Prior Null Response Research Articles

Simeprevir with peginterferon \u03b1-2a/ribavirin for chronic hepatitis C virus genotype 1 infection in treatment-experienced patients: an open-label, rollover study

BackgroundThis Phase 3, open-label, rollover study (NCT01323244) investigated the efficacy and safety of simeprevir plus peginterferon α-2a (PegIFNα-2a) and ribavirin (RBV) in a well-characterized population of HCV genotype 1 (GT1)-infected treatment-experienced patients.MethodsPatients who had failed PegIFNα/RBV treatment in the placebo arm of a previous Phase 2/3 simeprevir study (Phase 2/3 group, n = 125), or had been exposed to HCV direct-acting antivirals (simeprevir or other) for up to 14 days in a selected Phase 1 study (Phase 1 group, n = 16), were eligible. Phase 2/3 group patients were classified according to prior relapse, breakthrough, or non-response (null response, partial response, non-classifiable non-response) to PegIFNα/RBV. Eight patients in the Phase 1 group received short-term (≤14 days) simeprevir.Treatment comprised simeprevir 150 mg once daily (QD) plus PegIFNα-2a/RBV for 12 weeks followed by PegIFNα-2a/RBV for 12 or 36 weeks (using response-guided therapy [RGT] to determine total treatment duration in Phase 2/3 prior relapsers or breakthrough) or 36 weeks fixed (Phase 2/3 group non-responders and Phase 1 group). The primary endpoint was sustained virologic response 12 weeks after planned end of treatment (SVR12).ResultsPhase 2/3 group: SVR12 rate was 69.6% (87/125) overall; 92.7% (51/55), 60.0% (6/10), 64.3% (18/28), and 36.7% (11/30) in patients with prior relapse, viral breakthrough, partial response, or null response, respectively. SVR12 rates were similar for patients with HCV GT1a (66.0% [33/50]) and GT1b infection (72.0% [54/75]) and among HCV GT1a-infected patients with/without a baseline Q80K polymorphism (66.7% [8/12] and 65.8% [25/38], respectively). The majority of RGT-eligible patients (prior viral relapse or breakthrough) met RGT criteria (89.2% [58/65]); of these, 89.7% (52/58) achieved SVR12. Overall, 16.0% (20/125) of patients experienced on-treatment failure and 14.4% (18/125) experienced post-treatment failure (15 relapses, 3 missing data). Phase 1 group (simeprevir-naïve and -experienced patients combined): SVR12 rate was 37.5% (6/16). Safety and tolerability findings were comparable to those of the feeder studies.ConclusionsThe majority of RGT-eligible patients met criteria for shortening treatment to 24 weeks in total. Simeprevir 150 mg QD with PegIFNα-2a/RBV led to a high SVR rate among prior relapsers with HCV GT1 infection. No new safety signals were noted.Trial registrationNCT01323244. (date of registration: March 24, 2011).

Effectiveness of Elbasvir and Grazoprevir Combination, With or Without Ribavirin, for Treatment-Experienced Patients With Chronic Hepatitis C Infection

