Four-days-a-week antiretroviral maintenance therapy in virologically controlled HIV-1-infected adults: the ANRS 162-4D trial

Four-days-a-week antiretroviral maintenance therapy in virologically controlled HIV-1-infected... Abstract Background Intermittent treatment could improve the convenience, tolerability and cost of ART, as well as patients’ quality of life. We conducted a 48 week multicentre study of a 4-days-a-week antiretroviral regimen in adults with controlled HIV-1-RNA plasma viral load (VL). Methods Eligible patients were adults with VL < 50 copies/mL for at least 1 year on triple therapy with a ritonavir-boosted PI (PI/r) or an NNRTI. The study protocol consisted of the same regimen taken on four consecutive days per week followed by a 3 day drug interruption. The primary outcome was the proportion of participants remaining in the strategy with VL < 50 copies/mL up to week 48. The study was designed to show an observed success rate of > 90%, with a power of 87% and a 5% type 1 error. The study was registered with ClinicalTrials.gov (NCT02157311) and EudraCT (2014-000146-29). Results One hundred patients (82 men), median age 47 years (IQR 40–53), were included. They had been receiving ART for a median of 5.1 (IQR 2.9–9.3) years and had a median CD4 cell count of 665 (IQR 543–829) cells/mm3. The ongoing regimen included PI/r in 29 cases and NNRTI in 71 cases. At 48 weeks, 96% of participants (95% CI 90%–98%) had no failure while remaining on the 4-days-a-week regimen. Virological failure occurred in three participants, who all resumed daily treatment and became resuppressed. One participant stopped the strategy. No severe treatment-related events occurred. Conclusions Antiretroviral maintenance therapy 4 days a week was effective for 48 weeks in 96% of patients, leading to potential reduction of long-term toxicities, high adherence to the antiretroviral regimen and drug cost saving. Introduction The treatment goal in HIV infection is to achieve continuous viral suppression, which has been shown to reduce morbidity and mortality and to reduce the risk of viral transmission. Current guidelines on combined ART (cART) recommend the use of two nucleoside analogues and a third agent chosen from the following classes: NNRTI, boosted PI and integrase strand transfer inhibitors (INSTIs).1,2 cART achieves complete viral suppression in most patients,3 but treatment has to be continued lifelong, with a risk of poor adherence, viral escape and long-term toxicity, particularly in ageing patients with comorbidities. Moreover, with growing economic constraints and increasing numbers of patients on therapy, the use of antiretroviral combinations with lower cost becomes essential. Several attempts have been made to lower drug exposure during maintenance therapy, including dose reductions,4,5 dual-agent combinations6 and boosted PI monotherapy.7 Although feasible in patients with fully suppressed viral load (VL), these strategies are not applicable to all patients and might be associated with low-level viral escape.7 After Dybul et al.,8 several teams tested short-cycle structured intermittent maintenance therapy, mostly with a 5 days on/2 days off efavirenz-based regimen, as in the BREATHER randomized trial.9,10 We have previously observed no virological failures in a cohort of 98 patients treated for 1 year with a 4 days on/3 days off maintenance regimen.11 Here we report the results of a multicentre pilot study (ANRS 162-4D) designed as a proof-of concept study to assess the efficacy and tolerability of a 4 days on/3 days off maintenance regimen in patients already on effective standard antiretroviral regimens. On this maintenance regimen with potential reduced long-term exposure to antiretroviral drugs, we also assessed the evolution of the viral reservoir, the inflammatory markers and the modification of plasma drug concentrations. Methods Study design and participants ANRS 162-4D was a 48 week, single-arm, prospective multicentre trial, conducted between July 2014 and January 2016. Patients were eligible if they were ≥18 years; had confirmed HIV-1 infection; had been receiving cART for >12 months, based on two nucleoside/tide analogues (tenofovir disoproxil fumarate, abacavir, lamivudine or emtricitabine) and a third agent consisting of a boosted PI (darunavir, lopinavir or atazanavir) or NNRTI (efavirenz, rilpivirine or etravirine), all given at standard recommended dosages, with no change in regimen in the previous 4 months; had VL ≤50 RNA copies/mL for at least 1 year; had a CD4 cell count >250 cells/mm3 for at least 6 months; had available genotypic results showing no evidence of resistance to any of the drugs in the ongoing regimen and no history of previous virological failure under the drugs used in the current antiretroviral combination; had acceptable laboratory values at screening [glomerular filtration rate calculated with the Modification of Diet in Renal Disease Study equation (MDRD) >60 mL/min, AST-ALT <3×ULN (upper limit of normal), haemoglobin >10 g/dL, >100 000 platelets/mm3]; a negative pregnancy test at screening and agreed to use contraception during the study for women of childbearing age; and provided written informed consent. Ethics The trial was conducted in accordance with Good Clinical Practices and the ethical principles of the Helsinki Declaration and followed ANRS recommendations for clinical research. The Ile-de-France XI Ethics Review Committee approved the study on 13 February 2014 and all the participants gave their written informed consent before entering the study. The study was registered with ClinicalTrials.gov (NCT02157311) and EudraCT (2014-000146-29). Procedures The screening visit [week 4 (W4)] was designed to obtain informed consent and to check the inclusion criteria. The RNA sequence of any previous drug resistance genotype was collected and analysed (ANRS-AC11 resistance algorithm, v. 0.24-2014, http://www.frenchresistance.org/). Four weeks later, inclusion in the study was confirmed and short-cycle maintenance therapy was started at the day 0 (D0) visit. The patients chose three consecutive days off therapy (Friday–Sunday or Saturday–Monday) and continued this 4/7 strategy until the end of the study. They were assessed clinically and biologically every 4 weeks from D0 to W16, then every 8 weeks until W48. A last blood sample was taken at W51 to confirm the final end point result. Laboratory tests were scheduled at the end of the 3 day off-treatment period, except at W16 and W40 (on treatment). Laboratory tests VL (Roche Cobas TaqMan HIV-1 v. 1.2 or Abbott Real-Time HIV-1) and T cell subpopulations were measured at every visit in the local laboratories. VL values >50 copies/mL were confirmed on a new sample taken 2–4 weeks later and events were classified as virological failure if VL at control was >50 copies/mL and as viral blip otherwise. An additional plasma sample was obtained and frozen at each visit for VL assay, drug resistance genotyping and drug assays. Whole-blood samples for centralized total cell-associated DNA measurement (real-time PCR, Biocentric, Bandol, France) and serum samples for inflammatory marker assays [C-reactive protein (CRP), IL-6, soluble CD14 (CD14s), IFN-γ-inducible protein 10 (IP-10) and monokine induced by γ-IFN (MIG-1)] were taken at D0, W24 and W48 (ProcartaPlex® Multiplex Immunoassays, Affymetrix, Vienna, Austria; and Magnetic Luminex® Screening Assay, RαD Systems, Minneapolis, MN, USA). Pharmacological evaluation The residual plasma concentrations of the third agent (PI or NNRTI) used in the antiretroviral combination were determined on treatment at D0, W16 and W40, and off treatment (D3) at W4, W8, W12, W24, W32 and W48, using a validated turbulent flow chromatographic method with triple quadrupole MS detection and electrospray ionization interface (Thermo Fisher, Les Ulis, France). The results were interpreted according to quantification and efficacy thresholds (respectively, in ng/mL, 100 and 1000 for efavirenz, 10 and 50 for etravirine, 5 and 40 for rilpivirine, 20 and 2000 for darunavir, 20 and 200 for atazanavir, and 20 and 4000 for lopinavir).12 Tolerability, quality of life and adherence Clinical and biological tolerability was evaluated at each visit. Lipodystrophy (waist and hip size, waist/hip ratio) and metabolic changes (fasting glucose, total cholesterol, HDL cholesterol, LDL cholesterol and triglycerides) were assessed at D0, W24 and W48. Adherence to the study strategy was assessed with a self-administered questionnaire based on last-week recall at each visit and by plasma drug measurements on and off treatment. In addition, a Medication Event Monitoring System (MEMS) capped-container substudy was conducted in a subgroup of participants treated with drugs contained in bottles with compatible caps (Truvada®, Atripla®, Eviplera®, Viread®) in five of the centres. Satisfaction with the strategy and quality of life, assessed with the PROQOL-HIV questionnaire13 and a questionnaire of perceived symptoms, was assessed at D0, W24 and W48. Outcomes The primary endpoint was therapeutic success, defined by the absence of virological failure and strategy failure up to W48. Virological failure was defined as a first VL >50 copies/mL, confirmed on a second sample 2–4 weeks later. Strategy failure was defined as discontinuation of the 4/7 strategy for 30 days or more, because of adverse events, the patient’s or investigator’s decision, or loss to follow-up (absence at more than two consecutive visits). Switches to a drug of the same class were not considered as failure and neither was interruption of the 4/7 strategy for pregnancy. Secondary outcomes included the proportion of patients with viral blips, the proportion of patients without any signal of viral replication (subgroup of patients tested with Roche-Taqman VL); the occurrence of grade 3/4 adverse events; changes in plasma creatinine, estimated glomerular filtration rate (eGFR) calculated with the MDRD equation, metabolic parameters and hepatic transaminases from D0 to W48; the occurrence of genotypic resistance in case of failure; changes in the CD4 and CD8 cell counts and the CD4/CD8 ratio from D0 to W48, changes in total HIV-DNA in PBMC from D0 to W24 and W48; changes in inflammatory markers from D0 to W48; the dynamics of residual NNRTI or PI concentrations during the on- and off-treatment phases; adherence to the study strategy; and changes in quality of life from D0 to W48. To assess adherence to the study strategy, we assessed the number of days that the MEMS-cap was opened, divided by number of days that the MEMS-cap was in use during the trial;9 the number of weeks that the MEMS-cap was opened exactly 4 days a week, or more or less than 4 days a week; the observance rate, estimated as the number of pills consumed (recorded using the self-reported questionnaire) divided by the number of pills that should theoretically have been consumed, classified as low (<80%), medium (80%–95%), high (95%–100%) or higher than expected (>100%); and changes in drug concentrations between the average of values recorded during the on-treatment period (last intake <48 h previously) and during the off-treatment period (last intake ≥48 h previously). Statistical considerations The study was designed to detect the difference between the null hypothesis proportion of 80% and the alternative proportion of 90% (an expected success rate) with a type 1 error of 5% and a power of 85%. An estimated 95 patients were required to achieve these goals. Enrolment of 95 patients, increased to 100 patients to account for non-evaluable patients, was requested to achieve these goals. The primary efficacy endpoint was analysed with an ITT approach. The 95% CI of the observed proportion of patients reaching the efficacy endpoint was calculated with the Kaplan–Meier method. Variables were summarized as proportions for categorical variables, median and IQR for continuous baseline variables and mean and SD for continuous variables used as endpoints. Changes in continuous variables between baseline and W48 were compared using the Wilcoxon paired test, except for quality-of-life (see below). All continuous variables used as endpoints were analysed