Baraclude

CLINICAL PHARMACOLOGY

Mechanism Of Action

Entecavir is an antiviral drug [see Microbiology].

Pharmacokinetics

The single- and multiple-dose pharmacokinetics of entecavir were evaluated in healthy subjects and subjects with chronic hepatitis B virus infection.

Absorption

Following oral administration in healthy subjects, entecavir peak plasma concentrations occurred between 0.5 and 1.5 hours. Following multiple daily doses ranging from 0.1 to 1.0 mg, Cmax and area under the concentration-time curve (AUC) at steady state increased in proportion to dose.

Steady state was achieved after 6 to 10 days of once-daily administration with approximately 2-fold accumulation. For a 0.5 mg oral dose, Cmax at steady state was 4.2 ng/mL and trough plasma concentration (Ctrough) was 0.3 ng/mL. For a 1 mg oral dose, Cmax was 8.2 ng/mL and Ctrough was 0.5 ng/mL.

In healthy subjects, the bioavailability of the tablet was 100% relative to the oral solution. The oral solution and tablet may be used interchangeably.

Effects of food on oral absorption: Oral administration of 0.5 mg of entecavir with a standard high-fat meal (945 kcal, 54.6 g fat) or a light meal (379 kcal, 8.2 g fat) resulted in a delay in absorption (1.0–1.5 hours fed vs. 0.75 hours fasted), a decrease in Cmax of 44%–46%, and a decrease in AUC of 18%–20% [see DOSAGE AND ADMINISTRATION].

Distribution

Based on the pharmacokinetic profile of entecavir after oral dosing, the estimated apparent volume of distribution is in excess of total body water, suggesting that entecavir is extensively distributed into tissues.

Binding of entecavir to human serum proteins in vitro was approximately 13%.

Metabolism and Elimination

Following administration of 14C-entecavir in humans and rats, no oxidative or acetylated metabolites were observed. Minor amounts of phase II metabolites (glucuronide and sulfate conjugates) were observed. Entecavir is not a substrate, inhibitor, or inducer of the cytochrome P450 (CYP450) enzyme system [see DRUG INTERACTIONS, below].

After reaching peak concentration, entecavir plasma concentrations decreased in a bi-exponential manner with a terminal elimination half-life of approximately 128–149 hours. The observed drug accumulation index is approximately 2-fold with once-daily dosing, suggesting an effective accumulation half-life of approximately 24 hours.

Entecavir is predominantly eliminated by the kidney with urinary recovery of unchanged drug at steady state ranging from 62% to 73% of the administered dose. Renal clearance is independent of dose and ranges from 360 to 471 mL/min suggesting that entecavir undergoes both glomerular filtration and net tubular secretion [see DRUG INTERACTIONS].

Special Populations

Gender: There are no significant gender differences in entecavir pharmacokinetics.

Race: There are no significant racial differences in entecavir pharmacokinetics.

Elderly: The effect of age on the pharmacokinetics of entecavir was evaluated following administration of a single 1 mg oral dose in healthy young and elderly volunteers. Entecavir AUC was 29.3% greater in elderly subjects compared to young subjects. The disparity in exposure between elderly and young subjects was most likely attributable to differences in renal function. Dosage adjustment of BARACLUDE should be based on the renal function of the patient, rather than age [see DOSAGE AND ADMINISTRATION].

Pediatrics: Pharmacokinetic studies have not been conducted in children.

Renal impairment: The pharmacokinetics of entecavir following a single 1 mg dose were studied in subjects (without chronic hepatitis B virus infection) with selected degrees of renal impairment, including subjects whose renal impairment was managed by hemodialysis or continuous ambulatory peritoneal dialysis (CAPD). Results are shown in Table 5 [see DOSAGE AND ADMINISTRATION].

