Euro-HDV:Epidemiology and Clinical Course in Patients With HIV and Hepatitis B/D -Coinfection
Conditions: Hepatitis D
Sponsor: University Hospital, Bonn

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UKB Research protocol 
 
HDV-Europe: Prevalence and Outcome 
                                                           Version: 1 
                                              Date: 31.10.2023 
 
 
 
Contact:     Prof. Dr. Jürgen K. Rockstroh  
                   Department of Internal Medicine I 
 
                   University of Bonn 
 
                   Venusberg-Campus 1 
 
                   53127Bonn 
 
                   Germany 
 
 
                    Tel.:  
+49-228-287-16558   
                    Fax: 
+49-228-287-15034  
                    email: 
juergen.rockstroh@ukbonn.de 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Table of content: 
 
1.   
Background and Objective of the Study 
2.   
Cohort Design and Methods 
3.   
Patient Inclusion and Exclusion Criteria 
4.   
Study Procedures 
5.   
Plan of Analyses 
6.   
Study withdrawals 
7.   
Ethics and research governance 
8.   
Milestones 
9.   
Data Protection 
10. 
Literature 
 
 
 
 
 
 
 
 

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1.Background and Objective of Study 
1.1 Background 
Hepatitis D is caused by a defective RNA-virus,  that is known to be among the smallest 
human pathogenic viruses. As it partly shares the viral entry into hepatocytes with HBV, 
a coinfection is mandatory (1). Besides a simultaneous infection with HBV and HDV, 
it might also occur in the sense of a superinfection to a preexisting HBV-infection (2).  
Though most of the acute infections recover spontaneously, a progression to chronic 
disease is well described (3).  The persistence of HDV leads to an accelerated fibrosis 
progression and eventually to cirrhosis and an increased risk of developing 
hepatocellular carcinoma (HCC) as well (4, 5). With the widely established feasibility 
of immunization against viral Hepatitis B, numbers of HDV-infection in high-income 
countries are quite low. Nevertheless, the burden of chronic HDV-infection worldwide 
is high, as different studies estimate the number of patients from 12 million to up to 72 
million (6-8).  
In the subgroup of people living with HIV (PLWH), who are at increased risk for 
acquiring viral hepatitis in general, rates of HDV infection have been reported between 
10%-20% of HIV/HBV-coinfected people, with variations according to region as well 
as transmission group. Particularly, early in the HV epidemic higher rates of HDV have 
been reported for HIV/HBV coinfected drug users. More recently, a shift from people 
who acquired HIV through drug injection (PWID) to men who have sex with men 
(MSM) has been reported with HDV coinfection rates of around 8% (9).  Common for 
all PLWH with HBV/HDV-coinfection is a more rapid progression in liver disease (10), 
resulting in increased rates of decompensated cirrhosis and higher mortality (11, 12). 
Therefore, mandatory screening for HDV was implemented into current EACS 
guideline recommendations.  However, there is still a lack of testing in daily routine, 
even at sites where testing is easily accessible and reimbursed. Moreover, most PLWH 

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who are coinfected with HBV are tested at initial HBV diagnosis, but after being put on 
antiretroviral treatment, which usually includes a tenofovir-based therapy a follow-up 
testing of HDV does not take place routinely.  
 
1.2 Objective 
The aim of this project is to set up a cross-sectional cohort study (France, Germany, The 
Netherlands, Poland, Spain, Switzerland, Italy, United Kingdom and Portugal) to assess 
the implementation of EACS guidelines for HDV-testing among PLWH with positive 
HbsAg and thereby evaluate the prevalence of HDV infection among HIV/HBV-
coinfected in 2023, as well as corresponding risk factors. In addition to the testing itself, 
this study will also set up a cohort and databasee for future HDV studies among PLWH, 
including clinical, virological und laboratory parameters.  
1. Analyze the rate of HDV-testing and evaluate the prevalence of HDV-infection by 
testing. 
a. Evaluation of former screening of HDV by assessing existing data at study sites. 
b. Determination of the HDV prevalence in European PLWH and HBV 
coinfection.  
2. Setting up a database of all PLWH with HBV/HDV coinfection 
a. Analysis of transmission risk factors for HDV coinfection 
 
b. Asses the rate of HDV positive patients with ongoing HDV replication. 
c. Define the liver disease state by APRI score, fibroscan, ultrasound and routine 
laboratory test results. 
 
 
 
 

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2.Cohort Design and Methods 
2.1 General 
In this multi-center cohort study patients with documented HIV/HBV-coinfection (2 
measurements of positive HBsAg > 6month interval and Anti-HBc-positive) will be 
evaluated for past HDV screening (last 24 months).  
Eligible participants must be 18 years of age or older.  
 
