A376s in the connection subdomain of HIV-1 reverse transcriptase confers increased risk of virological failure to nevirapine therapy

Roger Paredes; Maria Carmen Puertas; Wendy Bannister; Mónica Kisic; Alessandro Cozzi-Lepri; Christian Pou; Rocío Bellido; Gilberto Betancor; Johannes Bogner; Panagiotis Gargalianos; Dénes Bánhegyi; Bonaventura Clotet; Jens Lundgren; Luis Menéndez-Arias; Javier Martinez-Picado; M. Losso; C. Elias; N. Vetter; R. Zangerle; I. Karpov; A. Vassilenko; V. M. Mitsura; O. Suetnov; N. Clumeck; S. De Wit; B. Poll; R. Colebunders; L. Vandekerckhove; V. Hadziosmanovic; K. Kostov; J. Begovac; L. Machala; H. Rozsypal; D. Sedlacek; J. Nielsen; G. Kronborg; T. Benfield; M. Larsen; J. Gerstoft; T. Katzenstein; A. B.E. Hansen; P. Skinhøj; C. Pedersen; L. Oestergaard; K. Zilmer; Jelena Smidt; M. Ristola; C. Katlama; J. P. Viard; P. M. Girard; J. M. Livrozet; P. Vanhems; C. Pradier; F. Dabis; D. Neau; J. Rockstroh; R. Schmidt; J. Van Lunzen; O. Degen; H. J. Stellbrink; S. Staszewski; G. Fätkenheuer; J. Kosmidis; G. Xylomenos; J. Perdios; G. Panos; A. Filandras; E. Karabatsaki; H. Sambatakou; D. Banhegyi; F. Mulcahy; I. Yust; D. Turner; M. Burke; S. Pollack; G. Hassoun; S. Maayan; S. Vella; R. Esposito; I. Mazeu; C. Mussini; C. Arici; R. Pristera; F. Mazzotta; A. Gabbuti; V. Vullo; M. Lichtner; A. Chirianni; E. Montesarchio; M. Gargiulo; G. Antonucci; F. Iacomi; P. Narciso; C. Vlassi; M. Zaccarelli; A. Lazzarin; R. Finazzi; M. Galli; A. Ridolfo; A. D'Arminio Monforte; B. Rozentale; P. Aldins; S. Chaplinskas; R. Hemmer; T. Staub; P. Reiss; V. Ormaasen; A. Maeland; J. Brunn; B. Knysz; J. Gasiorowski; A. Horban; E. Bakowska; D. Prokopowicz; R. Flisiak; A. Boron-Kaczmarska; M. Pynka; M. Beniowski; E. Mularska; H. Trocha; E. Jablonowska; E. Malolepsza; K. Wojcik; F. Antunes; E. Valadas; K. Mansinho; F. Maltez; D. Duiculescu; A. Rakhmanova; E. Vinogradova; S. Buzunova; D. Jevtovic; M. Mokráš; D. Staneková; J. Tomazic; J. González-Lahoz; V. Soriano; L. Martin-Carbonero; P. Labarga; S. Moreno; A. Jou; C. Tural; J. Puig; I. Bravo; J. M. Gatell; J. M. Miró; P. Domingo; M. Gutierrez; G. Mateo; Ma Sambeat; A. Karlsson; P. O. Persson; L. Flamholc; B. Ledergerber; R. Weber; P. Francioli; M. Cavassini; B. Hirschel; E. Boffi; H. Furrer; M. Battegay; L. Elzi; E. Kravchenko; N. Chentsova; G. Kutsyna; S. Servitskiy; M. Krasnov; S. Barton; A. M. Johnson; D. Mercey; A. Phillips; M. A. Johnson; A. Mocroft; M. Murphy; J. Weber; G. Scullard; M. Fisher; C. Leen; J. Gatell; B. Gazzard; O. Kirk; A. Cozzi-Lepri; D. Grint; M. Ellefson; D. Podlekareva; J. Kjær; L. Peters; J. Reekie; J. Kowalska; J. Tverland; A. H. Fischer

doi:10.1093/infdis/jir385

A376s in the connection subdomain of HIV-1 reverse transcriptase confers increased risk of virological failure to nevirapine therapy

