Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

58th Annual Meeting of the American Association for the Study of Liver Diseases

Boston, Massachusetts / November 2-6, 2007

Hepatitis C virus (HCV) is estimated to infect a total of 300,000 Canadians. While roughly 50% of patients do not respond to therapy, Dr. Saya Victor Feinman, Professor of Medicine (Gastroenterology), University of Toronto, Ontario, mentioned that 10% to 20% of those develop cirrhosis of the liver, while 1% to 4% develop hepatocellular carcinoma. “Hepatitis C is the leading indication for liver transplant in North America and probably globally,” stated Dr. Paul Marotta, Medical Director, Liver Transplantation, London Health Sciences Centre, and Associate Professor of Medicine, University of Western Ontario. Dr. Marotta told delegates that he anticipates a sharp rise in the number of cases over the next 10 to 15 years.

POWeR Study: Efficacy in Community Settings

Findings from two major international clinical trials of pegylated interferon alfa-2b in combination with ribavirin (PEG-IFN alfa-2b/RBV) have demonstrated sustained virologic response (SVR) rates of 54% and 56% (Manns et al. Lancet 2001;358:958-65, Fried et al. N Engl J Med 2002;347:975-82). The primary goal of the more recent POWeR (Pegetron Prospective Optimal Weight-Based Dosing Response) study was to determine whether such results could be obtained in the general patient population in community settings, explained Dr. Marotta. To that end, it was an open-label, prospective, observational, non-interventional outcomes study conducted in centres across Canada among treatment-naive patients with chronic hepatitis C.

Patients infected with genotypes 2 and 3 (G2 and G3) were treated for 24 weeks and those with G1 for 48 weeks, according to standard care in Canada. Overall, 1977 patients initiated treatment but 177 of these were excluded due to co-infection with HIV, undetectable HCV RNA at treatment end but lack of six-month follow-up, or lack of treatment data. Patients who stopped treatment due to non-response, side effects or personal reasons were included in the per-protocol population of 1800.

The study succeeded in demonstrating efficacy in community settings. The end-of-treatment (EOT) response rates, SVR and relapse rates were 61.7%, 54.3%, and 11.9%, respectively. The overall SVR was virtually identical to that seen in Manns et al., as was the subgroup SVR for patients infected with G1 HCV at 42%. The SVRs for G2 and G3 were 72% and 79% for POWeR and 82% for the Manns trial. The excellent relapse rate in POWeR was consistent with that seen in the registration trial (Figure 1).

“It’s good to know that in real life, you can reproduce the Manns trial results because they exclude everyone who has any reason not to respond to treatment,” noted POWeR co-investigator Dr. Frank Anderson, Liver and Intestinal Research Centre, and Associate Professor Emeritus, University of British Columbia, Vancouver.

“Our low-volume treaters can feel their outcomes will be as good [as the Manns trial],” remarked Dr. Marotta.” That encourages the low-volume treaters not to wait too long to treat. The earlier they treat, the better for the patient.”

Earlier Treatment Is Better

The primary driver in the data behind the need for early treatment came from the patients who had had liver biopsy. “As fibrosis and cirrhosis become more advanced, the overall sustained response rates gradually decrease,” noted Dr. Marotta. Overall SVR rates for patients with fibrosis scores ranging from F1 (mild) through F4 (cirrhosis) inclusively were 66%, 56%, 40% and 29%, respectively (P<0.001).

Similarly, low baseline viral load had a positive impact on outcomes. Overall, SVR was 56.5% in patients with low baseline viral load (<600,000 IU/mL) compared to 49.6% in their high-viral load counterparts (P=0.009). Baseline viral load was not found to be a predictor of relapse.

Figure 1. POWeR Relapse Rates

Consistent Response Across All Weight Categories

Results from the study suggest that weight-based dosing of both PEG-IFN alfa-2b and RBV improved outcomes. In the Manns study, among those patients who received a flat dose of 800 mg/day RBV with PEG-IFN alfa-2b, there was an inverse relationship between response and patient weight. In the POWeR study, SVR rates did not differ significantly across weight categories, either overall or within each genotype, noted Dr. Feinman.

In this, POWeR results confirm those from the recently published US-based WIN-R study. In WIN-R, the overall SVR was 44.2% in patients on weight-based RBV vs. 40.5% in those taking flat-dose RBV (P=0.008); the overall SVR from POWeR was 54.3%. Dr. Marotta did stress that the WIN-R results for patients on weight-based RBV might have suffered relative to POWeR. He attributed this development to the fact that Canada has very strong nursing support, which is critical for helping patients remain on treatment despite frequent highly unpleasant side effects; and because African Americans, who form a much greater percentage of the US population, do not respond as well to therapy as Caucasians. The limiting factors in setting the RBV dose are potential damage to the kidney and causing anemia, noted Dr. Feinman.

Dr. Marotta emphasized that with weight-based dosing of both treatment components, “weight has no bearing on the overall response rate.”

Genotypes 2 and 3: Two Solitudes?

The study also allowed a much closer look than has previously been possible at the differences in the way G2 and G3 patients respond to treatment. “In many of the earlier studies, [G3] was lumped in with G2 in an easier-to-treat category, in contrast with the notoriously difficult G1,” explained Dr. Robert Bailey, Clinical Professor of Medicine, University of Alberta, Edmonton, at his poster session. The ample number of patients in POWeR, 276 with G2 and 389 with G3, enabled his team to sort out important differences between the two. For example, a high baseline viral load (>600,000 IU/mL) portended negative results in G3 (and G1) but not in G2. “G2 patients respond well regardless of baseline; G3 patients with poor prognostic factors don’t respond so well,” Dr. Bailey stated.

Similarly, response rates of G2 patients “do not vary according to fibrosis,” indicated Dr. Marotta. “It doesn’t matter if they are cirrhotic—they still enjoy a very good response rate.” But for G3s, “fibrosis matters, much like in G1 patients. G3 patients are a subgroup that don’t do as well as the G2s.”

“New treatment strategies, such as increased dose or duration, are needed for G3 cirrhotic patients,” said Dr. Bailey. “Future studies should avoid combining [G2 and G3].”

New Questions Arise

One counter-intuitive result of the POWeR study was that among cirrhotic patients (F3-F4, n=378), the rate of SVR was higher in heavier patients, reported Dr. Feinman, rising from 29% in patients 50 kg to 64 kg to 37% in patients weighing 75 kg or more. He added that French studies have shown similar results. Dr. Marotta noted that G3 patients have a reduction in SVR compared to G2 patients for similar fibrosis scores (and worse as fibrosis worsens) and for high viral load or fibrosis.

Summary

Physicians should treat hepatitis C as early as possible in order to have the best chance of success. Results from POWeR demonstrate that dosing both PEG-IFN alfa-2b and RBV according to individual patients’ weight provides consistency of response across all weight categories. The low relapse rate in a “real-life” heterogeneous patient population provides clinically useful information on the durability of treatment with individual dosing of both drug components. Finally, the study revealed important differences between G2 and G3 patients, indicating that future clinical trials should investigate these groups separately.