BMJ m216 Full

STATE OF THE ART REVIEW
Current and future treatments for tuberculosis
BMJ: first published as 10.1136/bmj.m216 on 2 March 2020. Downloaded from http://www.bmj.com/ on 22 May 2020 by guest. Protected by copyright.
Anthony Lee,1,2 Yingda Linda Xie,2,3 Clifton E Barry,2 Ray Y Chen2
A BST RAC T
1
Guidelines on the treatment of tuberculosis (TB) have essentially remained the same
Medical Research Scholars
Program, National Institutes of for the past 35 years, but are now starting to change. Ongoing clinical trials will
Health, Bethesda, MD, USA
2
hopefully transform the landscape for treatment of drug sensitive TB, drug resistant
Tuberculosis Research
Section, Laboratory of Clinical TB, and latent TB infection. Multiple trials are evaluating novel agents, repurposed
Immunology and Microbiology,
Division of Intramural Medicine, agents, adjunctive host directed therapies, and novel treatment strategies that will
National Institute of Allergy and
Infectious Diseases, National
increase the probability of success of future clinical trials. Guidelines for HIV-TB co-
Institutes of Health, Bethesda, infection treatment continue to be updated and drug resistance testing has been
MD, USA
3
Division of Infectious Diseases, revolutionized in recent years with the shift from phenotypic to genotypic testing and
Department of Medicine,
Rutgers New Jersey Medical
the concomitant increased speed of results. These coming changes are long overdue
School, Newark, NJ, USA and are sorely needed to address the vast disparities in global TB incidence rates.
Correspondence to: RY Chen
ray.chen@nih.gov TB is currently the leading cause of death globally from a single infectious agent, but
Cite this as: BMJ 2020;368:m216 the work of many researchers and the contributions of many patients in clinical trials
http://dx.doi.org/10.1136/bmj.m216
Series explanation: State of the
will reduce the substantial global morbidity and mortality of the disease.
Art Reviews are commissioned
on the basis of their relevance
to academics and specialists
in the US and internationally. Introduction Incidence/prevalence
For this reason they are written Tuberculosis (TB) is the leading cause of death According to WHO estimates, in 2018 10 million
predominantly by US authors. globally from a single infectious agent, even people developed TB globally, for an incidence of
surpassing HIV.1 To achieve the World Health 132/100 000 people. This global average, however,
Organization’s End TB Strategy (a 90% decrease in hides the vast disparities between developed
TB incidence and 95% decrease in TB mortality by and developing countries. Almost all cases are
2035 compared with 2015) requires shorter and concentrated in South East Asia (44%), Africa
more effective treatment regimens for drug sensitive (24%), and the western Pacific (18%) regions. The
(DS) and multidrug resistant (MDR) TB (disease eastern Mediterranean accounts for 8.1%, Americas
resistant to the two first line drugs isoniazid and 2.9%, and Europe 2.6% of cases. The highest income
rifampin). Treatment for latent TB infection also countries have incidence rates of <10/100 000
needs to be shorter in duration and targeted to people, while the countries with the highest rates
individuals at risk of progression to be practical and are >50-fold higher, exceeding 500/100 000 people.
effective globally. The current poor global control of Although global rates of DS-TB are slowly decreasing,
TB is due in part to the lack of research innovation rates of MDR-TB are decreasing less quickly, affecting
over the past few decades; current DS-TB treatment 3.4% of new TB cases and 18% of previously treated
guidelines have been essentially unchanged for cases. Even more challenging to treat is XDR-TB: MDR-
35 years and treatment still takes a minimum six TB with additional resistance to fluoroquinolones
months. Randomized controlled clinical trials for and injectable aminoglycosides. An estimated 6.2%
TB treatments are often challenging to complete of MDR-TB cases were actually XDR-TB in 2018.1
because of the extended duration of treatment (six
months for DS-TB and up to 24 months for MDR/ Sources and selection criteria
extensively drug resistant (XDR)-TB) and follow-up We searched PubMed for clinical trials of treatments
times (often one year after treatment completion) for active and latent TB, including host directed
required to confirm cure in standard of care control therapies (HDT), through September 2019 and
arms. The good news is that multiple clinical trials for included only English language peer reviewed
DS-TB, MDR-TB, XDR-TB, and latent TB are ongoing, articles. We used terms including “active tuberculosis
and early results have led to important changes in clinical trial,” “latent tuberculosis clinical trial,”
the MDR-TB treatment guidelines. Unlike the last “drug sensitive,” “drug resistant,” and “HDT.” We
30+ years, the next five years should continue to prioritized randomized controlled trials, but we also
bring about major changes in the treatment of TB. included some notable non-controlled interventional
This review summarizes the current state of TB trials. Case reports, case series, and observational
treatment with an emphasis on the ongoing clinical trials were generally excluded. We also searched the
trials to anticipate how guidelines may change in the references used in current TB treatment guidelines
coming years. and relevant systematic review articles, prioritizing
the bmj | BMJ 2020;368:m216 | doi: 10.1136/bmj.m216 1

the most recent articles. In addition, because ongoing In the 1980s results from subsequent trials led to
trials do not yet have published results, we searched formation of the currently recommended regimen of
clinical trials registries, primarily www.clinicaltrials. isoniazid, rifampin, pyrazinamide, and ethambutol
gov. We conducted a general internet search to look for six months. The duration of treatment was
for additional information on registered clinical established after increased relapse rates were seen in
trials or to identify clinical trials registered with other trials of less than six months’ duration.3-7 Incredibly,
clinical trials registries. despite the advent of newer drugs, this first line
regimen has not changed for more than 35 years.
Active TB treatment The coming decade is likely to change this for DS-
History of TB treatment TB and MDR-TB, with many clinical trials expected
Treatment of tuberculosis has relied on multidrug to be completed in the next several years (fig 1).
chemotherapy to achieve three objectives: However, the factors that allowed testing every
combination of drug, dose, and duration viable in
• To rapidly reduce mycobacterial burden to
the 1940s through 1970s—limited numbers of drugs,
decrease disease morbidity, mortality, and
abundance of patients, and relatively few concurrent
transmission
trials competing to enroll—are no longer true today.
• To eradicate persistent mycobacterial
To optimize the limited resources and increase the
populations to prevent relapse
chance of clinical trials success, better methodologies
• To prevent acquisition of drug resistance.
are needed, possibly based on optimized biomarkers
Before the development of effective chemotherapy, such as the NexGen EBA trial (described below), to
TB treatment was essentially palliative care in determine the best combinations of drugs to take
sanatoriums with fresh air and sunlight. The age of forward into advanced stage clinical trials.
TB chemotherapy began with the discovery of anti-
tuberculosis compounds, beginning with streptomycin Trials of shortening treatment for drug sensitive TB
and para-aminosalicylic acid (PAS) in 1944. Recent efforts to shorten duration of chemotherapy
Reviews of historical TB treatment trials date back for DS-TB have focused on incorporating a
to the 1940s, including the initial trial of PAS versus fluoroquinolone or using higher doses of a rifamycin.
streptomycin to treat TB in 1944, which was one of the The fluoroquinolone based strategies faced a major
first randomized controlled chemotherapy trials ever setback with the failure of three large trials in 2014,8-10
conducted.2 These landmark studies encompassed despite higher rates of sputum culture conversion at
dozens of randomized controlled trials of a few two months in the fluoroquinolone arms in two of
hundred participants each across Africa, India, Hong these trials.8 9 There is only one ongoing trial to our
Kong, and the UK, and investigated the most optimal knowledge, conducted by the Beijing Chest Hospital,
drug doses and combinations. These trials resulted in which is still attempting a fluoroquinolone strategy
an initial “triple therapy” combination of isoniazid, by continuing all four intensive phase drugs with or
PAS, and streptomycin for 24 months in the 1950s without levofloxacin for 4.5 months (table 1). Data
that cured 90-95% of patients. from trials conducted in the 1970s and 1980s by the

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Fig 1 | Timeline of ongoing active TB clinical trials with start dates and projected end dates
2 doi: 10.1136/bmj.m216 | BMJ 2020;368:m216 | the bmj

