Cobicistat-boosted darunavir in HIV-1-infected adults: week 48 results of a Phase IIIb, open-label single-arm trial
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AIDS Research and Therapy 2014
Dec 1 2014
Karen Tashima1*, Gordon Crofoot2, Frank L Tomaka3, Thomas N Kakuda3, Anne Brochot4, Tom Van de Casteele5, Magda Opsomer5, William Garner6, Nicolas Margot6, Joseph M Custodio6, Marshall W Fordyce6 and Javier Szwarcberg6
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.
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.
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/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.
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.
Cobicistat; Darunavir; Safety; Efficacy; Virology; Pharmacokinetics
Treatment guidelines for HIV-1 infection [1-4] include the recommendation of a ritonavir-boosted protease inhibitor (PI), such as darunavir/ritonavir, in combination with other antiretrovirals. In two randomized, controlled Phase III trials, darunavir/ritonavir 800/100 mg once daily demonstrated antiviral efficacy with long-term tolerability in treatment-naïve (ARTEMIS; TMC114-C211) [5-7] and treatment-experienced patients with no darunavir resistance-associated mutations (RAMs) (ODIN; TMC114-C229) .
Low-dose ritonavir (100 mg once daily or twice daily) is used as a pharmacokinetic enhancer . Ritonavir is a potent inhibitor of cytochrome P450 (CYP) 3A, and thereby increases the oral bioavailability of most HIV-1 PIs, including darunavir [9,10]. Low-dose ritonavir is associated with gastrointestinal disorders, such as diarrhea and nausea , hyperlipidaemia , and also clinically significant drug-drug interactions .
Cobicistat (GS-9350) is also a potent inhibitor of CYP3A and a pharmacoenhancer [13-16]. Cobicistat has no antiviral activity, does not induce CYP isozymes, and is more selective than ritonavir in terms of CYP3A inhibition [13,14].
Cobicistat can be coformulated into fixed-dose combinations , thereby reducing pill burden and medication errors [18-22]. Cobicistat has been evaluated as part of a single-tablet regimen with elvitegravir, emtricitabine and tenofovir in clinical studies of HIV-1-infected, antiretroviral treatment-naïve adults [15,16,23-28]. Cobicistat 150 mg once daily for 144 weeks was generally well tolerated. Small decreases in estimated glomerular filtration rate calculated using the Cockcroft-Gault method (eGFRCG) were observed with cobicistat in these studies, which are attributable to inhibition of the tubular secretion of creatinine leading to creatinine increases as early as Week 2 and stabilizing by Week 24 through Week 144, without affecting renal function (actual GFR, aGFR) as measured by iohexol renal clearance .
A fixed-dose formulation of darunavir/cobicistat has been developed. A Phase I study demonstrated comparable darunavir pharmacokinetic parameters following darunavir 800 mg once daily co-administered with cobicistat 150 mg once daily, either as single agents  or as two candidate fixed-dose combination formulations  to those of darunavir/ritonavir 800/100 mg once daily. Bioequivalence of darunavir administered as a fixed-dose combination with cobicistat vs. single agents, was established under fasted or fed conditions .
The aim of this Phase IIIb study was to evaluate the safety, tolerability, efficacy and pharmacokinetics of darunavir in combination with cobicistat (as single agents) with a background regimen of two, fully active, investigator-selected nucleoside/tide reverse transcriptase inhibitors (N[t]RTIs) in HIV-infected treatment-naïve and -experienced adults with no darunavir RAMs.
Patient disposition and baseline characteristics
The first patient in the study began treatment on October 24 2011, and the last patient in the study had their Week 48 visit on January 31 2013.
