Modulation of TB-HIV drug interaction by host genetic influences

Lead Research Organisation: University of Liverpool
Department Name: Biomedical Sciences

Abstract

Tuberculosis (TB) and HIV are leading causes of death from infection worldwide, and co-infection is common with each epidemic fuelling the other. Concurrent treatment of both diseases is necessary, yet complex because of drug interactions. Efavirenz (EFV) is the HIV drug of choice when using rifampicin (RIF)-based TB regimens, and likely to remain so for the foreseeable future. EFV exposure is decreased by RIF, but less so than for other HIV drugs. However, people differ considerably in EFV exposure despite standardised dosing: pharmacogenetic variation in their genes (principally cytochrome P450 CYP2B6) accounts for most of these differences. CYP2B6 variant genes are particularly prevalent in some populations, such as black Africans, South Indians and SE Asians, and these are populations where HIV-TB coinfection is also widespread.

We want to investigate whether the impact of RIF on EFV exposure is different in people who are CYB2B6 poor metabolisers. Our hypothesis is that in these individuals, accessory pathways of EFV elimination are consequently more important, and a ?second hit? on these accessory pathways either through inhibition by another TB drug (isoniazid), or else the added effect of other common genetic variants which impair these pathways, makes these individuals behave differently when RIF is added to EFV.

We will evaluate this hypothesis firstly through an interaction study of isoniazid given to healthy volunteers receiving EFV+RIF, in whom CYP2B6 genotype has been characterised. Secondly, we will genotype DNA from up to 347 HIV-positive patients receiving EFV+RIF, together with an equivalent number of HIV-positive patients receiving EFV but not RIF, to examine for secondary exposure-modifying genetic effects.

This proposal combines research expertise from Liverpool with a strong clinical trials environment in Singapore, and an ideal study population where CYP2B6 poor metabolisers are prevalent. The interaction studied is of huge clinical importance. Knowledge gained will inform treatment guidelines for HIV-TB coinfection, and allow disease management to be optimised through a personalised medicines (genotyping) approach, or approach which stratifies treatment strategies for at-risk populations. If proven, these strong pharmacogenetic influences will also impact on the design and selection of partner drugs for new TB regimens.

Technical Summary

Tuberculosis (TB) and HIV are leading causes of death from infection worldwide, and co-infection is common with each epidemic fuelling the other. Concurrent treatment of both diseases is necessary, yet complex because of drug interactions. Efavirenz (EFV) is the antiretroviral of choice when using rifampicin (RIF)-based TB regimens, and likely to remain so for the foreseeable future. However, strong pharmacogenetic influences result in excessive variability in EFV exposure to the extent that EFV concentrations are not compromised, and may paradoxically increase in a subgroup of cytochrome P450 CYP2B6 ?poor metabolisers?.

Our hypothesis is that in CYP2B6 poor metabolisers, secondary ?exposure modifying? influences such as other genetic polymorphisms affecting the accessory pathway of EFV metabolism, or inhibition of that pathway by isoniazid (another component of TB therapy) become consequently more important. We will evaluate this hypothesis firstly through an interaction study of isoniazid given to individuals receiving EFV+RIF, stratified by CYP2B6 genotype. Healthy volunteers (N=150) will be screened for CYB2B6 516G T polymorphism, and homozygous GG (N=24) and TT (N=12) individuals recruited into a proportionally unbalanced, factorial, crossover design study of single dose EFV+RIF with, and without isoniazid. Secondly, we will genotype DNA from up to 347 HIV-positive patients receiving EFV+RIF, together with an equivalent number of HIV-positive patients receiving EFV but not RIF, to examine for secondary exposure-modifying genetic effects. Candidate genes included in this analysis are SNPs and other genetic variants in CYP2B6, CYP 2A6, CYP 3A4/5, PXR, ABCB1 and SLCO1B1. For both studies, we will validate genotype:phenotype associations by measuring EFV and its major metabolites in plasma.

