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What’s new in TB in 2018:

are we ready to embrace new approaches?

Maunank Shah, MD PhD

Associate Professor
Center for Tuberculosis Research
(some slides adapted from presentations by Kelly Dooley,
Linda Xie, and Claudia Denkinger)
• I am the inventor of video-DOT technology
that has been licensed to emocha mobile
health, net royalties are less than <$2000
Case 1
• 27 y/o US born female, HIV-negative, presented to local hospital
in Jan 2017 with 3 months of cough
• CXR: “Diffuse micronodular pattern”
• Treated for Community Acquired Pneumonia and discharged
• Team did consider malignancy and MTB
– Sputum AFB smear-negative,
– No Sputum GeneXpert done
– Cultures pending (grow M. tuberculosis 1 month later)BCHD
alerted and track her down
• Already hospitalized at another hospital in MICU
– Being treated for bacterial sepsis
• M. tuberculosis therapy is started, but patient passes away a few
days later
• Why do we need new drugs and tests?

• What’s new in TB diagnostics

• What’s new in TB treatment

– Rethinking our current drug regimens
– New drugs

• Caveat: this talk will be focused on active TB

Global burden of TB disease

In 2014, TB surpassed HIV as the #1 infectious disease killer worldwide

In 2015, 10.4M cases

WHO Global Tuberculosis Report 2016:
Tuberculosis – the deadliest infectious disease

Undiagnosed TB Facts about TB:

Undiagnosed TB
• 10.4m cases per year
• 1.8m deaths
• Most common cause of death
among HIV
Untreated TB
• >4m never get diagnosed and
MDR treated
All cases of TB

Facts about resistant TB

• 600 000 Rifampicin resistant
• Less than 25% are recognized

WHO Global TB report 2017

Need for New Diagnostics
• WHO estimates
– One third of cases are not notified, and many patients do not receive
drug susceptibility testing.
– Global Case detection rates remain suboptimal: <70%
– Only 25% of MDR-TB cases are currently diagnosed

Case Detection Rate: WHO estimates
What do we need?
• “To achieve targets for TB prevention, care,
and control…new diagnostic tools are
critically important”

• Four ‘target product profiles’ (TPP) identified:

1. Point of Care non-sputum based test
that detects all forms of TB
• Candidate: Urine LAM
2. Point of Care sputum test to replace
• Candidate: NAATs
3. Rapid Drug Susceptibility test that can
be used at microscopy level
• Candidate: NAATs, LPA
4. Point of Care ‘triage test’
• Not going to discuss
TPP #1
Non-Sputum test to
identify all forms of TB
Urine Antigen Detection: Lipoarabinomannan
• Lipoarabinomannan (LAM)
– component of mycobacterial cell walls
• Detectable in patients with active disease
– Pulmonary and extra-pulmonary disease
• Detectable intact in urine
– Heat stable
– Chemically stable
• Sensitivity is poor in HIV-negative patients

• Sensitivity is highest in immunosuppressed

patients, with severe disease (inpatients)

• Rapid—results available in 20 minutes

• 10 Commercially available
Test performance: meta-analysis

Circle represents the pooled estimates (median), with bars representing 95% credible intervals.
• The test has highest sensitivity with disseminated disease and low CD4 counts

• Test specificity remains a concern, and declines with lower CD4 counts
• There may be bias in the diagnostic accuracy studies which rely on sputum
as the reference standard (i.e. misclassification bias)
Source: Shah et al. Cochrane 2016
LF-LAM for HIV+ patients:
• the first point of care test for TB
• first ‘niche’ test for TB
• first test that is not ‘site-specific’
• RCT of implementation in hospitalized patients showed mortality benefit
• But…with limitations (poor sensitivity, uncertainty around specificity)
Peter et al. “Effect on mortality… “Lancet 2016
Non-sputum based tests for diagnosis or triage

Active TB Incipient TB tests (blood) http://lnbd.techni
Pediatric TB - QIA-Predict (Qiagen)

