Management of HBV Infection During Immunosuppressive
Division of Gastroenterology and Hepatology, San Giovanni
Battista Hospital, Turin, Italy
Alfredo Marzano, Division of Gastroenterology, AOU San
Giovanni Battista, Corso Bramante 88, 10125, Torino. E-mail: firstname.lastname@example.org
Published: December 22, 2009
Received: December 17, 2009
Accepted: December 21, 2009
Medit J Hemat Infect Dis 2009, 1(3): e2009025 DOI 10.4084/MJHID.2009.025
This article is available from: http://www.mjhid.org/article/view/5226
This is an Open Access article
distributed under the terms of the
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which permits unrestricted use, distribution, and reproduction in any
medium, provided the original work is properly cited
literature on hepatitis B virus (HBV) in immunocompromised patients is
heterogeneous and refers mainly to the pre-antivirals era. Currently, a
rational approach to the problem of hepatitis B in these patients
provides for: a) the evaluation of HBV markers and of liver condition
in all subjects starting immunosuppressive therapies (baseline), b) the
treatment with antivirals (therapy) of active carriers, c) the
pre-emptive use of antivirals (prophylaxis) in inactive carriers,
especially if they are undergoing immunosuppressive therapies judged to
be at high risk, d) the biochemical and HBsAg monitoring (or universal
prophylaxis in case of high risk immunosuppression, as in
onco-haematologic patients and bone marrow transplantation) in subjects
with markers of previous contact with HBV (HBsAg-negative and
antiHBc-positive), in order to prevent reverse seroconversion. Moreover
in solid organ transplants it is suggested a strict adherence to the
criteria of allocation based on the virological characteristics of both
recipients and donors and the universal prophylaxis or therapy with
B virus infection is a major public and medical concern. Two billion
people are overt carriers of HBV worldwide; of them, 360 million suffer
from chronic HBV infection and over 520,000 die each year, 50,000 from
acute hepatitis B and 470,000 from cirrhosis or liver cancer. Moreover
many subjects have only markers of previous contact with the HBV
(antiHBc+/- antiHBs), which can indicate an Occult HBV Infection (OBI).
Immunodepression due to the underlying disease or to drugs used in
immunosuppressive, anticancer therapy and in organ transplants can
influence the hepatitis B virus (HBV), both in terms of reactivation
and in terms of the acceleration of a pre-existing chronic hepatitis.
In this situation the possibility of HBV relapse has been known for
years, with clinical manifestations ranging from selflimiting anicteric
to fulminant forms or to chronic hepatitis with an accelerated clinical
course towards liver decompensation. Hepatitis reacti-vation may
influence the continuation of the specific treatments and the survival
of immuno-depressed or transplanted patients
The risk of clinical events is mainly observed in overt carriers of
HBV, but can also develop in the OBI condition which has been widely
described in the literature of the last decade.
Progress in the diagnostic procedures of the various virological
conditions associated with HBV, the recent availability of effective
antiviral treatments, the growing incidence of immunocompromised
patients attributable to the evolution of immunosuppressive therapies
and organ transplants and the expectation of an important future
increase of HBV reactivation have brought this problem to the fore,
although the rational approach and management of these patients is
HBV infection is defined as overt when the hepatitis B surface antigen
(HBsAg) is present in amounts well-detectable by sensitive immune
assays and occult in HBsAg-negative subjects with evidence of
intrahepatic and/or serum HBV DNA.
carriers, HBsAg can be
completely absent (real OBI) or undetectable for very low amounts or
polymorphisms (false OBI).
- A. HBV carriers
(HBsAg-positive). In accordance with the international definitions,
they can be identified as: 1) active carriers, in presence of HBeAg or
of anti-HBe antibodies and of a viral load ≥ 2-20,000 IU/ml; this
condition is associated with the presence of hepatic disease in the
most part of cases, or 2) inactive carriers,in case of subjects
HBeAg-negative and antiHBe-positive, whose alanine aminotransferase
(ALT) levels are persistently within the normal range, HBV DNA below
2,000 IU/ml in the most part of cases and IgM antiHBc levels < 0.20
IMx Index. In the majority of these subjects the histological finnding,
when available, does not reveal a significant liver disease
(necro-inflammatory activity < 4 HAI), while in a small minority of
cases it is possible to observe the effects of a chronic liver disease
which became silent spontaneously or following antiviral treatment [3,4].
- B. Occult HBV
carriers (HBsAg-negative).The difficulty in determining HBV DNA in the
liver biopsy (frequently not justified in subjects without clinical
signs of hepatitis), the rare presence of detectable viremia in serum
even with sensitive techniques, and the frequent presence in occult
carriers of markers of previous contact with the HBV (antiHBc+/-
antiHBs), leads one to consider all anti-HBc
(anti-core)-positivesubjectsas potential occult carriers. Instead there
are no serum determinants in the minority (about 20%) of occult
carriers who are negative for all HBV markers.
