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ORIGINAL ARTICLE
Year : 2017  |  Volume : 5  |  Issue : 3  |  Page : 218-223

Evaluation of response to hepatitis B vaccination in chronic hemodialysis patients


Department of Internal Medicine, King Fahd Hospital of the University, Imam Abdulrahman Bin Faisal University, Al Khobar, Saudi Arabia

Date of Web Publication21-Aug-2017

Correspondence Address:
Samir H Almueilo
King Fahd Hospital of the University, P. O. Box 40154, Al Khobar 31952
Saudi Arabia
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DOI: 10.4103/1658-631X.213302

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  Abstract 

Background: Hemodialysis (HD) patients are at an increased risk of acquiring hepatitis B virus (HBV) infection. Active HBV immunization in these patients is recommended. A response rate in HD patients is variable but generally lower than healthy individuals.
Objective: The aim of this study is to assess the response of HD patients to the HBV vaccine and correlate response and long-term immunity to various clinical and biomedical factors.
Patients and Methods: One hundred and one patients, with a mean age 48.7 ± 18.5 years, received 40 μg of HBV vaccine administered intramuscularly in the deltoid region at 0, 1, 2 and 6 months. The patients' responses to the vaccine were determined by measuring hepatitis B surface antibody (HBsAb) 6 weeks after the last injection and monitored thereafter at 3-month intervals.
Results: Seventy-one patients (70.3%) mounted a response with HBsAb >10 mIU/ml 6 weeks following the fourth dose of vaccine, and thus were considered considered as adequate responders. Forty-nine (48.5%) patients mounted an excellent response with HBsAb >100 mIU/ml 6 weeks after the fourth dose. Thirty patients (29.7%) were nonresponders. Responders were significantly younger than nonresponders (P = 0.01). Gender, hemoglobin level, serum albumin, ferritin, parathyroid hormone level and hepatitis C virus infection had no effect on the response to the vaccine. Similarly, there was no difference in diabetic state and adequacy of HD between the two groups. Fifty-nine patients (88%) had persistent protective antibodies at 1 year, while eight (12%) lost such protection. Predictors of persistent immunity at 1 year were high HBsAb level at the completion of the vaccination regime and, to a lesser extent, young age.
Conclusion: A 70% response rate to HBV vaccine was observed in the cohort of this study. Young age predicts a favorable response to HBV vaccine in HD patients. High (>100 mIU/ml) HBsAb levels achieved at vaccine completion predict persistent immunity at 1 year.

Keywords: Hemodialysis, hepatitis B virus, seroconversion, vaccine


How to cite this article:
Almueilo SH. Evaluation of response to hepatitis B vaccination in chronic hemodialysis patients. Saudi J Med Med Sci 2017;5:218-23

How to cite this URL:
Almueilo SH. Evaluation of response to hepatitis B vaccination in chronic hemodialysis patients. Saudi J Med Med Sci [serial online] 2017 [cited 2017 Sep 22];5:218-23. Available from: http://www.sjmms.net/text.asp?2017/5/3/218/213302


  Introduction Top


Approximately 2 billion people worldwide have been exposed to hepatitis B virus (HBV) infection and 350 million people have chronic HBV infection. It is estimated that 500,000–1.2 million people die every year because of diseases attributable to chronic HBV infection, such as liver failure and hepatocellular carcinoma.[1] Chronic hemodialysis (HD) patients are particularly prone to HBV infection. Increased risk in this population is related to excessive exposure to blood products, repeated vascular access entry and a state of immune deficiency. Hepatitis B (HB) infection in such patients may be associated with significant morbidity, such as acute and chronic hepatitis, liver cirrhosis and hepatocellular carcinoma, and may adversely affect the prospect of kidney transplant in these patients.[2] Furthermore, HD patients tend to become chronic carriers post-HBV infection more commonly than the general population.[3] Therefore, they potentially become a source of infection to fellow patients and medical staff.

Universal precautions, including dedicated rooms and equipment to treat HBV patients, are important steps in limiting the risk of spreading the infection among HD patients. Moreover, active HB vaccination in the HD population is crucial. Chronic HD patients who develop immunity after HB vaccination have a 70% lower risk of HBV infection and have a better survival and lower morbidity than no responders.[4],[5] Despite utilizing the high-dose (40 mg) four-injection HB vaccine protocol, the response rate in HD patients remains significantly lower than the rate observed in the general population.[6],[7]

In this study, the author presents a single-center experience with HB vaccination in chronic HD patients. Correlation between a response to the vaccine and several clinical and biological factors is analyzed and the relationship between the magnitude of response and persistent immunity at 1 year is examined.


