Recent guidelines for tuberculosis in India

1. Recent guidelines in treatment of tuberculosis with regimen
involving all category
Dr Shoebul Haque
PG Resident
Department of Pharmacology & Therapeutics
King George’s Medical University, Lucknow
Email:-shoeb_ulhaque@yahoo.com

2. Objectives
• Global Tuberculosis WHO Report
• Milestones in evolution of PMDT in India
• CASCADE OF CARE Approach
• Diagnostic algorithm for pulmonary TB
• Tuberculosis Preventive Therapy (TPT)
• Guidelines for PMDT in India
• Regimen and Duration of short course Bedaquiline/Longer oral Regimen
• Management of MDR-TB patients during pregnancy
• Bedaquiline, Pretomanid, Linezolid (BPaL) regimen
• INDIA-Committed to End TB by 2025

3. Global Tuberculosis WHO Report
• One fourth of the population is infected with Tuberculosis (67 million
children)
• Globally, 10 (8.9 to 11) million people fell ill with TB in 2019
• Of these, 7.1 million people were officially notified
• 0.5 million people developed MDR/RRTB in 2019

4. Milestones in evolution of PMDT in India

5. CASCADE OF CARE APPROACH
• All target population are
systematically reached
out
• Screened for TB disease
and after ruling out
• Provided TPT as a part of
care

6. Pillars of Indian TB Elimination Program
• Prevent new
infections
• Prevent active
breakdown of
infection to
disease
• Prevent
emergence of
resistance to
drugs
• Prevent death
• Diagnose all TB
cases including
DRTB
• Notification of all
cases
• Quality assured
treatment
• Case finding
systems
• Laboratory
networks
Prevent Treat
Detect Build

7. Summary of Diagnostic Protocols
• Smear microscopy and CXR
• CBNAAT-CXR suggestive TB
• CBNAAT upfront- Children, PLHIV and
Extra pulmonary
• Cytology, Histopathology, Radio-
imaging are used
• All TB patients to be tested for drug
susceptibility
• All Rif Resistance TB patients tested for
second line drug susceptibility
• All R Sensitive TB patients tested for
first line drugs susceptibility
• All INH Resistance TB patients tested
for second line drug susceptibility
Diagnosis of TB Diagnosis of DRTB

8. Diagnostic algorithm for pulmonary TB
Presumptive TB patient
Smear Examination CXR
Smear +ve; CXR
suggestive of TB
Smear +ve; but
CXR not
suggestive of TB
Smear -ve; but
CXR suggestive of
TB
Smear -ve/ not
available; CXR not
suggestive of TB
Clinical Suspicion
High
CBNAAT
MTB detected MTB not detected or
CBNAAT not available
Consider
alternate
diagnosis and
refer to
specialist
Clinically
Diagnosed TB
Alternate
Diagnosis
Rif sensitive
Rif
intermediate
Rif
Resistance
Refer to
management
of Rif
resistance
Repeat CBNAAT on 2nd
sample
Intermediate on 2nd sample, collect fresh
sample or liquid Culture/LPA
PLHIV
Microbiologically
confirmed TB
PMDT criteria, high
MDR settings

9. Treatment of drug sensitive TB
Type of TB Case Treatment regimen in IP Treatment regimen in CP
New or Previously Treated (2) HRZE (4) HRE

10. Treatment of drug sensitive TB
• The drugs are given daily, dose of drugs are according to body weight
• FDC tablets are used, Loose drugs would be needed as substitutions in case
of adverse drug reaction
• No need of extension of IP
• CP may be extended by 12-24 weeks in certain forms like CNS TB, Skeletal
TB, Disseminated TB etc
• Extension beyond 12 weeks should only be on recommendation of experts