British Medical Research Council suggested that the sputum, urine, and other imaging biomarkers that
sterilizing activity of pyrazinamide was limited to the correlate with PET/CT results and are more amenable
initial eight weeks of treatment, owing to the acidic to being scaled up globally.
environment required for pyrazinamide activation.11 In contrast to PredictTB, which only uses the
It remains to be seen whether the extension of four first line TB drugs, TRUNCATE-TB is a multi-
intensive phase treatment and adding levofloxacin arm, multi-stage trial that incorporates high dose
to 4.5 months will be sufficient for successful rifamycins and various combinations of linezolid,
shortening of treatment. clofazimine, levofloxacin, or bedaquiline into four
Two other ongoing trials attempt to shorten two month treatment regimens. Patients who relapse
treatment by increasing the dose of the rifamycin, are retreated with standard four drug therapy for
rifampin, or rifapentine. There is substantial evidence six months with the hypothesis that this overall
to support that rifampin dosed at the recommended strategy will be non-inferior to standard six month
10 mg/kg is well below its therapeutic threshold and treatment outcomes at two years.19 Both PredictTB
that much higher doses, even ≥35 mg/kg, may be safe and TRUNCATE-TB build on previously gathered
and effective.12 13 These studies suggest that high data that show most patients are successfully treated
dose rifampin may shorten treatment based on faster before six months.3 The PredictTB strategy identifies
rates of sputum culture conversion achieved.14-16 these patients prospectively, then shortens treatment
The caveat is that earlier sputum culture conversion only for this cohort. The TRUNCATE-TB strategy
may not result in earlier cure, as shown by the failure shortens treatment for everyone to two months using
of the fluoroquinolone treatment shortening trials. a more intense intensive phase regimen, assuming
The RIFASHORT trial takes the surrogate results that those who relapse will not develop resistance
to a phase III trial, testing a standard of care (SOC) and can still be cured with subsequent standard six
arm with rifampin 600 mg (10 mg/kg) daily against month therapy. In the end, a combination of these two
two experimental four month treatment arms using strategies may be the most successful in maximizing
rifampin 1200 mg or 1800 mg. The TBTC Study cure rates with minimal treatment burden.
31 trial tests a SOC arm against two experimental
rifapentine 1200 mg daily arms (instead of rifampin), Drug resistant TB treatment shortening trials
with the second arm also adding moxifloxacin An estimated 8% of TB patients globally have
400 mg daily. Results are expected in 2020 and, if isoniazid resistant but rifampin susceptible TB. In
successful, would be the first successful four month 2018, WHO updated its treatment guidelines for
DS-TB trials to date. isoniazid resistant TB to recommend levofloxacin,
In contrast to these trials which evaluate new or rifampin, pyrazinamide, and ethambutol for six
modified drug regimens, two trials are investigating months.20 More worrisome, however, is rifampin
treatment shortening strategies—PredictTB and resistance. WHO estimates that only 55% of the
TRUNCATE-TB. The presentation of TB is quite estimated 558 000 incident cases of rifampin
variable, so some individuals will likely need longer resistant (RR-TB) and MDR-TB in 2017 successfully
therapy than others no matter what regimen is used. completed treatment.1
Prospectively identifying this higher risk group can The landscape of RR-TB and MDR-TB treatment
help target treatment duration appropriately. was, for many years, defined by prolonged treatment
PredictTB is based on a previously conducted (20-24 months) with older drugs that had substantial
trial that shortened therapy to four months among side effects and required daily injections for the
394 pulmonary TB patients with less severe disease initial eight months. This began to change with the
at baseline, defined as no cavity on baseline chest publication of the “Bangladesh regimen” in 2010,
radiograph, and with sufficient early treatment which touted a successful nine month treatment
response, defined as conversion of month 2 sputum regimen with daily injections only for the initial
culture to negative.17 Although this trial failed to four months.21 However, because the trial was an
achieve its predefined 5% non-inferiority margin, uncontrolled observational study of sequential
the researchers’ algorithm for patient stratification treatment arms, questions were raised about the
increased the treatment success rate in the four validity of these results.
month arm from around 80% seen in other non- A slightly modified Bangladesh regimen was
stratified four month treatment trials to 93% in their therefore tested within a rigorous randomized
trial. The PredictTB trial revises the baseline disease controlled trial (Standard Treatment Regimen of
stratification from chest radiograph to FDG-positron Anti-Tuberculosis Drugs for Patients with MDR-TB
emission tomography/computed tomography (PET/ [STREAM]) comparing the nine month experimental
CT) scan. Appropriate disease response is also arm with a 20 month SOC control arm that followed
changed from month 2 sputum culture conversion the 2011 WHO guidelines. This trial enrolled
to reduction in PET/CT disease burden at month 1 424 participants and showed that the shortened
and sputum GeneXpert cycle threshold increase at nine month arm was non-inferior (using a 10%
month 4.18 If the trial is successful, this strategy of margin) to the standard 20 month arm.22 WHO had
shortening treatment only among those less severely recommended the shortened nine month treatment
diseased could also be evaluated among MDR-TB regimen for uncomplicated MDR-TB (no additional
cases. In addition, investigation will focus on blood, resistance to fluoroquinolones or injectable agents) in

4
Table 1 | Ongoing trials of shortening treatment for drug sensitive, multi-drug resistant, and extensively drug resistant TB
Include Study Estimated Website/clinical trials
Name Study design Arms HIV+? Sites started completion date registration Notes
Drug sensitive (DS) TB trials
Shortened regimens for Randomized, controlled, Arm 1: Control 2HRZE/4HR No China Aug-16 Dec-20 https://clinicaltrials.gov/ct2/
drug sensitive pulmonary TB non-inferiority trial show/NCT02901288
(Beijing Chest Hospital)
Non-inferiority margin 5% Arm 2: HRZELe ×4.5 months https://www.ncbi.nlm.nih.gov/
pubmed/28629333
Sample size: 3900 Arm 3: HRZE ×4.5 months
Randomized trial to evaluate Randomized controlled Arm 1: Control 2HRZE/4HR; No Botswana, Uganda, Peru Feb-17 Jan-20 https://www.newtbdrugs.org/
toxicity and efficacy of 1200 phase III trial rifampin dosed at 600 mg (10 pipeline/trials/rifashort
mg and 1800 mg rifampicin mg/kg)
for pulmonary tuberculosis
(RIFASHORT)
Sample size: 654 Arm 2: 2HRZE/2HR; rifampin https://clinicaltrials.gov/ct2/

dosed at 1200 mg show/NCT02581527
Primary outcome: failure/ Arm 3: 2HRZE/2HR; rifampin http://apps.who.int/trialsearch/
relapse 12 months after dosed at 1800 mg Trial2.aspx?TrialID=PER-007-17
enrollment
Rifapentine containing Randomized phase III trial Arm 1: Control 2HRZE/4HR Yes, USA, Brazil, China, Haiti, Jan-16 Dec-20 https://clinicaltrials.gov/ct2/
treatment shortening CD4 ≥100 India, Kenya, Malawi, show/NCT02410772
regimens for pulmonary TB Peru, South Africa,
(TBTC study 31/ACTG study Thailand, Uganda,
A5349) Vietnam, Zimbabwe
Sample size: 2516 Arm 2: 2HPZE/2HP; rifapentine
1200 mg daily
Primary outcome: disease Arm 3: 2HPZM/2HPM;
free survival 12 months after rifapentine 1200 mg daily
enrollment
Using biomarkers to predict Partially randomized phase Arm 1: 2HRZE/4HR (non- No South Africa, China Jun-17 Dec-22 https://clinicaltrials.gov/ct2/ Strategy trial
TB treatment duration II study randomized) show/NCT02821832
(PredictTB)
Sample size: 310 to Arm 2: 2HRZE/4HR (randomized https://www.ncbi.nlm.nih.gov/
randomized arms (2 and 3) control) pubmed/29528048
More heavily diseased Arm 3: 2HRZE/2HR (randomized
stratified to arm 1. Less experimental)
heavily diseased randomized
to arms 2 and 3.
Two month regimens Randomized multi-arm, Arm 1: 2HRZE/4HR (control) No Philippines, Singapore, Mar-18 Mar-22 https://clinicaltrials.gov/ct2/ Primary outcome is unfavorable
using novel combinations multi-stage adaptive study Thailand show/NCT03474198 outcome at 96 weeks with
to augment treatment hypothesis that TRUNCATE
effectiveness for DS-TB management strategy non-
(TRUNCATE-TB) inferior to standard treatment
Relapses will be re-treated Arm 2: 2HR35ZELi* https://www.ijidonline.
with standard 6-month com/article/S1201-
therapy 9712(16)30842-6/fulltext
Sample size 900 (180/arm) Arm 3: 2HR35ZEC*
Severe disease excluded Arm 4: 2HPZLiLe*
(smear 3+, chest radiograph
cavity >4 cm), poorly
controlled diabetes mellitus
Hypothesis is non-inferiority Arm 5: 2HZELiB*
at 2 years
doi: 10.1136/bmj.m216 | BMJ 2020;368:m216 | the bmj

