***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 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: GS-5816 is an inhibitor of the hepatitis C virus ( HCV ) NS5A protein that has demonstrated pan-genotypic activity and a high barrier to resistance in HCV replicon assays . The aim of this study was to evaluate the safety , antiviral activity and pharmacokinetics of once-daily doses of GS-5816 in patients with genotype 1 - 4 HCV infection . Patients with genotype 1 - 4 HCV infection were r and omized to 3 days of GS-5816 at doses ranging from 5 to 150 mg or placebo .  Adverse events were recorded , and plasma sample s obtained for analysis of pharmacokinetics , HCV RNA and NS5A sequencing studies . GS-5816 5 - 150 mg for 3 days was well tolerated and result ed in rapid declines in HCV RNA that were sustained over the dosing period . In patients treated with the 150 mg dose of GS-5816 , the mean maximal HCV RNA declines were 4.0 , 4.0 , 4.4 , 3.3 and 3.5 log10 IU/mL in patients with genotype 1a , 1b , 2 , 3 and 4 HCV infection , respectively . Pretreatment NS5A resistance-associated polymorphisms were detected in 31 % ( 22/70 ) of patients . Genotype 1 and 3 HCV-infected patients without pretreatment NS5A resistance-associated polymorphisms had greater declines in HCV RNA than patients with resistance-associated polymorphisms . Plasma pharmacokinetics were supportive of once-daily dosing . GS-5816 demonstrated pangenotypic antiviral activity in patients with genotype 1 - 4 HCV infection . It will be further evaluated in combination with other pangenotypic direct-acting antivirals to achieve the goal of developing a well-tolerated , highly effective treatment for all HCV genotypes BACKGROUND Patients chronically infected with hepatitis C virus ( HCV ) genotype 2 or 3 for whom treatment with peginterferon is not an option , or who have not had a response to prior interferon treatment , currently have no approved treatment options . In phase 2 trials , regimens including the oral nucleotide polymerase inhibitor sofosbuvir have shown efficacy in patients with HCV genotype 2 or 3 infection . METHODS We conducted two r and omized , phase 3 studies involving patients with chronic HCV genotype 2 or 3 infection . In one trial , patients for whom treatment with peginterferon was not an option received oral sofosbuvir and ribavirin  ( 207 patients ) or matching placebo ( 71 ) for 12 weeks . In a second trial , patients who had not had a response to prior interferon therapy received sofosbuvir and ribavirin for 12 weeks ( 103 patients ) or 16 weeks ( 98 ) . The primary end point was a sustained virologic response at 12 weeks after therapy . RESULTS Among patients for whom treatment with peginterferon was not an option , the rate of a sustained virologic response was 78 % ( 95 % confidence interval [ CI ] , 72 to 83 ) with sofosbuvir and ribavirin , as compared with 0 % with placebo ( P<0.001 ) . Among previously treated patients , the rate of response was 50 % with 12 weeks of treatment , as compared with 73 % with 16 weeks of treatment ( difference , -23 percentage points ; 95 % CI , -35 to -11 ; P<0.001 ) . In both studies , response rates were lower among patients with genotype 3 infection than among those with genotype 2 infection and , among patients with genotype 3 infection , lower among those with cirrhosis than among those without cirrhosis . The most common adverse events were headache , fatigue , nausea , and insomnia ; the overall rate of discontinuation of sofosbuvir was low ( 1 to 2 % ) . CONCLUSIONS In patients with HCV genotype 2 or 3 infection for whom treatment with peginterferon and ribavirin was not an option , 12 or 16 weeks of treatment with sofosbuvir and ribavirin was effective . Efficacy was increased among patients with HCV genotype 2 infection and those without cirrhosis . In previously treated patients with genotype 3 infection , 16 weeks of therapy was significantly more effective than 12 weeks . ( Funded by Gilead Sciences ; POSITRON and FUSION Clinical