Hepatitis B Virus Reinfection Research Articles

(−)-Epigallocatechin-3-gallate inhibits entry of hepatitis B virus into hepatocytes

Hepatitis B virus (HBV) is a major cause of liver disease and hepatocellular carcinoma. Chronic HBV infection is currently managed with either nucleoside/nucleotide-based or interferon-based therapies, but fails to clear infection in a substantial proportion of cases, and antiviral strategies targeting the early stages of infection are therefore required for the prevention of HBV infection. In this study, we examined some common phytochemicals and identified epigallocatechin-3-gallate (EGCG) as a new inhibitor of HBV entry. EGCG, a flavonoid present in green tea extract, belongs to the subclass of catechins. We demonstrated that EGCG at a concentration of 50μM inhibited HBV entry into immortalized human primary hepatocytes by more than 80%, whereas the other four catechins tested had much weaker inhibitory effects. DMSO-differentiated HuS-E/2 cells expressed sodium taurocholate cotransporting polypeptide (NTCP), which is a receptor for HBV. Application of EGCG during HBV inoculation markedly inhibited infection in both DMSO-differentiated HuS-E/2 cells and HA-NTCP-expressing Huh7 cells. Interestingly, EGCG induced clathrin-dependent endocytosis of NTCP from the plasma membrane followed by protein degradation. In addition, EGCG inhibited the clathrin-mediated endocytosis of transferrin. Treatment of cells with EGCG had no effect on HBV genome replication or virion secretion. Moreover, the characteristic of HBV virion and the expression of known HBV entry factors were unaltered by EGCG. Finally, the antiviral activity of EGCG on HBV entry was observed using four different genotypes, A to D. These results show that the green tea-derived molecule EGCG potently inhibits HBV entry and could be used in prevention of HBV reinfection.

Acute disseminated encephalomyelitis associated with hepatitis B virus reinfection – Consequence or coincidence?

Acute disseminated encephalomyelitis (ADEM) is an idiopathic inflammatory demyelinating disease of the CNS that is particularly difficult to differentiate from the first episode of multiple sclerosis. ADEM typically occurs as a post-infectious phenomenon, and usually presents a monophasic episode, but also includes recurrent and multiphasic forms. We report a case of ADEM associated with hepatitis B virus (HBV) reinfection. After steroid and IV immunoglobulin treatment, neurologic symptoms were improved. We suppose that the HBV reinfection was the cause of ADEM, but possible pathogenetic mechanism is still obscure.

Liver transplantation for hepatitis B liver disease and concomitant hepatocellular carcinoma in the United States With hepatitis B immunoglobulin and nucleoside/nucleotide analogues

Reinfection with hepatitis B virus (HBV) after liver transplantation (LT) may favor the recurrence of hepatocellular carcinoma (HCC), and combination therapy with hepatitis B immunoglobulin (HBIG) and nucleoside/nucleotide analogues may reduce HBV recurrence after LT. To test associations between HBV, HCC, and survival, we performed a retrospective chart review of patients undergoing LT for HBV between January 1985 and December 2010 at 7 US transplant centers. After we divided the patients into 3 eras based on evolving strategies in antiviral therapy (1985-1994, 1995-2004, and 2005-2010), we reviewed 16 variables to determine whether there were associations between survival and HCC recurrence. Seven hundred thirty-eight patients underwent transplantation for HBV, and 354 (48.0%) had concomitant HCC, which recurred in 58 patients (16.4%). Three-year survival was much better in era 3 versus era 1 (87% versus 40%, P = 0.001), and the incidence of HCC recurrence was lower (12% versus 29%, P = 0.009). The lungs were the most frequent first site of HCC recurrence, and they were followed by the liver. A multivariate analysis showed that HBV reinfection, HCC recurrence, and HBIG use were associated with worse survival (P < 0.001, P < 0.001, and P = 0.002, respectively); HCC recurrence and stage 3 HCC, among other factors, were associated with HBV reinfection (P < 0.001 and P = 0.004); and stage 3 HCC, vascular invasion of the explanted tumor, and post-LT chemotherapy were associated with HCC recurrence (P = 0.008, P < 0.001, and P < 0.001, respectively). Patients with HBV reinfection were 3.6 times more likely than patients without HBV to have HCC recurrence. These data suggest further study of attempts at LT for patients with HBV and HCC beyond the Milan criteria if their HBV is aggressively and successfully treated.

