Transcript Poster

Temporal patterns in the rate of transmitted resistance in the UK
Hannah Green1, Anton Pozniak2 and Kholoud Porter1 on behalf of the
UK Collaborative Group on HIV Drug Resistance and the UK Register of HIV Seroconverters
1 MRC Clinical Trials Unit, London, UK 2 Chelsea & Westminster Hospital, London, UK
269 of the 2025 drug naive patients (13%) had evidence of
resistant HIV. For the time periods 1996-1998, 1999-2000
and 2001-2003, resistance to any ART class was 10%,
14% and 16% respectively. The prevalence of resistance
between 2001 and 2002/3 appears to have increased
sharply to 21% but due to the relatively small number of
tests in 2002/3, the estimate of resistance is less precise in
this time period. NRTI resistance followed a similar pattern
and there has also been a steady increase in the frequency
of NNRTI mutations. PI resistance has remained at a low
level over the study period.
BACKGROUND
The transmission of drug resistant variants of HIV-1 has
the potential to seriously limit the therapeutic options for
newly infected individuals. Furthermore it is essential to
monitor the level of transmitted drug resistance to
understand the spread of resistant virus. The prevalence
of transmitted drug resistance is also a major consideration
in assessing the need for drug resistance testing before
the start of ART treatment and as an indirect marker of
transmission from persons known to be infected.
We describe the prevalence of resistance in treatment
naïve patients in the UK HIV drug resistance database.
These include patients where the date of seroconversion is
well estimated (recently infected naives) and in whom the
date is not known (chronically infected naives). The
database pools genotypic resistance, virological and
clinical data from all virology laboratories providing
resistance testing and major clinical centres in the UK.
METHODS
Treatment status
Resistance tests performed on patients naïve to
antiretroviral treatment were identified using the resistance
test request form or from clinical data where available.
One major source of clinical data was the UK
Collaborative HIV Cohort Study (UK CHIC), which
includes 6 of the largest HIV clinical centres in the UK.
A random sample of records on patients apparently naïve
at the time of the genotypic resistance test were checked
using patient/clinical notes. A small proportion of these
were found to be treatment experienced and were
therefore excluded from the analyses.
Resistance
Resistance was defined as at least one key (primary)
mutation according to a modified version of the IAS-USA
(2002) list to reflect recent advances in knowledge of HIV
resistance (additional mutations: 69N, 106M and any
amino acid change at positions 215 and 190. All lopinavir
mutations were excluded except 54L/V). The analysis
was based on the first test for each patient whilst naïve to
ART.
Recent infections
Tests reported to have been undertaken in
‘seroconverters’ are followed up through the UK Register
of Seroconverters to establish whether they fulfil a
common case definition; that the resistance test was
performed within 18 months of a documented negative
HIV antibody test or laboratory confirmed acute infection
in an ART-naïve individual. This subset of treatment naïve
patients are identified on the resistance database.
Treatment naïve:
% of patients with  1 primary mutation by calendar year
Temporal and demographic patterns
As of May 2003, 9847 test results, obtained since 1996,
from 6733 patients have been entered into the database.
60% of these patients have clinical data in the UK CHIC
database. 2025 patients (30%) had a resistance test
whilst naïve to ART treatment of whom 152 were during
recent infection.
20
15
15
10
10
5
0
5
1996-1998
100
0
1996-7
1998
1999
2000
2001
2002-3
1999-2000
Chronically infected naive
0
1996-7
1998
1999
NRTI
PI
2000
NNRTI
2001
Any class
n
Prevalence (%)
1140
12
318
11
52
10
Risk group
Homosexual
Heterosexual
IDU
Recent infection
Prevalence of resistance for the 1873 drug naïve patients
whose tests were not during recent infection (chronically
infected naives) was lower than those recently infected at
9%, 13% and 15% respectively.
Prevalence of resistance by demographic factors
Factor
2001-2003
2002-3
Prevalence of resistance was not associated with risk
group, ethnicity or CD4 count at time of resistance test.
Whilst the prevalence observed in seroconverters is likely
to be a true measure of transmission of resistance at a
given time point (in contrast to chronically infected), this
population may not be representative of those patients
starting ART for the first time in the UK. Testing for drug
resistance in naïve patients was not routine practice in
most patients in the period assessed and a patient was
more likely to get a resistance test if there was suspicion
they may be drug resistant to HIV.
