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1 Thank you for viewing this presentation. We would like to remind you that this material is the property of the author. It is provided to you by the ERS for your personal use only, as submitted by the author.2012 by the author
2 From traditional bacteriology to rapid molecular methods: the revolution is going on (September 2012; Vienna)Keertan Dheda, MB.BCh, FCP(SA), FCCP, PhD (Lond), FRCP (Lond)Professor and Head:Lung Infection and Immunity UnitDivision of Pulmonology & UCT Lung Institute,Department of Medicine,Conflict of interest: none
3 1 in 100 South Africans have TB “If TB and AIDS are a snake, then the head is in South Africa while the tail is quickly moving through other African countries… And if the head of the snake is in South Africa then the teeth are in Durban”Dr Aaron Motsaledi (SA minister of Health)World TB Day, 24 March 20111 in 100 South Africans have TBcases per annum (1000 new cases every day!)
4 OverviewEpidemiology of DR-TB, TB control, and the unmet need for diagnosticsAppreciating phenotype and sampling error and its implicationsNAATS: Gene Xpert MTB-RIFHain MDR TB plus (including new version)Hain MDR TB slPlex ID (combination of mass spec and NAAT)Newer and novel approaches: HRM assayMDR on a chip (array and microfuidics) SequencingLateral flow assaysSummary and conclusionsWhole bunch of diagnostic tests in the pipeline and many in development- I will focus predominantly on newer tools are are already available or imminently available to practising clinicians
5 What is the size of the problem globally? Worldwide prevalent cases of MDR-TB in 2010 (5·4% of the 12 million prevalent cases)( new cases; 3.4% of new cases and 20% of retreatment cases)WHO. Global TB ControlXDR-TB: globally~ XDR-TB cases annually
6 MDR-TB in SA 80% of MDR-TB results from ongoing transmission Streicher and Warren, Infect Gen Evol, 2011In Khayelitsha, Cape Town, 81% of MDR-TB likely due to primary transmissionCox HS, PLoS One, 2010Therefore any cost saving strategy that targets testing, only to those with risk factors, will miss a substantial number of cases and fail to supress on-going transmissionAlthough MDR was initailly acquired…………
7 N= 46 isolates from the WCGenotyping and mutational analysis = 81% acquired resistance
8 N= 199 XDR-TB60 to 70% of our MDR-TB cases are also smear negative so the better performance of Xpert in smear negative TB is gratifying
9 Major unmet diagnostic need Only 7% MDR-TB reported and 1-2% actually treated to WHO standardsLess than 2% of cases have available DST resultVery few reference laboratories in the 22 high burden countriesNeed user-friendly rapid tools, preferably at point of care, given decentralised MDR treatment programmes
10 Approach to diagnosisMajor problem is that DRTB cannot be diagnosedVisualise the bug- LED microscopy, various techniques to concentrate the bugs (AB, magnets, spin filters)Pai et al. Sem Resp Crit Care Med 2008
11 Approach to diagnosis and new technologies Major problem is that takes several weeks, significant contamination rate, MOD suited to resource-poor settings but very labour intensive and cannot be sited at point of careGrow the bug- liquid culture, MODSPai et al. Sem Resp Crit Care Med 2008
12 Diagnostic test impact PatientSampleDiagnostic testResultInitiate treatmentMaintain treatmentDiagnostic only one element of DR-TB control
13 TB diagnosis and control in HIV-infected persons ~ 20% are sputum scarce20% have extrapulmonary TB (paucibaciliary)~ 30 to 40% are smear negative- often poor qualitySmaller volume of sputum and lower concentration of M.tbPulmonary infiltrates atypical or chest x-ray may be normalLOW CD4 count < 200 cells/ mlHave an extended length of stay before diagnosis is made and treatment is initiatedMany patients die undiagnosedwith TB1st 2 points even in HIV uninfected personsTheron and Dheda, AJRCCM, 2011
14 Problem of sample aquisition Even with tests like Xpert about 1/3 of TB will probably remain undiagnosed without additional interventions (sputum scarce PTB, undiagnosed fraction of smear negative TB, and EPTB)Sputum induction and bronchoscopy- only available in tertiary care facilitiesAny diagnostic test is dependent on acquiring a suitable sample
15 What is Xpert MTB/RIF?Xpert is an automated real-time PCR for the diagnosis of TB and genotypic rifampicin resistanceWHO approved: frontline dx for individuals suspected of TB-HIV co-infectionSA DoH has initiated the replacement of smear by Xpert for TB suspectsScott, PLoS Med, 2011
