Hepatitis B Annual
Home

Current Issue  

Back Issues   

Instructions   

Search Login    Users online: 255 Print this page  Email this page Small font sizeDefault font sizeIncrease font size 
>>> Ahead of Print <<<


 
REVIEW ARTICLE Table of Contents   
Year : 2006  |  Volume : 3  |  Issue : 1  |  Page : 76-105
Management of chronic hepatitis B infection in patients with end-stage renal disease and dialysis


Division of Nephrology, Department of Medicine and Geriatrics, Kwong Wah Hospital, Hong Kong SAR, China

Click here for correspondence address and email
 

   Abstract 

Chronic hepatitis B virus (HBV) infection is an important issue among dialysis patients. It could result in nosocomial transmission and infection outbreaks in dialysis units. Vaccination, in addition to universal precautions, regular virologic screening and segregation policy, appear to be of paramount importance in the effective control of HBV infection in a hemodialysis unit, especially in view of the recent discovery of occult hepatitis B infection. Apart from infection control considerations, chronic HBV infection also poses particular problems to dialysis patients in terms of diagnosis and treatment of hepatic complications and pre-transplant management. This review summarizes the recent knowledge and understanding regarding the natural history, clinical presentation and outcome of chronic hepatitis infection in uremic patients and limitations of various existing diagnostic measures in the management of hepatic complications. It seems that chronic HBV infection is associated with high risk of hepatic complications in uremic individuals. Biochemical markers and HBV DNA are, however, inconclusive and liver biopsy remains the only definitive means to establish the activity of liver disease in dialysis patients. In this review, we propose an algorithm for approaching this group of patients and discuss the indications of liver biopsy, options of anti-viral therapy and pre-transplant workup in dialysis patients with chronic hepatitis B infection.

How to cite this article:
Wong PN, Mak SK, Wong AK. Management of chronic hepatitis B infection in patients with end-stage renal disease and dialysis. Hep B Annual 2006;3:76-105

How to cite this URL:
Wong PN, Mak SK, Wong AK. Management of chronic hepatitis B infection in patients with end-stage renal disease and dialysis. Hep B Annual [serial online] 2006 [cited 2019 Nov 21];3:76-105. Available from: http://www.hepatitisbannual.org/text.asp?2006/3/1/76/32774



   Introduction Top


Since its discovery in 1965 known as 'Australian antigen,' hepatitis B virus (HBV) infection has been a worldwide health problem.[1] It is associated with many serious manifestations and complications including acute and chronic hepatitis, cirrhosis, hepatocellular carcinoma (HCC) and hepatic failure. For patients on dialysis, HBV infection represents an exceptional threat. In the past, it has caused major outbreaks with horizontal viral transmission within dialysis units involving patients and clinical staff. Although the situation has improved in developed countries, HBV infection remains highly prevalent in dialysis units of many developing countries. Besides, the clinical course and presentation of dialysis patients with HBV infection are distinguished from non-dialysis patients and there are uncertainties with regard to the efficacy and long-term outcomes of treatment with currently available antiviral agents. Other than that, the preparation for renal transplantation in dialysis patients with chronic HBV infection also deserves special attention.


   Epidemiology Top


It is estimated that more than 350 million people are infected with HBV worldwide.[2] Among all, 75% of them are from Asia, of which about 40 million people are from India.[3],[4] Within the Asia-pacific region, the prevalence varies from 2.8% in Korea to 20% in Taiwan and Vietnam.[5] Indeed, hepatitis B surface antigen (HBsAg) positivity rate in dialysis patients also mirror the local endemicity in the general population of the region. For examples, HBsAg positivity rates among dialysis patients range from 0.9% in United States, 1.6% in Japan, 10% in Brazil, 10% in Hong Kong, 11.8% in Saudi Arabia, to 16.8% in Taiwan. [6],[7],[8],[9],[10],[11] In general, the overall incidence of HBV infection in dialysis patients is decreasing over the years, consequent to routine screening of blood products for HBsAg and anti-hepatitis B core (anti-HBc) antibody, advent of recombinant human erythropoietin, HBV vaccination and implementation of infection control measures


   Preventive measures Top


HBV is transmitted through blood and body fluids including semen, saliva, sweat, tears or even breast milk. Therefore, blood transfusions, sexual contacts and needle stick injury are the major modes of transmission. In addition, vertical transmission during pregnancy also represents another important mode of transmission in endemic regions such as Asia.

HBV is highly infectious. The concentration of viral particles in an infected patient is much higher than its hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infected counterparts. The virus is relatively stable in the environment and rather resistant to heat and chemical disinfectants. It could remain viable for at least 7 days on environmental surfaces at room temperature.[12] Being a blood handling procedure, hemodialysis, therefore, poses an exceptional risk to dialysis patients as well as clinical staff in terms of nosocomial transmission of HBV. The patients could acquire the infection through injections of contaminated material, having mucosal membrane or breached skin exposed to infective material or being dialyzed with contaminated equipment. Indeed, HBsAg had been detected on various environmental surfaces such as clamps, scissors, doorknobs and dialysis machine control knobs in dialysis centers with HBsAg positive patients.[12],[13] HBV DNA had been detected even in the dialysate and ultrafiltrate of those HBsAg positive undergoing high-flux hemodialysis, although the quantity was small and the clinical significance is unknown.[14]

By contrast, patients on peritoneal dialysis were reported to have a lower prevalence of HBV infection as compared with their hemodialysis counterparts. Before routine viral screening of blood donors and the advent of recombinant human erythropoietin, blood transfusions had represented another common mode of viral transmission among dialysis patients requiring blood transfusions. In order to prevent the occurrence of nosocomial HBV transmission, it is recommended that there should be regular screening of HBsAg screening of patients, routine viral screening of blood donors and strict adherence of universal precautions as promulgated by Centers for Disease Control and Prevention (CDC) of the United States, which include hand washing after handling blood or body fluids, use of protective barriers such as gloves, gowns, masks and protective eyewear or face fields when exposure is anticipated.[15] Reuse of dialyzers and blood lines should be avoided as far as possible.[8] In fact, in view of the recent findings of occult HBV infection in some patients without serological markers of infection, in whom HBV genomes are detectable in their serum, liver and peripheral blood mononuclear cells (PMNC) of patients, a strict adherence and enforcement of universal precautions seems particularly important in this regard.[16],[17],[18] In addition, HBsAg seroclearance does not necessarily mean complete eradication of virus even in non-dialysis patients. In a study, 37% of this kind of patients was found to be positive for intrahepatic DNA, with the majority (71-100%) in the form of cccDNA.[19]

Apart from that, in order to minimize potential cross contamination of equipments via clinical staff, segregation policy should also be considered for HBsAg positive patients during hemodialysis. There should be no sharing of supplies, vials, medications, instruments and even ancillary items such as clamps, scissors, blood pressure cuffs and other non-disposable items. Previous studies, indeed, showed that non-separation of infected from non-infected patients was associated with an increased risk of infection while segregation has been shown to be effective in reducing HBV transmission with dialysis centers.[20] Lastly, the role of active vaccination could not be overemphasized.


