1. Name Of The Medicinal Product
Baraclude
Baraclude
Baraclude
2. Qualitative And Quantitative Composition
Each tablet contains 0.5 mg or 1 mg entecavir (as monohydrate).
Excipients: each 0.5 mg tablet contains 120.5 mg lactose and each 1 mg tablet contains 241 mg lactose.
Each ml oral solution contains 0.05 mg entecavir (as monohydrate).
Excipient:
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380 mg maltitol/ml
1.5 mg methylhydroxybenzoate/ml
0.18 mg propylhydroxybenzoate/ml
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For a full list of excipients, see section 6.1.
3. Pharmaceutical Form
Film-coated tablet (tablet)
Baraclude 0.5 mg film-coated tablets
White to off-white and triangular-shaped tablet with “BMS” debossed on one side and “1611” on the other.
Baraclude 1 mg film-coated tablets
Pink and triangular-shaped tablet with “BMS” debossed on one side and “1612” on the other.
Oral solution
Clear, colourless to pale yellow solution
4. Clinical Particulars
4.1 Therapeutic Indications
Baraclude is indicated for the treatment of chronic hepatitis B virus (HBV) infection (see section 5.1) in adults with:
• compensated liver disease and evidence of active viral replication, persistently elevated serum alanine aminotransferase (ALT) levels and histological evidence of active inflammation and/or fibrosis.
• decompensated liver disease (see section 4.4)
For both compensated and decompensated liver disease, this indication is based on clinical trial data in nucleoside naive patients with HBeAg positive and HBeAg negative HBV infection. With respect to patients with lamivudine-refractory hepatitis B, see sections 4.4 and 5.1.
4.2 Posology And Method Of Administration
Therapy should be initiated by a physician experienced in the management of chronic hepatitis B infection.
Baraclude should be taken orally, once-daily.
Compensated liver disease
Nucleoside naïve patients: the recommended dose is 0.5 mg once daily, with or without food.
Lamivudine-refractory patients (i.e. with evidence of viraemia while on lamivudine or the presence of lamivudine resistance [LVDr] mutations) (see sections 4.4 and 5.1): the recommended dose is 1 mg once daily, which must be taken on an empty stomach (more than 2 hours before or more than 2 hours after a meal) (see section 5.2).
Decompensated liver disease
The recommended dose for patients with decompensated liver disease is 1 mg once daily, which must be taken on an empty stomach (more than 2 hours before or more than 2 hours after a meal) (see section 5.2). For patients with lamivudine-refractory hepatitis B, see sections 4.4 and 5.1.
Duration of therapy
The optimal duration of treatment is unknown. Treatment discontinuation may be considered as follows:
• In HBeAg positive patients, treatment should be administered at least until HBe seroconversion (HBeAg loss and HBV DNA loss with anti-HBe detection on two consecutive serum samples at least 3-6 months apart) or until HBs seroconversion or there is loss of efficacy (see section 4.4).
• In HBeAg negative patients, treatment should be administered at least until HBs seroconversion or there is evidence of loss of efficacy. With prolonged treatment for more than 2 years, regular reassessment is recommended to confirm that continuing the selected therapy remains appropriate for the patient.
In patients with decompensated liver disease or cirrhosis, treatment cessation is not recommended.
Elderly: no dosage adjustment based on age is required. The dose should be adjusted according to the patient's renal function (see dosage recommendations in renal impairment and section 5.2).
Gender and race: no dosage adjustment based on gender or race is required.
Renal impairment: the clearance of entecavir decreases with decreasing creatinine clearance (see section 5.2). Dose adjustment is recommended for patients with creatinine clearance < 50 ml/min, including those on haemodialysis or continuous ambulatory peritoneal dialysis (CAPD). A reduction of the daily dose using Baraclude oral solution, as detailed in the table, is recommended. As an alternative, in case the oral solution is not available, the dose can be adjusted by increasing the dosage interval, also shown in the table. The proposed dose modifications are based on extrapolation of limited data, and their safety and effectiveness have not been clinically evaluated. Therefore, virological response should be closely monitored.
