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Population-based Surveillance show Transmission
Cascades of HIV-1 Variants harbouring Drug
Resistance BG Brenner1,2, D Moisi1, M Roger3, JP
Routy2, J Cox2, MA Wainberg1,2 and the Quebec
Primary HIV Infection (PHI) Study Group McGill
AIDS Centre Jewish General Hospital1, the Centre
Hospitalier de lUniversité de McGill2 and
lUniversité de Montréal3, Quebec Canada
Background The period following primary HIV-1
infection (PHI) may account for a significant
proportion of new transmission events. Our recent
study used a population-based genotyping strategy
to show that gt50 of primary infections segregate
into clusters, suggestive of high rates of
forward transmission events (J Infect Dis 2007
195951). This study ascertained the cumulative
implications of clustering on transmitted drug
resistance.
Results Viral sequences were obtained from
primary infections (4.9 mean months
post-seroconversion). Phylogenetic analysis
showed that infections segregated into 338 unique
primary infections, 82 small clusters (2.6 0.8
PHI, n 216) and 23 large clusters (9.2 1.0
PHI, n224) representing 43.3, 27.8 and 28.9
of transmission events, respectively. TAMs and
215 revertants were significantly less frequent
in clustered transmissions (8.3 vs. 5.0 vs.
0.8 and 6.2 vs. 1.9 vs. 0.4, p 0.0001 and
p0.0002, respectively). In contrast,
transmission cascades led to higher frequencies
of NNRTIs (K103N/R and G190A) in large clusters
(gt5 PHI), as compared to small clusters (1-4
PHI), (14.3 vs. 5.6, p lt0.0001). Chronic
infections that co-clustered with PHI included
wild-type (WT) infections, as well as sixteen
chronic infections harbouring M184V where WT
ancestral forms were transmitted. Four NNRTI
transmission cascades were noted.
Conclusions In a North American setting
offering universal access to health care,
antiretroviral therapy and genotyping, the
majority of new infections arise from untreated
persons at early stages of infection, often
unaware of their HIV serostatus. This may result
in onward transmission of HIV drug-resistant
infections. Prevention and diagnostic strategies,
as well as routine genotyping, are needed for
early stage infections.
Distribution of Transmitted Drug Resistance in
Clustered Transmissions 1
Methods
HIV-1 pol subtype B sequences from early stage
infections (lt6 months post-PHI) were obtained
from the Quebec PHI cohort and the provincial
genotyping programs (n778, 1998-2006).
Phylogenetic and maximum likelihood analyses
were performed to determine interrelationships
among early stage infections and identify
sequence clustering having high bootstrap values
(gt98) and genetic distances of gt0.015.
Comparative analysis linked sequences of
genotyped PHI with infections from
chronically-infected potential transmitter
populations (n990). The distributions of
mutations conferring resistance to thymidine
analogues (TAMs), nucleoside and non-nucleoside
RT inhibitors (NRTIs and NNRTIs), and protease
inhibitors (PIs) were ascertained.
Acknowledgements This study has been
approved by the Quebec Commission for Access of
Information, respecting ethical, privacy and
confidentiality guidelines. Funding for this
project has been provided by the Fonds de
Recherche du Santé du Québec-SIDA Network, and
the Canadian Institutes for Health Research
(CIHR).
For further information Bluma G. Brenner McGill
AIDS Centre 3755 Cote Ste. Catherine
Rd. Montreal, PQ, Canada H3T 1E2 bluma.brenner_at_mcg
ill.ca TEL [phone] FAX [phone]