Emerging resistance mutations in PI-naive patients failing an atazanavir-based regimen (ANRS multicentre observational study)

Emerging resistance mutations in PI-naive patients failing an atazanavir-based regimen (ANRS... Abstract Background Atazanavir is a PI widely used as a third agent in combination ART. We aimed to determine the prevalence and the patterns of resistance in PI-naive patients failing on an atazanavir-based regimen. Methods We analysed patients failing on an atazanavir-containing regimen used as a first line of PI therapy. We compared the sequences of reverse transcriptase and protease before the introduction of atazanavir and at failure [two consecutive viral loads (VLs) >50 copies/mL]. Resistance was defined according to the 2014 Agence Nationale de Recherche sur le SIDA et les Hépatites Virales (ANRS) algorithm. Results Among the 113 patients, atazanavir was used in the first regimen in 71 (62.8%) patients and in the first line of a PI-based regimen in 42 (37.2%). Atazanavir was boosted with ritonavir in 95 (84.1%) patients and combined with tenofovir/emtricitabine or lamivudine (n = 81) and abacavir/lamivudine or emtricitabine (n = 22). At failure, median VL was 3.05 log10 copies/mL and the median CD4+ T cell count was 436 cells/mm3. The median time on atazanavir was 21.2 months. At failure, viruses were considered resistant to atazanavir in four patients (3.5%) with the selection of the following major atazanavir-associated mutations: I50L (n = 1), I84V (n = 2) and N88S (n = 1). Other emergent PI mutations were L10V, G16E, K20I/R, L33F, M36I/L, M46I/L, G48V, F53L, I54L, D60E, I62V, A71T/V, V82I/T, L90M and I93L/M. Emergent NRTI substitutions were detected in 21 patients: M41L (n = 2), D67N (n = 3), K70R (n = 1), L74I/V (n = 3), M184V/I (n = 16), L210W (n = 1), T215Y/F (n = 3) and K219Q/E (n = 2). Conclusions Resistance to atazanavir is rare in patients failing the first line of an atazanavir-based regimen according to the ANRS. Emergent NRTI resistance-associated mutations were reported in 18% of patients. Introduction Although many antiretroviral drugs have been developed, PIs remain the treatment of choice for HIV-1 therapy because their exceptionally high potency means that the emergence of antiretroviral resistance is rare.1 Indeed when administered with low doses of ritonavir, PIs offer a high genetic barrier against the selection of drug-resistant variants of HIV and are therefore especially reliable options for patients for whom poor antiretroviral adherence is anticipated.2,3 Based on high rates of discontinuation owing to adverse events among patients treated with atazanavir/ritonavir in ACTG 5257 (a randomized trial comparing the efficacy of atazanavir/ritonavir-, darunavir/ritonavir- and raltegravir-based therapy),4 atazanavir/ritonavir was reclassified as an ‘alternative’ to darunavir/ritonavir in the most recent iteration of the European5 and French guidelines,6 and in the Department of Health and Human Services (DHHS) guidelines in certain clinical situations.7 However, boosted atazanavir combined with tenofovir/emtricitabine or tenofovir/lamivudine or abacavir/lamivudine remains recommended as the initial ART in pregnant women in DHHS perinatal guidelines.8 Atazanavir nevetheless remains widely used as a third agent in combination ART. Indeed, atazanavir is a potent, well-tolerated, once-daily PI with a resistance profile that is generally different to that of other drugs in the same class.9,10 Atazanavir boosted with ritonavir is more potent, with the ability to treat infection caused by resistant HIV-1 strains without causing significant toxicity.11 Therefore, we aimed to determine emergent resistance mutations in the protease and reverse transcriptase (RT) genes and to describe mutational patterns of resistance in PI-naive patients failing an atazanavir-based regimen in a real-life clinical setting over a follow-up period of 10 years. Methods Between the years 2005 and 2015, a national multicentre observational retrospective study was conducted in France involving patients exhibiting virological failure with a boosted or unboosted atazanavir-based regimen. All 17 participating laboratories belong to the Agence Nationale de Recherche sur le SIDA et les Hépatites Virales (ANRS) AC11 network. Patients were defined as failing on atazanavir/ritonavir or atazanavir when two consecutive >50 copies/mL HIV-1 viral loads (VLs) were measured. We analysed 190 genotypic tests from patients failing on an atazanavir-containing regimen used as a first line of PI therapy. Genotype results were available both at failure and before atazanavir or atazanavir/ritonavir initiation for 113 patients. In this group, we compared the sequences of RT and protease genes before the introduction of atazanavir and at failure. In accordance with the 2014 ANRS list,12 a resistance mutation was considered to be selected if it was not present in previous genotypes. Drug resistance was defined according to the 2014 ANRS algorithm and the genotypic susceptibility score (GSS) of treatment at baseline was calculated on antiretrovirals currently available (n = 18) as follows: 1 for a susceptible drug, and 0 for a resistant or possibly resistant drug. Major atazanavir-associated resistance mutations—I50L, M84V, N88S—were defined according to the IAS-USA list.13 The following factors associated with selection of at least one PI resistance mutation were studied: age, gender, prior ART, subtypes, baseline HIV-1 VL, baseline CD4, associated antiretrovirals, baseline GSS, ART duration, first line of ART or first line of PI therapy, boosted atazanavir or not, and the presence of an RT M184I/V mutation at baseline. Statistical analysis Quantitative variables were summarized by means of median and IQR and discrete variables by sample size and percentage. Comparisons between groups were performed using either exact Fisher or Kruskal–Wallis tests. The analysis was done with SAS (version 9.4). Results Since 2005, from 17 ANRS centres we have recorded 3197 patients treated with an atazanavir-containing regimen used as the first line of PI treatment (associated with two NRTIs) (no available data for one centre). Among these patients, 558 (17.4%) experienced virological failure, and genotypic data at failure were available for 190 of them (34.1%). We studied the selection of resistance mutation in a group of 113 patients who had available genotypes both at baseline and at failure. In this group, atazanavir was used in the first regimen for 71 (62.8%) patients and in the first line of a PI-based regimen for 42 (37.2%) (Table 1). Atazanavir was boosted with ritonavir in 95 (84.1%) patients and combined with tenofovir/lamivudine or emtricitabine (n = 81, 71.7%) and abacavir/lamivudine or emtricitabine (n = 22, 19.5%). At failure, the median VL was 3.05 log10 copies/mL and the median CD4+ T cell count was 436 cells/mm3. The median time on atazanavir was 22 months. Fifty-one percent of patients were infected with subtype B virus. Another 77 patients for whom only genotype at failure was