The safety and efficacy of GM-CSF as an adjuvant in hepatitis B vaccination of chronic hemodialysis patients who have failed primary vaccination

BACKGROUND: End-stage renal disease and the need for chronic hemodialysis is an indication for hepatitis B vaccination, but up to half of dialysis patients fail to respond to a 40 microg/dose i.m. three-dose primary series of recombinant hepatitis B vaccine. Only another 10-20% respond to additional boosting doses of vaccine. PATIENTS AND METHODS: Since GM-CSF has been shown to be an effective adjuvant for hepatitis B vaccine in healthy subjects and multiple animal vaccine models, we conducted a randomized, double-blind trial of GM-CSF with recombinant hepatitis B vaccine in chronic hemodialysis patients. Patients with negative hepatitis B surface antibody and antigen who had received at least three doses of recombinant hepatitis B vaccine without response (antibody titre < 10 mIU/ml) were randomized to placebo, 40 microg, or 80 microg of GM-CSF given with 40 microg recombinant hepatitis B vaccine i.m. at the same site. Clinical and laboratory studies for safety assessment were done on days 1 and 3, and hepatitis B surface antibody titres were measured at baseline and days 21 and 180 after the study injections. RESULTS: No significant local or systemic toxicity was noted from the co-injections. The rates of response and geometric mean titre (GMT) were equivalent among all three study groups: placebo 6/10 developed antibodies, GMT 22.1 mIU/ml; 40 microg GM-CSF 3/10 developed antibodies, GMT 5.4 mIU; and 80 microg GM-CSF 3/8 developed antibodies, GMT 9.7 mIU/ml. Six months after vaccination, antibody titres were available for 11 of the 12 day 21 positive responders; only 4 of these 11 patients remained antibody positive at 6 months. CONCLUSION: GM-CSF given in a single 40 microg and 80 microg i.m. dose was not an effective adjuvant with hepatitis B vaccine in chronic hemodialysis patients who had previously failed to respond to hepatitis B immunization.     

Granulocyte-macrophage colony-stimulating factor as an adjuvant to hepatitis B vaccination in maintenance hemodialysis patients

Patients on maintenance hemodialysis (HD) have poor seroconversion rate after hepatitis B vaccination. The present study was designed to test the efficacy of granulocyte-macrophage colony-stimulating factor (GM-CSF) as an adjuvant to hepatitis B vaccination for improving seroconversion rate in maintenance HD patients. Twelve chronic HD patients were randomly assigned to receive either hepatitis B vaccination alone or hepatitis B vaccination 24 h after 1 dose of GM-CSF for primary immunization. A group of 16 chronic HD patients who had not seroconverted after a standard two-dose hepatitis B vaccination were randomly assigned either to a booster dose of hepatitis B vaccine alone or a booster dose given 24 h after one dose of GM-CSF. In the primary immunization group only 2 of 6 patients (33%) who had received vaccination alone, versus 5 of 6 patients (83%) who had received hepatitis B vaccine after one dose of GM-CSF, developed seroprotective antibody titers. Moreover, seroprotective antibody titers (IU/ml) were significantly higher in the latter group (275 +/- 286.5 vs. 14 +/- 22, p < 0.05). In patients who had not seroconverted with prior hepatitis B vaccination, GM-CSF adjuvant therapy significantly increased the seroconversion rate versus booster dose alone (87.5 vs. 25%, respectively, p < 0.02), with significantly higher seroprotective antibody titers (84 +/- 80 vs. 19 +/- 33 IU/ml, respectively, p < 0. 05). These findings suggest that administration of one dose of GM-CSF, as adjuvant therapy, prior to primary or booster dose hepatitis B vaccination may significantly increase seroconversion rate and seroprotective antibody titers in chronic HD patients.     

