Treatment for preventing tuberculosis in children and adolescents: a randomized clinical trial of a 3-month, 12-dose regimen of a combination of rifapentine and isoniazid
M Elsa Villarino, Nigel A Scott, Stephen E Weis, Marc Weiner, Marcus B Conde, Brenda Jones, Sharon Nachman, Ricardo Oliveira, Ruth N Moro, Nong Shang, Stefan V Goldberg, Timothy R Sterling, International Maternal Pediatric and Adolescents AIDS Clinical Trials Group, Tuberculosis Trials Consortium, Stephen E Weis, Michel Fernandez, Barbara King, Lee Turk, Norma Shafer, Gloria Stevenson, Guadalupe Bayona, Randy Dean, Joseph Helal, Gerry Burgess, Richard Wing, Diane Wing, Diana Valenzuela, Josefina Gonzalez, Brian R Smith, Juan Uribe, Clementino Fraga Filho, Richard E Chaisson, Marcus B Conde, Fernanda C Q Mello, Anne Efron, Carla Loredo, Millene Barty, S Fortuna, Michelle Cailleaux-Cezar, Renata L Guerra, Gisele Mota, Cristina Felix, Valéria de Oliveira, Claudeci dos S Sacramento, Brenda E Jones, Patricio Escalante, Peregrina Molina, Claudia Silva, Angela Grbic, Maria Brown, Bonifacia Oamar, Ermelinda Rayos, Celia Luken, Patricia Lopez, Michiko Otaya, Marc Weiner, Melissa Engle, Jose A Jimenez, Hipolito Pavon, Victoria Rodriguez, John Nava, William Burman, Randall Reves, Robert Belknap, David Cohn, Jan Tapy, Grace Sanchez, Laurie Luna, Jacquie Moore, Antonino Catanzaro, Philip LoBue, Kathleen Moser, Mark Tracy, Peach Francisco, Judy Davis, Neil Schluger, Joseph Burzynski, Vilma Lozano, Magda Wolk, Marta Scotto, Carol Dukes Hamilton, Jason Stout, Ann Mosher, Emily J Hecker, Elle Rich, Masahiro Narita, Charles M Nolan, Stefan Goldberg, Debra Schwartz, Linh Le, Marcia Stone, Connie Friedly, Payam Nahid, Philip Hopewell, Charles Daley, Robert Jasmer, Cindy Merrifield, William Stanton, Irina Rudoy, Jill Israel, Bonita T Mangura, Lee B Reichman, George McSherry, Alfred Lardizabal, Maria Corazon Leus, Marilyn Owens, Eileen Napolitano, Laurie Kellert, Veronica Anokute, Iram Bakhtawar, Frank Wilson, Pauline Wassler, Annette Arnold, Kathy Haden, Jamie Owens, Timothy R Sterling, Amy Kerrigan, Alicia Wright, Linda R Hammock, Belinda Redd, Camille Campbell, Diedra Freeman, Susan M Ray, David P Holland, Deirdre Dixon, Omar Mohamed, Kanoa Folami, Jane Bush, Cheryl D Simpson, Gibson Barika, Wenona N Favors, Nicole Snow, Dick Menzies, Kevin Schwartzman, Christina Greenaway, Larry Lands, Sharyn Mannix, Paul Brassard, Bérénice Mortezai, Barry Rabinovitch, Marthe Pelletier, Chantal Valiquette, Joanne Tremblay, Paul Anglade Plaisir, Rebecca Binet, Amina Ahmed, Jennifer Reeves, Richard E Chaisson, Susan Dorman, Jim Fisher, Gina Maltas, Judith Hackman, John Bernardo, Jussi Saukkonen, Claire Murphy, Denise Brett-Curran, Wayne Kepron, Earl Hershfield, Marian Roth, Gerry A Izon, J Mark Fitzgerald, Kevin Elwood, Eduardo Hernandez, Banafsheh Peyvandi, Kadria Alasaly, Chi-Chiu Leung, Kwok-Chiu Chang, Sik-Wai Tam, Cheuk-Ming Tam, Sau-Yin Tam, Ida Ka-Yun Mak, Ka-Lin Fong, Nai-Chung Lee, Kai-Man Kam, Chi-Wai Yip, Judy Yee-Man Lam, Chi-Wai