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HBV Clinical Trials Abstracts

 

476. Continued Efficacy and Safety Through 4 Years of Tenofovir Disoproxil Fumarate (TDF) Treatment in HBeAg-Negative Patients with Chronic Hepatitis B (Study 102): Preliminary Analysis.  P. Marcellin; M. Buti; Z. Krastev; S. Gurel; A. M. Di Bisceglie; J. A. Odin; G. M. Dusheiko; E. Heathcote; K. Borroto-Esoda; D. H. Coombs; E. Mondou; J. Anderson

Background: Tenofovir disoproxil fumarate (TDF) is a nucleotide analog approved for HIV-1 in 2001 and approved in 2008 for the treatment of chronic hepatitis B (CHB) with potent antiviral activity.

Methods: Patients with HBeAg-negative, CHB mono-infection were randomized 2:1 to double-blind, once daily TDF 300 mg (N=250) or adefovir dipivoxil (ADV) 10 mg (N=125) in the phase 3 study 102. After 48 weeks, patients with a week (W) 48 biopsy were switched to open-label (OL) TDF for up to 7 additional years with option to add emtricitabine (FTC) to TDF (as a fixed dose combination tablet FTC/TDF) at/after W72 for confirmed HBV DNA ≥ 400 copies (c)/mL (69 IU/mL). HBV DNA was measured using the Roche COBAS TaqMan assay (LLQ=169 c/mL=29 IU/mL). W 192 (Year 4) data from this ongoing trial are presented.

Results: Overall, 315 patients completed W192 (84% retention). In an ITT analysis (ITT), 86% of patients had HBV DNA <400 c/mL (85% TDF-TDF; 87% ADV-TDF). In an on-treatment analysis 99% of patients treated with TDF for 4 years had HBV DNA <400 c/mL at W192. 100% of ADV treated patients (regardless of their prior response to ADV treatment, i.e., viremic or suppressed on ADV therapy at W48) responded favorably to TDF treatment with HBV DNA <400 c/mL at W192. Four patients (3 on TDF monotherapy) had HBV DNA ≥400 c/mL at W192 or time of discontinuation. Two of these patients were either confirmed to be off drug or had a history of noncompliance. Resistance analyses showed no amino acid substitutions that could be associated with TDF resistance in patients with detectable HBV DNA at W192, at discontinuation or when FTC was added. Of the 12 patients who were eligible to add FTC between W72 and W192 for confirmed HBV DNA ≥400 c/mL, 4 patients added FTC and 8 patients remained on TDF monotherapy. Of the patients who remained on TDF monotherapy, 6 had HBV DNA <400 c/mL at W192. Overall mean ALT at W192 was 33 U/L or less than the upper limit of the normal laboratory range. Safety was good through year 4. Of the 13 patients who discontinued treatment during year 4, one had an AE that led to discontinuation (considered unrelated to TDF). Cumulatively, 4 cases (1%) of hepatocellular carcinoma were reported during OL TDF treatment. Creatinine remained stable through year 4. Two patients experienced a 0.5 mg/dL increase in creatinine, one associated with advanced hepatocellular carcinoma and the other improved with QOD dosing.

Conclusion: TDF was well tolerated and produced potent, continuous viral suppression through 4 years of TDF treatment and no mutations developed in association with TDF resistance in this HBeAg-negative patient population.


477. Long Term (4 Year) Efficacy and Safety of Tenofovir Disoproxil Fumarate (TDF) Treatment in HBeAg-Positive Patients (HBeAg+) with Chronic Hepatitis B (Study 103): Preliminary AnalysisE. Heathcote; E. J. Gane; R. A. deMan; S. Chan; J. George; N. C. Tsai; P. Marcellin; A. Snow-Lampart; D. H. Coombs; E. Mondou; J. Anderson

Background: TDF is a potent nucleotide analog approved for the treatment of chronic hepatitis B (CHB). Treatment of patients with HBeAg+ CHB over three years in a long term ongoing trial was associated with HBV DNA suppression in 78% (intent-to-treat analysis; ITT) and HBsAg loss in 8% of patients (Kaplan-Meier Estimate).

Methods: Patients with HBeAg+ CHB mono-infection were randomized 2:1 to once daily, double-blind TDF 300 mg (N=176) or adefovir dipivoxil (ADV) 10 mg (N=90) for the first 48 weeks. After week (W) 48, patients with a W 48 liver biopsy were switched to open-label TDF for 7 additional years with an option to add emtricitabine (FTC) (as a fixed dose combination tablet FTC/TDF) at or after W72 for confirmed HBV DNA ≥400 copies (c)/mL (69 IU/mL). W192 (Year 4) data are presented.

Results: Overall, 198 patients completed W192 (74% retention). In an ITT analysis 77% of patients had HBV DNA <400 c/mL (74% TDF-TDF; 84% ADV-TDF). In an on-treatment analysis 96% (TDF-TDF) and 99% (ADV-TDF) had HBV DNA <400 c/mL at W192. 100% of patients virally suppressed on ADV and 98% of suboptimal responders on ADV, responded favorably to a switch to TDF with HBV DNA <400 c/mL at W192. Overall 7 patients (2 on TDF monotherapy and 5 on FTC/TDF) had HBV DNA ≥400 c/mL at W192 or after discontinuing between W144 and W192. Both patients on TDF monotherapy experienced an unconfirmed rebound in HBV DNA at W192 with a subsequent return to undetectable HBV DNA at the next visit. Resistance analyses showed no amino acid substitutions that could be associated with TDF resistance in patients with detectable HBV DNA at W192, at discontinuation or when FTC was added. 34 patients added FTC to TDF between W72 and W192 and of the 23 patients remaining on treatment at W192, 83% achieved HBV DNA <400 c/mL. 9 patients were eligible to add FTC, but did not, and of the 6 patients on treatment at W192, 100% had HBV DNA <400 c/mL. At W192 the mean ALT was 35.2 U/L and HBeAg loss/seroconversion were observed in 41%/31% of patients (on-treatment analysis). Cumulatively, 10% of patients lost HBsAg and 7.5% seroconverted to anti-HBs (Kaplan-Meier Estimate). Creatinine levels remained stable through Year 4. One patient who remains on study experienced a 0.5 mg/dL increase in serum creatinine during Year 4.

Conclusion: TDF was well tolerated and produced potent, continuous viral suppression with increasing HBeAg and HBsAg loss, and no mutations developed in association with TDF resistance in this HBeAg+ patient population.


478. Long-Term Entecavir Treatment for up to 5 Years in Asians with HBeAg-positive Nucleos(t)ide naďve Chronic Hepatitis B: Results from ETV-022 and -901C. Pan; M. J. Tong; K. V. Kowdley; K. Hu; T. Chang; C. Lai; S. Yoon; S. S. Lee; D. S. Cohen; H. Tang; N. C. Tsai

Background: Entecavir (ETV) through 5 years resulted in significant and durable virological suppression with minimal resistance. We present long-term efficacy results for a subset of Asian patients.

Methods: The nucleos(t)ide-naďve HBeAg-positive ETV long-term cohort includes patients who received ETV 0.5 mg in ETV-022 and subsequently entered ETV-901 (and received ETV 1.0 mg) with a treatment gap ≤ 35 days. Asian patients with Week 240-evaluable samples were assessed for proportions with HBV DNA <300 copies/mL, ALT ≤1 x ULN, HBeAg loss and HBe seroconversion.

Results: 94 Asian patients (male 81%, mean age 35) met criteria for inclusion in the long-term Asian sub-cohort. Baseline characteristics included: mean HBV DNA 10.08 log10 copies/mL and mean ALT 123 U/L; genotype A (6%); B (40%); C (41%); D (1%); other (6%).  By year five, 26 patients (40%) achieved HBeAg Loss an12 patients (18%) achieved HBeAg seroconversion.

Conclusions: ETV through 5 years achieved and maintained high rates of HBV DNA suppression and ALT normalization, with no resistance detected in nucleos(t)ide-naďve HBeAg-positive Asian CHB patients. The efficacy and safety profile of ETV was consistent with the observations made in the overall population.

 

Long-term Asian sub-cohort

Week 48

Week 96

Week 144

Week 192

Week 240

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

55/94 (59)

78/93 (84)

79/88 (90)

67/72 (93)

63/66 (95)

ALT ≤1 x ULN, n(%)

59/94 (63)

70/93 (75)

65/89 (73)

65/75 (87)

50/66 (76)

 


479. Early On-Treatment HBsAg and HBV DNA Levels Identify HBeAg-Negative Patients Not Responding to 48 or 96 Weeks of Peginterferon Alfa-2a Therapy.  V. Rijckborst; B. E. Hansen; P. Ferenci; M. R. Brunetto; F. Tabak; Y. Cakaloglu; A. G. Lanza; V. Messina; C. Iannacone; B. Massetto; E. B. Martins; M. Colombo; H. L. Janssen; P. Lampertico

Background and aims It was recently shown in the PARC trial that HBeAg-negative patients without a decrease in serum HBsAg and <2 log HBV DNA decline at week 12 of treatment had no chance of achieving a sustained response (SR) to 48 weeks of peginterferon alfa-2a (PEG-IFN). In this study we aimed to validate this stopping rule in two independent trials.

Methods HBeAg-negative patients who received 48/96 weeks of PEG-IFN in the phase III registration trial and PegBeLiver study who completed 24 weeks of post treatment follow-up were eligible if HBsAg (Abbott ARCHITECT) and HBV DNA levels were available at baseline and week 12. Patients were stratified according to HBsAg decline and/or ≥2 log HBV DNA decline at week 12 of therapy. For this study, SR was defined as HBV DNA <2,000 IU/mL combined with normal ALT at 24 weeks of post treatment follow-up.

Results The original PARC trial included 102 patients (genotype A/D/other: 14/81/7) of whom 25 (25%) had a SR. A total of 160 patients (126 treated for 48 weeks, 34 for 96 weeks) were included in the validation dataset: 75 patients in PegBeLiver (genotype D/other: 70/5) and 85 in phase III (genotype A/B/C/D/other: 8/18/34/21/4). A SR occurred in 25 of 75 (33%) and 32 of 85 (38%) patients, respectively. The stopping rule performed well across the 2 studies (p=0.001 with correction for study), but its performance was best among genotype D infected patients: 19% would be allowed to discontinue therapy, while maintaining all sustained responders on treatment (table). Also among the 34 patients treated for 96 weeks none of the 7 (21%) without HBsAg decline and <2 log HBV DNA decline at week 12 achieved a SR. For application of the stopping rule in clinical practice, measurement of HBsAg is only required in case of <2 log HBV DNA decline at week 12 to identify patients with no or a very low chance of SR.

Conclusion We confirmed in two large trials that a combination of HBsAg and HBV DNA levels at week 12 identifies HBeAg-negative patients who have no or a very low chance of SR to either 48 or 96 weeks of PEG-IFN. The performance of the stopping rule was best in genotype D infected patients.

Table: Chance of SR based on (1) HBsAg decline and (2) HBV DNA decline 2 log at week 12

 

PARC (N=102)

Validation trials (N=160)

HBsAg
decline

No
54 (53%)

Yes
48 (47%)

No
84 (53%)

Yes
76 (48%)

HBV DNA
decline
2 log

No
20
(20%)

Yes
34
(33%)

No
20
(20%)

Yes
28
(27%)

No
22
(14%)

Yes
62
(39%)

No
22
(14%)

Yes
54
(34%)

SR

0/20
0%

9/34
(26%)

5/20
(25%)

11/28
(39%)

1/22
(5%)

23/62
(37%)

10/22
(45%)

23/54
(43%)

 

Genotype D (N=81)

Genotype D (N=91)

HBsAg
decline

No
43 (53%)

Yes
38 (47%)

No
60 (66%)

Yes
31 (34%)

HBV DNA
decline
2 log

No
15
(19%)

Yes
28
(35%)

No
14
(17%)

Yes
24
(30%)

No
17
(19%)

Yes
43
(47%)

No
14
(15%)

Yes
17
(19%)

SR

0/15
(0%)

9/28
(32%)

5/14
(36%)

10/24
(42%)

0/17
(0%)

12/43
(28%)

6/14
(43%)

7/17
(41%)

 


481. Four Years Efficacy and Safety of Tenofovir Disoproxil Fumarate (TDF) in Asians with HBeAg-positive and HBeAg-negative Chronic Hepatitis B (CHB), Preliminary Analysis.  E. J. Gane; S. S. Lee; E. Heathcote; W. Sievert; H. N. Trinh; K. D. Kaita; Z. M. Younossi; J. George; P. Marcellin; D. H. Coombs; J. Anderson; E. Mondou

Background: An analysis of efficacy and safety was performed in a subset of patients of Asian ethnicity enrolled in 2 Phase 3 pivotal trials of TDF in CHB (Studies 102 and 103). Long-term evaluation in Asians is important given the endemnicity of CHB in this population.

Methods: Patients in each study were randomized 2:1 to double-blind TDF 300 mg or adefovir dipivoxil (ADV) 10 mg once daily for 48 weeks. Patients were eligible following a Week (W) 48 liver biopsy to receive open-label TDF for 7 more years; after W72 if HBV DNA was confirmed ≥ 400 copies (c)/mL (69 IU/mL) investigators could choose to start emtricitabine (FTC)/TDF fixed dose combination. Entry criteria included elevated ALT (> 34 U/L women; > 43 U/L men) and HBV DNA >100,000 c/mL with Roche COBAS TaqMan assay. Virologic (HBV DNA <400 c/mL [69 IU/mL]) and biochemical (ALT) response were prospectively evaluated among patients of self-reported Asian ethnicity through W192 in the combined studies.

Results: Among 641 total patients enrolled in both studies, 189 (29%) were Asian (94 HBeAg-neg CHB; 95 HBeAg+ CHB). Mean age at entry for Asians was 40 years and 68% were male. Mean baseline HBV DNA levels were 7.66 log c/mL for both Asians and non-Asians. As expected, most Asian patients had HBV genotype B or C (n=166). 163 Asians entered the open-label phase and 145 completed W192. Overall at W192, HBV DNA was <400 c/mL in 79% of all Asians (74% HBeAg+, 84% HBeAg-neg) and 83% of all non-Asians (79% HbeAg+, 86% HBeAg-neg) (intent-to-treat analysis) (p≥0.2 for all comparisons). 97% of Asians and 99% of non-Asians had HBV DNA <400 c/mL by on-treatment analysis. 7 Asian patients (3.7%) started FTC+TDF (none in year 4), 1 discontinued, and 4 of 6 remaining on study had HBV DNA <400 c/mL. Among Asian patients on treatment 86% had ALT within normal range: mean value of 31 U/L (vs. 79% of non-Asian patients, p=0.100). Of 65 HBeAg+ Asian patients with W192 serology results 35%/26% had HBeAg loss/HBeAg seroconversion (none had HBsAg loss). During open-label TDF treatment the safety profile was similar for both groups: serious adverse events (AEs) developed in 6%/14%, Grade 3/4 AEs in 10%/12%, and Grade 3/4 laboratory abnormalities in 15%/16% of Asian/non-Asian patients, respectively. There was 1 Asian patient with confirmed phosphorus <2 mg/dL (normal at W192), and 1 had a confirmed creatinine 0.5 mg/dL greater than baseline and remains on study; none had creatinine clearance <50 mL/min.

Conclusion: Antiviral efficacy and safety of TDF were similar in Asians and non-Asians over 192 weeks of treatment with good tolerability congruent with the results of the overall studies.

