JID 1992; 165 (April)

Correspondence

Richard M. Rose, Jorge Rey-Martinez, Christine Croteau, Ronald C. Silvestri, Kathleen Haley, Jean DePamphilis, and George R. Siber Division of Pulmonary and Critical Care Medicine. New England Deaconess Hospital, and Division of Infectious Disease. Dana Farber Cancer Institute, and Harvard Medical School. Boston. Massachusetts; Hoffman-Lakoche. Nutley. New Jersev References

Is Nonresponsiveness to Hepatitis B Vaccine Due to Latent Hepatitis B Virus Infection? Colleagues-It has been reported that ~ 10%of volunteers who received vaccines for hepatitis B failed to produce antibodies to hepatitis B virus (HBV) surface antigen (anti-HBsAg) [I]. This type of nonresponsiveness was thought to be associated with certain immunogenetic status. For example. Watanabe et al. [2) reported that the nonresponders to hepatitis B vaccines had a human leukocyte antigen (HLA)-linked immune suppression gene that is in strong linkage disequilibrium with the HLABw54-DR4-DRw53 haplotype and may control the nonresponsiveness to HBsAg through HBsAg-specific suppressor T cells. Alper et al. [3) claimed that the nonresponsiveness was due to the absence of a dominant immune response gene that controls the usual response to HBsAg. However, Chiou et al. [4] reported that the nonresponsiveness to hepatitis B vaccine was mainly due to a defect of the B cell repertoire at the early stage and the existence of HBsAg-specific suppressor T cells at the late stage, but the reason is unclear. Recently. we selected two groups of healthy volunteers from China for hepatitis B vaccination. In group A. 115 males and 99 females aged I 1-60 years received one hepatitis B vaccine (Merck Sharp & Dohme, West Point, PA). In group B, 96 men aged 18-44 years received a different hepatitis B vaccine (National Vaccine and Serum Institute. Beijing) . All subjects in both groups were HBsAg-negative at screening before vaccination. Each volunteer was vaccinated with three 10-/oLg doses of vaccine at 0, I, and 6 months. respectively. Blood was sampled I month after the third immunization . Anti-HBsAg and other serum HBV markers. such as HBsAg and antibodies to HBV

Reprints or correspondence: Dr. Shibo Jiang. Lahoratory of Biochemical Virology . New York Blood Center. 310 E. 67th si., New York . NY 10021. The Journal of Infectious Diseases 1992;165:777-8 © 1992 by The University ofChieago. All rights reserved. 0022-1899/92/6504-0035$01.00

4. Collier AC, Corey L, Murphy VI. , Handsfield HH . Antibody to human immunodeficiency virus (HIV) a nd suboptimal response to hepatitis B vaccination. Ann Intern Med 1988;109:101-5. 5. Hibberd PL. Ruhin RH . Immunization strategies for the immunocompromised host: th e need for im m unoa dj uva nts. Ann Intern Med 1989;110:955-6. 6. Callard RE . Smith SH, Shields JG , Levinsky RJ . T cell help in human antigen-specific antibody responses can be replaced hy interleukin 2. Eur J Immunol 1986; 16: 1037-42. 7. Good MF. Pombo D, Lunde MN, et al. Recombinant human IL-2 overcomes genetic nonresponsiveness to malaria spo rozoite peptides. J Immunol 1988; 141 :972-7. 8. Kawamura H. Rosenberg SA, Berzofsky HA. Immunization with antigen and interleukin-2 in vivo ov ercomes Ir gene low respon siveness. J Exp Med 1985;162:381-6. 9. Meuer SC, Dumann H. Meyer Zum Busch enflcdc KH , Kohler H. Lowdose interleukin-2 induces syst emic immune responses aga inst HBsAg in immunodeficient non-responders to hepatitis B vaccination . Lancet 1989;1:15-7.

