Bulevirtide Combined with Pegylated Interferon for Chronic Hepatitis D.

BACKGROUND: In a phase 3 trial, bulevirtide monotherapy led to a virologic response in patients with chronic hepatitis D. Pegylated interferon (peginterferon) alfa-2a is recommended by guidelines as an off-label treatment for this disease. The role of combination therapy with bulevirtide and peginterferon alfa-2a, particularly with regard to finite treatment, is unclear. METHODS: In this phase 2b, open-label trial, we randomly assigned patients to receive peginterferon alfa-2a alone (180 µg per week) for 48 weeks; bulevirtide at a daily dose of 2 mg or 10 mg plus peginterferon alfa-2a (180 µg per week) for 48 weeks, followed by the same daily dose of bulevirtide for 48 weeks; or bulevirtide at a daily dose of 10 mg alone for 96 weeks. All the patients were followed for 48 weeks after the end of treatment. The primary end point was an undetectable level of hepatitis D virus (HDV) RNA at 24 weeks after the end of treatment. The primary comparison was between the 10-mg bulevirtide plus peginterferon alfa-2a group and the 10-mg bulevirtide monotherapy group. RESULTS: A total of 24 patients received peginterferon alfa-2a alone, 50 received 2 mg and 50 received 10 mg of bulevirtide plus peginterferon alfa-2a, and 50 received 10 mg of bulevirtide monotherapy. At 24 weeks after the end of treatment, HDV RNA was undetectable in 17% of the patients in the peginterferon alfa-2a group, in 32% of those in the 2-mg bulevirtide plus peginterferon alfa-2a group, in 46% of those in the 10-mg bulevirtide plus peginterferon alfa-2a group, and in 12% of those in the 10-mg bulevirtide group. For the primary comparison, the between-group difference was 34 percentage points (95% confidence interval, 15 to 50; P<0.001). At 48 weeks after the end of treatment, HDV RNA was undetectable in 25% of the patients in the peginterferon alfa-2a group, in 26% of those in the 2-mg bulevirtide plus peginterferon alfa-2a group, in 46% of those in the 10-mg bulevirtide plus peginterferon alfa-2a group, and in 12% of those in the 10-mg bulevirtide group. The most frequent adverse events were leukopenia, neutropenia, and thrombocytopenia. The majority of adverse events were of grade 1 or 2 in severity. CONCLUSIONS: The combination of 10-mg bulevirtide plus peginterferon alfa-2a was superior to bulevirtide monotherapy with regard to an undetectable HDV RNA level at 24 weeks after the end of treatment. (Funded by Gilead Sciences; MYR 204 ClinicalTrials.gov number, NCT03852433.).

Daclatasvir plus peginterferon and ribavirin is noninferior to peginterferon and ribavirin alone, and reduces the duration of treatment for HCV genotype 2 or 3 infection.

BACKGROUND & AIMS: Twenty-four weeks of treatment with peginterferon and ribavirin for chronic hepatitis C virus (HCV) genotype 2 or 3 infection produces a sustained virologic response (SVR) in 70%-80% of patients. We performed a randomized, double-blind, phase 2b study to assess whether adding daclatasvir, a nonstructural protein 5A (NS5A) inhibitor that is active against these genotypes, improves efficacy and shortens therapy. METHODS: Patients with HCV genotype 2 or 3 infection (n = 151), enrolled at research centers in North America, Europe, or Australia, were assigned randomly to groups given 12 or 16 weeks of daclatasvir (60 mg once daily), or 24 weeks of placebo, each combined with peginterferon alfa-2a and ribavirin. Treatment was extended to 24 weeks for recipients of daclatasvir who did not meet the criteria for early virologic response. The primary end point was SVR at 24 weeks after treatment (SVR24). RESULTS: Baseline characteristics were similar among patients within each HCV genotype group. However, the 80 patients with HCV genotype 3, compared with the 71 patients with HCV genotype 2, were younger (mean age, 45 vs 53 y, respectively), and a larger proportion had cirrhosis (23% vs 1%, respectively). Among patients with HCV genotype 2 infection, an SVR24 was achieved by 83%, 83%, and 63% of those in the daclatasvir 12-week group, the daclatasvir 16-week group, or the placebo group, respectively; among patients with HCV genotype 3 infection, an SVR24 was achieved by 69%, 67%, and 59% of patients in these groups, respectively. Differences between genotypes largely were attributable to the higher frequency of post-treatment relapse among patients infected with HCV genotype 3. In both daclatasvir arms for both HCV genotypes, the lower bound of the 80% confidence interval of the difference in SVR24 rates between the daclatasvir and placebo arms was above -20%, establishing noninferiority. Safety findings were similar among groups, and were typical of those expected from peginterferon alfa and ribavirin therapy. CONCLUSIONS: Twelve or 16 weeks of treatment with daclatasvir, in combination with peginterferon alfa-2a and ribavirin, is a well tolerated and effective therapy for patients with HCV genotype 2 or 3 infections. Daclatasvir-containing regimens could reduce the duration of therapy for these patients. Clinicaltrials.gov number: NCT01257204.

