Early virologic response to treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C

Interferon-based regimens for the treatment of chronic hepatitis C have become increasingly effective and are able to eradicate virus in more than one half of cases. Early identification of patients who will not respond is desirable because treatment might be stopped, thereby avoiding the expense and inconvenience of unnecessary therapy. We examined the accuracy of different degrees of viral inhibition during the early weeks of treatment (early virologic response [EVR]) with pegylated interferon alfa-2b and ribavirin (PEG/R) in identifying patients who would not respond to therapy. The best definition of EVR was a reduction in hepatitis C virus (HCV) RNA by at least 2 logs after the first 12 weeks of treatment compared with baseline. Between 69% and 76% of patients achieved this threshold, depending on the treatment regimen, and sustained virologic response (SVR) occurred in 67% to 80% of these patients. Patients who did not reach EVR did not respond to further therapy. If treatment had been stopped in patients without EVR, drug costs would have been reduced by more than 20%. In conclusion, early confirmation of viral reduction following initiation of antiviral therapy for chronic hepatitis C is worthwhile. It provides a goal to motivate adherence during the first months of therapy and a milepost at which to reassess the need for continued treatment. Most patients who are able to complete the first 12 weeks of therapy achieve EVR and have a high probability of SVR. Patients who fail to achieve EVR will not clear virus even if an additional 9 months of therapy is received. Therapy can be confidently discontinued in those cases.     

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

BackgroundAn 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).ObjectiveTo estimate the long-term cost-effectiveness of treatment of patients with chronic hepatitis C with peginterferon alfa-2a (180 μg/week) plus ribavirin (800–1200 mg/day) vs. alfa-2b (1.5 μg/kg/week) plus ribavirin (800–1400 mg/day), from the perspective of the Spanish National Health System.MethodsA 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.ResultsSVR 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.ConclusionsAccording 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.     

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

BACKGROUND: Peginterferon alpha-2b plus ribavirin therapy in previously untreated patients with chronic hepatitis C yields the highest sustained virological response rates of any treatment strategy but is expensive. AIMS: To estimate the cost effectiveness of treatment with peginterferon alpha-2b plus ribavirin compared with interferon alpha-2b plus ribavirin for initial treatment of patients with chronic hepatitis C. METHODS: Individual patient level data from a randomised clinical trial with peginterferon plus ribavirin were applied to a previously published and validated Markov model to project lifelong clinical outcomes. Quality of life and economic estimates were based on German patient data. We used a societal perspective and applied a 3% annual discount rate. RESULTS: Compared with no antiviral therapy, peginterferon plus fixed or weight based dosing of ribavirin increased life expectancy by 4.2 and 4.7 years, respectively. Compared with standard interferon alpha-2b plus ribavirin, peginterferon plus fixed or weight based dosing of ribavirin increased life expectancy by 0.5 and by 1.0 years with incremental cost effectiveness ratios of 11,800 euros and 6600 euros per quality adjusted life year (QALY), respectively. Subgroup analyses by genotype, viral load, sex, and histology showed that peginterferon plus weight based ribavirin remained cost effective compared with other well accepted medical treatments. CONCLUSIONS: Peginterferon alpha-2b plus ribavirin should reduce the incidence of liver complications, prolong life, improve quality of life, and be cost effective for the initial treatment of chronic hepatitis C.     

