Using interferon monotherapy to treat hepatitis C in patients who have failed to respond to other treatments did not improve mortality rates and may actually cause harm, according to a Cochrane Collaboration review.
Although interferon does appear to reduce the levels of hepatitis C virus in the blood, this reduced viral load does not translate to increased survival or quality of life.
Dr. Ronald L. Koretz, a gastroenterologist and internal medicine specialist in Granada Hills, Calif., and his associates reported that they could not recommend interferon monotherapy because of the increased risk of all-cause mortality paired with a higher number of adverse events. The report was published online Jan. 30 (Cochrane Database Syst. Rev. 2013 Jan. 30 [doi:10.1002/14651858.CD003617.pub2]).
Interferon is typically used in hepatitis C retreatment when ribavirin or protease inhibitors have not been effective (or are contraindicated or not tolerated). The outcome goal is sustained viral response (SVR), referring to no measurable viral RNA in the blood for 6 months after treatment.
However, using SVR as a surrogate outcome for hepatitis C improvement had not been validated due to the dearth of randomized clinical trials with mortality data.
Dr. Koretz and his colleagues investigated randomized trials in which interferon was compared with a placebo or no treatment at all in chronic hepatitis C patients who had severe fibrosis (grade 3 or 4) and who had not responded to another treatment or had relapsed following interferon treatment. Patients were excluded if they had undergone a liver transplant, had HBV and/or HIV, or had evidence of hepatic decompensation.
Primary outcomes included all-cause and hepatic death, quality of life, and adverse events. Secondary outcomes included liver-related morbidity, SVR, biochemical responses, and histological responses. The researchers identified seven trials with a total of 1,976 patients, but five of these (n = 300) were at high risk of bias due to lack of blinding and, in four, possible selection and reporting bias.
Only three trials included outcomes on mortality and hepatic morbidity: HALT-C (Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis) and EPIC 3 (Evaluation of PegIntron in Control of Hepatitis C Cirrhosis), which tracked patients who had severe fibrosis for 3-5 years, and a third trial that was ended before its 48-week endpoint because of the former trials’ results.
When the researchers analyzed only the two larger trials with low bias risk, they found all-cause mortality among the 1,676 patients to be significantly higher in the patients receiving pegylated interferon. The all-cause mortality rate was 9.4% (78/828) among interferon patients, compared with 6.7% (57/848) in patients receiving a placebo or no treatment (RR, 1.41; 95% CI: 1.02-1.96).
The additional deaths among interferon recipients appeared to be unrelated to liver function. Liver-related mortality in the large 5-year trial (low bias risk) showed no significant difference between interferon patients and untreated patients alone or when analyzed along with a trial at high bias risk (RR, 1.07; 95% CI: 0.7-1.63). In the one large trial whose 622 patients began without cirrhosis, interferon recipients were no less likely to develop cirrhosis (RR, 0.93; 95% CI: 0.69-1.25).
Interferon recipients did experience less variceal bleeding: 0.5% (4/843) in interferon recipients, compared with 2.1% (18/867) in untreated patients. No significant differences were seen for fibrosis markers or for encephalopathy, ascites, hepatocellular carcinoma, or liver transplantation. Only one small trial reported quality of life scores with pain scores among interferon patients to be "significantly higher, P < .001," but without numbers provided.
In the two large trials with low bias risk, interferon recipients also experienced significantly more adverse events (RR, 1.18; 95% CI: 0.99-1.41, P = .07), primarily infections, rash, irritability, fatigue, headaches, muscle pain, flu-like symptoms, and hematologic complications such as neutropenia and thrombocytopenia.
Analysis of four trials did show that 3.6% (20/557) of interferon recipients achieved SVR, compared with 0.2% (1/579) of untreated patients (RR, 15.38; 95% CI: 2.93-80.71). Interferon was also linked to reduced inflammation – but not reduced fibrosis – as measured by METAVIR activity scores. Among interferon recipients, 65% (36/55) had improved METAVIR activity scores, compared with 43.5% (20/46) of untreated patients (RR, 1.49; 95% CI: 1.02-2.18).
But these surrogate outcome improvements did not translate to better clinical outcomes. "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)," the researchers wrote.
The review did not receive internal or external funding support. The authors reported no permanent financial contracts with companies producing interferon or other conflicts of interest. Dr. Pilar Barrera Baena receives research funding from Centro de Investigacion Biomedica en Red en Enfermedades Hepaticas y Digestivas (CIBERehd).
