Download HDIN_EN - Protocol Hepatitis Delta International

a project
under the auspices of the
German Liver Foundation
HepNet Study-House
Hepatitis Delta International Network
Contents
Prinicipal Investigators:
1.
Introduction .....................................1
2.
Aims of the Hepatitis Delta
International Network .....................3
Prof. Dr. med. Heiner Wedemeyer
Phone: +49 511/532 - 6814
Fax: +49 511/532 - 8662
Email: [email protected]
3.
Study population .............................3
4.
Inclusion criteria ...............................3
5.
Register design ................................3
Patient Form (PF) ............................... 4
Centre Form (CF) .............................. 4
Assessments and procedures................ 4
Case report form (CRF) and
electronic case report form (eCRF) ........4
Analytical plan ................................5
Anonymity: patient’s code .................. 6
6.References ......................................6
Prof. Dr. med. Michael P. Manns
Phone: +49 511/ 532 - 3305
Fax: +49 511/ 532 - 4896
Email: [email protected]
Co-ordinators:
Beatriz Calle Serrano
Email: [email protected]
Dr. rer.nat. Svenja Hardtke
Phone: +49 511/532 - 6057
Fax: +49 511/6820
Email: [email protected]
Dr. med. Benjamin Heidrich
Email: [email protected]
1. Introduction
The hepatitis delta virus (HDV) causes what is considered one of the most severe forms of chronic viral hepatitis in
humans. Compared to chronic hepatitis B mono-infection or chronic hepatitis C, chronic hepatitis delta leads to a
much faster progression to liver cirrhosis1–3, which determines the earlier occurrence of major liver complications
such as ascites, hepatic encephalopathy or esophageal bleeding4–6.
The delta antigen (HDAg) was first identified by Mario Rizzetto and colleagues in 1977 as they were studying
liver biopsies of chronic hepatitis B patients who had a particularly severe course of the infection 7. Some years
later, the complete hepatitis delta virus was identified 8. HDV is a very small RNA virus that lacks intrinsic enzymatic activity and requires the presence of HBV – more specifically, of its surface antigen (HBsAg) – to infect
human hepatocytes. Hence hepatitis delta can only occur in the presence of hepatitis B. This way only two forms
of HDV infection are possible: super-infection with HDV on a chronic hepatitis B patient or simultaneous acute
HBV and HDV co-infection. However, once the acute phase is over, differentiating these two forms of infection is
rather complicated and sometimes impossible. Thus, to simplify the terminology we will refer to both super- and
simultaneous infections as co-infections.
Page 1 of 6
Deutsche Leberstiftung/German Liver Foundation | Carl-Neuberg-Straße 1 | D-30625 Hannover | Germany
| [email protected]
a project
under the auspices of the
German Liver Foundation
HepNet Study-House
Hepatitis Delta International Network
Thus far, eight HDV genotypes have been identified. Overall, HDV genotype 1 is the most common and has a
broad spectrum of pathogenicity. Genotype 2 is particularly prevalent in the Japan and Taiwan and usually takes
a milder course of disease. Genotype 3 is observed almost exclusively in South America and it is associated to
severe and fulminant hepatitis 9. Genotype 4 can mainly be found in the far East, and finally, genotypes 5 –8
have primarily been identified in Africa and African immigrants in France (fig. 1)10,11.
Worldwide, more than 350
million people are infected
with HBV, and 15–20 million
of these individuals are thought
to be co-infected with HDV.
The prevalence of hepatitis
delta varies widely throughout
the world and even within different regions of a country2. In
Europe around 8-12% of HBsAg positive patients are coinfected with HDV. Relatively
higher prevalence has been
observed in Asian countries
such as Taiwan or Pakistan,
where HDV affects 15 % and
17% of the HBsAg-positive poFigure 1. Global epidemiology of HDV infection according to viral genotype.
pulation respectively. Strikingly
higher prevalence of hepatitis
delta has been observed in some areas of Eastern Turkey (up to 27%) 2, Brazil (>50%) 12 or Pakistan 13. Finally,
limited data is available on the epidemiology of HDV in the American continent, Africa and Oceania.
