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Vol. 114, No. 3, 2010
Issue release date: February 2010
Nephron Clin Pract 2010;114:c194–c203
(DOI:10.1159/000262302)

Antibodies to Core Antigen of Hepatitis B Virus in Patients on Renal Replacement Therapy: Association with Demographic, Clinical and Laboratory Data

Grzegorzewska A.E.a · Kurzawska-Firlej D.b · Ratajewski W.c · Frankiewicz D.d · Niepolski L.e · Kaczmarek A.f
aDepartment of Nephrology, Transplantology and Internal Diseases, Poznań University of Medical Sciences and bInternational Dialysis Center, Poznań, cPublic Regional Hospital, Kalisz, dPublic Regional Hospital, Konin, eB. Braun Avitum, Nowy Tomyśl, and fFresenius Nephrocare, Pleszew, Poland
email Corresponding Author

Abstract

Background: Total antibodies to core antigen of hepatitis B virus (anti-HBc) are a marker for previous or current infection with hepatitis B virus (HBV). Our aim was to examine the prevalence and incidence of anti-HBc in relation to demographic, clinical and laboratory data of patients treated with intermittent hemodialysis (IHD). Methods: Predictors for anti-HBc positivity were evaluated in prevalence IHD patients with negative testing for surface antigen of HBV (HBsAg, n = 1,105) using the stepwise backward regression analysis. Patients starting IHD (n = 336) were introduced into the one-year prospective study evaluating seroconversion for anti-HBc. Results: Anti-HBc positivity (19.5% of all patients) was predicted by lack of vaccination against HBV with developed protective titer of antibodies to HBsAg (β = 0.592, p = 0.000), vintage of renal replacement therapy (RRT, β = 0.206, p = 0.000), history of hepatitis (β = 0.101, p = 0.000), and activity of alanine aminotransferase (β = 0.057, p = 0.037). In 85 prospective patients who finished first IHD year, seroconversion rate for anti-HBc was 1.23 episodes/100 patient-years. Conclusions: Lack of or not effective vaccination against HBV is the strongest predictor for prevalence of anti-HBc positivity in RRT patients. Periodical determination of anti-HBc, usually not required, may be helpful in evaluation of current epidemiological status and risk for further HBV infection in dialysis centers.


 Outline


 goto top of outline Key Words

  • Antibodies core antigen hepatitis B virus
  • Renal replacement therapy
  • Hemodialysis
  • Vaccination
  • Seroconversion
  • Sex
  • Antibodies hepatitis C virus

 goto top of outline Abstract

Background: Total antibodies to core antigen of hepatitis B virus (anti-HBc) are a marker for previous or current infection with hepatitis B virus (HBV). Our aim was to examine the prevalence and incidence of anti-HBc in relation to demographic, clinical and laboratory data of patients treated with intermittent hemodialysis (IHD). Methods: Predictors for anti-HBc positivity were evaluated in prevalence IHD patients with negative testing for surface antigen of HBV (HBsAg, n = 1,105) using the stepwise backward regression analysis. Patients starting IHD (n = 336) were introduced into the one-year prospective study evaluating seroconversion for anti-HBc. Results: Anti-HBc positivity (19.5% of all patients) was predicted by lack of vaccination against HBV with developed protective titer of antibodies to HBsAg (β = 0.592, p = 0.000), vintage of renal replacement therapy (RRT, β = 0.206, p = 0.000), history of hepatitis (β = 0.101, p = 0.000), and activity of alanine aminotransferase (β = 0.057, p = 0.037). In 85 prospective patients who finished first IHD year, seroconversion rate for anti-HBc was 1.23 episodes/100 patient-years. Conclusions: Lack of or not effective vaccination against HBV is the strongest predictor for prevalence of anti-HBc positivity in RRT patients. Periodical determination of anti-HBc, usually not required, may be helpful in evaluation of current epidemiological status and risk for further HBV infection in dialysis centers.

Copyright © 2009 S. Karger AG, Basel


goto top of outline Introduction

Persons with positive surface antigen of hepatitis B virus (HBsAg) are considered as infectious because their blood and other body fluids usually contain DNA of the hepatitis B virus (HBV DNA) which may be transmitted to other people [1]. Such transmission is especially possible during repeated invasive medical procedures, among them, intermittent hemodialysis (IHD) sessions [2]. After widespread introduction of vaccination against the hepatitis B virus (HBV), cross-sectional epidemiological examinations indicate a decreasing relative number of IHD patients with positive HBsAg. The risk for HBV infection was estimated to be 70% lower in vaccinated dialysis patients [3]. In Poland, the percentage of IHD patients with positive HBsAg is also decreasing: from 17.6% in 1995 to 4.4% in 2006 [4]. In 2007, the prevalence of HBsAg-positive IHD patients in the Wielkopolska region was 3.4%, with a significantly higher number of HBsAg-positive men (82.1%) [5]. The percentage of patients with positive antibodies against hepatitis C virus (anti-HCV) is also decreasing: from 36% in 1997 to 12.2% in 2006 [4]. The decrease in hepatitis C virus (HCV) infection occurs due to improvement in dialysis technique and more rigorous enforcement of general prophylactic measures. Thus, a decrease in the percentage of HBsAg-positive patients, occurring during the same period, has to be related to both vaccination and higher standards in the dialysis procedure.

HBsAg is usually eliminated during recovery after HBV infection, especially when acute HBV infection is associated with positive testing for the hepatitis B envelope antigen [6]. Total antibodies against core antigen of HBV (anti-HBc) are the established marker for previous or current infection with HBV. Their prevalence may reflect epidemiological status in regard to HBV infection.

The aim of our study was to examine: (1) the prevalence of anti-HBc in HBsAg-negative patients currently treated with IHD in relation to their demographic, clinical and laboratory data, (2) the prevalence and incidence of anti-HBc in patients starting IHD as the first method of renal replacement therapy (RRT).

