1. Drug Resistant (DR) TB (Back to Basics)
9th International TB and HIV Management course
Nesri Padayatchi MBChB PhD
Deputy Director CAPRISA
Presented on 5th August 2016 at University of Pretoria

2. OUTLINE
Terminology
Grouping of Drugs
Epidemiology
Management

3. Definitions Type of TB Definition Treatment Drug Sensitive
MTB sensitive to Group 1 drugs
RHZE- 2 M
RH M
RR TB
MTB Resistant to Rifampicin +/ - resistance to other TB medicines
MDR Treatment + INH
INH Mono-resistant
Resistance to INH only
RHZE for 6-9 month
MDR TB
MTB Resistant to Rif & INH, with/without resistance to other 1st line anti-TB drugs
MDR TB Treatment
XDR TB
Extensive Drug Resistant TB
MTB Resistant to Rifampicin, INH, the Fluoroquinolones AND to at least one 2nd line Injectable drugs (CM,KM,AM)
Treatment +/ - INH + New drugs

4. Definitions Type of TB Definition Treatment R H Z E Drug Sensitive
MTB sensitive to standard TB drugs
R H Z E

5. Definitions Type of TB Definition Treatment R H Z E Drug Sensitive
MTB sensitive to standard TB drugs
R H Z E
INH Mono-resistant
Resistance to INH only

6. Definitions Type of TB Definition Treatment R H Z E
Drug Sensitive
MTB sensitive to standard TB drugs
R H Z E
INH Mono-resistant
Resistance to INH only
RR TB
MTB Resistant to Rifampicin +/ - resistance to other TB medicines
R H Z E (treat as MDRTB)
The prevalence of PZA resistance is strongly correlated with resistance to rifampicin and increases with additional resistance in MDR and XDR-TB strains. The presence of rifampicin-resistance could then be considered as an indicator to perform DST to PZA.
Consideration should also be given when defining the role of PZA in future TB treatment regimens.

7. Definitions Type of TB Definition Treatment R H Z E
Drug Sensitive
MTB sensitive to standard TB drugs
R H Z E
INH Mono-resistant
Resistance to INH only
RR TB
MTB Resistant to Rifampicin +/ - resistance to other TB medicines
R H Z E (treat as MDRTB)
MDR-TB
MTB Resistant to Rifampicin & INH, with/without resistance to other first line anti-TB drugs
Quinolone
Injectable, other Core drugs

8. Definitions Type of TB Definition Treatment R H Z E
Drug Sensitive
MTB sensitive to standard TB drugs
R H Z E
INH Mono-resistant
Resistance to INH only
RR TB
MTB Resistant to Rifampicin +/ - resistance to other TB medicines
R H Z E (treat as MDRTB)
MDR-TB
MTB Resistant to Rifampicin & INH, with/without resistance to other first line anti-TB drugs
Quinolone
Injectable, other Core drugs
XDR TB
Extensive Drug Resistant
MTB Resistant to Rifampicin, INH, the Quinolones AND at least one 2nd line Injectable drugs
Individualised regimen

9. Definitions Type of TB Definition Treatment R H Z E
Drug Sensitive
MTB sensitive to standard TB drugs
R H Z E
INH Mono-resistant
Resistance to INH only
RR TB
MTB Resistant to Rifampicin +/ - resistance to other TB medicines
R H Z E (treat as MDRTB)
MDR-TB
MTB Resistant to Rifampicin & INH, with/without resistance to other first line anti-TB drugs
Quinolone
Injectable, other Core drugs
XDR TB
Extensive Drug Resistant
MTB Resistant to Rifampicin, INH, the Quinolones AND at least one 2nd line Injectable drugs
Individualised regimen
Pre-XDR TB
MTB Resistant to Rifampicin, INH, the Quinolones OR at least one 2nd line Injectable drug

11. Source: WHO Global Tuberculosis Report 2014

13. Resistance in previously treated (acquired drug resistance)
is the result of
Inadequate
Incomplete
poor treatment quality that allows the selection of mutant resistant strains

14. Global MDR-TB Epidemiology
In 2013, more than 50% of New cases of MDR-TB were among people never before treated for TB, highlighting the importance of Transmission and the lack of appropriate Infection Control Measures, particularly at Community level
WHO. Drug-Resistant TB. Supplement Global TB Report 2014