with an ITT approach, with the last observation carried forward. The PROQOL-HIV questionnaire includes eight dimensions with scores ranging from 0 to 100.13 To assess quality of life and perceived symptoms, we created 10 datasets in which missing data were imputed from each participant’s other covariables. In these imputations, missing values were randomly sampled from their predicted distributions.14 Changes in quality of life dimensions were compared using Student’s t-test. Analyses were run on each of the 10 datasets, including the imputed values, and the results were combined with Rubin’s rules.14 Changes in satisfaction with care were estimated with a five-point scale item of the questionnaire, using the generalized estimating equation (GEE) model with a multinomial distribution. All reported P values are two-tailed, with significance set at 0.05. All analyses were done with SAS version 9.4 for Windows. Results Patient characteristics Between July and October 2014, 119 patients were screened and 103 patients from 17 sites were enrolled in the study (Figure 1). Three patients did not initiate the short-cycle strategy and 100 patients were included: 79 patients chose Friday–Sunday as the off period and the other 21 patients chose Saturday–Monday. No patients were lost to follow-up. One patient resumed a 7/7 strategy because of pregnancy. Figure 1. View largeDownload slide Study flow chart. HBc, hepatitis B core. Figure 1. View largeDownload slide Study flow chart. HBc, hepatitis B core. The patients’ baseline characteristics are shown in Table 1. The median prior duration of viral suppression was 4.0 (2.3–6.4) years. ART consisted of two nucleoside analogues (tenofovir disoproxil fumarate + emtricitabine, 89 patients; abacavir + lamivudine, 10 patients; tenofovir disoproxil fumarate + abacavir, 1 patient), plus either an NNRTI (71 patients) or a boosted PI (29 patients). Table 1. Baseline characteristics   Main study, n = 100  MEMS substudy, n = 26  Age (years), median (IQR)  47 (40–53)  44 (36–49)  Male, n (%)  82 (82.0)  23 (88.5)  Origin, n (%)   Caucasian  78 (78.0)  24 (92.3)   sub-Saharan African  10 (10.0)  0 (0.0)   North African  3 (3.0)  1 (3.8)   Asian  1 (1.0)  0 (0.0)   other  8 (8.0)  1 (3.8)  Transmission group, n (%)   MSM  65 (65.0)  18 (69.2)   heterosexual  31 (31.0)  7 (26.9)   other/unknown  4 (4.0)  1 (3.8)  Prior AIDS event, n (%)  9 (9.0)  4 (15.4)  Year of HIV diagnosis, median (IQR)  2006 (1999–2011)  2007 (2005–2011)  Total HIV DNA (copies/million PBMC), median (IQR)  2.4 (1.6–2.9)  2.3 (1.6–2.7)  CD4 cell nadir (cells/mm3), median (IQR)  282 (207–356)  285 (228–370)  CD4 cell count at baseline (cells/mm3), median (IQR)  665 (543–829)  666 (578–806)  CD4/CD8 ratio at baseline, median (IQR)  1.1 (0.8–1.4)  1.1 (0.9–1.5)  ART duration (years), median (IQR)  5.1 (2.9–9.3)  4.8 (2.8–7.2)  Duration of suppressed HIV viraemia (<50 copies/mL) (years), median (IQR)  4.0 (2.3–6.4)  3.9 (1.8–5.1)  Duration of the last cART (months), median (IQR)  32 (19–57)  21 (13–49)  cART at screening, n (%)   2 NRTI + NNRTI  71 (71.0)  21 (80.8)    efavirenz  40 (40.0)  7 (26.9)    etravirine  5 (5.0)  2 (7.7)    rilpivirine  26 (26.0)  12 (46.2)   2 NRTI + PI/r  29 (29.0)  5 (19.2)    darunavir/ritonavir  15 (15.0)  2 (7.7)    atazanavir/ritonavir  13 (13.0)  3 (11.5)    lopinavir/ritonavir  1 (1.0)  0 (0.0)    Main study, n = 100  MEMS substudy, n = 26  Age (years), median (IQR)  47 (40–53)  44 (36–49)  Male, n (%)  82 (82.0)  23 (88.5)  Origin, n (%)   Caucasian  78 (78.0)  24 (92.3)   sub-Saharan African  10 (10.0)  0 (0.0)   North African  3 (3.0)  1 (3.8)   Asian  1 (1.0)  0 (0.0)   other  8 (8.0)  1 (3.8)  Transmission group, n (%)   MSM  65 (65.0)  18 (69.2)   heterosexual  31 (31.0)  7 (26.9)   other/unknown  4 (4.0)  1 (3.8)  Prior AIDS event, n (%)  9 (9.0)  4 (15.4)  Year of HIV diagnosis, median (IQR)  2006 (1999–2011)  2007 (2005–2011)  Total HIV DNA (copies/million PBMC), median (IQR)  2.4 (1.6–2.9)  2.3 (1.6–2.7)  CD4 cell nadir (cells/mm3), median (IQR)  282 (207–356)  285 (228–370)  CD4 cell count at baseline (cells/mm3), median (IQR)  665 (543–829)  666 (578–806)  CD4/CD8 ratio at baseline, median (IQR)  1.1 (0.8–1.4)  1.1 (0.9–1.5)  ART duration (years), median (IQR)  5.1 (2.9–9.3)  4.8 (2.8–7.2)  Duration of suppressed HIV viraemia (<50 copies/mL) (years), median (IQR)  4.0 (2.3–6.4)  3.9 (1.8–5.1)  Duration of the last cART (months), median (IQR)  32 (19–57)  21 (13–49)  cART at screening, n (%)   2 NRTI + NNRTI  71 (71.0)  21 (80.8)    efavirenz  40 (40.0)  7 (26.9)    etravirine  5 (5.0)  2 (7.7)    rilpivirine  26 (26.0)  12 (46.2)   2 NRTI + PI/r  29 (29.0)  5 (19.2)    darunavir/ritonavir  15 (15.0)  2 (7.7)    atazanavir/ritonavir  13 (13.0)  3 (11.5)    lopinavir/ritonavir  1 (1.0)  0 (0.0)  Treatment outcomes The overall success rate at W48 was 96% (95% CI 90%–98%) (Figure 2). Virological failure occurred in three cases, at W4 (VL: 271 copies/mL, confirmed at 785 copies/mL; PI-based therapy), W12 (VL: 124 and 55 copies/mL; NNRTI-based therapy) and W40 (VL: 969 and 227 copies/mL; PI-based therapy) (Table 2). These three patients resumed 7/7 treatment with the same drug combinations, leading to virological suppression. No genotypic resistance mutations were detected at the time of failure. Another patient decided to resume continuous therapy at W4 and was therefore considered as a therapeutic failure. Table 2. Therapeutic failures (virological failure or strategy stop) Patient  cART  Age (years)  Gender  CDC stage  Duration of suppressed HIV (pVL <50 copies/mL, years)  Pre-cART VL (copies/mL)  CD4 nadir (cells/mm3)  CD4 (cells/mm3)   pVL (copies/mL)   Dosage of ART at first pVL rebound  Dosage of ART at pVL control  Resistance profile  Observance at the time of failure (questionnaire)  D0  W48  D0  failure  W48  1  ABC; 3TC; LPV/r  48  male  C  6.8  206 681  125  1119  814  <40  271 (W4); CTR (13 days after): 785  <40  dosage OFF; LPV: <2 ng/mL  dosage OFF; LPV: <75 ng/mL; RTV: <10 ng/mL  no resistance  100%  2  TDF; FTC; EFV  52  male  A  5.9  311 000  209  574  605  40  124 (W12); CTR (9 days after): 55  47  dosage OFF; EFV: 1543 ng/mL  dosage ON; TDF: 71 ng/mL; FTC: 207 ng/mL; EFV:  3669 ng/mL  no resistance  100%  3  ABC; 3TC; ATV/r  31  female  A  4.2  61 500  422  1136  1229  <20  969 (W40); CTR (22 days after): 227  <20  dosage ON; ATV: <20 ng/mL  dosage ON; ATV: 4190 ng/mL; RTV: 1080 ng/mL  no resistance  100%  4  TDF; FTC; EFV  35  male  A  3  18 498  330  500    <20  <20 (W4)    dosage OFF; EFV: 709 ng/mL  discontinuation by patient decision at W4, related to the study strategy  100%  Patient  cART  Age (years)  Gender  CDC stage  Duration of suppressed HIV (pVL <50 copies/mL, years)  Pre-cART VL (copies/mL)  CD4 nadir (cells/mm3)  CD4 (cells/mm3)   pVL (copies/mL)   Dosage of ART at first pVL rebound  Dosage of ART at pVL control  Resistance profile  Observance at the time of failure (questionnaire)  D0  W48  D0  failure  W48  1  ABC; 3TC; LPV/r  48  male  C  6.8  206 681  125  1119  814  <40  271 (W4); CTR (13 days after): 785  <40  dosage OFF; LPV: <2 ng/mL  dosage OFF; LPV: <75 ng/mL; RTV: <10 ng/mL  no resistance  100%  2  TDF; FTC; EFV  52  male  A  5.9  311 000  209  574  605  40  124 (W12); CTR (9 days after): 55  47  dosage OFF; EFV: 1543 ng/mL  dosage ON; TDF: 71 ng/mL; FTC: 207 ng/mL; EFV:  3669 ng/mL  no resistance  100%  3  ABC; 3TC; ATV/r  31  female  A  4.2  61 500  422  1136  1229  <20  969 (W40); CTR (22 days after): 227  <20  dosage ON; ATV: <20 ng/mL  dosage ON; ATV: 4190 ng/mL; RTV: 1080 ng/mL  no resistance  100%  4  TDF; FTC; EFV  35  male  A  3  18 498  330  500    <20  <20 (W4)    dosage OFF; EFV: 709 ng/mL  discontinuation by patient decision at W4, related to the study strategy  100%  ABC, abacavir; 3TC, lamivudine; TDF, tenofovir disoproxil fumarate; FTC, emtricitabine; EFV, efavirenz; LPV/r, lopinavir/ritonavir; ATV/r, atazanavir/ritonavir; RTV, ritonavir; pVL, plasma VL; CTR, control. Figure 2. View largeDownload slide Probability of therapeutic success (Kaplan–Meier). Data for one patient were excluded at week 12 because of study treatment discontinuation due to pregnancy. Figure 2. View largeDownload slide Probability of therapeutic success (Kaplan–Meier). Data for one patient were excluded at week 12 because of study treatment discontinuation due to pregnancy. Four viral blips were observed in three patients, at W4 and W8 (rilpivirine-based therapy, VL 77 and 51 copies/mL, each point controlled with a subsequent VL measure <50 copies/mL), W24 (rilpivirine-based therapy, VL 182 copies/mL with control <50 copies/mL) and W48 (boosted atazanavir-based therapy, VL 142 copies/mL with control <50 copies/mL). In the substudy of 62 patients analysed with Roche Cobas Taqman HIV-1 2.0 assay, the proportions of patients with no signal of replication at D0, W12, W24 and W48 were respectively 71%, 69%, 77% and 70%, with no significant change over time (McNemar test, P > 0.513). No patient had the baseline ART switched throughout the trial. No HIV-related events occurred during the study. Seven severe adverse events were reported [trauma after sport (2), programmed surgery (2), cutaneous abscess, epileptic crisis, transient neutropenia], none being considered related to the study strategy. There was no statistically significant change in the total number of perceived symptoms recorded with the self-administered questionnaire (data not shown). Biological outcomes Changes in the main biological parameters between D0 and W48 are shown in Table 3. A significant increase in the CD4 cell count (+39 ± 168 cells/mm3, P = 0.023) and in the CD4/CD8 ratio (+0.04 ± 0.21, P = 0.034) was observed from D0 to W48. No significant changes in eGFR or lipid values were noted. Table 3. Changes from baseline in biological parameters and quality of life domains at W48   Baseline, n = 100  Δ(W48–BSL), n = 100  P  Biological parameters   CD4 cells/mm3  708 (243)  +39 (168)  0.023   CD4/CD8 ratio  1.15 (0.43)  +0.04 (0.21)  0.034   total HIV DNA, log10 copies/million PBMC, n = 96  2.4 (0.7)  0.0 (0.6)  0.765   AST, IU/L  26 (9)  −2 (8)  <0.001   ALT, IU/L  31 (16)  −3 (12)  0.007   GGT, IU/L  41 (55)  −9 (39)  <0.001   eGFR using CKD-EPI, mL/min  94.5 (15.4)  +1.2 (9.7)  0.195   glycaemia, mmol/L  5.0 (0.6)  +0.2 (0.6)  0.028   triglycerides, mmol/L  1.5 (0.8)  +0.7 (6.7)  0.598   total cholesterol, mmol/L  5.0 (0.9)  0.0 (0.8)  0.685   HDL cholesterol, mmol/L  1.3 (0.3)  0.0 (0.2)  0.635   LDL cholesterol, mmol/L, n = 99  3.0 (0.7)  0.0 (0.7)  0.324   markers of inflammation and cell activation, n = 96    IP-10, pg/mL  26.4 (19.3)  −0.5 (13.3)  0.550    IL-6, pg/mL  2.5 (12.5)  +4.0 (32.7)  0.367    MIG-1, pg/mL  34.3 (32.3)  −1.5 (29.9)  0.102    CRP, ng/mL, n = 93  885.2 (1496.3)  −80.2 (1589.8)  0.787    CD14s, ng/mL  1016.1 (725.5)  −200.4 (759.4)  0.001  Quality of life assessed with the PROQOL-HIV questionnaire, n = 92   physical health and symptoms  86.6 (1.6)  −1.5 (1.4)  0.253   body change  84.9 (2.2)  +1.8 (1.8)  0.313   social relationship  95.2 (1.7)  −0.4 (1.7)  0.809   intimate relationship  79.1 (2.9)  +2.4 (2.7)  0.367   stigma  62.4 (3.9)  +8.8 (3.6)  0.016   emotional distress  85.1 (2.2)  +1.3 (1.7)  0.452   health concern  71.6 (2.7)  +4.5 (1.9)  0.019   treatment impact  87.1 (1.3)  +3.2 (0.9)  0.001    Baseline, n = 100  Δ(W48–BSL), n = 100  P  Biological parameters   CD4 cells/mm3  708 (243)  +39 (168)  0.023   CD4/CD8 ratio  1.15 (0.43)  +0.04 (0.21)  0.034   total HIV DNA, log10 copies/million PBMC, n = 96  2.4 (0.7)  0.0 (0.6)  0.765   AST, IU/L  26 (9)  −2 (8)  <0.001   ALT, IU/L  31 (16)  −3 (12)  0.007   GGT, IU/L  41 (55)  −9 (39)  <0.001   eGFR using CKD-EPI, mL/min  94.5 (15.4)  +1.2 (9.7)  0.195   glycaemia, mmol/L  5.0 (0.6)  +0.2 (0.6)  0.028   triglycerides, mmol/L  1.5 (0.8)  +0.7 (6.7)  0.598   total cholesterol, mmol/L  5.0 (0.9)  0.0 (0.8)  0.685   HDL cholesterol, mmol/L  1.3 (0.3)  0.0 (0.2)  0.635   LDL cholesterol, mmol/L, n = 99  3.0 (0.7)  0.0 (0.7)  0.324   markers of inflammation and cell activation, n = 96    IP-10, pg/mL  26.4 (19.3)  −0.5 (13.3)  0.550    IL-6, pg/mL  2.5 (12.5)  +4.0 (32.7)  0.367    MIG-1, pg/mL  34.3 (32.3)  −1.5 (29.9)  0.102    