Ritonavir-boosted danoprevir-based regimens in treatment-naive and prior null responders with HCV genotype 1 or 4 and compensated cirrhosis

Background and aim

Effective and safe antiviral treatment regimens are needed for patients with chronic hepatitis C (CHC) and cirrhosis.

Methods

An international open-label trial was conducted in CHC patients with genotype (G)1/4 infection, compensated cirrhosis, HCV RNA ≥ 50,000 IU/mL and body mass index 18–35 kg/m². Treatment-naive patients (Cohort 1) received a triple therapy regimen [danoprevir/r 100/100 mg twice daily (bid), ribavirin 1000/1200 mg/day and peginterferon alfa-2a 180 µg/week] for 24 weeks. Prior null responders (Cohort 2) received a quadruple therapy regimen (danoprevir/r 100/100 mg bid, mericitabine 1000 mg bid and peginterferon alfa-2a/ribavirin). The primary efficacy outcome was sustained virological response (HCV RNA < limit of quantification, target not detected) at end of the 24-week follow-up period (SVR24).

Results

In Cohort 1 (n = 23), 73.9 and 65.2 % of patients had a virological response at Weeks 4 and 24, respectively; 39.1 % achieved SVR24 (G1a = 1/13; G1b = 8/9; G4 = 0/1). In Cohort 2 (n = 20), 100 % achieved virological response at Weeks 4 and 24; 65 % achieved SVR24 (G1a = 4/8; G1b = 7/10; G4 = 2/2). Treatment failure was more common in G1a than G1b-infected patients and less common in patients receiving quadruple therapy. Treatment failure was associated with emergence of resistance to danoprevir, but not mericitabine. The safety profile was typical of that associated with peginterferon alfa-2a/ribavirin. No deaths/episodes of hepatic decompensation occurred.

Conclusions

Treatment with danoprevir/r-based regimens for 24 weeks is safe and well tolerated in CHC patients with compensated cirrhosis. A quadruple therapy regimen (danoprevir/r, mericitabine, peginterferon alfa/ribavirin) produced high SVR24 rates in prior null responders, particularly among G1b patients.

     

Response to Peginterferon-alfa 2b and Ribavirin in Japanese Patients with Chronic Hepatitis C Genotype 2

Background

The current standard treatment for patients infected with hepatitis C virus (HCV) of genotype 2 is the combination of peginterferon (PEG-IFN) plus ribavirin (RBV) for 24 weeks.

Aims

We assessed the sustained virological response (SVR) rates in HCV genotype 2-infected Japanese patients in relation to the duration of treatment.

Methods

Between 2006 and 2009, among 147 patients with HCV genotype 2-infection in Chiba Prefecture, 138 consecutive patients were finally enrolled. Twenty-one, 97 and 20 patients were treated with PEG-IFN-alfa 2b plus RBV for 16, 24 and 48 weeks, respectively. Epidemiological data and treatment outcomes were retrospectively evaluated. HCV RNA was measured with COBAS AMPLICOR HCV Monitor Test v. 2.0.

Results

The overall SVR rate was 82.6% (114 of 138): treatment-naïve patients, 86.4% (89 of 103); patients with history of previous treatment, 71.4% (25 of 35). Patients treated for 16, 24 and 48 weeks obtained SVR rates of 66.6% (14 of 21), 86.5% (84 of 97) and 80.0 (16 of 20), respectively.

Conclusions

The SVR rates of PEG-IFN-alfa 2b plus RBV in Japanese patients were similar to those in previous studies. Combination treatment for 24 weeks for some patients infected with HCV genotype 2 may be superior to that for 16 weeks. More precise patient selection will be needed to shorten the combination treatment.     

Response to peginterferon-alpha 2b and ribavirin in Japanese patients with chronic hepatitis C genotype 1

Purpose

Patient age and gender may be associated with response to peginterferon alpha plus ribavirin, the current standard of care (SOC) for chronic hepatitis C genotype 1. We queried whether there was an association between age, gender, and treatment response to SOC in Japanese patients infected with hepatitis C virus (HCV) genotype 1.

Methods

Between 2006 and 2009, HCV-infected Japanese patients treated with peginterferon alpha-2b plus ribavirin for 48 weeks were enrolled. Patients were allocated into four groups according to age and gender, and epidemiological data and treatment outcomes were retrospectively analyzed. HCV RNA was measured with COBAS AMPLICOR HCV Monitor Test v. 2.0.

