Chronic viral hepatitis infection in patients on renal replacement therapy

Thomas Fehr and Patrice M. Ambühl

Division of Nephrology, Department of Internal Medicine,
University Hospital, Zurich, Switzerland

thomas.fehr@tbrc.mgh.harvard.edu

The magnitude of the problem

In the up-coming year 2004 two ground-breaking medical achievements will be celebrated: 60 years of the first successful haemodialysis treatment in acute renal failure (Willem J. Kolff, Boston 1944) and 50 years of the first successful renal transplantation (Joseph E. Murray, Boston 1954). These two therapeutic options have saved lives of patients with renal failure, that would have died prior to the availability of facilities for long-term chronic dialysis in the sixties. Since that time more than 500’000 renal transplants have been performed in the whole world. At the beginning of the third millennium, when dialysis and transplantation have become medical routine, we face two new and major problems: (i) Dialysis patients still have a very poor outcome with a mean survival time of only 4 years [1]. (ii) After successful management of acute renal allograft rejection, half of the kidney grafts are now lost within 12 years due to chronic allograft nephropathy [2], which has become the third or fourth most important reason for renal transplantation in certain centres (after diabetes, hypertension and glomerulonephritis).

There are two main reasons for these problems: cardiovascular complications and infections. Patients on renal replacement therapy are prone to infectious complications: dialysis patients are immunosuppressed due to the uraemic milieu and due to repetitive invasive diagnostic and therapeutic procedures (operations, arterial punctures for dialysis and for radiocontrast investigations, permanent catheters), whereas renal allograft recipients are at risk because of chronic immunosuppressive medication. In both populations chronic hepatitis B and C virus (HBV and HCV, respectively) infections are a major problem for the following reasons: (i) HBV and HCV can cause renal failure due to different types of glomerulonephritis (mainly membranous and membrano-proliferative); these diseases may also recur in the renal transplant [3]. (ii) Patients with chronic renal failure are prone to acquire HBV and HCV infection due to a higher rate of blood transfusions, which were necessary to treat hyporegenerative anaemia of chronic renal failure. Fortunately, this has become a minor cause due to highly successful anaemia treatment with recombinant human erythropoietin and aggressive supplementation of iron and vitamins. However, repetitive invasive diagnostic and therapeutic interventions may still cause major bleeding episodes in the context of uraemic platelet dysfunction. (iii) HBV and HCV infections are hard to treat because the available drugs have only limited efficacy and a high rate of side effects (especially interferon and ribavirin). These side effects may be accentuated and the drug dosage is difficult in the context of renal failure. (iv) No vaccination for HCV infection is available.

The following paragraph will illustrate epidemiological aspects of hepatitis virus infections in the patient population on renal replacement therapy. The subsequent two parts will address the diagnostic and therapeutic approach.

Epidemiology

The prevalence of HBV and HCV infection in patients on renal replacement therapy considerably varies between different regions (Table 1; [4]). It is usually similar in dialysis patients and renal transplant recipients, but clearly higher compared to the general population of the respective country indicating that most of the infections occur during the time on dialysis.

Two epidemiological patterns for hepatitis virus infections in patients on renal replacement therapy can be observed. First a geographical distribution becomes apparent, which reflects the disease burden in the general population: in a global perspective, a higher prevalence is observed in the Middle and Far East compared to Europe and the United States. Within Europe a north – south gradient of increased prevalence has been reported. Second, countries with a lower socio-economical status tend to have a higher prevalence of HBV and HCV infection among dialysis patients, probably indicating lower resources for technical equipment of haemodialysis units, for HBV vaccination programs and for erythropoietin treatment of renal anaemia. Repetitive blood transfusions are still the single most important factor for HBV and HCV infection in this patient population, whereas infection through contamination of haemodialysis machines is rarer [5]. In renal transplant patients transmission of hepatitis virus infections with the transplanted organ have been reported [6].

