Dr Ping-Nam Wong, Renal Unit, Department of Medicine and Geriatrics, Kwong Wah Hospital, 25 Waterloo Road, Kowloon, Hong Kong. Email: email@example.com
Abstract Hepatitis B virus (HBV) infection remains a major issue among dialysis patients. It is associated with a high risk of hepatic complication. The liver disease runs a unique clinical course in dialysis patients, as it can progress with modest hepatic inflammation and prominent fibrosis. The conventional cut-off level of serum alanine aminotransferase (ALT) for commencing antiviral therapy may prove too high and inappropriate for dialysis patients, and liver biopsy appears to be the only definitive means to establish the activity of liver disease in dialysis patients. Liver biopsy should be considered in patients with a serum ALT level that is persistently greater than 30 IU/L, or 0.75-fold the upper limit of the normal level, and/or other clinical and laboratory findings that suggest active liver disease. For antiviral treatment, preliminary reports have shown that lamivudine is effective and well tolerated in dialysis patients. However, the long-term efficacy of lamivudine and its optimal effective dose in dialysis patients remain unknown. The prevention of nosocomial transmission among dialysis patients is also important. Universal precaution measures should be strictly observed and the segregation of hepatitis B surface antigen-positive hemodialysis patients should be considered. For HBV non-immune patients, the importance of HBV vaccination should not be overemphasized. Until a new generation of highly immunogenic vaccines that are proven to be safe and effective in patients with end-stage renal disease becomes available, early vaccination before the development of end-stage renal failure remains the best way to secure immunological protection against HBV infection in dialysis patients.
Hepatitis B virus (HBV) infection is a major clinical condition, as it can lead to many serious consequences, including acute and chronic hepatitis, cirrhosis, hepatocellular carcinoma (HCC) and hepatic failure. For patients on dialysis, HBV infection represents a unique clinical problem. As a result of the immunosuppressive effect of renal failure, the clinical course and presentation of patients on dialysis are distinguished from non-dialysis patients. In addition, the repeated exposure to body fluids during dialysis procedures predisposes dialysis patients to nosocomial transmission of HBV. Furthermore, despite recent advances in antiviral therapy, there are still many uncertainties in regards to the efficacy and long-term outcomes of treatment with these antiviral agents. This review focuses on the prevention of nosocomial transmission and the diagnosis and management of hepatic complications of HBV infection in dialysis patients. It also discusses the preparation for renal transplantation in dialysis patients with chronic HBV infection.
IMMUNE DYSFUNCTION IN DIALYSIS PATIENTS
Infection is a major cause of morbidity and mortality in dialysis patients, second only to cardiovascular disease. One of the major predisposing factors for susceptibility to infection in dialysis patients is uremia-associated immunodeficiency. In fact, an array of immune system dysregulation involving both the humoral and cellular axes of the immune system has been reported in uremic patients, which might be present even before the commencement of dialysis. In addition to susceptibility to bacterial and viral infection, in uremic patients, immune abnormalities have also resulted in cutaneous anergy in delay-type hypersensitivity reaction to common antigens and a suboptimal response to vaccination.1 Deficient monocyte function could also be an important factor contributing to the immunodeficiency of uremic patients. In a study by Meuer et al., the degree of monocyte dysfunction in vitro was correlated to the same patients’in vivo responses to HBV vaccination.2 As monocytes are crucial for interleukin-2 production and T-cell proliferation, the metabolic monocyte defect associated with uremia might lead to failure of the monocyte population to support the process of primary T-cell activation.