Table 1 | Continued
*If persistent symptoms and
smear+ at week 8, extend
treatment to week 12; if
persistent symptoms and
smear+ at week 12, switch to
standard treatment and extend
to 24 weeks
R35: rifampin 35 mg/kg
(standard is 10 mg/kg)
NC-008 trial to evaluate Partially randomized phase Arm 1: Control 2HRZE/4HR Yes, Brazil, Ethiopia, Georgia, Aug-18 Jan-22 https://clinicaltrials.gov/ct2/ Although this trial follows
the efficacy, safety, and IIc trial CD4 ≥100 Malaysia, Philippines, show/NCT03338621 patients for two years after
tolerability of PaMZ in DS-TB Russian Federation, enrollment, primary outcome
adult patients and DR-TB South Africa, Tanzania, measure is time to culture
the bmj | BMJ 2020;368:m216 | doi: 10.1136/bmj.m216

adult patients (SimpliciTB) Thailand, Uganda conversion over eight weeks.
Unfavorable outcomes at 52
and 104 weeks are secondary
outcome measures
Sample size: 450 Arm 2 (DS-TB):
2B200PaMZ/2B100PaMZ
Fluoroquinolone-sensitive Arm 3 (DR-TB):
2B200PaMZ/4B100PaMZ
DR-TB: resistant to H and/ B200: bedaquiline 200 mg
or R daily; B100: bedaquiline 100
mg daily
Multidrug resistant (MDR) TB trials
NC-008 Trial to evaluate Partially randomized phase Arm 1: Control 2HRZR/4HR Yes, Jul-18 Jan-22 https://clinicaltrials.gov/ct2/ Although this trial follows
the efficacy, safety and IIc trial CD4 ≥100 show/NCT03338621 patients for two years after
tolerability of BPaMZ in DS- enrollment, primary outcome
TB adult patients and DR-TB Brazil, Ethiopia, Georgia, measure is time to culture
adult patients (SimpliciTB) Malaysia, Philippines, conversion over eight weeks.
Russian Federation, Unfavorable outcomes at 52
South Africa, Tanzania, and 104 weeks are secondary
Thailand, Uganda outcome measures
Sample size: 450 Arm 2 (DS-TB): https://pubmed.ncbi.nlm.nih.
2B200PaMZ/2B100PaMZ gov/31732485
Fluoroquinolone sensitive Arm 3 (DR-TB):
2B200PaMZ/4B100PaMZ
DR-TB: resistant to H and/ B200: bedaquiline 200 mg
or R daily; B100: bedaquiline 100
mg daily
Efficacy and safety of
levofloxacin for the Arm 1: optimized background
treatment of MDR-TB regimen (OBR) with levofloxacin https://clinicaltrials.gov/ct2/
(Opti-Q) Randomized clinical trial 11 mg/kg daily (control) Yes Peru, South Africa Jan-15 Mar-20 show/NCT01918397
Arm 2: OBR with levofloxacin 14 https://www.ncbi.nlm.nih.gov/
Sample size: 111 enrolled mg/kg daily pubmed/29178937
Primary outcome is time
to culture conversion over Arm 3: OBR with levofloxacin 17
initial 6 months of treatment mg/kg daily
Arm 4: OBR with levofloxacin 20
mg/kg daily
5
6
Table 1 | Continued
Evaluation of a standard Randomized controlled Arm 1: WHO standard of care Yes, Ethiopia, Georgia, India, Apr-16 Jun-22 https://clinicaltrials.gov/ct2/
treatment regimen for phase III trial; superiority (2011 guidelines) ×20-24 CD4 ≥50 Moldova, Mongolia, show/study/NCT02409290
anti-tuberculosis drugs trial of arm 3 v 2; non- months (Stage 1 control arm) South Africa, Uganda
for patients with MDR-TB inferiority trial with margin
(STREAM) stage 2 10% comparing arms 2 v 3
and 2 v 4
Arm 2: MCEZ ×40 weeks
with HKPr for initial 16 week
intensive phase (stage 2 control http://www.isrctn.com/
Sample size: 1155 arm) ISRCTN18148631
Arm 3: LeCEZB ×40 weeks https://www.newtbdrugs.org/
Fluoroquinolone and with HBPr for initial 16 week pipeline/trials/stream-trial-
aminoglycoside sensitive intensive phase stage-2

Arm 4: LeCZB ×28 weeks with
HK for initial 8 weeks intensive https://www.ncbi.nlm.nih.gov/
phase pubmed/26929418
https://www.ncbi.nlm.nih.gov/
pubmed/30865791
Treatment shortening of Randomized controlled Arm 1: WHO standard of care Yes South Korea Jan-16 Jun-21 https://clinicaltrials.gov/ct2/
MDR-TB using existing and phase II/III trial; non- ×20-24 months (control) show/NCT02619994
new drugs (MDR-END) inferiority trial with margin
10%
Sample size: 238 Arm 2: DLiLeZ ×9-12 months
depending on time of sputum https://www.ncbi.nlm.nih.gov/
culture conversion pubmed/30651149
Fluoroquinolone resistance
excluded
Evaluating a new treatment Randomized controlled trial Arm 1: WHO standard of Yes South Africa Oct-15 Jan-19 https://clinicaltrials.gov/ct2/ contact is Keertan Dheda
regimen for patients with care×20-24 months (control) show/NCT02454205
MDR-TB (NEXT)
Arm 2: BLiLeZ plus (Eth or
H high dose or T) based on
individualized, gene directed
testing×6-9 months; treatment
complete after 3 consecutive
Sample size: 300 negative sputum cultures
No fluoroquinolone or SLID
resistance
Randomized controlled Arm 1: WHO standard of care Yes Georgia, Kazakhstan, Dec-16 Apr-21 https://clinicaltrials.gov/ct2/
Evaluating newly approved phase III non-inferiority trial ×20-24 months (control) Kyrgyzstan, Lesotho, show/NCT02754765
drugs for MDR-TB (endTB) with margin 12% Peru, South Africa
Sample size: 750 Arm 2: BLiMZ ×9 months (39
weeks)
Fluoroquinolone resistance Arm 3: BLiLeCZ ×9 months (39
excluded weeks)
Arm 4: BDLiLeZ ×9 months (39
weeks)
Arm 5: DLiLeCZ ×9 months (39
weeks)
Arm 6: DCMZ ×9 months (39
weeks)

Table 1 | Continued
Pragmatic clinical trial for a Randomized controlled Arm 1: WHO standard of care Yes Belarus, South Africa, Jan-17 Mar-21 https://clinicaltrials.gov/ct2/
more effective concise and phase II/III trial with multi- Uzbekistan show/NCT02589782
less toxic MDR-TB treatment arm, multi-stage adaptive
regimen (TB-PRACTECAL) design
XDR-TB allowed Arm 2: BPaLiM ×24 weeks
Sample size: 630 Arm 3: BPaLiC ×24 weeks
Arm 4: BPaLi ×24 weeks
Refining MDR-TB treatment
regimens for ultra short Arm 1: WHO standard of care ×9 https://clinicaltrials.gov/ct2/
therapy (TB-TRUST) Randomized controlled trial months (control) No China May-19 Dec-22 show/NCT03867136
Arm 2: LiLeZCCy ×4 months
(extend to 6 months if no smear
conversion) then LeZCCy ×2
Sample size: 220 months
Fluoroquinolone and PZA

