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.     

Predictors of viral kinetics to peginterferon plus ribavirin combination therapy in Japanese patients infected with hepatitis C virus genotype 1b

For chronic hepatitis C virus (HCV) infection, evaluation of response to peginterferon (PEG-IFN) plus ribavirin (RBV) therapy based on viral kinetics is useful as an early predictor of treatment efficacy, but the underlying mechanisms of the different viral kinetics to treatment are still unclear. The response to 48-week PEG-IFN-RBV combination therapy was evaluated in 160 Japanese adult patients infected with HCV genotype 1b and determined the rapid virological response (at 4 weeks), early virological response (at 12 weeks), end-of treatment response, and sustained virological response (6 months after end of treatment). The proportion of patients who showed rapid, early and sustained virological, and end-of treatment responses were 50%, 73%, 47%, and 71%, respectively. Furthermore, 66% of patients who achieved early virological response also showed sustained virological response. Multivariate analysis identified substitutions of amino acid (aa) 70 and 91 in the HCV core region (double-wild-type) as a predictor of early HCV-RNA negativity, rapid, early, and sustained virological responses and end-of treatment response, and lipid metabolic factors (high levels of LDL cholesterol and total cholesterol) as predictors of early and rapid virological responses and end-of treatment response. Male sex and low levels of alpha-fetoprotein were other predictors of sustained virological response. Furthermore, female sex and severity of liver fibrosis were determinants of lack of sustained virological response in spite of early virological response. This study identified predictors of efficacy of PEG-IFN-RBV therapy based on viral kinetics in Japanese patients infected with HCV genotype 1b.     

The prognostic value of changes in serum ferritin levels during therapy for hepatitis C virus infection

An increase in serum ferritin levels during combined interferon-ribavirin treatment in chronic patients infected with hepatitis C virus (HCV) can occur. A study was conducted to determine whether observing the kinetics of serum ferritin levels during antiviral therapy, may assist in predicting the rate of sustained virological response. The kinetics of serum ferritin levels during antiviral therapy in treatment-naive, adherent patients with chronic HCV who had early virological response were characterized. Thirteen patients achieved sustained virological response (group 1) while eight patients did not (group 2). Pre-treatment serum ferritin levels were higher in group 2 patients. During antiviral therapy, serum ferritin levels increased in both groups. On treatment, the median increase (compared to baseline) and the calculated rate of the increase in serum ferritin levels was higher in group 1 patients (874% vs. 272%, P < 0.05, 63%/week vs. 13%/week, P = 0.024, respectively). Red blood cell lysis did not contribute to the increase in serum ferritin level. Post-treatment (1st month) serum ferritin levels in group 1 patients were lower than in group 2 patients. In addition, the degree of decline in the 1st month serum ferritin levels (from peak levels) in group 1 patients was higher (76% vs. 49%, P = 0.039). Measuring serum ferritin levels during antiviral therapy in HCV patients who had an early virological response may assist in predicting sustained virological response.     

Association of interleukin-28B rs12979860 and rs8099917 polymorphisms with sustained viral response in hepatitis C virus genotype 1 and 3 infected patients from the Indian subcontinent

Background: Polymorphisms of the IL28B gene (rs12979860 and rs8099917) have been shown to impact treatment responses in hepatitis C virus (HCV) infected patients. The association of these polymorphisms with sustained viral response (SVR) has been studied in HCV genotype 3 infected patients in India, but not in genotype 1. Objectives: This study aimed to determine the association of IL28B gene polymorphisms and other host and viral factors with treatment response in patients with HCV genotype 1 and 3 infection. Materials and Methods: DNA from 42 HCV-infected patients on antiviral therapy was analysed for the IL28B polymorphisms using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Bidirectional sequencing was performed on a subset of samples for verification of PCR-RFLP results. Information on age, weight, height, diabetic status, pre-treatment viral load and alanine aminotransferase (ALT) levels was obtained from clinical records. The IL28B genotypes and the other factors were analysed for their association with SVR. Results: The frequency distribution of rs12979860 CC/CT/TT genotypes was found to be 66.7%, 26.2% and 7.1%, respectively. For rs8099917 genotype, the TT/GT/GG distribution was 73.8%, 21.4% and 4.8%, respectively. SVR was seen in 61.9% of cases (55.6% in genotype 1 and 62.5% in genotype 3). CC genotype at rs12979860 and TT genotype at rs8099917 were significantly higher in responders (P = 0.013 and 0.042, respectively). Lower baseline ALT and rapid viral response were also found to be associated with SVR. On logistic regression analysis, CC genotype at rs12979860 emerged as the most powerful predictor of treatment response. Conclusion: IL28B polymorphisms are strong predictors of SVR in patients from the Indian subcontinent infected with HCV genotype 3 and genotype 1.     

