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.     

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.     

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.     

Different viral kinetics between hepatitis C virus genotype 1 and 2 as on-treatment predictors of response to a 24-week course of high-dose interferon-alpha plus ribavirin combination therapy

To elucidate the genotype-specific virus-host-drug interaction and the on-treatment viral kinetics in predicting sustained virologic response (SVR), serial serum hepatitis C virus (HCV) ribonucleic acid (RNA) levels at baseline, treatment week 2 (W2), treatment week 4 (W4), and treatment week 12 (W12) were measured in 199 chronic HCV-infected Taiwanese patients receiving interferon-alpha (INF-alpha) 6 million units (MU) three times weekly plus 1000 to 1200 mg/day of ribavirin for 24 weeks. The SVR rate was 90.5% (95/105) for HCV genotype 2 (HCV-2) patients and 47.9% (45/94) for HCV-1 patients (P < 0.0001). HCV-2 patients had a significantly higher rate of rapid virologic response (RVR) at W2 than HCV-1 patients. HCV RNA negativity at W4 had the highest accuracy of prediction (80%) of SVR with sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 81%, 79%, 78%, and 82%, respectively, for HCV-1 patients. HCV RNA negativity or 2 logs drop at W4 had the highest accuracy of prediction (92%) with sensitivity, specificity, PPV, and NPV of 100%, 20%, 92%, and 100%, respectively, for HCV-2 patients. In multivariate analysis, the significant factors associated with SVR in HCV-1 patients were HCV RNA negativity at W12 and W4. HCV RNA negativity or 2 logs drop was the only significant factor associated with SVR in HCV-2 patients. In conclusion, a RVR at W4 could predict an SVR with a high degree of accuracy to a 24-week course of high-dose IFN/ribavirin for both HCV-1 patients and HCV-2 patients. With respect to each HCV genotype, the on-treatment virologic responses are the most important factors associated with SVR.     

Monitoring response during a randomised controlled trial of escalating interferon dose for chronic hepatitis C infection: predictive value of quantitative and qualitative HCV RNA assays.

BACKGROUND: In chronic hepatitis C infection, raising the interferon dose in initial non-responders may increase the generally poor sustained response rates. Monitoring virological response is essential in this kind of individual patient based approach. Quantitative HCV RNA assays are increasingly used for this purpose. However, their additional value as compared to strictly qualitative HCV RNA assays should be evaluated before they are implemented as a routine measurement, since these assays are more expensive and time consuming than qualitative assays. OBJECTIVES: Goals of this study were (1) to test the hypothesis that increasing interferon dose in initial non-responders results in permanent viral clearance in more patients and (2) evaluation of the predictive value of quantitative versus qualitative HCV RNA assays before and during treatment. STUDY DESIGN: 63 patients were treated in a randomised controlled trial of escalating interferon dose. In the standard treatment group patients received 6 MU alpha-2a thrice weekly for 3 months followed by 3 MU thrice weekly for 3 months. In the experimental group interferon dose was escalated at 6 weeks to 9 MU if HCV RNA was still detectable at 4 weeks. Predictors of response were analyzed at various time points before and during treatment and the predictive value of quantitative HCV RNA measurements was compared to that of qualitative HCV RNA assays. RESULTS: No significant difference in sustained response rate was found between the treatment groups at the end of follow-up. At baseline, the strongest independent predictor for a sustained response was a viral load level below 10(6) copies/ml and age younger than 40 years. During treatment a negative HCV RNA status at week 4 was the strongest predictor of a sustained response. Viral load levels during treatment did not independently predict a sustained response. CONCLUSIONS: While on treatment, qualitative HCV RNA assays should be used to monitor response.     

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.     