susceptible
Extensively drug resistant (XDR) TB trials
Evaluating newly approved Randomized controlled Arm 1: WHO standard of care Yes India, Kazakhstan, Jun-19 Dec-22 https://clinicaltrials.gov/ct2/
drugs in combination phase III non-inferiority trial per latest guidelines Lesotho, Pakistan, Peru, show/NCT03896685
regimens for MDR-TB with with margin 12% South Africa
fluoroquinolone resistance
(endTB-Q)
Sample size: 500 Arm 2: BDCLi ×24 weeks
Fluoroquinolone resistance Arm 2: BDCLi ×39 weeks
required
A phase III study assessing Single arm interventional Arm: BPaLi ×6 months; Yes, CD4 South Africa Mar-15 Oct-21 https://clinicaltrials.gov/ct2/ 2018 Union World
the safety and efficacy of trial for XDR-TB or bedaquiline dosed 400 mg >50 show/NCT02333799 Conference slide deck:
bedaquiline plus PA-824 unresponsive MDR-TB once daily ×2 weeks, then 200 https://www.dropbox.com/s/
plus linezolid in subjects mg thrice weekly; linezolid gu8l27grq38psul/Nix%20
with drug resistant dosed 1200 mg once daily TB%20interim%20results%20
pulmonary TB (Nix-TB) -%2010-25-18.pdf?dl=0
FDA advisory vote press release:
https://www.tballiance.org/
news/fda-advisory-committee-
votes-favorably-question-
Sample size: 109 effectiveness-and-safety-
(enrollment complete) pretomanid-combination
Primary outcome is failure/
relapse at 12 months
Safety and efficacy of Phase III randomized Arm 1: B200PaLi1200 ×8 Yes, CD4 Georgia, Moldova, Nov-17 Dec-21 https://clinicaltrials.gov/ct2/
various doses and treatment partially blinded clinical trial weeks, then B100PaLi1200 ≥100 Russian Federation, show/NCT03086486
durations of linezolid plus ×18 weeks South Africa
bedaquiline and pretomanid
in participants with
pulmonary TB, XDR-TB pre-
XDR-TB or non-responsive/
intolerant MDR-TB (ZeNix)
Primary outcome is relapse Arm 2: B200PaLi1200 ×8
or failure through 26 weeks weeks, then B100Pa ×18 weeks
after end of treatment
Linezolid dose/duration Arm 3: B200PaLi600 ×8 weeks,
blinded by placebo then B100PaLi600 ×18 weeks
Sample size: 180 Arm 4: B200PaLi600 ×8 weeks,
then B100Pa ×18 weeks
7
H=isoniazid; R=rifampin; Z=pyrazinamide; E=ethambutol; P=rifapentine; Le=levofloxacin; M=moxifloxacin; B=bedaquiline; D=delamanid; Pa=pretomanid; Li=linezolid; C=clofazimine; Cy=cycloserine; Pr=prothionamide; t=terizidone
2016 and affirmed this recommendation with the control arm was used. Applying control arm results of
results of the STREAM trial. For patients ineligible a separately conducted study can interject misleading
for the nine month regimen, the recommended comparisons owing to varying populations and
treatment duration remains 18-20 months. methodologies, and thus comparing with a historical
WHO 2019 guidelines now recommend an all oral, control increases the risk of unrecognized biases and
bedaquiline-containing regimen to replace injectable confounding factors in the data.25
agents as the preferred treatment regimen.23 24 WHO’s
move toward shorter and all oral regimens for MDR- Pretomanid
TB is also reflected in the ongoing MDR-TB clinical On 14 August 2019, the US Food and Drug
trials. Almost all experimental regimens being tested Administration approved pretomanid, its second
(except for Opti-Q, which began in 2015) are six to novel anti-tuberculous drug in 40 years (bedaquiline
nine months long, and most of the experimental arms was approved in 2012). While additional agents
are completely oral (except for Opti-Q and STREAM against drug resistant TB are critically needed,
stage 2 six month arm intensive phase; table 1). the basis on which pretomanid was approved is
The change in the recommended WHO SOC regimen somewhat controversial.26 27
in duration and composition has implications for Pretomanid was approved only in combination
ongoing trials using the now obsolete 20-24 month with bedaquiline and linezolid to treat XDR-TB
regimens for their control arm (Opti-Q, MDR-END, and non-responsive MDR-TB because this is how it
NEXT, endTB, and TB-PRACTECAL). If enrollment was used in the Nix-TB trial. In that study, 95/107
is ongoing, these trials face the decision of whether (89%) patients had successful outcomes at one
to update their control arm treatment regimen or year and six months after the end of treatment.28 As
duration mid-trial. previously discussed, the Nix-TB trial was a small
Even more problematic are the trials that have single arm trial that relied on a historical control
experimental regimens that are now obsolete, either for comparison, which is problematic given that
because of their duration or inclusion of injectable bedaquiline and linezolid were not included in many
agents. The Opti-Q trial is one of these but, notably, its historical controls. In addition, all patients received
primary endpoint is not final treatment outcome but the same three drugs, two of which are already
the surrogate endpoints of time to culture conversion known to be very active against drug resistant TB. For
by month 6 and safety of higher levofloxacin dosing. example, when single drug linezolid was added to a
The only other trial that still uses an injectable agent failing treatment regimen in XDR-TB patients, 34/39
is the STREAM stage 2 trial six month arm. If the other (87%) converted their sputum culture to negative
trials with all oral six month arms are successful, by six months of treatment.29 Thus, the individual
particularly in the XDR-TB trials, then injectable potency of pretomanid against TB is unknown and
agents will phase out of first line therapy regardless more studies are needed to determine this.
of the treatment duration and level of resistance (eg, Unfortunately, it is unlikely that any of the
MDR-TB plus fluoroquinolone resistance). currently ongoing trials using pretomanid
Among the MDR/XDR-TB trials, there are two other (SimpliciTB, TB-PRACTECAL, Nix-TB, ZeNix) will
major differences between the trials: 1) whether the reveal pretomanid’s potency because of the lack of
trial incorporates a concurrent control arm compared an appropriate comparison arm for this purpose. TB-
with a historical control; and 2) the treatment regimen PRACTECAL, for example, has a WHO SOC control
and duration (six versus nine months). The MDR (non- arm but all three experimental arms contain the
XDR) TB trials all have a WHO standard control arm. Nix-TB regimen just with or without moxifloxacin or
Of the three XDR-TB trials, however, only endTB-Q clofazimine (table 1), leaving the same conundrum
has a concurrent WHO standard control arm. Both where the individual effect of pretomanid cannot be
Nix-TB and ZeNix only include experimental arms differentiated from that of bedaquiline and linezolid.
with no concurrent SOC control arm, with the primary Pretomanid is a bicyclic 4-nitroimidazole, which is
outcome being relapse or failure at 12 months after the same class as delamanid, another novel anti-TB
enrollment. The benefits of not including a control agent that is still trying to find its proper place in the
arm are a smaller sample size and a much shorter landscape of treating drug resistant TB.30
trial, since the WHO SOC control was 20-24 months
at the time these trials began. However, these studies Adjunctive and host directed therapies (HDT)
also incur considerable risk, because if the treatment Augmentation of the host immune response is an
success rate in the experimental arm is below 95%, additional strategy of growing interest to improve
the benefit of the experimental arm may not be clear. treatment efficacy. Current HDT candidates are
In the three contemporaneous fluoroquinolone largely repurposed drugs with pre-clinical evidence
DS-TB treatment shortening trials8-10 for example,
the per protocol favorable outcomes of the control
arms, despite using the same regimen, varied from Table 2 | Study control arm favorable outcome
88.7% (OFLOTUB trial) to 92.0% (REMoxTB trial) to Modified intent to treat Per protocol
95.1% (RIFAQUIN trial; table 2). If the experimental RIFAQUIN 85.6% 95.1%
arm favorable outcome was 85%, whether this was REMoxTB 84.0% 92.0%
a success or failure may differ depending on which OFLOTUB 82.8% 88.7%

for counteracting Mycobacterium tuberculosis in development33 and the more limited number
pathogenesis and survival, augmenting protective of patients available to enroll in trials, testing
immune responses, and/or modulating detrimental every possible combination as done previously is
inflammatory responses that exacerbate disease. impractical. Improved methodologies are needed to
These therapies encompass agents used to treat allow rational selection of the optimal combinations
metabolic and psychiatric conditions, parasitic and durations to take forward into clinical trials.
infections, cancer, and inflammatory conditions, and Current methods rely heavily on early bactericidal
span various stages of pre-clinical and early clinical activity studies,34 which measure the decline in serial
development. sputum colony forming units (CFU) over the initial 14
Treatment endpoints of culture conversion and days of treatment as a measure of sterilizing potency.
durable cure remain relevant to clinical trials of This approach is endorsed by the Global Alliance
most HDTs. However, further considerations include for TB Drug Development35 and the US FDA36 but
how and when to utilize HDTs to complement EBA does not appear to reflect durable cure.37
antibacterial treatment, and how to incorporate Certain drugs, such as rifampin, pyrazinamide, and
clinical biomarkers to investigate or validate linezolid, have relatively low EBA but have been
therapeutic mechanisms. For example, the IMPACT- shown repeatedly to be instrumental in killing TB.
TB study (NCT03891901) evaluating safety and Other drugs, like ethambutol and the
pharmacokinetics of imatinib at varying doses fluoroquinolones, have high EBA but are not
with and without isoniazid and rifabutin in healthy assumed to be very potent clinically (ethambutol
adults, will measure myelopoietic effects, proposed at currently used doses) or have not been
as a key therapeutic mechanism of imatinib (table 3). successful in contributing to treatment shortening
Stage 2 of the StAT-TB trial will evaluate (fluoroquinolones). One possible explanation for
pravastatin as an adjunct to HRZE against time to this is that sputum based methodologies, like EBA,
sputum culture conversion as well as the secondary only sample changes in bacillary populations on
endpoint of improvement of pulmonary function airway or cavity surfaces rather than deep necrotic
among individuals with drug sensitive pulmonary lesion compartments which harbor recalcitrant TB
TB (NCT03456102). Relevant study populations populations that are killed more slowly.
and biomarkers will also depend on the targeted A drug’s ability to shorten treatment may be more
intervention. HDTs targeted to modulate detrimental related to how well it penetrates into necrotic, caseous
inflammatory responses, such as dexamethasone lesions than airway surfaces.38 39 For example, both
(NCT03092817), may include or target individuals pyrazinamide and rifampin diffuse into caseous
with TB meningitis where uncontrolled inflammation lesions well whereas moxifloxacin does not.40 which
is closely associated with morbidity and mortality. may explain why pyrazinamide and rifampin have both
Finally, HDTs that act directly or indirectly via host contributed to DS-TB regimen treatment shortening
responses to disrupt M tuberculosis pathogenesis but moxifloxacin has not. Combining drugs with
may have the greatest impact in treating patients different lesion pharmacokinetic profiles is therefore
with high burden disease or DR-TB, where cure rates an important consideration in rational regimen design.
are lower and disease chronicity and treatment Furthermore, relying only on sputum measurements to
duration are longer. reflect the myriad changes occurring throughout the
Several HDT clinical trials, including a lungs on treatment is likely to be imprecise.
completed phase II study of adjunctive ibuprofen We are conducting a trial called Radiologic and
(NCT02781909; no results posted) and an ongoing Immunologic Biomarkers of Sterilizing Drug Activity
phase II/III study of recombinant human IL-2 in Tuberculosis (NexGen EBA; NCT02371681) that
(NCT03069534)31 have targeted sputum culture attempts to augment a traditional EBA study with
conversion in MDR/XDR-TB. Vitamin D has been PET/CT imaging biomarker data to additionally
evaluated as an adjunct to standard therapy in capture sterilizing activity of first line drugs and
multiple trials with conflicting results, suggesting their combinations which have previously been
that any effect relative to anti-tuberculous clinically and pharmacokinetically characterized.
chemotherapy is modest at best. This topic has been While sputum based measurements average all
reviewed, including the ongoing randomized trials.32 changes across the lungs into one result, a PET/
If results support robust efficacy endpoint data, we CT image of the lungs can quantitate differential
may anticipate future trials evaluating HDTs as a changes in different lesions. We hypothesize that,
complementary treatment shortening strategy. owing to different lesion pharmacokinetics, different
treatment effects—including early bactericidal
Capturing heterogeneity of drug responses in early activity important for initial culture conversion and
phase clinical evaluation sterilizing activity important for durable cure—can
When viewing the TB trials together (fig 2), it be captured in different lesion types. This trial has
appears that almost all possible combinations of the been completed and data analyses are ongoing,
newer drugs are tested for either six or nine months with results expected in 2020. With this knowledge,
without a clear rationale for how one combination rational combinations of drugs and HDTs can be
or duration was selected compared with another. selected and taken forward to later phase clinical
With the number of new compounds and HDTs trials with better chances of success.