Table 5: Pharmacokinetic Parameters in Subjects with Selected Degrees of Renal Function

  Renal Function Group
Baseline Creatinine Clearance (mL/min) Severe Managed with Hemodialysisa
n=6
Severe Managed with CAPD
n=4
Unimpaired > 80
n=6
Mild > 50- ≤ 80
n=6
Moderate 30-50
n=6
Severe < 30
n=6
Cmax (ng/mL) (CV%) 8.1 (30.7) 10.4 (37.2) 10.5 (22.7) 15.3 (33.8) 15.4 (56.4) 16.6 (29.7)
AUC(O-T) (ng•h/mL) (CV) 27.9 (25.6) 51.5 (22.8) 69.5 (22.7) 145.7 (31.5) 233.9 (28.4) 221.8 (11.6)
CLR (mL/min) (SD) 383.2 (101.8) 197.9 (78.1) 135.6 (31.6) 40.3 (10.1) NA NA
CLT/F (mL/min) (SD) 588.1 (153.7) 309.2 (62.6) 226.3 (60.1) 100.6 (29.1) 50.6 (16.5) 35.7 (19.6)
a Dosed immediately following hemodialysis.
CLR = renal clearance; CLT/F = apparent oral clearance.

Following a single 1 mg dose of entecavir administered 2 hours before the hemodialysis session, hemodialysis removed approximately 13% of the entecavir dose over 4 hours. CAPD removed approximately 0.3% of the dose over 7 days [see DOSAGE AND ADMINISTRATION].

Hepatic impairment: The pharmacokinetics of entecavir following a single 1 mg dose were studied in subjects (without chronic hepatitis B virus infection) with moderate or severe hepatic impairment (Child-Turcotte-Pugh Class B or C). The pharmacokinetics of entecavir were similar between hepatically impaired and healthy control subjects; therefore, no dosage adjustment of BARACLUDE is recommended for patients with hepatic impairment.

Post-liver transplant: Limited data are available on the safety and efficacy of BARACLUDE in liver transplant recipients. In a small pilot study of entecavir use in HBV-infected liver transplant recipients on a stable dose of cyclosporine A (n=5) or tacrolimus (n=4), entecavir exposure was approximately 2-fold the exposure in healthy subjects with normal renal function. Altered renal function contributed to the increase in entecavir exposure in these subjects. The potential for pharmacokinetic interactions between entecavir and cyclosporine A or tacrolimus was not formally evaluated [see Use In Specific Populations].

Drug Interactions

The metabolism of entecavir was evaluated in in vitro and in vivo studies. Entecavir is not a substrate, inhibitor, or inducer of the cytochrome P450 (CYP450) enzyme system. At concentrations up to approximately 10,000-fold higher than those obtained in humans, entecavir inhibited none of the major human CYP450 enzymes 1A2, 2C9, 2C19, 2D6, 3A4, 2B6, and 2E1. At concentrations up to approximately 340-fold higher than those observed in humans, entecavir did not induce the human CYP450 enzymes 1A2, 2C9, 2C19, 3A4, 3A5, and 2B6. The pharmacokinetics of entecavir are unlikely to be affected by coadministration with agents that are either metabolized by, inhibit, or induce the CYP450 system. Likewise, the pharmacokinetics of known CYP substrates are unlikely to be affected by coadministration of entecavir.

The steady-state pharmacokinetics of entecavir and coadministered drug were not altered in interaction studies of entecavir with lamivudine, adefovir dipivoxil, and tenofovir disoproxil fumarate [see DRUG INTERACTIONS].

Microbiology

Mechanism Of Action

Entecavir, a guanosine nucleoside analogue with activity against HBV reverse transcriptase (rt), is efficiently phosphorylated to the active triphosphate form, which has an intracellular half-life of 15 hours. By competing with the natural substrate deoxyguanosine triphosphate, entecavir triphosphate functionally inhibits all three activities of the HBV reverse transcriptase: (1) base priming, (2) reverse transcription of the negative strand from the pregenomic messenger RNA, and (3) synthesis of the positive strand of HBV DNA. Entecavir triphosphate is a weak inhibitor of cellular DNA polymerases α, β, and δ and mitochondrial DNA polymerase γ with Ki values ranging from 18 to > 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 lamivudine-resistant HBV (rtL180M, rtM204V) was 0.026 μM (range 0.010–0.059 μM).

