DDW 2007:  Sunday Abstracts – HBV:

 

Topic: Pathogenesis and Treatment

 

90. HBV replication can be controlled through TLR-induced production of IFN-beta by non-parenchymal liver cells. 

J. Wu; M. Lu; M. Roggendorf; G. Gerken; J. F. Schlaak

 

Background and aims:

Recent studies suggested that TLR-based therapies may represent a promising approach in the treatment of HBV infection. Therefore, we have studied the role of the local innate immune system of the liver (Kupffer cells (KC) and liver sinusoidal endothelial cells (LSEC)) as possible mediators of this effect.

 

Methods:

Murine KC were enriched by counterflow elutriation and LSEC were isolated by anti-LSEC microbeads to a purity >99% as controlled by FACS. Dendritic cells were used as controls. Cells were stimulated by TLR1-9 ligands. The culture supernatants were collected and tested for their antiviral activity in a viral protection assay. Antibodies to type I and II IFNs were added to assess the nature of cytokines produced by activated KC and LSEC. The culture supernatants were added to differentiated HBV-Met cells, a mouse hepatocyte line with a stably integrated 1.3 fold HBV genome. HBV gene expression and replication in treated cells was analyzed by ELISA (HBsAg, HBeAg), southern blot and northern blot.

 

Results:

Only TLR 3 and 4 ligands were able to stimulate the production of high amounts of antiviral mediators by KC and LSEC, while, in contrast to dendritic cells, other TLR ligands failed to show an effect on KC and LSEC. Using neutralizing antibodies to type I and II IFNs, we could demonstrate that the TLR-mediated antiviral effect of KC and LSEC is exclusively mediated through IFN-β. The culture supernatants of KC and LSEC, when applied on the HBV-met cells, were able to potently suppress HBV gene expression and replication as assessed by HBsAg and HBeAg ELISA and southern blot while HBV-RNA levels remained unchanged.

 

Conclusions:

Our data indicate for the first time that TLR 3 and -4 mediated stimulation of non-parenchymal liver cells leads to the production of IFN-β which can potently suppress HBV replication and gene expression. This is of relevance for the local control of HBV infection by the innate immune system of the liver as well as the use of TLR-based new therapeutic approaches and sheds new light on the interaction of HCV (TLR 3 stimulator) and HBV.

 


91. Prognosis following hepatitis B surface antigen seroclearance: a systematic review of 9 cohort studies and 1398 patients.

A. K. Retana; A. Rajendra; J. B. Wong

 

Aims:

Seroclearance of hepatitis B surface antigen (HBsAg) remains the goal of antiviral therapy, but recent reports suggest continued risk for hepatic complications. Our aim was to quantify prognosis following seroclearance of HBsAg and identify risk factors for hepatic progression.

 

Methods:

In a systematic review of MEDLINE, Web of Science and bibliographies, we identified 9 retrospective cohort studies (1398 patients) that reported on clinical course after HBsAg seroclearance. We extracted data regarding development of hepatocellular carcinoma (HCC), hepatic decompensation (ascites or varices), and liver-related death. In 4 studies with controls, we compared outcomes in those who had HBsAg seroclearance with those who did not. To identify risk factors for progression among those with HBsAg seroclearance, we compared outcomes of patients with and without cirrhosis and of co-infected individuals (hepatitis C, D, or HIV) with mono-infected ones. Data were pooled using the DerSimonian and Laird random effects model.

 

Results:

Of 9 studies 7 involved Asians. The mean age 46 (42-51) years; 80% (78-88) were men; 31% (0-100) had evidence of cirrhosis. The mean length of follow-up was 47 months (19-78). At the end of follow-up, HBV was detectable in the serum of 32 out of 395 (8%) and in liver biopsies of 50 out of 62 (81%) patients. When comparing patients with and without seroclearance, the odds ratios (OR) were 0.6 (95% CI 0.2-1.3) for developing any liver complication; 0.6 (0.2-1.4) for HCC; 1.1 (0.5-2.6) for hepatic decompensation; and 0.3 (0.04-2.2) for liver-related mortality. The risk of complications in patients with HBsAg seroclearance was higher in those with cirrhosis or with co-infection. Compared to patients without cirrhosis, those with cirrhosis had OR of 17.0 (2.5-116.6) for developing HCC; 16.8 (0.7-406.6) for liver failure; and 4.8 (0.5-50) for liver-related death. For patients with any co-infection versus those with mono-infection, the OR were 10.9 (1.3-95.4) for any hepatic complication in patients with cirrhosis and 4.5 (0.06-347.5) in those without cirrhosis. For hepatitis C co-infection, the OR for developing any hepatic complication was 17.4 (3.9-77.5).

 

Conclusion:

Patients with HBsAg seroclearance had lower risks of developing complications, but none of these results were statistically significant. In those with HBsAg seroclearance, the presence of cirrhosis or co-infection was associated with a statistically significant increase in HCC or hepatic complications respectively. Additional studies or longer follow-up in those with HBsAg seroclearance are needed to clarify risks and identify markers of progression.

 


93. Genotypic Analysis of Patients with Evaluable HBV DNA After 1 Year of Telbivudine Therapy in the GLOBE Registration Trial. 

M. Seifer; A. Patty; C. Chapron; L. van Doorn; B. Belanger; N. A. Brown; D. N. Standring

 

Introduction:

The safety and efficacy of telbivudine was evaluated in the international GLOBE trial of 1367 patients with chronic hepatitis B. Here we report the genotypic analysis at week 48 of 165 telbivudine patients with HBV of >1,000 copies per mL.

 

Methods:

HBV genomes were amplified from sera of study patients by RT PCR. The entire polymerase RT domain was sequenced to determine HBV genotypes at screen. For 165 telbivudine patients with HBV DNA >1,000 copies per mL at week 48 or 52, sera were re-sequenced at week 48 (or post virologic breakthrough) to identify genotypic mutations. These included all patients who had met previous virologic breakthrough criteria at week 48.

 

Results:

Sequences were obtained from 115/165 evaluable patients (with amplifiable HBV DNA and at least 16 weeks on therapy). RtM204I was the most frequent genotypic change seen (in 46/115 patients, including 9 mixed mutants) and is the only mutant to date that has been causally linked to genotypic/phenotypic telbivudine resistance and virologic rebound: at week 48, M204I was detected in 28 of 32 telbivudine patients experiencing a 1 log above nadir breakthrough (Standring et al, DDW 2007). Other genotypic changes among the 115 patients included rtL80 (n=26), rtL180 (4), and rtL229 (6). These were only associated with virologic rebound when rtM204I was present. There was no evidence for the L180M/M204 resistance pattern for telbivudine.

 

The genotypic analysis revealed rtA181T/S substitutions (n=15/1) that did not co-segregate with M204I or virologic rebound. These mutants result in a prematurely terminated S protein, likely ablating viable virus production. The mutation was absent in the 5 A181T patients who went on to year 2 breakthrough (3 with M204I, 2 with wild-type M204). Thus, the biological relevance and role in resistance of this variant is obscure.

 

Conclusions:

In the large GLOBE study, telbivudine primarily elicited M204I genotypic changes (n= 46). M204I, with or without secondary mutation (primarily L80I), is the signature telbivudine mutation associated with virologic rebound. No L180M/M204V-based resistance/changes were seen for telbivudine.

 


94. Presence of Biopsy-Proven Histologic Damage (Necroinflammation And Fibrosis) is Common Even When ALT is Less Than 2X ULN in Patients With Chronic Hepatitis B (CHB). 

 N. Terrault; W. Kim; S. Lim; G. V. Papatheodoridis; A. Alberti; M. Yuen; Z. D. Goodman; J. Vaughan; R. Wilber; B. Kreter

 

Introduction:

Current treatment guidelines for chronic hepatitis B recommend initiation in patients with alanine aminotransferase (ALT) levels ≥2X upper limit of normal (ULN). However, some patients with ALT below this threshold may have evidence of liver damage when biopsied and treatment decisions should consider this risk.

 

Methods:

We determined the distribution of Knodell necroinflammatory (NI) and Ishak fibrosis (IF) scores within groups determined by current breakpoints of baseline ALT categories (<2X; 2-5X; >5X ULN) in 1253 patients from Phase III studies of nucleoside- naďve HBeAg-positive (ETV-022) and HBeAg-negative (ETV-027) CHB. The patients’ mean viral loads at baseline met the criteria for treatment according to current treatment guidelines: 9.6 log10(ETV-022) and 7.6 log10(ETV-027). Association of histologic scores with viral load was not performed due to study inclusion criteria which constrained enrollment to patients with elevated HBV DNA.

 

Results: See table

 

Conclusions:

Over two-thirds of nucleoside-naďve HB patients with elevated VL demonstrate clinically significant (NI >7) necroinflammation, despite ALT values <2X ULN. Consistent with the natural history of CHB in this population, fewer patients demonstrate advanced fibrosis or cirrhosis than elevated NI scores, but advanced fibrosis is common even when ALT is <2X ULN. Patients with elevated VL frequently demonstrate clinically relevant changes in histopathology which merit treatment even when ALT values are not elevated >2X ULN.

 

Frequency of Baseline NI and IF Thresholds by ALT Categories

 

ALT <2 ULN

ALT 2-5 ULN

ALT >5 ULN

All patients

ETV- 022 (HBeAg(+))

n=234

n=305

n=113

n=652

NI≥7

68%

80%

95%

78%

IF≥4

11%

15%

20%

14%

ETV- 027 (HBeAg(-))

n=217

n=283

n=101

n=601

NI≥7

75%

83%

81%

80%

IF≥4

17%

17%

21%

18%

 


95. Tenofovir (TDF) monotherapy is effective in suppressing serum HBV DNA in chronic hepatitis B (CHB) patients with primary nonresponse to adefovir (ADV) but not those with ADV-resistant HBV. 

J. Tan; S. N. Wong; M. T. Hussain; K. Oberhelman; A. Lok

 

Background:

Adefovir (ADV) results in primary non-response in as many as 50% of patients (pts) with CHB. Tenofovir (TDF), a nucleotide analogue closely related and with equimolar potency as ADV, may result in more marked viral suppression as it is administered at a dosage that is 30 times that of ADV.