17 C Boehme, FIND Diagnostics Overlapping primers specific for the rpoB gene hotspot, if there is fidelity, probes bind to primers dissociated the dye ad the quencher resulting in fluouresence which can be measured and coresponds to a Ct value. Thus, the higher the amount of input DNA the lower the Ct valueC Boehme, FIND Diagnostics
18 Gene Xpert (WHO endorsed) Cost: R1003 (Path Care)- Jan 2012R 80 per cartridge (excludes capital cost and labour)How good is it: Sensitivity= 97% in smear +ve and 70% in smear negative; Specificity = 99%User-friendly and quick- POC. Closed system.However, only R resistance (not I, FQ, Cap, Etham like Hain)Currently being rolled out in SATiered developing country price- R for the hardware (4 module machine and about R150 per cartridge
19 How does Xpert MTB/RIF perform? Rif RBoehme et al, NEJM, 2010 (N= 1730); Boehme et al, Lancet, 2011 (n= 5000)
20 Gene Xpert (WHO endorsed) Drawbacks:(i) Expensive.(iii) Negative test high rule-out value in uninfected but not HIV-infected persons.Theron and Dheda, AJRCCM, 2011(iii) PPV for DR-TB locally is sub-optimal so may be overcalling DR-TB- new cartridge being trialled (G5).
21 Has already been rolled out in 12 clinics in Cape Town in the Klipfontein district (16 module Xpert machine at GP). 3 national phases. Phase 1 in the 1st quarter of each of the provinces (DH and day hospitals); phase 2 in quarter 3 (go to full capacity in phase 1 clinics and co-opt additional sites); phase 3- bigger centresDiscordance between genotypic and phenotypic because samples used are different ie unprocessed vs processed (false-ve phenotypic if mixed strains and disproportionate killing on the R strain by NaOH because it is less fit or problem with mixing the drug or drug quality). False +ve phenotypic with contamination.False –ve genotypic as 5 % of mutations outside the rpoB gene hot spotFalse +genotypic with contamination (unusual with Xpert)VAN RIE AND WARREN MIXED INFECTION
22 HIV-infected persons: Studies from ARV clinic in CT (n= 468 patients) If no sputum- 2 induced samplesOtherwise 1 spot and 1 induced sample10% of cases no samples could be obtainedLawn SD, PLoS Med, 2011
23 Studies from primary care TB clinics- Cape Town (n=480 with suspected TB) Theron and Dheda, AJRCCM, 2011
24 NPV was 91·3% (389/426; 95% CI 88·3–93·6) in HIV-infected Boehme C, Lancet, 2011 Multisite evaluation study Comment by Theron, Lancet, 2011 (letter)NPV was 91·3% (389/426; 95% CI 88·3–93·6) in HIV-infectedversus 96·0% (748/779; 94·4–97·2;p<0·001) in the uninfected;the respective negative LRs were 0·18 (0·17–0·19) versus 0·09 (0·09–0·10).Thus, about one in ten people that have active tuberculosis will have a negative test result.No difference in sensitivity in HIV-infected and uninfected
25 Studies from primary care TB clinic- Johannesburg (n= 311 TB suspects) Sensitivity in HIV-infected persons not significantly different from the CT studyOnly 73 culture pos patients vs 128 in the CT study vs 44 in RCT prelim dataScott and Stevens, PLoS Med, 2011
26 Xpert MTB/RIF research gaps Beyond diagnostic accuracy to patient outcomes Early proof of concept studiesLarge scale evaluation studies: What is the diagnostic accuracy?Phased demonstration and implementation studies: What is the technical feasibility? What are the short-term patient outcomes?Diagnostic RCTs addressing long-term patient outcomes (morbidity, morality etc.)What impact will this technology have given that case finding is passive and that treatment compliance is poor……….and do we need integration with other measures to make this technology effective
27 Xpert RCT: Patient flow Hypothesis: One sputum Xpert MTB/RIF performed at the point-of-treatment is feasible and will improve TB-related morbidity and patient-level costs in individuals suspected of TB who present to primary level clinics in Africa
28 TB-NEAT study- N= 508 participants in Durban and CT (of 600 participants) Xpert MTB/RIF sensitivity is significantly diminished in HIV infected vs. uninfected patients (p= )
29 What currently available approaches can be used if Xpert is negative? Perform CXR (rule out test)Await culturePerform a second XpertRefer for further investigationHain not an option in smear negative personsTreat empirically for TB (commonest approach)Hain MDRplus good tool in smear positive- main drawback is poor efficacy in smear negatives and open system. Still useful as Xpert capacity is very limited, Xpert inconclusive, SL testing.
