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*TITLE: *Quasispecies analysis of HBV strains isolated from chronic hepatitis B patients treated with Peg-interferon+Tenofovir therapy
*AUTHORS (FIRST NAME, LAST NAME): *_Olivier Lada_^1 , Qian Zhang^1 , Martine Lapalus^1 , Francoise Cluzeaud^1 , Michelle Martinot-Peignoux^1 , Cédric Laouénan^2 , Emilie Estrabaud^1 , Nathalie Boyer^1 , Tarik Asselah^1 , Patrick Marcellin^1
*Institutional Author(s): *
*INSTITUTIONS (ALL): *1. Hepatologie, Hopital Beaujon and INSERM U773 CRB3, , Clichy, France.
2. Modèles et Méthodes de l'évaluation thérapeutique des maladies chroniques, Inserm UMR 738, UFR de Médecine-- Université de Paris Diderot
-- Paris 7 -- Site Bichat, Paris, France.
*ABSTRACT BODY: *Background: In chronic Hepatitis B (CHB), loss of hepatitis B surface antigen (HBsAg) and seroconversion to anti-HBs is generally considered as the ultimate goal of antiviral therapy. New combination therapy of Pegylated interferon (PegIFN) with potent HBV Inhibitors such as tenofovir (TDF) is assessed in order to improve the rate of HBsAg loss. The aim of this study is to investigate the S-gene variability of patients treated with combination of PegIFN with TDF.
Methods: Patients received 180 ?g of Peg-IFN/week plus 300 mg of TDF /day during 48 week. Patients were seen every 3 months. Sustained virologic response (SVR) was defined as HBV DNA< 2000UI/mL 48 weeks after end of therapy (EOT). Non response (NR) was defined as HBV DNA > 2000 UI/mL 48 weeks after EOT. HBs Ag-encoding gene from each patient's serum at baseline was PCR-amplified and cloned. At least 15 clones per patient were analysed.
Results: Twenty-six patients were included in this analysis. Baseline characteristics were: median age 44 years (range=27-67 years), 80.8% male, mean of HBV DNA 6.8 log UI/mL (range 3.6- 7.9 log UI/mL) and mean of serum ALT 102 IU/L (range 24-287 IU/L). Nine patients (34.6%) were HBeAg-negative. After the 48 weeks of follow-up, 6/26 patients (23%) achieved a SVR and 5/26 patients (19%) had a loss of HBsAg. Comparison of variability along the S protein indicated a marked difference between patients with SVR vs NR. When considering the full-length S coding region, the number of residues substitutions was 1.66 times more frequent in NR patients than SVR patients (p=0.048). The residue substitutions frequency of the "a" determinant located in the major hydrophilic region (MHR) was higher in NR vs SVR patients; 8.77 vs 10.53 mutated residues per 100 amino acids respectively. This determinant is one of the main targets of anti-HBs antibodies. The highest frequency of residue changes was observed in the C-terminal part of the S protein from NR compared to SVR patients with 25.01 vs 20.11 mutated residues per 100 amino acids respectively. This region overlaps the polymerase ORF and is likely affected by resistance mutations induced by treatment with nuclos(t)ide analogues. The most frequent substitutions observed in NR patients were located at position s129, s133, s145, which are known as immune escape variants.
Conclusion: In patients receiving PEG-IFN plus tenofovir, a SVR was observed in 23% and an HBsAg loss in 19%. NR patients showed more variability along the S protein. The Accumulation of residue substitutions in and around the "a" determinant at baseline should be a sensitive predictor of response to combination of PegIFN and TDF therapy in CHB patients.
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