core antigen . were detected with RIA as described before [5]. The results showed that 6.4% of the vaccinees in group A and 12.5% in group B failed to produced anti-HBsAg after the vaccination. in agreement with the findings reported previously [I]. However, it is interesting that 61 .5% of the nonresponders in group A and 66.7% in group B were positive for serum HBV DNA. detected by a highly sensitive technique of polymerase chain reaction as previously described [5], while none of the responders had detectable serum HBV DNA (figure I). Since all of the HBV DNA-positive nonresponders were negative for HBsAg and had normal transaminase levels , they should be considered to have latent HBV infection . Therefore, these results

GROUP A

38,5%

"

HIlV DNA-

Nql~~ e s pond er s

61.5% IIIlV DNA+

"

.,

GROUP B

"

33.3% IIIlV DNA-

12. 5 % Res po n d e r s

N..o n res po n de rs

'.

66.7% IIBV DNA+

Fi/:ure 1. Serum hepatitis B virus (HBV) DNA in responders and nonrespo nde rs to hepatitis B vaccines were detected by polymerase chain reaction as described befo re [5). No respo nders in groups A and B had detectable serum HBV DNA (data not shown). while more than halfofnonresponders were positive for serum HBV DNA (black bar s).

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I. Leads from the Morbidity and Mortality Weekly Report. Recommendations o f the immunization practices advi sory committee update on hep atitis B prevention . JAMA 1987;258:437-49. 2. Nowicki MJ . Tong MJ , Bohman RE . Alterations in the immune response of non responders to the hepatitis B vaccine. J Infect Dis 1985; 152: 1245-8. 3. McLean AA , Hilleman MR . McAl eer WJ. Buynak EB. Summ ary of worldwide clini cal experience with H-B-Vax (B. MSD). Br Soc Study Infect 1983;7(suppl 1):95-104.

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778

Correspondence

may suggest that the nonresponsiveness to hepatitis B vaccine is due to the immunotolerance or immunosuppression induced by latent HBV infection. It has been demonstrated that HBV antigens such as HBV e antigen could induce immunotolerance and cause chronic HBV infection [6]. Also, HBV itself may cause immunotolerance by directly infecting T and B lymphocytes, resulting in the viral persistence [7]. Immunosuppression may occur during viral infection through different mechanisms, such as the viral-triggered imbalance in immunoregulation with resultant overactivity of suppressor T lymphocytes [8]. However, what mechanism caused the latent HBV infection in the nonresponders in the present study is unclear; further investigation on this issue is being done in our laboratory.

Division of Infectious Diseases, Nanfang Hospital, First Medical College of the People's Liberation Army. Guangzhou, People's Republic of China; Laboratory of Biochemical Virology. New York Blood Center. New York City

Effect of Interferon-a2b on Cryoglobulinemia Related to Hepatitis C Virus Infection Colleagues-Cryoglobulinemia has been reported in association with hepatitis B virus (HBV) [1] and more recently with hepatitis C virus (HCV) infection [2]. There seems to be a relationship between hepatotropic viruses and essential mixed cryoglobulinemia [3]. To support this association, we report the effect.of interferon-zeZb (lFN-a2b) in two patients with chronic hepatitis due to HCV and mixed cryoglobulinemia. Patient 1, a 65-year-old white woman with non-insulin-dependent diabetes for 10 years was admitted for thrombocytopenia. Past history revealed polyarthralgia for 3 years before admission. Diabetes was controlled with gliclazide (Diamicron). There was no previous history of blood transfusion or known exposure to hepatitis. Clinical examination revealed mild hepatosplenomegaly. Laboratory findings included erythrocyte sedimentation rate, 40/65 mrn/h; platelet count, 72 X 109/1; serum bilirubin, 9 ,umoljl; aspartate aminotransferase, 130 IU/l; alanine aminotransferase, 188 IU/l (normal, 7-29); alkaline phosphatase, 315 IU/l (normal, 90-250); latex circulating immune complexes, 6 ,ug/ml (normal, 0-1.5), and C4 level, 0.11 gil; (normal, 0.24-0.5 gil). Mixed cryoglobulinemia with polyclonal IgG and IgMX was present. IgM antibodies to hepatitis A and B surface antigen were not detected. Reprints or correspondence: Dr. Jean Marc Durand, Department of Internal Medicine, CHU de Sainte-Marguerite. 270 Bd. de Sainte-Marguerite. 13274 Marseille Cedex 9, France. The Journal of Infectious Diseases 1992;165:778-9 © 1992 by The University of Chicago. All rights reserved. 0022-1899/92/6504-0036$01.00

