Dr. Manoj Verma I/C IRL Department Bhopal District Tuberculosis - - PowerPoint PPT Presentation

Burden of TB

• Dr. Manoj Verma

I/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 patients Presumptive 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 patients Presumptive 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
• ther 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

• r 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

• f 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

• n 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

• n 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

• n 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

• n 2 GpC + 1GpD1

DST guided regimen with or without newer drugs for initiating treatment

• f 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/ kg Ethionamide 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/poly 3 months +3 months 6 months 9-12 months Shorter MDR-TB regimen 4 months +2 months 5 months 9-11 months Conventional MDR-TB regimen (Regimen with or without new drugs for MDR-TB + FQ / SLI resistance) 6 months +3 months 18 months 24-27 months XDR-TB regimen (Regimen with or without new drugs for XDR-TB, mixed pattern XDR- TB) 6 months +6 months 18 months 24-30 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 India

Estimated 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

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