LB6. A Randomized, Double-Blind, Comparison of Tenofovir DF (TDF) versus Adefovir Dipivoxil (ADV) for the Treatment of HBeAg Positive Chronic Hepatitis B (CHB): Study GS-US-174-0103

E. Heathcote; E. Gane; R. DeMan; S. Lee; R. Flisiak; M. P. Manns; K. Tchernev; O. Kurdas; M. L. Shiffman; J. Sorbel; J. Anderson; E. Mondou; F. Rousseau

 

Background

Tenofovir Disoproxil (TDF) is a nucleotide analogue approved for the treatment of HIV-1 with activity against hepatitis B virus (HBV). The primary objective of this Phase III, 5 year study was to compare the safety and efficacy of 300 mg TDF versus 10 mg ADV at 48 weeks in subjects with HBeAg+ CHB.

 

Methods

This was a double-blind, active-controlled, study of mono-infected subjects with HBeAg+ CHB who were randomized in a 2:1 ratio to TDF:ADV. Entry criteria included subjects 18-69 years of age with compensated liver disease, ALT>2xULN, HBV DNA>106copies/mL and a Knodell necroinflammatory score3. Biopsies were performed pre-treatment and Week 48. HBV DNA was measured using the Roche COBAS TaqMan assay (LLQ=169c/mL). The primary efficacy endpoint at Week 48 was the proportion of randomized and treated subjects with complete response [HBV DNA<400 c/mL and histologic improvement (2-point reduction in the Knodell necroinflammatory score without worsening in fibrosis)].

 

Results

We randomized and treated 266 subjects (176 TDF:90 ADV); groups were well balanced at baseline with an overall mean age of 34 years, 69% male, 52% white, 36% Asian and 55% from Europe. At baseline, mean HBV DNA was 8.72 log10c/mL, 71% had ALT4xULN, 33% Genotype D and 26% Genotype C. Mean Knodell necroinflammatory and fibrosis scores were 8.4 and 2.4 respectively with 20% cirrhotic. Evaluation of resistance surveillance data are ongoing. Safety and tolerability were comparable between TDF and ADV. Early (within first 8 weeks) transient Grade 3 or 4 ALT flares associated with strong declines in HBV DNA were more frequent in the TDF group (19%) vs ADV group (10%). Renal safety was excellent; no TDF subject had a confirmed 0.5 mg/dL creatinine increase or creatinine clearance <50 mL. TDF was well tolerated with no TDF subject discontinuing due to an AE and with the majority completing primary endpoint assessments (90%TDF;93%ADV). Primary and secondary efficacy endpoints are summarized below.

 

Conclusion

TDF, at a dose of 300 mg QD, was well tolerated and demonstrated superior efficacy to ADV through 48 weeks as illustrated by the higher percentage of HBeAg+ subjects achieving the primary efficacy endpoint and most secondary end-points.

 

Efficacy Endpoints

TDF 300 mg

N=176

ADV 10mg

N=90

p-value

Primary Composite Endpoint

67%

12%

<0.001

Histologic Response

74%

68%

NS

%HBV DNA<169 c/mL (LLQ)

69%

9%

<0.001

%HBV DNA <300 c/mL

74%

12%

<0.001

Normal ALT

69%

54%

0.018

HBeAg Seroconversion

21%

18%

NS

HBsAg Loss

3%

0%

0.018

 


83. First Multicenter Evaluation of the Efficacy of Tenofovir in Nucleos(t)ide Analog Experienced Patients with HBV Monoinfection

F. van Bömme; R. A. De Man; A. Erhardt; D. Hüppe; K. Stein; P. Buggisch; W. Böcher; C. Sarrazin; J. Trojan; U. Spengler; J. G. Reijnders; B. Möller; H. E. Wasmuth; P. Rohde; H. Feucht; B. Wiedenmann; T. Berg

 

Background

Tenofovir disoproxil fumarate (TDF), an acyclic nucleotide reverse transcriptase inhibitor is approved for the treatment of HIV infections and has shown activity in HBV/HIV co-infected patients harboring both wild type and lamivudine resistant hepatitis B virus (HBV). In this retrospective multi center analysis we studied the effectiveness of TDF monotherapy in patients with HBV monoinfection with respect to virologic parameters and resistance.