  Patients and Methods Top


A total of 101 patients, aged 16–81 years, who were negative for HB surface antigen and HB surface antibody (HBsAb) were included in this study that was conducted between January 1, 2008, and December 31, 2012. Patients receiving immunosuppressive drugs or with a history of cancer or chronic liver disease were excluded from the study. Thirty-nine patients were diabetic and 12 patients were positive for hepatitis C virus (HCV) antibody. The patients received 40 μg of recombinant HB vaccine (Engerix B, SmithKline Beecham Biologicals, Rixensart, Belgium) administered intramuscularly (IM) in the deltoid region at 0, 1, 2 and 6 months. The patients' responses to the vaccine were determined by measuring HBsAb 6 weeks following the last injection and monitored thereafter at 3-month intervals. Achieving a serum HBsAB level ≥10 mUI/ml was considered as protective conversion. Responders with a development of HBsAb >10 mUI/ml and <100 mUI/ml at 6 weeks after the last injection were categorized as low immune responders, while those with levels >100 mUI/ml were considered as high immune responders. The medical records were analyzed to correlate the response to the vaccine with several clinical and biological factors. These included age, sex, diabetic state, time from onset of dialysis to vaccine administration, HCV status, hemoglobin (Hb) level, serum ferritin, adequacy of HD as measured by percent reduction of urea (PRU) and Kt/V, intact parathyroid hormone (iPTH) level and C-reactive protein (CRP) level. Normalized protein catabolic rate (nPCR) as a measure of protein intake was calculated utilizing the following formula:

nPCR in g/kg/day = 0.22 + [(0.036 × blood urea nitrogen rise in mg/dl since last HD session × 24)/hours since last HD].[8]

Statistical significance was calculated for differences between the means using unpaired t-test and Mann–Whitney test. The χ2 test was performed for categorical data. Data are presented as a mean ± standard deviation or as an absolute number and percentage when needed. P < 0.05 was considered statistically significant.

The general consent was taken when patients underwent hemodialysis treatments and the associated interventions such as HB vaccination, erythropoietin treatments, etc. Because this study was descriptive in nature with no further intervention, this study was exempt from ethical approval.


  Results Top


A total of 101 end-stage renal disease patients admitted to the chronic HD program between January 1, 2008, and December 31, 2012, received the hepatitis vaccine. The patients were aged 16–81 years, with a mean age of 48.7 ± 18.5 years and a median of 48 years. Of the 101 patients, 65 (64.4%) were male, 39 (38.6%) were diabetic and 12 (11.9%) were positive for HCV antibody. [Table 1] describes the clinical and biochemical characteristics of the patient population.
Table 1: Demographic and clinical characteristics of all patients (n = 101)

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Seventy-one patients (70.3%) mounted an HBsAb level >10 mIU/ml 6 weeks following the fourth dose of vaccine, and thus were considered to be adequate responders. Forty-nine (48.5%) patients mounted an excellent response with HBsAb levels >100 mIU/ml 6 weeks postcompletion of the vaccine series. Twenty-two (21.8%) patients had a weak response with HB antibody levels >10 mIU/ml and <100 mIU/ml. Thirty patients (29.7%) were nonresponders.

Responders were significantly younger than nonresponders. Responders had a mean age of 45.7 ± 18.9 versus 55.8 ± 15.3 in nonresponders (P = 0.01) [Table 2]. Of the 52 patients aged <50 years, 42 (80.8%) mounted an adequate response compared with 29 of the 49 (59.2%) patients who were aged >50 years (P = 0.018) [Figure 1]. There was no difference between responders and nonresponders with respect to gender distribution, Hb level, serum albumin level, ferritin, PTH level and CRP levels. There was no significant difference in the prevalence of diabetes mellitus (DM) in responders and nonresponders. Adequacy of HD, as determined by PRU and Kt/V, was similar in the two groups. Duration on HD before vaccination had no effect on the response to the vaccine. [Table 2] compares the clinical and biochemical parameters between responders and nonresponders. [Table 3] compares the low and high responders.
Table 2: Patients' demographic and clinical characteristics according to response to hepatitis B vaccine

