Immune response to hepatitis B vaccine in parenteral drug abusers

Immune response to hepatitis B vaccine in parenteral drug abusers J.M. Rodrigo *§, M.A. Serra*, L. Aparisi*, A. Escudero*, M.S. Gilabert*, F. Garcia*, R. Gonzalez*, J.A. del Olmo*, A.H. Wassel*, A. Artero t and J.M. Nogueira ~ Responsiveness was assessed to a programme of vaccination of hepatitis B vaccine in a cohort of 197 intravenous drug addicts (mean age, 23.7 years) and their antibody response was compared with that of 271 healthy controls (mean age, 24.2 years). All participants were seronegative for hepatitis B surface antigen (HBsAg) and antibody to HBsAg (anti-HBs). The vaccination schedule consisted of three intramuscular injections (deltoid area) at months O, 1 and 2. Although 70% of parenteral drug abusers received the three doses of vaccination, only 43.6% were evaluable for immune response. Fifty-eight per cent of heroin addicts and80% of controls had evidence of anti-HBs seroconversion at i month after vaccination (Z 2 = 15.52, p < 0.001). Geometric mean antibody titres were also significantly higher in controls (69.1 IU l- 1; confidence interval 95%, 56.83 and 84.04) than in parenteral drug abusers (18.2 IU l-1; confidence interval 95%, 12.85 and 25.73) ( F = 20.951, p < 0.0001). The anti-HBs response was not influenced by coexistent anti-HBc, H C V antibody or H I V antibody seropositivity. Keywords:Hepatitis B; vaccine; intravenous drug addicts

INTRODUCTION Hepatitis B virus (HBV) infection has been a major health problem among intravenous drug addicts and is potentially preventable by vaccination 1. Although hepatitis B vaccine has been shown to be safe and immunogenic for certain high-risk groups, the response of intravenous drug addicts to immunization has received limited attention 2-4. A number of factors including failure to complete vaccination, combined immunosuppressive effect of polydrug abuse, and high prevalence of seropositivity to HIV may account for a lower immune response to hepatitis B vaccine than that observed in healthy subjects, and may interfere with the implementation of widespread vaccination programmes in this population. We examined vaccine responsiveness in a cohort of intravenous drug addicts and compared their antibody response with that of healthy controls. MATERIALS AND METHODS A group of 197 intravenous heroin addicts (mean age,

*Liver Unit, tSection of Drug Addiction, and tDivision of Microbiology, Hospital Clinico Universitario, Valencia, Spain. §To whom correspondence should be addressed at: Servicio de Aparato Digestivo, Hospital Clinico Universitario, Avda. Blasco Ib~fiez 17, 46010 Valencia, Spain. (Received 16 October 1991; revised 25 March 1992; accepted 30 March 1992) 0264-410)(/92/110798-04 © 1992 Butterworth-Heinemann Ltd

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23.7 years) seronegative for hepatitis B surface antigen (HBsAg) and antibody to HBsAg (anti-HBs) were eligible for the study. Subjects were recruited from among patients attending the Section of Drug Addiction of our Hospital, and were enrolled from January 1989 to December 1990. A group of family members (mean age, 24.2 years) of chronic HBV carriers served as controls after they provided informed consent. All controls demonstrated negative results for anti-HBs and HBsAg before vaccination. Three vaccinations were administered intramuscularly into the deltoid area on each subject: one upon admission into the study (time 0), the second at 1 month, and the third at 2 months. Each vaccination consisted of 20/~g ( l m l ) recombinant hepatitis B vaccine (Engerix B; Smith, Kline and French). Blood was collected from each subject immediately before immunization and 1 month after the third dose of vaccination for antibody measurements. Hepatitis B surface (HBs) antibody and hepatitis B core (HBc) antibody were measured by enzyme immunoass~y (Ausab and Corzyme respectively, Abbot Laboratories, North Chicago, IL). The assay for anti-HBs was used both quantitatively, to measure the antibody response by comparing suitably diluted test serum samples with a calibration curve of World Health Organization standards for hepatitis B surface antibody 5 in the range 5-120 IU1-1, and qualitatively a s a screening test ( > 10 IU 1-1 ). All participants were screened for anti-HIV- 1 (enzyme immunoassay, Abbott Laboratories, North Chicago, IL, confirmed by Western blot) and

Hepatitis B vaccine and drug addicts: J.M. Rodrigo

anti-HCV screening test (Ortho Diagnostic System and Johnson and Johnson Company, Ravitan, N J). Statistical analyses were performed on a personal computer using the Statgraphics program. Results were expressed as geometric means and 95% confidence limits of logarithmic distribution of data. Analysis of variance was applied for comparison of means. Qualitative variables were compared with the X2 test. A p value less than 0.05 was accepted as significant.

