The authors have declared that no competing interests exist.
Conceived and designed the experiments: H-YS W-CK H-HL C-CH. Performed the experiments: W-CL P-YW C-HW. Analyzed the data: H-YS C-YC N-YL C-JY S-HL M-ST W-CL P-YW C-HW. Wrote the paper: H-YS H-HL C-CH.
Seroprevalence of hepatitis B virus (HBV) after implementation of universal neonatal HBV vaccination and catch-up vaccination programs remains rarely investigated among the adults who were born in the vaccination era (in or after 1986) and engaged in high-risk sexual behaviors.
Between 2006 and 2012, we determined HBV surface antigen ([HBsAg), anti-HBs, and HBV core antibody (anti-HBc), hepatitis C virus antibody (anti-HCV) and rapid plasma reagin titers among HIV-infected men who have sex with men (MSM) born during 1984–1985 (Group I: 244 persons) and those born in or after 1986 (Group II: 523), and HIV-uninfected MSM (Group III: 377) and heterosexuals (Group IV: 217) born in or after 1986. Prevalence and incidence of HBV infection were estimated and multivariate analysis was performed to identify factors associated with HBsAg positivity.
Compared with Group I, Groups II-IV had a significantly lower prevalence of HBsAg positivity (7.8% vs 3.7%, 2.4%, and 3.2%, respectively); and the prevalence of anti-HBc positivity was also lower for Groups III and IV (30.3% vs. 19.6%, and 18.0%, respectively), but no difference was observed between Groups I and II (30.3% vs. 26.3%). In multivariate analysis, HBsAg positivity was significantly associated with syphilis (adjusted odds ratio, 2.990; 95% confidence interval, 1.502–5.953) and anti-HCV positivity (adjusted odds ratio, 3.402; 95% confidence interval, 1.091–10.614). In subjects of Group II with all-negative HBV markers at baseline, the incidence rate of HBsAg seroconversion was 0.486 episodes per 100 person-years; and for those who received combination antiretroviral therapy containing lamivudine and/or tenofovir, none developed HBsAg seroconversion during the follow-up.
Among the adults who were born in or after 1986 and engaged in high-risk sexual behaviors in Taiwan, neonatal HBV vaccination and catch-up vaccination programs conferred long-term protection against HBsAg seroconversion and HBsAg positivity was associated with syphilis and anti-HCV positivity.
Hepatitis B virus (HBV) vaccination with high immunogenicity of 90 to 95% in healthy adults aged less than 40 years has effectively decreased the incidence of acute HBV infection
Despite a low incidence, cases of HBV infection among adults who had undergone HBV vaccination at birth in Alaska and Taiwan have been reported
Given the shared transmission routes of HIV and HBV, co-infection with HBV and HIV is common. It has been shown that seropositivity for syphilis and HIV infection, and the number of lifetime sexual partners are associated with increased risk of HBV infection
In this study, we aimed to investigate whether neonatal HBV vaccination and catch-up vaccination could confer long-term protection against HBV infection among HIV-infected patients and adults at risk for HIV infection; to identify factors associated with HBV infection; and to estimate the incidence of HBV surface antigen (HBsAg) seroconversion among HIV-infected patients in Taiwan where the background prevalence of HBsAg positivity was estimated 13–25% among the unvaccinated adults
Nationwide HBV vaccination program in Taiwan was initially implemented to vaccinate newborns of HBsAg-positive mothers alone with administration of immunoglobulin to infants born to mothers who tested positive for HBV envelope antigen (HBeAg) in July 1984, which subsequently extended to cover all newborns after July 1986
In April 2006, an expanded program of free-of-charge, anonymous counseling and testing (VCT) for HIV infection for persons who considered themselves at risk for HIV infection and related sexually transmitted diseases (STDs) was implemented at the National Taiwan University Hospital
From April 2006 to December 2012, we enrolled individuals born in or after 1986 who sought VCT or HIV care, and those born during 1984–1985 who sought HIV care at this university hospital and four other major designated hospitals in Taiwan (three in northern and two southern Taiwan). Those born in or after 1986 consisted of three groups: HIV-infected MSM (Group II), HIV-uninfected MSM (Group III), and HIV-uninfected heterosexuals (Group IV), while HIV-infected MSM born during 1984–1985 (Group I) were comparators. The incidence of HBsAg seroconversion was assessed in HIV-infected patients with all-negative HBV markers at baseline. The date of HBsAg seroconversion was arbitrarily defined as the mid-point between the date of the last negative and that of the first positive HBsAg results. The data were censored on the last sampling date for determination of HBV serostatus if the results of HBsAg remained negative. National Taiwan University Hospital Research Ethics Committee approved the study and waived for the need of informed consent.
