SUMMARY: Increasing doses of interferon alfa may compensate for decreased interferon sensitivity and reduced response to hepatitis C treatment among HCV genotype 1 prior non-responders with the unfavorable IL28B T/T genetic variation, according to findings presented at the recent American Association for the Study of Liver Diseases "Liver Meeting" (AASLD 2010) in Boston. Continuous treatment using an interferon pump may also be beneficial for individuals with poor initial response.

By Liz Highleyman

In 2009, researchers first reported that specific variations in the IL28B gene region -- which encodes interleukin 28, also known as interferon lambda -- are associated with both spontaneous clearance of hepatitis C virus (HCV) and response to interferon-based therapy for chronic infection. Different teams have implicated several single nucleotide polymorphisms (SNPs), or changes at a single local in the genetic sequence. The same genetic variation may also influence hepatitis B outcomes.

Each individual carries 2 copies of the relevant gene. People with the C/C genetic pattern -- that is, 2 copies of the "C" allele, or variant -- are more likely to clear HCV without treatment and to respond well to interferon alfa if chronically infected. People with the T/T pattern have the least favorable response. Those who carry 1 "C" and 1 "T" allele fall somewhere in between. Different racial/ethnic groups are more likely to have specific patterns -- the protective C/C pattern, for example, is more common among people of European descent -- which may help explain disparate treatment response rates.

In the study described at the Liver Meeting, Robert Roomer from Erasmus University Medical Center in Rotterdam and colleagues explored links between IL28B patterns and treatment outcomes among chronic hepatitis C patients who did not respond to a prior course of therapy. Standard therapy using once-weekly pegylated interferon alfa plus weight-adjusted daily ribavirin produces a sustained virological response (SVR) rate of only about 10% in this population.

The researchers hypothesized that continuous delivery of high-dose interferon by an external pump might improve SVR rates in previous non-responders. The pegylation process enables interferon alfa to remain active in the body longer than the conventional formulation, but a pump allows for a stable high concentration.

A total of 30 chronic hepatitis C patients with prior treatment failure where given interferon alfa-2b (the type in Intron A and PegIntron) continuously administered via subcutaneous infusion using a modified Medtronic Minimed insulin pump. Participants were randomly assigned to receive cumulative daily doses of 6, 9, or 12 MU of interferon, combined with weight-adjusted daily ribavirin.

Viral kinetics were measured at baseline, weekly until week 4, and then at weeks 8, 12, 24, and 48. The IL28B SNP rs12979860 -- dubbed the "Duke SNP" -- was assessed using competitive allele-specific PCR genotyping.

Results

	In this cohort, 3 patients carried the protective IL28B C/C gene pattern, 6 had the unfavorable T/T pattern, and 20 had the mixed C/T pattern (1 person was undetermined).
	There researchers observed differences between the gene pattern groups with regard to HCV RNA decay or decrease at week 4, independent of interferon dose:
	C/C pattern: 2.9 log decline; C/T pattern: 1.65 log decline; T/T pattern: 1.25 log decline.
	Only 2 of the 6 people in the T/T group achieved a > 1 log reduction at 4 weeks.
	Regardless of IL28B genotype, all 10 patients who received the highest (12 MU/day) interferon dose achieved an HCV RNA decline > 2 log at week 4.
	6 patients overall (20%) achieved SVR, with results differing according to IL28B pattern:
	2 people in the C/C group (1 in the 6 MU and 1 in the 9 MU interferon dose groups); 4 in the C/T group (all receiving 12 MU/day). 0 in the T/T group.
	In a multivariate analysis, both IL28B gene pattern (P = 0.036) and interferon alfa dose (P = 0.002) were significantly associated with viral decay at week 4.

These results show that the IL28B genotype can be a strong predictor of both viral decay rates and subsequent SVR," the investigators concluded.

Moreover, they added, "high doses of interferon can potentially overcome the innate lack of interferon sensitivity" associated with unfavorable IL28B gene patterns in prior studies of treatment-naive patients.

Finally, they noted, "these results also support the concept that continuous delivery of interferon in previous therapy failures can be a successful treatment strategy," especially for those with C/C and C/T gene patterns.

Investigator affiliations: Department of Gastroenterology and Hepatology, Erasmus University Medical Center, Rotterdam, Netherlands; Ventures & New Therapies, Medtronic, Inc., Minneapolis, MN, and Los Angeles, CA.

11/12/10

Reference
R Roomer, RJ de Knegt, JF Bergmann, and others. Non response to peginterferon alfa and ribavirin in IL28B CC & CT patients can be overcome by high dose continuous interferon alfa-2b administration in combination with ribavirin for chronic hepatitis C. 61st Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2010). Boston, October 29-November 2, 2010. Abstract LB-13.