To mount a public health response, we need a better description of the HDV epidemic, standardized testing strategies and better treatment options. Co-infection of an HBV infected person with HDV worsens the outcome, with higher rates of cirrhosis and hepatocellular carcinoma. The prevention components of the GHSS e. In recent two meta-analyses, the global prevalence had been estimated to be 0. Several reviews summarized the landscape in epidemiology [ 13 , 14 ], testing [ 15 ], or treatment [ 16 ].
However, these did not address HDV care from a public health perspective. We therefore performed a current literature review in terms of epidemiology by WHO regions, genotypes distribution and their pathogenicity, factors associated with HDV infection, mortality due to HDV infection, testing strategies and treatment.
Reasonable to refer patients to specialized centers that offer access to experimental therapies. Recent review estimated 12 million people worldwide have experienced HDV infection. The geographic distribution of HDV infection is heterogeneous [ 17 ]. Geographical location of studies reporting high prevalence of HDV infection among HBV infected people, in all ages, worldwide, — From to , age-standardized mortality rates due to HDV were much higher in the North region of 2.
In Pakistan, there is a high prevalence belt in the rural Sindh province [ 24 ]. In Mongolia, where hepatocellular carcinoma HCC is the most common cancer annual rate: There are at least eight HDV genotypes 1 to 8.
HDV genotypes differ in terms of clinical outcomes. Genotype 1 is prevalent worldwide and has a variable course of infection. Genotype 2 is mostly reported from the Yakutia region of Russia, the Taiwan province of China, and Japan [ 28 ]. It possibly derives from a common genotype 2 prototype [ 28 ]. Genotype 2 is associated with higher rate of remission than genotype 1 [ 58 ]. Genotype 4 is reported in the Far East and often leads to mild liver disease. However, a variant of genotype 4 on the Miyako Islands in Japan is associated with greater progression to cirrhosis than genotype 4 in the Taiwan province ofChina [ 60 ].
Genotypes 5—8 are reported in Africa and in African migrants to Europe [ 14 , 61 , 62 ], but the natural history is not well characterised [ 14 , 63 , 64 ]. Sex workers also often have a higher prevalence of anti-HDV, especially if they inject drugs [ 68 ]. Migration from high HDV infection prevalence countries affects the epidemiology of the host country, explaining an increasing prevalence in France [ 69 ], Greece [ 70 ], Italy [ 71 ], Spain [ 72 ], Germany [ 73 ], and the United Kingdom [ 67 ].
Among persons with HBV infection, clinical guidelines recommend testing for HDV infection in patients who migrated from high prevalence areas, in those with cirrhosis, and those who have elevated liver tests while receiving appropriate treatment for HBV infection [ 8 , 12 ]. However, new medicines have been explored for the management of HDV [ 16 ]. Furthermore, novel therapeutics that target HDV entry, prenylation and nucleic acid replication now offer a promise of more effective treatment for HDV infection [ 77 ].
Stopping PegIFN prematurely is not recommended if treatment is well tolerated. Late responses may occur in patients and long-term follow-up studies indicate that IFN based therapy is associated with a lower disease progression. NA do not impact HDV replication and related disease, because the virus uses host enzymes for replication and thus lacks enzyme targets. Tenofovir was reported to have an effect when used for longer treatment duration in HIV-HDV co-infection [ 86 , 87 ], although these results have not been confirmed [ 88 , 89 ].
Adding lamivudine [ 92 , 93 ], ribavirin [ 83 , 94 ], adefovir [ 90 ], tenofovir [ 88 ], or entecavir [ 95 ] to PegIFN does not provide additional benefits over monotherapy. Myrcludex B is a hepatocyte entry inhibitor that interferes with HDV entry [ 96 , 97 ]. It reduces the population of HDV-positive cells and allows HDV-free hepatocytes to regenerate, which might ultimately lead to eradication of the virus [ 98 ]. In a phase 2b open label study, Myrcludex B in combination with tenofovir led to a dose-dependent HDV-RNA decline associated with clinical [ ] and virological [ ] improvements.
Myrcludex B has been well tolerated with no dose limiting toxicity [ ]. In a new phase 2 study suggested a synergistic effect of myrcludex B in combination with pegylated interferon [ ]. However, asymptomatic dose-dependent increases in bile acid levels were reported in study participants. Lonafarnib is a prenylation inhibitor that inhibits virion assembly. However, serum HBsAg levels did not change and adverse events were frequent [ ].
Nine among 12 patients were negative at the end of treatment, 7 were negative at the end of the one-year follow-up, and 5 maintained HBsAg-suppression at the end of follow-up. Functional remission is stable at 1. However, hematological adverse events were reported. On-treatment ALT flares may be a concern [ ]. There is extremely high variation in HDV prevalence and genotype distribution worldwide.
Prevalence is declining because of HBV immunization, but epidemiological data in many countries remain scant. Risk behaviours associated with HDV infection are also unclear.
Consequently, the global HDV prevalence has been difficult to describe precisely so far and more information is necessary. Thus, clinical guidelines [ 5 , 9 ] often recommend testing in such priority populations and in high endemicity countries. However, testing approaches from a public health perspective require data on national and global epidemiology and evidence to guide how to test. However, it is not widely available, and not yet standardized.
