***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
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    Input: BACKGROUND Interferon-based treatment is not suitable for many patients with hepatitis C virus ( HCV ) infection because of contraindications such as psychiatric illness , and a high burden of adverse events . We assessed the efficacy and safety of an interferon-free regimen -- a fixed-dose combination of the nucleotide polymerase inhibitor sofosbuvir ( 400 mg ) and the HCV NS5A inhibitor ledipasvir ( 90 mg ) , with and without ribavirin -- in patients with genotype-1 hepatitis C infection who were treatment-naive or previously treated with a protease-inhibitor regimen . METHODS For this open-label study , we enrolled 100 adult patients ( > 18 years ) with HCV infection at a centre in the USA between Nov 2 , 2012 , and Dec 21 , 2012 . In cohort A , we used a computer-generated sequence to r and omly assign ( 1:1:1 ; stratified by HCV genotype [ 1a vs 1b ] ) 60 non-cirrhotic , treatment-naive patients to receive sofosbuvir plus ledipasvir for 8 weeks ( group 1 ) , sofosbuvir plus ledipasvir and ribavirin for 8 weeks ( group 2 ) , or sofosbuvir plus ledipasvir for 12 weeks ( group 3 ) . In cohort B , we r and omly allocated ( 1:1 ; stratified by genotype and presence or absence of cirrhosis ) 40 patients who previously had virological failure after receiving a protease inhibitor regimen to receive sofosbuvir plus ledipasvir for 12 weeks ( group 4 ) or sofosbuvir plus ledipasvir and ribavirin for 12 weeks ( group 5 ) . 22 ( 55 % ) of 40 patients in cohort B had compensated cirrhosis . The primary endpoint was sustained virological response 12 weeks after treatment ( SVR12 ) , analysed by intention to treat . This study is registered with Clinical Trials.gov , number NCT01329978 . FINDINGS In cohort A , SVR12 was achieved by 19 ( 95 % ) of 20 patients ( 95 % CI 75 - 100 ) in group 1 , by 21 ( 100 % ) of 21 patients ( 84 - 100 ) in group 2 , and by 18 ( 95 % ) of 19 patients ( 74 - 100 ) in group 3 . In cohort B , SVR12 was achieved by 18 ( 95 % ) of 19 patients ( 74 - 100 ) in group 4 and by all 21 ( 100 % ) of 21 patients ( 84 - 100 ) in group 5 . Two patients had viral relapse ; one patient was lost to follow-up after achieving sustained virological response 8 weeks after treatment . The most common adverse events were nausea , anaemia , upper respiratory tract infection , and headache . One patient in group five had a serious adverse event of anaemia , thought to be related to ribavirin treatment . INTERPRETATION These findings suggest that the fixed-dose combination of sofosbuvir-ledipasvir alone or with ribavirin has the potential to cure most patients with genotype-1 HCV , irrespective of treatment history or the presence of compensated cirrhosis . Further clinical trials are needed to establish the best treatment duration and to further assess the contribution of ribavirin . FUNDING Gilead Sciences Flaws in the design , conduct , analysis , and reporting of r and omised trials can cause the effect of an intervention to be underestimated or overestimated . The Cochrane Collaboration ’s tool for assessing risk of bias aims to make the process clearer and more BACKGROUND The phase 2 C-SALVAGE study ( Hepatitis C-Salvage Study for Patients who Failed DAA/PR Therapy ) demonstrated a 96.2 % sustained virologic response at 12 weeks ( SVR12 ) rate using the NS3/4A protease inhibitor grazoprevir and the NS5A inhibitor elbasvir together with ribavirin in treatment-experienced patients with chronic hepatitis C virus ( HCV ) genotype 1 infection . METHODS C-SALVAGE was a prospect i ve open-label trial of grazoprevir 100 mg once daily and elbasvir 50 mg once daily coadministered with weight-based ribavirin twice daily for 12 weeks in genotype 1-infected cirrhotic and noncirrhotic patients who had failed treatment with ≥ 4 weeks of pegylated interferon and ribavirin plus either boceprevir , telaprevir , or simeprevir .  