Isolated antibody to hepatitis B core antigen (anti-HBc) is defined as seropositivity for anti-HBc in the absence of hepatitis B surface antigen (HBsAg) and antibody to HBsAg (anti-HBs). Isolated anti-HBc seropositivity may represent the following: (1) resolved hepatitis B virus (HBV) infection, in which anti-HBs titers are below the level that defines positivity; (2) occult chronic HBV infection, with levels of HBsAg below the limits of detection; or (3) a false-positive test result.1,2 The clinical significance of isolated anti-HBc requires further investigation. Whether patients with isolated anti-HBc require vaccination against HBV remains controversial.
Isolated anti-HBc is a common finding in HIV-infected persons (∼17%-81%)3-8 compared with healthy blood donors (∼2%-5%).1,9-11 An association between isolated anti-HBc and hepatitis C virus (HCV) infection has been reported in HIV-infected and HIV-uninfected persons.2-5,7,8,12-14 It has been hypothesized that HCV infection may impair the antibody response to HBsAg,15 may cause false-positive anti-HBc results,5 or may cause false-negative HBsAg results.16 However, in small series studies done in Taiwan,6,17 where HBV infection is considered hyperendemic,18,19 isolated anti-HBc was not associated with HCV infection in HIV-infected patients.
Injection drug use is one of the strongest risk factors for HCV infection. Earlier studies revealed a higher prevalence of HCV infection among injection drug users (IDUs) (∼53%-82.2%)20-23 compared with non-IDUs20,22 and the general population.24,25
In this study, we aimed to elucidate the association between HIV infection, HCV infection, and isolated anti-HBc to determine the risk factors for isolated anti-HBc in these high risk groups, including IDUs with a high prevalence of HCV infection and HIV-infected patients.
MATERIALS AND METHODS
Patients and Data Collection
The study protocol was approved by the Institutional Review Board (EMRP-098-004) at E-Da Hospital, a major university-affiliated referral hospital for HIV and AIDS care in southern Taiwan. Highly active antiretroviral therapy has been provided at no charge to all HIV-infected patients at designated hospitals and clinics according to the treatment guidelines in Taiwan since April 1, 1997.26 E-Da Hospital is also one of the major hospitals designated for methadone maintenance therapy for IDUs in southern Taiwan since August 2007. This cross-sectional study prospectively recruited a cohort of consecutive, nonhemophiliac, HIV-infected patients, diagnosed between 1988 and 2009, and HIV-uninfected IDUs attending the methadone clinic between August 2007 and May 2009, at E-Da Hospital. A complete HBV and HCV serological profile was tested, and the medical records were reviewed to identify the risk factors associated with seropositivity of isolated anti-HBc.
HIV-1 infection was diagnosed by detecting HIV antibody in serum with a single microparticle enzyme immunoassay (IMx HIV-1/HIV-2 III plus; Abbott GmbH and Co, KG, Delkenheim, Germany) and confirmed by Western blot (New Lav Blot I; Bio-Rad, Marnes la Coquette, France). CD4 cell counts were determined with flow cytometry (BDIS FACScan; BD Biosciences, San Jose, CA) in units of cells per microliter. Plasma HIV RNA loads were quantified with a branched DNA technique [VERSANT HIV-1 RNA 3.0 (bDNA); Siemens, Tarrytown, NY], with a lower detection limit of 50 (1.7 log10) copies per milliliter. HBV DNA was extracted from frozen plasma (stored at −80°C) obtained from patients who tested positive for isolated anti-HBc and was quantified using real-time polymerase chain reaction (COBAS TaqMan HBV Test; Roche Molecular Biochemicals, Branchburg, NJ), with a threshold of detection of 6 IU/mL. HBsAg, anti-HBs, anti-HBc, antibody to hepatitis A virus (anti-HAV), and antibody to HCV (anit-HCV) were determined using a chemiluminescent microparticle immunoassay (CMIA, ARCHITECT; Abbott Laboratories, Abbott Park, IL). All assay protocols, cut-offs, and interpretations were carried out according to the manufacturers' instructions.
