NATAP Reports

Highlights from Digestive Disease Week

May 20-23, 2001 Atlanta, Georgia

Patient's Ability to Mount an Immune Response Appears Associated with Response to HCV Therapy

Pegylated Interferon May Improve Immune Response Better Than Standard Interferon: comparison of Pegasys to standard interferon

This study was reported at the 2001 DDW Conference in May in Atlanta by Sanaa Kamal from University of Freiburg, Germany. The mechanism for interferon's effectiveness in treating HCV is not completely understood. Several recent studies have suggested that response to HCV & therapy by patients may be related to the patient's ability to mount an HCV specific cd4 response. This study (n=28) from Kamal compares Pegasys to standard interferon to evaluate the of HCV specific immune responses on the outcome of therapy. Prior to treatment patients these immune responses were weak. Kamal suggests that sustained virologic response was associated with strong HCV specific immune responses. These responses were seen as early as week 4 in patients receiving Pegasys and were maintained. Kamal suggests that Pegasys was more efficient than standard interferon in producing more vigorous and broad immune response.

14 patients received Pegasys for 28 weeks (180 ug qw) and 14 patients received interferon a-2a 6 MIU for 12 weeks followed by 3 MIU for 36 weeks. 42% receiving Pegasys had a sustained response compared to 14% receiving standard interferon. Patients receiving Pegasys had stronger, more frequent, and broader HCV specific cd4 responses early in treatments soon as 4 weeks after starting therapy) and the strength & breadth of the responses were more sustained compared to patients receiving standard interferon. Even among nonresponders during and after treatment the HCV cd4 responses, although not as good as in responders, were better in patients receiving Pegasys. The authors say Pegasys efficacy appears due to enhanced HCV specific cd4 t-helper-1 responses.

PEG (40KDA) INTERFERON a-2A THERAPY ENHANCES HCV SPECIFIC CD4+ T HELPER 1 RESPONSES DURING AND AFTER TREATMENT
     Sanaa M. Kamal, Harvard Inst of Medicine, Boston, MA; Thomas Peter, Jens W. Rasenack, Univ of Freiburg, Freiburg Germany

BACKGROUND: Phase III studies showed that PEG(40kDa)IFN a-2a improves sustained viral response in patients with chronic hepatitis C virus infection (CHC) compared to standard IFN a-2a monotherapy. OBJECTIVES: To evaluate the impact of HCV specific immune responses in determining the therapeutic outcome, HCV specific CD4+ and cytokine responses were compared in patients with CHC treated with PEG (40kDa) IFN a-2a vs. standard IFNa-2a.

METHODS: 28 previously untreated patients with CHC were randomized to either PEG (40kDa) IFN a-2a 180 µg qw (Group A; n=14) for 48 weeks or IFN a-2a 6 MIU tiw for 12 weeks then 3 MIU tiw (Group B; n=14) for 36 weeks as part of 72 week randomized controlled multicenter trial. HCV specific CD4+ proliferative response in PBMCs & cytokines: IFNg, TNFa, IL10 production in response to HCV core, NS3, NS4, NS5 or PHA were prospectively assessed before, during, at end of treatment(week 48)& end of follow up (week 72). Liver biopsies were performed before and after treatment.

RESULTS: There was no significant difference in age, HCV RNA titers, HCV genotype between the 2 groups at entry. Pre-treatment HCV specific CD4+ responses were either weak or narrowly focused targeting only HCV core (9 patients in Group A & 10 in Group B) or absent (5 in Group A & 4 in Group B). PEG (40kDa)IFN a-2a treated patients had significant increase in strength, frequency of HCV specific CD4+ responses & number of antigens recognized as early as week 4, suggesting that PEG (40kDa) IFN a-2a is more efficient than standard IFN a-2a in enhancing and broadening the immune response. Whereas PEG (40kDa)IFN a-2a treated patients had early significant IFNg production upon stimulation of PBMCs by core, NS3 &NS5 peaking around treatment weak 4 & maintained through follow up, group B patients had lower fluctuating IFNg. PEG (40kDa)IFN a-2a treated patients had significantly lower post treatment IL10 production in response to HCV antigens compared to group B. There was no significant difference in TNFa production between the 2 groups. Patients achieving sustained viral response (8/14 in group A and 3/14 in group B) had multi specific strong maintained HCV specific CD4+ responses with high IFNg and low IL10 production.

CONCLUSION: Treatment with PEG (40kDa) IFN a-2a is associated with more vigorous and multispecific immune responses compared to standard IFN a-2a monotherapy. The efficacy of PEG (40kDa) IFN a-2a in inducing higher rates of sustained virological responses may be due to enhancement of HCV specific T helper 1 responses.