Patients infected with hepatitis C virus (HCV) genotype 1, 4, or 6, with or without cirrhosis, previously treated with peg-interferon and ribavirin, are a challenge to treat. We performed a phase 3 randomized controlled open-label trial to assess the effects of 12 or 16 weeks of treatment with once-daily elbasvir (an HCV NS5A inhibitor, 50 mg) and grazoprevir (an HCV NS3/4A protease inhibitor, 100 mg), in a fixed-dose combination tablet, with or without twice-daily ribavirin, in this patient population. We analyzed data from 420 patients (35% with cirrhosis, 64% with a null or partial response to peg-interferon and ribavirin) who were randomly assigned (1:1:1:1) to groups given elbasvir and grazoprevir once daily, with or without twice-daily ribavirin, for 12 or 16 weeks, at 65 study centers in 15 countries in Europe, Asia, and Central and North America. Randomization was stratified by cirrhosis status and type of peg-interferon and ribavirin treatment failure. HCV RNA was measured using COBAS TaqMan v2.0. The primary end point was HCV RNA <15 IU/mL, 12 weeks after completion of treatment (SVR12). We aimed to determine whether the proportion of patients achieving an SVR12 in any group was greater than the reference rate (58%). With 12 weeks of treatment, an SVR12 was achieved by 92.4% of patients given elbasvir and grazoprevir and 94.2% of patients given elbasvir and grazoprevir with ribavirin. With 16 weeks of treatment, an SVR12 was achieved by 92.4% of patients given elbasvir and grazoprevir and 98.1% of patients given elbasvir and grazoprevir with ribavirin. Among patients treated for 12 weeks without ribavirin, virologic failure occurred in 6.8%, 0%, and 12.5% of patients with HCV genotype 1a, 1b, or 4 infection, respectively. Among patients given elbasvir and grazoprevir for 12 weeks, virologic failure occurred in 0% of patients infected with HCV genotypes 1 and 4 who relapsed after completing peg-interferonand ribavirin, and 7.5% infected with HCV genotypes 1 and 4, respectively, with a null or partial response to peg-interferon and ribavirin. Among patients treated for 16 weeks who received ribavirin, there were no incidences of virologic failure. Common adverse events were fatigue (23.1%), headache (19.8%), and nausea (11.0%). The combination tablet of elbasvir and grazoprevir, with or without ribavirin, was highly efficacious in inducing an SVR12 in patients with HCV genotype 1, 4, or 6 infection failed by previous treatment with peg-interferon and ribavirin, including patients with cirrhosis and/or a prior null response. The treatment was generally well tolerated. ClinicalTrials.gov Number: NCT02105701.

Sustained Virologic Response Rate of 96% in HCV Genotype 1a-Infected Patients Treated With Ombitasvir/Paritaprevir/r and Dasabuvir With Ribavirin

Introduction: The interferon-free 3 direct-acting antiviral (3D) regimen of ombitasvir (an NS5A inhibitor), paritaprevir (an HCV NS3/4A protease inhibitor identified by AbbVie and Enanta, boosted with ritonavir [r]) and dasabuvir (a non-nucleoside NS5B RNA polymerase inhibitor) is approved to treat patients infected with HCV genotype (GT) 1. Using pooled data from four phase 3 studies in treatmentnaïve and prior pegIFN/RBV-experienced patients with GT1a infection, with or without cirrhosis, we report the safety and efficacy in patients who received the label-recommended 3D regimen plus ribavirin (RBV). Methods: Genotype 1a-infected patients from the PEARL-IV, SAPPHIRE-I, SAPPHIRE-II, and TUR-QUOISE-II studies were included in this post-hoc analysis. Efficacy was assessed by the proportion of patients achieving sustained virologic response (HCV RNA < 25 IU/mL) 12 weeks after completion of treatment (SVR12). Per the US Prescribing Information and European SmPC, the label-recommended regimen for GT1a infection is 3D+RBV for 12 weeks in non-cirrhotic patients, and 3D+RBV for 24 weeks in patients with cirrhosis. Adverse events (AEs) and laboratory measures are reported for all patients receiving the label-recommended regimen. Results: Among 714 HCV GT1a-infected patients treated with the label-recommended 3D+RBV regimen, 64% were male, 33% were treatment-experienced, 17% had cirrhosis, and 85% had baseline viral loads ≥800,000 IU/mL. Sustained virologic response was achieved in 96% (95% CI, 94-97%) of patients (Table). Response rates were similar regardless of the presence or absence of cirrhosis (95 versus 96%, respectively). Virologic failure was observed in 18 (2.5%) patients, 5 (0.7%) with on-treatment breakthrough and 13 (1.8%) with post-treatment relapse. Seven patients (1.0%) discontinued treatment due to AEs, 4 of whom subsequently achieved SVR12. The most common AEs were fatigue (41%), headache (33%), nausea (23%), and insomnia (17%). Grade 3+ laboratory abnormalities were infrequent for ALT (0.9%), AST (0.6%), hemoglobin (0.3%), and total bilirubin (2.8%). Conclusion: In HCV GT1a-infected patients, the label-recommended 3D regimen with RBV achieved high SVR12 rates, including historically difficult-to-cure subgroups of patients with prior PR null response and/or cirrhosis.Table 1

Effectiveness of triple therapy with simeprevir for chronic hepatitis C genotype 1b patients with prior telaprevir failure.

