InFocus: Professor Stephen Gillespie on Lifesaving Tuberculosis Treatment

Outgoing News Editor Hannah Kershaw explores a new treatment for Tuberculosis, the disease that killed her literary heroes, and the new drug’s potential to save millions of lives.

To refresh my knowledge of Tuberculosis in preparation for this interview, I returned to my vandalised A-level copy of John Keats poems. Three years after writing the perfect sonnet, When I Have Fears That I May Cease To Be, John Keats had indeed ceased. He died of Tuberculosis at the grand old age of 25.

In fact, all my literary heroes died from the disease – Keats, Kafka, most of the Bronte family. RLS probably had it, Dostoevsky’s books are littered with consumptive nihilists, and George Orwell’s lungs would have been disintegrating when he wrote 1984. Six months after its publication, he died at 46.

Keats’ death was shrouded in the Victorian fantasy that Tuberculosis was romantic and edifying, cutting a young life short. Symptoms of the disease also coincided with the ideals of Victorian beauty (and the worst in high fashion today) including exposed collarbones, rosy cheeks, and a waifish or ghostly appearance.

As much as I want to discuss the myth of “Consumption Chic” or what Susan Sontag says in Illness as Metaphor, I am more excited about the lifesaving Tuberculosis treatment that has been trialed by scientists at the University of St Andrews.

Tuberculosis (TB) is the biggest infectious disease killer in the world, accounting for over a million deaths each year, and has become more serious after COVID-19.

TB bacteria are airborne and infect our lungs. In many cases, our immune response is effective and clears the bacteria. Individuals whose immune response is compromised whether by diabetes, pregnancy, malnutrition, or HIV are at risk of severe disease. In these cases, TB bacteria will continue to reproduce in the lung tissue and infect more cells. The bacteria employ cell-degrading enzymes that destroy the infected tissue – causing chest pain and the coughing up of blood.

Tuberculosis was once known as the white plague or, more accurately, consumption as the disease driven in part by the body’s immune response, wastes away. It took an enormous toll in the 19th century.

It was only in the 1950’s that an effective treatment became available, but this took two years at first. By 1980 treatment duration had reduced to six months and there it remained. The explanation for this is that TB bacteria can be dormant which means that they are much harder to kill with the usual antibiotics. With the availability of a six month regimen many researchers lost interest in tuberculosis and no new drugs were developed in the last 50 years.

World-leading scientists at the School of Medicine have revealed a new treatment that could shorten the treatment by up to two months – potentially saving millions of lives.

The SimpliciTB trial aimed to better understand how a prescribed course of drugs could work against drug-sensitive and drug-resistant TB. Results of the international SimpliciTB trial were announced in Seattle at the end of February. Congratulations are in order for the naming of the trial SimpliciTB.

The drug used in the clinical trial consists of bedaquiline (B), pretomanid (Pa), moxifloxacin (M), and pyrazinamide (Z), BPaMZ.

In what appears to be an organisational nightmare, the trial involved 455 patients at 26 sites across eight countries: South Africa, Tanzania, Georgia, Brazil, Russia, the Philippines, Uganda, and Malaysia.

Treatment shortening potential was found in the BPaMZ regimen, proving to be effective against the TB bacteria.

Professor Stephen Henry Gillespie of the School of Medicine was the coordinating investigator and lead medical monitor of the clinical trial.

Professor Gillespie told The Saint, “That gave me a role in ensuring patient safety by answering questions from the clinical trial sites about how the participants should be managed within the study protocol. I also had a role in preparing the final clinical study report by making clinical judgements on the data, and the significance of any deviations from the protocol.”

“As well as that, I was the coordinator of the European Developing Country Clinical Trials Partnership (EDCTP) project that includes the trial but also the development of the capacity of the African sites to deliver high quality clinical care and outstanding trial results.”

Whilst an early interest in infection helped, Professor Gillespie was inspired to go into the area of improving diagnostics and antibiotic treatment because of the potential that he saw in the field.

He said, “Tuberculosis was an attractive subject because, when I started my research, it was neglected by the global research community. There had been no new treatments or diagnostics for 30 years! More than that, my colleagues questioned the choice as they thought there was nothing new to discover about TB, then along came HIV which makes TB more common and deadly and multiple drug resistant disease that threatened to take us back to the pre-antibiotic era.”

The success of the trial was facilitated by the organisational skills of the Global Alliance for TB Drug Development (TB Alliance) who brought together an international consortium and were responsible for the organisational side of the trial.

Professor Gillespie said, “Any trial on this scale is an enormous endeavour. The TB Alliance led the management of the sites and important legal responsibilities which meant that the St Andrews team could focus on supporting the patients and the clinicians managing the patients at the recruitment sites to generate high quality clinical trial data.”

Professor Gillespie said that the next steps involve understanding how the effect of the novel drug combination can be implemented in clinical practice.

He said, “This will take some time though, and perhaps another trial but progress could be made in the next three years. “

“We are also working on a new regimen and trial OptiRiMox which trials a four month regimen of higher-dose rifampicin, moxifloxacin, pyrazinamide and ethambutol that we are very hopeful of. This will be studied at the sites we have developed through the SimpliciTB programme.”

The impact of COVID loomed large during the trial, particularly on the management end. Professor Gillespie recalled, “There were local travel restrictions and patients were unable to attend their regular review meetings. We had a taskforce that met every week examining every aspect of the trial to adapt it so the work could continue safely. COVID also meant that the people that monitor our trial were unable to visit the clinical sites and the laboratory. We adapted our methodology to reduce the face-to-face requirements without compromising the study.”

Professor Gillespie is continuing to work on improving TB diagnosis and on a new study UNITE4TB.

Whilst slightly less appealing than the name SimpliciTB, it is also doing significant work to build a Europe-wide network of trial capacity that can evaluate the new drugs that are finally coming through the pipeline for testing.

Professor Gillespie concluded, “Much of my work is around developing and evaluating our molecular bacterial load assay, which is a two-hour test to detect and count the number of live tuberculosis bacteria present in a sample. It is, as it were a molecular culture method of 2 hours rather than 42 days. This assay has been developed by LifeArc and is in trial through our network of colleagues in East Africa after which we hope it will be made available for clinical use.”

“This could make a major impact on the diagnosis and monitoring of treatment in tuberculosis.”

Professor Gillespie underscored how there had been no new treatments for the disease when he entered the field.

“The situation is completely transformed and that is, in part, due to the efforts of the St Andrews team and their collaborators across the globe.”

Illustration: Aimee Robbins