Sustained Virological Response Rates In Patients Research Articles

New treatments for chronic hepatitis C.

Treatments for chronic hepatitis C has evolved significantly in the past 15 years. The standard of care (SOC) is peginterferon alfa-2a/-2b with ribavirin for 48 weeks or 24 weeks in patients infected with HCV genotype 1 or 2/3, respectively. The treatment duration can be individualized based on the baseline viral load and the speed of the virologic response during treatment. However, current therapies are associated with side effects, complications, and poor patient tolerability. Therefore, there is an urgent need to identify better strategies for treating this disease. An improved sustained virologic response (SVR) can be achieved with new HCV-specific inhibitors against NS3/4A and NS5B polymerases. Recent trials have found SVR rates in patients with HCV genotype 1 infection of 61~68% and 67~75% for combining the SOC with the protease inhibitors telaprevir and boceprevir, respectively. Several new HCV-specific inhibitors such as protease inhibitors and nucleoside and non-nucleoside polymerase inhibitors as well as non-HCV-specific compounds with anti-HCV activity are currently in clinical evaluation. In this review we discuss these new treatments for chronic hepatitis C.

Similar Treatment Response to Peginterferon and Ribavirin in Asian and Caucasian Patients With Chronic Hepatitis C

Previous studies have found ethnicity to be an important predictor of outcomes of treatment with peginterferon (PEG-IFN) and ribavirin (RBV) in chronic hepatitis C. Although the expected sustained virological response (SVR) rates of Hispanics and African Americans are lower than those of Caucasians, SVR rates in Asians appear to be more favorable. However, in some of these studies, hepatitis C virus (HCV) genotype was identified by INNO-LiPA assay, which can mistype the easier-to-treat HCV genotype 6 as genotype 1. Our goal was to compare SVR rates among Caucasian and Asian-American patients with genotype 1 and 2/3 infection whose HCV genotypes were accurately classified by core sequencing testing. A cohort of 269 consecutive treatment-naive HCV-infected patients with genotype 1 or 2/3 (157 Caucasians and 112 Asians) treated with PEG-IFN+RBV from January 2001 to November 2007 at four community-based gastroenterology clinics in Northern California were studied. The analysis of data was by intention-to-treat. The SVR rates for patients with genotype 1 were 45% for Caucasians and 52% for Asians (P=0.37). The SVR rates for patients with genotype 2/3 infection was 77% for Asians and 74% for Caucasians (P=0.7). On multivariate logistic regression analyses adjusting for age, alanine aminotransferase (ALT), baseline viral load, HCV genotype, and treatment adherence, we did not find Asian ethnicity to predict SVR. On a separate analysis, we found that Asians who had HCV genotype 1 or 1b by the less accurate INNO-LiPA assay had significantly higher SVR rates than Caucasians with genotype 1 (64% vs. 45%, respectively, P=0.03). SVR rates were similar in Asian Americans and Caucasians infected with HCV genotype 1 or 2/3 when HCV genotype classification was accurately determined.

Antiviral Treatment of Patients with Recurrent Hepatitis C After Liver Transplantation with Pegylated Interferon

The recurrence of hepatitis C virus (HCV) after liver transplantation (OLT) leads to recurrent cirrhosis in up to 40% of patients. To identify patients who profit the most from antiviral therapy and to delineate whether early treatment after OLT is effective to reach sustained virological response (SVR), we analyzed factors associated to SVR during pegylated interferon/ribavirin (PegIFN/RBV) therapy. A retrospective analysis of efficiency and viral decline kinetics in 83 HCV-infected liver transplant recipients who received therapy with PegIFN/RBV was carried out. Forty-one of 83 (49.4%) patients became HCV RNA-negative. SVR was achieved in 26/83 (31.3%) patients. Viral decline of at least 2 log 10 (n = 47) at week 12 was significantly associated with an end-of-treatment (EOT) response. Eleven early viral response patients were not able to clear HCV RNA, whereas five patients without a 2 log decline achieved SVR. The highest predictive value for SVR was an undetectable viremia at week 24 (92%). The outcome of antiviral combination therapy for HCV reinfection after OLT can be best predicted by week-24 virologic response. The high SVR rates in patients with detectable HCV RNA at week 12 might suggest a prolonged treatment protocol in liver transplant recipients.

