HBsAg-negative Recipients Research Articles

#2231 The efficacy of anti-viral therapies for hepatitis B in kidney transplant recipients

Abstract Background and Aims The efficacy and long-term outcomes of anti-viral therapies used for hepatitis B treatment or prevention continue to be a challenging area in kidney transplantation practice. This study aimed to determine the effectiveness of anti-viral treatment in a hepatitis B kidney transplant cohort and its effect on long-term graft and overall survival. Method We reviewed the data of 589 patients who were followed up on at our clinic between January 1, 2002, and December 31, 2023. Recipients who were AntiHbc IgG positive and received Rituximab and HbsAg negative recipients whose donor was HbsAg positive were included in the prophylaxis group, and recipients who were HbsAg positive were included in the treatment group. Age- and gender-matched recipients who did not use anti-viral treatment constituted the control group. HBV-DNA positivity in the prophylaxis group and an increase in HBV-DNA titers in the treatment group were indicators of treatment ineffectiveness. Anti-viral treatment-related side effects were noted. Graft functions, graft, and overall survival rates were examined at the beginning of treatment and at the last visit. Results A total of 30 patients receiving anti-viral therapy (prophylaxis n = 15, treatment n = 15) were included and compared with 32 control patients. The median age of the prophylaxis group was 49 (13–60) years, the median age of the treatment group was 46 (15–63) years, and the median age of the control group was 44 (22–71) years (p = 0.846). No difference was detected between the groups in terms of gender distribution. Entecavir was used in 17 patients, tenofovir in 7, and lamivudine in 6 patients. Hepatitis B activation was not observed in any patient in the prophylaxis group. An increase in HBV-DNA level was observed in 2 of 5 patients (40%) in the treatment group, followed by lamivudine. No treatment unresponsiveness was observed with other agents. No anti-viral drug-related side effects were reported in any patient. While there was no graft loss in the anti-viral treatment groups during follow-up, overall survival was determined as 100% in the prophylaxis group, 80% in the treatment group, and 90.6% in the control group (log rank p = 0.404). No hepatitis B-related mortality was reported. The findings are summarized in Tables 1 and 2. Conclusion Kidney transplant recipients using anti-viral medications for Hepatitis B, either for treatment or prophylaxis, showed similar graft and patient survival compared to the control group. Entecavir is the most commonly used anti-viral agent. Our findings support that it is advisable to consider alternative anti-viral medications instead of lamivudine, as there is a potential risk of non-response.

Expanding the donor pool: Kidney transplantation from serum HBV DNA or HBeAg-positive donors to HBsAg-negative recipients.

HBsAg-positive (HBsAg[+]) donors are rarely accepted for kidney transplantation (KT), especially when the donor is also HBV DNA-positive (HBV DNA[+]) or HBeAg-positive (HBeAg[+]) serologically. This study aimed to report kidney transplant outcomes from HBsAg(+) donors to HBsAg(-) recipients. Consecutive cases were retrospectively identified from 1 July 2017 to 31 December 2020. KTs from HBsAg(-)/HBcAb-positive (HBcAb[+]) donors to HBcAb(-) recipients were selected as the control group. The primary outcomes were de novo HBV infection (DNH), graft and patient survival. We identified 105 HBsAg(-) recipients who received HBsAg(+) kidneys and 516 HBcAb(-) recipients who received HBcAb(+) kidneys. A higher DNH rate was observed after receiving HBsAg(+) kidneys than after receiving HBcAb(+) kidneys after a median follow-up of 23.0 months (4/105[3.8%] vs. 2/516[0.4%], p = .009). All four infected recipients receiving HBsAg(+) kidneys had HBsAg clearance after treatment. Graft and patient survival were comparable between the groups (p = .630, p = .910). The DNH rates were 0/22(0%), 3/70(4.3%) and 1/13(7.7%) after receiving HBsAg(+), HBV DNA(+) and HBeAg(+) kidneys, respectively (p = .455). The DNH rate was lower if the donor had received antiviral treatment (4/42[9.5%] vs. 0/63[0%], p = .023). HBsAb(-) recipients had a higher DNH incidence than HBsAb(+) recipients (3/25[12.0%] vs. 1/80[1.3%], p = .041). The use of HBsAg(+) donors contributed to comparable graft and patient survival, but HBV DNA(+) or HBeAg(+) donors and HBsAb(-) recipients maybe associated with a higher risk of HBV infection. These findings help expand the donor pool and emphasize the role of donor antiviral treatment and recipient HBV immunity in establishing optimal prophylactic regimens.

Kidney Transplantation From Hepatitis B Surface Antigen (HBsAg)-Positive Living Donors to HBsAg-Negative Recipients: Clinical Outcomes at a High-Volume Center in China.

