj2 "5816")).ti,ab. 16 (voxilaprevir or gs9857 or (gs adj2 "9857")).ti,ab. 17 exp daclatasvir/ or daclatasvir plus sofosbuvir/ or exp asunaprevir/ 18 (daclatasvir or bms790052 or (bms adj2 "790052")).ti,ab. 19 (asunaprevir or bms650032 or (bms adj2 "650032")).ti,ab. 20 exp simeprevir/ or simeprevir plus sofosbuvir/ or exp odalasvir/ 21 (simeprevir or tmc435 or (tmc adj2 "435")).ti,ab. 22 (odalasvir or ach3102 or (ach adj2 "3102")).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 sch503034 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 31 Epclusa or Sofosvel or Velpanat or Daklinza or Sunvepra or Technivie or Viekira or Holkira or Exviera).ti,ab. 32 or/4-31 33 clinical trial/ 34 randomized controlled trial/ 35 controlled clinical trial/ 36 multicenter study/

37 phase 2 clinical trial/ 38 phase 3 clinical trial/ 39 phase 4 clinical trial/ 40 exp randomization/ 41 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. 51 placebo$.tw. 52 prospective study/ 53 or/33-52 54 clinical study/ 55 case control study/ 56 family study/ 57 longitudinal study/ 58 retrospective study/ 59 prospective study/ 60 cohort analysis/ 61 (cohort adj (study or studies)).mp. 62 (case control adj (study or studies)).tw. 63 (follow up adj (study or studies)).tw. 64 (observational adj (study or studies)).tw. 65 (epidemiologic$ adj (study or studies)).tw. 66 (cross sectional adj (study or studies)).tw. 67 or/54-66 68 53 or 67 69 case study/ 70 case report.tw. 71 abstract report/ or letter/ 72 conference proceeding.pt. 73 conference abstract.pt. 74 editorial.pt. 75 letter.pt. 76 note.pt. 77 or/69-76 78 68 not 77 79 3 and 32 and 78 80 limit 79 to english language

Table A62: Search strategy for MEDLINE

No. Query 1 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/1-2 4 (grazoprevir or mk5172 or (mk adj2 "5172")).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. 10 exp sofosbuvir/ 11 (sofosbuvir or gs7977 or (gs adj2 "7977")).mp. 12 (ledipasvir or gs5885 or (gs adj2 "5885")).mp. 13 (velpatasvir or gs5816 or (gs adj2 "5816")).mp. 14 (voxilaprevir or gs9857 or (gs adj2 "9857")).mp. 15 (daclatasvir or bms790052 or (bms adj2 "790052")).mp. 16 (asunaprevir or bms650032 or (bms adj2 "650032")).mp. 17 exp simeprevir/ 18 (simeprevir or tmc435 or (tmc adj2 "435")).mp. 19 (odalasvir or ach3102 or (ach adj2 "3102")).mp. 20 (al335 or (al adj2 "335")).mp. 21 (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 sch503034 or (sch adj2 "503034")).mp. 25 (telaprevir or teleprevir or telepravir or vx950 or (vx adj2 "950")).mp. (Incivek or Incivo or Victrelis or Olysio or Galexos or Sovriad or Valdi or Virunon or Harvoni or 26 Epclusa or Sofosvel or Velpanat or Daklinza or Sunvepra or Technivie or Viekira or Holkira or Exviera).mp. 27 or/4-26 28 randomized controlled trials as topic/ 29 randomized controlled trial/ 30 random allocation/ 31 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.

37 clinical trial, phase iv.pt. 38 controlled clinical trial.pt. 39 randomized controlled trial.pt. 40 multicenter study.pt. 41 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$).tw. 49 or/28-48 50 epidemiologic studies/ 51 exp case control studies/ 52 exp cohort studies/ 53 case control.tw. 54 (cohort adj (study or studies)).tw. 55 cohort analy$.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. 61 cross-sectional studies/ 62 or/50-61 63 49 or 62 64 case report.tw. 65 letter/ 66 historical article/ 67 or/64-66 68 63 not 67 69 3 and 27 and 68 70 limit 69 to english language

Table A63: Search strategy for CENTRAL

No. Query 1 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/1-2 4 (grazoprevir or mk5172 or (mk adj2 "5172")).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. 10 exp sofosbuvir/ 11 (sofosbuvir or gs7977 or (gs adj2 "7977")).mp. 12 (ledipasvir or gs5885 or (gs adj2 "5885")).mp. 13 (velpatasvir or gs5816 or (gs adj2 "5816")).mp. 14 (voxilaprevir or gs9857 or (gs adj2 "9857")).mp. 15 (daclatasvir or bms790052 or (bms adj2 "790052")).mp. 16 (asunaprevir or bms650032 or (bms adj2 "650032")).mp. 17 exp simeprevir/ 18 (simeprevir or tmc435 or (tmc adj2 "435")).mp. 19 (odalasvir or ach3102 or (ach adj2 "3102")).mp. 20 (al335 or (al adj2 "335")).mp. 21 (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 sch503034 or (sch adj2 "503034")).mp. 25 (telaprevir or teleprevir or telepravir or vx950 or (vx adj2 "950")).mp. (Incivek or Incivo or Victrelis or Olysio or Galexos or Sovriad or Valdi or Virunon or Harvoni or 26 Epclusa or Sofosvel or Velpanat or Daklinza or Sunvepra or Technivie or Viekira or Holkira or Exviera).mp. 27 or/4-26 28 3 and 27 29 limit 28 to english language

Appendix B: Publication eligibility assessment process

Table B1: Exclusion hierarchy for abstract screening

Hierarchy Reason Exclude if: 1 Duplicate publications Multiple entries for same publication 2 Other Published prior to 2015 Review/editorial/letter/comment/meta-analysis 3 Study design Pre-clinical/In-vitro studies Not chronically infected with HCV 4 Populations Not adult population (<18 years of age) 5 Interventions Not specified treatment

Table B2: Exclusion hierarchy for full text screening

Hierarchy Reason Exclude if: 1 Other Published prior to 2015* 2 Study design Review/editorial/letter/comment/meta-analysis Pre-clinical/In-vitro studies Not chronically infected with HCV 3 Populations Not adult population (<18 years of age) 4 Interventions Not specified treatment 5 Outcomes At least 1 outcome of interest is not reported *If not evaluable at abstract screening phase

Appendix C: Included studies

Table C1: List of included studies, with treatments and study design categorization

Study design

Observational Study name Registration Treatment arms Trial study Abdel-Aziz 201710 – DAC 60 mg qd 12 weeks + SOF 400 mg qd 12 weeks Yes – DAC 60 mg 24 weeks + SOF 400 mg 24 weeks AI444-040187 NCT01359644 Yes – DAC 60 mg 12 weeks + SOF 400 mg 12 weeks AI447-017139,191,225 NCT01051414 DAC 60 mg 24 weeks + ASV 200 mg bid 24 weeks Yes – AI447-031102 NCT01718145 DAC 60 mg qd 24 weeks + ASV 100 mg bid 24 weeks Yes – DAC 60 mg qd 12 weeks + SOF 400 mg qd 12 weeks + RBV 1000 mg/day (<75 kg) or 1200 mg/day (≥75 kg), 12 weeks ALLY 3+126,137 NCT02319031 Yes – DAC 60 mg qd 16 weeks + SOF 400 mg qd 16 weeks + RBV 1000 mg/day (<75 kg) or 1200 mg/day (≥75 kg), 16 weeks DAC 60 mg qd 8 weeks + SOF 400 mg qd 8 weeks ALLY-224,131,137,220-222 NCT02032888 Yes – DAC 60 mg qd 12 weeks + SOF 400 mg qd 12 weeks ALLY-325,111,137,148,149 NCT02032901 DAC 60 mg 12 weeks + SOF 400 mg 12 weeks Yes –

ANRS CO22 DAC 60 mg qd 12 weeks + SOF 400 mg qd 12 weeks 55,164 NCT01953458 – Yes HEPATHER DAC 60 mg qd 24 weeks + SOF 400 mg qd 24 weeks ASCEND103 – LDV 2, 3, or 6 months + SOF 2, 3, or 6 months Yes –

ASTRAL- SOF 400 mg qd 12 weeks + VEL 100 mg qd 12 weeks 49,71,73,94,146,219,229 NCT02201940 Yes – 1 PBO SOF 400 mg qd 12 weeks + VEL 100 mg qd 12 weeks ASTRAL- 59,71,73,94,146,185,219,231 NCT02220998 Yes – 2 SOF 400 mg qd 12 weeks + RBV bid 12 weeks for 1000 mg daily (body weight <75 kg) or 1200 mg daily (body weight ≥75 kg) SOF 400 mg qd 12 weeks + VEL 100 mg qd 12 weeks ASTRAL- NCT02201953 Yes – 359,71,73,94,146,219,231 SOF 400 mg qd 24 weeks + RBV bid 24 weeks for 1000 mg daily (body weight <75 kg) or 1200 mg daily (body weight ≥75 kg) ASTRAL- SOF 400 mg qd 12 weeks + VEL 100 mg qd 12 weeks 29,37,38,146,157,228 NCT02201901 Yes – 4 SOF 400 mg qd 24 weeks + VEL 100 mg qd 24 weeks ASTRAL- 109,146,218,219,232 NCT02480712 SOF 400 mg qd 12 weeks + VEL 100 mg qd 12 weeks Yes – 5

Study design

Observational Study name Registration Treatment arms Trial study Autorisation DAC 30/60/90 qd 12 weeks + SOF 400 mg qd 12 weeks Temporaire – – Yes d’Utilisation DAC 30/60/90 qd 24 weeks + SOF 400 mg qd 24 weeks (ATU) Program120 LDV ≤12 weeks + SOF ≤12 weeks Backus 201618 – – Yes PTV/r ≤12 weeks + OMV ≤12 weeks + DBV ≤12 weeks DAC 60 mg 12 weeks + SOF 400 mg 12 weeks

19 DAC 60 mg 12 weeks + SOF 400 mg 12 weeks + RBV 1000 mg/day (<75 kg) or 1200 Bansal 2017 – mg/day (≥75 kg), twice per day 12 weeks – Yes DAC 60 mg 24 weeks + SOF 400 mg 24 weeks + RBV 1000 mg/day (<75 kg) or 1200 mg/day (≥75 kg), twice per day 24 weeks SOF 400 mg qd 16 weeks + RBV 1000 mg/day (<75 kg) or 1200 mg/day (≥75 kg), twice per day 16 weeks BOSON62,63 – Yes – SOF 400 mg qd 24 weeks + RBV 1000 mg/day (<75 kg) or 1200 mg/day (≥75 kg), twice per day 24 weeks ESV 50 mg qd 12 weeks + GZR 100 mg qd 12 weeks C-CORAL72,205,212 – Yes – PBO 12 weeks C-EDGE 172 NCT02105662 ESV 50 mg qd 12 weeks + GZR 100 mg qd 12 weeks Yes – CO-INFECTION C-EDGE ESV 50 mg qd 12 weeks + GZR 100 mg qd 12 weeks 45,46 NCT02105688 Yes – CO-STAR PBO C-EDGE 179,180 NCT02358044 ESV 50 mg qd 12 weeks + GZR 100 mg qd 12 weeks Yes – HEAD-2-HEAD ESV 50 mg qd 12 weeks + GZR 100 mg qd 12 weeks C-EDGE IBLD75-78,181 NCT02252016 Yes – PBO C-EDGE ESV 50 mg qd 12 weeks + GZR 100 mg qd 12 weeks Treatment- NCT02105701 Yes – Experienced115-117 ESV 50 mg qd 16 weeks + GZR 100 mg qd 16 weeks C-EDGE ESV 50 mg qd 12 weeks + GZR 100 mg qd 12 weeks Treatment- NCT02105467 Yes – Naïve152,224,243-245 PBO CERTAIN-1, 30,31,198 NCT02707952 GCR 300 mg qd 12 weeks + PBV 120 mg qd 12 weeks Yes – Sub-study 2 CERTAIN-231,198 NCT02723084 GCR 300 mg qd 8 weeks + PBV 120 mg qd 8 weeks Yes – Chamorro-de-Vega PTV/r 150/100 mg qd 12 weeks + OMV 25 mg qd 12 weeks + DBV 250 mg bid 12 28 – – Yes 2016 weeks

Study design

Observational Study name Registration Treatment arms Trial study DAC 60 mg/day 12 or 24 weeks + SOF 400 mg/day 12 or 24 weeks Chen 201732 – – Yes LDV 90 mg/day 12 or 24 weeks + SOF 400 mg/day 12 or 24 weeks Chuang 2016 - 34,127,186 NCT02021656 LDV 90 mg qd 12 weeks + SOF 400 mg qd 12 weeks Yes – Korea Chuang 2016 - 34,127,186 NCT02021656 LDV 90 mg qd 12 weeks + SOF 400 mg qd 12 weeks Yes – Taiwan ESV 50 mg qd 12 weeks + GZR 100 mg qd 12 weeks C-WORTHY70,121,184,224 NCT01717326 Yes – ESV 50 mg qd 18 weeks + GZR 100 mg qd 18 weeks Dashtseren 201739,40 – LDV 80 mg qd 12 weeks + SOF 400 mg qd 12 weeks Yes – DAC 60 mg qd 12 weeks + SOF 400 mg qd or tiw 12 weeks Desnoyer 201641 – – Yes DAC 60 mg qd 24 weeks + SOF 400 mg qd or tiw 24 weeks Deterding 201542,83 – SOF + RBV – Yes ELECTRON69 NCT01260350 SOF 400 mg 12 weeks + LDV 90 mg 12 weeks Yes – ELECTRON-264,66,67,125 NCT01826981 SOF 400 mg 12 weeks + LDV 90 mg 12 weeks Yes – GCR 300 mg qd 12 weeks + PBV 120 mg qd 12 weeks ENDURANCE-360 NCT02640157 DAC 60 mg qd 12 weeks + SOF 400 mg qd 12 weeks Yes – GCR 300 mg qd 8 weeks + PBV 120 mg qd 8 weeks ERADICATE158,159,196,19 NCT01878799 SOF 400 mg 12 weeks + LDV 90 mg 12 weeks Yes – 7 SOF 400 mg qd 12 weeks + VEL 25 mg qd 12 weeks SOF 400 mg qd 12 weeks + VEL 100 mg qd 12 weeks Everson 201548 NCT01858766 Yes – SOF 400 mg qd 8 weeks + VEL 25 mg qd 8 weeks SOF 400 mg qd 8 weeks + VEL 100 mg qd 8 weeks EXPEDITION-156-58 NCT02642432 GCR 300 mg qd 12 weeks + PBV 120 mg qd 12 weeks Yes – GCR 300 mg qd 8 weeks + PBV 120 mg qd 8 weeks EXPEDITION-2171 NCT02738138 Yes – GCR 300 mg qd 12 weeks + PBV 120 mg qd 12 weeks Fierer 201754 – LDV 8 weeks + SOF 8 weeks Yes – DAC 60 mg qd 12 weeks + SOF 400 mg qd 12 weeks Foster 201661 – – Yes LDV 90 mg qd 12 weeks + SOF 400 mg qd 12 weeks

Study design

Observational Study name Registration Treatment arms Trial study DAC 60 mg qd 12 weeks + SOF 400 mg qd 12 weeks + RBV Clinician discretion SOF 400 mg qd 12 weeks + RBV 1000-1200 mg/day 12 weeks FUSION26,52,147,234 NCT01604850 Yes – SOF 400 mg qd 16 weeks + RBV 1000-1200 mg/day 16 weeks LDV 90 mg qd 12 weeks + SOF 400 mg qd 12 weeks Gane 201768 NCT02202980 Yes – LDV 90 mg qd 8 weeks + SOF 400 mg qd 8 weeks

213,214 PTV/r 150 mg/100 mg qd 8 weeks + OMV 25 mg qd 8 weeks + DBV 250 mg bid 8 GARNET NCT02582632 Yes – weeks GECCO-0189 – LDV 8 weeks + SOF 8 weeks – Yes German Hepatitis C- LDV 12 weeks + SOF 12 weeks Registry – – Yes (GT1 patients)202 LDV 8 weeks + SOF 8 weeks German Hepatitis C- Registry – SOF 12 weeks + RBV 12 weeks – Yes (GT2 patients)136,192 SOF 24 weeks + RBV 24 weeks DAC 12 weeks + SOF 12 weeks German Hepatitis C- Registry – DAC 12 weeks + SOF 12 weeks + RBV 12 weeks – Yes (GT3 patients)36 DAC 24 weeks + SOF 24 weeks DAC 24 weeks + SOF 24 weeks + RBV 24 weeks GS-US-334-0118/ GS-US-337-0113 – LDV 12 weeks + SOF 12 weeks Yes – (Pooled)230,239 GS-US-337-1119 NCT02081079 LDV 90 mg qd 12 weeks + SOF 400 mg qd 12 weeks Yes – [Genotype 4]12,66 GS-US-337-1119 11,66 NCT02081079 LDV 90 mg qd 12 weeks + SOF 400 mg qd 12 weeks Yes – [Genotype 5] HALLMARK DAC 60 mg qd 24 weeks + ASV 100 mg bid 24 weeks 100,101,135 NCT01581203 Yes – DUAL PBO HCV Research UK – DAC 12 weeks + SOF 12 weeks – Yes (HCVRUK)33 SOF 400 mg qd 12 weeks + RBV Clinician discretion 12 weeks HCV- TARGET50,161,169,194,215,2 NCT01474811 SOF 400 mg qd 16 weeks + RBV Clinician discretion 16 weeks – Yes 27 SOF 24 weeks + RBV Clinician discretion 24 weeks

Study design

Observational Study name Registration Treatment arms Trial study LDV 90 mg qd 8, 12, or 24 weeks + SOF 400 mg qd 8, 12, or 24 weeks ESV + GZR SOF + VEL + VEL HepNet Acute HCV IV 43,44 NCT02309918 LDV 90 mg qd 6 weeks + SOF 400 mg qd 6 weeks Yes – Study Hezode 201779,80 – DAC 60 mg qd 8 weeks + SOF 400 mg qd 8 weeks Yes – SOF 400 mg qd 24 weeks + RBV 15 mg/kg/day 24 weeks Hlaing 201781 – LDV 90 mg qd 12 weeks + SOF 400 mg qd 12 weeks – Yes DAC 60 mg qd 12 weeks + SOF 400 mg qd 12 weeks + RBV 15 mg/kg/day 12 weeks DAC 24 weeks + ASV 24 weeks Ide 2016a84 – – Yes LDV 12 weeks + SOF 12 weeks Ide 2016b85 – DAC 60 mg qd 24 weeks + ASV 100 mg bid 24 weeks Yes – Iio 2017a86 – DAC 60 mg qd 24 weeks + ASV 100 mg bid 24 weeks Yes – Iio 2017b87 – LDV 90 mg qd 12 weeks + SOF 400 mg qd 12 weeks Yes – Ikeda 201788 – DAC 60 mg qd 24 weeks + ASV 100 mg bid 24 weeks Yes – LDV 90 mg 12 weeks + SOF 400 mg 12 weeks ION-114-16,74,216,233,235 NCT01701401 Yes – LDV 90 mg 24 weeks + SOF 400 mg 24 weeks LDV 90 mg 12 weeks + SOF 400 mg 12 weeks ION-213,15,16,74,216,233,235 NCT01768286 Yes – LDV 90 mg 24 weeks + SOF 400 mg 24 weeks LDV 90 mg 12 weeks + SOF 400 mg 12 weeks ION-315,16,74,110,216,233,235 NCT01851330 Yes – LDV 90 mg 8 weeks + SOF 400 mg 8 weeks ION-4144,145,236 NCT02073656 SOF 400 mg 12 weeks + LDV 90 mg 12 weeks Yes – Isakov 201690,247 – LDV 90 mg qd 8 weeks + SOF 400 mg qd 8 weeks Yes – Ishigami 201791 – DAC + ASV – Yes Itoh 201692 – ESV qd 12 weeks + GZR qd 12 weeks Yes – DAC 12 weeks + SOF 12 weeks Iwamoto 201793 – – Yes DAC 24 weeks + SOF 24 weeks

Study design

Observational Study name Registration Treatment arms Trial study Jargalsaikhan 201797 – LDV 12 weeks + SOF 12 weeks Yes – DAC 60 mg/day 12 weeks + SOF 400 mg/day 12 weeks Ji 201698 – – Yes LDV 90 mg qd 12 weeks + SOF 400 mg qd 12 weeks LDV 8 weeks + SOF 8 weeks Johnson 201799 – LDV 12 weeks + SOF 12 weeks – Yes LDV 24 weeks + SOF 24 weeks ESV 50 mg qd 12 weeks + GZR 50 mg qd 12 weeks Kawada 2015104 – Yes – ESV 50 mg qd 12 weeks + GZR 100 mg qd 12 weeks Kawakami 2016105 UMIN000015539 DAC 60 mg qd 24 weeks + ASV 100 mg bid 24 weeks – Yes Korenaga 2017108 – LDV 12 weeks + SOF 12 weeks Yes – Kumada 2014113,139,225 NCT01497834 DAC 60 mg 24 weeks + ASV 100 mg bid 24 weeks Yes – Kumada 2016a112 NCT01718145 DAC 60 mg qd 24 weeks + ASV 100 mg bid 24 weeks Yes – ESV 50 mg qd 12 weeks + GZR 50 mg qd 12 weeks Kumada 2016b114,190 NCT02203149 Yes – ESV 50 mg qd 12 weeks + GZR 100 mg qd 12 weeks Kwo 2016119 – GCR 300 mg qd 12 weeks + PBV 120 mg qd 12 weeks Yes – Lawitz 2017122,124 NCT02536313 SOF 400 mg qd 12 weeks + VEL 100 mg qd 12 weeks + VOX 100 mg qd 12 weeks Yes – DAC 24 weeks + SOF 24 weeks + RBV 922 ± 200 mg/day 24 weeks Lionetti 2017128 – – Yes DAC 24 weeks + SOF 24 weeks Liu 2017129 – LDV 90 mg qd 12 weeks + SOF 400 mg qd 12 weeks Yes – Lok 2012130 NCT01012895 DAC 60 mg 24 weeks + ASV 600 mg bid 24 weeks Yes – LDV 90 mg 12 weeks + SOF 400 mg 12 weeks LONESTAR123 NCT01726517 Yes – LDV 90 mg 8 weeks + SOF 400 mg 8 weeks

