TB Elimination and TB drugs: can we make it? · 2019. 12. 21. · review of data, assessment of validity of surrogate markers for MDR-TB outcome, and cost-effectiveness study In January

TB Elimination and TB drugs: can we make it?

Dr Mario Raviglione

Director, Global TB Programme

World Health Organization, Geneva, Switzerland

Photo: Riccardo Venturi

Keynote Address, Washington, DC, 2 October 2013

GLOBAL TB PROGRAMME

//upload.wikimedia.org/wikipedia/commons/5/53/Bedaquiline.svg

Overview

Quick overview of global burden of TB

Impact of interventions and progress

Is elimination possible in our lifetime?

What is needed to accelerate incidence decline?

What can be done today?

GLOBAL TB PROGRAMME

Overview






GLOBAL TB PROGRAMME

Estimated number of cases

Estimated number of deaths

1.4 million* (1.3–1.6 million)

8.7 million (8.3–9.0 million)

Up to 0.5 million

All forms of TB

Multidrug-resistant TB

HIV-associated TB 1.1 million (13%) (1.0–1.2 million)

430,000 (400,000–460,000)

Source: WHO Global Tuberculosis Report 2012 * Including deaths attributed to HIV/TB

The Global Burden of TB -2011

Unknown, but probably > 150,000

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Incidence rates, 2011

Highest rates in Africa, linked to high rates of HIV infection ~80% of HIV+ TB cases in Africa

Per 100 000 population

≥300 150–299 50–149

0–24 25–49

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Estimated number of MDR-TB Cases, 2011 2/3 of all cases are in 7 countries

Russian Federation 44,000

(14% of global MDR burden)

India 66,000


China 61,000


Philippines 11,000


Pakistan 10,000


South Africa 8,100

Based on old survey data

Ukraine 9,000

Based on old survey data

WHO 2012

GLOBAL TB PROGRAMME

Overview






GLOBAL TB PROGRAMME

The global response: Targets, Global Plan, and Stop TB Strategy

1. Pursue high-quality DOTS expansion

2. Address TB-HIV, MDR-TB, and needs of the poor and vulnerable

3. Contribute to health system

strengthening

4. Engage all care providers

5. Empower people with TB and communities

6. Enable and promote research

Goal 6: to have halted by 2015 and begun to reverse the incidence…

2015: 50% reduction in TB prevalence and deaths compared to 1990

2050: elimination (<1 case per million population)

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TB cases and deaths, 1990–2011: achievements of control efforts with available tools (absolute numbers)

Incidence Mortality

HIV-negative mortality

Mill

ion

s

Total mortality peaked early 2000s at >1.8 million 1.4 million in 2011

1.5

0 0

10

1.0

0.5

5

2.5

7.5

Peak > 9 in early 2000s 8.7 million in 2011

HIV-positive mortality

All cases

HIV-positive cases

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7.8 8.7

3.7

5.8

Global notifications Estimated incidence

TB c

ase

s (m

illio

ns)

1990 2000 2010

10

5

0

The case detection/notification gap

Nearly 3 million TB cases either not notified or not

detected

NO elimination without “capturing”

them

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Global Progress on impact

51 million patients cured, 1995-2011

20 million lives saved since 1995

2015 MDG and other international targets on track

BUT, TB incidence declining far too slowly, 1/3 of cases not in the system, MDR-TB un-tackled etc.

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Overview






GLOBAL TB PROGRAMME

Full implementation of Global Plan: 2015 MDG target reached but TB not eliminated by 2050

Current rate of decline -2%/yr

W Europe after WWII -10%/yr

China, Cambodia -4%/yr

Elimination target:<1 / million / yr -20%/yr


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-3.4%/yr -5%/yr

Incidence Prevalence

-3%/yr

-7%/yr

China

Cambodia

Sustained socio-

economic development

Stop TB Strategy with adequate resources

TB care subsidized and decentralised

Decline in TB burden in China and Cambodia

Recipe:

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GLOBAL TB PROGRAMME

Nat Rev Microbiol 2012; 10: 407–16.

-10%/year Sustained socio-economic

development

Universal health coverage & social protection

TB care widely accessible Screening of high-risk groups

(but limited impact)

Infection control practices (?)

