GASTROENTEROLOGY 2002;123:719 727

CLINICALLIVER, PANCREAS, AND BILIARY TRACT

Determinants of Early Mortality in Patients With Decompensated
Chronic Hepatitis B Treated With Antiviral Therapy
ROBERT J. FONTANA,* HIEWON L. HANN, ROBERT P. PERRILLO, JOHN M. VIERLING,
THERESA WRIGHT, JORGE RAKELA,# GAYA ANSCHUETZ,** RANDY DAVIS,**
STEPHEN D. GARDNER,** and NATHANIEL A. BROWN**
*Department of Medicine, University of Michigan, Ann Arbor, Michigan; Department of Medicine, Jefferson Medical College, Philadelphia,
Pennsylvania; Department of Medicine, Ochsner Clinic, New Orleans, Louisiana; Department of Medicine, Cedars Sinai Medical Center,
Los Angeles; Department of Medicine, University of California San Francisco, San Francisco, California; #Department of Medicine,
University of Pittsburgh, Pittsburgh, Pennsylvania; and **GlaxoSmithKline, Research Triangle Park, North Carolina

Background & Aims: Chronic hepatitis B is a leading cause

of death worldwide. To identify patients who might require
urgent liver transplantation despite antiviral therapy, we
investigated the determinants of early mortality in a large
cohort of patients with decompensated chronic hepatitis B
treated with lamivudine. Methods: One hundred fty-four
North American patients with decompensated chronic hepatitis B received lamivudine for a median of 16 months.
Univariate and multivariate Cox regression modeling was
used to develop a model of 6-month mortality. Results: A
biphasic survival pattern was observed, with most deaths
occurring within the rst 6 months of treatment (25 of 32,
78%) because of complications of liver failure. The estimated actuarial 3-year survival of patients who survived at
least 6 months was 88% on continued treatment. In multivariate modeling, elevated pretreatment serum bilirubin
and creatinine levels as well as the presence of detectable
hepatitis B virus (HBV) DNA (by the bDNA assay) pretreatment were signicantly associated with 6-month mortality.
An equation approximating the probability of early mortality was developed from these variables. Conclusions: Our
data demonstrate a distinct alteration in the slope of the
survival curve after 6 months of lamivudine treatment
for decompensated chronic hepatitis B. An equation consisting of 3 widely available pretreatment laboratory parameters was developed that can be used to predict the
likelihood of early death in patients receiving lamivudine
for decompensated chronic hepatitis B. These observations may help identify patients who can be stabilized with
suppressive antiviral therapy vs. those who require urgent
liver transplantation.

remission during early stage disease.3 However, the spontaneous resolution rate is low, and the 5-year mortality
rate is high in patients with untreated HBV-related
cirrhosis (15% to 45%) and particularly in those with
active HBV replication (50% to 80%).4 7 Liver transplantation with antiviral prophylaxis is available as a
potential salvage therapy for some patients with advanced disease.8 However, liver transplantation is not
widely available in regions of the world where HBV is
endemic, and the majority of patients with advanced
hepatitis B receive only palliative care prior to death.1
Continuing advances in antiviral therapy for HBV
infection offer an opportunity to reassess the feasibility of
treating patients with both compensated and decompensated cirrhosis. Interferon (IFN)- therapy may have
clinical benet in carefully selected patients with compensated HBV cirrhosis.9 However, IFN- is contraindicated in patients with decompensation because of the
risk of potentially life-threatening complications.10,11 In
contrast, lamivudine seems to be generally well tolerated
in patients with both compensated and decompensated
HBV cirrhosis.12,13 In uncontrolled studies involving
small numbers of patients, lamivudine led to a rapid
suppression of HBV replication and demonstrated promising therapeutic effects with regard to reversal or partial
reversal of signs of liver failure.1315 With study periods
varying from 1 to 3 years, many patients with previously
irreversible HBV-related liver failure showed clinical and

hronic hepatitis B virus (HBV) infection remains a

major global public health problem, with more than
1 million deaths per year because of hepatitis Brelated
liver failure and hepatocellular carcinoma.1,2 Some patients with chronic HBV infection achieve spontaneous

