Predictive value of early HCV RNA quantitation for sustained response in nonresponders receiving daily interferon and ribavirin therapy

The prognostic value of early hepatitis C virus (HCV)-RNA load was evaluated among nonresponder patients to previous interferon (IFN) therapy treated with daily IFN and ribavirin. One hundred-six nonresponders (83 men), mean age 44.8 +/- 11 years, were treated with IFN-alpha 2b 3 MU/day for 24 weeks, followed by 3 MU x 3/week for 24 weeks plus ribavirin 1-1.2 g/day for 48 weeks. HCV RNA was quantified by Versant HCV RNA 3.0 assay (Bayer). The predictive values of the baseline and the change in viral load at week 1, 4, and 12 for sustained virological responses were analyzed using receiver operating characteristic (ROC) curves, as well as predictive values of >2 log(10) drop from baseline by weeks 1, 4, and 12 in combination with undetectable HCV RNA for sustained virological response. Thirty-two patients (30.2%) were sustained virological responders. The highest area under the curve was obtained at week 4. The unquantifiable HCV RNA level, in combination with at least a 2 log(10) drop in viral load by week 4 and week 12, had a negative predictive value of 96% and 97%, respectively. Nonresponse can be predicted as early as week 4 or week 12 in nonresponders treated with daily IFN and ribavirin.     

Influence of HCV genotype 1 subtypes on the virus response to PEG interferon alpha-2a plus ribavirin therapy

New factors that influence the viral response in HCV non-genotype 2/3 patients must be identified in order to optimize anti-HCV treatment. This multicenter prospective study evaluates the influence of HCV variability and pharmacological parameters on the virological response of these patients to pegylated interferon α2a (peg-IFN-α2a: 180 μg/week) and ribavirin (RBV; 800-1,200 mg/day) for 48 weeks. HCV subtypes were identified by sequencing the NS5B region. Serum RBV and peg-IFN-α2a concentrations were measured at weeks 4 and 12. The 115 patients (67 men; median age = 49, range 31-76) included 64 who had never been treated and 27 co-infected with HIV. The mean baseline HCV RNA was 6.30 ± 0.06 log IU/ml and the HCV genotypes were: G1 (n = 93) with 1a (n = 37) and 1b (n = 50), G4 (n = 20) and G5 (n = 2). Most patients (79/108; 73%) had an early virological response. Independent predictors of an early virological response were interferon naive patients (OR= 2.98, 95% CI: 1.15-7.72) and RBV of >2,200 ng/ml at week 12 (OR = 3.41, 95% CI: 1.31-8.90). Forty of 104 patients (38%) had a sustained virological response. The only independent predictors of a sustained virological response were subtype 1b (OR = 6.82, 95% CI: 1.7-26.8), and HCV RNA <15 IU/ml at week 12 (OR = 25, 95% CI: 6.4-97.6). Thus a serum RBV concentration of >2,200 ng/ml was associated with an early virological response and patients infected with HCV subtype 1b had a better chance of a sustained virological response than did those infected with subtype 1a.     

Clinical Utility of a New Automated Hepatitis C Virus Core Antigen Assay for Prediction of Treatment Response in Patients with Chronic Hepatitis C

Hepatitis C virus core antigen (HCV Ag) is a recently developed marker of hepatitis C virus (HCV) infection. We investigated the clinical utility of the new HCV Ag assay for prediction of treatment response in HCV infection. We analyzed serum from 92 patients with HCV infection who had been treated with pegylated interferon and ribavirin. HCV Ag levels were determined at baseline in all enrolled patients and at week 4 in 15 patients. Baseline HCV Ag levels showed good correlations with HCV RNA (r = 0.79, P < 0.001). Mean HCV Ag levels at baseline were significantly lower in patients with a sustained virologic response (SVR) than in those with a non SVR (relapse plus non responder) based on HCV RNA analysis (2.8 log₁₀fmol/L vs. 3.27 log₁₀fmol/L, P = 0.023). Monitoring of the viral kinetics by determination of HCV RNA and HCV Ag levels resulted in similarly shaped curves. Patients with undetectable HCV Ag levels at week 4 had a 92.3% probability of achieving SVR based on HCV RNA assay results. The HCV Ag assay may be used as a supplement for predicting treatment response in HCV infection, but not as an alternative to the HCV RNA assay.     

