Tuesday Posters: HBV May 23rd 8:00 AM-8:00 AM

 

T1840. Baseline HBV DNA level >6 log is the most important factor associated with viral breakthrough (BT) during lamivudine (LAM) therapy for chronic hepatitis B (CHB)

H. Chae; H. Hann

 

High incidence of viral BT has been the major disadvantage of lamivudine (LAM) in the treatment of CHB. With the advent of new antivirals, LAM may become less in demand as the first line drug. Nevertheless, it is becoming increasingly clear that the management of CHB requires a long term therapy and the cost of treatment becomes an important issue for those with low income/without medical insurance. Therefore, in a retrospective study, we investigated if there are factors most closely associated with viral BT during LAM therapy, and thus, we could identify a subgroup of patients (pts) who may still benefit from LAM without developing BT at an early stage of treatment.

 

Materials and Methods:

Of the CHB pts treated during the period of 2000-2004, the study included only those; 1) who received LAM >12 months, 2) whose baseline HBV DNA levels were ≥3 log (by PCR ) and 3) who showed optimal response (HBV DNA decrease >2 log and/or HBV DNA < 4 log after 1 year treatment). Viral BT was defined as > 1 log HBV DNA increase following the initial viral suppression.

 

Results:

88 pts (59 males) met the eligibility criteria. They were all Asian Americans, with the mean age of 4612 years (yr). Of the 88 pts, 38 (43%) were infected at birth. The median duration of therapy was 25 (12-57) months (mos). At baseline, median ALT was 66 IU/L (11-3395), the mean log HBV DNA level for 88 pts was 6.11.6; for 39 HBeAg(+)pts was 6.6 1.5 and for 45 HBeAg(-)pts, 5.61.5 (HBeAg data missing in 4). The mean log reductions of HBV DNA from baseline for all pts were 3.72.1 at 6 mos, 4.12.1 at 1 yr, but 2.73.0 at 2 year due to the presence of BT in some patients. HBeAg loss was 17%, 23% and 28 % at yr 1, 2, and 3. Excluding those with normal or missing ALT, normalization of ALT was 81% and 84% at 6 and 12 mos. The %BT for pts with HBV DNA >6 log (n=40) was 10%, 30%, and 72% at yr 1, 2, and 3, and for pts with HBV DNA ≤ 6 log (n=41) %BT was 2%, 12% and 41% at yr 1, 2, and 3. When all factors (gender, duration of infection, baseline HBV DNA, HBeAg status, and baseline ALT) were analyzed by Cox regression, the most important factor associated with viral BT was the baseline HBV DNA level. Pts with baseline HBV DNA > 6 log had higher %BT than those with HBV DNA <6 log (p=0.04).

 

Conclusions:

Our study indicates that the most important factor associated with the development of viral BT with LAM is the baseline HBV DNA level regardless of HBeAg status. Therefore, pts with baseline HBV DNA level ≤ 6 log may benefit from LAM therapy. For CHB pts with low level of viral replication, and with financial disadvantages, LAM may still remain an affordable and effective therapy.

 


T1841. Tenofovir(TNV) has a stronger antiviral effect than adefovir dipivoxil(ADV) against lamivudine(LAM) resistant hepatitis B virus(HBV)

H. L. Hann; H. Chae; S. R. Dunn

 

Patients with chronic hepatitis B (CHB) who developed LAM resistance were treated with TNV or ADV. In some, LAM was continued or added later. In this retrospective study we compared the suppressive activities of TNV and ADV against LAM resistant HBV.

 

Materials and Methods:

109 patients (86 M, 23 F), all Asian Americans except 1 Caucasian male, were included in the study. All had viral breakthrough during LAM therapy and received TNV or ADV for ≥ 6 months (mos). Reduction of HBV DNA and ALT normalization were assessed at 6 and 12 mos. HBeAg loss was examined within 24 mos.

 

Results:

44 patients (37M, 7F) received TNV (12 with LAM) and 65 (49M, 16F) received ADV (18 with LAM). Median ages for TNV and ADV groups (grps) were 49 years (32-68) and 45 years (22-68) respectively. Median duration of therapy was 13 mos (ranges 6-38) for TNV grp and 17 mos (ranges 6-34) for ADV grp. Baseline ALT levels (IU/L) were 77.0 86.2 and 100.4 195.0 for TNV and ADV (P=0.46).

