Darunavir Resistance-associated Mutations Research Articles

Simultaneous quantification of Darunavir and Ritonavir in human plasma and pharmacokinetic study by LC MS/MS

The combination of Darunavir (DRV) and Ritonavir (RTV) at a dose of 800/100mg has exhibit durable efficacy in both untreated and treated HIV positive patients with no observed DRV resistance-associated mutations (RAMs) and the RTV improves the pharmacokinetic profile of DRV by enhancing its bioavailability. Hence a sensitive high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS/MS) method has been developed and validated for the simultaneous quantification of Darunavir (DRV) and Ritonavir (RTV) in human plasma. The chromatographic separation has been accomplished on Thermo Hypersil Gold (50×4.6mm, 3μ) analytical column using isocratic elution using 0.1% Formic Acid buffer solution/Acetonitrile (50:50, v/v) at a flow rate of 0.6 mL/min. The linearity of the method ranged 150.000 ng/mL to 15000.000 ng/mL & 10.000 ng/mL to 3000.00 ng/mL for DRV & RTV respectively, using 100 μL of plasma. The method was completely validated for its sensitivity, selectivity, linearity, accuracy and precision, recovery, matrix effect, stability, and dilution integrity. The absolute recovery for DRV ranged from 79.12 to 72.71 % while for RTV it ranged from 63.39% to 66.99 %. For DRV-D9 and RTV-D6 the recovery rates are 94.19 and 80.05% respectively. The method exhibit good intra-day and inter-day precision with low % CV of less than 5.0% at each quality control level for both the analytes. The developed method has been applied successfully for pharmacokinetic study in healthy humans by oral administration of Darunavir/Ritonavir tablets 400/50 mg (dose; 02x400/50 mg) in 77 healthy male volunteers under fed condition.

A Low Level of Darunavir Resistance-Associated Mutation Emergence in Patients With Virological Failure During Long-term Use of Darunavir in People With HIV. The ANRS CO3 Aquitaine Cohort.

BackgroundRitonavir-boosted darunavir (DRV/r) is a protease inhibitor (PI) indicated for the treatment of naïve and pretreated HIV-infected patients since 2007. Our study aims to describe DRV/r-treated patients experiencing virological failure (VF) documented with HIV resistance testing.MethodsData from patients belonging to the ANRS CO3 Aquitaine Cohort treated with a regimen including DRV/r between February 2007 and December 2015 were analyzed. Baseline characteristics of patients experiencing VF (defined by 2 consecutive plasma viral loads >50 copies/mL) were compared with those without VF. We then described factors associated with VF as emergence of IAS DRV resistance–associated mutations (RAMs).ResultsAmong the 1458 patients treated at least once with a DRV/r-based regimen, 270 (18.5%) patients experienced VF during follow-up, including 240 with at least 1 genotype resistance test (GRT). DRV RAMs were detected in 29 patients (12%). Among them, 25/29 patients had ≥2 DRV RAMs before DRV/r initiation, all of whom had experienced VF during previous PI treatments. For 18/29, DRV/r was maintained after VF, and controlled viremia was restored after modification of DRV-associated antiretroviral molecules or increased DRV dose. Finally, only 6/29 patients selected new DRV RAMs after DRV/r initiation. All of these experienced previous VFs while on other PIs.ConclusionsThese results highlight the efficacy and robustness of DRV/r, as the emergence of DRV RAMs appeared in <0.4% of patients receiving a DRV/r-based regimen in our large cohort.

Clinical outcomes of once-daily darunavir in treatment-experienced patients with darunavir resistance-associated mutations through 48 weeks of treatment.

Darunavir (DRV) is approved for once-daily use in patients with no DRV resistance-associated mutations (RAMs) and twice-daily use in those with DRV RAMs. Several studies suggest that once-daily DRV retains efficacy in the setting of 1-2 DRV RAMs whereas three or more DRV RAMs are needed for DRV resistance. There are few data to support the long-term use of once-daily DRV in patients with DRV RAMs. This observational study evaluated 48-week clinical outcomes of 22 treatment-experienced patients with ≥1 DRV RAMs switched to once-daily DRV between 2014 and 2017. The primary endpoint was HIV-1 RNA <50 copies/ml at week 48. Safety parameters were analyzed throughout the study. The median age of the sample was 53 years, 18 (82%) had baseline HIV-1 RNA <50copies/ml, and the median number of historical DRV RAMs was 2. At week 48, 20 (91%) had HIV-1 RNA < 50copies/ml, and 2 (9%) had HIV-1 RNA of 82 and 59,637copies/ml and reported non-adherence. No adverse drug reactions were observed through week 48. Once-daily DRV maintained virologic control in patients with ≥1 historical DRV RAMs and was safe and well-tolerated. Further data are needed to validate this as a viable treatment option in this population.