A computerized data collection form was used to retrieve the demographic and clinical data of all subjects, which included birth year, gender, risk behaviors, and test results of anti-HCV antibody, HBsAg, anti-HBs antibody, and anti-HBc antibody at baseline; and data of baseline CD4+ lymphocyte count and plasma HIV RNA load of HIV-infected patients.
HBsAg, anti-HBs antibody, and anti-HBc antibody were determined with the use of enzyme immunoassay (Abbott Laboratories, Abbott Park, IL). Antibodies to HCV were determined with the use of a third-generation enzyme immunoassay (Ax SYM HCV III, Abbott Laboratories, North Chicago, IL). Plasma HIV RNA load were quantified using RT-PCR (Roche Amplicor, version 1.5, NJ) with a lower detection limit of 400 (2.60 log10) copies/mL, and CD4 counts were determined using FACFlow (BD FACS Calibur, Becton Dickinson, CA). The diagnosis of syphilis was made on the basis of a titer of rapid plasma reagin (RPR) ≧1:4 (RPR Card test; Becton-Dickinson) and confirmed by
All-negative HBV markers were defined as HBsAg (−)/anti-HBs (−)/anti-HBc (−); serological markers for immunity against HBV after vaccination as HBsAg (−)/anti-HBs (+)/anti-HBc (−); isolated anti-HBc pattern as HBsAg (−)/anti-HBs (−)/anti-HBc (+); HBsAg carriage as HBsAg (+)/anti-HBs (−)/anti-HBc (+); and natural infections as anti-HBc (+) regardless of status of HBsAg and anti-HBs.
All statistical analyses were performed using SPSS software version 17.0 (SPSS Inc., Chicago, IL). Categorical variables were compared using χ2 or Fisher's exact test whereas non-categorical variables were compared using Mann-Whitney U test. A multivariable logistic model was used to estimate the effects of multiple variables on the HBsAg positivity. The incidence rate of HBV seroconversion during the study period was calculated as the number of episodes of HBV seroconversion per 100 persons-years of follow-up (100 PYFU). All tests were two-tailed and a
During the 6.5-year study period, 244 HIV-infected MSM who were born during 1984–1985 (Group I), and 523 HIV-infected MSM (Group II), 377 HIV-uninfected MSM (Group III), and 217 HIV-uninfected heterosexuals (Group IV) who were born in or after 1986 were included (
Group I: HIV- infected MSM, 1984–1985 | Group II: HIV- infected MSM, 1986 | Group III: HIV- uninfected MSM, 1986 | Group IV: HIV-uninfected heterosexuals, 1986 | ||||
Case no. | 244 | 523 | 377 | 217 | NA | NA | NA |
Age, mean (SD), year | 28.5 (0.5) | 24.8 (1.9) | 25.6 (1.4) | 25.4 (1.6) | <0.001 | <0.001 | <0.001 |
HIV infection | |||||||
CD4 count, mean (SD), cells/μL | 370.4 (215.8) | 401.9 (276.5) | NA | NA | NA | 0.197 | NA |
CD4<200 cells/μL, % (n) | 21.7 (39/180) | 16.7 (46/275) | NA | NA | NA | 0.186 | NA |
PVL, mean (SD), log10 copies/mL | 4.31 (1.28) | 4.43 (1.11) | NA | NA | NA | 0.303 | NA |
PVL <200 copies/mL, % (n) | 12.4 (22/177) | 6.1 (7/114) | NA | NA | NA | 0.080 | NA |
HBV markers, % (n) | |||||||
All-negative | 14.1 (28/198) | 39.2 (188/479) | 38.5 (145/377) | 41.5 (90/217) | <0.001 | <0.001 | 0.765 |
Isolated anti-HBc | 6.1 (12/198) | 9.6 (46/479) | 6.9 (26/377) | 5.1 (11/217) | 0.127 | 0.134 | 0.087 |
