Evaluation of Transmitted Drug Resistance (TDR): Comparison of...
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Federico García H. U. San Cecilio, Granada [email protected]
Evaluation of Transmitted Drug Resistance (TDR): Comparison of two different approaches and
implications for recommendations.
S. Monge1, V. Guillot2, M. Alvarez2, L. Anta3, S. García-Bujalance4, A. Peña2, J.A. Iribarren5, M. Masiá6, J.R. Blanco7, F. Garcia2.
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Background
Transmitted Drug Resistance currently evaluated by WHO List, Bennett et al PlosOne 2009.
Evaluates TDR to a whole class, based on a single mutation.
Resistance to PIs seems to be affected by natural non-B polymorphisms, Frentz et al JAIDS 2011
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Background
WHO List, does not: give information on individual drugs take into account the genetic barrier of drugs give information on the therapeutic barrier of a
regimen
WHO list information may not be clinically relevant
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Aim
To compare two different approaches to evaluate TDR To evaluate differences in implications for
clinical recommendations
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Patients & Methods
TDR evaluation of 2781 newly diagnosed HIV-1 patients from CoRIS (2007-2011) : WHO list update in 2009. Stanford Resistance: Abacavir, Emtricitabine,
Lamivudine and Tenofovir; Efavirenz and Nevirapine; Atazanavir, Darunavir and Lopinavir.
Stanford categorization Any resistance (I+R); GSS(0=R, 0.5=I, 1=S) Linear trend over the study period
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Trends in TDR: WHO estimates
02
46
8
Res
ista
nce
Pre
vale
nce
(%)
2007 2008 2009 2010 2011Year
8.3%7.9%
8.4%7.8%
7.2%
3.3%
4.6%3.9%
2.9%
3.6%
5.2%
3.4% 3.5% 3.4%2.8%
1.2% 1.0%
2.7%2.1%
1.1%
p*= 0.62
p*= 0.11
p*= 0.53
p*= 0.44
Total
NNRTI
NRTI
PI
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Prevalence of mutations: WHO list
NRTI mutations NNRTI mutations PI mutations Mutation n (Pv, %) Mutation n (Pv, %) Mutation n (Pv, %) M41L 32 (1.15) L100I 2 (0.07) L24I 2 (0.07) K65R 1 (0.04) K101EP 8 (0.29) D30N 1 (0.04) D67EGN 23 (0.83) K103N/S 77 (2.77) V32I 2 (0.07) T69D 5 (0.18) Y181CIV 9 (0.32) M46IL 26 (0.93) K70ER 5 (0.18) Y188CHL 5 (0.18) I47AV 2 (0.07) L74IV 3 (0.11) G190AES 11 (0.40) F53LY 2 (0.07) F77L 2 (0.07) P225H 3 (0.11) I54ALMSTV 2 (0.07) Y115F 2 (0.07) M230L 1 (0.04) V82ACFLMST 5 (0.18) M184IV 13 (0.47) N83D 1 (0.04) L210W 12 (0.43) I85V 1 (0.04) T215REV* 37 (1.33) N88DS 2 (0.07) T215YF 2 (0.07) L90M 10 (0.36) K219EQNR 29 (1.04) 1 mut. 56 (2.01) 1 mut. 87 (3.13) 1 mut. 45 (1.62) 2 mut. 32 (1.15) 2 mut. 13 (0.47) 2 mut. 2 (0.07) ≥3 mut. 13 (0.47) ≥3 mut. 2 (0.07) ≥3 mut. 1 (0.04)