Serum concentrations of ribavirin and pegylated interferon and viral responses in patients infected with HIV and HCV

The hepatitis C virus (HCV) infects a substantial proportion of patients infected with human immunodeficiency virus (HIV). Patients infected with both HCV and HIV respond poorly to anti-HCV treatment with pegylated interferon alpha and ribavirin. But few data are available on the influence of ribavirin and interferon concentrations on treatment outcome for these patients. This study investigated the relationship between the serum pegylated interferon and ribavirin concentrations 3 and 6 months after treatment initiation, and treatment outcome in 35 HCV-HIV coinfected patients. The pegylated interferon and ribavirin concentrations at months 3 and 6 were similar. The pegylated interferon concentrations at 3 months in responders and nonresponders were similar. However, responders tended to have higher ribavirin concentrations (2,322 ng/ml) than nonresponders (1,833 ng/ml; P = 0.08). Responders infected with HCV genotype 1 or 4 had higher ribavirin concentrations (2,672 ng/ml) than did similarly infected nonresponders (1,758 ng/ml; P = 0.04). ROC curve analysis showed that a ribavirin concentration of 2,300 ng/ml was the best threshold for predicting a nonresponse (ROC area = 0.80 +/- 0.12). Thus ribavirin concentrations influence treatment outcome in HIV patients infected with HCV genotype 1 or 4. Monitoring ribavirin concentrations could help adapt ribavirin concentrations and improve the sustained virological response.     

Predicting sustained virological response in chronic hepatitis C patients treated with pegylated interferon and ribavirin using a novel highly sensitive Real-time detection PCR assay

The Abbott Real Time HCV assay (lower limit of detection 12 IU/ml) was developed as a highly sensitive HCV RNA quantitative assay using real-time detection PCR(RTD-PCR). We assessed whether the new assay more effectively predicts sustained virological response (SVR) than conventional PCR (PCR) in 38 chronic hepatitis patients infected with HCV genotype 1b and treated with pegylated interferon alpha2b plus ribavirin. Sixteen patients reached SVR, 10 patients relapsed, 9 patients did not respond, 3 patients discontinued treatment. Positive predictive value (PPV) for SVR of undetectable HCV RNA at W4, 8, 12 by RTD-PCR and PCR was (100% vs. 100% at W4), (100% vs. 100% at W8), (83.3% vs. 72.7% at W12). HCV RNA undetectable at W12 had a higher PPV for SVR when measured by RTD-PCR than by conventional PCR.     

Response to pegylated interferon alfa‐2a and ribavirin in chronic hepatitis C genotype 4

The safety and efficacy of pegylated interferon (PEG‐IFN) alfa‐2a and ribavirin were studied among patients treated for genotype 4 chronic hepatitis C. Ninety‐five patients with chronic hepatitis C genotype 4 were treated with PEG‐IFN alfa‐2a (180 µg/week) plus ribavirin (≥11 mg/kg/day) for 48 weeks. The primary end point was sustained virological response, defined as non‐detectable levels of HCV RNA at the end of follow up (week 72). The proportion with sustained virological response was 58/95 = 61.1% (95% CI = 50.5–70.9%). Side effects were generally mild, well managed by dose reductions (in 62% of patients); in only two patients were side effects sufficiently severe to require treatment interruption. Ninety percent of patients adhered to treatment up to week 12, and their sustained virological response rate was higher compared to non‐adherent (65% vs. 22%, respectively, P = 0.012). None of the patients who failed to achieve 1 log reduction of viral load by week 8 (n = 15), or 2 log reduction by week 12 (n = 17), had a sustained virological response. In conclusion, sustained virological response in genotype 4 Egyptian patients treated with PEG‐IFN alfa‐2a and ribavirin was estimated around 60%, intermediate between sustained virological response observed in genotype 1 and genotype 2–3 patients in Western countries. The early virological response (week 4 or week 8) should be investigated as a criterion to decide whether the patient may benefit from a shorter duration of therapy. J. Med. Virol. 81:1576–1583, 2009. © 2009 Wiley‐Liss, Inc.     