Vaccination-type | 55.1 (109/198) | 35.7 (171/479) | 41.9 (158/377) | 40.6 (88/217) | <0.001 | <0.001 | 0.153 |
HBsAg-positive | 7.8 (18/232) | 3.7 (19/507) | 2.4 (9/377) | 3.2 (7/217) | 0.009 | 0.020 | 0.522 |
Anti-HBc-positive | 30.3 (63/208) | 26.3 (131/499) | 19.6 (74/377) | 18.0 (39/217) | 0.003 | 0.273 | 0.015 |
Anti-HBs-positive | 71.3 (154/216) | 48.0 (245/510) | 52.3 (197/377) | 50.2 (109/217) | <0.001 | <0.001 | 0.460 |
Anti-HBs titer, median, mIU/mL | 96.55 | 63.25 | NA | NA | NA | 0.029 | NA |
<10 mIU/mL, % (n) | 27.6 (58/210) | 49.9 (225/451) | NA | NA | NA | <0.001 | NA |
>100 | 32.4 (68/210) | 21.1 (95/451) | NA | NA | NA | ||
10–100 | 40.0 (84/210) | 29.0 (131/451) | NA | NA | NA | ||
RPR >4, % (n) | 19.8 (46/232) | 21.2 (91/430) | 2.8 (10/352) | 0.5 (1/204) | <0.001 | 0.686 | <0.001 |
Anti-HCV-positive, % (n) | 4.3 (10/232) | 3.5 (18/520) | 1.1 (4/376) | 1.4 (3/214) | 0.031 | 0.570 | 0.045 |
Comparison among the four groups.
Comparison between Groups I and II.
Comparison among the three groups born in or after 1986 (Groups II-IV).
The different serological patterns for the four study groups are shown in
Among the 107 MSM in Group I and 154 MSM in Group II whose serological data of HBV and anti-HBs titers were available, MSM in Group I had a higher median anti-HBs antibody titer than those born in or after 1986 (96.55 vs. 63.25 mIU/mL,
Among the subjects in Groups II-IV, HIV-infected MSM in Group II had a higher prevalence of syphilis (21.2% vs. 2.8% and 0.5%,
Compared with the patients without positive HBsAg, those with positive HBsAg were older, and more likely to have HIV infection, to be born in 1984–1985, and to have syphilis and anti-HCV positivity than those without in univariate analysis (all
Positive HBsAg | Negative HBsAg | ||
Patient no. | 53 (4.0%) | 1280 (96.0%) | |
Age, mean (SD), years | 26.8 (1.8) | 25.7 (2.0) | <0.001 |
MSM, % (n) | 84.8 (39/46) | 82.5 (993/1203) | 0.694 |
HIV infection | 69.8 (37) | 54.8 (702) | 0.032 |
Born during 1984–1985 | 34.0 (18/53) | 16.7 (214/1280) | 0.001 |
Born in or after 1986 | 66.0 (35/53) | 83.3 (1066/1280) | 0.001 |
RPR titer >4 | 31.9 (15/47) | 11.1 (128/1148) | <0.001 |
Positive anti-HCV | 7.5 (4/53) | 2.2 (28/1271) | 0.03 |
Variables | Reference | Odds ratio | 95% confidence interval | |
HIV infection | No HIV infection | 1.169 | 0.531–2.577 | 0.698 |
Born in or after 1986 | Born during 1984–1985 | 0.421 | 0.208–0.854 | 0.017 |
RPR>4 | RPR <4 | 2.990 | 1.502–5.953 | 0.002 |
Positive anti-HCV | Negative anti-HCV | 3.402 | 1.091–10.614 | 0.035 |
Among the 188 MSM in Group II who had all-negative HBV markers at baseline, 64 (34.0%) had follow-up of HBV serology for assessment of seroconversion for HBsAg, anti-HBs, anti-HBc as of 30 June, 2103. Compared with 124 MSM (66.0%) without follow-up of HBV serological markers, the 64 MSM had a similar age (24.8 [1.8] vs. 24.2 [2.1] years,
Crude incidence | Incidence rate (episodes per 100 person-years of follow-up) | |
All-negative HBV markers at baseline (n = 64), % (n) | ||
HBsAg seroconversion | 1.6 (1/64) | 0.486 |
Anti-HBs seroconversion | 28.1 (18/64) | 9.897 |
Anti-HBc seroconversion | 10.9 (7/64) | 3.576 |