MAGELLAN-1, GCR 200 mg qd 12 weeks + PBV 80 mg qd 12 weeks 165,166 NCT02446717 Yes – Part 1 GCR 300 mg qd 12 weeks + PBV 120 mg qd 12 weeks

MAGELLAN-1, GCR 300 mg qd 12 weeks + PBV 120 mg qd 12 weeks 167,168 NCT02446717 Yes – Part 2 GCR 300 mg qd 16 weeks + PBV 120 mg qd 16 weeks

Study design

Observational Study name Registration Treatment arms Trial study

35,47 PTV/r 150 mg/100 mg qd 12 weeks + OMV 25 mg qd 12 weeks + DBV 250 mg bid 12 MALACHITE-I NCT01854697 Yes – weeks DAC 60 mg qd 12 weeks + SOF 400 mg qd 12 weeks Mangia 2016a132 – – Yes DAC 60 mg qd 24 weeks + SOF 400 mg qd 24 weeks

133 EUDRACT Mangia 2017a LDV 90 mg qd 12 weeks + SOF 400 mg qd 12 weeks Yes – 2015-002401-1 SOF 400 mg qd 16 weeks + RBV 1000 or 1200 mg/day 16 weeks Mangia 2017b134 – – Yes SOF 400 mg qd 20 weeks + RBV 1000 or 1200 mg/day 20 weeks LDV 90 mg qd 12 weeks + SOF 400 mg qd 12 weeks DAC 60 mg qd 12 weeks + SOF 400 mg qd 12 weeks Mehta 2017138 – – Yes 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 1000 mg/day (<75 kg) or 1200 mg/day (>75 kg), divided doses 24 weeks Mizokami 2015140 NCT01975675 LDV 90 mg qd 12 weeks + SOF 400 mg qd 12 weeks Yes – Nagao 2017143 – LDV 90 mg qd 12 weeks + SOF 400 mg qd 12 weeks – Yes LDV 90 mg qd 8 weeks + SOF 400 mg qd 8 weeks Nguyen 2017150,151 – Yes – LDV 90 mg qd 12 weeks + SOF 400 mg qd 12 weeks Ogawa 2016155 – SOF 400 mg qd 12 weeks + RBV Weight-adjusted (600-1000 mg/day) 12 weeks – Yes Ogawa 2017a156 UMIN000015627 DAC 60 mg qd 24 weeks + ASV 100 mg bid 24 weeks Yes – Ogawa 2017b153,154 UMIN000024007 LDV 90 mg qd 12 weeks + SOF 400 mg qd 12 weeks – Yes PTV/r 12 weeks + OMV 12 weeks + DBV 12 weeks ONYX-I206,207 – Yes – PBO 12 weeks PEARL-II17,208 NCT01674725 PTV/r 150/100 mg 12 weeks + OMV 25 mg 12 weeks + DBV 250 mg bid 12 weeks Yes – PEARL-III53,208 NCT01767116 PTV/r 150/100 mg 12 weeks + OMV 25 mg 12 weeks + DBV 250 mg bid 12 weeks Yes – PEARL-IV53 NCT01833533 PTV/r 150/100 mg 12 weeks + OMV 25 mg 12 weeks + DBV 250 mg bid 12 weeks Yes – Persico 2017162 – LDV 90 mg qd 12 weeks + SOF 400 mg qd 12 weeks – Yes SOF 400 mg qd 24 weeks + RBV 1000 mg/day (<75 kg) or 1200 mg/day (≥75 kg), twice per day 24 weeks PHOTON-2141,142,234 NCT01783678 Yes – SOF 400 mg qd 12 weeks + RBV 1000 mg/day (<75 kg) or 1200 mg/day (≥75 kg), twice per day 12 weeks

Study design

Observational Study name Registration Treatment arms Trial study SOF 400 mg qd 12 weeks + VEL 25 mg qd 12 weeks Pianko 2015163 NCT01909804 Yes – SOF 400 mg qd 12 weeks + VEL 100 mg qd 12 weeks SOF 400 mg qd 12 weeks + VEL 100 mg qd 12 weeks + VOX 100 mg qd 12 weeks POLARIS-121,22 NCT02607735 Yes – PBO SOF 400 mg qd 8 weeks + VEL 100 mg qd 8 weeks + VOX 100 mg qd 8 weeks POLARIS-296 NCT02607800 Yes – SOF 400 mg qd 12 weeks + VEL 100 mg qd 12 weeks SOF 400 mg qd 8 weeks + VEL 100 mg qd 8 weeks + VOX 100 mg qd 8 weeks POLARIS-396 NCT02639338 Yes – SOF 400 mg qd 12 weeks + VEL 100 mg qd 12 weeks SOF 400 mg qd 12 weeks + VEL 100 mg qd 12 weeks + VOX 100 mg qd 12 weeks POLARIS-421,242 NCT02639247 Yes – SOF 400 mg qd 12 weeks + VEL 100 mg qd 12 weeks POSITRON26,95 NCT01542788 SOF 400 mg qd 12 weeks + RBV 1000-1200 mg/day 12 weeks Yes – Reddy 2017170 – DAC + ASV – Yes Sezaki 2017175 – DAC 60 mg qd 24 weeks + ASV 100 mg bid 24 weeks – Yes SOF 400 mg qd 16 weeks + RBV 1000 mg/day (<75 kg) or 1200 mg/day (≥75 kg), twice per day 16 weeks Shah 2016176 NCT02074514 Yes – SOF 400 mg qd 24 weeks + RBV 1000 mg/day (<75 kg) or 1200 mg/day (≥75 kg), twice per day 24 weeks LDV 8 weeks + SOF 8 weeks Shiha 2017177 – Yes – LDV 12 weeks + SOF 12 weeks SIRIUS20,23,27,203,237,238 NCT01965535 SOF 400 mg 24 weeks + LDV 90 mg qd 24 weeks Yes – Slash C160 – LDV 90 mg qd 12 weeks + SOF 400 mg qd 12 weeks Yes – Suda 2016182 UMIN000016355 DAC 60 mg qd 24 weeks + ASV 100 mg bid 24 weeks – Yes Suda 2017183 UMIN000020301 DAC 60 mg qd 24 weeks + ASV 100 mg bid 24 weeks – Yes Sung 2016188 – DAC 60 mg qd 24 weeks + ASV 100 mg bid 24 weeks – Yes GCR 200 mg qd 12 weeks + PBV 120 mg qd 12 weeks GCR 200 mg qd 12 weeks + PBV 40 mg qd 12 weeks SURVEYOR-I65,118 NCT02243280 Yes – GCR 300 mg qd 8 weeks + PBV 120 mg qd 8 weeks GCR 300 mg qd 12 weeks + PBV 120 mg qd 12 weeks

Study design

Observational Study name Registration Treatment arms Trial study GCR 300 mg qd 12 weeks + PBV 120 mg qd 12 weeks GCR 200 mg qd 12 weeks + PBV 120 mg qd 12 weeks SURVEYOR-II65,118 NCT02243293 Yes – GCR 200 mg qd 12 weeks + PBV 40 mg qd 12 weeks GCR 300 mg qd 8 weeks + PBV 120 mg qd 8 weeks Suzuki 2017189 – DAC 60 mg qd 24 weeks + ASV 100 mg bid 24 weeks – Yes SYNERGY66,106,107,178,19 7,217 NCT01805882 LDV 90 mg qd 12 weeks + SOF 400 mg qd 12 weeks Yes –

Terashita 2017193 – DAC + ASV Yes – LDV + SOF Torres 2017195 – SOF + VEL – Yes DAC + SOF Toyoda 2016200 UMIN000017023 DAC 60 mg qd 24 weeks + ASV 100 mg bid 24 weeks Yes – Toyoda 2017199 UMIN000017020 DAC 60 mg qd 24 weeks + ASV 100 mg bid 24 weeks Yes – PTV/r 150/100 mg qd 12 weeks + OMV 25 mg qd 12 weeks + DBV 250 mg bid 12 TURQUOISE-III51 NCT02219503 Yes – weeks UNITY-3201 NCT02123654 DAC 60 mg qd 24 weeks + ASV 100 mg bid 24 weeks Yes – SOF 400 mg qd 12 weeks + RBV 1000 mg/day (<75 kg) or 1200 mg/day (≥75 kg), twice per day 12 weeks VALENCE125,234,241,246 NCT01682720 SOF 400 mg qd 24 weeks + RBV 1000 mg/day (<75 kg) or 1200 mg/day (≥75 kg), Yes – twice per day 24 weeks PBO

82 SOF 400 mg qd 12 weeks + RBV Weight-adjusted (1000-1200 mg/day divided doses) VALOR-HCV NCT02128542 Yes – 12 weeks DAC 60 mg qd 12 weeks + SOF 400 mg qd 12 weeks VASCUVALDIC 2173,174 NCT02856243 – Yes DAC 60 mg qd 24 weeks + SOF 400 mg qd 24 weeks Vierling 2015204 – ESV 50 mg 8 weeks + GZR 100 mg 8 weeks Yes – Wei 2016211 NCT01995266 DAC 60 mg qd 24 weeks + ASV 100 mg bid 24 weeks Yes – SOF 400 mg 12 weeks + RBV 1000-1200 mg divided daily dose 12 weeks Wei 2017a210 – Yes – SOF 400 mg 24 weeks + RBV 1000-1200 mg divided daily dose 24 weeks Wei 2017b209 – DAC 60 mg qd 24 weeks + ASV 100 mg bid 24 weeks Yes –

Study design

Observational Study name Registration Treatment arms Trial study PBO DAC (generic) 60 mg/day 12 weeks + SOF (generic) 400 mg/day 12 weeks 223 ACTRN Yakoot 2017 Yes – 12617000263392 DAC (generic) 60 mg/day response-tailored duration + SOF (generic) 400 mg/day response-tailored duration Younossi 2016226 – LDV 12 weeks + SOF 12 weeks Yes – Zeng 2017240 – LDV (generic) 90 mg qd 8 weeks + SOF (generic) 400 mg qd 8 weeks – Yes

Appendix D: GRADE evidence profiles

Table D1: GRADE evidence profile for patients treated with daclatasvir + asunaprevir, all-comer analysis, arranged by genotype

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations Genotype 1, All-treatment experience population SVR12 0.89 Trial 15 0 0 0 0 0 3642 (0.87, ⨁⨁⨁⨁ Critical evidence 0.92) 0.89 All 21 0 0 0 0 0 6341 (0.87, ⨁⨁⨁⨁ Critical evidence 0.91) Genotype 2, All-treatment experience population SVR12 – Trial – – – – – – – – – evidence – All – – – – – – – – – evidence Genotype 3, All-treatment experience population SVR12 – Trial – – – – – – – – – evidence – All – – – – – – – – – evidence Genotype 4, All-treatment experience population SVR12 – Trial – – – – – – – – – evidence – All – – – – – – – – – evidence Genotype 5, All-treatment experience population SVR12 – Trial – – – – – – – – – evidence – All – – – – – – – – – evidence

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations – All – – – – – – – – – evidence Genotype 5, Treatment-naïve population SVR12 – Trial – – – – – – – – – evidence – All – – – – – – – – – evidence Genotype 6, Treatment-naïve population SVR12 – Trial – – – – – – – – – evidence – All – – – – – – – – – evidence Mixed genotype group, Treatment-naïve population SVR12 – Trial – – – – – – – – – evidence – All – – – – – – – – – evidence Genotype 1, Treatment-experienced population SVR12 0.85 Trial d 4 0 0 0 -1 0 484 (0.76, ⨁⨁⨁ Critical evidence 0.94) All 4 Same as trial-only evidence evidence Genotype 2, Treatment-experienced population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 3, Treatment-experienced population SVR12 – Trial – – – – – – – – –

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations evidence – All – – – – – – – – – evidence Genotype 4, Treatment-experienced population SVR12 – Trial – – – – – – – – – evidence – All – – – – – – – – – evidence Genotype 5, Treatment-experienced population n SVR12 – Trial – – – – – – – – – evidence – All – – – – – – – – – evidence Genotype 6, Treatment-experienced population SVR12 – Trial – – – – – – – – – evidence – All – – – – – – – – – evidence Mixed genotype group, Treatment-experienced population SVR12 – Trial – – – – – – – – – evidence – All – – – – – – – – – evidence Discontinuations due to adverse events 0.04 Trial a 12 -1 0 0 0 0 3496 (0.02, ⨁⨁⨁ Critical evidence 0.05) 0.04 All a 18 -1 0 0 0 0 7186 (0.03, ⨁⨁⨁ Critical evidence 0.05) Serious adverse events 9 Trial 0 0 0 0 0 1940 0.05 ⨁⨁⨁⨁ Critical

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations evidence (0.03, 0.07) 0.03 All 12 0 0 0 0 0 2422 (0.02, ⨁⨁⨁⨁ Critical evidence 0.04) Mortality 0 Trial 7 0 0 0 0 0 1863 (0, ⨁⨁⨁⨁ Critical evidence 0.01) All 11 0 0 0 0 0 4832 0 (0, 0) ⨁⨁⨁⨁ Critical evidence 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 10% (±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 evidence profile for patients treated with daclatasvir + sofosbuvir, all-comer analysis, arranged by genotype

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations 0.98) Genotype 2, All-treatment experience population SVR12 Trial – – – – – – – – – – evidence 0.94 All d h 2 0 0 0 -1 -2 21 (0.86, ⨁ Critical evidence 1.00) Genotype 3, All-treatment experience population SVR12 0.92 Trial 3 0 0 0 0 0 293 (0.88, ⨁⨁⨁⨁ Critical evidence 0.97) 0.89 All g 9 0 0 0 0 -1 895 (0.85, ⨁⨁⨁ Critical evidence 0.94) Genotype 4, All-treatment experience population SVR12 0.97 Trial 2 0 0 0 0 0 180 (0.95, ⨁⨁⨁⨁ Critical evidence 1.00) 0.97 All 3 0 0 0 0 0 183 (0.95, ⨁⨁⨁⨁ Critical evidence 1.00) Genotype 5, All-treatment experience population SVR12 Trial – – – – – – – – – – evidence 0.88 All f h 2 0 0 0 -2 -2 8 (0.70, ⨁ Critical evidence 1.00) Genotype 6, All-treatment experience population SVR12 Trial – – – – – – – – – – evidence 1 All 0 0 0 0 -2h 123 0.94 ⨁⨁ Critical

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations evidence (0.90, 0.98) Mixed genotype group, All-treatment experience population SVR12 0.94 Trial d 2 0 0 0 -1 0 233 (0.88, ⨁⨁⨁ Critical evidence 0.99) 0.92 All a g 5 -1 0 0 0 -1 591 (0.88, ⨁⨁ Critical evidence 0.97) Genotype 1, Treatment-naïve population SVR12 0.98 Trial 1 0 0 0 0 0 70 (0.96, ⨁⨁⨁⨁ Critical evidence 1.00) 0.94 All g 4 0 0 0 0 -1 196 (0.90, ⨁⨁⨁ Critical evidence 0.99) Genotype 2, Treatment-naïve population SVR12 Trial – – – – – – – – – – evidence 0.75 All f h 1 0 0 0 -2 -2 1 (0.15, ⨁ Critical evidence 1.00) Genotype 3, Treatment-naïve population SVR12 0.94 Trial 3 0 0 0 0 0 242 (0.89, ⨁⨁⨁⨁ Critical evidence 0.98) 0.93 All 6 0 0 0 0 0 470 (0.88, ⨁⨁⨁⨁ Critical evidence 0.98) Genotype 4, Treatment-naïve population SVR12 1 Trial 0 0 0 -1e 0 60 0.93 ⨁⨁⨁ Critical

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations evidence (0.87, 1.00) 0.93 All d 2 0 0 0 -1 0 61 (0.87, ⨁⨁⨁ Critical evidence 0.99) Genotype 5, Treatment-naïve population SVR12 Trial – – – – – – – – – – evidence 0.83 All f h 2 0 0 0 -2 -2 2 (0.41, ⨁ Critical evidence 1.00) Genotype 6, Treatment-naïve population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Mixed genotype group, Treatment-naïve population SVR12 0.91 Trial d 2 0 0 0 -1 0 181 (0.82, ⨁⨁⨁ Critical evidence 1.00) All 2 Same as trial-only evidence evidence Genotype 1, Treatment-experienced population SVR12 0.98 Trial f 1 0 0 0 -2 0 21 (0.92, ⨁⨁ Critical evidence 1.00) 0.97 All g 5 0 0 0 0 -1 573 (0.95, ⨁⨁⨁ Critical evidence 0.98) Genotype 2, Treatment-experienced population SVR12 – Trial – – – – – – – – –

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations evidence 0.75 All f h 1 0 0 0 -2 -2 1 (0.15, ⨁ Critical evidence 1.00) Genotype 3, Treatment-experienced population SVR12 0.86 Trial e 1 0 0 0 -1 0 51 (0.77, ⨁⨁⨁ Critical evidence 0.96) 0.85 All d 3 0 0 0 -1 0 110 (0.78, ⨁⨁⨁ Critical evidence 0.92) Genotype 4, Treatment-experienced population SVR12 Trial – – – – – – – – – – evidence 0.83 All f h 1 0 0 0 -2 -2 2 (0.41, ⨁ Critical evidence 1.00) Genotype 5, Treatment-experienced population n SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 6, Treatment-experienced population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Mixed genotype group, Treatment-experienced population SVR12 0.98 Trial e 1 0 0 0 -1 0 52 (0.94, ⨁⨁⨁ Critical evidence 1.00)

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations All 1 Same as trial-only evidence evidence Discontinuations due to adverse events Trial a 0.01 (0, 5 -1 0 0 0 0 650 ⨁⨁⨁ Critical evidence 0.01) 0.01 All a 12 -1 0 0 0 0 1955 (0.01, ⨁⨁⨁ Critical evidence 0.01) Serious adverse events Trial 0.01 (0, 5 0 0 0 0 0 650 ⨁⨁⨁⨁ Critical evidence 0.02) 0.03 All g 10 0 0 0 0 -1 1875 (0.01, ⨁⨁⨁ Critical evidence 0.05) Mortality Trial 0.01 (0, 4 0 0 0 0 0 535 ⨁⨁⨁⨁ Critical evidence 0.01) All 0.01 (0, 11 0 0 0 0 0 2156 ⨁⨁⨁⨁ Critical evidence 0.01) 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 10% (±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 evidence profile for patients treated with elbasvir + grazoprevir, all-comer analysis, arranged by genotype

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations 0.97 Trial 10 0 0 0 0 0 1975 (0.96, ⨁⨁⨁⨁ Critical evidence 0.98) 0.97 All 11 0 0 0 0 0 1996 (0.96, ⨁⨁⨁⨁ Critical evidence 0.98) Genotype 2, All-treatment experience population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 3, All-treatment experience population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 4, All-treatment experience population SVR12 0.96 Trial 5 0 0 0 0 0 66 (0.92, ⨁⨁⨁⨁ Critical evidence 1.00) All 5 Same as trial-only evidence evidence Genotype 5, All-treatment experience population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 6, All-treatment experience population SVR12 0.62 Trial d 4 0 0 0 -1 0 52 (0.39, ⨁⨁⨁ Critical evidence 0.85)

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations All 4 Same as trial-only evidence evidence Mixed genotype group, All-treatment experience population SVR12 0.94 Trial d 2 0 0 0 -1 0 317 (0.88, ⨁⨁⨁ Critical evidence 0.99) All 2 Same as trial-only evidence evidence Genotype 1, Treatment-naïve population SVR12 0.96 Trial 6 0 0 0 0 0 1112 (0.95, ⨁⨁⨁⨁ Critical evidence 0.97) All 6 Same as trial-only evidence evidence Genotype 2, Treatment-naïve population SVR12 – Trial – – – – – – – – – evidence – All – – – – – – – – – evidence Genotype 3, Treatment-naïve population SVR12 – Trial – – – – – – – – – evidence – All – – – – – – – – – evidence Genotype 4, Treatment-naïve population SVR12 0.96 Trial 4 0 0 0 0 0 60 (0.92, ⨁⨁⨁⨁ Critical evidence 1.00) All 4 Same as trial-only evidence evidence Genotype 5, Treatment-naïve population