Roger Paredes, Maria Carmen Puertas, Wendy Bannister, Mónica Kisic, Alessandro Cozzi-Lepri, Christian Pou, Rocío Bellido, Gilberto Betancor, Johannes Bogner, Panagiotis Gargalianos, Dénes Bánhegyi, Bonaventura Clotet, Jens Lundgren, Luis Menéndez-Arias, Javier Martinez-Picado^*, M. Losso, C. Elias, N. Vetter, R. Zangerle, I. KarpovA. Vassilenko, V. M. Mitsura, O. Suetnov, N. Clumeck, S. De Wit, B. Poll, R. Colebunders, L. Vandekerckhove, V. Hadziosmanovic, K. Kostov, J. Begovac, L. Machala, H. Rozsypal, D. Sedlacek, J. Nielsen, G. Kronborg, T. Benfield, M. Larsen, J. Gerstoft, T. Katzenstein, A. B.E. Hansen, P. Skinhøj, C. Pedersen, L. Oestergaard, K. Zilmer, Jelena Smidt, M. Ristola, C. Katlama, J. P. Viard, P. M. Girard, J. M. Livrozet, P. Vanhems, C. Pradier, F. Dabis, D. Neau, J. Rockstroh, R. Schmidt, J. Van Lunzen, O. Degen, H. J. Stellbrink, S. Staszewski, G. Fätkenheuer, J. Kosmidis, G. Xylomenos, J. Perdios, G. Panos, A. Filandras, E. Karabatsaki, H. Sambatakou, D. Banhegyi, F. Mulcahy, I. Yust, D. Turner, M. Burke, S. Pollack, G. Hassoun, S. Maayan, S. Vella, R. Esposito, I. Mazeu, C. Mussini, C. Arici, R. Pristera, F. Mazzotta, A. Gabbuti, V. Vullo, M. Lichtner, A. Chirianni, E. Montesarchio, M. Gargiulo, G. Antonucci, F. Iacomi, P. Narciso, C. Vlassi, M. Zaccarelli, A. Lazzarin, R. Finazzi, M. Galli, A. Ridolfo, A. D'Arminio Monforte, B. Rozentale, P. Aldins, S. Chaplinskas, R. Hemmer, T. Staub, P. Reiss, V. Ormaasen, A. Maeland, J. Brunn, B. Knysz, J. Gasiorowski, A. Horban, E. Bakowska, D. Prokopowicz, R. Flisiak, A. Boron-Kaczmarska, M. Pynka, M. Beniowski, E. Mularska, H. Trocha, E. Jablonowska, E. Malolepsza, K. Wojcik, F. Antunes, E. Valadas, K. Mansinho, F. Maltez, D. Duiculescu, A. Rakhmanova, E. Vinogradova, S. Buzunova, D. Jevtovic, M. Mokráš, D. Staneková, J. Tomazic, J. González-Lahoz, V. Soriano, L. Martin-Carbonero, P. Labarga, S. Moreno, A. Jou, C. Tural, J. Puig, I. Bravo, J. M. Gatell, J. M. Miró, P. Domingo, M. Gutierrez, G. Mateo, Ma Sambeat, A. Karlsson, P. O. Persson, L. Flamholc, B. Ledergerber, R. Weber, P. Francioli, M. Cavassini, B. Hirschel, E. Boffi, H. Furrer, M. Battegay, L. Elzi, E. Kravchenko, N. Chentsova, G. Kutsyna, S. Servitskiy, M. Krasnov, S. Barton, A. M. Johnson, D. Mercey, A. Phillips, M. A. Johnson, A. Mocroft, M. Murphy, J. Weber, G. Scullard, M. Fisher, C. Leen, J. Gatell, B. Gazzard, O. Kirk, A. Cozzi-Lepri, D. Grint, M. Ellefson, D. Podlekareva, J. Kjær, L. Peters, J. Reekie, J. Kowalska, J. Tverland, A. H. Fischer

