Paul J. Pockros

Peginterferon-alpha2a and ribavirin combination therapy in chronic hepatitis C: a randomized study of treatment duration and ribavirin dose

BACKGROUND Treatment with pegylated interferon (peginterferon) and ribavirin for 48 weeks is more effective than conventional interferon and ribavirin in patients with chronic hepatitis C. OBJECTIVE To assess the efficacy and safety of 24 or 48 weeks of treatment with peginterferon-alpha2a plus a low or standard dose of ribavirin. DESIGN Randomized, double-blind trial. SETTING 99 international centers. PATIENTS 1311 patients with chronic hepatitis C. INTERVENTION Peginterferon-alpha2a, 180 microg/wk, for 24 or 48 weeks plus a low-dose (800 mg/d) or standard weight-based dose (1000 or 1200 mg/d) of ribavirin. MEASUREMENT Sustained virologic response: undetectable HCV RNA concentration at the end of treatment and during 12 to 24 weeks of follow-up. RESULTS Overall and in patients infected with HCV genotype 1, 48 weeks of treatment was statistically superior to 24 weeks and standard-dose ribavirin was statistically superior to low-dose ribavirin. In patients with HCV genotype 1, absolute differences in sustained virologic response rates between 48 and 24 weeks of treatment were 11.2% (95% CI, 3.6% to 18.9%) and 11.9% (CI, 4.7% to 18.9%), respectively, between standard- and low-dose ribavirin. Sustained virologic response rates for peginterferon-alpha2a and standard-dose ribavirin for 48 weeks were 63% (CI, 59% to 68%) overall and 52% (CI, 46% to 58%) in patients with HCV genotype 1. In patients with HCV genotypes 2 or 3, the sustained virologic response rates in the 4 treatment groups were not statistically significantly different. CONCLUSION Treatment with peginterferon-alpha2a and ribavirin may be individualized by genotype. Patients with HCV genotype 1 require treatment for 48 weeks and a standard dose of ribavirin; those with HCV genotypes 2 or 3 seem to be adequately treated with a low dose of ribavirin for 24 weeks.

Telaprevir for retreatment of HCV infection.

BACKGROUND Up to 60% of patients with hepatitis C virus (HCV) genotype 1 infection do not have a sustained virologic response to therapy with peginterferon alfa plus ribavirin. METHODS In this randomized, phase 3 trial, we evaluated the addition of telaprevir to peginterferon alfa-2a plus ribavirin in patients with HCV genotype 1 infection who had no response or a partial response to previous therapy or who had a relapse after an initial response. A total of 663 patients were assigned to one of three groups: the T12PR48 group, which received telaprevir for 12 weeks and peginterferon plus ribavirin for a total of 48 weeks; the lead-in T12PR48 group, which received 4 weeks of peginterferon plus ribavirin followed by 12 weeks of telaprevir and peginterferon plus ribavirin for a total of 48 weeks; and the control group (PR48), which received peginterferon plus ribavirin for 48 weeks. The primary end point was the rate of sustained virologic response, which was defined as undetectable HCV RNA 24 weeks after the last planned dose of a study drug. RESULTS Rates of sustained virologic response were significantly higher in the two telaprevir groups than in the control group among patients who had a previous relapse (83% in the T12PR48 group, 88% in the lead-in T12PR48 group, and 24% in the PR48 group), a partial response (59%, 54%, and 15%, respectively), and no response (29%, 33%, and 5%, respectively) (P<0.001 for all comparisons). Grade 3 adverse events (mainly anemia, neutropenia, and leukopenia) were more frequent in the telaprevir groups than in the control group (37% vs. 22%). CONCLUSIONS Telaprevir combined with peginterferon plus ribavirin significantly improved rates of sustained virologic response in patients with previously treated HCV infection, regardless of whether there was a lead-in phase. (Funded by Tibotec and Vertex Pharmaceuticals; REALIZE ClinicalTrials.gov number, NCT00703118.).

Ledipasvir and sofosbuvir for previously treated HCV genotype 1 infection

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, randomized, 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 randomly 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 randomization 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 resulted 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 ClinicalTrials.gov number, NCT01768286.).

