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Conference Reports

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Digestive Disease Conference: HBV Abstracts

Alan Franciscus
Editor-in-Chief, HCV Advocate

Abstract 337
A Dose Escalating Trial Evaluating the Safety and Antiviral Activity of Clevudine in Patients with Chronic HBV Infection.

Abstract 338
Predictors of Virologic Response after Lamivudine Treatment in Children with Chronic Hepatitis B

Abstract 339
Comparison of Viral Replication Fitness of Wild-Type and Lamivudine-Resistant HBV in Patients

Abstract 342
Tenofovir and HBV Mutants After Liver Transplantation

Abstract 507
Adefovir Dipivoxil Results in a Consistent and Significant Improvement in Liver Histology and Virological Status Regardless of Baseline Knodell Fibrosis Score in Patients with HBeAg+ Chronic Hepatitis B

Abstract 508
Changes in Alanine Aminotransferase (ALT) and YMDD Mutation Profile Associated with Switching from Lamivudine (LAM) to Either Adefovir Dipivoxil (ADV) or Combination LAM Plus ADV in Chronic Hepatitis B (CHB) Patients with LAM Resistance

Abstract 337
A Dose Escalating Trial Evaluating the Safety and Antiviral Activity of Clevudine in Patients with Chronic HBV Infection.

Patrick Marcellin, Steve Sacks, George Kk Lau, Herve Mommeja-Marin, Dominique Sereni, Jean-Pierre Bronowicki, Brian Conway, Christian Trepo, Elsa Mondou, Andrea Snow, B. C. Yoo, H.-S. Lee, Franck Rousseau

Background:

Clevudine (CLV, L-FMAU) is a potent inhibitor of HBV replication in vitro. In woodchucks, CLV produced a potent and sustained viral suppression following a 12 weeks dosing period.

Methods:

This was a multicenter, open-label, dose escalation study evaluating 10, 50, 100 and 200 mg Clevudine QD for 28 days (n=5, 10, 10 and 7/arm, respectively). Patients were followed post-treatment for 24 weeks. Eligible patients had chronic HBV infection, Baseline HBV DNA levels (VL) =3x106 copies/mL, were nucleoside treatment naive and without HIV or HCV co-infection. VL was assayed using Digene Hybrid Capture II (with a lower limit of detection of 4700 c/mL) and genotype by di-deoxy sequencing.

Results:

32 patients were enrolled, 81% were male, 81% Asian, 88% HBeAg positive. At Baseline, median VLs were 7.3, 8.0, 8.8 and 8.4 log10 c/mL and median ALTs were 55, 119, 106 and 64 IU/L in the 10, 50, 100 and 200 mg QD cohorts, respectively.

After 28 days of dosing, the median log10 VL change from Baseline was -2.5, -2.7, -3.0 and -2.6 and median change in ALT from Baseline was -13, -14.5, +37 and -14 U/L, in the 10, 50, 100 and 200mg cohorts, respectively.

At 6 months post-dose, sustained biochemical and virologic responses were observed: 71% of the patients overall had normal ALT levels and median log10 VL changes from Baseline were -1.2, -1.4, -2.7 and -1.6 in the 10, 50, 100 and 200mg arms, respectively.

During the study, 8 patients lost HBeAg (30%) of whom 5 seroconverted to HBeAb (19%). Clevudine was well tolerated, without dose related adverse events. A transient increase in ALT was observed in the 100 mg cohort but not in the 200 mg group. The pharmacokinetics of Clevudine were dose proportional with a long plasma half-life supporting a once daily regimen. No treatment emergent mutations in the HBV DNA pol domain were observed 5 months after treatment.

Conclusion:

These results confirm the antiviral activity of once daily clevudine and further demonstrate, in humans the uniquely sustained post-treatment antiviral effect seen previously in woodchucks. Despite the short (4 weeks) duration of therapy very favorable rates of HBeAg loss and seroconversion were observed without evidence to date of acquired resistance on Clevudine therapy.

