JAIDS Journal of Acquired Immune Deficiency Syndromes:
Brief Report: Clinical Science
A Randomized Double-Blind Comparison of Coformulated Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Disoproxil Fumarate Versus Efavirenz/Emtricitabine/Tenofovir Disoproxil Fumarate for Initial Treatment of HIV-1 Infection: Analysis of Week 96 Results
Zolopa, Andrew MD*; Sax, Paul E. MD†; DeJesus, Edwin MD‡; Mills, Anthony MD§; Cohen, Calvin MD, MSc‖; Wohl, David MD¶; Gallant, Joel E. MD, MPH#; Liu, Hui C. MD, PhD**; Plummer, Andrew BS**; White, Kirsten L. PhD**; Cheng, Andrew K. MD, PhD**; Rhee, Martin S. MD**; Szwarcberg, Javier MD, MPH**; for the GS-US-236-0102 Study Team
*Division of Infectious Diseases and Geographic Medicine, Stanford University, Palo Alto, CA;
†Division of Infectious Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA;
‡Orlando Immunology Center, Orlando, FL;
§Anthony Mills MD Inc., Los Angeles, CA;
‖Community Research Initiative of New England, Boston, MA
¶Division of Infectious Diseases, University of North Carolina, Chapel Hill, NC;
#Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, MD; and
**Gilead Sciences, Foster City, CA.
Correspondence to: Andrew Zolopa, MD, Division of Infectious Diseases and Geographic Medicine, Stanford University, 300 Pasteur Dr, Rm S-156 Grant Bldg, Stanford, CA 94305 (e-mail: firstname.lastname@example.org).
This work has previously been presented at the 11th International Congress on Drug Therapy in HIV Infection, November 11–15, 2012, Glasgow, United Kingdom.
Conflicts of interest for all authors: A.Z. has received research grant support from Gilead Sciences, consulting fees as an advisory board member for Bristol-Myers Squibb, Gilead Sciences, and Janssen Therapeutics. P.E.S. has received research support from Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck Laboratories, and Tibotec; consulting fees from Abbott Laboratories, Aeliron Scientific, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck Laboratories, and Janssen Therapeutics. E.D.J. has received research grant support from Abbott Laboratories, Achillion Pharmaceuticals, Avexa, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Hoff mann LaRoche, Idenix, Janssen, Merck, Pfizer, Sangamo, Taimed, Tobira, and Vertex; and consulting fees as a member of advisory boards for Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, and Vertex. A.M. has received research support from Boehringer Ingelheim, Gilead Sciences, GlaxoSmithKline, Janssen Therapeutics, Kowa, Merck, Pfizer, Tobira, and ViiV; and consulting fees for speakers bureaux and advisory boards from Bristol-Myers Squibb, Gilead Sciences, Janssen Therapeutics, and Merck. C.C. has received research grant support from Gilead Sciences, Bristol-Myers Squibb, Merck, Janssen, and Viiv; and receives consulting fees from Gilead Sciences, Bristol-Myers Squibb, Merck, Janssen, Viiv, and Tobira. D.W. has received research grant support from Merck and GlaxoSmithKline, and receives consulting fees from Janssen Therapeutics and Gilead Sciences. JEG has received research support from Gilead Sciences; and consulting fees from Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Merck, and Janssen Therapeutics. D.W. has received grant support from Merck & Co, and GlaxoSmithKline; and has been on advisory boards for Janssen Therapeutics and Gilead Sciences. H.C.L., A.P., K.L.W., A.K.C., M.S.R., and J.S. are employees of Gilead Sciences. A.Z., P.E.S., E.D.J., A.M., C.C., and D.W. are all principal investigators. H.C.L., A.P., K.L.W., A.K.C., M.S.R., and J.S. are employees of the Sponsor of this study, Gilead Sciences; and were the scientific, medical, and operational leaders responsible for this study’s design, conduct, oversight, and analyses.
All authors have reviewed the results of this study and the article.
Received October 18, 2012
Accepted January 22, 2013
Abstract: We report week 96 results from a phase 3 trial of elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil fumarate (EVG/COBI/FTC/TDF, n = 348) vs efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF, n = 352). At week 48, EVG/COBI/FTC/TDF was noninferior to EFV/FTC/TDF (88% vs 84%, difference +3.6%, 95% confidence interval: −1.6% to 8.8%). Virologic success (HIV-1 RNA <50 copies/mL) was maintained at week 96 (84% vs 82%, difference +2.7%, 95% CI: −2.9% to 8.3%). Discontinuation due to adverse events was low (5% vs 7%). Median changes in serum creatinine (mg/dL) at week 96 were similar to week 48. These results support the durable efficacy and long-term safety of EVG/COBI/FTC/TDF.
