![Page 1: Drug resistance surveys - WHO...March 19-21, 2014 –Hanoi, Viet Nam Second-line drug resistance • Globally, 6.2% of MDR-TB cases have XDR-TB • Short-course MDR/RR-TB and INH-monoresistance](https://reader035.vdocuments.mx/reader035/viewer/2022070217/6122d46cec541c6271740448/html5/thumbnails/1.jpg)
Drug resistance surveys: an overview of progress and latest developments
Anna Dean
TB Monitoring & Evaluation
Global TB Programme
WHO
![Page 2: Drug resistance surveys - WHO...March 19-21, 2014 –Hanoi, Viet Nam Second-line drug resistance • Globally, 6.2% of MDR-TB cases have XDR-TB • Short-course MDR/RR-TB and INH-monoresistance](https://reader035.vdocuments.mx/reader035/viewer/2022070217/6122d46cec541c6271740448/html5/thumbnails/2.jpg)
1Meeting of the Tuberculosis Surveillance and Research Unit (TSRU)March 19-21, 2014 – Hanoi, Viet Nam
Objectives:
• To estimate the magnitude of drug resistance
• To determine trends over time
• To enable a prompt and effective public health response
Main technical partners:
• Project hosted by WHO
• NTPs, Supranational TB Reference Laboratories (SRLs), US CDC, KNCV, The Union
Main donor agencies:
• The Global Fund, USAID, PEPFAR, BMGF
Global project on anti-TB drug resistance surveillance since 1994
![Page 3: Drug resistance surveys - WHO...March 19-21, 2014 –Hanoi, Viet Nam Second-line drug resistance • Globally, 6.2% of MDR-TB cases have XDR-TB • Short-course MDR/RR-TB and INH-monoresistance](https://reader035.vdocuments.mx/reader035/viewer/2022070217/6122d46cec541c6271740448/html5/thumbnails/3.jpg)
Overview of progress
![Page 4: Drug resistance surveys - WHO...March 19-21, 2014 –Hanoi, Viet Nam Second-line drug resistance • Globally, 6.2% of MDR-TB cases have XDR-TB • Short-course MDR/RR-TB and INH-monoresistance](https://reader035.vdocuments.mx/reader035/viewer/2022070217/6122d46cec541c6271740448/html5/thumbnails/4.jpg)
3Meeting of the Tuberculosis Surveillance and Research Unit (TSRU)March 19-21, 2014 – Hanoi, Viet Nam
Data sources, 1994-2017
90 countries with continuous surveillance (representing only 4% of the TB burden)70 countries with surveys Data available for
- 97% of global TB burden- 37 of 40 high MDR-TB and/or TB burden countries
![Page 5: Drug resistance surveys - WHO...March 19-21, 2014 –Hanoi, Viet Nam Second-line drug resistance • Globally, 6.2% of MDR-TB cases have XDR-TB • Short-course MDR/RR-TB and INH-monoresistance](https://reader035.vdocuments.mx/reader035/viewer/2022070217/6122d46cec541c6271740448/html5/thumbnails/5.jpg)
4Meeting of the Tuberculosis Surveillance and Research Unit (TSRU)March 19-21, 2014 – Hanoi, Viet Nam
Criteria for representative surveillance data
• WHO Global TB Report - ≥80% new cases have rifampicin testing result
• WHO Standards and Benchmarks- ≥75% new cases have rifampicin testing result
![Page 6: Drug resistance surveys - WHO...March 19-21, 2014 –Hanoi, Viet Nam Second-line drug resistance • Globally, 6.2% of MDR-TB cases have XDR-TB • Short-course MDR/RR-TB and INH-monoresistance](https://reader035.vdocuments.mx/reader035/viewer/2022070217/6122d46cec541c6271740448/html5/thumbnails/6.jpg)
5Meeting of the Tuberculosis Surveillance and Research Unit (TSRU)March 19-21, 2014 – Hanoi, Viet Nam
Global coverage of data since 2007
Approximately 10 surveys underway and 10 in planning phase each year
