Dr. J.N.

Banavaliker, MD,DTCD,MBA

Definitions

MDR-TB: resistance to isoniazid and rifampicin, independent of any other resistance

XDR TB is defined as

TB which is resistant to isoniazid and rifampin, plus resistant to any fluoroquinolone and at least one of three injectable second-line drugs (i.e., amikacin, kanamycin, or capreomycin).

The global TB situation

Estimated number of cases, 2010 Estimated number of deaths, 2010

All forms of TB HIV-associated TB Multidrugresistant TB

8.8 million
(8.59.2 million)

1.1 million*
(0.91.2 million)

1.1 million
(1.01.2 million)

350,000
(320,000390,000)

~ 650,000
out of 12 million (11-14 million) prevalent TB cases

* Excluding deaths attributed to HIV/TB Source: WHO Global Tuberculosis Control Report 2011 (www.who.int/tb/publications/global_report/2011/gtbr11_full.pdf)

Proportion of MDR among new TB cases Latest available data, 1994-2010

0-<3 3-<6 6-<12 12-<18 >18 No data available Subnational data only

The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. WHO 2011. All rights reserved

Proportion of MDR among previously treated TB cases Latest available data, 1994-2010

0-<6 6-<12 12-<30 30-<50 >50 No data available Subnational data only

The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. WHO 2011. All rights reserved

Causes of inadequate treatment

Providers/Programmes: Inadequate regimens Drugs: Inadequate supply/quality -Non-availability of certain drugs (stock-outs or delivery disruptions) -Poor quality -Poor storage conditions -Wrong dosages or combination Patients: Inadequate drug intake

-Absence of guidelines or inappropriate guidelines -Non-compliance with guidelines -Inadequate training of health staff -No monitoring of treatment -Poorly organized or funded TB control programmes

Poor adherence (or poor DOT) -Lack of information -Non-availability of free drugs -Adverse drug reactions -Social and economic barriers -Malabsorption -Substance abuse disorders

DIAGNOSIS OF M(X)DR TB
Drug Resistant TB

HAINS TEST

BACTEC MGIT 960

GeneXpert Clinical Radiological Molecular

Rapid MDR Screen

Bacteriological C/S or DST

Least reliable

Less reliable

Gold Standard

How Is Tuberculosis Diagnosed?

Pulmonary TB:
SPUTUM

AFB smear

EP TB: Other Body

Fluids
Patients of TB are diagnosed with the help of microscopic examination of Sputum, body fluids or tissue samples for mycobacteria. A specimen of body fluids or tissue samples is spread on a slide (smear) and stained by Ziehl-Nielsen method

AFB (shown in red) are tubercle bacilli

AFB SMEAR

Inexpensive Rapid (1 day) Specific (99%) Less Sensitive (50-60%)

LOW SENSITIVITY

Mycobacterial Cultures

GOLD STANDARD LJ: Takes Long Time

Colonies of M. tuberculosis growing on media

Culture

media
960

Solid media (Lowenstein-Jensen media) 6-8 Weeks Liquid media (BACTEC CULTURE) MGIT

RAPID TB Culture- MGIT 960

Use to confirm diagnosis of TB Results in 10 to 14 days when liquid medium systems used (BACTEC CULTURE: MGIT 960)

Sensitivity of Diagnostic tests

Microscopy: 1,00,000 bacilli per ml LJ culture: 100-1000 bacilli per ml BACTEC CULTURE MGIT 960: 10-100 bacilli per ml TB PCR: <10 bacilli per ml

TIME TO DIAGNOSIS IN MDR TB

Diagnosis of MDR / XDR TB

Limitations of Culture technique

Difficult to implement in the field

Dedicated and trained staff required

Use of different media by different labs Prolonged period for getting results

Molecular Diagnostic Tests For Tuberculosis

Nucleic Acid Based Tests- NAAT: Nucleic Acid Amplification Tests

TB PCR (POLYMERASE CHAIN REACTION)

The key advantages are speed, sensitivity & specificity

It is a rapid method; (within 24 hours).

It is a very sensitive method (less than 10 bacilli per ml of the specimen).

Culture: MGIT 960 Bactec culture. Molecular techniques: Detection of MTB:- GeneXpert MTB/RIF.

HAINS Test

Alternative method of grouping anti-TB agents

Grouping Group 1: First-line oral anti-TB agents Group 2: Injectable anti-TB agents Drugs Isoniazid (H); Rifampicin (R); Ethambutol (E); Pyrazinamide (Z) Streptomycin (S); Kanamycin (Km); Amikacin (Am); Capreomycin (Cm); Viomycin (Vm).

