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Burden of TB
Dr. Manoj VermaI/C IRL Department Bhopal
District Tuberculosis Officer Bhopal
Suptd. TB Hospital, Idgah Hills, Bhopal
ROBERT KOCH
ACID FAST
STAINIG OF
MTB
ELECTRON
MICROGRAPH
OF MTB
TRANSMISSION OF TB
PREVENTION OF TUBERCULOSIS
“Safe in-patient”
Practices
–Masks to patients, cough hygiene
DOTS Plus DOTS
OUT COME
• CURE 85%
• SUCCESS 90-95%
• DEFAULT 5%
• DEATH 3%
• FAILURE 3-5%
• CURE 34 %
• SUCCESS 49 %
• DEFAULT 26 %
• DEATH 22 %
• FAILURE 18 %
Newer anti TB drugs
• Bedaquiline (BDQ)
– New class of drug, diarylquinoline
– Targets mycobacterial ATP synthase,
– Strong bactericidal
– Extensive tissue distribution up to 5.5 months
post stopping BDQ.
– Significant benefits in improving the time to
culture conversion in MDR-TB patients.
– Active drug safety monitoring (aDSM)
– Cross-resistance with Clofazimine.
• Delamanid
Newer anti-TB drugs
• Bedaquiline The new drug with anti-TB effect, was approved
for treatment of multidrug resistant TB by US FDA in late
2012
• Strong bactericidal and sterilizing activities against M.tb
• The drug has an extended half-life up to 5.5 months post
stopping BDQ due to high volume of distribution, with
extensive tissue distribution, highly bound to plasma proteins
• shown significant benefits in improving the time to culture
conversion in MDR-TB patients
• Indication: pulmonary adult MDR-TB patients
– when an effective treatment regimen containing at least four second-
line drugs in addition to Z cannot be designed or
– when there is documented evidence of resistance to any FQ and/or
SLI in addition to MDR TB
Newer anti-TB drugs
• BDQ was followed by the approval of another
new drug Delamanid (Dlm) by the stringent
regulatory authority of various countries
• introduction of Dlm under RNTCP is ongoing
and guidance for the same will be released
subsequently as an addendum to these
guidelines
Integrated Drug Resistant TB Algorithm
# Conventional MDR TB Regimen (24 m) for pregnant women or for EP TB patients those who are not eligible for shorter regimen.
*Offer molecular testing and treatment for H mono/poly resistance to TB patients prioritized by risk as per the available lab capacity
**LC DST (Mfx 2.0, Km, Cm, Lzd) will be done only for patients with any resistance on baseline SL-LPA. DST to Z, Cfz, Bdq & Dlm would be
considered for policy in future, whenever available, standardized & WHO endorsed.
$ States to advance in phased manner as per PMDT Scale up plan for universal DST based on lab capacity and policy on use of diagnostics
All diagnosed TB patientsPresumptive TB
Key/Vulnerable populations
• Paediatric age group
• People living with HIV
• EPTB sites
• Smear negative/NA with X-
ray suggestive of TB
• Non responders to
treatment
• DR-TB contacts
• Previously treated TB
• TB-HIV co-infection
• New TB cases $
CBNAAT
RR TB RS TB
FL-LPA*SL - LPA**
Shorter MDR TB
Regimen (9-11 m)#
First line
treatment
FQ and SLI Sensitive FQ and/or SLI Resistance H Sensitive
Newer Drugs & DST
guided treatment
Continue same regimen
(shorter MDR or H
mono/poly regimen)
In case of addl resistance, failing regimen, drug intolerance, return after
interruption (>1 m) or emergence of any exclusion criteria
H mono/poly
resistant TB
regimen
H Resistant
Continue First line
treatment
For discordance on LPA for RR-TB
– repeat CBNAAT at LPA lab
Integrated Drug Resistant TB Algorithm
# Conventional MDR TB Regimen (24 m) for pregnant women or for EP TB patients those who are not eligible for shorter regimen.
*Offer molecular testing and treatment for H mono/poly resistance to TB patients prioritized by risk as per the available lab capacity
**LC DST (Mfx 2.0, Km, Cm, Lzd) will be done only for patients with any resistance on baseline SL-LPA. DST to Z, Cfz, Bdq & Dlm would be
considered for policy in future, whenever available, standardized & WHO endorsed.
