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1. Prevalence and Outcomes for Heavily Treatment-Experienced Individuals Living With Human Immunodeficiency Virus in a European Cohort

Author

Pelchen-Matthews, A., Borges, A. H., Reekie, J., Rasmussen, L. D., Wiese, L., Weber, J., Pradier, C., Degen, O., Paredes, R., Tau, L., Flamholc, L., Gottfredsson, M., Kowalska, J. D., Jablonowska, E., Mozer-Lisewska, I., Radoi, R., Vasylyev, M., Kuznetsova, A., Begovac, J., Svedhem, V., Clark, A., Cozzi-Lepri, A., Harxhi, A., Losso, M., Kundro, M., Schmied, B., Zangerle, R., Karpov, I., Vassilenko, A., Mitsura, V. M., Paduto, D., Clumeck, N., De Wit, S., Delforge, M., Florence, E., Vandekerckhove, L., Hadziosmanovic, V., Machala, L., Jilich, D., Sedlacek, D., Kronborg, G., Benfield, T., Gerstoft, J., Katzenstein, T., Pedersen, C., Johansen, I. S., Ostergaard, L., Moller, N. F., Nielsen, L. N., Zilmer, K., Smidt, J., Aho, I., Viard, J. -P., Girard, P. -M., Fontas, E., Duvivier, C., Rockstroh, J., Behrens, G., Stellbrink, H. J., Stephan, C., Goethe, J. W., Bogner, J., Fatkenheuer, G., Chkhartishvili, N., Sambatakou, H., Adamis, G., Paissios, N., Szlavik, J., Kelly, C., Turner, D., Burke, M., Shahar, E., Hassoun, G., Elinav, H., Haouzi, M., Elbirt, D., D'Arminio Monforte, A., Esposito, R., Mazeu, I., Mussini, C., Mazzotta, F., Gabbuti, A., Lazzarin, A., Castagna, A., Gianotti, N., Galli, M., Ridolfo, A., Uzdaviniene, V., Matulionyte, R., Staub, T., Hemmer, R., Dragas, S., Stevanovic, M., Reiss, P., Trajanovska, J., Reikvam, D. H., Maeland, A., Bruun, J., Knysz, B., Gasiorowski, J., Inglot, M., Bakowska, E., Flisiak, R., Grzeszczuk, A., Parczewski, M., Maciejewska, K., Aksak-Was, B., Beniowski, M., Mularska, E., Kamerys, J., Wojcik, K., Rozplochowski, B., Zagalo, A., Mansinho, K., Maltez, F., Oprea, C., Yakovlev, A., Trofimora, T., Khromova, I., Kuzovatova, E., Borodulina, E., Vdoushkina, E., Ranin, J., Tomazic, J., Miro, J. M., Laguno, M., Martinez, E., Garcia, F., Blanco, J. L., Martinez-Rebollar, M., Mallolas, J., Callau, P., Rojas, J., Inciarta, A., Moreno, S., del Campo, S., Clotet, B., Jou, A., Puig, J., Llibre, J. M., Santos, J. R., Domingo, P., Gutierrez, M., Mateo, G., Sambeat, M. A., Laporte, J. M., Falconer, K., Thalme, A., Sonnerborg, A., Treutiger, C. J., Scherrer, A., Weber, R., Cavassini, M., Calmy, A., Furrer, H., Battegay, M., Schmid, P., Mikhalik, J., Sluzhynska, M., Milinkovic, A., Johnson, A. M., Simons, E., Edwards, S., Phillips, A., Johnson, M. A., Mocroft, A., Orkin, C., Winston, A., Leen, C., Wandeler, G., Lundgren, J., Guaraldi, G., Kirk, O., Peters, L., Bojesen, A., Raben, D., Hansen, E. V., Kristensen, D., Larsen, J. F., Fischer, A. H., Amele, S., and Roen, A.

