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      Baseline resistance-guided therapy does not enhance the response to interferon-free treatment of HCV infection in real life

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          Abstract

          Hepatitis C virus (HCV) response to direct-acting antivirals (DAAs) may be influenced by the presence of resistance-associated substitutions (RASs). This study aimed to assess if NS5A baseline RAS-guided treatment enhances the rate of sustained viral response (SVR) in naïve HCV-infected patients in clinical practice. All HCV-infected patients who initiated treatment with interferon (IFN)-free DAA-based regimens between March 2016 and May 2017 in 17 Spanish hospitals and who had evaluable SVR 12 weeks (SVR12) after the end of therapy were included. Patients had to be DAA naïve, with the exception of sofosbuvir with/without IFN. In one hospital, participants received therapy guided by the presence of NS5A-RASs (RGT population). Patients enrolled in the remaining hospitals, without baseline RASs testing, constituted the control population. A total of 120 and 512 patients were included in the RGT and control populations, respectively. Nine (7.5%) individuals in the RGT population showed baseline NS5A-RASs. All of them achieved SVR12. The SVR12 rate in the RGT population was 97.2% (three relapses) whereas it was 98.8% (six relapses) in the control population (p = 0.382). Our findings suggest that testing for baseline NS5A-RASs in naïve HCV-infected patients does not enhance the rate of SVR to DAA-based IFN-free therapy in clinical practice.

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          Most cited references22

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          Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis.

          High rates of sustained virologic response were observed among patients with hepatitis C virus (HCV) infection who received 12 weeks of treatment with the nucleotide polymerase inhibitor sofosbuvir combined with the NS5A inhibitor ledipasvir. This study examined 8 weeks of treatment with this regimen. In this phase 3, open-label study, we randomly assigned 647 previously untreated patients with HCV genotype 1 infection without cirrhosis to receive ledipasvir and sofosbuvir (ledipasvir-sofosbuvir) for 8 weeks, ledipasvir-sofosbuvir plus ribavirin for 8 weeks, or ledipasvir-sofosbuvir for 12 weeks. The primary end point was sustained virologic response at 12 weeks after the end of therapy. The rate of sustained virologic response was 94% (95% confidence interval [CI], 90 to 97) with 8 weeks of ledipasvir-sofosbuvir, 93% (95% CI, 89 to 96) with 8 weeks of ledipasvir-sofosbuvir plus ribavirin, and 95% (95% CI, 92 to 98) with 12 weeks of ledipasvir-sofosbuvir. As compared with the rate of sustained virologic response in the group that received 8 weeks of ledipasvir-sofosbuvir, the rate in the 12-week group was 1 percentage point higher (97.5% CI, -4 to 6) and the rate in the group that received 8 weeks of ledipasvir-sofosbuvir with ribavirin was 1 percentage point lower (95% CI, -6 to 4); these results indicated noninferiority of the 8-week ledipasvir-sofosbuvir regimen, on the basis of a noninferiority margin of 12 percentage points. Adverse events were more common in the group that received ribavirin than in the other two groups. No patient who received 8 weeks of only ledipasvir-sofosbuvir discontinued treatment owing to adverse events. Ledipasvir-sofosbuvir for 8 weeks was associated with a high rate of sustained virologic response among previously untreated patients with HCV genotype 1 infection without cirrhosis. No additional benefit was associated with the inclusion of ribavirin in the regimen or with extension of the duration of treatment to 12 weeks. (Funded by Gilead Sciences; ION-3 ClinicalTrials.gov number, NCT01851330.).
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            Sofosbuvir and Velpatasvir for HCV in Patients with Decompensated Cirrhosis.

            As the population that is infected with the hepatitis C virus (HCV) ages, the number of patients with decompensated cirrhosis is expected to increase.
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              All-Oral 12-Week Treatment With Daclatasvir Plus Sofosbuvir in Patients With Hepatitis C Virus Genotype 3 Infection: ALLY-3 Phase III Study

