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.     

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.     

Kinetics of hepatitis C virus RNA load during pegylated interferon alpha-2a and ribavirin treatment in naïve genotype 1 patients

Background

Pegylated interferon given for 24 or 48 weeks constitutes the most effective initial therapy for the treatment of chronic hepatitis C. It has been shown that viral load at week 2 appears the best time for predicting response to treatment. The objectives of this study were to assess whether the hepatitis C virus (HCV) RNA viral decline is predictive of sustained virological response (SVR) and to determine the best time for predicting complete response in our cohort of naïve patients treated with pegylated interferon alpha-2a (Peg-IFN alpha-2a) and ribavirin.

Results

Twenty patients treated with Peg-IFN alpha-2a and ribavirin for 48 weeks were studied. Six months after the end of treatment, a SVR (negative HCV RNA measured by PCR six months after the end of therapy) was obtained in 9 patients. Samples were obtained before and at week 2, 4, 8, and 12. At the end of week 2, viral load decreased more than 1.39 log in 8 out of the 9 patients with SVR and in 1 out of the 11 other patients. When we considered the viral load reduction from baseline to each week of treatment, week 2 appeared to be the best point time for predicting SVR, with a sensitivity of 91% (95%CI: 59;99), a specificity of 89% (52;98), a positive predictive value of 91% (59;99) and a negative predictive value of 89% (57;98).

Conclusion

During treatment with Peg-IFN alpha-2a plus ribavirin in genotype 1 patients, when the main objective of the treatment is viral eradication, viral kinetics showed that week 2 appeared to be the best time point for predicting SVR. Our results must be further confirmed on a larger cohort.

     

Retreatment of hepatitis C patients with pegylated interferon combined with ribavirin in non-responders to interferon plus ribavirin. Is it different in real life?

Background  

More than 50% of hepatitis C viruses (HCV)-infected patients do not respond to the classical Interferon (IFN)/Ribavirin (RBV) combination therapy. The aim of this study was to evaluate the efficacy of retreatment with Peg-Interferon alpha-2b (PEG-IFN alpha-2b) plus RBV, in patients with HCV, genotypes 1 or 3, who were non-responders to the previous standard treatment with IFN/RBV.     

Extended treatment duration for treatment naïve chronic hepatitis C genotype 1 late viral responders: a meta-analysis comparing 48 weeks vs 72 weeks of pegylated interferon and ribavirin

Summary. Patients with genotype I chronic hepatitis C virus (HCV) infection with late virological response to therapy have low sustained viral response (SVR) with standard 48 weeks of therapy and may benefit from extended therapy. We performed a systematic review and meta‐analysis of five studies to compare the outcome of 48 weeks vs 72 weeks treatment in treatment naïve chronic hepatitis C genotype I patients with late virological response. The end of treatment response with extended 72 weeks of treatment compared to standard 48 weeks of treatment was similar 48% and 56%, respectively, with pooled odds ratio (OR) (0.85; 95% CI 0.52–1.37). However, the SVR rates were higher with 72 weeks of treatment compared to 48 weeks treatment 32%vs 25% with pooled OR of 1.67 in favour of extended duration therapy (95% CI 1.16–2.40). This was because of lower relapse rates with extended duration therapy (35%vs 55%) with OR of 0.39 in favour of 72 weeks therapy (95% CI 0.25–0.61). There was no heterogeneity. No publication bias was noted as assessed by Egger’s test. Extending the treatment duration from 48 to 72 weeks in genotype 1 infected patients with late virological response improves SVR. Thus, therapy extension in genotype 1 late viral responders (LVR) may be a consideration to improve treatment response; however, the proportion of patients with LVR that might benefit from 72‐week therapy appears to be small.     

