Team:Paris Bettencourt/Human Practice/TB France

While looking at TB facts and thinking on how could synthetic biology be useful to deal with TB, we asked Christopher Dye, Director of Health Information in the Office of HIV/AIDS, Tuberculosis, Malaria and Neglected Tropical Diseases at the World Health Organization (WHO) , that very question. Here are some elements of his answers : « Differently, depending on where you are – you have to do the local research on this » « Yes very interdisciplinary – try to see problems from the viewpoint of others »
Therefore we followed his advice and tried to investigate locally (in France) and to meet different actors (Medical Personnal, Patients, Political and social actors). Why France? First, it was the easiest to meet people and to get reports. Secondly, it is very interesting, to look at TB in a country, where people thing TB is completely controlled and see what are the new problems linked with TB.



I) General overview of Tuberculosis in France : epidemiological, medical and political perspectives
a) Epidemiological view of TB in France in the last ten years.
1) A very slow decrease of the incidence rate
TB was a huge problem at the beginning of the century but with emergence of antibiotics and vaccines, it was thought that the disease would be eradicated by the end of the 20th century. Even if the TB incidence rate has been going down, this sinking rate has been less important than what could be expected. People living in precarious situations, migrants, immuno depressed people (especially HIV patient) still suffer from TB and keep the number of TB case per year from going too low. Therefore in France, 4991 cases of Tuberculosis were diagnosed in 2011.

(Plotted from data from INVS)

2) Some departments and class of people are more affected than others
TB does not affect French Territory the same way. On 22 regions, Ile de France (Paris region) represents 1768 cases (more than 1/3rd). This epidemiological différence can be explained by the different demographic profile of the French Regions. Il de France is by far the most urbanized and dense region of France. Promiscuity being a very important in the transmission of TB, it is logical to see those kind of differences.

Population groups are also affected differently. Infant and young people are qui protected. This is mainly due to a very strong vaccination policy that will be explained a bit later. The most affected age group is adults under 60. Indeed, this corresponds to migrants and a lot of HIV patients.

Number of cases of TB-disease according to group age in 2011 in France (Data from INVS) Age 0-20 20-40 40-60 60-80 +80 Number of cases 435 1777 1338 680 499

3) The problem of the rise of MDR forms

The most interesting factor is the apparition of Multi-drug resistance TB (MDR TB)in the last years. Even if the incidence rate has decreased, the number of MDR TB has risen and is expected to continue to rise. Those forms comes mainly from foreign patients arriving in France mainly from the former Soviet Union and South Africa. This aspect will be developed a bit later

b) A patient arrives in a French hospital, what happens ?
1) General medical description of TB

The infection with Mycobacterium tuberculosis doesn’t necessary evolve in a disease. Most of the time, the infection is controlled by the immune system (even if the pathogen remains latent somewhere).
When the tuberculose remains latent (no symptoms), it will not be treated except for very specific cases (immunodeficient patient, people that will receive a transplant …)
When patient becomes symptomatic (long lasting cough, spitting, fiever, loss of wheigh, night sweats…), TB-disease becomes contagious ( droplets produced when coughing or sneezing).
During the tuberculosis-disease we have 3 kinds of bacilli’s populations:
• extracellular bacilli = 95% of bacilli, active, fast multiplication, responsible of contamination and symptoms.
• intra-cellullar quiescent bacilli, in macrophages, slow multiplication.
• extracellular bacilli in the caseous and some other extra-pulmonary locations, latent, responsible of the risk of relapse, very slow multiplication.
The tubercle bacillus is known as an intracellular pathogen. However it is the extracellular population that clinicians aim to eliminate.
When a TB case is diagnosed in France it has to be reported to the ARS (Agence Régionale de la Santé), French Regional Agency of Health.
2) Diagnostical tools
When a patient expresses symptoms or corresponds to categories of when TB latent has to be treated, different diagnostic tests are run to dertermine if those sympthoms are caused by a Mycobacterium or not.
The first test is to get an inoculum by having the patient spit or by getting this with a tube near the lungs. The sample is then analyzed under the microscope. The unit that is looked at is the number of “bar” in the sample, meaning the number of bacteria resembling M. Tuberculosis. If the test is negative, it is done at least three times to be sure. Samples are then culture and a PCR is ran to confirm the strain and to check the most common resistance. It takes approximatively a week to get the results. No treatment is given before getting those results, the worst fear being of selecting resistant forms.
Finally there is a third test that is not used by every hospital because it can be difficult to interpret : the intra Dermo Reaction. Basically, a droplet of liquid containing TB antigenes is put on the skin of the arm of the patient. If the patient has ever been exposed to a mycobacterium in his life,an inflammatory reaction happens. This test is difficult to analyze because it does not give the type of Mycobacterium the patient has been exposed to nor if the patient is still infected with Mycobacterium nor the stage of the TB.
Of course, in extreme cases of pulmonary TB, a lung radio can reveal some elements called “cavern” which directly confirm the TB-disease.

