UK HIV Drug Resistance Database

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UK HIV Drug Resistance Database
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Background (1)

• HIV drug resistance testing first became
  available in UK in 1997-8
• At least 10 laboratories currently perform
  testing
• Variety of in-house and commercial systems all
  based on DNA sequencing of the pol gene
• British HIV Association guidelines recommend
  resistance testing at treatment initiation and at
  each therapeutic failure

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Background (2)

• Recognised that routine resistance tests
  represented a valuable scientific resource but
  that reports were just being filed in patients
  notes
• UK HIV Drug Resistance Database was established
  in 2001 as central repository of resistance tests
  performed as part of routine clinical care

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Study Governance (1)

• Overseen by UK Collaborative Group on HIV Drug
  Resistance which includes representatives from
• each laboratory contributing resistance data
• major clinical centres
• academic specialists
• MRC Clinical Trials Unit (study coordination,
  site of database)
• UCL Centre for Virology (main bioinformatic
  input)
• UK CHIC study (clinical data that links to
  resistance data)
• HPA (surveillance expertise)

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  UK Collaborative Group on HIV Drug Resistance
Steering Committee David Dunn, Esther
Fearnhill, Hannah Green, Kholoud Porter, (MRC
Clinical Trials Unit), Rob Gifford, Paul Kellam,
Deenan Pillay, Andrew Phillips, Caroline Sabin
(Royal Free and University College Medical
School), Sheila Burns (City Hospital,
Edinburgh), Sheila Cameron (Gartnavel General
Hospital, Glasgow), Pat Cane (Health Protection
Agency), Ian Chrystie (St. Thomas Hospital,
London), Duncan Churchill (Brighton and Sussex
University Hospitals NHS Trust), Valerie Delpeche
(Health Protection Agency, London), Philippa
Easterbrook, Mark Zuckerman (Kings College
Hospital, London), Anna Maria Geretti (Royal Free
NHS Trust, London), David Goldberg (Scottish
Centre For Infection and Environmental Health),
Mark Gompels (Southmead Hospital, Bristol), Tony
Hale (PHLS, Leeds), Andrew Leigh-Brown
(University of Edinburgh), Anton Pozniak (Chelsea
Westminster Hospital, London), Gerry Robb
(Department of Health, London), Ras Smit (Health
Protection Agency, Birmingham Heartlands
Hospital), Peter Tilston (Manchester Royal
Infirmary), Steve Kaye (St. Marys Hospital,
London), Ian Williams (Mortimer Market Centre,
RFUCMS).  
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Study Governance (2)

• All participants agree to abide by Principles of
  Collaboration which covers data confidentiality,
  access to data, publication policy, etc.
• Steering Committee meets every 6 months
• All participants are encouraged to submit
  analysis proposals, which are vetted by Steering
  Committee

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Virology labs
Nucleotide sequences patient identifiers
basic clinical information on request form
Central database (SQL-Server)
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gt 00F6296_16_10_03 Wed Oct 29 104753 GMT0000
2003. 1302 bases.   CCTCAAATCACTCTTTGGCAGCGACCCCTT
GTYWCAATAAAAGTAGGGGG CCAGACAAARGARGCCCTCTTAGACACAG
GAGCAGATGATACAGTATTAG ARGAAATAAATTTGCCAGGAAAATGGAA
ACCAAAAATGATAGGRGGAATT GGAGGTTTTATCAAAGTAAGACAGTAT
GATCAAATACAGATAGAAATTTG TGGAAAAAAGGCTATAGGTACAGTAT
TAGTRGGACCTACACCTGTCAACA TAATTGGAAGAAATCTGTtGACTCA
GCTTGGATGCACACTAAATTTTCCA aTCAgtCCCATtGAAACTGTACCA
GTMAAATTAAAGCCAGGAATGGATGG CCCAAGGGTTAAACAATGGCCAT
TGACAGAAGAGAAAATaaAAGCATTAA CAGCAATTTGTGAAGAWATGGA
RAAGGAAGGAAAAATTACAAAAATTGGG CCYGAAAATCCATATAACACT
CCAGTATTTGCCATAAAAAAGAAGGACAG TAcTAAGTGGAGAAAATTAG
TAGATTTCAGGGAGCTCAATAAAAGAACTC AAGACTTTTGGGAAGTTCA
ATTAGGAATACCACACCCAGSAGGGTTAAAA AAGAAAAAATCAGTGACA
GTACTGGATGTGGGGGATGCATATTTTTCAGT TCCTTTAGATGAAGRCT
TCAGGAAATATACTGCATTCACCATACCTAGTA TAAACAATGAAACACC
AGGGATTAGATATCAATATAATGTGCTTCCACAG GGATGGAAGGGATCA
CCAGCAATATTCCAGAGTAGCATGACAAAAATCTT AGagCCCTTTAGGG
CACAAAAYCCAGAAATAGTCATYTGTCAATATATGG ATGACTTRTATGT
AGSATCAGACTTAGAAATAGGGCAACATAGAGCAAAA ATAGAGGAGTTA
AGAgAACATCTRTTGAAGTGGGGAYTTACCACACCAGA CAAGAAACATC
AGAAAGAACCCCCATTTCRTTGGATGGGGTATGAACTCC ATCCTGACAA
RTGGACAGTACAGCCTATACAGCTGCCAGAAAAGGATAGC TGGACTGTC
AATGATATACAGAAGTTAGTGGGAAAATTAAACTGGGCAAG TCAGATWT
ACCARGGGATYAAAGTAAAGCAACTTTGTAAACTCCTTAGRG GRACCAA
AGCACTAACAGACATAGTACCACTAACTGAAGAAGCAGAATTA GAATTG
GCAGAGAATAGGGARATTCTAAAAGAAACAGTACATgGAGTATA TTATG
acCCaTCAAAAGACTTAATAGCTGAAATACAGAAACAGGGGCATG AC
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Virology labs
Batch file of nucleotide sequences (FASTA) DB
identifier
Nucleotide sequences patient identifiers
basic clinical information on request form
Central database (SQL-Server)
Centre for Virology, UCL
Text files of mutations, subtype, drug
susceptibility, ...
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Virology labs
Batch file of nucleotide sequences (FASTA) DB
identifier
Nucleotide sequences patient identifiers
basic clinical information on request form
Central database (SQL-Server)
Centre for Virology, UCL
Patient identifiers detailed clinical
information (ART history, viral loads, ...)
Text files of mutations, subtype, drug
susceptibility, ...
Clinics
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The UK CHIC study

