Cobicistat-boosted darunavir in HIV-1-infected adults: week 48 results of a Phase IIIb, open-label single-arm trial.

BACKGROUND: Cobicistat is an alternative pharmacoenhancer to ritonavir. In healthy volunteers, darunavir exposure was comparable when darunavir 800 mg once daily was co-administered with cobicistat 150 mg once daily (as single agents or a fixed-dose combination) vs. with ritonavir 100 mg once daily. METHODS: This 48-week, Phase IIIb, single-arm, US multicenter study (NCT01440569) evaluated safety, efficacy and pharmacokinetics of darunavir/cobicistat 800/150 mg once daily (as single agents) plus two investigator-selected nucleoside/tide reverse transcriptase inhibitors (N[t]RTIs) in HIV-1-infected adults. Patients had no darunavir resistance-associated mutations (RAMs), plasma viral load (VL) ≥1000 HIV-1 RNA copies/ml, eGFR ≥80 ml/min and genotypic sensitivity to the two N[t]RTIs. The primary endpoint was any treatment-emergent grade 3 or 4 adverse events (AEs) through Week 24. RESULTS: The majority of the 313 intent-to-treat patients were treatment-naïve (295/313; 94%), male (89%), White (60%) and received a tenofovir-based regimen (99%). Median baseline VL and CD4(+) count overall were 4.8 log10 HIV-1 RNA copies/ml and 361 cells/mm(3), respectively. Overall, 86% of patients (268/313) completed the study. The majority of discontinuations were for AEs (15/313; 5%). The incidence of treatment-emergent grade 3 or 4 AEs regardless of causality was 6% through Week 24 and 8% through Week 48. Most common AEs through Week 48 were diarrhea (27%) and nausea (23%), which were grade 1 or 2 in severity. Week 48 virologic response rates (% with VL <50 HIV-1 RNA copies/ml; Snapshot analysis) were 81% overall and 83% in treatment-naïve patients; median increases in CD4(+) count at 48 weeks were 167 and 169 cells/mm(3), respectively. Of 15/313 patients who met the criteria for resistance analysis, one developed a darunavir RAM as a mixture with wild-type (I84I/V), without phenotypic resistance to darunavir. The mean population pharmacokinetic-derived darunavir areas under the plasma concentration-time curve were 102,000 overall and 100,620 ng•h/ml in treatment-naïve patients. No clinically relevant relationships were seen between darunavir exposure and virologic response, AEs or laboratory parameters. CONCLUSION: Darunavir/cobicistat 800/150 mg once daily was generally well tolerated through Week 48, with no new safety concerns. Pharmacokinetics, virologic and immunologic responses for darunavir/cobicistat were similar to previous data for darunavir/ritonavir 800/100 mg once daily.

The DIANA Study: Continued Access to Darunavir/Ritonavir (DRV/r) and Long-Term Safety Follow-Up in HIV-1-Infected Pediatric Patients Aged 3 to < 18 Years.

INTRODUCTION: Darunavir is a human immunodeficiency virus type 1 (HIV-1) protease inhibitor boosted with ritonavir (DRV/r) or cobicistat. OBJECTIVE: This study provided continued access to DRV/r and assessed long-term safety in patients aged 3 to < 18 years. METHODS: Patients who had completed treatment in the DELPHI (TMC114-C212), DIONE (TMC114-TiDP29-C230), or ARIEL (TMC114-TiDP29-C228) studies were eligible to participate if they derived benefit from using DRV/r in countries where it was not available to them. DRV/r dosing was continued based on original study protocols. Only safety data were collected. Reportable adverse events (AEs) included AEs considered at least possibly related to treatment with DRV/r, AEs leading to discontinuation or treatment interruption, and serious AEs (SAEs). RESULTS: Forty-six patients rolled over to this study and received at least one dose of DRV/r. Median duration of DRV/r intake was 4.2 years. Overall, 15/46 patients experienced one or more reportable AEs, 10/46 patients experienced one or more grade 3 or 4 AEs, and 12/46 patients experienced one or more SAEs. The most common grade 3 or 4 and SAEs were pneumonia (3/46) and asthma (2/46). Only one AE (grade 1 lipoatrophy) was considered probably related to DRV/r (DIONE, n = 1). Overall, 3/46 patients experienced an HIV-related AE (grade 3 pneumonia SAE; grade 2 tuberculosis SAE, and grade 2 lipoatrophy AE), none of which were considered related to DRV/r or led to study discontinuation. Two AEs leading to discontinuation were pregnancies. CONCLUSION: These long-term safety results continue to support DRV/r as a valuable therapeutic option for the treatment of HIV-1 infection in pediatric patients aged ≥ 3 years. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01138605/EudraCT number: 2009-017013-29; first submitted 8 April 2010.

Etravirine in treatment-experienced HIV-1-infected children 1 year to less than 6 years of age.