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Figure 1: Response rate to hepatitis B vaccination among hemodialysis patients according to age

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Table 3: Comparison between low responders (hepatitis B surface antibody >10, <100 mIU/ml 6 weeks postvaccine) and high responders (>100 mIU/ml)

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Immune status at 1 year after completion of the HB vaccination was made available for 67 initial responders. Of these, 59 (88%) had persistent protective antibodies at 1 year, while 8 (12%) lost such protection. All but 1 of the 47 patients (97.9%) who mounted an excellent initial response had persistent immunity 1 year after completion of the vaccination series. However, 13 of 20 patients (65%) who had an initial weak response to the vaccine maintained immunity at 1 year. The odds ratio for losing protective immunity at 1 year following the completion of the vaccine in weak initial responders was 24.7 [95% confidence interval (CI): 2.8–220, P = 0.0040]. Predictors of persistent immunity at 1-year postvaccination are HbsAb level achieved at 6 weeks postimmunization (P 0.0005) and, to a lesser extent, younger age (P = 0.04).


  Discussion Top


An HB vaccine seroconversion rate of 70.3% was achieved in 101 HD patients. Forty-nine patients (48.5%) mounted a high response with an HbsAb level >100 mIU/ml. A younger age predicted a positive response to the vaccine. No statistically significant difference was observed between responders and nonresponders with regards to gender, diabetic state, time on HD before vaccination, HCV infection, Hb, ferritin and PTH levels. The adequacy of dialysis, as measured by urea reduction ratio and Kt/V, was similar in the two groups. There was no difference between the two groups in nutritional markers, as measured by serum albumin and nPCR. Persistent protective levels of HbsAb at 1 year were observed in 88% of the initial responders. Predictors of immunity maintenance at 1 year were high initial response and younger age.

The prevalence of HB infection among chronic HD patients had decreased significantly over the past decades.[9] Several factors have contributed to this decline such as implementation of policies regarding room segregation, equipment dedication and stopping the use of multidose medication vials. Routine use of erythropoiesis-stimulating agents in chronic HD patients has helped in reducing the exposure of such patients to blood products. Active HB immunization in these patients remains necessary, as sporadic outbreaks of HB infection in HD patients continue to occur.[10] HB vaccine introduced in the 1980s has definitely played a role in limiting HBV infection in HD patients. The Center for Disease Control recommends administering HB vaccine at a dose 40 μg by IM route in the deltoid region in HD patients at 0, 1 and 6 months. Most centers, however, incorporate the fourth dose given at month 2.[11] Despite the use of such high, more frequent dosing schedule, HD patients often develop a suboptimal response compared with the general population.[12]

The only readily available correlate of immune protection after HB vaccine administration is attaining an HBsAb level >10 mIU/ml 1–3 months after the last dose of the vaccine regimen. In fact, seroprotection may persist even if the level drops <10mlU/ml on subsequent testing. However, the recommendation is to administer a booster dose at that point. The protective efficacy of HB vaccine also involves the induction of memory B and T cells.

Various rates of seroprotection following HB vaccination in chronic HD patients have been reported. Such conflicting figures are owing to various factors such as sample size, age, weight and gender distribution; prevalence of DM; prevalence of HCV infection; duration on HD before the vaccine administration, adequacy of HD treatment and, possibly, genetic differences between populations. Variable dosing and scheduling regimens of the vaccine also contribute to the variable response rate in the HD population.

Peces et al. reported a seroconversion rate of 77.5% 1 month after vaccination in 80 seronegative HD patients who received a four-dose vaccination schedule (0, 1, 2 and 6 months), with 40 μg DNA-recombinant HB vaccine. A high antibody response was observed in 72.5% of patients, and nonresponse in 22.5% patients. Similar to the findings of the current study, a higher response rate was observed in younger patients. There was no difference between responders and nonresponders with respect to sex, duration of HD, HD dose and nutritional status. Erythropoietin use and HCV infection had no influence on antibody responses to HB immunization.[13] The author observed similar findings in the cohort of the current study. Bel'eed et al. reported the outcome of HB vaccination in 247 renal patients, 149 of whom were chronic HD patients. They noted a seroconversion rate of 66% in HD patients. Responders tended to be younger and had a higher level of serum albumin.[14] An older report by Köhler et al. using three IM doses of 40 μg of HB vaccine in 99 HD patients resulted in a response rate of 50% in males and 66% in females. This is in contrast to a response rate of 95% in 29 healthy medical staff using a dose of 20 μg. The fourth dose given at 12 months improved the response rate from 56.5% to 71.7% in HD patients. The type of renal disease, length of time on dialysis and hematocrit did not influence the rate of immunization.[15]