available showed similar characteristics (data not shown). Table 1. Characteristics of patients at failure (N = 113) Male, n (%)  82 (72.6)  Age (years), median (IQR)  44 (37–52)  CD4+ cell count (cells/mm3), median (IQR)  436 (289–639)  Plasma HIV-1 VL (log 10 copies/mL), median (IQR)  3.05 (2.50–4.02)  Duration of ART (months), median (IQR)  25 (10–67)  Duration of atazanavir treatment (months), median (IQR)  22 (10–35)  Patients with boosted atazanavir, n (%)  95 (84.1)  Subtype B, n (%)  58 (51.3)  First line of ART, n (%)  71 (62.8)  First line of PI therapy, n (%)  42 (37.2)  NRTI backbone, n (%)     abacavir/lamivudine or emtricitabine  22 (19.5)   tenofovir/lamivudine or emtricitabine  81 (71.7)  Baseline resistance or possible resistance to at least one NRTI, n (%)  20 (17.7)  M184I/V at baseline, n (%)  14 (12.4)  Male, n (%)  82 (72.6)  Age (years), median (IQR)  44 (37–52)  CD4+ cell count (cells/mm3), median (IQR)  436 (289–639)  Plasma HIV-1 VL (log 10 copies/mL), median (IQR)  3.05 (2.50–4.02)  Duration of ART (months), median (IQR)  25 (10–67)  Duration of atazanavir treatment (months), median (IQR)  22 (10–35)  Patients with boosted atazanavir, n (%)  95 (84.1)  Subtype B, n (%)  58 (51.3)  First line of ART, n (%)  71 (62.8)  First line of PI therapy, n (%)  42 (37.2)  NRTI backbone, n (%)     abacavir/lamivudine or emtricitabine  22 (19.5)   tenofovir/lamivudine or emtricitabine  81 (71.7)  Baseline resistance or possible resistance to at least one NRTI, n (%)  20 (17.7)  M184I/V at baseline, n (%)  14 (12.4)  Table 1. Characteristics of patients at failure (N = 113) Male, n (%)  82 (72.6)  Age (years), median (IQR)  44 (37–52)  CD4+ cell count (cells/mm3), median (IQR)  436 (289–639)  Plasma HIV-1 VL (log 10 copies/mL), median (IQR)  3.05 (2.50–4.02)  Duration of ART (months), median (IQR)  25 (10–67)  Duration of atazanavir treatment (months), median (IQR)  22 (10–35)  Patients with boosted atazanavir, n (%)  95 (84.1)  Subtype B, n (%)  58 (51.3)  First line of ART, n (%)  71 (62.8)  First line of PI therapy, n (%)  42 (37.2)  NRTI backbone, n (%)     abacavir/lamivudine or emtricitabine  22 (19.5)   tenofovir/lamivudine or emtricitabine  81 (71.7)  Baseline resistance or possible resistance to at least one NRTI, n (%)  20 (17.7)  M184I/V at baseline, n (%)  14 (12.4)  Male, n (%)  82 (72.6)  Age (years), median (IQR)  44 (37–52)  CD4+ cell count (cells/mm3), median (IQR)  436 (289–639)  Plasma HIV-1 VL (log 10 copies/mL), median (IQR)  3.05 (2.50–4.02)  Duration of ART (months), median (IQR)  25 (10–67)  Duration of atazanavir treatment (months), median (IQR)  22 (10–35)  Patients with boosted atazanavir, n (%)  95 (84.1)  Subtype B, n (%)  58 (51.3)  First line of ART, n (%)  71 (62.8)  First line of PI therapy, n (%)  42 (37.2)  NRTI backbone, n (%)     abacavir/lamivudine or emtricitabine  22 (19.5)   tenofovir/lamivudine or emtricitabine  81 (71.7)  Baseline resistance or possible resistance to at least one NRTI, n (%)  20 (17.7)  M184I/V at baseline, n (%)  14 (12.4)  At failure, virus-selected resistance mutation to atazanavir/ritonavir was seen in 4/113 patients (3.5%) with the ANRS algorithm with the selection of major atazanavir-associated resistance mutations: I50L (n = 1), I84V (n = 2) and N88S (n = 1). Other emergent PI mutations (L10V, G16E, K20I/R, L33F, M36I/L, M46I/L, G48V, F53L, I54L, D60E, I62V, A71T/V, V82I/T, L90M and I93L/M) were selected in 15 patients (4 presenting major atazanavir-associated mutations). Emergent NRTI substitutions were seen in 21 patients: M41L (n = 2), D67N (n = 3), K70R (n = 1), L74I/V (n = 3), M184V/I (n = 16), L210W (n = 1), T215Y/F (n = 3) and K219Q/E (n = 2). In summary, we showed selection of NRTI and/or PI resistance mutations in viruses of 29 out of 113 patients (25.7%), whose characteristics are described in Table 2. Table 2. Therapeutic and virological characteristics of the 29 patients with emergence of resistance mutations Patient  ART exposure  Time to failure (months)  VL at failure (copies/mL)  Emergent mutations at virological failure   RT  PI  1  first line  16.1  54    M36I, I62V  2  experienced  24.8  160  L74I    3  first line  no data  234  M41L    4a  experienced  46.6  125  M184V    5  first line  33.8  415  D67N, K70R, M184V, L210W    6  experienced  32.2  414  D67N, M184V  L33F, F53L, I54L, D60E, A71V, V82T, I84V, L90M  7  first line  39.8  479  M184I    8  first line  10.8  501  M184I    9  first line  6.0  562  M184I    10  first line  34.2  636    M36L  11  first line  4.6  769  M184V    12  first line  66.7  800  M184I  M36L  13  first line  2.9  831  M184V, M184I    14  experienced  44.6  921  K219Q  A71V  15  experienced  45.8  1000  L74V  L10V, A71V  16  experienced  6.7  1086  M184V    17  first line  9.8  1949  M184I  I93M  18  experienced  8.0  2085  M184V    19  first line  23.3  2155    I62V  20  experienced  29.8  2357    M36L, V82I  21  experienced  48.4  3810  M184V    22  experienced  21.2  4603  L74V, M184V    23  experienced  20.5  5790    D60E  24  first line  23.3  6684  M184V, T215F  L33F, I50L  25a  experienced  65.7  6948    G16E  26  first line  27.6  9135    K20I  27  first line  6.2  37 000  D67N, M184V, T215F, K219E  K20R, M36I, G48V, I54L I62V, A71V, G73T, V82T, I84V, I93L  28  experienced  22.8  43 000  M41L, T215Y    29  first line  6.5  232 200    M46I, A71T, N88S  Patient  ART exposure  Time to failure (months)  VL at failure (copies/mL)  Emergent mutations at virological failure   RT  PI  1  first line  16.1  54    M36I, I62V  2  experienced  24.8  160  L74I    3  first line  no data  234  M41L    4a  experienced  46.6  125  M184V    5  first line  33.8  415  D67N, K70R, M184V, L210W    6  experienced  32.2  414  D67N, M184V  L33F, F53L, I54L, D60E, A71V, V82T, I84V, L90M  7  first line  39.8  479  M184I    8  first line  10.8  501  M184I    9  first line  6.0  562  M184I    10  first line  34.2  636    M36L  11  first line  4.6  769  M184V    12  first line  66.7  800  M184I  M36L  13  first line  2.9  831  M184V, M184I    14  experienced  44.6  921  K219Q  A71V  15  experienced  45.8  1000  L74V  L10V, A71V  16  experienced  6.7  1086  M184V    17  first line  9.8  1949  M184I  I93M  18  experienced  8.0  2085  M184V    19  first line  23.3  2155    I62V  20  experienced  29.8  2357    M36L, V82I  21  experienced  48.4  3810  M184V    22  experienced  21.2  4603  L74V, M184V    23  experienced  20.5  5790    D60E  24  first line  23.3  6684  M184V, T215F  L33F, I50L  25a  experienced  65.7  6948    G16E  26  first line  27.6  9135    K20I  27  first line  6.2  37 000  D67N, M184V, T215F, K219E  K20R, M36I, G48V, I54L I62V, A71V, G73T, V82T, I84V, I93L  28  experienced  22.8  43 000  M41L, T215Y    29  first line  6.5  232 200    M46I, A71T, N88S  Bold formatting indicates major atazanavir-associated mutations according to the IAS-USA list,13 and underlining indicates A71V. a Received unboosted atazanavir. Table 2. Therapeutic and virological characteristics of the 29 patients with emergence of resistance mutations Patient  ART exposure  Time to