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Hepatitis B vaccine in hemodialysis patients with hepatitis C viral infection
Vaccine, Vol. 15, No. 12/13, pp. 1353-1357. 1997 0 1997 Elsevier Science Ltd. All rights reserved Printed in Great Britain 0264-410X/97 $17+0.00
PII: SO264-410X(97)00037-6 ELSEVIER
Hepatitis B vaccine in hemodialysis patients with hepatitis C viral infection Chi-Hung Cheng*-i_, Chiu-Ching Chun-Yi Fan Chiang”, Mai-Szu
Huang*, Mei-Ling Leu”, Wu* and Ping-Chin Lai”
Patients on hemodialysis therapy are at a relatively high risk of exposure to hepatitis B virus (HBV) infection. The prevalence of hepatitis C virus (HCV) infection is even higher and was reported as 33.2% in Taiwan. Although the ej$cacy of hepatitis B vaccine was well documented, the vaccination schedule in hemodialysis patients is not clearly defined. And under such a high prevalence of HCV infection, little is known about the influence of HCV imposing on HBV vaccination. We studied 50 chronic hemodialysis patients who were serologic&& negative for the hepatitis B sueace antigen (HBsAg), the antibody to the hepatitis B sur$ace antigen (anti-HBs) and the antibody to the hepatitis B core antigen (anti-HBc); 26 of them were positive for the antibody to hepatitis C virus (anti-HCV) test. Recombinant hepatitis B vaccine (Engerix-B) 40 ,ug per dose was administered by the intramuscular route at deltoid region at 0, 1, 2, 6 and 12 months respectively to all the patients. Forty-six patients had completed the study. The effective seroconversion rate (serum anti-HBs titer > 10 mIU ml-‘) at 1 month after the final vaccine was 76.1% (35/46). The effective conversion rates of the antiHCV (+) group to the anti-HCV( -) were 75% versus 77.3% (P = 0.857). Geometric mean anti-HBs titers were 177.67 mIU ml-’ versus 189.28 mIU ml-’ (P = 0.867). 0 ur results showed that jive-dose injections of HBV vaccine do not present a superior outcome to the four-dose regimen comparing to published data. The status of positivity of anti-HCV do not pose an suboptimal effect on HBV vaccination of hemodialysis patients. 0 1997 Elsevier Science Ltd. Keywords:
hepatitis
B
vaccine, hepatitis C infection, hemodialysis patients. immunogenicity
The prevalence of hepatitis B and C viral infections remains a major problem in chronic hemodialysis patients throughout the world’. With the excellent efficacy of hepatitis B virus (HBV) vaccination in preventing this viral infection in healthy people, it has become a general consensus to provide HBV vaccine to susceptible hemodialysis patients2. However, the vaccine seroconversion rate of hemodialysis patients is much lower than that of healthy subjects”,4. To achieve an optimal response in such patients, higher dose and larger number of vaccine injections have been widely tried and obtained favorable results5.“. Despite all these trials, the vaccine schedule is not yet standardized to form a definite recommendation. Furthermore, under the high incidence of hepatitis C virus (HCV) infection in these patients, little is known if HCV could modify the effectiveness of HBV vaccine. The present study was undertaken to test the immune response with a higher dose (40 pg) and more frequent injections (five *Division of Nephrology, Chang Gung Memorial Hospital, 199, Tung-Hwa North Road, Taipei, Taiwan. tAuthor to whom all correspondence should be addressed. (Received 11 October 1996 revised version received 14 January 1997; accepted 14 January 1997)
doses). The influence also evaluated. MATERIALS
AND
of HCV on the HBV vaccine
was
METHODS
From April 1994 to August 1995, 50 chronic hemodialysis patients in our hemodialysis center were enrolled in the study. All subjects were tested serologically negative for hepatitis B surface antigen (HBsAg), the antibody to the hepatitis B surface antigen (anti-HBs) and the antibody to the hepatitis B core antigen (antiHBc) and had no previous HBV vaccination. Twentysix of them were positive for anti-HCV and 24 were negative. None of them had ever received renal transplant and no one was receiving immune modifying drugs. No one had evidence of liver decompensation (hypoalbuminemia, prolonged prothrombin time, jaundice, encephalopathy or ascites). Recombinant yeast-derived HBV vaccine (EngerixB, SmithKline Biologicals, Rixensart, Belgium) 40 pg was administered to all patients in each dose at deltoid region according to a 0, 1, 2, 6 and 12 months time schedule. Serum markers to hepatitis B were tested with radioimmunoassay (Ausria II, Corab, Abbott Labora-
Vaccine
1997 Volume
15 Number
12/13
1353
Hepatitis B vaccine in hemodialysis
patients with hepatitis C infection:
tories, Chicago, IL). HBsAg and anti-HBc were followed every 6 months. Anti-HBs titer was checked monthly and expressed in mIU ml ‘. Subjects with anti-HBs titer > 10 mIU ml ’ was considered effective seroconversion. Antibody to hepatitis C virus (antiHCV) was performed by a second generation of ELISA test (General Biologicals Co., Taiwan) and positive cases were confirmed by a second generation recombinant immunoblot assay test (Chiron RIBA HCV test system). Anti-HCV was followed every 6 months and seroconversive cases during the study would be excluded. Twenty-six patients with positive anti-HCV served as group 1 and was compared with 24 patients who were negative for anti-HCV as group 2. Serum alanine aminotransferasc (ALT) were checked monthly spectrophotometrically. In the antiHCV+ group, patients with elevated serum levels ( > 40 IU 1 ‘) of ALT for > 6 months during the study year were defined as chronic hepatitis. Seroconversion rates were analysed by x2. Anti-HBs titers (geometric mean titers; GMTs) wcrc compared using analysis of variance (ANOVA) repeated measures and the Wilcoxon rank sums test. A P value <0.05 was considered statistically significant.