Although the primary efficacy outcome was SVR12 , patients were also evaluated 24 weeks after cessation of study therapy . Population sequencing was performed at baseline and periodically in virologic failures throughout the 24-week posttherapy follow-up period . RESULTS SVR24 rates were 76 of 79 ( 96.2 % ) overall , with all 3 relapses occurring by posttherapy week 8 . Every NS3 and NS5A variant detected at baseline reappeared at the time of relapse and persisted throughout the available follow-up period . NS3_A156 T emerged in virus from each patient at relapse , but rapidly disappeared over the ensuing 2 weeks in 2 patients . NS5A_Y93H emerged in virus from 2 patients at relapse and persisted for the entire follow-up period . CONCLUSIONS Grazoprevir and elbasvir with ribavirin for 12 weeks maintained HCV suppression for at least 24 weeks posttherapy without late relapses . Baseline resistance-associated variants ( RAVs ) stably reappeared at relapse in all 3 patients with virologic failure . NS5A_RAVs emerging at relapse persisted for the full 24-week follow-up period . If confirmed , this finding could complicate retreatment of the small number of patients failing regimens containing an NS5A inhibitor . CLINICAL TRIALS REGISTRATION NCT02105454 BACKGROUND Effective treatment for hepatitis C virus ( HCV ) genotype 1 infection in patients who have not had a sustained virologic response to prior interferon-based therapy represents an unmet medical need . METHODS We conducted a phase 3 , r and omized , open-label study involving patients infected with HCV genotype 1 who had not had a sustained virologic response after treatment with peginterferon and ribavirin , with or without a protease inhibitor .  Patients were r and omly assigned to receive the NS5A inhibitor ledipasvir and the nucleotide polymerase inhibitor sofosbuvir in a once-daily , fixed-dose combination tablet for 12 weeks , ledipasvir-sofosbuvir plus ribavirin for 12 weeks , ledipasvir-sofosbuvir for 24 weeks , or ledipasvir-sofosbuvir plus ribavirin for 24 weeks . The primary end point was a sustained virologic response at 12 weeks after the end of therapy . RESULTS Among the 440 patients who underwent r and omization and were treated , 20 % had cirrhosis and 79 % had HCV genotype 1a infection . The rates of sustained virologic response were high in all treatment groups : 94 % ( 95 % confidence interval [ CI ] , 87 to 97 ) in the group that received 12 weeks of ledipasvir-sofosbuvir ; 96 % ( 95 % CI , 91 to 99 ) in the group that received 12 weeks of ledipasvir-sofosbuvir and ribavirin ; 99 % ( 95 % CI , 95 to 100 ) in the group that received 24 weeks of ledipasvir-sofosbuvir ; and 99 % ( 95 % CI , 95 to 100 ) in the group that received 24 weeks of ledipasvir-sofosbuvir and ribavirin . No patient discontinued treatment owing to an adverse event . The most common adverse events were fatigue , headache , and nausea . CONCLUSIONS Treatment with a once-daily , single-tablet regimen of ledipasvir and sofosbuvir result ed in high rates of sustained virologic response among patients with HCV genotype 1 infection who had not had a sustained virologic response to prior interferon-based treatment . ( Funded by Gilead Sciences ; ION-2 Clinical Trials.gov number , NCT01768286 . ) A new class of highly potent NS5A inhibitors with an unsymmetric benzimidazole-difluorofluorene-imidazole core and distal [2.2.1]azabicyclic ring system was discovered . Optimization of antiviral potency and pharmacokinetics led to the identification of 39 ( ledipasvir , GS-5885 ) . Compound 39 ( GT1a replicon EC50 = 31 pM ) has an extended plasma half-life of 37 - 45 h in healthy volunteers and produces a rapid > 3 log viral load reduction in monotherapy at oral doses of 3 mg or greater with once-daily dosing in genotype 1a HCV-infected patients . 