Evolution of Sjögren syndrome associated with hepatitis C virus when chronic hepatitis C is treated by interferon or the association of interferon and ribavirin

Hepatitis C virus is one of the most likely candidates as a potential pathogenic agent causing Sjogren's syndrome (SS) in a subset of patients. Nobody has until now described the evolution of SS associated with HCV when chronic hepatitis C is treated with antiviral therapy, interferon being an auto-immunity inductor. This is the purpose of our study. METHODS: Prospective study of 12 patients with a HCV-associated SS defined as certain according to the first european criteria and treated with interferon or interferon/ribavirin for their chronic hepatitis C. RESULTS: More than fifty percent of these patients developed a severe immunological complication especially when they were treated with interferon alone. Ribavirin may have had a protective role on interferon-mediated immunological complications. These complications went on after cessation of therapy. Sicca syndrome was improved only in the patients treated with the association (in 50% of the cases), but these patients also had a sustained virological response. It is difficult to tell if this improvement was due to the hepatitis C virus eradication or ribavirin treatment. CONCLUSION: Hepatitis C virus is implicated in the development of SS in a specific subset of patients for which we can propose the term SS "secondary to HCV" and this disease is not utterly benign especially after the introduction of interferon therapy. Ribavirin when associated with interferon gives a significative sustained virological response and could lower the incidence of immunological interferon-mediated complications with a favorable outcome of sicca syndrome.     

Different doses of consensus interferon plus ribavirin in patients with hepatitis C virus genotype 1 relapsed after interferon monotherapy： A randomized controlled trial

INTRODUCTION Retreatment of hepatitis C patients who relapsed after recombinant interferon (rIFN) monotherapy has a fair rate of success when ribavirin is added to the original protocol. About 30% of patients infected with hepatitis C virus (HCV) genotype…     

Interferon-λ polymorphisms and response to pegylated interferon in Iranian hepatitis C patients

AIM: To evaluate the efficacy of pegylated interferon in Iranian chronic hepatitis C patients in relation to interferon-λ(IFNL) polymorphisms. METHODS: This study enrolled patients with chronic hepatitis C referred to the Tehran Blood Transfusion Hepatitis Clinic in 2011. Patients were included in the study if they had no concomitant hepatic illness, were negative for human immunodeficiency virus antibodies, and had no prior history of treatment with any type ofpegylated interferon. Patients were treated with 180 μg pegylated interferon alpha-2a(Pegaferon#174;) weekly and 800-1200 mg ribavirin daily for 24 or 48 wk depending on weight and hepatitis C virus(HCV) genotype. Blood samples were collected from patients to obtain DNA for determination of IFNL rs12979860 and rs8099917 polymorphisms. The virologic response in patients was then evaluated and compared between the different IFNL genotypes.RESULTS: A total of 152 patients with a mean age of 41.9 ± 10.0 years were included in the study, of which 141/152 were men(92.8%). The most frequent HCV genotype was type-1, infecting 93/152(61.2%) patients. Sustained virologic response(SVR) was achieved in 81.9% of patients with HCV genotype-1 and 91.1% of patients with HCV genotype-3. Treatment success was achieved in 91.2%(52/57) of patients with the IFNL rs12979860 CC genotype and 82.1%(78/95) in those with other genotypes. Similar treatment response rates were also observed in patients with rs8099917 TT(39/45; 86.7%) and non-TT(61/68; 89.7%) genotypes. Univariate analyses identified the following factors which influenced treatment response for inclusion in a multivariate analysis: age, HCV RNA level, stage of liver fibrosis, rs12979860 CC genotype, and aspartate transaminase level. A logistic regression analysis revealed that only the rs12979860 CC genotype was significantly associated with achievement of SVR(OR = 6.2; 95%CI: 1.2-31.9; P = 0.03).CONCLUSION: The rs12979860 CC genotype was associated with SVR in patients receiving pegylated interferon plus ribavirin, however, the SVR rate in other rs12979860 genotypes was also relatively high.     