Chi-Hung Cheng et al.
response after vaccination of both groups are depicted in Figure IFigure 2, respectively. The immune response expressed as GMT is shown in Figure 3. Anti-HBs titers rose after starting the vaccination in both groups, but soon declined after the third injection. The peak GMT was seen at 1 month after the fourth dose and dropped again in the vaccine free 6-month interval. A tifth hoostcr injection was given in month 12 to create the other peak, which did not reach the height of previous one. The GMTs of group 1 were consistently lower than those of group 2 throughout the course, which did not show statistical difference. The overall effective seroconversion rate (antiHBs> 1OmlU ml ‘) was 76.1% (35146) at I month after the final fifth-dose injections. The conversion rates wcrc 75% (18124) in group 1 and 77.3% (17122) different, in group 2, which was not statistically (P = 0.857). Figure 4. When the anti-HBs titer was set at 100 mIU ml ‘. the overall conversion rate and that of group I and group 2 were 43.5% (20146). 37.5% (9/24) and 50% (1 l/22), respectively. There was no Table 1
Comparison between the two groups
No. of patients Age (years) Sex M/F Body weight (kg) Etiology
RESULTS The two groups of patients existed no significant difference in age and body weight as shown in Table I. The mean duration of hemodialysis of anti-HCV+ group was 65.4k48.1 months (7-169months) at the beginning of study (till March 1994) and that of the antiHCV-group was 29.1 f25.3 months (5-132 months). This difference was significant (P = 0.01). All patients were tested negative for HBsAg, antiHBs and anti-HBc. The profiles of monthly immune
HD duration (months) Seroconversion rate (%) > 10 mlU ml-’ ~100mlUml ’
HCV+
HCVP
26 53.6k10.8 15/l 1 55.6k7.9 CGN 17TCC 1 DM 7 IGA N 1 65.4k48.1
24 50.4i18.7 13111 55.7*10.7 CGN 16 DM 8 29.1 +25.3
0.01
75 37.5
77.3 50
0.86 0.39
P
0.22 0.47
Characteristics of the HCV+ and HCVgroups: CGN, chronic glomerulonephritis; DM, diabetes mellitus; TCC, transitional cell carcinoma; l&A N, IgA nephropathy
Anti-HCV
+
4500 4000
UJ
2500
!z .+
2000
a
0
1
2
4
3
5
6
7
8
9
10
11
12
13
14
15
16
month Figure 1 Profile of monthly 12 months
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1997 Volume
of anti-HCV+
15 Number
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patients depicted
with the anti-H&
titer (mlU ml-‘)
vaccined
at 0, 1, 2, 6 and
Hepatitis 6 vaccine in hemodialysis
patients with hepatitis C infection:
Anti-HVC
Chi-Hung Cheng et al.
-
6000 z w
5000
1000
0 2
0
4
6
8
10
12
14
16
month Figure 2 Profile of monthly immune response of anti-HCV12-months
patients depicted with the anti-HBs titer (mlU ml-‘) vaccined at 0, 1, 2, 6 and
these infections during treatments’. They also show poorer responsiveness in HBV vaccination due to impaired cellular and humoral immune responsesx. Several strategies have been tried to improve the immune response of vaccination to date including higher dose and larger number of vaccine administrations”.“‘, combined hepatitis B immune globulin injecinterleukin’j, interferon usage”, tion”, adjuvant thymopentin14 or zincI supplementations. A new form of recombinant vaccine (GenHevac B) which contains pre-sl and s2 domains in addition to the s antigen of HBV has also obtained a favorable outcome’“.“. Of all the above mentioned, higher dose and larger number of vaccine administrations have been persistently proved effective and widely suggested’x,‘“. However, the optima1 way of vaccination is still not well defined. While doubling the vaccine dosage has become the and timing of general consensusy~“‘~‘5~‘y, the number
difference between the two groups either (P = 0.392). The effective conversion rate at 1 month after the fourth injection was 64% (32/50), which was not significantly different to the final five-dose conversion rate (P = 0.197). In the anti-HCV+ group, 24 patients completed the study. Seven of them had elevated ALT for > 6 months during the study year. When compared with the remaining 17 patients, the effective seroconversion rates were 71.4% (five out of seven) versus 76.4% (13/17), which did not show significant difference (P = 0.79). significant
DISCUSSION Chronic hepatitis
hemodialysis viral infections
patients because
are susceptible of high prevalence
to of
Anti-HBs titers mlU/ml 600
o,,
,, 1
Vaccination Figure 3
2
1‘ 7 t
,, 3
4
,, 5
6
,, 7
t
8
,, 9
10 11
,, 12 13
, 14
, 15
16
month
T
Monthly changes of anti-HBs GMTs of both groups
Vaccine 1997 Volume 15 Number 12/13
1355
Hepatitis 6 vaccine in hemodialysis
patients with hepatitis C infection:
Effective seroconversion
Chi-Hung Cheng et al.
