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Efficacy and Safety of Entecavir Versus Adefovir in Chronic Hepatitis B Patients with Evidence of Hepatic Decompensation
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Reported by Jules Levin
AASLD Nov 3 2009 Boston, MA
Yun-Fan Liaw1, Maria Raptopoulou-Gigi2, Hugo Cheinquer3, Shiv Kumar Sarin4, Tawesak Tanwandee5, Nancy Leung6, Robert P. Myers7, Robert S. Brown Jr8, Mitchell Shiffman9, Jolanta Bialkowska10, Shijie Tang11, Elizabeth Cooney11
1Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan; 2Department of Internal Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece; 3Universidade Federal Do Rio Grande Do Sul, Porto Alegre, Brazil; 4Department of Gastroenterology G B Pant Hospital and Institute of Liver and Biliary Sciences, New Delhi, India; 5Department of Medicine, Siriraj Hospital, Mahidol University, Bangkok, Thailand; 6Alice Ho Miu Ling Nethersole Hospital, Hong Kong, China; 7Liver Unit, University of Calgary, Alberta, Canada; 8Center for Liver Disease and Transplantation, Columbia University Medical Center, New York, USA;
9McGuire VA Medical Center, Richmond, Virginia, USA; 10Department of Infectious Diseases, Medical University, Lodz, Poland; 11Research and Development, Bristol-Myers Squibb Company, Wallingford, USA
Summary of Results
ETV 1.0 mg was superior to ADV 10 mg for the primary efficacy endpoint
of HBV DNA change from baseline at Week 24
A greater proportion of ETV- versus ADV-treated patients achieved HBV
DNA <300 copies/mL at Weeks 24 and 48
ETV provided clinical benefit in this setting, as shown by change in CTP and MELD scores, and normalization of measures of hepatic function through Week 48
Short-term death rates observed in both groups are consistent with on-treatment results previously reported for this population (16%)2,3
Cumulative death and HCC event rates were 23% and 12% in ETV group and 33% and 20% in the ADV group, respectively. Clinical outcome events, such as death and HCC, may require more patients followed for a longer period of time to demonstrate any potential differences between the two treatment groups
Conclusions
Both therapies were well tolerated, and the safety experience in each group was comparable and consistent with what would be expected in a CHB population with decompensated liver disease
Entecavir demonstrated superior antiviral activity to adefovir in this patient population
Entecavir provided clinical benefit in patients with CHB infection and decompensated cirrhosis
Introduction
Decompensated cirrhosis is one of the major sequelae of longstanding hepatitis B virus (hbv) infection. At 5 years, survival of patients with decompensated cirrhosis was 14%, compared to 84% for patients with compensated cirrhosis1
Suppression of viral replication with antiviral therapy has been shown to result in clinical improvement and increased survival2,3
Interferons are contraindicated in this patient population4,5
Data on the safety and efficacy of nucleos(t)ide therapy in patients with chronic hepatitis B (chb) and decompensated liver disease are limited
Entecavir (ETV) has demonstrated superior virologic, histologic and biochemical efficacy compared to lamivudine (LVD) in nucleoside-naïve patients with CHB and compensated liver disease at Week 486,7
Long-term ETV therapy resulted in durable suppression of viral replication and regression of fibrosis/cirrhosis in CHB patients with compensated liver disease8
We present Week 48 results from a randomized, open-label, comparative study of ETV versus adefovir (ADV) in CHB patients with decompensated liver disease
RESULTS
* Two patients were randomized to ADV but were treated with ETV. Efficacy analyses are based on treated patients analyzed as randomized (ETV n=100; ADV n=91). Safety analyses are based on treated patients analyzed as treated (ETV n=102; ADV n=89); AE, n=2; AE, n=1; AE, n=2; AE, n=2
Other reasons for discontinuations included subject withdrew consent, lack of efficacy, lost to follow-up, patient no longer meets study criteria, and poor/non-compliance
The difference in HBV DNA responses favoring ETV persisted when analyzed by subgroup (LVDr or HBeAg status), although the magnitude of the differences varied across subgroups
* The difference in HBV DNA responses favoring ETV persisted when analyzed by subgroup (LVDr or HBeAg status), although the magnitude of the differences varied across subgroups
Analysis limited to patients with abnormal ALT at baseline
Analysis limited to HBeAg(+) patients at baseline, non-completer = Failure
* Non-completer = Failure
CTP class C/B to class A only
In Figures 4 and 5, interpretation of data beyond Week 48 is limited at
the time of this analysis. Subsequent data from this ongoing study will
provide more robust estimates
Death and HCC include events which occurred on and off treatment, all other parameters measure on-treatment events only
* One additional event occurred off treatment in the ADV group
Other remaining malignancies (both in ETV group) were: recurrent non-Hodgkin lymphoma (n=1), basal cell carcinoma (n=1)
Safety in patients with high MELD scores
A case series using ETV in decompensated cirrhotic patients has documented a risk for lactic acidosis in patients with high MELD scores (≤22)9
In the study protocol, a total of 22 patients had a baseline MELD score ≤22 (15 ETV and 7 ADV)
The study design did not include prospective measurements of serum lactate levels
Clinical safety observation within these patients with high MELD score ≤22 were as follows
- Deaths: 7/15 ETV; 5/7 ADV
- One AE of "lactic acidosis" in an ETV-treated patient required no treatment and resolved on continued ETV treatment, it occurred on study day 1293 with bicarbonate 16 mmol/L and creatinine 1.4 mg/dL (no lactate level reported). Lactate levels reported on Days 1340 and 1417 were 2.5 and 2.8 mmol/L, respectively
Among all treated patients (ETV 102; ADV 89), the following AEs related to lactate or low bicarbonate were identified: 1 event of lactic acidosis described above and 5 events of low bicarbonate (3 ETV and 2 ADV)
References
[1] Zoulim E, et al. Liver Transpl 2008;14:S1-S7.
[2] Fontana R, et al. Gastroenterology 2002;123:719-27.
[3] Schiff E, et al. Liver Transpl 2007;13:349-60.
[4] Lok ASF & McMahon BJ. Hepatology 2009;50:1-36.
[5] European Association for the Study of the Liver. J Hepatol 2008;50:227-42.
[6] Chang TT, et al. N Engl J
Med 2006;354:1001-10.
[7] Lai C-L, et al. N Engl J Med 2006;354:1011-20.
[8] Liaw YF, et al. Hepatology
2009;48:706A.
[9] Sarrazin et al. Hepatology 2009;HEP-09-0827
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