Full text of DOI:10.1053/jlts.2000.18501

Clinical Improvement in Patients With Decompensated
Liver Disease Caused by Hepatitis B After Treatment
With Lamivudine
Craig A. Sponseller, Bruce R. Bacon, and Adrian M. Di Bisceglie
Lamivudine is effective in inhibiting hepatitis B virus
(HBV) replication, and its clinical use in patients with
chronic hepatitis B is associated with improvements in
serum aminotransferase levels and liver histopathologic
characteristics. Few data are available on its use in patients
with advanced liver disease. We report on the outcomes of
5 patients with hepatic decompensation caused by chronic
hepatitis B treated long term with lamivudine. All patients
were adult white men seropositive for hepatitis B surface
antigen (HBsAg) and hepatitis B e antigen (HBeAg) be-
fore therapy. All 5 patients had biopsy-proven cirrhosis
with clinical and biochemical evidence of hepatic decom-
pensation. Two patients had Child’s class C cirrhosis;
2 patients, class B; and 1 patient, class A (although this
patient had persistent portasystemic encephalopathy and
developed variceal bleeding). HBV DNA became unde-
tectable in all patients and remained so throughout the
study. Both patients with Child’s class C and 1 patient
with class B cirrhosis had significant clinical improve-
ment. Child-Pugh scores improved from 12 to 7 and 11 to
7 in the 2 patients with Child’s class C cirrhosis, and the
patient with class B cirrhosis had complete resolution of
troublesome encephalopathy. Serum aminotransferase,
albumin, and total bilirubin levels improved significantly
in 3 of 5 patients. One patient with Child’s class B cirrho-
sis underwent orthotopic liver transplantation at week 13
after dramatic increases in liver tests and clinical worsen-
ing. The patient subsequently cleared HBeAg and HBsAg
from serum posttransplantation. In conclusion, pro-
longed therapy with lamivudine resulted in improved se-
rum biochemical values and loss of HBV DNA in patients
with decompensated cirrhosis. Clinical improvements, re-
flected in Child-Pugh classification and functional status,
may also occur, particularly among those with Child’s
class C disease initially. (Liver Transpl 2000;6:715-720.)
feron for treatment of chronic HBV suggests nearly a
33% response, gauged by hepatitis B e antigen (HBeAg)
clearance.3 Most of these data are reflective of patients
with compensated liver disease compared with those
with advanced stages and decompensation, who appear
to have unfavorable responses and severe complica-
tions. HBV–related end-stage liver disease remains a
controversial indication for transplantation because of
the high incidence of posttransplantation recurrence,
estimated at 60% to 90% of all cases, and inferior
survival rates compared with other forms of chronic
liver failure.4
Trials using interferon have been discouraging in
patients with advanced disease, and the success seen
with long-term perioperative and postoperative hyper-
immune B immunoglobulin (HBIG) has met with high
costs and limited supplies.5-7 Lamivudine, an (–) enan-
tiomer of 3-thiacytidine with potent antiviral inhibi-
tory effects against HBV,8 markedly reduced serum
HBV DNA levels and improved biochemical and his-
tological parameters in patients with chronic HBV in-
fection.8,9 However, few data exist evaluating long-term
lamivudine therapy in patients with decompensated
liver disease caused by HBV for the effect on serum
markers of HBV replication, liver function, and the
safety profile.
Recently, a series of 35 patients with decompensated
cirrhosis caused by HBV were treated with lamivudine,
and long-term biochemical and clinical outcomes were
evaluated.10 Here, we report and compare our findings
on the biochemical and clinical outcomes of a small
number of patients with decompensated cirrhosis
treated with lamivudine.
hronic infection with hepatitis B virus (HBV) is a
C
leading cause of chronic hepatitis, cirrhosis, and
hepatocellular carcinoma, affecting more than 350 mil-
lion people. It is responsible for approximately 1 mil-
lion deaths yearly worldwide.1 A reported 1.25 million
people in the United States are infected with HBV, and
20% to 25% of these individuals have no documented
risk factors.2 The World Health Organization estimates
that nearly 400 million people will be carriers of HBV
by the year 2000. Until vaccination and immunization
are universally accepted throughout the world, this
trend can only get worse.
