Retrospective evaluation of the risk of hepatitis B virus reactivation after transplantation

Abstract: Numerous case reports describe patients with previously documented immunity developing active hepatitis B virus (HBV) infection after transplantation. However, the risk of reactivation of HBV under long‐term immunosuppression in hepatitis B core antibody (HBcAb)‐positive, hepatitis B surface antigen (HBsAg)‐negative transplant recipients has not been clearly described. Herein, we present a long‐term follow‐up for 49 HBcAb‐positive, HBsAg‐negative recipients (27 liver, 18 kidney, 4 pancreas) transplanted between June 1996 and April 2001. Among these, 37 recipients (76%) were HBsAb positive at transplantation. Immunosuppression consisted of various antibody induction regimens in 20 (41%) of the recipients with either tacrolimus (33 [67%])‐ or cyclosporine (16 [33%])‐based maintenance immunosuppression. The incidence and duration of HBV prophylaxis was not significant. No patient received hepatitis B immunoglobulin (HBIG) before or after transplantation. Additionally, only two patients received lamivudine, which was started post transplant without clinical indication. The mean length of follow‐up was 3.1±1.4 years. At the last follow‐up, overall patient and graft survival were 98% and 96%, respectively. Patient survival was 96% in liver, 100% in kidney, and 100% in pancreas transplant recipients. The graft survival for each organ type was 93% in liver, 100% in kidney, and 75% in pancreas transplant recipients at the end of follow‐up. There was no incidence of HBV reactivation defined as recurrence of HBsAg and/or HBV DNA positivity. These data suggest that the risk of reactivation of HBV in HBcAb‐positive, HBsAg‐negative transplant recipients under immunosuppression is negligible, regardless of immunosuppressive regimen, lamivudine prophylaxis, or HBsAb status. These patients should have access to transplantation as they enjoy excellent patient and graft survival rates.     

Late onset of hepatitis B virus reactivation following hematopoietic stem cell transplantation: successful treatment with combined entecavir plus tenofovir therapy

L. Milazzo, M. Corbellino, A. Foschi, V. Micheli, A. Dodero, A. Mazzocchi, V. Montefusco, G. Zehender, S. Antinori. Late onset of hepatitis B virus reactivation following hematopoietic stem cell transplantation: successful treatment with combined entecavir plus tenofovir therapy.
Transpl Infect Dis 2011. All rights reserved Abstract: Prophylaxis with lamivudine (LAM) is recommended for hepatitis B core antibody‐positive allogenic hematopoietic stem cell transplant (HSCT) recipients, but the optimal timing for the institution and duration of the prophylaxis is still unknown. Furthermore, considering the high rate of mortality associated with hepatitis B virus reactivation (HBV‐R), the most potent and long‐term effective antiviral regimen should be considered. We report here a case of late onset of HBV‐R after a long‐term prophylaxis with LAM in a patient who underwent HSCT for non‐Hodgkin lymphoma and who was successfully treated with a combination antiviral regimen including entecavir and tenofovir disoproxil fumarate.     

Hepatitis B reactivation after kidney transplantation in hepatitis B surface antigen‐negative,core antibody‐positive recipients

Nowadays, intensive immunosuppressive therapy including rituximab is commonly used prior to kidney transplantation (KT), raising concerns over hepatitis B virus (HBV) reactivation among hepatitis B surface antigen (HBsAg)‐negative and anti‐hepatitis B core (HBc)‐positive KT recipients. Recent practice guidelines suggested watchful monitoring or antiviral prophylaxis for the first 6‐12 months, the period of maximal immunosuppression. However, the actual risk for HBV reactivation, and whether short‐term antiviral therapy in the early period is necessary, remains unclear. A total of 449 HBsAg‐negative and anti‐HBc‐positive KT recipients were analysed for HBV reactivation. During a median follow‐up of 6.7 (interquartile range: 4.2‐9.4) years, HBV reactivation was observed in 9 patients (2.0%). The median time of HBV reactivation from KT was 2.8 years (range: 1.4‐11.5 years), with cumulative incidence rates of 0%, 1% and 2% for 1, 3 and 5 years, respectively. There were no severe adverse outcomes, including liver transplantation or mortality related to HBV reactivation. The risk of HBV reactivation was not high, even in anti‐HBs‐negative patients (n = 60, 4% at 5 years), ABO mismatch (n = 92, 4% at 5 years), use of rituximab (n = 66, 3% at 5 years) or plasmapheresis (n = 17, 7% at 5 years), and acute rejection (n = 169, 3% at 5 years). In conclusion, the HBV reactivation risk was not high and the time of detection was not clustered in the early post‐KT period. Our findings favour continued watchful monitoring over antiviral prophylaxis in the early period.     

