Download Treatment of Hepatitis B in Patients With Chronic Kidney Disease

Hepatitis B Treatment
Hepatitis B Treatment
Chapter 2
Abstract
Treatment of Hepatitis B in Patients With
Chronic Kidney Disease
Samuel Chan1,2*, Magid A Fahim1,2,3, Graeme A Macdonald2,4
and David W Johnson1,2,3
Department of Nephrology, Princess Alexandra Hospital,
Australia
2
School of Medicine, The University of Queensland, Australia
3
Translational Research Institute, Australia
4
Department of Gastroenterology and Hepatology, Princess
Alexandra Hospital, Australia.
1
Corresponding Author: Prof. David Johnson, Department of Nephrology, Princess Alexandra Hospital,
Brisbane, Queensland, Australia; School of Medicine,
The University of Queensland, Brisbane, Queensland,
Australia, Tel: +61 7 3176 5080; Fax: +61 7 3176 5480;
Email: [email protected]
First Published April 02, 2016
Copyright: © 2016 David Johnson et al.
*
This article is distributed under the terms of the Creative
Commons Attribution 4.0 International License
(http://creativecommons.org/licenses/by/4.0/), which
permits unrestricted use, distribution, and reproduction
in any medium, provided you give appropriate credit to
the original author(s) and the source.
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Hepatitis B virus (HBV) is a significant global pathogen, infecting more than 240 million people worldwide.
It is a frequent infection in chronic kidney disease (CKD)
patients. It negatively impacts long term outcomes reducing graft and patient survival. Current guidelines clearly
define who will benefit from antiviral therapy; when to
start; what is first-line therapy; how to monitor treatment
response; if it may be possible to stop; and how patients
should be monitored on therapy. Furthermore, there are
some data showing a favourable safety and efficacy profile of nucleos (t) ide analogues in patients with CKD. An
important issue for patients with CKD is the risk of life
threatening flares of HBV with immunosuppression, either as therapy for their renal disease or following transplantation. The aims of this chapter are to review the epidemiology, risk factors for acquisition and transmission,
prognosis, and prevention of HBV infection in individuals with CKD. Thereafter, the treatment options available
for HBV infection in individuals with co-morbid CKD,
dialysis and renal allografts are discussed.
Key words
Chronic Kidney Disease; Hepatitis B; Treatment
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Introduction
Approximately 1.8% of the world’s population are
estimated to have been infected by the hepatitis B virus
(HBV), which is an important cause of both morbidity
and mortality (0.2 deaths/100 person years) worldwide
[1]. HBV infection has a complex interplay with chronic
kidney disease (CKD) whereby it is able to cause CKD
directly through immune related mechanisms, including
polyarteritis nodosa and membranous and membranoproliferative glomerulonephritidies, and indirectly by
exacerbating metabolic complications including hypertension and diabetes mellitus [2,3]. In addition, CKD
portends a poor outcome in individuals with HBV infection, reduces tolerability of HBV therapies, and is itself a
risk factor for the acquisition of de novo HBV infection
through the need for dialysis, operative procedures, and
blood transfusions [1,2]. The aims of this chapter are to
review the epidemiology, risk factors for acquisition and
transmission, prognosis, and prevention of HBV infection
in individuals with CKD. Thereafter, the treatment options available for HBV infection in individuals with comorbid CKD, dialysis and renal allografts are discussed.
Natural History of Hepatitis B
Infection
HBV is a blood borne virus that can also be transmitted through exposure to body fluids including sexual ex-
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posure and around the time of birth. Exposure to the virus
can result in acute hepatitis B, a usually self-limiting disease in immune-competent adults; or progress to chronic
HBV infection. Age of exposure has a significant effect on
the risk of developing chronic infection as ~40% of infants
<2 years old exposed to HBV will develop chronic infection, compared to ~4% if they are ≥2years old. Immunocompromise, including from chronic illness, has a similar
effect on the risk of developing chronic infection.
Although acute infection occasionally results in lifethreatening acute liver failure, most of the morbidity and
mortality from HBV occurs with chronic infection. The
outcome of chronic HBV infection depends on an interplay of viral, host and environmental factors. For example,
in South Africa, chronic HBV and dietary aflatoxin exposure are linked to specific mutations in the p53 tumoursuppressor gene and an aggressive form of hepatocellular
carcinoma. The risk of these cancers developing appears
increased in individuals with specific isoforms of enzymes
involved in aflatoxin metabolism.
In patients with CKD, the major risk of chronic HBV
infection relates to liver injury and the development of
cirrhosis and related complications. The risk of progressive liver injury in patients with CKD is not just related to
the virus. In the immunocompetent host, the hepatitis B
virus is not considered cytopathic, that is, it does not appear to directly injure liver cells. Most of the liver injury
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is mediated by the immune system attempting to clear infected hepatocytes. This is primarily mediated by T-cells
and augmented by innate immune responses. These result
in necro-inflammation that stimulates hepatic fibrogenesis and, over time, progression to cirrhosis. The picture is
not as clear in immunosuppressed individuals where viral
replication occurs at an increased rate and viral proteins
can interfere with cellular processes and lead to cell injury
and death.
