Dr. Vaibhav Watts JR GMC, Amritsar

1. Moderator- Dr Jaswant Rai
Presenter-Dr Vaibhav Watts
Recent advances in
management of Tuberculosis

2. Overview
Introduction
Epidemiology
WHO update
RNTCP 2017
New Drugs

3. Tuberculosis
The Captain of men of death
Chronic granulomatous disease caused by
Mycobacterium tuberculosis (MTB)
Lungs most commonly effected: Pulmonary
Tuberculosis (PTB)
Inhalation of infected droplet nuclei

4. Epidemiology
Up to 1/3rd world's population is infected
More than 95% of all TB cases and 98% of
all deaths due to TB occur in developing
countries
Estimated 79,000 multi-drug resistant TB
patients among the notified cases of
pulmonary TB each year
India accounts for about a quarter of the
global TB burden
In March 2017 the Government of India
(GoI) announced that the new aim with
regard to TB in India was the elimination
of TB by 2025.

5. WHY HIGH INCIDENCE ?
ENVIRONMENT
FACTORS
• Acidic pH inside
macrophages
• Low oxygen
tension
• Avascular
caseous material
PATIENT
FACTORS
• Poor compliance
due to prolonged
therapy
TREATMENT
FACTORS
• Multiple drugs
• Long course
treatment
Bacteria related factors
Rapid multiplication
 Slow multiplication
Dormant phase
Occasional Spurters
Shifting between population

6. Classification Of ATT Drugs
First Line Essential Drugs: Core components of ATT regimen
Isoniazid (H)
Rifampicin (R)
Pyrazinamide (Z)
Ethambutol (E)
First Line Supplemental Drugs:
Reserved drugs, to be used in special settings
Streptomycin, Rifabutin and Rifapentine
Second Line Drugs:
Fluoroquinolones ( Ciprofloxacin, Ofloxacin, Levofloxacin,
Moxifloxacin)
Amikacin, Capreomycin
Ethionamide, PAS, Cycloserine, Thiacetazone
 NEW DRUGS

7. Testing and diagnosis
Microbiological confirmation on sputum
Chest X-ray as a screening tool
Cartridge Based Nucleic Acid Amplification Test
(CBNAAT) also known as GeneXpert in many countries
Serological tests for TB are banned in India
Tuberculin Skin Test (TST) & Interferon Gamma
Release Assays (IGRA)s are also not recommended
TrueNat is being developed in India, should be a
cheaper option

8. Definitions
New case: A TB patient who has never had treatment for TB
or has taken ATD for < 1 month
Recurrent TB case – A TB patient previously declared as
successfully treated (cured/treatment completed) and who
is subsequently found to be microbiologically confirmed TB
case is a recurrent TB case (Previously called relapse)
Treatment after failure – Patients are those who have
previously been treated for TB and whose treatment failed
at the end of their most recent course of treatment
Previously called failure where a TB patient is
sputum-positive at 5 months or more after initiation
of treatment

9. Treatment after loss to follow-up – A TB patient
previously treated for TB for one month or more and who
was declared LFU in their most recent course of
treatment and subsequently found microbiologically
confirmed TB cases.(Defaulter)
CURED-Microbiologically confirmed TB patients at the
beginning of treatment who was smear or culture
negative at the end of the complete treatment

10. Failure to Respond: A case of paediatric TB who fails to
have bacteriological conversion to negative status or fails
to respond clinically / or deteriorates after 12 weeks of
compliant intensive phase shall be deemed to have failed
response provided alternative diagnoses / reasons for
non‐response have been ruled out
Treatment Regimen Changed: A TB patient who is on first
line regimen and has been diagnosed as having DRTB and
switched to drug resistant TB regimen prior to being
declared as failed

11. Multi-drug resistance (MDR) – A TB patient whose
biological specimen is resistant to both INH and
Rifampicin with or without resistance other first-line
ATD
Extensive drug resistance (XDR) – MDR TB case whose
biological specimen is resistant to a Fluroquinolone
(FQ) and a second-line injectable TB drug
Totally drug resistant TB - Resistance to all the first and
second line TB drugs (Referred as XXDR TB or
extremely drug resistant TB)

12. WHO guidelines 2017

13. The previous WHO evidence based guidelines were
published in 2010
Recommendations were developed using the
GRADE method for assessment of quality of
evidence
In 2017 guidelines some of the recommendations
have remain unchanged and few have been
updated
The 2017 guideline update is broader than the
2010 as it includes additional evidence-based
recommendations on issues of patient care and
support for patients with drug-susceptible or drug-
resistant TB.

