Post on 26-Mar-2015
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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%
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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%
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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