Hepatitis B in Dialysis and Transpantation

Dr. Sandeep G. HuilgolMBBS., DNB (Int.Med)., MMedSci

(Nephro)

Hepatitis B virus (HBV) infection can lead to acute or chronic hepatitis, cirrhosis, or hepatocellular carcinoma.

Despite the availability of effective vaccines since 1982, HBV infection has remained endemic in many localities, with more than 350 million chronic HBV carriers worldwide.

HBV infection in dialysisImmunosuppressive effect of renal failure.

The susceptibility for de novo infection and nosocomial transmission,

The long-term implications on morbidity and mortality, and

The change in clinical course after kidney transplantation.

The majority of newly HBV-infected dialysis patients have a relatively mild clinical course .

Infected patients are often asymptomatic, and have normal or only slightly elevated serum transaminase levels.

Data from patients on peritoneal dialysis showed that the impact of HBV infection per se on the survival of dialysis patients was relatively small

Significant risk of clinical deterioration in the HBV infected renal transplant recipient.

The risk of severe life-threatening complications is highest when de novo HBV infection occurs shortly after transplantation.

Hepatitic flares and liver-related complications can occur at any time after kidney transplantation in HBsAg-positive kidney transplant recipients, including those who have been asymptomatic HBV carriers during dialysis.

Therefore, despite the relatively benign clinical disease in dialysis patients, the importance of preventing and treating HBV infection in dialysis patients must be underscore

INCIDENCE AND PREVALENCEDecreased due to various reasons

◦1 percent in United States ◦5.9 percent in Italy ◦12 percent in Brazil◦1.3 to 14.6 percent in Asian Pacific

countries◦ The prevalence of HBV in the dialysis

population in India is reported to range between 3.4% and 42% ( S K Agarwal et al.)

Even in HBsAg-negative dialysis patients with a history of resolved HBV infection, minute amounts of transcriptionally active HBV DNA can be detected by polymerase chain reaction in peripheral blood mononuclear cells and serum samples from about 50 percent of patients.

This phenomenon is associated with deletions in the pre-S1 region of the viral genome, which affected the S promoter, thereby reducing the production of HBsAg.

Patients on peritoneal dialysis have a lower risk of acquiring HBV infection compared to those on long-term hemodialysis.

There is a reported 19-fold difference in seroconversion rates.

In the majority of dialysis patients, testing for HBsAg is sufficient for the diagnosis of HBV infection.

Negative HBsAg test does not preclude absolutely the presence of occult HBV infection.

Occult HBV infection has been defined by positivity in nested PCR assays with sensitivity down to 10 copies/mL ( 9% in a canadian study)

PreventionIn addition to these standard precautions, measures

specific to hemodialysis units are also important to prevent nosocomial HBV infection .

Wearing gloves before contact with patients or dialysis equipments

Routine cleaning and disinfection procedures Prohibition of sharing instruments or medications

among patients Preparing and distributing medications from a

centralized area Avoiding the use of medication supply carts Regular screening of HBsAg status in non-immune

individuals Hepatitis B vaccination of patients and staff

Segregation and reuse of dialyzers

Failure to segregate and use dedicated hemodialysis machines for HBsAg positive patients is associated with an increased incidence of HBV infection.

United States national surveillance in 1997 showed no difference in the incidence of HBV infection between centers that practiced segregation of dialysis rooms and those that did not

Dialyzer reuse was also not associated with a higher risk of HBV infection both in patients and in staff.

Nevertheless, the Centers for Disease Control (CDC) recommended that dialyzers from HBsAg-positive patients be excluded from reuse programs

Laboratory testing during the acute or chronic phases of HBV infection can reveal elevations in the concentration of alanine and aspartate aminotransferase levels (ALT and AST).

Hypotransaminasemia is a well-recognized feature in dialysis patients with or without liver disease.

The normal range of transaminases should be adjusted downwards, otherwise the incidence or severity of clinical liver disease might be underestimated.

Levels of 24 IU/L and 17 IU/L have been recommended as the upper limits of normal for AST and ALT, respectively, in dialysis patients

Acute hepatitis B in dialysis patients is more likely to result in chronic infection compared to non immunosuppressed individuals.

Up to 80 percent of acutely infected dialysis patients may become chronic carriers

The manifestations of chronic hepatitis B or HBV-induced cirrhosis in dialysis patients are identical to those without renal failure.

Aminotransferase levels indicate hepatitic activity, but need to be interpreted according to the adjusted normal ranges.