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Baraclude dosage*
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Creatinine clearance (ml/min)
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Nucleoside naïve patients
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Lamivudine-refractory or decompensated liver disease
|
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0.5 mg once daily
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1 mg once daily
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30 - 49
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0.25 mg once daily*
OR
0.5 mg every 48 hours
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0.5 mg once daily
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10 - 29
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0.15 mg once daily*
OR
0.5 mg every 72 hours
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0.3 mg once daily*
OR
0.5 mg every 48 hours
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< 10
Haemodialysis or CAPD**
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0.05 mg once daily*
OR
0.5 mg every 5-7 days
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0.1 mg once daily*
OR
0.5 mg every 72 hours
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* for doses < 0.5 mg Baraclude oral solution is recommended.
** on haemodialysis days, administer entecavir after haemodialysis.
Hepatic impairment: no dose adjustment is required in patients with hepatic impairment.
Paediatric population: the safety and efficacy of Baraclude in children below 18 years of age have not yet been established. No data are available.
4.3 Contraindications
Hypersensitivity to the active substance or to any of the excipients.
4.4 Special Warnings And Precautions For Use
Renal impairment: dosage adjustment is recommended for patients with renal impairment (see section 4.2). The proposed dose modifications are based on extrapolation of limited data, and their safety and effectiveness have not been clinically evaluated. Therefore, virological response should be closely monitored.
Exacerbations of hepatitis: spontaneous exacerbations in chronic hepatitis B are relatively common and are characterised by transient increases in serum ALT. After initiating antiviral therapy, serum ALT may increase in some patients as serum HBV DNA levels decline (see section 4.8). Among entecavir-treated patients on-treatment exacerbations had a median time of onset of 4-5 weeks. In patients with compensated liver disease, these increases in serum ALT are generally not accompanied by an increase in serum bilirubin concentrations or hepatic decompensation. Patients with advanced liver disease or cirrhosis may be at a higher risk for hepatic decompensation following hepatitis exacerbation, and therefore should be monitored closely during therapy.
Acute exacerbation of hepatitis has also been reported in patients who have discontinued hepatitis B therapy (see section 4.2). Post-treatment exacerbations are usually associated with rising HBV DNA, and the majority appears to be self-limited. However, severe exacerbations, including fatalities, have been reported.
Among entecavir-treated nucleoside naive patients, post-treatment exacerbations had a median time to onset of 23-24 weeks, and most were reported in HBeAg negative patients (see section 4.8). Hepatic function should be monitored at repeated intervals with both clinical and laboratory follow-up for at least 6 months after discontinuation of hepatitis B therapy. If appropriate, resumption of hepatitis B therapy may be warranted.
Patients with decompensated liver disease: a higher rate of serious hepatic adverse events (regardless of causality) has been observed in patients with decompensated liver disease, in particular in those with Child-Turcotte-Pugh (CTP) class C disease, compared with rates in patients with compensated liver function. Also, patients with decompensated liver disease may be at higher risk for lactic acidosis and for specific renal adverse events such as hepatorenal syndrome. Therefore, clinical and laboratory parameters should be closely monitored in this patient population (see also sections 4.8 and 5.1).
Lactic acidosis and severe hepatomegaly with steatosis: occurrences of lactic acidosis (in the absence of hypoxaemia), sometimes fatal, usually associated with severe hepatomegaly and hepatic steatosis, have been reported with the use of nucleoside analogues. As entecavir is a nucleoside analogue, this risk cannot be excluded. Treatment with nucleoside analogues should be discontinued when rapidly elevating aminotransferase levels, progressive hepatomegaly or metabolic/lactic acidosis of unknown aetiology occur. Benign digestive symptoms, such as nausea, vomiting and abdominal pain, might be indicative of lactic acidosis development. Severe cases, sometimes with fatal outcome, were associated with pancreatitis, liver failure/hepatic steatosis, renal failure and higher levels of serum lactate. Caution should be exercised when prescribing nucleoside analogues to any patient (particularly obese women) with hepatomegaly, hepatitis or other known risk factors for liver disease. These patients should be followed closely.