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.     

Chemiluminescence enzyme immunoassay for monitoring hepatitis C virus core protein during interferon-alpha2b and ribavirin therapy in patients with genotype 1 and high viral loads

This study evaluated an updated chemiluminescence enzyme immunoassay (CLEIA) for hepatitis C virus (HCV) core protein for monitoring viral kinetics during treatment with interferon (IFN)-alpha and ribavirin. Using the CLEIA, serum levels of HCV core protein were measured in 17 patients with genotype 1 and high baseline viral loads during the first 4 weeks of combination therapy. HCV RNA was measured by the Amplicor Monitor test for comparison. At the start of therapy, the median HCV level (interquartile range) was 700 (540-940) kIU/ml of viral RNA and 11,310 (5,528-14,238) fmol/L of core protein. HCV RNA was above the upper limit of the linear range of the Amplicor Monitor test in 13 of the 17 patients, while the core protein level was within the linear range of the CLEIA in all patients. During therapy, the proportion of patients with HCV levels below the cutoff values at each time point was less with the Amplicor Monitor test than with CLEIA. Serum HCV core protein level decreased rapidly during the first 24 hr of therapy and more slowly thereafter, with median exponential decays of 1.08 and 0.046 log10/day, respectively. In the second phase, between day 1 and 28, the median decrease in HCV core protein level was higher in four patients with sustained virologic response (0.13 log10/day) than in 13 patients with no response (0.028 log10/day, P = 0.042). The wide linear range of the HCV core protein assay is appropriate for measuring viral loads during therapy with IFN-alpha and ribavirin.     

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.     

Prediction of response to peginterferon-alfa-2b plus ribavirin therapy in Japanese patients infected with hepatitis C virus genotype 1b

Variation at the IL‐28B locus was recently reported to be a significant predictive factor of viral response to pegylated‐interferon plus ribavirin combination therapy against chronic hepatitis C. Predictive factors for the effect of therapy, including IL‐28B polymorphism rs8099917 and viral and clinical factors were investigated. A total of 288 patients were enrolled who were chronically infected with hepatitis C virus (HCV) genotype 1b and treated with combination therapy. Among them, 87 patients completed 48 weeks of therapy without dose reduction or discontinuation. In multivariate regression analysis, the rs8099917 TT genotype was the only independent factor significantly associated with sustained viral response (P = 0.016, OR 61.5), whereas substitutions at amino acid 70 (aa 70) of the HCV core protein (P = 0.038, OR 5.9) and non‐TT genotypes (P = 0.002, OR 17.2) were associated with nonvirological response. Both factors were also associated with viral dynamics during the initial stage of the therapy. Correlation analysis revealed that rs8099917 genotype was correlated with γ‐glutamyl transpeptidase, hyaluronic acid, and HCV core aa 70. In conclusion, host (IL‐28B polymorphism) and viral (aa 70) factors independently affect response to combination therapy. J. Med. Virol. 83:981–988, 2011. © 2011 Wiley‐Liss, Inc.     

