MDR and XDR TB Challenges to TB Control

1
MDR and XDR - TB Challenges to TB Control

• Dr Sarabjit Chadha
• WHO Consultant-RNTCP
• Central TB Division, Nirman Bhavan, New Delhi

2
Challenges to TB Control

• Wide variations in capacity of Health Systems
  across the country
• Burden due to TB-HIV Co-infection
• Ensuring adherence of treatment for migratory
  population
• Large and unregulated Private Sector
• Limited availability of new rapid diagnostic
  tools, drugs and vaccine
• Drug Resistance

3
Causes of Drug resistance

• Microbial As a result of genetic mutation
• Caused by random chromosomal mutations at
  predictable frequencies (?1 H resistant bacilli
  in 106, R 1 in 108, HR 1 in 1014)
• Essentially drug resistance is a man made
  phenomenon

4
4th Global Project on Anti-TB Drug Resistance
Surveillance
2002-2006 138 settings surveyed in 114 countries

• Global Estimate of MDR-TB
• 489,139 (110,132)
• (95 CI, 455,093 614,215) incident cases
• in 2006
• 4.8 (4.9)
• (95 CI, 4.6 6.0) of all
• TB cases notified in 2006

5
Three countries bear majority of global MDR-TB
burden
6
Drug resistance in India

• The level of drug resistance among new cases is
  an epidemiological indicator to
• assess the success of the TB control programme
• efficacy of the treatment regimens
• State representative surveillance data of DR
  among TB patients undertaken
• DRS survey completed in Gujarat and Maharashtra
  (2005-06) (Results)
• Review of studies with representative samples do
  not indicate any increase in the prevalence of DR
  over the years
• To further substantiate the results from Gujarat
  and Maharashtra DRS surveys undertaken in Andhra
  Pradesh and Western UP and Orissa

7
Many failures are due to failure to take the
treatmentand not failure of the treatment
8
Extensively drug resistant tuberculosis (XDR-TB)
9
(No Transcript)
10
Extensively drug resistant tuberculosis (XDR-TB)

• Sub-class of MDR-TB
• XDR-TB was first described in March 2006
  following a joint survey of WHO Supra-National
  Reference Laboratories by the WHO and CDC
• 17690 isolates tested from 49 countries
• 20 MDR-TB and 2 XDR-TB
• Resistance to INH, Rifampicin and 3 out of 6
  classes of SLDs
• Definition as of Oct 2006 resistance to
• at least INH and Rifampicin (i.e. MDR-TB), and
• any fluoroquinolone, and
• to at least one of the three injectable drugs
  (capreomycin, kanamycin and amikacin)

11
(N41)

• XDR TB found to exist in all regions of the
  world
• Extent and magnitude of this problem is yet to
  be determined due to lack of quality-assured
  labs which can conduct DST for Second line drugs
• Regardless of HIV status, XDR-TB is extremely
  difficult to treat, and poor treatment outcomes
  are expected

12
XDR-TB in India

• Very little data available on resistance to SLD
• In a non-representative sample, 1 XDR-TB case
  identified from 66 MDR-TB (May 1999 - Dec 2003),
  and 2 developed XDR-TB during treatment (TRC
  study)1
• XDR-TB also reported from Hinduja Hospital
  Mumbai, KGMU Lucknow and AIIMS Delhi from highly
  selected clinical samples issues around QA of
  DST results, especially for SLDs

1 A Thomas, R Ramachandran, F Rehaman, et al.
Management of MDR-TB in the field Tuberculosis
Research Centre Experience. Indian J Tuberc 2007
54 117-124.
13
Causes of emergence and potential threat of
XDR-TB

• Like all forms of drug-resistant tuberculosis,
  XDR-TB is human-made
• MDR-TB can be amplified into XDR-TB by
• Inadequate/interrupted treatment with second line
  anti-TB drugs
• Indiscriminate use of second-line drugs
• Non-adherence to national and/or international
  guidelines
• Wide-spread availability of SLDs
• Increasing use of fluoroquinolones in combination
  with standard first-line drugs esp. in new cases
  outside RNTCP
• Weak systems to ensure standardized regimens and
  treatment adherence for MDR-TB outside RNTCP

14
RNTCP response to MDR-TB and XDR-TB
15
RNTCP response .1

• MDR-TB prevention through sustained high quality
• DOTS implementation by all providers in the
  public
• and private sector
• This can be achieved by
• Ensuring accurate categorization and quality DOT
  
• Reducing initial default and default
• Improving reach of DOTS services
• PPM activities and uptake of DOTS by private
  sector and medical colleges
• Advocacy for DOTS in other sectors
• Promote the endorsement and application of the
  International Standards of TB Care through the
  IMA and other professional societies
• Promote good Air-borne Infection Control
  Practices

