Clinical trial: peg-interferon alfa-2b and ribavirin for the treatment of genotype-1 hepatitis C recurrence after liver transplantation

Background  Treatment of hepatitis C virus (HCV) recurrence after liver transplantation (LT) is difficult with low response rates.
Aim  To assess the safety and efficacy of pegylated-interferon (PEG-IFN) alfa-2b + ribavirin (RBV) in patients with post-LT recurrent genotype-1 HCV and to establish stopping rules according to response.
Methods  Fifty-three patients with post-LT HCV recurrence were enrolled. Patients received PEG-IFN alfa-2b 1.0 μ/kg/week plus RBV 8–10 mg/kg/day for 24 weeks. Those with 'early virological response at week 24' (EVR24) continued treatment for 24 weeks (group A). Patients without EVR24 were randomized to continue (group B) or to discontinue (group C).
Results  Overall sustained virological response (SVR) was 26% (14/53). Alanine aminotransferase, rapid virological response, EVR12, EVR24, undetectable serum HCV-RNA at weeks 12 (cEVR12) and 24 (cEVR24) were related to SVR. cEVR12 and cEVR24 (OR: 14.7; 95% CI: 2.02–106.4) were independent predictors of SVR. All patients with SVR, had cEVR12. No patient in groups B and C achieved end-of-treatment response. One patient in group B had SVR.
Conclusions  Pegylated-interferon alfa-2b was effective in one of four of patients with HCV genotype 1 after LT. Treatment should be discontinued in patients with no virological response at week 12. Further studies are needed to evaluate whether a longer treatment period may be beneficial in patients with ≥2 log₁₀ drop in HCV-RNA at week 24.     

Clinical trial: exposure to ribavirin predicts EVR and SVR in patients with HCV genotype 1 infection treated with peginterferon alpha-2a plus ribavirin

Background  The impact of reduced drug exposure on outcomes in patients with chronic hepatitis C has not been determined in routine clinical practice.
Aim  To examine the impact of exposure to peginterferon alfa-2a and ribavirin on early virological response (EVR) and sustained virological response (SVR) in treatment-naïve patients with HCV genotype 1 infection enrolled in a large expanded access programme.
Methods  Eight hundred and ninety-one patients treated for 48 weeks with an initial ribavirin dose of 800 or 1000/1200 mg/day were evaluated. Ribavirin 1000 mg/day (<75 kg) or 1200 mg/day (≥75 kg) and peginterferon alfa-2a 180 μg/week were considered optimal. The impact of reduced drug exposure (expressed as a percentage of optimal) on EVR and SVR was evaluated.
Results  Mean ribavirin exposure in week 0–12 was 70% and 96% in patients assigned to ribavirin 800 and 1000/1200 mg/day, respectively. EVR and SVR rates were lower in patients assigned to ribavirin 800 than 1000/1200 mg/day (EVR, 75% vs. 84%, respectively, P  < 0.001; SVR, 45% vs. 54%, respectively, P  = 0.011). Furthermore, there was a strong correlation between achievement of EVR and SVR and ribavirin dose over the first 12 weeks expressed either as absolute dose or proportion of optimal dose received ( P  < 0.001 for both).
Conclusions  Ribavirin exposure to week 12 is significantly associated with EVR and SVR in genotype 1 patients. Maintenance of an optimal ribavirin dose is the most important modifiable factor during combination therapy for chronic hepatitis C.     

Safety, tolerability, and efficacy of pegylated-interferon alfa-2a plus ribavirin in HCV-related decompensated cirrhotics

Background  Pretransplantation clearance of hepatitis C virus (HCV)-RNA reduces the risk of HCV recurrence after transplantation. Furthermore, a sustained virological response could reduce disease progression and slow clinical deterioration in nontransplanted patients.
Aim  To evaluate the safety, tolerability and efficacy of pegylated-interferon (PEG-IFN) alfa-2a plus ribavirin therapy in HCV-related decompensated cirrhotics.
Methods  Twenty HCV-related decompensated cirrhotics (44–67 years, 12 males, six Child–Pugh score A, 14 Child–Pugh score B, all with genotype 1b) were enrolled into the study. Treatment with PEG-IFN alfa-2a (135 μg, once a week) plus ribavirin (1000–1200 mg/day) was commenced. A 48-week treatment was planned in patients who had early virological response.
Results  Treatment was stopped in 8 (40%) patients. The remaining 12 (60%) patients completed 48 weeks of therapy; nine (45%) of them obtained end-of-therapy virological response and six (30%) of them obtained sustained virological response. Living donor liver transplantation was performed in three (15%) patients. Eight (40%) and six (30%) patients needed to reduce PEG-IFN alfa-2a and ribavirin dosages, respectively. No patient died during the follow-up period.
Conclusion  PEG-IFN alfa-2a plus ribavirin therapy is safe, tolerable and efficacious in selected HCV-related decompensated cirrhotics.     