10
Table 3 | Host directed therapy (HDT) TB treatment trials
Study Estimated Website/clinical trials
Name Study design Study population Arms Sites started completion date registration
Clinical Trial of the Safety, Sequential, dose escalating for HIV negative healthy adults Arm 1a: imatinib 50 mg/day ×28 days USA (Emory Nov-19 Jun-20 https://clinicaltrials.gov/ct2/
Pharmacokinetics and safety, pharmacokinetics, and with isoniazid 300 mg/day and rifabutin University) show/NCT03891901
Hematologic Effects of myelopoiesis effects 300 mg/day added for last 14 days
Imatinib on Myelopoiesis
in Adults When Given With
and Without Isoniazid and
Rifabutin (IMPACT-TB)
Arm 1b: imatinib 100 mg/day ×28 days
with isoniazid 300 mg/day and rifabutin
300 mg/day added for last 14 days
Arm 1c: imatinib 200 mg/day ×28 days
Arm 1d: imatinib 400 mg/day ×28 days

Arm 2a: isoniaid 300 mg/day and
rifabutin 300 mg/day ×28 days with
imatinib added for last 14 days. Imatinib
dose to be determined from arm 1 data
Arm 2b: isoniaid 300 mg/day and
rifabutin 300 mg/day ×28 days with
imatinib added for last 14 days. Imatinib
dose to be determined from arm 1 data
Statin Adjunctive Therapy for Sequential, dose escalating for HIV infected (CD4 ≥100) and Arm 1: Pravastatin 80 mg with HRZE ×14 USA (Johns Hopkins Dec-19 Apr-21 https://clinicaltrials.gov/ct2/
TB (StAT-TB) safety and pharmacokinetics uninfected adults with drug days University) show/NCT03456102
sensitive pulmonary TB
Arm 2: Pravastatin 120 mg with HRZE
×14 days
Arm 3: Pravastatin 160 mg with HRZE
×14 days
Arm 4: Pravastatin 40 mg with HRZE ×14
days
Adjunctive Corticosteroids Randomized, double blind, HIV infected adults with clinical Arm 1: Standard anti-TB drugs Indonesia, Vietnam May-17 Apr-22 https://clinicaltrials.gov/ct2/
for Tuberculous Meningitis placebo controlled phase III trial diagnosis of tuberculosis (2HRZE/4HR) plus placebo for 6-8 weeks show/NCT03092817
in HIV-infected Adults (ACT for overall survival at 12 month meningitis
HIV Trial) (primary outcome)
Arm 2: Standard anti-TB drugs plus
dexamethasone for 6-8 weeks
Potential Efficacy and Randomized, controlled phase Individuals ≥16 years of age Arm 1: National and WHO standard of Georgia Sep-16 Jan-19 https://clinicaltrials.gov/ct2/
Safety of Using Adjunctive II trial for sputum culture with confirmed XDR-TB care for pulmonary XDR-TB show/NCT02781909
Ibuprofen for XDR-TB conversion, radiologic changes,
(NSAIDS-XDRTB) and treatment outcomes
Arm 2: National and WHO standard
of care for pulmonary XDR-TB plus
ibuprofen 400 mg/day ×2 months
Study of Adjunctive Randomized, controlled phase HIV negative adults with Arm 1: Standard MDR-TB treatment ×24 China Jun-09 Mar-20 https://clinicaltrials.gov/ct2/
Recombinant Human II/III trial evaluating sustained pulmonary MDR-TB months show/NCT03069534
Interleukin-2 Therapy in sputum conversion during final 12
Patients with MDR-TB months of treatment and sputum
(rhIL-2) smear/culture conversion at end
of 24 months of treatment
Arm 2: Standard MDR-TB treatment ×24
months plus low dose IL-2 SC every other
day ×30 days during months 1, 3, 5, 7

Preventive TB treatment
EncHid=&userName=011176
https://clinicaltrials.gov/ct2/ Updates to treatment of latent TB infection (LTBI)
https://clinicaltrials.gov/ct2/
Unlike DS-TB treatment guidelines, LTBI treatment
Website/clinical trials
Clinicaltrials/showallp.
guidelines have changed in the last decade. The
http://www.ctri.nic.in/
show/NCT02968927
show/NCT03251196
php?mid1=20868&
biggest change was the introduction of isoniazid/
rifapentine once weekly for 12 weeks as a successful
completion date registration
LTBI treatment regimen.41-43 In addition, rifampin

dosed daily for four months was confirmed to be as
effective as isoniazid for nine months but with better
treatment completion rates and fewer side effects.44
Additional latent TB clinical trials are ongoing and
span the scope of DS and MDR latent TB treatment,
Estimated
as well as HIV negative and HIV positive populations
Nov-21
Dec-20
Oct-20
(table 4, figs 3and 4). Three DS latent TB trials are

ongoing (2R2, ASTERoiD, and SCRIPT-TB), all of
which test shorter, regimens of one to two months
started
Nov-16
Nov-18
Mar-19
of higher dose rifamycins compared with the SOC

Study
regimen and vary in target LTBI populations and

endpoints of completion/safety versus efficacy.
Even if rifapentine based trials are successful in
shortening LTBI treatment duration, uptake of
Arm 1: Rifabutin modified anti-TB therapy South Africa
rifapentine based regimens is currently limited by

Tanzania
cost and availability,45 with only one manufacturer

Sites
India
making this drug globally. This situation will

hopefully change as generic manufacturers enter
(2HRZE/4HR) with N-acetylcysteine 1200
Arm 3: Auranofin 6 mg+2HRbZE/4HRb
this market.46 Three ongoing trials are testing LTBI

Arm 2: HRZE+metformin for 8 weeks
treatment regimens with MDR-TB exposure (table 4,

Arm 4: Vitamin D3+2HRbZE/4HRb
Arm 5: CC-11050+2HRbZE/4HRb
mg twice a day for first 4 months
fig 3, fig 4). Two trials, V-QUIN MDR and TB-CHAMP,

Randomized, controlled substudy Drug sensitive TB patients with Arm 1: Standard anti-TB drugs
Arm 2: Standard anti-TB drugs
both test levofloxacin for six months compared

Arm 2: Everolimus 0.5 mg
Adults with smear positive, drug Arm1: HRZE for 8 weeks
with placebo. The third trial, PHOENIx MDR-TB,

compares six months of isoniazid against six months
(2HRbZE/4HRb)
+2HRbZE/4HRb
of delamanid.
advanced pulmonary disease by (2HRZE/4HR)
Targeted treatment of incipient TB infection

Arms
While TB treatment and control efforts are currently

dichotomized around “latent” and “active” TB
infection, neither of the two available methods to
smear positive, drug sensitive
identify latent TB infection (tuberculin skin test

HIV negative adults with
and interferon gamma release assays) distinguish

sensitive pulmonary TB
the few asymptomatic individuals who will develop

Study population
evaluate N-acetylcysteine effects chest radiograph
active TB (estimated to be 5-10% lifetime risk) from

pulmonary TB
the majority of individuals who will never develop

active TB. Treating all M tuberculosis latently infected
individuals for months is not feasible in most areas of
the world. Rather, evidence is emerging of a spectrum
of TB disease activity, and new approaches attempt to
conversion and normalization of
inflammatory markers), sputum
Randomized, controlled phase
therapy in patients with new, pharmacokinetics, and time to
predict asymptomatic individuals who will progress

of TB-SEQUEL cohort study to
on sustained sputum culture

II trial for safety, biomarker
sputum culture conversion

responses (PET/CT, serum
to active TB disease (incipient TB infection).

