I nfectlon with the hepatitis. B virus remains an important compbication in chronic hemodialysis. (HD) patients. These patients are at risk for developing acute.
Successful Vaccination With Intradermal Hepatitis B Vaccine in Hemodialysis Patients Previously Nonresponsive to Intramuscular Hepatitis B Vaccine Nancy
M. Waite,
Lisa G. Thomson,
and
Marc
B. Goldstein3 decrease
Waite. L.G. Thomson. MB. Goldstein. St. Michael’s Hospital and UniVersity of Toronto, Toronto. Ontario, Canada N.M.
(J. Am.
Soc.
Nephrol.
1995;
5:1930-1934)
ABSTRACT Seventy-seven
chronic
hemodialysis
patients
were
vaccinated against hepatitis B virus with an intramuscular (im) hepatitis B vaccine (HBV), 40 g at 0, 1 2, and 6 months. Fifty-seven patients (74%) developed antibodies (anti-HB5). The im-responsive patients were ,
significantly younger than < 0.05). Nineteen of received HBV intradermally
the nonresponsive patients the 20 im nonresponders (id), 5 g every 2 wk until developed; the 20th patient died before rethe id vaccine. Three patients were lost to Fifteen (94%) of the 16 developed anti-HBs
(P
anti-HBs ceiving follow-up.
5.2 ± 4.7 months. The peak anti-HBs titers were 726 ± 426 (im) and 211 260 (id) lU/I (P < 0.05). Twelve (21 %) of the 57 im-responsive patients and 8 after
(53%) ofthe 15 id-responsive patients than 20 IU/L at 18 and 8 months respectively
cate
(P
that
crease
0.05).
10 IU/L)
at
least
2 months after the last im injection were eligible for the protocol. This regimen was 5 g (0.25 mL) of Engerix-B every 2 wk until an anti-HBs titer > 10 IU/L developed. The injections
The time measured presence mented. Patients
were
given
in
ofdevelopment from the date of a cutaneous In
whom
the
lateral
aspect
of the
ofanti-HBs and ofthe institution bleb and side the
anti-HBs
Volume
titer
5
upper
their duration ofvaccination. effects were fell
-
to
Number
am.
were The docu-
10
of whom thereafter JU/L; one failed
to
developed respond
anti-HBs in but developed
HBs with the Id regimen, and one unrelated complications ( 1 .5 months No significant adverse reactions were ther the im or the id protocols.
patient after noted
a titer anti-
died of booster). with ei-
DISCUSSION With the decreasing incidence of hepatitis B carriers in the HD popubation one might assume that there is a smaller risk of patients contracting hepatitis B. However, a large proportion (79%) ofHD patients have no anti-HBs and the hepatitis B carrier rate remains 1 .3%, which is not insignificant ( 1 ). One of the obstades to the vaccination of this group of patients with renal failure is the cost of the vaccine in relation to the low response rate obtained. Various strategies to improve the responsiveness of HD patients to HBV have been used. The concomitant administration of immunostimulants such as thymopentin , interleukin-2, and a- and ‘y-interferon has had limited success in potentiating the immunogenicity of the vaccine (1621), and the cost of these adjuvant agents remains substantial. The Id administration
of HBV
has
been
considered
as an alternative uals, with the
to im vaccination in healthy individgoal being the minimization of vaccina-
tion costs and large vaccination effectiveness
the of
facilitation programs the vaccine.
of the without Many
implementation decreasing of these
of the studies
have shown similar or slightly bower rates of development of anti-HBs as compared with standard im regimens (9-12). Currently, the CDC does not recommend the routine use of the Id route of vaccination because of the possibility of lower rates of development ofanti-HBs as well as lower anti-HBs titers (15). However, it is important to appreciate that these studies used only three Id injections of a total of 6 g of vaccine; the standard three-dose im protocol administers 1 20 g of vaccine. Ono and Kashiwagi, using various Id regimens, reported a rate of 100% seroconverslon in 35 patients who had not previously received HBV ( 14). The rate of response was fastest in the 14 patients who received
1932
HBV, 5 ;ig Id every 2 wk. We therefore chose this vaccination regimen to apply to a different population of HD patients, a group who had been nonresponsive to an initial
im im
vaccination vaccination
regimen. protocol
The was
response at the
to
Id
the end
high
(74%) of the reported range. Of the 16 chronic HD patients nonresponsive to the im regimen who completed the id protocol, 15 or 94% successfully developed anti-HBs. The sequential administration of im HBV and then id HBV to im-nonresponsive patients enabled the seroconversion of 99% of the previously unprotected HD population. One other study used a similar two-step protocol (im, then id) to successfully vaccinate four patients by the Id route who had previously been nonresponsive to im vaccination (22). One difficulty healthy individuals and decreased with results with peak response nonresponsive),
encountered has duration im HBV was 21 1 which was
with Id administration in been lower anti-HBs titers of immunity as compared (7, 8, 1 1 ). In this study, the IU/L in the Id group (im significantly lower than in
the im-responsive patients (726 IU/L). Another concern is that it has been shown that the duration of immunity is proportional to the height of the peak antl-HBs titer (23). This was also the case in our study with the id-responsive patients, demonstrating a shorter duration of immunity; as a result, reinitiation of the Id regimen was required in 53% of patients. However, all of these patients were successfully protected with an additional id regimen and would have been totally unprotected with the im regimen alone. Anti-HBs