2.2 Study Centers and Accrual of Patients 
To secure representative data, each cohort or clinic network will aim to enroll a sample size 
of at least 20% of all HIV/HBV-coinfected individuals in each country. France, Switzerland, 
Italy, and The Netherlands already have well established national cohorts which are 
representing more than 50% of all PLWH in their respective countries. In the remaining 
countries (Germany, Spain, Poland, Portugal, UK) well-defined cohorts in specialized HIV-
clinics or networks of HIV-centers are existing, which allow for a sufficient recruitment. 
The overall number of participants is planned to reach at least 8000 HIV/HBV-coinfected 
persons. With an estimated 800.000 PLWH in the following 9 countries: Spain 150.00, 
France 190.000, Germany 93.000, England 106.000, Portugal 61.000, Italy 140.000, Poland 
20.000, Switzerland 16.000, Netherlands 24.000, and an estimated HBV-Prevalence of 5%, 
this would lead to a cohort of around 40.000 HIV/HBV coinfected individuals. According 
to current data, 20% of HIV/HBV-coinfected PLWH are expected to have an HDV-
infection, which should add up to 8000 individuals that would be needed to be studied. This 
should guarantee a representative sample size and would represent a highly meaningful 
European cohort for future HDV studies. 
 
 

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2.3 Accrual goal 
A cohort of 8000 HIV/HBV-coinfected individuals with serological HDV-screening 
evidence. 
 
3.Patient Inclusion and Exclusion Criteria 
3.1 Inclusion-Criteria 
Documented HIV-infection with current Hepatitis B infection, who are serological positive 
for HBSAg  
Both, HIV- and HBV Infection must be confirmed by HIV ELISA and HBV HBsAg-testing 
(2 measurements of positive HBsAg > 6month interval).The viral load results will be 
included into the analyses, but are not part of the inclusion criteria.  
As patients are enrolled retrospectively, data on liver enzymes (transaminases, gamma GT, 
AP, bilirubin) and viral load will be available, though this is not compulsory. Written 
informed consent will be provided prior to inclusion, or, if adequate, used from pre-exisitng 
cohort studies. 
 
3.2. Exclusion-Criteria 
PLWH with a cleared HBV-infection will be considered as HIV-monoinfected 
persons.Individuals younger than 18 years of age will be excluded from the analysis. 
Patients with any social condition or living circumstances which may interfere with the 
conduct of the study, as anticipated by the investigator, such as incapacity to adequately 
understand the study content or not willing to cooperate will be excluded from the study. 
For France, patients without adequate social security will be excluded. 
 
 

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4. Study Procedures 
All participating PLWH will be recruited from the already existing national cohorts and 
defined networks of specialized HIV-clinics, respectively. This database will allow for 
the initial analysis of whether HDV screening was performed and allow to determine 
the HDV prevalence in the participating countries as well as study risk factors for HDV 
transmission.  
Only patients who were alive in 2022 will be included into the study. 
 
 
5. Plan of Analysis 
Because of the observational nature of the study no predefined statistical power calculations 
can be made. Descriptive statistics will be used.  
5.1 Epidemiology 
 Prevalence of HDV among HBV-coinfected PLWH 
 Description of populations at risk 
 Transmission risk factors 
Methods:  
 Prevalence: Number of HDV-positive persons in relation to all HBV/HIV individuals of the 
database.  
 Risk populations and transmission factors: Descriptive methods will be used to investigate 
populations at risk and transmission risk factors.  
 
5.2 Define burden of disease  
 Asses the rate of HDV-positive patients with ongoing HDV replication 
 Define the liver disease stage by non-invasive methods (APRI, Fibroscan) 
 
 

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Methods:  
 HDV-replication will be measured by commercially used PCR-testing kits. The 
proportion of HDV serological positive individuals with ongoing viral replication will 
be determined. This will be collected for all patients with positive HDV serology.  
 The liver disease stage, which is expressed by the fibrosis stage, will be determined by 
APRI score. Furthermore, other non-invasive imaging techniques, including standard 
ultrasound as well as Fibroscan will be used where available to evaluate the degree of 
liver disease. In addition, standard laboratory parameters (see, eCRF codebook, annex 
xyz), which are part of the routine testing among PLWH control visits, will be 
documented. Changes over time will be evaluated and put in relation to medical 
imaging, as far as available.  
 
6. Study withdrawals 
Patients will be free to withdraw their consent at any time and without any reason. 
Withdrawal of consent will not affect the rights of the patient or their access to continuing 
medical care or treatment.  
 
7. Ethics and research governance 
7.1 Ethics 
This retrospective muti-national cohort analysis has been submitted for ethical review to 
the ethics committee at Bonn University.  
 
7.2 Good Clinical Practice 
It is the responsibility of the treating physician to ensure that the collection of all diagnostic 
tests and other data for the study is in accordance with the principles of the declaration of 
Helsinki and its Tokyo, Venice, Hongkong, Somerset West and Edinburgh amendments, as 

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well as in agreement with further loco-regional laws and regulations. The study should be 
conducted according to ICH-Good  Clinical Practice (GCP) Guidelines. 
 
