From our March Newsletter!

1. Triumph and Tragedy of 21st Century Tuberculosis Drug Development.
N Engl J Med. 2020 Mar 5;382(10):959-960. doi: 10.1056/NEJMe2000860.

Thwaites G(1), Nahid P(1).

Comment on
    N Engl J Med. 2020 Mar 5;382(10):893-902.

DOI: 10.1056/NEJMe2000860
PMID: 32130819  [Indexed for MEDLINE]

This article is not available via open access. 

2. Treatment of Highly Drug-Resistant Pulmonary Tuberculosis.
N Engl J Med. 2020 Mar 5;382(10):893-902. doi: 10.1056/NEJMoa1901814.

Conradie F(1), Diacon AH(1), Ngubane N(1), Howell P(1), Everitt D(1), Crook
AM(1), Mendel CM(1), Egizi E(1), Moreira J(1), Timm J(1), McHugh TD(1), Wills
GH(1), Bateson A(1), Hunt R(1), Van Niekerk C(1), Li M(1), Olugbosi M(1),
Spigelman M(1); Nix-TB Trial Team.

Collaborators: Mvuna N, Upton C, Vanker N, Greyling L, Eriksson M, Fabiane SM,
Canseco JO, Solanki P.

Comment in
    N Engl J Med. 2020 Mar 5;382(10):959-960.

BACKGROUND: Patients with highly drug-resistant forms of tuberculosis have
limited treatment options and historically have had poor outcomes.
METHODS: In an open-label, single-group study in which follow-up is ongoing at
three South African sites, we investigated treatment with three oral drugs –
bedaquiline, pretomanid, and linezolid – that have bactericidal activity against
tuberculosis and to which there is little preexisting resistance. We evaluated
the safety and efficacy of the drug combination for 26 weeks in patients with
extensively drug-resistant tuberculosis and patients with multidrug-resistant
tuberculosis that was not responsive to treatment or for which a second-line
regimen had been discontinued because of side effects. The primary end point was
the incidence of an unfavorable outcome, defined as treatment failure
(bacteriologic or clinical) or relapse during follow-up, which continued until 6
months after the end of treatment. Patients were classified as having a favorable
outcome at 6 months if they had resolution of clinical disease, a negative
culture status, and had not already been classified as having had an unfavorable
outcome. Other efficacy end points and safety were also evaluated.
RESULTS: A total of 109 patients were enrolled in the study and were included in
the evaluation of efficacy and safety end points. At 6 months after the end of
treatment in the intention-to-treat analysis, 11 patients (10%) had an
unfavorable outcome and 98 patients (90%; 95% confidence interval, 83 to 95) had
a favorable outcome. The 11 unfavorable outcomes were 7 deaths (6 during
treatment and 1 from an unknown cause during follow-up), 1 withdrawal of consent
during treatment, 2 relapses during follow-up, and 1 loss to follow-up. The
expected linezolid toxic effects of peripheral neuropathy (occurring in 81% of
patients) and myelosuppression (48%), although common, were manageable, often
leading to dose reductions or interruptions in treatment with linezolid.
CONCLUSIONS: The combination of bedaquiline, pretomanid, and linezolid led to a
favorable outcome at 6 months after the end of therapy in a high percentage of
patients with highly drug-resistant forms of tuberculosis; some associated toxic
effects were observed. (Funded by the TB Alliance and others;
number, NCT02333799.).

Copyright © 2020 Massachusetts Medical Society.

DOI: 10.1056/NEJMoa1901814
PMCID: PMC6955640
PMID: 32130813  [Indexed for MEDLINE]

Read the full article here.
3. Drug-associated adverse events in the treatment of multidrug-resistant tuberculosis: an individual patient data meta-analysis.

Lancet Respir Med. 2020 Mar 16. pii: S2213-2600(20)30047-3. doi:
10.1016/S2213-2600(20)30047-3. [Epub ahead of print]

Lan Z(1), Ahmad N(2), Baghaei P(3), Barkane L(4), Benedetti A(1), Brode SK(5),
Brust JCM(6), Campbell JR(1), Chang VWL(7), Falzon D(8), Guglielmetti L(9),
Isaakidis P(10), Kempker RR(11), Kipiani M(12), Kuksa L(4), Lange C(13),
Laniado-Laborín R(14), Nahid P(15), Rodrigues D(16), Singla R(17), Udwadia
ZF(18), Menzies D(19); Collaborative Group for the Meta-Analysis of Individual
Patient Data in MDR-TB treatment 2017.

Collaborators: Ahmad N, Baghaei P, Barkane L, Benedetti A, Brode SK, Brust J,
Campbell JR, Chang V, Falzon D, Guglielmetti L, Isaakidis P, Kempker RR, Kipiani
M, Kuksa L, Lan Z, Lange C, Laniado-Laborín R, Nahid P, Rodrigues D, Singla R,
Udwadia ZF, Menzies D.

