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7
Case Detection Rate: WHO estimates
What do we need?
• “To achieve targets for TB prevention, care,
and control…new diagnostic tools are
critically important”
• 10 Commercially available
Test performance: meta-analysis
SENSITIVITY BY CD4 SPECIFICITY BY CD4
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)
11
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)
http://www.who.int/tb/publications/use-of-lf-lam-tb-hiv/en/
Peter et al. “Effect on mortality… “Lancet 2016
Non-sputum based tests for diagnosis or triage
Source:
Active TB Incipient TB tests (blood) http://lnbd.techni
Pediatric TB - QIA-Predict (Qiagen)
on.ac.il
Source: https://www.whatisepigenetics.com
15
NAAT: GeneXpert (Cepheid)
• Molecular beacon technology
• Sensitivity
– Smear-positive: 95–100%
– Smear-negative: ~30-70%
• Specificity: ~98%
• http://www.stoptb.org/wg/gli/assets/documents/Xpert%20Meeting%20Report%202410201
3%20%20Pre%20publication%20FINAL.pdf
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
Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q4
TB MultiTest
(SelfDiagnostics)
Xpert Ultra
(Cepheid)
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
• MGIT (BD)
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.
Lancet ID 2018
Improved limit of detection: but
comes with reduced specificity
Molecular detection of
drug resistance
MDR- and XDR-TB: Global Health
Emergencies
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
25
Phenotypic Drug
Susceptibility Testing
Sputum
Culture
media
Growth of
MTB Growth
detected=
Culture Resistance
media
with drugs Growth
inhibited=
Susceptible
TIME
Molecular Detection of Drug Resistance
• Drug resistance in MTB is mediated by several mutations
1. MOLECULAR BEACON ASSAYS
3. SEQUENCING
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
INH R
katG Mutation
embB Mutation EMB R
pncA Mutation Cannot rule out PZA resistance
• WHO recommended line probe assays for rapid resistance testing (2008):
Rifampin resistance
Sensitivity: ~97–100%
Specificity: ~98–100%
29
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%
– SLID
• Sensitivity 77%
• Specificity 99.5%
30
Source: Theron et al. Cochrane 2014
Xpert XDR
Amikacin,
1401, 1402 ✔ ✔
rrs
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
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)
• 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?
The “least restrictive public health interventions that are effective are
used to achieve adherence”
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
constraints
this.”
Video-DOT achieves similar or better outcomes and is
cost-effective/saving: Maryland Study
48
New in 2016: WHO Short-Course MDR-TB Rx
(9-12 months)
Cumulative Probability
0.8
• Several case-series suggesting
of Conversion
clinical benefit 0.6
0.4
• Clinical Trial of 41 Smear-positive
0.2
XDR-TB patients
0
0 30 60 90 120 150 180
• 87% (34/39) with negative sputum Days Since Start of LZD
culture within 6 mos
L-Ala
D-Ala
4 D-Glu
D-Ala
mDap mDap 3 3
3
Peptidoglycan layer
Transpeptidase D-Glu D-Ala
L-Ala
MTB Transpeptidase
Membrane
Cytosol
Clinical Studies: 8 studies—case
reports
• Limited data with heterogenous usage
– Backbone regimen, dosing, clavulanic acid, duration, outcome
Drug Studies Dosing Outcome Side Effects
summary
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
patients
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
Patients (%)
pulmonary MDR-TB 60
P = .04
45.4 41.9
40 29.6
• Delamanid significantly increased
20
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
Follow up for
relapse-free cure
Pretomanid 200 mg
over 24 months
58
STREAM-2
9-month
Fully oral
6-month,
With
Injectable
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
http://www.croiwebcasts.org/console/player/37077?mediaType=slideVideo&&crd_fl
=1&ssmsrq=1520431783538&ctms=5000&csmsrq=799
Conclusions
• New Diagnostics are coming!
– But we have to advocate for their availability
– Need to determine how they all fit together in the diagnostic
pathway