 

As shown in the table, baseline HBV DNA levels were similar for both grps. Mean HBV DNA reduction (Log10 copies/ml) at 6 and 12 mos was stronger for TNV than ADV. Viral reduction>3 log (at 12 mos) was greater for TNV than ADV. HBeAg loss in 24 mos showed no difference. ALT normalization (6 mos) was 55% and 66% for TNV and ADV respectively. Using single factor, two-tailed ANOVA, 4 grps, TNV (n=32), TNV+LAM (n=12), ADV (n=47) and ADV+LAM (n=18), were compared. There was no difference in 4 grps with respect to the baseline DNA or baseline ALT. However, HBV DNA reduction at 6 mos was greater for TNV+LAM grp than either ADV grps. Furthermore, no patient developed viral breakthrough during the 6- 38 mos observation period.

 

Conclusion:

Our results suggest that for LAM resistant HBV, TNV, alone or combined with LAM exerts a greater viral reduction than ADV. However, there is no difference in HBeAg loss or ALT normalization. It appears that stronger HBV DNA reduction may not necessarily speed up the HBeAg loss. Viral breakthrough appears low with TNV with or without LAM.

 

 

TNV

ADV

p value

No. Pts

44 (12 with LAM)

65 (18 with LAM)

 

Duration of Treatment

13 mos (6-38)

17 mos (6-34)

 

Baseline HBV DNA (log10 copies/ml)

6.23+/-1.66

6.49+/-1.56

0.404

Mean HBV DNA log reduction (6 mos)

3.65+/-1.75 (n=30)

1.94+/-1.98 (n=45)

0.00

Mean HBV DNA log reduction(12 mos)

5.03+/-1.64 (n=15)

2.36+/-2.37 (n=42)

0.00

DNA reduction>3 log

63%

28%

0.013

HBeAg loss (in 24 mos)

4.5% (2/44)

7.7%
(5/65)

0.699


T1842. Predicting Liver Disease Complications (Hcc And Cirrhosis) In Patients With Chronic Hepatitis B Infection Using A Risk Function Model: The R.E.V.E.A.L.- HBV Study

C. Chen; H. Yang; U. H. Iloeje; C. Jen; S. You; Y. Liaw

 

Background & Aims:

Predicting CHB patients at risk of progressing to liver complications is a clinical challenge. Our objective was to develop a prediction model using readily available non-invasive clinical information in CHB infected subjects.

 

Methods:

Information from HBsAg-positive (anti-HCV-negative) subjects recruited from 7 townships in Taiwan between 1991 and 1992 was used for these analyses. Subjects were randomized into two groups (training and validation) on a 1:1 basis. HCC and cirrhosis cases were ascertained via computerized linkage to the Taiwanese National Cancer Registry and Death Certificates Profiles or by ultrasound examination. Additionally, medical charts were reviewed using a structured abstraction form to confirm the diagnoses. HCC was confirmed by one of the following: cyto-histopathology; focal liver lesions by two coincident imaging studies (ultrasonography, CT Scan, MRI and/or angiography); focal liver lesion on one imaging study and an alpha fetoprotein (AFP) level >400 ng/mL. Multivariate logistic regression models were used to identify the predictive variables, and the model accuracy determined by the Area Under the Receiver Operator Characteristic curves (AUROC).

 

Results:

N=3582/3653 without baseline cirrhosis were included. The mean follow-up time was 11 years. The training set 1791/3582 (50%), was comparable to the validation set for all variables and outcome events (p>0.05). The best fitting models had Age and HBV DNA as the strongest predictors of future liver complications. For HCC only model AUROC=0.8450; concordant percent 96.4%; discordant percent 3.6%; model goodness of fit p=0.49. The risk (OR [95% CI]) associated with age 60-65 was 17.5 [6.4-47.5] [reference group 30-39]; and HBV DNA >= 105 copies/mL was 8.9[4-19.9] [reference<300 copies/mL]. For HCC/cirrhosis model AUROC=0.7713; concordant percent 88.5%; discordant percent 11.5%; model goodness of fit p=0.71. The risk (OR [95% CI]) associated with age 60-65 was 4.3 [2.5-7.5] [reference group 30-39]; and HBV DNA >= 105 copies/mL was 4.9 [3.3-7.5] [reference <300 copies/mL]. AUROC in the validation group was 0.86 (HCC model); 0.79 (HCC/cirrhosis model).

 

Conclusion:

Risk stratification for liver disease complications in CHB-infected persons is possible using a model comprised of readily available non-invasive clinical information. This model may be useful in making management decisions.

