1 HIV Group, Medical Research Council Clinical Trials Unit, London, UK 2Department of Clinical Virol

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The impact of different definitions on the
estimated rate of transmitted HIV drug
resistance in the UK
The UK HIV Drug Resistance Database Development
and use for national surveillance
Hannah Green1, Peter Tilston2, Esther Fearnhill1
and David Dunn1 on behalf of the UK
Collaborative Group on HIV Drug Resistance
1 HIV Group, Medical Research Council Clinical
Trials Unit, London, UK 2Department of Clinical
Virology, Manchester Royal Infirmary,
Manchester, UK.
Transmitted HIV drug resistance (THDR) has the
potential to limit a patients future treatment
options, due to decreased effectiveness of
first-line and subsequent antiretroviral
regimens. At a population level, the
surveillance of THDR can provide useful
information on spread of drug resistant HIV and
inform public health policy makers.
Surveillance programs exist in many countries
and provide estimates of the rate of transmitted
drug resistance. However, differences in the
definition of transmitted drug resistance and the
use of different lists of resistance mutations in
these studies has resulted in estimates of THDR
that are often not comparable 1. To try and
overcome this problem a recent list has been
developed specifically for epidemiological
estimates of transmitted drug resistance 2. In
this list the mutations included should not only
be recognised as causing or contributing to
resistance but should also be non-polymorphic in
untreated patients and should be applicable to
all subtypes. Here we assess the extent to
which the estimated rate of THDR in the UK is
altered by using the new list, compared to the
IAS-USA list which has previously been used in
studies in the UK 3,4. We also compare the
rates of THDR estimated by these 2 lists with
rates obtained using the Stanford HIVdb genotypic
interpretation system.
Findings are based on genotypic test results
reported to the UK HIV Drug Resistance Database,
which aims to collect all tests conducted as part
of routine clinical care nationwide.
Participating virology laboratories provide data
on an annual basis this analysis includes
resistance tests reported up to the end of 2005.
Analysis was restricted to the first test on
patients older than 16 years who were ART-naïve
at the time of sampling. Patients antiretroviral
treatment status was classified from information
recorded on the resistance test request form and
via linkage with UK CHIC 5. Estimates of
transmitted drug resistance were based on three
definitions 1) One or more major mutations in
the latest (2006) International AIDS Society-USA
guidelines 6, plus selected additional
mutations (in reverse transcriptase, any mutation
at G190 or T215 in protease, V32I and I47V/A in
combination, or seven or more minor lopinavir
mutations). 2) One or more mutations as
proposed by Shafer et al 2. 3) Low level,
intermediate or high level resistance to one or
more drugs, as interpreted by the Stanford HIVdb
algorithm (version 4.3.0, July 2007) 7. The
algorithm is based on a matrix of scores for each
drug-mutation combination these are summed
across all mutations in the sample and individual
drugs susceptibility is classified as sensitive
(total score lt9), possible low level (10-14),
low level (15-29), intermediate (30-59), or
high level resistance (60).
Mutations included in the 2 lists are shown
below. Amino acids in bold represent mutations
which on their own would be classified as THDR
using the Stanford HIVdb algorithm definition
given opposite.
IAS list both V32I and I47V/A are required in
combination. NB IAS list 7 or more minor LOP
mutations are also counted as a major mutation

• Overall prevalence of transmitted HIV drug
  resistance
• Overall 956 of the 8272 (11.5) samples
  available for analysis were classified as having
  THDR by at least one of the 3 definitions (Table
  1).
• For 706 samples (74 of 956) the 3 definitions
  agreed.
• However, 72 (7) samples were classified as
  having THDR by IAS only, largely driven by
  mutations 62V (n17) and 108I (n33) in RT and
  33F (n12) in protease.
• 14 (2) samples were classified as having THDR
  by Shafer only all protease mutations, 53L
  (n11) and 73C/S (n3).
• 72 (7) samples were classified as having THDR
  by Stanford only, largely driven by low level,
  intermediate or high level resistance to the
  NNRTIs (n61), in particular low level resistance
  to TMC125 caused by the 179E mutation (n28). NB
  resistance to TMC125 is not included on the
  current IAS or Shafer lists which are updated
  annually the Stanford algorithm is updated
  regularly as necessary.
• 48 (5) samples were classified as THDR by IAS
  and Stanford but not Shafer (protease mutations
  46L (n26), 82L (n17)). 38 (4) samples were
  classified as THDR by Shafer and Stanford but not
  IAS (RT mutations 69D (n8), 101E (n15)).