![Page 7: Drug resistance surveys - WHO...March 19-21, 2014 –Hanoi, Viet Nam Second-line drug resistance • Globally, 6.2% of MDR-TB cases have XDR-TB • Short-course MDR/RR-TB and INH-monoresistance](https://reader035.vdocuments.mx/reader035/viewer/2022070217/6122d46cec541c6271740448/html5/thumbnails/7.jpg)
6Meeting of the Tuberculosis Surveillance and Research Unit (TSRU)March 19-21, 2014 – Hanoi, Viet Nam
Proportion of new TB cases with MDR/RR-TB, 2016
Global: 4.1%European Region: 19%
![Page 8: Drug resistance surveys - WHO...March 19-21, 2014 –Hanoi, Viet Nam Second-line drug resistance • Globally, 6.2% of MDR-TB cases have XDR-TB • Short-course MDR/RR-TB and INH-monoresistance](https://reader035.vdocuments.mx/reader035/viewer/2022070217/6122d46cec541c6271740448/html5/thumbnails/8.jpg)
Proportion of previously treated TB cases with MDR/RR-TB, 2016
Global: 19%European Region: 55%
![Page 9: Drug resistance surveys - WHO...March 19-21, 2014 –Hanoi, Viet Nam Second-line drug resistance • Globally, 6.2% of MDR-TB cases have XDR-TB • Short-course MDR/RR-TB and INH-monoresistance](https://reader035.vdocuments.mx/reader035/viewer/2022070217/6122d46cec541c6271740448/html5/thumbnails/9.jpg)
Estimated incidence of MDR/RR-TB, 2016
47% from India, China, Russian Federation
![Page 10: Drug resistance surveys - WHO...March 19-21, 2014 –Hanoi, Viet Nam Second-line drug resistance • Globally, 6.2% of MDR-TB cases have XDR-TB • Short-course MDR/RR-TB and INH-monoresistance](https://reader035.vdocuments.mx/reader035/viewer/2022070217/6122d46cec541c6271740448/html5/thumbnails/10.jpg)
9Meeting of the Tuberculosis Surveillance and Research Unit (TSRU)March 19-21, 2014 – Hanoi, Viet Nam
Proportion of isoniazid resistance among new cases
New cases: 7.2% isoniazid-resistant and rifampicin-susceptiblePreviously treated cases: 10.1% isoniazid-resistant and rifampicin-susceptible
![Page 11: Drug resistance surveys - WHO...March 19-21, 2014 –Hanoi, Viet Nam Second-line drug resistance • Globally, 6.2% of MDR-TB cases have XDR-TB • Short-course MDR/RR-TB and INH-monoresistance](https://reader035.vdocuments.mx/reader035/viewer/2022070217/6122d46cec541c6271740448/html5/thumbnails/11.jpg)
10Meeting of the Tuberculosis Surveillance and Research Unit (TSRU)March 19-21, 2014 – Hanoi, Viet Nam
![Page 12: Drug resistance surveys - WHO...March 19-21, 2014 –Hanoi, Viet Nam Second-line drug resistance • Globally, 6.2% of MDR-TB cases have XDR-TB • Short-course MDR/RR-TB and INH-monoresistance](https://reader035.vdocuments.mx/reader035/viewer/2022070217/6122d46cec541c6271740448/html5/thumbnails/12.jpg)
11Meeting of the Tuberculosis Surveillance and Research Unit (TSRU)March 19-21, 2014 – Hanoi, Viet Nam
Second-line drug resistance
• Globally, 6.2% of MDR-TB cases have XDR-TB
• Short-course MDR/RR-TB and INH-monoresistance regimens rely on fluoroquinolones
• Globally, 20% of MDR/RR-TB cases have resistance to one or more fluoroquinolone
- moxifloxacin resistance varied from 8-27% acrossfive settings studied
Zignol et al. Lancet Infect Dis. 2016; 16(10):1185-92
![Page 13: Drug resistance surveys - WHO...March 19-21, 2014 –Hanoi, Viet Nam Second-line drug resistance • Globally, 6.2% of MDR-TB cases have XDR-TB • Short-course MDR/RR-TB and INH-monoresistance](https://reader035.vdocuments.mx/reader035/viewer/2022070217/6122d46cec541c6271740448/html5/thumbnails/13.jpg)
Developments:
Xpert MTB/RIF and sequencing