 

Methods

We treated 121 patients with chronic HBV infection (m/f 87/34, mean age 45±12 years [19-74], 70 HBeAg positive) with HBV DNA levels > 105 copies/mL with TDF 300 mg daily in 13 centers in Germany and The Netherlands for > 6 months and retrospectively analyzed. A screening for resistance to nucleoside/nucleotide analogues at baseline was performed in 85 patients with available serum samples stored at -20 degree by direct sequencing of the polymerase gene spanning a polymerase region from codon rt88 to codon rt282. ALT, creatinine, and HBV DNA levels were measured every three months.

 

Results

Before the beginning of TDF treatment 105 patients had been treated with lamivudine and 75 patients consecutively with adefovir dipivoxil due to lamivudine resistance (mean duration 27 and 23 months, respectively). Fourteen patients with genotypic ADV resistance were excluded due to potential cross resistance (evaluated separately) and 6 due to non-compliance to TDF. In the remaining 101 patients during TDF treatment (mean duration 14.8±12, range 6 to 63 months) HBV DNA levels decreased from a mean baseline level of 6.7±1.3 [4.9-9.7] by a mean of 3.8±1.1 [1-6.8] and 4.1±1.2 [1.4-6.7] log copies/ml at week 24 and 48, respectively. HBV DNA was undetectable (<400 copies/mL) in 72% and 91% of the patients at week 24 and week 48. There was no evidence of TDF resistance development as a rebound of HBV DNA >1log was not observed in any of the patients studied. HBeAg seroconversion was documented in 23% of the patients after a mean TDF treatment duration of 9±3 [2-33] months, and HBsAg loss in 4% after 13±6 [9-18] months. 85 patients (70%) had elevated ALT levels at baseline while 78% had normal ALT levels at week 48 of TDF treatment. Patient’s characteristics at baseline as age, gender or presence of liver cirrhosis as well as viral characteristics as HBeAg status or the presence of lamivudine resistance showed no influence on response to TDF. No significant side effects associated with TDF were noted.

 

Conclusions

Our results demonstrate the high efficacy and lack of resistance of TDF monotherapy in nucleoside/nucleotide analogues experienced and therefore difficult-to-treat HBV mono-infected patients.

 


LB2. A Randomized, Double-Blind, Comparison of Tenofovir DF (TDF) versus Adefovir Dipivoxil (ADV) for the Treatment of HBeAg-Negative Chronic Hepatitis B (CHB): Study GS-US-174-0102

P. Marcellin; M. Buti; Z. Krastev; G. Germanidis; K. D. Kaita; I. Kotzev; P. Buggisch; F. Weilert; H. N. Trinh; J. Sorbel; J. Anderson; E. Mondou; F. Rousseau

 

Background

Tenofovir Disoproxil (TDF) is a nucleotide analogue approved for the treatment of HIV-1 with activity against hepatitis B virus (HBV). The primary objective of this Phase III, 5-year study was to compare the safety and efficacy of 300 mg TDF versus 10 mg ADV at 48 weeks in subjects with HBeAg-negative (HBeAg-) CHB.

 

Methods

This was a double-blind, active-controlled, multi-national study of mono-infected subjects with HBeAg- CHB who were randomized in a 2:1 ratio to TDF:ADV. Entry criteria included subjects 18-69 years of age with compensated liver disease, ALT > ULN, HBV DNA > 105 copies/mL and a Knodell necroinflammatory score 3. Biopsies were performed pretreatment and Week 48. HBV DNA was measured using the Roche COBAS TaqMan HBV assay (LLQ=169 c/mL). The primary efficacy endpoint at Week 48 was the proportion of randomized and treated subjects with complete response [i.e., HBV DNA < 400 c/mL and histologic improvement (2-point reduction in the Knodell necroinflammatory score without worsening in fibrosis)].

 

Results

We randomized and treated 375 subjects (250 TDF:125 ADV). Treatment groups were well balanced at baseline with an overall mean age of 44 years, 77% male, 65% white, 25% Asian, 62% from Europe and 18% lamivudine or emtricitabine experienced. At baseline, mean HBV DNA was 6.9 log10 c/mL, 64% had ALT>2xULN and 64% were Genotype D. Mean Knodell necroinflammatory and fibrosis scores were 7.8 and 2.3, respectively with 19% cirrhotic. Evaluation of resistance surveillance data are ongoing. Safety and tolerability were comparable between TDF and ADV treatment groups. Renal safety was excellent; no TDF treated subject had a confirmed 0.5 mg/dL creatinine increase or creatinine clearance value <50 mL. The majority of patients in both treatment groups (TDF:ADV) completed primary endpoint assessments (96%; 93%). Primary and secondary efficacy endpoints are summarized below.