   HBV vaccination Top


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 by the current HBV vaccines among dialysis patients remains relatively low and far from satisfactory. By conventional intramuscular (i.m.) route, only about 50-73% of dialysis patients could develop sufficient anti-hepatitis B surface antibodies (anti-HBs) after vaccination.[21],[22] Apart from that, the antibody response in patients with end-stage renal disease (ESRD) also tends to be short-lived, in which 23-57% of responder patients had the antibodies become undetectable within 6-12 months.[23],[24] Various strategies have been developed to improve the response rate to HBV vaccination in dialysis patients, which include increasing the dose and frequency of vaccination, alternative route of administration, addition of adjuvants and the development of novel immunogenic vaccines.[25],[26],[27],[28] In general, there are only few studies on last two strategies and the results remain preliminary and have not yet been conclusive. On the other hand, there are many studies on changing the dose, frequency and route of vaccine administration. Indeed, it is recommended that an augmented regimen with the vaccine delivered in a four-dose schedule, 40 g per dose given at 0, 1, 2, 6 months, instead of conventional 3-dose schedule, 20 g per dose given at 0, 1, 6 months, should be administered for patients with end-stage renal disease.[22] Nevertheless, the superiority of this regimen has not yet been confirmed and even has been disputed by some clinical studies.[28],[29] Alternatively, there are also many studies on intradermal (i.d.) administration of the vaccine. It has been suggested that by activating epidermal Langerhan cells and keeping the antigen in the tissue for longer time, intradermal administration might reverse the dysfunctional antigen presentation associated with uremia and facilitate antigen presentation leading to enhanced T and B lymphocytes responses. By far, the results of these studies have been mixed and the efficacy of intradermal hepatitis B vaccination remains very controversial.[30],[31],[32] 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 g and a mean cumulative dose 40-57.3 g, i.d. administration was no better than i.m. vaccination. Another study on dialysis patients comparing 20 g i.d. with 40 g i.m, both given for three doses, also showed no difference in the anti-HBsAb seroconversion rate.[33] In contrast, with an individual dose of 20 g and cumulative dose of 100 g, Propst et al[34] showed that i.d. vaccination was superior to i.m. administration with four dose-dose schedule (40 g/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.[22] 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 kidney disease, the higher the glomerular filtration rate; the better the response to HBV vaccination,[35] it would be highly recommended to consider vaccinating all HBV non-immune patients once they are diagnosed to have renal disease or implementing universal vaccination in endemic areas.

Natural history, clinical presentations and outcomes of HBV disease in dialysis patients

HBV is not a cytopathic virus under normal situation and hepatitis is caused by the host's immune reaction mounted against infected hepatocytes. Only in an exceptional circumstance where the host immunity is severely depressed such as transplant recipients taking immunosuppressant or untreated HIV infected patients, there could be a fatal condition called fibrosing cholestatic hepatitis (FCH), in which unchecked viral replication leads to a extremely high viral load and cytopathic hepatic damage. Uremia is associated with various immune defects in vivo and in vitro such as depressed peripheral lymphocyte count, impaired granulocyte phagocytic ability, monocyte dysfunction and T cell pre-activation, especially in hemodialysis patients who have repeated exposure of their blood to dialysis membranes.[36],[37],[38] Besides, uremic patients are also susceptible to various co-morbidities such as malnutrition, hyperparathyroidism, anemia and vascular disease. With all these abnormalities, on one hand, uremia is associated with elevated inflammatory markers such as C-reactive protein and a chronic inflammatory state which might predispose to the development of accelerated atherosclerosis and cardiovascular disease.[39],[40] On the other hand, uremia is also an immunocompromized state, which is associated with impaired immune responses and increased susceptibility to infection, cutaneous anergy, prolonged survival of skin grafts and suboptimal response to vaccination.[37],[41] Indeed, FCH-like condition due to unchecked viral replication has been reported in an otherwise non-immunosuppressed hemodialysis patient suffering from chronic hepatitis B infection.[42] It is therefore not surprising that, in contrast to normal adults, acute HBV infection in dialysis patients is often mild or asymptomatic and upto 72% of these patients might become chronic carriers due to impaired viral clearance,[43],[44],[45],[46] which is much higher than the 3-5% of normal adults and is comparable to the extremely high rate of 90% reported in neonates and children below 1 year of age.[47]

Chronic hepatitis, cirrhosis and HCC are the major complications of concern in patients with chronic hepatitis B and it is estimated that 15-40% of HBV carriers would develop serious sequelae during their lifetime. In India, HBV infection has contributed to 70% of chronic hepatitis, 80% of cirrhosis and 60% of HCC.

While chronic hepatitis, cirrhosis and HCC remain major complications commonly encountered in hepatitis B infected dialysis patients, study on the natural history and histological progress of chronic hepatitis B liver disease in this group of patients is scarce. There is only one histological study in the literature.[46] The study was performed on 51 HBsAg positive hemodialysis patients, who acquired the HBV infection after receiving dialysis, of whom 37 (72%) developed biopsy-proven chronic hepatitis over 8 years of follow-up. Of these 37 patients, 25 (49%) had chronic active hepatitis (CAH), in which four patients actually had chronic persistent hepatitis and lobular in the initial biopsies and progressed to CAH subsequently. The symptoms of these 25 CAH patients were mild with only asthenia, abdominal pain and nausea noted. In addition, liver cell necrosis and inflammatory infiltration in the histology were remarkably mild and the increases in serum transaminase levels were relatively modest. On the other hand, fibrosis was rather extensive.

From this histological study, it seems that HBsAg positive dialysis patients are at a high risk of developing active progressive liver disease. At the same time, the disease tends to run a distinct clinical course in which the liver disease could progress with a relatively less pronounced degree of hepatic inflammation.[48] Indeed, a recent multi-center study also found that dialysis patients was at a higher risk of developing liver cancer as compared with the general population.[49]

However, the survival data are conflicting. Some studies from the United States did not reveal any difference in the mortality between HBsAg positive and negative dialysis patients, whereas a retrospective study performed in India reported a higher mortality among hepatitis B positive dialysis patients compared with HBsAg negative dialysis patients.[44],[50],[51] It is possibly because majority of the patients from the United States acquired the hepatitis B infection after receiving dialysis and hence, their follow-up periods were relatively short. Given the multiple co-morbidities commonly encountered in dialysis patients, the time interval for the development of HBV related hepatic complications might therefore exceed the life expectancy of many of the dialysis patients. The impact of HBV infection may therefore come only after the development of advanced complications such as liver cirrhosis, in which case it was then associated with 35% increase in patient mortality.[52]

Chronic hepatitis B infection is associated with the development of severe hepatic complications including CAH, cirrhosis and HCC. As previous studies had showed that CAH (chronic hepatitis with portal and periportal lesions), especially in the presence of repeated episodes of acute exacerbation, is associated with increased risk of cirrhosis and HCC,[53],[54] early identification of patients with CAH who require antiviral treatment or surgery has become one of the key issues in the management of chronic hepatitis B infection. On the other hand, progression to cirrhosis can be rather silent and could still occur in the absence of obvious active hepatitis. In some situation, cirrhosis and HCC may develop even after complete seroclearance of HBV viral markers.[55] In this context, it is recommended that a follow-up protocol should include detailed history taking, thorough physical examination and regular laboratory investigations such as liver function tests, complete blood counts, prothrombin time, alpha-fetal protein and yearly liver ultrasound. Nevertheless, even with all these things, early identification of high-risk patients, especially in dialysis patients, remains a big challenge due to the following limitations and considerations.

Liver enzymes

While liver biopsy remains the gold standard in establishing the diagnosis and the assessment of hepatic damage in patients suffering liver disease, it is an invasive procedure carrying significant risk of mortality and morbidity especially for patients with bleeding tendency such as dialysis patients who are known to have uremic state related platelet dysfunction. Therefore, based on previous studies which demonstrated a significant association between serum hepatic transaminase levels and hepatic inflammation shown in histology, biochemical parameters including alanine aminotransferase (ALT) and aspartate aminotransferase (AST) have long been playing a major role serving as non-invasive surrogate parameters to reflect the activity and severity of liver disease in patients with HBV infection. Indeed, these biochemical parameters are very often the key factors to be considered before initiation of anti-viral treatment.[56],[57],[58] The relationship between these biochemical parameters and hepatic activity is far from perfect. The hepatic transaminase levels of normal individuals vary with their body mass index, gender and other factors. Moreover, the serum ALT levels are erratic in patients with HBeAg negative chronic hepatitis. Even a normal ALT level does not necessarily mean that there is no underlying hepatic inflammation. In fact, a recent study done in China on 183 HBsAg-positive patients with persistently normal ALT levels showed greater than grade 2 inflammation in 40% and greater than grade 2 fibrosis in 35% of patients, respectively.[59] Another recent longitudinal study also showed that chronic hepatitis B patients with serum ALT >0.5 times of ULN were at a increased risk of developing hepatic complications as compared with those patients with ALT value <0.5 times the upper limit of normal (ULN).[60] The issue is even more complicated in patients with end-stage renal disease. First, for unknown reasons, the serum transaminase levels of uremic patients are lower than normal population. It has been postulated that it could be due to reduction in pyridoxal-5-phosphate (a coenzyme of transaminases), the presence of UV-absorbing materials, suppression of ALT synthesis and release into the blood stream in hepatocytes and accelerated clearance from serum. For this reason, it has been suggested that the upper limits of normal for AST and ALT should be decreased to 24 IU/L and 17 IU/L instead of 40 IU/L in uremic patients.[61],[62],[63] Apart from that, the interpretation of serum alkaline phosphate level could be complicated by the presence of secondary hyperparathyroidism. Second, the hepatic inflammation in dialysis patients with progressive liver disease also appears less intense and relatively modest as compared with their non-uremic counterparts. Third, undulating transaminase levels, in association with possible fluctuation in viral loads and differential virulence of HBV strains, further hamper a proper interpretation of serum transaminases in the assessment of underlying activity and severity of hepatic disease. Therefore, although the positive relationship between HBsAg positivity and serum transaminase activities still exist in dialysis patients, interpretation of these biochemical parameters in uremic patients have to be made in accordance with adjusted normal ranges and with reference to the overall clinical condition and results of other investigations.[64]