Hepatitis C--treatment of untreated (naive) patients

The most important therapeutic advance in recent years considering chronic HCV infection has occurred with the introduction of pegylated interferon (PEG IFN) in the combination therapy with ribavirin, which results in better sustained virologic response (SVR). Although an SVR is difficult to correlate with improved survival because of the necessity for long-term follow up, the absence of detectable serum HCV RNA has been associated with resolution of liver injury, reduction in hepatic fibrosis, and a low likelihood of a relapse of the HCV infection. Two large pivotal trials examined the efficacy of PEG IFN plus ribavirin in the treatment of chronic HCV infection. Overall, PEG IFN plus ribavirin was more effective than the standard interferon-ribavirin combination. SVR rates were similar with both forms of PEG IFN (PEG IFN alfa-2a and PEG IFN alfa-2b) when used in combination with ribavirin. SVR rates of 42% and 46% were achieved in patients with genotype 1 compared to rates of 76% and 82% in patients with genotypes 2 and 3. Factors associated with successful therapy included genotypes other than 1, lower baseline viral levels, less fibrosis or inflammation on liver biopsy, and lower body weight or body surface area. Twenty four weeks of treatment with a combination of PEG IFN and ribavirin appears to be sufficient for patients infected with genotypes 2 and 3, while patients with genotype 1 need 48 weeks of treatment. Early virologic response (EVR), defined as undetectable HCV RNA or a minimum 2 log decrease in viral load (relative to baseline) after the first 12 weeks of treatment, is predictive of SVR and should be a routine part of monitoring patients with genotype 1. Patients who fail to achieve an EVR have only a small chance of achieving an SVR, therefore treatment should be discontinued after 12 weeks. It is also recommended to treat patients with acute hepatitis C to reduce the risk of developing chronic infection. Treatment should start 12 weeks after the onset of symptoms and includes 24 weeks of monotherapy with PEG IFN.     

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.     

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.     

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.     

The predictive value of core antigen testing for the management of hepatitis C patients receiving pegylated interferon/ribavirin treatment

A new quantitative marker of HCV viremia based on the detection of the core antigen of the virus has recently become commercially available in Europe. The usefulness of this test was examined for the management of patients treated with pegylated interferon/ribavirin. One hundred twenty-eight pegylated interferon/ribavirin treated patients were studied. Serum samples were available at baseline, week 4 and week 12 time-points, respectively. Core antigen was quantified using the trak-C assay (Ortho Clinical Diagnostics, Raritan, NJ). For all genotypes at week 4, the positive and negative predictive values of HCV core antigen were 81.4 and 92.9%, respectively, while at week 12 they were 67.9 and 100%, respectively. These predictive values varied substantially according to viral genotype. Among patients with a negative core antigen level (<1.5 pg/ml) at week 12, only 33% of those who were positive at week 4 achieved a sustained virological response whereas 85% of those who were already negative did (P < 0.001). The core antigen assay may be used at week 4 and week 12 to distinguish patients who will achieve a sustained virological response from those who will relapse/breakthrough. This assay is a new reliable alternative for early prediction of virological non-response in patients treated with pegylated interferon/ribavirin.     

Predictive value of early virologic response in HIV/hepatitis C virus-coinfected patients treated with an interferon-based regimen plus ribavirin

BACKGROUND: As a result of adverse events, a moderate rate of virologic response, and high costs associated with hepatitis C virus (HCV) therapy, finding early markers of sustained treatment response is a clinical priority. In the HCV-monoinfected population, a reduction >or=2 log in plasma HCV RNA at week 12 of therapy (early virologic response [EVR]) predicts a sustained virologic response (SVR). Few data are available in HIV/HCV-coinfected patients, however. METHODS: A subanalysis of data from HIV/HCV-coinfected patients treated with pegylated interferon-alpha-2b (PEG, 100-150 mug/wk) or interferon-alpha-2b (IFN, 3 MIU 3 times per week) plus ribavirin (RBV, 800-1200 mg/d) was conducted in a randomized single-center clinical trial. The duration of treatment was 48 weeks (only 24 weeks for HCV genotype 2 or 3 with a baseline HCV RNA level <800,000 IU/mL). RESULTS: Ninety-five patients were randomized (43 assigned to IFN + RBV and 52 assigned to PEG + RBV). Eighty patients completed at least 12 weeks on therapy and were included in the EVR analysis. Thirty-five (43%) of them attained an SVR (56% and 30% of patients treated with PEG and IFN, respectively; P = 0.026). An EVR occurred in 55 (69%; 80% of PEG + RBV group and 56% of IFN + RBV group). Overall, 35 of 55 patients with an EVR were sustained responders, yielding a positive predictive value of 64% (70% in PEG + RBV arm and 55% in IFN + RBV arm). None of the patients who demonstrated an HCV RNA decline of <2 logs at week 12 reached an SVR (negative predictive value of 100%). CONCLUSION: Our results confirm the utility of an EVR to predict the chance of the lack of an SVR in HIV/HCV-coinfected patients, particularly those treated with PEG.     

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.     

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.     

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.     

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.     

