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Ira S. Goldman, MD; John L. Gollan, MD, PhD; Kris V. Kowdley, MD; Paul Martin, MD;
Marion G. Peters, MD |
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HEPATOLOGY WATCH® |
Special Issue Featuring Clinical Study Highlights in Hepatitis C
38th Annual Meeting of the European Association for the Study
of the Liver (EASL)
PHARMACOKINETICS OF PEGINTERFERONS
Once-weekly administration of peginterferon alfa-2b is
insufficient. R. Bruno and colleagues prospectively compared the
pharmacokinetics of PEG-IFN α-2a and PEG-IFN α-2b in 22 previously
untreated chronic hepatitis C (CHC) patients randomized to two treatment
groups: Group A (n=10) received 180 µg/wk PEG-IFN α-2a; and Group B (n=12)
received PEG-IFN α-2b 1 µg/kg/wk. Ribavirin (RBV) 1000-1200 mg/d was administered
to both groups. Serum samples for PK analysis were collected at baseline and
24, 48, 120 and 168 hr after administration. After dosing, serum levels of
PEG-IFN α-2b achieved maximum levels at 24 hr and then decreased rapidly;
no drug was detected at 120 hr in 7 subjects and at 168 hr in 11 subjects. In
contrast, PEG-IFN α-2a concentrations increased continuously over time,
reaching maximum levels in 48-168 hr; drug levels were detectable in all
patients at 168 hr post-dosing. Based on these findings, the authors concluded
that once-weekly administration of PEG-IFN α-2b is not sufficient for
continuous exposure to IFN over a period of more than 120 hr, suggesting the
need for twice-weekly administration. (R. Bruno et al. J Hepatology 2003;38:443A)
CLINICAL TRIAL RESULTS WITH INTERFERON (IFN) IN CHC
The impact of antiviral therapy with IFN on the course of
chronic HCV infection: a systematic review. P. Amasio and colleagues
performed a systematic review of published data on long-term follow-up of patients
with persistent HCV suppression and the rate of cirrhosis and HCC in responders
as compared to nonresponders after IFN therapy. In patients achieving a
sustained virological response (SVR), relapse was observed in about 13% and
progression to cirrhosis was uncommon. The vast majority of patients in
remission during the first 6 months after antiviral treatment will remain so
long-term. Cumulative data from the literature showed a significant reduction
in the rate of progression to cirrhosis and HCC in patients with a SVR as
compared to nonresponders or relapsers. (P. Almasio et al. J Hepatology 2003;38:421A)
Long-term durability of SVR achieved with peginterferon
alfa-2a. M. Swain and colleagues reported long-term follow-up data from 463
patients who had been enrolled in one of 3 phase II/III pivotal controlled
trials with PEG-IFN α-2a monotherapy (180 µg/wk) or one of 2 phase III
pivotal controlled trials with combination PEG-IFN α-2a/RBV therapy (180
µg/wk + 1000/1200 mg/d RBV). Patients had achieved an SVR and not received any
further treatment for CHC. After a mean duration of follow-up of ~2 years, 459
of 463 patients (99.1%) remain HCV RNA negative. SVR was durable in all CHC
patient groups, including those with HCV genotype 1 (48% of patients) and
cirrhosis. (M. Swain et al. J Hepatology
2003;38:603A)
Low fixed-dose combination peginterferon alfa-2b plus RBV is
effective in CHC genotype 1 naïve patients. S. Bruno and colleagues
reported the results of a multicenter clinical trial in 313 CHC genotype 1
naive patients who were randomized to receive standard IFN 6 MU qod for 48 wk
(n=150) or PEG-IFN α-2b 100 µg/wk x 8 wk followed by 50 µg/wk x 40 wk
(n=163). RBV 1000 or 1200 mg/d was given in both groups for the entire period.
Low fixed-dose combination PEG-IFN α-2b + RBV produced significant
improvements in SVR as compared with high dose standard IFN/RBV (41.1% vs
29.3%, p=0.037). Treatment withdrawal for side effects was significantly more
frequent with the IFN/RBV group than in the PEG-IFN α-2b/RBV group (32% vs
20%, p=0.014). With a fixed dose (not weight-based) of PEG-IFN α-2b, there
was no significant difference in SVR rate based on patient weight or BMI.
Patients <50 years of age and with mild fibrosis had the highest likelihood
of response to PEG-IFN α-2b/RBV therapy. (S. Bruno et al. J Hepatology 2003;38:450A)
HCV genotype 2/3 infection: a curable disease? M.
Shiffman and colleagues investigated the virological response in 617
treatment-naïve patients infected with HCV genotypes 2/3 from 2 randomized,
multicenter trials during and after therapy with PEG-IFN α-2a + RBV. SVR was obtained in 80.6% of patients and was
not compromised when RBV was given at a dosage of 800 mg/d or administered for
24 rather than 48 wk. The results show that, regardless of baseline viral load,
patients with HCV genotype 2/3 can be treated for 24 wk without sacrificing
efficacy. (M. Shiffman et al. J
Hepatology 2003;38:590A)
Improved liver histology with peginterferon alfa-2a. C. Camma
et al. performed a meta-analysis of data on 1013 naïve patients with pre- and
post-treatment biopsies from 3 randomized clinical trials to assess the
differences between PEG-IFN α-2a and standard IFN on liver histology, to
assess whether the benefit is related to virological response, and to identify
predictors of histological improvement. In patients with CHC with or without
cirrhosis, PEG-IFN α-2a significantly improved fibrosis compared to
standard IFN. An impressive reduction in fibrosis after treatment was observed
in patients with a SVR or relapse. SVR and baseline BMI were significant predictors
of improvement. (C. Camma et al. J
Hepatology 2003;38:94A)
Combination peginterferon alfa-2a plus RBV is safe and
effective in CHC patients with compensated cirrhosis. P.