Ng, Oi-Wah Fong, Edman Tin-Keung Lam, Chung-Ying Wong, Joan A Cayla, Jose M Miró, Maria Antonia Sambeat, Jose L López Colomés, José A Martinez, Xavier Martinez-Lacasa, Angels Orcau, Paquita Sanchez, Cecilia Tortajada, Imma Ocana, Juan P Millet, Antonio Moreno, Jeanne Nelson, Omar Sued, Maria Luiza de Souza, María A Jiménez, Lucía del Baño, Laia Fina, Ricardo Hugo Oliveira, Maria C Chermont Sapia, Luiz Marcelo Lira, Humberto Carreira Junior, Cristina Hofer, Thalita Fernandes de Abreu, Anna Cisne Frota, Luanda Papi, Jose Henrique Pilotto, Andrea dos Santos Gouveia, Ana Valeria Cordovil, Ivete Martins Gomes, Priscila Mazucanti, Aves Carneiro Junior, Maria Leticia Santos Cruz, Esau Joao, Leon Sidi, José Carlos Cruz, Fellipe Lattanzi, Elaine Santos, Deisi Scheiner Torgecki, Marisa Márcia Mussi-Pinhata, Marcia de Lima Isaac, Julio Cesar Gabaldi, Adriana A Tiraboschi Barbaro, Bento Vidal de Moura Negrini, Fernanda Tome Sturzbecher, Maria Celia Cervi, Jorge Andrade Pinto, Fabiana Maria Kakehasi, Juliana Ribeiro Romeiro, Marcelle Martins Maia, Flavia Faleiro Ferreira, Christine Eng, Awal Khan, George McSherry, Timothy R Sterling, Elsa Villarino, Constance Benson, Andrey Borisov, Nong Shang, Richard E Chaisson, Carol Dukes Hamilton, Fred Gordin, Judith Hackman, C Robert Horsburgh Jr, Amy Kerrigan, Erin Bliven-Sizemore, Richard I Menzies, Sharon Nachman, Amina Ahmed, Constance Benson, Kenneth G Castro, Mark Cotton, John Johnson, Wing-wai Yew, George McSherry, Jeffrey Starke, M Elsa Villarino, Nigel A Scott, Stephen E Weis, Marc Weiner, Marcus B Conde, Brenda Jones, Sharon Nachman, Ricardo Oliveira, Ruth N Moro, Nong Shang, Stefan V Goldberg, Timothy R Sterling, International Maternal Pediatric and Adolescents AIDS Clinical Trials Group, Tuberculosis Trials Consortium, Stephen E Weis, Michel Fernandez, Barbara King, Lee Turk, Norma Shafer, Gloria Stevenson, Guadalupe Bayona, Randy Dean, Joseph Helal, Gerry Burgess, Richard Wing, Diane Wing, Diana Valenzuela, Josefina Gonzalez, Brian R Smith, Juan Uribe, Clementino Fraga Filho, Richard E Chaisson, Marcus B Conde, Fernanda C Q Mello, Anne Efron, Carla Loredo, Millene Barty, S Fortuna, Michelle Cailleaux-Cezar, Renata L Guerra, Gisele Mota, Cristina Felix, Valéria de Oliveira, Claudeci dos S Sacramento, Brenda E Jones, Patricio Escalante, Peregrina Molina, Claudia Silva, Angela Grbic, Maria Brown, Bonifacia Oamar, Ermelinda Rayos, Celia Luken, Patricia Lopez, Michiko Otaya, Marc Weiner, Melissa Engle, Jose A Jimenez, Hipolito Pavon, Victoria Rodriguez, John Nava, William Burman, Randall Reves, Robert Belknap, David Cohn, Jan Tapy, Grace Sanchez, Laurie Luna, Jacquie Moore, Antonino Catanzaro, Philip LoBue, Kathleen Moser, Mark Tracy, Peach Francisco, Judy Davis, Neil Schluger, Joseph Burzynski, Vilma Lozano, Magda Wolk, Marta Scotto, Carol Dukes Hamilton, Jason Stout, Ann Mosher, Emily J Hecker, Elle Rich, Masahiro Narita, Charles M Nolan, Stefan Goldberg, Debra Schwartz, Linh Le, Marcia Stone, Connie Friedly, Payam Nahid, Philip Hopewell, Charles