Randomized, open label
culture conversion, and
containing antituberculosis trial to evaluate safety,
Many retrospective studies of biomarker

combination with rifampicin controlled phase II/III
pulmonary function
cellular glutathione
signatures, particularly transcriptomic, have been

published identifying incipient or active TB in
Study design
different cohorts47 but these signatures generally

do not work well across populations and more work
is needed to identify consistent signatures across
cohorts. In addition, retrospective correlations of
Evaluation of metformin in
biomarker signatures ultimately need to be confirmed

smear-positive pulmonary
TB Host Directed Therapy
Patients With Pulmonary

Adjunctive NAC in Adult
prospectively.
Table 3 | Continued
Tuberculosis (NAC-TB)
tuberculosis (METRIF)
The Correlate of Risk Targeted Intervention Study

(CORTIS; NCT02735590) is currently evaluating a
host transcriptional signature previously found to
(TBHDT)
have 66% prognostic sensitivity and 81% specificity

Name
for incident TB disease within 12 months48 to see

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Fig 2 | Ongoing active TB treatment shortening clinical trials with duration and drug composition of the experimental
regimens tested
how well treatment with three months of weekly enzyme inducer than rifampin and can substitute
isoniazid/rifapentine reduces the incidence of TB in for rifampin to allow certain antiretroviral drugs
individuals who test positive.49 The ability to both to be used. Drug-drug interactions are complex,
shorten and target preventive TB therapy to the and current guidelines continuously update tables
few asymptomatic individuals at greatest risk of TB on recommended combinations and dosing.50 51
progression will greatly increase the global feasibility The recommended first line treatment is to use a
of treating LTBI. rifampin based TB regimen with an efavirenz based
antiretroviral therapy regimen. Options include
Treatment of HIV/TB co-infection using raltegravir instead of efavirenz or a ritonavir
Active TB boosted protease inhibitor in conjunction with
Many of the ongoing TB clinical trials include rifabutin. More studies are needed to define better
individuals who are HIV positive (table 1, table 4). drug-drug interactions for the newer anti-TB drugs,
The recent WHO recommendation of nine months such as pretomanid.
of treatment for MDR-TB also applies to individuals The other major consideration in HIV-TB co-
infected with HIV.23 The treatment of active TB in infection is the timing of treatment. When HIV is
HIV co-infected patients is generally the same as in diagnosed first, earlier initiation of antiretroviral
patients uninfected with HIV, but with additional therapy and isoniazid preventive therapy
attention to overlapping toxicities and drug-drug independently reduce the development of active TB
interactions between commonly used HIV and and death.52-54 When TB is diagnosed first, there is
TB drugs, particularly rifampin. Rifampin is a a clear mortality benefit to starting antiretroviral
potent inducer of cytochrome P4503A4, uridine therapy shortly after anti-TB therapy, despite the
diphosphate glucuronosyltransferase 1A1, and increased risk of developing immune reconstitution
P-glycoprotein enzymes, and thus will typically inflammatory syndrome.55-57 According to current
reduce the levels of drugs metabolized by these guidelines,58 ART should begin within two weeks
enzymes. Some drugs should not be used in for those with CD4 cell counts <50 cells/mm3. For
conjunction with rifampin, while others can be patients with higher CD4 cell counts, antiretroviral
used with dose adjustments. Rifabutin is less of an therapy should begin no later than eight weeks after

Table 4 | Ongoing latent TB treatment shortening trials
Name Study design Arms HIV+? Sites started completion date registration
Drug sensitive latent TB trials
Higher dose rifampin for 2 months v standard Randomized phase IIb partially Arm 1: Control rifampin 10 mg/kg (600 mg Yes, unless Canada, Indonesia, Aug-19 Apr-23 https://clinicaltrials.gov/
dose rifampin for latent TB (2R2) blind, controlled trial max) daily ×120 doses (4R10) rifampin DDI Vietnam ct2/show/NCT03988933
Sample size: 1359 (453/arm) Arm 2: rifampin 20 mg/kg (1200 mg max)
daily ×60 doses (2R20)
Primary endpoint is treatment Arm 3: rifampin 30 mg/kg (1800 mg max)
completion and safety. Efficacy daily ×60 doses (2R30)
at 2 years from randomization is
secondary endpoint
Assessment of the safety, tolerability, and Phase II-III randomized controlled Arm 1: Possible control regimens: 1) Yes, unless USA, UK, other Jul-19 Dec-23 https://clinicaltrials.gov/
effectiveness of rifapentine given daily for LTBI non-inferiority trial rifapentine 900 mg/isoniazid 900 mg once rifamycin DDI countries with low- ct2/show/NCT03474029
(ASTERoiD) weekly ×12 weeks (3HP); 2) rifampin 600 mod TB incidence
mg/isoniazid 300 mg once daily for 12 (<100 cases/100 000)
weeks (3HR); or 3) rifampin 600 mg daily
×16 weeks (4R)
Sample size: 3400 (1700/arm) Arm 2: rifapentine 600 mg daily ×6 weeks

(6wP)
Primary endpoint: diagnosis of TB
within 2 years of enrollment
Short course rifapentine and isoniazid for the Open label, non-randomized trial Arm: rifapentine 450 mg/isoniazid 400 mg No China Dec-18 Jun-22 https://clinicaltrials.gov/
preventive treatment of tuberculosis (SCRIPT-TB) 3 ×/week ×4 weeks (12 doses; 1HP) ct2/show/NCT03900858
Sample size: 566
Primary endpoint: TB diagnosis
within 3 years
Inclusion criterion: silicosis patients
Multidrug resistant latent TB trials
Randomized controlled trial of six months Randomized placebo controlled trial Arm 1: placebo Yes Vietnam Mar-16 Jan-22 https://anzctr.org.au/Trial/
of daily levofloxacin for the prevention of Registration/TrialReview.
tuberculosis among household contacts of aspx?id=369817
patients with MDR-TB (V-QUIN MDR Trial)
Sample size: 2006; all ages eligible Arm 2: levofloxacin ×6 months; dosing
weight based, 750 mg for ≥50 kg
Primary endpoint: incidence of TB at
30 months after randomization
Tuberculosis child multidrug-preventive therapy Phase III randomized placebo Arm 1: placebo Yes South Africa Jan-16 Dec-19 http://www.isrctn.com/
(TB-CHAMP) controlled trial ISRCTN92634082
For children ≤5 years who live with Arm 2: levofloxacin 15-20 mg/kg (max dose
adults diagnosed with MDR-TB 750 mg) daily ×24 weeks
Primary endpoint: incident TB by 48
weeks after randomization
Sample size: 778 households (1556
children)
Protecting households on exposure to Randomized controlled trial Arm 1: delamanid 200 mg daily ×26 weeks Yes Botswana, Brazil, Peru, Jun-19 Jun-25 https://clinicaltrials.gov/
newly diagnosed index multidrug-resistant Philippines, South ct2/show/NCT03568383
tuberculosis patients (PHOENIx MDR-TB) Africa, Thailand
Sample size: 5610; all ages eligible Arm 2: isoniazid 300 mg daily ×26 weeks
Primary endpoint: TB diagnosed
within 96 weeks
Latent TB trials in HIV+
Tuberculosis preventive therapy among Phase III randomized trial Arm 1: control 12-weekly isoniazid/ Yes, required Thailand Mar-19 Mar-23 https://clinicaltrials.gov/
latent tuberculosis infection in HIV-infected rifapentine (3HP) ct2/show/NCT03785106
individuals (HIV-NAT 225)
Sample size: 2500 Arm 2: 4 week daily isoniazid/rifapentine
Primary endpoint: Prevention of TB
13
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starting anti-TB therapy because of known benefits of months.61 A similar trial, HIV-NAT 225, started in
earlier initiation of antiretroviral therapy.54 59 60 Thailand in 2019 (table 4). Rifapentine/INH once
daily for one month may become a recommended
Latent TB regimen in guidelines, but few antiretroviral drugs
The treatment of LTBI in individuals infected with are recommended to be co-administered with
HIV is also like that of uninfected individuals, with rifapentine.50 Protease inhibitors and the CCR5
attention paid to rifamycin drug-drug interactions inhibitor maraviroc are contraindicated. Among the
and the possibility of an additional, even shorter one non-nucleoside reverse transcriptase inhibitors,
month regimen. Rifapentine is a key component of only efavirenz is approved for co-administration,
shortened LTBI treatment regimens, with rifapentine/ although a phase I drug interaction study with
INH once weekly×12 weeks currently recommended doravirine is ongoing (NCT03886701). Another trial
for HIV infected individuals if drug-drug interactions is testing the steady state pharmacokinetic effects of
are manageable. The recent BRIEF TB/A5279 trial once-weekly rifapentine with tenofovir alafenamide
showed that in HIV infected individuals, weight fumarate, a preferred backbone nucleoside reverse
based rifapentine and isoniazid 300 mg daily transcriptase inhibitor (NCT03510468). Among the
for one month was non-inferior in preventing TB integrase strand transfer inhibitors, only raltegravir is
compared with the standard isoniazid daily for nine currently recommended to be dosed with rifapentine
only at the once weekly dose. Another trial
(DOLPHIN) tested the safety and pharmacokinetics of
dolutegravir with rifapentine/isoniazid once weekly
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including most current active and latent TB clinical
7ULDO
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2010.63 Xpert was the first fully integrated, automated
genotypic test and provided a direct readout of TB
Fig 4 | Ongoing latent TB treatment shortening clinical trials with duration and drug
composition of the experimental regimens tested and rifampin resistance within two hours. Recent

