Report from EASL; The European Association for the Study of the Liver Conference, Rotterdam, April 28-May 3, 2000 - Report 6

Monday at EASL, April 27-May 3, Rotterdam

The highlights of the EASL Conference are the following reports on the two pegylated interferons. Pegylation is a process whereby polyethylene glycol (also known as PEG) is attached to the interferon and prevents the interferon from being rapidly eliminated from the body. Normally interferon stays in the body for about 24 hours but with pegylation it stays in the body for 7 days at longer lasting and higher levels. This permits once weekly injections. Currently, the only FDA approved administration of interferon is three times weekly subcutaneous injections. However, it is considered by many that the FDA approved dosing was inadequate because on days in between dosing the hepatitis C virus was left to replicate without any antiviral pressure from drug therapy. So currently, daily dosing of interferon is practiced. As well, dosing with higher levels is also practiced.  The expectation is that increased blood drug levels of pegylated interferon will increase the antiviral activity against HCV. The preliminary data below supports this. Over the course of a week interferon blood levels are kept high.

Pegylated Interferon Alfa-2b (Peg-Intron) Monotherapy and in Combination with Ribivarin

C Trepo reported for the Hepatitis Interventional Therapy Group on this phase III study comparing 3 doses of Schering-Plough's Pegylated-Intron alfa-2b. Following the first study report is a preliminary report comparing Peg Intron+ribavirin to Peg Intron alone. This study compares Pegylated Intron monotherapy to IFNalfa-2b 3 Million Units three times per week. It's a randomized, double-blinded, dose finding efficacy study of 1,200 treatment-naÔve individuals with chronic hepatitis C, elevated ALT and compensated liver disease. Study participants received 1 of 3 doses of Peg IFN alfa-2b: 0.5 ug/kg (n=315) once weekly by subcutaneous injection, 1.0 ug/kg (n=297) once weekly, or 1.5 ug/kg (n=304) once weekly. Or they were randomized to the control arm of IFN alfa-2b 3 MIU three times per week (n=303). Participants received drug for 48 weeks and there was 24 weeks follow-up. A liver biopsy was performed at baseline and after 72 weeks. The primary endpoint was a sustained loss of HCV viral load 24 weeks after treatment stopped.

The age across all 4 treatment groups was about the same at 43 years. There were about the same percent of men in all arms (63%). About 5% in each arm were Black. In the two low dose Peg IFN arms there were 67% genotype 1. In the Peg IFN 1.5 ug/kg arm there were 73% genotype 1 and 72% in the IFN alfa-2b arm. So 26-29% across all 4 arms were genotypes 2/3. Each arm had about 73% with HCV viral load >2 million.

Sustained Virologic Responses (at week 72)

Sustained Response by Genotype & HCV Viral Load

Overall, 49% and 23% at the end of treatment and the end of follow-up, respectively, in the Peg IFN 1.5 ug/kg dose arm had HCV RNA undetectable (<100 copies/ml). In the IFN alfa-2b MIU 3x/wk arm, 24% and 12% had undetectable HCV RNA at the end of treatment and after follow-up. In the Peg IFN 1.0 dose arm 41% and 25% had undetectable, respectively, at the end of treatment and after follow-up. And in the Peg 0.5 dose arm, 33% and 18% had undetectable.

White blood cell, platelets, and neutrophil counts went down during treatment but bounced back to normal after treatment ended. The WBC and the platelets went down a little more in the two high Peg IFN dose arms than the low Peg dose arm and the IFN alfa-2b arm. The difference in the platelets could be 50,000 between the arms. Depression, irritability and other psychiatric related adverse events were the same between arms.

Dose Discontinuation & Reduction

Dose discontinuation was 9%, 11%, and 9% in the three Peg IFN alfa-2b dose arms (0.5, 1.0, and 1.5 ug/kg), and 6% in the IFN alfa-2b 3 MIU 3x/wk arm, although the presenter said there was no real difference between the arms. The discontinuations occurred moreso in the earlier parts of treatment. Discontinuations during weeks 1-24 were 4%, 7%, 6%, and 4% in the 4 arms. While discontinuations were 4%, 4%, 3%, and 2% during weeks 24-48. Dose reduction was more in the Peg arms--9%, 14%, 15%, and 6% in the 4 arms, respectively, but the presenter said this was due in part to more aggressive dose reduction as part of the protocol.