DISCUSSION
Ethnicity
White
1062
13
218
12
Black African
CD4 count at test
• Over 10 % of drug naïve patients who have had a
resistance test are infected with virus with at least one key
resistance associated mutation.
(cells/mm3)
0-199
434
10
200-349
409
12
350-
769
13
•These data may not be representative of treatment naïve
individuals in the UK. As resistance testing is not routine
for newly diagnosed individuals in all clinical centres during
this period, persons genotyped may be more likely to have
been infected with drug-resistant HIV than those not genotyped.
Furthermore, work is ongoing to verify the accuracy of clinic
records of all patients reported to be naïve.
168 of the 269 patients (62%) with resistance had one or
more mutations conferring reduced NRTI susceptibility
only. Of the 415 NRTI mutations observed in these
patients, 98 were an amino acid change at the 215 position
of the RT gene. V118I was the second most frequent,
however this secondary mutation if present alone is
unlikely to be of clinical significance.
48 of the 269 patients (18%) had evidence of resistance to
more than one class; 20 patients to NRTIs and NNRTIs, 14
to NRTIs and PIs and 14 to all 3 classes. The most
frequently observed mutation associated with resistance to
NNRTIs was 103N and 90M for PIs.
Frequently observed mutations
NRTI
200
30
20
500
300
% of patients with  1 primary mutation (any class)
25
Number of tests performed in treatment naïve patients
per calendar year
400
Of the 152 seroconverters fulfilling the UK Register case
definition, 31 (20%) had evidence of transmitted resistant
HIV. Resistance to any ART class increased over time
from 16% in 1996-1998 to 20% and then 24% in 19992000 and 2001-2003 respectively.
25
Mutations
RESULTS
Recent infection
NNRTI
PI
Mutation
n
Mutation
n
Mutation
n
215any*
98
103N
35
90M
22
118I
61
181C/I
15
46I/L
22
41L
56
190any
14
82A/F/T
13
69D/N
34
108I
11
54L/V
12
184V/I
30
67N
26
* F/Y (n=25), I/V/S/C/N/D (n=61), A/E/L (n=12)
•Current definitions of key mutations associated with drug
resistance are largely based on treated individuals for whom
treatment failed. The applicability of these to persons who are
naïve to treatment has not been well established and needs
further work.
• Prevalence of resistance in recently infected patients
appears to be higher than in chronically infected naïves.
Further work is required to explore whether this is a
temporal phenomenon or whether the 2 groups represent
different risk groups.
UK Collaborative Group on HIV Drug Resistance Steering Committee:
Judy Breuer, Sheila Burns, Sheila Cameron, Ian Chrystie, Duncan Churchill,
John Clarke, David Dunn, Philippa Easterbrook, Barry Evans, David Goldberg,
Mark Gompels, Teresa Hill, Paul Kellam, Andrew Leigh-Brown, Clive Loveday,
Ryanne Matthias, Anna Maria Geretti, Andrew Phillips, Deenan Pillay, Kholoud
Porter, Anton Pozniak, Caroline Sabin, Peter Tilston, Ian Williams
Coordinator: David Dunn
UK Register of HIV Seroconverters Steering Committee:
Abdel Babiker, Valerie Beral (Chair), Ray Brettle, Chris Carne, Janet
Darbyshire, Philippa Easterbrook, Noël Gill, Richard Gilson, David Goldberg,
David Hawkins, Don Jeffries, Anne Johnson, Margaret Johnson, George
Kinghorn, Linda Lazarus, Ken McLean, Philip Mortimer, Andrew Phillips,
Deenan Pillay, Sarah Rowland-Jones, Jonathan Weber, Ed Wilkins
Coordinator: Kholoud Porter
UK Collaborative HIV Cohort Study Steering Committee:
Abdel Babiker, David Dunn, Philippa Easterbrook, Martin Fisher, Richard
Gilson, Margaret Johnson, Janet Mortimer, Barry Peters, Andrew Phillips,
Kholoud Porter, Caroline Sabin, George Scullard, Brian Gazzard (Chair),
Ryanne Matthias, Teresa Hill
Coordinator: Caroline Sabin
Contact: [email protected]