failure (months)  VL at failure (copies/mL)  Emergent mutations at virological failure   RT  PI  1  first line  16.1  54    M36I, I62V  2  experienced  24.8  160  L74I    3  first line  no data  234  M41L    4a  experienced  46.6  125  M184V    5  first line  33.8  415  D67N, K70R, M184V, L210W    6  experienced  32.2  414  D67N, M184V  L33F, F53L, I54L, D60E, A71V, V82T, I84V, L90M  7  first line  39.8  479  M184I    8  first line  10.8  501  M184I    9  first line  6.0  562  M184I    10  first line  34.2  636    M36L  11  first line  4.6  769  M184V    12  first line  66.7  800  M184I  M36L  13  first line  2.9  831  M184V, M184I    14  experienced  44.6  921  K219Q  A71V  15  experienced  45.8  1000  L74V  L10V, A71V  16  experienced  6.7  1086  M184V    17  first line  9.8  1949  M184I  I93M  18  experienced  8.0  2085  M184V    19  first line  23.3  2155    I62V  20  experienced  29.8  2357    M36L, V82I  21  experienced  48.4  3810  M184V    22  experienced  21.2  4603  L74V, M184V    23  experienced  20.5  5790    D60E  24  first line  23.3  6684  M184V, T215F  L33F, I50L  25a  experienced  65.7  6948    G16E  26  first line  27.6  9135    K20I  27  first line  6.2  37 000  D67N, M184V, T215F, K219E  K20R, M36I, G48V, I54L I62V, A71V, G73T, V82T, I84V, I93L  28  experienced  22.8  43 000  M41L, T215Y    29  first line  6.5  232 200    M46I, A71T, N88S  Patient  ART exposure  Time to failure (months)  VL at failure (copies/mL)  Emergent mutations at virological failure   RT  PI  1  first line  16.1  54    M36I, I62V  2  experienced  24.8  160  L74I    3  first line  no data  234  M41L    4a  experienced  46.6  125  M184V    5  first line  33.8  415  D67N, K70R, M184V, L210W    6  experienced  32.2  414  D67N, M184V  L33F, F53L, I54L, D60E, A71V, V82T, I84V, L90M  7  first line  39.8  479  M184I    8  first line  10.8  501  M184I    9  first line  6.0  562  M184I    10  first line  34.2  636    M36L  11  first line  4.6  769  M184V    12  first line  66.7  800  M184I  M36L  13  first line  2.9  831  M184V, M184I    14  experienced  44.6  921  K219Q  A71V  15  experienced  45.8  1000  L74V  L10V, A71V  16  experienced  6.7  1086  M184V    17  first line  9.8  1949  M184I  I93M  18  experienced  8.0  2085  M184V    19  first line  23.3  2155    I62V  20  experienced  29.8  2357    M36L, V82I  21  experienced  48.4  3810  M184V    22  experienced  21.2  4603  L74V, M184V    23  experienced  20.5  5790    D60E  24  first line  23.3  6684  M184V, T215F  L33F, I50L  25a  experienced  65.7  6948    G16E  26  first line  27.6  9135    K20I  27  first line  6.2  37 000  D67N, M184V, T215F, K219E  K20R, M36I, G48V, I54L I62V, A71V, G73T, V82T, I84V, I93L  28  experienced  22.8  43 000  M41L, T215Y    29  first line  6.5  232 200    M46I, A71T, N88S  Bold formatting indicates major atazanavir-associated mutations according to the IAS-USA list,13 and underlining indicates A71V. a Received unboosted atazanavir. At failure, of the 190 available genotypes, 103 patients (54.2%) presented a virus with at least one PI resistance mutation, and 65 patients (34.2%) with at least one RT resistance mutation (23.8% and 19.3% with an NRTI and/or an NNRTI resistance mutation, respectively). The percentage of patients harbouring a virus resistant to atazanavir/ritonavir was 3.7% (which was in accordance with our result of 3.5% in 113 patients); no patients harboured a virus resistant to darunavir/ritonavir. The percentage of patients harbouring virus resistant to abacavir, tenofovir and lamivudine or emtricitabine was 4.3%, 0.5% and 21.5%, respectively. Factors associated with the selection of at least one PI resistance mutation (according to the 2014 ANRS algorithm) were having taken zidovudine (P = 0.05) and didanosine (P = 0.02) in previous treatment, and having taken abacavir associated with an atazanavir-containing regimen (P = 0.02). Having M184I/V at baseline did not affect the selection of a PI resistance mutation at failure. Discussion Our retrospective study analysed over 10 years of resistance in PI-naive patients failing on an atazanavir-based regimen. In this French cohort, virological failure, defined as two consecutive VLs >50 copies/mL, occurred with 17.4% of patients, confirming previous findings from atazanavir/ritonavir clinical trials.14–16 At failure, 25.7% of our patients presented a virus with NRTI and PI resistance mutations, but only 3.5% selected major PI mutations to atazanavir/ritonavir: I50L (n = 1), I84V (n = 2) and N88S (n = 1); 23.8% selected NRTI mutations (M184I/V, n = 16). In the CASTLE clinical trial,15 6% of virological failures occurred in the atazanavir/ritonavir arm. Two patients taking atazanavir/ritonavir showed emergence of non-polymorphic PI resistance mutations on treatment. In one patient, the N88S substitution, associated with atazanavir resistance, emerged. The second patient receiving atazanavir/ritonavir with emergent non-polymorphic PI resistance mutations had six PI mutations at baseline, and rebounded rapidly at week 24 after suppression to an HIV RNA of <50 copies/mL. Our proportion of virological failure (17.4%) is also concordant with an observational European cohort based on 517 patients.17 Indeed, in that earlier study 85 (16.4%) patients presented virological failure and 9 of them (22.4%) had treatment-emergent minor PI resistance mutations, but contrary to our study no patient had treatment-emergent major PI resistance mutations. The ACTG 5257 study4 showed similar results: in the atazanavir arm, 95 patients (16%) presented a virological failure without PI resistance detected, and NRTI resistance was detected in 8 patients (10.8%). Our study focused on mutation both at failure and before atazanavir or atazanavir/ritonavir initiation, and permitted both described and undescribed mutations to be highlighted. We showed the occurrence of new selected substitutions (A71V/T) in 5 patients among the 29 virological failures with resistance. After several months of culture, in atazanavir-resistant variants, the mutation A71V was selected in vitro in association with other mutations.18 In the CASTLE study, one patient in the atazanavir/ritonavir group had major and minor PI emerging substitutions and ultimately failed at week 67. This patient had baseline T12A/S, I13I/V, M36I, N37D, I62V, L63P, A71A/T, I72V and I93L, with an atazanavir fold change of 0.78.14 In an unplanned atazanavir-based treatment interruption, one A71V and one A71I were selected among emergent resistance mutations.19 In conclusion, development of atazanavir resistance is low (3.5%) in patients failing the first line of an atazanavir-based regimen, and all patients remained susceptible to darunavir/ritonavir. In this population of naive and NRTI-experienced patients, emergence of NRTI resistance in 14% of patients is not negligible. Evidence of new selected substitutions (A71V/T) in the protease gene with atazanavir/ritonavir-based ART has enabled the algorithms for the interpretation of French ANRS atazanavir/ritonavir resistance to be updated to 2015.12 Acknowledgements Members