Dallas Liver Conference- Report 6
50th Annual AASLD Meeting- American Ass for Study of Liver Diseases, Dallas - Nov 7

Preliminary data from Schering Plough's pegylated interferon; early prediction and mechanism of RBV-IFN effect on chronic HCV

In a talk with Avi Neumann, the author of study below, he told me that he did not think high IFN dosing 3 times per week would be successful in achieving long term sustained virologic response. The effect of high dosing 3x/week would be to increase phase 1 initial viral load decline but not phase 2 decline. Both Neumann and Alan Perelson believe phase 2 decline is associated with sustained virologic and long term response to IFN+RBV. In addition, dosing 3x/week regardless of dose permits for low drug blood levels and increase of viral replication in between dosing. He felt daily dosing would be effective in improving sustained virologic responses. These could be reasons why induction studies show mixed results. It may depend on the dosing scheme used in the study—high dose 3 times per week with or without daily dosing.

Ribavarin added to interferon appears to improve phase 1 viral load decline, and response at one week appears associated with end-of-treatment and sustained virologic response

Avidan Neumann and others reported on this study comparing IFN+RBV to IFN alone, and looking at the early viral response of both and their predictive value for achieving sustained virologic response. The authors said it was recently shown that dual HCV treatment with RBV and IFN significantly the success rate of treatment for HCV. In previous work by Neumann et al (Science, 1998) they found that the major anti-viral effect of IFN is to block production or release of virions from infected cells. However, the mechanism behind the synergistic effect of RBV is not yet well understood.

A subset of 50 patients from the large McHutchison study which compared IFN+RBV to IFN alone (NEJM, 1998) was randomly chosen to look at more frequent quantification (at 1 and 2 weeks of treatment) of HCV viral load (Superquant, NGI). In this study patients received IFN 3 MIU 3x/week with (1000-1200 mg; n=26) or without ribavarin for 24-48 weeks.

A viral decrease of more than 1 log HCV RNA at one week of treatment was predictive in 24/25 patients of end-of-treatment virologic response (ETR), while only 1/25 patients with no such decrease had ETR (R=0.8; p=below 0.001). The predictive value of the response at 1 week of treatment was valid for both the single and dual drug regimens. However, a significantly (p=below 0.02) larger fraction of patients receiving IFN+RBV (65%, 17/26) responded after a week, as compared to patients receiving IFN alone (33%, 16/24). Why do 35% not respond? Neumann said a person’s immune system is a factor in response. Improving the immune system may help improve response. 

Among the 25 patients who had above 1 log reduction in viral load at 1 week, sustained response was 70.5% (12/17) of those who received IFN+RBV compared to only 12.5% (1/8) among those who received IFN alone (p below 0.01). Neumann however reported there was no difference found in the second phase slope of HCV decline between sustained responders versus responder-relapsers or between patients receiving RBV or not. 

These viral kinetics can be simulated by a mathematical model that includes early and productive stages of infected cells, and assuming that RBV partially blocks de-novo infection of target cells, while IFN blocks virion production and prevents infected cells from becoming productive.

Neumann concluded –
(1) ETR can be predicted as early as the first week of treatment by a viral decrease of more than 1 log of HCV RNA in the vast majority of patients receiving 3 MIU 3x/week with or without ribavarin; 
(2) the addition of ribavarin has a synergistic effect both during the first week of treatment and in increasing the sustained response rate among those with an early response; 
(3) this is in agreement with earlier reported findings (Pawlotsky et al, Hepatology 1998) showing that treatment with RBV alone gives rise to a modest transient reduction in viral load during the second day of therapy. All these results can be explained consistently if RBV blocks de-novo infection of target cells.

It appears progress is being made in understanding HCV disease, and the effects of therapy. I think increased understanding will continue over time. The developments below related to IFN response and resistance I think reflects that. Still, more effective drugs are needed.

Two oral reports in this afternoon’s session discussed preliminary findings in the potential relationship between resistance and IFN treatment. Jean-Baptiste Nousbaum said the HCV non-structural 5A (NS5A) protein has been controversially implicated in the inherent resistance of HCV to IFN antiviral therapy in clinical studies. In other words, resistance to IFN can be present and may affect the success of treatment. Nousbaum found more amino acid changes (mutations) were observed in isolates from IFN sensitive patients, especially in the previously reported NS5a/vS region. In other words, having more mutations was associated with a better response to IFN. He found no evidence of a consensus sequence associated with IFN resistance, except for Ala245 in HCV genotype 1a. In the second oral report Thomas Berg found that the mean (median) number of mutations within the PKR-binding region but not within the previously described IFN sensitivity determining region (ISDR) was significantly higher in patients with sustained virologic response. Antibodies against the NS5A protein were observed in all sustained responders. He also reported that no specific mutation or mutation a pattern was associated with sustained virologic response.

Also today in the oral session initial preliminary data on Schering Plough’s pegylated IFN was presented. This early open-label, randomized, active controlled study was to assess safety, PK, and efficacy of PEG IFN + RBV in various doses. 72 Patients (20-68 yrs age) with chronic HCV received either PEG IFN 0.35, 0.7, or 1.4 ug/kg s.c. weekly for 24 weeks alone or in combination with ribavarin 600, 800, or 1000-1200 mg oral daily.

Investigators reported that PEG IFN alone produced expected dose-related reductions in white cells, neutrophils, and platelets. Addition of RBV reduced hemoglobin levels in a dose related way, did not further reduce PEG IFN induced neutrophil or white cell count decreases, and increased platelet counts. Neutrophil function tests were unaltered. Reported adverse events were qualitatively similar in all dose groups. Ribavarin did not alter PK profile of PEG IFN. Anti-HCV activity, as measured by loss of detectable serum HCV RNA (below 100 copies/ml) at week 4 of follow-up showed dose response trends for PEF IFN alone, and additional dose response trends with increasing daily doses of RBV. 

They showed preliminary HCV RNA reductions. When looking at the antiviral activity at 24 and 28 weeks of various IFN doses, those individuals receiving highest dose of 1.4 (ug/kg once weekly) + RBV had 81% undetectable compared to 50% receiving PEG IFN alone (24 weeks). At week 28 (4 weeks of follow-up) 73% receiving IFN+RBV were undetectable and 57% receiving PEG IFN alone were undetectable. Although you are not supposed to compare studies due to differences in study populations, study design and additional potential differences, the preliminary data from the Roche PEG IFN study they reported 80% had below 100 copies/ml at week 24, and 70% at week 48. . The speaker said a higher dose of I think 3.0 ug/kg was being explored and data would be available in 2000.