This proposal combines research expertise from Liverpool with a strong clinical trials environment in Singapore, and an ideal study population where CYP2B6 poor metabolisers are prevalent. The interaction studied is of huge clinical importance. Knowledge gained will inform treatment guidelines for HIV-TB coinfection, and allow disease management to be optimised through a personalised medicines (genotyping) approach, or approach which stratifies treatment strategies for at-risk populations. If proven, these strong pharmacogenetic influences will also impact on the design and selection of partner drugs for new TB regimens.

Publications

10 25 50

publication icon
British HIV Association (2012) Standards of Care for People living with HIV 2013

publication icon
British Thoracic Society Standards Of Care Committee And Joint Tuberculosis Committee (2010) Guidelines for the prevention and management of Mycobacterium tuberculosis infection and disease in adult patients with chronic kidney disease. in Thorax

 
Description BHIVA Guidelines committee
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
Impact Uk TB treatment guidelines
 
Description British Guidelines for Managment of opportunistic infections in HIV
Geographic Reach National 
Policy Influence Type Membership of a guidance committee
 
Description British HIV Association HIV Treatment Gidelines
Geographic Reach Asia 
Policy Influence Type Membership of a guidance committee
Impact BHIVA standards are universally implemented in the UK, Republic of Ireland and elsewhere, and form national Standards for care.
 
Description British HIV Association Standards for HIV care
Geographic Reach National 
Policy Influence Type Membership of a guidance committee
Impact Universally implemented across UK Forms commissioning and service auditing standards.
 
Description British HIV Association TB guidelines
Geographic Reach National 
Policy Influence Type Membership of a guideline committee
Impact Input into British HIV Association TB guidelines
 
Description British Thoracic Society Guidelines on TB drug dosing in renal disease
Geographic Reach National 
Policy Influence Type Membership of a guidance committee
 
Description WHO Think Tank for Antiretroviral Treatment
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guideline committee
Impact Review of new HIV treatment guidelines
 
Description WHO revised Adult Antiretroviral Guidelines
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in a national consultation
 
Description A randomised, double-blind, placebo-controlled, clinical trial to compare the safety and efficacy of reduced dose efavirenz (EFV) with standard dose EFV
Amount £130,000 (GBP)
Organisation University of New South Wales 
Sector Academic/University
Country Australia
Start 06/2012 
End 05/2014
 
Description A randomised, double-blind, placebo-controlled, clinical trial to compare the safety and efficacy of reduced dose efavirenz (EFV) with stardard dose EFV
Amount £224,114 (GBP)
Organisation University of New South Wales 
Sector Academic/University
Country Australia
Start 06/2012 
End 12/2014
 
Description A single arm, 3 phase study to determine the effect of intermittent dosing of rifampicin on the pharmacokinetics of raltegravir in healthy volunteers
Amount £113,048 (GBP)
Funding ID 38283 
Organisation Merck 
Sector Private
Country Germany
Start 08/2011 
End 07/2013
 
Description Computer-aided decision support for electronic prescribing, dispensing and health records of HIV positive patients
Amount £47,000 (GBP)
Organisation National Institute for Health Research 
Department NIHR Liverpool Pancreatic Biomedical Research Unit
Sector Academic/University
Country United Kingdom
Start 09/2011 
End 02/2013
 
Description ENCORE Studies (Bill & Melinda Gates Foundation)
Amount £130,000 (GBP)
Organisation University of New South Wales 
Department Kirby Institute
Sector Academic/University
Country Australia
Start 11/2012 
End 11/2014
 
Description HEP Drug-drug Interactions Website (BI)
Amount £25,000 (GBP)
Organisation Boehringer Ingelheim 
Sector Private
Country Germany
Start 01/2012 
End 12/2013
 
Description HEP Drug-drug Interactions Website (Gilead)
Amount £100,000 (GBP)
Organisation Gilead Sciences, Inc. 
Department Gilead
Sector Private
Country United Kingdom
Start 01/2011 
End 12/2015
 
Description HEP Drug-drug Interactions Website (Janssen)
Amount £149,954 (GBP)
Organisation Johnson & Johnson 
Department Janssen Pharmaceutica
Sector Private
Country Global
Start 01/2011 
End 12/2015
 