of the ANRS AC-11 Resistance Group Paris area Avicenne: Chakib Alloui; Bichat: Diane Descamps, Charlotte Charpentier, Benoit Visseaux; Cochin: Anne Krivine; Henri Mondor: Magali Bouviers-Alias; Paul Brousse: Coralie Pallier; Pitié-Salpêtrière: Cathia Soulie, Marc Wirden, Anne-Genevieve Marcelin, Vincent Calvez; Saint-Antoine: Laurence Morand-Joubert, Sidonie Lambert-Niclot, Djeneba Fofana; Saint-Louis: Nadia Mahjoub, Constance Delaugerre, Marie-Laure Chaix; Tenon: Corinne Amiel, Veronique Schneider. Outside Paris area Amiens: Catherine Roussel; Angers: Helene Le Guillou-Guillemette; Argenteuil: Laurence Courdavault; Bordeaux: Sandrine Reigadas, Patricia Recordon-Pinson, Herve Fleury; Brest: Sophie Vallet; Caen: Julia Dina, Astrid Vabret; Clermont-Ferrand: Audrey Mirand, Cecile Henquell; Dijon: Christelle Auvray, Alexis De Rougemont, Helene Giraudon, Ali Si-Mohammed; Garches: Dominique Mathez; Grenoble: Anne Signori-Schmuck, Patrice Morand; Lille: Laurence Bocket; Lyon: Mary Anne Trabaud; Montpellier: Brigitte Montés; Nantes: Laura Le Guen, Audrey Rodallec, Virginie Ferre; Nancy: Helene Jeulin, Evelyne Schvoerer; Nice: Jacqueline Dufayard; Nîmes: Annick Allardet-Servent, Marie-Josee Carles; Orléans: Jerome Guinard, Aurelie Guigon; Poitiers: Genevieve Giraudeau, Agnes Beby-Defaux; Rennes: Anne Maillard; Rouen: Jean Christophe Plantier, Marie Leoz, Thomas Mourez; Saint-Etienne: Thomas Bourlet; Strasbourg: Samira Fafi-Kremer; Toulouse: Julie Chiabrando, Stephanie Raymond, Jacques Izopet; Tours: Francis Barin; Versailles: Stephanie Marque-Juillet. Switzerland Genève: Sabine Yerly. Funding The research leading to these results has received funding from the Agence Nationale de Recherches sur le SIDA et les Hépatites virales. Transparency declarations S. L.-N. has received travel grants from ViiV Healthcare. C. C., T. M. and D. D. have received honoraria and travel grants from ViiV Healthcare, Janssen-Cilag, Gilead Sciences and Merck Laboratories MSD. H. L. G.-G. has received honoraria from Gilead Sciences and Merck Laboratories MSD and research funding from Hologic. A. G. M. has received honoraria for advisories or invited talks or conferences and research grants from Abbvie Labs, Gilead Sciences, Merck Laboratories MSD, Janssen Pharmaceuticals and ViiV Healthcare. C. D. has received honoraria for collaboration from ViiV and Merck Laboratories MSD and scientist board participation from Gilead Sciences, Merck Laboratories MSD, Janssen Pharmaceuticals and ViiV Healthcare. L. M.-J. has received honoraria from BMS, Mylan, Gilead Sciences, Merck Laboratories MSD, Janssen Pharmaceuticals and ViiV Healthcare. All other authors: none to declare. References 1 Walmsley S. Protease inhibitor-based regimens for HIV therapy: safety and efficacy. J Acquir Immune Defic Syndr  2007; 45 Suppl 1: S5– 13; quiz S28–31. Google Scholar CrossRef Search ADS PubMed  2 Shuter J. Forgiveness of non-adherence to HIV-1 antiretroviral therapy. J Antimicrob Chemother  2008; 61: 769– 73. Google Scholar CrossRef Search ADS PubMed  3 Zeldin RK, Petruschke RA. Pharmacological and therapeutic properties of ritonavir-boosted protease inhibitor therapy in HIV-infected patients. J Antimicrob Chemother  2004; 53: 4– 9. Google Scholar CrossRef Search ADS PubMed  4 Lennox JL, Landovitz RJ, Ribaudo HJ et al.   A Phase III comparative study of the efficacy and tolerability of three non-nucleoside reverse transcriptase inhibitor-sparing antiretroviral regimens for treatment-naïve HIV-1-infected volunteers: a randomized, controlled trial. Ann Intern Med  2014; 161: 461– 71. Google Scholar CrossRef Search ADS PubMed  5 European AIDS Clinical Society Guidelines. http://www.eacsociety.org/files/guidelines_9.0-english.pdf. 6 Prise en Charge Médicale des Personnes Vivant Avec le VIH. Recommandations du Groupe d’Experts. Rapport 2013. http://www.sante.gouv.fr/IMG/pdf/Rapport_Morlat_2013_Mise_en_ligne.pdf. 7 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV. https://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf. 8 Recommendations for the Use of Antiretroviral Drugs in Pregnant Women with HIV Infection and Interventions to Reduce Perinatal HIV Transmission in the United States. https://aidsinfo.nih.gov/contentfiles/lvguidelines/PerinatalGL.pdf. 9 Colonno RJ, Thiry A, Limoli K et al.   Activities of atazanavir (BMS-232632) against a large panel of human immunodeficiency virus type 1 clinical isolates resistant to one or more approved protease inhibitors. Antimicrob Agents Chemother  2003; 47: 1324– 33. Google Scholar CrossRef Search ADS PubMed  10 Colonno R, Rose R, McLaren C et al.   Identification of I50L as the signature atazanavir (ATV)-resistance mutation in treatment-naive HIV-1-infected patients receiving ATV-containing regimens. J Infect Dis  2004; 189: 1802– 10. Google Scholar CrossRef Search ADS PubMed  11 Johnson M, Grinsztejn B, Rodriguez C et al.   Atazanavir plus ritonavir or saquinavir, and lopinavir/ritonavir in patients experiencing multiple virological failures. AIDS  2005; 19: 153– 62. Google Scholar CrossRef Search ADS PubMed  12 HIV French Resistance—HIV-1 Genotypic Drug Resistance Interpretation’s Algorithms. http://www.hivfrenchresistance.org/. 13 Wensing AM, Calvez V, Günthard HF et al.   2017 update of the drug resistance mutations in HIV-1. Top Antivir Med  2017; 24: 132– 3. Google Scholar PubMed  14 Molina J-M, Andrade-Villanueva J, Echevarria J et al.   Once-daily atazanavir/ritonavir compared with twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 96-week efficacy and safety results of the CASTLE study. J Acquir Immune Defic Syndr  2010; 53: 323– 32. Google Scholar CrossRef Search ADS PubMed  15 Molina J-M, Andrade-Villanueva J, Echevarria J et al.   Once-daily atazanavir/ritonavir versus twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 48 week efficacy and safety results of the CASTLE study. Lancet  2008; 372: 646– 55. Google Scholar CrossRef Search ADS PubMed  16 Daar ES, Tierney C, Fischl MA et al.   Atazanavir plus ritonavir or efavirenz as part of a 3-drug regimen for initial treatment of HIV-1. Ann Intern Med  2011; 154: 445– 56. Google Scholar CrossRef Search ADS PubMed  17 Teófilo E, Rocha-Pereira N, Kuhlmann B et al.   Long-term efficacy, tolerability, and renal safety of atazanavir/ritonavir-based antiretroviral therapy in a cohort of treatment-naïve patients with HIV-1 infection: the REMAIN study. HIV Clin Trials  2016; 17: 17– 28. Google Scholar CrossRef Search ADS PubMed  18 Gong YF, Robinson BS, Rose RE et al.   In vitro resistance profile of the human immunodeficiency virus type 1 protease inhibitor BMS-232632. Antimicrob Agents Chemother  2000; 44: 2319– 26. Google Scholar CrossRef Search ADS PubMed  19 Tinago W, O’Halloran JA, O’Halloran RM et al.   Characterization of associations and development of atazanavir resistance after unplanned treatment interruptions. HIV Med  2014; 15: 224– 32. Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com. 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© The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.