Isolated anti-HBc was defined as a blood sample seropositive for anti-HBc but negative for both HBsAg and anti-HBs. Nonisolated anti-HBc was defined as any combination of hepatitis B serological patterns (HBsAg, anti-HBs, and anti-HBc) other than isolated anti-HBc. Occult HBV infection was defined as the detection of HBV DNA in patients in the absence of HBsAg.16,27
All statistical analyses were performed with the use of Stata (Version 10.0; Stata, College Station, TX). Continuous data are presented as the mean value ± SD, or when indicated, as an absolute number and percentage. The 95% confidence interval (95% CI) was calculated. Categorical variables were analyzed using the Pearson χ2 test or Fisher exact test, as appropriate. Continuous variables were analyzed using Student t test. All P values were 2-tailed, and a P value <0.05 was considered to be statistically significant. χ2 test for trend was used to test for trend. Logistic regression was used to analyze risk factors for acquiring isolated anti-HBc. All variables with a P < 0.10 were considered for inclusion in the multivariable model. Forward selection, using the likelihood ratio test, was used to select the final multivariable model for risk factors for isolated anti-HBc. Age, sex, HIV, and HCV was included in the model a priori.
Subject Disposition and Demographics
The study population consisted of 1598 consecutive patients, including 955 HIV-positive patients and 643 HIV-negative IDUs. A representative proportion of each group of interest was present, including: 211 (13.2%) HIV infected, 554 (34.7%) HCV infected, 744 (46.6%) HIV HCV coinfected, and 89 (5.6%) individuals negative for both HIV and HCV. Of the 1598 patients, HBsAg, anti-HBs, and anti-HBc were tested in 1579, 1535, and 1194 subjects, respectively; 365 (23.1%) had positive HBsAg, 980 (63.8%) had anti-HBs, 74 (4.6%) had no markers of HBV infection (HBsAg, anti-HBs, and anti-HBc were all negative), and 193 (12.1 %) had isolated anti-HBc. The demographics and clinical characteristics of the subjects are shown in Table 1.
Comparing patients with and without isolated anti-HBc, those with isolated anti-HBc antibody were significantly older (40.7 ± 9.3 versus 36.9 ± 8.0, respectively, P < 0.0001). The prevalence of isolated anti-HBc antibody was also significantly higher among HIV-infected subjects [14.0% (134 of 955)] than non-HIV-infected subjects [9.2% (59 of 643); P < 0.01], and in the male gender (P = 0.02). The prevalence of isolated anti-HBc was significantly increased with age, from 4.0% (5 of 124) before 30 years of age; to 10.1% (76 of 749) between 30 and 39 years of age; 12.7% (66 of 521) between 40 and 49 years of age; and 22.5% (46 of 204) after 50 years of age (Fig. 1 and Table 1). There was a significant increasing trend of isolated anti-HBc positivity with each decade increase in age (odds ratio: 1.64, 95% CI: 1.37 to 1.98, test for trend: P < 0.0001). The 2 groups (patients with and without isolated anti-HBc) were similar in terms of prevalence of anti-HCV and anti-HAV antibody, history of percutaneous exposure to blood, proportion that were born before implementation of nation-wide HBV vaccination (before July 1984), and level of aspartate aminotransferase and alanine aminotransferase. Factors not associated with isolated anti-HBc seropositivity among the 955 HIV-infected patients (134 with isolated anti-HBc and 821 without isolated anti-HBc) included the risk factors for acquiring HIV, mean and nadir CD4 count, plasma HIV RNA, and receipt of antiretroviral therapy.
In the multivariate analysis, increasing age and HIV infection were significantly associated with isolated anti-HBc (Table 2) but HCV antibody status (adjusted odds ratio, 1.33; 95% CI: 0.88 to 2.03; P = 0.18) and the male gender were not.
Of 193 patients who had isolated anti-HBc at baseline, only 3 (1.6%) of 185 tested for the presence of HBV DNA (130 HIV-infected patients and 55 HIV-uninfected patients, respectively) had detectable but low levels of HBV DNA (6, 62, and 69 IU/mL, respectively) and all were HIV infected (2.3%, 3 of 130). The majority (91.2 %, 176 of 193) had low titers of anti-HBs (3.6 ± 2.9 IU/L) that are below the laboratory definition of a positive result (<10 IU/L). Complete loss of anti-HBs (anti-HBs = 0 IU/L) among patients with isolated anti-HBc in those aged <30, 30-39, 40-49 and ≥50 years were 0% (0 of 5), 7.9% (6 of 76), 7.6% (3 of 66) and 13.0% (6 of 46), respectively (P = 0.72). Low levels of anti-HBs antibody was not associated with HIV infection (121 of 134, 90.3% versus 55 of 59, 93.2%, P = 0.59), levels of immunity in HIV-infected individuals, as represented by CD4 count (P = 0.29), nadir CD4 count (P = 0.09), and plasma HIV RNA load (P = 1.00).
