Introduction Sustained virological response (SVR) is commonly used as an indicator of treatment success in people with chronic hepatitis C virus (HCV) infection. However, there is uncertainty on whether SVR is a validated surrogate marker of successful treatment of chronic HCV infection. Aim To evaluate whether SVR is a good surrogate for all-cause mortality, decompensated cirrhosis, or any specific aspect of liver decompensation (jaundice, ascites, hepatic encephalopathy, hepatorenal syndrome, or variceal haemorrhage), or hepatocellular carcinoma in people with chronic HCV infection eligible to receive direct-acting antiviral drugs. Methods Data source Two ongoing systematic reviews on the effectiveness of direct-acting antiviral drugs in chronic HCV infection. Analysis 1. Estimate the regression coefficients or between-studies correlation between SVR and the event by three different Bayesian approaches with OpenBUGS, as outlined in the guidance by the Evidence Synthesis Unit (Technical support document 20). 2. Estimate the average proportion of the effect mediated through SVR by causal mediation analysis using R. Discussion We will use the German Institute of Quality and Efficiency in Health Care (IQWiG) criterion for surrogacy for cancer and at least 50% of the treatment effect mediated through SVR but will report the information in a way that allows people to interpret the information using their own criteria. Funding No external funding. Conflicts of interest The salary and promotions of Kurinchi Gurusamy are dependent on high-quality research.

The salary and promotions of Kurinchi Gurusamy are dependent on high-quality research.

This study did not receive any funding

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Two ongoing systematic reviews on the effectiveness of direct-acting antiviral drugs in chronic HCV infection (update of Jakobsen JC, Nielsen EE, Feinberg J, Katakam KK, Fobian K, Hauser G, et al. Direct-acting antivirals for chronic hepatitis C. Cochrane Database Syst Rev. 2017;9(9):Cd012143 and Kumburegama BWMB, Kristensen AT, Bjelakovic G, Nikolova D, Asante MA, Bjelakovic M, et al. Direct-acting antivirals for chronic hepatitis C infection: a protocol for a systematic review of observational studies. medRxiv. 2024:https://www.medrxiv.org/content/10.1101/2024.10.21.24315594v1 (accessed on 22 October 2022)

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The summary data will be available from the systematic review update and all authors of the two reviews will be invited to co-author the results of this research. The data and codes used for this research will be shared via www.zenodo.org. Attempts will be made to publish the report in a journal. If this is not possible, we will share the report of our results through www.zenodo.org.