 

goto top of outline Material and Methods

goto top of outline The Cross-Sectional Study

Twenty IHD centers of one region of Poland (Wielkopolska) participated in the study. All patients currently treated in these centers were included into the cross-sectional examination of prevalence of HBV and HCV seromarkers with relation to patients’ demographic, clinical and laboratory data.

The median total number of patients in separate centers was 59, range 4–145 persons. There were 19 centers for adults with 1,131 patients and 1 pediatric center with 4 patients. None of the patients showed a clinical manifestation of acute infection with hepatotropic viruses at the time of examination.

In accordance to European recommendations [7], in dialysis units cooperating in this study, HBsAg-positive patients were dialyzed in separate rooms with dedicated machines in addition to anti-HCV patients being in separate rooms or areas with dedicated machines. However, dialyzers from HBsAg-negative, anti-HCV-negative, HCV ribonucleic acid (HCV RNA)-negative, and from anti-HBc positive/HBV DNA-negative patients were still reused up to 4 times in 1 center.

In IHD centers, patients were assumed to be vaccinated against HBV according to standard rules [2]. In brief, all HBsAg-negative patients showing anti-HBs below 10 IU/l, without acute hepatitis, were vaccinated or revaccinated, usually independently on results of anti-HBc testing. When patients underwent vaccination before commencement of dialysis treatment, serological testing for anti-HBc was usually not performed before vaccination. After the completion of the primary vaccination series, effectiveness of vaccination was not checked in the majority of pre-dialysis vaccinated patients. It was only done at the start of dialysis.

All patients had routinely determined HBsAg and anti-HCV at the start of IHD and every 3 months, and antibodies against surface antigen of hepatitis B virus (anti-HBs) – at the start of IHD, 1–2 months after the last dose of vaccine against HBV and every 6–12 months. Testing of anti-HBc was performed usually 2 times in each patient, dependently on IHD duration. In the case of discrepancies between consecutive anti-HBc results, determinations were additionally repeated to establish a true result. All patients with isolated anti-HBc positivity (HBsAg negative, anti-HBc positive, anti-HBs negative) had 2–3 determinations of all 3 HBV seromarkers (sometimes in different laboratories) in at least 1-week intervals for obtaining a reliable diagnosis of HBV status.

At the study entry, 67 persons from 215 anti-HBc positive, HBsAg-negative patients had HBV DNA determined. For purpose of this study, the number of tested patients was increased to 164 persons. Determinations of HBV DNA depended on patient agreement for such testing and internal regulations, financial possibilities and logistic abilities of dialysis units.

All anti-HCV-positive patients (n = 127) had valid testing for detection of HCV RNA; 853 patients from the anti-HCV negative group (n = 978) also underwent HCV RNA examination.

The results of HBV (HBsAg, anti-HBc, anti-HBs, HBV DNA) and HCV (anti-HCV, HCV RNA) seromarkers were collected and analyzed. The results of serum activities of aspartate aminotransferase – AST, alanine aminotransferase – ALT and gamma-glutamyltranspeptidase – GGT were used as biochemical signs of liver disease. Analyzed demographic and clinical data included race, gender, age, diagnosis of end-stage renal disease, total duration of RRT, history of acute hepatitis, undergoing full vaccination series against HBV and its effectiveness, current anti-HBs titer (>10 vs. ≤10 IU/l) and result of anti-HIV1/HIV2 testing.

goto top of outline The Prospective Study

Sixteen IHD centers started to participate in the prospective study. Patients beginning IHD in these centers underwent testing of anti-HBc, additionally to standard determinations. They were prospectively evaluated for 1 year for seroconversion in anti-HBc and anti-HCV. The number of included patients equaled 336 persons.

goto top of outline Laboratory Methods

HBsAg and anti-HBc were determined by the Microparticle Enzyme Immunoassay (MEIA) technology (AxSYM; Abbott Laboratories, Abbott Park, Ill., USA). For anti-HBs and anti-HCV detections, MEIA technology was used also (ABBOTT, Wiesbaden, Germany). Anti-HCV testing was performed by the AxSYM HCV VERSION 3.0 assay based in the 4 recombinant HCV proteins HCr43, c200, c100–3 and NS5.

HBV DNA and HCV RNA were determined using a quantitative real-time polymerase chain reaction (PCR) with a lower limit of detection of 200 IU/ml (RoboGene® Quantification of HBV Genomes, AJ Roboscreen GmbH, Leipzig, Germany, and RoboGene® Quantification of HCV Genomes, AJ Roboscreen GmbH, Leipzig, Germany, respectively).

Serum activities of AlAT, AspAT and GGTP were determined by routine laboratory methods.

goto top of outline Statistical Methods

The normality of distribution of variables was checked by the Shapiro-Wilk test. Descriptive statistics are presented as percentage for categorical variables, as mean with one standard deviation (SD) for normally distributed continuous variables, or as median with range for not-normally distributed continuous variables. The prevalence of variables was assessed by the χ2 test or McNemara test. The stepwise backward regression analysis was used to show independent variables that predicted anti-HBc positivity. The Spearmann correlation was performed between examined parameters in IHD centers. A p < 0.05 was judged to be significant. Statistical analysis was performed using STATISTICA PL 8.0.

This study was reviewed and approved by the Institutional Review Board of Poznań University of Medical Sciences.

 

goto top of outline Results

Among 1,135 patients dialyzed in 20 centers, there were 1,105 HBsAg-negative patients and 30 HBsAg-positive ones (23 men, 7 women). Overall, HBsAg prevalence was 2.64% (1.90, 0–6.15% in separate centers).

