• New baseline liver biopsy information
• Treatment results, including ribavirin concentration analysis

Michael P. Manns, MD of the Medical School in Hanover, Germany presented an update of the phase III results of pegylated interferon alfa 2b (PegIntron) plus ribavirin at a satellite symposium sponsored by Schering-Plough. Much information about this study previously had been presented by Dr. Manns at last year's 51st AASLD November 2000 meeting in Dallas. Attaching polyethylene glycol to standard interferon-alfa prolongs the half-life leading to inhibition of elimination of interferon from the body and thus dosing that is only once weekly.

The purpose of the study was to compare the efficacy of 2 different doses of pegylated interferon alfa 2b plus ribavirin to non-pegylated (standard) interferon alfa 2b (Intron A) plus ribavirin (together as Rebetron) for the treatment of chronic hepatitis C. A total of 1,530 treatment-naïve (no previous therapy) patients were included in the randomized, open-label, "active control parallel" study. Criteria for inclusion were: positive HCV RNA in blood plasma (no cells), increased ALT (alanine aminotransferase, liver enzyme) and compensated (stable) liver disease. The 3 study arms also were stratified by HCV genotype and by the presence or absence of cirrhosis on liver biopsy.

The 3 treatment arms were:

Arm 1: peginterferon alfa 2b, 1.5 micrograms per kilogram (mg/kg) injected once weekly for 4 weeks, then 0.5 mg/kg once weekly for 44 weeks, plus oral ribavirin 1,000-1,200 mg once daily (1,000 mg if 75 kg or less [165 pounds or less] or 1,200 mg if greater than 75 kg or 165 pounds);

Arm 2: peginterferon alfa 2b, 1.5 mµg/kg injected once weekly for 48 weeks plus oral ribavirin 800 mg once daily; or

Arm 3: interferon alfa 2b (Intron A), 3 MIU (million international units) injected 3-times weekly for 48 weeks plus daily, oral ribavirin 1,000-1,200 mg (1,000 mg if 75 kg or less [165 pounds or less] or 1,200 mg if greater than 75 kg or 165 pounds).

The baseline characteristics were: mean age 43-44 years; 67% male (arms 1 and 2) and 63% male (arm 3); 88-91% Caucasian; mean weight 82 kilograms (181 pounds); HCV genotype 1 (most difficult to treat) 68%; genotypes 2 or 3: 29-30%; genotypes 4, 5, or 6: 2-3%; baseline HCV RNA greater than 2 million copies per milliliter: 67-69%; and baseline liver biopsy with "bridging fibrosis or cirrhosis: ("Knodell" fibrosis score F3 or F4) 40-44%. (Manns presented this data on his slides in oral presentation at EASL. However, in the Schering Peg-Intron Product Monograph distributed at EASL, they reported Knodell IV score (liver histology as determined by the local pathologist) combined F3/F4 as 28%-30%).

The results were as follows. Using a strict "intent-to-treat" analysis (all patients included), for all genotypes, the sustained virologic response (SVR, undetectable viral load with lower limit of 100 copies/mL using NGI test) 6 months after the end of treatment was: 47% (arms 1 and 3) and 54% (arm 2). The difference between arms 2 and 3 was statistically significant (p=0.01). For genotype 1 patients, the SVR was 34% (arm 1); 42% (arm 2); and 33% (arm 3), also statistically significant (p=0.02). For genotypes 2 and 3, the SVR was 80% (arm 1); 82% (arm 2); and 79% (arm 3), a non-significant difference.

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

(Editorial note from Jules Levin: bear in mind the 47% SVR reported for arm 3 which is the standard interferon + 1000 or 1200 mg ribivarin regimen. In the US & Intl studies of standard IFN +RBV, patients received 1000-1200 mg of RBV. In the US study, conducted at 44 sites in the US, the SVR was 38%6 months after 48 weeks of combination therapy. In the Intl study, conducted at 43 sites outside of the US, the SVR was 43% 6 months after 48 weeks of combination treatment. Data suggests response rates are better in Europe than in US.Perhaps importantly, these figures of 38% and 43% can be compared to the 47% SVR seen in this Peg Intron study for patients in arm 3 receiving standard IFN +1000-1200 mg RBV. As Iíve previously reported, itís been suggested that the improved 47% SVR (compared to the 38% & 43%) were because of improved patient management redflected by more dose adjustments and less discontinuations due to adverse events in this Peg Intron study than in the two US & Intl IFN studies).

