FORGOTTEN BUT NOT GONE

Lee B. Reichman, MD, MPH Lille, France October 2011

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 Isnt Eliminated
Because:
Nobody seems to care This wouldnt be tolerated for any other disease

Deaths Due To:

TB (annually) 1,770,000

SARS
Avian Influenza

813
18,000

Anthrax
Mad Cow Disease Smallpox

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

The Global Burden of TB 2010

Estimated number of cases

Estimated number of deaths

All forms of TB HIV-associated TB Multidrug-resistant TB (Prevalent)

8.8 million
(range: 8.59.2 million)

1.45 million
(range: 1.21.6 million)

1.1 million (13%)

(range: 1.01.2 million)

350,000
(range: 320,000390,000)

650,000 about 150,000 (460,000 870,000)

Source: WHO Global Tuberculosis Control Report 2011

Estimated MDR-TB incidence rates, 2009 (new and previously treated)

Selected countries of the former Soviet Union: Estonia: 7 / 100,000 Kazakhstan: 57 / 100,000 Russia: 27 / 100,000 Tajikistan: 59 / 100,000

African countries with estimated MDR-TB incidence rates 15 MDR-TB cases per 100,000 population Botswana: 27 / 100,000 Mozambique: 16 / 100,000 Namibia: 17 / 100,000 Rwanda: 16 / 100,000 South Africa: 26 / 100,000 Swaziland: 23 / 100,000 Zimbabwe: 19 / 100,000

MDR-TB cases emerging annually, per 100,000 population

China: 7 / 100,000

India: 8 / 100,000

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 the 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

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

700

Zimbabwe Tanzania
600

Kenya Cote d'Ivoire

Malawi South Africa

Notification rate (all forms)/100k

500

400

300

200

100

1980

1985

1990

1995

2000

2005

Drug Resistant TB
Man-made phenomenon
Causes: Inadequate or incomplete treatment Interruption in the supply of essential drugs Poor quality drugs

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

Treatment of MDR-TB Very long 18-24 months Toxic 2nd line drugs Expensive

Pathogenesis of Drug Resistance 1

INH RIF PZA
I
R I

INH

I I

I I I

Pathogenesis of Drug Resistance 2

I I I I I I I I I I I I I IP I

IR
I

INH RIF
IR IR IR
IR
IRP

I
I I

IR IR

IR IR IR

IR 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 everybodys 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 worlds 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, 1974 US) Most widely used diagnostic test Tuberculin (1890) Ineffective most widely used vaccine BCG (1919)
Wouldnt one think that largest killer of any single infection deserves better, newer tools?

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 14 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

Based on impact and feasibility

TB Alliance Priorities

1. Active disease
2. MDR-TB 3. TB/HIV co-infection 4. 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 dont 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
18004TBDOCS (482-3627) www.umdnj.edu/globaltb