From our January 2020 Newsletter!

1. Early Bactericidal Activity of Different Isoniazid Doses for Drug Resistant TB (INHindsight): A Randomized Open-label Clinical Trial.
Am J Respir Crit Care Med. 2020 Jan 16. doi: 10.1164/rccm.201910-1960OC. [Epub
ahead of print]

Dooley KE(1), Miyahara S(2), von Groote-Bidlingmaier F(3), Sun X(2), Hafner R(4),
Rosenkranz SL(2)(5), Ignatius EH(6), Nuermberger EL(7), Moran L(8), Donahue K(5),
Swindells S(9), Vanker N(10), Diacon AH(11); A5312 Study Team.

RATIONALE: High-dose isoniazid is recommended in short-course regimens for
multidrug-resistant TB (MDR-TB). The optimal dose of isoniazid and its individual
contribution to efficacy against TB strains with inhA or katG mutations are
unknown.
OBJECTIVE: 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 controls with drug-sensitive TB received
standard dose (5 mg/kg/day). Overnight sputum cultures were collected daily. The
7-day early bactericidal activity of isoniazid was estimated as the average daily
change in log10 colony forming units on solid media (EBACFU0-7) or as time to
positivity in liquid media in hours (EBATTP0-7) using nonlinear mixed effects
models.
MEASUREMENTS AND MAIN RESULTS: Fifty-nine participants, 88% with cavitary
disease, 20% HIV-positive, 16 with isoniazid-sensitive and 41 with isoniazid
mono-resistant or MDR TB, were enrolled at one site in South Africa. Mean
EBACFU0-7 at doses of 5, 10 and 15 mg/kg in the inhA group was 0.07, 0.17 and
0.22 log10CFU/mL/day, respectively, and 0.16 log10CFU/mL/day in controls.
EBATTP0-7 patterns were similar. There were no drug-related Grade >3 adverse
events.
CONCLUSIONS: Isoniazid 10-15 mg/kg daily had similar activity against TB strains
with inhA mutations as 5 mg/kg against drug-sensitive strains. The activity of
high-dose isoniazid against strains with katG mutations will be explored next.
Clinical trial registration available at www.clinicaltrials.gov, ID: NCT01936831.

DOI: 10.1164/rccm.201910-1960OC
PMID: 31945300

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2. “A very humiliating illness”: a qualitative study of patient-centered Care for Rifampicin-Resistant Tuberculosis in South Africa

Jennifer Furin, Marian Loveday, Sindisiwe Hlangu, Lindy Dickson-Hall, Sacha le Roux, Mark Nicol and Helen Cox

Background: Patient-centered care is pillar 1 of the “End TB” strategy, but little has been documented in the literature about what this means for people living with rifampicin-resistant (RR-TB). Optimizing care for such individuals requires a better understanding of the challenges they face and the support they need.
Methods: A qualitative study was done among persons living with RR-TB and members of their support network. A purposive sample was selected from a larger study population and open-ended interviews were conducted using a semi-standard interview guide. Interviews were recorded and transcribed and the content analyzed using an iterative thematic analysis based in grounded theory.
Results: 16 participants were interviewed from three different provinces. Four distinct periods in which support was needed were identified: 1) pre-diagnosis; 2) pre-treatment; 3) treatment; and 4) post-treatment. Challenges common in all four periods included: socioeconomic issues, centralized care, and the need for better counseling at multiple levels.
Conclusions: Beyond being a “very humiliating illness”, RR-TB robs people of their physical, social, economic, psychological, and emotional well-being far beyond the period when treatment is being administered. Efforts to tackle these issues are as important as new drugs and diagnostics in the fight against TB. Keywords: South Africa, Costs, Challenges, Social support, Counseling

DOI https://doi.org/10.1186/s12889-019-8035-z

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3. Outcomes of Community-Based Systematic Screening of Household Contacts of Patients with Multidrug-Resistant Tuberculosis in Myanmar.
Trop Med Infect Dis. 2019 Dec 25;5(1). pii: E2. doi: 10.3390/tropicalmed5010002.

Kyaw NTT(1), Sithu A(1), Satyanarayana S(2)(3), Kumar AMV(2)(3)(4), Thein S(5),
Thi AM(1), Wai PP(1), Lin YN(1), Kyaw KWY(1), Tun MMT(1), Oo MM(1), Aung ST(5),
Harries AD(3)(6).

Screening of household contacts of patients with multidrug-resistant tuberculosis
(MDR-TB) is a crucial active TB case-finding intervention. Before 2016, this
intervention had not been implemented in Myanmar, a country with a high MDR-TB
burden. In 2016, a community-based screening of household contacts of MDR-TB
patients using a systematic TB-screening algorithm (symptom screening and chest
radiography followed by sputum smear microscopy and Xpert-MTB/RIF assays) was
implemented in 33 townships in Myanmar. We assessed the implementation of this
intervention, how well the screening algorithm was followed, and the yield of
active TB. Data collected between April 2016 and March 2017 were analyzed using
logistic and log-binomial regression. Of 620 household contacts of 210 MDR-TB
patients enrolled for screening, 620 (100%) underwent TB symptom screening and
505 (81%) underwent chest radiography. Of 240 (39%) symptomatic household
contacts, 71 (30%) were not further screened according to the algorithm. Children
aged <15 years were less likely to follow the algorithm. Twenty-four contacts
were diagnosed with active TB, including two rifampicin- resistant cases (yield
of active TB = 3.9%, 95% CI: 2.3%-6.5%). The highest yield was found among
children aged <5 years (10.0%, 95% CI: 3.6%-24.7%). Household contact screening
should be strengthened, continued, and scaled up for all MDR-TB patients in
Myanmar.

