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Phase 2 Study of Cobicistat versus Ritonavir each with Atazanavir plus Fixed-Dose Emtricitabine/Tenofovir DF in the Initial Treatment of HIV Infection
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POST ACCEPTANCE, 1 August 2011
Elion, Richard; Cohen, Calvin; Gathe, Joseph; Shalit, Peter; Hawkins, Trevor; Liu, Hui C.; Mathias, Anita A.; Chuck, Steven L.; Kearney, Brian P.; Warren, David R.; for the GS-US-216<0105 Study Team
Objective: Assess efficacy and safety of cobicistat versus ritonavir as pharmacoenhancers for atazanavir when administered with emtricitabine/tenofovir df as initial treatment for HIV-1 infection.
Design: Randomized, partially placebo-controlled, double-blind, multicenter study
Subjects: Antiretroviral treatment-naive adults, screening HIV-1 RNA >=5000 copies/mL, and CD4 cell count > 50 cells/[mu]L.
Intervention: Randomized 2:1 (stratified by HIV RNA <= or > 100,000 copies/mL) to receive placebo-blinded once-daily cobicistat 150 mg or ritonavir 100 mg with open-label atazanavir plus fixed-dose emtricitabine/tenofovir df Main outcome measures: Efficacy and safety at Weeks 24 and 48.
Results: Eighty-four percent of ATV/co subjects and 86% of ATV/r subjects suppressed HIV-1 RNA (<50 copies/ mL) at Week 24, and 82% and 86% at Week 48, respectively, and mean CD4 count (cells/[mu]L) increased 203 and 199 at Week 24, and 208 and 177 at Week 48.
Study treatment discontinuation due to adverse event occurred 4% ATV/co and 3% ATV/r subjects through 48-weeks. Treatment-related adverse events occurred in 36% ATV/co and 48% ATV/r subjects; hyperbilirubinemia occurred in 96% and 100%, and ocular icterus or jaundice occurred in 14% and 17%, respectively. Mean estimated glomerular filtration rate (Cockcroft-Gault, mL/min) decreased occurred in both treatment groups and was evident at Week 2 (ATV/co, -9 and ATV/r, -4), reached a nadir by Week 24 (-15 and -14), and did not progress further through Week 48 (-13 and -14).
Conclusion: Using cobicistat and ritonavir as pharmacoenhancers for atazanavir and administered with emtricitabine/tenofovir df achieved comparable rates of virologic suppression and CD4 count increase with satisfactory safety profiles.
Mechanism-based inhibition (MBI) of cytochrome P4503A (CYP3A) enzymes by low doses (100< 400mg/day) of the HIV-1 protease inhibitor (PI) ritonavir (RTV) to pharmacologically enhance ('boost') plasma levels of other PIs (PI/r) that are metabolized by CYP3A enzymes was a serendipitous therapeutic advancement early in the use of PIs as components of highly active antiretroviral therapy (HAART) [1, 5]. Pharmacologic boosting of PIs has several desirable outcomes: (a) raises pharmacologic barrier to the development of virologic resistance; (b) the PI may be administered at lower dose and decreased pill burden; (c) often decreases dosing frequency; and (d) may decrease side effects, thereby improving a HAART regimen [6]. RTV is used primarily to boost the eight approved PIs [7,10].
Cobicistat (COBI, formerly GS-9350) is a more specific MBI of CYP3A without antiretroviral activity. In vitro studies demonstrate COBI, compared to ritonavir, is a weak inhibitor of CYP2D6 (IC50 1U4 9.2 mM), does not inhibit other CYP isoforms, and displays low liability for induction; thus COBI exhibits a PK profile associated with fewer clinically significant drug-drug interactions. Other favorable characteristics of COBI include reduced perturbation of the normal adipocyte functions such as lipid accumulation and/or response to insulin that may offer the potential for fewer adverse biochemical effects relative to ritonavir [11,13].