Interestingly, apart from immunodeficiency, there could also be a coexisting activation of immunocompetent cells in the immune system in uremia-associated immune dysregulation.3 This finding is, in fact, consistent with the close association observed between uremia and chronic inflammation, which can lead to accelerated atherosclerosis and excessive cardiovascular mortality in uremic patients.4,5
HEPATITIS B VIRUS VACCINATION
The HBV vaccine has been available since 1982. Nevertheless, in dialysis patients, the percentage of seroconversion after HBV vaccination by the conventional i.m. route with the production of sufficient anti-hepatitis B surface (anti-HBs) antibodies (50–73%) has long been unsatisfactory. This figure is significantly lower than the seroconversion rate observed in healthy individuals (>90%).6,7 This suboptimal seroconversion rate is probably related to the progressive impairment in cellular immune response associated with deteriorated renal function. In a recent study, patients with a higher glomerular filtration rate (GFR) showed a better serological response to HBV vaccination compared with patients with a lower GFR.8 Within the group of dialysis patients, the seroconversion rate was further predicted by the age, weight, albumin level, male sex, presence of diabetes and serological positivity for hepatitis C virus of individual patients.8
Because of the apparent suboptimal response to the conventional regimen, it is recommended that for uremic patients, a four-dose schedule (40 µg/dose given at 0, 1, 2 and 6 months) instead of the conventional three-dose schedule (20 µg/dose given at 0, 1 and 6 months) should be given. Nevertheless, the superiority of this augmented regimen of vaccination compared with the conventional protocol has been disputed by a randomized, controlled clinical trial performed on 24 hemodialysis patients, which showed no difference in the seroconversion rate between the two regimens.9 Alternatively, some reports have shown that by activating specific epidermal cells, i.d. administration of the vaccine might improve lymphocyte responses and increase the seroconversion rate, despite using lower individual and cumulative doses. Nevertheless, the possible improved efficacy with i.d. vaccination is probably dose-related and could only be achieved with high individual and cumulative doses of vaccine. It has been found that using a low individual dose of 5.0 µg and a mean cumulative dose of 40.0–57.3 µg, anti-HBs antibody titers induced by i.d. vaccination are low and short-lived, and the overall efficacy is not superior to an i.m. route.10–12
In contrast, using high individual and mean cumulative doses of 20 and 100 µg, respectively, Propst et al. showed that i.d. vaccination is superior to conventional i.m. vaccination (individual and mean cumulative doses of 40 and 160 µg, respectively), in regards to the seroconversion rate (i.d., 94% vs i.m., 76%) and peak anti-HBs titer, although the duration of immunity was shorter and local skin reactions at the i.d. inoculation site were common (>50%).13
Apart from seroconversion rate, another important consideration is the durability of the induced immunity. It is considered unnecessary to maintain an anti-HBs greater than 10 mIU/mL for a low-risk, healthy population after successful vaccination and initial seroconversion because of the presence of an immunological memory; however, a booster dose of vaccine is generally recommended for dialysis patients because of their immunosuppressive state, poor responses to vaccination and environmental risks for cross-infection.7
In this context, the shorter durability of immunity for i.d. administration compared with i.m. administration of the vaccine is particularly relevant. Despite the promising seroconversion rate for high-dose i.d. vaccination, further studies are needed to clarify the costs of vaccination using i.d. versus i.m. administration before its widespread application can be recommended. Finally, a preliminary study has reported on the improved immunogenicity of a novel third-generation recombinant HBV vaccine in patients with end-stage renal disease, in which a seroconversion rate of 86% was achieved after three standard i.m. doses.14 However, further study would be required to confirm its enhanced efficacy in dialysis patients before it could be applied and recommended in daily clinical practice.
INCIDENCE AND PREVALENCE OF HEPATITIS B VIRUS INFECTION IN DIALYSIS UNITS
The hepatitis B surface antigen (HBsAg) positivity rate in dialysis patients varies among different localities and correlates with the endemicity in the general population of the region. For example, HBsAg positivity rates among dialysis patients are reported to be 0.9% in the USA, 1.6% in Japan, 10.0% in Brazil, 10.0% in Hong Kong, 11.8% in Saudi Arabia and 16.8% in Taiwan, which grossly correspond to the endemicity of the infection in the respective localities.15–20
In general, the overall incidence of HBV infection in dialysis patients is decreasing over the years as a result of routine screening of blood products for HBsAg and anti-hepatitis B core (anti-HBc) antibody, the advent of recombinant human erythropoietin, HBV vaccination and the implementation of infection control measures.