OBJECTIVE: To describe the pharmacokinetics, safety, and efficacy of etravirine (ETR) in HIV-infected children 1 to less than 6 years of age. DESIGN: Phase I/II, open-label, multicenter, dose-finding study. METHODS: Antiretroviral therapy (ART)-experienced children in two age cohorts (I: 2 to <6 years; II: 1 to less than 2 years) received weight-based ETR, swallowed whole or dispersed in liquid, with optimized ART including a ritonavir-boosted protease inhibitor. Intensive pharmacokinetics occurred 7-18 days after starting ETR. Participants with ETR AUC12h less than 2350 ng h/ml had a dose increase and repeat pharmacokinetics. RESULTS: Twenty-six children enrolled and 21 (15 in cohort I and 6 in cohort II) had evaluable intensive pharmacokinetics sampling at the final weight-based dose. On the final dose, the geometric mean ETR AUC12h was 3823 ng h/ml for cohort I and 3328 ng h/ml for cohort II. Seven children (33.3%) on the final dose, all taking ETR dispersed, had an AUC12  h less than 2350 ng h/ml and underwent a dose increase. ETR AUC12  h was 3.8-fold higher when ETR was swallowed whole vs. dispersed, P less than 0.0001. On the final dose, 75 and 33.3% in cohorts I and II, respectively, had HIV-1 RNA 400 copies/ml or less or at least 2 log reductions from baseline at week 48. Three children (11.5%) experienced a grade at least 3 adverse event related to ETR but only 1 discontinued. CONCLUSION: ETR was well tolerated. Predefined pharmacokinetics targets were met but overall exposures were low vs. historical data in adults, particularly in young children taking dispersed tablets. A high rate of viral efficacy was observed among those aged 2 to more than 6 years but not in those less than 2 years.

Week 96 results of a phase 3 trial of darunavir/cobicistat/emtricitabine/tenofovir alafenamide in treatment-naive HIV-1 patients.

BACKGROUND: Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg was investigated through 96 weeks in AMBER (NCT02431247). METHODS: Treatment-naive, HIV-1-positive adults [screening plasma viral load ≥1000 copies/ml; CD4 cell count >50 cells/µl) were randomized (1 : 1) to D/C/F/TAF (N = 362) or D/C plus emtricitabine/tenofovir-disoproxil-fumarate (F/TDF) (N = 363) over at least 48 weeks. After week 48, patients could continue on or switch to D/C/F/TAF in an open-label extension phase until week 96. RESULTS: At week 96, D/C/F/TAF exposure was 626 patient-years (D/C/F/TAF arm) and 109 patient-years (control arm post switch), week 96 virologic suppression (viral load <50 copies/ml; FDA-Snapshot, from baseline) was 85.1% (308/362) (D/C/F/TAF) and 83.7% (304/363) (control). Week 96 virologic failure (viral load ≥50 copies/ml; FDA-Snapshot) was 5.5% (20/362) and 4.4% (16/363), respectively. No darunavir, primary protease inhibitor or tenofovir resistance-associated mutations (RAMs) were observed post baseline. In one patient in each arm, an M184I and/or V RAM was detected. Few adverse event-related discontinuations (3% D/C/F/TAF; <1% control post switch) and no deaths occurred on D/C/F/TAF. Improved renal and bone parameters were maintained in the D/C/F/TAF arm and observed in the control arm post switch. Increases in total-cholesterol/high-density-lipoprotein--cholesterol rtio at week 96 were +0.25 versus baseline (D/C/F/TAF) and +0.24 versus switch (control). CONCLUSION: At week 96, D/C/F/TAF resulted in high virologic response and low virologic failure rates, with no resistance development to darunavir or TAF/TDF. Bone, renal and lipid safety were consistent with known D/C/F/TAF component profiles. Control arm safety post switch was consistent with the D/C/F/TAF arm. AMBER week 96 results confirm the efficacy, high barrier to resistance and bone/renal safety benefits of D/C/F/TAF for treatment-naive patients.

Week 48 Resistance Analyses of the Once-Daily, Single-Tablet Regimen Darunavir/Cobicistat/Emtricitabine/Tenofovir Alafenamide (D/C/F/TAF) in Adults Living with HIV-1 from the Phase III Randomized AMBER and EMERALD Trials.

Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg is being investigated in two Phase III trials, AMBER (NCT02431247; treatment-naive adults) and EMERALD (NCT02269917; treatment-experienced, virologically suppressed adults). Week 48 AMBER and EMERALD resistance analyses are presented. Postbaseline samples for genotyping/phenotyping were analyzed from protocol-defined virologic failures (PDVFs) with viral load (VL) ≥400 copies/mL at failure/later time points. Post hoc analyses were deep sequencing in AMBER, and HIV-1 proviral DNA from baseline samples (VL <50 copies/mL) in EMERALD. Through week 48 across both studies, no darunavir, primary PI, or tenofovir resistance-associated mutations (RAMs) were observed in HIV-1 viruses of 1,125 participants receiving D/C/F/TAF or 629 receiving boosted darunavir plus emtricitabine/tenofovir-disoproxil-fumarate. In AMBER, the nucleos(t)ide analog reverse transcriptase inhibitor (N(t)RTI) RAM M184I/V was identified in HIV-1 of one participant during D/C/F/TAF treatment. M184V was detected pretreatment as a minority variant (9%). In EMERALD, in participants with prior VF and genoarchive data (N = 140; 98 D/C/F/TAF and 42 control), 4% had viruses with darunavir RAMs, 38% with emtricitabine RAMs, mainly at position 184 (41% not fully susceptible to emtricitabine), 4% with tenofovir RAMs, and 21% ≥ 3 thymidine analog-associated mutations (24% not fully susceptible to tenofovir) detected at screening. All achieved VL <50 copies/mL at week 48 or prior discontinuation. D/C/F/TAF has a high genetic barrier to resistance; no darunavir, primary PI, or tenofovir RAMs were observed through 48 weeks in AMBER and EMERALD. Only one postbaseline M184I/V RAM was observed in HIV-1 of an AMBER participant. In EMERALD, baseline archived RAMs to darunavir, emtricitabine, and tenofovir in participants with prior VF did not preclude virologic response.