Abbreviations used in this paper: CTP, Child-Turcotte-Pugh; HBsAg,

hepatitis B surface antigen; HBeAg, hepatitis B e antigen; HBV, hepatitis B virus; HCV, hepatitis C virus; HDV, hepatitis D virus; HIV, human
immunodeciency virus; IFN, interferon.
2002 by the American Gastroenterological Association
0016-5085/02/$35.00
doi:10.1053/gast.2002.35352

720

FONTANA ET AL.

biochemical improvements, and overall survival appeared

to be improved compared with historical controls.1316 In
several of these studies, it was noted that most patient
deaths occurred within the rst few months after initiation of antiviral therapy.13,16 Further understanding of
the mortality pattern in HBV-related cirrhosis and the
clinical predictors of response to antiviral therapy may
help optimize the care of many patients with advanced
stages of chronic hepatitis B worldwide. The aim of the
present study was to investigate the mortality pattern
and pretreatment determinants of early (6 months) mortality in a large cohort of North American patients with
decompensated HBV cirrhosis who were treated with
lamivudine in prospectively conducted clinical trials.16 18 Our study results indicate a biphasic survival
pattern in patients with advanced HBV-related cirrhosis
treated with lamivudine and a reduced annualized death
rate for those who survive the rst 6 months of therapy.
Our data also provide pretreatment risk proles that may
help identify patients who will survive for prolonged
periods with antiviral therapy vs. those who will require
urgent liver transplantation.

Patients and Methods

Patient Population
Data for 154 North American patients with advanced
HBV cirrhosis enrolled in 3 multicenter, prospective studies of
lamivudine were integrated into a single electronic database.
The study group included 84 hepatitis B surface antigen
(HBsAg)-positive liver transplantation candidates who received lamivudine without undergoing transplantation in 2
multicenter studies.16,18 In addition, 70 HBsAg-positive patients with decompensated cirrhosis who were not considered
immediate candidates for liver transplantation and received
lamivudine were included.17 Inclusion criteria for the studies
were clinically well-documented chronic hepatitis B with detectable HBsAg, decompensated HBV-related cirrhosis, age
13 years, serum HBV DNA positive or negative, and ability
to provide informed consent. Exclusion criteria included pregnancy or breast feeding, acute liver failure, severe pancreatitis,
prior liver transplantation, or the need for mechanical ventilation at enrollment. Written informed consent for study
participation was obtained from all subjects per local IRB
guidelines.

Study Protocols
Patients were prospectively monitored at weeks 0, 2, 4,
6, and 8 and every 4 to 8 weeks thereafter until study completion. Centralized laboratory monitoring was performed at
the same facility for all 3 studies (Covance Laboratories, Indianapolis, IN) and included complete blood counts, serum
electrolytes, amylase, serum aspartate aminotransferase (AST),
alanine aminotransferase (ALT) levels, bilirubin, and albumin.

GASTROENTEROLOGY Vol. 123, No. 3

Hepatitis B serologies, including HBsAg, anti-HBs, hepatitis

B e antigen (HBeAg), and anti-HBe, were measured every 4
months using commercially available enzyme-linked immunosorbent (ELISA) assays (Abbott Laboratories, Abbott Park,
IL). In 29 patients, serum HBV DNA levels were measured
using the solution hybridization assay (Abbott Laboratories)
during the rst year of the study.19 In all of the other patients
and in these 29 patients from year 2 onward, serum HBV
DNA levels were measured at the central laboratory using the
branched-chain amplication (bDNA) assay (Chiron Corp.,
Emeryville, CA) with a lower limit of detection of 0.7 Meq/mL
(7 105 genome equivalents/mL).
Open-label lamivudine (Epivir HBV; GlaxoSmithKline, Research Triangle Park, NC) was orally administered as a single
100 mg tablet daily. Patients with an estimated creatinine
clearance of 50 mL/min received reduced doses of lamivudine oral suspension.20 Patient compliance was reviewed at
each study visit, and unused study drug was collected.

