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"Combination of Pegylated IFN and Lamivudine is superior to Lamivudine alone in the treatment of HBV"
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Reported by Jules Levin
Brief summary: 100 patients were randomized into the 2 treatment groups. Sustained virological response was significantly higher in combination therapy than lamivudine monotherapy (36% vs 14%, adjusted odds ratio=3.74). At the end of treatment, patients received combination therapy had a higher rate of virological response (60% vs 28%), had more substantial reduction of log10 HBV DNA (3.91 vs 2.83) and were less likely to have lamivudine resistant mutant (21% vs 40% p=0.045) than those who received lamivudine monotherapy. The combination arm had more adverse events requiring discontinuations and dose reductions. Sustained responders had more reduction in cccDNA and intrahepatic HBV DNA. See details below.
J Sung (Prince of Wales Hospital, The Chinese University of Hong Kong) reported on this study at DDW May 2004 in the oral Hepatitis Plenary Session. The treatment of HBV remains in development regarding use of peginterferon and orals antivirals: should IFN be used in combination with oral drugs and how should they be combined? Will combination therapy with oral drugs be effective?
Treatment of chronic hepatitis B infection is still unsatisfactory and previous studies combining conventional interferon with lamivudine yielded conflicting results. Aim: This prospective randomized study set to evaluate the efficacy and safety of peginterferon alfa-2b and lamivudine combination for chronic hepatitis B infection.
HBeAg-positive treatment-naive patients were randomized to receive either a combination of 32-week peginterferon alfa-2b (1.5mcg/kg/wk, max 100mcg) and 52-week lamivudine (100mg daily) (the PegIFN was started 8 weeks before Lamivudine) or 52-week lamivudine (100mg) monotherapy alone.
HBV DNA levels (measured by TaqMan real-time PCR assay), HBeAg status, HBV genotype, drug resistant mutant (INNO-LiPA HBV DR line probe assay), serum transaminase levels were monitored. Pre- and post-treatment liver histology (necro-inflammatory score according to Knodell system and fibrosis score according to Ishak system) were compared. The primary endpoint was sustained virological response (HBeAg seroconversion and HBV DNA <500,000 copies/ml) at 24 weeks after finishing medication. Secondary endpoints include end-of-treatment virological response, reduction in HBV DNA levels, biochemical responses and histologic necro-inflammatory and fibrosis scores.
Inclusion criteria: age 18-65; HbsAg for at least 6 months; evidence of HBV replication: HBV DNA >500,000 copies/ml, HBeAg+; previously untreated for HBV-infection; ALT 1.3-5 x ULN within 1 month.
Exclusion- any other cause of liver disease: HCV, HIV, Wilson's disease, Hemochromatosis, AIH, ALD. Evidence of decompensated liver disease: Child's B cirrhosis, ascites, variceal bleeding, HE; hypersplenism; coagulopathy (PT>13s); previous use or allergy to IFN.
TREATMENT
GROUP A
PegIFN a-2b
--BW>65 kg: 100 ug sc 1x per week; BW <65: 1.5 ug/kg sc 1x per week
Lamivudine
--100mg/day
GROUP B
Lamivudine
--100mg/day
Group A received PegIFN for 8 weeks when Lamivudine was added. Patients continued PegIFN for total of 32 weeks. Lamivudine was used for total of 52 weeks.
Histologic response was >=2 points improvement in Knodell score; >=2 points improvement in Ishak score.
ITT analysis-all randomized patients who received at least one dose of the study medication were included in the analysis.
RESULTS
Between April 2000 and March 2002. 182 patients were screened. 100 patients randomized 1:1 ratio to receive PIFN+LAM (50) or LAM (50). 82 not randomizedL 69 did not meet criteria, 13 defaulted.
48 patients in each arm completed treatment & followup.
DEMOGRAPHICS: no diiferences-age: 32-34; male: 31-36%; body weight: 64-68 kg; BMI: 22-25 kg/m2.
BIOCHEMISTRY: ALT normal: 4-6%; >1-2xULN: 13-21% (NS); >2-5xULN: 54-40% (NS); >5xULN 16-12% (NS); ALT 144 IU/l in combination arm vs 119 IU/l in LAM arm (p-0.20).
VIROLOGY:
HBeAg+: 100% in combination & 98% in LAM arms
HBV DNA >500,000 c/ml: 100% in both arms
Log HBV DNA: 8.04 in combination, 7.67 in LAM
HBV Genotype (p=0.96):
B- 30% in combination, 32% in LAM
C- 64% in combination, 64% in LAM
B+C- 6% in combination, 6% in LAM
HISTOLOGY
Necroinflammatory score: 5 in combination, 5 in LAM (p=0.89)
Fibrosis score: 1 in combination, 1 in LAM (P=0.34)
VIROLOGIC RESPONSE
End of Treatment (p=0.001)
--60% for PIFN/Lam
--28% for Lam
Sustained Response (p=0.011)
--36% for PIFN/Lam
--14% for Lam
ETR
--OR=5.08 (1.74-14.88)
--p=0.003
6 months after finishing treatment
--OR=3.74 (1.14-12.29)
--p=0.03
DNA UNDETECTABLE
--5 in combination, 2 in Lam
log10 DNA reduction
--3.91 (range 1.59-6.35) in combination, 2.83 (range 0.78-5.68) in Lam
HBsAg
--1 in combination, 0 in Lam
HBV Level
--after stopping treatment HBV DNA increased in both arms.
Biochemical response
ETR: 90% PIFN, 78% Lam (p=0.1)
SR: 50% PIFN, 30% Lam (p=0.04)
ALT Level
--after stopping treatment ALT increased in both arms.
Necro-Inflammation
In PIFN: 60% >2 point improvement, 10% >2 pt deterioration
Lam: 58% >2 pt improved, 9% >2 pt deterioration (p=1.0)
Fibrosis
PIFN: 15% > 2 pt improved, 10% >2 pt deterioration
Lam: 9% >2 pt improved, 4% >2 pt deterioration
P=0.59, improved; p=0.57, deteriorated
Lamivudine resistant mutant p=0.045
--lam: 40%
--combination: 21%
Serious adverse events
Disct treatment: 4 in combination arm (1 depression, 1 thyroid disease, 1 pulmonary TB, 1 local reaction); 0 in Lam.
Required dose reduction: 7 in combination (1 anemia, 2 neutropenia, 3 thrombocytopenia, 1 hepatic flare), 0 in Lam.
AUTHOR'S CONCLUSIONS
Combination therapy was associated with
--higher rate of sustained viral response
--more potent HBV suppression
--lower incidence of Lam resistance
RESPONSE TO ANTI-VIRAL THERAPY
| Overall | SR n=18 | Nonrsp/relap n=29 | | Log HBV DNA (serum) | 4.36 | 4.06 | 4.43 (p=0.038) | | Log ccc DNA | -0.57 | -1.22 | -0.28 (<0.001) | | Log intrahepatic HBV DNA | 0.20 | -0.27 | 0.49 (<0.001) | | YMDD mutant | 13% | 17% | 10% (0.56) |
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