The level of gamma glutamyltranspeptidase may be increased, which could signify bile duct injury.

Progression of liver disease manifests as hypoalbuminemia, coagulopathy, and development of complications such as hypersplenism, ascites, esophageal varices, or hepatic encephalopathy.

Considerations for combined liver and renal transplantation may be warranted in dialysis patients with severe irreversible liver disease.

Co-infection with the hepatitis D virus can lead to more severe liver disease, and needs to be investigated when clinically indicated.

TreatmentClinical course of HBV infection in dialysis patients

appears less severe.

The aim of management is to minimize the progression of liver disease and for the early detection of liver complications including hepatocellular carcinoma.

Treatment is indicated in HBsAg-positive patients with evidence of disease activity, as indicated by viral replication and abnormal transaminase levels, preferably corroborated by examination of liver histology.

A level of 4 to 5 log10 copies/mL for HBV DNA is usually taken as the threshold to start treatment.

With the advent of more sensitive quantitative assays, it remains to be investigated whether the treatment level needs to be adjusted downwards.

HBeAg can be negative in patients with precore- or core promotor-mutant infection despite active disease.

In view of the side effects of interferon in patients on dialysis, nucleotide or nucleoside analogues are better choices.

Entecavir is the recommended first-line oral therapy in patients with kidney diseases.

The doses of all medications must be adjusted appropriately according to renal function.

Hep B and renal TransplantationAmong HBsAg positive patients, reactivation of

HBV replication is variably defined by the appearance of HBV DNA in a patient who has had undetectable HBV DNA previously, or by a >1 to 2 log increase in HBV DNA.

Among HBsAg negative, anti-HBc positive patients, reactivation is defined by the reappearance of HBsAg or HBV DNA or an increase in HBV DNA in those with detectable HBV DNA prior to start of immunosuppressive therapy.

The risk of reactivation of HBV replication following transplantation is related to the status of serologic and virologic markers at the time of kidney transplantation.

Patients who are HBsAg positive have higher risk than patients who are HBsAg negative, anti-HBc positive.

Among those who are HBsAg positive, patients who are HBeAg positive or have high levels of HBV DNA in serum have higher risk.

Reactivation can also occur in patients who were HBeAg negative or had undetectable serum HBV DNA prior to transplant.

Reactivation of HBV replication has also been reported in those who were HBsAg negative but anti-HBc positive

Risk factors for liver failure among infected patients

Immunosuppression can accelerate progression of HBV-related liver disease.

Hepatitis associated with HBV reactivation can lead to liver failure; the risk is higher in patients with cirrhosis.

Among HBsAg positive patients, a liver biopsy, performed prior to and, if indicated, after renal transplant, can help determine the stage of liver disease and assess the risk of liver failure.

Administration of prophylactic or pre-emptive antiviral therapy - liver failure should be very low

Risk factors for de novo HBV infection following transplantation De novo infection may occur through receipt of a kidney

from an infected donor.

The kidney from an HBsAg positive donor must not be transplanted into an HBsAg-negative and anti-HBs-negative recipient.

There is a low risk of transmission of HBV infection from HBsAg-negative, anti-HBc positive donors to HBsAg negative recipients;

The risk is even lower if the recipient is anti-HBs positive

EVALUATION PRIOR TO TRANSPLANT

All patients who are being evaluated for renal transplantation should be tested for HBV infection.

Standard tests in the evaluation of potential kidney transplant recipients and

kidney donors include HBsAg and anti-HBs, and if both are negative anti-HBc should be tested.

Alternatively, all three markers can be tested at the same time

Chronic HBV infection is not a contraindication to kidney transplantation.

HBV-infected patients should be further evaluated prior to transplantation.

Patients should be tested for HBeAg and serum HBV DNA in order to determine the risk for reactivation of HBV infection.

Patients who are HBeAg-positive or have high levels of HBV DNA prior to transplantation are at higher risk for reactivation.

It is advisable that HBsAg-positive patients undergo liver biopsy to determine whether cirrhosis is present.

Patients with cirrhosis are at higher risk for hepatic failure following transplantation because of the immunosuppressive therapy that is used to prevent rejection.

Such patients used to be ineligible for renal transplantation because of an unacceptably high rate of liver-related mortality .

Patients with cirrhosis may be considered for kidney transplantation, providing cirrhosis is compensated (ie, without complications and providing there is no evidence of portal hypertension indicated by hepatic venous pressure reading or reduced platelet count.

