Efficacy of the accelerated hepatitis B vaccination schedule used in haemodialysis patients post-exposure to virus: a single-centre experience

Kevin S. Eardley1,, Helen E. Jones2, Husam Osman2 and Steve A. Smith1

1 Department of Nephrology and 2 Public Health Laboratory Service, Birmingham Heartlands and Solihull NHS Trust, Birmingham, UK



   Abstract
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Background. The hepatitis B (HB) vaccination regime currently recommended for use in the UK for both preventative and post-exposure purposes is the accelerated regime, although there have been no recent reports of its efficacy. This observational study reports on the response rate achieved and longevity of protection conferred with this regime in a large number of haemodialysis patients following an episode of HB exposure.

Methods. One-hundred and five patients received primary vaccination (vaccine administered at 0, 1 and 2 months). Eighty-six completed the regime, receiving a booster dose at month 12. Measuring antibodies to HB surface antigen (anti-HBS) 6 weeks after receiving the third and fourth doses assessed patients’ response. Seventy-seven patients subsequently had anti-HBs measured at month 24.

Results. The response rate (anti-HBS >10 mIU/ml) to primary vaccination and the complete regime was 33 and 73%, respectively. Non-European patients responded better to primary vaccination than Europeans (P=0.014). Those receiving steroids responded less well to the complete vaccination regime (P=0.007). Patient's age, sex, renal diagnosis, diabetes mellitus, time on dialysis, dialysis adequacy, erythropoietin dose, hepatitis C or body weight did not affect response rates. By month 24, 24 responders (44%) had lost seroprotection. Antibody levels achieved with vaccination by transient responders was significantly lower than persistent responders. No patients became HB surface antigen positive during the 2-year study.

Conclusion. Reserving the accelerated vaccination to the post-exposure scenario will expose many more patients to the risk of HB cross-infection than if used prophylactically. Regular monitoring is required if seroprotection is to be maintained.

Keywords: chronic renal failure; exposure; hepatitis B; recombinant hepatitis B vaccine



   Introduction
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Despite the introduction of stringent universal practice procedures and the more widespread use of erythropoietin (Epo), leading to a reduction in the requirement for transfusions, haemodialysis patients remain at high risk of contracting hepatitis B. In recognition of this, the Renal Association and Department of Health in the UK, and the Centers for Disease Control and Prevention in the US have published guidelines recommending the routine vaccination of all dialysis patients against hepatitis B [13]. Many differing hepatitis B vaccination regimes with modern recombinant vaccines have been described but in, general have been perceived as disappointing, often eliciting only a poor immune response that is short lived. Consequently, many UK renal units do not follow the guidance, but reserve vaccination for those patients who have been exposed to hepatitis B [4]. Those units that are routinely vaccinating their dialysis population are, however, often using previously recommended schedules [4]. The vaccination regime currently recommended for use in the UK for both preventive and post-exposure purposes is the accelerated vaccination regime [1]. This observational study reports on the response rate achieved and assessed the longevity of protection conferred with this regime in a large number of haemodialysis patients following an episode of exposure to hepatitis B.



   Subjects and methods
 Top
 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Birmingham Heartlands and Solihull NHS Trust serves a population of 600 000 to the north and east of the city of Birmingham, UK. One hospital and two satellite dialysis units serve a population of ~240 haemodialysis patients. Patients’ mean age is high relative to other units in the UK and a high proportion is from the ethnic minority communities [5]. However, other demographic variables, patients’ dialysis adequacy, haemoglobin levels and Epo use are typical of most UK renal units [5]. Bicarbonate dialysis is performed for all patients for 3–4 h thrice-weekly using polysulfone haemodialysers (Fresenius F6 or F8, Bad Homburg, Germany) to achieve the minimum UK Renal Association standard of dialysis adequacy (1.2 Kt/V urea) [5].

In February 1999, a haemodialysis patient received blood contaminated with hepatitis B virus. This was not realised until April 1999 when the Blood Transfusion Service was informed that the blood donor had developed acute hepatitis B. The dialysis patient was traced and tests confirmed seroconversion to a carrier state. During this 2-month period, 151 patients used a dialysis machine that had also been used by the hepatitis B-positive patient, potentially exposing them to virus. Prior to this event, hepatitis B vaccination was not routinely offered to dialysis patients on the unit. All 151 patients were immediately offered the accelerated vaccination regime.

Vaccination regime
The accelerated regime involved administering, by deltoid intramuscular injection, 40 mcg of the recombinant hepatitis B vaccine HB Vax II (Aventis MSD) at time 0, 1 and 2 months. Following this primary vaccination, a booster was given to all patients at 12 months to complete the regime [1].