Diagnostic approach

Since the therapeutic options for HBV and HCV infection are limited and the success of HBV vaccination reduced in patients on renal replacement therapy (see next paragraph), a great effort should be made towards early diagnosis of hepatitis virus infections during the period of chronic renal failure (ideally at a creatinine clearance of 30-60 ml/min). For patients with various types of glomerulonephritis, determination of serological hepatitis parameters are part of the diagnostic work-up of the primary renal disease irrespective of renal function at presentation. All the mentioned tests can be used in patients with moderate to severe renal failure, in patients on dialysis and after renal transplantation. However, the sensitivity of serological (antibody-based) tests is generally lower in renal patients due to immunological hyporesponsiveness induced by uraemia or drug-induced immunosuppression.

Diagnosis of infection

HBV infection. Patients at risk are screened for hepatitis B by detection of surface antigen (HBsAg) in serum. HBsAg positivity indicates HBV infection with continuous presence of viral antigen. However, it is not equivalent with active viral replication, which should be assessed by a qualitative (HBeAg) or a quantitative test (HBV DNA PCR or hybridisation). We suggest to always use a DNA-based quantitative test to assess HBV replication for two reasons: (a) Guidelines for therapy decisions are based on these tests. Whether PCR has any advantage over hybridisation is unresolved. Low PCR titres (< 1x10⁶ copies/ml) are usually associated with negative hybridisation tests, and the benefit of therapy in these patients has not been established so far. (b) A positive HBeAg test always reflects viral replication. However, a negative test may either result from absence of replication or from a mutation of the virus in the pre-core region, which is often associated with even higher viral titres.

HCV infection. The screening for HCV infection is performed by anti-HCV antibody test, which is cheap and easy to perform. However, serology is associated with problems of specificity as well as sensitivity in patients on renal replacement therapy. False-positive results may occur due to polyclonal B cell stimulation in the context of other infections (i.e. human immunodeficiency virus) or autoimmune diseases (i.e. systemic lupus erythematosus) [7, 8]. Fortunately, this problem could be ameliorated with the introduction of newer generation anti-HCV screening tests [9]. False-negative results have been described in dialysis patients. A recent report from Israel indicated that 9% of seronegative haemodialysis patients had positive HCV RNA tests by PCR [10]. This is a compelling finding that profoundly influences infection containment programs in haemodialysis units. We therefore suggest the following procedure: all patients with moderate to severe renal failure should receive a HCV screening test by serology. In case of a positive result, it should be followed by HCV RNA PCR to determine the viral load, which is the basis for therapeutic decisions. Usually around 80-90% of patients harbour replicating virus, whereas the others have successfully cleared HCV infection [11]. In contrast, all patients entering a renal replacement program (dialysis or renal transplantation) should at least undergo one HCV RNA PCR test irrespective of their serological status, since active viral replication has profound implications regarding both individual as well as epidemiological aspects.

Assessment of the severity of liver disease and decision for therapy

In the case of HBV and HCV infection, therapeutic decisions are based on the following three requirements : (i) demonstration of viral replication by HBV DNA and HCV RNA PCR or by HBV DNA hybridisation; (ii) biochemical activity of hepatitis shown by repeatedly elevated transaminase levels (usually > 1.5x the upper normal value); (iii) liver biopsy showing at least either mild inflammatory and/or mild fibrosing liver disease. A number of studies have tried to determine a single test or a combination of serological tests (usually transaminases and a panel of fibrosis markers) to assess severity of liver disease in order to avoid liver biopsy, which may be associated with a high risk of bleeding in uraemic patients and patients on haemodialysis, which receive anticoagulation therapy with heparin on a regular base during dialysis treatment. The most promising combination of 6 markers has been published as FibroTest [12]. However, it was not evaluated in immunosuppressed and in dialysis patients. We recently compared determination of transaminase and hyaluronate (a fibrosis marker) serum concentrations to liver biopsy results in over 40 renal allograft recipients and found no correlation between serological and histological findings (Figure 1, [11]). Therefore, we suggest to perform liver biopsy in all patients with moderate to severe renal failure and patients on renal replacement therapy, if they have replicating HBV or HCV infection and elevated transaminases and if a drug therapy would be feasible and accepted by the patient in case of positive histological findings. In patients with a high risk of bleeding, prophylaxis with Deamino-D-arginine vasopressin for uraemic platelet dysfunction is recommended [13], and a transjugular biopsy approach should be evaluated.

