Research in Tuberculosis: y Translation into Practice 5... · Translation into Practice Michael Lauzardo, MD, MSc Principal Investigator, Southeastern National Tuberculosis Center

Research in Tuberculosis:Research in Tuberculosis:Translation into PracticeTranslation into Practice

Michael Lauzardo, MD, MScMichael Lauzardo, MD, MScPrincipal Investigator, Southeastern National Tuberculosis CentePrincipal Investigator, Southeastern National Tuberculosis CenterrAssistant Professor, Div. of Pulmonary and Critical Care MedicinAssistant Professor, Div. of Pulmonary and Critical Care Medicine,e,

University of Florida College of MedicineUniversity of Florida College of MedicineDeputy Health Officer for TB Deputy Health Officer for TB –– State of FloridaState of Florida

Case Case –– History History

This is a 6This is a 6--yearyear--old Bosnian male, who presented old Bosnian male, who presented to ER with oneto ER with one--week history of fever and occasional week history of fever and occasional vomiting. No cough, difficulty breathing or weight loss. vomiting. No cough, difficulty breathing or weight loss.

Evaluation revealed right lobar pneumonia. Evaluation revealed right lobar pneumonia. Patient was admitted to the hospital and started on IV Patient was admitted to the hospital and started on IV antibiotics (Ceftriaxone).antibiotics (Ceftriaxone).

Case Case –– HistoryHistory

PMHPMH

–– No significant illnesses in the past, no surgeries.No significant illnesses in the past, no surgeries.

Social HistorySocial History

–– Patient lives with both parents and a younger sibling. Patient lives with both parents and a younger sibling. They all immigrated to U.S. from Bosnia about six They all immigrated to U.S. from Bosnia about six months PTA. At that time, they all had PPD placed. months PTA. At that time, they all had PPD placed. Both parents tested positive, but elected not to take Both parents tested positive, but elected not to take meds. Both children tested negative. meds. Both children tested negative.

Case Case –– Physical ExaminationPhysical Examination

T: 103.2T: 103.2°°

P: 154P: 154

R: 24R: 24

BP: 111/70.BP: 111/70.

O2 Sat. on RA: 96O2 Sat. on RA: 96––97%.97%.

Patient was awake, Patient was awake, alert, in no apparent distressalert, in no apparent distress

ChestChest

–– Markedly decreased Markedly decreased BS in the right lung fieldBS in the right lung field

Rest of exam was within Rest of exam was within normal limitsnormal limits

Case Case

CXRCXR

–– PAPA

Large opacity that filled the lower 2/3 of the right hemithorax,Large opacity that filled the lower 2/3 of the right hemithorax,heart slightly displaced to the left, heart slightly displaced to the left, clear left lung field. clear left lung field.

–– Right lateral decubitusRight lateral decubitus

Mass or large organized pleural effusion without Mass or large organized pleural effusion without free layering.free layering.

2008 HEALTH RESEARCH IN THE AMERICAS IV: HIV/TB MODULE 5 TRANSLATION TO PRACTICE

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Case Case

Patient continued having daily fever spikes, but Patient continued having daily fever spikes, but without changes in his respiratory status.without changes in his respiratory status.

–– Would you do any further evaluation?Would you do any further evaluation?

–– Repeat TST?Repeat TST?

–– Do we need gastric aspirates versus sputum?Do we need gastric aspirates versus sputum?

–– Spinal tap?Spinal tap?

–– Other cultures?Other cultures?

–– Other tests?Other tests?

Case Case –– Hospital CourseHospital Course

TST was placed and read in 48 hours as 22 mm of induration. TST was placed and read in 48 hours as 22 mm of induration.

Induced sputum/early morning gastric aspirates were obtained. Induced sputum/early morning gastric aspirates were obtained.

Chest US showed a loculated, organized pleural effusionChest US showed a loculated, organized pleural effusion

Surgery was consulted and they performed a videoSurgery was consulted and they performed a video--assisted assisted thoracotomy and decortication. Pleural biopsy and AFB cultures thoracotomy and decortication. Pleural biopsy and AFB cultures were sent.were sent.