Given the simple structure of HDV and the lack of antiviral targets it determines, therapy of chronic hepatitis delta
is challenging and has barely improved since the identification of the virus3. Current standard antiviral regimes
consist of 1-2 year interferon-based therapies that are rather inefficient quite expensive and riddled with side
effects. Indeed, it was recently shown that only about one quarter of the patients are able to clear the HDV
after treatment with peg-interferon alfa-2a for 48 weeks14. New antiviral options are eagerly awaited. For the
development of new antiviral compounds, clinical studies are essential. However, because of the relatively low
prevalence of HDV in developed countries – where most of these studies take place – and the lack of resources
in those regions where hepatitis delta is endemic, the organization of clinical trials is rather difficult.
To sum up, HDV causes the most aggressive form of chronic viral hepatitis, leading to early occurrence of liver
complications and death4–6 and is present worldwide1,2. Thus, chronic hepatitis delta represents a major public
health burden. The only present available therapeutic option, interferon, is expensive, poorly tolerated and rather
ineffective14. Hence, the importance of developing novel antiviral treatments. In order to achieve more efficient
therapies, a better understanding of the disease is essential. However, research on chronic hepatitis delta is difficult
given the irregular distribution of this co-infection and the relatively low prevalence of the disease in developed
countries, where the resources for clinical studies are available.
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Deutsche Leberstiftung/German Liver Foundation | Carl-Neuberg-Straße 1 | D-30625 Hannover | Germany
| [email protected]
a project
under the auspices of the
German Liver Foundation
HepNet Study-House
Hepatitis Delta International Network
2.
Aims of the Hepatitis Delta International Network
Hepatitis delta is a major health problem, not only because of the severity of the disease, but also due to the
lack of effective antiviral treatment. To improve the current therapeutic options, a better understanding of the
pathophysiology is essential. Reliable research in this direction is only possible with large patient study groups.
However, given the geographic distribution of hepatitis delta, larger patient cohorts would only be possible
through multicenter collaboration.
The aims of this project are:
i. Collect clinical information from hepatitis delta patients from multiple centers distributed worldwide in
order to build up a large database that will enable and facilitate further research on chronic hepatitis
delta.
ii. To better inform patients about their viral infection, present status and evolution of liver disease
throughout time. To give them the tools needed to inform other peers and medical professionals about
the significance and consequences of a chronic hepatitis delta infection.
iii. To allow the participating physicians to track course of the disease, therapies, signs and symptoms of
the hepatitis delta patients included by their center.
3.
Study population
Patients with chronic hepatitis delta will be screened regardless of HDV or HBV genotype. There will be no limit
in the number of patients recruited. Our first aim would be to collect information from around 1000 patients in
the first two years of the Hepatitis Delta International Network and 300 new HDV patients yearly thereafter.
4.
Inclusion criteria
• Positive HBs antigen and antiHDV for longer than 6 months.
• Signed informed consent.
• Absence of any cause of relevant liver disease other than HDV (i.e. hemochromatosis, autoimmune
hepatitis, alcoholic or toxic liver disease, etc.)
5.
Register design
The Hepatitis Delta International Network is not a conventional register since it is not only meant to collect and
manage patients’ information, but it also serves as source of information for both patients and physicians with the
Patient’s Form (PF) and the Center Form (CF).
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Deutsche Leberstiftung/German Liver Foundation | Carl-Neuberg-Straße 1 | D-30625 Hannover | Germany
| [email protected]
a project
under the auspices of the
German Liver Foundation
HepNet Study-House
Hepatitis Delta International Network
Patient Form (PF)
The Patient’s Form is automatically created by our system once the patient’s information has been fed in. It is
a document that contains a synthesis of the patient’s clinical history, it contains charts and figures showing the
progression of the liver disease since enrollment, and some important facts and tips about hepatitis delta that will
help patients take better care of both their own health and that of those around them. The PF also contains information to be shown to other health professionals who might not be familiar with the disease, making it easier for
them to understand the underlying condition and therefore offer the best treatment to our Hepatitis Delta patients.