Daley, Robert Jasmer, Cindy Merrifield, William Stanton, Irina Rudoy, Jill Israel, Bonita T Mangura, Lee B Reichman, George McSherry, Alfred Lardizabal, Maria Corazon Leus, Marilyn Owens, Eileen Napolitano, Laurie Kellert, Veronica Anokute, Iram Bakhtawar, Frank Wilson, Pauline Wassler, Annette Arnold, Kathy Haden, Jamie Owens, Timothy R Sterling, Amy Kerrigan, Alicia Wright, Linda R Hammock, Belinda Redd, Camille Campbell, Diedra Freeman, Susan M Ray, David P Holland, Deirdre Dixon, Omar Mohamed, Kanoa Folami, Jane Bush, Cheryl D Simpson, Gibson Barika, Wenona N Favors, Nicole Snow, Dick Menzies, Kevin Schwartzman, Christina Greenaway, Larry Lands, Sharyn Mannix, Paul Brassard, Bérénice Mortezai, Barry Rabinovitch, Marthe Pelletier, Chantal Valiquette, Joanne Tremblay, Paul Anglade Plaisir, Rebecca Binet, Amina Ahmed, Jennifer Reeves, Richard E Chaisson, Susan Dorman, Jim Fisher, Gina Maltas, Judith Hackman, John Bernardo, Jussi Saukkonen, Claire Murphy, Denise Brett-Curran, Wayne Kepron, Earl Hershfield, Marian Roth, Gerry A Izon, J Mark Fitzgerald, Kevin Elwood, Eduardo Hernandez, Banafsheh Peyvandi, Kadria Alasaly, Chi-Chiu Leung, Kwok-Chiu Chang, Sik-Wai Tam, Cheuk-Ming Tam, Sau-Yin Tam, Ida Ka-Yun Mak, Ka-Lin Fong, Nai-Chung Lee, Kai-Man Kam, Chi-Wai Yip, Judy Yee-Man Lam, Chi-Wai Ng, Oi-Wah Fong, Edman Tin-Keung Lam, Chung-Ying Wong, Joan A Cayla, Jose M Miró, Maria Antonia Sambeat, Jose L López Colomés, José A Martinez, Xavier Martinez-Lacasa, Angels Orcau, Paquita Sanchez, Cecilia Tortajada, Imma Ocana, Juan P Millet, Antonio Moreno, Jeanne Nelson, Omar Sued, Maria Luiza de Souza, María A Jiménez, Lucía del Baño, Laia Fina, Ricardo Hugo Oliveira, Maria C Chermont Sapia, Luiz Marcelo Lira, Humberto Carreira Junior, Cristina Hofer, Thalita Fernandes de Abreu, Anna Cisne Frota, Luanda Papi, Jose Henrique Pilotto, Andrea dos Santos Gouveia, Ana Valeria Cordovil, Ivete Martins Gomes, Priscila Mazucanti, Aves Carneiro Junior, Maria Leticia Santos Cruz, Esau Joao, Leon Sidi, José Carlos Cruz, Fellipe Lattanzi, Elaine Santos, Deisi Scheiner Torgecki, Marisa Márcia Mussi-Pinhata, Marcia de Lima Isaac, Julio Cesar Gabaldi, Adriana A Tiraboschi Barbaro, Bento Vidal de Moura Negrini, Fernanda Tome Sturzbecher, Maria Celia Cervi, Jorge Andrade Pinto, Fabiana Maria Kakehasi, Juliana Ribeiro Romeiro, Marcelle Martins Maia, Flavia Faleiro Ferreira, Christine Eng, Awal Khan, George McSherry, Timothy R Sterling, Elsa Villarino, Constance Benson, Andrey Borisov, Nong Shang, Richard E Chaisson, Carol Dukes Hamilton, Fred Gordin, Judith Hackman, C Robert Horsburgh Jr, Amy Kerrigan, Erin Bliven-Sizemore, Richard I Menzies, Sharon Nachman, Amina Ahmed, Constance Benson, Kenneth G Castro, Mark Cotton, John Johnson, Wing-wai Yew, George McSherry, Jeffrey Starke
Abstract
Importance: Three months of a once-weekly combination of rifapentine and isoniazid for treatment of latent tuberculosis infection is safe and effective for persons 12 years or older. Published data for children are limited.