COBI has high aqueous solubility allowing formulation as a tablet and co-formulation with other drugs [11,15]. COBI is being developed specifically as a pharmacoen- hancer for drugs metabolized by CYP3A to improve pharmacokinetic (PK) exposure to decrease total daily dose and/or less frequent dosing [13]. COBI and RTV boost plasma levels of ATV and DRV comparably when coadministered to HIV-1 uninfected adults [14,15]. These results formed the rationale for initiating a Phase 2 clinical trial in HIV-1 infected antiretroviral treatment- naive adults to test efficacy and safety of HAART consisting of COBI compared to RTV as pharmacoen- hancers for ATV coadministered with fixed-dose emtricitabine/tenofovir df (FTC/TDF).
randomized to ATV/co never received study treatment. Thus 79 randomized subjects constituted the intent-to- treat analysis efficacy and safety populations: ATV/co (n =50) and ATV/r (n = 29). Table 1 displays baseline characteristics (demographic and disease), efficacy (primary and secondary endpoints), and safety (adverse events and laboratory abnormalities through Week 48) for both treatment groups with post-hoc intertreatment group statistical comparisons. Baseline demographics and disease characteristics were similar between treatment groups. Seventy-six percent of ATV/co subjects had HIV-1 RNA 100,000 copies/mL, and ATV/r subjects had 62% and 38%, respectively.
The stratum-weighted difference in the response rate (ATV/co < ATV/r) was -1.9% (-18.4% to 14.7%) at Week 24. The other efficacy endpoints were similar between the treatment arms. No subject experienced virologic failure.
Ten percent (8/79) of subjects discontinued study treatment prematurely. Five of the 8 subjects discontinued prior to Day 28; 5/50 (10%) ATV/co and 3/29 (10%) ATV/r subjects. Three of 79 (4%) subjects discontinued study treatment prematurely due to adverse event related to study treatment; 2/50 (4%) ATV/co (moderate vomiting, Day 3; and severe generalized maculopapular rash, Day 11), and 1/29 (3%) ATV/r subjects (mild ocular icterus, Day 21). Of the remaining 5 subjects, 1 on each treatment was lost to follow-up, 1 ATV/co subject withdrew consent and another was discontinued at the investigator's discretion due to nonadherence to protocol, and 1 ATV/r subject had a protocol violation.
Through 48 weeks, 39/50 (78%) ATV/co and 24/29 (83%) ATV/r subjects experienced >/=1 one treatment- emergent adverse event (TEAE) and the majority was assessed as mild or moderate severity. Three serious adverse events occurred in 3 subjects and were assessed as unrelated to study treatment: pneumonia (1 on each treatment) and cellulitis (ATV/co). Study treatment- related TEAEs in >/= 5% of subjects were reported in 18/ 50 (36%) ATV/co and 14/29 (48%) ATV/r subjects; ocular icterus occurred most commonly 6/50 (12%) and 4/29 (14%) subjects, respectively, followed by fatigue, diarrhea, nausea, and flatulence.
Hyperbilirubinemia was reported in 96% ATV/co and 100% ATV/r subjects. Sixty-three percent of ATV/co and 45% of ATV/r subjects developed ??Grade 3 hyperbilirubinemia. Mean indirect bilirubin (mg/dL) was numerically higher among the ATV/co versus ATV/ r subjects, but was statistically significant only at Week 2 (3.2 and 2.1, respectively) (p = 0.05). Intertreatment group statistical comparison of mean change from baseline in fasting lipids revealed no statistically significant difference between treatment groups. Mean percent change from baseline in estimated glomerular filtration rate (eGFR) was significantly decreased only at Week 2, - 8% (ATV/co group) versus -3% (ATV/r group) (p = 0.02), but not at Week 24 or 48.
Atazanavir exposure (Cmax and AUCtau; mean % [Coefficient of Variation, CV]) was estimated from the intensive pharmacokinetic samples: ATV/co subjects (n = 8): Cmax, 3880 ng/mL (36%) and AUCtau 41,300 ng.hr/mL (33%); and ATV/r subjects (n = 10): Cmax: 4390 ng/mL (47%) and AUCtau 49,900 ng.hr/ mL (47%). Figure 1 illustrates the values for geometric mean ATV trough at week 8 for both treatment groups. Figure 1 Table Inset shows the ATV Ctrough (geometric mean) at Weeks 8, 24, and 48 for both treatments as well as their respective geometric mean ratio [90% confidence interval].
