High virological suppression regardless of the genotypic susceptibility score after switching to a dolutegravir-based regimen: week 48 results in an observational cohort

High virological suppression regardless of the genotypic susceptibility score after switching to... Abstract Objectives To assess, in a clinical cohort, the efficacy of switching current ART in virologically suppressed patients to a dolutegravir-based regimen, regardless of the genotypic susceptibility score (GSS). Patients and methods This was an observational single-centre study assessing ART-treated patients with plasma viral load (pVL) <50 copies/mL who were switched to a dolutegravir-based regimen with 1 year of follow-up. PCR negative was defined as an undetected PCR signal. Trough plasma concentration (C24) was determined using UPLC-MS/MS. Results Two hundred and thirty-nine patients initiated a dolutegravir-based regimen: 12%, 29% and 59% had a total GSS of 1 or 1.5 (group 1), 2 or 2.5 (group 2) and 3 (group 3), respectively. At switch initiation, the median time since first ART and the median duration with pVL <50 copies/mL were 13 years (IQR = 6–19) and 3 years (IQR = 1–6), respectively. Median times since last genotype were 9, 10 and 5 years for groups 1, 2 and 3, respectively. Twenty patients (8.4%) discontinued the dolutegravir-based regimen due to adverse events. During the study, 96.4% (n = 661/686) of all pVL were <50 copies/mL. Four patients (1.7%) experienced virological failure (two pVL >50 copies/mL) without emergence of resistance; these patients’ GSSs were 2, 2.5, 3 and 3. The median dolutegravir C24 was 1545 ng/mL (IQR = 1150–2097). Of the patients with pVL <20 copies/mL, 72% were PCR negative during the follow-up, with no difference between the three groups of patients. Conclusions This observational cohort study showed a high level of virological suppression maintenance in the first year following the switch to a dolutegravir-based regimen, even in patients with GSS ≤2. Introduction Dolutegravir, the newest integrase inhibitor (INI) on the market, exhibits a higher genetic barrier to resistance than the first-generation INI compounds raltegravir and elvitegravir. The STRIIVING study (a Phase 3, randomized, open-label, multicentre clinical trial) assessed the effect of switching from triple combination ART (cART) to the coformulated abacavir/lamivudine/dolutegravir single-tablet regimen (STR) compared with continuing cART.1 This trial included moderately pretreated patients undergoing first- or second-line therapy who did not have a history of virological failure (VF) and who had maintained plasma viral load (pVL) <50 copies/mL for at least 6 months under their current cART.1 The study demonstrated the non-inferiority of switching, with 85% of the participants in the switch group maintaining pVL <50 copies/mL at week (W) 24.1 Other studies have tested specific switch regimens, for example, to dolutegravir-based STR,2 to dolutegravir + rilpivirine3 and dolutegravir + lamivudine4,5 dual therapy, and even to the non-recommended dolutegravir monotherapy.6,7 Given that most of these studies included patients without a history of VF, there is a scarcity of data evaluating the effectiveness of different switch strategies in large populations of patients with varied genotypic susceptibility scores (GSSs). There are few data available on the efficacy of switching to a dolutegravir-based regimen in maintaining virological suppression in a clinical cohort of patients with longer and more diverse therapeutic histories. Additionally, no cohort study has assessed the impact on residual viraemia of switching to a dolutegravir-based regimen. Previous studies have shown that residual viraemia is detected more frequently with boosted PI than with NNRTI.8,9 The aim of this study was to determine the virological and pharmacological efficacy of switching from ongoing cART to a dolutegravir-based regimen in maintaining virological suppression in a clinical cohort of virologically suppressed patients at W48, depending on the GSS for the dolutegravir-based regimen. The study also evaluates the impact of this switch on residual viraemia. Patients and methods Study population We conducted a prospective observational single-centre cohort study, enrolling all patients successfully treated with cART (i.e. with pVL <50 copies/mL) whom physicians had decided to switch to a dolutegravir-based regimen between September 2014 and March 2016 and for whom a plasma historical genotypic resistance test was available. Ethics All the patients enrolled in this study gave their written informed consent to having their medical chart stored in the Nadis® electronic medical record system, which was designed for medical follow-up of HIV-infected patients, including the use of their biological data for research studies (www.dataids.org Fedialis Medica, Marly Le Roi, France; CNIL number: 1171457; 24 May 2006). Virological analysis Historical genotypic resistance tests of HIV protease, reverse transcriptase and integrase regions, available before ART initiation and/or at time of previous VF, were performed according to the complete sequencing procedures and primers sequences described at www.hivfrenchresistance.org. Sequences were interpreted using the Agence Nationale de Recherches sur le SIDA et les hépatites virales (ANRS) resistance algorithm (www.hivfrenchresistance.org; September 2016; version 26). The GSS of the cART regimen was calculated based on the cumulative historical genotypic resistance tests using the ANRS algorithm, including dolutegravir, translating the interpretations ‘susceptible’, ‘possible resistance’ and ‘resistance’ into scores of 1, 0.5 and 0, respectively. Thus, we defined three groups of patients: (i) those with a GSS equal to 1 or 1.5 (group 1), i.e. essentially receiving dolutegravir as ‘functional monotherapy’; (ii) those with a GSS equal to 2 or 2.5 (group 2); and (iii) those with a GSS equal to 3, i.e. receiving fully active triple therapy. pVL data were collected from patients’ regular biological monitoring. Patients had at least two pVL during the year of follow-up sampled at W4, W12, W24, W36 or W48, with an acceptable interval of 1 month, except for the W4 sample. Plasma HIV-1 RNA quantification was performed using the COBAS® AmpliPrep/COBAS® TaqMan® HIV-1 Test, version 2.0 (Roche Molecular Systems, Branchburg, NJ, USA) with a limit of quantification of 20 copies/mL. PCR negative was defined as an undetected PCR signal, corresponding to an absence of residual viraemia. A viral blip was defined as a transient pVL >50 copies/mL (but <1000 copies/mL) and VF was defined as two consecutive pVL >50 copies/mL. Pharmacological analysis Steady-state plasma drug concentrations sampled 24 h post-dose (C24) were measured at at least one timepoint for each patient during the follow-up (between W4 and W48). C24 values were measured using UPLC combined with tandem MS (UPLC-MS/MS) (Waters Corporation Milford, MA, USA).10 Dolutegravir C24 values were interpreted according to effective cut-offs of 1000 and 600 ng/mL, based on the pharmacokinetic (PK)–pharmacodynamic relationship found in the SAILING trial.11,12 The inter- and intra-patient variability of plasma concentrations were also investigated and presented as a coefficient of variation (%) based on four measurements taken from patients during the study follow-up. Statistical analysis Non-parametric Mann–Whitney tests were used to statistically compare patient characteristics. Non-parametric Kruskal–Wallis one-way analyses of variance were performed to compare PK parameters. Results Patient characteristics Our observational cohort study assessed 239 virologically suppressed patients with historical genotypes who switched to a dolutegravir-based regimen during the study period; their characteristics are depicted in Table 1. A large proportion of patients (n = 229, 96%) received 50 mg of dolutegravir once daily. Table 1. Baseline characteristics of patients Characteristic Group 1 (GSS = 1 or 1.5), N = 28 Group 2 (GSS = 2 or 2.5), N = 70 Group 3 (GSS = 3), N = 141 Male, n (%) 22 (78.6) 37 (53) 99 (70) Age (years), median (IQR) 51 (47–57) 52 (46–58) 51 (42–58) Active hepatitis coinfection, n (%)  HBV (HBs Ag positive) 3 (11) 5 (7) 8 (6)  HCV (HCV RNA positive) 0 (0) 4 (6) 13 (9) Time since HIV diagnosis (years), median (IQR) 19 (14–24) 20 (16–25) 11 (6–20) Duration of prior ART (years), median (IQR) 17 (10–21) 18 (14–20) 8 (4–17) Number of previous ART lines, median (IQR) 8 (5–10) 7 (4–10) 4 (2–6) Duration of plasma HIV-1 RNA <50 copies/mL before switch (years), median (IQR) 3 (2–7) 4 (1–8) 3 (1–5) Baseline CD4 cell count (cells/mm3), median (IQR) 670 (435–863) 580 (508–913) 600 (415–786) Nadir CD4 cell count (cells/mm3), median (IQR) 197 (80–236) 198 (100–264) 244 (103–344) Zenith plasma HIV-1 RNA level (log10 copies/mL), median (IQR) 5.0 (4.6–5.3) 5.1 (4.7–5.5) 5.1 (4.5–5.4) Previous ART, n (%)  2 NRTI + 1 NNRTI 4 (14) 8 (11) 40 (28)  2 NRTI + 1 PI/r 15 (54) 31 (44) 63 (45)  INI-based treatment 5 (18) 25 (36) 31 (22)   2 NRTI + RAL 0 5 15   TDF/FTC/EVG/c 0 0 4   other RAL-based treatment 5 20 12  other ART 4 (14) 6 (9) 7 (5) HIV-1 subtype, n (%)  B 18 (64) 43 (62) 76 (54)  CRF02_AG 2 (7) 12 (17) 32 (23)  other non-B subtypes 8 (29) 15 (21) 33 (23) Number of NRTI drug resistance mutations, median (IQR) 3 (1–5) 3 (1–5) 0 (0–0) M184I/V mutations, n (%) 28 (100) 46 (66) 6 (4) NNRTI drug resistance mutations, n (%) 18 (64) 37 (53) 39 (28) Major PI drug resistance mutations, n (%) 10 (36) 17 (24) 8 (6) Time since last genotypic resistance test (years), median (IQR) 9 (4–12) 10 (3–13) 5 (2–8) Antiretroviral drugs associated with DTG, n (%)  ABC/3TC 20 (71) 8 (11) 96 (68)  TDF/FTC 2 (7) 6 (9) 27 (19)  RPV 2 (7) 24 (34) 0 (0)  DRV/r 0 (0) 5 (7) 0 (0)  ATV/r 1 (4) 7 (10) 0 (0)  RPV + NRTI 0 (0) 6 (9) 11 (8)  2 or 3 NRTIs 0 (0) 8 (11) 0 (0)  other antiretroviral drugs 3 (11) 6 (9) 7 (5) Characteristic Group 1 (GSS = 1 or 1.5), N = 28 Group 2 (GSS = 2 or 2.5), N = 70 Group 3 (GSS = 3), N = 141 Male, n (%) 22 (78.6) 37 (53) 99 (70) Age (years), median (IQR) 51 (47–57) 52 (46–58) 51 (42–58) Active hepatitis coinfection, n (%)  HBV (HBs Ag positive) 3 (11) 5 (7) 8 (6)  HCV (HCV RNA positive) 0 (0) 4 (6) 13 (9) Time since HIV