Brief Highlights From AASLD:
HCV Specific CD4 T Cell Response & Immune Response in Clearing HCV
Robert Kimme from Scripps Research Institute talked about what appears to be a growing focus of interest: the role of HCV specific T cell responses in clearing HCV and in response to therapy. Several reports in Dallas said they believe such a response is crucial. Kimme studied the peripheral & intrahepatic HCV specific T cell response and intrahepatic cytokine profile in 3 chimps that developed chronic HCV and in 1 chimp that cleared the virus, following infection of HCV by intravenous infection or cloned HCV-RNA.
RESULTS
| CD4 Response |
| All chimps showed a peripheral (in the blood) multispecific CD4 T cell response within 5 weeks after exposure to HCV, regardless of whether they became chronic or cleared HCV. But, the T cells homed to the liver very inefficiently in the chimps that developed chronic HCV. They displayed only transient monospecific intrahepatic CD4 T cell responses. In contrast, the chimp who cleared HCV displayed an early, strong and sustained and multi-specific intrahepatic CD4 T cell response. |
| CD8 Response |
| The peripheral CD8 T cell response was delayed and relatively narrowly focused in the chimps with chronic HCV. But in the chimp who cleared HCV he mounted an early CD8 T cell response to seven different virus epitopes. |
| Cytokine Response |
| 25OAS is a marker for type 1 IFN and
strongly emerged within 1
week of exposure to HCV in all chimps irrespective of whether or not the
chimp cleared HCV. Kimme said this suggests HCV is a strong inducer of
type 1 IFN but is resistant to its antiviral effect. Further, viral
clearance was associated with the intrahepatic induction (emergence) of
IFN gamma in all chimps that cleared acute HCV. This suggests that IFN
gamma might either help virus get exposed to HCV specific CD4 T cells or
have a direct antiviral effect itself
Kimme concluded by saying that innate and acquired immune response might help in viral clearance in chronic HCV. To test this hypothesis in humans will be difficult because they would have to identify newly infected individuals through blood banks. |
Maximine
Maximine is an immune based therapy with application for certain cancers. It is supposed to inhibit oxidative stress which can cause irreversible damage to lymphocytes which are essential for viral killing. Maxim Pharma reported 48 week results of a 72 week study on 129 treatment-naÔve HCV-infected individuals receiving interferon+Maxima. Maxima was given at various dosing regimens and is administered by subcutaneous injections. This was an open-label multicenter, international study. At baseline mean age was young (30), Viral load was high at 6.7 million, and 53% with >2 million copies/ml. 47% had genotype 1, and about 49% had genotype 2. Patients were randomized to 1 of 4 dosing regimens of Maxima.
A limitation of this study is that all patients received Maximine and IFN so its difficult to tell how much benefit Maximine is giving. Another limit is viral response is defined as <1000 copies/ml. In brief, after 48 weeks-
58% of all patients (57-69% across all 4 dose arms) had virologic response AND virologic response is defined as >1000 copies/ml
58% with genotype 1b (range 36-88%) had viral response
70% with genotypes 2/3 (58-80%) had viral response
48% with high viral load (33-57%) had viral response
Drug administration resulted in mild transient side effects. It induced short lasting flush in most patients and a short lasting headache, hypotension, and lachycardia in some patients. They said overall it was well tolerated. 5% discontinued study by week 48.
Another unusual aspect of results is that genotype 1 patients did better than genotype 2/3. They reported drug has an acceptable safety profile. They reported preliminary 12 week data from small ongoing study of IFN+Maxima+RBV who did not respond to previous therapy (nonresponders & relapsers). 15/18 are genotype 1. After 8 weeks patients can increase IFN dose ftom 3 MIU three times per week to 3-6 MIU daily. Maxima dose was 1 mg bid, tiw subcutaneous injection with option to escalate to 1 mg bid, once weekly. After 12 weeks, 4/13 were serum HCV RNA negative. Obviously too soon to tell anything. And 8/13 had 2 or more log decrease in viral load. 5/18 discontinued therapy. There were no unexpected and/or irreversible adverse events.
PEG INTRON
Schering reported data on PEG INTRON+Ribivarin in large study. Patients received Peg Intron (n=514) or regular IFN with RBV in 2 different dosing regimens (about 500 in each arm) for 48 weeks and there is a 24 week follow-up. 67% were genotype 1. About 68% had viral load >2 million, and 10% cirrhotic. One arm dosed IFN+RBV 1000/1200 daily. A second arm dosed Peg IFN 1.5 ug/kg once weekly +RBV 800 mg daily. The third arm dosed Peg IFN 1.5 ug/kg once weekly for 4 weeks followed by 0.5 ug/kg for 44 weeks.
Sustained Virologic Response for All Genotypes
47% regular IFN+RBV
54% PEG INTRON+RBV (1.5 ug/kg dose)
Schering thinks that with >80% adherence response rate will be 61%
|
Viral Response By Genotype |
||
| 42% Peg 1.5 + RBV genotype 1 |
vs |
82% genotype 2/3 |
| regular IFM (3 MIU)+RBV: 33% genotype 1 | 79% genotype 2/3 | |
Responses were broken down by weight and we'll report that in next report. Lighter weighing individuals appeared to have better responsev rates. Ribivarin it appears can be dosed by weight. Patient weight and recommended dosing from Schering: <65 kg 800 mg/day; 65-85 kg 1000 mg/day; >85 kg 1200 mg/day.
They reported 18% grade 3 neutropenia in Peg 1.5 dose group vs 7% in regular IFN dose group. And it was 4% (Peg 1.5) vs 2% (IFN) for grade 4. Discontinuation was 0.2% in IFN arm vs 1% in Peg 1.5 arm. Hemoglobin below 10g was about the same in both groups, 11% (IFN) vs 9% (Peg 1.5). Discontinuation due to anemia was 0.2% in IFN vs 0.8% in Peg 1.5.
Overall discontinuations were about 13% in both arms; dose modifications 34% IFN 42% Peg 1.5.
Pegasys
Roche reported response rates from a total of 1130 IFN-naÔve cirrhotic & non-cirrhotic patients followed for 72 weeks. Patients received either IFN 3 MIU for 48 weeks or 6 MIU for first 12 weeks followed by 3 MIU for remaining 36 weeks, or Pegasys. Again, standard IFN+RBV dosing has shown about 40% viral sustained virologic response rates.
|
Individuals with Low Grade Fibrosis (0,1) |
|
| Genotype 1- | 25% <100
copies/ml Pegasys vs 8% regular IFN |
| Genotype non-1- | 54% undetectable
<100 copies/ml (n=149) receiving Pegasys vs 34% (n=132) getting regular IFN |
| More Advanced Fibrosis (grade 4)- | Overall, 30%
(n=108) undetectable <100 copies/ml with Pegasys vs 6% IFN. |
| Genotype 1- | 16% (8/51) Pegasys vs 3% (2/64) IFN |
| Genotype non-1 | 49% Pegasys vs 12% IFN |
There are no results yet from studies combining Pegasys with RBV but studies are ongoing.