Bioequivalence of the Once-Daily Single-Tablet Regimen of Darunavir, Cobicistat, Emtricitabine, and Tenofovir Alafenamide Compared to Combined Intake of the Separate Agents and the Effect of Food on Bioavailability.

The effect of food on the bioavailability of the components of the once-daily, single-tablet human immunodeficiency virus (HIV) type 1 regimen containing darunavir (DRV 800 mg), cobicistat (COBI 150 mg), emtricitabine (FTC 200 mg), and tenofovir alafenamide (TAF 10 mg) (D/C/F/TAF) (NCT02475135) and the bioequivalence of D/C/F/TAF versus combined intake of the separate agents (NCT02578550) were evaluated. These were 2 phase 1, open-label, randomized, 2-period crossover studies (7-day washout between treatments) in HIV-negative healthy volunteers. Twenty-four participants each received a single dose of D/C/F/TAF in fasted conditions (test) or after a standardized high-fat breakfast (reference). Ninety-six participants each received a single dose of D/C/F/TAF (test) or combined intake of a single DRV 800-mg tablet, a COBI 150-mg tablet, and an FTC/TAF 200/10-mg tablet (reference), both after a standardized regular-calorie, regular-fat breakfast. Pharmacokinetic profiles for all D/C/F/TAF components, safety, and tolerability were assessed. Following D/C/F/TAF in fasted conditions, DRV peak concentration, area under the concentration-time curve from time of administration until the last time point with a measurable concentration (AUC)last , and extrapolated to infinity (AUCinf ) were lower by 45%, 34%, and 30%, respectively, compared with fed conditions, with no clinically relevant differences in COBI, FTC, or TAF exposures between fed and fasted conditions. In the bioequivalence study 90% confidence intervals of the geometric mean ratios of all main pharmacokinetic parameters were within the 80.00% to 125.00% bioequivalence limits for DRV, COBI, FTC, and TAF. No grade 3/4 adverse events (AEs), serious AEs, deaths, or discontinuations due to AEs occurred. D/C/F/TAF is bioequivalent to combined administration of the separate agents. Consistent with other (co)formulations of DRV, DRV exposure was lower in fasted than in fed conditions as evaluated when taken with food, so D/C/F/TAF should be taken with food.

Week 96 efficacy and safety results of the phase 3, randomized EMERALD trial to evaluate switching from boosted-protease inhibitors plus emtricitabine/tenofovir disoproxil fumarate regimens to the once daily, single-tablet regimen of darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) in treatment-experienced, virologically-suppressed adults living with HIV-1.

Darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg was investigated through 96 weeks in EMERALD (NCT02269917). Virologically-suppressed, HIV-1-positive treatment-experienced adults (previous non-darunavir virologic failure [VF] allowed) were randomized (2:1) to D/C/F/TAF or boosted protease inhibitor (PI) plus emtricitabine/tenofovir-disoproxil-fumarate (F/TDF) over 48 weeks. At week 52 participants in the boosted PI arm were offered switch to D/C/F/TAF (late-switch, 44 weeks D/C/F/TAF exposure). All participants were followed on D/C/F/TAF until week 96. Efficacy endpoints were percentage cumulative protocol-defined virologic rebound (PDVR; confirmed viral load [VL] ≥50 copies/mL) and VL < 50 copies/mL (virologic suppression) and ≥50 copies/mL (VF) (FDA-snapshot analysis). Of 1141 randomized patients, 1080 continued in the extension phase. Few patients had PDVR (D/C/F/TAF: 3.1%, 24/763 cumulative through week 96; late-switch: 2.3%, 8/352 week 52-96). Week 96 virologic suppression was 90.7% (692/763) (D/C/F/TAF) and 93.8% (330/352) (late-switch). VF was 1.2% and 1.7%, respectively. No darunavir, primary PI, tenofovir or emtricitabine resistance-associated mutations were observed post-baseline. No patients discontinued for efficacy-related reasons. Few discontinued due to adverse events (2% D/C/F/TAF arm). Improved renal and bone parameters were maintained in the D/C/F/TAF arm and observed in the late-switch arm, with small increases in total cholesterol/high-density-lipoprotein-cholesterol ratio. A study limitation was the lack of a control arm in the week 96 analysis. Through 96 weeks, D/C/F/TAF resulted in low PDVR rates, high virologic suppression rates, very few VFs, and no resistance development. Late-switch results were consistent with D/C/F/TAF week 48 results. EMERALD week 96 results confirm the efficacy, high genetic barrier to resistance and safety benefits of D/C/F/TAF.

