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The global hepatitis delta virus (HDV) epidemic: what gaps to address in order to mount a public health response?

Abstract

Background

Co-infection between hepatitis B virus (HBV) and hepatitis delta virus (HDV) causes the severest chronic hepatitis and is associated with a high risk of cirrhosis and hepatocellular carcinoma (HCC). The Global Health Sector Strategy on Viral Hepatitis called for the elimination of hepatitis (− 65% mortality and − 90% incidence) by 2030. Our aims were to summarize key points of knowledge and to identify the gaps that need to be addressed to mount a public health response to HDV.

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. Persons who inject drugs (PWID) and migrants from highly endemic areas are highly affected. While antibody detection tests are available, HDV RNA tests of current infection are not standardized nor widely available. The few therapeutic options, including lofartinib, are not widely available; however several new and promising agents have entered clinical trials.

Conclusion

HDV infection is an poorly known cause of chronic liver disease. To mount a public health response, we need a better description of the HDV epidemic, standardized testing strategies and better treatment options.

Peer Review reports

Background

Of the viruses causing hepatitis, Hepatitis delta Virus (HDV) is unique in that it needs the helper function of Hepatitis B Virus (HBV) to infect hepatocytes [1]. The World Health Organization (WHO) estimates that in 2015, 257 million people (3.5% of the world’s population) were infected with HBV [2]. However, WHO does not have estimates of prevalence or mortality for HDV. Co-infection of an HBV infected person with HDV worsens the outcome, with higher rates of cirrhosis and hepatocellular carcinoma. Most published reviews quote 5% as an estimate of the prevalence of HDV coinfection among persons with HBV infection (about 13 million persons worldwide) [3], mostly in high endemicity foci or among immigrants from highly endemic regions [4].

In 2016, the Global Health Sector Strategy (GHSS) on Viral Hepatitis [5] called for the elimination of hepatitis (− 65% mortality and − 90% incidence) by 2030. The prevention components of the GHSS (e.g., HBV immunization, blood and injection safety programmes) will prevent HBV infection and thus HDV infection. However, the GHSS provides limited solutions for HDV infection from a testing and treatment perspective. In recent two meta-analyses, the global prevalence had been estimated to be 0.8–0.98% in the general population, and 13–14% in the HBsAg-positive population, which corresponds to around 60 million infections globally [6, 7].

A number of professional associations [8,9,10,11,12] address hepatitis D in their care and treatment guidelines (Table 1). 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. Our aims were to summarize key points of knowledge and to identify the gaps that need to be addressed to mount a public health response to HDV.

Epidemiology by WHO regions

Recent review estimated 12 million people worldwide have experienced HDV infection. The geographic distribution of HDV infection is heterogeneous [17]. Among HBV infected persons, HDV infection is particularly common in Central and West Africa, Central and Northern Asia, Viet Nam, Mongolia, Pakistan, Japan, the Taiwan province of China, Pacific Islands (Kiribati, Nauru), the Middle East, Eastern Europe (e.g., Turkey), South America (the Amazone basin), and Greenland [8, 18] (Fig. 1).

Fig. 1
figure1

Geographical location of studies reporting high prevalence of HDV infection among HBV infected people, in all ages, worldwide, 2008–2017

Africa

In a 2017 systematic review, HDV antibody (anti-HDV) prevalence among HBV-infected persons varied from 26% in Central Africa, 7% in West Africa, to only 0.05% in Eastern and Southern Africa. High-prevalence spots were reported in Gabon (45%, 2015), Democratic Republic of the Congo (26%, 2017), Mauritania (19%, 2009), Cameroon (14–35%, 2011) and Nigeria (5%, 2014) in the general HBV infected population. Among HIV-HBV co-infected persons, high prevalence spots were reported in Guinea-Bissau (25%, 2011), Cameroon (12%, 2010) and Nigeria (7%, 2004) [14].

The Americas

HBV mostly affects Indigenous Populations in the Americas. In the Amazon region of North Brazil, in 2003–2009, anti-HDV prevalence was 29%. among HBV infected persons [19, 20]. Anti-HDV prevalence in indigenous populations with HBV infection was 39% of Peru, 13% in Brazil, 8% in Colombia, and 4–6% in Venezuela [21]. In the United States, anti-HDV prevalence among HBV-infected persons was around 3% [22] between 2012 and 2016. Advanced fibrosis was associated with high HDV viral load in the western Amazon Basin of Brazil [23]. From 2008 to 2014, age-standardized mortality rates due to HDV were much higher in the North region of 2.2 per million compared to all regions of 0.28 per million [19].

Eastern Mediterranean

A 2010, a systematic review estimated that anti-HDV prevalence was 15% in persons with HBV infection (pooled prevalence: 25% in Sudan, 18% in Pakistan, 16% in Tunisia, 11% in Egypt, 7% in Saudi Arabia, 5% in Iran, and 2% in Yemen) [13]. In Pakistan, there is a high prevalence belt in the rural Sindh province [24]. In other countries, one study was available that reported 29% in Afghanistan, 17% in Somalia, 2% in Jordan, 2% in Djibouti, and 0.9% in Lebanon [14].

Europe

In Europe, areas reporting high prevalence of anti-HVD among HBV infected persons include Romania (23%, 2015) [25], Eastern Turkey (15%, 2012–2014 [26], higher than in western Turkey (3%) [27], Yakutia, Siberia, Russia (18–20%, 1996–1998) [28], and Greenland, among Inuits [29, 30] (6%, 2011) [31]. In Austria, Belgium, Bulgaria, Czech Republic, Croatia, France, Greece, Ireland, Poland, and Switzerland, HDV is uncommon [32].

South-East Asia

In Bangladesh, 22% of HBV infected persons were anti-HDV positive in 2003 [33]. In New Delhi, India, a 11% anti-HBV prevalence was reported in HBV infected persons in 2005 [34]. In others areas with high prevalence of HBV such as Indonesia [35] and Thailand [36], HDV is uncommon [24].