When stratified by body weight, there was a significant positive relationship (using statistical "logistic regression analysis" with all patients, independent of other factors) between SVR and either peginterferon concentration dosing or ribavirin concentration dosing in both arms of peginterferon. Specifically, for arms 1 and 2 (peginterferon), a higher SVR rate was significantly associated with increasing ribavirin concentrations in mg per kilogram (p= 0.013) and increasing peginterferon concentrations in µg per kilogram (p=0.001). This was further demonstrated when stratified into 3 categories of body weight: less than 65 kg (143 pounds), 65-85 kg (143-187 pounds), and greater than 85 kilograms (187 pounds). For both arms 2 and 3, there was a decreased SVR with increasing body weight. Specifically, for arm 2, the SVR by body weight (including all genotypes) was 62% (less than 65 kg); 55% (65-85 kg); and 49% (greater than 85 kg). For arm 1 patients, this trend did not occur, with SVR rates of 47% (<65 kg); 49% (65-85 kg); and 46% (>85 kg). For arm 3 (standard interferon), the trend emerged again, with SVR rates of 57% (<65 kg); 48% (65-85 kg); and 41% (>85 mg).

As was presented at last year's AASLD meeting, Dr. Manns reviewed that, based upon the above analyses and safety data (see below), the optimal dosing of ribavirin is at least 10.6 mg per kilogram. This approximately equals 800 mg (exactly 795 mg) for an average person who weighs 75 kg or 165 pounds.

When considering a break point of 10.6 mg/kg of ribavirin, a significantly higher SVR rate occurred among those patients with a concentration greater than that in arm 2 (61%) than those with a concentration less than that (50%), including all genotypes (p=0.02). The same trend existed for those in arm 3 (standard interferon), with 47% of those with a concentration greater than that having a SVR, compared to only 27% of those with a concentration less than that (p=0.02). With lower overall SVR rates, a similar trend emerged for those with genotype 1: among those with a concentration greater than the break point in arm 2, the SVR was 48%, versus 38% for those with a concentration less than that (significance not reported). And similarly for genotype 1 patients randomized to arm 3 (standard interferon), those with a ribavirin concentration greater than the break point had a higher SVR rate (34%) than those with a ribavirin concentration less than the break point (20%). The trend of a higher SVR rate by ribavirin concentration greater than break point also emerged for those with genotypes 2 or 3, with SVR rates of 88% (greater than break point) and 79% (less than break-point) in arm 2 and of 80% (greater than break point) and 50% (less than break point) in arm 3.

Other ribavirin break point analyses were presented by baseline liver "Knodell" fibrosis scores. For both arms 2 and 3, lower baseline fibrosis scores were associated higher SVR rates, a trend that has occurred in previous studies. For patients in arm 2, those with a higher ribavirin concentration (greater than break point) and a baseline fibrosis score of F0 (no fibrosis) or F1 ("portal expansion") had a SVR rate of 61%, compared to those with a baseline score of F3 ("bridging fibrosis") or F4 (cirrhosis) who had a SVR rate of 55% (significance not reported). For patients in arm 3, those with a higher ribavirin concentration and a baseline fibrosis score of F0-F1 had a SVR rate of 50%, compared to those with a baseline score of F3-F4, who had a SVR rate o 43%. SVR rates in arms 2 and 3 for those with a lower ribavirin concentration (stratified by baseline fibrosis scores) were not reported.

Dr. Manns concluded that the dosing in arm 2 (1.5 µg/kg once weekly dosing of peginterferon alfa 2b plus ribavirin 800 mg once daily) was significantly more effective in achieving a sustained virologic response (SVR) than the doses in either arms 1 or 3. Also, those whose baseline body weight led to a higher ribavirin concentration (greater than 10.6 mg/kg) achieved a higher SVR rate in arms 2 and 3, particularly for those with genotype 1. Lastly, Dr. Manns concluded, "Weight adjusted dosing of ribavirin with peginterferon alfa 2b will be confirmed in prospective studies."

This reviewer found the term "weight adjusted" for ribavirin in the 1.5 µg/kg dosing arm (arm 2) to be somewhat misleading, since no patient in that arm had their ribavirin dose adjusted: all received 800 mg. The only ribavirin dose adjusting was in arms 1 and 3, with 1,000 mg once daily for those weighing 75 kg or less or 1,200 mg for those weighing more than that, as per the FDA-approved product information (package insert). Whether "adjusting the ribavirin dose" based upon body weight (with 1.5 µg/kg peginterferon dosing) will increase the SVR rate has yet to be shown and was not shown in the current study. It is possible that those with higher baseline body weights in arms 2 and 3 had lower SVR rates due to factors other than ribavirin concentration, e.g., increased "steatosis" (fat) in the liver or increased "insulin resistance" (diabetes or pre-diabetes).

(Editorial note from Jules Levin: studies have shown data that people with lower body weight tend to respond better to HCV therapy. So, is the better response seen in this study due to lower body weight or receiving more ribivarin concentration based on mgís per kg because weight was lower. As Dr Bartnof mentions just above all patients in arm 2 receiving Peg IFN 1.5 ug/kg received the same dose of RBV (800 mg per day). Dr Manns said weight adjusted dosing of RBV will be confirmed in prospective studies).

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.