Tuesday May 23rd 8:30- 10am Session Title: Therapy of Hepatitis B
AASLD Topic Forum
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.
|
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 |
LVD 100 mg |
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 |
% ALT |
% HBeAg loss |
|
Telbivudine |
44 |
6.37* |
95%* |
38.6%* |
61.4% |
16% |
|
Adefovir |
89 |
5.11 |
58% |
12.4% |
62.9% |
10% |
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.
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 |
- |
- |