Western Pacific

In Mongolia, where hepatocellular carcinoma (HCC) is the most common cancer (annual rate: 54.1 cases per 100,000 people) [37], anti-HDV prevalence among HBV infected perons was 45% in 2013 [37] (60% in 2017 when using a novel quantitative microarray antibody capture assay) [38]. In China, 4% of persons with HBV infection were anti-HDV positive in Inner Mongolia, Xinjiang and Tibet, where ethnic minorities live [39]. The Taiwan province of China was endemic for HBV, but following immunization, the prevalence of HBV and HDV infection decreased. However, anti-HDV was more common in the south than in the north (6% vs 2%) [40]. In Japan, HDV is highly prevalent in the Miyako Islands (24% in one of these islands in 1997 [41]) [42]. The distribution of anti-HDV in the Pacific is highly heterogeneous, with reports in Nauru, Kiribati [43], Niue and Western Samoa while It is extremely low or absent in other Islands [44, 45]. In Viet Nam, in 2000–2009, 15% of HBsAg positive people were HDV-RNA positive [46]. In Australia, Malaysia, Philippines and the Republic of Korea, HDV is uncommon in the general HBV infected population [39].

Genotypes distribution and their pathogenicity

There are at least eight HDV genotypes (1 to 8). Viral genotypic diversity is related to the geographical location (Table 2). HDV genotypes differ in terms of clinical outcomes. Genotype 1 is prevalent worldwide and has a variable course of infection. In Europe, North America and South Asia,Central and Northern Asia, eastern Mediterranian, and Middle East, genotype 1 is the most prevalent [47,48,49,50,51,52,53,54,55,56,57], while others are extremely rare. Genotype 1 was the most prevalent in Africa (median 88%) [14]. 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 3 is common in the Amazon Basin (90% of HDV-infected people) [20], and is associated with more severe forms of the disease, earlier onset of HCC and outbreaks of fatal acute liver failure [59]. 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].

Table 1 Key elements regarding hepatitis D in the guidelines addressing hepatitis B
Table 2 HDV genotypes and their geographical distribution

Factors associated with HDV infection

An association between prevalent HDV infection and injection drug use was reported the USA [65, 66], United Kingdom [67], and Iran [9, 12]. The high prevalence of anti-HDV in PWIDs suggests that injecting drug use is a risk factor for HDV super-infection. 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]. In Western European countries, 55 to 95% of HDV infections are reported in more affected population groups, including PWID, and immigrants from highly endemic areas [16].

Mortality due to HDV infection

The International Agency for Research on Cancer estimated that in 2012, around 430,000 (56%) of new HCC cases were attributable to HBV [74, 75]. WHO reported that in 2015, approximately 380,000 people died of liver cancer secondary to HBV and 490,000 people died of cirrhosis due to HBV [76]. While the HDV coinfection worsens the outcomes of patients infected with HBV, very few studies estimated the proportion of HBV deaths that are also attributable to HDV infection.

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]. In highly endemic areas, HBsAg positive patients may need to be tested at least once for anti-HDV. In other areas, testing may be restricted to HBsAg positive persons with abnormal ALT and low HBV DNA and those not responding well to appropriate treatment, irrespective of HBV DNA level. In terms of cancer prevention, some clinical guidelines recommend screening persons with HDV infection with ultrasonography every 6 months [8].

Treatment

The management of HDV infection has not changed in over 30 years and consists of treatment with interferon. 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].

Standard therapies

Pegylated interferon (PegIFN) is the only medicine mentioned as effective against HDV in the WHO guidelines [78]. Other guidelines recommend PegIFN for at least 48 weeks irrespective of response patterns [8, 10,11,12, 79]. Of patients who receive PegIFNα for 48 weeks, 17–43% of treated patients had undetectable HDV RNA [80,81,82,83]. Sustained virological response remains uncommon, and late relapses occurred in more than 50% of responders [84]. 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. Long-term follow-up and HDV RNA monitoring is recommended for all treated patients as long as HBsAg is present.

Nucleotide analogues

WHO recommends Nucleot(s) ide analogues (NA) for the treatment of chronic HBV infecton [2, 6]. NA do not impact HDV replication and related disease, because the virus uses host enzymes for replication and thus lacks enzyme targets. NA analogs have been tested for a duration of 6 to 18 months in chronic hepatitis D and were ineffective (NAs do not affect HBsAg synthesis, the main function needed by HDV for propagation) [85]. 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].

Nucleotide analogs in combination with interferons

A trial compared 48 weeks pegylated interferon with or without adefovir with adefovir monotherapy 28% of patients receiving pegylated interferon with or without adefovir (compared to none on adefovir) achieved undetectable HDV-RNA level 24 weeks after completing therapy [90]. A similar effect on HBsAg levels was not reported in a follow up study, which compared PegIFN-tenofovir combination with PegIFN monotherapy [91]. 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

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 2a study of patients HBV-DNA and HDV-RNA positive, myrcludex B led to HDV RNA decline, and 1 of 7 patients became HDV-RNA negative. Moreover, 5 of 7 patients became HDV-RNA negative in combination with PegIFN, suggesting a synergistic effect of myrcludex B and PegIFN [99]. In a phase 2b open label study, Myrcludex B in combination with tenofovir led to a dose-dependent HDV-RNA decline associated with clinical [100] and virological [101] improvements. However, HDV-RNA levels rebounded after Myrcludex B was discontinued [102]. Myrcludex B has been well tolerated with no dose limiting toxicity [101]. In a new phase 2 study suggested a synergistic effect of myrcludex B in combination with pegylated interferon [103]. However, asymptomatic dose-dependent increases in bile acid levels were reported in study participants.

Lonafarnib

Lonafarnib is a prenylation inhibitor that inhibits virion assembly. In a phase 2 double-blinded, randomized, placebo-controlled trial, oral lonafarnib (100 mg or 200 mg) twice daily for 28 days significantly reduced viremnia [104]. However, serum HBsAg levels did not change and adverse events were frequent [101]. Combining lonafanib with PegIFN achieved more substantial and rapid HDV-RNA reduction, compared to historical responses with PegIFN alone.

Ritonavir

Ritonavir (a protease inhibitor) inhibits one of the cytochrome P− 450 systems that metabolizes lonafarnib, leading to higher serum levels with minimal side effects [104, 105]. Lonafarnib plus ritonavir yielded a better antiviral response RNA after 8 weeks of therapy [102], which did not last after the therapy was discontinued [106]. However, in a subset of patients, 8 to 12 weeks of therapy with a lonafarnib based regimen, led to a post-treatment biochemical flare with subsequent normalization of ALT and undetectable viruses [104]. Tiple therapy with low dose (either 25 mg, bid or 50 mg, bid) in combination with ritonavir for 24 weeks appears synergistic [107].