 


482. REP 9AC: A Potent HBsAg Release Inhibitor That Can Rapidly Restore Immunocompetence in Patients with Chronic Hepatitis B.  M. A. Mahtab; M. Bazinet; A. Vaillant

Background:  Many groups have suggested that HBsAg may play a role in suppressing the immune system and may allow the infection to be chronically maintained in the liver. REP 9AC is a DNA-based amphipathic polymer which has been shown to potently inhibit the release of HBsAg from infected hepatocytes. In preclinical studies in DHBV infected ducks, DHBsAg seroclearance was observed in all ducks after only two weeks of treatment. Four weeks of REP 9AC therapy resulted in 55% of ducks achieving a SVR 16 weeks after cessation of treatment. The ability of REP 9AC to treat human patients with chronic hepatitis B (CHB) is currently being evaluated in a proof of concept clinical trial.

Methods: All patients were HBeAg+, HBsAg+ with pre-treatment HBV DNA titers between 106 and 1012 copies/ml. Additionally, all patients were shown to have significant liver fibrosis as assessed by pre-treatment liver biopsy. Patients with CHB were subjected to parenteral REP 9AC therapy. Safety and virologic response (HBV DNA, HBsAg, anti-HBs) were assessed weekly during treatment, either at the trial site or by confirmatory testing (HBsAg, HBeAg, anti-HBs, anti-HBe) of frozen serum samples at a separate location using the Architect™ testing platform.

Results: Interim data shows that 5 out of 6 patients treated to date have cleared serum HBsAg and anti-HBsAg antibodies have been observed in all patients. Clearance of HBsAg and development of anti-HBs have been observed as early as 7 days and no later than 15 weeks following initiation of treatment at higher doses. At the time of abstract submission, 3 patients have achieved a 3 to 7 log reduction in their HBV DNA titers from pre-treatment levels after 7-13 weeks of treatment. Additionally, two other patients have achieved a complete control of their infection after 23 or 24 weeks of treatment (HBV DNA -, HBsAg -, HBeAg -, anti-HBs +, anti-HBe +) and are being followed off treatment. One of these patients is currently maintaining control over his infection 6 months after stopping treatment.

Conclusions: These results demonstrate that REP 9AC can rapidly and effectively clear HBsAg from the serum of infected patients. This rapid HBsAg seroclearance appears to allow the restoration of an effective immune response, as evidenced by substantial reductions in serum HBV DNA, seroconversion for HBsAg and HBeAg, and the achievement of a 6 month SVR in at least one patient to date. These results suggest that REP 9AC may become an important new tool in the treatment of chronic hepatitis B.

 


483. Significance of Serum HBsAg Levels for the Definition of the Inactive Hepatitis B Carrier StateE. K. Manesis; G. V. Papatheodoridis; E. Hadziyannis

Background: Serum HBsAg levels are currently investigated as possible predictors of response or the duration of treatment of patients with chronic hepatitis B. Their levels differ at the various stages of the natural course of chronic hepatitis B. We investigated, therefore, their usefulness as markers of the inactive carrier state.

Methods: 242 HBeAg-negative patients with chronic HBV infection, including 164 hepatitis cases (CHBe-; males 70.6%, age 51.2±13.0) and 78 inactive carriers (ICs; males 52.6%, age 46.2±13.6) were prospectively followed [median follow-up ICs, 6.4 (interquartile range, IQR 2.2-10.9) years] with frequent ALT and HBV DNA measurements and since 2006 with serum HBsAg determinations every 6 months. Patients with hepatitis were biopsied and treated. A liver biopsy was also performed in apparent ICs with HBV DNA >2000 IU/mL. We report the pretreatment laboratory values for hepatitis cases and the first and last laboratory measurement for ICs.

Results: ICs compared to CHBe- patients had significantly lower baseline values of HBsAg [541 (72-1,953) vs 3,523 (1,435-7,473) IU/mL], HBV DNA [4,383 (1,399-21,198) vs 982,550 (17,418-14,815,000) copies/mL] and ALT [18 (12-29) vs 71 (28-139) IU/L] (P<0.0001 for all comparisons). In CHBe- patients, normal ALT, HBsAg <1000 IU/mL and HBV DNA <10,000 copies/mL was observed in 31.1%, 16.5% and 18.0%, while in ICs, in 97.3%, 56% and 63.6%, respectively. Of patients with normal ALT and HBV DNA <10,000 copies/mL, a measurement of HBsAg <1000 IU/mL could correctly classify ICs vs CHBe- with 74.3% sensitivity, 87.5% specificity and 89.7% predictive value and possibility of correct classification was higher compared to a single normal ALT measurement (97.3%, 67.9%, 59.0%, respectively) or a single HBV DNA determination of <10,000 copies/mL (63.6%, 66.7%, 44.3%, respectively). ICs of >40 years age had significantly lower median (IQR) serum HBsAg [206 (54-1431) vs 1514 (863-16,422) IU/mL, P=0.001] and ALT [16 (12-26) vs 23 (16-35) IU/L, P=0.023] but no significant difference in HBV DNA levels. Within an observation time of 25.4 (12.6-75.4) months median baseline serum HBsAg levels in ICs fell from 541 to 128 IU/mL representing a drop of 16 IU per month.

Conclusions:

1. ICs have significantly lower serum HBsAg levels compared to CHBe- patients.

2. Finding HBsAg <1000 IU/mL in a patient with normal ALT and HBV DNA <10,000 copies/mL is highly predictive of IC state.

3. Younger ICs have significantly higher serum HBsAg and ALT levels and should be followed more closely for possible reversion to CHBe- state.

 


484. Adding Adefovir Compared with Switching to Entecavir in Patients with Lamivudine-Resistant Chronic Hepatitis B (ACE Study) - A Multicenter Prospective Randomized Study: One-Year Interim AnalysisH. . Yim; Y. Seo; J. Kim; C. Kim; C. Lee; S. Park; M. Lee; C. n. Park; H. Chae; M. Kim; S. Baik; Y. Kim; J. Kim; J. Lee; S. Um

Background/Aims: Still now, standard treatment for the lamivudine-resistant chronic hepatitis B has yet to be determined. It has been reported that adding adefovir on lamivudine is superior to adefovir alone. However, comparison between adding adefovir and switching to entecavir monotherapy has not been performed in a head-to-head manner. This study is designed to prospectively compare the efficacy of two strategies, combination of lamivudine and adefovir vs. entecavir monotherapy in patients with lamivudine resistance.

Methods: 219 chronic hepatitis B patients who had been receiving lamivudine, and developed virologic and biochemical breakthrough were consecutively enrolled at 9 university hospitals between April 2007 and March 2009. HBV DNA undetectability, ALT normalization, HBeAg seroconversion, degrees of HBV DNA reduction, and incidence of anti-viral resistance were determined.

Results: 110 patients were randomized to adefovir and lamivudine combination group, and 109 patients were to entecavir monotherapy group. Baseline characteristics of the patients such as age, sex, proportion of patients with liver cirrhosis, HBeAg positivity, HBV DNA, AST, ALT, bilirubin, and albumin were not significantly different between the groups (p>0.05). HBV DNA PCR negativity (<60 IU/mL) was 44.7% vs 32.7% at month 12, respectively (p=0.103). However, HBV DNA less than 400 IU/mL, which is a lower detection limit of bDNA assay, was more frequently observed in the adefovir and lamivudine combination group compared to entecavir monotherapy group at month 12 (55.3% vs 36.7%, respectively, p=0.014). Degree of HBV DNA reduction was significantly greater in the adefovir and lamivudine combination group compared to entecavir group at month 6 (4.01 vs 3.44 log IU/mL, respectively, p=0.003), and at month 12 (4.49 vs 3.65 IU/mL, respectively, p=0.001). Mean HBV DNA level was significantly lower in the combination group at month 6 (3.03 vs 3.56 log IU/mL, respectively, p=0.012), and at month 12 (2.58 vs 3.30 IU/mL, respectively, p=0.004). Rates of ALT normalization (82.8% vs 87.6%), HBeAg loss (19.2% vs 21.1%), or HBeAg seroconversion (9.6% vs 12.0%), incidence of antiviral resistance (7.5% vs 7.6%) were not significantly different between the groups (P>0.05).

Conclusion: The antiviral efficacy was significantly better in the adefovir and lamivudine combination group compared to entecavir monotherapy group at month 12 in the treatment of lamivudine resistant chronic HBV infection.

 


485. Efficacy and Safety of Entecavir in Nucleos(t)ide Naďve Asians with HBeAg-Positive and -Negative Chronic Hepatitis B: Results from Studies ETV-022/027R. G. Gish; N. C. Tsai; C. Pan; K. V. Kowdley; K. Hu; C. Lai; T. Chang; K. Han; D. S. Cohen; H. Tang; M. J. Tong

Background: Entecavir (ETV) 0.5 mg demonstrated superior virologic, histologic, and biochemical response compared to lamivudine (LVD) 100 mg in nucleoside-naďve HBeAg-positive and -negative CHB patients (Phase III studies ETV-022/027). The safety profile of ETV was comparable to LVD in the two studies. We present the efficacy and safety data of ETV among Asian patients with CHB participating in the two Phase III studies.

Methods: Randomized (1:1), double-blind, comparison of ETV 0.5 mg versus LVD 100 mg for a minimum of 52 weeks. Primary end point was histologic improvement (≥2-point reduction in the Knodell Necroinflammatory Score, without worsening of the Knodell Fibrosis Score) at Week 48. The other key end points were virologic and biochemical response at Week 48, and overall safety.

Results: Asians comprised 49% (657/1347) of all patients, 48% (326/679) on ETV, and 50% (331/668) on LVD. Among 657 Asian patients enrolled in the two studies, 406 were HBeAg-positive and 251 were HBeAg-negative.

Summary:

·        In this sub-analysis of Asian patients enrolled in studies ETV-022/027, ETV use at week 48 demonstrated:

o   Histologic improvement in 70% of patients

o   HBV DNA <300 copies/mL in 78% of patients

o   ALT normalization in 68% of patients with HBeAg loss seroconversion occurring in 16% of HBeAg (+) patients

·        Resistance did not develop in any Asian patient in ETV-022/027

·        Safety was comparable to previously reported data

Conclusions:

·        ETV 0.5 mg demonstrated significant histologic, virologic and biochemical responses compared to LVD 100 mg in nucleoside-naďve Asian patients with HBeAg positive and negative chronic hepatitis B at Week 48.  .

·        The efficacy and safety profile of ETV in Asians was similar and consistent with the findings in the overall studies.   

 


486. Serum HBsAg Levels Decrease Through Long-Term Follow-Up in HBeAg-Negative Patients Achieving a Sustained Response to Peginterferon Alfa-2a.  V. Rijckborst; B. E. Hansen; B. Pinarbasi; M. Akdogan; M. J. ter Borg; P. Ferenci; K. Simon; R. Flisiak; U. S. Akarca; M. Raptopoulou-Gigi; E. Verhey; A. J. van Vuuren; C. A. Boucher; H. L. Janssen

Background and Aims: In a recently reported international multicenter trial 48 weeks of peginterferon alfa-2a (PEG-IFN) induced a combined response (HBV DNA <10,000 copies/mL + normal ALT) at 24 weeks after treatment discontinuation in 20% of patients with HBeAg-negative chronic hepatitis B. Addition of ribavirin (RBV) did not improve response rates. We aimed to evaluate the long-term response to PEG-IFN in HBeAg-negative patients.

Methods: All patients enrolled in the PARC trial who completed the treatment phase were eligible for this long-term follow-up (LTFU) study. Patients received PEG-IFN alfa-2a (180 μg weekly) ± RBV (1000-1200 mg daily) for 48 weeks and had at least one additional LTFU visit after completing the initial follow-up phase of 24 weeks (mean follow-up duration 2.1 ± 0.2 years). Given the similar response rate for PEG-IFN ± RBV, results are presented for both treatment arms combined. Re-treated patients were considered non-responders.

Results: Of 117 patients who completed the treatment phase of the initial study, 79 (68%) were included in the LTFU study. Sixty-one (77%) patients had HBV genotype D. The table shows response rates at end of treatment (week 48), end of initial follow-up (week 72) and at LTFU. Among 19 patients with a combined response at week 72, 12 (63%) sustained this response through LTFU. Three additional patients developed a combined response at LTFU, resulting in a combined response in a total of 15 (19%) patients at LTFU. Five patients were HBsAg negative at LTFU. Levels of HBsAg at LTFU were available in 35 of 38 patients who had not been re-treated. The mean HBsAg decline compared to baseline in patients who had a combined response progressed from 1.9 to 2.6 log IU/mL between W72 and LTFU (p=0.046). In contrast, the corresponding values in non-responders were 0.3 log IU/mL at both time points (p<0.01 for both comparisons).

Conclusion: About one third of HBeAg-negative patients with a response to PEG-IFN at 24 weeks post treatment relapse during 2 years of follow-up, resulting in an sustained response rate of 19%. Despite the limited overall efficacy of PEG-IFN, a high degree of serum HBsAg decline was observed in sustained responders resulting in HBsAg loss in 6% of patients. These results further emphasize the need for predictors of response to PEG-IFN in HBeAg-negative disease.

 

Endpoints

Week 48
(N=79)

Week 72
(N=79)

LTFU
(N=79)

HBV DNA <10,000 cp/mL

68%

25%

20%

HBV DNA <400 cp/mL

44%

10%

11%

Normal ALT

52%

53%

34%

Combined response*

42%

24%

19%

HBsAg loss

1%

1%

6%

* HBV DNA <10,000 cp/mL + normal ALT

 


489. Stronger HBV DNA Suppression in Patients with HBeAg-Positive Chronic Hepatitis B Achieving HBeAg Clearance During Peginterferon Alfa-2b Therapy Compared with PlaceboB. E. Hansen; V. Rijckborst; M. J. ter Borg; H. L. Janssen

Aim: The aim of this study was to compare the decline of HBV DNA during peginterferon (PEG-IFN) therapy with spontaneous fluctuations in viral load in placebo-treated HBeAg-positive patients.

Methods: 136 patients who participated in a randomized trial received PEG-IFN alfa-2b for 52 weeks. Using linear mixed regression analysis, this group was compared with 167 patients who received placebo for 48 weeks and served as control group in another randomized trial. All patients were HBeAg positive with elevated ALT levels. HBV DNA was measured every 4 weeks. For this analysis response was defined as negative HBeAg at the end of treatment (EOT).

Results: Overall, HBV DNA decline at EOT was larger in the PEG-IFN group compared with the placebo group (mean decline 2.3 vs 1.0log; p<0.001). Correcting for baseline ALT, HBV DNA decline was larger in the PEG-IFN group compared with placebo (p<0.001) from week 4 and this difference remained significant throughout the treatment period. The pattern of HBV DNA decline varied according to genotype. In genotype A and B patients, PEG-IFN therapy resulted in a significantly stronger decline compared with placebo from week 20 (p<0.04) and 36 (p<0.04), whereas this difference was already significant after 4 (p<0.01) and 12 (p<0.04) weeks of therapy in genotype C and D. The response rate was higher for PEG-IFN than placebo (32% vs 11%; p<0.001). The figure shows HBV DNA declines according to response. Among responders, HBV DNA decline was stronger for PEG-IFN than placebo. At week 4 already, the mean difference in HBV DNA decline in responders was 0.7log (p=0.001), which further increased to 2log at week 20 and remained around 2log until EOT.

Conclusion: This study shows that HBV DNA decline was faster and stronger in HBeAg-positive patients who lose HBeAg during PEG-IFN therapy compared to placebo. Furthermore, the pattern of HBV DNA decline differed between genotypes.


http://aasld2010.abstractcentral.com/user_images/aasld2010/1909/890087/figure_AASLD-hansen1.jpg

 


491. Telbivudine Switch in Lamivudine Pretreated Chronic Hepatitis B Patients Provides Sustained Viral Suppression for 2 YearsQ. Xie; G. Shi; S. Thongsawat; Y. Liaw; H. Chan; R. Safadi; M. Wan; S. Hwang; L. Wei; H. Ren; T. Tanwandee ; W. Bao; A. Trylesinski

Background/Aim:  Lamivudine (LAM) was the first nucleoside agent approved for the treatment of Chronic Hepatitis B (CHB) providing good viral suppression compromised by high rates of genotypic resistance rising up to 80% by year 5. In the GLOBE study, telbivudine (LDT) showed superior antiviral efficacy vs LAM over 2 years and significantly lower rates of genotypic resistance. We aimed to evaluate the durability of viral suppression over 2 years after switching LAM patients with undetectable viral load to LDT.

