Hepatitis delta virus infection prevalence, diagnosis and treatment in the Middle East: A scoping review

Hepatitis D virus (HDV) infection is a global public health concern, especially because of its unique existence in the presence of hepatitis B virus infection. HDV infection is estimated to affect 12 million people globally. Having a clearer understanding of its prevalence in all regions of the world is essential for helping direct preventive and early interventional treatment. This mini‐review assessed the literature over the last 10 years to determine the prevalence, diagnostic means and treatment guidelines available for HDV in the Middle East. The search found limited data available in 21 articles, of which 18 were studies focused on Iran. Prevalence rates ranged dramatically among the countries, and none of the 12 countries included in the search had specific HDV guidelines. This review highlights the urgent need for more precise data for the Middle East region to help establish early diagnosis and treatment options for HDV.


| INTRODUC TI ON
Hepatitis D virus (HDV) is a virus that exists only in the presence of hepatitis B virus (HBV); the latter is estimated to affect 300 million people globally. 1 A recent meta-analysis estimated the HDV prevalence in the global general population to be 0.16%, corresponding to approximately 12 million infections globally. 2 HDV has a high prevalence in central Asia, eastern Europe and central and west sub-Saharan Africa. 3 Amongst HBV carriers, HDV prevalence estimates vary widely, with 5% being the most commonly accepted figure. 4 HBV/HDV co-infection is the most severe form of chronic viral hepatitis infection because of its rapid progression to liver disease and associated complications. 5 HDV is an important contributor to liver disease. Of those with HDV infection, 10%-20% progress to cirrhosis within 2 years and 70%-80% within 5-10 years. 6 In addition, HDV causes about 18% of cirrhosis and 20% of hepatocellular carcinoma (HCC) cases amongst people with chronic HBV infection. 2 To date, there is no effective, extensively tested treatment for HDV. From 1980 until recently, pegylated interferon (PEG-IFN) was the only approved drug against HDV. However, response rates are relatively low, with only about a quarter to one-half of people responding at the end of therapy and over half the responders relapsing after treatment. 7 In 2020, bulevirtide was approved in the European Union (EU), but to date, only a few patients have used this treatment outside of clinical trials. 6,8 The burden of HDV in the Middle East is heterogeneous in terms of geographical distribution and is not well documented, 9,10 with estimates varying greatly between countries. International guidelines recommend HDV testing for all hepatitis B surface antigen (HBsAg) positive patients, particularly for at-risk and vulnerable populations. [11][12][13] The prevalence of HBV in the wider Eastern Mediterranean Region is estimated to be 3.3%, corresponding to approximately 21 million people with chronic HBV infection. 14 In this region, HDV is an endemic infection. 15,16 A global review and meta-analysis of HDV seroprevalence studies from 2020 reported a prevalence of 0.12% in the general population and 3.5% in people with HBV in the Eastern Mediterranean Region. 2 However, this region includes countries that are not part of the Middle East and, in addition, the majority of the studies included in this analysis were over 10 years old. Therefore, the current HDV prevalence in the Middle Eastern region remains unknown. Here, we summarize the recent literature on HDV prevalence, testing and treatment in the Middle East.

| RE SULTS
A total of 21 articles were identified to be included for review (Table 1). Studies were from Iran (n = 18), Iraq (n = 1), Saudi Arabia (n = 1) and Yemen (n = 1). No data were found for Bahrain, Jordan, Kuwait, Lebanon, Oman, Qatar, Syria and the United Arab Emirates (See Figure 1).

| Prevalence
For Iran, studies in different regions of the country showed a high variation in prevalence, ranging from 0.0% to 0.53% in the general population and from 0.0% to 21.8% amongst HBV-positive individuals. Six studies tested for HDV antibodies in a sample from the general population and found a prevalence of 0.0% in Kurdistan (n = 1613) and South Khorasan Another study in Kermanshah found an HDV seroprevalence of 1.7% in people with HBV (n = 1749), of which 48.3% tested positive for HDV RNA. 24 In the South Khorasan province, amongst 155 HBsAgpositive people, 0.0% tested positive for HDV. 18 In Birjand, South Khorasan, from 85 HBsAg-positive samples, 1.2% tested positive for HDV antibodies. 19 Amongst HBsAg positive people, the HDV antibodies prevalence was found to be 2.1% in both the Qom region (n = 48) 20 and an Iranian national study (n = 854). 25 In addition, the latter found a 0.6% HDV RNA prevalence among HBV-positive individuals. Similarly, a 2.2% HDV antibody prevalence was found in both Azar (n = 46) 26 and Tehran (n = 660); in the latter study, 60.9% of those antibody-positive tested positive for HDV RNA. 27 Two studies in Birjand, South Khorasan, found HDV antibodies in 3.1%