TB incidence declined 10%/year after WWII in Europe (the Netherlands)

Recipe:

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Eskimos > 10 ; < 20

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Eskimos in Alaska, NW Canada and Greenland: 15% per year incidence decline

Highly focused & high intensity interventions

Screening and massive TLTBI

TB care decentralised

BCG vaccination

Improved health access & social protection

Economic development (?)

Recipe:

-17%/year (1955-74) -8.7%/year

(1972-74)

Grzybowski S, Styblo K, Dorken E. Tuberculosis in Eskimos. Tubercle 1976; (suppl.) 57: 1-58

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Can TB control among Eskimos be generalised to the world?

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Elimination target:<1 /million/yr -20%/yr

GLOBAL TB PROGRAMME

Overview






GLOBAL TB PROGRAMME

Economic development: better nutrition & housing Universal health coverage & social protection TB care widely accessible to all and of high-standards Focused, high-intensity interventions Screening of high-risk groups and mass TLTBI Infection control practices

However… while incidence decline can accelerate, “elimination” is

another story, as it requires major reduction of:

This translates into…new tools and increased financing

(i) transmission rate, and (ii) reactivation of latent infection among the already infected

What is needed to accelerate incidence decline and target "elimination"?

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What is in the pipelines for new diagnostics, drugs and vaccines in 2013?

Diagnostics: ₋7 new diagnostics or diagnostic methods endorsed by WHO since 2007; ₋6 in development; ₋yet no PoC test envisaged Drugs: -1 new drug approved in late 2012, but probably little impact on epidemiology; -1 new drug submitted for approval in 2013 and rejected by EMA; -a regimen and other 2-3 drugs likely to be introduced in the next 4-7 years Vaccines: ₋11 vaccines in advanced phases of ₋development; ₋1 just reported with no detectable efficacy

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Diagnostic development pipeline, 2013

Source: Stop TB Partnership Working Group on New TB Diagnostics

2-specimen approaches

7 new diagnostics or diagnostic methods approved by WHO since 2007

3 diagnostics commercially available, not yet WHO-endorsed

6 diagnostics in development

LED microscopy

Xpert MTB/RIF

Liquid culture + DST

Rapid speciation

LPA for MDR-TB

Non-commercial

culture + DST

LPA for XDR-TB

LPA for MDR-TB, 2nd generation

Manual

NAAT

Xpert 2nd

generation

Rapid colorimetric DST

REFERENCE LEVEL

INTERMEDIATE LEVEL

PERIPHERAL LEVEL

VOC detection

Enzymatic detection

Ag and Ab detection

NAAT 2nd generation

2007 2008 2009 2010 2011 2012 2013 2014 2015 2016

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Pipeline promising, but what do we need to eliminate TB? Potential impact of new diagnostics on TB incidence in S-E Asia

Sourc

e: L. A

bu R

addad e

t al, P

NA

S 2

009

•Led & NAAT at microscopy lab level

•Dipstick at point of care

To contribute to elimination of TB: 1.Rapid diagnostic test at point-of-care 2.Rapid drug susceptibility testing at point-of-care 3.As a result, possibility to treat with the proper regimen from day 1

GLOBAL TB PROGRAMME

Pipeline promising, but what do we need to eliminate TB? Potential impact of new tools on TB incidence in S-E Asia

Sourc

e: L. A

bu R

addad e

t al, P

NA

S 2

009

Add. Effects = effects also on latency

and infectiousness of cases in vaccinated

•Regimen 1 = 4-month, no effect on DR

•Regimen 2 = 2-month, 90% effective in M/XDR

•Regimen 3 = 10-day, 90% effective in M/XDR

To eliminate TB: 1.Not just a single drugs, but… 2.Very short potent regimen for all forms of TB, and 3.Simple regimen for mass chemoprophylaxis

And/Or: Mass pre- and post-exposure vaccine

Synergy of interventions ! Action on both transmission and reactivation pathways

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27 27

Ad5 Ag85A McMaster CanSino

VPM 1002 Max Planck, VPM,

TBVI

Hybrid-I + IC31

SSI, TBVI, EDCTP,

Intercell

Phase II Phase III Phase IIb

Immunotherapeutic:

Mycobacterial – whole cell

or extract

ID93 + GLA-SE IDRI, Aeras

Hyvac 4/ AERAS-404 + IC31

SSI, sanofi-pasteur, Aeras, Intercell

H56 + IC31 SSI, Aeras, Intercell

MVA85A/AERAS-485

OETC, Aeras

AERAS-402/ Crucell Ad35

Crucell, Aeras

RUTI

Archivel Farma, S.L

M. Vaccae

Anhui Longcom,

China

M72 + AS01

GSK, Aeras

MTBVAC TBVI, Zaragoza,

Biofabri

rBCG

Viral vector

Protein/adjuvant

Attenuated M.tb

Hybrid-I + CAF01

SSI, TBVI

Global TB Vaccine Pipeline 2013: good but needs to keep growing

GLOBAL TB PROGRAMME

Mass vaccination with a potent vaccine:

– pre-exposure:

– post-exposure:

Tools required for eradication in our lifetime – Vaccines : Perspectives for a potent vaccine

would prevent infection to occur, and therefore disease, but impact would take a long time to appear

would prevent “reactivation”, and would have impact on transmission as new cases will not emerge any longer out of the pool of already infected. However, it would not prevent new infection

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BCG evidence and MVA85A phase 2b trial results

Safe Showing it is feasible to test vaccine candidates in large trials, but…

No detectable efficacy

• BCG: efficacy in disseminated pediatric forms proven. Efficacy against adult contagious forms variable. Revaccination efficacy nihil or dubious

• MVA85A:

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Reality check about vaccines 1.Today we do not have a potent pre- and post-exposure vaccine, we have BCG

2.Today we do not have yet clarity about correlates of immunity and bio-markers

3.Today, we do not fully understand pathogenesis and immunity

GLOBAL TB PROGRAMME

Ideally, we need as short a regimen as possible active against all types of TB, transforming TB into a “normal” infectious disease. However, we only have “short-course chemotherapy”

Ideally, we need mass chemoprophylaxis (TLTBI), as TLTBI prevents reactivation with up to 70% efficacy. However:

Safety issue on a mass scale: fatal hepatitis

• 4.13 (95% CI 0.5-34) Risk Ratio (vs placebo) (Cochrane Review, 2010);

• 4-7/100,000 incidence (Millard PS et al. West J Med. 1996;164:486-91.)

Single dose treatment not available: no existing drug kills intracellular bacteria (such as M. tuberculosis) in a non-replicative state

Screening of truly infected or at real risk not available: no “IGRA-plus”

Tools required for eradication in our lifetime - Drugs: Do we have potent regimen for (a) treatment and (b) prevention?

GLOBAL TB PROGRAMME

New drugs: 1. Bedaquiline (BDQ) - First drug in forty years

Only data from Phase IIb trials available , further

efficacy and safety data needed from rigorously

conducted Phase III trials

On December 28, 2012, the U.S. FDA approved

BDQ

In early 2013, WHO commissioned independent

review of data, assessment of validity of

surrogate markers for MDR-TB outcome, and

cost-effectiveness study

In January 2013, WHO held an Expert Committee

meeting to get advice

In June 2013, after STAG-TB endorsement and

through publication of interim guidelines, WHO

recommended BDQ use for MDR-TB under five

strict conditions

WHO has disseminated its guidelines to all

Member States and is working on operational

manual and other guidance

GLOBAL TB PROGRAMME

Bedaquiline: Interim WHO policy guidance

BDQ may be added to a WHO-recommended regimen in adult patients with pulmonary MDR-TB, under five specific conditions:

(conditional recommendation, very low confidence in estimates of effect)

1.Treatment under close monitoring (sound protocols)

2.Proper patient selection (caution: PLHIV and >65; no: children & pregnancy)

3.Patient informed consent required

4.Treatment design based on WHO recommendations (DST, dose, never adding a single drug to a failing regimen)

5.Active pharmacovigilance (esp. cardiac, liver and renal toxicities)

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Acceleration of BDQ phase III clinical trials

Development of accurate and reproducible BDQ DST method

Prospective collection of operational data on BDQ implementation

Bedaquiline: Urgent WHO call for:

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New drugs: 2. Delamanid Negative opinion from European Medicines Agency

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Assessment of fluoroquinolone trials in early 2014

Three trials: OFLOTUB/Gatifloxacin for TB Phase III trial: gatifloxacin substituted for ethambutol – 4

months Rx - results expected end 2013

ReMox: moxifloxacin substituted for ethambutol or isoniazid – 4 months Rx - results expected early 2014

Rifaquin trial: moxifloxacin substituted for ethambutol (intensive phase), associated with rifapentine once weekly in continuation phase – presentation at CROI 2013. 4-month arm did not work

