shorter oral bedaquiline regimen released by NTEP 2022 guidelines for the management of DRTB (R and /or H resistant).

1. SHORTER ORAL BEDAQUILINE
REGIMEN
Dr. Ankur Gupta
S.M.O. Nodal DRTB Centre
J.L.N. Medical College, Ajmer

2. • Tuberculosis is a communicable disease and the
leading cause of death from a single infectious
agent (ranking above HIV/AIDS).
• About a half million new cases of rifampicin
resistant TB (RR-TB) occurred in 2019 with 78% of
them having confirmed MDR-TB
• DR-TB regimens require a longer course, higher
pill burden and higher toxicity profile
Lower adherence and poorer treatment
outcomes

3. Goals of TB treatment
• Render the patient non-infectious, break the
chain of transmission and decrease pool of
infection.
• Decrease TB deaths and related comorbidity.
• Minimize & prevent development and
amplification of drug resistance.

4. • DSTB – Workup  2 HRZE / 4 HRE.
• DRTB – 3 subgroups
– H mono/poly resistant TB - (6 or 9) Lfx R E Z
– MDR/RR Resistant TB - Shorter oral bedaquiline-
containing MDR/RR-TB regimen.
– MDR + FQ (Pre XDR/XDR TB) – All Oral Longer
regimen.

5. BEDAQUILINE
• Bedaquiline (formerly R207901 and TMC207)
– First of a new class of antimycobacterial agents
(Diarylquinoline)
– MOA - Specific inhibition of mycobacterial ATP
synthase with selectivity index of >20000.

6. Pharmacokinetics of Bdq
• Bedaquiline is well absorbed following oral
administration (Cmax) 4–6 h (Tmax).
• Bactericidal activity of bedaquiline is
concentration dependent.
• Mean target plasma concentration is 0.600
mg/L.
• Concomitant food intake increases the oral
bioavailability of bedaquiline (2 to 2.4 times)

7. Pharmacokinetics of Bdq
• Bedaquiline is >99 % bound to protein.
• Primarily metabolized in the liver by
cytochrome P450 (CYP) isoenzyme 3A4.
• Faeces is the major elimination route for
bedaquiline. Urinary excretion of bedaquiline
was negligible in clinical studies.

8. Pharmacokinetics of Bdq
• The mean t1/2 is 164 days (range 62–408
days) for bedaquiline.
• This is likely due to a cationic amphiphilic
characteristics of Bdq  bind to intracellular
phospholipids  drug accumulation in tissues
 slow release from peripheral tissues
(dependent on the dissociation rate constant
from the phospholipid and the elimination
rate from the tissue)

9. Grouping of anti-TB drugs

10. Shorter oral bedaquiline-
containing MDR/RR-TB regimen
• NTEP Guidelines has transitioned from the
current shorter injectable containing MDR/RR-
TB regimen to the shorter oral bedaquiline-
containing MDR/RR-TB regimen in child >5
years of age weighing 15kg or more.

11. Inclusion criteria - DST based
► Rifampicin resistance detected/inferred
► MDR/RR-TB with H resistance
InhA mutation only , or
KatG mutation only
Not both
► MDR/RR-TB with FQ resistance not detected

12. Inclusion criteria – non DST based
► Children(5-18 years) and weighing at least 15 kg,
in consultation with the pediatrician
► No history of exposure to previous treatment
with second-line medicines in the regimen (Bdq,
Lfx, Eto or Cfz) for more than 1 month (unless
susceptibility to these medicines is confirmed)
► No extensive TB disease
► No severe extra-pulmonary TB
► Women who are not pregnant or lactating

13. Exclusion criteria
1. DST based exclusion criteria
► MDR/RR-TB patients with H resistance
detected with both KatG and InhA mutation
► MDR/RR-TB patients with FQ resistance
detected.

14. Exclusion criteria
2. Other exclusion criteria
– >1 month of Bdq/Lfx/Eto/Cfz in absence of SLLPA.
– Intolerance or risk of toxicity.
– Extensive Disease
• Adult = B/L cavity, extensive parenchymal damage
• Child= cavity, bilateral disease on cxr.
– Severe EP disease
• Adult= Miliary, meningitis/CNS TB
• Child= EP other than LAP.
– Pregnancy and Lactation
– Childen < 5 years

16. Additional considerations for the use
of Bdq
• Inclusion criteria
• Bdq can also be provided to children aged 5
– 18 years of age and weighing at least 15 kg,
in consultation with pediatrician.
• Patients with controlled stable arrhythmia
can be considered after obtaining cardiac
consultation
• Pregnancy & lactating women

17. Additional considerations for the use
of Bdq
• Exclusion criteria
• Currently having uncontrolled cardiac arrhythmia
that requires medication.
• Having any of the following QTcF interval
characteristics at screening .
► QTcF > 500 at baseline & normal electrolytes
repeat ECG after 6 hours both ECGs show QTcF >500
then the patient should not be challenged with
cardiotoxic drugs; and
► History of additional risk factors for Torsade de
Pointes, e.g. heart failure, hypokalemia, family history
of long QT syndrome.