From the Department of Internal Medicine, Division of Gastroen-
terology and Hepatology, Saint Louis University School of Medicine, St
Louis, MO.
Supported in part by Glaxo Wellcome.
Address reprint requests to Adrian M. Di Bisceglie, MD, Department
of Internal Medicine, Saint Louis University School of Medicine, 1402
South Grand Blvd, St Louis, MO 63104. Telephone: 314-577-8762;
FAX: 314-268-5108; E-mail: dibiscam@slu.edu
©
Copyright 2000 by the American Association for the Study of
Liver Diseases
Interferon-␣ has been the mainstay of therapy for
chronic hepatitis B. Published clinical data on inter-
1527-6465/00/0606-0010$3.00/0
doi:10.1053/jlts.2000.18501
Liver Transplantation, Vol 6, No 6 (November), 2000: pp 715-720
715

716
Sponseller, Bacon, and Di Bisceglie
Patients and Methods
Results
Five subjects with a clinical diagnosis of chronic hepatitis B,
documented positive test results for hepatitis B surface anti-
gen (HBsAg) and HBeAg, and evidence of hepatic decompen-
sation were screened and enrolled onto the study. Exclusion
criteria were acute fulminant hepatitis, significant clinical
pancreatitis, need for ventilatory support, current use of lami-
vudine for HIV-related diseases, HIV seropositivity, and se-
ropositivity for antibodies to hepatitis C virus and hepatitis D
virus. None of the subjects were previously or concurrently
treated with alternative antiviral regimens at the time of entry
onto the study. A detailed medical history, hepatitis history,
review of systems, and physical examination were performed
at baseline and at regular intervals during follow-up. These
5 patients were treated at Saint Louis University (St Louis,
MO) as part of a national compassionate use program spon-
sored by Glaxo-Wellcome (Durham, NC) aimed at patients
who did not fit into the usual trials, including those with
decompensated cirrhosis, liver transplantation candidates,
and patients with recurrent HBV infection after liver trans-
plantation. Data analysis was performed at Saint Louis Uni-
versity.
Each subject was treated with lamivudine, 100 mg/d, for
an indefinite period. Clinical assessment and serological anal-
ysis were performed at regular intervals. Clinical assessment
included degree of ascites and presence of encephalopathy and
gastrointestinal bleeding, and patients were scored and classi-
fied according to the modifications described by Pugh et al.11
Hematologic and serum chemistry profiles were performed at
a central clinical laboratory weeks 0, 2, and 4; months 2, 3,
and 4; and every 2 months thereafter. Virologic response was
assessed by HBsAg, antibody to HBsAg (anti-HBs), HBeAg,
and antibody to HBeAg (anti-HBe; Abbott Laboratories,
North Chicago, IL), performed at baseline and every
4 months thereafter. Additionally, serial tests of serum HBV
DNA (Chiron branched DNA assay; Chiron Laboratories,
Emoryville, CA) were performed at baseline and every
2 months to assess appropriateness for continued therapy and
development of antiviral resistance. Child-Pugh scores were
tabulated at baseline and every 12 to 14 weeks.
We studied 5 patients, all white men ranging in age
from 46 to 71 years (mean, 61.4 years) with hepatic
decompensation caused by chronic HBV infection who
were treated with lamivudine, 100 mg/d, for 36 to 77
weeks. The biochemical, serological, and clinical course
of each patient is shown in Figure 1. Brief summaries of
each patient’s progress to date are given.
Patient 1
This 65-year-old patient initially presented with as-
terixis and hypoalbuminemia, serum albumin level of
3.0 g/dL, and Child-Pugh score of 7. During the first
few weeks of therapy, he had severe encephalopathy
requiring hospitalization 3 times over the course of 10
to 12 weeks. Once started on lamivudine therapy, se-
rum HBV DNA became undetectable during the study
period. By week 24, serum alanine aminotransferase
(ALT) values normalized, and at 48 weeks of treatment,
albumin level increased to 3.3 g/dL and total bilirubin
level decreased from 1.6 to 1.2 mg/dL. This patient had
2 episodes of variceal bleeding during the 48 weeks of
treatment; however, his troublesome portasystemic en-
cephalopathy (PSE) virtually resolved on therapy.
Thus, he was noted to have asterixis on only 1 occasion
subsequently and did not require hospitalization for
this complication again.