Disposable - QIA-TB Signature (Qiagen)

Squeeze Bottle - mRNA Signatures Breath Tests and
for Stool (Stanford, Zak et al.)
- T-cell Immune Profiling (BD)
Skin Patches
Processing prior Latent TB - breathtec/Technion
- RTT TB (Lophius)
Xpert - Incipient TB Assay (Abbott)
(FIND, Elma Fdn & - eNose

2017 2018 2019 2020-2025

TB antigen POC
Next-generation assays (blood)
LAM POC assays Blood host marker
Determine TB LAM Ag - Arizona State Univ.
(urine, blood) POC tests - Tufts Univ.
(urine) for HIV co- - TransDot signature
infected with low CD4 - Fujifilm/FIND - and others
- and others (ScreenTB consortium)
counts - SomaLogic signature
(Alere) (SomaLogic, FIND) cfDNA in blood or urine
- and others - Standford Univ.
Source: http://precision- - Cornell Univ. - Karius
- and others

Negative recommendation for

Serological assays by the WHO


Slide from Claudia Denkinger, FIND

TPP #2
Sputum test to replace
smear microscopy
Nucleic Acid Amplification Tests
• Amplify nucleic acid segments that are specific for M. tuberculosis
• Rapid: results in 24–48 hours
• Commercially available
– Mycobacterium Tuberculosis Direct (MTD)
– Amplicor MTB Test (Amplicor)
– Loop-mediated isothermal amplification (LAMP)
– Cepheid GeneXpert
– Line probe assays (HAIN)

• Recommendations (CDC) :At least one respiratory sample should be sent

for NAAT testing (in addition to smear microscopy/cx)

NAAT: GeneXpert (Cepheid)
• Molecular beacon technology

• Self-contained, closed, fully

automated system
• Detects M.tb and Rifampin resistance
• Use in low levels of health system
(peripheral labs)

• Sensitivity
– Smear-positive: 95–100%
– Smear-negative: ~30-70%

• Specificity: ~98%

• Can it really be placed at low levels of

the health system?
Emerging tools
• WHO Policy Recommendation 2011

For discussion: what is the role of smear in an era of molecular testing?

• GXP now has FDA approval for usage in respiratory isolation as well
• More sensitive and specific than Smear
Xpert in Extrapulmonary: 2013

US FDA approval only for respiratory specimens:

Are we maximizing diagnostic opportunities?

Xpert in CSF: example
• CSF: Pooled sensitivity and specificity:
– Culture reference: 79.5% sens; 98.6% spec
– Clinical Reference Standard: 55.5% sens, 98.8% spec
– “Expert Group recommended Xpert should be used in
preference to conventional microscopy and culture as the
initial diagnostic test in CSF…”
Cost-effectiveness of Xpert

Implementing NAAT testing in the US would be highly cost-effective,

And in some instances, cost-saving
Choi, Shah 2013 IJTLD
Can we do better?
Low cost, easy to use NGS
(Illumina, Genoscreen)


FluoroType MDRTB
Realtime MTB Rif/Inh QMAC QDST Hybridisation
(Hain Lifescience)
(Abbott) (QuantaMatrix) (Nano4Global, Scanogen)
Cobas Taqman MDR TB

