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HIV treatment simplification to elvitegravir/cobicistat/emtricitabine/tenofovir disproxil fumarate (E/C/F/TDF)… Harris, Marianne; Ganase, Bruce; Watson, Birgit; Harrigan, P. R; Montaner, Julio S G; Hull, Mark W Nov 2, 2017

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Harris et al. AIDS Res Ther  (2017) 14:59 DOI 10.1186/s12981-017-0185-4RESEARCHHIV treatment simplification to elvitegravir/cobicistat/emtricitabine/tenofovir disproxil fumarate (E/C/F/TDF) plus darunavir: a pharmacokinetic studyMarianne Harris1,2,3,4*, Bruce Ganase2, Birgit Watson1, P. Richard Harrigan1,4, Julio S. G. Montaner1,4 and Mark W. Hull1,4Abstract Background: As a simplification strategy for treatment-experienced HIV-infected patients who have achieved viro-logic suppression on a multi-drug, multi-class antiretroviral regimen, the aim of this study was to evaluate the safety, efficacy, and pharmacokinetics of once-daily elvitegravir/cobicistat/emtricitabine/tenofovir disproxil fumarate (E/C/F/TDF) with darunavir.Methods: A single arm, open-label 48-week study was conducted of regimen simplification to E/C/F/TDF plus darunavir 800 mg daily from stable therapy including two nucleoside/nucleotide reverse transcriptase inhibitors, a ritonavir-boosted protease inhibitor, and an integrase inhibitor. Participants had plasma HIV viral load consistently < 200 copies/mL for ≥ 6 months, estimated glomerular filtration rate (eGFR) ≥ 60 mL/min, and no genotypic resist-ance to major components of the study regimen. Plasma viral load was measured at weeks 2 and 4, then every 4 weeks throughout the study. Safety laboratory assessments were conducted at baseline and at weeks 12, 24, 36, and 48. Antiretroviral drug concentrations were measured at baseline and once ≥ 2 weeks after the regimen change.Results: Ten HIV-infected adults (8 male and 2 female; median age 50.5 years) were enrolled. All maintained viro-logic suppression on the new regimen for 48 weeks. One subject experienced a decrease in eGFR from 62 mL/min at baseline to 52 mL/min at week 12; study medications were continued and his eGFR remained stable (50–59 mL/min) thereafter. No subjects discontinued study medications for renal function changes or other adverse events. Darunavir trough concentration were lower on the new regimen than on darunavir/ritonavir 800/100 mg (n = 5; p < 0.05).Conclusions: Despite low darunavir trough concentrations, treatment simplification to a two-pill, once-daily regi-men of E/C/F/TDF plus darunavir was safe and effective for 48 weeks among 10 selected treatment-experienced HIV-infected patients.Trial registration The study protocol was registered with ClinicalTrials.gov (NCT02199613) on July 22, 2014Keywords: HIV, Antiretrovirals, Elvitegravir, Cobicistat, Darunavir© The Author(s) 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.BackgroundDespite the success of current highly active antiretrovi-ral therapy regimens, some HIV-infected patients require regimens encompassing multiple drug classes because of transmitted or acquired drug-resistant virus [1, 2]. Such regimens usually include a ritonavir-boosted protease inhibitor and generally comprise several pills in two or more daily doses, making adherence a challenge for many patients [3]. For example, the TRIO regimen (raltegravir 400  mg twice daily, etravirine 200  mg twice daily, and Open AccessAIDS Research and Therapy*Correspondence:  mharris@cfenet.ubc.ca 1 British Columbia Centre for Excellence in HIV/AIDS, Vancouver, BC, CanadaFull list of author information is available at the end of the articlePage 2 of 9Harris et al. AIDS Res Ther  (2017) 14:59 darunavir/ritonavir 600 mg/100 mg twice daily), which is effective and often used in patients harboring multi-drug resistant HIV, comprises six pills twice daily, and more if nucleoside reverse transciptase inhibitors (NRTIs) are taken as well (as was the case in the majority of subjects in the ANRS 139 TRIO study) [4]. Over the longer term, high pill burden is a major factor contributing to treat-ment fatigue among HIV-infected patients prescribed antiretroviral therapy, with important consequences including medication nonadherence and treatment fail-ure [5].In recent years, first-line regimens have