Immunological predictors of different responses to combination therapy with interferon α and ribavirin in patients with chronic hepatitis C

Background: This study aimed to investigate peripheral blood CD4+ T-helper (Th) and CD8+ cytotoxic T-lymphocyte (CTL) responses to combination treatment with interferon (IFN) α and ribavirin in 59 patients with chronic hepatitis C, and to correlate the results with the therapy outcome. Methods: The expression of activation molecules on the surface of CD8+ T cells and cytokine production by in-vitro activated CTLs and Th lymphocytes were examined before and at the end of the therapy, using flow cytometry. Results: There were 36 complete responders to the treatment and 23 transient responders who relapsed after withdrawal of the therapy. A significant increase in the production of Th1-type cytokines [IFNγ, interleukin 2 (IL2), and tumor necrosis factor-α (TNFα)] was found at the end of the treatment in complete responders compared with baseline values (P < 0.001). In contrast, transient responders had a marked decrease in the percentage of activated CD8+ T cells expressing CD28 or HLA-DR costimulatory molecules in peripheral blood, and a lower production of TNFα by CTLs and Th cells at the end of the therapy with respect to pretreatment values (P < 0.001). Conclusions: The efficacy of IFNα and ribavirin combination therapy for chronic hepatitis C is associated with a vigorous response of peripheral blood Th1 cells, whereas weak CTL responses at the end of the therapy might predict a further relapse of the disease. Received: March 26, 2002 / Accepted: August 30, 2002 Acknowledgments. This work was supported by grants MZd CzR 5740-3, 6015-3/00. Reprint requests to: R. Amaraa Editorial on page 302     

Response of TT virus to IFN plus ribavirin treatment in patients with chronic hepatitis C

AIM:TT virus (TTV) is a newly described DNA virus relatedto postransfusion hepatitis that produces persistent viremiain the absence of clinical manifestations.PEG-IFN plusribavirin have been useful in the treatment of chronic hepatitisC infection.This study investigated the responses of TT virus(TTV) and hepatitis C virus (HCV) to PEG-IFN plus ribavirintherapy.METHODS:Fifteen patients infected with HCV were treatedwith PEG-IFN(0.5 μg/body weight/week) and ribavirin(1000 mg-1 200 mg/daily) for 48 weeks,Blood samples weredrawn at the beginning and the end of the therapy.SerumTTV DNA and HCV RNA were quantified by real time PCR.RESULTS:At the beginning of treatment,TTV infection wasdetected in 10/15 (66.6%) of HCV-infected patients.Lossof serum TTV DNA at the end of therapy occurred in 6/10(60%) patients.Out of these 6 patients,4 (67%) becamepositive for TTV DNA after 6 months of therapy.RegardingHCV viremia,11/15 (73%) patients were negative for serumHCV RNA after 48 weeks of therapy,7/11 (64%) of thesecases also became negative for TTV DNA following thecombined treatment.In the 3/4 (75%) patients who werepositive for HCV RNA at the end of therapy,TTV DNA wasdetected as well.Sustained HCV response at 6 months aftertreatment was 53% (8/15).CONCLUSION:No TTV sustained response can be achievedin any patient after PEG-IFN plus ribavirin administration.     

Immunogenicity of recombinant hepatitis B vaccine in treatment-nave and treatment-experienced chronic hepatitis C patients: The effect of pegylated interferon plus ribavirin treatment

AIM: To retrospectively evaluate the vaccination-induced anti-HBs seroconversion rates in treatment-naive and treatment-experienced chronic hepatitis C (CHC) patients. Also to prospectively evaluate the seroconversion rates in CHC patients during pegylated interferon (PEG) plus ribavirin (RIB) treatment. METHODS: Seventy treatment-naive CHC patients (group A), 22 sustained virological responders-SVR following interferon (IFN) plus RIB treatment CHC patients (group B) and 121 healthy subjects (group C) had been participated in the same HBV vaccination schedule (20μg, 0-1-6 mo). Seroconversion was considered if anti-HBs levels were above 10 mIU/mL within 3 mo following the third dose of the vaccine. Moreover, we prospectively selected 30 non-cirrhotic CHC patients and evaluated them for the efficacy of the same vaccine schedule randomizing them in two groups: Group-1, 15 CHC patients received the first dose of the vaccine in parallel with the initiation of PEG plus RIB treatment and Group-2, 15 patients received the same vaccination schedule without concomitant treatment. Determination of anti-HBs was performed at mo 1, 2, and 7. Statistical analysis of data was based on ANOVA student's t-test and chi-square analysis (P < 0.05). RESULTS: Fifty-eight of 70 group A patients (82.85%), 20/22 group B (90.9%) and 112/121 healthy subjects (92.56%) had been seroconverted. The seroconversion rates were significantly higher in the control group than in treatment-naive CHC patients (P = 0.04). The corresponding rates were comparable between group A and group B CMC patients (P = 0.38). The vast majority of non-responders (10/14, 71.43%) had been infected by genotype-1 of HCV. The seroconversion rates were comparable between group 1 and 2 CHC patients at mo 1 (20% versus 26.7%, P = 0.67), mo 2 (46.7% vs 60%, P = 0.46) and mo 7 (86.7% versus 93.3%, P = 0.54) of follow-up. CONCLUSION: The immunogenicity of HBV vaccine seems to be lower in CHC patients compared to healthy subjects. SVR following IFN plus RIB treatment does not affect the antibody response to HBV vaccine. Infection by genotype-1 seems to negatively influence the seroconversion rates. Vaccination against HBV during PEG plus RIB combination treatment is not beneficial in terms of anti-HBs seroconversion rates.     

