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

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.

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.

JUMP-C: a randomized trial of mericitabine plus pegylated interferon alpha-2a/ribavirin for 24 weeks in treatment-naïve HCV genotype 1/4 patients.

UNLABELLED: Mericitabine is a selective nucleoside analog inhibitor of the hepatitis C virus (HCV) NS5B RNA-dependent RNA polymerase, with activity across all HCV genotypes. Treatment-naïve patients infected with HCV genotype 1 or 4 were randomized to 24 weeks of double-blind treatment with either mericitabine 1,000 mg (N = 81) or placebo (N = 85) twice-daily (BID) in combination with pegylated interferon alpha-2a (Peg-IFNα-2a)/ribavirin (RBV). Patients randomized to mericitabine with HCV RNA <15 IU/mL from week 4 to 22 (extended rapid virologic response; eRVR) stopped all treatment at week 24; all other patients continued Peg-IFNα-2a/RBV to complete 48 weeks of treatment. The primary efficacy endpoint was sustained virologic response (SVR; HCV RNA <15 IU/mL after 24 weeks of treatment-free follow-up). SVR was achieved in 56.8% (95% confidence interval [CI]: 45.9-67.0) of mericitabine-treated patients and 36.5% (95% CI: 27.0-47.1) of placebo-treated patients (Δ = 20.3%; 95% CI 5.5-35.2). SVR rates were higher in mericitabine- than placebo-treated patients when subdivided by IL28B genotype (CC, 77.8% versus 56.0%; non-CC, 44.1% versus 16.2%) and hepatic fibrosis (noncirrhotic, 63.3% versus 41.9%; cirrhotic, 38.1% versus 21.7%). Overall relapse rates were 27.7% and 32.0% in mericitabine- and placebo-treated patients, respectively. No evidence of NS5B S282T-variant virus or phenotypic resistance to mericitabine was observed in the one patient who experienced partial response. No S282T variants were detected in any baseline samples. The safety profile of mericitabine was similar to that of, and fewer patients in the mericitabine than in the placebo group discontinued treatment for safety reasons. CONCLUSION: A 24-week response-guided combination regimen of mericitabine 1,000 mg BID plus Peg-IFNα-2a/RBV is well tolerated and more effective than a standard 48-week course of Peg-IFNα-2a/RBV.

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.

Balapiravir plus peginterferon alfa-2a (40KD)/ribavirin in a randomized trial of hepatitis C genotype 1 patients.

INTRODUCTION: Balapiravir (R1626, RG1626) is the prodrug of a nucleoside analogue inhibitor of the hepatitis C virus (HCV) RNA-dependent RNA polymerase (R1479, RG1479). This phase 2, double-blind international trial evaluated the optimal treatment regimen of balapiravir plus peginterferon alfa-2a (40KD)/ribavirin. MATERIAL AND METHODS: Treatment-naive genotype 1 patients (N = 516) were randomized to one of seven treatment groups in which they received balapiravir 500, 1,000, or 1,500 mg twice daily, peginterferon alfa-2a (40KD) 180 or 90 µg/week and ribavirin 1,000/1,200 mg/day or peginterferon alfa-2a (40KD)/ribavirin. The planned treatment duration with balapiravir was reduced from 24 to 12 weeks due to safety concerns. RESULTS: The percentage of patients with undetectable HCV RNA was consistently higher in all balapiravir groups from week 2 to 12. However, high rates of dose modifications and discontinuations of one/all study drugs compromised the efficacy assessment and resulted in similar sustained virological response rates in the balapiravir groups (range 32-50%) and the peginterferon alfa-2a (40KD)/ribavirin group (43%). Balapiravir was discontinued for safety reasons in 28-36% of patients (most often for lymphopenia) and the percentage of patients with serious adverse events (especially hematological, infection, ocular events) was dose related. Serious hematological adverse events (particularly neutropenia, lymphopenia) were more common in balapiravir recipients. Two deaths in the balapiravir/peginterferon alfa-2a/ribavirin combination groups were considered possibly related to study medication. CONCLUSION: Further development of balapiravir for the treatment of chronic hepatitis C has been halted because of the unacceptable benefit to risk ratio revealed in this study (www.ClinicalTrials.gov NCT 00517439).

Histologic outcomes in hepatitis C-infected patients with varying degrees of virologic response to interferon-based treatments.