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations SVR12 – Trial – – – – – – – – – evidence – All – – – – – – – – – evidence Genotype 6, Treatment-naïve population SVR12 0.62 Trial d 4 0 0 0 -1 0 52 (0.39, ⨁⨁⨁ Critical evidence 0.85) All 4 Same as trial-only evidence evidence Mixed genotype group, Treatment-naïve population SVR12 0.87 Trial e i 1 0 0 0 -1 -1 53 (0.78, ⨁⨁ Critical evidence 0.96) All 1 Same as trial-only evidence evidence Genotype 1, Treatment-experienced population SVR12 0.95 Trial a i 1 -1 0 0 0 -1 65 (0.90, ⨁⨁ Critical evidence 1.00) All 1 Same as trial-only evidence evidence Genotype 2, Treatment-experienced population SVR12 – Trial – – – – – – – – – evidence – All – – – – – – – – – evidence Genotype 3, Treatment-experienced population SVR12 – Trial – – – – – – – – – evidence

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations – All – – – – – – – – – evidence Genotype 4, Treatment-experienced population SVR12 – Trial – – – – – – – – – evidence – All – – – – – – – – – evidence Genotype 5, Treatment-experienced population n SVR12 – Trial – – – – – – – – – evidence – All – – – – – – – – – evidence Genotype 6, Treatment-experienced population SVR12 – Trial – – – – – – – – – evidence – All – – – – – – – – – evidence Mixed genotype group, Treatment-experienced population SVR12 0.95 Trial 2 0 0 0 0 0 264 (0.90, ⨁⨁⨁⨁ Critical evidence 1.00) All 2 Same as trial-only evidence evidence Discontinuations due to adverse events Trial a 0.01 (0, 11 -1 0 0 0 0 2084 ⨁⨁⨁ Critical evidence 0.01) All a 0.01 (0, 12 -1 0 0 0 0 2105 ⨁⨁⨁ Critical evidence 0.01) Serious adverse events 0.02 Trial 10 0 0 0 0 0 2022 (0.01, ⨁⨁⨁⨁ Critical evidence 0.02)

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations All 10 Same as trial-only evidence evidence Mortality Trial 0 (0, 8 0 0 0 0 0 1741 ⨁⨁⨁⨁ Critical evidence 0.01) All 0 (0, 9 0 0 0 0 0 1762 ⨁⨁⨁⨁ Critical evidence 0.01) 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 10% (±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 D4: GRADE evidence profile for patients treated with glecaprevir + pibrentasvir, all-comer analysis, arranged by genotype

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations Genotype 1, All-treatment experience population SVR12 0.98 Trial 3 0 0 0 0 0 231 (0.97, ⨁⨁⨁⨁ Critical evidence 1.00) All 3 Same as trial-only evidence evidence Genotype 2, All-treatment experience population SVR12 0.98 Trial 4 0 0 0 0 0 242 (0.96, ⨁⨁⨁⨁ Critical evidence 1.00) All 4 Same as trial-only evidence evidence Genotype 3, All-treatment experience population SVR12 0.95 Trial 2 0 0 0 0 0 533 (0.93, ⨁⨁⨁⨁ Critical evidence 0.97) All 2 Same as trial-only evidence evidence Genotype 4, All-treatment experience population SVR12 0.97 Trial f i 1 0 0 0 -2 -1 16 (0.89, ⨁ Critical evidence 1.00) All 1 Same as trial-only evidence evidence Genotype 5, All-treatment experience population SVR12 0.83 Trial f i 1 0 0 0 -2 -1 2 (0.41, ⨁ Critical evidence 1.00) All 1 Same as trial-only evidence evidence

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations Genotype 6, All-treatment experience population SVR12 0.94 Trial f i 1 0 0 0 -2 -1 7 (0.77, ⨁ Critical evidence 1.00) All 1 Same as trial-only evidence evidence Mixed genotype group, All-treatment experience population SVR12 0.97 Trial 3 0 0 0 0 0 276 (0.93, ⨁⨁⨁⨁ Critical evidence 1.00) All 3 Same as trial-only evidence evidence Genotype 1, Treatment-naïve population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 2, Treatment-naïve population SVR12 – Trial – – – – – – – – – evidence – All – – – – – – – – – evidence Genotype 3, Treatment-naïve population SVR12 0.95 Trial 2 0 0 0 0 0 419 (0.93, ⨁⨁⨁⨁ Critical evidence 0.97) All 2 Same as trial-only evidence evidence Genotype 4, Treatment-naïve population SVR12 – Trial – – – – – – – – –

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations evidence – All – – – – – – – – – evidence Genotype 5, Treatment-naïve population SVR12 – Trial – – – – – – – – – evidence – All – – – – – – – – – evidence Genotype 6, Treatment-naïve population SVR12 – Trial – – – – – – – – – evidence – All – – – – – – – – – evidence Mixed genotype group, Treatment-naïve population SVR12 – Trial – – – – – – – – – evidence – All – – – – – – – – – evidence Genotype 1, Treatment-experienced population SVR12 – Trial – – – – – – – – – evidence – All – – – – – – – – – evidence Genotype 2, Treatment-experienced population SVR12 – Trial – – – – – – – – – evidence – All – – – – – – – – – evidence Genotype 3, Treatment-experienced population SVR12 1 Trial 0 0 0 -2f -1i 24 0.92 ⨁ Critical

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations evidence (0.81, 1.00) All 1 Same as trial-only evidence evidence Genotype 4, Treatment-experienced population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 5, Treatment-experienced population n SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 6, Treatment-experienced population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Mixed genotype group, Treatment-experienced population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Discontinuations due to adverse events 0.01 Trial a 10 -1 0 0 0 0 1333 (0, ⨁⨁⨁ Critical evidence 0.01) All 10 Same as trial-only evidence evidence Serious adverse events 9 Trial 0 0 0 0 0 1309 0.02 ⨁⨁⨁⨁ Critical

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations evidence (0.01, 0.02) All 9 Same as trial-only evidence evidence Mortality 0.01 Trial 3 0 0 0 0 0 539 (0, ⨁⨁⨁⨁ Critical evidence 0.02) All 3 Same as trial-only evidence evidence 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 10% (±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 D5: GRADE evidence profile for patients treated with ledipasvir + sofosbuvir, all-comer analysis, arranged by genotype

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations Genotype 1, All-treatment experience population SVR12 0.98 Trial 18 0 0 0 0 0 3032 (0.98, ⨁⨁⨁⨁ Critical evidence 0.99) 0.97 All 30 0 0 0 0 0 13327 (0.96, ⨁⨁⨁⨁ Critical evidence 0.98) Genotype 2, All-treatment experience population SVR12 0.86 Trial e i 1 0 0 0 -1 -1 53 (0.65, ⨁⨁ Critical evidence 1.00) All 1 Same as trial-only evidence evidence Genotype 3, All-treatment experience population SVR12 0.64 Trial f i 1 0 0 0 -2 -1 25 (0.45, ⨁ Critical evidence 0.83) 0.65 All c d 3 0 -1 0 -1 0 42 (0.51, ⨁⨁ Critical evidence 0.79) Genotype 4, All-treatment experience population SVR12 0.96 Trial 4 0 0 0 0 0 188 (0.93, ⨁⨁⨁⨁ Critical evidence 0.99) 0.96 All 5 0 0 0 0 0 458 (0.93, ⨁⨁⨁⨁ Critical evidence 0.98) Genotype 5, All-treatment experience population SVR12 Trial e 0.95 1 0 0 0 -1 0 41 ⨁⨁⨁ Critical evidence (0.89,

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations 1.00) All 1 Same as trial-only evidence evidence Genotype 6, All-treatment experience population SVR12 0.97 Trial 2 0 0 0 0 0 85 (0.93, ⨁⨁⨁⨁ Critical evidence 1.00) 0.90 All c d 3 0 -1 0 -1 0 124 (0.81, ⨁⨁ Critical evidence 0.99) Mixed genotype group, All-treatment experience population SVR12 0.95 Trial 7 0 0 0 0 0 1228 (0.92, ⨁⨁⨁⨁ Critical evidence 0.99) 0.95 All 10 0 0 0 0 0 1421 (0.92, ⨁⨁⨁⨁ Critical evidence 0.97) Genotype 1, Treatment-naïve population SVR12 0.98 Trial 9 0 0 0 0 0 1263 (0.97, ⨁⨁⨁⨁ Critical evidence 0.99) 0.97 All a 13 -1 0 0 0 0 5457 (0.95, ⨁⨁⨁ Critical evidence 0.99) Genotype 2, Treatment-naïve population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 3, Treatment-naïve population SVR12 1 Trial 0 0 0 -2f -1i 25 0.64 ⨁ Critical

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations evidence (0.45, 0.83) All 1 Same as trial-only evidence Critical evidence Genotype 4, Treatment-naïve population SVR12 0.97 Trial 2 0 0 0 0 0 108 (0.93, ⨁⨁⨁⨁ Critical evidence 1.00) All 2 Same as trial-only evidence evidence Genotype 5, Treatment-naïve population SVR12 0.95 Trial f i 1 0 0 0 -2 -1 21 (0.86, ⨁ Critical evidence 1.00) All 1 Same as trial-only evidence evidence Genotype 6, Treatment-naïve population SVR12 0.97 Trial 2 0 0 0 0 0 70 (0.93, ⨁⨁⨁⨁ Critical evidence 1.00) All 2 Same as trial-only evidence evidence Mixed genotype group, Treatment-naïve population SVR12 0.96 Trial 3 0 0 0 0 0 223 (0.93, ⨁⨁⨁⨁ Critical evidence 0.98) All 3 Same as trial-only evidence evidence Genotype 1, Treatment-experienced population SVR12 Trial 0.97 9 0 0 0 0 0 561 ⨁⨁⨁⨁ Critical evidence (0.94,

100

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations 0.99) 0.96 All 13 0 0 0 0 0 1620 (0.94, ⨁⨁⨁⨁ Critical evidence 0.98) Genotype 2, Treatment-experienced population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 3, Treatment-experienced population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 4, Treatment-experienced population SVR12 0.94 Trial d 2 0 0 0 -1 0 58 (0.87, ⨁⨁⨁ Critical evidence 1.00) All 2 Same as trial-only evidence evidence Genotype 5, Treatment-experienced population n SVR12 0.95 Trial f i 1 0 0 0 -2 -1 20 (0.85, ⨁ Critical evidence 1.00) All 1 Same as trial-only evidence evidence Genotype 6, Treatment-experienced population SVR12 0.87 Trial f i 1 0 0 0 -2 -1 15 (0.70, ⨁ Critical evidence 1.00) 1 All Same as trial-only evidence

101

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations evidence Mixed genotype group, Treatment-experienced population SVR12 0.97 Trial 2 0 0 0 0 0 222 (0.95, ⨁⨁⨁⨁ Critical evidence 1.00) All 2 Same as trial-only evidence evidence Discontinuations due to adverse events Trial a 0 (0, 20 -1 0 0 0 0 3102 ⨁⨁⨁ Critical evidence 0.01) All a 0 (0, 29 -1 0 0 0 0 4678 ⨁⨁⨁ Critical evidence 0.01) Serious adverse events 0.02 Trial 19 0 0 0 0 0 2572 (0.01, ⨁⨁⨁⨁ Critical evidence 0.03) 0.02 All 23 0 0 0 0 0 2747 (0.01, ⨁⨁⨁⨁ Critical evidence 0.03) Mortality Trial 0.01 (0, 13 0 0 0 0 0 1177 ⨁⨁⨁⨁ Critical evidence 0.01) All 20 0 0 0 0 0 2317 0 (0, 0) ⨁⨁⨁⨁ Critical evidence 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 10% (±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

102

103

Table D6: GRADE evidence profile for patients treated with paritaprevir/ritonavir + ombitasvir + dasabuvir, all-comer analysis, arranged by genotype

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations Genotype 1, All-treatment experience population SVR12 0.99 Trial 7 0 0 0 0 0 1139 (0.98, ⨁⨁⨁⨁ Critical evidence 1.00) 0.98 All 9 0 0 0 0 0 1457 (0.97, ⨁⨁⨁⨁ Critical evidence 0.99) Genotype 2, All-treatment experience population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 3, All-treatment experience population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 4, All-treatment experience population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 5, All-treatment experience population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 6, All-treatment experience population SVR12

104

105

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations Genotype 5, Treatment-naïve population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 6, Treatment-naïve population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Mixed genotype group, Treatment-naïve population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 1, Treatment-experienced population SVR12 1.00 Trial 2 0 0 0 0 0 232 (0.99, ⨁⨁⨁⨁ Critical evidence 1.00) 0.99 All 4 0 0 0 0 0 307 (0.98, ⨁⨁⨁⨁ Critical evidence 1.00) Genotype 2, Treatment-experienced population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 3, Treatment-experienced population SVR12 Trial – – – – – – – – – – evidence

106

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations All – – – – – – – – – – evidence Genotype 4, Treatment-experienced population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 5, Treatment-experienced population n SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 6, Treatment-experienced population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Mixed genotype group, Treatment-experienced population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Discontinuations due to adverse events Trial a 0 (0, 6 -1 0 0 0 0 938 ⨁⨁⨁ Critical evidence 0.01) All a 0 (0, 7 -1 0 0 0 0 973 ⨁⨁⨁ Critical evidence 0.01) Serious adverse events 0.02 Trial 6 0 0 0 0 0 938 (0.01, ⨁⨁⨁⨁ Critical evidence 0.02) 6 All Same as trial-only evidence

107

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations evidence Mortality Trial 0 (0, 5 0 0 0 0 0 878 ⨁⨁⨁⨁ Critical evidence 0.01) All 0 (0, 6 0 0 0 0 0 913 ⨁⨁⨁⨁ Critical evidence 0.01) 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 10% (±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

108

Table D7: GRADE evidence profile for patients treated with sofosbuvir + velpatasvir, all-comer analysis, arranged by genotype

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations Genotype 1, All-treatment experience population SVR12 0.96 Trial 7 0 0 0 0 0 1011 (0.95, ⨁⨁⨁⨁ Critical evidence 0.98) All 7 Same as trial-only evidence evidence Genotype 2, All-treatment experience population SVR12 0.99 Trial 7 0 0 0 0 0 395 (0.97, ⨁⨁⨁⨁ Critical evidence 1.00) All 7 Same as trial-only evidence evidence Genotype 3, All-treatment experience population SVR12 0.89 Trial c 8 0 -1 0 0 0 776 (0.85, ⨁⨁⨁ Critical evidence 0.93) All 8 Same as trial-only evidence evidence Genotype 4, All-treatment experience population SVR12 0.99 Trial 4 0 0 0 0 0 184 (0.98, ⨁⨁⨁⨁ Critical evidence 1.00) All 4 Same as trial-only evidence evidence Genotype 5, All-treatment experience population SVR12 0.97 Trial e i 1 0 0 0 -1 -1 35 (0.92, ⨁⨁ Critical evidence 1.00) All 1 Same as trial-only evidence evidence

109

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations Genotype 6, All-treatment experience population SVR12 0.99 Trial 3 0 0 0 0 0 51 (0.95, ⨁⨁⨁⨁ Critical evidence 1.00) All 3 Same as trial-only evidence evidence Mixed genotype group, All-treatment experience population SVR12 0.99 Trial 2 0 0 0 0 0 485 (0.97, ⨁⨁⨁⨁ Critical evidence 1.00) 0.99 All 3 0 0 0 0 0 489 (0.97, ⨁⨁⨁⨁ Critical evidence 1.00) Genotype 1, Treatment-naïve population SVR12 0.95 Trial b 1 -2 0 0 0 0 114 (0.90, ⨁⨁ Critical evidence 1.00) All 1 Same as trial-only evidence evidence Genotype 2, Treatment-naïve population SVR12 0.84 Trial b e i 1 -2 0 0 -1 -1 52 (0.73, ⨁ Critical evidence 0.95) All 1 Same as trial-only evidence evidence Genotype 3, Treatment-naïve population SVR12 0.98 Trial 3 0 0 0 0 0 337 (0.96, ⨁⨁⨁⨁ Critical evidence 0.99) All 3 Same as trial-only evidence evidence

110

111

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations 1.00) All 1 Same as trial-only evidence evidence Genotype 3, Treatment-experienced population SVR12 0.85 Trial d 4 0 0 0 -1 0 312 (0.78, ⨁⨁⨁ Critical evidence 0.92) All 4 Same as trial-only evidence evidence Genotype 4, Treatment-experienced population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 5, Treatment-experienced population n SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 6, Treatment-experienced population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Mixed genotype group, Treatment-experienced population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Discontinuations due to adverse events 10 Trial -1a 0 0 0 0 2445 0 (0, ⨁⨁⨁ Critical

112

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations evidence 0.01) All 10 Same as trial-only evidence evidence Serious adverse events 0.03 Trial 10 0 0 0 0 0 2445 (0.02, ⨁⨁⨁⨁ Critical evidence 0.04) All 10 Same as trial-only evidence evidence Mortality Trial 10 0 0 0 0 0 2445 0 (0, 0) ⨁⨁⨁⨁ Critical evidence All 10 Same as trial-only evidence evidence 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 10% (±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

113

Table D8: GRADE evidence profile for patients treated with sofosbuvir + velpatasvir + voxilaprevir, all-comer analysis, arranged by genotype

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations Genotype 1, All-treatment experience population SVR12 0.96 Trial 4 0 0 0 0 0 485 (0.94, ⨁⨁⨁⨁ Critical evidence 0.99) All 4 Same as trial-only evidence evidence Genotype 2, All-treatment experience population SVR12 0.98 Trial 3 0 0 0 0 0 99 (0.95, ⨁⨁⨁⨁ Critical evidence 1.00) All 3 Same as trial-only evidence evidence Genotype 3, All-treatment experience population SVR12 0.98 Trial 4 0 0 0 0 0 334 (0.96, ⨁⨁⨁⨁ Critical evidence 0.99) All 4 Same as trial-only evidence evidence Genotype 4, All-treatment experience population SVR12 0.94 Trial 3 0 0 0 0 0 104 (0.90, ⨁⨁⨁⨁ Critical evidence 0.99) All 3 Same as trial-only evidence evidence Genotype 5, All-treatment experience population SVR12 0.94 Trial d 2 0 0 0 -1 0 19 (0.83, ⨁⨁⨁ Critical evidence 1.00) All 2 Same as trial-only evidence evidence

114

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations Genotype 6, All-treatment experience population SVR12 0.98 Trial d 2 0 0 0 -1 0 36 (0.94, ⨁⨁⨁ Critical evidence 1.00) All 2 Same as trial-only evidence evidence Mixed genotype group, All-treatment experience population SVR12 0.81 Trial f i 2 0 0 0 -2 -1 3 (0.46, ⨁ Critical evidence 1.00) All 2 Same as trial-only evidence evidence Genotype 1, Treatment-naïve population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 2, Treatment-naïve population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 3, Treatment-naïve population SVR12 0.96 Trial 1 0 0 0 0 0 75 (0.92, ⨁⨁⨁⨁ Critical evidence 1.00) All 1 Same as trial-only evidence evidence Genotype 4, Treatment-naïve population SVR12 – Trial – – – – – – – – –

115

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations evidence All – – – – – – – – – – evidence Genotype 5, Treatment-naïve population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 6, Treatment-naïve population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Mixed genotype group, Treatment-naïve population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 1, Treatment-experienced population SVR12 0.97 Trial 3 0 0 0 0 0 252 (0.96, ⨁⨁⨁⨁ Critical evidence 0.99) All 3 Same as trial-only evidence evidence Genotype 2, Treatment-experienced population SVR12 0.98 Trial 2 0 0 0 0 0 36 (0.94, ⨁⨁⨁⨁ Critical evidence 1.00) All 2 Same as trial-only evidence evidence Genotype 3, Treatment-experienced population

116

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations SVR12 0.96 Trial 3 0 0 0 0 0 167 (0.92, ⨁⨁⨁⨁ Critical evidence 0.99) All 3 Same as trial-only evidence evidence Genotype 4, Treatment-experienced population SVR12 0.96 Trial i 2 0 0 0 0 -1 41 (0.90, ⨁⨁⨁ Critical evidence 1.00) All 2 Same as trial-only evidence evidence Genotype 5, Treatment-experienced population n SVR12 0.75 Trial f i 1 0 0 0 -2 -1 1 (0.15, ⨁ Critical evidence 1.00) All 1 Same as trial-only evidence evidence Genotype 6, Treatment-experienced population SVR12 0.93 Trial f i 1 0 0 0 -2 -1 6 (0.74, ⨁ Critical evidence 1.00) All 1 Same as trial-only evidence evidence Mixed genotype group, Treatment-experienced population SVR12 0.75 Trial f i 1 0 0 0 -2 -1 1 (0.15, ⨁ Critical evidence 1.00) All 1 Same as trial-only evidence evidence Discontinuations due to adverse events 5 Trial -1a 0 0 0 0 1080 0 (0, 0) ⨁⨁⨁ Critical

117

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations evidence All 5 Same as trial-only evidence evidence Serious adverse events 0.02 Trial 5 0 0 0 0 0 1080 (0.02, ⨁⨁⨁⨁ Critical evidence 0.03) All 5 Same as trial-only evidence evidence Mortality Trial 5 0 0 0 0 0 1080 0 (0, 0) ⨁⨁⨁⨁ Critical evidence All 5 Same as trial-only evidence evidence 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 10% (±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

118

Table D9: GRADE evidence profile for patients treated with daclatasvir + asunaprevir, patients with cirrhosis analysis, arranged by genotype