Re-purposed Drugs: A potent regimen for treatment

Novel regimens investigated by the TB Alliance including: PA824, Moxi, PZA, BDQ, CLO in various combinations (NC-001, NC-002, NC-003)

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1. WHO recommends treatment of LTBI for: • People living with HIV (PLHIV) • Children <5 contacts of a TB case • Recent TST converters

2. IPT prevents TB with around 70% efficacy

3. Isoniazid 5 mg/kg daily (max 300 mg) for at least

6 months. Other shorter regimens efficacious (12wHP, 3HR)

4. Individual benefits clear, population level less clear (40% reported)

5. Modelling shows potential, but feasibility and scale-up remain an issue

Tools required for eradication in our lifetime: do we have a potent regimen for prevention?

GLOBAL TB PROGRAMME

Number of PLHIV on IPT increased in the past few years

But…only 450,000 started on IPT out of 3.2 million people screened for TB in HIV care settings in 2011

Completion rate in various studies varies 47-94%

Concerns by providers over side effects (real) and creation of drug resistance (not substantiated)

Implementation of IPT on a large scale is a challenge even in PLHIV

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Open-label, randomized non-inferiority trial 12 weeks of 1-weekly rifapentine (P) (900 mg) + isoniazid (H) (900 mg) (DOT) vs. 9 months H

(300 mg) self-administered daily Subjects: close contacts of culture+ TB cases enrolled in USA, Canada, Brazil and Spain -

followed-up for 33 months

Active TB: 7/3986 in the 12wPH group (cumulative rate, 0.19%) vs. 15/3745 in the H group (cumulative rate, 0.43%), (rate difference: 0.24%)

PREVENT-TB Study: Methods & Outcomes

Sterling et al, NEJM, 2011

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Treatment completion rates: 82.1% in the 12wPH group vs. 69.0% in the H group (P<0.001)

Permanent drug discontinuation owing to an adverse event: 4.9% in the 12wPH group vs. 3.7% in the H group (P = 0.009)

Rates of investigator-assessed drug-related hepatotoxicity: 0.4% and 2.7%, respectively (P<0.001)

PREVENT-TB Study: Methods & Outcomes

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1. Today we do not have a potent treatment regimen that lasts <2 months and treats TB and M/XDR-TB. It will probably not be available for at least 5-10 years

2. Today we do have a treatment for latent TB infection that is 70% efficacious, but difficult to scale-up to whole population (? 2 billion infected) or even to high-risk groups

3. Today we do not have a test capable of identifying who will progress to active TB among the ?2 billion infected

Reality check about treatment and chemoprophylaxis

GLOBAL TB PROGRAMME

Overview






GLOBAL TB PROGRAMME

1. Enhance strategy and approach to TB care, control and research

2. Mobilize resources for research

3. Build full commitment

What can be done?

GLOBAL TB PROGRAMME

INTEGRATED, PATIENT-CENTRED CARE AND

PREVENTION

BOLD POLICIES

AND SUPPORTIVE

SYSTEMS

INTENSIFIED RESEARCH

AND INNOVATION

Post-2015 Global TB Strategy Proposed Pillars and Principles

GLOBAL TB PROGRAMME

INTEGRATED, PATIENT-CENTRED CARE AND

PREVENTION

Early diagnosis of TB including universal drug susceptibility testing; systematic screening of contacts and high-risk groups

Treatment of all people with TB, including drug-resistant TB with patient support

Collaborative TB/HIV activities; and management of co-morbidities

Preventive treatment of persons at high-risk and vaccination for TB

BOLD POLICIES AND SUPPORTIVE SYSTEMS

Political commitment with adequate resources for TB care and prevention

Engagement of communities, civil society organizations, and public and private care providers

Universal Health Coverage policy; and regulatory frameworks for case notification, vital registration, drug quality and rational use, and infection control

Social protection, poverty alleviation and actions on other TB determinants

INTENSIFIED RESEARCH AND INNOVATION

Discovery, development and rapid uptake of new tools, interventions, and strategies

Research to optimize implementation and impact, and promote innovations

VISION: A WORLD FREE OF TB – ZERO DEATHS, DISEASE AND SUFFERING DUE TO TB

Post-2015 Global TB Strategy

PRINCIPLES Government stewardship and accountability, with monitoring and evaluation

Strong coalition with civil society and communities Protection and promotion of human rights, ethics and equity