Favourable efficacy and safety profiles for simeprevir in combination with pegylated interferon alpha (PEG-IFNα) and ribavirin (triple therapy) have been shown in clinical trials. This study was carried out to evaluate the effectiveness of simeprevir-based triple therapy for patients with prior telaprevir treatment failure. This multicentre, observational cohort consisted of 345 consecutive Japanese patients infected with HCV genotype 1b, including 20 who had experienced telaprevir-based triple therapy. Amino acid substitutions in the NS3/4A region were identified by direct sequencing at the time of relapse or breakthrough in treatment with telaprevir and at the initiation of treatment with simeprevir. Patients were stratified according to prior response to PEG-IFNα and ribavirin. Of the 20 patients with telaprevir treatment failure, 10 (50.0%) achieved sustained virological response at week 12 after the end of treatment (SVR12). For patients treatment naïve [3/4 (75.0%)] or with prior relapse [1/1 (100%)] or partial response [5/6 (83.3%)] to PEG-IFNα and ribavirin, almost all achieved SVR12, mainly because of the improvement of treatment adherence, especially to direct-acting antiviral agent and ribavirin. However, of the nine patients with prior null response to PEG-IFNα and ribavirin, only one (11.1%) achieved SVR12, despite all having received an adequate treatment dosage, and five (55.6%) achieved rapid virological response. The treatment outcome of simeprevir-based triple therapy for HCV genotype 1b patients with prior telaprevir failure depended on the prior response to PEG-IFNα and ribavirin. For patients with prior null response to PEG-IFNα and ribavirin, retreatment with simeprevir-based triple therapy is not a useful option.

Treatment of Chronic Hepatitis C with Viral-Suppression linked to Restoration of Innate-Immune Responses with Induction-Therapy with n-IFN-beta followed by Simeprevir

Complications associated with hepatitis C virus (HCV) infection may be prevented by viral eradication. Response rates with direct-acting antivirals regimens are generally lower in chronic hepatitis C (CHC) patients who have failed to respond to previous interferon (IFN) treatments. HCV persistence in the host results from in efficient innate and adaptive immune responses. The resolution of a HCV infection may restore impairments in innate and adaptive immunities. Our previous study suggested that induction treatment with natural (n)-IFN-beta followed by maintenance treatment with n-IFN-alpha restored innate immune responses, as indicated by the significant increase of IL-12, and IL-15 and significant decrease of CXCL-8. Persistent virologic clearance and the restoration of innate immune responses with Simeprevir plus Pegylated (Peg) - IFN-alpha/ribavirin (RBV) were more likely to result in a sustained virologic response (SVR). On the basis of these findings, we conducted to treat a CHC patient with genotype 1b, a high viral load, a prior null response to IFN treatments and chronic active hepatitis with advanced fibrosis using induction therapy with n-IFN-beta followed by Simeprevir plus Peg- IFN-alpha-2b/RBV. This is the first case of difficult-to-treat CHC with genotype 1b, a high viral load, null response to previous IFN treatment and advanced hepatic fibrosis that was successfully treated with induction therapy using n-IFN-beta, which induced the viral clearance of serum HCV RNA, followed by Simeprevir plus Peg-IFN-alpha-2b/RBV. Persistent viral clearance linked to restoration of innate immune responses and SVR were achieved 12 weeks after cessation of the treatment without virologic breakthrough or relapse and sustained biochemical response. Anemia and thrombocytopenia were managed without discontinuation of the treatment. Induction therapy with n-IFN-beta followed by Simeprevir plus Peg-IFN-alpha-2b/RBV was tolerated well and only mild adverse effects were noted. It also effectively eradicated HCV infection in a difficult-to-treat CHC patient with advanced fibrosis.

