Clinical Therapeutics/Volume 37, Number 9, 2015

New Drug Review

Cobicistat: Review of a Pharmacokinetic Enhancer for HIV Infection Elizabeth M. Sherman, PharmD, AAHIVP1; Marylee V. Worley, PharmD, BCPS1; Nathan R. Unger, PharmD2; Timothy P. Gauthier, PharmD, BCPS-AQ ID3; and Jason J. Schafer, PharmD, MPH, BCPS, AAHIVP4 1

College of Pharmacy, Nova Southeastern University, Fort Lauderdale, Florida; 2College of Pharmacy, Nova Southeastern University, Palm Beach Gardens, Florida; 3Department of Pharmacy, Miami Veterans Affairs Healthcare System, Miami, Florida; and 4Jefferson School of Pharmacy, Thomas Jefferson University, Philadelphia, Pennsylvania

ABSTRACT Purpose: This article reviews the clinical pharmacology, pharmacodynamic and pharmacokinetic (PK) properties, clinical efficacy and tolerability, drug interactions, and dosing and administration of cobicistat. Methods: Searches of MEDLINE and International Pharmaceutical Abstracts from 1964 to February 2015 were conducted using the search terms cobicistat and GS-9350. Relevant information was extracted from the identified clinical trials and review articles. Abstracts from the Conference on Retroviruses and Opportunistic Infections (2014–2015) and the Interscience Conference on Antimicrobial Agents and Chemotherapy (2013–2014) were also searched. Findings: Cobicistat is a PK enhancer lacking antiviral activity that, via selective cytochrome P-450 (CYP) 3A inhibition, inhibits the metabolism of certain antiretroviral medications and is used for prolonging their effect. Cobicistat has been studied as a booster of elvitegravir, a second-generation integrase inhibitor, and of the protease inhibitors atazanavir and darunavir. Data on its clinical efficacy and tolerability have been presented in 2 Phase II trials and in 9 Phase III trials, which reported durable efficacy in terms of achievement of sustained suppression of HIV-1 RNA levels to o50 copies/mL for at least 48 weeks. Cobicistat was generally well-tolerated in these studies. Cobicistat may increase serum creatinine levels via the inhibition of proximal renal tubular cell transporters and thus reduce estimated glomerular filtration rate, although it does not appear to affect actual glomerular filtration rate. Given the potent CYP3A inhibition

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by cobicistat, its coadministration with drugs metabolized by CYP3A may result in increased plasma concentrations of such agents. Moreover, as cobicistat is metabolized predominantly by CYP3A, plasma concentrations may increase or decrease on coadministration with CYP3A inhibitors or inducers, respectively. Implications: With potent durability through 48 weeks, a tolerability profile comparable to other firstand second-line antiretroviral therapies, and a convenient dosing schedule with low daily pill burden in fixed-dose combination tablets, cobicistat is a potential addition to the management of HIV infection as a PK enhancer. However, the effects of cobicistat on serum creatinine and its considerable drug-interaction potential may warrant additional monitoring. (Clin Ther. 2015;37:1876– 1893) & 2015 Elsevier HS Journals, Inc. All rights reserved. Key words: booster, cobicistat, GS-9350, HIV, pharmacokinetic enhancer.

INTRODUCTION Worldwide an estimated 35.3 million people were living with HIV-1 in 2012, including 1.2 million people in the United States.1,2 In the United States, the management of patients infected with HIV is directed by the guideline set forth by the Department of Accepted for publication July 30, 2015. http://dx.doi.org/10.1016/j.clinthera.2015.07.022 0149-2918/$ - see front matter & 2015 Elsevier HS Journals, Inc. All rights reserved.

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E.M. Sherman et al. Health and Human Services (DHHS).3 Management strategies outlined in this guideline, including combination antiretroviral (ARV) therapy, have been reported to decrease both morbidity and mortality in HIV-infected patients.3 Ideal characteristics of an ARV therapy regimen include virologic potency, tolerability, and a small pill burden, all of which can facilitate improved medication adherence. Recommended initial ARV therapy options for treatment-naive patients include regimens that combine 2 nucleos(t)ide reverse transcriptase inhibitor (NRTI) agents with either an integrase strand transfer inhibitor or a ritonavir-boosted protease inhibitor (PI). However, ritonavir, itself a PI—even at low doses—has been associated with gastrointestinal intolerance and metabolic abnormalities. Additionally, although low-dose ritonavir does not appear to possess substantial antiviral activity, a theoretical concern remains that it may contribute to the emergence of drug resistance. In addition, ritonavir possesses broad, potent inhibitory effects on cytochrome P-450 (CYP) isozymes and drug transporters, resulting in a significant number of drug interactions. Ritonavir is also difficult to coformulate with other ARV agents due to poor solubility. Consequently, an alternative pharmacokinetic (PK) enhancer (booster) was developed. Cobicistat* (formerly GS-9350) is a PK enhancer that inhibits the metabolism of the ARV medications elvitegravir, atazanavir, and darunavir and is used for prolonging their effects. Initially approved by the US Food and Drug Administration (FDA) in 2012 as a part of a fixed-dose combination tablet containing elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (EVG/COBI/FTC/TDF),† the use of cobicistat administered as a single entity was approved in 2014. The EVG/COBI/FTC/TDF fixed-dose combination tablet represents a complete regimen containing 2 NRTIs, an integrase strand transfer inhibitor, and a PK enhancer. EVG/COBI/FTC/TDF is indicated for use in adult patients who have no ARV treatment history or for replacing the current ARV regimen in those who are virologically suppressed despite treatment with a stable regimen for at least 6 months and who have had no known substitutions associated with resistance to the individual components of the combination tablet. The DHHS guideline on the management of HIV

infection in adults lists EVG/COBI/FTC/TDF as a recommended regimen in treatment-naive patients with a pretreatment estimated creatinine clearance (CrCl) rate of Z70 mL/min. More recently, cobicistat has been coformulated into 2 distinct fixed-dose combination tablets, one containing atazanavir/cobicistat (ATV/COBI)‡ and another containing darunavir/cobicistat (DRV/ COBI),§ both approved in 2015. The use of ATV/COBI in combination with other ARV agents is indicated for use in treatment-naive and treatment-experienced adults, although its use in treatment-experienced patients should be guided by the number of baseline primary PI-resistance mutations. The use of DRV/COBI in combination with other ARV agents is indicated for treatment-naive and treatment-experienced adults with no darunavir resistance–associated substitutions. On the basis of data on efficacy and tolerability from clinical trials, the DHHS guideline on the treatment of adults with HIV infection lists these cobicistat-boosted PIs, combined with 2 NRTIs, as alternative initial regimen options for treatment-naive adult patients.3 Additional cobicistat-based combination tablets may be forthcoming. The FDA is currently reviewing a new drug application for an investigational single-tablet regimen (STR) containing elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (EVG/COBI/ FTC/TAF).4 The present review focuses on the clinical pharmacology, pharmacodynamic and PK properties, clinical efficacy and tolerability, drug interactions, and dosing and administration of cobicistat.

MATERIALS AND METHODS MEDLINE and International Pharmaceutical Abstracts were searched for articles published in English from 1964 to February 2015, using the terms cobicistat and GS-9350. The same terms were used for searching the abstracts from the Conference on Retroviruses and Opportunistic Infections (2014–2015) and the Interscience Conference on Antimicrobial Agents and Chemotherapy (2013–2014). Clinical data were limited to those from in-human Phase ZIIa clinical trials. Relevant information was extracted from the identified clinical trials and review articles. The reference lists of the retrieved articles were reviewed for additional pertinent articles. ‡

*

s

Trademark: Tybost (Gilead Sciences, Inc, Foster City, California). † Trademark: Stribilds (Gilead Sciences).

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Trademark: EvotazTM (Bristol-Myers Squibb Company, Princeton, New Jersey). § Trademark: PrezcobixTM (Janssen Therapeutics, Titusville, New Jersey).