Methods: ITT population consisted of 391 (237 HBeAg+ and 154 HBeAg-) compensated CHB patients, treated for 2 years in the LAM arm of the GLOBE and 015 (China) studies, excluding patients with established genotypic resistance to LAM. Patients were switched to LDT for 2 additional years in extension study 2303. Efficacy was evaluated in all patients with undetectable HBV DNA (<300 copies/mL) at the time of switch and is defined as maintained HBV DNA undetectable at 2 years based on the ITT population (using Last observation carried forward method). Safety was evaluated in all patients enrolled.

Results: 81% of patients were Asian (Chinese 65%). 57% were HBV Genotype C, 25% genotype B. At the time of switch, 171 HBeAg+ and 128 HBeAg- patients were HBV DNA undetectable and were evaluated for efficacy. 86% of patients completed 2 years of telbivudine treatment. After LDT switch, 94% and 92% of HBeAg+ patients maintained undetectable HBV DNA for 1 and 2 years respectively. 54% had HBeAg seroconversion and 4 patients achieved HBsAg clearance at 2 years. Among HBeAg- patients, 94% and 92% remained HBV DNA undetectable at 1 and 2 years after LDT switch respectively. Safety in this cohort was similar to the LDT safety profile reported during GLOBE 2 year study: We observed 2.8% of serious adverse events. 0.8% patients had ALT flares, 6.6 % had CK elevations. Muscle symptoms over 2 years were reported in 2.3%. Only 1 case of myopathy (0.2%) and no peripheral neuropathy, lactic acidosis or rhabdomyolysis was observed.

Conclusion: Switching well controlled lamivudine treated patients to telbivudine provides high rates of viral load suppression and HBeAg seroconversion combined with a favorable safety profile.

 


LB-17. Immunogenicity of Two Doses of Investigational HEPLISAV™ (HBsAg-ISS) Compared to Three Doses of Licensed Hepatitis B Vaccine (ENGERIX-B®) in Diabetics.  W. L. Heyward; F. Xie; S. Halperin; J. Martin

Background: Diabetics are known to be at higher risk for hepatitis B infection and commonly hypo-/non-responsive to currently licensed hepatitis B vaccines. A multicenter, observer-blinded phase 3 study was conducted among 2428 persons 11-55 years of age, comparing two doses of HBsAg-ISS (20μg HBsAg combined with 3000μg 1018 immunostimulatory sequence, a Toll-like receptor agonist) given at 0 and 4 weeks (placebo at 24 weeks) to Engerix-B given at 0, 4 and 24 weeks.

Methods: This study was randomized in a 3:1 ratio, HBsAg-ISS to Engerix-B. The aim of this study was to determine if the immunogenicity of 2 doses of HBsAg-ISS at Week 12 is non-inferior/superior to 3 doses of Engerix-B at Week 28 by comparing seroprotection rates (SPR = anti-HBs ≥ 10mIU/mL). An ad-hoc analysis was conducted to compare the immunogenicity of these two vaccine regimens among diabetics. Diabetes was assessed by the review of recorded subject medical history and prior/concomitant medication use.

Results: Of the 2101 subjects in the overall per protocol study population (1566 HBsAg-ISS; 535 Engerix-B), the SPR was 95% at Week 12 in the HBsAg-ISS group and 81% at Week 28 in the Engerix-B group (p<0.001), indicating non-inferiority/superiority of HBsAg-ISS. Among the 62 diabetics in the per protocol population, 45 were in the HBsAg-ISS group and 17 in the Engerix-B group. Of these subjects, 38 (84%) in the HBsAg-ISS group achieved SPR compared to 0 (0%) in the Engerix-B group at Week 12 (p<0.001), and 42 (93%) vs 6 (35%) respectively at Week 28 (p<0.001). For the primary comparison of the study, 38 (84%) in the HBsAg-ISS group achieved SPR at Week 12 compared to 6 (35%) in the Engerix-B group at Week 28 (p=0.001).

Conclusion: In a subset analysis of adults with diabetes, HBsAg-ISS given as 2 doses over 4 weeks demonstrated superior SPR compared to Engerix-B given as 3 doses over 24 weeks.

 


133. A Head-to-Head Comparison of Peginterferon α-2b Treatment Regimens in the Treatment of Chinese and South-East Asian Patients with HBeAg Positive Chronic Hepatitis B.  X. Fan; Y. Wang; D. Luo; J. Hou; Z. Huang; Y. Zhang; D. Xu; J. Cheng

Introduction: This study assessed the safety and efficacy of Peginterferon α-2b 1.5 mcg/kg/week for 48 weeks in comparison to a regimen of 1.0 mcg/kg/week for 24 weeks, as well as a third regimen of 1.5 mcg/kg/week for 24 weeks in Chinese and South-East Asian patients with HBeAg positive chronic Hepatitis B

Methods: 670 patients (including 657 from China) who were serum HBeAg positive, serum Anti-HBsAg negative, serum Anti-HBeAg negative, plasma PCR HBV-DNA >20,000 IU/ml, serum HBsAg positive ≥6 months, with ALT levels 2-10 fold higher than the upper limit of normal, were selected for study participation. Patients were randomized in a 1:1:1 ratio to receive Peginterferon α-2b 1.0 mcg/kg/week for 24 weeks (Arm A), Peginterferon α-2b 1.5 mcg/kg/week for 24 weeks (Arm B), or Peginterferon α-2b 1.5 mcg/kg/week for 48 weeks (Arm C). Efficacy parameters including the proportion of patients with HBeAg loss (primary endpoint), HBe seroconversion, PCR HBV-DNA <20,000 IU/ml, ALT normalization, and combined response (HBe seroconversion, PCR HBV-DNA <20,000 IU/ml, ALT normalization) were assessed 24 weeks after the end of treatment (Full Analysis Set). Safety and tolerability were assessed in all treated subjects.

Results: Peginterferon α-2b 1.5 mcg/kg/week for 48 weeks was more efficacious than Peginterferon α-2b 1.0 mcg/kg/week for 24 weeks regarding the proportion of patients with HBeAg loss, HBe seroconversion, PCR HBV-DNA <20,000 IU/ml, ALT normalization and combined response. There were no differences between Peginterferon α-2b 1.5 mcg/kg/week for 24 weeks and 1.0 mcg/kg/week for 24 weeks. In terms of safety, 182 (81%), 183 (83%) and 196 (88%) patients reported adverse events in Arms A, B and C, respectively. The most frequently reported adverse events were pyrexia, myalgia, headache, fatigue, arthralgia, dizziness, alopecia, asthenia, chills, decreased appetite, nausea and weight loss. Serious adverse events were reported in 10 (4%), 11 (5%) and 15 (7%) patients in Arms A, B and C, respectively.

Conclusion: For treatment of patients with HBeAg positive chronic hepatitis B, a regimen of Peginterferon α-2b 1.5 mcg/kg/week for 48 weeks was more efficacious than 1.0 mcg/kg/week for 24 weeks. The safety and tolerability profiles of all regimens were comparable.

 

PEG 1.0/24W
(Arm A)
n=225

PEG 1.5/24W
(Arm B)*
n=221

PEG 1.5/48W
(Arm C)**
n=224

HBeAg loss
HBe seroconversion
HBV DNA <20000 IU/ml
ALT normalization
Combined response

17.3%
16.9%
19.6%
28.0%
8.0%

18.1% (p=0.860)
16.3% (p=0.830)
21.3% (p=0.662)
36.2% (p=0.067)
10.4% (p=0.389)

31.3% (p<0.001)
29.9% (p<0.001)
33.5% (p<0.001)
46.0% (p<0.001)
20.1% (p<0.001)

* Comparison between Arm B and Arm A, ** Comparison between Arm C and Arm A

 


134. HBV rtN236T Mutant Subpopulations Respond Like Wild-Type During Tenofovir DF (TDF) Monotherapy or Combination Therapy with Emtricitabine (FTC): an Evaluation of Early Viral Load Decay Kinetics.  M. Curtis; E. S. Svarovskaia; Y. Zhu; K. J. Peschell; M. D. Miller; K. Borroto-Esoda

Objective: To date, no reports of HBV clinical resistance to TDF have been confirmed. In vitro, the rtN236T adefovir dipivoxil (ADV)-associated resistance mutation confers low-level cross-resistance to tenofovir; 4-fold change in EC50 from wild-type (WT). The aim of this study was to evaluate the clinical response to TDF therapy of the rtN236T mutation by comparing the early viral load (VL) decay kinetics of mutant vs. WT virus in chronic hepatitis B monoinfected patients harboring the rtN236T prior to initiating therapy with TDF or TDF/FTC.

Methods: An allele-specific PCR assay (AS-PCR) was designed to detect the HBV rtN236T mutant and N236N WT subpopulations (sensitivity = 0.5% of the total viral population) in serum samples with VL of ≥1000 cp/mL. Baseline (BL) samples (n=105) from patients with persistent HBV replication on ADV enrolled in Study 0106, a study evaluating TDF vs. FTC/TDF, were tested for rtN236T. Patients with the mutation at BL were tested for the levels of rtN236T at each visit through week 24 (W24) of therapy or until VL became <1,000 cp/mL. Differences in VL decline rates were evaluated using Wilcoxon signed rank and rank sum tests.

Results: The rtN236T mutation was detected at BL by AS-PCR in 13.3% (14/105) of ADV refractory patients at levels ranging from 0.5% to 93.2% (median 11.2%) of the total viral population. Patients with rtN236T responded to TDF (n=5) and FTC/TDF (n=9) similarly to WT (n=90) with a median change in total HBV DNA from BL of -3.9, -3.3, and -3.2 log10 cp/mL respectively at W24 of treatment; 3/5 patients on TDF and 6/9 patients on FTC/TDF had HBV DNA <1000 cp/mL at W24. The rtN236T mutant virus showed similar rates of HBV DNA decline to that of WT as determined by AS-PCR quantification of each population at each study visit; no statistical difference was observed in these rates at W4 of TDF (p=0.375) or FTC/TDF (p=0.109) therapy. There was no significant difference in VL decline rates through W4 for the rtN236T virus when comparing TDF to FTC/TDF treatment (p=0.933). Secondly, the relative proportions of rtN236T to WT did not increase during therapy with TDF or FTC/TDF and the percent change from BL to W4 or W12 in the relative levels of rtN236T was not significantly different with either therapy.

Conclusions: The rtN236T mutant virus showed similar kinetics of HBV DNA decline to that of WT virus by AS-PCR quantification of each population in ADV refractory patients who switched to TDF monotherapy or TDF/FTC combination therapy. These results indicate that despite the low levels of cross resistance observed in vitro, the rtN236T mutant virus is fully susceptible to TDF in vivo.

 


135. Safety and Tolerability of Extended (96 Weeks) Treatment with Peginterferon Alfa-2a [40KD] in Genotype D Patients with HBeAg-Negative Chronic Hepatitis BP. Lampertico; M. Viganň; G. Di Costanzo; E. Sagnelli; M. Fasano; V. Di Marco; S. Boninsegna; P. Farci; S. Fargion; T. Giuberti; C. Iannacone; B. Massetto; E. B. Martins; M. Colombo

Purpose: A preliminary analysis of the PegBeLiver study showed that extended therapy (96 weeks) with peginterferon alfa-2a (PEG-IFNα-2a) improves sustained virologic response in patients with HBeAg-negative, genotype D chronic hepatitis B compared with standard (48-week) therapy. Here we compare the safety and tolerability of PEG-IFNα-2a for 96 weeks and 48 weeks in this study population.

Methods: 131 patients were randomized to treatment, with 128 (intent-to-treat population) going on to receive PEG-IFNα-2a 180 μg/week for 48 weeks (Group A; N=51) or PEG-IFNα-2a 180 μg/week for 48 weeks followed by PEG-IFNα-2a 135 μg/week for 48 weeks (Group B; N=52). An experimental arm investigated PEG-IFNα-2a 180 μg/week plus lamivudine 100 mg/day for 48 weeks followed by PEG-IFNα-2a 135 μg/week for 48 weeks (Group C; N=25). Adverse events (AEs) recorded from the day of first dosing until 8 weeks after the final dose were regarded as related to the treatment period, and are reported here.

Results: A virologic response (HBV DNA <2000 IU/mL) 12 months post-treatment was achieved by 11.8% in Group A, 28.8% in Group B (p=0.03 for the difference between Groups A and B) and 20.0% in Group C. One patient from Group A was excluded from the safety analysis due to a lack of post-baseline safety data, so the safety analysis consisted of 50, 52 and 25 patients, respectively. The proportion of patients with at least one treatment-related AE was similar between groups (84.0%, 78.8% and 80.0%, respectively). The most commonly reported AEs were those known to occur with IFN-based therapy – asthenia, pyrexia, flu-like symptoms and headache. No unexpected AEs were reported. 17 serious adverse events (SAEs) were reported by 16 patients; all were single cases in a variety of body systems. Incidence of SAEs was highest in Group C (24.0% compared with 14.0% in Group A and 5.8% in Group B). One patient in Group A died due to hepatocellular carcinoma during follow-up. The incidence of laboratory abnormalities in Groups A, B and C were: alanine aminotransferase increased (4.0%, 1.9% and 4.0%), neutropenia (24.0%, 17.3% and 12.0%), thrombocytopenia (12.0%, 11.5% and 4.0%) and anemia (8.0%, 5.8% and 4.0%). Dose was modified in 29.4%, 13.5% and 36.0% of patients, respectively and the incidence of withdrawal due to AE was 16.0%, 11.5% and 24.0%.

Conclusions: Increasing the duration of PEG-IFNα-2a treatment from 48 weeks to 96 weeks in a genotype D-infected population improved sustained response, was well tolerated and did not result in an increase in adverse events or in withdrawals. Further studies are required to determine the benefits of extension therapy in different patient populations. 

 


136. Tenofovir Disoproxil Fumarate (TDF) Versus Emtricitabine Plus TDF (FTC/TDF) for Treatment of Chronic Hepatitis B (CHB) In Patients with Persistent Viral Replication Receiving Adefovir Dipivoxil: Final Week 168 Results.  T. Berg; P. Marcellin; B. Moeller; H. N. Trinh; S. Chan; E. Suarez; A. Snow-Lampart; K. J. Peschell; K. Borroto-Esoda; K. R. Hirsch; D. Frederick

Background: This trial compared TDF monotherapy versus combination FTC/TDF therapy in mono-infected CHB patients who had incomplete virologic response after receiving adefovir dipivoxil (ADV) for at least 6 months. In both blinded treatment arms, patients were permitted to change to open-label FTC/TDF after 24 weeks if persistent viremia (HBV DNA > 400 copies/mL) was confirmed.

Methods: This randomized, double-blind, multinational study enrolled patients with CHB monoinfection, randomized in a 1:1 ratio to receive TDF or FTC/TDF. Entry criteria included age 18-69 years, compensated liver disease, current treatment with ADV (lamivudine [LAM] experience allowed, TDF naďve), plasma HBV DNA >/= 1000 cp/mL, ALT < 10 x the upper limit of normal, and no evidence of hepatocellular carcinoma. HBV DNA was measured using the Roche COBAS TaqMan HBV assay (LLOQ=169 cp/mL; 29 IU/mL). An intention-to-treat analysis was conducted using non-completion=failure.