 


T1843. Occurrence of Primary Adefovir Resistance Mutation in Hepatitis B Patients with YMDD Mutation and Lamivudine Resistance

D. Kim; J. Lee; D. Lee; M. Choi; K. Koh; S. Paik; B. Yoo

 

Backgrounds and Aims:

It is suggested that various mutations in the hepatitis B virus (HBV) polymerase genes, such as rtA181V/T, rtN236T, and rtP237H, could induce resistance to adefovir dipivoxil. A recent research has reported that primary resistance to adefovir can occur as a consequence of a long-term lamivudine treatment. The aim of this study was to elucidate the incidence of primary resistance mutation to adefovir in patients with YMDD mutation and to assess the clinical course of those patients.

 

Patients and Methods:

A total of 293 patients with hepatitis B were enrolled. In those patients, lamivudine had been switched to adefovir because of YMDD mutation and lamivudine resistance. Twenty-eight patients (13 with prior lamivudine use) without YMDD mutation were selected as controls. Serum samples were obtained before commencement of adefovir therapy. Adefovir resistance mutations were screened by restriction fragment mass polymorphism (RFMP) for rt181, rt236, rt237 and rt238 and confirmed by direct sequencing of the HBV polymerase gene.

 

Results:

Out of the included patients, 11 patients (3.7%) were found to have primary adefovir resistance mutation (rtA181V/T in 2 and rtP237H in 9 patients). None of the control patients was found to have any adefovir resistance mutation. During a median follow-up of 14 months (9-25 months) after initiation of adefovir therapy, alanine aminotransferase (ALT) levels decreased to below upper normal limit and remained normal (239 IU/L) in all patients. HBV DNA levels decreased to undetectable level (<0.5 pg/ml by Digene Hybrid Capture Assay II) and remained undetectable in all patients except in one patient in whom the lowest level was 13.7 pg/ml. There were no significant differences in the duration of lamivudine use, pretreatment ALT levels, pretreatment HBV DNA levels, and frequency of pretreatment HBeAg positivity between the patients who developed a resistance mutation and those who did not (p>0.05).

 

Conclusion:

The incidence of primary adefovir resistant mutation was 3.7% in patients with YMDD mutation and resistance to lamivudine. Although phenotypic resistance was rare among the patients with primary resistance mutation in a short-term follow-up, long-term observation may be required to clarify the clinical significance of those mutations.


T1844. Durability of HBeAg Seroconversion Following Adefovir Dipivoxil Treatment for Chronic Hepatitis B (CHB)

T. Chang; M. L. Shiffman; M. Tong; Y. Liaw; P. Komolmit; J. Sorbel; S. Arterburn; E. Mondou; S. Chuck; P. Marcellin

 

Background and aims:

HBeAg seroconversion (HBeAg loss with development of anti-HBe) has been considered an important therapeutic marker in the treatment of CHB in HBeAg+ patients. Study 481 evaluated the durability of seroconversion following adefovir dipivoxil (ADV) treatment.

 

Methods:

Study 481 enrolled CHB patients with compensated liver function who had confirmed seroconversion to anti-HBe and HBV DNA < 100,000 copies/mL by Roche Amplicor PCR assay during treatment with adefovir dipivoxil 10 mg once daily. Patients were followed off treatment with serologic assessments at least every 24 weeks.

 

Results:

At entry (n=45) median age was 34 years, 64% male, 73% Asian, 27% Caucasian, median serum HBV DNA 3.00 log copies/mL (min-max, 2.6, 3.2), and median ALT 25 IU/L (min-max, 9,110). Median duration of ADV treatment before seroconversion was 54.4 weeks (Q1, Q3; 24.1, 75.4) and after seroconversion was 37 weeks (Q1, Q3; 27.0, 72.1). Median follow-up off drug was 143 weeks (Q1, Q3, 110, 193; range 13-245). Four patients (9%) did not maintain seroconversion at follow-up weeks 12 (n=3) and 16 (n=1) (at the time of seroreversion all had HBV DNA >100,000 copies/mL; ALT 84-222 IU/L). Forty-one patients (91%) maintained durable seroconversion at the last 2 assessments and most were followed for several years: 15 (37%) for 2-3 years and 19 (46%) for over 3 years. There was no difference in entry characteristics (serum HBV DNA, ALT, age, gender) for patients with and without durable seroconversion. Median duration of ADV treatment before seroconversion was longer (108 versus 48 weeks) for patients who seroreverted. Seroreverters received less ADV after seroconversion than those with durable seroconversion (median 22 versus 41 weeks). All 4 seroreverters were Asian and all had HBV genotype C. The distribution of genotype among durable seroconverters was 10 A; 9 B; 17 C; 4 D; 1 G. For all patients, the median HBV DNA at the last timepoint off drug was 3.04 log copies/mL (Q1, Q3; 3.00, 4.15; 44% < 1000 copies/mL), and median absolute ALT was 28 IU/mL (Q1, Q3; 21, 41).