Cost-efficacy analysis of peginterferon alfa-2b plus ribavirin compared with peginterferon alfa-2a plus ribavirin for the treatment of chronic hepatitis C

OBJECTIVE: Combination therapy with pegylated interferon (Peg) and ribavirin (RBV) is the standard of care for the treatment of chronic hepatitis C virus (HCV) infection. This analysis compares the cost efficacy of treatment with pegylated interferon alfa-2b plus ribavirin (Peg-2b plus RBV) with pegylated interferon alfa-2a plus ribavirin (Peg-2a plus RBV) in hypothetical cohorts of 100 chronic HCV patients comprised 75% of genotype 1. METHODS: A decision analysis model was constructed from the viewpoint of a managed care organization to compare Peg-2b plus RBV (1.5 mcg per kilogram per week plus RBV 800 mg per day) and Peg-2a plus RBV (180 mcg per week plus RBV 1,000-1,200 mg per day) pursuant to the label dosing approved by the U.S. Food and Drug Administration. The model also included the so-called weight-based dosing regimen with Peg-2b plus RBV (1.5 mcg per kilogram per week plus RBV 10.6 mg/kg per day). Patient weight was assumed to be 80 kg. For purposes of this analysis, early virologic response (EVR), defined as viral negative or 2-log drop in viral load, was assessed at 12 weeks for only genotype 1 patients, and nonresponders were assumed to discontinue therapy. The positive predictive value (PPV) was calculated for each treatment group for genotype 1 patients, which is determined from the values for EVR and sustained viral response (SVR). Genotype 2 and genotype 3 patients were assumed to be treated for 24 weeks. Treatment duration and efficacy data were obtained from the published literature. Product pricing was based on average wholesale price, October 2004, and sensitivity analysis was performed using prices from the Federal Supply Schedule. Economic outcomes were determined from hypothetical 100-patient cohorts assumed to be comprised 75% of genotype 1 HCV. RESULTS: Taking into account both EVR and SVR, the PPV for genotype 1 patients was 0.63 and 0.57 for Peg-2b plus RBV and Peg-2a plus RBV, respectively. The proportion of treated patients achieving SVR would be nearly identical, (53.6%) and (53.8%) for Peg-2a plus RBV and Peg-2b plus flat RBV, respectively. For Peg- 2b plus weight-based RBV, the proportion of patients achieving SVR was higher (61.4%). Consequently, this leads to fewer overall treatment weeks for the Peg- 2b plus RBV cohorts. Therefore, the cost per successful treatment (defined as SVR) was 19.4% less (37,638 US dollars) for Peg-2b plus flat dosing of RBV as compared with Peg-2a plus RBV (46,717 US dollars). When Peg-2b plus RBV was dosed 1.5 mcg per kilogram per week plus RBV 10.6 mg/kg/day, then the cost per SVR was 39,045 US dollars. The cost for the 100-patient cohort was 2,024,846 US dollars for Peg-2b plus RBV, 2,397,529 US dollars for Peg-2b plus weight-based RBV, and 2,505,317 US dollars for Peg-2a plus RBV. This difference is due to a lower PPV in the Peg-2a plus RBV groups and hence more patients treated in spite of a low probability of achieving SVR. CONCLUSION: The results of this cost-efficacy analysis suggest that treating HCV genotype 1 patients with Peg-2b plus RBV may result in savings to a health care system because fewer of these patients are treated beyond 12 weeks when achieving sustained viral clearance is unlikely.     