拉米夫定对异基因造血干细胞移植患者乙型肝炎病毒再激活的预防作用

目的探讨拉米夫定对异基因造血干细胞移植患者乙型肝炎病毒再激活的预防作用。方法2003年1月至2004年1月南京市鼓楼医院血液科3例行异基因造血干细胞移植的白血病患者中,2例乙型肝炎病毒表面抗原(HBsAg)阳性,HBV DNA分别为4.75×106拷贝·mL-1和1.15×106拷贝·mL-1。另1例HBsAg阴性,但其供者HBsAg阳性,HBV DNA为3.48×107拷贝·mL-1。对2例HBsAg阳性受者,移植前用拉米夫定;对HbsAg阴性受者干细胞回输时开始用拉米夫定,剂量均为0.1g每日1次,用至移植后1年。结果其中1例HBsAg阳性患者在移植后1个月内HBV DNA较高,波动于(1~1.2)×105拷贝·mL-1,1个月后HBV DNA降低,<3×104拷贝·mL-1。移植后1周丙氨酸转氨酶(ALT)升高,最高达152U/L,持续1周后恢复正常。另1例移植后HBV DNA较低,持续<1×105拷贝·mL-1。无明显肝功能损害,ALT最高达56U/L。接受供者HB-sAg阳性患者移植后HBeAb阳性,HBcAb阳性,HBV DNA<1×103拷贝·mL-1。移植后10dALT升高,最高达205U/L,持续1周后恢复正常。3例患者长期服用拉米夫定耐受性好,无明显毒副反应。结论初步观察表明,拉米夫定可以预防异基因造血干细胞移植患者乙型肝炎病毒再激活,无明显毒副反应。     

Hepatitis B virus reactivation during belatacept treatment after kidney transplantation

We report a case of HBV reactivation following belatacept treatment in a patient who underwent kidney transplantation in 2015 for HIV‐associated nephropathy (HIVAN). Human immunodeficiency virus viral load was undetectable prior to transplantation, and CD4+ lymphocyte count was greater than 300/mL. Baseline HBV serology at transplantation was HBsAg negative, anti‐HBcAb positive, anti‐HBsAb 312 UI/L, and HBeAg negative/anti‐HBeAb positive. Liver function tests were normal, and viral DNA was undetectable. Two years later, the patient presented with severe acute hepatitis after a progressive disappearance of anti‐HbsAb, quickly followed by HBV reactivation. Immunosuppressive treatment was drastically reduced, and treatment with entecavir was started. The outcome was favorable, and HBV DNA became undetectable after 9 weeks of treatment. This is the first report of acute hepatitis related to HBV reactivation in a kidney transplant recipient treated with belatacept. The risk for HBV reactivation in patients treated with belatacept should not be underestimated, especially in those with resolved HBV infection.     

Re‐appearance of hepatitis B virus following therapy with rituximab for lymphoma is not rare in Japanese patients with past hepatitis B virus infection

Background and aim: De novo hepatitis B virus (HBV)‐related hepatitis is a well‐known fatal complication following chemo‐immunosuppressive therapy in patients with past HBV infection (HB surface antigen and serum HBV DNA negative, but HB core antibody and/or HB surface antibody positive). This research was conducted to evaluate the incidence of and clinical features associated with re‐appearance of serum HBV DNA following chemo‐immunosuppressive therapy in Japanese patients with past HBV infection. Methods: This is a retrospective review. Forty‐five patients with past HBV infection who had received chemo‐immunosuppressive therapy for haematological disease were followed up for >6 months, to determine whether the serum test for HBV changed from negative to positive (i.e. re‐appearance of serum HBV DNA following chemo‐immunosuppressive therapy). Results: Re‐appearance of serum HBV DNA was confirmed in five (20.8%) of the 24 patients who had received treatment regimens containing rituximab, but in none of the 21 patients who had not received treatment regimens containing rituximab (P=0.035). The HBV genotype could be determined in four of the five aforementioned patients, and in all four, HBV genotype C, which is the most prevalent genotype in Japan, was identified. Conclusion: This research showed that re‐appearance of serum HBV DNA is not rare in Japanese patients treated with chemotherapy regimens containing rituximab, and no other factors related to such re‐appearance of serum HBV DNA could be identified. Well‐designed clinical studies, including immunological and genetic analyses of the host and of the HBV, are required for further elucidation.     

