Tuberculosis control

Translating new knowledge into policy in tuberculosis control work -what is needed for research results to be picked up? Dag Gundersen Storla : 

Translating new knowledge into policy in tuberculosis control work -what is needed for research results to be picked up? Dag Gundersen Storla Department of International Health, Institute of General Practice and Community Medicine, University of Oslo Centre for Imported and Tropical Diseases Ullevål University Hospital Norwegian Institute of Public Health

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Some scientific achievements through 125 years

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International Union Against Tuberculosis and Lung Diseases

World Situation : 

World Situation 10 million new cases of TB, 100 000 daily 14 million prevalent cases Half million cases of multidrug- resistant TB 2 million deaths from TB Source: WHO 2008

Important issues that need to be addressed in tuberculosis control work : 

Important issues that need to be addressed in tuberculosis control work Emerging successful strains (ESS) – particularly Bejing lineage Increasing resistance to primary drugs and lack of drug susceptibility testing facilities. Diagnostic delay and lack of feasible screening tests at primary level. Doubts about the direct observed treatment strategy.

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ISSUE 1 THREE LESSONS LEARNT FROM DNA FINGERPRINTING: New understanding of emerging successful strains High reinfection rates Multiple strains in each patient Emerging Successful Strains

LESSON 1: The global emergency : 

LESSON 1: The global emergency After 1980: a worldwide resurge of TB Fueled by emerging successful strains Rapidly spreading CAS Central Asian family in East Africa Outbreak in South Africa by LAM Latin American Mediterranian family The Beijing lineage family

The Beijing Lineage (BL) : 

The Beijing Lineage (BL) DNA fingerprinting: 73-93% BL in China BL in high numbers in the neighbouring South Asian countries BL the dominating strains of urban areas in the whole region Information on remote rural areas is scarce Source: van Soolingen 1995

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Percent of tuberculosis due to Beijing lineage strains based on spoligotyping © 2006 European Concerted Action on New Generation Genetic Markers and Techniques for the Epidemiology and Control of Tuberculosis

Beijing Lineage and BCG : 

Beijing Lineage and BCG Several studies indicate: BCG does not induce protective immunity towards some BL strains strains Sources: Kremer 2009, Tsenova 2007, Aguilar 2006

A majority of BL haveincreased virulence : 

A majority of BL haveincreased virulence 1 Reed 2004 & Sinsimer 2008, 2 Mustafa 2007 & Rioas-Barrera 2006, 3 Rindi 2007, Pheiffer 2005, Manca 2004 & Sun 2006

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LESSON 2: Reinfection rates are high, increasing with increasing incidence Wang 2009, modified by van Helden 2009  reinfection Incidence 

LESSON 3: TB patients have mixed infections : 

LESSON 3: TB patients have mixed infections Mixed infections with multiple strains in the same patient found in 13-55%. Multiple infections with sensitive and resistant strains throughout the same treatment scheme, often changing from sensitive to resistant Van Rie 2005, Shamputa 2006, Baldeviano-Vidalon 2005

Merging the knowledge from lessons 1+2+3 : 

Merging the knowledge from lessons 1+2+3 Hotspots of highly virulent emerging SS Reinfection rates are high Mixed infections common There are hotspot areas were the current tuberculosis control strategies are not effective to prevent the spread of emerging successful strains. To bring TB patients together on a daily base, as is often the case in DOT, is not a good idea

Beijing Lineage and BCG : 

Beijing Lineage and BCG Kremer 2009, Tsenova 2007, Aguilar 2006, Areas 2009 Should BCG immunisation be discontinued, as it seems to be favourating the spread of Beijing linage strains? NO! – The task is to IMPROVE the effect MVA85A from AERAS “The most promising new candidate in 80 years” Given AFTER BCG  constant strong cellular immunity  prevents pulmonary TB? Enters phase 2b  2700 South African Children

Increasing resistance to primary drugs and lack of drug susceptibility testing fascilities. : 

Increasing resistance to primary drugs and lack of drug susceptibility testing fascilities. ISSUE 2 LESSONS LEARNT FROM (LACK OF) SUSCEPTIBILTY TESTING

Increasing resistance to primary TB drugs : 

Increasing resistance to primary TB drugs Source: WHO 2008)

Percent incidence of MDR-TB : 

Percent incidence of MDR-TB

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Source: TB Alliance for Drug Development.

