Hepatitis B Surface Antigenemia in ChronicHemodialysis Patients: Effect of Hepatitis BImmunizationDavid Ly, Hal F. Yee, Jr., M.D., Ph.D., Maria Brezina, B.S., Paul Martin, M.D., Gary Gitnick, M.D., andSammy Saab, M.D.Division of Digestive Diseases, Department of Medicine, Department of Physiology, and Dumont-UCLA LiverTransplant Program, University of California; and Liver Transplant Program, Cedars-Sinai Medical Center,Los Angeles, California

OBJECTIVE: Hemodialysis patients with hepatitis B surfaceantigen (HBsAg) are considered to have the hepatitis B virus(HBV) and are segregated to limit transmission. However,transient de novo HBsAg has been identified in hemodial-ysis patients shortly after vaccination. Our hypothesis is thatimmunization rather than actual HBV infection is the mostcommon cause of de novo HBsAg among hemodialysispatients.

METHODS: We performed a prospective study between Jan-uary, 1998 and June, 2000 of de novo HBV infection in over2400 hemodialysis patients who were screened monthly forHBsAg using a standard enzyme immunoassay. Positiveresults were confirmed with a neutralization assay. If theconfirmatory test was positive, anti–hepatitis B core anti-body IgM testing was performed.

RESULTS: We identified nine patients with de novo HBsAgconfirmed with the neutralization assay. In eight of the ninepatients with de novo HBsAg (89%), HBsAg was tempo-rally related to HBV immunization. In none of these eightpatients was there a detectable anti–hepatitis B core anti-body IgM, an elevated ALT level, or clinical history sug-gestive of recent hepatitis. The mean age (� SD) of the fourmen and four women was 56.4 � 18.8 yr. HBsAg wasdetectable within 3 days of immunization in most patients.

CONCLUSION: Our results suggest that HBV immunizationis the most common cause of detectable HBsAg in hemo-dialysis patients. Hemodialysis patients should not bescreened for HBV within a week of immunization, andcaution should be exercised when interpreting HBsAg se-ropositivity within 4 wk of HBV immunization. (Am JGastroenterol 2002;97:138–141. © 2002 by Am. Coll. ofGastroenterology)

INTRODUCTION

In chronic hemodialysis patients, the current Centers forDisease Control recommendations are for regular hepatitisB surface antigen (HBsAg) screening of susceptible pa-tients, along with the use of dedicated work areas andmachines for HBsAg-positive patients. These measurementshelped decrease the yearly incidence of hepatitis B virus(HBV) infection in hemodialysis centers from 6.2% in 1974to 1% in 1980 (1, 2).

In addition to serological screening for HBsAg, immuni-zation has also had an impact on the incidence and, conse-quently, the complications of HBV infection (3–8). Cur-rently recombinant HBV vaccines are used, and incorporatehighly purified HBsAg from Saccharomyces cerevisiae (9).In the hemodialysis population, the practice of HBV immu-nization has further decreased the incidence to 0.05% in1997 (10). Because hemodialysis patients do not respond tothe vaccine as well as the general population, repeatedcourses of vaccination may be required (11). The recom-mended HBV immunization series for hemodialysis patientsconsist of three or four separate doses of 40 �g, in contrastto three doses of 20 �g in healthy adults (11). Whereas only60% of hemodialysis patients who follow this regimen de-velop protective anti-HBs levels within 1 month of com-pleting the immunization series, 90% of healthy adults de-velop adequate anti-HBs levels after completion of thestandard series (2, 12).

HBsAg has been transiently observed in hemodialysispatients after HBV immunization, and is felt to be a resultof the recombinant HBsAg rather than actual infection (9,13–15). This phenomenon occurs in approximately 13–31.6% of hemodialysis patients after immunization (13, 14).It may be a reflection of the higher vaccine dosage and/orfrequency, prolonged time for HBsAg neutralization, andperhaps the advanced age of hemodialysis patients (13, 16,17). Transient HBsAg can occur after any of the vaccines inthe immunization series (14). There exists a potential riskfor hemodialysis patients who have transient detectableHBsAg after immunization, because they may be inappro-Both D.L. and H.F.Y. contributed equally to this work.

THE AMERICAN JOURNAL OF GASTROENTEROLOGY Vol. 97, No. 1, 2002© 2002 by Am. Coll. of Gastroenterology ISSN 0002-9270/02/$22.00Published by Elsevier Science Inc. PII S0002-9270(01)03999-5

priately assigned to dialysis machines dedicated to HBV-infected individuals. Hemodialysis patients with transienthepatitis B surface antigenemia may experience anxiety dueto the misdiagnosis of HBV. Finally, resources such as staffand space may be unnecessarily used to segregate a patientwith transient HBsAg.

