- Email: [email protected]
P1064 RANDOMIZED TRIAL OF TENOFOVIR MONOTHERAPY VERSUS TENOFOVIR PLUS ENTECAVIR COMBINATION THERAPY IN CHRONIC HEPATITIS B PATIENTS WITH GENOTYPIC RESISTANCE MUTATIONS TO ADEFOVIR
POSTERS P1062 3-YEAR TREATMENT WITH TENOFOVIR IN REAL-LIFE IS EFFECTIVE AND WELL TOLERATED IN CHB PATIENTS, INCLUDING THE ELDERLY AND PATIENTS WITH COMORBIDITIES X. Causse1 , G.-P. Pageaux2 , F. Zoulim3 , D. Larrey2 , D. Ouzan4 , R. Truchi5 , A. Pauwels6 , D. Guyader7 , V. De Ledinghen8 , V. Tilliet9 , J.-F. Cadranel10 , C. Stern9 , O. Libert9 , P. Marcellin11 , VIREAL Group. 1 CHR Orl´eans, Orl´eans, 2 CHU Saint-Eloi, Montpellier, 3 CHU Croix Rousse, Lyon, 4 Institut Arnault Tzanck, Saint-Laurent du Var, 5 CHU Nice, Nice, 6 CH, Gonnesse, 7 CHU Rennes, Rennes, 8 CHU Bordeaux, Pessac, 9 Gilead Sciences, Boulogne-Billancourt, 10 CH, Creil, 11 CHU Beaujon, Clichy, France E-mail: [email protected] Background and Aims: Phase III trials have reported high VR and favorable safety profile of TDF up to 7-year. However, patients with older age and comorbidities are excluded from clinical trials. Thus, long-term data from real-life cohorts are needed. The aim was to analyze the 3-year data of TDF in a real-life cohort, especially in elderly patients. Methods: 440 monoinfected TDF-naïve CHB patients were prospectively enrolled into a French real-life multicenter cohort (VIREAL study). Clinical, serological and virological data were collected at baseline and every 6 months. Analyses at 3-year were performed in the overall population and a subgroup of elderly patients (≥65 years). VR: HBV-DNA <69 IU/mL. Results: Baseline characteristics (n = 440): mean age 45±14 years, 71% male, 43% abnormal ALT, 74% HBeAg-negative, 33% F3/F4 and 59% treatment-experienced (TE). VR = 96% at 3-year. HCC was reported in 3 cirrhotic patients. No major safety issues were reported. The most common AE were asthenia (n = 14) and gastrointestinal disorders (abdominal pain, nausea, vomiting, diarrhea). Forty-eight elderly patients were subsequently analyzed: mean age 71±6 years, 73% male, 35% hypertension, 17% diabetes, 58% F3/F4, 77% TE. VR didn’t differ between elderly and younger: 100% (26/26) vs 95% (222/233) at 3-year. HBsAg-loss in 11 patients (2 aged ≥65 years). Mean eGFR (CKD-EPI) was 97, 95, 95 and 94 mL/min at baseline, 1, 2 and 3 years and respectively 77, 71, 71 and 71 mL/min in elderly patients. Conclusions: After 3 years in clinical practice, TDF treatment was associated with a high virological response and a low number of HCC in accordance with phase III studies. Long term TDF-treatment presented a favorable safety profile in younger and elderly patients with comorbidities such as hypertension and diabetes. P1063 THE CHARACTERISTICS OF THE SYNONYMOUS CODON USAGE PATTERN OF rtN236T MUTATION IN CHRONIC HEPATITIS B PATIENTS TREATED WITH ADEFOVIR DIPIVOXIL: PYROSEQUENCING ANALYSIS OF 1418 CASES W. Hou, W. Lu. Tianjin Second People’s Hospital and Tianjin Institute of Hepatology, Tianjin, China E-mail: [email protected] Background and Aims: The rtN236T mutation in the D domain of the HBV DNA polymerase gene is associated with adefovir dipivoxil (ADV) treatment. The synonymous codon usage pattern of asparagine (N) substitution instead of threonine (T) is still unknown. The aim of this study was to analyze the codon usage pattern of rtN236T in chronic hepatitis B (CHB) patients treated with ADV. Methods: 1418 CHB inpatients and outpatients with ADV treatment from our hospital were enrolled in this study between Jan 2008 and Oct 2013. The rtN236T mutation of these HBV isolates was analyzed using a pyrosequencing method. Results: The synonymous codon usage patterns of rtN236T (N =AAC or AAU; T=ACC, ACU, ACA, or ACG) were as follows: For 1362 wide-type isolates, N/AAC (1246, 91.48%) > N/AAU (116, 8.52%).