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations Genotype 1, All-treatment experience population SVR12 0.89 Trial 5 0 0 0 0 0 388 (0.85, ⨁⨁⨁⨁ Critical evidence 0.93) 0.89 All 7 0 0 0 0 0 919 (0.86, ⨁⨁⨁⨁ Critical evidence 0.91) Genotype 2, All-treatment experience population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 3, All-treatment experience population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 4, All-treatment experience population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 5, All-treatment experience population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 6, All-treatment experience population SVR12

119

120

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations Genotype 5, Treatment-naïve population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 6, Treatment-naïve population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Mixed genotype group, Treatment-naïve population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 1, Treatment-experienced population SVR12 0.83 Trial 1 0 0 0 0 0 174 (0.75, ⨁⨁⨁⨁ Critical evidence 0.91) All 1 Same as trial-only evidence evidence Genotype 2, Treatment-experienced population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 3, Treatment-experienced population SVR12 Trial – – – – – – – – – – evidence – All – – – – – – – – –

121

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations evidence Genotype 4, Treatment-experienced population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 5, Treatment-experienced population n SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 6, Treatment-experienced population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Mixed genotype group, Treatment-experienced population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence 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 10% (±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

122

123

Table D10: GRADE evidence profile for patients treated with daclatasvir + sofosbuvir, patients with cirrhosis analysis, arranged by genotype

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations Genotype 1, All-treatment experience population SVR12 Trial – – – – – – – – – – evidence 0.93 All h 3 0 0 0 0 -2 467 (0.88, ⨁⨁ Critical evidence 0.99) Genotype 2, All-treatment experience population SVR12 Trial – – – – – – – – – – evidence 0.96 All f h 2 0 0 0 -2 -2 11 (0.85, ⨁ Critical evidence 1.00) Genotype 3, All-treatment experience population SVR12 0.63 Trial e i 1 0 0 0 -1 -1 32 (0.46, ⨁⨁ Critical evidence 0.80) 0.79 All c d 4 0 -1 0 -1 0 85 (0.68, ⨁⨁ Critical evidence 0.89) Genotype 4, All-treatment experience population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 5, All-treatment experience population SVR12 Trial – – – – – – – – – – evidence 0.75 All f h 1 0 0 0 -2 -2 1 (0.15, ⨁ Critical evidence 1.00)

124

125

126

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations SVR12 0.69 Trial f i 1 0 0 0 -2 -1 13 (0.44, ⨁ Critical evidence 0.94) 0.82 All d f 2 0 0 0 -1 -2 24 (0.61, ⨁ Critical evidence 1.00) Genotype 4, Treatment-experienced population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 5, Treatment-experienced population n SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 6, Treatment-experienced population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Mixed genotype group, Treatment-experienced population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence 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 10% (±5%)

127 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

128

Table D11: GRADE evidence profile for patients treated with elbasvir + grazoprevir, patients with cirrhosis analysis, arranged by genotype

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations Genotype 1, All-treatment experience population SVR12 0.96 Trial a 2 -1 0 0 0 0 95 (0.92, ⨁⨁⨁ Critical evidence 1.00) All 2 Same as trial-only evidence evidence Genotype 2, All-treatment experience population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 3, All-treatment experience population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 4, All-treatment experience population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 5, All-treatment experience population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 6, All-treatment experience population SVR12 – Trial – – – – – – – – –

129

130

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 6, Treatment-naïve population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Mixed genotype group, Treatment-naïve population SVR12 0.98 Trial 2 0 0 0 0 0 105 (0.95, ⨁⨁⨁⨁ Critical evidence 1.00) All 2 Same as trial-only evidence evidence Genotype 1, Treatment-experienced population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 2, Treatment-experienced population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 3, Treatment-experienced population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence

131

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations Genotype 4, Treatment-experienced population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 5, Treatment-experienced population n SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 6, Treatment-experienced population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Mixed genotype group, Treatment-experienced population SVR12 0.92 Trial 1 0 0 0 0 0 74 (0.86, ⨁⨁⨁⨁ Critical evidence 0.98) All 1 Same as trial-only evidence evidence 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 10% (±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

132

133

Table D12: GRADE evidence profile for patients treated with glecaprevir + pibrentasvir, patients with cirrhosis analysis, arranged by genotype

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations Genotype 1, All-treatment experience population SVR12 0.99 Trial 1 0 0 0 0 0 90 (0.97, ⨁⨁⨁⨁ Critical evidence 1.00) All 1 Same as trial-only evidence evidence Genotype 2, All-treatment experience population SVR12 0.98 Trial i 2 0 0 0 0 -1 49 (0.95, ⨁⨁⨁ Critical evidence 1.00) All 2 Same as trial-only evidence evidence Genotype 3, All-treatment experience population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 4, All-treatment experience population SVR12 0.97 Trial f i 1 0 0 0 -2 -1 16 (0.89, ⨁ Critical evidence 1.00) All 1 Same as trial-only evidence evidence Genotype 5, All-treatment experience population SVR12 0.83 Trial f i 1 0 0 0 -2 -1 2 (0.41, ⨁ Critical evidence 1.00) All 1 Same as trial-only evidence evidence Genotype 6, All-treatment experience population

134

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations SVR12 0.94 Trial f i 1 0 0 0 -2 -1 7 (0.77, ⨁ Critical evidence 1.00) All 1 Same as trial-only evidence evidence Mixed genotype group, All-treatment experience population SVR12 0.93 Trial f i 1 0 0 0 -2 -1 15 (0.81, ⨁ Critical evidence 1.00) All 1 Same as trial-only evidence evidence Genotype 1, Treatment-naïve population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 2, Treatment-naïve population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 3, Treatment-naïve population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 4, Treatment-naïve population SVR12 Trial – – – – – – – – – – evidence – All – – – – – – – – –

135

136

137

138

Table D13: GRADE evidence profile for patients treated with ledipasvir + sofosbuvir, patients with cirrhosis analysis, arranged by genotype

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations Genotype 1, All-treatment experience population SVR12 0.97 Trial 7 0 0 0 0 0 404 (0.95, ⨁⨁⨁⨁ Critical evidence 0.98) 0.96 All 11 0 0 0 0 0 744 (0.95, ⨁⨁⨁⨁ Critical evidence 0.98) Genotype 2, All-treatment experience population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 3, All-treatment experience population SVR12 Trial – – – – – – – – – – evidence 0.58 All a c d h 2 -1 -1 0 -1 -2 14 (0.33, ⨁ Critical evidence 0.83) Genotype 4, All-treatment experience population SVR12 0.94 Trial f i 1 0 0 0 -2 -1 26 (0.84, ⨁ Critical evidence 1.00) All 1 Same as trial-only evidence evidence Genotype 5, All-treatment experience population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 6, All-treatment experience population

139

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations SVR12 0.97 Trial e i 1 0 0 0 -1 -1 27 (0.91, ⨁⨁ Critical evidence 1.00) 0.75 All c d 2 0 -1 0 -1 0 44 (0.38, ⨁⨁ Critical evidence 1.00) Mixed genotype group, All-treatment experience population SVR12 0.97 Trial 2 0 0 0 0 0 83 (0.92, ⨁⨁⨁⨁ Critical evidence 1.00) 0.94 All d 4 0 0 0 -1 0 118 (0.88, ⨁⨁⨁ Critical evidence 0.99) Genotype 1, Treatment-naïve population SVR12 0.97 Trial 2 0 0 0 0 0 78 (0.93, ⨁⨁⨁⨁ Critical evidence 1.00) All 2 Same as trial-only evidence evidence Genotype 2, Treatment-naïve population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 3, Treatment-naïve population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 4, Treatment-naïve population SVR12

140

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations 0.86 Trial f i 1 0 0 0 -2 -1 7 (0.60, ⨁ Critical evidence 1.00) All 1 Same as trial-only evidence evidence Genotype 5, Treatment-naïve population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 6, Treatment-naïve population SVR12 0.98 Trial f i 1 0 0 0 -2 -1 21 (0.92, ⨁ Critical evidence 1.00) All 1 Same as trial-only evidence evidence Mixed genotype group, Treatment-naïve population SVR12 0.85 Trial f i 1 0 0 0 -2 -1 20 (0.69, ⨁ Critical evidence 1.00) 0.85 All d i 2 0 0 0 -1 -1 33 (0.73, ⨁⨁ Critical evidence 0.97) Genotype 1, Treatment-experienced population SVR12 0.97 Trial 3 0 0 0 0 0 148 (0.95, ⨁⨁⨁⨁ Critical evidence 1.00) 0.98 All 4 0 0 0 0 0 175 (0.95, ⨁⨁⨁⨁ Critical evidence 1.00) Genotype 2, Treatment-experienced population SVR12

141

142

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations 1.00) 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 10% (±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

143

Table D14: GRADE evidence profile for patients treated with paritaprevir/ritonavir + ombitasvir + dasabuvir, patients with cirrhosis analysis, arranged by genotype

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations Genotype 1, All-treatment experience population SVR12 0.99 Trial 1 0 0 0 0 0 60 (0.97, ⨁⨁⨁⨁ Critical evidence 1.00) 0.99 All 3 0 0 0 0 0 73 (0.97, ⨁⨁⨁⨁ Critical evidence 1.00) Genotype 2, All-treatment experience population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 3, All-treatment experience population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 4, All-treatment experience population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 5, All-treatment experience population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 6, All-treatment experience population SVR12

144

145

146

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 5, Treatment-experienced population n SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 6, Treatment-experienced population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Mixed genotype group, Treatment-experienced population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence 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 10% (±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

147

Table D15: GRADE evidence profile for patients treated with sofosbuvir + velpatasvir, patients with cirrhosis analysis, arranged by genotype

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations Genotype 1, All-treatment experience population SVR12 0.90 Trial 1 0 0 0 0 0 139 (0.85, ⨁⨁⨁⨁ Critical evidence 0.95) All 1 Same as trial-only evidence evidence Genotype 2, All-treatment experience population SVR12 0.86 Trial f i 1 0 0 0 -2 -1 8 (0.64, ⨁ Critical evidence 1.00) All 1 Same as trial-only evidence evidence Genotype 3, All-treatment experience population SVR12 0.86 Trial c d 3 0 -1 0 -1 0 215 (0.77, ⨁⨁ Critical evidence 0.96) All 3 Same as trial-only evidence evidence Genotype 4, All-treatment experience population SVR12 0.88 Trial f i 1 0 0 0 -2 -1 6 (0.66, ⨁ Critical evidence 1.00) All 1 Same as trial-only evidence evidence Genotype 5, All-treatment experience population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 6, All-treatment experience population

148

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations SVR12 0.75 Trial f i 1 0 0 0 -2 -1 1 (0.15, ⨁ Critical evidence 1.00) All 1 Same as trial-only evidence evidence Mixed genotype group, All-treatment experience population SVR12 0.97 Trial 4 0 0 0 0 0 293 (0.94, ⨁⨁⨁⨁ Critical evidence 1.00) All 4 Same as trial-only evidence evidence Genotype 1, Treatment-naïve population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 2, Treatment-naïve population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 3, Treatment-naïve population SVR12 0.97 Trial 2 0 0 0 0 0 120 (0.92, ⨁⨁⨁⨁ Critical evidence 1.00) All 2 Same as trial-only evidence evidence Genotype 4, Treatment-naïve population SVR12 Trial – – – – – – – – – – evidence

149

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations All – – – – – – – – – – evidence Genotype 5, Treatment-naïve population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 6, Treatment-naïve population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Mixed genotype group, Treatment-naïve population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 1, Treatment-experienced population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 2, Treatment-experienced population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 3, Treatment-experienced population SVR12 Trial d 0.90 2 0 0 0 -1 0 69 ⨁⨁⨁ Critical evidence (0.83,

150

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations 0.97) All 2 Same as trial-only evidence evidence Genotype 4, Treatment-experienced population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 5, Treatment-experienced population n SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 6, Treatment-experienced population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Mixed genotype group, Treatment-experienced population SVR12 0.86 Trial i 1 0 0 0 0 -1 69 (0.77, ⨁⨁⨁ Critical evidence 0.94) All 1 Same as trial-only evidence evidence 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 10% (±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

151 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

152

Table D16: GRADE evidence profile for patients treated with sofosbuvir + velpatasvir + voxilaprevir, patients with cirrhosis analysis, arranged by genotype

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations Genotype 1, All-treatment experience population SVR12 0.96 Trial f i 1 0 0 0 -2 -1 11 (0.85, ⨁ Critical evidence 1.00) All 1 Same as trial-only evidence evidence Genotype 2, All-treatment experience population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 3, All-treatment experience population SVR12 0.96 Trial 1 0 0 0 0 0 110 (0.93, ⨁⨁⨁⨁ Critical evidence 1.00) All 1 Same as trial-only evidence evidence Genotype 4, All-treatment experience population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 5, All-treatment experience population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 6, All-treatment experience population SVR12

153

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Mixed genotype group, All-treatment experience population SVR12 0.95 Trial 3 0 0 0 0 0 295 (0.91, ⨁⨁⨁⨁ Critical evidence 0.98) All 3 Same as trial-only evidence evidence Genotype 1, Treatment-naïve population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 2, Treatment-naïve population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 3, Treatment-naïve population SVR12 0.96 Trial i 1 0 0 0 0 -1 75 (0.92, ⨁⨁⨁ Critical evidence 1.00) All 1 Same as trial-only evidence evidence Genotype 4, Treatment-naïve population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence

154

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations Genotype 5, Treatment-naïve population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 6, Treatment-naïve population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Mixed genotype group, Treatment-naïve population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 1, Treatment-experienced population SVR12 0.96 Trial f i 1 0 0 0 -2 -1 11 (0.85, ⨁ Critical evidence 1.00) All 1 Same as trial-only evidence evidence Genotype 2, Treatment-experienced population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 3, Treatment-experienced population SVR12 0.97 Trial e i 1 0 0 0 -1 -1 35 (0.92, ⨁⨁ Critical evidence 1.00)

155

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations All 1 Same as trial-only evidence evidence Genotype 4, Treatment-experienced population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 5, Treatment-experienced population n SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 6, Treatment-experienced population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Mixed genotype group, Treatment-experienced population SVR12 0.96 Trial 2 0 0 0 0 0 205 (0.92, ⨁⨁⨁⨁ Critical evidence 1.00) All 2 Same as trial-only evidence evidence 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 10% (±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

156 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

157

Table D17: GRADE evidence profile for patients treated with daclatasvir + sofosbuvir + ribavirin, patients with cirrhosis analysis, arranged by genotype

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations Genotype 2, All-treatment experience population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 3, All-treatment experience population SVR12 0.86 Trial e i 1 0 0 0 -1 -1 36 (0.76, ⨁⨁ Critical evidence 0.97) 0.91 All 6 0 -1c 0 0 -1h 361 (0.86, ⨁⨁ Critical evidence 0.97) Genotype 2, Treatment-naïve population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 3, Treatment-naïve population SVR12 0.83 Trial f i 1 0 0 0 -2 -1 6 (0.54, ⨁ Critical evidence 1.00) 0.98 All c h 2 0 -1 0 0 -2 80 (0.95, ⨁ Critical evidence 1.00) Genotype 2, Treatment-experienced population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence

158

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations Genotype 3, Treatment-experienced population SVR12 0.87 Trial e i 1 0 0 0 -1 -1 30 (0.75, ⨁⨁ Critical evidence 0.99) All 1 Same as trial-only evidence evidence Discontinuations due to adverse events Genotypes 2 and 3 only 0.03 Trial a 1 -1 0 0 0 0 72 (0, ⨁⨁⨁ Critical evidence 0.07) 0.02 All a 2 -1 0 0 0 0 126 (0, ⨁⨁⨁ Critical evidence 0.04) Serious adverse events Genotypes 2 and 3 only Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Mortality Genotypes 2 and 3 only 0.04 Trial 1 0 0 0 0 0 72 (0, ⨁⨁⨁⨁ Critical evidence 0.09) 0.04 All 2 0 0 0 0 0 93 (0, ⨁⨁⨁⨁ Critical evidence 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 10% (±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

159 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

160

Table D18: GRADE evidence profile for patients treated with sofosbuvir + ribavirin, patients with cirrhosis analysis, arranged by genotype

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations Genotype 2, All-treatment experience population SVR12 0.79 Trial c d 5 0 -1 0 -1 0 107 (0.72, ⨁⨁ Critical evidence 0.87) 0.86 All c h 10 0 -1 0 0 -1 486 (0.81, ⨁⨁ Critical evidence 0.90) Genotype 3, All-treatment experience population SVR12 0.69 Trial c d 7 0 -1 0 -1 0 369 (0.58, ⨁⨁ Critical evidence 0.80) 0.67 All c d 12 0 -1 0 -1 0 603 (0.58, ⨁⨁ Critical evidence 0.76) Genotype 2 or 3 (mixed), All-treatment experience population SVR12 0.61 Trial e i 1 0 0 0 -1 -1 33 (0.44, ⨁⨁ Critical evidence 0.77) All 1 Same as trial-only evidence evidence Genotype 2, Treatment-naïve population SVR12 0.77 Trial d i 2 0 0 0 -1 -1 48 (0.65, ⨁⨁ Critical evidence 0.88) 0.85 All c d 4 0 -1 0 -1 0 132 (0.73, ⨁⨁ Critical evidence 0.97) Genotype 3, Treatment-naïve population SVR12 Trial c d 0.79 4 0 -1 0 -1 0 105 ⨁⨁ Critical evidence (0.69,

161

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations 0.89) 0.74 All c d 6 0 -1 0 -1 0 198 (0.64, ⨁⨁ Critical evidence 0.84) Genotype 2 or 3 (mixed), All-treatment experience population SVR12 0.61 Trial e i 1 0 0 0 -1 -1 33 (0.44, ⨁⨁ Critical evidence 0.77) All 1 Same as trial-only evidence evidence Genotype 2, Treatment-experienced population SVR12 0.79 Trial c d 2 0 -1 0 -1 0 40 (0.67, ⨁⨁ Critical evidence 0.91) 0.82 All d 4 0 0 0 -1 0 132 (0.76, ⨁⨁⨁ Critical evidence 0.88) Genotype 3, Treatment-experienced population SVR12 0.57 Trial c d 4 0 -1 0 -1 0 180 (0.38, ⨁⨁ Critical evidence 0.75) 0.55 All c d 6 0 -1 0 -1 0 260 (0.41, ⨁⨁ Critical evidence 0.70) Discontinuations due to adverse events Genotypes 2 and 3 only 0.02 Trial a 3 -1 0 0 0 0 736 (0.01, ⨁⨁⨁ Critical evidence 0.03) 0.02 All a 4 -1 0 0 0 0 908 (0.01, ⨁⨁⨁ Critical evidence 0.03) Serious adverse events

162

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations Genotypes 2 and 3 only 0.05 Trial 3 0 0 0 0 0 736 (0.03, ⨁⨁⨁⨁ Critical evidence 0.07) All 3 Same as trial-only evidence evidence Mortality Genotypes 2 and 3 only 0 Trial 3 0 0 0 0 0 736 (0, ⨁⨁⨁⨁ Critical evidence 0.01) 0.01 All 6 0 0 0 0 0 939 (0, ⨁⨁⨁⨁ Critical evidence 0.01) 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 10% (±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

163

Table D19: GRADE evidence profile for patients treated with daclatasvir + asunaprevir, patients with HIV co-infection analysis, arranged by genotype

No evidence available

164

Table D20: GRADE evidence profile for patients treated with daclatasvir + sofosbuvir, patients with HIV co-infection analysis, arranged by genotype

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations Genotype 1, All-treatment experience population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 2, All-treatment experience population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 3, All-treatment experience population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 4, All-treatment experience population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 5, All-treatment experience population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 6, All-treatment experience population SVR12 – Trial – – – – – – – – –

165

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations evidence All – – – – – – – – – – evidence Mixed genotype group, All-treatment experience population SVR12 Trial – – – – – – – – – – evidence 0.87 All b h 2 -2 0 0 0 -2 347 (0.69, ⨁ Critical evidence 1.00) 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 10% (±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

166

Table D21: GRADE evidence profile for patients treated with elbasvir + grazoprevir, patients with HIV co-infection analysis, arranged by genotype

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations Genotype 1, All-treatment experience population SVR12 0.92 Trial d 2 0 0 0 -1 0 248 (0.85, ⨁⨁⨁ Critical evidence 0.99) All 2 Same as trial-only evidence evidence Genotype 2, All-treatment experience population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 3, All-treatment experience population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 4, All-treatment experience population SVR12 0.96 Trial e i 1 0 0 0 -1 -1 28 (0.90, ⨁⨁ Critical evidence 1.00) All 1 Same as trial-only evidence evidence Genotype 5, All-treatment experience population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 6, All-treatment experience population SVR12

167

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations 0.83 Trial f i 1 0 0 0 -2 -1 2 (0.41, ⨁ Critical evidence 1.00) All 1 Same as trial-only evidence evidence Mixed genotype group, All-treatment experience population SVR12 0.83 Trial f i 1 0 0 0 -2 -1 6 (0.54, ⨁ Critical evidence 1.00) All 1 Same as trial-only evidence evidence 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 10% (±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

168

Table D22: GRADE evidence profile for patients treated with glecaprevir + pibrentasvir, patients with HIV co-infection analysis, arranged by genotype

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations Genotype 1, All-treatment experience population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 2, All-treatment experience population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 3, All-treatment experience population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 4, All-treatment experience population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 5, All-treatment experience population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 6, All-treatment experience population SVR12 – Trial – – – – – – – – –

