Weight-Based Dosing of Ribavirin and Pegylated Interferon Is Useful for Hepatitis C

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Weight-Based Dosing of Ribavirin and Pegylated Interferon Is Useful for Hepatitis C CME

News Author: Laurie Barclay, MDCME Author: Laurie Barclay, MD

October 5, 2007 — Weight-based dosing (WBD) of ribavirin in combination with pegylated interferon (PEG-IFN) is better than standard flat dosing (FD) for treating chronic hepatitis C (HCV), particularly in African-American patients with HCV genotype 1, according to 2 reports from the Weight-Based Dosing of Peginterferon alfa-2b and Ribavirin (WIN-R) trial published in the October issue of Hepatology.

"With pegylated interferon (PEG-IFN) and ribavirin (RBV) therapy, more than 50% of patients with compensated liver disease from hepatitis C virus (HCV) infection attain sustained virologic response (SVR)," write Ira M. son, from the Medical College of Cornell University in New York, and colleagues from the WIN-R Study Group. "Several factors influence treatment response, including baseline viral load and HCV genotype; optimizing drug dosing and treatment duration is essential to maximizing response."

This prospective, open-label efficacy and safety trial took place at 236 US community and academic sites. Treatment-naive adult patients with chronic HCV and compensated liver disease (n = 5027) were randomized to receive PEG-IFN alfa-2b at 1.5 µg/kg/week plus FD (800 mg/day) or WBD (800 - 1400 µg/day) ribavirin for 48 weeks (patients with genotype 1, 4, 5, or 6) and for 24 or 48 weeks (patients with genotype 2 or 3). WBD ribavirin was 800 mg/day for weight less than 65 kg, 1000 mg/day for 65 to 85 kg, 1200 mg/day for more than 85 to 105 kg, or 1400 mg/day for more than 105 to less than 125 kg.

The main outcome measure was SVR, defined as undetectable (< 125 IU/mL) serum HCV RNA at 24-week follow-up in patients weighing more than 65 kg.

Compared with FD ribavirin, WBD ribavirin was associated with significantly higher SVR, but not end-of-treatment, rates (44.2% vs 40.5%; P = .008). Intent-to-treat analysis revealed SVR rates of 34.0% and 28.9%, respectively, in patients with genotype 1 (P = .005) and 31.2% and 26.7%, respectively, in patients with genotype 1 with a high baseline viral load (P = .056). Regardless of treatment duration, rates were not significantly different between groups of patients with genotypes 2 and 3 (61.8% and 59.5%, respectively).

Reductions in hemoglobin levels were greater with WBD ribavirin, but safety profiles were otherwise similar across ribavirin dosing groups, including the 1400-mg/day group.

"PEG-IFN alfa-2b plus weight-based RBV is more effective than flat-dose RBV, particularly in genotype 1 patients, providing equivalent efficacy across all weight groups," the study authors write. "RBV 1400 mg/day is appropriate for patients 105 to 125 kg. For genotype 2/3 patients, 24 weeks of treatment with flat-dose RBV is adequate; no evidence of additional benefit of extending treatment to 48 weeks was demonstrated."

Limitations of the study include inability to determine whether therapy duration could be shortened to less than 24 weeks based on viral clearance by week 4; inability to draw definitive conclusions about duration of therapy in selected subgroups of patients with genotypes 2 and 3, such as patients with advanced fibrosis or those with slow therapeutic response; restriction to US patients; and loss of patients to follow-up.

"The WIN-R trial shows both the power and the limitations of investigator-initiated trials to evaluate therapeutic issues for which very large populations are necessary," the study authors conclude. "This trial confirmed that WBD RBV is superior to FD RBV for patients with HCV G1 [genotype 1]; established the efficacy and safety of a new dosage of 1400 mg/day for patients who weigh >105 kg; demonstrated equivalent rates of SVR across a spectrum of body weights with WBD dosing of RBV and PEG-IFN alfa-2b; and showed, in a larger study population than hitherto reported, equivalent SVR rates between 24 and 48 weeks of treatment for patients with HCV G2 and G3."

Schering-Plough Corp. supported this study and employs 2 of its authors. Some of the other authors have disclosed various financial relationships with Schering-Plough, Merck, GlobeImmune, Human Genome Sciences, Coley, Gilead, Vertex, Intermune, Intarcia, Valeant, GlaxoKline, Idenix, Novartis, Bristol-Myers Squibb, Boehringer Ingelheim, XTL, and Roche.