CRP, ng/mL, n = 93  885.2 (1496.3)  −80.2 (1589.8)  0.787    CD14s, ng/mL  1016.1 (725.5)  −200.4 (759.4)  0.001  Quality of life assessed with the PROQOL-HIV questionnaire, n = 92   physical health and symptoms  86.6 (1.6)  −1.5 (1.4)  0.253   body change  84.9 (2.2)  +1.8 (1.8)  0.313   social relationship  95.2 (1.7)  −0.4 (1.7)  0.809   intimate relationship  79.1 (2.9)  +2.4 (2.7)  0.367   stigma  62.4 (3.9)  +8.8 (3.6)  0.016   emotional distress  85.1 (2.2)  +1.3 (1.7)  0.452   health concern  71.6 (2.7)  +4.5 (1.9)  0.019   treatment impact  87.1 (1.3)  +3.2 (0.9)  0.001  BSL, baseline. Data are mean and SD. Changes from baseline in biological parameters at W48 were compared using the non-parametric Wilcoxon paired test. Missing values at W48 were replaced using the last observation carried forward (LOCF) method. To assess quality of life in the PROQOL-HIV questionnaire, each item was scored on a 0–100 scale and the multiple imputation method was used to estimate missing values. Ten datasets in which missing data were imputed from each patient’s other covariables, including all items in the PROQOL-HIV questionnaire, age, sex, transmission group, origin, prior AIDS events, the type of treatment (2 INSTI + PI/r versus 2 INSTI + NNRTI), time of suppressed HIV viraemia <50 copies/mL and duration of ART. Changes from baseline at W48 in quality of life dimensions were compared using Student’s t-test. Analyses were run on each of the 10 datasets, including the imputed values, and the results were combined with Rubin’s rules. Total HIV-1 DNA in PBMC was stable between D0 (2.4 ± 0.7 log10 copies/106 PBMC) and W48 (2.4 ± 0.7 log10 copies/106 PBMC). No significant increase in markers of immune activation was observed (IP-10, IL-6, MIG-1 and CRP), but the CD14s level fell significantly (–200 ± 759 ng/mL, P = 0.001). Pharmacological data and adherence to therapy In total, 877 plasma samples were analysed for antiretroviral drug plasma concentrations (292 on treatment and 585 off treatment). All on-treatment concentrations were within the range of efficacy. Residual off-treatment concentrations were significantly lower (−47% to −99% depending on class and drug used) than on-treatment concentrations (Table 4), as would be expected with good adherence to the strategy. No significant modification of the concurrent medications taken by the participants was reported, so the changes in drug concentrations both on and off treatment cannot be explained by variation in drug–drug interactions. Table 4. Drug concentrations: mean values off and on therapy for each drug (ng/mL) Antiretroviral  n  ‘ON’, mean (SD)  ‘OFF’, mean (SD)  Δ(OFF − ON), mean (SD)  Percentage of change Δ(OFF − ON)/ON, mean (SD)  P  Efavirenz  38  2218 (1046)  692 (391)  −1526 (781)  −69% (10)  <0.0001  Etravirine  5  447 (360)  269 (266)  −179 (101)  −47% (11)  0.0625  Rilpivirine  26  106 (51)  39 (20)  −66 (40)  −63% (13)  <0.0001  Atazanavir  12  1087 (644)  52 (146)  −1035 (637)  −96% (11)  0.0005  Darunavir  15  2587 (1393)  17 (18)  −2570 (1382)  −99% (0)  <0.0001  Lopinavir  1  3922  0  −3922  −100%    Antiretroviral  n  ‘ON’, mean (SD)  ‘OFF’, mean (SD)  Δ(OFF − ON), mean (SD)  Percentage of change Δ(OFF − ON)/ON, mean (SD)  P  Efavirenz  38  2218 (1046)  692 (391)  −1526 (781)  −69% (10)  <0.0001  Etravirine  5  447 (360)  269 (266)  −179 (101)  −47% (11)  0.0625  Rilpivirine  26  106 (51)  39 (20)  −66 (40)  −63% (13)  <0.0001  Atazanavir  12  1087 (644)  52 (146)  −1035 (637)  −96% (11)  0.0005  Darunavir  15  2587 (1393)  17 (18)  −2570 (1382)  −99% (0)  <0.0001  Lopinavir  1  3922  0  −3922  −100%    Limits of quantification: <20 ng/mL for darunavir, atazanavir and lopinavir; <100 ng/mL for efavirenz; <10 ng/mL for etravirine; and <5 ng/mL for rilpivirine. Efficacy cut-offs: darunavir >2000 ng/mL; atazanavir >200 ng/mL; lopinavir >4000 ng/mL; efavirenz >1000 ng/mL; etravirine >50 ng/mL; and rilpivirine >40 ng/mL. The time between the last medication intake and sample collection was considered as ‘off period’ if ≥ 48 h and as ‘on period’ if < 48 h. For each participant and each drug, we calculated the mean of all measurements during the ‘on period’ (‘ON’) and all measurements during the ‘off period’ (‘OFF’). The Wilcoxon paired test was used to compare changes in residual antiretroviral concentrations between ‘ON’ and ‘OFF’. Self-reported adherence was high (95%–100% of doses taken) in >90% of patients (90.4%–98.8%) at each visit from D0 to W48. The proportion of patients who reported having taken <80% of their treatment in the previous week was between 1.1% and 7.5% at each visit. The proportion of patients who reported taking their treatment for >4 days in the previous week ranged from 0% to 4.4% at each visit (Figure 3a). Figure 3. View largeDownload slide Adherence to the study strategy. (a) Assessment of treatment adherence with a self-reported questionnaire based on last-week recall at each visit. The adherence rate for each participant was estimated as the number of pills consumed divided by the number of pills that should theoretically have been consumed and was classified as low (<80%), medium (80%–95%), high (95%–100%) or higher than expected (>100%). (b) Proportion of days on which MEMS-caps were opened according to the chosen weekly schedule (Monday–Thursday or Tuesday–Friday). The proportion was calculated as the number of days that the MEMS-cap was opened at least once divided by the total number of days under study. Figure 3. View largeDownload slide Adherence to the study strategy. (a) Assessment of treatment adherence with a self-reported questionnaire based on last-week recall at each visit. The adherence rate for each participant was estimated as the number of pills consumed divided by the number of pills that should theoretically have been consumed and was classified as low (<80%), medium (80%–95%), high (95%–100%) or higher than expected (>100%). (b) Proportion of days on which MEMS-caps were opened according to the chosen weekly schedule (Monday–Thursday or Tuesday–Friday). The proportion was calculated as the number of days that the MEMS-cap was opened at least once divided by the total number of days under study. Adherence was assessed during 51 weeks in 26 of the 29 participants enrolled in the MEMS substudy for whom data were available. As shown in Table 1, the 26 participants received tenofovir disoproxil fumarate/emtricitabine, plus an NNRTI in 21 cases and a boosted PI in 5 cases. Their baseline data were comparable to those of the entire group. Bottle openings were consistent with the 4/7 regimen in 90% of patients each week (89.9%–96.9%) (Figure 3b). For each of the 26 patients, the median number of weeks with bottle opening exactly 4 days a week was 44/51 weeks; bottle opening was <4 days in 5/51 weeks and >4 days in 2/51 weeks. The patients expressed a high degree of satisfaction with the 4/7 strategy: 78.6% were fully satisfied at W48, versus 57.5% at D0 (on the 7/7 strategy); 9.1% were not satisfied (versus 19.3% at D0), with an OR of 5.2 (95% CI 2.0–13.7, P < 0.001). Three of the eight PROQOL-HIV dimensions improved over time (stigma: +8.8 ± 3.6, P = 0.016; health concerns: +4.5 ± 1.9, P = 0.019; and treatment impact: +3.2 ± 0.9, P = 0.001). Discussion The 96% success rate observed here at W48 with a 4-days-a-week antiretroviral regimen compares favourably with other triple-agent maintenance strategies and simplified regimens (PI/r monotherapy or dual combinations), for which 1 year success rates ranged from 65% to 88%.7,15–19 The amount of proviral DNA, a surrogate size marker of the HIV-1 reservoir, which reflects the potential for viral rebound during and after treatment interruption,20–22 was remarkably stable from D0 to W48. Similarly, no increase in markers of inflammation was observed during the study. These data support the hypothesis of absence of immune degradation or inflammatory activation under reduced maintenance therapy: continued CD4 elevation and improvement of the CD4/CD8 ratio, stability of the viral reservoir attested by absence of HIV-DNA increase, absence of elevation of inflammatory markers and even a tendency to a decrease in monocyte activation markers (CD14s), indicating a low probability of viral reactivation. Although genital compartment HIV-1 shedding was not measured, it is unlikely that there was any change in the seminal HIV-1 VL, given that no change was seen in HIV DNA level over the course of the trial. Adherence questionnaires, together with low residual drug levels during the 3 day off-treatment period and the results of the MEMS-cap substudy, showed good adherence to the 4/7 strategy. Short-cycle structured intermittent maintenance therapy was first evaluated in a 7 days on/7 days off regimen as proof of concept,8 and then in a 5 days on/2 days off strategy in small or uncontrolled studies, with relative success.10,23,24 Recently, the multicentre, randomized BREATHER study, involving 199 young patients, demonstrated the non-inferiority of 5-days-a-week efavirenz-based therapy compared with daily therapy (virological failure: 6% versus 7%, difference: −1.2%, 90% CI −7.3% to –4.9%).9 We report a high level of efficacy with our 4 days on/3 days off NNRTI- and PI-based triple-agent maintenance strategy in this multicentre prospective trial. The very low rate of virological rebound observed here is compatible with the results of treatment discontinuation studies that indicate a latency period of 5–8 days before the resumption of viral replication.25,26 This latency may be related to the long half-life of NNRTI, as confirmed here by noteworthy residual plasma concentrations (>IC90) of efavirenz, rilpivirine and etravirine on the third day of treatment interruption. In three ART interruption studies, viral escape occurred after at least 5–7 days after stopping NNRTI.27–29 However, this pharmacological explanation does not seem suitable for PI-based therapy in which residual concentrations after ART interruption are low, with a shorter plasmatic half-life than NNRTI. In this case, the latency before VL rebound after treatment interruption could partially be explained by the long intracellular half-life of PIs, owing to their high binding affinity, especially for darunavir which has a dissociative half-life >240 h.30 Owing to the high efficiency of the 4/7 day regimen, the cost–benefit evaluation is obviously positive, with a 40% reduction in the cost of antiviral drugs, i.e. a saving of about €4800 per patient-year of maintenance therapy. The ‘3 day therapeutic weekend’ was greatly appreciated by the participants, demonstrated by a high level of satisfaction with the study regimen, being easy to remember and allowing them a standard lifestyle (e.g. ease of visiting friends or family on weekends without being disturbed by treatment intake). Evaluation of clinical or biological benefit is limited in our study because patients were maintained under their previous successful and well-tolerated ART combination and the lack of a control group. In addition to a cost reduction, the overall 40% reduction in drug exposure could reduce long-term toxicity. Other maintenance strategies currently under evaluation, such as the use of long-acting agents in patients with controlled VL, will not present the same advantages. In conclusion, in a population of patients on effective long-term NNRTI- or boosted-PI-based ART, short-cycle maintenance therapy with 4 days on and 3 days off treatment was safe, well accepted and virologically effective for 1 year. A longer, randomized study with other ART combinations, including integrase inhibitors, is warranted to confirm the benefits and effectiveness of a 4-days-a-week maintenance strategy. Acknowledgements This study was presented in part at the Twenty-First International AIDS Conference, Durban, South Africa, 2016 (THPEB063).  