Pegylated interferon alfa-2b plus ribavirin for treatment of chronic hepatitis C

AIM: To study the safety and efficacy of pegylated interferon alfa-2b, indigenously developed in India, plus ribavirin in treatment of hepatitis C virus(HCV). METHODS: One-hundred HCV patients were enrolled in an open-label, multicenter trial. Patients were treated with pegylated interferon alfa-2b 1.5 μg/kg per week subcutaneously plus oral ribavirin 800 mg/d for patients with genotypes 2 and 3 for 24 wk. The same dose of peginterferon plus weight-based ribavirin(800 mg/d for ≤ 65 kg; 1000 mg/d for 65-85 kg; 1200 mg/d for 85-105 kg; 1400 mg/d for 105 kg body weight) was administered for 48 wk for patients with genotypes 1 and 4. Serological and biochemical responses of patients were assessed.RESULTS: Eighty-two patients(35 in genotypes 1 and 4 and 47 in 2 and 3), completed the study. In genotype 1, 25.9% of patients achieved rapid virologic response(RVR): while the figures were 74.1% for early virologic response(EVR) and 44.4% for sustained virologic response(SVR). For genotypes 2 and 3, all patients bar one belonged to genotype 3, and of those, 71.4%, 87.5%, and 64.3% achieved RVR, EVR, and SVR, respectively. In genotype 4, 58.8%, 88.2%, and 52.9% of patients achieved RVR, EVR, and SVR, respectively. The majority of patients attained normal levels of alanine aminotransferase by 4-12 wk of therapy. Most patients showed a good tolerance for the treatment, although mild-to-moderate adverse events were exhibited; only two patients discontinued the study medication due to serious adverse events(SAEs). Eleven SAEs were observed in nine patients; however, only four SAEs were related to study medication.CONCLUSION: Peginterferon alfa-2b, which was developed in India, in combination with ribavirin, is a safe and effective drug in the treatment of HCV.     

Cost-effectiveness of peginterferon alfa-2b in combination with ribavirin as initial treatment for chronic hepatitis C in Sweden

The aim of the study was to assess the cost-effectiveness of peginterferon alfa-2b (pegIFN) compared to interferon alfa-2b (IFN), both in combination with ribavirin, as initial therapy for chronic hepatitis C in Sweden. A computer based Markov model describing the natural course of chronic hepatitis C was used to assess costs and quality-adjusted life-y (QALY) for the treatment strategies. Study population was a cohort of hepatitis C patients from the age of 43 y until death. Natural history and response data were obtained from the literature and from Swedish clinical experts. Costs were obtained from different health care providers in Sweden and based on Swedish clinical practice. In our base case analysis for genotype 1 patients, pegIFN plus ribavirin therapy generated 0.29 incremental QALYs and was cost saving (dominant strategy). Corresponding results for genotype 2/3 patients were 0.09 QALYs at an incremental cost of 941 euros (10,500 euros/QALY). A probabilistic sensitivity analysis was performed to study the stability of our results. From the results we conclude that for genotype 1 patients treatment with pegIFN and ribavirin increased quality-adjusted life expectancy and was cost-effective as initial therapy for hepatitis C. The cost-effectiveness for patients infected with genotype 2/3 was less obvious.     

Peginterferon alfa-2b plus ribavirin for the treatment of chronic hepatitis C genotype 4

