Effect of interferon and ribavirin combined with amantadine in interferon and ribavirin non-responder patients with chronic hepatitis C （genotype 1）

AIM: To evaluate the efficacy of amantadine plus interferon-alpha and ribavirin in non-responder patients with chronic hepatitis C. METHODS: Twenty-six non-responder patients received the regimen of IFN-α-2a at a dose of 6 million units three times a week, 1 000-1 200 mg of ribavirin daily, and 200 mg of amantadine daily in divided doses over 48 wk. After the end of treatment, at the 72nd wk, a sustained viral response rate was determined. RESULTS: An early (after 12 wk of therapy) response was seen in 34.6% (9/26) of patients. Response rate at the 24th wk was 42.3% (11/26). End of treatment response (ETR) was 53.8% (14/26). Sustained viral response (SVR) was 42.3% (11/26). There was a statistically significant difference between 0 and 12 wk (P= 0.04), 0 and 24 wk (P= 0.01), 0 and 48 wk (P= 0.00), and 0 and 72 wk (P= 0.001). No patient had severe adverse effects during the treatment. CONCLUSION: Combination regimen of interferon-α, ribavirin and amantadine can enhance sustained viral response on IFN-α and ribavirin non-responder patients with HCV. Triple therapy with amantadine should be evaluated in further studies.     

Re-treatment of previous non-responders and relapsers to interferon plus ribavirin with peginterferon alfa-2a (40KD), ribavirin ± amantadine in patients with chronic hepatitis C: randomized multicentre clinical trial

Introduction. A large number of patients with chronic hepatitis C have not been cured with interferon-based therapy. Therefore, we evaluated the efficacy of amantadine combined with the standard of care (pegylated interferon plus ribavirin) in patients who had not responded to or had relapsed after ≥ 24 weeks of treatment with conventional interferon plus ribavirin.Material and methods. Patients stratified by previous response (i.e., non-response or relapse) were randomized to 48 weeks of open-label treatment with peginterferon alfa-2a (40KD) 180 μg/week plus ribavirin 1,000/1,200 mg/day plus amantadine 200 mg/ day (triple therapy), or the standard of care (peginterferon alfa-2a [40KD] plus ribavirin).Results. The primary outcome was sustained virological response (SVR), defined as undetectable hepatitis C virus RNA in serum (< 50 lU/mL) at end of follow-up (week 72). Among patients with a previous non-response, 12/53 (22.6%; 95% confidence interval [CI] 12.3-36.2%) randomized to triple therapy achieved an SVR compared with 16/52 (30.8%; 95% CI 18.7-45.1%) randomized to the standard of care. Among patients with a previous relapse 22/39 (56.4%; 95% CI 39.6-72.2%) randomized to triple therapy achieved an SVR compared with 23/38 (60.5%; 95% CI 43.4-76.0%) randomized to the standard of care. Undetectable HCV RNA (< 50 IU/mL) at week 12 had a high positive predictive value for SVR. A substantial proportion of non-responders and relapsers to conventional interferon plus ribavirin achieve an SVR when re-treated with peginterferon alfa-2a (40KD) plus ribavirin.Conclusion. Amantadine does not enhance SVR rates in previously treated patients with chronic hepatitis C and cannot be recommended in this setting.     

Triple antiviral therapy in HCV positive patients who failed prior combination therapy

INTRODUCTIONWhile advances in the treatment of HCV chronic hepatitis have markedly improved outcomes for treatment-na?ve patients, a large number of patients still fail to eradicate HCV infection[1-4], and improving the re-treatment success rates of these…     

Triple therapy of initial high-dose interferon with ribavirin and amantadine for patients with chronic hepatitis C