Study Endpoints
Subjects were prospectively followed until completion
of study or death. The primary analytic goals for the integrated
database were to characterize overall patient survival and to
identify predictors of early mortality through univariate and
multivariate regression modeling. Other correlative study
analyses included virologic response (achievement and maintenance of nondetectable serum HBV DNA levels, HBeAg
loss, and anti-HBe seroconversion), biochemical response (ALT
normalization or improvement), and changes in serum bilirubin and albumin levels as measures of hepatic excretory and
synthetic functions, respectively. Child-Turcotte-Pugh (CTP)
scoring was performed in 2 of the 3 studies and was available
for 125 of the 154 patients.21
Virologic breakthrough on treatment was dened as the
reappearance of detectable serum HBV DNA for 2 or more
consecutive visits (including the last visit) in patients who
were HBV DNA positive at baseline or who had detectable
serum HBV DNA at last visit by the solution hybridization or
bDNA assay. Serum HBV DNA levels were available to the
clinical investigators on a real-time basis during the course of
the studies. When virologic breakthrough was suspected, the
clinical investigators were encouraged to send the patients sera
to the central virology laboratory for HBV genotyping by
PCR-based methods.22

Data Analyses
Data were entered into a centralized database using
SAS software (SAS, Cary, NC). Descriptive statistics were
calculated and reported as median and range unless indicated
otherwise. Follow-up period for survival analysis began on the
rst day of treatment. All deaths occurring within the rst 6
months of treatment (group NS) were considered to be events,
whereas deaths after 6 months were censored on the day of
death. Similarly, all patients who didnt experience death
during the study were censored at the last study visit day. In
analyses other than the Cox regression, the 19 patients who did

September 2002

LAMIVUDINE IN DECOMPENSATED HEPATITIS B

721

other patients followed for more than 6 months. Reasons

for early discontinuation from the study in these 19
patients included investigator preference (8), completion
of study observation (7), patient relocation (3), and noncompliance (1). Therefore, for the analyses of baseline
characteristics and on treatment response, the 19 early
discontinuation patients were combined with the 110
patients who survived 6 months (designated as the
SURV group, n 129).

not die and whose follow-up was less than 6 months were
combined with those who survived at least 6 months (group
SURV). The probability of death within 6 months was examined for the 154 subjects by tting univariate and multivariate
Cox regression models. The covariates that were tested included age, gender, ethnicity, albumin, bilirubin, creatinine,
HBV DNA, and serum ALT. Those variables found to be
signicant in the univariate models were tested in a multivariate setting. A separate model with CTP scores was tted
because only a subset of subjects had CTP data at baseline.
Model estimation was obtained using the PHREG procedure
with backwards elimination of variables and retaining variables with P 0.05. Generalized estimating equations (GEE)
methodology was used to examine differences in serum albumin, bilirubin, and HBV DNA levels over time during the
rst 24 weeks of treatment in NS and SURV patients.

Patient Survival
During study observation, 32 of the 154 (21%)
patients died, with most of the deaths (25 of 32, 78%)
occurring within the rst 6 months. Overall patient
survival is depicted in Figure 1 and reveals a biphasic
survival pattern with a distinct alteration in the slope of
the survival curve at 6 months after initiation of treatment. Although 7 patients died after the rst 6 months,
the estimated actuarial 3-year survival of patients who
survived at least 6 months was remarkably good (88%).
The mean patient death rate during the rst 6 months of
treatment was 0.42 deaths per patient year of follow-up
compared with 0.04 deaths per patient year of follow-up
after 6 months of treatment.
As expected, most of the 32 patient deaths were due to
complications of advanced HBV-related cirrhosis. The
reported causes of the 25 early deaths in the NS group
included complications of liver failure (22), suicide (1),
intracranial hemorrhage (1), and cardiac arrest (1). The
reported causes of the 7 later deaths in the SURV group