HBV carriers (occult or overt) the following virological events are
considered significant: 1) in anti-core subjects the reemergence of
HBsAg(sero-reversion), 2) in inactive carriers the appearance of a
significant viremia (≥20,000 IU/ml) (reactivation), as this is
frequently associated with liver damage due to HBV, 3) in active
carriers the persistence of a significant viremia (> 20,000 IU/ml in
HBeAg positive patients and > 2,000 IU/ml in HBeAg negative
subjects) (activity), as this is frequently associated with progression
of liver damage due to HBV, 4) in all the virological categories
(whether or not during prophylaxis or therapy with antivirals), the
increase in at least one logarithm of HBV DNA, compared to its nadir,
reconfermed in two consecutive serum tests during monitoring (virologic
breakthrough) (Table 1
assessment of chronic liver disease is the fundamental event of the
diagnostic picture (baseline) (Table 2
and requires the use of all the instruments usually utilised in
hepatology including, if necessary, trans-cutaneous or trans-jugular
liver biopsy in subjects with coagulation problems (for example
patients with blood or kidney diseases).
The baseline diagnosis of the disease is pivotal in the choice of which
treatment to adopt, as the risk of severe complications is related to
the severity of the underlying liver disease 
In order to standardize the deȚ nitions the following terms were
suggested: 1) infection (not necessarily associated with reactivation
of hepatitis) in the case of the detection of HBV DNA by sensitive HBV
assays and/or of HBsAg in patients in whom these markers were
originally negative, 2) reactivation of hepatitis B (hepatitis), in the
presence of a significant viremia and ALT levels above the upper normal
The term prophylaxis was used to mean treatment with antiviral drugs of
an inactive or occult infection, with the aim of preventing hepatitis
reactivation. Prophylaxis was defined as: 1) universal prophylaxis
(UP), if it is carried out on the entire population potentially at risk
(inactive carriers and/or anti-core), 2) or targeted prophylaxis (TP),
if it is subordinate to the appearance of infection markers (HBV DNA
and/or HBsAg) in the absence of hepatitis reactivation (Table 3
Therapy (T) was understood to mean the treatment of hepatitis B (i.e.
chronic hepatitis in active carriers or hepatitis reactivation)
In Italy the following drugs are available at present: interferons,
either standard or peghilated (both little tolerated in the condition
of immunodepression, especially in transplant patientsfor the potential
risk of rejection) and the nucleos(t)ides analogs(NAs), which currently
include lamivudine, adefovir-dipivoxil , entecavir, telbivudine and
tenofovir and and emtricitabine for patients with HBV-HIV co-infection.
In naive patients lamivudine, which has a considerable antiviral
effect, frequently (50-60% at 4 years, low genetic barrer) induces the
selection of lamivudine-resistant mutants in locus YMDD of the
polymerase gene (YMDD). However, adefovir-dipivoxil has a low antiviral
effect but induce a lower selection of mutants, while
Telbivudine is more potent with an intermediate genetic barrer.
Finally, third generation NAs (Entecavir and Tenofovir) have both a
high potency and a high genetic barrer
Data from experience in liver transplanted and HIV patients have shown
a relation between the original viremia, the degree of
immunosuppression and the selection of mutants during prophylaxis with
Consequently a careful monitoring of
the response to
treatment and of the resistance is suggested in immunocompromised
patients treated with Nas.
Hereafter are reported the statements of the Italian guidelines
referred to hepatitis B and recently updated with a special attention
to the different therapeutic options available nowadays.
Screening. It is recommended that all immunocompromised patients
and those candidate to chemotherapy, immunosuppressive therapy
and/or transplantion are screened for HBsAg and anti-HBc. Seronegative
patients should be vaccinated preferibly with a reinforced course of
vaccination for the diminished vaccinal response linked to the
Chronic carriers with active HBV replication (HBV DNA > 2.000
IU/mL). They should be treated as immune-competent patients. NAs
are the first choice, regardless of the clinical setting (oncology,
haematology, rheumatology, nephrology, gastroenterology, dermatology,
solid organ transplantation). Pegylated interferon is contraindicated
in most cases. NAs with high potency and low resistance should be used,
such as Entecavir or Tenofovir. Telbivudine could be considered in
those with HBV DNA < 2,000,000 IU/ml.