Pegylated interferon alpha‐2b (Peg‐IFN α‐2b) affects early virologic response dose‐dependently in patients with chronic hepatitis C genotype 1 during treatment with Peg‐IFN α‐2b plus ribavirin

Chronic hepatitis C (CH-C) genotype 1 patients who achieved early virologic response have a high probability of sustained virologic response (SVR) following pegylated interferon (Peg-IFN) plus ribavirin therapy. This study was conducted to evaluate how reducing drug doses affects complete early virologic response (c-EVR) defined as hepatitis C virus (HCV) RNA negativity at week 12. Nine hundred eighty-four patients with CH-C genotype 1 were enrolled. Drug doses were evaluated independently on a body weight base from doses actually taken. From multivariate analysis, the mean dose of Peg-IFN alpha-2b during the first 12 weeks was the independent factor for c-EVR (P = 0.02), not ribavirin. The c-EVR rate was 55% in patients receiving > or = 1.2 microg/kg/week of Peg-IFN, and declined to 38% at 0.9-1.2 microg/kg/week, and 22% in patients given <0.9 microg/kg/week (P < 0.0001). Even with stratified analysis according to ribavirin dose, the dose-dependent effect of Peg-IFN on c-EVR was observed, and similar c-EVR rates were obtained if the dose categories of Peg-IFN were the same. Furthermore, the mean dose of Peg-IFN during the first 12 weeks affected HCV RNA negativity at week 24 (P < 0.0001) and SVR (P < 0.0001) in a dose-dependent manner. Our results suggest that Peg-IFN was dose-dependently correlated with c-EVR, independently of ribavirin dose. Thus, maintaining the Peg-IFN dose as high as possible during the first 12 weeks can yield HCV RNA negativity and higher c-EVR rates, leading to better SVR rates in patients with CH-C genotype 1.

Impact of High-Dose Peginterferon Alfa-2A on Virological Response Rates in Patients with Hepatitis C Genotype 1: a Randomized Controlled Trial† ‡

This study tested the hypothesis that high-dose peginterferon alfa-2a (PEG-IFNalpha-2a) for the first 12 weeks would increase early and sustained virological response (SVR) rates in patients with chronic hepatitis C genotype 1. Eight hundred ninety-six patients were randomized 1:1 to 360 microg (n = 448) or 180 microg (n = 448) PEG-IFNalpha-2a weekly plus ribavirin at 1000-1200 mg/day for 12 weeks, followed by 36 weeks of 180 microg PEG-IFNalpha-2a weekly plus ribavirin at 1000-1200 mg/day with 871 patients evaluable for the intention-to-treat analysis. Virological responses were assessed by TaqMan (limit of detection 15 IU/mL) at week 4, 8, 12, 24, 48 (end of therapy), and 24 weeks following therapy (SVR). Undetectable hepatitis C virus RNA rates were significantly higher among patients receiving high-dose induction therapy at week 4 (36% versus 26%, P < 0.005), week 8 (61% versus 50%, P < 0.005), and week 12 (74% versus 62%, P < 0.005). However, SVR was not significantly different between patients receiving high-dose (53%) and standard (50%) therapy. Significant baseline prognostic factors for SVR included age, sex, race, histological stage, and viral load. SVR was considerably higher among patients with no or minimal fibrosis (64% and 60%, respectively) compared to those with severe fibrosis/cirrhosis (28% and 24%, respectively). The frequency of serious adverse events and drug discontinuations were similar in both groups, whereas PEG-IFN dose modification, weight and appetite reduction, and grade IV neutropenia were significantly higher in the induction arm. Induction dosing with 360 microg/week PEG-IFNalpha-2a for 12 weeks was well tolerated and enhanced early virological response but not SVR rates. The high SVR rates in patients with minimal fibrosis highlight the benefit of early treatment in patients with hepatitis C virus genotype 1.