advances to the GeneXpert platform include the are from WHO, which released its latest version in
Xpert MTB/RIF Ultra that is more sensitive 64 and 2019.23 24 Recent reviews have been published for
the Xpert XDR that detects genotypic resistance to the management of drug resistant TB.74 75
isoniazid, fluoroquinolones, and aminoglycosides.65 For the treatment of LTBI, WHO and the CDC have
However, detection of point mutations in specific released updated treatment guidelines in 2020.76 77
target regions does not capture all phenotypic Both guidelines recommend targeted testing and
resistance, will continue to lag identification of new treatment of LTBI with slight differences in the
genetic resistance mechanisms, and may become recommended treatment regimens. The regimens
irrelevant with the changing landscape of preferred recommended by both guidelines are: 1) isoniazid
second line drugs. with rifapentine once weekly for three months, and
To that end, whole genome sequencing (WGS) 2) isoniazid with rifampin daily for three months. In
provides more comprehensive information and addition, WHO also recommends isoniazid daily for
has high sensitivity and specificity for isoniazid, six or nine months as a primary regimen, whereas
rifampin, pyrazinamide, and ethambutol compared the CDC now lists these as alternative rather than
with phenotypic resistance testing.66 WGS can also preferred regimens. In contrast, the CDC recommends
provide useful information to characterize mixed rifampin daily for four months as a preferred regimen,
infections, differentiate relapsed infections from re- whereas WHO lists this as an alternative. The WHO
infections, and contribute to transmission tracing. guidelines also include two other regimens that the
Governmental programs in England, the Netherlands, CDC guidelines do not: 1) isoniazid with rifapentine
and New York are shifting resources from phenotypic daily for one month, as an alternative regimen; and 2)
testing to WGS to save time and money.67 for HIV infected individuals in high TB transmission
Recent advances in highly portable, miniature settings, isoniazid daily for 36 months.
sequencing platforms may facilitate access to
TB WGS in resource limited settings.68 Although Emerging treatments
WGS is typically done from a cultured sample of Owing to the number of ongoing TB clinical trials,
M tuberculosis, which adds two to four weeks to the next several years will hopefully be a time of
the result time, efforts are under way to perform marked changes in treatment guidelines to include
analyses directly on sputum. Sputum, however, is newer drugs, shorter regimens, and perhaps even
complicated by human and other bacterial DNA.69 HDTs. Future trials being planned for DS-TB will
The interpretation of genotypic results is also not not only include treatment shortening but will
always straightforward and large standardized also include newer drug such as bedaquiline.
databases with user friendly software are needed.68 70 One recent result for MDR-TB treatment is the
Finally, although overall sequencing costs continue ACTG5343 (DELIBERATE) trial that tested the safety
to decline, startup capital costs for the machines are of combining bedaquiline and delamanid to treat
still prohibitive.71 The notably faster time to results MDR-TB, focusing on cardiac QTc prolongation
of genotypic over phenotypic testing make it far more since both drugs are known to have this side
clinically relevant and the test of choice for the future. effect. Early results showed patients had a mean
As more advances are made and costs decline, WGS QTcF prolongation from baseline of 11.9 ms in the
will likely become more and more accessible globally. bedaquiline arm, 8.6 ms in the delamanid arm,
and 20.7 ms in the combined arm. Thus, the
Guidelines combination of bedaquiline and delamanid appears
The international TB community jointly released DS- to be safe from a cardiac standpoint, with only a
TB treatment guidelines in 2016.72 This effort was modest additive effect on QTcF prolongation, in
sponsored by the American Thoracic Society, the patients with normal QTcF interval at baseline.78
Centers for Disease Control and Prevention (CDC),
and the Infectious Diseases Society of America and Conclusions
was endorsed by the European Respiratory Society With the recent advances in TB treatment and
and the US National Tuberculosis Controllers diagnostics, and many ongoing trials, the next five
Association. The American Academy of Pediatrics, years will likely see major changes to TB treatment
the Canadian Thoracic Society, the International approaches. However, the future trend is clear and
Union Against Tuberculosis and Lung Disease, is already arriving for drug resistant TB—shorter,
and WHO also participated. These guidelines all oral regimens incorporating newer drugs. The
note that treatment by directly observed therapy question is which drugs, how short, and what
(DOT) by trained personnel compared with self- patients. Will treatment of TB continue to be a one
administered therapy (SAT) is the standard of care size fits all with the same regimen and duration
in most TB programs in the US and Europe. WHO recommended for all patients? Will patients be
released another version in 2017 with some updates stratified into risk categories with treatment
primarily focused on patient care aspects.73 The regimens and durations tailored for each? How will
WHO guidelines allow for SAT but conditionally all the novel TB compounds currently in clinical
recommends either DOT in the community or home development be incorporated effectively and
by trained providers or video observed therapy over efficiently to create optimal treatment combinations?
SAT. For drug resistant TB, the primary guidelines What role will HDTs play in shortening treatment

2 Jaillon P. [Controlled randomized clinical trials]. Bull Acad Natl

RESEARCH QUESTIONS Med 2007;191:739-56, discussion 756-8. doi:10.1016/S0001-
• What biomarkers will predict the development of 4079(19)33007-9
3 Fox W. Whither short-course chemotherapy? Br J Dis Chest
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1981;75:331-57. doi:10.1016/0007-0971(81)90022-X
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• What biomarkers will predict treatment outcomes tuberculosis units, 1946-1986, with relevant subsequent
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more personalized treatment algorithms rather than 5 Iseman MD. Tuberculosis therapy: past, present and future. Eur Respir
J Suppl 2002;36:87s-94s. doi:10.1183/09031936.02.00309102
the current one-size-fits-all approach? 6 Mitchison DA. The diagnosis and therapy of tuberculosis during
• What biomarkers will predict the development of the past 100 years. Am J Respir Crit Care Med 2005;171:699-706.
relapsed TB after completion of treatment for active TB? doi:10.1164/rccm.200411-1603OE
7 Murray JF, Schraufnagel DE, Hopewell PC. Treatment of tuberculosis.
• How should novel and existing drugs be combined A historical perspective. Ann Am Thorac Soc 2015;12:1749-59.
to determine the best regimens to bring forward into doi:10.1513/AnnalsATS.201509-632PS
phase III clinical trials testing of shortened treatment 8 Gillespie SH, Crook AM, McHugh TD, et al, REMoxTB Consortium. Four-
month moxifloxacin-based regimens for drug-sensitive tuberculosis.
regimens for drug sensitive and drug resistant TB? N Engl J Med 2014;371:1577-87. doi:10.1056/NEJMoa1407426
9 Jindani A, Harrison TS, Nunn AJ, et al, RIFAQUIN Trial Team. High-dose
rifapentine with moxifloxacin for pulmonary tuberculosis. N Engl J
HOW PATIENTS AND THE PUBLIC WERE INVOLVED IN Med 2014;371:1599-608. doi:10.1056/NEJMoa1314210
THE CREATION OF THIS ARTICLE 10 Merle CS, Fielding K, Sow OB, et al, OFLOTUB/Gatifloxacin for
Tuberculosis Project. A four-month gatifloxacin-containing regimen
This article was reviewed by two people who had been for treating tuberculosis. N Engl J Med 2014;371:1588-98.
doi:10.1056/NEJMoa1315817
successfully treated for TB, one from the US and one 11 Zhang Y, Mitchison D. The curious characteristics of pyrazinamide: a
from South Africa. The patient from the US received review. Int J Tuberc Lung Dis 2003;7:6-21.
12 Abulfathi AA, Decloedt EH, Svensson EM, Diacon AH, Donald P, Reuter
treatment by DOT, which “felt both like a hassle H. Clinical pharmacokinetics and pharmacodynamics of rifampicin
(because I had two young children and was busy caring in human tuberculosis. Clin Pharmacokinet 2019;58:1103-29.
for them at home) and like a good safeguard against doi:10.1007/s40262-019-00764-2
13 Dooley KE. High-dose rifampin: shall we be bolder?Am J Respir Crit
forgetfulness (as one prone to getting caught up in Care Med 2018;198:558-60. doi:10.1164/rccm.201806-1140ED
caring for the kids).” She was interested in research on 14 Dorman SE, Savic RM, Goldberg S, et al, Tuberculosis Trials
how current treatments could be implemented more Consortium. Daily rifapentine for treatment of pulmonary
tuberculosis. A randomized, dose-ranging trial. Am J Respir Crit Care
successfully The patient from South Africa stated, Med 2015;191:333-43. doi:10.1164/rccm.201410-1843OC
“I don’t have any comments and any questions or 15 Velásquez GE, Brooks MB, Coit JM, et al. Efficacy and safety of high-
comments I thought of while reading were inevitably dose rifampin in pulmonary tuberculosis. A randomized controlled
trial. Am J Respir Crit Care Med 2018;198:657-66. doi:10.1164/
answered further down.” rccm.201712-2524OC
16 Boeree MJ, Heinrich N, Aarnoutse R, et al, PanACEA consortium. High-
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and reducing functional impairment? Is a one a multi-arm, multi-stage randomised controlled trial. Lancet Infect
month or even a two week treatment regimen for Dis 2017;17:39-49. doi:10.1016/S1473-3099(16)30274-2
17 Johnson JL, Hadad DJ, Dietze R, et al. Shortening treatment in adults
TB realistic in the next 10 years? The results of with noncavitary tuberculosis and 2-month culture conversion. Am J
ongoing and future trials will help answer these Respir Crit Care Med 2009;180:558-63. doi:10.1164/rccm.200904-
questions. However, even with these biomedical 0536OC
18 Chen RY, Via LE, Dodd LE, et al, Predict TB Study Group. Using
advances toward shorter, oral regimens, we biomarkers to predict TB treatment duration (Predict TB): a
continue to face fundamental challenges along the prospective, randomized, noninferiority, treatment shortening
path to comprehensive, accessible, effective, and clinical trial. Gates Open Res 2017;1:9. doi:10.12688/
gatesopenres.12750.1
reliable delivery of treatment. Concerted efforts of 19 Papineni P, Phillips P, Lu Q, et al. TRUNCATE-TB: an innovative trial
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TB programs, healthcare delivery systems, and 20 World Health Organization. WHO treatment guidelines for isoniazid-
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bitstream/handle/10665/260494/9789241550079-eng.
advances and end the TB epidemic.79-81 pdf;jsessionid=9E2BD49130618683CDA3C9
Acknowledgment: This research was supported by the Intramural 87CABB97D1?sequence=1
Research Program of the US National Institutes of Health, National 21 Van Deun A, Maug AKJ, Salim MAH, et al. Short, highly effective,
Institute of Allergy and Infectious Diseases. and inexpensive standardized treatment of multidrug-resistant
tuberculosis. Am J Respir Crit Care Med 2010;182:684-92.
Contributorship: YLX, CEB, and RYC developed the idea for this
doi:10.1164/rccm.201001-0077OC
review. AL, YLX, and RYC performed the literature search. AL, YLX, CEB, 22 Nunn AJ, Phillips PPJ, Meredith SK, et al, STREAM Study Collaborators.
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author attests that all listed authors meet authorship criteria and that J Med 2019;380:1201-13. doi:10.1056/NEJMoa1811867
no others meeting the criteria have been omitted. 23 World Health Organization. Consolidated guidelines on drug-resistant
Competing interests: The BMJ has judged that there are no tuberculosis treatment. 2019. https://apps.who.int/iris/bitstream/ha
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declares the following other interests: none. 24 World Health Organization. Rapid Communication: Key changes to
the treatment of drug-resistant tuberculosis. 2019. https://www.who.
Further details of The BMJ policy on financial interests are here: int/tb/publications/2019/WHO_RapidCommunicationMDR_TB2019.
https://www.bmj.com/about-bmj/resources-authors/forms-policies- pdf?ua=1
and-checklists/declaration-competing-interests 25 Sacks H, Chalmers TC, Smith HJr. Randomized versus historical
Provenance and peer review: commissioned; externally peer controls for clinical trials. Am J Med 1982;72:233-40.
reviewed. doi:10.1016/0002-9343(82)90815-4
26 Krishnan V. Tuberculosis: experts question evidence and safety data
1 World Health Organization. Global TB Report 2019. 2019. https:// used to approve latest drug. BMJ 2019;367:l6832. doi:10.1136/
www.who.int/tb/publications/global_report/en/ bmj.l6832