Aims: We previously reported the potential effect of combination therapy of an initial high‐dose interferon (IFN) and amantadine on the eradication of HCV‐RNA in patients with chronic hepatitis C. The additive effects of amantadine on interferon and ribavirin combination therapy remain controversial. In this study we investigated the efficacy of initial high‐dose IFN with ribavirin and amantadine on the virological response in patients with chronic hepatitis C with a high viral load of genotype 1b. Methods: Twenty‐two patients with high viral loads of genotype 1b hepatitis C virus were enrolled in this pilot study. Patients were administered IFN‐beta for four weeks and then IFN‐alpha2b for 22 weeks with daily oral administration of ribavirin and amantadine. Results: A sustained virological response (SVR) was shown in 31.8% (seven of 22 patients). With the naïve patients, the SVR rate was 21.4% (three of 14 patients). In patients who could not eradicate HCV‐RNA by previous IFN monotherapy, the SVR rate was 50% (four of eight patients). Conclusion: Triple therapy with an initial high dose of IFN with ribavirin and amantadine may be effective, especially for chronic hepatitis C IFN‐retreatment patients with a high viral load of genotype 1b.     

Kinetics of hepatitis C virus RNA load during pegylated interferon plus ribavirin therapy in Treatment-naive Chinese patients

BACKGROUND/AIMS: To investigate the viral kinetics of Chinese CHC patients received pegylated interferon plus ribavirin and examine the impact of HCV genotypes and severity of liver disease. METHODOLOGY: 65 treatment-naove CHC patients who finished a 24-week therapy with peginterferon (alpha-2b (1.5 mcg/kg/week) plus ribavirin (1000-1200 mg /day) and 24 weeks of follow-up were enrolled. Hepatic fibrosis was graded by the METAVIR scoring system. Serum quantitative HCV RNA was determined by Versant HCV RNA 3.0 assay (Bayer Inc.). RESULTS: Genotype non-1 patients responded quickly and a higher percentage of them achieved undetectable HCV RNA (< 615 IU/mL) at week 4 compared with genotype 1 patients (93% vs. 69%, p = 0.018). Degree of hepatic fibrosis significantly affected end-of-treatment and sustained response (SVR). For patients who did not achieve early virological response (EVR), the negative predictive value for SVR was 100%. In genotype 1 patients, undetectable HCV RNA by week 4 was a good marker to predict treatment response, with a positive predictive value of 84% and a negative predictive value of 82%. CONCLUSIONS: EVR can be applied to Chinese patients as an early stopping rule. A 24-week duration of pegylated IFN/ribavirin might be adequate for genotype 1 patients who rapidly responded to therapy.     

Pegylated interferon plus ribavirin for genotype Ib chronic hepatitis C in Japan

AIM：To evaluate the efficacy of pegylated interferon α-2b（peg-IFNα-2b） plus ribavirin（RBV） therapy in Japanese patients with chronic hepatitis C（CHC） genotype Ib and a high viral load.METHODS：One hundred and twenty CHC patients（58.3% male） who received peg-IFNα-2b plus RBV therapy for 48 wk were enrolled.Sustained virological response（SVR） and clinical parameters were evaluated.RESULTS：One hundred（83.3%） of 120 patients completed 48 wk of treatment.53 patients（44.3%） achieved SVR.Early virological response（EVR） and end of treatment response（ETR） rates were 50% and 73.3%,respectively.The clinical parameters（SVR vs non-SVR） associated with SVR,ALT（108.4 IU/L vs 74.5 IU/L,P = 0.063）,EVR（76.4% vs 16.4%,P 〈 0.0001）,adherence to peg-IFN（≥ 80% of planned dose） at week 12（48.1% vs 13.6%,P = 0.00036）,adherence to peg-IFN at week 48（54.7% vs 16.2%,P 〈 0.0001） and adherence to RBV at week 48（56.1% vs 32.1%,P = 0.0102） were determined using univariate analysis,and EVR and adherence to peg-IFN at week 48 were determined using multivariate analysis.In the older patient group（〉 56 years）,SVR in females was significantly lower than that in males（17% vs 50%,P = 0.0262）.EVR and adherence to Peg-IFN were demonstrated to be the main factors associated with SVR.CONCLUSION：Peg-IFNα-2b plus RBV combination therapy demonstrated good tolerability in Japanese patients with CHC and resulted in a SVR rate of 44.3%.Treatment of elderly female patients is still challenging and maintenance of adherence to peg-IFNα-2b is important in improving the SVR rate.     