 

Conclusion

TDF, at a dose of 300 mg QD, was well tolerated and demonstrated superior efficacy to ADV through 48 weeks as illustrated by the higher percentage of HBeAg- subjects achieving the primary efficacy endpoint.

 

Efficacy Endpoints

TDF 300 mg

N=250

ADV 10 MG

N=125

p-value

Primary Composite Endpointe

71%

49%

<0.001

Histologic Response

72%

69%

NS

%HBV DNA<169 c/mL (LLQ)

91%

56%

<0.001

%HBV DNA <300 c/mL

92%

59%

<0.001

Normal ALT

77%

78%

NS

 


960. Tenofovir Shows Limited Efficacy in Treatment of HBV Infections Resistant Against Adefovir

F. van Bömmel; J. Trojan; H. Feucht; B. Möller; D. Hüppe; B. Wiedenmann; T. Berg

 

Background

Genotypic HBV resistance against adefovir dipivoxil (ADV) develops rarely during the first two years of treatment. However with increasing treatment duration ADV-resistant HBV mutants are selected in up to 28% of the patients after 5 years which is often associated with viral rebound. In vitro, these mutations cause a 3- to 14-fold decrease of ADV efficacy. Tenofovir (TDF), a nucleotide analogue approved for HIV therapy, is closely related to ADV, shows equipotent antiviral activity against HBV on molar basis and is cross resistant to ADV in vitro. However, due to the 25-fold higher dosage of TDF (300 mg/d) as compared to ADV (10 mg/d), TDF might still be effective in ADV resistant HBV infections.

 

Methods

The efficacy of TDF monotherapy was retrospectively evaluated in 10 HBV monoinfected patients (m/f 9/1, mean age 47±11[27-67] years, 6 HBeAg positive) with initial lamivudine resistance who had developed genotypic ADV resistance (rtN236T and/or rtA181V/T) after consecutive 11-45 (mean 24±9) months of ADV monotherapy. HBV DNA and ALT values were measured every three months (HBV Monitor, Roche, detection limit 400 copies/mL). In six patients, during TDF treatment the HBV polymerase gene was sequenced from codon rt88 to rt282 after PCR products were cloned in E. coli (TOPO-TA cloning system, Invitrogen; minimum of 10 clones sequenced each).

 

Results

At the beginning of TDF treatment (mean duration 16±3 [12-21] months), the mean HBV DNA was 7.5±1.3[4.6-9.4] log copies/mL and nine patients had elevated ALT levels (mean 151±118 [34-358] U/mL). The mutations associated with ADV resistance N236T, A181T and combination of both were detected in 3, 2 and 5 patients. During TDF treatment, HBV DNA decreased by a mean of 3.6±1 [2-5] and 4.3±1.2[2-6.2] log copies/mL at week 24 and week 48, respectively. HBV DNA was still detectable in 9, 8 and 6 patients while ALT levels remained elevated in 8, 8 and 6 patients at week 24, week 48 and at the end of observation. Subspecies analysis in six patients showed that ADV resistance mutations remained detectable throughout the whole observation period in increasing ratio as compared to HBV wild type.

 

Combination therapy with TDF and lamivudine was started in two patients at month 12 and lead to undetectable HBV DNA and normal ALT levels after two months.

 

Conclusion

Although TDF shows significant antiviral efficacy in patients with genotypic ADV resistance, HBV DNA can be completely suppressed only in a minority of the patients and the selection of ADV resistant mutations is not prevented. Therefore, patients with genotypic ADV resistance should receive combination treatment with TDF or ADV plus lamivudine or entecavir.


938. Four-Year Entecavir Treatment in Nucleoside-Naïve HBeAg(+) Patients: Results from Studies ETV-022 and -901

S. Han; T. Chang; Y. Chao; S. Yoon; R. G. Gish; H. Cheinquer; F. Carrillho; H. Zhang; H. Brett-Smith; R. Hindes

 

Background

Entecavir (ETV) 0.5 mg demonstrated superior virologic suppression compared to lamivudine (LVD) 100 mg in study ETV-0221. One hundred and eighty-three entecavir-treated patients from ETV-022 enrolled in rollover study ETV-901. We present efficacy and safety results in a cohort of patients from ETV studies -022 and -901 who received a total of 4 years of therapy with ETV.