27 McKenna L, Furin J. Are pretomanid-containing regimens for prevention. Tuberculosis (Edinb) 2018;109:61-8. doi:10.1016/j.
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28 US Food and Drug Administration. FDA approves new drug for Guidelines for the use of antiretroviral agents in adults and
treatment-resistant forms of tuberculosis that affects the lungs. https:// adolescents with HIV. 2019. https://aidsinfo.nih.gov/contentfiles/
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drug-treatment-resistant-forms-tuberculosis-affects-lungs 51 Panel on Opportunistic Infections in HIV-Infected Adults and
29 Lee M, Lee J, Carroll MW, et al. Linezolid for treatment of Adolescents. Guidelines for the prevention and treatment of
chronic extensively drug-resistant tuberculosis. N Engl J opportunistic infections in HIV-infected adults and adolescents:
Med 2012;367:1508-18. doi:10.1056/NEJMoa1201964 recommendations from the CDC, the NIH, and the IDSA. 2019.
30 Centis R, Sotgiu G, Migliori GB. Delamanid: does it have a role https://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf
in tuberculosis treatment?Lancet Respir Med 2019;7:193-5. 52 Badje A, Moh R, Gabillard D, et al, Temprano ANRS 12136 Study
doi:10.1016/S2213-2600(18)30455-7. Group. Effect of isoniazid preventive therapy on risk of death in
31 Zhang R, Xi X, Wang C, et al. Therapeutic effects of recombinant west African, HIV-infected adults with high CD4 cell counts: long-
human interleukin 2 as adjunctive immunotherapy against term follow-up of the Temprano ANRS 12136 trial. Lancet Glob
tuberculosis: A systematic review and meta-analysis. PLoS Health 2017;5:e1080-9. doi:10.1016/S2214-109X(17)30372-8
One 2018;13:e0201025. doi:10.1371/journal.pone.0201025 53 TEMPRANO ANRS 12136 Study Group, Danel C, Moh R, et al. A trial of
32 Brighenti S, Bergman P, Martineau AR. Vitamin D and tuberculosis: early antiretrovirals and isoniazid preventive therapy in Africa. N Engl
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doi:10.1586/14787210.2014.870884 56 Blanc F-X, Sok T, Laureillard D, et al, CAMELIA (ANRS 1295–CIPRA
35 O’Brien RJ, Global Alliance for TB Drug Development. Tuberculosis. KH001) Study Team. Earlier versus later start of antiretroviral
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36 US Food and Drug Administration. Guidance for industry: pulmonary 57 Havlir DV, Kendall MA, Ive P, et al, AIDS Clinical Trials Group Study
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38 Tanner L, Denti P, Wiesner L, Warner DF. Drug permeation and initiation of highly active antiretroviral therapy for HIV-positive
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39 Strydom N, Gupta SV, Fox WS, et al. Tuberculosis drugs’ distribution 3099(14)70733-9
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STATE OF THE ART REVIEW

Current and future treatments for tuberculosis

the bmj | BMJ 2020;368:m216 | doi: 10.1136/bmj.m216 1

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2 doi: 10.1136/bmj.m216 | BMJ 2020;368:m216 | the bmj

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Sample size: 654 Arm 2: 2HRZE/2HR; rifampin https://clinicaltrials.gov/ct2/

doi: 10.1136/bmj.m216 | BMJ 2020;368:m216 | the bmj

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aminoglycoside sensitive intensive phase stage-2

doi: 10.1136/bmj.m216 | BMJ 2020;368:m216 | the bmj

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with isoniazid 300 mg/day and rifabutin

doi: 10.1136/bmj.m216 | BMJ 2020;368:m216 | the bmj

LTBI treatment regimen.41-43 In addition, rifampin

as well as HIV negative and HIV positive populations

(table 4, figs 3and 4). Three DS latent TB trials are

of higher dose rifamycins compared with the SOC

regimen and vary in target LTBI populations and

rifapentine based regimens is currently limited by

cost and availability,45 with only one manufacturer

making this drug globally. This situation will

this market.46 Three ongoing trials are testing LTBI

treatment regimens with MDR-TB exposure (table 4,

mg twice a day for first 4 months

fig 3, fig 4). Two trials, V-QUIN MDR and TB-CHAMP,

Arm 2: Standard anti-TB drugs

both test levofloxacin for six months compared

Adults with smear positive, drug Arm1: HRZE for 8 weeks

with placebo. The third trial, PHOENIx MDR-TB,

Targeted treatment of incipient TB infection

While TB treatment and control efforts are currently

identify latent TB infection (tuberculin skin test

and interferon gamma release assays) distinguish

the few asymptomatic individuals who will develop

evaluate N-acetylcysteine effects chest radiograph

active TB (estimated to be 5-10% lifetime risk) from

the majority of individuals who will never develop

therapy in patients with new, pharmacokinetics, and time to

predict asymptomatic individuals who will progress

on sustained sputum culture

sputum culture conversion

to active TB disease (incipient TB infection).

containing antituberculosis trial to evaluate safety,

Many retrospective studies of biomarker

signatures, particularly transcriptomic, have been

different cohorts47 but these signatures generally

biomarker signatures ultimately need to be confirmed

Patients With Pulmonary

The Correlate of Risk Targeted Intervention Study

have 66% prognostic sensitivity and 81% specificity

for incident TB disease within 12 months48 to see

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viral suppression.62 Additional trials testing similar

Genotypic and phenotypic drug resistance testing

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No commercial reuse: See rights and reprints http://www.bmj.com/permissions Subscribe: http://www.bmj.com/subscribe