Effectiveness of add-on pegylated interferon alfa-2a therapy in a lamivudine-treated patient with chronic hepatitis B.

Abstract

Hepatitis B virus (HBV) surface antigen (HBsAg) to anti-HBsAg (anti-HBs) antibody seroconversion is the best, final objective for all available chronic hepatitis B (CHB) treatments. Unfortunately, this goal is rarely obtained with the currently utilized therapeutic approaches. Here we describe the case of a CHB patient who was very successfully treated with a particular therapeutic schedule. The patient was initially treated with lamivudine for four years. Subsequently, pegylated interferon alpha-2a was introduced for a period of one year. During this period of combined therapies, the patient showed a flare of aminotransferase values followed by complete normalization of liver biochemistry parameters and HBsAg/anti-HBs seroconversion that persisted up to 24 months after all therapies had been stopped.

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Mangano C, et al. , 2011; 10 (1): 84-87
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Effectiveness of add-on Pegylated interferon alfa-2a therapy in a
Lamivudine-treated patient with chronic hepatitis B
Carmelo Mangano,* Giovanni Squadrito,** Irene Cacciola,**
Mariastella Carpentieri,* Giuseppe Foti,* Giovanni Raimondo**
* Division of Infectious Disesases, Bianchi-Melacrino-Morelli Hospital, Reggio Calabria.
* * Clinical and Molecular Hepatology Operative Unit, Department of Internal Medicine, University Hospital of Messina-ITALY
ABSTRACT
Hepatitis B virus (HBV) surface antigen (HBsAg) to anti-HBsAg (anti-HBs) antibody seroconversion is the
best, final objective for all available chronic hepatitis B (CHB) treatments. Unfortunately, this goal is rarely
obtained with the currently utilized therapeutic approaches. Here we describe the case of a CHB patient
who was very successfully treated with a particular therapeutic schedule. The patient was initially treated
with Lamivudine for four years. Subsequently, pegylated interferon alpha-2a was introduced for a period of
one year. During this period of combined therapies, the patient showed a flare of aminotransferase values
followed by complete normalization of liver biochemistry parameters and HBsAg/anti-HBs seroconversion
that persisted up to 24 months after all therapies had been stopped.
Key words. Chronic Hepatitis. HBV. Peg-IFN. Lamivudine.
Correspondence and reprint request: Carmelo Mangano
Division of Infectious Diseases
Bianchi-Melacrino-Morelli Hospital
Via Giuseppe Melacrino, 89100 - Reggio Calabria, Italy
Tel. +39.(0)965.5397861
E-mail: carmelo.mangano@tele2.it
Manuscript received: August 25, 2010.
Manuscript accepted: November 19, 2010.
January-March, Vol. 10 No.1, 2011: 84-87
CASE REPORT
INTRODUCTION
Hepatitis B virus (HBV) chronic hepatitis (CHB)
may be a severe and progressive form of liver disea-
se.1 Although a substantial improvement in the the-
rapeutic treatment of CHB has been obtained in the
last decade, the possibility of a complete cure of this
disease is still far from being achieved since thera-
pies available at present are incapable of eradicating
the viral genomes from the liver cells.2 The currently
approved anti-HBV therapies are based on the use of
either Interferon-α (IFNα) 2a and 2b, or Pegylated
IFN-α-2a (PEG- IFN-α-2a) or nucleoside/nucleotide
analogues (NUCs) inhibiting the viral reverse
transcriptase (namely, Lamivudine, Adefovir Dipi-
voxil, Entecavir, Telbivudine, Tenofovir).3 The main
objective that these therapies can achieve is the per-
manent suppression of viral replication and - above
all-the HBV surface antigen (HBsAg) seroclearence
with the appearance of the corresponding antibody
(anti-HBs). However, this HBsAg/anti-HBs serocon-
version can be obtained only in few IFN-treated ca-
ses and even more rarely in patients treated with
NUCs.3 Since IFN and NUCs have different and
theoretically complementary modes of action, a the-
rapeutic approach combining both drugs might
hypothetically be a good option for the treatment of
CHB.4-13 However, this combination therapy has
been insufficiently investigated so far, and in parti-
cular no valid information is available on possible
therapeutic schedules foreseeing different timing in
the administration of the IFN and NUC. Here we re-
port the case of a CHB patient showing a very favo-
urable clinical and virological outcome by means of
treatment with Lamivudine and subsequent PE G-
IFN-α-2a add-on.
CASE REPORT
A 20 year old Italian male was admitted to the
outpatients clinic of the Infectious Diseases Divi-
sion of the “Bianchi-Melacrino-Morelli Hospital” of
Reggio Calabria (Italy) in March 2003 because of a
previously diagnosed –but never treated– CHB. He
denied familial history of HBV infection as well as
major risk factors for viral infection. He declared
that he had occasionally been found to be HBsAg
positive in infancy and to have had fluctuating va-
lues of aminotransferase values over time. A needle

