New TB Diagnostics

New TB Diagnostics Pamela Hepple Laboratory Specialist MSF-UK August 2013

Plan  Focus on Xpert® MTB/RIF and the Hain MTBDRplus

systems  Implementation of Xpert by MSF globally and in Myanmar  The role of line probe assays in TB diagnosis  The tuberculosis diagnostic test pipeline

Xpert® MTB/RIF • Multicentric study (Boehme, 2010) • MTB detection (one sample) • Sensitivity: • 92.2% for all patients • 72.5% for smear-negative patients • Specificity: • 99.2% • Rifampicin resistance (allows presumptive MDR diagnosis) • Sensitivity: 97.6% • Specificity: 98.1% (->100% when sequencing used to resolve discordance)

Source: http://who.int/tb/laboratory/mtbrifrollout/en/

DistributionMSF of Projects Xpert速 MTB/RIF sites Ukraine (Donetsk)

02

High MDR >10% Uzbekistan (Chimbay, Nukus)

Grozny, Russian Federation Abkhazia

Kyrgyzstan (Bishkek, Osh)

Myanmar (Yangon) Ethiopia (Dire Dawa) South Sudan (Loki)

Tajikistan (Dushanbe) India (Manipur) Cambodia (Kampong Cham)

Colombia CAR (Zemio)

Uganda (Arua)

DRC, Kinshasa

Somalia (Galcayo) Kenya (Mathare, Kibera, Homabay) Malawi(Chiradzulu, Thyolo) Mozambique (Moatize, Mavalane)

Zimbabwe(Birchenough, Murambinda,Epworth, Gutu, Gokwe)

Swaziland (Nhlangano, Hlatikulu, Mankayane, Matsapha , Matsanjeni)

SA (Eshowe, Mbongolwane)

Lesotho (Roma)

High MDR Low MDR

High HIV

Low HIV

8 9 17

7 1 8

Total 15 10 25

High HIV > 1%

Xpert® MTB/RIF relative gain vs microscopy Fluorescence microscopy

Ziehl–Neelsen

130% 115%

120%

110%

110% 95%

100% 90% 80% 70%

62%

60% 50% 40% 30%

57%

51%

73%

72%

72%

69%

74%

56%

48% 23%

10%

20% 10% 0%

Sm+ Xpert+ Relative gain

• Relative gain varies from 10% to 115% • Relative gain: 38.3% vs. FM and 90.6% vs. ZN

56%

69%

Frequency of inconclusive results • Out of 36,540 samples tested, 2,461 (6.7%) gave inconclusive results, with large variation between projects: median of 5.3% (range 0-17%) At least 11 faulty modules were replaced • Only 7/25 sites had inconclusive results ≤ the 3% benchmark • An improvement over time has been observed, with the rate of inconclusive results decreasing. Main factors contributing to this improvement are: i) Replacement of devices faulty modules ii) Introduction of new cartridge version (G4 cartridge)

MSF OCA Myanmar data March – December 2012

January – June 2013 Detected Not Indet. Total detected

Detected Not Indet. Total detected MTB

419

648

RIF

72

338

9

Inconcl.

1067

MTB

604

1001

419

RIF

88

508

21

Inconcl.

1605 11

607 70

 Data is for Xpert used as a first-line test for Yangon MSF TB

suspects, and MDR suspects from non-Yangon project sites  Inconclusive results: 2012 - 21/1067 (2%);  2013 – 70/1605 (4%)

XPERT MTB/RIF: lab feasibility aspects •Relatively easy to use but not «plug and play» device : training is essential

•Substantial logistical and financial investments required in particular for implementation at decentralized level : -stable power supply -air conditioning to maintain operating temperature at < 30 C - Example of start-up cost from MSF site in Mozambique: 25,000 euro excluding cost of cartridges •Turn-around-time (TAT) to result: -Most of the projects reported a TAT of 1-3 days.

-The TAT is longer when specimens are being sent from one facility to another for testing.

In order to decrease TAT, investments are required in: - specimen transport (incl. cold chain) - transmission of the Xpert result (preferably electronically)

XPERT MTB/RIF: CONSIDERATION FOR SCALE-UP •

DIAGNOSIS: Essential to not address Xpert MTB/RIF in a vacuum but to make sure a full and effective “package” for TB diagnosis is implemented and supported - Infrastructures upgrade - Transport and cold chain - Training (for lab staff and for medical staff) - Lab capacity for confirmatory test and full DST available - More active case detection strategies – outreach testing, use of lay health workers will improve case finding (especially mobile-based community testing)

Need for rapid DST beyond rifampicin- culture and phenotypic DST too challenging and slow

Current algorithms in use in Myanmar

Dx of MDR-TB

TAF-1, TAF-2, TAD, Relapse, Relapse-suspect, MDR-Contact with TB symptoms Facility with Xpert MTB/RIF

