By Brian Boyle, MD

Now that the FDA has approved the use of combination therapy with pegylated interferon (IFN) and ribavirin (RBV) for the treatment of hepatitis C virus (HCV) infection, that is rapidly becoming the standard of care. Still, some patients cannot tolerate RBV or have contraindications to its use. Several studies have found that pegylated IFN is superior to standard IFN in the treatment of HCV, but few have evaluated the safety and efficacy of the weight-based dosing of PEG-Intron (peginterferon alfa-2b).

A study recently published in Hepatology evaluated whether varying doses of PEG-Intron (0.5 mg/kg, 1.0 mg/kg, or 1.5 mg/kg) were safe and effective relative to Intron A (IFN-alfa 2b, 3 million units thrice weekly) in adult patients with clinically compensated HCV who had never been treated with IFN. The study was multicenter, randomized, and double-blind. It enrolled 1,219 patients, 943 (77%) of whom completed the study. All of the enrolled patients had active liver disease based upon liver biopsies and ALT levels. The majority of the patients had HCV RNA levels >2 million copies/mL (74%) and were infected with HCV genotype 1 (70%). The enrolled patients were randomized to receive one of three doses of PEG-Intron or Intron A; however, a higher proportion of subjects with HCV genotype 1 were randomized to the 1.5 mg/kg PEG-Intron dose (73%) than the other treatment arms (67%). All patients were treated for a total of 48 weeks and then followed for an additional 24 weeks.

The end-of-treatment response virologic response (ETVR) was superior in the PEG-Intron treated patients and was dose related. Of the patients that received Intron A or 0.5 mg/kg, 1.0 mg/kg, or 1.5 mg/kg of PEG-Intron, 24%, 33%, 41%, and 49% had an ETVR and all 3 of the PEG-Intron arms were superior to the Intron A (p=.01). Further, the higher ETVR seen in the 1.5 mg/kg PEG-Intron group relative to the 1.0 mg/kg PEG-Intron group was the result of a significantly higher response rate in HCV genotype 1 infected patients, 39% versus 25% (p=.002).

The Intron A arm also had significantly lower sustained virologic response (SVR) rates than the three PEG-Intron treatment arms, with 12%, 18%, 25% and 23%, respectively, achieving an SVR. Unlike the ETVR, however, the 1.0 and 1.5 mg/kg PEG-Intron groups had equivalent SVR rates and this was related to a higher relapse rate in the patients with genotype 1, with a 46% versus 66% relapse rate, respectively (p=.025).

The combined end-of-treatment virologic and biochemical response was significantly higher in the 1.0 and 1.5 mg/kg PEG-Intron groups when compared with the Intron A group, with response rates of 31%, 33% and 20%, respectively. (p<.01) The combined sustained virologic and biochemical response also was significantly higher in the 1.0 and 1.5 mg/kg PEG-Intron groups when compared with the Intron A group, with sustained response rates of 24%, 23% and 12%, respectively. (p<.001). Liver histologic changes were similar between the 4 arms, but were highly correlated with SVR.

In this study, predictors of SVR included an HCV genotype other than 1, HCV RNA not greater than 2 million copies/mL and an early virologic response. The likelihood of SVR was highest in patients with a negative HCV RNA at 4 weeks with 77-86% achieving an SVR, and decreased thereafter, with a 32-52% and 13-20% SVR rate among patients whose first negative HCV RNA occurred at week 12 or week 24, respectively.

The 4 arms of the study appeared equally safe and well tolerated, but PEG-Intron was associated with twice as many injection site reactions as the Intron A and the higher doses of PEG-Intron were associated with a higher rate of fever and chills.

8/15/01

Reference
K Lindsay and others. A Randomized, Double-Blind Trial Comparing Pegylated Interferon Alfa-2b to Interferon Alfa-2b as Initial Treatment for Chronic Hepatitis C. Hepatology. 2001;34:395-403.

