Successful hepatitis B vaccination in liver transplant recipients with donor-specific hyporesponsiveness

Currently, patients are prescribed lifelong treatment with hepatitis B immunoglobulin (HBIg) after liver transplantation (LT) for hepatitis B virus (HBV)-related diseases in order to prevent reinfection with HBV. Active immunization with an HBV vaccine would be a preferable alternative; however, the immunosuppressive environment in LT recipients is believed to elicit a poor response to vaccination. Minimizing the exposure of the HBV-infected LT recipients to immunosuppressants would be beneficial in inducing adaptive immunity against HBV by vaccination. In this study, in addition to efforts to minimize immunosuppression, prophylaxis with HBV vaccination combined with continuous HBIg administration was performed in 17 LT recipients who had undergone transplantation attributable to HBV-related diseases. During the observation period, the overall response rate to HBV vaccination was 64.7%. The immune status of the recipients was evaluated by a mixed lymphocyte reaction assay in response to allostimulation. Patients showing a donor-specific hyporesponse with a well-maintained response to the third-party stimulus always achieved a sustained immune response to the vaccine, whereas patients showing a hyporesponse to both the donor and the third-party stimulus were unable to do so. Thus, inducing an anti-donor-specific immunosuppressive status by minimizing immunosuppression should enable post-transplant HBV vaccination to be a promising prophylactic strategy.     

Immunization and vaccination protocol in hemodialysis patients with naturally acquired hepatitis B antibody.

Long-term behavior of naturally acquired anti-HBs antibody was tested every 6 months for 3 years in 22 dialysis patients. Fifteen of them maintained protective levels throughout follow-up (102 and 85.5 mUI/ml at the beginning and the end, respectively). Seven of them became anti-HBs and were submitted to a 40-micrograms booster injection of hepatitis B vaccine. Seroconversion was observed in 6 of 7 patients (85.7%) with a mean anti-HBs titer of 90.4 and 47.3 mUI/ml after 3 and 6 months, respectively. Protective anti-HBs level may be maintained longer in patients with natural immunity than in HBsAg-negative vaccinated subjects. Effectiveness of a reduced vaccination protocol in patients who have lost their natural immunization should be confirmed with further studies.     

Immunogenicity of hepatitis B vaccine in renal transplant recipients

To evaluate the immunogenicity of hepatitis B vaccine in renal transplant recipients, we administered three 40-microgram doses of vaccine to 17 patients who had previously undergone transplantation and were on immunosuppressive therapy. Life-table analysis revealed a cumulative antibody response rate of only 17.6% at 12 months, and the three responders had low titers of antibody to hepatitis B surface antigen. There were no serious adverse effects and no episodes of graft rejection in responders or nonresponders. In addition, the ratio of helper/inducer (T4) to suppressor/cytotoxic (T8) T cells in vaccinees bore no relationship to the immunogenicity of the vaccine. These data indicate that hepatitis B vaccine is weakly immunogenic in renal transplant recipients and illustrate the need for vaccination prior to transplantation for maximal protection against hepatitis B virus infection.     

Failure of hepatitis B vaccination with conventional HBsAg vaccine in patients with continuous HBIG prophylaxis after liver transplantation.

Hepatitis B vaccination after liver transplantation for hepatitis B-related liver disease has been investigated as an alternative strategy to reinfection prophylaxis with hepatitis B immunoglobulin (HBIG) with conflicting results. In most studies, HBIG treatment was discontinued before vaccination. An outstanding good response was achieved with vaccination under continuous HBIG administration using hepatitis B surface antigen (HBsAg)-based vaccine containing special adjuvants. Both, adjuvants and continuous HBIG administration have been discussed as crucial factors for good response. Twenty-four patients were vaccinated with conventional double dose recombinant vaccine containing 40 microg HBsAg up to 12 times at weeks 0, 2, 4 (cycle 1), 12, 14, 16 (cycle 2), 24, 26, 28 (cycle 3), and 36, 38, 40 (cycle 4). All patients received 2,000 IU HBIG every 6 weeks (4 times intravenously and 4 times intramuscularly). A significant response was defined as reconfirmed increase of anti-HBs-antigen (anti-HBs) unexplained by HBIG administration or lack of anti-HBs decrease below 100 IU/L after discontinuation of HBIG treatment after week 48. Only 2 of 24 patients (8.3%) responded significantly. Anti-HBs started to increase after the seventh vaccination (cycle 3, during intramuscular HBIG administration) in 1 patient and after 12th vaccination (cycle 4, during intravenous HBIG administration) in the other. Maximum anti-HBs levels were >1,000 IU/L in both patients and decreased significantly slower as compared to passive prophylaxis during follow-up. In conclusion, the conventional HBsAg vaccine failed to induce a significant humoral immune response in most patients despite continued HBIG treatment. Further studies should address the question, of whether the use of potent adjuvant systems results in higher response rates.     