One of the features of chronic HBV infection is that
it evolves over time in response to environmental immunological pressures from the host. In an attempt to understand this process, chronic HBV infection is typically
depicted as having four phases that reflect the interactions
between the immune system and the virus. These are often
shown as a continuum (Table 1), implying patients move
sequentially through these phases, but in reality an individual’s clinical course can jump forwards or backwards
through this sequence and not necessarily encompass all
four phases.
These four phases include the immune tolerant phase;
hepatitis B e antigen (HBeAg)–positive immune active
phase; inactive chronic hepatitis B phase, and the HBeAgnegative immune reactivation phase [4,5]. Phases vary in
length from months to decades and while the terminology describing the phases may not accurately reflect the
immunological status of the patient in each phase, they
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are useful for prognosis and guiding the need for therapy
[5,6].
Table 1: Natural history of Hepatitis B infection.
ALT
HBV DNA
HBeAg
Liver histology
Immune tolerant
phase
Normal
Elevated, typically >1 million
IU/mL
Positive
Minimal inflammation and fibrosis
HBeAg-positive immune-active phase
Elevated
Elevated
>20,000 IU/mL
Positive
Moderate to severe
inflammation or
fibrosis
Inactive Chronic
Hepatitis B phase
Normal
Low or undetectable <2,000
IU/mL
Negative
Minimal necroinflammation but
viable fibrosis
HBeAg-negative
immune reactivation
phase
Elevated
Elevated >2,000
IU/mL
Negative
Moderate-to-severe
inflammation or
fibrosis
The immune tolerant phase typically occurs early in
chronic infection (often starting in the prenatal period)
and is characterised by high HBV DNA and low serum
ALT, reflecting a high rate of viral replication and a low inflammatory response. With increasing age, the probability of transitioning to the immune active phase increases.
The latter is characterised by both elevated HBV DNA and
ALT concentrations reflecting T-cell mediated liver injury.
Among individuals in the immune active phase, 70-90%
transition to the inactive CHB phase characterised by low
or undetectable HBV DNA, normal serum ALT. In some
patients, antibody against the HBV e antigen (aHBe) apwww.avidscience.com
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pears. The final phase is HBeAg-negative immune reactivation phase characterised by elevated ALT and HBV
DNA concentrations and absent HBeAg. This picture is
typically found late in the infection, with eAg loss due to
a combination of immunological pressure and selection
for eAg negative mutants. This combination of longstanding disease and immunological pressure against infected
hepatocytes means that patients with HBeAg – CHB are
more likely to have advanced fibrosis and typically have
lower viral loads than those with eAg + disease. This lower
viral load means that patients with HBeAg – immune reactivation CHB appear more likely to respond to oral antiviral therapies than those that are HBeAg+.
Pathophysiology of Hepatitis B
Infection
Our understanding of the molecular mechanisms by
which HBV infects hepatocytes and replicates has grown
recently; providing new insights into the mechanisms of
action of current anti-HBV medication as well as potential
novel targets for therapeutic development.
One of the features of the cccDNA is that it is very
stable. At present, there is no effective therapy to eradicate
HBV cccDNA from infected hepatocytes. Clearance of cccDNA will occur slowly, but only as infected hepatocytes
die. This means that antiviral therapies that suppress viral
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replication are in general only effective as long as they are
taken. Once these agents are ceased, the cccDNA provides
a template to resume viral replication [7,8].
There are two important feature of the HBV DNBA
polymerase. Firstly, it is an attractive therapeutic target as
blocking the polymerase effectively blocks viral replication. Secondly, the HBV DNA polymerase has a relatively
high rate of making errors during DNA replication. This
means that at any time there are likely to be the full spectrum of possible mutations of the virus in circulation. This
provides an inherent flexibility in responding to environmental pressure. As an example, the eAg is typically present early in the course of chronic HBV infection. As the
immune system increasingly responds to the eAg, there
is pressure for the virus to lose the eAg. This typically occurs through specific mutations in the pre-core region of
the eAg (the so called pre-core mutant), or a mutation in
the basal core promoter; and these changes result in eAg
negative chronic HBV infection. This mutagenic potential also allows the development of resistance to antiviral
agents [7,8].
Epidemiology
Hepatitis B affects approximately 350 million people worldwide and is associated with high mortality and
morbidity [9,10]. Deaths from cirrhosis and hepatocellular carcinoma were estimated at 310,000 and 340,000 per
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year, respectively [1].
continuing high prevalence rates of HBV infection among
haemodialysis populations [17]. Although acute infection
tends to be mild and asymptomatic in dialysis patients,
up to two-thirds may progress to chronic carriage, with
significant risk of chronic liver disease, premature death
from cirrhosis or liver cancer and nosocomial transmission within haemodialysis units [17].
Apart from major liver complications, clinical evidence suggests that chronic HBV infection has a negative
impact on renal function [11]. HBV infection can lead to
glomerulonephritis, even in the absence of cirrhosis [12].