Patient 2
This 67-year-old patient initially had mild to moderate
ascites, prothrombin time of 16.9 seconds, albumin
level of 2.0 g/dL, and total serum bilirubin level of 3.5
mg/dL, classifying him as Child’s class C. Before ther-
apy with lamivudine, he was seropositive for HBsAg,
HBeAg, and anti-HBe. Serum HBV DNA was unde-
tectable at baseline and remained so during the treat-
ment period. Two weeks into treatment, this patient
had a gastrointestinal bleed believed to be secondary
to portal hypertensive gastropathy after esophago-
gastroduodenoscopy. On therapy, total bilirubin level
decreased to 2.0 mg/dL, albumin level increased to
2.7 g/dL, and by week 28, the patient became anti-HBe
All subjects had a previous liver biopsy performed within
6 months of beginning therapy to assess the severity of HBV-
associated hepatitis and cirrhosis and help rule out other as-
sociated causes of liver dysfunction. Histological analysis was
performed by a single pathologist at Saint Louis University,
and all 5 subjects had biopsy-proven cirrhosis before enroll-
ment.
‹
Figure 1. Patient 1, resolution of PSE, increase in albumin level to 3.3 g/dL, normalization of ALT level, and decrease
in total bilirubin (T Bili) level to 1.2 mg/dL at 48 weeks. Patient 2, resolution of gastrointestinal bleeding, less frequent
PSE, increase in albumin level to 2.7 g/dL, decrease in ALT level, and decrease in T Bili level to 2.0 mg/dL at 73 weeks.
Patient 3, no adverse clinical events, increase in albumin level to 3.4 g/dL, normalization of ALT level, and decrease in
T Bili level to 2.6 mg/dL at 77 weeks. Patient 4, rapid decompensation by week 13, subsequent liver transplantation,
anti-HBs positive and HBsAg, HBeAg, and HBV DNA negative posttransplantation. Patient 5, resolution of variceal
bleeding, less frequent PSE, and no significant change biochemically. All HBV DNA values were estimated by Chiron
branched DNA assay and expressed as milliequivalents per milliliter (lower limit of detection, 0.7 mEq/mL).

Decompensated Hepatitis B Treated With Lamivudine
717
Figure 1.

718
Sponseller, Bacon, and Di Bisceglie
negative. Although the coagulopathy did not improve,
there were no further episodes of gastrointestinal bleed-
ing. The patient continued to have a stable clinical
course with only occasional occurrences of PSE and
improved his Child-Pugh score from 12 to 7 at week 23
after initiating lamivudine therapy.
In summary, 3 patients improved clinically. One
patient had resolution of PSE, and 2 patients had reso-
lution of variceal bleeding and less frequent PSE during
the treatment period. Of the remaining 2 patients,
1 patient continued to be clinically stable and the other
patient decompensated significantly, requiring trans-
plantation. Biochemically, 3 of 5 patients (60%) had
significant elevations in serum albumin levels and de-
creases in total bilirubin levels during therapy. All
5 subjects were HBsAg and HBeAg positive at the be-
ginning of treatment and remained positive throughout
therapy, except for patient 4, who became HBeAg and
HBsAg negative and anti-HBs positive posttransplan-
tation. Patients 1, 3, 4, and 5 were anti-HBe negative
before therapy with lamivudine and remained negative
throughout treatment. Patient 2 was initially anti-HBe
positive but became negative by week 28. Collectively,
5 of 5 patients became HBV DNA negative on therapy.
With respect to the development of lamivudine resis-
tance, none of the 5 patients developed the YMDD
variant phenotype. Thus, no patient had the reappear-
ance of HBV DNA in serum after initial clearance, and
all remained with persistently undetectable levels of
HBV DNA to the time of this report.
Patient 3
Patient 3 is a 71-year-old man who had a Child-Pugh
score of 11 before therapy with lamivudine. He had an
albumin level of 2.5 g/dL, prothrombin time of 14.9
seconds, and total serum bilirubin level of 3.8 mg/dL.