References I. Eddleston A. Modern vaccines: hepatitis. Lancet 1990;335: 1142-4. 2. Watanabe H, Matsushita S, Kamikawaji N, et al. Immune suppression gene on HLA-Bw54-DR4-DRw53 haplotype controls nonresponsiveness in humans to hepatitis B surface antigen via CD8+ suppressor T cells. Hum Immunol 1988;22:9-17. 3. Alper CA, Kruskall MS, Marcus-Bagley 0, et al. Genetic predication of nonresponse to hepatitis B vaccine. N Engl J Med 1989:321 :708-12. 4. Chiou SS, Yamauchi K, Nakanishi T, et al. Nature of immunological non-responsiveness to hepatitis B vaccine in healthy individuals. Immunology 1988;64:545-50. 5. Luo KX, Zhou R, He C. et al. Hepatitis B virus DNA in sera of virus careers positive exclusively for antibodies to the hepatitis B core antigen. J Med Virol 1991;35:55-9. 6. Brunetto MR. Giarin MM, Oliveri F, et al. Wild-type and e antigenminus hepatitis B viruses and course of chronic hepatitis. Proc Natl Acad Sci USA 1991 ;88:4186-90. 7. Oldstone MBA. Viral persistence. Cell 1989;56:517-20. 8. Paller AS, Mallory SB. Acquired forms of immunosuppression. J Am Acad Dermatol 1991 ;24:482-8.

A quantitative test for antibodies to HCV in serum (anti-Hf.V EIA; Ortho Diagnostics, Raritan, NJ) was positive (optical density, 2.3; cutoff, 0.452) as were recombinant immunoblot assay (second-generation RIBA; Ortho) and polymerase chain reaction (PCR). PCR amplification for HVC RNA in serum was done by modified nested PCR with primers from the 5' noncoding, highly conserved region of the HCV genome followed by ethidium bromide staining and by hybridization with an internal oligonucleotidic probe as previously described [4]. Results of bone marrow aspiration were normal. Liver biopsy disclosed chronic active hepatitis with cirrhosis. Staining for hepatitis B core antigen by immunofluorescence was negative. The patient was treated with IFN-a2b (Intron-A: Schering Plough, Bloomfield, NJ), 3 million units subcutaneously, three times weekly. After 3 months arthralgias subsided, and the search for cryoglobulinemia was negative. The patient has remained well for the past 12 months, but transaminases have remained elevated. The clinical presentation for patient 2, a 51-year-old white woman, has been previously reported [5]; it included associated recurrent tender nodules over the legs, arthralgias, and Raynaud's phenomenon. She had been diagnosed 4 years earlier with non-A, non-B hepatitis. Mixed cryoglobulinemia with polyclonal IgG and IgMX was present. IgM antibodies to hepatitis A and B surface antigen were not detected. EIA for HeV in serum was positive (optical density, >3) as were RIBA and PCR. Skin biopsy revealed lymphocytic vasculitis. Liver biopsy showed chronic persistent hepatitis with a negative stain for hepatitis B core antigen by immunofluorescence. IFN-a2b (Intron-A), 3 million units subcutaneously, three times a week was administered. We observed a disappearance of the cryoglobulinemia within 2 months. During 4 months of follow-up, the pa-

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Kang-Xian Luo, Leng-Ping Wang, Jun Nie, and Shibo Jiang

110 1992;165 (April)

Is nonresponsiveness to hepatitis B vaccine due to latent hepatitis B virus infection?

JID 1992; 165 (April) Correspondence Richard M. Rose, Jorge Rey-Martinez, Christine Croteau, Ronald C. Silvestri, Kathleen Haley, Jean DePamphilis,...
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