DOCTORAL THESIS OF THE YEAR. Jesper Sundell’s thesis concerns ways of improving treatment for tuberculosis, especially for the vulnerable group of patients who also have the human immunodeficiency virus (HIV). The thesis has now been named Sahlgrenska Academy’s 2021 Doctoral Thesis of the Year.

Dr. Arnt Vestby’s Research Foundation funds the Doctoral Thesis of the Year award. Seven theses publicly defended last year have received awards, one for each department and an additional award for Doctoral Thesis of the Year at Sahlgrenska Academy. This goes to Jesper Sundell and his thesis on optimizing treatment for tuberculosis in patients with HIV.

“I am very proud and extremely honored. The award came as a happy surprise, and I am really pleased that the team and the research field are being recognized in this way,” says Sundell, who defended his thesis in October last year.

Samples from Rwanda

Tuberculosis (TB) kills over a million people worldwide every year. TB bacteria can remain in the body for many years without causing disease, but they can be activated if the immune system is weakened by other diseases, such as HIV. Tuberculosis is currently one of the leading causes of death for people living with HIV.

Jesper Sundell, a pharmacist by training, conducted his thesis work with Professor Michael Ashton as his principal supervisor. The studies used samples taken during previous clinical research by the team, which provides access to frozen blood and plasma samples from HIV patients with tuberculosis in Rwanda. To measure concentrations of the pharmaceuticals and the products into which they break down, he began to? work on his thesis by developing the method he needed. It combines mass spectrometry with liquid chromatography.

Substances interact

The standard treatment for active tuberculosis is a combination of three or four pharmaceuticals at the same time (isoniazid, rifampicin, pyrazinamide, and ethambutol). Jesper Sundell’s thesis shows that two of these standard pharmaceuticals – rifampicin and isoniazid – interact with each other. The interaction between them is previously known, but the thesis shows that rifampicin seems to accelerate the formation of the metabolite isonicotinic acid directly from isoniazid.

“Isoniazid has a complex degradation scheme. The substance is broken down into the metabolites isonicotinic acid and acetyl-isoniazid, but acetyl-isoniazid can then break down into isonicotinic acid, so it is difficult to know where the metabolite comes from,” says Sundell, who used mathematical models to describe the origin of the metabolite.

He notes that the dose of rifampicin seems to play a role, with a higher dose accelerating the formation of isonicotinic acid from isoniazid. Clinical trials currently underway are testing much higher doses of rifampicin for the treatment of tuberculosis. As a result, the finding that rifampicin accelerates the degradation of isoniazid is highly relevant.

“The interaction between these pharmaceuticals could accelerate the formation of other toxic metabolites and increase the risk of dangerous side effects at higher doses of rifampicin,” says Sundell.

Since the study is small, the results need to be confirmed. The thesis also describes an interaction between rifampicin and one of the HIV medications.

Precision Medicine

For two of the tuberculosis medications, Jesper Sundell’s thesis suggests how precision dosing could improve treatment for individual patients using dosing algorithms based on patient-specific characteristics.

Genetic information from the patient samples was analyzed in the study. By analyzing different enzymes that can affect the rate at which the body metabolizes pharmaceuticals, some genetic variants have been identified that are potentially interesting for precision medicine, where genetic analysis can provide a better individual dosage.

The thesis also proposes a mathematical approach to personalizing treatment by measuring the sensitivity of the bacteria of a person with tuberculosis to a particular pharmaceutical and then using that information to adjust the dosage.

“Studies show that the sensitivity of non-resistant TB bacteria has an important bearing on the success of treatment. Precision dosing based on the characteristics of both the patient and the bacteria in combination would probably be optimal for curing tuberculosis, while minimizing the risk of side effects”, says Sundell.

Nominated by colleagues in the team

Mikael Boberg and Emma Eckernäs, Sundell’s colleagues, nominated his thesis for the Doctoral Thesis of the Year award. In the nomination, they cite the thesis as an impressive example of how doctoral students at Sahlgrenska Academy should plan, carry out, and present their work.

Jesper Sundell is now a postdoctoral researcher at Lund University, where he collaborates with mathematicians and engineers on the use of artificial intelligence, with the aim of creating better methods for precision medicine.

All 2021 award-winners

2021 Thesis of the Year at Sahlgrenska Academy
Jesper Sundell’s thesis ”Optimization of first-line anti-tuberculosis therapy in patients co-infected with HIV” (Institute of Neuroscience and Physiology)

2021 Thesis of the Year at the Institute of Biomedicine
Erik Ehrencrona’s thesis “The Role of FCGBP in Mucus – Structure, Processing and Function”

2021 Thesis of the Year at the Institute of Clinical Sciences
Maria Siekkeri Vandika’s thesis “Vitamin D and Vitamin D-binding Protein in Psoriasis and Effects of Treatment”

2021 Thesis of the Year at the Institute of Medicine
Sofia Manousou’s thesis “Iodine intake and uptake in populations at risk for iodine deficiency”

2021 Thesis of the Year at the Institute of Neuroscience and Physiology
Johan Lönnbro’s thesis “The medical perspective in prescribing: measurements and educational strategies”

2021 Thesis of the Year at the Institute of Odontology
Agnes Dahlstrand Rudin’s thesis “Neutrophil recruitment in periodontal disease”

2021 Thesis of the Year at the Institute of Health and Care Sciences
Malin Hansson’s thesis ”A meaningful work in a strained context – exploring midwives’ work situation and professional role”.

BY: ELIN LINDSTRÖM