2482. Clinical Outcomes of Once-Daily Darunavir in Treatment-Experienced Patients with Darunavir Resistance Associated Mutations Through 48 Weeks of Treatment

BackgroundDarunavir (DRV) is a well-tolerated, potent protease inhibitor used once-daily in patients with no DRV resistance-associated mutations (RAMs) and twice-daily in those with DRV RAMs. Treatment guidelines encourage use of once-daily regimens to optimize patient adherence, convenience and tolerability. Several studies suggest that once-daily DRV retains efficacy in the setting of 1–2 DRV RAMs whereas 3 or more DRV RAMs (with multiple background PI RAMs) is needed for DRV resistance. Currently, there is little clinical data to support the long-term use of once-daily DRV in patients with DRV RAMs.MethodsThis is a retrospective study evaluating the 48-week clinical outcomes of 22 treatment-experienced patients with DRV RAMs switched to once-daily DRV between 2014 and 2017 at the Orlando Immunology Center. The primary endpoint was the proportion with virologic suppression (HIV-1 RNA< 50 copies/mL) at Week 48. Adherence, adverse events (AEs) and laboratory parameters were analyzed throughout the study.ResultsThe median age (range) of the sample was 53 (21–77) years, median baseline CD4+ count was 609 cells/mm3, 18 (82%) had baseline HIV-1 RNA <50 copies/mL, 15 (69%) had previously used 1 or more PIs and median number (range) of baseline DRV RAMs was 2 (1–5) (Table 1). At Week 48, 20 (91%) had HIV-1 RNA <50 copies/mL; 2 (9%) virologic non-responders had HIV-1 RNA of 82 and 59,637 copies/mL and reported noncompliance (Figure 1). There was no significant change in median CD4+ count from baseline to Week 48 (+22, 95% confidence interval (CI): [−116.5; 56.0]). Once-daily DRV was associated with a significant median increase in HDL cholesterol (+82, 95% CI: [37.0; 101.0]) and a significant median decrease in LDL cholesterol (-60, 95% CI: [-89.5; -31.0]). There were no significant changes in the proportion of patients on lipid lowering therapy at baseline and week 48 (p = 0.33). There were no self-reported AEs or Grade 3–4 lab abnormalities through Week 48.ConclusionOnce-daily DRV maintained virologic control in this cohort of treatment-experienced patients with 1 or more baseline DRV RAMs and was safe and well-tolerated. This suggests that once-daily DRV may be effective in this population however further data are needed to validate this as a viable treatment option. Disclosures All authors: No reported disclosures.

2509. Pooled Resistance Analyses of Darunavir (DRV) Once Daily (QD) Regimens and Formulations Across 10 Clinical Studies of Treatment-Naïve (TN) and Treatment-Experienced (TE) Patients with Human Immunodeficiency Virus (HIV)-1 Infection

BackgroundDRV has demonstrated high efficacy and barrier to resistance development across diverse populations, from TN to heavily TE patients. We evaluated resistance data from 10 clinical studies of different DRV 800 mg QD–based antiretroviral regimens and formulations.MethodsThe analysis included patients from 10 phase 2/3 studies (48–192 weeks in duration) of ritonavir- and cobicistat-boosted DRV 800 mg QD–based regimens in TN and virologically failing or suppressed TE patients with HIV-1 (table). Three were phase 3 studies of the DRV/cobicistat/emtricitabine/tenofovir alafenamide (D/C/F/TAF) 800/150/200/10 mg single-tablet regimen (STR). Post-baseline resistance was evaluated in patients experiencing protocol-defined virologic failure (PDVF); definitions and criteria for resistance testing varied slightly among studies. Resistance-associated mutations (RAMs) were based on respective International Antiviral Society–USA mutation lists over time.ResultsOf the 3,635 patients evaluated, 250 met PDVF criteria and 205 had post-baseline genotypes/phenotypes. Overall, 4 (0.1%) patients developed (or had identified [switch studies]) ≥1 DRV and/or primary protease inhibitor (PI) RAM (table), and only 1 (< 0.1%, ODIN) patient lost DRV phenotypic susceptibility; this TE patient had prior VF with lopinavir. Among those who used a nucleos(t)ide reverse transcriptase inhibitor (NRTI) backbone (mostly emtricitabine [FTC] + tenofovir [TFV]), 12 (0.4%) patients had ≥1 NRTI RAM, including 10 with M184I/V associated with FTC resistance. No TFV RAMs were observed. Among patients receiving D/C/F/TAF (n = 1,949), none had post-baseline DRV, primary PI, or TFV RAMs; only 2 (0.1%) patients developed an FTC RAM.ConclusionAcross a large, diverse population using DRV 800 mg QD–based regimens and formulations, resistance development remains rare; 0.1% of patients had ≥1 DRV and/or primary PI RAM post-baseline. Among 3 trials of the D/C/F/TAF STR, no patients developed a DRV or primary PI RAM. After > 10 years of investigating DRV 800 mg QD–based regimens in clinical trials, loss of phenotypic susceptibility to DRV has never been observed in TN or TE virologically suppressed patients and was only once observed in a TE patient with prior VF on multiple antiretrovirals, including a PI. Disclosures All authors: No reported disclosures.

