Drug resistance common among European patients with chronic hepatitis B
Mon, 07/13/15 - 09:19 By Anne Harding
NEW YORK (Reuters Health) - Rates of lamivudine resistance are high among patients with chronic hepatitis B (CHB) infection across Europe, with many patients developing cross-resistance to entecavir, according to a new report.
Among 1,568 patients under treatment who had detectable serum hepatitis B virus (HBV) DNA, nearly three-quarters had received lamivudine monotherapy, and just over half had drug resistant strains of HBV, Dr. Annemarie M. J. Wensing of University Medical Center Utrecht in the Netherlands and her colleagues found.
"The burden of historical and continuous lamivudine use in Europe is very large," Dr. Wensing told Reuters Health by email. "This has resulted in many patients with lamivudine resistance and cross-resistance to entecavir. This may not seem to be an issue since no cross-resistance to tenofovir or interferon is induced. However a considerable group has renal toxicity and those patients should be treated with entecavir. For these patients pretreatment fully compromises HBV treatment options."
Currently, European guidelines recommend patients with CHB be treated with entecavir or tenofovir, and discourage monotherapy with lamivudine, adefovir, and telbivudine. But many patients are still being treated with older drugs, which carry a greater risk of treatment failure and drug resistance, Dr. Wensing and her team note in the Journal of Infectious Diseases, online July 1.
To investigate the prevalence and characteristics of nucleoside analog resistance among CHB patients, the researchers looked at genotypic resistance testing results from patients with CHB who were undergoing routine monitoring, gathering data from 18 countries across Europe.
Sample draw dates were divided into four time periods based on when different nucleoside analogs became available in Europe: 1998-2002 for lamivudine; 2003-2005 for adefovir; 2006-2008 for entecavir; and 2009-2012 for tenofovir.
The researchers identified at least one drug-resistance mutation in 52.7% of patients. The most common mutation identified was rtM204V/I, found in 48.7% of all patients studied, which is associated with lamivudine and telbivudine use. Most of these patients had additional mutations. About 6% of patients carried one of two mutations that conferred adefovir resistance. Among the 1,175 patients who had been exposed to lamivudine, 56.6% had drug resistance, while 22.3% of adefovir-exposed patients and 35.3% of entecavir-exposed patients had drug resistance.
Multivariate analysis identified age, HBV-DNA levels and lamivudine use as independent risk factors for resistance, while patients with viral genotype A were also at increased risk of resistance. Samples collected in 2003-2005 and 2006-2008 were more likely to be drug-resistant than samples collected later. Samples from northern and western Europe were less likely to be drug-resistant.
Although European guidelines recommend against lamivudine use for HBV, the drug is still being used, especially in countries with limited resources, due to its lower cost, Dr. Wensing told Reuters Health.
"We would indeed recommend not to use lamivudine. Lamivudine is obsolete, and risky," she said. "For treatment as well as for prophylaxis lamivudine should not be used. Each country should take clinical decisions on the base of the cost and efficacy, but the rate of damage often driven by lamivudine in terms of failures and resistance does not justify an 'in full' approach with this drug only because it is inexpensive."
"For HIV it has been shown that it is possible to supply patients in very resource-limited settings with tenofovir," Dr. Wensing added. "We cannot accept that this treatment option will not be made available for patients with HBV."
HBV infection is much more common than infection with hepatitis C virus (HCV) or HIV, the researcher noted. While patients with HCV or HIV are often treated by doctors who specialize in these infections, she added, non-specialist clinicians often treat patients with HBV.
"However, HBV infection is a far larger threat than what is commonly thought, even in patients who have seroconverted since the virus is not eliminated from the body," Dr. Wensing said. "With the rise of patients with iatrogenic immunosuppression we will experience more HBV reactivation and clinical risks. Proper use of drugs is important in this vulnerable population."
SOURCE: http://bit.ly/1furVof
J Infect Dis 2015.
