HIV infection worsens the course and the natural

history of chronic hepatitis B (HBV) leading to rapid

progression to cirrhosis and to end-stage liver disease.
Highly active antiretroviral therapy (HAART) regimens
including nucleoside and/or nucleotide analogues with
activity against both HIV reverse transcriptase and
hepatitis B virus polymerase have clearly improved the
survival rates of HIV/HBV-coinfected patients. How
HAART beneficially affects the natural course of chronic
hepatitis B in coinfected patients is not known. We
report a biopsy-proven case of reversal of HBV-related
cirrhosis in a coinfected patient, parallelling long-term
suppression of HBV replication with tenofovir disoproxil
fumarate as part of a HAART. Pathological reversibility
of cirrhosis was ascertained by normalization of
biochemical (platelet count) and morphological
(abdominal ultrasonography and gastrointestinal
endoscopy) tests as well as non-invasive markers of
fibrosis. In conclusion, a HAART regimen including
tenofovir disoproxil fumarate in a HBV/HIV-coinfected
cirrhotic patient might lead to sustained HBV viral
suppression and result in cirrhosis reversal.
Case report
Reversibility of cirrhosis in HIV/HBV coinfection
Vincent O Mallet
1,2,3
*, Valrie Dhalluin-Venier
1,2
, Virginie Verkarre
1,4
, Jean-Michel Correas
1,5
,
Marie-Laure Chaix
1,6
, Jean-Paul Viard
7
and Stanislas Pol
1,2,3
1
Universit Paris-Descartes, Paris, France
2
APHP, Hpital Cochin, Hpatologie, Paris, France
3
INSERM U. 567, Institut Cochin, Paris, France
4
APHP, Hpital Necker, Anatomo-Pathologie, Paris, France
5
APHP, Hpital Necker, Radiologie, Paris, France
6
APHP, Hpital Necker, Virologie, Paris, France
7
APHP, Hpital Necker, Maladies Infectieuses, Paris, France
*Corresponding author: Tel: +33 1 58 41 30 14; Fax: +33 1 58 41 30 12; E-mail: vincent.mallet@cch.aphp.fr
Antiviral Therapy 12:279283
In chronic hepatitis B, the achievement of sustained
viral suppression is associated with clinical, biochem-
ical and pathological benefits. Control of hepatitis B
virus (HBV) replication decreases hepatic necro-
inflammatory activity and limits the progression of
fibrosis [1,2]. Cases of reversal of cirrhosis after
successful therapeutic intervention have been reported
in HBV-monoinfected patients [35], and also in
several liver disorders [69], including chronic viral
hepatitis [4,1012]. However these pathological obser-
vations are still debated [5]. Though antiviral treat-
ment in monoinfected HBV patients has been shown to
reduce the occurrence of cirrhosis complications and to
improve the overall survival of cirrhotic patients [2],
there is yet no clear demonstration that these beneficial
effects are linked to cirrhosis reversal.
HIV infection negatively influences the course of
HBV infection, causing a faster progression to
cirrhosis and to end-stage liver disease [13]. Highly
active antiretroviral therapy (HAART) might posi-
tively influence HBV infection. On the one hand, it
restores immunity and improves the cellular control
of HBV replication but, on the other hand, some
nucleoside and nucleotide reverse transcriptase
inhibitors have activity on both HIV reverse tran-
scriptase and HBV DNA polymerase. Several studies
have shown that HAART regimens including these
drugs can efficiently control HIV and HBV replica-
tion [14], but it is not known whether these regimens
modify the natural course of chronic hepatitis B in
coinfected patients.
We describe the case of a HBV/HIV-coinfected
patient treated with tenofovir disoproxil fumarate as
part of a HAART regimen that strongly suggests that a
sustained viral suppression might result in the reversal
of cirrhosis.
Introduction
2007 International Medical Press 1359-6535 279
16_0117_mallet 13/3/07 11:17 Page 279
Case report
A 29-year-old Caucasian male with chronic HBV
(serum hepatitis B surface antigen [HBsAg]-posi-
tive) and HIV coinfection presented with abnormal
liver function tests. The viral risk factors were
unprotected sexual promiscuity and one incident of
homosexual intercourse. The patient had no history
of opportunistic infections, no alcohol or drug use
and took no medication.