Preventing HBV Reinfection After Liver Transplantation with Oral Antivirals Alone

Daily lamivudine plus monthly hepatitis B immune globulin (HBIG) injections after liver transplant for hepatitis B virus (HBV) infection has reduced

Hepatitis B Prophylaxis Using Lamivudine and Individualized Low-dose Hepatitis B Immunoglobulin in Living Donor Liver Transplantation

BackgroundCurrently, most available experience concerning prophylaxis against hepatitis B virus (HBV) recurrence after living donor liver transplantation (LDLT) is limited to studies of small size and short follow-up. The objective of this study was to evaluate the efficacy of a prophylactic regimen using lamivudine and individualized low-dose intramuscular hepatitis B immunoglobulin (HBIG) in LDLT. MethodsWe used a database of adult-to-adult right-lobe LDLT procedures performed from June 2002 to April 2012 at our center for HBV-related end-stage liver diseases. Patients were divided into 3 groups: group A, HBV-related decompensated liver cirrhosis; group B, fulminant hepatitis B; and group C, hepatocellular carcinoma (HCC). ResultsDuring a mean follow-up of 38.3 ± 28.9 months, 8 of 165 (4.8%) recipients developed HBV recurrences. The mean time for HBV reinfection was 15.8 + 11.0 months after transplantation. The overall 1-, 3-, and 5-year HBV recurrence rates were 3%, 7%, and 8.2%, respectively. Both patients with fulminant hepatitis B or HCC seemed to have higher rates of HBV recurrence than those with decompensated liver cirrhosis, albeit not significantly. The independent predictor of HBV recurrence was high HBV DNA level (≥105 copies/mL) at LDLT. ConclusionsLamivudine and individualized low-dose intramuscular HBIG provides effective prophylaxis against HBV recurrence after LDLT. Pre-LDLT HBV DNA of ≥ 105 copies/mL was associated with HBV recurrence.

Significance of hepatitis B virus core‐related antigen and covalently closed circular DNA levels as markers of hepatitis B virus re‐infection after liver transplantation

Currently, hepatitis B virus (HBV) re-infection after liver transplantation (LT) can be almost completely suppressed by the administration of HBV reverse transcriptase inhibitors and hepatitis B immunoglobulins. However, after transplantation, there is no indicator of HBV replication because tests for the serum hepatitis B surface antigen and HBV-DNA are both negative. Therefore, the criteria for reducing and discontinuing these precautions are unclear. In this study, we examined the serum HBV core-related antigen (HBcrAg) and intrahepatic covalently closed circular DNA (cccDNA) in order to determine if these could be useful markers for HBV re-infection. Thirty-one patients underwent LT for HBV-related liver disease at Nagasaki University Hospital from 2001 to 2010. Of these, 20 cases were followed up for more than 1 year (median follow-up period, 903 days). We measured serum HBcrAg and intrahepatic cccDNA levels in liver tissue. In addition, in nine cases, we assessed the serial changes of HBcrAg and intrahepatic cccDNA levels from preoperative periods to stable periods. We examined serum HBcrAg and intrahepatic cccDNA levels in 20 patients (35 samples). HBcrAg and cccDNA levels were significantly correlated with each other (r = 0.616, P < 0.001). From a clinical aspect, the fibrosis stage was significantly lower in both HBcrAg- and cccDNA-negative patients than in HBcrAg- or cccDNA-positive patients. HBcrAg and cccDNA were useful as HBV re-infection markers after LT. Keeping patients' HBcrAg and cccDNA negative after LT might contribute to long-term graft survival.