Daclatasvir plus peginterferon alfa and ribavirin for treatment-naive chronic hepatitis C genotype 1 or 4 infection: a randomised study.

OBJECTIVE: To evaluate the safety and efficacy of daclatasvir, an HCV NS5A inhibitor with pangenotypic activity, administered with peginterferon-alfa-2a/ribavirin. DESIGN: In this Phase 2b double-blind, placebo-controlled study, treatment-naive adults with HCV genotype 1 (N=365) or 4 (N=30) infection were randomly assigned (2:2:1) to daclatasvir 20 mg or 60 mg, or placebo once daily plus weekly peginterferon-alfa-2a and twice-daily ribavirin. Daclatasvir recipients achieving protocol-defined response (PDR; HCV-RNA

PegIFNα/ribavirin/protease inhibitor combination in severe hepatitis C virus-associated mixed cryoglobulinemia vasculitis.

BACKGROUND & AIMS: The aim of this study was to analyse the safety and efficacy of the PegIFNα/ribavirin/protease inhibitor combination in severe and/or refractory hepatitis C virus (HCV)-mixed cryoglobulinemia (MC) vasculitis. METHODS: This prospective cohort study included 30 patients (median age 59 years [53-66] and 57% of women) with HCV-MC vasculitis. PegIFNα/ribavirin (for 48 weeks) was associated with telaprevir (375 mg three times daily, for 12 weeks, [n = 17]) or boceprevir (800 mg three times daily, for 44 weeks, (n = 13]). RESULTS: Twenty three patients (76.7%) were non-responders to previous antiviral therapy. At week 72, twenty patients (66.7%) were complete clinical and sustained virological responders. The cryoglobulin level decreased from 0.45 to 0 g/L (p<0.0001) and the C4 level increased from 0.09 to 0.14 g/L (p = 0.017). Complete clinical responders had a higher frequency of purpura (16/20 [80%] vs. 4/10 [40%], p = 0.045), and a trend towards lower frequency of neuropathy (9/20 (45%) vs. 8/10 [80%], p = 0.12) compared with partial responders. Serious adverse events occurred in 14 patients (46.6%) during the 72 weeks of follow-up. Twenty eight patients (93.3%) received erythropoietin, 14 (46.6%) had red blood cell transfusion and 2 (6.6%) received granulocyte stimulating agent. The baseline factors associated with serious adverse events included liver fibrosis (p = 0.045) and a low platelet count (p = 0.021). CONCLUSIONS: The PegIFNα/ribavirin/protease inhibitor combination is highly effective in severe and/or refractory HCV-MC at the cost of frequent side effects. Baseline platelet count and liver fibrosis are useful in guiding treatment decisions.

Daclatasvir and asunaprevir plus peginterferon alfa and ribavirin in HCV genotype 1 or 4 non-responders.

BACKGROUND & AIMS: Improved therapies for peginterferon/ribavirin null or partial responders are needed. This study evaluated daclatasvir (NS5A inhibitor) and asunaprevir (NS3 protease inhibitor) plus peginterferon alfa-2a and ribavirin in this patient population. METHODS: This open-label, phase 3 study (HALLMARK-QUAD; NCT01573351) treated patients with chronic hepatitis C virus (HCV) genotype 1 (n=354) or 4 (n=44) infection who had a prior null or partial response to peginterferon/ribavirin. Patients received daclatasvir 60 mg once-daily plus asunaprevir 100mg twice-daily, with weekly peginterferon alfa-2a and weight-based ribavirin for 24 weeks. The primary endpoint was sustained virological response at post-treatment week 12 (SVR12) among genotype 1-infected patients. RESULTS: Daclatasvir plus asunaprevir and peginterferon/ribavirin demonstrated SVR12 rates of 93% (95% CI 90-96) in prior non-responders infected with HCV genotype 1. SVR12 rates among genotype 4-infected patients were 98% (95% CI 93-100); one patient had a missing post-treatment week-12 HCV-RNA measurement, but achieved an SVR at post-treatment week 24, yielding a 100% SVR rate in genotype 4 patients. Prior peginterferon/ribavirin response, sex, age, IL28B genotype, or cirrhosis status did not influence SVR12 rates. Serious adverse events occurred in 6% of patients; 5% discontinued treatment due to an adverse event. Grade 3/4 laboratory abnormalities included neutropenia (22%), lymphopenia (16%), anemia (6%), thrombocytopenia (4%), and ALT/AST elevations (3% each). CONCLUSIONS: Daclatasvir plus asunaprevir and peginterferon/ribavirin demonstrated high rates of SVR12 in genotype 1- or 4-infected prior null or partial responders. The combination was well tolerated and no additional safety and tolerability concerns were observed compared with peginterferon/ribavirin regimens.