DOI: 10.3390/tropicalmed5010002
PMID: 31881646

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4. Population pharmacokinetics and dosing of ethionamide in children with tuberculosis.
Antimicrob Agents Chemother. 2019 Dec 23. pii: AAC.01984-19. doi:
10.1128/AAC.01984-19. [Epub ahead of print]

Bjugård Nyberg H(1), Draper HR(2), Garcia-Prats AJ(2), Thee S(3), Bekker A(2),
Zar HJ(4), Hooker AC(1), Schaaf HS(2), McIlleron H(5), Hesseling AC(2), Denti
P(6).

Ethionamide has proven efficacy against both drug-susceptible and some
drug-resistant strains of Mycobacterium tuberculosis Limited information is
available on its pharmacokinetics in children, and current doses are extrapolated
from weight-based adult doses. Paediatric doses based on more robust evidence is
expected to improve antituberculosis treatment, especially in small children. In
this analysis, ethionamide concentrations in children were pooled from 2
observational clinical studies conducted in Cape Town, South Africa. All children
received ethionamide once-daily with weight-based dosing of approximately 20
mg/kg [range 10.4-25.3], in combination with other first- or second-line
antituberculosis medications, and with antiretroviral therapy in cases of HIV
co-infection. Pharmacokinetic parameters were estimated using nonlinear
mixed-effects modelling. MDR-PK1 contributed 110 children on treatment for
multidrug-resistant tuberculosis, while DATiC contributed 9 children treated for
drug-susceptible tuberculosis, with a combined median [range] age of 2.6 years
[0.23-15], weight of 12.5 kg [2.5-66]. A one-compartment, transit absorption
model with first-order elimination best described ethionamide pharmacokinetics in
children. Allometric scaling of clearance (typical value 8.88 L/h), volume of
distribution (typical value 21.4 L), and maturation of clearance and absorption
improved the model fit. HIV co-infection decreased ethionamide bioavailability by
22%, rifampicin co-administration increased clearance by 16%, and nasogastric
tube administration increased the rate, but not extent, of absorption. The
developed model was used to predict paediatric doses achieving the same drug
exposure as in 50-70 kg adults receiving 750-mg once-daily dosing. Based on model
predictions, we recommend a weight-banded paediatric dosing scheme using scored
125-mg tablets.

Copyright © 2019 American Society for Microbiology.

DOI: 10.1128/AAC.01984-19
PMID: 31871093

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5. Feasibility of Identifying Household Contacts of Rifampin-and Multidrug-resistant Tuberculosis Cases at High Risk of Progression to Tuberculosis Disease.
Clin Infect Dis. 2020 Jan 16;70(3):425-435. doi: 10.1093/cid/ciz235.

Gupta A(1)(2), Swindells S(3), Kim S(4), Hughes MD(5), Naini L(6), Wu X(5),
Dawson R(7), Mave V(1)(2), Sanchez J(8), Mendoza A(9), Gonzales P(8), Kumarasamy
N(10), Comins K(11), Conradie F(12), Shenje J(13), Fontain SN(14), Garcia-Prats
A(15), Asmelash A(16), Nedsuwan S(17), Mohapi L(18), Lalloo UG(19), Ferreira
ACG(20), Mugah C(21), Harrington M(22), Jones L(4), Cox SR(1), Smith B(23), Shah
NS(24), Hesseling AC(15), Churchyard G(25)(26)(27).

BACKGROUND: We assessed multidrug-resistant tuberculosis (MDR-TB) cases and their
household contacts (HHCs) to inform the development of an interventional clinical
trial.
METHODS: We conducted a cross-sectional study of adult MDR-TB cases and their
HHCs in 8 countries with high TB burdens. HHCs underwent symptom screenings,
chest radiographies, sputum TB bacteriologies, TB infection (TBI) testing
(tuberculin skin test [TST] and interferon gamma release assay [IGRA]), and human
immunodeficiency virus (HIV) testing.
RESULTS: From October 2015 to April 2016, 1016 HHCs from 284 MDR-TB cases were
enrolled. At diagnosis, 69% of MDR-TB cases were positive for acid-fast bacilli
sputum smears and 43% had cavitary disease; at study entry, 35% remained smear
positive after a median MDR-TB treatment duration of 8.8 weeks. There were 9 HHCs
that were diagnosed with TB prior to entry and excluded. Of the remaining 1007
HHCs, 41% were male and the median age was 25 years. There were 121 (12%) HHCs
that had new cases of TB identified: 17 (2%) were confirmed, 33 (3%) probable,
and 71 (7%) possible TB cases. The TBI prevalence (defined as either TST or IGRA
positivity) was 72% and varied by age, test used, and country. Of 1007 HHCs, 775
(77%) were considered high-risk per these mutually exclusive groups: 102 (10%)
were aged <5 years; 63 (6%) were aged ≥5 and were infected with HIV; and 610
(61%) were aged ≥5 years, were negative for HIV or had an unknown HIV status, and
were TBI positive. Only 21 (2%) HHCs were on preventive therapy.
CONCLUSIONS: The majority of HHCs in these high-burden countries were at high
risk of TB disease and infection, yet few were receiving routine preventive
therapy. Trials of novel, preventive therapies are urgently needed to inform
treatment policy and practice.

© The Author(s) 2019. Published by Oxford University Press for the Infectious
Diseases Society of America. All rights reserved. For permissions, e-mail:
journals.permissions@oup.com.

DOI: 10.1093/cid/ciz235
PMID: 30942853

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