Challenges in containing the burden of hepatitis B infection in dialysis and transplant patients in India

Aim: Whether or not completing the hepatitis B vaccination in patients who have undergone kidney transplantation in the middle of incomplete vaccination schedule leads to development of protective antibody titres is not known. This study was designed to determine whether the strategy of completing hepatitis B virus (HBV) vaccination after transplantation is efficacious. Methods: Sixty‐four end‐stage renal disease (ESRD) patients were screened for hepatitis B surface antigen (HBsAg), antibodies to hepatitis B surface antigen (anti‐HBs), hepatitis B e‐antigen (HBeAg) and HBV DNA. HBsAg negative patients received four doses of 40 µg recombinant HBV vaccine. Schedule was continued in after transplantation period if it was incomplete before transplant. Anti‐Hbs titres were evaluated at 1, 3, 6, 9 and 12 months. Results: Past HBV infection was noted in 12 patients: 10 by serology plus viraemia and two by viraemia alone. Of the 46 patients without current or past HBV infection who had received at least two doses of the vaccine before transplant, 17 each had received two and three doses and 12 had completed the schedule. Seventeen (37%) exhibited protective titres. Patients who had completed vaccination were more likely to have protective titres than those incompletely vaccinated (P = 0.02). Five patients responded to post‐transplant vaccination. Conclusion: Partially vaccinated patients do not mount an adequate antibody response despite continued vaccination in the post‐transplant period, whereas complete vaccination provides protection in 60%. The present study data highlights the need of administration of a full schedule of HBV vaccination before kidney transplantation. Nucleic acid‐based tests can identify occult HBV infection.     

A prospective study of hepatitis B vaccination - a comparison of responders versus nonresponders

Herein we present one of the largest single-center reports of the response of hemodialysis patients to a two-vaccine hepatitis B virus vaccination protocol in a European dialysis population. A hepatitis B recombinant DNA vaccine, HBvaxPRO, was given at a dose of 40 μg intramuscularly using a four-dose schedule at 0, 1, 2, and 12 months. Responses were (1) a titer >100 mIU/mL = patient immune, (2) a titer level 10-99 mIU/mL = give a booster dose and recheck level 2 months later, and (3) 0 ≤ 10 mIU/mL = repeat vaccination course using a different vaccine, Engerix-B. We compared responder groups in terms of titer levels for each vaccine and variables including age, gender, serum albumin, parathyroid hormone (PTH), calcium, phosphate, hemoglobin, years on dialysis, and type of dialysis access. Of the 176 patients who received the first vaccine course, 71 patients achieved immunity, that is, 40% uptake for the first vaccine. Of the 105 who failed, 72 received the second vaccine with 46 responders, that is, 64% uptake for the second vaccine. Overall, 143 of the 176 patients who entered the vaccination program completed the protocol with 117 achieving immunity, representing an 82% success rate. The only variable overall to show significance in achieving seroconversion was serum albumin (p = 0.03). Using a two-vaccine protocol, hepatitis B vaccination response was high in our population of end-stage renal disease patients.     

A Prospective Study of Hepatitis B Vaccination – A Comparison of Responders versus Nonresponders

Herein we present one of the largest single-center reports of the response of hemodialysis patients to a two-vaccine hepatitis B virus vaccination protocol in a European dialysis population. A hepatitis B recombinant DNA vaccine, HBvaxPRO®, was given at a dose of 40 µg intramuscularly using a four-dose schedule at 0, 1, 2, and 12 months. Responses were (1) a titer >100 mIU/mL = patient immune, (2) a titer level 10–99 mIU/mL = give a booster dose and recheck level 2 months later, and (3) 0 £ 10 mIU/mL = repeat vaccination course using a different vaccine, Engerix-B®. We compared responder groups in terms of titer levels for each vaccine and variables including age, gender, serum albumin, parathyroid hormone (PTH), calcium, phosphate, hemoglobin, years on dialysis, and type of dialysis access. Of the 176 patients who received the first vaccine course, 71 patients achieved immunity, that is, 40% uptake for the first vaccine. Of the 105 who failed, 72 received the second vaccine with 46 responders, that is, 64% uptake for the second vaccine. Overall, 143 of the 176 patients who entered the vaccination program completed the protocol with 117 achieving immunity, representing an 82% success rate. The only variable overall to show significance in achieving seroconversion was serum albumin (p?=?0.03). Using a two-vaccine protocol, hepatitis B vaccination response was high in our population of end-stage renal disease patients.     