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O

N O N

N

S

O H N

N H

N H

O

O

S N

Figure. The chemical structure of cobicistat.

RESULTS Pharmacology Cobicistat (Figure) is an inhibitor of human cytochrome P-450 (CYP) 3A isoforms and is used for increasing systemic exposure to elvitegravir, atazanavir, and darunavir—ARV therapies metabolized by CYP3A enzymes. The chemical name for cobicistat is 1,3-thiazol-5-ylmethyl [(2R,5R)-5-{[(2S)-2-[(methyl {[2-(propan-2-yl)-1,3-thiazol-4-yl]methyl}carbamoyl) amino]-4-(morpholin-4-yl)butanoyl]amino}-1,6-diphenylhexan-2-yl]carbamate. It has a molecular formula of C40H53N7O5S2 and a molecular weight of 776.0. By reducing ARV metabolism, cobicistat serves as a PK enhancer—or a “booster”—to help optimize ARV activity. Table I5-8 compares the pharmacology of and other information on cobicistat versus ritonavir. In contrast to ritonavir, which is also a PK enhancer, cobicistat does not have reported activity against HIV. Cobicistat was synthesized from ritonavir to maintain potent CYP3A enzyme inhibition while eliminating anti-HIV activity.9 The removal of an important hydroxyl group that interacts with the pharmacologically active site of the HIV protease enzyme, combined with the addition of a morpholine group, was associated with the elimination of HIV protease inhibition while retaining CYP3A enzyme inhibition.9 An additional improvement was found when comparing the solubility of cobicistat to that of ritonavir, with improved aqueous solubility of cobicistat in both neutral and acidic pH conditions making cobicistat easier to coformulate with other agents.9

Pharmacodynamic Properties Similar to that of ritonavir, cobicistat CYP3A inactivation is both concentration and time dependent.9,10 The inhibition of hepatic enzymes is extended even beyond

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the elimination of these agents, with de novo protein synthesis required for the restoration of enzymatic activity.11 Cobicistat has reported potent inhibitory activity: At a dose of 50 mg, CYP3A activity was decreased by 89%, and at a dose of 200 mg, CYP3A activity was decreased by 95%.10 This inhibition is comparable to that with a 100-mg dose of ritonavir, with which CYP3A activity was decreased by 96%.10 In a midazolam model as the specific CYP3A substrate, kinetic inactivation constants for the maximum rate of inactivation (kinact) were 0.44 min–1 with cobicistat and 0.23 min–1 with ritonavir; inhibitor concentrations yielding 50% maximal inactivation (kI) were 939 nM with cobicistat and 256 nM with ritonavir.9 Taking concentration into consideration, the kinact/kI ratios— established measures of inactivation efficiency—were 0.57 min–1/mM–1 with cobicistat and 0.9 min–1/mM–1 with ritonavir, indicating similarly efficient inactivation based on kinetic parameters.9,12 Thus, both the inhibitory kinetic parameters and the inhibitory activity of cobicistat are comparable to those of ritonavir. Cobicistat is a more selective inhibitor of CYP3A compared with ritonavir and has no reported inhibitory activity against CYP1A2, CYP2C9, or CYP2C19.9 Cobicistat also has been reported to have significantly less inhibition of CYP2D6 compared with ritonavir. Cobicistat has not been reported to induce uridine 50 -diphospho-glucuronosyltransferase and, compared with ritonavir, has been reported to have a reduced activation of pregnane X receptor.5,6 This increased selectivity may contribute to a lower potential for interactions with drugs metabolized through uridine 50 -diphospho-glucuronosyltransferase, CYP1A2, CYP2C9, CYP2C19, and other metabolic pathways induced by the pregnane X receptor.9,10 Cobicistat, like ritonavir, inhibits P-glycoprotein and breast cancer resistance protein. The inhibition of P-glycoprotein when cobicistat is coadministered with atazanavir, darunavir, or elvitegravir leads to increased ARV absorption—an additional mechanism of PK enhancement.13 Cobicistat inhibits renal cation transporters, specifically multidrug and toxin extrusion protein 1 and organic anion-trasporting polypeptide 1 B1 and B3.13 Consequently, cobicistat may decrease tubular creatinine secretion, increase serum creatinine levels, and reduce creatinine-based estimates of CrCl. Additional information regarding elevations in serum creatinine with cobicistat use is discussed in the Safety Profile section.

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E.M. Sherman et al. Table I. Cobicistat versus ritonavir as a pharmacokinetic enhancer.5-8 Parameter Year of FDA approval Place in therapy

Boosting dose Dosage formulations and coformulations

Metabolism

Adverse events

Pregnancy category Pediatric use

Cobicistat

Ritonavir

2012 (as part of the EVG/COBI/ FTC/TDF fixed-dose combination tablet) Pharmacokinetic enhancer lacking anti-HIV activity; used for boosting levels of the HIV integrase inhibitor EVG and the HIV protease inhibitors ATV and DRV 150 mg/d PO Single agent: 150-mg tablet; coformulations: EVG/COBI/FTC/TDF 150/150/200/300-mg tablet, ATV/COBI 300/150-mg tablet, DRV/COBI 800/150-mg tablet

1996 (as a sole HIV protease inhibitor at a dose of 600 mg BID)

Pharmacokinetic enhancer with activity against HIV; used for boosting levels of the HIV protease inhibitors ATV, DRV, FPV, LPV, SQV, TPV, IDV and the hepatitis C protease inhibitor paritaprevir 100–200 mg/d PO Single agent: 100-mg tablet or capsule, 80-mg/mL oral solution; coformulations: LPV/RTV 200/50-mg tablet, LPV/RTV 100/25-mg tablet, LPV/RTV 400/100 mg per 5-mL oral solution Metabolized by CYP3A (major) and Metabolized by CYP3A (major) and CYP2D6 (minor); inhibits CYP3A and CYP2D6 (minor); inhibits CYP3A, CYP2D6 (weak); inhibits P-gp, BCRP, CYP2D6, CYP2C8, and CYP2C9; OATP1B1 and OATP1B3 transporters induces CYP3A, CYP1A2, CYP2C9, CYP2C19, and CYP2B6, as well as other enzymes including glucuronosyl transferase; inhibits P-gp Most commonly reported adverse Most commonly reported adverse events: events: nausea (18%), diarrhea (15%), diarrhea (20%), headache (16%), headache (11%), nasopharyngitis (11%); nasopharyngitis (15%), and nausea median increase in triglycerides and (16%); median increase in triglycerides total cholesterol, 19 and 5 mg/dL, and total cholesterol, 32 and 9 mg/dL, respectively; significant median increase respectively; median increase in SCr, in SCr, 0.13 mg/dL, and reduction 0.09 mg/dL, and reduction in CrCl, in CrCl, 13 mL/min; discontinuation 9 mL/min; discontinuation due to renal due to renal adverse events, 1.7% adverse events, 1.4% B B No dosing recommendations in patients Not approved for use in patients aged o1 aged o18 y mo

ATV ¼ atazanavir; BCRP ¼ breast cancer–resistance protein; COBI ¼ cobicistat; CrCl ¼ creatinine clearance; CYP ¼ cytochrome P-450; DRV ¼ darunavir; EVG ¼ elvitegravir; FDA ¼ US Food and Drug Administration; FPV ¼ fosamprenavir ; FTC ¼ emtricitabine; IDV ¼ indinavir; LPV ¼ lopinavir; OATP ¼ organic anion-transporting polypeptide; P-gp ¼ P-glycoprotein; SCr ¼ serum creatinine; SQV ¼ saquinavir; TDF ¼ tenofovir disoproxil fumarate; TPV ¼ tipranavir.

Pharmacokinetic Properties PK data on the FDA-approved 150-mg dose of cobicistat are reviewed, and relevant PK data from additional studied doses are discussed. The PK parameters of cobicistat 150 mg are summarized in Table II.5,6,14,15

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The effects of cobicistat, compared with those of ritonavir, on the PK properties of atazanavir and darunavir are summarized in Table III. As shown, the effects are comparable, with the exception of Cτ with DRV/COBI.