Results: One-hundred and five patients were randomized and treated with TDF (N=53) or FTC/TDF (N=52); 58% had prior LAM experience. Thirteen had LAM-associated mutations (LAM-r, rtM204V/I+/-rtL180M) and 10 had ADV-associated mutations (ADV-r, rtN236T+/-rtA181V/T) at baseline (population sequencing). Sixteen and 9 patients in the TDF and FTC/TDF arms, respectively, switched to open-label FTC/TDF after Week 24. Through W156 (study is ongoing through Week 168), 88% and 85% of patients randomized to TDF and FTC/TDF, respectively, had HBV DNA < 400 cp/mL (p=0.757); 13/13 with LAM-r and 9/10 with ADV-r were < 400 cp/mL. ALT normalization occurred in 71% (TDF) and 77% (FTC/TDF) of patients (p=0.521). No unexpected adverse events (AEs) or clinically important AEs related to renal function were reported, and no patient had confirmed ≥ 0.5 mg/dL increase in serum creatinine, calculated creatinine clearance < 50 mL/min or serum phosphorus < 2.0 mg/dL.

Conclusions: Through 156 weeks, greater than 85% of patients on either blinded treatment or open-label FTC/TDF had HBV DNA < 400 cp/mL. This response was even higher in patients with baseline LAM-r or ADV-r (100% and 90%, respectively). No efficacy difference was observed between initial TDF monotherapy, with the option to add FTC, or FTC/TDF combination therapy. Both TDF and FTC/TDF were well-tolerated and no changes in renal laboratory parameters were observed.

 


137. 4 Year Efficacy of Tenofovir Disoproxil Fumarate (TDF) in Chronic Hepatitis B Patients with High Viral Load (HBV DNA ≥9 log10 copies/mL): Preliminary AnalysisS. C. Gordon; P. Marcellin; Z. Krastev; A. Horban; J. Petersen; J. Sperl; V. K. Rustgi; E. Heathcote; E. Mondou; D. H. Coombs; J. Anderson

Background: TDF is a potent antiviral with activity against hepatitis B virus. Year 3 data demonstrated 95-99% of HBeAg+ and HBeAg− patients on treatment at week(W)144 achieved HBV DNA <400 copies (c)/mL (69 IU/mL).

Goal: To evaluate the antiviral response over 4 years in both HBeAg− and HBeAg+ patients with high baseline viral load, as defined by HBV DNA ≥9 log10 c/mL (8.24 log10 IU/mL).

Methods: 129 chronic hepatitis B (CHB) patients (11 HBeAg− and 118 HBeAg+) with high viral load were enrolled across the pivotal studies 102 and 103 and were randomized to TDF 300 mg (N=82) or 10 mg adefovir dipivoxil (ADV) (n=47). After W48, eligible patients (with a W48 liver biopsy) initiated open-label TDF for 7 additional years. On or after W72 patients with a confirmed HBV DNA ≥400 c/mL had the option to add emtricitabine (FTC) at the discretion of the investigator.

Results: Overall, approximately 20% (129/641) of patients enrolled in the pivotal studies 102 and 103 had an HBV viral load ≥9 log10 copies/mL. Baseline disease and demographic characteristics were: median age 32 years, 74% male, 67% Caucasian, 22% Asian, median baseline HBV DNA 9.52 log10 c/mL (9.01-10.92) and median ALT 111 U/L (30-670). 97% of patients on treatment at W192 achieved HBV DNA <400 c/mL (and 71% of 129 patients by an intent-to-treat analysis). Twenty-nine patients (out of 38 who were eligible) opted to add FTC between W72 and W192 for confirmed HBV DNA ≥400 c/mL: 17 successfully achieved HBV DNA <400 c/mL at W192, 3 patients had HBV DNA ≥400 c/mL at W192, and 9 did not complete W192 (3 of whom had HBV DNA <400 c/mL at their last time point). Additionally, of the 9 patients who were eligible but did not add FTC, 8 achieved HBV DNA <400 c/mL by W192 (N=6) or time of discontinuation (N=2). For patients on study at W192, median (range) HBV DNA was 2.23 log10c/mL (2.23, 3.23) and median decline from baseline was 7.26 log10c/mL. Median (range) ALT was below the upper normal laboratory range, i.e., 30 U/L (13, 163) and 77% of patients normalized ALT. At W192 35% of HBeAg+ patients achieved HBeAg loss and 23% seroconversion to anti-HBe. Cumulatively, 17 (15.2%) of HBeAg+ patients lost HBsAg (Kaplan-Meier estimate). Resistance analyses showed no amino acid substitutions that could be associated with TDF resistance in patients with detectable HBV DNA at week 192, at discontinuation or when FTC was added.

Conclusion: TDF monotherapy is highly efficacious in patients with high baseline HBV viral load ≥9 log10 c/mL. Greater than 95% of patients achieved HBV DNA <400 c/mL, and high rates of HBeAg and HBsAg loss were achieved and no resistance to TDF was observed.


138. Tenofovir (TDF) for Chronic Hepatitis B Patients with Suboptimal Response to Adefovir (ADV) or ADV/LAM Treatment: Results of the OptiB Italian Multicenter Prospective Open Label Study.  M. Levrero; L. Cimino; P. Lampertico; M. Viganň; G. B. Gaeta; G. Brancaccio; E. Sagnelli; V. Messina; G. Raimondo; A. Marzano; S. Fagiuoli; G. A. Niro; T. Santantonio; V. Di Marco; G. Mazzella; G. Di Costanzo; M. Angelico; S. Pierconti; C. C. Sava'

Background and Aim: Tenofovir disoproxil fumarate (TDF) displays a potent activity against HBV replication, including lamivudine (LAM)-resistant HBV and patients with incomplete virological response to adefovir (ADV). OptiB was designed to evaluate the long term efficacy and safety of TDF in chronic hepatitis B patients with suboptimal response to ADV or ADV/LAM treatment.

Patients and methods: Adults with HBV mono-infection and HBV-DNA >103cp after 48 weeks of ADV±LAM were enrolled and switched to TDF 300 mg daily±LAM. Study endpoints were complete HBV suppression at 24 weeks (primary), early (4-12 weeks) and long term HBV suppression, HBsAg and HBeAg seroconversion, viral resistance and safety surveillance. Genotypic analysis are performed by direct sequencing (TrueGene 2.0) and reverse hybridization (InnoLIPA V3). HBV-DNA is measured using the Roche COBAS TaqMan assay.

Results: 91 patients were screened and 85 have been enrolled. 13 (15.3 %) patients were switched from ADV to TDF and 72 (84.7%) to the TDF/LAM combination. 70 (82.4%) were male, median age 54.8 years (range 21-75). 35 (41.2%) patients were HBeAg+ve. Median duration of prior ADV therapy was 29.2 months. Baseline median viral load was 5.7 log10 UI/ml (range 2.31-7.3). 95.8% of patients had resistance mutations at baseline (ADV-R [A181V, N236T, A181V/T+N236T, I233V] in 46.5%; LAM-R [L180M, L180M+M204V/I; M204I] in 56.3%; A181T in 9.9% and ETV-R [S202C/G/I, M250I/V and T184S/A/I/L/G/C/M in 9.9%).

62% and 81.0% of patients had HBV-DNA levels <69 UI/ml at 24 and 48 weeks of treatment, respectively. 12 patients had HBV-DNA levels <69 UI/ml but >12 UI/ml at week 48. The proportion of patients reaching HBV-DNA levels <12 UI/ml by week 12, 24 and 48 were 35%, 49% and 65%, respectively. Virological response was not correlated with HBeAg status or the presence of ADV resistance mutations at baseline. 7 patients dropped out (through week 48) [1 virologic breakthrough (wk 44); 1 primary non response (wk 12); 4 “worsening” of liver disease (2 HCC-related); 1 “renal failure” (week 24, upon initiation of NSAIDs use). None of the remaining patients showed creatinine levels > 1.5 mg/dl or creatinine elevation > 0.5 mg/dl. Median creatinine levels were: 0.89+0.23 mg/dl at baseline; 0.94+0.22 at 24 weeks; 1.04+0.74 at 48 weeks.

Conclusions: TDF shows significant and sustained antiviral activity against HBV in patients who have failed lamivudine and are sub-optimal responders to ADV.


212. A Prospective and Open-Label Study for the Efficacy and Safety of Telbivudine(Ltd) in Pregnancy for the Prevention of Perinatal Transmission of Hepatitis B Virus (HBV) to the Infants.  G. Han; W. Zhao; M. Cao; H. Jiang; C. Pan

Despite the use of HBIg and HBV vaccination, HBV perinatal transmission (PT) occurs in ~10-30% of infants born to highly viremic mothers. We evaluated the efficacy and safety of Ltd use during late pregnancy in reducing HBV transmission in highly viremic HBeAg+ mothers

Methods: HBeAg+ mothers between Weeks (W)20-32 of gestation with HBV DNA > 1.0 x 6log10 c/mL were eligible for enrollment and treated with either Ltd 600 mg/d from W20-32 of gestation to W4 postpartum or no treatment. Subjects with active CHB in Ltd arm continued Ltd until W28 postpartum. All infants in both arms received 200 IU of HBIg within 24 hrs postpartum and recombinant HBV vaccine of 20 ug at 0,1 and 6m. HBsAg and HBV DNA results from infants at W28 were used to determine PT rate.

Results: 190 Asian HBeAg+ CHB mothers enrolled: 4 consent withdrawls, 94 in Ltd arm and 92 in control arm. All Ltd treated subjects were registered in the Antiretroviral Pregancy Registry. Maternal baselines values are shown in Table 1. Prior to delivery, maternal HBV DNA mean(SD)levels were 2.35(1.79) vs. 7.83(0.67)log10 c/mL in Ltd and control arm(P<0.001) respectively. At birth, 6.32% of newborns were HBsAg+ in Ltd arm compared to 30.43% in the control arm(P<0.001). At W28, the primary ITT analyses (missing = failures) has 2.11% of infants with HBsAg+ and/or detectable HBV DNA in the Ltd arm vs 13.04% in the control arm (P=0.004). For sensitivity analysis, 0% of the infants from Ltd treated mothers were HBsAg+ compared with. 8.70% in the untreated control arm (P=0.003); HBV DNA levels were only detectable in HBsAg+ infants. No Ltd discontinuations occurred from adverse events nor congenital deformities noted. Maternal ALT flares (2-5xULN ALT) were observed 7.45% and 18.48% in Ltd and control arms respectively. 36 mothers discontinued Ltd at W4 postpartum as per protocol with no cases of severe hepatitis (ALT>10XULN). No differences for postpartum hemorrhage, gestational age, infants’ height/weight or Apgar scores were found between both arms.

Conclusions: Ltd used during late pregnancy in CHB HBeAg+ highly viremic mothers can safely reduce perinatal HBV transmission. Ltd was well-tolerated with no safety concerns in the Ltd-treated mothers or their infants on short term follow up. These data support the use of Ltd in this special population.

Table 1

Median(range)

Ltd
N= 94

Control
N = 92

t or χ2

P

Age,years

27
(20-38)

26
(20-35)

0.045

0.964

Prior pregancy (delivery)

1
(1-2)

1
(1-3)

-0.039

0.969

HBV DNA log10 c/mL

8.19
(6.11-9.45)

7.96
(6.42-9.18)

1.504

0.134

ALT
U/L

22.35
(8.20-407.00)

27.60
(8.10-262.50)

-0.632

0.528

ALT > UNL=40U/L n (%)

31(33%)

35(38%)

0.521

0.470

Prior antiviral use – n(%)

10(10.6%)

0(0%)

10.343

0.002

 


215. Shorter Duration and Lower Dose of Peginterferon Alfa-2a Therapy Results in Inferior Hbeag Seroconversion Rates Compared with the Duration and Dose of 48 Weeks and 180 µg: NEPTUNE StudyY. Liaw; Q. Xie; K. Han; E. J. Gane; T. Piratvisuth; P. I. McCloud; C. Wat; J. Jia

Objective: The NEPTUNE study investigated the efficacy and safety of peginterferon alfa-2a [40KD] (PEG-IFNα-2a) given for either 24 or 48 weeks and at either 90 or 180 µg weekly doses in the treatment of HBeAg-positive patients with chronic hepatitis B (CHB).

Methods: In this double-blind non-inferiority study, adults with HBeAg-positive CHB were randomized to treatment with PEG-IFNα-2a in a 2×2 factorial design of treatment duration (24 or 48 weeks) and dose (90 or 180 μg), giving 4 treatment combinations: 24@90, 24@180, 48@90 and 48@180.

The primary endpoint was HBeAg seroconversion 24 weeks after the end of treatment. The per protocol population (PPP) was used for the primary analysis and patients randomized to the 48-week group who received <28 weeks of treatment were assigned to the 24-week group for this analysis, as is standard practice for non-inferiority studies.

For treatment duration, the null hypothesis assumed that 24 weeks was inferior to 48 weeks. The primary analysis was logistic regression stratified by genotype and screening alanine aminotransferase. The primary test statistic was odds ratio (OR48/24). The OR48/24 non-inferiority margin was pre-specified as 1.88 with a one-sided level of significance of 0.025. OR48/24 was significant if the upper limit of the 95% CI was <1.88; consequently the null hypothesis of inferiority would be rejected. The test of non-inferiority for dose (OR180/90) was conducted with the same non-inferiority margin.

Results: 551 patients were randomized, and 544 were eligible for the PPP analysis. The HBeAg seroconversion rate was highest in the 48@180 group (36.2%; 47/130), followed by 48@90: 25.8% (34/132); 24@180: 22.9% (32/140) and 24@90: 14.1% (20/142). There was no evidence of an interaction between duration and dose (p=0.896). Therefore, the main effects of duration and dose were analyzed for the primary non-inferiority analyses (table). The OR48/24 [95% CI] for non-inferiority of 24 weeks vs 48 weeks was 2.17 [1.43, 3.31; p=0.749 for non-inferiority]. The OR180/90 [95% CI] for non-inferiority of 90 vs 180 µg was 1.79 [1.18, 2.72; p=0.410]. The two null hypotheses of inferiority for 24 weeks and 90 µg were retained.

Conclusions: The data from NEPTUNE demonstrate that the shorter duration of 24 weeks of PEG-IFNα-2a was inferior to 48 weeks and that the lower 90 µg dose was inferior to 180 µg, for HBeAg seroconversion 24 weeks post-treatment, the study primary endpoint.

 

Post-treatment HBeAg seroconversion rates according to duration and dose of PEG-IFNα-2a

Duration
(24 vs 48 weeks)

24 weeks n=282
18.4%*

48 weeks n=262
30.9%

Dose
(90 vs 180 µg)

90 µg n=274
19.7%*

180 µg n=270
29.3%

 

*null hypothesis of inferiority was retained


 

403. Efficacy and tolerance of tenofovir disoproxil fumarate plus emtricitabine combination in patients with chronic hepatitis B – A European multicenter study

S. Si-AhmedP. Pradat; M. Buti; R. Zoutendijk; V. Mallet; C. Cruiziat; K. Deterding; J. Dumortier; H. L. Janssen; H. Wedemeyer; F. Zoulim

Background and aims: Tenofovir disoproxil fumarate (TDF) plus emtricitabine (FTC) combination is used extensively for HIV treatment and has a potent activity on hepatitis B virus (HBV). The aim was to assess the efficacy and tolerance of a TDF+FTC combination in chronic hepatitis B (CHB).

Methods: Eighty-two consecutive mono-infected CHB patients from 5 European Centers were included. All started a TDF+FTC between October 2005 and March 2010. Virological, biochemical and clinical data were recorded during follow-up. Tolerance was also monitored. Patients were classified in two groups at the discretion of the investigator: treatment simplification (TS) when efficacy of the previous treatment was obtained at TDF+FTC initiation, and treatment intensification (TI) in case of failure of the previous line of therapy.