Marcellin and colleagues investigated the safety and efficacy of PEG-IFN
α-2a + RBV in patients with CHC and compensated cirrhosis who were
enrolled in 2 pivotal phase III studies (n=377). Cirrhotic patients treated for
48 wk with PEG-IFN α-2a 180 µg/wk + 1000 or 1200 mg/d RBV achieved a
significantly higher SVR than those treated with standard IFN alfa-2b + RBV
(49% vs 33%). SVR rates were higher in patients with non-1 genotypes and with
lower viral loads (<2 million copies/mL). There were no significant
differences in SVR rates when the data were grouped by body weight. The overall
safety profile, incidence of serious adverse events and premature withdrawal of
PEG-IFN α-2a + RBV in patients with compensated cirrhosis was similar to
that in the overall population in the 2 studies. (P. Marcellin et al. J Hepatology 2003:38:530A)
Predictors of virologic relapse in CHC patients receiving
peginterferon alfa-2a alone or with RBV. V. Balan and colleagues
determined the frequency of relapse and identified baseline parameters
associated with relapse among 1375 CHC patients who received PEG-IFN α-2a
180 µg/wk ± RBV 800-1200 mg/d for 24 or 48 weeks based on 2 phase III pivotal
trials. High baseline viral load, and, to a lesser degree, cirrhosis, were
found to be associated with relapse, particularly in HCV genotype 1 patients.
Combination therapy vs monotherapy results in lower relapse rates. CHC
genotypes 2/3 patients experience lower relapse rates regardless of RBV dose
given, compared with genotype 1 patients in whom relapse is dependent on RBV
dose and duration of treatment. More
than 48 weeks of treatment for patients with high baseline viral loads,
genotype 1, and cirrhosis may be necessary and should be investigated. (V.
Balan et al. J Hepatology 2003;38:52A)
Efficacy of peginterferon alfa-2b plus RBV in nonresponders.
M. Chousterman and colleagues compared the safety and efficacy of two
dose regimens of PEG-IFN α-2b + RBV in 233 nonresponders to standard IFN
monotherapy or combination therapy. Group 1 received PEG-IFN α-2b 2.0
µg/kg/wk + RBV 800 mg/d x 8 wk, then PEG-IFN α-2b 1.0 µg/kg/wk + RBV 800
mg/d x 40 wk. Group 2 received PEG-IFN
α-2b 1.0 µg/kg/wk + RBV 800 mg/d x 48 wk.
226 patients have completed 48 wk of therapy. End-of-treatment (ETR)
virological response at 48 wk was higher in group 1 than in group 2 (32% vs
18%). The rate of EVR was higher among nonresponders to prior monotherapy in
group 1 than in group 2 (44% vs 17%), and among patients with non-1 genotypes
in group 1 vs group 2 (58% vs 24%). At wk 48, the induction dose is more
effective than the fixed dose in nonresponders. (M. Chousterman et al. J Hepatology 2003;38:457A)
Efficacy of peginterferon alfa-2a plus RBV in nonresponders
and relapsers. E. Parise et al. investigated the safety and
efficacy of PEG-IFN α-2a + RBV in CHC patients who either relapsed or did
not respond to initial therapy with standard IFN/RBV. 131 patients (98
nonresponders, 35 relapsers) have completed 24 wk of treatment and 107 patients
(77 nonresponders, 30 relapsers) have completed 48 wk of treatment with PEG-IFN
α-2a 180 µg/wk + RBV 800 mg/d. After 48 wk, the overall ETR was 64% (80%
in relapsers, 58% in nonresponders). These preliminary findings are
encouraging, especially since only 800 mg/d RBV was used. (E. Parise et al. J Hepatology 2003;38:555A)
CLINICAL TRIAL RESULTS IN HIV/HCV COINFECTED PATIENTS
Week 48 data from Ribavic Trial. S. Pol and
colleagues conducted a randomized trial in HIV/HCV coinfected patients,
comparing the safety and efficacy of a 48-wk course of standard IFN α-2b
(3 MU tiw, n=210) vs PEG-IFN α-2b (1.5 µg/kg/wk, n=206) + RBV 800 mg/d.
ETR at 48 wk has been analyzed in 158 patients receiving the standard IFN
combination and 157 patients receiving PEG-IFN α-2b combination therapy.
Preliminary ETR rates at wk 48 were 37% for the PEG-IFN α-2b combination
and 24% for the standard IFN combination. Serious adverse events, including
psychiatric events and sepsis, were very frequent, occurred more frequently in
the PEG-IFN α-2b group, and resulted in a high rate of therapy
discontinuation (34% PEG-IFN α-2b combination, 35% standard IFN
combination). (S. Pol et al. J Hepatology
2003;38:92A)
HCV relapses following the end of anti-HCV therapy are more
frequent in HIV-coinfected patients. M. Perez-Olmeda and colleagues
examined the rate of HCV relapse in 58 HIV-HCV coinfected patients who had an
ETR (48 wk ETR for genotype 1/4 patients; 24 wk ETR for genotype 2/3 patients)
after receiving combination IFN (31 PEG-IFN, 27 standard IFN) + RBV (800 mg/d)
therapy. The overall relapse rate was 32.7%, which is significantly higher than
that reported in HIV-negative patients with HCV. The relapse rate was not
influenced by genotype, form of IFN, CD4 count, HIV RNA level, or the use of
antiretroviral therapy. HCV relapses after treatment are more frequent in
HIV-coinfected patients. The efficacy of extended periods of anti-HCV therapy
should be examined in HIV/HCV coinfected patients who are initial responders.
(M. Perez-Olmeda et al. J Hepatology
2003;38:561A)
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