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Table

II. Pharmacokinetic properties cobicistat 150 mg.5,6,14,15

Parameter

Fed State

Fasting State*

Protein-Rich Drink*

1027 24 2 –

1137 23 3.5 –

7324

7507

3.4

3.3

990–1570 Cmax, ng/mL 16–50 Cmin, ng/mL 2.5–4.5 Tmax, h 7600–10,400 AUCτ, ng  h/mL 6720 AUC0–1, ng  h/mL* 2.99–4 t½, h *

of

Results from a single-dose study.

The absorption of cobicistat has been evaluated only when cobicistat was administered in combination with other ARV agents. Absorption did not differ between the fasting, fed, and protein-rich conditions.14,15 A study examined the PK properties of a single dose of a EVG/COBI/FTC/TDF combination tablet administered to 11 healthy, HIV-negative, Japanese men in various fed conditions.15 Using a standardized breakfast meal (413 kcal) as the reference, no differences in the least squares mean ratios of cobicistat Cmax and AUC0–1 were observed in the fasted (0.93 and 1.06, respectively) or protein-rich (1.05 and 1.11, respectively) conditions. Although the PK properties of cobicistat were similar in various fed conditions, the bioavailability of coadministered medications (elvitegravir, TDF, darunavir, and atazanavir) was affected

by food intake.5,6,16,17 Therefore, in a clinical setting, it is recommended that all cobicistat-containing products are taken with food.5,6,16,17 After the administration of multiple doses of cobicistat 150 mg, Cmax was 1000 ng/mL, Tmax was 3 to 4 hours, and t½  2 was 3 hours. Cobicistat is highly protein bound (97%–99%), and its distribution is nonlinear and dose dependent.5,10 After the administration of multiple doses of 50 mg (n = 12), 100 mg (n = 11), 200 mg (n = 12), and 300 mg (n = 12) to healthy, HIV-negative subjects, Vdz values were 316, 152, 100, and 85.3 L, respectively.10 A similar dose-dependent effect was seen with clearance. As the dose was increased from 50 to 300 mg, a 95% reduction (from 154 to 8.28 L/h) in the apparent clearance at steady state was observed. In both the single- and multiple-dose cohorts, doses exceeding 200 mg approached the nadir value of cobicistat clearance. The metabolism of cobicistat is predominantly via CYP3A4 oxidation and, to a lesser extent, CYP2D6. Cobicistat does not undergo glucuronidation.10 Overall drug metabolism is minimal. Ninety-nine percent of cobicistat remains unchanged, and resultant metabolites do not exert clinically relevant inhibitory activity.18 With the administration of cobicistat to healthy male subjects for 6 days, followed by a single radiolabeled dose on day 7, 86% was excreted in the feces and 8% was excreted in the urine.5,18 The effects of moderate hepatic impairment (ChildPugh Class B) on cobicistat were investigated in a Phase I open-label study in HIV-uninfected subjects.19 Ten hepatically impaired subjects, matched with 10 subjects with normal hepatic function, were given

Table III. Pharmacokinetic properties of atazanavir 300 mg and darunavir 800 mg coadministered with cobicistat 150 mg or ritonavir 100 mg once daily.5 Data are given as mean (SD) unless otherwise noted. Atazanavir

Darunavir

Property

þ Cobicistat

þ Ritonavir

þ Cobicistat

þ Ritonavir

Cmax, ng/mL Cτ, μg/mL C0h, μg/mL AUCτ, ng  h/mL

3.91 (1.94) 0.80 (0.72) NR 46.13 (26.18)

4.76 (1.94) 0.85 (0.72) NR 47.59 (24.38)

7.74 (1.69) 1.33 (0.89) 2.40 (1.22) 81.08 (25.15)

7.46 (1.52) 1.87 (1.56) 2.48 (0.85) 79.99 (27.20)

NR ¼ not reported.

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E.M. Sherman et al. cobicistat 150 mg with elvitegravir, daily for 10 days. The geometric mean ratios (90% CI) of the AUCτ, Cmin, and Cmax values were 99.7% (76%–131%), 208% (117%–368%), and 86.1% (65.4%–113%), respectively.19 The increase in Cmin was not deemed clinically relevant. Based on these data, cobicistat does not require dose adjustment in patients with mild or moderate hepatic impairment. However, cobicistat is not recommended for use in patients with severe hepatic impairment (Child-Pugh Class C), as its use has not yet been studied in this population.5,6,16,17 Similarly, the impact of severe renal impairment, defined as CrCl o30 mL/min (not on dialysis) calculated using the Cockcroft-Gault (CG) method, on the PK properties of cobicistat was explored in an open-label, multidose study.20 Patients with severe renal impairment (n ¼ 12), matched with patients with normal renal function (CrCl Z90 mL/min), were given cobicistat 150 mg with elvitegravir, daily for 7 days. The geometric mean ratios (90% CI) of the AUCτ, Cmin, and Cmax values were 125% (98.6%– 160%), 113% (56.8%–224%), and 122% (99.8%– 150%), respectively. Based on these data, cobicistat does not require dose adjustments in patients with renal impairment, including those with severe renal impairment.5 Cobicistat has not been studied in patients receiving dialysis.

Clinical Trials Patients’ characteristics and the designs of the clinical trials that have evaluated the efficacy of ARV regimens used in combination with cobicistat are summarized in Table IV. Two Phase II trials that evaluated the dosing and efficacy of cobicistat used as a PK enhancer in treatment-naive and treatmentexperienced HIV-infected patients were identified.21,22 Nine similarly designed Phase III trials that evaluated the efficacy and safety profile of cobicistat used as a PK enhancer in HIV-infected, treatment-naive, and treatment-experienced patients were identified.7,23,26,29–34

Phase II GS-US-236-010421 and GS-US-216-010522 were Phase II, multicenter, randomized, double-blind trials that investigated the efficacy and tolerability of cobicistat used as an ARV PK enhancer for the treatment of HIV infection (Table IV). GS-US-236-010421 was a

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Phase II, multicenter, randomized, double-blind, double-dummy, active-controlled trial from the United States that compared the efficacy and tolerability of 2 STRs of EVG/COBI/FTC/TDF versus efavirenz (EFV)/ FTC/TDF. Eligible patients were treatment-naive adults with plasma HIV RNA Z5000 copies/mL, CD4 cell count 450 cells/mm3, CrCl Z80 mL/min, and no NRTI, non-nucleoside reverse transcriptase inhibitor (NNRTI), or primary PI genotypic resistance mutations. Seventy-one patients were randomized, with 65 participants on blinded study drug through weeks 24 and 48, for analysis. The primary end point was the proportion of patients with viral suppression, defined as HIV RNA o50 copies/mL at 24 weeks. At week 24, the percentage of patients with viral suppression was 90% (43/48) in the EVG/COBI/FTC/ TDF group compared with 83% (19/23) in the EFV/ FTC/TDF group, with a stratum-weighted difference of 5% (95% CI, –11% to 21.1%) (Table V). At week 48, response rates for viral suppression were identical to those at week 24 in both treatment arms, with 90% and 83% of participants achieving HIV RNA o50 copies/mL (difference, 8.4%; 95% CI, –8.8 to 25.6%) in the EVG/COBI/FTC/TDF and comparator groups, respectively. The median increases in CD4 cell count in the EVG/COBI/FTC/TDF group were 123 and 205 cells/mm3 at weeks 24 and 48, respectively. Patients receiving EFV/FTC/TDF experienced increases in CD4 cell counts of 124 and 139 cells/mm3 at weeks 24 and 48, respectively. Both regimens were well-tolerated, with fewer participants in the EVG/COBI/FTC/TDF group experiencing psychiatric disorders (8 [17%] vs 10 [43%]; P ¼ 0.02). None of the participants in the EVG/COBI/FTC/TDF group discontinued medication due to an adverse event, whereas 1 participant in the EFV/FTC/TDF group discontinued use due to suicidal ideation. GS-US-216-010522 was a Phase II, multicenter, randomized, double-blind, partially placebocontrolled study from the United States that compared ritonavir and cobicistat with both atazanavir and fixed-dose FTC/TDF (Table IV). Eligible patients were treatment-naive adults with plasma HIV RNA Z5000 copies/mL, CD4 cell count 450 cells/mm3, CrCl Z80 mL/min, and no NRTI, NNRTI, or primary PI genotypic resistance mutations. Patients were randomized in a 2:1 ratio and stratified based on screening HIV RNA of less than or greater than

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Table IV. Baseline characteristics of the patients in the Phase II and III studies of the efficacy of cobicistat.

