Understanding pharmacokinetic - pharmacodynamic determinants of outcome to inform dose optimisation for non-MDR TB re-treatment patients in Vietnam

TB remains a major global public health problem burden, with 9.6 million new cases and 1.2 million deaths in 2014. Vietnam is ranked 12th among the 22 highest TB burden countries (TB). 140 new cases were reported per 100,000 population in 2014. National TB Control Programme data indicates that 6 months of first-line month therapy for new TB patients is not successful in 10% of cases (some patients are still unwell at the end, and others relapse after apparent cure). Only 20-30% of unsuccessful treatments can be attributed to major problems with antibiotic resistance, which requires specialist management. The remainder go on to receive a standard "Category 2" treatment regimen, which is internationally approved but has not been carefully studied. Unfortunately, re-treatment patients on this regimen do not always do well; in Vietnam, the Category 2 regimen results in only 60-75% treatment success. The reason why patients may fail two rounds of treatment is not well understood. One reason could be that the levels of drug in the body (a study known as pharmacokinetics) of some patients is too low to kill the infection. This problem could also be worsened by the fact that the drug levels required to kill the bacteria causing TB (known as Mycobacterium tuberculosis) are not the same in every patient i.e. some patients are infected with a strain of the M. tuberculosis bacteria which can survive higher concentrations of drugs than others. In this project we will focus on the retreatment patient group to determine whether clinical outcome can be explained by measuring individual patient drug levels and carefully studying the ability of TB drugs to kill M tuberculosis. The project will use advanced analytical techniques to measure drug level in patient's blood samples and a number of new laboratory techniques to study how well the drugs kill each M. tuberculosis strain. All of this information will then be combined and analysed using mathematical models to; (i) determine whether the laboratory/analytical measurements can explain the low treatment success rates and (ii) determine whether this information can be used in the future to improve treatment by predicting bad outcomes at an early stage and recommending a better drug course. Data obtained from this study will be shared with other researchers working on TB around the world and will contribute to the wider discussion on tackling TB by designing better treatment. Significantly, this project aims to also increase the local capacity for advanced studies of this type by providing training and mentoring to our Vietnamese colleagues in all of the methodological areas described.

In many countries, patients presenting with a second episode of non-multidrug resistant (MDR) pulmonary tuberculosis (TB) are treated a WHO approved Category 2 re-treatment regimen. Despite widespread use, this regimen has never been assessed in clinical trials and outcomes are variable (60-75% treatment success in Vietnam). This study will assess whether careful study of pharmacokinetic/pharmacodynamic (PK/PD) parameters can explain treatment failure and relapse amongst Vietnamese non-MDR pulmonary TB patients. PK/PD modelling will be used to develop target parameters for treatment success.

Design: Non-MDR pulmonary TB patients due to initiate the Category 2 re-treatment regimen will be longitudinally followed. PK exposure to first-line TB drugs will be determined from plasma sampling on day 14 of therapy. PD parameters will be recorded at baseline (MIC of the infecting Mycobacterium tuberculosis isolate to first-line drugs, and time-kill phenotyping assays using a high-content imaging platform to study antibiotic effects on intracellular organisms). Time to positivity measurements from liquid culture of serial sputum samples will be used to generate a Bacillary Elimination Rate (BER) during the first 8 weeks. PK/PD models will be developed to establish the exposure-effect relationship between TB drugs and clinical outcomes. A parallel cohort of new TB patients will be studied to determine differences in the PK/PD characteristics of new and re-treatment patients.

The new clinical PK/PD datasets, including the under-studied Category 2 regimen and using new intra-cellular PD assays, from a high-burden TB setting in Vietnam will inform meta-analyses and simulations of dose-optimisation strategies to predict and improve treatment. Establishment of clinical, microbiological and pharmacological capacity for novel and advanced PK/PD studies in Vietnam will lay essential and sustainable foundations for future pharmacology studies and clinical trials.

All participants have extensive academic publication records and have given presentations at international meetings, demonstrating a commitment to communication with academic partners. LSTM has a track record of translational research throughout the developmental timeline from lab-based discovery science, through clinical trials to monitoring and evaluation of healthcare effectiveness. Most relevant to this application, the Liverpool team have a strong track record in drug development and optimisation of dosing regimens in the treatment of global infectious diseases.

The primary objective of the project is to determine whether PK/PD parameters describing inadequate drug exposure of first-line anti-TB drugs can explain or predict treatment failure/relapse amongst non-MDR pulmonary TB re-treatment patients in Vietnam.

Data derived from this work will be submitted for presentation at scientific meetings in Vietnam and internationally as soon as it is available. The UK partners have a track record in the organisation and participation of major international TB meetings e.g. Gordon Conference and Keystone.

As detailed in the data management plan, the Co-Is are committed to knowledge exchange with academic and industrial partners. PK-PD data will be made accessible (see data management plan) to both UK and international researchers and we will use our networks e.g. via the PreDICT-TB consortium, TB alliance and PANACEA consortium to actively share data and influence practice/policy.

It is the expectation that an output from the study will be the identification of putative optimal dosing regimens. We envisage that this data would then form the basis of clinical pilot studies performed in target populations to determine exposure profiles for subsequent clinical phase 2 clinical trials. It is our intension that this work will inform discussions with the Vietnam NTP, regarding the ongoing effectiveness and utility of the Category 2 regimen. Ultimately, the clinical and PK/PD data will also be useful to inform global discussion about optimal management of the re-treatment regimen with WHO and the International Union Against Tuberculosis and Lung Disease.

A further specific objective for this MRC VN Newton project is local capacity building. As described elsewhere, the UK team will train Vietnamese colleagues in analytical (LC-MS/MS) platforms, pharmacodynamic methodologies (high content imaging of intracellular M. tuberculosis, BER, etc) and PK-PD modelling. A key impact of this project will also therefore include establishment of clinical, microbiological and pharmacological capacity for novel, advanced PK/PD studies in Vietnam which is currently absent within the national research network in Vietnam.