included the use of a fixed-dose once-daily combination tablet con-sisting of the integrase inhibitor elvitegravir 150  mg (E) with a pharmacologic boosting agent (cobicistat 150 mg [C]) and two reverse transcriptase inhibitors (a nucleo-side: emtricitabine or FTC 200 mg [F] and a nucleotide: tenofovir disoproxil fumarate 300  mg [TDF]) [6]. Cobi-cistat has been shown to also adequately boost plasma levels of protease inhibitors including darunavir [7]. In addition, there is evidence that once-daily boosted daru-navir 800  mg is as effective as the twice-daily boosted darunavir 600  mg in treatment-experienced patients in the absence of darunavir resistance-associated mutations [8]. Pharmacokinetic studies support the use of once daily darunavir 800 mg in this population: 24-h post-dose minimum plasma concentrations of darunavir (when given with ritonavir 100 mg) remain above 55 ng/mL, the half maximal effective concentration  (EC50) for wild-type (non-protease inhibitor-resistant) virus [9]. The elvitegra-vir/cobicistat/emtricitabine/tenofovir DF (E/C/F/TDF) fixed-dose formulation may allow construction of a two-pill once-daily salvage regimen containing an integrase inhibitor, two nucleoside/nucleotides, and a boosted pro-tease inhibitor: E/C/F/TDF and darunavir 800 mg. Since both E/C/F/TDF and darunavir are recommended to be taken once a day with food [6, 10], this constitutes a truly compact once-daily multi-class regimen.Some early pharmacokinetic (PK) studies suggested that steady-state trough concentrations  (Ctrough,ss) of both darunavir and elvitegravir may be lower when E/C/F/TDF and darunavir are given together, compared to lev-els obtained when elvitegravir/cobicistat and darunavir (boosted either with cobicistat or ritonavir) are given separately [11, 12]. However, the clinical implications of a potential decrease in  Ctrough,ss are unclear, particularly given the potency of boosted protease-inhibitor-based regimens. Given the potential benefits of treatment sim-plification in patients receiving complex salvage regi-mens, we undertook to evaluate the use of once-daily E/C/F/TDF with darunavir as a simplification strategy for treatment-experienced patients who had already achieved virologic suppression on a multi-drug, multi-class antiretroviral regimen, with one-time PK testing and longitudinal viral load monitoring. In view of the known potential for TDF to cause nephrotoxicity [13–15], we also monitored renal function and other safety parameters.MethodsStudy designWe conducted a single arm, open-label study of regimen simplification to E/C/F/TDF plus darunavir 800 mg daily from stable therapy including two nucleoside/nucleotide reverse transcriptase inhibitors, a ritonavir-boosted pro-tease inhibitor (atazanavir or darunavir), and raltegravir or dolutegravir.Study populationThe study enrolled HIV positive adults (≥  19  years of age) with plasma viral load consistently <  200 copies/mL for ≥ 6 months. Subjects were excluded if they had prior documented virologic rebound >  1000 copies/mL on an integrase inhibitor-containing regimen; had evi-dence on any previous genotypic testing of resistance mutations which would compromise activity of elvitegra-vir, darunavir, or tenofovir; were currently receiving any nonnucleoside reverse transcriptase inhibitor (NNRTI); were pregnant or breast-feeding; or had any contrain-dications to tenofovir DF, emtricitabine, elvitegravir, or cobicistat (e.g. previous significant toxicity, intolerance, or were receiving medications with significant drug interactions with the study drugs). The eligibility crite-ria included having estimated glomerular filtration rate (eGFR) ≥ 70 mL/min, as recommended by the manufac-turer of E/C/F/TDF [6]; however, waivers were allowed for participants with a stable eGFR ≥ 60 mL/min, based on available evidence indicating the safety of E/C/F/TDF in HIV-infected patients with this degree of mild renal impairment [16].Determination of plasma concentration of study drugsA plasma sample for measurement of darunavir  Ctrough,ss (pre-dose) was collected at baseline before the switch in subjects receiving once-daily darunavir in their pre-switch regimen.All subjects took study medication (E/C/F/TDF and darunavir) with food under observation in the clinic