1Dialysis Unit, Groupe Médical dOnex, Onex and 2Bioanalytique-Riotton, Geneva, Switzerland
Correspondence and offprint requests to: Hans Freudiger, Dialysis Unit, Groupe Médical dOnex, CH-1213 Onex, Switzerland. Email: freudigerh{at}bluewin.ch
Keywords: case report; haemodialysis; hepatitis B; lamivudine; reverse seroconversion
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Introduction |
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Hepatitis B infection is still a major concern in haemodialysis units, responsible for considerable morbidity among these patients. In Switzerland the prevalence of HBV infection among haemodialysis patients reported in 2000 was 1.63%, which is comparable with the incidence of 1.2% found in 1993 in the USA for a similar population [5]. Reverse seroconversion of HBV in HBsAg negative, anti-HBs and anti-HBc-positive haemodialysis patients, however, is not described in the literature.
We describe a reverse seroconversion of HBV in a 73-year-old patient subjected to thrice weekly haemodialysis for 5 years, who never received immunosuppressive therapy or corticosteroids.
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Case |
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At the age of 18 years, asymptomatic proteinuria was found, but no specific diagnostic tests were performed and no treatment was given. At the age of 59 years, a renal biopsy was performed for persistent proteinuria, hypertension and progressive renal insufficiency. The histology was consistent with focal segmental glomerulosclerosis. No treatment other than for hypertension was given. Haemodialysis was started in 1995 at the age of 65 years.
The patient smoked one pack of cigarettes per day (40 UPA), suffered from chronic obstructive lung disease with chronic bronchitis and occasional acute decompensation necessitating antibiotic treatments. No steroids were given.
At the age of 58 years, cholecystectomy for cholelithiasis was performed. The postoperative evolution was uneventful.
At the age of 63 years she underwent aorto-bifemoral bypass surgery with sympathectomy for severe peripheral vascular disease.
In 1995, at the age of 65 years, she was admitted to the university hospital with severe fatigue and advanced renal failure. Severe anaemia was diagnosed and two units of packed red cells were transfused. Chronic thrice-weekly haemodialysis was commenced shortly thereafter. Initial screening for HBsAg, hepatitis C antibodies (HCV Ab) and HIV was negative and liver function tests (aminotransferases, bilirubin and alkaline phosphatase) were within normal limits. Anti-HBs and anti-HBc were not obtained.
Treatment with erythropoietin and i.v. iron substitution was started to maintain haemoglobin at 110 g/l, and to obtain this goal no blood transfusions were given.
Osteoporosis was treated with regular i.v. applications of bisphosphonates. Calcium carbonate and 1-25 dihydroxy cholecalciferol were given to control hyperparathyryoidism and serum phosphorus. The patient had not been vaccinated against hepatitis B.
In January 1999, a pyloric ulcer was found and a Helicobacter pylori infection treated with the usual therapy combining antibiotics and proton blockers. The patient did not travel outside of the country, and all dialysis treatments were given in centres not accepting HBsAg-positive patients.
Routine monthly liver function tests and 6-monthly screening for HBsAg, HCV Ab and HIV were persistently negative until 4 years after the beginning of haemodialysis treatment, when HBsAg was found to be slightly positive with one test (MEIA, AxSYM Abott), but could not be confirmed with another test (ELFA, Vidas bioMérieux). HBV DNA was negative. This serological constellation was considered as a non-specific reaction, although an early state of a viral reactivation could not be excluded (Table 1). The patient remained asymptomatic and liver function tests remained within normal limits. One month later HBsAg was again negative and anti-HBs remained, at least for a year, at a low titre, considered however sufficient to give immunity.
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Antiviral therapy with lamivudine 100 mg/day was started at the end of February 2001. Viral replication became rapidly undetectable, assessed by a hybridization method and liver function tests normalized. No seroconversion was observed and HBsAg remained postive during a 12-month observation period (Table 1). One year after lamivudine was started the patient died of an unrelated cause.