Rapid viral response and treatment outcome in genotype 2 and 3 chronic hepatitis C: comparison between two HCV RNA quantitation methods

Fifty consecutive patients with genotype 2 or 3 chronic hepatitis C were treated with peg-IFN alfa-2a 135 microg weekly and ribavirin (11 mg/kg body weight) daily during 24 weeks. Rapid viral response treatment week 4, end-of-treatment response, and sustained viral response were analyzed by two different HCV RNA quantitation methods, the Cobas Amplicor Monitor test and the TaqMan test with a sensitivity of 600 and 15 IU/ml, respectively. The TaqMan test differentiated patients with rapid viral response finally achieving sustained viral response better. Hence, patients with and without rapid viral response as tested by the TaqMan test finally achieved sustained viral response in 97% (32/33) versus in 75% (12/16), P < 0.017. The corresponding figures for the Cobas Amplicor test was 91% (41/45) versus (80%) 4/5 a non-significant difference. In conclusion, the more sensitive TaqMan test yielded a lower number of patients with rapid viral response than the less sensitive Amplicor Monitor test, but predicted sustained viral response in a higher percentage of patients with rapid viral response than the Amplicor Monitor test. A rapid viral response meaning HCV RNA levels <15 IU/ml predicted a sustained viral response in 97% of patients with genotype 2 or 3.     

An early viral response to standard interferon‐alpha identifies resistance to combination therapy with peginterferon and ribavirin in patients infected by HCV genotype 1

As combination therapy with peginterferon (PEG‐IFN) and ribavirin has a high morbidity, identifying individuals with hepatitis C virus (HCV) who will not respond to the treatment would be beneficial. The early responses of serum HCV RNA levels to standard interferon (IFN) and PEG‐IFN were examined to determine if it was possible to identify resistance to combination therapy. One hundred thirty‐one patients infected with HCV genotype 1b were enrolled. Patients were given 6 MU of standard IFN alpha‐2b at least 2 weeks before initiating combination therapy. Serum HCV RNA levels were measured before, 24 hr after the administration of standard IFN, and 24 hr after the administration of PEG‐IFN (at the start of the combination therapy). The association between reductions in HCV RNA levels at 24 hr after the administration of standard IFN and PEG‐IFN and the outcome of combination therapy were analyzed. Reductions in HCV RNA levels were poorer in patients who did not respond than in those with a sustained virologic responses or relapses (P < 0.0001), both 24 hr after the administration of standard IFN and 24 hr after the administration of PEG‐IFN. Reductions in HCV RNA levels 24 hr after the administration of standard IFN were an independent factor associated with non‐response by multivariate analysis. An early reduction in viral load to a single administration of standard IFN is a useful predictor of non‐response in patients with HCV genotype 1, allowing for pretreatment identification of patients who will not benefit from combination therapy. J. Med. Virol. 82:1537–1544, 2010. © 2010 Wiley‐Liss, Inc.     

Modifications of haematological series in patients co-infected with human immunodeficiency virus and hepatitis C virus during treatment with interferon and ribavirin: differences between pegylated and standard interferon

Therapy with interferon and ribavirin for hepatitis C virus (HCV) infection induces a decrease in several haematological population counts. It is unclear whether haematological toxicity is more severe in patients co-infected with HCV and human immunodeficiency virus (HIV). This study analysed the evolution of haematological population counts during and after interferon and ribavirin therapy for chronic HCV infection. Eleven patients co-infected with HIV and HCV and treated with pegylated interferon plus ribavirin, and ten treated with standard interferon plus ribavirin, were analysed. With reference to baseline values, neutrophil counts decreased by an average of 45% (range 18-67%), total lymphocytes by 50% (16-63%), CD4 lymphocytes by 54% (16-61%), haemoglobin by 9% (5-16%) and platelets by 31% (16-45%). The nadir of the decrease was reached in the first weeks of therapy and was maintained while patients were receiving treatment. The reduction in all series was higher with pegylated interferon. Patients recovered their baseline counts after finishing the treatment. No cases of haemorrhage or outstanding infection were detected during follow-up.     