HIV antibody: negative HIV antibody: negative

Case Case –– Hospital CourseHospital Course

Patient was started on INH, Rif, PZA and Ethambutol.Patient was started on INH, Rif, PZA and Ethambutol.

He improved with resolution of fever in three days. He improved with resolution of fever in three days.

He was discharged home to continue meds under DOT.He was discharged home to continue meds under DOT.

Case Case –– Final ResultsFinal Results

Gastric aspirates X 3Gastric aspirates X 3

–– AFB smear and cultures were negativeAFB smear and cultures were negative

Induced sputum AFB smear was negative Induced sputum AFB smear was negative

Pleural BiopsyPleural Biopsy

–– Multiple caseating granulomasMultiple caseating granulomas

Pleural fluid/biopsyPleural fluid/biopsy

–– AFB smear and PCR for AFB smear and PCR for M.TbM.Tb were negative were negative

Sputum and pleural cultures grew Sputum and pleural cultures grew M. tuberculosisM. tuberculosis, resistant to , resistant to INHINH

Case Case –– Final DiagnosisFinal Diagnosis

Tuberculous empyemaTuberculous empyema INHINH--resistant TBresistant TB


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TB EpidemiologyTB Epidemiology

<1%<1%Up to 15%Up to 15%(DR and Ecuador)(DR and Ecuador)MDRMDR

1,000 1,000 –– 2,000/year2,000/year1.9 million/year1.9 million/yearDeathsDeaths

30,00030,0004040--50 million50 millionCase prevalenceCase prevalence

~ 18,000/year~ 18,000/year88--10 million/year10 million/yearCase incidenceCase incidence

10 million10 million(4% population)(4% population)

1.7 billion1.7 billion(33% population)(33% population)Infected casesInfected cases

USAUSAGLOBALGLOBAL

A Silent Global EpidemicA Silent Global Epidemic

OneOne--third of the worldthird of the world’’s population infecteds population infected

Eight million new cases of active disease per yearEight million new cases of active disease per year

Two to three million deaths per yearTwo to three million deaths per year

One person is newly infected every second and one person dies One person is newly infected every second and one person dies every 10 secondsevery 10 seconds

Rising incidence of drugRising incidence of drug--resistant diseaseresistant disease

Billions of dollars in lost productivityBillions of dollars in lost productivity

Global TB RatesGlobal TB Rates Tuberculosis in the United States: Epidemic Tuberculosis in the United States: Epidemic Under ControlUnder Control

14,781 cases (5.1/100,000) 14,781 cases (5.1/100,000)

10th year of decline (down 1.3% from 2002)10th year of decline (down 1.3% from 2002)

138 cases (0.9%) of MDR138 cases (0.9%) of MDR--TB in 2002TB in 2002

23 states meet year 2000 elimination target23 states meet year 2000 elimination target(< 3.5/100,000)(< 3.5/100,000)

Completion of therapy exceeds 90% Completion of therapy exceeds 90%

Reported TB Cases Reported TB Cases United States, 1982United States, 1982--20022002

10000

12000

14000

16000

18000

20000

22000

24000

26000

28000

1982 1984 1986 1988 1990 1992 1994 1996 1998 2000 2002Year

Num

ber o

f Cas

es

TB MorbidityTB MorbidityUnited States, 1998 United States, 1998 –– 20022002

5.25.215,07515,07520022002

5.65.615,98915,98920012001

5.85.816,37716,37720002000

6.46.417,53117,53119991999

6.86.818,36118,36119981998

RATE*RATE*CASESCASESYEARYEAR

*Cases per 100,000


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TB Case RatesTB Case RatesUnited States 2002United States 2002

< 3.5 (year 2000 target)3.6 - 5.2> 5.2 (national average)

D.C.