Effectiveness of Once/Day Dolutegravir Plus Boosted Darunavir as a Switch Strategy in Heavily Treated Patients with Human Immunodeficiency Virus.

Dual therapy with once/day dolutegravir (DTG) plus boosted darunavir (DRV/b) may be a suitable and effective strategy with a high genetic barrier to resistance in patients infected with human immunodeficiency virus (HIV). Our aim was to evaluate the effectiveness of DTG plus DRV/b (DTG+DRV/b) as a switch strategy in HIV-infected patients, irrespective of their history of virologic failure (VF). Multicenter retrospective cohort study. Human immunodeficiency outpatient treatment clinics at three university hospitals in Spain. Fifty HIV-infected adults who had a stable antiretroviral treatment (ART) regimen and an undetectable viral load for at least 6months, and whose ART was switched to once/day DTG+DRV/b between January 2015 and January 2018 were included in the analysis. Historical genotype at the time of VF was available in 44 patients. Patients were followed until VF or treatment discontinuation for any reason. The primary outcome was the percentage of patients with a viral load of 50 copies/mL or lower at the last follow-up visit. Secondary outcomes included changes in CD4+ cell count, lipid profile, and renal function. Of the 50 patients included, median time of viral suppression was 52 months (interquartile range [IQR] 18-103 mo) and nadir CD4+ 89 cells/mm3 (IQR 37-241 cells/mm3 ). Patients had a history of a median of 8 ART combinations (IQR 4-11 combinations) and 3 VFs (IQR 2-8 VFs). The historical genotypes from 44 patients showed 41 patients (93.2%) with nucleoside/nucleotide reverse transcriptase inhibitor (NRTI) resistance-associated mutations (RAMs), 32 (72.7%) with nonnucleoside reverse transcriptase inhibitor (NNRTI) RAMs, and 12 (27.3%) with primary protease inhibitor (PI) RAMs; 7 (15.9%) had darunavir RAMs, and no patients had baseline integrase strand transfer inhibitor RAMs. Thirty-seven patients (84.1%) had resistance to at least two antiretroviral classes. After a median of 25 months (IQR 17-28 mo) of follow-up, 49 patients (98%) maintained a viral load of 50 copies/mL or lower, and 1 patient (2%) had VF. No new RAMs emerged at VF. At week 4, serum creatinine concentration increased a median of 0.12 mg/dl (0.03-0.23 mg/dl). At last visit, total cholesterol and low-density lipoprotein cholesterol levels increased by a median of 9 mg/dl (IQR -18 to 40 mg/dl) and 16 mg/dl (IQR -9 to 40 mg/dl), respectively, whereas CD4+ cell count remained stable (median +13 cell/mm3 ). In this cohort of heavily treated HIV-infected patients with virologic suppression, switching to the combination of DTG+DRV/b was a convenient regimen that was highly effective and had good tolerability.

Prevalence of Darunavir Resistance in the United States from 2010 to 2017.