To differentiate between elevations in aminotransferases due to response to treatment and increases potentially related to lactic acidosis, physicians should ensure that changes in ALT are associated with improvements in other laboratory markers of chronic hepatitis B.
Resistance and specific precaution for lamivudine-refractory patients: mutations in the HBV polymerase that encode lamivudine-resistance substitutions may lead to the subsequent emergence of secondary substitutions, including those associated with entecavir associated resistance (ETVr). In a small percentage of lamivudine-refractory patients, ETVr substitutions at residues rtT184, rtS202 or rtM250 were present at baseline. Patients with lamivudine-resistant HBV are at higher risk of developing subsequent entecavir resistance than patients without lamivudine resistance. The cumulative probability of emerging genotypic entecavir resistance after 1, 2, 3, 4 and 5 years treatment in the lamivudine-refractory studies was 6%, 15%, 36%, 47% and 51%, respectively. Virological response should be frequently monitored in the lamivudine-refractory population and appropriate resistance testing should be performed. In patients with a suboptimal virological response after 24 weeks of treatment with entecavir, a modification of treatment should be considered (see sections 4.5 and 5.1).
Pre-existing lamivudine-resistant HBV is associated with an increased risk for subsequent entecavir resistance regardless of the degree of liver disease; in patients with decompensated liver disease, virologic breakthrough may be associated with serious clinical complications of the underlying liver disease. Therefore, in patients with both decompensated liver disease and lamivudine-resistant HBV, combination use of entecavir plus a second antiviral agent (which does not share cross-resistance with either lamivudine or entecavir) should be considered in preference to entecavir monotherapy.
Liver transplant recipients: there are limited data on efficacy and safety of entecavir in liver transplant recipients. Renal function should be carefully evaluated before and during entecavir therapy in liver transplant recipients receiving cyclosporine or tacrolimus (see section 5.2).
Co-infection with hepatitis C or D: there are no data on the efficacy of entecavir in patients co-infected with hepatitis C or D virus.
Human immunodeficiency virus (HIV)/HBV co-infected patients not receiving concomitant antiretroviral therapy: entecavir has not been evaluated in HIV/HBV co-infected patients not concurrently receiving effective HIV treatment. Emergence of HIV resistance has been observed when entecavir was used to treat chronic hepatitis B infection in patients with HIV infection not receiving highly active antiretroviral therapy (HAART) (see section 5.1). Therefore, therapy with entecavir should not be used for HIV/HBV co-infected patients who are not receiving HAART. Entecavir has not been studied as a treatment for HIV infection and is not recommended for this use.
HIV/HBV co-infected patients receiving concomitant antiretroviral therapy: entecavir has been studied in 68 adults with HIV/HBV co-infection receiving a lamivudine-containing HAART regimen (see section 5.1). No data are available on the efficacy of entecavir in HBeAg-negative patients co-infected with HIV. There are limited data on patients co-infected with HIV who have low CD4 cell counts (< 200 cells/mm3).
General: patients should be advised that therapy with entecavir has not been proven to reduce the risk of transmission of HBV and therefore appropriate precautions should still be taken.
Tablets
Lactose: this medicinal product contains 241 mg of lactose in each 1 mg daily dose120.5 mg of lactose in each 0.5 mg daily dose.
Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption should not take this medicine. A lactose-free Baraclude oral solution is available for these individuals.
Oral Solution
Maltitol: Baraclude oral solution contains maltitol. Patients with rare hereditary problems of fructose intolerance should not take this medicine. Baraclude tablets do not contain maltitol and can be taken by patients with fructose intolerance.