The coadministration of HIV nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) with BARACLUDE is unlikely to reduce the antiviral efficacy of BARACLUDE against HBV or of any of these agents against HIV. 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 was not antagonistic to the cell culture anti-HIV activity of these six NRTIs or emtricitabine at concentrations greater than 100 times the Cmax of entecavir using the 1 mg dose.

Antiviral Activity against HIV

A comprehensive analysis of the inhibitory activity of entecavir against a panel of laboratory and clinical HIV type 1 (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 in HIV reverse transcriptase at micromolar concentrations, confirming inhibitory pressure at high entecavir concentrations. HIV variants containing the M184V substitution showed loss of susceptibility to entecavir.

Resistance

In Cell Culture

In cell-based assays, 8- to 30-fold reductions in entecavir phenotypic susceptibility were observed for lamivudine-resistant strains. Further reductions ( > 70-fold) in entecavir phenotypic susceptibility required the presence of amino acid substitutions rtM204I/V with or without rtL180M along with additional substitutions at residues rtT184, rtS202, or rtM250, or a combination of these substitutions with or without an rtI169 substitution in the HBV reverse transcriptase.

Clinical Studies

Nucleoside-na´ve subjects: Genotypic evaluations were performed on evaluable samples ( > 300 copies/mL serum HBV DNA) from 562 subjects who were treated with BARACLUDE for up to 96 weeks in nucleoside-na´ve studies (AI463022, AI463027, and rollover study AI463901). By Week 96, evidence of emerging amino acid substitution rtS202G with rtM204V and rtL180M substitutions was detected in the HBV of 2 subjects (2/562= < 1%), and 1 of them experienced virologic rebound ( ≥ 1 log10 increase above nadir). In addition, emerging amino acid substitutions at rtM204I/V and rtL180M, rtL80I, or rtV173L, which conferred decreased phenotypic susceptibility to entecavir in the absence of rtT184, rtS202, or rtM250 changes, were detected in the HBV of 3 subjects (3/562= < 1%) who experienced virologic rebound. For subjects who continued treatment beyond 48 weeks, 75% (202/269) had HBV DNA < 300 copies/mL at end of dosing (up to 96 weeks).

HBeAg-positive (n=243) and -negative (n=39) treatment-na´ve subjects who failed to achieve the study-defined complete response by 96 weeks were offered continued entecavir treatment in a rollover study. Complete response for HBeAg-positive was < 0.7 MEq/mL (approximately 7 x 105 copies/mL) serum HBV DNA and HBeAg loss and, for HBeAg-negative was < 0.7 MEq/mL HBV DNA and ALT normalization. Subjects received 1 mg entecavir once daily for up to an additional 144 weeks. Of these 282 subjects, 141 HBeAg-positive and 8 HBeAgnegative subjects entered the long-term follow-up rollover study and were evaluated for entecavir resistance. Of the 149 subjects entering the rollover study, 88% (131/149), 92% (137/149), and 92% (137/149) attained serum HBV DNA < 300 copies/mL by Weeks 144, 192, and 240 (including end of dosing), respectively. No novel entecavir resistance-associated substitutions were identified in a comparison of the genotypes of evaluable isolates with their respective baseline isolates. The cumulative probability of developing rtT184, rtS202, or rtM250 entecavir resistance-associated substitutions (in the presence of rtM204V and rtL180M substitutions) at Weeks 48, 96, 144, 192, and 240 was 0.2%, 0.5%, 1.2%, 1.2%, and 1.2%, respectively.

