Monday, January 24, 2011

U.S. Multicenter Pilot Study of Daily Consensus Interferon (CIFN) Plus Ribavirin for “Difficult-to-Treat” HCV Genotype 1 Patients

Digestive Diseases and Sciences
© The Author(s) 2011
Original Article

U.S. Multicenter Pilot Study of Daily Consensus Interferon (CIFN) Plus Ribavirin for “Difficult-to-Treat” HCV Genotype 1 Patients

Samuel B. Ho1, 2 , Bashar Aqel3, Eric Dieperink4, Shanglei Liu1, Lori Tetrick4, Yngve Falck-Ytter5, Charles DeComarmond6, Coleman I. Smith7, Daniel P. McKee8, William Boyd9, Clark C. Kulig10, Edmund J. Bini11 and Marcos C. Pedrosa12

Received: 9 February 2010 Accepted: 17 November 2010 Published online: 11 January 2011


Patients with chronic hepatitis C genotype 1 (HCV-1) and difficult-to-treat characteristics respond poorly to pegylated interferon alfa and ribavirin (RBV), and could benefit from an interferon with increased activity (consensus interferon or CIFN), favorable viral kinetics from daily dosing, and a longer duration of therapy. The purpose of this pilot study was to determine the efficacy and safety of daily CIFN + RBV for initial treatment of patients with HCV-1 infection.

Patients with difficult-to-treat characteristics (92% male, 33% African American, 78% Veterans Affairs [VA]; 67% high viral load, 59% stage 3–4 fibrosis, and mean weight of 204 lbs) were enrolled at seven VA and two community medical centers. They were randomized to daily CIFN (15 mcg/day SQ) and RBV (1–1.2 g/d PO) given for either 52 weeks (group A, n = 33) or 52–72 weeks (from time of viral response +48 weeks) (group B, n = 31).

Intention to treat analysis for treatment groups A and B demonstrated 33% (11/33) and 32% (10/31) sustained virologic response (SVR), respectively. Only 2/31 patients in group B received more than 52 weeks of treatment. The overall group demonstrated a 31% (20/64) rapid virologic response rate (RVR), 54% (34/64) end of treatment virologic response and a 33% (21/64) SVR. Patients with RVR at 4 weeks, early virologic response from 8–12 weeks, and late virologic response from 16–24 weeks demonstrated SVR of 75% (15/20), 31% (4/13), and 22% (2/9), respectively. Overall early non-protocol discontinuation occurred in 26/64 (40%) patients.

Daily CIFN and ribavirin for initial treatment of HCV-1 patients has potential for achieving a relatively high RVR rate, but discontinuations are frequent and successful use of this regimen is highly dependent on adequate patient support to maintain adherence.
Keywords Consensus interferon – Hepatitis C – Ribavirin – Veterans Affairs

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Discussion Only/See Full Data

The purpose of this study was to determine the efficacy and safety of a regimen of daily CIFN and ribavirin in HCV genotype 1 patients with “difficult to treat” characteristics. This multicenter study enrolled patients that were 94% male and 33% African American, with 80% of patients at VA medical centers. In addition, the majority of these patients had advanced fibrosis and a high viral load. On an intention to treat basis we found that 31% achieved a rapid virologic response and an overall 33% SVR rate. This trial failed to test the difference between 52 weeks of treatment vs. variable treatment duration of 52–72 weeks, due to the fact that so few patients required or were able to comply with therapy beyond 52 weeks of treatment. Overall, we observed frequent early discontinuation of therapy due to noncompliance or side effects; however, there was a wide variation in patient compliance between sites. Patients that adhered with at least 80% of the prescribed dose of CIFN and ribavirin for 80% of the prescribed duration to 52 weeks achieved an 85% SVR rate.