Subjects
Adult, Male, antiretroviral treatment, medicine.medical_specialty, Anti-HIV Agents, Human immunodeficiency virus (HIV), non-AIDS-defining clinical conditions, Comorbidity, Rate ratio, medicine.disease_cause, symbols.namesake, heavily treatment experienced, Acquired immunodeficiency syndrome (AIDS), Antiretroviral Therapy, Highly Active, Internal medicine, medicine, Humans, Pharmacology (medical), Prospective Studies, Poisson regression, Prospective cohort study, Acquired Immunodeficiency Syndrome, business.industry, Confounding, HIV resistance, acquired immunodeficiency syndrome, Middle Aged, Viral Load, prevalence, outcomes, heavily, treatment-experienced, individuals, HIV, medicine.disease, Europe, AIDS, Treatment Outcome, Infectious Diseases, Cohort, symbols, Female, business, Viral load
Abstract

Background: Although antiretroviral treatments have improved survival of persons living with HIV, their long-term use may limit available drug options. We estimated the prevalence of heavily treatment-experienced (HTE) status and the potential clinical consequences of becoming HTE. Setting: EuroSIDA, a European multicenter prospective cohort study. Methods: A composite definition for HTE was developed, based on estimates of antiretroviral resistance and prior exposure to specific antiretroviral regimens. Risks of progressing to clinical outcomes were assessed by Poisson regression, comparing every HTE individual with 3 randomly selected controls who never became HTE. Results: Of 15,570 individuals under follow-up in 2010-2016, 1617 (10.4%, 95% CI: 9.9% to 10.9%) were classified as HTE. 1093 individuals became HTE during prospective follow-up (HTE incidence rate 1.76, CI: 1.66 to 1.87 per 100 person-years of follow-up). The number of HTE individuals was highest in West/Central Europe (636/4019 persons, 15.7%) and lowest in East Europe (26/2279 persons, 1.1%). Although most HTE individuals maintained controlled viral loads (

Published
2021

2. Observational cohort study of rilpivirine (RPV) utilization in Europe

Author

Cozzi-Lepri, Alessandro, Peters, Lars, Pelchen-Matthews, Annegret, Neesgaard, Bastian, de Wit, Stephane, Johansen, Isik Somuncu, Edwards, Simon, Stephan, Christoph, Adamis, Georgios, Staub, Therese, Zagalo, Alexandra, Domingo, Pere, Elbirt, Daniel, Kusejko, Katharina, Brännström, Johanna, Paduta, Dzmitry, Trofimova, Tatyana, Szlavik, Janos, Zilmer, Kai, Losso, Marcello, van Eygen, Veerle, Pai, Helen, Lundgren, Jens, Mocroft, Amanda, Harxhi, A., Losso, M., Kundro, M., Schmied, B., Karpov, I., Vassilenko, A., Paduto, D., Mitsura, V. M., Clumeck, N., de Wit, S., Delforge, M., Hadziosmanovic, V., Begovac, J., Machala, L., Jilich, D., Gerstoft, J., Pedersen, C., Sedlacek, D., Kronborg, G., Benfield, T., Johansen, I. S., Ostergaard, L., Wiese, L., Moller, N. F., Nielsen, L. N., Zilmer, K., Smidt, Jelena, Aho, I., Viard, J. P., Girard, P. M., Pradier, C., Fontas, E., Duvivier, C., Rockstroh, J., Degen, O., Hoffmann, C., Stellbrink, H. J., Stefan, C., Bogner, J., Fätkenheuer, G., Chkhartishvili, N., Sambatakou, H., Adamis, G., Paissios, N., Uzdaviniene, V., Staub, T., Dragas, S., Reiss, P., Trajanovska, J., Reikvam, D. H., Maeland, A., Bruun, J., Knysz, B., Szetela, B., Inglot, M., Bakowska, E., Flisiak, R., Grzeszczuk, A., Parczewski, M., Maciejewska, K., Aksak-Was, B., Beniowski, M., Mularska, E., Jablonowska, E., Kamerys, J., Wojcik, K., Mozer-Lisewska, I., Rozplochowski, B., Zagalo, A., Radoi, R., Oprea, C., Yakovlev, A., Trofimora, T., Khromova, I., Kuzovatova, E., Borodulina, E., Vdoushkina, E., Ranin, J., Tomazic, J., Miro, J. M., Laguno, M., Martinez, E., Garcia, F., Blanco, J. L., Martinez-Rebollar, M., Mallolas, J., Callau, P., Rojas, J., Moreno, S., del Campo, S., Jou, A., Paredes, R., Puig, J., Llibre, J. M., Santos, J. R., Domingo, P., Gutierrez, M., Mateo, G. M., Sambeat, A., Laporte, J. M., Svedhem, V., Thalme, A., Sonnerborg, A., Flamholc, L., Kusejko, K., Weber, R., Calmy, A., Furrer, H., Battegay, M., Schmid, P., Kuznetsova, A., Mikhalik, J., Sluzhynska, M., Milinkovic, A., Johnson, A. M., Simons, E., Edwards, S., Phillips, A. M., Johnson, A., Mocroft, A., Orkin, C., Winston, A., Clarke, A., Leen, C., Study group members AMC, van der Valk, Marc, Global Health, Infectious diseases, AII - Infectious diseases, APH - Aging & Later Life, APH - Digital Health, APH - Personalized Medicine, and APH - Global Health

