# Clinical trials for Hepatitis Delta Virus in the WHO African region: A neglected virus among neglected viruses

Marion Delphin, James Campbell, Eloi R Verrier, Motswedi Anderson, Gloria Sukali, Tongai Maponga, Alexander Stockdale, Philippa Matthews

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## To cite this version:

Marion Delphin, James Campbell, Eloi R Verrier, Motswedi Anderson, Gloria Sukali, et al., Clinical trials for Hepatitis Delta Virus in the WHO African region: A neglected virus among neglected viruses. Journal of Infection, 2025, 91 (1), pp.106514. 10.1016/j.jinf.2025.106514. hal-05219072

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Review

# Clinical trials for Hepatitis Delta Virus in the WHO African region:
A neglected virus among neglected viruses

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Marion Delphin<sup>a, *, e</sup>, James Campbell<sup>a</sup>, Eloi R. Verrier<sup>b</sup>, Motswedi Anderson<sup>a, c, d</sup>, Gloria Sukali<sup>a, c, e</sup>, Tongai Maponga<sup>f, g</sup>, Alexander Stockdale<sup>h, i</sup>, Philippa C. Matthews<sup>a, j, k, l</sup>

ARTICLE INFO

Article history:

Accepted 17 May 2025

Available online 22 May 2025

Keywords:

Hepatitis Delta Virus

Clinical trials equity

Health equity

WHO African region

SUMMARY

**Objectives:** We set out to evaluate the extent to which Hepatitis Delta Virus (HDV) Clinical Trials (CT) include populations from the World Health Organisation (WHO) African region, aiming to highlight inequities and advocate for global investment in inclusive HDV research.

**Methods:** We screened the clinicaltrials.gov and the WHO International Clinical Trials Registry Platform (ICTRP) repositories for 'Hepatitis Delta virus' and 'HDV' related CT. Datasets were merged using R v.4.2.1. We classified studies according to location and associated WHO region.

**Results:** We identified a total of 47 CT on HDV, mainly conducted in Europe (69.3%), Western Pacific (19.6%) and the Americas (8.5%). Despite the highest estimated anti-HDV seroprevalence in the general population, there were no CT registered in the WHO African region. CT are still predominantly done in the regions of initial drug discovery, as seen with bulevirtide (Europe) and lonafarnib (Americas).

**Conclusion:** HDV-focused CT are needed in the WHO African region, as the region with the highest disease burden, and unique genotypes (5-8); to evaluate efficacy of novel anti-HDV compounds and to ensure that new treatments can be distributed and deployed as they become available.

© 2025 The Authors. Published by Elsevier Ltd on behalf of The British Infection Association. This is an open access article under the CC BY license ([http://creativecommons.org/licenses/by/4.0/](http://creativecommons.org/licenses/by/4.0/)).

Introduction

Chronic Hepatitis Delta, caused by the Hepatitis Delta Virus (HDV), is the most severe form of chronic viral hepatitis.¹ HDV is a defective virus, meaning it does not encode an envelope protein, but instead hijacks the Hepatitis B Virus (HBV) surface antigen (HBsAg)

for efficient propagation.²,³ An estimated 12–20 million people are living with HDV (PLWHD) worldwide⁴; however, access to screening is not routinely available in many settings, and even when diagnostic tests can be accessed, a lack of awareness and cost implications are barriers to systematic screening. Whilst some individual countries have a high HDV seroprevalence at the national level; for example, it is estimated that in Mongolia, ~60% of people living with HBV - PLWHB - have HDV coinfection; the World Health Organization (WHO) African region is considered the area of highest HDV prevalence in the general population (6.0%),⁴ with infection especially concentrated in West (7.3%) and Central (25.6%) Africa.⁵

Prevention of the acquisition of infection and reduction of morbidity and mortality in PLWHD are challenging due to insufficient

<footnote><sup>a</sup>The Francis Crick Institute, 1 Midland Road, NW1 1AT London, United Kingdom</footnote>

<footnote><sup>b</sup> University of Strasbourg, Inserm, Institute for Translational Medicine and Liver Disease (ITM), UMR_S1110, Strasbourg, France</footnote>

<footnote><sup>c</sup>Africa Health Research Institute, KwaZulu Natal, South Africa</footnote>

<footnote><sup>d</sup>Botswana Harvard Health Partnership, Gaborone, Botswana</footnote>

<footnote><sup>e</sup>University College London, London, United Kingdom</footnote>

<footnote><sup>f</sup>Division of Medical Virology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa</footnote>

