Hepatitis C virus-specific T-cell reactivity during interferon and ribavirin treatment in chronic hepatitis C

BACKGROUND & AIMS: The role of virus-specific T-helper lymphocyte reactivity in determining the therapeutic response in chronic hepatitis C virus (HCV) infection is not fully understood. METHODS: We studied CD4(+) T lymphocyte proliferation together with interferon (IFN)-gamma and interleukin (IL)-10 production from peripheral blood mononuclear cells in response to 4 HCV antigens (core, NS3, NS4, and NS5) in 25 patients with chronic hepatitis C undergoing antiviral therapy with IFN alone or in combination with ribavirin, prospectively, before, during, and after treatment. RESULTS: HCV-specific T-cell reactivity was uncommon at baseline but increased markedly during antiviral therapy, peaking around treatment weeks 4-8. Resolution of hepatitis C viremia was significantly more likely in patients who developed HCV-specific T-cell proliferation with increased IFN-gamma production. The main difference in T-cell reactivity of patients treated with IFN plus ribavirin was a significantly lower production of IL-10, whereas lymphocyte proliferation was similar to that in patients receiving IFN monotherapy. CONCLUSIONS: Treatment-induced control of hepatitis C viremia is associated with the development of HCV-specific T-cell responses with enhanced IFN-gamma and low IL-10 production. The greater efficacy of combination therapy with IFN-alpha plus ribavirin may be related to its ability to suppress HCV-specific IL-10 production.     

IL28B polymorphisms determine early viral kinetics and treatment outcome in patients receiving peginterferon/ribavirin for chronic hepatitis C genotype 1

Summary. Single nucleotide polymorphisms (SNPs) upstream of IL28B predict the outcome of treatment in chronic hepatitis C virus (HCV) infection, but their impact on viral kinetics and relation to other predictors are not well known. Here, two SNPs, rs12979860 and rs8099917, were analysed and related to early viral kinetics during treatment in 110 patients with HCV genotype 1 infection. The reduction of HCV RNA after 7 days of therapy was more pronounced (P < 0.0001) in patients with CC_rs12979860 or TT_rs8099917 than in patients carrying TT_rs12979860 or GG_rs8099917, respectively. The two SNPs were in linkage disequilibrium (d’ = 1, r² = 0.44), but CC_rs12979860 was less common (43%vs 71%) than TT_rs8099917. Patients carrying both CC_rs12979860 and TT_rs8099917 genotypes achieved lower levels of HCV RNA at week 4 than those with CT or TT at rs12979860 and TT_rs8099917 (P = 0.0004). The viral elimination was significantly influenced by rs12979860 independently of baseline viral load, age or fibrosis. This translated into high rates of sustained viral response (SVR) among patients carrying CC_rs12979860 despite the presence of high viral load at baseline (SVR 74%), high age (SVR 79%) or severe liver fibrosis (SVR 83%). We conclude that the IL28B variability influences the antiviral efficiency of interferon/ribavirin therapy and has a strong impact on SVR, independently of traditional response predictors. A combined assessment of these SNPs in conjunction with other response predictors may better predict outcome in difficult‐to‐treat patients.     

Pretreatment prediction of response to peginterferon plus ribavirin therapy in genotype 1 chronic hepatitis C using data mining analysis

Background  

This study aimed to develop a model for the pre-treatment prediction of sustained virological response (SVR) to peg-interferon plus ribavirin therapy in chronic hepatitis C.     

Treatment of chronic hepatitis C virus genotype 1 with peginterferon, ribavirin, and epoetin alpha