Description HEP Drug-drug Interactions Website (Merck)
Amount £67,500 (GBP)
Organisation Merck 
Sector Private
Country Germany
Start 01/2011 
End 12/2015
 
Description HEP Drug-drug Interactions Website (Roche)
Amount £40,000 (GBP)
Organisation F. Hoffmann-La Roche AG 
Department Roche Diagnostics
Sector Private
Country Global
Start 01/2012 
End 12/2014
 
Description HEP Drug-drug Interactions Website (Vertex)
Amount £104,000 (GBP)
Organisation Vertex Pharmaceuticals 
Sector Private
Country United States
Start 01/2011 
End 12/2013
 
Description HIV Drug-drug Interactions Website
Amount £50,000 (GBP)
Organisation International Congress on Drug Therapy in HIV Infection 
Sector Academic/University
Country Global
Start 01/2010 
End 12/2013
 
Description HIV Drug-drug Interactions Website (Abbott)
Amount £30,000 (GBP)
Organisation Abbott 
Department Abbott UK
Sector Private
Country United Kingdom
Start 01/2010 
End 12/2010
 
Description HIV Drug-drug Interactions Website (BHIVA)
Amount £53,772 (GBP)
Organisation British HIV Association (BHIVA) 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2011 
End 12/2015
 
Description HIV Drug-drug Interactions Website (BI)
Amount £25,000 (GBP)
Organisation Boehringer Ingelheim 
Sector Private
Country Germany
Start 01/2010 
End 12/2012
 
Description HIV Drug-drug Interactions Website (BMS)
Amount £57,883 (GBP)
Organisation Bristol-Myers Squibb 
Sector Private
Country United States
Start 01/2011 
End 12/2015
 
Description HIV Drug-drug Interactions Website (EACS)
Amount £38,772 (GBP)
Organisation European Aids Clinical Society 
Sector Charity/Non Profit
Country Belgium
Start 01/2011 
End 12/2015
 
Description HIV Drug-drug Interactions Website (EJAF)
Amount £105,431 (GBP)
Organisation Elton John AIDS Foundation 
Sector Charity/Non Profit
Country United Kingdom
Start 08/2011 
End 08/2013
 
Description HIV Drug-drug Interactions Website (Janssen)
Amount £115,118 (GBP)
Organisation Johnson & Johnson 
Department Janssen Pharmaceutica
Sector Private
Country Global
Start 01/2010 
End 12/2015
 
Description HIV Drug-drug Interactions Website (Merck)
Amount £85,600 (GBP)
Organisation Merck 
Sector Private
Country Germany
Start 01/2010 
End 12/2015
 
Description HIV Drug-drug Interactions Website (VIIV)
Amount £140,000 (GBP)
Organisation Viiv Healthcare 
Sector Private
Country United Kingdom
Start 01/2010 
End 12/2014
 
Description HIV drug interactions website
Amount £15,000 (GBP)
Organisation Bristol-Myers Squibb 
Sector Private
Country United States
Start 01/2016 
End 12/2016
 
Description HIV drug interactions website
Amount £10,000 (GBP)
Organisation Johnson & Johnson 
Department Janssen Pharmaceutica
Sector Private
Country Global
Start 01/2016 
End 12/2016
 
Description Innovative Medicines Initiative (EU)
Amount £1,439,979 (GBP)
Funding ID Predict TB Consortium (PI Davies) 
Organisation European Commission 
Department Seventh Framework Programme (FP7)
Sector Public
Country European Union (EU)
Start 07/2012 
End 07/2019
 
Description Integrated Project Special populations and label expansion studies with the fixed dose combinations artemether-lumefantrine, amodiaquine-artesunate, and dihydroartemisinin-piperaquine in Zambia, Malawi and Mozambique
Amount € 50,000 (EUR)
Funding ID IP2007.31060.003 
Organisation Sixth Framework Programme (FP6) 
Department European and Developing Countries Clinical Trials Partnership
Sector Public
Country Netherlands
Start 08/2009 
End 07/2014
 