Results
Patient Demographics and Disease
Characteristics
The 154 patients with HBV-related cirrhosis received lamivudine for a median of 16 months (range,
0.537) and had baseline characteristics consistent with
varying degrees of hepatic decompensation (Table 1).
Patients were predominantly male (80%) and either
white (56%) or Asian (36%). None of the patients had
HIV coinfection, whereas 9 (6%) had hepatitis C virus
(HCV) and 6 (4%) had hepatitis D virus (HDV) coinfection. The baseline characteristics of the 19 patients
who withdrew from the study during the rst 6 months
of treatment were not substantially different from the

Table 1. Pretreatment Characteristics of 154 Patients With Decompensated HBV Cirrhosis

Group NS
Total
(n 154)
Demographics
Med age, (yr) (range)
Male (%)
Ethnic background (%)
White
Asian
Other
Disease parameters
Med ALT (IU/L)
Med bilirubin (mg/dL)
Med albumin (g/dL)
Med CTP score
HBeAg (%)
HBV DNA (%)
Med HBV DNA (mEq/mL)
Elevated creatinine (%)
Med creatinine (mg/dl)

(survived 6 months;
n 25)

Group SURV
(survived 6 months;
n 110)

Withdrawn prior to 6
months (n 19)

50 (1978)
80

54 (3466)
76

49 (2378)
81

50 (1978)
84

56
36
8

48
36
16

58
34
8

47
53
0

71 (15695)
1.8 (0.230.4)
2.9 (1.54.5)
9 (514) (n 124)
64
74
39.3 (0.3514,301)
(n 152)
13
0.9 (0.413.7)

75 (20326)
4.0 (0.430.4)
2.4 (1.73.4)
11 (514) (n 19)
70
92
99.3 (0.356,787)
(n 24)
44
1.2 (0.68.8)

NOTE. All data expressed as median (range) unless indicated otherwise.

73 (15695)
1.6 (0.230.1)
3.0 (1.54.5)
9 (512) (n 88)
65
66
38.6 (0.3514,301)
(n 109)
8
0.9 (0.413.7)

61 (31326)
2.0 (0.67.4)
2.8 (1.94.4)
10 (513) (n 17)
53
53
1.9 (0.353,181)
(n 19)
0
0.8 (0.61.1)

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FONTANA ET AL.

GASTROENTEROLOGY Vol. 123, No. 3

Figure 1. Kaplan-Meier plot of patient survival in the entire cohort

(n 154), NS patients surviving 6 months (n 25), and SURV
patients, which includes patients surviving 6 months and those with
less than 6 months of follow-up (n 129). The actuarial 3-year
survival in the SURV group was 88% and 73% in the overall group.

included complications of liver failure (6) and metastatic

lung cancer (1).
Inspection of the pretreatment data indicated that the
patients in the NS group appeared to have evidence of
more advanced liver failure at study entry than the
SURV group (Table 1). Specically, the NS group
tended to have higher pretreatment serum bilirubin,
lower serum albumin, and higher serum creatinine levels
than SURV patients. In addition, the CTP scores in
evaluable NS patients tended to be higher than in the
SURV patients.
Predictors of 6-Month Survival
Because of the observed break in the overall survival curve at approximately 6 months, early mortality
was dened as death within 6 months of initiation of
antiviral treatment. Univariate Cox regression analyses
were undertaken to examine pretreatment clinical and
laboratory characteristics for associations with early mortality. As seen in Table 2, there were strong univariate
associations of elevated serum bilirubin, low serum al-