Immunization of renal transplant recipients with pneumococcal polysaccharide vaccine

BACKGROUND: Streptococcus pneumoniae, a common pathogen leading to pneumonia, is a cause of morbidity and mortality in immunosuppressed patients. Vaccination against this agent can be recommended for immunosuppressed patients, including those with chronic renal failure, nephrotic syndrome and renal transplant recipients; however, a diminished immune response and loss of protective antibodies have been observed. PATIENTS AND METHODS: In our prospective study, the efficacy and side effects of polyvalent pneumococcal vaccination were investigated in renal transplant recipients. A total of 21 patients (6 female, 15 male) with well-functioning renal allografts, who had transplant surgery at least 2 months before, were included in the study. The patients were stratified according to the immunosuppressive protocol and 8 received double, while 13 received triple, immunosuppressive agents. After obtaining basal serum samples, all cases were vaccinated with the 0.5 mL intramuscular administration of polyvalent polysaccharide pneumococcal vaccine (Pneumo 23 Pasteur Merieux, lot No: K 1131). RESULTS: Following a mean of 6 wk in all patients and also a mean of 12 wk in 12 patients, serum samples were again obtained to measure pneumococcal antibodies. Antibody titers following 6 and 12 wk of vaccination were significantly higher, as compared with basal values in all patients, except one. These titers did not show any statistically significant difference between double and triple therapies. There was no significant difference between the 12th and 6th wk postvaccination antibody titers. No systemic or local adverse effects were observed. CONCLUSION: Pneumococcal vaccination is safe and effective in patients with well-functioning renal allografts, at least in the short term. This vaccination policy may be useful for preventing invasive pneumococcal disease in immunosuppressed patients.     

Influenza vaccination in liver transplant recipients

BACKGROUND: The immunogenicity of the trivalent inactivated influenza split virus vaccine (Infusplit SSW 97/98) containing A/Bayern/07/95 (H1N1)-like (A/Johannesburg/82/96 [NIB-39]), A/Wuhan/359/95 (H3N2)-like (A/Nanchang/933/95 [Resvir-0]), and B/Beijing/184/93-like (B/Harbin/7/94) hemagglutinin antigens was tested in liver transplant recipients (TXL-R). SUBJECTS AND METHODS: Serum antibody titers were determined 21+/-2 days after a single vaccination in 62 adult TXL-R and 59 adult volunteers. RESULTS: Protective postimmunization antibody titers for the three antigens were similar in TXL-R (protection rates 92%, 92%, and 95%) and the comparison group (97%, 100%, and 100%). Adverse reactions were mild and less frequent in TXL-R. A significant decrease of CD8+CD38+ lymphocytes after vaccination was found in TXL-R. No association between antibody response and age, gender, time interval since transplantation, anti-hepatitis B surface antigen immunoprophylaxis, or immunosuppressive medication was detected. CONCLUSION: Our results show that the vaccine is safe and effective and should be recommended to TXL-R.     

