Impact of reverse transcriptase resistance on the efficacy of TMC125 (etravirine) with two nucleoside reverse transcriptase inhibitors in protease inhibitor-naïve, nonnucleoside reverse transcriptase inhibitor-experienced patients: study TMC125-C227
K Ruxrungtham, R J Pedro, G H Latiff, F Conradie, P Domingo, S Lupo, W Pumpradit, J H Vingerhoets, M Peeters, I Peeters, T N Kakuda, G De Smedt, B Woodfall, TMC125-C227 study group, Pedro Cahn, Patricia Patterson, Carlos Zala, Alejandro Krolewiecki, Claudia Elena Ochoa, Pablo Parenti, Claudia Suarez, Marcelo Losso, Silvia Ivalo, Adriana Duran, Leonardo Lourteau, Javier Toibaro, Isabel Cassetti, Claudia Vanzulli, Marcelo Laurido, Gabriela Bugarin, Gabriela Trinidad, Analia Urueña, Rosa Bologna, Jorge Benetucci, Artur Timerman, Ricardo Vipich, Sandra Tardochi, Juvencio Furtado, José Valdez Madruga, Roberta Noguiera, Suzane Leme, Denise Estevam, Marta Ramalho, Fabio Araujo, Mylva Fonsi, Eduardo Franco, Rita Sartio, Maura Silveira, Dinalda Monteiro, Mariana Carvalho, Mariangela Resende, Monica de Moraes, William Abreu, Ana Lucia Krzesinski, Clóvis Arns da Cunha, Rodrigo Reis, Jaime Rocha, Maria Kuchiki, Paula Toledo, Silvia De Rossi, Mirian Carvalho, Monica da Silva, Beatriz Grinsztejn, Jorge Ribeiro, Jose Pilotto, Anita Silva, Junia Rodrigues, Ruth Friedman, Valeria Rolla, Brenda Hoagland, Carla Vorsatz, Monica Barros, Sandra Cardoso, Jaime Andrade Villanueva, Gemma Chávez, Luz Alicia Gonzalez, Fernando Amador, Elena Vinogradova, Natalia Zakharova, Anna Vinogradova, Olga Leonova, Ludmila Krutitskaya, Natalia Badosova, Yelena Semushina, Alexey Yakovlev, Nadezhda Burova, Ludmila Abrosimova, Zoya Kingo, Grigory Moshkovich, Stella Minaeva, Mariya Goryaeva, Oleg Kozyrev, Igor Malyuzhenko, Maria Malyuzhenko, Oleg Romanenko, Margarita Makarova, Elina Zamyatina, Faniya Siraziyeva, Rostislav Mikusev, Vladimir Koksin, Valery Shoshokin, Lerato Mohapi, Mellicent Khosa, Ditabe Mohohlo, Prudensce Ive, Melanie-Ann John, Dennis Rubel, Ian Sanne, Cynthia Firnhaberr, David Spencer, Joyce Marshall, Mukesh Raniga, Ezio Baraldi, Mauricio Itturalde, Daniel Podzamczer, Elena Corbera, Montserrat Plaza, Pilar Guillen, Montse Fuster, Maria-Antonia Sambeat, Gracia García, Josep Cadafalch, Maria del Mar Gutiérrez Macià, Koldo Aguirrebengoa, Josune Goicoetxea, Miguel Montejo, Ignacio de los Santos Gil, Raquel Carrillo Gómez, Jesús Sanz, Chaiwat Ungsedhapand, Chris Duncomb, Juntanat Ananworanich, Saskia Autar, Anchalee Avihingsanon, Torsak Bunupuradah, Phillip Hay, Prasad Velisetty, Derek Macallan, Tariq Sadiq, Richard Lau, Paul Brennan-Benson, Mark Pakianathan, Janet Mantell, Brian Gazzard, Desmond Maitland, Akil Jackson, Alastair Teague, K Ruxrungtham, R J Pedro, G H Latiff, F Conradie, P Domingo, S Lupo, W Pumpradit, J H Vingerhoets, M Peeters, I Peeters, T N Kakuda, G De Smedt, B Woodfall, TMC125-C227 study group, Pedro Cahn, Patricia Patterson, Carlos Zala, Alejandro Krolewiecki, Claudia Elena Ochoa, Pablo Parenti, Claudia Suarez, Marcelo Losso, Silvia Ivalo, Adriana Duran, Leonardo Lourteau, Javier Toibaro, Isabel Cassetti, Claudia Vanzulli, Marcelo Laurido, Gabriela Bugarin, Gabriela Trinidad, Analia Urueña, Rosa Bologna, Jorge Benetucci, Artur Timerman, Ricardo Vipich, Sandra Tardochi, Juvencio Furtado, José Valdez Madruga, Roberta Noguiera, Suzane Leme, Denise Estevam, Marta Ramalho, Fabio Araujo, Mylva Fonsi, Eduardo