Evaluation of Cardiovascular Disease Risk in HIV-1-Infected Patients Treated with Darunavir.

INTRODUCTION: We evaluated cardiovascular disease (CVD) risk associated with darunavir treatment and examined the demographic/clinical characteristics of darunavir users based on data from Janssen-sponsored clinical trials, post-marketing pharmacovigilance databases, and administrative claims databases. METHODS: First, selected CVD events [myocardial infarction, stroke, sudden death, invasive cardiovascular procedures (coronary artery angioplasty or bypass, or carotid endarterectomy)] were analyzed in 19 Janssen-sponsored phase 2-4 studies (incidence rates estimated from pooled data; 95% confidence intervals derived from Poisson distribution). Second, analyses were conducted to identify spontaneously reported CVD events in post-marketing pharmacovigilance databases and evaluate disproportional reporting of CVD events for darunavir (using Empirical Bayesian Geometric Mean scores). Third, baseline demographic/clinical characteristics of human immunodeficiency virus-1 (HIV-1)-infected patients in general and new users of darunavir and atazanavir were explored using three US administrative claims databases. RESULTS: Among 19 Janssen-sponsored clinical trials (treatment durations ≤ 6 years), the CVD event rate (95% CI) per 1000 person-years (pooled population; n = 5713) was 6.15 (2.91-11.89), and was lower for patients who used once-daily darunavir/ritonavir 800/100 mg [0.71 (0.16-3.05); n = 1326] versus twice-daily darunavir/ritonavir 600/100 mg [9.21 (4.94-16.04); n = 3058]. Trend analysis of post-marketing pharmacovigilance data showed that cumulative CVD event reporting rates for darunavir users (any dose) generally declined over time. Spontaneously reported CVD events were not disproportionately reported with darunavir versus other protease inhibitors. Compared with the general HIV-1-infected population and atazanavir users, higher proportions of darunavir users were male, older, and had comorbidities associated with CVD risk based on results from US administrative claims databases. CONCLUSIONS: This comprehensive review of Janssen-sponsored clinical trial, post-marketing, and epidemiological data does not suggest that CVD should be considered an important risk for users of darunavir.

Correction to: Evaluation of Cardiovascular Disease Risk in HIV­1-Infected Patients Treated with Darunavir.

In the original publication of the article, Table 2 has been published incorrectly.

Efficacy and safety of switching from boosted protease inhibitors plus emtricitabine and tenofovir disoproxil fumarate regimens to single-tablet darunavir, cobicistat, emtricitabine, and tenofovir alafenamide at 48 weeks in adults with virologically suppressed HIV-1 (EMERALD): a phase 3, randomised, non-inferiority trial.

BACKGROUND: Simplified regimens with reduced pill burden and fewer side-effects are desirable for people living with HIV. We investigated the efficacy and safety of switching to a single-tablet regimen of darunavir, cobicistat, emtricitabine, and tenofovir alafenamide versus continuing a regimen of boosted protease inhibitor, emtricitabine, and tenofovir disoproxil fumarate. METHODS: EMERALD was a phase-3, randomised, active-controlled, open-label, international, multicentre trial, done at 106 sites across nine countries in North America and Europe. HIV-1-infected adults were eligible to participate if they were treatment-experienced and virologically suppressed (viral load <50 copies per mL for ≥2 months; one viral load of 50-200 copies per mL was allowed within 12 months before screening), and patients with a history of virological failure on non-darunavir regimens were allowed. Randomisation was by computer-generated interactive web-response system and stratified by boosted protease inhibitor use at baseline. Patients were randomly assigned (2:1) to switch to the open-label study regimen or continue the control regimen. The study regimen consisted of a fixed-dose tablet containing darunavir 800 mg, cobicistat 150 mg, emtricitabine 200 mg, and tenofovir alafenamide 10 mg, which was taken once per day for 48 weeks. The primary outcome was the proportion of participants with virological rebound (confirmed viral load ≥50 copies per mL or premature discontinuations, with last viral load ≥50 copies per mL) cumulative through week 48; we tested non-inferiority (4% margin) of the study regimen versus the control regimen in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT02269917. FINDINGS: The study began on April 1, 2015, and the cutoff date for the week 48 primary analysis was Feb 24, 2017. Of 1141 patients (763 in the study group and 378 in the control group), 664 (58%) had previously received five or more antiretrovirals, including screening antiretrovirals, and 169 (15%) had previous virological failure on a non-darunavir regimen. The study regimen was non-inferior to the control for virological rebound cumulative through week 48 (19 [2·5%] of 763 patients in the study group vs eight (2·1%) of 378 patients in the control group; difference 0·4%, 95% CI -1·5 to 2·2; p<0·0001). No resistance to any study drug was observed. Numbers of discontinuations related to adverse events (11 [1%] of 763 patients in the study group vs four [1%] of 378 patients in the control group) and grade 3-4 adverse events (52 [7%] patients vs 31 [8%] patients) were similar between the two groups. There was a small non-clinically relevant but statistically significant (0·2 [SD 1·1] vs 0·1 [1·1], p=0.010) difference between the two groups in change from baseline in total cholesterol to HDL-cholesterol ratio. Only one serious adverse event (pancreatitis in the study group) was deemed as possibly related to the study regimen. INTERPRETATION: Our findings show the safety and efficacy of single-tablet darunavir, cobicistat, emtricitabine, and tenofovir alafenamide as a potential switch option for the treatment of HIV-1 infection in adults with viral suppression. FUNDING: Janssen.