NOSOCOMIAL TRANSMISSION OF HEPATITIS B VIRUS INFECTION IN DIALYSIS UNITS
Nosocomial transmission of HBV infection is a major risk for patients undergoing chronic dialysis. Previous epidemiological studies have shown that, apart from the number of blood units transfused and local endemicity, the duration of hemodialysis, presence of HBsAg-positive patients in the units and non-separation of infected from non-infected patients are also associated with an increased risk of HBV infection.15,17,18,20,21 In addition, a molecular biological study of patients receiving treatment in the same hemodialysis units showed a relative homogeneity of HBV subtypes, which supports the existence of patient-to-patient transmission of HBV infection in hemodialysis units.17
There are certain characteristics of HBV that render it particularly susceptible to environmental contamination, especially nosocomial transmission. HBV is relatively stable in the environment and can remain viable for at least 7 days on environmental surfaces at room temperature.22 HBsAg has been detected on various environmental surfaces, such as clamps, scissors, doorknobs and dialysis machine control knobs, in dialysis centers with HBsAg-positive patients.23 The hemodialysis procedure itself poses an exceptional risk to dialysis patients, who could acquire a HBV infection on various occasions during the dialysis procedure. In contrast, patients on peritoneal dialysis are reported to have a lower prevalence of HBV infection compared with hemodialysis patients. During hemodialysis, patients could be injected with contaminated material, have mucosal membrane or breached skin exposed to infective material, or be dialyzed with contaminated equipment. In this regard, when HBV-DNA has been detected in the dialysate and ultrafiltrate of HBsAg-positive patients undergoing high-flux hemodialysis, the risk of environmental contamination and nosocomial transmission of the infection among other hemodialysis patients could be further increased.24
In fact, it has been clearly demonstrated in previous reports that outbreaks of HBV infection in dialysis units are mostly a result of failing to follow standard infection practices; for example, sharing multidose vials or blood-contacted equipment, omitting the periodic screening of HBsAg status and not vaccinating susceptible patients.25 To reduce the possibility of nosocomial infection, it is of paramount importance to ensure the strict adherence to universal precautions for all patients regardless of their HBsAg and serological status because HBV genomes can be present in the serum, liver or peripheral blood mononuclear cells (PMNC) with the absence of serological markers of infection.26 A study on 67 hemodialysis patients with no serological markers for HBV infection showed that 2.9% of patients had HBV-DNA detectable in their PMNC.27 A study on 13 HBsAg-negative chronic hemodialysis patients and eight HBsAg-negative staff members from the same dialysis units, who had suffered from acute HBV but in whom the virus had resolved 13–21 years later, also showed that minute amounts of transcriptionally active, covalently closed, circular HBV-DNA could be detected by polymerase chain reaction in 47% of the PMNC samples.28 The findings could be a result of the deletions in the pre-S1 region of the viral genome affecting the S promoter, which causes a reduced production of HBsAg.28
Although the clinical significance of the contribution to nosocomial transmission of HBV infection in dialysis units remains unclear, it clearly underlines the importance of strictly enforcing all recommendations in universal precautions and hemodialysis procedures for the prevention of blood borne infections among all patients in dialysis units. In addition, a segregation policy should be considered for HBsAg-positive patients during hemodialysis because it has been shown to be effective in reducing HBV transmission among patients in dialysis centers.29 Finally, vaccination of non-immune patients also plays an important role in preventing the spread of infection within dialysis units.
CLINICAL PRESENTATIONS AND OUTCOMES OF HEPATITIS B VIRUS INFECTION IN DIALYSIS PATIENTS
Under most circumstances, HBV is not a cytopathic virus. Except for a rare condition, fibrosing cholestatic hepatitis (typically occurring in heavily immunosuppressed post-transplant patients), in which a high viral load as a result of unchecked viral replication leads to direct cytopathic liver damage, liver injury in otherwise immunocompetent individuals is largely caused by a complex interplay between the host immunity and the HBV. Therefore, with a compromised immune system, it is not surprising that acute HBV infection in dialysis patients is often mild or asymptomatic, and a high percentage of between 30 and 72% of these patients might become chronic carriers because of an impaired viral clearance.30–33
For non-dialysis patients with chronic HBV infection, the major complications of concern have been chronic hepatitis, cirrhosis and HCC and these complications have contributed to a large number of cases of hepatic failure in HBV-endemic areas. It has been estimated that approximately 15–40% of HBV carriers will develop serious sequelae during their lifetimes.34