Results

The overall sustained virological response (SVR) rate was 49.8%: patients aged ≤65 and >65 years, 50.9 and 44.0%, respectively; male and female, 56.5 and 39.0%. SVR rates of SOC against HCV genotype-1 females aged >65 years (19.0%) were inferior to those in males aged >65 years (57.8%) in Japan. Multivariate logistic regression analysis showed that SVR was attained independently of adherence 80/80/80 in all groups.

Conclusions

Adherence to medication is also a key factor for the eradication of HCV in patients aged >65 years. As the SVR rate of patients aged ≤65 years was similar to that of patients aged >65 years, SOC could be useful for treating some of the elderly patients.     

The virological response in Koreans infected with HCV genotype 1 did not differ between groups treated with a full dose or reduced dose (≥80 % full dose) of peginterferon alfa-2a: a prospective randomized multicenter trial

Purpose

A high rate of sustained viral response (SVR) in Koreans with chronic hepatitis C (CHC) is related to a favorable IL28B genotype. We compared two dosing strategies for peginterferon alfa-2a in Koreans with CHC and defined the combined effect of polymorphisms and dosing on the virological response.

Methods

A total of 178 treatment-naïve patients with CHC genotype 1 were prospectively enrolled. All patients were randomly assigned to treatment with one of two peginterferon alfa-2a regimens: 180 μg per week for 48 weeks (full-dose group) or 180 μg per week during the first 12 weeks followed by 135 μg per week for the next 36 weeks (dose-reduction group). Polymorphisms related to IL28B, ITPA, C20orf194 and SLC29A1 were studied.

Results

SVR rates did not differ between the full-dose and dose-reduction groups (56.5 and 51.2 %, respectively, p = 0.474). The frequency of additional reductions of the peginterferon dose because of adverse events was higher in the full-dose group than in the dose-reduction group. SVR rates in patients homozygous for the IL28B major allele were higher than those in patients for the other IL28B alleles. For patients with unfavorable IL28B genotypes, SVR was less likely to be achieved in the dose-reduction group than in the full-dose group.

Conclusions

In Koreans with HCV genotype 1, the virological response to treatment did not differ between a full dose and reduced dose (≥80 % of full dose) of peginterferon alfa-2a. However, in the patients with unfavorable IL28B genotypes, the full-dose treatment of peginterferon alfa-2a may be beneficial.     

Estimates of HCV-1 Patients Attaining RVR Following Dual Therapy with Peg-Interferon and Ribavirin

Background

Given the significant side-effects and healthcare costs associated with telaprevir- or boceprevir-combination therapy, identifying patients likely to respond to dual therapy peg-interferon (Peg-IFN)/ribavirin is highly desirable. Since the perception of how large the pool of patients who may achieve rapid virologic response (RVR) is vaguely ascertained, we searched the literature for this information.

Methods

Studies on patients treated with Peg-IFN/ribavirin were identified by searching MEDLINE and analyzed by meta-analysis. The primary end point was weighted estimates of RVR. The influence on race/ethnicity, baseline viremia, type of Peg-IFN, ribavirin dosage, and significant hepatic fibrosis on the results was evaluated.

Results

Across 38 studies on 13,219 patients, the fraction of RVR patients was 19.6 %. The only baseline factor influencing RVR was race/ethnicity, with higher rates in Asian (26.7 %) and Caucasian patients (22.5 %). Of the 1,735 RVR patients, 85.1 % attained sustained virologic response (SVR). In these, SVR was influenced by ribavirin dose (86.8 vs. 72.8 % for high or low), type of Peg-IFN (91.8 % for alpha-2b vs. 82.9 % for alpha-2a), and treatment duration (91.7 % for 48 weeks vs. 79.4 % for 24 weeks).

Conclusions

One fifth to one fourth of hepatitis C virus genotype 1 (HCV-1) patients can be safely treated with dual therapy of Peg-IFN/ribavirin, and may be spared from cost and inconvenience of regimens considering the addition of HCV protease inhibitors.     