A small controlled prospective study indicated that individual estimated glomerular filtration rate declined by approximately 2mL/min/year in 60 untreated HBV-infected
patients without pre-existing renal disease, diabetes or
hypertension during the median follow-up of 24 months
[13]. A two-year cross sectional Hepatitis and Renal Parameters Evaluation (HARPE) study observed that 64.6%
of treatment-naive patients with chronic HBV infection
had evidence of CKD [14]. A two year GLOBE study indicated that telbivudine, one of the agents that inhibits DNA
replication, improved renal function in patients with
chronic HBV infection [15].
Over the past few decades, there has been a substantial decrease in the incidence of HBV infection in haemodialysis patients, probably attributable to screening of
blood donors, a decline in blood transfusion requirements
with increased erythropoietin use, and authoritative
guidelines relating to infection control and vaccination
[16]. Despite this progress, haemodialysis patients remain
at increased risk of acquiring HBV because of increased
exposure to blood products, shared haemodialysis equipment, frequent breaching of skin, immunodeficiency, and
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Hepatitis B Infection as a Risk Factor
for Chronic Kidney Disease
HBV can cause CKD directly through immunological mechanisms or indirectly through metabolic complications. HBV has been implicated in the genesis of polyarteritis nodosa, membranous glomerulonephritis and
membranoproliferative glomerulonephritis [2,9,18]. The
pathogenic role of HBV in these processes issecondary to
the formation of hepatitis B antigen-antibody complexes
and their deposition in the medium sized arteries and glomeruli.
In polyarteritis nodosa, a medium-sized vessel vasculitis, antibody-antigen complexes are deposited in vessel walls [9]. In membranous nephropathy, it has been
proposed that deposition of HBeAg and anti-HBe antibody forms the classic subepithelial immune deposits [2].
Both HBsAg and HBeAg have been implicated in membranoproliferative glomerulonephritis, which has been
characterised by deposits of circulating antigen-antibody
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complexes. In addition, hepatitis B is a risk factor for the
development of hypertension and diabetes mellitus, which
are present among 6% and 9% of patients with hepatitis B,
respectively [18]. These metabolic complications are established risk factors for the development of CKD.
Impact of Chronic Kidney Disease on
Hepatitis B
Renal parameters are of utmost importance in CHB
patients since renal dysfunction impacts clinical outcomes.
In a prospective study including patients with HBV infection, an elevated serum creatinine at baseline was significantly associated with mortality rates at 6 months in
multivariate analysis, with a hazard ratio (HR) for death of
5.23 [17]. Additionally, it has been shown that HBV infection increases the risk of occurrence of kidney disease in
Chinese diabetic patients [17]. Furthermore, therapeutic
management of HBV infection is potentially modified in
the presence of CKD, while antiviral drugs dosages must
be adjusted to renal function and potential renal toxicity
of antivirals may further damage the kidneys and lead to
clinical complications [17].
Diagnosis of Hepatitis B Infection
The diagnosis of hepatitis B relies on serological testing. There are five routine tests used that, in combination
with HBV DNA testing, provide a guide to the stage of
infection. The antibody to HBV core antigen (aHBc) pro12
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vides evidence that an individual has been exposed to the
HBV virus. (The HBV core antigen itself is not found in
peripheral blood, but is present on hepatocytes). If a patient is aHBc IgM positive, then this exposure was within
the last 6 months. On the other hand, if aHBc IgG is present, it is taken as evidence that the HBV exposure was >6
months ago [19].
The HBV surface antigen (HBsAg) is a marker of current infection, and in combination with aHBc IgM indicates this is an acute infection; or with aHBc IgG, a chronic
infection. The antibody to HBsAg (aHBs) is a neutralizing
antibody that blocks infection. If a patient has aHBs then
they are immune to HBV or have resolved infection [20].
The remaining two serological tests are the HBV e antigen and the antibody to this antigen (HBeAg and aHBe
respectively). In chronic infection, these tests are useful to
distinguish the stage of disease, as discussed above. The
other essential HBV test is HBV DNA testing. The viral
load in particular is useful in determining the need for
antiviral therapy. If the viral load is low, then oral antiviral
therapy is unlikely to add further benefit in suppressing
necro-inflammation. However, in chronic hepatitis B, a
high HBV DNA in the presence of advanced liver disease
or raised liver enzymes indicates there may be a benefit
from viral suppression. Viral load testing is also used to
monitor response to therapy, and typically should fall over
three to six months after commencing oral agents [20].
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Other tests that are available include HBV DNA sequencing for mutations, and HBV genotyping. DNA sequencing is generally used to look for mutations that
confer resistance to oral antiviral agents, but is occasionally used to look for other clinically relevant mutations.
Resistance testing is particularly useful in determining
whether apparent failure of oral agents may be due to
non-compliance, or the emergence of specific mutations,
in which case the results may be used to guide changes to
therapy. Genotyping is variably used in clinical practice,
but does provide information on risk of disease progression and potential for response to different antiviral therapies [19,20].
Finally, there are imaging and other modalities, such
as ultrasound, liver biopsy, fibroscan and serological tests
for hepatic fibrosis that are used to determine the stage of
disease; whether cirrhosis is present; and to look for complications of chronic hepatitis B infection, such as portal
hypertension and hepatocellular carcinoma [19,20].