Nucleic acid polymers

Nucleic acid polymers (NAPs) can lead to dramatic declines in HBsAg for HBV-HDV co-infected patients after 6 months or less. REP2139 is one of these NAPs and an inhibitor of HBsAg release. A phase 2 proof of concept trial combined REP2139 with PegIFN. 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 1.5 years follow-up and is associated with persistently normal liver function and progressive reduction in median hepatic stiffness [108]. However, hematological adverse events were reported. On-treatment ALT flares may be a concern [109].

Ezetimibe

Ezetimibe inhibits NTCP and therapy with ezetimibe may lead to a decline in HDV levels. A clinical phase 2 trial is recruiting (NCT03099278).

Discussion: next steps from a public health perspective

Epidemiology

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. From a mortality perspective, if we assume that the prevalence of HDV infection is 5–10% in the 390,000 persons who died from HBV associated HCC and in the 480,000 persons associated cirrhosis in 2015 [2], then at least 19,500–39,000 cases of HCC deaths and 24,000–48,000 cases of cirrhosis deaths could be HDV related [76, 110].

Testing

HDV prevalence is higher in PWID, sex workers, and migrants from highly HDV endemic countries. 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. While detection of anti-HDV-IgG is commonly used to test for HDV infection, HDV-RNA testing can be used to confirm infection. 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 [111]. Effective fibrosis score specifically developed for chronic HDV infection is necessary.

Treatment

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, 10,11,12]. However, none of these NAs affect HDV RNA replication per se. 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 [112].

Limitations

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. We therefore defined HDV infection as positive for IgG anti-HDV. 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.

Conclusion

Our review supports three conclusions. First, while certain countries and risk/ethnic groups have very high HDV prevalence, there is a lot of heterogeneity and many data gaps. 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. Third, researchers, clinicians, academia, funding/donor institutions and governments will need to work closely with each other to make sure that treatment options identified as promising can be further evaluated and scaled for access to those infected with HDV in line with the global goal of hepatitis elimination by 2030.

Availability of data and materials

All data generated or analysed during this study are included in this published article.

Abbreviations

Anti-HDV:

Hepatitis delta virus antibody

HBV:

Hepatitis B virus

HDV:

Hepatitis delta virus

HCC:

Hepatocellular carcinoma

PWID:

Persons who inject drugs

WHO:

World Health Organization

GHS:

Global Health Sector Strategy

PegIFN:

Pegylated interferon

NA:

Nucleot(s) ide analogues

References

  1. 1.

    Makino S, Chang MF, Shieh CK, Kamahora T, Vannier DM, Govindarajan S, et al. Molecular cloning and sequencing of a human hepatitis delta virus RNA. Nature. 1986;329(6137):343–6. https://doi.org/10.1038/329343a0.

    Article  Google Scholar 

  2. 2.

    World Health Organization. Global hepatitis report. Geneva: World Health Organization; 2017.

    Google Scholar 

  3. 3.

    Farci P. Delta hepatitis: an update. J Hepatol. 2003;39:S212–9. https://doi.org/10.1016/S0168-8278(03)00331-3.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  4. 4.

    Rizzetto M, Hepatitis D. Virus: introduction and epidemiology. Cold Spring Harb Perspect Med. 2015;5:a021576.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  5. 5.

    World Health Organization. Global health sector strategy on viral hepatitis 2016-2021. Geneva: World Health Organization; 2016.

    Google Scholar 

  6. 6.

    Chen HY, Shen DT, Ji DZ, Han PC, Zhang WM, Ma JF, et al. Prevalence and burden of hepatitis D virus infection in the global population: a systematic review and meta-analysis. Gut. 2018. https://doi.org/10.1136/gutjnl-2018-316601.

  7. 7.

    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. 2019. https://doi.org/10.1093/infdis/jiz633.

  8. 8.

    Terrault NA, Lok ASF, McMahon BJ, Chang KM, Hwang JP, Jonas MM, et al. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018;67:1560–99.

    PubMed  PubMed Central  Article  Google Scholar 

  9. 9.

    European Association For The Study Of The Liver. EASL clinical practice guidelines: management of chronic hepatitis B virus infection. J Hepatol. 2012;57(1):167–85. https://doi.org/10.1016/j.jhep.2012.02.010.

    Article  Google Scholar 

  10. 10.

    European Association for the Study of the Liver; European Association for the Study of the Liver. EASL 2017 clinical practice guidelines on the management of hepatitis B virus infection. J Hepatol. 2017;67:370–98.

    Article  Google Scholar 

  11. 11.

    Sarin SK, Kumar M, Lau GK, Abbas Z, Chan HL, Chen CJ, et al. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update. Hepatol Int. 2016;10(1):1–98. https://doi.org/10.1007/s12072-015-9675-4.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  12. 12.

    Feld J, Janssen HL, Abbas Z, Elewaut A, Ferenci P, Isakov V, et al. World gastroenterology organisation global guideline hepatitis B: September 2015. J Clin Gastroenterol. 2016;50(9):691–703. https://doi.org/10.1097/MCG.0000000000000647.

    Article  PubMed  PubMed Central  Google Scholar 

  13. 13.

    Amini N, Alavian SM, Kabir A, Aalaei-Andabili SH, Saiedi Hosseini SY, Rizzetto M. Prevalence of hepatitis d in the eastern mediterranean region: systematic review and meta analysis. Hepat Mon. 2013;13(1):e8210. https://doi.org/10.5812/hepatmon.8210.

    Article  PubMed  PubMed Central  Google Scholar 

  14. 14.

    Stockdale AJ, Chaponda M, Beloukas A, Phillips RO, Matthews PC, 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(10):e992–e1003. https://doi.org/10.1016/S2214-109X(17)30298-X.

    Article  PubMed  PubMed Central  Google Scholar 

  15. 15.

    El Bouzidi K, Elamin W, Kranzer K, Irish DN, Ferns B, Kennedy P, et al. Hepatitis delta virus testing, epidemiology and management: a multicentre cross-sectional study of patients in London. J Clin Virol. 2015;66:33–7. https://doi.org/10.1016/j.jcv.2015.02.011.

    Article  Google Scholar 

  16. 16.

    Yurdaydin C. Recent advances in managing hepatitis D. F1000Res. 2017;6:1596.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  17. 17.

    Stockdale AJ, Kreuels B, Henrion MYR, 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 Sep;73(3):523–32. https://doi.org/10.1016/j.jhep.2020.04.008.

    Article  PubMed  PubMed Central  Google Scholar 

  18. 18.

