Janice Wahl

Grazoprevir plus elbasvir in treatment-naive and treatment-experienced patients with hepatitis C virus genotype 1 infection and stage 4–5 chronic kidney disease (the C-SURFER study): a combination phase 3 study

BACKGROUND Chronic hepatitis C virus (HCV) infection in patients with stage 4-5 chronic kidney disease increases the risk of death and renal graft failure, yet patients with hepatitis C and chronic kidney disease have few treatment options. This study assesses an all-oral, ribavirin-free regimen in patients with HCV genotype 1 infection and stage 4-5 chronic kidney disease. METHODS In this phase 3 randomised study of safety and observational study of efficacy, patients with HCV genotype 1 infection and chronic kidney disease (stage 4-5 with or without haemodialysis dependence) were randomly assigned to receive grazoprevir (100 mg, NS3/4A protease inhibitor) and elbasvir (50 mg, NS5A inhibitor; immediate treatment group) or placebo (deferred treatment group) once daily for 12 weeks. Randomisation was done centrally with an interactive voice response system. An additional cohort of patients who were not randomised received the same regimen open-label and underwent intensive pharmacokinetic sampling. The primary efficacy outcome was a non-randomised comparison of sustained virological response at 12 weeks (SVR12) after the end of therapy for the combined immediate treatment group and the pharmacokinetic population with a historical control. The primary safety outcome was a randomised comparison between the immediate treatment group and the deferred treatment group. After 4 weeks of follow-up (study week 16), unmasking occurred and patients in the deferred treatment group received grazoprevir and elbasvir. The primary efficacy hypothesis was tested at a two-sided significance level (type I error) of 0·05 using an exact test for a binomial proportion. Safety event rates were compared between immediate treatment and deferred treatment groups using the stratified Miettinen and Nurminen method with baseline dialysis status as the strata. The study is registered at ClinicalTrials.gov, number NCT02092350. FINDINGS 224 patients were randomly assigned to the immediate treatment group with grazoprevir and elbasvir (n=111) or the deferred treatment group (n=113), and 11 were assigned to the intensive pharmacokinetic population. Overall, 179 (76%) were haemodialysis-dependent, 122 (52%) had HCV genotype 1a infection, 189 (80%) were HCV treatment-naive, 14 (6%) were cirrhotic, and 108 (46%) were African American. Of the 122 patients receiving grazoprevir and elbasvir, six were excluded from the primary efficacy analysis for non-virological reasons (death, lost-to-follow-up [n=2], non-compliance, patient withdrawal, and withdrawal by physician for violent behaviour). No patients in the combined immediate treatment group and intensive pharmacokinetic population and five (4%) in the deferred treatment group discontinued because of an adverse event. Most common adverse events were headache, nausea, and fatigue, occurring at similar frequencies in patients receiving active and placebo drugs. SVR12 in the combined immediate treatment group and intensive pharmacokinetic population was 99% (95% CI 95·3-100·0; 115/116), with one relapse 12 weeks after end of treatment when compared with a historical control of 45%, based on meta-analyses of interferon-based regimens used in clinical trials of patients infected with HCV who are on haemodialysis. INTERPRETATION Once-daily grazoprevir and elbasvir for 12 weeks had a low rate of adverse events and was effective in patients infected with HCV genotype 1 and stage 4-5 chronic kidney disease. FUNDING Merck Sharp & Dohme Corp.

Grazoprevir–Elbasvir Combination Therapy for Treatment-Naive Cirrhotic and Noncirrhotic Patients With Chronic Hepatitis C Virus Genotype 1, 4, or 6 Infection: A Randomized Trial