30 How should Xpert be integrated with existing diagnostic algorithms? Assessed the diagnostic accuracy and/or cost-effectiveness of smear-microscopy, chest-radiography, IGRAs combined with a single Xpert-MTB/RIF assay in 480 patients with suspected TBXpert negative- although CXR has poor rule-in value, it can reliably rule-out TB in approximately 1 in 4 of such cases.Theron and Dheda, Eur Resp J, 2011
31 What currently available approaches can be used if Xpert is negative? Perform CXR (rule out test)Await culturePerform a second Xpert (10% increase yield in SM-ve)Refer for further investigationHain not an option in smear negative personsBlood cultureTreat empirically for TB (commonest approach)Hain MDRplus good tool in smear positive- main drawback is poor efficacy in smear negatives and open system. Still useful as Xpert capacity is very limited, Xpert inconclusive, SL testing.
32 Other applications of Xpert: Bacterial burden and infectiousness Smear microscopy though a crude predictor of infectiousness it is used to risk stratify patients for isolation and contact tracingTheron, Peter and Dheda, AJRCCM, 2011
33 Bacterial burden and infectiousness Evaluated CT values in 496 patients with suspected TBXpert CT values have poor rule-in[cut-point ≤20.2; sensitivity 32.3%; specificity 97.1%]Moderately good rule-out value for smear positivity[NPV 80.0%]. Thus, 20% of individuals with CT values >31.8 were smear-positive patients erroneously ruled out as smear-negatives.But smear status a crude proxy of infectiousness and Xpert may also detect intact but dead bugs!Same considerations apply to disease monitoring in MDR patientsTheron, Peter and Dheda, Clin Infect Dis, 2011So relationship unclear
34 Urine-orientated approach in HIV-infected sputum-scarce persons? Sputum-based diagnostic unhelpful in 20-30% HIV-infected patients116/242 culture +ve patients (54/116 i.e. 48% SS or SN)18% (20/116) of all culture +ve were sputum scarceIn this group (using urine) sensitivity:Xpert % (95%CI: 22-61)LAM 58% (95%CI: 49-67)LAM and Xpert 68% (95%CI: 60-77) [better than either;p= 0.003]In 6/14 +ve urine cases, LAM was exclusively positiveWe investigated the sensitivity of urine-based methods (Xpert MTB/RIF, LAM strip test and LAM ELISA) in such patients.Methods: 281 HIV-infected hospitalised patients with clinically suspected TB provided a spot urine sample. The reference standard was culture positivity for Mycobacterium tuberculosis on ≥1 sputum or extra-pulmonary sample. MTB/RIF was performed using 1ml of both unprocessed and, when possible, concentrated urine. Each unconcentrated urine sample was also tested using the Clearview LAM ELISA and Alere LAM strip test.Results: 42% (116/242) of patients had culture-proven TB. 18% (20/54) were sputum scarce. In sputum-scarce patients, the sensitivity of urine MTB/RIF and LAM ELISA was 40% (95%CI: 22-61) and 58% (95%CI: 49-67), respectively. Urine MTB/RIF specificity was 98% (95%CI: ). Combined sensitivity of urine LAM ELISA and MTB/RIF was better than MTB/RIF or LAM strip tests alone [MTB/RIF and LAM: 68% (95%CI: 60-77) vs. either MTB/RIF or LAM strip: 48% (95%CI: 39-57), p=0.003]. Significant predictors of urine MTB/RIF positivity were CD4<50 cells/ml (p=0.001), elevated protein-to-creatinine ratio (p<0.001) and LAM ELISA positivity (p<0.001). Urine centrifugation and pelleting significantly increased the sensitivity of MTB/RIF over unprocessed urine in paired samples [42% (95%CI: 26-58) vs. 8% (95%CI: 0-16), p<0.001]. Urine MTB/RIF-generated CT values correlated poorly with markers of bacillary burden (smear grade and time-to-positivity).Conclusions: This preliminary study indicates that urine-based MTB/RIF, alone or in combination with LAM antigen detection, may potentially aid the diagnosis of TB in HIV-infected patients with advanced immunosuppression when sputum-based diagnosis is not possible. Concentration of urine prior to MTB/RIF-testing significantly improves sensitivity.Peter and Dheda, PLoS One, 2012