Key points
• Globally, about 12 million people are estimated to have hepatitis D virus (HDV), which can lead to cirrhosis and liver cancer.
• We assessed the literature to determine the prevalence, diagnostic means and treatment guidelines available for HDV in the Middle East.
• The limited available data reported dramatically ranging prevalence rates amongst the countries and no countryspecific HDV guidelines.
• This review highlights an urgent need for more precise data for the Middle East to contribute to early diagnosis and treatment options for HDV.
(n = 413) 28 and 3.3% (n = 300) 29 of HBV-positive samples. A study in the Hormozgan province found that among 562 individuals, 11.6% had anti-hepatitis B core antibodies, of which 5% had anti-HDV antibodies. 23 A study from Sistan and Baluchistan (n = 135) found HDV antibodies in 5.9% of HBV-positive samples. 22 Three studies in Tehran found an HDV antibody prevalence of 7.7% (n = 509), 30 10.1% (n = 237) 31  In Saudi Arabia, A single-centre study (n = 169) in Jeddah found an HDV seroprevalence of 7.7% in HBV-positive patients, of which 30.7% tested positive for HDV RNA. 35 A 2015 study from Iraq reported a 6.6% prevalence of anti-HDV antibodies in people with HBV (n = 45). 36 A 2015 study from Yemen tested 501 people for HBsAg, of which 14 tested positive, none of which tested positive for anti-HDV. 37 Table 2 presents an overview of the prevalence of HDV in both HBV-infected people and the general population in select countries of the Middle East.
Regarding transmission, 15 of the studies reported risk factors within the sample of HBV or HDV patients. The main factors that correlated with HBV were dental surgery, 17,18,21,33,36,37 tattoos, 21,33 family history, 18,33,36 sexual relations, 17 renal dialysis, 37 history of cupping or bloodletting procedures, 18,37 surgical operation, 36,37 blood transfusion, 36 history of prison 18 and addiction. 22 In addition, some studies reported frequent risk factors for HDV as a history of surgery, 24,30 dental procedures 30

| Diagnosis and treatment guidelines
HDV-specific guidelines were not found for any of the 12 coun-  38 The HBV treatment guidelines for Saudi Arabia recommend testing for HDV during the pre-treatment assessment of HBV. 39 They state that HDV should be detected by the presence of HDV antibody positivity (IgM) and HDV RNA. 40 The guidelines mention that PEG-IFN treatment for 1 year appears to have positive long-term effects in patients, and the risk of viral relapse is emphasized. 40 Table 3 12,15,56 In 2020, the EU approved bulevirtide to treat adults with chronic HDV and compensated liver disease and a positive HDV RNA viremia. 8 The optimal treatment period has not yet been defined. The recommended dosage is 2 mg/day, either in monotherapy or combined with a nucleos(t)ide analogue. 6 Currently, only a few patients have been treated with bulevirtide, and the first real-life data show good efficacy and safety of the drug. However, more studies are needed to confirm these findings and explain the lack of HBsAg level decline and the HDV RNA relapse, which is often reported after discontinuation. 8 We did not find any studies that specifically use PEG-IFN or bulevirtide for HDV in the Middle East.
The results presented in this review are limited by the significant gaps in the literature and the quality of the studies included.
With a new treatment option on the horizon, further steps can be taken to combat HDV in the Middle East, in addition to HBV prevention. However, for patients to obtain the best benefit, HDV cases must be identified. HBV screening in collaboration with HDV screening for all HBsAg positive cases is paramount. With more routinely identified cases, linkage to care and the opportunity to be treated can be improved. In addition, the routine availability of HDV RNA assays is crucial to understanding the natural history of HBV/HDV co-infected populations and paving the path for adopting evolving therapies. This would also allow for reflex testing, in which all HBsAg-positive individuals are automatically tested for HDV.

| CON CLUS ION
This review highlights the strong need for current data on HDV prevalence, testing, and treatment in the Middle East, especially for countries without data available at any point in time or countries that previously reported a high HDV prevalence. In addition, it shows that most countries do not regularly report HDV prevalence and treatment data. In line with efforts for HBV and HCV elimination set out by WHO in 2016, 58 efforts tailored to the region's epidemiology and health systems will contribute to eliminating HDV as a public health threat.

ACK N OWLED G EM ENTS
JVL and LVS acknowledge support to ISGlobal from the Spanish Ministry

FU N D I N G I N FO R M ATI O N
This study was funded in full by Gilead Sciences.

CO N FLI C T O F I NTE R E S T
JVL acknowledges grants and speaker fees from AbbVie, Gilead Sciences and MSD and speaker fees from Genfit Intercept and