50% (58/116) N/AAU wide-type isolates mixed with N/AAC widetype isolates. For 56 rtN236T variants, T/ACC (52, 92.86%) > T/ACU (4, 7.14%) > T/ACA (0%) or T/ACG (0%). For T/ACC variants, only 46.15% (24/52) of T/ACC variants were completely mutated, however, more than half of T/ACC (53.85%, 28/52) variants were always mixed with N/AAC wide-type isolates. For T/ACU variants, most of T/ACU (3.75%) variants were completely mutated, while only 25% (1/4) of T/ACU variants mixed with N/AAU wide-type isolates. Conclusions: We firstly show the synonymous codon usage pattern of rtN236T variants in HBV isolates. The synonymous codons of rtN236T variants are not chosen equally and randomly. N/AAC to T/ACC is predominant for rtN236T mutation. Supported partially by the National Natural Science Foundation of China (30800974, 81271845) and Tianjin Municipal Health Bureau of science and Technology Fund (2012KR02, 12KG118). P1064 RANDOMIZED TRIAL OF TENOFOVIR MONOTHERAPY VERSUS TENOFOVIR PLUS ENTECAVIR COMBINATION THERAPY IN CHRONIC HEPATITIS B PATIENTS WITH GENOTYPIC RESISTANCE MUTATIONS TO ADEFOVIR Y.-S. Lim1 , B.C. Yoo2 , K.S. Byun3 , S.Y. Kwon4 , Y.J. Kim5 , J. An1 , H.C. Lee1 , Y.S. Lee1 . 1 Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, 2 Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 3 Department of Internal Medicine, Korea University College of Medicine, Guro Hospital, 4 Department of Internal Medicine, Konkuk University School of Medicine, 5 Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea, Republic of E-mail: [email protected] Background and Aims: Antiviral efficacy of tenofovir monotherapy in patients who harbor adefovir-resistant hepatitis B virus (HBV) is controversial. Methods: In this multi-center open-label trial, patients who had HBV with genotypic resistance mutations to adefovir and serum HBV DNA concentration >60 IU/mL were randomized to tenofovir disoproxil fumarate (TDF, 300 mg/day) monotherapy (n = 50) or to TDF (300 mg/day) plus entecavir (ETV, 1 mg/day) combination therapy (n = 52), and were included in the intention-to-treat analyses. Results: At baseline, patients’ mean serum HBV DNA was 3.9 log10 IU/mL (SD 1.6). All 102 patients had documented adefovir-resistance mutations; 66 rtA181V/T, 6 rtN236T, and 30 rtA181V/T+rtN236T. Fifty-one patients also harbored lamivudine-resistance mutations, and 35 had resistance mutations to all of adefovir, lamivudine and entecavir. Two patients in TDF+ETV group withdrew at 4 weeks and 12 weeks, respectively. One-hundred patients completed 36 weeks of treatment. The number of patients with serum HBV DNA <15 IU/mL was similar between TDF group (n = 30, 60%) and TDF+ETV group (n = 30, 58%) at week 36 (P = 0.81). The mean reduction in HBV DNA levels from baseline was also similar between the two groups (−2.9 log10 IU/mL vs. −3.2 log10 IU/mL; P = 0.42). Virological breakthrough was observed in a patient in TDF group at 36 weeks of treatment, which was attributed to documented low adherence and resolved afterward. Safety and adverse event profiles were similar in the two groups. Conclusions: TDF monotherapy provides similar virological response compared with TDF+ETV combination therapy during 36 weeks of treatment in patients who have adefovir-resistant HBV. No patient developed virological breakthrough associated with TDFresistance.