on Day 14 or later after starting the new regimen. Plasma samples for drug level testing were drawn immediately pre-dose  (Ctrough,ss) and at 1, 2, 3, 4, 5, 6, and 8  h post-dose, then once on the following day for a 24-h post-dose  Ctrough,ss. Plasma samples were frozen and stored at – 80 °C until analysis.Page 3 of 9Harris et al. AIDS Res Ther  (2017) 14:59 Darunavir in stored plasma samples was measured in the BC Centre for Excellence in HIV/AIDS Laboratory using a fully validated method [17]. Addition of elvite-gravir and cobicistat to the method was partly validated, including selectivity, linearity, accuracy and recovery, inter- and intra-run repeatability, and stability. External controls were included for darunavir and elvitegravir, but were not available for cobicistat. Lower limits of quantifi-cation were 70 ng/mL for darunavir, 80 ng/mL for elvite-gravir, and 50 ng/mL for cobicistat. Plasma tenofovir and emtricitabine levels were not measured.Safety and efficacy assessmentsMedical history and physical exam were conducted at base-line, and clinical adverse event assessment and medica-tion update performed at weeks 2, 12, 24, 36, and 48. HIV plasma viral load (COBAS Ampliprep Taqman HIV-1 assay, Roche Diagnostics Systems, Laval, Quebec, Canada) was measured at baseline, at weeks 2 and 4, then every 4 weeks throughout the study. The following laboratory assessments were conducted at baseline and at weeks 12, 24, 36, and 48: CD4 cell counts (absolute and fraction), CD4/CD8 ratio, renal function (serum creatinine, eGFR, serum phospho-rus, urinalysis, urine albumin to creatinine ratio [UACR]), AST, ALT, total bilirubin, fasting blood sugar, fasting lipid parameters (total cholesterol, LDL, HDL, total cholesterol/HDL, triglycerides, and apolipoprotein B [apoB]), high-sen-sitivity C-reactive protein (hsCRP), and pregnancy test for women of child-bearing potential .Study endpoints and statistical analysesThe primary endpoint was the proportion of subjects with plasma viral load <  200  copies/mL at week 12 fol-lowing the regimen switch, with secondary endpoints at weeks 24 and 48. The threshold of 200  copies/mL was chosen based on data showing that low level viremia between 50–199  copies/mL is not associated with viro-logical failure or clinical outcomes [18], and is consistent with the definition of virologic failure in international antiretroviral treatment guidelines [19, 20]. Changes in CD4 cell count (absolute and fraction), CD4/CD8 ratios, creatinine, eGFR, serum phosphorus, ALT, AST, total bil-irubin, fasting glucose and lipid parameters, and hsCRP between baseline and week 48 were determined using a Wilcoxon signed rank sum test with significance level 0.05. For subjects receiving once daily darunavir prior to switching to the study regimen, darunavir  Ctrough,ss at baseline and day 14 were compared using Wilcoxon signed rank sum test. Elvitegravir and cobicistat concen-trations were compared to historical controls.No sample size calculation was performed for this study. A convenience sample of ten patients was enrolled.ResultsBaseline characteristicsTen HIV-infected subjects, 8 men and 2 women, were enrolled and started study medications between Octo-ber 2014 and February 2016 (Table  1). Median age was 50.5  years (range 33–71), weight was 87.5  kg (range 56–101.5), and CD4 cell count was 505 cells/mm3 (range 50−1020). All had viral load <  40  copies/mL except one whose viral load was 134  copies/mL, considered to be within the limits of error of the assay [21]. Median eGFR at baseline was 81  mL/min (range 60–102). The two subjects who entered the study with eGFR < 70 mL/min had stable renal function, with mildly decreased eGFR between 60 and 70 mL/min for at least 6 months prior to the study baseline visit. All study subjects were receiving tenofovir DF and emtricitabine; 9 were receiv-ing raltegravir and one dolutegravir; 7 were receiving ritonavir-boosted darunavir (6 once daily and one twice daily) and 3 were receiving ritonavir-boosted atazanavir. No subjects were receiving any concomitant medications that would be expected to affect the plasma levels of the antiretrovirals.Archived antiretroviral drug resistance mutationsNine subjects had evidence of archived drug-resistant virus on previous genotypic  