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Abstract

Abstract Background Atazanavir is a PI widely used as a third agent in combination ART. We aimed to determine the prevalence and the patterns of resistance in PI-naive patients failing on an atazanavir-based regimen. Methods We analysed patients failing on an atazanavir-containing regimen used as a first line of PI therapy. We compared the sequences of reverse transcriptase and protease before the introduction of atazanavir and at failure [two consecutive viral loads (VLs) >50 copies/mL]. Resistance was defined according to the 2014 Agence Nationale de Recherche sur le SIDA et les Hépatites Virales (ANRS) algorithm. Results Among the 113 patients, atazanavir was used in the first regimen in 71 (62.8%) patients and in the first line of a PI-based regimen in 42 (37.2%). Atazanavir was boosted with ritonavir in 95 (84.1%) patients and combined with tenofovir/emtricitabine or lamivudine (n = 81) and abacavir/lamivudine or emtricitabine (n = 22). At failure, median VL was 3.05 log10 copies/mL and the median CD4+ T cell count was 436 cells/mm3. The median time on atazanavir was 21.2 months. At failure, viruses were considered resistant to atazanavir in four patients (3.5%) with the selection of the following major atazanavir-associated mutations: I50L (n = 1), I84V (n = 2) and N88S (n = 1). Other emergent PI mutations were L10V, G16E, K20I/R, L33F, M36I/L, M46I/L, G48V, F53L, I54L, D60E, I62V, A71T/V, V82I/T, L90M and I93L/M. Emergent NRTI substitutions were detected in 21 patients: M41L (n = 2), D67N (n = 3), K70R (n = 1), L74I/V (n = 3), M184V/I (n = 16), L210W (n = 1), T215Y/F (n = 3) and K219Q/E (n = 2). Conclusions Resistance to atazanavir is rare in patients failing the first line of an atazanavir-based regimen according to the ANRS. Emergent NRTI resistance-associated mutations were reported in 18% of patients. Introduction Although many antiretroviral drugs have been developed, PIs remain the treatment of choice for HIV-1 therapy because their exceptionally high potency means that the emergence of antiretroviral resistance is rare.1 Indeed when administered with low doses of ritonavir, PIs offer a high genetic barrier against the selection of drug-resistant variants of HIV and are therefore especially reliable options for patients for whom poor antiretroviral adherence is anticipated.2,3 Based on high rates of discontinuation owing to adverse events among patients treated with atazanavir/ritonavir in ACTG 5257 (a randomized trial comparing the efficacy of atazanavir/ritonavir-, darunavir/ritonavir- and raltegravir-based therapy),4 atazanavir/ritonavir was reclassified as an ‘alternative’ to darunavir/ritonavir in the most recent iteration of the European5 and French guidelines,6 and in the Department of Health and Human Services (DHHS) guidelines in certain clinical situations.7 However, boosted atazanavir combined with tenofovir/emtricitabine or tenofovir/lamivudine or abacavir/lamivudine remains recommended as the initial ART in pregnant women in DHHS perinatal guidelines.8 Atazanavir nevetheless remains widely used as a third agent in combination ART. Indeed, atazanavir is a potent, well-tolerated, once-daily PI with a resistance profile that is generally different to that of other drugs in the same class.9,10 Atazanavir boosted with ritonavir is more potent, with the ability to treat infection caused by resistant HIV-1 strains without causing significant toxicity.11 Therefore, we aimed to determine emergent resistance mutations in the protease and reverse transcriptase (RT) genes and to describe mutational patterns of resistance in PI-naive patients failing an atazanavir-based regimen in a real-life clinical setting over a follow-up period of 10 years. Methods Between the years 2005 and 2015, a national multicentre observational retrospective study was conducted in France involving patients exhibiting virological failure with a boosted or unboosted atazanavir-based regimen. All 17 participating laboratories belong to the Agence Nationale de Recherche sur le SIDA et les Hépatites Virales (ANRS) AC11 network. Patients were defined as failing on atazanavir/ritonavir or atazanavir when two consecutive >50 copies/mL HIV-1 viral loads (VLs) were measured. We analysed 190 genotypic tests from patients failing on an atazanavir-containing regimen used as a first line of PI therapy. Genotype results were available both at failure and before atazanavir or atazanavir/ritonavir initiation for 113 patients. In this group, we compared the sequences of RT and protease genes before the introduction of atazanavir and at failure. In accordance with the 2014 ANRS list,12 a resistance mutation was considered to be selected if it was not present in previous genotypes. Drug resistance was defined according to the 2014 ANRS algorithm and the genotypic susceptibility score (GSS) of treatment at baseline was calculated on antiretrovirals currently available (n = 18) as follows: 1 for a susceptible drug, and 0 for a resistant or possibly resistant drug. Major atazanavir-associated resistance mutations—I50L, M84V, N88S—were defined according to the IAS-USA list.13 The following factors associated with selection of at least one PI resistance mutation were studied: age, gender, prior ART, subtypes, baseline HIV-1 VL, baseline CD4, associated antiretrovirals, baseline GSS, ART duration, first line of ART or first line of PI therapy, boosted atazanavir or not, and the presence of an RT M184I/V mutation at baseline. Statistical analysis Quantitative variables were summarized by means of median and IQR and discrete variables by sample size and percentage. Comparisons between groups were performed using either exact Fisher or Kruskal–Wallis tests. The analysis was done with SAS (version 9.4). Results Since 2005, from 17 ANRS centres we have recorded 3197 patients treated with an atazanavir-containing regimen used as the first line of PI treatment (associated with two NRTIs) (no available data for one centre). Among these patients, 558 (17.4%) experienced virological failure, and genotypic data at failure were available for 190 of them (34.1%). We studied the selection of resistance mutation in a group of 113 patients who had available genotypes both at baseline and at failure. In this group, atazanavir was used in the first regimen for 71 (62.8%) patients and in the first line of a PI-based regimen for 42 (37.2%) (Table 1). Atazanavir was boosted with ritonavir in 95 (84.1%) patients and