Hepatitis B Treatment  11/14/2005 8:00 AM - 6:30 PM

 

 

Poster 960

Abstract ID: 66805

Category: J1O: Hepatitis B: Treatment

One-year treatment of entecavir results in reduction in intrahepatic covalently closed circular DNA level.

D. K. Wong, The University of Hong Kong, Hong Kong, Hong Kong, M. Yuen, The University of Hong Kong, Hong Kong, Hong Kong, V. Ngai, The University of Hong Kong, Hong Kong, Hong Kong, C. Kwok, The University of Hong Kong, Hong Kong, Hong Kong, C. Lai, The University of Hong Kong, Hong Kong, Hong Kong

 

Background:

Two phase 3, multicenter, double-blind trials on HBeAg-positive and HBeAg-negative patients demonstrate that, compared with lamivudine, entecavir is superior in inducing histologic improvement, serum HBV DNA suppression and transaminase normalization. Since intrahepatic HBV DNA and covalently closed circular (ccc) DNA are important for control of viral replication, the efficacy of entecavir vs. lamivudine in achieving suppression of these entities should be studied.

 

Methods and Patients:

The patients involved in this study were recruited from patients

participating in the two phase 3 entecavir trials at our center in Hong Kong. Forty chronic hepatitis B patients (14 HBeAg-positive and 26 anti-HBe-positive) were randomized to receive either entecavir (0.5 mg once daily) or lamivudine (100 mg once daily). Paired liver biopsy and serum samples were collected both at baseline and week 48 of treatment. Total intrahepatic HBV DNA and cccDNA were measured by the Invader® assay.i Serum HBV DNA was measured by the COBAS Amplicor HBV Monitor Test.

 

Results:

This is an interim report for the 14 HBeAg-positive patients. (The findings of the 26 anti-HBe-positive patients will be analyzed later.) For the 14 HBeAg-positive patients, 7 were randomized to receive entecavir, while the rest received lamivudine.

 

 

Conclusion:

The preliminary results of this study showed that 1 year of entecavir was

superior to lamivudine in suppression of total intrahepatic and ccc DNA in liver biopsies. The addition of the data from the 26 anti-HBe patients may confirm these results.

 

i Wong et al, Hepatology (2004) 40:727-737.

 


Poster 961

Abstract ID: 61589

Category: J1O: Hepatitis B: Treatment

 

High prevalence of significant fibrosis in patients with immunotolerance to chronichepatitis B infection.

C. Wang, University of Washington, Seattle, WA, H. Deubner, University of Washington, Seattle, WA, M. Shuhart, University of Washington, Seattle, WA, J. N. Manansala, University of Washington, Seattle, WA, L. Corey, University of Washington, Seattle, WA, K. V. Kowdley, University of Washington, Seattle, WA

 

OBJECTIVE:

To determine the extent of liver disease in patients with chronic hepatitis

B and normal serum ALT.

 

METHODS:

Patients were eligible with HBeAg positive CHB, serum HBV DNA > 106

copies/mL, and 2 ALT measurements within normal limits in the 2 years prior to liver biopsy. The mean value of the 2 ALT measurements was calculated. Liver biopsies were scored using the Batts and Ludwig scoring method with a 4-point scoring scale for inflammation and fibrosis.

 

RESULTS:

9 men and 4 women were enrolled. Median age was 26 (range 19-46). All

had endemically-acquired infection by history. Nine patients were born in China, 2 in Vietnam, 1 in Korea, and 1 in Cambodia. Median ALT was 28 U/L (range 13-77) and median serum HBV DNA was 5.1 x 107 (range 4.5 x 104 – 3.4 x108). On biopsy, 10 of 13 (77%) had evidence of fibrosis: None had cirrhosis or septal fibrosis; 6 of 13 (46%) had periportal fibrosis or rare portal-portal septa, resulting in fibrosis scores of 2, and 4 of 13 (31%) patients had portal fibrosis with at most mild periportal fibrosis, yielding fibrosis scores of 1 or 1-2. Mean liver biopsy grade was 1.23 (range 1-2) and mean stage was 1.30 (range 0-2). The R-square coefficient for a correlation between ALT and liver biopsy stage was .07, indicating that ALT was poorly correlated with liver biopsy fibrosis score (see graph). Four of 5 patients with a liver fibrosis stage of 2 had serum ALT < 30 IU/L.

 

CONCLUSIONS:

A high proportion of Asian immunotolerant HBeAg positive patients

have hepatic fibrosis on biopsy. Serum ALT level may not accurately predict histologic stage in these patients. These preliminary findings support recent recommendations to perform liver biopsy to guide treatment decisions in HBeAg positive patients even if serum ALT is normal. Supported by a research grant from Gilead Sciences (Wang) and by K24 DK02957 (Kowdley).

 


Poster 962

Abstract ID: 67445

Category: J1O: Hepatitis B: Treatment

Entecavir Two Year Resistance Update: No Resistance Observed in Nucleoside Naïve Patients and Low Frequency Resistance Emergence in Lamivudine Refractory Patients.

 

R. Colonno, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT, R. Rose, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT, S. Levine, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT, J. Baldick, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT, K. Pokornowski, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT, M. Plym, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT, C. Yu, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT, C. Mazzucco, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT, J. Fang, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT, M. Hsu, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT, A. Walsh, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT, B. Eggers, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CO, A. Thiry, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT, D. Tenney, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT

 

Background:

Entecavir (ETV) is a potent inhibitor of hepatitis B virus (HBV) with proven

clinical efficacy. High level ETV resistance (ETVr) requires pre-existing lamivudine (LVD)- resistance (LVDr) substitutions and additional changes at HBV RT residues rtT184, rtS202 or rtM250. Patients receiving ETV for 1 year showed no evidence of emerging ETVr in nucleoside naïve patients and virologic rebounds due to ETVr in only 1% of LVD refractory patients.

 

Methods:

Virologic rebounds (confirmed ³1 log increase from nadir by PCR) observed in patients from studies AI463-022 & AI463-027 (nucleoside naïve), AI463-014 & AI463-026 (LVD refractory), and AI463-901 (extended treatment) were analyzed for emerging ETVr. Genotypic analysis compared patient HBV RT sequences with those at study entry and with WT HBV. Phenotypes of emerging substitutions were determined using antiviral assays measuring HBV DNA yields from HepG2 cells transfected with plasmids expressing patient RT sequences.

 

Results:

Among >650 nucleoside naïve, HBeAg pos & HBeAg neg patients completing at least 24 wk of ETV therapy, 93% achieved HBV DNA reductions to <300 copies/ml. Over 200 patients completed ≥ 90 wks of therapy. Genotypic analysis of the 18 observed virologic rebounds (2 year treatment period) failed to show any evidence of emerging ETVr substitutions, with population phenotypes at the time of rebound essentially unchanged from baseline or WT. Four additional patients failing to achieve HBV DNA reductions <100,000 copies/ml on ETV also had HBV fully susceptible to ETV. Therefore, there is no evidence of ETVr emerging in nucleoside naïve patients treated with ETV. Virologic rebounds due to resistance were observed in 10% of LVD refractory patients treated with ETV for 2 years. In all cases, ETVr variants had pre-existing LVDr substitutions and emerging changes at residues rtT184 and/or rtS202. Of the 12 patients exhibiting a rebound, 2 had been on suboptimal ETV therapy (0.5 mg) and 3 others received ETV/LVD combination therapy. Subsequent analysis of baseline viral samples demonstrated selection of ETVr substitutions during prior LVD treatment.

 

Summary:

There was no evidence of emerging ETVr in nucleoside treatment naïve subjects undergoing 2 years of ETV therapy, coinciding with substantial suppression of viral DNA levels. Among LVD refractory patients,

10% experienced virologic rebounds due to emerging ETVr by the 2nd yr of therapy. Phenotypic ETVr required the presence of pre-existing LVDr substitutions, which can be selected with exposure to LVD. Therefore, LVD treatment results in frequent emergence of LVDr and may negatively impact future HBV treatment options.

 

 


Poster 963

Abstract ID: 61542

Category: J1O: Hepatitis B: Treatment

 

REAPPEARANCE OF WILD-TYPE HEPATITIS B VIRUS DURING ADEFOVIR MONOTHERAPY FOR PATIENTS WITH LAMIVUDINE RESISTANCE.

 

H. Hann, Jefferson Medical College of Thomas Jefferson University, Philadelphia, PA, J. L. Platt, Questdiagnostics Nichols Institute, San Juan Capistrano, CA Disclosures: Hie-Won Hann - Speakers Bureau(s):GlaxoSmtihkline Gilead Sciences,Inc., Consultant for: GlaxoSmtihkline Gilead Sciences,Inc., Grant / Research Support by: GlaxoSmtihkline Gilead Sciences,Inc.; Jamie Platt

 

Background?:

No relationships to disclose Adefovir Dipivoxil (ADV) is effective for both wild type (WT) and YMDD variant (YMDDv) HBV which is resistant to Lamivudine (LAM). While the majority of LAM resistant patients respond well to ADV, some patients show slow/poor antiviral responses and even have an increase in HBV DNA levels while on ADV therapy. We investigated if this poor/worsening response was the result of ADV resistance.

 

Materials and Methods:

133 patients after LAM resistance, were treated with ADV for varying periods. Good responses to ADV were seen in 87/133 patients while 46 showed slow /poor virologic responses although biochemical improvement was noted. Pre-ADV and on-ADV therapy serum samples were available from 13/46 patients. For the remaining 33, Pre-ADV and on-ADV specimens were unavailable since HBV DNA levels were measured elsewhere. To understand the nature of slow/poor responses, HBV polymerase genotypes were investigated using an YMDD PCR-RFLP assay and sequencing of the HBV pol gene. The PCR-RFLP assay examined the presence of mutations at 2 sites (rtL180 and rtM204)). The sequencing assay assessed mutations at codons, rt180, rt181, rt204, and rt236. Analytes of the sequencing assay included genotype and PMUL and PMUA, polymerase mutants for LAM and for ADV espectively. These 13 patients were Asian Americans, aged 19-67 years, 9 males and 4 females. Treatment with LAM lasted 12-60 months until viral breakthroughs were noted. Median pre-ADV HBV DNA levels were 5 x 106 copies/mL (range 1.2 x 106-2.5 x 108) while median on-ADV HBV DNA levels were 9 x 106 (range 1.7x 104 - 8 x 106). The median duration of ADV therapy for 13 patients was 13 months (range 6-30).

 

Results:

Polymerase genotypes were examined on 10 pre-ADV and 13 on-ADV samples, all of HBV genotype C. Among 10 pre-ADV samples, 8 contained YMDDv HBV and 5/8 also contained a small portion of mixed population; surprisingly 2/10 had mostly WT-HBV although they had viral breakthrough. Following ADV therapy (6-30 months), 10/13 patients had a return of WT-HBV; 3 of these10 contained a small portion of YMDD and 3/13 had YMDDv-HBV. One patient with 18months on ADV, showed WTHBV return mixed with ADV resistant HBV (N236T). It appeared that YMDDv-HBV were suppressed by ADV but in some WT-HBV was strong enough to return even under ADV effect.

 

Conclusion:

These results suggest that in patients with LAM resistance who did not

respond well to ADV, the majority of poor responses were due to the return of WT HBV and not due to ADV resistance. Continuation of LAM in combination with ADV, at least for a period of time, may therefore be the preferred management in patients with LAM

resistance.

 


Poster 964

Abstract ID: 63945

Category: J1O: Hepatitis B: Treatment

 

First line combination therapy of chronic hepatitis B with tenofovir plus lamivudine versus sequential therapy with tenofovir monotherapy after lamivudine failure.

 

S. Mauss, Center for HIV and Hepatogastroenterology, Duesseldorf, AE, Germany, M. Nelson, Kobler Clinic, Chelsea, AE, United Kingdom (Great Britain), T. Lutz, HIVPractice,Frankfurt, AE, Germany, J. Sheldon, Hospital Carlos III, Madrid, AE, Spain, R. Bruno, San Matteo Hospital, Pavia, AE, Italy, F. van Boemmel, Charite, Berlin, AE, Germany, J. Rockstroh, Med. Klinik I, Bonn, AE, Germany, E. Wolf, MUC Research, Muenchen, AE, Germany, A. Stoehr, Infektiologie, Hamburg, AE, Germany, V. Soriano, Hospital Carlos III, Madrid, AE, Spain, F. Berger, Center for HIV and Hepatogastroenterology, Duesseldorf, AE, Germany, T. Berg, Charite, Berlin, AE, Germany, A. Carlebach, HIV-practice, Frankfurt, AE, Germany, C. Schwarze-Zander, Med. Klinik I, Bonn, AE, Germany, T. Wunsche, Charite, Berlin, AE, Germany, H. Jaeger, MUC Research, Muenchen, AE, Germany, G. Schmutz, Center for HIV and Hepatogastroenterology, Duesseldorf, AE, Germany

 

Therapy with HBV-polymerase inhibitors is based on long term suppression of viral replication. At present sequential monotherapy is standard of care, however combination therapy with at least two HBV-polymerase inhibitors is considered a promising alternative approach. It is unknown to date whether combination therapy with lamivudine plus tenofovir could be superior to sequential therapy with tenofovir after the occurrence of lamivudine resistance for chronic hepatitis B treatment in coinfected patients.

 

We conducted a multicenter, 1:2 matched pair analysis comparing patients with HBV/HIV-coinfection starting an antiretroviral regimen including tenofovir plus lamivudine with patients who had highly replicative, lamivudine resistant hepatitis B (> 100,000 copies/mL) and started therapy with tenofovir as the only active HBV-polymerase inhibitor. Resistance to lamivudine was demonstrated by HBVgenotyping. The lower limit of detection of HBV-DNA was 1000 copies/mL. At baseline patients starting with tenofovir plus lamivudine (n=23) had a median HBV-DNA of 59,000,000 copies/mL compared to 120,000,000 copies/mL in the tenofovir arm (n=46) (p=0.75). After 3 months on treatment, median HBV-DNA decreased to 138,450 copies/mL in the tenofovir plus lamivudine group compared to 27,950 copies/mL in the tenofovir group (p=0.26). After 12 months and 24 months median HBV-DNA was <1000 copies/mL in patients taking either tenofovir plus lamivudine or tenofovir alone (p=0.46, p=0.24). A sustained undetectable HBV-DNA <1000 copies/mL was achieved in 19/23 (83%) patients on tenofovir plus lamivudine and in 38/46 (83%) patients on tenofovir (p = 1.00). A loss of HBe-antigen was observed in 7/22 HBe-antigen positive patients on tenofovir plus lamivudine and in 11/44 patients on tenofovir (p=0.57). HBsantigen loss was found in 1/23 and 2/46 patients, respectively.

 

In conclusion in this cohort of HBV/HIV-coinfected individuals, full virologic HBVDNA suppression was achieved in the majority of patients independent of treatment allocation. In addition loss of HBe- and HBs-antigen was not different in both arms. Over a median observational period of 24 months tenofovir alone was as effective as tenofovir plus lamivudine in HBV/HIV-coinfected patients with highly replicative chronic hepatitis B.


Poster 965

Abstract ID: 64736

Category: J1O: Hepatitis B: Treatment

 

Hepatitis B Virus with rtL80V/I Mutation Associates with Poor Response to Adefovir Dipivoxil Therapy.

Y. Lee, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea,Republic of, Y. Chung, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea, Republic of, S. Ryu, University of Inje College of Medicine, Seoul Paik Hospital, Seoul, Korea, Republic of, J. A. Kim, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea, Republic of, M. Choi, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea, Republic of, S. Jung, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea, Republic of, S. Kim, Korea Veterans' Hospital, Seoul, Korea, Republic of, J. Shin, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, Korea, Republic of, N. Park, University of Ulsan College of Medicine, Ulsan University Hospital, Ulsan, Korea, Republic of, K. Kim, University of Ulsan College of Medicine, Seoul, Korea, Republic of,  Y. Lim, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea, Republic of, Y. Lee, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea, Republic of, D. Suh, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea, Republic of

 

Background/Aims:

Resistance occurs frequently during long-term lamivudine (LAM)

therapy, mostly associated with YMDD mutants (rtM204V/I). Besides rtM204V/I mutation, rtL80V/I and rtL180M mutations have been reported to be associated commonly in patients with LAM resistance. In this study, we intended to examine the effects of a certain type of mutations at polymerase domain of Hepatitis B Virus (HBV) on the antiviral efficacy following adefovir dipivoxil (ADV) therapy in patients with LAM-resistant chronic hepatitis B (CHB).

 

Methods:

One hundred and nineteen patients with LAM-resistant CHB were treated with ADV at a dose of 10mg daily for >12 weeks. The entire polymerase domain of HBV in the sera obtained just before ADV therapy was sequenced using direct sequencing method. Genotypes of HBV were determined by restriction fragment length polymorphism (RFLP) following polymerase chain reaction (PCR). Serum HBV-DNA levels were quantified by real-time PCR method. The antiviral responses, which were evaluated by the change of serum alanine aminotransferase (ALT) and HBV-DNA levels at 12 weeks following ADV therapy, were compared in relation to the preexisting mutations at HBV polymerase domain.

 

Results:

All of 119 subjects revealed to have HBV of genotype C. Out of them, 105 patients (88%) had YMDD mutations; 70 (67%) rtM204I, 28 (27%) rtM204V variant and 7 (6%) both. In addition to mutations at YMDD motif, rtL80V/I mutation was found in 70 (59%) and rtL180M in 72 (61%). The rtM204I variant was accompanied by rtL80V/I (p<0.001) and rtM204V was associated with rtL180M mutation more frequently (p<0.005). Median serum HBV DNA level at baseline was 7.82 log(10) copies/mL and the median change of serum HBV DNA levels from baseline were -2.40 log(10) copies/mL at week 12. The rate of serum ALT normalization was 42% following 12 weeks of ADV therapy. The rate of serum ALT normalization (45% vs. 35%; p>0.05) and the changes of serum HBV DNA level (median, -2.43 vs. -2.93 log(10) copies/mL; p>0.05) at 12 weeks following ADV therapy were not significantly different between patients with rtM204I and those with rtM204V variant. Very interestingly, the change of serum HBV-DNA levels was significantly greater in patients with rtL80V/I mutation compared with those without it. (Median, -2.10 vs. -2.83 log(10) copies/mL; p<0.05) However, the presence of rtL180M mutation did not affect the change of serum HBV-DNA level following ADV therapy. (Median, -2.53 vs. -2.20 log(10) copies/mL; p>0.05)

 

Conclusions:

It is suggested that rtL80V/I variants of HBV may associate with poor antiviral response to ADV therapy.


