Team:Paris Bettencourt/Human Practice/TB France

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  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 20^th 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 dta 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. Ile 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)

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 BAAR (Acid-alcohol resistant bacillus) using Ziehl-Neelsen stain. The test is done at least three times on 3 different samples taken at 24 hours intervals. 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.

3) 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).

4) 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.

5) 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).

c) Public policies put in place to deal with TB

1) The fight against tuberculosis : a multiplicity of actors

As everything in French public policy systems, missions to fight tuberculosis are divided between several institutions and types of administrations. In a few words, French policy system has three main types of structures :

- The government represented by the ministries and what is called “services déconcentrés”, services that are responsible at a departmental and regional level of the application of the government policies

- The local powers or “collectivités territoriales” : from the city, to the department or regions, those administration are run by people elected locally and are responsible of making the specific interest of a defined territories known and put in place

- Public or semi-public institutions : Might they be firms like the “SNCF” which is responsible for the train or research institutions or monitoring administrations, they are quite independent but under the general direction of ministry and have one or several specific missions.

In order to see clearly who does what, here is a synthetic table which underlines who deals with what in the general monitoring of TB.

2) The French “Plan de lutte anti Tuberculeuse 2007-2009 “ aka plan for the fight against TB.

This national plan was created in 2006 after TB was put in the 100 highest priorities for health policy par the French Parliament. It’s goal is to improve the fight against TB.

Its implementation revolves around six main axis. has 6 axis :

- to ensure an early diagnosis and an adapted treatment for all TB disease cases

- To improve the detection of TB

- TO optimize the vaccinale strategy of TB

- to maintain resistance to antibiotics to a low level

- to improve the epidemiological monitoring and the knowledge about determinants of TB

- to improve the coordination of the fight against TB

This plan mainly changed 2 things. : the vaccination policy and the delegation to local powers (CLAT) the main concrete actions.

Until 2007, vaccination was mandatory for every child. The vaccination coverage was higher than 90%. Due to a lack of efficiency of the vaccine (BCG) and the idea that TB was almost eradicated, the vaccination stopped being mandatory. Today, it is highly recommended, especially when the children start going to school. However, this led to a drastic reduction of vaccinated children (only 59% today). Vaccination is still mandatory for all medical personnal. A lot of pediatrician think this was a huge mistake and keep on vaccinating all the children they see. However, the evaluation of this policy by the HCSP (High Council for public health) lead to the conclusion that no strong problem has been reported until nowand that therefore this policy should be maintained.

The second main change was the delegation of power to the CLAT. The CLAT located in every department coordinates medical centers, leads teams of investigators, organize detection activities … The efficacity of the active detection has been questioned. Indeed, out of more than 1000 detection done, only a few cases (less than 5) have been reported in the last year. Moreover the evaluation of the HCSP has concluded, more means should be given to CLAT which perform most of the action and don’t benefit from enough fundings.

II)Tuberculosis,a social disease

A) TB, a social stigma ?

A striking fact when talking to professional people dealing with TB is the social aspect of disease. In France, TB is known among medical personnal as the disease of poor people. Doctors mainly diagnose TB according to “the environmental context” that is to say the appearance and life conditions of the patient.
To illustrate this fact, a story of a patient was told to us. A white female 40 years old women, coughed for months, spit blood and expressed all the symptoms of TB. She was seen by more than 10 doctors but no one could figure out what she had because
- she was not living in a precarious situation
- she was not HIV positiv or immunodepressed
Basically, she did not fit the profile. She got tuberculosis while working in Hahiti and living in promiscuity with people affected by tuberculosis. In France, this past few years, patients suffering from TB have been more and more coming from a foreign country. In 2010 , the number of foreign patients treated for TB was higher than the number of native ones.

B) Semi efficient Health Care systems, the story of the rise of MDR forms

What scares the medical personnal is the rise of MDR forms. Indeed, it is strongly believed in the French medical community that those bacteria are found on migrants who had TB for a long time but a one that were already treated.
Indeed, most of the migrants, who are treated in Paris come from the foreign Soviet Union and South Africa. This can be surprising at first, becquse it could be expected that because of the strong presence of migrants from north and central Africa in France, TB would mainly be found in those populations.
However, the story is a bit more complicated. South Africa and the former Soviet Union have both in common the fact that they have a funcitonning health care system. However, they are not as efficient as occidental ones, especially because they don’t have the financial means to treat every disease as it should be.
Therefore, most patients suffering of TB were treated with one or maybe two antibiotics. This did not lead to the disease being cured but to the development of resistances. How does this concern France ? In fact, a lot of migrants coming to France from those countries carry an MDR form of TB leading to a rise of the number of MDR forms treated.