BACKGROUND: The hepatitis C virus (HCV) genotype is an important predictive parameter for the success of pegylated interferon plus ribavirin therapy. To date, most published therapeutic trials have enrolled patients infected mainly with HCV genotypes 1, 2, and 3. Data regarding the responsiveness of genotype 4, the predominant type of HCV in the Middle East, are very limited. OBJECTIVE: To assess the efficacy of peginterferon alfa-2b in combination with ribavirin for the treatment of chronic hepatitis caused by HCV genotype 4. METHODS: Sixty-six treatment-naive patients infected with HCV genotype 4 were enrolled in this open label, prospective study. Cohort characteristics included the following: 48 M/18 F, mean age 45 +/- 9 years, and mean weight 74 +/- 8 kg. All patients had raised alanine aminotransferase (ALT) and were compensated. The mean pretreatment HCV-RNA level was 4.2 x 10(6) copies/ml (8.4 x 10(5) iu/ml) and median was 2.15 x 10(6) copies/ml. Twenty patients (29%) exhibited cirrhosis or severe fibrosis on pretreatment liver biopsy specimens. Participants were to receive peginterferon alfa-2b, 1.5 mcg/kg/wk plus ribavirin 1,000-1,200 mg/day for 48 wk. Patients were followed up for 24 wk after completing therapy. End of treatment viral response and sustained viral response (SVR) were defined as the absence of HCV-RNA from serum (<100 copies/ml) at 48 wk of treatment and at the end of follow-up, respectively. Data were analyzed on an intention-to-treat basis. RESULTS: End of treatment and sustained virologic response were 77% and 68%, respectively. Among patients with pretreatment HCV-RNA > or =2 x 10(6) SVR was 55% compared with SVR of 86% among patients with HCV-RNA < 2 x 10(6) (p= 0.05). Patients with cirrhosis or severe fibrosis had significantly lower SVR rate compared to those with mild or no fibrosis (29 vs 84%; p < 0.0002). Three patients (4%) discontinued therapy because of severe flu-like symptoms. Four patients developed hypothyroidism. Dose reduction of ribavirin and peginterferon alfa-2b was necessary in 15% and 6% of the patients, respectively. CONCLUSION: Peginterferon alfa-2b in combination with ribavirin is effective in the treatment of HCV genotype 4. The treatment was well tolerated by most of the patients.     

Early virologic response after peginterferon alpha-2a plus ribavirin or peginterferon alpha-2b plus ribavirin treatment in patients with chronic hepatitis C

Patients infected with hepatitis C virus (HCV) genotype 1 and with serum HCV RNA concentrations over 800 000 IU/mL have relatively low rates of virologic response to pegylated interferons. The 2 forms of pegylated interferon have different pharmacokinetic profiles, and pilot studies comparing them have yielded varying results. We compared the virologic response to 12 weeks of treatment with peginterferon alpha-2a plus ribavirin vs peginterferon alpha-2b plus ribavirin in 380 patients who were infected with HCV genotype 1 and had high viral loads. We observed no between-group differences in viral load reduction over time and no differences in the percentage of patients treated with peginterferon alpha-2a or peginterferon alpha-2b plus ribavirin who achieved early virologic response (EVR), defined as >/=2-log reduction in HCV RNA concentration or undetectable HCV RNA at 12 weeks (66%vs 63%). Serum levels of interferon were more frequently below the level of quantitation in patients treated with peginterferon alpha-2b plus ribavirin (58-68%) than in those treated with peginterferon alpha-2a plus ribavirin (1-2%). Patients treated with peginterferon alpha-2b plus ribavirin had higher rates of discontinuation for safety reasons (6%vs 1%). In conclusion, a substantial percentage of patients infected with HCV genotype 1 and high viral load can achieve EVR when treated with peginterferon and ribavirin. The 2 pegylated interferons showed comparable anti-HCV activity during the first 12 weeks of treatment when combined with the same doses of ribavirin (1000-1200 mg/day), but discontinuations for safety reasons were higher in the patients treated with peginterferon alpha-2b plus ribavirin.     

Antinuclear antibody titer and treatment response to peginterferon plus ribavirin for chronic hepatitis C patients

Positive serum antinuclear antibody (ANA) is not infrequent in chronic hepatitis C virus (HCV)-infected patients. This prospective study evaluated the impact of ANA on the response to and safety of peginterferon/ribavirin combination therapy for chronic hepatitis C patients in clinical practice. We enrolled 243 consecutive patients who were treated with a 24-week regimen of peginterferon-α plus ribavirin, with a 24-week follow-up period. ANA titer was determined before antiviral treatment. The primary end-point was sustained virological response (SVR), defined as HCV RNA <50 IU/mL throughout the follow-up period. Overall, 187 (77.0%) patients experienced a SVR. In the 105-patient HCV genotype non-1 group, patients with ANA titer ≥1:80 had a significantly lower SVR rate than those with ANA titer <1:80 (67.7% vs. 95.8%, respectively, p = 0.013). In contrast, in the 138-patient HCV genotype 1 group, the SVR rate did not differ between patients with and without ANA titer ≥1:80. Multivariate regressive analyses showed that ANA ≥1:80, age and HCV RNA levels were independent factors associated with SVR in HCV genotype non-1 patients; whereas HCV RNA levels and hepatic fibrosis were prognostic predictors of SVR in HCV genotype 1 patients. The frequencies of adverse events were similar between patients with and without ANA seropositivity. Peginterferon/ribavirin combination therapy is effective and safe in ANA-positive chronic hepatitis C patients. A high ANA titer was a negative prognostic factor for treatment response in HCV genotype non-1 patients.     