 

Aims:

To determine viral response to TDF or TDF+emtricitabine (FTC) therapy in pts with suboptimal response to ADV.

 

Methods:

Pts with suboptimal virological response (HBV DNA >4 log10 c/mL after > 6 months of treatment) to ADV were switched to TDF (n=9) or TDF+FTC (n=2). HBV DNA by PCR and liver chemistries were monitored every 3-6 months. Viral resistant mutations were determined using direct sequencing. Cloning of serial samples was performed for pts with known ADV-resistance and pts with a suboptimal virological response to TDF.

 

Results:

At the start of TDF, median age was 51 years (35-72), 9 were HBeAg+ve. Two pts had viral breakthrough and genotypic resistance (rtA181V) to ADV. Pt #1 had an initial decrease in HBV DNA from 7.6 to 5.1 log10 c/mL after 3 months of TDF, HBV DNA levels plateaued for the next 11 months and then decreased to 3.7 log10 c/mL, 4 months after the addition of FTC. The percentage of clones with rtA181V and rtN236T mutations was 100% and 3% at the start of TDF and 100% and 8% after 13 months of TDF. Pt #2 had decrease in HBV DNA from 7.3 log10 c/mL to 2.6 log10 c/mL after 9 months of TDF+FTC. The percentage of clones bearing the rtA181V mutants was 100% at the start of TDF and 96 % after 3 months of TDF; rtN236T was not detected in any of the clones. Nine pts did not have ADV-resistant mutations, and median HBV DNA at the start of TDF was 6.8 log10 c/mL. After a median of 13 months on TDF, 6 had undetectable HBV DNA, 2 had HBV DNA of 2.5 log10 c/mL. The remaining pt had suboptimal virological response on TDF, with HBV DNA decreasing from 7.6 to 5.1 log10 c/mL after 21 months treatment. None of the clones had any ADV-resistant mutation at baseline, but 17% of the clones had rtA181T mutation at the last visit.

 

Conclusions:

TDF is effective in suppressing HBV replication in most patients with suboptimal response to ADV. However, TDF alone may be less effective in pts with ADV resistance as ADV-resistant mutations persist and are further selected. Our data suggest that mutations resistant to ADV are cross resistant to TDF.

 


Session Title: Clinical: Hepatocellular Carcinoma and Cholangiocarcinoma

 

S1004. A Comparison of Alphafetoprotein, AFP-L3% and Des-Gamma Carboxyprothrombin in Patients with Chronic Hepatitis, Cirrhosis and Hepatocellular Carcinoma. 

F. A. Durazo; M. J. Tong; L. M. Blatt; W. G. Corey; J. Lin; S. Han; S. Saab; R. W. Busuttil

 

 


S1013. Blood Folate Levels And Risk Of Liver Damage And Hepatocellular Carcinoma: A Prospective Study In A Chinese High Risk Cohort.

T. M. Welzel; H. A. Katki; L. Sakoda; A. A. Evans; A. A. Evans; W. London; G. Chen; S. O'Broin; F. Chen; W. Lin; K. A. McGlynn

 


S1016. Changes Of Cytokines In Liver Cirrhosis Patients With Advanced Hepatocellular Carcinoma Treated By Combined Intra-Arterial Chemotherapy. 

H. NAGAI; D. Miyaki; T. Matsui; M. Kanayama; K. Higami; K. Momiyama; T. Ikehara; K. Matsumaru; M. Watanabe; K. Ishii; Y. Sumino; K. Miki

 


S1022. Outcome Of Patients With Recurrent Hepatocellular Carcinoma After Liver Transplantation . 

I. W. Graziadei; G. Millonig; M. Kern; W. Mark; R. Margreiter; W. Vogel

 


Clinical Epidemiology I

S1055. Comorbid Medical and Psychiatric Illness and Substance Abuse in HCV-Infected and Uninfected Veterans. 

U. A. Khan; K. McGinnis; M. Skanderson; A. Butt

 

Background:

We undertook this study to determine the prevalence of comorbidities in HCV infected and uninfected persons.

 

Methods:

Demographic/comorbidity data for HCV infected persons and age, race and gender matched HCV uninfected controls were retrieved from the VA National Patient Care Database using ICD-9 codes. We used logistic regression to determine the odds of comorbidities in HCV infected subjects.

 

Results:

We identified 126,926 HCV infected subjects and 126,926 controls. HCV infected subjects had a higher prevalence of diabetes, anemia, hypertension, COPD/asthma, cirrhosis, HBV, cancer, psychiatric comorbidities and substance abuse but a lower prevalence of coronary artery disease (CAD) and stroke.

 

In HCV infected persons, the odds of being diagnosed with congestive heart failure, diabetes, anemia, hypertension, COPD/asthma, cirrhosis, HBV and cancer were higher, but lower for CAD and stroke. After adjusting for substance abuse, the odds of psychiatric comorbidities were not higher in HCV infected persons. (Table)

 

Conclusions:

The prevalence of comorbidities differs in HCV infected and uninfected veterans. The association between HCV and psychiatric diagnoses is partially attributable to substance abuse. These factors should be considered when evaluating patients for treatment and designing new intervention strategies.

 

Odds of co-morbid diagnoses in HCV-infected veterans compared with HCV uninfected veterans.

 

 

Unadjusted OR (95% CI)*

Adjusted OR (95% CI)â€

Medical Comorbidities

 

 

Coronary artery disease

0.75 (0.73-0.77)

0.74 (0.71-0.760

Stroke

0.90 (0.86-0.95)

0.86 (0.82-0.90)

Peripheral Vascular Disease

0.97 (0.92-1.02)

0.95 (0.90-1.00)

Cancer

1.09 (1.05-1.13)

1.15 (1.10-1.20)

Diabetes

1.10 (1.08-1.13)

1.20 (1.17-1.23)

COPD/Asthma

1.26 (1.23-1.30)

1.05 (1.02-1.08)

Anemia

1.83 (1.76-1.90)

1.53 (1.47-1.60)

ESLD/Cirrhosis

12.0 (11.04-13.12)

8.24 (7.54-9.00)

Hepatitis B

21.58 (17.31-26.89)

13.34 (10.67-16.67)

Psychiatric Comorbidities

 

 

Schizophrenia

1.24 (1.20-1.28)

0.80 (0.77-0.82)

PTSD

1.58 (1.54-1.62)

1.05 (1.02-1.08)

Major Depression

1.62 (1.57-1.66)

0.93 (0.90-0.96)

Mild Depression

1.73 (1.69-1.77)

1.03 (1.01-1.06)

Bipolar Disorder

1.85 (1.79-1.92)

0.96 (0.92-1.00)

Alcohol and Drug Use

 

 

Drug Use Disorder

4.71 (4.60-4.82)

---

Alcohol Use Disorder

3.92 (3.84-4.00)

---

*The two groups were matched for age (5 year blocks), race and gender. â€Adjusted for age, race, gender, drug use and alcohol use.


Clinical Hepatitis 

S1226. Diagnostic value of biochemical markers for prediction of liver fibrosis and inflammation in pediatric patients. 

Y. Bujanover; R. Klar; M. Kori; E. Granot; R. Shoul; V. Nachmias

 

Background:

In the past several noninvasive laboratory methods were suggested as an alternative to liver biopsy .Recently a panel of six serum markers -Fibro test(FT) – Actitest(AT) was validated in the prediction of liver fibrosis and inflammatory activity in adult patients with liver disease.

 

Aim:

The aim of the present study was to assess the diagnostic utility of the Fibrotest – Actitest in pediatric patients with viral and autoimmune hepatitis.

 

Subjects and methods:

Twenty four patients were studied, 14 female, 10 male, age range 2-18 yr (m-12.4yr). Diagnosis : HCV-13; HBV-3;HCV+HBV-1; HCV+HIV-1;Autoimmune hepatitis-4. Liver biopsy was performed in 23 patients.

 

Six biochemical markers were evaluated using commercial kits : Total bilirubin, GGT, alfa2 macroglobulin, haptoglobin, apolipoprotein A1, ALT. Those parameters were used for the calculation of the FT-AT scores according to the patent algorithm of Biopredictive (France) ranging from 0-1. Liver biopsy was compared to the results of the FT and AT using AUROC statistical analysis.

 

Results:

FT- 75% of the patients were F0; F0-F1 12%, F1- 4%, F1-F2- 8%, AT-A0 41%, A0- A1 -20%, A1- 12%, A1-A2 -20%, A3 – 4%. The AUROC comparing FT with the liver biopsy results were 0.85 for F0 , 0.87 for F0-F1, 0.88 for F1-F2. FT yielded a higher AUROC than AT .85 VS .70 respectively.

 

Conclusions:

Fibrotest – Actitest is a simple and effective method to assess fibrosis and inflammation in pediatric patients with liver disease. The correlation with liver histology was high. The biochemical markers may serve as an alternative to liver biopsy in pediatric patients

 


S1227. Prevalence and risk factors associated with hepatitis B and hepatitis C virus infections among healthy population in an urban community in Dhaka, Bangladesh.

  H. Ashraf; C. Rothermundt; N. H. Alam; P. K. Bardhan; A. Brooks; S. Hassan; N. Gyr

 

Introduction:

Prevalence data of Hepatitis B virus (HBV) and Hepatitis C virus (HCV) infections among healthy population in Bangladesh is rare. However, chronic HBV and HCV infected individuals remain asymptomatic for many years. A population-based study was conducted to estimate the prevalence of HBV and HCV infections including their risk factors, which might eventually guide the development of prevention strategies.

 

Methods:

Asymptomatic subjects of either gender of all ages residing at an urban community of Kamalapur, Dhaka were randomly enrolled into the study after written consent. Information was collected on demographic, occupational and behavioural characteristics including their education, marital status, previous surgical and dental procedures and receiving injections and blood transfusions. HBV infection was diagnosed by performing HBsAg and Anti-HBc by ELISA and HCV was diagnosed by Anti-HCV screening test (ELISA-3).

