Tuesday May 23rd  8:30- 10am    Session Title: Therapy of Hepatitis B AASLD Topic Forum

 

477. Final Analysis of Virological Outcomes and Resistance During 5 Years of Adefovir Dipivoxil Monotherapy in HBeAg-Negative Patients

K. Borroto-Esoda; S. Arterburn; A. Snow; S. Chuck; S. Hadziyannis; S. Locarnini; F. Zoulim; J. Pawlotsky

 

Background/Objectives:

Treatment with adefovir dipivoxil (ADV) for up to 5 years provides clinical and histological improvement, but long-term therapy with HBV inhibitors can select for mutations in the HBV polymerase associated with resistance. Definitions of resistance have varied widely for different antivirals, making it difficult to compare incidence rates.

 

Methods:

We investigated the incidence and course of three categories of events in Study 438: 1) ADV-associated mutations regardless of HBV DNA level and ALT outcomes (“mutations”; M), 2) mutations with >=1 log10 copies/mL increase from nadir (confirmed or last measurement), or never suppressed to <4 log10 copies/mL (“virologic resistance”; M+VR) or 3) mutations with virologic resistance and ALT elevations (ALT >1X ULN after normalizing ALT; M+VR+ALT). Patients were evaluated every 4 weeks (years1+2) and every 3 months thereafter for HBV DNA (Roche PCR assays) and ALT. Sequencing was performed yearly on all samples with detectable HBV DNA.

 

Results:

Over five years, 29 patients developed mutations (M) in HBV polymerase associated with ADV resistance (rtN236T and/or rtA181V). Eighteen patients with mutations experienced virologic resistance (M+VR). The median time of follow-up on ADV monotherapy was 36 weeks in these patients compared to 12 weeks in those who had mutations without virologic resistance. Thirteen patients had virologic resistance and ALT elevations (M+VR+ALT). The median time of follow-up on ADV monotherapy was 36 weeks in these patients compared to 18 weeks in the patients without ALT elevations. Eleven patients received lamivudine therapy (monotherapy or in addition to ongoing ADV) subsequent to development of ADV mutations which resulted in a 2-6 log10 drop in HBV DNA.

 

Conclusions:

At five years, monotherapy with ADV in HBeAg-negative patients results in cumulative rates of 29% for mutations, 16% for mutations and virologic resistance, and 11% for mutations, virologic resistance, and ALT elevations.

 

 

Year 1

Year 2

Year 3

Year 4

Year 5

M

0%

3%

11%

18%

29%

M+VR

0%

3%

8%

13%

16%

M+VR+ALT

0%

2%

6%

10%

11%

 


478. Entecavir Results In Continued Virologic And Biochemical Improvement And HBEAG Seroconversion Through 96 Weeks Of Treatment In Lamivudine-Refractory, HBEAG(+) Chronic Hepatitis B Patients (ETV-026)

M. Sherman; P. Martin; W. M. Lee; C. Yurdaydin; J. D. Sollano; J. Vaughan; R. G. Hindes

 

Background:

In lamivudine (LVD)-refractory, HBeAg(+) chronic hepatitis B (CHB) patients, switching to entecavir (ETV) was superior to continued LVD at Week 48 for achieving histologic improvement, undetectable HBV DNA and ALT normalization. Long-term data for efficacy and safety through 96 weeks of treatment are reported here.

 

Methods:

286 HBeAg(+) CHB patients who were refractory to current LVD therapy were randomized 1:1 to ETV 1.0 mg (N=141) or continued LVD 100 mg (N=145). At Week 48, patients who achieved Virologic Response (HBV bDNA <0.7 MEq/mL but positive for HBeAg) could continue blinded therapy through Week 96. A patient was a responder for a cumulative end point if the patient had a confirmed response (two sequential measurements) for the end point at any time during treatment.