 

Methods

The nucleoside-naïve HBeAg(+) 4-year cohort consists of ETV patients who completed ETV-022 and enrolled into ETV-901 with a treatment gap ≤35 days. In ETV-901, patients were treated with 1 mg of ETV. The proportions of patients with HBV DNA <300 copies/mL by PCR assay, ALT normalization, HBeAg loss and HBeAg seroconversion were evaluated among patients with available samples at week-192.

 

Results

The nucleoside-naïve HBeAg(+) 4-year ETV treatment cohort consists of 146 patients. Efficacy parameters through 4 years of ETV therapy are presented below. The safety profile of ETV was consistent with previously reported experience.

 

Conclusions

At Week 192, 91% of patients who received ETV treatment during 4 years achieved undetectable HBV-DNA and 86% had ALT normalization, with patients continuing to experience HBeAg loss and HBeAg seroconversion during Years 3 and 4. The safety profile was consistent with previously reported experience.

1 Chang TT, et al, N Engl J Med 2006;354:1001-1010.

 

Endpoint

Week 192*

HBV DNA <300 copies/mL, n (%)

98/108 (91)

ALT ≤ 1 x ULN, n (%)

96/112 (86)

HBeAg loss**, n (%)

39/96 (41)

HBeAg seroconversion**, n (%)

15/96 (16)

 

*Denominator represent patients with available samples ** Numbers/proportions represent additional patients achieving HBeAg loss or HBeAg seroconversion during treatment in ETV-901; serology tests were performed by local laboratories.

 


951. Entecavir: A Rescue Therapy for Chronic Hepatitis B Patients with a Limited Virological Response to Adefovir?

J. G. Reijnders; R. A. De Man; S. D. Pas; M. Schutten; H. L. Janssen

 

Background

The frequency of detection of drug resistant HBV mutants correlates with the rapidity of initial decline of viral load. In treatment-naive patients with HBeAg-positive hepatitis B entecavir (ETV) achieves approximately 6log10 HBV DNA decline and PCR-negativity in 45% of the patients after 24 weeks of treatment. In lamivudine (LAM)-refractory patients who are subsequently switched to ETV, it has shown to be less effective. Here we describe 12 patients with chronic HBV infection and a persistently high viral replication after one year of treatment with ADV, who were switched to ETV as rescue therapy.

 

Methods

Limited ADV response was defined as presence of HBV DNA levels greater than 5log10 copies/mL after 48 weeks of treatment. Patients were directly switched from ADV to ETV at a daily dose of 1 mg. ALT and HBV DNA levels were assessed at baseline and after 24 weeks of treatment (detection limit 400 copies/ mL). All subjects were screened for resistance-associated mutations within the HBV polymerase gene using Inno Lipa HBV DR v2 and v3 (Innogenetics).

 

Results

The baseline characteristics of the 12 patients with limited ADV response were: median age 44 [range 23-73]; m/f: 9/3; 11 HBeAg+; 3 cirrhosis; genotype A: 3, B: 3, C:1, D: 5. Six patients had a prior history of LAM-resistance. Median period of ADV administration was 79 weeks [range 49-135]. HBV DNA levels ranged between 5.2 to 10.1 log10 copies/mL (median 7.7 log10 copies/mL). At baseline three patients had ADV-resistance substitutions (N236T ± A181V/T), and in only one patient also LAM-resistance was detected (M204I). After 24 weeks of treatment the median decrease of HBV DNA was 3.7 log10 copies/mL [range 1.9-5.9]. There was no difference in decline between patients with or without a prior history of LAM-resistance (3.7 vs. 3.7). Median HBV DNA level at 24 weeks was 3.8 log10 copies/mL. None of the patients reached HBV DNA levels below the detection limit. The proportion of patients with ≤ 3 log10, 3.1-5 log10, > 5 log10 copies/mL was 33%, 42%, and 25%, respectively. HBeAg-seroconversion occurred in one patient after 12 weeks of treatment. After 24 weeks of treatment two patients showed LAM-resistance (M204I), no ETV-resistance substitutions were detected (I169, T184, S202, M250).

 

Conclusion

Entecavir treatment leads to a suboptimal viral decline in patients with a limited response to adefovir, even in the absence of ADV or LAM resistance. Our finding that none of these patients achieved HBV DNA negativity by 24 weeks necessitates close monitoring for potential development of ETV resistance in ADV nonresponders.