In the cohort of the current study, a similar response rate was observed in HD patients with DM and those without DM. Most reported studies on this point support a notion that HD patients with DM respond less favorably to the vaccine. Chin, in a report of 97 HD patients vaccinated against HB, noted that 33 nonresponders, compared with 64 responders, had a higher prevalence of DM (70% vs. 39%). In addition, nonresponders were older, had lower serum albumin level and had higher dry weights than responders before HD was initiated.[16] Ocak and Eskiocak, in an HD patient cohort from Turkey, noted a lower but statistically insignificant seroconversion rate of 57.8% in 19 HD patients with DM compared with a rate of 70% in patients without DM. After the administration of additional booster doses during a 12-month period, the protective HBsAb levels in patients with DM improved but remained lower than levels in patients without DM.[17] A study conducted in Riyadh, Saudi Arabia, similarly, did not demonstrate a significant difference between responders and nonresponders with respect to DM.[18] Such conflicting influence of the diabetic state on the response to HB vaccine between populations may be related to genetic differences between populations.[19],[20] Fabrizi et al. performed a systematic review of literature, looking at the impact of DM on the response to HB vaccine in dialysis patients. They identified 12 studies involving 1002 unique patients. Aggregation of study results showed a significant decrease in response rates among patients with DM versus patients without DM [pooled odds ratio = 0.52 (95% CI 0.38–0.71)].[21]

In the current study, the response to the vaccine in 12 patients with HCV infection was not significantly different from patients negative for HCV, a result which is comparable with that of other studies. Peces et al. reported that HCV infection did not influence the response to HB vaccination in their group of 80 HD patients.[13] However, some small studies observed a lower response rate in HCV-infected HD patients. Navarro et al. studied 36 chronic HD patients, 9 of whom were diagnosed as having HCV infection. The effective immunization rate was lower in HCV-infected patients (33.3% vs. 70.3%; P < 0.05).[22] In another study by the same group, it was concluded that HCV infection influenced the level of immunity. Of the 43 HCV-negative cases, 27 (62.7%) obtained HBsAb levels >100 IU/L, but only 3 of the 13 HCV-infected patients (23%) had an HBsAb >100 IU/L (P < 0.01, c 2).[23] A systematic review conducted by Fabrizi et al. to determine the effect of HCV infection on the immunological response to HBV vaccine in dialysis populations identified eight studies with 520 unique patients on long-term dialysis and found no significant decrease in response rates among HCV-infected versus noninfected patients (pooled odds ratio = 0.621 [95% CI: 0.285–1.353]). These results were in concordance with the findings of the current study.[24]

A working strategy to improve the rate of successful immunization against HB in chronic HD patients would be to identify patients with chronic kidney disease (CKD) at an earlier stage, such as Stages 2 and 3, and offer vaccination to patients who are neither infected nor immune to the virus. Such a policy should be adopted in nephrology clinics providing care for CKD patients. This approach stems from the fact that a response rate to the HB vaccine is higher at the earlier stages of CKD.[25],[26],[27]


  Conclusion Top


Chronic HD patients have a lower response rate to the HB vaccine than healthy individuals, despite utilizing a more high frequent dosing protocol. Younger patients respond better to the vaccine. Obtaining high HBsAb levels (>100 mIU/ml) at the completion of the vaccine ensures long-term immunity. Various demographic and biochemical factors including HCV infection and DM had no influence on the patients' response to the vaccine.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest

 
  References Top

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Lavanchy D. Hepatitis B virus epidemiology, disease burden, treatment, and current and emerging prevention and control measures. J Viral Hepat 2004;11:97-107.  Back to cited text no. 1
    
2.
Fabrizi F, Messa P, Martin P. Hepatitis B virus infection and the dialysis patient. Semin Dial 2008;21:440-6.  Back to cited text no. 2
    
3.
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Miller ER, Alter MJ, Tokars JI. Protective effect of hepatitis B vaccine in chronic hemodialysis patients. Am J Kidney Dis 1999;33:356-60.  Back to cited text no. 4
    