Context Various oral interferon- and ribavirin-free regimens are becoming available to treat chronic hepatitis C virus (HCV) infection. A grazoprevirelbasvir combination regimen has shown promise in phase 2 trials. Contribution This phase 3 trial found a once-daily grazoprevirelbasvir regimen to be effective and well-tolerated in patients with HCV genotype 1, 4, or 6 infection. Outcomes were similar in patients with and without cirrhosis. Caution The study did not include an active comparator, so how this regimen compares with others is unknown. Implication Grazoprevirelbasvir represents a new therapeutic option for chronic HCV infection. Chronic hepatitis C virus (HCV) infection remains a growing cause of cirrhosis, hepatocellular carcinoma, hepatic decompensation, and liver transplantation (1). Effective therapy for HCV infection diminishes long-term liver-related complications and mortality (2). Convenient, oral, direct-acting antiviral regimens are being investigated for chronic HCV infection (3). Grazoprevir is an NS3/4A protease inhibitor that has high potency in vitro against HCV genotype (GT) 1, GT2, GT4, GT5, and GT6 but is less active against GT3 (4). Grazoprevir retains substantial activity against resistance-associated variants (RAVs) commonly detected after failed therapy with first-generation protease inhibitors (4, 5). Elbasvir is an NS5A inhibitor active against GT1, GT2a, GT3, GT4, GT5, and GT6, even in the presence of RAVs associated with failure of other NS5A inhibitors, such as daclatasvir and ledipasvir (6, 7). Grazoprevirelbasvir has been evaluated in an extensive phase 2 clinical development program (5, 810). The C-WORTHY study indicated that grazoprevirelbasvir with or without ribavirin for 12 weeks provided efficacious and well-tolerated therapy for monoinfected and HIVco-infected patients, treatment-naive and treatment-experienced patients, and noncirrhotic and cirrhotic patients (9, 10). The objective of the phase 3 C-EDGE Treatment-Naive trial was to evaluate the efficacy and safety profile of a once-daily, fixed-dose, oral, 12-week regimen of grazoprevirelbasvir without interferon or ribavirin in treatment-naive monoinfected patients with and without cirrhosis and with GT1, GT4, or GT6 infection. Methods Study Design The C-EDGE Treatment-Naive study was an international, randomized, blinded, placebo-controlled, parallel-group trial of a fixed-dose combination of grazoprevir 100 mg/elbasvir 50 mg for treatment-naive cirrhotic and noncirrhotic patients with chronic HCV GT1, GT4, or GT6 infections. A historical SVR12 rate was used as the comparator for efficacy. A deferred-treatment group was included as a concurrent placebo group to assess safety; after the follow-up period, placebo recipients received open-label grazoprevirelbasvir so that all participants would receive therapy during the study. Recruitment of Study Participants Patients were recruited from general medical clinics at 60 trial centers: 4 in Australia, 4 in the Czech Republic, 5 in France, 5 in Germany, 5 in Israel, 3 in Puerto Rico, 3 in South Korea, 4 in Sweden, 3 in Taiwan, and 24 in the United States. Patients who fulfilled inclusion criteria were asked to participate in the trial. Selected clinical sites were experienced in the management and care of HCV-infected patients, with a history of successful study conduct and the capability for rapid enrollment. Sites were chosen to allow a wide geographic distribution and to ensure that requirements for minority representation, enrollment of patients with cirrhosis, and genotype distribution were met. Eligibility Criteria Adults (aged >18 years) with HCV RNA levels greater than 104 IU/mL were eligible. Hepatic fibrosis was staged by biopsy or noninvasive assessment (Appendix 1) (11). Exclusion criteria were decompensated liver disease, hepatocellular carcinoma, HIV or hepatitis B virus co-infection, uncontrolled diabetes mellitus (hemoglobin A1c level >10%), elevated prothrombin time unrelated to anticoagulation, creatinine clearance less than 50 mL/min, hemoglobin level less than 95 g/L, thrombocytopenia (platelet count <50109 cells/L), aminotransferase levels more than 10 times the upper limit of normal, or hypoalbuminemia (albumin level <30 g/L). Enrollment was constrained to meet the following targets: 20% of the participants having cirrhosis and 15% having GT4 or GT6 infection. All participants provided written informed consent. The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. Independent ethics committees reviewed and approved the protocol and applicable amendments for each institution. Randomization and Masking After stratification by presence or absence of cirrhosis and GT1, GT4, or GT6, patients were randomly assigned in a 3:1 ratio to receive immediate or deferred therapy with grazoprevirelbasvir through a central interactive voice-response system according to a computer-generated random allocation schedule. Patients took 