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1. Transmission of HIV Drug Resistance and the Predicted Effect on Current First-line Regimens in Europe

Author

Hofstra, L.M. (Marije), Sauvageot, N. (Nicolas), Albert, J. (Jan), Alexiev, I. (Ivailo), Garcia, F. (Federico), Struck, D. (Daniel), Vijver, D.A.M.C. (David) van de, Åsjö, B. (Birgitta), Beshkov, D. (Danail), Coughlan, S. (Suzie), Descamps, D. (Diane), Griskevicius, A. (Algirdas), Hamouda, O. (Osamah), Horban, A. (Andrzej), Kasteren, M.E.E. (Marjo) van, Kolupajeva, T. (Tatjana), Kostrikis, L.G. (Leondios), Liitsola, K. (Kirsi), Linka, M. (Marek), Mor, O. (Orna), Nielsen, C. (Claus), Otelea, D. (Dan), Paraskevis, D. (Dimitrios), Paredes, R. (Roger), Poljak, M. (Mario), Puchhammer-Stockl, E. (Elisabeth), Sonnerborg, A. (Anders), Stanekova, D. (Danica), Stanojevic, M. (Maja), Van Laethem, K. (Kristel), Zazzi, M. (Maurizio), Zidovec Lepej, S. (Snjezana), Boucher, C.A.B. (Charles), Schmit, J.-C. (Jean-Claude), Wensing, A.M.J. (Annemarie), Hofstra, L.M. (Marije), Sauvageot, N. (Nicolas), Albert, J. (Jan), Alexiev, I. (Ivailo), Garcia, F. (Federico), Struck, D. (Daniel), Vijver, D.A.M.C. (David) van de, Åsjö, B. (Birgitta), Beshkov, D. (Danail), Coughlan, S. (Suzie), Descamps, D. (Diane), Griskevicius, A. (Algirdas), Hamouda, O. (Osamah), Horban, A. (Andrzej), Kasteren, M.E.E. (Marjo) van, Kolupajeva, T. (Tatjana), Kostrikis, L.G. (Leondios), Liitsola, K. (Kirsi), Linka, M. (Marek), Mor, O. (Orna), Nielsen, C. (Claus), Otelea, D. (Dan), Paraskevis, D. (Dimitrios), Paredes, R. (Roger), Poljak, M. (Mario), Puchhammer-Stockl, E. (Elisabeth), Sonnerborg, A. (Anders), Stanekova, D. (Danica), Stanojevic, M. (Maja), Van Laethem, K. (Kristel), Zazzi, M. (Maurizio), Zidovec Lepej, S. (Snjezana), Boucher, C.A.B. (Charles), Schmit, J.-C. (Jean-Claude), and Wensing, A.M.J. (Annemarie)

Abstract

Background. Numerous studies have shown that baseline drug resistance patterns may influence the outcome of antiretroviral therapy. Therefore, guidelines recommend drug resistance testing to guide the choice of initial regimen. In addition to optimizing individual patient management, these baseline resistance data enable transmitted drug resistance (TDR) to be surveyed for public health purposes. The SPREAD program systematically collects data to gain insight into TDR occurring in Europe since 2001. Methods. Demographic, clinical, and virological data from 4140 antiretroviral-naive human immunodeficiency virus (HIV)-infected individuals from 26 countries who were newly diagnosed between 2008 and 2010 were analyzed. Evidence of TDR was defined using the WHO list for surveillance of drug resistance mutations. Prevalence of TDR was assessed over time by comparing the results to SPREAD data from 2002 to 2007. Baseline susceptibility to antiretroviral drugs was predicted using the Stanford HIVdb program version 7.0. Results. The overall prevalence of TDR did not change significantly over time and was 8.3% (95% confidence interval, 7.2%-9.5%) in 2008-2010. The most frequent indicators of TDR were nucleoside reverse transcriptase inhibitor (NRTI) mutations (4.5%), followed by nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations (2.9%) and protease inhibitor mutations (2.0%). Baseline mutations were most predictive of reduced susceptibility to initial NNRTI-based regimens: 4.5% and 6.5% of patient isolates were predicted to have resistance to regimens containing efavirenz or rilpivirine, respectively, independent of current NRTI backbones. Conclusions. Although TDR was highest for NRTIs, the impact of baseline drug resistance patterns on susceptibility was largest for NNRTIs. The prevalence of TDR assessed by epidemiological surveys does not clearly indicate to what degree susceptibility to different drug classes is affected.