Even though chronic hepatitis, cirrhosis and HCC are major complications commonly encountered in HBV-infected dialysis patients, there are few published reports on the natural history and histological progress of liver disease associated with HBV infection in this group of patients. From the limited data available, the complication rate of HBV infection in dialysis patients appears to be quite high, and in a study by Harnett et al., chronic elevation of liver enzymes was reported in 29% of HBV-positive dialysis patients.31 In a study on 51 HBsAg carriers who acquired HBV infection after receiving dialysis, 37 (72%) developed biopsy-proven chronic hepatitis over 8 years of follow up. Of these 37 patients, 25 (49%) had chronic active hepatitis (CAH), and four patients had chronic persistent hepatitis, lobular in the initial biopsies, which subsequently progressed to CAH. 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. In contrast, fibrosis was rather extensive.33
Hepatitis B surface antigen-positive dialysis patients therefore seem to be at a high risk of developing active progressive liver disease. The disease tends to run a characteristic course and can progress with a relatively less pronounced degree of hepatic inflammation.35
However, the exact impact of HBV infection on the clinical outcomes of infected dialysis patients remains controversial. A retrospective study performed in India reported a higher mortality among HBV-positive dialysis patients compared with HBsAg-negative dialysis patients, and there are also studies that showed no difference in the morbidity and mortality rates be-tween HBsAg-positive and HBsAg-negative dialysis patients.31,36,37
For the studies that showed no difference in outcome, the patients were mostly from centers in the USA, where the majority acquired the HBV infection after receiving dialysis. The follow-up period after acquiring the infection was relatively short; therefore, there might not have been enough time for the liver disease to impact on the clinical outcomes. In addition, dialysis patients also tend to have multiple comorbidities, such as cardiovascular disease, cerebrovascular disease and recurrent infection. All of these comorbidities might markedly compromise patient survival and mask the effects of the liver problem. Therefore, the impact of HBV infection only becomes obvious with the development of advanced complications, such as liver cirrhosis, in which case it is then associated with a 35% increase in patient mortality.38
DIAGNOSTIC APPROACH FOR HEPATITIS B VIRUS-RELATED HEPATIC COMPLICATIONS
For patients with chronic HBV infection, it is important to identify the patients with active liver disease warranting antiviral treatment, and early HCC amenable to curative surgery. In this regard, early identification of patients with CAH is especially important and relevant, as previous studies have shown that CAH (chronic hepatitis with portal and periportal lesions), especially in the presence of repeated episodes of acute exacerbation, is associated with an increased risk of cirrhosis and HCC.39,40
Therefore, follow-up protocol for patients with chronic HBV infection should include detailed history-taking, thorough physical examinations and regular laboratory investigations, such as liver function tests, complete blood counts, prothrombin time, alpha-fetal protein and yearly liver ultrasound. Nevertheless, for dialysis patients, there are some special considerations in the use of some of these tests for monitoring and evaluating the disease.
Elevations in serum hepatic transaminase levels, including ALT and aspartate aminotransferase (AST), are key biochemical markers indicating hepatitic activity in acute and chronic phases of HBV infection. Previous studies have revealed that hepatitis B e antigen (HBeAg), HBV-DNA positivity and elevated transaminase are associated with higher lobular inflammatory activity of the liver in HBV-positive patients, and normal ALT activity in HBsAg carriers is associated with low risk (0.63–3.40%) of CAH and/or cirrhosis.41–43
However, these findings, which were derived from the general population, do not always hold true when applied to dialysis patients. Although the serum transaminase activities of HBsAg-positive dialysis patients are generally found to be higher than HBsAg-negative patients,44 the serum ALT levels do not appear to correlate well to the severity of liver disease in dialysis patients. To a certain extent, it might be related to the relatively modest hepatic inflammation associated with disease progression in dialysis patients. In addition, differential virulence of HBV strains and fluctuation in viral load and transaminase levels might also be contributing factors. Furthermore, there is a well-recognized occurrence of hypo-transaminases in dialysis patients. Various reasons have been postulated to account for this interesting finding. These include the reduction in pyridoxal-5′-phosphate (a coenzyme of transaminases), the presence of ultraviolet-absorbing materials, the suppression of ALT synthesis and release into the blood stream in hepatocytes, and the accelerated clearance from serum. In fact, the conventional upper limit of normal (ULN) for AST and ALT of 40 IU/L is deemed too high for dialysis patients, and it has been suggested that the cut-off point of AST and ALT for evaluating viral hepatitis should be reset to the lower levels of 24 and 17 IU/L, respectively. In this regard, the interpretation of these biochemical parameters in uremic patients needs to be made in accordance with adjusted normal ranges.45–47
Apart from aminotransferase levels, the interpretation of serum alkaline phosphatase is also slightly more complicated in dialysis patients because some of these patients might have coexisting secondary hyperparathyroidism, which could give rise to an increase in serum alkaline phosphatase of bone origin. In this circumstance, fractionation of serum alkaline phosphatase and measuring other enzymes, such as 5-nucleotidase and γ-glutamyltransferase, would be helpful in pinpointing the cause of elevation.
