TB BASICS Refresher ² What is tuberculosis?

The Lung Health Program International Journalists as Global Health Advocates
Lee Reichman, MD, MPH Cancun, Mexico December 1-7, 2009

TB Historical Permutation
‡ 17th - 18th centuries TB took 1 in 5 adult lives ‡ 1850 - 1950 one billion people died of TB ‡ Current decade 2000-2010
± 300 million new infections ± 90 million new cases ± 30 million deaths

‡ More people died from TB last year than any year in history

TB Could Be Eliminated Because We Understand It We know its:
‡ Cause ‡ Transmission ‡ Treatment ‡ Prevention

TB Isn·t Eliminated
Because: ‡ Nobody seems to care
This wouldn¶t be tolerated for any other disease

Deaths Due To:
TB (annually) SARS Avian Influenza Anthrax Mad Cow Disease Smallpox 1,770,000 813 6,250 5 1 (Cow) 0

What is Tuberculosis?
‡ Infectious disease caused by a germ called Mycobacterium tuberculosis ‡ It is spread through the air ‡ Usually affects the lungs although it can affect any organ ‡ Is spread when someone who is sick with TB disease of the lungs coughs or sneezes, releasing germs and a person nearby breathes in these infected droplets

What happens when you breathe in TB germs?
‡ A person infected with the TB bacteria is not necessarily sick
± TB infection: The natural defense system can keep the bacteria under control and person is not sick ± TB disease (active TB) : Immune system cannot keep the bacteria under control and they multiply rapidly, making the person sick

Factors that impact transmission
‡ Infectiousness of the person with TB disease
± Number of bacteria ± Type of TB: pulmonary vs. extra-pulmonary

‡ Environment
± Volume of shared space ± Ventilation and direct sunlight

‡ Length of exposure ‡ Intensity of exposure
± Disease of lungs, upper airways, larynx ± Cough ± Incorrect or incomplete treatment

Most effective way to stop transmission
‡ Isolate patients with suspected or confirmed TB disease immediately ‡ Start treatment with anti-TB medicine

As long as TB patient is on appropriate TB medicines and takes medications as directed, the potential to infect other people will decline rapidly.

Development of TB disease
‡ HIV-negative: about 10% of people infected with TB will develop TB disease within their lifetime ‡ Anyone can get TB! ‡ However, there are some groups at greater risk for developing TB disease:
± ± ± ± ± People with HIV infection Those infected in the last 2 years Babies and young children People who inject illegal drugs or abuse alcohol People sick with other diseases that weaken the immune system ± Elderly people

Diagnosis of TB Disease
‡ A person suspected of having TB disease may have these symptoms:
± Fever, cough (•3 weeks), chest pain, night sweats, weight loss, fatigue, coughing up blood, decreased appetite

‡ Diagnosis: ± Patient history and clinical exam ± Laboratory tests ± Chest x-rays

Treatment of TB Disease
‡ TB is curable! ‡ TB treatment strategy (DOTS)
± Standardized, short-course ± Proper patient management

‡ Treatment
± 6 months
‡ 4 antibiotic-drugs for 2 months ‡ 2 antibiotic-drugs for 4 months

TB/HIV
‡ TB/HIV is a lethal combination, each speeding the other¶s progress ‡ Risk of progression of TB disease much greater in HIV-infected persons ± About 10% chance every year ‡ TB is leading cause of death in those with HIV

Co-Existence of HIV & TB infection

TB Infection

HIV Infection

10% per lifetime

10% per year .0017% per year

Risk of Active TB

HIV Drives the TB Epidemic: TB Trends in Africa 1980-2006 198000

Zim a e T a n a n ia
600

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a a i th A fric a

f rm s 1 N tific a ti n ra te a

00

400

00

200

100

0

1980

198

1990

199

2000

200

Drug Resistant TB
‡ Man-made phenomenon ‡ Causes: ± Inadequate or incomplete treatment ± Interruption in the supply of essential drugs ± Poor quality drugs ‡ Treatment of MDR-TB ± Very long ± 18-24 months ± Toxic 2nd line drugs ± Expensive ‡ Persons at increased risk ± With history of TB treatment ± Received inadequate treatment for >2 weeks ± Contacts of known drugresistant patients ± Born or living in areas with high prevalence of drug-resistant TB