Predictive value of FIB-4 and APRI versus METAVIR on sustained virologic response in genotype 1 hepatitis C patients

Purpose

Advanced liver fibrosis is a negative predictor of virologic response in genotype 1 chronic hepatitis C (CHC) patients. Biopsy, however, is invasive, costly, and carries some risk of complications.

Methods

Using data from the prospective, international cohort study PROPHESYS, we assessed two alternative noninvasive measures of fibrosis, the FIB-4 and AST-to-platelet ratio index (APRI), to predict virologic response in CHC patients.

Results

CHC genotype 1, monoinfected, treatment-naive patients prescribed peginterferon alfa-2a (40 KD)/ribavirin in accordance with country-specific legal and regulatory requirements and who had baseline METAVIR, FIB-4, and APRI scores (N = 1,592) were included in this analysis. Patients were stratified according to the baseline METAVIR, FIB-4, or APRI score to assess virologic response [hepatitis C virus (HCV) RNA <50 IU/mL] by week 4 of treatment (rapid virologic response) and 24 weeks after untreated follow-up ]sustained virologic response (SVR)]. Baseline predictors of SVR were explored by multiple logistic regression, and the strength of the association between each fibrosis measure and SVR was evaluated. Both FIB-4 and APRI scores increased with increasing levels of biopsy-assessed fibrosis. The association between FIB-4 and SVR (p < 0.1 × 10^?30) was stronger than that between METAVIR (p = 3.86 × 10^?13) or APRI (p = 5.48 × 10^?6) and SVR. Baseline factors significantly associated with SVR included male gender, lower HCV RNA, lower FIB-4 score, no steatosis, and higher alanine aminotransferase ratio.

Conclusion

The FIB-4 index provides a valuable, noninvasive measure of fibrosis and can be used to predict virologic response in patients treated with peginterferon alfa-2a (40  KD)/ribavirin.     

Interferon-associated hepatic steatosis is related to discrepancies in biochemical and virological responses of chronic hepatitis C to IFN-based therapy

Background and aims

A discrepancy in virological and biochemical responses may occur throughout interferon-based therapy for hepatitis C virus (HCV). We aimed to explore the risk, associated factors, potential mechanisms, and impact on the treatment outcome of the discrepancy.

Subjects and methods

Consecutive 496, chronic HCV-infected patients receiving interferon/ribavirin or peginterferon/ribavirin for 24 weeks with a 24-week follow-up period were enrolled. Of 433 patients with pretreatment liver biopsy, 46 received serial liver biopsies at the end of treatment and end of follow-up to explore the corresponding change in liver histopathology. A virological/biochemical discrepancy was defined as persistently elevated alanine aminotransferase levels throughout the treatment period, despite the seronegativity for HCV RNA at least at the end of treatment. The sustained virological response (SVR) was defined as seronegativity for HCV RNA 6 months after the end of treatment.

Results

Virological/biochemical discrepancy was observed in 28.7 % (137/478) patients. The SVR rate was comparable between patients with (75.2 %, 103/137) and without discrepancy (81.2 %, 277/341, p = 0.14). For patients with discrepancy and SVR, 78 (75.7 %) had a subsequent normalization of alanine aminotransferase. Hepatic steatosis, advanced fibrosis, obesity, older age, peginterferon preparation, and low viral load were independently predictive of a virological/biochemical discrepancy. Serial liver histology showed that significant transient aggravation of hepatic steatosis during interferon-based therapy was observed among patients with a virological/biochemical discrepancy (difference 0.64 ± 0.93, p = 0.022), but not among those without it (difference 0.09 ± 0.69, p = 0.447).

Conclusions

A virological/biochemical discrepancy no longer exists after treatment cessation in most patients, and had little impact on the HCV treatment outcome. Treatment-related hepatic steatosis might play an important role in the pathogenesis of the discrepancy.     

