STARTVerso1: A randomized trial of faldaprevir plus pegylated interferon/ribavirin for chronic HCV genotype-1 infection.

BACKGROUND & AIMS: The efficacy and tolerability of faldaprevir, a potent hepatitis C virus (HCV) NS3/4A protease inhibitor, plus peginterferon (PegIFN) and ribavirin (RBV) was assessed in a double-blind, placebo-controlled phase 3 study of treatment-naïve patients with HCV genotype-1 infection. METHODS: Patients were randomly assigned (1:2:2) to PegIFN/RBV plus: placebo (arm 1, n = 132) for 24 weeks; faldaprevir (120 mg, once daily) for 12 or 24 weeks (arm 2, n = 259); or faldaprevir (240 mg, once daily) for 12 weeks (arm 3, n = 261). In arms 2 and 3, patients with early treatment success (HCV-RNA <25 IU/ml at week 4 and undetectable at week 8) stopped all treatment at week 24. Other patients received PegIFN/RBV until week 48 unless they met futility criteria. The primary endpoint was sustained virologic response 12 weeks post-treatment (SVR12). RESULTS: SVR12 was achieved by 52%, 79%, and 80% of patients in arms 1, 2, and 3, respectively (estimated difference for arms 2 and 3 vs. arm 1: 27%, 95% confidence interval 17%-36%; and 29%, 95% confidence interval, 19%-38%, respectively; p < 0.0001 for both). Early treatment success was achieved by 87% (arm 2) and 89% (arm 3) of patients, of whom 86% and 89% achieved SVR12. Adverse event rates were similar among groups; few adverse events led to discontinuation of all regimen components. CONCLUSIONS: Faldaprevir plus PegIFN/RBV significantly increased SVR12, compared with PegIFN/RBV, in treatment-naïve patients with HCV genotype-1 infection. No differences were seen in responses of patients given faldaprevir once daily at 120 or 240 mg.

Safety and efficacy of triple therapy with peginterferon, ribavirin and boceprevir within an early access programme in Spanish patients with hepatitis C genotype 1 with severe fibrosis: SVRw12 analysis.

BACKGROUND & AIMS: The addition of protease inhibitors (PIs) changed the hepatitis C virus (HCV) treatment standards and improved sustained viral response (SVR) rates in patients with genotype 1 HCV infection. METHODS: Prospective, multicentre, national registry that includes naïve and treatment-experienced patients with HCV genotype 1 infection, who had bridging fibrosis or cirrhosis and were treated with triple therapy (peginterferon alfa-2a or alfa-2b, ribavirin and boceprevir) as compassionate use, and in accordance with the Summary of Product Characteristics. RESULTS: Most of the patients (68.2%) were male, with a mean age of 53 years, 75% (n = 128) had HCV 1b genotype and baseline viral load of 6.2 log. According to prior treatment, 20% of patients were treatment-naïve and 80% had received prior treatment. Approximately 36.5% of patients (n = 62) reported at least one serious adverse events (SAEs) (total SAEs = 103). The most common SAEs were neutropenia (57.6%), anaemia (47.6%) and grade 3 thrombopenia (25.9%). Patients with albumin <3.5 g/dl and bilirubin >2 mg/dl had an increased relative risk (greater than one-fold) for SAEs, including infections and hepatic decompensation. In the intent-to-treat analysis (n = 170), the overall percentage of patients with SVRw12 was 46.5%. In patients with 1 log decrease at week 4 (lead-in phase), the overall SVRw12 rate was 67.0%. In the patients initiating triple therapy with boceprevir (n = 139), the global response rate was 56.4%. In a multivariate analysis, an increased probability of achieving SVR was associated with response to prior treatment (relapsers), >1 log decrease in viral load in the lead-in phase and baseline albumin >3.5 g/dl. CONCLUSIONS: Triple therapy in patients with severe fibrosis/cirrhosis is associated with a higher rate of SAE and a lower rate in comparison with patients with mild disease. However, for patients with intact liver function, it could be considered as a treatment option, when other alternatives would not be available.

[Lead-in period and week 8 as predictive tools for response to boceprevir therapy: a retrospective study of Spanish real clinical practice]. / Período de lead-in y semana 8 como herramientas de predicción de la respuesta en el tratamiento con boceprevir: estudio retrospectivo de la práctica clínica real en España.

INTRODUCTION: Most discontinuations due to lack of virological response occur during the first few weeks of hepatitis C virus (HCV) triple therapy. Improved knowledge of baseline factors and their correlation with boceprevir decision points may predict treatment success. METHODS: An observational, retrospective study was conducted to describe the lead-in period as a clinical decision tool in HCV genotype 1 patients treated with boceprevir. Data were collected from the medical records of 186 consecutive patients distributed across 20 Spanish general hospitals. RESULTS: This study included 171 patients. A total of 80% had fibrosis F3/F4, 74% were previously treated, and 26% were treatment-naïve. After the lead-in period, 54.5% of the patients had a reduction of ≥1 log10; this reduction occurred in 52.5% of those with advanced fibrosis. Boceprevir therapy was started in 94% of the patients. Discontinuations at week 4 were limited to null responders with cirrhosis. The baseline factors associated with virological response at week 4 were IL28B, previous response, and fibrosis score. At week 8, HCV-RNA was undetectable in 48.8% of the patients. The correlation between responses at weeks 8 and 12 was 88%. CONCLUSION: In the Spanish clinical setting, lead-in was mainly used as a clinical decision point for non-responders with cirrhosis. The good correlation between stopping rules at weeks 8 and 12 could be used to anticipate discontinuation, thus saving adverse events and costs.