Parahydroxybenzoates: Baraclude oral solution contains the preservatives methylhydroxybenzoate and propylhydroxybenzoate, that may cause allergic reactions (possibly delayed).
4.5 Interaction With Other Medicinal Products And Other Forms Of Interaction
Since entecavir is predominantly eliminated by the kidney (see section 5.2), coadministration with medicinal products that reduce renal function or compete for active tubular secretion may increase serum concentrations of either medicinal product. Apart from lamivudine, adefovir dipivoxil and tenofovir disoproxil fumarate, the effects of coadministration of entecavir with medicinal products that are excreted renally or affect renal function have not been evaluated. Patients should be monitored closely for adverse reactions when entecavir is coadministered with such medicinal products.
No pharmacokinetic interactions between entecavir and lamivudine, adefovir or tenofovir were observed.
Entecavir is not a substrate, an inducer or an inhibitor of cytochrome P450 (CYP450) enzymes (see section 5.2). Therefore CYP450 mediated drug interactions are unlikely to occur with entecavir.
4.6 Pregnancy And Lactation
Women of childbearing potential: given that the potential risks to the developing foetus are unknown, women of childbearing potential should use effective contraception.
Pregnancy: there are no adequate data from the use of entecavir in pregnant women. Studies in animals have shown reproductive toxicity at high doses (see section 5.3). The potential risk for humans is unknown. Baraclude should not be used during pregnancy unless clearly necessary. There are no data on the effect of entecavir on transmission of HBV from mother to newborn infant. Therefore, appropriate interventions should be used to prevent neonatal acquisition of HBV.
Breastfeeding: it is unknown whether entecavir is excreted in human milk. Available toxicological data in animals have shown excretion of entecavir in milk (for details see section 5.3). A risk to the infants cannot be excluded. Breastfeeding should be discontinued during treatment with Baraclude.
Fertility: toxicology studies in animals administered entecavir have shown no evidence of impaired fertility (see section 5.3).
4.7 Effects On Ability To Drive And Use Machines
No studies on the effects on the ability to drive and use machines have been performed. No effect on such activities is expected based on the pharmacodynamic profile of entecavir. Dizziness, fatigue and somnolence are common side effects which may impair the ability to drive and use machines.
4.8 Undesirable Effects
a. Summary of the safety profile
In clinical studies in patients with compensated liver disease, 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%). Exacerbations of hepatitis during and after discontinuation of entecavir therapy have also been reported (see section 4.4 and c. Description of selected adverse reactions).
b. Tabulated list of adverse reactions
Assessment of adverse reactions is based on experience from postmarketing surveillance and four clinical studies in which 1,720 patients with chronic hepatitis B infection and compensated liver disease received double-blind treatment with entecavir (n = 862) or lamivudine (n = 858) for up to 107 weeks (see section 5.1). In these studies, the safety profiles, including laboratory abnormalities, were comparable for entecavir 0.5 mg daily (679 nucleoside-naive HBeAg positive or negative patients treated for a median of 53 weeks), entecavir 1 mg daily (183 lamivudine-refractory patients treated for a median of 69 weeks), and lamivudine.
Adverse reactions considered at least possibly related to treatment with entecavir are listed by body system organ class. Frequency is defined as very common (
Immune system disorders:
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rare: anaphylactoid reaction
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Psychiatric disorders:
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common: insomnia
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Nervous system disorders:
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common: headache, dizziness, somnolence
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Gastrointestinal disorders:
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common: vomiting, diarrhoea, nausea, dyspepsia
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Hepatobiliary disorders
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common: increased transaminases
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Skin and subcutaneous tissue disorders:
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uncommon: rash, alopecia
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General disorders and administration site conditions:
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common: fatigue
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Cases of lactic acidosis have been reported, often in association with hepatic decompensation, other serious medical conditions or drug exposures (see section 4.4).