 

Results:

From June 2005-April 2006, 1844 healthy subjects were enrolled, 37% males, 22% gave previous history of jaundice. HBsAg was positive in 121 (6.6%) subjects: 14 (0.8%) were only HBsAg positive and 107 (5.8%) were both HBsAg and Anti-HBc positive. Only Anti-HBc was positive in 420 (23%) subjects and HCV was positive in 9 (0.5%) subjects: 4 (0.2%) were only Anti-HCV positive and 5 (0.3%) were both Anti-HCV and Anti-HBc positive. About half of the HBV positive subjects were between ages 20-40 years, which was rare (4%) among under-5 children. Some factors such as previous jaundice (OR 1.33; p=0.01), exposure to a community barber for shaving (OR 2.29; p=0.00), received treatment from unregistered health care providers (OR 1.44; p=0.005), received treatment for sexually transmitted diseases (OR 1.77; p=0.002), being married (OR 2.23; p=0.00), and multiple sex partners (OR 2.57; p=0.00) were significantly associated with HBV infection. Similarly, receiving illicit drug injections (OR 11.86; p=0.01), needle-stick injuries (OR 2.11; p=0.001), needle piercing of ear, nose and body (OR 1.3; p=0.01), surgical operation (OR 1.3; p=0.02), circumcision (OR 1.47; p=0.00) and animal bites (OR 1.68; p=0.00) like dog, cat, monkey-bites were associated with HBV infection.

 

Conclusion:

The finding of the study demonstrates a high endemicity of HBV infection in an urban community in Dhaka, Bangladesh. However, HCV infection is rare. Prevention of HBV infection in Bangladesh is urgently necessary by hepatitis B vaccination and creating public awareness for practicing one-time-use-only needles and syringes and ensuring safe blood transfusions and maintaining strict aseptic precautions during surgical and dental procedures.

 


S1230. Sequential Treatment With Lamivudine And Alpha-Interferon In Chronic Hepatitis B: A Pilot Study. 

G. A. Niro; R. Fontana; D. Gioffreda; S. Fiorella; A. Iacobellis; P. Conoscitore; A. Andriulli

 

Background:

Monotherapy with alpha interferon (α-IFN), effective in a small subset of patients with chronic hepatitis B (CHB), is limited by relevant side effects. Long-term treatment with nucleosides/nucleotides analogues is burdened by drug-resistant mutants occurrence. Sequential therapy of IFN with nucleos(t)ide analogues might represent a strategy to delay emergence of drug resistance.

 

Aim:

To evaluate the efficacy of sequential lamivudine and IFNα 2b monotherapies in preventing the occurrence of YMDD mutants and in achieving a virologic and biochemical response at the end of therapy and at the end of 12-month follow up.

 

Methods:

Fifteen patients with HBsAg, anti-HBe positive chronic hepatitis, HBV-DNA > 100.000 copies/ml, and ALT > 2x ULN received 4 consecutive courses, each lasting for 6 months, of monotherapy with lamivudine (100 mg/day), followed by IFN α 2b (5 MU/tiw), lamivudine (100 mg/day) and IFNα 2b (5 MU/tiw). At the end of the 24 months of therapy patients were followed up for 12 months. Quantitative HBV-DNA was evaluated during and off treatment, and, whenever positive, HBV polymerase and precore/core regions sequenced.

 

Results:

All patients completed the 24 month treatment period. End of treatment response was achieved in 10 patients (67%). One pt did not respond to therapy although viremia levels declined in respect to baseline, and a second pt with undetectable viremia at week 16 experienced a genotypic resistance at week 24 and a phenotypic resistance at week 72. A rebound of viremia occurred in the remaining three pts at week 48, that was followed by self-limiting acute hepatitis in a single pt. At the end of follow up six pts (40%) remained sustained responders. At baseline the precore stop codon mutation (G1896A) was found in 80% of patients and was equally distributed between responders and non responders. The A1762T mutation was observed in 8 patients (53%), 4 responders (40%) and 4 (80%) non responders, while the G1764A mutation was detected in 9 patients (60%), 5 responders (50%) and 4 non responders (80%). When taken collectively, the group of triple promoter mutations at nucleotide 1762-1764-1896 prevailed in non responders (60% vs 20%). Mutations L180M and M204V were identified in the single pt with breakthrough.

 

Conclusion:

Sequential therapy with lamivudine/interferon was efficacious in maintaining virological response in 40% of patients and capable of inhibiting the emergence of resistance to lamivudine. Genetic alterations of the HBV genome within the basic core promoter influenced response to therapy.

 


Esophagus

S1340. Clinical Predictors for Recurrence of Esophageal Varices after Obliteration by Endoscopic Band Ligation. 

V. Chandrasekhara; J. Yepuri; J. Sreenarasimhaiah

 

Background:  

There is no universal standard of care for endoscopic follow-up after obliteration of esophageal varices by esophageal variceal ligation (EVL).

AIM: Identify clinical predictive factors and rate of varices recurrence following EVL.

 

Methods:  

All patients presenting to Parkland Memorial Hospital for EVL were evaluated since October 2005. Those with prior bleeding gastric varices, portal decompressive procedures, or variceal sclerotherapy were excluded. Patients consented to repeate EVL every 3 weeks until obliteration, and then repeat endoscopy every 3 months for 1 year. Clinical and laboratory parameters were monitored continuously over this period.

 

Results:

Of 31 patients enrolled to date, 35% were Caucasian and 65% were Hispanic. 71% of patients were male and 29% female with mean age of 48 years. At the initial time of EVL, 39% were still consuming alcohol. The cause of cirrhosis was alcohol alone (26%), hepatitis C (HCV) alone (26%), combined HCV and alcohol (23%), cryptogenic (9%), nonalcoholic fatty liver (3.2%), primary biliary cirrhosis (3.2%), combined hepatitis B (HBV)/HCV (3.2%), and combined alcohol/HBV/HCV (3.2%). Noncompliance with the EVL protocol was noted in 10/31 (32%) patients. Of these, 4/10 (40%)were Caucasian, 6/10 (60%) were Hispanic, 3/10 (30%) were non-English speaking, and 8/10 (80%)were actively consuming alcohol. Variceal rebleeding was noted in 8/31 (26%) within 1 year of initial EVL. Of these, 4/8 (50%) were non-compliant with the EVL protocol. Alcoholic cirrhosis was noted in 5 of 8 (62.5%) patients. Moreover, 4/5 (80%) were still actively drinking. For all 31 patients, the mean MELD score was 13.3 and the mean CPT score was 8.1. The mean MELD score was 16.1 for those with variceal rebleeding and 12.3 for those without rebleeding (p=0.013). The mean INR in the rebleeding group was 1.64 and in the non-rebleeding group was 1.37 (p=0.017). The average age for the two groups was 49.2 and 47.5 years, respectively. There has been one death thus far due to a bleeding gastric lesion.

 

Conclusions:  

Recurrence of variceal bleeding after EVL obliteration occurred in those patients with a higher MELD score and specifically a higher INR level when compared to those who did not bleed. Patients with alcoholic cirrhosis had a higher rate of rebleeding. There was no correlation with patient age. Rebleeding was higher in those who were noncompliant with the EVL protocol including patients who were non-English speaking as well as those with active alcohol consumption. Therefore, efforts needed to be directed to facilitating patient compliance with medical care and abstinence from alcohol.

 


ALF/Experimental and Clinical Liver Transplantation

S1728. The Prevalence and Significance of Occult Hepatitis B In A Liver Transplant population with Chronic Hepatitis C. 

K. Shetty; M. T. Hussain; L. Nei; K. Reddy; A. Lok

 

Background:

Occult hepatitis B virus(HBV)is defined as the detection of HBV DNA in the serum or liver of those who test negative for hepatitis B surface antigen (HBsAg).It has been implicated in HBV reactivation within immunosuppressed populations, and in the development of hepatitis C virus (HCV)-associated cirrhosis and hepatocellular carcinoma (HCC) in non-transplant settings. The significance of occult HBV following orthotopic liver transplantation (OLT) is incompletely understood.

 

Aims:

1.     Determine the prevalence of occult HBV in a HCV-infected transplant population

2.     Examine the course of occult HBV post-OLT

3.     Assess the effect of occult HBV on the histological recurrence rate of post-OLT HCV.

 

Methods:

Those with HCV cirrhosis listed for OLT were prospectively followed. PCR techniques were utilized to test for serum HBV DNA at enrollment,within the explant and at 8 and 24 weeks post-OLT.

 

Results:

56 patients with HCV cirrhosis were enrolled,44 underwent OLT. The overall prevalence of occult HBV based on positive serum HBV DNA was 8/56(14%),and based on positive hepatic HBV DNA was 19/44(43%).The presence of serum hepatitis B core antibody (anti-HBc)and a history of injection drug use correlated with occult HBV.Explant-proven HCC was found in 63% of patients with occult HBV compared to 32% of those without occult HBV (p = 0.02, odds ratio 4.3)(table 1).An overall histological HCV recurrence rate of 51% was noted, with no significant difference between groups.Multivariate analysis showed HCV recurrence to be associated with donor age,and HCV viral load. No detectable serum or explant HBsAg was noted at 8 or 24 weeks in any patient.

 

Conclusion:

occult HBV is far more prevalent in patients with end-stage HCV than would be expected from its prevalence in the general population. It is strongly associated with the presence of anti-HBc, history of injection drug use and explant-proven HCC. No effect of occult HBV is noted on HBV reactivation,HCV recurrence or post-OLT patient survival.

 

Comparison of demographics/HCV recurrence

Variable

Occult HBV
(N=19)

Standard
deviation

No Occult HBV
(N=25)

SD

p Value

Mean age
at OLT

52.7

5.4

51.9

6.3

NS

MELD at OLT

19.7

10.6

20.6

7.9

NS

IVDA(%)

72

 

56

 

0.03*

Anti-HBc positive(%)

12(63)

 

6(24)

 

0.01*

Anti HBs positive(%)

7(36)

 

8(32)

 

0.6

ACR(%)

6(32)

 

2(8)

 

0.04*

HCC (%)

12(63)

 

8(32)

 

0.02

Recurrent HCV(%)

11(56)

 

13(51)

 

0.9

 

IVDA : intravenous drug abuse;ACR : acute cellular rejection.* p = significant


S1730. Beneficial effects of Short-Term Lamivudine Treatment for de novo Hepatitis B Virus Reactivation After Liver Transplantation. 