Lamivudine-refractory subjects: Genotypic evaluations were performed on evaluable samples from 190 subjects treated with BARACLUDE for up to 96 weeks in studies of lamivudinerefractory HBV (AI463026, AI463014, AI463015, and rollover study AI463901). By Week 96, resistance-associated amino acid substitutions at rtS202, rtT184, or rtM250, with or without rtI169 changes, in the presence of amino acid substitutions rtM204I/V with or without rtL180M, rtL80V, or rtV173L/M emerged in the HBV from 22 subjects (22/190=12%), 16 of whom experienced virologic rebound ( ≥ 1 log10 increase above nadir) and 4 of whom were never suppressed < 300 copies/mL. The HBV from 4 of these subjects had entecavir resistance substitutions at baseline and acquired further changes on entecavir treatment. In addition to the 22 subjects, 3 subjects experienced virologic rebound with the emergence of rtM204I/V and rtL180M, rtL80V, or rtV173L/M. For isolates from subjects who experienced virologic rebound with the emergence of resistance substitutions (n=19), the median fold-change in entecavir EC50 values from reference was 19-fold at baseline and 106-fold at the time of virologic rebound. For subjects who continued treatment beyond 48 weeks, 40% (31/77) had HBV DNA < 300 copies/mL at end of dosing (up to 96 weeks).

Lamivudine-refractory subjects (n=157) who failed to achieve the study-defined complete response by Week 96 were offered continued entecavir treatment. Subjects received 1 mg entecavir once daily for up to an additional 144 weeks. Of these subjects, 80 subjects entered the long-term follow-up study and were evaluated for entecavir resistance. By Weeks 144, 192, and 240 (including end of dosing), 34% (27/80), 35% (28/80), and 36% (29/80), respectively, attained HBV DNA < 300 copies/mL. The cumulative probability of developing rtT184, rtS202, or rtM250 entecavir resistance-associated substitutions (in the presence of rtM204I/V with or without rtL180M substitutions) at Weeks 48, 96, 144, 192, and 240 was 6.2%, 15%, 36.3%, 46.6%, and 51.5%, respectively. The HBV of 6 subjects developed rtA181C/G/S/T amino acid substitutions while receiving entecavir, and of these, 4 developed entecavir resistance-associated substitutions at rtT184, rtS202, or rtM250 and 1 had an rtT184S substitution at baseline. Of 7 subjects whose HBV had an rtA181 substitution at baseline, 2 also had substitutions at rtT184, rtS202, or rtM250 at baseline and another 2 developed them while on treatment with entecavir.

Cross-resistance

Cross-resistance has been observed among HBV nucleoside analogues. In cell-based assays, entecavir had 8- to 30-fold less inhibition of HBV DNA synthesis for HBV containing lamivudine and telbivudine resistance substitutions rtM204I/V with or without rtL180M than for wild-type HBV. Substitutions rtM204I/V with or without rtL180M, rtL80I/V, or rtV173L, which are associated with lamivudine and telbivudine resistance, also confer decreased phenotypic susceptibility to entecavir. The efficacy of entecavir against HBV harboring adefovir resistance associated substitutions has not been established in clinical trials. HBV isolates from lamivudinerefractory subjects failing entecavir therapy were susceptible in cell culture to adefovir but remained resistant to lamivudine. Recombinant HBV genomes encoding adefovir resistance-associated substitutions at either rtN236T or rtA181V had 0.3- and 1.1-fold shifts in susceptibility to entecavir in cell culture, respectively.

Clinical Studies

The safety and efficacy of BARACLUDE were evaluated in three Phase 3 active-controlled trials [see Outcomes at 48 weeks]. These studies included 1633 subjects 16 years of age or older with chronic hepatitis B virus infection (serum HBsAg-positive for at least 6 months) accompanied by evidence of viral replication (detectable serum HBV DNA, as measured by the bDNA hybridization or PCR assay). Subjects had persistently elevated ALT levels at least 1.3 times ULN and chronic inflammation on liver biopsy compatible with a diagnosis of chronic viral hepatitis. The safety and efficacy of BARACLUDE were also evaluated in a study of 191 HBV-infected subjects with decompensated liver disease and in a study of 68 subjects coinfected with HBV and HIV [see Outcomes beyond weeks].