Non-invasive assessments of liver fibrosis and cirrhosis with panels of routine laboratory tests or special biomarkers such as FibroTest, and with measurement of liver stiffness using ultrasound.

These tests have been validated in patients with hepatitis C, and are more accurate in detecting cirrhosis than in differentiating different stages of hepatic fibrosis.

The validity of these tests in patients with hepatitis B, particularly those with kidney failure or kidney transplantation is less certain, however.

PREVENTION OF REACTIVATION OF HBV REPLICATION AFTER TRANSPLANTATION

HBsAg positive patients

Prophylactic strategy: antiviral agents are administered to all patients.

Preemptive approach: transplant recipients are periodically (ie, at least every two months for the first year and every six months thereafter) monitored for viremia using the polymerase chain reaction (PCR) assay to permit prompt treatment after the detection of HBV DNA in a patient who previously had undetectable serum HBV DNA or a marked increase (eg, 10-fold or 1 log) in serum HBV DNA in a patient who previously had a low serum HBV DNA level

Reduction of immunosuppression

For patients at risk for reactivation of HBV replication, use lowest level of immunosuppression that is necessary to prevent rejection of the transplanted kidney.

The specific immunosuppressive regimen varies between centers and depending upon individual patient characteristics such as immunologic risk for rejection, tolerance to specific immunosuppression medications, and the absence or presence of prior antibody induction therapy.

For patients who are at low risk for rejection, aim to reduce the dose of prednisone to 5 mg daily or below.

The 2009 KDIGO clinical practice guidelines suggest, among patients who are at low-immunologic risk and who also receive induction therapy, glucocorticoids may be discontinued during the first week after transplantation

All HBV-infected transplant recipients who have an increase in HBV DNA concentration either with or without abnormal ALT, should be treated with an antiviral agent.

Antiviral therapies are effective in treating reactivation of HBV infection among transplant recipients, even when there is evidence of hepatic failure (ie, when used as salvage treatment)

However, antiviral therapy is less effective when administered as salvage treatment.

The optimal antiviral agent depends upon the preventive therapy used.

Entecavir for both prophylaxis and for treatment of reactivation of HBV replication in lamivudine-naïve patient.

Although most of the experience in renal transplant patients is with lamivudine, lamivudine is associated with a high rate of resistance.

Entecavir is among the most potent agents, has a low rate of resistance with long-term treatment (approximately 1 percent after five years of therapy), and is not nephrotoxic compared with adefovir or tenofovir.

Tenofovir may be an acceptable alternative particularly in patients with lamivudine resistance, but it has been associated with nephrotoxicity.

For patients who have been treated with prophylactic lamivudine and have developed resistance, adefovir or tenofovir (preferred to adefovir in countries where this is available) can be added to lamivudine (rather than stopping lamivudine), since combination therapy may reduce the development of resistance to the second drug.

These patients may respond to entecavir, but lamivudine-resistant HBV is less sensitive to entecavir compared with wildtype HBV (without lamivudine-resistant mutations).

Despite the use of a higher dose of entecavir, the rate of entecavir resistance is higher in patients with prior lamivudine resistance compared with patients who have not been exposed to lamivudine.

The addition of adefovir or tenofovir is thus preferred in patients with lamivudine-resistant HBV

FibroScan testHow does the Fibroscan device work?The Fibroscan device (Echosens) works by measuring

wave velocity.

In this technique, a 50-MHz wave is passed into the liver from a small transducer on the end of an ultrasound probe .

The probe also has a transducer on the end that can measure the velocity of the shear wave (in meters per second) as this wave passes through the liver.

The shear wave velocity can then be converted into liver stiffness, which is expressed in kilopascals.

FibroTestFibroTest involves assessment of alpha-2-macroglobulin,

alpha-2-globulin (haptoglobin), gammaglobulin, apolipoprotein A1, GGT, and total bilirubin

Patient's age, and sex.

Results from the individual assays are combined and are used to classify patients having mild fibrosis (F0-F1), significant fibrosis (F2-F4), or an indeterminate stage of fibrosis.

The sensitivity and specificity for detection of significant fibrosis are approximately 75 and 85 percent, respectively

ActiTest is a modification of the FibroTest that incorporates ALT and reflects both liver fibrosis and necroinflammatory activity.

ActiTest appears to improve identification of more advanced fibrosis associated with histological inflammation.

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Reference : Uptodate.com

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