Serum HBV DNA level

A persistently positive HBV DNA level has been shown to be associated with higher aminotransferase activities as compared with intermittently HBV DNA positive or persistently HBV negative states[50] and an arbitrary HBV DNA level of >10 5 copies/mL was chosen as a diagnostic criterion for chronic hepatitis B for the initiation of treatment at a recent National Institutes of Health conference in United States. However, the optimal cutoff value of HBV DNA level for starting treatment remains controversial and largely unknown. Indeed, a strict adoption of this criterion might exclude some patients who might otherwise benefit from the treatment. It is especially a concern in patients suffering from HBeAg-negative chronic hepatitis and those receiving dialysis, as these two groups of patients have been observed to have fluctuating HBV DNA levels during serial blood monitoring, in which the levels might occasionally fall below this arbitrarily defined cutoff value.[65] In addition, although it is intuitively thought that dialysis patients might be predisposed to unchecked HBV viral replication and higher viral load due to their immuno-suppressed states as compared with normal individuals, this assumption has been disputed by a recent study by Fabrizi

et al.
[25] who serially monitored the HBV DNA levels of 29 HBsAg positive dialysis patients using a highly sensitive polymerase chain reaction (PCR)-based assays. In the study, the authors noticed three distinct patterns, namely persistent HBV DNA, intermittent HBV DNA and persistently HBV DNA negative, in which the overall viral load was not particularly high and their median HBV DNA level at study entry was only 4.0910 2 copies/mL.[66] While the exact reasons behind these observations remain unknown, they could be related to the passage of HBV viral genome into the dialysate effluent during peritoneal dialysis and hemodialysis and decreased clearance of interferon activity in the uremic population.[14],[67],[68]

PCR-based assays, the clinical use and interpretation of HBV DNA levels become even more complex and challenging due to additional technical issues such as limited dynamic ranges of quantification and different expression of results of various assays.[69] After all, it remains very difficult to predict the severity and outcome of liver disease based on the HBV DNA level per se .[70]

Liver biopsy

Liver biopsy allows a direct assessment of the degree of liver damage in patients with chronic hepatitis B infection. Apart from assessing the degree of liver damage, liver biopsy could also be used for immunohistochemical staining for HBsAg and hepatitis B core antigen and could be of help in ruling out alternative diagnosis and predicting prognosis.

Depending on the histological findings, the estimated 5-year survival rates were found to be 97% for patients with chronic persistent hepatitis, 86% for those with CAH and 55% for those with CAH with cirrhosis.[71] For patients with compensated cirrhosis, the survival was 84% at 5 years and 68% at 10 years, with active HBV replication, age, poor hepatic reserve and established portal hypertension being the poor prognostic indicators.[72] For patients with decompensated cirrhosis, 5-year survival was only 14%.[73] Nevertheless, the histology might change spontaneously and after treatment.

In view of the aforementioned limitations in using serum biochemical markers and HBV DNA as monitoring tools, liver biopsy appears to be the only definitive and reliable means to establish the activity of liver disease in dialysis patients and it is highly recommended before starting anti-viral therapy and undergoing kidney transplantation


   Treatment of chronic HBV infection Top


Selection of candidates indicated for anti-viral treatments

In an ideal situation, the primary goal of treatment should be complete eradication of the virus. However, it is rarely achieved in real life due to the persistence of covalently closed circular DNA (ccc DNA), a replication immediate of HBV, in the hepatic nuclei, which is difficult to be eradicated and is not targeted by the currently available anti-viral agents. Therefore, a pragmatic approach is to suppress HBV replication with anti-viral therapy in order to prevent the development of complications such as cirrhosis and HCC. In the event of advanced liver disease, liver transplantation should then be considered. Nevertheless, all the available therapies including interferon-a, nucleoside or nucleotide analogues are not ideal and each individual therapy is limited by its own efficacy, adverse effects, emergence of resistance and the cost of treatment. Therefore, before deciding on the candidacy of an individual patient with regard to anti-viral treatment, one should balance the pros and cons, including the treatment cost. As previous studies have showed that satisfactory responses to current anti-viral therapies were observed only in patients with certain well-defined clinical characteristics, the decision to start is, therefore, relying on the demonstrations of active viral replication (HBeAg and/or serum HBV DNA detectable by branched DNA or hybrid capture assays) and active liver disease (elevated serum ALT concentrations >1.5 times ULN and/or evidence of moderate/severe chronic hepatitis on liver biopsy).[74]

Nevertheless, as mentioned before, dialysis patients are used to have depressed baseline serum ALT levels and their serum ALT levels could remain normal despite the presence of significant liver disease. The conventional cut-off value with serum ALT level >1.5 times ULN therefore might prove too high and not sensitive enough for the identification of HBV infected dialysis patients with significant hepatic inflammation who otherwise warrant anti-viral treatment. As such, it has been suggested that if a dialysis patient with chronic HBV infection has otherwise unexplained elevation in serum ALT level persistently above 30 IU/L or 0.75 times ULN or if the serum ALT level does not reach that level but there is clinical evidence of progressive liver disease, significant hepatic inflammation should be suspected and liver biopsy should be considered.[75]

Choice of therapy

While many anti-viral agents have been shown to be effective among general population in terms of normalization of serum ALT level, suppression of HBV DNA, HBeAg seroconversion and improvement in liver histology, data in dialysis patients remains scarce.[70]

Interferon-α

It is an antiviral, anti-proliferative and immunomodulatory glycoprotein. When it is given in a dose of 5-10 MU subcutaneous thrice weekly in patients with a serum ALT level three times of ULN, HBsAg and HBeAg seroconversion could be achieved in 10% and 30-40% of patients, respectively after 6 months of therapy. However, it is contraindicated in patients with significant liver cirrhosis and it has so far little role in treating patients with ESRD. First, possibly because of drug accumulation as a result of decreased metabolism of interferon-α by renal tubules in uremic patients, side effects such as flu-like symptoms, neutropenia, thrombocytopenia, neuropsychiatric symptoms, anaemia and malnutrition commonly occur and have led to cessation of therapy in more than 50% of patients in one study.[68] Second, there are very little data, in which there was only one anecdotal report on two patients about the efficacy of this drug in treating dialysis patients. In fact, given the fact that the overall efficacy of interferon-a is highly dependent on the activity of liver disease as reflected by the serum ALT level and histological findings, it is doubtful whether reasonable response could be achieved in dialysis patients who have relatively modest serum ALT levels and histological inflammatory activities. Nevertheless, with the recent advent of pegylated forms of interferon (PEG-IFN), especially PEG-IFN-α2a, a preparation mostly excreted by hepatic route with a larger molecular weight, a lower volume of distribution and longer half-life as compared with conventional non-pegylated form, the scenario might change and this new form of interferon might possibly play a more important role in treating HBV infected dialysis patient in the future. While being used in patients with ESRD, there is less fluctuation in serum level, less drug accumulation and better tolerability.[76] Besides, there is also improvement in the clinical efficacy. The combined treatment response rate (HBeAg loss, HBV DNA <500,000 copies/mL, ALT normalization) is increased to 24% as compared with 12% in conventional interferon in general population.[77]

Nevertheless, HBV genotypes might affect the treatment response, in which among the eight identified HBV genotypes, genotypes A and B were associated with a higher HBeAg seroconversion rate as compared with genotypes C and D.[78] The local prevalence of individual genotype might affect the usefulness of this agent in different localities.


