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Daley: Global Scale-up of the Programmatic Management of MDR-TB (PMDT)
2/25/16-Comstock Lecture
1
Global Scale-up of the Programmatic Management of MDR-TB (PMDT)
Charles L. Daley, M.D.National Jewish Health
University of Colorado Denver
Why is this so hard?
"George Comstock was a model to generations of epidemiologists, as a researcher and teacher and above all as a caring person who worked tirelessly to make the world healthier." Jonathan Samet, MD, former chair, Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health
Disclosures
• Chair, Data Monitoring Commi/ee for delamanid trials in adults (Otsuka)
• Member, Data Monitoring Commi/ee for delamanid trials in children (Otsuka)
• Chair, Data Monitoring Commi/ee for clofazimine trial (Novar?s)
Daley: Global Scale-up of the Programmatic Management of MDR-TB (PMDT)
2/25/16-Comstock Lecture
2
Global Scale Up Of PMDT
• Current Burden Of Disease • Evolu?on Of Drug-‐resistance • Evolu?on Of Global Scale-‐up of PMDT • Barriers To Scale-‐up Of PMDT
– The Gap Between Diagnosis And Treatment – Introduc?on Of New Drugs
Why is this so hard?
The Global Burden of TB
Estimated number of cases, 2014
Estimated number of deaths, 2014
1.5 million 9.6 million
480,000
All forms of TB
MulEdrug-‐resistant TB
HIV-‐associated TB 1.2 million 400,000
Source: WHO Global Tuberculosis Control Report 2015
190,000
Drug-‐resistant Tuberculosis, 2014
480,000 MDR-TB
XDR-TB 9.7%
Monoresistant TB
Polyresistant TB
9.6 million TB cases
XDR-TB: MDR plus resistance to FQNs and one of the 2nd-line injectables
MDR-TB: Resistance to at least isoniazid and rifampin
Mono-R: Resistance to one drug
Poly-R: Resistance to at least two drugs but not isoniazid and rifampin
WHO, Global Tuberculosis Report 2015
Daley: Global Scale-up of the Programmatic Management of MDR-TB (PMDT)
2/25/16-Comstock Lecture
3
WHO, Global Tuberculosis Report 2015
EsEmated ProporEon of TB Cases with MDR-‐TB by WHO Region
Percentage of New TB Cases with MDR-‐TB
WHO, Global Tuberculosis Report 2015
Percentage of Previously Treated TB Cases with MDR-‐TB
WHO, Global Tuberculosis Report 2015
Daley: Global Scale-up of the Programmatic Management of MDR-TB (PMDT)
2/25/16-Comstock Lecture
4
Countries (n=105) that NoEfied at least One Case of XDR-‐TB
9.7% of MDR-TB cases are estimated to have XDR-TB
17.0% of MDR cases resistant to FQN 30.0% of MDR cases resistant to FQN, SLI, or both
EvoluEon of Drug Resistant TB
Go back! We screwed up everything.
Pathogenesis and Transmission of Drug-‐resistant TB
M. tuberculosis
Resistant Mutants
Acquired Resistance
Primary Resistance
Mutation
Selection
Transmission HIV Inadequate infection control Diagnostic delay
Inadequate treatment
Nature
Daley: Global Scale-up of the Programmatic Management of MDR-TB (PMDT)
2/25/16-Comstock Lecture
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The Evolution of Drug Resistance
Adapted from Paul Nunn, Global Task Force on XDR TB, Geneva, 2006
Drug susceptible TB
MDR TB XDR TB SM, INH resistance
1950s 1980s 1990s 2000s
XDR TB+
EvoluEon of Global Scale-‐up of PMDT
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
Global DRS project launched
Green Light Committee established
The first WHO MDR-TB guidelines
100,000 patients approved by GLC for treatment.