Group 3: Fluoroquinolones

Ciprofloxacin (Cfx); Ofloxacin (Ofx); Levofloxacin (Lvx); Moxifloxacin (Mfx); Gatifloxacin (Gfx)
Ethionamide (Eto); Prothionamide (Pto); Cycloserine (Cs); Terizadone (Trd); para-aminosalicylic acid (PAS) Clofazimine (Cfz); Linezolid (Lzd); Amoxicillin/Clavulanate (Amx/Clv); thioacetazone (Thz); imipenem/cilastatin (Ipm/Cln); high-dose isoniazid (high-dose H); Clarithromycin (Clr)

Group 4: Oral second-line anti-TB agents

Group 5: Agents with unclear efficacy (not recommended by WHO for routine use in MDR-TB patients)

MDR-TB MANAGEMENT
1. Standardized

RNTCP CATEGORY IV REGIMEN: 6 (9) Km Ofx (Lvx)

Eto Cs Z E / 18 Ofx (Lvx)Eto Cs ET

2. Individualized

Dosage and weight band recommendations

S.No 1. 2. Drugs Kanamycin Ofloxacin (Levofloxacin) 16-25 Kgs 500 mg 400 mg (200 mg) 26-45 Kgs 500 mg 600 mg (500 mg) >45 Kgs 750 mg 800 mg (750 mg)

3.
4. 5. 6. 7.

Ethionamide
Ethambutol Pyrazinamide Cycloserine PAS (80% Bioavailability)

375 mg
400 mg 500 mg 250 mg 5 gm

500 mg
800 mg 1250 mg 500 mg 10 gm

750 mg
1000 mg 1500 mg 750 mg 12 gm

Adverse effects of drugs

1.

2.
3. 4. 5. 6. 7. 8.

9.
10. 11.

Gastro-intestinal symptoms (nausea and vomiting) Giddiness Ocular toxicity Renal toxicity Arthralgia Cutaneous reactions Hepatitis Neurological symptoms Psychiatric disturbances Vestibulo-auditory disturbances Hypothyroidism

Outcomes of MDR-TB treatment For MDR-TB patients started on treatment in 2008*

100%

80%

60%

40%

20%

0%

Kazakhstan (2268)

Turkey (263)

Uzbekistan (294)

Ecuador (210)

Georgia (417)

Democratic Republic of the Congo (202)

Philippines (520)

Namibia (221)

Russian Federation (1537)

Brazil (444)

Kyrgyzstan (262)

Republic of Moldova (522)

South Africa (4383)

Romania (816)

Success

Died

Failed

Defaulted

Not evaluated

* In countries reporting outcomes for >200 MDR-TB cases with <20% unevaluated (cohort size shown below country names)

MDR-TB with HIV co-infection

CD 4 Cell count ART Recommendation Timing of ART in relation to treatment for MDR TB

350 cells/mm3

Recommend ART

After 2 weeks, as soon as the treatment for MDR TB is tolerated Re-evaluate patient monthly for consideration of ART. CD4 testing is recommended every 3 months during treatment for MDR TB
After 2 weeks, as soon as the treatment for MDR TB is tolerated

> 350 cells/mm3

Defer ART

Not available

Recommend ART

XDR-TB
May 2006 Partners Meeting, Atlanta, Georgia, USA XDR-TB with HIV in Tugela Ferry, KwaZulu- Natal Province, South Africa August 2006 Neel Gandhi of Albert Einstein College of Medicine of Yeshiva University at XVI International AIDS Conference in Toronto, 1539 Patients 221 had MDR TB 53 of these had XDR-TB 52 of 53 patients died within 25 days 44 were HIV Positive
Ref: Gandhi NR et al; Extensively Drug Resistant Tuberculosis as a cause of death in patients co-infected with tuberculosis & HIV in rural area of South Africa; Lancet 2006,368;1575-80

XDR-TB
Place of Study Year of Study No. of MDR TB strains tested 83 43 113 No. of XDR resistant strains (%) 8 (14.3) 3 (10.3) 4% 12 (10.9) References Italy Germany France Iran 1993-2004 1993-2004 2006 2006 Migliori GB, et al. Migliori GB, et al. Bouvet E., et al. Masjedi MR, et al.