   Nucleoside and nucleotide analogues Top


Lamivudine

Lamivudine is a pyrimidine nucleoside analogue working as a HBV DNA polymerase inhibitor and it is effective in terms of suppression of HBV replication, ALT normalization and reduction in histologic necroinflammation in chronic hepatitis B infection. HBeAg seroconversion rate is 16-18% after 12 months of treatment and increase to 47% at 4 years. In 30-80% of them, the seroconversion could be sustained even after cessation of lamivudine.[70],[79],[80] The treatment response is, however, closely linked with patient's pretreatment serum ALT level. Patients with pre-treatment ALT level more than five times of ULN enjoyed the best 1-year HBeAg seroconversion rate while those with ALT level less that two times of ULN had the 1-year HBeAg seroconversion rate less than 10%.[81]

The efficacy of lamivudine in HBeAg negative patients has also been demonstrated in long-term studies. However, it is difficult to define treatment end-point in this group of patients and relapse is common after cessation of drug therapy.[82] A recent large randomized controlled study showed that lamivudine treatment could reduce disease progression in patients with chronic hepatitis B and advanced cirrhosis by decreasing the risk of hepatic decompensation and HCC.[83] Nevertheless, despite its promising short-term efficacy, the emergence of lamivudine resistant tyrosine, methionine, aspartate, aspartate (YMDD) variants after prolonged treatment, which has been observed 69% of patients after being treated for 5 years, is a major concern. Although most patients remaining on lamivudine treatment after the emergence of YMDD variants still have serum ALT and HBV DNA levels lower than pre-treatment levels, the rebound in viral replication sometimes lead to severe flares of hepatitis and hepatic decompensation.[84]

Lamivudine is a drug primarily excreted by renal route and is readily dialyzable by haemodialysis and peritoneal dialysis.[85] However, because of the large volume of distribution, only a small proportion of drug is removed during dialysis. Therefore, dialysis by itself has little impact on the overall dosing regimen although dosing after hemodialysis would be advisable.[86] When lamivudine is used for the treatment of HBV infection, the usual recommended dose is 100 mg daily. On the other hand, lamivudine has also been used in the treatment of HIV infection at a dose of 300 mg daily with minimal side effects. With such wide therapeutic window, it is therefore not surprising that although one-tenth of the normal dose is recommended in patients with ESRD, dosage much higher than this recommended level is also well tolerated. For example, no obvious adverse effects was observed in human immunodeficiency virus infected hemodialysis patients who received lamivudine 150 mg daily, six times the recommended renal dose, for several months.[86]

By far, there are only few studies on the use of lamivudine in the treatment of chronic hepatitis B in dialysis patients. All studies reported in the literature belong to case series and were of small sample size.[87],[88],[89],[90],[91] Various different dosages were used, ranging from 10 mg daily to 300 mg weekly. The baseline ALT levels of the involved patients were mostly above two times of ULN. The largest series involved 16 hemodialysis patients, who were treated with lamivuidine 300 mg per week. After 12 months of treatment, normalization of ALT and HBeAg loss were found in 94 and 38% of patients, respectively, with no significant side effects.[91]

From this limited data, lamivudine appears to be effective and well tolerated with little side effect in patients with advanced renal impairment. Nevertheless, there are still unresolved issues concerning overall effects and outcomes of lamivudine therapy and its relationship with ALT level in dialysis patients. In addition, the optimal dose of lamivudine in dialysis patients is also unknown. All these would require further study to clarify.

Adevofir dipivoxil

Adevofir dipivoxil, an oral prodrug of adefovir, is a nucleotide analogue of adenosine monophosphate inhibiting both HBV reverse transcriptase and DNA polymerase. Although it has demonstrated safety and efficacy in treatment-naοve and lamivudine-resistant chronic HBV infection and has been considered by some authors as an ideal first-line agent for patients with HBeAg-negative agent due to its low resistance rate, experience in using this drug in treating hepatitis B infection in dialysis patients remains very limited.[92] In addition, adevofir is associated with dose and treatment duration related nephrotoxicity. For example, proximal renal tubular nephropathy with increase in serum creatinine, decrease in serum phosphate, glycosuria or even Fanconi syndrome have been observed in 13, 27 and 50% of patients being treated with a daily dose of 30, 60 and 120 mg, respectively. By contrast, no renal toxicity was detected in patients receiving a lower dose at 10 mg daily after 1 year.[93],[94] However, little data are available on its impact on residual renal function in patients with advanced renal impairment. The exact mechanism of renal toxicity is not entirely clear. It is probably related to its effect in depleting mitochondrial DNA from proximal tubular cells resulting in acute tubular necrosis.[95] Due to the uncertain efficacy and possible renal toxicity, routine first-line use of this drug in dialysis patients, other than serving as a rescue therapy for lamivudine resistant cases, especially for those patients with significant residual renal function, could not be recommended at this moment.

Other new nucleoside and nucleotide analogues

There are new nucleoside and nucleotide analogous becoming available such as entecavir, telbivudine, tenofovir, which are more potent anti-viral agents with high resistance threshold. They have been tried in general population with promising results. However, no data are available in patients with ESRD or receiving dialysis.


   Pre -renal transplant preparation Top


HBsAg positive dialysis patients

Historically, HBsAg positivity has been a poor prognostic factor for renal transplant due to the common occurrence of hepatitis B reactivation post-transplant in 70-90% of patients related to the use of immunosuppressive agents.[96] The 10-year survival of HBsAg positive renal transplant patient was once reported to be only 55% as opposed to the 80% in HBsAg negative recipients.[97],[98] Nevertheless, thanks to the advent of effective anti-viral therapy, the scenario has changed.[99] Indeed, a recent study by Chan et al.[99] on the 11 HBsAg positive kidney recipients being treated with lamivudine pre-emptively according to HBV DNA levels reported a 5-year patient survival of 98% comparable to their HBsAg negative counterparts. However, the timing of starting treatment seems to be of paramount importance in determining the final outcome. First, it has been shown that early treatment is associated with better clinical outcome and lower risk of severe and irreversible liver damage due to HBV reactivation, which sometimes could be fatal.[100] Second, for patients receiving treatment with nucleoside or nucleotide analogues, the emergence of drug resistance is a major concern. Despite a lower susceptibility to the development, resistance to adefovir could still be observed in 5.9% of patients after 144 weeks of treatment.[101] As high pretreatment HBV DNA level has been found to be one of the major factors predisposing to the development of drug resistance in patients treated with lamivudine, it might be desirable to treat the patients early before the development of immunosuppressive therapy induced HBV viral replication and hepatitis reactivation.[102] In this regard, some authors actually suggest that anti-viral therapy such as lamivudine should be started preemptively immediately after transplantation regardless of the HBV DNA level or even before transplantation.[103],[104] Nevertheless, the appropriate timing in the latter situation, except for living related transplantation, would be difficult to determine without causing concern on the emergence of resistant mutants after prolonged use.