Results: TDF+FTC was given as a TI in 59 patients (72%) and as a TS in 23 (28%). Among patients with TI, 83% were males (M/F 49/10). The median baseline HBV-DNA was 4.5log10IU/mL, and the median ALT 1.24xULN. Sixty percent were HBeAg positive, 53% had significant fibrosis (>=F3 METAVIR equivalent), and 33% had confirmed cirrhosis. Median treatment duration was 15 months (range 1-53). At already 6 months after initiation of TI, the mean reduction in HBV-DNA was 2.9log10IU/mL with 55% being undetectable. Kaplan-Meier analysis showed that 12 months after TI, the probability of being HBV-DNA undetectable was 82%.

Patients with TS (M/F 19/4, median baseline HBV-DNA 1.08log10IU/mL, median ALT 0.80xULN, 44% HBeAg positive, 47% with significant fibrosis) were treated for a median duration of 17 months. In this subgroup, all patients remained HBV DNA undetectable and no ALT flare occurred during follow-up.

In both groups, no viral breakthrough occurred. Decompensation occurred in 4 patients with TI; HBV-DNA was undetectable at decompensation in 3 patients. Creatinin levels did not show kidney function deterioration in both groups of patients.

Conclusions:

·        After a follow-up of at least 12 months, results of TDF+FTC combination in clinical practice are encouraging with antiviral efficacy and good safety profile in all patients.

·        TDF+FTC combination may represent an interesting clinical option to increase the barrier to resistance which should be assessed on the long term.

·        The follow-up of the remaining 18% of patients will determine whether the objective of viral suppression can be reached in this difficult population to treat. 

 


 

433. Response to Alternative Therapies in Patients with Chronic Hepatitis B (CHB) and Entecavir (ETV) Partial Response (PR)

B. Yip; H. N. Trinh; H. A. Nguyen; K. T. Chaung; M. H. Nguyen

Purpose: Despite its known high potency, a significant proportion of patients treated with ETV only achieve PR at 6-12 months. Treatment outcomes of alternative therapies in these patients are not well known. Our goal was to examine the rate of complete viral suppression (CVS) with alternative therapies such as tenofovir (TDF), ETV+adefovir (ADV), or ETV+TDF in such patients.

Methods: We retrospectively studied 42 consecutive patients with PR to ETV monotherapy (detectable HBV DNA before treatment modification after ≥ 6 months of therapy) who were evaluated at 3 gastroenterology and liver clinics in the U.S. with new therapies as follows: ETV+TDF (n=31), ETV+ADV (n=5), and TDF (n=6). CVS was defined as undetectable HBV DNA PCR (<60 IU/mL). Antiviral resistance was excluded by negative mutation analysis and/or the absence of virologic breakthrough (increase >1 log10IU/ml from nadir) on ETV.

Results: All patients were Asian and 57% were male with a median age of 36 (22-64). The majority of patients (86%) were treatment naďve, with a few having prior exposure to LAM (7%) or ADV (7%). All patients had either genotypes B or C and 95% had positive HBeAg. After a median 25 months (6-47) on ETV therapy, the median log10 HBV DNA (IU/mL) for the total cohort decreased from 8.2 (5.0-9.9) to 3.4 (1.8-4.6). Higher rates of CVS were seen after 6 months of ETV+TDF or TDF than with ETV+ADV (Figure). All 3 patients without CVS on ETV+ADV achieved CVS 6 months after switching to ETV+TDF. One patient experienced HBeAg loss on ETV+TDF and no patients achieved HBeAg seroconversion.

Conclusion: In our study of Asian Americans with mostly HBeAg-positive CHB, a higher proportion of patients with ETV PR achieved CVS after 6 months of switching to ETV+TDF compared to TDF monotherapy and ETV+ADV therapy. CHB patients with ETV PR can be treated effectively with ETV+TDF combination therapy. TDF monotherapy also appears promising, but this result is limited by our small sample size in this group (n=6).

 


 

405. A prospective randomized comparison of 96 weeks treatment efficacy between entecavir and adefovir in treatment naďve patients with chronic hepatitis B: Association with Change in Serum Hepatitis B Surface Antigen Level

H. Woo; J. Heo; K. Yoon; M. Cho; G. Song

 

Background/Aims: This study was to compare the treatment efficacy at week 96 in associated with change in hepatitis B surface antigen (HBsAg) level between entecavir (ETV) and adefovir (ADV) in treatment naďve patients with chronic hepatitis B (CHB).

 

Methods: We had prospectively randomized nucleoside-naďve CHB patients to open-label treatment with either ETV 0.5mg once daily or ADV 10mg once daily. Forty-nine hepatitis B e antigen (HBeAg)-positive patients randomized to ETV group (21 patients) or to ADV group (28 patients). Twenty-four HBeAg-negative patients randomized to either ETV or ADV group with 12 patients, respectively. All patients were complete the treatment duration of 96 weeks. Antiviral efficacy was evaluated as undetectable serum HBV DNA (<12 IU/mL) by polymerase chain reactive (PCR) assay at week 96. HBsAg was measured before treatment and at 12, 24, 48, 96 weeks after treatment using the Architect HBsAg QT assay (Abbott Diagnostics Division).

 

Results: In HBeAg-positive patients, the proportion of patients achieving undetectable HBV DNA was greater in ETV group (61.9%) than ADV group (32.1%) at weeks 96 (P=0.038). ETV group (-4.56±1.43 log IU/mL) showed more reduction of HBV DNA from baseline than ADV group (-3.18±1.78 log IU/mL) at week 96 (P<0.001). At 96 weeks, there was no difference in the rate of HBeAg seroconversion between two groups (9.5% in ETV group vs. 25% in ADV group, P=0.166). In HBeAg-negative patients, the proportion of patients achieving undetectable HBV DNA was greater in ETV group (100%) than ADV group (58.3%) at week 96 (P=0.012). ETV group (-4.26±1.79 logIU/mL) showed more reduction of HBV DNA, but there was no statistic significance, from baseline than ADV group (-3.52±1.33 logIU/mL) at week 96. Baseline HBsAg titer was 3.86 ± 0.62 log IU/mL and it was well correlated with baseline HBV DNA titer (r=0.333, P=0.012). In either HBeAg-positive or HBe-negative patients, HBsAg titer after treatment was not decreased significantly from baseline and the change in HBsAg titer from baseline at week 96 was not associated with undetectable HBV DNA at week 96 nor correlated with change in HBV DNA at week 96 in both ETV and ADV group. Also, the change in HBsAg titer at week 96 of ETV group was not different from that of ADV group (-0.20±0.55 log IU/mL in ETV vs. -0.22±0.29 log IU/mL in ADV, P=0.406).

Conclusions: The change in HBsAg titer during nucleos(t)ide treatment was not correlated with antiviral efficacy. ETV treatment showed the more potent efficacy compared at 96 weeks with ADV group in both HBeAg-positive and HBeAg-negative nucleoside-naďve patients with CHB.

 


 

464. Evaluation of the efficacy of entecavir versus adefovir in HBeAg-positive chronic hepatitis B patients therapy at 96 weeks

A. Sun; H. Cheng; L. Zhao; H. Yang; G. Yang

 

Objective: To investigate the efficacy and safety of entecavir versus adefovir in HBeAg-positive chronic hepatitis B patients therapy at 96 weeks.

Methods: According to “Chinese guideline of chronic hepatitis B prevention and therapy”, 105 nucleotide(side)-naďve patients with HBeAg-positive chronic hepatitis B were enrolled in a random and open clinical trial. The patients were divided into two groups; 50 patients received treatment with entecavir 0.5mg and 55 patients received treatment with adefovir 10mg once daily. Serum ALT, HBV DNA and immunological HBV markers were detected per 12 weeks of treatment. At the same time, safety of drugs was observed. Both of HBV DNA and immunological HBV markers were detected by given central laboratory and our academy laboratory respectively.

Results: There are 38 males and 12 females in entecavir group, the average age is 29.98±7.62y, the baseline of ALT and DNA is 191.68±147.41u/L and 7.26±1.75 lg; there are 45 males and 10 females in adefovir group, the average age is 31.45±10.45y, the baseline of ALT and DNA is 188.16±142.19u/L and 7.19±1.14 lg; the characters of larithmic and baseline had no obvious difference in two groups. At week 96 of treatment, in enticarvir group and adefovir group, the rate of undetectable serum HBV DNA was 80.0% and 45.5% respectively (p<0.05), the mean reduction of serum HBV DNA from the basline was 6.63±2.33log and 5.67±2.19log respectively (p<0.05). There was 0 and 4 patients appered virological breakthrough, 0 and 3 patients had primary non-response in the two groups respectively (p<0.05). The rates of HBeAg became negative in enticarvir group and adefovir group were 50.0%and 49.1% respectively (p>0.05). The rates of HBeAg seroconversion in enticarvir group and adefovir group were 10.0% and 3.6%respectively (p>0.05). There was 1 patient HBsAg became negative in the two groups respectively. The rates of alanine aminotransferase normaliization in enticarvir group and adefovir group were 88.0%and 87.3% (p>0.05). The difference of rates of adverse events has no statistical significance in two groups.

Conclusion: The mean reduction of serum HBV DNA from the basline in enticarvir group was more than that in adefovir group. Enticarvir showed its potent and rapid effect in inhibiting virus replication. The difference of rates of alanine aminotransferase normalization has no statistical significance in two groups, which may be associated with application of ALT-lowering drugs in the treatment. The rates of adverse events were similar in two groups.

 


 

437. Outcomes of Treatment for Chronic Hepatitis B with Entecavir Therapy

S. Lim; M. Aung; D. Sutedja; Y. Lee; G. Lee; M. L. Fernandes; V. Lai1; Y. Dan

 

Background: A number of clinical trials of chronic hepatitis B (CHB) patients treated with entecavir treated patients show good viral suppression and low resistance rate but few studies have reported outcomes of unselected clinic patients.

 

Method: CHB Clinic patients who were treated with entecavir were followed for outcomes, and predictors of these outcomes were evaluated by multivariate analysis. Outcomes of viral suppression, viral resistance and breakthrough, and clinical outcomes of ascites, encephalopathy, hepatocellular carcinoma (HCC), progression in Child-Pugh score, MELD score and mortality were assessed. Data were analysed by Kaplan Meier graphs, log rank test.

Results: There were 335 chronic hepatitis B patients but 139 were excluded due to comorbidities such as liver transplant, HCC, malignancy, renal failure or <6 months of entecavir therapy. Of the 196 evaluable patients, 25.7% had cirrhosis and 18.9% had prior lamivudine-resistance but 44.4% had previous exposure to lamivudine or adefovir. Over a mean followup of 25.6 months, HBeAg seroconversion was 40% at 4 years, and liver disease progression was 11.36% at 5 years. HBeAg negative patients became HBV DNA negative earlier than HBeAg positive patients (p<0.001) median duration to HBV DNA undetecability was 4.3 and 8.8 months respectively. Overall, the proportion of patients with undetectable HBV DNA in HBeAg negative patients was 92.85% and for HBeAg positive patients was 75.78%. HCC development was higher in cirrhotic patients 12% compared to 3% at 4 years in non-cirrhotics (p=0.045). Liver disease progression was related to the baseline Child-Pugh score (p<0.001). Those with higher baseline HBV DNA≥ 6 log were less likely to become HBV DNA negative (p<0.001). In lamivudine exposed patients, those with lamivudine resistance took longer to become HBV DNA negative (p=0.0163). Baseline predictors of liver disease progression include cirrhosis (OR 6.5, 95% CI 1.3-32.3), and serum albumin (OR1.14, 95% CI 1.02-1.26). Only one case of entecavir resistance was found, and this was in a patient who had no prior exposure to oral antiviral agents.

Conclusion: Entecavir treated clinic patients had good outcomes despite previous nucleoside analogue therapy and a wide spectrum of disease states. HBV DNA undetectability was very high and entecavir resistance very low even in those with previous lamivudine resistance.

 


 

367. Reduction of liver stiffness of chronic hepatitis B patients by antiviral therapy

K. Yoshioka; M. Harata; K. Osakabe; S. Hashimoto; N. Kawabe; Y. Nitta; M. Murao; T. Nakano; Y. Arima; H. Shimazaki; N. Ichino; T. Nishikawa

Backgroud and Aim: Liver stiffness (LS) measured by FibroScan has been reported to correlate with fibrosis stage in various liver diseases. In chronic hepatitis C, IFN treatment has been reported to reduce LS. In the present study, the correlation between LS and fibrosis stage and the reduction of LS by antiviral therapy were examined in the patients with chronic hepatitis B.

Methods: LS were measured in 270 HBV infected patients by FibroScan. In 43 patients, liver biopsies were done. In 35 patients treated with nucleotide or nucleoside analogs and 52 patients without antiviral therapy, the changes of LS were assessed.

Results: LS was 5.1 ± 1.7 kPa in F0-1 (n=3), 8.6 ± 3.2 kPa in F2 (n=15), 10.6 ± 4.6 kPa in F3 (n=13) and 18.3 ± 5.9 kPa in F4 (n=12).

LS was significantly higher in F4 than in F0-1, F2 and F3 (p<0.005). LS was significantly correlated with fibrosis stage (r=0.666, p<0.0001).

By ROC analysis, the cutoff values of LS were determined to be 6.7 kPa for F > or = 2, 10.7 kPa for F > or =3 and 16.0 kPa for F4. In the patients with antiviral therapy, LS was 13.9 ± 7.8 kPa at the 1st measurement and significantly reduced to be 7.9 ± 5.1 kPa at the latest measurement (p<0.0001). 2-point or greater reduction of deduced stage by antiviral therapy was observed in 10 of 18 patients in whom LS at the 1st measurement was 10.7 kPa or higher and fibrosis stages were deduced as F3-4. The longer periods between the two measurements were associated with a 2-point or greater decrease of deduced fibrosis stage in tendency (p=0.0914). In the patients without antiviral therapy, LS was 6.7 ± 3.7 kPa at the 1st measurement and increased to be 7.9 ± 4.4 kPa at the latest measurement (p=0.0682). A 1-point or greater increase of deduced stage was observed in 11 of 50 patients without antiviral therapy in whom LS at the 1st measurement was less than 16.0 kPa and fibrosis stages were deduced as F0-3. The higher AST levels (p=0.0592), the higher hyaluronic acid levels (p=0.0893) and the lower albumin levels (p=0.0092) were associated with a 1-point or greater increase of deduced fibrosis stage.

Conclusions: LS was significantly correlated with fibrosis stage in the patients with chronic hepatitis B, and was suggested to be useful to assess liver fibrosis stage noninvasively. Significant reduction of LS was observed in the patients treated with antiviral therapy and can be attributed to the regression of fibrosis. Increase of LS of the patients without antiviral therapy was observed and can indicate the progression of fibrosis.

 


 

412. Nucleotide analogues may prolong survival time without recurrence and overall survival time for HBV-related liver diseases after curative treatment of hepatocellular carcinoma.

T. Inuzuka

Objective: To evaluate the effects of Nucleotide Analogues (NA) on survival and recurrence in patients with HBV-related hepatocellular carcinoma (HCC) who were curatively treated with resection or radiofrequency ablation (RFA).

Methods: Patients who undergo curative resection or RFA for HCC will be enrolled in this study if they fulfill the following criteria: (1) solitary tumor less than 5 cm in diameter or 2-3 tumors with the largest one no more than 3 cm in diameter, (2) positive for serum hepatitis B surface antigen (HBsAg) and negative for hepatitis C virus antibody (HCVAb). The study population consists of 68 subjects (age 56±10, 54 men and 14 women).

Patients are divided to 2 groups, with or without NA treatment, and evaluated on (1) overall survival (OS) and (2) cumulative risk of recurrence (CRR) by retrospective analysis with Kaplan-Meier method, Log-rank test and Cox proportional hazard analysis.

Results: The NA group consists of 39 cases who were given NA during the time between the first HCC treatment and first non-primary site recurrence, and was evaluated on OS in comparison with 22 cases of non-NA group (7 patients out of 29 were excluded because 7 were given NA after recurrence). The observation period was 52.1±33.9 months.

