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Hepatitis B Treatment Hepatitis B Treatment

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AbstractHepatitis B virus (HBV) is a significant global patho-

gen, infecting more than 240 million people worldwide. It is a frequent infection in chronic kidney disease (CKD) patients. It negatively impacts long term outcomes reduc-ing 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 pro-file 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, ei-ther as therapy for their renal disease or following trans-plantation. The aims of this chapter are to review the epi-demiology, risk factors for acquisition and transmission, prognosis, and prevention of HBV infection in individu-als with CKD. Thereafter, the treatment options available for HBV infection in individuals with co-morbid CKD, dialysis and renal allografts are discussed.

Key wordsChronic Kidney Disease; Hepatitis B; Treatment

Chapter 2

Treatment of Hepatitis B in Patients With Chronic Kidney DiseaseSamuel Chan1,2*, Magid A Fahim1,2,3, Graeme A Macdonald2,4 and David W Johnson1,2,3

1Department of Nephrology, Princess Alexandra Hospital, Australia2School of Medicine, The University of Queensland, Australia3Translational Research Institute, Australia4Department of Gastroenterology and Hepatology, Princess Alexandra Hospital, Australia.

*Corresponding Author: Prof. David Johnson, Depart-ment 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, 2016Copyright: © 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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IntroductionApproximately 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 membrano-proliferative glomerulonephritidies, and indirectly by exacerbating metabolic complications including hyper-tension and diabetes mellitus [2,3]. In addition, CKD portends a poor outcome in individuals with HBV infec-tion, 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 op-tions available for HBV infection in individuals with co-morbid CKD, dialysis and renal allografts are discussed.

Natural History of Hepatitis B InfectionHBV is a blood borne virus that can also be transmit-

ted through exposure to body fluids including sexual ex-

posure and around the time of birth. Exposure to the virus can result in acute hepatitis B, a usually self-limiting dis-ease 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 infec-tion, compared to ~4% if they are ≥2years old. Immuno-compromise, including from chronic illness, has a similar effect on the risk of developing chronic infection.

Although acute infection occasionally results in life-threatening acute liver failure, most of the morbidity and mortality from HBV occurs with chronic infection. The outcome of chronic HBV infection depends on an inter-play of viral, host and environmental factors. For example, in South Africa, chronic HBV and dietary aflatoxin expo-sure are linked to specific mutations in the p53 tumour-suppressor 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 progres-sive 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 ap-pear to directly injure liver cells. Most of the liver injury



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is mediated by the immune system attempting to clear in-fected hepatocytes. This is primarily mediated by T-cells and augmented by innate immune responses. These result in necro-inflammation that stimulates hepatic fibrogen-esis 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 immu-nological pressures from the host. In an attempt to un-derstand 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 indi-vidual’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 HBeAg-negative immune reactivation phase [4,5]. Phases vary in length from months to decades and while the terminol-ogy describing the phases may not accurately reflect the immunological status of the patient in each phase, they

are useful for prognosis and guiding the need for therapy [5,6].

Table 1: Natural history of Hepatitis B infection.

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 in-flammatory response. With increasing age, the probabil-ity 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) ap-

ALT HBV DNA HBeAg Liver histology

Immune tolerant phase

Normal Elevated, typi-cally >1 million

IU/mL

Positive Minimal inflamma-tion and fibrosis

HBeAg-positive im-mune-active phase

Elevated Elevated >20,000 IU/mL

Positive Moderate to severe inflammation or

fibrosis

Inactive Chronic Hepatitis B phase

Normal Low or unde-tectable <2,000

IU/mL

Negative Minimal necro-inflammation but

viable fibrosis

HBeAg-negative immune reactivation phase

Elevated Elevated >2,000 IU/mL

Negative Moderate-to-severe inflammation or

fibrosis



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pears. The final phase is HBeAg-negative immune reac-tivation 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 longstand-ing 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 re-activation CHB appear more likely to respond to oral an-tiviral therapies than those that are HBeAg+.