Sequence variations of precore/core and precore promoter regions of hepatitis B virus in patients with or without viral reactivation during cytotoxic chemotherapy

Reactivation of the hepatitis B virus (HBV) is a well-described complication among cancer patients undergoing cytotoxic chemotherapy. Mutations in the preC/C and the preC promoter regions of HBV have been reported in some patients who developed this condition. A G-to-A mutation at nt 1896 in the preC/C region (HBeAg negative/ anti-HBe positive) has been associated with more severe liver disease than that caused by wild type virus. In addition, it has been suggested that patients with these mutations may be more likely to reactivate than those with the wild type virus. Whether or not such mutations were present before the commencement of or developed during the course of cytotoxic chemotherapy is not known. In this study, 28 cancer patients (consisting of 14 consecutive patients who developed HBV reactivation and another 14 who had no reactivation during cytotoxic chemotherapy) are reported. The objectives were firstly, to determine the prechemotherapy HBeAg status and nucleotide sequences of the preC/C and preC promoter regions of HBV in order to determine if these parameters affected the rate of reactivation, and secondly, for those who developed reactivation, to determine whether the mutations were present before chemotherapy or developed during, possibly as a result of, cytotoxic chemotherapy. HBV DNA was amplified by PCR and nucleotide sequencing performed on samples taken prior to chemotherapy and at the time of reactivation. Results revealed that 16 of the 28 patients were HBeAg negative/anti-HBe positive. Of these 16, four (57%) of the seven patients who had nt 1896 mutation, but only one (17%) of the six who had the wild type HBV genome, developed reactivation. Three had no detectable HBV DNA. In the majority of cases, the type of virus, i.e. wild/mutant at preC/C, that was detected during the reactivation was identical to that detected in the pretreatment samples. With respect to the preC promoter region, the two commonest mutations detected were at nt 1762 (A to T) and nt 1764 (G to A). When this region was translated into amino acid sequences, stop codons leading to truncated X protein at carboxyl terminus were found in four patients, three of whom developed HBV reactivation. We conclude that chronic HBV carriers who are HBeAg negative/anti-HBe positive with nt 1896 mutation (G to A) may be more likely to develop HBV reactivation during cytotoxic chemotherapy than those with the wild type virus. Cytotoxic chemotherapy does not appear to select out mutant HBV, or to be consistently mutagenic in patients who develop HBV reactivation. The occurrence of stop codons in the amino acid sequences of the X protein in three patients who developed HBV reactivation, including one who was detected only at the time of reactivation, is of particular interest, as such mutant viruses remain replication competent.     

T‐ and B‐cell responses and previous exposure to hepatitis B virus in ‘anti‐HBc alone’ patients

A serologic response to hepatitis B virus (HBV) defined as ‘anti‐HBc alone’ is commonly observed, but its significance remains unclear. This study aimed to define the relationship between ‘anti‐HBc alone’ serostatus and HBV infection, including HBV‐specific T‐ and B‐cell memory responses. We enrolled 31 ‘anti‐HBc alone’ patients. Total HBV DNA and cccDNA were tested by nested polymerase chain reaction (PCR) analysis in liver samples from 22 ‘anti‐HBc alone’ patients vs controls (chronic or resolved HBV infection), followed by HBsAg/HBcAg immunohistochemical (IHC) staining. IFN‐γ secretion by HBV‐specific T cells was compared in individuals who were ‘anti‐HBc alone’ (n = 27), resolved HBV (n = 21), chronic HBV (n = 24) and 12 healthy controls using enzyme‐linked immunospot (ELISpot) assays. An HBsAg‐IgG B‐cell ELISpot assay was performed in ‘anti‐HBc alone’ patients before and after one dose of recombinant HBsAg vaccine. The majority (23/31, 74.2%) of the ‘anti‐HBc alone’ individuals were co‐infected with HCV. Infrequent intrahepatic total HBV DNA (2/22, 9.1%) and cccDNA (1/22, 4.5%) were detected in biopsies; HBsAg and HBcAg IHC staining was negative. HBV‐specific T‐cell responses were similar between ‘anti‐HBc alone’ individuals and HBV resolvers. Circulating HBV‐memory B‐cell responses were detected in all ‘anti‐HBc alone’ individuals, consistent with an HBsAg‐specific memory pool. After one HBV vaccine dose, increased anti‐HBs antibody levels were observed, accompanied by an expansion of HBsAg‐specific memory B cells (P = 0.0226). ‘Anti‐HBc alone’ individuals showed HBV‐specific T‐cell and memory B‐cell responses typical of previous viral exposure and protective memory, suggesting a resolved infection.     

