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.
|
|
Unadjusted
OR (95% CI)* |
Adjusted
OR (95% CI)†|
|
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
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
Methods:
Asymptomatic subjects of either
gender of all ages residing at an urban community of Kamalapur,
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
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
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.
|
Variable
|
Occult
HBV |
Standard
|
No
Occult HBV |
SD |
p
Value |
|
Mean age |
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
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
Results:
Among the 138 patients with HCC, 98
(71%) received an ECD liver. Preoperatively, 43/138 (31.2%) were outside
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
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
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.
|
|
β-Coefficient |
Hazard
ratio |
95%
CI |
P
value |
|
Gender (referent: female) |
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) |
0.54473 |
1.7 |
1.2-2.5 |
0.0040 |
|
ALT, U/L (referent: <45) |
0.55669 |
1.7 |
1.1-2.7 |
0.0104 |
|
HBeAg (referent: negative) |
0.96885 |
2.6 |
1.7-4.1 |
<0.0001 |
|
HBV DNA / genotype (referent: <100 / not tested) |
0.80015 |
2.2 |
0.9-5.3 |
0.0700 |
|
Family history of HCC (referent: no) |
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
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
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
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
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
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
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.
|
|
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
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 |
Genotype |
Genotype |
Genotype |
Genotype |
Genotype |
|
|
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 (
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.