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Effectiveness and Safety of Sofosbuvir Plus Ribavirin for the Treatment of HCV Genotype 2 Infection

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Effectiveness and Safety of Sofosbuvir Plus Ribavirin for the Treatment of HCV Genotype 2 Infection Hepatology ORIGINAL ARTICLE Effectiveness and safety of sofosbuvir plus ribavirin Gut: first published as 10.1136/gutjnl-2016-311609 on 13 July 2016. Downloaded from for the treatment of HCV genotype 2 infection: results of the real-world, clinical practice HCV-TARGET study Tania M Welzel,1 David R Nelson,2 Giuseppe Morelli,2 Adrian Di Bisceglie,3 Rajender K Reddy,4 Alexander Kuo,5 Joseph K Lim,6 Jama Darling,7 Paul Pockros,8 Joseph S Galati,9 Lynn M Frazier,10 Saleh Alqahtani,11 Mark S Sulkowski,11 Monika Vainorius,7 Lucy Akushevich,7 Michael W Fried,7 Stefan Zeuzem,1 for the HCV-TARGET Study Group ► Additional material is ABSTRACT published online only. To view Objective Due to a high efficacy in clinical trials, Significance of this study please visit the journal online sofosbuvir (SOF) and ribavirin (RBV) for 12 or 16 weeks (http://dx.doi.org/10.1136/ gutjnl-2016-311609). is recommended for treatment of patients with HCV genotype (GT) 2 infection. We investigated safety and What is already known on this subject? For numbered affiliations see effectiveness of these regimens for GT2 in HCV-TARGET ▸ fi end of article. Due to a high ef cacy in clinical trials, the participants. all-oral combination of sofosbuvir (SOF) and Correspondence to Design HCV-TARGET, an international, prospective ribavirin (RBV) for 12 weeks is currently Dr Tania Mara Welzel, JW observational study evaluates clinical practice data on considered standard of care in patients with Goethe University Hospital, novel antiviral therapies at 44 academic and 17 HCV genotype 2 (GT2) infection. Department of Medicine 1, community medical centres in North America and ▸ Based on limited data from clinical trials, Theodor-Stern-Kai 7, Frankfurt Europe. Clinical data were centrally abstracted from am Main 60596, Germany; treatment extension to 16 weeks is [email protected] medical records. Selection of treatment regimen and recommended by international HCV treatment duration was the investigator’s choice. The primary guidelines for patients with negative predictors Received 6 February 2016 fi ef cacy outcome was sustained virological response of treatment response, including patients with http://gut.bmj.com/ Revised 1 June 2016 12 weeks after therapy (SVR12). liver cirrhosis. Accepted 4 June 2016 ▸ Published Online First Results Between December 2013 and April 2015, 321 Information on the effectiveness and safety of 12 July 2016 patients completed 12 weeks (n=283) or 16 weeks SOF and RBV for treatment of HCV GT2 in (n=38) of treatment with SOF and RBV. Prior treatment real-world, clinical practice is limited. experience and cirrhosis was more frequent among patients in the 16-week regimen compared with What are the new findings? ▸ 12 weeks (52.6% vs 27.6% and 63.2% vs 21.9%, Sustained virological response 12 weeks after on September 26, 2021 by guest. Protected copyright. respectively). Overall, SVR12 was 88.2%. The SVR12 in therapy (SVR12) rates as observed in patients without cirrhosis was 91.0% and 92.9% for 12 HCV-TARGET, a prospective, international, or 16 weeks of therapy, respectively. In patients with multicentre ‘real-word’ study that included a cirrhosis treated for 12 or 16 weeks, SVR12 was 79.0% larger number of patients with HCV GT2 and 83%. In the multivariate analysis, liver cirrhosis, infection than any pivotal study generally lower serum albumin and RBV dose at baseline were confirm the effectiveness and safety of SOF and significantly associated with SVR12. Common adverse RBV for treatment of GT2. events (AEs) included fatigue, anaemia, nausea, ▸ While response rates in patients without headache, insomnia, rash and flu-like symptoms. cirrhosis were high and comparable with those Discontinuation due to AEs occurred in 2.8%. reported in clinical trials, liver cirrhosis, lower Conclusions In this clinical practice setting, SOF and serum albumin levels and RBV dose at baseline RBV was safe and effective for treatment of patients were associated with lower SVR12 rates. with HCV GT2 infection. ▸ Only a small proportion of patients with Trial registration number NCT01474811. cirrhosis (27%) were treated for 16 weeks, and response rates were similar to those treated for 12 weeks. Larger, randomised and adequately powered trials would be necessary to assess To cite: Welzel TM, INTRODUCTION the benefit of treatment extension to 16 weeks Nelson DR, Morelli G, et al. Chronic infection with HCV is a major cause of in cirrhotics. Gut 2017;66:1844–1852. end-stage liver disease and hepatocellular 1844 Welzel TM, et al. Gut 2017;66:1844–1852. doi:10.1136/gutjnl-2016-311609 Hepatology MATERIALS AND METHODS Significance of this study Patients HCV-TARGET is a prospective, longitudinal, observational Gut: first published as 10.1136/gutjnl-2016-311609 on 13 July 2016. Downloaded from study conducted at 44 academic and 17 community medical How might it impact on clinical practice in the centres in North America (57 centres) and Europe (4 centres). foreseeable future? The registry enrolls adult patients with HCV (≥18 years), who ▸ This large, international cohort study confirms the initiated HCV treatment with DAA agents according to the rec- effectiveness and safety of the all-oral combination of SOF ommendation of the site investigator. For participation, patients and RBV for treatment of HCV GT2. had to provide informed consent within 4 weeks after treatment ▸ The results from recent phase III studies demonstrating that initiation. This study includes data from patients with HCV SOF and velpatasvir is superior to SOF plus RBV must be GT2 infection sequentially enrolled in HCV-TARGET between confirmed in real-world studies. 