diagnosis (years), median (IQR) 19 (14–24) 20 (16–25) 11 (6–20) Duration of prior ART (years), median (IQR) 17 (10–21) 18 (14–20) 8 (4–17) Number of previous ART lines, median (IQR) 8 (5–10) 7 (4–10) 4 (2–6) Duration of plasma HIV-1 RNA <50 copies/mL before switch (years), median (IQR) 3 (2–7) 4 (1–8) 3 (1–5) Baseline CD4 cell count (cells/mm3), median (IQR) 670 (435–863) 580 (508–913) 600 (415–786) Nadir CD4 cell count (cells/mm3), median (IQR) 197 (80–236) 198 (100–264) 244 (103–344) Zenith plasma HIV-1 RNA level (log10 copies/mL), median (IQR) 5.0 (4.6–5.3) 5.1 (4.7–5.5) 5.1 (4.5–5.4) Previous ART, n (%)  2 NRTI + 1 NNRTI 4 (14) 8 (11) 40 (28)  2 NRTI + 1 PI/r 15 (54) 31 (44) 63 (45)  INI-based treatment 5 (18) 25 (36) 31 (22)   2 NRTI + RAL 0 5 15   TDF/FTC/EVG/c 0 0 4   other RAL-based treatment 5 20 12  other ART 4 (14) 6 (9) 7 (5) HIV-1 subtype, n (%)  B 18 (64) 43 (62) 76 (54)  CRF02_AG 2 (7) 12 (17) 32 (23)  other non-B subtypes 8 (29) 15 (21) 33 (23) Number of NRTI drug resistance mutations, median (IQR) 3 (1–5) 3 (1–5) 0 (0–0) M184I/V mutations, n (%) 28 (100) 46 (66) 6 (4) NNRTI drug resistance mutations, n (%) 18 (64) 37 (53) 39 (28) Major PI drug resistance mutations, n (%) 10 (36) 17 (24) 8 (6) Time since last genotypic resistance test (years), median (IQR) 9 (4–12) 10 (3–13) 5 (2–8) Antiretroviral drugs associated with DTG, n (%)  ABC/3TC 20 (71) 8 (11) 96 (68)  TDF/FTC 2 (7) 6 (9) 27 (19)  RPV 2 (7) 24 (34) 0 (0)  DRV/r 0 (0) 5 (7) 0 (0)  ATV/r 1 (4) 7 (10) 0 (0)  RPV + NRTI 0 (0) 6 (9) 11 (8)  2 or 3 NRTIs 0 (0) 8 (11) 0 (0)  other antiretroviral drugs 3 (11) 6 (9) 7 (5) 3TC, lamivudine; ABC, abacavir; ATV, atazanavir; DTG, dolutegravir; DRV, darunavir; EVG, elvitegravir; FTC, emtricitabine; HBs Ag, Hepatitis B surface antigen; RAL, raltegravir; RPV, rilpivirine; TDF, tenofovir disoproxil fumarate; /r, boosted with ritonavir; /c, boosted with cobicistat. Table 1. Baseline characteristics of patients Characteristic Group 1 (GSS = 1 or 1.5), N = 28 Group 2 (GSS = 2 or 2.5), N = 70 Group 3 (GSS = 3), N = 141 Male, n (%) 22 (78.6) 37 (53) 99 (70) Age (years), median (IQR) 51 (47–57) 52 (46–58) 51 (42–58) Active hepatitis coinfection, n (%)  HBV (HBs Ag positive) 3 (11) 5 (7) 8 (6)  HCV (HCV RNA positive) 0 (0) 4 (6) 13 (9) Time since HIV diagnosis (years), median (IQR) 19 (14–24) 20 (16–25) 11 (6–20) Duration of prior ART (years), median (IQR) 17 (10–21) 18 (14–20) 8 (4–17) Number of previous ART lines, median (IQR) 8 (5–10) 7 (4–10) 4 (2–6) Duration of plasma HIV-1 RNA <50 copies/mL before switch (years), median (IQR) 3 (2–7) 4 (1–8) 3 (1–5) Baseline CD4 cell count (cells/mm3), median (IQR) 670 (435–863) 580 (508–913) 600 (415–786) Nadir CD4 cell count (cells/mm3), median (IQR) 197 (80–236) 198 (100–264) 244 (103–344) Zenith plasma HIV-1 RNA level (log10 copies/mL), median (IQR) 5.0 (4.6–5.3) 5.1 (4.7–5.5) 5.1 (4.5–5.4) Previous ART, n (%)  2 NRTI + 1 NNRTI 4 (14) 8 (11) 40 (28)  2 NRTI + 1 PI/r 15 (54) 31 (44) 63 (45)  INI-based treatment 5 (18) 25 (36) 31 (22)   2 NRTI + RAL 0 5 15   TDF/FTC/EVG/c 0 0 4   other RAL-based treatment 5 20 12  other ART 4 (14) 6 (9) 7 (5) HIV-1 subtype, n (%)  B 18 (64) 43 (62) 76 (54)  CRF02_AG 2 (7) 12 (17) 32 (23)  other non-B subtypes 8 (29) 15 (21) 33 (23) Number of NRTI drug resistance mutations, median (IQR) 3 (1–5) 3 (1–5) 0 (0–0) M184I/V mutations, n (%) 28 (100) 46 (66) 6 (4) NNRTI drug resistance mutations, n (%) 18 (64) 37 (53) 39 (28) Major PI drug resistance mutations, n (%) 10 (36) 17 (24) 8 (6) Time since last genotypic resistance test (years), median (IQR) 9 (4–12) 10 (3–13) 5 (2–8) Antiretroviral drugs associated with DTG, n (%)  ABC/3TC 20 (71) 8 (11) 96 (68)  TDF/FTC 2 (7) 6 (9) 27 (19)  RPV 2 (7) 24 (34) 0 (0)  DRV/r 0 (0) 5 (7) 0 (0)  ATV/r 1 (4) 7 (10) 0 (0)  RPV + NRTI 0 (0) 6 (9) 11 (8)  2 or 3 NRTIs 0 (0) 8 (11) 0 (0)  other antiretroviral drugs 3 (11) 6 (9) 7 (5) Characteristic Group 1 (GSS = 1 or 1.5), N = 28 Group 2 (GSS = 2 or 2.5), N = 70 Group 3 (GSS = 3), N = 141 Male, n (%) 22 (78.6) 37 (53) 99 (70) Age (years), median (IQR) 51 (47–57) 52 (46–58) 51 (42–58) Active hepatitis coinfection, n (%)  HBV (HBs Ag positive) 3 (11) 5 (7) 8 (6)  HCV (HCV RNA positive) 0 (0) 4 (6) 13 (9) Time since HIV diagnosis (years), median (IQR) 19 (14–24) 20 (16–25) 11 (6–20) Duration of prior ART (years), median (IQR) 17 (10–21) 18 (14–20) 8 (4–17) Number of previous ART lines, median (IQR) 8 (5–10) 7 (4–10) 4 (2–6) Duration of plasma HIV-1 RNA <50 copies/mL before switch (years), median (IQR) 3 (2–7) 4 (1–8) 3 (1–5) Baseline CD4 cell count (cells/mm3), median (IQR) 670 (435–863) 580 (508–913) 600 (415–786) Nadir CD4 cell count (cells/mm3), median (IQR) 197 (80–236) 198 (100–264) 244 (103–344) Zenith plasma HIV-1 RNA level (log10 copies/mL), median (IQR) 5.0 (4.6–5.3) 5.1 (4.7–5.5) 5.1 (4.5–5.4) Previous ART, n (%)  2 NRTI + 1 NNRTI 4 (14) 8 (11) 40 (28)  2 NRTI + 1 PI/r 15 (54) 31 (44) 63 (45)  INI-based treatment 5 (18) 25 (36) 31 (22)   2 NRTI + RAL 0 5 15   TDF/FTC/EVG/c 0 0 4   other RAL-based treatment 5 20 12  other ART 4 (14) 6 (9) 7 (5) HIV-1 subtype, n (%)  B 18 (64) 43 (62) 76 (54)  CRF02_AG 2 (7) 12 (17) 32 (23)  other non-B subtypes 8 (29) 15 (21) 33 (23) Number of NRTI drug resistance mutations, median (IQR) 3 (1–5) 3 (1–5) 0 (0–0) M184I/V mutations, n (%) 28 (100) 46 (66) 6 (4) NNRTI drug resistance mutations, n (%) 18 (64) 37 (53) 39 (28) Major PI drug resistance mutations, n (%) 10 (36) 17 (24) 8 (6) Time since last genotypic resistance test (years), median (IQR) 9 (4–12) 10 (3–13) 5 (2–8) Antiretroviral drugs associated with DTG, n (%)  ABC/3TC 20 (71) 8 (11) 96 (68)  TDF/FTC 2 (7) 6 (9) 27 (19)  RPV 2 (7) 24 (34) 0 (0)  DRV/r 0 (0) 5 (7) 0 (0)  ATV/r 1 (4) 7 (10) 0 (0)  RPV + NRTI 0 (0) 6 (9) 11 (8)  2 or 3 NRTIs 0 (0) 8 (11) 0 (0)  other antiretroviral drugs 3 (11) 6 (9) 7 (5) 3TC, lamivudine; ABC, abacavir; ATV, atazanavir; DTG, dolutegravir; DRV, darunavir; EVG, elvitegravir; FTC, emtricitabine; HBs Ag, Hepatitis B surface antigen; RAL, raltegravir; RPV, rilpivirine; TDF, tenofovir disoproxil fumarate; /r, boosted with ritonavir; /c, boosted with cobicistat. Taking into account all historical plasma genotypes, 28 (12%), 70 (29%) and 141 (59%) patients had a total GSS equal to 1 or 1.5 (group 1), 2 or 2.5 (group 2) or 3 (group 3), respectively. The most common antiretroviral drugs associated with dolutegravir were abacavir/lamivudine for group 1 (n = 20/28, 71%), rilpivirine for group 2 (n = 24/70, 34%) and abacavir/lamivudine for group 3 (n = 96/141, 68%) (Table 1). Only a few patients previously treated with an INI-containing regimen were switched to dolutegravir-based regimens, namely raltegravir (8.4%) and elvitegravir/cobicistat (1.7%). Similarly, only five patients in the whole cohort received dolutegravir and darunavir/ritonavir dual therapy, most likely due to the deleterious drug–drug interaction.13 Median times since first ART before the switch were 17 years (IQR = 10–21), 18 years (IQR = 14–20) and 8 years (IQR = 4–17) for groups 1, 2 and 3, respectively. Median times with pVL <50 copies/mL before the switch were 3 years (IQR = 2–7), 4 years (IQR = 1–8) and 3 years (IQR = 1–5) for groups 1, 2 and 3, respectively. Median times since the last historical resistance genotype were 9 years (IQR = 4–12), 10 years (IQR = 3–13) and 5 years (IQR = 2–8) for groups 1, 2 and 3, respectively. Regarding drug resistance mutations, the M184V mutation was present in 100%, 66% and 4% of historical resistance genotypes for groups 1, 2 and 3, respectively. Clearly, patients in groups 1 and 2 are more advanced in terms of resistance than those in group 3. Viruses with NNRTI resistance mutations were found in 64% and 53% of patients in groups 1 and 2, respectively, compared with 28% for group 3. Similarly, 36% and 24% of patients in groups 1 and 2, respectively, exhibited major PI resistance mutations, compared with 6% for group 3. Immunovirological outcome In this observational study, plasma specimens were available for 119 patients at W4, 140 patients at W12, 151 patients at W24, 129 patients at W36 and 147 patients at W48. During the first year following the switch to the dolutegravir-based regimen, 96.4% (n = 661/686) of all pVL measurements obtained were <50 copies/mL. Four patients (1.7%) experienced VF and 16 patients (6.7%) had a viral blip during this first year of follow-up based on the available samples. The proportion of viral blips did not differ between the different GSS groups: two (7.1%) in group 1, eight (11.4%) in group 2 and six (4.2%) in group 3. For two patients, there were no pVL control samples available, since treatment was stopped just after the first measurement of pVL >50 copies/mL. Plasma drug concentrations were available for 13 of the 16 patients who experienced a viral blip, showing dolutegravir C24 >1000 ng/mL in 12 (92%) of them. Median CD4 cell counts at baseline, W24 and W48 of the switch were 600/mm3 (IQR = 457–820), 670/mm3 (IQR = 469–890) and 680/mm3 (IQR = 500–914), respectively. Safety Between baseline and W48 of the switch, 20 patients (8.4%) discontinued treatment due to adverse events: nine due to neuropsychiatric side effects, two due to renal toxicities (both with increased plasma creatinine), two due to cutaneous side effects, one due to headache, three patients for personal reasons and three for other reasons. No differences were observed between the different GSS groups in terms of the proportion of patients who discontinued dolutegravir. In addition, three women stopped the dolutegravir-based regimen due to pregnancy. Assessment of residual viraemia The proportion of patients with pVL <20 copies/mL was 91%, 93%, 91%, 89%, 92% and 90% at baseline, W4, W12, W24, W36 and W48 of the switch, respectively (Figure 1). Among those with pVL <20 copies/mL, the proportion of patients with no PCR signal (PCR negative) was 72%, 79%, 71%, 68%, 71% and 72% at baseline, W4, W12, W24, W36 and W48, respectively (Figure 1). The longitudinal evolution of residual viraemia was similar between the different GSS groups. Figure 1. View largeDownload slide Distribution of HIV-1 pVL at baseline, W4, W12, W24, W36 and W48. Figure 1. View largeDownload slide Distribution of HIV-1 pVL at baseline, W4, W12, W24, W36 and W48. Pharmacological