2017 2018 2019 2020


Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q4

TB MultiTest

Xpert Ultra
Line probe assays: EasyNat MDR TB
• MTBDRplus and sl (Hain Lifescience) TrueLab MDR/TB (Ustar)
• Lipa MTBDR (Nipro)
(Molbio) Xpert XDR
• Reba MTB-MDR (YD) MGIT - (Cepheid)
• TBmodule (AID) TruArray MDRTB /
Liquid culture: Bedaquiline Mtb Drug Resistance
XDRTB (Akonni) Delamanid (BD) DX (Omniome)
• TREK Sensitive (Thermofisher)
• Mycolor TR BNP (Salubris)
NAAT: First sequencing solutions FluoroType XDR
▪ Xpert MTB/RIF (Cepheid) (Genoscreen, BMS, Longhorn) (Hain Lifescience)
▪ TB-LAMP (Eiken)
▪ Mycobacteria RT PCR (CapitalBIo)
▪ Anyplex MTB/XDR (Seegene) Q-POC TB/MDR
▪ Infiniti MDR TB (Autogenomics)
TB (QuantuMDx)
▪ VereMTB/Rif/Inh (Veredus Laboratories)
▪ MeltPro MDR (Zeesan Biotech)
▪ Genedrive TB/Rif (Epistem)
▪ AccuPower TB/MDR (Bioneer) Omni Platform (Cepheid)
DISCLAIMER: Images & time estimates are to be taken as indicative only.

Slide from Claudia Denkinger, FIND

Can we do better: GXP ULTRA

Xpert Ultra Benefits

Target Single copy Multi-copy Increased sensitivity: 20 CFU/ml vs 130
rpoB IS6110 & IS1081 CFU/ml
+ rpoB
Cartridge 25mcl tube 50 mcl tube
Analysis Real time Melt curve • Improved ability to detect mutations in
PCR curves analysis mixtures.
• Robust detection of all mutations
associated to Rifampin resistance (i.e. rpoB
533 C to G mutations).
• Avoid false + for Rifampin resistance in
samples with low bacterial load

Lancet ID 2018
Improved limit of detection: but
comes with reduced specificity

Dorman et al. “Xpert Ultra for detection…” Lancet 2018

TPP #3
Rapid drug susceptibility
testing available at the
microscopy level

Molecular detection of
drug resistance
MDR- and XDR-TB: Global Health

Multidrug-resistant TB:
Mycobacterium tuberculosis resistant Extensively drug-resistant TB:
to isoniazid and rifampin: M. tuberculosis resistant to isoniazid, rifampin,
480,000 incident cases in 2015 fluoroquinolones, and injectable agents

Phenotypic Drug
Susceptibility Testing


Growth of
MTB Growth
Culture Resistance
with drugs Growth

Molecular Detection of Drug Resistance
• Drug resistance in MTB is mediated by several mutations


CDC offers molecular detection of drug resistance
– DNA sequencing (after cultures isolated MTB, or
NAAT+ with identification of Rifampin resistance)
– Pyrosequencing (for NAAT+ isolates)
Locus Result Interpretation
rpoB Mutation Rif R
inhA No mutation
katG Mutation
embB Mutation EMB R
pncA Mutation Cannot rule out PZA resistance

gyrA No mutation Cannot rule out quinolone R

rrs Mutation
AMK and KAN R, possible
eis No mutation
Capreo R
tlyA No mutation
Line Probes and Molecular Beacon

• WHO recommended line probe assays for rapid resistance testing (2008):

Rifampin resistance
Sensitivity: ~97–100%
Specificity: ~98–100%

Source: Barnard et al. (2008). AJRCCM, vol. 177., Nathavitharana et al. ERJ 2017
Second line molecular drug resistance testing
• Genotype®MTBDRsl (MTBDRsl): commercially available
– Detects resistance to key second line drugs:
– Fluoroquinolones(FQ): ofloxacin, moxifloxacin, levofloxacin
– Second Line Injectable Drugs (SLID, amikacin, kanamycin, capreomycin)
• Performance (pooled results)
– FQ:
• Sensitivity 83%
• Specificity 98%
• Sensitivity 77%
• Specificity 99.5%