We acknowledge the members of the Independent Monitoring Committee: F. Bani Sadr, C. Delaugerre, R. Garaffo, M. Korzec, T. May, P. Morlat and R. Thiebaut. We thank all the participants of the ANRS 162-4D trial, the patients’ associative organizations and TRT5 group for advice and support, and the staff from the centres participating in the 4D trial. Members of the ANRS 162-4D Study Group Hôpital Avicenne, Bobigny: Olivier Bouchaud, Irène Zamord; Hôpital Bicêtre, Le Kremlin Bicêtre: Cécile Goujard, Frédéric Fourreau; Hôpital Bichat, Paris: Véronique Joly, Bao Phung; Hôpital européen Georges Pompidou, Paris: Laurence Weiss, Lio Collias; Hôpital Necker, Paris: Claire Rouzaud, Fatima Touam; Hôpital Pitié-Salpêtrière, Paris: Christine Katlama, Luminita Schneider; Hôpital Raymond Poincaré, Garches: Stéphanie Landowski, Huguette Berthe; Hôpital Saint Antoine, Paris: Karine Lacombe, Jean-Luc Meynard; Hôpital Tenon, Paris: Julie Chas, Pélagie Thibault; Hôpital de la Côte de Nacre, Caen: Arnaud de la Blanchardiere, Sylvie Dargere; Centre Hospitalier Sud-Francilien, Corbeil-Essonnes: Alain Devidas, Amélie Chabrol; Hôpital du Bocage, Dijon: Lionel Piroth, Sandrine Gohier; Hôpital Pierre Zobda-Quitman, Fort de France: André Cabié, Mathilde Pircher; Hôpital Gui de Chauliac, Montpellier: Jacques Reynes, Vincent Le Moing; Hôpital Foch, Suresnes: David Zucman, Dominique Bornarel; Hôpital Bretonneau, Tours: Louis Bernard, Adrien Lemaignen; Hôpital Purpan, Toulouse: Pierre Delobel, Noemie Biezunski; Institut Médecine Epidémiologie Appliquée, Paris: Karine Amat, Aida Benalicherif, Babacar Sylla; INSERM-ANRS, Paris: Severine Gibowski, Soizic Le Mestre, Jean-François Delfraissy. Funding The ANRS 162-4D trial was supported and funded by the Agence Nationale de Recherche sur le Sida et les Hépatites Virales (ANRS), part of the Institut National de la Santé et de la Recherche Médicale (INSERM). Transparency declarations P. d. T. reports having received consultancy fees and/or travel grants from Bristol-Myers Squibb, Gilead Sciences, Janssen Pharmaceuticals, Merck-Sharp-Dohme and ViiV Healthcare. R. L. reports having received consultancy fees and travel grants from BMS, Gilead Sciences and ViiV Healthcare. C. K. reports having received consultancy fees and/or travel grants from MSD, BMS, ViiV Healthcare, Gilead Sciences and Janssen Pharmaceuticals. G. G. reports having received consultancy fees and/or travel grants from BMS, Gilead Sciences, Janssen Pharmaceuticals, MSD and ViiV Healthcare. O. B. reports having received grants from MSD and ViiV Healthcare, personal fees from Gilead Sciences and MSD, and non-financial support from Janssen Pharmaceuticals. M. D. reports having received grants, personal fees and research support from Gilead Sciences, Janssen Pharmaceuticals and ViiV Healthcare. J. L. is a member of FOURVIRKS biotheque company. D. C. was a member of the French Gilead board from 2011 to 2015, gave lectures for Janssen-Cilag, MSD and ViiV Healthcare, received travel, accommodation and meeting expenses from Gilead Sciences, Janssen and ViiV Healthcare, received grants from Janssen-Cilag, MSD and ViiV, and is a consultant for Innavirax. P.-M. G. reports having received personal fees from Abbvie, BMS, Gilead and ViiV Healthcare, and research grants from BMS and Janssen Pharmaceuticals. All others authors: none to declare. Author contributions The 4D trial was designed by P. d. T., D. M., D. L. D., J.-C. M., J. L., D. C., P.-M. G. and C. P. The methodology and analysis plan was built by L. A. and D. C., and reviewed by the other authors and members of the scientific committee (chaired by C. P.). P. d. T., R. L., D. L. D., C. K., G. G., O. B., J.-C. M. and P.-M. G. contributed to recruitment and follow-up of participants, along with all the staff members listed in the ANRS 162-4D Study Group. R. L., K. A., J. S. and L. A. carried out the data monitoring. Coordination of assessment of virological and immunological data was conducted by D. M. and J. I., pharmacological data by E. A. and J.-C. A., and quality-of-life questionnaires by M. D. The statistical analysis was undertaken by J. B., L. A. and D. C., and all the authors reviewed the final data. P. d. T., L. A., R. L., D. C. and P.-M. G. drafted the manuscript, which was critically revised by all the authors who approved the final version. References 1 Gunthard HF, Saag MS, Benson CA et al.   Antiretroviral drugs for treatment and prevention of HIV infection in adults: 2016 recommendations of the International Antiviral Society-USA Panel. JAMA  2016; 316: 191– 210. Google Scholar CrossRef Search ADS PubMed  2 Ryom L, Boesecke C, Gisler V et al.   Essentials from the 2015 European AIDS Clinical Society (EACS) guidelines for the treatment of adult HIV-positive persons. HIV Med  2016; 17: 83– 8. Google Scholar CrossRef Search ADS PubMed  3 Delaugerre C, Ghosn J, Lacombe JM et al.   Significant reduction in HIV virologic failure during a 15-year period in a setting with free healthcare access. Clin Infect Dis  2015; 60: 463– 72. Google Scholar CrossRef Search ADS PubMed  4 Bunupuradah T, Kiertiburanakul S, Avihingsanon A et al.   Low-dose versus standard-dose ritonavir-boosted atazanavir in virologically suppressed Thai adults with HIV (LASA): a randomised, open-label, non-inferiority trial. Lancet HIV  2016; 3: e343– 50. Google Scholar CrossRef Search ADS PubMed  5 Group ES, Carey D, Puls R et al.   Efficacy and safety of efavirenz 400 mg daily versus 600 mg daily: 96-week data from the randomised, double-blind, placebo-controlled, non-inferiority ENCORE1 study. Lancet Infect Dis  2015; 15: 793– 802. Google Scholar CrossRef Search ADS PubMed  6 Baril JG, Angel JB, Gill MJ et al.   Dual therapy treatment strategies for the management of patients infected with HIV: a systematic review of current evidence in ARV-naive or ARV-experienced, virologically suppressed patients. PLoS One  2016; 11: e0148231. Google Scholar CrossRef Search ADS PubMed  7 Arribas JR, Girard PM, Paton N et al.   Efficacy of protease inhibitor monotherapy versus. triple therapy: meta-analysis of data from 2303 patients in 13 randomized trials. HIV Med  2016; 17: 358– 67. Google Scholar CrossRef Search ADS PubMed  8 Dybul M, Nies-Kraske E, Dewar R et al.   A proof-of-concept study of short-cycle intermittent antiretroviral therapy with a once-daily regimen of didanosine, lamivudine, and efavirenz for the treatment of chronic HIV infection. J Infect Dis  2004; 189: 1974– 82. Google Scholar CrossRef Search ADS PubMed  9 The Breather (PENTA16) Trial Group. Weekends-off efavirenz-based antiretroviral therapy in HIV-infected children, adolescents, and young adults (BREATHER): a randomised, open-label, non-inferiority, phase 2/3 trial. Lancet HIV  2016; 3: e421– 30. CrossRef Search ADS PubMed  10 Reynolds SJ, Kityo C, Hallahan CW et al.   A randomized, controlled, trial of short cycle intermittent compared to continuous antiretroviral therapy for the treatment of HIV infection in Uganda. PLoS One  2010; 5: e10307. Google Scholar CrossRef Search ADS PubMed  11 Leibowitch J, Mathez D, de Truchis P et al.   Four days a week or less on appropriate anti-HIV drug combinations provided long-term optimal maintenance in 94 patients: the ICCARRE project. FASEB J  2015; 29: 2223– 34. Google Scholar CrossRef Search ADS PubMed  12 Schoenenberger JA, Aragones AM, Cano SM et al.   The advantages of therapeutic drug monitoring in patients receiving antiretroviral treatment and experiencing medication-related problems. Ther Drug Monit  2013; 35: 71– 7. Google Scholar CrossRef Search ADS PubMed  13 Duracinsky M, Lalanne C, Le Coeur S et al.   Psychometric validation of the PROQOL-HIV questionnaire, a new health-related quality of life instrument-specific to HIV disease. J Acquir Immune Defic Syndr  2012; 59: 506– 15. Google Scholar CrossRef Search ADS PubMed  14 Rubin D. Multiple Imputation for Nonresponse in Surveys . New York: Wiley, 1987. Google Scholar CrossRef Search ADS   15 Paton NI, Stohr W, Arenas-Pinto A et al.   Protease inhibitor monotherapy for long-term management of HIV infection: a randomised, controlled, open-label, non-inferiority trial. Lancet HIV  2015; 2: e417– 26. Google Scholar CrossRef Search ADS PubMed  16 Girard PM, Antinori A, Arribas JR et al.   Week 96 efficacy and safety of darunavir/ritonavir monotherapy vs. darunavir/ritonavir with two nucleoside reverse transcriptase inhibitors in the PROTEA trial. HIV Med  2017; 18: 5– 12. Google Scholar CrossRef Search ADS PubMed  17 Valantin MA, Lambert-Niclot S, Flandre P et al.   Long-term efficacy of darunavir/ritonavir monotherapy in patients with HIV-1 viral suppression: week 96 results from the MONOI ANRS 136 study. J Antimicrob Chemother  2012; 67: 691– 5. Google Scholar CrossRef Search ADS PubMed  18 Arribas JR, Girard PM, Landman R et al.   Dual treatment with lopinavir-ritonavir plus lamivudine versus triple treatment with lopinavir-ritonavir plus lamivudine or emtricitabine and a second nucleos(t)ide reverse transcriptase inhibitor for maintenance of HIV-1 viral suppression (OLE): a randomised, open-label, non-inferiority trial. Lancet Infect Dis  2015; 15: 785– 92. Google Scholar CrossRef Search ADS PubMed  19 Perez-Molina JA, Rubio R, Rivero A et al.   Simplification to dual therapy (atazanavir/ritonavir + lamivudine) versus standard triple therapy [atazanavir/ritonavir + two nucleos(t)ides] in virologically stable patients on antiretroviral therapy: 96 week results from an open-label, non-inferiority, randomized clinical trial (SALT study). J Antimicrob Chemother  2017; 72: 246– 53. Google Scholar CrossRef Search ADS PubMed  20 Eriksson S, Graf EH, Dahl V et al.   Comparative analysis of measures of viral reservoirs in HIV-1 eradication studies. PLoS Pathog  2013; 9: e1003174. Google Scholar CrossRef Search ADS PubMed  21 Saez-Cirion A, Bacchus C, Hocqueloux L et al.   Post-treatment HIV-1 controllers with a long-term virological remission after the interruption of early initiated antiretroviral therapy ANRS VISCONTI Study. PLoS Pathog  2013; 9: e1003211. Google Scholar CrossRef Search ADS PubMed  22 Williams JP, Hurst J, Stohr W et al.   HIV-1 DNA predicts disease progression and post-treatment virological control. Elife  2014; 3: e03821. Google Scholar PubMed  23 Cohen C, Colson A, Pierone G et al.   O214 the FOTO study: 24-week results support the safety of a 2-day break on efavirenz-based antiretroviral therapy. J Int AIDS Soc  2008; 11 Suppl 1: O19. Google Scholar CrossRef Search ADS   24 Rudy BJ, Sleasman J, Kapogiannis B et al.   Short-cycle therapy in adolescents after continuous therapy with established viral suppression: the impact on viral load suppression. AIDS Res Hum Retroviruses  2009; 25: 555– 61. Google Scholar CrossRef Search ADS PubMed  25 Pinkevych M, Cromer D, Tolstrup M et al.   HIV reactivation from latency after treatment interruption occurs on average every 5-8 days–implications for HIV remission. PLoS Pathog  2015; 11: e1005000. Google Scholar CrossRef Search ADS PubMed  26 Hill AL, Rosenbloom DIS, Siliciano JD et al.   Correction: real-time predictions of reservoir size and rebound time during antiretroviral therapy interruption trials for HIV. PLoS Pathog  2016; 12: e1005778. Google Scholar CrossRef Search ADS PubMed  27 Jackson A, Moyle G, Watson V et al.   Tenofovir, emtricitabine intracellular and plasma, and efavirenz plasma concentration decay following drug intake cessation: implications for HIV treatment and prevention. J Acquir Immune Defic Syndr  2013; 62: 275– 81. Google Scholar CrossRef Search ADS PubMed  28 Parienti JJ, Das-Douglas M, Massari V et al.   Not all missed doses are the same: sustained NNRTI treatment interruptions predict HIV rebound at low-to-moderate adherence levels. PLoS One  2008; 3: e2783. Google Scholar CrossRef Search ADS PubMed  29 Pogany K, van Valkengoed IG, Prins JM et al.   Effects of active treatment discontinuation in patients with a CD4+ T-cell nadir greater than 350 cells/mm3: 48-week Treatment Interruption in Early Starters Netherlands Study (TRIESTAN). J Acquir Immune Defic Syndr  2007; 44: 395– 400. Google Scholar CrossRef Search ADS PubMed  30 Dierynck I, De Wit M, Gustin E et al.   Binding kinetics of darunavir to human immunodeficiency virus type 1 protease explain the potent antiviral activity and high genetic barrier. J Virol  2007; 81: 13845– 51. Google Scholar CrossRef Search ADS PubMed  © The Author 2017. 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. http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Antimicrobial Chemotherapy Oxford University Press