Use of peginterferon alfa-2a (40 KD) (Pegasys) for the treatment of hepatitis C

Thrice-weekly interferon alfa-2b plus ribavirin has been the standard of care for chronic hepatitis C; however, a majority of patients fail to achieve a sustained virological response with this treatment. Peginterferon alfa-2a (40 KD), interferon alfa-2a conjugated to a 40 kDa branched polyethylene glycol moiety, exhibits sustained absorption and reduced renal clearance, resulting in antiviral pressure throughout a once-weekly dosing schedule. Peginterferon alfa-2a (40 KD) has superior virological efficacy to interferon alfa-2a, and elicits histological improvements in patients with and without sustained virological response. Peginterferon alfa-2a (40 KD) is effective in patients infected with viral genotype 1 and those with liver cirrhosis. Viral RNA measurements at 12 weeks can be used to predict the probability of achieving sustained virological response to peginterferon alfa-2a (40 KD) therapy. Peginterferon alfa-2a (40 KD) has comparable safety to interferon alfa-2a. The addition of ribavirin to peginterferon alfa-2a (40 KD) further enhances the therapeutic benefit for patients with hepatitis C.     

Follow-up of adverse drug reactions from peginterferon alfa-2b-ribavirin therapy

STUDY OBJECTIVE: To investigate the adverse drug reactions (ADRs) from peginterferon alfa-2b plus ribavirin in patients infected with the hepatitis C virus (HCV). DESIGN: Prospective, observational, pharmacovigilance study. SETTING: Gastroenterology department of a French university hospital. PATIENTS: A cohort of consecutive outpatients who were treated with peginterferon alfa-2b plus ribavirin for viral hepatitis. INTERVENTION: During the 1-year period of HCV therapy visits, a medical staff member trained in pharmacovigilance interviewed the patients about all ADRs and their use of other drugs. The ADRs assessed as serious were confirmed from regular review of the medical records. MEASUREMENTS AND MAIN RESULTS: A total of 87 patients were treated for HCV. Among these, peginterferon alfa-2b plus ribavirin therapy was started in 51 patients; one patient was lost to follow-up after 1 month. The ADRs were assessed as serious in 10 patients (20%): suicide (one patient), hospitalization (three patients), and definitive discontinuation of peginterferon alfa-2b plus ribavirin (six patients). The ADRs contributed to or were the main reason for withdrawing HCV drugs in 8 patients (16%). Dosage reductions of ribavirin and/or peginterferon alfa-2b were required in 10 patients (20%) and seemed less frequent than that needed in clinical trials. Compared with results of clinical trials, a similar frequency of hair loss, higher frequency of injection-site reactions, lower frequency of depression or insomnia, and higher frequency of endocrine ADRs or blurred vision were detected. CONCLUSION: Results suggest some differences in the frequencies of ADRs compared with data from clinical trials. A longer period of monitoring is warranted to improve knowledge about ADRs of pegylated interferon. A medical staff member trained in pharmacovigilance is useful to collect quantitative and qualitative data about ADRs.     

Clinical trial: extended treatment duration of peginterferon-alpha2b plus ribavirin for 72 and 96 weeks in hepatitis C genotype 1-infected late responders

Background  The benefits of prolonging peginterferon and ribavirin after 48 weeks of treatment to maximize sustained virological responses (SVR) in hepatitis C virus (HCV) genotype 1-infected patients remain to be understood.
Aim  To investigate whether extended treatment longer than 72 weeks may be superior to 72-week treatment.
Methods  A total of 120 treatment-naïve or retreated patients with HCV genotype 1 were treated with peginterferon-alpha-2b (1.5 μg/kg/week) plus weight-based ribavirin. We had 34 late responders, in whom HCV RNA first became undetectable at week 12–48, and randomized them into three groups receiving standard-dose peginterferon-alpha-2b plus low-dose ribavirin (200 mg/day) for extended 24 weeks (group A), receiving low-dose peginterferon-alpha-2b (0.75 μg/kg/week) plus low-dose ribavirin for extended 48 weeks (group B) or no extended treatment (group C), and evaluated the outcome according to their virological response.
Results  Multivariate analysis showed that the treatment for 96 weeks was identified as a significant, independent factor associated with SVR in HCV genotype 1-infected late responders in comparison with group A [odds ratio (OR), 10.002; P  =   0.080] and group C (OR, 17.748; P  =   0.025).
Conclusion  Extending the treatment duration from 48 weeks to 96 weeks improves SVR rates in genotype 1-infected patients with late virological response to peginterferon-alpha-2b and ribavirin.     