Response to a Vaccination Schedule With 4 Doses of 40 μg Against Hepatitis B Virus in Cirrhotic Patients Evaluated for Liver Transplantation

We conducted a retrospective study to evaluate the response to recombinant hepatitis B vaccine after 4 intramuscular doses (40 μg) administered at 0, 1, 2, and 6 months in 157 cirrhotic patients who were liver transplant candidates. Seventeen nonresponders were revaccinated with the same schedule. We studied the association between the following variables and the vaccine response: age, gender, etiology of cirrhosis, diabetes, severity of liver disease (Child-Pugh class and Model for End-Stage Liver Disease [MELD] score), and the number of administered doses. The response rates were: 1 dose, 40% (2/5); 2 doses, 0% (0/7); 3 doses, 32.7% (16/49); and 4 doses, 31.3% (30/96) of patients. The median hepatitis B surface antibody (anti-HBs) titer was 45 mU/mL (range, 11-620 mU/mL). The response rate to revaccination was 41.2% (median anti-HBs titer, 88 mU/mL; range, 18-190 mU/mL). Diabetics showed a lower response rate than nondiabetic patients (17.2% vs 35.3%; P = .046). No association was observed between the response rate to vaccine and the other variables. In conclusion, the response rate to hepatitis B vaccine reached a little more than 30% in cirrhotic patients who received 3 or 4 doses. No higher response rate was observed among patients who received 4 doses. Diabetes was associated with a lower response rate. Anti-HBs seroconversion rates were not associated with the other variables. Revaccination may significantly increase the response rate to hepatitis B vaccine in cirrhotic patients, and may be considered in nonresponders after the third dose. Early vaccination against HBV should be considered in such patients.     

Hepatitis B vaccination in haemodialysis patients: A randomized clinical trial

Aim:   A short vaccination protocol against hepatitis B was compared to the standard approach in patients under haemodialysis who were primarily non-responsive to the vaccine.
Methods:   This randomized, controlled open trial included 51 chronic haemodialysis subjects previously vaccinated against hepatitis B and with anti-HBs levels of less than 10 IU/mol/L. Twenty-six patients received 20 µg i.m. once a week for 8 weeks (short protocol) and 25 subjects three doses of 40 µg i.m. at months 0, 1 and 6 (standard protocol). Clinical and laboratory data were compared between responders and non-responders. A logistic regression model included selected parameters to assess risk factors for non-seroconversion.
Results:   Seroconversion rates to vaccine at 2 months were 80% and 78% in the short and standard protocol groups, respectively ( P  = 0.99). Median of anti-HBs levels were similar up to 6 months of follow up, but patients in the standard protocol showed a trend to higher anti-HBs in month 3 and a more steady decline in antibody titres. Non-responders were older, had longer duration of dialysis and a higher prevalence of a prior renal transplant and hepatitis C. In multivariate analysis, only advanced age and hepatitis C remained independently associated with non-responsiveness to vaccination.
Conclusion:   In haemodialysis patients, a short vaccination protocol against hepatitis B did not provide any benefit compared to the standard approach with respect to peak anti-HBs titres or a higher rate of seroprotection at the end of follow up. Other strategies to increase seroconversion rates should be explored, especially in the elderly and in patients with hepatitis C.     

Comparison of Intramuscular and Intradermal Applications of Hepatitis B Vaccine in Hemodialysis Patients

This study compared the application of intramuscular recombinant hepatitis B vaccine in hemodialysis patients with the application of accelerated intradermal recombinant hepatitis B vaccine, which can be applied with one-tenth of the standard dose. Sixty seronegative patients for hepatitis B were randomly separated into two groups. Twenty μg of the recombinant hepatitis B vaccine was intramuscularly applied at 0-, 1-, 2-, and 6-month intervals to the first group (32 cases). One more dose was applied at month 12 to those whose anti-HBs titers remained below 100 mIU/mL at month 7. The same vaccine was intradermally applied at 2μg dose six times with one-month intervals to the second group (28 cases). Vaccine applications were continued in those whose anti-HBs titers remained below 100 mIU/mL at month 7 until antibody titers reached above this value or until the dose number became 12. Measurements of antibody titers were repeated at month 13 in both groups. As a result, in the vaccination of hemodialysis patients against hepatitis B, the accelerated ID application of hepatitis B vaccine with a dose reduced to one-tenth is more cost-effective than the standard dose vaccination schedules. Especially for hemodialysis patients, the time has come for routine application of ID hepatitis B vaccine as an alternative vaccination method.     