Therapy
Current Therapies of Hepatitis B
Seven drugs have received approval for the treatment
of chronic HBV infection, including interferon-α, PEGylated interferon-α, the nucleoside analogues lamivudine, telbivudine and entecavir, and the nucleotide analogues, adefovir and tenofovir, referred to as a group as
NAs.
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The NAs as a group share a number of characteristics.
They all act to inhibit the HBV DNA polymerase by sitting
in the enzymatic pocket of the enzyme and blocking DNA
chain elongation. Mutations of the HBV DNA polymerase
that change the configuration of the pocket may block the
entry of a specific agent and confer resistance to the agent.
With the first generation agent lamivudine, this could occur with one mutation. However for later agents, such as
entecavir and tenofovir, multiple mutations are required
to confer resistance. This need for multiple mutations is
said to confer “a high genetic barrier to resistance”, and
means that it is unlikely to occur spontaneously. There is
cross reaction in terms of the development of resistance, so
that the development of resistance to lamivudine makes it
more likely that resistance will occur with telbivudine and
entecavir. However, the configuration of adefovir/ tenofovir are such that lamivudine resistance does not appear to
confer a major increase in the risk of resistance developing
for these agents. Another factor that can contribute to the
development of resistance is inadequate initial response or
poor compliance. Resistance can develop in these settings
because the inherent mutagenic potential of the DNA polymerase will allow the eventual emergence resistant species unless viral replication is fully suppressed.
In terms of potency, entecavir, telbivudine, and tenofovir are the most potent, followed by lamivudine and
then adefovir. Entecavir and tenofovir are associated with
the lowest risk of drug resistance, followed by adefovir, telwww.avidscience.com
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bivudine, and lamivudine, in that order [9].
Interferon-α
Interferon-α, an antiproliferative and immunomodulatory agent, was the first available antiviral drug for
chronic HBV infection. This agent is metabolized by renal tubules. In dialysis patients, it has been found that
interferon-α’s half-life is greatly enhanced, and prolonged
treatment can lead to drug accumulation; hence, its adverse effects are magnified. The most problematic of these
are neuropsychiatric side effects (including irritability,
impaired concentration and depression), leucopeniaand
thrombocytopenia; but also include flu-like symptoms,
nausea, diarrhea, fatigue, thyroid dysfunction, and alopecia [21]. Therefore, interferon-α is poorly tolerated by
dialysis patients who have a frequent occurrence of sideeffects, such as exacerbation of anaemia, neutropenia, and
protein malnutrition. Scarce data exist on treatment with
interferon-α among infected dialysis patients with HBV.
In one study, the adverse effects were so severe that withdrawal of the drug was required in more than 50% of patients [22]. Newer PEGylated interferon, an agent with a
longer half-life, is no better tolerated in patients with renal
failure. Interferons are not recommended in dialysis patients with HBV infection.
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Lamivudine
Lamivudine was the first nucleoside analogue antiviral approved worldwide for the treatment of chronic hepatitis B. Its major advantages include ease of administration
(oral), potent antiviral activity, and favourable safety profile. Lamivudine has also been shown to be effective in the
treatment of HBV-associated, acute glomerulonephritis
[23]. Good results were obtained in a series of 16 dialysis
patients: 56% were able to eliminate HBV DNA and 36%
were able to clear HbeAg [24]. The main disadvantages of
lamivudine include risk for drug resistance and the need
for usually indefinite treatment. Lamivudine-resistant
HBV developed in 39% of dialysis patients after a median
of 16.5 months of treatment [25]. The prevalence of drug
resistance increases with the duration of the therapy, and
is present in 14% of patients treated for one year, and in
69% of patients after 5 years of antiviral therapy [22]. The
development of drug-resistanceis a major limitation to its
long term use [20,25]. Another potential issue is the need
for dose adjustment in renal impairment.
Adefovir dipivoxil
Adefovir dipivoxil, a nucleotide analogue, is the second oral agent approved for the treatment of chronic HBV
infection. It has generally been used as additive therapy
for lamivudine-resistant CHB [26] because lamivudine
resistance does not impact on adefovir efficacy or the risk
of adefovir resistance [27,28]. Resistance is less of an issue
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than with lamivudine; 0% at one year and 29% at 5 years
[29]. One limitation to its use in CKD is that adefovir is a
nephrotoxic agent [22], and worsened renal function has
been reported in 2.5 to 28.0% of cases after 1 to 2 years of
therapy [22]. Limited data about adefovir administration
exist in the chronic kidney disease population [30,31].
Adefovir is eliminated via the kidneys; thus, a dose adjustment is required in CKD patients to prevent drug accumulation and toxicities [27].