Rate: cases per 100,000

Trends in TB Cases in ForeignTrends in TB Cases in Foreign--Born Persons, Born Persons, United States, 1986United States, 1986--20022002

0

2,000

4,000

6,000

8,000

10,000

1986 1988 1990 1992 1994 1996 1998 2000 20020

10

20

30

40

50

60

No. of Cases Percentage of Total Cases

# ofCases Percentage

Percentage of TB Cases AmongPercentage of TB Cases AmongForeignForeign--Born Persons United StatesBorn Persons United States

>50%25%-49%<25%

1992 2002

Countries of Birth for ForeignCountries of Birth for Foreign--Born Persons Born Persons Reported with TB, U.S. 2002Reported with TB, U.S. 2002

Mexico (25%)

Philippines(11%)

Vietnam (8%)India(7%)

China (5%)Haiti (3%)

S. Korea (3%)

OtherCountries

(38%)

TB in ForeignTB in Foreign--BornBornUnited States 2003United States 2003

53.3% of total cases53.3% of total cases

23.4 cases / 100,000 population23.4 cases / 100,000 population

Rate ratio: 8.7 relative to U.S.Rate ratio: 8.7 relative to U.S.--bornborn

25 states reported > 50% foreign25 states reported > 50% foreign--born casesborn cases

Number of TB Cases inNumber of TB Cases inU.S.U.S.--Born vs. ForeignBorn vs. Foreign--born Persons,born Persons,

United States 1993United States 1993--2003*2003*

0

5000

10000

15000

20000

1993 1995 1997 1999 2001 2003

US-Born Foreign-Born

Numberof Cases


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ChallengesChallenges The Global Expansion of The Global Expansion of Drug Resistant Strains of TBDrug Resistant Strains of TB

MultiMulti--Drug Resistant (MDR) TBDrug Resistant (MDR) TB

Defined as resistance to isoniazid and rifampinDefined as resistance to isoniazid and rifampin

Created by poorly managed TB programsCreated by poorly managed TB programs

–– NonNon--adherence to therapyadherence to therapy

–– Poor quality drugs or supplyPoor quality drugs or supply

Leads to bad outcomesLeads to bad outcomes

–– Longer treatment (go from 6Longer treatment (go from 6--24 months)24 months)

–– Toxic regimensToxic regimens

–– Cost increases 10Cost increases 10--100 fold100 fold

–– High death rates High death rates

–– Disastrous outcomes in HIV settingsDisastrous outcomes in HIV settings

FirstFirst--line Therapy for Cases of Drug Susceptible TBline Therapy for Cases of Drug Susceptible TB

IsoniazidIsoniazid

RifamycinsRifamycins

PyrazinamidePyrazinamide

EthambutolEthambutol

AminoglycosidesAminoglycosides

CapreomycinCapreomycin

QuinolonesQuinolones

ThioamidesThioamides

CycloserineCycloserine

PASPAS

Therapy is standardizedTherapy is standardized

4 drugs for 64 drugs for 6--9 months9 months

Safe effective and cheapSafe effective and cheap

95% cure rate 95% cure rate

Cost about $20Cost about $20

Extensive evidence base of Extensive evidence base of RCTsRCTsto support practiceto support practice

SecondSecond--line Drugs for Drug Resistant TBline Drugs for Drug Resistant TB

IsoniazidIsoniazid

RifamycinsRifamycins

PyrazinamidePyrazinamide

EthambutolEthambutol

AminoglycosidesAminoglycosides

CapreomycinCapreomycin


ThioamidesThioamides

CycloserineCycloserine

PASPAS

Need lab testing and or Need lab testing and or epiepiinformation on prevalent resistant information on prevalent resistant strainsstrains

44--6 drugs for 2 years6 drugs for 2 years

Less effectiveLess effective

<80% cure rate<80% cure rate

$3500 to $5000 cost for drugs$3500 to $5000 cost for drugs

No clinical trials to supportNo clinical trials to support

Extensively Drug Resistant TB Extensively Drug Resistant TB XDR TBXDR TB

Results from inadequate MDR TB treatment and leads to Results from inadequate MDR TB treatment and leads to secondsecond--line drug resistanceline drug resistance

Defined from October 2006 as being:Defined from October 2006 as being:

–– MDR TB plus resistance to at least a fluoroquinolone and any MDR TB plus resistance to at least a fluoroquinolone and any sescondsescond--line injectable (amikacin, kanamycin, and capreomycin)line injectable (amikacin, kanamycin, and capreomycin)

–– If Fluoroquinolone and injectable are available then If Fluoroquinolone and injectable are available then outcmeoutcme of of MDR is better (69% cure rate MDR is better (69% cure rate vsvs 30%)30%)


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XDR TB Outbreak, South AfricaXDR TB Outbreak, South Africa20052005--20062006

119 patients in TB/ARV integration study119 patients in TB/ARV integration study

–– 14 deaths of which 10 were MDR14 deaths of which 10 were MDR

–– 6 of 10 isolates were resistant to all the drugs tested6 of 10 isolates were resistant to all the drugs tested

Suggested that the facility likely had high rates of resistanceSuggested that the facility likely had high rates of resistance

Prompted a survey from Jan 2005 through March 2006Prompted a survey from Jan 2005 through March 2006

South Africa Drug Resistance Survey South Africa Drug Resistance Survey

Of 542 M. TB cultures 221 (41%) Of 542 M. TB cultures 221 (41%) were MDR TBwere MDR TB

53 (10%) XDR TB53 (10%) XDR TB

52 of the 53 patients died within 52 of the 53 patients died within 25 days of the diagnosis25 days of the diagnosis

All were HIV positive and those All were HIV positive and those that died included those on antithat died included those on anti--retroviral therapyretroviral therapy

XDR likely has spread to XDR likely has spread to neighboring African countriesneighboring African countries

From NEJM 356;7:2007

TB Drug ResistanceTB Drug Resistance Global Burden of Drug Resistant TBGlobal Burden of Drug Resistant TB

The XDR outbreak in South Africa led to prevalence surveys of The XDR outbreak in South Africa led to prevalence surveys of national labsnational labs

The global burden of MDR or XDR TB is now estimated to be The global burden of MDR or XDR TB is now estimated to be over 450,000over 450,000

Over 28 countries now have confirmed cases of XDR with likely Over 28 countries now have confirmed cases of XDR with likely spread in subspread in sub--Saharan Africa in populations with high rates of Saharan Africa in populations with high rates of HIV HIV

HIV / TB CoHIV / TB Co--InfectionInfection

HIV and TB:HIV and TB:Twin EpidemicsTwin Epidemics


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HIV and TBHIV and TB

The twin epidemics of HIV and TB are the single biggest threat The twin epidemics of HIV and TB are the single biggest threat to global TB controlto global TB control

The WHO strategy of DOTS fails to decrease the incidence of TB The WHO strategy of DOTS fails to decrease the incidence of TB in settings of high HIV prevalencein settings of high HIV prevalence

Expansion of ARV therapy is good overall for TB control efforts Expansion of ARV therapy is good overall for TB control efforts however, it may lead to drug interactions that may worsen MDR however, it may lead to drug interactions that may worsen MDR TB epidemicTB epidemic

May lead to a paradoxical worsening of the TB burden by May lead to a paradoxical worsening of the TB burden by improving survival in HIV positive individuals who would be at improving survival in HIV positive individuals who would be at risk for TB risk for TB

Poverty and TBPoverty and TB

Responding to the ChallengesResponding to the Challenges

Technological AdvancesTechnological Advances

Whole Blood GammaWhole Blood GammaInterferon Assay for LTBIInterferon Assay for LTBI

Quantiferon gold recently approved by FDA utilizing early Quantiferon gold recently approved by FDA utilizing early secretory antigenic target 6 (ESATsecretory antigenic target 6 (ESAT--6) and culture filtrate protein 6) and culture filtrate protein 10 (CFP 10) [present in TB and bovis absent from BCG and 10 (CFP 10) [present in TB and bovis absent from BCG and most NTM except kansasii, szulgai and marinum) by ELISAmost NTM except kansasii, szulgai and marinum) by ELISA

May be able to discern reaction to BCG and NTMMay be able to discern reaction to BCG and NTM

More studies needed to discern role in LTBI diagnosisMore studies needed to discern role in LTBI diagnosis


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Vaccine HistoryVaccine History

BCG was developed by Albert Calmette and Camille Guerin who BCG was developed by Albert Calmette and Camille Guerin who attenuated a strain of M. bovis by growing it on culture medium attenuated a strain of M. bovis by growing it on culture medium for 13 years.for 13 years.