Antibody response
Antibodies to hepatitis B surface antigen (anti-HBS) were measured using enzyme immunoassay (Dia-Sorin) 6–8 weeks after the third dose, to assess response to primary vaccination, and again after the booster dose on completion of the course. A subject had responded to the vaccine if the anti-HBS level was >10 mIU/ml. Those with levels 10–100 mIU/ml were termed ‘poor responders’, whereas those with levels >100 mIU/ml were termed ‘good responders’. Anti-HBS levels were subsequently checked 24 months after the first dose of vaccine.

Patients
Twelve of the 151 patients at risk were subsequently found to already be naturally immune to hepatitis B due to previous hepatitis B exposure, and therefore did not complete the vaccination course. Of the 139 non-immune patients, 23 refused to be vaccinated from the outset, either because they perceived it to be an unnecessary inconvenience or due to anxiety about potential side effects. A further 11 refused to complete primary vaccination, having experienced some discomfort from the initial injections. The non-immune cohort who completed primary vaccination numbered 105. The demographic details of these patients are shown (Table 1Go). Other diagnoses included autoimmune multi-systemic disease (n=4), light chain disease (n=3) and bilateral nephrectomy for renal tumours (n=1). None of the patients were hepatitis B core antibody positive, and only five were hepatitis C antibody positive.


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Table 1.  Patient demographic characteristics when vaccination commenced

 
Eighty-six of the 105 (82%) patients received the fourth ‘booster’ dose to complete the vaccination regime. Reasons for not receiving this dose included patient death in 13 (68%) cases, transfer to another renal unit in four cases (22%) and renal transplantation in two (10%).

Of the 86 patients who completed the vaccination course, 77 were available to have their anti-HBS titres measured 12 months after their booster dose (i.e. 24 months after initiating the vaccination regime). Reasons for not being available included patient death in five (56%) cases, transplantation in two (22%), and transfer to another unit in two (22%).

Patients' monthly dialysis adequacy measurements during vaccination were recorded, as was their weekly-prescribed Epo dose.

Statistical analysis
Statistical analysis was performed to assess factors that impinged on patients’ response to vaccine. The chi-square statistic test and the Fisher's exact test (for 2x2 tables) were used to test for differences between proportions. The Student's t-test (unpaired, two-tailed) was used for comparison of means of normally distributed samples, whilst a Mann–Whitney U-test was used for non-parametric samples.



   Results
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
Antibody response to vaccination
Thirty-five patients (33%) had responded to primary vaccination (Table 2Go). Of these patients, eight were good and 27 were poor responders. Of those good responders, seven had anti-HBS levels in the range 100–1000 mIU/ml whilst the remaining patient had a level >1000 mIU/ml. Fifty-six patients who had not responded to primary vaccination received a fourth dose, as did 23 poor and seven good responders. This further dose led to a significant improvement in the response rate ({chi}2=49, P<0.001). Sixty-three (73%) responded to a complete vaccination regime. Similarly, the anti-HBS levels achieved by those who had responded on completion of the regime were significantly better than those found after three doses ({chi}2=28.13, P<0.001).


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Table 2.  Response rates to vaccination

 

Factors affecting antibody response
Non-European patients' response to primary vaccination was significantly better than the Europeans. After three doses, 11 (52%) patients from the Indian subcontinent, four (67%) Afrocarribean and 20 (26%) European patients developed anti-HBS levels >10 mIU/ml ({chi}2=8.5, P=0.014). However, for those who completed the regime, the response rates did not differ significantly between the races. Use of steroids, either inhaled (high dose) or oral, during primary vaccination was associated with reduced response rates. After primary vaccination, two (6%) responders were receiving steroid medication compared with 12 (17%) non-responders. On completion of the regime this difference reached statistical significance, with four (6%) responders on steroids compared with seven (30%) non-responders (P=0.007). There was no significant difference in the mean serum albumin between responders and non-responders, although a larger proportion of non-responders had an abnormally low serum albumin (<33 g/dl) at the start of the regime (30%) than responders (13%, P=0.1). There was no statistically significant difference in age, sex, renal diagnosis, diabetes mellitus, time on dialysis, dialysis adequacy, Epo dose, hepatitis C or body weight between responders and non-responders after receiving primary vaccination or the complete regime (Table 3Go).