New framework for the PMDT
WHO Working Group on DOTS-Plus for MDR-TB
The 1st DOTS-Plus project launched
Ministerial meeting in Beijing: "Call for Action" 62nd WHA resolution on MDR-TB
Green Light Commi^ee to New Framework for PMDT to Global Drug Resistant TB IniEaEve (GDI)
Global Drug Resistant TB Initiative
Daley: Global Scale-up of the Programmatic Management of MDR-TB (PMDT)
2/25/16-Comstock Lecture
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DecentralizaEon Establishment of Regional GLCs, 2011
6 rGLCs
1 gGLC
GDI -‐ Global Drug-‐resistant TB IniEaEve
Ultimate aim: Universal access to care and appropriate treatment for all DR−TB patients
GDI -‐ Global Drug-‐resistant TB IniEaEve
Research Advocacy DR-‐TB STAT GLI-‐GDI
Daley: Global Scale-up of the Programmatic Management of MDR-TB (PMDT)
2/25/16-Comstock Lecture
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GDI Core Group Members (1) Member ConsEtuency Represented OrganizaEon
Amy Bloom Donor/funding agency USAID
Chen-‐Yuan Chiang Technical agencies/implementa?on partners The Union
Daniela Cirillo Technical agencies/implementa?on partners St. Rafaele Hospital, Italy
Charles Daley (chair) Academic ins?tu?ons Na?onal Jewish Health, USA
Dalene von Del^ Civil society TB Proof
Agnes Gebhard (VC) Non-‐governmental sector partners KNCV
Saira Khowaja Private for profit sector Interac?ve Research and Development
Kuldeep Sachdeva Na?onal TB programs of high DR-‐TB burden countries
NTP, India
KJ Seung Technical agencies /implementa?on partners Partners in Health
Sirinappa Ji?manee Medical and nursing associa?ons Intern. Council of Nurses
GDI Core Group Members (2)
Regional Green Light Commi^ee (rGLC) Chairs
Hind Sac rGLC -‐ AFR
Raimond Armengol rGLC -‐ AMR
Essam Emoghazy rGLC -‐ EMR
Andrey Olegorich Maryandyshev rGLC -‐ EUR
Rohit Sarin rGLC -‐ SEAR
Lee B. Reichman rGLC – WPR
Observers
Tom Shinnick Global Laboratory Ini?a?ve
Joel Keravac Global Drug Facility
Global Fund
480,000 es?mated new cases
300,000 (63%) es?mated cases among no?fied TB pa?ents
123,000 (41%) no?fied MDR-‐TB pa?ents
111,000 (90%) started on treatment
>50,000 had outcomes reported
50% treatment success 25% lost or no data
Reporting/ Detection Gap
Treatment Gap
Outcome Gap
Success Gap
Diagnosis Gap
Gaps in Global MDR-TB Control
12,000 waiting
357,000 missing
50% suffering
Daley: Global Scale-up of the Programmatic Management of MDR-TB (PMDT)
2/25/16-Comstock Lecture
8
480,000 es?mated new cases
300,000 (63%) es?mated cases among no?fied TB pa?ents
123,000 (41%) no?fied MDR-‐TB pa?ents
Reporting/ Detection Gap
Diagnosis Gap
Gaps in Global MDR-TB Control Missing Cases
Includes: • No?fied cases • Diagnosed but not no?fied • Not yet diagnosed with TB
Low case detection Poor recording/reporting Lack of electronic records
Poor access/awareness Lack of diagnostics Lack of infrastructure
• In 2014, MDR-‐TB detecEon gaps were worse in the Western Pacific Region where the number of cases detected was only 19% of the noEfied cases esEmated to have MDR-‐TB
Global Trends in NoEfied Cases and EsEmated TB Cases
WHO, Global Tuberculosis Report 2015
DST Coverage Among TB and MDR-‐TB Cases, Globally
WHO, Global Tuberculosis Report 2015
Daley: Global Scale-up of the Programmatic Management of MDR-TB (PMDT)
2/25/16-Comstock Lecture
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ContribuEon of Public-‐Private Mix to NoEficaEons of TB Cases, 2014
WHO, Global Tuberculosis Report 2015
123,000 (41%) no?fied MDR-‐TB pa?ents
111,000 (90%) started on treatment
Treatment Gap
Gaps in Global MDR-TB Control Waiting for Treatment
• Lack of diagnostic/treatment algorithms • Physicians do not "trust" rapid test results • MDR-TB Treatment Committee Review • Unavailability of second-line drugs • Treatment costs are high • Treatment capacity is limited (requires
hospitalization) Patient delays and refusing therapy
Diagnosis/Treatment Gap
DST Coverage Among New Bacteriologically Confirmed Cases Enrolment on MDR-TB Treatment
Global Tuberculosis Report 2015
Daley: Global Scale-up of the Programmatic Management of MDR-TB (PMDT)
2/25/16-Comstock Lecture
10