C)Treat everyone, at what cost ?

In France, even if there is no emergency, everyone is treated and given medical attention. The health care system is national and people who cannot pay don’t. For TB most of the patients who are treated don’ have the financial means to pay, therefore, it is basically paid by the Infectiology department that treat them and in the end by French taxes. The treatment of TB as described previously , is a long and costly one. Indeed, it is not only about the antibiotics. When a patient is diagnosed, everyone living with him is also screened for TB and the patient is given an appropriate housing situation at least for the duration of the treatment. Social workers are also paid to dispense preventive measures and to practice “active detection of the disease".
Those economical cost get much worst when dealing with resistant forms of TB. For example, when a XDR for is detected, the patient is put in a clean room (where the air going outside of the room is clean). Only essential medical personal is allowed in the room. Very extreme treatments are used like surgery or ECMO.
Today, patients come from Former Soviet Union countries with signs saying “Professeur Caumes, Head Of Infectiology Department, Hopital Pitié Salpetriere , Paris”. This trend scares clinicians because at one point, they might be able to treat all the patients in the right condition but also because one day, the disease might spread to the more general population. They therefore justify those costs to the authorities’ by invoking the universal right of everyone to be treated for their disease but also by evoking the possibility of a new epidemy of tuberculosis in France.

III)Tuberculosis,a therapeutic impass?

A)Outcomes and treatment of multiresistant forms

As it was explained before, TB outcome for non resistant form is mostly good, as showed on the graph. However the treatment of MDR and XDR form is really not as good. Clinicians treat the patients with molecules they know are not really effective just in case they might work. In some countries, barbarian methods are used , methods that were used before the appearance of antibiotics. For example, a patient treated in France, had already been treated in its home country by creating intentionally a pneumothorax, that is to say to make the lung collapse on purpose to crush the mass of bacteria. Lungs can also be filled with liquid for a small period of time to drown the mycobacterium.
The entire medical community is definitely in need of new therapies

B) New treatments, a political problem?

No new anti-tb molecule have been developed for 40 years. Indeed, as the disease was easily cured with existing antibiotics and more present in poor countries, it was not profitable for pharmaceutical companies to work on TB. However, in the last few years, the need of new treatments had led to the development of new drugs. However only a handful are near to be marketed.
Up to now, two drugs have been submitted to marketing authorizations : bedaquiline and delamid. Both drugs have led to huge debate in the scientific community for very different reasons.

Bedaquiline developped by Janssen Pharmaceutica under the name Sirturo, inhibits a mycobacterial ATP synthetase. The FDA granted a “fast-track” approval, which means assessing its efficacy by a surrogate measure rather than an actual clinical outcome. This decision was based on the criterion that the drug in addition to a standard MDR TB regimen could change a patient sputum from positive to negative.

However in clinical studies, it was found that 10 out of 79 patients taking the drug died, vs 2 of 81 in the control group. Different medical explanations have been raised to explain this (50% died of TB, others might have suffered from hepatotoxicity …). The fast track approaval requires proprer clinical studies to be done, but those have to be achieved in 2022. The WHO had the drug evaluated by an expert group which reported “bedaquiline may be added to a WHO-recommended regimen in adult MDR-TB patients under the following conditions (conditional recommendation, very low confidence in estimates of effect, i.e. very low quality of evidence) » and listed actions that should be followed before and when giving the drug.

Around the same time, an application for market authorization was submitted to the EMA (European Medicine Agency) for a drug called Delamid. Delamid precised mechanism of action is unknown but it targets the cell wall of Mycobacterium Tuberculosis. During the clinical trial of Delamid , the researchers reported that “while two of 192 patients – 1 percent – taking the drug for six months died, the comparable mortality rate for those on existing regimens is in the range of 10 to 15 percent ». The authorization was denied in July 2013 on the basis that the drug « did not outweigh its risks.” . Criticism were raised accusing the lobby of Jaansen Pharmaceutics to have pressured in order for bedaquiline to remain the only new drug on the market to fight TB.
Therefore, even if new drugs are developed right now, it is still a long and uncertain way to an actual use of new efficient therapies.