Combination Therapy with Interferon-α and Ribavirin for Hepatitis C

Combination therapy with ribavirin and interferon (IFN)-α for 6 to 12 months is currently the treatment of choice for chronic hepatitis C infection. The overall sustained response rate to treatment, defined as loss of hepatitis C virus (HCV) from serum 6 months after completion of treatment, is 40%. The indications for treatment are serum HCV RNA positivity, abnormal serum transaminases and the presence of portal fibrosis and/or moderate/severe inflammation. Response rates are lower in genotype 1 than in genotype 2 or 3 and in the presence of a high viral load. Anaemia is the most common adverse event and is due to ribavirin; neuropsychiatric adverse effects due to IFNα lead to premature cessation of therapy in 10 to 20% of patients. The current recommended dose of interferon is 3MU given subcutaneously 3 times a week. However, it is likely that longer-acting pegylated interferons, which may be more effective and can be administered once weekly, will in the future replace currently used IFNα.     

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.     

Comparative evaluation of the total hepatitis C virus core antigen,branched-DNA,and amplicor monitor assays in determining viremia for patients with chronic hepatitis C during interferon plus ribavirin combination therapy

An assay prototype designed to detect and quantify total hepatitis C virus [HCV] core antigen (HCV core Ag) protein in serum and plasma in the presence or absence of anti-HCV antibodies has been recently developed by Ortho-Clinical Diagnostics. The aim of the study was to evaluate the sensitivity, specificity, and reproducibility of the Total HCV core Ag assay in comparison with two quantitative assays for HCV RNA: Quantiplex HCV RNA 2.0 (bDNA v2.0) or Versant HCV RNA 3.0 (bDNA v3.0) assays and the Cobas Amplicor HCV Monitor version 2.0 (HCM v2.0) test. We have studied samples of a well-characterized panel and samples from patients with chronic hepatitis C treated with interferon alone or with ribavirin. We have also compared the kinetics of HCV core Ag and HCV RNA in the follow-up of treated patients. The HCV core Ag assay exhibited linear behavior across samples from different genotypes. The coefficients of variation for intra- and interassay performance were 5.11 and 9.95%, respectively. The specificity of the assay tested in blood donors was 99.5%. Samples from HCV-infected patients showed that the correlation between the HCV core Ag and the two HCV RNA quantitative assays (bDNA and HCM v2.0) was 0.8 and 0.7, respectively. This correlation was maintained across different genotypes of HCV (r(2) = 0.64 to 0.94). Baseline HCV core Ag values were significantly lower in sustained responders to interferon (IFN) than in other groups of patients (5.31 log(10) [10(4) pg/ml] versus 5.99 log(10) [10(4) pg/ml]; P < 0.001). In patients treated with IFN or combination therapy, we found an association between a decrease of more than 2 log IU/ml in viral load, undetectable HCV core Ag, and sustained response. Among sustained responders to IFN alone or combination therapy and among relapsers after IFN alone, 84 out of 101 (83.2%) had undetectable HCV core Ag, and 76 out of 96 (79.2%) had a viral load decrease of >/=2 log IU/ml, after 1 month of treatment. In conclusion, the Total HCV core Ag assay is a new useful test for the detection of HCV viremia and the monitoring of patients treated with IFN alone or in combination with ribavirin.     

Interferon-alpha (IFN alpha) daily dose versus IFN alpha plus ribavirin for treatment-naive chronic hepatitis c patients infected by genotype 1b

INTRODUCTION: Infection with hepatitis C virus genotype 1b (HCV1b) is known to be a predictive factor of poor response to both interferon-alpha (IFN alpha) alone and IFN alpha plus ribavirin combination therapy.STUDY DESIGN, PATIENTS AND METHODS: This randomised study evaluated the efficacy and safety of daily IFN alpha administration versus the combination of IFN alpha plus ribavirin in treatment-naive patients infected with chronic HCV1b. Sixty-two patients were randomised to receive either human leucocyte IFN alpha 6MU three times weekly for 12 months plus ribavirin 15 mg/kg/day for the first 6 months (group A: 29 patients), or human leucocyte IFN alpha 3MU daily for 12 months (group B: 33 patients). Response was evaluated by monitoring serum alanine aminotransferase (ALT) and HCV-RNA levels during treatment and follow-up (12 months). RESULT AND CONCLUSION: Both treatment schedules were relatively well tolerated. Normal ALT levels and negative serum HCV-RNA were observed in 16 of 29 patients (55%) of group A and in 18 of 33 patients (54.5%) of group B at the end of treatment, as well as in 10 of 29 patients (34.5%) of group A and in 12 of 33 patients (36%) of group B at the end of the follow-up. There was no significant difference between the response rates obtained with the two regimens. In naive patients with chronic HCV1b infection, the efficacy of daily administration with IFN alpha is similar to that of IFN alpha plus ribavirin administered three times a week.