 

Conclusions:

Seroconversion to anti-HBe was durable off ADV treatment in 91% of patients over a median follow-up of 3 years. Four patients (9%) lost seroconversion and reverted to HBeAg+ within 16 weeks of the end of treatment; these 4 patients were genotype C and received less ADV after seroconversion (maximum 32 weeks) than patients with durable seroconversion.

 


T1845. Entecavir (Etv) Is Associated With An Improvement In Liver Histology And A Reduction In Hbv Dna In Patients With Lamivudine-Refractory Hbeag(+) Regardless Of Baseline Characteristics

M. L. Shiffman; Z. Goodman; P. J. Paul; T. D. Boyer; M. Sherman; Y. Batur; A. Boron-Kaczmarska; J. Vaughan; R. G. Hindes

 

Background:

In a recently conducted prospective, randomized controlled trial patients with lamivudine (LVD)-refractory (LVDR) chronic HBV were treated with entecavir (ETV) or remained on LVD for at least 48 weeks. At Week 48, ETV treatment resulted in an HBV DNA reduction of 5.11 log10 copies/mL versus 0.48 log10 copies/mL for LVD, while histologic improvement occurred in 55% of ETV and 28% of LVD patients. The present analysis evaluates whether baseline factors are predictive of response to ETV/LVD at 48 weeks.

 

Methods:

All patients with LVDR enrolled in this trial were analyzed according to whether they developed histologic improvement and/or HBV DNA <300 copies/mL. The relationship between efficacy results and baseline disease and demographic subgroups was then assessed. Disease-related variables included baseline ALT, HBV DNA, and HBV genotype. Demographic variables included geographic region, race, age and gender. Histologic improvement was defined as a ≥2-point decrease in Knodell necroinflammatory score and no worsening of fibrosis (worsening: ≥1-point increase in Knodell fibrosis score).

 

Results:

No relationship between patient demographic variables and disease-related variables existed with respect to either histologic or virologic response to ETV.

 

Conclusions:

The proportion of patients with LVDR who exhibit histologic improvement and HBV DNA <300 copies/mL is significantly greater when converted to ETV as opposed to remaining on LVDR. Such improvement occurs in patient groups regardless of demographic characteristics, HBV genotype and the serum level of ALT or HBV DNA.

 

 

Histologic Improvement
at Week 48

HBV DNA <300 copies/mL
at Week 48

Baseline Variable

ETV n (%)
N=124

LVD n (%)
N=116

ETV n (%)
N=141

LVD n (%)
N=145

HBV Genotype
A
B
C
D

 

18/33 (55)
14/21 (67)
14/26 (54)
17/35 (49)

 

7/28 (25)
6/16 (38)
2/26 (8)
16/37 (43)

 

12/37 (32)
6/23 (26)
5/27 (19)
3/45 (7)

 

0/32 (0)
1/17 (6)
0/28 (0)
1/56 (2)

ALT
<2 x ULN
25 x ULN
>5 x ULN

 

27/58 (47)
28/59 (57)
13/17 (76)

 

17/59 (29)
12/43 (28)
3/14 (21)

 

8/66 (12)
13/55 (24)
6/20 (30)

 

0/76 (0)
0/53 (0)
2/16 (13)

HBV DNA
<107 c/mL
107-<108 c/mL
108-<109 c/mL
109-<1010 c/mL
≥1010 c/mL

 

8/11 (73)
4/11 (36)
17/29 (59)
22/44 (50)
17/29 (59)

 

5/9 (56)
2/9 (22)
10/33 (30)
13/47 (28)
2/18 (11)

 

9/22 (41)
5/33 (15)
6/52 (12)
7/34 (21)

 

0/25(0)
0/37 (0)
1/57 (2)
1/26 (4)

<108 copies/mL HBV DNA

 


T1846. Hepatitis B screening and prevention - Is our knowledge adequate for the future?