Data on kidney transplantation (KTx) from hepatitis B surface antigen (HBsAg)-positive (HBsAg+) donors to HBsAg-negative (HBsAg-) recipients [D(HBsAg+)/R(HBsAg-)] are limited. We aimed to report the outcomes of D(HBsAg+)/R(HBsAg-) KTx in recipients with or without hepatitis B surface antibody (HBsAb). Eighty-three D(HBsAg+)/R(HBsAg-) living KTx cases were retrospectively identified. The 384 cases of KTx from hepatitis B core antibody-positive (HBcAb+) living donors to HBcAb-negative (HBcAb-) recipients [D(HBcAb+)/R(HBcAb-)] were used as the control group. The primary endpoint was posttransplant HBsAg status change from negative to postive (-- →+). Before KTx, 24 donors (28.9%) in the D(HBsAg+)/R(HBsAg-) group were hepatitis B virus (HBV) DNA positive, and 20 recipients were HBsAb-. All 83 D(HBsAg+)/R(HBsAg-) recipients received HBV prophylaxis, while no D(HBcAb+)/R(HBcAb-) recipients received prophylaxis. After a median follow-up of 36 months (range, 6-106) and 36 months (range, 4-107) for the D(HBsAg+)/R(HBsAg-) and D(HBcAb+)/R(HBcAb-) groups, respectively, 2 of 83 (2.41%) D(HBsAg+)/R(HBsAg-) recipients and 1 of 384 (0.26%) D(HBcAb+)/R(HBcAb-) became HBsAg+, accompanied by HBV DNA-positive (P = .083). The 3 recipients with HBsAg-→+ were exclusively HBsAb-/HBcAb- before KTx. Recipient deaths were more frequent in the D(HBsAg+)/R(HBsAg-) group (6.02% vs 1.04%, P = .011), while liver and graft function, rejection, infection, and graft loss were not significantly different. In univariate analyses, pretransplant HBsAb-/HBcAb- combination in the D(HBsAg+)/R(HBsAg-) recipients carried a significantly higher risk of HBsAg-→+, HBV DNA-→+, and death. Living D(HBsAg+)/R(HBsAg-) KTx in HBsAb+ recipients provides excellent graft and patient survivals without HBV transmission. HBV transmission risks should be more balanced with respect to benefits of D(HBsAg+)/R(HBsAg-) KTx in HBsAb-/HBcAb- candidates.

Liver transplantation using hepatitis B core positive grafts with antiviral monotherapy prophylaxis

The impact of hepatitis B core antibody (anti-HBc) positive liver grafts on survival and the risk of de novo hepatitis B virus (HBV) infection after liver transplantation (LT) remain controversial. Therefore, we aimed to analyze this risk and the associated outcomes in a large cohort of patients. This was a retrospective study that included all adults who underwent LT at Queen Mary Hospital, Hong Kong, between 2000 and 2015. Data were retrieved from a prospectively collected database. Antiviral monotherapy prophylaxis was given for patients receiving grafts from anti-HBc positive donors. A total of 964 LTs were performed during the study period, with 416 (43.2%) anti-HBc positive and 548 (56.8%) anti-HBc negative donors. The median follow-up time was 7.8 years. Perioperative outcomes (hospital mortality, complications, primary nonfunction and delayed graft function) were similar between the 2 groups. The 1-, 5- and 10-year graft survival rates were comparable in anti-HBc positive (93.3%, 85.3% and 76.8%) and anti-HBc negative groups (92.5%, 82.9% and 78.4%, p = 0.944). The 1-, 5- and 10-year patient survival rates in anti-HBc positive group were 94.2%, 87% and 79% and were similar to the anti-HBc negative group (93.5%, 84% and 79.7%, p = 0.712). One-hundred and eight HBsAg negative recipients received anti-HBc positive grafts, of whom 64 received lamivudine and 44 entecavir monotherapy prophylaxis. The risk of de novo HBV was 3/108 (2.8%) and all occurred in the lamivudine era. There were 659 HBsAg-positive patients and 308 (46.7%) received anti-HBc positive grafts. The risk of HBV recurrence was similar between the 2 groups. Donor anti-HBc status did not impact on long-term patient and graft survival, or the risk of hepatocellular carcinoma recurrence after LT. De novo HBV was exceedingly rare especially with entecavir prophylaxis. Anti-HBc positive grafts did not impact on perioperative and long-term outcomes after transplant. The risk of de novo hepatitis B infection after liver transplantation was rare when using hepatitis B core positive liver grafts with entecavir monotherapy prophylaxis. Hepatitis B core antibody status did not impact on perioperative and long-term outcomes after liver transplantation. This provides support for the clinical use of hepatitis B core positive liver grafts when required.