Successful treatment of chronic HCV with peginterferon (PEGIFN) and ribavirin (RVN) is often limited by anemia. We performed the present study to determine if utilizing epoetin alpha (EPO) with or without a higher dose of RVN could enhance sustained virologic response (SVR). We randomized 150 treatment-naive patients with chronic HCV genotype 1 into 3 treatment groups: (1) PEGIFN alpha-2b (1.5 microg/kg/week) + weight-based RVN (WBR) 13.3 mg/kg/day (800 to 1400 mg/day); (2) PEGIFN alpha-2b + WBRVN + EPO (40,000 U/week); or (3) PEGIFN alpha-2b + higher dose WBR 15.2 mg/kg/day (1000 to 1600 mg/day) + EPO. We initiated EPO at the onset of therapy to maintain the hemoglobin between 12 and 15 g/dL. When required, we reduced RVN by 200-mg steps. African Americans compose 36% of the population. A significantly smaller percentage of group 2 patients had a decline in hemoglobin to less than 10 g/dL (9% versus 34%; P < 0.05) and required that the RVN dose be reduced (10% versus 40%; P < 0.05) compared to group 1 patients. Despite this, SVR was similar in these groups (19% to 29%). SVR was significantly greater (P < 0.05) in group 3 patients (49%). This resulted from a significant decline (P < 0.05) in relapse rate; only 8% versus 38% for groups 1 and 2. CONCLUSION: We conclude that using EPO in all subjects at the initiation of PEGIFN and RVN treatment will not enhance SVR given the same starting dose of RVN. In contrast, a higher starting dose of RVN was associated with a lower relapse rate and higher rate of SVR.     

Pre-treatment prediction of response to peginterferon plus ribavirin in chronic hepatitis C genotype 3

AIM: To evaluate pre-treatment factors associated with sustained virological response(SVR) in patients with hepatitis C virus(HCV) genotype 3 treated with peginterferon and ribavirin(RBV). METHODS: We retrospectively analyzed treatment naive, mono-infected HCV genotype 3 patients treated with peginterferon and RBV. Exclusion criteria included presence of other liver disease, alcohol consumption and African American or Asian ethnicity. The variables collected and compared between patients who achieved an SVR and patients who did not were as follows: gender, age, fibrosis stage, diabetes, body mass index,steatosis, INFL3 polymorphism, pre-treatment HCVRNA, type of peginterferon, RBV dose and adherence. RESULTS: A total of 107 patients treated between June, 2004 and March, 2013 were included. Mean treatment duration was 25.1(± 1.8) wk. Overall, 58%(62/107) of the patients achieved an SVR and 42%(45/107) did not. In the multivariate logistic regression analysis, pre-treatment HCV-RNA ≥ 600000 UI/m L(OR = 0.375, 95%CI: 0.153-0.919, P = 0.032) and advanced fibrosis(OR = 0.278, 95%CI: 0.113-0.684,P = 0.005) were significantly associated with low SVR rates. In patients with pre-treatment HCV-RNA ≥600000 UI/m L and advanced fibrosis, the probability of achieving an SVR was 29%(95%CI: 13.1-45.2).In patients with pre-treatment HCV-RNA 600000UI/m L and mild to moderate fibrosis, the probability of achieving an SVR was 81%(95%CI: 68.8-93.4).CONCLUSION: In patients with HCV genotype 3infections the presence of advance fibrosis and high pre-treatment viral load might be associated with poor response to peginterferon plus RBV. These patients could benefit the most from new direct antiviral agentsbased regimes.     

Retreatment with peginterferon and ribavirin in chronic hepatitis C

The development of boceprevir and telaprevir was a major step forward in the treatment of chronic hepatitis C.In addition,the treatment of these infections has been recently revolutionized by the approval of sofosbuvir and simeprevir.However,there are several challenges associated with the application of noveldrugs,such as new and more frequent adverse events,new drug interactions,and excessively high treatment costs.An additional concern is viral resistance.These considerations highlight the fact that direct-acting antiviral agents are not a panacea and may not be the best option for all patients who are in need of therapy.This retrospective study revealed that the sustained virologic response was not significantly reduced following peginterferon and ribavirin retreatment compared with the new therapy.We suggest that patients who experience relapse shortly after completing treatment with peginterferon and ribavirin have a reasonable chance of achieving a sustained virologic response when retreated with these drugs alone.     

Occurrence of porphyria cutanea tarda during peginterferon/ribavirin therapy for chronic viral hepatitis C

Porphyria cutanea tarda (PCT) is a metabolic disorder characterized by a reduced hepatic activity of uroporphynogen decarboxylase (URO-D), an enzyme of the heme synthesis. The clinical features of PCT may be brought into light by hepatic injury induced by hepatitis C virus (HCV). A significant association between HCV and PCT is well recognized, although the role of HCV in the appearance of PCT is still debated because confounding factors often coexist, such as alcohol, other viruses, drugs or iron overload (). HCV therapy may improve PCT although PCT was rarely reported as a de novo occurrence during an interferon/ribavirin therapy (Jessner et al. Hepatology 2002;36:1301-1302); here, we describe two such other cases.     