Study (Design)/Treatment Groups

CD4, Median, cells/mm3

HIV RNA, Median, log copies/mL

36 35

354 436

4.59 4.58

37 34

365 343

4.56 4.69

37 38

376 383

4.75 4.78

38 39

351 366

4.8 4.8

37 38 54

353 351 627

4.8 4.8 o50 copies/mL

35

361

4.8

31 36 44

368 433 714

4.7 4.6 o50 copies/mL

41 41

604 624

o50 copies/mL o50 copies/mL

42 40

586 593

o50 copies/mL o50 copies/mL

Age, % Mean, Men y

Phase II GS-US-236-010421 (48-wk, randomized [2:1], double-blind) EVG/COBI/FTC/TDF (n ¼ 48) 92 EFV/FTC/TDF (n ¼ 23) 91 GS-US-216-010522 (48-wk, randomized [2:1], double-blind) ATV þ COBI þ FTC/TDF (n ¼ 50) 94 ATV þ RTV þ FTC/TDF (n ¼ 29) 86 Phase III GS-US-236-010223–25 (144-wk, Randomized [1:1], double-blind) EVG/COBI/FTC/TDF (n = 348) 88 EFV/FTC/TDF (n = 352) 90 GS-US-236-010326–28 (144-wk, randomized [1:1], double-blind) EVG/COBI/FTC/TDF (n = 353) 92 ATV þ RTV þ TDF/FTC (n = 355) 89 GS-US-216-01147 (48-wk, randomized [1:1], double-blind) ATV þ COBI þ FTC/TDF (n ¼ 344) 83 ATV þ RTV þ FTC/TDF (n ¼ 348) 82 82 GS-US-236-011829 (48-wk, open-label, single-arm study of switch from [ATV þ RTV] or [DRV þ RTV] þ 2 NRTIs to [ATV þ COBI] or [DRV þ COBI] þ 2 NRTIs; n ¼ 73) GS-US-215-013030 (48-wk, open-label, single-arm study of 89 DRV þ COBI þ 2 NRTIs; n ¼ 313) GS-US-235-011931 (48-wk, randomized [2:1], double-blind) DRV/COBI/FTC/TAF (n ¼ 103) 92 DRV þ COBI þ FTC/TDF (n ¼ 50) 94 GS-US-236-012332 (48-wk, open-label, single-arm study of 96 switch from RAL þ FTC/TDF to EVG/COBI/FTC/TDF; N ¼ 48) GS-US-236-011533 (48-wk, randomized 2:1, open-label switch) Switch to EVG/COBI/FTC/TDF (n ¼ 290) 85 Continue on PI þ RTV þ FTC/TDF (n ¼ 139) 86 GS-US-236-012134 (48-wk, randomized [2:1], open-label switch) Switch to EVG/COBI/FTC/TDF (n ¼ 290) 92 Continue on NNRTI þ FTC/TDF (n ¼ 143) 94

ATV ¼ atazanavir; COBI ¼ cobicistat; DRV ¼ darunavir; EFV ¼ efavirenz; EVG ¼ elvitegravir; FTC ¼ emtricitabine; NNRTI ¼ non-nucleoside reverse transcriptase inhibitor; NRTI ¼ nucleos(t)ide reverse transcriptase inhibitor; PI ¼ protease inhibitor; RAL ¼ raltegravir; RTV ¼ ritonavir; TAF ¼ tenofovir alafenamide; TDF ¼ tenofovir disoproxil fumarate.

100,000 copies/mL. Seventy-nine patients were randomized, received study treatment, and included in the intent-to-treat analysis. The primary efficacy

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end point was the proportion of participants with HIV RNA o50 copies/mL at week 24, and secondary efficacy end points were the proportion of participants

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E.M. Sherman et al.

Table V. Efficacy of cobicistat-containing regimens in Phase II and III clinical trials. % Patients With HIV RNA o50 copies/mL, Mean (95% CI)

Study Phase II GS-US-236-010421 Wk 24 Wk 48 GS-US-216-010522 Wk 24 Wk 48 Phase III GS-US-236-010222,31,32 Wk 48 Wk 96 Wk 144 GS-US-236-010324,33,34 Wk 48 Wk 96 Wk 144 GS-US-216-011425 GS-US-236-011826 GS-US-215-013027 GS-US-235-011928 GS-US-236-01237 GS-US-236-011529 GS-US-236-012130

Treatment Treatment þ – Cobicistat Cobicistat

Difference (95% CI)

Δ vs Baseline in CD4 Cell Count, Mean (95% CI), cells/mm3 Treatment Treatment þ – Cobicistat Cobicistat

P

90 90

83 83

5 (–11 to 21.1) 8.4 (–8.8 to 25.6)

þ123 þ205

þ124 þ139

NR NR

84 82

86 86

–4.6 (–21.7 to 12.5) –1.9 (–18.4 to 14.7)

þ203 þ230

þ199 þ206

0.92 0.43

87.6 84 80.2

84.1 82 75.3

3.6 (–1.6 to 8.8) 2.7 (–2.9 to 8.3) 4.9 (–1.3 to 11.1)

þ239 þ295 þ321

þ206 þ273 þ300

0.009 0.19 NR

89.5 83.3 77.6 85.2 82.2 81 76.7 100 93.8 93

86.8 82.3 74.6 87.4 – – 84 – 87.1 88

3.0 (–1.9 to 7.8) 1.1 (–4.5 to 6.7) 3.1 (–3.2 to 9.4) –2.2 (–7.4 to 3); P ¼ 0.4 – – –6.2 (–19.9 to 7.4) – 6.7 (0.4 to 13.7); P ¼ 0.025 5.3 (–0.5 to 12); P ¼ 0.066

207 256 280 þ213 –7 þ167 þ231 þ12 þ40 þ56

211 261 293 þ219 – – þ212 – þ32 þ58

NR NR NR NR – – 0.5 – NR NR

NR ¼ not reported.

with HIV RNA o50 copies/mL at week 48 and CD4 cell count at weeks 24 and 48. Per the 24-week primary efficacy end point, assessed utilizing intent-to-treat analysis, with missing data considered as failures, the cobicistat and ritonavir groups achieved HIV RNA o50 copies/mL at rates of 84% and 86%, respectively, with a stratum-weighted difference of –4.6% (95% CI, –21.7% to 12.5%) (Table V). Per the secondary end point at week 48, the cobicistat and ritonavir groups achieved HIV RNA o50 copies/mL at rates of 82% and 86%, respectively, with a stratum-weighted differ-

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ence of –1.9% (95% CI, –18.4 to 14.7%). The mean percentage changes from baseline in CrCl at week 2 were –8% in the cobicistat group and –3% in the ritonavir group (P ¼ 0.02). The difference was not significant at week 48 (–12% in the cobicistat group vs –11% in the ritonavir group; P ¼ 0.8).