    World Health Organization. Hepatitis D: Fact Sheet. In: Media Centre. Geneva: World Health Organization; 2017. [cited 2018 Apr 16]. Available from: http://www.who.int/mediacentre/factsheets/hepatitis-d/en/.

    Google Scholar 

  19. 19.

    Perazzo H, Pacheco AG, Luz PM, Castro R, Hyde C, Fittipaldi J, et al. Age-standardized mortality rates related to viral hepatitis in Brazil. BMC Infect Dis. 2017;17:527. https://doi.org/10.1186/s12879-017-2619-y.

    Article  PubMed  PubMed Central  Google Scholar 

  20. 20.

    Crispim MA, Fraiji NA, Campello SC, Schriefer NA, Stefani MM, Kiesslich D. Molecular epidemiology of hepatitis B and hepatitis delta viruses circulating in the Western Amazon region, North Brazil. BMC Infect Dis. 2014;14:94. https://doi.org/10.1186/1471-2334-14-94.

    Article  PubMed  PubMed Central  Google Scholar 

  21. 21.

    di Filippo VD, Cortes-Mancera F, Payares E, Montes N, de la Hoz F, Arbelaez MP, et al. Hepatitis D virus and hepatitis B virus infection in Amerindian communities of the Amazonas state, Colombia. Virol J. 2015;12:172. https://doi.org/10.1186/s12985-015-0402-5.

    CAS  Article  Google Scholar 

  22. 22.

    Safaie P, Razeghi S, Rouster SD, Privitera I, Sherman KE. Hepatitis D diagnostics:utilization and testing in the united states. Virus Res. 2018. https://doi.org/10.1016/j.virusres.2018.03.013 [Epub ahead of print].

  23. 23.

    Braga WS, de Oliveira CM, de Araújo JR, Castilho Mda C, Rocha JM, Gimaque JB, et al. Chronic HDV/HBV co-infection: predictors of disease stage---a case series of HDV-3 patients. J Hepatol. 2014;61(6):1205–11. https://doi.org/10.1016/j.jhep.2014.05.041.

    Article  PubMed  PubMed Central  Google Scholar 

  24. 24.

    Khan AU, Waqar M, Akram M, Zaib M, Wasim M, Ahmad S, et al. True prevalence of twin HDV-HBV infection in Pakistan: a molecular approach. Virol J. 2011;8(1):420. https://doi.org/10.1186/1743-422X-8-420.

    Article  PubMed  PubMed Central  Google Scholar 

  25. 25.

    Gheorghe L, Csiki IE, Iacob S, Gheorghe C, Trifan A, Grigorescu M, et al. Hepatitis delta virus infection in Romania: prevalence and risk factors. J Gastrointestin Liver Dis. 2015;24:413–21.

    PubMed  Article  PubMed Central  Google Scholar 

  26. 26.

    Dulger AC, Suvak B, Gonullu H, Gonullu E, Gultepe B, Aydın İ, et al. High prevalence of chronic hepatitis D virus infection in eastern Turkey: urbanization of the disease. Arch Med Sci. 2016;12(2):415–20. https://doi.org/10.5114/aoms.2015.52030.

    Article  PubMed  PubMed Central  Google Scholar 

  27. 27.

    Uzun B, Şener AG, Güngör S, Afşar I, Demirci M. Evaluation of hepatitis delta virus (HDV) infection in blood donors in western Turkey. Transfus Apher Sci. 2014;50:388–91.

    PubMed  Article  PubMed Central  Google Scholar 

  28. 28.

    Ivaniushina V, Radjef N, Alexeeva M, Gault E, Semenov S, Salhi M, et al. Hepatitis delta virus genotypes I and II cocirculate in an endemic area of Yakutia, Russia. J Gen Virol. 2001;82:2709–18.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  29. 29.

    Børresen ML, Olsen OR, Ladefoged K, McMahon BJ, Hjuler T, Panum I, et al. Hepatitis D outbreak among children in a hepatitis B hyper-endemic settlement in Greenland. J Viral Hepat. 2010;17:162–70.

    PubMed  Article  PubMed Central  Google Scholar 

  30. 30.

    Langer BC, Frösner GG, von Brunn A. Epidemiological study of viral hepatitis types A, B, C, D and E among Inuits in West Greenland. J Viral Hepat. 1997;4:339–49.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  31. 31.

    Rex KF, Krarup HB, Laurberg P, Andersen S. Population-based comparative epidemiological survey of hepatitis B, D, and C among Inuit migrated to Denmark and in high endemic Greenland. Scand J Gastroenterol. 2012;47(6):692–701. https://doi.org/10.3109/00365521.2011.634026.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  32. 32.

    Rizzetto M, Ciancio A. Epidemiology of hepatitis D. Semin Liver Dis. 2012;32(3):211–9. https://doi.org/10.1055/s-0032-1323626.

    Article  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Zaki H, Darmstadt GL, Baten A, Ahsan CR, Saha SK. Seroepidemiology of hepatitis B and delta virus infections in Bangladesh. J Trop Pediatr. 2003;49:371–4.

    PubMed  Article  Google Scholar 

  34. 34.

    Chakraborty P, Kailash U, Jain A, Goyal R, Gupta RK, Das BC, et al. Seroprevalence of hepatitis D virus in patients with hepatitis B virus-related liver diseases. Indian J Med Res. 2005;122:254–7.

    PubMed  PubMed Central  Google Scholar 

  35. 35.

    Mulyanto, Depamede SN, Surayah K, Tsuda F, Ichiyama K, Takahashi M, et al. A nationwide molecular epidemiological study on hepatitis B virus in Indonesia: identification of two novel subgenotypes, B8 and C7. Arch Virol. 2009;154:1047–59.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  36. 36.

    Louisirirotchanakul S, Myint KS, Srimee B, Kanoksinsombat C, Khamboonruang C, Kunstadter P, et al. The prevalence of viral hepatitis among the Hmong people of northern Thailand. Southeast Asian J Trop Med Public Health. 2002;33:837–44.

    CAS  PubMed  Google Scholar 

  37. 37.

    Baatarkhuu O, Uugantsetseg G, Munkh-Orshikh D, Naranzul N, Badamjav S, Tserendagva D, et al. Viral hepatitis and liver diseases in Mongolia. Hepato-Gastroenterol. 2017;7(1):68–72. https://doi.org/10.5005/jp-journals-10018-1215.

    Article  Google Scholar 

  38. 38.