Comparison of intramuscular and intradermal applications of hepatitis B vaccine in hemodialysis patients

This study compared the application of intramuscular recombinant hepatitis B vaccine in hemodialysis patients with the application of accelerated intradermal recombinant hepatitis B vaccine, which can be applied with one-tenth of the standard dose. Sixty seronegative patients for hepatitis B were randomly separated into two groups. Twenty mug of the recombinant hepatitis B vaccine was intramuscularly applied at 0-, 1-, 2-, and 6-month intervals to the first group (32 cases). One more dose was applied at month 12 to those whose anti-HBs titers remained below 100 mIU/mL at month 7. The same vaccine was intradermally applied at 2 microg dose six times with one-month intervals to the second group (28 cases). Vaccine applications were continued in those whose anti-HBs titers remained below 100 mIU/mL at month 7 until antibody titers reached above this value or until the dose number became 12. Measurements of antibody titers were repeated at month 13 in both groups. As a result, in the vaccination of hemodialysis patients against hepatitis B, the accelerated ID application of hepatitis B vaccine with a dose reduced to one-tenth is more cost-effective than the standard dose vaccination schedules. Especially for hemodialysis patients, the time has come for routine application of ID hepatitis B vaccine as an alternative vaccination method.     

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.     

Efficacy of GM-CSF as an adjuvant to hepatitis B vaccination in patients with chronic renal failure--results of a prospective,randomized trial

BACKGROUND: Chronic renal failure patients on hemodialysis are at an increased risk of acquiring hepatitis B infection. Hence vaccination against hepatitis B assumes great importance in these patients. However, the response to hepatitis B vaccination is poor, even when 4 double doses (40 microg) of the vaccine are given. This study was conducted to determine the efficacy of GM-CSF as an adjuvant to hepatitis B vaccine in CRF patients. METHODS: CRF patients including both hemodialysis (HD) and non-dialysis (ND) patients were randomized to receive either placebo or a single injection of GM-CSF (in varying doses of 50 microg, 100 microg, 150 microg) a day prior to the 1st dose of recombinant hepatitis B vaccine (40 microg). Three more doses of the vaccine were given at 1, 2, and 6 months. The anti-HBs antibody titres were measured by ELISA at 3 and 7 months. Patients having antibody titres less than 10 IU/L were considered non-responders. The response rate and mean antibody titers were compared between the control (I) and GM-CSF (II) groups. RESULTS: In group I, 31 and 27 patients were available for evaluation at 3 and 7 months respectively. In group II, 33 and 28 patients could be evaluated at the same time points. Within the control group (group I), the response rate in hemodialysis patients (63.6%) was lower as compared to non-dialysis patients (81.2%). The response rate in group II was higher than that in group I at both 3 months as well as 7 months (78.1% vs. 62.3% and 89.3% vs. 74.1%, p = ns). The best response rates in group II were observed when GM-CSF was used in a dose of 150 microg (90.9% at 3 months and 100% at 7 months). The mean antibody titers were also found to be higher in the group II as compared to group I (409.6 vs. 243.9 IU/L, p = 0.01). CONCLUSION: The results of this randomized, prospective study suggest that: 1. Patients with chronic renal failure should be vaccinated for hepatitis B as chronic renal insufficiency is established. 2. GM-CSF is an effective adjuvant to hepatitis B vaccine in these patients especially when a priming dose of 150 microg is used prior to 1st dose of hepatitis B vaccination.     