The use of hepatitis B immunoglobulin with or without hepatitis B vaccine to prevent de novo hepatitis B in pediatric recipients of anti-HBc-positive livers.

Prophylactic measures are used to reduce DNHB after HBsAg-negative patients receive anti-HBc-positive liver grafts. This study investigated the incidence of DNHB and clinical outcomes in pediatric LT recipients under HBIG prophylaxis, with or without hepatitis B vaccination. Between 1995 and 2013, 51 HBsAg-negative pediatric recipients underwent living-donor LT from anti-HBc-positive donors. The median (range) age was 4 (0.1-17) years, 23 (45%) were male, and 71% were negative for both anti-HBc and anti-HBc. During a median follow-up of 12.1 (0.06-19.9) years, 13 (25.4%) developed DNHB; 7 of the 13 achieved HBsAg seroconversion after administration of LAM or ETV. Among studied patients, 20 (39%) received hepatitis B vaccination, and 2 of them (10%) developed DNHB. At last follow-up, 41% (21/51) discontinued HBIG either after successful HBV vaccination (n=17) or retransplantation with anti-HBc-negative grafts (n=4). In conclusion, pediatric LT recipients of anti-HBc-positive grafts, most of them were naïve to HBV infection, were at high risk of DNHB, and consistent monitoring for the early detection of DNHB was necessary. A combination use of post-LT vaccination is promising prophylactic strategy against DNHB.

Outcomes of kidney transplantation in patients with hepatitis B virus infection: A systematic review and meta-analysis.

AIMTo assess outcomes of kidney transplantation including patient and allograft outcomes in recipients with hepatitis B virus (HBV) infection, and the trends of patient’s outcomes overtime.METHODSA literature search was conducted using MEDLINE, EMBASE and Cochrane Database from inception through October 2017. Studies that reported odds ratios (OR) of mortality or renal allograft failure after kidney transplantation in patients with HBV [defined as hepatitis B surface antigen (HBsAg) positive] were included. The comparison group consisted of HBsAg-negative kidney transplant recipients. Effect estimates from the individual study were extracted and combined using random-effect, generic inverse variance method of DerSimonian and Laird. The protocol for this meta-analysis is registered with PROSPERO (International Prospective Register of Systematic Reviews; no. CRD42017080657).RESULTSTen observational studies with a total of 87623 kidney transplant patients were enrolled. Compared to HBsAg-negative recipients, HBsAg-positive status was significantly associated with increased risk of mortality after kidney transplantation (pooled OR = 2.48; 95%CI: 1.61-3.83). Meta-regression showed significant negative correlations between mortality risk after kidney transplantation in HBsAg-positive recipients and year of study (slopes = -0.062, P = 0.001). HBsAg-positive status was also associated with increased risk of renal allograft failure with pooled OR of 1.46 (95%CI: 1.08-1.96). There was also a significant negative correlation between year of study and risk of allograft failure (slopes = -0.018, P = 0.002). These associations existed in overall analysis as well as in limited cohort of hepatitis C virus-negative patients. We found no publication bias as assessed by the funnel plots and Egger’s regression asymmetry test with P = 0.18 and 0.13 for the risks of mortality and allograft failure after kidney transplantation in HBsAg-positive recipients, respectively.CONCLUSIONAmong kidney transplant patients, there are significant associations between HBsAg-positive status and poor outcomes including mortality and allograft failure. However, there are potential improvements in patient and graft survivals in HBsAg-positive recipients overtime.

Prevalent use of combined prophylaxis of hepatitis B after liver transplantation in Italy: results of a national survey in a large cohort.

Prophylaxis of hepatitis B after liver transplantation with antiviral(s) and immunoglobulins efficiently protect the majority of recipients; however recent experiences suggest a decline of HBsAg-positive candidates and the use of hepatitis B Immunoglobulin-free schedules. This national survey evaluated the epidemiology and clinical results of hepatitis B prophylaxis among 10,365 liver transplants performed in 25 years in 13 Italian centers. With a percentage of 22, 2260 procedures were performed in HBsAg-positive recipients and 714 out of 1080 anti-HBc-positive grafts were used in HBsAg-negative recipients; a total of 2974 patients (29%) were considered at risk of hepatitis B after liver transplantation. Similar rates (18% of HBsAg-positive candidates and 15% of anti-HBc-positive grafts) were registered in the last collected year. Combined prophylaxis with Hepatitis B Immunoglobulins remained prevalent among centers and was effective in 96% of HBsAg-positive recipients and in 94% of HBsAg-negative recipients of anti-HBc-positive grafts. Data from this survey confirm: the excellent results of combined prophylaxis; the past and persistent use of Hepatitis B Immunoglobulin-on and only rare -off prophylactic regimens, in contrast with the newest reports; the increasing use of anti-HBc-positive grafts; the past and present high prevalence of HBsAg-positive recipients, due to an increase in candidates with either hepatocellular carcinoma and Hepatitis Delta Virus coinfection in the last years.