Randomized study of danoprevir/ritonavir-based therapy for HCV genotype 1 patients with prior partial or null responses to peginterferon/ribavirin.

BACKGROUND & AIMS: Chronic hepatitis C treatment for prior non-responders to peginterferon (PegIFN)/ribavirin remains suboptimal. The MATTERHORN study evaluated regimens containing ritonavir-boosted danoprevir (danoprevir/r) in prior PegIFN alfa/ribavirin non-responders. METHODS: Prior partial responders (N=152) were randomized to 24 weeks of twice-daily danoprevir/r 100/100mg, mericitabine 1000 mg and ribavirin 1000/1200 mg (IFN-free); danoprevir/r plus PegIFN alfa-2a/ribavirin (triple); or danoprevir/r, mericitabine and PegIFN alfa-2a/ribavirin (Quad). Prior null responders (N=229) were randomized to 24 weeks of IFN-free therapy, or quad alone (Quad 24) or quad plus 24-weeks of PegIFN alfa-2a/ribavirin (Quad 48). The primary endpoint was sustained virological response (HCV RNA <25 IU/ml) 24 weeks after end-of-treatment (SVR24). Due to high relapse rates, genotype (G) 1a patients in IFN-free arms were offered additional PegIFN alfa-2a/ribavirin. RESULTS: Among prior partial responders, SVR24 rates were 46.2%, 51.0%, and 86.0%, in the IFN-free, Triple and Quad arms, respectively; among prior null responders, SVR24 rates were 45.5%, 80.5%, and 83.8% respectively. Relapse rates were lower and SVR24 rates higher in G1b-infected than G1a-infected patients. SVR24 rates in G1a and G1b patients randomized to Quad were 75.0% and 96.2%, respectively, in the partial Quad arm, and 68.1% and 100%, respectively, in the null Quad 24 arm. Treatment failure was associated with resistance to danoprevir, but not to mericitabine, and was more common in G1a infected patients. Treatment was well-tolerated. CONCLUSIONS: Danoprevir/r, mericitabine plus PegIFN alfa-2a/ribavirin was well-tolerated and produced high overall SVR24 rates in prior partial and null responders to PegIFN alfa/ribavirin. In contrast, IFN-free regimens were associated with unacceptably high relapse rates.

Effectiveness of telaprevir or boceprevir in treatment-experienced patients with HCV genotype 1 infection and cirrhosis.

BACKGROUND & AIMS: We investigated the effectiveness of the protease inhibitors peginterferon and ribavirin in treatment-experienced patients with hepatitis C virus (HCV) genotype 1 infection and cirrhosis. METHODS: In the Compassionate Use of Protease Inhibitors in Viral C Cirrhosis study, 511 patients with HCV genotype 1 infection and compensated cirrhosis who did not respond to a prior course of peginterferon and ribavirin (44.3% relapsers or patients with viral breakthrough, 44.8% partial responders, and 8.0% null responders) were given either telaprevir (n = 299) or boceprevir (n = 212) for 48 weeks. We assessed percentages of patients with sustained viral responses 12 weeks after therapy and safety. This observational study did not allow for direct comparison of the 2 regimens. RESULTS: Among patients given telaprevir, 74.2% of relapsers, 40.0% of partial responders, and 19.4% of null responders achieved SVR12. Among those given boceprevir, 53.9% of relapsers, 38.3% of partial responders, and none of the null responders achieved SVR12. In multivariate analysis, factors associated with SVR12 included prior response to treatment response, no lead-in phase, HCV subtype 1b (vs 1a), and baseline platelet count greater than 100,000/mm(3). Severe adverse events occurred in 49.9% of cases, including liver decompensation, severe infections in 10.4%, and death in 2.2%. In multivariate analysis, baseline serum albumin level less than 35 g/L and baseline platelet counts of 100,000/mm(3) or less predicted severe side effects or death. CONCLUSIONS: Relatively high percentages of real-life, treatment-experienced patients with HCV genotype 1 infection and cirrhosis respond to the combination of peginterferon and ribavirin with telaprevir or boceprevir. However, side effects are frequent and often severe. Baseline levels of albumin and platelet counts can be used to guide treatment decisions. ClinicalTrials.gov number: NCT01514890.