Although current practices of surveillance, vaccination,and segregation have markedly diminished dialysis-associ-ated acquisition of HBV, they have also introduced the riskof misdiagnosis in hemodialysis patients. Therefore, wehypothesized that a frequent cause of de novo HBsAgamong hemodialysis patients may be HBV immunizationrather than actual infection.

MATERIALS AND METHODS

The University of California Los Angeles Hepatitis Screen-ing Program prospectively collected data on all HBsAgseroconverters from January, 1998 to June, 2000, screeningapproximately 2400 patients from 39 hemodialysis centers.ALT was measured monthly on all patients using an opti-mized ultraviolet-kinetic method (Abbott Laboratories, Ab-bott Park, IL). HBsAg was measured monthly in all new orsusceptible hemodialysis patients using an enzyme immu-noassay (Abbott Laboratories). Positive results were con-firmed by a neutralizing antibody assay. Antibodies toHBsAg (anti-HBs) and the IgM antibody to hepatitis B coreantigen (anti-HBc IgM) were measured by an enzyme-linked immunoassay and an enzyme immunoassay, respec-tively (Abbott Laboratories). Screening for hepatitis C wasperformed using a commercial ELISA (Ortho HCV Version3.0 ELISA, Ortho-McNeil Pharmaceutical, Raritan, NJ).

The referring dialysis center was immediately contactedupon the identification of a specimen with de novo HBsantigenemia. The patient was asked about symptoms sug-gestive of acute viral hepatitis such as flulike complaints,jaundice, myalgia, and arthralgia. In addition, the respectivedialysis center was asked to identify other patients withHBV infection who may have been a potential source ofinfection. ALT values were reviewed for 1–3 months beforeseroconversion. Immunization records were also obtained.

RESULTS

Since January, 1998 we have identified nine hemodialysispatients who developed confirmed de novo hepatitis B sur-face antigenemia. None of these nine patients had an ictericillness or elevated ALT values suggestive of acute viralhepatitis. Of the nine patients, eight had transient antigen-emia and one had persistent HBsAg. The patient with per-sistent HBsAg also developed anti-HBc IgM. This patienthad been dialyzed in a unit with an HBV-infected patient.

In eight of the nine patients, HBV immunization precededHBsAg within 28 days (Table 1). Three patients receivedRecombivax (Merck, Whitehouse Station, NJ), and threeother patients received EngerixB (GlaxoSmithKline, Lon-don, United Kingdom) vaccine. The vaccine type and man-ufacturer in the other two patients was not known. Onepatient received his first vaccination, another was on hissecond vaccination, and two patients were on their thirdvaccinations of the immunization series. The patients didnot test seropositive for anti-HBc IgM. The mean (� SD)ALT value was 12.3 (� 8.4) IU/L, which did not exceed thereference range. Antibodies to the hepatitis C virus were

Table 1. Result Summary on Hemodialysis Patients With Transient Detectable Hepatitis B Surface Antigen

Patient Sex Age (yr) Date ALT HBsAg Anti-HBsDays AfterVaccination

1 M 63 Sep. 15, 1998 � �Oct. 13, 1998 8 � � 3Nov. 12, 1998 � �

2 M 61 Nov. 9, 1998 � �Dec. 14, 1998 29 � � 3Jan. 14, 1999 � �

3 F 36 July 30, 1998 � �Aug. 20, 1998 6 � � 1Sep. 17, 1998 � �

4 F 78 July 30, 1998 � �Oct. 29, 1998 6 � � 2Nov. 18, 1998 � �

5 F 64 May 8, 1998 14 � � 26 M 54 Jan. 5, 1999 � � 1

Feb. 2, 1999 9 � � 28Feb. 11, 1999 � NA

7 F 73 July 26, 1999 � �Aug. 16, 1999 20 � � 3Sep. 16, 1999 � NA

8 M 22 Nov. 15, 1999 � �Feb. 17, 2000 6 � NA 2June 22, 2000 � �

� � detectable; � � not detectable; anti-HBs � antibodies to HBsAg; NA � not available.

