Impact of ribavirin dose on retreatment of chronic hepatitis C patients

World J Gastroenterol. 2012 Jun 21;18(23):2966-72.

Impact of ribavirin dose on retreatment of chronic hepatitis C patients.

Stern C, Martinot-Peignoux M, Ripault MP, Boyer N, Castelnau C, Valla D, Marcellin P.

Source
Christiane Stern, Michelle Martinot-Peignoux, Marie Pierre Ripault, Nathalie Boyer, Corinne Castelnau, Dominique Valla, Patrick Marcellin, Service d'Hépatologie and INSERM U773-CRB3, Hôpital Beaujon, University Paris-Diderot, 92110 Clichy, France.

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Abstract
AIM:
To study the efficacy and factors associated with a sustained virological response (SVR) in chronic hepatitis C (CHC) relapsing patients.

METHODS:
Out of 1228 CHC patients treated with pegylated interferon (PEG-IFN) and ribavirin (RBV), 165 (13%) had a relapse. Among these, 62 patients were retreated with PEG-IFN-α2a or -α2b and RBV. Clinical, biological, virological and histological data were collected. Initial doses and treatment modifications were recorded. The efficacy of retreatment and predictive factors for SVR were analyzed.

RESULTS:
An SVR was achieved in 42% of patients. SVR was higher in young (< 50 years) (61%) than old patients (27%) (P = 0.007), and in genotype 2 or 3 (57%) than in genotype 1 or 4 (28%) patients (P = 0.023). Prolonging therapy for at least 24 wk more than the previous course was associated with higher SVR rates (53% vs 28%, P = 0.04). Also, a better SVR rate was observed with RBV dose/body weight > 15.2 mg/kg per day (70% vs 35%, P = 0.04). In logistic regression, predictors of a response were age (P = 0.018), genotype (P = 0.048) and initial RBV dose/body weight (P = 0.022). None of the patients without a complete early virological response achieved an SVR (negative predictive value = 100%).

CONCLUSION:
Retreatment with PEG-IFN/RBV is eff-ective in genotype 2 or 3 relapsers, especially in young patients. A high dose of RBV seems to be important for the retreatment response

DISCUSSION Only
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Retreatment of CHC patients who have failed prior antiviral therapy is an important clinical issue. Our study evaluated the efficacy of retreatment of CHC patients who relapsed after combination therapy with PEG-IFN plus RBV. The overall SVR rate achieved was 42%. An important point of our study is the inclusion of a homogeneous population of prior relapsers to the PEGIFN-α plus RBV combination therapy. Most previous studies analyzed the efficacy of retreatment with PEG IFN plus RBV based on groups composed mainly of patients who failed conventional IFN-based therapy without distinguishing between non-responders and relapsers,or between monotherapy and combination therapy.

Jacobson et al[21] demonstrated that SVR rates decreased according to previous conventional IFN-based therapy status: 42% in conventional IFN (cIFN) plus RBV relapsers,21% in cIFN monotherapy non-responders, and 8% in cIFN plus RBV non-responders. These data were also confirmed by several other studies: retreatment of previous relapsers to cIFN plus RBV could achieve SVR rates of 41%-58%, while for patients who were non-responders, only 4%-26% achieved an SVR [17-21]. The same relationship was observed in previous failures to PEGIFN and RBV: 33% in prior relapsers and 14% in prior non-responders, with an overall SVR of 22% [23].


The SVR rate of 42% observed in our study was slightly higher than that described in the EPIC3 clinical trial, where prior PEG-IFN plus RBV relapsers attained an SVR of 33% [23]. In our study, HCV genotype was an important predictor for SVR. Patients infected with genotype 2 or 3 attained the highest rates of SVR (60% in genotype 2 and 56% in genotype 3). Thus, a higher proportion of genotype non-1 infected patients in the current study (52% vs 20% in EPIC3 trial) could account for this difference. In addition, the EPIC trial used less sensitive qualitative assays that could result in misclas sification of EOT responders, increasing the number of relapsers that were in fact non-responders, with a lower probability of SVR.

Young age and genotype 2 or 3 were factors associated with treatment response as previously reported [2,13,15].

We did not find a relationship between low baseline viral load or low fibrosis stage and better response to therapy. These factors have been described in controversial studies with the treatment of naïve and IFN-experienced patients, and their impact on the response in relapsers could have less strength [7,13,19,23,24].

Retreatment with only PEG-IFN-α in patients who failed to respond to the other PEG-IFN-α has been described as an alternative strategy. However, in our study no gain was observed in patients who received a different type of PEG-IFN-α. This finding is consistent with the REPEAT trial, where prior non-responders to PEG-IFN-α2b were retreated with PEG-IFN-α2a.

Only 9% of SVR was observed in the regimen of 48 wk retreatment [25]. Besides, this trial demonstrated higher SVR rates in the group retreated for 72 wk (14%) [26]. In the current study, the SVR rate was also improved with longer duration of therapy. Thus, retreatment for at least 24 wk longer than the previous course is important to increase the probability of SVR in relapsers and nonresponders.

