Randomized Controlled Trial
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Nov 7, 2017; 23(41): 7459-7469
Published online Nov 7, 2017. doi: 10.3748/wjg.v23.i41.7459
Tenofovir vs lamivudine plus adefovir in chronic hepatitis B: TENOSIMP-B study
Manuel Rodríguez, Juan Manuel Pascasio, Enrique Fraga, Javier Fuentes, Martín Prieto, Gloria Sánchez-Antolín, José Luis Calleja, Esther Molina, María Luisa García-Buey, María Ángeles Blanco, Javier Salmerón, María Lucía Bonet, José Antonio Pons, José Manuel González, Miguel Ángel Casado, Francisco Jorquera, the TENOSIMP-B Research Group
Manuel Rodríguez, Division of Gastroenterology and Hepatology. Hospital Universitario Central de Asturias, Oviedo 33011, Spain
Juan Manuel Pascasio, Unit for the Clinical Management of Digestive Diseases, IBIS, Hospital Universitario Virgen del Rocío, Sevilla 41013, Spain and CIBERehd
Enrique Fraga, Liver Transplantation and Hepatology Unit, Gastroenterology Service, Hospital Universitario Reina Sofía, Córdoba 14004, Spain
Javier Fuentes, Digestive Medicine Service, Hospital Universitario Miguel Servet, Zaragoza 50009, Spain
Martín Prieto, Hepatology Unit, Digestive Medicine Service, Hospital Universitari i Politècnic La Fe, Valencia 46026, Spain and CIBERehd
Gloria Sánchez-Antolín, Hepatology Unit, Hospital Universitario Rio Hortega, Valladolid 47012, Spain
José Luis Calleja, Liver Unit, Hospital Universitario Puerta de Hierro de Majadahonda, Universidad Autónoma de Madrid, Madrid 28049, Spain
Esther Molina, Digestive Medicine Service, Hospital Clínico de Santiago de Compostela, La Coruña 15706, Spain
María Luisa García-Buey, Liver Unit, Hospital Universitario de La Princesa, Madrid 28006, Spain and CIBERehd
María Ángeles Blanco, Digestive Medicine Service, Hospital General Universitario Gregorio Marañón, Madrid 28007, España
Javier Salmerón, Digestive Medicine Unit, Complejo Hospitalario de Granada, Granada 18014, Spain
María Lucía Bonet, Digestive Medicine Service, Hospital Universitario Son Espases, Palma de Mallorca 07120, Spain
José Antonio Pons, Hepatology Unit, IMIB Hospital Universitario Virgen de la Arrixaca, Murcia 30120, Spain
José Manuel González, Digestive Medicine Service, Hospital Clínico Universitario de Valladolid, Valladolid 47003, Spain
Miguel Ángel Casado, Pharmacoeconomics and Outcomes Research Iberia, Madrid 28224, Spain
Francisco Jorquera, Division of Gastroenterology and Hepatology, Complejo Asistencial Universitario de León, León 24001, Spain CIBERehd and IBIOMED León.
Author contributions: Rodríguez M and Jorquera F participated in the recruitment of patients, data collection and wrote the manuscript; Pascasio JM, Fraga E, Fuentes J, Prieto M, Sánchez-Antolín G, Calleja JL, Molina E, García-Buey ML, Blanco MÁ, Salmerón J, Bonet ML, Pons JA, González JM participated in the recruitment of patients and data collection; Casado MA was involved in data analysis and wrote the manuscript.
Institutional review board statement: The study was approved and authorized by the Medication Research Ethics Committee [Comité de Ética de la Investigación con medicamentos (CEIm)] of the Hospital Universitario Central de Asturias (Oviedo, Asturias, Spain), and the Spanish Pharmaceutical and Healthcare Products Agency [Agencia Española de Medicamentos y Productos Sanitarios (AEMPS)] was notified of the study.
Conflict-of-interest statement: Manuel Rodríguez consults for and is on the speaker’s bureau for Gilead and AbbVie. Juan Manuel Pascasio consults for and expert advice for BMS, Gilead, AbbVie, MSD and Janssen. Enrique Fraga consults for and is on the speaker’s bureau for Gilead, MSD, BMS and AbbVie. Martín Prieto participates in advisory board for AbbVie, Bristol-Myers, Gilead, Janssen and MSD and in lectures for Bristol-Myers, Gilead, Janssen, Janssen and MSD. José Luis Calleja consults for and is on the speaker’s bureau for: BMS and Gilead. María Luisa Garcia-Buey consults for and is on the speakers´s bureau for AbbVie, Janssen, and Gilead. The remaining authors declare that they have no conflicts of interest.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Manuel Rodríguez, MD, Liver Unit, Division of Gastroenterology and Hepatology, Hospital Universitario Central de Asturias, 33011 Oviedo, Spain. amunoz@porib.com
Telephone: +34-609-744058
Received: March 25, 2017
Peer-review started: March 29, 2017
First decision: April 20, 2017
Revised: May 22, 2017
Accepted: June 18, 2017
Article in press: June 19, 2017
Published online: November 7, 2017
Processing time: 224 Days and 9.5 Hours
Abstract
AIM