Early identification of HCV genotype 1 patients responding to 24 weeks peginterferon alpha-2a (40 kd)/ribavirin therapy

Approximately one third of hepatitis C virus (HCV) genotype 1 patients achieved a sustained virological response (SVR) after 24 weeks of treatment with peginterferon alpha-2a (40 kd) plus ribavirin in a randomized, multinational trial. We aimed to identify factors associated with a rapid virological response (RVR) at week 4 (HCV RNA <50 IU/mL) and a SVR (HCV RNA <50 IU/mL at the end of follow-up) in these patients. Stepwise multiple logistic regression analysis was used to explore the prognostic factors for a RVR and SVR in genotype 1 patients treated for 24 weeks. Fifty-one of 216 (24%) genotype 1 patients in the 24-week treatment groups had a RVR. SVR rates were considerably higher in patients with than without [corrected] a RVR (89% vs. 19%, respectively). Patients with a baseline HCV RNA of less than 200,000 IU/mL (OR 9.7, 95% CI 4.2-22.5; P < .0001) or 200,000-600,000 IU/mL (OR 5.6, 95% CI 1.5-9.1; P = .0057) were more likely to achieve a RVR than those with HCV RNA greater than 600,000 IU/mL. HCV subtype (1b vs. 1a) was also independently associated with RVR (OR 1.8, 95% CI 0.9-3.7; P = .0954). RVR (OR 23.7 vs. no RVR, 95% CI 9.1-61.7) and baseline HCV RNA less than 200,000 IU/mL (OR 2.7 vs. > 600,000 IU/mL, 95% CI 1.1-6.3; P < .026) were significant and independent predictors of SVR in patients treated for 24 weeks. In conclusion, patients infected with HCV genotype 1 and treated with peginterferon alpha-2a/ribavirin sustained a RVR 24% of the time. This portends an 89% probability of a SVR after 24 weeks of treatment.     

Treatment of Genotype 4 Hepatitis C Recurring After Liver Transplantation Using a Combination of Pegylated Interferon Alfa-2a and Ribavirin

Background

Hepatitis C virus (HCV) recurrence after liver transplantation (LT) is universal and tends to be more aggressive. Data on post-transplant HCV genotype 4 treatment is scarce. The aim of this study is to assess the safety and efficacy of pegylated interferon alpha-2a (PEG-IFN) in combination with ribavirin in the treatment of recurrent HCV genotype 4 after LT.

Methods

Twenty-five patients infected with HCV genotype 4 were treated with PEG-IFN alpha-2a at a dose of 180 ??g/week in addition to 800 mg/day of ribavirin (the dose was adjusted within the tolerated range of 400?C1,200 mg). Pretreatment liver biopsies were obtained from all patients. Biochemical and virological markers were assessed before, during, and after treatment.

Results

Twenty-two patients (88%) achieved an early virological response (EVR) (12 patients tested negative for HCV-RNA). Fifteen (60%) and 14 patients (56%) achieved an end of treatment virological response (ETVR) and a sustained virological response (SVR), respectively. Five patients had advanced pretreatment liver fibrosis. Pretreatment ALT was elevated in 24 patients (96%). The most common adverse effects were flu-like symptoms and cytopenia. Eighteen patients (72%) required erythropoietin alpha and/or granulocyte-colony stimulating factor as a supportive measure. One patient developed severe rejection complicated by sepsis, renal failure, and death. Other adverse effects included depression, mild rejection, impotence, itching, and vitiligo.

Conclusions

Post-transplant treatment with pegylated interferon alpha-2a and ribavirin achieved SVR in 56% of liver transplant recipients with chronic HCV genotype 4 infection. The combination was relatively safe and exhibited a low rate of treatment withdrawal.     

Eight‐week regimen of antiviral combination therapy with peginterferon and ribavirin for patients with chronic hepatitis C with hepatitis C virus genotype 2 and a rapid virological response

Background: It remains unclear how we can shorten the treatment duration of antiviral combination therapy with peginterferon and ribavirin for patients with chronic hepatitis C virus (HCV) genotype 2 infection who achieved a rapid virological response (RVR). Aim: We compared the efficacy of antiviral combination therapy with peginterferon and ribavirin for 8 vs. 24 weeks for the treatment of patients with HCV genotype 2 infection and with RVR. Methods: Sixty‐one patients were enrolled. Serum HCV RNA was not detected at 4 weeks after the start of treatment in 32 patients with an RVR. These 32 patients were randomly assigned to 8‐week (n=15) or 24‐week (n=17) treatment regimens. Patients in the 8‐week group who relapsed underwent a 24‐week retreatment. Results: No significant difference in patient characteristics was observed between the 8‐ and the 24‐week treatment groups. A sustained virological response (SVR) was seen in five of 15 patients (33.3%) in the 8‐week treatment group and 14 of 17 (82.4%) in the 24‐week treatment group; the rate was significantly higher in the 24‐week treatment group (P=0.0140). Nine of 10 relapsed patients in the 8‐week treatment group underwent a 24‐week retreatment, and seven achieved an SVR. Conclusion: An 8‐week regimen of combination antiviral therapy with peginterferon and ribavirin yielded an increase in the relapse rate, indicating the limitation of a reduction of treatment below 12 weeks in patients with genotype 2, after RVR.     