Source: Theron et al. Cochrane 2014
Xpert XDR

Gene Encoded drug Mutation Xpert XDR Hain MTBDRsl (v2)

resistance (2 hours) (24-48 hours)

katG Isoniazid Codons 315 ✔ ✔

inhA Promoter -8 to -15 ✔ ✔

(M.tb detection) Promotor -16 ✗ ✔
gyrA Fluoroquinolones (codons 88-94) ✔ ✔

gyrB Fluoroquinolones Codon 500* ✔ ✗

gyrB Fluoroquinolones Codons 538-540 ✔ ✔

1401, 1402 ✔ ✔
kanamycin 1484 ✗ ✔
Promoter -10 ✔ ✔
eis Kanamycin
Promotor -37 ✔ ✗
What’s new in TB treatment?
How should we dose and monitor
current therapy?
New guidelines prioritize daily therapy
• Accurate dose counting is required but difficult
• Studies have not evaluated 5 vs 7 days

For Discussion: Have local guidelines and practices reflected

national recommendations?
Slide adapted from Susan Dorman, Maryland TB update 2017
Exposure-response for rifampin

Early Bactericidal Activity in smear-

Dose-response in mouse model positive pulmonary TB patients

Rifampin is currently dosed at the low end of the therapeutic spectrum

Jayaram et al, AAC (2003); 47:2118; Diacon et al, AAC 2007; 51(8)
Role of Drug level monitoring for TB patients?

• Cohort of slow-responders:
– >50% had low drug levels despite DOT
– Diabetes was associated with low
Rifampin levels (AOR 5.7 CI 1.2-25.7)

• Cohort of HIV-infected TB pts:

– 86% with rifampin or INH levels below
the lower limit of reference range (all
receiving DOT)

• Babalik et al. Therapeutic drug monitoring in treatment of active TB. Can Respir J. 2011 Jul-Aug; 18(4): 225–229.
• Heysell et al. TDM for slow response to TB treatment in a State Control Program. EID 2010 Oct
• Holland et al. TDM of antimycobacterial drugs in patients with TB and advanced HIV 2009. Pharmacotherapy
What is the right dose?

• Higher doses of rifampin appear to be well

tolerated and more effective AJRCC 2015
Therapeutic intensification?
• RCT showed improved CSF concentrations and
reduced mortality (HR 0.42 [0.2-0.9]:
– High dose IV Rifampin +/- Moxifloxacin with HZE (with steroids)
– Standard RHZE (with steroids)

Ruslami et al. Lancet ID 2013

DOT remains the preferred standard, but acknowledge
uncertainty in the data

Key principles: “To be consistent with principles of patient-centered care, decisions

regarding use of DOT must be made in concert with the patient”

The “least restrictive public health interventions that are effective are
used to achieve adherence”

“Implementation of DOT may not be readily feasible when resources

are limited”

“DOT has expanded to other modalities such as web-based video

and mobile phones which have been well received by both patients
and health dept staff”
Video-DOT being evaluated and scaled up in
US and abroad
Video-DOT can reduce stigma and improve adherence

Theme Qualitative themes arising from pre/post interviews

patient privacy
Patient “…sometimes they meet me … at work … I’m afraid ill be seen.”

miDOT improves
Patient “It was as least invasive possible, I'd say. That was probably the best part
patient privacy [of miDOT].”

“… the fact that someone in a county car [is] not coming up to their
Provider house or their job in the community, [video DOT] definitely increases
privacy for patients.”

In-person DOT is
Patient “I'm about to start a [school] … [and] the schedule doesn't really match
limited by logistical
… I won't be able to do the class, and I need class more than I need
Video-DOT achieves similar or better outcomes and is
cost-effective/saving: Maryland Study

DOT strategy Equipment Consumables Labore Total Incremental

In-person DOT $176a $57c $1,838 $2,022 Reference

(range) ($0-$562) ($17-$1,179) ($521-$6,169) ($512-$8,019)

miDOT $48b $495d $144 $687 -$1,335

(range) ($4-$136) ($0-$900) ($37-$752) ($42-$1,788)

Holzman et al. OFID 2018 in press: :

Can we repurpose other drugs for
treatment of TB?
Effects of replacing ethambutol with a
FQ* in the first-line therapy of TB

Lancet 2009; 373:1183

Int J TB Lung Dis 2008; 12:128

*FQ = fluoroquinolone
What about MDR-TB?