11. Treatment of TB-Adult
Weight Category Number of Tablets
Intensive Phase Continuation Phase
HRZE HRE
75/150/400/275 75/150/275
25-34 kg 2 2
35-49 kg 3 3
50-64 kg 4 4
65-75 kg 5 5
≥ 75 kg 6 6
• If weight increases or decreases by 5 kg or more, weight band must be changed
at the time of next dispensation of drugs

12. Treatment of TB- Paediatric (0-18 years)
Weight
Category
Number of Tablets
Intensive Phase Continuation Phase
HRZ E HR E
50/75/150 100 50/75 100
4-7 kg 1 1 1 1
8-11 kg 2 2 2 2
12-15 kg 3 3 3 3
16-24 kg 4 4 4 4
25-29 kg 3 + 1A 3 3 + 1A 3
30-39 kg 2 + 2A 2 2 + 2A 2

13. Policy Updated on TPT on 4th April 2021
• Expansion of TB Preventive Treatment (TPT) with test and treat policy
• Includes all adolescent and adults close contacts (above 5 years) of
Pulmonary TB patients
• Public and private sector both
• Isoniazid Preventive Therapy (IPT) is given to prevent breakdown of
TB infection to TB disease

14. TB Preventive Treatment (TPT)
a. Expanded eligible group
Target population Treatment option
• People living with HIV (adults and children
>12 months)
• Infants <12 months in contact with active TB
• 6-months daily isoniazid (6H)
• 3-month weekly Isoniazid and Rifapentine in
persons older than 2 years
b. Other risk groups expansion
• Children/adult on immunosuppressive
therapy, silicosis, anti-TNF treatment,
dialysis, transplantation
• 3-month weekly Isoniazid and Rifapentine
• 6-months daily isoniazid (6H)

15. Contraindications for TPT
• Active TB disease
• Acute or chronic hepatitis
• Concurrent use of other hepatotoxic medications
• Regular and heavy alcohol consumption
• peripheral neuropathy -persistent tingling, numbness
• Allergy or known hypersensitivity to any drugs being considered for TPT
Note
• Pregnancy or a previous history of TB are not contraindications for TPT

16. NIKSHAY Poshan Yojana
• Applicable on all cases notified after 1st April 2018
• Incentives for Patients:
• Rs. 500 / month per patient till completion of the treatment
• intensives will be extended as long as the patient is on ATT

17. NIKSHAY Poshan Yojana
• Incentives to providers/Intensive for treatment support:
1. New Case: Rs. 1000/- at completion of treatment
2. Previously treated cases: Rs. 1500/- at completion of treatment
3. Drug resistance case:
Rs. 2000/- at completion of intensive phase
Rs. 3000/- at completion of treatment

19. Causes of Drug Resistance TB
Microbial Clinical Programmatic
Genetic mutation
• Caused by random
chromosomal
mutations at
predictable
frequencies
Inadequate drug intake
• Lack of information
• Adverse drug reaction

20. Causes of Drug Resistance TB
Programmatic
Inadequate supply of
Drugs
• Non-availability of certain
drugs (stock-outs)
• Poor quality
• Poor storage conditions
• Wrong dosage or
combination
Inadequate regimen
• Unsupervised treatment
• Absence of guidelines
• Inadequate training of
health staff

21. Pre-treatment Counselling
Contact
investigation
of family and
TPT
Information
on lab test
Pre-
treatment
counseling
Importance
of early
initiation of
treatment
Reassurance
to the family
Family
Planning
Infection
control
precautions
Care and
support
under
NTEP
Possible
changes in
the
treatment
Nature and
duration of
treatment

22. Drug-TB counselling Tool

23. Newer Treatment Regimen
• shorter oral Bedaquiline-containing MDR/RR-TB regimen
• longer oral M/XDR-TB regimen
• Guidance is also provided for using Bdq for children above 5 years and Dlm for
above 6 years
• Use of BPaL regimen consisting of Bdq, pretomanid (Pa) & linezolid (Lzd) are
ongoing in select group of patients