A week-48 randomized phase-3 trial of darunavir/cobicistat/emtricitabine/tenofovir alafenamide in treatment-naive HIV-1 patients.

OBJECTIVES: To investigate efficacy and safety of a single-tablet regimen of darunavir/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg vs. darunavir/cobicistat plus emtricitabine/tenofovir disoproxyl fumarate (TDF) (control) in antiretroviral-treatment-naive, HIV-1-infected adults. DESIGN: Phase-3, randomized, active-controlled, double-blind, international, multicenter, noninferiority study (NCT02431247). METHODS: Seven hundred and twenty-five participants were randomized (1 : 1) to D/C/F/TAF (362) or control (363). The primary objective was to demonstrate noninferiority of D/C/F/TAF vs. control for percentage viral load less than 50 copies/ml (FDA-snapshot analysis) at 48 weeks (10% margin). RESULTS: At week 48, D/C/F/TAF was noninferior to control (91.4 vs. 88.4% achieved viral load <50 copies/ml, respectively; difference 2.7%; 95% CI -1.6 to 7.1; P < 0.0001), with 4.4 vs. 3.3% of patients, respectively, having viral load greater or equal to 50 copies/ml. No treatment-emergent mutations associated with darunavir or TAF/TDF resistance were observed in either group. One patient (D/C/F/TAF) was identified with M184I/V conferring resistance to emtricitabine. Incidences of grades 3 and 4 adverse events (5 vs. 6%), serious adverse events (5 vs. 6%) and adverse event-related discontinuations (2 vs. 4%) were low and similar between groups. Mean decrease in urine protein/creatinine ratio was greater with D/C/F/TAF than control (-22.42 vs. -10.34 mg/g, P = 0.033). Mean percentage change in bone mineral density with D/C/F/TAF vs. control was 0.21 vs. -2.73%, P < 0.0001 (hip), -0.68 vs. -2.38%, P = 0.004 (lumbar spine), and -0.26 vs. -2.97%, P < 0.0001 (femoral neck). Median change from baseline in total cholesterol/HDL-cholesterol ratio was 0.20 vs. 0.08, P = 0.036. CONCLUSION: D/C/F/TAF achieved a high virologic suppression rate (91.4%) and was noninferior to darunavir/cobicistat with F/TDF. D/C/F/TAF also demonstrated the bone and renal safety advantages of TAF in combination with darunavir/cobicistat.

Etravirine combined with antiretrovirals other than darunavir/ritonavir for HIV-1-infected, treatment-experienced adults: Week 48 results of a phase IV trial.

OBJECTIVE: VIOLIN (TMC125IFD3002; NCT01422330) evaluated the safety, tolerability, and pharmacokinetics of etravirine with antiretrovirals other than darunavir/ritonavir in HIV-1-infected patients. METHODS: In a 48-week, phase IV, single-arm, multicenter study, patients on prior antiretroviral therapy (⩾8 weeks) who needed to change regimen for virologic failure (viral load ⩾ 500 copies/mL) or simplification/adverse events (viral load < 50 copies/mL) received etravirine 200 mg bid with ⩾1 other active antiretroviral, excluding darunavir/ritonavir or only nucleoside/tide reverse transcriptase inhibitors. RESULTS: Of 211 treated patients, 73% (n = 155) had baseline viral load ⩾ 50 copies/mL and 27% (n = 56) had baseline viral load < 50 copies/mL. Protease inhibitors were the most common background antiretrovirals (83%). Diarrhea was the most frequent adverse event (17%). Serious adverse events (no rash) occurred in 5% of patients; none were etravirine related. Overall, median etravirine AUC12h was 5390 ng h/mL and C0h was 353 ng/mL (N = 199). Week 48 virologic response rates (viral load < 50 copies/mL; Food and Drug Administration Snapshot algorithm) were 48% (74/155) (baseline viral load ⩾ 50 copies/mL) and 75% (42/56) (baseline viral load < 50 copies/mL). Virologic failure rates were 42% and 13%, respectively. The most frequently emerging etravirine resistance-associated mutations in virologic failures were Y181C, E138A, and M230L. Virologic response rates for patients with baseline viral load ⩾ 50 copies/mL were 38% (30/79) (non-adherent) versus 64% (44/69) (adherent subset). CONCLUSION: Etravirine 200 mg bid in combination with antiretrovirals other than darunavir/ritonavir was well tolerated in the studied treatment-experienced HIV-1-infected population. The overall etravirine safety and tolerability profile and pharmacokinetics (specifically in those patients who were adherent) were similar to those previously observed for etravirine in HIV-1-infected adults. The relatively high level of non-adherence, also observed in the pharmacokinetic assessments, negatively impacted virologic response, especially in patients with ⩾50 copies/mL at baseline.

