Sex: U
Vaccine: HEP
Symptoms: Hepatitis B core antibody positive, Hepatitis B reactivation, Hepatitis B surface antigen negative, Vaccination failure
Clinical narrative: This case was reported in a literature article and described the occurrence of suspected vaccination failure in a adult patient who received Hepatitis B vaccine for prophylaxis. The subject's past medical history included kidney transplant (kidney transplant recipient who transplanted between January 2010 and January 2020). Previously administered products included prednisone. On an unknown date, the patient received Hepatitis B vaccine. On an unknown date, unknown after receiving Hepatitis B vaccine, the patient experienced vaccination failure (serious criteria GSK medically significant) and Hepatitis B reactivation (serious criteria GSK medically significant). On an unknown date, the outcome of the vaccination failure and hepatitis b reactivation were unknown. The reporter considered the vaccination failure and hepatitis b reactivation to be related to Hepatitis B vaccine. Additional details were reported as follows: This case was reported in a literature article and described the suspected vaccination failure in a patient aged 18 years or older of unspecified gender, who was vaccinated with unspecified hepatitis B virus (HBV) vaccine (manufacturer unknown) for prophylaxis. This case corresponds to table 4 reported in this literature article. The patient was a part of the multicenter retrospective study which was conducted to evaluate the prevalence of HBV reactivation in hepatitis B surface antigen (HBsAg) negative and hepatitis B core IgG or total antibody (anti-HBc) positive kidney transplant recipients who did or did not receive hepatitis B antiviral prophylaxis, and to identify risk factors associated with HBV reactivation. [The authors included HBsAg-negative anti-HBc-positive kidney transplant recipients transplanted between January 2010 and January 2020 who were 18 years of age or older. Recipients were excluded if they had a history of previous transplant, were on immunosuppression at the time of transplantation, received a kidney transplant from an HBsAg-positive, HBV NAT-positive, or anti-HBc-positive donor, were HBsAg-positive at the time of transplant, were taking HBV antiviral therapy at the time of transplant, or had a known viral infection pre-transplant including human immunodeficiency virus or hepatitis C virus. The authors identified 259 potentially eligible patients; however, only 161 met inclusion criteria. The primary outcome of the study was the prevalence of hepatitis B reactivation, defined as a positive HBV PCR of any viral load at or above the minimal detection level, in kidney transplant recipients receiving antiviral prophylaxis, compared to those not receiving antiviral prophylaxis targeted toward HBV. Secondary outcomes included 1-year graft survival (graft failure defined as a return to hemodialysis or retransplant), 1-year all-cause mortality, biopsy-proven acute rejection (BPAR), and antibody-mediated rejection (AMR)]. The patient had HBsAg-negative and anti-HBc-positive and was kidney transplant recipient who transplanted between January 2010 and January 2020. The patient received maintenance immunosuppression with prednisone. No information on patient's medical history, family history, or concomitant medication was provided. On an unspecified date, the patient received unspecified Hepatitis B virus (HBV) vaccine (administration route and site unspecified, dosage unknown; batch number not provided) pre-transplant. The age of vaccination was not provided. On an unspecified date, an unknown period after the vaccination, the patient developed HBV reactivation. [161 (one hundred and sixty-one) patients were eligible for study inclusion: 147 patients in the non-hepatitis B prophylaxis group and 14 patients in the hepatitis B prophylaxis group. The mean age in years was 59.7 ± 9.8 and 58.1 ± 14.9 in the non-prophylaxis group and prophylaxis group, respectively. Other similarities between the two groups included the etiology of renal disease, most commonly being diabetes and hypertension or a combination of the two conditions. With respect to anti-HBs titers pre-transplant, 79.6% of patients who did not receive antiviral prophylaxis had reactive anti-HBs titers, compared to 78.6% in the group that did receive prophylaxis. Induction immunosuppression used at the time of transplantation was similar between the groups. Rabbit anti-thymocyte globulin was used in 76.2% of patients in the non-prophylaxis group versus 71.4% of patients in the prophylaxis group. Maintenance immunosuppression between the two groups was similar with a majority of patients in the entire cohort (82.6%) receiving triple maintenance immunosuppression with tacrolimus, mycophenolate, and prednisone. There was also no difference with respect to the usage of steroid maintenance immunosuppression between the two groups (87.8% vs. 92.9%). All patients in the prophylaxis group received entecavir for hepatitis B prophylaxis, and the median duration of antiviral prophylaxis was 615 days, with three patients receiving indefinite prophylaxis. The overall prevalence of HBV reactivation in the entire study cohort was 3.7%. There was no statistically significant difference between the two cohorts with respect to the primary outcome of study. Of the 147 patients who did not receive prophylaxis, only five (3.4%) experienced HBV reactivation, whereas one (7.1%) of 14 patients who did receive prophylaxis experienced reactivation. This was over a median follow-up period of 1103 days for the entire cohort. The one patient who developed HBV reactivation in the prophylaxis group was on antiviral prophylaxis for 1064 days post transplantation before antiviral discontinuation. HBV reactivation occurred in this patient 504 days after discontinuation of antiviral prophylaxis. With respect to all secondary outcomes, no differences were observed between the two cohorts. Death-censored graft loss occurred in seven (4.8%) patients in the non-prophylaxis group, compared to zero patients in the prophylaxis group. One-year all cause mortality occurred in four (2.7%) patients in the non-prophylaxis group, compared to zero patients in the prophylaxis group. BPAR occurred in 23 (15.8%) patients who did not receive prophylaxis, while only two (14.3%) patients in the hepatitis B prophylaxis group developed BPAR. BPAR did not precede any of the six cases of HBV reactivation. Moreover, only one patient who experienced HBV reactivation 2 days after transplantation had an episode of BPAR diagnosed 1641 days post transplantation. This patient had Banff 1a acute cellular rejection and was treated with a cumulative dose of 1000 mg of intravenous