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Hepatitis D: not a rare disease anymore: global update for 2017–2018
  1. Dan-Ting Shen1,
  2. Dong-Ze Ji2,
  3. Hai-Yan Chen1,
  4. Hemant Goyal3,
  5. Shiyang Pan1,
  6. Hua-Guo Xu1
  1. 1Department of laboratory Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
  2. 2Department of Pathology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
  3. 3Department of Internal Medicine Macon, Mercer University School of Medicine, Georgia, USA
  1. Correspondence to Dr Shiyang Pan and Dr Hua-Guo Xu, Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China; sypan{at}, huaguoxu{at}

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We sincerely appreciate Stockdale and colleagues1 for their critical consideration of our article. Herein, we tried to answer their concerns about the methodology of our meta-analysis.2

We used hepatitis D virus (HDV) antibody (both IgM and IgG) seropositivity as a measure of overall burden of HDV seroprevalence. Although anti-HDV IgM Ab assays may fail to detect low titres of antibodies and underestimate HDV seroprevalence,3 patients with a negative anti-HDV IgM results are less likely to progress into clinical disease.4 Majority of the included studies in our article used anti-HDV antibody assays and only two mentioned the use of RNA assays for the prevalence of HDV. Therefore, considering the wide application of the anti-HDV antibody assay as a measure of HDV seroprevalence,5 we used the similar method in our meta-analysis.

We do not think it would be correct to extrapolate the prevalence of HBsAg based on our estimates of HDV seroprevalence among general population and mixed population (HBsAg carriers without risk factors such as intravenous drug use and high-risk sexual behaviours). This is because the general population and the mixed population were independent, and only overlapped in 46 of 177 studies in the mixed population.

Our analysis took country population size into consideration by extrapolating the burden of each country.2 We agree that the study from France contributed most of the sample size in the general population. However, even if we exclude this datum, the overall HDV seroprevalence of general population will only change from 0.98% to 1.02% (p=0.865). To clarify it further, we considered the recent data from several countries, and have further updated the HDV seroprevalence globally.

We searched the PubMed, Embase, Cochrane Library and CNKI databases from 1 January 2017 to 2 February 2019. The search strategy, selection criteria, statistical analysis methods, sensitivity analysis, anti-HDV antibody detection methods and quality assessment were shown in online supplementary tables S1 and S2 and figure S1. From a total of 954 initially identified studies, 30 articles (online supplementary table S3) from 18 countries met the final inclusion criteria (table 1). Our statistical analysis showed that the overall seroprevalence of HDV was 1.06% (95% CI 0.46% to 1.89%) (online supplementary figure S2) in 2017–2018, no significant difference was found when compared with the corresponding data in 1977–2016 (p=0.827). Also, HDV seroprevalence declined to 7.66% (95% CI 4.42% to 11.59%) in mixed population in 2017–2018, p=0.179, when compared with the corresponding data in 1977–2016.

Table 1

Summary of country and regional HDV seroprevalence estimates in general population and mixed population in 2017–2018

We combined these data with those we have published before and found that the overall seroprevalence of HDV was 1.00% (95% CI 0.68% to 1.38%) in 1977–2018 (figure 1), which means the global burden of HDV infection is approximately 74 (95% CI 50 to 102) million individuals (online supplementary table S4). Seroprevalence was 10.07% (95% CI 8.74% to 11.49%) in mixed population in 1977–2018. China still shares the largest burden, representing 7.37% of the total sample. Pakistan comes second with its estimated high HDV seroprevalence of 2.43%. These results indicated that HDV seroprevalence has been underestimated before,6 which was consistent with the conclusion of our previous article.

Figure 1

Forest plots of hepatitis D virus seroprevalence among general population and mixed population in 2017–2018 (A) and in 1977–2018 (B). Data were from a random effects model. Estimates and 95% CIs were shown. Full data in 2017–2018 were available in online supplementary table S5. Data in 1977–2016 came from our previous article. General population: people without any risk factors. Mixed population: HBsAg carriers without risk factors such as intravenous drug use (IVDU) and high-risk sexual behaviours (HRSB).

We do agree that future research could focus on more specific individuals recruited from hospital settings, as individuals recruited from hospital settings vary, such as antenatal clinic attendees, inpatients or outpatients seeking care for non-hepatic illnesses. Studies among special groups such as individuals with HIV should be treated with caution.7 Further larger studies are needed to be performed on aiming to specifically identify HDV seroprevalence in these groups. Additionally, the use of HDV RNA as a diagnostic test of choice needs to be standardised.8 The consistency of HDV RNA and anti-HDV antibody detection is yet to be assessed to find the clinical relationship between them.


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  • D-TS and D-ZJ contributed equally.

  • Contributors D-TS and D-ZJ are cofirst authors. H-GX and D-TS designed the study. All the authors contributed to the generation, collection, assembly, analysis and/or interpretation of data. D-TS and D-ZJ wrote the manuscript. H-GX and HG revised the manuscript. All the authors have read and approved the final manuscript.

  • Funding This work was supported by the National Natural Science Foundation of China (81302531), the Natural Science Foundation of Jiangsu Province of China (SBK2018022334), the Talents Planning of Six Summit Fields of Jiangsu Province (2013-WSN-037), the Postgraduate Research and Practice Innovation Program of Jiangsu Province (KYCX17_1287, SJCX18_0435), the National Key Clinical Department of Laboratory Medicine of China in Nanjing, theKey Laboratory for Laboratory Medicine of Jiangsu Province (ZDXKB2016005) and the Priority Academic Program Development of Jiangsu Higher Education Institutions.

  • Disclaimer The funder of the study had no role in the study design, data collection, data analysis, data interpretation or writing of the manuscript. The corresponding author had full access to all the data in the study and has final responsibility for the decision to submit for publication.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; internally peer reviewed.

  • Patient consent for publication Not required.

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