Assessment of etravirine resistance in HIV-1-infected paediatric patients using population and deep sequencing: final results of the PIANO study.

BACKGROUND: We assessed etravirine resistance in treatment-experienced, HIV-1-infected children (n=41)/adolescents (n=60) who received twice-daily etravirine 5.2 mg/kg and a background regimen (boosted protease inhibitor plus nucleoside/nucleotide reverse transcriptase inhibitors, optional enfuvirtide/raltegravir) in a Phase II, open-label, multicentre trial (PIANO). METHODS: In addition to phenotypes, viral genotypes were assessed by population and deep sequencing (PS and DS) in virological failures (VFs; baseline and end point) and responders (baseline). Minority resistance-associated mutations (RAMs) were defined as those with frequencies above 1% and not detected with PS. RESULTS: By week 48, 41/101 (40.6%) patients experienced VF; 17/41 (41.5%) VFs and 22/54 (40.8%) responders had ≥1 baseline etravirine RAM by PS, mainly A98G, K101E, V106I and G190A. Baseline minority etravirine RAMs (n) were detected in 8/40 VFs (V90I [2], A98G [1], L100I [1], V106I [1], E138G [1] and Y181C [2]) and 5/38 responders (V90I [3], A98G [1], V106I [1] and E138G [1]). The most frequent emerging non-nucleoside reverse transcriptase inhibitor RAMs detected by PS (≥3 VFs; n) were the etravirine RAMs Y181C (8), V90I (3), L100I (3) and E138A (3). In 15 of 29 (51.7%) VFs with baseline DS/PS and end point PS data, ≥1 emerging etravirine RAM was detected by PS, which was not detected at baseline by DS in most cases (12/15 [80.0%]). In 10/26 (38.5%) VFs with baseline/end point DS data, ≥1 additional emerging minority etravirine RAM was detected. CONCLUSIONS: Patterns of etravirine resistance in adults, adolescents and children experiencing VF are similar. The presence of minority etravirine RAMs at baseline was not consistently associated with treatment failure. ClinicalTrials.gov: NCT00665847.

Pharmacokinetics and Pharmacokinetic/Pharmacodynamic Relationships of Etravirine in HIV-1-Infected, Treatment-Experienced Children and Adolescents in PIANO.

PIANO (NCT00665847) investigated etravirine pharmacokinetics, efficacy, and safety in children and adolescents. Treatment-experienced, HIV-1-infected patients (≥6 to <18 years) received etravirine 5.2 mg/kg twice daily (maximum 200 mg twice daily) plus background antiretrovirals. A population pharmacokinetic model was developed, and etravirine C0h and AUC0-12h were estimated. Relationships among intrinsic/extrinsic factors and etravirine pharmacokinetics and pharmacokinetics with pharmacodynamics were assessed. The best model describing etravirine pharmacokinetics consisted of a single compartment with sequential zero- and first-order absorption following a lag time. Interindividual variability terms were included on clearance (CL/F) and the first-order input rate constant (KA). The final model estimates (coefficient of variation, %) for CL/F and KA were 46.3 (11) L/h and 1.07 (34) h-1 , respectively. Overall, median (range) estimated etravirine C0h and AUC0-12h were 287 (2-2276) ng/mL and 4560 (62-28,865) ng · h/mL, respectively. Exposure was slightly lower in adolescents vs children. Sex and adherence did not affect etravirine pharmacokinetics. Factors significantly affecting etravirine exposure were body weight (higher with lower weight), race (lower in Asians than in white or black patients), and the use of certain HIV protease inhibitors. Virologic response (<50 copies/mL at week 48) was lower in the lowest etravirine AUC0-12h quartile vs the upper 3 quartiles (41% vs 67% to 76%). Rash occurred more frequently in the highest quartile than in the lower 3 quartiles (52% versus 8% to 20%). Etravirine 5.2 mg/kg twice daily in treatment-experienced, HIV-1-infected children and adolescents provides comparable exposure to that in adults receiving etravirine 200 mg twice daily and is the recommended dose for children and adolescents.

Darunavir/cobicistat once daily for the treatment of HIV.

A current focus in HIV management is improving adherence by minimizing pill burden with convenient formulations, including fixed-dose combinations (FDCs). Darunavir, a HIV protease inhibitor, co-administered with low-dose ritonavir (800/100 mg once daily), is recommended in guidelines in combination with other antiretrovirals for HIV patients with no darunavir resistance-associated mutations. Cobicistat is an alternative agent to ritonavir for boosting plasma drug levels of darunavir among other antiretrovirals. Cobicistat is a more specific cytochrome P450 3A inhibitor than ritonavir without enzyme-inducing properties. This review describes the differing effects of cobicistat and ritonavir on metabolic enzymes, which explains their differing drug-drug interactions, and summarizes some of the studied drug-drug interactions for cobicistat. It also outlines the clinical development and data for a once-daily darunavir/cobicistat FDC. This FDC thus allows for a once-daily treatment regimen (including background antiretrovirals) with reduced pill burden.

Safety and efficacy of darunavir/ritonavir in treatment-experienced pediatric patients: week 48 results of the ARIEL trial.