Subjects
Real-world effectiveness, Anti-HIV Agents, Rilpivirine, Eviplera™, HIV Infections, Viral Load, Edurant™, Europe, Treatment Outcome, Virology, HIV-1, Humans, Molecular Medicine, Pharmacology (medical), Cohort Study, Europe, Edurant™, Eviplera™, Efavirenz, Real-world efectiveness, Real-world efectiveness, Efavirenz, Cohort Study
Abstract

Introduction Data on safety and effectiveness of RPV from the real-world setting as well as comparisons with other NNRTIs such as efavirenz (EFV) remain scarce. Methods Participants of EuroSIDA were included if they had started a RPV- or an EFV-containing regimen over November 2011-December 2017. Statistical testing was conducted using non-parametric Mann–Whitney U test and Chi-square test. A logistic regression model was used to compare participants’ characteristics by treatment group. Kaplan–Meier analysis was used to estimate the cumulative risk of virological failure (VF, two consecutive values > 50 copies/mL). Results 1,355 PLWH who started a RPV-based regimen (11% ART-naïve), as well as 333 initiating an EFV-containing regimen were included. Participants who started RPV differed from those starting EFV for demographics (age, geographical region) and immune-virological profiles (CD4 count, HIV RNA). The cumulative risk of VF for the RPV-based group was 4.5% (95% CI 3.3–5.7%) by 2 years from starting treatment (71 total VF events). Five out of 15 (33%) with resistance data available in the RPV group showed resistance-associated mutations vs. 3/13 (23%) among those in the EFV group. Discontinuations due to intolerance/toxicity were reported for 73 (15%) of RPV- vs. 45 (30%) of EFV-treated participants (p = 0.0001). The main difference was for toxicity of central nervous system (CNS, 3% vs. 22%, p Conclusion Our estimates of VF > 50 copies/mL and resistance in participants treated with RPV were similar to those reported by other studies. RPV safety profile was favourable with less frequent discontinuation due to toxicity than EFV (especially for CNS).

