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Rationale: Observational studies suggest that high-dose isoniazid may be efficacious in treating multidrug-resistant tuberculosis. However, its activity against Mycobacterium tuberculosis ( M.tb ) with katG mutations (which typically confer high-level resistance) is not established. Objectives: To characterize the early bactericidal activity (EBA) of high-dose isoniazid in patients with tuberculosis caused by katG -mutated M.tb . Methods: A5312 was a phase IIA randomized, open-label trial. Participants with tuberculosis caused by katG- mutated M.tb were randomized to receive 15 or 20 mg/kg isoniazid daily for 7 days. Daily sputum samples were collected for quantitative culture. Intensive pharmacokinetic sampling was performed on Day 6. Data were pooled across all A5312 participants for analysis (drug-sensitive, inhA -mutated, and katG -mutated M.tb ). EBA was determined using nonlinear mixed-effects modeling. Measurements and Main Results: Of 80 treated participants, 21 had katG -mutated M.tb . Isoniazid pharmacokinetics were best described by a two-compartment model with an effect of NAT2 acetylator phenotype on clearance. Model-derived maximum concentration and area under the concentration-time curve in the 15 and 20 mg/kg groups were 15.0 and 22.1 mg/L and 57.6 and 76.8 mg ⋅ h/L, respectively. Isoniazid bacterial kill was described using an effect compartment and a sigmoidal maximum efficacy relationship. Isoniazid potency against katG -mutated M.tb was approximately 10-fold lower than in inhA -mutated M.tb . The highest dose of 20 mg/kg did not demonstrate measurable EBA, except against a subset of slow NAT2 acetylators (who experienced the highest concentrations). There were no grade 3 or higher drug-related adverse events. Conclusions: This study found negligible bactericidal activity of high-dose isoniazid (15-20 mg/kg) in the majority of participants with tuberculosis caused by katG- mutated M.tb . Clinical trial registered with www.clinicaltrials.gov (NCT01936831).

Rationale: There is accumulating evidence that higher-than-standard doses of isoniazid are effective against low-to-intermediate-level isoniazid-resistant strains of Mycobacterium tuberculosis , but the optimal dose remains unknown. Objectives: To characterize the association between isoniazid pharmacokinetics (standard or high dose) and early bactericidal activity against M. tuberculosis (drug sensitive and inhA mutated) and N-acetyltransferase 2 status. Methods: ACTG (AIDS Clinical Trial Group) A5312/INHindsight is a 7-day early bactericidal activity study with isoniazid at a normal dose (5 mg/kg) for patients with drug-sensitive bacteria and 5, 10, and 15 mg/kg doses for patients with inhA mutants. Participants with pulmonary tuberculosis received daily isoniazid monotherapy and collected sputum daily. Colony-forming units (cfu) on solid culture and time to positivity in liquid culture were jointly analyzed using nonlinear mixed-effects modeling. Measurements and Main Results: Fifty-nine adults were included in this analysis. A decline in sputum cfu was described by a one-compartment model, whereas an exponential bacterial growth model was used to interpret time-to-positivity data. The model found that bacterial kill is modulated by isoniazid concentration using an effect compartment and a sigmoidal Emax relationship (a model linking the drug concentration to the observed effect). The model predicted lower potency but similar maximum kill of isoniazid against inhA-mutated compared with drug-sensitive isolates. Based on simulations from the pharmacokinetics-pharmacodynamics model, to achieve a drop in bacterial load comparable to 5 mg/kg against drug-sensitive tuberculosis, 10- and 15-mg/kg doses are necessary against inhA-mutated isolates in slow and intermediate N-acetyltransferase 2 acetylators, respectively. Fast acetylators underperformed even at 15 mg/kg. Conclusions: Dosing of isoniazid based on N-acetyltransferase 2 acetylator status may help patients attain effective exposures against inhA-mutated isolates. Clinical trial registered with www.clinicaltrials.gov (NCT01936831).