<footnote><sup>g</sup>National Health Laboratory Service Tygerberg Business Unit, Cape Town, South Africa</footnote>

<footnote><sup>h</sup>Malawi Liverpool Wellcome Research Programme, Blantyre, Malawi</footnote>

<footnote><sup>i</sup>Department of Clinical Infection, Microbiology and Immunology, Institute of Infection, Veterinary and Ecological Sciences, University of Liverpool, Liverpool, United Kingdom</footnote>

<footnote><sup>j</sup>Nuffield Department of Medicine, Medawar Building for Pathogen Research, University of Oxford, Oxford, UK</footnote>

<footnote><sup>k</sup>Department of Infectious Diseases, University College London Hospital, London, United Kingdom</footnote>

<footnote><sup>l</sup>Division of Infection and Immunity, University College London, London, United Kingdom</footnote>

<footnote>* Corresponding author.</footnote>

<footnote>E-mail addresses: marion.delphin@crick.ac.uk (M. Delphin), james.campbell@crick.ac.uk (J. Campbell), e.verrier@unistra.fr (E. Verrier), motswedi.anderson@crick.ac.uk (M. Anderson), gloria.sukali@crick.ac.uk (G. Sukali), tongai@sun.ac.za (T. Maponga), a.stockdale@liverpool.ac.uk (A. Stockdale), philippa.matthews@crick.ac.uk (P. Matthews).</footnote>
coverage of HBV vaccination (which also protects against HDV), while current treatments for HBV have no effect on HDV. Interferon alpha-2a (IFNα) is the only internationally recommended treatment, but it comes with a low rate of sustained virological response, and a substantial burden of adverse side-effects.⁶ Bulevirtide, (originally known as myrcludex B) is a sodium taurocholate co-transporting polypeptide (NTCP) inhibitor,⁷ which blocks viral entry, and shows promise in reduction of HDV viraemia, associated with normalisation of Alanine Aminotransferase (ALT) and regression of liver fibrosis.⁸,⁹ It has recently been approved in the European Union and Australia. Other agents under development include interferon lambda, lonafarnib (a prenylation inhibitor)¹⁰ and drugs targeting HBsAg production and/or entry into hepatocytes,⁷ such as iRNAs, neutralising antibodies (nAb) and Nucleic Acid Polymers (NAPs).⁷,¹⁰ As more agents are developed and become available, there is a pressing need for Clinical Trials (CT) to represent the populations at the highest risk of HDV infection and its complications. We therefore set out to describe the distribution of CT related to HDV worldwide.

## Methods

### *Search strategy and selection criteria*

We searched the WHO International CT Registry Platform (ICTRP) and the website 'clinicaltrials.gov' for CT on 18th December 2024. We used 'Hepatitis Delta Virus' and 'HDV' as search terms (Fig. 1). We did not set any limitations regarding the start year, and obtained CT from 2001 to 2024 registered in English. For each study, we extracted the following variables: 'trial ID', 'study title', 'condition' (of the participants), 'interventions', 'phase' (of the trial), 'start year', 'location' and 'URL'.

Studies from each registry were collated, and duplicates were removed based on trial ID and study URL. Exclusion criteria were: (1) CT without a recorded study location, (2) CT that were categorised as 'observational' (Fig. 1). Manual screening of condition, study title and, when required, further investigation via the study website, was performed to ensure all remaining CT were involving PLWHD and/or drug development of HDV therapeutics (Fig. 1). The final selected CT were collated in an excel spreadsheet which was locked prior to further analysis (available online¹¹).

<figure><img src="image_5.png" /><figcaption>**Fig. 1.** Protocol and decision tree associated with investigation of HDV CT. Green boxes follow the selection process, light grey the exclusion criteria and orange the selected entries. CT: Clinical Trials; HDV: Hepatitis Delta Virus; WHO: World Health Organisation.</figcaption></figure>

### *Data analysis and presentation*

The frequency of CT per country and associated WHO region was categorised using R (Version 4.2.1; script made publicly available¹²). For studies spanning multiple WHO regions, we counted each region separately (therefore, the number of studies reported by region exceeds the total number of studies). Changes in distribution of CT over time were analysed using the 'Start Year' variable, phases of the CT using 'Phases' and intervention based on 'Study Title' and further manual investigation (i.e extraction of information from study details using study URL) when required. To compare the number of registered CT per region with the local HDV seroprevalence, prevalence maps were drawn on R (Version 4.2.1) based on data extracted from a previous meta-analysis by Stockdale et al.⁴

Figures were generated using GraphPad Prism (v.9.5.1), Adobe Illustrator (v.27.5) and R (v.4.2.1).