14. 2010 Guidelines 2017 update
Effectiveness of shortened
FQ-containing regimens- No
recommendation
UPDATED
In patients with drug-susceptible
pulmonary TB,
4-month FQ-containing regimens
should not be used and the 6-month
rifampicin based
regimen 2HRZE/4HR remains the
recommended
Use of FDC formulations or separate
drug formulations- NO EXISTING
SPECIFIC RECOMMENDATION
UPDATED
FDC tablets recommended

15. 2010 Guidelines 2017 update
Effectiveness of intermittent
dosing (thrice weekly) of TB
medications, both in the intensive
phase and in the continuation
phase of treatment, when
compared to daily treatment
UPDATED
In all patients the use of thrice-
weekly dosing is not
recommended in both the
intensive and continuation phases
of therapy, and daily dosing
remains recommended
The effectiveness of a TB
treatment period > 8 months
compared to the standard 6-
month treatment period for HIV
co-infected patients
UPDATED
Pulmonary TB patients who are
living with HIV and receiving
antiretroviral therapy during TB
treatment, a 6-month standard
treatment regimen is
recommended over an extended
treatment for 8 months or more

16. 2010 Guidelines 2017 update
Treatment extension in new
pulmonary TB patients-
In new pulmonary TB patients
treated with
the regimen containing rifampicin
throughout treatment, if a positive
sputum smear is found at
completion of the intensive phase,
the extension of the intensive phase
is not recommended, DST done
REMAINS VALID
The use of adjuvant steroids in the
treatment of extrapulmonary TB
disease- no existing specific
recommendation
UPDATED
In patients with TB meningitis, an
initial adjuvant therapy with
dexamethasone or prednisolone
tapered over 6-8 weeks should be
used
In patients with TB pericarditis, an
initial adjuvant corticosteroid
therapy may be used

17. 2010 Guidelines 2017 update
The empirical use of the WHO
category II regimen in patients who
require retreatment for TB
UPDATED
In patients who require TB
retreatment, the category II
regimen should no longer be
prescribed and drug-susceptibility
testing conducted to inform the
choice of treatment regimen

18. Initiation of antiretroviral treatment (ART) in TB
patients living with HIV
Recommendation:-
 ART should be started in all TB patients living with HIV
regardless of their CD4 cell count
 TB treatment should be initiated first, followed by ART
as soon as possible within the first 8 weeks of treatment
 HIV-positive patients with profound immunosuppression
(e.g. CD4 counts less than 50 cells/mm3) should receive
ART within the first 2 weeks of initiating TB treatment.

19. Patient care and support
Cross-cutting interventions for drug-susceptible TB
and drug-resistant TB
Recommendation:-
 Health education and counselling
 Psychological support & material support (e.g. food,
financial incentive, and transport fee);
 Tracers such as home visits or digital health
communications (e.g. SMS, telephone calls),
medication monitor
 DOT or VOT over unsupervised treatment
MERM- Medication Event and Reminder Monitor

20. Update on MDR-TB

21. 2011 guidelines 2016 guidelines
Use of sputum-smear microscopy
and culture both to monitor
response to treatment
Remains valid
Use of a shorter MDR-TB treatment
regimen - NO SPECIFIC
RECOMMENDATION
UPDATED
Patients who were not previously
treated with second-line drugs and
in whom resistance to FQ and
second-line injectable agents was
excluded A shorter MDR-TB regimen
of 9–12 months may be used instead
of the longer regimens