![Page 14: Drug resistance surveys - WHO...March 19-21, 2014 –Hanoi, Viet Nam Second-line drug resistance • Globally, 6.2% of MDR-TB cases have XDR-TB • Short-course MDR/RR-TB and INH-monoresistance](https://reader035.vdocuments.mx/reader035/viewer/2022070217/6122d46cec541c6271740448/html5/thumbnails/14.jpg)
WHO’s End TB Strategy - universal drug susceptibility testing
• Countries should focus on continuous surveillance among:
- previously treated cases
- high risk groups (contacts of RR-TB patients)
- certain patient groups (PLWHA, children)
• Subsequent expansion of testing to new cases
• Ultimately, broadening scope from rifampicin to other drugs
Molecular tools will facilitate this transition
![Page 15: Drug resistance surveys - WHO...March 19-21, 2014 –Hanoi, Viet Nam Second-line drug resistance • Globally, 6.2% of MDR-TB cases have XDR-TB • Short-course MDR/RR-TB and INH-monoresistance](https://reader035.vdocuments.mx/reader035/viewer/2022070217/6122d46cec541c6271740448/html5/thumbnails/15.jpg)
Xpert MTB/RIF in surveys
• Logistically easier
- surveys can be repeated more frequently
• Strengthens sample transport and testing network
- facilitates transition to continuous surveillance
• But information beyond rifampicin resistance may be limited (depending on diagnostic algorithm)
![Page 16: Drug resistance surveys - WHO...March 19-21, 2014 –Hanoi, Viet Nam Second-line drug resistance • Globally, 6.2% of MDR-TB cases have XDR-TB • Short-course MDR/RR-TB and INH-monoresistance](https://reader035.vdocuments.mx/reader035/viewer/2022070217/6122d46cec541c6271740448/html5/thumbnails/16.jpg)
15Meeting of the Tuberculosis Surveillance and Research Unit (TSRU)March 19-21, 2014 – Hanoi, Viet Nam
Sequencing approaches
• Analysis of genetic make-up of M. tuberculosis
• Whole genome sequencing on culture- up to 200 strains per run (3-4 days per run)
• Targeted gene sequencing on preserved sputum (Deeplex-MycTB assay from GenoScreen)
- bypasses need for culture- less information than whole genome
![Page 17: Drug resistance surveys - WHO...March 19-21, 2014 –Hanoi, Viet Nam Second-line drug resistance • Globally, 6.2% of MDR-TB cases have XDR-TB • Short-course MDR/RR-TB and INH-monoresistance](https://reader035.vdocuments.mx/reader035/viewer/2022070217/6122d46cec541c6271740448/html5/thumbnails/17.jpg)
16Meeting of the Tuberculosis Surveillance and Research Unit (TSRU)March 19-21, 2014 – Hanoi, Viet Nam
Sequencing as a tool for surveillance
• Estimate prevalence of resistance to a range of drugs at population level
• Inform development of molecular diagnostics - now and in the future
• Predict resistance to new drugs
WHO guidance to be released in late 2018
![Page 18: Drug resistance surveys - WHO...March 19-21, 2014 –Hanoi, Viet Nam Second-line drug resistance • Globally, 6.2% of MDR-TB cases have XDR-TB • Short-course MDR/RR-TB and INH-monoresistance](https://reader035.vdocuments.mx/reader035/viewer/2022070217/6122d46cec541c6271740448/html5/thumbnails/18.jpg)
17Meeting of the Tuberculosis Surveillance and Research Unit (TSRU)March 19-21, 2014 – Hanoi, Viet Nam
Sequencing in surveys (2013-2018)
• WHO coordinating a multi-country project funded by BMGF, TB Alliance, USAID
• First global initiative using sequencing at the population levelamong all TB cases (background documents 3d, 3e)
- Prevalence of resistance to a range of drugs - Agreement between sequencing and phenotypic tests
• Over 7,000 isolates sequenced and phenotypically tested from surveys in 8 countries