methylprednisolone. Three patients in the non-prophylaxis group did experience AMR; however, they received treatment with intravenous immune globulin (IVIG) with or without plasmapheresis, and no patient in either cohort received rituximab. The average age of patients who experienced HBV reactivation was 57 years, and 50% were Asian. Four patients had reactive anti-HBs titers pre-transplantation, with quantitative levels considered protective in the general patient population. Interestingly, most patients with HBV reactivation also had delayed graft function (83.3%), defined as return dialysis within 7 days of transplantation. Of the six patients who had HBV reactivation, only one received HBV antiviral prophylaxis, and the median time to HBV reactivation for the cohort was 232 days. The single patient who did receive HBV antiviral prophylaxis and experienced HBV reactivation had a total bilirubin of 1.8 mg/dl at the time of reactivation; however, it is important to note that the patient was diagnosed with Gilbert's syndrome and did not have hepatic complications. Importantly, one of the patients who did not receive antiviral prophylaxis went on to develop HBV reactivation, and subsequently Stage F3 liver fibrosis on the Metavir histological index of grading fibrosis, indicating severe liver fibrosis. Potential risk factors for HBV reactivation on the univariate analysis included delayed graft function and IVIG use for the treatment of allograft rejection. These factors were included in a backward stepwise logistic regression model. HBV antiviral prophylaxis was also included in the model to determine if it truly influenced protection against HBV reactivation, despite the results of primary outcome. Age has been shown to be a factor associated with HBV reactivation based on a previous study; therefore, it was also included in model. The authors' multivariate logistic regression model demonstrated that the absence of HBV prophylaxis did not predict the development of HBV reactivation in patient population. However, delayed graft function was found to be a significant risk factor for HBV reactivation. The authors' multivariate model generated a receiver operating characteristic (ROC) curve with an area under the curve of 0.75 with a standard error of 0.09, demonstrating a fair model of fit]. The case has been considered as suspected vaccination failure being full schedule and the time to onset were unknown. Treatment was unknown. The outcome of the event was not reported. The authors commented, "Our study reviewed the use of hepatitis B antiviral prophylaxis to no hepatitis B antiviral prophylaxis on the prevalence of HBV reactivation in HBsAg-negative anti-HBc-positive kidney transplant recipients at a multicenter level. There is no consensus on when to use antiviral prophylaxis in HBsAg-negative anti-HBc-positive kidney transplant recipients, and there is limited evidence identifying patients at high risk for HBV reactivation that may warrant prophylaxis. The results of our study concur with the recommendations provided by AASLD and AST ID COP in that antiviral prophylaxis targeted toward HBV may not be indicated in HBsAg-negative anti-HBc-positive kidney transplant recipients. Given the historical data and the results of our study, we suggest that standard maintenance immunosuppression post kidney transplantation may not significantly increase the risk for HBV reactivation. However, it is important to note that our multicenter retrospective study did not evaluate overall glucocorticoid exposure, which future studies should aim to report. But it is the authors' opinion that since the median days to HBV reactivation in the non-prophylaxis group and the prophylaxis group were 108 and 1568 days, respectively, these patients would have been on minimal doses of oral prednisone. Although there seemed to be a trend toward a higher prevalence of HBV reactivation in the group that did receive hepatitis B antiviral prophylaxis (7.1%), compared to the non-prophylaxis group (3.4%), this was not statistically significant. Interestingly, of the six patients experiencing HBV reactivation, only two patients had quantitative HBV viral loads. The HBV viral load of the remaining four patients, including one of the patients on antiviral prophylaxis, was detected but at the minimum detection level and was not quantified. Our study did not evaluate anti-HBc titers, and we did not find age to be a significant risk factor for reactivation. However, we did find delayed graft function to be a significant predictor of HBV reactivation. We acknowledge that our study was not powered to detect significant factors associated with HBV reactivation; however, our study contained a larger sample size. Interestingly, of the five patients who experienced HBV reactivation in the non-prophylaxis group, three had reactive anti-HBs titers with concentrations of 86 mIU/ml, 722 mIU/ml, and 230 mIU/ml, well above the protective level defined of 10 mIU/ml. Although our study is limited in size, the results suggest that protective anti-HBs concentrations in immunocompromised kidney transplant recipients may not be protective as they are in immunocompetent individuals. The authors of the study do acknowledge limitations of the study design including the retrospective nature and inability to control for confounding factors such as hepatitis B vaccination administration, tacrolimus trough concentrations, immunosuppression dosing, and inappropriate entecavir dosing. Our study population was robust with 161 patients; however, only 14 of these patients received antiviral prophylaxis which limited our ability to match the cohorts." The authors concluded, "In summary, our study found that the prevalence of HBV reactivation in HBsAg-negative anti-HBc-positive kidney transplant recipients is low, and there is a low incidence of significant clinical implications with appropriate medical follow-up. Based on our results, monitoring of liver enzymes and viral load may be the best approach for both practitioners and patients rather than using antiviral prophylaxis targeted toward HBV. The authors of this study also recommend that HBsAg-negative anti-HBc-positive kidney transplant recipients should receive routine follow-up with a hepatologist. With already complicated medication regimens post-transplant, this approach minimizes polypharmacy and cost-sharing of antiviral medications for kidney transplant recipients. Larger prospective studies with matched groups are warranted to evaluate the true impact hepatitis B antiviral prophylaxis has on this population of kidney transplant recipients." This case is 1 of the 2 cases reported in the literature article.; Sender's Comments:  US-GLAXOSMITHKLINE-US2021GSK259201:Same reporter