Vaccine-type serology | 21.9 (21/64) | 7.406 |
Natural HBV infections | 10.9 (7/64) | 3.578 |
Receiving anti-HBV agents (n = 37), % (n) | ||
HBsAg seroconversion | 0 (0/37) | 0 |
Anti-HBs seroconversion | 18.9 (7/37) | 14.788 |
Anti-HBc seroconversion | 8.1 (3/37) | 6.338 |
Vaccine-type serology | 13.5 (5/37) | 10.563 |
Natural HBV infection | 8.1 (3/37) | 6.338 |
Among the 64 patients, 37 (57.8%) had follow-up of HBV markers when receiving combination antiretroviral therapy (cART) containing lamivudine or tenofovir disoproxil fumarate (TDF). During the treatment course for 47.334 PY, none developed HBsAg seroconversion, 7 (14.788 episodes per 100 PYFU) developed anti-HBs seroconversion, and 3 (6.338 episodes per 100 PYFU) developed anti-HBc seroconversion, 5 (10.563 episodes per 100 PYFU) developed vaccine-type serology, and 3 (6.338 episodes per 100 PYFU) developed HBV infection (
In this study, we demonstrate that the prevalence of HBsAg positivity was similar between HIV-infected MSM and HIV-uninfected individuals (Group II-IV) who were born in the era of universal HBV vaccination (in or after 1986) despite the fact that HIV-infected MSM (Group II) were more likely to have syphilis and had a higher prevalence of anti-HBc positivity, while HIV-infected MSM born in 1984–1985 (Group I) had a significantly higher prevalence of HBsAg positivity than HIV-infected MSM in or after 1986 (Group II) (
The latest seroepidemiologic survey in 2009 that was conducted 25 years after implementation of the universal HBV vaccination program to evaluate the effectiveness of program in the general population in Taiwan has shown that the prevalence of HBsAg positivity was 0.9%, and that of anti-HBs and anti-HBc positivity was 55.9% and 10.0%, respectively, in the subjects born in the vaccination era
In the four consecutive surveys conducted in 1994, 1999, 2004, and 2009, the prevalence of anti-HBc positivity, a surrogate marker of natural infection, increased gradually in the longitudinal follow-up of all birth cohorts, suggesting that exposure to HBV in the general population continued with age; however, HBsAg seropositivity did not increase among the cohorts
Compared with the findings of the survey in 2009
CART containing lamivudine or TDF has been recently shown to provide protection against HBV infection in HIV-infected Japanese
Revaccination is not recommended for vaccinated immunocompetent persons and adults with high-risk sexual behaviors
There are several limitations to the present study. First, because of the retrospective study design, we were not able to document the HBV vaccination status and the date of vaccination at birth or revaccination of each person. However, given the high coverage rate of nationwide HBV vaccination program (86.9–98.0%)
In summary, the prevalence of HBsAg positivity has significantly declined in the adults engaged in high-risk sexual behaviors who were born in the era of nationwide HBV vaccination. While the prevalence of HBV infection remains low, safe sex counseling cannot be overemphasized because HBV infection is strongly associated with syphilis and positive anti-HCV.