Revisiting the estimation of hepatitis D global prevalence

The global prevalence of hepatitis D virus infection: Systematic review and meta-analysisJournal of HepatologyVol. 73Issue 3PreviewThere are uncertainties about the epidemic patterns of HDV infection and its contribution to the burden of liver disease. We estimated the global prevalence of HDV infection and explored its contribution to the development of cirrhosis and hepatocellular carcinoma (HCC) among HBsAg-positive people. Full-Text PDF Open AccessReply to: “Revisiting the estimation of hepatitis D global prevalence”Journal of HepatologyVol. 73Issue 5PreviewWe are grateful to Miao and Pan for their interest in our global meta-analysis of hepatitis D prevalence. The points raised merit careful consideration.1 Full-Text PDF We read the meta-analysis on global prevalence of HDV by Stockdale et al. with interest.[1]Stockdale A.J. Kreuels B. Henrion M.Y.R. Giorgi E. Kyomuhangi I. de Martel C. et al.The global prevalence of hepatitis D virus infection: systematic review and meta-analysis.J Hepatol. 2020; 73: 523-532Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar They estimated HDV prevalence as 4.5% among the general HBV carriers and 16.4% among carriers attending hepatology clinics. They translated the rate of 4.5% into a prevalence of 0.16% in the global population, corresponding to 12 million people worldwide. This topic has been extensively studied and emphasized historically by different research teams (Table 1). But the authors have largely avoided presenting their study in this existing context. Herein, we have several concerns regarding their study design and findings.[1]Stockdale A.J. Kreuels B. Henrion M.Y.R. Giorgi E. Kyomuhangi I. de Martel C. et al.The global prevalence of hepatitis D virus infection: systematic review and meta-analysis.J Hepatol. 2020; 73: 523-532Abstract Full Text Full Text PDF PubMed Scopus (168) Google ScholarTable 1Historical estimates of regional and global prevalence and burden of hepatitis D virus infection.StudyaTwo are regional estimates, Torres 1996 targeting South America and Stockdale et al. 2017 targeting sub-Saharan Africa, others are global estimates.TimeHDV prevalencebHDV prevalence is defined either among general population or among HBV carriers, and the latter can be further categorized into general carriers without risk factors, carriers with liver diseases (nearly equivalent to hepatology clinic populations), and mixed carriers (all types of HBV carriers).Estimate (million, M)General populationHBV carriersLiver diseaseGeneralMixedTorres 1996[9]Torres J.R. Hepatitis B and hepatitis delta virus infection in South America.Gut. 1996; 38: S48-S55Crossref PubMed Google ScholarTo 19965.00%0.3Stephanos 1997[8]Hadziyannis S.J. Review: hepatitis delta.J Gastroenterol Hepatol. 1997; 12: 289-298Crossref PubMed Scopus (82) Google ScholarTo 19965.00%15Heiner et al. 2010[7]Wedemeyer H. Manns M.P. Epidemiology, pathogenesis and management of hepatitis D: update and challenges ahead.Nat Rev Gastroenterol Hepatol. 2010; 7: 31-40Crossref PubMed Scopus (287) Google ScholarTo 201015–20Stockdale et al. 2017[6]Stockdale A.J. Chaponda M. Beloukas A. Phillips R.O. Matthews P.C. Papadimitropoulos A. et al.Prevalence of hepatitis D virus infection in sub-Saharan Africa: a systematic review and meta-analysis.Lancet Glob Health. 