testing, all of whom had M184V/I (conferring resistance to lamivudine and emtricitabine) (Table  2). Five subjects had had thymi-dine analogue mutations including 41L and 215Y or F, associated with reduced susceptibility to tenofovir DF: enrolment in the study was judged to be safe for these subjects because the other study drugs (darunavir and elvitegravir) were fully active. Six subjects had resistance to NNRTIs, and four had protease-inhibitor-associated mutations, but retained susceptibility to darunavir.Efficacy resultsAll 10 subjects had plasma viral load < 200 copies/mL at baseline and at every time point during the study. Nine subjects had viral load <  40  copies/mL at baseline, and viral load remained < 40 copies/mL in 9 at week 12, in 8 at week 24, and in 8 at week 48 (Fig. 1); the subject whose viral load was detectable at week 48 had a viral load of 41 copies/mL. Subject 10’s viral load remained detectable at < 200 copies/mL at each time point during the study, and was 174 copies/mL at week 48 (Fig. 2). Among all 10 subjects, no significant changes were observed between baseline and week 48 in absolute CD4 cell count (median 505 and 440  cells/mm3, respectively) (Fig.  3), CD4 frac-tion (median 25 and 26%, respectively), or CD4/CD8 ratio (median 0.61 and 0.63, respectively) (p  >  0.05 for all).Page 4 of 9Harris et al. AIDS Res Ther  (2017) 14:59 Table 1 Baseline characteristics of study participants (n = 10)eGFR estimated glomerular filtration rate, RAL raltegravir, DTG dolutegravir, DRV darunavir, ATV atazanavirSubject no. Gender Age, years Weight, kg eGFR, mL/minViral load,  copies/mLCD4, cells/mm3 Antiretroviral regimen (with tenofovir DF and emtricitabine)1 Male 59 92.5 78 < 40 180 RAL 400 mg twice dailyDRV 800 mg dailyRitonavir 100 mg daily2 Male 47 89.5 60 < 40 510 RAL 400 mg twice dailyDRV 800 mg dailyRitonavir 100 mg daily3 Male 71 63 62 < 40 400 RAL 400 mg twice dailyATV 300 mg dailyRitonavir 100 mg daily4 Male 55 101.5 85 < 40 900 RAL 400 mg twice dailyDRV 800 mg dailyRitonavir 100 mg daily5 Female 42 56 84 < 40 900 RAL 400 mg twice dailyDRV 600 mg twice dailyRitonavir 100 mg twice daily6 Male 33 85.5 102 < 40 410 RAL 400 mg twice dailyATV 300 mg dailyRitonavir 100 mg daily7 Male 53 72 95 < 40 500 RAL 400 mg twice dailyDRV 800 mg dailyRitonavir 100 mg daily8 Male 56 95.5 74 < 40 700 DTG 50 mg dailyDRV 800 mg dailyRitonavir 100 mg daily9 Female 48 84 100 < 40 50 RAL 400 mg twice dailyDRV 800 mg dailyRitonavir 100 mg daily10 Male 47 98.5 75 134 1020 RAL 400 mg twice dailyATV 300 mg dailyRitonavir 100 mg dailyTable 2 Archived antiretroviral drug resistance mutations among study participantsReference: Stanford HIV Drug Resistance Database. Major HIV-1 Drug Resistance Mutations, Updated summary March 9, 2015. http://hivdb.stanford.eduNRTI nucleoside analogue reverse transcriptase inhibitor, TAMs thymidine analogue mutations, NNRTI nonnucleoside analogue reverse transcriptase inhibitor,  PI protease inhibitor, ND none detecteda Although not listed as major NNRTI mutation, 98G confers resistance to nevirapineSubject no. Major NRTI resistance mutations Major NNRTI resistance mutations Major PI resistance mutationsNon-TAMs TAMs1 184V 67N, 70R, 219Q 103N ND2 184V, 74V 67N, 70R, 219Q 181C, 190A ND3 184V 41L, 210W, 215Y ND ND4 184V 70R ND ND5 184V, 74I 41L, 67N, 70R, 215F, 219Q 103N 84V, 90M6 184V 41L, 67N, 70R, 215Y, 219Q 103N, 181C, 190S 30N, 88D7 184V 41L, 215Y 103N 54V, 82A8 184V 41L, 215Y 98Ga 46L9 184I, 70E ND ND ND10 ND ND ND NDPage 5 of 9Harris et al. AIDS Res Ther  (2017) 14:59 Safety resultsIn the group as a whole, no significant changes were observed between baseline and week 48 in creatinine, eGFR, serum phosphorus, ALT, AST, total bilirubin, glucose, lipid parameters, or hsCRP (p  >  0.05 for all). No subjects discontinued study medications during the 48-week study for renal function changes or other adverse events. Subject three experienced a decrease in eGFR from 62 mL/min at baseline to 52 mL/min at week 12; study medications were continued and his eGFR remained stable (50–59  mL/min) thereafter. At study entry, this patient had been receiving a tenofovir DF-containing regimen for 29  months and had hypophos-phatemia (serum phosphorus 0.66  mmol/L, lower limit of normal 0.80 mmol/L) and