$ States to advance in phased manner as per PMDT Scale up plan for universal DST based on lab capacity and policy on use of diagnostics
All diagnosed TB patientsPresumptive TB
Key/Vulnerable populations
• Paediatric age group
• People living with HIV
• EPTB sites
• Smear negative/NA with X-
ray suggestive of TB
• Non responders to
treatment
• DR-TB contacts
• Previously treated TB
• TB-HIV co-infection
• New TB cases $
CBNAAT
RR TB RS TB
FL-LPA*SL - LPA**
Shorter MDR TB
Regimen (9-11 m)#
First line
treatment
FQ and SLI Sensitive FQ and/or SLI Resistance H Sensitive
Newer Drugs & DST
guided treatment
Continue same regimen
(shorter MDR or H
mono/poly regimen)
In case of addl resistance, failing regimen, drug intolerance, return after
interruption (>1 m) or emergence of any exclusion criteria
H mono/poly
resistant TB
regimen
H Resistant
Continue First line
treatment
For discordance on LPA for RR-TB
– repeat CBNAAT at LPA lab
Integrated Drug Resistant TB Algorithm
MDR/RR-TB with additional resistance to
any/all FQ or SLI
• All patients with additional resistance to FQ
class AND/OR SLI class on SL-LPA would be
assessed for eligibility for newer drug containing
regimen.
• Patients who have consented and are found to
be eligible would be initiated on newer drugs
containing the regimen while rest of the patients
would be initiated on a DST guided regimen and
reclassified.
Inclusion criteria
The criterion for patients to receive BDQ as approved by
the Apex Committee is:
• Adults aged > 18 years having pulmonary MDR-TB.
Additional requirements
• Non pregnant females or females not on effective
hormonal birth control methods are eligible
• Willing to continue practicing birth control methods
throughout the treatment period or
• have been post-menopausal for the past 2 years.
• Patients with controlled stable arrhythmia can be
considered after obtaining cardiac consultation.
Exclusion criteria
Currently having uncontrolled cardiac arrhythmia that
requires medication
Has any of the following QT/QTc interval characteristics at
screening:
– A marked prolongation of QT/QTc interval, e.g.
repeated demonstration of QTcF (Fredericia correction)
interval > 450 ms;
– A history of additional risk factors for Torsade de
Pointes, e.g. heart failure, hypokalaemia, family
history of long QT syndrome;
– has evidence of chorioretinitis, optic neuritis, or
uveitis at screening which precludes long term linezolid
(Lzd) therapy;
Eligibility for Bedaquiline
Bdq is indicated in adult MDR-TB patients not eligible for the
newly WHO-recommended shorter regimen.
These may include:
• MDR/RR-TB patients with resistance to any/all FQ OR to
any/all SLI
• XDR-TB patients
• Mixed pattern resistant TB patients
• Treatment failures of MDR-TB + FQ/SLI resistance OR
XDR-TB
• MDR/RR-TB patients with extensive pulmonary lesions,
advanced disease and others deemed at higher baseline
risk for poor outcomes
Bedaquiline: Dosage
• Week 0–2: BDQ 400 mg (4 tablets of 100 mg) daily (7 days per week) + OBR
• Week 3–24: BDQ 200 mg (2 tablets of 100 mg) 3 times per week (with at least 48 hours between doses) for a total dose of 600 mg per week + OBR
• Week 25 (start of month 7) to end of treatment: Continue other second-line anti-TB drugs only as per RNTCP recommendations
The dosage of BDQ would apply to all weight bands while the dosage of other
drugs in the OBR would be as per the weight bands in accordance to the RNTCP
PMDT guidelines.
Bedaquiline: Administration
Management of patients found to be ineligible
or who did not consent for BDQ
“Patients who could not be initiated on a
BDQ containing regimen (either found
ineligible or who did not consent for BDQ)
would be treated with treatment regimen
tailored as per the DST guided treatment”
DST guided regimen with or without newer drugs for initiating treatment
of MDR/RR-TB patients with additional resistance to FQ class and/or SLI
class, at nodal DR-TB centre based on SL-LPA
Resistance
Pattern
DST Guided
Regimen class
Intensive Phase Continuation
Phase
Principle of
regimen design
Regimen with New drugs for MDR-TB + FQ / SLI resistance
MDR/RR +
resistance to FQ
class / SLI1 class
MDR/RR + resistance
to FQ class
(6-9) Km Eto Cs Z
Lzd3 Cfz + (6) Bdq
(18) Eto Cs
Lzd3 Cfz
0 GpA + 1GpB + 2
GpC + Z + add on
2 GpC + 1 GpD2
MDR/RR+ resistance
to SLI1 class
(6-9) Lfx Cm1 Eto
Cs Z Lzd3 Cfz +
(6) Bdq
(18) Lfx Eto
Cs Lzd3
1 GpA + 1 GpB1 +
2 GpC + Z + add
on 2 GpC + 1
GpD2
Regimen MDR-TB + FQ / SLI resistance: (without new drugs)