In addition, the PF serves as double-check of the information that has been typed in by the center since no one
knows better about their medical condition than patients themselves.
Center Form (CF)
The Center Form offers doctors an analysis of the complete group of patients they have included in HDIN, the
therapies they have followed, their evolution through time etc. And like the PF, the CF helps in identifying inconsistencies or misprints.
Assessments and procedures
During a routine visit to the clinic, patients who fulfill all the inclusion criteria and none of the exclusion criteria will
be briefed about the Hepatitis Delta International Network by their physician. The register will be established in
several countries, it is necessary that the patients have a copy of the Informed Consent and the patient’s information
in their mother tongue. If these documents are not yet available in the appropriate language, the investigating
doctors on site will be required to translate them. An adaptation of these documents to better suit the local culture
might be necessary, doctors are therefore asked to send a copy of the retranslation (in English).
Once the patient has signed the informed consent, collection of clinical information and blood can proceed. The
blood tests that will be required comprise routine check-ups to determine liver and kidney function, differential
blood counts and hepatitis serology. Furthermore, patients’ personal and disease specific data will be registered.
Patients should be followed up every 6-12 months during their routine visits to the center. Once the patients’ data
has been collected, it should be updated in the eCRF (electronic case report form).
The written consent and one serum/plasma sample will be stored in the corresponding center. Within Germany
these samples will be centrally tested in Hannover Medical School (MHH), internationally this should take place
in the respective centers. The participating physicians will store the signed Informed Consents and will be responsible for them.
Case report form (CRF) and electronic case report form (eCRF)
Patients’ data to be collected is listed in table 1. Patients’ information will be electronically registered in the eCRF.
To facilitate on-site data collection, an additional CRF will be provided. These will be stored in the recruiting center.
The observation period will be unlimited but the patient can withdraw his consent at any time without
difficulties.
The first interim analysis is planned by the time the threshold of 500 recruited patients has been achieved
Page 4 of 6
Deutsche Leberstiftung/German Liver Foundation | Carl-Neuberg-Straße 1 | D-30625 Hannover | Germany
| [email protected]
a project
under the auspices of the
German Liver Foundation
HepNet Study-House
Hepatitis Delta International Network
Table 1. Required data.
PATIENT BASIC DATA
•
•
•
•
Date of visit
Country ID
Center ID
Patient ID
SCREENING FORM (only necessary at baseline)
•
•
•
•
1st Diagnosis of chronic Hepatitis D: month-year
1st Diagnosis of chronic Hepatitis B: month-year
Informed consent given, discussed and signed
Presence of a other condition associated with chronic liver disease
DEMOGRAPHICS (only necessary at baseline)
•
•
•
•
•
Sex
Date of birth: month-year
Country of birth and family origin
Education and occupation
Risk factors: tattoo/piercing, blood transfusion; IVDA, infected
relatives, risk sexual behavior.
CONCOMITANT MEDICATIONS
• Compound
• Dosis
• Start date
CONCOMITANT CONDITIONS
•
•
•
•
•
•
Infections: HCV and/or HIV
Diabetes mellitus, arterial hypertension
Dialysis
Organ transplantation with existing functional graft
Alcohol intake, nicotine use, drug abuse
Pregnancy
PHYSICAL EXAMINATION
• Weight And height
• Hepato/splenomegaly
LIVER-RELATED COMPLICATION
•
•
•
•
Cirrhosis, date of 1st diagnosis
Hepatocellular carcinoma, date of 1st diagnosis
Liver transplantation, date
Liver decompensation, date
ANTIVIRAL THERAPY
• Total undergone tratments
• Compound, dosis, start and end of therapy
HEMATOLOGY
Hemoglobin
Leucocytes
Neutrophils
Thrombocytes
INR
VIROLOGY
antiHAV IgG
antiHAV IgM
antiHCV
HCV-RNA
HBsAg qual.
HBsAg quant.
antiHBs
HBeAg
antiHBe
HBV-DNA qual.