Telbivudine
Telbivudine is a synthetic thymidine nucleoside analogue that inhibits HBV DNA polymerase [32], and provides effective and sustained viral suppression [33]. In
clinical trials, telbivudine has been superior to lamivudine in HBV patients in terms of treatment outcomes and
HBV DNA suppression [33,34]. When compared with
lamivudine, telbivudine has greater HBVDNA suppression, and HBeAg seroconversion rates are significantly
greater with telbivudine than with lamivudine [35]. In
addition, telbivudine-treated subjects are less likely to develop viral resistance than lamivudine-treated individuals
[33,36]. Nonetheless, rates of resistance developing were
still higher than with the more potent agents, Tenofovir
and entecavir and this has limited the uptake of telbivudine therapy.
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Entecavir
Entecavir is a nucleoside analogue drug that has selective anti-HBV activity. The incidence of entecavir resistance appears to be minimal, only about 1% after 3 years
of monotherapy [37]. Entecavir is effective in viral suppression [38,39]. In addition, entecavir is more potent at
suppressing HBV replication than lamivudine and adefovir [21]. Although there is little information on the therapeutic impact of entecavir in dialysis patients with chronic
HBV infection, it is often recommended as a first-line oral
therapy in patients with kidney disease [21]. Because entecavir is primarily eliminated by the kidneys, dose reduction is recommended for patients with reduced GFR [40].
Moreover, the drug should be administered after haemodialysis. Continuous ambulatory peritoneal dialysis can
remove approximately 0.3% of the dose over 7 days. Entecavir should be administered on an empty stomach (at
least 2 hours after a meal or 2 hours before the next meal).
Tenofovir
The nucleotide analogue tenofovir is the other agent
recommended as a first-line oral antiviral in the treatment
of chronic HBV patients with normal renal function [19].
It is the most potent agent against HBV infection within
the first year of treatment [41]. Tenofovir can also be an
effective alternative in patients with lamivudine-resistant
HBV infection and is more potent and efficacious than
adefovir [42]. However, nephrotoxicity and acute kidney
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injury have been reported in some patients treated with
tenofovir [43,47]; therefore, the drug should be used with
care in dialysis patients with residual renal function.
Impact of Antiviral Agents on Renal Function
Nucleoside and nucleotide analogues are primarily
eliminated without changes in the urine following ingestion, and appropriate dose modifications are recommended for patients with impaired renal function (GFR < 50
mL/min). Treatment guidelines recommend that all patients initiating NA treatment should be tested for serum
creatinine levels and estimated creatinine clearance before
therapy; and baseline renal risk should be assessed for all
of them [19,48]. High baseline renal risk includes one or
more of the following clinical situations: decompensated
cirrhosis, creatinine clearance < 60 mL/min, poorly controlled hypertension, proteinuria, uncontrolled diabetes, active glomerulonephritis, concomitant nephrotoxic
medications and solid organ transplantation. In consequence, dialysis recipients may have many of these basal
renal risk factors.In clinical trials outside renal transplant
setting, minimal decline in renal function has been shown
with all NAs, except for telbivudine which appears to improve renal function [49,50].
First line NAs, entecavir and tenofovir, appear to have
little impact on renal function in the general population
when compared with untreated controls and with the
other NAs. Although there is some evidence of renal dys-
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function in entecavir-treated patients, its clinical significance remains unclear as it may represent a physiological
decrease in renal function in this group and/or reflect the
potential limitations of standard biochemical tests of renal
function in patients with liver disease [51]. Baseline renal
risk factors may play a role in the nephrotoxic effects of
NAs. Therefore, it is recommended that patients going on
these agents should have baseline measures of serum creatinine and estimated creatinine clearance. For adenoviror tenofovir-treated patients, it is also advised to measure
serum phosphate levels, especially in patients at high renal
risk. In patients at low renal risk, these tests can be performed every 3 months during the first year and every 6
months thereafter, if there are no renal adverse events. In
patients at high renal risk these tests can be performed
every month for the first 3 months, every 3 months until
the end of the first year and every 6 months thereafter,
if there are no renal adverse events. Closer renal monitoring is required in patients who develop reductions in
creatinine clearance < 60 mL/min or reductions in serum
phosphate levels < 2 mg/dL (0.65 mmol/L) [19,48,52,53].
