Hepatitis Delta International Network

Transcription

1 Contents 1. Introduction Aims of the Hepatitis Delta International Network Study population Inclusion criteria 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 References... 6 Prinicipal Investigators: Prof. Dr. med. Heiner Wedemeyer Phone: / Fax: / Wedemeyer.Heiner@mh-hannover.de Prof. Dr. med. Michael P. Manns Phone: / Fax: / Manns.Michael@mh-hannover.de Co-ordinators: Beatriz Calle Serrano CalleSerrano.Beatriz@mh-hannover.de Dr. rer.nat. Svenja Hardtke Phone: / Fax: / Hardtke.Svenja@mh-hannover.de Dr. med. Benjamin Heidrich Heidrich.Benjamin@mh-hannover.de 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 cirrhosis 1 3, which determines the earlier occurrence of major liver complications such as ascites, hepatic encephalopathy or esophageal bleeding 4 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

2 Thus far, eight HDV genotypes have been identifi ed. 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 fi nally, genotypes 5 8 have primarily been identifi ed in Africa and African immigrants in France (fi g. 1) 10,11. Worldwide, more than 350 million people are infected with HBV, and 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 country 2. 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 population respectively. Strikingly Figure 1. Global epidemiology of HDV infection according to viral genotype. 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 identifi cation of the virus 3. Current standard antiviral regimes consist of 1-2 year interferon-based therapies that are rather ineffi cient 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 weeks 14. 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 diffi cult. To sum up, HDV causes the most aggressive form of chronic viral hepatitis, leading to early occurrence of liver complications and death 4 6 and is present worldwide 1,2. Thus, chronic hepatitis delta represents a major public health burden. The only present available therapeutic option, interferon, is expensive, poorly tolerated and rather ineffective 14. Hence, the importance of developing novel antiviral treatments. In order to achieve more effi cient therapies, a better understanding of the disease is essential. However, research on chronic hepatitis delta is diffi cult 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. Page 2 of 6

3 2. Aims of the 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 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 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). Page 3 of 6

4 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 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

5 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. 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. CONCOMITANT MEDICATIONS Compound Dosis Start date OTHER AMA, ANA IL28B PBMCs available? 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 BIOCHEMISTRY ALT / GPT AST / GOT Bilirrubin total Alkaline phosphatase Albumin BUN Creatinine Sodium Cholinesterase Creatinine clearance AFP LIVER-RELATED COMPLICATION Cirrhosis, date of 1st diagnosis Hepatocellular carcinoma, date of 1st diagnosis Liver transplantation, date Liver decompensation, date OTHER EXAMINATIONS Liver Biopsy: date, Ishak score, available tissue USG: date, spleen size, steatosis, nodules, ascites Transient elastography: date, elasticity, variability Endoscopy: date, varices ANTIVIRAL THERAPY Total undergone tratments Compound, dosis, start and end of therapy END OF FOLLOW UP Date Reason of discontinuation Page 5 of 6

6 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): References 1. Rizzetto, M. Hepatitis D: thirty years after. J Hepatol 50, (2009). 2. Wedemeyer, H. & Manns, M. P. Epidemiology, pathogenesis and management of hepatitis D: update and challenges ahead. Nat Rev Gastroenterol Hepatol 7, (2010). 3. Hughes, S. A., Wedemeyer, H. & Harrison, P. M. Hepatitis delta virus. Lancet 378, (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, (2009). 5. Niro, G. A. et al. Outcome of chronic delta hepatitis in Italy: a long-term cohort study. J Hepatol 53, (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] /j 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, (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, (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, (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, (2004). 11. Le Gal, F. et al. Eighth major clade for hepatitis delta virus. Emerging Infect. Dis. 12, (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, (2005). 13. Abbas, Z., Jafri, W. & Raza, S. Hepatitis D: Scenario in the Asia-Pacific region. World J Gastroenterol 16, (2010). 14. Wedemeyer, H. et al. Peginterferon plus adefovir versus either drug alone for hepatitis delta. N Engl J Med 364, (2011). Page 6 of 6