Comparison of serum hepatitis C virus (HCV) RNA and core antigen levels in patients coinfected with human immunodeficiency virus and HCV and treated with interferon plus ribavirin

Trak-C (Ortho-Clinical Diagnostics) is an enzyme-linked immunosorbent assay-based method capable of quantifying hepatitis C virus (HCV) core antigen (CA) in serum and could be an alternative to molecular detection and quantification of HCV RNA. We have evaluated the Trak-C assay in comparison with an HCV RNA quantitative assay (Versant HCV v3.0; Bayer Diagnostics) in the follow-up of 348 treated, human immunodeficiency virus (HIV)/HCV-coinfected patients included in the ANRS HC02 RIBAVIC trial. ANRS HC02 RIBAVIC is a therapeutic, multicenter, randomized protocol comparing the efficacy of alpha interferon 2b (IFN-alpha2b) (3 million units three times a week)-ribavirin (800 mg/day) to that of pegylated IFN-alpha2b (1.5 mug/kg of body weight/week)-ribavirin (800 mg/day) during 48 weeks of treatment of HIV/HCV-coinfected patients na?ve to HCV treatment. Patients were assessed for virological analysis at day 0 and weeks 4, 12, 24, 48, and 72. Correlation of HCV RNA and HCV CA at the initiation of treatment was excellent (r = 0.92). HCV RNA and CA kinetics were similar during follow-up of HCV treatment from day 0 to week 72 whatever the group of response and genotype. The positive and negative predictive values of response to the treatment at week 4 were 59 and 94%, respectively, for HCV RNA load reduction of >2 log and 54 and 94%, respectively, for HCV CA below the threshold value (4.18 log(10) pg/ml . 10(4)). Trak-C, a new assay able to quantify CA in HIV/HCV-coinfected patients, correlates well with quantitative HCV RNA assays and is cheaper and easier to perform than molecular technology. HCV CA could be a valuable alternative test for therapeutic follow-up of coinfected patients treated with IFN plus ribavirin in developing countries.     

Early anemia and rapid virological response improve the predictive efficiency of IL28B-genotype for treatment outcome to antiviral combination therapy in patients infected with chronic HCV genotype 1

IL28B genotypes and virological response within 4 weeks are predictors of sustained virological response in patients infected with chronic hepatitis C virus (HCV) genotype 1 treated with antiviral dual combination therapy. The predictive value of “early” anemia (within 4 weeks) alone or in combination with the two other predictors has not been studied yet. A total of 305 pegylated interferon‐α and ribavirin‐treated patients with HCV genotype 1 were included in this study. Hemoglobin values at week 0, 4, 8, and 12 as well as the predictive efficiency of early anemia (hemoglobin value below the gender‐specific lower limit: female < 11.5; male < 13.5 g/dl) during therapy were assessed with IL28B genotypes and rapid virological response. Forty‐eight percent of treated patients developed early anemia. In both females and males (64%), a decrease of hemoglobin concentration of 3 g/dl (female: 14.7 ± 1.1 to 11.4 ± 1.3; male: 15.2 ± 1.2 to 12.2 ± 1.5) significantly correlated with sustained virological response. 64% of IL28B‐CC patients showed a sustained virological response. Seventy‐eight percent of patients with rapid virological response definitively eliminated the virus. Early anemia (81:48:41%) and rapid virological response (83:91:92%) increased the predictive efficiency of IL28B rs12979860 genotype distribution (CC:CT:TT). IL28B‐CC and early anemia as well as IL28B‐CC and rapid virological response had an Odds ratio of 42.4 or 75 to achieve a sustained virological response compared to TT without early anemia or rapid virological response. This finding may help to early identify responders to standard PEG‐IFN‐α and ribavirin treatment even within those with unfavorable IL28B genotype. J. Med. Virol. 84: 1208–1216, 2012. © 2012 Wiley Periodicals, Inc.     