Phase III Studies Cobicistat Boosting of Elvitegravir GS-US-236-010222 and GS-US-236-010326 are ongoing Phase III, double-blind, randomized, placebo-

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Clinical Therapeutics controlled trials of the therapeutic efficacy of EVG/ COBI/FTC/TDF in treatment-naive, HIV-infected adults (Table IV). GS-US-236-010222 is a Phase III, multicenter, double-blind, double-dummy trial from North America comparing the efficacy of EVG/COBI/ FTC/TDF to that of EFV/FTC/TDF, both used as STRs, in subjects with HIV RNA Z5000 copies/mL, CrCl Z70 mL/min, and susceptibility to efavirenz, emtricitabine, and TDF by HIV genotype. Patients’ characteristics at baseline were similar in the 2 treatment groups. A total of 348 patients were treated with EVG/COBI/ FTC/TDF and 352 with EFV/FTC/TDF. The primary end point was the proportion of patients in the intentto-treat population with undetectable (o50 copies/mL) HIV RNA at 48 weeks. At week 48 noninferior efficacy was achieved, with 87.6% and 84.1% (difference, 3.6%; 95% CI, –1.6% to 8.8%) of EVG/COBI/FTC/TDF and EFV/FTC/TDF patients, respectively, achieving HIV RNA o50 copies/mL (Table V). No marked between-group differences in treatment efficacy were observed in the subgroup analyses at week 48, including assessments in patients with high (4100,000 copies/mL) HIV RNA at baseline. The CD4 cell count at week 48 was significantly higher in the EVG/COBI/FTC/TDF group than in the EFV/FTC/TDF group (239 vs 206 cells/mm3; P ¼ 0.009). The rates of treatment discontinuations due to adverse events were similar between groups (4% in the EVG/COBI/FTC/TDF group vs 5% in the EFV/FTC/TDF group). Nausea was more commonly reported with EVG/COBI/FTC/ TDF use (21% vs 14%; P ¼ 0.016), whereas dizziness (7% vs 24%; P o 0.001), abnormal dreams (15% vs 27%; P o 0.001), insomnia (9% vs 14%; P ¼ 0.031), and rash (6% vs 12%; P ¼ 0.009) were more commonly reported with EFV/FTC/TDF use. As pharmacodynamic data predicted, serum creatinine concentration was increased more by week 48 (median [interquartile range], 13 μmol/L [5 to 20] vs 1 μmol/L [–6 to 8]; P o 0.001) in the EVG/COBI/FTC/TDF group. Increases in total cholesterol (0.25 vs 0.49 mmol/L; P o 0.001), low-density lipoprotein cholesterol (0.26 vs 0.44 mmol/L; P ¼ 0.001), and highdensity lipoprotein cholesterol (0.13 vs 0.20 mmol/L; P ¼ 0.001) were more commonly reported in patients receiving EFV/FTC/TDF. At 96 weeks, 84% and 82% (difference, 2.7%; 95% CI, –2.9 to 8.3%) of EVG/COBI/FTC/TDF and EFV/FTC/TDF patients, respectively, maintained HIV RNA o50 copies/

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mL.24 At 144 weeks, noninferior efficacy continued, with 80% and 75% (difference, 4.9%; 95% CI, –1.3% to 11.1%) of EVG/COBI/FTC/TDF and EFV/FTC/TDF patients maintaining HIV RNA o50 copies/mL.25 GS-US-236-010326 is a Phase III, multicenter (Australia, Europe, North America, and Thailand), randomized, double-blind trial comparing EVG/ COBI/FTC/TDF (353 patients) to another once-daily regimen of ritonavir-boosted atazanavir (ATV/r) þ FTC/TDF (355 patients) in treatment-naive, HIV-infected patients (Table IV). The study enrolled patients with HIV RNA Z5000 copies/mL, CrCl Z70 mL/min, and susceptibility to emtricitabine, TDF, and atazanavir by HIV genotype. Patients’ baseline characteristics were similar between groups. The primary end point was the difference in the proportions of patients in the intent-to-treat population achieving viral suppression (HIV RNA o50 copies/mL) at week 48. At 48 weeks, noninferior virologic efficacy was demonstrated, with 89.5% and 86.8% (difference, 3.0%; 95% CI, –1.9% to 7.8%) of the EVG/COBI/ FTC/TDF and ATV/r þ FTC/TDF groups, respectively, achieving HIV RNA o50 copies/mL (Table V). Efficacy was similar for patients with various CD4 cell counts and HIV RNA levels at baseline. Similar improvements from baseline in CD4 cell counts were observed between the treatment groups at 48 weeks (207 and 211 cells/mm3 in the EVG/COBI/ FTC/TDF and comparator groups, respectively). Both regimens had favorable tolerability profiles, with similar rates of diarrhea (22% and 27%) and nausea (20% and 19%) in the EVG/COBI/FTC/TDF and ATV/r þ FTC/TDF groups. More patients in the ATV/r þ FTC/TDF group experienced ocular icterus (51 [14%]) than in the EVG/COBI/FTC/TDF group (2 [1%]). Discontinuation from study drug was infrequent in either group, with 13 (3.7%) versus 18 (5.1%) patients discontinuing treatment because of adverse events in the EVG/COBI/FTC/TDF and comparator groups, respectively. A greater statistically significant increase from baseline in median triglyceride level occurred in the patients receiving ATV/r þ FTC/TDF than in the patients receiving EVG/COBI/FTC/TDF. Differences in other median increases in lipid parameters were not significant (total cholesterol, 0.26 vs 0.21 mmol/L; low-density lipoprotein cholesterol, 0.28 vs 0.27 mmol/L; and

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E.M. Sherman et al. high-density lipoprotein cholesterol, 0.15 vs 0.13 mmol/L) in the EVG/COBI/FTC/TDF and ATV/r þ FTC/TDF groups. Severe or life-threatening hyperbilirubinemia was more commonly reported in patients receiving ATV/r þ FTC/TDF (58.2%) than in patients receiving EVG/COBI/FTC/TDF (0.6%). The increase in serum creatinine at 48 weeks was greater in the patients receiving EVG/COBI/FTC/TDF than in the comparator group (median changes, þ11 vs þ7 μmol/L; P o 0.001). At 96 weeks, 83% and 82% (difference, 1.1%; 95% CI, –4.5% to 6.7%) of EVG/COBI/FTC/TDF and ATV/r þ FTC/TDF patients, respectively, maintained HIV RNA o50 copies/mL.27 At 144 weeks, noninferior efficacy continued, with 77.6% and 74.6% (difference, 3.1%; 95% CI, –3.2 to 9.4%) of the EVG/COBI/FTC/TDF and ATV/r þ FTC/TDF patients maintaining HIV RNA o50 copies/mL.28 Genotypic and phenotypic characterization of HIV resistance in patients through week 144 of GS-US-236-010335 were examined. Data from all patients with virologic failure, or HIV RNA Z400 copies/mL, at weeks 48, 96, and 144 or at the time of drug discontinuation were analyzed with genotyping and phenotyping assays for protease, reverse transcriptase, and integrase. Forty patients met these criteria and were included in the resistance analysis (21 patients in the EVG/COBI/FTC/TDF group and 19 patients in the ATV/r þ FTC/TDF group). The difference in emergent resistance between the 2 groups was not significant (P ¼ 0.063). In the EVG/ COBI/FTC/TDF group, HIV from 8 of 353 patients (2.3%) developed primary integrase (n ¼ 6) and/or reverse transcriptase (n ¼ 7) substitutions, including E92Q, N155H, or Q148R (n ¼ 2 each) and T66I or T97A (n ¼ 1 each) in integrase and M184V/I (n ¼ 7) and K65R (n ¼ 1) in reverse transcriptase. All 8 isolates had reduced susceptibility to elvitegravir, emtricitabine, or TDF. In the ATV/r þ FTC/TDF group, HIV from 2 patients (0.6%) developed the resistance substitution M184V/I in reverse transcriptase. The remaining patients in both groups lacked emergent mutations for resistance to the drugs in their regimens and were phenotypically susceptible to all of the drugs in their regimens, suggesting poor drug adherence as the underlying cause of virologic failure. A recent abstract reported data from a pooled 144-week analysis in patients in GS-US-236-0102