Loading next page...
 
/lp/ou_press/four-days-a-week-antiretroviral-maintenance-therapy-in-virologically-mTb8Szvics
Publisher
Oxford University Press
Copyright
© The Author 2017. 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.
ISSN
0305-7453
eISSN
1460-2091
D.O.I.
10.1093/jac/dkx434
Publisher site
See Article on Publisher Site

Abstract

Abstract Background Intermittent treatment could improve the convenience, tolerability and cost of ART, as well as patients’ quality of life. We conducted a 48 week multicentre study of a 4-days-a-week antiretroviral regimen in adults with controlled HIV-1-RNA plasma viral load (VL). Methods Eligible patients were adults with VL < 50 copies/mL for at least 1 year on triple therapy with a ritonavir-boosted PI (PI/r) or an NNRTI. The study protocol consisted of the same regimen taken on four consecutive days per week followed by a 3 day drug interruption. The primary outcome was the proportion of participants remaining in the strategy with VL < 50 copies/mL up to week 48. The study was designed to show an observed success rate of > 90%, with a power of 87% and a 5% type 1 error. The study was registered with ClinicalTrials.gov (NCT02157311) and EudraCT (2014-000146-29). Results One hundred patients (82 men), median age 47 years (IQR 40–53), were included. They had been receiving ART for a median of 5.1 (IQR 2.9–9.3) years and had a median CD4 cell count of 665 (IQR 543–829) cells/mm3. The ongoing regimen included PI/r in 29 cases and NNRTI in 71 cases. At 48 weeks, 96% of participants (95% CI 90%–98%) had no failure while remaining on the 4-days-a-week regimen. Virological failure occurred in three participants, who all resumed daily treatment and became resuppressed. One participant stopped the strategy. No severe treatment-related events occurred. Conclusions Antiretroviral maintenance therapy 4 days a week was effective for 48 weeks in 96% of patients, leading to potential reduction of long-term toxicities, high adherence to the antiretroviral regimen and drug cost saving. Introduction The treatment goal in HIV infection is to achieve continuous viral suppression, which has been shown to reduce morbidity and mortality and to reduce the risk of viral transmission. Current guidelines on combined ART (cART) recommend the use of two nucleoside analogues and a third agent chosen from the following classes: NNRTI, boosted PI and integrase strand transfer inhibitors (INSTIs).1,2 cART achieves complete viral suppression in most patients,3 but treatment has to be continued lifelong, with a risk of poor adherence, viral escape and long-term toxicity, particularly in ageing patients with comorbidities. Moreover, with growing economic constraints and increasing numbers of patients on therapy, the use of antiretroviral combinations with lower cost becomes essential. Several attempts have been made to lower drug exposure during maintenance therapy, including dose reductions,4,5 dual-agent combinations6 and boosted PI monotherapy.7 Although feasible in patients with fully suppressed viral load (VL), these strategies are not applicable to all patients and might be associated with low-level viral escape.7 After Dybul et al.,8 several teams tested short-cycle structured intermittent maintenance therapy, mostly with a 5 days on/2 days off efavirenz-based regimen, as in the BREATHER randomized trial.9,10 We have previously observed no virological failures in a cohort of 98 patients treated for 1 year with a 4 days on/3 days off maintenance regimen.11 Here we report the results of a multicentre pilot study (ANRS 162-4D) designed as a proof-of concept study to assess the efficacy and tolerability of a 4 days on/3 days off maintenance regimen in patients already on effective standard antiretroviral regimens. On this maintenance regimen with potential reduced long-term exposure to antiretroviral drugs, we also assessed the evolution of the viral reservoir, the inflammatory markers and the modification of plasma drug concentrations. Methods Study design and participants ANRS 162-4D was a 48 week, single-arm, prospective multicentre trial, conducted between July 2014 and January 2016. Patients were eligible if they were ≥18 years; had confirmed HIV-1 infection; had been receiving cART for >12 months, based on two nucleoside/tide analogues (tenofovir disoproxil fumarate, abacavir, lamivudine or emtricitabine) and a third agent consisting of a boosted PI (darunavir, lopinavir or atazanavir) or NNRTI (efavirenz, rilpivirine or etravirine), all given at standard recommended dosages, with no change in regimen in the previous 4 months; had VL ≤50 RNA copies/mL for at least 1 year; had a CD4 cell count >250 cells/mm3 for at least 6 months; had available genotypic results showing no evidence of resistance to any of the drugs in the ongoing regimen and no history of previous virological failure under the drugs used in the current antiretroviral combination; had acceptable laboratory values at screening [glomerular filtration rate calculated with the Modification of Diet in Renal Disease Study equation (MDRD) >60 mL/min, AST-ALT <3×ULN (upper limit of normal), haemoglobin >10 g/dL, >100 000 platelets/mm3]; a negative pregnancy test at screening and agreed to use contraception during the study for women of childbearing age; and provided written informed consent. Ethics The trial was conducted in accordance with Good Clinical Practices and the ethical principles of the Helsinki Declaration and followed ANRS recommendations for clinical research. The Ile-de-France XI Ethics Review Committee approved the study on 13 February 2014 and all the participants gave their written informed consent before entering the study. The study was registered with ClinicalTrials.gov (NCT02157311) and EudraCT (2014-000146-29). Procedures The screening visit [week 4 (W4)] was designed to obtain informed consent and to check the inclusion criteria. The RNA sequence of any previous drug resistance genotype was collected and analysed (ANRS-AC11 resistance algorithm, v. 0.24-2014, http://www.frenchresistance.org/). Four weeks later, inclusion in the study was confirmed and short-cycle maintenance therapy was started at the day 0 (D0) visit. The patients chose three consecutive days off therapy (Friday–Sunday or Saturday–Monday) and continued this 4/7 strategy until the end of the study. They were assessed clinically and biologically every 4 weeks from D0 to W16, then every 8 weeks until W48. A last blood sample was taken at W51 to confirm the final end point result. Laboratory tests were scheduled at the end of the 3 day off-treatment period, except at W16 and W40 (on treatment). Laboratory tests VL (Roche Cobas TaqMan HIV-1 v. 1.2 or Abbott Real-Time HIV-1) and T cell subpopulations were measured at every visit in the local laboratories. VL values >50 copies/mL were confirmed on a new sample taken 2–4 weeks later and events were classified as virological failure if VL at control was >50 copies/mL and as viral blip otherwise. An additional plasma sample was obtained and frozen at each visit for VL assay, drug resistance genotyping and drug assays. Whole-blood samples for centralized total cell-associated DNA measurement (real-time PCR, Biocentric, Bandol, France) and serum samples for inflammatory marker assays [C-reactive protein (CRP), IL-6, soluble CD14 (CD14s), IFN-γ-inducible protein 10 (IP-10) and monokine induced by γ-IFN (MIG-1)] were taken at D0, W24 and W48 (ProcartaPlex® Multiplex Immunoassays, Affymetrix, Vienna, Austria; and Magnetic Luminex® Screening Assay, RαD Systems, Minneapolis, MN, USA). Pharmacological evaluation The residual plasma concentrations of the third agent (PI or NNRTI) used in the antiretroviral combination were determined on treatment at D0, W16 and W40, and off treatment (D3) at W4, W8, W12, W24, W32 and W48, using a validated turbulent flow chromatographic method with triple quadrupole MS detection and electrospray ionization interface (Thermo Fisher, Les Ulis, France). The results were interpreted according to quantification and efficacy thresholds (respectively, in ng/mL, 100 and 1000 for efavirenz, 10 and 50 for etravirine, 5 and 40 for rilpivirine, 20 and 2000 for darunavir, 20 and 200 for atazanavir, and 20 and 4000 for lopinavir).12 Tolerability, quality of life and adherence Clinical and biological tolerability was evaluated at each visit. Lipodystrophy (waist and hip size, waist/hip ratio) and metabolic changes (fasting glucose, total cholesterol, HDL cholesterol, LDL cholesterol and triglycerides) were assessed at D0, W24 and W48. Adherence to the study strategy was assessed with a self-administered questionnaire based on last-week recall at each visit and by plasma drug measurements on and off treatment. In addition, a Medication Event Monitoring System (MEMS) capped-container substudy was conducted in a subgroup of participants treated with drugs contained in bottles with compatible caps (Truvada®, Atripla®, Eviplera®, Viread®) in five of the centres. Satisfaction with the strategy and quality of life, assessed with the PROQOL-HIV questionnaire13 and a questionnaire of perceived symptoms, was assessed at D0, W24 and W48. Outcomes The primary endpoint was therapeutic success, defined by the absence of virological failure and strategy failure up to W48. Virological failure was defined as a first VL >50 copies/mL, confirmed on a second sample 2–4 weeks later. Strategy failure was defined as discontinuation of the 4/7 strategy for 30 days or more, because of adverse events, the patient’s or investigator’s decision, or loss to follow-up (absence at more than two consecutive visits). Switches to a drug of the same class were not considered as failure and neither was interruption of the 4/7 strategy for pregnancy. Secondary outcomes included the proportion of patients with viral blips, the proportion of patients without any signal of viral replication (subgroup of patients tested with Roche-Taqman VL); the occurrence of grade 3/4 adverse events; changes in plasma creatinine, estimated glomerular filtration rate (eGFR) calculated with the MDRD equation, metabolic parameters and hepatic transaminases from D0 to W48; the occurrence of genotypic resistance in case of failure; changes in the CD4 and CD8 cell counts and the CD4/CD8 ratio from D0 to W48, changes in total HIV-DNA in PBMC from D0 to W24 and W48; changes in inflammatory markers from D0 to W48; the dynamics of residual NNRTI or PI concentrations during the on- and off-treatment phases; adherence to the study strategy; and changes in quality of life from D0 to W48. To assess adherence to the study strategy, we assessed the number of days that the MEMS-cap was opened, divided by number of days that the MEMS-cap was in use during the trial;9 the number of weeks that the MEMS-cap was opened exactly 4 days a week, or more or less than 4 days a week; the observance rate, estimated as the number of pills consumed (recorded using the self-reported questionnaire) divided by the number of pills that should theoretically have been consumed, classified as low (<80%), medium (80%–95%), high (95%–100%) or higher than expected (>100%); and changes in drug concentrations between the average of values recorded during the on-treatment period (last intake <48 h previously) and during the off-treatment period (last intake ≥48 h previously). Statistical considerations The study was designed to detect the difference between the null hypothesis proportion of 80% and the alternative proportion of 90% (an expected success rate) with a type 1 error of 5% and a power of 85%. An estimated 95 patients were required to achieve these goals. Enrolment of 95 patients, increased to 100 patients to account for non-evaluable patients, was requested to achieve these goals. The primary efficacy endpoint was analysed with an ITT approach. The 95% CI of the observed proportion of patients reaching the efficacy endpoint was calculated with the Kaplan–Meier method. Variables were summarized as proportions for categorical variables, median and IQR for continuous baseline variables and mean and SD for continuous variables used as endpoints. Changes in continuous variables between baseline and W48 were compared using the Wilcoxon paired test, except for quality-of-life (see below). All continuous variables used as endpoints were analysed with an ITT approach, with the last observation carried