Serum hepatitis B virus DNA level
With our experiences with other HBV infected immunosuppressed patients, one might expect that there would be an increase in viral replication and hepatitis reactivation in dialysis patients with chronic hepatitis infection.48 Nevertheless, there are very few studies on the biological dynamics of HBV loads in dialysis patients. Not until recently did Fabrizi et al. carry out a study on 29 HBsAg dialysis patients using highly sensitive polymerase chain reaction (PCR)-based assays for HBV-DNA detection, with the lower limit of detection as low as 102−103 HBV copies/mL.49 Three distinct patterns were identified in the study by Fabrizi et al.: persistent HBV-DNA, intermittent HBV-DNA and persistently HBV-DNA-negative individuals.49
Interestingly, the overall viral load among those patients was not particularly high. The median HBV-DNA level at study entry was only 4.09 × 102 copies/mL, and it remained quite stable throughout the 12-month follow-up period. The reason for the relatively low level of viral replication remains unclear. The authors have suggested that it could be related to the passage of HBV viral genome into the dialysate effluent during peritoneal dialysis and hemodialysis, and a decreased clearance of interferon activity in the uremic population.24,50,51
However, this issue remains far from settled and there are no long-term data available. In this context, the clinical role and significance of HBV-DNA monitoring are also unknown. Although an arbitrary value of >105 copies/mL was chosen as a diagnostic criterion for chronic HBV at a recent National Institutes of Health conference, and aminotransferase activities were significantly greater in persistently HBV-DNA-positive patients than in intermittently HBV-DNA-positive or persistently HBV-negative individuals,49 it remains very difficult to predict the severity and outcome of liver disease based on the HBV-DNA level per se.34
Liver biopsies allow a direct assessment of the degree of liver damage in patients with chronic HBV infection. Apart from assessing the degree of liver damage, liver biopsies can also be used for immunohistochemical staining for HBsAg and hepatitis B core antigen, and could assist in ruling out alternative diagnoses and prognoses.
Depending on the histological findings, the estimated 5-year survival rates have been found to be 97% for patients with chronic persistent hepatitis, 86% for patients with CAH and 55% for patients with CAH and cirrhosis.52 For patients with compensated cirrhosis, the survival rate was found to be 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.53 For patients with decompensated cirrhosis, 5-year survival was found to be only 14%.54 Nevertheless, the histology might change spontaneously after treatment.
In view of the above limitations to 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 antiviral therapy and undergoing kidney transplantation.
TREATMENT OF HEPATITIS B VIRUS-RELATED HEPATIC COMPLICATIONS
For patients with chronic HBV infection, the primary goal of treatment is to suppress HBV replication using antiviral therapy before any irreversible damage occurs. In the event of advanced liver disease, liver transplantation should be considered. Current antiviral therapy includes α-interferon and nucleoside analogs, such as lamivudine and adefovir dipivoxil, or their combinations. As not all patients respond satisfactorily to antiviral therapy, and previous studies have shown that only patients with certain clinical characteristics may benefit, the decision to commence antiviral therapy is reliant 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-fold the ULN and/or evidence of moderate/severe chronic hepatitis on liver biopsy).55
Nevertheless, for dialysis patients with a depressed baseline serum ALT level, the conventional cut-off value with a serum ALT level of >1.5-fold the ULN might prove too high and unreliable for identifying patients with significant hepatic inflammation warranting specific antiviral treatment. In fact, the authors of the present study have come across a HBV-positive dialysis patient with serum ALT levels fluctuating between 20 and 50 IU/L, with values rarely exceeding 60 IU/L (1.5-fold the ULN) throughout the clinical course despite clinical disease progression. Unfortunately, there are no published data specifically on dialysis patients that could help us to determine the best cut-off value for ALT elevation in this circumstance. At best, one could only adopt the <20 IU/L level, or 0.5-fold the ULN, as suggested by some authors as the working “ULN” of serum ALT for dialysis patients, and exercise their clinical judgment when deciding whether further investigations and treatment are necessary. In this context, dialysis patients with chronic HBV infection and an otherwise unexplained elevation in serum ALT level persistently above 30 IU/L (20 × 1.5 IU/L), or 0.75-fold the ULN, should probably be suspected to have significant hepatic inflammation and be considered for liver biopsy. However, even if the serum ALT level does not reach that high, but there is clinical evidence of progressive liver disease, one might still consider liver biopsy to determine the disease activity and the need for treatment.