UNLABELLED: Patients with chronic hepatitis C with partial virologic response or nonresponse to interferon-based therapies can experience treatment-related improvements in liver histology. This retrospective analysis assessed the histologic response to treatment in patients with varying degrees of virologic response (sustained virologic response [SVR], breakthrough, relapse, or nonresponse), time to hepatitis C virus (HCV) RNA undetectability, and duration of viral suppression. Patients (HCV genotypes 1-6) with baseline and follow-up liver biopsies from eight phase 2 to phase 4 interferon-based trials were analyzed. Blinded biopsies were evaluated by a single pathologist. Improvements or worsening of METAVIR necroinflammatory activity and fibrosis were defined as increase or decrease of ≥1 grading category from baseline to 24 weeks after end of treatment. A majority of the 1571 patients with paired biopsy data were white, male, with HCV genotype 1/4, baseline HCV RNA levels >800,000 IU/mL, and baseline alanine aminotransferase levels ≤3 × upper limit of the normal range; mean baseline activity and fibrosis scores were 1.8 and 1.7, respectively. Overall, 80% of patients received peginterferon alfa-2a monotherapy or peginterferon alfa-2a/ribavirin combination therapy. Mean treatment duration was 46 weeks. There was a positive correlation between the degree of virologic response and improvements in METAVIR activity and fibrosis, and an inverse correlation with worsening activity and fibrosis (all comparisons, P < 0.0001). Patients with SVR had the greatest histologic benefit. As a combined group, relapsers and patients with breakthrough had significantly greater benefits than nonresponders (activity, P = 0.0001; fibrosis, P = 0.003). Consistent with these results, a better histologic response was correlated with a shorter time to undetectable HCV RNA and a longer duration of viral suppression (all comparisons, P < 0.0001). CONCLUSION: In patients with chronic hepatitis C who were treated with interferon-based therapies, histologic benefits may be observed even in the absence of an SVR.

A phase III study of the safety and efficacy of viramidine versus ribavirin in treatment-naïve patients with chronic hepatitis C: ViSER1 results.

UNLABELLED: Pegylated interferon (peg-IFN) and ribavirin (RBV) are effective in eradicating the hepatitis C virus in more than half of patients. However, anemia arising from RBV-induced hemolysis can prompt dose reductions and lower sustained virologic response (SVR) rates. In early clinical trials, Viramidine (VRD, renamed taribavirin), an RBV prodrug, was associated with less anemia and VRD given at 600 mg twice daily (BID) appeared to provide the best safety with comparable efficacy to RBV. The phase III Viramidine's Safety and Efficacy versus Ribavirin 1 (ViSER1) study randomized 972 treatment-naïve patients with chronic hepatitis C to fixed-dose VRD (600 mg BID) or weight-based RBV (1000 or 1200 mg/day), each given with peg-IFN alfa-2b at 1.5 microg/kg/week. The primary efficacy endpoint was SVR rate, and the primary safety endpoint was hemoglobin (Hb) event rate (percent of patients with Hb < 10 g/dL or at least a 2.5-g/dL decrease from baseline). SVR rates were 37.7% with VRD (244/647) and 52.3% with RBV (170/325). Thus, the ViSER1 study failed to demonstrate the primary noninferiority efficacy endpoint. Significantly fewer patients had Hb events with VRD (353/647; 54.6%) compared to those with RBV (272/325; 83.7%) (P < 0.001), and significantly fewer developed anemia (Hb < 10 g/dL) with VRD (34/647; 5.3%) compared to those with RBV (76/325; 23.5%) (P < 0.001). CONCLUSION: Fixed doses of VRD failed to demonstrate noninferiority to RBV in producing SVR rates. The incidence of anemia was approximately four-fold significantly lower with VRD than with RBV. These results suggest fixed-dose VRD given 600 mg BID is insufficient to treat patients with chronic hepatitis C; a weight-based dosing trial of viramidine is currently under way.

R1626 plus peginterferon Alfa-2a provides potent suppression of hepatitis C virus RNA and significant antiviral synergy in combination with ribavirin.

UNLABELLED: R1626, a prodrug of the hepatitis C virus (HCV) RNA polymerase inhibitor R1479, showed time-dependent and dose-dependent reduction of HCV RNA levels in a previous study. The present study evaluated the efficacy and safety of R1626 administered for 4 weeks in combination with peginterferon alfa-2a +/- ribavirin in HCV genotype 1-infected treatment-naive patients. Patients were randomized to: DUAL 1500 (1500 mg R1626 twice daily [bid] + peginterferon alfa-2a; n = 21); DUAL 3000 (3000 mg R1626 bid + peginterferon alfa-2a; n = 32); TRIPLE 1500 (1500 mg R1626 bid + peginterferon alfa-2a + ribavirin; n = 31); or standard of care (SOC) (peginterferon alfa-2a + ribavirin; n = 20). At 4 weeks HCV RNA was undetectable (<15 IU/mL) in 29%, 69%, and 74% of patients in the DUAL 1500, DUAL 3000, and TRIPLE 1500 arms, respectively, compared with 5% of patients receiving SOC, with respective mean reductions in HCV RNA from baseline to week 4 of 3.6, 4.5, 5.2, and 2.4 log(10) IU/mL. Synergy was observed between R1626 and peginterferon alfa-2a and between R1626 and ribavirin. There was no evidence of development of viral resistance. Adverse events (AEs) were mainly mild or moderate; seven patients had nine serious AEs (including one patient with one serious AE in SOC). The incidence of Grade 4 neutropenia was 48%, 78%, 39%, and 10% in DUAL 1500, DUAL 3000, TRIPLE 1500, and SOC, respectively, and was the main reason for dose reductions. CONCLUSION: A synergistic antiviral effect was observed when R1626 was combined with peginterferon alfa-2a +/- ribavirin; up to 74% of patients had undetectable HCV RNA at week 4. Dosing of R1626 was limited by neutropenia; a study of different dosages of R1626 in combination with peginterferon alfa-2a and ribavirin is underway.