Objectives: To compare treatment safety and assess noninferiority treatment effectiveness of combination therapy with rifapentine and isoniazid vs 9 months of isoniazid treatment for latent tuberculosis infection in children.
Design, setting, and participants: A pediatric cohort nested within a randomized, open-label clinical trial conducted from June 11, 2001, through December 17, 2010, with follow-up through September 5, 2013, in 29 study sites in the United States, Canada, Brazil, Hong Kong (China), and Spain. Participants were children (aged 2-17 years) who were eligible for treatment of latent tuberculosis infection.
Interventions: Twelve once-weekly doses of the combination drugs, given with supervision by a health care professional, for 3 months vs 270 daily doses of isoniazid, without supervision by a health care professional, for 9 months.
Main outcomes and measures: We compared rates of treatment discontinuation because of adverse events (AEs), toxicity grades 1 to 4, and deaths from any cause. The equivalence margin for the comparison of AE-related discontinuation rates was 5%. Tuberculosis disease diagnosed within 33 months of enrollment was the main end point for testing effectiveness. The noninferiority margin was 0.75%.
Results: Of 1058 children enrolled, 905 were eligible for evaluation of effectiveness. Of 471 in the combination-therapy group, 415 (88.1%) completed treatment vs 351 of 434 (80.9%) in the isoniazid-only group (P = .003). The 95% CI for the difference in rates of discontinuation attributed to an AE was -2.6 to 0.1, which was within the equivalence range. In the safety population, 3 of 539 participants (0.6%) who took the combination drugs had a grade 3 AE vs 1 of 493 (0.2%) who received isoniazid only. Neither arm had any hepatotoxicity, grade 4 AEs, or treatment-attributed death. None of the 471 in the combination-therapy group developed tuberculosis vs 3 of 434 (cumulative rate, 0.74%) in the isoniazid-only group, for a difference of -0.74% and an upper bound of the 95% CI of the difference of +0.32%, which met the noninferiority criterion.
Conclusions and relevance: Treatment with the combination of rifapentine and isoniazid was as effective as isoniazid-only treatment for the prevention of tuberculosis in children aged 2 to 17 years. The combination-therapy group had a higher treatment completion rate than did the isoniazid-only group and was safe.
Trial registration: clinicaltrials.gov Identifier: NCT00023452.
Conflict of interest statement
Conflict of Interest Disclosures: Mr Scott and Dr Moro report being employed by the CDC Foundation, which receives funds for rifapentine research from Sanofi. Dr Weiner reports receiving a grant to perform rifapentine pharmacokinetics studies in children and adults for the University of Texas Health Science Center at San Antonio from Sanofi. Dr Sterling reports giving a 1-day consultation for Sanofi for presentation of PREVENT TB study data to the US Food and Drug Administration and being on the data safety monitoring board for a clinical trial sponsored by Otsuka Pharmaceutical. No other disclosures were reported.
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Source: PubMed