2017; 5: e992-e1003Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar1995–20160.70%15.03%8.39%7Chen et al. 2018[2]Chen H.Y. Shen D.T. Ji D.Z. Han P.C. Zhang W.M. Ma J.F. et al.Prevalence and burden of hepatitis D virus infection in the global population: a systematic review and meta-analysis.Gut. 2019; 68: 512-521Crossref PubMed Scopus (164) Google Scholar1977–20160.98%12.60%10.58%14.57%62–72Stockdale et al. 2020a[3]Stockdale A.J. Kreuels B. Henrion M.R.Y. Giorgi E. Kyomuhangi I. Geretti A.M. Hepatitis D prevalence: problems with extrapolation to global population estimates.Gut. 2020; 69: 396-397Crossref PubMed Scopus (24) Google Scholar1977–20160.82%61Shen et al. 2020[5]Shen D.T. Ji D.Z. Chen H.Y. Goyal H. Pan S. Xu H.G. Hepatitis D: not a rare disease anymore: global update for 2017-2018.Gut. 2020; 69: 786-788Crossref PubMed Scopus (19) Google Scholar1977–20181.00%10.07%74Miao et al. 2019[4]Miao Z. Zhang S. Ou X. Li S. Ma Z. Wang W. et al.Estimating the global prevalence, disease progression and clinical outcome of hepatitis delta virus infection.J Infect Dis. 2020; 221: 1677-1687Crossref PubMed Scopus (100) Google ScholarTo 20190.80%17.93%13.02%48–60Stockdale et al. 2020b[1]Stockdale A.J. Kreuels B. Henrion M.Y.R. Giorgi E. Kyomuhangi I. de Martel C. et al.The global prevalence of hepatitis D virus infection: systematic review and meta-analysis.J Hepatol. 2020; 73: 523-532Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar1998–20190.16%16.40%4.50%12ProposedTo 2019~0.70%16.40%4.50%13.02%~50a Two are regional estimates, Torres 1996 targeting South America and Stockdale et al. 2017 targeting sub-Saharan Africa, others are global estimates.b HDV prevalence is defined either among general population or among HBV carriers, and the latter can be further categorized into general carriers without risk factors, carriers with liver diseases (nearly equivalent to hepatology clinic populations), and mixed carriers (all types of HBV carriers). Open table in a new tab Firstly, the authors only included data from 1998 to 2019. Omission of studies prior to 1998 would result in great loss of valuable information.[2]Chen H.Y. Shen D.T. Ji D.Z. Han P.C. Zhang W.M. Ma J.F. et al.Prevalence and burden of hepatitis D virus infection in the global population: a systematic review and meta-analysis.Gut. 2019; 68: 512-521Crossref PubMed Scopus (164) Google Scholar The authors may justify their exclusion of old studies, but it would be better to objectively present the evolving dynamics of HDV burden by including those data. Secondly, they only included studies reporting total or IgG anti-HDV antibody, but excluded studies detecting markers for acute infection or viral replication including anti-HDV IgM antibody, viral antigen or viral RNA as an initial test. Anti-HDV IgG antibody indicates previous exposure of HDV, while the other markers indicate acute or active infection. Therefore, all these markers were used to define HDV infection.2Chen H.Y. Shen D.T. Ji D.Z. Han P.C. Zhang W.M. Ma J.F. et al.Prevalence and burden of hepatitis D virus infection in the global population: a systematic review and meta-analysis.Gut. 2019; 68: 512-521Crossref PubMed Scopus (164) Google Scholar, 3Stockdale A.J. Kreuels B. Henrion M.R.Y. Giorgi E. Kyomuhangi I. Geretti A.M. Hepatitis D prevalence: problems with extrapolation to global population estimates.Gut. 2020; 69: 396-397Crossref PubMed Scopus (24) Google Scholar, 4Miao Z. Zhang S. Ou X. Li S. Ma Z. Wang W. et al.Estimating the global prevalence, disease progression and clinical outcome of hepatitis delta virus infection.J Infect Dis. 2020; 221: 1677-1687Crossref PubMed Scopus (100) Google Scholar Unnecessary exclusion of studies would further aggravate the shortage of available data on HDV epidemiology. Most importantly, the included populations are insufficient to represent the global population. In total, they included 24,024 general HBV carriers and 88,201 hepatology clinic populations. These probably only represent 20% of the global population. Particularly, less than half of the general HBV carriers are actually from the general community, but over one-third of them are composed by blood donors. The prevalence of HDV in blood donors is expected to be very low, but would be much higher among high-risk carriers, such as intravenous drug users and carriers with liver diseases.