The emergence and transmission of antiretroviral drug resistance have been and remain a concern among people living with human immunodeficiency virus (HIV)-1 infection. The protease inhibitor (PI) darunavir has been approved for use in the United States for more than 10 years and has demonstrated a high barrier to resistance. Previous analyses identified significant reductions in the prevalence of samples with darunavir resistance-associated mutations (RAMs) and with phenotypic resistance to darunavir and other PIs between 2006 and 2012. This analysis extends those findings by evaluating darunavir and PI resistance among clinical samples submitted for routine drug resistance testing (combined genotyping and phenotyping) in the United States from 2010 to 2017. Frequencies of 11 darunavir and 23 primary PI RAMs, and phenotypic susceptibility, were assessed yearly among all samples and in a subset of samples with distinct phenotypic resistance to one or more PIs. Among all samples (N = 60,760), the proportion with 0 darunavir RAMs was 91.7% in 2010 and 95.8% in 2017. The proportions of all samples with phenotypic susceptibility to darunavir, atazanavir, and lopinavir were, respectively, 97.4%, 94.2%, and 94.7% in 2010 and 98.6%, 97.7%, and 97.5% in 2017. Among the 4,799 samples with phenotypic resistance to one or more PIs, the proportions with phenotypic susceptibility to darunavir, atazanavir, and lopinavir were, respectively, 73.3%, 41.5%, and 46.0% in 2010 and 70.7%, 53.7%, and 48.8% in 2017. The prevalence of darunavir RAMs among commercially tested HIV-1 samples remained low and generally stable from 2010 to 2017, and high proportions showed phenotypic darunavir susceptibility.

Evaluating the role of atazanavir/cobicistat and darunavir/cobicistat fixed-dose combinations for the treatment of HIV-1 infection.

Atazanavir/cobicistat (ATV/c) and darunavir/cobicistat (DRV/c) are newly approved once daily fixed-dose protease inhibitor combinations for the treatment of HIV-1 infection. Studies in healthy volunteers have established bioequivalence between cobicistat and ritonavir as pharmacoenhancers of both atazanavir (ATV) and darunavir (DRV). In addition, two randomized clinical trials (one Phase II and one Phase III noninferiority trial with a 144-week followup period) demonstrated that cobicistat had sustainable and comparable efficacy and safety to ritonavir as a pharmacoenhancer of ATV through 144 weeks of treatment in HIV-1-infected patients. Furthermore, one Phase III, open-label, single-arm, clinical trial reflected virologic and immunologic responses and safety outcomes consistent with prior published data for DRV/ritonavir 800/100 mg once daily, supporting the use of DRV/c 800/150 mg once daily for future treatment of treatment-naïve and -experienced HIV-1-infected patients with no DRV resistance-associated mutations. Low rates of virologic failure secondary to resistance to antiretroviral regimens were present in these clinical studies. Most notable adverse events in the ATV studies were hyperbilirubinemia and in the DRV study rash. Small increases in serum creatinine and minimally reduced estimated glomerular filtration rate Cockcroft–Gault calculation (eGFRCG) were observed in ATV/c and DRV/c clinical studies consistent with other studies evaluating elvitegravir/cobicistat/tenofovir/emtricitabine for the treatment of HIV-1 infection. These renal parameter changes occurred acutely in the first few weeks and plateaued off for the remaining study periods and are not necessarily clinically relevant. Cobicistat has numerous advantages compared to ritonavir such as fewer drug–drug interactions, being devoid of anti-HIV-1 activity, as well as it has better solubility affording coformulation with other antiretrovirals as simplified fixed-dose combinations. Overall, the recent approval of ATV/c and DRV/c offers HIV patients opportunities for improved adherence to lifelong treatment. Future studies are warranted to determine the efficacy and safety of ATV/c and DRV/c in treatment-experienced patients.

Unique Flap Conformation in an HIV-1 Protease with High-Level Darunavir Resistance.

Darunavir (DRV) is one of the most powerful protease inhibitors (PIs) for treating human immunodeficiency virus type-1 (HIV-1) infection and presents a high genetic barrier to the generation of resistant viruses. However, DRV-resistant HIV-1 infrequently emerges from viruses exhibiting resistance to other protease inhibitors. To address this resistance, researchers have gathered genetic information on DRV resistance. In contrast, few structural insights into the mechanism underlying DRV resistance are available. To elucidate this mechanism, we determined the crystal structure of the ligand-free state of a protease with high-level DRV resistance and six DRV resistance-associated mutations (including I47V and I50V), which we generated by in vitro selection. This crystal structure showed a unique curling conformation at the flap regions that was not found in the previously reported ligand-free protease structures. Molecular dynamics simulations indicated that the curled flap conformation altered the flap dynamics. These results suggest that the preference for a unique flap conformation influences DRV binding. These results provide new structural insights into elucidating the molecular mechanism of DRV resistance and aid to develop PIs effective against DRV-resistant viruses.

Trends in darunavir resistance-associated mutations and phenotypic resistance in commercially tested United States clinical samples between 2006 and 2012.