Treatment beyond 48 weeks: continued treatment with entecavir for a median duration of 96 weeks did not reveal any new safety signals.
c. Description of selected adverse reactions
Laboratory test abnormalities: In clinical studies with nucleoside-naive patients, 5% had ALT elevations > 3 times baseline, and < 1% had ALT elevations > 2 times baseline together with total bilirubin > 2 times upper limit of normal (ULN) and > 2 times baseline. Albumin levels < 2.5 g/dl occurred in < 1% of patients, amylase levels > 3 times baseline in 2%, lipase levels > 3 times baseline in 11% and platelets < 50,000/mm3 in < 1%.
In clinical studies with lamivudine-refractory patients, 4% had ALT elevations > 3 times baseline, and < 1% had ALT elevations > 2 times baseline together with total bilirubin > 2 times ULN and > 2 times baseline. Amylase levels > 3 times baseline occurred in 2% of patients, lipase levels > 3 times baseline in 18% and platelets < 50,000/mm3 in < 1%.
Exacerbations during treatment: in studies with nucleoside naive patients, on treatment ALT elevations > 10 times ULN and > 2 times baseline occurred in 2% of entecavir treated patients vs 4% of lamivudine treated patients. In studies with lamivudine-refractory patients, on treatment ALT elevations > 10 times ULN and > 2 times baseline occurred in 2% of entecavir treated patients vs 11% of lamivudine treated patients. Among entecavir-treated patients, on-treatment ALT elevations had a median time to onset of 4-5 weeks, generally resolved with continued treatment, and, in a majority of cases, were associated with a 10/ml reduction in viral load that preceded or coincided with the ALT elevation. Periodic monitoring of hepatic function is recommended during treatment.
Exacerbations after discontinuation of treatment: acute exacerbations of hepatitis have been reported in patients who have discontinued anti-hepatitis B virus therapy, including therapy with entecavir (see section 4.4). In studies in nucleoside-naive patients, 6% of entecavir-treated patients and 10% of lamivudine-treated patients experienced ALT elevations (> 10 times ULN and > 2 times reference [minimum of baseline or last end-of-dosing measurement]) during post-treatment follow-up. Among entecavir-treated nucleoside-naive patients, ALT elevations had a median time to onset of 23-24 weeks, and 86% (24/28) of ALT elevations occurred in HBeAg negative patients. In studies in lamivudine-refractory patients, with only limited numbers of patients being followed up, 11% of entecavir-treated patients and no lamivudine-treated patients developed ALT elevations during post-treatment follow-up.
In the clinical trials entecavir treatment was discontinued if patients achieved a prespecified response. If treatment is discontinued without regard to treatment response, the rate of post-treatment ALT flares could be higher.
d. Other special populations
Experience in patients with decompensated liver disease: the safety profile of entecavir in patients with decompensated liver disease was assessed in a randomized open-label comparative study in which patients received treatment with entecavir 1 mg/day (n = 102) or adefovir dipivoxil 10 mg/day (n = 89) (study 048). Relative to the adverse reactions noted in section b. Tabulated list of adverse reactions, one additional adverse reaction [decrease in blood bicarbonate (2%)] was observed in entecavir-treated patients through week 48. The on-study cumulative death rate was 23% (23/102), and causes of death were generally liver-related, as expected in this population. The on-study cumulative rate of hepatocellular carcinoma (HCC) was 12% (12/102). Serious adverse events were generally liver-related, with an on-study cumulative frequency of 69%. Patients with high baseline CTP score were at higher risk of developing serious adverse events (see section 4.4).
Laboratory test abnormalities: through week 48 among entecavir-treated patients with decompensated liver disease, none had ALT elevations both > 10 times ULN and > 2 times baseline, and 1% of patients had ALT elevations > 2 times baseline together with total bilirubin > 2 times ULN and > 2 times baseline. Albumin levels < 2.5 g/dl occurred in 30% of patients, lipase levels > 3 times baseline in 10% and platelets < 50,000/mm3 in 20%..
