Key Selected Highlights From Day One Hepatitis C Oral Presentations
Reported by Jules Levin
More comprehensive and detailed reports will be forthcoming by two
hepatologists reporting for NATAP at this conference, David Bernstein, MD
from North Shore Hospital in Long Island, NY, and Andrew Talal, MD from
Cornell Hospital in NYC. I have to go to a meeting tonite si I'm reviewing
only a few studies below.
In an overview of Hep C, Charles Howell, MD, from the University of Maryland
reported there are 3 million persons infected with HCV in the USA. There are
8-10,000 deaths annually but the number of deaths is declining to the current
level of about 36,000. It is projected that in 2000-2020 there will be a 61%
increase in cirrhosis; there will be a 6-8 fold increase in liver
transplantation; and a 2-3 fold increase in death. About i.8% of the US
population has HCV, but 1.5% are white, 3.2% are black, 2.1% are latino, 1.2%
are female, and 2.69% are male. The incidence of hepatocelluar carcinoma
(liver cancer) is increasing. The increase appears to have leveled off among
white males but appears to be comtinuing to increase among black males. The
mortality rates due to HCV are increasing among both black & white males.
IVDU accounts for 60% of persons with HCV. After the drug supply was cleaned
up in 1992, IVDU probably accounts for a higher proportion. Among IVDUs 80%
have HCV. 90% of hemophiliacs have HCV. Liver biopsy is recommended by Dr
Howell for patients with HCV. For prevention measures, he recommended not to
share items that may have blood on them: razors, toothbrushes, and cover cuts
and sores on the skin; avoid direct exposure to blood.
Pegylated Interferon alfa-2B (PegIntron) plus Ribavirin in Prior Nonresponders
Ira Jacobson, MD, from Cornell Hospital reported preliminary results for this
study conducted at multiple sites in NYC. Patients received one of two dosing
regimens: group 1- PegIFN a-2b 1.0 mcg/kg + ribavirin 1000/1200 mg/day
(n=160) , or Peg IFN a-2b 1.5 mcg/kg + ribavirin 800 mg/day (n=161). 87% had
genotype 1 in both groups; 7-9% had genotype 2. Mean fibrosis stage was 2.2
in both groups. 75% were men in both groups. Patients were 49 years of age.
69% had >1 million viral load in both groups and about 40% had stage 3-4
histology in both groups (38% in group 1 and 42% in group 2). Among genotype
1 nonresponders to previous combination therapy (IFN+RBV) about 10% in either
group were PCR negative after week 24 of followup (SVR). At week 72 there
were only 49 evaluable patients in group 1 out of 160 initially in that arm,
and there were 35 in group 2 evaluable at week 72 out of total 160 patients
initially in the arm, so the results are preliminary. These are preliminary
results as all the patients in the study have not been fully evaluated yet.
After 48 weeks of therapy 20% in group 2 were PCR negative (ETR) compared to
10% in group 1. So patients in group 2 appeared to respond better at weeks 24
(29%) and 48 (20%) but since there was a 10% SVR the rest of the patients
relapsed. Patients who previously relapsed from prior therapy had better
results: after 72 weeks 60% in group 2 and 43% in group 1 had SVR (numbers of
patients are relatively small).
Based on a small number of patients there appears to be a trend for
breakthroughs and relapse: 20-25% breakthrough (4/20); 4/12 relapsers (33%).
In his summary Jacobson said about 40% relapsed or broke-through, and
therefore he suggested that greater than 12 months therapy may be needed in
some patients. Jacobson said adherence appears to improve response. And he
said we should wait for final study results.
One of the concerns is will reimbursers cover retreatment for nonresponders.
If the data is not supportive it becomes it cost issue. But for the
individual patient denial of treatment for nonresponders can be unfair.
Pegylated Interferon alfa-2a (Pegasys) and Ribavirin in Treatment-Naive
Patients with Advanced Fibrosis/Cirrhosis: preliminary results
Beat Helbling from Switzerland reported on a study conducted in Switzerland
where there are less genotype 1 than in the USA. Patients received the
standard dose of Pegasys (180 mcg per week) plus one of 2 doses of ribavirin
(1000/1200 mg/day or 600/800 mg/day; high dose [n=28] vs low dose [n=33]).
About 50% of patients had genotype where in the US its about 70%. Viral load
was 3.3 million IUin the standard dose arm of ribavirin vs 2.1 million IU in
the low dose RBV arm. After 24 weeks of therapy the preliminary results
showed 93% of patients receiving standard RBV dose were PCR negative and 82%
were negative in the low dose regimen. Over the first 24 weeks of therapy the
numbers of patients reaching undetectable increased from week 2 until week
24. After week 24 genotype 1 patients had an 86% response and genotype 2/3
had a 92% response. There did not appear to be a difference in clinical
adverse events between the 2 different RBV dose regimens. Surprisingly, the
low dose arm had more depression. Neutrophils were 3.3 at baseline and 1.6 at
week 24, platelets were 154 at baseline and 99 at week 24. Hemoglobin was
14.5 at baseline and 11.7 at week 24. About 50% of evaluable patients had
neuropenia (<1000/ul) regardless of RBV dose; about 1/6th of patients in both
arms had thrombocytopenia (<50,000/ul), regardless of RBV dose. But 21% in
the standard RBV dose group had hemoglobin <10 compared to 6% in the low-dose
RBV group. There were more Peg-IFN and RBV dose reduction in the standard RBV
dose arm, and more doses were withheld in that arm. There were 10% serious
adverse events (4 depression).
Helbling summarized that although there were frequent dose modifications
there were only 10% discontinuations, so far. We need to wait for the final
study results but these interim results appear promising.
Pegylated Interferon a-2b (PegIntron) plus Ribavirin for HCV/HIV Coinfected
V Cargnel from Italy reported on a study conducted at the University of
Milan. She reported that in 1990 5% of HIV+ patients died of liver disease
and in 2000 it was 38%. Patients received one of 2 regimens: PegIntron 1.5
mcg/kg plus ribavirin 800 mg/day (n=59) or PegIntron 1.5 mcg/kg
monotherapy(n=63) for 48 weeks with a 24 week followup period. About 50% of
patients were IVDUs, ALT 144, viral load 1 million; 25% genotype 1, 30%
49 patients have completed at least 24 weeks of therapy. 17 patients (35%)
have negative PCR: 14/25 receiving Peg/RBV and 3/24 receiving only PEG). 56%
(14/25) were PCR negative at week 24 on Peg/RBV but this was an on-treatment
analysis. In other words 30% of patients receiving Peg/RBV discontinued
therapy mostly in the first month, due mostly to side effects and they were
not counted as failures. If they were counted as failures the 56% rate would
be lower. 17% (4/23) with genotype 1 had negative PCR compared to 50% (13/26)
with genotype 2/3, of patients receiving Peg/RBV. Intolerance or flulike
symptoms were the most common cause for discontinuation (13%). Responders
tended to have much steeper reduction in viral load in the first month than
nonresponders. Cd4s decreased from 581 to 452, but there was no change in HIV
PegIntron was reduced to 0.75 mcg/kg in 12 patients; ribavirin to 600 mg in 2
patients. No lactic acidosis was observed, nor any life threatening adverse