              Treatment options for patients with hepatitis C virus (HCV) genotype 3 infection are limited, with the currently approved all-oral regimens requiring 24-week treatment and the addition of ribavirin (RBV). This phase III study (ALLY-3; http://ClinicalTrials.gov: NCT02032901) evaluated the 12-week regimen of daclatasvir (DCV; pangenotypic nonstructural protein [NS]5A inhibitor) plus sofosbuvir (SOF; pangenotypic NS5B inhibitor) in patients infected with genotype 3. Patients were either treatment naïve (n = 101) or treatment experienced (n = 51) and received DCV 60 mg plus SOF 400 mg once-daily for 12 weeks. Coprimary endpoints were the proportions of treatment-naïve and treatment-experienced patients achieving a sustained virological response (SVR) at post-treatment week 12 (SVR12). SVR12 rates were 90% (91 of 101) and 86% (44 of 51) in treatment-naïve and treatment-experienced patients, respectively; no virological breakthrough was observed, and ≥99% of patients had a virological response (VR) at the end of treatment. SVR12 rates were higher in patients without cirrhosis (96%; 105 of 109) than in those with cirrhosis (63%; 20 of 32). Five of seven patients who previously failed treatment with an SOF-containing regimen and 2 of 2 who previously failed treatment with an alisporivir-containing regimen achieved SVR12. Baseline characteristics, including gender, age, HCV-RNA levels, and interleukin-28B genotype, did not impact virological outcome. DCV plus SOF was well tolerated; there were no adverse events (AEs) leading to discontinuation and only 1 serious AE on-treatment, which was unrelated to study medications. The few treatment-emergent grade 3/4 laboratory abnormalities that were observed were transient. Conclusion: A 12-week regimen of DCV plus SOF achieved SVR12 in 96% of patients with genotype 3 infection without cirrhosis and was well tolerated. Additional evaluation to optimize efficacy in genotype 3–infected patients with cirrhosis is underway. (Hepatology 2015;61:1127–1135)
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                Author and article information

                Contributors
                lmreal67b@gmail.com
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                8 October 2018
                8 October 2018
                2018
                : 8
                : 14905
                Affiliations
                [1 ]ISNI 0000 0004 1768 1690, GRID grid.412800.f, Unidad Clínica de Enfermedades Infecciosas y Microbiología, , Hospital Universitario de Valme, ; Sevilla, Spain
                [2 ]GRID grid.459499.c, Servicio de Microbiología, , Complejo Hospitalario Universitario de Granada-Hospital PTS, ; Granada, Spain
                [3 ]Instituto de Investigación Biosanitaria (IBS), Granada, Spain
                [4 ]GRID grid.414974.b, Unidad de Enfermedades Infecciosas, , Hospital Juan Ramón Jiménez, ; Huelva, Spain
                [5 ]ISNI 0000 0004 0399 7109, GRID grid.411250.3, Unidad de Enfermedades Infecciosas, , Hospital Universitario de Gran Canaria Dr. Negrín, ; Las Palmas, de Gran Canaria Spain
                [6 ]Unidad de Patología Infecciosa, Hospital Universitario Alvaro Conqueiro. Instituto de Investigación Galicia Sur, Vigo, Spain
                [7 ]GRID grid.411457.2, Servicio de Enfermedades Infecciosas, , Hospital Regional de Málaga, ; Málaga, Spain
                [8 ]ISNI 0000 0004 1768 164X, GRID grid.411375.5, Unidad de Enfermedades Infecciosas, , Hospital Universitario Virgen Macarena, ; Sevilla, Spain
                [9 ]Servicio de Medicina Interna, Unidad de VIH. Hospital General Universitario Virgen Arrixaca, Murcia, Spain
                [10 ]ISNI 0000 0004 1770 977X, GRID grid.106023.6, Unidad de Enfermedades Infecciosas, , Consorcio Hospital General Universitario de Valencia, ; Valencia, Spain
                Author information
                http://orcid.org/0000-0003-4932-7429
                http://orcid.org/0000-0001-7611-781X
                Article
                33367
                10.1038/s41598-018-33367-1
                6175866
                30297726
                58bf6405-3a23-4996-88da-c1b6640b343a
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 16 May 2018
                : 25 September 2018
                Funding
                Funded by: FundRef https://doi.org/10.13039/501100004587, Ministry of Economy and Competitiveness | Instituto de Salud Carlos III (Institute of Health Carlos III);
                Award ID: RD16/0025/0040, RD12/0017/0012
                Award ID: RD16/0025/0040, RD12/0017/0012, I3SNS
                Award Recipient :
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