 

Results:

77 ETV-treated and 3 LVD-treated patients continued blinded therapy to a second year of therapy. In this cohort, the proportion of ETV-treated patients with HBV DNA <300 copies/mL increased from 21% at Week 48 to 40% at end of dosing, ALT normalization increased from 65% to 81% and mean HBV DNA reduction from baseline increased from 5.7 to 5.9 log10 copies/mL. In a cumulative analysis of all treated patients, viral rebound with ETV resistance mutations occurred in 9% of patients through Week 96. The cumulative analysis of efficacy end points for all treated patients through Week 96 is presented in Table 1. The Week 96 cumulative safety profile of ETV was comparable to that for LVD.

 

Conclusions:

Through 96 weeks of treatment, ETV 1.0 mg results in continued clinical benefit in LVD-refractory HBeAg(+) patients as measured by the proportion of patients achieving an HBV DNA <300copies/mL, ALT normalization and HBeAg seroconversion. Patients treated for a second year experienced incremental benefit in viral load reduction and ALT normalization.

 

Cumulative Confirmed Virologic, Serologic, and Biochemical Endpoints Through Week 96 (%)

 

ETV 1.0 mg
N=141

LVD 100 mg
N=145

p-value

HBV DNA <300 copies/mL

30

1

<0.0001

HBeAg seroconversion

16

4

0.0011

ALT ≤1 x ULN

85

29

<0.0001

 


479. A Randomized Trial of Telbivudine (LdT) vs. Adefovir for HBeAg-Positive Chronic Hepatitis B: Results of the Primary Week 24 Analysis

E. Heathcote; H. L. Chan; M. Cho; C. Lai; Y. Moon; Y. Chao; R. Myers; G. Minuk; P. Marcellin; L. Jeffers; W. Sievert; R. Kaiser; G. Chao; N. Brown; 0. Study Group

 

Background:

For optimizing patient management with the current antiviral armamentarium for hepatitis B, additional comparative studies are needed. Adefovir dipivoxil has significantly greater efficacy than placebo treatment but has not been evaluated in comparative trials. Telbivudine exhibited superior antiviral activity vs lamivudine in a large phase III trial, and those study results indicated that optimal viral suppression and clinical efficacy (ALT normalization, HBeAg loss/seroconversion) at 1 year were associated with maximal HBV DNA reductions in the first 6 months of treatment.

 

Methods:

This ongoing 1-year international trial is comparing the antiviral efficacy and safety of telbivudine vs adefovir. The enrolled ITT population is 133 adults with HBeAg-positive chronic hepatitis B. Key entry criteria were HBsAg+, HBeAg+, HBV DNA >6 log10 copies/mL by COBAS Amplicor PCR assay, ALT 1.3-10 xULN, and compensated liver disease. Patients were randomized (2:1) to treatment with adefovir 10 mg/d or telbivudine 600 mg/d; at Week 24, half the adefovir cohort is secondarily randomized to switch to telbivudine. Completion of study treatment is at Week 52. The primary endpoint defined by the study protocol is HBV DNA reduction at Week 24, with secondary antiviral and clinical efficacy and safety endpoints assessed at Weeks 24 and 52.

Results:

Treatment groups were well-matched at baseline. Telbivudine was superior to adefovir on the primary efficacy endpoint (HBV DNA reduction at Week 24) and all other measures of direct antiviral efficacy (Table). ALT normalization was similar at Week 24. Both treatments have been well-tolerated to date.

 

Conclusion:

After 24 weeks, telbivudine exhibited significantly greater and more consistent antiviral efficacy than adefovir in HBeAg+ patients with chronic hepatitis B. One-year data, to be presented at the meeting, will assess the association of this difference in antiviral effect with subsequent clinical efficacy outcomes.

 

 

N

Log10
HBV DNA ↓

% HBV DNA
< 5 log10†

% HBV DNA
PCR-neg

% ALT
normalized

% HBeAg loss

Telbivudine

44

6.37*

95%*

38.6%*

61.4%

16%

Adefovir

89

5.11

58%

12.4%

62.9%

10%

 


480. Safety and efficacy of adefovir dipivoxil in patients with lamivudine-resistant chronic hepatitis B undergoing liver transplantation

E. Schiff; C. Lai; P. Neuhaus; H. Tillmann; D. Samuel; J. Villeneuve; S. Hadziyannis; S. Arterburn; H. Mommeja-Marin; S. Chuck

 

Background:

Lamivudine and HBIg prevent reinfection of the graft following liver transplantation for chronic hepatitis B (CHB), however, lamivudine resistance can develop and HBIg is costly. The efficacy and safety of adefovir dipivoxil (ADV) and lamivudine in preventing reinfection in patients with lamivudine-resistant CHB were investigated.