C) Synthetic biology a solution ?

What could be the role of synthetic biology considering those factors? First, it can be noticed, that the new therapies that are developed right now all consist of new drugs to enrich the regimen. We used synthetic biology to at the same time try to improve existing therapies and develop new ones.

According to Christopher Anderson « there is considerable work to be done on diagnostics that will allow the efficient choice of appropriate therapy for each patient diagnosed with TB”, therefore one part of the team worked on developing a new diagnostic tool which could easily and quickly determine the presence of TB and the resistance that it carries. This would help determine the right treatment for the patient more quickly and more efficiently.
In order to develop new drugs, a second project was to reconstruct in E. Coli a pathway metabolizing sulfur, specific to Mycobacterium. This new type of drug sreening would solve a lot of experimental issues faced when dealing with TB like slow growth as well as targeting specifically new pathways. This could lead to a new drug to enrich existing regimens.
Synthetic biology can also be used to develop new types of therapies. The team worked on developing bacteria specifically designed to penetrate the macrophages and kill the mycobacterium present in the cytoplasm of those cells. This “bacterial therapy” could become a unique tool, to treat TB-disease but also latent TB especially for immuno depress people or HIV patients.

In order to specifically address the problem of multiresistance, a project consisting of a engineered phages silencing antibiotic resistance genes was designed. The idea being to develop a sequential therapy using phage therapy to silence the resistances of the Mycobacterium and then give the classical regimen to better eliminate the bacteria.

1) Regulation and synthetic biology

According to current national regulation, two out of our four biosynthetic devices could be readily used: our biosensor-based diagnostic test and our safe drug screen. We can improve the diagnostic test by adding TDMH (which will lyse the Mycobacteria cell wall and improve the sensibility of the test). As Christopher Dye pointed out to us, “ If you want to develop a diagnostic test, you can follow the well-documented path for Xpert (editor’s note: new diagnostic system recommended by the WHO…. Add something), though diagnostics are not so well served by guidelines as drugs and vaccines”. Diagnostic tests do not involve any direct contact between the patient and the genetically engineered organism. They must comply with the European regulation of medical devices and be subject to the EC labeling. Even though therapies based on bacterial vectors could stir doubts regarding their safety, they are no less “natural” than antibiotics : after all, we have 100 times more bacteria in our gut than cells in our organism. Refusing to use bacteria as part of “cellular therapies” would therefore be only a waste for humanity. Guidelines for drugs involving living genetically engineered organisms do not exist yet. Although many of these therapeutic devices have proved to be very promising, authorities do not seem to know how to evaluate them. As we can read on the EMEA website,

“Advanced therapy medicinal products are new medical products based on genes (gene therapy), cells (cell therapy) and tissues (tissue engineering). These advanced therapies herald revolutionary treatments of a number of diseases or injuries, such as skin in burns victims, Alzheimer's, cancer or muscular dystrophy. They have huge potential for patients and industry. The lack of an EU-wide regulatory framework in the past led to divergent national approaches which hindered patients' access to products, hampered the growth of this emerging industry and ultimately affected EU competitiveness in a key biotechnology area. The EU institutions agreed on a Regulation on advanced therapies (Regulation (EC) 1394/2007), designed to ensure the free movement of advanced therapy products within Europe, to facilitate access to the EU market and to foster the competitiveness of European companies in the field, while guaranteeing the highest level of health protection for patients.”

However, none of these advanced medical products involves living organisms.

2) Safety and acceptance

  We therefore have to understand and anticipate possible negative responses to our systems, by investigating people’s attitude towards it. For this reason it is important for us, to “prepare the ground carefully learning from others”.   When asking the professionals and patients about how they would feel about using new therapies based on synthetic biology, no major problems emerged. Indeed, clinicians are in need of new treatments and patients trust completely their doctors. However, according to the very skeptical climate about GMOs in France, the major issue that might arise for the use in synthetic biology for TB in France would be a political one. Even if everything would work perfectly, the marketing authorization would be a very hard thing to get, especially considering the precedents of Delamid. Therefore, even if new synthetic biology therapies are not for today, the use of them for applied research like in the new method for the drug screen is definitely a way synthetic biology could use to tackle today main issues of TB.