18. Pre-treatment evaluation
• Since the drugs used for the treatment of DR-
TB have significant adverse effects and to rule
out any underlying co-morbid conditions or
radiological or ECG or biochemical
derangements, a pre-treatment evaluation is
essential to identify patients not eligible for
shorter oral bedaquiline-containing MDR/RR-
TB regimen, those requiring special attention
and regimen modifications from the beginning
of treatment.

19. Pre-treatment evaluation

20. Regimen and duration
• Initial Phase [IP] = (4-6) Bdq (6 m), Lfx, Cfz, Z,
E, Hh, Eto
• Continuation Phase [CP] = (5) Lfx, Cfz, Z, E

21. S.no DRUGS 16-29 KG 30-45 KG 46-70 KG >70 KG
1 BEDAQUILNE WEEK 0-2 = 400 MG DAILY
WEEK 3-24 = 200 MG 3 TIMES PER WEEK (M/W/F)
2 ISONIAZID (HGH
DOSE)
300 MG 600 MG 900 MG 900 MG
3 ETHAMBUTOL 400 MG 800 MG 1200 MG 1600 MG
4 PYRAZINAMIDE 750 MG 1250 MG 1750 MG 2000 MG
5 LEVOFLOXACIN 250 MG 750 MG 1000 MG 1000 MG
6 CLOFAZIMINE 5O MG 100 MG 100 MG 200 MG
7 ETHIONAMIDE 375 MG 500 MG 750 MG 1000 MG
8 PYRIDOXIN 50 MG 100 MG 100 MG 100 MG
Dosage of shorter oral Bdq-containing
MDR/RR-TB regimen drugs for adults

22. Drug dose – Important Points
• All drugs in the regimen are to be given daily
under observation.
• All morning doses are to be supervised by the
treatment supporter.
• Eto can be given in divided doses.
• If weight band changes during the course of
treatment
– Adults = adjust dose in next month box.
– Children = adjust dose immediately.

23. Treatment extension
• 4 month Sm AFB – NEG  start CP
4 month Sm AFB – POS  extent IP to 5 month.
Send LPA and CDST.
• 5 month Sm AFB – NEG  start CP.
5 month Sm AFB – POS  extent IP to 6 m.
• 6 month Sm AFB – NEG  start CP.
6 month Sm AFB – POS  send cultures/ review
LPA / label outcome as TREATMENT FAILURE.

24. Drugs to be avoided along with Bdq

26. Follow-up evaluation

27. MDR/RR-TB in children - Principles for
management
• Always treat in consultation with an expert.
• Include at least 4-5 effective medicines from
group A and B to which the Mtb strain is
known or likely to be susceptible.
• Do not add a single drug to a failing regimen.
• Strict monitoring of treatment by clinical
examination, radiology and culture response
to be undertaken by pediatrician/ expert
available/ linked to DR-TBC.

28. MDR/RR-TB in children - Principles for
management
• Child-friendly formulations of most of the
component drugs of shorter and longer MDR-
TB regimen will be made available under
NTEP.
• The dosages for drugs used in various DR-TB
regimens by weight bands for paediatric DRTB
patients are as recommended in the WHO
consolidated guidelines

29. Adverse drug events

30. Management of Adverse Event

31. Management of Adverse Event

32. How to calculate QTcF

34. QT prolongation
• Suspected agent(s): Bdq, FQ, Cfz
• Values above QTc fridericia correction (QTcF)
450ms in male and 470ms in female are
referred to as prolonged.
• QT prolongation can result in ventricular
arrhythmias (Torsades de Pointes) and sudden
death.

35. Management of QT prolongation

36. Management of QT prolongation

37. Special situations
• Pregnancy and lactation.
• People living with HIV.
• Role of surgery.
• Renal impairment.
• Pre-existing liver disease.
• Seizure disorders.
• Psychiatric illness.