Influence of the HCV subtype on the virological response to pegylated interferon and ribavirin therapy

The hepatitis C virus genotype is considered to be the most important baseline predictor of a sustained virological response in patients with chronic hepatitis C treated with pegylated interferon and ribavirin. The influence of the subtype on the sustained virological response was investigated in patients infected with genotypes 1, 4, 5, or 6. This study was done on 597 patients with chronic hepatitis C who were given pegylated interferon and ribavirin for 48 weeks. The overall rate of sustained virological response in the 597 patients was 37.8%. Univariate analysis indicated that the sustained virological response of patients infected with subtype 1b (39%) tended to be higher than that of patients infected with subtype 1a (30.6%; P = 0.06) and it was similar to those patients infected with subtypes 4a (51.3%; P = 0.12) or 4d (51.7%; P = 0.16). Multivariate analysis indicated that five factors were independently associated with sustained virological response: the age (OR 0.97; 95% CI = 0.95–0.99), absence of cirrhosis (OR: 2.92; 95% CI = 1.7–5.0; P < 0.01), absence of HIV co‐infection (OR: 2.08; 95% CI = 1.2–3.5; P < 0.01), low baseline plasma HCV RNA concentration (OR: 1.74; 95% CI = 1.2–2.6; P < 0.01), and the subtype 1b (OR: 1.61; 95% CI = 1.0–2.5; P = 0.04) or subtypes 4a and 4d (OR: 2.03; 95% CI = 1.1–3.8; P = 0.03). In conclusion, among difficult‐to‐treat genotypes, the subtype 1a is associated with a lower response to anti‐HCV therapy than subtypes 1b, 4a, and 4d. J. Med. Virol. 81:2029–2035, 2009. © 2009 Wiley‐Liss, Inc.     

Determinants of response to triple therapy of telaprevir, peginterferon, and ribavirin in previous non-responders infected with HCV genotype 1

Patients who do not achieve sustained virological response to telaprevir/peginterferon (PEG-IFN)/ribavirin need to be identified. Predictive factors of virological response to the triple therapy in non-responders to previous PEG-IFN/ribavirin therapy are not clear. The aims of this study were to determine the predictive factors of virological response to a 24-week regimen of triple therapy in 15 non-responders to previous PEG-IFN/ribavirin therapy among 61 Japanese adults infected with HCV genotype 1. Overall, sustained virological response and end-of-treatment response were achieved by 27% and 60%, respectively. Telaprevir-resistant variants (by direct sequencing) appeared during or after treatment in 82% of patients who did not show sustained virological response, but disappeared at the end of study, except for one patient with resistant variant at baseline. Substitution at aa 70 (Arg70) and type of previous response to PEG-IFN/ribavirin (partial response) were identified as significant determinants of sustained virological response. In addition, alpha-fetoprotein level (<10 μg/L) and type of previous response (partial response) were identified as significant determinants of end-of-treatment response. Prediction of response to therapy based on the combination of these factors had high sensitivity, specificity, positive, and negative predictive values. In conclusion, this study identified amino acid substitution of the core region, alpha-fetoprotein level, and type of previous response as predictors of virological response to telaprevir/PEG-IFN/ribavirin in patients infected with HCV genotype 1b who had not responded to previous PEG-IFN/ribavirin therapy.     

Secondary structure of the amino‐terminal region of HCV NS3 and virological response to pegylated interferon plus ribavirin therapy for chronic hepatitis C