Without causing concern on the emergence of resistant mutants after prolonged use of resistant mutants. As such, an alternative approach would be to identify patients with significant liver disease and treat them before proceeding to transplantation. In fact, apart from suppression of hepatic inflammation and viral replication, lamivudine therapy could also reduce established fibrosis and prevent the progression of cirrhosis by allowing hepatocyte regeneration and collegen resorption in patients with cirrhosis. Therefore, in an ideal situation, it would be advisable to have all patients have liver biopsy done before renal transplantation so that patients indicated for anti-viral therapy could be duly identified and treated and combined liver-kidney transplant instead of isolated kidney transplantation could be considered in patients with advanced cirrhosis. However, in the event of a long waiting time for cadaveric transplantation, the optimal timing for this procedure would also be difficult to determine.

In this context, we have suggested the following algorithm in the management of hepatitis B dialysis awaiting kidney transplantation.[75]

1) All patients should be regularly monitored by detailed history, physical examination and screening investigations including blood tests and ultrasound as described in previous discussion.

2) Liver biopsy should be performed in the following situations to assess the liver condition and decide on the need of treatment:

a) if there is an otherwise unexplained elevation in serum ALT level of >30IU/L or 0.75 times ULN or

b) if there is any clinical, radiological or laboratory evidence of active liver disease even if serum ALT level is below 30IU/L or 0.75 times ULN or

c) if the patient is pending for a living related kidney transplant.

3) Give lamivudine therapy in an adjusted renal dose for patients with significant liver disease as shown in liver biopsy and consider deferring the operation or switching to combined liver-kidney transplantation in patients with advanced liver cirrhosis.

Dialysis patients with occult hepatitis B infection

With the advance of laboratory diagnosis and the advent of highly sensitive tests for HBV DNA, there is a recent recognition of occult hepatitis B infection, in which HBV infection persists in the absence of HBsAg positivity. The occurrence of viral DNA persistence has been found in HBsAg negative patients with or without detectable anti-HBc and anti-HBs. Studies on blood donors showed that the prevalence could range from 0 to 17%, higher in anti-HBc positive but anti-HBs negative individuals.[105] In hemodialysis, the reported prevalence of occult HBV infection varied from 0 to 58%, dependent on the local prevalence of HBV infection, past history of HBV infection and individual laboratory technique.[16],[17],[18] In this context, it seems prudent to consider a HBV DNA testing and/or liver biopsy in HBsAg negative patients with clinical evidence of active liver disease and hepatic inflammation before transplantation. On the other hand, viral DNA persistence in HBsAg negative patients with or without detectable anti-HBc and anti-HBs is usually associated a low level of HBV viremia and the overall risk of developing hepatic complications attributable to the persistence of this very low HBV multiplication per se remains low. However, there is still a residual risk of blood transfusion and organ transplant related hepatitis B infection in recipients of HBsAg-negative anti-HBc-positive donors.[105] In addition, in patients receiving renal transplants, it could sometimes result in major reactivation of HBV infection with reappearance of HBsAg in serum and clinical hepatitis.[96],[97] In this regard, dialysis patients on list for renal transplant and the kidney donor, who are negative for HBsAg and HBsAb should be tested for anti-hepatitis B core antibody, in which a positive finding would warrant a close monitoring for possible HBV reactivation or transmission after transplantation.


   Conclusions Top


Hepatitis B infection is a unique clinical issue in dialysis patients, in which the proper management necessitates special attention on various different aspects including prevention of nosocomial transmission, monitoring and treatment of liver disease and preparation for renal transplantation. Despite recent advances in the diagnosis and management of chronic hepatitis B infection among non-dialysis patients, little progress is made in these aspects among dialysis patients and leaving many questions remains unanswered. Additional studies are required to address all these issues. With a high prevalence of hepatitis B in certain locality and dialysis units, together with the recent discovery of occult hepatitis B infection, vaccination of non-immune clinical staff and renal patients preferably before the development of advanced renal failure appears particularly important in the control of HBV nosocomial transmission, in addition to the other infection control measures. After all, prevention remains the cornerstone of a successful management of chronic hepatitis B infection in this population.