Close virologic monitoring is mandatory during
immunosuppression. The addition of a second drug (a nucleotide in
patients treated with a nucleoside and vice versa) is advisable in
cases of incomplete virologic response, or primary non-response to
monotherapy. In immunocompromised patients the dose of NA(s) should be
adjusted according to the renal function, co-morbidities and drugs
Inactive HBsAg carriers (HBV DNA persistently < 2,000 IU/ml). In
patients undergoing solid organs transplant or autologous or allogenic
bone marrow transplantation or high risk immune suppressive treatment
(anti-TNF, anti-CD20, anti-CD56, medium/high dose of steroids
(>10 mg/die) for prolonged periods, ciclofosphamide, metotrexate,
leflunomide, cyclosporine, tacrolimus, azathioprine and micofenolate)
antiviral prophylaxis with a NA is recommended, starting from the
beginning of the immune-suppressive treatment or preferibly 2-4 weeks
before. In other conditions patients should be only monitored for
HBV DNA reactivation.
If the duration of immunosuppressive therapy is limited, the
pharmacologic risk of resistence is diminished; therefore a low cost
NA, such as Lamivudine, may be used. In patients who need prolonged
immunosuppression the use of more potent NAs at lower risk to induce
resistance can be considered).
HBsAg-negative, anti-HBc positive patients. In these subjects HBV DNA
should be tested at baseline in order to distinguish real from false
OBI. Viremic HBsAg-negative patients should be treated with a NA.
Anti-HBc positive subjects with haematological diseases undergoing
strongly immunosuppressive treatments such as: fludarabine, dose-dense
regimens, autologous or allogenic bone marrow transplant, treatment
with monoclonal antibodies (anti – CD-20 and anti CD52) should be
treated with a NA (preferably Lamivudine for short term
therapies),independently of anti- HBs reactivity.
Anti-HBc positive patients in other clinical settings should not
be treated but only monitored for liver enzymes and the emergence of
serum HBsAg every 1-3 months. Some experts recommend prophylaxis
with a NA also in non-haematological patients if they are treated with
Monitoring During Therapy
Once NAs therapy or prophylaxis has been started, monitoring will
essentially be through testing serum HBV DNA and ALT levels every three
months, to assess: 1) response to treatment (i.e. reduction of HBV DNA,
preferably below the limit of sensitivity of the amplified techniques
and ALT normalization) and 2) drug-resistance, which should be
suspected in the case of virologic breakthrough while ontreatment, in
order to activate an early rescue therapy[3,11]
. Resistance can be
defined clinically by the virologic breakthrough 
but a genotypic
testing is reccomended and should be used in order to better define the
different mutations and to choose the rescue therapy [3,8]
Impact on Different Specialist
Data regarding hepatitis B in immunocompromised patients are very
heterogeneous. As a result there is a strong indication to promote
studies aimed at defining the natural history of hepatitis B in these
patients, to assess – also prospectively - different treatment
protocols and to promote close cooperation among different specialists.
Oncology, Hematology and
Hematopoietic Stem Cell Transplantation (HSCT)
chemotherapy hepatitis B can make its appearance in two different
phases: 1) during the treatment, in relation to the intense bone marrow
suppression, which is associated with a strong viral replication and,
sometimes, with the emergence of a fulminant hepatitis in the form of
fibrosing cholestasis, 2) after the end of therapy, as during the
immuno-reconstitution phase the immune response can bring on a
reactivation of hepatitis whose clinical course may be more or less
severe depending on the baseline condition of the liver and other
possible factors that may contribute to the damage.
In oncology the prevalence of HBsAg-positive patients ranges between
5.3% (in Europe) and 12% (in China). In these patients the frequency of
clinical HBVreactivation ranges between 20 and 56%, correlating with
the use of steroids, anthracyclines, 5-fluouracil with some virological
indicators (presence of HBeAgor of e-minus variants and/or of a
detectable HBV DNA prior to therapy). Theclinical significance of
relapse has been clearly associated with the pre-chemotherapy liver
function, with a mortality of 5-40%.
The reactivation of hepatitis, moreover, influences the continuation of
the chemotherapy, inducing its suspension and not infrequently posing
problems of differential diagnosis with regard to drug toxicity.
Hepatitis B can develop both in active and in inactive carriers and it
is generally associated with the reappearance of a significant viremia
in the preceding 2-3 weeks.
In hematology the frequency of HBsAg positive patients is higher (12.2%
in Greece and 8.8% in a recent study from Italy) and the risk of
reactivation appears to be greater than in other settings of oncology,
depending on the degree of immunosuppression. In this setting, control
of the HBV infection assumes great importance in order to prevent
HBV-related complications, but also so as not to modify a highly
successful therapeutic schedule.In this field the main prognostic
indicators unfavorably associated with hepatitis B reactivation are,
besides those already cited, hyper-transaminasemia and the condition of
second or third cycle compared to the first [1,12- 14]
In hematology, a 21-67% (median 50%) risk of reactivation has been
described, with an average mortality of 20%. In this setting, the
available literature is not clear whether the severity of hepatitis in
HBsAg-positive patients is directly due to the liver damage caused by
HBV reactivation or by other causes (i.e. VOD, GvHD or MOF) and also
the degree of risk in relation to the condition of active or inactive
carrier is not clearly determinable.