1 fixed-dose combination tablet of grazoprevirelbasvir (immediate-treatment group) or matching placebo (deferred-treatment group) once daily at approximately the same time, without regard to food, for 12 weeks. Patients, clinical site, and sponsor personnel were blinded to treatment assignment (except for a separate unblinded medical team that monitored virologic failures and serious adverse events). Four weeks after completion of therapy, treatment allocation was unblinded, and patients in the deferred-treatment group then received open-label grazoprevirelbasvir for 12 weeks. All patients were to be followed for 24 weeks after cessation of active study therapy (Figure 1). Figure 1. Diagram of study design. DFW = deferred follow-up week; DTW = deferred-treatment week; FU = follow-up; FW = follow-up week; GZREBR = grazoprevirelbasvir; TW = treatment week. Outcome Measures This report describes the efficacy among patients enrolled in the immediate-treatment group through 12 weeks after treatment and the safety findings among patients enrolled in both groups through 14 days after the end of therapy in the initial treatment period. Efficacy and safety results for both groups through follow-up week 24 are still being collected and will be presented in a future report. The primary efficacy outcome variable was the proportion of patients in the immediate-treatment group achieving unquantifiable HCV RNA 12 weeks after the end of study treatment (SVR12). Virologic failures encompassed breakthrough viremia (confirmed HCV RNA level at or above the lower limit of quantification [LLOQ] during treatment after previously being below the LLOQ) and relapse (confirmed HCV RNA level at or above the LLOQ subsequent to cessation of study therapy after becoming undetectable at the end of treatment). Viral and Resistance Assays Plasma HCV RNA levels were measured by the COBAS AmpliPrep/COBAS TaqMan HCV test, version 2.0 (Roche Molecular Diagnostics, Branchburg, NJ), with an LLOQ of 15 IU/mL. Specimens for viral load measurements were collected at screening; baseline; treatment weeks 4, 8, and 12; and follow-up weeks 4, 12, and 24. Circulating viral quasi-species at baseline or at the time of virologic failure underwent population sequencing with a detection limit for variants of approximately 25% prevalence (12). The complete NS3 and NS5A genes were amplified from samples with RNA levels of 1000 IU/mL or greater by using reverse transcription polymerase chain reaction (5, 12, 13). Resultant amino acid sequences were compared with wild-type GT1a (H77; accession number NC004102), GT1b (Con1; AJ238799), GT4a (ED43; GU814265), or GT6a (EUHK2; Y12083) reference sequences. To assess the effect of baseline NS3 variants, specific amino acid loci prone to selection by early-generation NS3/4A protease inhibitors (positions 36, 54, 55, 56, 80, 107, 122, 132, 155, 156, 158, 168, 170, and 175) were studied in replicon cell lines encoding mutations in a GT1a backbone (5, 14). These substitutions were categorized according to whether they conferred a greater than 5-fold reduced susceptibility to grazoprevir. Likewise, to assess the effect of baseline NS5A variants, amino acid loci selected by NS5A inhibitors (positions 28, 30, 31, 58, and 93) were categorized according to whether they conferred a greater than 5-fold reduced susceptibility to elbasvir in the replicon assay. Statistical Analysis The C-EDGE Treatment-Naive study was designed to randomly assign approximately 400 patients, with 300 patients in the immediate-treatment group and 100 patients in the deferred-treatment group (which served as the placebo control group for the first 12 weeks). After a 4-week follow-up period, placebo recipients were unblinded at study week 16 and received open-label grazoprevirelbasvir. The primary efficacy hypothesis exclusively applied to patients in the immediate-treatment group. Assuming a response rate of 85% or greater, the study had more than 99% power to demonstrate an SVR12 rate superior to the reference rate of 73% at an overall 1-sided value of 0.025. The historical reference rate of 73% was derived from phase 3 trials of simeprevir/peginterferon + ribavirin in treatment-naive monoinfected patients, after adjustment for the expected proportion of cirrhotic patients and the anticipated improved tolerability with an interferon-free regimen (Appendix 1) (15, 16). The primary efficacy and safety analyses were performed on the full data set, which included all patients receiving at least 1 dose of the study treatment. The primary efficacy end point was prespecified as the proportion of patients with an HCV RNA level below the LLOQ 12 weeks after the end of treatment (SVR12) (17). Missing outcome data were imputed as failures unless the values immediately before and after the missing result were both successes, in which case the absent value was imputed as a success. The 95% CIs were computed by the conservative ClopperPear