22. 2011 GUIDELINES 2016 UPDATE
Composition of longer MDR-TB
treatment regimens
a fluoroquinolone
a later-generation FQ rather than
an earlier-generation FQ
Ethionamide
Regimens should include at least
pyrazinamide, a fluoroquinolone, a
parenteral agent, ethionamide (or
prothionamide), and either
cycloserine or p-aminosalicylic acid
(PAS)
four second-line drugs likely to be
effective (including a parenteral
agent), as well as pyrazinamide,
should be included in the intensive
phase
UPDATED
a regimen with at least five
effective TB medicines during the
intensive phase is recommended,
including pyrazinamide and four
core second-line drugs one chosen
from Group A, one from Group B,
and at least two from Group C
If the minimum number of
effective TB medicines cannot be
composed as given above, an agent
from Group D2 and other agents
from Group D3 may be added to
bring the total to five
it is recommended that the
regimen be further strengthened
with high-dose isoniazid and/or
ethambutol
Group A- FQ: Levofloxacin , Moxifloxacin, Gatifloxacin
Group B-Second-line injectable agent:Amikacin, Capreomycin,
Kanamycin
Group C-Other core second-line agents:Ethionamide / prothionamide,
Cycloserine / terizidone, Linezolid, Clofazimine
Group D. Add-on agents:
D1-Pyrazinamide, Ethambutol, High-dose isoniazid
D2- Bedaquiline, Delamanid
D3-p-aminosalicylic acid, Imipenem–cilastatin, Meropenem,
Amoxicillin-clavulanate, Thioacetazone
HIV-status must be confirmed to be negative before thioacetazone is
started.

23. High dose isoniazid in MDR-TB
INH blocks mycolic acid synthesis and kills the bacteria
High-dose isoniazid (16-20 mg/kg) is one of the core
components of the shorter MDR-TB treatment regimen
Strains bearing mutations in the inhA gene may have a
minimum inhibitory concentration (MIC) to isoniazid that is
low enough to be overcome by high dose isoniazid
Also, strains of MTB in INH resistant cases often contain a
mix of susceptible and resistant organisms
Use of high dose INH eliminates susceptible and low level
resistance

24. It has been seen that bacteria resistant to low dose
INH are also resistant to E & Z too
High dose isoniazid, by killing bacteria that are
resistant to low dose isoniazid, may also eliminate
resistance to ethionamide and pyrazinamide too

25. 2011 GUIDELINES 2016 UPDATE
Treatment of patients with RR-TB-
NO SPECIFIC RECOMMENDATION
Any patient with RR-TB in whom
INH resistance is absent or
unknown be treated with MDR-TB
regimen, either a shorter MDR-TB
regimen, or a longer MDR-TB
regimen to which isoniazid is added
Duration of longer MDR-TB
treatment regimens-
an intensive phase of eight months
is suggested for most patients; the
duration may be modified according
to the patient’s response to therapy
total treatment duration of 20
months is recommended
REMAINS VALID

26. 2011 GUIDELINES 2016 UPDATE
Start of antiretroviral therapy with
MDR-TB treatment- all patients,
irrespective of CD4 counts, asap
Remains valid
Use of surgery as part of MDR-TB
treatment- NO SPECIFIC
RECOMMENDATION
Elective partial lung resection may
be used alongside a recommended
MDR-TB regimen
Models of MDR-TB care
(ambulatory/hospitalization) -
Patients should be treated using
mainly ambulatory care rather than
models of care based principally on
hospitalization
Remains valid

27. RNTCP guidelines 2017

28. DAILY REGIMEN GUIDELINES
Daily treatment to be rolled out before 25th of
October 2017
Patients already on intermittent treatment will
continue the same till completion of their course.
Daily treatment to be initiated only to those cases
for whom fresh treatment course is initiated
All paediatric cases will continue intermittent
treatment, until paediatric FDC strips are received.

