Challenge in Lebanon as around the World

OPL 22nd Pharmaceutical Congress 2014 Tuberculosis A Continuing i Public Health Challenge in Lebanon as around the World Myrna Germanos Haddad Hematology/Immunology Lab Hotel-Dieu de France Hospital Beirut

Tuberculosis Key facts in 2013 Second only to HIV/AIDS as the greatest killer worldwide 9 million people infected (1/3) 1.5 million died from the disease. > 95% of TB deaths in low and middle income countries 550 000 children became ill with TB 80 000 HIV negative e children died of TB. Globally in 2013, an estimated 480 000 people developed multidrug resistant TB (MDR TB). The Millennium Development Goal : to reverse the spread of TB by 2015. Between 1990 and 2013,: 37 million lives were saved through TB diagnosis and treatment between 2000 and 2013 (45%)

Ministry of Labor August 2014

/ Health 22 October 2014 Last updated at 15:17 GMT WHO revises global tuberculosis estimate up by 500,000 : in 2013 9 million people had developed TB around the world, up from 8.6 million in 2012, the WHO said About 1.5 million people died from TB, including 360,000 people p who were HIV positive TB kills 1.3m, second only to HIV.

History of TB (1) TB has affected humans for millennia May have evolved from Mycobacterium bovis acquired by humans from domesticated animals ~15,000 years ago Endemic in humans in villages ~ 10,000 years Epidemic in the cities Europe after 1600 (cities)

Egyptian mommies History of TB (2)

History of TB (3) 354 322 BC Aristotle When one comes near consumptives one does contract their disease The reason is that the breath is bad and heavy In approaching the consumptive, one breathes this pernicious air. One takes the disease because in this air there is something disease producing. Described by Hippocrate

History of TB (4) Historically known by a variety of names, including: Consumption Wasting disease White plague TB was a death sentence for many Vintage image circa 1919 Image credit: National Library of Medicine

History of TB (5) Scientific Discoveries in 1800s Until mid 1800s, many believed TB was hereditary 1865 Jean Antoine Villemin proved TBwas contagious 1882 Robert Koch discovered M. tuberculosis, the bacterium that causes TB Mycobacterium tuberculosis Image credit: Janice Haney Carr

M tuberculosis as causative agent for tuberculosis Robert Koch 1882 1886

History of TB (6) 1882 Robert Koch one seventh of all human beings die of tuberculosis and if one considers only the productive middle age groups, tuberculosis carries away one third and often more of these

History of TB (7) Sanatoriums Before TB antibiotics, many patients were sent to sanatoriums Patients followed a regimen of bed rest, open air, and sunshine TB patients who could not afford sanatoriums often died at home Sanatorium patients resting outside 14

The Armenian Sanatorium (Azounieh). 11 1923

The Armenian Sanatorium (Azounieh). Patients from Lebanon and surrounding countries, (Syria, (y Iraq, Palestine, Saudi Arabia, Kuwait, and Egypt) The Iraqi and Saudi Arabian Governments have maintained beds for their respective destitute patients. However, after the Lebanese Civil War this no longer takes place.

The Bhannes sanatorium 1910 ( Filles de la Charité)

Breakthrough in the Fight Against TB (1) Drugs that could kill TB bacteria were discovered Streptomycin (SM) discovered in 1943 ( S.A. WAKSMANN) Isoniazid (INH) and p aminosalicylic acid (PAS) discovered between 1943 and 1952 Pyrazinamide, ethambutol, rifampicine

Breakthrough in the Fight Against TB (2) After 50 years : 2013 Bedaquiline (Sirturo ) FDA approved Only availbale in the US

Breakthrough in the Fight Against TB (3) TB death rates began to drop dramatically Each year, fewer people got TB Most TB sanatoriums ( US and Europe) had closed by mid 1970s

Breakthrough in the Fight Against TB (4) 1900 1940 1940 TB rates decreased before TB drugs available Better nutrition, less crowded ddhousing Public health efforts Earlier diagnosis Limit transmission to close contacts TB sanatoria Surgery