rate %
> 10 mlU/ml
month Vaccination Figure 4 Changes of effective seroconversion rates of all patients seroconversion was defined as anti-HBs > 10 mlU ml ’
and group
vaccine injections remain unsettled. Using four-dose vaccine injections seemed to produce better response rates than that obtained with three-dose injections recommended by the Center for Disease Control”.“““, but the seroconversion rates were still low-around 69-79%“,“.“, which were far inferior to that of healthy adults. Limited data has been concerned with five-dose injections. Drachman rt al. reported a 85.6%’ seroconversion rate with S-monthly consecutive vaccine injcctions2”, while Craven and Pasko casted doubt on the effectiveness of booster shots to primary nonrespondersx.‘5. Our study showed seroconversion rates of 64% at 1 month after the fourth injection and 76.1% in completing the vaccination course. These data did not demonstrate a better response with five-dose inoculation, which were in accordance with the observations of Craven and Pasko. The duration of antibody existence with effective protection was considered to correlate with the peak antibody titer after vaccination. In our study the antibody titers after the fourth administration declined more rapidly than that after the fifth administration (Figure 3). From this result it may suggest that five-dose injections be more effective than four-dose injections in terms of adequate antibody persistence. A fifth dose booster in the month 12 did create the other peak of antibody titer in both groups: however, the peaks were paradoxically lower than those obtained after the third and fourth injections in group 2. This phenomenon may tell us that the immune response was stronger with four intensive inoculations in a 6-month period (months l-6) than that with only two inoculations in a similar interval (months 6-12). But it may also partially be influenced by the patients with good immune response who dropped out from the study near the end. With five injections, our conversion rate was inferior to that of Drachman et al. (76.1% versus 85.6%). It is possible that this difference could be related to a different timing of vaccine administration. It is likely that five monthly consecutive inoculations of HBV vaccine could give a higher immune response compared to five doses over a l-year period. It is probable that the administration of five doses over a 12-month period could yield a higher persistence of anti-HBs antibody over time (i.e. 2 or 3 years after the completion of the vaccination program) compared to five monthly consecutive vaccine inoculations.
Could HCV infection affect the result of HBV vaccination? Kamel et al. reported that the presence of anti-HCV did not affect the immunogenicity to HBV vaccine in healthy adults”‘. As to hemodialysis patients, Navarro et al. obtained results suggesting the possibility of HC,V in modifying the effectiveness of HBV vaccine- , while Fabrizi et al. found that the immunogcnicity to Engerix-B was not influenced by the presence of anti-HCV”. Navarro et al. noted that HCV infected patients had a significantly lower seroconversion rate when the comparison antibody titer (GMT) was set at 100 mIU ml- . This phenomenon was not seen at the cut-off value of 10 mIU ml-‘. Our data presented a similar trend, that is, lower effective conversion rates in HCV infected patients, but no significant difference in both cut-off values was seen, Table I. In Fabrizi’s study, the protocol was different. They vaccinated all study subjects and obtained two groups of patients classified as responders (anti-HBs > 10 mIU ml ‘) and nonresponders (anti-HBs < 10 mIU ml-‘). Their results showed no ‘significant difference in anti-HCV positivity between the two groups. They concluded that the immune response to HBV vaccine was not affected by existence of antiHCV. Our finding seemed to support this statement in a different way of analysis. Concerning the way that HCV might influence immune response to HBV vaccination, two prospectives should be considered. First, the antibody response to the inoculation is a T-dependent B cell stimulation and is genetically linked to MHC class II antigens”. Hepatitis C viral infection has been proved to induce a series of immune response involving activation of T-lymphocyte and B-cell via MHC I and MHC II to mediate hepatotoxicity”“,“‘. These expressions immune reactions might be influential on the antibody production in HBV vaccination. From the result of our study, this phenomenon was not demonstrated. Second, HCV infection can evolve to chronic hepatitis and over time to liver cirrhosis or hepatocellular carcinoma. This is a putative negative effect on the immune system of dialysis patients. Concerning the severity of liver disease caused by HCV infection, we analysed antiHCV+ patients. No patient in this group had evidence of liver decompensation and the result showed no difference in the effective seroconversion rate between those with chronic hepatitis and those without. The
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1997 Volume
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12/13
anti-HCV+
and group
anti-HCV-
patients.
Positive
Hepatitis B vaccine in hemodialysis result may
seemed merely
against reflect
the
above fact
putative that
the
recognition duration
but HCV to cause
patients with hepatitis C infection: 10
of
infection in our patients was not long enough disease to affect the efficacy of HBV vaccination. On the other hand, in our study the duration of hemodialysis of the anti-HCV+ group was significantly longer than that of the anti-HCVgroup. This was consistent with the fact that the longer the patients receive hemodialysis therapy the more chance they get to be infected by HCV”. Fabrizi rt al. also noted that the responders had a significantly shorter duration of hemodialysis treatment compared to nonresponders. From this, it may suggest that in our study the persistent lower GMTs in the anti-HCV+ group be a result of the effect of a longer duration of hemodialysis treatment rather than the effect of the presence of anti-HCV. In conclusion, from our study the five-dose injections of the HBV vaccine do not increase the response rate compared to that of a four-dose regimen. We would suggest a four-dose vaccination for all HBV vulnerable hemodialysis patients as standard. Booster injections are mostly needed because of the fact that the antibody titer declines rapidly and the timing can be individualized. HCV infection did not influence the effect of HBV vaccination in our study. The HBV vaccination schedule should not be different between patients in regard to anti-HCV positivity.
11
12
13
14
15
16
17
18 19
20 21
ACKNOWLEDGEMENTS We would like to acknowledge all patients participating in this study and Associate Professor Sing-Kai Lo in the statistical analysis. We also thank SmithKline Beecham Pharmaceuticals Taiwan Ltd for their vaccine support.
