By Liz Highleyman

The Phase 3b IDEAL trial (Individualized Dosing Efficacy Versus Flat Dosing to Assess OptimaL Pegylated Interferon Therapy) compared 3 regimens of pegylated interferon plus ribavirin in patients with hard-to-treat genotype 1 hepatitis C virus (HCV).

The main IDEAL results were presented previously at the 43rd annual meeting of the European Association for the Study of the Liver (EASL) this past April.

At the 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008) this week in San Francisco, researchers presented data from several substudies of the IDEAL patient cohort.

Briefly, the IDEAL trial, sponsored by Schering-Plough, included 3070 previously untreated genotype 1 chronic hepatitis C patients at 118 U.S. sites. A majority (60%) were men, 71% were white, 19% were black, and the mean age was about 48 years. About 80% had a baseline HCV RNA level of 600,000 IU/mL or higher and about 10% had advanced liver fibrosis or cirrhosis.

Participants were randomly assigned to receive 1 of the following regimens for 48 weeks:

• Standard dose (1.5 mcg/kg/week) pegylated interferon alfa-2b (Schering-Plough's PegIntron) + 800-1400 mg/day weight-adjusted ribavirin;

• Low-dose (1.0 mcg/kg/week) PegIntron plus the same dose of ribavirin.

• Standard-dose (180 mcg/week) pegylated interferon alfa-2a (Roche's Pegasys) + 1000-1200 mg/day weight-adjusted ribavirin;

End-of-treatment (EOT) response rates were higher in the Pegasys arm, but relapse was less frequent with PegIntron, so rates of sustained virological response (SVR; continued undetectable HCV RNA 24 weeks after completion of treatment) were similar. Notably, some experts suggested that the study arms were not strictly comparable due to differing ribavirin doses.

Treatment of African-Americans

At the AASLD meeting, J. McCone from the Mount Vernon Endoscopy Center in Alexandria, VA, and colleagues presented data on SVR and predictors of response among African-American participants in the IDEAL trial -- a group that responds more poorly to interferon-based therapy.

IDEAL included 570 African-Americans and 2500 non-black patients. Baseline characteristics of the black participants was similar to those of the study population as a whole, except that African-Americans were slightly older and had a slightly heavier body mass index.

Results

• 48 week end-of-treatment response rates for African-Americans were 32% in the standard-dose PegIntron arm, 21% in the low-dose PegIntron arm, and 45% in the standard-dose Pegasys arm -- significantly lower that the EOT rates of 58%, 55%, and 69%, respectively, for non-black patients.

• Relapse rates, however, were similar regardless of race/ethnicity:

• 25% for blacks vs 23% for non-blacks in the standard-dose PegIntron arm;

• 6% vs 20%, respectively, in the low-dose PegIntron arm;

• 37% vs 31%, respectively, in the Pegasys arm.

• Blacks had a significantly lower SVR rate than whites across all arms:

• 23% vs 44% using standard-dose PegIntron;

• 17% vs 43% using low-dose PegIntron;

• 26% vs 44% using Pegasys.

• Rapid virological response (RVR) at week 4 of treatment and early virological response (EVR) at week 12 predicted SVR in black patients, as it does in non-blacks, though blacks were less likely to achieve early responses.

• Patients in either racial group in all treatment arms who experienced HCV RNA clearance by week 4 had a high likelihood of sustained response (77%-100%).

• Those who did not respond by week 24, however, had a much lower likelihood of achieving SVR (35%-54% across treatment arms).

• Low baseline HCV RNA, fasting glucose < 100 mg/dL, and baseline hemoglobin level were also significant predictors of sustained response.

• Adverse events (AEs) were similar in African-Americans and non-black patients across treatment arms.

• 8% of African-American patients in the standard-dose PegIntron arm, 11% in the low-dose PegIntron arm, and 12% in the Pegasys arm experienced serious AEs.

• 14%, 10%, and 14%, respectively, discontinued therapy due to AEs.

• Blacks did not have significantly higher rates of anemia (hemoglobin <10 g/dL) or neutropenia (white blood cell count < 750/mm3), as suggested by some prior research:

• Anemia rates for African-American patients were 28%, 31%, and 34% in the 3 treatment arms, respectively.

• Neutropenia rates were 21%, 12%, and 31%, respectively.

"Racial difference strongly influences SVR rates," the investigators concluded. "Higher relapse rate was not the primary difference in the lower SVR rates in African-Americans compared with non-African-Americans, rather early response was a more important factor in predicting SVR in each of the three treatment arms."

More on Early Response

Two poster presentations provided further details about early response to interferon-based therapy.

Looking at the full IDEAL study population including all racial/ethnic groups, L. Nyberg from the Southern California Permanente Medical Group in Los Angeles and colleague reported for the first time that data from a large randomized study indicate that very early treatment response at week 2 is "highly predictive of SVR."