Randomised, double blind, placebo controlled trial of interferon, ribavirin, and amantadine versus interferon, ribavirin, and placebo in treatment naïve patients with chronic hepatitis C

BACKGROUND AND AIM: In this study, we compared the efficacy of triple therapy (interferon alfa, ribavirin, and amantadine) with standard therapy (interferon alfa and ribavirin) in treatment na?ve patients with chronic hepatitis C virus (HCV). METHODS: In this prospective, randomised, double blind, placebo controlled, multicentre study, 85 patients (amantadine group) received a three drug regimen of interferon alfa-2b 3 million units three times per week, ribavirin 1000-1200 mg daily in divided doses, and amantadine 100 mg twice daily, and 86 patients (placebo group) received interferon alfa-2b, ribavirin, and identical placebo. Treatment was discontinued at 24 weeks if patients had detectable HCV RNA by polymerase chain reaction (PCR). All patients were followed for 24 weeks after completion of treatment. The primary end point was undetectable HCV-RNA by PCR at 24 weeks (sustained viral clearance) after completion of treatment. RESULTS: At the end of treatment, HCV RNA clearance was seen in 32.9% of the amantadine group and 38.4% of the placebo group (p=0.3). Sustained virological response was seen in 24.7% of the amantadine group and in 27.9% of the placebo group by intention to treat analysis; response rate was 30.4% and 34.8%, respectively, in those who completed 24 weeks of treatment. Poor response was seen in both groups among cirrhotics, African-Americans, genotype 1, and those with a higher viral load. By multivariate analysis, genotype 1, high viral load, and low serum albumin were the only predictors of poor response. Addition of amantadine to the standard regimen did not result in any unexpected side effects. CONCLUSION: Response to triple therapy of interferon alfa, ribavirin, and amantadine was similar to standard therapy of interferon alfa and ribavirin. Our results suggest that amantadine has no role in the management of HCV.     

Sustained Viral Response to Pegylated Interferon α-2b and Ribavirin in Chronic Hepatitis C Refractory to Prior Treatment

Hepatitis C virus (HCV) infection refractory to previous therapy is common. Treatment of patients with refractory disease is difficult and less studied. Pegylated interferon α-2b plus ribavirin is used for treatment of HCV patients naïve to therapy. We conducted a randomized study for refractory HCV patients using a high- vs. a low-dose pegylated interferon α-2b and ribavirin protocol. Our aim was (1) to determine the efficacy of pegylated interferon α-2b plus ribavirin to eradicate HCV in previously treated individuals and (2) to compare a low-dose to a high-dose regimen. One hundred fifty-two patients were initiated in the study, 112 (74%) were male and 40 (26%) female. Nineteen percent of patients obtained a sustained viral response (SVR) in the high-dose arm. Prior relapsers had the highest SVR rates: 50% in non-genotype 1 and 34% in genotype 1. The odds of achieving a SVR were six times higher in previous relapsers. The rate of SVR in genotype 1 patients who were nonresponders to prior therapy was only 8%. All patients who achieved a SVR had no detectable virus at week 24. However, only half of those who had undetectable viral titers at week 24 achieved a SVR. In conclusion, retreatment of patients with refractory hepatitis C infection with interferon α-2b and ribavirin combination therapy is well tolerated and gives modest response rates. The most important factor in predicting response to therapy is the manner of response to previous treatment. The likelihood of response to treatment can be predicted from the viral titers at 24 weeks.     