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Lamivudine and PEG-IFN add-on therapy. , 2011; 10 (1): 84-87
liver biopsy performed in another hospital in 2002
had shown a mild degree of chronic hepatitis [(G5/
F1, according to K nodel score)].14 At clinical obser-
vation the patient presented with normal body
mass index, mild hepatomegaly in the absence of
splenomegaly. He denied a history of drug or alco-
hol abuse, there was no evidence of other known
causes of liver disease, and he tested negative for
hepatitis Delta, hepatitis C and immunodeficiency
virus serum markers. T he alanine aminotransfera-
se (ALT ) levels were twice the upper normal levels
(UNL), the HBV profile showed the “e” antigen to
be negative and the corresponding antibody to be
positive and the viral DNA was 17,600 copies/mL
(Amplicore HBV Monitor kit, Roche Diagnostics).
At this time the patient was not treated. T wo mon-
ths later (May 2003) he had a hepatitis flair with
ALT levels 8 times the UNL and 450,000 copies/mL
of HBV DNA. At this point, treatment with Lami-
vudine 100 mg/day was started (Figure 1). T he pa-
tient –who attended all the scheduled follow-up
visits-had a prompt virological/biochemical respon-
se, achieving normal ALT values and undetectable
levels of HBV-DNA in six months. At the following
visits he always showed normal AL T levels toge-
ther with undetectable HBV DNA but with the per-
sistence of HBsAg. At the clinical check-up in
March 2007 (46 months after the start of therapy),
the patient expressed several doubts about taking
L amivudine every day for the rest of his life and
his intention to discontinue the treatment soon
was clear. Considering the high probability of HBV
reactivation in the event of discontinuing Lamivu-
dine treatment and, on the other hand, the fact
that the best chances of success of IFN therapy in
CHB appear to occur when the viremia levels are
low, we proposed a therapeutic schedule based on
the maintenance of Lamivudine and the add-on of
PE G-IFN-α-2a for a period of 12 months. Our hope
was that this regimen could help to permanently
transform the HBV infection from active to inactive
and, consequently, to avoid the reactivation of the
disease once the patient discontinued the Lamivu-
dine therapy. T he patient accepted this proposal,
providing his informed consent. T herefore, in Mar-
ch 2007 we added PE G- IF N-α-2a 180 µg/week to
the pre-existing L amivudine administration for a
subsequent period of 12 months. During the first
weeks of the combined therapy, the patient suffered
mild, typical IFN side effects such as fever and fati-
gue, whereas the liver function tests were persis-
tently normal with undetectable HBV DNA.
However, at the clinical check-up performed 8 wee-
ks after starting PE G- IF N-α-2a therapy a three
fold UNL increase of ALT was observed, with HBV
DNA values still undetectable. One month later (12
weeks after staring PE G- IFN-α-2a therapy) a flair
of aminotransferase (ALT up to 15 times the UNL
and aspartate aminotransferase up to 8 times UNL)
was detected. All known causes of liver damage
Figure 1. Patient’s virological profile and alanine aminotransferase levels (ALT) during the 46 months treatment with LAM alo-
ne, the 12 months treatment with LAM + PEG-IFN--α-2a, and the twenty-four months of follow-up after stopping all treatments.
HBV-DNA
(copies/mL)
109
108
107
106
105
104
103
102
ALT (UI/mL)
600
520
440
360
280
200
120
40

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Mangano C, et al. , 2011; 10 (1): 84-87
86
were excluded, including super-infection with other
hepatotropic viruses and toxics. Considering that
the patient had no subjective symptoms, the biliru-
bin, prothrombin and albumin values were normal
and HBV DNA was persistently undetectable, the
combined treatment was continued despite the flair
and more frequent clinical check-ups were establis-
hed. T he aminotransferase levels progressively de-
creased and definitively returned to normal values
in December 2007. Very surprisingly, at the Octo-
ber 2007 check-up the HBsAg tested negative and
one month later the anti-HBs became positive. At
the end of one year of Lamivudine + PE G- IFN-α-
2a treatment (February 2008), the patient had nor-
mal liver biochemistry and undetectable HBV-DNA
and he was HBsAg-negative and anti-HBs positive,
maintaining this status of complete biochemical/vi-
rological recovery at the check-ups performed 6,
12, 18 and 24 months after stopping all treatment
(Figure 1).
DISCUSSION
HBsAg/anti-HBs seroconversion marks the clini-
cal recovery of CHB and, consequently, it represents
the main objective of any therapy. Unfortunately,
however, the treatments available at present rarely
allow this objective to be achieved. In the case re-
ported here, the HBsAg/anti-HBs seroconversion
was achieved by the use of a particular therapeutic
schedule where PEG-IFN-α-2a was added-on in a pa-
tient who apparently had an optimal response to La-
mivudine administration
suppression of HBV replication and lack of emergen-
ce of any viral strain resistant to this particular
NUC. Intriguingly, the seroconversion occurred af-
ter a flare of aminotransferase values, an event that
is difficult to explain. In fact, the top level of the fla-
re was observed after three months of combination
therapy and appeared to be independent of a reacti-
vation of the HBV infection since the frequent viro-
logical follow up performed under treatment showed
persistently undetectable levels of serum HBV DNA.
One might explain the flare with the toxic effect that
PEG-IFN may exert on liver tissue,15,16 although it
has to be stressed that our patient experienced a
much more pronounced ALT increase (598 IU/mL)
than that usually associated with PEG-IFN therapy,
and –more importantly– liver biochemistry slowly
returned under the normal value levels even though
the PEG- IFN-α-2a administration was not interrup-
ted. Considering that liver cell expression of the
HBV proteins may persist independently of NUC-in-
with persistent
duced suppression of viral replication, we might
hypothesize that the ALT flare and subsequent HB-
sAg seroclearance observed in our patient might be
related to the lysis of hepatocytes expressing HBV
antigens and due to the restoration of an efficient
anti-HBV immunoresponse induced by the IFN
treatment.17,18 Combination therapy with PEG-IFN
and NUCs is an understudied approach for the cure
of CHB. In fact, there is no reliable information con-
cerning which NUC is best to combine with IFN,
the timing in giving each drug and the duration of
their administration. T he excellent outcome of our
case may encourage the design of the large scale cli-
nical trials necessary to definitively clarify the use-
fulness and the best schedule of this combination
therapy.
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