Weight-Based HCV Therapy Brings Better Outcomes

NEW YORK, Oct. 2 -- Giving bigger ribavirin doses to heavier hepatitis C patients appears to result in better outcomes, especially for African Americans, researchers here said.
The finding, from a prospective randomized trial of more than 5,000 treatment-naïve patients, supports the idea of so-called true weight-based dosing of ribavirin, in combination with pegylated interferon alfa-2b, according to Ira M. Jacobson, M.D., of Weill Cornell Medical College, and colleagues.
The combination of the two drugs has been used to treat HCV infection since 2001, with ribavirin given at 1,000 mg a day for patients who weigh less than 75 kg and 1,200 for those who weigh 75 kg or more, Dr. Jacobson and colleagues reported in the October issue of Hepatology.
But in this study, patients were randomized to a flat dose of 800 mg/day, regardless of weight, or to one of several doses adjusted for weight -- 800 mg for patients weighing less than 65 kg, 1,000 mg for patients from 65 to 85 kg, 1,200 mg for those from 85 to 105 kg, and 1,400 mg for patients from 105 to 125 kg.
Patients with genotypes G1, G4, G5, and G6 were treated for 48 weeks and followed for another 24. The primary endpoint was sustained virologic response, defined as less than 125 IU per milliliter of serum of HCV viral RNA, at the end of follow-up.
Patients with genotypes G2 and G3 -- regarded as easier to treat than the other types -- were treated for 24 or 48 weeks.
The study showed that patients in the weight based-arm did better, with a sustained virologic response of 44.2% compared to 40.5% for those in the flat-dose arm. The difference was significant at P=0.008.
Sustained virologic response rates by intention-to-treat analysis were 34.0% and 28.9%, respectively, in genotype 1 patients (P<0.005) and 31.2% and 26.7%, respectively, in genotype 1 patients with high baseline viral load (P < 0.056). In genotype 2-3 patients, rates were not significantly different (61.8% and 59.5%, respectively) regardless of treatment duration.
In a post hoc analysis, presented as a separate paper, the researchers analyzed outcomes for the 362 African-American patients in the primary efficacy analysis who had G1 virus, including 188 in the flat-dose arm.
Sustained virologic response was 21% for those getting weight-based dosing, compared with 10% for those in the flat-dose arm - a difference that was significant at P=0.0006.
Relapse rates were also lower -- 22% versus 30% -- in the weight-based arm, the researchers found.
Significant anemia (hemoglobin concentration <10 g/dL) occurred more frequently in the weight-based group (19.3% versus 12.5%). However, only 1% of patients discontinued treatment because of anemia. Mean hemoglobin concentrations were 0.5 g/dL lower throughout treatment in the weight based group than in the fixed dose group, but mean hemoglobin concentration decreases for all ribavirin doses in the weight-based group, including the 1,400-mg dose, were similar.
The issue of treating African Americans is important, the researchers noted, because the prevalence of HCV infection is higher in African Americans than in other ethnic groups, and up to 90% of infected African Americans have genotype G1a or G1b -- both associated with lower response to therapy.
Dr. Jacobson and colleagues noted that even in this study, African Americans had a lower response to treatment, although those in the weight-based arm did better.
Unexpectedly, the researchers said, heavier African Americans in the weight-based arm appeared to do better. The rate of sustained virologic response was 31% for those weighing between 105 and 125 kg, compared with 22% for those between 85 and 015 kg, and 13% for those between 65 and 85 kg.
The researchers said they had no clear explanation for the phenomenon.
The study "adds significantly to our understanding of interferon therapy in African-American patients," commented Steven-Huy Han, M.D., of the University of California Los Angeles and Jason Smith, PharmD, of the Greater Los Angeles Veterans Healthcare Administration Hospital, in an accompanying editorial.
They noted that the findings concerning this "difficult-to-treat population" arise from a secondary evaluation that was not powered for statistical analysis.
Nonetheless, they said, "many of their insights deserve a thoughtful discussion."
On the other hand, they said, the overall study shows that "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."
The study was supported by the Schering-Plough Corp., of Kenilworth, NJ. Among potential conflicts of interest, Dr. Jacobson reports consulting for and/or receiving research support from Schering-Plough, Merck, GlobeImmune, Human Genome Sciences, Coley, Gilead, Vertex, Intermune, Intarcia, Valeant, GlaxoSmithKline, Idenix, Novartis, Bristol-Myers Squibb, Boehringer Ingelheim, and XTL. Nine co-authors also report financial links with Schering-Plough or other pharmaceutical companies, including Roche, Valeant, Bristol-Myers Squibb, Gilead, GlaxoSmithKline, Axcan, Wyeth Gilead, and AstraZeneca. Two of the co-authors, Louis Griffel, M.D., and Clifford Brass, M.D., Ph.D., are employees of Schering-Plough.
Drs. Han and Smith reported no potential conflicts. Primary source: HepatologySource reference: Jacobson IM et al. "Peginterferon alfa-2b and Weight-Based or Flat-Dose Ribavirin in Chronic Hepatitis C Patients: A Randomized Trial." Hepatology 2007; 46:971-81. Additional source: HepatologySource reference: Jacobson IM et al. "Impact of Weight-Based Ribavirin with Peginterferon alfa-2b in African Americans with Hepatitis C Virus Genotype 1." Hepatology 2007;46:982-90. Additional source: HepatologySource reference: Jason Smith and Steven-Huy Han. "'True' Weight-Based Dosing Versus 'Flat' Dosing of Ribavirin: Will the WIN-R Please Come Forward?" Hepatology 2007;46:953-56.