HIVandHepatitis.com Highlights from the
56th Annual AASLD Conference
 November 11 - 15, 2005 San Francisco, California

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Does Weight-based Ribavirin Dosing Increase Sustained Viral Response in Patients with Chronic Hepatitis C? Final Results of the WIN-R Study

With almost 5,000 participants enrolled, the WIN-R study was the largest hepatitis C trial ever conducted in the US. The large size of the study resulted in a long period of time to complete enrollment at the 225 trial sites and more importantly, contributed to a long delay in finalizing data collection. These issues, in turn, have generated controversy about the trial results, centering primarily on the study’s high drop-out rate (37%).

Here we present a brief summary description of the study and the primary findings. Marina Nunez, MD, will provide a more complete analysis and commentary on the trial in a forthcoming edition of HIV and Hepatitis.com.

The primary objective of the prospective WIN-R trial was to compare the efficacy and safety of ribavirin (RBV) administered as a flat dose 800 mg/day (FD) versus RBV weight-based dosing (WBD) 800-1400 mg/day in combination with PEG IFN alfa-2b (PegIntron) 1.5 ug/kg/week in the treatment of chronic hepatitis C (CHC).

Patients in a community setting with CHC were randomized to PEG IFN alfa-2b 1.5 ug/kg once weekly plus RBV 800 mg/day or RBV based on weight: < 65 kg – 800 mg/day, 65 to <85 kg - 1000mg/day, 85 to < 105 kg - 1200 mg/day, and 105-125 kg - 1400 mg/day.

Treatment was 48 weeks for patients with HCV G1 while patients with genotype (G)2 or 3 were randomized to 24 or 48 weeks. Follow-up for all patients was 24 weeks. HCV RNA was determined by PCR (Taqman/SPRI, sensitivity 29 IU/ml) at weeks 24, 48 and 72.

Dose reduction of RBV was required for hemoglobin (Hgb) < 10 gm/dl and discontinuation of the drug for Hgb <8.5.

Results

225 sites enrolled 4913 patients (2444 FD and 2469 WBD) who received at least one dose of drug, resulting in the largest HCV therapeutic trial to date.

Intent-to-treat analysis showed a significant improvement (p=0.02) in SVR with WBD (44%) compared to FD (41%).

Relapse rate was lower with WBD (15%) vs FD (19%).

48 week therapy did not improve SVR in G2/3 patients;

WBD 24 vs 48 weeks 68% vs 60%, and FD 24 vs 48 weeks, 65% vs 58%, respectively.

Results of per protocol analysis (pts>65kg) are detailed in table 1 below:

                                    Table 1

Serious adverse events were similar (11%) in both arms. Hgb <11 gm/dL occurred in 32% FD patients vs 46% of WBD patients, but were comparable in all four WBD subgroups.

1,808 patients (37%) discontinued therapy (15% AEs, 7% lack of efficacy, 15%

non medical reasons).

Analysis excluding the 30% of patients discontinuing for AEs or non-medical reasons resulted in an SVR of 56% for WBD and 51% for FD (p=0.005).

In conclusion, the study authors state the following:

1. Weight-based dosing of RBV results in significantly greater sustained virological success (SVR) than FD, especially in difficult to treat genotype 1 patients.

2. 24 weeks of treatment is as effective as 48 weeks in patients with HCV-G2 or G3.

3. Weight-based RBV dosing results in higher rates of dose reduction for anemia but not higher rates of discontinuation.

4. 1,400 mg ribavirin appears to be a safe dose for patients >105 kg.

11/18/05

Reference
I M Jacobson and others. Weight-Based Ribavirin Dosing (WBD) Increases Sustained Viral Response (SVR) in Patients with Chronic Hepatitis C (CHC): Final Results of the WIN-R Study, a US Community Based Trial. Abstract LB03. Abstracts of the annual meeting of the American Association for the Study of Liver Diseases (56th AASLD). November 11-15, 2005. San Francisco, CA.

Schering-Plough Announcement on Final Results of the WIN-R Trial

Final results of the WIN-R trial, the largest hepatitis C study conducted in U.S. patients, showed that weight-based REBETOL (ribavirin, USP) in combination therapy with PEG-INTRON (peginterferon alfa-2b) achieved significantly higher rates of sustained virologic response (SVR) and lower rates of relapse compared to the combination therapy using a flat dose of ribavirin. 

The study also showed that, for patients infected with hepatitis C virus (HCV) genotype 2 or 3, a shorter, 24-week course of therapy was as effective as the standard 48-week course, with better tolerability. 

These results from WIN-R (Weight-Based Dosing of PEG-INTRON and REBETOL), a community-based access trial involving more than 4,900 patients at 225 centers across the United States, were reported in an oral presentation at the 56th annual meeting of the American Association for the Study of Liver Diseases (AASLD). 

“These findings help further define optimal therapy for U.S. hepatitis C patients treated in real-world community settings,” said principal investigator Ira M. Jacobson, M.D., Vincent Astor Professor of Clinical Medicine at Weill Medical College of Cornell University and chief of the division of  gastroenterology and hepatology at New York-Presbyterian Hospital/Weill Cornell Medical Center in New York City.