Safety and Efficacy of Subcutaneous Hepatitis B Immunoglobulin After Liver Transplantation: An Open Single-Arm Prospective Study

Life-long hepatitis B immunoglobulin (HBIG) administration is a main component of prophylactic strategy to prevent hepatitis B virus (HBV) reinfection after liver transplantation (LT). Long-term effects of HBIG treatment are known only for intravenous (IV) and intramuscular formulations. To evaluate safety and efficacy of self-administered SC HBIG, 135 LT patients receiving a 48-week treatment were analyzed. The dose of HBIG was 500 IU or 1000 IU if body weight was <75 kg or ≥75 kg, respectively. Patients were switched from the monthly IV HBIG treatment to weekly SC HBIG 2-3 weeks after the last IV dosage. All patients were able to SC self-injection after a single training. The treatment was effective in maintaining trough anti-HBs levels >100 IU/L. No severe drug-related side effects occurred. Fifteen injection-site small hematomas and four cases of mild itch occurred. At the end of the study, anti-HBs median titer was 232 IU/L (115-566 IU/L) and 97.8% of patients had an anti-HBs level >150 IU/L. Due to high mean level of anti-HBs titers observed during this study, individualized treatment schedules should be further investigated. In conclusion, SC HBIG for long-term prophylaxis of post-LT HBV reinfection resulted safe, well accepted, and effective in maintaining adequate anti-HBs levels.

Management of Hepatitis B Virus Infection in Liver Transplant Recipients

Hepatitis B virus (HBV)-related liver disease is a common indication for liver transplantation (LT) in Asian countries.1 When left untreated, the overall five-year survival rate in HBV-related cirrhosis is 71%, which in cases of decompensated cirrhosis decreases to 14%.2 In the 1980s, hepatitis B-related acute liver failure and chronic liver disease (CLD) were considered contraindications for LT because of almost universal graft reinfection and high rates of graft and recipient failure (&gt;50%).3-4 These patients had severe and rapidly progressive liver disease with a two-year graft and patient survival of 50% compared to 80% in those transplanted for non-HBV-related CLD.5 As a result, there were fewer LT for HBV liver disease for several years.6 However, with the introduction of nucleoside and nucleotide analogues and the use of intra and post- operative hepatitis B immunoglobulin (HBIG), there was renewed interest in the application of LT in these patients. There was a significant decrease in post-operative HBV recurrence rates.7-9 The current overall survival of patients transplanted for HBV-related cirrhosis has improved to 85% at one year, and 75% at five years.7,10-12 The present review highlights issues pertaining to HBV reinfection and de novo infection in LT recipients with recommendations for its management.

Variations in the S and P Regions of the Hepatitis B Virus Genome Under ImmunosuppressionIn VitroandIn Vivo

To provide a basis for improved prevention and treatment of hepatitis B virus (HBV) re-infection after liver transplantation, variations in the S and P genes of HBV under immunosuppression in vitro and their association with patient prognosis were investigated. For the in vitro study, HepG2.2.15 hepatocellular carcinoma cells stably producing HBV particles were treated with the immunosuppressants methylprednisolone (MP) and tacrolimus (FK506) at doses found to be non-toxic by the methylthiazolyl tetrazolium (MTT) cell viability assay. MP dose-dependently inhibited HBV DNA expression in HepG2.2.15 cells, while FK506 did not, as determined by quantitative real-time PCR (qRT-PCR). By gene sequencing, both MP and FK506 were found to cause variations in HBV S, P, and S/P overlapping regions. MP- but not FK506-induced mutations were common in the glucocorticoid response element of the P region, while both immunosuppressants caused mutations outside the nucleoside analogue resistance sites. For the in vivo study, 14 patients with HBV-related end-stage liver disease re-infected after liver transplantation, and 20 cases without HBV re-infection as controls, were studied. Seventy-five percent of re-infected recipients showed multi-loci amino acid mutations at different sites besides lamivudine (LAM)-resistant loci in the P region, including in the glucocorticoid response element. Fifty percent of re-infected recipients had mutations in the "a" determinant region and flanking sequences. Re-infection was associated with negative serum hepatitis B immunoglobulin (HBIG), as measured by a microparticle capture enzyme immunoassay. Nucleotide mutations in the S region caused missense or synonymous mutations, which caused synonymous mutations in the overlapping P region. These results showed that effects of immunosuppressants on HBV genes in vitro were different from those in clinical recipients. Positive HBV DNA and gene mutations pre-transplantation were factors affecting re-infection post-transplantation. Multiple mutations found in the P and S genes suggest that the formation of quasispecies contributes to HBV re-infection after liver transplantation.