Table 2 Seroconversion rates (anti-HBs > 10 lU I - ' ) at 1 month after vaccination in 86 heroin addicts and 271 controls: influence of anti-HBc, anti-HCV and ALT levels

Positive

Positive

A total of 197 intravenous heroin addicts were enrolled. Of these, 59 were excluded because of failure to maintain the vaccination schedule. Of the remaining 138 (70%) who received the three doses of vaccination, 52 defaulted at the control visit for seroconversion. The study population consisted of 86 heroin addicts, 68 men and 18 women with a mean age of 23.8 and 22.9 years, respectively. The control group consisted of 271 healthy young adults, 114 men and 157 women with a mean age of 25.2 and 23.5 years, respectively. Prevaccination biochemical and serological data are presented in Table 1. Anti-HBc was the only HBV marker in 49% of drug addicts and 8.5% of controls. Antibodies to hepatitis C virus and increased ALT levels were observed in almost 75% of heroin addicts. Anti-HIV-1 seropositivity was also frequent (43%). No cases of HIV-1 positivity or abnormal transaminase levels were found among healthy controls. All subjects denied clinical symptoms of hepatitis. All participants tolerated vaccination well, without significant side effects. Fifty (58%) out of 86 heroin addicts and 217 (80%) out of 271 controls had evidence of anti-HBs seroconversion at 1 month after vaccination. The difference was statistically significant (g 2 = 15.52, p < 0.001 ). Fifty-five per cent of male heroin addicts had evidence ofanti-HBs seroconversion compared with 74% of the men of the control group, this difference was statistically significant. Seventy per cent of female drug abusers showed evidence of anti-HBs seroconversion, while in the female control group, the figure was 83%. This difference was statistically significant. Geometric mean antibody titres were also significantly higher in controls (69.1 I U I - 1 ; confidence interval 95%, 56.83 and 84.04) than in parenteral drug abusers (18.2 IU 1-1; confidence interval 95%, 12.85 and 25.73) ( F = 20.951, p < 0.0001 ). As shown in Table2, there were no significant differences between seroconversion rate and the level of response in heroin addicts who were positive for anti-HBc, heigatitis C virus. In addition, control subjects

Table 1

Prevaccination biochemical and serological data in 86 heroin addicts and 271 controls Marker

Drug addicts ( % )

Controls ( % )

Anti-HBc alone Anti-HCV

42 63 61 37

23 (8.5)

Raised ALT levels Anti-HIV-1

(48.8) (73.2) (70.9) (43)

None None

Anti-HBc: hepatitis B core antibody; anti-HCV: antibodies to hepatitis C virus; ALT: alanine aminotransferase; anti-HIV-l: human immunodeficiency viral antibody

Drug addicts

Controls

(anti-HBs + )

(anti-HBs + )

Total

No.

%

Total

No.

%

42 44

25 25

56.8 ~ 59.5b

23 248

18 199

78.5" 80.2 b

63 23

38 12

60.3" 52.2~

61 25

36 13

59.0 a 52.0 ~

Anti-HBc Negative Anti-HCV

RESULTS

e t al.

Negative ALT levels Raised Normal

aversus b, p > 0.05; anti-HBc: hepatitis B core antibody; anti-HCV: antibodies to hepatitis C virus; ALT: alanine aminotransferase

Table 3 Seroconversion rates (anti-HBs > 10 IU 1-1) at 1 month after vaccination in 86 heroin addicts and 271 controls: influence of HIV Drug addicts ( % )

Controls ( % )

All Anti-HIV + Anti-HIV-

58" 54 c 61 ~

80"

Males

55' 53c 57 ~

74"