Treating U.S. hepatitis C patients can be especially challenging as they tend to have disease characteristics that are associated with poor response to treatment, including high prevalence of HCV genotype 1, the most difficult type of the virus to treat; high viral load; and advanced liver fibrosis.  Other factors such as age, high body weight and African-American ethnicity also have been shown to be associated with poor response.

“Our findings showed that the weight-based dosed combination therapy significantly increased efficacy compared to the flat-dosed ribavirin regimen, especially in more difficult-to-treat patient groups, such as patients with genotype 1 and African-American patients. 

This confirms what many treating physicians have come to know in their everyday practice and experience,” Jacobson said.  “Importantly, sustained virologic response rates in this community-based U.S. study were consistent with those seen in the U.S. cohorts of the earlier pivotal studies for the two approved peginterferon combination therapies.”

Study Design

In the WIN-R study, 4,913 patients were randomized to receive weight-based PEG-INTRON (1.5 mcg/kg weekly) in combination with REBETOL given either as a flat dose (800 mg daily) or a weight-based dose (800 mg, 1,000 mg, 1,200 mg or 1,400 mg daily for body weights of less than 65 kg, 65 to 85 kg, 86 to 105 kg, or 106 to 125 kg, respectively). 

Patients were treated for 48 weeks (genotype 1) or 24 weeks (genotype 2 or 3).  Patients in the treatment arms were evenly matched for gender, age, body weight, genotype, viral load and stage of liver fibrosis.

Key Results

A challenge with conducting large community-based HCV studies such as WIN-R, as opposed to registration trials with their more intensive monitoring capabilities, is the tendency for a high rate of patients to miss their follow-up HCV RNA (viral load) testing (PCR) visit 24 weeks after treatment ends due to the limited ability of many sites to conduct rigorous monitoring of patients once they have received their final treatment dose. 

In the WIN-R study, 13.1 percent (164/1,256) of patients in the weight-based dose group and 13.7 percent (163/1,193) of patients in the fixed-dose group who were responders at the end of treatment were lost to follow up and subsequently counted as treatment failures under a strict intent-to-treat (ITT) analysis.

Nonetheless, the WIN-R study showed significantly better outcomes for the weight-based combination regimen as compared to the flat-dosed ribavirin regimen, including:

Significantly higher SVR overall (44.3 percent vs. 40.6 percent, p=0.01, ITT) and for patients with genotype 1 (34 percent vs. 29 percent, p=0.004, ITT).  These SVR rates are consistent with those seen in the U.S. cohorts of the earlier pivotal studies for the two approved peginterferon combination therapies.

Using an estimated SVR analysis, based on results for patients who had undetectable virus at the end of treatment and were subsequently lost to follow up, SVR was 53 percent vs. 48 percent (p=0.008), respectively, for the weight-based vs. flat-dosed ribavirin groups.

Consistent SVR rates were seen across all weight groups for patients in the weight-based dosed regimen compared to the flat-dosed ribavirin regimen where SVR rates declined in the higher weight groups, ranging from 52 percent to 34 percent.  Consistent with other U.S. studies, patient weight tended to be high in the WIN-R study, with 45 percent of patients weighing 86 kg (189 lbs) or more. 

For patients with HCV genotype 2 or 3 virus, a 24-week course of the combination therapy was as effective as 48 weeks, with better tolerability.  In the weight-based dose arms, SVR was 68 percent for the 24-week course compared to 60 percent for the 48-week course, with the lower percentage attributable to more missing follow-up data.

Lower rates of relapse were seen for patients receiving the weight-based combination therapy compared to the flat-dosed ribavirin regimen, 15 percent vs. 19 percent overall, and 23 percent vs. 29 percent for patients with HCV genotype 1.  Relapse is defined as patients with undetectable virus levels at the end of treatment who subsequently had detectable virus at 24 weeks post-treatment.

Although there was a higher rate of anemia (hemoglobin < 10 gm/dl) in the weight-based dosing group and more dose reductions (29 percent vs. 23 percent), no difference was seen in the rate of occurrence of serious adverse events between the two groups (12 percent vs. 11 percent) and there were similar rates of discontinuations for adverse events (15 percent vs. 14 percent).  

WIN-R Study

Serving with Dr. Jacobson as co-principal investigator of the WIN-R study is Dr. Robert S. Brown Jr., associate professor of clinical medicine at Columbia University College of Physicians and Surgeons; and chief of clinical hepatology and medical director of the Center of Liver Disease and Transplantation at New York-Presbyterian Hospital/Columbia University Medical Center.  Drs. Jacobson and Brown are also co-directors of New York-Presbyterian Healthcare System’s Liver Clinical Trials Network (LCTN).

Dr. Jacobson also is medical director of the Center for the Study of Hepatitis C, a unique interdisciplinary center established jointly by The Rockefeller University, NewYork-Presbyterian Hospital and Weill Cornell Medical College in New York City.

WIN-R was an investigator-initiated clinical study supported by Schering-Plough Corporation and monitored by Schering-Plough Research Institute as part of a post-marketing commitment to the U.S. Food and Drug Administration (FDA).  PEG-INTRON and REBETOL are registered trademarks of Schering-Plough.