Entecavir
Entecavir
Entecavir
New Medicines Profile Produced for the Abu Dhabi Health Authority Poison and Drug Information Centre By Kifah Qawasme October 2007
Introduction
Approximately 400 million people worldwide are infected with chronic hepatitis B (CHB)1 In the Middle East and Indian subcontinent, about 5% of people in the general population are chronically infected.2
Many patients with CHB in Mediterranean and Asian countries carry a mutant virus strain that is not able to produce HBeAg (also known as precore mutant CHB or HBeAgnegative CHB). These patients are usually more resistant to conventional therapies.3
Treatment options
a)Subcutaneous interferon-alpha (IFN-a) b)Lamivudine resistance problem. c)Adefovir
Pharmacology
Entecavir is a guanosine nucleoside analogue. It undergoes intracellular phosphorylation to an active triphosphate form that inhibits hepatitis B virus (HBV) polymerase.
1
entecavir
HBV RNA
Viral polymerase
3.
Base priming 2 Reverse transcription of the negative strand from the pregenomic messenger RNA 3 Synthesis of the positive strand of HBV DNA
HBV RNA
entecavir
GTP
Baraclude (entecavir) Summary of Product Characteristics. Bristol-Myers Squibb Pharma EEIG. August 2007
FDA Approval
Indicated for the treatment of chronic hepatitis B virus infection in adults with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or Histologically active disease. This indication is based on histologic, virologic, biochemical, and serologic responses in nuceosidetreatment-naive and lamivudine-resistant adult subjects with HBeAg-positive or HBeAg-negative chronic HBV infection with compensated liver disease and on more limited data in adult subjects with HIV HBV co-infection who have received prior lamivudine therapy.
Entecavir
Brand Name, (Manufacturer): BARACLUDE , (BRISTOL MYERS SQUIBB) Therapeutic Class: Antiviral agent ( viral hepatitis B) Entecavir is rapidly absorbed from the gastrointestinal tract with peak plasma concentrations occurring within 1.5 hours of administration. Dosage and Administration: The dose in nucleoside nave patients is 0.5mg/day with or without food, whilst in lamviduine-refractory patients the dose is 1mg/day taken on an empty stomach. Marketing Authorization: FDA; March 2005, UK and EMEA; June 2006.
Comparative Efficacy
In HBeAg-positive patients, a significantly p = 0.009) greater proportion of entecavir than lamivudine recipients showed a histological improvement in their liver biopsy at 48 weeks (primary endpoint). Furthermore, at 48 weeks, entecavir generally showed better efficacy than lamivudine according to secondary endpoints. Response rates for undetectable serum HBV DNA by PCR and serum ALT normalisation favoured entecavir over lamivudine and the mean change from baseline in serum levels of HBV DNA by PCR was greater in entecavir than in lamivudine recipients (table I), as was the HBV bDNA response rate (91% vs 65%; p < 0.001). Ishak fibrosis scores improved in 39% of entecavir-treated patients and 35% of lamivudine-treated patients (p=0.41) and worsened in 8% and 10% respectively. Rates of loss of HBeAg (22% vs 20%) and HBsAg (2% vs 1%) did not differ between treatment groups.
The 3-year ETV cohort demonstrated the following results at 144 weeks:
90% achieved undetectable HBV DNA 80% achieved normalised ALT 33% experienced HBeAg loss in year 3 16% achieved HBeAg seroconversion in year 3
Among HBeAg-negative patients, a significantly (p = 0.01) greater proportion of entecavir than lamivudine recipients had a histological improvement in their liver biopsy at 48 weeks (primary endpoint). Entecavir also demonstrated generally greater efficacy than lamivudine according to secondary endpoints The composite-endpoint response rate also favoured entecavir, as did the HBV bDNA response rate (95% vs 89%; p = 0.005), whereas the rate of Ishak fibrosis score improvement did not differ between treatments. between treatment groups.