Peginterferon alfa-2b plus ribavirin treatment in children and adolescents with chronic hepatitis C

Peginterferon plus ribavirin is standard therapy for adults with chronic hepatitis C. As no data are available for children, the aim of the study was to evaluate the efficacy and tolerability of peginterferon alfa-2b in combination with ribavirin in chronically infected children. Genotypes, alanine aminotransferase levels, and different routes of viral transmission were considered. In an open-labeled, uncontrolled pilot study, 62 children and adolescents (range, 2-17 years) were treated with subcutaneous peginterferon alfa-2b at a dose of 1.5 microg/kg body weight once per week plus oral ribavirin (15 mg/kg x day) for 48 weeks. Sixty-one patients completed the study. Twenty-three children discontinued therapy after 6 months according to study protocol. Sustained viral response was documented in 22 (47.8%)of 46 patients with genotype 1, in 13 (100%) of 13 with genotype 2 or 3, in 1 of 2 with genotype 4, in 19 (70.4%) of 27 children with parenteral, in 12 (48%) of 25 with vertical, and in 5 of 9 with unknown route of infection. Overall, treatment was well tolerated. Nevertheless, some side effects were present in all treated patients. Eighty-three percent had leucopenia, but only 3 individuals required dose reduction and 10.3% developed thyroid autoantibodies and thyroid dysfunction. In conclusion, combination treatment of peginterferon alfa-2b with ribavirin showed encouraging results and was well tolerated in children and adolescents with chronic hepatitis C. Weekly dosing of peginterferon alfa-2b is a considerable advance for this age group. The treatment is not approved for children. Further controlled trials are needed.     

不同聚乙二醇化干扰素治疗丙型肝炎病毒感染临床观察

目的评价聚乙二醇化干扰素α-2a或α-2b(PEG-IFNα-2a/α-2b)联合利巴韦林治疗慢性丙型肝炎病毒感染的疗效与副作用,以优化慢性丙型肝炎治疗策略、提高临床治愈率。方法 60例慢性丙型肝炎患者随机分为A组和B组各30例,分别给予PEG-IFNα-2a加利巴韦林(A组)和PEG-IFNα-2b加利巴韦林(B组)治疗48周,检测基线及治疗4周、l2周、48周及治疗结束后24周时的血清HCV-RNA水平,比较两组快速病毒学应答(RVR)率、早期病毒学应答(EVR)率、治疗终点病毒学应答(ETVR)率、持续病毒学应答(SVR)以及复发率与不良反应。结果 A组和B组RVR、EVR、ETVR、SVR、复发率分别为46.7%、63.3%、86.7%、80.0%、6.7%和40.0%、56.7%、80.0%、76.7%、3.3%,组间比较,差异均无统计学意义(P0.05),两组的安全性情况相似,未见严重的不良事件,总体耐受性好。结论两种现有的聚乙二醇化干扰素α-2a或α-2b联合利巴韦林治疗丙型肝炎病毒感染的持续病毒学应答率和耐受性没有显著差异。     

Tongue hyperpigmentation resulting from peginterferon alfa-2b and ribavirin treatment in a patient with chronic hepatitis C