HBV DNA became undetectable at 8 weeks and re-
mained undetectable throughout treatment. ALT levels
normalized by week 12, and by 77 weeks, total bilirubin
level decreased to 2.6 mg/dL and serum albumin level
increased to 3.4 g/dL. No adverse clinical events oc-
curred throughout this period. His Child-Pugh classi-
fication improved to Childs’s class B, with a Child-
Pugh score of 7.
Patient 4
This 63-year-old man had mild to moderate ascites and
a serum albumin level of 2.7 g/dL, classifying him as
Child’s class B, with a Child-Pugh score of 8 before
entry onto the study. Although HBV DNA was nega-
tive within 8 weeks of treatment, by the 13th week of
therapy, his ALT level increased from 52 to 133 U/L
and serum bilirubin level increased from 1.7 to
2.6 mg/dL. An episode of variceal bleeding occurred
during week 8, accompanied by persistent PSE. His
hepatic synthetic function decreased dramatically as the
albumin level decreased to 1.7 g/dL and prothrombin
time increased from 11.0 to 19.4 seconds. He under-
went orthotopic liver transplantation at week 13 of
therapy and subsequently cleared HBsAg and HBeAg
from serum. The patient remained on lamivudine ther-
apy posttransplantation and currently remains HBsAg
and HBeAg negative, with undetectable HBV DNA in
serum.
Discussion
Long-term lamivudine therapy has an excellent safety
profile and effectively reduces serum HBV DNA levels,
necroinflammatory activity, and progression of fibrosis
in patients with compensated chronic HBV infection.
However, data evaluating the safety profile, biochemi-
cal parameters, and pretransplantation suppression of
HBV replication with prolonged treatment of lamivu-
dine are limited in patients with decompensated liver
disease caused by HBV infection.
We found that the use of lamivudine in decompen-
sated cirrhosis caused by HBV effectively and safely
suppressed viral replication and resulted in significantly
improved liver function or slowed progression of he-
patic decompensation, with improvement in clinical
outcome. This suggests the possibility of delaying the
time to transplantation or even avoiding transplanta-
tion altogether. Lamivudine therapy may be useful in
patients for whom liver transplantation is not an op-
tion, such as those with severe concurrent illnesses, or
perhaps in the elderly (3 of our 5 patients were aged
Ͼ65 years).
Patient 5
This 46-year-old man had a single episode of variceal
bleeding and persistent hepatic encephalopathy. His
initial viral load was significantly elevated; however, by
week 26, serum HBV DNA became undetectable. His
biochemical parameters changed very little during ther-
apy with lamivudine, maintaining Child’s class A. This
patient had no further variceal bleeding after initiation
of therapy and decreasing episodes of PSE to 52 weeks
of treatment.
Several investigational studies used lamivudine in
the setting of decompensated liver disease. Grellier et
al12 treated a series of patients with decompensated liver
disease with 100 mg of lamivudine before transplant-

Decompensated Hepatitis B Treated With Lamivudine
719
ation, resulting in HBsAg and HBV DNA clearance in
90% of the patients at 1 year. Bain et al13 reported on
5 patients treated with 100 mg of lamivudine for 1 to 8
weeks before transplantation. All patients were HBV
DNA negative within 1 to 2 weeks of treatment and
remainedHBeAgandHBsAgpositivebeforetransplant-
ation. Only 1 patient had some improvement in aspar-
tate aminotransferase level before transplantation, and
1 patient died after 1 week of therapy of advanced
hepatocellular carcinoma. In our preliminary study, all
5 patients became HBV DNA negative and remained
HBsAg and HBeAg positive while on treatment, except
for patient 4, who cleared both antigens posttransplant-
ation. Van Thiel et al14 treated 9 patients with advanced
liver disease from HBV. Four of the 9 patients went on
to transplantation. Biochemical improvement was
noted by ALT level normalizing in only 3 of 5 patients
who did not undergo transplantation. Only 1 of 5 pa-
tients who did not undergo transplantation had an ele-
vated serum bilirubin level (1.6 mg/dL) at entry.
Our patients included 2 patients with Child’s class C
cirrhosis, 2 patients with Child’s class B, and only
1 patient with Child’s class A. Four of 5 patients had
elevated bilirubin levels (1.6 to 3.8 mg/dL), and at last
follow-up, 3 of 5 patients (60%) had normal ALT levels
and significantly improved total bilirubin values. Im-
portantly, 2 of 5 patients (40%), both with Child’s class
C cirrhosis, clinically improved by a full Child’s class at
last follow-up. Patient 2 had no further gastrointestinal
bleeding, resolved ascites, and improved albumin and
bilirubin levels. Patient 3 had significant improvements
in bilirubin and albumin values and no clinical events
related to hepatic decompensation.