• Changes in the rate of THDR over time
• The number of tests on ART-naïve patients has
  increased rapidly in recent years (596 in 2002,
  935 in 2003, 1786 in 2004 and 2760 in 2005)
  reflecting changes in clinical guidelines.
• The three lists gave similar estimates of THDR
  (Figure 1). Regardless of which definition was
  used, the rate of THDR declined after a peak in
  2001-2 and appears to have now stabilised with no
  significant change between 2004 and 2005.
• .

Figure 1 Prevalence of THDR over time

• The choice of the IAS or the Shafer list of
  drug mutations, or resistance as defined by the
  Stanford algorithm had a minor influence on the
  estimated rate of THDR however some discordance
  in the classification of samples as THDR was
  seen.
• The Shafer list is to be preferred for
  surveillance as it is specially developed for
  epidemiology purposes. However, regular updates
  are required to capture resistance to new drugs.
• Continued surveillance of THDR is warranted to
  detect any changes from the currently stable
  situation.

• 46 (5 of 956) samples showed THDR to all 3 main
  ART classes by all 3 definitions. The greatest
  discordance was 72 samples classified as having
  THDR to just one class by the Stanford algorithm
  but not the IAS list or Shafer list (NRTI n15,
  NNRTI n51, PI n6), and 71 samples classified as
  having THDR to just one class by the IAS list but
  not the Shafer list or the Stanford algorithm
  (NRTI n28, NNRTI n34, PI n9).

1 Pillay D. Current patterns in the epidemiology
of primary HIV drug resistance in North America
and Europe. Antivir Ther 2004 9695-702. 2
Shafer RW, Rhee S, Pillay D, Miller V, Sandstrom
P, Schapiro JM et al. HIV-1 protease and reverse
transcriptase mutations for drug resistance
surveillance. AIDS 2007 21(2)215-23. 3 HIV Drug
Resistance in the United Kingdom. CDR Weekly.
Volume 16 Number 4. 26 January 2006. 4 UK
Collaborative Group on HIV Drug Resistance, UK
Collaborative HIV Cohort Study, and UK Register
of Seroconverters. Evidence of a decline in
transmitted HIV-1 drug resistance in the UK. AIDS
2007 211035-1039 5 Sabin CA, Hill T, Lampe F,
Matthias R, Bhagani S, Gilson R, et al. Treatment
exhaustion of highly active antiretroviral
therapy (HAART) among individuals infected with
HIV in the United Kingdom multicentre cohort
study. BMJ 2005 330695-98. 6 Johnson VA,
Brun-Vezinet F, Clotet B, Kuritzkes DR, Pillay D
et al. Update of the Drug Resistance Mutations in
HIV-1 Fall 2006. Top HIV Med. 2006 14(3)
125-130. 7 http//hivdb.stanford.edu/pages/algs/HI
Vdb.html (version 4.3.0, July 2007)
UK Collaborative Group on HIV Drug Resistance
Steering Committee Sheila Burns, Sheila
Cameron, Pat Cane, Ian Chrystie, Duncan
Churchill, Duncan Clark, Valerie Delpech, David
Dunn, Philippa Easterbrook, Esther Fearnhill,
Hannah Green, David Goldberg, Mark Gompels, Tony
Hale, Steve Kaye, Paul Kellam, Svilen Konov,
Linda Lazarus, Andrew Leigh-Brown, Anna Maria
Geretti, Chloe Orkin, Andrew Phillips, Deenan
Pillay (chair), Kholoud Porter, Anton Pozniak,
Caroline Sabin, Erasmus Smit, Peter Tilston, Ian
Williams, Hongyi Zhang, Mark Zuckerman Funding
The UK HIV Drug Resistance Database is partly
funded by the Department of Health the views
expressed in the poster are those of the authors
and not necessarily those of the Department of
Health. Additional financial support is provided
by Boehringer Ingelheim Bristol-Myers Squibb
Gilead Tibotec, a division of Janssen-Cilag Ltd
and Roche. Contact hannah.green_at_ctu.mrc.ac.uk