M. Umeda; H. Marusawa; Y. Ueda; M. Ueda; Y. Takada; H. Egawa; S. Uemoto; T. Chiba

 

Background and Aims:

Clearance of hepatitis B surface antigen (HBsAg) by lamivudine is achieved in only a small proportion of patients with chronic hepatitis B virus (HBV) infection. We investigated the effect of lamivudine on de novo HBV reactivation after living-donor liver transplantation when the number of HBV was expected to be very small.

 

Methods:

Thirty nine HBV-naive recipients who received liver grafts from antibodies to core antigen (anti-HBc) positive donors receiving hepatitis B immunoglobulin (HBIG) were studied.

 

Results:

HBsAg appeared in nine cases (23.1%) despite receiving HBIG for 12 to 71 months (mean: 35.1 months) after transplantation. The male/female ratio was 5/4 and the age range was 0-25 years (mean age: 14.1 years). The indications for LDLT in these recipients with HBV reactivation were biliary atresia (n = 7), Wilson’s disease (n = 1), and primary sclerosing cholangitis (n = 1). The possible risk factors for de novo HBV reactivation included noncompliance of HBIG, an immunosuppressive condition, and emergence of “surface” escape mutants. A liver biopsy was performed on five of the nine patients at the time of the de novo HBV recurrence and all exhibited evidence of chronic active hepatitis accompanied by mild inflammatory activity and mild fibrosis. Lamivudine treatment (100) was started in six recipients during the acute phase of HBV reactivation. After the administration of lamivudine, HBsAg decreased in the sera of all six recipients, and in all six cases, HBsAg disappeared from the sera at a median of 6.1 months (ranging from 21 to 330 days). Suppression of HBsAg by lamivudine treatment was invariably associated with a decline in serum transaminase levels in these six cases. Although lamivudine was stopped in four cases after 1.5, 4, 10, and 60 months of treatment, all remained negative for HBsAg. Moreover, intrinsic immunity against HBV developed after cessation of treatment in two cases.

 

Conclusions:

We have shown in this study that short-term use of lamivudine resulted in complete clearance of HBsAg in the majority of patients with de novo HBV reactivation, and that the effects of lamivudine were stronger in patients with de novo HBV reactivation than in patients with HBV-related chronic liver disease. We suggest that the timing of the lamivudine administration in patients with HBV activation, specifically in the acute phase of HBV reactivation, is important to achieve complete viral suppression and successful seroconversion from HBsAg to anti-HBs.

 


S1736. Impact of Extended Criteria Donor Livers on Survival of Patients with Hepatocellular Carcinoma. 

A. Cooper; R. S. Mangus; M. Maluccio; R. Vianna; J. A. Fridell; A. Tector

 

Purpose:

Liver transplantation is the most effective treatment for patients with hepatocellular carcinoma (HCC), with optimal outcomes in those meeting Milan criteria. With a growing shortage of donor livers, patients outside Milan criteria are rarely transplanted, though these patients have improved survival with transplantation. Extended criteria donor (ECD) organs are increasingly utilized to meet the demand for transplant livers. The purpose of this study is to evaluate the impact of ECD livers on post-transplant survival in patients with HCC, both inside and outside Milan criteria.

 

Methods:

Records from 698 consecutive adult liver transplants from July 2001 to June 2006 were reviewed. Of these patients, 138 (19.8%) had HCC and 489 (70%) received ECD livers. Primary ECD criteria included: age ≥ 60, BMI ≥ 35, maximum AST or ALT > 500, maximum bilirubin > 2.0, peak serum sodium > 170, HBV/HCV/HTLV reactive, non-heart beating donor, cold ischemia time > 12 hours, ICU stay > 5 days, ≥ 3 pressors simultaneously, and extensive chronic alcohol abuse. Outcomes included 1- and 2-year survival and HCC recurrence. Kaplan-Meier estimates of survival time for ECD vs. standard donor (SD) groups were compared using the log-rank test. The simultaneous impact of MELD score, primary diagnosis, recipient age, transplant year and Milan status for patients in the two groups was evaluated by a Cox proportional hazards model.

 

Results:

Among the 138 patients with HCC, 98 (71%) received an ECD liver. Preoperatively, 43/138 (31.2%) were outside Milan criteria. The perioperative death rate for the entire cohort was 7/138 (5.1%). With a median follow-up of 21 months, HCC recurrence was 12.3% for the whole group (10.2% ECD, 17.5% SD, p=NS). Overall survival at 1 year was 86.4% (ECD 86.0%, SD 87.4%), at 2-years 78.5% (ECD 78.5%, SD 78.3%). By log rank test the two Kaplan Meier curves were equivalent (p=0.90). When stratified by Milan status, the ECD and SD groups also did not differ in survival (p=.872). The Cox proportional hazards model did not demonstrate any significant survival difference when considering MELD score, Milan status, diagnosis, age, or transplant year.

 

Conclusion:

The use of extended criteria donor livers increases organ availability for patients with liver disease and provides acceptable survival in patients with HCC. There was no difference between the ECD and SD groups in tumor recurrence. Overall survival was also the same regardless of Milan criteria. These results suggest that ECD livers represent a viable avenue for expanding the opportunity to offer transplant to patients with HCC, even those who are not typically considered acceptable candidates.

 


Hepatitis B – Pathogenesis

S1758. Causes of Death Associated With Hepatitis B or Hepatitis C Virus Infections in a Long-Term Population-Based Cohort Study. 

H. Yang; C. Chen; C. Jen; U. H. Iloeje; J. Su; S. You

 

Background and Aims:

Chronic infections with hepatitis B virus (HBV) or hepatitis C virus (HCV) are well-documented risk factors for cirrhosis and hepatocellular carcinoma (HCC). We aimed to investigate mortality associated with the viruses in this study.

Methods:

The mortality of this cohort was follow-up between Jan 1, 1991 and Dec 31, 2004. Mortality was ascertained via data linkage to the Taiwanese National Death Certification Registry, which has been shown to be complete and accurate. Mortality rates for all causes, liver cancer, chronic liver disease and cirrhosis and others were derived. Survival curves with stratification by HBV/HCV infection status were derived by the Kaplan-Meier method. Cox proportional hazards models were used to estimate multivariable-adjusted relative risks (RRadj) and 95% confidence intervals (CIs).

 

Results:

Among a total of 23,186 cohort members (290872.7 person-years of follow-up), the number (prevalence) of HBV, HCV, HBV/HCV co-infection and neither HBV nor HCV infections was 3,895 (16.8%), 1040 (4.5%), 215 (0.9%) and 18,036 (77.8%), respectively. The all causes mortality per 100,000 person-years was 877.1, 1248.7, 1179.9, and 595.1 for HBV, HCV infections, HBV/HCV co-infection and neither HBV nor HCV infection, respectively (liver cancer mortality: 284.1, 257.6, 228.4, 12.3; mortality of chronic liver disease and cirrhosis: 85.0, 93.7, 152.2, 16.7; non-liver-related mortality: 508.0, 897.5, 799.3, 566.0). Taking those with neither HBV nor HCV infection as referent, the RRadj (95% CI) of all cause mortality adjusted for gender, age, cigarette smoking and alcohol consumption was 1.7 (1.5-1.9), 1.8 (1.6-2.2), and 1.9 (1.3-2.6) for HBV, HCV infections, and HBV/HCV co-infection, respectively [liver cancer mortality: 25.2 (16.8-37.9), 19.6 (11.8-32.5), 17.4 (7.2-42.1); mortality of chronic liver disease and cirrhosis: 5.5 (3.5-8.6), 5.3 (2.8-10.2), 9.0 (3.2-25.1); non-liver-related mortality: 1.1 (0.9-1.2), 1.4 (1.1-1.7), 1.3 (0.9-2.0)]. Subjects infected with HCV only had significantly higher risk of dying from cerebrovascular disease and renal failure with RRadj (95% CI), 2.2 (1.4-3.6) and 2.9 (1.3-6.1), respectively.

 

Conclusions:

HBV, HCV infections and HBV/HCV co-infection had elevated risk of liver-related mortality compared with neither HBV nor HCV infection. HCV infection may be associated with death from several extra-hepatic manifestations such as cerebrovascular disease and renal failure.

 


Hepatitis B – Treatment

S1766. A Risk Function Nomogram for Predicting HCC in Patients With Chronic Hepatitis B: The R.E.V.E.A.L.-HBV Study.

  C. Chen; H. Yang; U. H. Iloeje; J. Su; C. Jen; S. You; M. Sherman; Y. Liaw; P. Chen

 

Background and Aims:

Counseling CHB patients of their individual risk of progressing to liver complications is a clinical challenge. Our objective was to develop a simple risk function nomogram using noninvasive clinical information in CHB-infected subjects.

 

Methods:

Variables with a priori plausibility as risk factors were used (Gender, age, cigarette smoking, alcohol consumption, family history of HCC, ALT, HBeAg, HBV DNA, HBV genotype, BCP and precore mutations). Cox proportional hazards models were used to train models. Regression coefficients derived from the Cox models were converted into integer risk scores and the predicted risks of HCC over 5 and 10 years calculated for various risk scores. The risk scores and the predicted 5- and 10-year HCC risks were translated into normograms. The predictive accuracy was evaluated using Receiver Operator Characteristic (ROC) curve and area under the ROC curve (AUROC) and the calibration chart.

 

Results:

3644 subjects were included. The mean follow-up time was 11 years. Of eight different computer generated models, the best model had an AUROC of 0.8601 (5-year HCC prediction) and 0.8649 (10-year HCC prediction). Males were at higher risk of HCC development than females. For all HBV DNA levels, genotype C patients had a higher risk of HCC than genotype B patients. The resulting nomogram derived from the model had good calibration ability and the predicted risk approximated the actual risk.

 

Conclusion:

The predictive model has good characteristics as shown by the AUROC. The combination of HBV DNA ≥105 copies/mL and genotype C had the highest HCC risk. The derived nomogram, once validated, should simplify the communication of individual HCC risk using noninvasive variables.