Pegylated interferon alfa-2b plus ribavirin in the retreatment of interferon-ribavirin nonresponder patients

BACKGROUND & AIMS: Inadequate data are available about retreatment of nonresponders to interferon (IFN) and ribavirin. Thus, this study evaluated the efficacy and tolerability of a 48-week therapy with pegylated IFN-alpha-2b plus high-dose ribavirin in patients who have failed to respond to the combination. Treatment up to 48 weeks also in patients who have failed to clear hepatitis C virus (HCV) RNA by week 24 was also evaluated. METHODS: One hundred forty-one patients who previously did not respond to IFN and ribavirin, 86% with genotype 1 or 4 infection, 52% with high viral load (>800.000 IU/mL), 22% with cirrhosis, were retreated with pegylated IFN-alpha-2b 1.5 microg/kg per week and ribavirin 1000-1200 mg/day for 48 weeks and followed up for 24 weeks. RESULTS: By intent-to-treat analysis, 20% of patients achieved a sustained virologic response (SVR). SVR of genotype 1 patients was 19%. Independent predictors of SVR were low gamma-glutamyltransferase levels (OR, 22.9; 95% CI: 6.6-79.6) and low viral load (OR, 3.8; 95% CI: 1.1-12.6). Twelve (23%) out of 51 patients who were HCV RNA positive after 24 weeks of therapy achieved a late virologic response (after week 24) and 5 (10%) of them, all with genotype 1, achieved an SVR. Genotype was not associated with response (P = .2) or with early response (P = .3). CONCLUSIONS: Retreatment with pegylated IFN-alpha-2b and ribavirin of multi-experienced and "difficult to treat" nonresponder patients produced a very promising SVR. Accurate selection of patients, such as those with low viral load and low gamma-glutamyltransferase levels, and prolongation of therapy beyond 24 weeks also in HCV RNA-positive patients may further increase the rate of SVR.     

Combined treatment with pegylated interferon (alpha-2b) and ribavirin in the acute phase of hepatitis C virus recurrence after liver transplantation

BACKGROUND/AIMS: The efficacy and safety of treatment with pegylated interferon alpha-2b (Peg-Intron, 1.5 microg/kg) and ribavirin (400-800 mg) in the acute phase of recurrent HCV after LT is presented. METHODS: Twenty-four patients (17 men) transplanted for HCV-associated cirrhosis (genotype 1b) were treated for at least 6 months and compared with 24 consecutive transplant patients (16 men) without antiviral therapy (controls). RESULTS: At completion of treatment, 14/24 treated patients (58%) achieved HCV-RNA negativity, compared to none of controls (P<0.0001). Sustained virological response (SVR) occurred in 8/23 treated patients (34.7%) who reached week 24 after treatment and none of controls (P<0.005). At 12 weeks after treatment, 15/24 patients (62.5%) had an early virological response (EVR) (seven tested HCV-RNA negative). SVR was associated with absence of corticosteroid bolus administration (P=0.01), presence of EVR (P=0.002) and absence of cytomegalovirus infection (P=0.001). Haematological adverse effects included anaemia, 17/24 cases (71%) and leukopenia, 23/24 cases (96%). One patient presented mild acute rejection that resolved by adjusting immunosuppressive dose. CONCLUSIONS: Treatment with pegylated interferon alpha-2b plus ribavirin in the acute phase of HCV reinfection yielded an EVR of 62.5% and a SVR of 34.7%. The combination was safe, with a low rate of therapy withdrawal.     

Comparison of a 6-month course peginterferon alpha-2b plus ribavirin and interferon alpha-2b plus ribavirin in treating Chinese patients with chronic hepatitis C in Taiwan