A Randomized Study of Extended Treatment With Peginterferon α-2b Plus Ribavirin Based on Time to HCV RNA Negative–Status in Patients With Genotype 1b Chronic Hepatitis C

The treatment of patients with hepatitis C virus (HCV) genotype 1 with peginterferon plus ribavirin treatment for more than 48 weeks demonstrated high sustained virological response (SVR) rates. Although many studies extended the duration of therapy from 48 weeks to 72 weeks, the optimal duration has not yet been determined. A total of 113 genotype 1b patients with high viral load were randomized at baseline to the standard (n=56) or extended (n=57) treatment group. The standard group patients received 48 weeks of peginterferon plus ribavirin treatment. In the extended group, the treatment was performed for 44 weeks after patients became negative for HCV RNA (total duration 48-68 weeks). The SVR rate of the standard and extended group was 36% (20 of 56) and 53% (30 of 57; P=0.07). However, the extended group patients who became negative for HCV RNA between weeks 16 and 24 had a significantly higher SVR rate (78%; 7 of 9) than that of standard group (9%, 1 of 11; P=0.005). The predictive factors for the SVR were the treatment regimen (the standard vs. extended treatment) and the time to HCV RNA negative-status. The extended treatment significantly increased the SVR rate in patients who were HCV RNA negative at 16-24 weeks.

Chronic Hepatitis C Virus Genotype 6 Infection: Response to Pegylated Interferon and Ribavirin

To date, no study has evaluated pegylated interferon for the treatment of chronic infection with hepatitis C virus (HCV) genotype 6. We aimed to determine the efficacy of pegylated interferon plus ribavirin for treating infection with genotype 6 versus genotype 1. Forty-two patients chronically infected with HCV (for genotype 1, n = 21; for genotype 6, n = 21) were treated with pegylated interferon alpha-2a (n = 20) or alpha-2b (n = 22) combined with oral ribavirin for 48 weeks. There was no difference between genotypes 1 and 6 in the rates of early virological response (76% vs. 81%; P > .05) and end-of-treatment response (71% vs. 81%; ). Patients infected with genotype 6 had a higher rate of sustained virological response (SVR) than did patients infected with genotype 1 (86% vs. 52%; P = .019). The overall adverse-effects profile was similar in both genotype groups. There was no significant difference in the rate of SVR between patients receiving pegylated interferon alpha-2a and those receiving alpha-2b. Multivariate analysis showed that genotype was the only significant factor associated with SVR (P = .039). Treatment with pegylated interferon and ribavirin for 48 weeks resulted in a significantly higher rate of SVR in patients infected with genotype 6 than in those infected with genotype 1. Further studies are required to determine whether lower dosages and 24 weeks of therapy may be sufficient for the treatment of genotype 6 infection.

Scientific rationale and study design of the individualized dosing efficacy vs flat dosing to assess optimal pegylated interferon therapy (IDEAL) trial: determining optimal dosing in patients with genotype 1 chronic hepatitis C

Current standard-of-care antiviral treatment for patients with chronic hepatitis C is combination therapy with pegylated interferon (PEG-IFN) alfa plus ribavirin. Two large clinical trials determined that each PEG-IFN alfa compound, when given in combination with ribavirin, results in overall sustained virological response (SVR) rates of approximately 50%; SVR rates in patients infected with hepatitis C virus (HCV) genotype 1 are typically lower (42-46%). Differences in study design, treatment regimens, and patient populations preclude comparison of the data across trials; therefore, the most effective use of PEG-IFN alfa in combination with ribavirin is unclear. The Individualized Dosing Efficacy vs Flat Dosing to Assess Optimal Pegylated Interferon Therapy (IDEAL) study is a phase 3b, randomized, parallel-group, US multicentre trial in treatment-naive genotype 1 patients with chronic hepatitis C. Initially, this study was undertaken to evaluate the efficacy and safety of weight-based ribavirin dosing (800-1400 mg / day) and PEG-IFN alfa-2b dosing (arm 1: PEG-IFN alfa-2b 1.5 microg / kg / week; arm 2: PEG-IFN alfa-2b 1.0 microg / kg / week). However, because a clinical trial directly comparing the efficacy and safety of PEG-IFN alfa-2a and alfa-2b in combination with weight-based ribavirin dosing has not been performed, an additional arm (arm 3: PEG-IFN alfa-2a 180 microg / week plus ribavirin 1000-1200 mg / day) was included to address this important issue. IDEAL is fully enrolled (>3000 patients) and complete study data, including SVR rates, are expected in early 2008. Herein, we present the scientific rationale and study design, discuss key data from other trials, and summarize our expectations of this study.