Prior clinical studies of CIFN and ribavirin have indicated mixed results. Pockros et al. reported 40 treatment naïve patients in community/academic practices, 50–55% genotype 1, who received either CIFN 9 μg/day with ribavirin 1,000–1,200 mg/d or CIFN 9 μg/d alone [21]. They found that 65% of patients who received CIFN and ribavirin required dose reductions, with an overall 35% discontinuation rate. The overall SVR rate in patients receiving CIFN and ribavirin was 40%. On the other hand, several clinical studies reported greater antiviral responses with CIFN in patients with genotype 1 hepatitis C infection, particularly if given as a daily injection. Recent data indicate that 15 μg CIFN given three times a week with ribavirin has an equivalent SVR rate to pegylated interferon alfa-2a and ribavirin in patients with HCV genotype 1 [16].

Preliminary data have also indicated that up to 39–47% HCV genotype 1 patients who do not respond to interferon alfa-2b + ribavirin may respond to daily induction dosing of CIFN (18 or 27 μg/d for 4 weeks followed by 9 or 18 μg/d for 8 weeks, then 9 μg/d for 36 weeks) with the addition of ribavirin and have a sustained virologic response [14]. Furthermore, Kaiser et al. [15] have shown that daily high dose induction dosing of CIFN with ribavirin therapy results in sustained response rates in about one quarter of previous pegylated interferon and ribavirin non-responders. Kaiser et al. have also published preliminary data treating treatment-naive genotype 1 patients in Germany with daily high doses CIFN and ribavirin for 48 weeks. They found that 59–67% of genotype 1 patients experienced a sustained virologic response [14]. Leevy et al. [17] recently reported that U.S. patient nonresponders to pegylated interferon and ribavirin who receive daily CIFN (15 μg) and ribavirin can achieve a 37% sustained virologic response rate. Bacon et al. [18] in the multicenter DIRECT trial treated patients who were prior pegylated interferon and ribavirin nonresponders with CIFN (9 or 15 μg/d) and ribavirin and found an overall 6.9–10.7% SVR rate. In two relapse studies, CIFN was compared to pegylated interferon showing greater efficacy at either 15 or 9 μg/d (69% vs. 42% and 47% vs. 29%, respectively) [22, 23].

However, to date there have been no published direct comparisons of daily CIFN and ribavirin with pegylated interferon and ribavirin for HCV treatment naïve or nonresponder patients. Given the mixed results, our data emphasizes the difficulties in tolerance of this regimen, and adequate patient support is essential and may explain the differences reported between centers.

The overall 33% SVR rate obtained in the genotype 1 patients in this study compares favorably with the few prior reports of the efficacy of pegylated interferon and ribavirin for male predominant VA patients with HCV genotype 1. Backus et al. [9] reported an overall 20% SVR rate for HCV genotype 1 patients who received pegylated interferon and ribavirin in the national VA HCV registry database. Single VA centers have reported SVR rates of 15–33% in smaller numbers of patients [24–26].

Patients treated with daily CIFN and ribavirin demonstrated a 31% rapid virologic response rate, defined as a HCV PCR test below the limit of detection on a quantitative PCR assay at 4 weeks. One limitation of this study was the use of a quantitative PCR test during weeks 4–20, with lower limits of detection from 100 to 600 IU ml−1. In addition, the methods used for HCV PCR tests varied from site to site. Therefore the data presented may overestimate the true viral negative rate because of the sites using an assay with a lower limit of detection of 600 IU ml−1. If we limited the analysis to sites that used a quantitative assay with a lower limit of detection of 50 IU ml−1 we observe that 12/51 (23.5%) patients were HCV PCR negative at week 4 and therefore have a rapid virologic response.

This can be compared with another U.S. trial of genotype 1 treatment naïve patients treated with either pegylated interferon alfa-2a or alfa-2b and ribavirin, which demonstrated a 11.4–11.9% rapid virologic response rate [7]. In contrast, recent European trials examining the relevance of extended therapy based on virologic response in patients with HCV genotype 1 treated with pegylated interferon alfa and ribavirin used HCV PCR assays with a lower limit of detection of 50 IU ml−1 to determine virologic response at 4 weeks [19, 20]. These studies found that 19–22% of these patients had a rapid virologic response. In addition, it remains unknown how CIFN will be used in the upcoming era of targeted therapy, but treatment strategies associated with a high initial RVR may be important when considering the addition of more specific antivirals in order to reduce the chance of viral mutations and for determination of duration of therapy [27].

