Jeremy Day: Central nervous system and HIV infections in Vietnam
Brain infections such as meningitis and encephalitis are highly debilitating diseases, and an accurate diagnostic is essential to give patients the best treatment available. For cryptococcal meningitis, clinical trials focus on prevention, for an early diagnosis, and novel ways to use existing treatments or repurpose old drugs.
My name is Jeremy Day, I’m an infectious diseases physician and I’m based in Vietnam where I lead the central nervous system (CNS) and HIV infections research group. The central nervous system is the brain and spinal cord and the kinds of illness that we deal with therefore are things like meningitis and encephalitis.
I work mainly in two hospitals: in the Hospital for Tropical Diseases we see about 250-300 cases of CNS infections every year, and in Cho Ray Hospital a couple of kilometres away we see about 1000 cases per year, and this is in adult patients. I’m a clinician and my main interest is helping patients and particularly helping doctors at the point of diagnosis. When a patient comes into hospital, we assess that patient and we work out what the cause of that illness is, then having the information to know exactly what the treatment is we should be giving that patient now. That’s what our clinical trials are designed to do: to help doctors at the point of diagnosis give that patient the absolutely best available treatment for them.
We run two kinds of trials, the trial we run most frequently is large trials which are inclusive, that means that pretty much any patient that comes through the door will be eligible to enter the study if they agree to do so, and aimed at answering a simple question, usually which is how can we reduce the risk of death in this condition? I think a good clinical trial is one that is easy for the patient to see the value of, easy for the doctor to see the value of, and when it’s finished it’s applicable to not only the patients within your local population but also around the world.
I think the main challenge to clinical trials is that they are very resource intensive in terms of regulation and gathering high quality information. It’s really important that we run trials as carefully as we can, that we keep patients as safe as possible, and that we gather the highest quality data that we can trust. But we have to balance that with the amount of bureaucracy that that imposes and the problem is that as the amount of bureaucracy increases, it delays a number of trials that are done. If you took 100 trials in cancer therapy, half of them take more than 650 days from being funded to enrolling a patient; that’s nearly two years simply because it’s become so complex to set trials up and to get approvals. We need to understand that different kinds of trials might need different kinds of regulation, and whereas a novel agent that we don’t understand at all, we don’t understand the side-effect profile and so on, then that may need a different regulatory framework than where we’re repurposing an old drug.
Within my field of cryptococcal meningitis, the research efforts are focused towards prevention, so diagnosing infection early before people have really become ill, and novel ways of using the treatments that we already have, and that reflects the fact that we haven’t had any novel agents to treat this disease since the late 1980s, which is a problem. Finally the area that I’m particularly interested in is repurposing drugs that haven’t previously been used to treat cryptococcal meningitis, to try and identify drugs that we can add to our current therapy to improve outcomes.
Brain infections are a major problem because not only do they have high mortalities, recovery from brain infections is rarely complete. That results in disability, and disability is a major problem, especially in resource-poor settings where there are often very few community resources to enable patients to return as much to normality and have fulfilled lives as possible. There’s probably 6 million disability adjusted life years (a technical term for measuring the impact of a disease) lost per year globally from brain infections, and 4 million of those - two thirds of them - are occurring in low and middle income countries. For my particular interest, cryptococcal meningitis that results in 2,500-3,000 deaths every year, again predominately in low and middle income countries, and the death rate for that disease even on best treatment in those areas is in the order of 40-50% three months after diagnosis, and that’s why we need to work on it.
We do translational medicine in reverse: our research is absolutely at the bedside next to the patient and what we learn from patients and from clinical samples from patients we then take backwards into the laboratory. We use our insights from clinical presentations of patients to try and understand how pathogens or germs work at the population level. We’ve had some really interesting insights into how Cryptococcus neoformans causes meningitis, by comparing organisms that have come from people who have apparently normal immune systems with people who have damaged immune systems, often HIV patients. We are using those differences to try and understand how the organism as a whole causes disease and we hope that that will lead to us identifying novel drug targets, so we are sort of doing translational medicine in reverse at the moment and we hope to go back the other way in the future.