HEPATITIS DELTA VIRUS INFECTION IN MONGOLIA: ANALYSES OF GEOGRAPHIC DISTRIBUTION, RISK FACTORS, AND DISEASE SEVERITY

The American Journal of Tropical Medicine and Hygiene, Aug 2006

The prevalence and risk factors for hepatitis delta virus (HDV) infection among Mongolian school children were assessed by detecting the antibody against HDV and HDV RNA, and through structured interviews. The study subjects consisted of 181 children with the past or ongoing hepatitis B virus infection who were investigated during the nationwide serosurvey conducted in 2004. The prevalence of antibody to HDV was 6.1%, with the proportion of 13.6% among hepatitis B surface antigen (HBsAg)-positive subjects, all of whom had HDV RNA. Multivariate logistic regression analyses showed that injections (> 11 times) (odds ratio [OR] = 8.31, 95% confidence interval [CI] = 1.28–54.07) and blood sampling (> 3 times) (OR = 5.34, 95% CI = 1.12–25.53) in health care settings, hospitalization (> 3 times) (OR = 6.20, 95% CI = 1.18–32.71), and cohabitating with patients with chronic hepatitis (OR = 4.57, 95% CI = 1.26–16.55) predicted the seropositivity for antibody to HDV. These results suggest that parenteral exposures in health care settings and household transmission are the main routes of HDV transmission among Mongolian children.

A PDF file should load here. If you do not see its contents the file may be temporarily unavailable at the journal website or you do not have a PDF plug-in installed and enabled in your browser.

Alternatively, you can download the file locally and open with any standalone PDF reader:

https://www.ajtmh.org/content/75/2/365.full.pdf

HEPATITIS DELTA VIRUS INFECTION IN MONGOLIA: ANALYSES OF GEOGRAPHIC DISTRIBUTION, RISK FACTORS, AND DISEASE SEVERITY

DAMBADARJAA DAVAALKHAM 0 1 TOSHIYUKI OJIMA 0 1 RITEI UEHARA 0 1 MAKOTO WATANABE 0 1 IZUMI OKI 0 1 PAGVAJAV NYMADAWA 0 1 MASAHARU TAKAHASHI 0 1 HIROAKI OKAMOTO 0 1 YOSIKAZU NAKAMURA 0 1 0 Department of Public Health, and Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medicine , Tochigi-Ken , Japan; National Center for Communicable Diseases , Ulaanbaatar , Mongolia 1 Authors' addresses: Dambadarjaa Davaalkham, Toshiyuki Ojima, Ritei Uehara, Makoto Watanabe, Izumi Oki, and Yosikazu Naka- mura, Department of Public Health, Jichi Medical University School of Medicine , 3311-1 Yakushiji, Shimotsuke-Shi, Tochigi 329-0498, Ja- pan. Pagvajav Nymadawa , National Center for Communicable Dis- eases , Bayanzurkh District, Ulaanbaatar, Mongolia. Masaharu Taka- hashi, and Hiroaki Okamoto , Division of Virology, Department of Infection and Immunity, Jichi Medical University School of Medi- cine , 3311-1 Yakushiji, Shimotsuke-Shi, Tochigi 329-0498 , Japan The prevalence and risk factors for hepatitis delta virus (HDV) infection among Mongolian school children were assessed by detecting the antibody against HDV and HDV RNA, and through structured interviews. The study subjects consisted of 181 children with the past or ongoing hepatitis B virus infection who were investigated during the nationwide serosurvey conducted in 2004. The prevalence of antibody to HDV was 6.1%, with the proportion of 13.6% among hepatitis B surface antigen (HBsAg)-positive subjects, all of whom had HDV RNA. Multivariate logistic regression analyses showed that injections (> 11 times) (odds ratio [OR] 8.31, 95% confidence interval [CI] 1.28-54.07) and blood sampling (> 3 times) (OR 5.34, 95% CI 1.12-25.53) in health care settings, hospitalization (> 3 times) (OR 6.20, 95% CI 1.18-32.71), and cohabitating with patients with chronic hepatitis (OR 4.57, 95% CI 1.26-16.55) predicted the seropositivity for antibody to HDV. These results suggest that parenteral exposures in health care settings and household transmission are the main routes of HDV transmission among Mongolian children. - Hepatitis delta virus (HDV) is a defective single-stranded RNA virus that requires hepatitis B surface antigen (HBsAg) for packaging and transmission; thus, it always coexists with hepatitis B virus (HBV) in natural infections.13 Epidemiologic surveys have shown that HDV infection has a worldwide but nonuniform distribution, commonly found in the Mediterranean Basin, the Middle East, central Asia and east Africa, the Amazon Basin, and the South Pacific Islands. Hepatitis D, which is less common in Eastern Asia, is present in Taiwan, China, and India.46 Chronic HDV infections are associated with liver damage that progresses more rapidly than that seen in patients with HBV alone.7 Approximately 6079% of patients with chronic hepatitis D develop liver cirrhosis, which is nearly three times higher than for type B and C hepatitis, and a large number of these patients die of hepatic failure.4,8 The outcome of the disease largely depends on whether the two viruses infect simultaneously (co-infection) or whether the person who was newly infected with HDV is already an HBV carrier. Coinfections of HBV and HDV are usually acute, self-limited infections. In contrast, a superinfection causes a generally severe and acute hepatitis that most often results in chronic hepatitis D, with the suppression of HBV replication but persistence of HDV replication.79 Hepatitis D virus is transmitted mainly percutaneously through contact with infected blood or blood products. Although perinatal transmission may occur, it is rare.6,10 In countries where HBV endemicity is low, the prevalence of HDV infection is low, except among intravenous drug users and recipients of blood products. Sexual transmission also occurs. In areas of intermediate and high endemicity for HBV, the prevalence of HDV infection is highly variable and the predominant route of transmission is unknown.10,11 It has previously been reported that chronic HDV infection is highly prevalent among the adult population of Mongolia,1215 where HDV genotype I is predominant.14,15 Nevertheless, information on HDV infection among children is scarce and the main routes of HDV transmission among the general population are unknown. We report the epidemiology of HDV infection among Mongolian children with respect to geographic distribution, potential risk factors for transmission, and the disease severity in the subjects with a chronic HDV infection by studying the HDV viremia and liver function. MATERIALS AND METHODS Study subjects. Using serum samples from 181 children (107 boys and 74 girls) who were positive for HBsAg- and/or antibody to hepatitis B core antigen (HBc) and investigated during a nationwide cross-sectional survey (n 1,182, participation rate 93%) conducted between October and November 2004, we determined the presence of antibody to HDV and HDV RNA, and studied liver enzyme function. The design of the survey and sampling procedures have been described elsewhere.16,17 Because the