Treatment of chronic hepatitis C genotype 1 early responders with 36 week pegylated interferon and ribavirin therapy

Introduction. Standard treatment for patients with chronic hepatitis C genotype 1 (CHC G-1) infection includes pegylated interferon plus ribavirin (PEG-RBV) for 48 weeks. Shorter treatment regimen would be more acceptable due to lower cost and fewer side-effects. We aimed to compare the efficacy of 36 week PEG-RBV therapy with standard 48 week therapy in CHC G-1 patients who achieve complete early virological response (cEVR).Material and methods. Consecutive treatment-naïve patients with CHC G-1 were treated with pegylated interferon a2b (1.5 μg/kg/week) or α2a (180 μg/week) and weight based ribavirin. Patients who achieved cEVR at 12 weeks [undetectable HCV RNA irrespective of RVR (rapid virological response)] were randomized into- group A (48 weeks therapy) and group B (36 weeks therapy). Primary end-point was achievement of sustained virological response (SVR) at 24 weeks of follow up.Results. Out of the total 166 patients started on treatment, 112 (69.3%) achieved cEVR, and were randomized into group A (n = 59) and group B (n = 53). Fifty-five (93.2%) patients in group A and 50 (94.3%) in group B completed therapy. The overall SVR rate in group A was 79.6% (47/59) and group B was 84.9% (45/53) (p = 0.622). SVR rates in the two groups were comparable in all patient sub-groups according to factors like viral load (≤ or > 400,000 IU/mL), RVR (achieved/not achieved), age (≤ or > 40 years), body mass index (≤ or > 27) and cirrhosis (present/absent).Conclusion. In CHC G-1 patients who achieve cEVR, 36 weeks PEG-RBV therapy is as effective as standard 48 weeks therapy, irrespective of other host or virological factors.     

Association between HCV amino acid substitutions and outcome of peginterferon and ribavirin combination therapy in HCV genotype 1b and high viral load

Background and Aim: We prospectively compared the sensitivity to interferon (IFN) and the efficacy of antiviral combination therapy with peginterferon (PEG‐IFN) and ribavirin for chronic hepatitis C virus (HCV) genotype 1b infection according to the amino acid sequences of the HCV core, E1, and NS5A regions reported to be associated with the outcome of antiviral therapy. Methods: A total of 107 patients with HCV genotype 1b were investigated. All patients received combination therapy with PEG‐IFN alpha‐2b and ribavirin. Amino acids 70 and 91 (core), 139 (E1), and 2209–2248 (NS5A) of HCV were analyzed by direct nucleotide sequencing. Results: The reduction in HCV RNA concentration at 24 h after a single administration of conventional IFN‐alpha and after the start of combination therapy was significantly less marked, and rates of complete early virologic response, end‐of‐treatment response, and sustained virologic response (SVR) were significantly lower (all P < 0.0001) in patients with glutamine at amino acid 70 (n = 29) than in those with arginine at that position (n = 70). We found no differences associated with the other amino acid positions. Amino acid 70 was an independent factor for the responses to the therapy in multivariate analysis. Conclusion: The identity of amino acid 70 of the HCV core region affected the sensitivity to IFN; patients with glutamine at amino acid 70 of HCV showed resistance to IFN. Consequently, it strongly affected the outcome of combination therapy with PEG‐IFN and ribavirin in Japanese patients with HCV genotype 1b.     

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.     

Daclatasvir vs telaprevir plus peginterferon alfa/ribavirin for hepatitis C virus genotype 1

