• Safety and adverse events reveals no surprises.
• New adherence analysis shows adherence to dosing is very important for those with genotype 1

Safety and Adverse Events

Information about drug safety (adverse events), discontinuations and adherence was presented by John G. McHutchison, MD of Scripps Institute in La Jolla, California. All of the safety information that was presented was limited to those patients in arms 2 and 3 whose baseline body weights led to ribavirin concentrations that were greater than 10.6 mg per kilogram. Overall adverse events and discontinuation rates were not reported. In general, within that limitation, adverse events were somewhat similar with a "comparable safety profile," discontinuations were similar, yet dose modifications were more frequent among patients randomized to peginterferon 1.5 µg/kg. No new adverse events were reported.

For those patients in an upper concentration range of ribavirin (greater than 10.6 mg/kg), adverse events that occurred with a rate that was at least 10% higher in the peginterferon 1.5 µg/kg arm (PEG) than in the standard interferon arm (IFN) were as follows: fever (46% in PEG versus 33% in IFN); nausea (43% PEG vs. 33% IFN); weight loss (30% vs. 20%); hair loss (45% vs. 32%); weakness (asthenia, 28% vs. 18%); and skin reaction at injection site (58% vs. 36%). Other adverse events that occurred in at least 10% of both treatment arms included: malaise, fatigue, headache, chills, "flu"-like symptoms, sweating, loss of appetite, diarrhea, vomiting, muscle-bone pains, joint aches, muscle aches (myalgias), anxiety, concentration ("thinking") problems, depression, insomnia (difficulty sleeping), irritability, coughing, shortness of breath, itchy skin, rash, and dry skin.

Again, only for patients in an upper ribavirin concentration range, study discontinuation due to adverse events occurred among 14% of PEG patients and 12% of IFN patients. The total discontinuation rates due to any reasons were not presented. Anemia (decrease of hemoglobin to less than 10 grams per deciliter) occurred among 14% of those taking PEG 1.5, compared to 12% of those taking IFN. However, a dose reduction due to anemia took place among the opposite percentages: 12% of those taking PEG, compared to 14% of those taking IFN. Yet, discontinuation due to anemia occurred only among 2% of PEG patients and 0.2% of IFN patients. Neutropenia (low white cell count) led to a dose reduction in 21% of PEG patients, but in only 8% of IFN patients. Discontinuation due to neutropenia occurred in identical percentages as discontinuation due to anemia (2% in PEG, 0.2% in IFN). ALT (liver enzyme) increase to twice baseline levels and to at least 10 times the upper normal limit occurred in only 2 patients each in the PEG and IFN arms. Serious psychiatric events were similar in the 2 treatment arms: suicide (none); suicide attempts (one patient in PEG 1.5 arm, none in IFN arm); and suicidal ideation (suicide thoughts, 6 patients in PEG 1.5 arm versus 7 in IFN arm). Discontinuation due to psychiatric events occurred among 6% of PEG 1.5 patients and 4% of IFN patients. The overall modification rate of drug dosing (among patients in an upper ribavirin range) was 49% among PEG patients and 34% among IFN patients.

Phase III Results of Peginterferon Alfa 2b Plus Ribavirin versus Standard Interferon Alfa 2b Plus Ribavirin

# SVR = sustained virologic response (undetectable HCV RNA) 6 months after the 12 month treatment duration (see text);
## See text for exact drug dosing; the duration of therapy in all 3 treatment arms was 48 weeks;
* ITT= "intent-to-treat" analysis (anal), including all patients enrolled;
"As-treated" analysis (anal) excludes those patients who discontinued and who do not meet the specified criteria;
** 80% adherence defined as taking at least 80% of prescribed peginterferon + 80% of prescribed ribavirin, both for at least 80% of the treatment duration;
*** Upper ribavirin concentration (conc.) = greater than 10.6 mg per kilogram; lower concentration = less than 10.6 mg/kg;
µg/kg = micrograms per kilogram;
Kilograms (kg) ÷ 0.454 = weight in pounds; 65 kg = 143 pounds; 85 kg = 187 pounds;
> = Greater than
< = Less than

Adherence to Dosing is Important for Genotype 1

There were a series of new "as-treated" analyses that further evaluated results based upon adherence to dosing of medications. These were retrospective (after-the-fact) analyses that attempted to determine whether specific subsets of patients had higher SVR rates than other patients, based upon adherence. These results do not include patient discontinuations.

The as-treated analysis presented by Dr. McHutchison included only those patients who took at least 80% of the prescribed doses of peginterferon, at least 80% of the prescribed doses of ribavirin, and both drugs for at least 80% of the prescribed duration. In the entire study with 1,530 patients, 63% was adherent using the "80/80/80" criteria. When examining only the patients in arm 2 (PEG 1.5), men were significantly more likely to meet the "80/80/80" criteria (67%) than women who were significantly more likely not to meet those criteria (53%). (Note "non-adherence" here may include prescribed dose reductions.) Only 14% of those patients in arm 2 (PEG 1.5) with a baseline body weight less than 65 kg (143 pounds) met the 80/80/80 adherence criteria, while 26% of those in the same weight category were non-adherent by specified criteria*; however that difference was not statistically significant. Other baseline information was not significantly different when comparing those who were and were not adherent to at least 80% of drug dosing (age, race-ethnicity, duration of HCV infection, HCV genotype, HCV RNA, and ALT (liver enzyme).