29. Dispensing FDC strips
CAT I ATT –Issue drugs for a month and verify
empty blister packs while coming for next
month Drug collection.
CAT II ATT-Issue 1 Strip & Streptomycin for 10
days pending culture reports (LPA/CBNAAT)
and then issue monthly drugs
DOSAGES
Frequency of Dosage: DAILY (7 day/week)
Single daily dosage
4 weeks per month, i.e.: 28 doses

30. Anti TB treatment (daily)

31. FDC drugs

32. Injection streptomycin
15 mg/kg (12–18 mg/kg) daily
Maximum daily dose 1000 mg
Patients aged > 50 years may not tolerate
Streptomycin more than 750 mg
Similarly, patients weighing < 50 kg may not
tolerate doses above 500-750 mg daily

33. Situations where loose drugs to be
used for daily regimen
Adult weighing below 25 kg
Children weighing above 39 kg
NEW Cases of Neurological TB requiring CAT I ATT
HIV TB Coinfection cases on II Line ART/ Protease
Inhibitor based regimen
Drug Allergy
ADR’s (Adverse Drug Reactions) Due to ATT –example-
Jaundice

34. HIV TB
All HIV-TB co infection cases to be initiated on
ATT ,CPT Followed by ART irrespective of CD4
count.
CPT- Co-trimoxazole prophylaxis therapy for
Pneumocystis jirovecii

35. TB-HIV patients on I line ART(ZLN/TLN)-ART
Regimen modified (ZLE/TLE)
Nevirapine should be replaced by Efavirenz
TB HIV patients On II line ART or Alternative First line
ART (containing PI/NNRTI)-ATT Regimen modified
Rifampicin should be replaced by Rifabutin150 mg
But in paediatric cases-no need of change in ATT
regimen. ART super boosting will be done in ART
centre

36. EXTEND IP
 NO IP EXTENSION IN DAILY REGIMEN
EXTEND CP
 3 MONTHS---IN NEUROLOGICAL TB
 TB SPINE WITH NEUROLOGICAL INVOLVEMENT
 OSTEO ARTICULAR TB
 DISSEMINATED TB/MILIARY TB

37. Isoniazid chemoprophylaxis
< 6 yrs child
Contacts of smear positive TB
After ruling out active TB disease
Irrespective of BCG statusIsoniazid 10 mg/kg/day daily for 6 months

38. IPT regimen Plan
Adult and Adolescent: Isoniazid 300mg +
Pyridoxine 50mg (Vitamin B6) per day for 6
months
Children above 12 months: Isoniazid 10mg/kg +
Pyridoxine 25 mg (Vitamin B6) per day for 6
months

39. IPT in special circumstances
Patients previously treated for TB (Secondary
prophylaxis)-Initiate IPT for another 6 months
IPT with ART (Secondary prophylaxis)-Combined use of
IPT with ART irrespective of immune status, pregnancy,
previous TB treatment
Patient on IPT develops TB during IPT treatment
 Taken ATT in past OR taken IPT for >30 days -Cat-II
 No ATT or had IPT for<30 days- CAT-I

40. IPT and Pregnancy:-
 Start IPT irrespective of the gestation period & Advise to
complete even if becomes pregnant while taking
 Isoniazid is safe in pregnancy & breast feeding
IPT and MDR- Contacts of MDR TB and PLHIV who have
completed DRTB treatment are not eligible for IPT
IPT in children born to microbiologically confirmed TB
mothers:
 Assess the new born for TB, if ruled out give IPT for 6
months.
 Administer BCG at birth

41. TB and liver disease
Prevalence of TB in patients with liver cirrhosis is 15
times higher than in the general population
Absolute Contraindication – Z
R is relatively C/I
2(SHE) + 10 months HE
Severely ill patient – SE
Once Hepatitis resolved - reintroduce H

42. TB and pregnancy
Benefits of treating TB in pregnancy outweigh risk of
treatment
TB treatment is generally not considered a contra-
indication to breastfeeding
Aminoglycosides are avoided
4 HRZ + 4HR used
E can be added late in pregnancy
All women being treated with INH should receive
pyridoxine 10-25 mg/day

43. TB and renal disease
Renal failure is recognised as a risk factor for developing
tuberculosis.
H R & Z are metabolized by the liver and can be
administered in renal failure.
RFTs must be measured before the initiation of
antituberculous treatment.
Streptomycin levels must be closely monitored. If the
patient is under dialysis, streptomycin must be given 4-6
hours before dialysis, or after dialysis.
Ethambutol must be restricted in renal impairment.
Its usage will be avoided if the GFR is below 10
ml/min.