Demographic, clinical and laboratory data of all patients with negative testing for HBsAg are shown in table 1. All patients except 10 persons (8 Gypsies, 1 Vietnamese, and 1 African) were of Caucasian race. The women to men ratio was 1:1.25; 96.5% of the patients were aged >30 years. Causes of end-stage renal disease included diabetic nephropathy (n = 282, 25.5% of the entire group), chronic glomerulonephritis (n = 171, 15.5%), hypertensive nephropathy (n = 167, 15.1%), tubulointerstitial nephritis (n = 145, 13.1%), polycystic kidney disease (n = 61, 5.5%), obstructive uropathy (n = 48, 4.3%), renal stones (n = 36, 3.3%), amyloidosis (n = 16, 1.5%), systemic diseases (n = 16, 1.5%), renal cancer (n = 13, 1.2%), myeloma multiplex (n = 10, 0.9%), vascular diseases (n = 8, 0.7%), urinary tract malformations (n = 7, 0.6%), uric acid nephropathy (n = 6, 0.5%), other (n = 47, 4.3%), and unknown (n = 72, 6.5%). All patients were currently treated with IHD, but the total duration of their RRT was 2.2, 0.00–28.9 years (peritoneal dialysis, IHD, functioning renal graft). Forty-nine persons experienced acute hepatitis in the past (hepatitis B – 14 patients, hepatitis C – 33 patients, hepatitis of unknown cause – 2 patients). Seven percent of patients did not finish a full vaccination series against HBV or were not vaccinated as having known anti-HBs >10 IU/l. Nearly 63% of the vaccinated patients developed an anti-HBs titer >10 IU/l.

TAB01
Table 1. Demographic, clinical and laboratory data of hemodialysis patients with negative testing for surface antigen of HBV

The distribution of anti-HBc and anti-HCV results in all HBsAg-negative patients (n = 1,105) is presented on figure 1. False-positive anti-HBc (not confirmed in the repeated determinations) were shown in 3 cases (3 out of 1,105 cases, 0.27%). Among 1,105 IHD patients, there were 215 (19.5%) persons with positive anti-HBc. In this group, 14.0% (30/215) had isolated anti-HBc positivity, although 60.0% of these patients underwent a full series of vaccination against HBV. Anti-HCV-positive patients made 11.5% (127/1,105) of all examined subjects. The prevalence of anti-HBc positivity was significantly greater compared to anti-HCV prevalence (p = 0.000). Anti-HBc/anti-HCV-positive patients (n = 48) comprised 4.3% of all subjects; it counted for 22.3% of all anti-HBc-positive patients (48/215) and 37.8% of all anti-HCV-positive patients (48/127, p = 0.002). HBV DNA was detected in 1 anti-HBc-positive, HBsAg-negative patient (table 1). Among anti-HCV-positive patients (n = 127), there were 77 patients (60.6%) with positive PCR testing for the detection of HCV RNA. From anti-HCV-negative patients (n = 978), of whom 853 had PCR testing for HCV RNA, 2 cases (0.23%) showed a HCV RNA-positive result. One patient showed positive total antibodies against human immunodeficiency virus (HIV1/HIV2).

FIG01
Fig. 1. Distribution of results of antibodies to core antigen of hepatitis B virus (anti-HBc) and antibodies to hepatitis C virus (anti-HCV) in patients with negative antibodies to surface antigen of hepatitis B virus treated with intermittent hemodialysis (n = 1,105).

In the dialysis centers (n = 20), the prevalence of anti-HBc-positive patients was 18.8 ± 5.7% and anti-HCV-positive patients 11.3 ± 9.4%. The greater number of IHD patients in separate dialysis centers, the greater number of anti-HBc-positive persons (r = 0.904, p = 0.000), HBsAg-positive persons (r = 0.764, p = 0.000) and anti-HCV-positive patients (r = 0.738, p = 0.000). The number of anti-HBc-positive patients in separate IHD centers correlated also with the number of anti-HCV-positive patients (r = 0.800, p = 0.000) and the number of HBsAg-positive persons (r = 0.626, p = 0.003). However, the percent prevalence of anti-HBc, HBsAg and anti-HCV positivity did not correlate significantly with the total number of patients in dialysis centers. Percent prevalence of anti-HBc positivity did not correlate significantly with percent prevalence of HBsAg positivity, but it was in the case of percentage anti-HCV and anti-HBc positivity (r = 0.669, p = 0.001).

Significant differences between anti-HBc-positive and anti-HBc-negative patients are shown in table 1. Anti-HBc-positive patients presented a higher prevalence of women and persons aged >30 years, longer duration of RRT, more frequent history of hepatitis, a lower percentage of vaccinated persons and those with developed protective titer of anti-HBs in response to vaccination, a higher percentage of patients with current anti-HBs titer >10 IU/l, a higher prevalence of anti-HCV and HCV RNA positivity, and higher activity of AspAT.

Variables which significantly differed between anti-HBc-positive and anti-HBc-negative patients (sex, age >30/≤30 years, RRT vintage, history of hepatitis, vaccination with protective anti-HBs developed, results of anti-HCV and AspAT testing) were used in the stepwise backward regression analysis, performed for all IHD patients, as possible independent predictors of anti-HBc positivity. Additionally, race, the 4 most common causes of end-stage renal disease (diabetic nephropathy, chronic glomerulonephritis, hypertensive nephropathy and tubulointerstitial nephritis), and the results of AlAT and GGTP testing were included into this analysis. The lack of vaccination against HBV with developed anti-HBs titer >10 IU/l (β 0.592, p = 0.000), duration of RRT (β = 0.206, p = 0.000), history of acute hepatitis (β = 0.101, p = 0.000), and higher activity of AlAT (β = 0.057, p = 0.037) were recognized as significant predictors of anti-HBc positivity, with lack of effective vaccination being the strongest predictor. The variability of significant predictors could explain over 40% of the variability in anti-HBc testing in examined RRT patients (corrected R2 = 0.424).

Female sex and anti-HCV positivity, although not significant predictors for anti-HBc positivity, were significantly more frequent in anti-HBc-positive than in anti-HBc-negative patients (table 1). Tables 2 and 3 show the differences in prevalence of the predictors for anti-HBc positivity by gender group and anti-HCV-positive/negative groups, respectively. Prevalence of predictors was significantly greater in women than in men and in anti-HCV-positive than in anti-HCV-negative patients.