As would be expected, the overall SVR rate was higher among patients who adhered to the "80/80/80" criteria, except for patients in arm 2 (PEG 1.5) with genotypes 2 or 3, for whom there were no significant differences when comparing adherent to specified, partially non-adherent* patients. For patients with all genotypes in arm 2 (PEG 1.5), those who were adherent 80% of the time had a significantly higher SVR rate of 63% ("as-treated" analysis), compared to partially, non-adherent patients (52%, as-treated analysis, p=0.04) and the 54% rate in the ITT ("intent-to-treat") analysis (see table). When considering only genotype 1 patients in arm 2, "80% adherent" patients had a significantly higher SVR rate of 51% (as-treated), compared to 34% of partially, non-adherent patients (as-treated, p=0.011) and the 42% rate in the ITT analysis (see table). When considering only patients with genotypes 2 or 3 in arm 2, "80% adherent" patients had a similar SVR rate of 90% (as-treated) as partially, non-adherent patients (89%, as-treated, p=not significant), compared to 82% in the ITT analysis (see table).

When considering patients with all genotypes from arm 2 who had an upper ribavirin concentration (greater than 10.6 mg/kg), "80% adherent" patients trended towards a significantly higher SVR rate of 72% (as-treated), compared to 57% of partially, non-adherent patients (as treated, p=0.065), with an overall 61% SVR rate without taking into account adherence (see table). Lastly, when considering only genotype 1 patients from arm 2 with an upper ribavirin concentration, patients who were "80% adherent" had a significantly higher SVR rate (63%, as treated) than partially, non-adherent patients (34%, as treated, p=0.008), with an overall rate of 48% (as-treated) without taking adherence into account (see table).

* Partially, non-adherent patients were defined as those who took less than 80% of peginterferon alfa-2b and/or less than 80% of ribavirin and/or for at least 80% of the expected treatment duration, while excluding early discontinuations.

The conclusions from the adherence portion of the presentation were as follows: (1) adherence, when defined as taking at least 80% of the prescribed doses of peginterferon (1.5 µg/kg) plus ribavirin for at least 80% of the time, was somewhat higher among men than women that may, in part though not statistically significant, have been due to baseline differences in body weight; (2) that approximately 2/3 of patients were able to be adherent to at least 80% of dosing of peginterferon (1.5 µg/kg) plus ribavirin; (3) a major effect of adherence is an increased SVR among patients with HCV genotype 1; and (4) "every effort should be made to continue the maximum tolerable doses of therapy for the duration of treatment."

During Oral Session 8 of the EASL meeting itself, Dr. Manns presented an overview of the phase III results that included much of the information presented by Dr. McHutchison at the satellite symposium. However, he also included the "relapse" rates for patients in arms 2 and 3, but only for those who had upper ribavirin concentrations (greater than 10.6 mg/kg). Relapse refers to those who achieve an "end-of-treatment" response (undetectable viral load after 12 months of therapy), but who then have viral rebound that is detected 6 months later and therefore do not have a SVR (sustained virologic response). For patients in arm 2 (PEG 1.5) with an upper ribavirin concentration, the relapse rates were 12% (all genotypes), 17% (genotype 1), 7% (genotypes 2, 3), and zero (genotypes 4, 5, 6). For patients in arm 3 (IFN), the relapse rates were 14% (all genotypes), 21% (genotype 1), 6% (genotypes 2, 3), and zero (genotypes 4, 5, 6).

Dr. Manns concluded that when combined with peginterferon alfa-2b at a dose of 1.5 mg/kg once weekly, daily ribavirin dosing should be based upon body weight (although the phase III results did not document that such an approach actually leads to a higher SVR). The daily ribavirin doses he recommended was: 800 mg for those with a body weight less than 65 kg (143 pounds); 1,000 mg for those with a body weight between 65-85 kg (between 143-187 pounds); and 1,200 mg for those with a body weight greater than 85 kg (187 pounds).

Recommended Ribavirin Dosing by Body Weight *

References
Manns MP and others. Pegylated interferon alpha-2b (PEG IFN) plus ribavirin for treatment of chronic hepatitis C: optimization of ribavirin dose. Abstract and oral presentation 794 (added to Oral Session 8) at the 36th Annual Meeting of the European Association for the Study of the Liver (EASL 2001); April 18-22, 2001, Prague, Czech Republic

Manns MP. Phase III results: optimizing virologic response rates with weight adjusted peginterferon alfa-2b plus ribavirin therapy (24 week follow-up). Oral presentation at "Optimizing Response Rates with Weight Adjusted Combination Peginterferon Alfa-2b and Ribavirin Therapy," satellite symposium at the 36th Annual Meeting of the European Association for the Study of the Liver (EASL 2001); April 18-22, 2001, Prague, Czech Republic

Manns MP and others. Peginterferon alfa-2b plus ribavirin compared to interferon alfa-2b plus ribavirin for the treatment of chronic hepatitis C: 24-week treatment analysis of a multicenter, multinational, phase III, randomized, controlled trial. Oral presentation (Presidential Plenary Session II) and abstract 552 at the 51st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD), October 27-31, 2000; Dallas, Texas. Hepatology 2000;32:297A.

McHutchison JG. Safety profile and impact of adherence on sustained virologic response rates with peginterferon alfa-2b plus ribavirin therapy. Oral presentation at "Optimizing Response Rates with Weight Adjusted Combination Peginterferon Alfa-2b and Ribavirin Therapy," satellite symposium at the 36th Annual Meeting of the European Association for the Study of the Liver (EASL 2001); April 18-22, 2001, Prague, Czech Republic