Figure 1. Correlation of histological and biochemical parameters in 41 renal allograft recipients with chronic HBV or HCV infection [11].

Left panel:Correlation of the fibrosis marker hyaluronate with the histological score of liver fibrosis according to Ishak (scores of 5 and 6 reflect focal and diffuse cirrhosis, respectively; 6 is the maximum score). Right panel: Correlation of serum glutamate-oxalacetate transaminase (GOT) concentration at the time of biopsy with the histological score of necroinflammatory liver lesions (MHAI; maximum score is 18).

HBV and HCV infection harbour the risk of developing hepatocellular carcinoma. Therefore, and irrespective of therapeutic decisions, these patients should be followed by yearly sonogaphic evaluation of the liver and determination of alpha-fetoprotein every 6 months for early diagnosis of this otherwise inevitably fatal malignancy.

Therapeutic approach

General remarks: role and risk of interferon therapy

An overview of therapeutic options for hepatitis virus infections in renal patients is given in Table 2. The standard therapies for HBV and HCV infection involve application of interferon-. The main side effects of this treatment are a flu-like syndrome, myelotoxicity with development of single or multiple lineage cytopenias and neurologic/psychiatric symptoms. Therefore, patients with a neurologic and/or psychiatric disorder are usually excluded from therapy as are patients with anaemia, leukopenia and thrombocytopenia. All patients with advanced renal failure suffer from hyporegenerative anaemia, and some may have thrombocytopenia in the context of the primary disease and its treatment (e.g. systemic lupus erythematosus). Therefore, aggressive treatment of anaemia with erythropoietin, iron and vitamins should be performed in renal patients before beginning a therapy with interferon. When patients with autoimmune disorders are treated with interferon, they should be meticulously followed for symptoms and signs of their primary disease, since interferon may cause a flare-up. However, for virus-induced autoimmunity (such as HCV-mediated cryoglobulinaemia) antivirals are the mainstay of specific treatment.

Special emphasis should be given to renal allograft recipients with replicating HBV and HCV infection. Several reports of small case series indicate that interferon as non-specific immunostimulatory agent causes acute often humoral allograft rejection in about 20-30% of patients [14-16]. Therefore, interferon should be avoided in this patient population. However, a closer look reveals that rejection could be successfully treated in some cases by immediate stop of interferon and standard rejection treatment including steroids and anti-T cell antibodies [17]. Based on these findings we suggest to chose primarily a therapeutic strategy without interferon in renal transplant patients. In particularly desperate cases, interferon could be offered to a patient after open discussion on the risks of allograft rejection with subsequent intensified immunosuppressive treatment and potential graft loss [18]. These patients should be very closely monitored for acute allograft rejection during this treatment.

Specific therapeutic options in different patient groups

HBV infection. Mainstay of treatment of this disease is prevention! A highly efficient recombinant vaccine for HBV is available and has been effective also in renal patients. However, the response rate in patients with advanced renal failure and patients on dialysis is clearly lower [19]. Therefore, vaccination should be performed at an early stage of moderate renal failure (creatinine clearance > 40 ml/min). For patients with advanced renal failure and haemodialysis patients, a special vaccine with a four-fold higher dose can be used to obtain a better response rate.