analysis A total of 348 drug plasma C24 values, corresponding to 216 patients, were measured during the first year following the switch to a dolutegravir-based regimen. Overall, the median dolutegravir C24 value was 1675 ng/mL (IQR = 1205–2311) (Figure 2). During the follow-up period, 84% and 95% of dolutegravir C24 values were considered adequate according to the cut-offs of 1000 and 600 ng/mL, respectively. Figure 2. View largeDownload slide Distribution (as median and IQR) of plasma C24 for dolutegravir (DTG), abacavir (ABC), lamivudine (3TC), emtricitabine (FTC), tenofovir (TFV) and rilpivirine (RPV); all visits combined. CV, coefficient of variation. Figure 2. View largeDownload slide Distribution (as median and IQR) of plasma C24 for dolutegravir (DTG), abacavir (ABC), lamivudine (3TC), emtricitabine (FTC), tenofovir (TFV) and rilpivirine (RPV); all visits combined. CV, coefficient of variation. Inter-patient variability of dolutegravir C24 was 53%. Intra-patient variability of dolutegravir C24 was 27%. Associated antiretroviral C24 values (abacavir, lamivudine, emtricitabine, tenofovir and rilpivirine) are presented in Figure 2. No differences were reported in dolutegravir and associated antiretroviral C24 values between the different follow-up times (W4, W12, W24, W36 and W48). Plasma drug concentrations (dolutegravir C24) were available for 13 of the 20 patients who discontinued an INI-based regimen due to adverse events; the median was 2190 ng/mL (IQR = 1479–2303). Interestingly, the three patients with the highest dolutegravir C24 values discontinued the regimen due to neuropsychiatric side effects; these patients were also receiving abacavir/lamivudine in two cases and rilpivirine in one case. Description of VF Among the four patients who experienced VF, three were infected with a B subtype and one with a CRF12_BF recombinant. At the time of VF, which occurred at W4 (n = 1), W24 (n = 1) and W48 (n = 2), the four patients had low pVL values (91, 91, 101 and 200 copies/mL) (Table 2). Table 2. Description of patients experiencing VF Patient ID Antiretrovirals associated with DTG GSS First pVL >50 copies/mL pVL control RT historical genotype Previous antiretroviral regimen HIV-1 subtype Genotype at time of first pVL >50 copies/mL Genotype at time of pVL control C24 DTG (ng/mL) time value (copies/mL) time value (copies/mL) RT/ protease INT RT/ protease INT 8 DRV/r 2 W48 200 W60 89 WT RAL+DRV/r B WT WT NA NA 1444 17 ABC/3TC+DRV/r 2.5 W48 91 W52 84 M184V ABC/3TC+DRV/r B NA NA NA NA 554 67 TDF/FTC 3 W4 91 W8 64 T215F/I/L/Y TDF/FTC+ETR+RAL CRF12_BF NA NA NA WT 2843 130 ABC/3TC 3 W24 101 W30 73 WT ZDV/3TC+LPV/r B WT WT NA NA not available Patient ID Antiretrovirals associated with DTG GSS First pVL >50 copies/mL pVL control RT historical genotype Previous antiretroviral regimen HIV-1 subtype Genotype at time of first pVL >50 copies/mL Genotype at time of pVL control C24 DTG (ng/mL) time value (copies/mL) time value (copies/mL) RT/ protease INT RT/ protease INT 8 DRV/r 2 W48 200 W60 89 WT RAL+DRV/r B WT WT NA NA 1444 17 ABC/3TC+DRV/r 2.5 W48 91 W52 84 M184V ABC/3TC+DRV/r B NA NA NA NA 554 67 TDF/FTC 3 W4 91 W8 64 T215F/I/L/Y TDF/FTC+ETR+RAL CRF12_BF NA NA NA WT 2843 130 ABC/3TC 3 W24 101 W30 73 WT ZDV/3TC+LPV/r B WT WT NA NA not available 3TC, lamivudine; ABC, abacavir; DTG, dolutegravir; DRV, darunavir; ETR, etravirine; FTC, emtricitabine; INT, integrase; LPV, lopinavir; NA, not amplified; RAL, raltegravir; RT, reverse transcriptase; TDF, tenofovir disoproxil fumarate; ZDV, zidovudine; /r, boosted with ritonavir. Table 2. Description of patients experiencing VF Patient ID Antiretrovirals associated with DTG GSS First pVL >50 copies/mL pVL control RT historical genotype Previous antiretroviral regimen HIV-1 subtype Genotype at time of first pVL >50 copies/mL Genotype at time of pVL control C24 DTG (ng/mL) time value (copies/mL) time value (copies/mL) RT/ protease INT RT/ protease INT 8 DRV/r 2 W48 200 W60 89 WT RAL+DRV/r B WT WT NA NA 1444 17 ABC/3TC+DRV/r 2.5 W48 91 W52 84 M184V ABC/3TC+DRV/r B NA NA NA NA 554 67 TDF/FTC 3 W4 91 W8 64 T215F/I/L/Y TDF/FTC+ETR+RAL CRF12_BF NA NA NA WT 2843 130 ABC/3TC 3 W24 101 W30 73 WT ZDV/3TC+LPV/r B WT WT NA NA not available Patient ID Antiretrovirals associated with DTG GSS First pVL >50 copies/mL pVL control RT historical genotype Previous antiretroviral regimen HIV-1 subtype Genotype at time of first pVL >50 copies/mL Genotype at time of pVL control C24 DTG (ng/mL) time value (copies/mL) time value (copies/mL) RT/ protease INT RT/ protease INT 8 DRV/r 2 W48 200 W60 89 WT RAL+DRV/r B WT WT NA NA 1444 17 ABC/3TC+DRV/r 2.5 W48 91 W52 84 M184V ABC/3TC+DRV/r B NA NA NA NA 554 67 TDF/FTC 3 W4 91 W8 64 T215F/I/L/Y TDF/FTC+ETR+RAL CRF12_BF NA NA NA WT 2843 130 ABC/3TC 3 W24 101 W30 73 WT ZDV/3TC+LPV/r B WT WT NA NA not available 3TC, lamivudine; ABC, abacavir; DTG, dolutegravir; DRV, darunavir; ETR, etravirine; FTC, emtricitabine; INT, integrase; LPV, lopinavir; NA, not amplified; RAL, raltegravir; RT, reverse transcriptase; TDF, tenofovir disoproxil fumarate; ZDV, zidovudine; /r, boosted with ritonavir. One patient with VF had a GSS of 2, was receiving dual therapy with 50 mg of dolutegravir + 800/100 mg of darunavir/ritonavir once daily and had no historical resistance mutations. He showed adequate C24 at the time of VF (W48, 1444 ng/mL for dolutegravir and 2057 ng/mL for darunavir) but suboptimal C24 at the two preceding timepoints (297 and 485 ng/mL at W24 and W36, respectively). The second patient with VF had a GSS of 2.5 due to an historical M184V mutation, was receiving abacavir/lamivudine/dolutegravir once daily + 600/100 mg of darunavir/ritonavir twice daily and showed a suboptimal dolutegravir C24 (554 ng/mL). The two remaining patients with VF both had a GSS of 3 and were receiving 50 mg of dolutegravir once daily associated with two NRTIs (abacavir/lamivudine, n = 1; tenofovir disoproxil fumarate/emtricitabine, n = 1). One of these two patients had a thymidine-associated mutation (T215F/I/L/Y) in an historical plasma resistance genotype and showed adequate dolutegravir C24 at the time of VF (W48, 2843 ng/mL). HIV integrase Sanger sequencing was successful in three patients, two at the first VF timepoint and one at the second VF timepoint, showing no selection of resistance-associated mutations. Two of the four patients who experienced VF had been switched from a raltegravir-based regimen. One of these patients was therapeutically successful with all pVL <50 copies/mL during the raltegravir-based regimen. In contrast, the second INI-pretreated patient had experienced a previous VF during the raltegravir-based regimen without detectable integrase resistance mutations. Discussion In this study, based on an observational cohort of 239 patients switching to a dolutegravir-based regimen with a follow-up of 1 year, we observed a high level of maintenance of virological suppression, including in patients with a GSS ≤2. First, our patients’ characteristics differed according to their GSS. As might be expected, patients with a GSS between 1 and 2.5 were HIV infected and cART treated for a longer period and had received a higher number of ART regimens than those patients with a GSS of 3. Obviously, patients with a GSS between 1 and 2.5 exhibited more frequently archived resistance mutations than patients with a GSS of 3. In the present study, patients with a GSS ≤2.5 were cART treated for a longer period with a median of 18 years compared with only 4 years in the STRIIVING trial, in which moreover the patients had no previous VF.1 In our study, 33% of patients had experienced previous VF during their therapeutic history with the selection of at least the M184V mutation. These findings highlight the differences between populations assessed in randomized clinical trials and in observational cohorts. We observed a very high level of maintenance of virological suppression, with 92% of the patients having pVL <20 copies/mL at W48 and 96% of pVL values being <50 copies/mL during the study period. In the STRIIVING trial, 85% of patients had pVL <50 copies/mL at W24 following the switch to dolutegravir-based STR and 14% had no virological data.1 A similarly high level of maintained virological suppression has been observed in studies assessing the efficacy of switching to dolutegravir + lamivudine dual therapy; 101/104 patients exhibited therapeutic success at W48 in the LAMIDOL non-comparative trial,4 and 27/27 patients exhibited therapeutic success at W96 in the DOLULAM observational cohort.5 In our study, VF occurred in only 1.7% of patients, with low pVL and no emergence of resistance in the case of successful integrase amplification. Interestingly, no patients in VF were from the group with GSS equal to 1 or 1.5; one patient had a GSS of 2, one had a GSS of 2.5 and the remaining two had a GSS of 3. Furthermore, two of the four patients who experienced VF in our study had been pre-exposed to raltegravir, and, of these, one had persistent viral replication. Darunavir/ritonavir was associated with dolutegravir for 2 of the 4 patients with VF, while darunavir was included in cART for only 5 of the 239 patients in the cohort. It is known that this combination can result in drug–drug interactions.13 Although plasma dolutegravir C24 was >1000 ng/mL in the three assessed plasma samples, plasma darunavir C24 was suboptimal in one case. In our study, 20 (8.4%) of our patients discontinued the dolutegravir-based regimen due to adverse events, a higher proportion than observed in the STRIIVING randomized clinical trial, which reported only 4% discontinuing at W24 in the early switch arm and 2% in the late switch arm.1 However, this rate of discontinuation is similar to that observed in other clinical cohorts.14,15 Previous switch strategies conducted in the same centre showed discontinuation rates of 17% and 15% during the first year following the switch to the elvitegravir-based STR and during the first two years after the switch to the rilpivirine-based STR, respectively.14,15 Seventy-two percent of patients included in the present switch study had no detectable viraemia at initiation of the dolutegravir-based regimen, which is similar to the rate of 70% observed in our previous switch studies on initiation