The aim of the study was to identify a predictive marker for the virological response in hepatitis C virus 1b (HCV‐1b)‐infected patients treated with pegylated interferon plus ribavirin therapy. A total of 139 patients with chronic hepatitis C who received therapy for 48 weeks were enrolled. The secondary structure of the 120 residues of the amino‐terminal HCV‐1b non‐structural region 3 (NS3) deduced from the amino acid sequence was classified into two major groups: A and B. The association between HCV NS3 protein polymorphism and virological response was analyzed in patients infected with group A (n = 28) and B (n = 40) isolates who had good adherence to both pegylated interferon and ribavirin administration (>95% of the scheduled dosage) for 48 weeks. A sustained virological response (SVR) representing successful HCV eradication occurred in 33 (49%) in the 68 patients. Of the 28 patients infected with the group A isolate, 18 (64%) were SVR, whereas of the 40 patients infected with the group B isolate only 15 (38%) were SVR. The proportion of virological responses differed significantly between the two groups (P < 0.05). These results suggest that polymorphism in the secondary structure of the HCV‐1b NS3 amino‐terminal region influences the virological response to pegylated interferon plus ribavirin therapy, and that virus grouping based on this polymorphism can contribute to prediction of the outcome of this therapy. J. Med. Virol. 82:1364–1370, 2010. © 2010 Wiley‐Liss, Inc.     

Predictive factors of virological non-response to interferon-ribavirin combination therapy for patients infected with hepatitis C virus of genotype 1b and high viral load

Patients with high viral load (> or =1.0 x 10(5) IU/ml) of hepatitis C virus (HCV) genotype 1b do not achieve high sustained virological response rates to interferon (IFN)/ribavirin combination therapy. Previous studies suggested that pretreatment amino acid (aa) substitution patterns in the HCV core region could affect virological non-response especially in patients who could not achieve HCV-RNA negativity during treatment. The present study evaluated 167 consecutive Japanese adults with high HCV genotype 1b viral load who received combination therapy for > or =24 weeks. A case-control study matched for age, sex, genotype, and viral load was conducted to investigate the predictive factors for virological non-response, especially absolute virological non-response (patients who could not achieve >2 log decline of HCV RNA from baseline during the initial 24 weeks of therapy). Virological non-response was identified in 26.3% of patients, and 45.5% of these were absolute virological non-responders. Multivariate analysis identified ribavirin dose <11.0 mg/kg, moderate-to-severe hepatocyte steatosis, and substitutions of aa 70 and/or 91 in the core region as significant independent factors associated with virological non-response. The majority of absolute virological non-responders had such substitutions in the core region (95.0%), as well as substitution of glutamine at aa 70 and/or methionine at aa 91 (90.0%). In the present work, such substitutions significantly affected the viral kinetics in virological non-responders. The results suggest that viral, host, and treatment-related factors determine the response to IFN/ribavirin combination therapy in patients with high HCV genotype 1b viral load, and that amino acid substitution patterns in the core region is potentially useful pretreatment predictor of virological non-response.     

Association of IL28B genotype and viral response of hepatitis C virus genotype 2 to interferon plus ribavirin combination therapy

The impacts of IL28B genotype to treatment response of hepatitis C virus (HCV) genotype 2 are still not clear. A total of 381 consecutive Japanese patients infected with HCV genotype 2, who could complete combination therapy with interferon (IFN) plus ribavirin for 24 weeks, were evaluated to investigate pretreatment predictors. Patients, who could not achieve sustained virological response at the first course of 24‐week IFN plus ribavirin, were recruited into the study protocol of total 48‐week IFN plus ribavirin. In 24‐week regimen, rates of sustained virological response and rapid virological response were 82% and 50%, respectively. There were no significant differences in rates of sustained virological response and rapid virological response, according to IL28B genotype. Multivariate analysis identified younger age, higher level of albumin, absence of past history of IFN, and lower level of viremia as significant determinants of sustained virological response. As significant or marginal significant determinants of non‐sustained virological response regardless of rapid virological response, multivariate analysis identified IL28B rs8099917 genotype TG + GG and lower level of albumin. In 48‐week regimen to 10 patients of non‐sustained virological response at the first course of 24‐week regimen, sustained virological response rates were 70%. All of six patients, with IL28B TT and relapse at the first course of 24‐week regimen, could achieve sustained virological response, but two patients with IL28B TG could not achieve sustained virological response. In conclusion, the present results suggest that IL28B genotype might partly affect viral response of HCV genotype 2 to combination therapy. J. Med. Virol. 84:1593–1599, 2012. © 2012 Wiley Periodicals, Inc.     