7.3. Informed Consent 
It is the responsibility of the local investigator (including persons with delegated authority 
to consent patients) to obtain a written consent from each patient participating in the study 
prior to enrolment. Objective, methods, advantages as well as possible disadvantages of the 
study must be explained in an understandable way to the patient. Further, the patient must 
be informed that enrolment into the study is a voluntary. Enrolment must be signed by the 
patient, and signed written consent must be documented and a copy retained for the study 
documentation file.  
 
7.4. Data Management 
Data security will be assured for alle patients participating in the study. All data 
management will be performed according to GCP. Data analysis will be performed by 
Anders Boyd (cooperating scientist;Amsterdam University Medical Centers) conducting to 
GCP.  
 
 
8. Milestones 
The patients being recruited are already tied to the different center sites and preexisting data 
are available. After writing consent, a retrospective analysis of these data can take place. 
Recruitment of patients is planned to run from November 2023 until April 2024.  
 

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9. Data Protection 
All patient data that are used, have already been collected and country related databases have 
been set up. The included data are to be within the treating physicians keeping. The values 
that are evaluated in this study are shared with the other participating physicians, though 
data containing personal information are excluded from this. Collected data will be analyzed, 
evaluated and presented in an anonymous form, ensuring confidentiality of patient data 
towards third parties. 
 
MS 
Title 
Work 
pkg. 
(nr.) 
Institution 
Date (dd.mm.yyyy) 
Proof of 
achievement/fulfillment 
1 
Study 
protocol for 
multicentric 
approach 
1 
University 
Hospital Bonn 
15.11.2023 
Study protocol 
2 
Ethics 
approval 
1 
University 
Hospital Bonn 
30.11.2023 
Ethics approval achieved 
3 
Agreement 
with 
cooperating 
centers 
1 
University 
Hospital Bonn  
XX.XX.2023 
Signed agreement 
4 
Start of 
patient 
enrolment 
2 and 
3 
University 
hospital Bonn 
cooperating 
centers 
 
XX.XX.2023 
Electronic database 
established  
5 
Reaching 50% 
of respective 
HBs-Ag 
positive 
patients  
2 and 
3 
University 
Hospital Bonn 
and cooperating 
centers 
 
XX.XX.2024 
50% of eligible/reachable 
patient population enrolled 
6 
Finishing 
patient 
acquisition 
2 and 
3 
University 
Hospital Bonn  
and cooperating 
centers 
XX.XX.2024 
100% of patient population 
enrolled 
9 
Data Analysis 
4 
University 
Hospital Bonn 
and 
cooperating 
centers. Final 
data analyses 
by University 
Medical 
Centers 
Amsterdam 
XX.XX.2024 
Data analyses completed, and 
preparation of manuscript 

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10. Literature: 
1. Botelho-Souza LF, Vasconcelos MPA, Dos Santos AO, Salcedo JMV, Vieira DS. 
Hepatitis delta: virological and clinical aspects. Virol J. 2017;14(1):177. 
2. Rizzetto M. Hepatitis D: thirty years after. J Hepatol. 2009;50(5):1043-50. 
3. Caredda F, d'Arminio Monforte A, Rossi E, Farci P, Smedile A, Tappero G, et al. 
Prospective study of epidemic delta infection in drug addicts. Prog Clin Biol Res. 
1983;143:245-50. 
4. Fattovich G, Giustina G, Christensen E, Pantalena M, Zagni I, Realdi G, et al. Influence 
of hepatitis delta virus infection on morbidity and mortality in compensated cirrhosis type 
B. The European Concerted Action on Viral Hepatitis (Eurohep). Gut. 2000;46(3):420-6. 
5. Jachs M, Binter T, Schmidbauer C, Hartl L, Strasser M, Laferl H, et al. Hepatitis D virus 
(HDV) prevalence in Austria is low but causes considerable morbidity due to fast 
progression to cirrhosis. United European Gastroenterol J. 2021;9(10):1119-27. 
6. 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;73(3):523-32. 
7. 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. 2019;68(3):512-21. 
8. Miao Z, Zhang S, Ou X, Li S, Ma Z, Wang W, et al. Estimating the Global Prevalence, 
Disease Progression, and Clinical Outcome of Hepatitis Delta Virus Infection. J Infect Dis. 
2020;221(10):1677-87. 
9. Hung CC, Wu SM, Lin PH, Sheng WH, Yang ZY, Sun HY, et al. Increasing incidence 
of recent hepatitis D virus infection in HIV-infected patients in an area hyperendemic for 
hepatitis B virus infection. Clin Infect Dis. 2014;58(11):1625-33. 
10. Castellares C, Barreiro P, Martín-Carbonero L, Labarga P, Vispo ME, Casado R, et al. 
Liver cirrhosis in HIV-infected patients: prevalence, aetiology and clinical outcome. J Viral 
Hepat. 2008;15(3):165-72. 
11. 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(11):1549-53. 
12. Béguelin C, Moradpour D, Sahli R, Suter-Riniker F, Lüthi A, Cavassini M, et al. 
Hepatitis delta-associated mortality in HIV/HBV-coinfected patients. J Hepatol. 
2017;66(2):297-303.