Poster 966

Abstract ID: 67006

Category: J1O: Hepatitis B: Treatment

 

Delayed viral decline is associated with highest sustained response rate during PEGinterferon treatment for HBeAg-positive chronic hepatitis B.

M. J. ter Borg, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands, H. J. Flink, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands, H. L. Janssen, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands, B. E. Hansen, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands, R. A. de Man, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands, S. W. Schalm, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands

 

Little is known about the patterns of HBV-DNA decline and their relation to response for chronic hepatitis B patients treated with alpha-interferon. To investigate different patterns in viral decline during treatment and follow-up, we analyzed 254 HBeAg-positive chronic hepatitis B patients treated with pegylated interferon alpha-2b (PEG-IFN) 100 μg/week for 52 weeks with or without lamivudine 100 mg/day. PEG-IFN dose was reduced to 50 μg/week after 32 weeks of treatment. Endpoints were HBeAg-negativity, HBV-DNA < 400 copies/ml and HBsAg negativity 26 weeks after therapy.

 

The total trial population consisted of 266 patients. From 12 patients, insufficient HBV-DNA measurements were available to assess HBV-DNA patterns.

 

In the patients treated with PEG-IFN monotherapy (n=124), 5 different patterns of viral decline could be recognized: a. early decline of at least 1 log during week 0-4 of therapy; b. delayed decline of at least 2 log from baseline HBV-DNA during week 4-32; c. late decline of at least 2 log between week 32 and 52; d. post-treatment decline of 2 log from baseline HBV-DNA after week 52; e. no substantial decline at any time point. Endpoints for these different patterns are shown in the table. A delayed rather than early viral decline was associated with highest response rates at the end of follow-up (HBeAg response 63% vs. 52%, respectively).

 

Patients with a late or post treatment decline pattern had lower response rates (HBeAg response 31% and 27%, respectively).

 

Interestingly, 7 out of 8 patients (88%) with HBsAg loss and all patients with HBV-DNA <400 copies/ml at the end of follow-up exhibited a delayed HBV-DNA decline. In the patients treated with combination therapy (n=130), a similar biphasic pattern of decline in HBV-DNA was seen in nearly all patients with a fast decline in the first four weeks and a slower decline thereafter.

 

In conclusion, different patterns in HBV-DNA decline were found during PEG-IFN monotherapy. A delayed rather than early viral decline was associated with the highest response rate. This underlines the important immunomodulatory effect of PEG-IFN and the limited predictive value of early viral kinetics in PEG-IFN therapy for HBeAg-positive chronic hepatitis B.

 

PEG Monotherapy


Poster 967

Abstract ID: 67180

Category: J1O: Hepatitis B: Treatment

 

Effect of ethnicity, genotype, gender, age and bodyweight on sustained response in a large, randomised study of peginterferon alfa-2a (40KD) (PEGASYS®) +/- lamivudine versus lamivudine alone for HBeAg-positive chronic hepatitis B.

 

W. Chow, Singapore General Hospital, Singapore, Singapore, M. Manns, Medizinischen Hochschule, Hannover, Germany, S. Paik, Samsung Medical Center, Seoul, Korea, Republic of, T. Berg, Charité Universitätsmedizin Berlin, Berlin, Germany, T. Piratvisuth, Songklanakarin Hospital, Songkla, Thailand, W. Chang, Kaohsiung Medical University Hospital, Kaohsiung, Taiwan, G. K. Lau, Queen Mary Hospital, Hong Kong, China, P. Marcellin, Hôpital Beaujon, Clichy, France, E. Gane, Middlemore Hospital, Otahuhu, New Zealand, N. Pluck, Roche, Welwyn, United Kingdom (Great Britain)

 

Background:

Recent data have shown that baseline ALT, HBV DNA and HBeAg levels are strongly associated with sustained HBeAg seroconversion in patients treated with peginterferon alfa-2a and/or lamivudine for chronic hepatitis B (CHB).

 

Objective:

To investigate the effect of ethnicity, genotype, gender, age and bodyweight on response in patients receiving peginterferon alfa-2a ± lamivudine or lamivudine alone for CHB.

 

Methods:

HBeAg-positive patients (n=814) received 48 weeks of 180mg peginterferon alfa-2a (PEGASYS®) once-weekly (qw) + placebo daily (qd), 180mg peginterferon alfa-2a qw + 100mg lamivudine qd, or 100mg lamivudine qd. For this analysis, response was defined as HBeAg seroconversion 24 weeks post-treatment (week 72). Baseline variables included in multivariate (MV) analysis: ethnicity, genotype, gender, age, bodyweight, ALT, HBV DNA and HBeAg.

 

Results:

Most patients were of Asian origin (87%) and infected with HBV genotype C (59%) or B (28%). Response in Asian patients closely reflected overall results. Among Caucasians (n=79), the highest response rates were seen with peginterferon alfa-2a alone (50% [12/24]). Response rates were also high in patients with genotype A receiving peginterferon alfa-2a alone (52% [12/23]). Patients infected with genotype C or B had the same response to peginterferon alfa-2a alone (31% vs 30%). Response rates were higher in females than males in all treatment arms; 35% vs 31%, 37% vs 25%, and 26% vs 17% with peginterferon alfa-2a alone, combination therapy, and lamivudine alone. There was no clear relationship between patient age and response, regardless of treatment. In the two peginterferon alfa-2a arms, response rates were comparable in patients weighing ≤ 65 kg and >65 kg. Response rates in lamivudine-treated patients weighing ≤ 65 kg were slightly higher than in those >65 kg (22% vs16%). In MV analyses across all treatment arms, ethnicity, genotype, age and bodyweight were not significant predictors of response (P=0.757, ≥ 0.21, 0.716 and 0.790); gender was of borderline significance (P=0.077).

 

Conclusion:

Genotype was not a significant predictor of response by MV analysis. The rate of response was the same for patients with genotype B or C, the predominant genotypes in the study. This contrasts with previous studies of interferon-based therapy. Genotype A patients, who represented a minority of patients in our study, treated with peginterferon alfa-2a alone had the

highest rate of HBeAg seroconversion at week 72. Gender had a marginal effect on response and this was mostly seen with combination therapy and lamivudine alone. Patient bodyweight had no effect on response to peginterferon alfa-2a.


Poster 969

Abstract ID: 62802

Category: J1O: Hepatitis B: Treatment

 

A sensitive line probe assay to simultaneously detect Lamivudine and Adefovir resistant mutations.

 

M. T. Hussain, University of Michigan, Ann Arbor, MI, S. Fung, University of Michigan, Ann Arbor, MI, J. Doutreloigne, Innogenetics, Inc, Ghent, Belgium, E. Sablon, Innogenetics, Inc, Ghent, Belgium, A. S. Lok, University of Michigan, Ann Arbor, MI

 

Background:

Antiviral-resistant hepatitis B virus (HBV) mutations have become an increasing problem in the treatment of chronic hepatitis B. Development of rapid, simple, and sensitive assays that can detect antiviral-resistant HBV as they emerge may help improve patient management.

 

Aim:

To assess the accuracy of a line probe assay, INNOLiPA HBV DRv2 (Innogenetics NV, Ghent, Belgium), by comparing results of this assay with those of direct sequencing and to determine if DRv2 can detect antiviral-resistant HBV earlier.

 

Patients and Methods:

A total of 101 serum samples from 56 chronic HBV patients receiving Lamivudine and/or Adefovir were analyzed for the presence of antiviral-resistant mutations using both DRv2 and sequencing. The DRv2 involves reverse hybridization of PCR products onto strips coated with oligonucleotide probes. These probes can differentiate wild type vs. mutant sequences at codons 80, 173, 180 and 204 and at codons 181 and 236 of the HBV reverse transcriptase/polymerase, that are known to be associated with lamivudine and adefovir resistance, respectively. 

 

Results:

Complete concordance was observed for 573 (95%) of 606 analyzed codons (95% of samples analyzed for codon 80, 98% for codon 173, 87% for codon 180, 100% for codon 181, 90% for codon 204 and 97% for codon 236). Among the 33 discordant cases, DRv2 detected mutants while sequencing revealed wild type virus in 31 cases; sequencing of follow-up samples confirmed the presence of mutant sequences in all 27 cases with follow-up samples. In these 27 cases, DRv2 detected mutants earlier than sequencing by a mean of 6 months (range 2-11). In only 1 case sequencing detected mutant while DRv2 detected wild type virus; DRv2 of follow-up samples confirmed the presence of mutant sequence. Complete discordance was observed in only 1 case, where DRv2 showed wild type at position 80, whereas sequencing showed a STOP codon. The DRv2 assay is more rapid and amenable to high throughput compared to sequencing but it can only detect the presence of known drug-resistant mutations.

 

Conclusions:

Our study demonstrates that the INNO-LiPA HBV DRv2 can simultaneously detect the presence of Lamivudine and Adefovir-resistant mutations. The results of DRv2 show a high degree of concordance with sequencing and can detect mutants earlier, thus permitting prompt initiation of additional therapy.

 


Poster 970

Abstract ID: 64162

Category: J1O: Hepatitis B: Treatment

RECOGNITION OF MUTATED (G145R) HBsAg BY HEPEX-B (2 HUMAN MONOCLONAL ANTIBODIES) OFFERS A POTENTIAL TREATMENT FOR HBV IMMUNE ESCAPE PATIENTS.

R. Eren, XTL Biopharmaceuticals Ltd., Rehovot, Israel, D. Landstein, XTL Biopharmaceuticals Ltd., Rehovot, Israel, R. Kovjazin, XTL Biopharmaceuticals Ltd., Rehovot, Israel, O. Nussbaum, XTL Biopharmaceuticals Ltd., Rehovot, Israel, J. Ben- Porath, XTL Biopharmaceuticals Ltd., Rehovot, Israel, S. Shahar, XTL Biopharmaceuticals Ltd., Rehovot, Israel, T. Waisman, XTL Biopharmaceuticals Ltd., Rehovot, Israel, N. Haberman, XTL Biopharmaceuticals Ltd., Rehovot, Israel, D. Terkieltaub, XTL Biopharmaceuticals Ltd., Rehovot, Israel, S. Dagan, XTL Biopharmaceuticals Ltd., Rehovot, Israel

 

Introduction:

Long-term immunoprophylaxis with hepatitis B immunoglobulin (HBIG) is used for the prevention of recurrent hepatitis B virus (HBV) infection after liver transplantation. The most prevalent immune escape mutation from HBIG treatment is at position 145 (G145R) on the hepatitis B surface antigen (HBsAg). This mutation abolishes the neutralizing effect of HBIG, implying that neutralizing antibodies are directed to this region.

 

Purpose:

To test whether neutralizing monoclonal antibodies directed to different epitopes on HBsAg could be effective in decreasing selection pressure for the HBIGresistance mutation.

 

Methods:

HepeX-B consists of two human monoclonal antibodies (HumAbs): HBVAB17 that recognizes a conformational epitope and HBV-AB19 that recognizes a linear epitope on HBsAg. Epitope mapping was performed by reacting antibodies to overlapping 15-mer linear antigen-derived peptides. HBsAg harboring the G145R mutation was constructed and expressed in a baculovirus expression system.

 

Results:

The epitope to which HBV-AB19 binds was fully mapped. The core sequence of the epitope is CTKPTDGNC at positions 139-147. The cysteines surrounding this epitope are involved in binding, indicating that this is not a standard linear epitope. Changes at positions 141-145 resulted in a strong decrease of binding. The conformational epitope to which HBV-AB17 binds could not be mapped by this method. Western blot analysis showed that HBV-AB17 could recognize the wild type (wt) as well as the G145R mutated HBsAg whereas HBV-AB19 recognized only the wt antigen. Furthermore, FACS analysis of Hi-5 cells expressing the mutated HBsAg on their membrane demonstrated that only HBV-AB17 could bind to these cells. Cells expressing the wt HBsAg were recognized by both HumAbs. The neutralizing activity of HBV-AB17 and HBV-AB19 against virus harboring the G145R mutated HBsAg is being studied in a mouse model for HBV infection.

 

Conclusions:

The two HumAbs that comprise HepeX-B are directed against different epitopes on HBsAg. HBV-AB19 binds to a linear epitope that includes the sensitive site for the G145R immune escape mutation. Hence, HBV-AB19 did not recognize the G145R mutated HBsAg. The mutation at position 145 did not abolish the binding of HBV-AB17 to HBsAg. The binding to distinct epitopes on HBsAg and the fact that one of the HumAbs is not affected by the G145R mutation lower the probability of emergence of escape mutants due to HepeX-B therapy. Thus, HepeX-B could offer an alternative therapy to liver transplant patients who had escaped HBIG monotherapy.


Poster 971

Abstract ID: 65234

Category: J1O: Hepatitis B: Treatment

 

Impact of IFN on progression of liver disease in Hepatitis B “e” antigen (HBeAg) negative chronic hepatitis B (CHB) patients: a long term Italian multicenter A.I.S.F.study.

 

F. Oliveri, Uo Gastroenterologia e Epatologia, Az. Osp. Univ. Pisana, Pisa, Italy, M. Puoti, Clinica Malattie Infettive e Tropicali, AO Spedali Civili, Brescia, Italy, T. Santantonio, Clinica Malattie Infettive, Az. Osp. Policlinico Consorziale, Bari, Italy, P. Lampertico, Divisione di Epatologia, IRCCS Ospedale Maggiore Policlinico, Milano, Italy, G. Colloredo, Divisione Medicina, Policlinico San Pietro, Ponte San Pietro, Italy, G. Niro, Gastroenterologia Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy, G. Fattovich, Dipartimento di Gastroenterologia, Università di Verona, Verona, Italy, F. Morisco, Gastroenterologia, Dip. Scienza d. Alimenti, Univ. Napoli Federico II, Napoli, Italy, A. Marrone, Div. Medicina Interna ed Epatologia, Seconda Università di Napoli, Napoli, Italy, P. Costa, Divisione Malattie Infettive Ospedale "C. Poma", Mantova, Italy, M. Felder, Divisione di Gastroenterologia, Ospedale Centrale Bolzano, Bolzano, Italy, P. Cacciatore, Clinica Malattie Infettive, Università di Chieti, Chieti, Italy, A. Smedile, UO Gastroenterologia Ospedaliera, Osp S. Giovanni Battista "Molinette", Torino, Italy, M. R. Brunetto, Uo Gastroenterologia e Epatologia, Az Osp Univ. Pisana, Pisa, Italy

 

HBeAg negative CHB is a progressive disease with low spontaneous and drug induced resolution rates. We evaluated the Sustained Response (SR) rate to IFN and factors influencing both treatment and disease outcome in a large series of patients (pts).

 

We followed up prospectively 558 anti-HBe positive CHB pts (451 males and 107 females; mean age 41 y, range 12-66 y) from 13 Italian Centers. Patients were treated for at least 3 months (m) with alpha-IFN from 1985 to 2001: 437 (78%) pts experienced single IFN courses whereas 121 (22%) 2 or more courses. Mean follow up after end of treatment (EOT) 54 m (range 1-205 m). SR = normal ALT, HBV-DNA <10 pg/ml and IgM anti-HBc <0.2 IMx index for at least 12 m after EOT.

 

At baseline chronic hepatitis with cirrhosis was present in 150 (27%) pts, moderatesevere steatosis in 49 (9%). At first IFN treatment 319 (57,2%) pts achieved EOT response: 96 (17,2%) maintained response (SR), and 223 (40%) relapsed. The relapse occurred within 12 m after EOT in 183 (32,8%) pts, within 24 m in 24 (4,3%) pts, within 36 m in 10 (1,8%) pts and thereafter (till to 84 m) in the remaining 6. After relapse 14 (2,5%) pts developed persistently normal ALT and undetectable HBV-DNA (Persistent Remission after Relapse, PRR). The Long Term Response (LTR=SR+PRR) rate in naives (19,7%) was the same of that in retreated (19,8%) pts. At multivariate analysis (MVA) age younger than 40 y (p=0,011) and duration of treatment (p<0,000001) were independently associated with SR, that was observed in 6,8%, 15.9% and 30.7% of pts treated up to 6 m, 7-12 m and more than 1 y (mean 19 m) respectively. HBsAg clearance was observed in 47 (35%) of 134 LTR (anti-HBs seroconversion in 32). During follow up 43 (7,7%) pts developed End Stage Complications (ESC: jaundice, ascites, var.bleeding, encephalopathy) and/or Hepatocellular Carcinoma (HCC in 27, 4,8%). Four pts were transplanted because of HCC and 1 for terminal cirrhosis (t.c.); 14 (2,5%) died 15-100 m after EOT because of HCC (10), t.c.(3) and extraepatic tumor (1). Among 43 ESC pts 31 had baseline cirrhosis, only 1 was female. At MVA female sex, younger age, absent-mild steatosis, absence of cirrhosis and LTR to IFN were significantly and independently associated with a better outcome. In baseline cirrhotic pts, at MVA LTR was significantly associated with the absence of ESC except HCC.

 

Conclusions:

In HBeAg negative CHB standard IFN therapy warrants an overall LTR of 20%; a correct identification of SR requires a long term follow-up as relapse may occur late. LTR is associated with a better clinical outcome: in patients with cirrhosis IFN may avoid clinical decompensation, but not HCC.


Poster 973

Abstract ID: 66027

Category: J1O: Hepatitis B: Treatment

 

Unsuitability of Kaplan-Meier Estimates for determining long-term response rates in patients receiving treatment for chronic hepatitis B.

 

G. Cooksley, Royal Brisbane Hospital, Brisbane, Australia, G. K. Lau, Queen Mary

Hospital, Hong Kong, China, T. Piratvisuth, Songklanakarin Hospital, Songkla,

Thailand, M. Popescu, Roche, Basel, Switzerland, P. McCloud, Roche, Dee Why,

Australia

 

Background:

Kaplan-Meier (KM) estimates were originally developed to assess survival rates using death as the measured outcome. Recently, this statistical method has been used to assess the long-term efficacy of antiviral therapy for chronic hepatitis B (CHB). A basic assumption of the KM approach is that a patient who achieves an outcome (eg death) will always have that outcome whether they remain in the study or not. Since relapse occurs in CHB, we discuss the appropriateness of the KM approach in determining response to anti-HBV therapy.