bumin, and elevated serum creatinine levels with early

mortality. In addition, the presence of detectable HBV
DNA at baseline was associated with early mortality.
In a multivariate Cox regression model using backwards elimination of variables, the features that remained signicantly associated with early mortality
were elevated serum bilirubin, elevated serum creatinine, and detectable HBV DNA (Table 3). Of note,
serum albumin levels were not a signicant independent predictor of survival because its effects were
accounted for by the other variables, primarily because
of its correlation with serum bilirubin. When baseline
CTP scores (available in 125 patients) were incorporated into the multivariate model, serum bilirubin,
creatinine, and HBV DNA remained the most significant predictors of early mortality. Therefore, the original model without CTP scores was used.
Because pretreatment serum creatinine and bilirubin
levels and detectable HBV DNA were strongly associated with 6-month mortality, we derived a predictive
model of 6-month survival in patients with HBV-related
cirrhosis receiving suppressive antiviral therapy (lamivudine). A variable called Index was created as follows:
Index 0.5 bili 1.7 creatinine 1.8 HBV
DNA (0 or 1). Estimated survivor functions were generated for various values of the Index variable to examine
the probability of death within 6 months and are presented in Figure 2. For example, a subject with a serum
bilirubin of 2.0 mg/dL, creatinine of 1.2 mg/dL, and
undetectable HBV DNA (coded as 0) has an index score
of 3 and a 5% probability of 6-month mortality while
receiving lamivudine. Similarly, a patient with more
advanced liver failure at presentation with a serum bilirubin of 6.0 mg/dL, a serum creatinine of 2.0 mg/dL, and
detectable HBV DNA with an index score of 8.2 would
have a 95% probability of death within 6 months while
receiving lamivudine.

Table 2. Univariate Cox Regression Model of Pretreatment Characteristics and 6-Month Mortality (n 154)
Variable
Demographics
Age
Gender (M/F)
Ethnicity
Laboratory values
Albumin (g/dL)
Bilirubin (mg/dL)
Creatinine (mg/dL)
HBV DNA (/)
ALT (IU/L)
CTP scorea
aAvailable

in 125 patients.

Parameter estimate

SE of estimate

Risk ratio (95% CI)

P value

0.013
0.244
0.0051

0.02
0.47
0.42

1.10 (0.981.05)
0.78 (0.311.96)
0.99 (0.442.25)

0.49
0.60
0.99

1.32
0.447
1.26
1.640
0.00095
0.469

0.34
0.07
0.28
0.74
0.00162
0.139

0.27 (0.140.52)
1.56 (1.351.81)
3.54 (2.036.18)
5.16 (1.2121.93)
1.00 (0.9981.004)
1.60 (1.222.10)

0.0001
0.0001
0.0001
0.0264
0.5567
0.0007

September 2002

LAMIVUDINE IN DECOMPENSATED HEPATITIS B

723

Table 3. Multivariate Cox Regression Model of Pretreatment Characteristics and 6-Month Mortality (n 154)
Variable

Parameter estimate

SE of estimate

Risk ratio (95% CI)

P value

Creatinine
Bilirubin
HBV DNA (/)

1.655
0.523
1.814

0.311
0.084
0.751

5.23 (2.849.63)
1.69 (1.431.99)
6.13 (1.4126.76)

0.0001
0.0001
0.0158

Virologic Efcacy During Treatment

As seen in Figure 3A, more than 80% of patients
in both groups had suppression of HBV DNA to undetectable levels by the bDNA assay within 8 weeks of
initiating lamivudine treatment. Therefore, the early
antiviral response to lamivudine does not appear to predict patients who will survive 6 months. There was
also no consistent difference in serum ALT levels between the 2 groups of patients (data not shown). However, as seen in Figure 3B, median serum bilirubin levels
were consistently higher in NS compared with SURV
through week 16 of treatment (P 0.0035 by repeated
measures analysis of variance). Similarly, median serum
albumin levels were consistently lower in NS compared
with SURV through week 16 of treatment, although
both groups of patients demonstrated a trend towards
improved values over time (Figure 3C) (P 0.0002 by
repeated measures analysis of variance). Among the patients that were HBeAg positive at baseline, 15 of 16
(94%) NS patients remained HBeAg positive, whereas
51 of 78 (65%) SURV patients were HBeAg positive at
last available follow-up. Only 1 of the 12 (8%) NS
patients acquired HBeAb during follow-up, whereas 17
of the 83 (20%) SURV patients had acquired HBeAb at
last follow-up.
Virologic Breakthrough
Virologic breakthrough was observed in 22 of the
81(27%) patients who were HBV DNA positive at base-

Figure 2. Predicted 6-month survival in patients with HBV cirrhosis

receiving lamivudine, using the model derived from our data set.
Index 0.5 bili 1.7 creatinine 1.8 HBV DNA (0 or 1).