## Results

### *Description of search criteria*

From 76 ICTRP and 83 clinicaltrials.gov entries, we identified 119 unique CT. We further excluded CT that were considered 'observational' (n=46), CT with missing location (n=7) and CT that were not related to HDV drug development (n=20). Of note, for the latter, most CTs were related to PLWHB or living with Hepatitis C Virus (HCV), without HDV coinfection, or related to CT on 'Hepatic Directed Vesicle' Insulin, which shares the same HDV acronym. The remaining 47 entries were included and further analysed. No exclusions were made on the basis of language, as all CT were registered in English.

### *Geographical distribution of HDV seroprevalence and CT*

A previous meta-analysis of the geographic distribution of HDV seroprevalence estimated the highest prevalence in the WHO African (6.0%) and Americas (5.9%) regions in the general population, but Europe (19.5%) and Eastern Mediterranean (17.4%) in hepatology clinics (Fig. 2A-B) with significant heterogeneity at the sub-regional level.⁴ By contrast, CT were mostly located in Europe (69.3%), Western Pacific (19.6%) and the Americas (8.5%), with the leading countries being Germany (participated in 14 CT out of the 47 entries, 29.8%), USA (12/47, 25.5%), France (10/47, 21.2%), Italy (10/47, 21.2%) and New Zealand (10/47, 21.2%) (Fig. 2C). Whilst some CT were found in high-burden areas, such as Mongolia (3/47, 6.4%), Romania (9/47, 19.1%) and Moldova (9/47, 19.1%), other regions, particularly Central and Western Africa are missing. With a seroprevalence of 5.97% in the general population, 12.26% in hepatology clinics and the largest number of countries in the top 10 for both general and hepatology clinic populations, the WHO African region has the highest prevalence worldwide and no registered CT.

### *Temporal development of CTs*

We found the first HDV CT documented in 2001 with few or no CT conducted the following years. From 2014 onwards, CT started to increase exponentially in Europe, shortly followed by CT initiation in the Americas and Western Pacific regions. However, in other regions (WHO African, Eastern Mediterranean and South-East Asia), very few or no CTs were conducted (Fig. 3A).

Phase I (n=3) and I/II (n=2) CT (Fig. 3B) were mainly associated with the Western Pacific region and the investigation of nAb, combination of pegIFNα and nivolumab, and the discontinued inhibitor of prenyl transferase EBP-921 (Fig. 3B-C). Phases II and III were most commonly performed in Europe (II: 42.9%; III: 50.0%), followed equally by the Americas (II: 16.7%; III: 28.6%) and Western Pacific
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<figure><img src="image_11.png" /><figcaption>**Fig. 2.** Distribution of HDV seroepidemiology and CT worldwide. (A) Seroprevalence of anti-HDV amongst PLWHB in the general population. (B) Seroprevalence of anti-HDV amongst PLWHB in hepatology clinics. (C) Interventional CT attributed to HDV. CT: Clinical Trials; HDV: Hepatitis Delta Virus; PLWHB: People Living with Hepatitis B Virus; NA: not applicable/no data available. Data for panels (A) and (B) from.⁴</figcaption></figure>

regions (II: 33.3%; III: 14.2%). A single phase IV was registered, combining pegIFNα with ritonavir, in the Western Pacific region.

Bulevirtide CT are mainly conducted in Europe (5/7), given its initial development in Germany and France, and most of the CT on nAb (6/10) involved the Western Pacific region. Half of the CT on lonafarnib were based in the Americas (or multicentric with the US being part of the study), in line with its discovery and initial

development by Merck & Co and Eiger Biopharmaceuticals (US-based companies).

**Discussion**

Despite exciting developments in HDV drug discovery and the exponential increase of therapeutic CT over the past 10 years, the
<figure><img src="image_12.png" /><figcaption>**Fig. 3.** Distribution of HDV CT by WHO regions over time, by phases and interventions. (A) Cumulative number of CT per WHO region per year, (B) Number of CT per WHO region per phase and (C) Number of CT per WHO region per drug or drug combination used for intervention. CT: Clinical Trials; IFN: interferon; nAb: neutralising Antibodies; NA: Not Applicable or Not available; NTCP: Sodium Taurocholate Cotransporting Polypeptide; PIs: Protease Inhibitors; RNAi: RNA inhibitors.</figcaption></figure>

WHO African region, which has the highest seroprevalence of anti-HDV in the general population, is not represented in CT. Alignment between disease burden and location of CT has been more concordant in other regions, as seen for Mongolia, Romania, and Moldova, countries with a high number of CT in diverse drug development areas. We also observed few CT in the WHO Eastern Mediterranean and South-East Asia regions, as well as a large contribution of the US among CT coming from the Americas. This reflects an economic North-South divide, where high-income countries dominate CT, highlighting the need to address disparities

in research investment and accessibility in low- and middle-income regions.