[2]Chen H.Y. Shen D.T. Ji D.Z. Han P.C. Zhang W.M. Ma J.F. et al.Prevalence and burden of hepatitis D virus infection in the global population: a systematic review and meta-analysis.Gut. 2019; 68: 512-521Crossref PubMed Scopus (164) Google Scholar,[4]Miao Z. Zhang S. Ou X. Li S. Ma Z. Wang W. et al.Estimating the global prevalence, disease progression and clinical outcome of hepatitis delta virus infection.J Infect Dis. 2020; 221: 1677-1687Crossref PubMed Scopus (100) Google Scholar Thus, the low prevalence data from general HBV carriers are insufficient to represent the overall prevalence of HDV. Furthermore, the general HBV carriers are not the major reservoir of HDV burden. HBV carriers attending hepatology clinics are more likely have liver diseases. HDV prevalence in this population would be much higher compared to the general or asymptomatic HBV carriers.[4]Miao Z. Zhang S. Ou X. Li S. Ma Z. Wang W. et al.Estimating the global prevalence, disease progression and clinical outcome of hepatitis delta virus infection.J Infect Dis. 2020; 221: 1677-1687Crossref PubMed Scopus (100) Google Scholar Moreover, most HDV-positive patients are symptomatic, and thus prone to attending hepatology clinics.[4]Miao Z. Zhang S. Ou X. Li S. Ma Z. Wang W. et al.Estimating the global prevalence, disease progression and clinical outcome of hepatitis delta virus infection.J Infect Dis. 2020; 221: 1677-1687Crossref PubMed Scopus (100) Google Scholar Therefore, HBV carriers with liver diseases are the large contributor to HDV burden. This study interpreted HDV prevalence among the HBV population by only using data from general HBV carriers, thereby likely underestimating the prevalence rate. In fact, their estimates of 4.5% and 16.4% could only specifically reflect the prevalence of HDV among general HBV carriers and carriers with liver diseases, respectively. Taken together, inclusion of limited studies and selection of the low prevalence population for calculation could have caused their underestimation of HDV global prevalence.[1]Stockdale A.J. Kreuels B. Henrion M.Y.R. Giorgi E. Kyomuhangi I. de Martel C. et al.The global prevalence of hepatitis D virus infection: systematic review and meta-analysis.J Hepatol. 2020; 73: 523-532Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar To better estimate HDV burden, we revisited the previous studies on this topic (Table 1).1Stockdale A.J. Kreuels B. Henrion M.Y.R. Giorgi E. Kyomuhangi I. de Martel C. et al.The global prevalence of hepatitis D virus infection: systematic review and meta-analysis.J Hepatol. 2020; 73: 523-532Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar, 2Chen H.Y. Shen D.T. Ji D.Z. Han P.C. Zhang W.M. Ma J.F. et al.Prevalence and burden of hepatitis D virus infection in the global population: a systematic review and meta-analysis.Gut. 2019; 68: 512-521Crossref PubMed Scopus (164) Google Scholar, 3Stockdale A.J. Kreuels B. Henrion M.R.Y. Giorgi E. Kyomuhangi I. Geretti A.M. Hepatitis D prevalence: problems with extrapolation to global population estimates.Gut. 2020; 69: 396-397Crossref PubMed Scopus (24) Google Scholar, 4Miao Z. Zhang S. Ou X. Li S. Ma Z. Wang W. et al.Estimating the global prevalence, disease progression and clinical outcome of hepatitis delta virus infection.J Infect Dis. 2020; 221: 1677-1687Crossref PubMed Scopus (100) Google Scholar, 5Shen D.T. Ji D.Z. Chen H.Y. Goyal H. Pan S. Xu H.G. Hepatitis D: not a rare disease anymore: global update for 2017-2018.Gut. 2020; 69: 786-788Crossref PubMed Scopus (19) Google Scholar, 6Stockdale A.J. Chaponda M. Beloukas A. Phillips R.O. Matthews P.C. Papadimitropoulos A. et al.Prevalence of hepatitis D virus infection in sub-Saharan Africa: a systematic review and meta-analysis.Lancet Glob Health. 