In case of established replicating HBV infection with histological alterations antiviral therapy should be considered. In patients with advanced renal failure and in dialysis patients – especially transplant candidates – a therapeutic trial with interferon- should be performed, since it offers the highest efficacy. In case of treatment failure or serious contraindications, the antiviral drugs lamivudine and adefovir-dipivoxil can be used [20]. Whereas lamivudine has been a standard treatment for years, adefovir-dipivoxil has recently proven to be effective against lamivudine-resistant HBV. Combination treatment has equal primary response rates, but a lower rate of therapy failure due to lamivudine resistance than monotherapy with lamivudine. However, no controlled trials have been performed with adefovir-dipivoxil in patients with advanced renal failure or renal allograft recipients. HBV pre-core mutants (HBeAg-negative) are especially difficult to treat. Those patients as well as patients scheduled for renal transplantation with contraindications for interferon- should primarily be evaluated together with an experienced hepatologist. The risk of replicating HBV infection has to be balanced carefully to the risk of developing lamivudine resistance and therefore losing a treatment option for the time after transplantation.

For patients with a renal allograft we support first-line antiviral treatment with lamivudine, therefore avoiding the risk of rejection by interferon. A recent report has shown an excellent response rate (biochemical response 80-100%, virological response 67-100%; [21]). In case of treatment failure or development of lamivudine resistance, a trial with adefovir-dipivoxil or a combination of both antivirals can be performed, and the patient should be followed together with an experienced hepatologist.

HCV infection. Therapy of HCV infection in renal allograft recipients is difficult, since interferon should be avoided and other therapy regimens (mainly ribavirin alone) have failed to induce a sustained virological response or amelioration of liver histology [22]. However, our recent report of liver biopsy results in 23 long-term HCV-infected renal allograft recipients showed that none of them had developed cirrhosis after a mean follow-up of 12 years after renal transplantation [11]. It indicates that part of the liver tissue damage may be induced by immunopathology and not by HCV directly [23], and hence may even improve under immunosuppressive therapy. Therefore, renal allograft recipients with replicating HCV infection should not receive therapy to date except patients included in clinical studies and individual cases with very aggressive disease. These should be followed together with a hepatologist, and interferon may be offered under close monitoring of renal function [18].

Treatment of HCV infection should therefore be attempted in the pre-transplant period. Patients with moderate to severe renal failure can be treated according to the standard treatment protocols, which at the moment consist of PEG-interferon and ribavirin [24]. In dialysis patients ribavirin should only be given, when blood levels can be monitored due to a high risk of haemolytic anaemia if overdosed [25, 26]. When interferon treatment alone is used, the rate of sustained virological response is lower. However, two recent reports showed a response rate of 40-60% in this population. All patients that were subsequently transplanted, remained HCV RNA PCR-negative indicating definitive cure of disease [27], and only one developed recurrent glomerulonephritis [28].

Key messages

1. Every patient with moderate to severe chronic renal failure (creatinine clearance < 40 ml/min) should be evaluated for HBV and HCV infection by screening for HBsAg and anti-HCV antibodies, respectively.
2. Every patient entering a renal replacement program should undergo at least one evaluation by quantitative HCV RNA PCR to detect seronegative HCV infection.
3. Every patient with moderate to severe chronic renal failure (creatinine clearance < 40 ml/min) should be vaccinated against HBV.
4. Therapy decision for HBV and HCV infection is based on virological (PCR), biochemical (liver enzymes) and histological evidence of disease.
5. Treatment of HBV and HCV infection should be attempted prior to renal transplantation.
6. Interferon- is the first-line treatment in patients with chronic renal failure and patients on dialysis, but should be avoided as a first-line treatment in renal allograft recipients due to a high rate of allograft rejection.
7. Lamivudine has an excellent response rate for HBV infection in renal allograft recipients.
8. Ribavirin can be safely used for treatment of HCV infection in patients with chronic renal failure and in renal allograft recipients, but only with measurement of blood levels in dialysis patients.

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Correspondence to:
Thomas Fehr M.D., Transplantation Biology Research Center,
Massachusetts General Hospital,
MGH East CNY 149, 13th street,
Boston, Massachusetts 02129, USA;
Phone: +1 617 726 4070, Fax: +1 617 724 9892,
E-mail: thomas.fehr@tbrc.mgh.harvard.edu