Hepatology Research 2015; 45: E43–E52
doi: 10.1111/hepr.12454
Original Article
Efficacy of tenofovir disoproxil fumarate therapy in Chinese chronic hepatitis B patients after multiple antiviral failures Yingxia Liu,1 Ying Zhang,1 Jing Yuan,1 Wen Zeng,1 Guoliang Zhang,1 Simin Yao,1 Huijuan Li,1 Min Yang,1 Yong Deng,1 Rongrong Zou,1 Shaxi Li1 and Jia Xiao1,2,3 1
State Key Discipline of Infectious Diseases, Department of Infectious Diseases, Shenzhen Third People’s Hospital, Shenzhen, 2Department of Immunobiology, Institute of Tissue Transplantation and Immunology, Jinan University, Guangzhou, and 3Department of Anatomy, The University of Hong Kong, Hong Kong, China Aim: In this prospective study, we aimed to evaluate the efficacy and safety of tenofovir disoproxil fumarate (TDF) in Chinese chronic hepatitis B (CHB) patients after multiple nucleoside/nucleotide analog (NA) treatment failures. Methods: A total of 115 Chinese CHB patients with suboptimal response to two or more NA treatments were included in this study. All patients were changed to TDF (300 mg/day, oral administration) antiviral treatment for at least 72 weeks. Hepatitis B virus (HBV) polymerase (P) gene mutation screening for each patient was performed. In addition, virological, biochemical responses and estimated glomerular filtration rate (eGFR) of each patient at weeks 12, 24, 48 and 72 of TDF treatment were evaluated.
complete viral response (CVR) of HBV DNA (72 weeks) therapeutic efficacy and safety of TDF for CHB patients who developed multiple NA treatment failures in China. We also investigated the involvement of HBV polymerase (P) gene mutation in the TDF therapy.
METHODS
T
HIS IS A prospective study. All patients in this study provided informed written consent. The study protocol was approved by the ethics committee of Shenzhen Third People’s Hospital. CHB patients were enrolled at the Department of Liver Diseases, Shenzhen Third People’s Hospital, from March 2012 to December 2012. A total of 115 eligible patients from 139 selected CHB patients with two or more NA treatment failures were enrolled in the current study. There were 93 male patients (80.9%) and 22 female patients (19.1%), with a median age of 37 years (range, 22–67). All selected patients were in accordance with The Guideline of Prevention and Treatment for Chronic Hepatitis B (2010 version) edited by Chinese Society of Hepatology and Chinese Society of Infectious Diseases, Chinese Medical Association.11 Treatment failure was defined as: (i) suboptimal response (HBV DNA 3100 IU/mL) to single ADV treatment for over 48 weeks and then combined with or changed to one of the other NA treatments
© 2014 The Japan Society of Hepatology
Hepatology Research 2015; 45: E43–E52
(LMV, telbivudine [LDT] or entecavir [ETV]) for another 24 weeks; or (ii) suboptimal response to single NA treatment (LMV, LDT or ETV) for 24 weeks and then in association with or changed to ADV for another 48 weeks. Exclusion criteria included co-infection with HIV or hepatitis C virus, and history of underlying renal problems. Detailed information regarding the excluded patients was presented in Figure S1. At the beginning of the study, all patients were orally treated with TDF monotherapy (300 mg/day; Gilead Sciences, Foster City, CA, USA). At each time point (week 12, 24, 48 and 72 of the TDF treatment), biochemical and virological responses, hepatitis B e-antigen (HBeAg) clearance and surface antigen (HBsAg) quantitative change, as well as safety assessments (renal function by estimated glomerular filtration rate [eGFR]) were conducted. The