Although the majority of antiviral agents have been shown to be effective and can lead to normalization of the serum ALT level, suppression of HBV-DNA, HBeAg seroconversion and improvement in liver histology in non-dialysis patients,34 data on dialysis patients are scarce and few studies have been carried out to examine the use of α-interferon and lamivudine in treating chronic HBV infection in dialysis patients.
α-Interferon is an antiviral, antiproliferative and immunomodulatory agent, which can give rise to 30–40% of HBeAg seroconversion in patients with a serum ALT level of threefold the ULN after 6 months of treatment. Nevertheless, side-effects are common; these include flu-like symptoms, neutropenia, thrombocytopenia and neuropsychiatric symptoms. In addition, it can exacerbate hepatitis, which might lead to life-threatening hepatic decompensation in patients with underlying liver cirrhosis.34
Although α-interferon is generally effective and reasonably tolerable among non-dialysis patients, it does not have a big role in the treatment of dialysis patients. First, there is a lack of findings, as there has only been one anecdotal report on two patients, which suggests its efficacy in dialysis patients.56 Second, α-interferon is metabolized by renal tubules. It has an enhanced plasma half-life in patients with end-stage renal disease and prolonged treatment can lead to drug accumulation.51 Possibly because of this, α-interferon is poorly tolerated by dialysis patients who have a frequent occurrence of side-effects, such as exacerbation of anemia, leucopenia and malnutrition. In one study, the side-effects were so severe that cessation of therapy was required in more than 50% of patients.57,58
Lamivudine is the negative enantiomer of 2′-3′ dideoxy-3′-thiacytidine. It can be incorporated into the growing DNA chains of HBV after being converted into active triphosphate, by which it can lead to premature chain termination and cessation of HBV-DNA synthesis.
Controlled clinical trials have shown that lamivudine is effective in suppressing HBV replication, ALT normalization and improving histological necroinflammation, whereas it has been used for treating active liver disease caused by HBV infection in non-immunosuppressed patients without renal dysfunction. In these studies, HBeAg seroconversion was observed in 16–18% of treated patients after 12 months of treatment. The HBeAg seroconversion increased with the duration of treatment and reached 47% at 4 years, and, in 30–80% of patients, this seroconversion was sustained even after the cessation of lamivudine.34,59,60
In these studies, patients’ responses were closely linked with their pretreatment serum ALT levels. Patients with pretreatment ALT levels of more than five times the ULN enjoyed the best 1-year HBeAg seroconversion rate, whereas those with ALT levels of less that twofold the ULN had a 1-year HBeAg seroconversion rate of less than 10%.61
Although HBeAg-negative/HBV-DNA-positive patients appeared to show responses to lamivudine similar to those of the HBeAg-positive patients, it is difficult to define a treatment end-point in this group of patients and the patients also appeared to be less likely to have a sustained viral response.62 Lamivudine treatment might also be beneficial for patients with established liver cirrhosis. A recent randomized controlled study on 651 patients with chronic HBV, cirrhosis and advanced cirrhosis showed that over a median treatment period of 32 months, the disease progression of the 436 patients receiving lamivudine was reduced by 50% compared with the 215 controls.63 In addition, the occurrence of HCC was also significantly reduced from 7.4 to 3.9%. Nevertheless, despite its promising short-term efficacy, its long-term effectiveness is negated by the common emergence of lamivudine-resistant HBV variants with a mutation of the tyrosine-methionine-aspartate-aspartate (YMDD) motif at the catalytic domain of the viral reverse transcriptase/DNA polymerase after prolonged treatment. The prevalence of resistance increased with the duration of the treatment, and it was detectable in 14% of patients who were continuously treated for 12 months, and 69% of patients who were treated for 5 years. The emergence of resistance has led to rebound in viral replication, which can sometimes lead to severe flares of hepatitis and hepatic decompensation.64
By far, the findings on the use of lamivudine for the treatment of hepatitis B chronic hepatitis in dialysis patients remains scanty and preliminary. No controlled trials have yet been performed to examine the safety and effectiveness of lamivudine in this unique group of patients. All published studies have been case series that have used small sample sizes involving only four to seven patients with a short follow-up period, using various doses ranging from 10 to 40 mg daily.65–68 In addition, the studies have also mainly been from HBV non-endemic areas and the baseline ALT levels of the patients were mostly more than double the ULN.