A. Barmaki; R. Shandil; S. Mohanty; A. Sahota

 

BACKGROUND:

There are more than 1.25 million carriers of the Hepatitis B virus (HBV) in the United States, with an increased prevalence in populations with high-risk behaviors as well as specific ethnic subgroups from high endemic areas. Primary care physicians (PCP) are the first to encounter these patients and it is their duty to manage them appropriately. Multiple studies have assessed PCP's knowledge on hepatitis C, but none exist for HBV.

 

AIM/METHODS:

To determine internal medicine residents' practice knowledge on HBV screening, evaluation and prevention a survey was administered to members of a large university-based residency program.

 

RESULTS:

Eighty one (51%) out of 160 residents completed the survey, with an equal representation from each post graduate year; 70% were US graduates and 42% had managed more than 10 patients with HBV over the last year. Table 1 reflects HBV screening knowledge of internal medicine residents and Table 2 represents their vaccination knowledge. Only 48% of residents would vaccinate HBV infected patients for hepatitis A virus (HAV). 64% of residents knew the vaccination schedule for HBV and 37% for HAV. Although there is no vaccine for hepatitis C, 15% of residents replied they would vaccinate for it. Only 58% of residents correctly identified anti-HBs as the serological marker to be tested in patients vaccinated for HBV. In patients with chronic HBV, 44% of residents would not screen for co-infection with HCV, 38% would not check HBeAg and 62% would not check for HBeAb.

 

CONCLUSIONS:

We conclude that hepatitis B knowledge for early screening/evaluation is inadequate among internal medicine physicians in training. Future primary care providers should receive increased focused educational intervention on HBV to improve quality of care.

 

Undertested population
(% of residents who would not screen groups who should be screened)

Overtested population
(% of residents who would screen groups that do not need to be screened)

Pregnant females- 42%

History of blood transfusion in 1990- 42%

Multiple tattoos- 38%

Immigrants from Japan- 42%

Immigrants from Korea- 38%

History of alcohol abuse- 28%

Homosexual men- 37%

Everyone- 6%

Mother with hepatitis B- 30%

 

IV drug abuse- 20%

 

HIV- 14%

 

 

Undervaccinated population
(% of residents that would not vaccinate groups that should be vaccinated)

Overvaccinated population
(% of residents that would vaccinate groups that do not require vaccination)

Household members of HBV infected patients- 41%

Patients with congestive heart failure- 20%

Hemodialysis patients- 28%

Every patient- 14%

Newborns of HBV mothers- 16%

 

Healthcare workers- 6%

 

 


T1847. Telbivudine Preclinical Safety Studies Suggest Minimal Risk of Chronic Toxicity, Reproductive Toxicity or Carcinogenicity

E. Bridges

 

Background:

Telbivudine is a novel nucleoside presently undergoing phase III clinical evaluation for the treatment of chronic hepatitis B. A series of preclinical studies were undertaken to support clinical development of this agent, including chronic toxicity, carcinogenic potential, and reproductive toxicity. In these studies, telbivudine was investigated in large multiples of the human clinical maximum plasma concentrations (Cmax) and total exposure (area under the curve, AUC) achieved at the recommended human dose, 600 mg/day.

 

Methods & Results:

Chronic toxicologic studies were conducted over 6 months in rats, and 9 months in cynomolgus monkeys, with oral telbivudine doses of 0, 250, 500 and 1000 mg/kg/day. There were no telbivudine-related effects on physiology in either species. The no-observed-adverse-effect level for chronic dosing was considered to be 1000 mg/kg/day (10x Cmax, 6-8x AUC) in both species.

 

In a 2-year carcinogenicity study, Sprague-Dawley rats were dosed orally with telbivudine at 0, 500, 1000, or 2000 mg/kg/day. There was no evidence of oncogenicity in rats treated with telbivudine at dosages up to 2000 mg/kg/day (15x Cmax, 14x AUC) for ≥85 weeks.

 

Carcinogenicity was also evaluated in CB6F1-TgrasH2 transgenic-mice after 26 weeks of telbivudine doses of 0, 500, 1000 or 2000 mg/kg/day. No differences were found in the incidence of neoplastic or non-neoplastic changes, comparing the high-dose (2000 mg/kg; 31x Cmax, 14x AUC) group and control.

 

Developmental and reproductive toxicity was evaluated in ICH-recommended assays in rats and rabbits. No significant effects were observed in general reproductive fertility in rats treated with 2000 mg/kg/day (15 xCmax, 14x AUC). No effects on embryo-fetal or postnatal development were observed in rats and rabbits treated with 1000 mg/kg/day (10-19x Cmax, 6-37x AUC).