35 Urine diagnostics to target HIV-infected sputum-scarce persons Urine centrifugation and pelleting improved performance of Xpert in paired samples compared to unprocessed urine (42 vs 8%; p= 0.003)Urine-orientated approach feasible when a sputum-based tests are not feasibleWe investigated the sensitivity of urine-based methods (Xpert MTB/RIF, LAM strip test and LAM ELISA) in such patients.Methods: 281 HIV-infected hospitalised patients with clinically suspected TB provided a spot urine sample. The reference standard was culture positivity for Mycobacterium tuberculosis on ≥1 sputum or extra-pulmonary sample. MTB/RIF was performed using 1ml of both unprocessed and, when possible, concentrated urine. Each unconcentrated urine sample was also tested using the Clearview LAM ELISA and Alere LAM strip test.Results: 42% (116/242) of patients had culture-proven TB. 18% (20/54) were sputum scarce. In sputum-scarce patients, the sensitivity of urine MTB/RIF and LAM ELISA was 40% (95%CI: 22-61) and 58% (95%CI: 49-67), respectively. Urine MTB/RIF specificity was 98% (95%CI: ). Combined sensitivity of urine LAM ELISA and MTB/RIF was better than MTB/RIF or LAM strip tests alone [MTB/RIF and LAM: 68% (95%CI: 60-77) vs. either MTB/RIF or LAM strip: 48% (95%CI: 39-57), p=0.003]. Significant predictors of urine MTB/RIF positivity were CD4<50 cells/ml (p=0.001), elevated protein-to-creatinine ratio (p<0.001) and LAM ELISA positivity (p<0.001). Urine centrifugation and pelleting significantly increased the sensitivity of MTB/RIF over unprocessed urine in paired samples [42% (95%CI: 26-58) vs. 8% (95%CI: 0-16), p<0.001]. Urine MTB/RIF-generated CT values correlated poorly with markers of bacillary burden (smear grade and time-to-positivity).Conclusions: This preliminary study indicates that urine-based MTB/RIF, alone or in combination with LAM antigen detection, may potentially aid the diagnosis of TB in HIV-infected patients with advanced immunosuppression when sputum-based diagnosis is not possible. Concentration of urine prior to MTB/RIF-testing significantly improves sensitivity.Peter and Dheda, PLoS One, 2012
36 DST: Line probe assay (Hain) Hain Lifescience GenoType® MTBDRplusClinical samples (sens, spec): Rif (99; 99%) INH (85; 99)%Smear positive samplesMorgan M, BMC Infect Dis, 2005;Ling D, Eur Resp J, 2008Barnard M, AJRCCM, 2008….…metaanalysis of 14 studies…....promising test if these assays are consistently accurate when clinical samples like sputum are used.
37 DST: Line probe assay (Hain, InnoLip A) Hain MTBDRplus (version 2.0)In 104 smear-ve culture +ve sputum samples combined sensitivity (80%) and specificity (99%)Crudu V, J Clin Micro, 2012Hain Lifescience GenoType®MTBDRplusClinical samples (sens, spec):Rif (99; 99%) INH (85; 99)%Smear positive samplesMorgan M, BMC Infect Dis, 2005;Ling D, Eur Resp J, 2008Barnard M, AJRCCM, 2008….…metaanalysis of 14 studies…....promising test if these assays are consistently accurate when clinical samples like sputum are used.