The risk would appear to be heightened by the use of monoclonal
antibodies (antiCD20, antiCD52), with the possibility of hepatitis
reactivation (even after a cycle of 1-3 months of prophylaxis with
lamivudine) at a variable distance from the last administration of
these drugs, particularly in overt carriers, but also in anti-core
subjects. An analogous risk exists in the course of allogeneic HSCT, as
the immuno-suppressive effect in the conditioning phase is particularly
strong and is amplified by the subsequent anti-rejection therapy, so
the risk of hepatitis reactivation remains throughout the phase of
immuno-reconstitution (in some cases until 1-2 years from
Experiences in the different
Recommendations from the Italian
- Active HBsAg-carriers: In the onco-hematological setting
lamivudine therapy of chronic hepatitis in active carriers appears to
- Inactive HBsAg-carriers: The start of lamivudine therapy at
the time of the clinical relapse (hepatitis) in inactive
carriersmaintains a residual mortality of 20%, probably in relation to
the baseline conditions and to the delayed treatment.However, in
retrospective studies lamivudine has been shown to be effective in
prophylaxis of hepatitis B (0-9% of hepatitis reactivation compared to
25-85% in untreated patients) and in the only prospective study
hepatitis relapse developed in 5% of treated subjects and in 24% of
controls. Moreover, in the study the universal use of lamivudine was
better than the targeted prophylaxis (activated only at the appearance
of HBV DNA with a non-amplified technique, during bimonthly
monitoring), both in terms of survival and of hepatitis reactivation
(0% vs.53%, P=0.002)[1,17,18,49,50].Recently
many meta-analyses have
confirmed the signficant efficacy of lamivudine in preventing hepatitis
B in HBsAg positive patients, in reducing deaths and in reducing
chemotherapy discontinuation.Finally, as lately reported in literature,
lamivudine-prophylaxis in HBsAg-positive patients undergoing
chemotherapy has been shown to be cost-effectivein terms of HBV
reactivation (9.6% LAM+ vs. 43.8% LAM-), liver related deaths (0/500
LAM+ vs 20/500 LAM-), chemotherapy discontinuation and cancer deaths
(39/500 LAM+ vs 47/500 LAM-)[46-48].
- Anti-core patients (HBsAg-negative): In the oncological
setting there are few data, at present, for this virological category,
which can reach 20-40% in averagely endemic areas and 70-80% in highly
endemic areas.However, in the hematological setting, out of a total of
176 patients described in literature, sero-reversion has been reported
in 21 subjects (12%) during conventional chemotherapy, whether or not
this was associated with HSCT, with percentages of 4-30% during
chemotherapy and 14-50% in the course of autologous
autologous HSCT, hepatitis B developed in anti-HBc patients later (6-52
months, average 19 months) than in overt carriers (average 2-3 months)
and none of the patients described died of hepatitis B (in 7 cases
during therapy with lamivudine, started at the time of the clinical
relapse). After the reactivation nine of the 10 patients remained HBsAg
positive and one lost the HBsAg during follow-up. Instead, two deaths
out of 39 subjects with seroreversion have been reported in literature
after allogeneic HSCTand this appeared to have been significantly
linked to the absence of protective antibodies (antiHBs) in the donor
and to GVHD1.Recently the introduction in hematologic treatments of
monoclonal anti-lymphocyte B and T antibodies (anti-CD20 and
anti-CD52), used alone or together with chemotherapy, has been
associatedwith the signaling of some cases of sero-reversion in
anti-core subjects, sometimes with a fulminant form and death of the
patients, despite therapy with lamivudine1.HBV infection has been
described to be the most frequently (39%) experienced viral infection
in lymphoma patients treated with Rituximab. In a study about 50% of
Rituximab-related HBV infections resulted in death, whereas this was
the case in only 33% of the patients with other infections.An Italian
study has lately stressed a very low (1%) overall risk of
sero-reversion in a large series of patients treated for lymphoma, but
the risk of hepatitis B reactivation was 3.5 fold increased. Rituximab
therapy, compared to conventional chemotherapy (P < 0.005). Data
confirming the increased risk of HBV reactivation in patients
undergoing anti B-cell therapy have also emerged in a trial which
showed as alemtuzumab containing chemotherapy regimen was associated
with a high risk (29%) of reactivation of occult HBV infection and of
severe HBV-related hepatitis [51-54].