To demonstrate the non-inferiority (15% non-inferiority limit) of monotherapy with tenofovir disoproxil fumarate (TDF) vs the combination of lamivudine (LAM) plus adefovir dipivoxil (ADV) in the maintenance of virologic response in patients with chronic hepatitis B (CHB) and prior failure with LAM.

METHODS

This study was a Phase IV prospective, randomized, open, controlled study with 2 parallel groups (TDF and LAM+ADV) of adult patients with hepatitis B e antigen (HBeAg)-negative CHB, prior failure with LAM, on treatment with LAM+ADV for at least 6 mo, without prior resistance to ADV and with an undetectable viral load at the start of the study, in 14 Spanish hospitals. The follow-up time for each patient was 48 wk after randomization, with quarterly visits in which the viral load, biochemical and serological parameters, adverse effects, adherence to treatment and consumption of hospital resources were analysed.

RESULTS

Forty-six patients were evaluated [median age: 55.4 years (30.2-75.2); 84.8% male], including 22 patients with TDF and 24 with LAM+ADV. During study development, hepatitis B virus DNA (HBV-DNA) remained undetectable, all patients remained HBeAg negative, and hepatitis B surface antigen (HBsAg) positive. Alanine aminotransferase (ALT) values at the end of the study were similar in the 2 groups (25.1 ± 7.65, TDF vs 24.22 ± 8.38, LAM+ADV, P = 0.646). No significant changes were observed in creatinine or serum phosphorus values in either group. No significant differences between the 2 groups were noted in the identification of adverse effects (AEs) (53.8%, TDF vs 37.5%, LAM+ADV, P = 0.170), and none of the AEs which occurred were serious. Treatment adherence was 95.5% and 83.3% in the TDF and the LAM+ADV groups, respectively (P = 0.488). The costs associated with hospital resource consumption were significantly lower with the TDF treatment than the LAM+ADV treatment (€4943 ± 1059 vs €5811 ± 1538, respectively, P < 0.001).

CONCLUSION

TDF monotherapy proved to be safe and not inferior to the LAM+ADV combination therapy in maintaining virologic response in patients with CHB and previous LAM failure. In addition, the use of TDF generated a significant savings in hospital costs.

Keywords: Tenofovir; Lamivudine+Adefovir; Efficacy; Safety; Adherence; Costs; Hepatitis B

Core tip: The Tenosimp-B study was performed to demonstrate the non-inferiority (15% non-inferiority limit) of tenofovir disoproxil fumarate (TDF) monotherapy versus the combination of lamivudine+adefovir (LAM+ADF) in 46 patients with chronic hepatitis B (CHB) and resistance to LAM (22 with TDF and 24 with LAM+ADV). TDF demonstrated its safety (no significant differences in adverse events (AEs), kidney function or liver function) and non-inferiority in maintaining virologic response [undetectable hepatitis B virus DNA (HBV-DNA) and negative for hepatitis B e antigen (HBeAg)] during the study, without differences in adherence to treatment. Additionally, the use of TDF resulted in significant savings in hospital costs.