 


963. Emergence of Hepatitis B Virus Gene Mutation Related to Entecavir-resistance in Chronic Hepatitis B Patients Participating in the Phase 2 Clinical Studies of Entecavir in Japan

H. Kobashi; S. Fujioka; H. Kumada; O. Yokosuka; N. Hayashi; K. Suzuki; T. Okanoue; M. Sata; H. Tsubouchi; C. Sato; K. Kiyosawa; A. Takaki; Y. Iwasaki; K. Sakaguchi; Y. Shiratori; H. Ishikawa; T. Seriu; M. Omata

 

Background/Objective

The objective of this study was to elucidate the emergence rate of HBV DNA gene mutation related to entecavir-resistance (ETVr) in chronic hepatitis B patients participated in the phase 2 entecavir (ETV) clinical studies performed in Japan.

 

Method

The subjects of this study were 287 patients in total, consisted of (1) 137 nucleoside-naive patients in the ETV-047 study administered with 0.01, 0.1, 0.5 mg/day of ETV or 100mg/day of lamivudine (LVD) for 24 weeks, (2) 66 nucleotide-naive patients in the ETV-053 study administered with 0.1 or 0.5mg/day of ETV for 52 weeks, and (3) 84 LVD-refractory patients in the ETV-052 study administered with 0.5 or 1.0 mg/day of ETV for 52 weeks. After the studies, a total of 282 patients were enrolled in ETV-060 roll over study, and subsequently administered with ETV for another 2 years. Single-nucleotide-polymorphism(SNP)-PCR analysis for HBV polymerase was performed to detect the ETVr mutation for the patients who experienced viral rebound, defined as elevation in serum HBV DNA by greater than 1 log copy/mL.

 

Results

(Result-1: Nucleoside-naive patients).

Five out of 169 nucleoside-naive patients with ETV administration (comprising 103 from ETV-047 and 66 from ETV-053), experienced viral rebound before week 148. ETVr-related mutation (rtS202S/G) along with LVDr-related mutation (rtL180M and rtM204V) was detected in two patients (1.2%) between week 100 and 148. The two patients who developed ETVr never experienced a disappearance of serum HBV DNA. The 34 patients in ETV-047 study, who were administered with LVD for 24 weeks followed by administration with ETV 0.5mg, did not develop LVDr- or ETVr-related mutation throughout the study duration.

 

(Result-2: LVD-refractory patients).

Viral rebound developed in 21 patients out of 84 in ETV-052 study, before week 148, and LVDr-related mutation (rtM204I/V and/or rtL180M) along with ETVr-related mutation (rtS202 and/or rtT184 ), was detected in 19 patients (22.6%).

 

Conclusions

The cumulative number of patients who developed ETVr-related mutation were 0/0/2 at years 1/2/3 in nucleoside-naive group (total n=169 at baseline), and 0/10/19 at years 1/2/3 in LVD-refractory group (total n=84 at baseline), respectively. Development of ETVr-related gene mutation was rare in nucleoside-naive patients.

 


997. Long-term Follow-up of Entecavir Treated Protocol-defined Nonresponders in Rollover Study ETV-901

M. Sherman; M. Rizzetto; C. Lai; Y. Liaw; A. Gadano; I. M. Jacobson; E. R. Schiff; J. Yang; R. Colonno; B. Kreter; R. Hindes

 

Background

Entecavir’s (ETV) efficacy in nucleoside naïve HBeAg(+) [ETV-022] and HBeAg(-) [ETV-027] patients with chronic hepatitis B (CHB) has been demonstrated.1,2 Protocol-defined patient management criteria dictated that ‘Non-Responders’ in ETV-022 and ETV-027 discontinued study therapy. However, ‘Non-Responders’ who enrolled in rollover study ETV-901 continued to be monitored and are reported here.

 

Methods

679 nucleoside-naïve HBeAg(+) and HBeAg(-) patients were enrolled and treated with ETV in studies ETV-022 and ETV-027. Patients who failed to achieve HBV DNA <0.7 MEq/mL by bDNA at week 48 or during year-2 were classified as ‘Non-Responders’, discontinued study and were offered continued entecavir (1 mg) treatment in rollover study ETV-901 or at the discretion of the investigator, alternative off-study anti-HBV therapy. The proportions of patients with HBV DNA <300 copies/mL by PCR assay, ALT normalization and HBeAg seroconversion were assessed during long-term follow-up in ETV-901.

