What is new in tuberculosis

1. Tuberculosis is a disease of great antiquity
What is new in TB diagnosis, Treatment & Prevention

7. THE PRINCIPLES OF THE STRATEGY
• Government stewardship and accountability with monitoring and
evaluation
• Strong coalition with civil society organizations and communities
• Protection and promotion of human rights, ethics and equity
• Adaptation of the strategy and targets at country level, with global
collaboration
• Pillar 1. INTEGRATED, PATIENT-CENTRED CARE AND PREVENTION
• Pillar 2. BOLD POLICIES AND SUPPORTIVE SYSTEMS
• Pillar 3. INTENSIFIED RESEARCH AND INNOVATION

11. Key global indicators, milestones and targets
for the post-2015 tuberculosis strategy

15. What is new in TB ?
Change in classification of anti TB drugs
• Evidence has been accumulating that second line drug regimen
containing injectable aminoglycosides: kanamycin &/or Capreomycin
• Higher treatment failure
• Higher relapse rate
• Higher mortality & toxicity
• Success of BpaL & its registration with USA FDA indicated that it was
possible to have all oral treatment for DR TB

16. Group A Group B Group C
Include all three if possible Include one or both Make up depending upon resistance
Levofloxacin Lfx or Clofazimine Cfz Ethambutol E
Moxifloxacin Mfx Cycloserine Cs or Delamanid Dlm
Bedaquiline Bdq Terizidone Trd Pyrazinamide Z
Linezolid Lzd Imipenem-cilastatin Ipm- Cln or
Meropenem Mpm
Amikacin Am or
Streptomycin S
Ethionamide Eto or
Prothionamide Pto
Para amino salicyclic acid PAS
What is new in TB ?
Change in classification of anti TB drugs
Second Line

17. Possible Resistant patterns & treatment options

18. Grouping of
medicines
Medicine CB E2E LPA tNGS WGS pDST pBMD
First Line Drugs RIF x z x z z x z
INH z z x z z x z
EMB z z x z
PZA z z z x z
Group A Lfx / Mfx z x z z x z
BDQ x z z x z
LZD z z x z
Group B Cfz z z x z
CS
Group C Dlm z z x z
IMP Cln/MPM
Amk/ S z x z z x z
Eto / Pto z z x z
What is new in TB ?
Spectrum of diagnostics endorsed by WHO
X = endorsed; Z = in process

19. What is new in TB ?
Definition of pre XDR & Updated definition of XDR-TB
• Pre-XDR-TB: TB caused by Mycobacterium tuberculosis (M. tuberculosis)
strains that fulfil the definition of MDR/RR-TB and that are also resistant to
any fluoroquinolone
• XDR-TB: TB caused by Mycobacterium tuberculosis (M. tuberculosis)
strains that fulfil the definition of MDR/RR-TB and that are also resistant to
any fluoroquinolone and at least one additional Group A drug

20. • Key findings: High diagnostic accuracy and improved patient outcomes confirmed
for Xpert MTB/RIF as initial test to diagnose pulmonary TB (i.e. replacing smear
microscopy) and to simultaneously detect rifampicin resistance
• Intervention: Xpert MTB/RIF as replacement for sputum smear microscopy
(bacteriological culture as reference standard)
• Results also showed improved patient-important outcomes (cure rates, reduced
mortality and reduced pre-treatment loss) when Xpert MTB/RIF replaced
microscopy as the initial diagnostic test.
• Sensitivity 85% (smear + or --); specificity 98%
• Sensitivity for HIV infected persons 81%, specificity 98 %
• RR Detection: High overall sensitivity (96%) and specificity (98%) when compared
to phenotypic drug susceptibility testing.

21. High diagnostic accuracy of Xpert Ultra as initial test to
diagnose pulmonary TB (i.e. replacing smear microscopy)
and to simultaneously detect rifampicin resistance
• Intervention: Xpert Ultra as replacement for sputum smear microscopy
(bacteriological culture as reference standard)
• Results: High diagnostic accuracy of Xpert Ultra in adults with pulmonary TB:
Overall sensitivity (including ‘trace’ calls as positive) was 90% in all specimens
(smear-positive and smear-negative).. Excluding ‘trace’ calls resulted in a slight
increase in specificity to 98%. Sensitivity in sputum specimens from HIV co-
infected participants was 88% while specificity was retained at 95%.
• Intervention: Xpert Ultra for simultaneous detection of rifampicin resistance
(phenotypic drug susceptibility testing as reference standard)
• Results: High overall sensitivity (94%) and specificity (99%) when compared to
phenotypic drug susceptibility testing.

22. Use of Xpert MTB/RIF and Xpert Ultra to diagnose TB and
detect rifampicin resistance in children from sputum, stool,
nasopharyngeal and gastric specimens
• Intervention: Xpert MTB/RIF or Xpert Ultra as initial diagnostic test
for TB in children (bacteriological culture as reference standard)
• Results: Sensitivity varied by specimen type (46% for nasopharyngeal
specimens; 61% for stool; 65% for sputum; and 73% for gastric
specimens). Specificity for all specimens varied from 98% to 100%.
• Intervention: Xpert MTB/RIF to detect rifampicin resistance in
children (phenotypic drug susceptibility as reference standard)
• Results: High overall sensitivity (90%) and specificity (98%) when
compared to phenotypic drug susceptibility testing.