22
23
REFERENCES 1
2
3
4
5
6
7 8
9
Szmuness, W., Prince, A.M. and Grady, G.F. et al. Hepatitis B infection: a point prevalence study in 15 US hemodialysis centers. J. Am. Med. Assoc. 1974, 227, 901-906. Hardy, N.M.. Sandroni, S. and Danielson, S. et al. Antibody to hepatitis C virus increases with time on hemodialysis. C/in. Nephrol. 1992, 38, 44-48. Crosnier, J., Jungers, P. and Courouce, A.M. et al. Randomized placebo-controlled trial of hepatitis B surface antigen vaccine in French hemodialysis units II hemodialysis patients. Lancer 1981,1,797-800. Stevens, C., Alter, H.J. and Taylor, P.E. et al. Hepatitis B vaccine in patients receiving hemodialysis. N. Engl. J. Med. 1984, 311, 4966501. Benhamou, E., Courouce, A.M. and Jungers, P. et al. Hepatitis B vaccine: randomized trial of immunogenicity in hemodialvsis oatients. C/in. NeDhrol. 1984, 21, 143-l 47. El-Reshaib, K., Al-M&i, S., Johny, K.V. and- Sugathan, T.N. Comparison of two immunization schedules with recombinant hepatitis B vaccine and natural immunity acquired by hepatitis B infection in dialysis patients. Vaccine 1994, 12, 223-228. Boulton-Jones, J.M., Vick, Ft. and Cameron, J.S. et al. Immune response in uremia. C/in. Nephrol. 1973, 1, 351-360. Pasko, M.T., Pharm, D., Bartholomew, W.R., Beam, T.R., Amsterdam, D. and Cunning, E.E. Long term evaluation of hepatitis B vaccine (Heptavax-B) in hemodialysis patients. Am. J. Kidney Dis. 1988, 11,326-331. NicoLelie, R., Reesink, H.W. and de Jong-Von Manen, S.T. et a/. Immune response to a heat-inactivated hepatitis B vaccine in patients undergoing hemodialysis. Arch. Intern. Med. 1985, 145,305309.
24
25
26
27
28
29
30
31
32
Chi-Hung Cheng et al.
Van Geelen, J.A., Schalm, S.W. and de Visser, E.M. et al. Immune response to hepatitis B vaccine in hemodialysis patients. Nephron 1987, 45, 216-218. Goudeau, A., Dubois, F. and Geslin, N. et al. Hepatitis B vaccine: simultaneous passive and active immunization. Indications in pre- and post-exposure. Dev. Biol. Stand. 1983, 54, 259-266. Quiroga, J.A., Castillo, I. and Porres, J.C. et al. Recombinant ;,-interferon as adjuvant to hepatitis B vaccine in hemodialysis patients. Hepatology 1990, 12, 661-663. Meuer, SC., Duman, H. and Meyer zum Buschenfelde, K.H. et a/. Low-dose interleukin-2 induces systemic immune responses against HBsAg in immunodeficient non-responders to hepatitis B vaccination. Lancet 1989, 1, 15-l 8. Ervo, R., Faletti, P. and Magni, S. et al. Evaluation of treatments for the vaccination against hepatitis B+ thymopentine. Nephron 1992, 61,371-372. Rawer, P., Willems, W.R. and Breidenbach, T. et al. Seroconversion rate, hepatitis B vaccination, hemodialysis and zinc supplementation. Kidney Int. 1987, 32, (suppl. 22), sl49-s152. Gerlich, W.H., Deepen, R. and Heermann, K.H. et al. Protective potential of hepatitis B virus antigens other than the S gene protein. Vaccine 1990, 8, (suppl.), s63-~68. Jungers, P., Chauveau, P. and Courouce, A.M. et al. Immunogenicity of the recombinant GenHevac B Pasteur vaccine against hepatitis B in chronic uremic patients. J. Infect. Dis. 1994, 169,399-402. Nissenson, A.R. Clinical Dialysis, 3rd edn. Appleton and Lange, E. Norwalk, CT, 1995, pp. 5899591 Massary, S.G. and Glassock. R.J. Text Book of Nephroology. 3rd edn. Williams and Wilkins, Baltimore, MD, 1995, pp. 383-l 389 Center for Disease Control. Update on hepatitis B prevention. Ann. Intern. Med. 1987, 107, 353-357 Guan, R., Tay, H.H. and Choong, H.L. et al. Hepatitis B vaccination in chronic renal failure patients undergoing hemodialysis: the immunogenicity of an increased dose of a recombinant DNA hepatitis vaccine. Ann. Acad. Med. 1990, 19,259-266. Bruguera, M., Rodicio, J.L. and Alcazar, J.M. et al. Effects of different dose levels and vaccination schedules on immune response to a recombinant DNA hepatitis B vaccine in hemodialysis patients. Vaccine 1990, 8, (suppl.), s47-s49. Buti, M., Viladomiu, L. and Jardi, R. et al. Long-term immunoqenicitv and efficacv of hepatitis B vaccine in hemodialysis patients. Am. J. Nephrol. 1992, 12, 144-147. Drachman. R.. Isacsohn. M.. Rudenskv. B. and Drukker, A. Vaccination against hepatitis B in children and adolescent patients on dialysis, Nephrol. Dial. Transplant 1989, 4, 372-374. Craven, D.E., Awden, Z.L. and Kundres, L.M. Nonresponsiveness to hepatitis B vaccine in health care workers. Results of revaccination and genetic typings. Arm. Intern. Med. 1986, 105,356-360. Kamel, M., Manialawi, M.E. and Miller, F.D. Recombinant hepatitis B vaccine immunogenicity in presence of hepatitis C virus seropositivity (letter). L&et i994., 343, 552 Navarro. J.F.. Teruel. J.L.. Mateos. M. and Ortuno, J. Hepatitis C virus infection decreases the effective antibody response to hepatitis B vaccine in hemodialysis patients. C/in. Nephrol. 1994, 41, 113-116. Fabrizi, F., Di Filippo, S. and Marcelli, D. et al. Recombinant hepatitis B vaccine use in chronic hemodialysis patients. Nephron 1996,72,536-543. Jilg, W., Schmidt, M. and Deinhardt, F. et al. Hepatitis B vaccination: how long does protection last?. Lancet 1984, 2, 458 Botarelli, P., Brunetto, M.R. and Minutello, M.A. et al. T-lymphocyte response to hepatitis C virus in different clinical courses of infection. Gastroenterology 1993, 104, 580-587. Liaw, Y.F., Lee, C.S. and Tsai, S.L. et a/. T-cell-mediated autologous hepatocytoxicity in patients with chronic hepatitis C virus infection. Hepafology 1995, 22, 1368-1373. Knudsen, F., Wantzin, P. and Rasmussen, K. et al. Hepatitis C in dialysis patients: relationship to blood transfusion, dialysis and liver disease. Kidney Int. 1993, 43, 1353-l 356.