Previous studies in Caucasian patients showed treatment of chronic hepatitis C with pegylated interferon/ribavirin was well tolerated, and produced a higher response rate especially in genotype 1 infections. However, it is unknown whether this conclusion can be extrapolated to patients with Chinese ethnic origin. A total of 153 patients with biopsy-proven chronic hepatitis C were randomly assigned to receive either weekly injection of peginterferon alpha-2b 1.5 mcg/kg plus oral ribavirin (1000 or 1200 mg/day, depending on body weight) (PEG group, n = 76) or 3 MU of interferon alpha-2b t.i.w. plus ribavirin (IFN group, n = 77) for 24 weeks. Sustained virological response (SVR) was defined as the sustained disappearance of serum hepatitis C virus (HCV) RNA at 24 weeks after the end of treatment by polymerase chain reaction assay. Baseline demographic, viral and histological characteristics were comparable between the two groups. Using an intent-to-treat analysis, HCV genotype 1 patients showed a significantly higher SVR in patients receiving PEG-IFN rather than IFN (65.8%vs 41.0%, P = 0.019), but no difference was found in genotype non-1 patients (PEG vs IFN: 68.4%vs 86.8%, P = 0.060). Genotype 1 patients (28.6%) in the PEG-IFN group relapsed, as compared with 52.9% in the IFN group (P = 0.040). Multivariate analyses showed early virological response at week 12 of therapy and genotype non-1 were significant predictors to SVR. As compared with the IFN group, patients receiving PEG-IFN had a significantly higher rate of discontinuation, dose reduction, fever, headache, insomnia, leucopenia and thrombocytopenia. In genotype 1 chronic hepatitis C Chinese patient, PEG-IFNalpha2b ribavirin had significantly better SVR and lower relapse rate when compared to IFN/ribavirin. Both regimens can be recommended for genotype non-1 chronic hepatitis C Chinese patients. However, a higher rate of adverse events and discontinuance of therapy were noted in patients treated with PEG-IFNalpha2b ribavirin.     

Favorable factors for re-treatment with pegylated interferon α2a plus ribavirin in patients with high viral loads of genotype 1 hepatitis C virus

Aim: Effect of re‐treatment for pegylated interferon (PEG‐IFN) plus ribavirin was not fully evaluated. We examined the effects of re‐treatment with PEG‐IFN plus ribavirin in patients with high viral loads of genotype 1 hepatitis C virus who failed to achieve a sustained virological response (SVR) with combination therapy. Methods: We examined 38 patients who were re‐treated with PEG‐IFN α2a plus ribavirin for more than 60 weeks, among whom 14 were non‐responders and 24 were relapsers after previous treatment with PEG‐IFN α2b plus ribavirin. IL28B genotyping was done in 21 patients. Results: The overall SVR rate was 34%. Analysis of baseline characteristics showed that the relapsers had a significantly higher SVR rate than the non‐responders (50.0%, 12/24 vs. 7.1%, 1/14, respectively, P = 0.012) The SVR rates of re‐treated patients who had turned hepatitis C virus (HCV) RNA‐negative at weeks 8, 12, 24, and 48 of the previous therapy were 67% (4/6), 67% (4/6), 29% (2/7), and 25% (1/4), respectively. Re‐treatment achieved an SVR in five of 12 patients with IL28B major alleles and three of nine patients with IL28B minor alleles. During the re‐treatment, patients with complete viral suppression at week‐12 achieved a significantly higher SVR rate (P = 0.001). Conclusions: Re‐treatment with PEG‐IFN α2a plus ribavirin therapy is effective in patients who relapse after a course of PEG‐IFN α2b plus ribavirin therapy. Re‐treatment is a particularly useful option for patients who achieve early viral clearance during previous therapy.     

Daily or three times per week interferon alpha-2b in combination with ribavirin or interferon alone for the treatment of patients with chronic hepatitis C not responding to previous interferon alone

BACKGROUND/AIMS: We compared the efficacy and safety of the combined therapy of daily interferon alpha-2b and ribavirin with those of interferon alpha-2b three times per week alone or in combination with ribavirin in non-responder patients with hepatitis C virus (HCV) infection.METHODS: A total of 376 patients were randomly assigned to receive interferon alpha-2b (6 MU three times per week for 24 weeks followed by 3 MU three times per week for 24 weeks) alone (group A) or in combination with ribavirin for 48 weeks (group B), or daily interferon alpha-2b (3 MU per day for 24 weeks followed by 3 MU three times per week for 24 weeks) and ribavirin (group C).RESULTS: After 24 weeks of therapy, HCV RNA was undetectable in 11.7, 24.0, and 37.8% for groups A, B, and C, respectively. Sustained virological response was more frequent in patients who received combination therapy with three times weekly interferon (20.9%) or daily interferon (26.0%) than in patients who received interferon alone (5.8%) (P<0.001). The predictive HCV parameters for sustained response were a low viral load on day 7 and a negative HCV RNA on week 12.CONCLUSIONS: In conclusion, in non-responder patients with chronic hepatitis C, virological response with daily interferon and ribavirin, compared to interferon monotherapy, was significantly improved during treatment, although sustained virological response was similar for both combination therapies with ribavirin and three times a week or daily interferon.     