Sustained virological responses following standard anti-viral therapy in decompensated HCV-infected cirrhotic patients

Background  Little data is available about predictors of sustained virological response (SVR) during anti-viral therapy of patients with decompensated HCV cirrhosis.
Aims  To determine whether rapid and early virological responses (RVR and EVR) could predict SVR and help optimize treatment in these patients.
Methods  A total of 94 cirrhotics underwent treatment with peg-interferon alfa-2b (1.5 μg/kg weekly) and ribavirin (800/1200 mg daily) for 48 or 24 weeks for genotypes 1/4 or genotypes 2/3, respectively.
Results  Overall, SVR was achieved in 33 patients (35.1%), 16% with genotype 1/4 and 56.8% with genotype 2/3 ( P  < 0.01). At treatment week 4, 34 patients had undetectable HCV-RNA, 10 with genotype 1/4 and 24 with genotype 2/3. Of RVR patients, 24 achieved SVR (70.5%), 6 and 18 with genotypes 1 and non-1. At the multivariate analysis, only EVR, genotypes 2 and 3, and adherence to full course and dosage of therapy retained their independent predictive power, with corresponding ORs of 25.5 (95% CI 3.0–217.3), 4.2 (95% CI 1.2–15.3) and 9.1 (95% CI 2.2–38.0), respectively.
Conclusion  In decompensated cirrhotic patients, anti-viral therapy with current regimens is feasible and associated with an overall SVR rate of 35.1%. Treatment ought to be pursued among patients who attain an EVR, and maintain a full course and dosage of therapy.     

Histological benefits of virological response to peginterferon alfa-2a monotherapy in patients with hepatitis C and advanced fibrosis or compensated cirrhosis

Background  Patients with chronic hepatitis C virus and advanced fibrosis or cirrhosis are at risk for disease progression and hepatic decompensation.
Aim  To determine the effects on hepatic histology of treatment with peginterferon alfa-2a (90 or 180 μg/week) or interferon alfa-2a (3 million units three times weekly) for 48 weeks in patients with paired biopsies.
Methods  Liver biopsies were obtained at baseline and 6 months after end of treatment. Histological and virological responses were compared.
Results  Patients attaining sustained virological response ( n  = 40) demonstrated the greatest improvements in fibrosis (−1.0, P  < 0.0001) and inflammation (−0.65, P  < 0.0001). Patients who cleared hepatitis C virus during treatment, but later relapsed ( n  = 59), experienced less improvement in fibrosis (−0.04, P  < 0.0001) and inflammation (−0.14, P  = 0.0768). Nonresponders ( n  = 85) showed no significant improvement in inflammation or fibrosis. Multiple regression analysis showed that the only factors contributing to improvement in fibrosis were sustained virological response (vs. nonresponder, P  = 0.0005; vs. relapse, P  = 0.7525) and body mass index ≤30 kg/m² ( P  = 0.0995).
Conclusions  These findings indicate that virological response to peginterferon alfa-2a improves inflammation and fibrosis in hepatitis C virus patients with advanced fibrosis or cirrhosis. Improving virological response and maintaining ideal body weight are critical for achieving optimal histological outcomes in hepatitis C virus patients.     

Interferon alfa-2b and ribavirin: new indication. In children: more risks than in adults

(1) There is a far lower seroprevalence of hepatitis C virus (HCV) infection in children and adolescents (0.2% to 0.4%) than in adults. In childhood, the principal route of infection is mother-child transmission during pregnancy, while in adolescence transmission is mainly through certain at-risk behaviour (piercing, tattooing and drug injection). In adults with HCV infection, the standard treatment is a combination of peginterferon alfa and ribavirin. (2) 125 children aged 3 to 16 years were treated for 48 weeks in two non comparative trials. HCV RNA was undetectable in plasma in 46% of children six months after treatment cessation (36% for genotype 1 infection, 81% for other genotypes), a proportion similar to that generally seen in adults. It is not known whether the interferon alfa-2b + ribavirin combination slows the progression of histological lesions or prevents clinical complications of HCV infection. (3) Psychological disorders, particularly depression and suicidal tendencies, are the main adverse effects of treatment, especially in children. Growth retardation can also occur, mainly due to gastrointestinal disorders linked to interferon alfa-2b (loss of appetite, nausea and vomiting, diarrhoea). Catch-up growth appears to occur during the six months after treatment cessation. (4) The combination of interferon alfa-2b and ribavirin appears to have similar virological efficacy in children to that seen in adults. Adverse effects, especially those of a psychological nature, remain frequent.     