 
   References Top

1.Blumberg BS, Alter HJ, Visnich S. A "new" antigen in leukemia sera. JAMA 1965;191:541-6.  Back to cited text no. 1    
2.Purcell RH. The discovery of the hepatitis viruses. Gastroenterology 1993;104:955-63.  Back to cited text no. 2    
3.Merican I, Guan R, Amarapuka D, Alexander MJ, Chutaputti A, Chien RN, et al . Chronic hepatitis B virus infection in Asian countries. J Gastroenterol Hepatol 2000;15:1356-61.  Back to cited text no. 3    
4.Tandon BN, Acharya SK, Tandon A. Epidemiology of hepatitis B virus infection in India. Gut 1996;38:S56-9.  Back to cited text no. 4    
5.Mohamed R, Desmond P, Suh DJ, Amarapurkar D, Gane E, Guangbi Y, et al . Practical difficulties in the management of hepatitis B in the Asia-Pacific region. J Gastroenterol Hepatol 2004;19:958-69.  Back to cited text no. 5    
6.Tokars JI, Finelli L, Alter MJ, Arduino MJ. National surveillance of dialysis-associated diseases in the United States, 2001. Semin Dial 2004;17:310-9.  Back to cited text no. 6    
7.Oguchi H, Miyasaka M, Tokunaga S, Hora K, Ichikawa S, Ochi T, et al . Hepatitis virus infection (HBV and HCV) in eleven Japanese hemodialysis units. Clin Nephrol 1992;38:36-43.  Back to cited text no. 7    
8.Carrilho FJ, Moraes CR, Pinho JR, Mello IM, Bertolini DA, Lemos MF, et al . Hepatitis B virus infection in Haemodialysis Centres from Santa Catarina State, Southern Brazil. Predictive risk factors for infection and molecular epidemiology. BMC Public Health 2004;4:13.  Back to cited text no. 8    
9.Leung CB, Ho YW, Chau KF, Choy BY, Tsang WK, Lui SF. Renal replacement therapy for chronic hepatitis B carrier: A subgroup analysis from the Hong Kong Renal Registry 1995-1999 Hong. Kong. J Nephrol 2000;2:104-9.  Back to cited text no. 9    
10.Almawi WY, Qadi AA, Tamim H, Ameen G, Bu-Ali A, Arrayid S, et al . Seroprevalence of hepatitis C virus and hepatitis B virus among dialysis patients in Bahrain and Saudi Arabia. Transplant Proc 2004;36:1824-6.  Back to cited text no. 10    
11.Chen KS, Lo SK, Lee N, Leu ML, Huang CC, Fang KM. Superinfection with hepatitis C virus in hemodialysis patients with hepatitis B surface antigenemia: Its prevalence and clinical significance in Taiwan. Nephron 1996;73:158-64.  Back to cited text no. 11    
12.Froio N, Nicastri E, Comandini UV, Cherubini C, Felicioni R, Solmone M, et al . Contamination by hepatitis B and C viruses in the dialysis setting. Am J Kidney Dis 2003;42:546-50.  Back to cited text no. 12    
13.Favero MS, Maynard JE, Petersen NJ, Boyer KM, Bond WW, Berquist KR, et al . Hepatitis-B antigen on environmental surfaces. Lancet 1973;22:1455.   Back to cited text no. 13    
14.Kroes AC, van Bommel EF, Niesters HG, Weimar W. Hepatitis B viral DNA detectable in dialysate. Nephron 1994;67:369.  Back to cited text no. 14    
15.Centers for Disease Control (CDC). Update: Universal precautions for prevention of transmission of human immunodeficiency virus, hepatitis B virus and other bloodborne pathogens in health-care settings. MMWR 1988;37:377-82.  Back to cited text no. 15    
16.Oesterreicher C, Hammer J, Koch U, Pfeffel F, Sunder-Plassmann G, Petermann D, et al . HBV and HCV genome in peripheral blood mononuclear cells in patients undergoing chronic hemodialysis. Kidney Int 1995;48:1967-71.  Back to cited text no. 16    
17.Cabrerizo M, Bartolom J, Caramelo C, Barril G, Carreno V. Molecular analysis of hepatitis B virus DNA in serum and peripheral blood mononuclear cells from hepatitis B surface antigen-negative cases. Hepatology 2000;32:116-23.  Back to cited text no. 17    
18.Minuk GY, Sun DF, Greenberg R, Zhang M, Hawkins K, Uhanova J, et al . Occult hepatitis B virus infection in a North American adult hemodialysis patient population. Hepatology 2004;40:1072-7.  Back to cited text no. 18    
19.Yuen MF, Wong DK, Sablon E, Tse E, Ng IO, Yuan HJ, et al . HBsAg seroclearance in chronic hepatitis B in the Chinese: Virological, histological and clinical aspects. Hepatology 2004;39:1694-701.  Back to cited text no. 19    
20.Alter MJ, Favero MS, Maynard JE. Impact of infection control strategies on the incidence of dialysis-associated hepatitis in the United States. J Infect Dis 1986;153:1149-51.  Back to cited text no. 20    
21.Stevens CE, Alter HJ, Taylor PE, Zang EA, Harley EJ, Szmuness W. Hepatitis B vaccine in patients receiving hemodialysis. Immunogenicity and efficacy. N Engl J Med 1984;311:496-501.   Back to cited text no. 21    
22.Centers for Disease Control. Hepatitis B virus: A comprehensive strategy for eliminating transmission in the United States through universal childhood vaccination. Recommendations of the Immunization Practices Advisory Committee (ACIP). MMWR 1991;40:1-25.  Back to cited text no. 22    
23.Lacson E, Teng M, Ong J, Vienneau L, Ofsthun N, Lazarus JM. Antibody response to Engerix-B and Recombivax-HB hepatitis B vaccination in end-stage renal disease. Hemodial Int 2005;9:367-75.  Back to cited text no. 23    
24.Fleming SJ, Moran DM, Cooksley WG, Faoagali JL. Poor response to a recombinant hepatitis B vaccine in dialysis patients. J Infect 1991;22:251-7.   Back to cited text no. 24    
25.Fabrizi F, Dixit V, Martin P. Meta-analysis: The adjuvant role of thymopentin on immunological response to hepatitis B virus vaccine in end-stage renal disease. Aliment Pharmacol Ther 2006;23:1559-66.  Back to cited text no. 25    
26.Chow KM, Law MC, Leung CB, Szeto CC, Li PK. Antibody response to hepatitis B vaccine in end-stage renal disease patients. Nephron Clin Pract 2006;103:c89-93.  Back to cited text no. 26    
27.Weinstein T, Chagnac A, Boaz M, Ori Y, Herman M, Zevin D, et al . Improved immunogenicity of a novel third-generation recombinant hepatitis B vaccine in patients with end-stage renal disease. Nephron Clin Pract 2004;97:c67-72.  Back to cited text no. 27    
28.McNulty CA, Bowen JK, Williams AJ. Hepatitis B vaccination in predialysis chronic renal failure patients a comparison of two vaccination schedules. Vaccine 2005;23:4142-7.   Back to cited text no. 28    
29.Schroth RJ, Hitchon CA, Uhanova J, Noreddin A, Taback SP, Moffatt ME, et al . Hepatitis B vaccination for patients with chronic renal failure. Cochrane Database Syst Rev 2004;3:CD003775.  Back to cited text no. 29    
30.Mettang T, Schenk U, Thomas S, Machleidt C, Kiefer T, Fischer FP, et al . Low-dose intradermal versus intramuscular hepatitis B vaccination in patients with end-stage renal failure. A preliminary study. Nephron 1996;72:192-6.  Back to cited text no. 30    
31.Charest AF, McDougall J, Goldstein MB. A randomized comparison of intradermal and intramuscular vaccination against hepatitis B virus in incident chronic hemodialysis patients. Am J Kidney Dis 2000;36:976-82.  Back to cited text no. 31    
32.Chau KF, Cheng YL, Tsang DN, Choi KS, Wong KM, Chak WL, et al . Efficacy and side effects of intradermal hepatitis B vaccination in CAPD patients: A comparison with the intramuscular vaccination. Am J Kidney Dis 2004;43:910-7.  Back to cited text no. 32    
33.Roozbeh J, Moini M, Lankarani KB, Sagheb MM, Shahpoori S, Bastani B. Low dose intradermal versus high dose intramuscular hepatitis B vaccination in patients on chronic hemodialysis. ASAIO J 2005;51:242-5.  Back to cited text no. 33    
34.Propst T, Propst A, Lhotta K, Vogel W, Konig P. Reinforced intradermal hepatitis B vaccination in hemodialysis patients is superior in antibody response to intramuscular or subcutaneous vaccination. Am J Kidney Dis 1998;32:1041-5.  Back to cited text no. 34    
35.DaRoza G, Loewen A, Djurdjev O, Love J, Kempston C, Burnett S, et al . Stage of chronic kidney disease predicts seroconversion after hepatitis B immunization: Earlier is better. Am J Kidney Dis 2003;42:1184-92.   Back to cited text no. 35    
36.Meuer SC, Hauer M, Kurz P, Meyer zum Buschenfelde KH, Kohler H. Selective blockade of the antigen-receptor-mediated pathway of T cell activation in patients with impaired primary immune responses. J Clin Invest 1987;80:743-9.  Back to cited text no. 36    
37.Descamps-Latscha B. The immune system in end-stage renal disease. Curr Opin Nephol Hypertens 1993;2:883-91.  Back to cited text no. 37    