 

Objective:

To compare HBeAg response rates obtained using the intent-to-treat (ITT) principle, which assumes that patients with missing data do not have a response, with rates obtained by KM estimation in patients enrolled in a large, randomized clinical trial.

 

Methods:

HBeAg-positive patients were treated for 48 weeks with 180 mg peginterferon alfa-2a (40KD) (PEGASYS®) once-weekly (qw) + oral placebo once-daily (qd), 180 mg peginterferon alfa-2a qw + 100 mg lamivudine qd, or 100 mg lamivudine qd. HBeAg seroconversion rates during treatment and up to 24 weeks post-treatment (week 72) were reanalyzed using the KM method.

 

Results:

HBeAg seroconversion rates at the end of treatment (week 48) in the ITT population were 27% [72/271] with peginterferon alfa-2a alone, 24% [64/271] with peginterferon alfa-2a + lamivudine and 20% [55/272] with lamivudine alone. Corresponding KM estimates of HBeAg seroconversion at week 48 (day 337) were 36% with peginterferon alfa-2a (+9% over ITT), 29% with combination therapy (+5% over ITT) and 24% with lamivudine (+4% over ITT). In the ITT population, HBeAg seroconversion rates 24 weeks post-treatment (week 72) were significantly higher with peginterferon alfa-2a alone (32% [87/271]; P<0.001) and peginterferon alfa-2a + lamivudine (27% [74/271]; P=0.023) than with lamivudine alone (19% [52/272]). KM estimates of HBeAg seroconversion rates at week 72 (day 504) were 43% with peginterferon alfa- 2a (+11% over ITT), 38% with the combination therapy (+11% over ITT) and 30% with lamivudine (+11% over ITT).

 

Conclusions:

Using data from this large, randomized study, estimated rates of HbeAg seroconversion generated using the KM method were substantially higher than the HBeAg seroconversion rates generated using an ITT analysis. These findings suggest that KM estimation is not an appropriate statistical method for measuring long-term efficacy of antiviral therapy in patients with CHB as it biases the data. Results generated using KM estimates should be interpreted with caution especially when the associated rates of relapse are not also analyzed.


Poster 974

Abstract ID: 66851

Category: J1O: Hepatitis B: Treatment

 

VIROLOGICAL BREAKTHROUGH IS NOT A DETRIMENTAL PHENOMENON IN PATIENTS WITH COMPENSATED CIRRHOSIS: RESULTS OF A LONG TERM LAMIVUDINE THERAPY

.

Y. Cakaloglu, Istanbul Medical Faculty Department of Gastroenterohepatology, Istanbul, NJ, Turkey, S. Kaymakoglu, Istanbul Medical Facutly Department of Gastroenterohepatology, Istanbul, NJ, Turkey, F. Akyüz, Istanbul Faculty of Medicine, Istanbul, NJ, Turkey, D. Ibrisim, Istanbul Medical Faculty Department of Gastroenterohepatology, Istanbul, NJ, Turkey, K. Demir, Istanbul Medical Faculty Department of Gastroenterohepatology, Istanbul, NJ, Turkey, D. Onel, Istanbul Medical Facutly Department of Microbiology, Istanbul, NJ, Turkey, E. Ahishali, Istanbul Medical  Facutly Department of Gastroenterohepatology, Istanbul, NJ, Turkey, B. Pinarbasi, Istanbul Medical faculty Department of Gastroenterohepatology, Istanbul, NJ, F. Besisik, Istanbul Medical Faculty Department of Gastroenterohepatology, Istanbul, NJ, Turkey, Z. Mungan, Istanbul Medical faculty Department of Gastroenterohepatology, Istanbul, NJ, Turkey, S. Badur, Istanbul Medical Faculty Department of Microbiology, Istanbul, NJ, Turkey, A. Okten, Istanbul Medical Faculty Department of Gastroenterohepatology, Istanbul, NJ, Turkey

 

Development of virological breakthrough during long-term lamivudine (LMV) therapy may result in fatal exacerbations in decompensated cirrhosis. The clinical results of virological breakthrough are still controversial in compensated or mildly decompensated cirrhosis.

 

Aim:

To evaluate the clinical significance of virologic breakthrough which develops during the long-term lamivudine therapy in patients with HBV related cirrhosis and the effects on clinical course and complications.

 

Material-Methods:

A hundred patients with HBV related cirrhosis (Child A 50, B 40, C

10) were enrolled and continuously treated with lamivudine 100 mg/day for 30±19 (12- 84) months. Baseline HBV DNA was positive (Hybridization, Digene) and ALT levels were high (>1.5XULN) in all patients. Normalization of ALT, negativity of HBV DNA (PCR<400-2000 copy/ml) and HBeAg seroconversion were accepted as on-therapy response. Reappearance of HBV DNA during the treatment was accepted as virologic breakthrough. Clinical course and complications were evaluated in patients with and without virologic breakthrough.

 

Results:

End of follow-up virologic and biochemical response rates were 56% and 58%, respectively (65.2% and 63.2% in HBeAg negative 70 patients and 32% and 46.4% in HBeAg positive 30 patients respectively- p<0.05). Virologic breakthrough developed in 25 patients (10 HBeAg positive, 15 HBeAg negative) in mean 33±15 months during LMV therapy. Of these 25 patients 11 (44%) had normal ALT. None of 14 patients with elevated ALT (2 had ALT level >10XULN) developed decompensation in liver disease. Although, CPT score did not significantly changed in total group, an important decrease was detected in patients without virological breakthrough. On the contrary virologic breakthrough was associated with a statistically significant increase in CPT scores (from 6.08±1.2 to 7.2±2.3, p<0.02). Also the frequency of complications of cirrhosis decreased with LMV treatment in comparison to pretreatment period. There was no significant difference in rate of complications between patients with and without virologic breakthrough. Thirteen patients (3 virologic breakthrough) developed hepatocellular carcinoma (HCC) in mean 29±19 months (Cumulative HCC incidence 5.6%). Seven patients (2 virologic breakthrough) died within 41±21 months (5 HCC, 1 AML-M4, 1 hepatic encephalopathy and spontanoeus bacterial peritonitis). Three patients underwent liver transplantation.

 

Conclusion:

Long-term LMV therapy results in significant improvement in laboratory and clinical parameters of cirrhosis. Virologic breakthrough is not associated with clinical deterioration in compensated and mildly decompensated cirrhotics.


Poster 976

Abstract ID: 67260

Category: J1O: Hepatitis B: Treatment

 

Factors associated with sustained virologic response 1 year after treatment with peginterferon alfa-2a (40KD) (PEGASYS®) monotherapy for HBeAg-negative chronic hepatitis B.

P. Marcellin, Hôpital Beaujon, Clichy, France, F. Bonino, IRCCS, Milan, Italy, G. K. Lau, Queen Mary Hospital, Hong Kong, China, P. Farci, Universita di Cagliari, Cagliari  Italy, C. Yurdaydin, University of Ankara, Ankara, Turkey, T. Piratvisuth, Songklanakarin Hospital, Songkla, Thailand, R. Jin, Beijing You An Hospital, Beijing, China, S. Gurel, University of Uludag, Bursa, Turkey, S. Hadziyannis, Henry Dunant Hospital, Athens, Greece, Z. Lu, Ruijin Hospital, Shanghai, China, M. Popescu, Roche, Basel, Switzerland

 

Background:

In patients with HBeAg-negative chronic hepatitis B (CHB), peginterferon alfa-2a (40KD) (PEGASYS®) alone or combined with lamivudine provides significantly higher response rates 24 weeks post-treatment compared with lamivudine alone. Multivariate analysis identified age, baseline ALT and baseline HBV DNA as significant predictors of virologic response (HBV DNA <20,000 copies/ml) to peginterferon alfa-2a when assessed 24 weeks post-treatment.

 

Objective:

To evaluate factors associated with sustained virologic response (defined as 48 weeks post-treatment response) to peginterferon alfa-2a monotherapy.

 

Methods:

HBeAg-negative patients (n=177) were treated for 48 weeks with 180 mg peginterferon alfa-2a (40KD) (PEGASYS®) once-weekly. HBV DNA was measured regularly during the 48 week post-treatment follow-up period (weeks 48, 52, 56, 60, 64, 72, 84 and 96). Analyses performed to identify baseline and on-treatment factors associated with post-treatment virologic response included the following variables: gender; race; age; bodyweight; baseline ALT; baseline HBV DNA; end of treatment HBV DNA; and HBV genotype.

 

Results:

Of 144 patients who had a virologic response (<20,000 copies/ml) to peginterferon alfa-2a monotherapy at the end of treatment, 89 had available data 48 weeks post-treatment. Of these patients, 49 (55%) sustained HBV DNA levels <100,000 cp/mL during the 48 week follow-up period [among these, 22 (25%) had HBV DNA levels between 20,000 and 100,000 copies/ml; and 27 (30%) had HBV DNA <20,000 cp/mL]. atients with sustained virologic response had higher mean ALT levels at baseline (94.7 IU/L) compared with patients with relapse (77.6 IU/L). Mean baseline HBV DNA levels were 7.18 and 6.99 log for sustained responders and relapsers, respectively. HBV DNA level at the end of treatment was not different in patients with sustained response and those with relapse (2.5 and 2.6 log, respectively). The rate of sustained virologic response according to HBV genotype was 60% [3/5], 43% [12/28], 64% [27/42] and 50% [5/10] for genotypes A, B, C and D, respectively (P=0.08 for comparison of genotype B vs C).

 

Conclusions:

In patients with HBeAg-negative CHB, a finite 48-week course of peginterferon alfa-2a was able to induce virologic response that was sustained 48 weeks post-treatment in more than half of the patients. There was no clear predictor of sustained response to peginterferon alfa-2a. However, there was a trend toward better response in patients with high ALT at baseline or who were infected with HBV genotype C. Baseline or end-of-treatment HBV DNA levels were not indicative of sustained virologic response.


Poster 977

Abstract ID: 61484

Category: J1O: Hepatitis B: Treatment

 

Efficacy of Tenofovir against HBV in HIV/HBV coinfected patients.

G. Klausen, Praxiszentrum Kaiserdamm, Berlin, Germany, A. Moll, Praxiszentrum Kaiserdamm, Berlin, Germany, J. Gölz, Praxiszentrum Kaiserdamm, Berlin, Germany, D. Schleehauf, Praxiszentrum Kaiserdamm, Berlin, D. Prziwara, Praxiszentrum Kaiserdamm, Berlin, S. Nzimegne-Gölz, Praxiszentrum Kaiserdamm, Berlin

 

Backround:

Tenofovir (TDF) is licensed for the treatment of HIV and is known to be active and potent as well against hepatitis B virus. Anyhow, there is still a lack of data about the efficacy of TDF against HBV in HIV/HBV coinfected patients. In our center we treated 37 HIV/HBV coinfected patients with TDF containing antiretroviral therapies since January 2002. 21 of those had a viral load of hepatitis B of more than 100000 IE/ml bevor the start of TDF. 10 of these patients had previously shown a clinically diagnosed resistance of HBV against Lamivudine (LAM).

 

Methods:

Retrospective analysis of the virological effectiveness of TDF against HBV in 21 HIV patients with highly replicative HBV coinfection, who were treated with a TDF containing antiretroviral therapy. Previous LAM resistance of HBV was defined as an increase of HBV of 2 log or more under treatment with LAM.

 

Results:

The 21 patients were all male and were in average 41 years old (range: 37-49). The average time on TDF was 27 month (range: 12-39) and the average viral load of HBV (VL) at baseline was 1.7x10log12 IE/ml (range: 2x10log5-1x10log13; N=21). At month 6 after start of treatment, the average VL was 743042 IE/ml(n=19), at month 12 it was 3769 IE/ml (n=17) and at month 24 the average VL was 230 IE/ml (n=15). The 10 patients with HBV resistance against LAM showed the following results: Baseline: VL 1,2x10log12 IE/ml (n=10), month 6: 33425 IE/ml (n=8), month 12: 7019 IE/ml (n=9), month 24: 386 IE/ml (n=8). In the reported patients we did not see any viral break through of HBV of more than 1 log under therapy with TDF so fare.

 

Conclusion:

According to our experience TDF is a long-term effective drug against HBV in HIV/HBV coinfeted patients with or without HBV resistance against LAM.


Poster 978

Abstract ID: 62282

Category: J1O: Hepatitis B: Treatment

Hepatitis B Virus Genotype B Is Associated With Better Response to Thymosin alfa-1 Therapy Than Genotype C.

 

R. Chien, Chang Gung Memorial Hospital and University, Keelung, Taiwan, Keelung,

Taiwan, Y. Liaw, Liver Research Unit, Chang Gung Memorial Hospital, Taipei, Taiwan

 

Background:

Hepatitis B virus (HBV) genotype has been reported to correlate with response to interferon (IFN) treatment in several studies. The relationship between HBV genotype and thymosin α 1 (T 1) treatment is unknown. We retrospectively examine HBV genotypes, precore and core promoter mutations in patients treated by T α 1 and analyze the correlation between complete response (CR; ALT normalization plus seroclearance of HBeAg and HBV-DNA by solution hybridization) of T α 1 therapy and HBV genotype.

 

Patients and Methods:

98 patients with clinicopathologically proven chronic hepatitis B were randomized allocated to three groups: 1) T6 group (n=32) received a 26-week course of T α 1 with a 1.6 mg subcutaneous injection two times a week; 2) T12 group (n=34) received the same regimen as T6 group, but T α 1 therapy extended for 52 weeks; 3) T0 group (n=32) served as a control and was followed up for 18 months without specific treatment. Retrospectively analyze the HBV genotype, precore and core promoter mutation using stored serum and correlated with CR.

 

Results:

There were 90 stored serum available for HBV genotyping from patients completing the treatment and follow-up study (29 in T6 group; 31 in T12 group and 30 in T0 group). Of them, 49 (54%) were genotype B and 41 (46%) were genotype C. Genotype C had a higher frequency of core promoter mutation. Stepwise logistic regression analysis showed that genotype (odds ratio [1] OR, 3.747; 95% confidence interval [1] CI,1.066- 13.170; P=0.039), precore mutation (OR, 6.285; 95% CI, 1.874-21.086; P=0.003) and T α -1 treatment (OR, 12.045; 95% CI, 2.220-65.354; P=0.004) as independent factors associated with CR. The CR of T α -1 was higher in patients with genotype B compared to patients with genotype C (52% of genotype B vs 24% of genotype C; P=0.036) and in patients with precore mutation (14/22 or 64% in responder vs 6/31 or 19% in nonresponder; P=0.002).

 

Conclusion:

Genotype, presence of precore mutation and T α-1 therapy were independent predictors to CR. Genotype B, compared to genotype C, is associated with a higher response rate to T α 1 therapy.


Poster 979

Abstract ID: 63873

Category: J1O: Hepatitis B: Treatment

 

Long-term experience of adefovir dipivoxil add-on therapy in chronic hepatitis B patients co-infected with HIV and lamivudine-resistant HBV : Absence of adefovir resistance mutation selection.

V. THIBAULT, Virology lab. CERVI - GH PITIE SALPETRIERE, PARIS, France, Y. BENHAMOU, GH PITIE SALPETRIERE, PARIS, France, M. VALANTIN, GH PITIE SALPETRIERE, PARIS, France, C. L. BROSGART, GILEAD, Foster city, CA, S. XIONG, GILEAD, Foster city, CA

 

Sequential monotherapy with lamivudine (LAM) and adefovir dipivoxyl (ADV) for chronic hepatitis B may quickly lead to the selection of resistant HBV. By contrast, a strategy based on add-on ADV therapy after LAM resistance emergence may be more effective.

 

We have analyzed the incidence of ADV resistance in HIV patients who have been treated for up to 5 years with a combination of ADV and LAM after development of LAM-resistance (LAM-R). In 2000, 35 HIV-patients were enrolled in an open label study of ADV add-on therapy after emergence of LAM-R HBV. In this follow-up study, all patients who presented residual HBV replication by PCR between year 4 and 5 of treatment were studied for the presence of HBV polymerase resistance mutations on serum samples. The HBV-RT was sequenced and compared to the sequences obtained before ADV introduction.

 

Among the 35 patients included in the initial cohort, 29 were still followed at year 4 and 14 had an undetectable viral load by PCR (<200 copies/mL). 15 had available samples with a viral load high enough to perform sequencing analysis. Median duration of add-on ADV of these 15 patients was 235 weeks and the median HBVDNA was 3.55 log10 cop./mL. 14/15 patients had constant fluctuating low viral loads between 2.3 (LLD) and 5 log10 cop./mL with no evidence of viral breakthrough. 10/15 patients had the same LAM-resistant pattern as their baseline sequence rtV173L/L180M/M204V (n=2); rtL180M/M204V (n=8) and no noticeable change was observed in their RT sequences along time. 2/10 of them had ADV replaced by tenofovir (TDF) when the background HIV treatment required adjustment. 4/15 patients lost their LAM-R mutations. For 2 of them failure of compliance was documented. For the 2 remaining, analysis of their HIV and HBV viral load kinetics clearly suggested lack of compliance. 1/15 patient had a viral breakthrough with a HBVDNA rise over 1 log10 on two consecutive samples. At that time, LAM-R mutations rtV173L/L180M/M204V were still present but no ADV mutation (rtA181V/T or rtN236T) or new conserved site mutations were identified; ADV was replaced by tenofovir and HBV DNA started to decline. Sequential monotherapy, after LAM–R breakthrough, could potentially increase the risk of subsequent HBV resistance selection. A strategy based on ADV add-on therapy seems very effective and is very unlikely to select for double ADV and LAM resistant variants, even in difficult to treat patients such those with HIV coinfection. The persistence of initially present LAM-R mutations, the low variability of the RT sequence and the absence of selection of further compensatory mutation indicate a strong pressure on a replication impaired virus.


Poster 981

Abstract ID: 64190

Category: J1O: Hepatitis B: Treatment

 

SEQUENTIAL ANTIVIRAL THERAPY LEADS TO THE EMERGENCE OF MULTIPLE DRUG RESISTANT HEPATITIS B VIRUS.