The initial physical examination was normal
without any sign of chronic liver disease; the body mass
index (BMI) was 25.8 kg/m
2
. The aspartate amino-
transferase level was 173 IU/l (normal range: 730), the
alanine aminotransferase level was 508 IU/l (normal
range: 745), the -glutamyltransferase level was
52 IU/l (normal range: 733), the International
Normalized Ratio was 1.1 and the platelet count was
11010
9
/l. The CD4
+
T-cell count was 821/l with a
viral load of 21,000 HIV RNA copies/ml. The values
for urea nitrogen, creatinine, glucose, total protein,
albumin, globulins, electrolytes and total bilirubin were
normal. The patient was hepatitis B e antigen [HBeAg]
positive. HBV DNA viral load, measured with the
Digene Hybrid Capture II (Abbott Diagnostic, Rungis,
France), was 7.3 log
10
copies/ml. Markers for hepatitis
C and delta virus infection were negative and there was
no evidence of any other superimposed acute or
chronic liver disease.
A liver biopsy showed micro-nodular cirrhosis with
an Ishak Score of 16 (31246), a Metavir activity
score of 3 and a Metavir fibrosis score of 4 (Figure 1A).
Mild macro-vesicular steatosis was observed in 5% of
hepatocytes. One year after this first evaluation, signs
of portal hypertension were described on gastro-
intestinal endoscopy (hypertensive gastropathy, gastric
varices and grade I oesophageal varices) and abdominal
ultrasonography including enlargement of the portal
trunk up to 16 mm with a to-and-fro blood flow
pattern, enlargement of the superior and inferior
mesenteric vein to 6 and 9 mm in diameter, respectively,
and a 13 cm craniocaudal spleen length.
The patient was treated for the next 6 years by,
successively, anti-HBV vaccine therapy, two courses of
standard interferon- (5,000,000 units, three times
weekly) then lamivudine as a monotherapy. The evolu-
tion of HBV DNA viral load and the levels of amino-
transferase under treatment are presented in Figure 2.
Twenty months after the beginning of lamivudine, the
increase in HBV DNA levels suggested the selection of
viral resistance. HAART was started at that time.
HAART included tenofovir, azidothymidine and
didanosine for one year, then tenofovir, azidothymidine
and efavirenz.
One year after the beginning of HAART, HBV viral
load was undetectable (Digene Hybrid Capture II),
aminotransferase activities were normal and the platelet
count returned to normal values (Figure 2). Three years
after the beginning of HAART, the patient reported
being in good condition. The BMI was 29.9. The aspar-
tate aminotransferase, alanine aminotransferase and -
glutamyltransferase levels and the platelet count were
VO Mallet et al.
2007 International Medical Press 280
Figure 1. Regression of cirrhosis in HIV/hepatitis B virus coinfection
Liver biopsy specimen before highly active antiretroviral therapy (HAART) showed micronodular cirrhosis ([A], Massons trichrome, original magnification 2.5) and
after HAART showed a normal liver architecture with mild portal and periportal fibrosis ([B], Sirius red, original magnification 2.5).
A
B
16_0117_mallet 13/3/07 11:17 Page 280
normal. The CD4
+
T-cell count was 1,024/l with an
undetectable HIV RNA viral load. The patient was
positive for HBsAg, negative for HBeAg and negative
for HBeAg antibodies. HBV DNA was undetectable
(<2,000 copies/ml; bDNA, Bayer Diagnostics, Meylan,
France). A non-invasive assessment of the severity of the
liver disease (FibroTestActiTest, Biopredictive, Paris,
France) suggested a reduction of both activity (A1) and
fibrosis (F0F1). The endoscopic and unltrasono-
graphic signs of portal hypertension previously
described had disappeared with a craniocaudal spleen
length of 100 mm. The disappearance of the biochem-
ical, endoscopic and morphological signs of portal
hypertension and the histological improvement
suggested by the FibroTestActiTest implied histolog-
ical improvement. This was confirmed by examination
of a 25 mm liver biopsy showing regression of cirrhosis
with an Ishak score of 4 (00112), a Metavir
activity score of 1 and a Metavir fibrosis score of 1.
Mild macro-vesicular steatosis was observed in 10% of
hepatocytes (Figure 1B).
Discussion
We describe a HIV/HBV-coinfected cirrhotic patient in
whom cirrhosis reversed after 3 years of sustained HBV
suppression with tenofovir disoproxil fumarate as part
of a HAART regimen. After initiation of HAART, a
sustained suppression of both HIV and HBV replication
was observed with a rapid normalization of liver test
abnormalities such as aminotransferase levels and
platelet count. A liver biopsy performed 3 years after the
beginning of HAART showed reversal of cirrhosis and
mild steatosis, the latter probably being due to a meta-
bolic syndrome associated with overweightness (BMI
between 25 and 30 kg/m
2
) and/or a toxicity of HAART.