Increase in TB in mid 1980s TB Resurgence Contributing factors: Inadequate funding for TB control programs TB HIV co infection epidemic Increased dimmigration i i from countries where TB is common (globalization allows TB to travel) Increase and spread of March 16 1992 Newsweek Magazine Cover multidrug resistant TB March 16, 1992 Newsweek Magazine Cover

TB History Timeline 1993: TB cases decline due to increased funding and enhanced dtb control efforts 1865: Jean Antoine 1943: Streptomycin Villemin (SM) a drug used to proved TB is treat TB is contagious discovered Mid 1970s: Most TB sanatoriums closed 1840 1860 1880 1900 1920 1940 1960 1980 2000 1882: 1943 1952: Mid 1980s: Robert Koch discovers Two more drugs are Unexpected rise in TB M. tuberculosis discovered to treat TB: cases INH and PAS

TB Transmission (1) Transmission is defined as the spread of an organism, such as M. tuberculosis, fromone one person to another.

M. tuberculosis causes most TB Mycobacteria that cause TB: M. tuberculosis M. bovis M. africanum M. microti M. canetti TB Transmission (2) Types of Mycobacteria Mycobacteria that do not cause TB e.g., M. avium complex M. tuberculosis

TB Transmission (3) TB is spread person to person through the airvia droplet nuclei M. tuberculosis may be expelled when an infectious person: Coughs Sneezes Speaks Sings Transmission occurs when another person inhales droplet nuclei

TB Transmission (4) Dots in air represent droplet nuclei containing M. tuberculosis

TB Transmission (5) Probability that TB will be transmitted depends on: Infectiousness of person with TB disease Environment in which exposure occurred Length of exposure Virulence (strength) th) of the tubercle bacilli The best way to stop transmission is to: Isolate infectious persons Provide effective treatment to infectious persons as soon as possible

TB Pathogenesis

TB Pathogenesis (1) How an infection or disease develops in the body.

TB Pathogenesis (2) Latent TB Infection (LTBI) Occurs when tubercle bacilli arein the body, but the immune system is keeping them under control Dt Detected tdby the Mantoux tuberculin skin test t(tst) or by blood tests such as interferon gamma release assays (IGRAs) which include: QuantiFERON TB Gold test (QFT G) QuantiFERON TB Gold In Tube (QFT GIT) T Spot.TB test (T SPOT) People with LTBI are NOT infectious

TB Pathogenesis (3) TB Disease Develops when immune system cannot keep tubercle bacilli under control May develop very soon after infection or many years after infection About 10% of all people with normal immune systems who have LTBI will develop TB disease at some point in their lives People with TB disease are often infectious

TB Pathogenesis (4) Droplet nuclei containing tubercle bacilli areinhaled, Droplet nuclei containing tubercle bacilli are inhaled, enter the lungs, and travel to small air sacs (alveoli)

TB Pathogenesis (5) 2 bronchiole blood vessel tubercle bacilli alveoli li Tubercle bacilli multiply in alveoli, where infection begins

TB Pathogenesis (6) 3 bone brain lung kidney A small number of tubercle bacilli enter bloodstream and spread throughout body

TB Pathogenesis (7) LTBI 4 special immune cells form a barrier shell (in this example, bacilli are in the lungs) Within 2 to 8 weeks the immune system produces special immune cells called macrophages that surround the tubercle bacilli These cells form a barrier shell that keeps the bacilli contained and under control (LTBI) 38

TB Pathogenesis (8) TB Disease 5 shell breaks down and tubercle bacilli escape and multiply (in this example, TB disease develops in the lungs) If the immune system CANNOT keep tubercle bacilli under control, bacillibeginbegin to multiplyrapidly and cause TB disease This process can occur in different places in the body

TB Invades/Infects the Lung Effective immune response Infection limited it to small area of lung Immune response insufficient i

