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Isoniazid and rifapentine treatment effectively reduces persistent M. tuberculosis infection in macaque lungs
Riti Sharan, … , Jyothi Rengarajan, Deepak Kaushal
Riti Sharan, … , Jyothi Rengarajan, Deepak Kaushal
Published July 21, 2022
Citation Information: J Clin Invest. 2022;132(18):e161564. https://doi.org/10.1172/JCI161564.
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Research Article Infectious disease

Isoniazid and rifapentine treatment effectively reduces persistent M. tuberculosis infection in macaque lungs

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Abstract

A once-weekly oral dose of isoniazid and rifapentine for 3 months (3HP) is recommended by the CDC for treatment of latent tuberculosis infection (LTBI). The aim of this study is to assess 3HP-mediated clearance of M. tuberculosis bacteria in macaques with asymptomatic LTBI. Twelve Indian-origin rhesus macaques were infected with a low dose (~10 CFU) of M. tuberculosis CDC1551 via aerosol. Six animals were treated with 3HP and 6 were left untreated. The animals were imaged via PET/CT at frequent intervals. Upon treatment completion, all animals except 1 were coinfected with SIV to assess reactivation of LTBI to active tuberculosis (ATB). Four of 6 treated macaques showed no evidence of persistent bacilli or extrapulmonary spread until the study end point. PET/CT demonstrated the presence of significantly more granulomas in untreated animals relative to the treated group. The untreated animals harbored persistent bacilli and demonstrated tuberculosis (TB) reactivation following SIV coinfection, while none of the treated animals reactivated to ATB. 3HP treatment effectively reduced persistent infection with M. tuberculosis and prevented reactivation of TB in latently infected macaques.

Authors

Riti Sharan, Shashank R. Ganatra, Dhiraj K. Singh, Journey Cole, Taylor W. Foreman, Rajesh Thippeshappa, Charles A. Peloquin, Vinay Shivanna, Olga Gonzalez, Cheryl L. Day, Neel R. Gandhi, Edward J. Dick Jr., Shannan Hall-Ursone, Smriti Mehra, Larry S. Schlesinger, Jyothi Rengarajan, Deepak Kaushal

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Figure 1

Study outline and clinical parameters.

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Study outline and clinical parameters.
(A) The nonhuman primate (NHP) mo...
(A) The nonhuman primate (NHP) model of latent tuberculosis infection and treatment. Animals were infected with 10 CFU of M. tuberculosis CDC1551, and of the 12 animals that developed latent tuberculosis infection, 6 were left untreated, while 6 were treated weekly with isoniazid and rifapentine for 3 months (3HP) and rested for 1 month before coinfection with SIV. (30) Animals were monitored for signs of disease such as (B) C-reactive protein (CRP), (C) pyrexia, and (D) wasting throughout the study. The thin dotted lines represent the treatment period and the thick dotted line represents SIV coinfection. The solid lines are the corresponding trendlines for each set of data.(E) Survival kinetics shown as days after M. tuberculosis infection. (F) Blood biochemistry for serum albumin/globulin (A/G) (g/dL) ratio, aspartate aminotransferase or serum glutamic-oxaloacetic transaminase (ALT/SGOT) (units per liter of serum), blood urea nitrogen/creatinine (BUN/creat) (μmol/L) ratio, and alkaline phosphatase (Alk phos) (units per liter), at week 25 after TB infection or 1-week after treatment completion for both treated and control groups. The small dotted lines at weeks 12 and 23 mark the 3HP treatment period, while the bold dotted line at week 27 marks the SIV coinfection time point

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