Trials.gov numbers , NCT01542788 and NCT01604850 , respectively . ) BACKGROUND The uridine nucleotide analogue sofosbuvir is a selective inhibitor of hepatitis C virus ( HCV ) NS5B polymerase . We assessed the safety and efficacy of sofosbuvir in combination with pegylated interferon alfa-2a ( peginterferon ) and ribavirin in non-cirrhotic treatment-naive , patients with HCV . METHODS For this open-label , r and omised phase 2 trial , we recruited patients from 42 centres in the USA and Puerto Rico between March 23 , 2011 , and Sept 21 , 2011 . Patients were eligible for inclusion if they had chronic HCV infection ( genotypes 1 , 4 , 5 , or 6 ) , were aged 18 years or older , and had not previously received treatment for HCV infection . Using a computer-generated r and omisation sequence , we r and omly assigned patients with HCV genotype-1 to one of three cohorts ( A , B , and C ; in a 1:2:3 ratio ) , with r and omisation stratified by IL28B ( CC vs non-CC allele ) and HCV RNA ( < 800,000 IU/mL vs ≥800,000 IU/mL ) . Patients received sofosbuvir 400 mg plus peginterferon and ribavirin for 12 weeks ( cohort A ) or for 24 weeks ( cohort B ) , or 12 weeks of sofosbuvir plus peginterferon and ribavirin followed by 12 weeks of either sofosbuvir monotherapy or sofosbuvir plus ribavirin ( cohort C ) . We enrolled patients with all other eligible genotypes in cohort B. The primary efficacy endpoint was sustained virological response at post-treatment week 24 ( SVR24 ) by intention-to-treat analysis . This trial is registered with Clinical Trials.gov , number NCT01329978 . RESULTS We enrolled 316 patients with HCV genotype-1 : 52 to cohort A , 109 to cohort B , and 155 to cohort C. We assigned 11 patients with HCV genotype-4 and five patients with genotype-6 to cohort B ( we detected no patients with genotype 5 ) . In patients with HCVgenotype-1 , SVR24 was achieved by 46 patients ( 89 % , 95 % CI 77 - 96 ) in cohort A , 97 patients ( 89 % , 82 - 94 ) in cohort B , and by 135 ( 87 % , 81 - 92 ) in cohort C. We detected no difference in the proportion of patients achieving SVR24 in cohort A compared with cohort B ( p=0·94 ) , or in cohort C ( p=0·78 ) . Nine ( 82 % ) of 11 patients with genotype-4 and all five with genotype-6 achieved SVR24 . Seven patients , all with genotype-1 infection , relapsed after completion of assigned treatment . The most common adverse events that led to the discontinuation of any study drug -- anaemia and neutropenia -- were associated with peginterferon and ribavirin treatment . Three ( 6 % ) patients in cohort A , 18 ( 14 % ) patients in cohort B , and three ( 2 % ) patients in cohort C discontinued treatment because of an adverse event . INTERPRETATION Our findings suggest that sofosbuvir is well tolerated and that there is no additional benefit of extending treatment beyond 12 weeks , but these finding will have to be substantiated in phase 3 trials . These results lend support to the further assessment of a 12 week sofosbuvir regimen in a broader population of patients with chronic HCV genotype-1 infection , including those with cirrhosis . FUNDING Gilead Sciences Context Options are needed when initial therapy fails for hepatitis C virus ( HCV ) infection . Contribution In a phase 2 trial , treatment-experienced patients with genotype 3 HCV infection who either did not have cirrhosis or had compensated cirrhosis , as well as patients with genotype 1 HCV infection that was unsuccessfully treated with a protease inhibitor plus peginterferon or ribavirin  , received sofosbuvir plus 1 of 2 doses of velpatasvir with or without ribavirin .  