combined with tenofovir/lamivudine or emtricitabine (n = 81, 71.7%) and abacavir/lamivudine or emtricitabine (n = 22, 19.5%). At failure, the median VL was 3.05 log10 copies/mL and the median CD4+ T cell count was 436 cells/mm3. The median time on atazanavir was 22 months. Fifty-one percent of patients were infected with subtype B virus. Another 77 patients for whom only genotype at failure was available showed similar characteristics (data not shown). Table 1. Characteristics of patients at failure (N = 113) Male, n (%)  82 (72.6)  Age (years), median (IQR)  44 (37–52)  CD4+ cell count (cells/mm3), median (IQR)  436 (289–639)  Plasma HIV-1 VL (log 10 copies/mL), median (IQR)  3.05 (2.50–4.02)  Duration of ART (months), median (IQR)  25 (10–67)  Duration of atazanavir treatment (months), median (IQR)  22 (10–35)  Patients with boosted atazanavir, n (%)  95 (84.1)  Subtype B, n (%)  58 (51.3)  First line of ART, n (%)  71 (62.8)  First line of PI therapy, n (%)  42 (37.2)  NRTI backbone, n (%)     abacavir/lamivudine or emtricitabine  22 (19.5)   tenofovir/lamivudine or emtricitabine  81 (71.7)  Baseline resistance or possible resistance to at least one NRTI, n (%)  20 (17.7)  M184I/V at baseline, n (%)  14 (12.4)  Male, n (%)  82 (72.6)  Age (years), median (IQR)  44 (37–52)  CD4+ cell count (cells/mm3), median (IQR)  436 (289–639)  Plasma HIV-1 VL (log 10 copies/mL), median (IQR)  3.05 (2.50–4.02)  Duration of ART (months), median (IQR)  25 (10–67)  Duration of atazanavir treatment (months), median (IQR)  22 (10–35)  Patients with boosted atazanavir, n (%)  95 (84.1)  Subtype B, n (%)  58 (51.3)  First line of ART, n (%)  71 (62.8)  First line of PI therapy, n (%)  42 (37.2)  NRTI backbone, n (%)     abacavir/lamivudine or emtricitabine  22 (19.5)   tenofovir/lamivudine or emtricitabine  81 (71.7)  Baseline resistance or possible resistance to at least one NRTI, n (%)  20 (17.7)  M184I/V at baseline, n (%)  14 (12.4)  Table 1. Characteristics of patients at failure (N = 113) Male, n (%)  82 (72.6)  Age (years), median (IQR)  44 (37–52)  CD4+ cell count (cells/mm3), median (IQR)  436 (289–639)  Plasma HIV-1 VL (log 10 copies/mL), median (IQR)  3.05 (2.50–4.02)  Duration of ART (months), median (IQR)  25 (10–67)  Duration of atazanavir treatment (months), median (IQR)  22 (10–35)  Patients with boosted atazanavir, n (%)  95 (84.1)  Subtype B, n (%)  58 (51.3)  First line of ART, n (%)  71 (62.8)  First line of PI therapy, n (%)  42 (37.2)  NRTI backbone, n (%)     abacavir/lamivudine or emtricitabine  22 (19.5)   tenofovir/lamivudine or emtricitabine  81 (71.7)  Baseline resistance or possible resistance to at least one NRTI, n (%)  20 (17.7)  M184I/V at baseline, n (%)  14 (12.4)  Male, n (%)  82 (72.6)  Age (years), median (IQR)  44 (37–52)  CD4+ cell count (cells/mm3), median (IQR)  436 (289–639)  Plasma HIV-1 VL (log 10 copies/mL), median (IQR)  3.05 (2.50–4.02)  Duration of ART (months), median (IQR)  25 (10–67)  Duration of atazanavir treatment (months), median (IQR)  22 (10–35)  Patients with boosted atazanavir, n (%)  95 (84.1)  Subtype B, n (%)  58 (51.3)  First line of ART, n (%)  71 (62.8)  First line of PI therapy, n (%)  42 (37.2)  NRTI backbone, n (%)     abacavir/lamivudine or emtricitabine  22 (19.5)   tenofovir/lamivudine or emtricitabine  81 (71.7)  Baseline resistance or possible resistance to at least one NRTI, n (%)  20 (17.7)  M184I/V at baseline, n (%)  14 (12.4)  At failure, virus-selected resistance mutation to atazanavir/ritonavir was seen in 4/113 patients (3.5%) with the ANRS algorithm with the selection of major atazanavir-associated resistance mutations: I50L (n = 1), I84V (n = 2) and N88S (n = 1). Other emergent PI mutations (L10V, G16E, K20I/R, L33F, M36I/L, M46I/L, G48V, F53L, I54L, D60E, I62V, A71T/V, V82I/T, L90M and I93L/M) were selected in 15 patients (4 presenting major atazanavir-associated mutations). Emergent NRTI substitutions were seen in 21 patients: M41L (n = 2), D67N (n = 3), K70R (n = 1), L74I/V (n = 3), M184V/I (n = 16), L210W (n = 1), T215Y/F (n = 3) and K219Q/E (n = 2). In summary, we showed selection of NRTI and/or PI resistance mutations in viruses of 29 out of 113 patients (25.7%), whose characteristics are described in Table 2. Table 2. Therapeutic and virological characteristics of the 29 patients with emergence of resistance mutations Patient  ART exposure  Time to failure (months)  VL at failure (copies/mL)  Emergent mutations at virological failure   RT  PI  1  first line  16.1  54    M36I, I62V  2  experienced  24.8  160  L74I    3  first line  no data  234  M41L    4a  experienced  46.6  125  M184V    5  first line  33.8  415  D67N, K70R, M184V, L210W    6  experienced  32.2  414  D67N, M184V  L33F, F53L, I54L, D60E, A71V, V82T, I84V, L90M  7  first line  39.8  479  M184I    8  first line  10.8  501  M184I    9  first line  6.0  562  M184I    10  first line  34.2  636    M36L  11  first line  4.6  769  M184V    12  first line  66.7  800  M184I  M36L  13  first line  2.9  831  M184V, M184I    14  experienced  44.6  921  K219Q  A71V  15  experienced  45.8  1000  L74V  L10V, A71V  16  experienced  6.7  1086  M184V    17  first line  9.8  1949  M184I  I93M  18  experienced  8.0  2085  M184V    19  first line  23.3  2155    I62V  20  experienced  29.8  2357    M36L, V82I  21  experienced  48.4  3810  M184V    22  experienced  21.2  4603  L74V, M184V    23  experienced  20.5  5790    D60E  24  first line  23.3  6684  M184V, T215F  L33F, I50L  25a  experienced  65.7  6948    G16E  26  first line  27.6  9135    K20I  27  first line  6.2  37 000  D67N, M184V, T215F, K219E  K20R, M36I, G48V, I54L I62V, A71V, G73T, V82T, I84V, I93L  28  experienced  22.8  43 000  M41L, T215Y    29  first line  6.5  232 200    M46I, A71T, N88S  Patient  ART exposure  Time to failure (months)  VL at failure (copies/mL)  Emergent mutations at virological failure   RT  PI  1  first line  16.1  54    M36I, I62V  2  experienced  24.8  160  L74I    3  first line  no data  234  M41L    4a  experienced  46.6  125  M184V    5  first line  33.8  415  D67N, K70R, M184V, L210W    6  experienced  32.2  414  D67N, M184V  L33F, F53L, I54L, D60E, A71V, V82T, I84V, L90M  7  first line  39.8  479  M184I    8  first line  10.8  501  M184I    9  first line  6.0  562  M184I    10  first line  34.2  636    M36L  11  first line  4.6  769  M184V    12  first line  66.7  800  M184I  M36L  13  first line  2.9  831  M184V, M184I    14  experienced  44.6  921  K219Q  A71V  15  experienced  45.8  1000  L74V  L10V, A71V  