- In active carriers therapy is considered useful to control
the liver disease pre- and post-immunosuppressive treatments. In HSCT,
in particular, the control of the HBV-related disease permits a more
precise diagnosis and treatment of specific liver complications (GVHD
and VOD). In these patients, antiviral therapy should be continued
lifelong (due to the high risk of relapse after withdrawal) or at least
until the disappearance of HBsAg in serum. A strict monitoring of
mutants should be activated, in order to prevent hepatitis relapse with
- In the inactive carriers universal prophylaxis appears to
be indicated and should be continued for the entire phase of
chemotherapy, until at least 12-18months after the end of the
treatment.[1,18] The optimal
duration of the prophylaxis is still debated
and requires prospective studies. In any case, it is recommended the
monitoring of the viremia after suspension, for the prompt diagnosis
and return to treatment in the case of reactivation.
- In anti-HBc positive (HBsAg-negative) patients, two
different strategies can be identified:
- a) in oncology or in patients undergoing mild
hematological therapies (judged to be at low immunosuppressive
potential, such as the ABVD of the CHOP 21 days scheme), HBsAg
monitoring every 1-3 months is advised, with the activation of targeted
prophylaxis or therapy in the case of sero-reversion or hepatitis
reactivation, respectively. However,the use of HBV DNA monitoring for
targeted prophylaxis remains controversial because of the lack of data
referred to the timing and duration of the monitoring and to the
clinical significance of minimal levels of detectable viremia (i.e. the
presence of low levels of serum HBV DNA in OBI carriers after solid
organs transplantation has rarely a clinical impacts and is not
constantly associated with hepatitis relapse).
- b) In subjects who need to be treated with intense
immunosuppression(chemotherapy with fludarabine, dose-sense regimes,
allogeneic transplant, autologous myeloablative transplant, induction
in acute leukemia, use of monoclonal antibodies) universal prophylaxis
This approach is strongly indicated in the hematological setting and in
patients with signs of a chronic hepatitis (due to a previous history
of HBV-related disease and/or to other causes of chronic hepatitis)
and/or with a positive serum HBV DNA and/or positive for antiHBe
antibodies at the baseline evaluation.
Effects of different virological
conditions in donors (D) and recipients (R) of Allogeneic Hematopoietic
Stem Cell Transplantation (HSCT):
General recommendations in HSCT:
- D (HBsAg-/antiHBs+/antiHBc±)->R (HBsAg+):In the case of
transplant from an immunized (antiHBs-positive) donor to an overt
carrier (HBsAg-positive) recipient two possible scenarios have been
described: a) the chance of adoptive transfer of immunity with the
possible clearance of HBsAg (especially if recipients are treated with
lamivudine), b) an acute and sometimes fulminant hepatitis (in
- D (HBsAg-/antiHBs±/anti-HBc+)->R
(HbsAg-/antiHBs±/anti-HBc ±): Only few data are available, indicating
that in the case of transplant from an anti-HBc positive donor
the risk of sero-reversion in the recipient would appear to be
negligible in both anti-HBc positive and negative recipients .
- D (HBsAg+).>R (HBsAg-): In a few
studies, transplant from an HBsAg-positive donor was associated with
hepatitis in 44-62% of recipients, with generic hepatic mortality in
33-75% of cases, although the role of HBV in these clinical events was
not well defined. In a historical retrospective multicenter study
performed in the pre-antiviral phase, the anti-HBV specific
immunoglobulins (HBIG) were not protective against the transmission of
the infection. In contrast, in a recent study the activation of therapy
with lamivudine in donors and of prophylaxis with the same antiviral in
recipients significantly reduced the HBV-related hepatitis rate (48 vs.
7%, P=0.002) and mortality (24 vs. 0%, P=0.01) compared to a historical
control group. Furthermore two case reports have
efficacy of lamivudine-prophylaxis in this clinical setting in
preventing HBV related hepatitis[55,56].
Dialysis and Solid Organs
Transplants (Kidney, Heart and Lung)
- Vaccination of the recipient prior to transplant, if
possible, with accelerated protocols, (recombinant vaccine 40 ”g by
intramuscular route, time 0-1-2 months or 0-7-21 days), especially if
he/she is naïve.
- Vaccination of the donor not immunized prior to transplant,
with accelerated protocols (recombinant vaccine 20 ”g by intramuscular
route time 0-1-2 months or 0-7-21 days) in the case of allogeneic HSCT.
- Treatment of the HBsAg-positive donor with lamivudine pre-
HSCT in order to reduce infectivity through the reduction of viremia
(preferably below the limit of sensitivity of an amplified assay) and
universal prophylaxis of the recipient on the day before the transplant.
