50th Annual AASLD Meeting, Nov 8
Highlights from Liver Conference in Dallas - Report 8
Jules Levin, NATAP
Reports:
Jenny Heathcote reported this morning in the oral session a anticipated
preliminary report on a phase 2/3 trial of Roche’s Pegylated IFN versus standard interferon for treatment of patients with chronic hepatitis C and
cirrhosis. Response to current standard HCV treatment for those with compensated cirrhosis has efficacy and safety concerns. This study’s aim is
to explore both safety and efficacy of PEG IFN in this population. A 5-year follow-up is expected. HCV RNA responses are reviewed below but the
histological responses were not available yet. They will be in near future. Virologic response is not everything. If a person is unable to achieve
sustained virologic response an improved histology may be helpful. Histology is the condition of the liver. However, the follow-up will have to discern if
short-term histologic benefits translate into long term benefits including quality of life, safety, improved health and improved longevity.
271 IFN-naïve individuals were randomized but not blindly to one of 3 regimens:
Patients are treated for 48 weeks with a 24 week follow-up. To be included in
study patients had to have serologic evidence of hepatitis C infection, quantifiable HCV RNA by PCR (Amplicor), elevated serum ALT, biopsy proven
cirrhosis/incomplete cirrhosis, compensated liver disease (Child-Pugh Class A), absolute neutrophil count of 1.5 x 10(3rd) or greater, and platelet count
of 75,000 or greater.
The definition of response in this study is virologic: end-of-treatment (ETR) –single undetectable measure, and follow-up with 2 undetectable measures
using Amplicor (sensitivity of below 100 copies/ml. This analysis is intent-to-treat which includes two patients who never received drug after
randomization and 1 who received 1 dose and quit study.
The following baseline demographics were about the same in all 3 groups: 70% male, 47 yrs of age, and 88% male. Median baseline viral loads were 3.2
million in IFN 3 MIU, 2.6 million in PEG-IFN 90 mcg, and 2.3 million in PEG-IFN 180 mcg. Regarding genotype 1—53% in IFN 3 MIU, 60% in PEG-IFN 90 mcg
and 55% in PEG-IFN 180 mcg had genotype 1. Cirrhosis—76% in IFN 3 MIU, 79% in
PEG-IFN 90 mcg, and 79% in PEG-IFN 180 mcg. Transitional cirrhosis—24% in 3 MIU group, 20% in PEG-IFN 90 mcg, and 21% in PEG-IFN 180 mcg group.
Virologic Response
At the ETR 43% receiving PEG-IFN 180 mcg (n=87) had undetectable HCV RNA compared to 13% receiving IFN 3 MIU (n=88) and 43% receiving 90 mcg (n=96).
However, at the end of follow-up 29% in the 180 had undetectable while 13% in the 90 mcg group had undetectable. 8% in 3 MIU IFN group had response after
follow-up.
Sustained Response by Genotype
Only 10% (n=48) with genotype 1 receiving 180 mcg had undetectable HCV RNA. Adding ribavarin would be expected to improve response rate. 5% (n=58) receiving 90 mcg, and
0% (n=47) receiving 3 MIU had response. Individuals with non-genotype 1 virus had much better response: 53% (n=36) receiving 180 mcg, 25% receiving 90 mcg,
and 13% receiving 3 MIU.
Sustained Response by Baseline HCV RNA
Those receiving 180 mcg with 2 million viral load or below at baseline had 35% undetectable (n=43), while 18% (n=45) receiving 90 mcg, and 5% receiving
3 MIU (n=41) had sustained response.
Those with above 2 million had less of response: 23% receiving 180 mcg, 8% receiving 90 mcg (n=51), and 7% receiving 3 MIU (n=45).
Sustained Viral Response by Stage of Cirrhosis
30% of those receiving 180 mcg (n=69) with cirrhosis had sustained response compared to 13% receiving 90 mcg (n=76), and 4% receiving 3 MIU (n=87).
Those with transition to cirrhosis had 22% response rate in 180 mcg group, 11% in 90 mcg group, and 10% in 3 MIU group. Heathcote said there wasn’t much
difference between response of cirrhotics or transitional cirrhotics.
Safety
No patients were withdrawn due to absolute neutrophil counts. There was a decline in counts after starting therapy from about 3.5 to 2.0. On the graph
there appeared to be a difference (2.5 vs 2.0) in the level of absolute count during therapy between PEG IFN and 3 MIU. Doses had to be reduced in some
patients. 7 patients were withdrawn from therapy due to low platelet count. Mean baseline values were about 160,000 and declined to between 120,000 and
100,000 during therapy. But following therapy both neutrophil and platelet counts increased towards baseline.
Dose modifications- 37% in 180 mcg group, 25% in 90 mcg group, and 29% in 3 MIU group. Heathcote said dose modification was often for short period of
time. Withdrawn due to AE or abnormal lab—13%, 11%, and 10% in 180, 90, and 3 MIU groups, respectively. The total withdrawal rates were higher—27% in 3 MIU
group, 19% in 90 mcg group, and 23% in 180 mcg group. Heathcote said this was because at week 24 patients were told their HCV RNA and many not responding
withdrew.
One safety concern going into study was that compensated cirrhosis would turn into decompensated during therapy but Heathcote said she did not observe
this. In genotype 1 group response was only 10% but adding ribavarin ought to improve response, and improved histology (improved condition of liver) may
serve patients well over longer turn even without HCV RNA undetectable. The durability of virologic response in cirrhotics and longer term safety remain
to be followed.
Risk Factors For Progression of Fibrosis in Untreated Patients
In this morning’s second oral report S.D. Ryder, of the Queens Med Ctr in Nottingham UK, presented on progression of liver fibrosis in mild hepatitis
C. A number of possible risk factors for progression have been suggested and the natural history of hep C can be variable for individuals. This study
attempts to identify risk factors for progression of fibrosis in paired biopsies from untreated patients. 225 patients received paired biopsies. 132
were male, 93 were female, meadian age 37, 64% were IVDUs and 46% had genotype 1, 44% had genotype 3. During 3-4 month interval follow-up patients
had ALT and alcohol consumption monitored. The median time between biopsies was 31 months.
The risk factors studied included:
Initial (biopsy 1) Knodell score was 2 (0-14). Most had below 6. 60% had no
fibrosis on initial biopsy. 77% had a fibrosis score of 1. 63 patients (28%) showed progression of fibrosis by 1 or more points. Overall fibrosis
progression was 0.12 units per year (time to cirrhosis 33 years).
Factors Predicting Progression
Knodell inflammatory score was 4.5 in progressors and 1.1 in non-progressors at initial biopsy mean ALT was 112 for progressors and 79 for non-progressors at first
biopsy; the differences between progressors and non-progressors in both Knodell and ALT were significantalcohol intake was 12.6 units/week in progressors and 7.1 in
non-progressors (p=0.02)age at infection was 34.5 for progressors and 24,5 for
non-progressors (p=0.02)
Three variables predicted more rapid fibrosis progression:
no other variables reached statistical significance
In summary age, alcohol intake and male gender are high risk factors for increased liver fibrosis, and 28% of patients with mild hepatitis C show
progression of fibrosis over 28 months. These factors can be considered when deciding when to begin therapy.