Rationale: High-dose isoniazid is recommended in short-course regimens for multidrug-resistant tuberculosis (TB). The optimal dose of isoniazid and its individual contribution to efficacy against TB strains with inhA or katG mutations are unknown. Objectives: To define the optimal dose of isoniazid for patients with isoniazid-resistant TB mediated by inhA mutations. Methods: AIDS Clinical Trials Group A5312 is a phase 2A, open-label trial in which individuals with smear-positive pulmonary TB with isoniazid resistance mediated by an inhA mutation were randomized to receive isoniazid 5, 10, or 15 mg/kg daily for 7 days (inhA group), and control subjects with drug-sensitive TB received the standard dose (5 mg/kg/d). Overnight sputum cultures were collected daily. The 7-day early bactericidal activity (EBA) of isoniazid was estimated as the average daily change in log 10 cfu on solid media (EBA cfu0-7 ) or as time to positivity (TTP) in liquid media in hours (EBA TTP0-7 ) using nonlinear mixed-effects models. Measurements and Main Results: Fifty-nine participants (88% with cavitary disease, 20% HIV-positive, 16 with isoniazid-sensitive TB, and 43 with isoniazid-monoresistant or multidrug-resistant TB) were enrolled at one site in South Africa. The mean EBA cfu0-7 at doses of 5, 10, and 15 mg/kg in the inhA group was 0.07, 0.17, and 0.22 log 10 cfu/ml/d, respectively, and 0.16 log 10 cfu/ml/d in control subjects. EBA TTP0-7 patterns were similar. There were no drug-related grade ≥3 adverse events. Conclusions: Isoniazid 10-15 mg/kg daily had activity against TB strains with inhA mutations similar to that of 5 mg/kg against drug-sensitive strains. The activity of high-dose isoniazid against strains with katG mutations will be explored next.Clinical trial registered with www.clinicaltrials.gov (NCT01936831).

Rationale: New regimens to shorten tuberculosis treatment and manage patients with drug-resistant tuberculosis who are infected with HIV are urgently needed. Experimental and clinical evidence suggests that the new drugs bedaquiline (B) and pretomanid (Pa), combined with an existing drug, pyrazinamide (Z), and a repurposed drug, clofazimine (C), may assist treatment shortening of drug-susceptible and drug-resistant tuberculosis., Objectives: To evaluate the 14-day bactericidal activity of C and Z in monotherapy and in combinations with Pa and B., Methods: Groups of 15 treatment-naive, sputum smear-positive patients with pulmonary tuberculosis were randomized to receive combinations of B with Z-C, Pa-Z, Pa-Z-C, and Pa-C, or C or Z alone, or standard combination treatment for 14 days. The primary endpoint was the mean daily fall in log10 Mycobacterium tuberculosis CFU per milliliter sputum estimated by joint nonlinear mixed-effects Bayesian regression modeling., Measurements and Main Results: Estimated activities were 0.167 (95% confidence interval [CI], 0.075-0.257) for B-Pa-Z, 0.151 (95% CI, 0.071-0.232) for standard treatment, 0.124 (95% CI, 0.035-0.214) for B-Z-C, 0.115 (95% CI, 0.039-0.189) for B-Pa-Z-C, and 0.076 (95% CI, 0.005-0.145) for B-Pa-C. Z alone had modest activity (0.036; 95% CI, -0.026 to 0.099). C had no activity alone (-0.017; 95% CI, -0.085 to 0.053) or in combinations. Treatments were well tolerated and safe., Conclusions: B-Pa-Z, including two novel agents without resistance in prevalent M. tuberculosis strains, is a potential new tuberculosis treatment regimen. C had no measurable activity in the first 14 days of treatment. Clinical trial registered with www.clinicaltrials.gov (NCT 01691534).

Rationale: Inadequacy of T-cell responses may result in the development of tuberculosis (TB). Myeloid-derived suppressor cells (MDSCs) have been described as suppressors of T-cell function in cancer biology and recently in several infectious diseases., Objectives: To explore the presence and role of MDSCs in TB., Methods: We analyzed surface markers of MDSCs in peripheral blood and at the site of disease in TB cases and in patients with lung cancer, and in peripheral blood of asymptomatic tuberculin skin test-positive individuals with recent (household) or remote exposure to Mycobacterium tuberculosis (M.tb) and in uninfected healthy control subjects. To evaluate the suppressive capacity of MDSCs, cells of household contacts infected with M.tb and TB cases were isolated and cocultured with CD3(+) T cells., Measurements and Main Results: Our results demonstrate an increased presence of MDSCs after recent M.tb infection and disease. We confirm their suppression of CD4(+) T-cell function, including reduced cytokine responses and inhibition of CD4(+) T-cell proliferation. Only MDSCs from TB cases reduced T-cell activation, altered T-cell trafficking, and suppressed CD8(+) T-cell functions. M.tb-expanded MDSCs were associated with significantly higher IL-1β, IL-6, IL-8, granulocyte colony-stimulating factor, and monocyte chemotactic protein-1, and reduced granulocyte-macrophage colony-stimulating factor and macrophage inflammatory protein-1 beta levels in coculture., Conclusions: These data reveal that innate MDSCs are induced not only during active TB at similar levels as found in cancer, but also in healthy individuals after recent exposure to M.tb. These cells diminish protective T-cell responses and may contribute to the inability of hosts to eradicate the infection and add to the subsequent development of TB disease.