In a recent study, 13 potential candidates for OLT
were treated with lamivudine and reported 42% nor-
malization of ALT levels (no hepatitis C virus coinfec-
tion). Eight patients went on to transplantation,
whereas 3 patients improved to allow medical and/or
surgical management.15 Time to transplantation was
not reported. Markowitz et al16 evaluated the efficacy of
a prophylactic combination of lamivudine and HBIG
for HBV recurrence in 14 subjects posttransplantation.
All 4 patients positive for HBV DNA before transplant-
ation were negative a median of 28 days after the
initiation of 150 mg/d of lamivudine, and 1 patient
became HBsAg negative before transplantation. Post-
transplantation, 13 of 14 patients had undetectable
HBV DNA levels at a median of 346 days on the lami-
vudine-HBIG combination.
therapy with 100 mg/d of lamivudine, and 45 patients
were positive for serum HBeAg. After 52 weeks of treat-
ment, 60% cleared HBV DNA from serum, 31% lost
HBeAg, 71% had normalized ALT levels, and 27% had
detectable YMDD motif variants. Histologically, sig-
nificant reductions in periportal necrosis, lobular ne-
crosis, and portal inflammation were described.
Our experience is consistent with the results of a
larger trial recently reported by Villeneuve et al.10 Thir-
ty-five patients with severe HBV cirrhosis were treated
with 100 or 150 mg/d of lamivudine. All patients
cleared HBV DNA from serum after 6 months of treat-
ment, except for 3 patients who acquired a YMDD
motif mutation of the HBV DNA polymerase. Bio-
chemical and clinical improvement occurred in the ma-
jority of patients after 9 months of therapy. The
8 patients with Child’s class B improved clinically, and
14 of 15 patients with Child’s class C disease improved
to either class B or class A. In our pilot study, both
patients with Child’s class C disease reduced their
Child-Pugh scores on therapy to be designated Child’s
class B. One of 2 patients with Child’s class B and the
only patient with Child’s class A disease showed signif-
icant clinical improvement on lamivudine therapy.
Again, no phenotypic evidence of lamivudine resistance
was noted in any subject.
We do not have an explanation for the flare of hepa-
titis observed in patient 4, although this type of exa-
cerbation is well described in patients treated with in-
terferon and may also occur (although less likely and
usually milder) in patients with compensated liver dis-
ease administered lamivudine.
An important issue in the use of lamivudine in pa-
tients with decompensated cirrhosis caused by HBV is
the best timing relative to transplantation. Thus, the
longer the period of therapy beyond 6 to 9 months, the
greater the risk for the development of lamivudine re-
sistance. A preliminary report suggested that patients
developing lamivudine resistance during or after liver
transplantation have a poor prognosis.18 However, the
natural history of this clinical entity is not clear, partic-
ularly with the potential for using other antiviral agents,
such as adefovir or entecavir, to treat lamivudine-resis-
tant HBV infection.
In summary, our data show that 3 of 5 patients
(60%) with decompensated cirrhosis caused by HBV
had significant clinical improvement after prolonged
therapy with lamivudine, characterized by a reduction
in Child-Pugh score and stabilization of encephalopa-
thy and ascites. Thus, lamivudine treatment in patients
with hepatic decompensation caused by hepatitis B may
prolong pretransplantation survival and delay the time
In a study by Perrillo et al,17 lamivudine was evalu-
ated as a potential therapy for HBV posttransplanta-
tion. All 52 patients were HBV DNA positive before

720
Sponseller, Bacon, and Di Bisceglie
10. Villeneuve JP, Condreay LD, Willems B, Pomier-Layrargues G,
Fenyves D, Bilodeau M, et al. Lamivudine treatment for decom-
pensated cirrhosis resulting from chronic hepatitis B. Hepatol-
ogy 2000;31:207-210.
to transplantation, particularly in patients with Child’s
class C disease.