(c) Copyright Thomson Reuters 2015. Click For Restrictions - http://about.reuters.com/fulllegal.asp
Combined Analysis of the Prevalence of drug Resistant HBV in antiviral therapy Experienced patients in Europe (CAPRE)
L.E. Hermans1,2,*, V. Svicher3,*, S.D. Pas2, R. Salpini3, M. Alvarez4, Z. Ben Ari20, G. Boland1, B. Bruzzone5, N. Coppola6, C. Seguin-Devaux7, T. Dyda8, F. Garcia4, R. Kaiser9, S. Köse10, H. Krarup11, I. Lazarevic12, M.M. Lunar13, S. Maylin14, V. Micheli15, O. Mor16, S. Paraschiv17, D. Paraskevis18, M. Poljak13, E. Puchhammer-Stöckl19, F. Simon14, M. Stanojevic12, K. Stene-Johansen21, N. Tihic22, P. Trimoulet23, J. Verheyen24, A. Vince25, N. Weis26, T. Yalcinkaya27, S. Zidovec Lepej26, C. Perno3, C.A.B. Boucher2 and A.M.J. Wensing1 on behalf of the HEPVIR working group of the European Society for translational antiviral research (ESAR)
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Author Affiliations
1Department of Medical Microbiology, University Medical Centre Utrecht, Utrecht, The Netherlands
2Department of Virology, Erasmus Medical Centre, Rotterdam, The Netherlands
3Department of Experimental Medicine and Surgery, University of Rome “Tor Vergata”, Rome, Italy
4Servicio de Microbiología, Hospital San Cecilio, Instituto de Investigación Biosanitaria ibs.GRANADA, Hospitales Universitarios de Granada, Granada, Spain
5Hygiene Unit, IRCCS AOU San Martino - IST, Genoa, Italy
6Malattie Infettive, Seconda Università degli studi di Napoli, Naples, Italy
7Laboratory of Retrovirology, CRP-Santé, Luxembourg, Luxembourg
8Molecular Diagnostics Laboratory, Hospital of Infectious Diseases, Warsaw, Poland
9Institute of Virology, University of Cologne, Cologne, Germany
10Izmir Tepecik Education and Research Hospital, Clinic of Infectious Diseases and Clinical Microbiology, Izmir, Turkey
11Section of Molecular Diagnostics, Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark
12Institute of Microbiology and Immunology, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
13Institute of Microbiology and Immunology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
14Service de Microbiologie, University Paris Diderot, Hôpital Saint Louis, Paris, France
15“L. Sacco” Hospital, Milan, Italy
16National HIV Reference Laboratory, Central Virology Laboratory, Ministry of Health, Tel Hashomer, Ramat Gan, Israel
17Molecular Diagnostics Laboratory, National Institute for Infectious Diseases “Matei Bals”, Bucharest, Romania
18National Retrovirus Reference Centre, Department of Hygiene, Epidemiology and Medical Statistics, Faculty of Medicine, National and Kapodistrian University of Athens, Athens, Greece
19Department for Virology, Medical University of Vienna, Vienna, Austria
20Liver Disease Centre, Sheba Medical Centre, Ramat Gan, Israel
21Department of Virology, Norwegian Institute of Public Health, Oslo, Norway
22Institute of Microbiology, Polyclinic for Laboratory Diagnostics, University Clinical Centre Tuzla, Tuzla, Bosnia and Herzegovina
23Virology Laboratory, Centre Hospitalier Régional et Université "Victor Segalen", Bordeaux, France
24Institute of Virology, University-Hospital, University Duisburg-Essen, Essen, Germany
25University of Zagreb School of Medicine and University Hospital for Infectious Diseases “Dr. Fran Mihaljevic”, Zagreb, Croatia
26Department of Infectious Diseases, Copenhagen University Hospital, Hvidovre, Copenhagen, Denmark
27Refik Saydam National Public Health Agency, Ankara, Turkey
Corresponding author: Annemarie M.J. Wensing, MD PhD, University Medical Centre Utrecht – Virology, Dept of Medical Microbiology G04.614, Heidelberglaan 100, 3584 CX Utrecht, The Netherlands, Phone: +31 88 7556526, Fax: +31 88 7555426, [email protected]
↵* These authors contributed equally to the paper.
Abstract
Introduction. European guidelines recommend treatment of chronic Hepatitis B virus infection (CHB) with the nucleos(t)ide analogs (NAs) entecavir or tenofovir. However, many European CHB patients have been exposed to other NAs, which are associated with therapy failure and resistance. The CAPRE study was performed to gain insight in prevalence and characteristics of NA resistance in Europe.
Methods. A survey was performed on genotypic resistance testing results acquired during routine monitoring of CHB patients with detectable serum HBV-DNA in European tertiary referral centres.
Results. Data of 1568 patients was included. The majority (73.8%) was exposed to lamivudine monotherapy. Drug resistant strains were detected in 52.7%. The most frequently encountered primary mutation was M204V/I (48.7%), followed by A181T/V (3.8%) and N236T (2.6%). In patients exposed to entecavir (n=102), full resistance was present in 35.3%. Independent risk factors for resistance were age, viral load and lamivudine exposure (p<0.001).
Conclusion. These findings support resistance testing in cases of apparent NA therapy failure. This survey highlights the impact of exposure to lamivudine and adefovir on development of drug resistance and cross-resistance. Continued use of these NAs needs to be reconsidered at a pan-European level.