BACKGROUND: ARIEL (Darunavir in treatment-experienced pediatric population) was a phase II, open-label study assessing safety and antiviral activity of darunavir/ritonavir twice daily with an optimized background regimen (OBR) in treatment-experienced, HIV-1-infected pediatric patients (3 to <6 years, weighing 10 to <20 kg). METHODS: The study consisted of an initial 4-week screening period, 48 weeks of treatment and a 4-week follow-up period. Patients initially received darunavir/ritonavir 20/3 mg/kg twice-daily for 2 weeks. Following review of pharmacokinetic, safety and antiviral data, the doses of darunavir/ritonavir were adjusted to 25/3 mg/kg twice-daily for patients <15 kg, and 375/50 mg twice-daily for patients 15 to <20 kg. RESULTS: Of the 34 patients screened, 21 were treated (median treatment duration 48.6 weeks). Darunavir plus an OBR was well tolerated over 48 weeks, with no new safety concerns, and a comparable safety profile to that seen in older children and adults. All treatment-emergent lipid-related and glucose-related laboratory abnormalities were grade 1 or 2. At week 48, 17 of 21 patients (81.0%) had a confirmed virologic response (intent-to-treat, time-to-loss of virologic response). Improvements in height and weight were seen during the study. CONCLUSIONS: No new safety concerns were observed over a 48 week period. These results led to lowering the age to 3 years at which darunavir/ritonavir is indicated for use in treatment-experienced pediatric patients. This study also established doses of darunavir to use in treatment-experienced, HIV-1-infected patients aged 3 to <6 years. A high virologic response was observed with this dose. No development of resistance was observed in patients who experienced virologic failure.

Week 48 results of a Phase IV trial of etravirine with antiretrovirals other than darunavir/ritonavir in HIV-1-infected treatment-experienced adults.

INTRODUCTION: In DUET, etravirine (ETR) 200 mg bid had durable efficacy and a favourable safety profile versus placebo, both arms with an optimised background regimen (BR) including darunavir/ritonavir (DRV/r). TMC125IFD3002 (VIOLIN; NCT01422330) investigated ETR plus ARVs other than DRV/r. MATERIALS AND METHODS: This was a 48 week, Phase IV, open-label, single-arm, multicentre study. HIV-1-infected treatment-experienced adult patients on=8 weeks ARV therapy prior to screening, switching either for virologic failure (VF) (viral load [VL] =500 c/mL) or regimen simplification/AEs (RS/AE) (VL<50 c/mL), received active ETR 200 mg bid with an investigator-selected BR of =1 active ARVs, but excluding DRV/r or NRTIs only. The primary objective was to evaluate safety, tolerability and pharmacokinetics (PK). RESULTS: Of 211 treated patients, 55% were female, 61% black/African American. 155 patients (73%) had baseline (BL) VL=50 c/mL versus 56 (27%) with BL VL<50 c/mL. Between these two latter subgroups, median BL VL was 4.42 versus 1.28 log10 c/mL and CD4+ count 238 versus 410.5 cells/mm(3). Overall, 96% previously used <2 NNRTIs and 99% used=5 PIs; median number of BL NNRTI RAMs was 2, PI RAMs 5 and NRTI RAMs 1. Overall, most common BR ARVs were PIs (83%), mostly lopinavir/r (62%) and mostly used alone (20%) or with 1 or 2 NRTIs (61%). Raltegravir was used in 9% of patients. Most frequent AEs (any cause/grade) were diarrhoea (17%) and URTI (8%). Incidence of grade 3-4 AEs was 13%, serious AEs 5% (no rashes; none ETR related), AEs leading to discontinuation 4%, AEs possibly related to ETR 23% and AEs of interest: rash (any type) 4%, hepatic 6% and neuropsychiatric 3%. At week 48, VF and RS/AE virologic responses (% patients with VL<50 c/mL; FDA Snapshot) were: 48% (74/155) and 75% (42/56), respectively. VF rates were 42% and 13%; 10% and 13% had no VL data in the week 48 window. The percentage of patients adherent to treatment (assessed based on PK sampling plus ETR pill count) was 47% (69/148) and 57% (30/53), in VF and RS/AE, respectively. Median CD4+ count (NC=F) increases were 0.0 and 24.0 cells/mm(3). In 29/49 of VFs with genotypic data at failure, ETR RAMs emerging in =5 patients were Y181C, E138A and M230L. The geometric mean ETR AUC12h was 4877 ng.h/mL and C0h 293 ng/mL (N=199). CONCLUSIONS: RESULTS of this study were consistent with those for ETR in other similar populations and support the use of ETR 200 mg bid with a non-DRV/r based BR.

Efficacy and safety of darunavir/ritonavir at 48 weeks in treatment-naïve, HIV-1-infected adolescents: results from a phase 2 open-label trial (DIONE).