8 December 2013 and 15 April 2015. Patients completed treat- ment with SOF and weight-based RBV for a duration of either 12 or 16 weeks (with a duration window of ±2 weeks to account for practice variability). Patients were excluded from this analysis if they had undergone liver transplantation or had carcinoma (HCC).12Sustained virological response 12 weeks previously been treated with a prior DAA. after therapy (SVR12) is associated with a decreased risk for 34 liver-related morbidity and mortality. Treatments Among the seven HCV genotypes (GTs) isolated until now, SOF was prescribed at an oral standard dose of 400 mg once HCV genotype 2 (GT2) is the third most common GT with an daily. Selection of the appropriate RBV dose and determination estimated 16.5 million GT2-infected persons worldwide. of the treatment duration were the physician’s choice. According Relative proportions of HCV GT2 infections range from 10.8% to the label, the recommended RBV dose is 1000 mg/day and 12% in Western Europe and North America to higher pre- (≤75 kg) or 1200 (>75 kg) mg/day, divided into two daily doses. valences in Central Latin America (19.3%), Western Sub-Saharan Africa (23.0%) and Asia Pacific (24.5%).56 Data collection Compared with other HCV GTs such as GT1, GT3 and GT4, Demographic and clinical information, laboratory tests and historic therapy with pegylated interferon (PegIFN) and riba- technical exams were performed according to the site’s stan- virin (RBV) for 24 weeks yielded favourable response rates in dards. Data were collected within a centralised database using GT2-infected patients.7 However, the poor tolerability limited standardised source data abstraction as described previously.21 the clinical use of PegIFN-based therapies, in particular in The database was managed using Research Electronic Data patients with liver cirrhosis. Capture (REDCap) tools hosted at the University of North The availability of all-oral, direct-acting antiviral (DAA) drug Carolina, Chapel Hill.22 To optimise data quality, a trained combinations with high efficacy, favourable side-effect profile Centralized Chart Data Abstraction Team at the Clinical and easy applicability facilitated treatment of HCV infection in Coordinating Center at the University of Florida was established http://gut.bmj.com/ clinical practice.89Sofosbuvir (SOF), a first in-class nucleotide to enter de-identified copies of source data, that is, clinical NS5B polymerase inhibitor with a high barrier to resistance, records that were provided by participating sites. Special effort was approved for interferon-free treatment of HCV infection in was made to explore reasons for premature discontinuations the USA and Europe in early 2014.10 and to investigate the reasons for missing data and to minimise For HCV GT2, the efficacy and safety of SOF in combination loss to follow-up. Independent data monitors reviewed data with weight-based RBV for 12 weeks was investigated in several entries for completeness and accuracy. on September 26, 2021 by guest. Protected copyright. pivotal phase III trials: FISSION, POSITRON and Cirrhosis status was assessed by availability of a liver biopsy – VALENCE.11 13 In these trials, 94% of patients without cirrho- or a combination of several clinical and/or imaging criteria pre- sis and 90% of patients with cirrhosis achieved a SVR12. viously described.21 Briefly, cirrhosis was defined by (1) liver Another phase III study (FUSION) that compared SOF and RBV biopsy indicating liver fibrosis stage 4 (Metavir) prior to treat- for 12 or 16 weeks indicated that patients with liver cirrhosis ment initiation and (2) liver biopsy indicating stage 3 fibrosis may benefit from extended treatment duration.12 This study, prior to treatment initiation in combination with any of the fol- however, only included a small number of patients with cirrho- lowing clinical parameters: platelets <140 000/mL, oesophageal sis; SVR12 rates were 60% and 78% in patients treated for 12 varices on oesophagogastroduodenoscopy, cirrhosis and/or and 16 weeks, respectively. Based on these results, SOF and portal hypertension and/or of ascites by imaging methods, RBV for 12 weeks is currently recommended for most patients FibroSure (or equivalent) test, vibration-controlled transient with HCV GT2 infection by US, Canadian and European guide- elastography (VCTE) or equivalent compatible with fibrosis lines, although extension to 16 weeks may be considered for stage 4.
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