Hepatitis C virus (HCV) infection has been associated with several cutaneous diseases such as lichen planus, porphyria cutanea tarda, chronic pruritus, and cutaneous necrotizing vasculitis (Doutre, Arch Dermatol 135:1401–1403, 1999). The antiviral treatment for chronic HCV with interferon alfa (INF) or peginterferon alfa (PEG-INF) combined with rivabirin also leads to many skin side effects including injection site reaction, generalized skin rashes, pruritus, dry skin, alopecia, and exacerbation of autoimmune processes, particularly psoriasis, lichen planus or vitiligo (Dalekos et al., Eur J Gastroenterol Hepatol 10:933–939, 1998; Sookoian et al., Arch Dermatol 135:1000–1000, 1999). There are case reports of tongue hyperpigmentation during combination therapy of PEG IFN and RBV in chronic hepatitis C both in dark-skined as well as Caucasian. We report the first case of tongue hyperpigmentation associated with PEG-INF-2b plus ribavirin administration in a non-Caucasian patient with genotype 4.     

Pegylated interferon alfa-2b plus ribavirin for the treatment of chronic hepatitis C genotype 4 in adolescents

Background. Hepatitis C is endemic in the Middle East where genotype R accounts for most cases. Data regarding the safety and efficacy of peginterferon plus ribavirin for the treatment of chronic hepatitis C in children and adolescents, particularly those infected with genotype R is limited.Aim. To evaluate the efficacy and tolerability of peginterferon alfa-2b in combination with ribavirin in adolescents chronically infected with HCV genotype R.Patients and methods. In an open-labeled, uncontrolled pilot study, 12 adolescents (rangeIR-17 years) were treated with subcutaneous peginterferon alfa-2b at a dose of 1.5 mg/ kg body weight once per week plus oral ribavirin (15 mg/kg/day) for R8 weeks. Patients were followed for 2R weeks post-treatment. All patients had biopsy proven hepatitis without cirrhosis.Results. One patient withdrew from the study due to developing insulin dependent diabetes mellitus R months into treatment. The remaining patients received at least 80% of the prescribed dose of pegylated interferon and ribavirin. Sustained viral response was observed in 9 patients (75%). The most frequent side effect was flu like illness which was reported in all patients. Sixty seven percent had leucopenia, but only one individual required adjuvant therapy with hematologic growth factor. Four patients had anemia requiring ribavirin dose reduction. One patient developed hypothyroidism.Conclusion. Combination treatment of peginterferon alfa-2b with ribavirin appears to be efficacious and relatively safe in adolescents with chronic hepatitis C genotype R.B.     

聚乙二醇干扰素α-2b联合利巴韦林治疗慢性丙型肝炎的随机对照临床研究

目的评价小剂量聚乙二醇干扰素α-2b联合利巴韦林治疗慢性丙型病毒性肝炎的疗效和安全性.方法192例慢性丙型肝炎患者随机分为两组：聚乙二醇干扰素α-2b 0.5μg/kg每周一次联合利巴韦林750～1050 mg/d,或普通干扰素α-2b 3 MIU每周3次联合利巴韦林750～1050 mg/d.疗程48周,治疗结束后随访24周.结果聚乙二醇干扰素α-2b联合利巴韦林治疗的持续病毒学应答率为53.8%,而普通干扰素α-2b联合利巴韦林治疗的持续病毒学应答率为58.1%,两组持续病毒学应答率相当（P=0.966）.聚乙二醇干扰素α-2b治疗组的药物相关性不良反应发生率为100%,而普通干扰素α-2b治疗组的不良反应发生率为95.2%,两组间差异有统计学意义（P=0.033）.但是没有与干扰素α-2b聚乙二醇化相关的特有的新的不良反应发生.结论小剂量聚乙二醇干扰素α-2b联合利巴韦林治疗慢性丙型肝炎的疗效和安全性与普通干扰素α-2b联合利巴韦林治疗的疗效和安全性相当.     