High levels of serum hepatitis B virus DNA in patients with 'anti-HBc alone': role of HBsAg mutants

It remains unclear how the detection of hepatitis B core antibody (anti-HBc) in the absence of hepatitis B surface antigen (HBsAg) and antibody (anti-HBs) should be interpreted and whether all patients with this pattern need to be tested for hepatitis B virus (HBV)-DNA. This study aimed at reassessing the significance of 'anti-HBc alone' in unselected sera referred to the clinical laboratory and determining whether significant HBV viraemia can be found in this setting. Of the 6431 patients tested for HBsAg, total anti-HBc and anti-HBs in a Paris hospital over a 1-year period, 362 (5.6%) had 'anti-HBc alone' (24.8% of anti-HBc-positive patients). Only 11 of the 362 sera (3.0%) were found to be false positive. One patient was in the resolving phase of acute hepatitis B. HBV-DNA was detected in 10 of 362 (2.8%) patients, using a commercial standardized assay (threshold: 350 IU/mL). Viral loads exceeded 10(4) copies/mL in 6 of 10 patients. Mutations in the HBsAg immunodominant region were identified in seven of the viraemic patients. HBsAg was detected in only two cases when retested by one of the latest, multivalent assays. Neither human immunodeficiency virus nor hepatitis C virus serostatus distinguished between patients with and without HBV-DNA. In conclusion, 'anti-HBc alone' should be considered a risk marker for a so-called 'false occult' HBV infection with significant viraemia. Indeed, results in this hospital population indicate that a small proportion of patients with 'anti-HBc alone' have high viral loads, revealing the occurrence of infection with HBV mutants that escape detection even by multivalent HBsAg assays.     

High hepatitis B virus (HBV) DNA viral load is an important risk factor for HBV reactivation in breast cancer patients undergoing cytotoxic chemotherapy

Summary.  Hepatitis B virus (HBV) reactivation during cytotoxic chemotherapy for cancer may complicate treatment and cause liver damage. The complication has been reported to occur in 10% to over 50% of HBV carriers, but the factors that determine which patients will develop reactivation remain unclear. The objective of the study is to test the hypothesis that the prechemotherapy HBV DNA level is a risk factor for the development of HBV reactivation. We studied 41 women undergoing cytotoxic chemotherapy for breast cancer, 17 of whom developed reactivation and 24 who did not. We developed a novel, ultra-sensitive, real-time polymerase chain reaction assay for the measurement of HBV DNA. The sera of 37 patients (16 who developed reactivation and 21 who did not) were available for measurement of HBV DNA using this technique. The results showed that patients in the reactivation group had a significantly higher median HBV DNA load (1.03 × 10⁶ copies/mL; range <2.9 × 10³ to 8.723 × 10⁷) than did the nonreactivation group (<2.9 × 10³ copies/ml; range <2.9 × 10³ to 6.331 × 10⁷) ( P  < 0.001). The optimal cut-off between the two groups was found to be at serum HBV DNA level of 3 × 10⁵, which gave a sensitivity of 81.0% and a specificity of 85.0%. In conclusion, for breast cancer patients receiving standard cytotoxic chemotherapy, a high HBV viral load prior to the administration of cytotoxic chemotherapy is a significant predictive factor for the development of HBV reactivation. Such information may be useful in determining which patients would benefit most from prophylactic antiviral therapy during cytotoxic chemotherapy.     

Clinical and virological factors associated with hepatitis B virus reactivation in HBsAg‐negative and anti‐HBc antibodies‐positive patients undergoing chemotherapy and/or autologous stem cell transplantation for cancer

Summary. We studied clinical outcome and clinico‐virological factors associated with hepatitis B virus reactivation (HBV‐R) following cancer treatment in hepatitis B virus surface antigen (HBsAg)‐negative/anti‐hepatitis B core antibodies (anti‐HBcAb)‐positive patients. Between 11/2003 and 12/2005, HBV‐R occurred in 7/84 HBsAg‐negative/anti‐HBcAb‐positive patients treated for haematological or solid cancer. Virological factors including HBV genotype, core promoter, precore, and HBsAg genotypic and amino acid (aa) patterns were studied. Patients presenting with reactivation were men, had an hepatitis B virus surface antibody (HBsAb) titre <100 IU/L and underwent >1 line of chemotherapy (CT) significantly more frequently than controls. All were treated for haematological cancer, 3/7 received haematopoietic stem cell transplantation (HSCT), and 4/7 received rituximab. Using multivariate analysis, receiving >1 line of CT was an independent risk factor for HBV‐R. Fatal outcome occurred in 3/7 patients (despite lamivudine therapy in two), whereas 2/4 survivors had an HBsAg seroconversion. HBV‐R involved non‐A HBV genotypes and core promoter and/or precore HBV mutants in all cases. Mutations known to impair HBsAg antigenicity were detected in HBV DNA from all seven patients. HBV DNA could be retrospectively detected in two patients prior cancer treatment and despite HBsAg negativity. HBV‐R is a concern in HBsAg‐negative/anti‐HBcAb‐positive patients undergoing cancer therapy, especially in males presenting with haematological cancer, a low anti‐HBsAb titre and more than one chemotherapeutic agent. HBV DNA testing is mandatory to improve diagnosis and management of HBV‐R in these patients. The role of specific therapies such as rituximab or HSCT as well as of HBV aa variability deserves further studies.     