of elvitegravir- or rilpivirine-based STR.14,15 As in these previous studies, there was no evolution of residual viraemia following the switch to the dolutegravir-based regimen, even in patients with GSS ≤2. These findings suggest that maintenance strategies probably do not need the same high therapeutic pressure as initiation strategies, because patients with low GSSs had good virological response. However, we must stress several factors that could explain the efficacy of this strategy despite low GSSs: (i) our patients were treated for a long period of time and were in strict virological suppression (i.e. all pVL <50 copies/mL) for a median of 3 years; (ii) the most prevalent archived resistance mutation was the M184V mutation, which displays specific in vitro characteristics including a significant decrease in viral replicative capacity;16,17 (iii) historical plasma genotypes were performed >9 years before the switch, and the proportion of resistant viruses within the cellular reservoir at the time of the switch was unknown, though these were most likely present in a minority proportion. In the recent MOBIDIP trial, the maintenance arm with PI/ritonavir + lamivudine was associated with a high rate of success despite the presence of the M184V mutation in nearly all patients, while PI/ritonavir monotherapy was shown to be statistically inferior to PI/ritonavir + lamivudine dual therapy.18 Regarding the DOLULAM observational cohort, 17 of the 27 patients had the M184I/V mutation detected in DNA or RNA by Sanger or ultra-deep sequencing technology and no VF occurred during the first two years of dolutegravir + lamivudine dual therapy.19 Furthermore, the M184V mutation, detected in the historical genotypes of eight patients, was detected by ultra-deep sequencing technology in only five patients at the initiation of the DOLULAM study, suggesting that the proportion of M184V-mutated viruses in the cellular reservoir decreases over time.19 Therefore, the unexpected results obtained in patients with a low GSS in the present study cannot be extrapolated to other types of maintenance strategies combining dolutegravir with drugs other than lamivudine/emtricitabine with reduced antiviral activity due to the presence of resistance mutations. However, it is important to note that in this study, the M184V mutation was present in two-thirds of patients with a GSS of 2 or 2.5, which means that the low GSS of the remaining third did not result from the presence of the M184V mutation, but from other resistance profiles. PK analysis based on 348 drug plasma C24, corresponding to 216 patients, showed a good treatment adherence and a low PK variability. Thus, the dolutegravir C24 obtained were sufficient to effectively maintain virological suppression including in dual-therapy strategies. Interestingly, high dolutegravir C24 were found to be associated with the occurrence of neuropsychiatric side effects, and suboptimal dolutegravir C24 was observed in two cases among the three patients experiencing VF with available C24. This study has limitations because it is a retrospective observational cohort study with significant heterogeneity in patient characteristics. For the same reason, pVL and plasma drug concentrations are not available for all patients at all study timepoints, unlike the strength of randomized controlled trials. In conclusion, these findings suggest that in long-term virologically suppressed patients with previous VF and historical resistance mutations, a dolutegravir-based regimen can maintain virological suppression, including at residual viraemia levels. These results included patients receiving a dual therapy with two fully active antiretroviral drugs or a ‘functional’ dual therapy with an incompletely active backbone, mainly due to the presence of the M184V mutation. These observational results need to be confirmed in clinical trials. Acknowledgements We thank Sarah Peerbaccus for her helpful assistance.  We are indebted to the following for their assistance in data collection: E. Bouvet, S. Matheron, S. Lariven, C. Rioux, X. Lescure, M. Ahouanto, E. Casalino, G. Castanedo, X. Duval, Z. Eid, S. Fegueux, V. Gregoire, E. Papot, S. Legac, S. Harent, C. Jestin, K. Jidar, M. A. Khuong, N. Landgraf, Y. Latorre, C. Leport, A. Lepretre, F. Lheriteau, F. Michard, G. Morau, B. Phung, A. Pinto, M. H. Prevot, S. Puget, P. Ralaimazava, H. Rousselot, F. Louni, C. Godard, Z. Julia, M. Chansombat and K. Hamdoud. This work was presented at the 9th IAS Conference on HIV Science, 23–26 July 2017, Paris, France (Abstract number: MOPEB0316). Funding This work was supported by the French National Agency for Research on AIDS and Viral Hepatitis (ANRS). Transparency declarations C. C. and D. D. received honoraria and travel grants from ViiV Healthcare, Janssen-Cilag, Gilead Sciences and MSD. G. P. received travel grants, consultancy fees, honoraria or study grants from various pharmaceutical companies, including Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck and ViiV Healthcare. M. P. L. received travel grants from Janssen-Cilag. All other authors: none to declare. References 1 Trottier B , Lake JE , Logue K et al. Dolutegravir/abacavir/lamivudine versus current ART in virally suppressed patients (STRIIVING): a 48-week, randomized, non-inferiority, open-label, Phase IIIb study . Antivir Ther 2017 ; 22 : 295 – 305 . Google Scholar CrossRef Search ADS PubMed 2 Negredo E , Estrada V , Domingo P et al. Switching from a ritonavir-boosted PI to dolutegravir as an alternative strategy in virologically suppressed HIV-infected individuals . J Antimicrob Chemother 2017 ; 72 : 844 – 9 . Google Scholar PubMed 3 Llibre J , Hung C-C , Brinson C et al. Phase III SWORD 1&2: switch to DTG+RPV maintains virologic suppression through 48 wks. In: Abstracts of the Conference on Retroviruses and Opportunistic Infections, Seattle, WA, USA, 2017. Abstract 44LB. Foundation for Retrovirology and Human Health, Alexandria, VA, USA. 4 Joly V , Burdet C , Landman R et al. Promising results of dolutegravir+lamivudine maintenance in ANRS 167 LAMIDOL trial. In: Abstracts of the Conference on Retroviruses and Opportunistic Infections, Seattle, WA, USA, 2017. Abstract 458. Foundation for Retrovirology and Human Health, Alexandria, VA, USA. 5 Reynes J , Meftah N , Tuaillon E et al. Dual regimen with dolutegravir and lamivudine maintains virologic suppression even in heavily treatment experienced HIV-infected patients: 96 weeks results from maintenance DOLULAM study. In: Abstracts of the Ninth IAS Conference on HIV Science, Paris, France, 2017. Abstract MOPEB0322. 6 Katlama C , Soulié C , Caby F et al. Dolutegravir as monotherapy in HIV-1-infected individuals with suppressed HIV viraemia . J Antimicrob Chemother 2016 ; 71 : 2646 – 50 . Google Scholar CrossRef Search ADS PubMed 7 Oldenbuettel C , Wolf E , Ritter A et al. Dolutegravir monotherapy as treatment de-escalation in HIV-infected adults with virological control: doluMono cohort results . Antivir Ther 2017 ; 22 : 169 – 72 . Google Scholar CrossRef Search ADS PubMed 8 Haïm-Boukobza S , Morand-Joubert L , Flandre P et al. Higher efficacy of nevirapine than efavirenz to achieve HIV-1 plasma viral load below 1 copy/ml . AIDS 2011 ; 25 : 341 – 4 . Google Scholar CrossRef Search ADS PubMed 9 Bonora S , Nicastri E , Calcagno A et al. Ultrasensitive assessment of residual HIV viraemia in HAART-treated patients with persistently undetectable plasma HIV-RNA: a cross-sectional evaluation . J Med Virol 2009 ; 81 : 400 – 5 . Google Scholar CrossRef Search ADS PubMed 10 Jung BH , Rezk NL , Bridges AS et al. Simultaneous determination of 17 antiretroviral drugs in human plasma for quantitative analysis with liquid chromatography-tandem mass spectrometry . Biomed Chromatogr 2007 ; 21 : 1095 – 104 . Google Scholar CrossRef Search ADS PubMed 11 Min S , Sloan L , DeJesus E et al. Antiviral activity, safety, and pharmacokinetics/pharmacodynamics of dolutegravir as 10-day monotherapy in HIV-1-infected adults . AIDS 2011 ; 25 : 1737 – 45 . Google Scholar CrossRef Search ADS PubMed 12 Song I , Chen S , Piscitelli S et al. PK-PD relationship of dolutegravir in INI-naïve subjects. In: Abstracts of the Fifty-third Interscience Conference on Antimicrobial Agents and Chemotherapy, Denver, CO, USA, 2013. Abstract A-1573. American Society for Microbiology, Washington, DC, USA. 13 Lê MP , Pain J-B , Desnoyer A et al. Dolutegravir drug interaction with DRV/r or ATV/r: impact on its pharmacokinetic? In: Abstracts of the Sixteenth International Workshop on Clinical Pharmacology of HIV & Hepatitis Therapy, Washington, DC, 2015. Abstract 75. 14 Perrier M , Charpentier C , Peytavin G et al. Switch as maintenance to elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate: week 48 results in a clinical cohort . J Antimicrob Chemother 2017 ; 72 : 1745 – 51 . Google Scholar CrossRef Search ADS PubMed 15 Charpentier C , Lê MP , Joly V et al. Use of PCR signal and therapeutic drug monitoring in a switch cohort study to tenofovir/emtricitabine/rilpivirine: a W96 follow-up . PLoS One 2015 ; 10 : e0134430. Google Scholar CrossRef Search ADS PubMed 16 Boucher CA , Cammack N , Schipper P et al. High-level resistance to (−) enantiomeric 2′-deoxy-3′-thiacytidine in vitro is due to one amino acid substitution in the catalytic site of human immunodeficiency virus type 1 reverse transcriptase . Antimicrob Agents Chemother 1993 ; 37 : 2231 – 4 . Google Scholar CrossRef Search ADS PubMed 17 Back NK , Nijhuis M , Keulen W et al. Reduced replication of 3TC-resistant HIV-1 variants in primary cells due to a processivity defect of the reverse transcriptase enzyme . EMBO J 1996 ; 15 : 4040 – 9 . Google Scholar PubMed 18 Ciaffi L , Koulla-Shiro S , Sawadogo AB et al. Boosted protease inhibitor monotherapy versus boosted protease inhibitor plus lamivudine dual therapy as second-line maintenance treatment for HIV-1-infected patients in sub-Saharan Africa (ANRS12 286/MOBIDIP): a multicentre, randomised, parallel, open-label, superiority trial . Lancet HIV 2017 ; 4 : e384 – 92 . Google Scholar CrossRef Search ADS PubMed 19 Charpentier C , Montes B , Perrier M et al. HIV-1 DNA ultra-deep sequencing analysis at initiation of the dual therapy dolutegravir+lamivudine in the maintenance DOLULAM pilot study . J Antimicrob Chemother 2017 ; 72 : 2831 – 6 . 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) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Antimicrobial Chemotherapy Oxford University Press

