TB: A Global Emergency

• 1/3 of the world (2 billion people) infected

• 1 person infected/second resulting in >30 million new infections, 8 million new cases

• Left untreated 1/3 die, 1/3 self-cure, 1/3 remain infectious

• TB kills 1 person every 10 seconds = 5000/day = 2-3 million each year

22 High Burden Countries• India• China• Indonesia• Bangladesh• Pakistan• Nigeria• Philippines• South Africa• Ethiopia• Vietnam• Russian Federation

• Congo• Brazil• Tanzania• Kenya• Thailand• Myanmar• Afghanistan• Uganda• Peru• Zimbabwe• Cambodia

TB: Clinical Features

• TB is caused by Mycobacterium tuberculosis

• TB can affect any organ system: bone, kidney, CNS; 80% are pulmonary

• Classic pulmonary systems of active disease: cough > 3 weeks duration, chest pain, bloody sputum

• Classic systemic symptoms: fever, night sweats, weight loss, malaise

• Treated for many years with long hospitalization, surgery, myriad of drugs leading to belief that TB is not treatable or treatment worse than disease.

TB Infection vs TB Disease

• TB infection – organism is present, but dormant, cannot infect others

• TB disease – person is sick and can transmit disease to others if in lungs

• 10% of individuals with TB infection will develop TB disease

• Each individual with active TB can infect 10-15 people/year

When does TB infectionbecome disease?

• Most likely to occur in first two years after infection

• If person becomes immunocompromised– HIV– Cancer– Chemotherapy– Poorly controlled diabetes– malnutrition

The 5 Essential Components of the DOTS Strategy

• Government commitment to a National TB Program• Priority to detect infectious cases by sputum smear

microscopy• Standardized regimens of short-course

chemotherapy, given under direct observation for , at least, the intensive phase

• Regular, uninterrupted supply of anti-TB meds• Monitoring system for program supervision and

evaluation

1. Political/Administrative Commitment

• Perception of TB as a priority problem with real solution

• Government acknowledges importance of disease

• Public commitment to National TB Program (NTP)

• Support for personnel, training, transportation, drugs

2. Accurate Diagnosis=Sputum Microscopy

• Identification/cure of infectious cases (smear+) is highest priority of TB control – Smear+s 4-20 times more infectious; may infect

10-15/year; more likely to die if untreated

• Timely results to reduce potential for transmission

• Quality assurance/training--national reference lab is key

Diagnosis of pulmonary TB

Cough 3 weeks

AFB X 3

Broad-spectrum antibiotic 10-14 days

If symptoms persist, repeat AFB smears, X-ray

If consistent with TB

Anti-TB Treatment

If 1 positive, X-ray and evaluation

If 2/3 positive: Anti-TB Rx

If negative:

Chest X-ray (CXR) as Diagnostic Tool

• No CXR pattern is typical– Many TB cases are missed (10-15% culture+s)

– Many non-TB cases misdiagnosed (40% diagnosed by CXR alone do not have active TB

• Previous MD training emphasized CXR as best diagnostic tool

• Often reaction to poor, inaccurate, or unavailable lab services

0

20

40

60

80

100

Diagnosed by X-ray alone

Actual cases

X-ray-based evaluation causes over-diagnosis of TB

NTI, Ind J Tuberc, 1974

Over-diagnosis

50%

98%

0

20

40

60

80

100

AFB Microscopy X-ray

Microscopy is a more specific test than X-ray for TB diagnosis

Specificity

3. Adequate Supply of Drugs

• Treatment requires regular doses of combination regimens for >6 months

• Identification of an adequate supply of appropriate drugs for patients prior to initiation of treatment essential

• If regimens incomplete, real chance of development of drug-resistant strains which are hard or impossible to cure

• Requires continuum of drug management services: selection, procurement, distribution, use.