169

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations evidence All – – – – – – – – – – evidence Mixed genotype group, All-treatment experience population SVR12 1.00 Trial 1 0 0 0 0 0 151 (0.99, ⨁⨁⨁⨁ Critical evidence 1.00) All 1 Same as trial-only evidence evidence 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 10% (±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

170

Table D23: GRADE evidence profile for patients treated with ledipasvir + sofosbuvir , patients with HIV co-infection analysis, arranged by genotype

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations Genotype 1, All-treatment experience population SVR12 0.98 Trial 3 0 0 0 0 0 129 (0.95, ⨁⨁⨁⨁ Critical evidence 1.00) 0.96 All a 5 -1 0 0 0 0 383 (0.93, ⨁⨁⨁ Critical evidence 0.98) Genotype 2, All-treatment experience population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 3, All-treatment experience population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 4, All-treatment experience population SVR12 0.75 Trial f i 1 0 0 0 -2 -1 1 (0.15, ⨁ Critical evidence 1.00) All 1 Same as trial-only evidence evidence Genotype 5, All-treatment experience population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 6, All-treatment experience population SVR12

171

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Mixed genotype group, All-treatment experience population SVR12 0.96 Trial 1 0 0 0 0 0 335 (0.94, ⨁⨁⨁⨁ Critical evidence 0.98) 0.96 All 3 0 0 0 0 0 364 (0.94, ⨁⨁⨁⨁ Critical evidence 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 10% (±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

172

Table D24: GRADE evidence profile for patients treated with paritaprevir/ritonavir + ombitasvir + dasabuvir, patients with HIV co-infection analysis, arranged by genotype

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations Genotype 1, All-treatment experience population SVR12 Trial – – – – – – – – – – evidence 0.86 All b f h 1 -2 0 0 -2 -2 7 (0.60, ⨁ Critical evidence 1.00) Genotype 2, All-treatment experience population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 3, All-treatment experience population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 4, All-treatment experience population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 5, All-treatment experience population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Genotype 6, All-treatment experience population SVR12

173

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Mixed genotype group, All-treatment experience population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence 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 10% (±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

174

Table D25: GRADE evidence profile for patients treated with sofosbuvir + velpatasvir, patients with HIV co-infection analysis, arranged by genotype

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations Genotype 1, All-treatment experience population SVR12 0.95 Trial b 1 -2 0 0 0 0 78 (0.90, ⨁⨁ Critical evidence 1.00) All 1 Same as trial-only evidence evidence Genotype 2, All-treatment experience population SVR12 0.96 Trial b f i 1 -2 0 0 -2 -1 11 (0.85, ⨁ Critical evidence 1.00) All 1 Same as trial-only evidence evidence Genotype 3, All-treatment experience population SVR12 0.92 Trial b f i 1 -2 0 0 -2 -1 12 (0.76, ⨁ Critical evidence 1.00) All 1 Same as trial-only evidence evidence Genotype 4, All-treatment experience population SVR12 0.92 Trial b f i 1 -2 0 0 -2 -1 5 (0.70, ⨁ Critical evidence 1.00) All 1 Same as trial-only evidence evidence Genotype 5, All-treatment experience population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence

175

Quality assessment No. of No. of Risk of Other Effect Quality Importance Design Inconsistency Indirectness Imprecision patients studies bias considerations Genotype 6, All-treatment experience population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence Mixed genotype group, All-treatment experience population SVR12 Trial – – – – – – – – – – evidence All – – – – – – – – – – evidence 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 10% (±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

176

Table D26: GRADE evidence profile for patients treated with sofosbuvir + velpatasvir + voxilaprevir, patients with HIV co-infection analysis, arranged by genotype

No evidence available

177

REFERENCES

1. Viechtbauer W. Conducting Meta-Analyses in R with the metafor Package. Journal of Statistical Software 2010; 36(3): 48. 2. Wallace BC, Dahabreh IJ, Trikalinos TA, Lau J, Trow P, Schmid CH. Closing the Gap between Methodologists and End-Users: R as a Computational Back-End. Journal of Statistical Software 2012; 49(5): 15. 3. Higgins JP, Altman DG, Gotzsche PC, et al. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. Bmj 2011; 343: d5928. 4. Guyatt GH, Oxman AD, Vist GE, et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. Bmj 2008; 336(7650): 924-6. 5. Guyatt GH, Oxman AD, Vist G, et al. GRADE guidelines: 4. Rating the quality of evidence--study limitations (risk of bias). Journal of clinical epidemiology 2011; 64(4): 407-15. 6. Guyatt GH, Oxman AD, Kunz R, et al. GRADE guidelines: 7. Rating the quality of evidence-- inconsistency. Journal of clinical epidemiology 2011; 64(12): 1294-302. 7. Guyatt GH, Oxman AD, Montori V, et al. GRADE guidelines: 5. Rating the quality of evidence-- publication bias. Journal of clinical epidemiology 2011; 64(12): 1277-82. 8. Guyatt GH, Oxman AD, Kunz R, et al. GRADE guidelines: 8. Rating the quality of evidence-- indirectness. Journal of clinical epidemiology 2011; 64(12): 1303-10. 9. Guyatt GH, Oxman AD, Sultan S, et al. GRADE guidelines: 9. Rating up the quality of evidence. Journal of clinical epidemiology 2011; 64(12): 1311-6. 10. Abdel-Aziz AM, Ibrahim MA, El-Sheikh AA, et al. Effect of Sofosbuvir Plus Daclatasvir in Hepatitis C Virus Genotype-4 Patients: Promising Effect on Liver Fibrosis. Journal of Clinical and Experimental Hepatology 2017. 11. Abergel A, Asselah T, Metivier S, et al. Ledipasvir-sofosbuvir in patients with hepatitis C virus genotype 5 infection: an open-label, multicentre, single-arm, phase 2 study. The Lancet Infectious Diseases 2016; 16(4): 459-64. 12. Abergel A, Metivier S, Samuel D, et al. Ledipasvir plus sofosbuvir for 12 weeks in patients with hepatitis C genotype 4 infection. Hepatology 2016; 64(4): 1049-56. 13. Afdhal N, Reddy KR, Nelson DR, et al. Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection. New England Journal of Medicine 2014; 370(16): 1483-93. 14. Afdhal N, Zeuzem S, Kwo P, et al. Ledipasvir and sofosbuvir for untreated HCV genotype 1 infection. The New England journal of medicine 2014; 370(20): 1889-98. 15. Alqahtani S, Afdahl NH, Zeuzem S, et al. Safety of ledipasvir sofosbuvir with and without ribavirin for the treatment of patients with chronic HCV genotype 1 infection an analysis of the phase 3 ion trials. Hepatology international; 9(1 SUPPL. 1): S59-S60. 16. Alqahtani SAA, N.; Zeuzem, S.; Gordon, S. C.; Mangia, A.; Kwo, P.; Fried, M.; Yang, J. C.; Ding, X.; Pang, P. S.; McHutchison, J. G.; Pound, D.; Reddy, K. R.; Marcellin, P.; Kowdley, K. V.; Sulkowski, M. Safety and tolerability of ledipasvir/sofosbuvir with and without ribavirin in patients with chronic hepatitis C virus genotype 1 infection: Analysis of phase III ION trials. Hepatology (Baltimore, Md) 2015; 62(1): 25- 30. 17. Andreone P, Colombo MG, Enejosa JV, et al. ABT-450, ritonavir, ombitasvir, and dasabuvir achieves 97% and 100% sustained virologic response with or without ribavirin in treatment-experienced patients with HCV genotype 1b infection. Gastroenterology 2014; 147(2): 359-65.e1. 18. Backus LI, Belperio PS, Shahoumian TA, Loomis TP, Mole LA. Comparative effectiveness of ledipasvir/sofosbuvir +/- ribavirin vs. ombitasvir/paritaprevir/ritonavir + dasabuvir +/- ribavirin in 6961 genotype 1 patients treated in routine medical practice. Alimentary Pharmacology and Therapeutics 2016; 44(4): 400-10. 19. Bansal A, Goyal O. Treatment of Patients with Chronic Hepatitis Genotype 3 Infection with/without Cirrhosis with Sofosbuvir and Daclatasvir Therapy. Gastroenterology 2017; 152(5): S1091- S2. 20. Bourliere M, Bronowicki JP, de Ledinghen V, et al. Ledipasvir-sofosbuvir with or without ribavirin to treat patients with HCV genotype 1 infection and cirrhosis non-responsive to previous protease- inhibitor therapy: a randomised, double-blind, phase 2 trial (SIRIUS). Lancet Infect Dis 2015; 15(4): 397- 404. doi: 10.1016/S473-3099(15)70050-2. Epub 2015 Mar 13.

178

21. Bourliere M, Gordon SC, Flamm SL, et al. Sofosbuvir, velpatasvir, and voxilaprevir for previously treated HCV infection. New England Journal of Medicine 2017; 376(22): 2134-46. 22. Bourliere M, Gordon SC, Ramji A, et al. Sofosbuvir/velpatasvir/voxilaprevir for 12 weeks as a salvage regimen in NS5A inhibitor-experienced patients with genotype 1-6 infection: the phase 3 POLARIS-1 study. Hepatology 2016; Conference: 67th annual meeting of the american association for the study of liver diseases: the liver meeting. 2016. United states. Conference start: 20161111. Conference end: 20161115 63(1 Supplement 1): 102A-3A. 23. Bourliere MB, J. P.; de Ledinghen, V.; Hezode, C.; Zoulim, F.; Mathurin, P.; Tran, A.; Larrey, D. G.; Ratziu, V.; Alric, L.; Hyland, R. H.; Jiang, D.; Doehle, B.; Pang, P. S.; Symonds, W. T.; Subramanian, G. M.; McHutchison, J. G.; Marcellin, P.; Habersetzer, F.; Guyader, D.; Grange, J. D.; Loustaud-Ratti, V.; Serfaty, L.; Metivier, S.; Leroy, V.; Abergel, A.; Pol, S. Ledipasvir-sofosbuvir with or without ribavirin to treat patients with HCV genotype 1 infection and cirrhosis non-responsive to previous protease-inhibitor therapy: A randomised, double-blind, phase 2 trial (SIRIUS). The Lancet Infectious Diseases 2015; 15(4): 397-404. 24. Bristol-Myers Squibb. A Phase 3 Evaluation of Daclatasvir Plus Sofosbuvir in Treatment-naive and Treatment- experienced Chronic Hepatitis C (Genotype 1, 2, 3, 4, 5, or 6) Subjects Coinfected with Human Immunodeficiency Virus (HIV). 2015. 25. Bristol-Myers Squibb. A Phase 3 Evaluation of Daclatasvir and Sofosbuvir in Treatment-Naive and Treatment-Experienced Subjects with Genotype 3 Chronic Hepatitis C Infection 2015. 26. Carlin AFA, P.; Song, Q.; Wang, H.; Paulson, M. S.; Stamm, L. M.; Schooley, R. T.; Wyles, D. L. Temporal dynamics of inflammatory cytokines/chemokines during sofosbuvir and ribavirin therapy for genotype 2 and 3 hepatitis C infection. Hepatology 2015; 62(4): 1047-58. 27. Carrieri MPP, C.; Younossi, Z.; Vilotitch, A.; Fontaine, H.; Petrov-Sanchez, V.; Marcellin, F.; Carrat, F.; Hezode, C.; Bourliere, M.; Poncin, E.; Botta-Friedland, D.; Fontanges, T.; Arpurt, J. P.; Bacq, Y.; Cales, P.; Delasalle, P.; Ouzan, D.; Nousbaum, J. B.; Sylvain, C.; Ribard, D.; Gatineau-Sailliant, G.; de Montigny-Lenhardt, S.; Renard, P.; Pilette, C.; Denis, J.; Lascoux-Combe, C.; Abel, L.; Albert, M.; Chazouilleres, O.; Dubuisson, J.; Negro, F.; Pageaux, G. P.; Paradis, V.; Spire, B.; Taburet, A. M.; Trinchet, J. C.; Yazdanpanah, Y.; Dufour, C.; Frehaut, C.; Pirot, M.; Lesel, A.; Zahraa, N.; Chau, F. Health-Related Quality of Life in Chronic HCV-Infected Patients Switching to Pegylated-Interferon-Free Regimens (ANRS CO20 CUPIC Cohort Study and SIRIUS Trial). Patient 2017: 1-10. 28. Chamorro-de-Vega E, Gimenez-Manzorro A, Rodriguez-Gonzalez CG, et al. Effectiveness and Safety of Ombitasvir-Paritaprevir/Ritonavir and Dasabuvir With or Without Ribavirin for HCV Genotype 1 Infection for 12 Weeks Under Routine Clinical Practice. Annals of Pharmacotherapy 2016; 50(11): 901-8. 29. Charlton M, O'Leary J, Osinusi A, et al. Sofosbuvir/Velpatasvir for the treatment of HCV in patients with decompensated liver disease: the ASTRAL-4 study. Transplantation 2016; Conference: 22nd annual international congress of the international liver transplantation society, ILTS. 2016. South korea. Conference start: 20160504. Conference end: 20160507 100(5 Supplement 1): S102- S3. 30. Chayama K, Suzuki F, Karino Y, et al. CERTAIN-1: efficacy and safety of glecaprevir/pibrentasvir in Japanese patients with chronic genotype 1 hepatitis C virus infection with and without cirrhosis. Journal of Hepatology 2017; 66: S527. 31. Chayama K, Suzuki F, Sato K, et al. Efficacy and safety of glecaprevir/pibrentasvir in Japanese patients with chronic genotype 2 hepatitis C virus infection with and without cirrhosis. Journal of Hepatology 2017; 66: S528. 32. Chen JH, Zeng Z, Zhang XX, et al. Efficacy and safety of combined directly acting antivirals for treatment of Chinese chronic hepatitis C patients in a real-world setting. World Journal of Gastroenterology 2017; 23(22): 4072-9. 33. Cheung MCM, Walker AJ, Hudson BE, et al. Outcomes after successful direct-acting antiviral therapy for patients with chronic hepatitis C and decompensated cirrhosis. Journal of Hepatology 2016; 65(4): 741-7. 34. Chuang WL, Chien RN, Peng CY, et al. Ledipasvir/sofosbuvir fixed-dose combination tablet in Taiwanese patients with chronic genotype 1 hepatitis C virus. J Gastroenterol Hepatol 2016; 31(7): 1323- 9. 35. Conway B, Janczewska E, Luo Y, et al. Malachite-I: Phase 3B trial of ombitasvir/paritaprevir/R and dasabuvir +/- ribavirin or telaprevir + peginterferon/ribavirin in treatment-naive adults with HCV genotype 1. Gastroenterology; 148(4 SUPPL. 1): S1001-S2.

179

36. Cornberg MP, J.; Schober, A.; Mauss, S.; Boker, K. H. W.; Link, R.; Gunther, R.; Serfert, Y.; Pfeiffer-Vornkahl, H.; Manns, M. P.; Sarrazin, C.; Huppe, D.; Berg, T.; Niederau, C. Real-world use, effectiveness and safety of anti-viral treatment in chronic hepatitis C genotype 3 infection. Aliment Pharmacol Ther 2017; 45(5): 688-700. 37. Curry M, O'Leary J, Brown RS, et al. Clinical benefits of successful treatment in HCV infected patients with decompensated cirrhosis treated with sofosbuvir/velpatasvir. Transplantation 2016; Conference: 22nd annual international congress of the international liver transplantation society, ILTS. 2016. South korea. Conference start: 20160504. Conference end: 20160507 100(5 Supplement 1): S136. 38. Curry MP, O'Leary JG, Bzowej N, et al. Sofosbuvir and velpatasvir for HCV in patients with decompensated cirrhosis. New England Journal of Medicine 2015; 373(27): 2618-28. 39. Dashtseren B, Dendev B, Genden Z, et al. Hepatitis C treatment with sofosbuvir/ledipasvir single tablet regimen in Mongolia. Hepatology international 2017; Conference: 26th annual conference of the asian pacific association for the study of the liver, APASL. 2017. China 11(1 Supplement 1): S1036- S7. 40. Dashtseren B, Dendev B, Genden Z, et al. Hepatitis C treatment with sofosbuvir/ledispasvir single tablet regimen in Mongolia. Hepatology international 2017; Conference: 26th annual conference of the asian pacific association for the study of the liver, APASL. 2017. China 11(1 Supplement 1): S1034. 41. Desnoyer A, Pospai D, Le MP, et al. Pharmacokinetics, safety and efficacy of a full dose sofosbuvir-based regimen given daily in hemodialysis patients with chronic hepatitis C. Journal of Hepatology 2016; 65(1): 40-7. 42. Deterding K, Honer Zu Siederdissen C, Port K, et al. Improvement of liver function parameters in advanced HCV-associated liver cirrhosis by IFN-free antiviral therapies. Aliment Pharmacol Ther 2015; 42(7): 889-901. 43. Deterding K, Spinner CD, Schott E, et al. Ledipasvir plus sofosbuvir fixed-dose combination for 6 weeks in patients with acute hepatitis C virus genotype 1 monoinfection (HepNet Acute HCV IV): an open-label, single-arm, phase 2 study. Lancet infectious diseases 2017; 17(2): 215-22. 44. Deterding K, Spinner CD, Schott E, et al. Six weeks of sofosbuvir/ledipasvir treatment of acute hepatitis C virus genotype 1 monoinfection: final results of the The German HepNet Acute HCV IV Study. Hepatology 2016; Conference: 67th annual meeting of the american association for the study of liver diseases: the liver meeting. 2016. United states. Conference start: 20161111. Conference end: 20161115 63(1 Supplement 1): 416A-7A. 45. Dore GJ, Altice F, Litwin AH, et al. Elbasvir-grazoprevir to treat hepatitis C virus infection in persons receiving opioid agonist therapy a randomized trial. Annals of Internal Medicine 2016; 165(9): 625-34. 46. Dore GJ, Altice F, Litwin AH, et al. C-EDGE CO-STAR: risk of reinfection following successful therapy with elbasvir and grazoprevir in persons who inject drugs (PWID) receiving opioid agonist therapy (OAT). Journal of gastroenterology and hepatology 2016; 31: 70-1. 47. Dore GJ, Conway B, Luo Y, et al. Efficacy and safety of ombitasvir/paritaprevir/r and dasabuvir compared to IFN-containing regimens in genotype 1 HCV patients: The MALACHITE-I/II trials. Journal of Hepatology 2016; 64(1): 19-28. 48. Everson GT, Towner WJ, Davis MN, et al. Sofosbuvir with velpatasvir in treatment-naive noncirrhotic patients with genotype 1 to 6 hepatitis c virus infection. Annals of internal medicine 2015; 163(11): 818-26. 49. Feld JJ, Jacobson IM, Hode C, et al. Sofosbuvir and velpatasvir for hcv genotype 1, 2, 4, 5, and 6 infection. New England Journal of Medicine 2015; 373(27): 2599-607. 50. Feld JJ, Maan R, Zeuzem S, et al. Effectiveness and Safety of Sofosbuvir-Based Regimens for Chronic HCV Genotype 3 Infection: Results of the HCV-TARGET Study. Clinical Infectious Diseases 2016; 63(6): 776-83. 51. Feld JJ, Moreno C, Trinh R, et al. Sustained virologic response of 100% in HCV genotype 1b patients with cirrhosis receiving ombitasvir/paritaprevir/r and dasabuvir for 12 weeks. Journal of Hepatology 2016; 64(2): 301-7. 52. Feld JJ, Nelson DR, Kowdley KV, et al. All oral therapy with sofosbuvir + ribavirin for 12 or 16 weeks in treatment experienced genotype 2/3 HCV-infected patients: The fusion trial. Hepatology International 2013; 7: S436.