Interferon alfa-2b plus ribavirin for chronic hepatitis C patients who have not responded to interferon monotherapy

BACKGROUND: The role of combination therapy is poorly defined in chronic hepatitis C patients who are non-responders to interferon. AIM: To assess the efficacy, safety and tolerance of interferon alfa-2b plus ribavirin in chronic hepatitis C patients who do not respond to interferon monotherapy. METHODS: A total of 127 non-responder patients with chronic hepatitis C received 3 mU t.i.w. of interferon alfa-2b plus 1000-1200 mg ribavirin daily for 48 weeks. Effects of therapy were evaluated by serum aminotransferases and hepatitis C virus (HCV) RNA levels. RESULTS: Twenty-nine (23%) patients had an end-of-treatment response. Six months after treatment, 20 (16%) patients were sustained responders. Early loss of HCV RNA was the strongest predictor of a sustained response (P < 0.0001). Remission was also more frequent in patients with genotype 1b (P < 0.02), elevated alanine aminotransferase (P < 0.03) and low gamma glutamiltranspeptidase (P < 0.002). Treatment was discontinued in 21 (17%) patients: in 14 for intolerance and in seven due to side-effects. CONCLUSIONS: Combination therapy with interferon plus ribavirin produced a sustained response in 16% of chronic hepatitis C patients who were non-responders to interferon. This combination was safe and well tolerated.     

Peginterferon alfa-2a versus peginterferon alfa-2b as initial treatment of hepatitis C virus infection: a cost-utility analysis from the perspective of the Veterans Affairs Health Care System

Study Objective . To assess the cost-utility of peginterferon alfa-2a plus ribavirin, peginterferon alfa-2b plus ribavirin, and no therapy for treatment-naïve patients with chronic hepatitis C virus (HCV) infection from the perspective of the Veterans Affairs (VA) health care system by using patient-reported utility scores. Design . Cost-utility analysis using a Markov model. Setting . Veterans Affairs health care system. Data Source . Data for the model were obtained from clinical trials and published literature. Data from the VA health care system were used to define the patient cohorts. Measurements and Main Results . A Markov model incorporating transition probabilities between disease health states that depend only on the current health state was developed to simulate the progression of HCV disease. The patient cohorts were a 45-year-old male cohort and a 55-year-old male cohort, each with liver fibrosis but no cirrhosis. The lifetime expected costs, quality-adjusted life-years (QALYs) gained, and incremental net monetary benefit (INMB) with HCV treatments were determined for each cohort by genotype (genotype 1, and genotypes 2 and 3). Both peginterferon regimens were significantly more cost-effective than no treatment, although no significant differences in costs or QALYs were noted between peginterferon regimens. For the 45-year-old cohort with a genotype 1 infection, the INMB was $128,583 (95% confidence interval [CI] $79,279–$177,308) and $128,025 (95% CI $80,425–$173,448) versus no treatment for peginterferon alfa-2a plus ribavirin and peginterferon alfa-2b plus ribavirin, respectively. Treatment with either peginterferon regimen produced significantly lower lifetime HCV-related medical costs for genotype 2 or 3 infections, but not genotype 1. Conclusions . Peginterferon alfa-2a plus ribavirin and peginterferon alfa-2b plus ribavirin were found to be cost-effective treatments for patients with HCV infections, particularly with genotypes 2 and 3. However, no significant differences in costs or efficacy were observed between these peginterferon treatment regimens.     

Treating chronic hepatitis C with pegylated interferon alfa-2a (40 KD) and ribavirin in clinical practice