Peginterferon alfa-2b plus weight-based ribavirin for 24 weeks in patients with chronic hepatitis C virus genotype 1 with low viral load who achieve rapid viral response

In chronic hepatitis C (CHC), treatment duration may be individualized according to time to first undetectable hepatitis C virus (HCV) RNA, with patients who attain undetectable HCV RNA early in treatment being candidates for shorter regimens. The aim of this study was to determine the relapse rate in patients with CHC genotype (G) 1 infection and low baseline viral load who achieved undetectable HCV RNA by week 4 [rapid virologic response (RVR)] when treated for 24 weeks. This was an open-label, multicentre, noninterventional study. Adult patients with G1 CHC infection and baseline viral load <600,000 IU/mL who attained RVR were treated with peginterferon alfa-2b (1.5 μg/kg/week) plus ribavirin (800-1200 mg/day) for 24 weeks, then followed for a further 24 weeks. The primary endpoint was relapse rate, defined as the proportion of patients with undetectable HCV RNA at treatment week 24 and detectable HCV RNA at week 24 follow-up. The secondary efficacy endpoint was sustained virologic response (SVR). Overall, 170 patients were included in the efficacy-evaluable population. The relapse rate was 9.7% (16/165, 95% confidence interval: 0.06-0.15), and SVR was attained by 149 of 170 patients (87.6%). Virologic outcomes were consistent regardless of age, gender, body weight and genotype. Seven patients reported treatment-emergent serious adverse events (AEs), and four patients discontinued treatment because of an AE. This study further demonstrates that peginterferon alfa-2b plus weight-based ribavirin for 24 weeks is an effective treatment strategy for treatment-naive patients with G1 CHC and low viral load who attain RVR.     

Peginterferon alfa-2b and ribavirin for treatment-refractory chronic hepatitis C

BACKGROUND/AIMS: Treatment regimens with pegylated interferons have yielded improved response rates, compared with conventional interferon-based regimens, for chronic hepatitis C. However, little is known about the utility of such regimens for individuals who failed to respond to prior conventional interferon-based treatment. METHODS: 182 patients who had previously failed to eliminate circulating hepatitis C virus 24 weeks after completion of a multi-week course of either interferon monotherapy or interferon in combination with ribavirin were treated with peginterferon alfa-2b weekly and ribavirin daily for 48 weeks. RESULTS: The sustained viral response, was 20% (23/116) in previous non-responders and 55% (36/66) in previous relapsers (P<0.001). In previous non-responders, the sustained viral response in those with viral genotype 1 was 17% (19/109) compared to 57% (4/7) in those with genotypes 2 and 3 (P=0.03). In previous relapsers, the sustained viral response in those with viral genotype 1 was 53% (26/49) compared to 59% (10/17) with genotypes 2 and 3 (P=0.78). CONCLUSIONS: The response to pegylated interferon and ribavirin in previous non-responders with genotypes 2 and 3 and in prior relapsers with chronic hepatitis C is comparable to overall sustained viral response rates seen in previously untreated patients.     

Type 1 diabetes mellitus provoked by peginterferon alpha-2b plus ribavirin treatment for chronic hepatitis C

A 51-year-old man developed type 1 diabetes mellitus following 24 weeks of treatment with recombinant alpha-2b peginterferon plus ribavirin for chronic hepatitis C. Pancreatic autoantibody tests were negative before the start of therapy, but a significant increase in glutamic acid decarboxylase (GAD) antibody titer was seen after 24 weeks of treatment. Six months after the onset of type 1 diabetes mellitus, the patient continues to receive 40 units of insulin daily. The clinical course suggested that recombinant alpha-2b peginterferon plus ribavirin provoked type 1 diabetes mellitus, therefore, in patients who are candidates for interferon therapy the presence of pancreatic autoantibodies and the fasting plasma glucose level should be investigated before and during treatment.