Transcript Paediatric European Network for Treatment of AIDS (PENTA

UK HIV Drug
Resistance Database
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
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
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)
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 (King’s 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).
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
Virology labs
Nucleotide sequences +
patient identifiers +
basic clinical information
on request form
Central database
(SQL-Server)
> 00F6296_16_10_03
Wed Oct 29 10:47:53 GMT+00:00 2003. 1302 bases.
CCTCAAATCACTCTTTGGCAGCGACCCCTTGTYWCAATAAAAGTAGGGGG
CCAGACAAARGARGCCCTCTTAGACACAGGAGCAGATGATACAGTATTAG
ARGAAATAAATTTGCCAGGAAAATGGAAACCAAAAATGATAGGRGGAATT
GGAGGTTTTATCAAAGTAAGACAGTATGATCAAATACAGATAGAAATTTG
TGGAAAAAAGGCTATAGGTACAGTATTAGTRGGACCTACACCTGTCAACA
TAATTGGAAGAAATCTGTtGACTCAGCTTGGATGCACACTAAATTTTCCA
aTCAgtCCCATtGAAACTGTACCAGTMAAATTAAAGCCAGGAATGGATGG
CCCAAGGGTTAAACAATGGCCATTGACAGAAGAGAAAATaaAAGCATTAA
CAGCAATTTGTGAAGAWATGGARAAGGAAGGAAAAATTACAAAAATTGGG
CCYGAAAATCCATATAACACTCCAGTATTTGCCATAAAAAAGAAGGACAG
TAcTAAGTGGAGAAAATTAGTAGATTTCAGGGAGCTCAATAAAAGAACTC
AAGACTTTTGGGAAGTTCAATTAGGAATACCACACCCAGSAGGGTTAAAA
AAGAAAAAATCAGTGACAGTACTGGATGTGGGGGATGCATATTTTTCAGT
TCCTTTAGATGAAGRCTTCAGGAAATATACTGCATTCACCATACCTAGTA
TAAACAATGAAACACCAGGGATTAGATATCAATATAATGTGCTTCCACAG
GGATGGAAGGGATCACCAGCAATATTCCAGAGTAGCATGACAAAAATCTT
AGagCCCTTTAGGGCACAAAAYCCAGAAATAGTCATYTGTCAATATATGG
ATGACTTRTATGTAGSATCAGACTTAGAAATAGGGCAACATAGAGCAAAA
ATAGAGGAGTTAAGAgAACATCTRTTGAAGTGGGGAYTTACCACACCAGA
CAAGAAACATCAGAAAGAACCCCCATTTCRTTGGATGGGGTATGAACTCC
ATCCTGACAARTGGACAGTACAGCCTATACAGCTGCCAGAAAAGGATAGC
TGGACTGTCAATGATATACAGAAGTTAGTGGGAAAATTAAACTGGGCAAG
TCAGATWTACCARGGGATYAAAGTAAAGCAACTTTGTAAACTCCTTAGRG
GRACCAAAGCACTAACAGACATAGTACCACTAACTGAAGAAGCAGAATTA
GAATTGGCAGAGAATAGGGARATTCTAAAAGAAACAGTACATgGAGTATA
TTATGacCCaTCAAAAGACTTAATAGCTGAAATACAGAAACAGGGGCATG
AC
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, ...
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, ...
Patient identifiers +
detailed clinical information
(ART history, viral loads, ...)
Clinics
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 >16 years seen for care since
1/1/1996; participating centres must have electronic datasets
UKCHIC
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)
UKCHIC
Number of tests by calendar year
5000
4000
3000
2000
1000
0
<=1998
1999
2000
ART-naïve
2001
2002
ART-experienced
2003
2004
Number of tests by laboratory (to end 2004)
Glasgow
Leeds
Edinburgh
Kings
St.Thomas
Manchester
St.Marys
UCL
Royal Free
Birmingham
VIRCO
0
1000
2000
3000
4000
5000
6000
7000
8000
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 ARTexperienced patients
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,
19:487-94.
– Estimating HIV-1 drug resistance in antiretroviral-treated individuals
in the United Kingdom. Journal of Infectious Diseases 2005, 192:96773.
– Time trends in primary resistance to HIV drugs in the United
Kingdom: multicentre observational study. BMJ 2005, 331:1368-71.
– 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.
Prevalence of HIV drug resistance in
drug-naive patients
Percentage of tests
20
15
NRTI
PI
nNRTI
any class
10
5
0
1996-7
(n=310)
1998
(n=340)
1999
(n=358)
2000
(n=457)
2001
(n=516)
Year of sample
2002
(n=520)
2003
(n=764)
2004
(n=1185)
8
7
6
5
"R"
"I"
4
3
A
B
C
A
ZT
d4
T
dd
I
TD
F
EF
V
N
VP
A
PV
LP
V
N
FV
SQ
V
R
TV
A
TV
C
2
1
0
3T
prevalence (%)
Prevalence of resistance to individual drugs
Prevalence of HIV drug resistance in
drug-experienced patients
Percentage of tests
100
80
NRTI
PI
nNRTI
any class
60
40
20
0
1996-7
(n=232)
1998
(n=563)
1999
(n=1239)
2000
(n=1633)
2001
(n=1431)
Year of sample
2002
(n=1554)
2003
(n=1549)
2004
(n=1500)
Number of patients with MDR virus (minimum
estimates)
4000
Number with resistance
3500
3000
2500
2000
1500
1000
500
0
1998
1999
1 or more classes
2000
2001
2 or more classes
2002
3 classes
Percentage of recently-treated patients
with resistance or viral load failure
50
40
Percent
Viral load failure
30
20
Resistance mutation
10
0
0
1
2
3
4
5
Years from start of ART
6
7
Effect of initial regimen on rate of
detection of specific groups of mutations
Initial
regimen (+ 2
nucleosides)
Relative hazard
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
* P<0.01
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
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
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
Funding
• Initially funded by 2-year NHS R&D 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