Vaccine
1997 Volume 15 Number 12/13
1357
PII: SO264-410X(97)00037-6 ELSEVIER
Hepatitis B vaccine in hemodialysis patients with hepatitis C viral infection Chi-Hung Cheng*-i_, Chiu-Ching Chun-Yi Fan Chiang”, Mai-Szu
Huang*, Mei-Ling Leu”, Wu* and Ping-Chin Lai”
Patients on hemodialysis therapy are at a relatively high risk of exposure to hepatitis B virus (HBV) infection. The prevalence of hepatitis C virus (HCV) infection is even higher and was reported as 33.2% in Taiwan. Although the ej$cacy of hepatitis B vaccine was well documented, the vaccination schedule in hemodialysis patients is not clearly defined. And under such a high prevalence of HCV infection, little is known about the influence of HCV imposing on HBV vaccination. We studied 50 chronic hemodialysis patients who were serologic&& negative for the hepatitis B sueace antigen (HBsAg), the antibody to the hepatitis B sur$ace antigen (anti-HBs) and the antibody to the hepatitis B core antigen (anti-HBc); 26 of them were positive for the antibody to hepatitis C virus (anti-HCV) test. Recombinant hepatitis B vaccine (Engerix-B) 40 ,ug per dose was administered by the intramuscular route at deltoid region at 0, 1, 2, 6 and 12 months respectively to all the patients. Forty-six patients had completed the study. The effective seroconversion rate (serum anti-HBs titer > 10 mIU ml-‘) at 1 month after the final vaccine was 76.1% (35/46). The effective conversion rates of the antiHCV (+) group to the anti-HCV( -) were 75% versus 77.3% (P = 0.857). Geometric mean anti-HBs titers were 177.67 mIU ml-’ versus 189.28 mIU ml-’ (P = 0.867). 0 ur results showed that jive-dose injections of HBV vaccine do not present a superior outcome to the four-dose regimen comparing to published data. The status of positivity of anti-HCV do not pose an suboptimal effect on HBV vaccination of hemodialysis patients. 0 1997 Elsevier Science Ltd. Keywords:
hepatitis
B
vaccine, hepatitis C infection, hemodialysis patients. immunogenicity
The prevalence of hepatitis B and C viral infections remains a major problem in chronic hemodialysis patients throughout the world’. With the excellent efficacy of hepatitis B virus (HBV) vaccination in preventing this viral infection in healthy people, it has become a general consensus to provide HBV vaccine to susceptible hemodialysis patients2. However, the vaccine seroconversion rate of hemodialysis patients is much lower than that of healthy subjects”,4. To achieve an optimal response in such patients, higher dose and larger number of vaccine injections have been widely tried and obtained favorable results5.“. Despite all these trials, the vaccine schedule is not yet standardized to form a definite recommendation. Furthermore, under the high incidence of hepatitis C virus (HCV) infection in these patients, little is known if HCV could modify the effectiveness of HBV vaccine. The present study was undertaken to test the immune response with a higher dose (40 pg) and more frequent injections (five *Division of Nephrology, Chang Gung Memorial Hospital, 199, Tung-Hwa North Road, Taipei, Taiwan. tAuthor to whom all correspondence should be addressed. (Received 11 October 1996 revised version received 14 January 1997; accepted 14 January 1997)
doses). The influence also evaluated. MATERIALS
AND
of HCV on the HBV vaccine
was
METHODS
From April 1994 to August 1995, 50 chronic hemodialysis patients in our hemodialysis center were enrolled in the study. All subjects were tested serologically negative for hepatitis B surface antigen (HBsAg), the antibody to the hepatitis B surface antigen (anti-HBs) and the antibody to the hepatitis B core antigen (antiHBc) and had no previous HBV vaccination. Twentysix of them were positive for anti-HCV and 24 were negative. None of them had ever received renal transplant and no one was receiving immune modifying drugs. No one had evidence of liver decompensation (hypoalbuminemia, prolonged prothrombin time, jaundice, encephalopathy or ascites). Recombinant yeast-derived HBV vaccine (EngerixB, SmithKline Biologicals, Rixensart, Belgium) 40 pg was administered to all patients in each dose at deltoid region according to a 0, 1, 2, 6 and 12 months time schedule. Serum markers to hepatitis B were tested with radioimmunoassay (Ausria II, Corab, Abbott Labora-
Vaccine
1997 Volume
15 Number
12/13
1353
Hepatitis B vaccine in hemodialysis
patients with hepatitis C infection:
tories, Chicago, IL). HBsAg and anti-HBc were followed every 6 months. Anti-HBs titer was checked monthly and expressed in mIU ml ‘. Subjects with anti-HBs titer > 10 mIU ml ’ was considered effective seroconversion. Antibody to hepatitis C virus (antiHCV) was performed by a second generation of ELISA test (General Biologicals Co., Taiwan) and positive cases were confirmed by a second generation recombinant immunoblot assay test (Chiron RIBA HCV test system). Anti-HCV was followed every 6 months and seroconversive cases during the study would be excluded. Twenty-six patients with positive anti-HCV served as group 1 and was compared with 24 patients who were negative for anti-HCV as group 2. Serum alanine aminotransferasc (ALT) were checked monthly spectrophotometrically. In the antiHCV+ group, patients with elevated serum levels ( > 40 IU 1 ‘) of ALT for > 6 months during the study year were defined as chronic hepatitis. Seroconversion rates were analysed by x2. Anti-HBs titers (geometric mean titers; GMTs) wcrc compared using analysis of variance (ANOVA) repeated measures and the Wilcoxon rank sums test. A P value <0.05 was considered statistically significant.