Randomized trial of high‐dose interferon‐α‐2b combined with ribavirin in patients with chronic hepatitis C: Correlation between amino acid substitutions in the core/NS5A region and virological response to interferon therapy

The aim of this study was to compare the efficacy of high‐dose interferon (IFN)‐α‐2b with standard dose of IFN‐α‐2b in combination with ribavirin (RBV) for patients with chronic hepatitis C virus (HCV) infection, and to investigate the predictive factors associated with virological response. Two hundred Japanese patients with high HCV viral load (>100 KIU/ml) were randomized to 6 or 10 mega units (MU) of 24‐week IFN‐α‐2b with RBV. Predictive factors were investigated; including pretreatment amino acid (aa) sequences of the core region and the IFN‐sensitive determining region (ISDR). The sustained virological response rate was not different in the two groups (24% vs. 30%) but the incidence of depression was significantly higher in the 10 MU group than 6 MU group (7% vs. 0%, P = 0.02). Younger age (<60) and HCV genotype (2a/b) were significant predictors of sustained virological response. In patients infected with genotype 1b, substitutions of core aa 70 and/or 91 were predictive for non‐virological response (P < 0.001), and substitutions in the ISDR was observed frequently in virological responders. Early viral kinetics study showed that serum HCV core antigen decreased more slowly in both patients with aa 70 and/or 91 substitutions in the core and with absence of substitutions in the ISDR. In conclusion, the use of a higher dose of IFN‐α‐2b in combination with RBV did not improve virological response but resulted in higher incidence of depression. Amino acid substitutions in the core and ISDR are predictive of virological response to the therapy in patients with genotype 1b and high viral load. J. Med. Virol. 81:640–649, 2009 © 2009 Wiley‐Liss, Inc.     

Early viral kinetics and treatment outcome in combination of high-dose interferon induction vs. pegylated interferon plus ribavirin for naive patients infected with hepatitis C virus of genotype 1b and high viral load

An investigation was carried out to determine whether early viral monitoring could predict efficiently the virological response to combination therapy of two different regimens in treatment-naive chronic hepatitis C patients infected with genotype 1b with high baseline viral load. Patients were randomly assigned to receive interferon (IFN) alpha-2b induction (6 MU daily for 2 weeks) followed by 6 MU thrice weekly for 46 weeks (IFN/R group; n = 20), or pegylated IFN alpha-2b (1.5 microg/kg) weekly for 48 weeks (PEG/R group; n = 28), in combination with ribavirin (600-1,000 mg daily). Serum HCV RNA was quantitated at 0, 6, 12, 24, and 48 hr post-dose, weekly during the first 4 weeks, and thereafter viral kinetics were assessed every 4 weeks. The sustained virological response rates in the IFN/R and PEG/R groups were 40% (8/20) and 43% (12/28), respectively. The non-virological response rates were 40% (8/20) and 39% (11/28), respectively. The cumulative virological response rates were similar in both groups. Multivariate analyses identified no independent baseline variables linked to sustained virological or non-virological response. Early log viral load changes from baseline in both groups were significantly greater at all time-points after 24 hr in virological response patients than in non-virological response patients (P < 0.001 for all). On the receiver operating characteristics curves for prediction of non-virological response, the area under the curves (0.951-1.000), sensitivity (90%-100%), and negative predictive value (96%- 100%) were similar at any time-points after 24 hr. For prediction of sustained virological response, sensitivity of 80% with 86% negative predictive value was observed for negative HCV RNA at week 12, with the highest area under the curves value of 0.919. The results suggest that early monitoring of viral kinetics is a useful measure to predict virological response, and might facilitate development of rational and effective therapeutic strategies.     

