***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: BACKGROUND & AIMS SCH 503034 is a novel and potent oral hepatitis C virus ( HCV ) protease inhibitor . In this phase Ib study , we assessed safety parameters and virologic response of combination of SCH 503034 plus pegylated ( PEG ) interferon ( IFN ) alpha-2b in patients with HCV genotype 1 infections who were previously nonresponders to PEG-IFN-alpha-2b + /- ribavirin therapy . METHODS This was a multicenter , open-label , 2-dose level , 3-way crossover , r and omized ( to crossover sequence ) study carried out in 3 medical centers in Europe . Adult patients received SCH 503034 200 mg ( n = 14 ) or 400 mg ( n = 12 ) 3 times daily orally and PEG-IFN-alpha-2b 1.5 microg/kg subcutaneously once each week . Patients received SCH 503034 as monotherapy for 1 week , PEG-IFN-alpha-2b as monotherapy for 2 weeks , and combination therapy for 2 weeks with washout periods between each treatment period . RESULTS Combination therapy with SCH 503034 and PEG-IFN-alpha-2b was well tolerated , with no clinical ly significant changes in safety parameters . Mean maximum log(10 ) changes in HCV RNA were -2.45 + /- 0.22 and -2.88 + /- 0.22 for PEG-IFN-alpha-2b plus 200 mg and 400 mg SCH 503034 , respectively , compared with -1.08 + /- 0.22 and -1.61 + /- 0.21 for SCH 503034 200 mg and 400 mg , respectively , and -1.08 + /- 0.22 and -1.26 + /- 0.20 for PEG-IFN-alpha-2b alone in the 200 mg and 400 mg SCH 503034 groups , respectively . CONCLUSIONS SCH 503034 plus PEG-IFN-alpha-2b was well tolerated  in patients with HCV genotype 1 nonresponders to PEG-IFN-alpha-2b + /- ribavirin . These preliminary results of antiviral activity of the combination suggest a potential new therapeutic option for this hard-to-treat , nonresponder patient population The discovery of GS-9451 is reported . Modification of the P3 cap and P2 quinoline with a series of solubilizing groups led to the identification of potent HCV NS3 protease inhibitors with greatly improved pharmacokinetic properties in rats , dogs and monkeys BACKGROUND There is a need for interferon-free treatment regimens for hepatitis C virus ( HCV ) infection . The goal of this study was to evaluate ABT-450 , a potent HCV NS3 protease inhibitor , combined with low-dose ritonavir ( ABT-450/r ) , in addition to ABT-333 , a nonnucleoside NS5B polymerase inhibitor , and ribavirin , for the treatment of HCV infection . METHODS We conducted a 12-week , phase 2a , open-label study involving patients who had HCV genotype 1 infection without cirrhosis . All patients received ABT-333 ( 400 mg twice daily ) and ribavirin ( 1000 to 1200 mg per day ) and one of two daily doses of ABT-450/r . Groups 1 and 2 included previously untreated patients ; group 1 received 250 mg of ABT-450 and 100 mg of ritonavir , and group 2 received 150 mg and 100 mg , respectively . Group 3 , which included patients who had had a null or partial response to previous therapy with peginterferon and ribavirin , received daily doses of 150 mg of ABT-450 and 100 mg of ritonavir . The primary end point was an undetectable level of HCV RNA from week 4 through week 12 ( extended rapid virologic response ) . RESULTS A total of 17 of the 19 patients in group 1 ( 89 % ) and 11 of the 14 in group 2 ( 79 % ) had an extended rapid virologic response ; a sustained virologic response 12 weeks after the end of treatment was achieved in 95 % and 93 % of the patients , respectively . In group 3 , 10 of 17 patients ( 59 % ) had an extended rapid virologic response , and 8 ( 47 % ) had a sustained virologic response 12 weeks after therapy ; 6 patients had virologic breakthrough , and 3 had a relapse . Adverse events included abnormalities in liver-function tests , fatigue , nausea , headache , dizziness , insomnia , pruritus , rash , and vomiting . CONCLUSIONS This preliminary study suggests that 12 weeks of therapy with a combination of a protease inhibitor , a nonnucleoside polymerase inhibitor , and ribavirin may be effective for treatment of HCV genotype 1 infection . ( Funded by Abbott ; Clinical Trials.gov number , NCT01306617 . ) UNLABELLED In a sentinel cohort , hepatitis C virus ( HCV ) patients ( primarily genotype [ GT ] 1a ) were treated with daclatasvir ( NS5A inhibitor ) and asunaprevir ( NS3 protease inhibitor ) . Preexistence , emergence , and persistence of resistance variants in patients who failed this treatment are described . HCV-infected null responders received daclatasvir ( 60 mg once daily ) and asunaprevir ( 600 mg twice daily ) alone ( Group A , 11 patients ) or with peginterferon alfa-2a and ribavirin  ( Group B , 10 patients ) for 24 weeks . Resistance testing was performed on baseline sample s and sample s with HCV RNA ≥1,000 IU/mL at Week 1 through posttreatment Week 48 . Resistance substitution susceptibility to inhibition by asunaprevir and daclatasvir was assessed using HCV replicon assays . In Group A , six GT1a patients experiencing viral breakthrough and one GT1a patient who relapsed had detectable NS5A ( Q30E/R , L31V/M , Y93C/N ) and NS3 ( R155 K , D168A/E/V/Y ) resistance-associated variants at failure . Two of six viral breakthrough patients achieved SVR48 after treatment intensification with peginterferon alfa-2a and ribavirin . For 2/4 viral breakthrough patients not responding to treatment intensification , NS3 resistance variants changed ( D168Y to D168 T ; R155 K to V36M-R155 K ) . At posttreatment Week 48 , daclatasvir-resistant  variants persisted while asunaprevir-resistant variants were generally replaced by wild-type sequences . The NS3 sequence remained unchanged in the one patient with NS3-R155 K at baseline , relapse , and posttreatment Week 48 . In Group B , no viral breakthrough was observed . CONCLUSION The treatment failure of daclatasvir and asunaprevir in HCV GT1a patients was associated with both NS5A and NS3 resistance variants in prior null responders . NS5A resistance variants persisted while NS3 resistance variants generally decayed , suggesting a higher relative fitness of NS5A variants 
    Output:
    
By comparing substrate structural motifs and active site interactions with inhibitor recognition , we observed that the selection of drug resistance mutations correlates with how inhibitors deviate from viral substrates in molecular recognition .
Based on this observation , we conclude that guiding the design process with native substrate recognition features is likely to lead to more robust small molecule inhibitors with decreased susceptibility to resistance