Entecavir: new hepatitis B drug-phase III study results of 48-weeks therapy in HBeAg+ nucleoside-naïve patients
Written by Jules Levin
Results from 3 large phase III studies of entecavir are being presented at this conference (55th Annual American Association for the Study of Liver Diseases), as well as a number of substudies. At today's late afternoon oral sessions, Robert Gish reported results from ETV-022, a study in 700 patients comparing entecavir 0.5 mg once daily to lamivudine 100 mg once daily. This is an international randomized, double-dummy, double-blind study. Liver biopsies were performed within 52 weeks of randomization and at week 48.
BRIEF SUMMARY: ETV showed superiority with histolpgic improvement (72% vs 62%; mean viral load reduction by PCR; -6.98 vs -5.46 log; undetectable HBV DNA by PCR: 69% vs 38%; ALT normalization: 78% vs 79% <400 c/ml; (all significant). Loss of HBeAg & seroconversion were similar for both groups; safety profile was similar for both; fewer discontinuations due to adverse events for ETV; fewer ALT flares observed both on & off treatment for ETV; entecavir resistance was not observed. Up to 14 log viral load reductions were observed.
Patients were HBsAg+ for >24 weeks prior to screening for study; HBeAg-positive; HBV DNA >3 MEq/mL (by DNA); serum ALT 1.3-10 x ULN; compensated liver function; nucleoside-naïve (<12 weeks of therapy); last dose of anti-HBV therapy >24 weeks prior to randomization; I think Gish said 13% of patients had previously used IFN.
75% were men. Mean 35 yrs old. 40% Caucasian, 57% Asian. REGION: 24% Europe; 48% Asia; 13% North America; 13% South America.
BASELINE HISTOLOGY: comparable between arms
Knodell Necroinflammatory Score (0-18) Mean:
Knodell Fibrosis Score (0-4)
Mean: ETV 1.7, LAM 1.7
Ishak Fivbrosis Score (0-6) Mean
Score >=5, cirrhosis
--entecavir & LAM: 8%
HISTOLOGIC IMPROVEMENT (primary efficacy endpoint) Week 48
Improvement in Knodell necroinflammatory score by at least two points, plus no worsening of Knodell fibrosis score
ETV (n=314): 72%
LAM (n=314): 62%
IMPROVEMENT IN ISHAK FIBROSIS SCORE Week 48
Secondary Histologic Endpoint
PROPORTION OF PATIENTS WORSENED
MEAN CHANGE in HBV DNA from baseline by PCR
ETV: -6.98 log copies/ml
LAM: -5.46 log copies/ml
PROPORTION OF PATIENTS with HBV DNA <400 Copies/ml at Week 48
PROPORTION of PATIENTS with ALT NORMALIZATION (<1.25 x ULN)
LOSS of HBeAg & SEROCONVERSION at week 48
LOSS OF HBeAg
MOST FREQUENT ADVERSE EVENTS ON TREATMENT
Comparable across arms
Abdominal pain, upper 10%
CUMULATIVE SAFETY PROFILE
| ||ETV ||LAM |
|Any AE ||85% ||83% |
|SAE ||7% ||7% |
|G3/4 AE ||13% ||15% |
|D/C AE ||<1% ||3% |
|Deaths ||0 ||1% |
12 (3%) patients treated with ETV had on treatment ALT flares: 9/12 occurred between day 9 & 98 of treatment; 11/12 were self-limiting on continued therapy, resolving in 2 to 7 weeks. None of the ETV-treated patients had hepatic decompensation. 2 off treatment ALT flares.
20 (6%) patients treated with LAM had on-treatment ALT flares. 8 off treatment ALT flares.
On treatment ALT flare: ALT >2 x baseline and >10 x ULN
Off treatment ALT flare: ALT >2 reference (minimum of baseline and dosing) and >10 x ULN
PATIENT ENDPOINT MANAGEMENT
Complete Virologic Response
HBV DNA <0.7 q/mL by bDNA & loss of HBeAg
Virologic response Only
HBV DNA <0.7 MEq/mL by
bDNA but positive for HBeAg
HBV DNA >0.7 MEq/mL by bDNA