Reinforced intradermal hepatitis B vaccination in hemodialysis patients is superior in antibody response to intramuscular or subcutaneous vaccination

Since 1960, hepatitis B virus-associated chronic liver disease has been considered an important problem in dialysis units in both Europe and North America. Separate dialysis facilities for hepatitis B-infected patients, the implementation of universal precautions for the prevention of transmission, and the active immunization against hepatitis B have now reduced the yearly incidence to less than 0.05% in Western countries. However, only 50% to 60% of patients with renal insufficiency develop sufficient immune response after intramuscular hepatitis B vaccination. The aim of the current study was to determine whether the mode of vaccine application plays a role in vaccination response and whether increasing the vaccine dose of primary intradermal hepatitis B vaccination can reduce the number of vaccine injections in hemodialysis patients. We designed a prospective, randomized study of antibody responses to hepatitis B vaccine given intradermally, subcutaneously, or intramuscularly in 81 hemodialysis patients. Outcome measures were rates of seroconversion, mean levels of anti-Hbs antibodies, and antibody levels 8 years after vaccination. The results show that intradermal hepatitis B vaccination response with a higher vaccination dose than previously used in hemodialysis patients is superior to conventional intramuscular and subcutaneous vaccination and is also well tolerated. Five intradermal injections of 20 microg each induced the development of sufficient anti-Hbs antibody titer, which persisted in 70% of the patients over 3 years.     

Controlled trial of thymopentin in hemodialysis patients who fail to respond to hepatitis B vaccination

Uremic patients are at high risk of hepatitis B virus (HBV) infection and, despite the availability and efficacy of hepatitis B vaccine, a high rate of non responders has been reported. Forty uremic patients undergoing maintenance hemodialysis who failed to produce any measurable anti-HBs antibody response after 4 administrations of 5 micrograms of Hevac B Pasteur vaccine were admitted to a randomized controlled clinical trial. Group A (14 patients) received 3 doses of 5 micrograms s.c. each of vaccine at monthly intervals and 12 doses of 50 mg s.c. of thymopentin on alternate days between the first and the second vaccination. Group B (11 patients) received 3 doses of 5 micrograms s.c. each of vaccine at monthly intervals. Group C (15 patients) received 3 doses of 10 micrograms s.c. each of vaccine at monthly intervals. Immunization rates were 86% in group A (on both 1-month and 6-month checks), 36% on the 1-month and 27% on the 6-month check in group B, 53% on the 1-month and 47% on the 6-month check in group C. Anti-HBs antibody titers were similar in group A and C but notably lower in group B. Thymopentin seems as useful therapeutical tool for non responder patients. As it promotes T cell maturation and responsiveness, which are impaired in uremia, it could play a major part in the management of uremic immunodeficiency.     

Safety and efficacy of hepatitis A vaccination in liver transplantation recipients

OBJECTIVE: Vaccination against hepatitis A (HAV) has been shown to be safe and effective in healthy subjects and in patients with chronic liver disease (CLD). The safety and efficacy of HAV vaccines in liver transplant (OLT) recipients have not been established. The objective of this study is to assess the safety and efficacy of inactivated hepatitis A vaccine in OLT recipients. METHODS: Thirty-seven HAV seronegative OLT recipients were enrolled. Patients received two doses of vaccine 6 months apart. Postvaccination IgG anti-HAV were determined at 1, 6, and 7 months after the first vaccine dose. Side effects were monitored for 3 days after each vaccination shot. An unvaccinated control group (45 patients) was followed for evidence of seroconversion. Seroconversion rate was also compared with those reported in healthy patients and in patients with chronic liver disease. RESULTS: Testing was available for all the cases at 1 month, and for 26 and 23 patients at 6 and 7 months, respectively. Only 3 of 37 patients (8%) had seroconversion at 1 month. At 6- and 7-month time points, 5 of 26 (19%) and 6 of the 23 (26%) patients had seroconversion, respectively. Vaccine responders had higher total white blood cell count and lymphocyte count and were further out from transplant compared with nonresponders. None of the unvaccinated patients had seroconversion over the follow-up time. Seroconversion rates in OLT recipients were significantly lower than that reported in healthy individuals (P=0.001) or in pre-OLT patients with CLD (P=0.001). All patients tolerated the vaccine well. CONCLUSIONS: HAV vaccination is safe in OLT recipient. Efficacy of HAV vaccination in OLT recipients, as measured by a commercially available enzyme immunoassay, is low and alternative strategies should be developed to improve response rate.     