- The use of high doses of HBIG (intravenous 10,000 IU)
during infusion of hematopoietic stem cells from overt carriers (who
have been preventively treated with antivirals) in HBsAg-negative
recipients remains controversial. Because of the actual results of the
hepatologic and hematologic therapy there is no reason to deny
hematopoietic stem transplantation from an HBV positive donor (any
form) if the risk-benefit ratio is in favor of transplantation.
Moreover in the case of an HLA identical family HBV positive member
there is no point in wasting time and resources in searching for an
unrelated donor in the international bone marrow donor bank.
The incidence of overtcarriers of HBsAg among dialyzed patients is 0-7%
in developed countries and 10-20% in developing ones. In these subjects
the frequent normality of the transaminase makes clinical judgment
difficult, confirming the fundamental role of the virological markers
(quantitative HBV DNA) and of the liver biopsy to distinguish between
active and inactive carriers (baseline). In this setting data about the
condition of OBI carrier among anti-HBc patients are scarce and
consider the sole presence of viremia in serum, whose diagnostic
sensitivity is low.
In kidney transplant
condition of HBsAg carrier can be estimated in 10-20% of cases and is
associated with a significantly higher risk of death (OR 2.49, 95% CI),
independent of the viremic condition (active or inactive carrier), and
the chronic hepatitis presents an accelerated course towards cirrhosis
(5.3-12%-year), decompensation and hepatocarcinoma [23,24]
In heart and lung transplant
Italian reports have signalled HBsAg positivity in 2.3-3.7% of
recipients. In this setting the evolution of the HBV-related disease is
accelerated in active carriers and the risk of hepatitis B reactivation
post-transplant is over 50% in originally inactive subjects. Finally,
the risk of sero-reversion postsurgery (de-novo hepatitis B) in
HbsAg-negative/anti-HBc positive recipients seems to be lower than
Clinical experiences in
No controlled trials for the treatment of HBV with either interferon or
lamivudine in dialyzed patients or in kidney transplants are currently
available. Interferon can be used to treat dialyzed patients with
chronic hepatitis B, but it is contraindicated in transplanted
patients. Short-term administration of lamivudine monotherapy is
effective but when the drug is withdrawn, viremia rebounds and
hepatitis relapses in most cases. Continuous administration of
lamivudine monotherapy for 3 to 4 years is able to obtain long-term
suppression of HBV replication and may prevent the development of liver
related complications and mortality 
treatment failure is
caused by the emergence of YMDD which, in some patients, herald
hepatitic flares and progression of the liver disease.
Recommendations in relation to
transplant recipients from the Italian guidelines:
- Active carrier: In candidates for kidney, heart or lung
transplant the indication to therapy is confirmed, both in the
pre-transplant (with NAs or interferons, when they are tolerated) and
in the post-transplant phase (only NAs in view of the high risk of
- Inactive carrier: Pre-transplant and during dialysis there
is no indication for prophylaxis but biochemical and virological
monitoring is advised, if the diagnosis has been confirmed by strict
adherence to previously defined criteria. Instead, therapy should be
used in the re-activated forms (HBV DNA >20,000 IU/ml), especially
if associated with significant liver damage (HAI > 4 and/or signs of
Ț brotic disease by non-invasive methods). Post-transplant, however,
there is an indication to universal prophylaxis,in relation to the
available data on mortality in HBV carriers, independently from their
- Anti-HBc positive recipient: In these
recipients of kidney, heart and lung transplant the presence of
subclinical manifestations (low levels of circulating HBV DNA
detectable with very sensitive techniques post-transplant)
without sero-reversion in over 95% of cases[19,23,24,27] has been
In this condition only monitoring of the HBsAg is required, with the
activation of targeted prophylaxis or therapy onlyin the case of
sero-reversionand/or hepatitis, respectively.
Recommendations in relation to
- Anti-HBc positive donors: In the case of kidney, heart or
lung allocation from an HBsAg-negative/anti-HBc
ositive/antiHBs-positive or negative donor in a HBsAg-negative
recipient, the risk of hepatitis B appears to be less than 5% [27,29]. The
low risk does not justify preventive prophylaxis, but only HBsAg
monitoring (every 3-6 monthsand/or in the case of transaminase
increase) and the use of targeted prophylaxis or therapy only in the
case of sero-reversion.
- HBsAg-positive donors: In this condition the risk of
transmission of the HBV infection is very high in the absence of
prophylaxis, especially from HBeAg-positive donors.
reports have indicated the post-transplant control of hepatitis B in
HBsAg-negative/antiHBs-positive recipients of organs from
HBsAg-positive donors, while on lamivudine prophylaxis .