Natural History of TB Infection Exposure to TB No infection Infection (70-90%) (10-30%) Latent TB (90%) Never develop Active disease Untreated Active TB (10%) Treated Die within 2 years Survive Die Cured

LTBI vs. TB Disease Latent t TB Infection (LTBI) TB Disease (in the lungs) Inactive, contained tubercle bacilli in the body TST or blood test results usually positive Chest x-ray usually normal Active, multiplying tubercle bacilli in the body TST or blood test results usually positive Chest x-ray usually abnormal Sputum smears and cultures negative No symptoms Not infectious Not a case of TB Sputum smears and cultures may be positive Symptoms such as cough, fever, weight loss Often infectious before treatment A case of TB

Latent TB vs. Active TB Latent TB (LTBI) (Goal = prevent future active disease) = TB Infection = No Disease = NOT SICK = NOT INFECTIOUS Active TB (Goal = treat to cure, prevent transmission) = TB Infection which hhas progressed to TB Disease = SICK (usually) = INFECTIOUS if PULMONARY (usually) = NOT INFECTIOUS if not PULMONARY (usually)

TB Pathogenesis Progression from LTBI to TB Disease

Progression to TB Disease (1) Risk of developing TB diseaseis highest the first2 years after infection People with LTBI can be given treatment to prevent them from developing TB disease Detecting TB infection early and providing treatment helps prevent new cases of TB disease 45

Progression to TB Disease (2) Some conditions increase probability of LTBI progressing to TB disease Infection with HIV Organ transplant Chest x ray findings suggestive of previous TB Substance abuse Recent TB infection Prolonged therapy with corticosteroids and other immunosuppressive therapy, such as prednisone and tumor necrosis factor alpha [TNF α] antagonists Silicosis Diabetes mellitus Severe kidney disease Certain types of cancer Certain intestinal conditions Low body weight

Progression to TB Disease (3) People Exposed to TB Not TB Infected Latent TB Infection (LTBI) Not Infectious Not Infectious Negative TST or QFT-G test result No TB Infection Positive TST or QFT G test result Latent TB Infection May go on to develop TB disease

Progression to TB Disease (4) Inan HIV infected person, TB can develop in one of two ways: Person with LTBI becomes infected with HIV and then develops TB disease as the immune system is weakened TB and HIV Person with HIV infection becomes infected with M. tuberculosis and then rapidly develops TB disease Image credit: Mississippi State Department of Health

Progression to TB Disease (5) TB and HIV People who are infected with both M. tuberculosis and HIV are much more lk likely l to develop TB disease TB infection and NO risk factors TB infection and dhivi infection (pre-highly Active Antiretroviral Treatment [HAART]) Risk is about 5% in the Risk is about 7% to 10% first 2 years after PER YEAR, a very high infection and about 10% risk over a lifetime over a lifetime

TB Pathogenesis Sites of TB Disease 50

Sites of TB Disease (1) Bacilli may reach any part of the body, but common sites include: Brain Larynx Bone Kidney Lymph node Pleura Lung Spine

Sites of TB Disease (2) Location Frequency Pulmonary TB Lungs Most TB cases are pulmonary Extrapulmonary TB Places other than lungs such as: Larynx Lymph nodes Pleura Brain Kidneys Bones and joints Found more often in: HIV-infected or other immunosuppressed persons Young children Miliary TB Carried to all parts of body, through bloodstream Rare

Sites of TB Disease (2)

Diagnosis of LTBI Available testing methods for M. tuberculosis infection: Mantoux tuberculin skin test (TST) Blood tests known as interferon gamma release assays (IGRAs): QuantiFERON TB Gold test (QFT G) QuantiFERON TB Gold In Tube (QFT GIT) T SPOT TB 54

Mantoux Tuberculin Skin Test (1) TST is administered by injection Tuberculin is made from proteins derived from inactive tubercle bacilli Most people p who have TB infection will have a reaction at injection site Syringe being filled with 0.1 ml of liquid tuberculin 55