In general, lamivudine appears to be effective and well tolerated with few side-effects. Nevertheless, there are still some unresolved issues regarding the use of this drug in dialysis patients. First, given a close association between the treatment response and pretreatment immune response represented by serum ALT levels, and relatively modest elevation in transaminase level and hepatic inflammation in dialysis patients, the overall effects and outcomes of lamivudine therapy in dialysis patients remain unclear and further studies are required for clarification.
In addition, lamivudine is primarily excreted through the kidney unchanged, and renal impairment could lead to three-or fourfold the increase in its half-life. Because of this, it has been suggested that one-tenth of the normal dose should be given to patients with advanced renal impairment.69 For patients on dialysis with a low molecular mass of 229.3 Da and a low level of protein binding, lamivudine is readily dialyzable by hemodialysis and peritoneal dialysis.69 However, because lamivudine has a large volume of distribution, the amount of drug removed during dialysis is small compared with the total pool. Therefore, dialysis per se appears to have little impact on the overall dosing regimen, although dosing after hemodialysis is advisable.70
In contrast, despite the recommendation on dose adjustment for renal insufficiency, it has been reported that a dosage grossly higher than the recommended renal dose can still be well tolerated in dialysis patients. In the report, hemodialysis patients with HIV infection were treated with lamivudine 150 mg daily, sixfold the recommended renal dose, and yet no obvious adverse effects were observed after several months of treatment.70
Therefore, it appears that lamivudine is a safe drug with a high therapeutic index, even in patients with severe renal dysfunction. Although the recommended dose is 10 mg daily, based on pharmacokinetic studies for treating HBV infection in patients with end-stage renal failure with or without dialysis, the optimal effective dose of lamivudine and duration of treatment in this group of patients remain unclear. Further studies are required before these uncertainties are settled.
Other nucleoside analogs
Adevofir dipivoxil is a new nucleotide analog, which inhibits both HBV reverse transcriptase and DNA polymerase. Although it has been shown to be an effective antiviral agent in treating HBV infection in the non-dialysis population and is especially useful in suppressing lamivudine-resistant HBV mutants, there have been no published studies on the use of adevofir dipivoxil in the treatment of HBV infection in patients receiving chronic dialysis.71 In addition, adevofir is a nephrotoxic agent. Deterioration in renal function has been reported in 2.5–28.0% of patients after 1–2 years of therapy. The exact mechanism of renal toxicity is not entirely clear but it is probably related to its effect of depleting mitochondrial DNA from proximal tubular cells, resulting in acute tubular necrosis.72 As a result of the uncertain efficacy and possible renal toxicity, the routine use of adevofir dipivoxil in treating HBV infection in dialysis patients, especially patients with significant residual renal function, cannot be recommended at this stage.
PRE-RENAL TRANSPLANT PREPARATION
Hepatitis B virus replication can be enhanced by post-transplant immunosuppressive agents in many ways. First, it can be related to a generalized suppression of cytotoxic T-cell activity. In addition, the commonly used immunosuppressive agents, such as corticosteroids, azathioprine and calcineurin inhibitors, might also have a direct stimulating effect on HBV viral replication.73–75
In fact, HBV reactivation after transplant is extremely common, occurring in 70–90% of HBsAg-positive recipients regardless of their pretransplant HBeAg status, and reactivation with the reappearance of HBsAg in the serum has also been observed in patients with undetectable serum HBsAg after acute infection had been resolved.75,76
Before the advent of effective antiviral therapy, chronic HBV infection was considered to be a relative contraindication for renal transplantation, resulting from a common concern about the exacerbation of liver disease after transplantation, which frequently led to severe hepatic complications and diminished patient survival. A study by Mathurin et al. on 128 HBsAg-positive renal transplant recipients showed that the 10-year survival of patients was 55% compared with the significantly lower survival rate of the 490 HBsAg-negative patients, which was 80%.77 Nevertheless, with recent advances in antiviral therapy, the outcome of HBsAg-positive kidney recipients has significantly improved. Among all antiviral therapies, the advent of lamivudine has been the most important one. Lamivudine is effective in suppressing HBV-DNA and normalization of aminotransferase levels in HBsAg-positive renal transplant recipients with few side-effects.78 In fact, the treatment has given rise to an increase in patient survival. In particular, in a recent study by Chan et al., 11 HBsAg-positive kidney recipients were treated with lamivudine pre-emptively according to HBV-DNA levels and the 5-year patient survival was 98%, which was similar to the 5-year patient survival of HBsAg-negative patients. In contrast, the 5-year patient survival of the 15 HBsAg-positive patients who were treated with lamivudine years after transplantation was only 75%.79
Therefore, it seems that early administration of lamivudine is important to achieve an optimal outcome. Apart from avoiding severe or irreversible hepatic damage caused by HBV reactivation, which can sometimes be fatal, there is also evidence showing that early treatment might reduce the risk of inducing lamivudine resistance, which remains a real and major concern in patients receiving long-term treatment with this drug.80 In this context, some researchers have suggested that administering lamivudine should be commenced pre-emptively, immediately following transplantation regardless of the HBV-DNA level, or even before transplantation.81,82 Nevertheless, the appropriate timing in the latter situation, except for living–related transplantation, would be difficult to determine without causing concern over the emergence of lamivudine-resistant mutants after prolonged use.