Innovative methods such as point-of-care rapid diagnostic tests are not yet available. In addition, fibrosis staging of liver disease in HDV is challenging as non-invasive tests are impracticable [ ]. Effective fibrosis score specifically developed for chronic HDV infection is necessary. Therapeutic options for HDV infection are still limited and PegIFN and NA are the only medicines mentioned in the most recent hepatology society guidelines [ 8 , 10 — 12 ].
IFNs are of limited effectiveness and are associated with a high rate of relapse. New treatment strategies targeting different steps of the HDV life cycle are emerging and provide hope for the future for HDV co-infected patients. Some medicines appear more effective in combination with others, especially combined with PegIFN.
Clinical trials are still ongoing and limited evidence is available. Sustained HDV suppression or cure would be necessary for sustained clinical improvement. However, since new treatments of HDV are an urgent need, experts on HDV treatment have recommended that a 2 log decline of HDV RNA at end of treatment from baseline should represent a surrogate for initial treatment efficacy in clinical trials of novel therapies for patients with CHD [ ].
Our review suffers from a number of limitations. First, HDV RNA and genotype testing are not routinely done in most countries, therefore, relevant data are very limited. Second, sampling often included potentially biased populations, such as medical outpatients or health-care workers. Finally, we summarized epidemiological data but there were insufficient data in the literature to analyse the long-term outcome of HDV infection.
Long-term, multicenter prospective studies are needed to better understand the prognosis of HDV infection in different settings. Our review supports three conclusions. As a result, reliable global HDV prevalence estimates are unavailable.
Second, testing approaches have not been defined for HDV because of a lack of diagnostic tests and insufficient evidence to determine who needs to be tested. Third, few treatment options are currently available for HDV, but none are sufficiently effective, cost effective or affordable to allow delivery on a large scale. There are three areas of work that need to be undertaken to address these gaps.
First, the regional and global epidemiology need to be better characterised using systematic reviews and meta-analyses, with generation of more surveillance data at the country level. Second, we need to develop a public health testing approach for HDV, that would address who to test and how to test. In addition to the persons listed as authors, the staff at global hepatitis programme at WHO are gratefully acknowledged. TH and YT collected literatures and wrote the first draft of the manuscript, which was commented by all authors.
The author s read and approved the final manuscript. All data generated or analysed during this study are included in this published article. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. National Center for Biotechnology Information , U.
Journal List Arch Public Health v. Arch Public Health. Published online Oct Yvan J. Author information Article notes Copyright and License information Disclaimer. Tomoyuki Hayashi, Email: moc. Corresponding author. Received Sep 21; Accepted Sep The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
Associated Data Data Availability Statement All data generated or analysed during this study are included in this published article. Methods We performed a current literature review in terms of epidemiology by WHO regions, genotypes distribution and their pathogenicity, factors associated with HDV infection, mortality due to HDV infection, testing strategies and treatment.
Results Prevalence of infection and genotypes are heterogeneous distributed, with highest prevalence in foci around the Mediterranean, in the Middle East, and in Central, Northern Asia and Eastern Asia. Conclusion HDV infection is an poorly known cause of chronic liver disease. Table 1 Key elements regarding hepatitis D in the guidelines addressing hepatitis B.
It can be continued irrespective of on-treatment response pattern if well tolerated. Pegylated interferon is effective against HDV. HDV can cause severe liver injury that may result in fulminant hepatic failure and rapid progression to cirrhosis and hepatic decompensation, as well as an increased risk of liver cancer. Some endemic areas in the developing world may have much higher prevalence.
Should be evaluated particularly if hepatitis is present in the face of little or no HBV viral replication, or if they come from an HDV-endemic region or have acquired HBV through injection drug use. Open in a separate window. Genotypes distribution and their pathogenicity There are at least eight HDV genotypes 1 to 8. Table 2 HDV genotypes and their geographical distribution. Testing strategies Among persons with HBV infection, clinical guidelines recommend testing for HDV infection in patients who migrated from high prevalence areas, in those with cirrhosis, and those who have elevated liver tests while receiving appropriate treatment for HBV infection [ 8 , 12 ].
Lonafarnib Lonafarnib is a prenylation inhibitor that inhibits virion assembly. Discussion: next steps from a public health perspective Epidemiology There is extremely high variation in HDV prevalence and genotype distribution worldwide. Limitations Our review suffers from a number of limitations. Conclusion Our review supports three conclusions. Acknowledgements In addition to the persons listed as authors, the staff at global hepatitis programme at WHO are gratefully acknowledged.
Funding Dr. Availability of data and materials All data generated or analysed during this study are included in this published article. Declarations Ethics approval and consent to participate Not applicable.
Competing interests Dr. References 1. Molecular cloning and sequencing of a human hepatitis delta virus RNA. World Health Organization. Global hepatitis report. Geneva: World Health Organization; Farci P. Delta hepatitis: an update. J Hepatol. Rizzetto M, Hepatitis D. Virus: introduction and epidemiology. Cold Spring Harb Perspect Med. Global health sector strategy on viral hepatitis Prevalence and burden of hepatitis D virus infection in the global population: a systematic review and meta-analysis.
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Please contact DVH laboratory for help with testing options for hepatitis delta virus infection. All shipments must have completed HRL shipping manifests and HDV specimen submission forms and sent via overnight delivery at C to arrive at CDC no later than Thursday of any given week except holidays. Skip directly to site content Skip directly to page options Skip directly to A-Z link.
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