Facility that can refer to facility with Xpert MTB/RIF

Facility with no access to Xpert MTB/RIF Sputum for AFB Chest X-ray

Xpert MTB/RIF

No TB

Appropriate further clinical management

TB, No R-res

TB, R-res

TAF-1, TAF-2 TAD, Relapse

MDR Contact

Enrol on Cat 2

Enrol on Cat 1

DST

MDR-TB treatment

Manage as per DOTS guidelines

HIV-positive TB suspect

Dx of (MDR)TB in HIV+ TB suspect

Facility with Xpert MTB/RIF

Facility that can refer to facility with Xpert MTB/RIF

Facility with no access to Xpert MTB/RIF

Sputum for AFB Sputum for AFB Chest X-ray

AFB-pos/neg

Xpert MTB/RIF

TB, R-res

Xpert MTB-/RIFPTB unlikely

TB, No R-res TAF-1, TAF-2 TAD, Relapse

Assess for EPTB New

No EPTB

EPTB

DST MDR-TB treatment CPT - ART

Cat. 2 treatment CPT - ART

Cat 1 treatment CPT - ART

Investigate/treat for other disease / Reassess for TB if no improvement

Manage as per DOTS and TB/HIV guidelines

TB suspect

HIV-neg No risk for MDR

Facility with Xpert MTB/RIF

Facility that can refer to facility with Xpert MTB/RIF

Facility with no access to Xpert MTB/RIF

Sputum for AFB AFB-negative

Sputum for AFB

AFB-positive AFB-negative

Chest X-ray Normal

AFB-positive

Abnormal

Xpert MTB/RIF No TB

Investigate/treat for other disease / Reassess for TB if no improvement

TB, No R-res

Cat.1 treatment or Cat.2 treatment

TB, R-res DST MDR-TB treatment

Manage as per DOTS guidelines

Myanmar diagnostic algorithms  Xpert MTB/RIF is present in Myanmar diagnostic algorithm – first test for

MDR suspects and/or HIV+  Can treat for MDR only after phenotypic confirmation (unless HIV+ or very ill patient) – no empirical treatment based on Xpert results for routine patients.

Can do Hain test on SM 2+/3+ and if rifampicin resistance confirmed, and isoniazid resistance detected, can start MDR treatment  In all cases, confirm rifampicin resistance with phenotypic DST– if discordant, repeat; if remains discordant, go with culture result (reference standard)  Treatment is delayed if have to wait for phenotypic results  It is possible to get Xpert Rif-resistant/phenotypic Rif-sensitive results – some

evidence is emerging that the Xpert results may be true positives (van Deun 2013). Further evidence is required as genotypic testing becomes more widespread.

Role of Hain Genotype MTBDRplus and sl Source:

Hain MTBDRplus test  Endorsed by WHO in 2008 for use

   

on smear-positive sputum, and isolates. Version 2 test is not endorsed by WHO for smearnegative samples.

Technically-demanding, so based mostly in reference labs Detects rifampicin and isoniazid resistance – can diagnose MDR TB Can be automated for high through-put Second-line test is now available.

http://www.finddiagnostics.org/media/n ews/080227.html

The TB diagnostics pipeline Feasibility and proof of principle Seek TB Reference level

District, Subdistrict, microscopy

Evaluation studies

Abbott NAAT

TREK Sensititre

BD Max NAAT

NIPRO (LPA)

Qiagen (China) Colorimetric TLA (DST)

Epistem Genedrive

NAA based assays Alere Q

Ustar Biotechnologies EasyNatTB

Twist Dx; IonianTechn; Biohelix Techn; Enigma; Wave 80; NorthWestern Univ.

Antibody detection (MBio) Peripheral level

Development optimization (design lock)

Beta-lactamase assay (GlobalBio Diagnostics) VOC based assays

Demonstration studies

P O L I C Y

Hain Genotype MTBDR sl TB-LAMP (completed)

TrueNAT MTB

Alere Determine LAM (completed) Culture based test NAA based test FIND is a co-sponsor

Fast-Follower technologies for NAA-based test

_

+ + _ + ?

Adapted from :TB Diagnostic Technology Landscape. Semiannual Update. UNITAID. December 2012

Gates Foundation Next Generation Programme â&#x20AC;˘

To support the development of a low-cost, nucleic acid amplification based test suitable for implementation at microscopy level - First platform selected: AlereQ* - Alere Q HIV Viral load test on late stage of development - Gates Foundation provided a USD 21.6 M grant to support development of a TB diagnostic assay for detection of TB and drug resistance - Very early stage - Looking at Urine and sputum as sample types Expected timelines: 24-36 months

*http://www.alere.com/content/dam/alere/docs/pressreleases/Gates_Grant_Relea se_Alere_FINAL_19_FEB_v2.pdf

Conclusion  Xpert can increase case detection and get patients onto second 



 

line treatment faster than culture and DST Use of Xpert rifampicin resistance results can place people on empiric MDR treatment quickly – specificity is generally very high The Hain first-line test can add isoniazid information and is useful for MDR screening purposes; the second-line test lacks sensitivity at present Promising new diagnostics in the pipeline are focused on molecular techniques Swift access to second line testing is important for tailored second-line treatment regimens and detection of pre-XDR and XDR tuberculosis