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Hepatitis C Re-treatment with Interferon Monotherapy Provides Little Benefit

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Long-term re-treatment with pegylated interferon monotherapy offers little or no clinical benefit -- even though it may suppress hepatitis C virus (HCV) levels and improve liver fibrosis -- but it can cause adverse events and may be associated with higher mortality, according to a systematic review from the Cochrane Library.

For people who achieve sustained virological response (SVR) -- or undetectable HCV RNA 24 weeks after completing therapy -- first-line treatment with pegylated interferon (Pegasys or PegIntron) plus ribavirin has been shown to reduce the risk of progression to advanced liver disease including cirrhosis and hepatocellular carcinoma (HCC).

For non-responders -- including null responders who see little or no HCV RNA decline, partial responders, and relapsers who experience viral rebound after completing treatment -- researchers have studied re-treatment with dual therapy as well as interferon monotherapy, with mixed results. Interferon monotherapy may be used instead of the combination in an effort to reduce side effects and cost, and ribavirin is contraindicated for people trying to become pregnant because it can cause congenital abnormalities.

Ronald Koretz and colleagues with the Cochrane Hepato-Biliary Group conducted a systematic review and meta-analysis to evaluate the benefits and harms of re-treatment with interferon monotherapy for chronic hepatitis C patients. The Cochrane Collaboration is an international network of experts that collects and analyzes data from multiple studies to inform the practice of evidence-based medicine.

The authors also wanted to determine if surrogate outcomes including viral load suppression and improved liver fibrosis correlate with clinical outcomes such as decompensation and liver-related death. These outcomes are generally not the focus of clinical trials that support approval of new drugs because they typically occur many years or decades after initial infection.

The investigators searched the Cochrane Hepato-Biliary Group Controlled Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library, MEDLINE, EMBASE, and Science Citation Index Expanded through August 16, 2012. They looked for randomized trials comparing interferon versus placebo or no treatment for non-responders and relapsers to previous interferon-based therapy for chronic hepatitis C.

The primary outcomes were liver-related and all-cause mortality, quality of life, and adverse events. Secondary outcomes included liver-related morbidity, SVR, biochemical responses (liver enzyme levels), histologic improvement (reduced liver tissue damage), and cost.

The authors identified 7 relevant trials, with a total of 1976 participants. Of these, 2 studies (HALT-C and EPIC3) were considered to have a low risk of bias. These trials, which together included 1676 participants, looked at the effect of long-term low-dose pegylated interferon for patients with advanced fibrosis. The remaining 5 trials, which together included 300 patients, were considered high risk for bias (for example, not enrolling the planned number of participants or not including all participants in the analysis).

Results

  • Based on all trials reporting the outcomes of interest, there were no significant differences in clinical outcomes between people re-treated with interferon monotherapy and those who got placebo or no further treatment:

o   All-cause mortality (3 trials): 9.3% (78 of 843) vs 7.2% (62 of 867); risk ratio (RR) 1.30;

o   Liver-related mortality (2 trials): 7.7% (41 of 532) vs 7.2% (40 of 552); RR 1.07.

  • Looking only at the 2 trials with low risk of bias, all-cause mortality was significantly higher for people who received pegylated interferon monotherapy: 9.4% (78 of 828) vs 6.7% (57 of 848); RR 1.41, or about 40% higher risk.
  • Patients re-treated with interferon experienced less variceal bleeding (4 trials): 0.5% (4 of 843) vs 2.1% (18 of 867); RR 0.24.
  • However, there were no significant differences in other manifestations of decompensation including ascites or hepatic encephalopathy.
  • Interferon monotherapy also did not have a significant effect on development of HCC or need for liver transplantation.
  • In the single trial that reported quality of life data, pain scores were significantly worse for people on pegylated interferon monotherapy.
  • Overall, adverse effects tended to be more common among interferon recipients; side effects that were significantly more common included hematological abnormalities, infections, flu-like symptoms, and rash.
  • Patients who received interferon monotherapy were significantly more likely than those who received placebo or no re-treatment to see improvement in surrogate markers:

o   SVR (4 trials): 3.6% (20 of 557) vs 0.2% (1 of 579); RR 15.38;

o   Improved METAVIR histological activity/liver inflammation score (2 trials): 65% (36 of 55) vs 43.5% (20 of 46; RR 1.49.

  • No significant differences were observed, however, for liver fibrosis.

"The clinical data were limited to patients with histologic evidence of severe fibrosis who were retreated with pegylated interferon," the review authors summarized. "In this scenario, retreatment with interferon did not appear to provide significant clinical benefit and, when only the trials at low risk of bias were considered, retreatment for several years may even have increased all-cause mortality. Such treatment also produced adverse events."

"On the other hand, the treatment did result in improvement in some surrogate outcomes, namely sustained viral responses and histologic evidence of inflammation," they added.

"Interferon monotherapy retreatment cannot be recommended for these patients. No clinical data are available for patients with less severe fibrosis," they concluded. "The sustained viral response cannot be used as a surrogate marker for hepatitis C treatment in this clinical setting with low sustained viral response rates and needs to be validated in others in which higher sustained viral response rates are reported."

This analysis showed that interferon monotherapy re-treatment not only has a very low SVR rate -- under 4% -- but it may actually be harmful for some patients. The advent last year of the first direct-acting antiretroviral agents for HCV has significantly improved viral suppression rates, though prior null responders and people with advanced liver damage remain difficult to treat. All-oral, interferon-free regimens now under study promise higher efficacy with fewer side effects, but long-term follow-up will be needed to see if virological cure translates into less liver failure and death.

2/6/13

Reference

RL Koretz, M Pleguezuelo, V Arvaniti, et al. Interferon for interferon nonresponding and relapsing patients with chronic hepatitis C. Cochrane Database of Systematic Reviews 1:CD003617. January 21, 2013 (Epub).