AIM: To evaluate daclatasvir vs telaprevir, each combined with peginterferon alfa-2a/ribavirin (pegIFN/RBV), in treatment-naive hepatitis C virus (HCV) genotype (GT) 1-infected patients.METHODS: In this phase 3, randomized, open-label, noninferiority study, 602 patients were randomly assigned (2:1) to daclatasvir vs telaprevir, stratified by IL28B rs12979860 host genotype (CC vs non-CC), cirrhosis status (compensated cirrhosis vs no cirrhosis), and HCV GT1 subtype (GT1a vs GT1b). Patients were selected by study inclusion criteria from a total of 793 enrolled patients. Patients received daclatasvir 60 mg once daily or telaprevir 750 mg 3 times daily plus pegIFN/RBV. Daclatasvir recipients received 24 wk of daclatasvir plus pegIFN/RBV; those without an extended rapid virologic response (eRVR; undetectable HCV-RNA at weeks 4 and 12) received an additional 24 wk of pegIFN/RBV. Telaprevir-treated patients received 12 wk of telaprevir plus pegIFN/RBV followed by 12 (with eRVR) or 36 (no eRVR) wk of pegIFN/RBV. The primary objective was to compare for noninferiority of sustained virologic response rates at posttreatment week 12 (SVR12) in GT1b-infected patients. Key secondary objectives were to demonstrate that the rates of anemia (hemoglobin < 10 g/dL) and rash-related events, through week 12, were lower with daclatasvir + pegIFN/RBV than with telaprevir + pegIFN/RBV among GT1b-infected patients. Resistance testing was performed using population-based sequencing of the NS5A region for all patients at baseline, and for patients with virologic failure or relapse and HCV-RNA ≥ 1000 IU/mL, to investigate any link between NS5A polymorphisms associated with daclatasvir resistance and virologic outcome.RESULTS: Patient demographics and disease characteristics were generally balanced across treatment arms; however, there was a higher proportion of black/African Americans in the daclatasvir groups (6.0% and 8.2% in the GT1b and GT1a groups, respectively) than in the telaprevir groups (2.2% and 3.0%). Among GT1b-infected patients, daclatasvir plus pegIFN/RBV was noninferior to telaprevir plus pegIFN/RBV for SVR12 [85% (228/268) vs 81% (109/134); difference, 4.3% (95%CI: -3.3% to 11.9%)]. Anemia (hemoglobin < 10 g/dL) was significantly less frequent with daclatasvir than with telaprevir [difference, -29.1% (95%CI: -38.8% to -19.4%)]. Rash-related events were also less common with daclatasvir than with telaprevir, but the difference was not statistically significant. In GT1a-infected patients, SVR12 was 64.9% with daclatasvir and 69.7% with telaprevir. Among both daclatasvir and telaprevir treatment groups, across GT1b- or GT1a-infected patients, lower response rates were observed in patients with IL28B non-CC and cirrhosis - factors known to affect response to pegIFN/RBV. Consistent with these observations, a multivariate logistic regression analysis in GT1b-infected patients demonstrated that SVR12 was associated with IL28B host genotype (CC vs non-CC, P = 0.011) and cirrhosis status (absent vs present, P = 0.031). NS5A polymorphisms associated with daclatasvir resistance (at L28, R30, L31, or Y93) were observed in 17.3% of GT1b-infected patients at baseline; such variants did not appear to be absolute predictors of failure since 72.1% of these patients achieved SVR12 compared with 86.9% without these polymorphisms. Among GT1b-infected patients, treatment was completed by 85.4% (229/268) in the daclatasvir group, and by 85.1% (114/134) in the telaprevir group, and among GT1a-infected patients, by 67.2% (90/134) and 69.7% (46/66), respectively. Discontinuations (of all 3 agents) due to an AE were more frequent with telaprevir than with daclatasvir, whereas discontinuations due to lack of efficacy were more frequent with daclatasvir, due, in part, to differences in futility criteria.CONCLUSION: Daclatasvir plus pegIFN/RBV demonstrated noninferiority to telaprevir plus pegIFN/RBV for SVR12 and was well-tolerated in treatment-naive GT1b-infected patients, supporting the use of daclatasvir with other direct-acting antivirals.     

Refinement of stopping rules during treatment of hepatitis C genotype 1 infection with boceprevir and peginterferon/ribavirin