Baseline factors and early viral response (week 4) to antiviral therapy with peginterferon and ribavirin for predicting sustained virologic response in patients infected with hepatitis C virus genotype 1: A multicenter study

Both baseline predictive factors and viral response at week 4 of therapy are reported to have high predictive ability for sustained virologic response to peginterferon and ribavirin combination therapy in patients with hepatitis C virus (HCV) genotype 1. However, it is not clear how these baseline variables and week 4 response should be combined to predict sustained virologic response. In this multicenter study, the authors investigated the impact of baseline predictive factors on the predictive value of week 4 viral response. Receiver‐operating characteristic curve analyses were performed to evaluate the ability of week 4 reduction in HCV RNA levels to predict sustained virologic response in 293 Japanese patients infected with HCV genotype 1b. Analyses were performed in all patients and in patient subgroups stratified according to baseline variables. Overall, week 4 viral reduction demonstrates a high predictive ability for sustained virologic response. The sensitivity, specificity, positive predictive value (PPV), negative predictive value, and accuracy were higher than those of viral reduction at week 12. However, the best cut‐off levels differ depending on the baseline factors and they were lower in patients with unfavorable baseline predictors. When patients had the TG/GG rs8099917 genotype, the best cut‐off was markedly low with low PPV. Week 4 viral response can be a predictor of sustained virologic response in patients with HCV genotype 1 and is better than week 12 viral response. However, the cut‐off levels should be modified based on the baseline predictive variables. J. Med. Virol. 85:65–70, 2012. © 2012 Wiley Periodicals, 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.     

A mutation in the interferon sensitivity-determining region is associated with responsiveness to interferon-ribavirin combination therapy in chronic hepatitis patients infected with a Japan-specific subtype of hepatitis C virus genotype 1B

The interferon sensitivity-determining region (ISDR) is useful as a predictive marker of the response to interferon (IFN) therapy for chronic hepatitis patients with a Japan-specific subtype (J-type) of hepatitis C virus (HCV) genotype 1b. This marker is not useful for predicting responsiveness of a worldwide subtype (W-type) of HCV 1b, which could explain the restricted usefulness of this system only to Japan. In the present study, we examined the predictive value of the ISDR for ribavirin combination therapy. A total of 79 patients with HCV 1b comprising 35 patients with J-type and 44 patients with W-type were treated with IFN in combination with ribavirin for more than 48 weeks. Mutations in the ISDR were detected more frequently often seen in J-type HCV 1b than in W-type; however, the sustained virological response (SVR) rate for the combination therapy was similar between the two subtypes. Multivariate analysis revealed that factors associated with SVR were IFN dose and the number of amino acid substitutions in ISDR but not with subtypes J and W. The correlation between the number of substitutions in ISDR and responses to IFN-ribavirin combination therapy was restricted to patients with J-type HCV 1b. The ISDR is a useful predictive marker for response to IFN-ribavirin combination therapy in J-type HCV.     

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.     

Amino acid substitutions in the hepatitis C virus core region of genotype 1b affect very early viral dynamics during treatment with telaprevir,peginterferon, and ribavirin

Substitution of amino acid (aa) 70 and 91 in the core region of hepatitis C virus (HCV) genotype 1b can predict the response to pegylated interferon (PEG‐IFN)/ribavirin combination therapy, but its impact on triple therapy of telaprevir/PEG‐IFN/ribavirin is not clear. The aims of this study were to investigate the rate of HCV RNA loss following 12‐week triple therapy, and determine the effect of aa substitutions on very early (within 48 hr) viral dynamics. Sixty‐seven patients infected with HCV genotype 1b (HCV‐1b) and high viral load who received 12‐week triple therapy were studied. RNA loss could be achieved in 2%, 34%, 80%, 92%, 95%, 94%, and 90% of the patients after 1, 2, 4, 6, 8, 10, and 12 weeks of triple therapy, respectively. After 24‐hr treatment, the proportion of patients with Arg70 and Leu91 substitutions with ≥3.0 log fall in HCV RNA was significantly higher than those with <3.0 log fall (P = 0.008). However, the aa substitution patterns in the core region did not influence the fall in HCV RNA after 48‐hr treatment. Multivariate analysis identified substitutions of aa 70 and 91 (P = 0.014) and level of viremia at baseline (≥7.0 log IU/ml; P = 0.085) as independent parameters that determined the ≥3.0 log fall in HCV RNA level after 24‐hr triple therapy. It is concluded that 12‐week triple therapy achieved high rates of loss of HCV RNA in Japanese patients infected with HCV‐1b and high viral load, and that the aa substitution pattern in the core region seems to influence very early viral dynamics. J. Med. Virol. 82:575–582, 2010. © 2010 Wiley‐Liss, Inc.