Prevalence (95%CI) 3.6 (2.9-4.3) Prevalence
(95%CI) 3.7 (3.0-4.4) Prevalence (95%CI) 1.7 (1.2-2.2)
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Prevalence of mutations: WHO list
NRTI mutations NNRTI mutations PI mutations Mutation n (Pv, %) Mutation n (Pv, %) Mutation n (Pv, %) M41L 32 (1.15) L100I 2 (0.07) L24I 2 (0.07) K65R 1 (0.04) K101EP 8 (0.29) D30N 1 (0.04) D67EGN 23 (0.83) K103N/S 77 (2.77) V32I 2 (0.07) T69D 5 (0.18) Y181CIV 9 (0.32) M46IL 26 (0.93) K70ER 5 (0.18) Y188CHL 5 (0.18) I47AV 2 (0.07) L74IV 3 (0.11) G190AES 11 (0.40) F53LY 2 (0.07) F77L 2 (0.07) P225H 3 (0.11) I54ALMSTV 2 (0.07) Y115F 2 (0.07) M230L 1 (0.04) V82ACFLMST 5 (0.18) M184IV 13 (0.47) N83D 1 (0.04) L210W 12 (0.43) I85V 1 (0.04) T215REV* 37 (1.33) N88DS 2 (0.07) T215YF 2 (0.07) L90M 10 (0.36) K219EQNR 29 (1.04) 1 mut. 56 (2.01) 1 mut. 87 (3.13) 1 mut. 45 (1.62) 2 mut. 32 (1.15) 2 mut. 13 (0.47) 2 mut. 2 (0.07) ≥3 mut. 13 (0.47) ≥3 mut. 2 (0.07) ≥3 mut. 1 (0.04)
Prevalence (95%CI) 3.6 (2.9-4.3) Prevalence
(95%CI) 3.7 (3.0-4.4) Prevalence (95%CI) 1.7 (1.2-2.2)
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Prevalence of mutations: WHO list
NRTI mutations NNRTI mutations PI mutations Mutation n (Pv, %) Mutation n (Pv, %) Mutation n (Pv, %) M41L 32 (1.15) L100I 2 (0.07) L24I 2 (0.07) K65R 1 (0.04) K101EP 8 (0.29) D30N 1 (0.04) D67EGN 23 (0.83) K103N/S 77 (2.77) V32I 2 (0.07) T69D 5 (0.18) Y181CIV 9 (0.32) M46IL 26 (0.93) K70ER 5 (0.18) Y188CHL 5 (0.18) I47AV 2 (0.07) L74IV 3 (0.11) G190AES 11 (0.40) F53LY 2 (0.07) F77L 2 (0.07) P225H 3 (0.11) I54ALMSTV 2 (0.07) Y115F 2 (0.07) M230L 1 (0.04) V82ACFLMST 5 (0.18) M184IV 13 (0.47) N83D 1 (0.04) L210W 12 (0.43) I85V 1 (0.04) T215REV* 37 (1.33) N88DS 2 (0.07) T215YF 2 (0.07) L90M 10 (0.36) K219EQNR 29 (1.04) 1 mut. 56 (2.01) 1 mut. 87 (3.13) 1 mut. 45 (1.62) 2 mut. 32 (1.15) 2 mut. 13 (0.47) 2 mut. 2 (0.07) ≥3 mut. 13 (0.47) ≥3 mut. 2 (0.07) ≥3 mut. 1 (0.04)
Prevalence (95%CI) 3.6 (2.9-4.3) Prevalence
(95%CI) 3.7 (3.0-4.4) Prevalence (95%CI) 1.7 (1.2-2.2)
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Stanford Resistance: First Line ARVs
ARV class ARV drug # resistant Prevalence (95%CI)
NRTIs
Tenofovir 45 (2) 1.6 (1.1-2.1)
Emtricitabine 19 0.7 (0.4-1.0)
Lamivudine 19 0.7 (0.4-1.0)
Abacavir 62 (1) 2.2 (1.7-2.8)
NNRTIs Efavirenz 112 4.0 (3.3-4.8)
Nevirapine 127 4.6 (3.8-5.3)
PIs
Lopinavir 8 (1) 0.3 (0.1-0.5)
Atazanavir 20 (2) 0.7 (0.4-1.0)
Darunavir 4 (1) 0.1 (0.0-0.3)
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Trends in Resistance: First line & Stanford DB
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8
Res
ista
nce
Pre
vale
nce
(%)
2007 2008 2009 2010 2011Year
8.1% 8.3%
6.5%6.0%
4.7%
2.3%
5.3%
4.5%