Figure 3. (A) Proportion of NS and SURV patients who became HBV

DNA negative during the rst 24 weeks of lamivudine treatment. (B)
Median serum bilirubin levels in NS and SURV patients through week
24 of lamivudine treatment. (C) Median serum albumin levels in NS
and SURV patients through week 24 of lamivudine treatment. Error
bars for B and C represent 95% condence intervals.

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FONTANA ET AL.

GASTROENTEROLOGY Vol. 123, No. 3

line and who had adequate follow-up evaluation (Table

4). Conrmatory PCR-based genotype testing performed
in 11 of these 22 cases demonstrated the presence of
YMDD variants with mutations in the B and C domains
of the HBV genome in 10 patients.22,23 In 1 patient, only
wild-type HBV was detected, suggesting patient noncompliance. The median time to development of breakthrough infection was 13 months. The median duration
of total lamivudine therapy in the breakthrough patients
was 21.0 months (range, 236), compared with 14.5
months (range, 2.335) in the patients without breakthrough. At last follow-up, the median serum ALT levels
were signicantly higher in patients with breakthrough
infection, whereas albumin and bilirubin levels were
similar in the patients with and without virological
breakthrough. Three of the 22 patients with breakthrough (13%) infection died during follow-up compared with 10 of the 59 (17%) patients without breakthrough. Two of the deaths in patients with breakthrough
infection occurred at 1 month (multisystem organ failure) and 13 months (liver cancer) of lamivudine therapy
and were felt not to be related to virological breakthrough. However, the third death after 28 months of
lamivudine therapy was attributed to a combination of
breakthrough infection and multisystem organ failure.

Discussion
Our data demonstrate a remarkable biphasic pattern of survival in patients with decompensated hepatitis
B treated with suppressive antiviral therapy. There is a
distinct alteration in the slope of the survival curve after
6 months of treatment, suggesting that 2 patient subgroups exist pretreatment (Figure 1): those who will
experience prolonged survival with antiviral therapy and
those who will need urgent liver transplantation. The

Table 4. Comparison of Patients With and Without

Breakthrough Infection During
Lamivudine Treatment
Parameter at last visit

Breakthrougha
(n 22)

No breakthrougha
(n 59)

Med duration of lamivudine

(mo)
Med serum ALT (IU/L)b
Med albumin (g/dL)
Med bilirubin (mg/dL)

21.0 (236)
51 (18318)
3.6 (2.24.5)
1.4 (0.312.4)

14.5 (2.335)
32.5 (14702)
3.2 (1.44.5)
1.6 (0.319.4)

NOTE. Only 81 of the 154 (52%) patients are eligible for inclusion in
the breakthrough analysis because 48 subjects had undetectable
HBV DNA at baseline. Of the 104 subjects with detectable HBV DNA
at baseline, only 81 had more than 1 follow-up visit.
aData expressed as median (range).
bP 0.0038 using Wilcoxon rank-sum test.