Effect of levamisole supplementation on tetanus vaccination response rates in haemodialysis patients: A randomized double‐blind placebo‐controlled trial

Levamisole as an immunomodulator drug has been demonstrated to improve the immune response to hepatitis B virus vaccination in haemodialysis patients. The aim of this randomized double‐blind placebo‐controlled trial was to evaluate the effect of levamisole supplementation on tetanus‐diphtheria (Td) vaccine response rates in haemodialysis patients. Forty haemodialysis patients who had not received tetanus vaccination in a year before investigation and had unprotective anti‐tetanus immunoglobulin G (IgG) levels (<0.1 international unit/mL) were enrolled and randomized into two equal groups to receive one dose of intramuscular Td vaccine supplemented with either levamisole (100 mg) or placebo daily, for 6 days before and 6 days after vaccination. The anti‐tetanus IgG levels were measured 1 and 6 months after vaccination. One month post‐vaccination, four patients were excluded from the levamisole group and two from the placebo group because of either death or renal transplantation. At 1 month, 13 out of 16 (81%) patients in the levamisole group as compared with six out of 18 (33%) patients in the placebo group developed protective anti‐tetanus IgG levels (relative risk = 2.44, 95% confidence interval (CI) = 1.21, 4.88). From 1 to 6 months post‐vaccination, one more patient in the levamisole group and two more patients in the placebo group were excluded because of renal transplantation. At 6 months, 11 out of 15 (73%) patients in the levamisole group as compared with four out of 16 (25%) patients in the placebo group still had protective anti‐tetanus IgG levels (relative risk = 2.93, 95% CI = 1.19, 7.23). Supplementation of Td vaccination with levamisole may enhance seroconversion against tetanus in haemodialysis patients.     

Hepatitis B core antibody positive donors as a safe and effective therapeutic option to increase available organs for lung transplantation

BACKGROUND: The use of hepatitis B core antibody (HBcAb+) and hepatitis C antibody (HCV Ab+) positive donors represents one strategy to increase available donor organs, but this remains controversial because of concern for viral transmission to recipients. We hypothesized that isolated HBcAb+ donors represent minimal risk of viral transmission in vaccinated lung transplant (LTx) recipients. METHODS: A retrospective study was performed of LTx recipients who received HBcAb+ or HCV Ab+ pulmonary allografts. We analyzed liver function studies, viral hepatitis screening tests, quantitative polymerase chain reaction for hepatitis B viral DNA (HBV DNA) and hepatitis C viral RNA (HCV RNA), freedom from bronchiolitis obliterans syndrome, acute rejection, and survival. RESULTS: Between April 1992 and August 2003, 456 LTx operations were performed. Twenty-nine patients (HB group) received HBcAb+ allograft transplants with a median posttransplant follow-up of 24.5 months. Three critically ill patients (HC group) received HCV Ab+ allografts with a median follow-up of 21.5 months. One-year survival for the HB group is 83% versus 82% for all patients who received non-HB organs (P=0.36). No patient in the HB group developed clinical liver disease because of viral hepatitis, and all patients alive (n=21) at follow-up are, to date, HBV DNA and/or HBcAb negative. All patients in the HC group tested HCV RNA positive; one patient died of liver failure at 22 months. CONCLUSIONS: Risk of viral transmission with HCV Ab+ allografts seems high after LTx. However, the use of HBcAb+ pulmonary allografts in recipients with prior hepatitis B vaccination seems to be a safe and effective strategy to increase organ availability.     

Loss of hepatitis B immunity in hemodialysis patients acquired either naturally or after vaccination