15. 23 studies met the inclusion criteria.
Median estimates of delay:
patient: 18.4 days
diagnostic: 31.0 days
treatment: 2.5 days
Median total delay: days
48% of all patients first consulted private providers; an average of 2.7 health care providers were consulted before diagnosis

16. Even for countries with unlimited resources, the time to generate a MDR-TB case is less than the time required to cure it

17. TB Diagnostic Testing Gene Xpert Line Probe Assay (LPA) HAIN Test
Screens for MTB and Rif resistance
Done directly on sputum- more sensitive than smear with higher yield
Point of care test - Result in hours
Line Probe Assay (LPA) HAIN Test
Tests for Rif & INH resistance
Results in days
Line Probe Assay (LPA) SL second line
Tests for Kana/Amik & Moxi

18. Back to basics Early bactericidal activity (EBA)
The ability of a drug to kill tubercle bacilli in the first few days of treatment e.g INH
Sterilizing activity
The ability to remove so-called persisters –these are bacilli that have low metabolic activity and replicate slowly
Prevention of resistance to the companion drug
The ability of a drug to prevent selection of mutants resistant to the companion drug

19. Drugs recommended for RR, M(X)DRTB
Group
Name
Drugs A
Fluoroquinolones
(Core drugs)
Levofloxacin/ Moxifloxacin B
Second-line Injectable Drugs
Amikacin/ Capreomycin/ Kanamycin C
Other core 2nd-line agents
Ethionamide / Terizidone/ Cycloserine
Linezolid / Clofazamine D
Add-on-agents
(Not part of the core MDRTB Regimen) D1
Pyrazinamide (Z) / Ethambutol (E)
High Dose Isoniazid (H) D2
Bedaquiline / Delamanid D3
Para-Aminosalicylic Acid (PAS)
Imipenem- cilastatin
Meropenem / Augmentin
Carbapenems and amoxicillin –clavulanate must be used together
WHO treatment guidelines for MDR-TB 2016 update

20. Definitions Type of TB Definition Treatment R H Z E 2 mo RH 4 mo
Drug Sensitive
MTB sensitive to standard TB drugs
R H Z E 2 mo
RH mo
INH Mono-resistant
Resistance to INH only
R H Z E 6-9 mo

21. Treatment of INH mono resistance
Continue RHZE for 6-9 months based on symptom response
Minimum of 6 months after culture conversion
Could omit INH (H) but easier to use FDC’s
If poor response, consult MDR TB specialist unit

22. Definitions Type of TB Definition Treatment R H Z E
Drug Sensitive
MTB sensitive to standard TB drugs
R H Z E
INH Mono-resistant
Resistance to INH only
Rif Mono-resistance
RR TB
MTB Resistant to Rifampicin +/ - resistance to other TB medicines
R H Z E (treat as MDRTB)
The prevalence of PZA resistance is strongly correlated with resistance to rifampicin and increases with additional resistance in MDR and XDR-TB strains. The presence of rifampicin-resistance could then be considered as an indicator to perform DST to PZA.
Consideration should also be given when defining the role of PZA in future TB treatment regimens.

23. MDR-TB and RR-TB detected, compared with cases enrolled on MDR-TB treatment, 2009-2012
Falzon et al

24. Definitions Type of TB Definition Treatment R H Z E
Drug Sensitive
MTB sensitive to standard TB drugs
R H Z E
INH Mono-resistant
Resistance to INH only
RR TB
MTB Resistant to Rifampicin +/ - resistance to other TB medicines
R H Z E (treat as MDRTB)
MDR-TB
MTB Resistant to Rifampicin & INH, with/without resistance to other first line anti-TB drugs
Quinolone
Injectable, other Core drugs

25. Case study
A 41 year old female was referred to the clinic in November 2015 with a positive Xpert MTB/RIF result
She complained of cough, loss of weight and night sweats.
On examination, she was ambulant, wasted, but not distressed; with bilateral basal crackles.
CXR showed bilateral disease
She was cured of Drug Sensitive TB in 2001
In Feb 2012 she was diagnosed with HIV and started on Atroiza. Her baseline CD4 was 85c/ml