Sustained virologic response rates 12 weeks after treatment were high in all groups that received sofosbuvir plus 100 mg of velpatasvir . Treatment was well-tolerated . Caution The number of patients was small . Implication Larger trials of sofosbuvir plus velpatasvir are indicated for patients with HCV infection for whom initial therapy fails . Of the 6 hepatitis C virus ( HCV ) genotypes , 1 and 3 are the most common and account for approximately 46 % and 22 % of all global infections , respectively ( 1 ) . Chronic infection with genotype 1 HCV is most prevalent in the Americas , Europe , and China , and genotype 3 HCV infection is most prevalent in India , Pakistan , and Southeast Asia ( 1 ) . With the advent of direct-acting antiviral agents , effective interferon-free combination regimens are now available for most patients chronically infected with genotype 1 or 3 HCV ( 2 , 3 ) . However , some subgroups of patients do not achieve optimal rates of sustained virologic response ( SVR ) with existing 12-week regimensin particular , cirrhotic patients with genotype 1 or 3 HCV infection who previously received unsuccessful treatment of HCV infection ( 46 ) . These patients , who are at increased risk for progression to decompensated cirrhosis , hepatocellular carcinoma , and other liver complications , have a medical need for more effective and well-tolerated treatment ( 7 , 8) . Velpatasvir ( Gilead Sciences ) is a novel inhibitor of the HCV NS5A protein , which is involved in HCV replication , virion assembly , and modulation of host cellular response . Velpatasvir ( formerly GS-5816 ) has demonstrated potent pangenotypic antiviral activity in vitro ( 9 ) and in a 3-day monotherapy study in patients with genotype 1 , 2 , 3 , or 4 HCV infection ( 10 , 11 ) . Pharmacology studies showed no clinical ly important drug interactions between sofosbuvir and velpatasvir ( 12 ) . A recent phase 2 study demonstrated the safety and efficacy of 12 weeks of the combination of sofosbuvir and velpatasvir in treatment-naive patients with genotype 1 to 6 HCV infection , with rates of SVR at week 12 after treatment ( SVR12 ) of 93 % to 100 % ( 13 ) . We evaluated the antiviral activity , safety , and tolerability of sofosbuvir administered with 25 or 100 mg of velpatasvir with and without ribavirin for 12 weeks in treatment-experienced patients with genotype 1 or 3 HCV infection . Because previously treated patients have historically had a poorer response than treatment-naive patients , we chose to evaluate sofosbuvir plus velpatasvir with ribavirin , as well as sofosbuvir plus velpatasvir alone . Methods Design Overview This phase 2 , multicenter , r and omized , open-label study was conducted from June 2013 ( when the first patient was enrolled ) to August 2014 ( when the last patient completed follow-up ) . The study was originally design ed to enroll 2 cohorts of patients with chronic genotype 3 HCV infection who had not achieved SVR after previous therapy with an interferon-based regimenapproximately 100 patients without cirrhosis and 100 patients with compensated cirrhosis . Favorable results in treatment-naive patients with genotype 1 HCV infection in a phase 2 trial of similar design ( 13 ) prompted us to amend our protocol to enroll a third cohort of approximately 100 patients with chronic genotype 1 HCV infection who did not achieve SVR after previous therapy with an approved or experimental NS3/4A protease inhibitor in combination with peginterferon and ribavirin .  Up to 50 % of patients with genotype 1 HCV infection could have compensated cirrhosis . The protocol was approved by the institutional ethics committees at all sites , and the study was conducted in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki . Setting and Participants The study was conducted at 58 clinical sites : 7 in Australia , 2 in New Zeal and , and 49 in the United States . Some patients were recruited partly through a posting of study details on Clinical Trials.gov and others through referral by their treating physicians . Adults ( aged 18 years ) with HCV RNA levels greater than 10000 IU/ 
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In conclusion , the 12-week regimen of sofosbuvir plus velpatasvir was highly effective in HCV patients , including those with cirrhosis and former treatment experience .
Except for genotype-3 , adding ribavirin was not associated with significant improvements in SVR12 rates .