 

S. Villet, INSERM unit 271, Lyon, France, C. Pichoud, INSERM unit 271, Lyon, France, A. Ollivet, INSERM unit 271, Lyon, France, J. Villeneuve, Hôpital Saint-Luc , Division of Hepatology, Montreal, Canada, C. Trepo, INSERM unit 271, Lyon, France, F. Zoulim, INSERM unit 271, Lyon, France

 

We analysed the genotypic and phenotypic evolution of the viral quasi-species of 2 patients with chronic hepatitis B who failed antiviral therapy: one received successively lamivudine, add-on adefovir + lamivudine, followed by a lamivudine + adefovir + Hepatitis B immunoglobulins (HBIg) after liver transplantation, and the 2nd received IFN, lamivudine then entecavir. For genotypic analysis, a 1142 bp region of the polymerase gene encompassing the rt domain and overlapping the S gene was amplified by PCR for each sample, cloned and sequenced. For phenotypic analysis, an HBV replication-competent plasmid was constructed from HBV DNA isolated from patient serum (Durantel et al. Hepatology 2004). The rt gene from the selected clones previously sequenced was then subcloned in this vector. Transfection of these HBV mutants in hepatoma cell line led us to determine their replication efficiency and drug susceptibility.At baseline, all HBV genomes carried a wild-type (wt) rt gene but, for the first patient, 36 % harbored the P120S mutation within the S gene associated with vaccine escape. Following viral breakthrough to LAM monotherapy, a complex mixture of LAM-resistant HBV strains emerged, with the prevalence of the rtL180M+M204V mutant for the first patient and of the rtV173L+L180M+M204V mutant for the second. In vitro, all the tested mutants showed a 1000 fold resistance to LAM relative to wt HBV. Following the switch to ADV for the first patient, or to ETV for the second, the viral load dropped but rose again after 3 and 2 years of therapy respectively. During this rebound, we observed a complex mixture of LAM + ADV or ETV resistant strains. For the first patient, the selection of only one HBV mutant was finally observed. This mutant harbored the rtV173L+L180M+A181V+N236T mutations, a combination of resistance mutations to both drugs, and the sP120S mutation escaping to HBIg. Interestingly, the main LAM resistance mutation rtM204V disappeared from the viral population. The dominance of this complex rt mutant may be explained by our in vitro findings of a greater resistance to ADV+ LAM, and a level of replication equivalent to wt HBV. For the second patient, we observed a mixture of 3 mutants during rebound. All these mutants had the rtS202G mutation, not yet described, but also the rtL180M+M204V LAM resistance mutations despite the absence of LAM during ETV therapy. All these mutants were resistant to both LAM and ETV in vitro. Our results show the evolution of viral quasi-species towards the selection of mutants escaping to multiple selective pressures. This suggests that de novo combination therapy should be further evaluated to prevent drug resistance.


Poster 982

Abstract ID: 64393

Category: J1O: Hepatitis B: Treatment

 

HBV DNA levels at week 9 and number of HBV core gene mutations predict outcome of lamivudine/interferon á treatment in infancy-acquired chronic hepatitis B.

I. Kraslova-Carey, Institute of Liver Studies, London, United Kingdom (Great Britain), L. D'Antiga, Institute of Liver Studies, London, United Kingdom (Great Britain), M. Cavers, Institute of Liver Studies, London, United Kingdom (Great Britain), Y. Ma, Institute of Liver Studies, London, United Kingdom (Great Britain), S. Bansal, Institute of Liver Studies, London, United Kingdom (Great Britain), J. A. Byrne, Institute of Liver Studies, London, United Kingdom (Great Britain), G. Mieli-Vergani, Institute of Liver Studies, London, United Kingdom (Great Britain), D. Vergani, Institute of Liver Studies, London, United Kingdom (Great Britain)

 

Background:

During the immune tolerance phase that characterizes infancy-acquired chronic hepatitis B, hepatitis B virus (HBV) wild-type and variant strains coexist, although the wild-type dominates. During combination antiviral treatment most wild-type strains are eliminated and stable HBV core antigen variants become prevalent. The emergence of mutations within HBV core immunodominant epitopes may interfere with effective immune response and viral control.

 

Aim:

To evaluate the dynamic changes in serum HBV DNA levels during combined antiviral treatment in relation to the emergence of mutations within the HBV core gene and to study their contribution to treatment outcome.

 

Patients:

Twenty-three children (8 males, median age 10.2 years, range 2.9-16.8) with infancy-acquired hepatitis B (all HBeAg positive) were treated with lamivudine (3mg/kg/d) for 52 weeks and interferon α (5MU/m2 TIW) from week 9 for 44 weeks. According to treatment outcome, patients were divided into 5 responders (R) and 18 nonresponders (NR). Seven untreated HBeAg positive paediatric patients (3 males, median age 9.8 years, range 3.8-14.1) served as controls (C).

 

Methods:

HBV DNA levels were measured in serial serum samples by real-time TaqMan PCR before (treatment week 0– TW0), during (TW2, TW9, TW28, TW52) and after (follow-up week– FUW24) antiviral treatment. The number of HBV DNA copies per ng of genomic liver DNA was evaluated at baseline by the same method. Mutations within the HBV core gene were determined at baseline within the liver and in sequential serum samples by restriction fragment length polymorphism after nested PCR, and by direct sequencing at the same time-points as HBV DNA levels.

 

Results:

HBV DNA viral load in liver (log10 copies/ng of liver genomic DNA) and in serum (log10 copies/ml) is shown in the table (mean±SEM).

 

 

The decrease in the number of HBV DNA copies/ml in serum was significantly higher among responders (p=0.003) from TW9. The number of mutations within the HBV core gene was significantly higher in non-responders (4.38±0.6) than responders (1.25±0.5, p=0.023) at TW28. There was a strong correlation between serum HBV DNA levels and number of mutations in HBV core gene was found (p=0.002) among treated patients.

 

Conclusion:

A decrease of HBV DNA levels > 3.5 log10 copies/ml at TW9 predicts therapy outcome. The strong correlation between HBV DNA levels and the number of mutations within the HBV core gene suggests that variant strains contribute to virus control failure.


Poster 983

Abstract ID: 64955

Category: J1O: Hepatitis B: Treatment

 

FIVE YEARS OF SEQUENTIAL LAM TO LAM+ADV THERAPY SUPPRESSES HBV REPLICATION IN MOST HBEAg-NEGATIVE CIRRHOTICS, PREVENTING DECOMPENSATION BUT NOT HEPATOCELLULAR CARCINOMA.

 

P. Lampertico, IRCCS Maggiore Hospital, Milan, M. Vigano, IRCCS Maggiore Hospital, Milan, Italy, E. Manenti, IRCCS Maggiore Hospital, Milan, Italy, M. Iavarone, IRCCS Maggiore Hospital, Milan, Italy, G. Lunghi, IRCCS Maggiore Hospital, Milan, Italy, M. Colombo, IRCCS Maggiore Hospital, Milan, Italy

 

Background and Aim:

Lamivudine (LAM) monotherapy suppresses HBV replication in only 20-30% of HBeAg-negative cirrhotics treated for 5 years. Aim of the study was to assess in these patients the 5-yr efficacy of a sequential LAM to LAM+ADV therapy and its impact on disease progression and death.

 

Patients and Methods:

We prospectively followed up for 60 months (5-99) 124 HbeAg negative cirrhotic patients (106 males, 54 years) who were given lamivudine alone or LAM+ADV in patients developing lamivudine resistance (LAM-R). Patients were followed with LFTs and serum HBV-DNA (Versant 3.0, Bayer, LLQ 3.3 log10 copies/mL) every two months and with US scan every six months. Clinical LAM-R was when ALT peaked above the ULN and HBV-DNA >6 log and genotypic LAM-R when ALT remained within the normal range and HBV-DNA increased to below 6 log.

 

Results:

Of the 42 patients developing clinical LAM-R, 35 (83%) were rescued by adding ADV (Group A). By converse, 82 patients were either long-term responders to LAM monotherapy (n=54) or were added ADV to LAM at the time of genotypic LAM-R (n=28) (Group B). In the latter group, addition of ADV led HBV-DNA to became undetectable in all patients within 4 months and to remain so in the following years. Furthermore, ALT levels remained within the normal range throughout the study period. The 5-yr rates of undetectable HBV-DNA were 67% and 100% in Group A and B patients, respectively (p<0.001). None of the patients developed ADV-R, three patients of Group B seroconverted to anti-HBs and discontinued antiviral therapy. Clinical decompensation occurred in 19% patients from group A and in none of the Group B patients (p<0.001), whereas hepatocellular carcinoma developed in both groups with similar frequency (29% and 22%). Liver related deaths and liver transplantation occurred in 21% and 13% of the patients (ns).

 

Conclusions.

Sequential LAM to LAM+ADV therapy suppresses HBV replication for at least 5 years in all HBeAg-negative cirrhotics treated at the time of genotypic LAM-R, preventing clinical decompensation but not HCC.


Poster 984

Abstract ID: 65022

Category: J1O: Hepatitis B: Treatment

 

ROLE OF OCCULT INFECTION OF HEPATITIS B VIRUS ON VIRUSREACTIVATION OCCURING IN NON-HODGKIN LYMPHOMA (NHL) PATIENTS TREATED WITH CHEMOTHERAPY.

 

m. persico, second university of naples, chair of internal medicine, naples, Italy, E. Persico, Second University of, Naples Chair of Internal Medicine, naples, Italy, C. Marzocchella, Second University of Naples. Chair Of Internal Medicine, naples, Italy, M. Masarone, Second University of Naples, Chair Of Internal Medicine, Naples, Italy, V. Laura, Second Unibversity of Naples, Chair of Internal Medicine, Naples, Italy, F. Carrino, second university of Naples, Chair of Internal Medeicine, Naples, Italy, A. De Renzo, Federico II Universitty, Haematology Unit, Naples, Italy, R. Torella, Second university of naples, Chair of Internal Medicine, Naples, Italy

 

Based on the evidence on liver tissue and blood sera of specific gene fractions of HBV (core, s and x genes) the occult infection of HBV was demonstrated. Epidemiological evidences suggest the possible role of occult infection as cofactor of disease in hepatitis C virus (HCV) related chronic hepatitis and as possible aetiological agent of liver cancer (HCC). Aim of the present study was to test the role of occult HBV infection in HBV related reactivation in patients undergone to chemotherapy for NHL.

 

Patients and Methods:

a cohort of 55 consecutive patients with NHL were studied. They all were tested for routine blood examinations and among all the other examinations they were asked to perform liver biopsy prior the treatment. On liver tissue and serum of all patients, three gene fractions of HBV were assayed (core, s and x) by PCR according to Raimondo et al. Quantitative HBV-DNA on sera and liver tissue was assessed according to Real-Time PCR (RT-PCR) in HBsAg+ and HBcAB+ patients. All the patients were followed all over the time of exposure to the drug and after discontinuation.

 

Results:

18 out of 55 (33%) were HBcAb+; 15 were HCV-RNA+ (27%) and 6 HBsAg+ (10%). HBsAg+ patients were treated with pre-emptive lamivudine therapy. Five (15%) HBcAb+ patients experienced HBV related hepatitis reactivation and they were found positive for c and s genes on liver tissue (occult B virus)but not on serum samples. These subjects were compared to a historical group of HBsAg+ patients (n.9) who also had a disease reactivation under the same circumstances (pre lamivudine era). In both groups lamivudine promptly dominated the pathological process and all the patients recovered. HBV-DNA titration on liver tisssue was significantly higher in HBsAG+ (10^4 - 10^5 copies/ml) and occult B virus patients (10^3 - 10^4 copies/ml)compared to HBcAB+ subjects in whom the occult virus was not identified (<10^3 copies/ml). Levels of serum HBV-DNA (RT-PCR) were not useful to discriminate between “occult” HBcAB+ and “non-occult” HBcAB+ patients.

 

Conclusions:

In NHL the prevalence of HBcAB+ is higher than HBsAG+ and occult infection plays a major role in HBV reactivation as well as overt HBV infection. However,its onset is not as frequent as in HBsAg+ patients. At the moment routinely used blood test to identify occult B virus does not exist. Lamivudine pre-emptive treatment should be also considered in HBcAb+ subjects undergone chemotherapy for NHL.


Poster 985

Abstract ID: 65629

Category: J1O: Hepatitis B: Treatment

 

Long-term beneficial outcome of Chinese asymptomatic patients with HBeAg-positivechronic hepatitis B on continuous lamivudine therapy: 7-year experience.

 

M. Yuen, The University of Hong Kong, Hong Kong, China, W. Seto, The University of Hong Kong, Hong Kong, China, D. Chow, The University of Hong Kong, Hong Kong, China, K. Tsui, The University of Hong Kong, Hong Kong, China, D. Wong, The University of Hong Kong, Hong Kong, China, P. Chan, The University of Hong Kong, Hong Kong, China, D. But, The University of Hong Kong, Hong Kong, China, C. Lai, The University of Hong Kong, Hong Kong, China

 

Background

Three-year treatment of lamivudine reduces disease progression in patients with preexisting cirrhosis. The effect of longer duration of lamivudine treatment in asymptomatic patients is unknown.

 

Aim

To determine whether long-term lamivudine treatment in asymptomatic patients can reduce the risk of hepatocellular carcinoma (HCC) and cirrhosis-related complications.

 

Patients and Method

Two hundred and sixty-six HBeAg-positive patients (140 with lamivudine and 126 without treatment serving as controls) were recruited from the Hepatitis Clinic, Queen Mary Hospital, Hong Kong. They included all patients who participated in 3 controlled trials of lamivudine (NUCB 3009, 3018, 4003) and all the other patients who fulfilled the inclusion criteria but were not included in the trials seen at the same period of time (1994-1997). All lamivudine-treated patients were maintained on lamivudine throughout follow-up irrespective of HBeAg seroconversion.

 

Results

There were no differences in the baseline characteristics and liver biochemistry between the 140 treated patients (M:F 105:35; median age 33.9 years) and the 126 controls (M:F 92:34; median age 33.3 years). The follow-up duration was significantly longer in controls compared to that of lamivudine-treated patients (median 106.2 vs. 90 months respectively, p=0.004). There were no differences in the cumulative rates of HbeAg seroconversion and hepatitis flare between the two groups (p=NS). However lamivudinetreated patients had a slower decline in albumin levels during the follow-up period compared to controls (median drop 3 vs. 4 g/L respectively, p=0.025). 93 (66.4%) lamivudine-treated patients and 81 (64.3%) controls had normal ALT level at the last follow-up. HCC occurred in 1 lamivudine-treated patient and 3 controls. Cirrhosis developed in 6 lamivudine-treated patients and 15 controls. Using Kaplan-Meier analysis, lamivudine-treated patients had a significantly lower cumulative risk of development of complications compared to controls (log rank test, p=0.035). At the time of writing, YMDD mutations were determined in 38 lamivudine-treated patients with elevated transaminases during follow-up. 36 had YMDD mutations. At the last follow-up, there were no differences in the liver biochemistry between patients with YMDD mutations and controls; 24 (66.7%) of patients with YMDD mutations had normal ALT levels.

 

Conclusions

Long-term lamivudine treatment can reduce the risk of complications from CHB in asymptomatic HBeAg-positive patients. Development of YMDD mutations was not associated with more serious disease when compared to untreated patients.


Poster 986

Abstract ID: 65864

Category: J1O: Hepatitis B: Treatment

 

Efficacy And Safety Of Entecavir (ETV) And Lamivudine (LVD) In Compensated, Cirrhotic Patients With Chronic Hepatitis B.

E. Schiff, University of Miami, Miami, FL, W. M. Lee, The University of Texas Southwestern Medical Center, Dallas, TX, Y. Chao, Tri-Service General Hospital, Taipei, Taiwan, H. Sette, Hospital das Clinicas, Sao Paulo, Brazil, S. W. Schalm, Erasmus University Hospital, Rotterdam, Netherlands, H. Brett-Smith, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT, R. Zink, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT

 

Background:

The long-term outcome of chronic HBV treatment depends upon potent virologic control; antiviral treatment has been shown to slow or reverse disease progression in patients with advanced liver disease. ETV was superior to LVD in achieving histologic improvement in Phase III studies of compensated, treatment-naïve and LVD-refractory patients. This report investigates if severity of liver disease at baseline influenced treatment response in the ETV Phase III program.

 

Methods:

Study ETV-022 and ETV-027 enrolled treatment-naïve, HBeAg(+) and HBeAg(-) patients, respectively. ETV-026 enrolled LVD-refractory, HBeAg(+) patients. Liver biopsies were performed before study entry and after 48 weeks of therapy. Baseline cirrhosis was defined in patients with evaluable biopsies as a Knodell fibrosis score of 4.

 

Results:

Approximately 8% of patients had cirrhosis at baseline; the distribution of cirrhotic patients was balanced between treatment groups. Cirrhotic patients on ETV were more likely than those on LVD to have histologic improvement, ALT normalization and undetectable HBV DNA, although the relatively small patient number limits interpretation. Efficacy results after 48 weeks of therapy for treatment-naïve patients according to baseline cirrhosis status are presented below:

 

In LVD-refractory patients, the response in the overall population for ETV over LVD was also seen in cirrhotic patients. Histologic improvement occurred in 50% and 55% of ETV-treated cirrhotic and non-cirrhotic patients, and in 22% and 28% of LVD-treated cirrhotic and non-cirrhotic patients, respectively. In all patients, the incidence of ALT flares with ETV (2%) and LVD (5%) was the same in cirrhotic and non-cirrhotic patients. Serious adverse events were reported more frequently in cirrhotic (ETV 10%, LVD 14%) than non-cirrhotic patients (ETV 7%, LVD 8%). Baseline cirrhosis did not affect patient discontinuation. ALT >2x baseline + total bilirubin >2x baseline and 2x ULN was reported in no cirrhotic and in <1% of non-cirrhotic patients.

 

Conclusions:

ETV treatment was effective and well-tolerated in compensated, cirrhotic patients with chronic HBV. In general, ETV response was comparable between cirrhotic and non-cirrhotic patients.


Poster 988

Abstract ID: 66881

Category: J1O: Hepatitis B: Treatment

 

Lack of implementation of hepatitis B treatment guidelines: why effective antiviral treatment does not reach the patient.

W. F. Leemans, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands, H. L. Zaaijer, Academic Medical Centre, University of Amsterdam, Amsterdam, Netherlands, R. A. de Man, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands

 

In a previous study we described that only 30 % of chronic HBV patients with active disease (HBeAg(+) or raised ALT) identified by the primary care physician reach specialist care (J Hepatol 2004;41:1026-30). To standardise and improve HBV treatment in specialist care, treatment guidelines have been developed.