Published
2016
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2. Transmission of HIV drug resistance and the predicted effect on current first-line regimens in Europe

Author

Universitat Rovira i Virgili, Hofstra LM, Sauvageot N, Albert J, Alexiev I, Garcia F, Struck D, Van de Vijver DAMC, Åsjö B, Beshkov D, Coughlan S, Descamps D, Griskevicius A, Hamouda O, Horban A, Van Kasteren M, Kolupajeva T, Kostrikis LG, Liitsola K, Linka M, Mor O, Nielsen C, Otelea D, Paraskevis D, Paredes R, Poljak M, Puchhammer-Stöckl E, Sönnerborg A, Staneková D, Stanojevic M, Van Laethem K, Zazzi M, Zidovec Lepej S, Boucher CAB, Schmit JC, Wensing AMJ,, Puchhammer-Stockl E, Sarcletti M, Schmied B, Geit M, Balluch G, Vandamme AM, Vercauteren J, Derdelinckx I, Sasse A, Bogaert M, Ceunen H, De Roo A, De Wit S, Echahidi F, Fransen K, Goffard JC, Goubau P, Goudeseune E, Yombi JC, Lacor P, Liesnard C, Moutschen M, Pierard D, Rens R, Schrooten Y, Vaira D, Vandekerckhove LPR, Van den Heuvel A, Van Der Gucht B, Van Ranst M, Van Wijngaerden E, Vandercam B, Vekemans M, Verhofstede C, Clumeck N, Lepej SZ, Begovac J, Kostrikis L, Demetriades I, Kousiappa I, Demetriou V, Hezka J, Maly M, Machala L, Jørgensen LB, Gerstoft J, Mathiesen L, Pedersen C, Nielsen H, Laursen A, Kvinesdal B, Ristola M, Suni J, Sutinen J, Assoumou L, Castor G, Grude M, Flandre P, Storto A, Kücherer C, Berg T, Braun P, Poggensee G, Däumer M, Eberle J, Heiken H, Kaiser R, Knechten H, Korn K, Müller H, Neifer S, Schmidt B, Walter H, Gunsenheimer-Bartmeyer B, Harrer T, Hatzakis A, Zavitsanou A, Vassilakis A, Lazanas M, Chini M, Lioni A, Sakka V, Kourkounti S, Paparizos V, Antoniadou A, Papadopoulos A, Poulakou G, Katsarolis I, Protopapas K, Chryssos G, Drimis S, Gargalianos P, Xylomenos G, Lourida G, Psichogiou M, Daikos GL, Sipsas NV, Kontos A, Gamaletsou MN, Koratzanis G, Sambatakou H, Mariolis H, Skoutelis A, Papastamopoulos V, Georgiou O, Panagopoulos P, Maltezos E, De Gascun C, Byrne C, Duffy M, Bergin C, Reidy D, Farrell G, Lamber, Universitat Rovira i Virgili, and Hofstra LM, Sauvageot N, Albert J, Alexiev I, Garcia F, Struck D, Van de Vijver DAMC, Åsjö B, Beshkov D, Coughlan S, Descamps D, Griskevicius A, Hamouda O, Horban A, Van Kasteren M, Kolupajeva T, Kostrikis LG, Liitsola K, Linka M, Mor O, Nielsen C, Otelea D, Paraskevis D, Paredes R, Poljak M, Puchhammer-Stöckl E, Sönnerborg A, Staneková D, Stanojevic M, Van Laethem K, Zazzi M, Zidovec Lepej S, Boucher CAB, Schmit JC, Wensing AMJ,, Puchhammer-Stockl E, Sarcletti M, Schmied B, Geit M, Balluch G, Vandamme AM, Vercauteren J, Derdelinckx I, Sasse A, Bogaert M, Ceunen H, De Roo A, De Wit S, Echahidi F, Fransen K, Goffard JC, Goubau P, Goudeseune E, Yombi JC, Lacor P, Liesnard C, Moutschen M, Pierard D, Rens R, Schrooten Y, Vaira D, Vandekerckhove LPR, Van den Heuvel A, Van Der Gucht B, Van Ranst M, Van Wijngaerden E, Vandercam B, Vekemans M, Verhofstede C, Clumeck N, Lepej SZ, Begovac J, Kostrikis L, Demetriades I, Kousiappa I, Demetriou V, Hezka J, Maly M, Machala L, Jørgensen LB, Gerstoft J, Mathiesen L, Pedersen C, Nielsen H, Laursen A, Kvinesdal B, Ristola M, Suni J, Sutinen J, Assoumou L, Castor G, Grude M, Flandre P, Storto A, Kücherer C, Berg T, Braun P, Poggensee G, Däumer M, Eberle J, Heiken H, Kaiser R, Knechten H, Korn K, Müller H, Neifer S, Schmidt B, Walter H, Gunsenheimer-Bartmeyer B, Harrer T, Hatzakis A, Zavitsanou A, Vassilakis A, Lazanas M, Chini M, Lioni A, Sakka V, Kourkounti S, Paparizos V, Antoniadou A, Papadopoulos A, Poulakou G, Katsarolis I, Protopapas K, Chryssos G, Drimis S, Gargalianos P, Xylomenos G, Lourida G, Psichogiou M, Daikos GL, Sipsas NV, Kontos A, Gamaletsou MN, Koratzanis G, Sambatakou H, Mariolis H, Skoutelis A, Papastamopoulos V, Georgiou O, Panagopoulos P, Maltezos E, De Gascun C, Byrne C, Duffy M, Bergin C, Reidy D, Farrell G, Lamber