These findings suggest that, as in monoinfected patients,
cirrhosis might be reversible in coinfected patients when
efficient viral suppression is achieved.
As recently emphasized [5], it is impossible to confi-
dently exclude a false-negative result of liver biopsy
due to sampling variation on sequential liver biopsies.
However, (i) the size (25 mm) of the liver biopsy and
the examination of more than 12 portal tracts by the
pathologist, as recommended [15,16], minimized the
risk of sampling error [15]; (ii) the histopathological
regression of fibrosis was associated with an objective
disappearance of ultrasonographic and endoscopic
signs of portal hypertension; (iii) the non-invasive
markers of hepatic fibrosis such as platelet count [17]
and FibroTestActiTest [18] were in accordance with
the pathological finding of cirrhosis reversal.
HIV coinfection influences the course of HBV infec-
tion by impairing the immune response. The rate of
spontaneous resolution of acute hepatitis B is lower in
HBV/HIV-coinfected patients, who have higher levels
of HBV DNA, than in non-immunocompromised
patients [19]. Consequently, a faster progression to
cirrhosis and to end-stage liver disease has been asso-
ciated with HIV coinfection [13]. In the present case,
the restoration of the immune system with HAART
might have participated in the regression of fibrosis,
as described in chronically infected HIV/HCV
patients [20,21].
The patient was initially treated with vaccine
therapy and standard interferon- on the basis of three
previous pilot clinical studies establishing that specific
vaccine therapy can reduce HBV replication and
induce HBeAg seroconversion [2224]. A multicentre,
controlled trial later described the efficacy and the
limitations of vaccine therapy in chronic HBV infec-
tion [25]. The lack of control of HBV infection led
later to the introduction of lamivudine. The selection
Antiviral Therapy 12:2
281
Reversibility of cirrhosis in HIV/HBV coinfection
Figure 2. Treatments, pathological and biochemical profiles
during follow up
Vaccine therapy consisted of the quarterly injection of 20 g recombinant
hepatitis B surface antigen. The activity of alanine aminotransferase (ALT) is
plotted as the ratio to the upper limit of normal ALT activity (ULN). The detec-
tion cut-off of hepatitis B virus (HBV) viral load changes with the employed
method of detection, which accounts for its variation with time. Liver biopsy
specimens were read by the same pathologist and scored using the METAVIR
system. HAART, highly active antiretroviral therapy.
16_0117_mallet 13/3/07 11:17 Page 281
of a resistant strain 2 years after the initiation of
lamivudine, diagnosed by a HBV DNA breakthrough
and a moderate progression of HIV disease led to the
introduction of HAART including tenofovir disoproxil
fumarate. The emergence of resistant viral strains is
common in chronically HIV-infected and HBV-
infected patients on lamivudine [26,27] and the
prescription of lamivudine alone is not recommended
in the setting of HIV infection [28,29].
Most of the cases of cirrhosis reversibility in
humans are explained by the control of the underlying
liver disease. Examples include abstinence from
alcohol, surgical reversal of jejuno-ileal bypass [6],
immunosuppressive therapy for autoimmune hepatitis
[7], phlebotomy for haemochromatosis [8], ursodiol
plus methotrexate for primary biliary cirrhosis [9],
treatment of hepatitis C [10,11] and hepatitis D [12]
with interferon, and long-term viral suppression with
lamivudine or adefovir dipivoxil for chronic hepatitis
B in monoinfected patients [1,4]. Our observation is in
agreement with all these studies, strongly suggesting
that the sustained control of HBV replication with
tenofovir, an adenine nucleotide analogue with potent
activity against HBV, can reverse cirrhosis in
HBV/HIV-coinfected patients, even those who have
evidence of lamivudine-resistant virus [30,31].
This observation reinforces the conclusions of the
last European Consensus Conference on coinfection:
HBV infection must be diagnosed and its effect evalu-
ated in HIV-infected patients; in those patients with
significant viral replication and significant liver disease,
an antiviral treatment should be given, usually
combining two drugs active against both HBV and HIV
[32]. Cirrhotic patients and their physicians should be
informed that sustained viral suppression of HBV might
result in reversal of cirrhosis despite HIV coinfection.
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Accepted for publication 25 September 2006
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