The risk of
post transplantation hepatitis B is strictly influenced from both
recipient and donor virological characteristics:
Recommendations in relation to
- HBsAg-positive recipients:
in the absence of pre- and postoperative prophylaxis the risk of
post-transplantation hepatitis B is over 80%.In this condition the use
of antivirals before transplant (one single antiviral in the case of
wild type virus, combined with a second one that is active on the
mutants, in the condition of drug resistance with active replication),
associated with HBIG after surgery (combined prophylaxis), is
protective in more than 90% of patients [32,33].
in absence of prophylaxis the risk of sero-reversion after
transplantation (de-novo hepatitis B) is less than 5% from naïve liver
donors and 10-15% from anti-HBc positive donors[19,34].
- HBsAg-positive donors: the
risk of hepatitis B transmission from a HBsAg-positive donor is
high, as the neutralizing effect of HBIG is very low and the
reappearance of HDV, in co-infected recipients, is constant. In this
particular condition the reactivation of hepatitis would appear to be
controlled by the combination of two antivirals in the long term .
in this category the overall risk of HBV transmission and hepatitis is
high (33-78%), in the absence of prophylaxis, ranging from 70% in naïve
to 10-15% in anti-core recipients. Combined prophylaxis with
lamivudine±HBIG controls relapse in nearly all cases, while
personalized prophylaxis with only HBIG or only lamivudine has been
suggested in low risk recipients (anti-core positive).
studies are not available in this setting.
In all HBsAg-positive carriers there is an indication to universal
prophylaxis post-surgery according to their original virological
Recommendations in relation to
- in active carriers,
therapybefore surgery is indicated (with one or two antivirals in cases
of YMDD mutants), with the aim of achieving the reduction of HBV DNA
below the limit of sensitive HBV assays or at least below < 20,000
IU/ml, in association with combined prophylaxis (HBIG and one or two
antivirals, as previously reported) in the post-operative period;
- in inactive carriers,
the role of therapy before surgery remains controversial because of the
high (> 80%) protective effect of post-transplantation combined
prophylaxis. In these subjects a preventive reduction of HBV DNA before
surgery might not be necessary, with regard to the minimal residual
risk, but it could be desirable in order to save HBIG in the long
term after liver transplantation. Likewise, insubjects with spontaneous
undetectable viremia (PCR-negative) or with levels around the limit of
detectability (< 2,000 IU/ml), especially if co-infected with HDV,
the protective power of just HBIG seems to be very high. Although also
in this conditionthe use of the combined prophylaxis after liver
transplantation permits a considerable saving of HBIG in the long term.
HBsAg-negative/anti-HBc positive recipients,
in analogy with what has been described in the other transplants,
albeit in the presence of serum and intra-hepatic evidence of
re-infection by HBV in the post-transplant period, the risk of
sero-reversion is practically nil [36-37] and so
there is no indication
for any prophylaxis, but only the monitoring of the HBsAg.
use of organs from HBsAg-positive donors should be considered only in
conditions of emergency, avoiding their use in HDV recipients. In this
setting the use of universal prophylaxis with two antivirals
post-transplant could permit the control of clinical hepatitis B
recurrence in the long term. Instead the use of livers from
HBsAg-negative/anti-HBc positive donors is justified by the shortage of
organs but requires the adherence to specific rules in the
Donor/Recipient match (preferential allocation of anti-HBc positive
grafts to HBsAg positive or negative/anti-HBc positive recipients) and
the activation of universal prophylaxis with lamivudine±HBIG.
regarding the reactivation of HBV in the rheumatology setting are
episodic, during the course of hydroxychlorochine, azathioprine,
methotrexate and anti-Tumor Necrosis factor (TNF). The few data
available all refer to active and inactive HBsAg carriers. However,
reports on anti-CD20 derive from hematological experience, and like in
hematology the risk of HBV reactivation in the rheumatology setting
would appear to be linked both to the phase of immuno-suppression and
to that of immuno-reconstitution.
In the meantime no reactivations have been reported in the few
HbsAg-positive rheumatology patients undergoing universal prophylaxis
with lamivudine during immunosuppressive therapy.[38-41]
In the absence of data two risk categories have been identifiedwith
regard to the type and to the degree of immunosuppression: a) high risk
of HBV reactivationin patients undergoing the following therapy:
anti-TNF antibodies, medium to high dosage steroids (>7.5 mg/die)
for prolonged periods, immunosuppressors such as cyclophosphamide,
methotrexate, leflunomide, cyclosporine, tacrolimus, azathioprine and
mycophenolate. Although cases of viral reactivation have not yet been
described in rheumatology patients undergoing treatment with anti-CD20
antibodies, the data which have emerged in other specialist circles
suggest the inclusion in this group of these and other monoclonals; b)
low risk of HBV reactivation in patients treated with steroids at
<7.5 mg/die, sulfasalazine and hydroxychlorochine1.