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

17 Scopus citations

Abstract

Background. The clinical relevance of mutations in the connection subdomain and the ribonuclease (RNase) H domain of HIV-1 reverse transcriptase (RT) is uncertain. Methods. The risk of virological failure to nonnucleoside RT inhibitor (NNRTI)-based antiretroviral therapy (ART) was evaluated in NNRTI-naive patients who started NNRTIs in the EuroSIDA study after July 1997 according to preexisting substitutions in the connection subdomain and the RNase H domain of HIV-1 RT. An observed association between A376S and virological failure was further investigated by testing in vitro NNRTI susceptibility of single site-directed mutants and patient-derived recombinant viruses. Enzymatic assays also determined the effects of A376S on nevirapine and template-primer binding to HIV-1 RT. Results. Virological failure occurred in 142 of 287 (49%) individuals: 77 receiving nevirapine (67%) and 65 receiving efavirenz (38%) (P < .001). Preexisting A376S was associated with an increased risk of virological failure to nevirapine (relative hazard [RH] = 10.4; 95% confidence interval [CI], 2.0-54.7), but it did not affect efavirenz outcome the same way (RH = 0.5; 95% CI, 0.1-2.2) (P value for interaction 5 .013). A376S conferred selective low-level nevirapine resistance in vitro, and led to greater affinity for double-stranded DNA. Conclusions. The A376S substitution in the connection subdomain of HIV-1 RT causes selective nevirapine resistance and confers an increased risk of virological failure to nevirapine-based ART.

Original language	English
Pages (from-to)	741-752
Number of pages	12
Journal	Journal of Infectious Diseases
Volume	204
Issue number	5
DOIs	https://doi.org/10.1093/infdis/jir385
State	Published - 1 Sep 2011
Externally published	Yes

Funding

Funders	Funder number
AIDS network Red Temática Cooperativa de Investigación en SIDA	RD06/0006
Collaborative HIV and Anti-HIV Drug Resistance Network
European Commission FP6	LSHP-CT-2006-018632
Fundación para la Investigación y Prevención del Sida en España	36771/08
Boehringer Ingelheim
Pfizer
GlaxoSmithKline
Merck
Roche
Gilead Sciences
Seventh Framework Programme	223131
European Commission
Office Fédéral de l'Education et de la Science

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1093/infdis/jir385

Cite this

Paredes, R., Puertas, M. C., Bannister, W., Kisic, M., Cozzi-Lepri, A., Pou, C., Bellido, R., Betancor, G., Bogner, J., Gargalianos, P., Bánhegyi, D., Clotet, B., Lundgren, J., Menéndez-Arias, L., Martinez-Picado, J., Losso, M., Elias, C., Vetter, N., Zangerle, R., ... Fischer, A. H. (2011). A376s in the connection subdomain of HIV-1 reverse transcriptase confers increased risk of virological failure to nevirapine therapy. Journal of Infectious Diseases, 204(5), 741-752. https://doi.org/10.1093/infdis/jir385

@article{8d95e0ad4de84bed8b3d2449bbc0c4a7,

title = "A376s in the connection subdomain of HIV-1 reverse transcriptase confers increased risk of virological failure to nevirapine therapy",

abstract = "Background. The clinical relevance of mutations in the connection subdomain and the ribonuclease (RNase) H domain of HIV-1 reverse transcriptase (RT) is uncertain. Methods. The risk of virological failure to nonnucleoside RT inhibitor (NNRTI)-based antiretroviral therapy (ART) was evaluated in NNRTI-naive patients who started NNRTIs in the EuroSIDA study after July 1997 according to preexisting substitutions in the connection subdomain and the RNase H domain of HIV-1 RT. An observed association between A376S and virological failure was further investigated by testing in vitro NNRTI susceptibility of single site-directed mutants and patient-derived recombinant viruses. Enzymatic assays also determined the effects of A376S on nevirapine and template-primer binding to HIV-1 RT. Results. Virological failure occurred in 142 of 287 (49%) individuals: 77 receiving nevirapine (67%) and 65 receiving efavirenz (38%) (P < .001). Preexisting A376S was associated with an increased risk of virological failure to nevirapine (relative hazard [RH] = 10.4; 95% confidence interval [CI], 2.0-54.7), but it did not affect efavirenz outcome the same way (RH = 0.5; 95% CI, 0.1-2.2) (P value for interaction 5 .013). A376S conferred selective low-level nevirapine resistance in vitro, and led to greater affinity for double-stranded DNA. Conclusions. The A376S substitution in the connection subdomain of HIV-1 RT causes selective nevirapine resistance and confers an increased risk of virological failure to nevirapine-based ART.",