38.Girndt M, Kohler H, Schiedhelm-Weick E, Meyer zum Buschenfelde KH, Fleischer B. T cell activation defect in hemodialysis patients: Evidence for a role of the B7/CD28 pathway. Kidney Int 1993;44:359-65.   Back to cited text no. 38    
39.Pecoits-Filho R, Heimburger O, Barany P, Suliman M, Fehrman-Ekholm I, Lindholm B, et al . Associations between circulating inflammatory markers and residual renal function in CRF patients. Am J Kidney Dis 2003;41:1212-8.  Back to cited text no. 39    
40.Stenvinkel P, Pecoits-Filho R, Lindholm B. Coronary artery disease in end-stage renal disease: No longer a simple plumbing problem. J Am Soc Nephrol 2003;14:1927-39.  Back to cited text no. 40    
41.Kirkpatrick CH, Wilson WE, Talmage DW. Immunologic studies in human organ transplantation: Observation and characterization of suppressed cutaneaous reactivity in uremia. J Exp Med 1964;119:727-42.   Back to cited text no. 41    
42.Wong PN, Fung TT, Chan AN, Hui PK, Mak SK, Lo KY, et al . Unusual case of hepatitic cholestasis resembling fibrosing cholestatic hepatitis in a dialysis patient with chronic hepatitis B infection. J Gastroenterol Hepatol 2006.  Back to cited text no. 42    
43.Ribot S, Rothstein M, Goldblat M, Grasso M. Duration of hepatitis B surface antigenemia (HBs Ag) in hemodialysis patients. Arch Intern Med 1979;139:178-80.  Back to cited text no. 43    
44.Harnett JD, Parfrey PS, Kennedy M, Zeldis JB, Steinman TI, Guttmann RD. The long-term outcome of hepatitis B infection in hemodialysis patients. Am J Kidney Dis 1988;11:210-3.  Back to cited text no. 44    
45.London WT, Drew JS, Lustbader ED, Werner BG, Blumberg BS. Host responses to hepatitis B infection in patients in a chronic hemodialysis unit. Kidney Int 1977;12:51-8.  Back to cited text no. 45    
46.Degott C, Degos F, Jungers P, Naret C, Courouce AM, Potet F, et al . Relationship between liver histopathological changes and HBsAg in 111 patients treated by long-term hemodialysis. Liver 1983;3:377-84.  Back to cited text no. 46    
47.Hyams KC. Risks of chronicity following acute hepatitis B virus infection: A review. Clin Infect Dis 1995;20:992-1000.  Back to cited text no. 47    
48.Coughlin GP, Van Deth AG, Disney AP, Hay J, Wangel AG. Liver disease and the e antigen in HBsAg carriers with chronic renal failure. Gut 1980;21:118-22.  Back to cited text no. 48    
49.Maisonneuve P, Agodoa L, Gellert R, Stewart JH, Buccianti G, Lowenfels AB, et al . Cancer in patients on dialysis for end-stage renal disease: An international collaborative study. Lancet 1999;354:93-9.   Back to cited text no. 49    
50.Josselson J, Kyser BA, Weir MR, Sadler JH. Hepatitis B surface antigenemia in a chronic hemodialysis program: Lack of influence on morbidity and mortality. Am J Kidney Dis 1987;9:456-61.  Back to cited text no. 50    
51.Jha R, Kher BA, Naik S, Elhence R, Gupta A, Sharma RK. Hepatitis B associated liver disease in dialysis patients: Role of vaccination. J Nephrol 1993;6:98-103.  Back to cited text no. 51    
52.Marcelli D, Stannard D, Conte F, Held PJ, Locatelli F, Port FK. ESRD patients mortality with adjustment for comorbid conditions in Lombardy (Italy) versus the United States. Kidney Int 1996;50:1013-8.  Back to cited text no. 52    
53.Liaw YF, Tai DI, Chu CM, Chen TJ. The development of cirrhosis in patients with chronic type B hepatitis: A prospective study. Hepatology 1988;8:493-6.  Back to cited text no. 53    
54.Dragosics B, Ferenci P, Hitchman E, Denk H. Long-term follow-up study of asymptomatic HBsAg-positive voluntary blood donors in Austria: A clinical and histologic evaluation of 242 cases. Hepatology 1987;7:302-6.  Back to cited text no. 54    
55.Yuen MF, Lai CL. Natural history of chronic hepatitis B virus infection. J Gastroenterol Hepatol 2000;15:E20-4.   Back to cited text no. 55    
56.Paz MO, Brenes F, Karayiannis P, Jowett TP, Scheuer PJ, Thomas HC. Chronic hepatitis B virus infection. Viral replication and patterns of inflammatory activity: Serological, clinical and histological correlations. J Hepatol 1986;3:371-7.  Back to cited text no. 56    
57.de Franchis R, Meucci G, Vecchi M, Tatarella M, Colombo M, Del Ninno E, et al . The natural history of asymptomatic hepatitis B surface antigen carriers. Ann Intern Med 1993;118:191-4.  Back to cited text no. 57    
58.ter Borg F, ten Kate FJ, Cuypers HT, Leentvaar-Kuijpers A, Oosting J, Wertheim-van Dillen PM, et al . Relation between laboratory test results and histological hepatitis activity in individuals positive for hepatitis B. surface antigen and antibodies to hepatitis B e antigen. Lancet 1998;351:1914-8.  Back to cited text no. 58    
59.Yang LM, Xu KC, Zhao YL, Wu ZR, Chen TF, Qin ZY, et al . Clinical significance of liver biopsy in chronic hepatitis B patients with persistently normal transaminase. Chin J Dig Dis 2002;3:150-3.  Back to cited text no. 59    
60.Yuen MF, Yuan HJ, Wong DK, Yuen JC, Wong WM, Chan AO, et al . Prognostic determinants for chronic hepatitis B in Asians: Therapeutic implications. Gut 2005;54:1610-4.  Back to cited text no. 60    
61.Fabrizi F, Lunghi G, Finazzi S, Colucci P, Pagano A, Ponticelli C, et al . Decreased serum aminotransferase activity in patients with chronic renal failure: Impact on the detection of viral hepatitis. Am J Kidney Dis 2001;38:1009-15.  Back to cited text no. 61    
62.Guh JY, Lai YH, Yang CY, Chen SC, Chuang WL, Hsu TC, et al . Impact of decreased serum transaminase levels on the evaluation of viral hepatitis in hemodialysis patients. Nephron 1995;69:459-65.  Back to cited text no. 62    
63.Hung KY, Lee KC, Yen CJ, Wu KD, Tsai TJ, Chen WY. Revised cutoff values of serum aminotransferase in detecting viral hepatitis among CAPD patients: Experience from Taiwan, an endemic area for hepatitis B. Nephrol Dial Transplant 1997;12:180-3.  Back to cited text no. 63    
64.Fabrizi F, Lunghi G, Martin P. Hepatitis B virus infection in hemodialysis: Recent discoveries. J Nephrol 2002;15:463-8.  Back to cited text no. 64    
65.Manesis EK, Papatheodoridis GV, Sevastianos V, Cholongitas E, Papaioannou C, Hadziyannis SJ. Significance of hepatitis B viremia levels determined by a quantitative polymerase chain reaction assay in patients with hepatitis B e antigen-negative chronic hepatitis B virus infection. Am J Gastroenterol 2003;98:2261-7.   Back to cited text no. 65    
66.Fabrizi F, Lunghi G, Alongi G, Bisegna S, Campolo G, Mangano S, et al . Biological dynamics of hepatitis B virus load in dialysis population. Am J Kidney Dis 2003;41:1278-85.  Back to cited text no. 66    
67.Moynot A, Lazizi Y, Dubreuil P, Buisson C, Pillot J. Nature of HBsAg ultrafiltrate of haemodialyzed patients: Presence of viral DNA. Nephrol Dial Transplant 1988;49:88.   Back to cited text no. 67    
68.Rostaing L, Chatelut E, Payen JL, Izopet J, Thalamas C, Ton-That H, et al . Pharmacokinetics of alphaIFN-2b in chronic hepatitis C virus patients undergoing chronic hemodialysis or with normal renal function: Clinical implications. J Am Soc Nephrol 1998;9:2344-8.  Back to cited text no. 68    
69.Perrillo RP. Current treatment of chronic hepatitis B: Benefits and limitations. Semin Liver Dis 2005;25:20-8.  Back to cited text no. 69    
70.Lok AS, McMahon BJ. Practice Guidelines Committee, American Association for the Study of Liver Diseases. Chronic hepatitis B. Hepatology 2001;34:1225-41.  Back to cited text no. 70    
71.Weissberg JI, Andres LL, Smith CI, Weick S, Nichols JE, Garcia G, et al . Survival in chronic hepatitis B. An analysis of 379 patients. Ann Intern Med 1984;101:613-6.  Back to cited text no. 71    
72.Realdi G, Fattovich G, Hadziyannis S, Schalm SW, Almasio P, Sanchez-Tapias J, et al . Survival and prognostic factors in 366 patients with compensated cirrhosis type B: A multicenter study. The Investigators of the European Concerted Action on Viral Hepatitis (EUROHEP). J Hepatol 1994;21:656-6.  Back to cited text no. 72    