Recommendations from the Italian
HBsAg-positive patients, therapy is indicated in active carriers and
universal prophylaxis with a NA is suggested in inactive carriers who
underwent high-risk treatment, especially if they are subjects with
manifestations of chronic liver disease due to the previous activity of
HBV or other causes. Finally, in inactive HBsAg-carriers treated with
low risk therapies and in HbsAg-negative/ anti-HBc positive subjects
the proposal is a strategy of monitoring,with the activation of therapy
or targeted prophylaxis in the case of viral reactivation (HBV DNA >
20,000 IU/ml) or sero-reversion, respectively.
Prophylaxis should be started 2-4 weeks before the immunosuppressive
therapy, if possible, and continued for at least 6-12 months afterwards
(i.e. after immunosuppressive therapy has been suspended). Hematology
literature advises particular caution in suspending prophylaxis,
especially in subjects treated with repeated cycles of monoclonal
Peculiar conditions in the
Anti-HBV vaccination in rheumatology patients remains controversial and
its cost/benefit ratio should be carefully assessed in groups
particularly at risk of HBV (for example those living with
HBsAg-positive individuals or health workers).
Panarteritis nodosa (PAN) is a rare necrotizing vasculitis that affects
small and medium-sized arteries which presents, at least in a portion
of cases, a pathogenic correlation with HBV infection. In the treatment
of HBV-related PAN, the immunosuppressive therapy (which also poses the
question of an uncontrolled activation of the virus) should be
associated with an antiviral therapy (in active carriers) or universal
prophylaxis (in inactive carriers) to repress viral replication. In
this regard single cases and observational studies with small numbers
of cases have documented the efficacy of interferon (IFN) and
liver cancer are the second cause of death worldwide in HIV carriers
(3-4 million), 9% of whom have HBV infection. Co-infection with HIV
increases the rate of chronic HBV infection, reduces the annual rate of
seroconversion to antiHBe and to antiHBs and may be linked to the
reactivation of the occult infection in HBsAg-negative subjects in the
presence of severe immunodepletion.
Moreover co-infection with HIV accelerates progression towards
cirrhosis and liver decompensation and reduces survival in
decompensated cirrhotics. Therefore mortality due to liver disease in
those co-infected with HIV-HBV is higher compared to subjects with just
HBV infection [43-44]
Recommendations from the Italian
- Patients undergoing
Anti-Retroviral viral Therapy (ART): In
active and inactive carrierstherapy and universal prophylaxis with
antivirals(utilizing the same NAs effective on HBV used in the
treatment of HIV infection) are indicated, respectively. In
HbsAg-negative/anti-HBc positive subjects, the condition of occult
carrier, characterized by HBV DNA positivity in serum and/ or in the
liver, has been identified in 35-90% of subjects with HIV co-infection
using high sensitivity techniques, and only in 1% of cases with less
sensitive techniques. Even in the presence of anecdotal reports of
reactivation during immunodepletion and/or of suspension of lamivudine,
the risk of sero-reversion appears to be very low (0.23/100
patients/year) and it doesnot therefore justify any prophylaxis but
only monitoring .
- Patients who do not
In active carriers therapy with interferons or antivirals is indicated.
In these subjects treatment should preferably be administered using
drugs which do not have any effect on HIV and which do not, in the
future, induce resistance to ART Instead, in inactive carriers
and in anti-HBc positive subjects monitoring of HBV DNA or HBsAg,
respectively, is recommended, with activation of therapy or targeted
prophylaxis in the case of reactivation or sero-reversion.
on hepatitis B in immuno-compromised patients is very
heterogeneous. It refers mainly to the pre-NAs era and the period prior
to the introduction of the modern techniques of determination and
quantification of the viremia, which raises many doubts and
difficulties about the interpretation of the studies and leaves several
aspects still a matter of debate. This encourages a network of
communication and studies, in order to better define the natural
history, the potential risk of hepatitis B and the results of the
various strategies proposed in the management.
Even in the light of such premises today it appears to be justified to
propose a rational approach to the problem of hepatitis B in
immunocompromised patients, which provides for:a) screening of
HBV markers in all subjects starting immunosuppressive therapies
and the evaluation of their original liver condition (baseline; b)
therapy of active carriers, preferably with third generation NAs; c)
prophylaxis, preferentially with a low-cost NA, of inactive carriers
and anti-HBc positive patients at risk (onco-hematologic and BMT
patients); c) HBV DNA (in inactive overt carriers) or HBsAg (in
anti-HBc positive subjects) monitoring of the remaining patients at low
risk of reactivation. Finally, in the transplant setting, a precise
Donor/Recipient matching should be considered.
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