 

Methods:

Fifty-seven patients with lamivudine-resistant CHB, who were being treated with ADV added to ongoing lamivudine, underwent transplantation. Serum HBV DNA was centrally assessed using the Roche Amplicor Monitor assay with a lower limit of quantification (LLQ) of 1000 copies/mL.

 

Results:

At baseline, the patients were median age 52 years, 88% male, 77% Caucasian, 19% Asian, 100% HBsAg positive, 42% HBeAg positive, with median serum HBV DNA 4.6 log10 copies/mL, median ALT 1.0 times ULN, and 43%, 39% and 18% were CPT class A, B or C, respectively. The median duration of ADV therapy pre-transplantation was 15 weeks. Thirty-two patients (56%) also received HBIg. The median duration of follow-up post-transplantation was 36 weeks. Following transplantation, no patient was both HBsAg and HBV DNA positive. Four patients (7%) had HBsAg detected at their first measurement post-transplantation; of these, 2 patients had negative HBsAg on 5 and 2 subsequent measurements, and 2 patients had no additional HBsAg follow-up. Two of these 4 patients received HBIg. Four of 32 (13%) patients given HBIG had a single HBV DNA measurement >LLQ (max 3055 copies/mL) post-transplantation, and an additional 2/32(6%) had confirmed detectable HBV DNA on the first two measurements post-transplantation with subsequent measurements LLQ (max 2088 copies/mL) during follow-up. Four patients (7%) discontinued ADV due to an adverse event; only one event (psychosis) was “possibly related” to ADV. The maximum serum creatinine post-transplantation was grade II or higher in 9/57(16%) patients.

 

Conclusion:

The combination of ADV and lamivudine, started prior to liver transplantation and continued afterward, was safe and efficacious in preventing reinfection of the graft in lamivudine-resistant CHB either with or without concomitant HBIg. Over 80% of patients never had detectable HBV DNA and 93% never had detectable HBsAg post-transplantation.

 


481. Predictive Factors for Exacerbation of Hepatitis B After Discontinuation of Oral Therapy in HBeAg-negative Patients

Y. Murata; S. Arterburn; C. Pang; E. Mondou; F. Rousseau

 

Background:

Clinical and laboratory characteristics predictive of post-treatment exacerbation of hepatitis B have not been comprehensively studied.

 

Methods:

A retrospective analysis of factors predictive of post-treatment ALT exacerbation (>10xULN) was conducted in HBeAg-negative patients with compensated chronic hepatitis B participating in study 438 and randomized to adefovir dipivoxil (ADV) 10 mg QD in year 1 and placebo in year 2. Stepwise logistic regression analyses (entry and exit criteria p=0.10) were performed for flare (ALT>10xULN) versus no flare. Potential baseline predictors included age, race, gender, weight, ALT, HBV DNA, genotype, Knodell score (total and necroinflammatory), Ishak fibrosis score, history of flares, prior interferon or lamivudine treatment; potential week 48 predictors included ALT, HBV DNA, Knodell necroinflammatory score, Ishak fibrosis score and duration of HBV DNA suppression below LLQ (400 copies/mL) in year 1. Final models were confirmed using exact logistic regression (LR). Serum HBV DNA was measured by the Roche Amplicor Monitor assay.

 

Results:

Forty patients were included in the dataset (33 male, 7 female; 26 Caucasians, 13 Asians, 1 Black). At baseline, median age was 47, ALT 2.1xULN (IQ range 1.7-4.2 ULN), and serum HBV DNA 7.16 log copies/mL (IQ range 6.56-7.6). Post-treatment flare developed in 13 patients and was limited to isolated transaminase elevation in 12 patients; most flares occurred within 13 weeks after ADV treatment ended (9/13 [69%]). One patient had concurrent grade 3 bilirubin; no patients had concurrent abnormalities of albumin or PT. Among patients with flare in year 2, 10/13 never had HBV DNA below 400 copies/mL, and 12/13 patients never had confirmed HBV DNA < 400 copies/mL during year 1 on ADV. From the initial stepwise regression analyses of potential baseline and week 48 predictors, only baseline HBV DNA (p=0.006 exact LR) was significant. The multivariate analysis showed that duration of HBV DNA suppression below LLQ was highly predictive of flare (p=0.005), with baseline HBV DNA showing marginal correlation (p=0.060).