BACKGROUND: Pegylated interferon alfa-2a (40 KD) plus ribavirin therapy induces sustained virological response rates up to 63% in randomized-controlled trials. AIM: To conduct a prospective open-label programme to examine the efficacy and safety of this therapy in routine clinical practice. Methods: Treatment-naive patients with chronic hepatitis C received, at the discretion of the investigator, pegylated interferon alfa-2a 180 microg/week + ribavirin 800 mg/day for 24 or 48 weeks. In total, 508 patients were enrolled [334 non-cirrhotic; 174 cirrhotic (defined as stage F3 and F4)]. RESULTS: In genotype 1 patients treated for 48 weeks, sustained virological response rates were 41% in non-cirrhotics and 34% in cirrhotics. Sustained virological response rates in genotype 2 or 3 non-cirrhotics were 79% (24 weeks) and 72% (48 weeks). Corresponding values for cirrhotic genotype 2/3 were 66% and 44%. The negative predictive value of an early virological response at week 12 was 94%. Predictive factors for sustained virological response on multivariate analysis were genotype (2/3 vs. 1), low viral load and degree of fibrosis. Rates of serious adverse events (相似文献   

聚乙二醇干扰素α-2b联合病毒唑治疗慢性丙型肝炎的临床观察

目的评价聚乙二醇干扰素α-2b联合病毒唑治疗慢性丙型病毒性肝炎的临床效果及用药安全性,探讨临床慢性丙型肝炎的抗病毒方法。方法选择68例慢性丙型肝炎患者随机分成联合治疗组与对照组,联合治疗组38例,给予聚乙二醇干扰素α-2b80μg,1次/周皮下注射,加上病毒唑450mg,3次/d,疗程为6个月;对照组30例,用甘乐能干扰素α-2b3Mu隔日肌内注射1次,加上病毒唑450mg,3次/d,疗程6个月。两组停药后随访6个月。分别观察两组慢性丙肝患者治疗前后的临床症状、体征改善状况,生化应答率、病毒应答率和临床不良反应。结果治疗结束时联合治疗组显效率、有效率和总有效率分别是71.05%、18.42%和89.47%;对照组分别是66.67%、16.67%和83.34%;两组比较差异无统计学意义（P〉0.05）。随访6个月联合治疗组的持续应答率为47.37%,而对照组为16.67%,两组有统计学意义（P〈0.01）。两组副作用均有发热、乏力、胃肠道症状、白细胞下降、肌肉酸痛等（P〉0.05）。结论聚乙二醇干扰素α-2b联合病毒唑治疗慢性丙型肝炎,可迅速缓解患者的症状体征,促进HCV-RNA的阴转,临床用安全,停药6个月后的持续完全应答显著优于甘乐能干扰素。     

A cost-effectiveness analysis of peginterferon alfa-2b plus ribavirin for the treatment of naive patients with chronic hepatitis C

AIM: To estimate the cost-effectiveness of therapy and analyse the effect of therapy compliance in naive patients with chronic hepatitis C. METHODS: A decision analysis using the Markov model was performed for four different therapeutic strategies using peginterferon alfa-2b plus ribavirin or interferon alfa-2b plus ribavirin. Clinical data were obtained from available published reports and from the Spanish health system perspective. RESULTS: The incremental cost-effectiveness ratio of peginterferon alfa-2b plus ribavirin at a fixed dose, compared with interferon alfa-2b plus ribavirin, was 8478 euros per life year saved and 3737 euros per quality-adjusted life year gained. Good therapeutic compliance and weight-adjusted doses of ribavirin decreased the incremental cost-effectiveness ratio to 1636 euros per life year saved and 721 euros per quality-adjusted life year gained. In compliant genotype 1 patients, the incremental cost-effectiveness ratio decreased to 916 euros per life year saved and 404 euros per quality-adjusted life year gained, with an increase from 64 to 69 years in the threshold age at which therapy was cost-effective. The sensitivity analysis demonstrated that changes in the values of the most relevant parameters do not modify the study outcomes. CONCLUSION: From the clinical and pharmaco-economics perspective, the use of decision therapeutic analysis models suggests that the most effective therapy for chronic hepatitis C is peginterferon alfa-2b plus ribavirin adjusted to patient body weight and with good compliance, particularly in genotyped patients.     

