Ερευνητικό υλικό ΕΚΠΑ

Improved darunavir genotypic mutation score predicting treatment response for patients infected with HIRaben-1 subtype B and non-subtype B receiving a salvage regimen

Αγγλικά

Objectives: The objective of this studywas to improve the prediction of the impact of HIV-1 protease mutations in different viral subtypes on virological response to darunavir. Methods: Darunavir-containing treatment change episodes (TCEs) in patients previously failing PIs were selected from large European databases. HIV-1 subtype B-infected patients were used as the derivation dataset and HIV- 1 non-B-infected patients were used as the validation dataset. The adjusted association of each mutation with week 8 HIV RNA change from baseline was analysed by linear regression. A prediction model was derived based on best subset least squares estimation with mutational weights corresponding to regression coefficients. Virological outcome prediction accuracy was compared with that from existing genotypic resistance interpretation systems (GISs) (ANRS 2013, Rega 9.1.0 and HIVdb 7.0). Results: TCEs were selected from 681 subtype B-infected and 199 non-B-infected adults. Accompanying drugs were NRTIs in 87%, NNRTIs in 27%and raltegravir ormaraviroc or enfuvirtide in 53%. The predictionmodel included weighted protease mutations, HIV RNA, CD4 and activity of accompanying drugs. The model's association with week 8 HIV RNA change in the subtype B (derivation) set was R2=0.47 [average squared error (ASE)=0.67, P>10-6]; in the non-B (validation) set, ASE was 0.91. Accuracy investigated by means of area under the receiver operating characteristic curves with a binary response (above the threshold value of HIV RNA reduction) showed that our finalmodel outperformed models with existing interpretation systems in both training and validation sets. Conclusions: A model with a new darunavir-weighted mutation score outperformed existing GISs in both B and non-B subtypes in predicting virological response to darunavir. © The Author 2016.

2016

De Luca, A.
Flandre, P.
Dunn, D.
Zazzi, M.
Wensing, A.
Santoro, M.M.
Günthard, H.F.
Wittkop, L.
Kordossis, T.
Garcia, F.
Castagna, A.
Cozzi-Lepri, A.
Churchill, D.
De Wit, S.
Brockmeyer, N.H.
Imaz, A.
Mussini, C.
Obel, N.
Perno, C.F.
Roca, B.
Reiss, P.
Schülter, E.
Torti, C.
van Sighem, A.
Zangerle, R.
Descamps, D.
Mocroft, A.
Kirk, O.
Sabin, C.
Casadi, W.
Casabona, J.
Miró, J.M.
Touloumi, G.
Garrido, M.
Teira, R.
Wit, F.
Warszawski, J.
Meyer, L.
Dabis, F.
Krause, M.M.
Ghosn, J.
Leport, C.
Prins, M.
Bucher, H.
Gibb, D.
Fätkenheuer, G.
del Amo, J.
Thorne, C.
Stephan, C.
Pérez-Hoyos, S.
Hamouda, O.
Bartmeyer, B.
Chkhartishvili, N.
Noguera-Julian, A.
Antinori, A.
d'Arminio Monforte, A.
Prieto, L.
Conejo, P.R.
Soriano-Arandes, A.
Battegay, M.
Kouyos, R.
Tookey, P.
Konopnick, D.
Goetghebuer, T.
Sönnerborg, A.
Haerry, D.
Costagliola, D.
Raben, D.
Chêne, G.
Ceccherini-Silberstein, F.
Günthard, H.
Judd, A.
Barger, D.
Schwimmer, C.
Termote, M.
Campbell, M.
Frederiksen, C.M.
Friis-Møller, N.
Kjaer, J.
Brandt, R.S.
Berenguer, J.
Bohlius, J.
Bouteloup, V.
Davies, M.-A.
Dorrucci, M.
Egger, M.
Furrer, H.
Guiguet, M.
Grabar, S.
Lambotte, O.
Leroy, V.
Lodi, S.
Matheron, S.
Monge, S.
Nakagawa, F.
Paredes, R.
Phillips, A.
Puoti, M.
Schomaker, M.
Smit, C.
Sterne, J.
Thiebaut, R.
van der Valk, M.
Wyss, N.
Aubert, V.
Battegay, M.
Bernasconi, E.
Böni, J.
Burton-Jeangros, C.
Calmy, A.
Cavassini, M.
Dollenmaier, G.
Egger, M.
Elzi, L.
Fehr, J.
Fellay, J.
Furrer, H.
Fux, C.A.
Gorgievski, M.
Günthard, H.
Haerry, D.
Hasse, B.
Hirsch, H.H.
Hoffmann, M.
Hösli, I.
Kahlert, C.
Kaiser, L.
Keiser, O.
Klimkait, T.
Kouyos, R.
Kovari, H.
Ledergerber, B.
Martinetti, G.
Martinez de Tejada, B.
Metzner, K.
Müller, N.
Nadal, D.
Nicca, D.
Pantaleo, G.
Rauch, A.
Regenass, S.
Rickenbach, M.
Rudin, C.
Schöni-Affolter, F.
Schmid, P.
Schüpbach, J.
Speck, R.
Tarr, P.
Telenti, A.
Trkola, A.
Vernazza, P.
Weber, R.
Yerly, S.
CHAIN
COHERE in EuroCoord

The Journal of antimicrobial chemotherapy

Oxford University Press

71

5

1352-1360

darunavir plus ritonavir; efavirenz; enfuvirtide; etravirine; Human immunodeficiency virus proteinase; lopinavir; maraviroc; nevirapine; nonnucleoside reverse transcriptase inhibitor; raltegravir; RNA directed DNA polymerase inhibitor; tenofovir; tipranavir; anti human immunodeficiency virus agent; darunavir; Human immunodeficiency virus proteinase; p16 protease, Human immunodeficiency virus 1, adult; antibiotic resistance; antiviral therapy; Article; controlled study; female; gene mutation; human; Human immunodeficiency virus 1 infection; Human immunodeficiency virus type 1 subtype B; major clinical study; male; outcome variable; pharmacogenetics; salvage therapy; treatment outcome; treatment response; virus load; adolescent; aged; antiviral resistance; drug effects; Europe; genetics; genotyping technique; HIV Infections; Human immunodeficiency virus 1; isolation and purification; microbial sensitivity test; middle aged; mutation; procedures; prognosis; very elderly; virology; young adult, Adolescent; Adult; Aged; Aged, 80 and over; Anti-HIV Agents; Darunavir; Drug Resistance, Viral; Europe; Female; Genotyping Techniques; HIV Infections; HIV Protease; HIV-1; Humans; Male; Microbial Sensitivity Tests; Middle Aged; Mutation; Prognosis; Treatment Outcome; Young Adult

https://doi.org/10.1093/jac/dkv465

10.1093/jac/dkv465

https://pergamos.lib.uoa.gr/uoa/dl/object/3022429