Scourge of Tuberculosis: Infection marked a turning point in my life – Prof Grosset

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By Sola Ogundipe

In the mid 1950s, just as he was completing his medical studies, fate played a cruel trick on Professor Jacques Grosset, the world renowned tuberculosis researcher. He was just 25 when he was struck by the deadly tubercle pathogen which causes tuberculosis (TB). The occurrence was ironical because the young scientist was infected right in the same hospital where he was undergoing his clinical training.
It was a drug-resistant strain of TB, and there were few antibiotics at the time, so the infected parts of his lungs had to be removed.
That incident decisively marked the end of his dream to become a surgeon. Ever since, he has nursed a grudge against TB.
To extract his pound of flesh, Grosset dedicated his life to fighting TB to the finish. Today, at 82, the famed scientist relentlessly pursues his ambition to eliminate TB permanently by killing the tubercle bacteria.

For several years, he was at John Hopkins University, Baltimore, USA. Currently, he is Scientist in Residence at the Kwazulu-Natal Research Institute for Tuberculosis and HIV (K-RITH), Durban, South Africa, where he is developing and testing new drug candidates to help shorten TB treatment and find new medicines to confront drug-resistant TB.  Grosset is also aiming to break the unholy alliance between TB and HIV.
In this encounter, the legendary TB researcher tells Sunday Vanguard about his personal vendetta against TB. Excerpts:

Personal Enemy
I got tuberculosis when I was young and, since that time, I have had a personal enemy. You should not know me because you may not like me
because I am a killer. I kill the TB bacteria. My fight against TB is personal. People who do not like me call me ‘Jack the Ripper’. So you should not know me. I was infected with TB in the very hospital where I trained. It was a drug-resistant strain of TB and there were fewer antibiotics at the time — the mid-1950s— and the infected parts of my lungs had to be removed. I was 25 and had been planning to become a surgeon, but I changed my mind. I am from France, so I went to work at the Institut Pasteur in Paris, to take revenge on the bacteria that causes tuberculosis.

War in the lab
I am fighting in the laboratory. In the laboratory, we culture the bacteria and see if it is drug resistant and all that. We have facilities for rearing mice, then we infect and test the new drugs on them. I was at John Hopkins University in Baltimore, using mice to test new drugs for tuberculosis. Now I’m here at K-RITH, and I still work with mice to find better drugs to treat TB. There are two main reasons for finding new TB drugs – to shorten treatment and to find ways to treat drug resistant TB. TB is a curable disease now, and is more opportunistic than it is intelligent. It takes advantage of our poor defenses and so it remains difficult to treat.

Challenge
The challenge of the opportunistic effect of TB is very significant. One person coughs and others get the bacillus. That was the way I got TB in the hospital. I was a medical student. The bacteria wants tosurvive and the only way to do that is to jump from one person to another. However I do not want the bacteria to survive. I want to kill it.

Mentorship
I am from France and I worked at the Pasteur Institute. I had a very bright mentor – George Canetti. It was 50 years ago, and we were absolutely convinced that with the new drugs, we were going to win the war against TB. I remember a friend of my mentor who warned us not to win theoretically, but win practically. But we were so sure of victory. If my mentor, who died long ago, was alive today, he would be very sad that with all the weapons we have, we have not been totally successful against TB. It is surprising because TB is curable and can be eliminated. However the problem of organization is monumental.
Implementation can be better. It is a worldwide phenomenon, not just here in South Africa. It is everywhere. Every patient can get TB drugs free of charge, but that is not the problem. There is lack of strong political statement against TB infection without which success will be difficult. Organisation is key to defeating TB.

TB curable, but…
Years ago, we had already won the fight against TB. Compared to what it was before the antibiotics came, we did win. We succeeded in Western Europe and North America because, at the time when the antibiotics came, there were plenty of sanatoriums and it was easy for the patients to take their medicines, but the problem is now to organise the Directly Observed Treatment (DOT), which has nothing to do with the people coming or not.

Excuses

It is like this, when people have cold, they take drugs and, after a few days they feel well, they stop taking the drugs. Because people are the same, people with TB begin to take their drugs and, after one month of treatment or so, stop taking the drugs because they feel well. This is just part of the problem. There are plenty of other reasons and excuses. Human beings are human beings, and what is right for TB is right for HIV and diabetes, it is difficult for these people
to comply with their drug regimens.

Treatment problem

Multiple-drug-resistant tuberculosis is a major problem. The length of treatment is also a problem. Today, treatment for non-resistant tuberculosis lasts six months. When I got infected, treatment took up to two years. Now, even at six months, treatment is still a burden. The biggest problem is with compliance. Many patients stop taking their drugs before they’ve completed the full treatment course, which puts them at risk of a relapse—often, with a drug-resistant strain. Many people are infected with TB and HIV in Durban, where K-RITH is located, than any other place in Africa.

Research
Since the beginning of my career under the mentorship of George Canetti, my research has focused on improving the treatment of mycobacterial infections, mainly tuberculosis but also leprosy, Buruliulcer, and MAC (Mycobacterium avium complex) infections in the immune competent and immune deficient host. I am currently involved in the development and testing of new drugs and new drug regimens active against both fully drug susceptible and drug resistant Mycobacterium tuberculosis and Mycobacterium ulcerans.

Objective
Scientifically, my main objectives are to test the potential of new drugs and new drug regimens for shortening the duration of the current six-month drug regimen for drug-susceptible disease;  offering a shorter alternative to the long treatment duration for multi-drug resistant (MDR) TB, and  discovering the drug regimens that would be able to successfully treat patients with extremely drug resistant (XDR) tuberculosis. The great challenge of this endeavour is to identify the right in vitro and in vivo experimental models that will allow us to know that our results are accurate predictors of a true
clinical response.

HIV/TB alliance
The co-infection of HIV and TB requires that we understand how to deliver treatment and how to avoid drug resistance in immune-deficient patients. This explains why my lab is testing the value of mice with different immune backgrounds, including the athymic nu/nu mice. Similarly, I aim to compare the response of strains of different lineages of M. tuberculosis, as well as specific drug-resistance mutant strains, to different treatment regimens. For these strains, we are not only determining the natural prevalence of drug resistant mutants but also their genetic background.

Research
My research on drug activity against TB has led to the identification of  the strong synergistic effect of rifampin and pyrazinamide, the potent bactericidal activity of moxifloxacin and daily rifapentine, the antituberculosis activity of PA824. It is noteworthy that we demonstrated the synergistic activity of combination PA824 with pyrazinamide and moxifloxacin. This combination has the potential to be used for the treatment of MDR-TB patients because it contains no rifampin and no isoniazid, the two first line drugs for which resistance is most common.
I want to emphasize the translational nature of my work. My lab will not limit its activity to in vitro work and work with mice. It will be directly involved in the testing of new drug regimens in patients,particularly by conducting early bactericidal activity (EBA) studies and investigations of drug resistance.

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