 

Their impact on specialist care was studied. A questionnaire was sent to all gastroenterologists and infectious disease specialists in the Netherlands: 226/591 (38%) responded, 120 (53%) actually saw at least one HBV infected patient/year and were included in the analysis. Approximately half of the physicians (52%) saw a few patients a year, 36% a couple a month and 12% saw patients at least weekly. Most (70%) prescribe antiviral treatment themselves, increasing from 54% for doctors seeing only a few patients a year to 90% for those seeing more patients. Physicians who do not prescribe treatment refer in only 62% to a specialized centre. Less than half (46%) of the physicians seeing patients work according a protocol. However 72% express a need for a standardised protocol, independently of the amount of patients seen, ranging from 50% for those seeing many patients increasing to 94% for those seeing a few patients a month, suggesting that availability of protocols could be a problem.

 

Of those treating patients only 44% has ever used a nucleoside/nucleotide analogue (NUC), which use increases from 18% for those seeing only a few patients a year to 78% seeing patients more frequently. In addition, among those treating patients but not using NUC, 72% do not refer to a specialised centre. The majority (61%) prescribing NUC do not perform mutation analysis during treatment , although 91% (p<0.001) has access to these tests. The use of a protocol does not imply that physicians treat patients themselves or use nucleoside analogues more often. However among the specialists using a protocol the access to the standard laboratory tests (HBV DNA) and specialized tests (resistance, genotype) is higher and resistance testing is performed more often suggesting that monitoring is improved but there still is reluctance to initiate treatment.

 

In conclusion the more patients specialists see the more likely they will treat patients themselves. About one third of the physicians do not refer despite they do not treat patients and therefore deprive patients from treatment. Only 44% of the specialists ever used a NUC and most of them do not refer leaving e.g. interferon failures devoid of NUC treatment. In the development of HBV treatment guidelines more attention should be given to implementation of the guidelines especially with regard to initiation of treatment.


Poster 989

Abstract ID: 67344

Category: J1O: Hepatitis B: Treatment

 

Antiviral response and resistance surveillance for HBeAg negative patients enrolled in a combination study evaluating emtricitabine plus clevudine versus emtricitabine monotherapy for the treatment of chronic hepatitis B infection.

 

A. Snow, Gilead Sciences, Durham, NC, Z. Krastev, University Hospital Multiprofile Hospital for Active Treatment “St Iva, Sofia, Bulgaria, S. Lim, National University Hospital Singapore, Singapore, Singapore, T. Ng, Changi General Hospital Department of Medicine, Singapore, Singapore, . Kotzev, Multifunctional Active Treatment Hospital “St. Marina”, Varna , Bulgaria, S. Chan, 142-41 41st Avenue, Suite 10, Flushing , NY, P. Husa, University Hospital BRNO – BOHUNICE Department of Infectious Disease, CZECH REPUBLIC , Czech Republic, J. Sperl, Institute of Clinical & Experimental Medicine, Praha 4, Czech Republic, H. Mommeja-Marin, Gilead Sciences, Durham, NC, K. Borroto-Esoda, Gilead Sciences, Durham, NC, C. Moxham, Gilead Sciences, Durham, NC, J. Anderson, Gilead Sciences, Durham, NC, E. Mondou, Gilead Sciences, Durham, NC, J. Sorbel, Gilead Sciences, Durham, NC, F. Rousseau, Gilead Sciences, Durham, NC

 

Purpose:

Evaluate HBV viral load (VL) after 24 weeks of treatment with either emtricitabine 200 mg (FTC) plus clevudine 10 mg (CLV) versus FTC monotherapy and to perform resistance surveillance for viremic patients.

 

Methods:

Nucleoside naïve or experienced (48 weeks FTC 200 mg qd) patients were evaluated. Serum HBV DNA was assayed using a Real-Time PCR assay with a lower limit of detection (LOD) of 250 copies/mL (cp/mL). Genotypic analysis of the polymerase was performed at week 24 (W24) for viremic (>4700 cp/mL) patients.

 

Results:

Seventy-eight HBeAg- patients were enrolled; 38 (n=24 experienced and

n=14 naïve) received FTC+CLV and 40 (n=28 experienced and n=12 naïve) received FTC monotherapy. The median baseline HBV DNA VL was 4 log10 cp/mL. At W24 a -1.6 log10 and -1.4 log10 reduction in serum HBV DNA was observed for experienced patients in the combination and monotherapy arms, respectively, and a - 1.9 log10 reduction was observed among naïve patients, regardless of treatment arm. Among experienced patients, 86% given FTC+CLV versus 63% given FTC had HBV DNA <250 cp/mL at W24, and among naïve patients, the proportions were 69% and 67%, respectively. The W24 prevalence of FTC associated mutations was 7% and 0% among experienced and naïve patients, respectively.

 

Conclusion:

In this HBeAg- population, both emtricitabine plus clevudine and emtricitabine monotherapy produced a favorable antiviral response at week 24 as demonstrated by the median change from baseline in HBV DNA and by the proportion of patients with HBV DNA below the limit of detection. At week 24 no naïve patient presented with FTC resistance mutations whereas the rate was 7% among FTC experienced patients.


Poster 991

Abstract ID: 67742

Category: J1O: Hepatitis B: Treatment

 

Multiphase dynamics of HBeAg Negative and Positive Hepatitis B Virus Infections: evidence for synergistic antiviral effects of Peginterferon Alfa-2a and Lamivudine in high viral load patients.

 

P. Colombatto, Hepatology Unit at the Pisa Univerisity Hospital, Pisa, L. Civitano, Hepatology Unit, Pisa Univerisity Hospital, Pisa, R. Bizzarri, 2 NEST-INFM, Scuola Normale Superiore, Pisa, Italy, F. Oliveri, Hepatology Unit, Pisa Univerisity Hospital, Pisa, S. Choudhury, PD M. Roche USA, Nutley, CT, R. Gieschke, Roche, Basel, Basel, Switzerland, F. Bonino, Scientific Direction, Fondazione IRCCS Ospedale Maggiore Policlinico,, Milano, M. R. Brunetto, Hepatology Unit, Pisa Univerisity Hospital, Pisa

 

Background and Aims.

In HBeAg-positive chronic hepatitis B (CHB) patients (pts) serum HBV-DNA decline during the 1st month of antiviral therapy show either a classic biphasic or more complex profile. We studied and compared viral dynamics of HBeAgnegative and HBeAg-positive CHB pts treated with lamivudine (LMV) and/or with peginterferon alpha 2a (Peg-IFN2a).

 

Patients and Methods.

In our newly developed bio-mathematical model the 1st rapid drop of virus production (1st phase) can be followed by a further exponential decline (2nd phase) to an asymptotic value after which the immune clearance of infected cells becomes the major cause of HBV-DNA decline (3rd phase). Viral load was measured at days 0, 0.3, 1, 2, 4, 5, 7, 14, 21, 28, 35, 42, 56, 84 and every 6 weeks thereafter, in 72 HBeAg negative and 41 HBeAg-positive pts who received 48 weeks of either LMV (25 and 15 pts), Peg-IFN2a 180 mcg qw plus LMV (23 and 14 pts) or Peg-IFN2a 180 mcg qw plus placebo (24 and 12 pts).

 

Results and Conclusions.

Baseline HBV-DNA levels were higher in HBeAg-positive as compared to HBeAg negative pts (9.97 Log10 vs 6.79 Log10; P< 0.001). During the first month of therapy, viral load decreased more consistently in HBeAg positive pts (mean Delta variation 0-28 days: -3.59 Log10 vs -2.73 Log10; P = 0.013). However, the analysis by treatment group showed a significant difference between HBeAg positive and HBeAg negative pts only in the Peg-IFN2a+LMV group (Delta 0-28 days: -5.42 Log10 vs -3.28 Log10; P < 0.001), suggesting that in high viral load pts combination therapy accelerate the early HBV-DNA decline. In pts where viral load dynamics fit our model (87.5% of HBeAg negative and 61% of HBeAg positive pts), combination therapy showed significantly higher effectiveness of blocking virus production in HBeAg positive than in HBeAg negative pts (epsilon = 0.995 vs 0.868, P < 0.001) and faster 1st and 2nd phase HBV-DNA declines (1st phase = 7.52 vs 2.79 days-1, P = 0.022; 2nd phase = 0.72vs 0.44 days-1, P = 0.008). Accordingly, in HBeAg positive patients the 1st and 2nd phase decline were faster in pts treated with combination than in pts treated with LMV (1st phase = 0.995 vs 0.933, P = 0.044 and 2nd phase = 0.72 vs 0.35 days-1, P = 0.046).

 

Conclusion:

direct antiviral effects of LMV and PegIFN2a appear to be synergistic in patients with high levels of virus production.

 


Poster 992

Abstract ID: 60999

Category: J1O: Hepatitis B: Treatment

 

Cost-effective strategies in the treatment of chronic hepatitis B (CHB) with adefovir dipivoxil (ADV).

G. DUSHEIKO, CENTRE FOR HEPATOLOGY, ROYAL FREE HOSPITAL LONDON, UK, LONDON, United Kingdom (Great Britain), D. MUTIMER, LIVER AND HEPATOLOGY UNIT, QUEEN ELIZABETH HOSPITAL BIRMINGHAM, UK, EDGBASTON, United Kingdom (Great Britain), H. DAKIN, ABACUS INTERNATIONAL, BICESTER, United Kingdom (Great Britain), N. HUGHES, GILEAD SCIENCES, UK, CAMBRIDGE, United Kingdom (Great Britain)

 

BACKGROUND:

Lamivudine (LAM) was the first oral treatment for CHB, although its efficacy is limited by drug resistance, with 70% of patients becoming resistant within 4 years. ADV has a lower risk of resistance and is active against LAM-resistant HBV. This suggests ADV may be cost-effective if used first-line and/or second-line (after LAM resistance develops).

 

OBJECTIVES:

To assess the cost-effectiveness of first and second-line ADV in the treatment of CHB from the perspective of the UK NHS.

 

METHODS:

A Markov model using individual patient simulation was constructed to model disease progression in CHB and calculate the cost per quality-adjusted life year (QALY) gained. Unlike previous analyses, this model included patients with HBeAg-negative disease and/or drug resistance. Eleven disease states were modeled: immunotolerant; viral suppression; active CHB; HBsAg seroconverted; HBeAg seroconverted; compensated cirrhosis; decompensated cirrhosis; hepatocellular cancer; liver transplant; post-liver transplant; and death. Three treatment strategies were compared with LAM followed by no treatment after resistance develops (“LAM-NT”): continuing LAM irrespective of whether resistance develops (“LAM-LAM”); LAM followed by ADV after resistance develops (“second-line ADV”); and ADV followed by LAM after resistance develops (“first-line ADV”). Costs and resource use were based on a UK costing study and clinical opinion, disease progression rates with/without treatment were based on a systematic review and utility scores were based on published estimates. Costs and benefits were discounted at 3.5% per year.

 

RESULTS:

Both first and second-line ADV cost less than £30,000/QALY relative to LAM-NT. First-line ADV costs £66,000/QALY relative to second-line ADV. In contrast, the common practice of continuing LAM monotherapy in LAM-resistant patients (LAM-LAM) costs £33,097/QALY relative to stopping treatment, demonstrating that it is more cost-effective to switch to ADV when LAM resistance develops.
Poster 993

Abstract ID: 62050

Category: J1O: Hepatitis B: Treatment

 

RESISTANCE TO ADEFOVIR DIPIVOXIL IN PATIENTS WITH LAMIVUDINERESISTANT CHRONIC HEPATITIS B.

C. Osiowy, Public Health Agency of Canada, Winnipeg, Canada, J. Heathcote, Toronto Western Hospital, Toronto, Canada, F. Zoulim, INSERM Unit 271, Lyon, France, B. Willems, Centre Hospitalier de l'Université de Montréal, Hôpital Saint-Luc, Montreal, Canada, J. Villeneuve, CHUM - Hôpital Saint-Luc, Montreal, Canada

 

Background/Aim:

Adefovir dipivoxil (ADV) has demonstrated activity against wildtype and lamivudine-resistant strains of hepatitis B virus (HBV). The aim of this study was to document the efficacy and development of resistance to ADV in patients with lamivudine-resistant HBV infection treated with ADV.

 

Patients and methods: 116

patients with chronic hepatitis B and lamivudine resistance were treated with ADV 10mg/day. Following introduction of ADV, lamivudine was continued in 81 patients and stopped in 35. HBeAg was positive in 74 cases and negative in 42. Five patients had had liver transplantation (OLT) prior to starting ADV, and 8 underwent OLT after starting ADV. Follow-up ranged from 12 to 60 months (mean = 22 months). The presence of mutations of the HBV-polymerase gene conferring resistance to lamivudine and/or adefovir was examined using a new INNO-LiPA test (HBV DR v2, Innogenetics). The HBV-DNA polymerase was also sequenced to analyze nucleotide changes. Serum HBVDNA was measured by the Bayer b-DNA or the Roche PCR assay.

 

Results:

After one year of treatment with ADV, 61% of patients had HBV-DNA viral load below 100,000 copies/ml. This percentage increased to 77% after 2 years. Five patients developed phenotypic resistance to adefovir as evidenced by a 1 log increase in serum HBV-DNA during treatment (two OLT patients and 3 non-OLT). Resistance occurred after 1 year of treatment in 4 cases and after 3 years in the fifth case. The N236T mutation in domain D of the polymerase was detected in 4 of 5 cases. In one additional patient, the N236T mutation was detected after one year of treatment without evidence of phenotypic resistance. Among the cases with phenotypic resistance, 2 were receiving both adefovir and lamivudine (1 OLT, 1 non-OLT) and 3 were receiving adefovir only (1 OLT, 2 non- OLT).

 

Conclusion:

Patients with lamivudine-resistant HBV infection exhibit a slow, but

sustained response to adefovir in all but 2.9% of non-OLT patients after 1 year of treatment. The occurrence of resistance to ADV was more frequent in OLT patients (2 of 13 cases)


Poster 994

Abstract ID: 66086

Category: J1O: Hepatitis B: Treatment

 

Predictors of histologic improvement and relationship between sustained response and histology in patients with HBeAg-positive and HBeAg-negative chronic hepatitis B treated with peginterferon alfa-2a (40KD) (PEGASYS®).

 

G. K. Lau, Queen Mary Hospital, Hong Kong, China, G. Cooksley, Royal Brisbane Hospital, Brisbane, Australia, P. Marcellin, Hôpital Beaujon, Clichy, France, T. Piratvisuth, Songklanakarin Hospital, Songkla, Thailand, S. Hadziyannis, Henry Dunant Hospital, Athens, Greece, P. Farci, Universita di Cagliari, Cagliari, Italy, M. W. Fried, University of North Carolina, Chapel Hill, NC, F. Bonino, IRCCS, Milan, Italy, R. Jin, Beijing You An Hospital, Beijing, China, P. Button, Roche, Dee Why, Australia, M. Popescu, Roche, Basel, Switzerland

 

Background:

Established treatments for chronic hepatitis B (CHB) provide improvements in histologic activity that are generally associated with biochemical and virologic responses. Recent data have shown that peginterferon alfa-2a (40KD) (PEGASYS®) monotherapy provides histologic improvements in around half of all patients with HBeAg-positive or -negative CHB.

 

Objective:

To evaluate baseline predictors of histologic response and the association between biochemical and virologic outcomes and liver histology in patients treated with peginterferon alfa-2a monotherapy in two large, randomized studies.

 

Methods:

HBeAg-positive (n=271) and -negative (n=177) patients received 48 weeks of 180 mg peginterferon alfa-2a once-weekly. Histologic response, assessed 24-weeks post-treatment, was defined as a reduction in modified HAI score (Ishak) of at least 2 points compared with the pretreatment score. Multivariate analyses to identify predictors of histologic response included the following baseline variables: age, gender, genotype, ALT, HBV DNA, HBeAg titre [HBeAgpositive only], bodyweight and race.

 

Results:

Among patients with paired biopsy, histologic response rates at week 72 were 49% [102/207] and 59% [84/142] in the HBeAg-positive and -negative studies, respectively. High baseline ALT levels were significantly predictive of histologic response in the HBeAg-positive (P=<0.001) and -negative studies (P=0.005). In HBeAg-positive patients, low baseline HBeAg levels were also predictive of histologic response (P=0.001). Baseline HBV DNA was not a significant predictor of histologic response in either study. In both studies, there was a significant association between sustained virologic and biochemical response and improved liver histology at week 72 (P ≤ 0.001). In the HBeAg-positive study, histologic response was seen in 73% [55/75] of patients with sustained HBeAg seroconversion at week 72 vs 36% [47/132] of patients without. The rate of histologic response was highest in patients who had achieved HBeAg seroconversion by week 24 of treatment (30/35; 86%). In the HBeAg-negative study, histologic response was seen in 78% [39/50] of patients with a sustained combined response (normal ALT + HBV DNA <20,000 cp/mL) vs 49% [46/93] of patients without.

 

Conclusions:

High baseline ALT and low HBeAg levels are significantly associated with sustained histologic response to peginterferon alfa-2a. Rates of histologic response are highest in patients achieving HBeAg seroconversion by week 24 of treatment. In HBeAg-positive and - negative patients receiving peginterferon alfa-2a, there is a significant association between sustained response and improved liver histology.


Poster 995

Abstract ID: 66609

Category: J1O: Hepatitis B: Treatment

IN VITRO EFFECT OF THYMOSIN-ALPHA1 AND INTERFERON-ALPHA ON TH1 AND TH2 CYTOKINE SYNTHESIS IN PATIENTS WITH HBEAG-NEGATIVE CHRONIC HEPATITIS B.