 

Conclusions:

Large multiples of anticipated telbivudine exposure in humans were evaluated for chronic toxicity, carcinogenicity, and reproductive and developmental toxicity and shown to have no significant toxic effects in relevant animal models, suggesting minimal risk for cumulative toxicity, carcinogenicity, or reproductive toxicity in humans.

 


T1848. Cost-Effectiveness Of Antivirals In HBeAg-Positive Chronic Hepatitis B: Impact Of Seroconversion And Viral Suppression

D. L. Veenstra; U. H. Iloeje; E. Tafesse; S. D. Sullivan; A. Cross; A. M. Di Bisceglie; R. G. Gish

 

Background and Aims:

The objective of this study was to evaluate the impact of HBeAg seroconversion and viral suppression on the relative cost-effectiveness of antiviral therapies for HBeAg-positive chronic hepatitis B.

 

Methods:

We enhanced a previously validated disease simulation model to include assessment of the impact of HBV DNA viral load on disease progression. The model included 14 distinct health states, which were used to track clinical outcomes such as HBeAg and HBsAg seroconversion, drug resistance, disease progression, and death. Patients with drug resistance were switched to salvage therapy. A lifetime analysis was conducted from a US payer perspective. Efficacy data were derived only from randomized controlled clinical trials. The risk of cirrhosis based on HBV DNA viral load was derived from a population-based prospective cohort study of 3,582 untreated hepatitis B infected patients (the R.E.V.E.A.L.-HBV Study). One-way and probabilistic sensitivity analyses were conducted to evaluate uncertainty in the analyses.

 

Results:

Assessment of patients who did not seroconvert HBeAg but achieved complete (PCR negative) on-treatment viral suppression (48% of entecavir, 20% of lamivudine, and 9% of adefovir patients in year 1) increased the difference in life expectancy in an RCT-based analysis of 2-year entecavir vs. lamivudine treatment from 0.54 to 0.79 years per patient treated compared to evaluation of seroconversion only. Total discounted healthcare costs decreased from $3,574 to $3,245, and the discounted incremental cost-effectiveness ratio (ICER) decreased from $10,911 to $7,264 per quality-adjusted life-year (QALY). An analysis of 2-yr entecavir vs. adefovir treatment showed an increase in the difference in life expectancy from 0.16 to 0.43 years and a decrease in the ICER from $10,474/QALY to $3,050/QALY. In a projected analysis of 4-year entecavir vs. lamivudine treatment, the difference in life expectancy increased from 0.84 to 1.56 years, and the ICER was $4,214/QALY.

 

Conclusions:

Our results indicate entecavir is cost-effective compared to either lamivudine or adefovir, and that both seroconversion and complete viral suppression have an important impact on the long-term outcomes of HBV anti-viral therapy. Our analysis also highlights the importance of using randomized controlled clinical trial data to appropriately assess the cost-effectiveness of chronic HBV treatments.


T1850. Lamivudine Monotherapy In Hbeag-Negative Chronic Hepatitis B: Prediction Of Response-Breakthrough And Long-Term Clinical Outcome

S. Manolakopoulos; S. Bethanis; J. Elefsiniotis; S. Karatapanis; C. Triantos; G. Sourvinos; G. Touloumi; M. Economou; J. Vlachogiannakos; D. Spandidos; A. Avgerinos; D. Tzourmakliotis

 

Objectives:

The aim of this study was to determine the factors and characteristics associated with initial response, virological breakthrough (VBR) and biochemical breakthrough (BBR) in patients with HBeAg-negative CHB receiving long-term lamivudine.

 

Methods:

This retrospective study included 79 (M/F=64/15) consecutive adult patients with HBeAg-negative CHB who started lamivudine monotherapy 100mg daily between March 1999 and September 2003 at four centers in Greece. They were followed up until March 2004. Virological response was considered the clearance of serum HBV DNA by PCR assay and biochemical response as the decline of transaminase levels within normal range. VBR was considered as the reappearance of HBV DNA by PCR after initial response and BBR as the increase of AST/ALT levels to >1.5 ULN after initial biochemical response. The parameters examined at Cox proportional hazards model included: gender, age, past history of interferon-α treatment, transaminase levels, HBV DNA, BMI, necroinflammation and fibrosis, genotype, changes in precore and core variants and HBV DNA at 6 months of therapy.