    Chen X, Oidovsambuu O, Liu P, Grosely R, Elazar M, Winn VD, et al. A novel quantitative microarray antibody capture assay identifies an extremely high hepatitis delta virus prevalence among hepatitis B virus-infected mongolians. Hepatology. 2017;66(6):1739–49. https://doi.org/10.1002/hep.28957.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  39. 39.

    Abbas Z, Jafri W, Raza S. Hepatitis D: Scenario in the Asia-Pacific region. World J Gastroenterol. 2010;16:554–62. https://doi.org/10.3748/wjg.v16.i5.554.

    Article  PubMed  PubMed Central  Google Scholar 

  40. 40.

    Lin HH, Lee SS, Yu ML, Chang TT, Su CW, Hu BS, et al. Changing hepatitis D virus epidemiology in a hepatitis B virus endemic area with a national vaccination program. Hepatology. 2015;61:1870–9. https://doi.org/10.1002/hep.27742.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  41. 41.

    Sakugawa H, Nakasone H, Shokita H, Kawakami Y, Nakachi N, Adaniya H, et al. Seroepidemiological study on hepatitis delta virus infection in the Irabu Islands, Okinawa, Japan. J Gastroenterol Hepatol. 1997;12(4):299–304. https://doi.org/10.1111/j.1440-1746.1997.tb00425.x.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  42. 42.

    Sakugawa H, Nakasone H, Nakayoshi T, Kawakami Y, Miyazato S, Kinjo F, et al. Hepatitis delta virus genotype IIb predominates in an endemic area, Okinawa, Japan. J Med Virol. 1999;58:366–72.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  43. 43.

    Han M, Littlejohn M, Yuen L, Edwards R, Devi U, Bowden S, et al. Molecular epidemiology of hepatitis delta virus in the Western Pacific region. J Clin Virol. 2014;61(1):34–9. https://doi.org/10.1016/j.jcv.2014.05.021.

    Article  PubMed  PubMed Central  Google Scholar 

  44. 44.

    Dimitrakakis M, Gust I. HDV infection in the Western Pacific region. Prog Clin Biol Res. 1991;364:89–96.

    CAS  PubMed  PubMed Central  Google Scholar 

  45. 45.

    Tibbs CJ. Delta hepatitis in Kiribati: a pacific focus. J Med Virol. 1989;29(2):130–2. https://doi.org/10.1002/jmv.1890290210.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  46. 46.

    Sy BT, Ratsch BA, Toan NL, le Song H, Wollboldt C, Bryniok A, et al. High prevalence and significance of hepatitis D virus infection among treatment-naïve HBsAg-positive patients in Northern Vietnam. PLoS One. 2013;8:e78094. https://doi.org/10.1371/journal.pone.0078094.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  47. 47.

    Saudy N, Sugauchi F, Tanaka Y, Suzuki S, Aal AA, Zaid MA, et al. Genotypes and phylogenetic characterization of hepatitis B and delta viruses in Egypt. J Med Virol. 2003;70(4):529–36. https://doi.org/10.1002/jmv.10427.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  48. 48.

    Takahashi M, Nishizawa T, Gotanda Y, Tsuda F, Komatsu F, Kawabata T, et al. High prevalence of antibodies to hepatitis A and E viruses and viremia of hepatitis B, C, and D viruses among apparently healthy populations in Mongolia. Clin Diagn Lab Immunol. 2004;11:392–8.

    PubMed  PubMed Central  Google Scholar 

  49. 49.

    Tsatsralt-Od B, Takahashi M, Endo K, Buyankhuu O, Baatarkhuu O, Nishizawa T, et al. Infection with hepatitis A, B, C, and delta viruses among patients with acute hepatitis in Mongolia. J Med Virol. 2006;78(5):542–50. https://doi.org/10.1002/jmv.20574.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  50. 50.

    Khan A, Kurbanov F, Tanaka Y, Elkady A, Sugiyama M, Dustov A, et al. Epidemiological and clinical evaluation of hepatitis B, hepatitis C, and delta hepatitis viruses in Tajikistan. J Med Virol. 2008;80(2):268–76. https://doi.org/10.1002/jmv.21057.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  51. 51.

    Mohebbi SR, Zali N, Derakhshan F, Tahami A, Mashayekhi R, Amini-Bavil-Olyaee S, et al. Molecular epidemiology of hepatitis delta virus (HDV) in Iran: a preliminary report. J Med Virol. 2008;80(12):2092–9. https://doi.org/10.1002/jmv.21326.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  52. 52.

    Celik I, Karatayli E, Cevik E, Kabakçi SG, Karatayli SC, Dinç B, et al. Complete genome sequences and phylogenetic analysis of hepatitis delta viruses isolated from nine Turkish patients. Arch Virol. 2011;156:2215–20.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  53. 53.

    Perveen S, Nasir MI, Shahid SM, Azhar A, Khan OY. Phylogenetic analysis of HDV isolates from HBsAg positive patients in Karachi, Pakistan. Virol J. 2012;9:162. https://doi.org/10.1186/1743-422X-9-162.

    Article  PubMed  PubMed Central  Google Scholar 

  54. 54.

    Bulut Y, Bahcecioglu IH, Aygun C, Oner PD, Ozercan I, Demirdag K. High genetic diversity of hepatitis delta virus in eastern Turkey. J Infect Dev Ctries. 2014;8:74–8.

    PubMed  Article  PubMed Central  Google Scholar 

  55. 55.

    Attaran MS, Sharifi Z, Hosseini SM, Samei S, Ataee Z. Prevalence of hepatitis B and hepatitis D coinfection in asymptomatic blood donors in Iran. APMIS. 2014;122(3):243–7. https://doi.org/10.1111/apm.12137.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  56. 56.

    Shirvani-Dastgerdi E, Amini-Bavil-Olyaee S, Alavian SM, Trautwein C, Tacke F. Comprehensive analysis of mutations in the hepatitis delta virus genome based on full-length sequencing in a nationwide cohort study and evolutionary pattern during disease progression. Clin Microbiol Infect. 2015;21:510. e11–23. https://doi.org/10.1016/j.cmi.2014.12.008 Epub 2014 Dec 26.

    CAS  Article  Google Scholar 

  57. 57.

    Yacoubi L, Brichler S, Mansour W, Le Gal F, Hammami W, Sadraoui A, et al. Molecular epidemiology of hepatitis B and Delta virus strains that spread in the Mediterranean North East Coast of Tunisia. J Clin Virol. 2015;72:126–32. https://doi.org/10.1016/j.jcv.2015.10.002.