Published
2022

3. Long‐term effectiveness of recommended boosted protease inhibitor‐based antiretroviral therapy in Europe

Author

Santos, J. R., Cozzi-Lepri, A., Phillips, A., De Wit, S., Pedersen, C., Reiss, P., Blaxhult, A., Lazzarin, A., Sluzhynska, M., Orkin, C., Duvivier, C., Bogner, J., Gargalianos-Kakolyris, P., Schmid, P., Hassoun, G., Khromova, I., Beniowski, M., Hadziosmanovic, V., Sedlacek, D., Paredes, R., Lundgren, J. D., Losso, M., Kundro, M., Schmied, B., Zangerle, R., Karpov, I., Vassilenko, A., Mitsura, V. M., Paduto, D., Clumeck, N., Delforge, M., Florence, E., Vandekerckhove, L., Begovac, J., Machala, L., Jilich, D., Kronborg, G., Benfield, T., Gerstoft, J., Katzenstein, T., Moller, N. F., Ostergaard, L., Wiese, L., Nielsen, L. N., Zilmer, K., Smidt, J., Ristola, M., Aho, I., Viard, J. -P., Girard, P. -M., Pradier, C., Fontas, E., Rockstroh, J., Schmidt, R., Degen, O., Stellbrink, H. J., Stefan, C., Fatkenheuer, G., Chkhartishvili, N., Gargalianos, P., Xylomenos, G., Lourida, P., Sambatakou, H., Szlavik, J., Gottfredsson, M., Mulcahy, F., Yust, I., Turner, D., Burke, M., Shahar, E., Elinav, H., Haouzi, M., Elbirt, D., Sthoeger, Z. M., D'Arminio Monforte, A., Esposito, R., Mazeu, I., Mussini, C., Mazzotta, F., Gabbuti, A., Vullo, V., Lichtner, M., Zaccarelli, M., Antinori, A., Acinapura, R., Plazzi, M., Castagna, A., Gianotti, N., Galli, M., Ridolfo, A., Rozentale, B., Uzdaviniene, V., Matulionyte, R., Staub, T., Hemmer, R., Ormaasen, V., Maeland, A., Bruun, J., Knysz, B., Gasiorowski, J., Inglot, M., Horban, A., Bakowska, E., Flisiak, R., Grzeszczuk, A., Parczewski, M., Pynka, M., Maciejewska, K., Mularska, E., Smiatacz, T., Gensing, M., Jablonowska, E., Malolepsza, E., Wojcik, K., Mozer-Lisewska, I., Caldeira, L., Mansinho, K., Maltez, F., Radoi, R., Panteleev, A., Panteleev, O., Yakovlev, A., Trofimora, T., Kuzovatova, E., Borodulina, E., Vdoushkina, E., Jevtovic, D., Tomazic, J., Gatell, J. M., Miro, J. M., Moreno, S., Rodriguez, J. M., Clotet, B., Jou, A., Tural, C., Puig, J., Bravo, I., Domingo, P., Gutierrez, M., Mateo, G., Sambeat, M. A., Laporte, J. M., Falconer, K., Thalme, A., Sonnerborg, A., Flamholc, L., Scherrer, A., Weber, R., Cavassini, M., Calmy, A., Furrer, H., Battegay, M., Kuznetsova, A., Kyselyova, G., Gazzard, B., Johnson, A. M., Simons, E., Edwards, S., Johnson, M. A., Mocroft, A., Weber, J., Scullard, G., Clarke, A., Leen, C., Gatell, J., Ledergerber, B., Kirk, O., Peters, L., Matthews, C., Fischer, A. H., Bojesen, A., Raben, D., Kristensen, D., Gronborg Laut, K., Larsen, J. F., Podlekareva, D., Shepherd, L., Schultze, A., Thiebaut, R., Burger, D., Santos, J. R., Cozzi-Lepri, A., Phillips, A., De Wit, S., Pedersen, C., Reiss, P., Blaxhult, A., Lazzarin, A., Sluzhynska, M., Orkin, C., Duvivier, C., Bogner, J., Gargalianos-Kakolyris, P., Schmid, P., Hassoun, G., Khromova, I., Beniowski, M., Hadziosmanovic, V., Sedlacek, D., Paredes, R., Lundgren, J. D., Castagna, A, on behalf of the EuroSIDA study, Group, AII - Infectious diseases, APH - Aging & Later Life, Infectious diseases, Global Health, and Amsterdam institute for Infection and Immunity

Subjects
Male, 0301 basic medicine, antiretroviral therapy-naïve patients, Lopinavir/ritonavir, darunavir, HIV Infections, Antiretroviral therapy-experienced patient, Gastroenterology, antiretroviral therapy-experienced patients, 0302 clinical medicine, atazanavir/ritonavir, darunavir/ritonavir, lopinavir/ritonavir, Adult, Anti-HIV Agents, Antiretroviral Therapy, Highly Active, Europe, Female, Humans, Middle Aged, Prospective Studies, Treatment Outcome, Pharmacology (medical), 030212 general & internal medicine, atazanavir, Antiretroviral therapy-naïve patient, Health Policy, Lopinavir, Antiretroviral Therapy, Highly Active/methods, ritonavir, Infectious Diseases, Viral load, medicine.drug, medicine.medical_specialty, HIV Infections/drug therapy, Infectious Disease, antiretroviral therapy-naive patients, 03 medical and health sciences, Internal medicine, medicine, Protease inhibitor (pharmacology), Darunavir, business.industry, 030112 virology, Atazanavir, lopinavir, Regimen, Anti-HIV Agents/therapeutic use, Ritonavir, business
Abstract