Tu1013 On-Treatment HCV RNA As a Predictor of Sustained Virologie Response in HCV Genotype 3 - Infected Patients Treated With Daclatasvir and Sofosbuvir: Analysis of Phase 3 Ally-3 Study

A S L D A b st ra ct s rates in patients treated with DCV/ASV/BCV combined with RBV and in patients with GT1b subtype. Other baseline factors such as age, gender, BMI, IL28B genotype, HCV RNA >800,000 IU/mL, and platelet count <100 × 109/L did not appear to impact SVR12 rates in either cohort (Table). Similarly, race did not appear to influence SVR12 rates; of the 20 black patients enrolled in the study, all 20 achieved SVR12. Prior null response to pegIFN did not significantly impact outcome in the treatment-experienced cohort. Baseline resistanceassociated variants (RAVs) in NS5A (28, 30, 31, 93) or NS3 (168) did not impact SVR: 26/ 28 patients with NS5A RAVs and 2/2 patients with NS3 RAVs achieved SVR12. NS5B-P495 was not detected at baseline. Among patients with virologic failure, RAVs were detected in NS5A (Q30, Y93, L31), NS3 (R155, D168) and NS5B (P495, P421). Conclusion: The alloral fixed-dose combination of DCV, ASV, and BCV achieved high rates of SVR12 in patients with HCV genotype 1 infection and compensated cirrhosis. The strongest predictors of SVR12 were GT1b and use of RBV. Factors often associated with reduced responses to less potent regimens, such as advanced age, black race, prior null response to pegIFN, high baseline HCV RNA levels, low platelet counts, non-CC IL28B genotype, and baseline NS5A or NS3 RAVs did not appear to impact SVR12 rates.

Tu1015 MALACHITE-II: Phase 3b Trial of Ombitasvir/Paritaprevir/R and Dasabuvir + Ribavirin or Telaprevir + Peginterferon/Ribavirin in Peginterferon/Ribavirin Treatment-Experienced Adults With HCV Genotype 1

A S L D A b st ra ct s rates in patients treated with DCV/ASV/BCV combined with RBV and in patients with GT1b subtype. Other baseline factors such as age, gender, BMI, IL28B genotype, HCV RNA >800,000 IU/mL, and platelet count <100 × 109/L did not appear to impact SVR12 rates in either cohort (Table). Similarly, race did not appear to influence SVR12 rates; of the 20 black patients enrolled in the study, all 20 achieved SVR12. Prior null response to pegIFN did not significantly impact outcome in the treatment-experienced cohort. Baseline resistanceassociated variants (RAVs) in NS5A (28, 30, 31, 93) or NS3 (168) did not impact SVR: 26/ 28 patients with NS5A RAVs and 2/2 patients with NS3 RAVs achieved SVR12. NS5B-P495 was not detected at baseline. Among patients with virologic failure, RAVs were detected in NS5A (Q30, Y93, L31), NS3 (R155, D168) and NS5B (P495, P421). Conclusion: The alloral fixed-dose combination of DCV, ASV, and BCV achieved high rates of SVR12 in patients with HCV genotype 1 infection and compensated cirrhosis. The strongest predictors of SVR12 were GT1b and use of RBV. Factors often associated with reduced responses to less potent regimens, such as advanced age, black race, prior null response to pegIFN, high baseline HCV RNA levels, low platelet counts, non-CC IL28B genotype, and baseline NS5A or NS3 RAVs did not appear to impact SVR12 rates.