Baseline factors and very early viral response (week 1) for predicting sustained virological response in telaprevir-based triple combination therapy for Japanese genotype 1b chronic hepatitis C patients: a multicenter study

Background

Genetic polymorphisms near Interleukin 28B (IL28B) (rs8099917) and a rapid virological response (RVR) have been reported as predictors for a sustained virological response (SVR) to telaprevir (TVR)-based triple combination therapy. However, the association between SVR and viral kinetics earlier than week 4 after initiation of therapy remains unclear. Thus, we evaluated the SVR prediction ability of baseline factors and reduced hepatitis C virus (HCV) RNA levels at week 1 after the initiation of TVR-based therapy in Japanese genotype-1b chronic hepatitis C (CHC) patients.

Methods

A total of 156 Japanese CHC patients received a 24-week regimen of TVR-based therapy. Baseline factors and reduction in HCV RNA levels at weeks 1 and 4 after the initiation of therapy were analyzed for SVR prediction.

Results

Multiple logistic regression analysis for SVR in TVR-based therapy identified the IL28B TT genotype, a reduction of ≥4.7 log₁₀IU/mL in HCV RNA levels at week 1, RVR, and treatment-naïve/relapse. Whereas the SVR rate was higher than 90 % regardless of the reduction in HCV RNA levels at week 1 in patients with the TT genotype, a reduction of ≥4.7 log₁₀IU/mL in HCV RNA levels at week 1 was the strongest predictor of SVR in patients with the non-TT genotype, as determined by multiple logistic regression analysis (P = 0.0043).

Conclusions

The IL28B TT genotype is the most important baseline factor for predicting SVR, and a ≥4.7 log₁₀IU/mL reduction in HCV RNA at week 1 is a useful very early on-treatment predictor of SVR, especially in the non-TT genotype.     

Treatment of chronic genotype-3 hepatitis C virus infection using direct-acting antiviral agents: An Indian experience

Background

Direct-acting antiviral drugs (DAAs) are favored for the treatment of hepatitis C virus (HCV) infection. However, the experience with the DAAs currently available in India in the treatment of genotype-3 HCV is limited. We therefore reviewed our experience with these drugs in treating patients with chronic genotype-3 HCV infection, including those with cirrhosis.

Methods

We prospectively followed adult patients with genotype-3 HCV infection who had received treatment regimens containing sofosbuvir with/without daclatasvir. Patients were categorized as chronic hepatitis C (CHC), compensated cirrhosis (CC), and decompensated cirrhosis (DC). They received either (i) sofosbuvir and ribavirin, with or without pegylated interferon (Peg-IFN) for 12 or 24 weeks, or (ii) sofosbuvir and daclatasvir, with or without ribavirin for 12 or 24 weeks. Response was assessed using HCV RNA testing after 2 or 4 weeks of treatment (rapid virological response [RVR]), at treatment completion (end-of-treatment response [ETR]) or 12 weeks after treatment completion (sustained virological response [SVR12]).

Results

Of the 160 patients (90% treatment-naïve; CHC 49%, CC 32%, and DC 19%), 39 (24%) received Peg-IFN, sofosbuvir and ribavirin, 21 (13%) received sofosbuvir and ribavirin, and 100 (63%) received sofosbuvir and daclatasvir, with or without ribavirin. On intention-to-treat basis, RVR, ETR, and SVR12 in the entire cohort were 146/160 (91.3%), 151/160 (94.4%), and 147/160 (91.9%), respectively. Seven patients died (CC 2, DC 5) during treatment; four (2 CHC, 2 DC) patients discontinued treatment; and two patients with CC relapsed.

Conclusions

Dual-DAA-based regimens were safe and highly effective in treating genotype-3 HCV infection in CHC and CC patients.