forward. The PROQOL-HIV questionnaire includes eight dimensions with scores ranging from 0 to 100.13 To assess quality of life and perceived symptoms, we created 10 datasets in which missing data were imputed from each participant’s other covariables. In these imputations, missing values were randomly sampled from their predicted distributions.14 Changes in quality of life dimensions were compared using Student’s t-test. Analyses were run on each of the 10 datasets, including the imputed values, and the results were combined with Rubin’s rules.14 Changes in satisfaction with care were estimated with a five-point scale item of the questionnaire, using the generalized estimating equation (GEE) model with a multinomial distribution. All reported P values are two-tailed, with significance set at 0.05. All analyses were done with SAS version 9.4 for Windows. Results Patient characteristics Between July and October 2014, 119 patients were screened and 103 patients from 17 sites were enrolled in the study (Figure 1). Three patients did not initiate the short-cycle strategy and 100 patients were included: 79 patients chose Friday–Sunday as the off period and the other 21 patients chose Saturday–Monday. No patients were lost to follow-up. One patient resumed a 7/7 strategy because of pregnancy. Figure 1. View largeDownload slide Study flow chart. HBc, hepatitis B core. Figure 1. View largeDownload slide Study flow chart. HBc, hepatitis B core. The patients’ baseline characteristics are shown in Table 1. The median prior duration of viral suppression was 4.0 (2.3–6.4) years. ART consisted of two nucleoside analogues (tenofovir disoproxil fumarate + emtricitabine, 89 patients; abacavir + lamivudine, 10 patients; tenofovir disoproxil fumarate + abacavir, 1 patient), plus either an NNRTI (71 patients) or a boosted PI (29 patients). Table 1. Baseline characteristics   Main study, n = 100  MEMS substudy, n = 26  Age (years), median (IQR)  47 (40–53)  44 (36–49)  Male, n (%)  82 (82.0)  23 (88.5)  Origin, n (%)   Caucasian  78 (78.0)  24 (92.3)   sub-Saharan African  10 (10.0)  0 (0.0)   North African  3 (3.0)  1 (3.8)   Asian  1 (1.0)  0 (0.0)   other  8 (8.0)  1 (3.8)  Transmission group, n (%)   MSM  65 (65.0)  18 (69.2)   heterosexual  31 (31.0)  7 (26.9)   other/unknown  4 (4.0)  1 (3.8)  Prior AIDS event, n (%)  9 (9.0)  4 (15.4)  Year of HIV diagnosis, median (IQR)  2006 (1999–2011)  2007 (2005–2011)  Total HIV DNA (copies/million PBMC), median (IQR)  2.4 (1.6–2.9)  2.3 (1.6–2.7)  CD4 cell nadir (cells/mm3), median (IQR)  282 (207–356)  285 (228–370)  CD4 cell count at baseline (cells/mm3), median (IQR)  665 (543–829)  666 (578–806)  CD4/CD8 ratio at baseline, median (IQR)  1.1 (0.8–1.4)  1.1 (0.9–1.5)  ART duration (years), median (IQR)  5.1 (2.9–9.3)  4.8 (2.8–7.2)  Duration of suppressed HIV viraemia (<50 copies/mL) (years), median (IQR)  4.0 (2.3–6.4)  3.9 (1.8–5.1)  Duration of the last cART (months), median (IQR)  32 (19–57)  21 (13–49)  cART at screening, n (%)   2 NRTI + NNRTI  71 (71.0)  21 (80.8)    efavirenz  40 (40.0)  7 (26.9)    etravirine  5 (5.0)  2 (7.7)    rilpivirine  26 (26.0)  12 (46.2)   2 NRTI + PI/r  29 (29.0)  5 (19.2)    darunavir/ritonavir  15 (15.0)  2 (7.7)    atazanavir/ritonavir  13 (13.0)  3 (11.5)    lopinavir/ritonavir  1 (1.0)  0 (0.0)    Main study, n = 100  MEMS substudy, n = 26  Age (years), median (IQR)  47 (40–53)  44 (36–49)  Male, n (%)  82 (82.0)  23 (88.5)  Origin, n (%)   Caucasian  78 (78.0)  24 (92.3)   sub-Saharan African  10 (10.0)  0 (0.0)   North African  3 (3.0)  1 (3.8)   Asian  1 (1.0)  0 (0.0)   other  8 (8.0)  1 (3.8)  Transmission group, n (%)   MSM  65 (65.0)  18 (69.2)   heterosexual  31 (31.0)  7 (26.9)   other/unknown  4 (4.0)  1 (3.8)  Prior AIDS event, n (%)  9 (9.0)  4 (15.4)  Year of HIV diagnosis, median (IQR)  2006 (1999–2011)  2007 (2005–2011)  Total HIV DNA (copies/million PBMC), median (IQR)  2.4 (1.6–2.9)  2.3 (1.6–2.7)  CD4 cell nadir (cells/mm3), median (IQR)  282 (207–356)  285 (228–370)  CD4 cell count at baseline (cells/mm3), median (IQR)  665 (543–829)  666 (578–806)  CD4/CD8 ratio at baseline, median (IQR)  1.1 (0.8–1.4)  1.1 (0.9–1.5)  ART duration (years), median (IQR)  5.1 (2.9–9.3)  4.8 (2.8–7.2)  Duration of suppressed HIV viraemia (<50 copies/mL) (years), median (IQR)  4.0 (2.3–6.4)  3.9 (1.8–5.1)  Duration of the last cART (months), median (IQR)  32 (19–57)  21 (13–49)  cART at screening, n (%)   2 NRTI + NNRTI  71 (71.0)  21 (80.8)    efavirenz  40 (40.0)  7 (26.9)    etravirine  5 (5.0)  2 (7.7)    rilpivirine  26 (26.0)  12 (46.2)   2 NRTI + PI/r  29 (29.0)  5 (19.2)    darunavir/ritonavir  15 (15.0)  2 (7.7)    atazanavir/ritonavir  13 (13.0)  3 (11.5)    lopinavir/ritonavir  1 (1.0)  0 (0.0)  Treatment outcomes The overall success rate at W48 was 96% (95% CI 90%–98%) (Figure 2). Virological failure occurred in three cases, at W4 (VL: 271 copies/mL, confirmed at 785 copies/mL; PI-based therapy), W12 (VL: 124 and 55 copies/mL; NNRTI-based therapy) and W40 (VL: 969 and 227 copies/mL; PI-based therapy) (Table 2). These three patients resumed 7/7 treatment with the same drug combinations, leading to virological suppression. No genotypic resistance mutations were detected at the time of failure. Another patient decided to resume continuous therapy at W4 and was therefore considered as a therapeutic failure. Table 2. Therapeutic failures (virological failure or strategy stop) Patient  cART  Age (years)  Gender  CDC stage  Duration of suppressed HIV (pVL <50 copies/mL, years)  Pre-cART VL (copies/mL)  CD4 nadir (cells/mm3)  CD4 (cells/mm3)   pVL (copies/mL)   Dosage of ART at first pVL rebound  Dosage of ART at pVL control  Resistance profile  Observance at the time of failure (questionnaire)  D0  W48  D0  failure  W48  1  ABC; 3TC; LPV/r  48  male  C  6.8  206 681  125  1119  814  <40  271 (W4); CTR (13 days after): 785  <40  dosage OFF; LPV: <2 ng/mL  dosage OFF; LPV: <75 ng/mL; RTV: <10 ng/mL  no resistance  100%  2  TDF; FTC; EFV  52  male  A  5.9  311 000  209  574  605  40  124 (W12); CTR (9 days after): 55  47  dosage OFF; EFV: 1543 ng/mL  dosage ON; TDF: 71 ng/mL; FTC: 207 ng/mL; EFV:  3669 ng/mL  no resistance  100%  3  ABC; 3TC; ATV/r  31  female  A  4.2  61 500  422  1136  1229  <20  969 (W40); CTR (22 days after): 227  <20  dosage ON; ATV: <20 ng/mL  dosage ON; ATV: 4190 ng/mL; RTV: 1080 ng/mL  no resistance  100%  4  TDF; FTC; EFV  35  male  A  3  18 498  330  500    <20  <20 (W4)    dosage OFF; EFV: 709 ng/mL  discontinuation by patient decision at W4, related to the study strategy  100%  Patient  cART  Age (years)  Gender  CDC stage  Duration of suppressed HIV (pVL <50 copies/mL, years)  Pre-cART VL (copies/mL)  CD4 nadir (cells/mm3)  CD4 (cells/mm3)   pVL (copies/mL)   Dosage of ART at first pVL rebound  Dosage of ART at pVL control  Resistance profile  Observance at the time of failure (questionnaire)  D0  W48  D0  failure  W48  1  ABC; 3TC; LPV/r  48  male  C  6.8  206 681  125  1119  814  <40  271 (W4); CTR (13 days after): 785  <40  dosage OFF; LPV: <2 ng/mL  dosage OFF; LPV: <75 ng/mL; RTV: <10 ng/mL  no resistance  100%  2  TDF; FTC; EFV  52  male  A  5.9  311 000  209  574  605  40  124 (W12); CTR (9 days after): 55  47  dosage OFF; EFV: 1543 ng/mL  dosage ON; TDF: 71 ng/mL; FTC: 207 ng/mL; EFV:  3669 ng/mL  no resistance  100%  3  ABC; 3TC; ATV/r  31  female  A  4.2  61 500  422  1136  1229  <20  969 (W40); CTR (22 days after): 227  <20  dosage ON; ATV: <20 ng/mL  dosage ON; ATV: 4190 ng/mL; RTV: 1080 ng/mL  no resistance  100%  4  TDF; FTC; EFV  35  male  A  3  18 498  330  500    <20  <20 (W4)    dosage OFF; EFV: 709 ng/mL  discontinuation by patient decision at W4, related to the study strategy  100%  ABC, abacavir; 3TC, lamivudine; TDF, tenofovir disoproxil fumarate; FTC, emtricitabine; EFV, efavirenz; LPV/r, lopinavir/ritonavir; ATV/r, atazanavir/ritonavir; RTV, ritonavir; pVL, plasma VL; CTR, control. Figure 2. View largeDownload slide Probability of therapeutic success (Kaplan–Meier). Data for one patient were excluded at week 12 because of study treatment discontinuation due to pregnancy. Figure 2. View largeDownload slide Probability of therapeutic success (Kaplan–Meier). Data for one patient were excluded at week 12 because of study treatment discontinuation due to pregnancy. Four viral blips were observed in three patients, at W4 and W8 (rilpivirine-based therapy, VL 77 and 51 copies/mL, each point controlled with a subsequent VL measure <50 copies/mL), W24 (rilpivirine-based therapy, VL 182 copies/mL with control <50 copies/mL) and W48 (boosted atazanavir-based therapy, VL 142 copies/mL with control <50 copies/mL). In the substudy of 62 patients analysed with Roche Cobas Taqman HIV-1 2.0 assay, the proportions of patients with no signal of replication at D0, W12, W24 and W48 were respectively 71%, 69%, 77% and 70%, with no significant change over time (McNemar test, P > 0.513). No patient had the baseline ART switched throughout the trial. No HIV-related events occurred during the study. Seven severe adverse events were reported [trauma after sport (2), programmed surgery (2), cutaneous abscess, epileptic crisis, transient neutropenia], none being considered related to the study strategy. There was no statistically significant change in the total number of perceived symptoms recorded with the self-administered questionnaire (data not shown). Biological outcomes Changes in the main biological parameters between D0 and W48 are shown in Table 3. A significant increase in the CD4 cell count (+39 ± 168 cells/mm3, P = 0.023) and in the CD4/CD8 ratio (+0.04 ± 0.21, P = 0.034) was observed from D0 to W48. No significant changes in eGFR or lipid values were noted. Table 3. Changes from baseline in biological parameters and quality of life domains at W48   Baseline, n = 100  Δ(W48–BSL), n = 100  P  Biological parameters   CD4 cells/mm3  708 (243)  +39 (168)  0.023   CD4/CD8 ratio  1.15 (0.43)  +0.04 (0.21)  0.034   total HIV DNA, log10 copies/million PBMC, n = 96  2.4 (0.7)  0.0 (0.6)  0.765   AST, IU/L  26 (9)  −2 (8)  <0.001   ALT, IU/L  31 (16)  −3 (12)  0.007   GGT, IU/L  41 (55)  −9 (39)  <0.001   eGFR using CKD-EPI, mL/min  94.5 (15.4)  +1.2 (9.7)  0.195   glycaemia, mmol/L  5.0 (0.6)  +0.2 (0.6)  0.028   triglycerides, mmol/L  1.5 (0.8)  +0.7 (6.7)  0.598   total cholesterol, mmol/L  5.0 (0.9)  0.0 (0.8)  0.685   HDL cholesterol, mmol/L  1.3 (0.3)  0.0 (0.2)  0.635   LDL cholesterol, mmol/L, n = 99  3.0 (0.7)  0.0 (0.7)  0.324   markers of inflammation and cell activation, n = 96    IP-10, pg/mL  26.4 (19.3)  −0.5 (13.3)  0.550    IL-6, pg/mL  2.5 (12.5)  +4.0 (32.7)  0.367    MIG-1, pg/mL  34.3 (32.3)  −1.5 (29.9)  0.102    CRP, ng/mL, n = 93  885.2 (1496.3)  −80.2 (1589.8)  0.787    CD14s, ng/mL  1016.1 (725.5)  −200.4 (759.4)  0.001  Quality of life assessed with the PROQOL-HIV questionnaire, n = 92   physical health and symptoms  86.6 (1.6)  −1.5 (1.4)  0.253   body change  84.9 (2.2)  +1.8 (1.8)  0.313   social relationship  95.2 (1.7)  −0.4 (1.7)  0.809   intimate relationship  79.1 (2.9)  +2.4 (2.7)  0.367   stigma  62.4 (3.9)  +8.8 (3.6)  0.016   emotional distress  85.1 (2.2)  +1.3 (1.7)  0.452   health concern  71.6 (2.7)  +4.5 (1.9)  0.019   treatment impact  87.1 (1.3)  +3.2 (0.9)  0.001    Baseline, n = 100  Δ(W48–BSL), n = 100  P  Biological parameters   CD4 cells/mm3  708 (243)  +39 (168)  0.023   CD4/CD8 ratio  1.15 (0.43)  +0.04 (0.21)  0.034   total HIV DNA, log10 copies/million PBMC, n = 96  2.4 (0.7)  0.0 (0.6)  0.765   AST, IU/L  26 (9)  −2 (8)  <0.001   ALT, IU/L  31 (16)  −3 (12)  0.007   GGT, IU/L  41 (55)  −9 (39)  <0.001   eGFR using CKD-EPI, mL/min  94.5 (15.4)  +1.2 (9.7)  0.195   glycaemia, mmol/L  5.0 (0.6)  +0.2 (0.6)  0.028   triglycerides, mmol/L  1.5 (0.8)  +0.7 (6.7)  0.598   total cholesterol, mmol/L  5.0 (0.9)  0.0 (0.8)  0.685   HDL cholesterol, mmol/L  1.3 (0.3)  0.0 (0.2)  0.635   LDL cholesterol, mmol/L, n = 99  3.0 (0.7)  0.0 (0.7)  0.324   markers of inflammation and cell activation, n = 96    IP-10, pg/mL  26.4 (19.3)  −0.5 (13.3)  0.550    IL-6, pg/mL  2.5 (12.5)  +4.0 (32.7)  0.367    MIG-1, pg/mL  34.3 (32.3)  −1.5 (29.9)  0.102    CRP, ng/mL, n = 93  885.2 (1496.3)  −80.2 (1589.8)  0.787    CD14s, ng/mL  1016.1 (725.5)  −200.4 (759.4)  0.001  Quality of life assessed with the PROQOL-HIV questionnaire, n = 92   physical health and symptoms  86.6 (1.6)  −1.5 (1.4)  