Drug Resistant TB PMDT Status and Challenges

DR ROHIT SARIN MD, DTCD, FNCCP

DIRECTOR

NATIONAL INSTITUTE OF TB & RESPIRATORY DISEASES

SRI AUROBINDO MARG : NEW DELHI

Estimated number of MDR-TB Cases, 2012*

~ 2/3 third of all cases are in 4 countries Russian Federation

46,000 (15% of global MDR burden)

India 64,000

(22% of global MDR burden)

China 59,000

(20% of global MDR burden)

* among notified TB cases

South Africa 8,100

(3% of global MDR burden)

3.6% new cases 20.2% previously

treated cases

India v/s top 12 high MDR burden countries

26%

5%

190%

30%

87%

102%

Countries that had reported at least one XDR-TB case -

2012

92 countries

9.6% MDR TB cases have XDR TB

16.5%MDR-TB cases with additional resistance to

fluoroquinolones

• India has world’s highest MDR-TB burden

• 64,000 emerging annually among notified PTB cases

•Sub-national drug resistance surveys (2005-09)

• 2.4% MDR in new, 15% MDR in previously treated cases

• 21-24% Ofx resistance, 4-7% XDR in MDR isolates

•National drug resistance survey underway

Burden of DR TB- Indian Scenario

Is MDR-TB a real threat in India?

State Proportion of MDR amongst new TB cases

Proportion of MDR amongst re-treatment TB cases

Gujarat 2.4% 17.4%

Maharashtra 2.7% 14%

Andhra Pradesh 1.8% 11.8%

State representative DRS survey- (patients at entry from Public sector microscopy centres)

Is XDR TB a real threat in India?

High XDR / pre-XDR levels out of XDR suspects undergoing Second-line Drug Susceptibility Testing at NRLs

Source: National TB Institute, Bangalore

The case of Mumbai and the

“TDR-TB outbreak” – Jan 2012

Udwadia ZF, Amale RA, Ajbani KK, Rodrigues C. Totally drug-resistant tuberculosis in India. Clin Infect Dis. 2012 Feb 15;54(4):579–81.

March 2012 – WHO and CTD took a stand:

• Such cases pose a formidable challenge to clinicians

and public health authorities

• No reliable definition beyond XDR-TB

• Improvements in the accuracy of drug susceptibility

testing to certain drugs

• Release of innovative new drugs will, however,

change this position in future.

• India turned this crisis into opportunities for

improvements in Mumbai and country wide

RNTCP PMDT Vision

Plan of PMDT service expansion

By 2012-13:

o Complete geographical coverage for PMDT services (achieved)

o DST for all smear-positive re-treatment TB cases at diagnosis (597

districts achieved)

By 2015:

o + DST for all smear negative TB (re-treatment) cases & any HIV TB case

registered under RNTCP (expected by March 2014)

By 2017:

o 120 C-DST labs being established and strengthened

o Xpert-MTB-Rif in 950 sites at districts and medical colleges across the

country

o Treat at least 40,000 MDR cases annually by 2017 (120 DR TB Centers)

o Treat ~ 160,000 MDR-TB & ~4,100 XDR-TB cases over next 5 yrs (2012-17)

District wise coverage of RNTCP

PMDT services under various

MDR-TB suspect criteria by districts

–Feb 2014

CRITERIA A 107

CRITERIA B 151

CRITERIA C 446

PMDT Diagnostic Services

Status & Update

Technology used to diagnose MDR-TB by districts –Feb

2014

LPA 428

CBNAAT 208

A&N Islands

Arunachal Pradesh

Chandigarh

D&N Haveli

Daman & Diu

Goa

Karnataka

Lakshadweep

Meghalaya

Mizoram

Nagaland

Pondicherry

Sikkim

Tripura

Haryana

Delhi

Gujarat

Andhra Pradesh

Assam

Manipur

Punjab

Kerala

West Bengal

Jammu & Kashmir

Himachal Pradesh

Rajasthan

Maharashtra

Tamil Nadu

Orissa

Madhya Pradesh

Chhatisgarh

Uttar Pradesh

Uttaranchal

Jharkhand

Bihar

TRC

HARYANANDTC

AIIMS-2

RNTCP Culture & DST Labs Network

(January, 2014)

LRS

NTI

JALMA

Med Col / NGO / Private Labs (Certified)

IRL (Certified )

IRL (Under Process)

Med Col / NGO / Private Labs (Under Process)

National Reference Labs

Gurgaon

By Technology - Solid Culture: 37 - LPA: 43 - Liquid Culture:14 - CB-NAAT : 80

C-DST Labs - 54 SLDST - 6 (3 NRLs and 2 IRL, 1-NGO)