HBeAg positive (p=0.008) and NA treatment (p=0.048) were predictors of OS in univariate analysis, and only HBeAg positive (p=0.021) was a significant predictor of OS (HR was 5.85 (95%CI 1.38-24.8)) in the multivariate analysis.

In the univariate analysis, covariates found to be predictive of CRR were Child-Pugh score (p=0.005) and number of tumors (p=0.023).Only Child-Pugh score (p=0.030) was a significant predictor of CRR (Hazard ratio 2.61, 95%CI: 1.10-6.20) in multivariate analysis.

Among 34 cases who were free from recurrence during first 30 months, univariate analysis showed that NA treatment was significantly associated with reduced recurrence thereafter (p=0.033).

Discussion: Literatures have suggested that recurrence after 24 months after curative therapy is not mostly intrahepatic metastasis, but de novo HCC.We think NA treatment effect on viral load reduction brought the significant difference after 30 (24+alpha) months after curative therapy.

Conclusion: NA may prolong overall survival after curative treatment of HBV-related HCC, and make the recurrence suppression effect after 30 months.

 


 

368.Identification of patients at risk for the development of hepatocellular carcinoma in chronic hepatitis B and assessment of the impact of nucleoside analogue therapy on risk reduction: Evaluation of the current treatment guidelines and proposal of novel criteria by data mining analysis.

M. Kurosaki; N. Tamaki; Y. Yasui; T. Kuzuya; K. Tsuchiya; Y. Asahina; N. Izumi

 

Background and aims: The criteria for the treatment of chronic hepatitis B virus (HBV) infection in the current guidelines are based on hepatitis B e antigen (HBeAg) status, HBV DNA levels, and alanine aminotransferase. Since it is not known whether these criteria could sufficiently cover patients at risk for developing hepatocellular carcinoma (HCC), we validated the current guidelines based on the natural history of a cohort of chronic hepatitis B. Using data mining analysis, we also analyzed other risk factors for HCC and the efficacy of nucleoside analog therapy for the prevention of HCC.

Methods: A cohort of 613 patients with chronic hepatitis B at a single regional hospital in Japan was studied. Patients who were positive for HBeAg and had persistently normal value of ALT (immune-tolerant) were not included. Patients were screened for HCC for the average period of 5.5 years. The guideline criteria for antiviral treatment were applied to this cohort to evaluate their efficacy in identifying patients at risk for HCC. Factors associated with the development of HCC were analyzed by data mining analysis using the IBM-SPSS Modeler 13 software. Data from 197 patients on long-term nucleoside analogue therapy was applied on this model to evaluate the efficacy of antiviral therapy in preventing HCC.

Results: The 5 year cumulative incidence of HCC in this untreated cohort was 12%. According to the guideline criteria, only 7% of the patients who developed HCC had indication for antiviral therapy. Data mining analysis revealed that age older than 40, platelet lower than 150 (109/L), serum HBV DNA higher than 5.8 (log copies/ml), and double mutations in basic core promoter 1762/1764 were significant risk factors for HCC. The 5 year cumulative incidence of HCC in patients fulfilling 0, 1, 2-3, and 4 of these criteria was 0%, 0-5%, 14%, and 50%, respectively. If age and platelet counts were included in the criteria, sensitivity of identifying patients at risk for HCC improved to 83%. If mutations in basic core promoter 1762/1764 were also included, the sensitivity further improved to 91%. By long-term nucleoside analogue therapy, the 5 year cumulative incidence of HCC reduced by 9-41% among patients at high risk.

Conclusions: The current treatment guidelines for chronic hepatitis B excluded significant proportion of patients at high risk for HCC. Novel criteria based on age, platelet counts, serum levels of HBV DNA, and basic core promoter 1762/1764 mutations covered over 90% of patients at high risk. Nucleotide analogue therapy significantly reduced the incidence of HCC among these high risk patients.

 


 

375. A systematic review of oral antiviral agents in decompensated HBV cirrhosis.

A. K. Singal; R. J. Fontana

Purpose: Hepatitis B virus (HBV) is a leading cause of cirrhosis and HCC. Studies comparing oral nucleos(t)tide analogues in decompensated HBV pts are lacking. Aim of this systematic review is to compare efficacy and safety of oral agents for decompensated HBV cirrhosis.

Methods: Literature searched for English citations from ’95-’10 of oral agents in decompensated HBV cirrhotics (CTP score ≥ 7). Studies were graded on a scale of 0-10 for quality. 1-year efficacy and safety data in pts treated for > 6 mo were extracted. Odds ratio (OR) is reported for controlled studies and pooled proportion (95% CI) for open studies.

Results: 21 studies (quality score ≥ 5) included [13 on lamivudine (LAM); 3 on adefovir (ADV) in LAM resistant pts; and 5 on entecavir (ETV)]. Heterogeneity in inclusion/ exclusion criteria, access to OLT, selection of controls, and sensitivity of HBVDNA assay were noted. Pooled data on 6 controlled studies showed benefit favoring LAM (n=920) vs controls (n=1237) for undetectable HBVDNA (OR: 148 [6-3892; p=0.003]), normal ALT (76 [9-452; P<0.0001]) ≥ 2 dec. in CTP (9.2 [5-17; P<0.0001]), HCC (0.36 [0.24-0.54; P<0.0001]), and OLT (0.33 [0.23-0.48; P<0.0001]). However, pt survival was similar and LAM resistance occurred in 22%. ADV studies showed similar survival to LAM and lower resistance (1.5%) but lower potency with undetectable HBVDNA in 57% and normal ALT in 67%. ETV studies showed efficacy similar to LAM with 0% resistance. All drugs were safe without SAE’s except < 1% (2 of 226) renal insufficiency with ADV in one study. One RCT showed better efficacy of ETV (n=24) vs LAM (n=24) for undetectable HBVDNA (100 vs. 72%, P=0.02) at 1 yr.

Conclusions: Oral agents are effective and safe for treating decompensated HBV cirrhosis. LAM is limited by resistance at 1-yr and ADV is limited by potency. ETV has advantages of potency without resistance in treatment naďve patients. Direct comparative studies of potent agents with low resistance (TFV vs ETV) are needed to determine optimal agent in pts with decompensated HBV.

Pooled 1-yr data of LAM, ADV, and ETV

Outcome

LAM
(N=1242)

ADV
(N=340)

ETV
(N=200)

Decrease CTP ≥ 2 (%)

57
[45-69]

64

49

ALT normal (%)

87
[76-98]

67
[57-81]

60

HBVDNA
-ve (%)

90
[81-95]

57
[41-66]

86
[74-93]

HBeAg loss (%)

38
[25-54]

34
[14-61]

48

HBeAg sero-conversion (%)

22
[15-31]

21
[14-29]

22

Off OLT list (%)

27
[9-58]

20
[14-29]

NA

Increase CTP ≥ 2

5
[4-8]

NA

7

HCC (%)

6
[3-11]

1.3
[0.3-6]

7

OLT (%)

8
[2-26]

NA

13

1-Yr Survival (%)

84
[81-87]

88
[83-92]

88
[82-93]

Resistance (%)

22
[14-34]

1.5
[0.6-4]

0

 


 

414. High prevalence of reduced bone mineral density in patients with chronic hepatitis B under nucleos(t)ides analogues treatment

M. Viganň; P. Lampertico; C. Eller-Vainicher ; R. Soffredini; F. Facchetti; I. Chiodini; P. Beck-Peccoz; M. Colombo

Background and Aim: Reduced bone mineral density (BMD) has been reported in patients with cholestatic liver diseases or cirrhosis. However, little is known about the prevalence of low BMD in patients with chronic hepatitis B (CHB) under nucleos(t)ides analogues (NUCs).

Material and Methods: In 319 consecutive CHB patients (76% males, 63yr, 57% cirrhosis) under tenofovir/adefovir ± lamivudine for 42 (3-102) months (n=239), lamivudine for 37 (16-183) months (n=20) or entecavir for 18 (3-32) months (n=60), BMD was assessed by dual X-ray absorptiometry of the lumbar spine (LS) and femoral neck (FN). According to the WHO criteria, a T score of less than -2.5 and a T score between -1 and -2.5 identified osteoporosis and osteopenia, respectively. Reduced BMD was defined as the presence of one of these conditions.

Results: Osteoporosis at either LS or FN was present in 60 (19%) and osteopenia in 157 (49%) patients, overall 217 (68%) patients had reduced BMD. By univariate analysis, gender, age, nucleotide treatment, but not BMI, cirrhosis and time on antiviral treatment, were significantly associated with low BMD. Overall, a reduced BMD was present in 70% and 53% of patients treated with nucleotides or nucleosides analogues, respectively and in 65% and 78% of male and female, respectively. At multivariate analysis, male gender (OR 0.48, CI 0.25-0.91, p=0.02), older age (OR 1.03, CI 1.0-1.05, p=0.013) and nucleotides treatment (OR 0.57, CI 0.32-0.99, p=0.048) were independently associated with a reduced BMD.

Conclusions: Many patients under long-term treatment with NUCs for chronic hepatitis B showed reduced BMD, emphasizing the need for bone mineral assessment to early prevent or treat this condition.

 


 

396. Interferon is Underutilized in Hepatitis B (HBV) Patients Most Likely to Have Favorable Outcomes

N. Reau; C. E. Choi; H. S. Te; S. R. Mohanty; A. Aronsohn; K. G. Reddy; D. M. Jensen

Background: The goal HBV therapy is to prevent end stage liver disease and hepatocellular cancer through sustained suppression of HBV replication. 7 agents are approved for use in HBV. Although interferon (INF) (standard or pegylated) is the only finite HBV therapy, its use may be avoided due to anticipated side effects and perceived lack of response. Patients with increased ALT, low level HBV viremia and genotype A or B have an increased chance of responding to INF based treatment.

Aim: To determine if HBV patients most likely to respond to INF are treated with this agent.

Methods: 257 patients who received HBV therapy were identified from retrospective chart review of 525 HBV patients evaluated in our outpatient hepatology clinic between 2001-2009. Demographic and clinical data were extracted.

Results: Of 257 patients received anti-viral therapy, 48 (19%) received INF as part of their treatment regimen. Mean age was 45.5 (21-67), 77% male, 27% Asian, 27% African American, 38% Caucasian. 44% were HBeAg positive, mean HBV DNA 6.0x7 IU (50%<10x5 log), mean ALT 137 (60% >2ULN). 77% relapsed after treatment and received a nucleoside/tide analogue. Patients in whom therapy was indicated were then evaluated for characteristics associated with favorable response with INF therapy. 126 had an ALT >2 ULN and 163 had a low HBV DNA (<10x5). However, only 60 had both these variables, of whom 13 (22%) received INF as treatment. 3/13 (23%) were HBeAg positive. All 13 relapsed after discontinuation of INF. In this same population 50 patients had HBV genotype A or B (irrespective of viral load or ALT), of which 12 (24%) received INF therapy and 5 (42%) remained in remission after discontinuation.

Conclusion:

·        INF is underutilized in the population predicted to have the best response.

·        In those treated with INF, sustained suppression of HBV is rare confirming that physicians poorly select patients appropriate for INF therapy.

·        Sustained reposed was best in those with genotype A or B, despite viral load or ALT level. 


 

399. Peginterferon alfa-2b induced HBsAg decline is durable through long-term follow-up in HBeAg-positive patients

M. J. Sonneveld; V. Rijckborst; Y. Cakaloglu; K. Simon; J. Trojan; F. Tabak; T. H. Mach; C. A. Boucher; B. E. Hansen, 8; H. L. Janssen

Background: Recent studies show that lower HBsAg levels are associated with low replicative states of HBV infection, and that higher levels may predict reactivation of the disease. A durable suppression of HBsAg levels thus seems to reflect immunological control over the virus. The long-term sustainability of peginterferon (PEG-IFN) induced HBsAg decline is still unknown.

Methods: Serum HBsAg levels were assessed at baseline and on-treatment in 142 HBeAg-positive chronic hepatitis B patients who were previously enrolled in a multicenter randomized trial investigating the efficacy of 52 weeks of PEG-IFN±lamivudine. Patients were re-visited once more at a subsequent long-term follow-up (LTFU) visit; the mean follow-up was 3.0 years. HBsAg decline patterns were compared between responders and non-responders. Response was defined as post-treatment sustained HBeAg loss with HBV DNA <10,000 copies/mL at week 78.

Results: Of 142 patients with an LTFU sample available, 24 (17%) were responders. Mean baseline HBsAg levels were lower in patients with a response compared to those without: 4.4 versus 4.1 log IU/mL (p=0.08). However, on-treatment decline patterns were decidedly different: HBsAg decreased 3.25 versus 0.55 log IU/mL through 52 weeks of therapy in responders and non-responders (p<0.01). Within the group of non-responders, little difference was observed between those who lost HBeAg, but failed to achieve HBV DNA < 10,000 copies/mL (n=25, 18%), versus those who did not lose HBeAg: week 52 declines were 0.88 and 0.46 log IU/mL, respectively (p=0.18). Through LTFU, HBsAg declined further in patients with a response: HBsAg decline was 3.75 at LTFU, compared to 0.58 in non-responders (figure).

Conclusion: One year of PEG-IFN therapy induces a swift and pronounced decline in HBsAg levels in HBeAg-positive patients, particularly in those who achieve a response. Importantly, the decline was sustained through a mean of 3 years of post-treatment follow-up, reflecting a long-term sustained suppression after therapy discontinuation.

 


 

451. Physician Preference Drives Choice of Oral Hepatitis B Therapy

N. Reau; C. E. Choi; H. S. Te; S. R. Mohanty; A. Aronsohn; K. G. Reddy; D. M. Jensen

Several oral HBV therapies are approved; however utilization of each nucleoside analogue (NA) varies.

Aim: To evaluate if baseline patient characteristics or physician preferences determine the choice of NA

Methods: Retrospective analysis of 452 HBV patients first evaluated between 2001-9. Demographic and clinical data were extrapolated. Fisher’s exact test and polytomous logistic regression were used to test for associations between sex, race, physician, HBeAg+, age, ALT, Cr, and platelets and drug choice.

Results: 257 patients received NA therapy. 152 were treatment naďve at presentation. 9 excluded for pregnancy. (Table) Of the 143 patients 103 remained on the initial NA whereas 40 changed or transitioned to combination therapy. No baseline factor predicted initial oral agent other than physician preference (p = 0.005).Initial treatment with an agent with a high risk for viral resistance commonly resulted in a transition of the medical regimen to either combination therapy or a more potent single agent. In addition, increasing duration of medical management was associated with exposure to more than one NA as was race (p = 0.0123) and Cr (p = 0.0337).

Conclusion: Physician preference not patient or viral characteristics are associated with NA choice when managing HBV. Increasing duration of therapy and using LAM or ADV as first line therapy were more likely to result in exposure to more than 1 NA to manage chronic HBV.

Non-pregnant treatment-naďve patients

 

Single NA
N=103(%)

Multiple NAs
N=40(%)

DNA IU/ml

35789140.36

370691593.31

Age

75 (73)

32 (80)

Sex(male)

75 (73)

32 (80)

HBeAg +

47 (46)

19 (48)

 

 

 

Asian

25 (24)

11 (28)

African American

40 (39)

14 (35)

white

29 (11)

12 (30)

ALT

202 (7-3494)

119 (11-409)

Creatinine

2.03

1.26

Platelets

169

182

Time since 1st appt (yrs)

4.80

7.93

Cirrhosis

30 (29)

14 (35)

LAM

18 (17)

31 (78)

ADV

3 (3)

6 (15)

LdT

4 (4)

1 (3)

ETV

61 (59)

1 (3)

TdF

8 (8)

1 (3)

TdF 2nd line

 

11 (28)

ETV 2nd line

 

20 (50)

 

 

 

 


 

377. Treatment of HBeAg-positive CHB infection with peginterferon alfa-2a [40KD] plus lamivudine or adefovir for 96 weeks results in high rates of HBsAg clearance/ seroconversion

Z. Cao; Y. Zhang; L. Ma; Y. Jin; H. Yu; X. Zhang; Y. Liu; Y. Huang; B. Ma; S. Ren; L. Wang; X. Chen; L. Wei

Objective: To investigate the efficacy and safety of extended treatment with peginterferon alfa-2a [40KD] (PEG-IFN) in combination with lamivudine (LAM) or adefovir (ADV) for 96 weeks in Chinese patients with hepatitis ‘e’ antigen (HBeAg)-positive chronic hepatitis B (CHB).