Low-density lipoprotein and other predictors of response with telaprevir-based therapy in treatment-experienced HCV genotype 1 patients: REALIZE study.

BACKGROUND & AIMS: Predictors of response to treatment with peginterferon plus ribavirin are well established. In these post-hoc analyses of the REALIZE study, we sought to identify predictors of response for telaprevir-based triple therapy. METHODS: Patients from the REALIZE study with baseline data for all predictors evaluated (including baseline disease characteristics and demographics, prior treatment response and baseline laboratory assessments) were included in the post-hoc analyses (n = 465). Univariate and multivariate analyses were used to evaluate factors predicting treatment outcomes. RESULTS: Sustained viral response (SVR) rates were 86% in prior relapsers, 63% in prior partial responders and 32% in prior null-responders. In the final multivariate analysis, baseline factors predicting SVR were prior response to treatment [Odds ratio (OR) = 2.80; 95% confidence interval (CI), 2.13-3.69], low-density lipoprotein (LDL) (≥2.6 mmol/L) (OR = 2.11; 95% CI, 1.52-2.93), HCV genotype (OR = 0.58; 95% CI, 0.36-0.93), and maximum alanine amino transferase and aspartate amino transferase (OR = 0.62; 95% CI, 0.40-0.97). CONCLUSIONS: Prior response to peginterferon plus ribavirin treatment and LDL levels are the main independent predictive markers of response with telaprevir-based triple therapy.

Plasma apolipoprotein H limits HCV replication and associates with response to NS3 protease inhibitors-based therapy.

BACKGROUND & AIMS: Chronic infection with HCV remains a public health problem with approximately 150 million people infected worldwide. HCV intersects with lipid metabolism for replication and entry; and plasma concentrations of apolipoproteins have been identified as predictors for response to therapy. Herein, we conducted a screen of plasma proteins, including all apolipoproteins, to identify correlates of response to pegylated-interferon/ribavirin (PR) and HCV non-structural protein 3 (NS3) inhibitors (i.e., telaprevir/boceprevir) therapy in treatment-experienced cirrhotic patients from the ANRS CUPIC cohort. METHODS: We analysed 220 baseline plasma protein concentrations in 189 patients using Luminex technology and analyzed results. RESULTS: We identified baseline levels of apolipoprotein H (apoH) as a surrogate marker for sustained virological response (SVR). Notably, increased plasma concentration of apoH, used in combination with known clinical parameters, established a robust model with improved classification of patients as likely to achieve SVR (AUC = 0.77, Se = 66%, Sp = 72%, NRI = 39%). Moreover, we provide mechanistic information that indicates a previously unidentified role for apoH during viral entry. Using a human liver slices HCV infection model, we demonstrate that apoH limits replication. CONCLUSION: These data support testing of new biomarker strategies for the management of cirrhotic HCV patients and expand our understanding of how apoH may intersect with HCV infection.

Randomized trial of asunaprevir plus peginterferon alfa and ribavirin for previously untreated genotype 1 or 4 chronic hepatitis C.

BACKGROUND & AIMS: Asunaprevir is a selective HCV NS3 protease inhibitor, active against genotypes 1, 4, 5, and 6 in vitro. We evaluated asunaprevir plus peginterferon alfa-2a/ribavirin (PegIFNα/RBV) for genotype 1 and 4 chronic HCV. METHODS: In this phase 2b, double-blind, placebo-controlled study, treatment-naive adults with genotype 1 (n=213) or 4 (n=25) were randomly assigned (3:1) to asunaprevir 200mg or placebo twice daily plus PegIFNα/RBV. Asunaprevir recipients, achieving protocol-defined response (HCV-RNA below quantification limit at week 4 and undetectable at week 10), were rerandomized at week 12 to continue asunaprevir-based triple therapy or receive placebo plus PegIFNα/RBV for weeks 13-24. Patients without protocol-defined response (PDR) and placebo recipients continued PegIFNα/RBV through week 48. Co-primary end points were undetectable HCV-RNA at week 4 and 12 (eRVR) and 24 weeks posttreatment (SVR24). RESULTS: Most patients were male (64.3%), white (83.6%), and had non-CC IL28B genotypes (71.3%). Among genotype 1 patients, eRVR rates (asunaprevir vs. placebo) were 67% (80% CI 62, 72) vs. 6% (80% CI 2, 10); corresponding SVR24 rates were 64% (80% CI 59, 68) vs. 44% (80% CI 36, 53). SVR24 among genotype 4 patients was 89% (asunaprevir) vs. 43% (placebo). Rates of rash and haematologic adverse events were similar between treatment groups. Five asunaprevir-treated patients had grade 4 alanine aminotransferase elevations that resolved following discontinuation (n=4) or with continued dosing (n=1). CONCLUSIONS: Addition of asunaprevir to PegIFNα/RBV in treatment-naive genotype 1- or 4-infected patients improves response rates and is well tolerated, with aminotransferase elevations that were manageable with appropriate monitoring. ClinicalTrials.gov ID: NCT01030432.