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Edey M, Barraclough K, Johnson DW. Review article: Hepatitis B and dialysis. Nephrology (Carlton) 2010;15:137-45.  Back to cited text no. 6
    
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Rangel MC, Coronado VG, Euler GL, Strikas RA. Vaccine recommendations for patients on chronic dialysis. The Advisory Committee on Immunization Practices and the American Academy of Pediatrics. Semin Dial 2000;13:101-7.  Back to cited text no. 11
    
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13.
Peces R, de la Torre M, Alcázar R, Urra JM. Prospective analysis of the factors influencing the antibody response to hepatitis B vaccine in hemodialysis patients. Am J Kidney Dis 1997;29:239-45.  Back to cited text no. 13
    
14.
Bel'eed K, Wright M, Eadington D, Farr M, Sellars L. Vaccination against hepatitis B infection in patients with end stage renal disease. Postgrad Med J 2002;78:538-40.  Back to cited text no. 14
    
15.
Köhler H, Arnold W, Renschin G, Dormeyer HH, Meyer zum Büschenfelde KH. Active hepatitis B vaccination of dialysis patients and medical staff. Kidney Int 1984;25:124-8.  Back to cited text no. 15
    
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Chin AI. Hepatitis B virus vaccine response in hemodialysis: Baseline patient characteristics. Hemodial Int 2003;7:296-303.  Back to cited text no. 16
    
17.
Ocak S, Eskiocak AF. The evaluation of immune responses to hepatitis B vaccination in diabetic and non-diabetic haemodialysis patients and the use of tetanus toxoid. Nephrology (Carlton) 2008;13:487-91.  Back to cited text no. 17
    
18.
Al Saran K, Sabry A, Al Halawany Z, Ismail M. Factors affecting response to hepatitis B vaccine among hemodialysis patients in a large Saudi hemodialysis center. Saudi J Kidney Dis Transpl 2014;25:185-91.  Back to cited text no. 18
    
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Pol S, Legendre C, Mattlinger B, Berthelot P, Kreis H. Genetic basis of nonresponse to hepatitis B vaccine in hemodialyzed patients. J Hepatol 1990;11:385-7.  Back to cited text no. 19
    
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Alper CA, Kruskall MS, Marcus-Bagley D, Craven DE, Katz AJ, Brink SJ, et al. Genetic prediction of nonresponse to hepatitis B vaccine. N Engl J Med 1989;321:708-12.  Back to cited text no. 20
    
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Fabrizi F, Dixit V, Martin P, Messa P. Meta-analysis: The impact of diabetes mellitus on the immunological response to hepatitis B virus vaccine in dialysis patients. Aliment Pharmacol Ther 2011;33:815-21.  Back to cited text no. 21
    
22.
Navarro JF, Teruel JL, Mateos M, Ortuño J. Hepatitis C virus infection decreases the effective antibody response to hepatitis B vaccine in hemodialysis patients. Clin Nephrol 1994;41:113-6.  Back to cited text no. 22
    
23.
Navarro JF, Teruel JL, Mateos ML, Marcen R, Ortuno J. Antibody level after hepatitis B vaccination in hemodialysis patients: Influence of hepatitis C virus infection. Am J Nephrol 1996;16:95-7.  Back to cited text no. 23
    
24.
Fabrizi F, Dixit V, Martin P, Messa P. Hepatitis C virus and the immunological response to hepatitis B virus vaccine in dialysis patients: Meta-analysis of clinical studies. J Viral Hepat 2011;18:871-6.  Back to cited text no. 24
    
25.
DaRoza G, Loewen A, Djurdjev O, Love J, Kempston C, Burnett S, et al. Stage of chronic kidney disease predicts seroconversion after hepatitis B immunization: Earlier is better. Am J Kidney Dis 2003;42:1184-92.  Back to cited text no. 25
    
26.
Dukes CS, Street AC, Starling JF, Hamilton JD. Hepatitis B vaccination and booster in predialysis patients: A 4-year analysis. Vaccine 1993;11:1229-32.  Back to cited text no. 26
    
27.
Fraser GM, Ochana N, Fenyves D, Neumann L, Chazan R, Niv Y, et al. Increasing serum creatinine and age reduce the response to hepatitis B vaccine in renal failure patients. J Hepatol 1994;21:450-4.  Back to cited text no. 27
    


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