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 people/year

When does TB infection become 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 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

X-ray-based evaluation causes over-diagnosis of TB NTI, Ind J Tuberc, 1974 Over- diagnosis

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 dont 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 when drug supply ensured Chaulk CP. JAMA 1998;279:943-8 Treatment Success DOT No DOT

prolongs survival of HIV-infected TB patients SCC with DOT SCC without DOT

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

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 Annual percentage decline in incidence/prevalence

33 TB: the leading single infectious cause of death in SE Asia Number of deaths (1000s) Deaths from infectious agents in South-East Asia

TB is a Leading Killer of Women Deaths among women

Diagnosis of pulmonary TB l Patients with TB feel ill and seek care promptly l Active case finding is unnecessary and unproductive l Microscopy is appropriate technology, indicating infectiousness, risk of death, and priority for treatment l X-ray is non-specific for TB diagnosis l Serological and amplification technologies (PCR, etc.) currently of no proven value in TB control

Proportion of pulmonary TB patients with positive AFB smears 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 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 PericarditisBone (excluding spine) Bilateral or extensive pleural effusion SpinalIntestinal 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

Pyrazinamide essential for first two months of 6/8-month treatment Am Rev Respir Dis 1987;136: Relapses

Role of Ethambutol/ Streptomycin Prevent emergence of resistance to other drugs given Hasten sputum conversion Bacteriostatic or weakly bactericidal against rapidly dividing organisms

Relapse rates low with directly observed treatment in both HIV(+) and HIV(-) patients Am J Respir Crit Care Med 1996:154: Relapse rates Relapse (%)

Adverse reactions to anti-TB drugs Isoniazid l Peripheral neuropathy l Hepatitis Drugs Adverse reactions Pyrazinamide l Joint pains l Hepatitis Rifampicin l Gastroentestinal (anorexia, nausea, vomiting, abdominal pain) l Hepatitis l Reduced effectiveness of oral contraceptive pill Ethambutol l Optic neuritis Streptomycin l Auditory &vestibular nerve damage (also tofoetus) l Renal damage

Management of Drug Logistics Management of Stocks CHOICE USEPURCHASE DISTRIBUTION STORAGE Quantification Financing Tender bids Order Quality Control Re-packaging Transportation Information for user & for consumer Adequate buffer stocks must be maintained at national, state/regional, and local levels