Improved outcomes in patients with hepatitis C with difficult-to-treat characteristics: randomized study of higher doses of peginterferon alpha-2a and ribavirin.

UNLABELLED: Treatment response remains suboptimal for many patients with chronic hepatitis C, particularly those with genotype 1 and high levels of viremia. The efficacy of high-dose regimens of peginterferon alfa-2a and ribavirin was compared with conventional dose regimens in patients with features predicting poor treatment responses. Eligible treatment-naïve adults with genotype 1 infection, hepatitis C virus (HCV) RNA >800,000 IU/mL and body weight >85 kg were randomized to double-blind treatment with peginterferon alfa-2a at 180 or 270 microg/week plus ribavirin at 1200 or 1600 mg/day for 48 weeks (four regimens were evaluated). The primary endpoint was viral kinetics during the first 24 weeks of therapy. Among patients receiving peginterferon alfa-2a (270 microg/week) the magnitude of HCV RNA reduction was significantly greater than for patients randomized to the conventional dose of peginterferon alfa-2a (180 microg/week) for the pairwise comparison for ribavirin at 1600 mg/day (P = 0.036) and numerically greater for the pairwise comparison for ribavirin at 1200 mg/day (P = 0.060). Patients randomized to the highest doses of peginterferon alfa-2a (270 microg/week) and ribavirin (1600 mg/day) experienced the numerically highest rates of sustained virologic response (HCV RNA < 50 IU/mL) and the lowest relapse rate (47% and 19%, respectively). The arm with the higher doses of both drugs was less well-tolerated than the other regimens. CONCLUSION: Higher fixed doses of peginterferon alfa-2a (270 microg/week) and ribavirin (1600 mg/day) may increase sustained virologic response rates compared with lower doses of both drugs in patients with a cluster of difficult-to-treat characteristics.

Comparing the safety, tolerability and quality of life in patients with chronic hepatitis B vs chronic hepatitis C treated with peginterferon alpha-2a.

BACKGROUND/AIMS: Hepatitis B and C viruses (HBV and HCV) are two clinically distinct but related diseases. Pooled data from five studies of peginterferon alpha-2a in patients with chronic HCV infection (CHC) were compared with two studies of the drug in patients with chronic HBV infection (CHB). METHOD: The HBV studies included both hepatitis B e antigen (HBeAg)-positive (n=271) and HBeAg-negative (n=177) patients; 791 patients took part in the HCV trials. In all studies, patients were treated with 180 microg peginterferon alpha-2a monotherapy once weekly for 48 weeks. The number of adverse events (AEs), discontinuations and dose modifications were documented. Health-related quality of life (HRQL) was assessed using the Short-Form 36 questionnaire. Safety was assessed throughout the treatment period. A 24-week treatment-free follow-up period was also included. RESULTS: Differences (HBV vs HCV) were observed in the incidence of AEs (88-89 vs 96-100%), serious AEs (4-5 vs 7-16%) and treatment withdrawals (6-8 vs 17-33%). The frequency of depression-related events was lower in CHB patients (4 vs 22%, P<0.001), as was the impact of treatment on HRQL. CONCLUSIONS: The safety and tolerability of peginterferon alpha-2a in patients with CHB compares favourably with that observed in CHC patients, with a lower incidence of common interferon-related AEs and a significantly lower incidence of depression.

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.

Developments in the treatment of chronic hepatitis C.