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and GS-US-236-0103 (Table IV).36 The analysis involved 1408 participants from the 2 trials, 701 randomly assigned to receive EVG/COBI/FTC/TDF, 352 to EFV/FTC/TDF, and 355 to ATV/r þ FTC/ TDF. At week 144, 79%, 75%, and 75% of the EVG/ COBI/FTC/TDF, EFV/FTC/TDF, and ATV/r þ FTC/ TDF groups, respectively, achieved HIV RNA o50 copies/mL. Virologic response rates were similar across subgroups of age, sex, race, pretreatment HIV RNA, and CD4 cell count (Table V). Cobicistat Boosting of Atazanavir or Darunavir In the ongoing trial GS-US-216-0114,7 treatmentnaïve HIV-infected patients were randomly assigned to FTC/TDF and atazanavir boosted with either cobicistat (n ¼ 344) or ritonavir (n ¼ 348) (Table IV). The study enrolled patients with HIV RNA Z5000 copies/mL and CrCl Z70 mL/min. There were no differences in baseline characteristics. At week 48, HIV RNA o50 copies/mL was achieved in 85% of cobicistat recipients and in 87% of ritonavir recipients (difference, 2.2%; 95% CI, 7.4% to 3.0%) (Table V). The adverseevents profile was similar between the cobicistat and ritonavir groups, with no statistically significant differences observed in jaundice (20.9% vs 15.5%), scleral icterus (17.7% vs 18.4%), nausea (17.7% vs 16.4%), diarrhea (15.4% vs 20.4%), or headache (11.0% vs 15.5%). Median increases in serum creatinine were 0.13 and 0.09 mg/dL in the cobicistat and ritonavir recipients, respectively (Po 0.001). GS-US-236-0118,29 an open-label, single-arm study, examined the efficacy and tolerability of switching from a regimen containing 2 NRTIs plus either ATV/r or ritonavir-boosted darunavir (DRV/r) to those of a regimen containing 2 NRTIs plus a cobicistat-boosted PI (Table IV). The study enrolled patients who had HIV RNA o50 copies/mL for at least 6 months before study entry, were on either ATV/r (n ¼ 52) or DRV/r (n ¼ 21) plus 2 NRTIs, and had mild to moderate renal impairment (CrCl 50–89 mL/min). At week 48, 82.2% of all patients maintained HIV RNA o50 copies/mL (Table V). Serious adverse events were reported in 7% of patients, and adverse events were reported in 25% of patients, most commonly upper respiratory tract infection (19%), nasopha-

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Clinical Therapeutics ryngitis (12%), nausea (12%), and hyperbilirubinemia (11%). Treatment with the study drug was discontinued in 7 patients (9.6%), 2 due to renal consequences (hematuria, proteinuria, and abnormal glomerular filtration rate [GFR]), which were resolved with study drug discontinuation. A Phase IIIb, open-label, single-arm study of DRV/COBI (800 mg/150 mg) plus 2 NRTIs enrolled both treatment-naive (n ¼ 295) and treatment-experienced (n ¼ 18) patients with HIV RNA Z1000 copies/mL, normal renal function (CrCl Z80 mL/min), and no darunavir resistance–associated mutations (Table IV).30 At week 48, 81% achieved HIV RNA o50 copies/mL, with a median increase in CD4 cell count of 167 cells/mm3 (Table V). The most frequently reported adverse events were diarrhea (27%) and nausea (23%), grades 1 or 2 in severity. The median increase in serum creatinine throughout 48 weeks was 0.09 mg/dL, which remained stable during the study period. GS-US-235-011931 is the first study to evaluate an HIV PI (darunavir) as a component of an STR (Table IV). This randomized, double-blind, placebo-controlled trial enrolled treatment-naive patients with CrCl Z70 mL/min and HIV RNA Z5000 copies/mL. Patients were randomly assigned to receive either the once-daily STR containing DRV/COBI/FTC/TAF (n ¼ 103), or a oncedaily multitablet regimen (MTR) of darunavir, cobicistat, emtricitabine, and TDF. At 48 weeks, 76.7% and 84% of patients (difference, –6.2%; 95% CI, –19.9% to 7.4%) in the STR and MTR arms, respectively, achieved HIV RNA o50 copies/mL (Table V). Mean increases in CD4 cell count of 231 cells/mm3 in the STR arm and 212 cells/mm3 in the MTR arm (P ¼ 0.5) were observed. Serious adverse events were seen in 4.9% of STR participants and 4% of MTR participants, while 1.9% of STR participants (rash, substance dependence) and 4% of MTR participants (worsening of diarrhea, proximal renal tubulopathy) stopped treatment with the study drug due to adverse events. The most commonly reported adverse events in the STR and MTR arms were diarrhea (21.4% vs 26%, respectively), upper respiratory tract infection (15.5% vs 14%), fatigue (13.6% vs 18%), and nausea (12.6% vs 10%). The difference in the mean change from baseline in serum creatinine between groups was not significant (0.06 mg/dL in the STR arm vs 0.09 mg/dL in the MTR arm; P ¼ 0.053).

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Regimen Simplification GS-US-236-0123,32 GS-US-236-0115 (STRATEGY-PI),33 and GS-US-236-0121 (STRATEGY-NNRTI)34 were Phase IIIb studies of the efficacy and tolerability of switching HIV-infected adult patients on ARV therapy with CrCl Z70 mL/min and HIV RNA o50 copies/mL for at least 6 months before study entry to an STR of EVG/COBI/FTC/TDF (Table IV). GS-US-236-012332 was a 48-week, single-arm study wherein 100% of patients maintained HIV RNA o50 copies/mL at 48 weeks (the primary end point). In GS-US-236-0115 (STRATEGY-PI),33 in which the switch group was previously taking a PI-based regimen, the results demonstrated superior efficacy in the switch group, with 93.8% (272/290) and 87.1% (121/139) (difference, 6.7%; 95% CI, 0.4%–13.7%; P ¼ 0.025) of patients in the switch and no-switch groups, respectively, maintaining HIV RNA o50 copies/mL at week 48 (Table V).33 In GS-US-236-0121 (STRATEGY-NNRTI),34 in which the switch group was previously on an NNRTI-based regimen, 93% (271/290) and 88% (126/143) (difference, 5.3%; 95% CI, –0.5 to 12; P ¼ 0.066) of patients in the switch and no-switch groups, respectively, maintained HIV RNA o50 copies/mL at week 48. Changes from baseline in CD4 cell counts were similar between the switch and no-switch groups in the 2 comparison studies.33,34 No treatment-emergent resistance was seen in either group during these studies.33,34

Safety Profile According to the limited data from studies of the PK properties of cobicistat administered as a single entity, cobicistat appears well-tolerated.15,19,37 Adverse events observed in PK studies were predominately grade 1 or 2 in intensity and included diarrhea (8.3%), headache (8.3%), food intolerance (8.3%), somnolence (1.3%), and abnormal dreams (1.3%).10,37 Treatment-emergent laboratory abnormalities included mild liver abnormalities (1.3%), glycosuria (6-12%), and hematuria (1-3%).14,18,29,37 One patient experienced grade 3 left upper extremity dyscoordination that resolved after discontinuation of the study drug.6 When the combination tablet EVG/COBI/FTC/TDF was administered in Phase III clinical trials, the most commonly reported adverse events were diarrhea (12%) and nausea (16%), with grade 3 and 4 laboratory abnormalities in aspartate aminotransferase (3%), alanine aminotransferase (2%),