180

53. Ferenci P, Bernstein D, Lalezari J, et al. ABT-450/r-ombitasvir and dasabuvir with or without ribavirin for HCV. N Engl J Med 2014; 370(21): 1983-92. doi: 10.056/NEJMoa1402338. Epub 2014 May 4. 54. Fierer DS, El Sayed A, Palaniswami P. Treatment of “acute” hepatitis C virus in human immunodeficiency virus-infected men with short-course sofosbuvir/ledipasvir. Journal of Hepatology 2017; 66: S300. 55. Fontaine HH, C.; Roudot-Thoraval, F.; Pol, S. Safety and efficacy of the combination ombitasvir/ paritaprevir/ritonavir +/- dasabuvir in HCV genotype 1-or 4-mono-infected patients from the french ANRS Co22 hepather cohort. Hepatology 2016; Conference: 67th annual meeting of the american association for the study of liver diseases: the liver meeting. 2016. United states. Conference start: 20161111. Conference end: 20161115 63(1 Supplement 1): 453A. 56. Forns X, Lee S, Valdes J, et al. EXPEDITION-I: efficacy and safety of glecaprevir/pibrentasvir in adults with chronic hepatitis C virus genotype 1, 2, 4, 5 or 6 infection and compensated cirrhosis. Journal of Hepatology 2017; 66: S3. 57. Forns X, Lee S, Valdes JM, et al. EXPEDITION-I: Efficacy and Safety of Glecaprevir/Pibrentasvir in Adults with Chronic Hepatitis C Virus Genotype 1, 2, 4, 5 or 6 Infection and Compensated Cirrhosis. Gastroenterology 2017; 152(5): S1061. 58. Forns X, Lee SS, Valdes J, et al. Glecaprevir plus pibrentasvir for chronic hepatitis C virus genotype 1, 2, 4, 5, or 6 infection in adults with compensated cirrhosis (EXPEDITION-1): a single-arm, open-label, multicentre phase 3 trial. The Lancet Infectious diseases 2017. 59. Foster GR, Afdhal N, Roberts SK, et al. Sofosbuvir and velpatasvir for HCV Genotype 2 and 3 infection. New England Journal of Medicine 2015; 373(27): 2608-17. 60. Foster GR, Gane E, Asatryan A, et al. ENDURANCE-3: safety and efficacy of glecaprevir/pibrentasvir compared to sofosbuvir plus daclatasvir in treatment-naïve HCV genotype 3- infected patients without cirrhosis. Journal of Hepatology 2017; 66: S34. 61. Foster GR, Irving WL, Cheung MCM, et al. Impact of direct acting antiviral therapy in patients with chronic hepatitis C and decompensated cirrhosis. Journal of Hepatology 2016; 64(6): 1224-31. 62. Foster GR, Pianko S, Brown A, et al. Efficacy of Sofosbuvir Plus Ribavirin with or Without Peginterferon-Alfa in Patients with Hepatitis C Virus Genotype 3 Infection and Treatment-Experienced Patients with Cirrhosis and Hepatitis C Virus Genotype 2 Infection. Gastroenterology 2015; 149(6): 1462- 70. 63. Foster GR, Pianko S, Cooper C, et al. Sofosbuvir + peginterferon/ribavirin for 12 weeks vs sofosbuvir + ribavirin for 16 or 24 weeks in genotype 3 HCV infected patients and treatment-experienced cirrhotic patients with genotype 2 HCV: The boson study. Journal of hepatology 2015; 62(22). 64. Gane E, Hyland RH, An D, et al. Ledipasvir Plus Sofosbuvir With or Without Ribavirin for 12 Weeks in Patients With Hepatitis C Genotype 3 or 6 Infection. 2015. 65. Gane E, Poordad F, Wang S, et al. High Efficacy of ABT-493 and ABT-530 Treatment in Patients With HCV Genotype 1 or 3 Infection and Compensated Cirrhosis. Gastroenterology 2016; 151(4): 651- 9.e1. 66. Gane E, Stedman CAM, Asselah T, et al. Ledipasvir/sofosbuvir with or without ribavirin for the treatment of patients with genotype 2-6 chronic HCV infection: Summary results from four phase ii studies. American journal of gastroenterology 2015; 110(16). 67. Gane EJ, Hyland RH, An D, et al. Efficacy of ledipasvir and sofosbuvir, with or without ribavirin, for 12 weeks in patients with HCV genotype 3 or 6 infection. Gastroenterology 2015; 149(6): 1454-61.e1. 68. Gane EJ, Hyland RH, Yang Y, et al. Efficacy of Ledipasvir Plus Sofosbuvir for 8 or 12 Weeks in Patients With Hepatitis C Virus Genotype 2 Infection. Gastroenterology 2017; 152(6): 1366-71. 69. Gane EJ, Stedman CA, Hyland RH, et al. Efficacy of nucleotide polymerase inhibitor sofosbuvir plus the NS5A inhibitor ledipasvir or the NS5B non-nucleoside inhibitor GS-9669 against HCV genotype 1 infection. Gastroenterology 2014; 146(3): 736-43.e1. 70. Gane EN, R.; Luketic, V.; Asante-Appiah, E.; Hwang, P.; Robertson, M.; Wahl, J.; Barr, E.; Haber, B. Efficacy of 12 or 18 weeks of elbasvir plus grazoprevir with ribavirin in treatment-naive, noncirrhotic HCV genotype 3-infected patients. Journal of Viral Hepatitis 2017. 71. Gee Lim S, Patel K, Agarwal K, et al. Sofosbuvir/velpatasvir for 12 weeks results in high SVR12 rates in patients with indeterminate genotypes: an integrated analysis of efficacy from the ASTRAL-1, ASTRAL-2, and ASTRAL-3 studies. Hepatology international 2017; Conference: 26th annual

181 conference of the asian pacific association for the study of the liver, APASL. 2017. China 11(1 Supplement 1): S102-S3. 72. George J, Burnevich EZ, Sheen IS, et al. Efficacy and safety of elbasvir/grazoprevir in treatment- naive subjects with chronic HCV GT 1, GT 4 and GT 6 infection (C-CORAL): a phase III randomized multinational clinical trial. Hepatology 2016; Conference: 67th annual meeting of the american association for the study of liver diseases: the liver meeting. 2016. United states. Conference start: 20161111. Conference end: 20161115 63(1 Supplement 1): 41A. 73. Grebely J, Dore GJ, Zeuzem S, et al. Efficacy and safety of sofosbuvir/velpatasvir in patients with chronic hepatitis C virus infection receiving opioid substitution therapy: analysis of phase 3 ASTRAL trials. Clinical infectious diseases 2016; 63(11): 1479-81. 74. Grebely JM, S.; Brown, A.; Bronowicki, J. P.; Puoti, M.; Wyles, D.; Natha, M.; Zhu, Y.; Yang, J.; Kreter, B.; Brainard, D. M.; Yun, C.; Carr, V.; Dore, G. J. Efficacy and safety of ledipasvir/sofosbuvir with and without ribavirin in patients with chronic HCV genotype 1 infection receiving opioid substitution therapy: analysis of phase 3 ION trials. Clinical infectious diseases 2016; 63(11): 1405-11. 75. Hezode C, Colombo M, Bourliere M, et al. Elbasvir/Grazoprevir for Patients With Hepatitis C Virus Infection and Inherited Blood Disorders: A Phase III Study. Hepatology 2017; 03: 03. 76. Hezode C, Colombo M, Spengler U, et al. C-edge IBLD: efficacy and safety of elbasvir/grazoprevir (EBR/GZR) in patients with chronic hepatitis C virus (HCV) infection and inherited blood disorders (IBLD). Haematologica Conference: 21st congress of the european hematology association Denmark 2016; 101: 308-9. 77. Hezode C, Colombo M, Spengler U, et al. C-EDGE IBLD: efficacy and safety of elbasvir/grazoprevir (EBR/GZR) in subjects with chronic hepatitis Cvirus infection and inherited blood disorders. Journal of hepatology 2016; Conference: 51st annual meeting of the european association for the study of the liver, international liver congress. 2016. Barcelona spain. Conference start: 20160413. Conference end: 20160417. Conference publication:(var.pagings) 64(2 SUPPL. 1): S753. 78. Hezode C, Fried MW, Colombo M, et al. Efficacy and safety of elbasvir/grazoprevir in patients with chronic hepatitis c virus infection and inherited blood disorders: final data from the C-edge IBLD study. Blood Conference: 58th annual meeting of the american society of hematology, ASH 2016; 128(22). 79. Hezode C, Leroy V, Rosa I, Pawlotsky J-M, de Ledinghen V, Bronowicki J-P. Efficacy and Safety of Sofosbuvir and Daclatasvir for 8 Weeks in Treatment-Naive Non-Cirrhotic Patients with Chronic HCV Genotype 3 Infection. Gastroenterology 2017; 152(5): S1099. 80. Hezode C, Leroy V, Rosa I, et al. Efficacy and safety of sofosbuvir and daclatasvir for 8 weeks in treatment-naïve non-cirrhotic patients with chronic hepatitis C virus Genotype 3 Infection. Journal of Hepatology 2017; 66: S299. 81. Hlaing NKT, Mitrani RA, Aung ST, et al. Safety and efficacy of sofosbuvir-based direct-acting antiviral regimens for hepatitis C virus genotypes 1-4 and 6 in Myanmar: Real-world experience. Journal of Viral Hepatitis 2017. 82. Ho SB, Kaplan DE, Byrne S, et al. Efficacy of Sofosbuvir Plus Ribavirin in Veterans With Hepatitis C Virus Genotype 2 Infection, Compensated Cirrhosis, and Multiple Comorbidities. Clinical gastroenterology and hepatology 2017; 15(2): 282-8. 83. Honer Zu Siederdissen C, Maasoumy B, Deterding K, et al. Eligibility and safety of the first interferon-free therapy against hepatitis C in a real-world setting. Liver International 2015; 35(7): 1845-52. 84. Ide T, Eguchi Y, Harada M, et al. Efficacy and safety of DAAs therapy in hepatitis C: a multicenter real-world cohort of chronic hepatitis C patients. Hepatology 2016; Conference: 67th annual meeting of the american association for the study of liver diseases: the liver meeting. 2016. United states. Conference start: 20161111. Conference end: 20161115 63(1 Supplement 1): 459A. 85. Ide T, Eguchi Y, Harada M, et al. Evaluation of resistance-associated substitutions in NS5A using direct sequence and cycleave method and treatment outcome with daclatasvir and asunaprevir for chronic hepatitis C genotype 1. PLoS ONE 2016; 11 (9) (no pagination)(e0163884). 86. Iio E, Shimada N, Abe H, et al. Efficacy of daclatasvir/asunaprevir according to resistance- associated variants in chronic hepatitis C with genotype 1. Journal of gastroenterology 2017; 52(1): 94- 103. 87. Iio E, Shimada N, Takaguchi K, et al. Clinical evaluation of sofosbuvir/ledipasvir in patients with chronic hepatitis C genotype 1 with and without prior daclatasvir/asunaprevir therapy. Hepatology Research 2017.

182

88. Ikeda H, Watanabe T, Okuse C, et al. Impact of resistance-associated variant dominancy on treatment in patients with HCV genotype 1b receiving daclatasvir/asunaprevir. Journal of Medical Virology 2017; 89(1): 99-105. 89. Ingiliz P, Christensen S, Kimhofer T, et al. Sofosbuvir and Ledipasvir for 8 Weeks for the Treatment of Chronic Hepatitis C Virus (HCV) Infection in HCV-Monoinfected and HIV-HCV-Coinfected Individuals: results from the German Hepatitis C Cohort (GECCO-01). Clinical infectious diseases 2016; 63(10): 1320-4. 90. Isakov V, Gankina N, Salupere R, et al. Ledipasvir/Sofosbuvir for 8 weeks results in high SVR rates in treatment-naive patients with chronic HCV Infection and HIV/HCV Co-infection. Hepatology 2016; Conference: 67th annual meeting of the american association for the study of liver diseases: the liver meeting. 2016. United states. Conference start: 20161111. Conference end: 20161115 63(1 Supplement 1): 1010A. 91. Ishigami M, Hayashi K, Honda T, et al. Real World Data of Daclatasvir and Asunaprevir Combination Therapy for HCV Genotype 1b Infection in Patients With Renal Dysfunction. Clinical gastroenterology and hepatology 2017; 15(5): 787-8. 92. Itoh Y, Suzuki F, Karino Y, et al. Prevalence and impact of baseline resistance-associated variants on the efficacy of elbasvir / grazoprevir in hepatitis c genotype 1 infected Japanese patients. Hepatology 2016; Conference: 67th annual meeting of the american association for the study of liver diseases: the liver meeting. 2016. United states. Conference start: 20161111. Conference end: 20161115 63(1 Supplement 1): 420A. 93. Iwamoto M, Sonderup M, Fortas C, Maman D. Real-world effectiveness and safety of Daclatasvir/Sofosbuvir ± Ribavirin among genotype 5 and 6 patients: Medecins Sans Frontieres, 2017. 94. Jacobson I, Brau N, Bourgeois S, et al. The tolerability of SOF/VEL for 12 weeks in >1,000 patients treated in the astral-1, astral-2, and astral-3 studies: an integrated safety analysis. Journal of hepatology 2016; Conference: 51st annual meeting of the european association for the study of the liver, international liver congress. 2016. Barcelona spain. Conference start: 20160413. Conference end: 20160417. Conference publication:(var.pagings) 64(2 SUPPL. 1): S773-S4. 95. Jacobson I, Yoshida EM, Sulkowski M, et al. Treatment with sofosbuvir + ribavirin for 12 weeks achieves SVR12 of 78% in GT2/3 interferon-ineligible, -intolerant, or -unwilling patients: Results of the phase 3 positron trial. Journal of hepatology 2013; 58(24). 96. Jacobson IM, Lawitz E, Gane EJ, et al. Efficacy of 8 Weeks of Sofosbuvir, Velpatasvir, and Voxilaprevir in Patients With Chronic HCV Infection: 2 Phase 3 Randomized Trials. Gastroenterology 2017; 153(1): 113-22. 97. Jargalsaikhan G, Dashtseren B, Dendev B, et al. Active versus passive follow-up examination of patients with chronic hepatitis C during Sofosbuvir/Ledipasvir treatment. Journal of Hepatology 2017; 66: S501. 98. Ji D, Chen GF, Wang C, et al. Twelve-week ribavirin-free direct-acting antivirals for treatment- experienced Chinese with HCV genotype 1b infection including cirrhotic patients. Hepatology International 2016; 10(5): 789-98. 99. Johnson SW, Ammirati SR, Hartis CE, et al. Effectiveness of ledipasvir/sofosbuvir in real-world patients with chronic hepatitis C: a collaborative treatment approach. International Journal of Antimicrobial Agents 2017; 49(6): 778-81. 100. Kao JH, Lee YJ, Heo J, et al. All-oral daclatasvir plus asunaprevir for chronic hepatitis C virus (HCV) genotype 1b infection: a sub-analysis in Asian patients from the HALLMARK DUAL study. Liver International 2016; 36(10): 1433-41. 101. Kao JH, Peng CY, Chang TT, et al. All oral dual therapy with daclatasvir and asunaprevir in patients in Korea and Taiwan with HCV genotype 1B infection. Hepatology international; 9(1 SUPPL. 1): S74-S5. 102. Karino Y, Suzuki F, Suzuki Y, et al. All oral dual combination of daclatasvir plus asunaprevir compared with telaprevir plus peginterferon alfa ribavirin in treatment naive Japanese patients chronically infected with HCV genotype 1b results from a phase 3 study. Hepatology international; 9(1 SUPPL. 1): S72. 103. Kattakuzhy S, Emmanuel B, Gross C, et al. Adherence to prescriptions a better predictor than adherence to treatment visits for SVR among patients treated with DAA therapy in a task-shifting model. Journal of Hepatology 2017; 66: S706.

183

104. Kawada N, Suzuki F, Karino Y, et al. Efficacy, safety and pharmacokinetics of grazoprevir (MK- 5172) and elbasvir (MK-8742) In hepatitis C genotype 1 infected non-cirrhotic japanese patients (phase 2 portion in phase 2/3 combined study). Hepatology 2015; 62(13). 105. Kawakami Y, Imamura M, Ikeda H, et al. Pharmacokinetics, efficacy and safety of daclatasvir plus asunaprevir in dialysis patients with chronic hepatitis C: pilot study. Journal of Viral Hepatitis 2016; 23(11): 850-6. 106. Kohli AK, R.; Sims, Z.; Nelson, A.; Sidharthan, S.; Lam, B.; Silk, R.; Kotb, C.; Gross, C.; Teferi, G.; Sugarman, K.; Pang, P. S.; Osinusi, A.; Polis, M. A.; Rustgi, V.; Masur, H.; Kottilil, S. Ledipasvir and sofosbuvir for hepatitis C genotype 4: a proof-of-concept, single-centre, open-label phase 2a cohort study. The Lancet Infectious Diseases 2015; 15(9): 1049-54. 107. Kohli AO, A.; Sims, Z.; Nelson, A.; Meissner, E. G.; Barrett, L. L.; Bon, D.; Marti, M. M.; Silk, R.; Kotb, C.; Gross, C.; Jolley, T. A.; Sidharthan, S.; Petersen, T.; Townsend, K.; Egerson, D.; Kapoor, R.; Spurlin, E.; Sneller, M.; Proschan, M.; Herrmann, E.; Kwan, R.; Teferi, G.; Talwani, R.; Diaz, G.; Kleiner, D. E.; Wood, B. J.; Chavez, J.; Abbott, S.; Symonds, W. T.; Subramanian, G. M.; Pang, P. S.; McHutchison, J.; Polis, M. A.; Fauci, A. S.; Masur, H.; Kottilil, S. Virological response after 6 week triple- drug regimens for hepatitis C: a proof-of-concept phase 2A cohort study. Lancet 2015; 385(9973): 1107- 13. 108. Korenaga M, Izumi N, Yokosuka O, et al. Sustained virologic response by ledipasvir/sofosbuvir reduces the incidence of hepatocellular carcinoma in Japanese patients with HCV genotype 1 infection. – Comparison with Simeprevir with peginterferon plus ribavirin. Journal of Hepatology 2017; 66: S23. 109. Kottilil S, Wyles D, Brau N, et al. Sofosbuvir/velpatasvir fixed dose combination for 12 weeks in patients co-infected with HCV And HIV-1: the phase 3 ASTRAL-5 study. Hepatology international 2017; Conference: 26th annual conference of the asian pacific association for the study of the liver, APASL. 2017. China 11(1 Supplement 1): S111. 110. Kowdley KV, Gordon SC, Reddy KR, et al. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. New England Journal of Medicine 2014; 370(20): 1879-88. 111. Kowdley KVN, D. R.; Lalezari, J. P.; Box, T.; Gitlin, N.; Poleynard, G.; Rabinovitz, M.; Ravendhran, N.; Sheikh, A. M.; Siddique, A.; Bhore, R.; Noviello, S.; Rana, K. On-treatment HCV RNA as a predictor of sustained virological response in HCV genotype 3-infected patients treated with daclatasvir and sofosbuvir. Liver International 2016; 36(11): 1611-8. 112. Kumada H, Suzuki F, Suzuki Y, et al. Randomized comparison of daclatasvir + asunaprevir versus telaprevir + peginterferon/ribavirin in Japanese hepatitis C virus patients. Journal of gastroenterology and hepatology 2016; 31(1): 14-22. 113. Kumada H, Suzuki Y, Ikeda K, et al. Daclatasvir plus asunaprevir for chronic HCV genotype 1b infection. Hepatology 2014; 59(6): 2083-91. 114. Kumada H, Suzuki Y, Karino Y, et al. The combination of elbasvir and grazoprevir for the treatment of chronic HCV infection in Japanese patients: a randomized phase II/III study. Journal of gastroenterology 2016. 115. Kwo P, Gane E, Peng CY, et al. Efficacy and safety of grazoprevir/elbasvir +/- RBV for 12 weeks in patients with HCV G1 or G4 infection who previously failed peginterferon/RBV: C-EDGE treatment- experienced trial. Journal of hepatology 2015; 62(22). 116. Kwo P, Gane EJ, Peng CY, et al. Effectiveness of Elbasvir and Grazoprevir Combination, With or Without Ribavirin, for Treatment-Experienced Patients With Chronic Hepatitis C Infection. Gastroenterology 2017; 152(1): 164-75.e4. 117. Kwo PY, Gane E, Peng CY, et al. Efficacy and safety of grazoprevir/elbasvir +/- ribavirin (RBV) for 12 or 16 weeks in patients with HCV G1, G4, or G6 infection who previously failed peginterferon/RBV: C-EDGE treatment-experienced trial. Gastroenterology 2015; 148(4 SUPPL. 1): S1194-S5. 118. Kwo PY, Poordad F, Asatryan A, et al. Glecaprevir and pibrentasvir yield high response rates in patients with HCV genotype 1-6 without cirrhosis. Journal of Hepatology 2017; 67(2): 263-71. 119. Kwo PY, Wyles DL, Wang S, et al. 100% SVR4 with ABT-493 and ABT-530 with or without ribavirin in treatment-naive hcv genotype 3-infected patients with cirrhosis. Journal of hepatology 2016; Conference: 51st annual meeting of the european association for the study of the liver, international liver congress. 2016. Barcelona spain. Conference start: 20160413. Conference end: 20160417. Conference publication:(var.pagings) 64(2 SUPPL. 1): S208.