Chronic hepatitis C virus genotype 6 infection: response to pegylated interferon and ribavirin

BACKGROUND: To date, no study has evaluated pegylated interferon for the treatment of chronic infection with hepatitis C virus (HCV) genotype 6. We aimed to determine the efficacy of pegylated interferon plus ribavirin for treating infection with genotype 6 versus genotype 1. METHODS: Forty-two patients chronically infected with HCV (for genotype 1, [Formula: see text]; for genotype 6, [Formula: see text]) were treated with pegylated interferon alpha-2a ([Formula: see text]) or alpha-2b ([Formula: see text]) combined with oral ribavirin for 48 weeks. RESULTS: There was no difference between genotypes 1 and 6 in the rates of early virological response (76% vs. 81%; [Formula: see text]) and end-of-treatment response (71% vs. 81%; [Formula: see text]). Patients infected with genotype 6 had a higher rate of sustained virological response (SVR) than did patients infected with genotype 1 (86% vs. 52%; [Formula: see text]). The overall adverse-effects profile was similar in both genotype groups. There was no significant difference in the rate of SVR between patients receiving pegylated interferon alpha-2a and those receiving alpha-2b. Multivariate analysis showed that genotype was the only significant factor associated with SVR ([Formula: see text]). CONCLUSIONS: Treatment with pegylated interferon and ribavirin for 48 weeks resulted in a significantly higher rate of SVR in patients infected with genotype 6 than in those infected with genotype 1. Further studies are required to determine whether lower dosages and 24 weeks of therapy may be sufficient for the treatment of genotype 6 infection.     

Triple therapy of interferon and ribavirin with zinc supplementation for patients with chronic hepatitis C： A randomized controlled clinical trial

AIM: To study the therapeutic effect of interferon (IFN) and ribavirin with zinc supplement on patients with chronic hepatitis C viral (HCV) infection. METHODS: A total of 102 patients confirmed histologically to have chronic HCV infection with genotype 1b and more than 100 KIU/mL of HCV were randomly assigned to each arm of the study and each received 10 million units of pegylated interferon (IFN-alpha-2b) daily for 4 wk followed by the same dose every other day for 20 wk plus ribavirin (600 or 800 mg/d depending on body weight), with or without polaprezinc (150 mg/d) orally for 24 wk. The primary endpoint was sustained virological response (SVR) defined as negative HCV-RNA in the serum 6 mo after treatment. RESULTS: There were no differences in the clinical background between the two groups except for more females in the dual therapy group than in the other group (P<0.05). SVR was observed in 33.3% of the triple therapy group and 33.3% of the dual therapy group. The side effects were almost the same in both groups except for gastrointestinal symptoms, which were less in the triple therapy group (P=0.019). CONCLUSION: Considered together, triple therapy of zinc plus IFN and ribavirin for HCV infection patients with genotype 1b and high viral load is not better than dual therapy except for lower incidence of gastrointestinal side effects.     