Hong Kong
Industrialsed nations Eastern Europe and Russia Republic of Korea India India India India India India Delhi, India

2004
2000-04 2000-04

75
821 406

9 (12.01)
53 (6.5) 56 (13.6)

Kam K.M., et al.

Shah SN, et al. Shah SN, et al.

2000-04 2006 2008 2007 2007 2009 2009 2011

1298 68 12 326 66 211 216 223

200 (15.4) 5 (7.3) 4 (33.3) 36 (11) 1 (1.5) 5 (2.4) 7 (3.1) 45 (20.17)

Shah SN, et al. Mondal R, et al. Singh S, et al. Jain S, et al. Thomas A, et al. Sharma SK, et al. Ramachandran R, et al. Myneedu V.P., et al.

Source: Indian Journal of Tuberculosis, TAI, Apr.2011

XDR-TB

Predominant Reasons for resistance

Primarily due to poorly managed TB programme Incorrect drug prescribing practices Poor quality of drugs Erratic supply of drugs Non adherence to treatment by patients

XDR-TB - Diagnosis

Culture & Sensitivity of M.TB - Gold standard

Resistance to First Line Drugs

Resistance to Second Line Drugs Good History of Chemotherapy of Anti-TB Drugs

Serial X-rays of Chest

Countries that had reported at least one XDR-TB case by Oct 2011

Argentina Armenia Australia Austria Azerbaijan Bangladesh Belarus Belgium Benin Botswana Brazil

Burkina Faso Bhutan Cambodia Canada Chile China Colombia Czech Republic Dominican Republic Ecuador Egypt

Estonia Japan France Kazakhstan Georgia Kenya Germany Kyrgyzstan Greece Latvia India Lesotho Indonesia Lithuania Iran (Islamic Rep. of) Mexico Ireland Mongolia Israel Mozambique Italy Myanmar

Namibia Nepal Netherlands Niger Norway Pakistan Peru Philippines Poland Portugal Qatar

Republic of Korea Republic of Moldova Romania Russian Federation Slovenia South Africa Spain Swaziland Sweden Tajikistan Thailand

The Former Yugoslav Republic of Macedonia Togo Tunisia Turkey Ukraine United Arab Emirates United Kingdom United Republic of Tanzania United States of America Uzbekistan Viet Nam

TIME TO DIAGNOSIS IN XDR TB

XDR-TB REGIMENS

Intensive Phase (6-12 months7 drugs Capreomycin (Cm), PAS, Moxifloxacin (Mfx), High dose-INH, Clofazimine, Linezolid, and Amoxyclav The Continuation Phase (18 months) 6 drugs PAS, Moxifloxacin (Mfx), High dose-INH, Clofazimine, Linezolid, and Amoxyclav RNTCP Regimen for XDR TB: 6-12 Cm, PAS, Mfx, High dose-H, Cfz, Lzd, Amx/Clv /18 PAS, Mfx, High dose-H, Cfz, Lzd, Amx/Clv [Reserve/Substitute drugs: Clarithromycin, Thiacetazone]

Regimen for XDR TB dosage and weight band recommendations

DRUGS Inj. Capreomycin (Cm) PAS Moxifloxacin (Mfx) High dose INH (High dose-H) DOSAGE / DAY <45Kg 750 mg 10 gm 400 mg 600 mg >45Kg 1000 mg 12 gm 400 mg 900 mg

Clofazimine (Cfz)
Linezolid (Lzd) Amoxyclav(Amx/Clv) Pyridoxine Reserve/Substitute drugs Clarithromycin (Clr) Thiacetazone (Thz) #

200 mg
600 mg 875/125 mg BD 100 mg

200 mg
600 mg 875/125 mg BD 100 mg

500 mg BD 150 mg

500 mg BD 150 mg

# Depending on availability, not to be given to HIV positive cases

XDR-TB
Korean Study

155 patients

18 (12%) had MDR TB 81 (52%) had previously received treatment with first-line drugs 56 (36%) had received treatment with second-line drugs. 27 (17%) had extensively drug-resistant (XDR) TB at the start of treatment.