Pathogenesis of Drug Resistance ² 1
INH RIF P A
I R I

P

INH

I I

I I I

Pathogenesis of Drug Resistance ² 2
I I I I I I I I I I I I I I I I IP I IR I

INH RIF
IR IR IR IR IR IR IR IR IR IR
IRP

IR

Unsexy Tuberculosis
‡ Concern and attention re: XDR-TB is appropriate, but skips the more important message ‡ XDR-TB, MDR-TB, and drug-sensitive tuberculosis are all the same disease ‡ The only difference is that MDR-TB is drug-sensitive tuberculosis modified by inappropriate treatment or drug taking, and XDR-TB is MDR-TB thus modified ‡ We need to recognize that there are more than 9,000,000 new active drug-sensitive cases of tuberculosis globally that could be feeding drug resistance ‡ It might be a less sexy concept, but they all must be appropriately treated with current strategies (as well as new diagnostics, drugs, vaccines, and proper infection control measures) to avoid preventable MDR-TB and XDR-TB, which are always lurking ‡ Preventing active, drug-sensitive tuberculosis, or treating it properly, should be everybody¶s priority; it is the only way to prevent MDR-TB and XDR-TB - Reichman, LB: The Lancet, 2009

TB Remains a Global Killer Why does TB still infect one-third of the world¶s population and remain a global health threat despite the fact that highly cost-effective drugs are available to eradicate it?

The Global Burden of Tuberculosis NO NEW DRUGS / NO NEW TOOLS
‡ Last new drug class specifically for TB Rifampin (1968 Europe, 197 US) ‡ Most widely used diagnostic test Tuberculin (1890) ‡ Ineffective most widely used vaccine BCG (1919)
Wouldn¶t one think that largest killer of any single infection deserves better, newer tools?

Approved & Major Experimental ARV Drugs (1987-2008)
ARV Class Approved Experimental Under Investigation 12 9 10 2 1 0 0 25 55 5 17 5 3 10 2 0 0 30
Vitoria MAA, October 2008

Experimental Interrupted 8 6

NRTI NNRTI PI Entry Inhibitors Integrase Inhibitors Maturation Inhibitors Gene Therapy TOTAL

8

NEW TOOLS
‡ There are now 3 major global efforts to alleviate this problem ‡ Foundation for Innovative New Drugs (FIND) ‡ AERAS Global Vaccine Foundation ‡ Global Alliance for TB Drug Development

Aeras Global TB Vaccine Foundation
Mission: To develop new TB vaccines and ensure their availability to all who need them Goals: - To obtain regulatory approval and ensure supply of a new TB vaccine regimen to prevent TB in the next 7-10 years - To introduce 2nd generation vaccines with improved product profiles and efficacy against latent TB in 9-15 years

About Aeras
‡ International non-profit organization with 1 current partners, among them: ± Crucell NV (Netherlands), Statens Serum Institut (Denmark), GSK (Belgium), Max Planck Institute (Germany), UCLA (USA), University of Cape Town (S. Africa), St. Johns Medical College (India) ‡ Aeras forms joint development teams with partners to develop promising TB vaccine candidates ± currently there are 3 leading candidate regimens

‡ Primary funding provided by the Bill & Melinda Gates Foundation with additional funding from CDC, NIH, and Danida

Global Alliance for Tuberculosis Drug Development 
Growing Epidemic 5% increase in annual incidence in Africa 1% increase in annual incidence globally Current status 9 million new cases annually 2 million deaths annually
Reference: Global tuberculosis control: surveillance, planning, financing. WHO Report 2005.

The Problem:
Current TB therapy, though efficacious, is inadequate to control the global TB epidemic - too long and too complex

The TB Alliance
‡ ‡ ‡ ‡ Founded in 2000 (Cape Town Declaration) Independent Non-Profit Organization International Public-Private Partnership Based in New York with offices in Brussels and Cape Town

The TB Alliance
Mission ‡Develop new, better drugs for TB

‡Ensure affordability, access and adoption (AAA)
‡Coordinate and catalyze TB drug development activities worldwide

The Solution

New drugs combined into shorter, simpler regimens

TB Alliance Priorities
Based on impact and feasibility

1. Active disease 2. MDR-TB 3. TB/HIV co-infection . Latent infection (LTBI)

Challenges in TB Control
‡ Insufficient financial and human resources ‡ Inadequate healthcare infrastructure ‡ Weak laboratory capacity and lack of new rapid diagnostic tools ‡ Lack of new drugs that would cure TB in a shorter time ‡ Lack of effective vaccine that would prevent TB ‡ Poor use of infection control in healthcare settings ‡ Minimal social mobilization for TB control and minimal population awareness stigma ‡ HIV and MDR/XDR threats

Why do we need to care about TB in the rest of the world?

Lessons from Andrew Speaker
‡ TB has not gone away, it remains with us, highly prevalent and transmissible ‡ Anybody can get tuberculosis, not only poor people, minorities, or the foreign-born ‡ TB anywhere is TB everywhere ‡ All resistant TB, MDR and XDR TB is preventable by proper TB diagnosis and treatment ‡ Good public health is a silent secret, but when there is a small glitch, it becomes major news ‡ We desperately need new tools for TB diagnosis and treatment ‡ You don¶t want to sit on an airplane for 8 hours next to an untreated coughing person with any kind of TB, be it drug sensitive, MDR or XDR

INFORMATION LINE
1‡800‡4TB‡DOCS (482-3627) www.umdnj.edu/globaltb

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