nationwide survey was conducted throughout the country including the four main geographic regions and the metropolitan area of Mongolia with stratified, multistage, random cluster sampling to assess the universal vaccination program against hepatitis B, the subjects in this study were representative of different geographic regions, including urban and rural areas (Figure 1). The ages of the subjects ranged from 7 to 12 years (mean SD 8.8 0.9 years). Among the 181 serum samples, 122 were positive for antibody to HBsAg and/or antibody to HBc but negative for HBsAg, and 59 were positive for HBsAg and antibody to HBc. Evaluation of potential risk factors for HDV infection. Information on sociodemographic variables and potential risk factors for HDV infection was obtained with a standardized questionnaire, which included questions on sociodemographic variables and medical and family histories of the children. Assay for HBV markers. HBsAg, antibody to HBsAg, and antibody to HBc were analyzed with chemiluminescence immunoassays using kits from Abbott Japan Co., Ltd. (Tokyo, Japan). Specimens positive for HBsAg were also tested for hepatitis B e antigen (HBeAg) by the same method. The FIGURE 1. Map of Mongolia showing the regions of the country (shaded areas) and the study areas; the capital of Ulaanbaatar and the city of Darkhan (stars), province centers (triangles), and rural areas (dark shaded areas). specimens were considered negative for HBsAg if values were < 0.05 IU/mL and negative for antibody to HBc if values were less than a sample/cutoff ratio of 1.0. Specimens were considered positive for antibody to HBsAg if values were 10 mIU/mL. Assay for antibody to HDV and detection of HDV RNA. IgG antibody to HDV was detected with a newly developed enzyme-linked immunosorbent assay using recombinant hepatitis delta antigen as previously described.14 Samples with an optical density (OD) of 0.171 at 450 nm were considered positive for antibody to HDV. HDV RNA was detected by the nested reverse transcriptionpolymerase chain reaction (RT-PCR) method reported by Takahashi and others.15 The amplification products of first-round and second-round PCRs were 592 basepairs (nucleotides 7071298) and 565 basepairs (nucleotides 7191283), respectively. Analyses of liver enzymes. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and -glutamyl transpeptidase ( -GTP) were evaluated by standard methods of the Japan Society of Clinical Chemistry. For ALT, AST, and -GTP, the normal values were set as 540, 1040, and 70 IU/L for males and 30 IU/L for females, respectively. Statistical analyses. Statistical analyses were conducted by using SPSS version 12.0 (SPSS, Inc., Chicago, IL). The chisquare test or Fishers exact test was used for a comparison of categorical variables, and the Mann-Whitney test was used for a comparison of continuous variables. To examine the associations between seropositivity for antibody to HDV and hypothesized risk factors, crude odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were calculated by univariate analysis. Absence of neither history nor exposure to potential risk factors was used as a reference category for OR estimates. To assess the independent role of the different variables associated with HDV infection, multiple logistic regressions were carried out. The significance level was set at 0.05 and all P values were two-tailed. Ethics. The study procedures were explained to parents or legal guardians of each child and written informed consent was obtained. The study protocol was reviewed and approved by the Ethical Review Committees of the World Health Organization, the Ministry of Health, Mongolia, and Jichi Medical University, Japan. The distribution of HDV infection by demographic and geographic variables and vaccination status against hepatitis B is shown in Table 1. The prevalence of antibody to HDV among the study subjects (positive for HBsAg and/or antibody to HBc) was 6.1% (11 of 181, 95% CI 2.69.6%) with no significant association with age, sex, ethnicity, or housing type. Seropositivity for antibody to HDV varied throughout the country, ranging from 3.2% in Bayankhongor Province to 9.1% in Darkhan City and 6.9% in the capital of Ulaanbaatar. However, the variations in different geographic regions and between urban and rural areas were not significant. The comparison of HDV seroprevalence among children with a different status of hepatitis B vaccination revealed that completely vaccinated children showed the lowest rate of seropositivity for antibody to HDV (2.9%) in contrast to those with an incomplete vaccination (5.7%) or to children whose vaccination status was unknown (10.5%). However, these differences were not statistically significant. Table 2 shows the frequency of antibody to HDV and HDV RNA among 181 elementary school children according to the presence of HBsAg. The demographic and serologic variables of 11 children positive for antibody to HDV are shown in Table 3. Antibody to HDV was observed in 8 (13.6%) children positive for HBsAg and 3 (2.5%) children negative for HBsAg but positive for antibody to HBc (P=0.006). Among the 11 serum samples positive for antibody to HDV, 8 HBsAg-positive