Pegylated Interferon Superior to Standard Interferon (Again) in the Treatment of Hepatitis C

By Brian Boyle, MD
Now that the FDA has approved the use of combination therapy with pegylated interferon (IFN) and ribavirin (RBV) for the treatment of hepatitis C virus (HCV) infection, that is rapidly becoming the standard of care. Still, some patients cannot tolerate RBV or have contraindications to its use. Several studies have found that pegylated IFN is superior to standard IFN in the treatment of HCV, but few have evaluated the safety and efficacy of the weight-based dosing of PEG-Intron (peginterferon alfa-2b).

A study recently published in Hepatology evaluated whether varying doses of PEG-Intron (0.5 mg/kg, 1.0 mg/kg, or 1.5 mg/kg) were safe and effective relative to Intron A (IFN-alfa 2b, 3 million units thrice weekly) in adult patients with clinically compensated HCV who had never been treated with IFN. The study was multicenter, randomized, and double-blind. It enrolled 1,219 patients, 943 (77%) of whom completed the study. All of the enrolled patients had active liver disease based upon liver biopsies and ALT levels. The majority of the patients had HCV RNA levels >2 million copies/mL (74%) and were infected with HCV genotype 1 (70%). The enrolled patients were randomized to receive one of three doses of PEG-Intron or Intron A; however, a higher proportion of subjects with HCV genotype 1 were randomized to the 1.5 mg/kg PEG-Intron dose (73%) than the other treatment arms (67%). All patients were treated for a total of 48 weeks and then followed for an additional 24 weeks.

The end-of-treatment response virologic response (ETVR) was superior in the PEG-Intron treated patients and was dose related. Of the patients that received Intron A or 0.5 mg/kg, 1.0 mg/kg, or 1.5 mg/kg of PEG-Intron, 24%, 33%, 41%, and 49% had an ETVR and all 3 of the PEG-Intron arms were superior to the Intron A (p=.01). Further, the higher ETVR seen in the 1.5 mg/kg PEG-Intron group relative to the 1.0 mg/kg PEG-Intron group was the result of a significantly higher response rate in HCV genotype 1 infected patients, 39% versus 25% (p=.002).

The Intron A arm also had significantly lower sustained virologic response (SVR) rates than the three PEG-Intron treatment arms, with 12%, 18%, 25% and 23%, respectively, achieving an SVR. Unlike the ETVR, however, the 1.0 and 1.5 mg/kg PEG-Intron groups had equivalent SVR rates and this was related to a higher relapse rate in the patients with genotype 1, with a 46% versus 66% relapse rate, respectively (p=.025).

The combined end-of-treatment virologic and biochemical response was significantly higher in the 1.0 and 1.5 mg/kg PEG-Intron groups when compared with the Intron A group, with response rates of 31%, 33% and 20%, respectively. (p<.01) The combined sustained virologic and biochemical response also was significantly higher in the 1.0 and 1.5 mg/kg PEG-Intron groups when compared with the Intron A group, with sustained response rates of 24%, 23% and 12%, respectively. (p<.001). Liver histologic changes were similar between the 4 arms, but were highly correlated with SVR.

In this study, predictors of SVR included an HCV genotype other than 1, HCV RNA not greater than 2 million copies/mL and an early virologic response. The likelihood of SVR was highest in patients with a negative HCV RNA at 4 weeks with 77-86% achieving an SVR, and decreased thereafter, with a 32-52% and 13-20% SVR rate among patients whose first negative HCV RNA occurred at week 12 or week 24, respectively.

The 4 arms of the study appeared equally safe and well tolerated, but PEG-Intron was associated with twice as many injection site reactions as the Intron A and the higher doses of PEG-Intron were associated with a higher rate of fever and chills.

8/15/01

Reference
K Lindsay and others. A Randomized, Double-Blind Trial Comparing Pegylated Interferon Alfa-2b to Interferon Alfa-2b as Initial Treatment for Chronic Hepatitis C. Hepatology. 2001;34:395-403.