0.253   body change  84.9 (2.2)  +1.8 (1.8)  0.313   social relationship  95.2 (1.7)  −0.4 (1.7)  0.809   intimate relationship  79.1 (2.9)  +2.4 (2.7)  0.367   stigma  62.4 (3.9)  +8.8 (3.6)  0.016   emotional distress  85.1 (2.2)  +1.3 (1.7)  0.452   health concern  71.6 (2.7)  +4.5 (1.9)  0.019   treatment impact  87.1 (1.3)  +3.2 (0.9)  0.001  BSL, baseline. Data are mean and SD. Changes from baseline in biological parameters at W48 were compared using the non-parametric Wilcoxon paired test. Missing values at W48 were replaced using the last observation carried forward (LOCF) method. To assess quality of life in the PROQOL-HIV questionnaire, each item was scored on a 0–100 scale and the multiple imputation method was used to estimate missing values. Ten datasets in which missing data were imputed from each patient’s other covariables, including all items in the PROQOL-HIV questionnaire, age, sex, transmission group, origin, prior AIDS events, the type of treatment (2 INSTI + PI/r versus 2 INSTI + NNRTI), time of suppressed HIV viraemia <50 copies/mL and duration of ART. Changes from baseline at W48 in quality of life dimensions were compared using Student’s t-test. Analyses were run on each of the 10 datasets, including the imputed values, and the results were combined with Rubin’s rules. Total HIV-1 DNA in PBMC was stable between D0 (2.4 ± 0.7 log10 copies/106 PBMC) and W48 (2.4 ± 0.7 log10 copies/106 PBMC). No significant increase in markers of immune activation was observed (IP-10, IL-6, MIG-1 and CRP), but the CD14s level fell significantly (–200 ± 759 ng/mL, P = 0.001). Pharmacological data and adherence to therapy In total, 877 plasma samples were analysed for antiretroviral drug plasma concentrations (292 on treatment and 585 off treatment). All on-treatment concentrations were within the range of efficacy. Residual off-treatment concentrations were significantly lower (−47% to −99% depending on class and drug used) than on-treatment concentrations (Table 4), as would be expected with good adherence to the strategy. No significant modification of the concurrent medications taken by the participants was reported, so the changes in drug concentrations both on and off treatment cannot be explained by variation in drug–drug interactions. Table 4. Drug concentrations: mean values off and on therapy for each drug (ng/mL) Antiretroviral  n  ‘ON’, mean (SD)  ‘OFF’, mean (SD)  Δ(OFF − ON), mean (SD)  Percentage of change Δ(OFF − ON)/ON, mean (SD)  P  Efavirenz  38  2218 (1046)  692 (391)  −1526 (781)  −69% (10)  <0.0001  Etravirine  5  447 (360)  269 (266)  −179 (101)  −47% (11)  0.0625  Rilpivirine  26  106 (51)  39 (20)  −66 (40)  −63% (13)  <0.0001  Atazanavir  12  1087 (644)  52 (146)  −1035 (637)  −96% (11)  0.0005  Darunavir  15  2587 (1393)  17 (18)  −2570 (1382)  −99% (0)  <0.0001  Lopinavir  1  3922  0  −3922  −100%    Antiretroviral  n  ‘ON’, mean (SD)  ‘OFF’, mean (SD)  Δ(OFF − ON), mean (SD)  Percentage of change Δ(OFF − ON)/ON, mean (SD)  P  Efavirenz  38  2218 (1046)  692 (391)  −1526 (781)  −69% (10)  <0.0001  Etravirine  5  447 (360)  269 (266)  −179 (101)  −47% (11)  0.0625  Rilpivirine  26  106 (51)  39 (20)  −66 (40)  −63% (13)  <0.0001  Atazanavir  12  1087 (644)  52 (146)  −1035 (637)  −96% (11)  0.0005  Darunavir  15  2587 (1393)  17 (18)  −2570 (1382)  −99% (0)  <0.0001  Lopinavir  1  3922  0  −3922  −100%    Limits of quantification: <20 ng/mL for darunavir, atazanavir and lopinavir; <100 ng/mL for efavirenz; <10 ng/mL for etravirine; and <5 ng/mL for rilpivirine. Efficacy cut-offs: darunavir >2000 ng/mL; atazanavir >200 ng/mL; lopinavir >4000 ng/mL; efavirenz >1000 ng/mL; etravirine >50 ng/mL; and rilpivirine >40 ng/mL. The time between the last medication intake and sample collection was considered as ‘off period’ if ≥ 48 h and as ‘on period’ if < 48 h. For each participant and each drug, we calculated the mean of all measurements during the ‘on period’ (‘ON’) and all measurements during the ‘off period’ (‘OFF’). The Wilcoxon paired test was used to compare changes in residual antiretroviral concentrations between ‘ON’ and ‘OFF’. Self-reported adherence was high (95%–100% of doses taken) in >90% of patients (90.4%–98.8%) at each visit from D0 to W48. The proportion of patients who reported having taken <80% of their treatment in the previous week was between 1.1% and 7.5% at each visit. The proportion of patients who reported taking their treatment for >4 days in the previous week ranged from 0% to 4.4% at each visit (Figure 3a). Figure 3. View largeDownload slide Adherence to the study strategy. (a) Assessment of treatment adherence with a self-reported questionnaire based on last-week recall at each visit. The adherence rate for each participant was estimated as the number of pills consumed divided by the number of pills that should theoretically have been consumed and was classified as low (<80%), medium (80%–95%), high (95%–100%) or higher than expected (>100%). (b) Proportion of days on which MEMS-caps were opened according to the chosen weekly schedule (Monday–Thursday or Tuesday–Friday). The proportion was calculated as the number of days that the MEMS-cap was opened at least once divided by the total number of days under study. Figure 3. View largeDownload slide Adherence to the study strategy. (a) Assessment of treatment adherence with a self-reported questionnaire based on last-week recall at each visit. The adherence rate for each participant was estimated as the number of pills consumed divided by the number of pills that should theoretically have been consumed and was classified as low (<80%), medium (80%–95%), high (95%–100%) or higher than expected (>100%). (b) Proportion of days on which MEMS-caps were opened according to the chosen weekly schedule (Monday–Thursday or Tuesday–Friday). The proportion was calculated as the number of days that the MEMS-cap was opened at least once divided by the total number of days under study. Adherence was assessed during 51 weeks in 26 of the 29 participants enrolled in the MEMS substudy for whom data were available. As shown in Table 1, the 26 participants received tenofovir disoproxil fumarate/emtricitabine, plus an NNRTI in 21 cases and a boosted PI in 5 cases. Their baseline data were comparable to those of the entire group. Bottle openings were consistent with the 4/7 regimen in 90% of patients each week (89.9%–96.9%) (Figure 3b). For each of the 26 patients, the median number of weeks with bottle opening exactly 4 days a week was 44/51 weeks; bottle opening was <4 days in 5/51 weeks and >4 days in 2/51 weeks. The patients expressed a high degree of satisfaction with the 4/7 strategy: 78.6% were fully satisfied at W48, versus 57.5% at D0 (on the 7/7 strategy); 9.1% were not satisfied (versus 19.3% at D0), with an OR of 5.2 (95% CI 2.0–13.7, P < 0.001). Three of the eight PROQOL-HIV dimensions improved over time (stigma: +8.8 ± 3.6, P = 0.016; health concerns: +4.5 ± 1.9, P = 0.019; and treatment impact: +3.2 ± 0.9, P = 0.001). Discussion The 96% success rate observed here at W48 with a 4-days-a-week antiretroviral regimen compares favourably with other triple-agent maintenance strategies and simplified regimens (PI/r monotherapy or dual combinations), for which 1 year success rates ranged from 65% to 88%.7,15–19 The amount of proviral DNA, a surrogate size marker of the HIV-1 reservoir, which reflects the potential for viral rebound during and after treatment interruption,20–22 was remarkably stable from D0 to W48. Similarly, no increase in markers of inflammation was observed during the study. These data support the hypothesis of absence of immune degradation or inflammatory activation under reduced maintenance therapy: continued CD4 elevation and improvement of the CD4/CD8 ratio, stability of the viral reservoir attested by absence of HIV-DNA increase, absence of elevation of inflammatory markers and even a tendency to a decrease in monocyte activation markers (CD14s), indicating a low probability of viral reactivation. Although genital compartment HIV-1 shedding was not measured, it is unlikely that there was any change in the seminal HIV-1 VL, given that no change was seen in HIV DNA level over the course of the trial. Adherence questionnaires, together with low residual drug levels during the 3 day off-treatment period and the results of the MEMS-cap substudy, showed good adherence to the 4/7 strategy. Short-cycle structured intermittent maintenance therapy was first evaluated in a 7 days on/7 days off regimen as proof of concept,8 and then in a 5 days on/2 days off strategy in small or uncontrolled studies, with relative success.10,23,24 Recently, the multicentre, randomized BREATHER study, involving 199 young patients, demonstrated the non-inferiority of 5-days-a-week efavirenz-based therapy compared with daily therapy (virological failure: 6% versus 7%, difference: −1.2%, 90% CI −7.3% to –4.9%).9 We report a high level of efficacy with our 4 days on/3 days off NNRTI- and PI-based triple-agent maintenance strategy in this multicentre prospective trial. The very low rate of virological rebound observed here is compatible with the results of treatment discontinuation studies that indicate a latency period of 5–8 days before the resumption of viral replication.25,26 This latency may be related to the long half-life of NNRTI, as confirmed here by noteworthy residual plasma concentrations (>IC90) of efavirenz, rilpivirine and etravirine on the third day of treatment interruption. In three ART interruption studies, viral escape occurred after at least 5–7 days after stopping NNRTI.27–29 However, this pharmacological explanation does not seem suitable for PI-based therapy in which residual concentrations after ART interruption are low, with a shorter plasmatic half-life than NNRTI. In this case, the latency before VL rebound after treatment interruption could partially be explained by the long intracellular half-life of PIs, owing to their high binding affinity, especially for darunavir which has a dissociative half-life >240 h.30 Owing to the high efficiency of the 4/7 day regimen, the cost–benefit evaluation is obviously positive, with a 40% reduction in the cost of antiviral drugs, i.e. a saving of about €4800 per patient-year of maintenance therapy. The ‘3 day therapeutic weekend’ was greatly appreciated by the participants, demonstrated by a high level of satisfaction with the study regimen, being easy to remember and allowing them a standard lifestyle (e.g. ease of visiting friends or family on weekends without being disturbed by treatment intake). Evaluation of clinical or biological benefit is limited in our study because patients were maintained under their previous successful and well-tolerated ART combination and the lack of a control group. In addition to a cost reduction, the overall 40% reduction in drug exposure could reduce long-term toxicity. Other maintenance strategies currently under evaluation, such as the use of long-acting agents in patients with controlled VL, will not present the same advantages. In conclusion, in a population of patients on effective long-term NNRTI- or boosted-PI-based ART, short-cycle maintenance therapy with 4 days on and 3 days off treatment was safe, well accepted and virologically effective for 1 year. A longer, randomized study with other ART combinations, including integrase inhibitors, is warranted to confirm the benefits and effectiveness of a 4-days-a-week maintenance strategy. Acknowledgements This study was presented in part at the Twenty-First International AIDS Conference, Durban, South Africa, 2016 (THPEB063).  