AIM: The aim of our study was the long-term evolution of hepatitis B immunity and the titers of antibodies against the surface antigen (anti-HBs) acquired either naturally or after vaccination in hemodialysis (HD) patients with no history of hepatitis C virus (HCV) infection. METHODS: 36 HD patients were vaccinated with 4 doses of 40 microg recombinant B vaccine (Engerix, Rixensart, Belgium), intramuscularly at 0, 1, 2 and 6 months. 21 patients (60%) seroconverted developing anti-HBs titers > or = 10 IU/ml. Two patients were transferred to another unit before completion of 6 months after the last vaccine dose. We followed-up 19 HD patients who were immune against HBV after vaccination (Group A), and 30 immune patients (anti-HBs titers > or = 10 IU/ml) who had never been vaccinated and had antibodies against the core antigen (anti-HBc), diagnostic of natural HBV infection (Group B). In all patients of Groups A and B, anti-HBs were determined every 6 months, starting 6 months after the last dose in the vaccinated patients. Follow-up period lasted from October 2002 - April 2006. RESULTS: The mean follow-up in Group A was 21 +/- 12 months (range 6 - 36) and in Group B 29 +/- 12 months (range 6 - 42). Age, sex, presence of diabetes mellitus and duration of dialysis did not differ between the two groups. Five patients in Group A (26%) and 2 patients in Group B (9%) lost immunity (anti-HBs < 10 IU/ml) (p = 0.07). The median time to loss of immunity in Group A patients was 12 months (interquartile range 6 - 18 months), while in Group B patients it was 15 months (interquartile range 12 - 18 months). No booster dose was administered during the study. The 2 patients of Group B who lost immunity were the oldest of the group and redeveloped anti-HBs 6 and 12 months after they had lost it. During the first 6 months of the follow-up period, Group A had significantly higher anti-HBs titers than Group B (p < 0.05). However, this difference was lost later on, and after the first year of follow-up, anti-HBs titers were decreased significantly in Group A (p < 0.05), but remained unchanged in Group B throughout the follow-up period. CONCLUSIONS: In conclusion, HD patients lost hepatitis B immunity both after natural infection or vaccination, but naturally infected patients easily redeveloped protective anti-HBs titers. Anti-HBs titers decreased faster in vaccinated patients than in those with natural acquired immunity who held stable titers for a longer period. It is suggested that HD patients should be followed-up regularly for loss of HBV immunity after vaccination and receive a boosting dose when this occurs. In contrast, patients who acquired natural immunity do not need any anamnestic vaccination.     

Donor pool expansion in liver transplantation

INTRODUCTION: The shortage of donors has made it necessary to consider older subjects, those with mild or moderate steatosis, and those who are HBcAb- or hepatitis C virus (HCV)-positive as marginal donors. MATERIALS AND METHODS: From April 1986 to January 2002, 690 orthotopic liver transplantations (OLTs) were performed in 603 patients. In this series we used 68 donors older than 70 years, 51 with steatosis (38 mild, 12 moderate, and 1 severe), 44 were HBcAb-positive and 6 were HCV-positive. RESULTS: Of 68 grafts from donors older than 70 years, 65 were used as a first OLT. These grafts showed 3 PNF, 11 arterial complications, 12 re-OLTs, and 14 deaths with graft survival of 72.3% and 61.34% at 1 and 3 years, respectively. All patients who received the other 3 grafts, which were used for re-OLT, died between postoperative day 21 and 720. Among the 51 grafts with steatosis, we observed 2 PNF of those within the mild steatosis group and graft survival rates of 76.8% and 70.9% at 1 and 3 years, respectively. Forty-four grafts from HBcAb-positive subjects were used in 18 HBsAg-negative and 26 HBsAg-positive recipients. Among the untreated patient group, 1 patient demonstrated hepatitis B virus (HBV) reinfection and 1 patient had de-novo HBV. No reinfection or de novo infections were observed in the 13 patients treated with immunoglobulin or in the 19 patients treated with lamivudine plus immunoglobulin, or in the only patient treated with lamivudine. Graft survival rates were 64.1% and 54.7% at 1 and 3 years, respectively. Among who received 6 patients transplants from HCV-positive donors, we observed 1 recurrence of chronic hepatitis, 1 re-OLT for hepatic vein stenosis, and 1 PNF. CONCLUSION: Old donors, those with moderate steatosis, or those who are HBcAb- and HCV-positive can be safely used in selected recipients to reduce waiting list mortality.     