author = "Roger Paredes and Puertas, {Maria Carmen} and Wendy Bannister and M{\'o}nica Kisic and Alessandro Cozzi-Lepri and Christian Pou and Roc{\'i}o Bellido and Gilberto Betancor and Johannes Bogner and Panagiotis Gargalianos and D{\'e}nes B{\'a}nhegyi and Bonaventura Clotet and Jens Lundgren and Luis Men{\'e}ndez-Arias and Javier Martinez-Picado and M. Losso and C. Elias and N. Vetter and R. Zangerle and I. Karpov and A. Vassilenko and Mitsura, {V. M.} and O. Suetnov and N. Clumeck and {De Wit}, S. and B. Poll and R. Colebunders and L. Vandekerckhove and V. Hadziosmanovic and K. Kostov and J. Begovac and L. Machala and H. Rozsypal and D. Sedlacek and J. Nielsen and G. Kronborg and T. Benfield and M. Larsen and J. Gerstoft and T. Katzenstein and Hansen, {A. B.E.} and P. Skinh{\o}j and C. Pedersen and L. Oestergaard and K. Zilmer and Jelena Smidt and M. Ristola and C. Katlama and Viard, {J. P.} and Girard, {P. M.} and Livrozet, {J. M.} and P. Vanhems and C. Pradier and F. Dabis and D. Neau and J. Rockstroh and R. Schmidt and {Van Lunzen}, J. and O. Degen and Stellbrink, {H. J.} and S. Staszewski and G. F{\"a}tkenheuer and J. Kosmidis and G. Xylomenos and J. Perdios and G. Panos and A. Filandras and E. Karabatsaki and H. Sambatakou and D. Banhegyi and F. Mulcahy and I. Yust and D. Turner and M. Burke and S. Pollack and G. Hassoun and S. Maayan and S. Vella and R. Esposito and I. Mazeu and C. Mussini and C. Arici and R. Pristera and F. Mazzotta and A. Gabbuti and V. Vullo and M. Lichtner and A. Chirianni and E. Montesarchio and M. Gargiulo and G. Antonucci and F. Iacomi and P. Narciso and C. Vlassi and M. Zaccarelli and A. Lazzarin and R. Finazzi and M. Galli and A. Ridolfo and {D'Arminio Monforte}, A. and B. Rozentale and P. Aldins and S. Chaplinskas and R. Hemmer and T. Staub and P. Reiss and V. Ormaasen and A. Maeland and J. Brunn and B. Knysz and J. Gasiorowski and A. Horban and E. Bakowska and D. Prokopowicz and R. Flisiak and A. Boron-Kaczmarska and M. Pynka and M. Beniowski and E. Mularska and H. Trocha and E. Jablonowska and E. Malolepsza and K. Wojcik and F. Antunes and E. Valadas and K. Mansinho and F. Maltez and D. Duiculescu and A. Rakhmanova and E. Vinogradova and S. Buzunova and D. Jevtovic and M. Mokr{\'a}{\v s} and D. Stanekov{\'a} and J. Tomazic and J. Gonz{\'a}lez-Lahoz and V. Soriano and L. Martin-Carbonero and P. Labarga and S. Moreno and A. Jou and C. Tural and J. Puig and I. Bravo and Gatell, {J. M.} and Mir{\'o}, {J. M.} and P. Domingo and M. Gutierrez and G. Mateo and Ma Sambeat and A. Karlsson and Persson, {P. O.} and L. Flamholc and B. Ledergerber and R. Weber and P. Francioli and M. Cavassini and B. Hirschel and E. Boffi and H. Furrer and M. Battegay and L. Elzi and E. Kravchenko and N. Chentsova and G. Kutsyna and S. Servitskiy and M. Krasnov and S. Barton and Johnson, {A. M.} and D. Mercey and A. Phillips and Johnson, {M. A.} and A. Mocroft and M. Murphy and J. Weber and G. Scullard and M. Fisher and C. Leen and J. Gatell and B. Gazzard and O. Kirk and A. Cozzi-Lepri and D. Grint and M. Ellefson and D. Podlekareva and J. Kj{\ae}r and L. Peters and J. Reekie and J. Kowalska and J. Tverland and Fischer, {A. H.}",