Pathophysiology of Hepatitis B InfectionOur 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 cc-cDNA will occur slowly, but only as infected hepatocytes die. This means that antiviral therapies that suppress viral

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 replica-tion. 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 spec-trum of possible mutations of the virus in circulation. This provides an inherent flexibility in responding to environ-mental pressure. As an example, the eAg is typically pre-sent 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 oc-curs 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 poten-tial also allows the development of resistance to antiviral agents [7,8].

EpidemiologyHepatitis B affects approximately 350 million peo-

ple worldwide and is associated with high mortality and morbidity [9,10]. Deaths from cirrhosis and hepatocellu-lar carcinoma were estimated at 310,000 and 340,000 per



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year, respectively [1].

Apart from major liver complications, clinical evi-dence 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 indi-vidual estimated glomerular filtration rate declined by ap-proximately 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 Pa-rameters 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 indi-cated 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 substan-tial decrease in the incidence of HBV infection in hae-modialysis 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 equip-ment, frequent breaching of skin, immunodeficiency, and

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 transmis-sion within haemodialysis units [17].

Hepatitis B Infection as a Risk Factor for Chronic Kidney Disease

HBV can cause CKD directly through immunologi-cal mechanisms or indirectly through metabolic compli-cations. HBV has been implicated in the genesis of pol-yarteritis 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 glo-meruli.

In polyarteritis nodosa, a medium-sized vessel vas-culitis, antibody-antigen complexes are deposited in ves-sel walls [9]. In membranous nephropathy, it has been proposed that deposition of HBeAg and anti-HBe anti-body forms the classic subepithelial immune deposits [2]. Both HBsAg and HBeAg have been implicated in mem-branoproliferative 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 es-tablished 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 in-fection, an elevated serum creatinine at baseline was sig-nificantly 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 infec-tion 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 InfectionThe diagnosis of hepatitis B relies on serological test-

ing. 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) pro-

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 pa-tient is aHBc IgM positive, then this exposure was within the last 6 months. On the other hand, if aHBc IgG is pre-sent, it is taken as evidence that the HBV exposure was >6 months ago [19].

The HBV surface antigen (HBsAg) is a marker of cur-rent infection, and in combination with aHBc IgM indi-cates 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 an-tigen 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 se-quencing for mutations, and HBV genotyping. DNA se-quencing is generally used to look for mutations that confer resistance to oral antiviral agents, but is occasion-ally 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 progres-sion and potential for response to different antiviral thera-pies [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 com-plications of chronic hepatitis B infection, such as portal hypertension and hepatocellular carcinoma [19,20].

TherapyCurrent Therapies of Hepatitis BSeven drugs have received approval for the treatment

of chronic HBV infection, including interferon-α, PE-Gylated interferon-α, the nucleoside analogues lamivu-dine, telbivudine and entecavir, and the nucleotide ana-logues, adefovir and tenofovir, referred to as a group as NAs.

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 oc-cur 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/ tenofo-vir 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 pol-ymerase will allow the eventual emergence resistant spe-cies unless viral replication is fully suppressed.

In terms of potency, entecavir, telbivudine, and ten-ofovir 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, tel-



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bivudine, and lamivudine, in that order [9].

Interferon-αInterferon-α, an antiproliferative and immunomod-

ulatory agent, was the first available antiviral drug for chronic HBV infection. This agent is metabolized by re-nal 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 ad-verse 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 alo-pecia [21]. Therefore, interferon-α is poorly tolerated by dialysis patients who have a frequent occurrence of side-effects, 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 with-drawal of the drug was required in more than 50% of pa-tients [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 pa-tients with HBV infection.

LamivudineLamivudine was the first nucleoside analogue antivi-

ral approved worldwide for the treatment of chronic hepa-titis B. Its major advantages include ease of administration (oral), potent antiviral activity, and favourable safety pro-file. 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 dipivoxilAdefovir dipivoxil, a nucleotide analogue, is the sec-

ond 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 adjust-ment is required in CKD patients to prevent drug accu-mulation and toxicities [27].