HIV-1 samples submitted by clinicians from the United States for routine drug susceptibility testing (PhenoSense GT) were evaluated for genotypic and phenotypic resistance to darunavir and other protease inhibitors (PIs). Among these samples (Monogram Biosciences database January 2006-June 2012; N=78,843), isolates harboring zero IAS-USA darunavir resistance-associated mutations (RAMs) increased from 77.7% in 2006 to 92.8% through the first half of 2012 (H1 2012; upward trend, p=0.0008); a downward trend seen for samples with three or more darunavir RAMs (7.5% in 2006 and 2.6% in H1 2012; p=0.002). Among samples with any PI resistance (N=15,932), samples harboring zero darunavir RAMs gradually increased (39.9% in 2006 vs. 55.0% in H1 2012; upward trend, p=0.005), but three or more darunavir RAMs did not change over time (21.7% in 2006 and 19.2% in H1 2012; p=0.27). During this period, the frequency of the 11 individual darunavir RAMs (IAS-USA 2011 list) decreased among all samples. The frequency of each darunavir RAM in PI-resistant samples decreased or remained relatively stable. The prevalence of samples with phenotypic resistance to darunavir (partial-to-full) decreased over time in all samples (8.2% in 2006 vs. 2.3% in H1 2012), as did resistance to other PIs (p<0.006 for all PIs). Phenotypic resistance to darunavir and other PIs also decreased in PI-resistant samples (darunavir: 23.9% in 2006 vs. 17.1% in H1 2012; p<0.013 for all PIs). Since approval of darunavir in 2006, there was a significant decrease in prevalence of samples with genotypic and phenotypic resistance to darunavir in commercially tested HIV-1 isolates. Furthermore, the prevalence of phenotypic resistance to darunavir was lower than all other PIs.

Darunavir/cobicistat fixed-dose single tablet (Rezolsta™): a guide to its use in HIV-1 infection in adults in the EU

Oral darunavir/cobicistat 800 mg/150 mg fixed-dose single tablets [Rezolsta™ (EU); Prezcobix™ (USA, Canada)] are indicated as a component of antiretroviral treatment of HIV-1 infection in treatment-naive and treatment-experienced adults without known darunavir resistance-associated mutations. Treatment with cobicistat- or ritonavir-boosted regimens of the protease inhibitor darunavir have been shown to reduce viral load in these patient populations. Relative to the use of low-dose ritonavir to boost darunavir, the use of cobicistat reduces the potential for drug interactions involving enzymatic induction, provides bioequivalent exposure to darunavir, and has similar virological efficacy and tolerability profiles, and allows co-formulation of the agents in a single tablet.

Efficacy of Once Daily Darunavir/Ritonavir in PI-Naïve, NNRTI-Experienced Patients in the ODIN Trial.

Background. An exploratory subanalysis of the ODIN trial was performed to evaluate the efficacy of darunavir/ritonavir (DRV/r) 800/100 mg OD versus 600/100 mg BID in patients who were NNRTI-experienced but PI-naïve. Methods. ODIN was a phase III, 48-week study comparing DRV/r OD versus BID in 590 treatment-experienced patients with no DRV resistance-associated mutations (RAMs) at screening. Patients received DRV/r 800/100 mg OD or DRV/r 600/100 mg BID plus ≥2 NRTIs. Of the 590 patients randomized, 272 (46%) were NNRTI-experienced but PI-naïve. Results. Overall, 272 patients received DRV/r OD (n = 135) or BID (n = 137) plus ≥2 optimised NRTIs. The mean age was 39 years; 35% were female; 27% were Black, 24% Caucasian, 26% Oriental/Asian, and 23% other races; 17% were recruited in South Africa; and 48% had non-B HIV-1 subtypes. Mean baseline plasma HIV-1 RNA load was 4.10 log10⁡ copies/mL; median CD4 cell count was 258 cells/μL. At week 48, 111/135 (82%) of DRV/r OD and 109/137 (80%) of DRV/r BID patients achieved an HIV-1 RNA load <50 copies/mL. No patient developed primary PI RAMs. Conclusion. DRV/r 800/100 mg OD in combination with ≥2 optimised NRTIs led to virological suppression <50 copies/mL in 82% of NNRTI-experienced, PI-naïve patients by week 48.

Protease mutations emerging on darunavir in protease inhibitor-naïve and experienced patients in the UK.