Abstract

© The Author 2015. Background. Numerous studies have shown that baseline drug resistance patterns may influence the outcome of antiretroviral therapy. Therefore, guidelines recommend drug resistance testing to guide the choice of initial regimen. In addition to optimizing individual patient management, these baseline resistance data enable transmitted drug resistance (TDR) to be surveyed for public health purposes. The SPREAD program systematically collects data to gain insight into TDR occurring in Europe since 2001. Methods. Demographic, clinical, and virological data from 4140 antiretroviral-naive human immunodeficiency virus (HIV)-infected individuals from 26 countries who were newly diagnosed between 2008 and 2010 were analyzed. Evidence of TDR was defined using the WHO list for surveillance of drug resistance mutations. Prevalence of TDR was assessed over time by comparing the results to SPREAD data from 2002 to 2007. Baseline susceptibility to antiretroviral drugs was predicted using the Stanford HIVdb program version 7.0. Results. The overall prevalence of TDR did not change significantly over time and was 8.3% (95% confidence interval, 7.2%-9.5%) in 2008-2010. The most frequent indicators of TDR were nucleoside reverse transcriptase inhibitor (NRTI) mutations (4.5%), followed by nonnucleoside reverse transcriptase inhibitor (NNRTI) mutations (2.9%) and protease inhibitor mutations (2.0%). Baseline mutations were most predictive of reduced susceptibility to initial NNRTI-based regimens: 4.5% and 6.5% of patient isolates were predicted to have resistance to regimens containing efavirenz or rilpivirine, respectively, independent of current NRTI backbones. Conclusions. Although TDR was highest for NRTIs, the impact of baseline drug resistance patterns on susceptibi

Published
2016

3. Primary resistance to integrase strand-transfer inhibitors in Europe.

Author

Casadellá, M., van Ham, P.M. (Petra), Noguera-Julian, M., van Kessel, A., Pou, C., Hofstra, L.M. (Marije), Metcalf, G.A. (Ginger A.), Garcia, F., Struck, D. (Daniel), Alexiev, I. (Ivailo), Bakken Kran, A.M., Hoepelman, A.I.M., Kostrikis, L.G. (Leondios), Somogyi, S., Liitsola, K. (Kirsi), Linka, M. (Marek), Nielsen, C., Otelea, D. (Dan), Paraskevis, D. (Dimitrios), Poljak, M. (Mario), Puchhammer-Stöckl, E. (Elisabeth), Stanekova, D. (Danica), Stanojevic, M. (Maja), Van Laethem, K. (Kristel), Zidovec Lepej, S. (Snjezana), Clotet, B., Boucher, C.A.B. (Charles), Paredes, R. (Roger), Wensing, A.M.J. (Annemarie), Casadellá, M., van Ham, P.M. (Petra), Noguera-Julian, M., van Kessel, A., Pou, C., Hofstra, L.M. (Marije), Metcalf, G.A. (Ginger A.), Garcia, F., Struck, D. (Daniel), Alexiev, I. (Ivailo), Bakken Kran, A.M., Hoepelman, A.I.M., Kostrikis, L.G. (Leondios), Somogyi, S., Liitsola, K. (Kirsi), Linka, M. (Marek), Nielsen, C., Otelea, D. (Dan), Paraskevis, D. (Dimitrios), Poljak, M. (Mario), Puchhammer-Stöckl, E. (Elisabeth), Stanekova, D. (Danica), Stanojevic, M. (Maja), Van Laethem, K. (Kristel), Zidovec Lepej, S. (Snjezana), Clotet, B., Boucher, C.A.B. (Charles), Paredes, R. (Roger), and Wensing, A.M.J. (Annemarie)