 

Multiple Cox Proportional Hazards Model for Gender, Age, Alcohol Consumption, ALT, HBeAg, and the Combination of HBV DNA and Genotype (Model 5)

 

 

β-Coefficient

Hazard ratio

95% CI

P value

Gender (referent: female)
Male

1.13734

3.1

2.0-4.8

<0.0001

Age (1-yr increment)

0.09078

1.10

1.08-1.12

<0.0001

Alcohol consumption (referent: no)
Yes

0.54473

1.7

1.2-2.5

0.0040

ALT, U/L (referent: <45)
≥45

0.55669

1.7

1.1-2.7

0.0104

HBeAg (referent: negative)
Positive

0.96885

2.6

1.7-4.1

<0.0001

HBV DNA / genotype (referent: <100 / not tested)
100~<104 / B
100~<104 / C
104~<105 / B
104~<105 / C
≥105 / B
≥105 / C

0.80015
1.34494
1.10636
2.15516
1.95725
2.39034

2.2
3.8
3.0
8.6
7.1
10.9

0.9-5.3
1.6-9.3
1.3-6.9
3.6-20.9
3.4-14.8
5.0-24.1

0.0700
0.0028
0.0088
<0.0001
<0.0001
<0.0001

Family history of HCC (referent: no)
Yes

0.76773

2.2

1.2-3.8

0.0067

 


S1767. Lamivudine Prophylaxis is Effective in Reducing Reactivation and Reactivation Related Liver Mortality: A Meta-Analysis.

  L. A. Martyak; E. Taqavi; S. Saab

 

Background:

Hepatitis B viral (HBV) reactivation in patients undergoing cytotoxic chemotherapy is associated with significant morbidity and mortality. Lamivudine has been suggested to be useful as prophylactic therapy for HBV reactivation; however its impact on overall survival and HBV reactivation related liver disease survival is unclear.

 

Objective:  

To determine the effect of lamivudine prophylaxis on the rate of HBV reactivation, overall survival and HBV reactivation related liver disease survival in patients with HBV infection undergoing chemotherapy.

 

Methods:  

A systematic review of the literature was performed using MEDLINE and the Cochrane Collaboration Database. Hand searches of abstracts from national meetings as well as reference lists from relevant papers were reviewed. The main outcome was to evaluate the effects of Lamivudine prophylaxis on HBV reactivation, overall survival, and HBV reactivation liver disease survival.

 

Results:

Ten studies met the defined inclusion criteria and were included in the analysis. 214 patients received lamivudine prophylaxis and 391 did not receive prophylaxis. Patients given lamivudine prophylaxis during chemotherapy have an 87% decrease in HBV reactivation (risk ratio [RR] 0.13, 95% Confidence Interval [CI], 0.07-0.24; p < 0.01) than patients not given prophylaxis (absolute risk reduction [ARR] –0.46, 95% CI, -0.61-0.31). The number needed to treat to prevent reactivation was 3. Lamivudine prophylaxis group was also associated with a 70% reduction in reactivation related mortality (RR 0.30, 95% CI, 0.1-0.94; p =0.04) compared to controls (ARR –0.03, 95% CI, 0.07-0.00). There was a trend toward reduction in overall mortality (RR 0.77, 95% CI 0.56-1.06; p = 0.11) with lamivudine prophylaxis (ARR –0.04, 95% CI, –0.10-0.02). There was a reduction in chemotherapy treatment delays and premature termination of chemotherapy in the lamivudine prophylaxis arm (RR 0.41, 95% CI, 0.27-0.63; p < 0.01; ARR –0.33, 95% CI, -0.33--0.15). There was no significant heterogeneity in the comparisons.

 

Conclusion:  

Lamivudine prophylaxis during chemotherapy is effective in reducing the rate of HBV reactivation, and reactivation related liver mortality. There is a trend toward reducing overall related mortality. Patients with lamivudine prophylaxis had less chemotherapy treatment delays and premature termination of their chemotherapy. Few patients need to be treated to prevent reactivation. Patients undergoing chemotherapy should be screened for HBV, and started on lamivudine prophylaxis if infected.

 


S1768. A Phase III Comparative Trial of Telbivudine vs Lamivudine in Chinese Patients with Chronic Hepatitis B: Two-Year Results

Y. Wang; J. Jia; J. Hou; Y. Yin; D. Xu; D. Tan; J. Niu; X. Zhou; L. Zhu; N. A. Brown.

 

Background:

In a large international phase III trial (GLOBE), telbivudine showed greater efficacy vs lamivudine in adults with chronic hepatitis B. Chronic hepatitis B is endemic in China with a major health impact; therefore the present trial was undertaken to obtain additional data comparing the safety and efficacy of telbivudine 600 mg/day vs lamivudine 100 mg/day in Chinese adults with compensated chronic hepatitis B. The full ITT population results of this 2-year Phase III study are presented here.

 

Methods:

This randomized double-blind trial compared 2 years of treatment with telbivudine vs lamivudine in Chinese adults with chronic hepatitis B. Key entry criteria included HBV DNA >6 log10 copies/mL, ALT 1.3-10 xULN, HBeAg-positive or -negative, and compensated liver disease.

 

Results:

The intent-to-treat population comprised 332 patients (290 HBeAg-positive; 42 HBeAg-negative, pre-stratified). Treatment groups were well-matched at baseline for demographic and disease parameters. At week 104, telbivudine was superior (P<0.05) to lamivudine in HBV DNA suppression, the primary efficacy endpoint (Table). Telbivudine was also significantly more effective for achieving PCR nondetectable HBV DNA, ALT normalization, Therapeutic Response, and HBeAg loss in HBeAg-positive patients (all P<0.05 vs lamivudine; Table). Significantly fewer patients receiving telbivudine exhibited primary treatment failure, defined as serum HBV DNA levels never below <5 log10 copies/mL (3%, vs 15% for lamivudine, P=0.0001). Both treatments were well tolerated with similar adverse event profiles.

 

Conclusions:

After 2 years of treatment, telbivudine continued to exhibit greater antiviral and clinical efficacy compared to lamivudine in Chinese patients with compensated chronic hepatitis B, with significantly greater HBeAg clearance in HBeAg-positive patients.

 

Response at week 104

LdT

LAM

HBV DNA reduction (log10 copies/mL)

-5.43*

-3.97

HBV DNA non-detectable, (%)

104/167 (63%)*

64/165 (39%)

ALT normalization, (%)

125/160 (78%)*

96/153 (63%)

Therapeutic response, (%)

119/167 (71%)*

74/165 (45%)

HBeAg loss (HBeAg+ only)

56/138 (41%)*

39/138 (28%)

HBeAg seroconversion (HBeAg+ only)

41/138 (30%)

28/138 (20%)

* P<0.05, telbivudine (LdT) vs lamivudine (LAM)


S1770. Prophylactic Lamivudine for Prevention of Chemotherapy-induced Hepatitis B Virus Reactivation: Meta-analysis of Clinical Trials. 

F. I. Alsohaibani; K. M. Peltekian

 

Background:

Numerous studies and reports have appeared on lamivudine use as a primary prophylaxis to prevent chemotherapy induced hepatitis B virus (HBV) reactivation in hepatitis B surface antigen (HBsAg) seropositive cancer patients. The aim of this meta-analysis is to report and confirm the efficacy and safety of prophylactic lamivudine in prevention of chemotherapy induced Hepatitis B reactivation.

 

Methods:

By performing a systematic literature review with a meta-analysis of clinical trails, we evaluated the efficacy and safety of lamivudine prophylaxis in HBV carriers undergoing chemotherapy for malignancies. The primary outcomes were evidence for HBV reactivation and its associated morbidity and mortality. The secondary outcomes were disruption of chemotherapy, and lamivudine resistance and tolerability. Electronic searches of the National Library of Medicine were performed to identify all pertinent literature. The key words “hepatitis B”, “lamivudine”, “chemotherapy” and “prophylaxis” were used. The search was limited to randomized clinical trials and English language.

 

Results:

We identified 12 clinical trials (715 patients, 252 patients received Lamivudine and 463 patients as a control), seven of these were prospective cohort studies (two of them were randomized) and five were retrospective reviews. The test for heterogeneity showed no difference between these trials (P=0.96). In the treatment group 61% were males with mean age +/- SD 52+/- 8 years compared to 58% males and 42 +/-7 years in the control group .The mean overall estimate for HBV reactivation was significantly higher in the control group compared to treatment group (Odd ratio 0.08, P value <0.00001).Mortality rate was 0% in the Lamivudine group compared with 5% in the control group ( P value < 0.05). Requirements for chemotherapy disruption were less in the treatment group (11% Vs 31%).The median lamivudine dose was 100mg/day (50-300 mg/day). On average lamivudine was started 7 days (1-14 days) prior to chemotherapy and continued for a mean of 167 days (30-365 days) after discontinuation of the chemotherapy. Lamivudine was well tolerated and cases of lamivudine resistance were not reported.

 

Conclusion:

This meta-analysis confirm the safety and the efficacy of lamivudine as a primary prophylaxis for chronic HBV carrier cancer patients undergoing chemotherapy to reduce the incidence of reactivation of the HBV as well as the mortality with maintenance of the dosage of chemotherapy.

 


S1771. Hepatitis B Patient Survey: Disease Understanding and Compliance in the United States

S. Han; L. Griffith; T. Westphalen

 

Background:

Chronic Hepatitis B (CHB) infection requires patients to undergo lifelong disease monitoring and evaluation, and their knowledge, expectations, and compliance can impact long-term clinical outcomes. This survey was designed to assess the level of understanding about hepatitis B virus (HBV) infection and treatment in currently treated patients in the United States (US).

 

Methods:

Internet-based interviews were supplemented by telephone interviews between September 2006 and November 2006. Adult mono-infected CHB patients currently on antiviral treatment were eligible.

 

301 respondents were included, 24% were on interferon treatment. The majority were 31-50 years old, most were male patients and approximately half were of Asian descent. In total, 64% were from the Mid-Atlantic or Pacific regions of the US.