 

Results

At 48 weeks, 19 HBeAg(+) and 3 HBeAg(-) ETV-treated patients were classified as ‘Non-Responders’ (3%). Among patients treated during year-2, 8 additional HBeAg(+) patients became ‘Non-Responders’ (8/269 [3%]). Twenty-one HBeAg(+) patients from ETV-022 enrolled in ETV-901. Median HBV DNA and ALT at entry into ETV-901 were 3.3 log10 copies/mL and 37 IU/L respectively. The table below shows proportions of patients who achieved HBV DNA <300 copies/mL by PCR, ALT normalization and HBeAg seroconversion as well as the proportions of patients who maintained these endpoints at their last observation. Four patients experienced a virologic breakthrough. However, genotypic and phenotypic analysis failed to show any evidence of resistance. No patients discontinued due to adverse events.

 

Conclusions

Fewer than 5% (30/679) of nucleoside-naïve HBeAg(+) and HBeAg(-) patients treated in ETV-022 and ETV-027 met protocol-defined criteria of ‘Non-Response’. Substantial proportions of ‘Non-Responders’ subsequently achieved undetectable HBV DNA and ALT normalization in ETV-901. Approximately one third of patients also experienced HBeAg seroconversion.

 

References

1. Chang TT, et al. NEJM 2006;354:1001-1010.

2. Lai CL, et al. NEJM 2006; 354:1011-1020

 

Endpoint

Achieved endpoint in ETV-901

Maintained endpoint at last observation

HBV DNA < 300 copies/mL, n (%)

15/21 ( 71%)

12/21 (57%)

ALT normalization, n (%)

20/21 (95%)

13/21 (62%)

HBeAg seroconversion*, n (%)

7/21 (33%)

7/21 (33%)

*serology tests were performed by local laboratories

 


1003. Three-year Assessment of Entecavir Resistance in Genotype C Chronic Hepatitis B Patients in Japan Reveals Different Clinical Outcomes Regarding Breakthrough Hepatitis Predicted by the Resistance Substitutions Using Recently-developed INNO-LiPA HBV Assay

M. Mukaide; Y. Tanaka; E. Orito; F. Kurbanov; K. Fukai; O. Yokosuka; M. Sata; T. Ide; K. Yoshiyasu; Y. Goutaro; K. Sakaguchi; M. Mizokami

 

Background/Aim

Currently, entecavir (ETV) is being considered as s first- or second-choice treatment for nucleoside-naive or lamivudine (LVD)-refractory chronic hepatitis B patients. To assess frequency of ETV-resistance (ETVr) and the specific substitutions associated with breakthrough hepatitis (BTH) during 3-years ETV therapy, recently developed INNO-LiPA HBV DR v2 and ETV TDF assay was applied.

 

Methods

Forty-five patients including 25 chronic LVD-refractory genotype C patients (m/f: 22/23, mean age: 41.6 yrs, ALT: 129.1 HBeAg: 36 and HBV-DNA (TMA): 6.98) and 20 naïve patients were enrolled. Drug resistance was assessed by detection L80VI, V173GL, L180M/A181TV, M204VID, N236T for LVD (LVDr) and T184SCGAILMF, A194T, S202GCI, M250VL for ETVr.

 

Results

In 25 LVD-refractory patients, the ETVr substitutions (SCGA184, ILMF184, G202, C202, VL250) were present in 3/25 (12.5%) at baseline and emerged in 5/25 (20.8%), and 7/25 (29.4%) and 5/17 (29.2%) at weeks 48, 96, and 144, respectively (Table1). No patient was found with S202I during the 3 years. There was no evidence of ETVr substitutions in LVD naïve patients during 3 years. Percentage of typical LVD substitutions (M180, V204, I204) observed in LVD-refractory patients was 92%, 95%, 94%, and 100% at baseline, weeks 48, 96, and 144, respectively, versus 8%, 8%, 0%, and 13% in naïve patients, respectively. Five of the 25 LVD-refractory (20%) patients treated with 1.0 mg ETV had evidence of BTH after 72 to 136 weeks of the therapy. Of the all BTH patients, LDVr substitutions (M180 and V204) were detected at baselines, and an additional G202 ETVr substitution occurred (0-96 weeks), resulting in BTH 40-72 weeks later. Other substitutions emerged during ETV therapy, but none of them seemed to affect susceptibility to ETV or associated to BTH.

 

Conclusions

INNO-LiPA is useful in early ETVr detection. In LVD-refractory, genotype C, Japanese patients, LVDr (M180 and V204) plus G202 ETVr substitutions resulted in BTH. High and long-term efficacy of ETV was demonstrated in naïve patients, whereas adefovir add-on LVD should be considered as a first-, or second-line treatment option for LVD-refractory chronic hepatitis B patients.

 

Table1. EDVr associated substitutions emerged in LVDr cohort during follow up

LVD-refractory patients

 

 

 

 

 

 

weeks

No.