Description Liverpool Bioanalytical Facility
Amount £75,084 (GBP)
Organisation National Institute for Health Research 
Department NIHR Liverpool Pancreatic Biomedical Research Unit
Sector Academic/University
Country United Kingdom
Start 07/2010 
End 06/2011
 
Description Model-based preclinical development of anti-tuberculosis drug combinations (preDICT-TB)
Amount £1,439,979 (GBP)
Funding ID 115337 
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 05/2012 
End 07/2017
 
Description NIH RO1
Amount $1,531,703 (USD)
Organisation National Institutes of Health (NIH) 
Sector Public
Country United States
Start 01/2017 
End 12/2020
 
Description NIHR Biomedical Research Fellowship - Victoria Watson
Amount £100,003 (GBP)
Funding ID BRF-2011-029 
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 04/2012 
End 10/2013
 
Description NIHR Flexibility & Sustainability Funding
Amount £75,084 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 09/2010 
End 08/2011
 
Description North West England MRC Fellowships in Clinical Pharmacology and Therapeutics
Amount £198,162 (GBP)
Funding ID G1000417 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 10/2010 
End 09/2015
 
Description Prediction of drug-drug interaction between Rifampicin and Boosted Darunavir using pharmacokinetic modelling approaches
Amount £123,163 (GBP)
Organisation Johnson & Johnson 
Department Janssen Pharmaceuticals
Sector Private
Country United States
Start 10/2013 
End 09/2016
 
Description Raltegravir pharmacokinetics
Amount £143,878 (GBP)
Organisation Merck 
Sector Private
Country Germany
Start 01/2013 
End 12/2013
 
Description SSAT Trials
Amount £396,554 (GBP)
Organisation St Stephen's AIDS Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 04/2009 
End 03/2020
 
Title Bioanalytical Capability 
Description The Bioanalytical Facility gained GCLP accreditation in 2011- MRC funding was an important contributor to this success. Our project funded bioanalyst was initially the facility GCLP archivist, and in 2012 was promoted to Quality Manager 
Type Of Material Improvements to research infrastructure 
Year Produced 2013 
Provided To Others? Yes  
Impact GCLP accreditation has enabled us to undertake pivotal pharmacokinetic studies for submission to regulatory authorities. Since this was achieved, we have successfully gained master Service Agreements with Chelsea & Westminister Hospital, Service level agreements with Imperial, and Studies funded by Gates. Another service level agreement is currently in negotiation with the MRC HIV Clincial trials Unit. Bioanalytical research to a value of ~£300k/year for the past 2 years have resulted. 
 
Title GCLP Accreditation 
Description MRC funding helped to develop our bioanalytical facility, and we gained GCLP accreditation in 2011, and have maintained it annually thereafter 
Type Of Material Improvements to research infrastructure 
Year Produced 2013 
Provided To Others? Yes  
Impact 4 primary publications in 2013, 11 primary publications in 2012, 8 primary publications in 2011 
 
Title Renewal of GCP accrediation for labs 
Description GCP accreditation for highly secialised assays- measuring drug in tissues and cells 
Type Of Material Biological samples 
Year Produced 2011 
Provided To Others? Yes  
Impact Traction for research grants, high impact publications 
URL https://www.liverpool.ac.uk/translational-medicine/research/bioanalytical-facility/about/
 
Title efavirenz metabolite assay 
Description LC-MS assay for efavirenz and its 7- and 8-hydroxy metabolites, down to 5ng/mL sensitivity. Allows genotype-phenotype coorrelations, characterisation of poor metaboliser status, and investigation in plasma and CSF. 
Type Of Material Technology assay or reagent 
Year Produced 2014 
Provided To Others? Yes  
Impact Studies are in progress 
 
Description Makarere University 
Organisation Makerere University
Country Uganda 
Sector Academic/University 
PI Contribution Bioanalytical support for HIV/TB clinical drug interaction studies
Collaborator Contribution clinical recruitment
Impact Several research publications, which are listed separately EDCTP Research Fellowship for Dr Mohammed Lamorde
Start Year 2010
 