IntroductionDarunavir (DRV) is a preferred agent in treatment guidelines for ART-naïve and experienced patients [1]. It is considered to have a high genetic barrier to resistance and 11 resistance-associated mutations (RAMs) are recognized by IAS-USA [2]. These have largely been identified by analyses examining the correlation between baseline genotype and virological response [3]. However, there is little information on RAMs that are directly selected by DRV, outside of short-term clinical trials. We aimed to identify emerging mutations by comparing the genotypes of individuals before and after DRV exposure.Materials and MethodsThe UK HIV Drug Resistance Database was used to identify patients aged over 16 who had received at least 30 days of a DRV-containing regimen. Patients were included if they had a “baseline” resistance test, prior to DRV exposure, and a “repeat” test, either on DRV or within 30 days of stopping this agent. To avoid attributing the effects of other PIs on emerging RAMs to DRV, patients were excluded if they had received another PI for greater than 90 days between the baseline genotype and the start of DRV. The baseline and repeat tests were compared to determine the nature of mutations stratified by PI history.ResultsA total of 5623 patients had DRV, of whom 306 met the inclusion criteria. A total of 228 (74.5%) were male, median age at the start of DRV was 42 years (IQR 37–47), and half had subtype B infection. The mode of transmission was homosexual contact for 50%, heterosexual for 38%, and 3% were injection drug users. The median CD4 count at the start of DRV was 257 cells/mm3 (IQR 94–453). A total of 149 patients (49%) had a history of PI use prior to DRV, and 157 (51%) were PI-naïve. The most common previous PIs were lopinavir, atazanavir, and saquinavir. Baseline DRV RAMs were present in 1 (0.6%) PI-naïve and 20 (13.4%) PI-experienced patients. Mutations emerged under DRV pressure in a further 3 (1.9%) PI-naïve patients, and in 7 (4.7%) PI-experienced patients, 5 of whom had other DRV RAMs present at baseline (Table 1). The median time from the start of DRV to the repeat test was 196 days for PI-naïve patients and 296 days for PI-experienced.ConclusionsPI-experienced patients had a greater prevalence of DRV RAMs at baseline than PI-naïve individuals, probably due to the fact that some DRV RAMs can be selected by other PIs. This group also accumulated more RAMs during DRV exposure, possibly because previous PIs had caused minority variants which then emerged on DRV therapy. Overall, only 10 patients accumulated 16 RAMs, which supports the perception that DRV has a high genetic barrier to resistance. Repeat genotyping in the case of virological failure on DRV may still be warranted to detect emerging resistance and guide management decisions.

Pharmacokinetics and pharmacodynamics of boosted once-daily darunavir.

The ability to dose antiretroviral agents once daily simplifies the often complex therapeutic regimens required for the successful treatment of HIV infection. Thus, once-daily dosing can lead to improved patient adherence to medication and, consequently, sustained virological suppression and reduction in the risk of emergence of drug resistance. Several trials have evaluated once-daily darunavir/ritonavir in combination with other antiretrovirals (ARTEMIS and ODIN trials) or as monotherapy (MONET, MONOI and PROTEA trials) in HIV-1-infected adults. Data from ARTEMIS and ODIN demonstrate non-inferiority of once-daily darunavir/ritonavir against a comparator and, together with pharmacokinetic data, have established the suitability of once-daily darunavir/ritonavir for treatment-naive and treatment-experienced patients with no darunavir resistance-associated mutations. The findings of ARTEMIS and ODIN have led to recent updates to treatment guidelines, whereby once-daily darunavir/ritonavir, given with other antiretrovirals, is now a preferred treatment option for antiretroviral-naive adult patients and a simplified treatment option for antiretroviral-experienced adults who have no darunavir resistance-associated mutations. Once-daily dosing with darunavir/ritonavir is an option for treatment-naive and for treatment-experienced paediatric patients with no darunavir resistance-associated mutations based on the findings of the DIONE trial and ARIEL substudy. This article reviews the pharmacokinetics, efficacy, safety and tolerability of once-daily boosted darunavir. The feasibility of darunavir/ritonavir monotherapy as a treatment approach for some patients is also discussed. Finally, data on a fixed-dose combination of 800/150 mg of darunavir/cobicistat once daily are presented, showing comparable darunavir bioavailability to that obtained with 800/100 mg of darunavir/ritonavir once daily.

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

BackgroundCobicistat 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.MethodsThis 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.ResultsThe 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/mm3, 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/mm3, 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.ConclusionDarunavir/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.