 

Results:

The median duration of lamivudine monotherapy was 31(range 6-56) months. 27 patients had baseline cirrhosis. Initial virologic and biochemical response was observed in 73 (92.4%) and 70 (88.6%) patients respectively, while 34 (46.6%) and 15 (20.5%) patients developed VBR and BBR respectively. High levels of necroinflammation in biopsy were associated with a higher probability of initial virological and biochemical response. Patients with pretreatment serum HBV DNA of more than 1.000.000 copies/ml were 3.2 (1.47-6.95, p=0.003) times more likely to develop VBR. 46% of the patients with BBR had transaminase>3ULN after a median of 18 months from initial biochemical response. One patient developed HCC. Two patients died, one with baseline cirrhosis due to liver failure during breakthrough.

 

Conclusion:

In HBeAg-negative CHB, initial response to lamivudine therapy is associated with necroinflammation, while baseline serum HBV DNA exceeding 1.000.000 copies/ml is a strong predictor for breakthrough due to drug-resistant mutations. Severe complications are uncommon and are associated with BBR and pre-existing cirrhosis.

 


T1851. Continued Virologic Improvement Through 96 Weeks Of Entecavir Treatment In HBEAG(-) Chronic Hepatitis B Patients (STUDY ETV-027)

F. Poordad; D. T. Dieterich; A. D. Min; D. Shouval; C. Lai; H. Cheinquer; T. Chang; R. Zink; J. Zhu; H. Brett-Smith

 

Background:

Entecavir (ETV) demonstrated superior virologic, biochemical and histologic benefit compared to lamivudine (LVD) at Week 48 in HBeAg(-) chronic hepatitis B (CHB) patients. HBV DNA suppression to <300 copies/mL occurred in 90% of ETV patients and 72% of LVD patients. Efficacy and safety through 96-weeks of treatment is reported here.

 

Methods:

638 HBeAg(-) CHB patients were randomized 1:1 and treated with ETV 0.5 mg (N=325) or LVD 100 mg (N=313) for 1 year. At Week 52, patient management decisions were made based on Week 48 laboratory results: 85% (275/325) of ETV patients and 78% (245/313) of LVD patients achieved Response (HBV DNA <0.7 MEq/mL by bDNA assay and ALT <1.25 x ULN) and discontinued therapy. Non-responders (HBV DNA ≥0.7 MEq/mL) also discontinued therapy (3 ETV and 18 LVD patients). Eleven percent in both treatment groups (ETV 34/325, LVD 34/313) achieved Virologic Response (HBV DNA <0.7 MEq/mL but ALT ≥1.25 x ULN) and continued blinded therapy through Week 96. Efficacy and safety were evaluated at end of dosing.

 

Results:

26 ETV and 28 LVD patients continued to a second year of therapy. Of these, 96% of ETV-treated and 64% of LVD-treated patients maintained Virologic Response (HBV DNA <300 copies/mL by PCR) at end of dosing. 88% of ETV patients and 81% of LVD-treated patients had both HBV DNA <0.7 MEq/mL by bDNA assay and ALT <1.25 x ULN.

Safety profile for ETV was comparable to LVD.

 

Conclusions:

In HBeAg(-) CHB patients, treatment with ETV 0.5 mg up to 96 weeks results in a significantly better viral load reduction than LVD, with 96% of patients maintaining this end point through a second year of treatment and with a comparable safety profile to LVD.

 

Cumulative Confirmed Virologic and Biochemical Endpoints Through Week 96

 

ETV 0.5 mg
N=325

LVD 100 mg
N=313

p-value

HBV DNA
<300 copies/mL by PCR, %

94

77

<0.001

ALT ≤1 x ULN, %

89

84

>0.05

 


T1852. Nitazoxanide in Treating Chronic Hepatitis B: In vitro Activity and a Clinical Case Report

J. Rossignol; B. E. Korba; S. M. Kabil

 

Nitazoxanide is an anti-infective drug from a new class called the thiazolides. It is marketed in the United States for treating gastroenteritis caused by Cryptosporidium parvum and Giardia lamblia and is in late stages of development for treating Clostridium difficile-associated disease. Based on earlier screening suggesting antiviral properties of the thiazolides, we tested nitazoxanide and its active circulating metabolite, tizoxanide, against hepatitis B virus in cell cultures. We also report the results of a patient with chronic hepatitis B treated with nitazoxanide after previously failing a long course of lamivudine.

 

Methods.