    Article  PubMed  PubMed Central  Google Scholar 

  58. 58.

    Su CW, Huang YH, Huo TI, Shih HH, Sheen IJ, Chen SW, et al. Genotypes and viremia of hepatitis B and D viruses are associated with outcomes of chronic hepatitis D patients. Gastroenterology. 2006;130(6):1625–35. https://doi.org/10.1053/j.gastro.2006.01.035.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  59. 59.

    Borzacov LM, de Figueiredo Nicolete LD, Souza LF, Dos Santos AO, Vieira DS, Salcedo JM. Treatment of hepatitis delta virus genotype 3 infection with peg-interferon and entecavir. Int J Infect Dis. 2016;46:82–8.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  60. 60.

    Watanabe H, Nagayama K, Enomoto N, Chinzei R, Yamashiro T, Izumi N, et al. Chronic hepatitis delta virus infection with genotype IIb variant is correlated with progressive liver disease. J Gen Virol. 2003;84:3275–89.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  61. 61.

    Le Gal F, Gault E, Ripault MP, Serpaggi J, Trinchet JC, Gordien E, et al. Eighth major clade for hepatitisdelta virus. Emerg Infect Dis. 2006;12:1447–50.

    PubMed  PubMed Central  Article  Google Scholar 

  62. 62.

    Radjef N, Gordien E, Ivaniushina V, Gault E, Anaïs P, Drugan T, et al. Molecular phylogenetic analyses indicate a wide and ancient radiation of African hepatitis delta virus, suggesting a deltavirus genus of at least seven major clades. J Virol. 2004;78(5):2537–44. https://doi.org/10.1128/JVI.78.5.2537-2544.2004.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  63. 63.

    Gerber A, Gal FL, Dziri S, Alloui C, Roulot D, Abdesselam ZB, et al. Molecular diversity of HDV strains that spread in France: a study of 2224 clinical strains prospectively collected during fifteen years. J Hepatol. 2018;68:S783.

    Google Scholar 

  64. 64.

    Spaan M, Carey I, Bruce M, Shang D, Dusheiko G, Agarwal K. Are hepatitis delta virus (HDV) genotypes important to determine the disease progression and therapy responses? J Viral Hepat. 2018;25:S21.

    Google Scholar 

  65. 65.

    Kucirka LM, Farzadegan H, Feld JJ, Mehta SH, Winters M, Glenn JS, et al. Prevalence, correlates, and viral dynamics of hepatitis delta among injection drug users. J Infect Dis. 2010;202:845–52.

    PubMed  Article  PubMed Central  Google Scholar 

  66. 66.

    Kushner T, Serper M, Kaplan DE. Delta hepatitis within the veterans affairs medical system in the United States: prevalence, risk factors, and outcomes. J Hepatol. 2015;63(3):586–92. https://doi.org/10.1016/j.jhep.2015.04.025.

    Article  PubMed  PubMed Central  Google Scholar 

  67. 67.

    Cross TJ, Rizzi P, Horner M, Jolly A, Hussain MJ, Smith HM, et al. The increasing prevalence of hepatitis delta virus (HDV) infection in South London. J Med Virol. 2008;80:277–82.

    PubMed  Article  PubMed Central  Google Scholar 

  68. 68.

    Rosenblum L, Darrow W, Witte J, Cohen J, French J, Gill PS, et al. Sexual practices in the transmission of hepatitis B virus and prevalence of hepatitis delta virus infection in female prostitutes in the United States. JAMA. 1992;267(18):2477–81. https://doi.org/10.1001/jama.1992.03480180063030.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  69. 69.

    Servant-Delmas A, Le Gal F, Gallian P, Gordien E, Laperche S. Increasing prevalence of HDV/HBV infection over 15 years in France. J Clin Virol. 2014;59(2):126–8. https://doi.org/10.1016/j.jcv.2013.11.016.

    Article  PubMed  PubMed Central  Google Scholar 

  70. 70.

    Manesis EK, Vourli G, Dalekos G, Vasiliadis T, Manolaki N, Hounta A, et al. Prevalence and clinical course of hepatitis delta infection in Greece: a 13-year prospective study. J Hepatol. 2013;59(5):949–56. https://doi.org/10.1016/j.jhep.2013.07.005.

    Article  PubMed  PubMed Central  Google Scholar 

  71. 71.

    Sagnelli E, Taliani G, Castelli F, Bartolozzi D, Cacopardo B, Armignacco O, et al. Chronic HBV infection in pregnant immigrants: a multicenter study of the Italian Society of Infectious and Tropical Diseases. New Microbiol. 2016;39:114–8.

    CAS  PubMed  PubMed Central  Google Scholar 

  72. 72.

    Rivas P, Herrero MD, Poveda E, Madejón A, Treviño A, Gutiérrez M, et al. Hepatitis B, C, and D and HIV infections among immigrants from Equatorial Guinea living in Spain. Am J Trop Med Hyg. 2013;88:789–94.

    PubMed  PubMed Central  Article  Google Scholar 

  73. 73.

    Wedemeyer H, Manns MP. Epidemiology, pathogenesis and management of hepatitis D: update and challenges ahead. Nat Rev Gastroenterol Hepatol. 2010;7(1):31–40. https://doi.org/10.1038/nrgastro.2009.205.

    Article  PubMed  PubMed Central  Google Scholar 

  74. 74.

    Plummer M, de Martel C, Vignat J, Ferlay J, Bray F, Franceschi S. Global burden of cancers attributable to infections in 2012: a synthetic analysis. Lancet Glob Health. 2016;4(9):e609–16. https://doi.org/10.1016/S2214-109X(16)30143-7.

    Article  PubMed  PubMed Central  Google Scholar 

  75. 75.

    Maucort-Boulch D, de Martel C, Franceschi S, Plummer M. Fraction and incidence of liver cancer attributable to hepatitis B and C viruses worldwide. Int J Cancer. 2018;142(12):2471–7. https://doi.org/10.1002/ijc.31280.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  76. 76.

    World Health Organization. Summary tables of mortality estimates by cause, age and sex, globally and by region, 2000–2016. Geneva: World Health Organization; 2018. http://www.who.int/healthinfo/global_burden_disease/en/

    Google Scholar 

  77. 77.

    Yurdaydin C. New treatment options for delta virus: is a cure in sight? J Viral Hepat. 2019;26(6):618–26. https://doi.org/10.1111/jvh.13081.

    Article  Google Scholar 

  78. 78.