De novo hepatitis B virus infection developing after liver transplantation using a graft positive for hepatitis B core antibody.

PurposeThe use of hepatitis B core antibody (HBcAb)-positive grafts is increasing, especially where hepatitis B is endemic. However, this remains controversial because of the risk of development of de novo HBV infection.MethodsWe collected information obtained between January 2000 and December 2012 and retrospectively analyzed data on 187 HBsAg-negative donors and recipients were analyzed retrospectively. De novo HBV infection was defined as development of HBsAg positivity with or without detection of HBV DNA.ResultsForty patients (21.4%) received HBcAb-positive grafts. Survival rate did not differ by donor HBcAb status (P = 0.466). De novo HBV infection occurred in five patients (12.5%) who were not treated with anti-HBV prophylaxis, and was significantly more prevalent in hepatitis B surface antibody (HBsAb)- and HBcAb-negative than HBsAb- and HBcAb-positive recipients (50% vs. 4.2%, P = 0.049). All patients except one were treated with entecavir with/without antihepatitis B immunoglobulin and four were negative in terms of HBV DNA seroconversion. No patient died.ConclusionHBcAb-positive grafts are safe without survival difference. However, the risk of de novo hepatitis B virus infection was significantly increased in HBsAb- and HBcAb-negative recipients. All patients were successfully treated even after recurrence.

Reactivation of hepatitis B virus in hematopoietic stem cell transplant recipients in Japan: efficacy of nucleos(t)ide analogues for prevention and treatment.

We retrospectively reviewed 413 recipients with hematologic malignancies who underwent hematopoietic stem cell transplantation (HSCT) between June 1986 and March 2013. Recipients with antibody to hepatitis B core antigen (anti-HBc) and/or to hepatitis B surface antigen (anti-HBs) were regarded as experiencing previous hepatitis B virus (HBV) infection. Clinical data of these recipients were reviewed from medical records. We defined ≥1 log IU/mL increase in serum HBV DNA from nadir as HBV reactivation in hepatitis B surface antigen (HBsAg)-positive recipients, and also defined ≥1 log IU/mL increase or re-appearance of HBV DNA and/or HBsAg as HBV reactivation in HBsAg-negative recipients. In 5 HBsAg-positive recipients, 2 recipients initially not administered with nucleos(t)ide analogues (NUCs) experienced HBV reactivation, but finally all 5 were successfully controlled with NUCs. HBV reactivation was observed in 11 (2.7%) of 408 HBsAg-negative recipients; 8 of these were treated with NUCs, and fortunately none developed acute liver failure. In 5 (6.0%) of 83 anti-HBc and/or anti-HBs-positive recipients, HBV reactivation occurred. None of 157 (0%) recipients without HBsAg, anti-HBs or anti-HBc experienced HBV reactivation. In HSCT recipients, HBV reactivation is a common event in HBsAg-positive recipients, or in HBsAg-negative recipients with anti-HBc and/or anti-HBs. Further attention should be paid to HSCT recipients with previous exposure to HBV.

Transmisión de la infección B por injertos anti-HBc positivos

In Spain, the rate of anti-HBc positive, HBsAg-negative carriers is approximately 10% of adults between the ages of 26 and 65 years. It is therefore impossible to exclude these donors without increasing the mortality of recipients on waiting lists. The incidence of de novo hepatitis B infection in HBsAg-negative recipients of anti-HBc-positive donors is high without prophylaxis and is related to the serological state of the recipient against HBV. Anti-HBc and anti-HBs-positive recipients have low risk, with or without prophylaxis. This patient group therefore does not require prophylaxis but rather periodic posttransplantation checkups. For the other recipient groups (naïve, anti-Hbc and anti-HBs isolates), prophylaxis with IgG HB, lamivudine or combined therapy decreases the incidence of infection. These patients should be treated with prophylaxis immediately after transplantation. Depending on the risk, cost and benefit, patients should currently be treated with lamivudine 100mg/d indefinitely or for longer periods (>10 years). Periodic checkups of HBsAg should be conducted, and if there is graft dysfunction then HBV DNA should be checked. IF HBV DNA is discovered in the donor and found to be positive in serum or in the biopsy, the prophylaxis should be an analogue with a high barrier to resistance from the start. Grafts from anti-HBc-positive donors are not considered at-risk grafts and are used according to donor severity, without being determined by the recipient's serological profile.