Requires 4-6 medications

for long durations
Drugs for MDR-TB (generally 18-
24 months)

Fluoroquinolones** Generally well-tolerated

Injectables (e.g. amikacin) Hearing loss, nephrotoxicity, balance,
Cycloserine Central nervous system toxicity
Ethionamide Nausea/vomiting
Linezolid BM toxicity, peripheral neuropathy
Clofazimine** Skin discoloration
Para-aminosalicylic acid GI toxicity, hypersensitivity, drug-induced
**=cause QT prolongation

New in 2016: WHO Short-Course MDR-TB Rx
(9-12 months)

4-month intensive phase High-dose INH*

Clofazimine Is
5-month continuation phase Moxifloxacin clofazimine
Ethambutol* the key to
Pyrazinamide* treatment
Clofazimine shortening?
*Resistance likely for many MDR van Deun, et al. AJRCCM
patients 2010:182:684-92
How do these drugs fit in?
Trial of Linezolid in Patients With XDR-
Conversion Probability According to
• Good in vitro activity against M. Time on Treatment

Cumulative Probability
• Several case-series suggesting

of Conversion
clinical benefit 0.6

• Clinical Trial of 41 Smear-positive
XDR-TB patients
0 30 60 90 120 150 180
• 87% (34/39) with negative sputum Days Since Start of LZD
culture within 6 mos

Lee M, et al. N Engl J Med. 2012;367:1508-1518.

Carbapenems attack the cell wall of bacteria

Carbapenems can block the 3-3 linkage

β-lactam drugs: i.e. penicillin
In M. tuberculosis

4 D-Glu
mDap mDap 3 3
Peptidoglycan layer
Transpeptidase D-Glu D-Ala

MTB Transpeptidase


Clinical Studies: 8 studies—case
• Limited data with heterogenous usage
– Backbone regimen, dosing, clavulanic acid, duration, outcome
Drug Studies Dosing Outcome Side Effects
Meropenem 5 studies: total 59 --Some with Clavulanic acid ~49 of 59 with cure Diarrhea, GI
patients --1g TID to 2g TID or culture issues in a
All MDR or XDR --Some with linezolid conversion minority of
patients --Range 67days to 18 months patients
Imipenem 3 studies: total 18 --most without clavulanic acid ~14 of 18 with cure 1 drug rash, 1
patients --500mg QID to 1g BID or culture resistance, 2
All MDR or XDR --6mo to 18 months conversion with GI issues
Ertapenem 2 studies: total 23 -1g daily without clavulanic acid ~22 of 23 with cure 1 allergic
patients --77 to 430 days or improvement reaction, 1 lft, 2
--in 1 study, all --Majority with linezolid GI
initially received
mero or imi

Jaganath et al. IJTLD 2016

TB drug pipeline:
what’s new? what do we have to work with?

Drugs Owner MOA/class Phase

Bedaquiline TB Alliance/ ATP synthase inhibitor Registered
Delamanid Otsuka Nitroimidazole PhIII
Pretomanid TB Alliance Nitroimidazole PhII/III
Sutezolid TB Alliance/ oxazolidinone I/II
Q203 Qurient QcrB (respiration) inhibitor I, EBA soon
PBTZ-169 iM4TB/Nearmedic DprE1 (cell wall synthesis) II
BTZ-043 LMU DprE1 inhibitor I
OPC-167832 Otsuka DprE1 inhibitor I
TBA-7371 TB Alliance DprE1 inhibitor I
GSK070 GSK LeuRS (protein synthesis) I
Delamanid for treatment of MDR TB
• Nitro-dihydro-imidazooxazole

• Derivative of metronidazole Mycobacterial Growth Indicator Tube

Culture Conversion at Day 57
P = .008
• Multinational trial of pts with 80

Patients (%)
pulmonary MDR-TB 60
P = .04
45.4 41.9
40 29.6
• Delamanid significantly increased
culture conversion vs placebo
n/N = 64/141 57/136 37/125
after 2 mos of treatment 0
Delamanid Delamanid Placebo
100 mg 200 mg

• EMEA marketing approval; No

FDA approval, but may be
available by compassionate usage

Gler MT, et al. N Engl J Med. 2012;366:2151-2163.