High virological suppression regardless of the genotypic susceptibility score after switching to a dolutegravir-based regimen: week 48 results in an observational cohort

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Oxford University Press
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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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0305-7453
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1460-2091
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10.1093/jac/dky062
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Abstract

Abstract Objectives To assess, in a clinical cohort, the efficacy of switching current ART in virologically suppressed patients to a dolutegravir-based regimen, regardless of the genotypic susceptibility score (GSS). Patients and methods This was an observational single-centre study assessing ART-treated patients with plasma viral load (pVL) <50 copies/mL who were switched to a dolutegravir-based regimen with 1 year of follow-up. PCR negative was defined as an undetected PCR signal. Trough plasma concentration (C24) was determined using UPLC-MS/MS. Results Two hundred and thirty-nine patients initiated a dolutegravir-based regimen: 12%, 29% and 59% had a total GSS of 1 or 1.5 (group 1), 2 or 2.5 (group 2) and 3 (group 3), respectively. At switch initiation, the median time since first ART and the median duration with pVL <50 copies/mL were 13 years (IQR = 6–19) and 3 years (IQR = 1–6), respectively. Median times since last genotype were 9, 10 and 5 years for groups 1, 2 and 3, respectively. Twenty patients (8.4%) discontinued the dolutegravir-based regimen due to adverse events. During the study, 96.4% (n = 661/686) of all pVL were <50 copies/mL. Four patients (1.7%) experienced virological failure (two pVL >50 copies/mL) without emergence of resistance; these patients’ GSSs were 2, 2.5, 3 and 3. The median dolutegravir C24 was 1545 ng/mL (IQR = 1150–2097). Of the patients with pVL <20 copies/mL, 72% were PCR negative during the follow-up, with no difference between the three groups of patients. Conclusions This observational cohort study showed a high level of virological suppression maintenance in the first year following the switch to a dolutegravir-based regimen, even in patients with GSS ≤2. Introduction Dolutegravir, the newest integrase inhibitor (INI) on the market, exhibits a higher genetic barrier to resistance than the first-generation INI compounds raltegravir and elvitegravir. The STRIIVING study (a Phase 3, randomized, open-label, multicentre clinical trial) assessed the effect of switching from triple combination ART (cART) to the coformulated abacavir/lamivudine/dolutegravir single-tablet regimen (STR) compared with continuing cART.1 This trial included moderately pretreated patients undergoing first- or second-line therapy who did not have a history of virological failure (VF) and who had maintained plasma viral load (pVL) <50 copies/mL for at least 6 months under their current cART.1 The study demonstrated the non-inferiority of switching, with 85% of the participants in the switch group maintaining pVL <50 copies/mL at week (W) 24.1 Other studies have tested specific switch regimens, for example, to dolutegravir-based STR,2 to dolutegravir + rilpivirine3 and dolutegravir + lamivudine4,5 dual therapy, and even to the non-recommended dolutegravir monotherapy.6,7 Given that most of these studies included patients without a history of VF, there is a scarcity of data evaluating the effectiveness of different switch strategies in large populations of patients with varied genotypic susceptibility scores (GSSs). There are few data available on the efficacy of switching to a dolutegravir-based regimen in maintaining virological suppression in a clinical cohort of patients with longer and more diverse therapeutic histories. Additionally, no cohort study has assessed the impact on residual viraemia of switching to a dolutegravir-based regimen. Previous studies have shown that residual viraemia is detected more frequently with boosted PI than with NNRTI.8,9 The aim of this study was to determine the virological and pharmacological efficacy of switching from ongoing cART to a dolutegravir-based regimen in maintaining virological suppression in a clinical cohort of virologically suppressed patients at W48, depending on the GSS for the dolutegravir-based regimen. The study also evaluates the impact of this switch on residual viraemia. Patients and methods Study population We conducted a prospective observational single-centre cohort study, enrolling all patients successfully treated with cART (i.e. with pVL <50 copies/mL) whom physicians had decided to switch to a dolutegravir-based regimen between September 2014 and March 2016 and for whom a plasma historical genotypic resistance test was available. Ethics All the patients enrolled in this study gave their written informed consent to having their medical chart stored in the Nadis® electronic medical record system, which was designed for medical follow-up of HIV-infected patients, including the use of their biological data for research studies (www.dataids.org Fedialis Medica, Marly Le Roi, France; CNIL number: 1171457; 24 May 2006). Virological analysis Historical genotypic resistance tests of HIV protease, reverse transcriptase and integrase regions, available before ART initiation and/or at time of previous VF, were performed according to the complete sequencing procedures and primers sequences described at www.hivfrenchresistance.org. Sequences were interpreted using the Agence Nationale de Recherches sur le SIDA et les hépatites virales (ANRS) resistance algorithm (www.hivfrenchresistance.org; September 2016; version 26). The GSS of the cART regimen was calculated based on the cumulative historical genotypic resistance tests using the ANRS algorithm, including dolutegravir, translating the interpretations ‘susceptible’, ‘possible resistance’ and ‘resistance’ into scores of 1, 0.5 and 0, respectively. Thus, we defined three groups of patients: (i) those with a GSS equal to 1 or 1.5 (group 1), i.e. essentially receiving dolutegravir as ‘functional monotherapy’; (ii) those with a GSS equal to 2 or 2.5 (group 2); and (iii) those with a GSS equal to 3, i.e. receiving fully active triple therapy. pVL data were collected from patients’ regular biological monitoring. Patients had at least two pVL during the year of follow-up sampled at W4, W12, W24, W36 or W48, with an acceptable interval of 1 month, except for the W4 sample. Plasma HIV-1 RNA quantification was performed using the COBAS® AmpliPrep/COBAS® TaqMan® HIV-1 Test, version 2.0 (Roche Molecular Systems, Branchburg, NJ, USA) with a limit of quantification of 20 copies/mL. PCR negative was defined as an undetected PCR signal, corresponding to an absence of residual viraemia. A viral blip was defined as a transient pVL >50 copies/mL (but <1000 copies/mL) and VF was defined as two consecutive pVL >50 copies/mL. Pharmacological analysis Steady-state plasma drug concentrations sampled 24 h post-dose (C24) were measured at at least one timepoint for each patient during the follow-up (between W4 and W48). C24 values were measured using UPLC combined with tandem MS (UPLC-MS/MS) (Waters Corporation Milford, MA, USA).10 Dolutegravir C24 values were interpreted according to effective cut-offs of 1000 and 600 ng/mL, based on the pharmacokinetic (PK)–pharmacodynamic relationship found in the SAILING trial.11,12 The inter- and intra-patient variability of plasma concentrations were also investigated and presented as a coefficient of variation (%) based on four measurements taken from patients during the study follow-up. Statistical analysis Non-parametric Mann–Whitney tests were used to statistically compare patient characteristics. Non-parametric Kruskal–Wallis one-way analyses of variance were performed to compare PK parameters. Results Patient characteristics Our observational cohort study assessed 239 virologically suppressed patients with historical genotypes who switched to a dolutegravir-based regimen during the study period; their characteristics are depicted in Table 1. A large proportion of patients (n = 229, 96%) received 50 mg of dolutegravir once daily. Table 1. Baseline characteristics of patients Characteristic Group 1 (GSS = 1 or 1.5), N = 28 Group 2 (GSS = 2 or 2.5), N = 70 Group 3 (GSS = 3), N = 141 Male, n (%) 22 (78.6) 37 (53) 99 (70) Age (years), median (IQR) 51 (47–57) 52 (46–58) 51 (42–58) Active hepatitis coinfection, n (%)  HBV (HBs Ag positive) 3 (11) 5 (7) 8 (6)  HCV (HCV RNA positive) 0 (0) 4 (6) 13 (9) Time since HIV diagnosis (years), median (IQR) 19 (14–24) 20 (16–25) 11 (6–20) Duration of prior ART (years), median (IQR) 17 (10–21) 18 (14–20) 8 (4–17) Number of previous ART lines, median (IQR) 8 (5–10) 7 (4–10) 4 (2–6) Duration of plasma HIV-1 RNA <50 copies/mL before switch (years), median (IQR) 3 (2–7) 4 (1–8) 3 (1–5) Baseline CD4 cell count (cells/mm3), median (IQR) 670 (435–863) 580 (508–913) 600 (415–786) Nadir CD4 cell count (cells/mm3), median (IQR) 197 (80–236) 198 (100–264) 244 (103–344) Zenith plasma HIV-1 RNA level (log10 copies/mL), median (IQR) 5.0 (4.6–5.3) 5.1 (4.7–5.5) 5.1 (4.5–5.4) Previous ART, n (%)  2 NRTI + 1 NNRTI 4 (14) 8 (11) 40 (28)  2 NRTI + 1 PI/r 15 (54) 31 (44) 63 (45)  INI-based treatment 5 (18) 25 (36) 31 (22)   2 NRTI + RAL 0 5 15   TDF/FTC/EVG/c 0 0 4   other RAL-based treatment 5 20 12  other ART 4 (14) 6 (9) 7 (5) HIV-1 subtype, n (%)  B 18 (64) 43 (62) 76 (54)  CRF02_AG 2 (7) 12 (17) 32 (23)  other non-B subtypes 8 (29) 15 (21) 33 (23) Number of NRTI drug resistance mutations, median (IQR) 3 (1–5) 3 (1–5) 0 (0–0) M184I/V mutations, n (%) 28 (100) 46 (66) 6 (4) NNRTI drug resistance mutations, n (%) 18 (64) 37 (53) 39 (28) Major PI drug resistance mutations, n (%) 10 (36) 17 (24) 8 (6) Time since last genotypic resistance test (years), median (IQR) 9 (4–12) 10 (3–13) 5 (2–8) Antiretroviral drugs associated with DTG, n (%)  ABC/3TC 20 (71) 8 (11) 96 (68)  TDF/FTC 2 (7) 6 (9) 27 (19)  RPV 2 (7) 24 (34) 0 (0)  DRV/r 0 (0) 5 (7) 0 (0)  ATV/r 1 (4) 7 (10) 0 (0)  RPV + NRTI 0 (0) 6 (9) 11 (8)  2 or 3 NRTIs 0 (0) 8 (11) 0 (0)  other antiretroviral drugs 3 (11) 6 (9) 7 (5) Characteristic Group 1 (GSS = 1 or 1.5), N = 28 Group 2 (GSS = 2 or 2.5), N = 70 Group 3 (GSS = 3), N = 141 Male, n (%) 22 (78.6) 37 (53) 99 (70) Age (years), median (IQR) 51 (47–57) 52 (46–58) 51 (42–58) Active hepatitis coinfection, n (%)  HBV (HBs Ag positive) 3 (11) 5 (7) 8 (6)  HCV (HCV RNA positive) 0 (0) 4 (6) 13 (9) Time since HIV diagnosis (years), median (IQR) 19 (14–24) 20 (16–25) 11 (6–20) Duration of prior ART (years), median (IQR) 17 (10–21) 18 (14–20) 8 (4–17) Number of previous ART lines, median (IQR) 8 (5–10) 7 (4–10) 4 (2–6) Duration of plasma HIV-1 RNA <50 copies/mL before switch (years), median (IQR) 3 (2–7) 4 (1–8) 3 (1–5) Baseline CD4 cell count (cells/mm3), median (IQR) 670 (435–863) 580 (508–913) 600 (415–786) Nadir CD4 cell count (cells/mm3), median (IQR) 197 (80–236) 198 (100–264) 244 (103–344) Zenith plasma HIV-1 RNA level (log10 copies/mL), median (IQR) 5.0 (4.6–5.3) 5.1 (4.7–5.5) 5.1 (4.5–5.4) Previous ART, n (%)  2 NRTI + 1 NNRTI 4 (14) 8 (11) 40 (28)  2 NRTI + 1 PI/r 15 (54) 31 (44) 63 (45)  INI-based treatment 5 (18) 25 (36) 31 (22)   2 NRTI + RAL 0 5 15   TDF/FTC/EVG/c 0 0 4   other RAL-based treatment 5 20 12  other ART 4 (14) 6 (9) 7 (5) HIV-1 subtype, n (%)  B 18 (64) 43 (62) 76 (54)  CRF02_AG 2 (7) 12 (17) 32 (23)  other non-B subtypes 8 (29) 15 (21) 33 (23) Number of NRTI drug resistance mutations, median (IQR) 3 (1–5) 3 (1–5) 0 (0–0) M184I/V mutations, n (%) 28 (100) 46 (66) 6 (4) NNRTI drug resistance mutations, n (%) 18 (64) 37 (53) 39 (28) Major PI drug resistance mutations, n (%) 10 (36) 17 (24) 8 (6) Time since last genotypic resistance test (years), median (IQR) 9 (4–12) 10 (3–13) 5 (2–8) Antiretroviral drugs associated with DTG, n (%)  ABC/3TC 20 (71) 8 (11) 96 (68)  TDF/FTC 2 (7) 6 (9) 27 (19)  RPV 2 (7) 24 (34) 0 (0)  DRV/r 0 (0) 5 (7) 0 (0)  ATV/r 1 (4) 7 (10) 0 (0)  RPV + NRTI 0 (0) 6 (9) 11 (8)  2 or 3 NRTIs 0 (0) 8 (11) 0 (0)  other antiretroviral drugs 3 (11) 6 (9) 7 (5) 3TC, lamivudine; ABC, abacavir; ATV, atazanavir; DTG, dolutegravir; DRV, darunavir; EVG, elvitegravir; FTC, emtricitabine; HBs Ag, Hepatitis B surface antigen; RAL, raltegravir; RPV, rilpivirine; TDF, tenofovir disoproxil fumarate; /r, boosted with ritonavir; /c, boosted with cobicistat. Table 1. Baseline characteristics of patients Characteristic Group 1 (GSS = 1 or 1.5), N = 28 Group 2 (GSS = 2 or 2.5), N = 70 Group 3 (GSS = 3), N = 141 Male, n (%) 22 (78.6) 37 (53) 99 (70) Age (years), median (IQR) 51 (47–57) 52 (46–58) 51 (42–58) Active hepatitis coinfection, n (%)  HBV (HBs Ag positive) 3 (11) 5 (7) 8 (6)  HCV (HCV RNA positive) 0 (0) 4 (6) 13 (9) Time since HIV diagnosis (years), median (IQR) 19 (14–24) 20 (16–25) 11 (6–20) Duration of prior ART (years), median (IQR) 17 (10–21) 18 (14–20) 8 (4–17) Number of previous ART lines, median (IQR) 8 (5–10) 7 (4–10) 4 (2–6) Duration of plasma HIV-1 RNA <50 copies/mL before switch (years), median (IQR) 3 (2–7) 4 (1–8) 3 (1–5) Baseline CD4 cell count (cells/mm3), median (IQR) 670 (435–863) 580 (508–913) 600 (415–786) Nadir CD4 cell count (cells/mm3), median (IQR) 197 (80–236) 198 (100–264) 244 (103–344) Zenith plasma HIV-1 RNA level (log10 copies/mL), median (IQR) 5.0 (4.6–5.3) 5.1 (4.7–5.5) 5.1 (4.5–5.4) Previous ART, n (%)  2 NRTI + 1 NNRTI 4 (14) 8 (11) 40 (28)  2 NRTI + 1 PI/r 15 (54) 31 (44) 63 (45)  INI-based treatment 5 (18) 25 (36) 31 (22)   2 NRTI + RAL 0 5 15   TDF/FTC/EVG/c 0 0 4   other RAL-based treatment 5 20 12  other ART 4 (14) 6 (9) 7 (5) HIV-1 subtype, n (%)  B 18 (64) 43 (62) 76 (54)  CRF02_AG 2 (7) 12 (17) 32 (23)  other non-B subtypes 8 (29) 15 (21) 33 (23) Number of NRTI drug resistance mutations, median (IQR) 3 (1–5) 3 (1–5) 0 (0–0) M184I/V mutations, n (%) 28 (100) 46 (66) 6 (4) NNRTI drug resistance mutations, n (%) 18 (64) 37 (53) 39 (28) Major PI drug resistance mutations, n (%) 10 (36) 17 (24) 8 (6) Time since last genotypic resistance test (years), median (IQR) 9 (4–12) 10 (3–13) 5 (2–8) Antiretroviral drugs associated with DTG, n (%)  ABC/3TC 20 (71) 8 (11) 96 (68)  TDF/FTC 2 (7) 6 (9) 27 (19)  RPV 2 (7) 24 (34) 0 (0)  DRV/r 0 (0) 5 (7) 0 (0)  ATV/r 1 (4) 7 (10) 0 (0)  RPV + NRTI 0 (0) 6 (9) 11 (8)  2 or 3 NRTIs 0 (0) 8 (11) 0 (0)  other antiretroviral drugs 3 (11) 6 (9) 7 (5) Characteristic Group 1 (GSS = 1 or 1.5), N = 28 Group 2 (GSS = 2 or 2.5), N = 70 Group 3 (GSS = 3), N = 141 Male, n (%) 22 (78.6) 37 (53) 99 (70) Age (years), median (IQR) 51 (47–57) 52 (46–58) 51 (42–58) Active hepatitis coinfection, n (%)  HBV (HBs Ag positive) 3 (11) 5 (7) 8 (6)  HCV (HCV RNA positive) 0 (0) 4 (6) 13 (9) Time since HIV diagnosis (years), median (IQR) 19 (14–24) 20 (16–25) 11 (6–20) Duration of prior ART (years), median (IQR) 17 (10–21) 18 (14–20) 8 (4–17) Number of previous ART lines, median (IQR) 8 (5–10) 7 (4–10) 4 (2–6) Duration of plasma HIV-1 RNA <50 copies/mL before switch (years), median (IQR) 3 (2–7) 4 (1–8) 3 (1–5) Baseline CD4 cell count (cells/mm3), median (IQR) 670 (435–863) 580 (508–913) 600 (415–786) Nadir CD4 cell count (cells/mm3), median (IQR) 197 (80–236) 198 (100–264) 244 (103–344) Zenith plasma HIV-1 RNA level (log10 copies/mL), median (IQR) 5.0 (4.6–5.3) 5.1 (4.7–5.5) 5.1 (4.5–5.4) Previous ART, n (%)  2 NRTI + 1 NNRTI 4 (14) 8 (11) 40 (28)  2 NRTI + 1 PI/r 15 (54) 31 (44) 63 (45)  INI-based treatment 5 (18) 25 (36) 31 (22)   2 NRTI + RAL 0 5 15   TDF/FTC/EVG/c 0 0 4   other RAL-based treatment 5 20 12  other ART 4 (14) 6 (9) 7 (5) HIV-1 subtype, n (%)  B 18 (64) 43 (62) 76 (54)  CRF02_AG 2 (7) 12 (17) 32 (23)  other non-B subtypes 8 (29) 15 (21) 33 (23) Number of NRTI drug resistance mutations, median (IQR) 3 (1–5) 3 (1–5) 0 (0–0) M184I/V mutations, n (%) 28 (100) 46 (66) 6 (4) NNRTI drug resistance mutations, n (%) 18 (64) 37 (53) 39 (28) Major PI drug resistance mutations, n (%) 10 (36) 17 (24) 8 (6) Time since last genotypic resistance test (years), median (IQR) 9 (4–12) 10 (3–13) 5 (2–8) Antiretroviral drugs associated with DTG, n (%)  ABC/3TC 20 (71) 8 (11) 96 (68)  TDF/FTC 2 (7) 6 (9) 27 (19)  RPV 2 (7) 24 (34) 0 (0)  DRV/r 0 (0) 5 (7) 0 (0)  ATV/r 1 (4) 7 (10) 0 (0)  RPV + NRTI 0 (0) 6 (9) 11 (8)  2 or 3 NRTIs 0 (0) 8 (11) 0 (0)  other antiretroviral drugs 3 (11) 6 (9) 7 (5) 3TC, lamivudine; ABC, abacavir; ATV, atazanavir; DTG, dolutegravir; DRV, darunavir; EVG, elvitegravir; FTC, emtricitabine; HBs Ag, Hepatitis B surface antigen; RAL, raltegravir; RPV, rilpivirine; TDF, tenofovir disoproxil fumarate; /r, boosted with ritonavir; /c, boosted with cobicistat. Taking into account all historical plasma genotypes, 28 (12%), 70 (29%) and 141 (59%) patients had a total GSS equal to 1 or 1.5 (group 1), 2 or 2.5 (group 2) or 3 (group 3), respectively. The most common antiretroviral drugs associated with dolutegravir were abacavir/lamivudine for group 1 (n = 20/28, 71%), rilpivirine for group 2 (n = 24/70, 34%) and abacavir/lamivudine for group 3 (n = 96/141, 68%) (Table 1). Only a few patients previously treated with an INI-containing regimen were switched to dolutegravir-based regimens, namely raltegravir (8.4%) and elvitegravir/cobicistat (1.7%). Similarly, only five patients in the whole cohort received dolutegravir and darunavir/ritonavir dual therapy, most likely due to the deleterious drug–drug interaction.13 Median times since first ART before the switch were 17 years (IQR = 10–21), 18 years (IQR = 14–20) and 8 years (IQR = 4–17) for groups 1, 2 and 3, respectively. Median times with pVL <50 copies/mL before the switch were 3 years (IQR = 2–7), 4 years (IQR = 1–8) and 3 years (IQR = 1–5) for groups 1, 2 and 3, respectively. Median times since the last historical resistance genotype were 9 years (IQR = 4–12), 10 years (IQR = 3–13) and 5 years (IQR = 2–8) for groups 1, 2 and 3, respectively. Regarding drug resistance mutations, the M184V mutation was present in 100%, 66% and 4% of historical resistance genotypes for groups 1, 2 and 3, respectively. Clearly, patients in groups 1 and 2 are more advanced in terms of resistance than those in group 3. Viruses with NNRTI resistance mutations were found in 64% and 53% of patients in groups 1 and 2, respectively, compared with 28% for group 3. Similarly, 36% and 24% of patients in groups 1 and 2, respectively, exhibited major PI resistance mutations, compared with 6% for group 3. Immunovirological outcome In this observational study, plasma specimens were available for 119 patients at W4, 140 patients at W12, 151 patients at W24, 129 patients at W36 and 147 patients at W48. During the first year following the switch to the dolutegravir-based regimen, 96.4% (n = 661/686) of all pVL measurements obtained were <50 copies/mL. Four patients (1.7%) experienced VF and 16 patients (6.7%) had a viral blip during this first year of follow-up based on the available samples. The proportion of viral blips did not differ between the different GSS groups: two (7.1%) in group 1, eight (11.4%) in group 2 and six (4.2%) in group 3. For two patients, there were no pVL control samples available, since treatment was stopped just after the first measurement of pVL >50 copies/mL. Plasma drug concentrations were available for 13 of the 16 patients who experienced a viral blip, showing dolutegravir C24 >1000 ng/mL in 12 (92%) of them. Median CD4 cell counts at baseline, W24 and W48 of the switch were 600/mm3 (IQR = 457–820), 670/mm3 (IQR = 469–890) and 680/mm3 (IQR = 500–914), respectively. Safety Between baseline and W48 of the switch, 20 patients (8.4%) discontinued treatment due to adverse events: nine due to neuropsychiatric side effects, two due to renal toxicities (both with increased plasma creatinine), two due to cutaneous side effects, one due to headache, three patients for personal reasons and three for other reasons. No differences were observed between the different GSS groups in terms of the proportion of patients who discontinued dolutegravir. In addition, three women stopped the dolutegravir-based regimen due to pregnancy. Assessment of residual viraemia The proportion of patients with pVL <20 copies/mL was 91%, 93%, 91%, 89%, 92% and 90% at