Role of a 48-week pegylated interferon therapy in hepatitis B e antigen positive HIV-co-infected patients on cART including tenofovir: EMVIPEG study.

BACKGROUND & AIMS: In hepatitis B e antigen (HBeAg) positive-HIV co-infected patients treated with combined antiretroviral therapy (cART), including tenofovir disoproxil fumarate (TDF), the rate of HBe seroconversion remains low. Whether adding pegylated interferon alfa (PegIFN) could increase the likelihood of HBeAg loss and HBe seroconversion has not been assessed. METHODS: A 48-week PegIFN therapy was added to HBeAg positive-HIV co-infected patients on TDF and emtricitabine, or lamivudine for at least 6 months. The primary endpoint was HBV sustained response: HBe seroconversion with undetectable HBV DNA levels 24 weeks after completing PegIFN therapy (W72). RESULTS: Fifty-one patients (49 men, median age 46 years, range: 32-65), were included. Median duration of HIV, HBV infections and TDF therapy was 10.3 (0.6-22), 9.8 (0.5-16), and 3.3 (0.5-6.8)years, respectively. Median baseline CD4 count was 506 (175-1316)/mm(3). HIV viral load was <50 copies/ml in 49 (96%) patients. Nine (18%) patients stopped PegIFN prematurely. Ten (20%) patients experienced HBeAg loss at W72 and four (8%) patients had a HBV sustained response. No HBs seroconversion was observed. Only patients with more than 350 CD4/mm(3) at baseline achieved HBe loss. HBeAg level >10 PEIU/ml at W12 or a quantitative HBsAg decline <0.5 log IU/ml at W24 had 100% and 84% negative predictive values for response, respectively. CONCLUSIONS: 48-week PegIFN additional therapy to cART including TDF did not significantly increase the HBe seroconversion rate, despite an HBeAg loss in 20% of the patients. HBe and HBs kinetics may nevertheless be of help in tailoring and optimising this strategy.

Apolipoprotein H expression is associated with IL28B genotype and viral clearance in hepatitis C virus infection.

BACKGROUND & AIMS: HCV requires host lipid metabolism for replication, and apolipoproteins have been implicated in the response to treatment. METHODS: We examined plasma apolipoprotein concentrations in three cohorts of patients: mono-infected patients with symptomatic acute hepatitis C (aHCV); those undergoing treatment for chronic hepatitis C (cHCV); and HIV/HCV co-infected patients being treated for their chronic hepatitis C. We also evaluated associations between apolipoproteins and IL28B polymorphisms, a defined genetic determinant of viral clearance. RESULTS: Plasma apolipoprotein H (ApoH) levels were significantly higher in patients who achieved spontaneous clearance or responded to pegylated-interferon/ribavirin therapy. Strikingly, patients carrying the IL28B rs12979860 CC SNP correlated with the plasma concentration of ApoH in all three cohorts. Both ApoH and IL28B CC SNP were associated with HCV clearance in univariate analysis. Additional multivariate analysis revealed that the association between IL28B and HCV clearance was closely linked to that of Apo H and HCV clearance, suggesting that both belong to the same biological pathway to clearance. The association between IL28B CC SNP and ApoH was not observed in healthy individuals, suggesting that early post-infection events trigger differential ApoH expression in an IL28B allele dependent manner. CONCLUSIONS: This relationship identifies ApoH as the first induced protein quantitative trait associated with IL28B, and characterises a novel host factor implicated in HCV clearance.

Randomized trial of daclatasvir and asunaprevir with or without PegIFN/RBV for hepatitis C virus genotype 1 null responders.