HBV-DNA quant.
antiHDV
HDV RNA qual.
HDV RNA quant.
OTHER
AMA, ANA
IL28B
PBMCs available?
BIOCHEMISTRY
ALT / GPT
AST / GOT
Bilirrubin total
Alkaline phosphatase
Albumin
BUN
Creatinine
Sodium
Cholinesterase
Creatinine clearance
AFP
OTHER EXAMINATIONS
•
•
•
•
Liver Biopsy: date, Ishak score, available tissue
USG: date, spleen size, steatosis, nodules, ascites
Transient elastography: date, elasticity, variability
Endoscopy: date, varices
END OF FOLLOW UP
• Date
• Reason of discontinuation
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Deutsche Leberstiftung/German Liver Foundation | Carl-Neuberg-Straße 1 | D-30625 Hannover | Germany
| [email protected]
a project
under the auspices of the
German Liver Foundation
HepNet Study-House
Hepatitis Delta International Network
or 12 months after the first patient has been included. Subsequent analysis will be performed yearly.
Anonymity: patient’s code
To guarantee the anonymity of our patients, names will be substituted by patient’s codes and only month
and year of birth will be used instead of complete birthdates. Our coding system will follow the following
scheme:
Country
Center Patient
e.g. Patient number 5 in Medizinische Hochschule Hannover (Germany): 01-001-0005
6. References
1. Rizzetto, M. Hepatitis D: thirty years after. J Hepatol 50, 1043–50 (2009).
2. Wedemeyer, H. & Manns, M. P. Epidemiology, pathogenesis and management of hepatitis D: update and challenges ahead. Nat Rev Gastroenterol Hepatol 7, 31–40 (2010).
3. Hughes, S. A., Wedemeyer, H. & Harrison, P. M. Hepatitis delta virus. Lancet 378, 73–85 (2011).
4. Romeo, R. et al. A 28-year study of the course of hepatitis Delta infection: a risk factor for cirrhosis and hepatocellular carcinoma. Gastroenterology 136, 1629–38 (2009).
5. Niro, G. A. et al. Outcome of chronic delta hepatitis in Italy: a long-term cohort study. J Hepatol 53, 834–40
(2010).
6. Buti, M. et al. Clinical outcome of acute and chronic hepatitis delta over time: a long-term follow-up study. J
Viral Hepat (2010).doi:JVH1324 [pii] 10.1111/j.1365-2893.2010.01324.x
7. Rizzetto, M. et al. Immunofluorescence detection of new antigen-antibody system (delta/anti-delta) associated to
hepatitis B virus in liver and in serum of HBsAg carriers. Gut 18, 997–1003 (1977).
8. Rizzetto, M. et al. delta Agent: association of delta antigen with hepatitis B surface antigen and RNA in serum
of delta-infected chimpanzees. Proc Natl Acad Sci U S A 77, 6124–8 (1980).
9. Quintero, A. et al. Hepatitis delta virus genotypes I and III circulate associated with hepatitis B virus genotype F
in Venezuela. Journal of medical virology 64, 356–359 (2001).
10.Radjef, N. 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. 78, 2537–2544 (2004).
11.Le Gal, F. et al. Eighth major clade for hepatitis delta virus. Emerging Infect. Dis. 12, 1447–1450 (2006).
12.Viana, S., Parana, R., Moreira, R. C., Compri, A. P. & Macedo, V. High prevalence of hepatitis B virus and
hepatitis D virus in the western Brazilian Amazon. Am J Trop Med Hyg 73, 808–14 (2005).
13.Abbas, Z., Jafri, W. & Raza, S. Hepatitis D: Scenario in the Asia-Pacific region. World J Gastroenterol 16,
554–62 (2010).
14.Wedemeyer, H. et al. Peginterferon plus adefovir versus either drug alone for hepatitis delta. N Engl J Med
364, 322–31 (2011).
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Deutsche Leberstiftung/German Liver Foundation | Carl-Neuberg-Straße 1 | D-30625 Hannover | Germany
| [email protected]