Bedaquiline for MDR-TB
• Oral diarylquinoline

• Target: ATP synthase

Outcome BDQ Placebo P Value
– Activity specific to Median time to 83 125 < .0001
mycobacteria sputum conversion, (56-97) (98-168)
days (95% CI)
Pts with culture
• Bactericidal activity similar to conversion, %
 Wk 24 78.8 57.6 .008
RIF-INH-PZA in mice  Wk 72 71.2 56.1 .069
 Wk 120 62.1 43.9 .035
Proportion cured, % 57.6 31.8 .003

• Sterilizing activity comparable

to rifampin in mice Concerns: 30 deaths in BDQ arm at
followup, compared to 6 in placebo

• No cross-resistance CDC Guidance:

BDQ may be used as a component of TB
WHO. The use of BDQ in treatment of MDR-TB 2013.
Andreas K, et al. Science. 2005;307:223-227. therapy when an effective treatment
CDC. MMWR Morb Mortal Wkly Rep. 2013;62:1-12.
Diacon et al. NEJM 2014
regimen cannot otherwise be provided
Bedaquiline (SirturoTM) FDA approval December 2012
and WHO endorsement for MDR-TB treatment
• Shreya’s story: 18 year old fighting TB for 5 years
• Diagnosed when she was 13
• Failed first line therapy, dropped out of school, wheelchair bound
• Eventually diagnosed with ‘extremely’ drug resistant TB—resistant
to all first and second line drugs
• 5 years of failed treatments
• Sees a TB specialist in Mumbai—strongly advocates she be started
on Bedaquiline, along with some other 2nd line medications

• Indian Govt restricts access—will not provide it

– Not a resident of New Delhi (only 6 centers in the country approved)
– Later suggested she needed more tests
Nix-TB Trial in XDR-TB: Pretomanid + bedaquiline + linezolid
Patients with XDR-TB or Who Have Failed MDR-TB Treatment

Follow up for
relapse-free cure
Pretomanid 200 mg
over 24 months

XDR-TB Bedaquiline 200 mg 6 months of treatment

tiw after 2 week load
Additional 3 months if sputum
Linezolid 1200 mg culture positive at 4 months

**Just amended from

600 mg bid strategy
Sites: Sizwe and Brooklyn Chest, South Africa


Fully oral

What about LTBI?
• ACTG 5729 (presented at CROI 2018): Phase III
– Randomized Controlled Trial (non-inferiority)
– One month of daily Rifapentine/Isoniazid (1HP) vs.
– 9 months of Isoniazid (9H)
– People living with HIV
– 3000 people in 10 countries
– Primary Outcome: incidence of TB or death
• Outcomes: 1HP was Non-Inferior to 9H
– 9H: incidence rate 0.047 (IRR of 1.587 (1.09, 2.3))
– 1HP: incidence rate 0.029
• New Diagnostics are coming!
– But we have to advocate for their availability
– Need to determine how they all fit together in the diagnostic

• We can use our current drugs MORE EFFECTIVELY

• New drugs ARE HERE (for MDR-TB)

– But there is globally limited access

• Ongoing trials for new drug regimens

– All oral regimens
– All new drugs
• JH Center for Clinical Global Health Education
and Center for TB Research
• Susan Dorman
• Linda Xie
• Kelly Dooley
• Claudia Denkinger
• BCHD Team: Anna Schauer, Kathleen Page,
Emily Fogg, Siobain Fisher, Karla Alwood
• TB patients