70X 50c 77 ~

83 y

Anti-HIV + Anti-HIV--

Females Anti-HIV -tAnti-HIV--

• versus b: p < 0.05; ° versus ~ and x versus Y: p > 0.05

positive for anti-HBc did not show a statistically significant difference in immune response to vaccination than controls negative for anti-HBc. As shown in Table3, there were no significant differences between seroconversion rate and the level of response in heroin addicts who were positive for HIV antibody compared with those who were negative. DISCUSSION In our study, 70% of parenteral drug abusers received the three doses of vaccination but only 43.6% were evaluable for immune response. Although hepatitis B immunization of susceptible intravenous drug abusers should remain a priority, the social characteristics of this patient population represent a permanent obstacle to be overcome in widespread HBV vaccination programmes. The vaccination schedule of three injections 1 month apart has been shown to be as useful in terms of early seroconversion as vaccination at 0, 1 and 6 months in healthy young adults s. In addition, the timing of the third dose at months 2 or 6 would have a crucial influence on the vaccination compliance in the case of intravenous drug addicts. Our seropositivity rate of 58% is lower than 85% and 75% of anti-HBs-positive addicts noted by Andre z and Rumi et al. 6, respectively, with three vaccinations given at 0, 1 and 6 months. Concentrations of antibodies to HBsAg after the third injection are dependent on the interval between the second and the

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Hepatitis B vaccine a n d d r u g addicts: J.M. R o d r i g o et al.

third dose s. Therefore, vaccination at 0, 1 and 12 months seems clearly preferable to the regimen of vaccination at 0, 1 and 6 months, at least in young healthy adults where a high seroconversion rate and protective antibody levels are achieved with the first two doses of vaccine 5. However, as compliance decreases with time, a vaccination schedule of 0, 1 and 2 months appears justified for parenteral drug abusers. We also found that seroconversion rates and levels of antibody response were significantly lower in drug abusers than in controls. Although impaired responsiveness of HIV-seropositive homosexual men to hepatitis B vaccine has been reported by other investigators 7-9, the responsiveness in our population of heroin addicts was not influenced by coexistent HIV infection. The discrepancy between our results and those of authors who found suboptimal response to hepatitis B vaccination in HIV-seropositive patients 7-9 could be due to differences in the sample size of the populations studied. There is little information available about the anti-HBs responses in individuals with isolated anti-HBc 1°,11. The presence of anti-HBc without anti-HBs, HBsAg or IgM anti-HBc reactivity may be associated with a chronic carrier state in which HBsAg is not detectable 12 or remote infection with loss of measurable anti-HBs. In this study, the anti-HBs response to vaccination in drug addicts and control individuals with isolated anti-HBc was not significantly different when compared with those individuals with negative anti-HBc serum. According to Draelos and colleagues 13 the pattern of anti-HBs responsiveness observed in those subjects with isolated high-titre anti-HBc was intermediate between seronegative and anti-HBs-positive groups and may indicate a state of waning immunity after natural infection. Hepatitis B vaccination with follow-up anti-HBs testing should be done for those patients with isolated, high-titre anti-HBc to help exclude chronic infection and boost protective immunity. Non-responsiveness to hepatitis B vaccine has also been attributed to genetic markers 14. The findings of Craven and co-workers 15 suggest that genes present in the major histocompatibility complex may modulate the immune response to hepatitis B vaccine and that health care personnel who have low antibody levels or no response to an initial course of vaccination may benefit

Table 4 Geometric mean titres (GMT) and 95% confidence intervals (CI) (Anti-HBs, IU 1-1) to hepatitis B vaccine at 1 month after vaccination in 86 heroin addicts and 271 controls Heroin addicts

Anti-HBc Positive Negative Anti-HCV Positive Negative Anti-HIV-1 Positive Negative

Control subjects

GMT

95% CI

GMT

95% CI

17.63a 18.15b

10.73-28.97 11.53-30.43

58.49 a 70.18 ~

29.72-115.12 57.11-86.26

20.11" 13.09 b

8.72-30.71 6.71-25.55

12.41" 24.25b

7.35-20.96 15.39-38.23

a versus ~: p > 0.05; total numbers on Table 2; anti-HBc: hepatitis B core antibody; anti-HCV: antibodies to hepatitis C virus; anti-HIV-l: human immunodeficiency viral antibody

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from revaccination. However, this explanation for non-responsiveness does not appear to be a factor in our study. Protein-calorie malnutrition, polydrug abuse, and underlying debilitating disorders commonly occurring in intravenous heroin addicts can induce immunological alterations. Therefore, an altered response to vaccination in this patient population is not surprising. Alcoholics, especially those with liver injury, have been reported to have a markedly impaired immune response after hepatitis B vaccine 16. In our study, however, abnormal alanine transferase levels did not correlate with impaired antibody response and the positivity of anti-HCV antibody does not modify the response to vaccination. On the other hand, poor antibody responses to influenza vaccines among HIV-infected subjects have also been observed 17. In this study we have addressed the question of the immune response to hepatitis B vaccine in intravenous drug abusers. For those immunosuppressed individuals at high risk, whose seroconversion rates and maximal anti-HBs levels are usually lower, the schedule with three initial doses at months 0, 1 and 2 may be recommended to achieve seroconversion and higher antibody titres as early as possible. A fourth dose given at month 12 leads to a high anti-HBs concentration guaranteeing its long-lasting persistence. Additional efforts towards more timely screening and immunization of addicts are needed.