139AJG – January, 2002 HBs Antigenemia in Chronic Hemodialysis Patients

undetectable in all patients. In seven of those eight cases, theHBsAg was detected within 3 days of immunization. Al-though it is uncertain when one patient became seropositivefor HBsAg, the patient’s HBsAg levels were detectable 28days after the HBV vaccine. The mean age (� SD) of theeight patients with transient de novo HBsAg was 56.4 (�18.8) yr. HBsAg was negative upon retesting a mean of 1.3months later in eight of the nine patients.

DISCUSSION

Newly detected HBsAg occurred in the absence of otherserological and biochemical markers of HBV infection, andis attributed to HBV immunization in eight of nine patientswho seroconverted in our study. In seven of the eight he-modialysis patients who had detectable HBsAg related tem-porarily to immunization, HBsAg was detectable between 1and 3 days after immunization. This finding is consistentwith prior observations (Table 2) (13, 14). In addition, weidentified one patient who had HBsAg, which was detectedfor up to 28 days after HBV immunization. A study con-ducted by Janzen et al. (14) revealed that one of the sixpatients had detectable HBsAg for 20 days after HBV im-munization.

Eight of the nine patients had no corroborating evidenceof HBV infection such as jaundice, development of detect-able anti-HBc IgM, or elevation in ALT values. The otherpatient developed anti-HBc IgM and was likely to be in-fected at the dialysis center. The patient had not been pre-viously vaccinated. As hemodialysis patients are frequentlyasymptomatic during acute HBV infection, surveillance forde novo HBV infection remains important to limit spreadwithin hemodialysis units (10).

Prospective studies on the development of transient de-tectable HBsAg after HBV vaccination suggest an incidencebetween 13% and 32% based upon the number of subjectsvaccinated (13, 14). Because hemodialysis patients are morelikely than any other population to be regularly screened forHBV infection, transient detectable HBsAg is probablymore likely to be found in this setting. It is unclear whatproportion of healthy adults develop transient detectableHBsAg after HBV vaccination (18, 19). In one prospective

study, HBsAg was not detected within 24 h of vaccinationin normal patients. It is uncertain if the antigen could havebeen systematically absorbed during this interval (18).

A limitation of this study is that we were not able tocomment on the likelihood of developing transient HBsAgafter the initial HBV immunization series or during boostervaccination. Our large database does not include informa-tion on duration of hemodialysis. Therefore, separating newpatients from chronic hemodialysis ones is not possible.Because the dose of the individual vaccine is similar to theinitial HBV immunization series and booster vaccinations,transient HBsAg appears not to be dependent upon thevaccine dose series number (17, 20). In addition, the focusof the current study is to describe the relative frequency ofde novo HBsAg due to immunization.

Transient de novo HBsAg in the hemodialysis communityis a health concern because the consequences are important:patients may be put at risk for HBV infection due to seg-regation with HBV-infected individuals in hemodialysisunits, patient anxiety may increase, and hemodialysis cen-ters may experience increased resource utilization. Becauseeight of the nine patients (89%) developed vaccine-associ-ated transient HBsAg, we suggest that HBV immunizationis a substantial if not the most common cause of detectableHBsAg in chronic hemodialysis patients. These data suggestthat patients should not be screened for HBsAg within aweek of HBV immunization, and caution should be exer-cised when interpreting the detection of HBsAg within 4 wkof immunization.

Reprint requests and correspondence: Sammy Saab, M.D., Di-vision of Digestive Diseases, 44-138 CHS (MC 168417), UCLAMedical Center, 10833 Le Conte Avenue, Los Angeles, CA 90095.

Received Jan. 17, 2001; accepted June 13, 2001.

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Table 2. Transient Detectable Hepatitis B Surface Antigen in Healthy Adults and Hemodialysis Patients

Author

No. of Patients WithDetectable HBsAg/

Total Patients StudiedMean Age

(yr)

Duration of TransientDetectable HBsAg

(Days) Patient Population

Katkov et al. (18) 0/12 NA 0 Hospital employeesKloster et al. (19) 1/19 NA 1 Blood donorsBrodersen et al. (15) 1/1 55 7 Hemodialysis patientJanzen et al. (14) 6*/6 65 7–20 Hemodialysis patientsKear and Wright (9) 1/1 69 NA Hemodialysis patientSantana Rodriguez et al. (13) 6/19 62 2–7 Hemodialysis patientsPresent study 8/9† 63 1–28† Hemodialysis patients

NA � not applicable.* Four patients were found incidentally, and two patients were found during prospective surveillance.† One of the eight patients had de novo hepatitis B infection.

140 Ly et al. AJG – Vol. 97, No. 1, 2002

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141AJG – January, 2002 HBs Antigenemia in Chronic Hemodialysis Patients