Clinical study on prevention of HBV re‐infection by entecavir after liver transplantation

This aims to evaluate the effects of lamivudine (LAM) and entecavir (ETV) in preventing hepatitis B virus (HBV) re-infection after liver transplantation (LT). A retrospective matched case-control method was used in this study. From June 2005 to May 2007, the patients who received LAM (100 mg qd) or ETV (0.5 mg qd) were chosen. The LAM and ETV groups were matched using a 3:1 ratio based on the factors, such as age, gender, LAM or ETV antiviral duration, primary disease, and HBV DNA levels at the initiation of antiviral therapy. Data on serum HBV markers, HBV DNA, and cumulative recurrence were collected. Two hundred and fifty-two patients were enrolled. The average duration of follow-up was 38.5 and 41.2 months (LAM and ETV groups) (p>0.05). Duration of pre-operative antiviral therapy was 30.3 and 25.8 d (LAM and ETV groups) (p>0.05). The HBV DNA level decreased from 3.89×10(6) to 5.31×10(5) copies/mL before LT in the LAM group, and decreased from 8.74×10(6) to 5.49×10(4) copies/mL in the ETV group (p<0.05). Eighteen patients in LAM group developed HBV re-infection and 0 in ETV group. ETV is superior to LAM for preventing HBV re-infection following LT.

The role of hepatitis B immunoglobulin in hepatitis B related liver transplantation: Canadian Transplant Centre Position Paper

Introduction. Hepatitis B virus (HBV) related liver transplant (LT) recipients face a high risk of HBV reinfection in the absence of continuous post-operative HBV prophylaxis. Combination HBV prophylaxis with hepa-titis B immune globulin (HBIg) and nucleos(t)ide anti-viral agents prevents HBV recurrence in 90 to 100% of patients who undergo transplantation for hepatitis B and is considered the standard of care in Canada. Post liver transplant HBV prophylaxis protocols vary with regard to the dosing, duration and routes of HBIg administration. All Canadian transplant centres managing liver transplant patients were surveyed as to their HBV transplant protocols.Results. Results of the survey showed that the majority of the Canadian transplant centres use an oral antiviral in combination with long term or indefinite HBIg for prevention of HBV recurrence post liver transplantation. Studies were done to test new protocols using lower HBIg doses given intramuscularly or subcutaneously alone or in combination with antiviral agents.Conclusion. Long term HBIg administration post transplantation in combination with antiviral agents is an integral part of Canadian HBV related liver transplant protocol.

The role of HBIg as hepatitis B reinfection prophylaxis following liver transplantation

Without adequate prophylaxis, liver transplantation (LTx) is frequently followed by hepatitis B virus (HBV) reinfection, which results in rapidly progressing liver disease and significantly decreased overall survival. In the last two decades, significant progress has been made in the prophylaxis and treatment of HBV. We present an overview of different protocols and regimens used for prophylaxis of HBV reinfection after LTx and describe the protocol implemented at our center. Following LTx, HBV reinfection can be effectively prevented by administration of anti-hepatitis B immunoglobulin (HBIg) alone or more recently in combination with antiviral nucleoside/nucleotide analogs (NUCs). Several studies reported good results with the use of HBIg alone, but combination treatment with HBIg and NUCs has proven to be a superior prophylactic regimen for HBV recurrence. At present, combination therapy (HBIg and a nucleoside or nucleotide analog) is the gold standard used in many transplantation centers. This preventive regimen reduces the risk of a recurrence of HBV infection and thereby the need for re-transplantation. Future and ongoing studies will show how long HBIg must be given after transplantation, especially when used in combination with potent antivirals, such as entecavir or tenofovir.