Role of quantitative hepatitis B core antibody levels in predicting significant liver inflammation in chronic hepatitis B patients with normal or near‐normal alanine aminotransferase levels

Aim

Chronic hepatitis B (CHB) patients with normal alanine aminotransferase (ALT) levels are not free from significant hepatic lesions. Recently, there has been an improved understanding of the clinical significance of quantitative hepatitis B core antibody levels (qAnti‐HBc) during CHB management. In this cross‐sectional study, we evaluated the utility of qAnti‐HBc in identifying significant liver inflammation in CHB patients.

Methods

A total of 469 patients (training set, n = 363; validation set, n = 106) who underwent liver biopsy (LB) were included. The qAnti‐HBc levels were quantified and the relationship between histology and serum markers was systematically analyzed.

Results

In the training set, qAnti‐HBc levels were found to have significant diagnostic value for moderate to severe liver inflammation (≥G2) in all patients (area under the receiver operating characteristic curve [AUROC] = 0.768; 95% confidence interval [CI], 0.721–0.810; P < 0.001) and in patients with normal or near‐normal ALT levels (AUROC = 0.767; 95% CI, 0.697–0.828; P < 0.001). Our novel index (AC index) for the identification of ≥G2 inflammation, which combined the qAnti‐HBc and ALT levels, significantly improved diagnostic performance (AUROC = 0.813; 95% CI, 0.768–0.852) compared to the use of ALT alone (AUROC = 0.779; 95% CI, 0.732–0.821) in all patients. In the validation set, the AC index showed an improved AUROC of 0.890 (95% CI, 0.814–0.942) and 0.867 (95% CI, 0.749–0.943) in all patients and patients with normal ALT levels, respectively.

Conclusions

The qAnti‐HBc level predicts significant liver inflammation well, even in patients with normal or near‐normal ALT levels. Compared with the conventional ALT level, the AC index is a more reliable non‐invasive biomarker for significant liver inflammation in CHB patients.     

Occult hepatitis B virus infection in hematopoietic stem cell donors in a hepatitis B virus endemic area

BACKGROUND/AIMS: The acquisition of hepatitis B virus (HBV) infection following organ transplantation from donors with occult HBV infection is an important cause of morbidity and mortality. The aim of this study is to determine the prevalence of occult HBV in allogeneic hematopoietic stem cell (HSC) transplantation donors. METHODS: We performed a retrospective study on 124 consecutive hepatitis B surface antigen negative HSC donors. Their serum samples were analyzed by PCR for the pre-S/S, pre-core/core and X regions of the virus. Samples reactive by at least two PCR assays were considered HBV-DNA positive. RESULTS: Nineteen of the 124 HSC donors (15.3%) had occult HBV infection. Sixteen of these 19 donors with occult HBV infection (84.2%) tested positive for hepatitis B core antibody while 78 of 105 subjects (74.3%) without occult HBV infection were also positive (P=0.56). Fourteen of the 19 donors (73.7%) with occult HBV infection tested positive for hepatitis B surface antibody while 67 of the 105 subjects without occult HBV infection were also positive (P=0.45). CONCLUSIONS: The prevalence of occult HBV infection among HSC donors in Hong Kong is high. Anti-HBc and anti-HBs status had no significant correlation with the presence of occult HBV infection.     

Fulminant hepatitis due to reactivation of chronic hepatitis B virus infection after allogeneic bone marrow transplantation

Summary A case of hepatitis B reactivation following bone-marrow transplantation for leukemia in a previously healthy HB_sAg carrier is reported. A number of changes in HBV serum markers were contemporary to the acute episode. All of them (increase of HB_sAg concentration, conversion from anti-HB_e to HB_eAg, appearance of anti-HB_c IgM, and of serum HBV-DNA) were suggestive of a switching-on of viral replication. Institution of corticosteroid treatment at the onset of the acute phase did not prevent the fatal outcome.