Evolution of hepatitis B management in kidney transplantation

Chronic hepatitis B virus (HBV) infection adversely influences the clinical outcomes of renal transplant recipients owing to increased hepatic complications. Management of HBV infection in kidney transplant recipients presents a challenge to clinicians, especially in endemic regions. Interferon precipitates renal allograft dysfunction. Treatment with lamivudine, the first oral nucleoside analogue available, resulted in effective viral suppression, reduced liver-related complications, and improved patient survival so that medium-term data showed comparable patient survival rates between hepatitis B surface antigen-positive and HBsAg-negative kidney transplant recipients in the era of effective antiviral therapies. Entecavir has replaced lamivudine as first-line therapy for treatment-naïve subjects in view of the propensity for drug resistance with the latter. Management of HBV infection in kidney transplant patients needs to take into consideration the nephrotoxicity of nucleoside/tide analogues such as adefovir and tenofovir. Prevention of HBV-related complications in kidney transplant recipients starts much earlier prior to transplantation, with vaccination of patients with chronic kidney disease and donor-recipient matching with regard to HBV status. In addition to anti-viral treatment, patients with chronic HBV infection must have regular surveillance for liver cancer and assessment for the development of cirrhosis.

De novo hepatitis B virus infection from anti‐HBc‐positive donors in pediatric living donor liver transplantation

The aim of this study was to analyze the incidence and risk factors of de novo hepatitis B virus (HBV) infection from hepatitis B core antibody (anti-HBc)-positive donors in pediatric living donor liver transplantation (LDLT). We retrospectively analyzed 46 recipients without pre-liver transplantation (LT) HBV infection evidence who underwent LDLT from October 2006 to May 2011 in our center. HBV markers, including hepatitis B surface antigen (HBsAg) and antibody (anti-HBs), anti-HBc, hepatitis B e antigen (HBeAg) and antibody (anti-HBe) were determined in both donors and recipients before LT and in recipients after LT. HBV DNA titer was measured if the recipients were strongly suspected of de novo HBV infection. Without prophylaxis, de novo HBV infection occurred in 11 of 46 recipients (23.9%) 6-36 months after LT. All 11 patients received grafts from anti-HBc-positive donors. The donors' baseline status and the characteristics of recipients at the time of transplantation were not associated with the acquisition of de novo hepatitis B infection. The overall 2-year survival rate of patients from anti-HBc-positive donors was 84.2%. Two de novo HBV-infected patients who had YMDD mutation were given adefovir combined with lamivudine, and their liver function gradually improved during the follow-up period. Anti-HBc-positive donors can significantly increase the incidence of de novo HBV infection in HBsAg-negative recipients. Administration with adefovir in patients who are resistant to lamivudine seems to be an effective and safe way for de novo HBV infection.

Hepatitis B-core antibody positive donors in liver transplantation and their impact on graft survival: Evidence from the Liver Match cohort study

The appropriate allocation of grafts from HBcAb positive donors in liver transplantation is crucial, yet a consensus is still lacking. We evaluated this issue within Liver Match, a prospective observational Italian study. Data from 1437 consecutive, first transplants performed in 2007-2009 using grafts from deceased heart beating donors were analyzed (median follow-up: 1040 days). Of these, 219 (15.2%) were HBcAb positive. Sixty-six HBcAb positive grafts were allocated to HBsAg positive and 153 to HBsAg negative recipients. 329 graft losses occurred (22.9%): 66 (30.1%) among 219 recipients of HBcAb positive grafts, and 263 (21.6%) among 1218 recipients of HBcAb negative grafts. Graft survival was lower in recipients of HBcAb positive compared to HBcAb negative donors, with unadjusted 3-year graft survival of 0.69 (s.e. 0.032) and 0.77 (0.013), respectively (log-rank, p=0.0047). After stratifying for recipient HBsAg status, this difference was only observed among HBsAg negative recipients (log rank, p=0.0007), 3-year graft survival being excellent (0.88, s.e. 0.020) among HBsAg positive recipients, regardless of the HBcAb donor status (log rank, p=0.4478). Graft loss due to de novo HBV hepatitis occurred only in one patient. At Cox regression, hazard ratios for graft loss were: MELD (1.30 per 10 units, p=0.0002), donor HBcAb positivity (1.56, p=0.0015), recipient HBsAg positivity (0.43, p <0.0001), portal vein thrombosis (1.99, p=0.0156), and DRI (1.41 per unit, p=0.0325). HBcAb positive donor grafts have better outcomes when transplanted into HBsAg positive than HBsAg negative recipients. These findings suggest that donor HBcAb positivity requires more stringent allocation strategies.