2017; 5: e992-e1003Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar, 7Wedemeyer H. Manns M.P. Epidemiology, pathogenesis and management of hepatitis D: update and challenges ahead.Nat Rev Gastroenterol Hepatol. 2010; 7: 31-40Crossref PubMed Scopus (287) Google Scholar, 8Hadziyannis S.J. Review: hepatitis delta.J Gastroenterol Hepatol. 1997; 12: 289-298Crossref PubMed Scopus (82) Google Scholar, 9Torres J.R. Hepatitis B and hepatitis delta virus infection in South America.Gut. 1996; 38: S48-S55Crossref PubMed Google Scholar We re-estimated HDV prevalence using 2 approaches based on the general population or HBV carriers, respectively. Among the general population, we calculated the overlap interval of the lower bound of these previous meta-analyses, but excluded the current Stockdale study due to their bias.[1]Stockdale A.J. Kreuels B. Henrion M.Y.R. Giorgi E. Kyomuhangi I. de Martel C. et al.The global prevalence of hepatitis D virus infection: systematic review and meta-analysis.J Hepatol. 2020; 73: 523-532Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar This resulted in a prevalence rate of approximately 0.7% corresponding to 50 million of the global population. For HDV prevalence among HBV carriers, we recommend the previous estimation as 13.02%; because that study has comprehensively included different categories of HBV carriers.[4]Miao Z. Zhang S. Ou X. Li S. Ma Z. Wang W. et al.Estimating the global prevalence, disease progression and clinical outcome of hepatitis delta virus infection.J Infect Dis. 2020; 221: 1677-1687Crossref PubMed Scopus (100) Google Scholar,[10]Yurdaydin C. Toy M. Hepatitis delta virus infection: a large burden after all?.J Infect Dis. 2020; 221: 1573-1575Crossref PubMed Scopus (5) Google Scholar This corresponds to 32–61 million HDV infections depending on HBV burden estimates ranging from 250 to 500 million.[4]Miao Z. Zhang S. Ou X. Li S. Ma Z. Wang W. et al.Estimating the global prevalence, disease progression and clinical outcome of hepatitis delta virus infection.J Infect Dis. 2020; 221: 1677-1687Crossref PubMed Scopus (100) Google Scholar In summary, we have emphasized the critical concerns of the current Stockdale study,[1]Stockdale A.J. Kreuels B. Henrion M.Y.R. Giorgi E. Kyomuhangi I. de Martel C. et al.The global prevalence of hepatitis D virus infection: systematic review and meta-analysis.J Hepatol. 2020; 73: 523-532Abstract Full Text Full Text PDF PubMed Scopus (168) Google Scholar and revisited the estimation of HDV burden. We estimate that the global prevalence of HDV infection is approximately 50 million with a prevalence of 0.7% among the general population and 13% among HBV carriers. Nevertheless, we acknowledge estimating the global burden of HDV infection is a difficult task. Only when higher quality epidemiology studies become available in the future, the burden could be more precisely estimated. This work was supported by the following: the China Scholarship Council for funding PhD fellowships (201708530234 [to Z.M.]). Analysis: ZJM and QWP; Conception and writing: ZJM and QWP. The authors declare no conflicts of interest that pertain to this work. Please refer to the accompanying ICMJE disclosure forms for further details. Download .pdf (.15 MB) Help with pdf files disclosures.pdf