Boceprevir

Standard treatment for patients with genotype 1 chronic hepatitis C consists of a combination of peginterferon alfa and ribavirin, taken for 24 to 48 weeks. Boceprevir, a drug that inhibits the hepatitis C virus NS3/4A serine protease, is now authorised in the European Union as an adjunct to this standard treatment. In clinical trials, addition of boceprevir did not increase efficacy when the peginterferon alfa-2b + ribavirin combination reduced viral load during the first 4 weeks of treatment. A double-blind, randomised trial including 1097 previously untreated patients showed that adding boceprevir after 4 weeks of peginterferon alfa-2b + ribavirin combination therapy increased the rate of sustained virological response compared with adding placebo after 44 weeks of triple-agent therapy (66.1% versus 37.7%). In early responders, the rates of sustained virological response were similar after 24 weeks and 44 weeks of triple-agent therapy. After failure of standard therapy, a double-blind randomised trial in 403 patients showed that a new 44-week course of treatment induced a significantly higher rate of sustained virological response when boceprevir was added rather than placebo (66% versus 21%). In early responders, the rates of sustained virological response were not reduced by shortening treatment duration to 32 weeks. The main adverse effect of adding boceprevir was an increased incidence of haematological disorders, including anaemia (48% versus 28% with placebo add-on), neutropenia (23% versus 18%), and thrombocytopenia (32% versus 14%). Boceprevir is a potent inhibitor of cytochrome P450 isoenzyme CYP3A4; clinically relevant pharmacokinetic interactions can be thus anticipated when boceprevir is combined with drugs that have a narrow therapeutic margin. Boceprevirtherapy involves taking 4 capsules 3 times daily for 24 to 32 weeks. In practice, adding boceprevir to the peginterferon alfa + ribavirin combination is justified both for first-line treatment and after failure of standard treatment. The impact of the added virological efficacy on morbidity and mortality remains to be determined.     

Clinical trial: individualized treatment duration for hepatitis C virus genotype 1 with peginterferon-alpha 2a plus ribavirin

Background  Individualized treatment regimens, taking into account the heterogeneity of patients with chronic hepatitis C, are needed to improve treatment outcomes.
Aim  To investigate prospectively the period of undetectable viraemia required for a high rate of sustained virological response in patients with chronic hepatitis C genotype 1 and the relationship to early viral kinetics.
Methods  Forty-five chronic hepatitis C genotype 1 patients were given peginterferon-alpha 2a plus ribavirin. Viraemia and hepatocyte HCV-RNA levels were quantified using a TaqMan assay. Beyond the first time point of undetectable viraemia (<20 IU/mL) between baseline and treatment week 12, 32 of 45 (71%) patients were randomized to additional 12 weeks (G12); 24 weeks (G24) or 36 weeks therapy (G36). The remaining 13 patients received 48 weeks' treatment (G48).
Results  The sustained virological response rates were: G12 – five of 11 (45%); G24 – eight of 10 (80%); G36 – eight of 11 (73%); G48 – four of 13 (31%). The anti-viral efficacy (ε) and treatment-induced loss of infected hepatocytes ( M δ), were significantly higher in patients with early viral clearance. In G12, patients with sustained virological response had lower baseline viraemia than those who relapsed.
Conclusions  Early viraemia clearance is a better marker than baseline viral load and differentiates chronic hepatitis C genotype 1 with high or low probability of sustained virological response. In patients with viraemia clearance within 12 weeks of starting peg-interferon/ribavirin therapy, an additional period of undetectable viraemia of minimum 24 weeks is required for high sustained virological response.     

Cost effectiveness of peginterferon alpha-2a plus ribavirin versus interferon alpha-2b plus ribavirin as initial therapy for treatment-naive chronic hepatitis C

INTRODUCTION: In adults with previously untreated chronic hepatitis C (CHC), the combination of peginterferon alpha-2a plus ribavirin produces a higher rate of sustained virological response (SVR) than interferon alpha-2b plus ribavirin, but it is still unproven whether this increase is cost effective. The objective of this study was to determine if the gain in SVR with peginterferon alpha-2a plus ribavirin is worth the incremental cost. METHODS: We constructed a Markov model of disease progression in which cohorts of patients received peginterferon alpha-2a plus ribavirin or interferon alpha-2b plus ribavirin for 48 weeks (hepatitis C virus [HCV] genotype 1 and non-1 patients with fibrosis) or 24 weeks (genotype non-1 patients without fibrosis), and were followed for their expected lifetimes. The reference patient was a 45-year-old male with CHC without cirrhosis. The SVRs with peginterferon alpha-2a plus ribavirin and interferon alpha-2b plus ribavirin used to populate the model were 46% and 36% for patients infected with HCV genotype 1 and 76% and 61% for patients infected with HCV non-1 genotypes, respectively. QOL and costs for each health state were based on literature estimates and on Italian treatment patterns. Costs were in 2002 euros and benefits were discounted at 3%. Sensitivity analyses on key clinical and economic parameters were performed. The analysis was reported from the perspective of the Italian National Health Service. RESULTS: In patients infected with HCV genotype 1, peginterferon alpha-2a plus ribavirin increased life-years (LYs) by 0.78 years and QALYs by 0.67 years, compared with interferon alpha-2b and ribavirin. The incremental cost per LY and QALY gained was euro9433 and euro10 894, respectively. In patients infected with HCV non-1 genotypes, peginterferon alpha-2a plus ribavirin increased LYs by 1.17 and QALY by 1.01 years, compared with interferon alpha-2b plus ribavirin. The incremental cost per LY and QALY gained was euro3261 and euro3766, respectively. Using genotype distribution estimates, the weighted average ICER for all genotypes was euro6811 per LY gained and euro7865 per QALY gained. CONCLUSION: Our model suggests that peginterferon alpha-2a plus ribavirin is cost effective compared with conventional interferon alpha-2b plus ribavirin for treatment of naive adults with CHC, regardless of HCV genotype, under a wide range of assumptions regarding treatment effectiveness and costs.     