2) Treatment The treatment consists of 4 first-line drugs in combination during 2 months: isoniazid, rifampicine, ethambutol and pyrazinamide. Within the first 2 months of appropriate chemotherapy, the vast majority of bacilli have been killed. It allows clinicians to virtually eliminate the risk of transmission and the selection of drug-resistant mutants. The patient need to follow the treatment during 4 other months (bitherapy: isoniazid, rifampicin).

3) Pharmacological caracteristics of antituberculosis drugs Isoniazid: The most active drug for the treatment of tuberculosis. The mechanism of action is the Inhibition of synthesis of mycolic acids, which are main components of mycobacterial cell wall. As a result of the activity, tubercle bacilli lose their features of acid-resistance, water-resistance and proliferating ability, leading to death. Due to its mechanism of action, it is bactericidal against actively growing tubercle bacilli. For resting tubercle bacilli it is bacteriostatic. It is active both on intracellular and extracellular Mycobacteria. Good distribution, it can also penetrate inside the macrophages. It main problem are hepatotoxicity (20% of patients) and neurotoxicity.The metabolism is hepatic including by acetylation (interindividual pharmacogenetic variability). It is eliminated by the kidney. Rifampicine: The most colored drug for the treatment of tuberculosis. It Inhibits the transcription by binding to the subunit β of bacterian RNA-polymérase. (Funny fact: Occidental people don’t like it because they can’t wear lenses, it indeed color their urine and tears in orange… Whereas African people like it because they can “see” the effect) Bactericidal against intra and extra cellular Mycobacteria. Very good drug diffusion (pulmonary, meningeal, bones, ganglionary…). However, enzymatic induction of cytochrome P 450 result in a modification of other drugs metabolism (drug-drug interaction). Ethambutol: Mycobacteria catch ethambutol when they are in exponantial growth phase. Ethambutol inhibits acid mycolic or arabinose incorporation into the cell wall.

Bacteriostatic for extra-cellular bacilli. Good tissular diffusion. Renal elimination. The most common serious adverse effect is optic neuritis, causing loss of visual acuity and red-green color-blindness, but are reversible.

Pyrazinamid It Inhibits FAS (Fatty acids synthase), binds to the ribosomal protein S1 (RpsA) and inhibits trans-translation. This may explain the ability of the drug to kill dormant mycobacteria. Bactericidal for intra-cellular bacilli. Good diffusion inside the macrophages. Hepatic metabolism. Renal elimination.

4) Drug resistant form of TB A multidrug-resistant tuberculosis (MDR TB) is a tuberculosis resistant to isoniazid and rifampicine An extensively drug-resistant tuberculosis (XDR TB) is an MDR TB + a resistance to a second line drug treatment (fluoroquinolone and aminosids (kanamycine/amikacine/capreomycine). Mortality rate : 35%. One of the main concern of the clinicans is the appearance of those resistances. The main cause of apparition of resistances in a patient in France, is the patient’s lack of observance. In order to improve observance, some pills combining 3 drugs (rifampicine/isoniazide/pyrazinamide) have been developped. The treatment is accompanied by an educational monitoring. The patient is thouroughly explained the importance of observing the treatment as well as the best conditions to avoid contagion of their closed ones. This monitoring is mainly handled by the CLAT (Centre de Luttre Anti Tuberculeuse), Fight Against Tuberculosis Center.

In the end, for regular TB, the outcome is extremely good (almost 100% people cured).