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Abstract 338
Predictors of Virologic Response after Lamivudine Treatment in Children with Chronic Hepatitis B

Xenia Hom, Nancy R. Little, Maureen M. Jonas

Background:

Lamivudine is a therapeutic option for children with chronic hepatitis B (HBV). In adults, pretreatment ALT and/or histologic activity predict HBeAg loss with treatment.

Aim:

To identify the pretreatment variables that predict virologic response (VR)(defined as loss of HBeAg and undetectable HBV DNA in serum after 1 year of treatment) to lamivudine in children.

Methods:

A randomized, placebo-controlled trial of lamivudine (52 weeks) has been completed in 288 children (Jonas et al, NEJM 2002;346:1706-13). Exploratory analyses with prospectively defined baseline covariates of interest were used to evaluate potential predictors of virologic response. These included age, gender, race, weight, body mass index (BMI), ALT, HBV DNA, and Histologic Activity Index (HAI) score.

Initially, univariate analyses were conducted using logistic regression. Next, multivariate analysis was used to investigate the pattern of covariation of multiple factors with response (step-wise logistic model). Subgroup analyses were then performed to show response rates across different levels of baseline characteristics (Mantel-Haenszel test).

Results:

In the univariate model, there was no difference in rate of VR by age, gender, race (Asian vs non-Asian), weight, BMI, or previous interferon therapy after adjusting for treatment. Baseline ALT level (table below) and HAI scores {Odds Ratio of VR was 1.77 (95%CI 0.95-3.29) for HAI scores 5-9 and 2.57 (95%CI 0.81-8.17) for HAI scores 10-14 as compared to scores 0-2 (P=0.002)} were both strong predictors of VR and HBeAg seroconversion.

  Virologic Response HBeAg Seroconversion (3-comp) #
Pretreatment ALT (x ULN) Placebo (n=95) Lamivudine (n=191) Placebo (n=95) Lamivudine (n=191)
<=1 1/7(14%) 1/8 (13%) 1/7(14%) 1/8(13%)
<1-<=2 2/30(7%) 10/86(12%) 2/30(7%) 10/86(12%)
>2-5 5/41 (12%) 25/81 (31%) 5/41(12%) 23/81 (28%)
>5 4/17(24%) 8/16(50%) 4/17(24%) 8/16 (50%)
Overall 12/95(13%) 44/191(23%) 12/95(13%) 42/191(22%)
P-value* 0.111 0.001 0.111 0.001
*P-value based on Mantel-Haenszel test comparing response/no response by baseline ALT category, excluding patients with normal ALTs. #Defined as HBeAg-ve/HBeAb+ve/HBV DNA-ve

Conclusions:

As in adults, baseline ALT and HAI scores are important predictors of VR to lamivudine in children. The likelihood of response was not significantly affected by patient age or race.

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Abstract 339
Comparison of Viral Replication Fitness of Wild-Type and Lamivudine-Resistant HBV in Patients

William Delaney Iv, Christopher Westland, Huiling Yang, Hamid Namini, Vincent Thibault, Yves Benhamou, Carol Brosgart, Craig Gibbs, Michael Miller, Shelly Xiong

Background:

Lamivudine-resistant HBV has been described as replication defective based on early clinical observations and in vitro data for single mutations of M204V or M204I in the YMDD motif of HBV polymerase. However, recent data suggests that compensatory mutations also emerge and patients with long-term lamivudine resistance undergo disease progression.

Aims:

To compare levels of serum HBV DNA and ALT in patients with lamivudine-resistant and wild-type HBV. To determine the prevalence of compensatory mutations in YMDD-mutants and their contributions to replication fitness.