Methods: A total of 47 consecutive patients with HBeAg-positive chronic hepatitis B were randomized to receive PEG-IFN 135 µg weekly in combination with either LAM 100 mg daily (N=24) or ADV 10 mg daily (N=23). All patients have currently completed 48 weeks of treatment; 20 patients in the PEG-IFN plus LAM group and 21 in PEG-IFN plus ADV group have completed 96 weeks of therapy. Virological response (HBV DNA <500 copies/mL; Biosystems 5700) and serological responses (HBeAg and HBsAg measured using Abbott ARCHITECT) were measured at 3 month intervals during treatment.

Results: The majority of patients were infected with hepatitis B virus (HBV) genotype B or C. By the end of 48 weeks of treatment, 45/47 patients (96%) achieved virological response. All of those patients who had completed 96 weeks of treatment (41/41) achieved a virological response. After 48 weeks of therapy, 12/24 (50%) of patients treated with PEG-IFN plus LAM and 10/23 (44%) of patients treated with PEG-IFN plus ADV achieved HBeAg seroconversion. Of those patients who had completed 96 weeks of therapy, 15/20 (75%) and 15/21 (71%) patients, respectively, in each group achieved HBeAg seroconversion.

In the PEG-IFN plus LAM group, HBsAg seroconversion rates were 8% after 48 weeks of treatment, rising to 30% in those patients who had completed 96 weeks of therapy. In the PEG-IFN plus ADV group, the rate of HBsAg seroconversion was 4% after 48 weeks and 24% after 96 weeks of treatment. Extended treatment to 96 weeks was well tolerated. The safety profile of 96 weeks of treatment was similar to that seen in patients treated for 48 weeks.

Conclusions: Extended treatment of PEG-IFN in combination with nucleos(t)ide analogs in patients with HBeAg-positive CHB appears to be a promising treatment strategy, resulting in high HBsAg seroconversion rates, the closest outcome to cure in the management of CHB.

 


 

440. Long-term effect of lamivudine treatment on the incidence of hepatocellular carcinoma in patients with hepatitis B virus

M. Kurokawa; N. Hiramatsu; T. Oze; T. Yakushijin; K. Mochizuki; S. Iio; Y. Doi; A. Yamada; M. Oshita; A. Kaneko; H. Hagiwara; E. Mita; T. Ito; Y. Inui; K. Katayama; H. Yoshihara; Y. Imai; E. Hayashi; T. Miyagi; Y. Yoshida; H. Ishida; T. Tatsumi; T. Kanto; A. Kasahara; T. Takehara; N. Hayashi

Background & Aims: Nucleotide analogues have recently been approved for treatment of patients with hepatitis B virus (HBV). However, it is not yet clear whether treatment using nucleotide analogues can reduce hepatocellular carcinoma (HCC) development in HBV patients. The objectives of this study were to elucidate the long-term effect of lamivudine (LAM) and clarify whether this therapy could reduce HCC in HBV patients.

Patients & Methods: This study was conducted at Osaka University Hospital and institutions participating in the Osaka Liver Forum. A total of 294 HBV patients without HCC were enrolled in a multicenter trial. The mean age of the 215 men and 79 women was 48.0 ± 10.7 years. There were 163 HBe Ag-positive patients and 122 HBe Ag-negative patients. The median HBV-DNA level was 7.0 log copies/ml. The mean platelet count was 13.7 ± 5.4 ×104/μl, and the ALT level was 203 ± 252 IU/L. The mean observation period was 67.6 ± 27.4 months. All patients were treated with LAM for more than 48 weeks. Among the 294 patients, 88 had liver cirrhosis. Adefovil was added to LAM for the 129 LAM-resistant patients. The incidence of HCC was examined after the start of LAM therapy, and the risk factors for liver carcinogenesis were analyzed.

Results: Thirty-two patients with HBV developed HCC (10.9%) and the cumulative carcinogenic rate was 5.9% at 3 years and 11.8% at 5 years. Cox proportional hazard analysis indicated the following risk factors as independently significant in relation to HCC development : age > 50 years (Hazard ratio: HR, 3.20; 95% CI, 1.08–9.53; P = 0.036), platelet count < 14.0 ×104/μl (HR, 4.76; 95% CI, 0.05–0.96; P = 0.045), liver cirrhosis/chronic hepatitis (HR, 4.64; 95% CI, 1.75–12.4; P = 0.002), median HBV-DNA levels of > 4.0 log copies/ml during LAM treatment (HR, 2.70; 95% CI, 1.09–6.56; P = 0.032). The cumulative carcinogenic rate at 5 years was 3.2% in patients with chronic hepatitis B and 29.5% in those with liver cirrhosis with HBV. In patients with chronic hepatitis B, the log-rank test showed the significant risk factors related to HCC development to be age > 50 years (P = 0.002), platelet count < 14.0 ×104/μl (P = 0.004) and HBe Ag-negative (P = 0.005). Suppression of median HBV-DNA levels to < 4.0 log copies/ml by LAM treatment was not associated with the development of HCC. On the other hand, a suppressive effect of median HBV-DNA levels of < 4.0 log copies/ml during LAM treatment was found on HCC development in patients with liver cirrhosis by log-rank test (P = 0.029).

Conclusions: These results suggest that LAM therapy can reduce the incidence of HCC in patients infected with HBV, especially those with liver cirrhosis.

 


 

383. Complete viral suppression (CVS) by entecavir (ETV) in patients previously treated with adefovir (ADV): Interim report for a multicenter study.

M. H. Nguyen; H. N. Trinh6; S. T. Do; P. l. Tran; T. Nguyen; K. Nguyen; H. A. Nguyen; N. H. Nguyen; R. T. Garcia 

Background/Aims: Rapid CVS is correlated with a lower rate of resistance development in antiviral therapy. In-vitro and viral kinetics studies suggest ETV is more potent against HBV than ADV. Limited data is available on the treatment efficacy of ETV in ADV-experienced patients. Our goal was to study CVS (HBV DNA <60-100 IU/mL) and ALT normalization (<40 U/L) rates in patients who were switched to ETV due to suboptimal response, resistance prevention, or other physician/patient preferences.

Methods: We enrolled CHB patients with pretreatment HBV DNA≥2000 IU/mL and prior ADV who have been switched to ETV at 5 GI clinics in the United States. Patients were excluded if they had co-infection with HDV, HCV or HIV, lamivudine resistance, or recent/on-going immunosuppressive therapy. Patients were stratified into 2 groups: Group I - ADV partial responders (< 2-log reduction in HBV DNA at 6 months or no CVS at 12 months with ADV) and Group II - ADV responders (CVS with ADV but switched to ETV for physician/patient preferences). Only patients completed ≥6 months of ETV were analyzed.

Results: A total of 127 patients were screened and 21 were excluded: lamivudine resistance (n=4), prior combination therapy (n=2), HDV co-infection (n=2), failure to meet inclusion criteria (n=6), , did not complete EVR treatment (n=4)and refusal to participate (n=3). A total of 110 patients were enrolled, 106 of whom completed ≥6 months of ETV therapy and were analyzed: 71 in Group I and 35 in Group II. Most patients were male in Group I and II (65% and 63%, respectively). Group I, as compared to Group II, were younger (44±13 vs. 53±10), more likely to have HBeAg+ (49% vs. 16%), had higher baseline HBV DNA (6.0 [2.3-9.4] vs. 5.0 [3.6-8.7]), and shorter median treatment duration with ADV (73 [15-394] vs. 146 [36-307] weeks). Table 1 describes treatment response to ETV in group I. In group II, 100% of patients continued to have CVS and normal ALT during ETV therapy (up to 24 months). No side effects or resistance were observed after switch from ADV to ETV.

Conclusions: The majority (62%) of patients with prior partial response to ADV achieved CVS by 6 months after switch to ETV and this rate continued to increase to 82% at 24 months. In patients who have had CVS with ADV, all continued to have CVS and normal ALT after being switched to ETV.

Table 1. Treatment Response to Entecavir in Adefovir Partial Responders (Group I)

 

ALT Normalization
% (n/N)

Complete Viral Suppression
% (n/N)

At switch
(N = 71)

69% (49/71)

0% (0)

6 months after switch
(N = 71)

79% (56/71)

62% (44/71)

12 months after switch
(N = 67)

81% (54/67)

70% (47/67)

18 months after switch
(N = 61)

80% (49/61)

75% (46/61)

24 months after switch
(N = 45)

87% (39/45)

82% (37/45)

 


 

364. A Prospective Open-label Study to Evaluate the Efficacy, Safety and Tolerability of Telbuvidine (Ltd) in HBeAg + Chronic Hepatitis B (CHB) Pregnant Women

C. Pan; G. Han; W. Zhao; H. Jiang; M. Cao

 

We evaluated the virologic responses and safety parameters of Ltd treatment starting in 2nd to 3rd trimester until week(W)4 postpartum(P)in active CHB pregnant women.

Methods: HBeAg+ women at W12-32 of gestation with HBV DNA > 6log 10 cps/mL and ALT > ULN (40 IU/mL) but < 10x ULN were enrolled for Ltd 600mg/d treatment until PW4. Patients who refused Ltd but consented to the study were enrolled in the control arm. At PW4, all subjects either discontinued Ltd or transitioned to any commercially available CHB therapy. Subjects who discontinued Ltd were monitored for ≥ 12W. Maternal HBeAg, ALT and HBV DNA at PW4 were used to determine efficacy. Infants received HBIg(200IU) in 24 hrs of birth and HBV vaccination(20ug) at 0, 1 and 6 mo. HBV infection rate, Ltd adverse events, pregnancy complications and birth defects were evaluated.

Results: 88 patients were enrolled: 53 and 35 in the Ltd and control arm respectively. Baseline values were shown in Table 1. 53 subjects on Ltd were registered with the Antiretroviral Pregnancy Registry (46 in the 2nd trimester); the mean duration of Ltd exposure was 15.5 [6-28] Ws. Retention rate at PW4: 100% in Ltd vs. 92% (32/35) in control arm. Complete virologic response (DNA < 500 c/mL) was achieved in 53% patients prior to delivery (p<0.001); 62% patients at PW4 (p<0.001) vs. 0 % in the control arm at both time points. At PW4, ALT normalized was achieved in 77% and 29% in Ltd vs. control respectively(p<0.001); HBeAg titer decline was observed in 98% and 60% in Ltd vs. control respectively (p<0.001). At birth, 4% and 23% of the newborns in Ltd vs. control were HBsAg+(P<0.001). No patients had virologic breakthrough(HBV DNA > 1 log increase from <500 c/mL). HBsAg lost was not seen at PW4. Except 2 cases dropped out at PW4, Ltd were discontinued in 13/52 patients at PW4 and all had 24W follow up with no severe hepatitis (ALT>10XULN). There was no Ltd discontinuation due to adverse events, no congenital deformities reported at PW4 and no differences for postpartum hemorrhage, gestational age, infants’ height/weight or Apgar scores between two arms.

 

Conclusion: Active CHB mothers who received Ltd monotherapy during 2nd and 3rd trimester safely tolerated and benefited from treatment. Reduction in HBV infection with no birth defects was observed at W 4 infant visit.

Table 1

Median(range)

Ltd
N= 53

Control
N = 35

t or χ2

P

 

Age, years

27
(21-34)

27
(21-33)

0.235

0.815

 

HBV DNA
log10 c/mL

8.08
(6.62-9.45)

8.08
(6.76-9.08)

0.006

0.995

 

HBeAg titers

1238.00
(15.02-1673.00)

1337.00
(13.81-1895.00)

-1.544

0.127

 

ALT (UNL=40U/mL)

64.40
(41.40-852.30)

63.20
(42.40-262.50)

1.803

0.076

 

Prior antiviral use– n (%)

10 ( 19% )

0(0%)

7.450

0.005

 


 

372. Outcomes of Eight Chinese-Americans Pregnant Patients with Chronic Hepatitis B (CHB) Treated with Tenofovir DF (TDF) During Pregnancy

L. Mi; J. Karsdon; W. M. Huang; J. Zhang; F. Manheimer; T. T. Tran; R. S. Brown; M. G. Ghany

 

Background:  In the United States ~24,000 CHB women become pregnant annually. Perinatal HBV transmission occurs in 3–8% of infants despite standard immunoprophylaxis especially with high maternal viremia. Lamivudine (pregnancy category-C) has been used in the 3rd trimester of pregnancy to prevent perinatal transmission. TDF (pregnancy category-B), a more potent nucleotide analogue, has been used in over 600 HIV infected and HIV/HBV co-infected mothers. However, little is known about the efficacy, tolerability and safety of TDF in HBV monoinfected mothers. We report the outcomes of 8 pregnant CHB women treated with TDF during pregnancy along with infants' data.

Methods: Data was collected retrospectively from all 8 CHB women treated with TDF at New York Downtown Hospital and Cedars-Sinai Medical Center 2009-2010. TDF 300mg was given orally once daily. Treatment was initiated in 3rd trimester in all cases except one (case#3) in which pregnancy occurred during TDF treatment. 3 patients were treated for active disease, 4 for perinatal transmission prophylaxis. All were registered with The Antiretroviral Pregnancy Registry (www.APRegistry.com). Their HBV-DNA, ALT, lipase, and creatinine (Cr) levels were recorded at initiation of therapy, monthly, and at delivery, along with neonatal outcomes. All infants received HBIg and HBV vaccine at the proper age. All patients had the options of stopping treatment after delivery, and all chose to continue.

Results: See Table 1. TDF use in the 3rd trimester of pregnancy was associated with a 2–4 log10 HBV reduction during the first 4 weeks and an absolute level ≤10^4copies/ml at delivery. No HBV flares or increase in Cr were seen. No birth defects were noted. All newborns’ parameters were appropriate for gestational age. Infants’ HBsAg and anti-HBs are being monitored. CONCLUSIONS TDF appears to be safe, effective and well tolerated in pregnant CHB patients. Prospective studies on its role in preventing perinatal transmission are warranted.

Table 1. The Characteristics of the Eight Pregnant Women with CHB who are Treated with Tenofovir and the Outcomes of Their Newborns

Case#

Age
(years)

GA at initiation
of Rx (weeks)

Rx (wks)
prior to
delivery

GA at delivery
(weeks)

HBV-DNA
prior to Rx (copies/ml)

HBV-DNA
at delivery
(copies/ml)

ALT prior to Rx (U/L)

ALT at
delivery
(U/L)

Birth weight
(gms)

Birth
defect

HBsAg
at 9 months

Anti-HBs at 9 months

1

28.3

29.7

11.4

41.1

>2,500,000,000

9196

73

29

3669

None

Neg

Neg

2

31.7

29.7

11.8

41.6

>2,500,000,000

4263

806

17

3121

None

Neg

positive

3

26.7

0

38.7

38.7

<160

<160

18

14

3333

None

Neg

N/A

4

24.7

32.9

7.3

41.1

804,171,909

40790

29

42

3425

None

pending

pending

5

22.4

29.7

11.8

41.6

>2,500,000,000

18417

23

24

3276

None

pending

pending

6

25.5

36

1.6

37.6

99,170,787

N/A

85

57

3127

None

pending

pending

7

28.2

30

7.1

37.1

525,067,058

*5,640,703

448

338

3401

None

pending

pending

8

30

30

10

40

164,000,000

2590

14

22

3557

None

pending

pending

GA = gestational age; *done one month prior to delivery; N/A = not available; pending=babies are <9 month-old


 

457. Application of Alpha-fetoprotein to Identify Patients Who Need Antiviral Treatment in HBeAg-negative Chronic Hepatitis B

Y. Huang; I. Lee; C. Chan; T. Huo; C. Su; H. Lin; S. Lee

Background: It is unclear whether clinical indication for antiviral treatment is in agreement with histological indication in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB). Factors associated with significant liver pathology in patients who do or do not satisfy the clinical indication for treatment have not been well evaluated before. This study aimed to clarify this relationship and identify factors associated with liver histology.