2 years follow up
2-year cohort at week 9612:
96% ETV vs 64% LVD achieved undetectable HBV DNA 27% ETV vs 21% LVD achieved normalised ALT
Conclusion
In the two studies involving nucleoside nave patients, entecavir was associated with significantly higher rates of histologic, virologic and biochemical improvements compared with lamivudine. This appears to be due to its potent suppression of HBV replication.
Significantly (p < 0.0001) more entecavir than lamivudine recipients exhibited an improvement their co-primary endpoints, liver histology at 48 weeks or the composite endpoint (undetectable serum HBV bDNA and normalisation of serum ALT level) in lamivudine refractory HBeAg-positive patients. patients. Response rates in entecavir recipients were superior to those in lamivudine recipients in terms of Ishak fibrosis score, undetectable serum HBV DNA by PCR (<300 copies/mL), mean change in serum HBV DNA level by PCR, serum ALT normalisation and HBeAg loss (10% vs 3%; p = 0.0278). HBeAg seroconversion rates did not differ between treatment groups.
2 years follow up
Cumulative confirmed results for all treated patients up to 96 weeks were13:
30% ETV vs <1% LVD for HBV DNA <300 copies/mL by PCR (p<0.0001) 85% ETV vs 29% LVD for ALT normalisation
(p<0.0001)
Resistance
Resistance monitoring data over 96 weeks of entecavir treatment in both HBeAg positive and HBeAg negative nucleoside nave patients has been published8. The analysis failed to find any genotypic or phenotypic evidence of emerging entecavir resistance in nucleoside nave patients over 96 weeks of treatment.
Results from a Baraclude (entecavir) resistance monitoring programme, which were presented by BristolMyers Squibb Company at the 42nd Annual Meeting of the European Association for the Study of Liver Diseases (EASL). The main findings were: There was a continued low incidence of resistance in three studies of nucleoside-naive chronic hepatitis B patients through four years of treatment (n=663). Two patients (<1%) experienced virological breakthrough due to entecavir resistance during the third year, and no additional patients developed resistance in the fourth year. Lamivudine resistance seems to increase the risk of entecavir resistance emerging. In patients who were refractory to lamivudine, virological breakthrough due to entecavir resistance occurred in 1% (2/187) during the first year, 10% (14/146) in the second year, 16% (13/80 in the third year, and 15% (8/53) during year four.
10 Safety
Assessment of adverse reactions is based on four clinical studies in which 1,720 patients with chronic hepatitis B infection received double-blind treatment with entecavir 0.5 mg/day (n = 679), entecavir 1 mg/day (n = 183), or lamivudine (n = 858) for up to 107 weeks. The safety profiles of entecavir and lamivudine, including laboratory test abnormalities, were comparable in these studies
Selected Clinical Adverse Events of Moderate-Severe Intensity (Grades 2-4) Reported in Four Entecavir Clinical Trials Through 2 Years
Selected Treatment Laboratory Abnormalities Reported in Four Entecavir Clinical Trials Through 2 Years
The most common adverse reactions of any severity with at least a possible relation to entecavir were headache (9%), fatigue (6%), dizziness (4%) and nausea (3%).
Warnings
Lactic acidosis and severe hepatomegaly with steatosis, including fatal cases, have been reported with the use of nucleoside analogues alone or in combination with antiretrovirals. Severe acute exacerbations of hepatitis B have been reported in patients who have discontinued anti-hepatitis B therapy, including entecavir. Hepatic function should be monitored closely with both clinical and laboratory followup for at least several months in patients who discontinue anti-hepatitis B therapy. If appropriate, initiation of anti-hepatitis B therapy may be warranted
Limited clinical experience suggests there is a potential for the development of resistance to HIV (human immunodeficiency virus) nucleoside reverse transcriptase inhibitors if Entecavir is used to treat chronic hepatitis B virus infection in patients with HIV infection that is not being treated. Therapy with Entecavir is not recommended for HIV/ HBV co-infected patients who are not also receiving highly active antiretroviral therapy (HAART).