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E.M. Sherman et al. amylase (3%), creatinine kinase (8%), and hematuria (4%).6 When cobicistat was combined with an HIV PI (atazanavir or darunavir), adverse events were comparable to those of the combination with ritonavir.16,17 The adverse reactions most commonly reported with coadministered ATV/COBI in Phase II and III clinical trials included ocular icterus (15%), jaundice (13%), and nausea (12%).16 The most commonly reported grade 3 or 4 laboratory abnormalities were hyperbilirubinemia (65%), hematuria (3%), glycosuria (3%), and elevations in creatinine kinase (5%), amylase (4%), alanine aminotransferase (3%), aspartate aminotransferase (3%), and γ-glutamyl transpeptidase (2%).16 When comparing cobicistat-containing ARV therapy regimens to similar regimens using ritonavir, an increase in serum creatinine concentrations was observed in the cobicistat groups, correlating with a reduction in estimated (e)GFR of  15%.21,22 This effect is explained by the inhibition of tubular creatinine secretion by cobicistat. To further explore the elevation in serum creatinine and its impact on actual clearance, a randomized, double-blind, placebo-controlled trial compared cobicistat to ritonavir with regard to changes in eGFR in subjects with normal renal function (CrCl Z80 mL/min).37 Twelve subjects were randomly assigned to 1 of the 3 treatment arms: (1) active cobicistat with ritonavir-matched placebo, (2) active ritonavir with cobicistat-matched placebo, or (3) cobicistat-matched placebo with ritonavir-matched placebo. A second cohort of subjects (n ¼ 18) with mild to moderate renal impairment (CrCl 50–79 mL/min) received open-label, active cobicistat. Active and placebo treatments were taken once daily for 7 days, with renal assessments at baseline, day 7, and day 14. Renal function was estimated using both CG and modification of diet in renal disease (MDRD) methods. Iohexol, administered immediately after the ingestion of the study drug, was used for determining the reference, or actual (a), GFR. In the cohort with normal renal function receiving cobicistat, a significant reduction (P o 0.05) in mean eGFR (–9.9 mL/min using both CG and MDRD) was observed on day 7. This change in eGFR was reversed after discontinuation of the study drug and returned to baseline values by day 14 (1.4 mL/min [CG] and 1.1 mL/min [MDRD]). In contrast, the aGFR remained unchanged at both day 7 (–2.7 mL/min) and day 14 (–2.5 mL/min). Neither eGFR nor aGFR was significantly reduced with ritonavir use. Similar results were seen in the cohort with mild to moderate renal

September 2015

impairment receiving cobicistat. Significant mean reductions in eGFR (–11.9 mL/min [CG] and –13.9 [MDRD]) were observed at day 7. These changes were reversed after discontinuation of the study drug and returned to baseline values by day 14 (–2.2 mL/min [CG], –2.6 mL/min [MDRD]). Despite the observed reductions in eGFR, the aGFR values remained unchanged at days 7 and 14 (–3.6 and –5.8 mL/min, respectively). Given these data, cobicistat produces a benign reduction in eGFR but does not affect actual renal function. The DHHS guideline on the treatment of adults with HIV recommends a screening urinalysis for proteinuria at the initiation of care and annually thereafter. Serum basic chemistry analysis (including determination of renal function) is recommended at the initiation of care, every 6 to 12 months in untreated patients, at the time of ARV therapy initiation, 2 to 8 weeks after ARV therapy initiation, and then every 3 to 6 months thereafter.3 The cobicistat prescribing information5 recommends close monitoring for renal safety in patients with a confirmed increase from baseline in serum creatinine of 40.4 mg/dL.

Drug–Drug Interactions Cobicistat is both metabolized by, and an inhibitor of, CYP3A4 and therefore has considerable potential for interactions with other drugs whose metabolism is influenced by this pathway.5,6,16,17 Administration with other medications that induce or inhibit the CYP3A4 enzyme may serve to reduce or increase levels of cobicistat. Cobicistat is an inhibitor of CYP3A and CYP2D6. It also inhibits several transport proteins, including breast cancer resistance protein, organic anion transporter protein 1 B1 and B3, and P-glycoprotein.5,6,16,17 Coadministration with a drug metabolized by, or acting as a substrate of, any of these may result in an increased plasma concentrations of such drugs. Greater exposure may lead to an increased risk for adverse drug reactions. Caution is warranted when using cobicistat with other medication regimens, given the wide variety of drugs metabolized by the affected pathways. Table VI denotes cobicistat drug–drug interactions. Few studies have examined the explicit effects of cobicistat on other medications; however, many drug–drug interactions with cobicistat have been inferred from the data on ritonavir.

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Clinical Therapeutics Numerous drugs are contraindicated with cobicistat use due to the significant risk for drug–drug interactions that can diminish the intended therapeutic effects or produce serious and/or life-threatening adverse events. Table VII denotes medications contraindicated with cobicistat use. When cobicistat is used with atazanavir, additional contraindicated drugs include nevirapine, indinavir, and irinotecan.5,16 Cobicistat should not be combined with 41 ARV drug requiring PK enhancement and should not be used with PIs other than atazanavir or darunavir.5 To avoid therapeutic duplication, cobicistat should not be used with ritonavir or with the STR of EVG/COBI/ FTC/TDF.

life-years, quality-adjusted life-years (QALYs), virologic response, AIDS-related events, and adverse events between the fixed-dose combination of EVG/ COBI/FTC/TDF and EFV/FTC/TDF.40 The resultant incremental cost-effectiveness ratio of EVG/COBI/ FTC/TDF was $166,287 per QALY, based on the addition of 0.041 QALYs over a lifetime at a cost of $6886. Assuming equivalent efficacy, EFV/FTC/TDF was reported to have lower costs and higher QALYs. A conclusion regarding cost-effectiveness of cobicistat, however, requires the analysis of data from additional pharmacoeconomic studies of cobicistat used alone and in combination with other agents.

Dosage and Administration

DISCUSSION

Although cobicistat and ritonavir share many characteristics, they are not interchangeable. Cobicistat is available only for oral administration and should never be given alone. Table VIII lists cobicistat-containing products approved by the FDA, including renal and hepatic dose adjustments. The initiation of cobicistat-containing regimens with tenofovir is not recommended in patients with CrCl o70 mL/min. All cobicistat-containing products should be taken with food. Because atazanavir solubility decreases as pH increases, ATV/COBI should be administered separately from antacids (eg, aluminum, magnesium, calcium carbonate), H2-receptor antagonists (eg, famotidine), and proton pump inhibitors (eg, omeprazole).16 When cobicistat is administered as a part of the STR of EVG/COBI/FTC/TDF, antacids should be staggered by at least 2 hours to prevent the formation of ionic complexes in the gastrointestinal tract.6,39

Cobicistat, the second FDA-approved PK enhancer after ritonavir, is a new addition to currently available ARV therapies. Cobicistat-containing regimens can be used in treatment-naive and treatment-experienced adult patients. Data on the use of cobicistat during pregnancy, in the elderly, and in patients o18 years of age are not yet available. Data from Phase II and III clinical trials support the potency, efficacy, and tolerability of cobicistat used in combination with other agents. The effectiveness of cobicistat-containing regimens has similarly been demonstrated in multiple switch studies in virologically suppressed patients. Cobicistat has favorable PK properties, a small pill burden due to its ability to be coformulated with other agents, and an acceptable tolerability profile. Numerous drug–drug interactions, however, necessitate careful consideration and additional patient monitoring. Serum creatinine should be monitored routinely in patients using cobicistat. Both cobicistat and ritonavir are effective PK enhancers as related to their inhibition of CYP3A4 and, as such, drugs contraindicated with cobicistat use are consistent with those contraindicated with ritonavir use with respect to these interactions. The drugs differ in their ability to inhibit or induce other isoforms of the CYP450 enzyme system and other metabolic pathways. The tolerability, gastrointestinal, and lipid profile of cobicistat-containing regimens are comparable to those of ritonavir-containing regimens. Cobicistatcontaining regimens have consistently shown higher serum creatinine increases and CrCl decreases compared with those of ritonavir.