baseline, W4, W12, W24, W36 and W48 of the switch, respectively (Figure 1). Among those with pVL <20 copies/mL, the proportion of patients with no PCR signal (PCR negative) was 72%, 79%, 71%, 68%, 71% and 72% at baseline, W4, W12, W24, W36 and W48, respectively (Figure 1). The longitudinal evolution of residual viraemia was similar between the different GSS groups. Figure 1. View largeDownload slide Distribution of HIV-1 pVL at baseline, W4, W12, W24, W36 and W48. Figure 1. View largeDownload slide Distribution of HIV-1 pVL at baseline, W4, W12, W24, W36 and W48. Pharmacological analysis A total of 348 drug plasma C24 values, corresponding to 216 patients, were measured during the first year following the switch to a dolutegravir-based regimen. Overall, the median dolutegravir C24 value was 1675 ng/mL (IQR = 1205–2311) (Figure 2). During the follow-up period, 84% and 95% of dolutegravir C24 values were considered adequate according to the cut-offs of 1000 and 600 ng/mL, respectively. Figure 2. View largeDownload slide Distribution (as median and IQR) of plasma C24 for dolutegravir (DTG), abacavir (ABC), lamivudine (3TC), emtricitabine (FTC), tenofovir (TFV) and rilpivirine (RPV); all visits combined. CV, coefficient of variation. Figure 2. View largeDownload slide Distribution (as median and IQR) of plasma C24 for dolutegravir (DTG), abacavir (ABC), lamivudine (3TC), emtricitabine (FTC), tenofovir (TFV) and rilpivirine (RPV); all visits combined. CV, coefficient of variation. Inter-patient variability of dolutegravir C24 was 53%. Intra-patient variability of dolutegravir C24 was 27%. Associated antiretroviral C24 values (abacavir, lamivudine, emtricitabine, tenofovir and rilpivirine) are presented in Figure 2. No differences were reported in dolutegravir and associated antiretroviral C24 values between the different follow-up times (W4, W12, W24, W36 and W48). Plasma drug concentrations (dolutegravir C24) were available for 13 of the 20 patients who discontinued an INI-based regimen due to adverse events; the median was 2190 ng/mL (IQR = 1479–2303). Interestingly, the three patients with the highest dolutegravir C24 values discontinued the regimen due to neuropsychiatric side effects; these patients were also receiving abacavir/lamivudine in two cases and rilpivirine in one case. Description of VF Among the four patients who experienced VF, three were infected with a B subtype and one with a CRF12_BF recombinant. At the time of VF, which occurred at W4 (n = 1), W24 (n = 1) and W48 (n = 2), the four patients had low pVL values (91, 91, 101 and 200 copies/mL) (Table 2). Table 2. Description of patients experiencing VF Patient ID Antiretrovirals associated with DTG GSS First pVL >50 copies/mL pVL control RT historical genotype Previous antiretroviral regimen HIV-1 subtype Genotype at time of first pVL >50 copies/mL Genotype at time of pVL control C24 DTG (ng/mL) time value (copies/mL) time value (copies/mL) RT/ protease INT RT/ protease INT 8 DRV/r 2 W48 200 W60 89 WT RAL+DRV/r B WT WT NA NA 1444 17 ABC/3TC+DRV/r 2.5 W48 91 W52 84 M184V ABC/3TC+DRV/r B NA NA NA NA 554 67 TDF/FTC 3 W4 91 W8 64 T215F/I/L/Y TDF/FTC+ETR+RAL CRF12_BF NA NA NA WT 2843 130 ABC/3TC 3 W24 101 W30 73 WT ZDV/3TC+LPV/r B WT WT NA NA not available Patient ID Antiretrovirals associated with DTG GSS First pVL >50 copies/mL pVL control RT historical genotype Previous antiretroviral regimen HIV-1 subtype Genotype at time of first pVL >50 copies/mL Genotype at time of pVL control C24 DTG (ng/mL) time value (copies/mL) time value (copies/mL) RT/ protease INT RT/ protease INT 8 DRV/r 2 W48 200 W60 89 WT RAL+DRV/r B WT WT NA NA 1444 17 ABC/3TC+DRV/r 2.5 W48 91 W52 84 M184V ABC/3TC+DRV/r B NA NA NA NA 554 67 TDF/FTC 3 W4 91 W8 64 T215F/I/L/Y TDF/FTC+ETR+RAL CRF12_BF NA NA NA WT 2843 130 ABC/3TC 3 W24 101 W30 73 WT ZDV/3TC+LPV/r B WT WT NA NA not available 3TC, lamivudine; ABC, abacavir; DTG, dolutegravir; DRV, darunavir; ETR, etravirine; FTC, emtricitabine; INT, integrase; LPV, lopinavir; NA, not amplified; RAL, raltegravir; RT, reverse transcriptase; TDF, tenofovir disoproxil fumarate; ZDV, zidovudine; /r, boosted with ritonavir. Table 2. Description of patients experiencing VF Patient ID Antiretrovirals associated with DTG GSS First pVL >50 copies/mL pVL control RT historical genotype Previous antiretroviral regimen HIV-1 subtype Genotype at time of first pVL >50 copies/mL Genotype at time of pVL control C24 DTG (ng/mL) time value (copies/mL) time value (copies/mL) RT/ protease INT RT/ protease INT 8 DRV/r 2 W48 200 W60 89 WT RAL+DRV/r B WT WT NA NA 1444 17 ABC/3TC+DRV/r 2.5 W48 91 W52 84 M184V ABC/3TC+DRV/r B NA NA NA NA 554 67 TDF/FTC 3 W4 91 W8 64 T215F/I/L/Y TDF/FTC+ETR+RAL CRF12_BF NA NA NA WT 2843 130 ABC/3TC 3 W24 101 W30 73 WT ZDV/3TC+LPV/r B WT WT NA NA not available Patient ID Antiretrovirals associated with DTG GSS First pVL >50 copies/mL pVL control RT historical genotype Previous antiretroviral regimen HIV-1 subtype Genotype at time of first pVL >50 copies/mL Genotype at time of pVL control C24 DTG (ng/mL) time value (copies/mL) time value (copies/mL) RT/ protease INT RT/ protease INT 8 DRV/r 2 W48 200 W60 89 WT RAL+DRV/r B WT WT NA NA 1444 17 ABC/3TC+DRV/r 2.5 W48 91 W52 84 M184V ABC/3TC+DRV/r B NA NA NA NA 554 67 TDF/FTC 3 W4 91 W8 64 T215F/I/L/Y TDF/FTC+ETR+RAL CRF12_BF NA NA NA WT 2843 130 ABC/3TC 3 W24 101 W30 73 WT ZDV/3TC+LPV/r B WT WT NA NA not available 3TC, lamivudine; ABC, abacavir; DTG, dolutegravir; DRV, darunavir; ETR, etravirine; FTC, emtricitabine; INT, integrase; LPV, lopinavir; NA, not amplified; RAL, raltegravir; RT, reverse transcriptase; TDF, tenofovir disoproxil fumarate; ZDV, zidovudine; /r, boosted with ritonavir. One patient with VF had a GSS of 2, was receiving dual therapy with 50 mg of dolutegravir + 800/100 mg of darunavir/ritonavir once daily and had no historical resistance mutations. He showed adequate C24 at the time of VF (W48, 1444 ng/mL for dolutegravir and 2057 ng/mL for darunavir) but suboptimal C24 at the two preceding timepoints (297 and 485 ng/mL at W24 and W36, respectively). The second patient with VF had a GSS of 2.5 due to an historical M184V mutation, was receiving abacavir/lamivudine/dolutegravir once daily + 600/100 mg of darunavir/ritonavir twice daily and showed a suboptimal dolutegravir C24 (554 ng/mL). The two remaining patients with VF both had a GSS of 3 and were receiving 50 mg of dolutegravir once daily associated with two NRTIs (abacavir/lamivudine, n = 1; tenofovir disoproxil fumarate/emtricitabine, n = 1). One of these two patients had a thymidine-associated mutation (T215F/I/L/Y) in an historical plasma resistance genotype and showed adequate dolutegravir C24 at the time of VF (W48, 2843 ng/mL). HIV integrase Sanger sequencing was successful in three patients, two at the first VF timepoint and one at the second VF timepoint, showing no selection of resistance-associated mutations. Two of the four patients who experienced VF had been switched from a raltegravir-based regimen. One of these patients was therapeutically successful with all pVL <50 copies/mL during the raltegravir-based regimen. In contrast, the second INI-pretreated patient had experienced a previous VF during the raltegravir-based regimen without detectable integrase resistance mutations. Discussion In this study, based on an observational cohort of 239 patients switching to a dolutegravir-based regimen with a follow-up of 1 year, we observed a high level of maintenance of virological suppression, including in patients with a GSS ≤2. First, our patients’ characteristics differed according to their GSS. As might be expected, patients with a GSS between 1 and 2.5 were HIV infected and cART treated for a longer period and had received a higher number of ART regimens than those patients with a GSS of 3. Obviously, patients with a GSS between 1 and 2.5 exhibited more frequently archived resistance mutations than patients with a GSS of 3. In the present study, patients with a GSS ≤2.5 were cART treated for a longer period with a median of 18 years compared with only 4 years in the STRIIVING trial, in which moreover the patients had no previous VF.1 In our study, 33% of patients had experienced previous VF during their therapeutic history with the selection of at least the M184V mutation. These findings highlight the differences between populations assessed in randomized clinical trials and in observational cohorts. We observed a very high level of maintenance of virological suppression, with 92% of the patients having pVL <20 copies/mL at W48 and 96% of pVL values being <50 copies/mL during the study period. In the STRIIVING trial, 85% of patients had pVL <50 copies/mL at W24 following the switch to dolutegravir-based STR and 14% had no virological data.1 A similarly high level of maintained virological suppression has been observed in studies assessing the efficacy of switching to dolutegravir + lamivudine dual therapy; 101/104 patients exhibited therapeutic success at W48 in the LAMIDOL non-comparative trial,4 and 27/27 patients exhibited therapeutic success at W96 in the DOLULAM observational cohort.5 In our study, VF occurred in only 1.7% of patients, with low pVL and no emergence of resistance in the case of successful integrase amplification. Interestingly, no patients in VF were from the group with GSS equal to 1 or 1.5; one patient had a GSS of 2, one had a GSS of 2.5 and the remaining two had a GSS of 3. Furthermore, two of the four patients who experienced VF in our study had been pre-exposed to raltegravir, and, of these, one had persistent viral replication. Darunavir/ritonavir was associated with dolutegravir for 2 of the 4 patients with VF, while darunavir was included in cART for only 5 of the 239 patients in the cohort. It is known that this combination can result in drug–drug interactions.13 Although plasma dolutegravir C24 was >1000 ng/mL in the three assessed plasma samples, plasma darunavir C24 was suboptimal in one case. In our study, 20 (8.4%) of our patients discontinued the dolutegravir-based regimen due to adverse events, a higher proportion than observed in the STRIIVING randomized clinical trial, which reported only 4% discontinuing at W24 in the early switch arm and 2% in the late switch arm.1 However, this rate of