     

The safety and efficacy of peginterferon plus ribavirin in hepatitis C patients concomitant with malignancy other than hepatocellular carcinoma: a multicenter study

Purpose

Cancer patients were generally excluded from the therapeutic guidelines of antiviral therapy. We aimed to evaluate the efficacy and safety of antiviral therapy in patients with hepatitis C virus (HCV) infection concomitant with malignancy other than hepatocellular carcinoma (HCC).

Methods

Twenty-five HCV patients with curative malignancy other than HCC (group A) and 75 sex- and age-matched controls (group B) were recruited into a prospective and case–control analysis. All patients received peginterferon-alpha-2a (PegIFN-alpha-2a) and weight-based ribavirin according to the current treatment recommendations. The primary outcome measurement was sustained virological response (SVR). The safety issue between groups was also compared.

Results

There were 22 (88.0 %) patients of group A and 59 (78.7 %) patients of group B who achieved an SVR (p = 0.39). The SVR rate was comparable between groups both in genotype-1 (HCV-1) (81.8 vs. 72.7 %, p = 0.70) and in genotype-2 (HCV-2) (92.9 vs. 83.3 %, p = 0.66) patients. Multivariate logistic regression analysis demonstrated that the achievement of a RVR (viral clearance during first 4 weeks of treatment) was the strongest predictor of an SVR (odds ratio/95 % confidence intervals [OR/CI]: 6.357/1.50 ? 26.99, p = 0.01), followed by lower baseline viral loads (OR/CI: 0.403/0.174 ? 0.936, p = 0.034) and higher dose of ribavirin exposure (OR/CI: 1.287/1.092 ? 1.517, p = 0.003), whilst previous occurrence of cancer was not associated with SVR. Treatment adherence (76.0 vs. 72.0 %, p = 0.70) and the incidences of grade 3 or more adverse events (28.0 vs. 20.0 %, p = 0.40) were comparable between two groups.

Conclusions

Chronic hepatitis C patients with non-HCC malignancies receiving peginterferon/ribavirin combination therapy carried favorable efficacy and safety outcomes.     

Rapid Virological Response Represents the Highest Prediction Factor of Response to Antiviral Treatment in HCV-Related Chronic Hepatitis: a Multicenter Retrospective Study

Background:

Standard [i.e. pegylated interferon (Peg-IFN) + ribavirin] treatment of hepatitis C virus (HCV)-related chronic hepatitis is associated with a sustained virological response (SVR) in 50 - 90% of patients. A rapid virological response (RVR) (i.e. negative HCV-RNA after 4 weeks of treatment) predicts SVR in almost 90% of patients.

Objectives:

The main aim of this study was to assess the strength of RVR, as a predictive factor of antiviral treatment response.

Patients and Methods:

Using univariate and multivariate analysis, we retrospectively evaluated biochemical, metabolic, genetic and viral variables that might affect both RVR and SVR to Peg-IFN plus ribavirin, in 315 consecutive outpatients affected by HCV-related chronic hepatitis.

Results:

At univariate analysis, staging, body mass index, RVR, genotype and viral load were significantly related to SVR (P < 0.001). At multivariate analysis, RVR and genotype remained significant (P < 0.00001). The RVR had a predictive value of 83%. At univariate and multivariate analyses, diabetes (P = 0.003), genotype 2 (P = 0.000) and HCV-RNA values (P = 0.016) were independent predictors of RVR, even though at multivariate analyses, only genotype 2 was significantly related to RVR. When we stratified patients, according to genotype, no laboratory or clinical factors were predictive of RVR in genotype 1 patients at either univariate or multivariate analysis. In genotype 2 patients, staging (P = 0.029) and diabetes (P = 0.001) were the only significant predictors of RVR at univariate analyses, whereas no factor was independently related to RVR, at multivariate analysis.

Conclusions:

The RVR is the strongest factor of SVR and infection with HCV genotype 2 is significantly associated with RVR. Neither biochemical and/or metabolic factors seem to exert influence on RVR.     