39 has been shown to be safe and efficacious , with SVR12 rates up to 100 % when used in combination with direct-acting antivirals having complementary mechanisms BACKGROUND Compared with other countries , patients with chronic hepatitis C infection in Japan tend to be older , have more advanced liver disease , and are more likely to have been previously treated for hepatitis C. We aim ed to assess the efficacy and safety of an all-oral , fixed-dose combination of the hepatitis C virus NS5A inhibitor ledipasvir and the NS5B nucleotide polymerase inhibitor sofosbuvir with and without ribavirin for 12 weeks in treatment-naive and previously treated Japanese patients with chronic genotype 1 hepatitis C virus infection . METHODS In this r and omised , open-label study , we enrolled patients from 19 clinical Japanese centres . Patients were r and omly assigned ( 1:1 ) to receive either ledipasvir ( 90 mg ) and sofosbuvir ( 400 mg ) or ledipasvir , sofosbuvir , and ribavirin ( dosed according to the Japanese Copegus product label-ie , patients ≤60 kg received 600 mg daily , patients > 60 kg to ≤80 kg received 800 mg daily , and patients > 80 kg received 1000 mg daily ) orally once daily for 12 weeks . After completion or early discontinuation of treatment , patients were followed up off-treatment for 24 weeks . Eligible patients were at least 20 years of age with chronic genotype 1 hepatitis C virus infection with serum hepatitis C virus RNA concentrations of at least 5 log10 IU/mL , creatinine clearance of at least 1·0 mL/s , and a platelet count of at least 50 × 10(9 ) per L. An interactive web response system was used to manage patient r and omisation and treatment assignment . R and omisation was stratified by the presence or absence of cirrhosis for treatment-naive patients and stratified by presence or absence of cirrhosis and by previous treatment category ( relapser or breakthrough , non-responder , or interferon-intolerant ) for previously treated patients . Within each strata , patients were sequentially assigned to either treatment with ledipasvir-sofosbuvir or ledipasvir-sofosbuvir plus ribavirin in a 1:1 ratio with block size of 4 . The primary endpoint was sustained virological response 12 weeks after completion of treatment ( SVR12 ) assessed in all patients who were r and omly assigned and received at least one dose of study drug ; safety outcomes were assessed in all patients who received at least one dose of study drug . This trial is registered with Clinical Trials.gov , number NCT01975675 . FINDINGS Between Oct 15 , 2013 and Dec 13 , 2013 , 341 patients were r and omly assigned to treatment groups and received at least one dose of study treatment . SVR12 was achieved in all 171 ( 100 % ) patients ( 83 of 83 treatment naive and 88 of 88 treatment experienced ) receiving ledipasvir-sofosbuvir ( 95 % CI 98 - 100 ) and 167 ( 98 % ) of 170 patients ( 80 of 83 treatment naive and 87 of 87 treatment experienced ) receiving ledipasvir-sofosbuvir plus ribavirin ( 95 % CI 95 - 100 ) . Of the 76 patients with baseline NS5A resistant variants , 75 ( 99 % ) achieved SVR12 . Two ( 1·2 % ) of 170 patients in the ledipasvir-sofosbuvir plus ribavirin group discontinued treatment because of adverse events . The most common adverse events were nasopharyngitis ( 50 [ 29·2 % ] of 171 ) , headache ( 12 [ 7·0 % ] of 171 ) , and malaise ( nine [ 5·3 % ] of 171 ) in patients receiving ledipasvir-sofosbuvir ; and nasopharyngitis ( 40 [ 23·5 % ] of 1 
    Output:
    
Our findings suggest that 12 weeks of SOF/LDV can not be considered noninferior to 12 weeks of SOF/LDV/RBV to achieve SVR12 in patients with CHC who have cirrhosis and failed prior therapy