discontinuation is similar to that observed in other clinical cohorts.14,15 Previous switch strategies conducted in the same centre showed discontinuation rates of 17% and 15% during the first year following the switch to the elvitegravir-based STR and during the first two years after the switch to the rilpivirine-based STR, respectively.14,15 Seventy-two percent of patients included in the present switch study had no detectable viraemia at initiation of the dolutegravir-based regimen, which is similar to the rate of 70% observed in our previous switch studies on initiation of elvitegravir- or rilpivirine-based STR.14,15 As in these previous studies, there was no evolution of residual viraemia following the switch to the dolutegravir-based regimen, even in patients with GSS ≤2. These findings suggest that maintenance strategies probably do not need the same high therapeutic pressure as initiation strategies, because patients with low GSSs had good virological response. However, we must stress several factors that could explain the efficacy of this strategy despite low GSSs: (i) our patients were treated for a long period of time and were in strict virological suppression (i.e. all pVL <50 copies/mL) for a median of 3 years; (ii) the most prevalent archived resistance mutation was the M184V mutation, which displays specific in vitro characteristics including a significant decrease in viral replicative capacity;16,17 (iii) historical plasma genotypes were performed >9 years before the switch, and the proportion of resistant viruses within the cellular reservoir at the time of the switch was unknown, though these were most likely present in a minority proportion. In the recent MOBIDIP trial, the maintenance arm with PI/ritonavir + lamivudine was associated with a high rate of success despite the presence of the M184V mutation in nearly all patients, while PI/ritonavir monotherapy was shown to be statistically inferior to PI/ritonavir + lamivudine dual therapy.18 Regarding the DOLULAM observational cohort, 17 of the 27 patients had the M184I/V mutation detected in DNA or RNA by Sanger or ultra-deep sequencing technology and no VF occurred during the first two years of dolutegravir + lamivudine dual therapy.19 Furthermore, the M184V mutation, detected in the historical genotypes of eight patients, was detected by ultra-deep sequencing technology in only five patients at the initiation of the DOLULAM study, suggesting that the proportion of M184V-mutated viruses in the cellular reservoir decreases over time.19 Therefore, the unexpected results obtained in patients with a low GSS in the present study cannot be extrapolated to other types of maintenance strategies combining dolutegravir with drugs other than lamivudine/emtricitabine with reduced antiviral activity due to the presence of resistance mutations. However, it is important to note that in this study, the M184V mutation was present in two-thirds of patients with a GSS of 2 or 2.5, which means that the low GSS of the remaining third did not result from the presence of the M184V mutation, but from other resistance profiles. PK analysis based on 348 drug plasma C24, corresponding to 216 patients, showed a good treatment adherence and a low PK variability. Thus, the dolutegravir C24 obtained were sufficient to effectively maintain virological suppression including in dual-therapy strategies. Interestingly, high dolutegravir C24 were found to be associated with the occurrence of neuropsychiatric side effects, and suboptimal dolutegravir C24 was observed in two cases among the three patients experiencing VF with available C24. This study has limitations because it is a retrospective observational cohort study with significant heterogeneity in patient characteristics. For the same reason, pVL and plasma drug concentrations are not available for all patients at all study timepoints, unlike the strength of randomized controlled trials. In conclusion, these findings suggest that in long-term virologically suppressed patients with previous VF and historical resistance mutations, a dolutegravir-based regimen can maintain virological suppression, including at residual viraemia levels. These results included patients receiving a dual therapy with two fully active antiretroviral drugs or a ‘functional’ dual therapy with an incompletely active backbone, mainly due to the presence of the M184V mutation. These observational results need to be confirmed in clinical trials. Acknowledgements We thank Sarah Peerbaccus for her helpful assistance.  We are indebted to the following for their assistance in data collection: E. Bouvet, S. Matheron, S. Lariven, C. Rioux, X. Lescure, M. Ahouanto, E. Casalino, G. Castanedo, X. Duval, Z. Eid, S. Fegueux, V. Gregoire, E. Papot, S. Legac, S. Harent, C. Jestin, K. Jidar, M. A. Khuong, N. Landgraf, Y. Latorre, C. Leport, A. Lepretre, F. Lheriteau, F. Michard, G. Morau, B. Phung, A. Pinto, M. H. Prevot, S. Puget, P. Ralaimazava, H. Rousselot, F. Louni, C. Godard, Z. Julia, M. Chansombat and K. Hamdoud. This work was presented at the 9th IAS Conference on HIV Science, 23–26 July 2017, Paris, France (Abstract number: MOPEB0316). Funding This work was supported by the French National Agency for Research on AIDS and Viral Hepatitis (ANRS). Transparency declarations C. C. and D. D. received honoraria and travel grants from ViiV Healthcare, Janssen-Cilag, Gilead Sciences and MSD. G. P. received travel grants, consultancy fees, honoraria or study grants from various pharmaceutical companies, including Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck and ViiV Healthcare. M. P. L. received travel grants from Janssen-Cilag. All other authors: none to declare. References 1 Trottier B , Lake JE , Logue K et al. Dolutegravir/abacavir/lamivudine versus current ART in virally suppressed patients (STRIIVING): a 48-week, randomized, non-inferiority, open-label, Phase IIIb study . Antivir Ther 2017 ; 22 : 295 – 305 . Google Scholar CrossRef Search ADS PubMed 2 Negredo E , Estrada V , Domingo P et al. Switching from a ritonavir-boosted PI to dolutegravir as an alternative strategy in virologically suppressed HIV-infected individuals . J Antimicrob Chemother 2017 ; 72 : 844 – 9 . Google Scholar PubMed 3 Llibre J , Hung C-C , Brinson C et al. Phase III SWORD 1&2: switch to DTG+RPV maintains virologic suppression through 48 wks. In: Abstracts of the Conference on Retroviruses and Opportunistic Infections, Seattle, WA, USA, 2017. Abstract 44LB. Foundation for Retrovirology and Human Health, Alexandria, VA, USA. 4 Joly V , Burdet C , Landman R et al. Promising results of dolutegravir+lamivudine maintenance in ANRS 167 LAMIDOL trial. In: Abstracts of the Conference on Retroviruses and Opportunistic Infections, Seattle, WA, USA, 2017. Abstract 458. Foundation for Retrovirology and Human Health, Alexandria, VA, USA. 5 Reynes J , Meftah N , Tuaillon E et al. Dual regimen with dolutegravir and lamivudine maintains virologic suppression even in heavily treatment experienced HIV-infected patients: 96 weeks results from maintenance DOLULAM study. In: Abstracts of the Ninth IAS Conference on HIV Science, Paris, France, 2017. Abstract MOPEB0322. 6 Katlama C , Soulié C , Caby F et al. Dolutegravir as monotherapy in HIV-1-infected individuals with suppressed HIV viraemia . J Antimicrob Chemother 2016 ; 71 : 2646 – 50 . Google Scholar CrossRef Search ADS PubMed 7 Oldenbuettel C , Wolf E , Ritter A et al. Dolutegravir monotherapy as treatment de-escalation in HIV-infected adults with virological control: doluMono cohort results . Antivir Ther 2017 ; 22 : 169 – 72 . Google Scholar CrossRef Search ADS PubMed 8 Haïm-Boukobza S , Morand-Joubert L , Flandre P et al. Higher efficacy of nevirapine than efavirenz to achieve HIV-1 plasma viral load below 1 copy/ml . AIDS 2011 ; 25 : 341 – 4 . Google Scholar CrossRef Search ADS PubMed 9 Bonora S , Nicastri E , Calcagno A et al. Ultrasensitive assessment of residual HIV viraemia in HAART-treated patients with persistently undetectable plasma HIV-RNA: a cross-sectional evaluation . J Med Virol 2009 ; 81 : 400 – 5 . Google Scholar CrossRef Search ADS PubMed 10 Jung BH , Rezk NL , Bridges AS et al. Simultaneous determination of 17 antiretroviral drugs in human plasma for quantitative analysis with liquid chromatography-tandem mass spectrometry . Biomed Chromatogr 2007 ; 21 : 1095 – 104 . Google Scholar CrossRef Search ADS PubMed 11 Min S , Sloan L , DeJesus E et al. Antiviral activity, safety, and pharmacokinetics/pharmacodynamics of dolutegravir as 10-day monotherapy in HIV-1-infected adults . AIDS 2011 ; 25 : 1737 – 45 . Google Scholar CrossRef Search ADS PubMed 12 Song I , Chen S , Piscitelli S et al. PK-PD relationship of dolutegravir in INI-naïve subjects. In: Abstracts of the Fifty-third Interscience Conference on Antimicrobial Agents and Chemotherapy, Denver, CO, USA, 2013. Abstract A-1573. American Society for Microbiology, Washington, DC, USA. 13 Lê MP , Pain J-B , Desnoyer A et al. Dolutegravir drug interaction with DRV/r or ATV/r: impact on its pharmacokinetic? In: Abstracts of the Sixteenth International Workshop on Clinical Pharmacology of HIV & Hepatitis Therapy, Washington, DC, 2015. Abstract 75. 14 Perrier M , Charpentier C , Peytavin G et al. Switch as maintenance to elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate: week 48 results in a clinical cohort . J Antimicrob Chemother 2017 ; 72 : 1745 – 51 . Google Scholar CrossRef Search ADS PubMed 15 Charpentier C , Lê MP , Joly V et al. 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Boosted protease inhibitor monotherapy versus boosted protease inhibitor plus lamivudine dual therapy as second-line maintenance treatment for HIV-1-infected patients in sub-Saharan Africa (ANRS12 286/MOBIDIP): a multicentre, randomised, parallel, open-label, superiority trial . Lancet HIV 2017 ; 4 : e384 – 92 . Google Scholar CrossRef Search ADS PubMed 19 Charpentier C , Montes B , Perrier M et al. HIV-1 DNA ultra-deep sequencing analysis at initiation of the dual therapy dolutegravir+lamivudine in the maintenance DOLULAM pilot study . J Antimicrob Chemother 2017 ; 72 : 2831 – 6 . 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: Mar 8, 2018

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