HBV Vaccination
HBV vaccination represents one of the most important measures in the prevention of nosocomial transmission of HBV infection within a dialysis unit, especially in
endemic areas. Unfortunately, despite the high seroconversion rate of more 95% in general population, the seroconversion rate obtained using current HBV vaccination
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strategies in dialysis patients remains relatively low. With
conventional intramuscular (i.m.) vaccination, only 5073% of dialysis patientsdevelop protective levels of antihepatitis B surface antibodies (aHBs) [54,55]. In addition,
the antibody response in patients with end-stage renal disease (ESRD) tends to be short-lived, with 23-57% of initial
responders having undetectableaHBs within 6-12 months
[56,57]. Various strategies have been developed to improve the response rate to HBV vaccination in dialysis patients. These include increasing the dose and frequency of
vaccination, using analternative route of administration,
use ofadjuvants and the development of novel immunogenic vaccines [58-61]. There are only a few studies of the
last two strategies and the results remain preliminary and
inconclusive. However, there are many studies on changing the dose, frequency and route of vaccine administration and it is recommended that an augmented regimen
be employed for patients with end-stage renal disease with
the vaccine administered in a four-dose schedule, 40 µg
per dose given at 0, 1, 2, 6 months, instead of the conventional 3-dose schedule of 20 µg per dose given at 0, 1, 6
months [55]. Nevertheless, the superiority of this regimen
has not yet been confirmed [61,62]. There are also studies
on intradermal (i.d.) administration of the vaccine. It has
been suggested that by activating epidermal Langerhans
cells and keeping the antigen in the tissue for longer time,
intradermal administration might reverse the dysfunctional antigen presentation associated with uraemia and
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enhance T and B lymphocytes responses. To date, the results of these studies have been mixed and the efficacy of
intradermal hepatitis B vaccination remains controversial
[63-65]. From these studies, it seems that the efficacy of
i.d. vaccination is dose-related and superior efficacy probably could only be achieved with high individual and cumulative doses. For example, by using an individual dose
of 5.0 µg and a mean cumulative dose 40-57.3 µg, i.d. administration was no better than i.m. vaccination. Another
study on dialysis patients comparing 20 µg i.d. with 40 µg
i.m, both given for three doses, also showed no difference
in the aHBs seroconversion rate [66]. In contrast, with an
individual dose of 20 µg and cumulative dose of 100 µg,
Propst et al. [67] showed that i.d. vaccination was superior
to i.m. administration with four dose-dose schedule (40
µg/dose) in terms of the seroconversion rate (94 vs. 76%).
However, the induced immunity by i.d vaccination is less
durable than conventional i.m. administration. Although
it is considered unnecessary to maintain an anti-HBs
greater than 10 mIU/mL for low-risk healthy population
after successful vaccination and initial seroconversion because of the presence of immunologic memory, a booster
dose of vaccine is generally recommended for dialysis
patients due to their immunosuppressive state, poor responses to vaccination and environmental risks of cross
infection [55]. In this regard, the limited durability of i.d
vaccination would be another important consideration
and concern before routine application in daily practice.
With a recent study showing that in patients with chronic
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kidney disease, the higher the glomerular filtration rate;
the better the response to HBV vaccination [68], it would
be highly recommended to consider vaccinating all HBV
non-immune patients once they are diagnosed as having
renal disease or implementing universal vaccination in
endemic areas.
Dialysis Patients
Prevention of HBV transmission is a key consideration in the care of patients receiving haemodialysis. The
introduction of HBV immunization has significantly
lowered the HBV incidence in several endemic regions,
although CKD patients often have poor responses to vaccination as detailed above [69,70]. It should also be noted
that haemodialysis patients with chronic HBV infection
often present with moderate or no elevations of serum
aminotransferases owing to altered inflammatory response, lower serum HBV DNA levels due to its removal
by haemodialysis, higher risk of occult HBV infection
(usually aHBc-positive, HBsAg-negative, aHBs-negative),
and many comorbidities such as cardiovascular disease,
diabetes mellitus, and anemia [71-73]. All of these parameters may affect the clinical and laboratory presentation
and course of chronic HBV infection and the patients’ response to antiviral therapy.
The optimal therapy for chronic HBV infection in patients on haemodialysis depends on the clinical picture.
If patients have advanced liver disease or chronic HBV
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with raised liver enzymes and high DNA, they should be
treated. The difficulty is what to do with those who do
not have these biochemical parameters. If the HBV DNA
concentration is high but the ALT is normal, observation
with regular fibroscan monitoring is recommended [72].
A limited literature exists on IFN therapy on patients with
chronic HBV infection receiving haemodialysis. The experience in this patient group comes mostly from treatment of hepatitis C [72]. Although IFN-α administration
can lead to HBe seroconversion and improvement of liver
biochemistry, IFN side effects (mostly myelosuppression
and malnutrition) hamper its use in clinical practice.
There are limited data on NA therapies in haemodialysis patients that suggest they are safe and potent antivirals. There are three reports including five HBV patients
undergoing haemodialysis who were treated with adefovir
for 12–30 months [73]. Both liver and renal function improved in parallel with the serum HBV DNA clearance.
There are no data for telbivudine efficacy or safety in such
patients [73,74]. Long-term entecavir therapy seemed
to be safe and effective in nine patients on maintenance
haemodialysis. Given its high potency and high genetic
barrier in NA-naive patients profile, entecavir is the most
promising anti-HBV agent for patients undergoing haemodialysis and/or candidates for renal transplantation
[69,70]. As long-term entecavir therapy is not recommended in patients with lamivudine resistance, tenofovir
may be required in such cases, although caution should
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Hepatitis B Treatment
Hepatitis B Treatment
be exercised and doses should be appropriately adjusted
in patients with estimated glomerular filtration rates <50
ml/min [72-75].
Transplant Patients
Candidates for Renal Transplantation
HBsAg-positive patients with cirrhosis and end-stage
renal disease are at risk for hepatic decompensation after
isolated renal transplantation, and may require consideration for simultaneous liver and kidney transplantation
[99,76,77]. According to the current guidelines, all HBsAg-positive candidates for solid-organ transplantation
should be treated with NAs before renal transplantation
in order to maintain undetectable HBV DNA, reduce liver
fibrosis, and prevent hepatic decompensation after renal
transplantation [78]. In clinical practice, the optimal timing for treatment initiation in HBsAg-positive candidates
for renal transplantation is often individualized, taking
into account the recipient’s clinical status, dialysis-related
complications, and, most importantly, the expected waiting time on hemodialysis [77,78].