Safety and efficacy of treatment with pegylated interferon alpha-2a with ribavirin in chronic hepatitis C genotype 4.

The hepatitis C virus (HCV) genotype is an important predictive outcome parameter for pegylated interferon plus ribavirin therapy. Most published therapeutic trials to date have enrolled mainly patients with HCV genotypes 1, 2 and 3. Limited studies have focused on genotype 4 patients, who have had a poor representation in pivotal trials. Our aim was to evaluate the efficacy and safety of treatment with standard dose pegylated interferon alfa-2a in combination with weight-based ribavirin in patients with chronic hepatitis C genotype 4. In this prospective observational study, 198 patients with HCV-4 were included in this study from February 2004 to August 2005,188 patients who received at least 1 dose of drugs were included in the ITT analysis and they were treated with pegylated interferon alfa-2a and ribavirin for 48 weeks. Baseline and demographic characteristics, response to treatment at weeks 12, 48 and 72, and the nature and frequency of adverse effects were analyzed. Virological response at week 12 was achieved in 144 patients (76.6%). Virological response at the end of treatment was present in 110 patients (58.5%). At week 72, 99 patients presented SVR (52.7%). The reported adverse events were similar to those found in the literature for treatments of similar dose and duration. In conclusion, combined treatment with pegylated interferon alfa-2a and ribavirin was well tolerated and effective in chronic hepatitis C genotype 4, yielding response rates between those reported for genotype 1 and those of genotypes 2-3.

[Telaprevir in treatment-naïve patients with HCV monoinfection]. / Telaprevir en el paciente monoinfectado sin tratamiento previo.

Chronic hepatitis due to the hepatitis C virus (HCV) infection affects nearly 180 million people worldwide. This infection is curable. Until 1 year ago, the only treatment for genotype 1 HCV was the combination of pegylated interferon and ribavirin, which was only moderately effective (40-50%). The introduction of new antiviral agents, such as telaprevir, represents a change of paradigm and has revolutionized the treatment of this infection. This drug has increased the likelihood of viral response (to 80%) and has allowed treatment length to be shortened in more than 50% of patients. New stopping rules have been developed to avoid the development of resistances. Finally, special attention should be paid to potentially serious adverse effects, particularly anemia and cutaneous alterations.

Pharmacoeconomic analysis of the treatment of chronic hepatitis C with peginterferon alfa-2a or peginterferon alfa-2b plus ribavirin in Spain.

BACKGROUND: An independent meta-analysis of randomized comparative trials of peginterferons alfa-2a and alfa-2b, both combined with ribavirin, analyzed the probability of achieving a sustained virological response (SVR). OBJECTIVE: To estimate the long-term cost-effectiveness of treatment of patients with chronic hepatitis C with peginterferon alfa-2a (180µg/week) plus ribavirin (800-1200mg/day) vs. alfa-2b (1.5µg/kg/week) plus ribavirin (800-1400mg/day), from the perspective of the Spanish National Health System. METHODS: A Markov model was developed with 7 health states to simulate lifetime disease progression. SVR was calculated from the meta-analysis data. Transition probabilities and health state utilities were obtained from published literature. Direct healthcare costs were obtained from the drug catalog, while costs of disease-related complications were obtained from published studies and healthcare cost database. Costs were expressed in 2010€. The annual discount rate applied was 3.5% for both costs and benefits. RESULTS: SVR rate for treatment with alfa-2a was higher than with alfa-2b; the differences were 6.0%, 7.6% and 8.7% for all genotypes, genotypes 1/4 and genotypes 2/3, respectively. Each patient would gain 0.469, 0.600 and 0.685 life-years and 0.155, 0.198 and 0.227 quality-adjusted life-years with alfa-2a vs. alfa-2b, for the respective genotypes. The cost saving per patient treated with alfa-2a would be €705, €672 and €1900, for all genotypes and for genotypes 1/4 and 2/3, respectively, alfa-2a being dominant. CONCLUSIONS: According to the present model, treatment of patients with chronic hepatitis C with peginterferon alfa-2a is cost-effective compared with peginterferon alfa-2b, both combined with ribavirin.

Prediction of week 4 virological response in hepatitis C for making decision on triple therapy: the Optim study.

