Early Bactericidal Activity Of High-dose Isoniazid (INH ... Early Bactericidal Activity Of High-dose

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  • Early Bactericidal Activity Of High-dose Isoniazid (INH) Against Multi Drug Resistant Tuberculosis (MDR-TB)

    The INHindsight Trial

    For RESIST-TB 12 April 2019

    Dooley KE, Miyahara S, von Groote-Bidlingmaier F, Sun X, Hafner R, Rosenkranz S, Nuermberger E, Moran L, Donahue K, Swindells S, Diacon AH, and the A5312 Study Team

  • Background • Multidrug-resistant TB (TB resistant to isoniazid and rifampicin)

    remains a global health threat and is hard to treat

    • INH resistance is mediated by two key mechanisms, relevant mutations in M. tuberculosis can be detected by rapid molecular tests • katG mutations  high-level resistance • inhA mutations low-level resistance

    • High-dose isoniazid is a component drug in WHO-recommended short course treatment for MDR-TB, but the optimal dose is not known

    • ACTG A5312 measured the early bactericidal activity (EBA) of different doses of INH in patients with MDR-TB

  • Isoniazid: Mechanism of Action

    • INH activated by KatG to form INH-NAD adduct

    • Adduct inhibits InhA, the enoyl-ACP reductase of the fatty acid synthase type II system

    • Mycolic acid biosynthesis is inhibited

    • Cell death

    Vilcheze 2007 Annu Rev Microbiol 61: 35

    Note: Ethionamide is activated by EthA, not katG, but acts on inhA

  • Maximal EBA activity of isoniazid, for drug-sensitive TB Donald (1997) AJRCCM 156: 895.

    Maximum EBA achieved with dose of 300 mg (~5 mg/kg) for drug-sensitive TB n.b. There is measurable activity against DS isolates even with doses as small as 18.75 mg (0.38 mg/kg).

  • WHO Short-Course Treatment for MDR-TB

    4-month intensive phase

    High-dose INH Prothionamide/ethionamide Amikacin Moxifloxacin Ethambutol Pyrazinamide Clofazimine

    5-month continuation phase

    Moxifloxacin Ethambutol Pyrazinamide Clofazimine

  • ‘High-dose’ INH for MDR TB- is this dose really high?

    Isoniazid dose ~5 mg/kg (300 mg for all patients)

    Isoniazid dose ~10 mg/kg (300-600mg)

    Isoniazid dose ~10 mg/kg (300-600mg)

  • New (2018) Standard-Duration MDR Rx Group Medicine

    A Levofloxacin or moxifloxacin

    Bedaquiline

    Linezolid

    B Clofazimine

    Cycloserine or terizidone

    C Ethambutol

    Delamanid

    Pyrazinamide

    Imipenem-cilastin or meropenem (plus clavulanic acid)

    Amikacin

    Ethionamide or prothionamide

    p-aminosalicylic acid

    Include all 3 (unless they can’t be used)

    Add one or both, unless they can’t be used

    Add to complete the regimen and when medicines from Groups A and B cannot be used

    WHO Rapid Communication 2018

    Where is high dose INH?

  • Study Design: A5312

    INH-resistant TB

    M. tuberculosis with inhA mutation

    M. tuberculosis with katG mutation

    INH 15 or 20 mg/kg per day

    7-day EBA

    INH 5, 10, or 15 mg/kg per day

    Host: - Pharmacokinetics - Acetylator genotype

    INH-sensitive TB

    7-day EBA7-day EBA

    INH 5 mg/kg

    Treatment response: - PK/PD - Pharmacogenetics

    Pathogen: - Mutation type - Minimum inhibitory conc (MIC)

    Group 1 Group 2Group 3

  • CFU

    Days

    TTP

    Slide courtesy of A. Diacon

  • Objectives

    • Estimate the 7-day EBA, based on colony forming units (CFU) on solid culture, of INH among participants with TB in which infecting isolate has inhA mutations taking one of three doses of INH (5, 10, or 15 mg/kg daily), and participants with drug-susceptible TB taking standard-dose INH (5 mg/kg daily).

    • Estimate the 7-day EBA, as above, based on change in time to positivity (TTP) on liquid culture

    • Describe the safety and tolerability of doses of 5, 10, and 15 mg/kg of INH administered daily among participants with sputum smear- positive pulmonary TB.