TAB02
Table 2. Differences in prevalence of predictors for anti-HBc positivity in men and women treated with intermittent hemodialysis

TAB03
Table 3. Differences in prevalence of predictors for anti-HBc positivity in anti-HCV-positive and anti-HCV-negative patients treated with intermittent hemodialysis

In the prospective group (n = 336), there were 149 women and 187 men. Anti-HBc-positive women (n = 21) comprised 14.1% of all women and anti-HBc-positive men (n = 22) comprised 11.8% of all men (p = 0.526; not significant as compared to the anti-HBc prevalence in women). In 85 patients of the prospective group, who finished the first IHD year, the initial anti-HBc positivity was 10.6% and anti-HCV positivity 3.5%. Seroconversion rate for anti-HBc without detected HBsAg and clinical symptoms of hepatitis was 1.23 episodes per 100 patient-years. There was no seroconversion for anti-HCV.

 

goto top of outline Discussion

The prevalence of anti-HBc in the HBsAg-negative IHD population, living in one region of Poland (Wielkopolska), was 19.5% (215/1,105). Such prevalence is considered as high when shown in a community-based study [8], but may be reported as moderate compared to prevalence in specific patients groups, such as in HIV type-1-infected persons, showing 42% isolated anti-HBc-positive individuals [9]. The prevalence of anti-HBc in the chronic dialysis population ranges from 0–54% [10,11,12]. A wide range in anti-HBc positivity was also shown in our dialysis centers (9.8–30.0%).

Patients with isolated anti-HBc were not analyzed separately in our study because a majority of patients underwent first anti-HBc determination after they had been vaccinated against HBV. Anti-HBc was not found in vaccinated persons who have never been exposed to natural infection [13]. Patients, naturally infected in the past, easily redeveloped protective anti-HBs titers [14,15]. Despite this, still 14% of anti-HBc-positive patients, of whom 60% underwent a full series of vaccination against HBV, had isolated anti-HBc in repeated testing. It was stated that isolated anti-HBc indicate a false-positive result in dialysis patients [2]. False-positive anti-HBc results were shown in our study in 3 cases (0.27%). In other studies, false positivity resulting from diagnostic methods was found in 1–2% of cases [16].

A wide prevalence of anti-HBc positivity in RRT population occurs due to enrollment of anti-HBc-positive persons into this treatment and seroconversion during RRT. Some examined patients started RRT before 1990. These patients were not vaccinated before commencement for dialysis therapy; they recalled utilization of dialyzers in the majority of centers and a lower standard of dialysis therapy. It may explain, at least partially, the association of anti-HBc and anti-HCV positivity with RRT duration. Additionally, the number of anti-HBc-positive patients starting IHD may change over time, reflecting the epidemiological status of the society, improving decade by decade in our region of Poland (Wielkopolska), as in many former communist countries [17]. Thus, the prevalence of viral seropositivity cannot be totally attributed to RRT duration.

The more common prevalence of both anti-HBc (19.5%) than anti-HCV (11.5%) positivity in the examined RRT population, as well as no seroconversion into anti-HCV positivity, in comparison to one seroconversion into anti-HBc positivity in the prospective group during the 1-year observation, confirm and visualize the greater infectivity of HBV as compared to HCV infectivity. The difference in results of anti-HBc and anti-HCV positivity in the prevalence group may be also influenced by a probably higher anti-HBc positivity than anti-HCV positivity at the start or re-start of current IHD treatment. Such difference in seropositivity was shown in our prospective group.

Among anti-HBc-positive or anti-HCV-positive patients, one can find persons with positive HBV DNA or HCV RNA, respectively. Such persons are infectious for others and should be recognized, if possible.

For total anti-HBc-positive, HBsAg-negative patients it is generally assumed that they have undergone HBV infection and usually do not replicate HBV. They are thought to have no or minimal risk of reactivation. On the other hand, there are studies showing that anti-HBc-positive, HBsAg-negative patients may be HBV DNA-positive in up to 79% of cases [18,19,20,21,22,23,24] and isolated anti-HBc-positive patients – in up to 100% of cases – which indicates a high prevalence of occult chronic HBV hepatitis with potential infectivity to non-infected persons [23]. However, more recent studies estimate the prevalence of occult HBV hepatitis on 3–6% of non-dialyzed anti-HBc-positive subjects [16,18,24]. In anti-HBc-positive dialysis patients, HBV DNA seems to be found still more seldom [12,21]. In our study, we were able to show a single HBV DNA-positive patient in the examined group of 164 anti-HBc-positive RRT patients. In the study of Fabrizi et al. [12] among dialysis patients seropositive for anti-HBc none (0/123) had detectable HBV DNA by PCR technology. Out of 116 HBsAg-negative patients awaiting renal transplantation, 15 (13%) had anti-HBc, all had normal levels of serum liver enzymes and none had detectable HBV DNA [21].This may suggest that anti-HBc-positive IHD patients are stamped by HBV infection, but only occasionally replicating HBV, they practically cannot be a cause of infection in other patients. However, even IHD patients with chronic HBsAg positivity may show the rather low HBV DNA levels [25,26], of which one mechanism, perhaps more important, could be due to the elimination of serum HBV load by the IHD procedure [26]. In the study of Yakaryilmaz et al. [27], HBsAg-positive IHD patients had detectable HBV DNA in 16% of cases. According to another concept, HBV DNA remains detectable more so in the liver than in the serum of anti-HBc-positive persons [28]. HBV DNA was also detected in peripheral blood mononuclear cells of HBsAg-negative, anti-HBc-positive, anti-HBs-negative (66% of all cases) and HBsAg-negative, anti-HBc-positive, anti-HBs-positive (82% of cases) IHD patients [23], but not in all studies [10]. These data indicate that anti-HBc-positive patients may be a source of HBV infection under circumstances favorable for HBV replication. It is already concluded that all anti-HBc-positive, HBsAg-negative dialysis patients on the transplant waiting list should be regarded as at risk of HBV reactivation following immunosuppression due to renal transplantation, because such cases are reported [21]. Blanpain et al. [29] performed a retrospective analysis on 247 recipients transplanted between 1985 and 1997, finding that 49 had been anti-HBc-positive but HBsAg-negative before transplantation. Since 2 of these reactivated, they proposed that the risk of reactivation in this context was 5%. HBV can be also transmitted from anti-HBc-positive, HBsAg-negative organ donors (kidney, liver) recipients [30]. French et al. [31] showed that 2% of women with isolated anti-HBc positivity acquired HBsAg positivity at a median of 7.5 years after their study entry. These women have to be considered as having chronic HBV infection. In addition to the aforementioned clinical implications, the relationship between anti-HBc positivity and hepatic and pancreatic carcinogenesis, should be mentioned, although is still not clear [32,33,34].