4. Directly Observed Treatment• Why? Many patients don’t take medicines regularly,

even if excellent health education provided • Who? All patients... impossible to predict which

patient will take medicine (1/3 not adherent) • What? Observer watches and helps patient swallow

tablets • Where? Anywhere! (home, clinic, work, school, etc) • Who does it? HCW, community liaisons, teachers,

Direct observation ensures treatment for entire course with the right drugs, in the right doses, at the right intervals

DOT is necessary even whendrug supply ensured

88%

61%

0%

20%

40%

60%

80%

100%

Chaulk CP. JAMA 1998;279:943-8

Treatment Success

DOT No DOT

DOT prolongs survival ofHIV-infected TB patients

Survived 56.7%

Died43.3%

SCC with DOT

SCC without DOT

Survived85.4%

Died14.6%

5. Systematic Monitoring/Accountability

• Recording system is simple to use, essential, integrated component of DOTS enabling– Monitoring of patient outcomes– Evaluation of program performance– Analysis of epidemiologic data– Identification of areas for OR

• Every level of health system accountable for patient diagnosis and cure; “report card”

TB Register

TB and HIV/AIDS

• HIV negatively impacts TB and TB negatively impacts HIV

• HIV+ individuals infected with TB are 30x more likely to develop TB disease

• TB is leading cause of death among HIV+, accounting for ~40% of AIDS deaths

• HIV increases the prevalence of active TB in HIV- and HIV+ populations

Multidrug-Resistant TB (MDRTB)

• Defined as resistance to INH and RIF• Caused by inconsistent or partial treatment of

susceptible TB (primary)• Cure rates <70% cause the epidemic and drug

resistance to increase• Drugs are more toxic and expensive, and less

effective; treatment more difficult/expensive, and more likely fatal in developing world

• Poorly supervised, incomplete treatment is worse than no treatment at all: Prevention of MDRTB is the primary strategy to address MDRTB

USAID TB Strategy• Support for the STOP TB Initiative• Establishment of field sites/programs to serve

as models for innovative wide-scale TB control• Investigation/implementation of potential

technologies and methodologies for TB prophylaxis, diagnosis, and treatment

• Support for surveillance to monitor TB trends and identify MDRTB strains before they become widespread

USAID Expanded Response• Continued investments in global and regional

partnerships:– support for the Stop TB initiative– continued work with other USG agencies– Global partnership to develop new anti-TB drugs– Global Drug Facility– New International coalition of organizations and

agencies including KNCV, IUATLD, WHO, CDC, ALA/ATS to provide TA/develop TB expertise

– Continued support for coordinated research to optimize diagnostics and treatment regimens

USAID Expanded Response

• Expanded research investments– rapid and sensitive TB diagnostic tests– increase funding, work with our partners to

mobilize efforts and expertise of PH workers, industry, academic researchers, donors, other partners in lab/OR components

– Target collaborative efforts to develop cost-effective TB drugs and combination therapies

– Potential expansion to vaccine development

USAID Expanded Response

• Focused, expanded programs in key countries, targeting– countries of greatest need, defined by TB

burden– countries with high HIV/AIDS prevalence– countries at risk of escalating MDR

epidemics

TB Country ProgramsUSAID - 2001

New/Expanded Country ProgramsDR Congo Cambodia Russia*Ethiopia India*Kenya Indonesia BrazilMalawi Philippines* Dominican RepublicSenegal HaitiUganda Mexico

On-Going ProgramsSouth Africa, Bolivia, El Salvador, Honduras, Peru, Central Asian

Republics, Ukraine, Romania, SE Europe Regional

*Existing program

Partners/Implementers

• Current– WHO, CDC, Fogarty/NIH, IUATLD, Gorgas

Institute, MSH/RPM, PATH, QAP, FHI – TBCTA (TB Coalition for Technical

Assistance)

• Potential– NGOs (MSF, DOW, MERLIN)– Foundations, World Bank, US Model Centers

Global Programs/Mechanisms

• Global/Bureau umbrella agreements with WHO and CDC

• Multiple agreements to address technical areas: RPM, PATH, TBCTA

• New interagency alliances under development for drug procurement/ management/development

• Standard indicators already developed

Common Health Assumptions not applicable to TB

• Access is necessary but NOT sufficient– Drugs– Services

• Not every health center/NGO site appropriate as TB care center

• Poor program is worse than no program at all

Priorities of TB Control

• Make sure the person completes TB treatment!

• Do not cause drug resistance; a poor TB program is worse than no TB program!