Experience in patients co-infected with HIV: the safety profile of entecavir in a limited number of HIV/HBV co-infected patients on lamivudine-containing HAART (highly active antiretroviral therapy) regimens was similar to the safety profile in monoinfected HBV patients (see section 4.4).
Gender/age: there was no apparent difference in the safety profile of entecavir with respect to gender (≈ 25% women in the clinical trials) or age (≈ 5% of patients > 65 years of age).
4.9 Overdose
There is limited experience of entecavir overdose reported in patients. Healthy subjects who received up to 20 mg/day for up to 14 days, and single doses up to 40 mg had no unexpected adverse reactions. If overdose occurs, the patient must be monitored for evidence of toxicity and given standard supportive treatment as necessary.
5. Pharmacological Properties
5.1 Pharmacodynamic Properties
Pharmacotherapeutic group: nucleoside and nucleotide reverse transcriptase inhibitors
ATC code: J05AF10
Mechanism of action: entecavir, a guanosine nucleoside analogue with activity against HBV polymerase, is efficiently phosphorylated to the active triphosphate (TP) form, which has an intracellular half-life of 15 hours. By competing with the natural substrate deoxyguanosine TP, entecavir-TP functionally inhibits the 3 activities of the viral polymerase: (1) priming of the HBV polymerase, (2) reverse transcription of the negative strand DNA from the pregenomic messenger RNA, and (3) synthesis of the positive strand HBV DNA. The entecavir-TP Ki for HBV DNA polymerase is 0.0012 μM. Entecavir-TP is a weak inhibitor of cellular DNA polymerases α, β, and δ with Ki values of 18 to 40 μM. In addition, high exposures of entecavir had no relevant adverse effects on γ polymerase or mitochondrial DNA synthesis in HepG2 cells (Ki > 160 μM).
Antiviral activity: entecavir inhibited HBV DNA synthesis (50% reduction, EC50) at a concentration of 0.004 μM in human HepG2 cells transfected with wild-type HBV. The median EC50 value for entecavir against LVDr HBV (rtL180M and rtM204V) was 0.026 μM (range 0.010-0.059 μM). Recombinant viruses encoding adefovir-resistant substitutions at either rtN236T or rtA181V remained fully susceptible to entecavir.
An analysis of the inhibitory activity of entecavir against a panel of laboratory and clinical HIV-1 isolates using a variety of cells and assay conditions yielded EC50 values ranging from 0.026 to > 10 μM; the lower EC50 values were observed when decreased levels of virus were used in the assay. In cell culture, entecavir selected for an M184I substitution at micromolar concentrations, confirming inhibitory pressure at high entecavir concentrations. HIV variants containing the M184V substitution showed loss of susceptibility to entecavir (see section 4.4).
In HBV combination assays in cell culture, abacavir, didanosine, lamivudine, stavudine, tenofovir or zidovudine were not antagonistic to the anti-HBV activity of entecavir over a wide range of concentrations. In HIV antiviral assays, entecavir at micromolar concentrations was not antagonistic to the anti-HIV activity in cell culture of these six NRTIs or emtricitabine.
Resistance in cell culture: relative to wild-type HBV, LVDr viruses containing rtM204V and rtL180M substitutions within the reverse transcriptase exhibit 8-fold decreased susceptibility to entecavir. Incorporation of additional ETVr amino acid changes rtT184, rtS202 or rtM250 decreases entecavir susceptibility in cell culture. Substitutions observed in clinical isolates (rtT184A, C, F, G, I, L, M or S; rtS202 C, G or I; and/or rtM250I, L or V) further decreased entecavir susceptibility 16- to 741-fold relative to wild-type virus. The ETVr substitutions at residues rtT184, rtS202 and rtM250 alone have only a modest effect on entecavir susceptibility, and have not been observed in the absence of LVDr substitutions in more than 1000 patient samples sequenced. Resistance is mediated by reduced inhibitor binding to the altered HBV reverse transcriptase, and resistant HBV exhibits reduced replication capacity in cell culture.