Optimizing outcomes in patients with hepatitis C virus genotype 1 or 4

Currently, many decisions for the treatment of hepatitis C virus (HCV) are based on genotype, which is the most significant baseline predictor of response to therapy; however, it has become increasingly apparent that fixed treatment durations might not be appropriate for all patients. The use of on-treatment predictors such as rapid virological response (RVR) at week 4 and early virological response (EVR) at week 12 can be used to predict the likelihood of achieving a sustained virological response (SVR), helping to tailor treatment to the individual. Until now, EVR has been defined as achieving either undetectable HCV RNA (&lt;50 IU/ml) or a &gt;2 log drop in HCV RNA, but still detectable, at week 12. However, rates of SVR in patients achieving an EVR are heterogeneous. It has recently been suggested that by subdividing EVR into RVR (&lt;50 IU/ml at week 4), complete EVR (HCV RNA &lt;50 IU/ml at week 12) or partial EVR (HCV RNA &gt;2 log drop in HCV RNA but still detectable [&gt;50 IU/ml] at week 12), it might be possible to further improve the prediction of patients likely to achieve an SVR and may allow for tailoring of treatment duration. Genotype 1 and 4 patients achieving an RVR have high rates of SVR and may be candidates for shorter treatment duration. Patients with a complete EVR achieve high SVR rates with the current treatment duration of 48 weeks, whereas patients achieving a partial EVR have lower rates of SVR and could benefit from treatment intensification to 72 weeks. Here, we discuss the importance of baseline predictors of response and the emerging concept of response-guided therapy in genotype 1 and 4 patients.

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Peginterferon-Alfa2a Plus Ribavirin for 48 Versus 72 Weeks in Patients With Detectable Hepatitis C Virus RNA at Week 4 of Treatment

Patients with chronic hepatitis C who do not respond rapidly to therapy have a low chance of developing a sustained virologic response (SVR) when treated for 48 weeks. This study investigated whether treatment for 72 weeks increases the rate of SVR in patients with detectable hepatitis C virus (HCV)-RNA levels at week 4 of treatment. A total of 510 treatment-naive patients were treated with peginterferon-alfa2a (180 microg/wk) plus ribavirin (800 mg/day). Patients with detectable HCV-RNA levels at week 4 (n = 326) were randomized to complete 48 (group A, n = 165) or 72 weeks (group B, n = 161) of treatment. Patients with undetectable HCV-RNA levels at week 4 (n = 184) were allocated into group C (n = 148) or group D (n = 36), according to HCV genotype and baseline viremia, and treated for 24 or 48 weeks, respectively. All patients were followed-up for 24 weeks after the end of treatment. The end-of-treatment response rate (61%) was similar in groups A and B, but the SVR rate was higher in group B (45% vs 32% in A; P = .01). In genotype 1-infected patients randomized to group A (n = 149) or B (n = 142), SVR rates were 28% and 44%, respectively (P = .003). The incidence of adverse events was similar in all groups. Treatment discontinuation was more frequent in group B (36%) than in group A (18%) (P = .0004). SVR rates in groups C and D were 79% and 64%, respectively. Extension of treatment with peginterferon-alfa2a plus ribavirin from 48 to 72 weeks significantly increases the rate of SVR in patients with detectable viremia at week 4 of treatment.