samples with OD values for antibody to HDV 1.557 were positive for HDV RNA, indicating an Anti-HDV, no. (%) 8 (13.6) Optical density (OD) range 1.5573.000 Mean SD 2.779 0.499 HDV RNA, no. (%) 8 (100) * For definitions of abbreviations, see Table 1. OD values in the anti-HDV assay that the cut-off value are shown. Only subjects with anti-HDV tested positive for HDV RNA. ongoing co-infection of HBV and HDV. The remaining three samples with isolated antibody to HBc and with low OD values for antibody to HDV (0.615, 0.631, or 0.816) were negative for HDV RNA, indicating a previous infection with HBV and HDV. The difference in the OD values for antibody to HDV between HBsAg-negative and HBsAg-positive children was statistically significant (2.779 0.499 versus 0.687 0.112; P = 0.01). Children positive for antibody to HDV had a higher frequency of history of acute hepatitis (45.5% versus 10.2%; P = 0.005) and exhibited higher levels of ALT (63.9 43.6 versus 23.4 23.4 IU/L; P = 0.002), AST (47.6 20.5 versus 27.2 10.5 IU/L; P < 0.0001), and -GTP (19.9 13.6 versus 14.9 9.3 IU/L; P = 0.015) compared with those who were negative for antibody to HDV (Table 4). Associations between HDV infection and the potential risk factors are shown in Table 5. In multivariate logistic regression analyses, controlled for potential confounding factors of age, sex, and residence, significant associations with seropositivity for antibody to HDV were found among children with a history of hospitalization of more than three times (OR 6.2, 95% CI 1.1832.71), 11 injections in the previous year (OR 8.31, 95% CI 1.2854.07), blood sampling three or more times (OR 5.34, 95% CI 1.1225.53), and cohabitation with patients having chronic hepatitis (OR 4.57, 95% CI 1.2616.55). The risk for HDV infection also increased, although not significantly, in those subjects who reported that they had a mother with chronic hepatitis (OR 4.37, 95% CI 0.9819.57). Although impressive gains have been made through the national immunization program that was instituted in 1991, HDV HBsAg Anti-HBs Anti-HBc HBeAg RNA 16 9/M > 3.000 + + + + 19 9/M > 3.000 + + + + 24 8/M > 3.000 + + + + 35 8/M 1.557 + + + + 38 9/F 2.863 + + + + 42 8/F 2.808 + + + + 43 9/M > 3.000 + + + 47 8/M > 3.000 + + + + 108 8/M 0.615 + 140 8/F 0.631 + 163 10/F 0.816 + * HBeAg hepatitis Be antigen. For definitions of other abbreviations, see Tables 1 and 2. Age (years) 8.6 0.7 8.8 0.9 0.324 ALT (IU/L) 63.9 43.6 23.4 23.4 0.002 AST (IU/L) 47.6 20.5 27.2 10.5 < 0.0001 -GTP (IU/L) 19.9 13.6 14.9 9.3 0.015 History of acute heptatitis 45.5% 10.2% 0.005 * Results are mean SD unless otherwise stated. ALT alanine aminotransferase; AST aspartate aminotransferase; -GTP -glutamyl transpeptidase. For definitions of other abbreviations, see Table 1. Upper limits of the normal range are 40 international units per liter (IU/L) for ALT and AST, 70 IU/L for males, and 30 IU/L for females for -GTP. Mongolia continues to confront communicable diseases, including viral hepatitis.18 In 2004, a total of 6,164 cases of viral hepatitis (24.8 per 10,000 population), including 782 of hepatitis B, and 142 of hepatitis C, were reported, which comprised 19.7% of the total communicable diseases (http:// www.moh.mn). In the present study, we investigated the distribution of HDV infection and associated risk factors for its transmission among elementary school children. The overall prevalence of seropositivity for antibody to HDV was 6.1% among the study population, with no significant geographic and residential differences. Although epidemiologic studies on HDV infection among children are scarce, the rate of positivity for antibody to HDV found in this study was lower in comparison to an earlier study in 1988 among children of comparable ages who were positive for HBsAg and negative for antibody to HBc (31.5%).12 According to another study conducted in the Ulaanbaatar and its surrounding suburbs (n 249) in 2002, nearly 17% of the general population 2386 years of age tested positive for antibody to HDV.14 In addition, among the HBsAg carriers, antibody to HDV was detected in 92%, most (83.3%) of whom were positive for HDV RNA.15 The lower prevalence of HDV infection found in this study might be a consequence of the control of HBV infection achieved in recent years17,19 through the preventive measures used during the past few decades. These include a national immunization program for hepatitis B (since 1991) and introduction of disposable needles and syringes for phlebotomies and injections.18 All participants in the current study were born after the start of these programs, and children who were completely vaccinated against hepatitis B had the lowest rate of positivity for antibody to HDV (2.9%) compared with those with incomplete vaccinations (5.9%) or with an unknown status for hepatitis B vaccination (10.5%). Public health measures to interdict the transmission of blood-borne pathogens, combined with aggressive hepatitis B vaccination programs at the national level, offer great promise for the control of type D hepatitis because HDV uses the envelope proteins of HBV and has no detectable unique surface antigens.8,20,21 The incidence of HDV