102 patients (66%) were cured or completed therapy Surgical resection was performed more frequently for patients with XDR-TB than for those with non-XDR MDR TB (48% vs. 17%)

Ref: Kwon Y.S., Kim Y.H.,Suh G.Y. et al; Treatment Outcomes for HIV-Uninfected Patients with MultidrugResistant and Extensively Drug-Resistant Tuberculosis, Clin.Infect.Dis 2008; 47:496-5021

XDR-TB

XDR-TB is not a Death Sentence

Carole Mitnick, Harvard Medical School,2008

Peru 1999-2002

810 patients on individualized drug treatment Surgery Adverse event Management Nutritional support Psychological support 48 patients XDR-TB but HIV Negative 603 patients were MDR TB

Additional services

Received treatment at home at community based settings

Outcome of Treatment

60.4% of XDR-TB cured 66.3% of MDR TB cured

Ref: Minick C.D.,Shin S.S.,Seung K.J. et al; Comprehensive Treatment of Extensively Drug Resistant Tuberculosis; New Eng. J. Med.; 2008,359;563-74

XDR-TB - Diagnosis

Why XDR-TB is of Prime Importance

Due to increasing no. of HIV cases High mortality High infectivity Poor outcome of treatment Exorbitant cost of drugs

High in resource crunch places

High in poor developing countries

XDR-TB
Challenges

Health System Related

Absence of Data on drug resistance against second line drugs Daily DOTS for 2 year Large and unorganized private sector Lack of faith in Public sector Health Programmes Low priority for carrying out Public Health Programmes

Private Practitioner Related

Patient Related

Holding patients to defined geographical area for 2 year Lack of trust in the quality of care provided by Public Sector Issues of stigma and confidentiality

XDR-TB
Operational Problems

Setting up Proper linkages with peripheral DOTS Centres Managing severe adverse drug reactions in field conditions Lack of ready access to specialized lab facilities Arranging proper training to Medical, Laboratory and Non Medical workers for DOTS Plus programme

XDR-TB - Diagnosis
XDR-TB grave public health threat

Preventive Measures

Strengthen basic TB care to prevent the emergence of drug-resistance Ensure prompt diagnosis and treatment of drug resistant cases to cure existing cases and prevent further transmission Increase collaboration between HIV and TB control programmes to provide necessary prevention and care to co-infected patients Increase investment in laboratory infrastructures to enable better detection and management of resistant cases.

XDR-TB
Points to Ponder

Large diseased population Multiplicity of Health Units Over the counter availability of anti TB drugs Amplification of Resistance Quality Labs in India Specialized centre for treatment HIV Infection

Diagnosis of tuberculosis

Latent Infection

Active tuberculosis
AFB Smear examination

TST or Mantoux

Solid and liquid culture

Identification Susceptibility testing methods

IFN-/IGRA techniques TB feron Test T-SPOT TB Test

Molecular methods -Detection of MTB

-Detection of resistance

GeneXpert MTB/RIF HAINS MDR / XDR TB

TB & M(X)DR TB as per WHO endorsement

Relevance for HIV/TB or Pulmonary sputum Positive TB or Failure cases: Importance of a) early diagnosis & care; b) smear-positive TB, c) rapid MDR/XDR detection Year
Before 2007
2007

Technology
ZN microscopy Solid Culture Liquid Culture Rapid speciation Line Probe Assay (1st line, Rif & INH)

Turnaround time
2-3 days 30-60 days 15-30 days

Sensitivity gain
Baseline
+10% compared to LJ At this time for S+ only

2010

2-4 days

2011 GeneXpert MTB/RIF

1-2 Days

Sputum Negative

39

Conclusions..
Even if most TB patients in the world are not drugresistant, they present a formidable challenge to global TB control. Treatment of MDR-TB is longer, more complicated and less effective than for drug-susceptible TB. Most programmes in the world recruit small numbers of patients and successful outcome is achieved in <75% of individuals overall, the threshold envisaged for 2015 by the Global Plan.

Conclusions
Coverage of DST for TB patients remains low and resultantly a minority of drug-resistant TB patients are detected and notified. Information remains incomplete. To reach the Global Plan targets, substantial resource mobilization will be needed, both from domestic and from external sources. The price of treating a patient needs to be reduced.

Global coverage of drug resistance surveillance data

The boundaries and names shown and the designations used on this map do not imply the expression of any opinion whatsoever on the part of the World Health Organization concerning the legal status of any country, territory, city or area or of its authorities, or concerning the delimitation of its frontiers or boundaries. Dotted lines on maps represent approximate border lines for which there may not yet be full agreement. WHO 2011. All rights reserved

Looking to the Future

Overall goal of DOTS Plus strategy to reduce morbidity, mortality from MDR TB and cut the chain of transmission

New and Emerging best medical practices to supplement DOTS Plus

Evolving better, safer and effective services delivery WHO Target- To eliminate Tuberculosis by 2050

THANK YOU