184

120. Lacombe K, Fontaine H, Dhiver C, et al. Real-world efficacy of daclatasvir and sofosbuvir, with and without ribavirin, in HIV/HCV coinfected patients with advanced liver disease in a French early access cohort. Journal of Acquired Immune Deficiency Syndromes 2017; 75(1): 97-107. 121. Lawitz E, Gane E, Pearlman B, et al. Efficacy and safety of 12 weeks versus 18 weeks of treatment with grazoprevir (MK-5172) and elbasvir (MK-8742) with or without ribavirin for hepatitis C virus genotype 1 infection in previously untreated patients with cirrhosis and patients with previous null response with or without cirrhosis (C-WORTHY): A randomised, open-label phase 2 trial. The Lancet 2015; 385(9973): 1075-86. 122. Lawitz E, Poordad F, Wells J, et al. Sofosbuvir-velpatasvir-voxilaprevir with or without ribavirin in direct-acting antiviral-experienced patients with genotype 1 hepatitis C virus. Hepatology (baltimore, md) 2017; 65(6): 1803-9. 123. Lawitz E, Poordad FF, Pang PS, et al. Sofosbuvir and ledipasvir fixed-dose combination with and without ribavirin in treatment-naive and previously treated patients with genotype 1 hepatitis C virus infection (LONESTAR): an open-label, randomised, phase 2 trial. Lancet 2014; 383(9916): 515-23. 124. Lawitz EP, F.; Wells, J.; Hyland, R. H.; Yang, Y.; Dvory-Sobol, H.; Stamm, L. M.; Brainard, D. M.; McHutchison, J. G.; Landaverde, C.; Gutierrez, J. High efficacy of sofosbuvir/velpatasvir/GS-9857 with or without ribavirin for 12 weeks in direct acting antiviral-experienced patients with genotype 1 HCV infection. Journal of hepatology 2016; Conference: 51st annual meeting of the european association for the study of the liver, international liver congress. 2016. Barcelona spain. Conference start: 20160413. Conference end: 20160417. Conference publication:(var.pagings) 64(2 SUPPL. 1): S146. 125. Lawitz EZ, S.; Stedman, C. A.; Poordad, F.; Mir, H. M.; Seyedkazemi, S.; Hyland, R. H.; Pang, P.; Brainard, D. M.; McHutchison, J. G.; Gane, E. Sofosbuvir-based regimens for patients with hepatitis C virus genotype 3 infection: Summary results from the valence, lonestar-2, and electron-2 studies. Gastroenterology; 148(4 SUPPL. 1): S1085-S6. 126. Leroy V, Angus P, Bronowicki JP, et al. Daclatasvir, sofosbuvir, and ribavirin for hepatitis C virus genotype 3 and advanced liver disease: A randomized phase III study (ALLY-3+). Hepatology 2016; 63(5): 1430-41. 127. Lim YS, Ahn SH, Lee KS, et al. A phase IIIb study of ledipasvir/sofosbuvir fixed-dose combination tablet in treatment-naive and treatment-experienced Korean patients chronically infected with genotype 1 hepatitis C virus. Hepatology international 2016; 10(6): 947-55. 128. Lionetti R, Lenci I, Siciliano M, et al. Improved virological outcomes and excellent safety profile in genotype 3 HCV-infected cirrhotic patients after an extended 24- weeks course of daclatasvir, sofosbuvir + ribavirin: insights froma real-life multicenter study. Journal of Hepatology 2017; 66: S731. 129. Liu CJ, Chuang WL, Sheen IS, et al. Ledipasvir/sofosbuvir for 12weeks is safe and effective in patients with chronic hepatitis C and hepatitis B coinfection: A phase 3 study in Taiwan. Journal of Hepatology 2017; 66: S56. 130. Lok AS, Gardiner DF, Lawitz E, et al. Preliminary study of two antiviral agents for hepatitis C genotype 1. New England Journal of Medicine 2012; 366(3): 216-24. 131. Luetkemeyer AFM, C.; Ramgopal, M.; Noviello, S.; Bhore, R.; Ackerman, P. 12 Weeks of Daclatasvir in Combination With Sofosbuvir for HIV-HCV Coinfection (ALLY-2 Study): Efficacy and Safety by HIV Combination Antiretroviral Regimens. Clinical Infectious Diseases 2016; 62(12): 1489-96. 132. Mangia A, Arleo A, Copetti M, et al. The combination of daclatasvir and sofosbuvir for curing genotype 2 patients who cannot tolerate ribavirin. Liver International 2016; 36(7): 971-6. 133. Mangia A, Sarli R, Gamberini R, et al. Randomised clinical trial: sofosbuvir and ledipasvir in patients with transfusion-dependent thalassaemia and HCV genotype 1 or 4 infection. Aliment Pharmacol Ther 2017; 46(4): 424-31. 134. Mangia A, Susser S, Piazzolla V, et al. Sofosbuvir and ribavirin for genotype 2 HCV infected patients with cirrhosis: A real life experience. Journal of Hepatology 2017; 66(4): 711-7. 135. Manns M, Pol S, Jacobson IM, et al. All-oral daclatasvir plus asunaprevir for hepatitis C virus genotype 1b: a multinational, phase 3, multicohort study. Lancet 2014; 384(9954): 1597-605. 136. Mauss SG, R.; Buggisch, P.; Klinker, H. H.; Schober, A.; John, C.; Lutz, T.; Pfeiffer-Vornkahl, H.; Niederau, C.; Cornberg, M.; Sarrazin, C.; Tacke, F. Treatment of HCV genotype 2 with sofosbuvir and ribavirin results in lower SVR rates in real life than expected from clinical trials. Hepatology 2016; Conference: 67th annual meeting of the american association for the study of liver diseases: the liver meeting. 2016. United states. Conference start: 20161111. Conference end: 20161115 63(1 Supplement 1): 995A.

185

137. McPhee F, Hernandez D, Zhou N. Effect of minor populations of NS5A and NS5B resistance- associated variants on HCV genotype-3 response to daclatasvir plus sofosbuvir, with or without ribavirin. Antiviral Therapy 2017; 22(3): 237-46. 138. Mehta V, Mahajan R, Midha V, et al. Impact of Direct Acting Antiviral Therapy for Treatment of Hepatitis C Genotypes 1, 3 and 4: A Real Life Experience from India. Journal of Clinical and Experimental Hepatology 2017. 139. Miyaki E, Imamura M, Hiraga N, et al. Daclatasvir and asunaprevir treatment improves liver function parameters and reduces liver fibrosis markers in chronic hepatitis C patients. Hepatology Research 2016. 140. Mizokami M, Yokosuka O, Takehara T, et al. Ledipasvir and sofosbuvir fixed-dose combination with and without ribavirin for 12 weeks in treatment-naive and previously treated Japanese patients with genotype 1 hepatitis C: an open-label, randomised, phase 3 trial. The Lancet Infectious Diseases 2015; 15(6): 645-53. 141. Molina JM, Orkin C, Iser DM, et al. Sofosbuvir plus ribavirin for treatment of hepatitis C virus in patients co-infected with HIV (PHOTON-2): a multicentre, open-label, non-randomised, phase 3 study. Lancet 2015; 385(9973): 1098-106. doi: 10.16/S0140-6736(14)62483-1. Epub 2015 Feb 4. 142. Molina JMO, C.; Iser, D. M.; Zamora, F. X.; Nelson, M.; Stephan, C.; Massetto, B.; Gaggar, A.; Ni, L.; Svarovskaia, E.; Brainard, D.; Subramanian, G. M.; McHutchison, J. G.; Puoti, M.; Rockstroh, J. K. Sofosbuvir plus ribavirin for treatment of hepatitis C virus in patients co-infected with HIV (PHOTON-2): A multicentre, open-label, non-randomised, phase 3 study. The Lancet 2015; 385(9973): 1098-106. 143. Nagao A, Hanabusa H. The impact of ledipasvir/sofosbuvir on HIV-positive and HIV-negative Japanese hemophilia patients with 1, 4, and mixed-genotype HCV. Journal of Acquired Immune Deficiency Syndromes 2017; 74(4): 418-22. 144. Naggie S, Cooper C, Saag M, et al. Ledipasvir and Sofosbuvir for HCV in Patients Coinfected with HIV-1. 2015. 145. Naggie SC, C.; Saag, M.; Workowski, K.; Ruane, P.; Towner, W. J.; Marks, K.; Luetkemeyer, A.; Baden, R. P.; Sax, P. E.; Gane, E.; Santana-Bagur, J.; Stamm, L. M.; Yang, J. C.; German, P.; Dvory- Sobol, H.; Ni, L.; Pang, P. S.; McHutchison, J. G.; Stedman, C. A.; Morales-Ramirez, J. O.; Brau, N.; Jayaweera, D.; Colson, A. E.; Tebas, P.; Wong, D. K.; Dieterich, D.; Sulkowski, M.; I. O. N. Investigators. Ledipasvir and Sofosbuvir for HCV in Patients Coinfected with HIV-1. New England Journal of Medicine 2015; 373(8): 705-13. 146. Nehra VT, E. M.; Rizza, S. A.; Temesgen, Z. Ledipasvir/sofosbuvir fixed-dose combination for treatment of hepatitis C virus genotype 4 infection. Drugs of Today 2016; 52(2): 111-7. 147. Nelson D, Feld J, Kowdley KV, et al. All Oral Therapy With Sofosbuvir + Ribavirin for 12 or 16 Weeks in Treatment-Experienced Genotype 2/3 HCV-Infected Patients: Results of the Phase 3 FUSION Trial. International Liver Congress. Amsterdam; 2013. 148. Nelson DRC, J. N.; Lalezari, J. P.; Lawitz, E.; Pockros, P. J.; Gitlin, N.; Freilich, B. F.; Younes, Z. H.; Harlan, W.; Ghalib, R.; Oguchi, G.; Thuluvath, P. J.; Ortiz-Lasanta, G.; Rabinovitz, M.; Bernstein, D.; Bennett, M.; Hawkins, T.; Ravendhran, N.; Sheikh, A. M.; Varunok, P.; Kowdley, K. V.; Hennicken, D.; McPhee, F.; Rana, K.; Hughes, E. A.; Ally- Study Team. All-oral 12-week treatment with daclatasvir plus sofosbuvir in patients with hepatitis C virus genotype 3 infection: ALLY-3 phase III study. Hepatology 2015; 61(4): 1127-35. 149. Nelson DRC, J. N.; Lalezari, J. P.; Lawitz, E.; Pockros, P. J.; Gitlin, N.; Freilich, B. F.; Younes, Z. H.; Harlan, W.; Ghalib, R.; Oguchi, G.; Thuluvath, P.; Ortiz-Lasanta, G.; Rabinovitz, M.; Bernstein, D.; Bennett, M.; Hawkins, T.; Ravendhran, N.; Sheikh, A. M.; Varunok, P.; Kowdley, K.; Hennicken, D.; McPhee, F.; Rana, K.; Hughes, E. A. All-Oral 12-wek combination treatment with Daclatasvir (DCV) and Sofosbuvir (SOF) in patients infected with HCV genotype (GT) 3: aLLY-3 phase 3 study. Canadian journal of infectious diseases and medical microbiology 2015; Conference:. 2015 CACMID-AMMI canada annual conference. Canada 26(2): e32. 150. Nguyen MH, Trinh H, Do S, Nguyen T. Ledipasvir/sofosbuvir fixed-dose combination (LDV/SOF FDC) for 8 weeks for treatment-Naive, non-cirrhotic hepatitis C genotype 6 (HCV-6) and 12 weeks in those with cirrhosis and/ or prior treatment failure: a multicenter open-labelled clinical trial. Hepatology international 2017; Conference: 26th annual conference of the asian pacific association for the study of the liver, APASL. 2017. China 11(1 Supplement 1): S105. 151. Nguyen MH, Trinh HN, Do ST, Nguyen T. Ledipasvir/sofosbuvir fixed-dose combination (LDV/ SOF FDC) for 8 Weeks for treatment-naive, noncirrhotic hepatitis C genotype 6 (HCV-6) and for 12 weeks

186 for those with cirrhosis and/or prior treatment failure: an open-labeled clinical trial. Hepatology 2016; Conference: 67th annual meeting of the american association for the study of liver diseases: the liver meeting. 2016. United states. Conference start: 20161111. Conference end: 20161115 63(1 Supplement 1): 463A. 152. Nicoll A, Zeuzem S, Ghalib R, et al. Final SVR24 data from the phase 3 C-EDGE treatment-naive (TN) study of elbasvir (EBR)/ grazoprevir (GZR) in patients with chronic HCV genotype 1, 4 or 6 infection. Journal of gastroenterology and hepatology 2016; 31(80). 153. Ogawa E, Furusyo N, Nomura H, et al. NS5A resistance-associated variants undermine the effectiveness of ledipasvir and sofosbuvir for cirrhotic patients infected with HCV genotype 1b. Journal of Gastroenterology 2017; 52(7): 845-54. 154. Ogawa E, Furusyo N, Nomura H, et al. Effectiveness and safety of sofosbuvir plus ledipasvir for HCV genotype 1b patients with compensated cirrhosis. Hepatology international 2017; Conference: 26th annual conference of the asian pacific association for the study of the liver, APASL. 2017. China 11(1 Supplement 1): S1012. 155. Ogawa E, Furusyo N, Nomura H, et al. Effectiveness and safety of sofosbuvir plus ribavirin for HCV genotype 2 patients 65 and over with or without cirrhosis. Antiviral research 2016; 136: 37-44. 156. Ogawa E, Furusyo N, Yamashita N, et al. Effectiveness and safety of daclatasvir plus asunaprevir for patients with hepatitis C virus genotype 1b aged 75 years and over with or without cirrhosis. Hepatology Research 2017; 47(3): E120-E31. 157. O'Leary J, Brown RS, Reddy KR, et al. Baseline clinical and laboratory parameters associated with clinical benefits of successful hcvtreatment with sofosbuvir/velpatasvir in decompensated cirrhotic patients. Journal of hepatology 2016; Conference: 51st annual meeting of the european association for the study of the liver, international liver congress. 2016. Barcelona spain. Conference start: 20160413. Conference end: 20160417. Conference publication:(var.pagings) 64(2 SUPPL. 1): S774. 158. Osinusi A, Townsend K, Kohli A, et al. Virologic response following combined ledipasvir and sofosbuvir administration in patients with HCV genotype 1 and HIV co-infection. JAMA 2015; 313(12): 1232-9. doi: 10.001/jama.2015.1373. 159. Osinusi AT, K.; Kohli, A.; Nelson, A.; Seamon, C.; Meissner, E. G.; Bon, D.; Silk, R.; Gross, C.; Price, A.; Sajadi, M.; Sidharthan, S.; Sims, Z.; Herrmann, E.; Hogan, J.; Teferi, G.; Talwani, R.; Proschan, M.; Jenkins, V.; Kleiner, D. E.; Wood, B. J.; Subramanian, G. M.; Pang, P. S.; McHutchison, J. G.; Polis, M. A.; Fauci, A. S.; Masur, H.; Kottilil, S. Virologic response following combined ledipasvir and sofosbuvir administration in patients with HCV genotype 1 and HIV co-infection. Jama 2015; 313(12): 1232-9. 160. Patrick Basu P, Shah NJ, John N, Aloysius MM, Fortuzi K. Sofosbuvir and ledipasvir in attainment of SVR12 in Sickle Cell Disease (SCD) sub-population with Chronic Hepatitis C (CHC). A single center prospective open label clinical pilot study: slash C trial. Surgical endoscopy and other interventional techniques Conference 2017; 31. 161. Pearlman B, Lutchman G, Shiffman ML, et al. Safety and efficacy of elbasvir and grazoprevir with or without ribavirin for the treatment of hepatitis C virus genotype 1: results of the hepatitis C virus- TARGET study. Journal of Hepatology 2017; 66: S294. 162. Persico M, Aglitti A, Caruso R, et al. Efficacy and safety of new direct antiviral agents in HCV infected patients with Diffuse Large B Cell Non-Hodgkin Lymphoma. Hepatology 2017; 17: 17. 163. Pianko S, Flamm SL, Shiffman ML, et al. Sofosbuvir plus velpatasvir combination therapy for treatment- Experienced patients with genotype 1 or 3 hepatitis c virus infection. Annals of internal medicine 2015; 163(11): 809-17. 164. Pol S, Bourliere M, Lucier S, et al. Safety and efficacy of daclatasvir-sofosbuvir in HCV genotype 1-mono-infected patients. Journal of hepatology 2016; 10. 165. Poordad F, Felizarta F, Asatryan A, et al. Glecaprevir and pibrentasvir for 12 weeks for hepatitis C virus genotype 1 infection and prior direct-acting antiviral treatment. Hepatology 2017; (pagination). 166. Poordad F, Gordon SC, Asatryan A, et al. High efficacy of ABT-493 and ABT-530 in HCV genotype 1 infected patients who have failed direct-acting antiviral-containing regimens: the Magellan-i study. Journal of hepatology 2016; Conference: 51st annual meeting of the european association for the study of the liver, international liver congress. 2016. Barcelona spain. Conference start: 20160413. Conference end: 20160417. Conference publication:(var.pagings) 64(2 SUPPL. 1): S160- S1.

187

167. Poordad F, Pol S, Asatryan A, et al. MAGELLAN-1, Part 2: glecaprevir and pibrentasvir for 12 or 16 weeks in patients with chronic hepatitis C virus genotype 1 or 4 and prior direct-acting antiviral treatment failure. Journal of Hepatology 2017; 66: S83. 168. Poordad F, Pol S, Asatryan A, et al. MAGELLAN-1, Part 2: Glecaprevir and Pibrentasvir for 12 or 16 Weeks in Patients with Chronic HCV Genotype 1 or 4 and Prior Direct-Acting Antiviral Treatment Failure. Gastroenterology 2017; 152(5): S1057. 169. Reddy KRL, J. K.; Kuo, A.; Di Bisceglie, A. M.; Galati, J. S.; Morelli, G.; Everson, G. T.; Kwo, P. Y.; Brown, R. S.; Sulkowski, M. S.; Akuschevich, L.; Lok, A. S.; Pockros, P. J.; Vainorius, M.; Terrault, N. A.; Nelson, D. R.; Fried, M. W.; Manns, M. P. All-oral direct-acting antiviral therapy in HCV-advanced liver disease is effective in real-world practice: observations through HCV-TARGET database. Alimentary Pharmacology and Therapeutics 2017; 45(1): 115-26. 170. Reddy RK, Pol S, Thuluvath PJ, et al. A long-term, observational, follow-up study of patients treated in phase 2 and 3 clinical studies for chronic HCV infection with daclatasvir-based regimens: interim efficacy and safety outcomes. Hepatology international 2017; Conference: 26th annual conference of the asian pacific association for the study of the liver, APASL. 2017. China 11(1 Supplement 1): S295-S6. 171. Rockstroh J, Lacombe K, Viani RM, et al. Efficacy and safety of Glecaprevir/Pibrentasvir in patients coinfected with hepatitis C virus and human immunodeficiency virus-1: the EXPEDITION-2 Study. Journal of Hepatology 2017; 66: S102. 172. Rockstroh JK, Nelson M, Katlama C, et al. Efficacy and safety of grazoprevir (MK-5172) and elbasvir (MK-8742) in patients with hepatitis C virus and HIV co-infection (C-EDGE CO-INFECTION): A non-randomised, open-label trial. The Lancet HIV 2015; 2(8): e319-e27. 173. Saadoun D, Ferfar Y, Hezode C, et al. Sofosbuvir plus daclatasvir for hepatitis C virus- cryoglobulinemia vasculitis (HCV-CryoVas): VASCUVALDIC 2 Study. Journal of Hepatology 2017; 66: S56. 174. Saadoun D, Pol S, Ferfar Y, et al. Efficacy and Safety of Sofosbuvir Plus Daclatasvir for Treatment of HCV-Associated Cryoglobulinemia Vasculitis. Gastroenterology 2017; 153(1): 49-52.e5. 175. Sezaki H, Suzuki F, Hosaka T, et al. The efficacy and safety of dual oral therapy with daclatasvir and asunaprevir for genotype 1b in Japanese real-life settings. Liver International 2017. 176. Shah SR, Chowdhury A, Mehta R, et al. Sofosbuvir plus ribavirin in treatment-naive patients with chronic hepatitis C virus genotype 1 or 3 infection in India. Journal of viral hepatitis 2016; (pagination). 177. Shiha G, Waked I, Soliman R, et al. Ledipasvir/sofosbuvir for 8 or 12 weeks with or without ribavirin in HCV genotype 4 patients in Egypt. Hepatology international 2017; Conference: 26th annual conference of the asian pacific association for the study of the liver, APASL. 2017. China 11(1 Supplement 1): S109. 178. Sidharthan SK, A.; Sims, Z.; Nelson, A.; Osinusi, A.; Masur, H.; Kottilil, S. Utility of hepatitis C viral load monitoring on direct-acting antiviral therapy. Clinical Infectious Diseases 2015; 60(12): 1743-51. 179. Sperl J, Horvath G, Halota W, et al. C-edge head-to-head: Efficacyand safety of elbasvir and grazoprevir compared with sofosbuvir/pegylated interferon/ribavirin: A phase 3 randomized controlled trial. Journal of hepatology 2016; 64(2 SUPPL. 1): S136-S7. 180. Sperl J, Horvath G, Halota W, et al. Efficacy and safety of elbasvir/grazoprevir and sofosbuvir/pegylated interferon/ribavirin: A phase III randomized controlled trial. Journal of Hepatology 2016; 65(6): 1112-9. 181. Strasser S, Hezode C, Colombo M, et al. C-EDGE IBLD: efficacy and safety of elbasvir/ grazoprevir (EBR/GZR) in patients with chronic hepatitis C virus (HCV) infection and inherited blood disorders (IBLD). Journal of gastroenterology and hepatology 2016; 31: 82-3. 182. Suda G, Kudo M, Nagasaka A, et al. Efficacy and safety of daclatasvir and asunaprevir combination therapy in chronic hemodialysis patients with chronic hepatitis C. Journal of Gastroenterology 2016; 51(7): 733-40. 183. Suda G, Nagasaka A, Yamamoto Y, et al. Safety and efficacy of daclatasvir and asunaprevir in hepatitis C virus-infected patients with renal impairment. Hepatology research 2017; (pagination). 184. Sulkowski M, Hezode C, Gerstoft J, et al. Efficacy and safety of 8 weeks versus 12 weeks of treatment with grazoprevir (MK-5172) and elbasvir (MK-8742) with or without ribavirin in patients with hepatitis C virus genotype 1 mono-infection and HIV/hepatitis C virus co-infection (C-WORTHY): a randomised, open-label phase 2 trial. Lancet (London, England) 2015; 385(9973): 1087-97.