Peg IFN alfa-2b + Ribavirin vs.  Peg IFN alone

This is an open-label, randomized study for 72 IFN naÔve individuals with chronic compensated hepatitis C. This is preliminary data from a dose finding, safety and tolerability study. There are 35 males and 37 females in the study. Ages ranged from 20-68 years and overall 50% were genotype 1. The doses for Peg alfa-2b IFN are 0.35, 0.7 or 1.4 ug/kg subcutaneous injection once weekly taken for 24 weeks alone, or in combination with ribavirin 600, 800, or 1000-1200 mg daily. They looked at the PK of both drugs after weeks 1 and 4 and reported neither drug changed the PK of the other. The adverse events were reported to be typical for IFN treatment, so the addition of ribavirin did not alter the type and severity of side effects. As expected, hemoglobin decreased more in patients treated with Peg IFN alfa-2b + Ribavirin (2-2.5 g/dl) than Peg IFN alfa-2b (1 g/dl). Platelets/neutrophils similar decreases in Peg IFN + RBV and Peg IFN monotherapy arms. 

End Of Treatment and End of Follow-Up Virologic Response

These are only data available so far. In the combination arm of high dose of 1.4 ug/kg Peg IFN+ribavirin, for the end-of-treatment response 81% had undetectable HCV RNA while 50% in the Peg IFN alone arm had undetectable. In the 0.7 Peg IFN dose combination arm 69% vs 63% had undetectable, respectively, and in the low dose 0.35 ug/kg arm 58% in the combination arm and 50% in the Peg IFN alone arm had undetectable.

At the end of follow-up 60% had undetectable in the 1.4 ug/kg combination arm versus 42% in the monotherapy arm. In the 0.7 ug/kg arm 53% vs, 44% had undetectable; and in the 0.35 dose arm 17% and 0% had undetectable.

Pegasys-- PEG Interferon alfa-2a for Chronic Hepatitis C

S Zuezem reported for the Pegasys International Study Group on this phase III study of the safety and efficacy of this once weekly pegylated interferon from Roche. This study compares the efficacy and safety of Peg IFN alfa-2a administered once per week with an induction regimen of standard IFN alfa-2a administered 3 times weekly for 48 weeks. The primary study endpoint is undetectable HCV RNA (<100 copies/ml, Roche PCR assay), and normalized ALTs after a 24 week follow-up period. 531 patients were randomized to either 180 ug Peg IFN alfa-2a once weekly or to an induction regimen of 6 Million Intl. Units of IFN alfa-2a three times weekly for 12 weeks followed by a dose of 3 MIU three times weekly for 36 weeks. A biopsy was performed at baseline and after the 72 week period.

There were 67% men in both arms, average age 41 in both arms, 85% Caucasian in both arms, ALT 98 in Peg arm and 94 in other arm. Total HAI score was 8.6 in Peg arm and 9.0 in other arm. 12% had transition to cirrhosis or cirrhosis in Peg arm and 15% in other arm. Genotype 1 63% and 61% in Peg and other arm, respectively. Genotypes 2/3 also about same in both arms. HCV viral load 7.4 log in Peg arm and 8.2 in other arm.

At the end of follow-up (72 weeks) 45% normalized their ALTs in Peg arm and 25% in other arm. At the end of treatment (48 weeks), 46% and 35% normalized their ALTs in Peg and other arm, respectively (p<0.001). The overall virological response (<100 copies/ml) in the Peg arm was 69% at the end of treatment and 38% at the end of follow-up. For the other arm 28% at the end of treatment and 19% at the end of follow-up had undetectable HCV viral load (p<0.001). 38% in the Peg arm versus 17% in the other arm at the end of follow-up had both normalized ALT and undetectable viral load (p<0.001). In the Peg arm, 63% had histological improvement in their liver at the end of follow-up compared to 55% in the other arm. Histologic improvement was defined as a decrease of at least 2 points in the Knodell Histologic Activity Index.

Sustained Virologic Response (undetectable after 72 week follow-up) Analysis By Genotype

• Genotype 1: 28% in Peg arm; 7% in other arm
• Genotype 2: 64% in Peg arm; 50% in other arm
• Genotype 3: 54% in Peg arm; 32% in other arm

By Baseline Viral Load

• 2 million/copies/ml: 52% undetectable in Peg arm; 25% in other arm
• 2 million/copies/ml: 27% undetectable in Peg arm; 13% in other arm

Rates of Withdrawals and Dose Modifications

Discontinuation for any adverse event or lab abnormality was 7% in the Peg arm and 10% in the induction arm. Dose modification for adverse event (AE) or lab abnormality was 18% in both arms, for AE 8% and 12%, respectively, and 14% for lab abnormality in Peg arm and 9% in induction arm--mostly due to neutropenia (decreased neutrophils)- it was 11% in Peg arm and 7% in other arm. The side effect profile was similar for both arms except in a few instances where the higher side effect rate occurred in the induction arm.