  • Baseline Characteristics (inhA and drug-sensitive arms)

    Characteristic INH-resistant (inhA mutation) INH-susceptible TB All Groups

    5 mg/kg N=13

    10 mg/kg N=14

    15 mg/kg N=16

    5 mg/kg N=16 N=59

    Sex Male (n, %) 10 (77%) 11 (79%) 10 (63%) 12 (75%) 43 (73%)

    Race Black/African (n, %)

    12 (92%) 14 (100%) 16 (100%) 15 (94%) 57 (97%)

    Age (y) Median (IQR) 31 (26, 44) 32 (23, 41) 34 (22, 44) 30 (22, 41) 32 (23, 41)

    HIV status Positive (n, %) 2 (15%) 3 (21%) 4 (25%) 3 (19%) 12 (20%)

    Cavitary dz Yes (n, %) 11 (85%) 14 (100%) 15 (94%) 12 (75%) 52 (88%)

    Baseline bacillary load*

    Median (IQR) 5.65 (5.34, 7.02) 6.93 (6.56, 7.43) 7.04 (6.18, 7.33) 5.41 (4.81, 6.68) 6.56 (5.39,7.24)

    Baseline time to positivity**

    Median (IQR) 142 (110, 173) 127 (104, 143) 124 (100, 152) 97 (92, 120) 118 (97, 151)

    First enrollment: August 2014 Last patient visit (groups 1&2) : December 13, 2017

    *log10 colony forming units; ** in days

  • Safety, completion

    • Of 59 enrolled, 58 (98%) completed treatment

    • 9 Grade 3 adverse events, all unrelated or unlikely to be related to study treatments • Pneumothorax (x2), fever, pain, dyspnea, anemia (x4)

    • No Grade 4 AE, no SAE or deaths

    • After completion of study therapy, all patients referred to local TB treatment program to complete therapy

  • Results: EBAlog10CFU, model based estimates (solid media)

    Arm INH-R 5 mg/kg (n=13)

    INH-R 10 mg/kg (n=12)

    INH-R 15 mg/kg (n=15)

    INH-S (+ control) 5 mg/kg (n=15)

    EBACFU0-7

    Median 0.08 0.12 0.20 0.15

    IQR 0.01, 0.14 0.10, 0.23 0.11, 0.28 0.11, 0.25

    EBACFU0-2

    Median 0.13 0.08 0.08 0.26

    IQR 0.01, 0.38 0.01, 0.27 -0.19, 0.43 0.21, 0.66

    EBACFU2-7

    Median 0 0.17 0.25 0.09

    IQR -0.07, 0.04 0.05, 0.29 0.08, 0.38 -0.07, 0.18

    Median MIC 0.2 mg/LMedian MIC 1 mg/Lpreliminary

  • Mean (95% CI) EBACFU(0-7) based on log10 CFU count, by arm

    14

  • Mean (95% CI) EBATTP(0-7) based on time to positivity, by arm

    15

    Arm INH-R 5 mg/kg (n=13)

    INH-R 10 mg/kg (n=13)

    INH-R 15 mg/kg (n=16)

    INH-S (+ control) 5 mg/kg (n=16)

    EBATTP0-7

    Median -2 -4 -10 -9

    IQR -8, 3 -7, -3 -12, -6 -12, -8

  • Summary • Isoniazid has measurable, potent activity against M. tuberculosis strains with inhA

    mutations at doses of 10-15 mg/kg daily, supporting its use as a component of multidrug MDR-TB regimens

    • While MICs of isoniazid against MDR-TB strains with inhA mutations are typically about 5-fold higher than MICs against drug-sensitive strain, only a 2-3 fold increase in dose is needed to get same activity against inhA mutants as against drug-sensitive strains

    • Optimal dose of isoniazid in INH-resistant TB likely depends on NAT2 acetylator status (PG-PK-PD analysis coming soon)

    • Role of isoniazid against strains with katG mutations to be determined (arms opening soon)

    • Safety/tolerability must be established in longer-term studies

  • Acknowledgments

    17

    • Team Members: • Paolo Denti • Elisa Ignatius • Rachel Issa • Christopher Lane • Mark Lojacono • Rachel Mahachi • Helen McIlleron • Karla Mellet • Lynette Purdue • Maulik Shah • Akbar Shahkolahi • Ronald Ssenyonga • Xin Sun

    • Study participants • TASK clinical team and TASK lab • University of Cape Town

    Pharmacology Laboratory

  • Extra slides– context, for discussion

  • Can INH “resistance” be overcome?

    • RCT for MDR-TB: OBR (levo, kana, proth, cyclo, PAS) plus high- dose INH (16-18 mg/kg), standard INH (5 mg/kg), or placebo: • 6 mo culture conversion rate 74% vs. 45% vs. 49% • TTC conversion 3.4 months vs. 6.4 months vs. 6.6 months • More peripheral neuropathy in high-dose INH group, but no B6 given • No differences in hepatotoxicity

    Katiyar (2008) IJTLD 12: 39.

    N.B. Regimen included levofloxacin

  • Role of high dose INH in Bangladesh regimen

  • Isoniazid preventive therapy protects against tuberculosis among household contacts of isoniazid-resistant patients

    Huang et al NOT YET PEER REVIEWED

  • Hot off the presses…

  • Theories for why high-dose INH can work when katG is mutated

  • Control arm comparability (to past studies)

    De Jager 2017 AAC

    Mean Baseline bacillary load: 5.71 log10 CFU

    Mean EBA0-2: 0.39 ∆log10 CFU/mL/d