Tu1014 Single-Center Real-World Experience of Sofosbuvir Plus Simeprevir for 12 Weeks for Genotype 1 Chronic Hepatitis C With Advanced Fibrosis

A S L D A b st ra ct s rates in patients treated with DCV/ASV/BCV combined with RBV and in patients with GT1b subtype. Other baseline factors such as age, gender, BMI, IL28B genotype, HCV RNA >800,000 IU/mL, and platelet count <100 × 109/L did not appear to impact SVR12 rates in either cohort (Table). Similarly, race did not appear to influence SVR12 rates; of the 20 black patients enrolled in the study, all 20 achieved SVR12. Prior null response to pegIFN did not significantly impact outcome in the treatment-experienced cohort. Baseline resistanceassociated variants (RAVs) in NS5A (28, 30, 31, 93) or NS3 (168) did not impact SVR: 26/ 28 patients with NS5A RAVs and 2/2 patients with NS3 RAVs achieved SVR12. NS5B-P495 was not detected at baseline. Among patients with virologic failure, RAVs were detected in NS5A (Q30, Y93, L31), NS3 (R155, D168) and NS5B (P495, P421). Conclusion: The alloral fixed-dose combination of DCV, ASV, and BCV achieved high rates of SVR12 in patients with HCV genotype 1 infection and compensated cirrhosis. The strongest predictors of SVR12 were GT1b and use of RBV. Factors often associated with reduced responses to less potent regimens, such as advanced age, black race, prior null response to pegIFN, high baseline HCV RNA levels, low platelet counts, non-CC IL28B genotype, and baseline NS5A or NS3 RAVs did not appear to impact SVR12 rates.

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

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. 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. 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). 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.

Ombitasvir/paritaprevir/ritonavir and dasabuvir tablets for hepatitis C virus genotype 1 infection.

To review the data with ombitasvir/paritaprevir/ritonavir and dasabuvir for the treatment of chronic hepatitis C virus (HCV) genotype 1 infection. Phase I, II, and III trials and review articles were identified through MEDLINE (1996-January 2015) and PubMed (1996-January 2015), conference abstracts, and US national clinical trials registry, using the keywords NS3/4A protease inhibitor, NS5A inhibitor, NS5B polymerase inhibitor, ABT-450, ABT-267, ABT-333, paritaprevir, ombitasvir, and dasabuvir. Preclinical, phase I, II, and III studies describing pharmacology, pharmacokinetics, efficacy, safety, and tolerability were identified. Noncirrhotic patients with HCV genotype 1b experienced sustained virological response 12 weeks after completion of therapy (SVR12) rates of 96% to 100% when ombitasvir/paritaprevir/ritonavir and dasabuvir were administered for 12 weeks, regardless of inclusion of ribavirin. SVR12 rates of 95% to 97% were seen in noncirrhotic patients with HCV genotype 1a infection who received ombitasvir/paritaprevir/ritonavir and dasabuvir with ribavirin for 12 weeks. Patients with Child-Pugh Class A cirrhosis also experienced high SVR12 rates (91.8%) when ombitasvir/paritaprevir/ritonavir and dasabuvir were administered with ribavirin for 12 weeks. Cirrhotic patients with HCV genotype 1a and a history of prior null response to peginterferon/ribavirin have higher SVR12 rates when ombitasvir/paritaprevir/ritonavir and dasabuvir and ribavirin are administered for 24 instead of 12 weeks (94.2% vs 88.6%). Adverse events are typically mild, most commonly consisting of fatigue, headache, nausea, and diarrhea. The regimen consisting of ombitasvir/paritaprevir/ritonavir and dasabuvir is highly efficacious in the treatment of HCV genotype 1 infection, with minimal adverse events. It is expected to play an important role in the armamentarium of novel agents that have a high chance of curing HCV infection.