Clinical experience: the demonstration of benefit is based on histological, virological, biochemical, and serological responses after 48 weeks of treatment in active-controlled clinical trials of 1,633 adults with chronic hepatitis B infection, evidence of viral replication and compensated liver disease. The safety and efficacy of entecavir were also evaluated in an active-controlled clinical trial of 191 HBV-infected patients with decompensated liver disease and in a clinical trial of 68 patients co-infected with HBV and HIV.
In studies in patients with compensated liver disease, histological improvement was defined as a 10 copies/ml were both associated with higher rates of virologic response (Week 48 HBV DNA < 400 copies/ml) in nucleoside-naive HBeAg-positive patients. Regardless of baseline characteristics, the majority of patients showed histological and virological responses to treatment.
Experience in nucleoside-naive patients with compensated liver disease:
Results at 48 weeks of randomised, double blind studies comparing entecavir (ETV) to lamivudine (LVD) in HBeAg positive (022) and HBeAg negative (027) patients are presented in the table.
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Nucleoside Naive
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HBeAg Positive (study 022)
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HBeAg Negative (study 027)
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ETV 0.5 mg once daily
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LVD 100 mg once daily
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ETV 0.5 mg once daily
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LVD 100 mg once daily
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n
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314a
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314a
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296a
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287a
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Histological improvementb
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72%*
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62%
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70%*
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61%
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Ishak fibrosis score improvement
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39%
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35%
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36%
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38%
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Ishak fibrosis score worsening
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8%
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10%
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12%
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15%
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n
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354
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355
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325
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313
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Viral load reduction (log10 copies/ml)c
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-6.86*
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-5.39
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-5.04*
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-4.53
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HBV DNA undetectable (< 300 copies/ml by PCR)c
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67%*
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36%
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90%*
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72%
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ALT normalisation (
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68%*
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60%
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78%*
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71%
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|
|
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HBeAg Seroconversion
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21%
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18%
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*p value vs lamivudine < 0.05
a patients with evaluable baseline histology (baseline Knodell Necroinflammatory Score
b a primary endpoint
c Roche Cobas Amplicor PCR assay (LLOQ = 300 copies/ml)
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Experience in lamivudine-refractory patients with compensated liver disease:
In a randomised, double-blind study in HBeAg positive lamivudine-refractory patients (026), with 85% of patients presenting LVDr mutations at baseline, patients receiving lamivudine at study entry either switched to entecavir 1 mg once daily, with neither a washout nor an overlap period (n = 141), or continued on lamivudine 100 mg once daily (n = 145). Results at 48 weeks are presented in the table.
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Lamivudine-refractory
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HBeAg positive (study 026)
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ETV 1.0 mg once daily
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LVD 100 mg once daily
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n
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124a
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116a
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Histological improvementb
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55%*
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28%
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Ishak fibrosis score improvement
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34%*
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16%
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Ishak fibrosis score worsening
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11%
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26%
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n
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141
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145
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Viral load reduction (log10 copies/ml)c
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-5.11*
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-0.48
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HBV DNA undetectable (< 300 copies/ml by PCR)c
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19%*
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1%
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ALT normalisation (
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61%*
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15%
|
|
|
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HBeAg Seroconversion
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8%
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3%
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*p value vs lamivudine < 0.05
a patients with evaluable baseline histology (baseline Knodell Necroinflammatory Score
b a primary endpoint.
c Roche Cobas Amplicor PCR assay (LLOQ = 300 copies/ml)
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|
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Results beyond 48 weeks of treatment:
Treatment was discontinued when prespecified response criteria were met either at 48 weeks or during the second year of treatment. Response criteria were HBV virological suppression (HBV DNA < 0.7 MEq/ml by bDNA) and loss of HBeAg (in HBeAg positive patients) or ALT < 1.25 times ULN (in HBeAg negative patients). Patients in response were followed for an additional 24 weeks off-treatment. Patients who met virologic but not serologic or biochemical response criteria continued blinded treatment. Patients who did not have a virologic response were offered alternative treatment.