Abstract

The objective of this study was to define the natural genotypic variation of the HIV-1 integrase gene across Europe for epidemiological surveillance of integrase strand-transfer inhibitor (InSTI) resistance. This was a multicentre, cross-sectional study within the European SPREAD HIV resistance surveillance programme. A representative set of 300 samples was selected from 1950 naive HIV-positive subjects newly diagnosed in 2006-07. The prevalence of InSTI resistance was evaluated using quality-controlled baseline population sequencing of integrase. Signature raltegravir, elvitegravir and dolutegravir resistance mutations were defined according to the IAS-USA 2014 list. In addition, all integrase substitutions relative to HXB2 were identified, including those with a Stanford HIVdb score ≥ 10 to at least one InSTI. To rule out circulation of minority InSTI-resistant HIV, 65 samples were selected for 454 integrase sequencing. For the population sequencing analysis, 278 samples were retrieved and successfully analysed. No signature resistance mutations to any of the InSTIs were detected. Eleven (4%) subjects had mutations at resistance-associated positions with an HIVdb score ≥ 10. Of the 56 samples successfully analysed with 454 sequencing, no InSTI signature mutations were detected, whereas integrase substitutions with an HIVdb score ≥ 10 were found in 8 (14.3%) individuals. No signature InSTI-resistant variants were circulating in Europe before the introduction of

Published
2015
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4. Primary resistance to integrase strand-transfer inhibitors in Europe.

Author

UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service de microbiologie, UCL - (SLuc) Service d'hématologie, UCL - (SLuc) Service de médecine interne générale, Casadellà, M, van Ham, P M, Noguera-Julian, M, van Kessel, A, Pou, C, Hofstra, L M, Santos, J R, Garcia, F, Struck, D, Alexiev, I, Bakken Kran, A M, Hoepelman, A I, Kostrikis, L G, Somogyi, S, Liitsola, K, Linka, M, Nielsen, C, Otelea, D, Paraskevis, D, Poljak, M, Puchhammer-Stöckl, E, Staneková, D, Stanojevic, M, Van Laethem, K, Zidovec Lepej, S, Clotet, B, Boucher, C A B, Paredes, R, Wensing, A M J, SPREAD programme, Goubau, Patrick, Yombi, Jean Cyr, Vandercam, Bernard, Vekemans, Marie-Christiane, UCL - SSS/IREC/SLUC - Pôle St.-Luc, UCL - (SLuc) Service de microbiologie, UCL - (SLuc) Service d'hématologie, UCL - (SLuc) Service de médecine interne générale, Casadellà, M, van Ham, P M, Noguera-Julian, M, van Kessel, A, Pou, C, Hofstra, L M, Santos, J R, Garcia, F, Struck, D, Alexiev, I, Bakken Kran, A M, Hoepelman, A I, Kostrikis, L G, Somogyi, S, Liitsola, K, Linka, M, Nielsen, C, Otelea, D, Paraskevis, D, Poljak, M, Puchhammer-Stöckl, E, Staneková, D, Stanojevic, M, Van Laethem, K, Zidovec Lepej, S, Clotet, B, Boucher, C A B, Paredes, R, Wensing, A M J, SPREAD programme, Goubau, Patrick, Yombi, Jean Cyr, Vandercam, Bernard, and Vekemans, Marie-Christiane

Abstract

OBJECTIVES: The objective of this study was to define the natural genotypic variation of the HIV-1 integrase gene across Europe for epidemiological surveillance of integrase strand-transfer inhibitor (InSTI) resistance. METHODS: This was a multicentre, cross-sectional study within the European SPREAD HIV resistance surveillance programme. A representative set of 300 samples was selected from 1950 naive HIV-positive subjects newly diagnosed in 2006-07. The prevalence of InSTI resistance was evaluated using quality-controlled baseline population sequencing of integrase. Signature raltegravir, elvitegravir and dolutegravir resistance mutations were defined according to the IAS-USA 2014 list. In addition, all integrase substitutions relative to HXB2 were identified, including those with a Stanford HIVdb score ≥ 10 to at least one InSTI. To rule out circulation of minority InSTI-resistant HIV, 65 samples were selected for 454 integrase sequencing. RESULTS: For the population sequencing analysis, 278 samples were retrieved and successfully analysed. No signature resistance mutations to any of the InSTIs were detected. Eleven (4%) subjects had mutations at resistance-associated positions with an HIVdb score ≥ 10. Of the 56 samples successfully analysed with 454 sequencing, no InSTI signature mutations were detected, whereas integrase substitutions with an HIVdb score ≥ 10 were found in 8 (14.3%) individuals. CONCLUSIONS: No signature InSTI-resistant variants were circulating in Europe before the introduction of InSTIs. However, polymorphisms contributing to InSTI resistance were not rare. As InSTI use becomes more widespread, continuous surveillance of primary InSTI resistance is warranted. These data will be key to modelling the kinetics of InSTI resistance transmission in Europe in the coming years.

Published
2015

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