Darunavir: A Review of Its Use in the Management of HIV-1 Infection

The latest HIV-1 protease inhibitor (PI) darunavir (Prezista™) has a high genetic barrier to resistance development and is active against wild-type HIV and HIV strains no longer susceptible to some older PIs. Ritonavir-boosted darunavir, as a component of antiretroviral therapy (ART), is indicated for the treatment of HIV-1 infection in adult and paediatric patients (aged ≥3years), with or without treatment experience (details vary depending on region of approval). Several open-label or partially-blinded trials have evaluated the efficacy of ritonavir-boosted darunavir ART regimens for up to 192weeks in these settings. In treatment-naïve adults, once-daily boosted darunavir was no less effective in establishing virological suppression than once- or twice-daily boosted lopinavir, yet was more effective at maintaining suppression long term. Moreover, treatment-experienced adults with no darunavir resistance-associated mutations (RAMs) had no less effective viral load suppression with once-daily than with twice-daily boosted darunavir. In treatment-experienced adults, including some with multiple major PI RAMs, twice-daily boosted darunavir was more effective than twice-daily boosted lopinavir or boosted control PIs in reducing viral load, and provided virological benefit as part of a salvage regimen in those with few remaining treatment options. Boosted darunavir also reduced viral load when administered once-daily in treatment-naïve adolescents or twice-daily in treatment-experienced children and adolescents. Boosted darunavir is generally well tolerated, with gastrointestinal disturbances and lipid abnormalities among the most common tolerability issues. It has a lipid profile more favourable than that of boosted lopinavir in terms of total cholesterol and triglyceride changes and, when administered once daily, its lipid effects are generally similar to those of boosted atazanavir. Thus, boosted darunavir is a useful option for the ART regimens of adult and paediatric patients with HIV-1 infection.

Virologic and immunologic effectiveness of darunavir-based salvage therapy in HIV-1-infected adults in a Brazilian clinical practice setting: results of a multicenter and retrospective cohort study

BackgroundDarunavir has been proven efficacious for antiretroviral-experienced HIV-1-infected patients in randomized trials. However, effectiveness of darunavir-based salvage therapy is understudied in routine care in Brazil. MethodsRetrospective cohort study of HIV-1-infected patients from three public referral centers in Belo Horizonte, who received a darunavir-based therapy between 2008 and 2010, after virologic failure. Primary endpoint was the proportion of patients with viral load<50copies/mL at week 48. Change in CD4 cell count was also evaluated. Outcome measures were analyzed on an intent-to-treat basis applied to observational studies. Sensitivity analysis was conducted to evaluate the impact of missing data at week 48. Predictors of virologic failure were examined using rare-event, finite sample, bias-corrected logistic regression. ResultsAmong 108 patients, the median age was 44.2 years, and 72.2% were male. They had long-standing HIV-1 infection (median 11.6 years) and advanced disease (76.9% had an AIDS-defining event). All patients had previously received protease inhibitors and nucleoside reverse transcriptase inhibitors, 75% nonnucleoside reverse transcriptase inhibitors, and 4.6% enfuvirtide. The median length of protease inhibitor use was 8.9 years, and 90.8% of patients had prior exposure to unboosted protease inhibitor. Genotypic resistance profile showed a median of three primary protease inhibitor mutations and 10.2% had three or more darunavir resistance-associated mutations. Virologic success at week 48 was achieved by 78.7% (95% CI=69.7–86%) of patients and mean CD4 cell count increase from baseline was 131.5cells/μL (95% CI=103.4–159.6). In multiple logistic regression analysis, higher baseline viral load (RR=1.04 per 10,000copies/mL increase; 95% CI=1.01–1.09) and higher number of darunavir resistance-associated mutations (RR=1.23 per each; 95% CI=0.95–1.48) were independently associated with virologic failure. ConclusionVirologic suppression is a realistic endpoint for most treatment-experienced patients who begin a darunavir-based therapy outside the controlled conditions of a randomized trial, at routine care settings.

Virological Analysis of Once-Daily and Twice-Daily Darunavir/Ritonavir in the Odin Trial of Treatment-Experienced Patients