Chi-Hung Cheng et al.
response after vaccination of both groups are depicted in Figure IFigure 2, respectively. The immune response expressed as GMT is shown in Figure 3. Anti-HBs titers rose after starting the vaccination in both groups, but soon declined after the third injection. The peak GMT was seen at 1 month after the fourth dose and dropped again in the vaccine free 6-month interval. A tifth hoostcr injection was given in month 12 to create the other peak, which did not reach the height of previous one. The GMTs of group 1 were consistently lower than those of group 2 throughout the course, which did not show statistical difference. The overall effective seroconversion rate (antiHBs> 1OmlU ml ‘) was 76.1% (35146) at I month after the final fifth-dose injections. The conversion rates wcrc 75% (18124) in group 1 and 77.3% (17122) different, in group 2, which was not statistically (P = 0.857). Figure 4. When the anti-HBs titer was set at 100 mIU ml ‘. the overall conversion rate and that of group I and group 2 were 43.5% (20146). 37.5% (9/24) and 50% (1 l/22), respectively. There was no Table 1
Comparison between the two groups
No. of patients Age (years) Sex M/F Body weight (kg) Etiology
RESULTS The two groups of patients existed no significant difference in age and body weight as shown in Table I. The mean duration of hemodialysis of anti-HCV+ group was 65.4k48.1 months (7-169months) at the beginning of study (till March 1994) and that of the antiHCV-group was 29.1 f25.3 months (5-132 months). This difference was significant (P = 0.01). All patients were tested negative for HBsAg, antiHBs and anti-HBc. The profiles of monthly immune
HD duration (months) Seroconversion rate (%) > 10 mlU ml-’ ~100mlUml ’
HCV+
HCVP
26 53.6k10.8 15/l 1 55.6k7.9 CGN 17TCC 1 DM 7 IGA N 1 65.4k48.1
24 50.4i18.7 13111 55.7*10.7 CGN 16 DM 8 29.1 +25.3
0.01
75 37.5
77.3 50
0.86 0.39
P
0.22 0.47
Characteristics of the HCV+ and HCVgroups: CGN, chronic glomerulonephritis; DM, diabetes mellitus; TCC, transitional cell carcinoma; l&A N, IgA nephropathy
Anti-HCV
+
4500 4000
UJ
2500
!z .+
2000
a
0
1
2
4
3
5
6
7
8
9
10
11
12
13
14
15
16
month Figure 1 Profile of monthly 12 months
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immune response
1997 Volume
of anti-HCV+
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patients depicted
with the anti-H&
titer (mlU ml-‘)
vaccined
at 0, 1, 2, 6 and
Hepatitis 6 vaccine in hemodialysis
patients with hepatitis C infection:
Anti-HVC
Chi-Hung Cheng et al.
-
6000 z w
5000
1000
0 2
0
4
6
8
10
12
14
16
month Figure 2 Profile of monthly immune response of anti-HCV12-months
patients depicted with the anti-HBs titer (mlU ml-‘) vaccined at 0, 1, 2, 6 and
these infections during treatments’. They also show poorer responsiveness in HBV vaccination due to impaired cellular and humoral immune responsesx. Several strategies have been tried to improve the immune response of vaccination to date including higher dose and larger number of vaccine administrations”.“‘, combined hepatitis B immune globulin injecinterleukin’j, interferon usage”, tion”, adjuvant thymopentin14 or zincI supplementations. A new form of recombinant vaccine (GenHevac B) which contains pre-sl and s2 domains in addition to the s antigen of HBV has also obtained a favorable outcome’“.“. Of all the above mentioned, higher dose and larger number of vaccine administrations have been persistently proved effective and widely suggested’x,‘“. However, the optima1 way of vaccination is still not well defined. While doubling the vaccine dosage has become the and timing of general consensusy~“‘~‘5~‘y, the number
difference between the two groups either (P = 0.392). The effective conversion rate at 1 month after the fourth injection was 64% (32/50), which was not significantly different to the final five-dose conversion rate (P = 0.197). In the anti-HCV+ group, 24 patients completed the study. Seven of them had elevated ALT for > 6 months during the study year. When compared with the remaining 17 patients, the effective seroconversion rates were 71.4% (five out of seven) versus 76.4% (13/17), which did not show significant difference (P = 0.79). significant
DISCUSSION Chronic hepatitis
hemodialysis viral infections
patients because
are susceptible of high prevalence
to of
Anti-HBs titers mlU/ml 600
o,,
,, 1
Vaccination Figure 3
2
1‘ 7 t
,, 3
4
,, 5
6
,, 7
t
8
,, 9
10 11
,, 12 13
, 14
, 15
16
month
T
Monthly changes of anti-HBs GMTs of both groups
Vaccine 1997 Volume 15 Number 12/13
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Hepatitis 6 vaccine in hemodialysis
patients with hepatitis C infection:
Effective seroconversion
Chi-Hung Cheng et al.