Treatment of Chronic HCV With Sofosbuvir (SOF) and Simeprevir (SMV) in Patients With Cirrhosis and Contraindications to Peginterferon (PEGINF) and Ribavirin (RBV)

Introduction: Patients with HCV and cirrhosis have the greatest need for treatment. Many of these patients have failed previous treatment and are at high risk of decompensation if treated with a regimen containing PEGINF/RBV. SOF, a polymerase inhibitor, and SMV, a protease inhibitor, are highly effective in suppressing HCV genotype 1. SOF+SIM have been utilized together in patients with prior null response and cirrhosis. However, the safety and efficacy of SOF+SMV in patients with cirrhosis and contraindications to PEGINF/RBV has not yet been evaluated. Methods: Seventy-five consecutive patients with chronic HCV, cirrhosis, and contraindications to PEGINF/RBV initiated 12 weeks of treatment with SOF+SMV, since these agents were FDA-approved in December 2013. To date, all patients have received at least 2 weeks of treatment. Contraindications to PEGINF/RBV included platelet count <70 (30), hemoglobin <10 (3), previous complications of cirrhosis; ascites (10), variceal bleeding (8), hepatic encephalopathy (20), or HCC (1); age >65 years (15), symptomatic cryoglobulinemia (5), serum creatinine >1.5 mg/dL (5), and prior intolerance to PEGINF (4). Several patients had multiple contraindications. Results: The mean age was 60 years (29-79), 65% were male, 42% black, 67% genotype 1A, mean log HCV RNA 6.1 IU/mL, 94% IL28B non-CC, 43% treatment-naïve, 23% failed prior treatment with PEGINF, and 19% failed prior treatment with boceprevir or telaprevir. Mean MELD score at initiation of treatment was 13.2; 6 patients had a MELD >15. To date, the number of patients completing 4, 8, and 12 weeks of treatment are 64, 50, and 31, respectively. At weeks 2, 4, 8, and 12, HCV RNA was undetectable in 37%, 86%, 97%, and 100% of patients. Four out of 5 (80%) achieved SVR4. One patient relapsed. Two patients developed hepatic decompensation after becoming HCV RNA undetectable. Treatment was stopped in both; at week 10 in a patient who then achieved SVR4 and liver function stabilized, and at week 8 in a patient who died. Both patients had prior complications of cirrhosis and MELD of 18 when they initiated treatment. One patient with undetectable HCV RNA developed HCC at treatment week 8 and remains on treatment. Conclusion: This is the first study to evaluate SOF+SIM in patients with cirrhosis and contraindications to PEGINF/RBV. Treatment with SOF+SMV achieves rapid virologic clearance in these patients. Nearly 90% become HCV RNA undetectable within 4 weeks, and all patients appear to eventually become HCV RNA undetectable during the 12-week treatment regimen. Patients with advanced cirrhosis are at risk to develop complications during treatment, but it is unclear if this is increased by treatment. SVR4 will be available on all patients and SVR12 in 50 patients by the ACG meeting in October 2014. Disclosure - Dr Shiffman has participated in advisor meetings with Achillion, Bristol-Myers-Squibb, Boehringer-Ingelheim, Gilead, Gen-Probe, Globeimmune, GlaxoSmithKline, Janssen, Merck, Novartis, Roche/Genentech and Vertex; is a speaker for Bayer, Gilead, Janssen, Merck, Roche/Genentech and Vertex; and receives grant support from Abbott, Achillion, Beckman-Colter, Bristol-Myers-Squibb, Boehringer-Ingelheim, Gilead, Globeimmune, Idenix, Intercept, Merck, Mochida, Novartis and Roche/Genentech. Ms Long has participated in advisor meetings with Abbvie, Gilead, Janssen, Kadman, Merck and Vertex; and is a speaker for Merck, GlaxoSmithKline, Kadman, Salix and Vertex. Ms James has participated in advisor meetings with Gilead and Janssen and is a speaker for Janssen. Mr Alexander has participated in advisor meetings with Gilead.

Effectiveness of telaprevir and boceprevir triple therapy for patients with hepatitis C virus infection in a large integrated care setting.