observed early mortality pattern suggests that some patients with advanced HBV-related cirrhosis have irreversible liver damage, whereas others may be reversed or
stabilized with effective antiviral therapy.24
Pretreatment disease differences associated with early
death were characterized, providing potentially predictive proles for clinicians to use to distinguish patients
who may have a more favorable short-term prognosis
with antiviral therapy from those who may require urgent liver transplantation. Pretreatment age, gender,
ethnicity, CTP score, HBeAg serostatus, and serum ALT
levels did not appreciably inuence 6-month survival
(Table 2). However, elevated serum bilirubin and creatinine levels as well as the presence of detectable HBV
DNA (at levels 7 105 copies/mL) were strong and
independent predictors of 6-month mortality. The importance of these variables can be seen in our Index plot
of predicted patient survival, which provides risk contours for mortality during the rst 6 months of antiviral
therapy (Figure 2).
Assessment of early treatment efcacy (i.e., HBV
DNA response, ALT change, and bilirubin and albumin
improvements) did not appreciably augment the ability
to predict short-term mortality. Both the SURV and NS
groups of patients experienced a rapid suppression of
HBV DNA to undetectable levels within 8 weeks of
starting lamivudine (Figure 3A). If the HBV DNA
testing had been done using more sensitive, quantitative
PCR techniques, it is possible that more subtle differences in virologic response could have been observed in
the 2 patient groups. However, recent recommendations
indicate that the clinical correlations are uncertain for
low-level HBV DNA (i.e., levels below the lower limit of
detection of the bDNA assay of 105 copies/mL).25,26
There were also no signicant differences in serum ALT
levels during the rst 6 months of treatment in these 2
groups of patients. However, NS had signicantly higher
serum bilirubin and lower serum albumin levels than
SURV pretreatment and during the rst 6 months of
treatment (Figure 3).
These data demonstrate that in decompensated
chronic hepatitis B patients treated with lamivudine, the
pretreatment severity of liver disease is a more important
predictor of early mortality than antiviral response. Our
ndings are consistent with numerous other studies of
therapeutic interventions in patients with decompensated cirrhosis that demonstrate the importance of the
pretreatment severity of liver disease in predicting survival.27,28 Additionally, our results indicate that, in patients with decompensated HBV-related cirrhosis, 2
other factors inuence survival during the early months

September 2002

of antiviral therapy, i.e., renal function and the pretreatment level of HBV replication. The correlation between
detectable HBV DNA and 6-month mortality is consistent with other studies that demonstrate a negative
impact of active HBV replication on patient survival.4 7
Presumably, patients with detectable HBV DNA have a
greater burden of infected hepatocytes and are at increased risk of experiencing progressive liver disease.6
Unfortunately, pretreatment prothrombin time levels
were not available in all of the study patients to allow us
to calculate MELD or CTP scores.27,28 Standardized,
validated procedures for shipment and assay of prothrombin times at central laboratories were not commonly
adopted until 2 years after the initiation of this study.
The prothrombin times were performed at local laboratories, using a variety of methods and reference ranges
because of the need for freshly harvested and immediately
cooled samples for accurate test results. Nonetheless, in
the multivariate modeling involving the 125 patient
group with available CTP scores that incorporated locally
performed prothrombin times, it was notable that elevated serum bilirubin, creatinine, and detectable HBV
DNA remained the strongest predictors of 6-month mortality. Clearly, it will be of interest to determine if the
MELD score or our Index score are useful predictors of
early mortality in patients with decompensated HBVrelated cirrhosis receiving lamivudine in future prospective studies. Both survival models utilize commonly
available laboratory parameters and can be easily calculated. In addition, both scores have high coefcients for
serum bilirubin and creatinine levels, which have been
consistent predictors of poor survival in patients with
decompensated cirrhosis.29,30 However, it should be kept
in mind that the MELD score was developed to predict
3-month mortality in a broad variety of liver transplantation candidates and that our Index score was designed
to predict 6-month mortality in patients with decompensated HBV cirrhosis receiving lamivudine. Therefore,
it is possible that these survival algorithms will prove to
be complementary in caring for different groups of patients with decompensated cirrhosis.
In the 81 patients with detectable HBV DNA prior to
treatment, 22 (27%) developed evidence of virologic
breakthrough while receiving lamivudine. The time to
the development of breakthrough infection and the proportion of patients with breakthrough are comparable
with that reported in other studies.12,31 Virologic breakthrough was conrmed to be due to YMDD mutants in
10 of the 11 patients tested.22 Within the observation
periods available in this integrated clinical trial database,
patient survival was not appreciably different for patients