BACKGROUND & AIMS: Patients with chronic hepatitis C virus (HCV) infection and prior null response (<2 log HCV RNA decline after ⩾ 12 weeks of PegIFN/RBV) have limited options. We evaluated daclatasvir plus once- or twice-daily asunaprevir in non-cirrhotic genotype 1 null responders. METHODS: In this randomized, phase 2a, open-label, 24-week treatment study, 101 patients received daclatasvir (60 mg) once-daily. In addition, 38 genotype 1b patients received asunaprevir (200mg) twice- (DUAL A1) or once-daily (DUAL A2); 36 genotype 1a and 5 genotype 1b patients received asunaprevir twice- (QUAD B1) or once-daily (QUAD B2) plus PegIFN/RBV; and 18 genotype 1a and 4 genotype 1b patients received asunaprevir twice-daily plus ribavirin (TRIPLE B3). The primary endpoint was undetectable HCV RNA 12 weeks post-treatment (sustained virologic response, SVR12). RESULTS: Across all groups, mean HCV RNA was ⩾ 6 log IU/ml, and 99% of patients had a non-CC IL28B genotype. SVR12 rates were 78% (A1), 65% (A2), 95% (B1), and 95% (B2). In B3, most genotype 1a patients experienced virologic breakthrough. The most common adverse events were headache, diarrhea, and asthenia. Grade 3-4 aminotransferase elevations were infrequent and not treatment-limiting. CONCLUSIONS: In genotype 1 null responders, daclatasvir plus twice-daily asunaprevir DUAL therapy is effective for most genotype 1b patients, and daclatasvir, asunaprevir, and PegIFN/RBV QUAD therapy is effective for nearly all genotype 1a and 1b patients; but neither DUAL nor TRIPLE therapy is effective for genotype 1a patients. Interferon-free regimens including daclatasvir and twice-daily asunaprevir for genotype 1 null responders should be tailored to subtype.

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.).

Faldaprevir combined with peginterferon alfa-2a and ribavirin in chronic hepatitis C virus genotype-1 patients with prior nonresponse: SILEN-C2 trial.

UNLABELLED: Faldaprevir (BI 201335) is a potent, hepatitis C virus (HCV) NS3/4A protease inhibitor. In all, 290 noncirrhotic HCV genotype (GT)-1 patients with prior null (<1 log10 viral load [VL] drop at any time on treatment) or partial response (≥1 log10 VL drop but never undetectable on treatment) were randomized 2:1:1 to receive 48 weeks of peginterferon alfa-2a and ribavirin (PegIFN/RBV) in combination with faldaprevir 240 mg once daily (QD) with 3 days PegIFN/RBV lead-in (LI), 240 mg QD without LI, or 240 mg twice daily (BID) with LI. Patients in the 240 mg QD/LI group achieving maintained rapid virologic response (mRVR; VL <25 IU/mL [Roche TaqMan] at week 4 and undetectable at weeks 8 to 20) were rerandomized to cease all treatment at week 24 or continue PegIFN/RBV up to week 48. Sustained virologic response (SVR) rates were 32%, 50%, and 42% in prior partial responders, and 21%, 35%, and 29% in prior null responders in the faldaprevir 240 mg QD/LI, 240 mg QD, and 240 mg BID/LI groups, respectively. In the 240 mg QD/LI group, a significantly higher proportion of mRVR patients rerandomized to 48 weeks' treatment achieved SVR compared with those assigned to 24 weeks treatment (72% versus 43%; P = 0.035). Rates of gastrointestinal disorders, jaundice, dry skin, and photosensitivity were increased at 240 mg BID compared with the 240 mg QD dose. Faldaprevir discontinuations owing to adverse events occurred in 6%, 4%, and 23% of patients in the 240 mg QD/LI, 240 mg QD, and 240 mg BID/LI groups, respectively. CONCLUSION: Faldaprevir 240 mg QD with PegIFN/RBV was safe and tolerable and produced substantial SVR rates in prior null and partial responders. The 240 mg QD dose is currently undergoing phase 3 evaluation.

Homeostasis model assessment of insulin resistance does not seem to predict response to telaprevir in chronic hepatitis C in the REALIZE trial.