![Page 19: Drug resistance surveys - WHO...March 19-21, 2014 –Hanoi, Viet Nam Second-line drug resistance • Globally, 6.2% of MDR-TB cases have XDR-TB • Short-course MDR/RR-TB and INH-monoresistance](https://reader035.vdocuments.mx/reader035/viewer/2022070217/6122d46cec541c6271740448/html5/thumbnails/19.jpg)
18Meeting of the Tuberculosis Surveillance and Research Unit (TSRU)March 19-21, 2014 – Hanoi, Viet Nam
Sequencing in surveys (2013-2018)
Completed: Azerbaijan, Bangladesh, Belarus, Djibouti, Pakistan, Philippines, South Africa, Ukraine
Underway: DR Congo, Eritrea, Ethiopia, Indonesia, Swaziland
![Page 20: Drug resistance surveys - WHO...March 19-21, 2014 –Hanoi, Viet Nam Second-line drug resistance • Globally, 6.2% of MDR-TB cases have XDR-TB • Short-course MDR/RR-TB and INH-monoresistance](https://reader035.vdocuments.mx/reader035/viewer/2022070217/6122d46cec541c6271740448/html5/thumbnails/20.jpg)
19Meeting of the Tuberculosis Surveillance and Research Unit (TSRU)March 19-21, 2014 – Hanoi, Viet Nam
Analysis• Classify mutations using established framework
- associated or not associated with resistance
• Account for sensitivity and specificity using Bayesianapproach
Interpretation• Overall, sequencing produces consistent results and has
comparative advantages to phenotypic testing
Estimating prevalence of drug resistance by sequencing
![Page 21: Drug resistance surveys - WHO...March 19-21, 2014 –Hanoi, Viet Nam Second-line drug resistance • Globally, 6.2% of MDR-TB cases have XDR-TB • Short-course MDR/RR-TB and INH-monoresistance](https://reader035.vdocuments.mx/reader035/viewer/2022070217/6122d46cec541c6271740448/html5/thumbnails/21.jpg)
20Meeting of the Tuberculosis Surveillance and Research Unit (TSRU)March 19-21, 2014 – Hanoi, Viet Nam
Prevalence of isoniazid (INH) resistance by different methods
Zignol et al. Lancet Infect Dis. 2018
INH phenotypic testing versus katG/inhA sequencing
![Page 22: Drug resistance surveys - WHO...March 19-21, 2014 –Hanoi, Viet Nam Second-line drug resistance • Globally, 6.2% of MDR-TB cases have XDR-TB • Short-course MDR/RR-TB and INH-monoresistance](https://reader035.vdocuments.mx/reader035/viewer/2022070217/6122d46cec541c6271740448/html5/thumbnails/22.jpg)
21Meeting of the Tuberculosis Surveillance and Research Unit (TSRU)March 19-21, 2014 – Hanoi, Viet Nam
Requirements for scaling-up sequencing
• Reduced costs- sequencing already cheaper than full panel of first- and
second-line phenotypic testing in an SRL ($150 versus $230 per sample)
• Enhanced staff capacity
• Standardized methodology, e.g. DNA extraction and samplepreparation
• Standardized nomenclature to record, report and analyse data (current initiatives – ReSeq platform, CRyPTIC consortium)
• Quality assurance system
![Page 23: Drug resistance surveys - WHO...March 19-21, 2014 –Hanoi, Viet Nam Second-line drug resistance • Globally, 6.2% of MDR-TB cases have XDR-TB • Short-course MDR/RR-TB and INH-monoresistance](https://reader035.vdocuments.mx/reader035/viewer/2022070217/6122d46cec541c6271740448/html5/thumbnails/23.jpg)
22Meeting of the Tuberculosis Surveillance and Research Unit (TSRU)March 19-21, 2014 – Hanoi, Viet Nam
Conclusions
• TB has the largest and oldest antimicrobial resistance surveillance project globally
• Still require more country-specific data for
- a wider range of drugs
- more time points
• Promote molecular technologies as a means to achieving universal coverage of drug susceptibility testing