  In a survey, we asked people whether they were for or against synthetic biology. We then asked whether they agreed on GMOs or not. Surprisingly enough, even though GMOs are part of synthetic biology, in our survey they were mostly associated to food, in particular to Monsanto. This fact is remarkable, since the people we surveyed tended to be against GMO, yet in favour of synthetic biology.

  The synthetic biology community has thus not to repeat the mistakes made by GMO producers, who eventually lost the confidence of a large share of the public by arousing suspicion on their conduct.

  According to current scientific knowledge, commercialized GMOs do not pose major hazard to human health. However, scientists should always be aware that further evidence could reveal previously unknown dangers at any time. For this reason, constant risk assessment is of the utmost importance in the case of GMOs (as it has been done, for instance, with respect to potential allergenic effects). In France, this task is accomplished by the AFSSA (Agence Française de Sécurité Sanitaire et Alimentaire), the French Agency for Food and Drug Security. Risk assessment is even more vital for the development of synthetic biology in France because of the general sentiment of mistrust caused by past health crises, such as the “mad cow” epidemics and a scandal involving contaminated blood transfusions in public hospitals. Moreover, an actual anti-GMO movement has been taking place in recent years, even though resistance against new biotechnologies appear to be mainly driven by a “moral panic” (disproportionate response to novelties, which are perceived as dangerous by the public) rather than by actual scientific evidence.

  For this reason, it is important to bear in mind that any future application of genetically engineered systems to key domains, such as therapeutics, will be susceptible to elicit strong negative responses. Scientists should therefore be prepared to cope with opposition in a “sympathetic way and, at the same time, to pose ethical questions from their own standpoint: why should we refuse to test a therapy for which no hazardous effect has currently been proved? Is it ethically acceptable not to treat patients subject to treatment failure, who have no other alternative than death? We maintain that any application of synthetic biology to medicine should be handled with the same precaution as any other drug or clinical essay whose risks are not yet fully known. This implies that such technologies should be made freely available in case of favourable evidence. On the contrary, specific risk management plans should be designed and adopted as soon as hazardous consequences are proved.

3)Comparing synthetic biology to gene therapy or how to introduce synthetic biology in the therapeutical world

  In our opinion, synthetic biology should draw inspiration from other biological therapies, such as gene therapy. In spite of its well known shortcomings and risks, this therapy represents a valuable alternative for patients in a wide range of cases.

  The term “gene therapy” gained currency at the end of the 1990s, when a novel medical treatment was first tested in a trial for treating children with severe combined immune deficiency (SCID), the so-called “bubble boys”. This treatment aimed at replacing the defective genetic variants that were responsible for the disease with a “normally” functioning one, thus providing those young patients with an effective immune system. In 1999, however, an American “bubble boy” died during the trial, while in 2002 two French young patients were diagnosed with leukaemia. Gene therapy, which had previously been hailed as the treatment that would cure any disease, failed its first exam.

  This failure did not prevent Chinese authorities from authorising the first gene therapy treatments in 2003, in order to cure head and neck cancers. On the 1st November 2012, the European Union gave the green light to Glybera, the first gene therapy drug available on the continent. This drug allows to cure a rare, yet potentially mortal disease : lipoprotein lipase deficiency.

  The major shortcoming of gene therapy consists in its high costs (in the range of two millions Euro for patient). Synthetic biology could nevertheless help reduce this price, to the greatest benefit of potential patients. Since synthetic biology do not pose evident health hazard, we do not see strong objections to its application in the framework of life saving treatments for patients with no therapeutic alternative. In the case of tuberculosis, our device for TBception could offer a good alternative for XDR patients (who normally have a 35% mortality rate). However, animal studies and more in vitro tests are need before submitting it for approval to begin a clinical trial.

Bibliography
Interviews
Resident in Infectious Disease
Resident in Pediatrics
Attending in Ophtalmology
Christopher Dye, Director of Health Information in the Office of HIV/AIDS, Tuberculosis, Malaria and Neglected Tropical Diseases at the World Health Organization (WHO) ,
Christopher Anderson ,
A patient
Worker of the CLAT
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