Rapid virological response as a predictor of sustained response in HCV‐infected patients with persistently normal alanine aminotransferase levels: A multicenter study

Summary. Rapid virological response (RVR) is now considered the strongest predictor of sustained virological response (SVR) in patients with HCV undergoing antiviral treatment, and thus, shorter antiviral treatment for these patients has been suggested. However, no data exist on the predictive value of RVR in HCV carriers with normal ALT values. A total of 137 patients with persistently normal ALT treated with peginterferon alfa 2a and ribavirin were studied. Fifteen patients dropped out early because of side effects, and in 10 patients with HCV‐1 treatment was discontinued because of lack of early virological response (EVR). RVR was observed in 68% of the patients (42% patients with HCV‐1, 90% HCV‐2 and 64% HCV‐3). An end‐of‐treatment response was observed in 86% of the patients (68% HCV‐1, 100% HCV‐2 and 91% HCV‐3). SVR was maintained in 91 patients (46% HCV‐1, 97% HCV‐2 and 82% HCV‐3). Overall, 92% patients with rapid response did obtain HCV eradication vs only 38% of those without rapid response. HCV‐1 patients with baseline HCV RNA <400 × 10³ IU/mL were more likely to achieve RVR and SVR than those with higher HCV RNA levels. We conclude that patients with genotype 1 and normal ALT who achieve HCV RNA negativity at week 4 may have a higher probability of eradicating their infection. Because of the concomitant favourable demographic and virological features often found in this particular subset of patients, the duration of therapy in these people might be shortened in the case of RVR. Persistently normal alanine aminotransferase levels patients with genotype 2 or 3 have a high chance of achieving SVR, so retesting of HCV RNA during treatment may have no additional practical value in these subjects.     

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

Purpose/Aim

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

Material and Methods

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

Results

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

Conclusion

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

Early identification of achieving a sustained virological response in chronic hepatitis C patients without a rapid virological response

Background and Aim: A number of hepatitis C virus (HCV) patients without a rapid virological response (RVR) achieved a sustained virological response (SVR) with peginterferon‐α‐2a/ribavirin. The aim of this study was to identify factors associated with SVR in non‐RVR patients. Methods: Baseline and on‐treatment factors were used to explore the prognostic factors for SVR in 113 HCV genotype‐1 (HCV‐1) and 20 HCV‐2 non‐RVR patients in two randomized trials. Results: The SVR rate in HCV‐1 patients with a complete early virological response (cEVR) and partial early virological response was 91.9% versus 45% (P < 0.001) and 21.4% versus 10% (P = 0.62), respectively, after 48 and 24 weeks of treatment. The SVR rate in HCV‐2 patients with a cEVR was 90.9% versus 57.1% (P = 0.25), respectively, after 24 and 16 weeks of treatment. Multivariate analysis showed that cEVR and standard regimen were independently associated with SVR. Viral kinetic study revealed that HCV viral loads < 10 000 IU/mL at week 4 were the best predictor of cEVR for both HCV‐1 and HCV‐2 non‐RVR patients with the accuracy of 81% and 95%, respectively, and also of SVR with the accuracy of 78% and 92%, respectively, in patients receiving standard of care. The most important independent predictors for cEVR were HCV viral loads < 10⁴ IU/mL at week 4, followed by increased ribavirin dose within 12 weeks of treatment. Conclusions: Achieving a cEVR with standard of care is the most important predictor of SVR in non‐RVR patients. Week 4 viral loads < 10 000 IU/mL could accurately predict cEVR early and following SVR in non‐SVR patients.     

Antiviral effects and safety of telaprevir, peginterferon alfa-2a, and ribavirin for 28 days in hepatitis C patients

BACKGROUND/AIMS: This study assessed the safety and antiviral effects of telaprevir (VX-950) in combination with peginterferon alfa-2a and ribavirin. METHODS: Twelve treatment-nai ve patients with chronic genotype 1 hepatitis C virus infection received telaprevir (750mg q8h), peginterferon alfa-2a (180mug/week), and ribavirin (1000 or 1200mg/day) for 28 days. Patients could then start off-study treatment with peginterferon alfa-2a and ribavirin for up to 44 weeks, at the discretion of the investigator and patient. RESULTS: The combination of telaprevir, peginterferon alfa-2a, and ribavirin was well tolerated, with no serious adverse events or treatment discontinuations. Rash or pruritus occurred in 5 of the 12 patients; all cases resolved either during or after the end of telaprevir treatment. All 12 patients had undetectable HCV RNA levels by day 28 (rapid viral response, RVR). Eight patients completed 44 weeks of off-study peginterferon alfa-2a and ribavirin treatment. Eight patients achieved a sustained viral response (SVR), including one patient who received only 22 weeks of treatment. CONCLUSIONS: The combination of telaprevir, peginterferon alfa-2a, and ribavirin was generally well tolerated. Events of pruritus and rash resolved during or after end of telaprevir dosing. All 12 patients achieved an RVR.     