38 DST: Line probe assay (Hain) Hain MTBDRplus (version 2.0)In 104 smear-ve culture +ve sputum samples combined sensitivity (80%) and specificity (99%)R100 per test in public sector and R571 in private sectorCrudu V, J Clin Micro, 2012
39 Hain MDR+ sl version- to be used when R resistance is noted Hain MDR+ sl version- to be used when R resistance is noted. Rapid evaluation of drug-resistance for FQ,AG + capreomycin [SLID] and ethambutol
40 Hain MDR+ sl version- to be used when R resistance is noted Hain MDR+ sl version- to be used when R resistance is noted. Rapid evaluation of drug-resistance for FQ,AG + capreomycin [SLID] and ethambutolTotal 64 sputum samples ( 26 DR-TB))FQ (89%; 8/9), AG/capreo (87%; 7/8), and ethambutol (39%; 10/26); 100% specificityHilleman D, J Clin Micro, 2009Miotto P, ERJ, 2012 (10 clinical samples resistant to SLIDS)Lancoma A, JCM, 2012 (52 clinical samples resistant to SLIDS)
41 Hain MDR+ sl version Total 64 sputum samples (26 DR-TB) FQ (89%; 8/9), AG/capreo (87%; 7/8), and ethambutol (39%; 10/26); 100% specificityHilleman D, J Clin Micro, 2009Miotto P, ERJ, 2012 (10 clinical samples resistant to SLIDS)Lancoma A, JCM, 2012 (52 clinical samples resistant to SLIDS)
42 206 MDR or XDR culture isolates Excellent sensitivity and spec in isolatesMarkedly cuts down on time to diagnosis if patient is culture +ve
44 OVERALL SENSITIVITY AND SPEC IN SMEAR +VE AND -VES N= 158 sputum samples from patients with proven M and XDR-TBAll patients were culture positive
45 TOTAL INDETERMINATES= 3.19%= Smear positiveThus, MTBDRplus (version 2.0) very useful in smear +ve samples- make diagnosis of MDR immediatelyTOTAL INDETERMINATES= 3.19%=[9/19 (47.4%) indeterminate in scanty pos vs. 1/71 (0.01%) in 1+ to 3+ pos]If MTBDRplus or Xpert pos proceed to the Hain SL in smear positive casesTOTAL INDETERMINATES= 13%=[9/19 (47%) in scanty pos vs. 11/74 (15%) in 1+ to 3+ pos]Culture DST still required to clarify type of SLID resistance
46 In smear-ve samples 37% of SL were indeterminate Smear negativeMTBDR PLUS STILL EXCELLENT Sens and Spec IN SMEAR NEG SAMPLES but 39% of results indeterminate!In smear-ve samples 37% of SL were indeterminateThus, only useful in smear +ve samples
47 Combined approaches: PCR and mass spec (alternative to Hain and Xpert for isolate ID and DST) PCR for gene-specific mutations followed by R, I, E and FQ resistance; already commercially available
48 Why do we need new tests?Xpert is accurate & cost-effective but very costly (even at $10 per cartridge consume about 25% of SA NTP budget)- stable power supply- suited to centralised rather than decentralised use- in up to a third of cases diagnosis cannot be made (sputum scarce, EPTB, smear negative TB undiagnosed)Large burden of undiagnosed TB (cost and access)Lack of a cheap same day test (human aspect and poverty)Takes hours to get to the clinic, significant costs,
49 POC detection technologies NAAT with visual real-time readout including HRMNAAT with lateral flow readoutNAAT with calorimetric readout (including LAMP)NAAT with biosensor readout (electro-chemicaldetection, piezoelectric quartz crystal biosensors,magnetoeleastic biosensors)NAAT with SERS readoutBiochip readouts for DR TB (currently not automatedand uses DNA from isolates)Park H, JCM, 2006
50 Several new commercial platforms that lend themselves to POC NAAT detection are now available The Liat Analyzer automates all nucleic acid testing (NAT) processes, including reagent preparation, target enrichment, inhibitor removal, nucleic acid extraction, amplification and real-time detection. The system refines nucleic acid testing to three simple steps: collecting a raw biological sample such as whole blood into a Liat Tube and capping the tube, scanning the tube's barcode, and inserting the tube into the Liat Analyzer. The analyzer automatically executes all the required assay steps without further operator intervention. The test is completed and interpreted results are reported in as little as 20 minutes on the analyzer’s built-in touch screen, allowing accurate results to be delivered immediately for better and timely clinical decision making.