16  experienced  6.7  1086  M184V    17  first line  9.8  1949  M184I  I93M  18  experienced  8.0  2085  M184V    19  first line  23.3  2155    I62V  20  experienced  29.8  2357    M36L, V82I  21  experienced  48.4  3810  M184V    22  experienced  21.2  4603  L74V, M184V    23  experienced  20.5  5790    D60E  24  first line  23.3  6684  M184V, T215F  L33F, I50L  25a  experienced  65.7  6948    G16E  26  first line  27.6  9135    K20I  27  first line  6.2  37 000  D67N, M184V, T215F, K219E  K20R, M36I, G48V, I54L I62V, A71V, G73T, V82T, I84V, I93L  28  experienced  22.8  43 000  M41L, T215Y    29  first line  6.5  232 200    M46I, A71T, N88S  Bold formatting indicates major atazanavir-associated mutations according to the IAS-USA list,13 and underlining indicates A71V. a Received unboosted atazanavir. Table 2. Therapeutic and virological characteristics of the 29 patients with emergence of resistance mutations Patient  ART exposure  Time to failure (months)  VL at failure (copies/mL)  Emergent mutations at virological failure   RT  PI  1  first line  16.1  54    M36I, I62V  2  experienced  24.8  160  L74I    3  first line  no data  234  M41L    4a  experienced  46.6  125  M184V    5  first line  33.8  415  D67N, K70R, M184V, L210W    6  experienced  32.2  414  D67N, M184V  L33F, F53L, I54L, D60E, A71V, V82T, I84V, L90M  7  first line  39.8  479  M184I    8  first line  10.8  501  M184I    9  first line  6.0  562  M184I    10  first line  34.2  636    M36L  11  first line  4.6  769  M184V    12  first line  66.7  800  M184I  M36L  13  first line  2.9  831  M184V, M184I    14  experienced  44.6  921  K219Q  A71V  15  experienced  45.8  1000  L74V  L10V, A71V  16  experienced  6.7  1086  M184V    17  first line  9.8  1949  M184I  I93M  18  experienced  8.0  2085  M184V    19  first line  23.3  2155    I62V  20  experienced  29.8  2357    M36L, V82I  21  experienced  48.4  3810  M184V    22  experienced  21.2  4603  L74V, M184V    23  experienced  20.5  5790    D60E  24  first line  23.3  6684  M184V, T215F  L33F, I50L  25a  experienced  65.7  6948    G16E  26  first line  27.6  9135    K20I  27  first line  6.2  37 000  D67N, M184V, T215F, K219E  K20R, M36I, G48V, I54L I62V, A71V, G73T, V82T, I84V, I93L  28  experienced  22.8  43 000  M41L, T215Y    29  first line  6.5  232 200    M46I, A71T, N88S  Patient  ART exposure  Time to failure (months)  VL at failure (copies/mL)  Emergent mutations at virological failure   RT  PI  1  first line  16.1  54    M36I, I62V  2  experienced  24.8  160  L74I    3  first line  no data  234  M41L    4a  experienced  46.6  125  M184V    5  first line  33.8  415  D67N, K70R, M184V, L210W    6  experienced  32.2  414  D67N, M184V  L33F, F53L, I54L, D60E, A71V, V82T, I84V, L90M  7  first line  39.8  479  M184I    8  first line  10.8  501  M184I    9  first line  6.0  562  M184I    10  first line  34.2  636    M36L  11  first line  4.6  769  M184V    12  first line  66.7  800  M184I  M36L  13  first line  2.9  831  M184V, M184I    14  experienced  44.6  921  K219Q  A71V  15  experienced  45.8  1000  L74V  L10V, A71V  16  experienced  6.7  1086  M184V    17  first line  9.8  1949  M184I  I93M  18  experienced  8.0  2085  M184V    19  first line  23.3  2155    I62V  20  experienced  29.8  2357    M36L, V82I  21  experienced  48.4  3810  M184V    22  experienced  21.2  4603  L74V, M184V    23  experienced  20.5  5790    D60E  24  first line  23.3  6684  M184V, T215F  L33F, I50L  25a  experienced  65.7  6948    G16E  26  first line  27.6  9135    K20I  27  first line  6.2  37 000  D67N, M184V, T215F, K219E  K20R, M36I, G48V, I54L I62V, A71V, G73T, V82T, I84V, I93L  28  experienced  22.8  43 000  M41L, T215Y    29  first line  6.5  232 200    M46I, A71T, N88S  Bold formatting indicates major atazanavir-associated mutations according to the IAS-USA list,13 and underlining indicates A71V. a Received unboosted atazanavir. At failure, of the 190 available genotypes, 103 patients (54.2%) presented a virus with at least one PI resistance mutation, and 65 patients (34.2%) with at least one RT resistance mutation (23.8% and 19.3% with an NRTI and/or an NNRTI resistance mutation, respectively). The percentage of patients harbouring a virus resistant to atazanavir/ritonavir was 3.7% (which was in accordance with our result of 3.5% in 113 patients); no patients harboured a virus resistant to darunavir/ritonavir. The percentage of patients harbouring virus resistant to abacavir, tenofovir and lamivudine or emtricitabine was 4.3%, 0.5% and 21.5%, respectively. Factors associated with the selection of at least one PI resistance mutation (according to the 2014 ANRS algorithm) were having taken zidovudine (P = 0.05) and didanosine (P = 0.02) in previous treatment, and having taken abacavir associated with an atazanavir-containing regimen (P = 0.02). Having M184I/V at baseline did not affect the selection of a PI resistance mutation at failure. Discussion Our retrospective study analysed over 10 years of resistance in PI-naive patients failing on an atazanavir-based regimen. In this French cohort, virological failure, defined as two consecutive VLs >50 copies/mL, occurred with 17.4% of patients, confirming previous findings from atazanavir/ritonavir clinical trials.14–16 At failure, 25.7% of our patients presented a virus with NRTI and PI resistance mutations, but only 3.5% selected major PI mutations to atazanavir/ritonavir: I50L (n = 1), I84V (n = 2) and N88S (n = 1); 23.8% selected NRTI mutations (M184I/V, n = 16). In the CASTLE clinical trial,15 6% of virological failures occurred in the atazanavir/ritonavir arm. Two patients taking atazanavir/ritonavir showed emergence of non-polymorphic PI resistance mutations on treatment. In one patient, the N88S substitution, associated with atazanavir resistance, emerged. The second patient receiving atazanavir/ritonavir with emergent non-polymorphic PI resistance mutations had six PI mutations at baseline, and rebounded rapidly at week 24 after suppression to an HIV RNA of <50 copies/mL. Our proportion of virological failure (17.4%) is also concordant with an observational European cohort based on 517 patients.17 Indeed, in that earlier study 85 (16.4%) patients presented virological failure and 9 of them (22.4%) had treatment-emergent minor PI resistance mutations, but contrary to our study no patient had treatment-emergent major PI resistance mutations. The ACTG 5257 study4 showed similar results: in the atazanavir arm, 95 patients (16%) presented a virological failure