Outcomes At 48 Weeks

Nucleoside-na´ve Subjects with Compensated Liver Disease

HBeAg-positive: Study AI463022 was a multinational, randomized, double-blind study of BARACLUDE 0.5 mg once daily versus lamivudine 100 mg once daily for a minimum of 52 weeks in 709 (of 715 randomized) nucleoside-na´ve subjects with chronic hepatitis B virus infection, compensated liver disease, and detectable HBeAg. The mean age of subjects was 35 years, 75% were male, 57% were Asian, 40% were Caucasian, and 13% had previously received interferon-α. At baseline, subjects had a mean Knodell Necroinflammatory Score of 7.8, mean serum HBV DNA as measured by Roche COBAS Amplicor® PCR assay was 9.66 log10 copies/mL, and mean serum ALT level was 143 U/L. Paired, adequate liver biopsy samples were available for 89% of subjects.

HBeAg-negative (anti-HBe-positive/HBV DNA-positive): Study AI463027 was a multinational, randomized, double-blind study of BARACLUDE 0.5 mg once daily versus lamivudine 100 mg once daily for a minimum of 52 weeks in 638 (of 648 randomized) nucleoside-na´ve subjects with HBeAg-negative (HBeAb-positive) chronic hepatitis B virus infection and compensated liver disease. The mean age of subjects was 44 years, 76% were male, 39% were Asian, 58% were Caucasian, and 13% had previously received interferon-α. At baseline, subjects had a mean Knodell Necroinflammatory Score of 7.8, mean serum HBV DNA as measured by Roche COBAS Amplicor PCR assay was 7.58 log10 copies/mL, and mean serum ALT level was 142 U/L. Paired, adequate liver biopsy samples were available for 88% of subjects.

In Studies AI463022 and AI463027, BARACLUDE was superior to lamivudine on the primary efficacy endpoint of Histologic Improvement, defined as a 2-point or greater reduction in Knodell Necroinflammatory Score with no worsening in Knodell Fibrosis Score at Week 48, and on the secondary efficacy measures of reduction in viral load and ALT normalization. Histologic Improvement and change in Ishak Fibrosis Score are shown in Table 6. Selected virologic, biochemical, and serologic outcome measures are shown in Table 7.

Table 6: Histologic Improvement and Change in Ishak Fibrosis Score at Week 48, Nucleoside-Na´ve Subjects in Studies AI463022 and AI463027

  Study AI463022 (HBeAg-Positive) Study AI463027 (HBeAg-Negative)
BARACLUDE 0.5 mg
n=314a
Lamivudine 100 mg
n=314a
BARACLUDE 0.5 mg
n=296a
Lamivudine 100 mg
n=287a
Histologic Improvement (Knodell Scores)
Improvementb 72% 62% 70% 61%
No improvement 21% 24% 19% 26%
Ishak Fibrosis Score
Improvementc 39% 35% 36% 38%
No change 46% 40% 41% 34%
Worseningc 8% 10% 12% 15%
Missing Week 48 biopsy 7% 14% 10% 13%
a Subjects with evaluable baseline histology (baseline Knodell Necroinflammatory Score ≥ 2).
b ≥ 2-point decrease in Knodell Necroinflammatory Score from baseline with no worsening of the Knodell Fibrosis Score.
c For Ishak Fibrosis Score, improvement = ≥ 1-point decrease from baseline and worsening = ≥ 1-point increase from baseline.

Table 7: Selected Virologic, Biochemical, and Serologic Endpoints at Week 48, Nucleoside-Na´ve Subjects in Studies AI463022 and AI463027

  Study AI463022 (HBeAg-Positive) Study AI463027 (HBeAg-Negative)
5ARACLUDE 0.5 mg
n=354
Lamivudine 100 mg
n=355
BARACLUDE 0.5 mg
n=325
Lamivudine 100 mg
n=313
HBV DNAa
  Proportion undetectable ( < 300 copies/mL) 67% 36% 90% 72%
  Mean change from baseline (log10 copies/mL) -6.86 -5.39 -5.04 -4.53
ALT normalization ( ≤ 1 x ULN) 68% 60% 78% 71%
HBeAg seroconversion 21% 18% NA NA
a Roche COBAS Amplicor PCR assay [lower limit of quantification (LLOQ) = 300 copies/mL].