SCGA184

ILMF184

G202

C202

IL250

0

25

1(4%)

0

1(4%)

0

1(4%)

48

25

1(4%)

0

4(16%)

1(4%)

0

96

25

2(8%)

2(8%)

6(24%)

0

0

144

17

2(11.8%)

1(5.9%)

3(17.6%)

0

0

 


940. Creatine Kinase (CK) Elevations and Muscle Toxicities Associated with Chronic Telbivudine (LdT) Use in Prospective Clinical Trials

C. A. Brown; F. Smith; K. A. Laessig

 

Background

Nucleoside-associated myopathy has been well described in treatment of the Human Immunodeficiency Virus; however CK elevations and myopathy have been a more unusual adverse event with the use of nucleosides for treatment of Hepatitis B Virus (HBV). We reviewed the LdT approval database for CK elevations and adverse event patterns consistent with muscle toxicity.

 

Methods

Data were reviewed from trials that prospectively measured CK levels and recorded clinical adverse events, and in which LdT was used in at least one arm in New Drug Application 22-011. We examined the time to onset and frequency of CK elevations from the pivotal Phase 3 trial (52 week data) using Kaplan-Meier plots and Fisher’s Exact Analysis (LdT vs. lamivudine (LAM)). We also reviewed detailed event narratives of clinical adverse events (AE) for CK elevations or events suggestive of myopathy, the Food and Drug Administration Adverse Event Reporting System for reports of muscle toxicity since LdT market approval (10/25/06) and preclinical evaluations for mitochondrial toxicity submitted with the Application.

 

Results

The pivotal Phase 3 trial safety database included 680(LdT) and 687(LAM) subjects with HBeAg-positive and HBeAg-negative chronic HBV. More LdT subjects developed new-onset CK elevations compared to LAM subjects (Grade 1-4: 72% LdT, 42% LAM) after several months on study drug. After reviewing narratives for serious adverse events and study drug discontinuations/interruptions, there were a total of 16 LdT and 1 LAM subject with CK elevations or muscle symptoms; 6 of whom had a convincing picture of myopathy with muscle weakness, 2 of whom had biopsy confirmation, and 1 of whom was on a concomitant drug associated with myopathy. All presented after more than 300 days on study drug. History, degree and timing of CK elevations, and demographic characteristics were variable. No reports of LdT-associated CK elevations, myopathy or muscle weakness have been reported to our Adverse Event Reporting System since approval. No evidence of mitochondrial toxicity was found in review of preclinical studies.

 

Conclusions

We found an emerging pattern of a cumulative toxicity resulting in myopathy with chronic LdT that may or may not be associated with mitochondrial toxicity. The imperfect relationship between the timing and severity of CK elevations and myopathy, coupled with the variable demography and symptom presentation in these clinical trial settings suggest that further characterization of this toxicity, its mechanism and its predisposing factors is warranted. These toxicities may occur more frequently in the general population with longer-term use of LdT.

 


994. Baseline Parameters Predict Both Early Virologic Response and Longer Term Outcomes for Telbivudine-Treated Patients With Chronic Hepatitis B (The Globe Study)

S. Zeuzem; M. Buti; E. J. Gane; Y. Liaw; A. M. Di Bisceglie; E. Heathcote; N. V. Naoumov; J. Rasenack; S. Lim; J. Hou; X. Qiao; K. Galil

 

Background

Viral load at 24 weeks of telbivudine treatment has been linked to efficacy outcomes after 1 and 2 years. Studies have shown that pretreatment, elevated ALT and low HBV DNA levels predict higher responses to interferon, however few corresponding data are available for nucleos(t)ide therapies for hepatitis B. Here we report that baseline disease variables predict virologic responses to telbivudine at 24 weeks, which in turn predict efficacy outcomes at 2 years.

 

Methods

The GLOBE trial enrolled 1,367 HBeAg+ and HBeAg- hepatitis B patients with HBV DNA >6 log10 copies/mL, ALT 1.3-10 xULN, and compensated liver disease, randomized to receive telbivudine or lamivudine for 2 years. The influence of baseline parameters and early HBV DNA suppression on subsequent efficacy outcomes and resistance were evaluated by univariate and multivariate regression analyses.