UNLABELLED: Baseline homeostasis model assessment-estimated insulin resistance (HOMA-IR), a marker for insulin resistance, has been associated with poor virologic response to peginterferon alpha/ribavirin (PR) in chronic hepatitis C. We evaluated the association between baseline HOMA-IR and pretreatment factors on sustained virologic response (SVR) to telaprevir (TVR) in genotype 1 patients with hepatitis C and prior peginterferon/ribavirin (PR) treatment failure. Patients were randomized to 12 weeks of TVR (750 mg q8h) plus peginterferon (180 µg/week) and ribavirin (1,000-1,200 mg/day) (with or without a 4-week lead-in) followed by PR, or PR alone (PR48), for 48 weeks. Univariate and multiple logistic regression analyses explored the prognostic significance of baseline HOMA-IR alone and adjusted for other pretreatment factors and SVR. The TVR arms were pooled for the purposes of this analysis. In all, 662 patients were randomized; 578 had baseline HOMA-IR and other prognostic data and were included in this analysis. Median baseline HOMA-IR was 2.6 (interquartile range [IQR] 1.7-4.3); 207 (36%), 206 (36%), and 165 (29%) patients had baseline HOMA-IR <2, 2 to <4, and ≥ 4, respectively. Male gender, higher body mass index, triglycerides, gamma-glutamyl transpeptidase, maximum alanine aminotransferase/aspartate aminotransferase, and fibrosis stage were associated with higher baseline HOMA-IR. Baseline HOMA-IR was associated with SVR in univariate analysis, but not after adjustment for other baseline prognostic factors (TVR: OR = 0.95, 95% confidence interval [CI]: 0.71,1.29; PR48: 0.60; 95% CI: 0.25,1.43). CONCLUSION: In patients with prior PR treatment failure, baseline HOMA-IR correlated with SVR in univariate but not multivariate analyses, suggesting other factors have a more direct causal relationship with virologic response to TVR-based therapy than HOMA-IR.

Treatment of hepatitis C virus genotype 3-infection.

The treatment of hepatitis C virus (HCV) infection with pegylated interferon (PEG-IFN) alfa and ribavirin (800 mg daily) (RBV) is the standard of care (SOC) for hepatitis C virus genotype 3-infection leading to a sustained virological response (SVR) in around 65% of patients. A better understanding of the HCV life-cycle has recently resulted in the development of several potential direct-acting antiviral drugs (DAAs) targeting viral proteins (NS3/4A protease, NS5B nucleos(t)idic and non-nucleos(t)idic polymerase, NS5A viral replication complex). First generation protease inhibitors in combination with PEG-IFN/RBV are not efficient in genotype 3-infected patients. The combination of PEG-IFN/RBV with Daclatasvir, a NS5A inhibitor for 12-24 weeks results in a SVR in around 75% while the triple combination of PEG-IFN/RBV with the oral nucleotidic polymerase inhibitor Sofosbuvir (GS-7977) for 12 weeks in naïve patients results in a SVR in more than 95%. The results of the first oral combination of Sofosbuvir and RBV for 12 weeks in genotype 3-infected patients have been rather disappointing with a slightly lower SVR than after 24 weeks of PEG-IFN: around 60%, and only 30% in patients with cirrhosis. Extending treatment from 12 to 16 weeks in treatment experienced patients doubled the SVR rate and an 80% SVR rate is expected by extending treatment to 24 weeks. The best oral combination of new DAAs is probably the combination of Sofosbuvir and a NS5A inhibitor (Daclatasvir, Ledipasvir…) for 24 weeks, which resulted in a 100% SVR rate in a limited series. The use of cyclophilin inhibitors, a host-targeted antiviral, in association with DAAs and/or RBV may also be of interest. The oral combination of new DAAs (dual or triple combination of different antivirals) or of DAAs and host targets such as cyclophilin will probably become the SOC for genotype 3-infected treatment-naïve or -experienced patients.

Sustained virologic response rates with telaprevir by response after 4 weeks of lead-in therapy in patients with prior treatment failure.

BACKGROUND & AIMS: For hepatitis C virus (HCV)-infected patients who have not responded to previous PegIFN/ribavirin treatment, it is unclear whether subsequent direct-acting antiviral therapy outcomes are better predicted by prior treatment response or by on-treatment response to a PegIFN/ribavirin lead-in. METHODS: In REALIZE, treatment-experienced patients randomized to the lead-in telaprevir arm received 4 weeks of PegIFN-α-2a (180 µg/week) and ribavirin (1000-1200 mg/day), then 12 weeks of telaprevir (750 mg every 8h) plus PegIFN-α-2a/ribavirin, followed by 32 weeks of PegIFN-α-2a/ribavirin. This subanalysis only included patients in the lead-in telaprevir arm with available week 4 on-treatment response data (n=240). RESULTS: After 4weeks of PegIFN/ribavirin, 90% of relapsers, 60% of partial responders, and 41% of null responders in the lead-in telaprevir arm had ⩾1 log(10) HCV RNA reduction. Sustained virologic response (SVR) rates for telaprevir-treated patients with ≥1 versus <1 log(10) HCV RNA reduction after the PegIFN/ribavirin lead-in were 94% versus 62% in relapsers, 59% versus 56% in partial responders and 54% versus 15% in null responders. CONCLUSIONS: In prior relapsers and partial responders there is no apparent benefit of assessing response after a PegIFN/ribavirin lead-in with the aim of guiding telaprevir-based treatment. For patients known to be prior null responders, on-treatment response after a 4-week PegIFN/ribavirin lead-in may provide clinically useful prognostic information. However, withholding telaprevir-containing therapy in uncategorised treatment-experienced patient populations (i.e., that could include prior relapsers or partial responders), using response after a PegIFN/ribavirin lead-in could potentially exclude some patients with a high chance of SVR.