HBV-Positive Renal Transplant Recipients
IFN-α therapy is contraindicated in renal transplant
recipients owing to the increased risk of acute rejection
and low antiviral potency. In 2009, KDIGO recommended
prophylaxis with entecavir, tenofovir, or lamivudine for
HBsAg-positive transplant recipients [79]. The applica26
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tion of NAs prompted a new era in renal transplantation
of HBV-positive transplant recipients. Before their use,
HBsAg positivity was an independent and significant risk
factor for mortality and graft loss [79]. The effective NA
therapy permitted a striking increase in patient (81–89%)
and graft survival (86%) at 10 years, through the inhibition of viral replication, the retardation of liver disease
progression, and the lower incidence of hepatocellular
carcinoma (the cancer risk is not eliminated, and ongoing
HCC surveillance is recommended) [80].
The pre-emptive use of NA therapy is recommended
to all HBsAg-positive patients shortly before or at the time
of renal transplantation regardless of the baseline histological severity and serum HBV DNA level, because immunosuppressive therapy after renal transplantation has
been associated with a risk of rapidly progressing fibrosing
cholestatic hepatitis even in patients with mild or inactive
liver disease before renal transplantation [80]. Salvage NA
therapy after post-renal transplantation HBV exacerbation can be used, but it is a less effective approach compared with pre-emptive NA therapy and confers excessive
risk to patients. Treatment with a NA should usually continue for as long as immunosuppressive therapy lasts or at
least for 24 months if immunosuppression is withdrawn
before then. The need for HBV therapy in HBsAg-negative, anti-HBc-positive transplant recipients is debatable.
If the decision is made not to place this group on prophylactic therapy, then ongoing monitoring is necessary to
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Hepatitis B Treatment
Hepatitis B Treatment
detect HBV reactivation early prior to potentially serious
flares in HBV.
In non-renal patients, including those who undergo
liver transplantation, monotherapy with a NA with high
genetic barrier (entecavir or tenofovir) is currently recommended [81]. Although there are very limited data
in transplant recipients, entecavir is often considered as
a preferable initial option in this setting because of the
theoretical lower risk of nephrotoxicity compared with
tenofovir. Data for entecavir have included a total of 80
NA-naive or lamivudine- or adefovir-resistant HBV transplant recipients with satisfactory results [81]. Entecavir
given at a daily dose of 1 mg for a maximum of 33 months
was found to be effective, well tolerated, and without deterioration of renal function, microalbuminuria, or allograft
rejection [81,82]. Data for tenofovir have been reported
for only three HBV transplant recipients. Tenofovir given
at a dose of 245 mg adapted according to renal function
was found to be effective, well tolerated, and safe without changes in serum creatinine levels after 12 months of
therapy [82].
HBV-Positive Renal Transplant Donors
Kidneys from HBsAg-positive donors are not promoted for renal transplantation, because they have the
potential to transmit HBV to the recipient [83]. Nevertheless, the fundamental need for donor pool expansion urged some transplant centres to use kidneys from
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HBs-Ag positive, or anti HBc-positive/HBsAg negative
donors to HBsAg-positive and -negative transplant recipients [83,84]. Indeed, there are reports for safe and effective
lamivudine prophylaxis in HBsAg-negative transplant recipients of kidney grafts from anti-HBc-positive donors
and for lamivudine combined with immunoglobulin in
anti-HBs-positive recipients having received grafts from
HBsAg-positive donors (with or without detectable HBV
DNA) [84-86].
Immunosuppression in Patients with Renal
Disease
Patients with chronic renal failure are at high-risk for
infectious complications, similar to patients with other
types of acquired immune defects or those on immunosuppressive therapy. Secondary immune failure in uraemia
is multi-faceted and is influenced by uraemic intoxication
per se, by altered renal metabolism of immunologically
active proteins and by specific effects of renal replacement
therapy. Large inter-individual variability points to the
importance of individual factors. A high incidence of infection is found in uraemic patients and infections remain
the second most frequent cause of death.
One specific problem is hepatitis B. Vaccination
against hepatitis B is routinely performed in dialysis patients. Although effective in only 60–70% of patients, it
helped to eliminate the threat of hepatitis B from dialysis
centres. The response to hepatitis B vaccine proved to be
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Hepatitis B Treatment
Hepatitis B Treatment
a valid clinical index for individual immune reactivity in
dialysis patients.
Rituximab has been used in a variety of renal diseases
and in renal transplantation, with anecdotal success. It is
an engineered chimeric monoclonal antibody that contains murine heavy and light chain variable regions directed against CD20 plus a human IgG1 constant region.