 

Results

Pretreatment serum HBV DNA and ALT levels were significant predictors of virologic response at Week 24 and of efficacy outcomes and viral breakthrough at Week 104. Among HBeAg+ telbivudine recipients with ALT ≥2 xULN and HBV DNA <9 log10 copies/mL at baseline, 47% and 14% experienced HBeAg seroconversion and viral breakthrough at Week 104, respectively, vs. 30% and 29% among all HBeAg+ telbivudine recipients. 71% of patients in this subset were PCR-negative after 24 weeks of telbivudine, vs. 44% of HBeAg+ telbivudine recipients overall. HBV genotype had minor, generally nonsignificant effects on outcomes. Similar relationships were observed in HBeAg- patients with elevated ALT and serum HBV DNA <7 log10 copies/mL at baseline, however due to the higher overall rate of viral clearance in this group, baseline parameters had a less pronounced effect on virologic responses at Weeks 24 and 104, compared with HBeAg+ patients.

 

After initiation of treatment, multivariate analyses showed a diminished impact of baseline parameters on subsequent outcomes, and confirmed viral load at Week 24 as the most significant predictor of outcomes at Week 104. Among patients with HBV DNA <9 log10 copies/mL and elevated ALT at baseline, PCR negativity at Week 24 resulted in 52% HBeAg seroconversion and 3.6% viral breakthrough at 2 years.

 

Conclusions

High rates of efficacy responses after 2 years of telbivudine, and low resistance, occurred in patients with elevated ALT and HBV DNA <9 log10 (HBeAg+ patients) or <7 log10 (HBeAg patients) copies/mL pretreatment, coupled with optimal viral load reduction at Week 24. These results define patient characteristics associated with optimal responses to telbivudine and may contribute to on-treatment patient management strategies.

 


995. On-Treatment Virologic Suppression at Week 24 Decreases the Risk of Histologic Progression at One Year; Data from the GLOBE Trial

Y. Benhamou; A. M. Di Bisceglie; Z. D. Goodman; P. Lampertico; M. P. Manns; P. Vig; X. Qiao; K. Galil

 

Background

Serum HBV DNA and ALT level have been correlated with active liver disease in patients with chronic hepatitis B (CHB). However, on-treatment predictors of liver disease progression have been inadequately studied.

 

Objective

To identify on-treatment predictors of worsening of HBV-related liver disease.

 

Methods

The GLOBE trial enrolled 1367 compensated CHB patients with baseline HBV DNA >6 log10 copies/mL, ALT 1.3-10 xULN. Patients were randomized 1:1 to treatment [telbivudine (600 mg/d PO) or lamivudine (100 mg/d PO)] and stratified by HBeAg status and baseline ALT level. Predictors of histologic progression at Week 52 (W52) were evaluated using baseline (BL) and 24-week (W24) data from the GLOBE trial. Progressors (P) exhibited [1-unit increase in Ishak Fibrosis Score (IFS)] OR [2-unit increase in Knodell Necroinflammatory Score (KNS) with no decrease in IFS] at W52. All other patients were deemed non-progressors (NP). Stepwise logistic regression analysis of data from 549 telbivudine patients and 535 lamivudine patients compared P (n=142) to NP (n=942) after 52 weeks of treatment; p-values and odds ratios of being P at W52 were calculated. Factors were entered into the model using α=0.25, and retained in the model using α=0.1. BL factors included IFS, KNS, viral load, e-antigen status, genotype, ALT, BMI, age, gender, and treatment assignment. On-treatment factors were viral load reduction, ALT decline, and PCR negativity (all at week 24).

 

Results

BL IFS (OR=5.0) and KNS (OR=2.7) were the only significant factors predicting P (p <0.0001 for both), with lower scores being more predictive of P than higher scores, possibly due to higher IFS and KNS responding better to antiviral treatment. The only significant on-treatment predictor of P (p ≤ 0.05) was failing to achieve a decline in HBV DNA of >5 log10 copies/mL by W24 (p=0.0058), which increased the likelihood of P by 57%. Genotype, baseline BMI and treatment arm were retained in the model but were not significant at p =0.05. However, significantly more telbivudine-treated patients achieved ≥ 5 log10 decline in HBV DNA compared with lamivudine (69% vs. 55%, p<0.05).

 

Conclusion

Although baseline histology status was the most important predictor of disease progression at 1 year, the only significant on-treatment factor found to reduce the likelihood of progression was attaining HBV DNA decline >5 log by W24. These data suggest that using a more potent antiviral agent can result in histologic improvements over periods as short as one year. Longer term studies are needed to evaluate the effects over time.

 

Acknowledgment

D Walczak, Cayuga Consulting & V Mats, Quartesian LLC