Abu Dhabi Health Authority

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.

ETV mechanism of action

ETV inhibits all three activities of the HBV polymerase
1. 2.

1
entecavir
HBV RNA

entecavir 1st Base Pair 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

Positive strand DNA entecavir GTP

Negative strand DNA

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

Clinical studies nucleosidenave subjects

There have been two phase III randomized, double-blind studies in patients with chronic hepatitis B who have not previously been treated with a nucleoside analogue.4,5 One study was with patients who had HBeAg positive chronic hepatitis B4, the other was with patients who had HBeAgnegative chronic hepatitis B.5 The study design was similar for both.

Primary end point

The proportion of patients with histological improvements, defined as improvement by at least two points in the knodell necroinflammatory score, with no worsening in the knodel fibrosis score at week 48, relative to base line.

A comparison of Entecavir and Lamivudine for HBeAg-positive 4 chronic hepatitis B.

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.

3 year follow up7

Patients who had a HBV DNA <0.7 MEq/ml and remained HBeAg positive at week 96 were enrolled into a further cohort who were treated for a third year. 119 patients were enrolled and the efficacy and safety results at week 144 were presented at the Annual Meeting of the American Association for the Study of Liver Disease in 2006.

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

Entecavir versus Lamivudine for patietns with HBeAgNegative Chronic 6 Hepatitis B.

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.

Entecavir for Treatment of Lamivudine Refractory, HBeAgPositive Chronic 6 Hepatitis

Primary end point

The 2 coprimary efficacy end points were histological improvement, defined as a 2 points decrease in the kondell necroinflammatory score and no worsening of the score on the week 48 liver biopsy specimen compared with base line. The achievement of the composite end point, defined as serum HBV DNA < 0.7 MEq/ml by bDNA assay and ALT<1.25*UN at week 48.

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)

17% ETV vs 4% LVD for HBeAg seroconversion (p=0.0011)

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.

Incidence of Resistance in Patients Treated With Lamivudine, Adefovir, or Entecavir9

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)

Mafraq Chronic Hepatitis B infection(CHB) treatment guidelines

Patient with CHB infection HBsAg + Lamivudine:
100 mg orally daily. or 3mg/kg/d Dose reduction necessary for patients with renal insufficiency

Adefovir NO 10mg daily

NO Compensate d Liver YES

HBeAg +

NO Serum HBV DNA >20000IU/ml (105copies/ml)* YES

Lamivudine resistance

Naive Patient Entercavir 0.5 mg daily

Second choice First choice

NO

YES
Young Patient <40years

NO

Add Adefovir 10 mg daily Or switch to Entecavir 1 mg daily

NO

Naive Patient YES

Side Effects** or Refusal of injection

peginterferon alfa2a

1) Peginterferon alfa-2a OR 2)Entercavir 0.5 mg daily

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
1. 2. 3.

4.

5.

6.

7.

8.

9.

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).