• Collaboration of some of the largest HIV
  treatment centres in UK with the following aims
• To describe the characteristics of patients with
  HIV in UK
• To provide information on exposure to HAART and
  immunological and virological outcomes
• To monitor frequency of AIDS events and survival
• To use information gathered to describe the
  changing epidemic in the UK
• Study funded by the Medical Research Council
  since 2001
• Inclusion criteria Patients aged gt16 years seen
  for care since 1/1/1996 participating centres
  must have electronic datasets

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The UK CHIC Study (2)

• Centres provide data on all patients seen at
  their centre since 1st January 1996
• Includes historic data on each patient prior to
  1996 if patient was under follow-up at that time
• Data held in same database as resistance data,
  although some patients have clinical data and no
  resistance data and vice versa
• 21,256 patients in UK CHIC database (in 2005)

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Number of tests by calendar year
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Number of tests by laboratory (to end 2004)
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Scientific outputs (1)

• 12 Abstracts presented at major HIV conferences,
  including 8 at International HIV Drug Resistance
  Workshop
• 3 HPA surveillance reports on the prevalence and
  patterns of resistance in ART-naive and
  ART-experienced patients

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Scientific outputs (2)

• 4 papers in peer-reviewed journals
• Long term probability of detection of HIV-1 drug
  resistance and after starting antiretroviral
  therapy in routine clinical practice. AIDS 2005,
  19487-94.
• Estimating HIV-1 drug resistance in
  antiretroviral-treated individuals in the United
  Kingdom. Journal of Infectious Diseases 2005,
  192967-73.
• Time trends in primary resistance to HIV drugs in
  the United Kingdom multicentre observational
  study. BMJ 2005, 3311368-71.
• Assessment of automated genotyping protocols as
  tools for surveillance of HIV-1 genetic
  diversity. AIDS 2006 (in press).
• 2 papers about to be submitted
• Identification of accessory mutations associated
  with high level resistance in HIV-1 reverse
  transcriptase.
• Predictive factors and clinical outcomes in
  patients with multi-class drug resistant (MDR)
  HIV in the UK.

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Prevalence of HIV drug resistance in drug-naive
patients
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Prevalence of resistance to individual drugs
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Prevalence of HIV drug resistance in
drug-experienced patients
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Number of patients with MDR virus (minimum
estimates)
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Percentage of recently-treated patients with
resistance or viral load failure
Percent
Viral load failure
Resistance mutation
0 1 2 3 4
5 6 7
Years from start of ART
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Effect of initial regimen on rate of detection of
specific groups of mutations
Initial regimen ( 2 nucleosides) Relative hazard Relative hazard Relative hazard
Initial regimen ( 2 nucleosides) nucleoside mutation mutation to PI or NNRTI mutations to 2/3 drug classes
unboosted PI 1.59 0.79 1.19
boosted PI 0.74 0.31 0.43
abacavir 2.24 - 1.51
NNRTI 1.00 1.00 1.00
Plt0.01
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Examples of other analyses in progress

• Interaction between subtype and development of PI
  and NNRTI mutations
• Predicting virological response from genotypic
  patterns using Bayesian networks
• Characterisation of recombinant forms of HIV-1
• Clinical utility of HIV resistance testing in
  ART-naive individuals
• Frequency and determinants of different TAM
  pathways

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Future direction of work

• Analyses to date have been fairly broadly based
• UK CHIC provides opportunity to look at role of
  individual drugs which most other databases
  (including Stanford) cannot do
• In particular can construct complete ART history
  for each patient

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Possible drug-specific analyses

• Incidence of specific mutations developing on
  drug combination X
• Prevalence or numbers of specific mutations in
  drug experienced patients (e.g. PI experienced
  patients)
• Response of patients with mutational pattern X to
  drug Y

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Funding

• Initially funded by 2-year NHS RD grant
• Funded since 2003 by DoH ends in June 2006. DoH
  unable to continue support due to financial
  crisis in NHS.
• Requires 110,000 per annum to fund
  infrastructure of project
• UK CHIC has recently secured MRC funding until
  June 2009