proteinuria (UACR 19.2 mg/mmol, upper limit of normal 2.0 mg/mmol), which per-sisted over the course of the study; at week 48, his serum phosphorus was 0.72  mmol/L and UACR was 33.9  mg/mmol. After week 48, study medications were discontin-ued and replaced with abacavir, lamivudine, raltegravir, and darunavir/ritonavir; 3  months later, his eGFR was 63  mL/min, serum phosphorus was 0.92  mmol/L, and UACR was 2.3 mg/mmol. No significant clinical or labo-ratory adverse events were observed in any other study subjects.Pharmacokinetics of darunavir, elvitegravir, and cobicistatDarunavir levelsSix subjects were receiving darunavir/ ritonavir once daily prior to study entry, of whom 5 had 24-h post-dose darunavir  Ctrough,ss measured at both baseline and 2  weeks after the switch to E/C/F/TDF and darunavir (the other subject [number 7 in Tables 1 and 2] had taken his medications before the study baseline visit so a pre-dose sample could not be drawn). The median daruna-vir  Ctrough,ss for these 5 subjects decreased from 981 ng/mL (range 667–1150) at baseline to 431  ng/mL (range 96–784) at week 2 (p  ≤  0.05). Among all nine subjects who had plasma drug levels measured after the switch to E/C/F/TDF and darunavir (median 14  days, range 14–28 days after the switch; Subject 6 was not available for week 2 sampling), the median darunavir  Ctrough,ss was 482 ng/mL (range 96–848).Mean and median darunavir  Ctrough,ss are shown in Table 3 for the purpose of comparison with data from the literature. The darunavir  Ctrough,ss we observed with riton-avir prior to the switch to E/C/F/TDF tended to be lower than  Ctrough,ss published in the literature for darunavir/ritonavir 800  mg/100  mg once daily [22, 23]. After the switch to E/C/F/TDF, the darunavir  Ctrough,ss we observed were higher than the extrapolated  Ctrough,ss reported in the presence of E/C/F/TDF by Ricard et al [12], but lower than the measured 24-h darunavir  Ctrough,ss with the same regimen reported by Gutierrez-Valencia et al [24].The maximum observed darunavir level at 2 weeks was 5840 ng/mL (median), range 3590–7840 ng/mL (n = 9), and was reached at a median of 2.5 h (range 1–5 h) after dosing. This is generally similar to published data for 60 subjects receiving darunavir 800  mg/cobicistat 150  mg with two nucleoside/nucleotide reverse transcriptase 0102030405060708090100week 0 week 12 week 24 week 36 week 48% of parcipantsFig. 1 Proportion of participants (n = 10) with plasma viral load < 40 copies/mL020406080100120140160180200week 0 week 12 week 24 week 36 week 48Viral load, copies/mL1 to 8910Fig. 2 Viral load of each study participant020040060080010001200140016001800week 0 week 12 week 24 week 36 week 48CD4 count, cells/mm312345678910Fig. 3 CD4 cell count of each study participantPage 6 of 9Harris et al. AIDS Res Ther  (2017) 14:59 inhibitors: mean darunavir  Cmax 7663  ng/mL (standard deviation 1920), median  tmax 3.5  h (interquartile range [IQR] 2.5–4.3 h) [25].Elvitegravir and cobicistat levelsAmong the 9 subjects who had drug levels measured 2  weeks after switching to E/C/F/TDF and darunavir, the median elvitegravir  Ctrough,ss was 184  ng/mL (range < 80–296).Mean and median elvitegravir  Ctrough,ss are shown in Table 3 for the purpose of comparison with data from the literature. Our observed elvitegravir  Ctrough,ss were some-what lower than the manufacturer’s population pharma-cokinetic estimates for E/C/F/TDF without darunavir [26], but generally similar to 24-h  Ctrough,ss measured by Gutierrez-Valencia et  al. among patients taking E/C/F/TDF either with or without darunavir [24].The maximum observed elvitegravir level was 1230 ng/mL (median), range 651–2400  ng/mL (n =  9), and was reached at a median of 3  h (range 1–8  h) after dos-ing. In comparison, population PK data for E/C/F/TDF (n = 419) provide a mean  Cmax of 1731 ng/mL (standard deviation 23) with a  tmax of 4.0 h [6, 26].Cobicistat levels at 24 h post-dosing were < 50 ng/mL in all 9 of our study subjects with available drug levels. The maximum observed cobicistat level was 769  ng/mL (median), range 493–1090  ng/mL (n =  9), and was reached at a median of 2  h (range 2–4  h) after dos-ing. In published data for 60 subjects receiving daru-navir 800  mg/cobicistat 150  mg with two