HCV RNA is much more frequently present in the blood of anti-HCV-positive patients than HBV DNA in anti-HBc-positive persons. HCV RNA was detected in 52–93% of anti-HCV-positive dialysis patients [10,35,36]. In our study, it was 60.6% of cases, which is the most close to the finding of Ghafur et al. (58.3%) [36]. Additionally, HCV RNA was shown in 0.23% of anti-HCV-negative patients. In other studies, among anti-HCV-negative subjects, 0.4–12% tested HCV RNA positive [10,35,36,37,38].

Lack of vaccination against HBV with developed anti-HBs titer >10 IU/l considered as protective was the strongest predictor of anti-HBc positivity in RRT patients. Vaccination of IHD patients was obligatory, but its effectiveness was not satisfactory. Among anti-HBc-positive patients only 1.2% had anti-HBs titer >10 IU/l (but <70 IU/l) in response to vaccination against HBV. In some groups of patients, like HBsAg-negative children awaiting liver transplantation, anti-HBs titer >200 IU/l was advised to be sufficient to prevent de novo HBV infection [39]. Effective vaccination of IHD patients or better pre-dialysis patients usually helps to avoid both clinical hepatitis B and carrying replicable HBV. Anti-HBc are not generated in effectively vaccinated patients exposed to HBV. In response to such exposure, being so-called ‘natural boosting’, elevations in anti-HBs levels in vaccinated persons may occur in the absence of development of HBV infection. This is postulated to result from stimulation of immune memory [40].

The total duration of RRT was in our study the second strongest predictor of anti-HBc positivity. In 2000, Vladutiu et al. [17] reported that the anti-HBc-positive patients had been dialyzed for longer than the non-infected ones. Our data have confirmed results of their studies. Even the oldest patients with chronic HBV infection (HBsAg positive) were dialyzed in our region in separate rooms with dedicated machines. It may explain the lack of correlation between the percent prevalence of HBsAg positivity and anti-HBc positivity. However, a longer duration of RRT may enhance the risk of HBV infection in patients without effective vaccination, which was present in almost 40% of the examined patients. Since this part of the study was cross-sectional in nature, we cannot say whether seroconversion to anti-HBc positivity, expected during longer RRT vintage, was the only reason of higher prevalence of anti-HBc positivity. Differences in mortality and/or transplantation rate between patients with positive viral markers and those ones without such positivity could influence cross-sectional results of our study, and of previous studies [17]. To show an additive relationship between higher anti-HBc positivity and duration of RRT we have undertaken the prospective, observational study, including patients starting IHD as the first method of RRT. With anti-HBc positivity of 11.8% after 1 IHD year and any other changes in this prospective group (n = 85), stable seroconversion rate of 1.23 episodes per 100 patient-years predicts ≈18% of anti-HBc-positive patients after 5 further years and ≈24% after the next 5 years. Thus, duration of IHD as method of RRT may have significant impact on the occurrence of anti-HBc positivity.

In our cross-sectional examination of RRT patients, the history of acute hepatitis was found to be a predictor of anti-HBc positivity among other examined variables. Significance of this occurred, although only 28.6% of the patients with acute hepatitis had established acute HBV infection. In another study, a family history of hepatitis was significantly related to HBV seropositivity [41].

Serum AlAT activity was also identified as a predictor of anti-HBc positivity. In the study of Fabrizi et al. [12,] no relationship was observed between anti-HBc status and liver biochemical status. In their and also in our study, AlAT, AspAt and GGTP activities were influenced in anti-HBc-positive patients by anti-HCV positivity, occurring in 28.3% and 22.3% of these patients, respectively.

Seroprevalence of HBV positivity is frequently [42,43], but not always [40], reported to be higher in men than in women and relates to the risk behaviors more frequent in males than in females [44]. Recently, a life-time number of sexual partners >10 and non-use of condoms were shown as a significantly associated with HBV infection [24]. HBsAg-positive IHD patients were also predominantly men in this study and in our previous one [5]. Interestingly, the anti-HBc-positive group of our IHD patients consisted of a significantly greater number of women than the anti-HBc-negative group. There was no intersex difference in positivity for anti-HBc in IHD patients in previous studies [45,46], but the number of examined patients was smaller (55 and 101 patients, respectively). Fabrizi et al. [12] examined a greater number of patients (n = 585) and found using nominal regression logistic analysis that anti-HBc positivity was not significantly related to gender. However, this analysis included HBsAg-positive subjects, which was 5.1% of all anti-HBc-positive patients. The majority of women in our anti-HBc-positive group may be related to longer duration of their RRT and lower rate of effective vaccinations, both being significant predictors of anti-HBc positivity. A greater time-related anti-HBs decline in adult females than males was shown in the study of McMahon et al. [40]. In patients starting treatment with IHD (the prospective group) there were no significant differences in sex distribution of anti-HBc, which is in agreement with the results of aforementioned studies [12,45,46].