The aim of this analysis was to characterize viral resistance in the Phase III, randomized ODIN trial, which demonstrated non-inferiority of once-daily darunavir/ritonavir (DRV/r) 800/100 mg to DRV/r 600/100 mg twice daily, each combined with an optimized background regimen in treatment-experienced patients with no DRV resistance-associated mutations (RAMs) at screening. Virological failure (VF) was defined as never achieving or losing confirmed virological suppression after week 12, with patients being classed as 'never suppressed' (never achieved HIV-1 RNA<50 copies/ml) or 'rebounders' (achieved two consecutive HIV-1 RNA<50 copies/ml but then ≥ 50 copies/ml). Phenotypes and genotypes of plasma HIV-1 viruses, using population-based sequencing and Antivirogram(®), were determined at screening/baseline and on samples from VFs with HIV-1 RNA ≥ 50 copies/ml. Mean baseline HIV-1 RNA was 4.16 log10 copies/ml and 53.9% of patients were protease inhibitor (PI)-experienced at enrolment. VF rate was similar in both arms. A similar proportion of virologically failing patients in both arms developed PI RAMs (11.7% versus 9.5%, respectively) or nucleoside reverse transcriptase inhibitor RAMs (6.7% versus 7.1%). One patient with VF (once-daily arm) developed four primary PI mutations, three of which were also DRV RAMs. This patient was also the only VF to lose susceptibility to DRV. Loss of susceptibility to other PIs (once daily 3.4%; twice daily 0%) and nucleoside reverse transcriptase inhibitors (once daily 13.6%; twice daily 9.8%) in VF patients was infrequent and comparable between treatment arms. These analyses showed once-daily DRV/r 800/100 mg was associated with similar rates of VF and emergence of resistance as DRV/r 600/100 mg twice daily in treatment-experienced patients with no DRV RAMs.

Subgroup analysis of virological response rates with once‐ and twice‐daily darunavir/ritonavir in treatment‐experienced patients without darunavir resistance‐associated mutations in the ODIN trial

ODIN (once-daily darunavir in treatment-experienced patients) was a 48-week, phase III, randomized, open-label trial comparing once-daily (qd) darunavir/ritonavir (DRV/r) 800/100 mg with twice-daily (bid) DRV/r 600/100 mg, both with an optimized background regimen [OBR; at least two nucleoside reverse transcriptase inhibitors (NRTIs)], in treatment-experienced, HIV-1-infected adults with no DRV resistance-associated mutations (RAMs) at screening. Week 48 analyses of virological response by subgroups are reported. A total of 590 patients were randomized to receive qd (n=294) or bid (n=296) DRV/r. Virological response (HIV-1 RNA <50 copies/mL) was assessed according to: screening HIV-1 RNA (≥ or <50000 copies/mL), CD4 cell count, prior protease inhibitor (PI) use, number of active NRTIs in the OBR, presence of mutations (primary PI mutations, PI RAMs or M184V/I), gender, age, race, HIV-1 clade and adherence. Baseline characteristics were well balanced between arms and across subgroups. Response rates were comparable between qd and bid DRV/r treatments for all subgroups examined. Response rates were 78.4 and 76.8% in the qd and bid treatment arms, respectively, in patients with baseline HIV-1 RNA ≤ 50000 copies/mL and 52.8% in both arms in those with > 50000 copies/mL. Response rates for the qd and bid treatment arms by baseline CD4 cell count were also similar (69.6 vs. 65.2% for <200 cells/μL; 72.2 vs. 74.8% for 200- <350 cells/μL; 77.0 vs. 74.3% for ≥ 350 cells/μL). DRV/r administered either qd or bid provided effective treatment for antiretroviral treatment-experienced patients with no DRV RAMs, with comparable response rates across all subgroups studied. Low patient numbers in specific subgroups may limit interpretation of these specific subgroup results.

Darunavir Resistance in HIV Infecting Protease Inhibitor-Experienced Mexican Patients

Background: Darunavir (DRV) is a useful antiretroviral treatment in the salvage therapy of multiclass-resistant HIV-infected patients. This study’s aim was to determine the frequency and risk factors for DRV resistance-associated mutations (DRV-RAM) among DRV-naive Mexican patients with virologic failure after extensive antiretroviral treatment and exposure to at least one protease inhibitor (PI). Methods: HIV-infected patients with a history of at least 2 failed regimes were included and their clinical histories and genotype resistance tests were analyzed. Major PI resistance-associated mutations (PI-RAM), DRV-RAM and resistance to DRV were defined according to the IAS-USA criteria. Previous exposure to PI was compared between patients with DRV-resistant HIV and DRV-susceptible HIV-infected controls. Results: The median number of major PI-RAM was 2 (IQR = 0 - 3). In 54.7% (95% CI = 50.0% - 59.4%) of 631 subjects, no DRV-RAM were found on viral genotyping and 6.7% (95% CI = 4.8% - 8.6%) had 3 or more DRV-RAM. The two most frequently found DRV-RAM were in codons I84V (in 22.7% of cases) and L33F (in 20% of cases) in the viral protease gene. The number of major PI-RAM (as a surrogate marker of duration and number of PI used) and previous exposure to (fos) amprenavir or tipranavir were independently associated with DRV-resistant HIV infection. Conclusions: In this Mexican population, despite a high prior PI exposure, HIV-DRV resistance rate is relatively low and successful viral control with DRV-containing combined salvage therapy is expected in most patients.