nucleoside/nucleotide reverse transcriptase inhibitors, mean cobi-cistat  C0h was 76 ng/mL (standard deviation 186), mean  Cmax was 991  ng/mL (standard deviation 331), and median  tmax was 3.5 h (IQR 2.0–4.5) [25].DiscussionAmong 10 treatment-experienced HIV-infected patients who had viral load consistently <  200  copies/mL on a multiple-class antiretroviral regimen, a switch to a two-pill once-daily regimen of E/C/F/TDF and darunavir was safe and effective in maintaining virologic suppression for 48 weeks. One patient had pre-existing TDF-related renal tubular toxicity which persisted but did not worsen on the study regimen, and improved when he was changed to a non-TDF-containing regimen after completion of the study.Among the 5 patients receiving once-daily darunavir/ritonavir at baseline, darunavir  Ctrough,ss levels were sig-nificantly lower after the switch to E/C/F/TDF plus daru-navir (the  median decreased from 981 to 431  ng/mL), and darunavir  Ctrough,ss levels were low for all 9 subjects with drug levels available on E/C/F/TDF plus darunavir (median 482 ng/mL). Previous studies have shown daru-navir  Ctrough,ss to be lower when boosted with cobicistat than with ritonavir, both in healthy volunteers (21–24% lower with cobicistat) [27] and HIV-infected patients (30% lower with cobicistat) [24]. However, the magnitude of the effect we observed (> 50% reduction in darunavir  Ctrough,ss) was greater than that observed in the previous studies. This is particularly striking since our subjects’ Table 3 Plasma concentrations of darunavir and elvitegravir at 24 h post-doseCtrough,ss trough plasma concentration at steady-state, DRV darunavir, rtv ritonavir, cobi cobicistat, E/C/F/TDF elvitegravir/cobicistat/emtricitabine/tenofovir disproxil fumarate, E/C/F/TAF elvitegravir/cobicistat/ emtricitabine/ tenofovir alafenamide, IQR interquartile range, SD standard deviation, NA not availablea Population pharmacokinetic estimate; b estimatedStudy intervention N Darunavir  Ctrough,ss, ng/mL Elvitegravir  Ctrough,ss, ng/mL Refs.Median/mean Range Median/mean RangeDRV/rtv, pre-switch 5 981 (median)932 (mean)667–1150 –––E/C/F/TDF + DRV 9 482 (median)490 (mean)96–848 184 (median)200 (mean)<  80–435DRV/rtv 800/100 mg 335a 2041 (median) 368–7242 – – [22]119 1820 (mean) IQR 1470–2460 – – [23]DRV/cobi 800/150 mg 298a 2150 (mean) SD 1320 – – [25]59 1311 (mean) SD 969 – – [25]32 1319 (mean) 288–3641 – – [24]E/C/F/TDF (no DRV) 419a – – 451 (mean) 58–2341 [26]32 – – 250 (mean) 30–762 [24]E/C/F/TDF + DRV 24 1294 (mean) 163–3641 234 (mean) 92–432 [24]8 273 (median)b 164–501 (IQR)b – – [12]E/C/F/TAF + DRV 15 1250 (mean) NA 464 (mean) NA [36]Page 7 of 9Harris et al. AIDS Res Ther  (2017) 14:59 darunavir  Ctrough,ss levels on darunavir /ritonavir (median 981  ng/mL) were already more than 50% lower than those reported in the literature for HIV-infected patients receiving darunavir /ritonavir [22, 23]. The reason for this is unclear, as drug–drug interactions are not expected between darunavir and either raltegravir or dolutegravir (taken concomitantly by 4 subjects and 1 subject, respec-tively) [28–30]. Possibly as a result of these low baseline levels, our patients’ darunavir  Ctrough,ss levels on E/C/F/TDF plus darunavir were less than 40% of those expected with darunavir /cobicistat without elvitegravir (daruna-vir  Ctrough,ss approximately 1300 ng/mL) [24, 25]. The low darunavir  Ctrough,ss seen in our patients on E/C/F/TDF plus darunavir support an earlier retrospective study that used extrapolated levels and suggested a significant drug–drug interaction between darunavir and E/C/F/TDF [12]; however, a subsequent larger study showed darunavir  Ctrough,ss were similar in 24 patients receiving E/C/F/TDF plus darunavir as in 32 patients receiving darunavir /cobicistat without elvitegravir [24]. Although our study is small, we were able to prospectively measure darunavir  Ctrough,ss in the same patients before and after the switch from darunavir/ritonavir to E/C/F/TDF plus darunavir, and to demonstrate a statistically significant decrease in darunavir  Ctrough,ss after the switch. On the other hand, while the observed darunavir concentrations were low, they remained 2- to 15-fold higher than the protein-adjusted 50% inhibitory concentration  (IC50) for