51 BioCartisIntegrates all the diagnostic steps needed to provide true sample-in to result-out functionality, providing a significantly shorter turnaround time than current MDx technologies while requiring minimal hands-on time and training.Biocartis’ Molecular Diagnostics Platform features proprietary sample preparation technology that is suitable for a wide range of fluid and solid samples such as blood, urine or (tumor) tissue. The platform can be used to simultaneously detect and quantify up to 30 molecular biomarkers in a single assay. This level of multiplexing is required for more complex assays in which multiple biomarkers need to be analyzedOthers including Enigma, Idahotech,
52 TWISTDX http://www.twistdx.co.uk/products/twista/ TwistDx’s proprietary technology, RPA (Recombinase Polymerase Amplification), represents a complete revolution in DNA diagnostics, combining superiority in speed, portability and accessibility with exquisite sensitivity and specificity compared to other diagnostic testing systems now on the market. It is usable in nearly any setting, eliminating the need for a trained technician or laboratory environment.TwistDx’s RPA process employs enzymes, known as recombinases, which are capable of pairing oligonucleotide primers with homologous sequence in duplex DNA. Through this method, DNA synthesis is directed to defined points in a sample DNA. If the target sequence is indeed present, DNA amplification reaction is initiated; no other sample manipulation such as thermal or chemical melting is required. The reaction progresses rapidly and results in specific DNA amplification from just a few target copies to detectable levels typically within minutes. The entire reaction system is stable as a dried formulation and can be transported safely without refrigeration.RPA can be used to replace PCR (Polymerase Chain Reaction) in a variety of laboratory applications and end-users can design their own ultra-sensitive assays.
53 High resolution melt and PCR Species-specific DNArpoB-specific DNA mutationsNAAT with real-time readout using melting curves of amplified DNA amplicons- high sensitivity and specificity for MDR-TBRamirez MV, JCM, 2010Yadav R, J App Micro, 2012
54 Gold nanopartcles for detection of SNPs for rifampicin resistance using calorimetric readout Veigas B, Nanotech, 2010
55 Simplified NAAT: LAMP (loop mediated isothermal amplification) Rapid (1 hour), isothermal, high through-put, clinical samplesFeasible in high burden settings (hospital or central laboratories)Sens in sputum smear negative TB 49%Limited data in HIV+CheaperCannot multiplexFeasibility of this test was establishedBoehme CC, J Clin Micro, 2007
57 Best Cassette- detection platform The BioHelix® Express Strip (BESt™) Cassette is a novel, disposable, self-contained Amplicon Detection Device. It is designed for instrument-free, cross-contamination-proof detection of amplicons derived from HDA, PCR, and other nucleic amplification reactions.Features:Cross contamination proof - Detection takes place in an enclosed, disposable cassette.Sensitive - More sensitive than gel-based detection methods.Fast - Takes less than one minute to prepare and results are viewable in 5-10 minutes.detects two amplicons.
59 EC detection platform for NAAT products Gonzales- Diaz M, Biosens & Bioelec, 2005
60 Alternative detection technologies: Aptamers Aptamers, in contrast to protein-basedantibodies, are simply ‘chemical’ or NA antibodiesCSIR- ESAT and CFP-10 aptamers, LAM, IFN-g, and Tumi aptamer array
61 Aptamers and a SERS detection platform We have generated aptamers to TB-specific antigens (CSIR- Shooz Kathi)Grand Challenges Canada (J Blackburn) to develop a platform using antigen-specific aptamers and a SERS detection platformSurface enhanced resonance spectroscopy
62 Technological innovation is not enough- other challenges Lack of private investment because of perceived lack of return (changing rapidly)Need better regulatory standards for approval, and these need international harmonisationVariable quality of diagnostic services, need to improve quality controlMore innovation in developing countries (ANDI, Gates etc) including involvement from EDCTP, Wellcome etcNew ways to deal with IP and patent feesTranslation from research to policy- need streamlining of approval process and guidance for high burden settingsRobust health care systems with good supply chain managementBetter representation in medical and nursing curricula…the challenge will be
63 SummaryXpert- good test but expensive and suboptimal PPV for R resistance (no H, FQ, SLID readout)Hain MTBDRplus- main drawback was poor performance in smear negative TB (version 2.0)Hain SL- only useful in smear pos TB and does not distinguish SLIDsRevolution in the development of new and POC diagnostic platformsMajor challenge is to include DR-TB readoutsNeed platforms that will give multiplex readouts – TB, HIV, pneumonia, other OI, malaria etcChallenge of bringing these to market and incorporating them into clinical algorithms and niche areas taking into account clinical context…the challenge will be
65 Funding Agencies: EUFP7 EDCTP Discovery NIH Fogerty South African To give you a brief overview overview of my talk. I will 1st describe the epi of XDR-TB in Africa……..hardly any …………Hot of the pressSouth AfricanNational ResearchFoundationSouth AfricanMRCEDCTP
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