Serum hepatitis B virus DNA before liver transplantation correlates with HBV reinfection rate even under successful low-dose hepatitis B immunoglobulin prophylaxis

PurposeThe combination of hepatitis B immunoglobulin (HBIg) and nucleos(t)ide analogues has been accepted as the best treatment to control hepatitis B recurrence after orthotopic liver transplantation (OLT). However, the optimal dose of HBIg remains unclear. We have previously reported that high-dose HBIg in the early period followed by low-dose HBIg with nucleos(t)ide analogues offers reliable and cost-effective control of hepatitis B recurrence. The aim of this study was to investigate intrahepatic hepatitis B virus (HBV) reinfection status with our clinically successful protocol.MethodsWe quantified levels of intrahepatic HBV covalently closed circular (ccc) deoxyribonucleic acid (DNA) and serum hepatitis B core-related antigen (HBcrAg), a new serological marker that can estimate intrahepatic cccDNA levels. Nucleos(t)ide analogues were administered in all cases.ResultsNo patients showed recurrence of hepatitis B surface antigen (HBsAg) or HBV-DNA. However, HBV, cccDNA, and HBcrAg were positive in 57% and 48% of patients after OLT, respectively. Pre-OLT serum HBV-DNA and HBcrAg levels correlated linearly with post-OLT cccDNA levels (r = 0.534, P < 0.05, and r = 0.634, P < 0.05, respectively). High serum HBV-DNA and HBcrAg levels, particularly with >3 log10 copies/mL and >4 log10 IU/mL, respectively, at the time of OLT, were associated with high levels of post-OLT cccDNA. Even with our successful protocol, nearly half of patients showed HBV reinfection.ConclusionsPatients with high serum HBV-DNA and HBcrAg levels before OLT (particularly >3 log10 copies/mL and >4 log10 IU/mL, respectively) should be followed with care for HBV recurrence.

Hepatitis B virus infection and liver transplantation

Infection with hepatitis B virus (HBV) continues to be a major global cause of acute and chronic liver disease despite the existence of successful vaccine and antiviral therapies. As such, HBV-related liver disease remains one of the most common indications for liver transplantation. An understanding of the pathophysiology of hepatitis B viral infection including the potential sequelae of acute-liver failure, cirrhosis, and hepatocellular carcinoma (HCC) is important to the successful treatment of the patient. A better understanding of the differential immune response to hepatitis B viral infection has identified high hepatitis B viral load and persistent transaminitis to be important, modifiable risk factors for the development and progression of cirrhosis and HCC. Improved posttransplant prophylaxis with antiviral and immunoglobulin therapy has led to a low risk of HBV re-infection and excellent outcomes after liver transplantation for HBV-related liver disease. HBV-related liver diseases including acute-liver failure, cirrhosis, and HCC remain important and frequent indications for liver transplantation. With appropriate patient selection and posttransplant prophylaxis, excellent posttransplant outcomes can be achieved.

Escape hepatitis B virus mutations in recipients of antibody to hepatitis B core antigen-positive liver grafts receiving hepatitis B immunoglobulins

A variety of prophylactic strategies are used to prevent the risk of hepatitis B virus (HBV) transmission from antibody to hepatitis B core antigen (anti-HBc)-positive donors. The mechanisms underlying the failure of HBV immunoglobulin monoprophylaxis have been poorly evaluated. Seventy-seven anti-HBc-positive grafts were used in 21 hepatitis B surface antigen (HBsAg)-positive recipients and 56 HBsAg-negative recipients. HBsAg-positive recipients received prophylaxis comprising hepatitis B immunoglobulins (HBIG) and antiviral agents, 45 HBsAg-negative recipients received a modified HBIG regimen, and 11 HBsAg-negative recipients received no prophylaxis. Both donors and recipients were screened for HBsAg, antibody to HBsAg (anti-HBs) and anti-HBc in their sera and for HBV DNA in both their sera and liver. S gene mutations were investigated after HBV reinfection. HBV infection occurred in 15 HBsAg-negative recipients (19.4%) at a median interval of 16 months (range = 6-67 months) post-transplant and in none of the HBsAg-positive recipients. HBV infections were observed in 31.6% of HBV-naive recipients and 7.7% of HBV-immune recipients receiving HBIG prophylaxis versus 100% of HBV-naive recipients (P = 0.0068) and 33% of HBV-immune recipients (P = 0.08) with no such prophylaxis. S gene mutations were identified in 9 recipients. In conclusion, priority should be given to using anti-HBc positive grafts for HBsAg-positive or HBV-immune recipients. Our study has confirmed the high risk of HBV transmission to naive recipients. HBIG monoprophylaxis was associated with a significant risk of de novo HBV infection and HBV escape mutations. In these patients, we therefore recommend prophylaxis with lamivudine or new nucleos(t)ides analogues. The potential benefits of HBIG prophylaxis combined with antiviral drugs require further evaluations. Long-term prophylaxis is needed because of the long interval of de novo HBV infection post-transplant in some patients.