darunavir against wild-type virus (55  ng/mL) [31], and the study regimen maintained antiviral efficacy through-out the 48 week study in all 10 patients. As an alternative boosted protease inhibitor-elvitegravir combination regi-men, atazanavir would not be an ideal option; coadmin-istration with elvitegravir/cobicistat has been shown to result in significant lowering of atazanavir trough levels [32].The elvitegravir  Ctrough,ss in our patients receiving E/C/F/TDF plus darunavir (median elvitegravir  Ctrough,ss 184  ng/mL, mean 200  ng/mL) were about 40% of those reported by the manufacturer for E/C/F/TDF without darunavir based on population PK analysis (mean 451 ng/mL) [26]. This is despite the fact that our patients were instructed to take their medications with food, and were observed to do so on the day prior to the 24-h post-dose draw, as recommended to optimize elvitegravir exposure from the coformulation [6, 33]. However, the elvitegravir concentrations we observed were similar those observed by Gutierrez-Valencia et al. in patients receiving E/C/F/TDF, either with darunavir (mean elvitegravir  Ctrough,ss 234  ng/mL) or without darunavir (mean elvitegravir  Ctrough,ss 250  ng/mL) [24]. Since we do not have elvite-gravir levels in our patients in the absence of darunavir, we cannot comment on whether there is a significant drug–drug interaction which lowers elvitegravir  Ctrough,ss, but the study by Gutierrez-Valencia et  al. suggests that this may not be the case [24]. In 7 of 9 subjects in our study, the observed elvitegravir  Ctrough,ss were more than 2-fold above the protein-adjusted 95% inhibitory con-centration  (IC95) for elvitegravir against wild type virus (45  ng/mL) [34]; the other two patients had elvitegravir  Ctrough,ss of 82 and <  80  ng/mL. Nevertheless, virologic efficacy was maintained in all 10 patients.Cobicistat  Ctrough,ss were below the lower limit of the assay (< 50 ng/mL) in all cases, and consistent with pre-vious studies utilizing cobicistat as a booster for either elvitegravir or darunavir or both. Tashima et al. reported mean 24-h cobicistat levels of 33 ng/mL (standard devia-tion 95) among 59 HIV-infected patients taking daruna-vir/cobicistat with emtricitabine and tenofovir DF [25]. Gutierrez-Valencia et  al. reported mean 24-h cobicistat concentrations of 20.2 ng/mL (IQR 11.2–33.1) in patients taking E/C/F/TDF with darunavir, and similar concentra-tions among those taking E/C/F/TDF without darunavir [24]. While we were unable to quantify cobicistat levels below 50 ng/mL, it appears there was enough cobicistat present to adequately boost elvitegravir, so low cobicistat concentrations are unlikely to explain the low darunavir concentrations seen in our patients taking E/C/F/TDF plus darunavir. In any case, cobicistat  Ctrough,ss is prob-ably less important than area under the plasma concen-tration-time curve (AUC) in terms of its pharmacological boosting properties [35].Limitations of our study include the small sample size, non-randomized design, and the lack of full validation for the elvitegravir and cobicistat assays, although the darunavir assay was fully validated. Also our study was conducted with the older E/C/F/TDF formulation. Fur-ther investigation of this approach may be warranted, including the new tenofovir alafenamide (TAF) formula-tion. PK data are available for 15 treatment-experienced HIV patients participating in a switch study to E/C/F/TAF plus darunavir; their mean darunavir  Ctrough,ss was 1250 ng/mL and elvitegravir  Ctrough,ss was 464 ng/mL (no range or IQR available) [36]. There is no reason to expect a substantial difference in the interactions between elvitegravir, cobicistat, and darunavir when coadmin-istered with TAF vs. TDF. The main difference to be expected would be lower plasma tenofovir levels in the presence of darunavir with E/C/F/TAF than with E/C/F/TDF, due to P-glycoprotein induction by darunavir and the resultant decrease in intestinal absorption of TAF (a P-glycoprotein substrate) [10, 37]. Indeed, in the PK substudy of the E/C/F/TAF plus darunavir switch study, plasma concentrations of TAF were at the lower end of the efficacious range, and plasma tenofovir exposure was “markedly lower” than that observed with E/C/F/TDF Page 8 of 9Harris