CB-NAAT Sites

RNTCP Policy on CB-NAAT

• Use of CB-NAAT endorsed as a rapid molecular diagnostic tool

in following programmatic situations:

o For Diagnosis of Rif Resistance – MDR TB Suspects (A,B,C)

o For MTB positive results –

• Treat as per RNTCP guidelines

o For Rif Resistance results

• Re-treatment cases – Treat with MDR TB Regimen

• New cases – Re-confirm with LPA (LC/Solid in S-ve cases) and Treat

with MDR TB Regimen after confirming Rif Resistance

o For CB NAAT results from private sector

• For TB (acceptable if QA – Re-calibration of machine done annually)

• For R resistant results in new cases - re-confirm with

o LPA in S+ve cases or

o Liquid/Solid C-DST in S-ve Cases

RNTCP TB Xpert Project

supported by WHO, STOP TB Partnership,

UNITAID & USAID

• Under this project, 40 CB-NAAT machines and cartridges

are provided to the country to scale-up rapid molecular

diagnosis of TB and Rif resistance (MDR-TB)

• Innovate to engage private sector through public-private

mix (PPM) initiatives to improve access to rapid testing of

patients who attend both public and private sector

A&N Islands

Arunachal Pradesh

Chandigarh

D&N Haveli

Daman & Diu

Goa

Karnataka

Lakshadweep

Meghalaya

Mizoram

Nagaland

Pondicherry

Sikkim

Tripura

Haryana

Delhi

Gujarat

Andhra Pradesh

Assam

Manipur

Punjab

Kerala

West Bengal

Jammu & Kashmir

Himachal Pradesh

Rajasthan

Maharashtra

Tamil Nadu

Orissa

Madhya Pradesh

Chhatisgarh

Uttar Pradesh

Uttaranchal

Jharkhand

Bihar

TB Xpert Project Sites

X – Decentralized DST

P – PPM X

X

P

X

X

X

X

X

P

P

P

P

P

P

P

P

P

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X

X X

X

X

X

X

• GoI - place 10 urban site machines in Govt. institutes

• Advocacy to have PPM • All 40 sites innovate for PPM

models

TBXpert Project – Facility Reporting Sheet

All 40 sites to report on…

A. Number of patients referred from Private providers

B. Of A, Number of new and relapse cases detected with

MTB positive and Rif sensitive / indeterminate

C. Of A, Number of Rif resistant cases detected

D. Number of new cases with Rif Resistance sent to RNTCP

certified lab for re-confirmation

E. Of D, number re-confirmed

Second Line DST – Scale up Plan

• Existing SLDST – 7 Labs

• SL DST Proficiency Testing to be completed o In the 37 planned labs

• By 2Q 2014 –7 Labs JALMA Agra, IRLs -Hyderabad, Nagpur, Jaipur,

Delhi, Ajmer and JJ Mumbai )

• By 2014 – 13, IRLs-Pune, Bangalore, Cuttack, Puducherry, Karnal,

Chennai, Guwahati, Kolkata, Indore , Lucknow, PGI Chandigarh, GMC

Jamnagar, AIIMS New Delhi

• By 2015 – 16 IRL- Patiala, Agra, Raipur, Ranchi, Indore, Patna, GMC

Silliguri, RMRC Bhubaneswar, BMHRC-Bhopal, GMC-Vishakhapatnam,

BHU-Varanasi, KIMS- Hubli, Bhagalpur, Madurai, Raichur, Jodhpur

o Extended to private labs already certified by RNTCP for FLD

Priorities for lab strengthening

• Optimally utilize all existing technology for

diagnosis (LPA and CB-NAAT )and follow-up culture

(Solid and Liquid)

• Expedite the development and proficiency testing

for liquid culture

• Rapid Implementation of NIKSHAY PMDT module at

all laboratories

Innovative PPM initiatives to increase access

• Initiative for Promoting Affordable, Quality TB Tests (IPAQT) is a consortium of 50 private diagnostic laboratories

• Established agreements with Cepheid Inc, Hain LifeScience and Becton Dickenson to allow access to concessional prices for Xpert MTB/RIF, first-line line probe assays, and

liquid culture in the private sector

• Participating laboratories need to be accredited to assure quality; they must report confirmed cases to RNTCP; they must adhere to a ceiling price when charging patients

• Laboratories participating in IPAQT have approximately 3000 franchisee laboratories and over 10 000 specimen collection centres across India, thus increasing access to rapid, accurate and affordable diagnostics for patients seeking care in the country’s extensive private sector

Diagnostic Challenges & Solutions Deployed

Challenges

• Access to rapid molecular DST limited due to weak case finding systems and sample transport systems

• Setting up of Liquid Culture Labs – Infrastructure upgrades to BSL III & HR • Foreseeable follow up capacity crisis in most of the states on shift to Criteria C with rapid molecular tests