Levamisole treatment enhances protective antibody response to hepatitis B vaccination in hemodialysis patients

Hemodialysis shows a high risk for hepatitis B infection, and hepatitis B virus (HBV) vaccination has now become a routine procedure. Unfortunately, 40% to 50% of hemodialysis patients do not have adequate protective antibodies against the HBV vaccination which is thought to be due to depressed cell mediated immunity. Levamisole has been reported to stimulate depressed T-cell activity and enhance B lymphocyte function and restore delayed hypersensitivity reactions in immune-depressed patients. We studied the effects of levamisole, an immunomodulatory agent, on the protective antibody response of hemodialysis patients to the HBV vaccination. Our hemodialysis patients with negative anti-HBs antibody routinely received 40 microg doses of recombinant HBV vaccine intramuscularly at 0, 1, and 6 months, and we followed serum anti-HBs levels. Patients with a serum antibody level of >10 mIU/ml were considered as responders. Study groups were classified as follows. Group 1 was comprised of 96 chronic hemodialysis patients with negative anti-HBs and HBV core antibody (52 male, 44 female, mean age of 45 +/- 15 years and mean hemodialysis duration of 46 +/- 40 months) who received HBV vaccination; 55 patients (57%) were found to be responders. Group 2 was comprised of 19 randomly selected patients who had never received hepatitis B vaccine (13 male, 6 female, mean age of 42 +/- 14 years, mean duration of hemodialysis 31 +/- 27 months) and who were started on an HBV vaccination protocol with levamisole per os 80 mg after each hemodialysis session for 4 months and followed up on serum anti-HBs levels. Seventeen of the patients completed this levamisole treatment. Fourteen of the 17 patients had the levels of the protective serum antibody indicating a higher response rate when compared with patients who did not receive levamisole (82% versus 57%, respectively, p < 0.05). Group 3 was comprised of 19 patients randomly selected from persons who did not respond to previous vaccination programs (10 male, 9 female, mean age of 51 +/- 14 years, mean duration of hemodialysis 41 +/- 31 months). A second HBV vaccination program was started with the same levamisole protocol. In this group, 18 patients completed this treatment model. Fourteen of them responded to the vaccination model. In Group 4, a second HBV vaccination program was applied without levamisole to 20 randomly selected persons who did not respond to the previous routine vaccination program (12 male, 8 female, mean age of 53 +/- 17 years, mean duration of dialysis 51 +/- 38 months). Only 3 of them responded to a second vaccination program. Comparing Group 3 with Group 4, there was a higher responder rate to HBV vaccination (77% versus 15%, respectively, p < 0.0001). These results show that levamisole treatment increases the response rate to the first HBV vaccination and of the previously unresponsive cases by modulating possible cellular immune response.     

Low response to HBsAg vaccine in chronic renal failure patients is not due to intrinsic defect of B cells

OBJECTIVE: The aim of this study was to investigate whether the inability of chronic renal failure patients to mount an adequate antibody response following hepatitis B vaccination was due to an inherent defect in the antibody producing capacity of their B cells. MATERIAL AND METHODS: Peripheral blood mononuclear cells of end stage renal disease (ESRD) patients, who were not on maintenance hemodialysis (CRF) and those undergoing long-term hemodialysis (HD) were stimulated in vitro with pokeweed mitogen, a B cell mitogen or hepatitis B surface antigen. The total immunoglobulin (IgG, IgM and IgA) levels and anti-HBs specific IgM and IgG were quantitiated by sandwich ELISA and levels between patients who had a good antibody response in vivo and those who failed to mount an antibody response were compared. RESULTS: Spontaneous IgG production was significantly higher than normals in CRF and HD group; PWM induced IgM, IgG and IgA production was comparable to normals in both groups of patients. The spontaneous IgG and PWM stimulated IgM and IgG production was significantly higher in HD patients as compared to CRF. The in vitro Ig levels in the vaccine responders and non-responders was comparable except for the spontaneous IgG which was highest in the responders. The in vitro anti-HBs production was comparable in HB vaccine responders and non-responders; the in vivo and in vitro anti-HBs titers showed a significant correlation coefficient thereby indicating that the in vitro assay reflects the in vivo functional status of B cells. CONCLUSION: Our results demonstrate that the B cells in ESRD patients are functionally normal and cannot be the cause of the compromised vaccine response in these patients.