快速病毒学应答对干扰素治疗慢性丙型肝炎疗效的预测分析

目的 探讨干扰素治疗慢性丙型肝炎的快速病毒学应答(RVR)对疗效的预测及其相关因素.方法 对139例慢性丙型肝炎患者,根据其临床特点,给予标准干扰素(IFN)或聚乙二醇干扰素(PEG-IFN)治疗.IFN α3～5MU隔日注射1次;PEG-IFNα-2a 135～180 μg,或PEG-IFNα-2b 50～80 μg,每周注射1次.并根据患者的体质量给予600～1500 mg/d的利巴韦林,在治疗的0、4,12周和以后每间隔12周、治疗结束后的24周进行HCV RNA含量检测,根据患者治疗过程中的病毒学应答情况给予24～72周的疗程,以持续病毒学应答(SVR)作为疗效的评判指标.根据资料不同采用χ2检验或t检验.结果 132例患者完成了全程观察,其中4例治疗无效(3.0%),12例复发(9.1%),获得SVR有116例(87.9%).120例在治疗4周时检测了病毒学指标,101例(84.2%)获得了RVR,治疗前病毒载量为(5.883±1.246)lg拷贝/ml,19例无RVR,治疗前病毒载量为(6.502±0.693)lg拷贝/ml,两组比较,t:2.15,P=0.034,差异有统计学意义.97例完成全程观察的RVR患者中,88例(90.7%)获得SVR,17例无RVR的患者,14(82.4%)例获得了SVR,x3=0.371,P=0.543,差异无统计学意义.基因1型HCV感染患者的RVR为80.7%(46/57),非基因1型HCV感染患者的RVR率为92.6%(25/27),两组间比较,χ2=6.00,P=0.112,差异无统计学意义.初治患者的RVR率为87.8%,干扰素再治疗者的RVR率为65.0%,两组比较,χ2=4.651,P=0.031,差异有统计学意义. 结论 干扰素个体化抗病毒治疗慢性丙型肝炎,有较高的RVR获得率.RVR的获得与治疗前HCV RNA载量和患者是否为初次治疗相关,与基因型无关,RVR的获得可预测SVR的获得.     

Induction doses of interferon-alpha-2a in combination with ribavirin and/or amantadine for the treatment of chronic hepatitis C in non-responders to interferon monotherapy: a randomized trial

The benefit of the triple therapy (interferon + amantadine + ribavirim) is still unknown. The efficacy of induction doses of interferon-alpha-2a monotherapy or in combination with ribavirin and/or amantadine was evaluated in interferon non-responders with chronic hepatitis C. A total of 378 patients were randomized. All the groups received the same doses and duration of interferon-alpha-2a: (i) interferon 9 MUI/day for 4 weeks and then 3 MUI/3 t.i.w. for 44 weeks (n = 53); (ii) interferon in combination with amantadine 100 mg twice daily for 48 weeks (n = 111); (iii) interferon in combination with ribavirin 1000-1200 mg (n = 106); (iv) interferon in combination with amantadine and ribavirin (n = 108). Baseline parameters were similar in the four groups. Sustained virological and biochemical responses were 13%, 6%, 18% and 22% respectively. No significant differences were found between double ribavirin arm vs triple therapy, but the difference was significant between interferon-amantadine (P = 0.008) and triple therapy (P = 0.0005). Hence, the induction doses of interferon in combination with ribavirin or ribavirin plus amantadine showed encouraging results in patients with chronic hepatitis C who were resistant to interferon. However, triple therapy is not superior to double.     

Association of IL28B gene variations with mathematical modeling of viral kinetics in chronic hepatitis C patients with IFN plus ribavirin therapy

Asian patients with chronic hepatitis C (CHC) are known to have better virological responses to pegylated (Peg) IFN-based therapy than Western patients. Although IL28B gene polymorphisms may contribute to this difference, whether favorable hepatitis C virus (HCV) kinetics during treatment plays a role remains unclear. We enrolled 145 consecutive Taiwanese patients with CHC receiving Peg-IFN α-2a plus ribavirin for the study. Blood samples were taken more frequently at defined intervals in the first 3 d. Peg-IFN was administered at week 1. It was then administered weekly in combination with daily ribavirin for 24 or 48 wk. A mathematical model fitted to the observed HCV kinetics was constructed, which could interpret the transient HCV titer elevation after Peg-IFN treatment. The results demonstrated a comparable viral clearance rate (c = 3.45 ± 3.73) (day(-1), mean ± SD) but lower daily viral production rate (P = 10(6)-10(12)) in our patients than those reported previously in Western patients. Of 110 patients with a sustained virological response (SVR), 47 (43%) had a transient elevation of viral titer within 12 h (proportion of 12 h/3 d: 44% in non-SVR vs. 70% in SVR; P = 0.029). Among 91 patients with available rs8099917 data, patients with the TT genotype had an early surge of viral titer after therapy and a higher SVR and viral clearance rate than those with the GT genotype. In conclusion, Taiwanese patients with CHC receiving Peg-IFN plus ribavirin therapy have a lower daily viral production rate than Western patients, and the rs8099917 TT genotype may contribute to the increased viral clearance rate and better virological responses in these patients.     