titers
for
patients
in
the
Id
study
by
Ono
and
Kashiwagi also fell quickly, with some patients losing their anti-HBs by the 39th wk (14). The CDC states that, although in the general population, successful vaccination with anti-HBs production results in lasting immunity, in the HD population “protection may persist only as bong as antibody levels are 10 IU/L” (15). Because the duration of anti-HBs is proportional to the peak antibody titer, we postulated that we might enhance the peak antibody titer and prolong the duration of anti-HBs by continuing to administer the vaccine id after the development of anti-HBs. Prelimmary results indicate that one can achieve titers > 1 ,000 JU / L with continued id vaccination without local reactions (24). The duration ofanti-HBs with this protocol has not yet been established; although it is definitely longer than this study, it may be shorter than in those patients who have responded to im vaccination. A number of studies have looked for the host factors that determine whether patients develop antibodies to HBV (6, 25-28). Results from these studies have been somewhat inconsistent, although younger age, shorter duration on dialysis, concomitant erythropoietin administration, and increased interleukin-2 receptor concentration have been linked with increased responsiveness to im vaccination. Only older age was identified in this study as being associated with a
Volume
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1995
Waite
decreased im responsiveness, and although this is consistent with other studies, the basis is unclear. Gender (females more likely to develop seroprotection) almost reached significance, and although this is also consistent with other studies, the mechanisms have not been elucidated. The final parameter that approached sponders
a and
significant difference between the renonresponders (Table 1 ) was the predialysis blood urea concentration. In view of the lack of a difference in the degree of dialysis provided to the two groups (as reflected by the Kt/V urea), this difference could reflect a better nutritional state in the responders; however, there was no difference in the serum albumin, another parameter reflecting nutritional status. It Is of interest that, of the 10 patients in this study with anti-HBs and no history of vaccination (presumed “natural immunity”) in whom maintained, 3 of them had the anti-HBs IU/L. Although a more precise definition
follow-up was fall to 10 IU/L with an im booster but was successfully vaccinated with Id HBV. The cost of the vaccine for four im injections is $163.20 Canadian dollars ($20.40 per 1-mL vial), whereas each month of Id vaccination costs $10.20. Therefore, one can administer 1 6 months of Id vaccination for the cost of the im vaccine protocol. It is difficult to calculate whether there would be substantial cost savings from routine all of the Id patients were therefore, they are a subgroup represent the usual chronic
Id vaccination, im nonresponsive, that probably HD population.
because and does not Before
considering any cost saving from routine Id vaccination, one must demonstrate that an Id protocol bestows protection equivalent to that of an im protocol. It would be desirable to provide specific recommendations concerning the routine vaccination of chronic HD patients against hepatitis B. The vast majority of patients who are nonresponsive to an im vaccination protocol will indeed develop protective anti-HBs titers with an Id protocol. However, the anti-HBs titer and duration in this study were lower in the id group, which may be due to the basic differences between the two groups (the Id patients were a subgroup who were all im nonresponsive) or may in fact be in part a resubt of the Id protocol. Therefore, we cannot, at this time, recommend the use of an Id protocol for the routine vaccination of all chronic HD patients. A reasonable approach to hepatitis B vaccination in the chronic HD population would be that all patients who fail to develop anti-HBs in a titer of at least 20 IU / L subsequent to an im vaccination protocol should receive Id vaccination with 5 tg every 2 wk for 6 months, measured. should
at
which time, the anti-HBs If the titer exceeds 1 ,000 cease. If the titer is less than
Journal
of the
American
Society
titer should be IU/L, vaccination 200 IU/L, vacci-
of Nephrology
nation months.
should be continued In those patients
tween continue When should 100
for with
an anti-HBs
et al
additional titers
6 be-
200
and 1 ,000 IU/L, It would be reasonable to vaccination for an additional 3 months. vaccination has ceased, the anti-HBs titers be measured annually. If the titer Is less than
IU/L,
it should
be
rechecked
in 6 months.
When
the anti-HBs titer falls to less than 20 IU/L, a booster should be given. It is currently unknown whether patient who was im nonresponsive but Id responsive should receive his or her booster im or Id. Patients with
an
anti-HBs ofvaccination monitored annually, administered when
a
titer
exceeding 20 IU/L and no should have their anti-HBs titer and an im booster should be the titer falls below 20 IU/L.
history
ACKNOWLEDGMENTS We gratefully acknowledge the participation and commitment of the hemodlaiysis nurses at St. Michael’s Hospital for the critical role they played in the administration of the vaccIne. We sincerely appreciate the cooperation and contribution ofDr. Bannatyne and the staff of the Microbiology Department at St. Michael’s Hospital in the performance of the antigen and antibody assays.
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