 

Results:

When questioned about transmission, 36% of respondents believed the virus could be transmitted by sharing utensils with an infected person. 80% of respondents were aware of the long-term consequences of HBV infection. However, 50% believed in the existence of a cure for CHB, even though >60% had been treated for ≥1 year.

 

When questioned about routine tests, only 31% of respondents claimed to know the specific names of tests conducted for HBV, and only ~50% of these could explain what the tests measured. The majority of patients (85%) feel that viral load measurement is important but 27% didn’t know whether their doctors checked their viral load.

 

37% of respondents said they did not discuss treatment goals with their doctors, although 88% of these felt that doing so was important. About half (51%) of respondents felt involved in treatment decisions about type of treatment, while 54% were not sure why their current drug(s) were chosen.

 

When questioned about missing doses or not taking them at the right time, 12% admitted to noncompliance 1x per month, 7% once every 2 weeks, 7% once per week, 7% 2-3x per week, 1% 4-6x per week, and 4% 1x per day. The primary reason for noncompliance was forgetfulness, while injection anxiety and food restrictions each affected approximately 6% of patients. Responses indicate that 80% of patients take their medication within 2 hours of eating, and 49% said that taking their medication at least 2 hours before or after eating would make adherence more difficult than if taken at any time.

 

Conclusions:

The results of this survey highlight a significant deficiency in patient understanding of HBV infection, treatment goals, testing, and behaviors. Enhanced education is needed to improve patient involvement in disease management decisions, which can lead to improved adherence and clinical outcomes.

 


S1773. Entecavir (ETV) Results in Higher HBV-DNA Reduction vs Adefovir (ADV) In Chronically Infected HBeAg(+) Antiviral-Naive Adults: 48-Week Results (E.A.R.L.Y. STUDY). 

N. Leung; M. Sherman; C. Peng; J. D. Sollano; L. Lesmana; M. Yuen; L. Jeffers; H. Hann; K. Mencarini; R. Colonno; A. Cross; R. Wilber; J. C. Lopez-Talavera

 

Background:

Elevated HBV DNA is associated with increased risk of disease progression and complications in patients with chronic hepatitis B (CHB). The aim of antiviral therapy is to rapidly and profoundly reduce HBV DNA. We previously demonstrated that ETV results in superior early lowering of HBV DNA vs adefovir at Wk-12. We present 48-week results from this randomized, open-label, comparative study comparing ETV to ADV in HBeAg(+) CHB patients.

 

Methods:

Sixty nine HBeAg(+), antiviral-naďve, CHB patients were randomized 1:1 to receive either ETV (0.5 mg) or ADV (10 mg) QD for a minimum of 52 weeks. Measurements of serum HBV DNA by PCR assay were obtained through Wk-12 and Weeks 24, 36 and 48. HBV serology and safety laboratory testing were also performed. Evaluable patients were those who had baseline and Wk-12 HBV DNA by PCR and received their assigned treatment. The treatment difference in reduction of HBV DNA at Wk-48 is based on a linear regression model adjusted for baseline.

 

Results:

Mean baseline HBV DNA was 10.26 (ETV) and 9.88 (ADV) log10 copies/mL. ETV demonstrated superior early antiviral activity and viral kinetic profiles compared to ADV as early as Day 10, with superior reduction in HBV DNA at Wk-12 (6.23 vs 4.42 log10 copies/mL, p<0.0001). Mean HBV-DNA change from baseline at Wk-48 was -7.28 (ETV) vs -5.08 log10 copies/mL (ADV) [Difference (95% CI): -1.86 (-2.69, -1.03)]. At 48 weeks, 19 (58%) of ETV- vs 6 (19%) of ADV-treated patients achieved undetectable HBV DNA (<300 copies/mL) by PCR, 25 (76%) of ETV- vs 20 (63%) of ADV-treated patients achieved ALT ≤1 X ULN and 5 (15%) of ETV- vs 7 (22%) of ADV-treated patients achieved HBeAg seroconversion. Adverse events were comparable between the two groups. No patients discontinued due to adverse events.

 

Conclusion:

At Wk-48, ETV was observed to result in a greater decrease from baseline in HBV DNA than ADV (7.28 vs 5.08 log10 copies/mL), with 58% of ETV-treated patients achieving undetectable HBV DNA compared to 19% of ADV-treated patients. ETV was well tolerated.

 


S1774. A Randomized Trial of Telbivudine vs Adefovir for HBeAg-Positive Chronic Hepatitis B: Efficacy Through Week 76, Predictors of Response and Effects of Switching to Telbivudine. 

 N. Bzowej; P. Marcellin; H. Chan; C. Lai; M. Cho; E. Heathcote; Y. Moon; Y. Chao; R. P. Myers; G. Harb; N. A. Brown

 

Background:

Direct comparisons of anti-HBV agents are important for optimizing patient care. Here we compare telbivudine (LdT) vs adefovir (ADV) over 52 weeks, the effects of switching from ADV to LdT in patients with suboptimal initial response to ADV, and analyze the relationship of early virologic responses to subsequent efficacy outcomes.

 

Methods:

This randomized trial enrolled 135 adults with HBeAg+ chronic hepatitis B with HBV DNA >6 log10 cp/mL, ALT 1.3-10 xULN, and compensated liver disease. Patients were initially randomized 2:1 to ADV 10 mg/d or LdT 600 mg/d for 24 weeks, with a secondary 1:1 randomization of ADV recipients to either continue ADV or switch to LdT after Week 24 (W24). After W52, most patients received LdT in an open-label extension trial. We analyzed the effects of switching from ADV to LdT in patients with suboptimal response to ADV (HBV DNA >3 log at W24 or W52), and the effects of W24 viral load on efficacy outcomes at W52.

 

Results:

At W24, mean HBV DNA reduction from baseline was significantly greater with LdT vs ADV (–6.30 vs –4.97 log10 cp/mL; P<0.01). Viral load decreased sharply in ADV-treated patients after switching to LdT at W24. 78% (70/90) of patients in the ADV group had suboptimal response at W24; those switched to LdT (n=36) displayed an additional 2.1 log10 mean reduction between W24 and W52 vs 0.9 log10 for patients who remained on ADV. Similarly, 59% (26/44) of ADV recipients had persistent suboptimal response at W52 and a 2.1 log10 decrease in viral load occurred between W52 and W76 in patients who switched to LdT (n=20). In patients receiving continuous LdT, mean HBV DNA reduction from baseline was 6.3 log10, 6.8 log10, and 7.2 log10 at weeks 24, 52 and 76.

 

At W24, HBV DNA levels were reduced to <3 log10 cp/mL in significantly more LdT recipients vs ADV (49% vs 22%, P<0.01). Efficacy results at W52 correlated with HBV DNA level at W24 (Table). In patients with viral breakthrough at 1 year (2 LdT, 1 ADV), HBV DNA levels were >4 log10 cp/mL at W24.

 

Conclusions:

For patients with suboptimal initial response to ADV, switching from ADV to LdT after 24 or 52 weeks provided substantial additional reduction of serum HBV DNA that persisted through week 76. HBV DNA level after 24 weeks of treatment with LdT or ADV correlated with efficacy outcomes and viral breakthrough at one year.

 

Week 52 Efficacy

Serum HBV DNA at Week 24

<3 log10

>3 log10

HBV DNA PCR-negative (%)

94

23

ALT Normalization (%)

94

71

HBeAg Seroconversion (%)

44

11

 


S1775. A Survey of Hepatitis B Patient Demographics, Disease Characteristics and Management Practice in the United States.

V. K. Rustgi; L. Griffith; T. Westphalen; W. Johnson

 

Background:

1.25 million Americans are infected with HBV, but only ~25,000 are treated at any one time. This discrepancy may involve both patient- and physician-related factors. Little has been reported about the demographic and disease characteristics of treated and untreated patients with CHB in the USA. The objective was to evaluate whether patient management practices are consistent with AASLD treatment guidelines, which suggest treatment in patients with ALT >2xULN and HBV DNA >5 log10 copies/mL.

 

Methods:

An analysis was conducted of patient records in a database collected from a physician survey. To ensure a random selection of patient records, physicians completed a historical and prospective treatment record for their next 8 CHB patients. The database was then queried regarding treatment practices. Physicians were required to have responsibility for treatment decisions for ≥5 pts/mo.

 

Results:

77 US physicians reported on 606 patients. Most (74%) physicians were gastroenterologists or hepatologists. On average, treated patients were seen 6x per yr; untreated patients 3x per yr. Patient ethnicities included 35% Caucasian, 34% Asian, and 18% African American. 44% were born outside the USA, mostly Asia. 49% were HBeAg-, only 2% had evidence of HCC, and 22% had moderate liver damage. Therapy was initiated mostly by gastroenterologists (52%) but 45% were diagnosed by internists. The mean time between diagnosis and treatment was slightly longer in HBeAg- (23mo) vs HBeAg+ (21mo) patients.

 

Patient disease parameters at time of treatment initiation, diagnosis, or latest visit are presented (table). 65% of treated HBeAg+ patients had elevated ALT and 91% had elevated HBV DNA at the start of treatment. ALT and HBV DNA were elevated in 23% and 50%, respectively, of untreated HBeAg+ patients at their latest visit. 48% of treated HBeAg- patients had elevated ALT and 76% had elevated HBV DNA at the start of treatment. ALT and HBV DNA were elevated in 13% and 23%, respectively, of untreated HBeAg- patients at the time of diagnosis.

 

Conclusions:

Most treated patients with CHB fall within guideline-recommended ALT and HBV DNA criteria for treatment. However, there remains a large number of untreated patients who may benefit from antiviral therapy.

Patient disease parameters

 

HBeAg Positive

HBeAg Negative

 

Treated

Untreated

Treated

Untreated

 

Treatment Initiation

Diagnosis

Latest Visit

Treatment Initiation

Diagnosis

Latest Visit

ALT ≥2xULN

65%

33%

23%

48%

24%

13%

HBV DNA >5 log10 copies/mL

91%

61%

50%

76%

28%

23%

 


S1776. Salvage Therapy with Adefovir for Virologic Breakthrough in Telbivudine-Treated Patients from the GLOBE Study. 