A. Gramenzi, Dip. Med. Interna, Cardioangiologia, Epatologia. University of Bologna, Bologna, Italy, C. Cursaro, Dip. Med. Interna, Cardioangiologia, Epatologia. University of Bologna, Bologna, Italy, M. Margotti, Dip. Med. Interna, Cardioangiologia, Epatologia.University of Bologna, Bologna, Italy, I. Persico, Dip. Med. Interna, Cardioangiologia, Epatologia.University of Bologna, Bologna, Italy, A. Scuteri, Dip. Med. Interna, Cardioangiologia, Epatologia.University of Bologna, Bologna, Italy, E. Loggi, Dip. Med. Interna, Cardioangiologia, Epatologia. University of Bologna, Bologna, Italy, S. Lorenzini, Dip. Med. Interna, CardioAngiologia, Epatologia. University of Bologna, Bologna, Italy, M. Bernardi, Dip. Med. Interna, Cardioangiologia, Epatologia. University of Bologna, Bologna, Italy, P. Andreone, Dip. Med. Interna, Cardioangiologia, Epatologia. University of Bologna, Bologna, Italy

 

Introduction:

Thymosin alpha-1 (TA1) is an immune-modultaing peptide that has been demonstrated to enhance Th1 cytokine production as well as T-cell differentiation and maturation. Several clinical studies have shown that TA1 is effective in the treatment of chronic hepatitis B.

 

Aim

This study was to evaluate the antiviral and the Th1/Th2 cytokine response from peripheral blood mononuclear cells (PBMCs) of patients (pts) with HBeAg-negative chronic HBV and its modulation by TA1 and interferon-alfa (IFNa).

 

Methods:

106 PBMCs of 12 pts (mean age: 41±13 yrs; M/F: 9/3) with HbeAg negative chronic hepatitis B were isolated and cultured in absence (RPMI) or in presence of IFNa, TA1 or both. Th1 (IL-2, IFN-g) and Th2 cytokine (IL-4, IL-10) production and the synthesis of the IFN-induced antiviral protein 2’,5’-oligoadenylate synthetase (2- 5OAS) were directly assayed in the supernatants by commercial kits.

 

Results

Reported in the table:

 

 

No correlation was found between ALT or HBV-DNA serum levels and cytokines both in RPMI and in stimulated cultures. Similarly, no correlation was found with 2-5OAS.

 

Conclusion:

in PBMCs of patients with HBeAg-negative chronic hepatitis B, the stimulation with TA1 is able to induce a significant increase in production of IL-2 and 2- 5OAS and a significant decrease in the production of IL-10. On the contrary IFNa alone does not modify IL-2 production and significantly increases IL-10 synthesis. Incubation with TA1 and IFNa together led to an additive or even synergistic effect on the increase of IL-2 synthesis. Furthermore the addition of TA1 to IFNa significantly reversed the IFNa induced IL-10 increase. Based on this evidence it should be hypothesized that the efficacy of TA1 in treatment of HBV chronic infection could be ascribed to both the increase of the Th1 response and the decrease of the Th2 response, associated with persistence of viraemia


Poster 996

Abstract ID: 66942

Category: J1O: Hepatitis B: Treatment

 

Relapse in HBeAg-positive chronic hepatitis B after Peg-Interferon alpha-2b therapy alone or in combination with lamivudine.

H. J. Flink, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands, B. E. Hansen, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands, R. A. de Man, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands, S. W. Schalm, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands, H. L. Janssen, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands

 

Recurrence of serum HBeAg has been reported to be uncommon both after cessation of interferon and lamivudine therapy for HBeAg-positive chronic hepatitis B. We investigated the frequency of relapse after Peg-interferon alpha-2b therapy alone or in combination with lamivudine in chronic hepatitis B. A total of 266 chronic HBeAgpositive patients were treated with 100μg Peg-IFN weekly for 52 weeks combined with lamivudine (n = 130) 100 mg/day or placebo (n = 136). After week 32 the Peg-IFN dose was reduced to 50μg. The post-treatment follow-up lasted 26 weeks. At the end of treatment, HBeAg loss was seen in 44% in the combination group and 29% in the monotherapy group (p = 0.01). Overall, post-treatment HBeAg recurrence was seen in 27 patients (10%), but was strongly associated with treatment allocation. Twenty-two patients (17%) receiving the combination with lamivudine and 5 (4%: p < 0.0001) receiving Peg-IFN alone relapsed for HBeAg after treatment discontinuation. Except for treatment allocation, no other baseline variables could be identified as predictive factor for relapse. Among patients in the combination group post-treatment relapse occurred less frequently after HBeAg seroconversion (i.e. HBeAg clearance and development of anti-HBe) and was found in 8 (6%) patients versus 5 (4%, p = 0.35) receiving Peg-IFN alone. Multivariate analysis showed combination therapy with lamivudine (RR 3.8 CI95% 1.2 to 12, p = 0.02) and absence of anti-HBe at week 52 (RR 6.3 CI95% 2.2 to 16.7, p < 0.0001) as independent predictors for relapse.

 

In conclusion, recurrence of HBeAg is more often seen after combination of Peg-IFN with lamivudine than after Peg-IFN monotherapy. Treatment allocation and absence of anti-HBe at the end of therapy were the only independent predictors for post-treatment HBeAg relapse.


Poster 997

Abstract ID: 67313

Category: J1O: Hepatitis B: Treatment

 

EFFICACY OF TENOFOVIR IN PATIENTS WITH CHRONIC HEPATITIS B AND RESISTANCE OR SUB-OPTIMAL RESPONSE TO ADEFOVIR.

 

J. Villeneuve, CHUM - Hôpital Saint-Luc, Montreal, Canada, B. Willems, CHUM - Hôpital Saint-Luc, Montreal, Canada, F. Zoulim, INSERM U 271, Lyon, France

 

Background/Aim:

Adefovir dipivoxil has demonstrated activity against lamivudineresistant strains of hepatitis B virus (HBV). However, the N236T mutation in domain D of the hepatitis B virus (HBV) polymerase is associated with phenotypic resistance to adefovir. In vitro data suggest that the N236T mutant exhibits only a 4.5 fold decrease in sensitivity to tenofovir. We therefore examined the efficacy of tenofovir in patients with adefovir resistance. We also explored the usefulness of tenofovir in patients with suboptimal response to adefovir, but without genotypic resistance.

 

Methods:

Two patients who were receiving adefovir because of lamivudine resistance developed resistance to adefovir, after 36 and 12 months of treatment respectively. The first case was receiving lamivudine + adefovir and the second case adefovir monotherapy. The N236T mutation of the HBV-polymerase was demonstrated by the INNO-LiPA test (HBV DR v2, Innogenetics). They were treated with tenofovir 300mg id plus lamivudine 100mg id and adefovir was stopped. Four additional patients without genotypic resistance, but with sub-optimal response to adefovir were also switched to tenofovir 300mg id. They were also receiving adefovir + lamivudine because of lamivudine resistance. These 4 cases had HBV-DNA viral loads of 97 x 106, 42 x 106, 14 x 106 and 3.6 x 106 millions copies/ml after 13, 23, 29 and 25 months of treatment with adefovir respectively. HBV-DNA viral loads were measured by the Bayer b-DNA assay (lower limit of detection = 2000 copies/ml).

 

Results:

The two patients with resistance to adefovir showed a good response to tenofovir. In the first case, serum HBV-DNA decreased from 93 x 106 copies/ml at baseline to 9,300 copies/ml after 6 months of treatment with tenofovir. In the second patient, serum HBV-DNA decreased from > 100 x 106 copies/ml at baseline to 23,000 copies/ml after 7 months of treatment. In the 4 patients with sub-optimal response to adefovir, tenofovir treatment produced a > 1 log drop in viral load after 1 month and a > 2 log drop after 3 months of therapy.

 

Conclusion:

Treatment with tenofovir induces a rapid decrease of HBV-DNA viral load in patients with resistance or sub-optimal response to adefovir.


Poster 999

Abstract ID: 67594

Category: J1O: Hepatitis B: Treatment

 

Comparison of Tenofovir Versus Adefovir Based Combination Therapy in Subjects with Chronic Hepatitis B.

G. Y. Im, Mount Sinai Medical Center, New York, NY, A. J. Uriel, Mount Sinai Medical Center, New York, NY, D. Carriero, Mount Sinai Medical Center, New York, NY, J. Park, Mount Sinai Medical Center, New York, NY, D. L. Jaffe, Mount Sinai Medical Center, New York, NY, D. T. Dieterich, Mount Sinai Medical Center, New York, NY

 

Background

Treatment of chronic Hepatitis B (HBV) infection with lamivudine (3TC) or adefovir (ADV) monotherapy is associated with the development of resistance. Combination nucleoside/tide analogue (NA) therapy may maximize viral suppression and decrease the risk of viral resistance. There is limited data on the use of combination therapy in HBV, particularly involving tenofovir (TDF).

 

Aim

To compare the efficacy and tolerability of TDF and ADV based combination therapy in a cohort of pts with chronic HBV.

 

Methods

Pts receiving combination NA therapy for a minimum of 6 months (mo) were identified from our HBV database. Efficacy of TDF v ADV based regimens was assessed at 6 and 12 mo on therapy. Number of pts achieving undetectable HBV DNA (< 160 cps/ml), time to become undetectable, normalization of ALT, HBV eAg seroconversion, and adverse events were recorded.

 

Results

Data on 30 pts was analysed. 21/30 (70%) had previously received ADV or 3TC monotherapy and had been switched to combination due to failure to become undetectable or viral rebound. 10/30 (30%) were NA naïve. Median age was 35 years (23 – 68), 16/30 (53%) were Asian, 12/30 (40%) Caucasian, and 23/30 (77%) were male. 20/30 (67%) were HBV eAg +, all were HIV negative. 13 pts received TDF based regimens, (TDF + Emtricitabine (FTC) n=8, TDF + 3TC n=5), and 17 had ADV based regimens, (ADV + FTC, n=4, ADV + 3TC n=13). 13/30 (43%) had BL ALT > 2x ULN, median = 82 U/L (16 – 228). Median BL HBV DNA (n=29) was 1.4 x 105 cps/ml (2.0x10 2 - 2.0x10 9). Median length of therapy was 14 mo (6 – 31). Median time to HBV DNA < 160 cps/ml was shorter in NA naïve v experienced pts (4.5 v 6.5 mo) but longer in HBV eAg + v eAg – pts (7 v 5 mo). 6/13 (69%) normalised ALT and 2 pts seroconverted from HBV eAg + to HBV eAB + during therapy. Efficacy of TDF v ADV based regimens is outlined below.

 

 

3 pts in both ADV and TDF treatment groups achieved a mean log decrease in HBV DNA of 3.0 and 2.7 respectively, but did not fall to < 160 cps/ml. No adverse events were noted and serum creatinine was stable on therapy.

 

Conclusion

In our cohort, ADV based combination regimens achieved a more rapid fall in HBV DNA than TDF based regimens. Both appear potent and well tolerated. Further studies are needed to evaluate differences in efficacy between these 2 regimens. Long-term follow up is required to determine if the use of combination NA therapy will decrease the incidence of drug resistance.
Poster 1000

Abstract ID: 67971

Category: J1O: Hepatitis B: Treatment

Tenofovir rescue for patients with lamivudine resistant HBV infection with suboptimal virologic response to adefovir.

F. van Bömmel, Charité Campus Virchow Klinikum, Berlin, Berlin, H. Feucht, Institut

für Medizinische Mikrobiologie und Immunologie, Hamburg, Germany, B. Möller,

Hepatologische Schwerpunktpraxis in den Chackpoint Arkaden, Berlin, Germany, U.

Spengler, Zentrum für Innere Medizin, Universitätsklinikum Bonn, Bonn, Germany, B.

Zöllner, Institut für Medizinische Mikrobiologie und Immunologie, Hamburg, C.

Sarrazin, Universitätsklinikum des Saarlandes, Homburg/Saar, Germany, D. Hüppe,

Gastroenterologische Gemeinschaftspraxis Herne, Herne, B. Wiedenmann, Charité

Campus Virchow Klinikum, Berlin, Germany, T. Berg, Charité Campus Virchow

Klinikum, Berlin, Germany

 

Background:

Variable antiviral effects have been observed in adefovir dipivoxil (ADV)-treated patients with either wild type or lamivudine resistant (LAM-R) hepatitis B virus (HBV) infection. While a HBV DNA decline of &#8805; 4 log was demonstrated in the majority of patients after 48 weeks of ADV treatment, incomplete suppression of HBV DNA or null response to ADV were also found in large scale studies. Here we examined whether tenofovir disoproxil fumarate (TDF), which has been shown to be highly active against LAM-R HBV infections is an efficient drug in the treatment of HBV infections with suboptimal ADV responsiveness.

 

Methods:

Suboptimal ADV response (HBV DNA decline of less than 3 log or presence of high level viremia greater than 106 log in the absence of an ADV resistantce mutants) during ADV treatment was documented in 14 patients with LAM-R chronic HBV infection (mean age 45 years [range25-63]; m/f: 12/2; 13 HBeAg+). Mean period of ADV administration in these patients was 15 months (range 8-22 months). All 14 patients were directly switched from ADV to TDF at a daily dose of 300 mg. At this time, mean HBV DNA levels ranged between 5.0 to 7.6 log10 copies/mL (mean 6.6 log10 copies/mL) corresponding to a mean HBV DNA decline of HBV DNA -0.9 log10 copies/mL (range -3.4 - +1.9 log10copies/mL) during the ADV treatment phase. No patient had decompensated liver cirrhosis but 10 patients had elevated ALT levels. HBV DNA levels were measured on a monthly basis (HBV Monitor, Roche Diagnostics, detection limit 400 copies/ml) over a period of 6-14 months. All patients were screened for resistance-associated mutations within the HBV polymerase gene.

 

Results:

Following the start of tenofovir treatment, at month 3 and month 6 the mean decrease of HBV DNA was -3.1 log10 copies/mL [range 2.0-4.6] and -3.9 log10 copies/mL [range 1.9-4.6]. During the observed period, 13 patients reached HBV DNA levels below the detection limit (400 copies/ml) and 5 patients with initially elevated ALT reached normal liver enzymes after a mean duration of 4 months [range 1-9 months] and 6 months [range 1-12 months], respectively. Two patients lost the HBeAg after 3 and 5 months. At the start of TDF therapy, mutations at rtL180M and rtM204V were shown in 4 of the patients, however without effect on the antiviral response. Genotypic ADV resistance was excluded in all patients by direct sequencing of a region spanning the polymerase gene from rt103 to rt244 as previously described. No significant side effects were observed.

 

 

 

Conclusions:

Because of its high antiviral activity tenofovir might become a highly effective rescue drug for patients with suboptimal response to adefovil.


Poster 1001

Abstract ID: 63081

Category: J1O: Hepatitis B: Treatment

 

HBV GENOTYPE D AND SWITCH TO ADEFOVIR (ADV) MONOTHERAPY ARE ASSOCIATED WITH INCREASED RISK OF ADV RESISTANCE IN CHRONIC HEPATITIS B (CHB) PATIENTS.

 

S. K. Fung, University of Michigan, Ann Arbor, MI, H. Chae, University of Michigan, Ann Arbor, MI, R. Fontana, University of Michigan, Ann Arbor, MI, H. Conjeevaram, University of Michigan, Ann Arbor, MI, J. Marrero, University of Michigan, Ann Arbor, MI, K. Oberhelman, University of Michigan, Ann Arbor, MI, M. Hussain, University of Michigan, Ann Arbor, MI, A. Lok, University of Michigan, Ann Arbor, MI

 

Background:

Adefovir (ADV) resistance is less common and occurs later than lamivudine (LAM) resistance. A study of 67 HBeAg-ve patients reported that ADVresistant HBV mutants were detected in 0%, 3%, 11% and 18% after 1, 2, 3 and 4 years treatment, respectively. Aims: To characterize the virologic response to ADV, to determine the rate of ADV resistance, and to explore risk factors associated with suboptimal response and ADV resistance in patients referred to our Liver Clinic from 5/00 to 3/05.

 

Methods:

All patients who had received ADV for > 6 months and had virologic breakthrough (BT) or failed to achieve an initial virologic response (IVR) were tested for ADV resistance. LAM- and ADV-resistant mutations were detected by a line probe assay (InnoLipa, DR2) and confirmed by direct sequencing. HBV DNA was quantified using the Roche Cobas Amplicor assay (LLOD 200 copies/ml). BT was defined as > 1 log c/ml increase in HBV DNA after initial suppression; IVR was defined as serum HBV DNA <4 log c/ml after 6 months of ADV. The rate of ADV resistance was estimated by Kaplan-Meier analysis.

 

Results:

39 CHB patients (36M, 26 Caucasians and 11 Asians, mean age 48 years, 26 HBeAg+ve) were included and mean duration of treatment was 20 months (range 7-57). 30 (77%) patients had prior LAM (mean duration 25 months) of whom 14 were switched to ADV monotherapy and 16 received combination of LAM+ADV; 9 (23%) were started on ADV as de novo therapy. 25 (64%) patients had LAM breakthrough or confirmed resistance. IVR was observed in only 44% patients. Factors associated with an IVR included lower HBV DNA (p=0.03) and the absence of HBeAg (p=0.02) at the onset of ADV treatment. 16 patients had BT or lack of IVR on ADV and 5 were found to have ADV-resistant mutations (3 rtA181V, 2 rtN236T). All 5 patients with ADV resistance had prior LAM therapy. At the time ADV resistance was detected, 4 had viral rebound >5 logs and ALT flares >2XULN. The rate of ADV resistance at months 6, 12, 18, and 24 was 0%, 0%, 9%, and 19%, respectively. Patients with ADV resistance were more likely to have been switched to ADV monotherapy (100% vs. 36%, p=0.014) and to be infected with HBV genotype D (60% vs. 9%, p=0.019).

 

Conclusions:

Half of our patients failed to achieve IVR on ADV. Lack of IVR was associated with high baseline HBV DNA and presence of HBeAg. The high rate of ADV resistance (19% at yr 2) in our clinic population may be related to referral bias and predominance of patients with LAM resistance. ADV resistance was associated with HBV genotype D and switch to ADV monotherapy. Combination therapy in patients with LAM resistance may prevent the development of ADV resistance.


Poster 1002

Abstract ID: 65139

Category: J1O: Hepatitis B: Treatment

 

Pretreatment HBsAg Serum Levels Predict HBsAg Seroconversion in HBeAg-Negative Chronic Hepatitis B (CHBe-) Patients.