infection has decreased over the past decade in many countries, such as Taiwan,22,23 Italy,24 Greece,25 and Spain.26 Some researchers attributed this decrease in HDV infection to the introduction and widespread use of disposable needles and syringes in the injection practice.25 Others have suggested a natural decrease Dental treatment 0 6 (4.7) 12 3 (9.7) > 3 2 (18.2) Hospitalization 0 4 (4.5) 12 4 (6.6) > 3 3 (21.4) Surgical manipulations No 10 (6.3) Yes 1 (16.7) Acupuncture No 10 (6.3) Yes 1 (25.0) Blood tests 0 5 (4.2) 12 5 (13.5) > 3 1 (50.0) Injections in the previous year 0 8 (5.4) 110 1 (20.0) > 11 2 (25.0) Injection at the hospital No 5 (5.9) Yes 6 (8.7) Mother has chronic hepatitis No 6 (4.5) Yes 3 (17.6) Cohabitation with patients with chronic hepatitis No 6 (4.8) Yes 5 (17.9)* Sharing toothbrush No 10 (8.1) Yes 1 (2.4) * OR odds ratio; CI confidence interval. Adjusted for age, sex, and residence. in the rate of HBV infection as one of the major cause for this finding.24 Although the effective use of hepatitis B vaccines should eventually control hepatitis D in parallel with control of hepatitis B, individuals who are already chronically infected with HBV will continue to be at risk of contracting hepatitis D; prevention of HBV-HDV superinfection can be achieved only through reducing risk behavior.19,20 Therefore, implementation of better hygiene and the use of disposable needles may help to prevent the spread of HDV and other blood-borne viruses.21,27 In the present study, a history of hospitalization (three or more times), parenteral manipulations in the health care setting, including an injection in the previous year ( 11 times), blood sampling ( 3 times) and cohabitation with patients who have chronic hepatitis were significant predictors for HDV infection. To our knowledge, this is the first report on potential risk factors for HDV infection in Mongolia. These factors might be the main routes for HDV transmission in Mongolia, not only among the children but also in the adult population, because these parenteral procedures are very common at all age levels. Household transmission of HDV has been demonstrated to have had a substantial impact on the transmission of HDV28,29 and molecular evidence of this route of transmission has also been reported.30 In addition, it has been suggested that hepatitis C virus (HCV) and HDV infections may share similar transmission routes.3,31 In our previous study, HCV infection was also significantly associated with parenteral manipulations in the health care setting and household transmission.16 Unlike other forms of chronic viral hepatitis, chronic type D hepatitis is usually initiated by a clinically apparent acute infection, and HDV co-infection or super-infection generally results in a more severe clinical course than HBV alone.8 Symptoms are less severe in chronic viral hepatitis D than in acute infections; but ALT and AST values are elevated during the clinical course.2,8 Similarly, children positive for antibody to HDV reported a history of acute hepatitis more frequently than children negative for antibody to HDV (P = 0.005) in this study. Moreover, they were more likely to show liver dysfunction, as indicated by higher levels of ALT (P = 0.002), AST (P < 0.0001) and -GTP (P = 0.015). Serum HDV RNA was detected in 8 (72.7%) of the children positive for antibody to HDV. All eight children positive for HBsAg and antibody to HDV were also positive for HDV RNA, indicating ongoing co-infection with HBV and HDV and high infectivity of the latter virus. The remaining three samples with isolated antibody to HBc and lower OD values for antibody to HDV (P = 0.01) were negative for HDV RNA, indicating past infection with HBV and HDV. In summary, the overall prevalence of HDV infection among elementary school children positive for HBsAg and/or antibody to HBc was 6.1%. The potential routes of HDV transmission might be parenteral exposures in a health care setting that includes injection and blood sampling, and cohabitation with patients who have chronic hepatitis. Given the high prevalence of HDV infection among the population as well as high rates of chronic liver diseases associated with hepatitis viruses, further studies among the general population are urgently warranted to understand fully the main routes of HDV transmission and take preventive measures against the spread of parenterally transmitted viral hepatitis in Mongolia. Acknowledgments: We thank the study participants, field staffs, school teachers, nurses, and health sector personnel in each study area for cooperation and support. Financial support: This study was supported by grants from the World Health Organization (grant no. WP/MOG/IVD/216/XC/04991.00), and Jichi Medical University, Japan.


This is a preview of a remote PDF: https://www.ajtmh.org/content/75/2/365.full.pdf

DAMBADARJAA DAVAALKHAM, TOSHIYUKI OJIMA, RITEI UEHARA, MAKOTO WATANABE, IZUMI OKI, PAGVAJAV NYMADAWA, MASAHARU TAKAHASHI, HIROAKI OKAMOTO, YOSIKAZU NAKAMURA. HEPATITIS DELTA VIRUS INFECTION IN MONGOLIA: ANALYSES OF GEOGRAPHIC DISTRIBUTION, RISK FACTORS, AND DISEASE SEVERITY, The American Journal of Tropical Medicine and Hygiene, 2006, 365-369,