"Given the disproportionate prevalence of [chronic hepatitis C] in African American individuals and the lower rates of response to IFN-based therapy, it is important to evaluate ways of maximizing treatment response to HCV therapy," Dr. son and colleagues from the WIN-R Study Group write in the second report. "Tailoring therapy according to body weight may accomplish this, particularly in light of the finding that the prevalence of obesity is higher in African American persons, particularly women, than in other ethnic groups. The WIN-R study enrolled more than 400 African American patients, constituting the largest database available on treatment of African American individuals with HCV infection."

This subanalysis evaluated the efficacy of WBD among previously untreated African-American patients with genotype 1 infection who were enrolled in the WIN-R trial.

In the primary efficacy analysis, 188 of 362 African-American patients received ribavirin FD and 174 received WBD. Compared with the FD group, the WBD group had higher SVR rates (21% vs 10%; P = .0006) and lower relapse rates (22% vs 30%). Safety profiles and rates of drug discontinuation were similar in both groups.

"Weight-based dosing of RBV is more effective than flat dosing in combination with PEG-IFN alfa-2b in African American individuals with HCV genotype 1," the study authors write. "Even with weight-based dosing, response rates in African American individuals are lower than reported in other ethnic groups."

Limitations of the second study include a subanalysis that was not powered for statistical significance, high patient dropout rates and missing patient data, absence of rigorous compliance monitoring, lack of details concerning use of growth factor, difficulty extrapolating these findings to other relatively treatment-resistant populations, and incomplete data regarding use of erythropoietin.

"When combined with PEG-IFN alfa-2b, WBD RBV offers a significant advantage in efficacy, with acceptable tolerability, over FD of RBV in the treatment of African American patients infected with HCV G1," the study authors conclude. "However, even with WBD RBV, the rate of SVR in African American individuals is low. Studies designed to explain this phenomenon have been conducted, but further studies are needed to elucidate the fundamental basis for the impaired responsiveness in this population."

In an accompanying editorial, , PharmD, and -Huy B. Han, MD, AGAF, from the Greater Los Angeles Veterans Healthcare Administration Hospital and Geffen School of Medicine at the University of California Los Angeles, call these results "compelling" but recommend a large, prospective, randomized controlled trial.

"At least the traditional notion that ribavirin dosage should be fixed has now been sidelined by the idea that we should tailor ribavirin dosing to our patients," Drs. and Han write. "Despite our lack of confidence in secondary analysis, important information can be derived from this African American substudy and future studies that are inspired by this trial. The WIN-R subanalysis of African American patients may not have the power to detect its statistical goal, but it does have the power to change the way we think about ribavirin dosing in African Americans, who will benefit from the awareness derived herein and its translation into more vigilant care of this difficult-to-treat population."

Hepatology. 2007;46:953-956, 971-981, 982-990.

Clinical Context

More than half of patients with compensated liver disease from HCV infection achieve SVR with PEG-IFN and ribavirin therapy. Factors affecting treatment response include baseline viral load, HCV genotype, and optimal drug dosing and treatment duration.

The WIN-R trial tested the hypothesis that WBD of ribavirin is more effective than FD. This trial also enrolled a sufficiently large sample of African Americans to perform a subanalysis in this population, which has been underrepresented in pivotal trials of IFN-based therapies but which has an impaired response to HCV therapy.

