By Liz Highleyman

The large HALT-C study evaluating low-dose pegylated interferon monotherapy in chronic hepatitis C patients who were non-responders to prior standard therapy failed to find a benefit of long-term treatment after 3.5 years, according to a report the December 4, 2008 issue of The New England Journal of Medicine.

But 2 presentations at the recent 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008) suggest that long-term pegylated interferon maintenance therapy may offer benefits for selected patients.

HALT-C Sub-analysis

Chihiro Morishima and colleagues conducted a different analysis of data from HALT-C. Briefly, the trial included 1050 U.S. patients with advanced liver disease who did not respond to standard therapy with 180 mcg/week pegylated interferon alfa-2a (Pegasys) plus ribavirin, and were subsequently randomized to receive either low-dose (90 mcg/week) pegylated interferon monotherapy for 3.5 years, or else no further treatment.

In the study as a whole, though interferon maintenance did not affect overall liver fibrosis progression or clinical outcomes, ALT levels and hepatic necroinflammatory histological activity index scores were significantly reduced in treated patients.

In the present sub-analysis, the investigators evaluated the relationship between reduction in hepatic inflammation and decline in HCV RNA levels, and their impact on fibrosis progression and clinical outcomes, in 657 patients (328 in the interferon maintenance arm, 329 in the untreated control arm). Patients were categorized according to their degree of HCV suppression during lead-in treatment with full-dose pegylated interferon plus ribavirin.

• Histological activity index scores improved significantly from baseline to the 1.5 year biopsy in all subgroups:

• Pegylated interferon monotherapy arm:

- < 2 log HCV RNA reduction during lead-in: 26%;
- 2-4 log reduction during lead-in: 37%;
- 4 log reduction during lead-in: 65%.

• No further treatment arm:

- < 2 log HCV RNA reduction during lead-in: 17%;
- 2-4 log reduction during lead-in: 15%;
- 4 log reduction during lead-in: 41%.

• The percentage of patients with improved histological activity index scores was significantly higher in the maintenance arm, even after controlling for lead-in virological response.

• Patients who had improved inflammation at 1.5 years were more likely to have stable or improved (as opposed to worsened) fibrosis at this time point.

• Decreased liver inflammation at 1.5 years was associated with decreased mean ALT levels and fewer adverse clinical outcomes (death, hepatic decompensation, hepatocellular carcinoma, or increase in fibrosis score of 2 or more points).

Based on these findings the researchers concluded, "Patients with maximal virological response to [pegylated interferon] and ribavirin treatment may experience improvement in hepatic inflammation and decreased frequency of outcomes."

They added that patients who achieved a > 4 log decrease or undetectable HCV RNA at week 20 of lead-in combination therapy experienced the most improvement in fibrosis, even if they ultimately failed to achieve sustained virological response.

German Maintenance Study

Stephan Kaiser and colleagues from Germany also conducted a maintenance monotherapy study, but they used low-dose pegylated interferon alfa-2b (PegIntron), and participants could be prior non-responders to conventional or pegylated interferon, with or without ribavirin (the HALT-C population were all non-responders to pegylated interferon plus ribavirin, the current standard of care). About half had undergone more than 1 previous treatment attempt.

The study included 213 patients with significant fibrosis or cirrhosis (Ishak score 3-6) who were randomly assigned to receive 0.5 mcg/kg/week pegylated interferon monotherapy for 36 months or no further treatment.

Histological evaluation was done at baseline, 18 months, and 6 months after the end of treatment. At this point, 89 patients demonstrated a > 2 log decline in Ishak score and were offered continued maintenance therapy for an additional 3 years (67 accepted).

Results

• After the first 36 months, Ishak scores fell by 1.51 in the pegylated interferon maintenance arm, but rose by 0.87 in the untreated arm.

• After the full 72 months, Ishak scores fell by a 2.38 in the maintenance arm, while rising by 0.41 in the untreated arm.

• Overall rates of adverse events and serious adverse events were similar in the maintenance therapy and untreated arms.

• Symptoms of hepatic decompensation were slightly less frequent in the maintenance arm, but the difference did not reach statistical significance.

• 2 patients in the maintenance arm developed hepatocellular carcinoma, compared with 6 in the untreated arm.

• Long-term pegylated interferon monotherapy was generally well tolerated, with no severe neutropenia.

• About 20% of patients either discontinued therapy or reduced their pegylated interferon dose.

"Low-dose therapy with pegylated interferon alfa 2b for an extended period of up to 6 years in a subgroup of patients with HCV and advanced fibrosis or cirrhosis who are able to tolerate such a long treatment time, showed a significant and persistent decrease in fibrosis in comparison to an observational control groups," the investigators concluded.

"As treatment was well tolerated even for patients with cirrhosis, they continued, "this treatment could evolve as a salvage therapy for a specific subgroup of patients with advanced liver disease with HCV [for whom] standard antiviral therapy has failed."

12/09/08

References

C Morishima, ML Shiffman, K Lindsay, and others. Reduced hepatic inflammation is related to HCV RNA suppression and correlates with less fibrosis progression and fewer cirrhosis complications in the Hepatitis C Antiviral Long-term Treatment Against Cirrhosis (HALT-C) trial. 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008. Abstract 273.

S Kaiser, B Lutze, CR Werner, and others. Long-term Low Dose Treatment with Pegylated Interferon alpha 2b for 6 years leads to a significant Reduction in Fibrosis and Inflammatory Score in a Subgroup of Chronic Hepatitis C Nonresponder Patients with Fibrosis or Cirrhosis. 59th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2008). San Francisco. October 31-November 4, 2008. Abstract 117.