Virulence was monitored in animal models.Virulence was monitored in animal models.

In 1921 it was first administered widely in France where it In 1921 it was first administered widely in France where it reduced infant mortality from TB by 90%.reduced infant mortality from TB by 90%.

BCG TodayBCG Today

Now one of the most widely used vaccinesNow one of the most widely used vaccines

Very effective at reducing mortality in infantsVery effective at reducing mortality in infants

Protective effect lasts no more than 10Protective effect lasts no more than 10--15 years at best15 years at best

Efficacy has been shown to be highly variable (0Efficacy has been shown to be highly variable (0--80%) in 80%) in protecting against TB diseaseprotecting against TB disease

Reasons for this are unclear but likely involve the relationshipReasons for this are unclear but likely involve the relationships s between M. tuberculosis, BCG, and other environmental nonbetween M. tuberculosis, BCG, and other environmental non--tuberculous mycobacteriatuberculous mycobacteria

Immunology of TBImmunology of TB

Doherty et al. Clin Micro Rev. 2005 Vol. 18, p 687-702

Vaccine SummaryVaccine Summary

Unexpected advances in the field of immunology and vaccine Unexpected advances in the field of immunology and vaccine development hold great promise for the delivery of the most development hold great promise for the delivery of the most important new tool for the elimination of TB.important new tool for the elimination of TB.

Without a vaccine, the elimination of TB is likely impossible.Without a vaccine, the elimination of TB is likely impossible.

The current vaccine candidates are not ideal but even a less The current vaccine candidates are not ideal but even a less than ideal vaccine can potentially become a costthan ideal vaccine can potentially become a cost--effective effective valuable tool that can be applied globally.valuable tool that can be applied globally.

Diagnosis of TB in LowDiagnosis of TB in Low--Resource SettingsResource Settings MicroscopicMicroscopic--Observation DrugObservation Drug--Susceptibility TestingSusceptibility TestingMODSMODS

MODS is a rapid lowMODS is a rapid low--cost technique in which broth cultures are cost technique in which broth cultures are examined microscopically to detect characteristic growthexamined microscopically to detect characteristic growth

In a recent study in Peru the MODS assay was compared headIn a recent study in Peru the MODS assay was compared head--toto--head with two reference methodshead with two reference methods

Of 3760 sputum samples, 401(10.7%) yielded positive cultures Of 3760 sputum samples, 401(10.7%) yielded positive cultures for MTBfor MTB

Sensitivity of detection was 97.8% for MODSSensitivity of detection was 97.8% for MODS

Agreement between MODS and reference standard for Agreement between MODS and reference standard for susceptibility was 100% for rifampin, 97% for isoniazid, and susceptibility was 100% for rifampin, 97% for isoniazid, and 99% for both 99% for both


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The Effect of DOTS ExpansionThe Effect of DOTS Expansion

Global Collaborations Global Collaborations in the Fight Against TBin the Fight Against TB

Goals of the STOP TB PartnershipGoals of the STOP TB Partnership


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Developing New Drugs for TBDeveloping New Drugs for TB

New TB Drug PipelineNew TB Drug Pipeline

Early Bactericidal ActivityEarly Bactericidal Activity

In EBA studies, newly diagnosed patients with acidIn EBA studies, newly diagnosed patients with acid--fast fast bacillus (AFB)bacillus (AFB)--positive, pulmonary tuberculosis are treated for positive, pulmonary tuberculosis are treated for periods ranging from 2 to 14 days with single drugs or drug periods ranging from 2 to 14 days with single drugs or drug combinations. combinations.