Franco, Rita Sartio, Maura Silveira, Dinalda Monteiro, Mariana Carvalho, Mariangela Resende, Monica de Moraes, William Abreu, Ana Lucia Krzesinski, Clóvis Arns da Cunha, Rodrigo Reis, Jaime Rocha, Maria Kuchiki, Paula Toledo, Silvia De Rossi, Mirian Carvalho, Monica da Silva, Beatriz Grinsztejn, Jorge Ribeiro, Jose Pilotto, Anita Silva, Junia Rodrigues, Ruth Friedman, Valeria Rolla, Brenda Hoagland, Carla Vorsatz, Monica Barros, Sandra Cardoso, Jaime Andrade Villanueva, Gemma Chávez, Luz Alicia Gonzalez, Fernando Amador, Elena Vinogradova, Natalia Zakharova, Anna Vinogradova, Olga Leonova, Ludmila Krutitskaya, Natalia Badosova, Yelena Semushina, Alexey Yakovlev, Nadezhda Burova, Ludmila Abrosimova, Zoya Kingo, Grigory Moshkovich, Stella Minaeva, Mariya Goryaeva, Oleg Kozyrev, Igor Malyuzhenko, Maria Malyuzhenko, Oleg Romanenko, Margarita Makarova, Elina Zamyatina, Faniya Siraziyeva, Rostislav Mikusev, Vladimir Koksin, Valery Shoshokin, Lerato Mohapi, Mellicent Khosa, Ditabe Mohohlo, Prudensce Ive, Melanie-Ann John, Dennis Rubel, Ian Sanne, Cynthia Firnhaberr, David Spencer, Joyce Marshall, Mukesh Raniga, Ezio Baraldi, Mauricio Itturalde, Daniel Podzamczer, Elena Corbera, Montserrat Plaza, Pilar Guillen, Montse Fuster, Maria-Antonia Sambeat, Gracia García, Josep Cadafalch, Maria del Mar Gutiérrez Macià, Koldo Aguirrebengoa, Josune Goicoetxea, Miguel Montejo, Ignacio de los Santos Gil, Raquel Carrillo Gómez, Jesús Sanz, Chaiwat Ungsedhapand, Chris Duncomb, Juntanat Ananworanich, Saskia Autar, Anchalee Avihingsanon, Torsak Bunupuradah, Phillip Hay, Prasad Velisetty, Derek Macallan, Tariq Sadiq, Richard Lau, Paul Brennan-Benson, Mark Pakianathan, Janet Mantell, Brian Gazzard, Desmond Maitland, Akil Jackson, Alastair Teague
Abstract
Objectives: TMC125-C227, an exploratory phase II, randomized, controlled, open-label trial, compared the efficacy and safety of TMC125 (etravirine) with an investigator-selected protease inhibitor (PI) in nonnucleoside reverse transcriptase inhibitor (NNRTI)-resistant, protease inhibitor-naïve, HIV-1-infected patients.
Methods: Patients were randomized to TMC125 800 mg twice a day (bid) (phase II formulation; n=59) or the control PI (n=57), plus two nucleoside reverse transcriptase inhibitors (NRTIs).
Results: In an unplanned interim analysis, patients receiving TMC125 demonstrated suboptimal virological responses relative to the control PI. Therefore, trial enrolment was stopped prematurely and TMC125 treatment discontinued after a median of 14.3 weeks. In this first-line NNRTI-failure population, baseline NRTI and NNRTI resistance was high and reduced virological responses were observed relative to the control PI. No statistically significant relationship was observed between TMC125 exposure and virological response at week 12. TMC125 was better tolerated than a boosted PI for gastrointestinal-, lipid- and liver-related events.
Conclusions: In a PI-naïve population, with baseline NRTI and NNRTI resistance and NRTI recycling, TMC125 was not as effective as first use of a PI. Therefore the use of TMC125 plus NRTIs alone may not be optimal in PI-naïve patients with first-line virological failure on an NNRTI-based regimen. Baseline two-class resistance, rather than pharmacokinetics or other factors, was the most likely reason for suboptimal responses.
Trial registration: ClinicalTrials.gov NCT00225303.
Source: PubMed