Twenty-four Year Single-Center Experience of Hepatitis B Virus Infection in Heart Transplantation

ObjectiveHepatitis B virus (HBV) infection is hyperendemic in Taiwan. We have reported the outcome of (1) recipients with hepatitis B surface antigen (HBsAg)-positive; HBsAg-negative recipients who receive donor hearts from HBsAg-positive donors; and treatment with lamivudine of hepatitis B flare-ups after heart transplantation, using case numbers that range from 100 to 200. MethodsFrom July 1987 to May 2011, all 412 orthotopic heart transplant recipients and donors underwent routine preoperative screening for hepatitis B virus markers and liver function parameters. Lamivudine was prescribed prophylactically for recipients with elevated serum enzyme levels or an HBV DNA virus load before transplantation, or when there was evidence of hepatitis B flare-up after transplantation. Postoperative HBV markers and liver function parameters were collected over a mean follow-up time of 7.8 years. ResultsThirty-four recipients were HBsAg-positive before heart transplantation, and 23 experiencing HBV reactivation upon follow-up requiring lamivudine treatment. Clinical responses were achieved in all of them: 15 were complete and two, slow partial responses. Twenty-six recipients with an HBV naïve status at the time of heart transplantation, and three patients received donor hearts from an HBsAg-positive donor under perioperative hepatitis B immunoglobulin prophylaxis. HBV infection was successfully prevented in two patients, but the other one contracted HBV hepatitis, which was successfully treated with lamivudine. ConclusionsHBV reactivation after the heart transplantation was common but usually well controlled with lamivudine treatment. Although posttransplantation liver function deteriorated for a period, there was no HBV infection-related morbidity or mortality. Perioperative hepatitis B immunoglobulin prophylaxis can successfully prevent HBV naïve recipients from infection in some cases, but HBsAg-positive donors should only be considered in high risk situations.

Viral Hepatitis in Liver Transplantation

Liver transplantation is the only alternative for patients with end-stage liver disease. Viral hepatitis B and C are among the most common causes of cirrhosis and hepatocellular carcinoma and a frequent indication for liver transplantation. Hepatitis B virus immunoglobulin and nucleot(s)ide analogues have facilitated the management of patients with hepatitis B who have received liver transplants and resulted in excellent long-term outcomes. On the contrary, recurrence of hepatitis C is the main cause of graft loss in most transplant programs. Current therapeutic approaches are far from optimal, because sustained virologic responses are only achieved in one-third of treated patients, and adverse effects are common and severe. However, the rapid development of direct-acting antivirals against hepatitis C virus will change the management of this disease and in a few years prevent graft infection with this virus.

Assessment of organ transplants from donors with markers of hepatitis B

Organ transplantation (TX) is currently a therapeutic alternative in the management of end-stage or lethal diseases and, in some cases, for improving the quality of life and reducing the complications of chronic conditions. The scarcity of organ grafts or donors due to the limited number of deceased donors or to a lack of compatible living donors is one of the main limitations for the execution of organ TX. In Brazil, there is a great disparity between the number of patients on waiting lists and TX procedures, especially for liver and kidney TX. As a result of this inequality, grafts from donors who are considered marginal or not ideal have been used, including those with higher risk of failure following TX or those with potentially transmissible infections, involving donors with positive serologic markers for the hepatitis B virus (HBV). Donors who are positive for HBV markers have been routinely used in some TX centers. Four aspects should be considered for the assessment of the risk-benefit ratio of this procedure: 1. donor serologic profile, 2. recipient serologic profile, 3. TX variety and 4. the use of preventive therapy with human-specific HBV immunoglobulin and/or antiviral drugs. To establish recommendations, our group held discussions based on the data available in the medical literature and on the accumulated experience of the TX units at Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo. The definitions of serologic profiles for donors and recipients are described in Tables 1 and ​and2,2, respectively. The following transplants have been evaluated: liver, kidney, heart, lung, and hematopoietic stem cell transplants (HSCT). The IDSA (Infectious Diseases Society of America) rating system was used to assess the quality of evidence for graft acceptance and to identify the appropriate preventive strategy. Table 1 Definitions of HBV serologic profiles – Donors. Table 2 Definitions of HBV serologic profiles – Recipients. 1. Liver TX HBsAg-positive donor: few reports are available, under particular circumstances, and there is a high risk of “de novo” HBV infection. HBc-Ab-positive donor: HBsAg-positive recipient: regardless of the donor's serologic profile, this recipient must be administered combined prophylaxis with HBIG and an antiviral drug. The risk of viral reactivation does not seem to be increased by the involvement of an HBc-Ab-positive donor. Recipients who are positive for HBc-Ab and HBs-Ab: there are no reports of “de novo” HBV infection, with or without prophylaxis. Recipients with isolated HBc-Ab or a history of vaccination: the risk of “de novo” HBV is reduced in case series that described lamivudine and/or HBIG prophylaxis. Naive recipient: group at highest risk; case series that described lamivudine and HBIG prophylaxis have demonstrated a reduction in risk. Kidney TX The largest case series of donors with positive serologic markers for HBV were published in kidney TX. However, some studies describe only the post-TX clinical course and fail to assess HBV serology. HBsAg-positive donor: among 48 donors, “de novo” HBV infection has been detected in three recipients with variable pre-TX serologic profiles, while liver enzyme elevation has been detected in nine recipients. HBc-Ab-positive donor: HBsAg-positive recipient: when lamivudine is used as preventive therapy, the clinical evolution is similar to that of recipients whose donors have negative HBV serology. Recipients with isolated HBc-Ab: without any prophylaxis, the seroconversion of HBsAg has been observed in 0.5% of recipients after TX. No reports have described seroconversion under lamivudine prophylaxis. Vaccinated or Naive recipient: after TX, without any prophylaxis, seroconversion of HBc-Ab occurs in 2% of cases, and seroconversion of HBsAg occurs in less than 0.5% - without any impact on the clinical course. No reports have described seroconversion under lamivudine prophylaxis. Heart TX There are two case series on heart TX that report lamivudine prophylaxis in some recipients. Only one case of “de novo” HBV infection is reported in a naive recipient with an HBsAg-positive donor. Lung TX In two small case series of HBc-Ab-positive donors, no cases of recipient post-TX seroconversion were described. Among the two case series, one involved lamivudine prophylaxis. Hematopoietic Stem Cell Transplant In HSCT, the most relevant consideration is the risk of reverse seroconversion (loss of HBs-Ab after TX). HBsAg-positive donor: in a study of HBsAg-negative recipients with a historical control group, the risk of “de novo” HBV was significantly reduced with lamivudine prophylaxis. HBc-Ab-positive donor: when the bone marrow donor is naturally immunized (HBc-Ab and HBs-Ab positive), there is an unmistakable reduction in the risk of reverse seroconversion.