We acknowledge the members of the Independent Monitoring Committee: F. Bani Sadr, C. Delaugerre, R. Garaffo, M. Korzec, T. May, P. Morlat and R. Thiebaut. We thank all the participants of the ANRS 162-4D trial, the patients’ associative organizations and TRT5 group for advice and support, and the staff from the centres participating in the 4D trial. Members of the ANRS 162-4D Study Group Hôpital Avicenne, Bobigny: Olivier Bouchaud, Irène Zamord; Hôpital Bicêtre, Le Kremlin Bicêtre: Cécile Goujard, Frédéric Fourreau; Hôpital Bichat, Paris: Véronique Joly, Bao Phung; Hôpital européen Georges Pompidou, Paris: Laurence Weiss, Lio Collias; Hôpital Necker, Paris: Claire Rouzaud, Fatima Touam; Hôpital Pitié-Salpêtrière, Paris: Christine Katlama, Luminita Schneider; Hôpital Raymond Poincaré, Garches: Stéphanie Landowski, Huguette Berthe; Hôpital Saint Antoine, Paris: Karine Lacombe, Jean-Luc Meynard; Hôpital Tenon, Paris: Julie Chas, Pélagie Thibault; Hôpital de la Côte de Nacre, Caen: Arnaud de la Blanchardiere, Sylvie Dargere; Centre Hospitalier Sud-Francilien, Corbeil-Essonnes: Alain Devidas, Amélie Chabrol; Hôpital du Bocage, Dijon: Lionel Piroth, Sandrine Gohier; Hôpital Pierre Zobda-Quitman, Fort de France: André Cabié, Mathilde Pircher; Hôpital Gui de Chauliac, Montpellier: Jacques Reynes, Vincent Le Moing; Hôpital Foch, Suresnes: David Zucman, Dominique Bornarel; Hôpital Bretonneau, Tours: Louis Bernard, Adrien Lemaignen; Hôpital Purpan, Toulouse: Pierre Delobel, Noemie Biezunski; Institut Médecine Epidémiologie Appliquée, Paris: Karine Amat, Aida Benalicherif, Babacar Sylla; INSERM-ANRS, Paris: Severine Gibowski, Soizic Le Mestre, Jean-François Delfraissy. Funding The ANRS 162-4D trial was supported and funded by the Agence Nationale de Recherche sur le Sida et les Hépatites Virales (ANRS), part of the Institut National de la Santé et de la Recherche Médicale (INSERM). Transparency declarations P. d. T. reports having received consultancy fees and/or travel grants from Bristol-Myers Squibb, Gilead Sciences, Janssen Pharmaceuticals, Merck-Sharp-Dohme and ViiV Healthcare. R. L. reports having received consultancy fees and travel grants from BMS, Gilead Sciences and ViiV Healthcare. C. K. reports having received consultancy fees and/or travel grants from MSD, BMS, ViiV Healthcare, Gilead Sciences and Janssen Pharmaceuticals. G. G. reports having received consultancy fees and/or travel grants from BMS, Gilead Sciences, Janssen Pharmaceuticals, MSD and ViiV Healthcare. O. B. reports having received grants from MSD and ViiV Healthcare, personal fees from Gilead Sciences and MSD, and non-financial support from Janssen Pharmaceuticals. M. D. reports having received grants, personal fees and research support from Gilead Sciences, Janssen Pharmaceuticals and ViiV Healthcare. J. L. is a member of FOURVIRKS biotheque company. D. C. was a member of the French Gilead board from 2011 to 2015, gave lectures for Janssen-Cilag, MSD and ViiV Healthcare, received travel, accommodation and meeting expenses from Gilead Sciences, Janssen and ViiV Healthcare, received grants from Janssen-Cilag, MSD and ViiV, and is a consultant for Innavirax. P.-M. G. reports having received personal fees from Abbvie, BMS, Gilead and ViiV Healthcare, and research grants from BMS and Janssen Pharmaceuticals. All others authors: none to declare. Author contributions The 4D trial was designed by P. d. T., D. M., D. L. D., J.-C. M., J. L., D. C., P.-M. G. and C. P. The methodology and analysis plan was built by L. A. and D. C., and reviewed by the other authors and members of the scientific committee (chaired by C. P.). P. d. T., R. L., D. L. D., C. K., G. G., O. B., J.-C. M. and P.-M. G. contributed to recruitment and follow-up of participants, along with all the staff members listed in the ANRS 162-4D Study Group. R. L., K. A., J. S. and L. A. carried out the data monitoring. Coordination of assessment of virological and immunological data was conducted by D. M. and J. I., pharmacological data by E. A. and J.-C. A., and quality-of-life questionnaires by M. D. The statistical analysis was undertaken by J. B., L. A. and D. C., and all the authors reviewed the final data. P. d. T., L. A., R. L., D. C. and P.-M. G. drafted the manuscript, which was critically revised by all the authors who approved the final version. References 1 Gunthard HF, Saag MS, Benson CA et al.   Antiretroviral drugs for treatment and prevention of HIV infection in adults: 2016 recommendations of the International Antiviral Society-USA Panel. JAMA  2016; 316: 191– 210. Google Scholar CrossRef Search ADS PubMed  2 Ryom L, Boesecke C, Gisler V et al.   Essentials from the 2015 European AIDS Clinical Society (EACS) guidelines for the treatment of adult HIV-positive persons. HIV Med  2016; 17: 83– 8. Google Scholar CrossRef Search ADS PubMed  3 Delaugerre C, Ghosn J, Lacombe JM et al.   Significant reduction in HIV virologic failure during a 15-year period in a setting with free healthcare access. Clin Infect Dis  2015; 60: 463– 72. Google Scholar CrossRef Search ADS PubMed  4 Bunupuradah T, Kiertiburanakul S, Avihingsanon A et al.   Low-dose versus standard-dose ritonavir-boosted atazanavir in virologically suppressed Thai adults with HIV (LASA): a randomised, open-label, non-inferiority trial. Lancet HIV  2016; 3: e343– 50. Google Scholar CrossRef Search ADS PubMed  5 Group ES, Carey D, Puls R et al.   Efficacy and safety of efavirenz 400 mg daily versus 600 mg daily: 96-week data from the randomised, double-blind, placebo-controlled, non-inferiority ENCORE1 study. Lancet Infect Dis  2015; 15: 793– 802. Google Scholar CrossRef Search ADS PubMed  6 Baril JG, Angel JB, Gill MJ et al.   Dual therapy treatment strategies for the management of patients infected with HIV: a systematic review of current evidence in ARV-naive or ARV-experienced, virologically suppressed patients. PLoS One  2016; 11: e0148231. Google Scholar CrossRef Search ADS PubMed  7 Arribas JR, Girard PM, Paton N et al.   Efficacy of protease inhibitor monotherapy versus. triple therapy: meta-analysis of data from 2303 patients in 13 randomized trials. HIV Med  2016; 17: 358– 67. Google Scholar CrossRef Search ADS PubMed  8 Dybul M, Nies-Kraske E, Dewar R et al.   A proof-of-concept study of short-cycle intermittent antiretroviral therapy with a once-daily regimen of didanosine, lamivudine, and efavirenz for the treatment of chronic HIV infection. J Infect Dis  2004; 189: 1974– 82. Google Scholar CrossRef Search ADS PubMed  9 The Breather (PENTA16) Trial Group. Weekends-off efavirenz-based antiretroviral therapy in HIV-infected children, adolescents, and young adults (BREATHER): a randomised, open-label, non-inferiority, phase 2/3 trial. Lancet HIV  2016; 3: e421– 30. CrossRef Search ADS PubMed  10 Reynolds SJ, Kityo C, Hallahan CW et al.   A randomized, controlled, trial of short cycle intermittent compared to continuous antiretroviral therapy for the treatment of HIV infection in Uganda. PLoS One  2010; 5: e10307. Google Scholar CrossRef Search ADS PubMed  11 Leibowitch J, Mathez D, de Truchis P et al.   Four days a week or less on appropriate anti-HIV drug combinations provided long-term optimal maintenance in 94 patients: the ICCARRE project. FASEB J  2015; 29: 2223– 34. Google Scholar CrossRef Search ADS PubMed  12 Schoenenberger JA, Aragones AM, Cano SM et al.   The advantages of therapeutic drug monitoring in patients receiving antiretroviral treatment and experiencing medication-related problems. Ther Drug Monit  2013; 35: 71– 7. Google Scholar CrossRef Search ADS PubMed  13 Duracinsky M, Lalanne C, Le Coeur S et al.   Psychometric validation of the PROQOL-HIV questionnaire, a new health-related quality of life instrument-specific to HIV disease. J Acquir Immune Defic Syndr  2012; 59: 506– 15. Google Scholar CrossRef Search ADS PubMed  14 Rubin D. Multiple Imputation for Nonresponse in Surveys . New York: Wiley, 1987. Google Scholar CrossRef Search ADS   15 Paton NI, Stohr W, Arenas-Pinto A et al.   Protease inhibitor monotherapy for long-term management of HIV infection: a randomised, controlled, open-label, non-inferiority trial. Lancet HIV  2015; 2: e417– 26. Google Scholar CrossRef Search ADS PubMed  16 Girard PM, Antinori A, Arribas JR et al.   Week 96 efficacy and safety of darunavir/ritonavir monotherapy vs. darunavir/ritonavir with two nucleoside reverse transcriptase inhibitors in the PROTEA trial. HIV Med  2017; 18: 5– 12. Google Scholar CrossRef Search ADS PubMed  17 Valantin MA, Lambert-Niclot S, Flandre P et al.   Long-term efficacy of darunavir/ritonavir monotherapy in patients with HIV-1 viral suppression: week 96 results from the MONOI ANRS 136 study. J Antimicrob Chemother  2012; 67: 691– 5. Google Scholar CrossRef Search ADS PubMed  18 Arribas JR, Girard PM, Landman R et al.   Dual treatment with lopinavir-ritonavir plus lamivudine versus triple treatment with lopinavir-ritonavir plus lamivudine or emtricitabine and a second nucleos(t)ide reverse transcriptase inhibitor for maintenance of HIV-1 viral suppression (OLE): a randomised, open-label, non-inferiority trial. Lancet Infect Dis  2015; 15: 785– 92. Google Scholar CrossRef Search ADS PubMed  19 Perez-Molina JA, Rubio R, Rivero A et al.   Simplification to dual therapy (atazanavir/ritonavir + lamivudine) versus standard triple therapy [atazanavir/ritonavir + two nucleos(t)ides] in virologically stable patients on antiretroviral therapy: 96 week results from an open-label, non-inferiority, randomized clinical trial (SALT study). J Antimicrob Chemother  2017; 72: 246– 53. Google Scholar CrossRef Search ADS PubMed  20 Eriksson S, Graf EH, Dahl V et al.   Comparative analysis of measures of viral reservoirs in HIV-1 eradication studies. PLoS Pathog  2013; 9: e1003174. Google Scholar CrossRef Search ADS PubMed  21 Saez-Cirion A, Bacchus C, Hocqueloux L et al.   Post-treatment HIV-1 controllers with a long-term virological remission after the interruption of early initiated antiretroviral therapy ANRS VISCONTI Study. PLoS Pathog  2013; 9: e1003211. Google Scholar CrossRef Search ADS PubMed  22 Williams JP, Hurst J, Stohr W et al.   HIV-1 DNA predicts disease progression and post-treatment virological control. Elife  2014; 3: e03821. Google Scholar PubMed  23 Cohen C, Colson A, Pierone G et al.   O214 the FOTO study: 24-week results support the safety of a 2-day break on efavirenz-based antiretroviral therapy. J Int AIDS Soc  2008; 11 Suppl 1: O19. Google Scholar CrossRef Search ADS   24 Rudy BJ, Sleasman J, Kapogiannis B et al.   Short-cycle therapy in adolescents after continuous therapy with established viral suppression: the impact on viral load suppression. AIDS Res Hum Retroviruses  2009; 25: 555– 61. Google Scholar CrossRef Search ADS PubMed  25 Pinkevych M, Cromer D, Tolstrup M et al.   HIV reactivation from latency after treatment interruption occurs on average every 5-8 days–implications for HIV remission. PLoS Pathog  2015; 11: e1005000. Google Scholar CrossRef Search ADS PubMed  26 Hill AL, Rosenbloom DIS, Siliciano JD et al.   Correction: real-time predictions of reservoir size and rebound time during antiretroviral therapy interruption trials for HIV. PLoS Pathog  2016; 12: e1005778. Google Scholar CrossRef Search ADS PubMed  27 Jackson A, Moyle G, Watson V et al.   Tenofovir, emtricitabine intracellular and plasma, and efavirenz plasma concentration decay following drug intake cessation: implications for HIV treatment and prevention. J Acquir Immune Defic Syndr  2013; 62: 275– 81. Google Scholar CrossRef Search ADS PubMed  28 Parienti JJ, Das-Douglas M, Massari V et al.   Not all missed doses are the same: sustained NNRTI treatment interruptions predict HIV rebound at low-to-moderate adherence levels. PLoS One  2008; 3: e2783. Google Scholar CrossRef Search ADS PubMed  29 Pogany K, van Valkengoed IG, Prins JM et al.   Effects of active treatment discontinuation in patients with a CD4+ T-cell nadir greater than 350 cells/mm3: 48-week Treatment Interruption in Early Starters Netherlands Study (TRIESTAN). J Acquir Immune Defic Syndr  2007; 44: 395– 400. Google Scholar CrossRef Search ADS PubMed  30 Dierynck I, De Wit M, Gustin E et al.   Binding kinetics of darunavir to human immunodeficiency virus type 1 protease explain the potent antiviral activity and high genetic barrier. J Virol  2007; 81: 13845– 51. Google Scholar CrossRef Search ADS PubMed  © The Author 2017. 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.

Journal

Journal of Antimicrobial ChemotherapyOxford University Press

Published: Mar 1, 2018

There are no references for this article.

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Search

Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly

Organize

Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.

Access

Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve

Freelancer

DeepDyve

Pro

Price

FREE

$49/month
$360/year

Save searches from
Google Scholar,
PubMed

Create lists to
organize your research

Export lists, citations

Read DeepDyve articles

Abstract access only

Unlimited access to over
18 million full-text articles

Print

20 pages / month

PDF Discount

20% off