Histologic Improvement was independent of baseline levels of HBV DNA or ALT.

Lamivudine-refractory Subjects with Compensated Liver Disease

Study AI463026 was a multinational, randomized, double-blind study of BARACLUDE in 286 (of 293 randomized) subjects with lamivudine-refractory chronic hepatitis B virus infection and compensated liver disease. Subjects receiving lamivudine at study entry either switched to BARACLUDE 1 mg once daily (with neither a washout nor an overlap period) or continued on lamivudine 100 mg for a minimum of 52 weeks. The mean age of subjects was 39 years, 76% were male, 37% were Asian, 62% were Caucasian, and 52% had previously received interferon-α. The mean duration of prior lamivudine therapy was 2.7 years, and 85% had lamivudine resistance mutations at baseline by an investigational line probe assay. At baseline, subjects had a mean Knodell Necroinflammatory Score of 6.5, mean serum HBV DNA as measured by Roche COBAS Amplicor PCR assay was 9.36 log10 copies/mL, and mean serum ALT level was 128 U/L. Paired, adequate liver biopsy samples were available for 87% of subjects.

BARACLUDE was superior to lamivudine on a primary endpoint of Histologic Improvement (using the Knodell Score at Week 48). These results and change in Ishak Fibrosis Score are shown in Table 8. Table 9 shows selected virologic, biochemical, and serologic endpoints.

Table 8: Histologic Improvement and Change in Ishak Fibrosis Score at Week 48, Lamivudine-Refractory Subjects in Study AI463026

  BARACLUDE 1 mg
n=124a
Lamivudine 100 mg
n=116a
Histologic Improvement (Knodell Scores)
Improvementb 55% 28%
No improvement 34% 57%
Ishak Fibrosis Score
Improvementc 34% 16%
No change 44% 42%
Worseningc 11% 26%
Missing Week 48 biopsy 11% 16%
a Subjects with evaluable baseline histology (baseline Knodell Necroinflammatory Score ≥ 2).
b ≥ 2-point decrease in Knodell Necroinflammatory Score from baseline with no worsening of the Knodell Fibrosis Score.
c For Ishak Fibrosis Score, improvement = ≥ 1-point decrease from baseline and worsening = ≥ 1-point increase from baseline.

Table 9: Selected Virologic, Biochemical, and Serologic Endpoints at Week 48, Lamivudine-Refractory Subjects in Study AI463026

  BARACLUDE 1 mg
n=141
Lamivudine 100 mg
n=145
HBV DNAa
  Proportion undetectable ( < 300 copies/mL) 19% 1%
  Mean change from baseline (log10 copies/mL) -5.11 -0.48
ALT normalization ( ≤ 1 x ULN) 61% 15%
HBeAg seroconversion 8% 3%
a Roche COBAS Amplicor PCR assay (LLOQ = 300 copies/mL).

Histologic Improvement was independent of baseline levels of HBV DNA or ALT.

Subjects with Decompensated Liver Disease

Study AI463048 was a randomized, open-label study of BARACLUDE 1 mg once daily versus adefovir dipivoxil 10 mg once daily in 191 (of 195 randomized) adult subjects with HBeAg-positive or -negative chronic HBV infection and evidence of hepatic decompensation, defined as a Child-Turcotte-Pugh (CTP) score of 7 or higher. Subjects were either HBV-treatment-na´ve or previously treated, predominantly with lamivudine or interferon-α.