Real-time PCR assays for hepatitis C virus (HCV) RNA quantitation are adequate for clinical management of patients with chronic HCV infection

Because of the use of viral kinetics during polyethylene glycol (PEG)-interferon-ribavirin therapy and the development of specific new anti-hepatitis C virus (anti-HCV) drugs, assessment of the efficacy of anti-HCV drugs needs to be based not on end-point PCR assays but on real-time PCR. The aim of this study was to determine if the two available commercial real-time PCR assays, the Abbott RealTime HCV assay and the Roche Cobas TaqMan HCV assay, can become the standard for HCV RNA quantification. We investigated the prognostic relevance of HCV RNA viral loads at baseline, week 4, and week 12 to a rapid and early virological response to antiviral therapy by using the two assays. Of 59 na?ve patients chronically infected by HCV (41 infected with genotype 1) who were treated with ribavirin plus PEG-interferon alfa-2b for 48 weeks, 24 patients (41%) showed a sustained virological response (SVR). With the two assays, viral loads were highly correlated, irrespective of genotype (R2=0.94 for all cases). No difference in diagnostic value was found between the Abbott and Roche assays at week 4, with respective negative predictive values (NPVs) of 84% and 78% and positive predictive values (PPVs) of 62% and 56% (not significant), and at week 12, the respective NPVs were 91% and 90% and PPVs were 44% and 46% (not significant). At week 12, 83% (20/24) and 96% (23/24) of patients with SVR tested negative for HCV RNA by the Abbott and Roche assays, respectively (the difference is not significant). In conclusion, the high sensitivities and large dynamic ranges of the Abbott and Roche assays show that a single real-time quantitative PCR assay is fully adequate for clinical and therapeutic management of HCV.     

Amino acid substitution in the core protein has no impact on relapse in hepatitis C genotype 1 patients treated with peginterferon and ribavirin

Previous reports demonstrated that amino acid (aa) substitutions in the hepatitis C virus (HCV) core protein are predictors of non-virological responses to pegylated interferon (Peg-IFN) and ribavirin combination therapy. The aim of this study was to investigate the impact of core aa substitutions on viral kinetics during the treatment and relapse after the treatment. The 187 patients with HCV genotype 1 enrolled in this study were categorized into four groups according to core aa substitution patterns: double-wild group (n=92), Arg70/Leu91; 70-mutant group (n=42), Gln70/Leu91; 91-mutant group (n=31), Arg70/Met91; and double-mutant group (n=22), Gln70/Met91. The relationship between the core aa substitutions and the virological response was examined. Multivariate logistic regression analyses showed that substitution at aa 70 was significantly associated with a poor virological response during the first 12 weeks (decline of <1 log from baseline at week 4, <2 log at week 12), and substitution at aa 91 was significantly associated with detectable HCV RNA at week 24. With respect to relapse, only the ribavirin exposure (odds ratio (OR), 0.77; 95% confidence interval (CI), 0.60-0.98) and HCV RNA disappearance between weeks 13 and 24 (OR, 23.69; 95% CI, 5.44-103.08) were associated independently with relapse, with no correlation being found with the core aa substitutions and relapse. In conclusion, the results showed that core aa substitutions can be strong predictive factors at pretreatment of the non-response, but not for relapse, for virological responders with HCV RNA disappearance during treatment.     

Involvement of dendritic cell frequency and function in virological relapse in pegylated interferon-alpha and ribavirin therapy for chronic hepatitis C patients

A combination of pegylated interferon alpha (PEG-IFNalpha) and ribavirin has been used widely. Enhancement of immune response against hepatitis C virus (HCV) is known to be involved in the efficacy of the combination therapy. The aim of the study was to elucidate whether the frequency or function of immunocompetent blood cells is related to the outcome of the therapy. Twenty-five chronic hepatitis C patients with high viral load of HCV genotype 1 who underwent 48 weeks of PEG-IFNalpha2b and ribavirin therapy were examined. During the treatment, frequencies of dendritic cell subsets, helper T cell subsets, and NK cells were phenotypically determined. In some patients, the ability of dendritic cells to stimulate allogeneic CD4(+)T cells was examined at the end and after the therapy. Among the 25 patients, 11 showed a sustained virological response, 11 a transient response, and 3 no response. In comparison with sustained virological responders, non-sustained virological responders showed impaired dendritic cell function at the end and after the treatment. The transient responders showed a decline of plasmacytoid dendritic cell frequency from Weeks 1-12 and impaired dendritic cell function as well. Even in patients who attained negative serum HCV RNA at Week 12, the transient responders showed a significant decrease of plasmacytoid dendritic cell frequency and impaired dendritic cell function. In conclusion, in PEG-IFNalpha and ribavirin combination therapy for chronic hepatitis C patients, the early-phase plasmacytoid dendritic cell frequency and/or end-of-treatment dendritic cell function are related to the virological outcome of the therapy.     