Methods:

Patients analyzed were enrolled in trials of adefovir dipivoxil for the treatment of wild-type (2 trials, n=695) or lamivudine-resistant HBV (3 trials, n=203). Patients were required to have serum HBV DNA levels ?5 log10 copies/mL at entry. Serum HBV DNA was measured by Roche Amplicor PCR. DNA sequencing was used to identify resistance mutations at baseline. Results: At baseline, patients with lamivudine-resistant HBV had similar serum HBV DNA (medians 7.7, 8.1, and 8.8 log10 copies/mL) compared to patients with wild-type HBV (medians 7.1 and 8.4 log10 copies/mL); median ALT levels were 79-82 IU/L in lamivudine-resistant and 94-98 IU/L in wild-type patients.

Compensatory mutations (V173L, L180M) that enhance the replication of YMDD-mutant HBV in vitro were found in the majority (88%) of lamivudine-resistant patients. At baseline, four major mutational patterns were identified in patients with lamivudine-resistant HBV (L180M+M204V [58%], V173L+L180M+M204V [17%], M204I [12%], L180M+M204I [11%]); serum HBV DNA did not vary significantly across the different mutational patterns.

Conclusions:

Lamivudine-resistant HBV is capable of replicating to levels comparable to wild-type HBV and causing abnormally high ALT. Exclusion of patients with lower serum HBV DNA levels from eligibility preclude an assessment across a greater spectrum of viral load. The four patterns of lamivudine resistance mutations all had similar levels of serum HBV DNA.

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Abstract 342
Tenofovir and HBV Mutants After Liver Transplantation

Jose Nery, Daryl Lau, Caio Nery, Kamran Safdar, Maria Torres, Guy W. Neff, Marzia Montalbano, Doug Meyer, Debbie Weppler, Sylon Britto, Arie Regev, Seigo Nishida, David Levi, Juan Madariaga, Tomaki Kato, Eugene R. Schiff, Andreas Tzakis

Aim:

Resistant HBV strains develops in approximately 30% of post liver transplant (LTx) recipients treated with lamivudine(LAM) within 2 years from time of transplantation. Adefovir(ADV) has recently been reported to be effective against mutants, however its use may be limited by nephrotoxicity. We report our experience with tenofovir(TNV), another nucleotide analogue reverse transcriptase inhibitor, in LTx recipients developing lamivudine resistance.

Methods:

8 pts developed resistance to lamivudine 10 to 85 mos (median: 26) post-LTx. Tenofovir (300 mg/day, P.O.) was added 1 to 66 mos after breakthrough (BT), and continued for 2 to 12 mos (median: 4). Prior to receiving tenofovir, these patients had been excluded from receiving adefovir due to:

  • age> 60 y.o. (5)
  • HIV co-infection (1)
  • Enlistment in another drug study (1)
  • Potential non-compliance (1).

Criteria for BT included elevation of liver chemistries along with reappearance of HBsAg, HBeAg and/or HBVDNA. HBV genotype and YMDD variants were identified through DNA sequence analysis prior to and after TNV; sequential HBVDNA levels were measured by hybridization (pts 2,4,6,7&8) or PCR (pts 1,3&5).

Results:

No adverse reaction was associated with tenofovir. The tables below summarize the data pertaining the study patients.

Tenofovir Treatment Summarization

Patient Median Creatinine (mg/dl) Median ALT (IU/l) Log HBV DNA
Pre-TNV Post-TNV p TNV Post-TNV p Pre-TNV Post-TNV p
1 1.3 1.3 n.s. 17 65 n.s. 6.98 3.55 0.008
2 1.8 1.7 n.s 71 175 n.s 2.21 <-0.3 0.016
3 1.4 1.5 n.s. 103 68 n.s 4.04 2.57 0.001
4 1.4 1.5 n.s. 46 38 n.s 4.51 <-0.3 <0.001
5 1.0 1.1 n.s. 113 39 n.s. >8.70 7.11 <0.001
6 1.0 1.1 n.s. 122 104 n.s. >3.78 -0.16 <0.001
7 1.3 1.1 n.s 60 36 n.s. 3.53 0.62 0.004
8 0.9 0.9 n.s. 95 30 0.001 2.92 <-0.3 0.026

 


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