Patients in this trial were observed to have a relative high early discontinuation rate of 40% within the first 24 weeks and a 50% overall discontinuation rate due to adverse events and noncompliance. This is only somewhat higher than previous early discontinuation rates published for comparable male predominant VA type patient populations. For example, Brau et al. [28] reported a 30.5% discontinuation rate for adverse events during treatment in a 785 patient VA cohort treated with standard interferon alfa and ribavirin.

Backus et al. [9] reported that 62% of patients received less than the targeted full treatment duration in a retrospective analysis of 5,944 patients in the VA Clinical Case Registry for hepatitis C treated with pegylated interferon and ribavirin. Note that this includes patients that were discontinued for any reason, including lack of efficacy in addition to presumed adverse events, and the number of patients that discontinued within the first 24 weeks of treatment was not reported. In contrast, studies from registration trials of pegylated interferon and ribavirin reported discontinuation rates for adverse events of 14.0–22% [4, 5, 29].

In addition, Bacon et al. [18] reported a 21% discontinuation rate due to adverse events in the DIRECT registration trial patients treated with daily CIFN and ribavirin using dosing similar to the present study. Note that this trial included only patients with previous treatment experience, who were nonresponders to prior treatment with pegylated interferon and ribavirin and motivated to receive repeat treatment.

These data indicate that treatment discontinuation reflects the patient population in addition to the type of regimen used. Furthermore, we observed that compliance with treatment and discontinuation rates correlated with study site, which may be another explanation for the relatively overall high discontinuation rate observed in this study.

These data emphasize the importance of supportive care for continuing patients on daily CIFN and ribavirin treatment. Overall we found that daily CIFN and ribavirin was safe in these patients, with only 2 (3.1%) serious adverse events reported, which is comparable with the rate of serious adverse events in a recent U.S. trial of pegylated interferon alfa-2a and alfa-2b with ribavirin [7].

In conclusion, daily CIFN and ribavirin for initial treatment of HCV-1 patients with a high incidence of difficult-to-treat characteristics results has potential for achieving a relatively high rapid virologic response rate, but discontinuations are frequent and successful use of this regimen is highly dependent on adequate patient support to maintain adherence.

Acknowledgments The authors would like to acknowledge the assistance of Dr. Anastasios A. Mihas of the Hunter Holmes McGuire VA Medical Center, Richmond, VA, USA, and the Research Service of the VA San Diego Healthcare System.

Authors' declaration of personal interests
Samuel B. Ho, MD, has served as a speaker for Three Rivers Pharmaceuticals, and has received research funding from Three Rivers Pharmaceuticals, Valeant Pharmaceuticals International, and Human Genome Systems. Bashar Aqel, Eric Dieperink, Shanglei Liu and Lori Tetrick have no disclosures. Yngve Falck-Ytter: Research support and speaker’s honorarium from Roche Pharmaceuticals. Coleman Smith: Research support and speaker’s honorarium from Bristol-Myers Squibb, Novartis Pharmaceuticals, Schering-Plough Corporation, Gilead, and Roche Pharmaceuticals. Edmund J. Bini: Research support and speaker’s from Bristol-Myers Squibb, Pharmasset, Schering-Plough Corporation, Gilead, Roche Pharmaceuticals, Valeant, Vertex. Marcos C. Pedrosa: Research support and speaker’s honorarium from Schering-Plough Corporation.

Declaration of funding interests
This study was funded by Three Rivers Pharmaceuticals and Valeant Pharmaceuticals International and supported by the Veterans Affairs Research Service.

Open Access
This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.

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