In a landmark study that may herald a quicker, more tailored treatment for the millions of people around the world living with tuberculosis (TB), UK researchers have shown how our understanding of TB’s genetic code is now so detailed that we can now predict which commonly used anti-TB drugs are best for treating a patient’s infection and which are not.
This study, led by the international CRyPTIC consortium based at the University of Oxford and facilitated by the United Kingdom government’s 100,000 Genomes Project in partnership with Public Health England, is by far the largest of its kind, covering over 10,000 TB genomes from 16 equal partner countries around the globe.
The paper, ‘Prediction of Susceptibility to First-Line Tuberculosis Drugs by DNA Sequencing’, was published on Wednesday 26 September by the New England Journal of Medicine, and its findings announced at the United Nations General Assembly high-level meeting on tuberculosis.
The study revealed a much greater accuracy in predicting the susceptibility of the bacterium to anti-TB drugs than had been expected.
Paradigm shift
The lead investigator, Dr Tim Walker, Academic Clinical Lecturer in Microbiology and Infectious Diseases at the University of Oxford’s Nuffield Department of Medicine, said: “This study represents a paradigm shift away from a dependence on testing drugs against bacteria in culture and towards the genetic era.
“With ever-faster and more portable DNA sequencing technologies being developed, this advance means that we are now much closer to delivering tailored therapy to TB patients around the world whose treatments have so far been largely based on a ‘best guess’. Giving the correct drugs to more patients will improve cure rates and help stop the spread of drug-resistant strains,” said Dr Walker, who, like a number of partners in the research, is supported by the National Institute for Health Research (NIHR).
Professor Derrick Crook, Director of National Infection Service at Public Health England and Antimicrobial Resistance Theme Lead at the NIHR Oxford Biomedical Research Centre, said: “We are delighted by the results of this study which suggest that we will be able to treat patients with the right treatments more quickly.
“This is particularly important in an infection like TB where we know that many people who have the infection may be homeless or not have good access to the health system. Being able to choose the most effective drugs when starting treatment should lead to a quicker reduction in the infection being passed on to others.”
Professor Chris Whitty, Chief Scientific Adviser for the Department of Health and Social Care (DHSC), said: “Developing more effective approaches to treating multi-drug-resistant TB is crucial for the thousands of people affected in the UK and millions worldwide. This study is just one example of how the government is supporting research into how new technologies can help us tackle drug-resistant infections and thus preserve the effectiveness of current antibiotic treatments.”
Precision care
Professor Mark Caulfield, Chief Scientist at Genomics England, Co-Director of the Queen Mary University William Harvey Research Institute (WHRI) and Director of the NIHR Barts Biomedical Research Centre, said: “The 100,000 Genomes Project has amassed the largest collection of whole human genomes linked to direct healthcare. Here researchers working with Genomics England and with other agencies have demonstrated that DNA sequencing can be used to guide first-line treatment of tuberculosis. This shows that genomic medicine can enable precision care of millions of people, in the UK and around the world.”
Dr Jonathan Pearce, Head of Infections and Immunity at the MRC, said: “The results of this study represent an important step forward for rapid clinical decision-making and antibiotic stewardship for TB treatment, and also provide a potential precedent for a sequencing approach for other pathogens.”
Tuberculosis remains the world’s biggest infectious disease killer, claiming 1.7 million lives in 2016. The number of drug-resistant cases is rising, meaning new strategies and interventions are urgently needed if the World Health Organisation’s (WHO) target to end the global TB epidemic by 2035 is to be met.
One of the key interventions for achieving this target – and saving millions of lives – is getting the correct drugs to patients in a timely manner.
Since TB-antibiotics were first introduced 70 years ago, tests to determine which antibiotics will best treat an individual patient have depended on growing the bacteria in a laboratory, a process that takes weeks or even months. These difficult and slow tests remain out of reach for most of the world’s TB patients, leaving many on the wrong combination of drugs and with a reduced chance of cure and survival.
Accuracy
It is estimated that only 22 per cent of an estimated 600,000 patients requiring treatment for multi-drug-resistant tuberculosis received diagnoses and were treated in 2016, which has facilitated the spread of multidrug-resistant strains.
The analysis conducted by the researchers, who looked at all major strains of TB, “suggests that whole-genome sequencing can now characterise profiles of susceptibility to first-line anti-tuberculosis drugs with a degree of accuracy sufficient for clinical use.”
“The importance of this is twofold: first, it shows that the genomic approach could be used to guide the choice of which drugs to prescribe and not just which drugs to avoid, in a way similar to phenotyping; second, the data can be used to support plans to reduce the workload associated with culture and sensitivity analysis in places where routine whole-genome sequencing is performed.”
The improved knowledge of the genomic variations of TB should lead to more accurate PCR tests for the disease.
The results of this study have already led to decisions in England, the Netherlands and by the Wadsworth Centre for Public Health, New York State, to reduce reliance on bacterial culture and deliver treatment according to DNA sequencing results alone.
This international research was supported in the UK by the Department of Health and Social Care through the National Institute for Health Research, Public Health England and the 100,000 Genomes Project. The research also received support from the EMBL’s European Bioinformatics Institute (EMBL-EBI), the Medical Research Council, the Wellcome Trust, and the Bill and Melinda Gates Foundation.
As well as the University of Oxford, the University of Leeds, Imperial College London, and the London School of Hygiene & Tropical Medicine were involved in the research.