    World Health Organization. Guidelines for the prevention, care and treatment of persons with chronic hepatitis B infection. Geneva: World Health Organization; 2015.

    Google Scholar 

  79. 79.

    Wranke A, Serrano BC, Heidrich B, Kirschner J, Bremer B, Lehmann P, et al. Antiviral treatment and liver-related complications in hepatitis delta. Hepatology. 2017;65(2):414–25. https://doi.org/10.1002/hep.28876.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  80. 80.

    Erhardt A, Gerlich W, Starke C, Wend U, Donner A, Sagir A, et al. Treatment of chronic hepatitis delta with pegylated interferon-alpha2b. Liver Int. 2006;26(7):805–10. https://doi.org/10.1111/j.1478-3231.2006.01279.x.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  81. 81.

    Niro GA, Ciancio A, Gaeta GB, Smedile A, Marrone A, Olivero A, et al. Pegylated interferon alpha-2b as monotherapy or in combination with ribavirin in chronic hepatitis delta. Hepatology. 2006;44(3):713–20. https://doi.org/10.1002/hep.21296.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  82. 82.

    Wedemeyer H, Yurdaydìn C, Dalekos GN, Erhardt A, Çakaloğlu Y, Değertekin H, et al. Peginterferon plus adefovir versus either drug alone for hepatitis delta. N Engl J Med. 2011;364:322–31.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  83. 83.

    Castelnau C, Le Gal F, Ripault MP, Gordien E, Martinot-Peignoux M, Boyer N, et al. Efficacy of peginterferon alpha-2b in chronic hepatitis delta: relevance of quantitative RT-PCR for follow-up. Hepatology. 2006;44(3):728–35. https://doi.org/10.1002/hep.21325.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  84. 84.

    Yilmaz B, Can G, Ucmak F, Arslan AO, Solmaz I, Unlu O, et al. Polymorphisms in the IL28B gene (rs12979860, rs8099917) and the virological response to pegylated interferon therapy in hepatitis D virus patients. Acta Gastroenterol Belg. 2016;79:206–10.

    CAS  PubMed  PubMed Central  Google Scholar 

  85. 85.

    Yurdaydin C. Treatment of chronic delta hepatitis. Semin Liver Dis. 2012;32:237–44.

    CAS  PubMed  Article  PubMed Central  Google Scholar 

  86. 86.

    Sheldon J, Ramos B, Toro C, Ríos P, Martínez-Alarcón J, Bottecchia M, et al. Does treatment of hepatitis B virus (HBV) infection reduce hepatitis delta virus (HDV) replication in HIV-HBV-HDV-coinfected patients? Antivir Ther. 2008;13:97–102.

    CAS  PubMed  PubMed Central  Google Scholar 

  87. 87.

    Fernández-Montero JV, Vispo E, Barreiro P, Sierra-Enguita R, de Mendoza C, Labarga P, et al. Hepatitis delta is a major determinant of liver decompensation events and death in HIV-infected patients. Clin Infect Dis. 2014;58:1549–53.

    PubMed  Article  CAS  PubMed Central  Google Scholar 

  88. 88.

    Boyd A, Miailhes P, Brichler S, Scholtès C, Maylin S, Delaugerre C, et al. Effect of tenofovir with and without interferon on hepatitis D virus replication in HIV-hepatitis B virus-hepatitis D virus-infected patients. AIDS Res Hum Retrovir. 2013;29(12):1535–40. https://doi.org/10.1089/aid.2013.0008.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  89. 89.

    Béguelin C, Friolet N, Moradpour D, Sahli R, Suter-Riniker F, Lüthi A, et al. Impact of tenofovir on hepatitis delta virus replication in the Swiss human immunodeficiency virus cohort study. Clin Infect Dis. 2017;64:1275–8.

    PubMed  Article  PubMed Central  Google Scholar 

  90. 90.

    Wranke A, Yurdaydin C, Heidrich B, Kalliopi Z, Yalcin K, Fehmi Z, et al. A virological response to PEG-IFNa treatment of hepatitis delta is associated with an improved clinical long-term outcome: 10 years follow-up of the HIDIT-1 study. J Hepatol. 2018;68:FS507.

    Article  Google Scholar 

  91. 91.

    Wedemeyer H, Yurdaydin C, Ernst S, Caruntu FA, Curescu MG, Kendal YK, et al. 96 weeks of pegylated-Interferonalpha-2a plus tenofovir or placebo for the treatment of hepatitis delta: the HIDIT-2 study. Hepatology. 2013;58:222A–3A.

    Article  CAS  Google Scholar 

  92. 92.

    Canbakan B, Senturk H, Tabak F, Akdogan M, Tahan V, Mert A, et al. Efficacy of interferon alpha-2b and lamivudine combination treatment in comparison to interferon alpha-2b alone in chronic delta hepatitis: a randomized trial. J Gastroenterol Hepatol. 2006;21(4):657–63. https://doi.org/10.1111/j.1440-1746.2006.04082.x.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  93. 93.

    Yurdaydin C, Bozkaya H, Onder FO, Sentürk H, Karaaslan H, Akdoğan M, et al. Treatment of chronic delta hepatitis with lamivudine vs lamivudine + interferon vs interferon. J Viral Hepat. 2008;15(4):314–21. https://doi.org/10.1111/j.1365-2893.2007.00936.x.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  94. 94.

    Gunsar F, Akarca US, Ersoz G, Kobak AC, Karasu Z, Yuce G, et al. Two-year interferon therapy with or without ribavirin in chronic delta hepatitis. Antivir Ther. 2005;10(6):721–6.

    CAS  Google Scholar 

  95. 95.

    Abbas Z, Memon MS, Umer MA, Abbas M, Shazi L. Co-treatment with pegylated interferon alfa-2a and entecavir for hepatitis D: A randomized trial. World J Hepatol. 2016;8:625–31.

    PubMed  PubMed Central  Article  Google Scholar 

  96. 96.

    Soriano V, Sherman KE, Barreiro P. Hepatitis delta and HIV infection. AIDS. 2017;31(7):875–84. https://doi.org/10.1097/QAD.0000000000001424.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  97. 97.

    Yan H, Zhong G, Xu G, He W, Jing Z, Gao Z, et al. Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus. Elife. 2012;1:e00049. https://doi.org/10.7554/eLife.00049.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  98. 98.

    Rizzetto M. Targeting hepatitis D. Semin Liver Dis. 2018;38(01):66–72. https://doi.org/10.1055/s-0037-1621711.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  99. 99.