Anti-HBc-positive patients presented higher prevalence of anti-HCV and HCV RNA positivity than anti-HBc negative ones. Although anti-HBc and anti-HCV are markers of 2 different infections, their prevalence may correlate, because HBV and HCV share the same modes of transmission. There was a significant positive correlation between the percent prevalence of anti-HBc positivity and anti-HCV positivity in the 20 IHD centers contributing in the study. Additionally, anti-HCV-positive patients had significantly greater prevalence of all anti-HBc predictors than anti-HCV-negative subjects. In our study, dysfunctional antibody production in response to vaccination against HBV was more frequent in anti-HCV-positive than in anti-HCV-negative IHD patients. It was reported that HCV infection may favor anti-HBc as the only serological marker for HBV infection (49.2% of patients with isolated anti-HBc showed anti-HCV) [47]. In the multivariate regression model, hepatitis C viremia in women was a predictor of retained isolated anti-HBc positivity [31]. An increasing prevalence of anti-HCV positivity with IHD duration was already documented in previous studies [17,48,49]. Our study confirmed longer RRT in anti-HCV-positive patients compared to anti-HCV-negative ones. Thus, both anti-HBc positivity and anti-HCV positivity are related to RRT duration. Anti-HCV positivity was not associated with the prevalence of anti-HBc in IHD patients in the study of Hayashi et al. [50], but it was in other studies in various populations [12,24,47].

In the previous evidence, metrical age was either significantly related to HBV infection [24,41] or was not predictive for anti-HBc positivity [17,46]. In our study, in anti-HBc-positive IHD patients there was a greater prevalence of patients aged >30 years as compared to the anti-HBc-negative group. Similar results were obtained in a Brazilian non-injecting drug users study [24]. However, in our study, age was not an independent predictor of anti-HBc positivity.

Taking into account the possible consequences of long-term anti-HBc status, vaccination against HBV should be intensified in the pre-dialysis period, because the lack of effective vaccination is a main predictor of anti-HBc positivity in RRT patients. Increasing prevalence of anti-HBc-positive patients in dialysis centers indicates HBV transmission. Periodical determination of anti-HBc, which is usually not formally required, may be helpful in evaluation of epidemiological status and risk for HBV infection. Occurrence of seroconversions to anti-HBc positivity should make it mandatory to revise vaccination strategy, to enhance trials maintaining protective anti-HBs levels during RRT and to enforce general prophylactic measures. Additionally, anti-HBc-positive patients may suffer from occult HBV infection and should be tested for HBV DNA as possible source of HBV infectivity to other persons.

 

goto top of outline Conclusions

• The IHD patients are still under significant exposure on HBV, which results in formation of anti-HBc and occasionally in occult HBV infection.

• A lack of effective vaccination against HBV is a main predictor of anti-HBc positivity, which can be influenced by a revised vaccination strategy.

• A higher prevalence of anti-HBc positivity may be expected in RRT patients with longer duration of RRT, female sex, age >30 years, history of acute hepatitis and anti-HCV/HCV RNA positivity.

• The serological marker for HBV exposure (anti-HBc) occurs with higher frequency than the one for HCV exposure (anti-HCV), which may be related to greater infectivity of HBV.

• Periodic determination of anti-HBc in dialysis centers may be helpful in the evaluation of epidemiological status and risk for HBV infection, and useful in making a decision on commencement of more effective prophylactic measures.

 

goto top of outline Acknowledgements

The authors thank all physicians, technicians and nurses from dialysis centers in Wielkopolska, who participated in the collection of data and performed non-routine laboratory testing.


 goto top of outline References
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  2. Centers for Disease Control and Prevention: Recommendations for preventing transmission of infections among chronic hemodialysis patients. MMWR Recomm Rep 2001;50:1-43.
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  4. Rutkowski B, Lichodziejewska-Niemierko M, Grenda R, Czekalski S, Durlik M, Bautembach S: Report on the Renal Replacement Therapy in Poland – 2006. Gdańsk, Drukonsul, 2008, pp 29–32.
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    External Resources

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    External Resources

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  27. Yakaryilmaz F, Gurbuz OA, Guliter S, Mert A, Songur Y, Karakan T, et al: Prevalence of occult hepatitis B and hepatitis C virus infections in Turkish hemodialysis patients. Ren Fail 2006;28:729–735.
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  29. Blanpain C, Knoop C, Delforge ML, Antoine M, Peny MO, Liesnard C, Vereerstraeten P, Cogan E, Adler M, Abramowicz D: Reactivation of hepatitis B after transplantation in patients with pre-existing anti-hepatitis B surface antigen antibodies: report on three cases and review of the literature. Transplantation 1998;66:883–886.
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  35. Choo QL, Weiner AJ, Overby LR, Kuo G, Houghton M, Bradley DW: Hepatitis C virus: the major causative agent of viral non-A, non-B hepatitis. Br Med Bull 1990;46:423–441.
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 goto top of outline Author Contacts

Prof. Alicja E. Grzegorzewska, MD, PhD
Department of Nephrology, Transplantology and Internal Diseases
Karol Marcinkowski University of Medical Sciences
Al. Przybyszewskiego 49, PL–60-355 Poznań (Poland)
Tel. +48 61 8691 700, Fax +48 61 8691 688, E-Mail alicja_grzegorzewska@yahoo.com


 goto top of outline Article Information

Received: January 20, 2009
Accepted: September 4, 2009
Published online: November 28, 2009
Number of Print Pages : 10
Number of Figures : 1, Number of Tables : 3, Number of References : 50


 goto top of outline Publication Details

Nephron Clinical Practice

Vol. 114, No. 3, Year 2010 (Cover Date: February 2010)

Journal Editor: El Nahas M. (Sheffield)
ISSN: 1660-2110 (Print), eISSN: 1660-2110 (Online)