Limited impact of IL28B genotype on response rates in telaprevir-treated patients with prior treatment failure.

BACKGROUND & AIMS: Nucleotide polymorphisms upstream of the interleukin 28B (IL28B) gene are strongly associated with hepatitis C virus (HCV) clearance in treatment-naïve patients treated with peginterferon/ribavirin (PegIFN/RBV). This subanalysis of the REALIZE study evaluated the impact of IL28B polymorphisms on sustained virologic response (SVR) in telaprevir-treated, HCV genotype 1-infected patients with prior PegIFN/RBV treatment failure. METHODS: Treatment-experienced patients were randomized to 12 weeks of telaprevir (750 mg every 8h) with/without a 4-week PegIFN/RBV lead-in, or placebo, each with PegIFN-α-2a (180 µg/week) and ribavirin (1000-1200 mg/day) for 48 weeks overall. Data from telaprevir arms were pooled. RESULTS: Eighty percent (527/662) of patients consented to genetic testing and were included. Similar proportions of patients had IL28B CC, CT and TT genotypes across treatment arms; baseline characteristics were generally well balanced. SVR rates were higher in the pooled telaprevir versus placebo group for all IL28B genotypes; CC: 79% versus 29%, respectively; CT: 60% versus 16%, respectively; TT: 61% versus 13%, respectively. Within each prior response category (relapse, partial or null response), SVR and viral breakthrough rates with telaprevir-based treatment were comparable across IL28B genotypes. IL28B genotype did not significantly affect SVR (2-step multivariate analyses; p >0.16 in pairwise comparison among CC, TT, and CT). Variations in rapid virologic response and relapse rates were noted in certain patient subgroups. CONCLUSIONS: Our findings suggest that IL28B genotype has a limited impact on SVR rates with telaprevir-based therapy in treatment-experienced patients. IL28B genotyping may have limited utility in the baseline evaluation of similar patients considered for telaprevir-based therapy.

How to optimize HCV therapy in genotype 1 patients with cirrhosis.

Of all hepatitis C virus patients, those with cirrhosis are most in need of treatment owing to increased morbidity and mortality. Treatment with pegylated interferon and ribavirin (PEG-IFN/RBV) has clearly shown the benefits of successful treatment by improving fibrosis, causing the regression of cirrhosis and reducing and preventing cirrhosis-related complications. However, the sustained virological response (SVR) is lower in patients with cirrhosis. First generation protease inhibitors (boceprevir and telaprevir) in combination with PEG-IFN/RBV are a major advancement in the treatment of both naïve and treatment-experienced genotype 1 patients. In naïve patients, the SVR rate with the triple regimen with boceprevir increased by 14% in patients with severe fibrosis or cirrhosis compared to PEG-IFN/RBV compared by 30% in patients with mild or moderate fibrosis. The SVR rate of the triple regimen with telaprevir increased by 10-30% compared to PEG-IFN/RBV in patients with severe fibrosis or cirrhosis and by nearly 30% in patients with mild or moderate fibrosis. The greatest benefits seem to be found in patients with cirrhosis who have relapsed, and is limited in prior non-responder patients. Thus, the choice of triple therapy in the latter should be considered in relation to the increase in side effects. There are no data on the efficacy of the triple regimen in patients with decompensated cirrhosis. Results in real-life settings show that patients with cirrhosis need to be carefully followed-up during treatment due to the increase in side effects that are greater than in clinical studies. Next generation DAAs and PEG-IFN/RBV appear to be more effective and have fewer side effects in patients with cirrhosis. Ultimately, an interferon-free regimen of DAAs combinations will probably provide a SVR in patients with cirrhosis and will probably be proposed in patients with more advanced or decompensated cirrhosis.