Management of HBV resistance in the post-transplant setting

In western countries, about 10–25% of patients undergoing liver transplantation (LT) are HBsAg carriers. In Asia, HBV-related liver disease is the leading indication to LT. After surgery hepatitis B can develop in patients transplanted for HBV-related disease or in HBsAg-negative recipients of anti-HBc positive grafts. In the last years prophylaxis with HBIG and/or antivirals has been proposed in both conditions with excellent results. However, lack of efficacy of prophylaxis is frequently associated with the selection of HBV mutants resistant to the different drugs.

Allogeneic Hematopoietic Stem Cell Transplantation From HBsAg-Positive Donors Into HBsAg-Negative Recipients: A Safety and Practicable Regimen Under Active Prophylactic Anti-HBV Therapy

Abstract 1949 IntroductionTransmission of hepatitis B virus (HBV) may occur (de novo HBV infection) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) from HBsAg-positive donors into HBsAg-negative recipients. Increased HBV associated complications will cause high morbidity and mortality post-transplantation in such patients. China is an endemic area for HBV infection. The exclusion of HBsAg positive donors will greatly limit the application of HSCT. There are few published data on allo-HSCT from HBsAg-positive donors when no other alternatives can be available. Recently great advances in anti-HBV therapy and prophylaxis have been achieved. The efficacy of allo-HSCT combined with anti-HBV prophylaxis in such patients remains unknown. In the current study, we performed a retrospective analysis of the virologic and clinical outcomes of allo-HSCT from HBsAg-positive donors into HBsAg-negative recipients under active prophylactic anti-HBV therapy. Methods From 2005 to 2010, a total of 10 HBsAg-negative recipients undergoing allo-HSCT from HBsAg-positive donors in our single center were included as an observation group. We performed a matched case-controlled analysis, in which each HBsAg-positive transplantation was paired with 3 control subjects selected from among all seronegative transplantation defining as a matched control group (30 patients). Patients were matched on age, underlying disease, disease stage, conditioning regimen and donor type. All the enrolled patients underwent HLA-matched related (20% each group) and HLA-mismatched related (haploidentical, 80% each group) transplantation. For haploidentical HSCT, conditioning regimen consisted of Ara-C, busulfan (Bu), cyclophosphamide (Cy), Me-CCNU and ATG. For HLA-matched related HSCT, the conditioning regimen consisted of Bu and Cy. GVHD prophylaxis consisted of cyclosporine A, mycophenolate mofetil and short-term methotrexate. Anti-HBV therapy consisted of lamivudine or entecavir for HBsAg positive donors. Marrow harvest and HSCT were performed until donor’s serum HBV-DNA became undetectable. Hepatitis B immunoglobulin (HBIg) of 400 IU were administered to the recipients within 24 hours, 1 month and 2 months after stem cell infusion, respectively. HBsAb titers were detected once a month. If the titer was lower than 200IU/L, HBIg was injected rapidly. All the patients were followed-up weekly and HBV serology was detected once a month. Reults After transplantation, 1 and 0 patient developed HBV-related hepatitis in observation group and matched control group (P>0.05). The HBV-related hepatitis patient became positive for HBsAg 1 year post-transplantation with serum HBsAb loss. Interestingly, this patient became negative for HBsAg and positive for HBsAb after donor lymphocyte infusion due to the primary disease relapse. To date, none of the enrolled recipients in our study became positive for HBsAg. Veno-occlusive disease (VOD) is another kind of hepatic complication. One and 0 patient developed VOD in observation group and matched control group respectively (p>0.05). The presence of HBcAb in the absence of HBsAg in serum indicates past exposure to HBV. Despite the presumed resolution of the HBV infection in these patients, a minute amount of HBV DNA remains in the liver. So we analyzed HBcAb and HBsAb levels in the serum in both groups 1 year post-transplantation. Nine (90.0%) and 6 (20.0%) patients became positive for both HBcAb and HBsAb in observation group and matched control group respectively (p<0.01), suggesting possible occult HBV infection in recipients transplanted from HBsAg-positive donors. We also compared clinical outcomes between 2 groups. The incidence of aGVHD was 40.0% in obervation group and 30.0% in matched control group (p>0.05). The 1 year overall survival (OS) were 60.0% and 63.3% in observation group and matched control group respectively (p>0.05). The 1 year non-relapse mortality (NRM) were 10.0% and 13.3% in observation group and matched control group respectively (p>0.05). Conclusions Our data support that allo-HSCT from HBsAg-positive donors into HBsAg-negative recipients is a safety and practicable regimen under active prophylactic anti-HBV therapy, but these recipients are possibly complicated with occult HBV infection. A long-term prospective follow-up study on such patients is imperative currently. Disclosures:No relevant conflicts of interest to declare.