BACKGROUND: Virological response to peginterferon + ribavirin (P+R) at week 4 can predict sustained virological response (SVR). While patients with rapid virological response (RVR) do not require triple therapy, patients with a decline <1 log10 IU/ml HCVRNA (D1L) should have treatment discontinued due to low SVR rate. AIM: To develop a tool to predict first 4 weeks' viral response in patients with hepatitis C genotype 1&4 treated with P+R. METHODS: In this prospective and multicenter study, HCV mono-infected (n=538) and HCV/HIV co-infected (n=186) patients were included. To develop and validate a prognostic tool to detect RVR and D1L, we segregated the patients as an estimation cohort (to construct the model) and a validation cohort (to validate the model). RESULTS: D1L was reached in 509 (80.2%) and RVR in 148 (22.5%) patients. Multivariate analyses demonstrated that HIV co-infection, Forns' index, LVL, IL28B-CC and Genotype-1 were independently related to RVR as well as D1L. Diagnostic accuracy (AUROC) for D1L was: 0.81 (95%CI: 0.76 ̶ 0.86) in the estimation cohort and 0.71 (95%CI: 0.62 ̶ 0.79) in the validation cohort; RVR prediction: AUROC 0.83 (95%CI: 0.78 ̶ 0.88) in the estimation cohort and 0.82 (95%CI: 0.76 ̶ 0.88) in the validation cohort. Cost-analysis of standard 48-week treatment indicated a saving of 30.3% if the prognostic tool is implemented. CONCLUSIONS: The combination of genetic (IL28B polymorphism) and viral genotype together with viral load, HIV co-infection and fibrosis stage defined a tool able to predict RVR and D1L at week 4. Using this tool would be a cost-saving strategy compared to universal triple therapy for hepatitis C.

Development and validation of two models for early prediction of response to therapy in genotype 1 chronic hepatitis C.

Early prediction of response to therapy in genotype 1 chronic hepatitis C is difficult. Two predictive models, a pretreatment scoring model (PreT-SM) and a fourth week of therapy scoring model (4w-SM) were constructed in a cohort of 104 patients from a single center (estimation cohort) and validated in a cohort of 141 patients from four independent centers (validation cohort). Individual scores were calculated using variables independently associated with sustained virological response (SVR). Baseline viral load, aspartate aminotransferase/alanine aminotransferase ratio, serum cholesterol, and a numerical score for noninvasive estimation of liver fibrosis were included in the PreT-SM; HCV RNA clearance and PreT-SM scores were included in the 4w-SM. Receiver operating characteristic analysis revealed the area under the curve in the estimation cohort and in the validation cohort to be, respectively, 0.856 and 0.847 for the PreT-SM and 0.908 and 0.907 for the 4w-SM. Low scores were associated with SVR, high scores with non-SVR. The best cutoff scores from the PreT-SM (7 and 9.70) identified, respectively, 36% of patients with SVR and 41% of those with non-SVR from the validation cohort, with high accuracy (> or =90% positive predictive value [PPV] and specificity). Similarly, cutoff scores of 3.20 and 5.60 from the 4w-SM identified, respectively, 71% of patients with SVR and 53% of those with non-SVR from the same cohort with high accuracy (PPV and specificity >92%). In conclusion, these models predicted response to therapy before or after 4 weeks of treatment in approximately 60% of genotype 1 patients and may be valuable for the management of this condition.

Peginterferon-alfa2a plus ribavirin for 48 versus 72 weeks in patients with detectable hepatitis C virus RNA at week 4 of treatment.

BACKGROUND & AIMS: Patients with chronic hepatitis C who do not respond rapidly to therapy have a low chance of developing a sustained virologic response (SVR) when treated for 48 weeks. This study investigated whether treatment for 72 weeks increases the rate of SVR in patients with detectable hepatitis C virus (HCV)-RNA levels at week 4 of treatment. METHODS: A total of 510 treatment-naive patients were treated with peginterferon-alfa2a (180 microg/wk) plus ribavirin (800 mg/day). Patients with detectable HCV-RNA levels at week 4 (n = 326) were randomized to complete 48 (group A, n = 165) or 72 weeks (group B, n = 161) of treatment. Patients with undetectable HCV-RNA levels at week 4 (n = 184) were allocated into group C (n = 148) or group D (n = 36), according to HCV genotype and baseline viremia, and treated for 24 or 48 weeks, respectively. All patients were followed-up for 24 weeks after the end of treatment. RESULTS: The end-of-treatment response rate (61%) was similar in groups A and B, but the SVR rate was higher in group B (45% vs 32% in A; P = .01). In genotype 1-infected patients randomized to group A (n = 149) or B (n = 142), SVR rates were 28% and 44%, respectively (P = .003). The incidence of adverse events was similar in all groups. Treatment discontinuation was more frequent in group B (36%) than in group A (18%) (P = .0004). SVR rates in groups C and D were 79% and 64%, respectively. CONCLUSIONS: Extension of treatment with peginterferon-alfa2a plus ribavirin from 48 to 72 weeks significantly increases the rate of SVR in patients with detectable viremia at week 4 of treatment.