111,000 (90%) started on treatment
>50,000 had outcomes reported
50% treatment success 25% lost or no data
Outcome Gap
Success Gap
Gaps in Global MDR-TB Control Poor Treatment Outcomes
Poor recording Lack of electronic records
Delays in diagnosis Delays in initiation of appropriate therapy Poor infrastructure Lack of human resources Weak treatment regimens Long treatment regimens Toxic treatment regimens Poor adherence (see above)
Treatment Outcomes in PaEents with MDR-‐TB, 2007-‐2012 Cohorts
50%
WHO, Global Tuberculosis Report 2015
DR-‐TB Scale-‐up Treatment AcEon Team (DR-‐TB STAT)
• An officially recognized Task Force of the GDI in July 2015 • Formed in response to "Call to Ac?on" to new drug interac?on • Mul?ple stakeholders meet monthly to review the progress of
the introduc?on of new drugs country by country • Snapshot as of August, 2015
– No. of pa?ents on BDQ – 532 – No. of pa?ents on DLM – Approximately 100
• Snapshot as of February, 2016: – No. of pa?ents on BDQ – 2306 pa?ents under program condi?ons
• Current number of BDQ orders from GDF -‐ 3795
– No. of pa?ents on DLM – 180 • Current number of DLM orders from GDF -‐ 0
Daley: Global Scale-up of the Programmatic Management of MDR-TB (PMDT)
2/25/16-Comstock Lecture
11
IntroducEon of New Drugs
• Bedaquiline (Janssen), a diarylyquinoline, received condi?on approval by the FDA in 2012 – In June 2013, the WHO recommended BDQ for
PMDT under specific condi?ons
• Delamanid (Otsuka), nitroimidazole, received condi?onal marke?ng authoriza?on by the EMA in 2014 – In October 2014, the WHO recommended DLM for
PMDT under specific condi?ons
WHO RecommendaEons for Use of Bedaquiline and Delamanid
1. The drug is used under carefully monitored condi?ons. 2. Pa?ents to receive the drug are carefully selected. 3. The drug is used as part of a World Health Organiza?on–recommended treatment regimen. 4. Pa?ents to receive the drug sign an informed consent; for delamanid, the recommenda?on is only for “due process” for informed consent. 5. Adverse events, including ac?ve pharmacovigilance, are ac?vely managed.
Furin J, et al. EID 2016
Global Progress on Use of BDQ to Treat MDR-‐TB
Blue – using BDQ under programmatic conditions Green – awaiting arrival of BDQ Gray – no use of BDQ
Furin J, et al. EID 2016
Daley: Global Scale-up of the Programmatic Management of MDR-TB (PMDT)
2/25/16-Comstock Lecture
12
Global Progress on Use of DLM to Treat MDR-‐TB
Red – using DLM under programmatic conditions Gray – no use of DLM
Furin J, et al. EID 2016
Global Drug Facility (GDF)
• The GDF is an independent, organiza?on within the Stop TB Partnership that operates a unique procurement system – Low prices – Quality control – Standardiza?on – Pool procurement – Transparency – Procurement and supply
management
Challenges in Using New Drugs Under ProgrammaEc CondiEons (10)
1. Lack of awareness of drug availability and procurement process
2. Limited availability of adequate technical exper?se 3. Confusion around WHO “requirements”, most notably
pharmacovigilance 4. Limited availability of quality clinical trials data
suppor?ng 5. Concerns that the process of new drug introduc?on is
“too complicated” under programma?c condi?ons the use of new drugs
Furin J, et al. EID 2016
Daley: Global Scale-up of the Programmatic Management of MDR-TB (PMDT)
2/25/16-Comstock Lecture
13
Challenges in Using New Drugs Under ProgrammaEc CondiEons (10) 6. Challenges in sharing rapidly changing informa?on
about new drug introduc?on with key stakeholders and incorpora?ng such informa?on into na?onal guidelines
7. Prolonged turnaround ?me for drug procurement 8. Difficul?es in import and customs clearance 9. Limited access to companion MDR-‐TB drugs, especially
linezolid and clofazimine 10. Lack of high-‐level na?onal government support
Furin J, et al. EID 2016
What Needs To Be Done?
• Find the missing pa?ents – Improve case detec?on – Improve recording and repor?ng
• Close the diagnosis/treatment gap – Improve linkage between diagnosis and treatment
• Improve treatment outcomes – Be/er drugs, be/er regimens, be/er approaches and be/er access
• Close the funding gap