Successful rescue therapy with tenofovir in a patient with hepatic
decompensation and adefovir resistant HBV mutant
Vlad Ratziu1 , Vincent Thibault2 , Yves Benhamou1 and Thierry Poynard1

1Service d'Hépatogastroenterologie, Hôpital Pitié Salpêtrière and
Université Pierre et Marie Curie, Paris, France
2Laboratoire de Virologie, Hôpital Pitié Salpêtrière and Université Pierre
et Marie Curie, Paris, France


author email corresponding author email

Comparative Hepatology 2006, 5:1doi:10.1186/1476-5926-5-1

The electronic version of this article is the complete one and can be found
online at: http://www.comparative-hepatology.com/content/5/1/1

Received: 1 September 2005
Accepted: 11 January 2006
Published: 11 January 2006

© 2006 Ratziu et al; licensee BioMed Central Ltd.
This is an Open Access article distributed under the terms of the Creative
Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which
permits unrestricted use, distribution, and reproduction in any medium, provided
the original work is properly cited.

Abstract
Background
Prolonged adefovir therapy exposes to the emergence of adefovir resistant
hepatitis B virus mutants. Initial reports of the rtN236T mutation showed
preserved sensitivity to lamivudine; however, complex mutations are emerging
with reduced susceptibility to lamivudine.

Case presentation
After 2 years of therapy, a cirrhotic patient developed the rtN236T and rtA181T
adefovir resistant mutations. He had been previously treated with lamivudine,
developed lamivudine resistance and, despite good compliance, had an incomplete
response to adefovir. Adefovir resistance resulted in viral breakthrough with
hepatitis flare-up and liver decompensation. Tenofovir had an excellent
antiviral effect allowing sustained control of viral replication and reversal of
hepatic failure.

Conclusion
In patients with cirrhosis, adefovir resistance can lead to severe hepatitis.
Tenofovir appears to be an effective treatment of adefovir resistant mutants.
Incomplete control of viral replication with adefovir requires monitoring for
viral resistance and should prompt a change in antiviral treatment.

Background
In chronic hepatitis B, prolonged antiviral therapy with nucleoside analogues,
such as lamivudine, is often necessary but may result in the emergence of escape
mutants which can be detected in as many as 70% of patients, after 4 years of
therapy [1]. Adefovir dipivoxil has potent antiviral activity on
lamivudine-resistant hepatitis B virus (HBV) strains [2,3]; nonetheless, long
term use of this nucleotide analogue is also associated with resistance in up to
18% of patients, after 4 years of therapy [4]. In the few cases published thus
far, adefovir-resistant HBV displayed the rtN236T mutation and maintained
susceptibility to lamivudine in vivo [5,6]. However, new adefovir-resistant
mutations have been reported, such as the rtA181V mutation which is closely
located to the rtL180M mutation conferring resistance to lamivudine [4]. It is
uncertain whether those new adefovir escape mutants are susceptible to
lamivudine [7] and thus drugs active on both adefovir and lamivudine-resistant
HBV strains are needed.

We report on the case of a patient with HBV-related cirrhosis and
lamivudine-resistant HBV who developed adefovir resistance with viral
breakthrough and liver failure. The patient had both an rtN236T and a rare
rtA181T mutation. Tenofovir fumarate was highly effective in controlling viral
replication and reversing clinical symptoms.

Case presentation
In 1997, a 55 year-old Vietnamese man was diagnosed with HBV cirrhosis without
hepatitis delta virus (HDV), hepatitis C virus (HCV) or human immunodeficiency
virus (HIV) coinfections. Probably, the route of infection was vertical
transmission. Cirrhosis was confirmed by liver biopsy and was complicated only
by grade 1 oesophageal varices (Child Pugh score A5). HBe antigen was negative,
HBe antibody positive, HBV viral load (HBV-DNA) was 7.15 log10 copies/ml (Digene
hybrid capture assay) and the HBV genotype was B. Alanine aminotransferase (ALT)
values were twice the upper limit of normal (ULN).

In August 1998, lamivudine, 100 mg/day, was started. Three months later, HBV-DNA
was undetectable by Digene assay and, in February 1999, by qualitative PCR
(sensitivity limit at 4 log10). Lamivudine was inadvertently stopped after only
10 months of treatment, and then started again in January 2000 when a relapse
occurred with a rising HBV-DNA to 5.75 log10 and ALT values at 3.1 ULN. The next
2 years of treatment were uneventful with undetectable HBV-DNA by quantitative
PCR (cut-off at 2.3 log10, MONITOR COBAS, Roche) and normal ALT values.

In January 2002, after 24 months of uninterrupted lamivudine treatment, HBV-DNA
became detectable by PCR (2.6 log10), and, in June 2002, a viral breakthrough
was documented when HBV-DNA rose to 9.2 log10 with ALT at 2.7 ULN. The patient
was asymptomatic. Sequencing of the HBV polymerase revealed two common
lamivudine resistant mutations – rtL180M and rtM204V. Adefovir dipivoxil, 10
mg/day, was added to the ongoing lamivudine treatment. The evolution of HBV
viral load is shown in the Figure. Over the next 10 months, HBV-DNA never fell
below 5 log10. In June 2003, the HBV-DNA titer was 5.28 log10. Lamivudine was
then stopped, but adefovir was maintained; in addition, pegylated interferon
α-2a was introduced (180 μg/week). In August 2003, and after five injections,
the patient decided to stop pegylated interferon administration due to poor drug
tolerance: anorexia, dry mouth, diarrhoea, weight loss and back pain.
Thrombopenia was also detected.