Leucocytapheresis with Adacolumn enhances HCV-specific proliferative responses in patients infected with hepatitis C virus genotype 1

The most important aim in controlling virus infections is to destroy infected cells. Impaired cellular immunity in HIV and HCV infection leads to chronic infection. This study examined the effect of cytapheresis on the subsequent response to interferon/ribavirin treatment in patients infected with HCV. Adacolumn cytapheresis was carried out once a day for 5 consecutive days in patients who relapsed or did not respond to previous peginterferon and ribavirin combination treatment (n = 14: relapsers = 3, non-responders = 11). Peginterferon and ribavirin combination treatment was started after cytapheresis. During combination treatment, the proliferative response of peripheral blood mononuclear cells to HCV proteins (core, NS3, NS4, and NS5), tetanus toxoid, and phytohemagglutinin was measured, and compared to the early virological response. After treatment by leucocytapheresis, the proliferative response of peripheral blood mononuclear cells to HCV-core and tetanus toxoid increased significantly over the baseline (P < 0.05). A marked increase in the phytohemagglutinin response was observed after peginterferon and ribavirin combination treatment was started (P < 0.01 at week 5 and P < 0.005 at week 13). There were, however, no clear changes in the proliferative response to other antigens. Among the 14 patients, 12 (85.7%) achieved an early virological response by week 13 (12 weeks after the start of combination treatment). After treatment, nine patients (64.3%) had a significant proliferative response to HCV core antigen. Among the nine patients, eight patients (88.9%) achieved early virological response. The results indicate that activation of cellular immunity by leucocytapheresis facilitates an early virological response rate in HCV patients. This new therapy may, therefore, become an additional therapeutic measure for HCV.     

A matched case‐controlled study of 48 and 72 weeks of peginterferon plus ribavirin combination therapy in patients infected with HCV genotype 1b in Japan: amino acid substitutions in HCV core region as predictor of sustained virological response

Substitution of amino acid (aa) 70 and 91 in the core region of HCV genotype 1b is a useful pretreatment predictor of efficacy of 48‐week peginterferon (PEG‐IFN) plus ribavirin (RBV) therapy. Here, we determined the efficacy of 72‐week PEG‐IFN/RBV and the predictive factors to such therapy in a case–control study matched for sex, age, and periods from the start of treatment to initial point of HCV RNA‐negative. We compared the treatment efficacy of 72‐week regimen in 65 patients with that of 48‐week in 130 patients, who were infected with HCV genotype 1b and treated with PEG‐IFN/RBV. They consisted mainly of late virological responders (LVR) (HCV RNA‐positive at 12 weeks and negative at 24 weeks after start of treatment). Sustained virological response (SVR) was achieved by 61.5% and 32.3% of patients of the 72‐ and 48‐week groups, respectively, while non‐virological response was noted in 9.2% and 29.2% of the respective groups. Multivariate analysis identified substitution of aa 70 and 91 (Arg70 and/or Leu91) and duration of treatment (72‐week) as independent parameters that significantly influenced SVR. For Arg70 and/or Leu91 of core region, SVR rate was significantly higher in 72‐ (68.0%) than 48‐week group (37.8%). For wild‐type of ISDR, SVR rate was significantly higher in 72‐ (61.2%) than in 48‐week group (29.3%). We conclude that 72‐week PEG‐IFN/RBV improves SVR rate for LVR, especially those with Arg70 and/or Leu91 of core region or wild‐type of ISDR. Substitution of aa 70 and 91 is also a useful pretreatment predictor of response to 72‐week PEG‐IFN/RBV. J. Med. Virol. 81:452–458, 2009. © 2009 Wiley‐Liss, Inc.