Pharmacoeconomic Considerations When selecting an ARV regimen, out-of-pocket costs may directly affect a patient’s treatment adherence. Cobicistat 150 mg is commercially available at an average wholesale price of US $7.20/d.3 However, cobicistat is often administered in a coformulated fixed-dose combination tablet of EVG/COBI/FTC/ TDF, DRV/COBI, or ATV/COBI. As a consequence, the pharmacoeconomic evaluations of cobicistat are dependent on the combination products. One cost-effectiveness study has evaluated a cobicistat-coformulated product. A Markov cohort model was used for comparing projected total costs,

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E.M. Sherman et al. Table VI. Drug–drug interactions that may occur with cobicistat use.*,5 Drug Class/Agent(s) Antiarrhythmic agents: amiodarone, disopyramide, flecainide, mexiletine, propafenone, quinidine, digoxin Antibiotic agents, macrolide or ketolide: clarithromycin, erythromycin, telithromycin Anticoagulant agents: Rivaroxaban Warfarin Anticonvulsant agents: Amitriptyline, clonazepam, desipramine, imipramine, nortriptyline, trazodone Carbamazepine Oxcarbazepine Phenytoin, phenobarbital Antifungal agents: Itraconazole, ketoconazole Voriconazole Antigout agent: colchicine Antimycobacterial agent: rifabutin β-Agonists, inhalational: salmeterol β-Blockers: metoprolol, carvedilol, timolol Calcium channel blockers: amlodipine, diltiazem, felodipine, nifedipine, verapamil CCR5 agonist: maraviroc Contraceptives, hormonal: progestin, estrogen Corticosteroid agents, inhalational/intranasal: fluticasone, budesonide Endothelin receptor antagonist: bosentan Hepatitis C virus protease inhibitors: Simeprevir HMG-CoA reductase inhibitors (statins): atorvastatin, rosuvastatin Immunosuppressant agents: cyclosporine, everolimus, sirolimus, tacrolimus Analgesic agents, narcotic: Buprenorphine, buprenorphine/naloxone, methadone Fentanyl, tramadol

Interaction Implication Cobicistat may increase levels of drug

Cobicistat may increase levels of drug; cobicistat levels may be increased by drug Cobicistat may increase levels of drug Effect of cobicistat on drug unknown Cobicistat may increase levels of drug Cobicistat may increase levels of drug; cobicistat levels may be decreased by drug Cobicistat levels may be decreased by drug Cobicistat levels may be decreased by drug; effect of cobicistat on drug unknown Cobicistat may increase levels of drug; cobicistat levels may be increased by drug Effect of cobicistat on drug unknown; cobicistat levels may be increased by drug Cobicistat may increase levels of drug Effect of drug on cobicistat levels unknown; cobicistat may increase levels of drug Cobicistat may increase levels of drug Cobicistat may increase levels of drug Cobicistat may increase levels of drug Cobicistat may increase levels of drug Effects of cobicistat on drug unknown Cobicistat may increase levels of drug Cobicistat may increase levels of drug; cobicistat levels may be decreased by drug Cobicistat may increase levels of drug Cobicistat may increase levels of drug Cobicistat may increase levels of drug

Effect of cobicistat on drug unknown Cobicistat may increase levels of drug (continued)

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Clinical Therapeutics

Table VI. (continued). Drug Class/Agent(s)

Interaction Implication

Neuroleptic agents: perphenazine, risperidone, thioridazine Non-nucleoside reverse transcriptase inhibitors: efavirenz, etravirine, nevirapine Oncologic agents: dasatinib, nilotinib, vinblastine, vincristine Phosphodiesterase-5 inhibitors: avanafil, sildenafil, tadalafil, vardenafil Sedative/hypnotic agents: buspirone, diazepam, midazolam (parenteral) Selective serotonin reuptake inhibitor: paroxetine Systemic corticosteroid: dexamethasone

*

Cobicistat may increase levels of drug Cobicistat levels may be decreased by drug Cobicistat may increase levels of drug Cobicistat may increase levels of drug Cobicistat may increase levels of drug Effect of cobicistat on drug unknown Cobicistat may increase levels of drug; cobicistat levels may be decreased by drug

Lack of inclusion in this list does not suggest the lack of a drug–drug interaction.

The current DHHS guideline recommends EVG/ COBI/FTC/TDF as a preferred regimen and lists ATV/ COBI and DRV/COBI as regimen components alternative to initiating ARV therapy in HIV-infected patients with CrCl 470 mL/min. Given the therapeutic evidence of a PK enhancer coformulated in fixeddose combinations containing 2 to 4 drugs in a single tablet, cobicistat offers regimen simplification that may facilitate optimal ARV therapy adherence.

Cobicistat must be used in combination with other ARV agents. When prescribing cobicistat, clinicians should counsel patients about the importance of maintaining good adherence and about the potential for adverse events (with elvitegravir, nausea and diarrhea; with atazanavir, jaundice, scleral icterus, and nausea; with darunavir, diarrhea, nausea, rash, headache, abdominal pain, and vomiting). Further studies are necessary to provide data on interactions with drugs that

Table VII. Drugs contraindicated with cobicistat use.5,38 Drug Class α1-Adrenorecptor antagonist agent Antiarrhythmic agents Anticonvulsant agents Antimycobacterial agent Antineoplastic agent Ergot derivative agents Herbal product HMG-CoA reductase inhibitors (statins) Neuroleptic agents Phosphodiesterase-5 inhibitors Sedatives/hypnotic agents

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Agents Alfuzosin Amiodarone, dronedarone, quinidine Carbamazepine, phenobarbital, phenytoin Rifampin (rifampicin) Irinotecan Dihydroergotamine, ergotamine, ergometrine, methylergonovine St. John’s wort (Hypericum perforatum) Lovastatin, simvastatin Pimozide Sildenafil when used for pulmonary arterial hypertension Oral midazolam, triazolam

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E.M. Sherman et al.

Table VIII. Cobicistat-containing products approved for use by the US Food and Drug Administration (FDA).*,5,6,16,17 US Marketing Information

Product Cobicistat 150 mg Atazanavir 300 mg þ cobicistat 150 mg

Darunavir 800 mg þ cobicistat 150 mg

Elvitegravir 150 mg þ cobicistat 150 mg þ tenofovir DF 300 mg þ emtricitabine 200 mg

Tybosts (Gilead, Foster City, California) EvotazTM (BristolMyers Squibb Co, New York, New York)

PrezcobixTM (Janssen Therapeutics, Titusville, New Jersey) Stribilds (Gilead)

Renal and Hepatic Adjustments Avoid use with tenofovir DF if CrCl o70 mL/min Avoid use with tenofovir DF if CrCl o70 mL/min; avoid use in HIV treatment–experienced patients with ESRD receiving hemodialysis; avoid use in patients with hepatic impairment Avoid use with tenofovir DF if CrCl o70 mL/min; avoid use in patients with severe hepatic impairment Do not initiate use if CrCl o70 mL/min; discontinue use if CrCl o50 mL/min; avoid use in patients with severe hepatic impairment

Approval Date September 25, 2014 January 29, 2015

January 29,2015

August 29, 2012

CrCl = creatinine clearance; DF = disoproxil fumarate; ESRD = end-stage renal disease. All products are oral formulations recommended to be given once daily with food.

*

undergo CYP3A metabolism, the use of cobicistat in special populations, and pharmacoeconomic evaluations.

United States government. The authors have indicated that they have no conflicts of interest with regard to the content of this article.

CONCLUSIONS Cobicistat is a potent CYP3A inhibitor used for enhancing the PK properties of ARV in treatment-naive and treatment-experienced HIV-infected patients. It is commercially available as a single entity and as a part of EVG/COBI/FTC/TDF, ATV/COBI, and DRV/COBI. With potent durability through 48 weeks, a tolerability profile comparable to other first- and second-line ARV therapies, and a convenient dosing schedule with a low daily pill burden in fixed-dose combination tablets, cobicistat is a promising addition to ARV therapy. However, the effects of cobicistat on serum creatinine and its considerable drug-interaction potential may limit its utility. Cobicistat is a development in the evolution of ARV therapy, and its coformulations offer patients more compact regimens for the treatment of HIV infection.

CONFLICTS OF INTEREST The views expressed in this abstract are those of the authors and do not necessarily reflect the position or policy of the Department of Veterans Affairs or the

September 2015

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Address correspondence to: Elizabeth M. Sherman, PharmD, AAHIVP, Nova Southeastern University, College of Pharmacy, 3200 South University Drive, Fort Lauderdale, FL 33328. E-mail: esherman@nova. edu

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