    Bogomolov P, Alexandrov A, Voronkova N, Macievich M, Kokina K, Petrachenkova M, et al. Treatment of chronic hepatitis D with the entry inhibitor myrcludex B: first results of a phase Ib/IIa study. J Hepatol. 2016;65(3):490–8. https://doi.org/10.1016/j.jhep.2016.04.016.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  100. 100.

    Wedemeyer H, Bogomolov P, Blank A, Allweiss L, Dandri-Petersen M, Bremer B, et al. Final results of a multicenter, open-label phase 2b clinical trial to assess safety and efficacy of Myrcludex B in combination with Tenofovir in patients with chronic HBV/HDV co-infection. J Hepatol. 2018;68:S3.

    Article  Google Scholar 

  101. 101.

    Allweiss L, Dettmer C, Volz T, Giersch K, Alexandrov A, Wedemeyer H, et al. Strong intrahepatic decline of hepatitis D virus RNA and antigen after 24 weeks of treatment with Myrcludex B in combinationwith Tenofovir in chronic HBV/HDV infected patients: interim results from a multicenter, open-label phase 2b clinical trial. J Hepatol. 2018;68:S90. https://doi.org/10.1016/S0168-8278(18)30398-2.

    Article  Google Scholar 

  102. 102.

    Yurdaydin C, Idilman R, Kalkan C, Karakaya F, Kartal AC, Keskin O, et al. Exploring optimal dosing of Lonafarnib with ritonavir for the treatment of chronic delta hepatitis-interim results from the lowr HDV-2 study. Hepatology. 2016;64:910A.

    Google Scholar 

  103. 103.

    Wedemeyer H, Katrin Schöneweis K, Bogomolov PO, Voronkova NV, Chulanov V, Stepanova T, et al. Interim results of a multicentre, open-label phase 2 clinical trial (MYR203) to assess safety and efficacy of myrcludex B in combination with peg-interferon alpha 2a in patients with chronic HBV/HDV co-infection. Hepatology. 2018;68:16A.

    Google Scholar 

  104. 104.

    Koh C, Canini L, Dahari H, Zhao X, Uprichard SL, Haynes-Williams V, et al. Oral prenylation inhibition with lonafarnib in chronic hepatitis D infection: a proof-of-concept randomised, double-blind, placebo-controlled phase 2A trial. Lancet Infect Dis. 2015;15:1167–74.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  105. 105.

    Ghosal A, Chowdhury SK, Tong W, Hapangama N, Yuan Y, Su AD, et al. Identification of human liver cytochrome P450 enzymes responsible for the metabolism of lonafarnib (Sarasar). Drug Metab Dispos. 2006;34(4):628–35. https://doi.org/10.1124/dmd.105.007906.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  106. 106.

    Wedemeyer H, Port K, Deterding K, Wranke A, Kirschner J, Martins EB, et al. A phase 2 study of titrating dose lonafarnib plus ritonavir in patients with chronic hepatitis D: interim results from the lonafarnib with ritonavir in HDV-4 study. AASLD Hepatol. 2016;64(1):121A. https://doi.org/10.1016/S0168-8278(17)30310-0.

    Article  Google Scholar 

  107. 107.

    Yurdaydin C, Kalkan C, Karakaya F, Caliskan A, Karatayli S, Keskin O, et al. Subanalysis of the LOWR HDV-2 study reveals high response rates to Lonafarnib in patients with low viral loads. J Hepatol. 2018;68:S89. https://doi.org/10.1016/S0168-8278(18)30397-0.

    Article  Google Scholar 

  108. 108.

    Bazinet M, Pantea V, Cebotarescu V, Cojuhari L, Jimbei P, Vaillant A. Establishment of persistent functional remission of HBV and HDV infection following REP 2139 and pegylated interferon alpha 2a therapy in patients with chronic HBV/HDV co-infection: 18 month follow-up results from the REP 301-LTF study. J Hepatol. 2018;68:S509. https://doi.org/10.1016/S0168-8278(18)31266-2.

    Article  Google Scholar 

  109. 109.

    Bazinet M, Pântea V, Cebotarescu V, Cojuhari L, Jimbei P, Albrecht J, et al. Safety and efficacy of REP2139 and pegylated interferon alfa-2a for treatment-naive patients with chronic hepatitis B virus and hepatitis D virus co-infection (REP 301 and REP 301-LTF): a non-randomised, open-label, phase 2 trial. Lancet Gastroenterol Hepatol. 2017;2:877–89.

    PubMed  Article  PubMed Central  Google Scholar 

  110. 110.

    Farci P, Niro GA. Clinical features of hepatitis D. Semin Liver Dis. 2012;32:228–36.

    PubMed  Article  PubMed Central  Google Scholar 

  111. 111.

    Lutterkort GL, Wranke A, Yurdaydin C, Budde E, Westphal M, Lichtinghagen R, et al. Non-invasive fibrosis score for hepatitis delta. Liver Int. 2017;37(2):196–204. https://doi.org/10.1111/liv.13205.

    CAS  Article  PubMed  PubMed Central  Google Scholar 

  112. 112.

    Yurdaydin C, Abbas Z, Buti M, Cornberg M, Esteban R, Etzion O, et al. Treating chronic hepatitis delta: the need for surrogate markers of treatment efficacy. J Hepatol. 2019;70(5):1008–15. https://doi.org/10.1016/j.jhep.2018.12.022.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

In addition to the persons listed as authors, the staff at global hepatitis programme at WHO are gratefully acknowledged.

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Dr. Yurdaydin reports personal fees from Gilead Sciences BIOPHARMA, personal fees from Abbvie and, grants from Eiger, outside the submitted work.

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TH and YT collected literatures and wrote the first draft of the manuscript, which was commented by all authors. YJF, HH, PE, SH, JVH, EOO, SK, CY and MB reviewed the manuscript. The author(s) read and approved the final manuscript.

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Correspondence to Tomoyuki Hayashi.

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Hayashi, T., Takeshita, Y., Hutin, Y.JF. et al. The global hepatitis delta virus (HDV) epidemic: what gaps to address in order to mount a public health response?. Arch Public Health 79, 180 (2021). https://doi.org/10.1186/s13690-021-00693-2

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Keywords

  • Hepatitis delta
  • HDV
  • Hepatitis B virus
  • Prevalence
  • Superinfection
  • Novel therapeutic strategies
  • Cirrhosis
  • Hepatocellular carcinoma