Cyclical Treatment Interruption in Patients Taking Interferon-based Therapy for Chronic Hepatitis C

By Liz Highleyman

Periodic interruption of disease treatment may be an attractive option for a variety of reasons, including reducing drug side effects and costs. With antiviral therapy, some researchers have proposed that stopping treatment allows viral reproduction to resume and thereby repeatedly exposes the immune system to the invader, hopefully promoting a stronger immune response.

In the February 6, 2009 Journal of Clinical Virology, Gerond Lake-Bakaar of Weill Cornell University Medical College described a study of structured treatment interruption in patients with chronic hepatitis C.

"We have hypothesized that prolonged viral suppression partially reverses immune tolerance in chronic hepatitis C virus infection," Lake-Bakaar wrote as background. "Brief periods of treatment interruption can then simulate 'auto-vaccination' and evoke powerful secondary host immune responses."

The present study attempted to determine the effect of controlled interruption of therapy in patients who previously experienced relapse when treated with pegylated interferon plus ribavirin. After HCV had been maintained at an undetectable level for 2-8 weeks on treatment, pegylated interferon and ribavirin were briefly interrupted, with therapy restarting as soon as detectable viremia returned (cycle 1). After viral load was suppressed for at least a further 4 weeks, therapy was briefly interrupted again (cycle 2).

Results

All 4 patients experienced relapse of HCV viremia within 2-4 weeks after the first treatment interruption in cycle 1.

In Patient 1, time-to-relapse increased 7-fold with the second treatment interruption, followed by sustained virological response (SVR) with a third cycle of treatment interruption.

In Patient 2, time-to-relapse increased 3-fold after cycle 2 and subsequent cycles.

In this patient, serum ALT and bilirubin levels rose significantly during treatment interruption cycles 2 and 3, but returned to baseline levels when treatment was resumed; serum bilirubin rose to 12.3 mg/dl after the patient missed 2 doses of pegylated interferon during cycle 4.

In Patients 3 and 4, time-to-relapse was unchanged after 3 consecutive treatment interruption cycles, but HCV viral load remained more than 1 log below baseline for up to 18 months in both.

Based on these findings, Lake-Bakaar concluded, "These observations suggest that controlled treatment interruption exerts significant control of chronic hepatitis C viremia."

Structured treatment interruption for hepatitis C patients should be researched more thoroughly before it is adopted, given the unexpected outcomes of interruption of antiretroviral therapy for HIV.

While some early studies suggested that HIV treatment interruption might stimulate the immune response, later findings -- including results from the large SMART trial -- indicated that treatment interruption was a hazardous strategy, leading not only to a higher risk of AIDS-related opportunistic infections and death, but also a greater likelihood of serious non-AIDS heart, liver, and kidney disease, perhaps related to systemic inflammation triggered by ongoing HIV replication.

At this time, it is unknown whether ongoing HCV replication might have a similar effect, or whether starting and stopping treatment might have a detrimental impact on liver disease progression.

2/10/09

Reference
G Lake-Bakaar. The effect of controlled therapy interruption in chronic HCV infection: Enhanced host immune response? A hypothesis. Journal of Clinical Virology 44(2): 149-151. February 6, 2009. (Abstract).