Study Highlights

PEG-INF alfa-2b and WBD vs FD Ribavirin

WIN-R was a prospective, open-label efficacy and safety trial conducted at 236 US community and academic sites with treatment-naive adult patients with chronic HCV and compensated liver disease, 18 to 70 years of age, body weight less than 125 kg, with detectable serum HCV RNA determined by polymerase chain reaction or branched DNA assay (n = 5027). Patients were randomized to receive PEG-IFN alfa-2b at 1.5 µg/kg/week plus FD (800 mg/day) or WBD (800 - 1400 µg/day) ribavirin for 48 weeks (patients with genotype 1, 4, 5, or 6) and for 24 or 48 weeks (patients with genotype 2 or 3). WBD ribavirin was 800 mg/day for patients weighing less than 65 kg, 1000 mg/day for those weighing 65 to 85 kg, 1200 mg/day for those weighing more than 85 to 105 kg, or 1400 mg/day for those weighing more than 105 to less than 125 kg. Main outcome measure was SVR, defined as undetectable (< 125 IU/mL) serum HCV RNA at 24-week follow-up in patients weighing more than 65 kg. Compared with FD ribavirin, WBD ribavirin was linked with significantly higher SVR, but not end-of-treatment, rates (44.2% vs 40.5%; P = .008). Intent-to-treat analysis revealed SVR rates of 34.0% and 28.9%, respectively, in patients with genotype 1 (P = .005) and 31.2% and 26.7%, respectively, in patients with genotype 1 with a high baseline viral load (P = .056). Regardless of treatment duration, rates were not significantly different between groups of patients with genotype 2 or 3 (61.8% and 59.5%, respectively). Reductions in hemoglobin were greater with the WBD ribavirin group, but safety profiles were otherwise similar across ribavirin dosing groups. Discontinuation for adverse events occurred in 14.7% of patients. Rates of discontinuation and serious adverse events were equivalent in the WBD and FD groups. Psychiatric disorders were the most frequently reported serious adverse events (2.9%). Treatment compliance was more than 80% of expected duration for about two thirds of the patients in the trial. The study authors concluded that PEG-IFN alfa-2b plus WBD ribavirin was more effective than FD ribavirin, particularly in patients with genotype 1, and that WBD yielded equivalent efficacy across all weight groups. For patients with genotypes 2 and 3, 24 weeks of therapy with FD ribavirin was sufficient, with no evidence of additional benefit of extending treatment to 48 weeks.

Subanalysis of PEG-INF alfa-2b and WBD Ribavirin in African-American Patients

The second WIN-R trial enrolled more than 400 African-American patients, allowing a subanalysis of the efficacy of FD vs WBD ribavirin in previously untreated African Americans with HCV genotype 1 infection. In the primary efficacy analysis, 188 of 362 African-American patients received FD ribavirin and 174 received WBD ribavirin. Compared with the FD ribavirin group, the WBD ribavirin group had higher SVR rates (21% vs 10%; P = .0006) and lower relapse rates (22% vs 30%). Safety profiles and rates of drug discontinuation were similar in both groups. The study authors concluded that WBD ribavirin was more effective than FD ribavirin in combination with PEG-IFN alfa-2b in African Americans with HCV genotype 1. Even with WBD ribavirin, however, response rates in African Americans were lower than those reported in other ethnic groups. An unexpected finding was the increase in efficacy with increase in ribavirin dose in heavier patients, particularly in the 1400-mg dosing group.

Pearls for Practice

Compared with FD ribavirin in combination with PEG-IFN alfa-2b for treatment of chronic HCV, WBD ribavirin in combination with PEG-IFN alfa-2b was associated with significantly higher SVR rates overall, as well as in patients with genotype 1. In a subanalysis of African-American patients with HCV genotype 1, the WBD ribavirin group had higher SVR rates and lower relapse rates. Even with WBD ribavirin, however, response rates in African Americans were lower than those reported in other ethnic groups. Safety profiles and rates of drug discontinuation were similar in both groups.

1.

Based on the first WIN-R trial, which of the following statements is not correct regarding FD ribavirin vs WBD ribavirin in combination with PEG-IFN alfa-2b for treatment of chronic HCV in the overall study population? (Required for credit)

SVR rates were significantly higher overall with WBD ribavirin vs FD ribavirin

In patients with genotype 2 or 3, 48 weeks of therapy with FD ribavirin offered greater benefit than 24 weeks

SVR rates in patients with genotype 1 were significantly higher with WBD ribavirin vs FD ribavirin

Hemoglobin reductions were greater with WBD ribavirin vs FD ribavirin, but safety profiles were otherwise similar across ribavirin dosing groups

2.

Based on the subanalysis of African-American patients with HCV genotype 1 in the WIN-R trial, which of the following statements is correct? (Required for credit)

The WBD ribavirin group did not have higher SVR rates than the FD ribavirin group

The WBD ribavirin group did not have lower relapse rates than the FD ribavirin group

Safety profile was less favorable with WBD ribavirin vs FD ribavirin

Even with WBD ribavirin, response rates in African Americans were lower than those reported in other ethnic groups

http://www.medscape.com/viewarticle/563799