In Study AI463048, 100 subjects were randomized to treatment with BARACLUDE and 91 subjects to treatment with adefovir dipivoxil. Two subjects randomized to treatment with adefovir dipivoxil actually received treatment with BARACLUDE for the duration of the study. The mean age of subjects was 52 years, 74% were male, 54% were Asian, 33% were Caucasian, and 5% were Black/African American. At baseline, subjects had a mean serum HBV DNA by PCR of 7.83 log10 copies/mL and mean ALT level of 100 U/L; 54% of subjects were HBeAgpositive; 35% had genotypic evidence of lamivudine resistance. The baseline mean CTP score was 8.6. Results for selected study endpoints at Week 48 are shown in Table 10.

Table 10: Selected Endpoints at Week 48, Subjects with Decompensated Liver Disease, Study AI463048

  BARACLUDE 1 mg
n=100a
Adefovir Dipivoxil 10 mg
n=91a
HBV DNAb
  Proportion undetectable ( < 300 copies/mL) 57% 20%
Stable or improved CTP scorec 61% 67%
HBsAg loss 5% 0
Normalization of ALT ( < 1 x ULN)d 49/78 (63%) 33/71 (46%)
a Endpoints were analyzed using intention-to-treat (ITT) method, treated subjects as randomized.
b Roche COBAS Amplicor PCR assay (LLOQ = 300 copies/mL).
c Defined as decrease or no change from baseline in CTP score.
d Denominator is subjects with abnormal values at baseline. ULN=upper limit of normal.

Subjects Co-infected with HIV and HBV

Study AI463038 was a randomized, double-blind, placebo-controlled study of BARACLUDE versus placebo in 68 subjects co-infected with HIV and HBV who experienced recurrence of HBV viremia while receiving a lamivudine-containing highly active antiretroviral (HAART) regimen. Subjects continued their lamivudine-containing HAART regimen (lamivudine dose 300 mg/day) and were assigned to add either BARACLUDE 1 mg once daily (51 subjects) or placebo (17 subjects) for 24 weeks followed by an open-label phase for an additional 24 weeks where all subjects received BARACLUDE. At baseline, subjects had a mean serum HBV DNA level by PCR of 9.13 log10 copies/mL. Ninety-nine percent of subjects were HBeAg-positive at baseline, with a mean baseline ALT level of 71.5 U/L. Median HIV RNA level remained stable at approximately 2 log10 copies/mL through 24 weeks of blinded therapy. Virologic and biochemical endpoints at Week 24 are shown in Table 11. There are no data in patients with HIV/HBV co-infection who have not received prior lamivudine therapy. BARACLUDE has not been evaluated in HIV/HBV co-infected patients who were not simultaneously receiving effective HIV treatment [see WARNINGS AND PRECAUTIONS].

Table 11: Virologic and Biochemical Endpoints at Week 24, Study AI463038

  BARACLUDE 1 mga
n=51
Placeboa
n=17
HBV DNAb
  Proportion undetectable ( < 300 copies/mL) 6% 0
  Mean change from baseline (log10 copies/mL) -3.65 +0.11
ALT normalization ( < 1 x ULN) 34%c 8%c
a All subjects also received a lamivudine-containing HAART regimen.
b Roche COBAS Amplicor PCR assay (LLOQ = 300 copies/mL).
c Percentage of subjects with abnormal ALT ( > 1 x ULN) at baseline who achieved ALT normalization (n=35 for BARACLUDE and n=12 for placebo).

For subjects originally assigned to BARACLUDE, at the end of the open-label phase (Week 48), 8% of subjects had HBV DNA < 300 copies/mL by PCR, the mean change from baseline HBV DNA by PCR was -4.20 log10 copies/mL, and 37% of subjects with abnormal ALT at baseline had ALT normalization ( ≤ 1 x ULN).

