Charlotte Charpentier1, Guinevere Q Lee2, Christophe Rodriguez3, Benoit Visseaux4, Alexandre Storto5, Catherine Fagard6, Jean-Michel Molina7, Christine Katlama8, Yazdan Yazdanpanah9, P Richard Harrigan2, Diane Descamps4. 1. INSERM, IAME, UMR 1137, F-75018 Paris, France Université Paris Diderot, IAME, UMR 1137, Sorbonne Paris Cité, F-75018 Paris, France AP-HP, Hôpital Bichat-Claude Bernard, Laboratoire de Virologie, F-75018 Paris, France charlotte.charpentier@bch.aphp.fr. 2. BC Centre for Excellence in HIV/AIDS, Vancouver, BC, Canada University of British Columbia, Vancouver, BC, Canada. 3. Department of Virology, Hôpital Henri Mondor, Université Paris-Est, Créteil, France INSERM U955 Team 18, Créteil, France. 4. INSERM, IAME, UMR 1137, F-75018 Paris, France Université Paris Diderot, IAME, UMR 1137, Sorbonne Paris Cité, F-75018 Paris, France AP-HP, Hôpital Bichat-Claude Bernard, Laboratoire de Virologie, F-75018 Paris, France. 5. AP-HP, Hôpital Bichat-Claude Bernard, Laboratoire de Virologie, F-75018 Paris, France. 6. INSERM, ISPED, Centre INSERM U897-Epidemiologie-Biostatistique, F-33000 Bordeaux, France Université Bordeaux, ISPED, Centre INSERM U897-Epidemiologie-Biostatistique, F-33000 Bordeaux, France. 7. AP-HP, Hôpital Saint-Louis, Service de Maladies Infectieuses et Tropicales, INSERM U941, Université Paris Diderot, Paris, France. 8. AP-HP, Hôpital de la Pitié-Salpétrière, Service de Maladies Infectieuses et Tropicales, F-75013 Paris, France. 9. INSERM, IAME, UMR 1137, F-75018 Paris, France Université Paris Diderot, IAME, UMR 1137, Sorbonne Paris Cité, F-75018 Paris, France AP-HP, Hôpital Bichat, Service de Maladies Infectieuses et Tropicales, F-75018 Paris, France.
Abstract
OBJECTIVES: To assess the prevalence of minority resistant variants (MRVs) at baseline and their impact on the virological response. The ANRS 139 TRIO trial evaluated the combination of raltegravir, etravirine and darunavir, plus an optimized background therapy, in 87% of cases. Patients were highly experienced and harboured multiresistant viruses, but were naive to the three drugs, and showed a high level of virological suppression. METHODS: Ultra-deep sequencing of reverse transcriptase, protease and integrase regions was performed at the trial baseline, and sequences were interpreted according to the ANRS algorithm. MRVs were assessed using MiSeq and 454 technologies (limit of detection 1%). RESULTS: At baseline, minority variants with at least one NRTI, one NNRTI, one PI, one major PI or an integrase inhibitor resistance-associated mutation were present in 46%, 45%, 68%, 24% and 13% of patients, respectively. When minority variants are taken into account, the prevalence of resistance to etravirine, darunavir and raltegravir at baseline was 29%, 40% and 9%, respectively. No difference was observed in the prevalence of MRVs between patients with virological failure and those with virological success, except a trend for patients exhibiting baseline etravirine MRVs (50% versus 26%, P = 0.09). CONCLUSIONS: We have shown a high level of MRVs at baseline in highly pre-treated patients harbouring multiresistant viruses. However, these MRVs were not associated with an increased risk of virological failure, except for a trend for etravirine MRVs.
OBJECTIVES: To assess the prevalence of minority resistant variants (MRVs) at baseline and their impact on the virological response. The ANRS 139 TRIO trial evaluated the combination of raltegravir, etravirine and darunavir, plus an optimized background therapy, in 87% of cases. Patients were highly experienced and harboured multiresistant viruses, but were naive to the three drugs, and showed a high level of virological suppression. METHODS: Ultra-deep sequencing of reverse transcriptase, protease and integrase regions was performed at the trial baseline, and sequences were interpreted according to the ANRS algorithm. MRVs were assessed using MiSeq and 454 technologies (limit of detection 1%). RESULTS: At baseline, minority variants with at least one NRTI, one NNRTI, one PI, one major PI or an integrase inhibitor resistance-associated mutation were present in 46%, 45%, 68%, 24% and 13% of patients, respectively. When minority variants are taken into account, the prevalence of resistance to etravirine, darunavir and raltegravir at baseline was 29%, 40% and 9%, respectively. No difference was observed in the prevalence of MRVs between patients with virological failure and those with virological success, except a trend for patients exhibiting baseline etravirine MRVs (50% versus 26%, P = 0.09). CONCLUSIONS: We have shown a high level of MRVs at baseline in highly pre-treated patients harbouring multiresistant viruses. However, these MRVs were not associated with an increased risk of virological failure, except for a trend for etravirine MRVs.
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