24. Turnaround Time (TAT)
• Laboratory TAT refers to the time taken from receipt of a specimen at the
laboratory to issuing a laboratory test result
Pre-lab TAT Lab TAT Post-lab TAT
• Patient Identification
• Referral for testing
• Specimen collection
• Packaging an
transport
• Specimen receipt at
the laboratory
• Testing
• Reporting results
• Receipt of laboratory
results
• Pretreatment
evaluation
• Treatment
initiation/modification

25. Integrated drug-resistant TB algorithm
• Genotypic testing is much faster than phenotypic methods
• As these are not growth based tests, these include:
1. Nucleic Acid Amplification Tests (NAAT) which includes CBNAAT and Truenat
These tests detect R resistance; and
2. Line Probe Assay (LPA) which detects resistance to R, H, FQ and SLI drugs

26. Integrated Drug-resistant TB algorithm
• Rapid molecular tests such as NAAT are the preferred method for initial
detection of RR
• The following drugs are tested using this method:
• Group A - Levofloxacin, Moxifloxacin, Bedaquiline, Linezolid
• Group B- Clofazimine
• Group C- Delamanid, Pyrazinamide, Amikacin, Streptomycin

27. Grouping of drugs
• The anti-TB drugs recommended for treatment of MDR/RR-TB patients are
grouped based on
1. Efficacy
2. Experience of use
3. Drug class and aligned with revised classification as per WHO Consolidated
Guidelines

29. GROUPS & STEPS MEDICINE ABBREVIATION
Group A
Include all three medicines
Levofloxacin or
Moxifloxacin
Lfx
Mfx
Bedaquiline Bdq
Linezolid Lzd
Group B
Add one or both medicines
Clofazimine Cfz
Cycloserine or
Terizidone
Cs
Trd
Group C
Add to complete the regimen and
when medicines from Group A and B
cannot be used
Ethambutol E
Delamanid Dlm
Pyrazinamide Mpm
Imipenem-cilastatin or
Meropenem
Ipm-Cln
Mpm
Amikacin
(OR Streptomycin)
Am
(S)
Ethionamide or
Prothionamide
Eto
Pto
p-aminosalicylic acid PAS

30. Drugs that are not included in Groups A–C
• Kanamycin and capreomycin, which were associated with poorer outcomes
• Gatifloxacin were used in very few patients and thioacetazone was not used at
all
• Clavulanic acid should be included in MDR/RR-TB regimens only as a
companion agent to the carbapenems (Imp-Cln and Mpm)

31. Pre-treatment evaluation (PTE)
Clinical evaluation Laboratory based evaluation
History and physical examination Random blood sugar (RBS)
Height HIV testing following counselling
Weight Complete blood count (Hb, TLC, DLC, platelet count)
Psychiatric evaluation if required Liver function tests (including serum proteins)
TSH levels
Urine examination – routine and microscopic
Serum electrolytes (Na, K, Mg, Ca)
Urine pregnancy test (in women of reproductive age
group)
Chest X-ray
ECG

32. Regimen and Duration of short course Bedaquiline
• A shorter oral Bedaquiline-containing MDR/RR-TB regimen of 9–11 months
duration is recommended
• The regimen consists of an initial phase of 4 months that may be extended up
to 6 months
• Continuation phase of 5 months, giving a total duration of 9–11 months
• Bdq is used for a duration of 6 months

33. Regimen and Duration of short course Bedaquiline
• Points to remember:
(4-6) Bdq (6 m), Lfx, Cfz, Z, E, Hh , Eto (5) Lfx, Cfz, Z, E,
• If the IP is extended up to 6 months then all 3 drugs Bdq, Hh and Eto are stopped
together
From start to end of 4th month Bdq, Lfx, Cfz, Z, E, Hh , Eto
From start of 5th month to end of 6th
month– (If IP not extended)
Bdq, Lfx, Cfz, Z, E
From start of 7th month to end of 9th
month
Lfx, Cfz, Z, E