Maximum 10% will receive treatment under the Green Light Committee initiative : 

Maximum 10% will receive treatment under the Green Light Committee initiative 500 000 new MDR-TB Maximum 50 000 received second line treatment in 2008 Source: WHO 2008 Intention Realities

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WHO 2008

ISSUE 3 : 

ISSUE 3 Diagnostic delay and lack of feasible screening tests at primary level

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Early diagnosis and immediate initiation of treatment are ess- ential for an effective TB control program. Delay in diagnosis is significant to both disease prognosis at the individual level and transmission within the community.

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Prevalence of ss+ cases = POOL OF CONTAGEOUS CASES INFECTED/SS- POPULATION ON TREATMENT DEATH UNINFECTED POPULATION

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The vicious circle of repeated visits at the same level is the core problem of diagnostic delay REVIEW OF 58 STUDIES ON DIAGNOSTIC DELAY

ISSUE 4 : 

ISSUE 4 Doubts about the direct observed treatment strategy. LESSONS LEARNT FROM 15 YEARS OF WIDESPREAD USE OF THE DOTS STRATGY

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The DOTS strategy comprises five components: Political commitment Case-detection through sputum smear microscopy Directly observed treatment Uninterrupted supply of anti-TB drugs. A monitoring system of treatment outcome. Sandiford 1999, WHO 2008

Doubts about DOT : 

Doubts about DOT Volmink 2007

In defence of DOTS : 

In defence of DOTS Cox: DOTS has undoubtedly improved the outcomes for millions of patients. Obermeyer: Complete DOTS coverage = at least 18% increase in treatment success. Cox 2008, Obermeyer 2008 COMMUNITY BASED COMMITMENT The secret: not the direct observation of tablet intake More likely: the systematic commitment from the society and close follow up of each patient.

Merging the implications into an effective tuberculosis control strategy … : 

Merging the implications into an effective tuberculosis control strategy … SOME ELEMENTS ARE AVAILABLE SOME ELEMENTS ARE OUT IN THE PIPELINE SOME ELEMENTS ARE WITHIN REACH Available within 2010 Available beyond 2010

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SUSPECTS DECENTRALIZED TB PROGRAM SCREENING TEST FEASIBLE FOR PRIMARY LEVEL IMPROVED LED MICROSCOPY DRUG SUSCEPTIBILITY TESTING BASED TREATMENT DNA SPUTUM SPECIATION COMMUNITY BASED MODEL >95% DO NOT HAVE TB - + DRUG SUSC- EPTIBILITY TEST PERIPHERAL LABORATORY + EFFECTIVE DRUGS INCLUDING SECOND LINE DRUGS - AVAILABLE IN THE PIPELINE SOON

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HEALTH CARE DELAY PATIENT DELAY START OF TREATMENT SYMPTOM DEBUT INFECTED, HEALTHY ACTIVE TUBERCULOSIS FIRST VISIT A SCREENING TEST FEASIBLE FOR PRIMARY LEVEL

TB rapid test project (TBRT) : 

TB rapid test project (TBRT)

Prior to the RTBT, we had promising results utilizing the P8 and P9 peptides of RD1 : 

Prior to the RTBT, we had promising results utilizing the P8 and P9 peptides of RD1 UNIVERSITY OF BERGEN Harald Wiker SELECTION OF ANTIGENS: P8 and P9 from the RD1 encoded protein Rv3872 NORWEGIAN INSTITUTE OF PUBLIC HEALTH Dag Gundersen Storla, Terje Michaelsen Fredrik Oftung, Gro Ellen Korsvold, Carol Holm-Hansen THREE CLINICAL MATERIALS: Ss+ TB patients Bangladesh Healthy controls Bangladesh Latently infected healthy Norwegians Not infected healthy Norwegians

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(Sunamganj, Bangladesh) Preliminary pooled data Reproductivity is low We are currently repeating with branched peptides P8 and P9 peptides

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SUSPECTS DECENTRALIZED TB PROGRAM SCREENING TEST FEASIBLE FOR PRIMARY LEVEL IMPROVED LED MICROSCOPY DRUG SUSCEPTIBILITY TESTING BASED TREATMENT SPUTUM SPECIATION COMMUNITY BASED MODEL >95% DO NOT HAVE TB - + PERIPHERAL LABORATORY + EFFECTIVE DRUGS INCLUDING SECOND LINE DRUGS - AVAILABLE IN THE PIPELINE SOON DRUG SUSCEP-TIBILITY TESTING

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Ling 2008, Pai 2004+5, Flores 2005, Piersimoni 2003 NUCLEIC-ACID AMPLIFICATION TESTS FOR SPUTUM SPECIATION

LAMP - a ”PCR-free” loop-mediated isothermal amplification sputum assay : 

LAMP - a ”PCR-free” loop-mediated isothermal amplification sputum assay Smear-positives : Sensitivity 98% Smear-negatives: Sensitivity 50% Specificity 99% in both ss+ and ss- Technicians performed the assay after one week Boehme 2007.