The results of this phase 2 study demonstrated that HIV-1 infected treatment-naïve subjects using COBI or RTV as pharmacoenhancers for ATV coadministered with FTC/ TDF achieved and maintained similar rates of virologic suppression (82% and 86%, respectively) and CD4 count increase (?230 and ?206 CD4 cells/mL) through Week 48. These rates of virologic suppression are comparable to 48-week results from three randomized clinical trials wherein ATV/r plus FTC/TDF was compared to another HAART: fosamprenavir/r plus FTC/TDF once daily, 83% (ALERT) [16]; lopinavir/r twice daily plus FTC/TDF once daily, 78% (CASTLE) [17]; and efavirenz plus FTC/TDF or ATV/r plus abacavir/ lamivudine, both once daily, 84% ACTG 5202 [18].
Statistical analysis of rates AEs occurring between treatment groups is generally not preplanned for studies with 2:1 randomization of a relatively small number of subjects. Both treatment groups appeared to have similar numbers of subjects with treatment-related adverse events except for nausea, which occurred in 5 subjects receiving ATV/co versus 1 ATV/r subject and did not cause study drug interruption or discontinuation. One ATV/co subject reported an episode of vomiting on Day 3 which was assessed as related to study treatment. The subject discontinued study treatment and did not attend any postbaseline study visits. The AE profile for COBI when given with ATV ? FTC/TDF will be characterized more accurately with the accrual of additional safety data from the Phase 3 study with the same treatment groups.
Elevation of indirect bilirubin was the most common laboratory abnormality, a side-effect of atazanavir mediated through competitive inhibition of UGT1A1 enzyme and influenced by genetic factors. In one study, three MDR1 3435 genotypes were associated with: significantly higher plasma atazanavir plasma levels in subjects with CC, compared to CT and TT genotypes, and bilirubin levels correlated with atazanavir concen- trations [19]. In our study, the incidence of >/=Grade 3 hyperbilirubinemia was similar between treatment groups. Mean indirect bilirubin levels at most postbaseline time points were slightly higher in subjects receiving ATV/co compared to ATV/r however, there did not appear to be a disproportionate number of subjects manifesting clinical sequelae of elevated indirect bilirubin, namely ocular icterus and jaundice. A theoretical possibility might lie in the differences between cobicistat and ritonavir in affinity for off-target metabolic enzymes. For example, ritonavir is a better PXR activator than COBI and so might increase UGT1A1 levels and thus decrease indirect bilirubin by increased metabolism independent of ATV plasma level.
Mean eGFR decrease occurred in both treatment groups, was statistically significantly larger only at Week 2, reached a nadir by Week 24 and did not progress further through Week 48. Three ATV/co subjects had confirmed Grade 1 elevation of serum creatinine. No subject receiving either treatment developed persistent serum electrolyte or urinalysis abnormalities, or discontinued or interrupted study treatment due to change in serum creatinine or eGFR [20,21]. A pharmacokinetic/pharmacodynamic study in healthy HIV-uninfected adults using iohexol [22], which exclusively undergoes glo- merular filtration and is not secreted or reabsorbed, has shown that cobicistat can cause a mild increase in serum creatinine (mild decrease in eGFR) but does not affect iohexol-measured (actual) GFR, suggesting that the observed increase in serum creatinine may be due to an effect of COBI on the tubular secretion and not glomerular filtration of serum creatinine [20]. Additional in vitro and clinical studies of COBI in both HIV-infected and -uninfected subjects are in progress and may provide additional insight into the biological mechanism respon- sible for the mild increase in serum creatinine seen with COBI.
Pharmacokinetic analyses demonstrated that ATV exposures appear to be comparable including adequate ATV trough concentrations relative to its protein- binding adjusted EC90 (14ng/ml) when boosted with COBI or RTV. Greater than 90% of quantifiable values for ATV Ctrough at these visits were above the DHHS- recommended target of 150 ng/ml for both treatments. These ATV exposures are consistent with historical PK data from Phase 1 studies when ATV was boosted with COBI-boosted and RTV [13,15] and lend additional support for COBI as an appropriate pharmacoenhancer for the once-daily HAART regimen of ATV + FTC/ TDF.
The results of this Phase 2 study helped design and initiate a 96-Week Phase 3 randomized, partially double-blind study to evaluate the efficacy and safety of ATV/co versus ATV/r each administered with FTC/TDF in HIV-1 infected antiretroviral treatment-naive adults.
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