Tuberculosis treatment intermittency in the continuation phase and mortality in HIV-positive persons receiving antiretroviral therapy
Authors: Crabtree-Ramirez Brenda , Jenkins Cathy A. , Shepherd Bryan E. , Jayathilake Karu , Veloso Valdilea G. , Carriquiry Gabriela , Gotuzzo Eduardo , Cortes Claudia P. , Padgett Dennis , McGowan Catherine , Sierra-Madero Juan , Koenig Serena , Pape Jean W. , Sterling Timothy R. ,   the CCASAnet Region of IeDEA, Cahn Pedro , Cesar Carina , Fink Valeria , Ortiz Zulma , Cahn Florencia , Roldan Agustina , Aristegui Ines , Frola Claudia , Grinsztejn Beatriz , Veloso Valdilea G. , Luz Paula M. , Wagner Sandra Cardoso , Friedman Ruth , Moreira Ronaldo I. , Coelho Lara Esteves , Pedrosa Monica Derrico , Calvet Guilherme Amaral , Perazzo Hugo , Moreira Rodrigo , Ribeiro Maria Pia Diniz , Pereira Mario Sergio , Jalil Emilia Moreira , Pinto Jorge , Ferreira Flavia , Maia Marcelle , de Fátima Barbosa Gouvêa Aida , do Carmo Fabiana , Cortes Claudia , Wolff Marcelo , Rodriguez Maria Fernanda , Castillo Gabriel , Allendes Gladys , Pape Jean William , Marcelin Vanessa Rouzier Adias , Macius Youry , Preux Stephano Saint , Koenig Serena , Varela Marco Tulio Luque Diana , Chavez Magda , Mailhot Ada , Padgett Denis , Madero Juan Sierra , Ramirez Brenda Crabtree , Vega Yanink Caro , Gotuzzo Eduardo , Mejia Fernando , Carriquiry Gabriela , CMcGowan Catherine , Duda Stephany N. , Shepherd Bryan E. , Sterling Timothy , Person Anna K , Rebeiro Peter F. , Castilho Jessica , Wester William C. , Clouse Kate , Jayathilake Karu , Vansell Fernanda Maruri Hilary , Figueiredo Marina Cruvinel , Jenkins Cathy , Lotspeich Ahra Kim Sarah , Ranadive Paridhi , Clouse Kate 
Published: April 2022

Abstract
Background
Some tuberculosis (TB) treatment guidelines recommend daily TB treatment in both the intensive and continuation phases of treatment in HIV-positive persons to decrease the risk of relapse and acquired drug resistance. However, guidelines vary across countries, and treatment is given 7, 5, 3, or 2 days/week. The effect of TB treatment intermittency in the continuation phase on mortality in HIV-positive persons on antiretroviral therapy (ART), is not well-described.

Methods
We conducted an observational cohort study among HIV-positive adults treated for TB between 2000 and 2018 and after enrollment into the Caribbean, Central, and South America network for HIV epidemiology (CCASAnet; Brazil, Chile, Haiti, Honduras, Mexico and Peru). All received standard TB therapy (2-month initiation phase of daily isoniazid, rifampin or rifabutin, pyrazinamide ± ethambutol) and continuation phase of isoniazid and rifampin or rifabutin, administered concomitantly with ART. Known timing of ART and TB treatment were also inclusion criteria. Kaplan–Meier and Cox proportional hazards methods compared time to death between groups. Missing model covariates were imputed via multiple imputation.

Results
2303 patients met inclusion criteria: 2003(87%) received TB treatment 5–7 days/week and 300(13%) 2–3 days/week in the continuation phase. Intermittency varied by site: 100% of patients from Brazil and Haiti received continuation phase treatment 5–7 days/week, followed by Honduras (91%), Peru (42%), Mexico (7%), and Chile (0%). The crude risk of death was lower among those receiving treatment 5–7 vs. 2–3 days/week (HR = 0.68; 95% CI = 0.51—0.91; P = 0.008). After adjusting for age, sex, CD4, ART use at TB diagnosis, site of TB disease (pulmonary vs. extrapulmonary), and year of TB diagnosis, mortality risk was lower, but not significantly, among those treated 5–7 days/week vs. 2–3 days/week (HR 0.75, 95%CI 0.55–1.01; P = 0.06). After also stratifying by study site, there was no longer a protective effect (HR 1.42, 95%CI 0.83–2.45; P = 0.20).

Conclusions
TB treatment 5–7 days/week was associated with a marginally decreased risk of death compared to TB treatment 2–3 days/week in the continuation phase in multivariable, unstratified analyses. However, little variation in TB treatment intermittency within country meant the results could have been driven by other differences between study sites. Therefore, randomized trials are needed, especially in heterogenous regions such as Latin America.