Adult Living Donor Liver Transplantation Using Hepatitis B Core Antibody-Positive Grafts in Korea, a Hepatitis B-endemic Region

Background/AimsThe exclusion of hepatitis B core antibody (HBcAb)-positive donors from liver transplants (LTs) due to the risk of transmitting hepatitis B virus (HBV) does not appear to be practical in Korea, where hepatitis B is endemic. This study assessed the risk of de novo HBV infection in hepatitis B surface antigen (HBsAg)-negative LT recipients receiving a liver from HBcAb-positive donors.MethodsOf 341 adult living donor LTs conducted at our institution between March 2001 and September 2008, 176 donors (51.6%) were HBcAb-positive, and 26 HBcAb-positive grafts were transplanted to HBsAg-negative recipients. The median follow-up time after LT was 41.9 months.ResultsWithout anti-HBV prophylaxis, 2 out of 26 (7.7%) HBsAg-negative recipients who received grafts from HBcAb-positive donors developed de novo HBV infection 20 and 85 months after LT. These patients had been negative for all HBV serologic markers before transplantation. In both cases, there were no abnormalities in liver function tests upon diagnosis of de novo HBV infection.ConclusionsDe novo HBV infection from HBcAb-positive donors after LT does not appear to be of great concern in terms of the number of cases in Korea because high risk patients who are HBV-negative comprise only a small proportion of the recipients. However, HBV-naïve LT recipients still carry the risk of developing de novo HBV infection as in non-HBV endemic areas.

Lamivudine monoprophylaxis for de novo HBV infection in HBsAg-negative recipients with HBcAb-positive liver grafts

We followed the efficacy of long-term lamivudine monotherapy in preventing development of de novo hepatitis B (DNHB) in a large cohort of hepatitis B surface antigen (HBsAg)-negative recipients with grafts from hepatitis B core antibody (HBcAb)-positive donors. Recipients were observed over a long follow-up. Between July 1999 and December 2008, 45 patients (median age 54, range 19-67) who were HBsAg negative before transplantation were included in the study of monoprophylaxis with lamivudine starting on post-operative day 1, and continuing for life. Mean follow-up: 37.9 months; median 32.1 months (range 2.4-117). No suspension of therapy was reported during the study. Post-transplantation, no DNHB was observed in follow-up: all 45 HBsAg-negative recipients remained HBsAg and HBV DNA negative. Thirty-four of these HBsAg-negative recipients were alive at conclusion of the study. A total of 11 patients died, five of HCV recurrence, two of hepatocellular carcinoma (HCC) recurrence, two of disseminated KSV infection, and two of multiorgan failure because of early graft dysfunction. Patient and graft survival of HBsAg-negative recipients with HBcAb-positive donor grafts (45 cases) were not significantly different from those of the HBsAg-negative recipients with HBcAb-negative donor grafts (302 cases). In our experience, lamivudine monoprophylaxis provided complete protection against HBV reactivation and showed long-term efficacy.