complete virological response (CVR) was defined as a HBV DNA level of less than 100 IU/mL. The entire study design is presented in Figure S1. This study was registered at the Chinese Clinical Trial Registry (no. ChiCTR-OCH-14004224, http://www.chictr .org/en/proj/show.aspx?proj=6404). The mutation of the HBV drug-resistance gene was detected by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS; Massarray, Sequenom, San Diego, CA, USA) according to the protocols reported by previous published work.12 All primers were purchased from Invitrogen (Shanghai, China). All other reagents were purchased from Sequenom unless specified. In this study, nine drug-resistance mutation sites (rtM204I/V, rtL180M, rtN236T, rtA181V/T, rtT184G, rtS202I and rtM250V) were detected according to the manufacturer’s instructions. Hepatitis B virus DNA was quantified by quantitative polymerase chain reaction (PCR) in ABI 7500 real-time PCR system (Applied Biosystems, Carlsbad, CA, USA) using reagents from PG Biotech (Shenzhen, China) and TaqMan probe provided by Applied Biosystems. Primer sequences were: forward 5′-ACTCACCAACCTCCTGT CCT-3′, reverse 5′-GACAAACGGGCAACATACCT-3′; and TaqMan probe, 5′-carboxyfluorescein (FAM)-TAT CGCTGGATGTGTCTGCGGCGT-carboxytetramethylrhodamine (TAMRA)-3′. Reaction conditions were: 50°C or 2 min; 94°C for 10 min; 94°C for 15 s; and 60°C for 1 min; for a total of 50 cycles. The detectable baseline level of HBV DNA was 100 IU/mL. HBsAg and HBeAg were measured by electrochemiluminescence quantitative assay in the Architect i2000SR system (Abbott Diagnostics, Abbott Park, IL, USA). HBsAg of more than 0.05 IU/mL was considered as positive and HBeAg of
Hepatology Research 2015; 45: E43–E52
TDF in NA failure Chinese CHB patients E45
Table 1 HBsAg (log10 IU/mL) changes along with the TDF therapy duration Group
HBsAg (log10 IU/mL)
HBV genotypic resistance† HBV DNA load‡
ADV-related R+ (n = 27) LMV R+ (n = 49) R− (n = 39) 3106 IU/mL (n = 35)
doi: 10.1111/hepr.12454
Original Article
Efficacy of tenofovir disoproxil fumarate therapy in Chinese chronic hepatitis B patients after multiple antiviral failures Yingxia Liu,1 Ying Zhang,1 Jing Yuan,1 Wen Zeng,1 Guoliang Zhang,1 Simin Yao,1 Huijuan Li,1 Min Yang,1 Yong Deng,1 Rongrong Zou,1 Shaxi Li1 and Jia Xiao1,2,3 1
State Key Discipline of Infectious Diseases, Department of Infectious Diseases, Shenzhen Third People’s Hospital, Shenzhen, 2Department of Immunobiology, Institute of Tissue Transplantation and Immunology, Jinan University, Guangzhou, and 3Department of Anatomy, The University of Hong Kong, Hong Kong, China Aim: In this prospective study, we aimed to evaluate the efficacy and safety of tenofovir disoproxil fumarate (TDF) in Chinese chronic hepatitis B (CHB) patients after multiple nucleoside/nucleotide analog (NA) treatment failures. Methods: A total of 115 Chinese CHB patients with suboptimal response to two or more NA treatments were included in this study. All patients were changed to TDF (300 mg/day, oral administration) antiviral treatment for at least 72 weeks. Hepatitis B virus (HBV) polymerase (P) gene mutation screening for each patient was performed. In addition, virological, biochemical responses and estimated glomerular filtration rate (eGFR) of each patient at weeks 12, 24, 48 and 72 of TDF treatment were evaluated.
complete viral response (CVR) of HBV DNA (72 weeks) therapeutic efficacy and safety of TDF for CHB patients who developed multiple NA treatment failures in China. We also investigated the involvement of HBV polymerase (P) gene mutation in the TDF therapy.