note = "Funding Information: This work was supported by the Fundaci{\'o}n para la Investigaci{\'o}n y Prevenci{\'o}n del Sida en Espa{\~n}a (FIPSE) through Grant 36771/08, by the Spanish AIDS network Red Tem{\'a}tica Cooperativa de Investigaci{\'o}n en SIDA (RD06/0006), and the Collaborative HIV and Anti-HIV Drug Resistance Network (CHAIN), through integrated Project 223131, funded by the European Commission FP7. EuroSIDA is supported by the European Commission FP6 (Grant LSHP-CT-2006-018632); current support of EuroSIDA also includes unrestricted grants from Bristol-Myers Squibb, GlaxoSmithKline, Roche, Gilead, Pfizer, Merck, Tibotec, and Boehringer-Ingelheim. The participation of centers from Switzerland was supported by a grant from the Swiss Federal Office for Education and Science.",

year = "2011",

month = sep,

day = "1",

doi = "10.1093/infdis/jir385",

language = "אנגלית",

volume = "204",

pages = "741--752",

journal = "Journal of Infectious Diseases",

issn = "0022-1899",

publisher = "Oxford University Press",

number = "5",

}

Paredes, R, Puertas, MC, Bannister, W, Kisic, M, Cozzi-Lepri, A, Pou, C, Bellido, R, Betancor, G, Bogner, J, Gargalianos, P, Bánhegyi, D, Clotet, B, Lundgren, J, Menéndez-Arias, L, Martinez-Picado, J, Losso, M, Elias, C, Vetter, N, Zangerle, R, Karpov, I, Vassilenko, A, Mitsura, VM, Suetnov, O, Clumeck, N, De Wit, S, Poll, B, Colebunders, R, Vandekerckhove, L, Hadziosmanovic, V, Kostov, K, Begovac, J, Machala, L, Rozsypal, H, Sedlacek, D, Nielsen, J, Kronborg, G, Benfield, T, Larsen, M, Gerstoft, J, Katzenstein, T, Hansen, ABE, Skinhøj, P, Pedersen, C, Oestergaard, L, Zilmer, K, Smidt, J, Ristola, M, Katlama, C, Viard, JP, Girard, PM, Livrozet, JM, Vanhems, P, Pradier, C, Dabis, F, Neau, D, Rockstroh, J, Schmidt, R, Van Lunzen, J, Degen, O, Stellbrink, HJ, Staszewski, S, Fätkenheuer, G, Kosmidis, J, Xylomenos, G, Perdios, J, Panos, G, Filandras, A, Karabatsaki, E, Sambatakou, H, Banhegyi, D, Mulcahy, F, Yust, I, Turner, D, Burke, M, Pollack, S, Hassoun, G, Maayan, S, Vella, S, Esposito, R, Mazeu, I, Mussini, C, Arici, C, Pristera, R, Mazzotta, F, Gabbuti, A, Vullo, V, Lichtner, M, Chirianni, A, Montesarchio, E, Gargiulo, M, Antonucci, G, Iacomi, F, Narciso, P, Vlassi, C, Zaccarelli, M, Lazzarin, A, Finazzi, R, Galli, M, Ridolfo, A, D'Arminio Monforte, A, Rozentale, B, Aldins, P, Chaplinskas, S, Hemmer, R, Staub, T, Reiss, P, Ormaasen, V, Maeland, A, Brunn, J, Knysz, B, Gasiorowski, J, Horban, A, Bakowska, E, Prokopowicz, D, Flisiak, R, Boron-Kaczmarska, A, Pynka, M, Beniowski, M, Mularska, E, Trocha, H, Jablonowska, E, Malolepsza, E, Wojcik, K, Antunes, F, Valadas, E, Mansinho, K, Maltez, F, Duiculescu, D, Rakhmanova, A, Vinogradova, E, Buzunova, S, Jevtovic, D, Mokráš, M, Staneková, D, Tomazic, J, González-Lahoz, J, Soriano, V, Martin-Carbonero, L, Labarga, P, Moreno, S, Jou, A, Tural, C, Puig, J, Bravo, I, Gatell, JM, Miró, JM, Domingo, P, Gutierrez, M, Mateo, G, Sambeat, M, Karlsson, A, Persson, PO, Flamholc, L, Ledergerber, B, Weber, R, Francioli, P, Cavassini, M, Hirschel, B, Boffi, E, Furrer, H, Battegay, M, Elzi, L, Kravchenko, E, Chentsova, N, Kutsyna, G, Servitskiy, S, Krasnov, M, Barton, S, Johnson, AM, Mercey, D, Phillips, A, Johnson, MA, Mocroft, A, Murphy, M, Weber, J, Scullard, G, Fisher, M, Leen, C, Gatell, J, Gazzard, B, Kirk, O, Cozzi-Lepri, A, Grint, D, Ellefson, M, Podlekareva, D, Kjær, J, Peters, L, Reekie, J, Kowalska, J, Tverland, J & Fischer, AH 2011, 'A376s in the connection subdomain of HIV-1 reverse transcriptase confers increased risk of virological failure to nevirapine therapy', Journal of Infectious Diseases, vol. 204, no. 5, pp. 741-752. https://doi.org/10.1093/infdis/jir385