High predictive value of early viral kinetics in retreatment with peginterferon and ribavirin of chronic hepatitis C patients non-responders to standard combination therapy

BACKGROUND/AIMS: To evaluate the efficacy of peginterferon alfa-2b and ribavirin in unselected consecutive patients with chronic hepatitis C, treated outside of trials, who were relapsers or non-responders to interferon and ribavirin combination. METHODS: One hundred and fifty-four patients were evaluated. There were 101 non-responders and 53 relapsers to standard combination therapy. Patients were retreated with peginterferon alfa-2b 1.5 microg/kg/wk plus ribavirin 1000-1200 mg/day during 48 weeks. RESULTS: Forty-four patients (28.6%) achieved sustained virological response (SVR). Rapid (week 4) and early (week 12) virological response had high negative predictive values of SVR (94% and 97%, respectively); however positive predictive values were relatively low (52% and 49%, respectively). Relapsers had higher SVR rates (58.5%) than non-responders (13%) p<0.0001. In non-responders, SVR raised to 50% in patients with genotype non-1 and mild or moderate fibrosis. In multivariate analysis, predictors of SVR were: relapse after interferon plus ribavirin combination, mild or moderate fibrosis, genotype non-1 and baseline viral load <2 million copies/ml. CONCLUSIONS: Relapsers to interferon plus ribavirin therapy, and non-responders with genotype non-1 and mild or moderate fibrosis, achieved a relatively high SVR rate following retreatment with peginterferon plus ribavirin. Early viral kinetics had a high negative predictive value of SVR.     

Randomized, double-blind, placebo-controlled study of peginterferon alfa-2a (40KD) plus ribavirin with or without amantadine in treatment-naïve patients with chronic hepatitis C genotype 1 infection

BACKGROUND/AIMS: Amantadine may augment virological response rates to interferon-based therapy in chronic hepatitis C patients. Using a novel design, amantadine was studied in na?ve genotype 1 patients treated in combination with peginterferon alfa-2a (40KD)/ribavirin. METHODS: Patients enrolled in this randomized, placebo-controlled multicenter trial were stratified by single-dose interferon sensitivity (stratum I, 24-h HCV-RNA decline >1.4-log10; II, 0.8-1.39-log10; III, <0.8-log10; a reliable means of identifying nonresponders to interferon/ribavirin) and fibrosis grade (F0/1/2 vs. F3/4) at baseline. All patients received peginterferon alfa-2a (40KD) 180 microg/week plus ribavirin 1000-1200 mg/day and were randomized to receive amantadine 100 mg twice daily (N = 114) or placebo (N = 95) for 48 weeks. RESULTS: Week-24 virological response rates in strata II and III, the primary outcome, were similar in patients treated with amantadine (63.7%) or placebo (65.7%), as were sustained virological response rates at week 72 (46.5 and 51.6%, respectively). Adverse event profiles were similar and amantadine did not improve health-related quality of life compared with placebo. Interferon sensitivity was the only significant predictor of treatment outcome. CONCLUSIONS: Adding amantadine to peginterferon alfa-2a (40KD)/ribavirin combination therapy does not augment virological response rates in genotype 1 patients. Virological response was almost exclusively determined by interferon sensitivity at baseline.