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Hepatitis D virus infection - Not a vanishing disease in Europe!
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Hepatology
May 2007
Heiner Wedemeyer, Benjamin Heidrich, Michael P. Manns
Department of Gastroenterology, Hepatology, and Endocrinology, Medizinische Hochschule Hannover, Hannover, Germany
Letter
Hepatitis D Virus Infection - Not a Vanishing Disease in Europe!
To the Editor:
We read with interest the articles on the treatment of hepatitis D virus (HDV) infection using pegylated interferon alpha by Niro et al.[1] and Castelnau et al.,[2] which showed some efficacy but low sustained virological response rates. Consequently, the accompanying editorial by Patricia Farci very impressively highlighted the urgent need for further improvement of therapeutic options for patients with delta hepatitis.[3] Farci also addressed changes in the epidemiology of HDV infection in Europe during the last 2 decades, mentioning that the prevalence of HDV-infected patients among HBsAg-positive individuals had dramatically declined in Italy in the 1990s.[4] However, delta hepatitis is not a vanishing disease in other countries, mainly due to immigration of people from high endemic areas. For example, the epidemiology of delta hepatitis changed significantly in Germany because of large numbers of patients migrating to Germany from Eastern Europe and countries of the former Soviet Union.
We investigated the presence of anti-HDV antibodies in sera from 2354 consecutive HBsAg-positive patients sent to the diagnostic laboratory of our department between 1992 and April 30, 2006 (Fig. 1). Overall, 253 samples (11.3%) tested positive for anti-HDV. For 144 of those, we had information on the country of birth and, as expected, only 19% of the delta hepatitis patients were born in Germany whereas 26% had migrated to Germany from Turkey and 28% migrated from Eastern Europe or countries from the former Soviet Union. Studying HDV prevalences over time showed that the percentage of patients positive for anti-HDV among individuals positive for HBsAg declined from 18.6% in 1992 to 6.8% in 1997, confirming the Italian experience.[4] However and importantly, we observed no further decline thereafter. From 1999 on, between 8% and 14% of HBsAg-positive sera tested positive for anti-HDV with 13 to 27 new patients with HDV admitted to our institution each year. Although these numbers are certainly biased by a referral effect to our tertiary center, which performs more than 130 liver transplants per year, our data clearly demonstrate that HDV infection in Europe is no longer a disease found only in the Mediterranean area but also has become an important clinical consideration in central Europe. Unfortunately, oral nucleoside analogs used for treatment of hepatitis B are not effective against HDV.[5-8] Thus, treatment trials such as those reported by Niro and Castelnau as well as by Erhardt et al.[9] investigating the role of pegylated interferons for the treatment of HDV infection are urgently needed to develop therapies for delta hepatitis with a reasonable risk/benefit ratio. Final results of the Hep-Net/International Delta hepatitis intervention trial (HIDIT-1) that is studying 90 HDV patients will be available within a short time.[10] Thus, we have to congratulate the investigators for their efforts and Farci for highlighting the importance of continuous research in HDV infection.
Reply:
We would like to acknowledge H. Wedemeyer, B. Heidrich, and M. P. Manns for their comments and believe that it is important to consider that HDV is not a vanishing disease in several countries of Europe.[1] Indeed, in France too, we agree that the surveillance of hepatitis D has to be performed. It is however very difficult to obtain a good estimation of the prevalence of HDV among people infected by HBV. HDV is still not a major health problem in HBsAg-negative HBV-infected patients;[2][3] therefore, we encourage the search for HDV status at least once in the medical survey of an HBs-positive carrier. Search for total anti-delta antibodies in the serum might be sufficient for initial screening. Then the next question may be what proportion of patients with anti-HDV have ongoing replication of HDV? (i.e., patients who would be at risk of transmission and of potential liver damage and might get benefit from treatment). Considering results in 2005, among 122 new patients with serological reactivity for total HDV antibodies, 62 (50%) had a positive detection of HDV RNA using the recently described TaqMan-based real-time PCR approach.[4]
The graphs in Fig. 1 can be generated from results obtained at the Laboratoire Associe au Centre National de Reference des Hepatites B, C in France during the last 5 years by considering patients with detectable HDV RNA registered for the first time. Among 617 patients analyzed, the situation seems quite different than in Germany. Indeed, the proportion of HDV-infected patient from Western Europe is decreasing as described for Italy,[1] but we do not observe such a high prevalence of HDV-infected people from Eastern Europe, which represents in France only 12% in 2006. In contrast, new infection recognized as HDV concerns mostly African people migrating to France. This phenomenon leads us to extensively characterize the variability of HDV in Africa during recent years.[5][6] The results encourage a new HDV classification in which the Deltavirus genus consists of 8 major clades, 5 of them being present in Africa (i.e., clade 1, 5, 6, 7, and 8).[7] Interestingly, clade 5 isolates represent approximately 20% of HDV RNA-positive samples, which is stable for the time period in France. Collaborative studies that include a large number of HDV-infected patients will be necessary to evaluate whether HDV clades are associated with different response to pegylated interferon.
Frederic Le Gal 1, Corinne Castelneau 2, Elyanne Gault 1, Nasser al Hawajri 1, Emmanuel Gordien 1, Patrick Marcellin 2, Paul Deny 1 3
1Laboratoire Associe au Centre National de Reference des Hepatites B, C et
Delta, Hopital Avicenne, Universite Paris 13, Bobigny, France
2INSERM, U773 CRB3, Hopital Beaujon, Universite Paris 7, Clichy, France
3INSERM U871, 151 Cours Albert Thomas 69003, Lyon, France
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