Pegylated Intron a-2b + Ribivarin: 72 Weeks

Michael Mans from the Dept of GI & Hepatology at Hannover Medical School in Hannover Germany reported 72 weeks data comparing regular interferon a-2b + ribivarin to Pegylated Intron (Schering Plough brand as opposed to Pegasys the Roche brand) + ribivarin. The study objective was to evaluate the safety & efficacy of two regimens of Peg interferon a-2b + Ribivarin compared with a standard regimen of Interferon a-2b + Ribivarin.

The trial enrolled 1530 treatment-naÔve chronic HCV patients with elevated ALT and compensated liver disease. The primary endpoint was sustained loss of serum HCV-RNA at the end of 24 weeks follow-up after 48 weeks treatment (National Genetics Institute LLQ 100 copie/ml). The study was randomized and open label with an active control parallel group. Stratification was by genotype and cirrhosis.

Two interesting findings came from this study. The standard interferon+ribivarin arm had a sustained virologic response rate of 47% whlie previous studies showed a response rate of about 40%. Schering noted that investigators have improved management of patients on IFN+RBV which is reflected by the lower discontinuation rate compared to previous study and the higher dose modification rates. Such an improvement however would be reflected in all arms including the Peg arms. Another key finding reported by this study is that ribivarin should be dosed by weight and that using 800 mg per day should only be for individuals with lower weight of about 75 kg, which is the equivalent of about 160 lbs. The data suggests that higher doses of RBV may be more effective even in a person weighing less. Of course, this could increase potential anemia particularly in HIV-infected persons. This finding could spell an end to the notion that RBV could be dosed at 600 mg per day. A third point was that the SVR was about the same for genotype 2/3 for standard IFN+RBV as it was for Peg Intron + RBV.

The three study arms were:

• Peg IFN a-2b (1.5 ug/kg once weekly for 4 weeks)
  + Ribivarin 1000-1200 mg/daily and 0.5 Peg IFN ug/kg for the next 44 weeks;
  Peg IFN was administered by subcutaneous injection once per week
  (n=514)
  
  

• Peg IFN a-2b
  + Ribivarin 800 mg/daily
  (1.5 ug/kg once weekly for 48 weeks)
  (n=511)
  
  

• IFN a-2b
  + Ribivarin 1000-1200 mg/daily
  (IFN 3 MIU 3 times per week subcutaneous injections)
  (n=505)

There was 24 weeks follow-up after the end of treatment at week 48. Biopsies were performed 6 months before treatment and 6 months after treatment but they have not been evaluated yet.

DEMOGRAPHICS

• Mean age was about the same in each treatment group- about 43 years (range was 22-67 years).

• There were about 67% men in each treatment group

• About 90% caucasians were in each group

• The mean weight was about 82 kg in each group (range 43-163 IFN, 38-181 Peg 0.5, 43-159 Peg 1.5)

GENOTYPES

• Geno 1- about 68% in all 3 groups

• Geno - 2/3 - about 30% in each group

• Geno 4/5/6 - 2-3% in each group

 VIRAL LOAD

•  >2 million - 67-69% in each group

 CIRRHOSIS

• 10% in each group and it was determined by local pathologist.

 RESULTS

        Sustained Virologic Response

        Optimized Weight Based Dosing (>10.6 mg/kg/daily Ribivarin*)

        *10.6 mg/kg/daily Ribivarin is about 800 mg/daily for patient weighing 75 kg.

According to a logistic regression analysis Manns reported that 10.6 mg/kg /daily is the optimal dosing. For those receiving <10.6 mg/kg daily in the 3 arms the SVR rates were 27% IFN 3 MU, 41% Peg 0.5, and 50% Peg 1.5. Therefore, Schering recommended the optimum Ribivarin dosing with Peg IFN a-2b 1.5 ug/kg:

• <65 kg in weight ribivarin dose should be 800 mg/day

•   65-85 kg  =  1000 mg/day

• >85 kg       =  1200 mg/day

ADVERSE EFFECTS:
        Hematology

        Neutropenia

DISCONTINUATIONS and DOSE MODIFICATIONS

WARNING ABOUT PREGNANCY from Schering

IFN+RBV must not be used by women, or male partners of women who are or may become pregnant during therapy and during the 6 months after stopping therapy. Women of childbearing potential and men must use effective contraception (two reliable forms) during treatment and during the 6 month post-treatment follow-up period. Significant teratogenic and/or embriocidal effects have been demonstrated for ribivarin in all animal species in which adequate studies have been conducted. These effects occurred at doses as low as 1/20^th of the recommended human dose of RBV. If pregnancy occurs in a patient or partner of a patient during treatment or during the 6 months after treatment stops, physicians are encouraged to report such cases by calling 800 727-7064.