TelbivudineTelbivudine is a synthetic thymidine nucleoside ana-

logue that inhibits HBV DNA polymerase [32], and pro-vides effective and sustained viral suppression [33]. In clinical trials, telbivudine has been superior to lamivu-dine in HBV patients in terms of treatment outcomes and HBV DNA suppression [33,34]. When compared with lamivudine, telbivudine has greater HBVDNA suppres-sion, and HBeAg seroconversion rates are significantly greater with telbivudine than with lamivudine [35]. In addition, telbivudine-treated subjects are less likely to de-velop 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 telbivu-dine therapy.

EntecavirEntecavir is a nucleoside analogue drug that has selec-

tive anti-HBV activity. The incidence of entecavir resist-ance appears to be minimal, only about 1% after 3 years of monotherapy [37]. Entecavir is effective in viral sup-pression [38,39]. In addition, entecavir is more potent at suppressing HBV replication than lamivudine and adefo-vir [21]. Although there is little information on the thera-peutic 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 en-tecavir is primarily eliminated by the kidneys, dose reduc-tion is recommended for patients with reduced GFR [40]. Moreover, the drug should be administered after haemo-dialysis. Continuous ambulatory peritoneal dialysis can remove approximately 0.3% of the dose over 7 days. En-tecavir should be administered on an empty stomach (at least 2 hours after a meal or 2 hours before the next meal).

TenofovirThe 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 FunctionNucleoside and nucleotide analogues are primarily

eliminated without changes in the urine following inges-tion, and appropriate dose modifications are recommend-ed for patients with impaired renal function (GFR < 50 mL/min). Treatment guidelines recommend that all pa-tients 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 con-trolled hypertension, proteinuria, uncontrolled diabe-tes, active glomerulonephritis, concomitant nephrotoxic medications and solid organ transplantation. In conse-quence, 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 im-prove 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-

function in entecavir-treated patients, its clinical signifi-cance 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 cre-atinine and estimated creatinine clearance. For adenovir- or 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 per-formed 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 moni-toring 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 VaccinationHBV vaccination represents one of the most impor-

tant measures in the prevention of nosocomial transmis-sion of HBV infection within a dialysis unit, especially in endemic areas. Unfortunately, despite the high serocon-version rate of more 95% in general population, the sero-conversion rate obtained using current HBV vaccination



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strategies in dialysis patients remains relatively low. With conventional intramuscular (i.m.) vaccination, only 50-73% of dialysis patientsdevelop protective levels of anti-hepatitis B surface antibodies (aHBs) [54,55]. In addition, the antibody response in patients with end-stage renal dis-ease (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 im-prove the response rate to HBV vaccination in dialysis pa-tients. These include increasing the dose and frequency of vaccination, using analternative route of administration, use ofadjuvants and the development of novel immuno-genic 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 chang-ing the dose, frequency and route of vaccine administra-tion 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 conven-tional 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 dysfunc-tional antigen presentation associated with uraemia and

enhance T and B lymphocytes responses. To date, the re-sults 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 prob-ably could only be achieved with high individual and cu-mulative doses. For example, by using an individual dose of 5.0 µg and a mean cumulative dose 40-57.3 µg, i.d. ad-ministration 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 be-cause of the presence of immunologic memory, a booster dose of vaccine is generally recommended for dialysis patients due to their immunosuppressive state, poor re-sponses 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 PatientsPrevention of HBV transmission is a key considera-

tion 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 vac-cination 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 re-sponse, 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 param-eters may affect the clinical and laboratory presentation and course of chronic HBV infection and the patients’ re-sponse to antiviral therapy.

The optimal therapy for chronic HBV infection in pa-tients on haemodialysis depends on the clinical picture. If patients have advanced liver disease or chronic HBV

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 ex-perience in this patient group comes mostly from treat-ment 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 haemodi-alysis patients that suggest they are safe and potent anti-virals. 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 im-proved 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 hae-modialysis and/or candidates for renal transplantation [69,70]. As long-term entecavir therapy is not recom-mended in patients with lamivudine resistance, tenofovir may be required in such cases, although caution should



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be exercised and doses should be appropriately adjusted in patients with estimated glomerular filtration rates <50 ml/min [72-75].

