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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 TBn.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 INHProthionamide/ethionamideAmikacinMoxifloxacinEthambutolPyrazinamideClofazimine

5-month continuationphase

Moxifloxacin EthambutolPyrazinamideClofazimine

‘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 RxGroup 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/kgN=13

10 mg/kgN=14

15 mg/kgN=16

5 mg/kgN=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 2014Last 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-R5 mg/kg (n=13)

INH-R10 mg/kg (n=12)

INH-R15 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-R5 mg/kg (n=13)

INH-R10 mg/kg (n=13)

INH-R15 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 acetylatorstatus (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