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Table 3.  Patient variables of responders and non-responders to both the primary and complete vaccination regime

 

Longevity of antibody response
Seventy-seven patients completed 24 months of follow-up. Fifty-four of these had responded to the vaccine when assessed at 13 months. However, at 24 months, 24 (44%) of these patients had lost their antibody response (‘transient’ responders) and likewise, the magnitude of antibody levels of the remainder had decreased ({chi}2=26, P<0.001; Figure 1Go). Transient responders predictably had a significantly poorer antibody response to the vaccination regime, as assessed at 13 months, than persistent responders ({chi}2=15, P<0.001). There was no significant difference in sex, age, race, diabetes mellitus, weight, steroid use, starting serum albumin, duration of dialysis, dialysis adequacy or Epo dose between transient and persistent responders (Table 4Go).



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Fig. 1.  Longevity and magnitude of the anti-HBS antibody response in 54 patients followed to 24 months after the initiation of the vaccination regime.

 

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Table 4.  Characteristics of ‘transient’ and ‘persistent’ responders

 

Adverse events
Although a significant number of patients did not complete the primary vaccination course, there were no serious adverse events attributable to the vaccine. None of the patients became hepatitis B surface antigen positive during the 24-month period of follow-up.



   Discussion
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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 
In the 1970s, hepatitis B was very prevalent in the dialysis population and also in their health care professionals [6]. The introduction of universal precautions and the reduced use of blood products, facilitated by the widespread use of Epo, has contributed significantly in bringing the prevalence of hepatitis B down to <5% of dialysis patients in many parts of Europe [6,7]. With the introduction of hepatitis B vaccines in the 1980s, it was hoped that hepatitis B would be eliminated from the dialysis population. The vaccine has helped to decrease the incidence further, but with suboptimal efficacy in patients with chronic renal failure, hepatitis B has by no means been eradicated [8]. Compounding this problem, however, is the fact that not all UK units are vaccinating their dialysis population, although they are vaccinating their health care professionals [4]. A recent survey of renal units in the UK has found that seroconversion is not an uncommon occurrence, with 15% of respondents reporting at least one incident of hepatitis B seroconversion in their chronic renal failure patients in the last 3 years [4].

Hepatitis B vaccine, even when used at high dose, does not elicit as good a response in patients with chronic renal failure as it does with the normal population. Uraemia impairs antigen presentation to and activation of T cells, and subsequent antibody production [9]. Most frequently used regimes involve the intramuscular administration of three or four doses of a high-dose vaccine over a period of 6–12 months [1023]. Response rates are consistently disappointing though, even when adjuvants are used [2426]. Less conventional regimes have used multiple intra-dermal injections (low dose) over prolonged periods of time [23]. Response rates achieved have been comparable to the normal population. However, their seroprotective response is often poor, reflected by a transient production of low levels of anti-HBS. This lack of a simple effective vaccination regime has been given as an important factor by many UK renal units for not routinely offering vaccination to their patients [4]. Consequently, as was the case at our unit, hepatitis B vaccination of dialysis patients is often reserved for the ‘post-exposure’ scenario. Current guidance recommends the use of the accelerated regime, although there are no recent published series reporting its efficacy [1]. With the administration of vaccine on 3 consecutive months, a rapid immune response was anticipated, which would aid patients’ clearance of the virus, preventing chronic carriage and disease [11,12,18,21,22]. After completing primary vaccination, however, the response rate was poor at 33%, highlighting the importance of universal precautions in preventing cross infection.

Many factors impinge on the effectiveness of a vaccine. Not only is the antigenic potency of the vaccine important, but also patient characteristics. Along with uraemia, malnutrition, as indicated by a low albumin and pre-dialysis urea, low body weight, diabetes mellitus, increased age, seropositivity for antibody against hepatitis C, impaired T-cell receptor expression and HLA DR3, DR7, DQ2 have been associated with a poor response of haemodialysis patients to hepatitis B vaccine [1317,20,21]. Conversely, there is evidence that Epo therapy improves response rates [12]. Predictably, we observed that steroid use impaired a patient's response. When assessing the efficacy of a vaccine, most prospective studies excluded those patients receiving steroids. Excluding such patients in our results would have slightly increased the observed response rate to the accelerated regime to 36% (or 79% after the complete vaccination regime).

To complete the vaccination regime, a fourth dose of vaccine is given at month 12. We observed that this further dose led to a significant improvement in response rate (73%). Other published series using alternative regimes have also highlighted the need for multiple doses to achieve a response in many dialysis patients [12,20,23]. Peces et al. [20] achieved a response rate of 77.5% in 80 patients receiving high-dose vaccine at 0, 1, 2 and 6 months, raising the question of whether waiting 12 months before administering the fourth dose is necessary or possibly disadvantageous to those patients who had not responded to the previous three doses.