73.de Jongh FE, Janssen HL, de Man RA, Hop WC, Schalm SW, van Blankenstein M. Survival and prognostic indicators in hepatitis B surface antigen-positive cirrhosis of the liver. Gastroenterology 1992;103:1630-5.  Back to cited text no. 73    
74.Lai CL, Ratziu V, Yuen MF, Poynard T. Viral hepatitis B. Lancet 2003;362:2089-94.  Back to cited text no. 74    
75.Wong PN, Fung TT, Mak SK, Lo KY, Tong GM, Wong Y, et al . Hepatitis B virus infection in dialysis patients. J Gastroenterol Hepatol 2005;20:1641-51.  Back to cited text no. 75    
76.Koksal I. Pegylated interferon for treatment in hemodialysis patients with chronic hepatitis C. J Gastroenterol Hepatol 2006;21:491-4.  Back to cited text no. 76    
77.Cooksley WG, Piratvisuth T, Lee SD, Mahachai V, Chao YC, Tanwandee T, et al . Peginterferon alpha-2a (40 kDa): An advance in the treatment of hepatitis B e antigen-positive chronic hepatitis B. J Viral Hepat 2003;10:298-305.   Back to cited text no. 77    
78.Fung SK, Lok AS. Hepatitis B virus genotypes: Do they play a role in the outcome of HBV infection? Hepatology 2004;40:790-2.  Back to cited text no. 78    
79.Dienstag JL, Schiff ER, Wright TL, Perrillo RP, Hann HW, Goodman Z, et al . Lamivudine as initial treatment for chronic hepatitis B in the United States. N Engl J Med 1999;341:1256-63.  Back to cited text no. 79    
80.Lai CL, Chien RN, Leung NW, Chang TT, Guan R, Tai DI, et al . One-year trial of lamivudine for chronic hepatitis B. Asia Hepatitis Lamivudine Study Group. N Engl J Med 1998;339:61-8.  Back to cited text no. 80    
81.Chien RN, Liaw YF, Atkins M. Pretherapy alanine transaminase level as a determinant for hepatitis B e antigen seroconversion during lamivudine therapy in patients with chronic hepatitis B. Asian Hepatitis Lamivudine Trial Group. Hepatology 1999;30:770-4.  Back to cited text no. 81    
82.Tassopoulos NC, Volpes R, Pastore G, Heathcote J, Buti M, Goldin RD, et al . Efficacy of lamivudine in patients with hepatitis B e antigen-negative/hepatitis B virus DNA-positive (precore mutant) chronic hepatitis B. Lamivudine Precore Mutant Study Group. Hepatology 1999;29:889-96.  Back to cited text no. 82    
83.Liaw YF, Sung JJ, Chow WC, Farrell G, Lee CZ, Yuen H, et al . Lamivudine for patients with chronic hepatitis B and advanced liver disease. N Engl J Med 2004;351:1521-31.  Back to cited text no. 83    
84.Guan R, Lai CL, Liaw YF, Lim SG, Lee CM. Efficacy and safety of 5-years lamivudine treatment of Chinese patients with chronic hepatitis. Br J Gastroenterol Hepatol 2001;16:A60.   Back to cited text no. 84    
85.Izzedine H, Launay-Vacher V, Baumelou A, Deray G. An appraisal of antiretroviral drugs in hemodialysis. Kidney Int 2001;60:821-30.   Back to cited text no. 85    
86.Bohjanen PR, Johnson MD, Szczech LA, Wray DW, Petros WP, Miller CR, et al . Steady-state pharmacokinetics of lamivudine in human immunodeficiency virus-infected patients with end-stage renal disease receiving chronic dialysis. Antimicrobial Agents Chemother 2002;46:2387-92.   Back to cited text no. 86    
87.Fontaine H, Thiers V, Chretien Y, Zylberberg H, Poupon RE, Brechot C, et al . HBV genotypic resistance to lamivudine in kidney recipients and hemodialyzed patients. Transplantation 2000;69:2090-4.  Back to cited text no. 87    
88.Ben-Ari Z, Broida E, Kittai Y, Chagnac A, Tur-Kaspa R. An open-label study of lamivudine for chronic hepatitis B in six patients with chronic renal failure before and after kidney transplantation. Am J Gastroenterol 2000;95:3579-83.  Back to cited text no. 88    
89.Schmilovitz-Weiss H, Melzer E, Tur-Kaspa R, Ben-Ari Z. Excellent outcome of Lamivudine treatment in patients with chronic renal failure and hepatitis B virus infection. J Clin Gastroenterol 2003;37:64-7.  Back to cited text no. 89    
90.Boyacioglu S, Gur G, Gursoy M, Ozdemir N. Lamivudine in renal transplant candidates with chronic hepatitis B infection. Transplant Proc 2002;34:2131-2.  Back to cited text no. 90    
91.Lapinski TW, Flisiak R, Jaroszewicz J, Michalewicz M, Kowalczuk O. Efficiency and safety of lamivudine therapy in patients with chronic HBV infection, dialysis or after kidney transplantation. World J Gastroenterol 2005;11:400-2.  Back to cited text no. 91    
92.Lok AS, McMahon BJ. Practice Guidelines Committee, American Association for the Study of Liver Diseases (AASLD). Chronic hepatitis B: Update of recommendations. Hepatology 2004;39:857-61.  Back to cited text no. 92    
93.Izzedine H, Hulot JS, Launay-Vacher V, Marcellini P, Hadziyannis SJ, Currie G, et al . Renal safety of adefovir dipivoxil in patients with chronic hepatitis B: Two double-blind, randomized, placebo-controlled studies. Kidney Int 2004;66:1153-8.   Back to cited text no. 93    
94.Fontaine H, Vallet-Pichard A, Chaix ML, Currie G, Serpaggi J, Verkarre V, et al . Efficacy and safety of adefovir dipivoxil in kidney recipients, hemodialysis patients and patients with renal insufficiency. Transplantation 2005;80:1086-92.   Back to cited text no. 94    
95.Tanji N, Tanji K, Kambham N, Markowitz GS, Bell A, D'agati VD. Adefovir nephrotoxicity: Possible role of mitochondrial DNA depletion. Hum Pathol 2001;32:734-40.  Back to cited text no. 95    
96.Fabrizi F, Bunnapradist S, Martin P. HBV infection in patients with end-stage renal disease. Semin Liver Dis 2004;24:63-70.   Back to cited text no. 96    
97.Harnett JD, Zeldis JB, Parfrey PS, Kennedy M, Sircar R, Steinmann TI, et al . Hepatitis B disease in dialysis and transplant patients. Further epidemiologic and serologic studies. Transplantation 1987;44:369-76.  Back to cited text no. 97    
98.Mathurin P, Mouquet C, Poynard T, Sylla C, Benalia H, Fretz C, et al . Impact of hepatitis B and C virus on kidney transplantation outcome. Hepatology 1999;29:257-63.  Back to cited text no. 98    
99.Fabrizi F, Dulai G, Dixit V, Bunnapradist S, Martin P. Lamivudine for the treatment of hepatitis B virus-related liver disease after renal transplantation: Meta-analysis of clinical trials. Transplantation 2004;77:859-64.  Back to cited text no. 99    
100.Chan TM, Fang GX, Tang CS, Cheng IK, Lai KN, Ho SK. Preemptive lamivudine therapy based on HBV DNA level in HBsAg-positive kidney allograft recipients. Hepatology 2002;36:1246-52.  Back to cited text no. 100    
101.Hadziyannis SJ, Tassopoulos NC, Heathcote EJ, Chang TT, Kitis G, Rizzetto M, et al . Long-term therapy with adefovir dipivoxil for HBeAg-negative chronic hepatitis B. N Engl J Med 2005;352:2673-81.   Back to cited text no. 101    
102.Han DJ, Kim TH, Park SK, Lee SK, Kim SB, Yang WS, et al . Results on preemptive or prophylactic treatment of lamivudine in HBsAg (+) renal allograft recipients: Comparison with salvage treatment after hepatic dysfunction with HBV recurrence. Transplantation 2001;71:387-94.  Back to cited text no. 102    
103.Gane E, Pilmore H. Management of chronic viral hepatitis before and after renal transplantation. Transplantation 2002;74:427-37.  Back to cited text no. 103    
104.Perrillo RP. Hepatitis B and renal transplantation: Securing the sword of damocles. Hepatology 2002;36:1041-5.  Back to cited text no. 104    
105.Brechot C, Thiers V, Kremsdorf D, Nalpas B, Pol S, Paterlini-Brechot P. Persistent hepatitis B virus infection in subjects without hepatitis B surface antigen: Clinically significant or purely "occult"? Hepatology 2001;34:194-203.  Back to cited text no. 105    

Top
Correspondence Address:
Ping-Nam Wong
Renal Unit, Department of Medicine & Geriatrics, Kwong Wah Hospital, 25 Waterloo Road, Kowloon, Hong Kong, SAR
China
Login to access the Email id

Source of Support: None, Conflict of Interest: None


Rights and PermissionsRights and Permissions




 

Top
 
  Search
 
  
  
    Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
    Email Alert *
    Add to My List *
* Registration required (free)  


    Abstract
    Introduction
    Epidemiology
    Preventive measures
    HBV vaccination
    Treatment of chr...
    Nucleoside and n...
    Pre -renal trans...
    Conclusions
    References

 Article Access Statistics
    Viewed24877    
    Printed676    
    Emailed15    
    PDF Downloaded1459    
    Comments [Add]    

Recommend this journal