From the discovery of HDV in 1977¹³ to the early 2000s, there were few therapeutic strategies investigated for HDV, except repurposing of IFNα, which is associated with low response rates, relapse after treatment cessation, and a high rate of adverse side effects.⁶ In 2014–2015, the development of bulevirtide in Europe (Germany and France), as well as the characterisation of lonafarnib antiviral efficacy against HDV¹⁴ in the US, boosted the discovery and number of CT in both regions. Unfortunately, we show that CT are
still mainly conducted in areas of initial drug discovery, and even multicentre CT have had limited inclusion of countries outside of these regions, particularly low- and middle-income countries (LMIC) where the need for effective therapies is greatest. As a result, bulevirtide is now only accessible in Europe and Australia. In view of the association demonstrated in multiple cohort studies of increased incidence of Hepatocellular Carcinoma (HCC), cirrhosis and decom pensation in HDV infection, relative to HBV mono-infection, en suring access to therapeutics, including bulevirtide, is an ethical imperative.¹

Whilst not all countries are equipped to conduct CT for infectious diseases, we previously highlighted the readiness and capability of many countries in the WHO African region, as showcased by suc cessful CT for other infectious diseases (including HIV, malaria and SARS-CoV-2).¹⁵ The COVID-19 pandemic, in particular, drove ad vancements in infrastructure and capacity. Therefore, conducting HDV CT in the region is both feasible and necessary, as it would benefit the populations in most need, as well as improving our un derstanding of diverse factors associated with treatment efficacy (host genetic, environmental factors, and viral genetics could impact treatment outcomes) and acceptability (not all drug and drug for mulations are accepted or deliverable worldwide). As an example, HDV genotype 5, present in Western Africa, is associated with better response to IFNα than genotype 1, suggesting a genotype-specific antiviral response that needs to be investigated.¹⁶ However, for therapies to be efficiently rolled out, comprehensive implementation studies are needed. Bulevirtide, for instance, is a complex molecule requiring a high cost for production, medication is through daily injections and requires close monitoring and access to affordable diagnostic tools (HDV RNA quantification). The latter is currently almost completely inaccessible even in middle-income countries from the African region, such as South Africa. Appropriate access to diagnostic tools, not only for primary diagnosis but also for sub sequent follow-up, is crucial as an efficient roll-out requires streamlined identification associated with efficient linkage and re tention in care of PLWHD.¹⁷ At present, many health systems are hesitant to screen for HDV because of a lack of access to treatment options. However, epidemiological data are needed to make the public health and clinical case for investment in access to emerging therapies, and can inform clinicians in terms of identifying patients with elevated risk of disease progression, creating both a clinical incentive and a policy imperative to strengthen HDV diagnosis. A parallel can be drawn from the Hepatitis C response, where, fol lowing the discovery of HCV curative treatment in 2014, screening efforts expanded significantly and successfully and advocacy led to inclusion of therapies in the medicines patent pool, facilitating ac cess to generic therapies in LMICs.¹⁸ Association with efficient linkage to care resulted in decreased burden, with Egypt emerging as a leading example, having treated ~80% of people living with HCV,¹⁹,²⁰ and subsequently becoming the first country to receive WHO validation for being on the path to HCV elimination. Finally, frequent travel to clinical facilities and associated impact on family, education, and employment, as well as out-of-pocket costs, could be catastrophic for PLWHD, as described for PLWHB.²¹

Approval of novel HDV therapeutics from national or regional regulatory agencies requires evidence of clinical effectiveness, cost-effectiveness and implementation pathways. In the absence of such data, the populations at the highest risk of HDV and its complications will continue to suffer systematic health inequities in access to diagnostics, clinical assessment and therapies.