LAMIVUDINE IN DECOMPENSATED HEPATITIS B

725

with and without virologic breakthrough. In addition,

the median serum bilirubin and albumin levels in patients with and without breakthrough were not signicantly different at last available follow-up (Table 4).
However, breakthrough infection contributed to at least
2 of the late deaths, similar to other reports.13,16 Hence,
although this study and others indicate that lamivudine
therapy may stabilize or improve patients with decompensated HBV cirrhosis, it remains important to continue to develop improved long-term treatment strategies for patients with advanced hepatitis B. Of note, none
of the patients received adefovir, which appears to be a
promising salvage antiviral therapy for patients with
virologic breakthrough on lamivudine.32,33
In summary, our data demonstrate a distinct biphasic
survival pattern in patients with decompensated HBVrelated cirrhosis treated with suppressive antiviral therapy, with an approximately 10-fold reduction in the
annualized patient death rate after the rst 6 months of
therapy. The actuarial 3-year survival of all patients and
those who lived 6 months was excellent at 73% and
88%, respectively. This high rate of patient survival is
signicantly greater than the 40% reported in untreated
patients with decompensated HBV-related cirrhosis.6,7
Elevated pretreatment serum bilirubin and creatinine
levels as well as detectable HBV DNA were associated
with early mortality despite suppression of viral replication with lamivudine. This prospectively collected database of 154 patients allowed us to derive a risk index for
predicting 6-month survival in patients with advanced
HBV cirrhosis. Although our survival algorithm requires
validation in other large prospective studies, it may
provide the clinician with a simple and readily applicable
means of assessing prognosis. Such a strategy may help
clinicians prioritize decompensated hepatitis B patients
for liver transplantation and determine when and if
lamivudine should be started pretransplantation. In addition, in HBV endemic regions of the world where liver
transplantation is not readily available, these observations and survival algorithms should be useful to clinicians caring for patients with decompensated HBV-related cirrhosis and may facilitate the rational design of
new treatment approaches for such patients.

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Received May 17, 2002. Accepted May 23, 2002.

Address requests for reprints to: Robert J. Fontana, M.D., 3912
Taubman Center, Ann Arbor, Michigan 48109-0362. e-mail:
Rfontana@umich.edu; fax: (734) 936-7392.
Supported partly by GlaxoSmithKline, Research Triangle Park, North
Carolina.
The authors thank the following individuals for their contributions to
this study: Paul Adams, London Health Sciences Center; Bruce Bacon, St.
Louis University; Alfred Baker, University of Chicago; Vijayan Balan, University of Pittsburgh; Martin Black, Temple University Hospital; Robert
Brown, University of North Carolina; Jules Dienstag, Massachusettes General Hospital; Jeremiah Donovan, University of Nebraska; George Esham,
Portsmouth, Ohio; Gregory Everson, University of Colorado Heath Sciences; Robert Fontana, University of Michigan; Robert Gish, California

September 2002

Pacic Medical Center; Norman Gitlin, Emory University; Stuart

Gordon, Beaumont Hospital; Hie-Won Hann, Jefferson Medical College; Elias Herschman, Miami, Florida; Emmett B. Keeffe, Stanford
University; Michael Keegan, Washington Clinic; Kris V. Kowdley,
University of Washington, Seattle; William Lee, University of Texas
Southwestern; Dirk van Leeuwen, University of Alabama; Howard P.
Mansour, University of Texas Houston; John Pirsch, University of

LAMIVUDINE IN DECOMPENSATED HEPATITIS B

727

Wisconsin; Robert W. Reindollar, Carolinas Center for Liver Disease;

Caroline Riely, University of Tennessee; Lorenzo Rossaro, Pennsylvania State University; Eugene R. Schiff, University of Miami; Leonard Seeff, VA Medical Center, Washington DC; Carlo Tamburro,
University of Louisville; Theresa Wright, University of California San
Francisco; and Abbas Hamedani, Alfred Montalvo, and Lynn Condreay of GlaxoSmithKline, Research Triangle Park, North Carolina.