TY - JOUR

T1 - A376s in the connection subdomain of HIV-1 reverse transcriptase confers increased risk of virological failure to nevirapine therapy

AU - Paredes, Roger

AU - Puertas, Maria Carmen

AU - Bannister, Wendy

AU - Kisic, Mónica

AU - Cozzi-Lepri, Alessandro

AU - Pou, Christian

AU - Bellido, Rocío

AU - Betancor, Gilberto

AU - Bogner, Johannes

AU - Gargalianos, Panagiotis

AU - Bánhegyi, Dénes

AU - Clotet, Bonaventura

AU - Lundgren, Jens

AU - Menéndez-Arias, Luis

AU - Martinez-Picado, Javier

AU - Losso, M.

AU - Elias, C.

AU - Vetter, N.

AU - Zangerle, R.

AU - Karpov, I.

AU - Vassilenko, A.

AU - Mitsura, V. M.

AU - Suetnov, O.

AU - Clumeck, N.

AU - De Wit, S.

AU - Poll, B.

AU - Colebunders, R.

AU - Vandekerckhove, L.

AU - Hadziosmanovic, V.

AU - Kostov, K.

AU - Begovac, J.

AU - Machala, L.

AU - Rozsypal, H.

AU - Sedlacek, D.

AU - Nielsen, J.

AU - Kronborg, G.

AU - Benfield, T.

AU - Larsen, M.

AU - Gerstoft, J.

AU - Katzenstein, T.

AU - Hansen, A. B.E.

AU - Skinhøj, P.

AU - Pedersen, C.

AU - Oestergaard, L.

AU - Zilmer, K.

AU - Smidt, Jelena

AU - Ristola, M.

AU - Katlama, C.

AU - Viard, J. P.

AU - Girard, P. M.

AU - Livrozet, J. M.

AU - Vanhems, P.

AU - Pradier, C.

AU - Dabis, F.

AU - Neau, D.

AU - Rockstroh, J.

AU - Schmidt, R.

AU - Van Lunzen, J.

AU - Degen, O.

AU - Stellbrink, H. J.

AU - Staszewski, S.

AU - Fätkenheuer, G.

AU - Kosmidis, J.