rate %
> 10 mlU/ml
month Vaccination Figure 4 Changes of effective seroconversion rates of all patients seroconversion was defined as anti-HBs > 10 mlU ml ’
and group
vaccine injections remain unsettled. Using four-dose vaccine injections seemed to produce better response rates than that obtained with three-dose injections recommended by the Center for Disease Control”.“““, but the seroconversion rates were still low-around 69-79%“,“.“, which were far inferior to that of healthy adults. Limited data has been concerned with five-dose injections. Drachman rt al. reported a 85.6%’ seroconversion rate with S-monthly consecutive vaccine injcctions2”, while Craven and Pasko casted doubt on the effectiveness of booster shots to primary nonrespondersx.‘5. Our study showed seroconversion rates of 64% at 1 month after the fourth injection and 76.1% in completing the vaccination course. These data did not demonstrate a better response with five-dose inoculation, which were in accordance with the observations of Craven and Pasko. The duration of antibody existence with effective protection was considered to correlate with the peak antibody titer after vaccination. In our study the antibody titers after the fourth administration declined more rapidly than that after the fifth administration (Figure 3). From this result it may suggest that five-dose injections be more effective than four-dose injections in terms of adequate antibody persistence. A fifth dose booster in the month 12 did create the other peak of antibody titer in both groups: however, the peaks were paradoxically lower than those obtained after the third and fourth injections in group 2. This phenomenon may tell us that the immune response was stronger with four intensive inoculations in a 6-month period (months l-6) than that with only two inoculations in a similar interval (months 6-12). But it may also partially be influenced by the patients with good immune response who dropped out from the study near the end. With five injections, our conversion rate was inferior to that of Drachman et al. (76.1% versus 85.6%). It is possible that this difference could be related to a different timing of vaccine administration. It is likely that five monthly consecutive inoculations of HBV vaccine could give a higher immune response compared to five doses over a l-year period. It is probable that the administration of five doses over a 12-month period could yield a higher persistence of anti-HBs antibody over time (i.e. 2 or 3 years after the completion of the vaccination program) compared to five monthly consecutive vaccine inoculations.
Could HCV infection affect the result of HBV vaccination? Kamel et al. reported that the presence of anti-HCV did not affect the immunogenicity to HBV vaccine in healthy adults”‘. As to hemodialysis patients, Navarro et al. obtained results suggesting the possibility of HC,V in modifying the effectiveness of HBV vaccine- , while Fabrizi et al. found that the immunogcnicity to Engerix-B was not influenced by the presence of anti-HCV”. Navarro et al. noted that HCV infected patients had a significantly lower seroconversion rate when the comparison antibody titer (GMT) was set at 100 mIU ml- . This phenomenon was not seen at the cut-off value of 10 mIU ml-‘. Our data presented a similar trend, that is, lower effective conversion rates in HCV infected patients, but no significant difference in both cut-off values was seen, Table I. In Fabrizi’s study, the protocol was different. They vaccinated all study subjects and obtained two groups of patients classified as responders (anti-HBs > 10 mIU ml ‘) and nonresponders (anti-HBs < 10 mIU ml-‘). Their results showed no ‘significant difference in anti-HCV positivity between the two groups. They concluded that the immune response to HBV vaccine was not affected by existence of antiHCV. Our finding seemed to support this statement in a different way of analysis. Concerning the way that HCV might influence immune response to HBV vaccination, two prospectives should be considered. First, the antibody response to the inoculation is a T-dependent B cell stimulation and is genetically linked to MHC class II antigens”. Hepatitis C viral infection has been proved to induce a series of immune response involving activation of T-lymphocyte and B-cell via MHC I and MHC II to mediate hepatotoxicity”“,“‘. These expressions immune reactions might be influential on the antibody production in HBV vaccination. From the result of our study, this phenomenon was not demonstrated. Second, HCV infection can evolve to chronic hepatitis and over time to liver cirrhosis or hepatocellular carcinoma. This is a putative negative effect on the immune system of dialysis patients. Concerning the severity of liver disease caused by HCV infection, we analysed antiHCV+ patients. No patient in this group had evidence of liver decompensation and the result showed no difference in the effective seroconversion rate between those with chronic hepatitis and those without. The
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anti-HCV+
and group
anti-HCV-
patients.
Positive
Hepatitis B vaccine in hemodialysis result may
seemed merely
against reflect
the
above fact
putative that
the
recognition duration
but HCV to cause
patients with hepatitis C infection: 10
of
infection in our patients was not long enough disease to affect the efficacy of HBV vaccination. On the other hand, in our study the duration of hemodialysis of the anti-HCV+ group was significantly longer than that of the anti-HCVgroup. This was consistent with the fact that the longer the patients receive hemodialysis therapy the more chance they get to be infected by HCV”. Fabrizi rt al. also noted that the responders had a significantly shorter duration of hemodialysis treatment compared to nonresponders. From this, it may suggest that in our study the persistent lower GMTs in the anti-HCV+ group be a result of the effect of a longer duration of hemodialysis treatment rather than the effect of the presence of anti-HCV. In conclusion, from our study the five-dose injections of the HBV vaccine do not increase the response rate compared to that of a four-dose regimen. We would suggest a four-dose vaccination for all HBV vulnerable hemodialysis patients as standard. Booster injections are mostly needed because of the fact that the antibody titer declines rapidly and the timing can be individualized. HCV infection did not influence the effect of HBV vaccination in our study. The HBV vaccination schedule should not be different between patients in regard to anti-HCV positivity.
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20 21
ACKNOWLEDGEMENTS We would like to acknowledge all patients participating in this study and Associate Professor Sing-Kai Lo in the statistical analysis. We also thank SmithKline Beecham Pharmaceuticals Taiwan Ltd for their vaccine support.