Is pegylated interferon superior to interferon, with ribavarin, in chronic hepatitis C genotypes 2/3？

Over the past decade, significant improvements have been made in the treatment of chronic hepatitis C （CHC）, especially with the introduction of combined therapy using both interferon and ribavarin. The optimal dose and duration of treatment is still a matter of debate and, importantly, the efficacy of this combined treatment varies with the viral genotype responsible for infection. In general, patients infected with viral genotypes 2 or 3 more readily achieve a sustained viral response than those infected with viral genotype 1. The introduction of a pegylated version of interferon in the past decade has produced better clinical outcomes in patients infected with viral genotype 1. However, the published literature shows no improvement in clinical outcomes in patients infected with viral genotypes 2 or 3 when they are treated with pegylated interferon as opposed to nonpegylated interferon, both given in combination with ribavarin. This is significant because the cost of a 24-wk treatment with pegylated interferon in lessdeveloped countries is between six and 30 times greater than that of treatment with interferon. Thus, clinicians need to carefully consider the cost-versusbenefit of using pegylated interferon to treat CHC, particularly when there is no evidence for clinically measurable benefits in patients with genotypes 2 and 3 infections.     

Is combined treatment with interferon alpha and ribavirin for 3 months enough in selected patients with a genotype 2 or 3 hepatitis C virus?

Peginterferon plus ribavirin for 24 weeks is the recommended treatment, for previously untreated patients infected by genotype 2 or 3 hepatitis C virus. We report 2 patients with genotype 3 and 2a, with a sustained virological response, after bitherapy with interferon plus ribavirin with 16 and 14 weeks respectively. Thus in selected patients having genotype 2 or 3, and other predictive factors of a sustained virological response, shorter bitherapy could be enough and improve the effectiveness/tolerance ratio.     

Immunogenicity of recombinant hepatitis B vaccine in treatment-naive and treatment-experienced chronic hepatitis C patients： The effect of pegylated interferon plus ribavirin treatment