11. Pugh RNH, Murray-Lyon IM, Dawson JL, Pietroni MC, Wil-
liams R. Transection of the oesophagus for bleeding oesophageal
varices. Br J Surg 1973;60:646-649.
12. Grellier L, Mutimer D, Ahmed M, Brown D, Burroughs AK,
Rolles K, et al. Lamivudine prophylaxis against reinfection in
liver transplantation for hepatitis B cirrhosis. Lancet 1996;348;
1212-1215.
13. Bain VG, Kneteman NM, Ma MM, Gutfreund K, Shapiro JA,
Fischer K, et al. Efficacy of lamivudine in chronic hepatitis B
patients with active viral replication and decompensated cirrho-
sis undergoing liver transplantation. Transplantation 1996;62:
1456-1462.
14. Van Thiel DH, Friedlander L, Kania RJ, Molloy PJ, Hassanein
T, Wahlstrom E, et al. Lamivudine treatment of advanced and
decompensated liver disease due to hepatitis B. Hepatogastroen-
terology 1997;44:808-812.
15. Barcena R, Dominguez-Antonaya M, Lopez-Sanroman A, Mar-
tinez-Turnes A, Urman J, del Campo S, Moreno N. Lamivudine
therapy of hepatitis B virus-related liver disease. Cirrhosis post-
transplantation recurrence, and de novo infection. Transplant
Proc 1999;31:2457-2458.
16. Markowitz J, Martin P, Conrad A, Markmann J, Seu P, Yersiz H.
Prophylaxis against hepatitis B recurrence following liver trans-
plantation using combination lamivudine and hepatitis B im-
mune globulin. Hepatology 1998;28:585-589.
17. Perrillo R, Rakela J, Deinstag J, Levy G, Martin P, Wright T, et
al. Multicenter study of lamivudine therapy for hepatitis B after
liver transplantation. Hepatology 1999;29:1581-1586.
18. Balan V, Starzl TE, Dodson FS, Vargas HE, Shakil OA, Mari-
anne R, Fung JJ. Long term follow-up of lamivudine therapy for
hepatitis B before and after liver transplantation: Clinical impli-
cation of development of the YMDD mutant [abstract]. Hepa-
tology 1999;30:346A.
References
1. Purcell RH. The discovery of hepatitis viruses. Gastroenterology
1993;104:955-963.
2. Update: Recommendations to prevent hepatitis B virus transmis-
sion in the United States. JAMA 1995;274:603-604.
3. Wong DKH, Cheung AM, O’Rourke K, Naylor CD, Detsky
AS, Heathcote J. Effect of alpha interferon treatment in patients
with hepatitis B e antigen-positive chronic hepatitis B: A meta-
analysis. Ann Intern Med 1993;119:312-323.
4. Samuel D, Muller R, Alexander G, Fassati L, Ducot B, Ben-
hamou JP, Bismuth H. Liver transplantation in European pa-
tients with hepatitis B surface antigen. N Engl J Med 1993;329:
1842-1847.
5. Hopf U, Neuhaus P, Lobeck H, Konig V, Kuther S, Bauditz J.
Follow-up of recurrent hepatitis B and delta infection in liver
allograft recipients after treatment with recombinant interferon
alpha. J Hepatol 1991;13:339-346.
6. Marcellin P, Samuel D, Areias J, Loriot MA, Arulnaden JL,
Gigou M, et al. Pre-transplantation interferon treatment and
recurrence of hepatitis B virus infection after liver transplanta-
tion for hepatitis B-related end-stage liver disease. Hepatology
1994;19:6-12.
7. Perillo RP, Tamburro C, Regenstein F, Bolart L, Bodenheimer
H, Silva M, et al. Low-dose titratable interferon alpha in decom-
pensated liver disease caused by chronic infection with hepatitis
B virus. Gastroenterology 1995;109:908-916.
8. Dienstag JL, Perillo RP, Schiff ER, Bartholomew M, Vicary C,
Rubin M. A preliminary trial of lamivudine for chronic hepatitis
B infection. N Engl J Med 1995;333:1657-1661.
9. Lai CL, Chien RN, Leung NW, Chang TT, Guan R, Tai DI, et
al. A one-year trial of lamivudine for chronic hepatitis B. N Engl
J Med 1998;339:61-68.