34. Longer oral M/XDR-TB regimen
• Dose of Lzd will be tapered to 300 mg after the initial 6–8 months of treatment
• Bdq will be given for 6 months & extended beyond 6 months as an exception
• For XDR-TB patients the duration of longer oral XDR-TB regimen would be for 20
months with appropriate modifications
(18-20) Lfx Bdq (6 month or longer) Lzd# Cfz Cs

35. Caution to be exercised while choosing group A and B drugs
• Bdq & Cfz may lead to cardiotoxicity particularly QT prolongation
• Lzd may cause anaemia, thrombocytopenia, peripheral neuritis and optic neuritis
• Cs should be used carefully in pre-existing seizure disorders
• Cfz also causes dark brown discoloration of the skin

36. Additional considerations for the use of Bdq
Inclusion criteria:
• Bdq can be provided to adults and children aged (5 years to less than 18 years)
of age in consultation with pediatrician
• Patients with controlled stable arrhythmia can be considered after obtaining
cardiac consultation
• Pregnancy

37. Additional considerations for the use of Bdq
Exclusion criteria:
• Currently having uncontrolled cardiac arrhythmia that requires medication
• Having any of the following QT interval characteristics at screening
1. QTcF > 500 then the patient should not be challenged with cardiotoxic drugs
2. History of additional risk factors for Torsade de Pointes

38. PLHIV (People living with HIV)
• The shorter or longer oral MDR-TB regimen can be used in PLHIV
• In PLHIV with pulmonary MDR/RR-TB, drug-drug interactions between anti-TB
and ART medicines potentially overlap
E.g.
• Mfx and Cfz or
• Efavirenz and Bdq may potentially increase the risk of Bdq related adverse
events

39. Management of MDR-TB patients during pregnancy
Duration of pregnancy
< 20 weeks > 20 weeks
Advise MTP Pt unwilling for MTP
MTP done >32 weeks < 32 weeks
Start/continue shorter oral
Bedaquiline-containing MDR/RR-TB
regimen #
Start/continue longer oral
Bedaquiline-containing MDR/RR-TB
regimen @
Consultative decision b/w obstetrician and physician

40. Management of MDR-TB patients during pregnancy
• # Regimen: 4-6 Bdq (6m) Lfx, Cfz, Z, E, Eto, Hh / 5 Lfx, Cfz, Z, E. No modifications
allowed
• @ Regimen:18-20 Lfx, Bdq(6m or longer) Lzd#, Cfz, Cs
• Lzd dose to be tapered to half after 6-8 months based on bacteriological
response
• Modify regimen if one or more drug cannot be used due to any reasons

41. Pregnancy and Lactation
• Pregnancy is not a contraindication but poses great risk to both the mother
and foetus
• Second-line injectables are contraindicated throughout the pregnancy due to
its effect on the 8th cranial nerve (auditory) of the foetus
• Eto is contraindicated during the first 32 weeks of pregnancy due to teratogenic
effects
• Bdq and Dlm both are not recommended during lactating period

42. Treatment algorithm H mono/poly DR-TB regimen
Rifampicin resistance not detected 4
FL-LPA5 DS-TB regimen Non-responders
H resistance detected 4
Stop DS-TB
regimen
NAAT 3
Reflex testing for SL-LPA 6 + LC
DST 7 – Mfx, Z, Lzd, Cfz 8
H mono/poly DR-TB regimen
Additional resistance or intolerance or non-
availability of any drug in use or emergence of
exclusion criteria
Modify H mono/poly DR-TB
regimen as per replacement table
Non-responders
NO
YES

43. H mono/poly DR-TB regimen
Pre-treatment evaluation • History and physical examination
• Height/weight
• Random blood sugar (RBS)
• Chest X-ray
• HIV test
Inclusion Criteria H mono/poly DR-TB with confirmed result for
rifampicin resistance not detected
Exclusion Criteria No specific exclusion criteria
Regimen (6 or 9) Lfx R Z E
Duration 6 OR 9 months
No separate IP/CP