BACKGROUND: Treatment of multidrug-resistant tuberculosis requires long-term
therapy with a combination of multiple second-line drugs. These drugs are
associated with numerous adverse events that can cause severe morbidity, such as
deafness, and in some instances can lead to death. Our aim was to estimate the
absolute and relative frequency of adverse events associated with different
tuberculosis drugs to provide useful information for clinicians and tuberculosis
programmes in selecting optimal treatment regimens.
METHODS: We did a meta-analysis using individual-level patient data that were
obtained from studies that reported adverse events that resulted in permanent
discontinuation of anti-tuberculosis medications. We used a database created for
our previous meta-analysis of multidrug-resistant tuberculosis treatment and
outcomes, for which we did a systematic review of literature published between
Jan 1, 2009, and Aug 31, 2015 (updated April 15, 2016), and requested individual
patient-level information from authors. We also considered for this analysis
studies contributing patient-level data in response to a public call made by WHO
in 2018. Meta-analysis for proportions and arm-based network meta-analysis were
done to estimate the incidence of adverse events for each tuberculosis drug.
FINDINGS: 58 studies were identified, including 50 studies from the updated
individual patient data meta-analysis for multidrug-resistant tuberculosis
treatment. 35 of these studies, with 9178 patients, were included in our
analysis. Using meta-analysis of proportions, drugs with low risks of adverse
event occurrence leading to permanent discontinuation included levofloxacin (1·3%
[95% CI 0·3-5·0]), moxifloxacin (2·9% [1·6-5·0]), bedaquiline (1·7% [0·7-4·2]),
and clofazimine (1·6% [0·5-5·3]). Relatively high incidence of adverse events
leading to permanent discontinuation was seen with three second-line injectable
drugs (amikacin: 10·2% [6·3-16·0]; kanamycin: 7·5% [4·6-11·9]; capreomycin: 8·2%
[6·3-10·7]), aminosalicylic acid (11·6% [7·1-18·3]), and linezolid (14·1%
[9·9-19·6]). Risk of bias in selection of studies was judged to be low because
there were no important differences between included and excluded studies.
Variability between studies was significant for most outcomes analysed.
INTERPRETATION: Fluoroquinolones, clofazimine, and bedaquiline had the lowest
incidence of adverse events leading to permanent drug discontinuation, whereas
second-line injectable drugs, aminosalicylic acid, and linezolid had the highest
incidence. These results suggest that close monitoring of adverse events is
important for patients being treated for multidrug-resistant tuberculosis. Our
results also underscore the urgent need for safer and better-tolerated drugs to
reduce morbidity from treatment itself for patients with multidrug-resistant
FUNDING: Canadian Institutes of Health Research, Centers for Disease Control and
Prevention (USA), American Thoracic Society, European Respiratory Society, and
Infectious Diseases Society of America.

Copyright © 2020 World Health Organization. Published by Elsevier Ltd. All rights
reserved. Published by Elsevier Ltd.. All rights reserved.

DOI: 10.1016/S2213-2600(20)30047-3
PMID: 32192585

This article is not available via open access.

4. Sources of multi-drug resistance in patients with previous isoniazid resistant tuberculosis identified using whole genome sequencing: A longitudinal cohort study.
Clin Infect Dis. 2020 Mar 13. pii: ciaa254. doi: 10.1093/cid/ciaa254. [Epub ahead
of print]

Srinivasan V(1)(2), Ha VTN(1), Vinh DN(1), Thai PVK(3), Ha DTM(3), Lan NH(3), Hai
HT(1), Walker TM(2), Thu DDA(1), Dunstan SJ(4), Thwaites GE(1)(2), Ashton
PM(1)(2), Caws M(5), Thuong NTT(1).

BACKGROUND: Meta-analysis of patients with isoniazid-resistant tuberculosis given
standard first-line anti-tuberculosis treatment indicated an increased risk of
multi-drug resistant tuberculosis (MDR-TB) emerging (8%), compared to
drug-sensitive tuberculosis (0.3%). Here we use whole genome sequencing (WGS) to
investigate whether treatment of patients with pre-existing isoniazid resistant
disease with first-line anti-tuberculosis therapy risks selecting for rifampicin
resistance, and hence MDR-TB.
METHODS: Patients with isoniazid-resistant pulmonary TB were recruited and
followed up for 24 months. Drug-susceptibility testing was performed by
Microscopic observation drug-susceptibility assay (MODS), Mycobacterial Growth
Indicator Tube (MGIT) and by WGS on isolates at first presentation and in the
case of re-presentation. Where MDR-TB was diagnosed, WGS was used to determine
the genomic relatedness between initial and subsequent isolates. De novo
emergence of MDR-TB was assumed where the genomic distance was five or fewer
single nucleotide polymorphisms (SNPs) whereas reinfection with a different
MDR-TB strain was assumed where the distance was 10 or more SNPs.
RESULTS: 239 patients with isoniazid-resistant pulmonary tuberculosis were
recruited. Fourteen (14/239, 5.9%) patients were diagnosed with a second episode
of tuberculosis that was multi-drug resistant. Six (6/239, 2.5%) were identified
as having evolved MDR-TB de novo and six as having been re-infected with a
different strain. In two cases the genomic distance was between 5-10 SNPs and
therefore indeterminate.
CONCLUSIONS: In isoniazid-resistant TB, de novo emergence and reinfection of
MDR-TB strains equally contributed to MDR development. Early diagnosis and
optimal treatment of isoniazid resistant TB are urgently needed to avert the de
novo emergence of MDR-TB during treatment.