Boceprevir versus placebo with pegylated interferon alfa-2b and ribavirin for treatment of hepatitis C virus genotype 1 in patients with HIV: a randomised, double-blind, controlled phase 2 trial.

BACKGROUND Rates of sustained virological response (SVR) to peginterferon-ribavirin are low in patients with hepatitis C virus (HCV) genotype 1 and HIV. We aimed to assess efficacy and safety of triple therapy with boceprevir plus pegylated interferon alfa-2b (peginterferon) and ribavirin, which increases rates of SVR in patients with HCV alone. METHODS In our double-blind, randomised controlled phase 2 trial, we enrolled adults (18-65 years) with untreated HCV genotype 1 infection and controlled HIV (HIV RNA <50 copies per mL) at 30 academic and non-academic study sites. We randomly allocated patients (1:2) according to a computer generated sequence, stratified by Metavir score and baseline HCV RNA level, to receive peginterferon 1·5 μg/kg per week with weight-based ribavirin (600-1400 mg per day) for 4 weeks, followed by peginterferon-ribavirin plus either placebo (control group) or 800 mg boceprevir three times per day (boceprevir group) for 44 weeks. Non-nucleoside reverse-transcriptase inhibitors, zidovudine, and didanosine were not permitted. The primary efficacy endpoint was SVR (defined as undetectable plasma HCV RNA) at follow-up week 24 after end of treatment. We assessed efficacy and safety in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT00959699. FINDINGS From Jan 15, 2010, to Dec 29, 2010, we enrolled 99 patients, 98 of whom received at least one treatment dose. 40 (63%) of 64 patients in the boceprevir group had an SVR at follow-up week 24, compared with ten (29%) of 34 control patients (difference 33·1%, 95% CI 13·7-52·5; p=0·0008). Adverse events were more common in patients who received boceprevir than in control patients: 26 (41%) versus nine (26%) had anaemia, 23 (36%) versus seven (21%) pyrexia, 22 (34%) versus six (18%) decreased appetite, 18 (28%) versus five (15%) dysgeusia, 18 (28%) versus five (15%) vomiting, and 12 (19%) versus two (6%) neutropenia. Three patients who received boceprevir plus peginterferon-ribavirin and four controls had HIV virological breakthrough. INTERPRETATION Boceprevir in combination with peginterferon-ribavirin could be an important therapeutic option for patients with HCV and HIV. FUNDING Merck.

Efficacy and safety of grazoprevir (MK-5172) and elbasvir (MK-8742) in patients with hepatitis C virus and HIV co-infection (C-EDGE CO-INFECTION): a non-randomised, open-label trial

BACKGROUND Hepatitis C virus (HCV) infection is a leading cause of morbidity and mortality in patients with HIV-1. The C-EDGE CO-INFECTION study assessed the efficacy, safety, and tolerability of grazoprevir (MK-5172) plus elbasvir (MK-8742) in patients with HCV and HIV co-infection. METHODS In this uncontrolled, non-randomised, phase 3, open-label, single-arm study, treatment-naive patients with chronic HCV genotype 1, 4, or 6 infection and HIV co-infection, with or without cirrhosis, were enrolled from 37 centres in nine countries across Europe, the USA, and Australia. Patients were either naive to treatment with any antiretroviral therapy (ART) or stable on ART for at least 8 weeks. All patients received grazoprevir 100 mg plus elbasvir 50 mg in a fixed-dose combination tablet once daily for 12 weeks. The primary endpoint was sustained virological response (HCV RNA <15 IU/mL) 12 weeks after the end of therapy (SVR12). The primary population for efficacy analyses was all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, number NCT02105662. FINDINGS Between June 11, 2014, and Aug 29, 2014, 218 patients were enrolled and received grazoprevir plus elbasvir for 12 weeks, all of whom completed follow-up at week 12. SVR12 was achieved by 210 (96%) of 218 patients (95% CI 92·9-98·4). One patient did not achieve SVR12 because of a non-virological reason, and seven patients without cirrhosis relapsed (two subsequently confirmed as reinfections). All 35 patients with cirrhosis achieved SVR12. The most common adverse events were fatigue (29; 13%), headache (27; 12%), and nausea (20; 9%). No patient discontinued treatment because of an adverse event. Two patients receiving ART had transient HIV viraemia. INTERPRETATION This HCV treatment regimen seems to be effective and well tolerated for patients co-infected with HIV with or without cirrhosis. These data are consistent with previous trials of this regimen in the monoinfected population. This regimen continues to be studied in phase 3 trials. FUNDING Merck Sharp & Dohme Corp.