38. Pregnancy and lactation
• Shorter oral bedaquiline-containing MDR/RR-TB
regimen cannot be administered in pregnant
women before 32 weeks due to Eto led potential
teratogenicity in first trimester and risk of
hypothyroidism in the infant in second trimester.
• Beyond 32 weeks, the choice of regimen needs to
be a consultative decision between the
obstetrician and physician at the N/DDR-TBC

39. People living with HIV
• Additive toxicities or drug-drug interactions
between anti-TB and ART medicines potentially
overlap e.g. Mfx and Cfz or Efavirenz and Bdq,
ritonavir and Bdq.
• HIV infected DR-TB patients without the benefit
of ART may experience mortality rates exceeding
90%.
• PLHIV on shorter regimen and ART should also
receive prophylactic medication for opportunistic
infections as per WHO

40. People living with HIV
• Second-line anti-TB drugs should be initiated
first, followed by ART as soon as second-line
anti-TB drugs are tolerated, preferably within
the first two weeks of initiating DR-TB
treatment.
• IRIS syndrome.
• Effective TB infection control measures are
mandatory risk of developing primary DR-TB
among susceptible close contacts

41. Anti-retroviral regimen
• Patients of age > 10 years & weight > 30 kgs
should be initiated on FDC of tenofovir (300
mg), lamivudine (300 mg) and dolutegravir (50
mg) - single pill daily.
• Patients of age > 10 years & weight < 30 kgs
should be initiated on FDC of abacavir,
lamivudine as per weight and dolutegravir (50
mg) once daily.

42. Role of surgery
• When localized and unilateral resectable
disease is present, surgery should be
considered in the following patients-
– Absence of clinical or bacteriological response
– High risk of treatment failed or relapse
– Morbid complications of parenchymal disease e.g.
haemoptysis, bronchiectasis,broncho-pleural
fistula, or empyema
– Relapse after completion of anti-TB treatment

43. • WHO has recommended surgical procedures
like wedge resections or lobectomy in patients
with localized lesions.
• If surgical option is under consideration, at
least six to nine months of chemotherapy is
recommended prior to surgery to ensure
culture conversion.

44. Renal impairment

45. Pre-existing liver disease
• Hepatotoxic drugs in the shorter oral
bedaquiline-containing MDR/RR-TB regimen are
H, Z, Eto and Bdq.
• The potential for hepatotoxicity is increased in
the elderly, alcoholics, malnourished and in
patients with pre-existing liver disease.
• In patients with pre-existing liver disease with
persistently abnormal liver function test, a
shorter oral MDR/RR-TB regimen will be avoided
due to presence of H(h), Eto and Z.

46. Seizure disorders
• If the seizures are not under control, initiation or
adjustment of antiseizure medications will be
needed prior to the start of DR-TB treatment.
• Eto and FQ have been associated with seizures.
• When seizures present for the first time during
anti-TB treatment, they are likely to be the result
of an adverse effect of one of the anti-TB drugs

47. Psychiatric illness
• Depression and anxiety is often connected
with the chronicity and socioeconomic stress
factors related to the disease.
• Health-care provider should document any
psychiatric conditions the patient may have
and formal consultation with the psychiatrist
is adviseable.
• Treatment - psychiatric medication, individual
counselling and/or group therapy

48. • H(h), FQ and Eto have been associated with
psychosis.
• Pyridoxine prophylaxis may minimize the risk
of neurologic and psychiatric adverse events.
• Other etiologies such as psychosocial stresses,
depression, hypothyroidism, illicit drug and
alcohol use

49. Treatment outcome
Interim outcomes
• Bacteriological conversion- After bacteriological
confirmation of TB at least two consecutive cultures
(applicable for DR-TB ) taken on different occasions at
least 7 days apart are found to be negative.
• Bacteriological reversion- At least two consecutive
cultures (applicable for DR-TB) taken on different
occasions at least 7 days apart are found to be positive
either after the initial conversion or for patients
without bacteriological confirmation of TB

50. Treatment outcome
Final outcomes
1. Treatment failed- A patient whose treatment regimen
needs to be terminated or permanently changed to a
new regimen option or treatment strategy.
– Reasons for the change include:
• a) No clinical and/or bacteriological response (bacteriological
conversion with no reversion)
• b) Adverse drug reactions (ADRs),
• c) Evidence of additional drug resistance to medicines in the
regimen.
2. Cured- A pulmonary TB patient with bacteriologically
confirmed TB at the beginning of treatment who
completed treatment as recommended by the
national policy with evidence of bacteriological
response and no evidence of treatment failed.

51. Treatment outcome - Final outcomes
3. Treatment completed- A patient who completed
treatment as recommended by the national
policy whose outcome does not meet the
definition for cure or treatment failed.
4. Died- A patient who died before starting or
during the course of treatment.
5. Lost to follow-up- A patient who did not start
treatment or whose treatment was interrupted
for 2 consecutive months or more.
6. Not evaluated- A patient for whom no
treatment outcome was assigned.

52. W.H.O
A shorter all-oral bedaquiline-containing
regimen is recommended in eligible patients
with confirmed multidrug- or rifampicin-
resistant tuberculosis (MDR/RR-TB) who have
not been exposed to treatment with second-line
TB medicines used in this regimen for more than
1 month, and in whom resistance to
fluoroquinolones has been excluded.
(Conditional recommendation, very low certainty in
the evidence)

53. THANK YOU