After 4 months of uninterrupted adefovir monotherapy, HBV-DNA was still at 4.9
log10 and the same lamivudine resistant mutations were detected without adefovir
resistant mutations. In September 2004, while on adefovir monotherapy, and 15
months after having stopped lamivudine and 13 months after having stopped
pegylated interferon, HBV-DNA rose to 8.3 log10, ALT to 10 ULN and aspartate
aminotransferase to 7 ULN. Prothrombin time was 78%, and total bilirubin and
serum albumin were normal. Two adefovir resistant mutations, rtA181T and
rtN236T, were detected, whereas previous lamivudine resistant mutations, rtL180M
and rtM204V, were absent. Anti-HDV and anti-HCV antibodies detection remained
negative.

A test trial of a higher dose of adefovir (20 mg/day) was started. One month
later, HBV-DNA was at 7 log10 and ALT levels remained unchanged. The patient's
condition deteriorated with the occurrence of oedema, ascites, jaundice, mild
renal insufficiency (serum creatinine 110 μmol/l) and decreased prothrombin
time (47% of normal). Tenofovir fumarate was then started at a dose of 300
mg/day, while adefovir was continued for one month at 10 mg/day and then
stopped. Two months later, HBV-DNA became undetectable by PCR, prothrombin time
rose to 90% while jaundice and ascites resolved. HBV-DNA was still undetectable
by PCR after 8 months of tenofovir treatment, on three separate occasions. The
patient is currently listed for liver transplantation.

Figure 1. Virological and biochemical course before and after the emergence of
adefovir resistant mutations. LAM: lamivudine; ADV: adefovir dipivoxil; TDF:
tenofovir disoproxil fumarate.

Discussion
Despite good compliance, after developing lamivudine resistance the patient did
not respond to adefovir dipivoxil treatment. Although the reasons are unclear,
primary non-response to adefovir has been described in 8% to 15% of HIV-negative
[2,3] and HIV-positive [8] patients infected with lamivudine-resistant HBV.
Incomplete viral suppression could have contributed to the emergence of adefovir
resistant mutations. Indeed, it has already been shown that a high viral load
(>3 log10) after 6 months of lamivudine therapy predicted the emergence of
resistance [9,10]. The patient developed both rtN236T and rtA181T mutations
while under adefovir treatment for 2 years. The rtN236T and rtA181V are
well-described adefovir resistant mutations [5,6,11], whereas the rtA181T is
very rare and has only been described in 1 out of 22 patients with adefovir
resistance, after 4 years of treatment [4]. Viral breakthrough was associated
with severe hepatic decompensation, probably favoured by longstanding underlying
cirrhosis. Similar to lamivudine resistance, clinicians should be aware of the
possibility of severe hepatic decompensation in cirrhotic patients developing
adefovir resistance; therefore, clinicians should implement viral resistance
monitoring strategies.

Non-randomized studies suggested that tenofovir has a more potent antiviral
activity than adefovir on lamivudine-resistant HBV [12], whereas in HIV-HBV
patients with primary non-response to adefovir, tenofovir is highly effective
[8]. Because of the emergence of the rtA181T mutation (which is closely located
to codon 180), conferring resistance to lamivudine and closely related to
rtA181V, we chose to treat this patient with tenofovir rather than with
lamivudine. In fact, the rtA181V mutation reduces the susceptibility to
lamivudine 14 fold in vitro, while in vivo lamivudine has only a limited
antiviral effect on that mutant strain [13]. Brunelle et al. [14] reported
recently decreased in vitro susceptibility to both tenofovir and adefovir of two
HBV resistant mutants (N236T adefovir and L180M + M204V + N236T
lamivudine/adefovir resistant strains). A similar fold resistance over wild-type
HBV was reported for tenofovir and adefovir (4.5, and 3.2 to 6.4 fold,
respectively), suggesting a marginal benefit of tenofovir over adefovir.
However, one might question the in vivo relevance of those in vitro experiments.
In this patient with the double rtN236T and rtA181T mutations, the antiviral
response to tenofovir was excellent. A rapid and sustained inhibition of viral
replication, by sensitive PCR, was detected after only 2 months of treatment and
resulted in an improvement in liver function to a degree that could not be
anticipated from in vitro resistance studies. Discrepancies between in vitro
drug susceptibility and in vivo findings could be related to differences in
pharmacodynamics between the two drugs.

Conclusion
Adefovir resistant mutations can induce severe hepatic decompensation in
cirrhotic patients and can be preceded by incomplete viral suppression. In these
patients close viral monitoring is mandatory. For avoiding the emergence of
resistant mutants, incomplete viral response to adefovir should prompt a change
in antiviral treatment. Tenofovir appears to be an effective treatment of
adefovir resistant mutants.

Competing interests
The author(s) declare that they have no competing interests.

Authors' contributions
Vlad Ratziu provided clinical care for the patient, and wrote the manuscript.
Vincent Thibault carried out the virological analyses, helped interpret the data
and participated in the writing of the manuscript. Yves Benhamou and Thierry
Poynard helped interpret the data and critically revised the manuscript. All
authors read and approved the final manuscript.

References

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