Pharmacokinetics of intramuscular and intravenous HBIG: Which implications for practice?

A major achievement for patients transplanted for hepatitis B virus (HBV) associated end-stage liver disease is the successful prevention of reinfection with high dose of hepatitis B immunoglobulin (HBIG). The introduction of lamivudine in combination with HBIG reduces recurrence rates to less than 5% at 5 years. Currently, this combination is the accepted standard regimen in most transplantation units. However, a major drawback of this therapy is that high-dose intravenous (IV) HBIG is very expensive. Several strategies have been explored to reduce such costs. These include withdrawal of HBIG at some time after transplantation while continuing lamivudine, vaccination of patients prior to cessation of HBIG and substitution of high-dose IV HBIG by low-dose intramuscular (IM) HBIG. It has been demonstrated that crucial pharmacokinetic parameters, including anti-HBs antibodies through levels at time of HBIG re-administration, do not differ significantly after IV and IM administration in stable hepatitis B surface antigen (HBsAg) negative patients with at least 12 months follow-up after orthotopic liver transplantation, confirming the cost-effectiveness of IM HBIG administration. Recent studies suggest that, compared with combination of HBIG plus lamivudine prophylaxis, the combination of adefovir plus lamivudine prophylaxis provides equivalent protection against HBV reinfection with better tolerability at a significantly lower cost. Nonetheless, HBIG continue to be the cornerstone of HBV recurrence prevention.

Prevention of HBV recurrence after liver transplant: The role of combination therapy

The prognosis after liver transplantation is related to the efficacy of prophylaxis of hepatitis B virus (HBV) graft re-infection. The risk of HBV re-infection is directly related to HBV viral load at the time of transplantation. HBV prophylaxis after transplantation with long-term administration of hepatitis B immunoglobulins (HBIG) or monoprophylaxis with lamivudine can significantly reduce the risk of HBV recurrence. Antivirals can control HBV replication in patients with decompensated HBV cirrhosis awaiting transplantation. However, there is a risk of HBV viral breakthrough during nucleo(t)side antiviral treatment. Efficacy of antivirals and the risk of viral resistance should be taken into account. The post-transplant combination of antiviral therapy and HBIG prophylaxis is very effective in reducing the rate of HBV re-infection to less than 10%, increasing the survival rate. The current 5-year survival after transplantation for HBV related liver disease is 85%. In patients without active viral replication at transplantation, the possibility of discontinuing HBIG prophylaxis over the long-term after transplantation with maintenance of antiviral treatment or HBV vaccination is under evaluation. In conclusion, the prophylaxis of HBV re-infection combining antiviral therapy prior to transplantation, and combination of HBIG and antiviral therapy post-transplantation is effective in reducing the rate of HBV re-infection.

Recurrence of hepatocellular carcinoma and hepatitis B reinfection in hepatitis B surface antigen-positive patients after liver transplantation