© The Author(s) 2020. Published by Oxford University Press for the Infectious
Diseases Society of America.

DOI: 10.1093/cid/ciaa254
PMID: 32166306

Read the full article here.

5. Improving Quality of Patient Data for Treatment of Multidrug- or Rifampin-Resistant Tuberculosis.
Emerg Infect Dis. 2020 Mar;26(3). doi: 10.3201/eid2603.190997. Epub 2020 Mar 17.

Campbell JR, Falzon D, Mirzayev F, Jaramillo E, Migliori GB, Mitnick CD, Ndjeka
N, Menzies D.

International policy for treatment of multidrug- and rifampin-resistant
tuberculosis (MDR/RR TB) relies largely on individual patient data (IPD) from
observational studies of patients treated under routine conditions. We prepared
guidance on which data to collect and what measures could improve consistency and
utility for future evidence-based recommendations. We highlight critical stages
in data collection at which improvements to uniformity, accuracy, and
completeness could add value to IPD quality. Through a repetitive development
process, we suggest essential patient- and treatment-related characteristics that
should be collected by prospective contributors of observational IPD in MDR/RR

DOI: 10.3201/eid2603.190997
PMCID: PMC7045826
PMID: 31922953

Read the full article here.

6. Standardised shorter regimens versus individualised longer regimens for rifampin- or multidrug-resistant tuberculosis.
Eur Respir J. 2020 Mar 20;55(3). pii: 1901467. doi: 10.1183/13993003.01467-2019.
Print 2020 Mar.

Abidi S(1)(2), Achar J(3), Assao Neino MM(4), Bang D(5), Benedetti A(1)(2)(6),
Brode S(7), Campbell JR(1)(2), Casas EC(8), Conradie F(9), Dravniece G(10), du
Cros P(3)(11), Falzon D(12), Jaramillo E(12), Kuaban C(13), Lan Z(1)(2), Lange
C(14)(15)(16)(17), Li PZ(2), Makhmudova M(18), Maug AKJ(19), Menzies D(1)(2),
Migliori GB(20), Miller A(21), Myrzaliev B(22), Ndjeka N(23), Noeske J(24),
Parpieva N(25), Piubello A(19)(26), Schwoebel V(26), Sikhondze W(27), Singla
R(28), Souleymane MB(19), Trébucq A(26), Van Deun A(29), Viney K(30)(31)(32),
Weyer K(12), Zhang BJ(1)(2), Ahmad Khan F(33)(2).

Comment in
    Eur Respir J. 2020 Mar 20;55(3):.

We sought to compare the effectiveness of two World Health Organization
(WHO)-recommended regimens for the treatment of rifampin- or multidrug-resistant
(RR/MDR) tuberculosis (TB): a standardised regimen of 9-12 months (the “shorter
regimen”) and individualised regimens of ≥20 months (“longer regimens”).We
collected individual patient data from observational studies identified through
systematic reviews and a public call for data. We included patients meeting WHO
eligibility criteria for the shorter regimen: not previously treated with
second-line drugs, and with fluoroquinolone- and second-line injectable
agent-susceptible RR/MDR-TB. We used propensity score matched, mixed effects
meta-regression to calculate adjusted odds ratios and adjusted risk differences
(aRDs) for failure or relapse, death within 12 months of treatment initiation and
loss to follow-up.We included 2625 out of 3378 (77.7%) individuals from nine
studies of shorter regimens and 2717 out of 13 104 (20.7%) individuals from 53
studies of longer regimens. Treatment success was higher with the shorter regimen
than with longer regimens (pooled proportions 80.0% versus 75.3%), due to less
loss to follow-up with the former (aRD -0.15, 95% CI -0.17- -0.12). The risk
difference for failure or relapse was slightly higher with the shorter regimen
overall (aRD 0.02, 95% CI 0-0.05) and greater in magnitude with baseline
resistance to pyrazinamide (aRD 0.12, 95% CI 0.07-0.16),
prothionamide/ethionamide (aRD 0.07, 95% CI -0.01-0.16) or ethambutol (aRD 0.09,
95% CI 0.04-0.13).In patients meeting WHO criteria for its use, the standardised
shorter regimen was associated with substantially less loss to follow-up during
treatment compared with individualised longer regimens and with more failure or
relapse in the presence of resistance to component medications. Our findings
support the need to improve access to reliable drug susceptibility testing.

The content of this work is copyright of the authors or their employers. Design
and branding are copyright ©ERS 2020.

DOI: 10.1183/13993003.01467-2019
PMID: 31862767

Read the full article here.