METHODS
T
HIS IS A prospective study. All patients in this study provided informed written consent. The study protocol was approved by the ethics committee of Shenzhen Third People’s Hospital. CHB patients were enrolled at the Department of Liver Diseases, Shenzhen Third People’s Hospital, from March 2012 to December 2012. A total of 115 eligible patients from 139 selected CHB patients with two or more NA treatment failures were enrolled in the current study. There were 93 male patients (80.9%) and 22 female patients (19.1%), with a median age of 37 years (range, 22–67). All selected patients were in accordance with The Guideline of Prevention and Treatment for Chronic Hepatitis B (2010 version) edited by Chinese Society of Hepatology and Chinese Society of Infectious Diseases, Chinese Medical Association.11 Treatment failure was defined as: (i) suboptimal response (HBV DNA 3100 IU/mL) to single ADV treatment for over 48 weeks and then combined with or changed to one of the other NA treatments
© 2014 The Japan Society of Hepatology
Hepatology Research 2015; 45: E43–E52
(LMV, telbivudine [LDT] or entecavir [ETV]) for another 24 weeks; or (ii) suboptimal response to single NA treatment (LMV, LDT or ETV) for 24 weeks and then in association with or changed to ADV for another 48 weeks. Exclusion criteria included co-infection with HIV or hepatitis C virus, and history of underlying renal problems. Detailed information regarding the excluded patients was presented in Figure S1. At the beginning of the study, all patients were orally treated with TDF monotherapy (300 mg/day; Gilead Sciences, Foster City, CA, USA). At each time point (week 12, 24, 48 and 72 of the TDF treatment), biochemical and virological responses, hepatitis B e-antigen (HBeAg) clearance and surface antigen (HBsAg) quantitative change, as well as safety assessments (renal function by estimated glomerular filtration rate [eGFR]) were conducted. The complete virological response (CVR) was defined as a HBV DNA level of less than 100 IU/mL. The entire study design is presented in Figure S1. This study was registered at the Chinese Clinical Trial Registry (no. ChiCTR-OCH-14004224, http://www.chictr .org/en/proj/show.aspx?proj=6404). The mutation of the HBV drug-resistance gene was detected by matrix-assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS; Massarray, Sequenom, San Diego, CA, USA) according to the protocols reported by previous published work.12 All primers were purchased from Invitrogen (Shanghai, China). All other reagents were purchased from Sequenom unless specified. In this study, nine drug-resistance mutation sites (rtM204I/V, rtL180M, rtN236T, rtA181V/T, rtT184G, rtS202I and rtM250V) were detected according to the manufacturer’s instructions. Hepatitis B virus DNA was quantified by quantitative polymerase chain reaction (PCR) in ABI 7500 real-time PCR system (Applied Biosystems, Carlsbad, CA, USA) using reagents from PG Biotech (Shenzhen, China) and TaqMan probe provided by Applied Biosystems. Primer sequences were: forward 5′-ACTCACCAACCTCCTGT CCT-3′, reverse 5′-GACAAACGGGCAACATACCT-3′; and TaqMan probe, 5′-carboxyfluorescein (FAM)-TAT CGCTGGATGTGTCTGCGGCGT-carboxytetramethylrhodamine (TAMRA)-3′. Reaction conditions were: 50°C or 2 min; 94°C for 10 min; 94°C for 15 s; and 60°C for 1 min; for a total of 50 cycles. The detectable baseline level of HBV DNA was 100 IU/mL. HBsAg and HBeAg were measured by electrochemiluminescence quantitative assay in the Architect i2000SR system (Abbott Diagnostics, Abbott Park, IL, USA). HBsAg of more than 0.05 IU/mL was considered as positive and HBeAg of
Hepatology Research 2015; 45: E43–E52
TDF in NA failure Chinese CHB patients E45
Table 1 HBsAg (log10 IU/mL) changes along with the TDF therapy duration Group
HBsAg (log10 IU/mL)
HBV genotypic resistance† HBV DNA load‡
ADV-related R+ (n = 27) LMV R+ (n = 49) R− (n = 39) 3106 IU/mL (n = 35)