AU - Xylomenos, G.

AU - Perdios, J.

AU - Panos, G.

AU - Filandras, A.

AU - Karabatsaki, E.

AU - Sambatakou, H.

AU - Banhegyi, D.

AU - Mulcahy, F.

AU - Yust, I.

AU - Turner, D.

AU - Burke, M.

AU - Pollack, S.

AU - Hassoun, G.

AU - Maayan, S.

AU - Vella, S.

AU - Esposito, R.

AU - Mazeu, I.

AU - Mussini, C.

AU - Arici, C.

AU - Pristera, R.

AU - Mazzotta, F.

AU - Gabbuti, A.

AU - Vullo, V.

AU - Lichtner, M.

AU - Chirianni, A.

AU - Montesarchio, E.

AU - Gargiulo, M.

AU - Antonucci, G.

AU - Iacomi, F.

AU - Narciso, P.

AU - Vlassi, C.

AU - Zaccarelli, M.

AU - Lazzarin, A.

AU - Finazzi, R.

AU - Galli, M.

AU - Ridolfo, A.

AU - D'Arminio Monforte, A.

AU - Rozentale, B.

AU - Aldins, P.

AU - Chaplinskas, S.

AU - Hemmer, R.

AU - Staub, T.

AU - Reiss, P.

AU - Ormaasen, V.

AU - Maeland, A.

AU - Brunn, J.

AU - Knysz, B.

AU - Gasiorowski, J.

AU - Horban, A.

AU - Bakowska, E.

AU - Prokopowicz, D.

AU - Flisiak, R.

AU - Boron-Kaczmarska, A.

AU - Pynka, M.

AU - Beniowski, M.

AU - Mularska, E.

AU - Trocha, H.

AU - Jablonowska, E.

AU - Malolepsza, E.

AU - Wojcik, K.

AU - Antunes, F.

AU - Valadas, E.

AU - Mansinho, K.

AU - Maltez, F.

AU - Duiculescu, D.

AU - Rakhmanova, A.

AU - Vinogradova, E.

AU - Buzunova, S.

AU - Jevtovic, D.

AU - Mokráš, M.

AU - Staneková, D.

AU - Tomazic, J.

AU - González-Lahoz, J.

AU - Soriano, V.

AU - Martin-Carbonero, L.

AU - Labarga, P.

AU - Moreno, S.

AU - Jou, A.

AU - Tural, C.

AU - Puig, J.

AU - Bravo, I.

AU - Gatell, J. M.

AU - Miró, J. M.

AU - Domingo, P.

AU - Gutierrez, M.

AU - Mateo, G.

AU - Sambeat, Ma

AU - Karlsson, A.

AU - Persson, P. O.

AU - Flamholc, L.

AU - Ledergerber, B.

AU - Weber, R.

AU - Francioli, P.

AU - Cavassini, M.

AU - Hirschel, B.

AU - Boffi, E.

AU - Furrer, H.

AU - Battegay, M.

AU - Elzi, L.

AU - Kravchenko, E.

AU - Chentsova, N.

AU - Kutsyna, G.

AU - Servitskiy, S.

AU - Krasnov, M.

AU - Barton, S.

AU - Johnson, A. M.

AU - Mercey, D.

AU - Phillips, A.

AU - Johnson, M. A.

AU - Mocroft, A.

AU - Murphy, M.

AU - Weber, J.

AU - Scullard, G.

AU - Fisher, M.

AU - Leen, C.

AU - Gatell, J.

AU - Gazzard, B.

AU - Kirk, O.

AU - Cozzi-Lepri, A.

AU - Grint, D.

AU - Ellefson, M.

AU - Podlekareva, D.

AU - Kjær, J.

AU - Peters, L.

AU - Reekie, J.

AU - Kowalska, J.

AU - Tverland, J.

AU - Fischer, A. H.