188

185. Sulkowski MS, Brau N, Lawitz E, et al. A randomized controlled trial of sofosbuvir/GS-5816 fixed dose combination for 12 weeks compared to sofosbuvir with ribavirin for 12 weeks in genotype 2 HCV infected patients: The Phase 3 ASTRAL-2 Study. Hepatology 2015; 62(13). 186. Sulkowski MS, Chuang WL, Kao JH, et al. No Evidence of Reactivation of Hepatitis B Virus Among Patients Treated With Ledipasvir-Sofosbuvir for Hepatitis C Virus Infection. Clinical Infectious Diseases 2016; 63(9): 1202-4. 187. Sulkowski MS, Gardiner DF, Rodriguez-Torres M, et al. Daclatasvir plus sofosbuvir for previously treated or untreated chronic HCV infection.[Erratum appears in N Engl J Med. 2014 Apr 10;370(15):1469]. New England Journal of Medicine 2014; 370(3): 211-21. 188. Sung J, Uojima H, Ohtake T, et al. A prospective, multicenter study of daclatasvir and asunaprevir combination therapy for chronic hepatitis C virus genotype 1b infection on hemodialysis. Journal of gastroenterology and hepatology 2016; 31: 354-5. 189. Suzuki F, Hatanaka N, Bando E, Komoto A. Post marketing surveillance of daclatasvir/asunaprevir in Japanese patients with chronic hepatitis C: an interim report. Hepatology international 2017; Conference: 26th annual conference of the asian pacific association for the study of the liver, APASL. 2017. China 11(1 Supplement 1): S25. 190. Suzuki F, Karino Y, Chayama K, et al. Final results from phase 3 portion in phase 2/3 study of elbasvir / grazoprevir in hepatitis C genotype 1 infected japanese patients. Hepatology 2016; Conference: 67th annual meeting of the american association for the study of liver diseases: the liver meeting. 2016. United states. Conference start: 20161111. Conference end: 20161115 63(1 Supplement 1): 418A-9A. 191. Suzuki Y, Ikeda K, Suzuki F, et al. Dual oral therapy with daclatasvir and asunaprevir for patients with HCV genotype 1b infection and limited treatment options. Journal of Hepatology 2013; 58(4): 655-62. 192. Tacke FG, R.; Buggisch, P.; Klinker, H.; Schober, A.; John, C.; Lutz, T.; Pfeiffer-Vornkahl, H.; Niederau, C.; Cornberg, M.; Sarrazin, C.; Mauss, S. Treatment of HCV genotype 2 with sofosbuvir and ribavirin results in lower sustained virological response rates in real life than expected from clinical trials. Liver International 2017; 37(2): 205-11. 193. Terashita K, Suda G, Nakai M, et al. Safety and efficacy of direct acting antivirals (daclatasvir and asunaprevir) in hepatitis C virus infected patients with renal impairment. Hepatology international 2017; Conference: 26th annual conference of the asian pacific association for the study of the liver, APASL. 2017. China 11(1 Supplement 1): S295. 194. Terrault NA, Zeuzem S, Di Bisceglie AM, et al. Effectiveness of Ledipasvir-Sofosbuvir Combination in Patients With Hepatitis C Virus Infection and Factors Associated With Sustained Virologic Response. Gastroenterology 2016; 151(6): 1131-40.e5. 195. Torres HA, Economides MP, Kyvernitakis A, et al. Sofosbuvir-based therapy in patients with chronic hepatitis C virus infection and malignancies – A prospective observational study of 136 patients. Journal of Hepatology 2017; 66: S506. 196. Townsend KM, E. G.; Sidharthan, S.; Sampson, M.; Remaley, A. T.; Tang, L.; Kohli, A.; Osinusi, A.; Masur, H.; Kottilil, S. Interferon-Free Treatment of Hepatitis C Virus in HIV/Hepatitis C Virus- Coinfected Subjects Results in Increased Serum Low-Density Lipoprotein Concentration. AIDS Res Hum Retroviruses 2016; 32(5): 456-62. 197. Townsend KP, T.; Gordon, L. A.; Kohli, A.; Nelson, A.; Seamon, C.; Gross, C.; Tang, L.; Osinusi, A.; Polis, M. A.; Masur, H.; Kottilil, S. Effect of HIV co-infection on adherence to a 12-week regimen of hepatitis C virus therapy with ledipasvir and sofosbuvir. AIDS 2016; 30(2): 261-6. 198. Toyoda H, Chayama K, Suzuki F, et al. Efficacy and Safety of Glecaprevir/Pibrentasvir in Japanese Patients with Chronic Genotype 2 Hepatitis C Virus Infection. Hepatology 2017. 199. Toyoda H, Kumada T, Tada T, et al. Efficacy and tolerability of an IFN-free regimen with DCV/ASV for elderly patients infected with HCV genotype 1B. Journal of Hepatology 2017; 66(3): 521-7. 200. Toyoda H, Kumada T, Tada T, et al. Safety and efficacy of dual direct-acting antiviral therapy (daclatasvir and asunaprevir) for chronic hepatitis C virus genotype 1 infection in patients on hemodialysis. Journal of Gastroenterology 2016; 51(7): 741-7. 201. Toyota J, Karino Y, Suzuki F, et al. Daclatasvir/asunaprevir/beclabuvir fixed-dose combination in Japanese patients with HCV genotype 1 infection. Journal of gastroenterology 2017; 52(3): 385-95. 202. Vermehren J, Athmann C, Gunther R, et al. Use of the 6 million viral load cut-off to guide treatment duration with ledipasvir/sofosbuvir in patients with chronic hepatitis C virus genotype 1 infection: results from the German Hepatitis C-Registry (DHC-R). Journal of Hepatology 2017; 66: S519.

189

203. Vermehren JB, M.; Pol, S.; Marcellin, P.; Hyland, R. H.; Jiang, D.; Brainard, D. M.; Zeuzem, S.; Welzel, T. M. Comparison of on-treatment HCV RNA during direct antiviral therapy using two different COBAS TaqMan HCV assays. Journal of clinical virology 2017; 89: 51-6. 204. Vierling JM, Kugelmas M, Lawitz E, et al. Efficacy of an eight-week regimen of grazoprevir plus elbasvir with and without ribavirin in treatmentnaive, noncirrhotic HCV genotype 1B infection. Journal of hepatology 2015; 62(22). 205. Wei L, Burnevich E, Sheen IS, et al. Efficacy and Safety of elbasvir/grazoprevir in treatment-naive subjects with chronic HCV GT 1, GT 4 and GT 6 infection (CCORAL): a phase III randomized multinational clinical trial. Hepatology international 2017; Conference: 26th annual conference of the asian pacific association for the study of the liver, APASL. 2017. China 11(1 Supplement 1): S161- S2. 206. Wei L, Hou J, Luo Y, et al. ONYX-I: safety and efficacy of ombitasvir/paritaprevir/ritonavir and dasabuvir in asian adults with genotype 1b chronic hepatitis C virus (HCV) infection: a randomized, double-blind, placebocontrolled study. Hepatology international 2017; Conference: 26th annual conference of the asian pacific association for the study of the liver, APASL. 2017. China 11(1 Supplement 1): S3. 207. Wei L, Hou J, Luo Y, et al. ONYX-I: safety and efficacy of ombitasvir/paritaprevir/ ritonavir and dasabuvir in asian adults with genotype 1b chronic hepatitis C Virus (HCV) infection-a randomized, double-blind, placebo-controlled study. Hepatology 2016; Conference: 67th annual meeting of the american association for the study of liver diseases: the liver meeting. 2016. United states. Conference start: 20161111. Conference end: 20161115 63(1 Supplement 1): 432A-3A. 208. Wei L, Luo Y, Chuang WL, et al. Comparison of efficacy and safety of ombitasvir/paritaprevir/ritonavir and dasabuvir ± ribavirin between Asian and western HCV GT1b-infected patients. Journal of Hepatology 2017: S531. 209. Wei L, Wang FS, Zhang M, et al. A phase 3 evaluation of daclatasvir plus asunaprevir in treatmentnaive patients with chronic HCV genotype 1b infection. Hepatology international 2017; Conference: 26th annual conference of the asian pacific association for the study of the liver, APASL. 2017. China 11(1 Supplement 1): S186-S7. 210. Wei L, Xie Q, Hou J, et al. Sofosbuvir + Ribavirin-Pegylated-interferon in Genotype 1, 2, 3 or 6 HCV-infected patients: results from a phase 3 study in China. Hepatology international 2017; Conference: 26th annual conference of the asian pacific association for the study of the liver, APASL. 2017. China 11(1 Supplement 1): S157-S8. 211. Wei L, Zhang M, Xu M, et al. A phase 3, open-label study of daclatasvir plus asunaprevir in Asian patients with chronic hepatitis C virus genotype 1b infection who are ineligible for or intolerant to interferon alfa therapies with or without ribavirin. Journal of gastroenterology and hepatology (australia) 2016; 31(11): 1860-7. 212. Wei L, Zhdanov K, Burnevich E, et al. Efficacy and safety of elbasvir/grazoprevir in treatment- naïve patients with chronic HCVGT 1, GT 4 and GT 6 infection (C-CORAL): a phase III randomized multinational clinical trial. Journal of Hepatology 2017; 66: S529. 213. Welzel T, Zeuzem S, Dumas EO, et al. GARNET: 98% SVR rates following eight-week treatment with ombitasvir/paritaprevir/ritonavir + dasabuvir for patients with HCV genotype 1b infection without cirrhosis. Hepatology international 2017; Conference: 26th annual conference of the asian pacific association for the study of the liver, APASL. 2017. China 11(1 Supplement 1): S1002. 214. Welzel TM, Asselah T, Dumas EO, et al. Ombitasvir, paritaprevir, and ritonavir plus dasabuvir for 8 weeks in previously untreated patients with hepatitis C virus genotype 1b infection without cirrhosis (GARNET): a single-arm, open-label, phase 3b trial. The Lancet Gastroenterology and Hepatology 2017; 2(7): 494-500. 215. Welzel TM, Nelson DR, Morelli G, et al. Effectiveness and safety of sofosbuvir plus ribavirin for the treatment of HCV genotype 2 infection: Results of the real-world, clinical practice HCV-TARGET study. Gut 2016; 13. 216. Wilder JMJ, L. J.; Ravendhran, N.; Shiffman, M. L.; Poulos, J.; Sulkowski, M. S.; Gitlin, N.; Workowski, K.; Zhu, Y.; Yang, J. C.; Pang, P. S.; McHutchison, J. G.; Muir, A. J.; Howell, C.; Kowdley, K.; Afdhal, N.; Reddy, K. R. Safety and efficacy of ledipasvir-sofosbuvir in black patients with hepatitis C virus infection: A retrospective analysis of phase 3 data. Hepatology 2016; 63(2): 437-44. 217. Wilson EMK, S.; Sidharthan, S.; Sims, Z.; Tang, L.; McLaughlin, M.; Price, A.; Nelson, A.; Silk, R.; Gross, C.; Akoth, E.; Mo, H.; Subramanian, G. M.; Pang, P. S.; McHutchison, J. G.; Osinusi, A.; Masur,

190

H.; Kohli, A.; Kottilil, S. Successful Retreatment of Chronic HCV Genotype-1 Infection With Ledipasvir and Sofosbuvir After Initial Short Course Therapy With Direct-Acting Antiviral Regimens. Clinical Infectious Diseases 2016; 62(3): 280-8. 218. Wyles D, Brau N, Kottilil S, et al. Sofosbuvir and Velpatasvir for the Treatment of Hepatitis C Virus in Patients Coinfected with Human Immunodeficiency Virus Type 1: An Open-Label, Phase 3 Study. Clinical Infectious Diseases 2017; 65(1): 6-12. 219. Wyles D, Brau N, Naggie S, et al. SOF/VEL single-tablet regimen in HCV mono-infected and HIV/HCV co-infected patients: comparison of efficacy and safety data from phase 3 clinical trials. Journal of the international AIDS society Conference: international congress of drug therapy in HIV infection 2016; 19: 187-8. 220. Wyles D, Ruane P, Sulkowski M, et al. Daclatasvir in combination with sofosbuvir for hiv/HCV Coinfection: ALLY-2 Study. Top Antivir Med 2015; 23(62). 221. Wyles DLR, P. J.; Sulkowski, M. S.; Dieterich, D.; Luetkemeyer, A.; Morgan, T. R.; Sherman, K. E.; Dretler, R.; Fishbein, D.; Gathe, J. C., Jr.; Henn, S.; Hinestrosa, F.; Huynh, C.; McDonald, C.; Mills, A.; Overton, E. T.; Ramgopal, M.; Rashbaum, B.; Ray, G.; Scarsella, A.; Yozviak, J.; McPhee, F.; Liu, Z.; Hughes, E.; Yin, P. D.; Noviello, S.; Ackerman, P.; Ally- Investigators. Daclatasvir plus Sofosbuvir for HCV in Patients Coinfected with HIV-1. New England Journal of Medicine 2015; 373(8): 714-25. 222. Wyles DLR, P.; Sulkowski, M. S.; Dieterich, D.; Luetkemeyer, A. F.; Morgan, T. R.; Sherman, K. E.; Liu, Z.; Noviello, S.; Ackerman, P. Daclatasvir plus sofosbuvir for treatment of HCV genotypes 1-4 in HIV-HCV coinfection: The ALLY-2 study. Journal of hepatology 2015; 62(22). 223. Yakoot M, Abdo AM, Abdel-Rehim S, Helmy S. Response Tailored Protocol Versus the Fixed 12Weeks Course of Dual Sofosbuvir/Daclatasvir Treatment in Egyptian Patients With Chronic Hepatitis C Genotype-4 Infection: A Randomized, Open-label, Non-inferiority Trial. EBioMedicine 2017; 17: 17. 224. Yao Y, Yue M, Wang J, et al. Grazoprevir and Elbasvir in Patients with Genotype 1 Hepatitis C Virus Infection: A Comprehensive Efficacy and Safety Analysis. Can J Gastroenterol Hepatol 2017; 2017: 8186275. 225. Yoshimi S, Imamura M, Murakami E, et al. Long term persistence of NS5A inhibitor-resistant hepatitis C virus in patients who failed daclatasvir and asunaprevir therapy. Journal of Medical Virology 2015; 87(11): 1913-20. 226. Younossi Z, Stepanova M, Han KH, et al. Asian patients with hepatitis C (HCV) genotype 1 treated with ledipasvir and sofosbuvir (LDV/SOF) experience very high efficacy and improvement of health-related quality of life (HRQL). Journal of gastroenterology and hepatology 2016; 31(376). 227. Younossi ZM, Park H, Gordon SC, et al. Real-world outcomes of ledipasvir/sofosbuvir in treatment-naive patients with hepatitis C. American Journal of Managed Care 2016; 22(6 Spec No.): SP205-11. 228. Younossi ZM, Stepanova M, Charlton M, et al. Patient-reported outcomes with sofosbuvir and velpatasvir with or without ribavirin for hepatitis C virus-related decompensated cirrhosis: an exploratory analysis from the randomised, open-label ASTRAL-4 phase 3 trial. The lancet gastroenterology and hepatology 2016; 1(2): 122-32. 229. Younossi ZM, Stepanova M, Feld J, et al. Sofosbuvir/velpatasvir improves patient-reported outcomes in HCV patients: Results from ASTRAL-1 placebo-controlled trial. Journal of Hepatology 2016; 65(1): 33-9. 230. Younossi ZM, Stepanova M, Omata M, Mizokami M, Walters M, Hunt S. Quality of life of Japanese patients with chronic hepatitis C treated with ledipasvir and sofosbuvir. Medicine 2016; 95(33): e4243. 231. Younossi ZM, Stepanova M, Sulkowski M, et al. Ribavirin-Free Regimen With Sofosbuvir and Velpatasvir Is Associated With High Efficacy and Improvement of Patient-Reported Outcomes in Patients With Genotypes 2 and 3 Chronic Hepatitis C: Results From Astral-2 and -3 Clinical Trials. Clinical Infectious Diseases 2016; 63(8): 1042-8. 232. Younossi ZM, Stepanova M, Sulkowski M, Wyles D, Kottilil S, Hunt S. Patient-reported outcomes in patients co-infected with hepatitis C virus and human immunodeficiency virus treated with sofosbuvir and velpatasvir: The ASTRAL-5 study. Liver International 2017. 233. Younossi ZMS, M.; Afdhal, N.; Kowdley, K. V.; Zeuzem, S.; Henry, L.; Hunt, S. L.; Marcellin, P. Improvement of health-related quality of life and work productivity in chronic hepatitis C patients with early and advanced fibrosis treated with ledipasvir and sofosbuvir. Journal of Hepatology 2015; 63(2): 337-45.

191

234. Younossi ZMS, M.; Sulkowski, M.; Naggie, S.; Puoti, M.; Orkin, C.; Hunt, S. L. Sofosbuvir and Ribavirin for Treatment of Chronic Hepatitis C in Patients Coinfected With Hepatitis C Virus and HIV: The Impact on Patient-Reported Outcomes. Journal of Infectious Diseases 2015; 212(3): 367-77. 235. Younossi ZMS, M.; Marcellin, P.; Afdhal, N.; Kowdley, K. V.; Zeuzem, S.; Hunt, S. L. Treatment with ledipasvir and sofosbuvir improves patient-reported outcomes: Results from the ION-1, -2, and -3 clinical trials. Hepatology (Baltimore, Md) 2015; 61(6): 1798-808. 236. Younossi ZMS, M.; Sulkowski, M.; Naggie, S.; Henry, L.; Hunt, S. Sofosbuvir and ledipasvir improve patient-reported outcomes in patients co-infected with hepatitis C and human immunodeficiency virus. Journal of Viral Hepatitis 2016; 23(11): 857-65. 237. Younossi ZMS, M.; Pol, S.; Bronowicki, J. P.; Carrieri, M. P.; Bourliere, M. The impact of ledipasvir/sofosbuvir on patient-reported outcomes in cirrhotic patients with chronic hepatitis C: the SIRIUS study. Liver International 2016; 36(1): 42-8. 238. Younossi ZS, M.; Pol, S.; Bronowicki, J. P.; Carrieri, P.; Bourliere, M. The impact of ledipasvir (LDV)/sofosbuvir (SOF) combination on health-related quality of life (HRQL) and patient-reported outcomes (PROS) in cirrhotic patients with chronic hepatitis C (CH-C): The sirius study. Journal of hepatology 2015; 62(22). 239. Younossi ZS, M.; Omata, M.; Mizokami, M.; Walters, M.; Hunt, S. Health utilities using SF-6D scores in Japanese patients with chronic hepatitis C treated with sofosbuvir-based regimens in clinical trials. Health and Quality of Life Outcomes 2017; 15 (1) (no pagination)(25). 240. Zeng QL, Xu GH, Zhang JY, et al. Generic ledipasvir-sofosbuvir for patients with chronic hepatitis C: A real-life observational study. Journal of Hepatology 2017; 66(6): 1123-9. 241. Zeuzem S, Dusheiko GM, Salupere R, et al. Sofosbuvir and Ribavirin in HCV genotypes 2 and 3. New England Journal of Medicine 2014; 370(21): 1993-2001. 242. Zeuzem S, Flamm SL, Tong MJ, et al. A randomized, controlled, phase 3 trial of sofosbuvir/ velpatasvir/voxilaprevir or sofosbuvir/velpatasvir for 12 weeks in direct acting antiviral-experienced patients with genotype 1-6 HCV infection: the POLARIS-4 study. Hepatology 2016; Conference: 67th annual meeting of the american association for the study of liver diseases: the liver meeting. 2016. United states. Conference start: 20161111. Conference end: 20161115 63(1 Supplement 1): 59A. 243. Zeuzem S, Ghalib R, Reddy KR, et al. Final SVR24 data from the phase 3 c-edge treatment- naive study of elbasvir (EBR)/grazoprevir (GZR) in patients with chronic HCV genotype 1, 4 or 6 infection. Journal of hepatology 2016; Conference: 51st annual meeting of the european association for the study of the liver, international liver congress. 2016. Barcelona spain. Conference start: 20160413. Conference end: 20160417. Conference publication:(var.pagings) 64(2 SUPPL. 1): S821. 244. Zeuzem S, Ghalib R, Reddy KR, et al. The phase 3 c-edge treatment-naive (TN) study of a 12- week oral regimen of grazoprevir (GZR, mk-5172)/ elbasvir (EBR, mk-8742) in patients with chronic hcv genotype (GT) 1, 4, or 6 infection. Journal of hepatology 2015; 62(22). 245. Zeuzem S, Ghalib R, Reddy KR, et al. Grazoprevir-Elbasvir Combination Therapy for Treatment- Naive Cirrhotic and Noncirrhotic Patients With Chronic Hepatitis C Virus Genotype 1, 4, or 6 Infection: A Randomized Trial. Annals of internal medicine 2015; 163(1): 1-13. 246. Zeuzem SD, G. M.; Colombo, M.; Flisiak, R.; Hyland, R. H.; Illeperuma, A.; Brainard, D. M.; Symonds, W. T.; McHutchison, J. G.; Weiland, O.; Reesink, H. W.; Brown, A.; Pol, S.; Hezode, C.; Esteban, R. Early viral kinetics do not predict treatment outcome with sofosbuvir + ribavirin for 12 or 24 weeks in HCV genotype 2/3 patients in the valence trial. Journal of hepatology; 60(1 SUPPL. 1): S452. 247. Zhdanov K, Orlova-Morozova EA, Morozov V, et al. Ledipasvir/sofosbuvir in treatment-Naive patients with chronic HCV Infection and HIV/HCV co-infection and in SOFexperienced patients. Hepatology international 2017; Conference: 26th annual conference of the asian pacific association for the study of the liver, APASL. 2017. China 11(1 Supplement 1): S109-S10.

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