E. Heathcote; E. J. Gane; C. Lai; A. D. Min; T. Poynard; O. Ovunc Kurdas; J. Grange; N. A. Brown

 

Background:

The GLOBE trial is a 2-year Phase 3 randomized trial of telbivudine versus lamivudine in 1,367 patients with chronic hepatitis B. Patients experiencing Virologic Breakthrough (VB) while on the GLOBE study were, at the discretion of the investigator, offered adefovir to restore effective viral suppression. Results are presented here for telbivudine-treated patients from the GLOBE trial who received adefovir as salvage therapy.

 

Methods:

Twenty-two telbivudine-treated patients with VB (defined as a confirmed increase in HBV DNA of >1 log10 copies/mL from nadir) received adefovir either as follow-on monotherapy (n=17) or in combination with telbivudine (n=5). Patient responses were assessed by serum HBV DNA levels by COBAS™ Amplicor assay (LLOD ≤300 copies/mL), as well as clinical and laboratory safety monitoring. Resistance mutations associated with VB were assessed in PCR-amplified HBV gene sequences by automated DNA sequencing.

 

Results:

At the time of this analysis, 21/22 patients had received ≥16 weeks of adefovir salvage treatment. With 16 weeks of adefovir, HBV DNA levels decreased by a mean 4.1 log10 copies/mL, and ALT levels were reduced by 93.1 IU/L (Table). HBV DNA levels decreased by a mean 5.1 log10 copies/mL in the 5 patients who received adefovir in combination with telbivudine, compared to 3.8 log10 copies/mL in the 16 patients switched to adefovir monotherapy. All 21 patients in this analysis had M204I-mutant HBV strains. VB was not associated with hepatic decompensation in any case. Consistent with observations of increased risk for resistance in patients with persisting viremia after 6 months, 11/22 (50%) patients with VB had HBV DNA >4 log at Week 24 (vs 8% of patients without VB). Study treatments were generally well-tolerated; no serious adverse events were reported.

 

Conclusions:

Adefovir salvage therapy, administered as follow-on monotherapy or in combination with telbivudine, resulted in consistent viral suppression for telbivudine-treated patients experiencing virologic breakthrough

 

Measurement Time Point

HBV DNA (log10 copies/mL) Mean ± SD

ALT (IU/L) Mean ± SD

Baseline

10.0±2.5

105.9±36.3

Nadir on telbivudine monotherapy

3.5±1.0

56.5±31.8

Value at initiation of adefovir salvage Tx

8.9±2.1

144.0±172.4

Change following 16 weeks salvage Tx (all patients)

-4.1±1.8*

-93.1±181.3†

Change following 16 weeks in subset of patients (n=5) receiving adefovir + telbivudine combination

-5.1±1.5*

-103.8±94.6†

*p <0.001 for HBV DNA reduction at 16 weeks vs time point 3. †p=0.03 for ALT reduction at 16 weeks vs time point 3.

 


S1777. Telbivudine Globe Trial at Year Two: Efficacy, Safety, and Predictors of Outcome in Patients with Chronic Hepatitis B. 

S. Han; C. Lai; E. J. Gane; Y. Liaw; S. Thongsawat; Y. Wang; Y. Chen; E. Heathcote; J. Rasenack; N. Bzowej; N. V. Naoumov; N. A. Brown

 

Background:

After 1 year, telbivudine (LdT) demonstrated greater antiviral efficacy vs lamivudine (LAM) in the GLOBE trial, a phase III randomized trial in patients with chronic hepatitis B (CHB). Here we report results from GLOBE after 2 years, including efficacy, safety and relationships between viral load at week 24 and outcomes at week 104.

 

Methods:

The GLOBE trial enrolled 1367 CHB patients with baseline HBV DNA >6 log10 copies/mL, ALT 1.3-10 xULN, and compensated liver disease. Patients were randomized 1:1 to telbivudine (600 mg/d PO) or lamivudine (100 mg/d PO) and were pre-stratified for HBeAg status and baseline ALT levels.

 

Results:

Telbivudine was superior to lamivudine (all P<0.05) for the primary efficacy measure, therapeutic response (HBV DNA <5log10 cps/mL and ALT normalization or HBeAg loss; 63% vs 48% HBeAg+, 78% vs 66% HBeAg-), and other direct measures of antiviral efficacy (mean log10 HBV DNA reduction: -5.7 vs -4.4 HBeAg+, -5.0 vs 4.2 HBeAg-; PCR negativity: 56% vs 39% HBeAg+, 82% vs 57% HBeAg-; viral breakthrough: 19% vs 33% HBeAg+, 8% vs 16% HBeAg-; and primary treatment failure (HBV DNA never <5log10 cps/mL): 4% vs 12% HBeAg+, 0% vs 3% HBeAg-). Telbivudine also demonstrated significantly greater ALT normalization vs lamivudine (70% vs 62% HBeAg+, 78% vs 70% HBeAg-) and proportionally higher rates of HBeAg loss (35% vs 29%) and seroconversion (30% vs 25%).

 

Significantly more patients receiving telbivudine vs lamivudine had HBV DNA nondetectable by PCR at week 24 (45% vs 32%, P<0.05). Viral suppression at week 24 predicted efficacy outcomes at 2 years. Two-year response rates were highest for patients with HBV DNA nondetectable by PCR at week 24 (Table). Both treatments were well tolerated, with similar adverse event profiles.

 

Conclusion:

Telbivudine exhibited significantly greater antiviral and clinical efficacy vs lamivudine in HBeAg-positive and HBeAg -negative patients at 2 years. Better viral suppression at week 24 predicted greater efficacy responses at 2 years. Observed relationships between week 24 viral load and subsequent efficacy supports the potential of early virologic response for optimizing treatment outcomes.

 

Percent of patients PCR-negative at Week 24 who achieve outcome at Week 104

 

HBeAg+

HBeAg-

 

LdT

LAM

LdT

LAM

n

203

146

178

157

HBeAg Seroconversion

46%

47%

ALT Normalization

82%

79%

82%

79%

HBV DNA non-detectable by PCR

82%

73%

88%

68%

 


S1778. Hepatitis B Prophylaxis in Patients Undergoing Chemotherapy for Lymphoma: A Decision Analysis Model. 

S. Saab; M. H. Dong; T. A. Joseph; M. J. Tong

 

Introduction:

Hepatitis B reactivation is a major cause of morbidity and mortality in patients undergoing chemotherapy for lymphomas. Patients may experience direct liver-related complications or reduced cancer survival due to interruptions in chemotherapy.

 

Aim:

Our aim is to compare costs and outcomes of two different chronic hepatitis B management strategies.

 

Methods:

Using a Markov-based decision analysis model, we compared the costs and clinical outcomes of using lamivudine prophylaxis in all hepatitis B carriers undergoing chemotherapy versus initiating lamivudine only when clinically overt hepatitis occurs.

 

Results:

Our results show that the use of lamivudine prophylaxis is cost-effective. While the use of lamivudine prophylaxis is associated with an incremental cost of $1530 per patient ($18,707 versus $17,177), both the number and severity of hepatitis B reactivation flares is decreased. None of the patients in the prophylaxis group had liver-related deaths versus 20 in the no prophylaxis group. Cancer death was also decreased with prophylaxis from 47 to 39, presumably related to the increased need for cessation or modification of chemotherapy in patients who have severe HBV flares. The incremental cost-effectiveness ratio of using lamivudine prophylaxis was $33,514/life year saved.

 

Conclusion:

Thus, our results provide pharmacoeconomic support for the use of lamivudine prophylaxis in patients undergoing chemotherapy for lymphoma treatment.

 


S1779. Prevention Of Hepatitis B Reactivation In Hepatitis B Surface Antigen (Hbsag) Negative Liver Transplant Recipients From Hepatitis B Core Antibody (Anti-Hbc) Positive Grafts With Lamivudine Monotherapy.

M. Lee; A. Kamal; E. B. Keeffe; C. O. Esquivel; A. Ahmed

 

Background:  

Prophylaxis with long-term lamivudine monotherapy following liver transplantation of anti-HBc-positive grafts into HBsAg-negative recipients has been shown to prevent HBV infection/reactivation to a posttransplant median of 21 months. Our institutional experience confirms and extends this previous finding to a new median of 77 months.

 

Methods:  

Of 492 cadaveric adult liver transplantations performed at our institution between February 1995 and July 2006, 13 recipients (2.6%) received anti-HBc-positive grafts/donor livers. Excluded from our report, 1 recipient who died in the operating room and 1 recipient whose pretransplant HBsAg status was unavailable. The remaining recipients consisted of 7 HBsAg-negative patients and 4 HBsAg-positive patients; 2 females and 9 males, with ages ranging between 55 to 71 years (median 62 years). Posttransplantation, HBsAg-negative recipients received lamivudine 100-150mg daily. HBsAg-positive recipients received both lamivudine and HBIG per protocol. Standard posttransplant immunosuppression was given. Recipients were monitored (from 16 to 106 months, median 77 months) for the development of HBV infection.

 

Results:

Seven (7) HBsAg-negative patients received long-term lamivudine without evidence of HBV infection/reactivation at the end of follow-up. Four (4) HBsAg-positive patients received long-term lamivudine and HBIG and all converted to HBsAg-negative status at the end of follow-up.

 

Conclusion:  

Long-term lamivudine monotherapy is effective in preventing HBV reactivation in HBsAg-negative recipients of anti-HBc-positive grafts/donor livers up to a posttransplantation follow-up of 6 years. We recommend a larger multicenter controlled trial to compare the efficacy of lamivudine monotherapy versus HBIG infusion in preventing HBV reactivation in HBsAg-negative recipients of anti-HBc-positive grafts. The use of HBIG may not be necessary in this patient population. Lamivudine use may provide significant cost savings and effective HBV suppression.

 


S1781. Resistance Determination in Patients Experiencing Virologic Breakthrough Following Telbivudine or Lamivudine Therapy in the International GLOBE Trial. 

