Interferon May Be Harmful in Retreatment of Hepatitis C

Steven Fox

January 30, 2013

When patients with hepatitis C and chronic liver disease suffer relapses or fail to respond to initial treatment, monotherapy with interferon may not be a good idea, according to results from a recent meta-analysis. In fact, employing that approach may raise the risks for death and adverse effects.

The review is published in the January issue of the Cochrane Database of Systematic Reviews and was conducted by Ronald Koretz, MD, professor of medicine, digestive diseases and gastroenterology, David Geffen School of Medicine, University of California, Los Angeles, and colleagues.

"The widely-accepted treatment outcome for chronic hepatitis C is the sustained viral response (that is, no measurable viral RNA in blood six months after treatment). However, this surrogate outcome (as well as the previously employed biochemical and histologic ones) has never been validated," the authors write.

The lack of validation is not surprising, the authors say, because very few randomized clinical trials evaluating clinical outcomes (mortality or manifestations of cirrhosis) have been conducted, as patients usually do not die or develop cirrhosis until years after they have been infected.

Patients who undergo initial therapy but do not produce sustained viral responses become potential candidates for retreatment, the authors note, but for some patients in whom standard treatment with ribavirin or protease inhibitors cannot be tolerated, clinicians often consider retreatment with interferon to be a reasonable option.

All-Cause Mortality Worse

To find out more about the actual clinical effects of retreatment with interferon, the investigators reviewed data from 7 clinical trials in which monotherapy retreatment with interferon was compared with placebo or no treatment.

Two of the trials (the Hepatitis C Antiviral Long-term Treatment against Cirrhosis [HALT-C] and Evaluation of Peglntron in Control of Hepatitis C Cirrhosis [EPIC-3] trials) were considered to be at low risk for bias. Together, those trials included 1676 patients. Both assessed the clinical outcomes of patients with severe fibrosis who underwent long-term low-dose retreatment with pegylated interferon therapy.

The other 5 trials included a total of 300 patients and were considered to be at high risk for bias.

Dr. Koretz and colleagues report that when they included all trials with published outcomes in their review they saw no significant difference in all-cause mortality (78/843 [9.3%] vs 62/867 [7.2%]; risk ratio [RR], 1.30; 95% confidence interval [CI], 0.95 - 1.79; 3 trials). They also did not find a significant difference in hepatic-related mortality (41/532 [7.7%] vs 40/552 [7.2%]; RR, 1.07; 95% CI, 0.70 - 1.63; 2 trials).

However, when the reviewers included only the 2 trials considered at low risk for bias, they noted that all-cause mortality was significantly higher among patients who received interferon (78/828 [9.4%] vs 57/848 [6.7%]; RR, 1.41; 95% CI, 1.02 - 1.96).

They do note, however, that there was less variceal bleeding in patients who received interferon (4/843 [0.5%] vs 18/867 [2.1%]; RR, 0.24; 95% CI, 0.09 - 0.67; 3 trials). Still, the researchers comment that the prohibitive cost of interferon would not justify it for this indication alone.

Patients administered interferon were no more likely to develop ascites, encephalopathy, or hepatocellular carcinoma or to need liver transplants.

Only one of the trials included quality-of-life data, and in that trial pain scores were significantly worse in patients receiving interferon, the reviewers write. Patients receiving interferon were also more likely to suffer adverse effects, most commonly hematologic complications, infections, influenza-like symptoms, and rashes.

SVR a Surrogate Marker?

Interferon therapy did appear, however, to be associated with significantly better viral responses (20/557 [3.6%] vs 1/579 [0.2%]; RR, 15.38; 95% CI, 2.93 - 80.71; 4 trials). In addition, METAVIR activity scores, gauging degree of inflammation as well as the extent of fibrosis, also improved (36/55 [65%] vs 20/46 [43.5%]; RR, 1.49; 95% CI, 1.02 - 2.18; 2 trials). However, the reviewers say they saw no significant differences in histologic assessments of fibrosis.

The authors stress that the clinical data they reviewed were limited to patients with histologic evidence of severe fibrosis who were retreated with pegylated interferon.

"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," the authors note.

In conclusion, they write, "Two of the commonly employed surrogate markers, sustained viral response and markers of inflammation, failed to be validated since they improved even though the clinical outcomes did not (or may even have become worse). This failure to validate the sustained viral response in this group of patients with a low sustained viral response rate suggests that the presumed validity of the use of sustained viral responses in other groups of patients with chronic hepatitis C viral infections who receive treatment must be formally validated."

The authors have disclosed no relevant financial relationships.

Cochrane Database Syst Rev. 2013:1:CD003617.