E. K. Manesis, Academic Department of Medicine, Hippokration General Hospital, Athens, Greece, E. S. Hadziyannis, Academic Department of Medicine, Hippokration General Hospital, Athens, Greece, O. P. Angelopoulou, Academic Department of Medicine, Hippokration General Hospital, Athens, Greece, S. J. Hadziyannis, Department of Medicine & Liver Unit, Henry Dunant Hospital, Athens, Greece

 

Background:

Both interferon-alpha (IFN) and nucleos(t)ide analogues are prescribed in CHBe, but only IFN has lasting effects after therapy and 30% of IFN-sustained responders seroconvert HBsAg. Although recent evidence suggests that serum HBsAg levels may reflect the liver cccDNA pool, no information exists on the effect of IFN and lamivudine (LAM) treatment on serum HBsAg and on subsequent HBsAg seroconversion.

 

Methods:

HBsAg and HBV-DNA were quantitated in stored sera by ADVIA Centaur™ and Versant-3.0™, respectively (Bayer Diagnostics) with a level of detectability 0.066 IU/mL and 357 IU/mL (2000 copies/mL), respectively. 540 sera of 62 CHBe- patients were analyzed. 44 patients had received 52 IFN courses (18 sustained responders, including 7 HBsAg-seroconvertors; 17 non-responders, 17 respond-relapsers) for median 12.1 (3.8.26.7) months and 22 patients were on lamivudine (22 responders, including 1 HBsAg seroconvertor, 5 relapsers) with median virological response 46.8 (18.2-58.5) and 18.9 (6.3-43.8) months, respectively. The HBsAg levels were measured at baseline, at the end of interferon treatment (EOT), at the end of follow up (EFU) in all cases and in other instances depending on availability of samples.

 

Results:

Baseline HBsAg levels varied widely (median 3421.4, range 57.3-66000 IU/mL) and were similar in all groups except among seroconvertors, who had significantly lower levels compared to the other IFN- or LAM-treated patients (median 1652.1 vs 3478.9 IU/mL, P=0.004). At EOT, paired HBsAg levels were statistically unchanged in IFN-non-responders and all LAM-treated patients, compared to baseline, while all IFN-responding groups had significantly lower levels (median baseline 3723.4 vs EOT 1456.2, P<0.001). At EFU, paired HBsAg comparisons with the baseline were not significant in IFN-non-responders and –relapsers, but differed significantly in IFN– sustained responders (median EFU levels 194.8 IU/mL, P=0.043). Multivariate logistic regression analysis demonstrated that lower baseline HBsAg levels was the only significant covariate related to HBsAg seroconversion (P=0.006, relative hazard 0.105, 95% CI 0.021-0.516), whereas age, sex, type- (IFN or LAM) or duration of treatment, baseline HBV-DNA or ALT levels were not.

 

Conclusions:

Interferon, but not lamivudine, significantly suppresses serum HBsAg at the end of therapy in responding patients only. The effect is temporary in the respond-relapser group and lasting in the sustained-responder group. Sustained responders who become HBsAg seroconvertors have significantly lower pretreatment HBsAg and that is the only significant prognostic variable of seroconversion by multivariate analysis.
Poster 1003

Abstract ID: 67109

Category: J1O: Hepatitis B: Treatment

 

A MULTICENTER ITALIAN STUDY OF RESCUE ADEFOVIR DIPIVOXIL THERAPY IN LAMIVUDINE RESISTANT PATIENTS: A 2-YEAR ANALYSIS OF 604 PATIENTS.

 

P. Lampertico, Dept. Gastroenterology, IRCCS Maggiore Hospital, Milan, Italy, A. Marzano, Dept. Gastroenterology, Ospedale San Giovanni Battista, Molinette Hosp, Torino, Italy, M. Levrero, Dept. Internal Medicine, University of Rome La Sapienza, Roma, Italy, T. Santantonio, Clinic of Infectious Diseases, University of Bari, Policlinico, Bari, Italy, P. Andreone, Dept Internal Medicine, University of Bologna, Bologna, Italy,   M. Brunetto, Azienda Ospedaliera Universitaria Pisana, Pisa, Italy, V. Di Marco, Istituto di Clinica Medica, University of Palermo, Palermo, Italy, S. Fagiuoli, Gastroneterologia, Azienda Ospedale Università di Padova, Padova, Italy, G. Mazzella, Department of Internal Medicine and Gastroenterology, University of Bo, Bologna, Italy, G. Raimondo, Dipartimento di Medicina Interna,, Messina, Italy, f. Adefovir Study Group, IRCCS Maggiore Hospital, Milan, Italy

 

Intro:

Adefovir dipivoxil (ADV) halts progression of liver disease in lamivudine-resistant patients but its efficacy and safety in the general population is largely unknown. To further evaluate these aspects, the rates of virological response, adefovir resistance (ADV-R), side effects and liver related-complications were assessed in a large cohort of Italian patients treated with ADV for LAM-R.

 

Material and Methods.

604 LAM-R patients who started ADV treatment between 2002 and 2004 in 25 italian centers involved in the Gilead Sciences sponsored 435 and 550 studies, were enrolled in a prospective cohort study and followed for 18 months, on average. Mean age was 54 years, 81% were men, 85% HBeAg-negative, 49% cirrhotics, 53% had concomitant diseases and 46% received concomitant medications. 51% of the patients switched from LAM to ADV (ADV mono group) while 49% added ADV to LAM (combo group) throughout the study period. HBV-DNA was quantified by sensitive assays (LLQ: 2 o 3 log copies/mL); a virological response was defined as undetectable HBV-DNA, a virological rebound was defined as > 1 log increase of HBV-DNA compared to on treatment nadir and confirmed in at least two consecutive months. ADVR was confirmed by molecular analysis.

 

Results.

Overall, the 1 and 2 year cumulative probability of undetectable HBV-DNA was 62% and 78%, respectively. At multivariate analysis, patients with pre-treatment lower HBV-DNA (p<0.0001), higher ALT levels (p<0.005) and HBeAg negative (p<0.001) had higher chances of achieving undetectable HBV-DNA. Time to undetectable HBV-DNA was significantly shorter in patients with a pre-treatment HBV-DNA below 5 log, than in those with levels between 5 and 6 or above 6 log (p<0.00001). ALT became normal in 74% and 81% after 1 and 2 year of therapy, respectively. Older age, lower HBV-DNA and HBeAg negative were independent predictors of ALT normalization. 31 patients (6%) had a virological rebound while on ADV, between 7 to 41 months (median 15) from the start of therapy. ADV-R was looked for in 13 cases and confirmed in 3 patients. By multivariate analysis, patients treated with ADV monotherapy (p<0.0001) and those with detectable HBV-DNA at week 24 (p<0.0001) had higher chances of a virological rebound. ADV was discontinued or the dose was modified in 6% of the patients, mainly because of impaired renal function. Adverse events likely related to ADV were reported in 5% of the patients. HCC or clinical decompensation was observed in 16% of cirrhotics, and 17% died or underwent liver transplantation.

 

Conclusions.

ADV-LAM combination therapy in low viremic patients is the most effective approach to treat lamivudine resistance.


Poster 1004

Abstract ID: 67505

Category: J1O: Hepatitis B: Treatment

 

Antiviral response and resistance surveillance for HBeAg positive patients enrolled in a combination study evaluating emtricitabine plus clevudine versus emtricitabine monotherapy for the treatment of chronic hepatitis B infection.

A. Snow, Gilead Sciences, Durham, NC, Z. Krastev, University Hospital Multiprofile Hospital for Active Treatment “St Iva, Sofia, Bulgaria, S. Lim, National University Hospital Singapore, Singapore, Singapore, T. Ng, Changi General Hospital Department of Medicine, Singapore, Singapore, . Kotzev, Multifunctional Active Treatment Hospital “St. Marina”, Varna , Bulgaria, S. Chan, 142-41 41st Avenue, Suite 10, Flushing , NY, P. Husa, University Hospital BRNO – BOHUNICE Department of Infectious Disease, CZECH REPUBLIC , Czech Republic, J. Sperl, Institute of Clinical & Experimental Medicine, Praha 4, Czech Republic, H. Mommeja-Marin, Gilead Sciences, Durham, NC, K. Borroto-Esoda, Gilead Sciences, Durham, NC, C. Moxham, Gilead Sciences, Durham, NC, J. Anderson, Gilead Sciences, Durham, NC, E. Mondou, Gilead Sciences, Durham, NC, J. Sorbel, Gilead Sciences, Durham, NC, F. Rousseau, Gilead Sciences, Durham, NC

 

Purpose:

Evaluate HBV viral load (VL) after 24 weeks of treatment with either emtricitabine 200 mg (FTC) plus clevudine 10 mg (CLV) versus FTC monotherapy and to perform resistance surveillance for viremic patients.

 

Methods:

Nucleoside naïve or experienced (48 weeks FTC 200 mg qd) patients were evaluated. Serum HBV DNA was assayed using a Real-Time PCR assay with a lower limit of detection (LOD) of 250 copies/mL (cp/mL). Genotypic analysis of the polymerase was performed at week 24 (W24) for viremic (>4700 cp/ml) patients.

 

Results:

Eighty-five HBeAg+ patients were enrolled; 44 (n=30 experienced and n=14 naïve) received FTC+CLV and 41 (n=25 experienced and n=16 naïve) received FTC monotherapy. The median baseline HBV DNA VL was 7 log10 cp/mL. At W24 a - 3.2 log10 and -2.0 log10 reduction in serum HBV DNA was observed for experienced patients in the combination and monotherapy arms, respectively, and a -3.3log10 reduction was observed among naïve patients, regardless of treatment arm. Among experienced patients, 30% given FTC+CLV versus 28% given FTC had HBV DNA <250 cp/mL at W24, and among naïve patients, the proportions were 50% and 19%, respectively. The W24 prevalence of FTC associated mutations was 22% and 3% among experienced and naïve patients, respectively.

 

Conclusion:

 In this HBeAg+ population, both emtricitabine plus clevudine and emtricitabine monotherapy produced a favorable antiviral response at week 24 as demonstrated by the median change from baseline in HBV DNA and by the proportion of patients with HBV DNA below the limit of detection. The incidence of mutations associated with FTC resistance at week 24 was 3% among patients naïve to therapy.


Poster 1005

Abstract ID: 67520

Category: J1O: Hepatitis B: Treatment

 

Lamivudine and Adefovir Versus Adefovir Alone for HBeAg-Positive Chronic Hepatitis B.

 

M. Ghany, NIH, Bethesda, MD, G. Lutchman, NIH, Bethesda, MD, D. Kleiner, NIH, Bethesda, MD, B. Borg, NIH, Bethesda, MD, T. Heller, NIH, Bethesda, MD, J. Feld, NIH, Bethesda, MD, R. Loomba, NIH, Bethesda, MD, Y. Park, NIH, Bethesda, MD, T. Liang, NIH, Bethesda, MD, J. Hoofnagle, NIH, Bethesda, MD

 

Background:

Therapy of chronic hepatitis B is problematic. Monotherapy with approved agents is associated with lack of response over time either due to ineffective antiviral activity or the development of resistance. Combination therapy may be an attractive option to prevent emergence of resistance as well as to manage patients with established lamivudine resistance.

 

Patients and Methods:

We initiated a randomized controlled trial of lamivudine and adefovir versus adefovir alone for patients with HBeAg-positive and -negative chronic hepatitis B with or without prior lamivudine resistance. The 1-year trial endpoints were normalization of ALT (Biochemical), lack of detectable HBV DNA by polymerase chain reaction (Roche Amplicor assay), loss of HBeAg or HBsAg (Virologic), and improvement in HAI score by ³ 4 points (Histologic response). This analysis was restricted to the HBeAg positive cohort. Comparisons between groups were by unpaired t-test.

 

Results:

To date 26 HBeAg positive patients (22 males, mean age 43 years) have been enrolled, 9 of whom were previously treated and had lamivudine resistance and 4 of whom had cirrhosis. Results of ALT levels, HBV DNA testing and liver histology on 22 patients who have finished 1 year of therapy are shown in the Table.

* P value represents comparison between groups at year 1 by unpaired t-test.

 

The major difference in the two groups at 1 year was the degree of inhibition of HBV DNA. The combination group had more dramatic HBV DNA suppression compared to the monotherapy group, log change 5.94 vs 3.88 respectively, p=0.026. 10/11 patients receiving combination therapy suppressed HBV DNA <104 copies per ml versus only 6/11 receiving monotherapy. A combined response of normal ALT, undetectable HBV DNA and improvement in HAI score by ³4 was seen in 7 combination versus 3 monotherapy patients, (p NS). Notably no evidence of clinical resistance was seen in any patient at 1 year. Therapy was well tolerated.

 

Conclusions:

The combination of adefovir and lamivudine provided more potent and consistent inhibition of HBV DNA levels than adefovir alone, but was not associated with further improvements in biochemical or histological features of disease. Adefovir monotherapy was associated with an inadequate virologic response in a number of cases. Longer-term therapy may be required to observe further benefits of combination therapy over monotherapy.
Poster 1006

Abstract ID: 67026

Category: J1O: Hepatitis B: Treatment

Prediction of response based on viral decline during PEG-interferon alpha-2b therapy in HBeAg-positive chronic hepatitis B.

 

M. J. ter Borg, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands, B. E. Hansen, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands, R. A. de Man, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands, S. W. Schalm, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands, H. L. Janssen, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands

 

Treatment of chronic HBeAg-positive hepatitis B with pegylated interferon is effective in only 30-40% of the patients. The most important baseline predictors for response are HBV genotype, low baseline HBV-DNA and elevated ALT levels. Until now, there are no stopping rules for pegylated interferon treatment of chronic hepatitis B. To investigate whether viral dynamics during pegylated interferon alpha-2b (PEG-IFN) monotherapy can predict response (defined as serum HBeAg loss 26 weeks post treatment), we analyzed 136 HBeAg-positive chronic hepatitis B patients who participated in a global randomised trial and who were treated with PEG-IFN 100 μg/week for 52 weeks. PEG-IFN dose was halved after 32 weeks of treatment. Serum HBV-DNA levels were measured monthly during therapy and 26 weeks post treatment by Taqman PCR assay.

 

At the end of follow-up, response was achieved in 49 of 136 patients (36%). During therapy responders exhibited a 4.23 log and non-responders a 1.22 log HBV-DNA decrease. Overall, early viral kinetics were not predictive for response. Only for patients with genotype A, responders had a pronounced decline of HBV-DNA whereas nonresponders remained flat during the treatment period and follow-up. One log decline of HBV-DNA at week 32 of treatment was highly predictive for response in genotype A (table). In the other genotypes, i.e. B, C and D, both responders and non-responders showed a decline in HBV-DNA during treatment followed by a post-treatment HBV-DNA rebound in non-responders and a sustained low HBV-DNA in responders.

 

In conclusion, for HBeAg-positive patients with genotype A, 1 log HBV-DNA decline after 32 weeks of PEG-IFN was highly predictive for sustained response. For the other HBV genotypes, on-treatment HBV-DNA decline did not predict response sufficiently to be used in clinical practice.

 

(N = 45)

HBV-DNA at week 32 was available in 120 patients; 2 patients with genotypes G and F were not analyzed.


Poster 1007

Abstract ID: 67607

Category: J1O: Hepatitis B: Treatment

 

Adefovir alone or combination with lamivudine in patients with lamivudine-resistance chronic HBeAg-negative hepatitis B. A non randomized multicenter controlled study.

 

S. Manolakopoulos, Department of Gastroenterology, Polykliniki General Hospital, Athens, Greece, S. BETHANIS, Polykliniki General Hospital, Athens, Greece, S. Koutsounas, Reference Center of Hepatitis, IKA, Athens, Greece, J. Goulis, 4th Department of Internal Medicine, University of Thessaloniki, Thessaloniki, Greece, A. Saveriadis, 2nd Department of Gastroenterology, Evangelismos General Hospital, Athens, Greece, E. Xristias, 1st Department of Internal Medicine Naval Hospital of Athens, Greece, Athens, Greece, A. Christidou, Department of Gastroenterology, Polykliniki General Hospital, Athens, C. Pavlidis, 2nd Department of Internal Medicine, General Hospital of IKA, Athens, Greece, C. Toubanakis, Dpt of Gastroenterology, Polykliniki General Hospital, Athens, Greece, J. Vlachogiannakos, 2nd Department of Gastroenterology, Evangelismos General Hospital, Athens, Greece, C. Triantos, Department of Gastroenterology, Polykliniki General Hospital, Athens, Greece, A. Avgerinos, 2nd Department of Gastroenterology, Evangelismos General Hospital, Athens, Greece, D. Tzourmakliotis, Department of Gastroenterology, Polykliniki General Hospital, Athens, Greece

 

Adefovir dipivoxil (ADV) has been recently licensed for the treatment of chronic hepatitis B (CHB). The drug has been shown to be effective against wild, precore, lamivudine-resistant forms of CHB and is associated with a lower resistance rate compared to lamivudine. The efficacy of lamivudine and ADV combination therapy in patients with HBeAg-negative CHB who have developed YMDD mutant is not known.

 

Aim:

To test the hypothesis that ADV+lamivudine combination therapy in patients with HBeAg-negative lamivudine-resistant CHB is followed by higher efficacy and safety compared to ADV monotherapy.

 

Patients and methods:

In the analysis we included 64 adult patients (M/F=53/11, median age=58) with CHB who developed breakthrough due to lamivudine-resistant strains. All patients had compensated liver disease, elevated transaminse levels and serum HBV DNA¡Ý105 copies/ml before initiation of ADV. In all patients ADV (10mg once daily) was added to lamivudine(100mg/daily) for 3 months and thereafter patients were assigned to continue combination treatment(group 1, 44 patients) or to receive ADV monotherapy(group 2, 20 patients).

 

Results:

Baseline parameters were similar between the two groups. At the time of this analysis the total duration of treatment was 16 to 31, median 26 months. No difference was observed between two groups in the patients with normal ALT levels at 12th and 24th months ( group 1: 87% / 65%, group 2: 72%/ 92%). Median reduction of serum HBV DNA at 6th, 12th and 18th month was 3.17/3.29/4.34 logs respectively in group 1 and 3.41/3.32/3.39 logs in group 2. The difference became significant at the 18th month (p=0.027). At 12th month serum HBV DNA >105copies/ml was observed in 2 patients (one at each group) and at 18th month in one patient in group 2. Two patients on ADV monotherapy developed virological breakthrough at 12th and 15th months of treatment respectively. None of the patients receiving combination developed breakthrough phenomenon.

 

Conclusions:

Our data suggest that ADV is an effective antiviral agent in patients with HBeAg-negative CHB who developed YMDD mutations. However, ADV+lamivudine combination appears to confer higher antiviral efficacy and may prevent ADV-resistant CHB.