In 2011, the FDA approved telaprevir (TVR) and boceprevir (BOC) for use with pegylated interferon and ribavirin to treat hepatitis C virus (HCV) genotype 1. We aimed to evaluate the real-world application, tolerability, and effectiveness of TVR- and BOC-based HCV treatment in a large integrated care setting. We utilized Northern California Kaiser Permanente Medical Care Program (KPNC) electronic databases and medical records to study the experience of all KPNC patients who initiated TVR or BOC from June 2011 to March 2012. Compared with the pool of 5,194 treatment-eligible patients, the 352 treatment initiators were more likely to be cirrhotic (24 vs. 10%, p < 0.001) and treatment-experienced (44 vs. 22%, p < 0.001). Among the treatment initiators, 211 received TVR and 141 BOC. Overall, 31% discontinued treatment prematurely; 16% of patients stopped treatment early because of side effects. One patient with cirrhosis died of sepsis during treatment. Premature discontinuation was highest among TVR-treated cirrhotic patients (58%). Sustained virologic response (SVR) was achieved in 55% overall and was similar comparing the TVR (56%)- and BOC (53%)-treated groups. The only independent predictors of treatment failure were cirrhosis at baseline [odds ratio (OR) for SVR 0.44, p = 0.004] and prior partial or null response (OR for SVR 0.57, p = 0.02). In the initial application of TVR and BOC, patients with cirrhosis and prior treatment failure were prioritized for treatment. In this real-world experience, most patients successfully completed a full treatment course. However, side effect-related premature discontinuations were common, and SVR rates were lower than reported in clinical trials.

Viral Breakthrough Is Associated With Resistance Using Direct Acting Agents in Patients Treated for Chronic Hepatitis C Infection

Despite improved virologic response with the addition of direct acting agents to peginterferon and ribavirin treatment in chronic hepatitis C virus (HCV) genotype 1 infection, a subset of patients experience viral breakthrough while on therapy. Defining viral breakthrough and patient characteristics is important for ongoing and future HCV treatment. Thirty-four patients treated with telaprevir between June 2011 and July 2012 were retrospectively evaluated for presence of viral breakthrough. Baseline patient characteristics, time to viral breakthrough, and HCV resistance patterns were determined. Viral breakthrough was seen in 26.5% of patients treated. Eight of 9 patients experienced breakthrough in the peginterferon and ribavirin-only phase of treatment with mean (±SD) time to breakthrough of 21.3 (±6.4) weeks. Viral breakthrough was more frequently seen in patients with genotype 1a, advanced liver fibrosis, and prior null treatment response. A majority of patients had presence of resistant mutations upon testing. A significant proportion of patients experience viral breakthrough after completion of the direct acting agent portion of triple therapy. More frequent virologic assessments during the peginterferon and ribavirin treatment phase may be necessary to reduce cost and adverse effects of treatment.

Retreatment of HCV with ABT-450/r–Ombitasvir and Dasabuvir with Ribavirin

BackgroundIn this phase 3 trial we evaluated the efficacy and safety of the interferon-free combination of ABT-450 with ritonavir (ABT-450/r), ombitasvir (also known as ABT-267), dasabuvir (also known as ABT-333), and ribavirin for the retreatment of HCV in patients who were previously treated with peginterferon–ribavirin.MethodsWe enrolled patients with HCV genotype 1 infection and no cirrhosis who had previously been treated with peginterferon–ribavirin and had a relapse, a partial response, or a null response. Patients were randomly assigned in a 3:1 ratio to receive coformulated ABT-450/r–ombitasvir (at a once-daily dose of 150 mg of ABT-450, 100 mg of ritonavir, and 25 mg of ombitasvir) and dasabuvir (250 mg twice daily) with ribavirin (1000 or 1200 mg daily) or matching placebos during the 12-week double-blind period. The primary end point was the rate of sustained virologic response 12 weeks after the end of study treatment. The primary efficacy analysis compared this rate among patients assigned to the active regimen with a historical response rate (65%) among previously treated patients with HCV genotype 1 infection and no cirrhosis who had received retreatment with telaprevir and peginterferon–ribavirin.ResultsA total of 394 patients received at least one study-drug dose. In the active-regimen group, 286 of 297 patients had a sustained virologic response at post-treatment week 12, for an overall rate of 96.3% (95% confidence interval, 94.2 to 98.4). This rate was noninferior and superior to the historical control rate. Rates were 95.3% among patients with a prior relapse (82 of 86 patients), 100% among patients with a prior partial response (65 of 65 patients), and 95.2% among patients with a prior null response (139 of 146 patients). Pruritus occurred more frequently with the active regimen (in 13.8% of patients) than with placebo (5.2%, P=0.03). Three patients in the active-regimen group (1.0%) discontinued the study drugs owing to adverse events. Hemoglobin values of grade 2 (8.0 to <10.0 g per deciliter) and grade 3 (6.5 to <8.0 g per deciliter) occurred in 4.7% and 0.3% of patients in the active-regimen group, respectively.ConclusionsRates of response to a 12-week interferon-free combination regimen were more than 95% among previously treated patients with HCV genotype 1 infection, including patients with a prior null response. (Funded by AbbVie; SAPPHIRE-II ClinicalTrials.gov number, NCT01715415.)