• Limited access to Second Line DST due to lack of systems • Lack of clarity on RNTCP policy for CB-NAAT and R&R systems

Solutions

• Streamlining systems and training to improve suspect identification, prompt sample collection & transport systems from PHIs/DMCs

• State to take the ownership • Enhance coordination to fast-track BSL III & HRD for LC labs • FU capacity enhancement through — 1 sample per follow up culture policy — Fast track application of potential labs

to reach proficiency stage with NRLs — Budget for C-DST Schemes - private

labs

• State to expedite SLD PT • Clear policy on CB-NAAT, Lab SOP & QA updated with CB-NAAT indicators

PMDT Treatment Services

Status & Challenges

Y2007 Y2008 Y2009 Y2010 Y2011 Y2012 Y2013

Sum of MDRTB cases initiated on Rx 62 190 1174 2182 3369 14146 20765

Sum of MDRTB Suspects 309 1511 8144 11001 17696 105706 181021

0

20000

40000

60000

80000

100000

120000

140000

160000

180000

200000

0

5000

10000

15000

20000

25000

DRTB Case finding effort

Sum of MDRTB cases initiated on Rx Sum of MDRTB Suspects

Cumulative data up to December 2013

MDRTB Suspects tested 325316

MDRTB Put on Rx 41860

XDR TB Put on Treatment 490

Analysis of reasons of not initiating

lab confirmed MDR TB cases on treatment

Consolidated data for 1Q12

131, 5% 163, 6%

98, 4%

37, 1%

173, 7%

234, 9%

1819, 68%

Died

Referred

Not willing for Rx

Not traced

Being traced

PreRx eval

On MDR Rx

N = 2625

Interim 12 month outcomes

(latest 4 quarters 2Q11-1Q12)

Patients registered

Culture negative

Culture Positive

Culture not known

Death Default

4670 2392 (51%) 432 (9%) 517 (11%) 695 (15%) 597 (13%)

Patients registered

Success Rate

Failure Death Default

3606 1738 (48%) 263 (7%) 773 (21%) 708 (20%)

Treatment outcomes – Latest 4 Cohorts (2010)

• High level of second line drug resistance (Ofx ~ 24%) • Heavily treatment experienced cohorts • Gaps in case holding capacity

Attrition = Loss due to death, default, treatment stopped

due to any reason, failure and switched to XDR regimen

10% 9%

24%

12% 11% 11%

20% 16%

12%

17% 17% 16% 15% 19% 19%

16% 15% 17%

24%

18%

39%

19% 20% 21%

27% 25%

23%

31% 27% 27% 26% 26% 27% 27%

41%

55%

69%

54%

47%

54% 54%

44% 47%

55% 53%

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

1Q07

2Q07

3Q07

4Q07

1Q08

2Q08

3Q08

4Q08

1Q09

2Q09

3Q09

4Q09

1Q10

2Q10

3Q10

4Q10

1Q11

2Q11

3Q11

4Q11

1Q12

% loss at 6 month % loss at 12 month % loss at 24 month

Actions Required: • Review districts to address quality gaps with

indicators like • % put on Rx, • % culture not known and • % defaults

• Underperforming districts to be closely supervised and monitored

• Intensify supervision (use job-aides) and monitoring

Treatment Challenges & Solutions Deployed

Challenges

• ~ 10% loss from Dx to Rx : — Delay in treatment initiation in spite of

rapid DST — Tracing patients due to poor case

holding

• Limited DR TB Centers and bed capacity to cope with enhanced case load due to Criteria C with LPA/CB-NAAT

• Low treatment outcomes due to high interim attrition of patients – Culture Not Known, Default, Died

• Manual information management

• SLD logistic & supply chain management

Solutions

• Shift to Criteria C with LPA/CB-NAAT • CB-NAAT to offer decentralized DST and same day diagnosis • Improve DOTS, timely results and coordination

• Fast-track DR-TB Centre • Strengthen districts capacity for ambulatory PTE, ADR management • DR TB Centre Scheme in 2014

• Reinforce counseling, FU & ADR Mx •Intensify SME for improve case holding •Integrated Rx Algorithm for DR TB •Bedaquiline – controlled introduction

•NIKSHAY for PMDT in 2014

•Good packing & storage of PWBs • More Store Assist, Outsource SCM

Priorities in 2014

• Focus to enhance quality of services through intensified supervision and

monitoring

• Scaling up Second Line DST capacity across India

• Streamlining TB Notification, Lab surveillance and NIKSHAY

• Further strengthening PPM and developing Urban TB Control models

• Finalization and Dissemination of STCI & Partnership Guidelines

• Involvement of Large Corporate Hospitals under new RNTCP NGO PP

Schemes to facilitate

o TB Notification

o Sample collection centres under Private – Private partnership

o DR TB Centre

o C-DST Lab……….etc.

Thank You!