et al. AIDS Res Ther  (2017) 14:59 in previous studies [36]. Nevertheless, simplification to E/C/F/TAF plus darunavir was shown to be safe and efficacious, maintaining virologic suppression (viral load <  50 copies/mL) in 94% of 89 participants in the study [36]. Since we did not measure plasma tenofovir levels in the present study, we are unable to say whether the same effect occurred in our cohort.ConclusionsIn conclusion, E/C/F/TDF plus darunavir was safe and effective as a treatment simplification option for 10 selected treatment-experienced HIV-infected patients. Although darunavir  Ctrough,ss with E/C/F/TDF plus daru-navir were lower than with ritonavir-boosted darunavir in this small study, virologic suppression was maintained in all subjects for 48 weeks.AbbreviationsapoB: apolipoprotein B; AUC: area under the plasma concentration-time curve; C0h: plasma concentration at 0 h; Cmax: maximum plasma concentra-tion; Ctrough,ss: trough plasma concentration at steady state; EC50: half maximal effective concentration; E/C/F/TDF: elvitegravir/cobicistat/emtricitabine/tenofovir disproxil fumarate; eGFR: estimated glomerular filtration rate; FTC: emtricitabine; hsCRP: high-sensitivity C-reactive protein; IC50: 50% inhibitory concentration; IC95: 95% inhibitory concentration; IQR: interquartile range; NNRTI: nonnucleoside reverse transcriptase inhibitor; NRTI: nucleoside reverse transcriptase inhibitor; PK: pharmacokinetics; TAF: tenofovir alafenamide; TDF: tenofovir disoproxil fumarate; tmax: time to maximum plasma concentration; UACR: urine albumin to creatinine ratio.Authors’ contributionsMH contributed to the design of the study and to data analysis and interpreta-tion, and wrote the manuscript. BG enrolled and followed participants and collected data. BW performed the drug level assays and interpreted the data. PRH performed the drug level and genotypic assays and interpreted the data. JSGM contributed to the design of the study, data analysis and interpreta-tion. MWH designed the study, recruited and followed study participants, and contributed to data analysis and interpretation. All authors read and approved the final manuscriptAuthor details1 British Columbia Centre for Excellence in HIV/AIDS, Vancouver, BC, Canada. 2 AIDS Research Program, St. Paul’s Hospital, Vancouver, BC, Canada. 3 Depart-ment of Family Practice, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada. 4 Division of AIDS, Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada. AcknowledgementsThe authors would like to thank the study participants, and Jill Jackson for obtaining regulatory and ethical approvals.Competing interestsMH has received grants, paid to the institution, from the Canadian Institutes for Health Research (CIHR) and honoraria for consultancy and/or speaking engagements from Gilead Sciences Canada Inc., Merck Canada Inc., and ViiV Healthcare. BG and BW declare that they have no competing interests. PRH has received grants from Genome BC, Genome Canada, and CIHR, and limited unrestricted funding, paid to his institution, from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, and ViiV. JSGM has received support, paid to the institution, from CIHR, the Public Health Agency of Canada, the British Columbia Ministry of Health, US National Institutes of Health (NIDA R01DA036307 and CTN 248), Johnson & Johnson, and Merck. MWH has received grants, paid to the institution, from the US National Institutes of Health (NIDA Grant 1-RO1DA031043-01), and has received consultancy and speaker’s honoraria from Bristol-Myers Squibb, Merck, Gilead, Ortho-Janssen, and ViiV.Availability of data and materialsThe datasets used and analysed during the current study are available from the corresponding author on reasonable request.Consent for publicationNot applicable.Ethics approval and consent to participateThe study protocol and informed consent form were approved by the University of British Columbia/ Providence Health Care Research Ethics Board (H14-00490).FundingThis study was supported by a grant from Gilead Sciences Canada, Inc. (IN-CA-236-1313). The funder was not involved in the design of the study; in the collection, analysis, or interpretation of data; or in writing the manuscript. 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