Durability of the hepatitis B vaccination in pediatric renal transplant recipients

Since hepatitis B virus (HBV) vaccine implementation, HBV infection has significantly decreased. However, adult renal transplant recipients show a higher rate of seroreversion compared to the general population, leading to HBV infection risk. Data are limited in pediatric renal transplant recipients. Retrospective data were collected to determine the seroprotection and durability of HBV vaccination in pediatric renal transplant patients from 2004 to 2014. One hundred subjects were categorized based on pre‐ and post‐transplant hepatitis B surface antibody (HBsAb). Pretransplant, 85 recipients (85%) had a positive HBsAb compared to 15 (15%) with negative HBsAb. In univariable analyses, other than age (P < .05) no significant differences existed pretransplant by demographics, pretransplantation dialysis, or number of vaccinations. Of the 85 pretransplantation responders, 53 (62%) remained HBsAb positive post‐transplantation, 28 (32%) seroreverted, and 4 developed indeterminate titers. All seroreversions occurred within 5 years post‐transplant. Receipt of a living donor organ had higher risk of reversion (P = .005). No significant differences were found in demographics, pretransplantation dialysis, vaccination number, or acute rejection. Despite vaccination, 15% of pediatric renal transplant candidates were seronegative, and an additional 32% lost seroprotection within 5 years post‐transplantation leaving nearly half of transplant recipients at risk for HBV infection.     

Immunogenicity and safety of an experimental adjuvanted hepatitis B candidate vaccine in liver transplant patients.

Patients with chronic liver disease are at higher risk of hepatitis B (HB) virus infection before and after liver transplantation, and they commonly have a suboptimal immune response to HB vaccines. In this randomized trial, we compared the immunogenicity of primary vaccination with 2 doses of an experimental adjuvanted HB vaccine (adjuvant system 04 containing aluminium and monophosphoryl lipid A [HB-AS04]) to that of 3 double doses of a licensed HB vaccine in 93 liver transplant candidates. Depending on the waiting list for liver transplantation, a booster dose of HB-AS04 or double booster dose of the licensed HB vaccine was given before or after surgery, at 6 to 12 months after initiation of the vaccination course. The percentage of subjects with seroprotective anti-HB surface antibody concentrations 1 month after booster was twice as high in the HB-AS04 group (60.0%), vs. patients in the comparator group (32.0%) (P = 0.035). In subjects who did not undergo liver transplantation before administration of the booster, better immunogenicity results were obtained: 80% of subjects were seroprotected after HB-AS04 vaccination vs. 60% with the comparator (P = 0.2302). Despite a slightly higher reactogenicity, the safety profile of the HB-AS04 vaccine was clinically acceptable. In conclusion, an improved antibody response was observed in liver transplant candidates with 3 doses of HB-AS04, as compared to 4 double doses of a comparator. Liver transplant candidates could benefit from the use of this experimental adjuvanted HB vaccine to further increase their protection against HB infection.     

Lamivudine monoprophylaxis for liver transplant recipients with non-replicating hepatitis B virus infection

Background: The aim of this study was to evaluate the efficacy of lamivudine (LAM) monoprophylaxis for patients with non-replicating hepatitis B virus (HBV) infection at orthotopic liver transplantation (OLT). METHODS: Among 128 liver recipients with HBV infection between 1994 and 2004 transplanted at our institution, 60 had non-replicating HBV infection at the time of OLT. Of those, 26 patients received LAM prophylaxis (monoprophylaxis group) and 34 patients received LAM and hepatitis B immunoglobulin (HBIG) prophylaxis (combination group) after OLT. RESULTS: Median follow-up after OLT was 67 and 54 months, for monoprophylaxis and combination groups respectively. One and five yr patient/graft survival were 96/85% and 96/80% in monoprophylaxis group, and 85/79% and 67/55% in combination group. HBV DNA was re-detected or increased >10(5) IU/mL in four patients (15%) at 20-29 month in monoprophylaxis group and six (18%) at 4-35 months in combination group. Recurrent hepatitis was seen in two patients (8%) at 27 and 45 months and monoprophylaxis group and three (9%) at 21-35 months in combination group. The rate of recurrence was not statistically different between two groups. CONCLUSION: LAM monoprophylaxis seemed to be effective for OLT recipients with HBV infection who had non-replicating HBV at transplantation. HBIG administration may play a less valuable role in preventing HBV recurrence in this group of patients.     

