University of Liverpool

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The main focus of our research is on improving TB treatment using a spectrum of multidisciplinary
approaches at all stages of drug development.

Preclinical development
UoL was the academic co-ordinating institution for the highly successful PreDiCT-TB consortium,
a major public-private partnership involving 18 academic and 3 large industrial partners (GSK,
Sanofi and Janssen) funded by the EU Innovative Medicines Initiative (€15.3m). The consortium is
the first systematic re-appraisal of the value of in vitro and in vivo preclinical models for identifying
the best combinations of tuberculosis drugs to progress into clinical trials and will result in novel
approaches to the development pathway involving new biomarkers, experimental designs and
integration of information through mathematical models.

Pharmacokinetics and pharmacogenetics
UoL is the UK centre of pharmacokinetic expertise in tuberculosis, leading and collaborating on
numerous observational studies describing the behaviour of first-line drugs and drawing attention to
ways in which their dosing could be optimised in adults and children. These studies have also
explored the pharmacogenetic basis of variability in pharmacokinetics to explain differences
between populations worldwide (Peru, South Africa, Malawi and Thailand). UoL was the lead
institution of the Wellcome Trust-funded PKPDia consortium (£850k) which successfully
developed sustainable expertise in pharmacokinetic-pharmacodynamic modelling in TB, HIV and
Malaria in three WT-supported major overseas programmes.

Clinical studies
UoL collaborated with Harvard University on a key Phase II clinical trial of higher doses of
rifampicin which supported the safety and improved efficacy of doses of this key agent twice as
high as currently recommended using innovative methodology in Lima, Peru (HIRIF trial NIAID
£5.5m). Another major theme of our research has been the identification of better models and
biomarkers of treatment response. We developed a new approach to statistical modelling of
quantitative bacteriology data in clinical trials (Rustomjee IJTLD 2008) which has been
implemented in several studies and we have shown how to combine this with direct measurements
of persister-like organisms in sputum specimens in order to better predict long-term treatment
response (Sloan CID 2015).

Evidence synthesis
UoL has also been active in conducting systematic reviews of tuberculosis treatment in
collaboration with the Cochrane Infectious Diseases group (Davies CLSR 2007, Ziganshina CLSR
2013). As part of the activities of PreDiCT-TB, a comprehensive review of all existing Phase II and
III clinical trial data in the tuberculosis literature has recently been completed which summarises the
existing state of knowledge about the performance of current agents and the predictive performance
of early bacteriological data against long-term outcomes (Bonnett CID 2017). In addition, in
collaboration with Critical Path to TB Regimens in the US, PreDiCT-TB has helped to develop the
WHO-supported TB-PACTS data-sharing platform, the first viable repository for individual patient
data in TB clinical trials which will facilitate improved such analyses in the future.