This study showed that isolated anti-HBc was associated with older age and HIV infection. In contrast to previous studies, an association with HCV infection was not found. Our study included a representative proportion of each group of interest in sufficient numbers, including HIV infected, HCV infected, HIV HCV coinfected, and individuals negative for both HIV and HCV. This study design ensures that selection bias is minimized. The lower seroprevalence of isolated antiHBc observed in our study (12.1%), compared with previous studies (∼17%-81%),3-8 may be explained by inclusion of subgroups that are at a lower risk for isolated anti-HBc. However, the seroprevalence of isolated anti-HBc in our study remains higher than that observed among healthy blood donors (∼2%-5%).1,9-11
The mechanism by which HIV infection may cause isolated anti-HBc antibody remains unclear. It is known that HIV may cause B-cell dysfunction, and it is possible that those with HIV infection may have a higher incidence of false positive anti-HBc results or that the levels or durability of the anti-HBs response to natural HBV infection are perturbed.28 Our study did not demonstrate an association between isolated anti-HBc and the level of immune function as measured by CD4 cell count, nadir CD4 cell count, and plasma HIV RNA,3,5,7,8 which suggests that immunodeficiency is not the only explanation for the high frequency of isolated anti-HBc antibody found in HIV-infected patients. Although a high proportion of HIV-infected patients had low levels of anti-HBs antibody below the positive cut-off level (121 of 134, 90.3%), this was not associated with HIV infection status, level of immunosuppression in HIV-infected individuals, as represented by the CD4 count, nadir CD4 count, and plasma HIV RNA load.
Previous studies5,7 in Western countries have shown that subjects who were coinfected with HIV and HCV were more likely to have isolated anti-HBc antibody than were subjects infected with HIV-1 alone. In a study done in Taiwan,6 HCV infection was not associated with isolated anti-HBc antibody in HIV-infected patients. However, due to the small numbers of patients with HCV infection, that study did not have the power to detect an association between HCV infection and isolated anti-HBc, even if there was one. The study was conducted before 2003, before the outbreak of HIV infection in IDUs in Taiwan.29-31 This outbreak resulted in an increase in seroprevalence of HIV HCV coinfection from 8.8% to 9.1% before 2003,6,17 to 56.7% between 2000 to 2005,32 whereas the prevalence of HIV HBV coinfection remained similar (18.8%-23.6% before 20036,17 to 16.5% between 2000 to 200532). Our study included both HIV-infected and HIV-uninfected IDUs, who have a high prevalence of HCV infection, which more closely reflect the current epidemiology. In addition, a sufficient number of HCV-infected patients were included to ensure enough power to detect an association between HCV infection and isolated anti-HBc.
Wedemeyer et al14 reported that among HIV-uninfected patients, anti-HBc-alone phenotype was significantly more frequent in HCV viremic than in HCV recovered. French et al8 further pointed out that the prevalence of isolated anti-HBc in women is greater in the presence of ongoing HCV viremia, HIV positivity, a history of injection drug use, >10 lifetime sex partners, and plasma HIV RNA level >100,000 copies per milliliter. In contrast to previous studies, an association between HCV infection and isolated anti-HBc was not observed in our study.
There are several possible explanations for this. First, most previous studies only compared isolated anti-HBc with 1 or 2 of these specific hepatitis B serological patterns,2,3,5-8,33 which may cause selection bias and yield inconsistent results of risk factors associated with isolated anti-HBc (Table 3). Combinations of hepatitis B serological patterns other than isolated anti-HBc were termed as “nonisolated anti-HBc” in our study. This included: HBsAg(+)/anti-HBs(−)/anti-HBc(+), HBsAg(−)/anti-HBs (+)/anti-HBc(+), HBsAg(−)/anti-HBs(+)/anti-HBc(−), HBsAg(−)/anti-HBs(−)/anti-HBc(−), and HBsAg(+)/anti-HBs(+)/anti-HBc(+). In our study, the inclusion of various combinations of hepatitis B serological patterns ensured an appropriate representation of all subjects, which closely approximated the real clinical scenario, thereby minimizing selection bias.
Second, HBV, HCV and HIV share common routes of transmission, but the prevalence and main transmission routes differ by geographic region.34,35 HCV is not efficiently transmitted by perinatal or sexual exposures, which are important modes of transmission for HBV and HIV.34,36 In Piroth study done in France,4 a significantly higher proportion of patients with isolated anti-HBc had intravenous/percutaneous route as the transmission route for HIV infection (54.8% vs 12.6%, P < 0.0001) than patients with nonisolated anti-HBc. HCV infection is more efficiently transmitted percutaneously than sexually.36 The observed association between HCV infection and isolated anti-HBc may actually be due to the association between intravenous/percutaneous transmission and HCV infection. However, in our study, the risk factors for acquiring HIV infection was similar between those with and without isolated anti-HBc. This may partly explain why our results differ from previous studies done in Western countries.