OBJECTIVES: The aim of the study was to evaluate the long-term response to antiretroviral treatment (ART) based on atazanavir/ritonavir (ATZ/r)-, darunavir/ritonavir (DRV/r)-, and lopinavir/ritonavir (LPV/r)-containing regimens.METHODS: Data were analysed for 5678 EuroSIDA-enrolled patients starting a DRV/r-, ATZ/r- or LPV/r-containing regimen between 1 January 2000 and 30 June 2013. Separate analyses were performed for the following subgroups of patients: (1) ART-naïve subjects (8%) at ritonavir-boosted protease inhibitor (PI/r) initiation; (2) ART-experienced individuals (44%) initiating the new PI/r with a viral load (VL) ≤500 HIV-1 RNA copies/mL; and (3) ART-experienced patients (48%) initiating the new PI/r with a VL >500 copies/mL. Virological failure (VF) was defined as two consecutive VL measurements >200 copies/mL ≥24 weeks after PI/r initiation. Kaplan-Meier and multivariable Cox models were used to compare risks of failure by PI/r-based regimen. The main analysis was performed with intention-to-treat (ITT) ignoring treatment switches.RESULTS: The time to VF favoured DRV/r over ATZ/r, and both were superior to LPV/r (log-rank test; P < 0.02) in all analyses. Nevertheless, the risk of VF in ART-naïve patients was similar regardless of the PI/r initiated after controlling for potential confounders. The risk of VF in both treatment-experienced groups was lower for DRV/r than for ATZ/r, which, in turn, was lower than for LPV/r-based ART.CONCLUSIONS: Although confounding by indication and calendar year cannot be completely ruled out, in ART-experienced subjects the long-term effectiveness of DRV/r-containing regimens appears to be greater than that of ATZ/r and LPV/r.

Published
2018

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

Author

Moutschen, M., Casadellà, M., van Ham, P. M., Noguera-Julian, M., van Kessel, A., Pou, C., Hofstra, Laura Marije Arije, Santos, J. R., Garcia, F., Struck, D., Alexiev, Ivailo, Bakken Kran, A. M., Hoepelman, A. I., Kostrikis, Leontios G., Somogyi, Sybille, Liitsola, K., Linka, M., Nielsen, C., Otelea, D., Paraskevis, Dimitrios N., 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., Sarcletti, M., Schmied, B., Geit, M., Balluch, G., Vandamme, A. M., Vercauteren, J., Derdelinckx, I., Sasse, A., Bogaert, M., Ceunen, H., De Roo, A., De Wit, S., Echahidi, F., Fransen, K., Goffard, J. C., Goubau, P., Goudeseune, E., Yombi, J. C., Lacor, P., Liesnard, C., Pierard, D., Rens, R., Schrooten, Y., Vaira, D., Vandekerckhove, L. P., Van den Heuvel, A., Van Der Gucht, B., Van Ranst, M., Van Wijngaerden, E., Vandercam, B., Vekemans, M., Verhofstede, C., Clumeck, N., Beshkov, Danail, Begovac, J., Demetriades, Ioannis, Kousiappa, Ioanna, Demetriou, Victoria L., Hezka, Johana, Machala, L., Maly, M., Jørgensen, L. B., Gerstoft, J., Mathiesen, L., Pedersen, C., Nielsen, H., Laursen, A., Kvinesdal, B., Ristola, M., Suni, J., Sutinen, J., Hamouda, O., 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, Angelos E., Magiorkinis, Emmanouil N., Hatzitheodorou, Eleni, Haida, Catherine, Zavitsanou, Assimina, Magiorkinis, Gkikas, Lazanas, Marios C., Chini, Maria C., Magafas, N., Tsogas, Nickolaos, Paparizos, Vassilios A., Kourkounti, Sofia, Antoniadou, Anastasia C., Papadopoulos, Antonios I., Panagopoulos, Periklis, Poulakou, Garyphallia G., Sakka, V., Chryssos, Georgios, Drimis, Stylianos, Gargalianos, Panagiotis, Lelekis, Moyssis I., Chilomenos, G., Psichogiou, Mina A., Daikos, George L., Sabatakou, H., Panos, George, Haratsis, G., Kordossis, Theodore, Kontos, Athanasios N., Koratzanis, Georgios, Theodoridou, Maria C., Mostrou, Glykeria J., Spoulou, Vana I., Schmit, J. C., Hemmer, R., Arendt, V., Staub, T., Schneider, F., Roman, F., Wensing, A. M., Boucher, C. A., van de Vijver, D. A., van, P. H., Brinkman, K., Op de, E. L., van der Ende, M. E., Hoepelman, I. M., van Kasteren, M., Juttmann, J., Kuipers, M., Langebeek, N., Richter, C., Santegoets, R. M., Schrijnders-Gudde, L., Schuurman, R., van de Ven, B. J., Åsjö, Birgitta, Bakken, A. M., Ormaasen, V., Aavitsland, P., Paraschiv, S., Tudor, A. M., Jevtovic, D., Salemovic, D., Stanekova, D., Habekova, M., Mokráš, Miloš, Truska, P., Lunar, M., Babic, Dunja Z., Tomazic, J., Vidmar, L., Vovko, T., Karner, P., Domingo, P., Galindo, M. J., Miralles, C., Del, M. A., Ribera, E., Iribarren, J. A., Ruiz, L., de la Torre, J., Vidal, F., Kostrikis, Leontios G. [0000-0002-5340-7109], and Paraskevis, Dimitrios [0000-0001-6167-7152]