Description Urinary drug detection using aptamers 
Organisation University of Pittsburgh
Country United States 
Sector Academic/University 
PI Contribution Bioanalytical capacity
Collaborator Contribution clincial recruitment
Impact Discovery phase- drug detection in urine using aptamers
Start Year 2016
 
Title Liverpool HIV and Hepatitis Drug Interaction Websites 
Description We developed traffic lights based system of classification for HIV and hepatitis drugs, and a GRADE-based system of evidence evaluation to achieve consistency and transparency. Supporting software- including web-based decision support software, and iPhone/ tablet/Android apps. MOU in 2013 acknowledges full ownership by Liverpool of the software and content. 
IP Reference  
Protection Protection not required
Year Protection Granted 2013
Licensed No
Impact Websites: over 80,000 unique visitors/year Smartphone apps - over 40,000 downloads between 2011-2013 Incorporation of Liverpool Decision support into national/international treatment guidelines from over 17 countries.
 
Title Liverpool HIV and hepatitis drug interaction Apps 
Description Smartphone search tools for managing drug interactions. Available for iPhone, iPad and Android 
IP Reference  
Protection Copyrighted (e.g. software)
Year Protection Granted 2013
Licensed Yes
Impact over 50,000 downloads to date. Associated web stats- over 100,000 unique visitors/ year, incorporated into numerous national and international treatment guidelines.
 
Title HIV Drug interaction website 
Description www.hiv-druginteractions.org is now established as a decision support tool in around 30 guidelines from over 16 countries worldwide, as well as in WHO and European treatment guidelines 
Type Management of Diseases and Conditions
Current Stage Of Development Wide-scale adoption
Development Status Under active development/distribution
Impact see above 
URL http://www.hiv-druginteractions.org
 
Title HIV Drug interactions websites 
Description smartphone apps- iPhone/ Android/ iPad 
Type Support Tool - For Medical Intervention
Current Stage Of Development Wide-scale adoption
Year Development Stage Completed 2011
Development Status Under active development/distribution
Impact >22,000 downloads since introduction 18 months ago. 
 
Title PREDICT TB IMI Consortium (Eur 13M) 
Description Our work in Pk and pharmacogenetics of TB coupled with work on PK-PD relationship was instrumental in funding success. Liverpool is the lead institution on this grant. 
Type Therapeutic Intervention - Drug
Current Stage Of Development Refinement. Non-clinical
Year Development Stage Completed 2013
Development Status Under active development/distribution
Impact accelerate drug development process, from preclincial through early clinical to phase III studies 
 
Description Art Exhibition at World Museum, Liverpool 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Type Of Presentation Workshop Facilitator
Geographic Reach Local
Primary Audience Schools
Results and Impact Schools Art project with local artist (Gaynor Vane) - multimedia artwork depicting TB, HIV and other pathogens in tissue, and interaction between host and pathogen. This accompanied a year-long engagement with schools across Merseyside.

Exhibition at regional museum
Year(s) Of Engagement Activity 2011
 
Description Schools lecture series 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Type Of Presentation Workshop Facilitator
Geographic Reach Local
Primary Audience Schools
Results and Impact Our team (including post-docs) visited schools across Merseyside and gave talks on pathogen-host interactions. They were accompanied by a local artist who then developed artwork projects from these lectures.

exhibition at World Museum Liverpool in 2011.
Year(s) Of Engagement Activity 2010,2011
 
Description Video podcast for Greenwich School of Management 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Industry/Business
Results and Impact Podcast for students on Business managment courses at Greenwich School of Management on HIV. they will seek to raise awareness in their events management activities as part of their final year module.
Year(s) Of Engagement Activity 2015
 
Description World AIDS Day Schools Lecture & Roadshow 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach Local
Primary Audience Schools
Results and Impact over 100 pupils from 5 schools across Merseyside took part in this activity, which was organised by the University, and run in association with the local HIV patient group and a popular DJ from BBC radio Merseyside (Roger Phillips)

Schools asked for further contact and lectures
Year(s) Of Engagement Activity 2010