D. N. Standring; A. Patty; C. Chapron; L. van Doorn; B. Belanger; N. A. Brown; M. Seifer

 

Introduction:

Resistance to telbivudine and lamivudine was evaluated at week 48 of therapy in an international trial (GLOBE), involving 1367 patients with chronic hepatitis B who were randomized (1:1) to receive 600 mg telbivudine or 100 mg lamivudine daily. Here we report the genotypic analysis of patient samples showing viral breakthrough as outlined by EASL/EMEA guidelines (≥ log10 above nadir rebound in HBV DNA after a drop in viral load of at least 1 log10 copies/mL on drug therapy).

 

Methods:

Amplification and direct sequencing of the 344 codon HBV RT domain were performed at screen for the ITT population. Patients experiencing breakthrough were re-sequenced at week 48 or post-breakthrough to identify resistance mutations.

 

Results:

131 patients met the breakthrough definition; 32 were on telbivudine and 99 on lamivudine. All but 6 lamivudine samples were amplifiable. Genotypic resistance, all based on rtM204 variants, was confirmed in 28/32 telbivudine and 75/93 lamivudine patients; the remaining genomes were essentially wild-type, presumably reflecting patient non-compliance. Of the 28 telbivudine resistant patients, 27 exhibited the M204I mutation alone (10) or in combination with rtL80I/V substitutions (17); 1 showed a mixed codon 204 variant (M204M/I/V). Of the 75 lamivudine resistant patients, 34 were due to M204I (most with rtL80 substitutions), 25 to M204V/L180M, and 16 were mixed M204M/I/V mutants. No telbivudine-related M204V or M204/L180M mutants or novel resistance mutants were seen in association with breakthrough, without a detectable M204I mutation. The proportions of telbivudine recipients with breakthrough versus genotypically confirmed resistance (latter in parentheses) were 5.9/(5.0)% in HBeAg-positive and 2.25/(2.25)% in HBeAg-negative patients, versus 15.3/(11.2)% and 12.5/(10.3)%, respectively, for lamivudine. Analysis of year 2 data is ongoing, but to date M204I-mutant HBV strains continue to be the basis of genotypic resistance with virologic breakthrough for telbivudine.

 

In vitro phenotypic testing revealed that M204I and M204I/L80I variants were resistant to telbivudine (>1300 fold), but sensitivity to adefovir or tenofovir was only 3 to 5 fold reduced.

 

Conclusions:

In the large GLOBE trial, genotypic HBV resistance with virologic breakthrough on telbivudine is based on the M204I mutation, confirming our earlier findings (Standring et al., EASL 2005). Based on our in vitro data, the best agents for therapy of telbivudine resistant M204I and M20I/L80I mutant HBV strains would appear to be adefovir or tenofovir.

 


S1782. Absence of Pharmacokinetic Drug-Drug Interaction Between Telbivudine and Tenofovir. 

X. Zhou; K. Pietropaolo; M. Becker; J. Ke; N. A. Brown

 

Background:

The advent of new therapeutic agents for chronic hepatitis B may potentially provide the opportunity to improve clinical outcome by combining or alternating complementary antiviral agents, e.g. nucleosides and nucleotides. In this context, we evaluated pharmacokinetic (PK) interactions between telbivudine (Tyzeka™), a potent anti-HBV nucleoside, and tenofovir disoproxil fumarate (Viread®), an anti-HIV nucleotide with potent anti-HBV activity.

 

Methods:

Sixteen healthy subjects were enrolled and were randomized equally between 2 parallel groups to receive one of the two study drugs daily for 14 days, with the other drug added on day 8 and continued for 7 days. The studied doses were 600 mg/d for telbivudine and 300 mg/d for tenofovir. Steady-state PK of the study drugs alone and in combination were evaluated on days 8 and 14 respectively.

 

Results:

Plasma PK parameters of telbivudine at steady-state were similar when telbivudine was administered alone (Cmax=4.3±0.9 µg/mL, AUCss=33.7±5.3 µg●h/mL) and in combination with tenofovir (Cmax=3.7±0.7 µg/mL, AUCss=31.3±3.5 µg●h/mL). Similarly, steady-state PK parameters of tenofovir were also comparable when tenofovir was administered alone (Cmax=0.48±0.13 µg/mL, AUCss=3.3±0.7 µg●h/mL) and in combination with telbivudine (Cmax=0.50±0.15 µg/mL, AUCss=3.2±0.6 µg●h/mL). Study drugs were in general well tolerated when administered in the combination.

 

Conclusion:

Results from this study indicate that there is no appreciable PK drug-drug interaction between telbivudine and tenofovir in healthy human subjects, providing pharmacokinetic support for assessing combination anti-HBV treatment regimens involving these two drugs.

 


S1783. Cross Trial Comparison of Genotypic Response Rates with Adefovir, Entecavir or Telbivudine for Chronic Hepatitis B . 

A. Rajendra; J. B. Wong

 

Aim:

Hepatitis B virus (HBV) genotype influences response to interferon, peginterferon and lamivudine (Rajendra AASLD 2006). Our aim was to compare genotype-specific response rates with adefovir, entecavir, and telbivudine.

 

Methods:

We identified the registration trials for these drugs from MEDLINE, AASLD and EASL abstracts, and the FDA website and extracted undetectable HBV DNA response rates at week 48 or 52 by genotype (B, C and Other {A,D,E,F,G,H}) with separate analyses for HBeAg+ and HBeAg- patients. Chi-square tests were applied to determine statistical significance.

 

Results:

The 6 registration trials included 3414 patients with mean ages 35-46; 74-83% men; 30-82% Asians; mean viral load 6.9-9.7 million copies/mL; and 6-11% cirrhosis. Viral response to the 3 treatments was statistically significantly different for the HBeAg+ trials (21% adefovir, 70% entecavir, 60% telbivudine, p<0.001) and HBeAg- trials (51% adefovir, 91% entecavir, 88% telbivudine, p<0.001). The proportion of patients with each genotype however differed for the 3 HBeAg+ trials (B, C & Other: 20%, 36%, 44% adefovir; 20%, 28%, 52% entecavir; 26%, 56%, 18% telbivudine, p<0.001) and for the 3 HBeAg- trials (B, C & Other: 17%, 13%, 70% adefovir; 17%, 17%, 66% entecavir; 26%, 39%, 34% telbivudine, p<0.001) making cross trial comparisons inappropriate. Genotype-specific response rates were unavailable for adefovir, but entecavir had statistically significant higher undetectable HBV DNA response rates in HBeAg+ patients with genotype C and in both HBeAg+ and HBeAg- patients with genotype Other. The latter comparison could be confounded by different proportions of the 6 “Other” genotypes in the entecavir and telbivudine trials.

 

Conclusions:

The likelihood of undetectable HBV DNA responses differ for adefovir, entecavir and telbivudine, but our analysis demonstrates significantly different proportions of patients with each genotype in the major registration trials and significantly different responses to treatment by genotype. In addition to other patient characteristics that could potentially further confound cross trial comparisons, the proportion of patients with each genotype should be examined when comparing viral responses across different trials.

 

 

HBeAg-Positive

HBeAg-Negative

Genotype
B

Genotype
C

Genotype
Other

Genotype
B

Genotype
C

Genotype
Other

Telbivudine

0.57

0.65

0.48

0.90

0.93

0.79

Entecavir

0.66

0.78

0.65

0.89

0.97

0.91

 

p=0.26

p=0.01

p=0.01

p=0.84

p=0.63

p=0.02

 


Metabolic and Genetic Liver Disease, Including Non-alcoholic Fatty Liver Diseases

 

S2158. Prevalence and associated factors of nonalcoholic liver fatty disease and metabolic syndrome: results from a cross-sectional study . 

A. Colecchia; A. Vestito; E. Petracci; M. Bacchi-Reggiani; A. Morselli-Labate; A. Di Biase; G. Mazzella; F. Lodato; M. Montagnani; F. Pasqui; D. Festi

 

Introduction:

Nonalcoholic fatty liver disease (NAFLD) and metabolic syndrome ( MS) are considered closely related diseases, having insulin resistance as common pathogenetic mechianism. A few studies, however, have simultaneously assessed NAFLD and MS prevalence and associated factors in a general population.

 

Aim:

to evaluate by means of a cross-sectional study prevalence and associate factors of NAFLD and MS.

 

Material and Methods:

The cross sectional study was performed on a general population ,aged 28-84 yrs; 1534 out of 1646 ( 93%) subjects agreed to participate to the study. All subjects underwent abdominal ultrasound (US), physical examination, fasting blood specimen collection, seven day dietetic diary. NAFLD was evaluated by US and MS was defined according to ATP III criteria (presence of 3, or more, of the following parameters: waist circumference, fasting glucose, HDL-cholesterol, triglycerides, blood pressure). Insulin resistance was evaluated using the triglycerides/HDL-Cholesterol ratio ( Tg/Hdl ratio) ( n.v.< 3.5).

 

Results:

479 out of 1534 ( 31.2%) subjects were excluded because they presented other liver diseases (391 alcohol, 20 HBV, 63 HCV and 5 autoimmune). 382 out of 1055 subjects ( 36.1%) ( males 57.8%, mean age: 52.1 ± 12.7) had NAFLD, while 240 out of 1055 ( 22.7%) subjects had MS ( males 45.8%,mean age 55.5 ± 12.6). In NAFLD, MS prevalence was 41.6% (159 out of 382 subjects); at multivariate analysis, associate factors resulted: sex male (OR:1.89), systolic hypertension (OR:1.9), hyperglicemia (OR:1.9), visceral obesity (OR:4.9), Tg/HDL ratio (OR:2.9), ALT (OR:2,5), gGT (OR:1.8). NAFLD was present in 66.2% (159 out 240 subjects) of MS subjects: at multivariate analysis associated factors resulted: increasing age (OR:1.5); female sex (OR:1.05); fatty liver ( OR:5.22); Tg/Hdl ratio ( OR: 23.04).

 

Conclusions:

The present study confirm the strong association between NAFLD and MS; although NAFLD prevalence is higher. Subjects with NAFLD had higher risk (OR: 13.5) to have MS than vice-versa (OR: 5.22); this observation suggest that NAFLD could plays an early role in the development of M.S. Further epidemiologiocal and pathophysiological studies are needed to better define which is the killer or the victim.