Nucleoside-naive:
HBeAg positive (study 022): treatment with entecavir for up to 96 weeks (n = 354) resulted in cumulative response rates of 80% for HBV DNA < 300 copies/ml by PCR, 87% for ALT normalisation, 31% for HBeAg seroconversion and 2% for HBsAg seroconversion (5% for HBsAg loss). For lamivudine (n = 355), cumulative response rates were 39% for HBV DNA < 300 copies/ml by PCR, 79% for ALT normalisation, 26% for HBeAg seroconversion, and 2% for HBsAg seroconversion (3% for HBsAg loss).
At end of dosing, among patients who continued treatment beyond 52 weeks (median of 96 weeks), 81% of 243 entecavir-treated and 39% of 164 lamivudine-treated patients had HBV DNA < 300 copies/ml by PCR while ALT normalisation (
HBeAg negative (study 027): treatment with entecavir up to 96 weeks (n = 325) resulted in cumulative response rates of 94% for HBV DNA < 300 copies/ml by PCR and 89% for ALT normalisation versus 77% for HBV DNA < 300 copies/ml by PCR and 84% for ALT normalisation for lamivudine-treated patients (n = 313).
For 26 entecavir-treated and 28 lamivudine-treated patients who continued treatment beyond 52 weeks (median 96 weeks), 96% of entecavir-treated and 64% of lamivudine-treated patients had HBV DNA < 300 copies/ml by PCR at end of dosing. ALT normalisation (
For patients who met protocol-defined response criteria, response was sustained throughout the 24-week post-treatment follow-up in 75% (83/111) of entecavir responders vs 73% (68/93) for lamivudine responders in study 022 and 46% (131/286) of entecavir responders vs 31% (79/253) for lamivudine responders in study 027. By 48 weeks of post-treatment follow-up, a substantial number of HBeAg negative patients lost response.
Liver biopsy results: 57 patients from the pivotal nucleoside-naive studies 022 (HBeAg positive) and 027 (HBeAg negative) who enrolled in a long-term rollover study were evaluated for long-term liver histology outcomes. The entecavir dosage was 0.5 mg daily in the pivotal studies (mean exposure 85 weeks) and 1 mg daily in the rollover study (mean exposure 177 weeks), and 51 patients in the rollover study initially also received lamivudine (median duration 29 weeks). Of these patients, 55/57 (96%) had histological improvement as previously defined (see above), and 50/57 (88%) had a
Lamivudine-refractory:
HBeAg positive (study 026): treatment with entecavir for up to 96 weeks (n = 141) resulted in cumulative response rates of 30% for HBV DNA < 300 copies/ml by PCR, 85% for ALT normalisation and 17% for HBeAg seroconversion.
For the 77 patients who continued entecavir treatment beyond 52 weeks (median 96 weeks), 40% of patients had HBV DNA < 300 copies/ml by PCR and 81% had ALT normalisation (
Age/gender:
There was no apparent difference in efficacy for entecavir based on gender (≈ 25% women in the clinical trials) or age (≈ 5% of patients > 65 years of age).
Special populations
Patients with decompensated liver disease: in study 048, 191 patients with HBeAg positive or negative chronic HBV infection and evidence of hepatic decompensation, defined as a CTP score of 7 or higher, received entecavir 1 mg once daily or adefovir dipivoxil 10 mg once daily. Patients were either HBV-treatment-naïve or pretreated (excluding pretreatment with entecavir, adefovir dipivoxil, or tenofovir disoproxil fumarate). At baseline, patients had a mean CTP score of 8.59 and 26% of pa