44. NEWER DRUGS

45. Bedaquiline
Approved by (FDA) on 28th December 2012,
first new medicine for TB in more than 40
yrs.
Blocks the enzyme ATP synthase
Used in combination with other TB drugs in adults
when they have MDR-TB
Always used in combination with at least 3 other
TB (use with at least 4 other drugs, if drug
susceptibility testing is not available )

46. It should not be used for the treatment of:
 Latent TB infections
 Drug sensitive tuberculosis
 Extrapulmonary tuberculosis
 Infections caused by non tuberculosis
mycobacteria.
The safety and efficacy of the drug in the treatment
of HIV positive patients with MDR-TB has also not
yet been established.

47. Dosage
Recommended dose 400 mg OD* 2 weeks, then
200 mg taken 3 times a week for the next 22
weeks
If a dose is missed during the first 2 weeks of
treatment, the missed dose should not be made
up but doses should continue to be taken as
normal.
From week 3 onwards, if a dose is missed,
patients should take the missed dose as soon as
possible, and then resume the 3 times a week
regimen.
Adverse effects
 headache, dizziness, joint pain
 increase in liver enzymes
QTc prolongation

48. Sutezolid(PNU-100480)
An oxazolidinone like linezolid, improved safety
profile & better time-dependent killing
Orphan Drug designation in both US & E.U. for both
drug sensitive & drug resistant strains in adults
In vivo studies in the mouse model of TB
demonstrated that the addition of sutezolid to the
standard TB regimen significantly shortens treatment
& also reduced the numbers of bacteria

49. The mycobactericidal activity of sutezolid 600 mg
BD or 1200 mg OD was readily detected in sputum
and blood
Both schedules were generally safe and well
tolerated
Transient, asymptomatic ALT elevation seen
Currently in phase 2a trial

50. Delamanid
First in a new class of TB drugs called nitroimidazoles
Prodrug – activated by deazaflavin dependent
nitroreductase enzyme
Inhibit synthesis of mycobacterial cell
wall
Bactericidal, effective in MDR & XDR TB

51. Initially for adults with MDR-TB
Now may be used in age 6-17 yrs too
Available in 50mg tablets & the recommended dose is 2
tablets BD with food * 6months
Side effects: Nausea, vomiting and dizziness
QT prolongation

52. Pretomanid (PA-824)
Nitroimidazole-like molecule
It is active against both replicating and hypoxic, non-
replicating MTB
MOA:
inhibition of cell wall mycolic acid biosynthesis
(isoniazid)
Respiratory poisoning through nitric oxide
release(cyanide)

53. Currently undergoing phase 3 trial
Shown to be safe, well tolerated, and efficacious at
doses of 100–200 mg daily
Potential cornerstone of future TB and drug-resistant
TB treatment regimens.

54. Benzothiazinone (BTZ043)
A class of nitroaromatic molecules that kill MTB
Shown to block the biosynthesis of arabinans, vital
components of mycobacterial cell walls
Also penetrates human macrophages in which
mycobacteria survive
Currently in the late stages of preclinical development

55. Repurpose drugs
Imipenam + cilastatin
Amoxicillin / clavulanic acid
Clarithromycin
Linezolid
Sulfamethoxazole
Mefloquine
Evidence is needed

56. Take home message
CBNAAT on sputum for diagnosis
Daily regimen replaces intermittent one
FDCs to be used as per weight band
Bedaquilline & Delamanid have added a new dimension
Use of Repurpose drugs have been tried
High dose isoniazid in MDR-TB seems rational

57. Conclusion
Tuberculosis remains a major killer of adults worldwide.
Shifting of bacilli, longer treatment duration and poor
patient compliance are the biggest hurdles
An ideal preventive agent, an effective vaccine, is still
some time away
Eradication will only be possible through reductions in
poverty and overcrowding, political will and stability, and
containing co-drivers of tuberculosis, such as HIV,
smoking, and diabetes.

58. THANK YOU