Some controversial studies have suggested that exposure to RBV is critical for attaining an SVR. At first,adherence to therapy was considered extremely important. McHutchison et al[8] demonstrated that at least 80% adherence to therapy enhanced SVR. They found a continuous, increasing relationship between adherence and SVR in genotype 1. These findings were also observed in another study with genotype 1-naïve patients, where a linear relationship between exposure and the SVR rate was observed at the first 12 wk of treatment 7]. Also, a study with RBV discontinuation in a subset of HCV RNA-negative patients at week 24 showed an increase in the rate of virological breakthrough and relapse [9].

In contrast, in our study no relation was found between dose reduction of RBV and SVR. However, the rate of RBV reduction was 20% and only 2 patients did not have at least 80% of the predicted RBV doses.  Recent studies suggested that high-dose RBV schedules reduced relapse rates and increased SVR in difficult to-treat selected patients [10-12]. In a pilot study with 10 genotype 1 patients, higher RBV doses were associated with more frequent and serious adverse events, but the SVR rate was 90% [11]. Also, Fried et al[10] reported a study with 188 treatment-naïve, genotype 1 and high viral load patients. Patients who received an RBV dose of 1600 mg/d had superior SVR rates when compared with standard doses (1200 mg/d). Our data demonstrated a clear relation between high initial dose of RBV [22] and SVR rates. Patients with RBV dose >15.2 mg/kg per day achieved an SVR rate of 70%, while only 26% of patients with lower doses attained an SVR.

Our study demonstrates that an RVR in a relapser retreatment population is attained by 18%, of whom 71% achieved an SVR. Prediction of non response on treatment was more marked with EVR analyses. If the patient did not achieve a cEVR, no SVR was observed (NPV = 100%). Hence, the presence of detectable HCV RNA at week 12 is a good indication to stop treatment in relapsers and it is as relevant as for naïve or nonresponding patients[3,19,25].

Specifically targeted antiviral therapies for hepatitis C are currently under evaluation in clinical trials. These new drugs are mostly effective and have been studied in genotype 1 patients [27-29].

Telaprevir, an antiprotease NS3-NS4A, increases SVR rates in genotype 1 naïve and non-responding patients, but it has limited activity against genotype 2 and 3 [30]. Besides, even when these medications will be available outside trials, they will not be accessible worldwide. For these reasons, PEG-IFN and RBV still have a role on hepatitis C retreatment, in particular in young patients infected with non genotype 1.

In conclusion, our study shows that retreatment of prior relapsers after treatment with a combination of PEG-IFN plus RBV may be effective. As observed with naïve patients, genotype is crucial for a treatment response. Better results of retreatment are obtained in patients with genotype 2 or 3 and of younger age. In addition, in this subset of patients, higher SVR rates are achieved with increased doses of RBV, without a marked increase in adverse events or dose reductions.

Thus, a high dose schedule of RBV is recommended if retreatment is proposed. Also, prolonging therapy for at least 24 wk more than the previous course enhances SVR rates. Finally, the absence of a cEVR as defined by detectable HCV RNA at week 12 should be considered a stopping rule in the retreatment of relapsers.

COMMENTS

Background
Only 50% of chronic hepatitis C (CHC) patients treated with the combination of pegylated interferon (PEG-IFN)-α and ribavirin (RBV), the standard treatment,will achieve a sustained virological response (SVR). Therefore, patients with no response or relapse after PEG-IFN and RBV treatment are a major issue.  Approximately 30% of CHC patients with undetectable hepatitis C virus (HCV)
RNA at end of therapy (EOT) will experience relapse.

Research frontiers
Retreatment of CHC patients with relapse to antiviral therapy is a current clinical issue. There are no specific recommendations about type, dose and duration of retreatment in this particular situation. In this research area, different dose schedules and duration of PEG-IFN and RBV therapy have been evaluated in order to increase the SVR in patients with a previous relapse to this antiviral therapy.

Innovations and breakthroughs
This study shows in a real life cohort that retreatment of relapsers after prior treatment with a combination of PEG-IFN plus RBV may be effective. Better results of retreatment are obtained in patients with genotype 2 or 3 and of younger age as is observed in naïve patients. Moreover, in this subset of patients,higher SVR rates are achieved with increased doses of RBV (> 15.2 mg/kg per day), without a marked increase in adverse events or dose reductions. Also, lengthening therapy for at least 24 wk more than the previous course enhances SVR rates.

Applications
The study suggests that retreatment of patients with a relapse after treatment with PEG-IFN and RBV may be effective, especially in patients with genotype 2 or 3 who are of younger age. In order to increase SVR in this particular situation,high dose RBV and longer duration of therapy should be proposed.

Terminology
In CHC patients, treatment responses to the combination of PEG-IFN and RBV are defined by a virological parameter (HCV RNA analysis) rather than a clinical endpoint. The most important definitions are: SVR if HCV RNA remains undetectable 24 wk after EOT, non response if HCV RNA is positive at EOT, and relapse if HCV RNA is undetectable at EOT but detectable within 24-wk followup period.

Peer review
The authors revealed that SVR was achieved in 42% of the retreated patients,and that initial dose/weight of RBV was an important predictor of SVR.

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