Impact of ribavirin plasma level on sustained virological response in patients treated with pegylated interferon and ribavirin for chronic hepatitis C

Background  The main goal of therapy in hepatitis C virus (HCV) infection is to achieve a sustained virological response (SVR). However, the impact of the pharmacological properties of ribavirin on the SVR has not been fully investigated.
Aim  To evaluate, through a prospective study, the association between ribavirin plasma level and SVR response in HCV patients treated with pegylated interferon (PEG-IFN) and ribavirin.
Patients and methods  Patients treated with PEG-IFN and ribavirin had plasmatic ribavirin dosage at weeks 4 and 12. SVR was evaluated 6 months after the end of treatment.
Results  At week 4, a strong correlation was found between HCV-RNA and C _min of ribavirin plasma level ( r  = −0.376, P  = 0.002) and AUC _0→12h of ribavirin plasma level ( r  = −0.277, P  = 0.018). At week 12, a strong correlation was found between HCV-RNA and C _min of ribavirin plasma level ( r  = −0.384, P  < 0.0001) and AUC _0→12h of ribavirin plasma level ( r  = −0.257, P  = 0.002). In genotype 1 patients, AUC _0→12h ribavirin and C _min were significantly correlated with negative HCV-RNA at week 12 and SVR. In the multiple logistic regression model, the only factor independently associated with SVR in genotype 1 patients was negative HCV-RNA at week 12.
Conclusion  C_min of ribavirin at weeks 4 and 12 was significantly higher in sustained virological responders compared with relapser or nonresponder patients. However, in genotype 1 patients, plasma ribavirin level at weeks 4 and 2 was not associated with SVR.     

Meta-analysis: a randomized trial of peginterferon plus ribavirin for the initial treatment of chronic hepatitis C genotype 4

BACKGROUND: Guidelines for treatment of patients infected with hepatitis C virus genotype 4 are not available. AIM: To perform a meta-analysis of randomized controlled trials comparing peginterferon plus ribavirin with interferon plus ribavirin treatment in treatment-naive patients infected with chronic hepatitis C virus genotype 4. METHODS: The outcome measure was sustained virologic response. The measure of association employed was relative risk calculated by the random-effect model, with heterogeneity, sensitivity and subgroup analyses. RESULTS: Of the 565 studies screened, six randomized controlled trials including 424 patients (peginterferon plus ribavirin 219, interferon plus ribavirin 205) were analysed. Duration of therapy was 1 year in all trials. Sustained virological response obtained with peginterferon plus ribavirin (55%) was significantly higher than with interferon plus ribavirin (30%) [relative risk, 1.71 (95% confidence interval, 1.15-2.56); P = 0.0088]. In the subgroup analyses, sustained virological response in trials using standard-dose ribavirin (1000 or 1200 mg/day) was 72% as against 45.8% in trials using low-dose ribavirin (800 mg/day) (P = 0.01). Further sub-group analyses for treatment duration, body weight, viral load and cirrhosis could not be performed because of lack of relevant data. CONCLUSION: Treatment-naive patients infected with hepatitis C virus genotype 4 should be treated with peginterferon plus standard-dose ribavirin for 1 year, with an expected sustained virological response rate of 72%.