ACKNOWLEDGEMENTS The authors wish to thank Marta Pulido for editorial assistance and copy editing. This project was supported by 'Oficina del Comisionado para la lucha contra la droga', Conselleria de Sanitat i Consum. Generalitat Valenciana.

REFERENCES 1 Centers for Disease Control. Immunization Practices Advisory Committee: update on hepatitis B prevention. Morb. Mort. Week. Rep. 1987, 36, 363-370 2 Andre, F.E. Summary of safety and efficacy data on a yeast derived hepatitis B vaccine. Am. J. Med. 1989, 87(Suppl 3A), 14S-20S 3 Kunches, L.M., Craven, D.E. and Werner, B.G. Seroprevalence of hepatitis B virus and delta agent in parenteral drug abusers. Immunogenicity of hepatitis B vaccine. Am. J. Med. 1986, 81,591-595 4 Rumi, M.G., Bortolini, M., Romeo, R. et al. Low response rates to hepatitis B vaccine in former drug addicts. Hepatology 1988, 8,1319 5 Jilg, W., Schmidt, M. and Deinhardt, F. Vaccination against hepatitis B: comparison of three different vaccination schedules. J. Infect. Dis. 1989, 160, 766-769 6 Rumi, M.G., Bortolini, M., Romero, R. et al. Low response rates to hepatitis B vaccine in former drug addicts. Hepatology 1988, 8,1319 7 Collier, A.C., Corey, L., Murphy, V.L. and Handsfield, H.H. Antibody to human immunodeficiency virus (HIV) and suboptimal response to hepatitis B vaccination. Ann. Intern. Med. 1988, 109, 101-105 8 Carne, C.A., Weller, I.V.D., WaRe, J. et al. Impaired responsiveness of homosexual men with HIV antibodies to plasma derived hepatitis B vaccine. Br. Med. J. 1987, 294, 866-868 9 Goilav, C. and Piot, P. Vaccination against Hepatitis B in homosexual men. Am. J. Med. 1989, 87(Suppl 3A), 21S-25S 10 Wu, J.A. and Tam, K.M. Immune response to hepatitis B vaccine in subjects positive for serum hepatitis B core antibody alone. J. Formosan Med. Assoc. 1988, 87, 944-946. 11 Lok, A.S., Lai, C.H.L. and Wu, P.C. Prevalence of isolated antibody to hepatitis B core antigen in an area endemic for hepatitis B virus infection: implication in hepatitis B vaccination program. Hepatology 1988, 8, 766-770

Hepatitis B vaccine a n d drug addicts: J.M. Rodrigo et al. 12 Takahashi, H., Liang, T.J., Zeniya, M. eta/. Low level hepatitis B virus related infection as a cause of hepatitis B vaccine nonresponsiveness. Hepatology 1989, 10, 697 13 Draelos, M., Morgan, T., Schifman, R.B. and Sampliner, R.E. Significance of isolated antibody to hepatitis B core antigen determined by immune response to vaccination. J. Am. Med. Assoc. 1987, 258, 1193-1198 14 Alper, C.A., Kruskall, M.S., Marcus-Bagley, D. et el. Genetic prediction of nonresponse to hepatitis B vaccine. N. Engl. J. Med. 1989, 321,708-712

15 16 17

Craven, D.E., Awdeh, Z.L., Kunches, L.M. et al. Nonmsponsivcncss to hepatitis B vaccine in health care workers. Results of revaccination and genetic typings. Ann. Intern. Med. 1986, 105, 356-360 Mendenhall, C., Roselle, G.A., Lybecker, L.A. et el. Hepatitis B vaccination. Response of alcoholics with and without liver injury. Dig. Dis. Sci. 1988, 33, 263-269 Nelson, K.E., Clements, M.L., Miotti, P., Cohn, S. and Polk, F. The influence of human immunodeficiency virus (HIV)infection of antibody responses to influenza vaccines. Ann. Intern. Med. 1988, 105, 383-388

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