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

Abstract

Once-weekly oral dose of isoniazid and rifapentine for 12 weeks (3HP) is recommended by CDC for treatment of latent tuberculosis infection (LTBI). The aim of this study is to assess 3HPmediated clearance of Mtb bacteria in macaques with asymptomatic LTBI. Twelve Indian rhesus macaques were infected with low dose (~10 CFU) of Mtb CDC1551 via aerosol. Six animals were treated with 3HP and six were left untreated. The animals were imaged via positron emissions tomography -computed tomography (PET/CT) at frequent intervals. Upon treatment completion, all animals except one were coinfected with simian immunodeficiency virus to assess reactivation of LTBI to active TB disease. Four of six treated macaques showed no evidence of persistent bacilli or extrapulmonary spread until 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 TB reactivation following SIV coinfection while none of the treated animals reactivated to active TB disease (ATB). 3HP treatment effectively reduced persistent infection with Mtb and prevented reactivation of TB disease in latently infected macaques.

A world without tuberculosis: moving from imagination to reality

“…The combined results underscore the power of aerosol TB infection in the macaque model; it is possible to longitudinally evaluate TB disease in the lungs as a function of infection, coinfection, and treatment, but also possible to identify the total lung disease burden at necropsy. While this experiment is important because it validates earlier findings that 3HP treatment is efficacious for LTBI, it also opens the door for testing more chemotherapies and immunotherapies using the LTBI model and the SIV coinfection approach ( 3 ).…”

“…Sharan et al used the macaque model of aerosol-based M . tuberculosis infection to show that 3HP is indeed efficacious in these model animals, as has been found in humans ( 3 ). Importantly, this manuscript goes beyond just confirming what is known from human clinical studies and provides crucial knowledge using the macaque model that distinguishes this study from human studies.…”

“…To eradicate TB, we need to find effective ways to sterilize the persisters or prevent them from forming. In this issue of the JCI, the report by Sharan et al provides an incremental, but notable, step toward this goal ( 3 ).…”

“…The authors utilized SIV coinfection strategically — to observe if there were differences in the extent of persistent M . tuberculosis that remained as a function of 3HP treatment ( 3 ). This experiment was warranted because it is challenging to radiologically distinguish between macaques with LTBI and those that have cleared the infection.…”

“…Finally, it was possible for Sharan and colleagues to subject the lungs of treated and untreated macaques to CFU analysis at the endpoint to validate the imaging results, whereas it is impossible to carry out such a study in humans ( 3 ). Sharan et al conclusively showed that 3HP treatment reduced the levels of M .…”