Place in therapy
The American association for the study of liver diseases (AASLD)11 2007 update of CHB
Treatment may be initiated with any of the 6 approved antiviral medications but pegIFN-, adefovir or entecavir are preferred in view of the need for long-term treatment. (I for pegIFN-, adefovir, entecavir and telbivudine and II-1 for IFN- and lamivudine). Patients who failed to respond to prior IFN(standard or pegylated) therapy may be retreated with nucleoside analogues (NA)
NO
YES
Young Patient <40years
NO
NO
peginterferon alfa2a
Summary
In two-stage analyses, entecavir has been shown to be non-inferior and superior to lamivudine for the treatment of HBV in nucleoside-nave HBeAg positive and negative patients and in lamivudine-refractory patients with a similar adverse event profile. There are no published studies comparing the sustained antiviral effect of entecavir versus adefovir, the other oral HBV therapy. Unlike lamivudine and adefovir, entecavir is not licensed in patients with decompensated liver disease and there is limited evidence at present in liver transplant patients.
The optimum length of treatment is unknown and sustainability of response after discontinuation of treatment has still to be fully established. Development of resistance to entecavir therapy in nucleoside-nave patients has not been shown but resistance in patients who already carry important lamivudine mutations has led to virologic rebound.
The end
Thank you
References
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Lai CL, Ratziu V, Yuen MF, Poynard T. Viral hepatitis B. Lancet 2003; 362(9401): 20892094. World Health Organization Fact Sheet WHO/204; October 2000. Hadziyannis SJ, Papatheodoridis GV, Vassilopoulos D. Treatment of HBeAg-negative chronic hepatitis B. Semin Liver Dis 2003;23:81-8. Chang TT, Gish RG, de Man R, Gadano A, Sollano J, Chao YC et al. A comparison of entecavir and lamivudine for HBeAg-positive chronic hepatitis B. N Engl J Med 2006; 354:1001-1010. Lai CL, Shouval D, Lok AS, Chang TT, Cheinquer H, Goodman Z et al. Entecavir versus lamivudine for patients with HBeAg-Negative chronic hepatitis B. N Engl J Med 2006; 354:10111020. Sherman M, Yurdaydin C, Sollano J, Silva M, Liaw Y-F, Cianciara J et al. Entecavir for treatment of lamivudine refractory, HBeAg-positive chronic hepatitis B. Gastroenterology 2006;130:2039-2049. Chang TT, Chao YC, Kaymacoglu S, Cheinquer H, Pessoa M, Gish R et al. Entecavir maintained virologic suppression through 3 years of treatment in antiviral-naive HbeAg (+) patients (ETV 022/901) 57th Annual Meeting of the American Association for the Study of Liver disease, Boston Massachusetts, Oct 27-31 2006. Colonno R, Rose R, Baldick CJ, Levine S, Pokornowski K, Yu CF et al. Entecavir resistance is rare in nucleoside naive patients with Hepatitis B. Hepatology 2006; 44:1656-1665. Colonno R, Rose R, Levine S, et al. Entecavir two year resistance update: no resistance observed in nucleoside nave patients and low frequency resistance emergence in lamivudine refractory patients (abstr). Hepatology 2005;42:573A574A.
10. Baraclude (entecavir) FDA package insert, Bristol-Myers Squibb Company. July 2007. 11. Lok A, McMahon B. American Association for the Study of Liver Diseases (AASLD) PRACTICE GUIDELINES; Chronic Hepatitis B. HEPATOLOGY. 2007; 45:50739. 12. . Manns M, et al. 12th ISVHLD 2006; 15 July 2006; Paris, France. Poster
P082 13. Yurdaydin C, et al. 41st EASL; 2630 April 2006, Vienna, Austria. Oral Presentation. (Yurdaydin C, et al. J Hepatol 2006;44(suppl 2):v-viii, S1 300. Abstract 80).
Ishak score ,which stages fibrosis from 0-6 (1-2, portal fibrotic expansion; 3-4, bridging fibrosis; 5-6, cirrhosis).