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SUSPECTS DECENTRALIZED TB PROGRAM SCREENING TEST FEASIBLE FOR PRIMARY LEVEL IMPROVED LED MICROSCOPY SPUTUM SPECIATION COMMUNITY BASED MODEL >95% DO NOT HAVE TB - + DRUG SUSCEP-TIBILITY TESTING PERIPHERAL LABORATORY + EFFECTIVE DRUGS INCLUDING SECOND LINE DRUGS - AVAILABLE IN THE PIPELINE SOON DRUG SUSCEPTIBILITY TESTING BASED TREATMENT

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SUSCEPTIBILITY TESTING – FEASIBILITY IN A LOW- RECOURCE PERIPHERAL LABORATORY Fluoromyco- bacteriophages Automated systems on liquid media Rapid genotyping: DNA sequencing Micro- and macrorrays single-strand polymorphism Conventional methods on solid media COST - COMPLEXITY Bradey 2008, Piuri 2009 and ESCMID Review 2007: EUCAST document E.DEF 8.1 1 WEEK SEVERAL WEEKS DAYS <3$ Nitrate reductase Microscopic-observation MODS

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SUSPECTS DECENTRALIZED TB PROGRAM SCREENING TEST FEASIBLE FOR PRIMARY LEVEL IMPROVED LED MICROSCOPY DRUG SUSCEPTIBILITY TESTING BASED TREATMENT SPUTUM SPECIATION COMMUNITY BASED MODEL >95% DO NOT HAVE TB - + DRUG SUSCEP-TIBILITY TESTING PERIPHERAL LABORATORY + EFFECTIVE DRUGS INCLUDING SECOND LINE DRUGS - AVAILABLE IN THE PIPELINE SOON

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Worrying situation: Increasing MDR-TB and XDR-TB. Currently few new drugs in clinical devlopment phases.

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SUSPECTS DECENTRALIZED TB PROGRAM SCREENING TEST FEASIBLE FOR PRIMARY LEVEL IMPROVED LED MICROSCOPY DRUG SUSCEPTIBILITY TESTING BASED TREATMENT SPUTUM SPECIATION COMMUNITY BASED MODEL >95% DO NOT HAVE TB - + DRUG SUSCEP-TIBILITY TESTING PERIPHERAL LABORATORY + EFFECTIVE DRUGS INCLUDING SECOND LINE DRUGS - AVAILABLE IN THE PIPELINE SOON

BRAC´s community based TB program : 

BRAC´s community based TB program Bangladesh Rural Advancement Committee (BRAC) has implemented a TB program in Bangladesh since 1984 85% success rates In collaboration with the Government Covers a population of 83 million. Fazle Abed

DOTS with a strong community commiment : 

DOTS with a strong community commiment Shaisto Shebika: Identifies people with chronic cough  laboratory for microscopy. Initial 2 months: the patients come to the CHW’s home daily for drugs. For the remaining: the patients are given a week’s supply at a time.

Possible adjustments in the BRAC model to meet new knowledge : 

Possible adjustments in the BRAC model to meet new knowledge Not a good idea to bring TB patients together  Assure that they do not come at the same time, or go to each patient's home DOT seems to be unnecessary provided each patient is properly followed up.

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SUSPECTS DECENTRALIZED TB PROGRAM SCREENING TEST FEASIBLE FOR PRIMARY LEVEL IMPROVED LED MICROSCOPY DRUG SUSCEPTIBILITY TESTING BASED TREATMENT SPUTUM SPECIATION COMMUNITY BASED MODEL >95% DO NOT HAVE TB - + DRUG SUSCEP-TIBILITY TESTING PERIPHERAL LABORATORY + EFFECTIVE DRUGS INCLUDING SECOND LINE DRUGS - AVAILABLE IN THE PIPELINE SOON