Transplant PatientsCandidates for Renal TransplantationHBsAg-positive patients with cirrhosis and end-stage

renal disease are at risk for hepatic decompensation after isolated renal transplantation, and may require consid-eration for simultaneous liver and kidney transplantation [99,76,77]. According to the current guidelines, all HB-sAg-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 tim-ing 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 wait-ing time on hemodialysis [77,78].

HBV-Positive Renal Transplant RecipientsIFN-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 applica-

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 inhibi-tion 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 histo-logical severity and serum HBV DNA level, because im-munosuppressive 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 exacerba-tion can be used, but it is a less effective approach com-pared with pre-emptive NA therapy and confers excessive risk to patients. Treatment with a NA should usually con-tinue 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-nega-tive, anti-HBc-positive transplant recipients is debatable. If the decision is made not to place this group on prophy-lactic therapy, then ongoing monitoring is necessary to



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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 rec-ommended [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 trans-plant 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 dete-rioration 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 with-out changes in serum creatinine levels after 12 months of therapy [82].

HBV-Positive Renal Transplant DonorsKidneys from HBsAg-positive donors are not pro-

moted for renal transplantation, because they have the potential to transmit HBV to the recipient [83]. Never-theless, the fundamental need for donor pool expan-sion urged some transplant centres to use kidneys from

HBs-Ag positive, or anti HBc-positive/HBsAg negative donors to HBsAg-positive and -negative transplant recipi-ents [83,84]. Indeed, there are reports for safe and effective lamivudine prophylaxis in HBsAg-negative transplant re-cipients 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 immuno-suppressive 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 in-fection 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 pa-tients. 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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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 con-tains murine heavy and light chain variable regions di-rected 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 non-Hodgkin’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 solu-ble forms. Following treatment with rituximab, B cells are prevented from proliferating, and undergo apoptosis and lysis through complement-dependent and complement-independent mechanisms. These mechanisms include complement-dependent cytotoxicity, antibody-depend-ent 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 rituxi-mab and the Fcgr3a genotype indicates that antibody-de-pendent cell cytotoxicity is crucial; however, prolonging the ‘off rate’ of the monoclonal antibody seems to increase complement-dependent cytotoxicity and therapeutic effi-cacy, indicating that complement-dependent mechanisms

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 us-ing 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 rituxi-mab in CKD patients.

Prevention of Transmission of Hepatitis B within Dialysis UnitsInfection control precautions for dialysis services are

more stringent than standard precautions and are de-signed to prevent transmission of blood borne viruses and bacterial pathogens including Multi-Resistant Or-ganisms (MRO), in dialysis settings. They include all the components of standard precautions as well as routine se-rological testing, hepatitis B vaccination, surveillance for infections, additional cleaning procedures and the man-agement of equipment, medications and consumables.

To prevent the transmission of HBV, dialysis services should institute a comprehensive blood borne virus pre-vention plan, including a high level of compliance with BBV serological testing and HBV vaccination. The criteria for separating HBsAg reactive patients undergoing perito-neal dialysis should be the same as those undergoing hae-modialysis since peritoneal fluid can contain high levels of HBV and should managed in the same manner as the



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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 man-aging 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 ma-chines.

• Patients with aHBs greater than 10 IU/L may un-dergo 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 dia-lysed, the room/ area may be used for uninfected patients after cleaning and disinfection.

• 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 pos-sible, the machine should be disinfected using con-ventional 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 gen-eral use after standard cleaning and disinfection pro-cedures 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 dur-ing patient change-over).

• Staff members can care for HBsAg-reactive and patients with aHBs titre greater than 10 IU/L dur-ing the same shift.

• If dialysis staff members must bare for both HBV-positive 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 be-tween patients



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ConclusionThe primary effort for HBV eradication and thus re-

duction of HBV-associated kidney disease is based on global HBV immunisation and appropriate screening pro-grams. 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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