27. Symptoms of DR- TB Same symptoms as Drug Sensitive TB
Diagnosis of DR TB is microbiological
Persistent cough
Chest pain
Dyspnoea
Haemoptysis
LOA / LOW
Night sweats and chills
Fever
Tiredness/malaise

28. 37 studies were included. Inappropriate treatment regimens were prescribed in 67% of studies.
The percentage of patients receiving inappropriate regimens varied between 0.4% and 100%.
In 19 studies the quality of treatment regimen reporting was low

29. Principles of treatment of MDR-TB
Minimum of 4 effective drugs
2 core drugs (Fluoroquinolones and Injectables)
2 supporting drugs
Use Injectable agents for a minimum of 6 months (ideally 4 months after culture conversion)
Don’t rely on drugs to which:
Resistance is suspected or
To which the patient has been previously exposed
Include 1st line drugs the infecting strain is susceptible to (but do not count them if patient has been previously exposed)

30. Standard MDR treatment
Intensive phase (KMETZI)
Kanamycin or Amikacin (6 months)
Moxifloxacin
Ethionamide
Terizidone
PZA
May add INH if no katG mutation
Continuation Phase (min 18 months)
Moxifloxacin / Ethionamide / Terizidone / PZA (+/- INH)

31. Interpreting LPA Results
Mutation
Confers resistance to
Able to use
InhA
INH- Low level Ethionamide
High Dose INH
KatG
High dose INH
Ethionamide
InhA and KatG
PAS

32. In the Western Cape and Eastern Cape Provinces, the percentage of isolates exhibiting inhA promoter mutations increased significantly from respectively 48.4% and 62.4% in MDR-TB isolates to 85.5% and 91.9% in XDR isolates.
Data from the Western Cape revealed that significantly more XDR-TB isolates showed mutations in the inhA promoter than in katG (85.5% vs. 60.9%, P < 0.01), while the respective proportions were equal for INH-resistant non-MDR-TB isolates (~30%).
inhA promoter mutations are strongly associated with XDR-TB in South Africa

33. 10 Commandments of managing MDR TB
If a person infected with a strain, initially resistant to a specific medicine is treated with that medicine plus a new additional medicine, then there is a risk of developing resistance to the additional medicine
Step-wise additions of drugs may eventually lead to more severe patterns of drug resistance and

34. 10 Commandments of managing MDR TB

35. 10 Commandments of managing MDR TB
DO NOT ADD A SINGLE DRUG TO A FAILING REGIMEN

36. 10 Commandments of managing MDR TB
DO NOT ADD A SINGLE DRUG TO A FAILING REGIMEN
Commandment 2-10:

37. 10 Commandments of managing MDR TB
DO NOT ADD A SINGLE DRUG TO A FAILING REGIMEN
Commandment 2-10:

38. 10 Commandments of managing MDR TB
DO NOT ADD A SINGLE DRUG TO A FAILING REGIMEN
Commandment 2-10:
Step-wise additions of drugs may eventually lead to more severe patterns of drug resistance

39. One final remark, even considering the clear evidence that the prognosis of TB patients worsens when the pattern of resistance increases, it should never be accepted that a TB case is incurable.
All TB patients, even those with XDR-TB or beyond XDR-TB, should always have a chance to be treated using the available clinical and programmatic management strategies.

40. The first priority to fight against MDR/XDR-TB is to strengthen the NTP with good management of susceptible TB cases

41. Assuming adherence to national DR-TB management guidelines, the per patient cost of XDR-TB was $26,392, four times greater than MDR-TB ($6772), and 103 times greater than drug-sensitive TB ($257).
Despite DR-TB comprising only 2.2% of the case burden, it consumed, 32% of the total estimated 2011 national TB budget of US $218 million.
45% and 25% of the DR-TB costs were attributed to anti-TB drugs and hospitalization, respectively.
A decentralized XDR-TB treatment programme could potentially reduce costs by $6930 (26%) per case and reduce the total amount spent on DR-TB by ,7%.

42. Conclusion MDR/XDR-TB is a global threat
With adequate clinical and operational management, all TB cases have a chance to be cured, even those with very extensive pattern of resistance
The first priority to fight against MDR/XDR-TB is to strengthen the NTP with good management of susceptible TB cases
However, it is necessary to increase the rate of detection and cure of all DR-TB

43. Acknowledgments DR-TB Guidelines Doctors and staff of KDHC
Dr Jose Caminero