Undetectable HCV RNA at week 2 had a positive predictive value (PPV) for SVR of 96% in the standard-dose PegIntron arm, 90% in the low-dose PegIntron arm, and 84% in the Pegasys arm. This compared with PPVs of 89%, 80%, and 75%, respectively, for patients who achieved undetectable HCV RNA at week 4 (RVR); and 76%, 80%, and 70%, respectively, for those with undetectable viral load at week 12 (EVR).

However, the investigators noted, "the numbers of subjects who achieve an undetectable HCV RNA at treatment week 2 is small," at 4%.

Thus, they recommended, "Treatment weeks 4 and 12 remain the mainstay for physicians to make decisions regarding the ability of patients to achieve SVR."

In a related study, M. Sulkowski of Johns Hopkins University and colleagues found that regardless of regimen, "the magnitude of the change in HCV RNA after 4 weeks of treatment was predictive of subsequent SVR" in genotype 1 patients.

Patients who experienced > 3 log10 decline in HCV RNA from baseline had greater than a 61% probability of SVR, whereas those with a decline of < 1 log10 had less than a 5% probability of SVR.

"These data support the definition of 'Treatment Week 4 null response' as achieving less than 1 log10 decrease in HCV RNA from baseline and underscore the importance of monitoring HCV RNA response at Treatment Week 4 to determine an individual patient's probability of SVR," the researchers concluded.

Anemia and Treatment Response

Finally, Sulkowski and colleagues presented another study showing that patients with anemia were more likely to achieve sustained response.

Looking again at the full study population across race/ethnic groups, the researchers compared virological response in 3 subgroups: patients without anemia, patients with anemia who did not receive erythropoietin (EPO, used to stimulate blood cell production), and patients with anemia who did receive EPO.

Results

• 70% of study participants did not develop anemia, while 28% did; women were significantly more likely than men to have anemia.

• 44% of anemic patients received EPO (52%).

• Median nadir (lowest-ever) hemoglobin levels and median maximum declines in hemoglobin were similar in anemic patients who were and were not treated with EPO.

• More than 90% of patients in all 3 groups completed at least 12 weeks of therapy.

• 24-week end-of-treatment response rates were as follows:

• Patients without anemia: 50% in standard-dose PegIntron arm, 48% in low-dose PegIntron arm, 61% in Pegasys arm;

• Patients with anemia not receiving EPO: 61%, 53%, and 67%, respectively;

• Patients with anemia receiving EPO: 70%, 61%, and 78%, respectively.

Relapse rates were as follows:

• Patients without anemia: 26% in standard-dose PegIntron arm, 23% in low-dose PegIntron arm, 32% in Pegasys arm;

• Patients with anemia not receiving EPO: 13%, 12%, and 23%, respectively;

• Patients with anemia receiving EPO: 24%, 14%, and 37%, respectively.

Sustained virological response rates were as follows:

• Patients without anemia: 36% in standard-dose PegIntron arm, 35% in low-dose PegIntron arm, 38% in Pegasys arm;

• Patients with anemia not receiving EPO: 50%, 45%, and 48%, respectively;

• Patients with anemia receiving EPO: 53%, 50%, and 46%, respectively.

Based on these findings, the investigators concluded, "Compared to those with no anemia, anemic patients were less likely to have virologic nonresponse and significantly more likely to achieve SVR despite receiving less ribavirin (mg/kg/d) during treatment."

"Although potential selection bias for comparing the groups may exist, this suggests that other host and treatment factors (e.g., plasma ribavirin concentration) contribute to viral response in this group," they added. "Among anemic patients, EPO use was associated with lower AE-related discontinuation and higher on-treatment viral response, but not a substantially higher SVR rate."

11/07/08

References

J McCone, K Hu, JG McHutchison, and others. Sustained Virologic Response (SVR) and Predictors of Response in African American (AA) Patients in the IDEAL (Individualized Dosing Efficacy Versus Flat Dosing to Assess OptimaL Pegylated Interferon Therapy) Phase 3b Study. 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008. Abstract 268.

LM Nyberg, ML Shiffman, H Bonilla, and others. Predicting the Ability to Achieve a Sustained Virologic Response (SVR) in the First 12 Weeks: Results From the IDEAL Study. 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008. Abstract 1850.

M Sulkowski JM Vierling, KA Brown, and others. Probability of Sustained Virologic Response (SVR) Is Associated With the Magnitude of HCV RNA Reduction at Week 4 of Treatment With Peginterferon (PEG) Plus Ribavirin (RBV): Results of the IDEAL Trial. 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008. Abstract 1868.

M Sulkowski, ML Shiffman, NH Afdhal, and others. Treatment-related anemia but not epoetin use (EPO) is associated with higher SVR rates among persons treated with peginterferon (PEG)/ribavirin (RBV): Results from the IDEAL Study. 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008. Abstract 1851.