Mantoux Tuberculin Skin Test (2) 0.1 ml of 5 tuberculin units of liquid tuberculin are injected between the layers of skin on forearm HCW administering i i Mantoux TST 56

Mantoux Tuberculin Skin Test (3) Forearm should be examined within 48 72 hours by HCW Reaction is an area of induration (swelling) around injection site Induration is measured in millimeters Erythema (redness) )is not measured Only the induration is measured

Mantoux Tuberculin Skin Test (5) Interpreting the Reaction Induration of > 5 mm is considered positive for: People living with HIV Recent close contacts of people with infectious TB People with chest x ray findings suggestive of previous TB disease People with organ transplants Other immunosuppressed patients 58

Mantoux Tuberculin Skin Test (6) Interpreting the Reaction Induration of > 10 mm is considered a positive reaction for: People who have recently come from areas where TB is common People who inject drugs People who live or work in high risk congregate settings Mycobacteriology lb laboratory workers

Mantoux Tuberculin Skin Test (7) Interpreting the Reaction Induration of > 10 mm is considered d a positive reaction for: People with certain medical conditions that increase risk for TB Children younger than 4 years old Infants, children, or adolescents exposed to adults in high risk categories

Mantoux Tuberculin Skin Test (8) Interpreting the Reaction Induration of > 15 mm is considered a positive reaction for people who have no known risk factors for TB 61

IGRA guidelines consensus Guidelines on IGRAs are now published across much of Europe The newest are the UK NICE guidelines issued 23 rd March 2011, which reflect the most up todate data on IGRAs General consensus on features of IGRA vs TST IGRAs are more specific than the TST Hence preferred in BCG vaccinated persons and all positive TSTs should be confirmed with an IGRA IGRAs detect infected persons that the TST does not Hence IGRAs should be used instead of, or in addition to, the TST in immunosuppressed persons IGRAs bring bi logistical i ladvantages of only one patient visit ii Hence IGRA use is recommended in hard to reach populations Using IGRAs is more cost effective than not using them Using only the TST is the most expensive strategy IGRA use in children is still an area under debate National Institute for Health and Clinical Excellence (NICE) Tuberculosis. NICE Clinical Guideline 117. March 2011

/ Health In the last few years a new DNA detection technique called GeneXpert has been endorsed by the WHO From a sample of sputum it can detect whether a sample contains TB and whether it is resistant to rifampicin in about three hours But for full drug resistance information the patient has to wait longer.

/ Health 24 September 2014 Last updated at 09:37 GMT Breath test for TB developed By Michael Eyre Science reporter

/Health: Breath test for TB developed d It provides rapid information on drug resistance that takes up to six weeks using standard methods, US scientists report in the journal, Nature Communications. The bacteria emit nitrogen gas signature within 10 minutes of exposure to isoniazid in rabbits. Gas detected by a mass spectrometer

Rapid tuberculosis tests Blood Non accurate Non FDA approved False negative results

Diagnosis of TB Disease 1. Medical history 2. Physical examination 3. Test for TB infection 4. Chest x ray 5. Bacteriologic examinations : Acid fast bacilli (AFB), Nucleic Acid Amplification Tests (NAA) Culturing and Identifying Specimen Drug Susceptibility Testing

Patients who have any tubercle bacilli seen in their sputum have a positive smear. Patients who have positive smears areconsidered infectious because they can cough tubercle bacilli into the air.

Treatment of TB disease Most TB is curable, but Four or more drugs required for the simplest regimen 6 9 or more months of treatment required Person must be isolated until non infectious Directly observed therapy to assure adherence/completion is recommended Side effects and toxicity of drugs common May prolong treatment t t May prolong infectiousness Other medical and psychosocial py conditions complicate therapy TB may be more severe Drug drug interactions common

Treatment of LTBI (1) LTBI is treated to prevent the development of TB disease 70

High Priority for LTBI Treatment (2) High priority groups for LTBI treatment if positive IGRA or TST result of >10 mm: People who have come within last 5 years from countries where TB is common People who inject drugs People who live or work in high risk facilities People who work in mycobacteriology laboratories