The CD20 antigen, a transmembrane protein, is found
on immature and mature B cells, as well as on malignant
B cells; this antigen is found in more than 85% of nonHodgkin’s lymphoma. CD20 mediates B-cell proliferation
and differentiation. The CD20 antigen is not internalized
upon antibody binding, and is not shed or found in soluble forms. Following treatment with rituximab, B cells are
prevented from proliferating, and undergo apoptosis and
lysis through complement-dependent and complementindependent mechanisms. These mechanisms include
complement-dependent cytotoxicity, antibody-dependent cell cytotoxicity, and activation of tyrosine kinases as
a direct effect of the antibody binding to its CD20 ligand.
The exact contribution that each of these mechanisms
makes in vivo remains unclear. Evidence that the degree
of B-cell depletion correlates with levels of serum rituximab and the Fcgr3a genotype indicates that antibody-dependent cell cytotoxicity is crucial; however, prolonging
the ‘off rate’ of the monoclonal antibody seems to increase
complement-dependent cytotoxicity and therapeutic efficacy, indicating that complement-dependent mechanisms
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are also important. B-cell depletion generally persists for
6–9 months in over 80% of patients, although the degree
of depletion is highly variable. The concerns regarding using rituximab in patients with CKD is the activation of
Hepatitis B. Screening for prior exposure to Hepatitis B
is crucial when considering the commencement of rituximab in CKD patients.
Prevention of Transmission of
Hepatitis B within Dialysis Units
Infection control precautions for dialysis services are
more stringent than standard precautions and are designed to prevent transmission of blood borne viruses
and bacterial pathogens including Multi-Resistant Organisms (MRO), in dialysis settings. They include all the
components of standard precautions as well as routine serological testing, hepatitis B vaccination, surveillance for
infections, additional cleaning procedures and the management of equipment, medications and consumables.
To prevent the transmission of HBV, dialysis services
should institute a comprehensive blood borne virus prevention plan, including a high level of compliance with
BBV serological testing and HBV vaccination. The criteria
for separating HBsAg reactive patients undergoing peritoneal dialysis should be the same as those undergoing haemodialysis since peritoneal fluid can contain high levels
of HBV and should managed in the same manner as the
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Hepatitis B Treatment
Hepatitis B Treatment
patient’s blood.
The following approach to management of patients
infected with HBV is recommended. The measures are
ranked from the most to least preferred method for managing HBV-positive patients, and should be adopted based
on the number of adequately trained staff, the availability
of isolation facilities, and the ability to ensure patient and
staff safety:
• Dialyse HBV-positive patients in a separate room/
area designated only for HBV-positive patients.
This should include the use of separate dialysis
equipment including machines
- Patients with HBV should be managed
separately from other patients
• If there are no isolation facilities, HBV-positive
patients should be separated from susceptible
patients and undergo dialysis on dedicated machines.
• Patients with aHBs greater than 10 IU/L may undergo dialysis in the same area as HBsAg-reactive
patients, or they may serve as a geographic buffer
between HBsAg-reactive and susceptible patients
(non reactive for HBsAg, aHBs, aHBc).
• When HBV-positive patients are not being dialysed, the room/ area may be used for uninfected
patients after cleaning and disinfection.
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• Machines, equipment and consumables should be
managed appropriately.
- Ideally, the same dialysis equipment
should not be used for the HBV-positive patients and
seronegative patients; however, where this is not possible, the machine should be disinfected using conventional processes and the external surfaces cleaned
and disinfected thoroughly prior to use on another
patient
- When a machine is no longer required
for HBV-positive patients, it can be returned to general use after standard cleaning and disinfection procedures have been carried out.
• Dialysis staff members caring for HBV-positive
patients should not care for susceptible patients at
the same time (e.g. during the same shift or during patient change-over).
• Staff members can care for HBsAg-reactive and
patients with aHBs titre greater than 10 IU/L during the same shift.
• If dialysis staff members must bare for both HBVpositive patients and susceptible patients during
the same shift, they must meticulously adhere
to Standard Precautions i.e. change their apron,
gown and gloves, and perform hand hygiene between patients
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Hepatitis B Treatment
Hepatitis B Treatment
Conclusion
3. Papatheodoridis GV, Chrysanthos N, Savvas
S, Sevastianos V, Kafiri G. Diabetes mellitus in
chronic hepatitis B and C: prevalence and potential association with the extent of liver fibrosis. J
Viral Hepat. 2006; 13: 303-310.
The primary effort for HBV eradication and thus reduction of HBV-associated kidney disease is based on
global HBV immunisation and appropriate screening programs. NAs with high genetic barrier to HBV resistance
are the best options for HBV-positive patients with CKD
in order to minimise the consequences of HBV infection.
Combination with immunosuppressive agents may be
considered in cases of rapid renal function deterioration
and/ or severe proteinuria. All HBsAg-positive candidates
should be treated with NAs before renal transplantation
in order to maintain undetectable HBV DNA, reduce liver
fibrosis, and prevent hepatic decompensation after renal
transplantation. Ultimately, large multicenter controlled
studies are required to evaluate the therapeutic benefits,
the long-term safety and the optimal regimen of NAs for
different groups of chronic HBV patients with CKD.
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