Perspectivas futuras del tratamiento de la hepatitis C, ¿sin interferón y sin ribavirina?

The hepatitis C virus is an important health problem worldwide. Currently, the standard treatment of genotype 1 chronic hepatitis C is the combination of pegylated interferon, ribavirin and a first-generation protease inhibitor: telaprevir or boceprevir. This triple therapy has improved the efficacy of treatment but has also increased regimen complexity, costs, and the number of adverse effects (mainly hematological and cutaneous). Unfortunately, viral response rates are still suboptimal in patients with cirrhosis, particularly those with a prior null response. Moreover, studies carried out in clinical practice have shown that the presence of advanced fibrosis confers a high risk of developing severe adverse effects during treatment (infection, decompensation and even death). It is therefore essential to select candidates for triple therapy according to their risk of complications and possibilities for cure. In this scenario, interferon (and ribavirin)-free combinations are very safe and well tolerated first-line treatments.This review describes the current treatment of hepatitis C as well as the latest results of studies combining distinct direct antiviral agents without interferon. It is hoped that these drugs will be available shortly, although their cost may be high. Consequently, it is essential to identify those patients who could derive the greatest benefit from these treatments.

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

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. 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. 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. Re-treatment with BOC/PR improved SVR rates in all patient subgroups, including those with prior null response.

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

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. 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. 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. 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.

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

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. 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). 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. 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.

A Survey of Hepatitis C Treatment Clinical Practice Patterns Using the Newly Approved Protease Inhibitors

To describe current hepatitis C virus (HCV) treatment practices in the United States and identify physician characteristics associated with the use of first generation direct-acting antivirals (DAAs). HCV treatment practice patterns have not been assessed after the introduction of DAA, which are now considered standard of care for most HCV genotype 1 patients. We sampled nationally representative physicians treating HCV patients with DAAs through a web-based survey. Stepwise multivariate logistic regression was performed to identify physician characteristics associated with the use of DAAs in 4 clinical vignettes (early stage fibrosis, prior null response, human immunodeficiency virus (HIV) co-infection, and post-liver transplantation). Of 1658 deliverable emails, 337 (20.3%) clinicians responded. Fifty percent of providers recommended DAA therapy for treatment-naive patients with early stage fibrosis, whereas 49% of providers would await new therapies. For prior null responders with significant fibrosis, 74% would attempt retreatment using DAAs and 26% would await new therapies. Off-label use of DAAs was recommended by 69% of providers for patients with HIV infection and 48% of providers for post-liver transplant patients. Academic affiliation was significantly associated with higher rates of off-label use in both HIV and post-liver transplant patients. Despite more potent and less toxic therapies on the horizon, many physicians recommended DAAs in treatment-naive patients with early stage fibrosis. Providers also frequently recommended DAAs for off-label uses, such as treating post-liver transplant patients and those coinfected with HIV.

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

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. 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.