High Priority for LTBI Treatment (3) High priority groups for LTBI treatment if positive IGRA or TST result of > 10 mm: (cont.): People with medical conditions that increase risk of TB disease Children younger than 4 years old Infants, children, and adolescents exposed to adults in high risk groups 72

Low Priority for LTBI Treatment Individuals without any risk factors generally should not be tested for TB infection However, individuals with no risk factors who are tested and have a positive IGRA or TST result of >15 mm should be evaluated for LTBI treatment

Treatment tof LTB What is the preferred LTBI treatment regimen? INH given daily for 9 months. 74

Treatment of TB Disease Initial regimen should contain the following four drugs: Isoniazid (INH) Rifampin (RIF) Pyrazinamide (PZA) INH RIF Ethambutol (EMB) PZA EMB 75

Treatment of TB Disease Treatment must contain multiple drugs to which organisms are susceptible Treatment with a single drug can lead to the development of drug resistant resistant TB 76

Special Considerations for LTBI (1) Directly Observed Therapy (DOT) DOT is when a health care worker (HCW) or another designated person watches a patient swallow each dose of medication Used to hl help patients adhere to treatment Should be considered for people who are at high risk for TB or suspected to be non adherent 77

Drug Resistant TB 78

Drug Resistant TB (1) To at least one TB treatment drug Isoniazid (INH) Rifampin (RIF) Pyrazinamide (PZA) Ethambutol (EMB) d Resistant means drugs can no longer kill the bacteria

Primary Resistance Drug Resistant TB (2) Caused by person-to-person transmission i of drug-resistant t organisms Secondary Develops during TB treatment: t t Resistance Patient was not given appropriate treatment regimen OR Patient did not follow treatment regimen as prescribed

Drug Resistant TB (3) Mono-resistant Poly-resistant Multidrug resistant (MDR TB) Extensively drug resistant (XDR TB) Resistant to any one TB treatment drug Resistant to at least any 2 TB drugs (but not both isoniazid and rifampin) Resistant to at least isoniazid and rifampin, the 2 best first-line TB treatment drugs Resistant to isoniazid and rifampin, PLUS resistant to any fluoroquinolone AND at least 1 of the 3 injectable second-line drugs (e.g., amikacin, kanamycin, or capreomycin)

BCG No longer in use in many countries except in exposed children

Epidemiology

TB: the disease in Lebanon 2012 632 cases Smear positive: 251 cases (39.7%) Smear negative: 131 cases (20.8%) Extra pulmonary: 250 cases (39.5%) MDR TB : 7 cases TB HIV: 3 cases Children: 45 cases (7%)

Incidence in the origin countries of non national patients living in Lebanon Incidence in: Lebanon: 15/100 000 Syria: 19/100 00 Sri Lanka: 66/100 00 Sudan: 117/100 00 Bengladesh: 225/100 00 Ethiopia: 258/100 00 Philippines : 270/100 00

Trend of Tuberculosis incidence in Lebanon Had been declining till the year 2011. In 2012, the National TB Programme (NTP) observed that 48% of all notified cases were among non Lebanese. The 27% increase in TB incidence in 2012 is attributed to Syrian refugees population

Trend of TB cases notification in national and non national population by years.

Before the Syrian crisis, in 2011, the estimated prevalence of TB : in Syria was 23 per 100,000 population in Lebanon Lb 19 per 100,000000 population

NTP indicates that currently over half of the people referred to the programme for investigations and treatment are non Lebanese nationals. As of August 2013, according to the NTP, 100 Syrian refugees have been diagnosed with TB in Lebanon, including three cases of multi drug resistant (MDR) TB.

There has been Syrian and Lebanese returnees TB patients who were forced to interrupt their treatment because of the worsening security situation inside Syria. This interrupted TB treatment can lead to weaker identification of TB in the communities, low cure rate and potentially increase in multidrug resistant (MDR) TB, which is difficult and expensive to treat

The National Tuberculosis Programme (NTP) in Lebanon follows (Directly Observed Treatment Strategy), High treatment success rate of 87% among Lebanese nationals.