In comparison with peginterferon/ribavirin alone, boceprevir with peginterferon/ribavirin significantly improves sustained virological response (SVR) rates in patients with chronic hepatitis C virus (HCV) genotype 1 infections, but treatment failure remains a significant problem. Using phase 3 trial databases, we sought to develop stopping rules for patients destined to fail boceprevir-based combination therapy in order to minimize drug toxicity, resistance, and costs in the face of ultimate futility. Exploratory post hoc analyses using data from the Serine Protease Inhibitor Therapy 2 (SPRINT-2) study (treatment-naive patients) and the Retreatment With HCV Serine Protease Inhibitor Boceprevir and Pegintron/Rebetol 2 (RESPOND-2) study (treatment-experienced patients) were undertaken to determine whether protocol-specified stopping rules (detectable HCV RNA at week 24 for SPRINT-2 and at week 12 for RESPOND-2) could be refined and harmonized. In SPRINT-2, a week 12 rule with an HCV RNA cutoff of ≥ 100 IU/mL would have discontinued therapy in 65 of 195 failures (sensitivity = 33%) without sacrificing a single SVR among 475 successes (specificity = 100%). Viral variants emerged after week 12 in 36 of the 49 evaluable patients (73%) who would have discontinued at week 12 using a ≥ 100 IU/mL stopping rule. In RESPOND-2, five of six patients with week 12 HCV RNA levels between the lower limit of detection (9.3 IU/mL) and the lower limit of quantification (25 IU/mL) who continued therapy despite the protocol-stipulated futility rule achieved SVR; one additional patient with a week 12 HCV RNA level of 148 IU/mL also continued therapy, had undetectable HCV RNA at week 16, and attained SVR. CONCLUSION: Although a stopping rule of detectable HCV RNA at week 12 would have forfeited some SVR cases, week 12 HCV RNA levels ≥ 100 IU/mL almost universally predicted a failure to achieve SVR in both treatment-naive and treatment-experienced patients. In boceprevir recipients, the combination of 2 stopping rules-an HCV RNA level ≥ 100 IU/mL at week 12 and detectable HCV RNA at week 24--maximized the early discontinuation of futile therapy and minimized premature treatment discontinuation.     

Interferon and ribavirin therapy for chronic hepatitis C virus genotype 6: a comparison with genotype 1

Because there is a lack of data on the treatment outcome of patients who carry hepatitis C virus (HCV) genotype 6, we conducted a prospective study, to compare the effect of interferon and ribavirin therapy in HCV genotypes 1 and 6, of patients with seropositive anti-HCV, persistently elevated alanine transaminase levels, and detectable HCV RNA. Patients were treated with subcutaneous recombinant interferon alpha-2b and ribavirin for 12 months. Of 40 patients, 16 had genotype 6, and 24 had genotype 1. An end-of-treatment response was detected in 12 (75%) patients with genotype 6 and in 10 (41.6%) patients with genotype 1 (P=.05). A sustained virological response (SVR) was present in 10 (62.5%) patients with genotype 6 and in 7 (29.2%) patients with genotype 1 (P=.04). Genotype 6 has a better response than genotype 1 and is associated with a higher SVR.     

IFNL4 polymorphism effects on outcome of simeprevir,peginterferon, and ribavirin therapy for older patients with genotype 1 chronic hepatitis C

Aim

Older patients with chronic hepatitis C have a lower virological response to interferon (IFN)‐based treatments compared to younger patients. A single nucleotide polymorphism in the IFN‐λ‐4 (IFNL4) gene has a potent predictive effect on treatment response to IFN‐based treatments. The efficacy of simeprevir (SMV) plus pegylated‐IFN (PEG‐IFN) and ribavirin therapy and the predictive value of IFNL4 on the outcome of therapy for older patients have not been addressed.

Methods

This retrospective multicenter study included 234 consecutive Japanese patients with genotype 1 chronic hepatitis C. We assessed the predictive factors for sustained virological response (SVR) to SMV, PEG‐IFN, and ribavirin triple therapy in 170 younger (<70 years) and 64 older (≥70 years) patients. IFNL4 polymorphism ss469415590 was analyzed by Invader assay.

Results

The SVR rate for older patients was similar to that for younger patients (63.9% and 72.0%, respectively). The SVR rate for the IFNL4 TT/TT group was significantly higher than the IFNL4 TT/ΔG or ΔG/ΔG group both in younger (93.6% and 46.1%, respectively, P < 0.01) and older patients (84.4% and 33.3%, respectively, P < 0.001). In multivariate regression analysis, IFNL4 TT/TT genotype, response to previous treatment and IFNL4 TT/TT genotype were identified as independent predictive factors for SVR in older and younger patients, respectively. Decrease in hemoglobin level was similar between the two groups.

Conclusion

The virological response to SMV triple therapy in older patients was similar to that of younger patients. Analysis of IFNL4 polymorphisms is a valuable predictor in both younger and older patients.