We demonstrated an association between isolated anti-HBc and an increase in age. There was a significantly increasing trend in the prevalence of isolated anti-HBc antibody (P < 0.0001) per decade increase in age. Few studies have addressed the association between age and isolated anti-HBc. Our result contradicted some reports (Table 3),7,33 which showed a higher prevalence of isolated anti-HBc in the younger population. These studies carried potential selection bias which we avoided by including a wide range of study subjects with a variety of combination of hepatitis B markers seropositivity (Table 3). Knoll et al37 also found that “anti-HBc alone” seropositivity occurred more frequently in the older age groups (22.7% in the age group 71-80 years and 9.4% in the youngest group <30 years) in an unselected population of patients and employees of a university hospital in southern Germany. Averhoff et al38 found that aging was associated with a decline in anti-HBs titers. The aging process may lead to development of isolated anti-HBc by simple decline of anti-HBs to levels below the laboratory cut-off for a positive result. In our study, we found a trend toward an increasing proportion with complete loss of anti-HBs with increasing age, though not reaching statistical significance (P = 0.72). A possible hypothesis is that the aging process may cause the complete loss of anti-HBs, resulting in isolated anti-HBc. However, further studies are required to verify this finding and clarify the mechanisms involved.
In patients with isolated anti-HBc, determination of the HBV DNA level is important39,40 because occult HBV infection should be excluded before a HBV vaccine is administered. The frequency of occult hepatitis B in patients with isolated anti-HBc ranged from 0% to 89.5%,41-46 which may be due to different methods of quantifying HBV replication. Occult HBV infection previously accounted for 7.3% of HIV-infected patients with isolated anti-HBc in Taiwan,17 but occurred in only 8 of 400 (2%) HIV-infected women with isolated anti-HBc in the United States.46 In our study, occult HBV infection was found in only 3 of 130 (2.3%) HIV-infected patients with isolated anti-HBc. Thus, ongoing occult HBV infection in HIV-infected patients with isolated anti-HBc in our study was rare. In fact, most of the HIV-infected patients (90.3%, 121 of 134) with isolated anti-HBc in our study had low levels of anti-HBs below the laboratory definition of a positive result, which may represent a decline of anti-HBs. Therefore, vaccination may not be necessary among these patients in our study. Whether vaccination is required or not in this population deserves further investigation.
In Taiwan, the nation-wide HBV vaccination program was initiated in July 198447 with several catch-up programs in the subsequent years after July 1984.47,48 A high coverage rate (86.9%-98%) was achieved and has dramatically reduced HBV seroprevalence among persons born after July 1984.19,47,49 This decline has been shown to occur in both HIV-negative and HIV-positive persons born in the era of the nation-wide HBV vaccination in Taiwan.50 The widespread HBV vaccination program was expected to reduce the prevalence of isolated anti-HBc, but this was not observed in a study by Liang et al.51 on isolated anti-HBc in HIV-infected IDUs in Taiwan. In our study, the impact of the HBV vaccination program on the prevalence of isolated anti-HBc was negligible. Only 2 of 28 (7.1%) study subjects, born after widespread HBV vaccination, had isolated anti-HBc. However, the numbers are too small to be conclusive. Further investigation is required to clarify the impact of HBV vaccination on the prevalence of isolated anti-HBc in these young individuals.
Our study suffers from several limitations. First, HCV viral load was not determined and the HCV infection status in anti-HCV-positive subjects was unknown, though most of HIV-infected patients with anti-HCV had persistent HCV infection in 1 study.52 Whether HCV viremia is or is not associated with isolated anti-HBc requires further investigation. Second, HBV vaccine was not administered to the patients with isolated anti-HBc to determine whether an anamnestic or primary responses occurs, which provides indirect evidence indicating previous infection.53 Third, we did not repeat tests for isolated anti-HBc to rule out false positivity. However, because the overall sensitivity and specificity of anti-HBc in our study was estimated to be 98.6% and 99.4%,54 false positivity is less likely. A high false positive rate will lead to a recommendation to vaccinate these patients.
In conclusion, isolated anti-HBc seropositivity was significantly associated with HIV infection and older age. HCV infection was not associated with isolated anti-HBc in a country hyperendemic with HBV infection, even in populations with a high prevalence of HCV infection. The majority was not attributable to occult HBV infection but rather low level of anti-HBs, suggesting that HBV vaccination may not be required.
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