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Entecavir and Tenofovir combination therapy in chronic Hepatitis B: Rescue therapy in patients with advanced fibrosis and multiple previous treatment failures. Results from an international multicenter cohort study.
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Reported by Jules Levin
AASLD Oct 31-Nov 3 2009 Boston, MA
J. Petersen1, 2; M. Lutgehetmann2; F. Zoulim3; M. Sterneck4; H. L. Janssen5; T. Berg6; P. Buggisch1; P. Lampertico7; V. Ratziu8; M. Buti9; C. Sarrazin10
1. Asklepiosklinik St. Georg, Liver Center Hamburg IFI Institute, University of Hamburg, Germany.
2. Department of Gastroenterology, University Hospital Hamburg Eppendorf, Hamburg, Germany.
3. Department of Hepatology, Hotel Dieu Hospital Lyon, Lyon, France.
4. Department of Hepatobiliary Surgery and Transplantation, University Hospital Hamburg Eppendorf, Hamburg, Germany.
5. Department of Gastroenterology and Hepatology, University Medical Center, Rotterdam, Netherlands.
6. Department of Gastroenterology and Hepatology, Charite University Medical Center, Berlin, Germany.
7. I Division of Gastroenterology, Fondazione IRCCS Maggiore Hospital, University of Milan, Italy.
8. Service d Hepato-Gastroenterologie, Universite Pierre et Marie Curie (Paris 6), Paris, France.
9. Department of Hepatology, Hospital Vall de Hebron, Barcelona, Spain.
10. Department of Medicine, Goethe University Hospital, Frankfurt, Germany.
Background: Treatment of chronic HBV with nucleos(t)ide analogs using sequential monotherapy in the past has led to the selection of multiple resistant mutations, endangering patients with advanced liver disease due to hepatic flares.
Aim of this ongoing cohort study was to investigate the efficacy and safety of tenofovir and entecavir (1mg) in treatment experienced patients. Combination therapy was initiated as rescue therapy in 39 compliant HBV mono-infected patients with multidrug resistant HBV or only partial responses to previous lines of therapy and advanced liver disease.
Methods: Open label cohort, investigator initiated study from 8 European referral centers. Quantitative HBV-DNA measurement with LLOD < 80 IU/ml was used. Resistance und genotyping was determined using Innolipa line-probe-assay DRV2 and direct sequencing. ALT, HBV-DNA and HBsAg were quantitatively measured at baseline and every 3 months.
Results: 39 patients (23 HBeAg positive) with a median age of 48 years and 3 lines of pretreatment (median, range 1-6) were included. At baseline median ALT was 1.2 ULN (range 0.38-4.1) and HBV-DNA was 1.7x104 IU/ml (range 900- 1x1011 IU/ml). Median treatment duration after initiating combination therapy was 10.5 months (range 1-42 months), with no significant clinical side effects. The median HBV-DNA level dropped highly significant by 3.5 logs (range 0-8 log; p< 0.0001) and 31/39 patients became HBV-DNA undetectable (< 80 IU/ml). This was accompanied by a significant decline in ALT (median 0.68 ULN; range 0.2-2.9; p=0.001). Patients with detectable DNA all had treatment duration <6 months. Three patients lost HBe Ag (after 18, 21, and 24 months, respectively) and one patient showed HBs seroconversion. Patients with liver cirrhosis did not develop clinical decompensation, but two patients with cirrhosis and undetectable HBV DNA developed an HCC. There was no significant change in adherence.
Discussion: Rescue therapy with entecavir and tenofovir in HBV mono-infected patients harbouring complex viral resistance patterns or showing only partial antiviral responses to preceeding therapies was highly efficient, safe, and well tolerated in patients with advanced liver disease. More data are certainly needed to judge about the long-term safety, efficacy and prevention of emergence of new viral mutations in this difficult to treat patient population.
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