 

Conclusions:

Although limited by the small dataset, the incidence of post-treatment exacerbation was significantly increased among patients who had no or a short duration of HBV DNA <400 copies/mL in the first year of treatment, and was marginally correlated with higher baseline viral load.

 


482. Phase III Comparison of Telbivudine vs Lamivudine in Patients with Chronic Hepatitis B: Efficacy, Safety, and Predictors of Response at 1 Year

N. Bzowej; C. Lai; E. Gane; Y. Liaw; S. Thongsawat; Y. Wang; Y. Chen; J. Heathcote; J. Rasenack; N. Naoumov; G. Chao; B. Fielman; N. Brown

 

Background:

The GLOBE trial is a 2-year phase III randomized comparison of telbivudine (LdT) vs lamivudine (lam) in 921 HBeAg +ve and 446 HBeAg -ve adults with compensated chronic hepatitis B. We report primary efficacy and safety results at 52 weeks (wks) and preliminary results at 76 wks and determine predictors of efficacy.

 

Methods:

Key entry criteria were HBsAg+, HBeAg+ or HBeAg-, HBV DNA >6 log10 by PCR assay, and ALT 1.3-10 xULN. Outcomes were assessed according to baseline demography (age, gender, ethnicity) and disease factors (HBV genotype, HBV DNA and ALT levels), and early on-treatment responses (HBV DNA and ALT levels at Wks 12 and 24).

 

Results:

At Wk 52, LdT was superior to lam on all measures of direct antiviral efficacy in both HBeAg+ and HBeAg- pts (log10 HBV DNA reduction, % PCR -ve, resistance, treatment failure). HBeAg loss was higher in HBeAg+ pts with baseline ALT >2xULN (“interferon eligible” pts): 32% and 49% for LdT at Wks 52 and 76 respectively, vs. 27% and 29% for lam. Univariate analyses revealed that lower ALT and HBV DNA levels at wks 12 and 24, younger age, and Asian ethnicity were associated with improved 1-year efficacy outcomes. Multivariate analysis revealed that lower HBV DNA at Wk 24 was the best predictor of greater efficacy and less resistance at 1-year. Positive predictive values were high for pts who were PCR -ve at Wk 24: at 1 year, 36% of this group seroconverted HBeAg (HBeAg+ pts), and <1% developed resistance (both HBeAg+ and HBeAg-). For pts with HBV DNA >4 log10 at Wk 24, the negative predictive value for failure to HBeAg seroconvert was 93%. Clinical adverse events were similar for LdT and lam.

 

Conclusions:

After 1 year, LdT showed significantly greater direct antiviral efficacy than lam in HBeAg +ve and HBeAg -ve pts with chronic hepatitis B, with less treatment failure and resistance. Early HBV DNA response was the strongest predictor of 1-year efficacy outcomes.

 

 

HBeAg (+)

HBeAg (-)

 

Week 52

Week 76

Week 52

Week 76

Response

LdT

Lam

LdT

Lam

LdT

Lam

LdT

Lam

n

458

463

458

463

163

165

163

165

log10 HBV DNA ↓

6.5*

5.5

6.6*

5.2

5.2*

4.4

5.3

4.7

% PCR neg

60*

40

69*

41

88*

71*

84*

67

% Histologic Resp

65*

56

-

-

67

66

-

-

% ALT normalized

77

75

78*

68

74

79

76

64

% Therapeutic Resp

75*

67

75-

58

75

77

75

70

% HBeAg loss

26

23

40*

26

-

-

-

-

% HBV resist.

3*

8

-

-

2*

9

-

-

% 1° Treatment Failure†

5*

13

-

-

<1

3

-

-