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REFERENCES 1
2
3
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5
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9
Szmuness, W., Prince, A.M. and Grady, G.F. et al. Hepatitis B infection: a point prevalence study in 15 US hemodialysis centers. J. Am. Med. Assoc. 1974, 227, 901-906. Hardy, N.M.. Sandroni, S. and Danielson, S. et al. Antibody to hepatitis C virus increases with time on hemodialysis. C/in. Nephrol. 1992, 38, 44-48. Crosnier, J., Jungers, P. and Courouce, A.M. et al. Randomized placebo-controlled trial of hepatitis B surface antigen vaccine in French hemodialysis units II hemodialysis patients. Lancer 1981,1,797-800. Stevens, C., Alter, H.J. and Taylor, P.E. et al. Hepatitis B vaccine in patients receiving hemodialysis. N. Engl. J. Med. 1984, 311, 4966501. Benhamou, E., Courouce, A.M. and Jungers, P. et al. Hepatitis B vaccine: randomized trial of immunogenicity in hemodialvsis oatients. C/in. NeDhrol. 1984, 21, 143-l 47. El-Reshaib, K., Al-M&i, S., Johny, K.V. and- Sugathan, T.N. Comparison of two immunization schedules with recombinant hepatitis B vaccine and natural immunity acquired by hepatitis B infection in dialysis patients. Vaccine 1994, 12, 223-228. Boulton-Jones, J.M., Vick, Ft. and Cameron, J.S. et al. Immune response in uremia. C/in. Nephrol. 1973, 1, 351-360. Pasko, M.T., Pharm, D., Bartholomew, W.R., Beam, T.R., Amsterdam, D. and Cunning, E.E. Long term evaluation of hepatitis B vaccine (Heptavax-B) in hemodialysis patients. Am. J. Kidney Dis. 1988, 11,326-331. NicoLelie, R., Reesink, H.W. and de Jong-Von Manen, S.T. et a/. Immune response to a heat-inactivated hepatitis B vaccine in patients undergoing hemodialysis. Arch. Intern. Med. 1985, 145,305309.
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Van Geelen, J.A., Schalm, S.W. and de Visser, E.M. et al. Immune response to hepatitis B vaccine in hemodialysis patients. Nephron 1987, 45, 216-218. Goudeau, A., Dubois, F. and Geslin, N. et al. Hepatitis B vaccine: simultaneous passive and active immunization. Indications in pre- and post-exposure. Dev. Biol. Stand. 1983, 54, 259-266. Quiroga, J.A., Castillo, I. and Porres, J.C. et al. Recombinant ;,-interferon as adjuvant to hepatitis B vaccine in hemodialysis patients. Hepatology 1990, 12, 661-663. Meuer, SC., Duman, H. and Meyer zum Buschenfelde, K.H. et a/. Low-dose interleukin-2 induces systemic immune responses against HBsAg in immunodeficient non-responders to hepatitis B vaccination. Lancet 1989, 1, 15-l 8. Ervo, R., Faletti, P. and Magni, S. et al. Evaluation of treatments for the vaccination against hepatitis B+ thymopentine. Nephron 1992, 61,371-372. Rawer, P., Willems, W.R. and Breidenbach, T. et al. Seroconversion rate, hepatitis B vaccination, hemodialysis and zinc supplementation. Kidney Int. 1987, 32, (suppl. 22), sl49-s152. Gerlich, W.H., Deepen, R. and Heermann, K.H. et al. Protective potential of hepatitis B virus antigens other than the S gene protein. Vaccine 1990, 8, (suppl.), s63-~68. Jungers, P., Chauveau, P. and Courouce, A.M. et al. Immunogenicity of the recombinant GenHevac B Pasteur vaccine against hepatitis B in chronic uremic patients. J. Infect. Dis. 1994, 169,399-402. Nissenson, A.R. Clinical Dialysis, 3rd edn. Appleton and Lange, E. Norwalk, CT, 1995, pp. 5899591 Massary, S.G. and Glassock. R.J. Text Book of Nephroology. 3rd edn. Williams and Wilkins, Baltimore, MD, 1995, pp. 383-l 389 Center for Disease Control. Update on hepatitis B prevention. Ann. Intern. Med. 1987, 107, 353-357 Guan, R., Tay, H.H. and Choong, H.L. et al. Hepatitis B vaccination in chronic renal failure patients undergoing hemodialysis: the immunogenicity of an increased dose of a recombinant DNA hepatitis vaccine. Ann. Acad. Med. 1990, 19,259-266. Bruguera, M., Rodicio, J.L. and Alcazar, J.M. et al. Effects of different dose levels and vaccination schedules on immune response to a recombinant DNA hepatitis B vaccine in hemodialysis patients. Vaccine 1990, 8, (suppl.), s47-s49. Buti, M., Viladomiu, L. and Jardi, R. et al. Long-term immunoqenicitv and efficacv of hepatitis B vaccine in hemodialysis patients. Am. J. Nephrol. 1992, 12, 144-147. Drachman. R.. Isacsohn. M.. Rudenskv. B. and Drukker, A. Vaccination against hepatitis B in children and adolescent patients on dialysis, Nephrol. Dial. Transplant 1989, 4, 372-374. Craven, D.E., Awden, Z.L. and Kundres, L.M. Nonresponsiveness to hepatitis B vaccine in health care workers. Results of revaccination and genetic typings. Arm. Intern. Med. 1986, 105,356-360. Kamel, M., Manialawi, M.E. and Miller, F.D. Recombinant hepatitis B vaccine immunogenicity in presence of hepatitis C virus seropositivity (letter). L&et i994., 343, 552 Navarro. J.F.. Teruel. J.L.. Mateos. M. and Ortuno, J. Hepatitis C virus infection decreases the effective antibody response to hepatitis B vaccine in hemodialysis patients. C/in. Nephrol. 1994, 41, 113-116. Fabrizi, F., Di Filippo, S. and Marcelli, D. et al. Recombinant hepatitis B vaccine use in chronic hemodialysis patients. Nephron 1996,72,536-543. Jilg, W., Schmidt, M. and Deinhardt, F. et al. Hepatitis B vaccination: how long does protection last?. Lancet 1984, 2, 458 Botarelli, P., Brunetto, M.R. and Minutello, M.A. et al. T-lymphocyte response to hepatitis C virus in different clinical courses of infection. Gastroenterology 1993, 104, 580-587. Liaw, Y.F., Lee, C.S. and Tsai, S.L. et a/. T-cell-mediated autologous hepatocytoxicity in patients with chronic hepatitis C virus infection. Hepafology 1995, 22, 1368-1373. Knudsen, F., Wantzin, P. and Rasmussen, K. et al. Hepatitis C in dialysis patients: relationship to blood transfusion, dialysis and liver disease. Kidney Int. 1993, 43, 1353-l 356.
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