Elbasvir-grazoprevir to treat hepatitis C virus infection in persons receiving opioid agonist therapy a randomized trial

Background Hepatitis C virus (HCV) infection is common in persons who inject drugs (PWID). Objective To evaluate elbasvir-grazoprevir in treating HCV infection in PWID. Design Randomized, placebo-controlled, double-blind trial. (ClinicalTrials.gov: NCT02105688). Setting Australia, Canada, France, Germany, Israel, the Netherlands, New Zealand, Norway, Spain, Taiwan, the United Kingdom, and the United States. Patients 301 treatment-naive patients with chronic HCV genotype 1, 4, or 6 infection who were at least 80% adherent to visits for opioid agonist therapy (OAT). Intervention The immediate-treatment group (ITG) received elbasvir-grazoprevir for 12 weeks; the deferred-treatment group (DTG) received placebo for 12 weeks, no treatment for 4 weeks, then open-label elbasvir-grazoprevir for 12 weeks. Measurements The primary outcome was sustained virologic response at 12 weeks (SVR12), evaluated separately in the ITG and DTG. Other outcomes included SVR24, viral recurrence or reinfection, and adverse events. Results The SVR12 was 91.5% (95% CI, 86.8% to 95.0%) in the ITG and 89.5% (95% CI, 81.5% to 94.8%) in the active phase of the DTG. Drug use at baseline and during treatment did not affect SVR12 or adherence to HCV therapy. Among 18 patients with posttreatment viral recurrence through 24-week follow-up, 6 had probable reinfection. If the probable reinfections were assumed to be responses, SVR12 was 94.0% (CI, 89.8% to 96.9%) in the ITG. One patient in the ITG (1 of 201) and 1 in the placebo-phase DTG (1 of 100) discontinued treatment because of an adverse event. Limitation These findings may not be generalizable to PWID who are not receiving OAT, nor do they apply to persons with genotype 3 infection, a common strain in PWID. Conclusion Patients with HCV infection who were receiving OAT and treated with elbasvir-grazoprevir had high rates of SVR12, regardless of ongoing drug use. These results support the removal of drug use as a barrier to interferon-free HCV treatment for patients receiving OAT. Primary Funding Source Merck & Co.

Grazoprevir and elbasvir plus ribavirin for chronic HCV genotype-1 infection after failure of combination therapy containing a direct-acting antiviral agent

BACKGROUND & AIMS The Phase-2 C-SALVAGE study evaluated an investigational interferon-free combination of grazoprevir (a NS3/4A protease inhibitor) and elbasvir (a NS5A inhibitor) with ribavirin for patients with chronic HCV genotype-1 infection who had failed licensed DAA-containing therapy. METHODS C-SALVAGE was an open-label study of grazoprevir 100 mg and elbasvir 50 mg QD with weight-based ribavirin BID for 12 weeks in cirrhotic and non-cirrhotic patients with chronic HCV genotype-1 infection who had not attained SVR after ⩾4 weeks of peginterferon and ribavirin plus either boceprevir, telaprevir, or simeprevir. Exclusion criteria included decompensated liver disease, hepatocellular carcinoma, and HIV or HBV co-infection. The primary efficacy outcome was SVR12 defined as a HCV RNA level below the assay limit of quantification 12 weeks after the end of treatment. RESULTS Of the 79 patients treated with ⩾1 dose of study drug, 66 (84%) patients had a history of virologic failure on a regimen containing a NS3/4A protease inhibitor; 12 of the other 13 patients discontinued prior treatment because of adverse experiences. At entry, 34 (43.6%) of 78 evaluable patients harbored NS3 RAVs. SVR12 rates were 76/79 (96.2%) overall, including 28/30 (93.3%) patients with genotype 1a infection, 63/66 (95.5%) patients with prior virologic failure, 43/43 (100%) patients without baseline RAVs, 31/34 (91.2%) patients with baseline NS3 RAVs, 6/8 (75.0%) patients with baseline NS5A RAVs, 4/6 (66.7%) patients with both baseline NS3 and RAVs, and 32/34 (94.1%) cirrhotic patients. None of the five reported serious adverse events were considered drug-related. CONCLUSIONS Grazoprevir and elbasvir plus ribavirin for 12 weeks provides a promising new treatment option for patients after failure of triple therapy containing an earlier-generation protease inhibitor.