Methods: We investigated 152 consecutive, treatment-naďve, HBeAg-negative CHB patients who had undergone liver biopsies at a tertiary medical center in Taiwan. Clinical indication for treatment was defined as a serum alanine aminotransferase level more than twice the upper limit of normal and HBV DNA level >2,000 IU/mL. Factors associated with the histological indication (Ishak’s grade ≥7 and/or stage ≥2) were analyzed.

Results: The association between the clinical and the histological indications was significant (p=0.011). However, the agreement was poor (kappa value=0.197). In patients satisfying the clinical indication, age >52 years (odds ratio (OR)=2.669, p=0.042), serum alpha-fetoprotein (AFP) level >7 ng/mL (OR=7.070, p<0.001), and platelet count <130 ×109/L (OR=11.720, p=0.025) were identified to be independent factors associated with histological indication. In patients who did not satisfy the clinical indication, multivariate analysis revealed that only AFP level >7 ng/mL (OR=10.345, p=0.021) was independently associated with histological indication. Combining the clinical indication and/or AFP level >7 ng/mL to predict liver histology, the sensitivity and negative predictive value could improve from 86% to 94.4%, and 66.7% to 81%, respectively.

Conclusion: The currently used clinical indications for treatment can reflect the extent of histological change in the liver. Nevertheless, more than one-third of patients who did not satisfy the clinical indication needed antiviral treatment by histological findings. AFP level is associated with liver histology in HBeAg-negative CHB. Serum AFP level can serve as an adjuvant indicator to identify patients who need antiviral treatment.

 


 

787.Effectiveness of Hepatitis B Screening in Primary Care Setting

N. M. Loo; J. J. Larson; A. Wagie; A. Rahman; M. L. Wieland; R. Chaudhry; W. Kim

 

Background/Aims: According to the 2008 screening guideline by the Center for Disease Control and Prevention (CDC), all Americans with an anticipated hepatitis B virus (HBV) prevalence > 2% must be screened. This includes essentially all Asian Americans. Real-life data on HBV screening in the primary care setting are sparse. The aims of the study were (1) to determine the rate of HBV screening among Asian Americans at an academic adult (age >18) primary care internal medicine (PCIM) practice and (2) to describe the results of screening.

Methods: This study was conducted at the Division of PCIM of an academic medical center which consists of multidisciplinary teams to provide primary care to local residents. Of patients seen by PCIM providers over a 15-year period (1994-2009), adult Asian subjects were identified by ethnic group designations in the registration file as well as by common Asian last names used as search Boolean. In those subjects, all results of HBsAg, HBsAb, AST, and ALT were electronically extracted from the medical records.

Results: During the study period, there were 5,143 Asian American patients cared for by PCIM providers, out of whom 1,598 were tested for HBV. Thus, the HBV screening rate was only 31%. Of those screened, 8% (n=124) were positive for HBsAg. Of the remaining 1,474 that were HBsAg-, the majority (70%) was HBsAb+, whereas the remaining 30% showed no evidence of immunity against HBV. Overall, subjects that were screened were older compared to those who were not screened (mean: 33 years versus 25). Essentially all HBsAg+ patients were tested for AST and/or ALT, which were more frequently abnormal (62%) than in those who were HBsAg- (23%, p<0.01). Conversely, more than a third of HBsAg+ patients had normal AST/ALT, indicating, in support of the CDC guideline, that HBV screening in this population may not be guided by liver biochemical tests.

Conclusion: In this academic primary care internal medicine practice with a large Asian American patient population, HBV screening has been grossly inadequate. In those screened, the prevalence of HBV remained high. Despite publicity and awareness efforts, HBV remains one of the largest yet under-diagnosed health disparities in the US.

 

 

Screened
(n=1598)

Not Screened
(n=3545)

p

HBsAg+
(n=124)

HBsAg-
(n=1474)

HBsAb+
(n=1039)

HBsAb-
(n=331)

HBsAb N/A
(n=4)

Age

Mean ± SD

35.9 ± 15.7

32.4 ± 15.5

33.0 ± 16.8

28.1 ± 21.5

24.7 ± 22.2

<0.01

Gender

Male(%)

53%

37%

32%

25%

49%

<0.01

AST and/or ALT

Not done

1%

26%

27%

25%

64%

<0.01

Normal

37%

52%

48%

75%

29%

Abnormal

62%

22%

25%

0%

7%

 


 

788. Prevalence, Risk Factors, and Disease Knowledge of Chronic Hepatitis B Infection in Vietnamese Americans in California: A Cross-Sectional Study

N. B. Ha; H. N. Trinh; T. Leduc; C. Bui; T. T. Nguyen; A. Tran; N. B. Ha3; M. H. Nguyen

 

Purpose: Prevalence of CHB is high in Asian Americans. Our goal is to examine CHB prevalence in VA in California, an ethnic group with the highest HCC incidence even among Asians and to study general knowledge of CHB in this community.

Methods: We enrolled 698 VA who participated at 10 different HBV screening events from 3/09 to 5/10 in the San Francisco Bay area and Orange County, California. Screening subjects were recruited by Vietnamese radio programs and newspaper. HBV status was determined by hepatitis B surface antigen (HBsAg) and antibody (anti-HBs) (Quest Diagnostics Inc). Risk factors and general knowledge of CHB were examined by a prospective questionnaire. All patients gave written consent.

Results: All subjects were foreign-born with similar years in the U.S. (20±11 vs. 20±11, p=0.67). A total of 95 (13.6%) tested positive for HBsAg. The prevalence was significantly higher in males (16.4% vs. 11.3%, p=0.001), those between the ages of 30-39 (24.3% vs. 12.4%, p=0.006), those without healthcare coverage (18.4% vs. 9.2%, p=0.001), and those residing in Southern California (16.9% vs. 11.5%, p=0.045). There was a significantly higher proportion of those with a family history of HBV (55% vs. 25%, p<0.0001) and those with prior occupational exposure to blood (15.1% vs. 5.3%, p=0.002) in HBsAg-positive subjects. Upon adjusting for age, sex, and educational level, significant predictors for HBsAg positivity were lack of healthcare coverage (OR=2.2, p=0.005) and having a family history of CHB (OR=2.7, p<0.0001). Participants’ cultural beliefs and HBV treatment knowledge are summarized in Table 1.

Conclusion: The prevalence of HBV infection in foreign-born Vietnamese Americans residing in California is high, especially in those with age between 30-40 years, those with no healthcare coverage, and those with a family history of HBV. Patient knowledge of disease prevention and treatment is poor. More patient education and outreach is needed, especially in those without health care coverage.

 

http://aasld2010.abstractcentral.com/user_images/aasld2010/1909/896872/Table_1.jpg

 


 

1431Giving vaccine alone confers equal protection from chronic Hepatitis B infection to neonates born of HBsAg positive mothers as compared to vaccine plus HBIG: A large randomized controlled trial

C. Pande2; S. Patra; A. Kumar; S. K. Sarin

 

Background: Recombinant HBV vaccine and hepatitis B immunoglobulin (HBIG) given after delivery to the newborns of HBsAg positive mothers is the standard of care for prevention of HBV in babies. Some studies have however, shown that vaccine alone may be equally effective. The later approach, if well documented, would be more cost-effective.

Aim: We compared the efficacy of vaccine alone with that of vaccine plus HBIG to prevent HBV infection in babies and assessed the immune response.
Methods: Babies born of chronic HBV positive mothers were randomized after delivery to receive either: vaccine plus HBIG (group-A) or vaccine alone (group-B). Mothers on antivirals or with co-infections were excluded. The dose of HBIG was 0.5 mL, IM. The vaccine was given at birth, 6, 10 & 14 wks. Babies were assessed at minimum 18 wks for HBsAg, HBV-DNA & Anti-HBs. Primary endpoint (PEP) was remaining free of overt or occult HBV infection with adequate immune response (HBsAg neg, HBV-DNA neg, Anti-HBs ≥10 IU/mL). The babies not achieving PEP were categorized into those having overt HBV infection (HBsAg +ve); occult HBV infection (HBsAg -ve, HBV-DNA +ve); and no infection but poor immune response (HBsAg -ve, HBV-DNA -ve, Anti-HBs <10 IU/mL).

Results: 170 mothers (median HBV-DNA 26320 IU/mL) were enrolled. The newborns were randomized to gr-A (83) or gr-B (87). The mode of delivery was similar (88% vaginal) in both the groups. At minimum 18 wks, 32 (39%) babies in gr-A and 32 (37%) babies in gr-B achieved PEP (p=NS). Their median Anti-HBs was 200 (range 10-955) IU/mL, and it was similar in both groups. Among the babies who did not achieve PEP; 9 (5%) had overt HBV infection (gr-A 2, gr-B 7; p=NS); 81 (48%) had occult HBV infection (gr-A 42, gr-B 39; p=NS); and 16 (9%) had no HBV infection but poor immune response (gr-A 7, gr-B 9; p=NS). [Table]

Conclusion: Our study clearly documents that vaccine alone confers equal protection against HBV infection in newborns of chronic HBV infected mothers. However, in spite of this protection, a large number of babies in both the groups developed occult HBV infection, which may be due to intrauterine transmission of HBV infection. Trials using antivirals during pregnancy should be done to prevent this immunoprophylaxis failure.

HBV status of babies at minimum 18 weeks of age

At minimum 18 weeks

HBsAg neg
DNA neg
Anti-HBs Adequate

HBsAg neg
DNA neg
Anti-HBs Inadequate

HBsAg neg
DNA pos
Anti-HBs Adequate

HBsAg neg
DNA pos
Anti-HBs Inadequate

HBsAg pos
DNA neg
Anti-HBs Adequate

HBsAg pos
DNA neg
Anti-HBs Inadequate

HBsAg pos
DNA pos
Anti-HBs Adequate

HBsAg pos
DNA pos
Anti-HBs Inadequate

Primary endpoint

Poor immune response

Occult HBV infection

Overt HBV infection

Group A

32

7

29

13

0

0

0

2

Group B

32

9

26

13

0

0

0

7

P value

NS

NS

NS

NS

NS

NS

NS

NS

 


 

235. A Retrospective Study for Clinical Outcome of Caesarean Section on Perinatal Transmission of Hepatitis B Virus in Infants Born to HBeAg Positive Mothers with Chronic Hepatitis B (CHB)

H. Zou; Y. Chen; Z. Duan; H. Zhang; C. Pan

 

Aims and Background: Despite the use of HBIG and HB vaccination, HBV perinatal transmission (PT) occurs in ~10-30% of infants, born to highly viremic mothers. We evaluated if Caesarean Section would affect the clinical outcome of HBV immunoprophylaxis failure in the infants born to HBeAg + CHB mothers.

Methods: We retrospectively reviewed consecutive1027 patients followed from 1/2007 -3/2010 and identified 569 infants born to HBeAg+ mothers with vaginal delivery or caesarean section in our center. Mothers with co infection and use antiviral during pregnancy were excluded, Data collection included mothers’demography, HBV DNA, serology markers prior to the delivery, pregnancy complications and the mode of delivery( vaginal Vs elective/emergency C-section). The serum HBV-markers(HBsAg/anti-HBs,HBeAg/anti-HBe and anti-HBc) of the infants were assessed by microparticle enzyme immunoassy technique (Abbott kits,USA)at 1-5 months after the completion of HBV vaccination. HBV immunoprophylaxis failure defined by infants with hepatitis B surface antigen-seropositive at 7-12 months of age.

Results: All the infants had received 10μgHB vaccine and 200IU HBIG within 12 hours after birth, and then were given 200IU HBIG at 2 weeks of age and with 10μg HB vaccine at 1 and 6 months of age .Of 569 infants, 286 were vaginal delivery, 94 and 189 were emergency and elective caesarean respectively. All the HBV immunoprophylaxis failure infants born to mothers with serum HBV DNA high levels(>106copies/ml),but the maternal HBV DNA levels among the three groups had no significant difference (F=2.015,P=0.154). Perinatal transmission were found in 5.94%(17/286),8.51%(8/94) and 2.12%(4/189) among the infants born by vaginal delivery, emergency caesarean section and elective caesarean section, respectively(P=0.035). the difference of the HBV immunoprophylaxis failure between vaginal delivery group and elective caesarean section group had statistical significance(P=0.047 ) ,and the difference between the two caesarean section groups(emergency caesarean section versus elective caesarean section) had statistical significance(P=0.028 ),but the difference between vaginal delivery group and emergency caesarean section group had no significant difference (P=0.384).

Conclusion: In our study, compared with emergency caesarean section and vaginal delivery, elective caesarean section was the delivery mode resulting in lest perinatal transmission in the mothers with HBeAg+ and high level of HBV viremia. Our data support the use of elective C section in this population to reduce perinatal transmission. Prospective RTC is needed to confirm our findings.


 

LB-3. Controlled Attenuation Parameter: a novel FibroScan®-based tool to detect and quantify steatosis in chronic hepatitis B

A. F. Cardoso; M. C. Sasso; V. Miette; C. Fournier; L. Sandrin; M. Beaugrand; C. Douvin; V. de Ledinghen; R. Poupon; M. Ziol; P. Bedossa; P. Marcellin

 

Background and Aims: Steatosis may contribute to the progression of liver fibrosis in patients with chronic hepatitis B (CHB) but its evaluation by non invasive means is still a challenge. Since fat affects ultrasound propagation, a novel Controlled Attenuation Parameter (CAP) evaluated on the signals acquired by the FibroScan® has been developed. The aim of this work was to validate the CAP performance for detection and quantification of steatosis in CHB patients.

 

Methods: 133 consecutive CHB patients were prospectively included (62% men, age = 39±13 years). All patients underwent both liver biopsy (LB) and FibroScan® in 5 liver units within 60 days. The CAP was retrospectively evaluated on the raw data acquired by the FibroScan® and corresponds to the ultrasonic attenuation value in dB/m at the centre frequency of the probe (3.5 MHz). LBs were analysed by the same pathologist. Activity and fibrosis were staged according to the METAVIR classification. Steatosis was graded according to the following scale: S0: steatosis ≤10% of hepatocytes, S1: 11~33%, S2: 34~66%, S3: ≥67%. Proportions in each steatosis grade were: 77%, 11%, 9% and 3%, respectively. Performance was evaluated in terms of Area Under the Receiver Operating Characteristic (AUROC).

 

Results: In univariate analysis, liver stiffness (LS) was significantly (p<0.05) correlated to fibrosis (Spearman ρ=0.60), gender, activity, steatosis, age and sinusoidal fibrosis. By multivariate analysis, liver stiffness was associated only with liver fibrosis (OR=19.9 [6.65-59.8]). In univariate analysis, CAP was mainly correlated with steatosis (ρ=0.50, p<107) but also with BMI, presence of NASH and liver fibrosis. In multivariate analysis CAP was associated only with steatosis (OR=7e13 [4e8-1e19]). Performances in terms of AUROC (i) for LS were: 0.80 (0.72-0.89) for F≥2, 0.91 (0.84-0.99) for F≥3 and 0.91 (0.78-1.00) for F=4; (ii) for CAP: 0.82 (0.74-0.89) for S≥10% and 0.81 (0.72-0.90) for S≥30%. Similar results were obtained for both LS and CAP using jack-knife cross validation.

 

Conclusion: The CAP is an accurate new non invasive tool to detect and quantify steatosis in CHB patients.