Influenza vaccine antibody responses in lung transplant recipients

CONTEXT: Lung transplant recipients are at high risk of morbidity and mortality from influenza infection because of altered lung physiology and immunosuppression. Annual influenza immunization is recommended, but the ability to mount an antibody response may be limited by immunosuppressant medications. OBJECTIVE: To compare the antibody response rate to influenza vaccine in lung transplant recipients to healthy controls. DESIGN: Open label study. SETTING: Lung transplant clinic and General Clinical Research Center at a university hospital. SUBJECTS: Sixty-eight single and bilateral lung transplant recipients and 35 healthy controls were enrolled in October and November 2002. METHODS: Each individual underwent blood sampling before receiving the 2002-2003 influenza vaccine and 4 weeks later. Influenza antibody concentrations were measured by hemagglutination inhibition assay. Vaccine response rates (antibody concentration >40 hemagglutination units and at least 4-fold increase in antibody concentration) were compared using chi2. The influence of specific immunosuppressants on vaccine response was compared. RESULTS: The influenza vaccine response rate for lung transplant recipients was 29/68 (43%) and 22/35 (63%) for the healthy individuals (P < .05; chi2). Among the recipients, mycophenolate mofetil was associated with poorer influenza vaccine antibody response (> 40 hemagglutination units) (62% vs 91%; P = .01), whereas sirolimus (91% vs 63%; P = .02) was associated with better influenza antibody response compared to those not taking mycophenolate mofetil or sirolimus, respectively. CONCLUSION: Lung transplant recipients had lower influenza vaccine response rates than healthy individuals. Influenza vaccine antibody response is influenced by concomitant administration of mycophenolate mofetil or sirolimus. Future studies should measure protection from influenza infection conferred by immunization and alternative vaccination strategies.     

Treating hepatitis C infection in liver transplant recipients.

Chronic infection with hepatitis C virus (HCV) is a growing problem worldwide, with up to 300 million individuals infected, and those with chronic infection are at risk for cirrhosis and hepatocellular carcinoma. HCV infection is the most common indication for liver transplantation in the United States and Europe. Unfortunately, although transplantation is effective for treating decompensated cirrhosis and limited hepatocellular carcinoma associated with hepatitis C, HCV reinfection is virtually the rule among transplant recipients. Reinfection of the graft is associated with more rapidly progressive disease, with a median time to cirrhosis of 8 to 10 yr. Unfortunately, treatment of chronic HCV in liver transplant recipients is suboptimal. Combination therapy with interferon (pegylated and nonpegylated forms) plus ribavirin appears to provide maximum benefits. Drug therapy is usually administered for recurrent disease. No prophylactic therapy is available. Preemptive regimens offer no distinctive advantages over treatments begun for recurrent disease. Overall, treatment is poorly tolerated, with frequent need for dose reductions, especially from cytopenias, and drug discontinuations in up to 50% of patients. Optimizing drug doses is important in maximizing sustained virological response rates. Future therapies may include ribavirin alternatives with lower rates of anemia, alternative interferons with lower rates of cytopenias, and new antiviral drugs that can be used alone or in combination with either interferon or ribavirin to enhance sustained virological response rates and improve tolerability. Liver Transpl 12:1192-1204, 2006. (c) 2006 AASLD.     

Management of hepatitis B virus infection in liver transplant recipients: prospects and challenges

Although survival of liver transplantation for patients with hepatitis B infection is comparable to uninfected transplant recipients, prevention of hepatitis B virus (HBV) reinfection remains an important goal. In this article, several aspects of the hepatitis B reinfection and its management will be examined. Approximately 50% of the treatment failures that occur with hepatitis B immune globulin (HBIg) prophylaxis are due to mutations in the 'a' determinant of the HBV. In patients without mutations, failure of HBIg therapy may relate to the frequency and dose of HBIg, the type and amount of immunosuppression, and the pre-transplant replication status. Antiviral therapy with lamivudine and famciclovir has been used successfully to treat patients who have failed HBIg treatment and as monotherapies for liver transplant recipients. Combining antiviral and immunomodulatory therapies appears efficacious, at least in the short term. New developments related to immunotherapy predict three potential trends in future use: 1) i.v. formulated HBIg, 2) monoclonal antibodies, or 3) hepatitis B immune plasma. In conclusion, there are an increasing number of therapeutic options for the management of patients undergoing liver transplantation for hepatitis B infection. Continued improvement in patient outcomes requires further understanding of each therapeutic agent and the specific patient characteristics that may influence efficacy.     