Of the 397 patients screened, 313 were enrolled and included in the intent-to-treat (ITT) population (Figure 1). One patient was not treated. Most of the 83 screening failures were due to screening eGFRCG <80 ml/min or screening viral load (VL) <1000 HIV-1 RNA copies/ml. Of the 313 ITT patients, 295 were treatment-naïve and 18 were treatment-experienced with no darunavir RAMs. Overall, 86% of the ITT patients (268/313) completed the study and 14% (45/313) discontinued, mainly for AEs (n =15) and loss to follow-up (n =13) (Figure 1).
Overall, most patients were male (89%) and were White (60%) or Black or of African Heritage (35%). The median age was 35 years (range 18 to 72 years) (Table 1). Median (range) baseline VL and CD4+ cell count were 4.8 (2.6 to 7.0) log10 HIV-1 RNA copies/ml and 361 (5 to 1473) cells/mm3, respectively. Overall, 2% of patients were co-infected with hepatitis B and 3% with hepatitis C virus. Baseline characteristics of the treatment-naïve patient population are shown in Table 1.
At baseline, one or more primary PI RAMs were found in 10 patients (3%; nine treatment-naïve, and one treatment-experienced), most commonly M46I/L (three treatment-naïve and one treatment-experienced) and Q58E (four treatment-naïve). No patients had darunavir RAMs. Secondary PI RAMs were found in 96% of patients (300/313; 283 and 17 patients), reflecting the strong polymorphic nature of these mutations. Non-nucleoside reverse transcriptase inhibitor (NNRTI) RAMs were found in 28% of patients (87/313; 74 and 13 patients), most commonly K103N/S (13%; 41/313; 33 and eight patients). N[t]RTI RAMs were found in 14% of patients (43/313; 36 and seven patients), most commonly V118I (6%; 18/313; 18 and zero patients), T69D/N (3%; 8/313; eight and zero patients) and M184V/I (3%; 8/313; two and six patients).
Concomitant N[t]RTI use
The majority of patients (99%; 311/313 overall and 294/295 treatment-naïve patients) received tenofovir-based antiretroviral therapy during the study. The most frequently used N[t]RTI combination was emtricitabine/tenofovir (Table 1).
During the course of the study, median adherence to darunavir and cobicistat in the overall population through Week 48 as measured by pill count was 100%, and 299/313 patients (96%) had a ≥90% adherence rate. Median adherence to darunavir and cobicistat in the treatment-naïve population through Week 48 as measured by pill count was also 100%, and 283/295 patients (96%) had a ≥90% adherence rate.
Safety and tolerability
The overall median duration of exposure to study drugs was 64.3 weeks (58.3 to 69.3 weeks); 268/313 (86%) patients received the study drugs for ≥48 weeks.
The most commonly reported treatment-emergent AEs regardless of causality during the study were diarrhea, nausea, upper respiratory tract infection and headache (Table 2). The most common study drug-related AEs through Week 48 were diarrhea (15%; 47/313 overall and 15%; 43/295 treatment-naïve patients), nausea (14%; 45/313 and 15%; 44/295, respectively), headache (4%; 13/313 and 4%; 12/295) and flatulence (4%; 13/313 and 4%; 13/295).
Most adverse events (AEs) were grade 1 or 2 in severity. The incidence of any grade 3 or 4 treatment-emergent AEs regardless of causality through Week 24 (primary endpoint) was low (Table 2). Overall, 16 patients experienced grade 3 (5%) and two patients experienced grade 4 (0.6%) AEs. Among the treatment-naïve patients, through Week 48, the most common grade 3 or 4 AEs regardless of causality (occurring in ≥2 patients) were hypersensitivity (grade 3: two patients; grade 4: one patient), maculo-papular rash (grade 3: two patients) and peripheral neuropathy (grade 3: two patients). Any study drug-related grade 3 AE occurred in five patients (2%). These grade 3 AEs were immune reconstitution syndrome (one patient), hypersensitivity (two patients), maculo-papular rash (one patient), and allergic dermatitis, maculo-papular rash and vesicular rash (all occurring in the same patient), and all led to study drug discontinuation. One patient had grade 4 thrombocytopenic purpura, which was considered serious and led to study drug discontinuation, but was not considered related to study drug. Another patient had grade 4 hypersensitivity, which was considered serious and led to study drug interruption, but was not considered related to study drug, but related to concomitant lisinopril.
