Federico García H. U. San Cecilio, Granada fegarcia@ugr.es

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

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

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

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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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

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.

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

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