Ledipasvir and Sofosbuvir for 8 or 12 Weeks for Chronic HCV without Cirrhosis

BACKGROUND 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. METHODS 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. RESULTS 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. CONCLUSIONS 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.).

Simeprevir plus sofosbuvir, with or without ribavirin, to treat chronic infection with hepatitis C virus genotype 1 in non-responders to pegylated interferon and ribavirin and treatment-naive patients: the COSMOS randomised study

BACKGROUND Interferon-free regimens are needed to treat hepatitis C virus (HCV) infections. We investigated the efficacy of combined simeprevir and sofosbuvir. METHODS We enrolled patients with chronic HCV genotype 1 infections who had previously not responded to pegylated interferon (peginterferon) and ribavirin or were treatment naive. Patients were randomly assigned in a 2:1:2:1 ratio to receive 150 mg simeprevir and 400 mg sofosbuvir daily for 24 weeks with (group 1) or without (group 2) ribavirin or for 12 weeks with (group 3) or without (group 4) ribavirin, in two cohorts: previous non-responders with METAVIR scores F0-F2 (cohort 1) and previous non-responders and treatment-naive patients with METAVIR scores F3-F4 (cohort 2). The primary endpoint was sustained virological response 12 weeks after stopping treatment (SVR12). Analysis was done by intention to treat. Safety data from cohorts 1 and 2 were pooled for analysis. This study is registered with ClinicalTrials.gov, number NCT01466790. FINDINGS 168 patients were enrolled and randomised, and 167 started treatment (n=80 in cohort 1 and n=87 in cohort 2). SVR12 was achieved in 154 (92%) patients (n=72 [90%, 95% CI 81-96] in cohort 1 and n=82 [94%, 87-98] in cohort 2). The most common adverse events in the pooled groups were fatigue (n=52 [31%]), headache (n=33 [20%]), and nausea (n=26 [16%]). Grade 4 adverse events were seen in one (2%) of 54 patients in each of groups 1 and 3 and in three (10%) of 31 patients in group 2, whereas grade 3-4 events were reported in less than 5% of all patients, except increased blood amylase concentration. Serious adverse events were seen in four (2%) patients, all in groups 1 and 2. Four (2%) patients discontinued all study treatment because of adverse events, three before week 12. INTERPRETATION Combined simeprevir and sofosbuvir was efficacious and well tolerated. FUNDING Janssen.

Early identification of HCV genotype 1 patients responding to 24 weeks peginterferon α-2a (40 kd)/ribavirin therapy†‡§

Approximately one third of hepatitis C virus (HCV) genotype 1 patients achieved a sustained virological response (SVR) after 24 weeks of treatment with peginterferon α‐2a (40 kd) plus ribavirin in a randomized, multinational trial. We aimed to identify factors associated with a rapid virological response (RVR) at week 4 (HCV RNA <50 IU/mL) and a SVR (HCV RNA <50 IU/mL at the end of follow‐up) in these patients. Stepwise multiple logistic regression analysis was used to explore the prognostic factors for a RVR and SVR in genotype 1 patients treated for 24 weeks. Fifty‐one of 216 (24%) genotype 1 patients in the 24‐week treatment groups had a RVR. SVR rates were considerably higher in patients with than without a RVR (89% vs. 19%, respectively). Patients with a baseline HCV RNA of less than 200,000 IU/mL (OR 9.7, 95% CI 4.2‐22.5; P < .0001) or 200,000‐600,000 IU/mL (OR 3.6, 95% CI 1.5‐9.1; P = .0057) were more likely to achieve a RVR than those with HCV RNA greater than 600,000 IU/mL. HCV subtype (1b vs. 1a) was also independently associated with RVR (OR 1.8, 95% CI 0.9‐3.7; P = .0954). RVR (OR 23.7 vs. no RVR, 95% CI 9.1‐61.7) and baseline HCV RNA less than 200,000 IU/mL (OR 2.7 vs. >600,000 IU/mL, 95% CI 1.1‐6.3; P < .026) were significant and independent predictors of SVR in patients treated for 24 weeks. In conclusion, patients infected with HCV genotype 1 and treated with peginterferon α‐2a/ribavirin sustained a RVR 24% of the time. This portends an 89% probability of a SVR after 24 weeks of treatment. (HEPATOLOGY 2006;43:954–960.)