• Treating non-pulmonary cases and those infected without active disease are of lesser public health importance

With TB, treatment is more than treatment, treatment is

prevention

Role of Rifampicin

• Necessary for short-course treatment

• Essential for at least first 2 months of regimens

• Bactericidal for rapidly dividing and slow-growing organisms

• Prevents emergence of resistance to other drugs

• Intermittent treatment more effective than daily treatment in animal model; equally effective in clinical trials

Role of Isoniazid

• Mainstay of anti-TB treatment• Life saving in TB meningitis • Bactericidal for rapidly dividing organisms• Prevents emergence of resistance to other

drugs• Intermittent treatment more effective than daily

treatment in animal model; equally effective in clinical trials

• Safe and effective for preventive treatment

DOTS can reduce the TB burden

ChileUruguayS. KoreaCubaPeruNew YorkBeijingEdinburgh

-25

-20

-15

-10

-5

0

Annual percentage decline in incidence/prevalence

33

TB: the leading single infectious cause of death in SE Asia

0

100

200

300

400

500

600

700

800

Tuberculosis HIV STD Malaria TropicalDiseases

Measles

Number of deaths (1000s)

Deaths from infectiousagents in South-East

Asia

TB is a Leading Killer of Women

48,000101,000

493,000538,000

605,000

TropicalDiseases

STD MaternalMortality

Malaria TB

Deaths among women

Diagnosis of pulmonary TB

Patients with TB feel ill and seek care promptly Active case finding is unnecessary and

unproductive Microscopy is appropriate technology, indicating

infectiousness, risk of death, and priority for treatment

X-ray is non-specific for TB diagnosis Serological and amplification technologies (PCR,

etc.) currently of no proven value in TB control

Proportion of pulmonary TB patients with positive AFB smears

0

10

20

30

40

50

60

70 HIV Negative

Early HIV

Late HIV

AFB positivity in TB patients

Prompt treatment of infectious cases reduces spread of TB

• Smear-positive patients usually seek care

• Smear-positive patients are 4-20 times more infectious

• Untreated, a smear-positive patient may infect 10-15 persons/year

• Smear-positive patients are much more likely to die if untreated

Rouillon A. Tubercle 1976;57:275-99

Severe and less severe forms of extra-pulmonary TB

Severe

Meningitis

Less Severe

Lymph nodes

Miliary

Pericarditis Bone (excluding spine)

Bilateral or extensivepleural effusion

Spinal

Intestinal

TB/HIV, A Clinical Manual, World Health Organization 1996

Pleural effusion (unilateral)

Peripheral joint

Role of Pyrazinamide

• Essential for 6- and 8-month regimens

• No benefit if given > 2 months

• Relatively ineffective at preventing emergence of resistance to other drugs

3.4%10.3%

0

20

40

60

80

100

Pyrazinamide No Pyrazinamide

Rel

apse

s (%

)

Pyrazinamide essential for first two months of 6/8-month treatment

Am Rev Respir Dis 1987;136:1339-42

Relapses

Role of Ethambutol/ Streptomycin

• Prevent emergence of resistance to other drugs given

• Hasten sputum conversion

• Bacteriostatic or weakly bactericidal against rapidly dividing organisms

3% 5%

0

20

40

60

80

100

HIV-uninfected HIV-infected

Relapse rates low with directly observed treatment in both HIV(+)

and HIV(-) patients

Am J Respir Crit Care Med 1996:154:1034-38

Relapse rates

Rel

apse

(%

)

Adverse reactions to anti-TB drugs

Isoniazid Peripheral neuropathy

Hepatitis

Drugs Adverse reactions

Pyrazinamide Joint pains

Hepatitis

Rifampicin

Gastroentestinal (anorexia, nausea,vomiting, abdominal pain)

Hepatitis

Reduced effectiveness of oralcontraceptive pill

Ethambutol Optic neuritis

Streptomycin Auditory & vestibular nerve damage

(also to foetus)

Renal damage

Management of Drug Logistics

Managementof Stocks

CHOICE

USE PURCHASE

DISTRIBUTIONSTORAGE

QuantificationFinancing

Tender bidsOrder

Quality Control

Re-packagingTransportation

Informationfor user &

for consumer

Adequate buffer stocks must be maintained at national, state/regional, and local levels