The higher the antibody response achieved by vaccination, the longer the protection conferred [18,23]. Our experience was disappointing, with 56% of respondents having only transient protection, losing detectable anti-HBS antibodies within 12 months of receiving their last dose of vaccine. This represents a fall in response rate from a peak of 73% on completion of the regime to 43% of those followed to month 24. This is in contrast to Fabrizi et al.'s [19] experience with a three-dose vaccination regime where 78% of their respondents maintained protective antibody levels to month 24. Similarly, el-Rashaid et al. [18] observed that at month 24 of a four-dose vaccination regime, there was only a 4% drop from the initial 79% response rate. Our observation that a large proportion of patients lost seroprotection in a relatively short period of time post-vaccination reaffirms guidelines for the continued surveillance of patients’ antibody status, as a significant proportion may require frequent booster doses of vaccine [13,27].

Some attempts have been made to assess the cost-effectiveness of hepatitis B vaccination in patients with chronic renal failure. Analyses performed by Alter et al. [28] from the US, and Fabrizi et al. [19] from Italy, concluded that implementing a vaccination program conferred a net cost saving. Decreasing the need to repeatedly test patients’ viral status subsequently reduced annual costs. However, their calculations were based on clinical practice, which differs from our own. In particular, hepatitis B surface antigen status was checked more frequently than current UK practice, as they had higher prevalence rates of hepatitis B. Secondly, Fabrizi et al.'s [19] calculations were based on a vaccination regime that conferred a seroprotection rate similar to our own (67 and 73%, respectively), but achieved superior antibody protection of patients at 24 months (78 and 56%, respectively). This equates to a smaller proportion of patients requiring a booster dose at this stage, therefore making it less expensive. At 24 months, 44 out of our cohort of 54 (82%) patients required a booster dose, having had anti-HBS levels fall to 10–100 mIU/ml or lower compared with 33 out of 51 (65%) Italian patients. An analysis performed by Oddone et al. [29] is more detailed, and is more applicable to current UK experience. They used a complex decision analysis model, which took into account many more variables that would have an impact on cost. All the analyses were based on estimates derived from the medical literature. They estimated that the vaccine would have a response rate of 55%, conferring protection for 3 years, decreasing the 3-year infection rate from 0.6 to 0.09%. It was concluded that implementing a vaccination program, where all patients would be vaccinated on starting dialysis, would be more costly than having a no-vaccination strategy. They estimated that the cost of preventing infection of one additional dialysis patient or household contact would be considerable, at US$25313. Hepatitis B infection is associated with significant morbidity, and for infection control and public health reasons an attempt should be made to immunize successfully all patients who are receiving dialysis [30]. However, the expense may be deterring many renal units in the UK from implementing vaccination programs [4].

There is evidence that pre-dialysis patients’ immune response to hepatitis B vaccination is superior to those already on dialysis [31]. In recognition of this, more renal units are following the Renal Association's guidelines of vaccinating patients pre-dialysis [1]. However, it is not clear if this is a more cost-effective strategy. There has been no extensive study of the optimum time to vaccinate or longevity of any response achieved. Oddone et al. [29], using their computer model, estimated that the cost of preventing infection of one patient who would require dialysis within 3 years would be US$31111. Even though the vaccine was more efficacious than when used on patients starting dialysis, this benefit is offset by the fact that not all the patients ultimately start dialysis.

In conclusion, many UK renal units still do not routinely vaccinate their dialysis population, despite their high risk of hepatitis B exposure [4]. The accelerated vaccination regime is currently recommended for use in non-immune patients who have been exposed to hepatitis B, as well as when routinely vaccinating the dialysis population [1]. Whereas the primary component of this regime achieved a poor antibody response rate, the complete vaccination regime afforded seroprotection to the majority. This lack in early response to the regime meant that reserving vaccination to the post-exposure scenario exposed many more patients to the risk of hepatitis B cross-infection than if it had been used prophylactically. Clearly, the most appropriate use of vaccine follows national and international guidelines; however, this will have significant ongoing cost implications. Further studies are required, in particular to look at pre-dialysis vaccination programs, to help identify the most cost-effective strategy.



   Acknowledgments
 
The authors are indebted to Sister Karen Harris who coordinated the implementation of the vaccination program and collection of blood samples.



   Notes
 
Correspondence and offprint requests to: Kevin S. Eardley, Birmingham Heartlands and Solihull NHS Trust, Department of Nephrology, Birmingham, UK. Email: keardley1{at}yahoo.co.uk Back



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 Abstract
 Introduction
 Subjects and methods
 Results
 Discussion
 References
 

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Received for publication: 6.12.01
Accepted in revised form: 1. 7.02