Nitazoxanide, tizoxanide and lamivudine were evaluated for activity against hepatitis B virus in 2.2.15 cell cultures. A 48 year-old Egyptian male with chronic hepatitis B refractory to lamivudine was treated with nitazoxanide. He was HBeAg-positive before treatment with a viral load of 5,250,000 copies per mm3 and ALT of 53. Nitazoxanide was administered by oral route, 500 mg twice daily with food for 24 weeks, and the patient was evaluated every 4 weeks during treatment. Evaluations included physical examination, laboratory safety tests and RT PCR for quantitation of HBV DNA.

 

Results.

The activity of nitazoxanide, tizoxanide and lamivudine against HBV replication in 2.2.15 cell cultures is presented below:

 

 

Extracellular
Virion DNA

Intracellular
HBV R.I.

 

Selectivity Index

Compound

EC50 (M)

EC90 (M)

EC50 (M)

EC90 (M)

CC50 (M)

Virion

R.I.

Lamivudine

0.0580.006

0.1640.015

0.1720.020

0.6600.068

222976

12959

3377

Nitazoxanide

1.2 0.2

8.2 0.8

3.9 0.5

17 2.0

>1000

>122

>59

Tizoxanide

1.5 0.2

5.8 0.4

4.6 0.6

12 1.5

>1000

>172

>83

 

 

Further in vitro experiments showed that nitazoxanide suppressed HBeAg and HBsAg suggesting a mechanism of action that differs from other antiviral drugs. The patient treated with nitazoxanide was HBeAg-positive after 4 weeks of treatment with a 2 log10 reduction of viral load (51,000 copies per mm3 down from 5,250,000 at baseline) and a slight increase in ALT (60 up from 53 at baseline). At weeks 8, 12, 16, 20 and 24, he was HBeAg-negative with undetectable serum HBV DNA and normal ALT. No significant adverse events have been reported. The patient discontinued treatment after 24 weeks and is being followed up for 24 weeks to evaluate the duration of response.

 

Conclusions.

Our results suggest that nitazoxanide is effective in treating chronic hepatitis B with a mechanism of action that differs from traditional antiviral drugs. A double-blind placebo-controlled study is being conducted to evaluate the role of nitazoxanide in treating patients with chronic hepatitis B.

 

 


T1853. Modeling Clinical Benefits Of Suppressing Viral Replication In Hbeag-Negative Chronic Hepatitis B (Chb) Patients: A Number-Needed-To-Treat (Nnt) Analysis Of Entecavir And Adefovir

U. Iloeje; Y. Yuan; K. Klesczewski; J. W. Hay View Presentation

 

Background & Aims:

Treatment success in HBeAg-negative CHB patients is often measured by suppression of viral replication and normalization of serum ALT. We estimated the clinical value of entecavir versus adefovir in this population using estimates of disease progression based upon observed viral suppression from randomized clinical trials.

 

Methods:

Data on CHB progression by the level of viral replication from a large scale epidemiology study (The R.E.V.E.A.L.-HBV Study) were matched to data from two different randomized clinical trials; BMS AI-463027, and GS 438 with open label extension to five years. Projections of liver complications over a 10 year period were based on a hypothetical cohort of 1000 patients on either entecavir or adefovir treated for 5 years continuously. Viral suppression was defined as HBV DNA less than 1000 copies/ml. We assumed no incremental benefit for entecavir beyond one year of therapy, and adefovir results from the most recent 5 year analyzes were used (Hadzyannis Hepatology 2005;LB14:745A). The number needed to treat was calculated as the reciprocal of the projected absolute risk reduction at 10 years. The 95% confidence interval was used to estimate the uncertainty around the NNT.

 

Results:

Of the entecavir treated subjects in study 027 with observed week 48 PCR data, 96% had HBV DNA <1000 copies/ml after 48 weeks of therapy, compared to 67% of adefovir treated subjects after 5 years of therapy. Of the 1000 hypothetical patients, projected numbers of events over 10 years were: entecavir 29 HCC, 80 cirrhosis and 88 with at least one event; adefovir 75 HCC, 157 cirrhosis and 178 with at least one event. The projected ten-year risks of HCC and Cirrhosis were 2.9% and 8.0%; vs. 7.5% and 15.7% for entecavir and adefovir respectively. The projected ten-year risk of any liver complication were 8.8% and 17.8% for entecavir and adefovir respectively, resulting in an NNT of 11 patients (95% CI 8-17) needing to be treated with entecavir rather than adefovir to prevent one liver complication (cirrhosis or HCC) in 10 years.

 

CONCLUSIONS:

The results of this model in HBeAg-negative CHB patients suggest a very favorable clinical benefit profile for entecavir in this patient population.