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Discussion |
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To the best of our knowledge we herein describe for the first time a chronic haemodialysis patient with reverse seroconversion of hepatitis B. Since our patient had never presented with acute hepatitis B, we could not determine the HBV subtype strains and therefore we cannot exclude re-infection with another viral strain. Reactivation, however, appears more probable as re-infection by a viral subtype with a mutated S, preS1 or preS2 region would have been associated neither with disappearance of anti-HBs, nor with the reappearance of HBsAg, as observed in our patient [7,8]. Furthermore, mutant viruses may lead to severe hepatitis and decrease or eliminate the expression of HBeAg. Our patient had only mild elevation of liver enzymes and expressed HBeAg.
Ortiz-Interian et al. [9] describe a haemodialysis patient co-infected with HIV with reactivation of latent HBV with resurgence of HBsAg and concluded that immunosuppression associated with HIV and/or end-stage renal disease was responsible for this reactivation. Blanpain et al. [2] describe three patients with anti-HBs and anti-HBc who had clinically significant HBV reactivation within the first 3 years after solid organ transplantation and reviewed 16 other patients from the literature. All patients were immunosuppressed either by chemotherapy for neoplasia, received immunosuppressive therapy for transplantation, were infected with HIV or suffered from acquired immunodeficiency syndrome. As in our patient, all these patients redeveloped HBsAg and HBV DNA, lost their anti-HBs and, contrary to our patient, the anti-HBc. Clinical manifestations of HBV reactivation ranged from the absence of symptoms to fulminant hepatic failure and death. Sixteen per cent of these patients died as a direct result of HVB reactivation, and the incidence of HBV reactivation among patients with anti-HBs and anti-HBc was estimated at 5%.
The development of anti-HBs together with the concomitant disappearance of HBsAg is generally considered as evidence of HBV clearance. Sensitive polymerase chain reaction techniques have, however, revealed that some of these patients can still harbour small quantities of HBV DNA in their liver and blood despite the presence of anti-HBs [6,10], allowing reactivation of HBV to occur whenever there is a change in the immunological response to the HBV.
Whereas different clinical situations such as treatments of cancer with chemotherapy, anti-rejection drugs and corticosteroids in transplantation are known to trigger such exacerbation episodes, haemodialysis treatment by itself is not known to have this effect. Increased susceptibility to HBV reactivation in immunosuppressed patients has been related with an impairment of the T- and B-cell function induced by chemotherapy or by the human immunodeficiency virus infection. Furthermore, steroids stimulate HBV replication by a direct effect on a glucocorticoide responsive element present in the HBV genome [8].
Our patient was not receiving steroids, but the combination of relative malnutrition, chronic bronchitis, haemodialysis and a possible severe gastric ulcer with H.pylori infection probably induced sufficient immunosuppression to reactivate HBV DNA replication. The relatively low titre of anti-HBs might have been insufficient to protect against HBV viral replication. Furthermore, immunosuppression might blunt the anti-HBs production, usually occurring in the case of HBV synthesis. This may explain the persistence of HBsAg, and the only weak and fluctuating anti-HBs response in our patient, despite clearance of HBV DNA.
A booster dose of recombinant HBsAg vaccine might help to maintain protective immunity and may have to be considered in anti-HBs and anti-HBc-positive haemodialysis patients once the anti-HBs titre is considered too low. Such a therapeutic strategy has been proposed for anti-HBs and anti-HBc-positive patients after transplantation [7].
Reactivation of HBV may lead to serious and even fatal liver disease in a significant percentage of patients [14,7]. Prompt treatment with lamivudine is usually well tolerated and leads to suppression of viral replication and normalization of liver function tests [6]. Preliminary data suggest that HBeAg and HBsAg seroconversion may predict durable results after discontinuation of lamivudine. Unfortunately the rate of seroconversion is relatively low, even after prolonged treatment with lamivudine. Rare complications of lamivudine treatment include pancreatitis and lactic acidosis, and exacerbation of hepatitis following discontinuation of therapy. Drug resistance is common. Our patient had an excellent tolerance of the drug, prompt normalization of liver enzymes and clearance of HBV virus as assessed by a hybridization technique, but even after 12 months of therapy she had no seroconversion.
As the number of patients with serious co-morbidities starting haemodialysis treatment continues to rise, reverse seroconversion of HBV might become of considerable concern.
Conflict of interest statement. None declared.
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References |
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