Three serious AEs, all occurring in treatment-naïve patients, were felt to be related to study drug. One patient each reported immune reconstitution syndrome, rash and maculo-papular rash. There were no deaths. The most commonly reported AEs that led to discontinuation through Week 48 were rash and maculo-papular rash, nausea and hypersensitivity (Table 2). All these AEs were felt to be study drug-related and resolved upon discontinuation. One treatment-naïve patient discontinued because of renal tubular disorder, which was mild in severity, not serious and resolved following change in therapy to darunavir/ritonavir plus lamivudine and abacavir. Eight bone fractures were reported through Week 48, each with traumatic mechanisms and without features concerning for fragility fracture.
There was an increase in serum creatinine level from baseline occurring as early as Week 2 (median change = 0.10 mg/dl overall and in treatment-naïve patients), which remained stable throughout the Week 48 treatment period (median change =0.09 mg/dl and 0.08 mg/dl, respectively) and is consistent with cobicistat inhibition of creatinine secretion. There were no other clinically relevant changes from baseline in median values for other clinical laboratory parameters.
Overall, the virologic response rate (Food and Drug Administration [FDA] snapshot analysis) was 82% (258/313) (95% confidence interval [CI] 78%, 87%) at Week 24 and was sustained and durable through Week 48 (81%; 95% CI 76%, 85%; Table 3 and Figure 2). Virologic failure occurred in 11% of patients at Week 48, and 9% had no virologic data in the Week 48 window.
In treatment-naïve patients, the Week 48 virologic response rate was 83% (244/295; 95% CI 78%, 87%). Twenty four treatment-naïve patients (8%) were classed as virologic failures, and 27 treatment-naïve patients (9%) had no virologic data in the Week-48 window.
The Week 48 rates of virologic response were comparable in patients who had a baseline VL ≤100,000 HIV-1 RNA copies/ml or >100,000 HIV-1 RNA copies/ml, both overall (81% vs. 80%, respectively) (Table 3) and in treatment-naïve patients (84% vs. 81%).
Sensitivity analyses showed the Week 48 virologic response rate was 81% (253/313) overall and 83% (245/295) in treatment-naïve patients using the time-to-loss of virologic response (TLOVR) analysis, and it was 83% (260/313) and 85% (250/295), respectively, using the missing = failure (M = F) method.
There was an increase in CD4+ cell count from baseline at all timepoints following initiation of study drugs. At Weeks 24 and 48 in the overall population, the median (range) increases from baseline in CD4+ cell count (missing = excluded) were 131 (-471 to 596) cells/mm3 and 167 (-193 to 1086) cells/mm3, respectively (Figure 2). In treatment-naïve patients, the median (range) CD4+ cell count increased by 169 (-193 to 1086) cells/mm3 from baseline to Week 48.
Development of resistance
Of the 15 patients with samples eligible for resistance analysis (Table 4), three had suboptimal virologic response, eight had virologic rebound, and four who discontinued with VL ≥400 HIV-1 RNA copies/ml were analyzed at their last visit. Only one of these 15 patients who was treatment experienced (prior antiretrovirals included efavirenz, emtricitabine, tenofovir disoproxil fumarate, zidovudine, lamivudine, stavudine) developed a resistance mutation to darunavir (at position I84 as a mixture with wild-type, I84I/V) (Table 4); this was not associated with phenotypic resistance to darunavir or other PIs. Two patients (one treatment-experienced and one treatment-naïve) developed the M184V N[t]RTI RAM in reverse transcriptase while receiving emtricitabine (Table 4) that was associated with phenotypic resistance to emtricitabine and lamivudine. One patient (patient 14 in Table 4) showed the transient development of the N[t]RTI RAM L74I/L and the NNRTI RAM P225H/P at the Week 16 visit, which were not detected at the subsequent Week 48 visit analysis as shown in Table 4. These mutations were not associated with resistance to the agents in the patientŐs regimen (emtricitabine/tenofovir/zidovudine), and may reflect previous drug history. New primary RAMs were not detected in the 11 remaining patients.