Journal of Hepatology 2014 vol. 60 | S361–S522
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50% (58/116) N/AAU wide-type isolates mixed with N/AAC widetype isolates. For 56 rtN236T variants, T/ACC (52, 92.86%) > T/ACU (4, 7.14%) > T/ACA (0%) or T/ACG (0%). For T/ACC variants, only 46.15% (24/52) of T/ACC variants were completely mutated, however, more than half of T/ACC (53.85%, 28/52) variants were always mixed with N/AAC wide-type isolates. For T/ACU variants, most of T/ACU (3.75%) variants were completely mutated, while only 25% (1/4) of T/ACU variants mixed with N/AAU wide-type isolates. Conclusions: We firstly show the synonymous codon usage pattern of rtN236T variants in HBV isolates. The synonymous codons of rtN236T variants are not chosen equally and randomly. N/AAC to T/ACC is predominant for rtN236T mutation. Supported partially by the National Natural Science Foundation of China (30800974, 81271845) and Tianjin Municipal Health Bureau of science and Technology Fund (2012KR02, 12KG118). P1064 RANDOMIZED TRIAL OF TENOFOVIR MONOTHERAPY VERSUS TENOFOVIR PLUS ENTECAVIR COMBINATION THERAPY IN CHRONIC HEPATITIS B PATIENTS WITH GENOTYPIC RESISTANCE MUTATIONS TO ADEFOVIR Y.-S. Lim1 , B.C. Yoo2 , K.S. Byun3 , S.Y. Kwon4 , Y.J. Kim5 , J. An1 , H.C. Lee1 , Y.S. Lee1 . 1 Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, 2 Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, 3 Department of Internal Medicine, Korea University College of Medicine, Guro Hospital, 4 Department of Internal Medicine, Konkuk University School of Medicine, 5 Department of Internal Medicine and Liver Research Institute, Seoul National University College of Medicine, Seoul, Korea, Republic of E-mail: [email protected] Background and Aims: Antiviral efficacy of tenofovir monotherapy in patients who harbor adefovir-resistant hepatitis B virus (HBV) is controversial. Methods: In this multi-center open-label trial, patients who had HBV with genotypic resistance mutations to adefovir and serum HBV DNA concentration >60 IU/mL were randomized to tenofovir disoproxil fumarate (TDF, 300 mg/day) monotherapy (n = 50) or to TDF (300 mg/day) plus entecavir (ETV, 1 mg/day) combination therapy (n = 52), and were included in the intention-to-treat analyses. Results: At baseline, patients’ mean serum HBV DNA was 3.9 log10 IU/mL (SD 1.6). All 102 patients had documented adefovir-resistance mutations; 66 rtA181V/T, 6 rtN236T, and 30 rtA181V/T+rtN236T. Fifty-one patients also harbored lamivudine-resistance mutations, and 35 had resistance mutations to all of adefovir, lamivudine and entecavir. Two patients in TDF+ETV group withdrew at 4 weeks and 12 weeks, respectively. One-hundred patients completed 36 weeks of treatment. The number of patients with serum HBV DNA <15 IU/mL was similar between TDF group (n = 30, 60%) and TDF+ETV group (n = 30, 58%) at week 36 (P = 0.81). The mean reduction in HBV DNA levels from baseline was also similar between the two groups (−2.9 log10 IU/mL vs. −3.2 log10 IU/mL; P = 0.42). Virological breakthrough was observed in a patient in TDF group at 36 weeks of treatment, which was attributed to documented low adherence and resolved afterward. Safety and adverse event profiles were similar in the two groups. Conclusions: TDF monotherapy provides similar virological response compared with TDF+ETV combination therapy during 36 weeks of treatment in patients who have adefovir-resistant HBV. No patient developed virological breakthrough associated with TDFresistance.
Journal of Hepatology 2014 vol. 60 | S361–S522
S431