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Abstract H-457. Evaluation of Two doses of Peginterferon Alfa-2a (40KD)
(Pegasys) for the Treatment of Chronic Hepatitis C
Reported by Jules Levin
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Paul Pockros from the Division of Hepatology at Scripps Clinic in La Jolla,
CA. reported that for person with tolerability problems a lower dose of
Pegasys (135 ug/kg) has similar viral response and ALT response rate to the
full dose (180 ug); although, the histology response was not quite as good
using the lower dose. The adverse event profile was similar but favored the
lower dose a little.
The study aim was to examine the safety and efficacy of Pegasys 135 ug sc
once weekly vs Pegasys 180 ug sc once weekly and to determine the
effectiveness of 135 ug as a step down dose in previously untreated patients
with chronic HCV. 639 patients were randomized about equally to three arms.
The third arm was 3 MIU IFN a-2a three times per week. Patients were treated
for 48 weeks with a 24 week followup period. Biopsies were performed just
before study treatment was initiated and after the 24 week follow-up period.
This is a multinational study with 52 sites but most sites were in the US: 8
in Canada, 28 in USA, 11 in France, 2 in UK, and 3 in Australia.
The primary efficacy endpoint was undetectable serum HCV-RNA (<100 copies/ml,
or 50 IU) and normalized ALT at the end of 24 week treatment-free follow-up.
Other efficacy assessments included biochemical and virologic responses at
week 48 and histologic improvement at week 72.
Baseline characteristics (no major differences between arms)
male (%): 61% IFN, 73% 135 ug, 71% 180 ug
race-
caucasian: 86%, 86%, 84%
black: 7%, 4%, 6%
Asian 5%, 4%, 4%
Age: 42, 42, 42
Weight: 80 kg, 82 kg, 81 kg (pound equals 2.2 kg)
ALT: 85, 94, 88
HCV-RNA: 7.9, 7.5, 8.0 log
Mean HAI: 9.5, 9.2, 9.4
Histology-
cirrhosis: 7%, 9%, 5%
noncirrhosis: 83%, 80%, 82%
transition to cirrhosis: 10%, 11%, 13%
Genotype 1: 65%, 65%, 71%
non-genotype 1: 35%, 35%, 29%
RESULTS
Biochemical Response at End of Followup (week 72)
Pegasys 180 ug: 31%
Pegasys 135 ug: 32%
IFN a-2a 3 MIU tiw: 18%
Virologic Response
Pegasys 180 ug: 28%
Pegasys 135 ug: 28%
IFN a-2a 3 MIU tiw: 11%
Sustained Virologic response By Genotype
Genotype 1
Pegasys 180 ug: 22%
Pegasys 135 ug: 19%
IFN a-2a 3 MIU tiw: 7%
Genotype Non-1
Pegasys 180 ug: 41%
Pegasys 135 ug: 45%
IFN a-2a 3 MIU tiw: 19%
Pockros reported that the standard for determining the predictability of
response has historically been HCV-RNA at week 24. With peginterferon a-2a
180 ug the predictive values for either HCV-RNA <100 copies/ml or a 2-log
drop in viral load from baseline at week 12 is: negative predictive value
(NPV) = 0.98 (that is, if a patient has not achieved <100 or 2 log drop by
week 12 the chance of not achieving an SVR at week 72 is 98); the positive
predictive vale (PPV) = 0.45 (if a patient achieves <100 or a 2-log drop by
week 12 there chance of achieving an SVR at week 72 is 45%). This is based on
an intent-to-treat analysis of 210 patients receiving peginterferon a-2a 180
ug.
Histologic response
(defined as a 2 or more point improvement in HAI score from baseline to
post-treatment biopsy)
Pegasys 180 ug: 58% (p=0.017)
Pegasys 135 ug: 48%
IEFN a-2a 3 MIU tiw: 45%
Rate of Premature Withdrawal (due to intolerance)
10% in each arm.
Adverse Events
There was no difference in percent of many adverse events between the two
Pegasys doses but there were differences for a few.
Pyrexia: 27% in 135 dose vs 37% in 180 dose
Insomnia: 19% in 135 dose vs 29% in 180 dose
Alopecia: 18% in 135 dose vs 23% in 180 dose
Diarrhea: 21% in 135 dose vs 27% in 180 dose
Depression: 17% in 135 dose vs 21% in 180 dose
Dizziness: 13% in 135 dose vs 17% in 180 dose
Pockros then went on to compare the 28% SVR in this study to SVRs seen in 3
other Pegasys monotherapy studies. In those other 3 other studies they saw
36%, 30%, and 39% SVR, respectively. In the Fried study the momotherapy SVR
was 30%. Pockros compared the baseline characteristics between the study
showing a 39% SVR (n=267) and his study showing a 28% SVR (n=210). In the
Pockros study there were 4% more males (NS), patients were 2 yrs older (NS),
and 8% more had genotype 1 (NS); there was a significant difference in fi
brosis and percent of Blacks. In the Pockros study 18% vs 11% in other study
had Stage 3/4 fibrosis (p=0.02). There were 6% Blacks in the Pockros study vs
2% in the other study (p=0.01). There were 7% discontinuations in the other
study vs 10% in the Pockros study (NS). There were more dose modifications
(32%) in the Pockros study than in the other study (19%) (p=0.001).
Pockros concluded that Pegasys 180 ug remains the optimal dose but 135 ug
offers an effective step-down dose.
Independent Factors Associated with Sustained Virologic Response
pretreatment ALT
Baseline HCV-RNA
HCV genotype
Cirrhosis
Weight was not associated with response (<85 kg vs >85 kg)
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