Taylor W Foreman1, Allison N Bucşan1, Smriti Mehra1, Charles Peloquin2, Lara A Doyle1, Kasi Russell-Lodrigue1, Neel R Gandhi3, John Altman4,5, Cheryl L Day4,5, Joel D Ernst6, Henry M Blumberg7, Jyothi Rengarajan4,7, Deepak Kaushal1,8. 1. Tulane National Primate Research Center, Tulane University School of Medicine, Covington, Louisiana. 2. University of Florida College of Pharmacy, Gainesville, Florida. 3. Rollins School of Public Health and. 4. Emory Vaccine Center and Yerkes National Primate Center, Emory University, Atlanta, Georgia. 5. Department of Microbiology and Immunology and. 6. Division of Experimental Medicine, Department of Medicine, University of California, San Francisco, California; and. 7. Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, Georgia. 8. Southwest National Primate Research Center, Texas Biomedical Research Center, San Antonio, Texas.
Abstract
Rationale: Direct evidence for persistence of Mycobacterium tuberculosis (Mtb) during asymptomatic latent tuberculosis infection (LTBI) in humans is currently lacking. Moreover, although a 12-week regimen of once-weekly isoniazid and rifapentine (3HP) is currently recommended by the CDC as treatment for LTBI, experimental evidence for 3HP-mediated clearance of persistent Mtb infection in human lungs has not been established. Objectives: Using a nonhuman primate (NHP) model of TB, we sought to assess 3HP treatment-mediated clearance of Mtb infection in latently infected macaques. Methods: Sixteen NHPs were infected via inhalation with ∼10 cfu of Mtb CDC1551, after which asymptomatic animals were either treated with 3HP or left untreated. Pharmacokinetics of the 3HP regimen were measured. Following treatment, animals were coinfected with simian immunodeficiency virus to assess reactivation of LTBI and development of active TB disease.Measurements and Main Results: Fourteen NHPs remained free of clinical signs or microbiological evidence of active TB following infection with Mtb and were subsequently either treated with 3HP (n = 7) or left untreated (n = 7). Untreated NHPs were asymptomatic for 7 months but harbored persistent Mtb infection, as shown by reactivation of latent infection following simian immunodeficiency virus coinfection. However, none of the treated animals developed TB reactivation disease, and they remained without clinical or microbiological evidence of persistent bacilli, suggesting treatment-mediated clearance of bacteria.Conclusions: Mtb can persist in asymptomatic macaques for at least 7 months. Furthermore, 3HP treatment effectively cleared bacteria and prevented reactivation of TB in latently infected macaques.
Rationale: Direct evidence for persistence of Mycobacterium tuberculosis (Mtb) during asymptomatic latent tuberculosis infection (LTBI) in humans is currently lacking. Moreover, although a 12-week regimen of once-weekly isoniazid and rifapentine (3HP) is currently recommended by the CDC as treatment for LTBI, experimental evidence for 3HP-mediated clearance of persistent Mtb infection in human lungs has not been established. Objectives: Using a nonhuman primate (NHP) model of TB, we sought to assess 3HP treatment-mediated clearance of Mtb infection in latently infected macaques. Methods: Sixteen NHPs were infected via inhalation with ∼10 cfu of Mtb CDC1551, after which asymptomatic animals were either treated with 3HP or left untreated. Pharmacokinetics of the 3HP regimen were measured. Following treatment, animals were coinfected with simian immunodeficiency virus to assess reactivation of LTBI and development of active TB disease.Measurements and Main Results: Fourteen NHPs remained free of clinical signs or microbiological evidence of active TB following infection with Mtb and were subsequently either treated with 3HP (n = 7) or left untreated (n = 7). Untreated NHPs were asymptomatic for 7 months but harbored persistent Mtb infection, as shown by reactivation of latent infection following simian immunodeficiency virus coinfection. However, none of the treated animals developed TB reactivation disease, and they remained without clinical or microbiological evidence of persistent bacilli, suggesting treatment-mediated clearance of bacteria.Conclusions: Mtb can persist in asymptomatic macaques for at least 7 months. Furthermore, 3HP treatment effectively cleared bacteria and prevented reactivation of TB in latently infected macaques.
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