Outcomes Beyond 48 Weeks

The optimal duration of therapy with BARACLUDE is unknown. According to protocol-mandated criteria in the Phase 3 clinical trials, subjects discontinued BARACLUDE or lamivudine treatment after 52 weeks according to a definition of response based on HBV virologic suppression ( < 0.7 MEq/mL by bDNA assay) and loss of HBeAg (in HBeAg-positive subjects) or ALT < 1.25 x ULN (in HBeAg-negative subjects) at Week 48. Subjects who achieved virologic suppression but did not have serologic response (HBeAg-positive) or did not achieve ALT < 1.25 x ULN (HBeAg-negative) continued blinded dosing through 96 weeks or until the response criteria were met. These protocol-specified subject management guidelines are not intended as guidance for clinical practice.

Nucleoside-na´ve subjects: Among nucleoside-na´ve, HBeAg-positive subjects (Study AI463022), 243 (69%) BARACLUDE-treated subjects and 164 (46%) lamivudine-treated subjects continued blinded treatment for up to 96 weeks. Of those continuing blinded treatment in Year 2, 180 (74%) BARACLUDE subjects and 60 (37%) lamivudine subjects achieved HBV DNA < 300 copies/mL by PCR at the end of dosing (up to 96 weeks). 193 (79%) BARACLUDE subjects achieved ALT ≤ 1 x ULN compared to 112 (68%) lamivudine subjects, and HBeAg seroconversion occurred in 26 (11%) BARACLUDE subjects and 20 (12%) lamivudine subjects.

Among nucleoside-na´ve, HBeAg-positive subjects, 74 (21%) BARACLUDE subjects and 67 (19%) lamivudine subjects met the definition of response at Week 48, discontinued study drugs, and were followed off treatment for 24 weeks. Among BARACLUDE responders, 26 (35%) subjects had HBV DNA < 300 copies/mL, 55 (74%) subjects had ALT ≤ 1 x ULN, and 56 (76%) subjects sustained HBeAg seroconversion at the end of follow-up. Among lamivudine responders, 20 (30%) subjects had HBV DNA < 300 copies/mL, 41 (61%) subjects had ALT ≤ 1 x ULN, and 47 (70%) subjects sustained HBeAg seroconversion at the end of follow-up.

Among nucleoside-na´ve, HBeAg-negative subjects (Study AI463027), 26 (8%) BARACLUDE-treated subjects and 28 (9%) lamivudine-treated subjects continued blinded treatment for up to 96 weeks. In this small cohort continuing treatment in Year 2, 22 BARACLUDE and 16 lamivudine subjects had HBV DNA < 300 copies/mL by PCR, and 7 and 6 subjects, respectively, had ALT ≤ 1 x ULN at the end of dosing (up to 96 weeks).

Among nucleoside-na´ve, HBeAg-negative subjects, 275 (85%) BARACLUDE subjects and 245 (78%) lamivudine subjects met the definition of response at Week 48, discontinued study drugs, and were followed off treatment for 24 weeks. In this cohort, very few subjects in each treatment arm had HBV DNA < 300 copies/mL by PCR at the end of follow-up. At the end of follow-up, 126 (46%) BARACLUDE subjects and 84 (34%) lamivudine subjects had ALT ≤ 1 x ULN.

Lamivudine-refractory subjects: Among lamivudine-refractory subjects (Study AI463026), 77 (55%) BARACLUDE-treated subjects and 3 (2%) lamivudine subjects continued blinded treatment for up to 96 weeks. In this cohort of BARACLUDE subjects, 31 (40%) subjects achieved HBV DNA < 300 copies/mL, 62 (81%) subjects had ALT ≤ 1 x ULN, and 8 (10%) subjects demonstrated HBeAg seroconversion at the end of dosing.

Last reviewed on RxList: 1/6/2014
This monograph has been modified to include the generic and brand name in many instances.

A A A

Baraclude - User Reviews

Baraclude User Reviews

Now you can gain knowledge and insight about a drug treatment with Patient Discussions.

Here is a collection of user reviews for the medication Baraclude sorted by most helpful. Patient Discussions FAQs

Report Problems to the Food and Drug Administration

 

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit the FDA MedWatch website or call 1-800-FDA-1088.


Women's Health

Find out what women really need.


NIH talks about Ebola on WebMD