Sixty patients were enrolled in the pharmacokinetic substudy. Pharmacokinetic parameters were comparable to historic data. For darunavir, mean (standard deviation [SD]) maximum plasma concentration (Cmax) was 7663 (1920) ng/ml, minimum plasma concentration (Cmin) was 1310 (969) ng/ml and area under the concentration-time curve during a 24-hour interval (AUC24h) was 81,646 (26,322) ng·h/ml (Table 5). Pharmacokinetics of cobicistat, tenofovir and emtricitabine are shown in Table 5.
In the Bayesian feedback analysis for darunavir population pharmacokinetic parameters through Week 48 (n = 298), the overall mean (SD) population pharmacokinetic-derived darunavir AUC24h and trough plasma concentration (C0h; n = 298) at Week 48 were 102,000 (33,100) ng·h/ml and 2150 (1320) ng/ml, respectively. Data were available for 281 treatment-naïve patients. The mean (SD) darunavir AUC24h was 100,620 (32,366) ng·h/ml and C0h was 2105 (1289) ng/ml. In 17 treatment-experienced patients, the mean (SD) darunavir AUC24h was 119,747 (39,961) ng·h/ml and C0h was 2917 (1658) ng/ml. These values are comparable to those previously reported for darunavir/ritonavir 800/100 mg once daily (mean [SD] AUC24h and C0h were 93,026 [27,050] ng·h/ml and 2282  ng/ml, respectively, in antiretroviral-naïve patients  and 93,334 [28,626] ng·h/ml and 2160  ng/ml, respectively, in treatment-experienced patients with no darunavir RAMs ). There were no clinically relevant relationships between darunavir exposure and virologic response, AEs or laboratory parameters.
This Phase IIIb study was conducted to evaluate the safety, efficacy and pharmacokinetics of darunavir/cobicistat 800/100 mg once daily in HIV-1-infected adults with no darunavir RAMs who also received two fully active N[t]RTIs. We showed that darunavir/cobicistat 800/150 mg once daily was well tolerated, and the pharmacokinetics, virologic and immunologic responses were consistent with previously published data for darunavir/ritonavir 800/100 mg once daily.
Through Week 24, the onset of any grade 3 or 4 AEs regardless of causality was low (6% in the overall population). Five out of 313 patients (2%), all of whom were treatment-naïve, experienced any study drug-related grade 3 AE through Weeks 24 and 48. No patients experienced grade 4 drug-related AEs. The most commonly reported AEs of all grades during the study, diarrhea, nausea, upper respiratory tract infection and headache, have all been reported previously for darunavir and cobicistat [5-8,15,16]. Renal laboratory assessments showed small changes consistent with the inhibitory effects of cobicistat on renal tubular creatinine secretion rather than a true reduction in GFR [15,16,29].
Darunavir and cobicistat administered once daily with two fully active N[t]RTIs, gave a virologic response rate at Week 48 of 81% overall and 83% in treatment-naïve patients (FDA Snapshot analysis) and improved CD4+ cell counts over 48 weeks. The Week 48 FDA Snapshot response rate was consistent with responses using secondary analyses, including the TLOVR analysis (81% response overall and 83% in treatment-naïve patients), and with the Week 48 virologic response rate in treatment-naïve patients in ARTEMIS (84%; TLOVR, ITT analysis) . As in ARTEMIS, virologic responses were similar irrespective of baseline VL.