16
RNTCP response ....2

• Improve laboratory capacity for diagnosing
• MDR-TB
• Establish nation-wide RNTCP-accredited
  intermediate reference laboratory (IRL) network
  for culture and drug susceptibility testing (DST)
• Establishing nation-wide network of 25 RNTCP
  accredited state-level IRLs
• Accrediting existing medical college laboratories
  
• Contracting CDST services from labs in pvt.
  sector
• Ensure availability of trained microbiologists
  and laboratory technicians
• Promote and facilitate the accreditation of
  medical colleges to conduct quality-assured
  culture and DST

17
RNTCP response 3

• Prevention of XDR-TB by effective management of
  MDR-TB
• Create nation-wide network of 25 DOTS-Plus
  sites, liked to a network of accredited
  laboratories
• capable of enrolling, providing care and
  management for at least 5,000 new MDR-TB cases
  each year
• Ensure a stable supply of quality assured SLDs to
  all RNTCP DOTS-Plus sites
• Management of MDR TB as per DOTS Plus guidelines
• Consensus statement for management of MDR-TB
  outside RNTCP developed

18
RNTCP response .4

• Evaluate extent of threat of SLD resistance
  and XDR-TB
• Capacity building of NRLs to undertake SLD DST
• Second-line DST of all MDR-TB patients from
  DOTS-Plus sites (Gujarat and Maharashtra)
• Surveillance for SLD resistance levels is being
  conducted on isolates collected from Gujarat
  (2005-06) and Maharashtra (2005-06) drug
  resistance surveys
• Plan for a rapid case-control study of XDR-TB
  cases identified from the Gujarat DRS survey, to
  evaluate causes of XDR-TB

19
RNTCP response. 5

• Review the supply and availability of SLDs and
• address their irrational and indiscriminate use
  (study)
• A survey of the availability, supply and use of
  second-line drugs for TB treatment
• Highlight the challenge of XDR-TB and discuss
  options for XDR-TB prevention with National and
  State officials at all potential forums.
• Promote rational use of second line anti-TB drugs
  by an appropriate regulatory mechanism, supported
  by professional associations
• Development and introduction of a system of
  notification of MDR-TB patients who require
  treatment with second-line anti-TB drugs
• Wide dissemination of the Consensus statement

20
DOTS-Plus Management of MDR TB under RNTCP
21
MDR-TB and DOTS-Plus 1

• 5 areas defined under DOTS-Plus Framework
• Political, administrative commitment
  co-ordination
• Laboratory aspects - accurate, timely diagnosis
  through quality assured culture and drug
  susceptibility testing
• Treatment strategy - appropriate treatment
  utilizing second-line drugs under strict
  supervision
• Uninterrupted supply of quality assured anti-TB
  drugs
• Information systems and data management

22
MDR-TB and DOTS-Plus..2

• Political administrative commitment
  co-ordination
• DOTS-Plus activities approved under RNTCP Phase
  II PIP (2006-11)
• Adequate funds and additional support for
  infrastructure and HR provided
• National DOTS-Plus Committee formed (2005)
• DOTS Plus guidelines developed (2006)
  (ww.tbcindia.org)
• RNTCP DOTS-Plus training modules developed (2006)
• For disseminating operational and clinical
  protocols to ensure consistency
• State level DOTS-Plus committees
• To develop, implement and monitor the State
  DOTS-Plus operational plan consistent with the
  National guidelines

23
MDR-TB and DOTS-Plus..3

• Laboratory aspects
• Establishment of Intermediate Reference
  Laboratories (IRLs)
• At least one state level quality assured culture
  and DST lab in each large state
• Facilities for culture of M. tuberculosis on L-J
  media
• Facilities for DST for H, R , S and E
• Accreditation and Annual Proficiency testing by
  the National Reference Laboratories (NTI, TRC,
  LRS and JALMA)
• Identification and referral of MDR-TB suspects
  for culture and DST
• MDR-TB suspects defined as Category II cases
  who remain smear positive after 4 months of
  treatment or later

24
Patient flow .Diagnosis
MDR TB Suspect identified and referred by MO-PHI
to DTO
DTO confirms suspect and sends Patient/sputum to
IRL for culture and DST
Patient returns to continue Cat-II treatment
Results of culture and DST communicated to DTO by
IRL
Not an MDR (continue Cat-II)
MDR
Patient referred by the DTO to DOTS PLUS Site for
evaluation and initiation of treatment
25
MDR-TB and DOTS-Plus4

• Treatment strategy
• Confirmed MDR-TB cases referred to State level
  DOTS-Plus Site
• Specialized centre with in-door facility
• Availability of trained man-power
• DOTS-Plus site Committee responsible for
• evaluation and initiation of treatment
• monitoring and follow up of the patients
• drugs and logistics
• recording and reporting
• Initial hospitalization (preferable) at DOTS-
  Plus site for evaluation and treatment initiation
  