Our analysis of CT distribution comes with several limitations and challenges broadly reflecting the current status of the HDV field. First of all, HDV screening is only recommended in PLWHB, a population we know to be under-diagnosed (estimated 13.9% of PLWHB were aware of their status in 2022²²). Diagnostic tools also come with their own technical limitations,²³ are limited in availability and

prohibitively expensive, generating barriers to accurate estimation of population seroprevalence. Even in areas where it is implemented and accessible, there are only a few large epidemiological studies to date, and reflex testing for HDV in PLWHB was only started recently in some regions, so current figures may under or over-estimate the true scale of the pandemic or its endemicity in certain areas. Accurate population screening and recognition of the burden is required to put HDV onto the political health agenda as a priority, particularly in areas of high seroprevalence. In Mongolia, recognition of the burden of viral hepatitis and pressure from patient/clinician groups led to the government allocating the largest amount of funding ever alloted ($96 M) to the hepatitis program, leading to large population screening (everyone > 15yo), subsidising for HCV/HBV treatment and access to diagnosis tool required for patient monitoring.²³ Second, this neglect is also reflected in the very low number of HDV CT registered, with only 47 registered CT compared to 1804 for HBV, 3289 for Malaria, 20128 for HIV and 24697 for SARS-CoV-2, using a similar search strategy.¹⁵ In addition, we saw little to no phase I CT, and many HDV therapeutics have been repurposed from HBV drug design (bulevirtide, nAb, NAPs, RNAi) and the Hutchinson-Gilford progeria syndrome (lonafarnib). This highlights the lack of investment in drug development for HDV, relative to its high impact in driving HBV-associated liver disease. Third, whilst ICTRP and clinicaltrials.gov are relevant international registries, registration is not mandatory and prone to human error, leading to missingness of certain variables (such as locations) and putative under-estimation of HDV CT numbers.

Conclusion

In this study, we highlight a striking lack of investment in CT for HDV in many populations, with the highest case of need in the WHO African region, similar to what we previously observed for HBV. Support is required to scale up drug development (both discovery and roll-out of existing treatment) in the region, and more broadly in the global South, supported by access to affordable and accessible diagnostics and laboratory monitoring. This will ensure that the safety, efficiency, cost-effectiveness, acceptability, and feasibility for implementation of HDV therapeutics are appropriately studied, to reduce health inequities and to generate pathways to approval and drug deployment where the need is greatest.

Funding

MD, JC, MA and PCM are supported by core funding from the Francis Crick Institute ref. CC2223. PCM also receives funding support from University College London NIHR Biomedical Research Centre (BRC). PCM has previously received funding from GSK to support a doctoral student in her team, outside the scope of this paper. AS is supported by a Senior Clinical Lectureship from the National Institute for Health and Care Research (UK) at the University of Liverpool. ERV received funding from Eiger Biopharmaceuticals and EIT PHARMA, INC. in the frame of the DLIVR Phase III study. ERV acknowledges funding from the interdisciplinary Thematic Institute IMCBio+, as part of the ITI 2021–2028 program of the University of Strasbourg, CNRS and Inserm, supported by IdEx Unistra (ANR-10-IDEX-0002), and by SFRI-STRAT'US project (ANR-20-SFRI-0012) and EUR IMCBio (ANR-17-EURE-0023) under the framework of the French Investments for the Future Program.

CRediT authorship contribution statement

**MD:** Conceptualization, Data curation, Formal analysis, Methodology, Visualization, Writing – original draft, Writing – review & editing. **PCM:** Conceptualization, Methodology, Supervision,
Writing – original draft, Writing – review & editing. **AS:** Data cura-
tion, Writing – original draft, Writing – review & editing. **JC:**
Visualization, Writing – review & editing. **ERV:** Writing – review &
editing. **MA:** Writing – review & editing. **GS:** Writing – review &
editing. **TM:** Writing – review & editing. All authors confirm that
they had full access to all the data in the study and accept respon-
sibility to submit for publication.

Declaration of Competing Interest

The authors declare the following financial interests/personal
relationships, which may be considered as potential competing in-
terests: PCM has previously received funding from GSK to support a
doctoral student in her team, outside the scope of this paper. ERV
received funding from Eiger Biopharmaceuticals and EIT PHARMA,
INC. in the frame of the D-LIVR Phase III study. ERV acknowledges
funding from the interdisciplinary Thematic Institute IMCBio+, as
part of the ITI 2021–2028 program of the University of Strasbourg,
CNRS and Inserm, supported by IdEx Unistra (ANR-10-IDEX-0002),
and by SFRI-STRATUS project (ANR-20-SFRI-0012) and EUR IMCBio
(ANR-17-EURE-0023) under the framework of the French
Investments for the Future Program.

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