N1 - Funding Information: This work was supported by the Fundación para la Investigación y Prevención del Sida en España (FIPSE) through Grant 36771/08, by the Spanish AIDS network Red Temática Cooperativa de Investigación en SIDA (RD06/0006), and the Collaborative HIV and Anti-HIV Drug Resistance Network (CHAIN), through integrated Project 223131, funded by the European Commission FP7. EuroSIDA is supported by the European Commission FP6 (Grant LSHP-CT-2006-018632); current support of EuroSIDA also includes unrestricted grants from Bristol-Myers Squibb, GlaxoSmithKline, Roche, Gilead, Pfizer, Merck, Tibotec, and Boehringer-Ingelheim. The participation of centers from Switzerland was supported by a grant from the Swiss Federal Office for Education and Science.

PY - 2011/9/1

Y1 - 2011/9/1

N2 - Background. The clinical relevance of mutations in the connection subdomain and the ribonuclease (RNase) H domain of HIV-1 reverse transcriptase (RT) is uncertain. Methods. The risk of virological failure to nonnucleoside RT inhibitor (NNRTI)-based antiretroviral therapy (ART) was evaluated in NNRTI-naive patients who started NNRTIs in the EuroSIDA study after July 1997 according to preexisting substitutions in the connection subdomain and the RNase H domain of HIV-1 RT. An observed association between A376S and virological failure was further investigated by testing in vitro NNRTI susceptibility of single site-directed mutants and patient-derived recombinant viruses. Enzymatic assays also determined the effects of A376S on nevirapine and template-primer binding to HIV-1 RT. Results. Virological failure occurred in 142 of 287 (49%) individuals: 77 receiving nevirapine (67%) and 65 receiving efavirenz (38%) (P < .001). Preexisting A376S was associated with an increased risk of virological failure to nevirapine (relative hazard [RH] = 10.4; 95% confidence interval [CI], 2.0-54.7), but it did not affect efavirenz outcome the same way (RH = 0.5; 95% CI, 0.1-2.2) (P value for interaction 5 .013). A376S conferred selective low-level nevirapine resistance in vitro, and led to greater affinity for double-stranded DNA. Conclusions. The A376S substitution in the connection subdomain of HIV-1 RT causes selective nevirapine resistance and confers an increased risk of virological failure to nevirapine-based ART.

AB - Background. The clinical relevance of mutations in the connection subdomain and the ribonuclease (RNase) H domain of HIV-1 reverse transcriptase (RT) is uncertain. Methods. The risk of virological failure to nonnucleoside RT inhibitor (NNRTI)-based antiretroviral therapy (ART) was evaluated in NNRTI-naive patients who started NNRTIs in the EuroSIDA study after July 1997 according to preexisting substitutions in the connection subdomain and the RNase H domain of HIV-1 RT. An observed association between A376S and virological failure was further investigated by testing in vitro NNRTI susceptibility of single site-directed mutants and patient-derived recombinant viruses. Enzymatic assays also determined the effects of A376S on nevirapine and template-primer binding to HIV-1 RT. Results. Virological failure occurred in 142 of 287 (49%) individuals: 77 receiving nevirapine (67%) and 65 receiving efavirenz (38%) (P < .001). Preexisting A376S was associated with an increased risk of virological failure to nevirapine (relative hazard [RH] = 10.4; 95% confidence interval [CI], 2.0-54.7), but it did not affect efavirenz outcome the same way (RH = 0.5; 95% CI, 0.1-2.2) (P value for interaction 5 .013). A376S conferred selective low-level nevirapine resistance in vitro, and led to greater affinity for double-stranded DNA. Conclusions. The A376S substitution in the connection subdomain of HIV-1 RT causes selective nevirapine resistance and confers an increased risk of virological failure to nevirapine-based ART.

UR - http://www.scopus.com/inward/record.url?scp=80051742963&partnerID=8YFLogxK

U2 - 10.1093/infdis/jir385

DO - 10.1093/infdis/jir385

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AN - SCOPUS:80051742963

SN - 0022-1899

VL - 204

SP - 741

EP - 752

JO - Journal of Infectious Diseases

JF - Journal of Infectious Diseases

IS - 5

ER -

A376s in the connection subdomain of HIV-1 reverse transcriptase confers increased risk of virological failure to nevirapine therapy

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