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; 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)

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

Effect of peginterferon alfa‐2a on liver histology in chronic hepatitis C: A meta‐analysis of individual patient data

Multicenter randomized trials have shown that once‐weekly pegylated interferon (peginterferon) alfa‐2a is more efficacious than conventional interferon alfa‐2a (IFN) in patients with chronic hepatitis C. We performed a meta‐analysis of 1,013 previously untreated patients (from 3 randomized trials) with pretreatment and post‐treatment liver biopsies to assess the differences between peginterferon alfa‐2a and IFN in terms of their effects on liver histology. Reported values were standardized mean differences (SMD) between patients receiving peginterferon alfa‐2a and those receiving IFN (post‐treatment value minus baseline value for each group). We used a random‐effects model to quantify the average effect of peginterferon alfa‐2a on liver histology. Peginterferon alfa‐2a significantly reduced fibrosis compared with IFN (SMD, −0.14; 95% CI: −0.27, −0.01; P = .04). A reduction in fibrosis was observed among sustained virologic responders (SMD, −0.59; 95% CI: −0.89, −0.30; P < .0001) and patients with recurrent disease (SMD, −0.34; 95% CI: −0.54, −0.14; P = .0007), whereas no significant reduction was observed among nonresponders (SMD, −0.13; 95% CI: −0.32, 0.05; P = .15). Logistic regression analysis indicated that patients with sustained virologic responses (SVRs) had an odds ratio (OR) of 1.61 (95% CI: 1.14, 2.29) for reduction in fibrosis compared with patients without SVRs, whereas obese patients (body mass index [BMI] > 30 kg/m2) had an OR of 0.56 (95% CI: 0.35, 0.90) compared with normal‐weight (BMI < 25 kg/m2) and overweight patients (BMI, 25–30 kg/m2). In conclusion, in patients with chronic hepatitis C with or without cirrhosis, peginterferon alfa‐2a (relative to IFN) significantly reduced fibrosis. The beneficial effects of peginterferon on liver histology are closely related to virologic response. (HEPATOLOGY 2004;39:333–342.)

Simeprevir Increases Rate of Sustained Virologic Response Among Treatment-Experienced Patients With HCV Genotype-1 Infection: A Phase IIb Trial

BACKGROUND & AIMS Simeprevir (TMC435) is an oral NS3/4 protease inhibitor in phase III trials for chronic hepatitis C virus (HCV) infection. We performed a phase IIb, randomized, double-blind, placebo-controlled trial to evaluate the efficacy and safety of the combination of simeprevir, peginterferon-α2a (PegIFN), and ribavirin (RBV) in patients with HCV genotype-1 infection previously treated with PegIFN and RBV. METHODS We analyzed data from patients who did not respond (null response), had a partial response, or relapsed after treatment with PegIFN and RBV, randomly assigned to receive simeprevir (100 or 150 mg, once daily) for 12, 24, or 48 weeks plus PegIFN and RBV for 48 weeks (n = 396), or placebo plus PegIFN and RBV for 48 weeks (n = 66). All patients were followed for 24 weeks after planned end of treatment; the primary end point was the proportion of patients with sustained virologic response (SVR; undetectable HCV RNA) at that time point. RESULTS Overall, rates of SVR at 24 weeks were significantly higher in the groups given simeprevir than those given placebo (61%-80% vs 23%; P < .001), regardless of prior response to PegIFN and RBV (simeprevir vs placebo: prior null response, 38%-59% vs 19%; prior partial response, 48%-86% vs 9%; prior relapse, 77%-89% vs 37%). All groups had comparable numbers of adverse events; these led to discontinuation of simeprevir or placebo and/or PegIFN and RBV in 8.8% of patients given simeprevir and 4.5% of those given placebo. CONCLUSIONS In treatment-experienced patients, 12, 24, or 48 weeks simeprevir (100 mg or 150 mg once daily) in combination with 48 weeks PegIFN and RBV significantly increased rates of SVR at 24 weeks compared with patients given placebo, PegIFN, and RBV and was generally well tolerated. ClinicalTrials.gov number: NCT00980330.