Adaptation of the strategy and targets at country level, with global collaboration

GLOBAL TB PROGRAMME

GLOBAL TB PROGRAMME

DRAFT Post-2015 TB Strategy at a glance

A WORLD FREE OF TB: Zero deaths, disease and suffering due to TB

End the Global TB Epidemic

95% reduction in TB deaths (compared with 2015) Less than 10 cases per 100,000 population

75% reduction in TB deaths (compared with 2015) TB cases reduced to less than 50 per 100,000 population No affected families face catastrophic costs due to TB

VISION:

GOAL:

TARGETS FOR 2035:

MILESTONES FOR 2025:

TB deaths TB incidence

Mill

ion

s

Rat

e p

er

10

0,0

00

po

pu

lati

on

Proposed targets Goal: End the global TB epidemic

Existing tools + UHC/SP

New tools results of R&D

-75%

-95%

Existing tools + UHC/SP

New tools results of R&D

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2011 TB R&D investments witnessed an 82% increase over 2005 levels, but only 3% growth since 2010.

Total TB R&D Funding: 2005-2011: ¼ of the need

$700,000,000

$525,000,000

$350,000,000

$175,000,000

$0

2005 2006 2007 2008 2009 2010

$357,426,170

$417,824,708

$473,920,682 $491,476,917

$619,209,536 $630,446,462

2011

$649,648,183

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Annual Global Plan Research Funding Targets vs. 2011 Investments: for vaccines, ¼ available $800,000,000

$600,000,000

$400,000,000

$200,000,000

$0

Fundamental research

New diagnostics

New drugs New vaccines

$420,000,000

$340,000,000

$740,000,000

$380,000,000

$80,000,000

Operational research

Global Plan Annual Targets 2011 Investments

$120,361,419

$55,043,541 $95,446,326 $84,140,175

$250,038,877

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Investments in TB R&D 2005-2011. For drugs: the highest increase but enough?

$225,000,000

$75,000,000

$0 Drugs Basic Science Infrastructure/

Unspecified Operational

Research

$150,000,000

2005

2006

2007

2008

2009

2010

$114,862,738

Vaccines

$32,170,084

$144,336,532 $76,555,111 $30,194,127

$170,233,497 $73,225,383 $33,967,288

$174,178,052 $109,337,224 $34,411,742

$191,483,304 $110,133,485 $49,536,760

$230,540,443 $78,446,298 $60,895,355

Diagnostics

$81,892,167

$91,643,009

$113,325,202

$98,728,019

$172,447,841

$129,008,413

$40,741,527

$43,205,600

$40,734,199

$25,032,930

$56,686,918

$83,145,063

$19,408,124

$31,890,329

$42,435,113

$49,788,950

$38,921,229

$48,410,889

$68,351,530

2011 $250,038,877 $95,446,326 $84,140,175 $120,361,419 $44,617,845 $55,043,541

GLOBAL TB PROGRAMME

Top priority: commitment must change

"…

…"

GLOBAL TB PROGRAMME

1. The world is on track to achieve the (un-ambitious) 2015 target of incidence reduction, and current measures can reduce deaths and cure patients, but they cannot eliminate TB

2. For elimination one would need potent short treatments, mass TLTBI and potent pre- and post-exposure vaccines. None is available today

3. Three pillars will be the basis to accelerate incidence decline: (i) universal access to quality TB care and control, (ii) bold health system policies, and (iii) much intensified research efforts

4. Basic research is fundamental to gain further knowledge

5. R&D pipelines must be expanded , nurtured and well-financed. Development of a new regimen, shorter, simpler and cheaper, must be the ultimate aim

6. Increased financial resources for research: the TB community must keep working united to provide the right messages to investors and pursue progress

Conclusions and call to action

GLOBAL TB PROGRAMME

Eradication of tuberculosis: Will it be feasible?

" …there are three major weapons which can be

used in a policy of eradication: chemotherapy, vaccination, and chemoprophylaxis

GLOBAL TB PROGRAMME

…many thanks to all

Acknowledgments: Dr C. Lienhardt, Dr P. Glaziou, H. Getahun and our GTB teams

GLOBAL TB PROGRAMME

Documents

TB Elimination and TB drugs: can we make it? · 2019. 12. 21. · review of data, assessment of validity of surrogate markers for MDR-TB outcome, and cost-effectiveness study In January