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Re‐treatment of chronic hepatitis C patients after relapse: efficacy of peginterferon‐alpha‐2a (40 kDa) and ribavirin

We conducted a randomized multinational study to determine whether 48 weeks of re-treatment with peginterferon-alpha-2a (40 kDa) plus ribavirin would induce a sustained virological response (SVR) in relapsed chronic hepatitis C patients. Patients who had previously relapsed during 24 weeks of untreated follow-up, after having achieved an end-of-treatment virological response with 24 weeks of peginterferon-alpha-2a (40 kDa)/ribavirin combination therapy, within a phase III trial, were studied. Although the recommended dosage was the same as that used at the end of the initial trial, adjustments were permitted. Data on serious adverse events, or adverse events that resulted in dose reductions or discontinuations, were collected. Following re-treatment, the overall SVR rate in the 64 patients was 55%. The SVR rates in patients infected with hepatitis C virus (HCV) genotype 1 and non-1 genotypes were 51% and 63%, respectively. Early (week 12) virological responses were seen in 39 patients (61%) and were predictive of an SVR. Re-treatment was well tolerated. The most frequent adverse events recorded were fatigue (5%) and abdominal pain (3%). Dosages of peginterferon-alpha-2a (40 kDa) and/or ribavirin were modified because of adverse events in 3% and 13% of patients, and because of laboratory abnormalities in 23% and 5% of patients, respectively. Thus, a 48-week course of peginterferon-alpha-2a (40 kDa) plus ribavirin induces an SVR in 55% of patients who relapsed during follow-up after 24 weeks of combination therapy. Physicians should not hesitate to offer re-treatment to patients who relapse after an initial, 24-week course of combination therapy, or who have prematurely stopped treatment because, for example, of laboratory abnormalities.

Extended Treatment Duration for Hepatitis C Virus Type 1: Comparing 48 Versus 72 Weeks of Peginterferon-Alfa-2a Plus Ribavirin

The treatment of patients infected with hepatitis C virus (HCV) type 1 remains a challenge necessitating innovative strategies to improve treatment outcome. The extension of treatment duration beyond 48 weeks is one possible strategy to address this problem. The efficacy and safety of 48 weeks (group A, N = 230) vs 72 weeks (group B, N = 225) of treatment with pegylated-interferon-alfa-2a (180 microg/wk) plus ribavirin (800 mg/day) were studied in treatment-naive patients with HCV type 1 infection. On-treatment and sustained virologic response (SVR) 24 weeks after stopping treatment was assessed by qualitative reverse-transcription polymerase chain reaction (sensitivity 50 IU/mL). Overall, no significant differences could be observed in the treatment outcome between both groups. End-of-treatment and SVR rates in groups A and B were 71% vs 63% and 53% vs 54%, respectively. Patients with undetectable HCV-RNA levels already at weeks 4 and 12 had excellent SVR rates ranging from 76% to 84% regardless of treatment group, whereas patients shown to be still HCV-RNA positive at week 12 achieved significantly higher SVR rates when treated for 72 instead of 48 weeks (29% vs 17%, P = .040). A particular benefit from extended treatment duration was seen in patients with low-level viremia (<6000 IU/mL) at week 12. The frequency and intensity of adverse events was similar between the 2 groups. Extended treatment duration generally is not recommended in HCV type 1 infection and should be reserved only for patients with slow virologic response defined as HCV-RNA positive at week 12 but negative at week 24.