Hepatitis C virus is the most common chronic, blood-bourne infection, affecting 170 million people worldwide, approximately 3% of the global population. Of those infected with hepatitis C virus, 50 - 85% will develop chronic hepatitis C. Although hepatitis C is primarily a disease of the liver, a diagnosis is currently defined by the presence of the hepatitis C virus and treatment success is defined by the clearance of the virus. IFN-alpha is currently the mainstay of chronic hepatitis C therapy; the antiviral and anti-inflammatory components of IFN target both the infectious and the hepatic manifestations of the disease. However, even in combination with ribavirin, interferon therapy is not fully efficacious. Recently, the search for a more effective treatment has led investigators to optimise interferon therapy by developing pegylated interferons. Challenges facing our current treatment of hepatitis C virus include lack of efficacy in patients with difficult-to-treat disease, such as patients with cirrhosis or infected with hepatitis C virus genotype 1 (who represent a majority of US hepatitis C virus infections), the toxicity of combination therapy, the expense and difficulty of therapy and the poor reception of these treatments by many patients. The development of new hepatitis C antiviral agents is critical to our management of this disease. A number of approaches are under investigation, including long-acting interferons, immunomodulators, antifibrotics, specific hepatitis C virus-derived enzyme inhibitors, drugs that either block hepatitis C virus antigen production from RNA or prevent normal processing of hepatitis C virus proteins and other molecular approaches to treating hepatitis C virus, such as ribozymes and antisense oligonucleotides.

Simeprevir for the treatment of chronic hepatitis C.

INTRODUCTION: The addition of protease inhibitors such as telaprevir and boceprevir with PEGylated interferon and ribavirin has significantly improved cure rates for genotype 1 hepatitis C virus (HCV) infection. Simeprevir (TMC435) is a second-generation protease inhibitor that is in development for the treatment of genotype 1 HCV infection. AREAS COVERED: The authors present: i) an overview of Phases I - III clinical trials of simeprevir for HCV infection based on peer-reviewed literature and congress presentations and ii) an evaluation of the efficacy and safety of simeprevir in the treatment of HCV infection. EXPERT OPINION: Simeprevir is a once-daily oral medication that combined with PEGylated interferon and ribavirin appears to be a potent and safe agent to treat genotype 1 HCV infection for patients who are treatment-naïve and prior treatment-failures. Compared to telaprevir and boceprevir, simeprevir will likely be the protease inhibitor of choice for genotype 1 HCV infection based on ease of use, lower rates of adverse events, including rash and anemia, and no significant reported drug-drug interactions. Associated side effects inherent with interferon-based regimens may be problematic for patients. As HCV therapies evolve into interferon-free regimens, simeprevir may potentially be combined with other oral direct-acting agents without interferon to treat HCV infection.

Antifibrotics for chronic hepatitis C.

Development and testing of antifibrotic agents for the treatment of chronic hepatitis C have generally been targeted toward hepatic stellate cells, transforming growth factor-beta, the inflammatory response, or extracellular matrix accumulation. Although several agents such as interferon-gamma, long-term pegylated interferon, and caspase inhibitors have been studied, none have proved to be effective to date. There is a clear need for drugs that inhibit or reverse hepatic fibrosis as these would be immediately applicable to patients for whom antiviral therapy has failed or who have contraindications to antiviral therapy such as those with decompensated liver disease or renal failure. A major impediment in the development of new drugs in this field has been the inability to identify appropriate histologic or clinical end points within a reasonable period of study. Progress on providing suitable end points to therapy will then promote the development of newer agents.

Treatment of chronic hepatitis C patients with persistently normal alanine aminotransferase levels with the combination of peginterferon alpha-2a (40 kDa) plus ribavirin: impact on health-related quality of life.

BACKGROUND: Peginterferon alpha-2a (40 kDa) plus ribavirin is equally effective in chronic hepatitis C patients with normal or elevated alanine aminotransferase (ALT) values. This analysis, in patients with normal ALT levels, compared health-related quality of life (HRQoL) measurements between untreated control patients and treated patients grouped by virological response. HRQoL in the present population was also compared with HRQoL in patients with elevated ALT levels, observed in a previous study. METHODS: A total of 491 patients with persistently normal ALT levels were randomized to peginterferon alpha-2a (40 kDa)/ribavirin for 24 (group A) or 48 weeks (group B) or no treatment for 72 weeks (group C). Quality of life was assessed with valid instruments (self-administered Short Form (SF)-36 Health Survey and Fatigue Severity Scale). RESULTS: In groups A and B, patients with sustained virological responses after combination therapy had significantly better quality of life and less fatigue than patients without sustained responses. Differences were significant for five SF-36 domains, the SF-36 Physical Component score and both Fatigue Severity Scale scores. Viral clearance was not observed in any untreated patients (group C). Comparison with data from elevated ALT patients revealed little difference in baseline quality of life, although normal ALT patients had significantly higher scores related to mental health than elevated ALT patients. CONCLUSIONS: Eradication of HCV with peginterferon alpha-2a (40 kDa) plus ribavirin is associated with better quality of life and less fatigue in normal ALT patients. These patient benefits, coupled with the high probability of eradicating HCV, should be considered in making decisions about treating this population.

Early identification of HCV genotype 1 patients responding to 24 weeks peginterferon alpha-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 alpha-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 [corrected] 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 5.6, 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 alpha-2a/ribavirin sustained a RVR 24% of the time. This portends an 89% probability of a SVR after 24 weeks of treatment.