AIM: To retrospectively evaluate the vaccination-induced anti-HBs seroconversion rates in treatment-naive and treatment-experienced chronic hepatitis C (CHC) patients. Also to prospectively evaluate the seroconversion rates in CHC patients during pegylated interferon (PEG) plus ribavirin (RIB) treatment. METHODS: Seventy treatment-naive CHC patients (group A), 22 sustained virological responders-SVR following interferon (IFN) plus RIB treatment CHC patients (group B) and 121 healthy subjects (group C) had been participated in the same HBV vaccination schedule (20 microg, 0-1-6 mo). Seroconversion was considered if anti-HBs levels were above 10 mIU/mL within 3 mo following the third dose of the vaccine. Moreover, we prospectively selected 30 non-cirrhotic CHC patients and evaluated them for the efficacy of the same vaccine schedule randomizing them in two groups: Group-1, 15 CHC patients received the first dose of the vaccine in parallel with the initiation of PEG plus RIB treatment and Group-2, 15 patients received the same vaccination schedule without concomitant treatment. Determination of anti-HBs was performed at mo 1, 2, and 7. Statistical analysis of data was based on ANOVA student's t-test and chi-square analysis (P < 0.05). RESULTS: Fifty-eight of 70 group A patients (82.85%), 20/22 group B (90.9%) and 112/121 healthy subjects (92.56%) had been seroconverted. The seroconversion rates were significantly higher in the control group than in treatment-naive CHC patients (P = 0.04). The corresponding rates were comparable between group A and group B CHC patients (P = 0.38). The vast majority of non-responders (10/14, 71.43%) had been infected by genotype-1 of HCV. The seroconversion rates were comparable between group 1 and 2 CHC patients at mo 1 (20% versus 26.7%, P = 0.67), mo 2 (46.7% vs 60%, P = 0.46) and mo 7 (86.7% versus 93.3%, P = 0.54) of follow-up. CONCLUSION: The immunogenicity of HBV vaccine seems to be lower in CHC patients compared to healthy subjects. SVR following IFN plus RIB treatment does not affect the antibody response to HBV vaccine. Infection by genotype-1 seems to negatively influence the seroconversion rates. Vaccination against HBV during PEG plus RIB combination treatment is not beneficial in terms of anti-HBs seroconversion rates.     

Treatment of chronic hepatitis C with pegylated interferon plus ribavirin in treatment-naïve ‘real-life’ patients in India

Purpose/Aim

Results of treatment of chronic hepatitis C (CHC) with pegylated interferon plus ribavirin (PEG-RBV) are mainly available from well-designed clinical trials, and only few ‘real-life’ studies which give a true picture of success of therapy are available. Such data in Indian patients is scarce. This prospective study aimed to evaluate the efficacy, safety, and factors associated with sustained virological response (SVR) in Indian CHC patients treated with PEG-RBV in ‘real-life’ setting.

Material and Methods

All treatment-naïve patients with CHC/compensated cirrhosis treated with PEG-RBV between January 2004 and December 2010 were included.

Results

Of 592 patients started on treatment, 524 (88.5 %) completed therapy (mean?±?SD age—42.0?±?12.1 years; 74.3 % males). Genotype 3 (73.6 %) was the commonest, followed by genotype 1 (19.3 %). In intention to treat analysis, SVR rates for ‘all’ patients, genotype 1 and genotype 3 patients were 72.3 % (428/592), 57 % (65/114), and 78.2 % (341/436), respectively (in per-protocol analysis—81.7 %, 69.1 %, and 85.3 %, respectively). Noncirrhotics had better SVR rates compared to cirrhotics treated for the same duration. About 20 % patients had both low viral load and achieved rapid virological response (RVR). Factors significantly associated with SVR were age <40 years, absence of cirrhosis, RVR, and no reduction in interferon dose.

Conclusion

SVR rates in CHC patients treated in ‘real-life’ setting in India were better than those reported in western population. Therapy should be prolonged for patients with cirrhosis, while one-fifth of patients may qualify for abbreviated therapy. Factors significantly associated with SVR were age <40 years, absence of cirrhosis, RVR, and no reduction in interferon dose.     

Irreversible alopecia universalis during treatment with pegylated interferon–ribavirin for chronic hepatitis C virus infection: Case report and published work review

Hair disorders that have been described in association with pegylated interferon–ribavirin combination treatment include canities, hypertrichosis, telogen effluvium, and the most common cutaneous side-effect by far, alopecia. Alopecia is a heterogeneous disease characterized by hair loss on the scalp or any hair-bearing surface with a wide range of clinical presentations, from a single patch of hair loss to complete loss of hair on the entire body (alopecia universalis). Although some cases of reversible alopecia universalis associated with pegylated interferon–ribavirin combination therapy have been reported in the published work, irreversible alopecia universalis has not yet been reported in relation to pegylated interferon and ribavirin combination treatment. For the first time, we report a case of irreversible alopecia universalis during pegylated interferon–ribavirin combination therapy in a man infected with hepatitis C virus in the absence of clinical or biochemical evidence of immunological disorders or thyroid dysfunction at any time before, during or after antiviral therapy.