BACKGROUND: Twice-daily darunavir/ritonavir is indicated in treatment-experienced children (≥3 years). This study assessed once-daily administration in treatment-naïve adolescents. METHODS: Phase 2, 48-week, open-label, single-arm study evaluating pharmacokinetics, safety and efficacy of once-daily darunavir/ritonavir 800/100 mg in treatment-naïve, HIV-1-infected adolescents (≥12 to <18 years, ≥40 kg) with zidovudine/lamivudine or abacavir/lamivudine. RESULTS: Twelve patients (67% female; median 14.4 years) were enrolled. After 24 and 48 weeks, respectively, 11 of 12 (92%) and 10 of 12 (83%) patients achieved viral load <50 copies/mL (intent-to-treat time-to-loss of virologic response); all had ≥1 log10 drop in viral load versus baseline. Median CD4 cell count increased by 175 and 221 cells/mm (intent-to-treat-noncompleter = failure) after 24 and 48 weeks, respectively. Eighty-three percent of patients were adherent to darunavir/ritonavir. One patient was never suppressed and 1 patient rebounded. No patients developed darunavir resistance-associated mutations or lost phenotypic susceptibility to any commercially available protease inhibitor or any background nucleoside reverse transcriptase inhibitor. Eleven patients (92%) reported ≥1 adverse event (AE), considered in 2 patients to be at least possibly related to darunavir (gastrointestinal-related events and dizziness). Four patients had ≥1 serious AE. Three patients reported ≥1 grade 3/4 AE; no serious or grade 3/4 AEs were considered darunavir related. No patients discontinued because of AEs. CONCLUSIONS: Over 48 weeks, once-daily darunavir/ritonavir 800/100 mg plus NRTIs was effective and well-tolerated for treatment of HIV-1-infected, antiretroviral-naïve adolescents (≥12 to <18 years). These findings support use of once-daily darunavir/ritonavir 800/100 mg in this population.

Pharmacokinetics of darunavir in fixed-dose combination with cobicistat compared with coadministration of darunavir and ritonavir as single agents in healthy volunteers.

This study compared the bioavailability of two candidate fixed-dose combinations (FDCs: G003 and G004) of darunavir/cobicistat 800/150 mg with that of darunavir 800 mg and ritonavir 100 mg coadministered as single agents. Short-term safety and tolerability of the FDC formulations were also assessed. This open-label trial included 36 healthy volunteers and assessed steady-state pharmacokinetics of darunavir over 3 randomized, 10-day treatment sequences, under fed conditions. Blood samples for determination of plasma concentrations of darunavir and cobicistat or ritonavir were taken over 24 hours on day 10 and analyzed by liquid-chromatography tandem mass-spectroscopy. Darunavir AUC24h following administration of the FDCs (G003: 74,780 ng ∙ h/mL and G004: 76,490 ng ∙ h/mL) was comparable to that following darunavir/ritonavir (78,410 ng ∙ h/mL), as was Cmax (6,666 and 6,917 ng/mL versus 6,973 ng/mL, respectively). Modestly lower C0h (1,504 and 1,478 ng/mL versus 2,015 ng/mL) and Cmin (1,167 and 1,224 ng/mL versus 1,540 ng/mL) values were seen with the FDCs. Short-term tolerability of the FDCs was comparable to that of darunavir/ritonavir when administered as single agents. The most common adverse events reported were headache, gastrointestinal upset, or rash. Cobicistat is an effective pharmacoenhancer of darunavir when administered as an FDC. Short-term administration of darunavir/ritonavir or darunavir/cobicistat was generally well tolerated.

Bioequivalence of a darunavir/cobicistat fixed-dose combination tablet versus single agents and food effect in healthy volunteers.

BACKGROUND: Darunavir requires pharmacokinetic enhancement to increase its bioavailability. Cobicistat is potentially an alternative pharmacokinetic booster to ritonavir. Bioequivalence of a darunavir/cobicistat fixed-dose combination (FDC) versus darunavir and cobicistat co-administered as single agents and the effect of a high-fat meal on the pharmacokinetics of the FDC were evaluated. METHODS: In this Phase I, open-label, randomized, three-panel, crossover study (NCT01619527), healthy volunteers received a single dose of darunavir (800 mg) with cobicistat (150 mg) as either an FDC or as single agents co-administered under fasted (panel 1, n=74) or fed (breakfast, panel 2, n=40) conditions, or as the FDC under fasted versus fed (high-fat breakfast) conditions (panel 3, n=19), with a ≥7 day washout period between treatments. Pharmacokinetic profiles, safety and tolerability were assessed. RESULTS: 90% confidence intervals of the least square mean ratios for darunavir and cobicistat maximum plasma concentration and area under the plasma concentration-time curve (AUC) were all within 80.00% and 125.00% in panels 1 and 2. Administration of the FDC with a high-fat breakfast significantly increased darunavir maximum plasma concentration 2.27-fold and AUC 1.63-1.70-fold, whereas cobicistat pharmacokinetics were unaffected. No volunteers discontinued due to adverse events (AEs). All AEs were grade 1 or 2. Overall, 27 (20%) and 26 (20%) volunteers had ≥1 AE at least possibly related to darunavir and cobicistat, respectively. CONCLUSIONS: Bioequivalence of the darunavir/cobicistat 800/150-mg FDC was demonstrated versus darunavir and cobicistat co-administered as single agents under fasted or fed conditions. Food increased darunavir exposure, therefore, darunavir/cobicistat should be administered with food.