Subjects
sequence analysis, genotype, Human immunodeficiency virus 1, HIV Infections, RNA directed DNA polymerase inhibitor, integrase strand transfer inhibitor, HIV Integrase, molecular epidemiology, Human immunodeficiency virus prevalence, Risk Factors, Antiretroviral Therapy, Highly Active, genetic variability, genetics, Stanford HIVdb score, clinical trial, Human immunodeficiency virus infected patient, highly active antiretroviral therapy, Viral Load, unclassified drug, virology, health survey, dolutegravir, Europe, female, risk factor, Population Surveillance, virus gene, raltegravir, amino acid substitution, p31 integrase protein, Human immunodeficiency virus 1, DNA sequence, gene sequence, Article, male, antiviral resistance, Drug Resistance, Viral, proteinase inhibitor, Humans, cross-sectional study, controlled study, human, HIV Integrase Inhibitors, quality control, scoring system, CD4 lymphocyte count, integrase inhibitor, Sequence Analysis, DNA, virus load, nonnucleoside reverse transcriptase inhibitor, Human immunodeficiency virus 1 infection, major clinical study, drug efficacy, Cross-Sectional Studies, multicenter study, drug effects, genetic variation, HIV-1, integrase
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 InSTIresistant 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 InSTIswere detected. Eleven (4%) subjects hadmutations at resistance-associated positions with an HIVdb score =10. Of the 56 samples successfully analysed with 454 sequencing, no InSTI signature mutationsweredetected, whereas integrase substitutionswithanHIVdbscore=10were found in8(14.3%) individuals. Conclusions:No signature InSTI-resistant variantswere circulating in Europe before the introduction of InSTIs. However, polymorphisms contributing to InSTI resistancewere 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. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. 70 2885 2888 Cited By :15

Published
2015

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

Author

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, and UCL - (SLuc) Service de médecine interne générale

Subjects
DOLUTEGRAVIR, Male, HIV-1 INFECTION, Genotype, HIV Infections, HIV Integrase, Risk Factors, Antiretroviral Therapy, Highly Active, Drug Resistance, Viral, Humans, Pharmacology (medical), HIV Integrase Inhibitors, ELVITEGRAVIR, Pharmacology, MUTATIONS, RALTEGRAVIR, Genetic Variation, Sequence Analysis, DNA, Viral Load, CD4 Lymphocyte Count, Europe, Infectious Diseases, Cross-Sectional Studies, Population Surveillance, HIV-1, Female
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

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

Author

Casadella, 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., Kran, A. M. Bakken, Hoepelman, A. I., Kostrikis, L. G., Somogyi, S., Liitsola, K., Linka, M., Nielsen, C., Otelea, D., Paraskevis, D., and Poljak, M.

Subjects
HIV infection epidemiology, COMPARATIVE studies, DRUG resistance in microorganisms, GENETICS, HIV, HIV infections, RESEARCH methodology, MEDICAL cooperation, PROTEINS, PUBLIC health surveillance, RESEARCH, VIRAL load, EVALUATION research, HIGHLY active antiretroviral therapy, CROSS-sectional method, ANTI-HIV agents, CD4 lymphocyte count, HIV integrase inhibitors, SEQUENCE analysis, GENOTYPES, PHARMACODYNAMICS, THERAPEUTICS
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. [ABSTRACT FROM AUTHOR]

Published
2015
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