without PI resistance detected, and NRTI resistance was detected in 8 patients (10.8%). Our study focused on mutation both at failure and before atazanavir or atazanavir/ritonavir initiation, and permitted both described and undescribed mutations to be highlighted. We showed the occurrence of new selected substitutions (A71V/T) in 5 patients among the 29 virological failures with resistance. After several months of culture, in atazanavir-resistant variants, the mutation A71V was selected in vitro in association with other mutations.18 In the CASTLE study, one patient in the atazanavir/ritonavir group had major and minor PI emerging substitutions and ultimately failed at week 67. This patient had baseline T12A/S, I13I/V, M36I, N37D, I62V, L63P, A71A/T, I72V and I93L, with an atazanavir fold change of 0.78.14 In an unplanned atazanavir-based treatment interruption, one A71V and one A71I were selected among emergent resistance mutations.19 In conclusion, development of atazanavir resistance is low (3.5%) in patients failing the first line of an atazanavir-based regimen, and all patients remained susceptible to darunavir/ritonavir. In this population of naive and NRTI-experienced patients, emergence of NRTI resistance in 14% of patients is not negligible. Evidence of new selected substitutions (A71V/T) in the protease gene with atazanavir/ritonavir-based ART has enabled the algorithms for the interpretation of French ANRS atazanavir/ritonavir resistance to be updated to 2015.12 Acknowledgements Members of the ANRS AC-11 Resistance Group Paris area Avicenne: Chakib Alloui; Bichat: Diane Descamps, Charlotte Charpentier, Benoit Visseaux; Cochin: Anne Krivine; Henri Mondor: Magali Bouviers-Alias; Paul Brousse: Coralie Pallier; Pitié-Salpêtrière: Cathia Soulie, Marc Wirden, Anne-Genevieve Marcelin, Vincent Calvez; Saint-Antoine: Laurence Morand-Joubert, Sidonie Lambert-Niclot, Djeneba Fofana; Saint-Louis: Nadia Mahjoub, Constance Delaugerre, Marie-Laure Chaix; Tenon: Corinne Amiel, Veronique Schneider. Outside Paris area Amiens: Catherine Roussel; Angers: Helene Le Guillou-Guillemette; Argenteuil: Laurence Courdavault; Bordeaux: Sandrine Reigadas, Patricia Recordon-Pinson, Herve Fleury; Brest: Sophie Vallet; Caen: Julia Dina, Astrid Vabret; Clermont-Ferrand: Audrey Mirand, Cecile Henquell; Dijon: Christelle Auvray, Alexis De Rougemont, Helene Giraudon, Ali Si-Mohammed; Garches: Dominique Mathez; Grenoble: Anne Signori-Schmuck, Patrice Morand; Lille: Laurence Bocket; Lyon: Mary Anne Trabaud; Montpellier: Brigitte Montés; Nantes: Laura Le Guen, Audrey Rodallec, Virginie Ferre; Nancy: Helene Jeulin, Evelyne Schvoerer; Nice: Jacqueline Dufayard; Nîmes: Annick Allardet-Servent, Marie-Josee Carles; Orléans: Jerome Guinard, Aurelie Guigon; Poitiers: Genevieve Giraudeau, Agnes Beby-Defaux; Rennes: Anne Maillard; Rouen: Jean Christophe Plantier, Marie Leoz, Thomas Mourez; Saint-Etienne: Thomas Bourlet; Strasbourg: Samira Fafi-Kremer; Toulouse: Julie Chiabrando, Stephanie Raymond, Jacques Izopet; Tours: Francis Barin; Versailles: Stephanie Marque-Juillet. Switzerland Genève: Sabine Yerly. Funding The research leading to these results has received funding from the Agence Nationale de Recherches sur le SIDA et les Hépatites virales. Transparency declarations S. L.-N. has received travel grants from ViiV Healthcare. C. C., T. M. and D. D. have received honoraria and travel grants from ViiV Healthcare, Janssen-Cilag, Gilead Sciences and Merck Laboratories MSD. H. L. G.-G. has received honoraria from Gilead Sciences and Merck Laboratories MSD and research funding from Hologic. A. G. M. has received honoraria for advisories or invited talks or conferences and research grants from Abbvie Labs, Gilead Sciences, Merck Laboratories MSD, Janssen Pharmaceuticals and ViiV Healthcare. C. D. has received honoraria for collaboration from ViiV and Merck Laboratories MSD and scientist board participation from Gilead Sciences, Merck Laboratories MSD, Janssen Pharmaceuticals and ViiV Healthcare. L. M.-J. has received honoraria from BMS, Mylan, Gilead Sciences, Merck Laboratories MSD, Janssen Pharmaceuticals and ViiV Healthcare. All other authors: none to declare. References 1 Walmsley S. Protease inhibitor-based regimens for HIV therapy: safety and efficacy. J Acquir Immune Defic Syndr  2007; 45 Suppl 1: S5– 13; quiz S28–31. Google Scholar CrossRef Search ADS PubMed  2 Shuter J. Forgiveness of non-adherence to HIV-1 antiretroviral therapy. J Antimicrob Chemother  2008; 61: 769– 73. Google Scholar CrossRef Search ADS PubMed  3 Zeldin RK, Petruschke RA. Pharmacological and therapeutic properties of ritonavir-boosted protease inhibitor therapy in HIV-infected patients. J Antimicrob Chemother  2004; 53: 4– 9. 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Rapport 2013. http://www.sante.gouv.fr/IMG/pdf/Rapport_Morlat_2013_Mise_en_ligne.pdf. 7 Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV. https://aidsinfo.nih.gov/contentfiles/lvguidelines/adultandadolescentgl.pdf. 8 Recommendations for the Use of Antiretroviral Drugs in Pregnant Women with HIV Infection and Interventions to Reduce Perinatal HIV Transmission in the United States. https://aidsinfo.nih.gov/contentfiles/lvguidelines/PerinatalGL.pdf. 9 Colonno RJ, Thiry A, Limoli K et al.   Activities of atazanavir (BMS-232632) against a large panel of human immunodeficiency virus type 1 clinical isolates resistant to one or more approved protease inhibitors. Antimicrob Agents Chemother  2003; 47: 1324– 33. Google Scholar CrossRef Search ADS PubMed  10 Colonno R, Rose R, McLaren C et al.   Identification of I50L as the signature atazanavir (ATV)-resistance mutation in treatment-naive HIV-1-infected patients receiving ATV-containing regimens. 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Google Scholar CrossRef Search ADS PubMed  18 Gong YF, Robinson BS, Rose RE et al.   In vitro resistance profile of the human immunodeficiency virus type 1 protease inhibitor BMS-232632. Antimicrob Agents Chemother  2000; 44: 2319– 26. Google Scholar CrossRef Search ADS PubMed  19 Tinago W, O’Halloran JA, O’Halloran RM et al.   Characterization of associations and development of atazanavir resistance after unplanned treatment interruptions. HIV Med  2014; 15: 224– 32. Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

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Journal of Antimicrobial ChemotherapyOxford University Press

Published: Apr 27, 2018

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