Consensus interferon and ribavirin for patients with chronic hepatitis C and failure of previous interferon‐α therapy

The efficacy of consensus interferon (CIFN), a synthetic IFN with optimised in vitro activity, was assessed in chronic hepatitis C virus (HCV) patients who had failed the pretreatment with interferon-alpha (IFNalpha) and ribavirin. One hundred and three patients after non-response (n=69) or relapse (n=34) to IFNalpha+/-ribavirin were randomly assigned to high-dose induction (CIFN 27-->9 microg daily for 24 weeks, 9 microg t.i.w. for 24 weeks) or low-dose treatment (CIFN 18 microg t.i.w. for 12 weeks, 9 microg t.i.w. for 36 weeks); each with ribavirin 800 mg/day. Follow-up was 24 weeks. Non-responder patients treated with high-dose induction had higher early virological response rates (63% vs. 39%, P<0.05). This initial positive effect was lost during the last 24 weeks of treatment yielding sustained virological response (SVR) rates of 26% in both groups. Relapse patients revealed SVR in 70% and 38% in groups A and B (NS). Treatment was well tolerated with side effect-related preterm discontinuations in 8% and 5%. CIFN and ribavirin treatment induced considerable SVR rates in patients with non-response or relapse to IFNalpha+/-ribavirin. Viral elimination rates might be further increased by continuous daily administration of CIFN and weight-adjusted ribavirin dosing.

Induction therapy with twice-daily interferon-beta does not improve the therapeutic efficacy of consensus interferon monotherapy for chronic hepatitis C

We examined therapeutic superiority of induction therapy with twice-daily IFN-beta (3X2=6 million units/day) onto 6-months consensus interferon monotherapy for chronic hepatitis C. Patients were randomly assigned to monotherapy without (group I, n=16) and with induction therapy (group II, n=12). The mean age of group II was older than that of group I, and other baseline condition was not statistically significant. Sustained virological response (SVR) rates of group I and II were 81.3% (13/16) and 58.3% (7/12), respectively (p=0.365). SVR rates in patients with genotype 1b were 66.7% (4/6) and 0% (0/2, because of drop-out), and those with high viral load were 70% (7/10) and 75% (6/8) in group I and II, respectively (p=1.000). Drop-out rates during therapy were 6.3% (1/16) and 33.3% (4/12) in group I and II, respectively (p=0.176). Age less than 50 years was the only independent factor that was shown by multivariate logistic model analysis to be associated with a sustained virological response. Although randomization failed to produce and equal age distribution in the two groups in this study, our results suggest that induction therapy with twice-daily IFN-beta has no beneficial effect on the efficacy of monotherapy with consensus interferon, probably because of the higher drop-out rates and incidence of adverse reactions with induction therapy.

Impact of disease severity on outcome of antiviral therapy for chronic hepatitis C: Lessons from the HALT-C trial

In patients with chronic hepatitis C, advanced fibrosis and cirrhosis are associated with lower rates of sustained virologic response (SVR) to interferon (IFN)-based therapy. In this study, we assessed virologic response to retreatment with peginterferon alfa-2a and ribavirin (RBV), as a function of the baseline fibrosis score (Ishak staging) and platelet count, in 1,046 patients enrolled in the Hepatitis C Antiviral Long-term Treatment against Cirrhosis (HALT-C) Trial. All patients had failed prior treatment with IFN or peginterferon +/- RBV and had Ishak fibrosis scores > or = 3. Four groups of patients with increasingly severe liver disease were compared: (A) bridging fibrosis (Ishak 3 and 4) with platelet counts >125,000/mm3 (n = 559); (B) bridging fibrosis with platelet counts < or =125,000/mm3 (n = 96); (C) cirrhosis (Ishak 5 and 6) with platelet counts >125,000/mm3 (n = 198); and (D) cirrhosis with platelet counts < or =125,000/mm3 (n = 193). SVR rates were 23%, 17%, 10%, and 9% in groups A, B, C, and D, respectively (P < .0001 for trend). Reduction in SVR as a function of increasingly severe disease was independent of age, percent African American, HCV genotype, HCV level, and type of prior therapy. Dose reduction lowered SVR frequencies, but to a lesser extent than disease severity. By logistic regression, cirrhosis (P < .0001) was the major determinant that impaired virologic response, independent of dose reduction or platelet count. In conclusion, disease severity is a major independent determinant of rate of SVR in patients with advanced chronic hepatitis C. New strategies are needed to optimize antiviral therapy in these "difficult-to-cure" patients.