Impact of transmitted drug resistance on
virological and immunological response
to intial combination antiretroviral therapy
EuroCoord-CHAIN joint project
 EuroCoord (CASCADE, COHERE, EuroSIDA and PENTA)
and CHAIN (a pan-European project on HIV Drug resistance)
 largest database on this topic so far
L Wittkop on behalf of the EuroCoord-CHAIN joint project team
Geneviève Chêne (Project lead), Hannah Castro (née Green), Marie-Laure Chaix,
Bonaventura Clotet, Dominique Costagliola, Alessandro Cozzi-Lepri, David Dunn, Huldrych
Günthard, Ali Judd, Claudia Kücherer, Andrea de Luca, Jens D Lundgren, Bernard
Masquelier, Roger Paredes, Deenan Pillay, Andrew Phillips, Anton Pozniak, Rodolphe
Thiébaut, Frank de Wolf, Viktor von Wyl
Background
• Prevalence of transmitted drug resistance
– between 10 and 15% in Europe
– up to 25% in North America
• Genotypic testing is recommended for naïve patients
in recent treatment guidelines (EACS, BHIVA)
• Impact of transmitted drug resistance remains
controversial especially in patients who are prescribed
a fully active regimen
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Objective
• To assess the impact of transmitted drug resistance
mutations on virological and immunological response
up to 16 months after starting a combination
antiretroviral therapy (cART)
• Specific analyses:
– Transmitted drug resistance and fully active treatment
– 2NRTI + 1NNRTI or 2NRTI + 1boosted PI regimen
Study population
• HIV infected patients regardless of age
• Start of cART after 1.1.1998
• ≥1 sample taken before antiretroviral treatment for
genotypic testing
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Methods
• Virologic endpoint:
– time to first of two consecutive viral load>500 copies/mL
after six months of therapy
• Definition TDR (two steps):
WHO – list 20091
Patients having
at least one mutation
Stanford2 version 6.0.5
Group 0
Group 1
Group 2
Patients with no detected
mutation
(used as a reference group)
show no drug resistance to their
prescribed drug (classified as
‘susceptible’ or as
‘potential low level resistance’)
resistant to at least one
of their prescribed drugs
(classified as ‘Low-level resistance‘,
‘Intermediate' or as ‘High level resistance‘)
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1Bennett
PlosOne 2009, 2Liu CID 2006
Characteristics at the time of starting cART
• 10 458 patients from 25 cohorts
•
76% male
•
Median age 38 years
•
56% of European origin
•
62% harboured a subtype B virus
•
Pre-treatment viral load and CD4 counts were 5 log10 cp/mL and 217 cells/mm3
•
Transmission risk groups: 50% homosexual, 33% heterosexual, 8% IDUs and 2.1% perinatal
• 9.1% (n=953) patients harboured a virus with ≥1
mutation
• 4.5% (n=476) received a fully active treatment
• 4.6% (n=477) had virus predicted to have at least
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low level resistance for ≥1 prescribed drug
Virological failure according to TDR
In adjusted analysis*:
 Patients with resistance to ≥1 drug:
- significant higher risk of VF
compared to patients without
mutations
- HR: 2.6 [2.0; 3.4], P<10-4
 patients receiving a fully active cART
and patients with no mutation:
- risk of VF was not significantly
different
- HR: 1.2 [0.8; 1.8], P=0.34
% VF
16.2%
6.3%
6.0%
months
*All models stratified by cohort ; multivariable models ajusted for: Gender, age, pre-treatment
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viral load and CD4 count, year of treatment start, previous AIDS diagnosis, subtype, HIV
