| 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
| Introduction|| |
Since its discovery in 1965 known as 'Australian antigen,' hepatitis B virus (HBV) infection has been a worldwide health problem. 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|| |
It is estimated that more than 350 million people are infected with HBV worldwide. Among all, 75% of them are from Asia, of which about 40 million people are from India., Within the Asia-pacific region, the prevalence varies from 2.8% in Korea to 20% in Taiwan and Vietnam. 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. ,,,,, 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|| |
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. 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., 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.
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. Reuse of dialyzers and blood lines should be avoided as far as possible. 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.,, 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.
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. Lastly, the role of active vaccination could not be overemphasized.
| HBV vaccination|| |
HBV vaccination represents one of the most important measures in the prevention of nosocomial transmission of HBV infection within a dialysis unit especially in endemic areas. Unfortunately, despite the high seroconversion rate of more 95% in general population, the seroconversion rate obtained 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., 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., 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.,,, 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 µg per dose given at 0, 1, 2, 6 months, instead of conventional 3-dose schedule, 20 µg per dose given at 0, 1, 6 months, should be administered for patients with end-stage renal disease. Nevertheless, the superiority of this regimen has not yet been confirmed and even has been disputed by some clinical studies., 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.,, From these studies, it seems that the efficacy of i.d. vaccination is dose-related and superior efficacy probably could only be achieved with high individual and cumulative doses. For example, by using an individual dose of 5.0 µg and a mean cumulative dose 40-57.3 µg, i.d. administration was no better than i.m. vaccination. Another study on dialysis patients comparing 20 µg i.d. with 40 µg i.m, both given for three doses, also showed no difference in the anti-HBsAb seroconversion rate. In contrast, with an individual dose of 20 µg and cumulative dose of 100 µg, Propst et al showed that i.d. vaccination was superior to i.m. administration with four dose-dose schedule (40 µg/dose) in terms of the seroconversion rate (94 vs. 76%). However, the induced immunity by i.d vaccination is less durable than conventional i.m. administration. Although it is considered unnecessary to maintain an anti-HBs greater than 10 mIU/mL for low-risk healthy population after successful vaccination and initial seroconversion because of the presence of immunologic memory, a booster dose of vaccine is generally recommended for dialysis patients due to their immunosuppressive state, poor responses to vaccination and environmental risks of cross infection. 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, 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.,, 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., 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., 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. 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,,,, 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.
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. 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. 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.
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.,, 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.
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,, 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. 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.
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.,, 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. 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). 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.,, 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.
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 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. 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. 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 4.09´10 2 copies/mL. 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.,,
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. After all, it remains very difficult to predict the severity and outcome of liver disease based on the HBV DNA level per se .
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. 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. For patients with decompensated cirrhosis, 5-year survival was only 14%. 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|| |
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).
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.
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.
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. 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. 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.
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. The local prevalence of individual genotype might affect the usefulness of this agent in different localities.
| Nucleoside and nucleotide analogues|| |
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.,, 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%.
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. 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. 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.
Lamivudine is a drug primarily excreted by renal route and is readily dialyzable by haemodialysis and peritoneal dialysis. 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. 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.
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.,,,, 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.
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, 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. 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., 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. 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|| |
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. 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., Nevertheless, thanks to the advent of effective anti-viral therapy, the scenario has changed. Indeed, a recent study by Chan et al. 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. 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. 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. 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., 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.
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. 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.,, 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. 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., 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|| |
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.
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Renal Unit, Department of Medicine & Geriatrics, Kwong Wah Hospital, 25 Waterloo Road, Kowloon, Hong Kong, SAR
Source of Support: None, Conflict of Interest: None