Why is this so hard? - bc.lung.ca George Comstock... · 2/25/16-Comstock Lecture 1 Global Scale-up of the Programmatic Management of MDR-TB (PMDT) ... SM, INH MDR TB XDR TB resistance

Daley: Global Scale-up of the Programmatic Management of MDR-TB (PMDT)

2/25/16-Comstock Lecture

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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)



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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



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EsEmated ProporEon of TB Cases with MDR-‐TB by WHO Region

Percentage of New TB Cases with MDR-‐TB


Percentage of Previously Treated TB Cases with MDR-‐TB




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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



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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



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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



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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



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480,000 es?mated new cases

300,000 (63%) es?mated cases among no?fied 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


DST Coverage Among TB and MDR-‐TB Cases, Globally




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ContribuEon of Public-‐Private Mix to NoEficaEons of TB Cases, 2014




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



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>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%


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



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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




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Global Progress on Use of DLM to Treat MDR-‐TB

Red – using DLM under programmatic conditions Gray – no use of DLM


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




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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


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

Documents

Why is this so hard? - bc.lung.ca George Comstock... · 2/25/16-Comstock Lecture 1 Global Scale-up of the Programmatic Management of MDR-TB (PMDT) ... SM, INH MDR TB XDR TB resistance