transmission risk group, origin
Impact of TDR according to treatment strata
HR*
6
2NRTIs+1NNRTI
All
2NRTIs+1PI/rtv
5
Global interaction P=0.08
4
3
2
1
0
0
N: 9505
%VF at M12:
6.0
11
2
2
ALL
476
477
6.3
16.2
0
1
2
47032NRTI+1NNRTI
160
175
3.7
6.4
12.1
0
1
1
2881 2NRTI+1PI/r
237
4.3
3.7
2
132
11.7
*All models stratified by cohort ; multivariable models ajusted for: Gender, age, pre-treatment
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viral load and CD4 count, year of treatment start, previous AIDS diagnosis, subtype, HIV
transmission risk group, origin
Summary and conclusion
• Transmitted drug resistance was associated with a poorer
virological response if the treatment was not adapted to the
patients genotype
• In the presence of TDR and when an active regimen was used:
potential higher risk of virological failure if a combination of
NNRTI + 2 NRTIs was used, though not if boosted PI + 2 NRTIs
were prescribed
 Our results underscore that genotypic testing in treatment naive
patients in regions with medium to high prevalence TDR is
important to select a fully active regimen for treatment initiation
 In regions where genotypic testing is not routinely available but
high prevalence of TDR is suspected, first line regimens
containing boosted PI should be discussed
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Acknowledgments
EuroCoord-CHAIN project team:
EuroCoord-CHAIN Project Leader: Geneviève Chêne (Linda Wittkop, project
coordinator and statistician/epidemiologist) Statisticians/Epidemiologists: Hannah
Castro (née Green), Dominique Costagliola, Alessandro Cozzi-Lepri, David
Dunn, Ali Judd, Andrew Phillips, Rodolphe Thiébaut, Viktor von Wyl
Virologists: Marie-Laure Chaix, Claudia Kücherer, Bernard Masquelier, Deenan
Pillay, Frank de Wolf Clinicians: Bonaventura Clotet/Roger Paredes, Huldrych
Günthard, Andrea de Luca, Jens D Lundgren, Anton Pozniak
Contributing cohorts:
Giota Touloumi (AMACS), François Dabis (ANRS CO3 AQUITAINE), Catherine
Leport (ANRS CO8 COPILOTE), Frank de Wolf (ATHENA), Peter Reiss
(ATHENA), Kholoud Porter (CASCADE), Maria Prins (CASCADE), Caroline
Sabin (CHIC), Julia Del Amo (Co-RIS), Niels Obel (Danish HIV Cohort), Amanda
Mocroft (EuroSIDA), Ole Kirk (EuroSIDA), Christoph Stephan (Frankfurt), Andrea
Antinori (ICC), Antonella d’Arminio Monforte (ICONA), Patrick Francioli (SHCS),
Jordi Casabona (PISCIS), Jose M. Miró (PISCIS), Antonella Castagna (San
Raffaele), Stephane de Wit (St. Pierre Cohort), Carlo Torti (Italian Master
Cohort), Ramon Teira (VACH),Myriam Garrido (VACH), Ali Judd (PENTAEPPICC/CHIPS, UK and Ireland), Jose T Ramos (PENTA-EPPICC/Madrid
cohort, Spain), Dan Duiculescu (PENTA-EPPICC/Dr Victor Babes Hospital
cohort, Romania), Carlo Giaquinto (PENTA-EPPICC/PENTA, Europe), Magda
Marczynska (PENTA-EPPICC/Warsaw cohort, Poland), Tessa Goetghebuer
(PENTA-EPPICC/St Pierre, Belgium), Pat Tookey (PENTA-EPPICC/ National
Study of HIV in Pregnancy and Childhood, UK and Ireland), B Brichard (PENTAEPPICC/ Hospital UCL St Luc, Belgium), Niels Valerius (PENTA-EPPICC/Danish
Paediatric HIV Cohort Study), Josiane Warszawski (PENTA-EPPICC/EPF,
France), Christoph Rudin (PENTA-EPPICC/MOCHIV, Switzerland), Antoni
Noguera (PENTA-EPPICC/ CoRISPE-cat, Spain), Marc Lallemant (PENTAEPPICC/PHPT, Thailand)
To all patients
Datamanagers:
Céline Colin (COHERE, Bordeaux RCC), Jesper Kjaer (COHERE, Copenhagen
RCC, EuroSIDA), Charlotte Duff (PENTA-EPPICC), Keith Fairbrother
(CASCADE)
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