Despite the availability of effective antiviral therapy, the risk for patients with severe active liver disease and advanced liver cirrhosis to undergo renal transplant remains significantly increased, in which case renal transplantation should probably be deferred or combined as a liver–kidney transplantation instead. Therefore, it would be prudent and desirable to carry out a liver biopsy for assessment before transplantation. However, similar to the problem of administering pre-emptive lamivudine, the optimal timing for this procedure could be difficult to determine in the face of cadaveric transplantation with a long waiting period.
SUGGESTED ALGORITHM FOR THE MANAGEMENT OF HEPATITIS B SURFACE ANTIGEN-POSITIVE DIALYSIS PATIENTS AWAITING RENAL TRANSPLANT
A suggested algorithm for the management of HBsAg-positive dialysis patients is outlined in Figure 1. Patients who are negative for both HBsAg and anti-HBsAg antibody should be screened for anti-HBc antibody, in which case a positive finding would warrant a close monitoring for possible HBV reactivation after transplantation.
Dialysis patients who test positive for HBsAg should be closely monitored for clinical signs and symptoms of active liver disease, and be tested regularly for parenchymal and ductal liver enzymes, serum albumin level, complete blood counts, prothrombin time, serum alpha-fetal protein level and liver ultrasound. For those patients with persistently elevated ALT levels of >30 IU/L, or 0.75-fold the ULN, and/or other clinical or investigation findings suggestive of active liver disease, a liver biopsy is required to confirm the diagnosis and to determine the need for treatment. Patients pending a living–related renal transplant should also undergo a liver biopsy to determine the suitability for an isolated kidney transplantation, and pre-emptive lamivudine before or immediately after transplantation should be considered. For patients showing advanced liver cirrhosis or severe active liver disease on liver biopsy, lamivudine should be given, and the kidney transplant should be deferred or combined as a liver–kidney transplantation instead. At the moment, lamivudine appears to be the best possible treatment for dialysis patients with significant active liver disease on liver biopsy and evidence of active HBV replication (positive for HBeAg or HBV-DNA >105 copies/mL), although the long-term outcome is unclear and the emergence of lamivudine-resistant mutants remains a real concern. It is hoped that the newer generation of nucleoside analogs, such as adefovir and entecavir, might be helpful in dealing with lamivudine resistance and would be viable options for the long-term management of dialysis patients with active HBV infection.
Hepatitis B virus infection remains a major issue in dialysis patients, and it requires special attention in various aspects of management, including the prevention of nosocomial transmission, the monitoring and treatment of liver disease, and the preparation for renal transplantation. Despite recent advances in the diagnosis and management of chronic HBV infection among non-dialysis patients, there are still many unanswered questions in dialysis patients, such as the optimal timing of liver biopsy, the cut-off level of serum ALT that could best reflect the activity of liver disease and the response to antiviral treatment, the optimal effective dose, the long-term efficacy and outcome of lamivudine therapy, and the issue of lamivudine resistance. Further studies are required to address all of these issues. After all, prevention remains a priority, and vaccination of non-immune renal patients, especially before they develop advanced renal failure, is considered crucial in order to decrease the magnitude of the HBV-related problem in the dialysis population.