44. Treatment extension
• Treatment can be extended directly to 9 months in certain conditions:
1. In patients with extensive disease
2. Uncontrolled comorbidity
3. Extra- pulmonary TB
4. If smear at the end of month 4 is found positive, the treatment may be directly
extended to 9 months
(There would be no monthly extensions in this regimen)

45. Bedaquiline, Pretomanid, Linezolid (BPaL) regimen
New WHO recommendations:
• A treatment regimen lasting 6-9 months, composed of Bedaquiline,
pretomanid and linezolid (BPaL) may be used
BPaL regimen for MDR-TB with additional FQ resistance

46. Delamanid introduction in India
• Seven states have been identified as initial sites for the introduction of DLM
under the PMDT through conditional access
1. Punjab
2. Chandigarh
3. Rajasthan
4. Karnataka
5. Odisha
6. Kerala
7. Lakshadweep

47. Inclusion/Exclusion Criteria for patients to receive Delamanid
Inclusion criteria:
• Adults (≥18 yrs), including people living with HIV (PLHIV)
• People not eligible for a shorter MDR-TB regimen for reasons of resistance,
contraindication
• MDR/RR-TB with resistance to any/all FQ OR any/all SLI
• Mixed Pattern DR-TB

48. Inclusion/Exclusion Criteria for patients to receive Delamanid
Exclusion Criteria:
1. Children under 6 years
2. Pregnant & breastfeeding women
3. Patients with repeated demonstration of a QT interval >500 ms, history of
torsade's pointes
4. Hypersensitivity to the active substance or to any of the excipients

49. Delamanid Dosage
• All patients will receive Tab. Delamanid 100 mg (two tablets of 50 mg) orally
twice a day for 24 weeks (6 months)
• In combination with an optimized background regimen (OBR)
• The OBR will be continued beyond the 24 weeks of Dlm administration for the
RNTCP recommended duration of treatment

50. Delamanid Dosage
• Week 0–24: Delamanid 100 mg (two tablets of 50 mg) orally twice a day + OBR
• Week 25 (start of month 7) to end of treatment: Continue other second-line anti-
TB drugs only as per RNTCP recommendations

51. Delamanid Regimen
Resistance Pattern DST Guided Regimen class Intensive Phase Continuation Phase
Regimen with New drugs for MDR-TB + FQ / SLI resistance
MDR/RR + resistance to FQ
class OR SLI class
MDR/RR + res to FQ class (6-9) Km Eto Cs Z Lzd Cfz +
(6) Dlm
(18) Eto Cs Lzd Cfz
MDR/RR+ res to SLI class (6-9) Lfx Cm Eto Cs Z Lzd
Cfz + (6) Dlm
(18) Lfx Eto Cs Lzd
Regimen with New drugs for XDR-TB
XDR-TB (res to both FQ
and SLI class)
XDR-TB (6-12) Cm Eto Cs Z Lzd3 Cfz
E + (6) Dlm
(18) Eto Cs Lzd Cfz E
Regimen with New drugs for Mixed Pattern DR-TB
Mixed pattern DR-TB MDR/RR-TB + res to FQ /
SLI + Lzd or more
Modify the Regimen with New drugs for XDR-TB as per
the footnotes

52. INDIA-Committed to End TB by 2025
• Hon’ble PM declared the nation’s commitment to End TB strategy 5 years
ahead of SDG (Sustainable Development Goals) timelines
• This bold commitment is of global importance since India accounts for 26% of
the global TB burden

53. References
• National Guidelines for Programmatic Management of Tuberculosis Preventive
Treatment in India-2021
• Guidelines for Programmatic management of Drug Resistance Tuberculosis in
India-2021
• Guidelines for use of Delamanid for treatment of DR-TB in India-2021

54. THANK-YOU