In this study, only 15/313 patients met the criteria for resistance analysis. One of these 15 patients who was treatment experienced, developed a darunavir RAM at position I84 as a mixture with wild-type (I84I/V), which was not associated with phenotypic resistance to darunavir or other PIs. Two patients (one treatment experienced and one treatment naïve) developed the M184V RAM while receiving emtricitabine as part of their backbone N[t]RTI that was associated with phenotypic resistance to both lamivudine and emtricitabine. In the remaining 12 patients who were analyzed for resistance, no new primary RAMs were detected. The low rates of resistance development in this study confirms the high genetic barrier of darunavir whether boosted with cobicistat or ritonavir.
Steady-state darunavir pharmacokinetic parameters in the pharmacokinetic substudy were consistent with those observed in previous Phase I studies in healthy volunteers [30-32]. When data from all evaluable patients were included into a more robust dataset, the population-based darunavir pharmacokinetic parameters were consistent with previous data with darunavir/ritonavir 800/100 mg once daily in HIV-1-infected, treatment-naïve patients in ARTEMIS, and treatment-experienced patients with no darunavir RAMs in ODIN [33,34]. In the population pharmacokinetic model, the mean darunavir C0h of 2150 ng/ml was >37-fold above the protein-binding adjusted 50% effective concentration for wild-type virus (55 ng/ml) [33,35], indicating adequate pharmacokinetic boosting of darunavir by cobicistat.
The mean steady-state cobicistat pharmacokinetic parameters (AUCtau 7596 ng·h/ml and Cmax 991 ng/ml) were consistent with levels associated with pharmacokinetic enhancement and in the range of historical data in HIV-1-infected patients (AUCtau 8300 ng·h/ml and Cmax 1100 ng/ml). Steady-state emtricitabine and tenofovir pharmacokinetic parameters were also in the range of historical data [36-38].
No clinically relevant relationship was observed between darunavir AUC24h or C0h and virologic response or safety at Week 24 or 48 when given with cobicistat. This is consistent with previous data with darunavir/ritonavir in ARTEMIS  and ODIN .
The fixed-dose combination of darunavir and cobicistat reduces pill burden compared with separately administered darunavir and ritonavir. Accordingly, the fixed-dose combination is expected to improve convenience and simplicity, and therefore patient adherence to medication [18-22]. Cobicistat does not induce CYP isozymes and is a more selective inhibitor of CYP3A than ritonavir [13,14], so there is less potential for drug-drug interactions to occur than with ritonavir.
The study was limited in that it was an open-label, single-arm study. As such, it did not directly compare darunavir/cobicistat against darunavir/ritonavir. Nevertheless, previous studies have shown the fixed-dose combination of darunavir/cobicistat 800/150 mg once daily has darunavir pharmacokinetic parameters comparable to those of darunavir/ritonavir 800/100 mg once daily [30-32]. These comparable pharmacokinetic parameters are expected to translate into similar efficacy, as has been shown in an indirect comparison of darunavir/cobicistat data from the current study and combined darunavir/ritonavir data from ARTEMIS (treatment-naïve patients) and ODIN (treatment-experienced patients with no darunavir RAMs) .
Secondly, the study included a heterogeneous group of patients with no darunavir RAMs, consistent with the current prescribing information of darunavir 800 mg once daily; however, the majority (94%) was treatment naïve. Separate reporting of the treatment-experienced cohort would not be meaningful given the small number of these patients (n =18).
In conclusion, darunavir and cobicistat was generally well tolerated, and with a safety profile that was consistent with the one of each agent separately. The combination achieved high rates of virologic suppression over 48 weeks, with only one patient developing a darunavir RAM but without phenotypic resistance to darunavir or other PIs. The steady-state pharmacokinetic parameters for darunavir, cobicistat, emtricitabine and tenofovir following administration of darunavir and cobicistat once daily and two fully active N[t]RTIs were consistent with previously published data. These data support the use of darunavir/cobicistat in combination with N[t]RTIs for future treatment of HIV-1-infected patients with no darunavir RAMs.