0.7% 0.6%
5.4%
3.8%
0.8%
4.4%
2.8%
1.5%
0.3%
2.4%
1.6% 1.7%
p*= 0.02
p*= 0.09
p*= 0.07
p*= 0.31
Total
NNRTI
NRTI
PI
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Therapeutic Barrier: First line Regimens
ARV regimen GSS<2.5 GSS <3 n (%) n (%)
EFV TDF FTC /3TC 94 (3.4) 155 (5.6) ABC FTC /3TC 95 (3.4) 157 (5.7)
NVP TDF FTC /3TC 109 (3.9) 169 (6.1) ABC FTC /3TC 109 (3.9) 171 (6.2)
LPV TDF FTC /3TC 20 (0.7) 64 (2.3) ABC FTC /3TC 20 (0.7) 68 (2.5)
ATZ TDF FTC /3TC 25 (0.9) 72 (2.6) ABC FTC /3TC 26 (0.9) 75 (2.7)
DRV TDF FTC /3TC 19 (0.7) 61 (2.2) ABC FTC /3TC 19 (0.7) 65 (2.3)
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Trends: WHO vs Stanford
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46
8
Res
ista
nce
Pre
vale
nce
(%)
2007 2008 2009 2010 2011Year
8.3%7.9%
8.4%7.8%
7.2%
3.3%
4.6%3.9%
2.9%
3.6%
5.2%
3.4% 3.5% 3.4%2.8%
1.2% 1.0%
2.7%2.1%
1.1%
p*= 0.62
p*= 0.11
p*= 0.53
p*= 0.44
Total
NNRTI
NRTI
PI
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02
46
8
Res
ista
nce
Pre
vale
nce
(%)
2007 2008 2009 2010 2011Year
8.1% 8.3%
6.5%6.0%
4.7%
2.3%
5.3%
4.5%
0.7% 0.6%
5.4%
3.8%
0.8%
4.4%
2.8%
1.5%
0.3%
2.4%
1.6% 1.7%
p*= 0.02
p*= 0.09
p*= 0.07
p*= 0.31
Total
NNRTI
NRTI
PI
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Summary & Conclusions
Global prevalence of Transmitted Drug Resistance (TDR) for the period 2007-2011 in Spain lies far below 10%.
Evaluation of TDR using the WHO surveillance list results in lower NNRTI resistance but higher PI & NRTI resistance.
While results by WHO list are very relevant to evaluate the transmission of resistant strains, interpretation of resistance is more informative for recommendations and clinical practice.
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Baseline resistance to NNRTI containing regimens remains a problem of concern in Spain, through the period 2007-2011.
Resistance to first line PI containing regimens is less frequent, and very rare if a GSS <2.5 is considered.
Testing naïve patients initiating first line boosted-PIs may be not cost-effective in our setting.
Summary & Conclusions
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Gracias¡¡¡¡
Susana Monge & Julia del Amo
RETIC RD06/006
All the Members of CoRIS-Resistance study: CoRIS Executive Committee: Juan Berenguer, Julia del Amo, Federico García, Félix Gutiérrez, Pablo Labarga, Santiago Moreno y María Ángeles Muñoz. Field work, data management and analysis: Paz Sobrino Vegas, Victoria Hernando Sebastián, Belén Alejos Ferreras, Débora Álvarez, Susana Monge, Inma Jarrín, Santiago Pérez Cachafeiro. BioBank: M Ángeles Muñoz-Fernández, Isabel García-Merino, Coral Gómez Rico, Jorge Gallego de la Fuente y Almudena García Torre & Participating Centres:
All the patients