The NTP in Lebanon has eight TB control centers across the country.

WHO Lebanon is ensuring the provision of anti TB medication for 200 Syrian refugees/year in addition to the 600 Lebanese cases. TB as an airborne disease spreads especially in congested and unhygienic i living i conditions, i such as the ones many Syrian refugees in Lebanon as well as returning Lb Lebanese families from Syriaare exposed to. One important issue in TB control is the provision of TB services in remote areas and among mobile populations. p Weakened or disrupted services for these communities can complicate diagnosis and treatment potentially can complicate diagnosis and treatment, potentially leading to an increase in MDR TB.

LTBI: To treat or not to treat? 3 to 4 000 home workers tested for TST Very High rate of positive cases for TST Prophylactic treatment of LTBI not supported by WHO Heavy financial burden Prophylaxic treatment failed to lower the % of TBI in african fi countries ti LTBI treatment advised only in chidren

LTBI: To treat or not to treat? TBI : the disease has a huge cost on the Lebanese government (sana, drugs ) LTBI :decision for prophylactic treatment depends on the decision of the Minister of PH Under study by a committee

TB: What are the Challenges Guidelines, Laws andregulations Guidelines treatment, contact investigation, prevention data driven/expert opinion Laws case reporting, isolation of infectious individuals id Laws/regulations travel restrictions, entry into the country International travel regulations WHO

TB : Prevention and Control latiiti Activities Identification and treatment of TB cases Identification, evaluation and treatment of high risk close contacts of cases Surveillance/case reporting TB laboratory services Targeted testing and LTBI treatment for high risk populations Training/continuing i i i education for health h care providers Program evaluation

TB continues as a public health issue many problems to face: Old public health concepts (isolation of infectious individuals, closely monitored treatment, recognition and preventive treatment for infected contacts) are still critical, but will not eradicate TB Care providers not familiar with signs/symptoms of TB Diagnosis i delayed dl d Inappropriate treatment Drug resistance due to improper use of drugs Must address both nationals and newcomer populations Older, remote exposure Incarcerated, homeless, history of drug, alcohol use Newcomers from high TB prevalence areas

Challenges to Public Health System Public health workers must: Educate Identify support services (food, housing) Treat TB in geriatric populations Treat TB in children Deal with alcohol, drug abusing, incarcerated patients Manage TB in patients with underlying medical conditions Provide culturally appropriate care for non Lebanese /nonliterate populations Treat TB cases with drug resistant TB

World TB Day, 24 March 2014 To raise awareness about the burden of (TB) prevention and control efforts worldwide. Of the 9 million people a year who get sick ikwith ihtb, 3 million of them are "missed" by health systems. World TB Day provides the opportunity to call for further action to reach the 3 million.

The Stop TB Strategy WHO has developed da new six point Stop TB Strategy its goal: to dramatically reduce the global burden of tuberculosis by 2015 To ensure all TB patients benefit from universal access to high quality diagnosis and patient centered treatment. The development of new and effective tools to prevent, detect and treat TB. The engagement of all care providers

The Stop TB Strategy The Global Drug Facility GDF (created 2001) : TB treatments & diagnostics to population p in need. In 2014 > 24 million treatment courses to 133 countries Provides technical assistance and innovative tools to countries, and supports key projects like TB REACH, Expand TB,TBExpert in thediagnostic field.

A new vaccine development of shorter, simpler treatment regimens faster more accurate diagnostic tools(genexpert device) reduce the cost of innovative technologies and accelerate their adoption. Research

Theguardian.com, Monday 23 june 2014 «Genetictest for TB could dramatically improve diagnosis in children» Reports an article il published in the «NEJM» Identifies specific gene sequences that appear more frequently in TB infection I th f di i f i f t d Improve the accuracy of diagnosisof infected children in developing countries more difficult to diagnose thanadults

TB? STILL MILESTONES TO GO