MDR/RR +
resistance to FQ
class / SLI1 class
MDR/RR + resistance
to FQ class
(6-9) Mfxh2 Km Eto
Cs Z Lzd3 Cfz
(18) Mfxh2 Eto
Cs Lzd3 Cfz
1 GpA2 + 1GpB + 2
GpC + Z + add on
2 GpC
MDR/RR+ resistance
to SLI1 class
6-9) Lfx Cm1 Eto
Cs Z Lzd3Cfz
(18) Lfx Eto
Cs Lzd3
1 GpA + 1 GpB1 +
2 GpC + Z + add
on 2 GpC
1 If only Km resistant (at eis mutation), then add Cm in IP upfront in the regimen design.
2. In patients with MDR/RR + FQ Class resistance, XDR-TB and Mixed pattern resistance where a new drug is not considered in the
regimen for any reason, Mfxh would be added upfront in the regimen design and the decision to continue or replace it would be taken
based on LC-DST results to Mfx (2.0) by NDR-TBC
3. Lzd to be replaced with a suitable drug if found to be resistant on LC-DST. In such situation the patient must be reclassified as mixed
pattern DR-TB
Resistance Pattern DST Guided
Regimen class
Intensive Phase Continuation
Phase
Principle of
regimen design
Regimen with New drugs for XDR-TB
XDR-TB (Res to
both FQ and SLI1
class)
XDR-TB
(6-12) Cm1 Eto Cs
Z Lzd3 Cfz E + (6)
Bdq
(18) Eto Cs
Lzd3 Cfz E
0 GpA + 1 GpB1 +
2 GpC + Z + add
on 2 GpC + 1GpD1
+ 1 GpD2
Regimen for XDR-TB: (without new drugs)
XDR-TB
(resistance to both
FQ and SLI1 class)
XDR-TB
(6-12) Mfxh2 Cm1
Eto Cs Z Lzd3 Cfz
E
(18) Mfxh2 Eto
Cs Lzd3 Cfz E
1 GpA2 + 1 GpB1 +
2 GpC + Z + add
on 2 GpC + 1GpD1
DST guided regimen with or without newer drugs for initiating treatment
of XDR-TB patients with additional resistance to FQ class and/or SLI
class, at nodal DR-TB centre based on SL-LPA
1. If only Km resistant (at eis mutation), then add Cm in IP upfront in the regimen design.
2. In patients with MDR/RR + FQ Class resistance, XDR-TB and Mixed pattern resistance where a new drug is not considered in
the regimen for any reason, Mfxh would be added upfront in the regimen design and the decision to continue or replace it would
be taken based on LC-DST results to Mfx (2.0) by NDR-TBC
3. Lzd to be replaced with a suitable drug if found to be resistant on LC-DST. In such situation the patient must be reclassified as
mixed pattern DR-TB
Mixed pattern drug resistant TB
Following types of patients operationally re-classified as mixed pattern DR- TB
• H mono-poly DR-TB patients with additional resistance to FQ and/or SLI
and/or Lzd
• RR-TB patients with additional resistance to FQ and/or SLI with Lzd
resistance
• Any MDR/RR/XDR-TB patients if the following events prevent them to be
classify in define regimen class.
– who are failing any DR-TB regimen or
– who have drug intolerance or contraindications or emergence of any exclusion criteria
– who returns after interruption (>1 months) or
– with extensive pulmonary lesions, advanced disease and others deemed at higher
baseline risk for poor outcomes.
