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

Lead Research Organisation: Liverpool School of Tropical Medicine
Department Name: Parasitology

Abstract

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.

Technical Summary

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.

Planned Impact

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.
 
Description Patients with pulmonary tuberculosis (TB) who are not cured by a first course of standard anti-TB therapy are also at high risk of failure from re-treatment, even when multi-drug resistant (MDR) disease is not identified on re-presentation. In Vietnam, treatment success rates for non-MDR TB re-treatment patients are only 60-80%. Despite recent changes to WHO guidelines, the best approach to management of such patients is not evidence based.

In our MRC Newton-funded project, new and re-treatment adult Vietnamese patients with non-MDR pulmonary TB were recruited to a longitudinal cohort study. Treatment was administered using standard WHO antibiotic regimens. Serial sputum samples were collected during the first 8 weeks. Bacteriological response was monitored according to time to culture conversion and rate of change in time-to-positivity of liquid culture. Later clinical outcomes were available from national programmatic data. Plasma drug concentrations were measured from blood samples collected on day 10 - 14. Pharmacokinetic-pharmacodynamic (PK-PD) relationships between antibiotic exposure and treatment response were assessed.

130 patients (77 "new" and 53 "re-treatment" cases) were recruited. Re-treatment patients were confirmed to have non-MDR disease by baseline GeneExpert MTB/RIF assay. The rate of bacterial clearance from sputum was slower in re-treatment patients. Ca. 20% "re-treatment" patients resulted in failed treatment/relapse compared to only 1 % "new patient". There was no difference in plasma exposure to first-line anti-TB drugs between patient groups.

The study's initial conclusions are that bacteriological response and clinical outcomes are worse in re-treatment pulmonary TB patients, even in the apparent absence of acquired drug resistance. Pharmacokinetic variability in antibiotic exposure does not fully explain this.

The study's initial findings have been reported orally at the 50th Union World Conference on Lung Health (30 October - 2 November 2019) that took place in Hyderabad, India.

We are currently undertaking more detailed analysis of clinical and microbiological co-variates to identify factors contributing to unfavourable outcomes amongst re-treatment patients - we expect submission of this work in Q2 or Q3 of 2020.
Exploitation Route As described above, further analyses of the data is still in progress but we hope to develop a new scoring matrix that can be used to stratify TB patient groups. For non-MDR TB patients which have been scored to have a high likelihood of failing TB treatment, a different intervention would be required. Both the scoring matrix and the intervention would then required further clinical assessment - this is clearly an outcome that can be taken forward by other investigators and/or national TB programmes.
Sectors Healthcare,Pharmaceuticals and Medical Biotechnology

 
Description Further to the scientific impact that we hope will lead to changes in clinical practice (which we will report in due course), LifeArc, an independent medical charity (https://www.lifearc.org) have developed a diagnostic that measures the bacillary load of TB, known as the MBLA assay, into a commercial product for research purposes. Towards their aim of gaining further regulatory evidence for their kit, we will use our sputum samples from the observational trial and compare our MIGIT data etc with their MBLA kits. For this, they have offered to send their staff to Vietnam to undertake the MBLA assay and they will also train Vietnamese staff to use the new kit - all of this work and research capacity activities will be undertaken at no cost to the UK and VN researchers and will be a contribution in kind by Life Arc.
First Year Of Impact 2020
Sector Healthcare,Pharmaceuticals and Medical Biotechnology
Impact Types Societal,Policy & public services

 
Description Research Grant, BMC: DPFS Full
Amount £947,594 (GBP)
Funding ID MR/S00467X/1 
Organisation MRC Biomedical Catalyst Developmental Pathway Funding Scheme (DPFS) 
Sector Academic/University
Country United Kingdom
Start 01/2019 
End 12/2022
 
Description Collaboration with LifeArc 
Organisation LifeArc
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution LifeArc, an independent medical charity (https://www.lifearc.org) have developed the MBLA assay into a commercial product for research purposes. Towards their aim of gaining further regulatory evidence for their kit, we will use our sputum samples from the observational trial and compare our MIGIT data etc with their MBLA kits.
Collaborator Contribution LifeArc have offered to send their staff to Vietnam to undertake the MBLA assay and they will also train Vietnamese staff to use the new kit - all of this work and research capacity activities will be undertaken at no cost to the UK and VN researchers and will be a contribution in kind by Life Arc.
Impact Furthermore, LifeArc, an independent medical charity (https://www.lifearc.org) have developed the MBLA assay into a commercial product for research purposes. Towards their aim of gaining further regulatory evidence for their kit, we will use our sputum samples from the observational trial and compare our MIGIT data etc with their MBLA kits. For this, they have offered to send their staff to Vietnam to undertake the MBLA assay and they will also train Vietnamese staff to use the new kit - all of this work and research capacity activities will be undertaken at no cost to the UK and VN researchers and will be a contribution in kind by Life Arc.
Start Year 2020
 
Description Using pharmacokinetic - pharmacodynamic analyses to select optimal dosing for non-MDR pulmonary TB treatment failure patients in Vietnam 
Organisation Vietnam Academy of Science and Technology
Country Viet Nam 
Sector Academic/University 
PI Contribution This collaboration has been funded via the MRC-Newton call in collaboration with the MOST ministry of Vietnam
Collaborator Contribution The collaboration is between the UK and a number of institutions in VN (listed above). The project is specifically trying to address the underlying reasons for TB treatment failures but in terms of training, UK researchers are providing training in Pharmacology, specifically pharmacokinetics and PK-PD modelling, addressing a specific expertise gap in VN and the National TB Programme.
Impact Uk researchers have been involved in training VN researchers in the UK and Ethics applications have been submitted and approved for the clinical study due to begin in May 2017.
Start Year 2015
 
Description Using pharmacokinetic - pharmacodynamic analyses to select optimal dosing for non-MDR pulmonary TB treatment failure patients in Vietnam 
Organisation Vietnam National Lung Hospital
Country Viet Nam 
Sector Hospitals 
PI Contribution This collaboration has been funded via the MRC-Newton call in collaboration with the MOST ministry of Vietnam
Collaborator Contribution The collaboration is between the UK and a number of institutions in VN (listed above). The project is specifically trying to address the underlying reasons for TB treatment failures but in terms of training, UK researchers are providing training in Pharmacology, specifically pharmacokinetics and PK-PD modelling, addressing a specific expertise gap in VN and the National TB Programme.
Impact Uk researchers have been involved in training VN researchers in the UK and Ethics applications have been submitted and approved for the clinical study due to begin in May 2017.
Start Year 2015
 
Description Using pharmacokinetic - pharmacodynamic analyses to select optimal dosing for non-MDR pulmonary TB treatment failure patients in Vietnam 
Organisation Vietnam National University
Country Viet Nam 
Sector Academic/University 
PI Contribution This collaboration has been funded via the MRC-Newton call in collaboration with the MOST ministry of Vietnam
Collaborator Contribution The collaboration is between the UK and a number of institutions in VN (listed above). The project is specifically trying to address the underlying reasons for TB treatment failures but in terms of training, UK researchers are providing training in Pharmacology, specifically pharmacokinetics and PK-PD modelling, addressing a specific expertise gap in VN and the National TB Programme.
Impact Uk researchers have been involved in training VN researchers in the UK and Ethics applications have been submitted and approved for the clinical study due to begin in May 2017.
Start Year 2015