Occult hepatitis B virus infection in liver transplant recipients with recurrent hepatitis C: relationship with donor age and fibrosis progression

Abstract:  Liver transplantation (OLT) recipients who receive a graft from donors positive for hepatitis B virus (HBV) anti-core antibodies may develop overt " de novo " HBV infection. The study was undertaken to explore how often HBV infection may remain occult after OLT for hepatitis C, and whether it may represent a factor of graft fibrosis progression. We studied 30 consecutive patients transplanted for hepatitis C liver disease. Specimens from the native liver and from the graft were searched for occult HBV infection (O-HBV). In the native liver, 8/30 patients had detectable O-HBV; during the follow-up, O-HBV infection was demonstrated in 14 graft specimens. Graft O-HBV was associated with older donor age (≥50 yr; 8/9 vs. 6/21, p < 0.005). Recipients with graft O-HBV and no O-HBV in the native liver who received their grafts from donors aged >40 yr had faster fibrosis progression than recipients with no post-transplant O-HBV, whose grafts came from donors aged >40 yr and recipients whose grafts came from donors aged ≤40 yr (4/7 vs. 1/7 vs. 2/16, p < 0.05). In OLT recipients, O-HBV is more likely to occur when grafts are obtained from aged donors and may affect the rate of fibrosis progression because of recurrent hepatitis C.     

Entecavir treatment in kidney transplant recipients infected with hepatitis B

Although nucleotide/side analogs improve the clinical outcome of hepatitis B surface antigen‐positive (HBsAg+) kidney transplant recipients (KTR), a significant proportion of subjects have developed resistance to lamivudine (LAM). We retrospectively analyzed the efficacy and tolerability of entecavir (ETV) in HBsAg+ KTR at Queen Mary Hospital during 2005–2013. Twenty‐one patients (10 treatment‐naïve, 11 with LAM resistance) were included (duration of ETV treatment 34.7 ± 22.9 months, range 6–75 months). ETV treatment led to a decline of hepatitis B virus (HBV) DNA titer compared to baseline and is more significant in the treatment‐naïve group (treatment‐naïve: p = 0.028, <0.001 and <0.001; LAM‐resistant p = 0.273, 0.180, and 0.109 after 12, 24, and 36 months). The cumulative rate of HBV DNA undetectability at 12, 24, and 36 months was 60%, 100%, and 100% for treatment‐naïve group, and 27%, 45%, and 45% for LAM‐resistant group, respectively. Time‐to‐HBV DNA undetectability and time‐to‐alanine transaminase (ALT) normalization were 15.7 ± 4.6 and 12.6 ± 3.7 months for treatment‐naïve patients, and 24.5 ± 4.2 and 28.2 ± 3.5 months for those with LAM resistance. Genotypic resistance to ETV emerged after 20.0 ± 3.5 months with increase in ALT and HBV DNA in two patients with LAM resistance, but was not observed in the treatment‐naïve group. Allograft dysfunction, de novo cirrhosis, or hepatocellular carcinoma did not occur during follow‐up.     

Influenza vaccination in heart transplant recipients.

Seventy-nine heart transplant recipients were vaccinated with a trivalent influenza virus vaccine 1996/97 containing the strains A/Singapore/6/86 (H1N1), A/Wuhan/395/95 (H3N2), and B/Beijing/184/93. The proportions of patients with protective levels of antibody (HI > or = 40) after vaccination ranged from 100% (A/Singapore [H1N1]) to 31.6% (B/Beijing) and their mean fold titer increases were lower than those recorded for vaccination of 109 healthy subjects with the same batch of vaccine. The vaccinations were tolerated well and did not result in serious side effects, such as graft rejections. Our findings indicate that influenza vaccination can induce protective antibody levels in a substantial proportion of heart transplant recipients and lend support to the recommendation to vaccinate such patients annually against influenza.