Relevance of the Core 70 and IL-28B polymorphism and response-guided therapy of peginterferon alfa-2a ± ribavirin for chronic hepatitis C of Genotype 1b: a multicenter randomized trial,ReGIT-J study

Background

We conducted a multicenter randomized clinical trial to determine the optimal treatment strategy against chronic hepatitis C virus (HCV) with genotype 1b and a high viral load (G1b/high).

Methods

The study subjects included 153 patients with G1b/high. Patients were initially treated with PEG-IFNα-2a alone and then randomly assigned to receive different treatment regimens. Ribavirin (RBV) was administered to all patients with HCV RNA at week 4. Patients negative for HCV RNA at week 4 were randomly assigned to receive PEG-IFNα-2a (group A) or PEG-IFNα-2a/RBV (group B). Patients who showed HCV RNA at week 4 but were negative at week 12 were randomly assigned to receive weekly PEG-IFNα-2a (group C) or biweekly therapy (group D). Patients who showed HCV RNA at week 12 but were negative at week 24 were randomly assigned to receive PEG-IFNα-2a/RBV (group E) or PEG-IFNα-2a/RBV/fluvastatin (group F).

Results

Overall, the rate of sustained virological response (SVR) was 46 % (70/153). The total SVR rate in the group (A, D, and F) of response-guided therapy was significantly higher than that in the group (B, C, and E) of conventional therapy [70 % (38/54) versus 52 % (32/61), p = 0.049]. Although IL28-B polymorphism and Core 70 mutation were significantly associated with efficacy, patients with rapid virological response (RVR) and complete early virological response (cEVR) achieved high SVR rates regardless of their status of IL-28B polymorphism and Core 70 mutation.

Conclusion

In addition to knowing the IL-28B polymorphism and Core 70 mutation status, understanding the likelihood of virological response during treatment is critical in determining the appropriate treatment strategy.     

Peginterferon alfa-2a (40kDa) and ribavirin: comparable rates of sustained virological response in sub-sets of older and younger HCV genotype 1 patients

Summary.  The average age of patients initiating therapy for HCV is increasing, with older patients exhibiting lower responses to therapy than younger patients. Identification of those older patients likely to respond needs to be addressed. Using data from 569 genotype-1 patients enrolled in two phase III studies (NV15801/NV15942) randomized to peginterferon alfa-2a (40KDa) 180 μg/week plus ribavirin 1000/1200 mg/day for 48-weeks, we investigated factors associated with sustained virological response (SVR; undetectable HCV-RNA 24-weeks post-treatment) in patients >50 years. SVR rates among patients ≤50 was greater than those >50 years (52% vs 39%; P  = 0.0073). Older patients with a rapid virological response (RVR; undetectable HCV-RNA at treatment week 4) or complete early virological response (cEVR; detectable HCV-RNA at week 4 but HCV-RNA <50 IU/mL at week-12) demonstrated high SVR rates (83% and 61% respectively). Older patients had lower cumulative peginterferon alfa-2a exposure and significantly lower cumulative ribavirin exposure (252 g vs 304 g in younger patients; P  < 0.0001). Higher relapse rates were observed in older patients (41% vs 25%; P  = 0.0042). Cumulative drug exposure and achievement of RVR or cEVR were significantly predictive of SVR by multiple logistic regression analysis in patients >50 years. Other baseline characteristics predictive of SVR in those >50 years of age were lower baseline HCV-RNA level ( P  = 0.0067), higher ALT-ratio ( P  = 0.0113) and absence of cirrhosis ( P  = 0.0482). Response rates were high among patients >50 years without cirrhosis who maintained adequate drug exposure and those achieving an RVR or cEVR. More frequent dose modifications of ribavirin in those >50 years likely contributed to the observed higher relapse rates.