Shortening Treatment in Adults with Noncavitary Tuberculosis and 2-Month Culture Conversion

Johnson, John L.; Hadad, David Jamil; Dietze, Reynaldo; Maciel, Ethel Leonor Nóia; Sewali, Barrett; Gitta, Phineas; Okwera, Alphonse; Mugerwa, R.; Alcaneses, Mary Rose; Quelapio, M. I. D.; Tupasi, Thelma E.; Horter, Libby; Debanne, Sara M.; Eisenach, Kathleen D.; Boom, W. Henry

doi:10.1164/rccm.200904-0536oc

Cited by 129 publications

(115 citation statements)

References 31 publications

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“…The length of this standard regimen leads to poor compliance and completion rates. Availability of effective shorter regimens would have a major impact on treatment of tuberculosis worldwide (5).…”

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confidence: 99%

Metronidazole prevents reactivation of latentMycobacterium tuberculosisinfection in macaques

Lin

Dartois

Johnston

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

108

126

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Targeting Mycobacterium tuberculosis bacilli in low-oxygen microenvironments, such as caseous granulomas, has been hypothesized to have the potential to shorten therapy for active tuberculosis (TB) and prevent reactivation of latent infection. We previously reported that upon low-dose M. tuberculosis infection, equal proportions of cynomolgus macaques develop active disease or latent infection and that latently infected animals reactivated upon neutralization of TNF. Using this model we now show that chemoprophylaxis of latently infected cynomolgus macaques with 6 mo of isoniazid (INH) effectively prevented anti-TNF antibody-induced reactivation. Similarly, 2-mo treatment of latent animals with a combination of INH and rifampicin (RIF) was highly effective at preventing reactivation disease in this model. Metronidazole (MTZ), which has activity only against anaerobic, nonreplicating bacteria, was as effective as either of these treatments in preventing reactivation of latent infection. Because hypoxic lesions also occur during active TB, we further showed that addition of MTZ to INH/RIF effectively treated animals with active TB within 2 mo. Healing lesions were associated with distinct changes in cellular pathology, with a shift toward increasingly fibrotic and calcified lesions. Our data in the nonhuman primate model of active and latent TB supports targeting bacteria in hypoxic environments for preventing reactivation of latent infection and possibly shortening the duration of therapy in active TB.

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mentioning

confidence: 99%

Metronidazole prevents reactivation of latentMycobacterium tuberculosisinfection in macaques

Lin

Dartois

Johnston

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

108

126

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“…Other important risk factors include bilateral abnormalities and failure to convert sputum culture by 2 or 3 months. Combined cavitation and sputum culture conversion can significantly predict relapse in retrospective analyses, although prospectively they have had limited value thus far (10,32). Cavitary disease, of course, does not occur alone and tends to be associated with more severe disease manifestations.…”

Section: Discussionmentioning

confidence: 99%

“…An additional risk factor for relapse observed in larger phase 3 clinical trials is the presence of cavitary lesions at the time of initial diagnosis of disease (9). However, a clinical trial to shorten therapy to 4 months for patients who did not have cavitary disease by chest X-ray and were culture negative at 2 months was stopped early because of unacceptably high rates of relapse (10). Thus, while both of these biomarkers appear to be risk factors for relapse, even when combined, they are inadequate to predict therapeutic outcome in individual patients on regimens of shorter duration.…”

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confidence: 99%

A Sterilizing Tuberculosis Treatment Regimen Is Associated with Faster Clearance of Bacteria in Cavitary Lesions in Marmosets

Via

England

Weiner

et al. 2015

Antimicrob Agents Chemother

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g Shortening the lengthy treatment duration for tuberculosis patients is a major goal of current drug development efforts. The common marmoset develops human-like disease pathology and offers an attractive model to better understand the basis for relapse and test regimens for effective shorter duration therapy. We treated Mycobacterium tuberculosis-infected marmosets with two drug regimens known to differ in their relapse rates in human clinical trials: the standard four-drug combination of isoniazid, rifampin, pyrazinamide, and ethambutol (HRZE) that has very low relapse rates and the combination of isoniazid and streptomycin that is associated with higher relapse rates. As early as 2 weeks, the more sterilizing regimen significantly reduced the volume of lung disease by computed tomography (P ‫؍‬ 0.035) and also significantly reduced uptake of [18 F]-2-fluoro-2-deoxyglucose by positron emission tomography (P ‫؍‬ 0.049). After 6 weeks of therapy, both treatments caused similar reductions in granuloma bacterial load, but the more sterilizing, four-drug regimen caused greater reduction in bacterial load in cavitary lesions (P ‫؍‬ 0.009). These findings, combined with the association in humans between cavitary disease and relapse, suggest that the basis for improved sterilizing activity of the four-drug combination is both its faster disease volume resolution and its stronger sterilizing effect on cavitary lesions. Definitive data from relapse experiments are needed to support this observation.T reatment of drug-sensitive tuberculosis (TB) requires 6 months of chemotherapy with a combination of four agents, isoniazid (INH), rifampin (RIF), pyrazinamide (PZA), and ethambutol (EMB), to achieve a durable cure (1). The durability of a regimen is determined by carefully measuring the rate of disease recrudescence over 1 to 2 years in patients after completing chemotherapy. Under controlled conditions in the setting of a clinical trial, the rate of relapse with active disease using this fourdrug combination is typically 2 to 4% (2), while under more typical conditions in national TB control programs, this rate can be as high as 10 to 14% (3, 4). Shortening the duration of treatment would greatly simplify the management of this disease by improving adherence, reducing the rate of adverse events, and reducing costs (5-7).An inverse relationship between the risk of relapse and the killing of bacilli in the sputum of patients (culture conversion after 2 months of treatment) has been proposed. Although some risk of relapse is clearly related to culture positivity at 2 months, this association appears to be dependent on geography and extent of disease (8). An additional risk factor for relapse observed in larger phase 3 clinical trials is the presence of cavitary lesions at the time of initial diagnosis of disease (9). However, a clinical trial to shorten therapy to 4 months for patients who did not have cavitary disease by chest X-ray and were culture negative at 2 months was stopped early because of unacceptably high rates ...

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“…This higher relapse rate in the shorter duration treatment arm may be due to the failure to eradicate dormant bacilli. Therefore, successful regimens that shorten the duration of treatment need to focus on introducing new drugs with novel mechanisms of action (3). In that sense, fluoroquinolones might have an important role.…”

mentioning

confidence: 99%

New Drug Regimen for Tuberculosis

Mardani

2014

Arch Clin Infect Dis

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Shortening Treatment in Adults with Noncavitary Tuberculosis and 2-Month Culture Conversion

Cited by 129 publications

References 31 publications

Metronidazole prevents reactivation of latentMycobacterium tuberculosisinfection in macaques

Metronidazole prevents reactivation of latentMycobacterium tuberculosisinfection in macaques

A Sterilizing Tuberculosis Treatment Regimen Is Associated with Faster Clearance of Bacteria in Cavitary Lesions in Marmosets

New Drug Regimen for Tuberculosis

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