Hepatitis B virus (HBV) reinfection and recurrence of hepatocellular carcinoma (HCC) after orthotopic liver transplantation (OLT) are associated with increased graft failure and reduced patient survival. We evaluated the effects of both HCC recurrence and HBV reinfection on the long-term survival of these patients after OLT. One hundred seventy-five patients underwent OLT for HBV-related liver diseases and were the subjects of this retrospective study. We assessed risk factors for HBV reinfection, HCC recurrence, and survival post-OLT using univariate and multivariate analyses. During a mean follow-up of 43.0 +/- 42.0 months, 88 of 175 (50.3%) patients transplanted for HBV-related liver disease had HCC prior to OLT. Thirteen (14.8%) of these patients had HCC recurrence after OLT. The mean time for recurrence of HCC was 26.1 +/- 31.9 months. Twelve of 175 (6.9%) patients developed HBV reinfection after liver transplantation. The mean time for HBV reinfection was 28.7 +/- 26.4 months. Ten of these 12 (83.3%) patients had HCC prior to OLT, and 5 (50%) developed recurrence of HCC. On multivariate analyses, pre-OLT HCC and recurrence of HCC post-OLT were significantly associated with HBV reinfection after transplantation (P = 0.031 and P < 0.001, respectively). HCC recurrence after OLT was associated with lymphovascular invasion (P < 0.001) and post-OLT chemotherapy (P < or = 0.001). The 3- and 5-year survival rates were significantly decreased in patients with HBV reinfection (P = 0.007) and in patients with HCC recurrence after OLT (P = 0.03). In conclusion, pre-OLT HCC and HCC recurrence after transplantation were associated with HBV reinfection and with decreased patient survival. Hepatitis B immunoglobulin and antiviral therapy was only partially effective in preventing HBV reinfection in patients with HCC recurrence.

Prevention and management of hepatitis B virus reinfection after liver transplantation

To investigate the prevention and treatment of hepatitis B virus (HBV) reinfection and recurrence after orthotopic liver transplantation (OLT) for HBV related end-stage liver disease. The clinical data of 316 patients undergoing allograft orthotopic liver transplantation who lived more than 6 months and had HBV infection preoperative with complete data from March 2001 to March 2007 at the First Affiliated Hospital of Sun Yat-sen University. According to the HBV prevention strategy, these patients were divided into two groups: group with pure lamivudine (LAM) (n = 106) and group with lamivudine plus intramuscular injection of low dose anti-hepatis B immunoglobulin (HBIG) (n = 210). Mean follow-up was 33.6 months. The rate of HBsAg negative conversion 1 week after OLT of the LAM group was 82.1% (87/106), significantly lower than that of LAM + HBIG group [91.0% (191/210), P < 0.05]. The rates of HBV reinfection, HBV recurrence, and YMDD mutation of the lamivudine group was 17.0% (18/106), 11.3% (12/106) and 8.5% (9/106) respectively, all significantly higher than those of LAM + HBIG group [6.2% (13/210), 3.8% (8/210) and 2.4% (5/210) respectively, P < 0.05 respectively]. All patients with HBV reinfection or HBV recurrence were treated with Adefovir, Entecavir or increased dose of HBIG and achieved better curative effect. The therapy with high dose of HBIG combining with adefovir or entecavir is better for patients who have HBV reinfection. Patients with HBV recurrence after OLT should be administrated reasonable liver aid, immunity regulation and anti-hepatic fibrosis to obtain better transplant liver histological results and normal transplant liver function.

The option of liver transplantation for hepatitis B: Where are we?

Combination therapy with hepatitis B immunoglobulin (HBIG) plus nucleos(t)ide analogue have reduced the rate of hepatitis B virus (HBV) recurrence post-transplantation to less than 10% at long-term. HBV recurrence diagnosed after 3 years post-transplantation is extremely rare. Considering the cost and the constraints of HBV prophylaxis it was suggested to decrease the amount of HBIG given and possibly to discontinue HBIG administration. The additional debate was on the need to maintain or not any HBV prophylaxis at long-term or to maintain monoprophylaxis with one or two nucleos(t)ide analogues or to administer HBV vaccine: The supporters of this strategy argued that HBV recurrence can be easily controlled by administration of nucleos(t)ide analogues. However, it was shown that 50-80% of patients maintain HBV DNA in the liver, serum or peripheral mononuclear blood cells long-term after transplantation. In patients receiving monoprophylaxis with nucleos(t)ide analogues the risk of HBV reinfection increases with time due to HBV mutant strains. Vaccine protocols used to replace HBIG prophylaxis gave disappointing results. Combination protocols using low-doses of intramuscular HBIG plus nucleos(t)ide analogues have been associated with a low rate of HBV reinfection. In conclusion, long-term prophylaxis should be maintained in most patients except those with anti-HBs seroconversion.