Poster 1008

Abstract ID: 67711

Category: J1O: Hepatitis B: Treatment

 

Significant histologic disease in HBV-infected patients with normal to minimally elevated ALT levels at initial evaluation.

 

M. Nguyen, Stanford University Medical Center, Pacific Health Foundation, Palo Alto, CA, H. Trinh, Pacific Health Foundation, San Jose, CA, R. T. Garcia, Pacific Health Foundation, San Jose, CA, A. Ahmed, Stanford University Medical Center, Palo Alto, CA, E. Keeffe, Stanford University Medical Center, Palo Alto, CA

 

PURPOSE:

Current guidelines recommend antiviral therapy for chronic hepatitis B (CHB) patients with elevated ALT. However, many patients who present with “normal” ALT may not have persistently normal ALT on follow-up and may have significant histologic disease. The purpose of this study was to define the spectrum of histologic findings in such patients.

 

METHODS:

We performed a retrospective cohort study of all patients with active HBV infection (HBV DNA >10,000 copies/mL) and normal or minimally elevated ALT (up to 2x ULN) evaluated with liver biopsy at a single U.S. center. Independent predictors of significant histology (grade 2, stage II or higher) were identified by multivariate analysis.

 

RESULTS:

A total of 56 patients were included: ALT normal (n=39; 70%), up to 1.3x ULN (n=8; 14%), or 1.3-2.0x ULN (n=9; 16%). Mean age was 46±12, 64% were male, 20% had history of alcohol use, 18% had family history of liver cancer or liver-related death, all were Asian, 60% were HBeAg negative, and 43% had HBV DNA >1 million copies/mL at evaluation. Mean ALT at biopsy was 45±18. Mean ALT per patient was 57±55 (median, 45; range, 15-365). Average number of ALT tests per patient was4.9±2.6 over a mean follow-up of 31±29 months. Average number of ALT tests over a 6-month period per patient was 2.0±0.9. Of those with normal ALT at evaluation, 46% continued to have normal ALT on long-term follow-up. Of those with normal ALT at 6- month follow-up, 33% had an elevated ALT on further follow-up. Mild steatosis was seen in 5 and moderate in 1 patient. Figure shows histologic results. Significant histologic findings were found in 12% of patients with persistently normal ALT compared vs. 55% in those with elevated ALT (p=0.003). On multivariate analysis, only age >45 was an independent predictor of significant histology (OR=12.9, p=0.008) and only presence of persistently normal ALT on long-term follow-up (not ALT or HBV DNA levels at evaluation or 6-month follow-up) was an independent predictor of favorable histology (OR=0.04, p=0.003).

 

CONCLUSION:

Persistently normal ALT on long-term follow up is a strong predictor of favorable histology, but only 46% of the patients with normal ALT at evaluation and only 33% of patients with normal ALT at 6-month follow-up continued to have normal ALT. Patients who present with normal to minimally elevated ALT should be evaluated carefully with follow-up or liver biopsy, particularly those older than age 45.

 


Poster 1009

Abstract ID: 65612

Category: J1O: Hepatitis B: Treatment

 

More frequent and earlier emergence of adefovir (ADV) resistance mutations inlamivudine resistant patients treated with ADV compared to previously reportednucleoside-treatment naive patients.

 

C. Lee, Konkuk University Medical College, Seoul, Korea, Republic of, J. Yeon, Korea University Medical College, Seoul, Korea, Republic of, S. Hong, GeneMatrix Inc., Gyeonggi-do, Korea, Republic of, J. Kim, Korea University Medical College, Seoul, Korea, Republic of, Y. Seo, Korea University Medical College, Seoul, Korea, Republic of, H. Chung, GeneMatrix Inc., Yongin-si, Gyeonggi-do, Korea, Republic of, M. Moon, GeneMatrix Inc., Yongin-si, Korea, Republic of, S. Kim, GeneMatrix Inc., Yongin-si, Korea, Republic of, W. Yoo, GeneMatrix Inc., Yongin-si, Korea, Republic of, K. Byun, Korea University Medical College, Seoul, Korea, Republic of, S. Yu, Konkuk University Medical College, Seoul, Korea, Republic of

 

Background:

The cumulative incidence of adefovir (ADV) resistant mutations in the nucleoside-treatment naive chronic hepatitis B (CHB) patients at weeks 48, 96, 144 were known to be 0, 0.8-3% and ~5.9%, respectively. The aim of this study was to analyze the incidence and clinical consequence of ADV-resistant rtA181V/T and rtN236T mutation in lamivudine (LMV)-resistant CHB patients who were treated with ADV.

 

Materials and methods:

 Sera were collected from 106 genotypically confirmed LMVresistant CHB patients who were treated with ADV. The serum HBV DNA was quantified by real time PCR. The ADV mutant was detected by using matrix-assistedlaser desorption/ionization time of flight mass spectrometry  (MALDI-TOF MS)-based genotyping assays, termed Restriction Fragment Mass Polymorphism (RFMP).

 

Results:

RFMP analysis revealed that a total of 50 amino acid substitutions developed in the rt domain of the HBV polymerase in 41 of 106 patients. The rtA181V, rtN236T and rtA181T mutations were detected in 10, 6 and 34 patients at treatment weeks 3~96, 3~96and 0~96, respectively. The cumulative incidence of genotypic ADV resistance at weeks 48 and 96 was 32% and 58%, respectively. Serial quantification of the serum HBV DNA revealed that 16 of 41 patients with genotypic mutation displayed the HBV DNA rebound. The magnitude of the median log10 HBV DNA reductions at treatment months twelve was 2.2 vs 3.8 in patients with or without genotypic mutation (p<0.05).

 

Conclusion: The emergence of the ADV mutations in LMV resistant patients who are treated with ADV appeared to present earlier and is more frequent than in nucleosidetreatment na?e patients. Prolonged studies are needed to define the long-term clinical outcome in these types of patients.


Poster 1010

Abstract ID: 66669

Category: J1O: Hepatitis B: Treatment

 

Therapeutic role of preemptive lamivudine therapy for the prevention of hepatitis B virus reactivation in patients with hepatocellular carcinoma undergoing transarterial chemolipiodolization: a randomized controlled study.

 

J. W. Jang, Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea, Republic of, J. Y. Choi, Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea, Republic of, C. W. KIm, Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea, Republic of, S. H. Bae, Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea, Republic of, S. K. Yoon, Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea, Republic of, J. M. Yang, Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea, Republic of, C. D. Lee, Department of Internal Medicine, The Catholic University of Korea, Seoul, Y. S. Lee, Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea, Republic of, K. W. Chung, Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea, Republic of, H. S. Sun, Department of Internal Medicine, The Catholic University of Korea, Seoul, Korea, Republic of

 

Background/Aim:

Accumulating evidence indicates that most fatal cases of hepatitis B virus (HBV) reactivation occurring during chemotherapy are related to the late institution of lamivudine, raising the need for the preemptive use of antiviral agents. Given the potential risk of treatmentrelated hepatotoxicity and underlying cirrhosis in hepatocellular carcicnoma (HCC) patients, the optimal therapeutic strategy and identification of patients at risk for this complication should be made before transarterial approach. The aim of this study was to evaluate the efficacy of preemptive lamivudine therapy in reducing hepatic complications in patients with HBV-related HCC undergoing transarterial chemo-lipiodolization (TAC), and to seek predictors of the events.

 

Methods:

A prospective randomized study was conducted, recruiting 73 consecutive HCC patients undergoing TAC using combined epirubicin 50 mg/m2 and cisplatin 60 mg/m2 at monthly intervals. Patients were randomly assigned to receive lamivudine 100 mg daily before TAC (preemptive group) or not (control group). Hepatitis due to HBV reactivation was defined as a 3-fold or greater increase of serum ALT in patients with HBV reactivation (a 10-fold increase of viral load). Virological test was serially done at monthly intervals, and alanine aminotransferase (ALT) level was measured at biweekly intervals.

 

Results:

During the study period, 11 (29.7%) of 37 patients in the control group and 1 (2.8%) of 36 patients in the preemptive group developed hepatitis due to HBV reactivation. There was a significantly more occurrence of hepatitis due to HBV reactivation in the control group than in the preemptive group (P=0.002). In addition, moderate (ALT >2´the upper limit of normal [ULN]) or severe (ALT >5´ULN) grade of hepatitis of all causes were more frequently observed in the control group as compared with the preemptive group (51.4% vs. 27.8%, P=0.040), irrespective of viral reactivation. There was a tendency towards more episodes of treatment disruptions in the control group than in the preemptive group (40.5% vs. 22.2%, P=0.092). With multivariate Cox regression model, baseline HBV DNA level of >104 copies/ml was independently predictive of hepatitis due to HBV reactivation during TAC (P=0.046).

 

Conclusion:

This study provided support for the concept of preemptive antiviral therapy during transarterial chemo-lipiodolization. The preemptive use demonstrated an excellent efficacy of reducing HBV reactivation, overall hepatic morbidity, and treatment disruptions in this setting. This approach should be considered in all HCC patients with HBV DNA level of >104 copies/ml before transarterial chemotherapy.


Poster 1011

Abstract ID: 66860

Category: J1O: Hepatitis B: Treatment

 

MECHANISTIC BASIS FOR HEPATITIS B VIRUS RESISTANCE TO ACYCLIC NUCLEOSIDE PHOSPHONATE ANALOGUES, ADEFOVIR AND TENOFOVIR.

 

A. Bartholomeusz, Victorian Infectious Diseases Reference Laboratory, North Melbourne, Australia, S. Locarnini, Victorian Infectious Diseases Reference Laboratory, North Melbourne, Australia, A. Ayres, Victorian Infectious Diseases Reference Laboratory, North Melbourne, Australia, G. Thompson, Victorian Infectious Diseases Reference Laboratory, North Melbourne, Australia, S. Bowden, Victorian Infectious Diseases Reference Laboratory, North Melbourne, Australia, V. Sozzi, Victorian Infectious Disease Reference Laboratory, North Melbourne, Australia, P. Angus, Austin Hospital, Heidelberg, Australia, W. Sievert, Monash Medical Centre, Clayton, Australia, J. Sasadeusz, Victorian Infectious Diseases Service, Parkville, Australia, D. Chalmers, Victorian College Pharmacy, Parkville, Australia, M. Kuiper, Victorian Partnership for Advanced Computing, Carlton, B. Rodes, Hospital Carlos III, Madrid, Spain, J. Sheldon, Hospital Carlos III, Madrid, Spain, V. Soriano, Hospital Carlos III, Madrid, Spain

 

Background/Aims:

Patients with chronic hepatitis B are being treated with Lamivudine (LMV) and/or Adefovir (ADV) whilst patients co-infected with HBV and HIV can be treated with LMV and/or Tenofovir (TDF) to control HBV replication. Resistance to ADV has been associated with three clusters of mutations, (i) D and A domains of the HBV polymerase (pol) which includes the mutation at rtN236T (ii) the B domain mutations at rtA181T/V and (iii) the C-D interdomain mutations rtV214A, rtQ215S which are distal to the active site. Resistance to TDF is associated with a mutation at rtA194T in the B-C interdomain region. The aim of this study was to determine the crossresistance profiles of these mutations in vitro and analyse the molecular basis for resistance using molecular modelling.

 

Methods:

The ADV and TDF resistance HBV mutations were created by site-directed mutagenesis in an HBV infectious clone. In vitro phenotypic analysis of the HBV clones was performed by transient transfection in the presence of ADV, or TDF or LMV using standard techniques and the IC50 determined from dose-response curves using Table Curve 2D software [Hepatology. 2003;37:27]. A three dimensional model of the HBV pol based on the HIV reverse transcriptase crystal structures was used to analyse the HBV mutations.

 

Results:

In vitro antiviral testing of the C-D interdomain HBV mutants demonstrated a 4 to 10 fold increase in IC50 to ADV consistent with drug resistance and also a 10 fold increase in IC50 to LMV. HBV encoding the TDF resistance mutation at rtA194T showed a 7 fold increase in IC50. Molecular modelling of the two groups of B-C and CD interdomain mutations revealed that these mutations are in loop regions at the opposite ends of the beta sheets that encompass the YMDD loop region. These two interdomain regions appear to be involved in structural integrity of the polymerase active site even though they are not located within the nucleotide binding pocket, nor directly interacting with the DNA. Mutations in these regions can result in conformational changes within the active site, affecting the cross-sensitivity profile to a number of antiviral agents including LMV.

 

Conclusion:

We have identified two distal regions in the HBV polymerase within the HBV polymerase that are associated with potential multidrug resistance to the class of acyclic phosphonate nucleoside analogues such as TDF and L-nucleoside analogues such as LMV. Molecular modelling in association with in vitro testing can aid in determining the significance of mutations in the context of chemical class resistance and thus may aid in the choice of the next therapeutic agent.


Abstract ID: 67426

Category: LO1: Public Policy, Epidemiology, and Decision Analysis

Treatment Alternatives for Hepatitis B Cirrhosis: A Cost-Effectiveness Analysis.

F. Kanwal, West Los Angeles VA, Los Angeles, CA, Los Angeles, CA, M. Farid,

Greater Los Angeles Healthcare System at West LA, Los Angeles, CA, P. Martin,

Mount Sinnai Medical School, New York, NY, G. Chen, Cedar Sinnai Medical Center,

Los Angeles, CA, I. M. Gralnek, Greater Los Angeles Healthcare System at West LA,

Los Angeles, CA, G. S. Dulai, David Geffen School of Medicine at UCLA, Los Angeles,

CA, B. M. Spiegel, Greater Los Angeles Healthcare System at West LA, Los Angeles,

CA

 

 

Background:

Hepatitis B virus (HBV) patients with cirrhosis are at high risk for developing costly, morbid, or mortal events, and therefore require effective therapies. Lamivudine (LAM) is effective in HBV cirrhosis but is associated with a high rate of viral resistance. In contrast, newer agents like adefovir dipivoxil (ADV) and entecavir (ETV) have less viral resistance, but are more expensive. Because patients with cirrhosis can ill-afford the emergence of viral resistance and potentially life-threatening viral flares, there is a delicate balance between avoiding resistance and minimizing cost in the

treatment of HBV cirrhosis. The most cost-effective approach is uncertain.

 

Methods:

We performed an economic analysis to estimate the cost-effectiveness of four treatment strategies in a hypothetical cohort of 50-year old patients with chronic HBV cirrhosis and active viral replication: (1) No HBV treatment (“do nothing”), (2) LAM monotherapy, (3) ADV monotherapy, or (4) LAM with cross-over to ADV upon resistance (“ADV salvage”). In order to emulate the case-mix in clinical practice, we included patients with compensated and decompensated cirrhosis. Because there are currently limited data regarding ETV, we did not include this agent in the primary

analysis. We instead performed a hypothesis generating sensitivity analysis incorporating current drug prices to estimate the potential cost-effectiveness of ETV. We incorporated probability estimates derived from a systematic review, and adopted cost estimates from a third party payer perspective. Monthly prices for LAM, ADV, and ETV were $158, $528, and $720, respectively. The primary outcome was the incremental cost per quality adjusted life-year (QALY) gained.

 

Results:

The “do nothing” strategy was least effective yet least expensive. Compared

with “do nothing,” using ADV cost an incremental $20,011 per QALY-gained. LAM monotherapy was more expensive yet less effective than ADV. Compared with ADV, in turn, “ADV salvage” cost an incremental $107,165. ADV monotherapy was the most cost-effective strategy in HBV patients with both compensated and decompensated cirrhosis. ETV revealed “diminishing returns” compared to ADV on the basis of the current 22% higher cost of ETV.

 

Conclusions:

These data indicate that ADV may be the most cost-effective strategy in

patients with HBV cirrhosis, regardless of the stage of liver disease. Among the new generation of antiviral agents for HBV, the least expensive agent is likely to remain the most cost-effective. These findings should be confirmed in prospective clinical trials that measure the accrued costs and effectiveness of competing agents in HBV cirrhosis.

Abstract ID: 63446

Category: LO1: Public Policy, Epidemiology, and Decision Analysis

LONG-TERM TREATMENT WITH ADEFOVIR DIPIVOXIL IS MORE COST EFFECTIVE THAN LAMIVUDINE FOR HBeAg-NEGATIVE PATIENTS WITH CHRONIC HEPATITIS B.

M. Buti, Hospital General Universitari Vall d'Hebron, Barcelona, Spain, M. A. Casado,

Pharmacoeconomics & Outcomes Research Iberia, Pozuelo de Alarcón, Spain, J. L.

Calleja, Hospital Puerta Hierro, Madrid, Spain, J. Salmerón, Hospital Clínico San

Cecilio, Granada, Spain, J. Aguilar, Hospital Virgen del Rocio, Seville, Spain, M.

Rueda, Gilead Sciences, Inc., Madrid, Spain, R. Esteban, Hospital General Universitari

Vall d'Hebron, Barcelona, Spain

 

 

Aim:

To estimate the cost-effectiveness of long-term therapy with adefovir dipivoxil (ADV) or lamivudine (LAM) as therapies for patients with HBeAg-negative chronic hepatitis B (CHB).

 

Methods:

A decision analysis model has been designed for a panel of experts to perform a cost effectiveness analysis of LAM (100 mg/daily) and ADV (10 mg/daily) over three years of therapy. Data for each strategy were obtained from published clinical trials. Virological response was defined by undetectable HBV DNA. The study was performed from the perspective of the Spanish Public Health System considering the following direct health costs (in US$): drug acquisition, visits, diagnostic or laboratory tests to determine virologic response and HBV drug resistance.

 

Results:

The following table shows the results of the base-case analysis (with a 3% annual discount for costs):

 

 

The costs associated with three years therapy with ADV were 2.2 times greater than those of LAM. Virological response achieved with ADV was 2.5 times greater than that of LAM. Despite the higher costs associated with ADV, the incremental cost-effectiveness ratio of ADv versus LAM was lower than the average cost-effectiveness ratios of ADV or LAM. The sensitivity analysis demonstrated the robustness of the model, being the response to ADV and LAM at year 3 the factors that most influence the cost-effectiveness.

 

Conclusion:

Long-term treatment with ADV is a cost-effective strategy in patients with chronic HBeAg-negative hepatitis. Therefore, adefovir dipivoxil should be used as a first line treatment due to the high percentage of virological response obtained at year 3 and because its cost per responding patient is lower than that of LAM.