During this period, quantitative counts of viable tubercle bacilDuring this period, quantitative counts of viable tubercle bacilli li from carefully collected sputum specimens are made, with the from carefully collected sputum specimens are made, with the EBA traditionally expressed as logEBA traditionally expressed as log--decrease in colony forming decrease in colony forming units/ml sputum/day over the first 48 hours,units/ml sputum/day over the first 48 hours,

Generally this technique is used as a proof of concept.Generally this technique is used as a proof of concept.

Usually follows inUsually follows in--vitro and animal studies.vitro and animal studies.

What are clinical trial phases?What are clinical trial phases?

Phase 1 clinical trials, researchers test a new drug or Phase 1 clinical trials, researchers test a new drug or treatment in a small group of people (20treatment in a small group of people (20--80) for the first time 80) for the first time to evaluate its safety, determine a safe dosage range, and to evaluate its safety, determine a safe dosage range, and identify side effects.identify side effects.

Phase 2 clinical trials, the treatment is given to a larger grouPhase 2 clinical trials, the treatment is given to a larger group p of people (40of people (40--100) to see if it is effective and to further 100) to see if it is effective and to further evaluate its safety.evaluate its safety.

Phase 3 studies, the study drug or treatment is given to large Phase 3 studies, the study drug or treatment is given to large groups of people (more than 200) to further determine its groups of people (more than 200) to further determine its effectiveness, monitor side effects, and compare it to effectiveness, monitor side effects, and compare it to commonly used treatments, commonly used treatments,

NitroimidazolesNitroimidazoles Diarylquinoline (TMC207)Diarylquinoline (TMC207)

Effective against DSEffective against DS--TB and TB and MDRMDR--TB as well as other TB as well as other clinically important clinically important Mycobacterial speciesMycobacterial species

Has a novel mechanism of Has a novel mechanism of actionaction

Phase I studies among Phase I studies among healthy males was very well healthy males was very well toleratedtolerated

Phase II studies about to Phase II studies about to begin in MDRbegin in MDR--TB patientsTB patients


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Pyrrole (LL3858)Pyrrole (LL3858)

Currently being evaluated in a Phase I study in India with Currently being evaluated in a Phase I study in India with healthy volunteers.healthy volunteers.

Mechanism of action is uncertain but has MICMechanism of action is uncertain but has MIC’’s for DSs for DS--TB and TB and MDRMDR--TB are similar,TB are similar,

The sterilizing activity of this agent in the spleen and lungs oThe sterilizing activity of this agent in the spleen and lungs of f mice is faster than that of the conventional INH/RIF/PZA mice is faster than that of the conventional INH/RIF/PZA regimen.regimen.

Also has some effect against nonAlso has some effect against non--TB mycobacterial species.TB mycobacterial species.


Originally looked at to treat Originally looked at to treat MDRMDR--TB.TB.

More interest now in its role More interest now in its role to shorten the regimen.to shorten the regimen.

Report from Chennai India Report from Chennai India showed remarkable sputum showed remarkable sputum conversion rates at 2 conversion rates at 2 months (92%months (92%--98% rather 98% rather than expected 80% with than expected 80% with conventional therapyconventional therapy).).

An Alternative View:An Alternative View:Back to the FutureBack to the Future

Who says that currently available drugs are not sufficient for Who says that currently available drugs are not sufficient for treating drug resistant TB?treating drug resistant TB?

In the 1960In the 1960’’s it took 8 years to get a new drug to market, now s it took 8 years to get a new drug to market, now it takes 20 years.it takes 20 years.

The data to justify the current dosing is weak and there is littThe data to justify the current dosing is weak and there is little le evidence to support our current strategiesevidence to support our current strategies

Would it not make sense to fund studies to evaluate the dose Would it not make sense to fund studies to evaluate the dose used in currently used regimens while we wait for new drugs?used in currently used regimens while we wait for new drugs?

ConclusionConclusion


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Research in Tuberculosis: y Translation into Practice 5... · Translation into Practice Michael Lauzardo, MD, MSc Principal Investigator, Southeastern National Tuberculosis Center

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