26
Patient flow . Treatment and follow up
DOTS Plus Site MDR TB Case admitted for
evaluation and treatment initiation
Patient discharged to the home district with
information to DTO
Daily DOT continued by a trained DOT Provider

• Follow up Protocol
• Smear and Culture monthly during IP and Quarterly
  during CP
• Physical evaluation monthly during IP and
  Quarterly during CP by the DTO
• KFT and other investigations at regular
  intervals

27
MDR-TB and DOTS-Plus4 (Contd..)

• Treatment regimen
• Standardised regimen
• Two weight bands ( 45 Kg and gt 45 Kgs)
• Intensive phase of 6(9) months
• Km (6 days/wk) / Ofx / Cs / Eto / E / Z
• Continuation phase of 18 months
• Ofx / Cs / Eto / E
• Daily directly observed treatment
• Standardized follow up schedule (table)
• Smear and Culture monthly during IP and Quarterly
  during CP
• Physical evaluation monthly during IP and
  Quarterly during CP by the DTO
• KFT and other necessary investigations at regular
  intervals
• Detailed protocol for monitoring and management
  of adverse reactions
• Challenges
• Daily DOT for 24-27 months (Injectables for 6-9
  months)
• SLDs are toxic hence require frequent follow up
• Poorer response to treatment

28
MDR-TB and DOTS-Plus5

• Uninterrupted supply of quality assured 2nd line
  drugs (SLDs)
• SLDs procured at National Level and supplied to
  the DOTS-Plus sites
• Ancillary drugs, if required, to be provided by
  the State
• Challenges
• SLD treatment over 300 times more expensive than
  the 1st line treatment (Average cost of Rx is
  120,000)
• Global production of quality assured drugs is
  limited
• Shorter shelf life of SLDs

29
MDR-TB and DOTS-Plus ..6

• Information system and data management
• Electronic HMIS being established
• Records and Reports
• DOTS Plus-TB Register, Lab Register and Treatment
  Card
• Quarterly reports on Case Finding, Culture
  Conversion and Treatment Outcome
• Six Monthly Interim or preliminary report on
  outcome
• Drug and lab consumables
• All patients initiated on treatment will be
  accounted for outcomes
• Project monitoring and evaluation
• Supervision and regular monitoring of activities

30
RNTCP Status and Plan

• DOTS Plus services initiated in Gujarat and
  Maharshtra in 2007
• 2008 Expand it to 7 more states in 2008 (AP,
  Haryana, Kerala, Rajasthan, WB, Delhi and TN)
• By 2010, to have a network of at least 24
  DOTS-Plus sites across the country , linked to a
  network of accredited state level culture and DST
  laboratories, capable of enrolling at least 5,000
  new MDR-TB cases annually

31
Summary

• Prevention of MDR-TB and XDR TB through the
  provision of quality DOTS services remains the
  core focus of RNTCP
• To address the existing MDR-TB burden, RNTCP has
  introduced quality assured diagnostic and
  standardized treatment services for MDR-TB which
  will be scaled up in a phased manner across the
  country
• Promoting the rational use of second line drugs

32
Ensuring adherence to a full course of treatment
is the key to curing TB patients and preventing
the emergence of drug resistance (Stop TB
strategy 2006)
33
Thank You
34
A wife mentioned to her husband that for her
birthday,she would like something that
accelerates from 0 to 100 in four seconds. She
was expecting something like this............
A wife mentioned to her husband that for her
birthday, she would like something that
accelerates from 0 to 100 in four seconds. She
was expecting something like this............
35
Guess what her husband presented her on her
birthday.????????
36
The husband is in a critical but stable
condition!!!!
37
DRS Results -Gujarat
DRS Results -Maharashtra
(Go Back)
38
SLD market in India estimated at USD 8M

• 2nd line drugs
• Led by Macleods (1) and Lupin (2)
• Mainly a private sector market
• Growth between 2005 and 2006 driven by an
  increased use of fluoroquinolones

Value Sales of SLDs
USD millions
(Go Back)
2nd line drugs adjusted to screen out use in
other indications Note Does not include 1st line
drugs that may be used in 2nd line treatment of
patients
Source ORG-IMS stockist data RNTCP 2006 Annual
Report Interviews
39
RNTCP Plan for scale up of DOTS Plus
2007
2008
2009
2010
(Go Back)
40
Follow up schedule
No IP extension
IP extension 1 month
IP extension 2 months
IP extension 3 months

• Monthly weight
• Physician evaluation including adverse drug
  reaction monitoring every month for six months,
  then every three months for two years
• Creatinine and electrolytes monthly for 3 months,
  then every 3 months during injectable phase
• chest radiograph every six months

Go Back
41
New Smear Positive Case Detection Rate of
India Second Quarter, 2007
Cure Rate by district, India Second Quarter, 2006
gt85
gt70
80 84.9
50 - 69.9
lt80
30 49.9
lt30
Go Back