23. Use of Xpert MTB/RIF and Xpert Ultra to diagnose TB and detect
rifampicin resistance in adults with extra-pulmonary TB
• Intervention: Xpert MTB/RIF as initial diagnostic test in adults with extra-
pulmonary TB (bacteriological culture as reference standard)
• Results: Sensitivity of Xpert MTB/RIF varied by specimen type (from 50% for
pleural fluid up to 97% for synovial fluid). The specificity of Xpert MTB/RIF also
varied by specimen type (from 79% for lymph node biopsy up to 99% for pleural
fluid).
• Intervention: Xpert Ultra as initial diagnostic test in adults with extra-pulmonary
TB (bacteriological culture as reference standard)
• Results: Sensitivity of Xpert Ultra varied by specimen type (from 71% for pleural
fluid up to 100% for lymph node biopsy). The specificity of Xpert Ultra also
varied by specimen type (from 71% for pleural fluid up to 100% for urine).
• Detection of Rif Resistance: Data showed overall high performance of both
assay for detection of rifampicin resistance: sensitivity 96-97% and specificity
99%.

24. High diagnostic accuracy of Truenat as initial test to
diagnose TB (i.e. replacing sputum smear microscopy) and to
sequentially detect rifampicin resistance
• Intervention: Truenat MTB and MTB Plus as replacement for sputum smear
microscopy (bacteriological culture as reference standard)
• Results: Overall sensitivity of the Truenat MTB assay was 83% and that of the
MTBPlus assay 89%. Specificity was 99% for the MTB and 98% for the MTBPlus
assay.
• Intervention: Truenat MTB-Rif Dx for sequential detection of rifampicin
resistance (phenotypic drug susceptibility testing as reference standard)
• Results: Sensitivity of the Truenat MTB-Rif Dx assay was 93% and specificity
was 95%.

25. True Nat

27. • Key Changes Recommended: Shorter, all-oral, bedaquiline-containing
regimen for eligible MDR/RR-TB patients
• Replacing the injectable with bedaquiline resulted in significantly better
treatment success and a considerable reduction in loss-to-follow up in
MDR/RR-TB patients without previous exposure to second-line drugs and
with confirmed fluoroquinolone susceptible disease. The outcomes were
similar irrespective of HIV status.
• The evidence assessment showed that in eligible MDR/RR-TB patients a
shorter, all-oral, bedaquiline-containing regimen may be used instead of the
standardized shorter regimen with an injectable

28. Novel treatment regimen - BPaL
• The BPaL regimen showed high treatment success when used in XDR-TB
patients in South Africa.
• Limitations in study design and the small number of participants (108),
• observed adverse events (including blood disorders, liver toxicity, peripheral
and optic neuropathy) preclude programmatic implementation of the regimen
worldwide until additional evidence has been generated.
• However, BPaL regimen may be used under operational research conditions
conforming to WHO standards
• (patient-centered care and support,
• proper patient inclusion,
• principles of good clinical practice,
• active drug safety monitoring and management, treatment monitoring,
• outcome evaluation and comprehensive,
• standardized data collection).

29. • In individual patients for whom design of an effective regimen based on
existing recommendations is not possible,
• the BPaL regimen may offer benefits despite potential harms and may be
considered under prevailing ethical standards.
BPaL : Bedaquiline 400 mg QID 2 wks &
200 mg TDS 24 wks
Pretomanid 200 mg QID 26 wks
Linezolid 1200 mg OD 26 wks
• In such patients the use of BPaL should be accompanied by
• individual consent,
• adequate counselling on potential benefits and harms and
• active monitoring and management of adverse events.
• Patients should also be advised that reproductive toxicities have been observed in animal
studies and that the potential effects on human male fertility have not been adequately
evaluated at this point in time.

30. Summary of key changes to Treatment
• MDR/RR-TB patients with extensive TB disease, severe forms of extra-pulmonary TB,
those with resistance to fluoroquinolones or
• who have been exposed to treatment with second-line drugs
• will benefit from an individualized longer regimen designed using the WHO priority
grouping of medicines
• For MDR/RR-TB patients without previous exposure to second-line treatment
(including bedaquiline), without fluoroquinolone resistance and no extensive TB
disease or severe extra-pulmonary TB,
• the preferred treatment option is a shorter, all-oral, bedaquiline-containing regimen.
In this group of patients, national TB programmes are advised to phase out use of the
injectable-containing shorter regimen.
• Access to rapid drug susceptibility testing, especially for ruling out fluoroquinolone
resistance, is required before starting the shorter, all-oral, bedaquiline-containing
MDR-TB regimen

31. • BPaL regimen may be used under operational research conditions in
patients with XDR-TB who have not had previous exposure to bedaquiline
and linezolid (defined as less than two weeks).
• This regimen may not be considered for programmatic use worldwide until
additional evidence on efficacy and safety has been generated.
• However, in individual patients for whom design of an effective regimen
based on existing recommendations is not possible, BPal regimen may be
considered as a last resort under prevailing ethical standards.
• Decisions made according to patient preference and clinical judgement, also
considering the results of susceptibility testing, patient treatment history
and severity and site of the disease.
• All treatment should be delivered under WHO-recommended standards,
• including patient-centered care and support,
• informed consent where necessary,
• principles of good clinical practice,
• active drug safety monitoring and management, and
• regular patient monitoring to assess regimen effectiveness

32. Rapid Communication
on forthcoming changes to the programmatic
management of tuberculosis preventive treatment
• Requires programmatic coordination at several key steps
• identifying individuals at highest risk,
• testing them for infection,
• excluding active TB disease,
• choosing the treatment option that is best suited to an individual,
• managing adverse drug reactions,
• supporting medication adherence and monitoring programmatic performance.
• one month of daily rifapentine plus isoniazid (“1HP”) and
• another regimen of four months of daily rifampicin (“4R”) are now proposed as TPT
options for both high- and low- TB incidence settings.
• aligning the durations of certain regimens to the ones most often used; and merging
the four previous algorithms into one
• Will be released in WHO Consolidated TB guidelines