For additional information: http://www.karger.com/NEC


Copyright / Drug Dosage / Disclaimer

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

Abstract

Background: Total antibodies to core antigen of hepatitis B virus (anti-HBc) are a marker for previous or current infection with hepatitis B virus (HBV). Our aim was to examine the prevalence and incidence of anti-HBc in relation to demographic, clinical and laboratory data of patients treated with intermittent hemodialysis (IHD). Methods: Predictors for anti-HBc positivity were evaluated in prevalence IHD patients with negative testing for surface antigen of HBV (HBsAg, n = 1,105) using the stepwise backward regression analysis. Patients starting IHD (n = 336) were introduced into the one-year prospective study evaluating seroconversion for anti-HBc. Results: Anti-HBc positivity (19.5% of all patients) was predicted by lack of vaccination against HBV with developed protective titer of antibodies to HBsAg (β = 0.592, p = 0.000), vintage of renal replacement therapy (RRT, β = 0.206, p = 0.000), history of hepatitis (β = 0.101, p = 0.000), and activity of alanine aminotransferase (β = 0.057, p = 0.037). In 85 prospective patients who finished first IHD year, seroconversion rate for anti-HBc was 1.23 episodes/100 patient-years. Conclusions: Lack of or not effective vaccination against HBV is the strongest predictor for prevalence of anti-HBc positivity in RRT patients. Periodical determination of anti-HBc, usually not required, may be helpful in evaluation of current epidemiological status and risk for further HBV infection in dialysis centers.



 goto top of outline Author Contacts

Prof. Alicja E. Grzegorzewska, MD, PhD
Department of Nephrology, Transplantology and Internal Diseases
Karol Marcinkowski University of Medical Sciences
Al. Przybyszewskiego 49, PL–60-355 Poznań (Poland)
Tel. +48 61 8691 700, Fax +48 61 8691 688, E-Mail alicja_grzegorzewska@yahoo.com


 goto top of outline Article Information

Received: January 20, 2009
Accepted: September 4, 2009
Published online: November 28, 2009
Number of Print Pages : 10
Number of Figures : 1, Number of Tables : 3, Number of References : 50


 goto top of outline Publication Details

Nephron Clinical Practice

Vol. 114, No. 3, Year 2010 (Cover Date: February 2010)

Journal Editor: El Nahas M. (Sheffield)
ISSN: 1660-2110 (Print), eISSN: 1660-2110 (Online)

For additional information: http://www.karger.com/NEC


Copyright / Drug Dosage

Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in goverment regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

References

  1. Kidd-Ljunggren K, Holmberg A, Bläckberg J, Lindqvist B: High levels of hepatitis B virus DNA in body fluids from chronic carriers. J Hosp Infect 2006;64:352–357.
  2. Centers for Disease Control and Prevention: Recommendations for preventing transmission of infections among chronic hemodialysis patients. MMWR Recomm Rep 2001;50:1-43.
  3. Miller ER, Alter MJ, Tokars JI: Protective effect of hepatitis B vaccine in chronic hemodialysis patients. Am J Kidney Dis 1999;33:356–360.
  4. Rutkowski B, Lichodziejewska-Niemierko M, Grenda R, Czekalski S, Durlik M, Bautembach S: Report on the Renal Replacement Therapy in Poland – 2006. Gdańsk, Drukonsul, 2008, pp 29–32.
  5. Grzegorzewska AE, Kurzawska-Firlej D, Świderski A, de Mezer-Dambek M, Frankiewicz D, Zaremba-Drobnik D, Banachowicz W, Dumanowska-Żmuda A, Ratajewski W, Niepolski L, Krawczyk R, Sobolewski J, Pulchny J, Molenda J, Wojciechowski J, Mikstacki Z, Zachwieja J: Infections with hepatitis B virus in hemodialysis units of Wielkopolska (in Polish). Przegl Epidemiol 2008;62:29–37.

    External Resources

  6. Yen-Xuan NT, Dieu-Hien PT, Nga CN, Crocè LS: Clinical and virological features of acute HBV-related hepatitis in southern Vietnam. Ann Hepatol 2006;5:92–96.