Grazoprevir, Elbasvir, and Ribavirin for Chronic Hepatitis C Virus Genotype 1 Infection After Failure of Pegylated Interferon and Ribavirin With an Earlier-Generation Protease Inhibitor: Final 24-Week Results From C-SALVAGE

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 prospective 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_A156T 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.

11 SUSTAINED VIROLOGIC RESPONSE (SVR) IN PRIOR PEGINTERFERON/RIBAVIRIN (PR) TREATMENT FAILURES AFTER RETREATMENT WITH BOCEPREVIR (BOC)-+-PR: THE PROVIDE STUDY INTERIM RESULTS

1University Henri Poincare of Nancy, Vandoeuvre-les-Nancy, France; 2South Florida Center of Gastroenterology, Wellington, FL; 3Northwestern Feinberg School of Medicine, Chicago, IL; 4Henry Ford Hospital, Detroit, MI; 5Alamo Medical Research, San Antonio, TX; 6University of British Columbia and Vancouver General Hospital, Vancouver, BC, Canada; 7Liver Specialists of Texas, Houston, TX; 8Virginia Commonwealth University School of Medicine, Richmond, VA; 9Mt. Vernon Endoscopy Center, Alexandria, VA; 10Weill Cornell Medical College, New York, NY; 11Universite Denis Diderot-Paris, Paris; 12Hopital Beaujon, Clichy, France; 13Duke University School of Medicine, Durham, NC; 14Cedars-Sinai Medical Center, Los Angeles, CA; 15Merck Sharp & Dohme Corp, Whitehouse Station, NJ; 16Baylor College of Medicine, Houston, TX

Boceprevir for chronic HCV genotype 1 infection in patients with prior treatment failure to peginterferon/ribavirin, including prior null response

BACKGROUND & AIMS Boceprevir with peginterferon/ribavirin (BOC/PR) leads to significantly higher sustained virological response (SVR) rates in patients with chronic hepatitis C and partial response or relapse after prior treatment with peginterferon/ribavirin. We studied the efficacy of BOC/PR in patients with prior treatment failure, including those with a null response (<2-log10 decline in HCV RNA), to peginterferon/ribavirin. METHODS Patients in the control arms of boceprevir Phase 2/3 studies who did not achieve SVR were re-treated with BOC/PR for up to 44 weeks. Patients enrolling >2 weeks after end-of-treatment in the prior study received PR for 4 weeks before adding boceprevir. RESULTS Of 168 patients enrolled, four discontinued from the PR lead-in and 164 received BOC/PR. Baseline viral load was >800,000 IU/ml in 77% of patients; 62% had HCV genotype 1a, and 10% were cirrhotic. In the ITT analysis (all 168 patients), SVR was achieved in 20 (38%) of 52 patients with prior null response, 57 (67%) of 85 with prior partial response, and 27 (93%) of 29 with prior relapse. In the mITT analysis (164 BOC/PR-treated patients), SVR rates were 41% (20/49), 67% (57/85), and 96% (27/28), respectively. SVR was achieved by 48% of patients with <1-log10 decline in HCV-RNA after lead-in and 76% of those with ⩾ 1-log10 decline or undetectable HCV-RNA after lead-in. The most common adverse events were anemia (49%), fatigue (48%), and dysgeusia (35%); 8% of patients discontinued due to adverse events. CONCLUSIONS Re-treatment with BOC/PR improved SVR rates in all patient subgroups, including those with prior null response.

O006 : C-swift: grazoprevir/elbasvir + sofosbuvir in cirrhotic and noncirrhotic, treatment-naive patients with hepatitis C virus genotype 1 infection, for durations of 4, 6 or 8 weeks and genotype 3 infection for durations of 8 or 12 weeks

O005 RETREATMENT OF PATIENTS WHO FAILED 8 OR 12 WEEKS OF LEDIPASVIR/SOFOSBUVIR-BASED REGIMENS WITH LEDIPASVIR/SOFOSBUVIR FOR 24 WEEKS E. Lawitz, S. Flamm, J.C. Yang, P.S. Pang, Y. Zhu, E. Svarovskaia, J.G. McHutchison, D. Wyles, P. Pockros. Texas Liver Institute, University of Texas Health Science Center, San Antonio, TX, Feinberg School of Medicine, Northwestern University, Chicago, IL, Gilead Sciences, Foster City, CA, University of California, San Diego, CA, Scripps Clinic, La Jolla, CA, United States E-mail: jenny.yang@gilead.com