• These patients would be initiated on a DST guided regimen
• regimen proposed for mixed pattern regimen should be designed using
drugs considered to be effective-based on previous use
• use a minimum of 5 drugs and maximum 8-9 drugs in the regimen
Dosage of DR-TB drugs for adults
1For H mono/poly resistant TB; 2For adult more than 60 yrs of age, dose of SLI should be reduced to 10mg/kg (max up
to 750 mg) 3In patient of PAS with 80% weight/volume the dose will be changed to 7.5gm (16-29Kg); 10 gm (30-45 Kg);
12 gm (46-70 Kg) and 16 gm (>70 Kg) 4 drugs can be given in two divided doses in a day in the event of intolerence
S.No Drugs 16-29 Kgs 30-45 Kgs 46-70 Kgs >70 Kgs
1 Rifampicin(R)1 300mg 450mg 600mg 600mg
2 High dose H (Hh) 300 mg 600 mg 900 mg 900 mg
3 Ethambutol(E) 400 mg 800 mg 1200 mg 1600 mg
4 Pyrazinamide(Z) 750 mg 1250 mg 1750 mg 2000 mg
5 Kanamycin(Km) 2 500 mg 750 mg 750 mg 1000 mg
6 Capreomycin (Cm) 500 mg 750 mg 750 mg 1000 mg
7 Amikacin (Am) 500 mg 750 mg 750 mg 1000 mg
8 Levofloxacin(Lfx) 4 250 mg 750 mg 1000 mg 1000 mg
9 Moxifloxacin (Mfx) 4 200 mg 400 mg 400 mg 400 mg
10 High Dose Mfx (Mfxh) 4 400mg 600mg 800mg 800mg
11 Ethionamide(Eto) 4 375 mg 500 mg 750 mg 1000 mg
12 Cycloserine(Cs)4 250 mg 500 mg 750 mg 1000 mg
13 Na-PAS (60% weight/vol) 3,4 10 gm 14 gm 16 gm 22 gm
14 Pyridoxine(Pdx) 50 mg 100 mg 100 mg 100 mg
15 Clofazimine (Cfz) 50 mg 100 mg 100 mg 200 mg
16 Linezolid (Lzd) 300 mg 600 mg 600 mg 600 mg
17 Amoxyclav(Amx/Clv)
(In child: WHO 80mg/Kg in 2
divided doses)
875/125 mg
BD
875/125 mg
BD
875/125 mg(2 morning +1
evening)
875/125 (2 morning +1
evening)
18 Bedaquiline (Bdq) Week 0–2: Bdq 400 mg daily
Week 3–24: Bdq 200 mg 3 times per week
Dosage of DR-TB drugs for children*
(< 30 kg body weight)
Drug Daily Doses*
Kanamycin / Capreomycin 15-30 mg/kg (SM 20-40 mg/kg)
Levofloxacin / Moxifloxacin Lfx <5 yrs: 15-20 mg/kg split dose
Lfx >5 yrs: 10-15 mg/kg once day
Mfx 7.5-10 mg/kg
Mfxh 12 mg/ kgEthionamide 15-20 mg/kg
Cycloserine 10-20 mg/kg
Ethambutol 15-25 mg/kg
Pyrazinamide 30-40 mg/kg
(Na-PAS ) <30 kg: 200-300 mg/kg
High dose H (h) 15-20 mg/kg*
Clofazimine (Cfz) 1 mg/kg (max. 200 mg / day) limited data
Linezolid (Lzd) 10 mg/kg TDS (max. 600mg /day) with pyridoxine
Amoxyclav(Amx/Clv) 80 mg/kg (based on the amoxicillin component) in
two divided doses (max. 4gm Amox+0.5gm clav)* as per Companion handbook to the WHO guidelines for the programmatic management of drug-resistant
TB 2014# till the time data are available, adult dose is used
Duration of regimen
Regimen Intensive
Phase
Extended
Intensive
Phase
Continuous
Phase
Total
duration
H mono-poly DR-TB regimen
& Mixed pattern H mono/poly3 months +3 months 6 months
9-12
months
Shorter MDR-TB regimen 4 months +2 months 5 months9-11
months
Conventional MDR-TB
regimen
(Regimen with or without
new drugs for MDR-TB + FQ
/ SLI resistance)
6 months +3 months 18 months24-27
months
XDR-TB regimen (Regimen
with or without new drugs for
XDR-TB, mixed pattern
XDR- TB)
6 months +6 months 18 months24-30
months
Fully Susceptible TB
Rif. Resistance or MDR-TB
MDR.TB plus Fq
Resistance
XDR-TB
XDR + all
SLDI
TDR
?
Worsening the Prognosis Increasing M. TB Pattern of Resistance
Consequences of MDR/XDR-TB
• Poor response to standardised treatment
• Long duration of contagiousness
• High risk of morbidity and mortality
• Individualised treatment more costly
Difficult management --> requires specialized Training
NTF Presentations for RNTCP
Sensitization First edition 10th Nov 06
Social and Economic Burden of TB in
IndiaEstimated burden per year
• Indirect costs to society $3 billion
• Direct costs to society $300 million
• Productive work days lost due to TB illness 100 million
• Productive work days lost due to TB deaths 1.3 billion
• School drop-outs due to parental TB 300,000
• Women rejected by families due to TB 100,000
TRC, Socio-economic impact of TB on patients and family in India, Int J Tub Lung Dis 1999 3: 869-877
Source: WHO Global Tuberculosis Report 2014
Source: WHO Global Tuberculosis Report 2014
THANK YOU