    External Resources

  7. European Best Practice Guidelines. Prevention and management of HBV, HCV and HIV in HD patients. Nephrol Dial Transplant 2002;17(suppl 7):78–87.
  8. Veldhuijzen IK, van Driel HF, Vos D, de Zwart O, van Doornum GJ, de Man RA, Richardus JH: Viral hepatitis in a multi-ethnic neighborhood in The Netherlands: results of a community-based study in a low prevalence country. Int J Infect Dis 2009;13:e9–e13.
  9. Gandhi RT, Wurcel A, Lee H, McGovern B, Boczanowski M, Gerwin R, Corcoran CP, Szczepiorkowski Z, Toner S, Cohen DE, Sax PE, Ukomadu C: Isolated antibody to hepatitis B core antigen in human immunodeficiency virus type-1-infected individuals. Clin Infect Dis 2003;36:1602–1605.
  10. Oesterreicher C, Hammer J, Koch U, Pfeffel F, Sunder-Plassmann G, Petermann D, Müller C: HBV and HCV genome in peripheral blood mononuclear cells in patients undergoing chronic hemodialysis. Kidney Int 1995;48:1967–1971.
  11. Minuk GY, Sun DF, Greenberg R, Zhang M, Hawkins K, Uhanova J, Gutkin A, Bernstein K, Giulivi A, Osiowy C: Occult hepatitis B virus infection in a North American adult hemodialysis patient population. Hepatology 2004;40:1072–1077.
  12. Fabrizi F, Messa PG, Lunghi G, Aucella F, Bisegna S, Mangano S, Villa M, Barbisoni F, Rusconi E, Martin P: Occult hepatitis B virus infection in dialysis patients: a multicentre survey. Aliment Pharmacol Ther 2005;21:1341–1347.
  13. Good practice guidelines for renal dialysis/transplantation units. Prevention and control of blood-borne virus infection. Recommendations of a working group convened by the Public Health Laboratory Service (PHLS) on behalf of the Department of Health. London, Department of Health, 2002.
  14. Tsouchnikas I, Dounousi E, Xanthopoulou K, Papakonstantinou S, Thomoglou V, Tsakiris D: Loss of hepatitis B immunity in hemodialysis patients acquired either naturally or after vaccination. Clin Nephrol 2007;68:228–234.
  15. Barałkiewicz G, Juszczyk J, Grzegorzewska A, Czarnecki R: The results of the vaccination against hepatitis B (‘Engerix B’) in dialysed uaemic patients (in Polish). Hepatologia Pol 1996;3:11–14.
  16. Findik D, Arslan U, Baykan M: Determination of hepatitis B virus DNA incidence, viral load, and mutations in blood donors with HBsAg and anti-HBs-negative serology and antibodies to hepatitis B core antigen. Eur J Intern Med 2007;18:571–575.
  17. Vladutiu DS, Cosa A, Neamtu A, State D, Braila M, Gherman M, Patiu IM, Dulau-Florea I: Infections with hepatitis B and C viruses in patients on maintenance dialysis in Romania and in former communist countries: yellow spots on a blank map? J Viral Hepat 2000;7:313–319.
  18. Gibney KB, Torresi J, Lemoh C, Biggs BA: Isolated core antibody hepatitis B in sub-Saharan African immigrants. J Med Virol 2008;80:1565–1569.
  19. Gutiérrez C, León G, Loureiro CL, Uzcátegui N, Liprandi F, Pujol FH: Hepatitis B virus DNA in blood samples positive for antibodies to core antigen and negative for surface antigen. Clin Diagn Lab Immunol 1999;6:768–770.
  20. Silva AE, McMahon BJ, Parkinson AJ, Sjogren MH, Hoofnagle JH, Di Bisceglie AM: Hepatitis B virus DNA in persons with isolated antibody to hepatitis B core antigen who subsequently received hepatitis B vaccine. Clin Infect Dis 1998;26:895–897.
  21. Roberts RC, Lane C, Hatfield P, Clutterbuck E, Atkins M, Brown A, Dorling A: All anti-HBc-positive, HBsAg-negative dialysis patients on the transplant waiting list should be regarded as at risk of hepatitis B reactivation post-renal transplantation – report of three cases from a single centre. Nephrol Dial Transplant 2006;21:3316–3319.
  22. Grob P, Jilg W, Bornhak H, Gerken G, Gerlich W, Günther S, Hess G, Hüdig H, Kitchen A, Margolis H, Michel G, Trepo C, Will H, Zanetti A, Mushahwar I: Serological pattern ‘anti-HBc alone’: report on a workshop. J Med Virol 2000;62:450–455.
  23. Cabrerizo M, Bartolomé J, De Sequera P, Caramelo C, Carreño V: Hepatitis B virus DNA in serum and blood cells of hepatitis B surface antigen-negative hemodialysis patients and staff. J Am Soc Nephrol 1997;8:1443–1447.
  24. Ferreira RC, Rodrigues FP, Teles SA, Lopes CL, Motta-Castro AR, Novais AC, et al: Prevalence of hepatitis B virus and risk factors in Brazilian non-injecting drug users. J Med Virol 2009;81:602–609.
  25. Fabrizi F, Lunghi G, Martin P: Hepatitis B virus infection in hemodialysis: recent discoveries. J Nephrol 2002;15:463–468.
  26. Tseng GY, Lin HJ, Fang CT, Cheng YT, Huang CH, Tseng GC, et al: Hemodialysis reduces the viral load in uremic patients with chronic hepatitis B infection. Ren Fail 2008;30:1000–1005.
  27. Yakaryilmaz F, Gurbuz OA, Guliter S, Mert A, Songur Y, Karakan T, et al: Prevalence of occult hepatitis B and hepatitis C virus infections in Turkish hemodialysis patients. Ren Fail 2006;28:729–735.
  28. Lok AS, McMahon BJ: Chronic hepatitis B. Hepatology 2007;45:507–539.
  29. Blanpain C, Knoop C, Delforge ML, Antoine M, Peny MO, Liesnard C, Vereerstraeten P, Cogan E, Adler M, Abramowicz D: Reactivation of hepatitis B after transplantation in patients with pre-existing anti-hepatitis B surface antigen antibodies: report on three cases and review of the literature. Transplantation 1998;66:883–886.
  30. Wachs ME, Amend WJ, Ascher NL, Bretan PN, Emond J, Lake JR, Melzer JS, Roberts JP, Tomlanovich SJ, Vincenti F, et al: The risk of transmission of hepatitis B from HBsAg(–), HBcAb(+), HBIgM(–) organ donors. Transplantation 1995;59:230–234.
  31. French AL, Lin MY, Evans CT, Benning L, Glesby MJ, Young MA, et al: Long-term serologic follow-up of isolated hepatitis B core antibody in HIV-infected and HIV-uninfected women. Clin Infect Dis 2009;49:148–154.
  32. Hassan MM, Li D, El-Deeb AS, Wolff RA, Bondy ML, Davila M, Abbruzzese JL: Association between hepatitis B virus and pancreatic cancer. J Clin Oncol 2008;26:4557–4562.
  33. Adachi S, Shibuya A, Miura Y, Takeuchi A, Nakazawa T, Saigenji K: Impact of occult hepatitis B virus infection and prior hepatitis B virus infection on development of hepatocellular carcinoma in patients with liver cirrhosis due to hepatitis C virus. Scand J Gastroenterol 2008;43:849–856.
  34. Kim MJ, Kwon OS, Chung NS, Lee SY, Jung HS, Park DK, Ku YS, Kim YK, Kim YS, Kim JH: The significance of anti-HBc and occult hepatitis B virus infection in the occurrence of hepatocellular carcinoma in patients with HBsAg and anti-HCV negative alcoholic cirrhosis (in Korean). Korean J Hepatol 2008;14:67–76.
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