A new single-tablet regimen that combines elvitegravir (EVG), an integrase strand transfer inhibitor, cobicistat (COBI), a pharmacoenhancer, emtricitabine (FTC), and tenofovir disoproxil fumarate (TDF) (EVG/COBI/FTC/TDF) was recently approved by the US Food and Drug Administration (FDA) based on the week 48 data from 2 randomized controlled trials (studies 102 and 103). In addition, the 2 US guidelines recommend EVG/COBI/FTC/TDF as an alternative regimen in treatment-naive patients.1,2
In study 102 at week 48, EVG/COBI/FTC/TDF demonstrated noninferior efficacy to efavirenz (EFV)/FTC/TDF with a comparable proportions of patients discontinuing study drug due to adverse events (AEs).3 The tolerability profile of the 2 regimens was different for mild subjective side effects, with more neuropsychiatric and rash events with EFV/FTC/TDF and more nausea with EVG/COBI/FTC/TDF.
In this report, we present week 96 efficacy and safety data from study 102.
A full description of the methods has been published.3 A brief description is provided below.
Study Design and Patients
Study 102 is an ongoing, randomized, double blind, double dummy, active-controlled, phase 3 study being conducted in North America and was approved by institutional review boards at all sites. Participants are HIV-1–infected adults ≥18 years with HIV-1 RNA ≥5000 copies per milliliter, and no previous use of antiretroviral drugs. An estimated glomerular filtration rate (eGFR) ≥70 mL/min and susceptibility of the virus to EFV, FTC, TDF by genotype (GeneSeq assay; Monogram Biosciences, South San Francisco, CA) was required. Eligible patients were randomized in a 1:1 ratio to receive either EVG/COBI/FTC/TDF (150/150/200/300 mg) or EFV/FTC/TDF (600/200/300 mg) with matching placebo tablets.
After week 48, study visits occurred every 12 weeks until week 96. Prespecified AEs of interest were bone fractures and renal events, and those of importance were rash and neuropsychiatric events. In patients taking study drugs, who had confirmed virologic rebound of HIV-1 RNA >400 copies per milliliter, they did not achieve >1 log reduction in HIV-1 RNA by week 8, or had HIV-1 RNA >400 copies per milliliter at week 48, 96, or last visit. Protease, reverse transcriptase, and integrase genotyping and phenotyping assays were done on the confirmatory sample with PhenoSense GT, PhenoSense Integrase, and GeneSeq Integrase (Monogram Biosciences). Study drug was continued, if no reverse transcriptase or integrase resistance was detected. Adherence was assessed by pill count.
The primary endpoint was the proportion of patients in the intention-to-treat population with viral suppression (HIV-1 RNA <50 copies/mL) at week 48 and was assessed with a prespecified noninferiority margin of 12% according to snapshot analysis as defined by the US FDA.3 Participants with HIV-1 RNA <50 copies per milliliter at week 48 (primary endpoint) and 96 (secondary endpoint) were classified as virologic success. The difference, weighted by baseline HIV-1 RNA stratum, for response rate and its 95% confidence interval (CI) were calculated based on stratum-adjusted Mantel–Haenszel proportions. The snapshot analysis was also conducted in subgroups. Per-protocol snapshot analysis included all randomized and treated participants who did not meet any of the following prespecified criteria: discontinuation of study drug before week 96, HIV-1 RNA results missing in the week 96 analysis window, or adherence <2.5th percentile. Other endpoints were viral suppression (HIV-1 RNA <50 copies/mL) at week 96 according to snapshot analysis, achievement and maintenance of HIV-1 RNA <50 copies per milliliter (based on the FDA-defined time to loss of virologic response algorithm),4 viral suppression when treating missing as failure and missing as excluded, and change in CD4 cell count from baseline. This study is registered with clinicaltrials.gov, number NCT01095796.
Of the 917 screened patients, 707 were randomized and 700 received at least 1 dose of study drug (EVG/COBI/FTC/TDF: 348 vs EFV/FTC/TDF: 352). Baseline characteristics, efficacy, and safety through week 48 have been reported previously.3 Through week 96, a similar number of patients discontinued study drug [EVG/COBI/FTC/TDF: 53 (15.2%) vs EFV/FTC/TDF 61 (17.3%)]; after week 48, 16 vs 15 patients discontinued for reasons of loss to follow-up (7 vs 5), AEs (4 vs 6), or others (5 vs 4). Median adherence to active study drug up to week 96 was similar (EVG/COBI/FTC/TDF: 98.0% vs EFV/FTC/TDF: 98.1%). Most patients had an adherence rate of at least 95% up to the week 96 visit (EVG/COBI/FTC/TDF: 74.0% vs EFV/FTC/TDF: 75.4%).
The noninferior efficacy of EVG/COBI/FTC/TDF to EFV/FTC/TDF at week 48 was confirmed (margin: 12%) using the week 96 data set (88% vs 84%, difference +3.6%, 95% CI: −1.6% to 8.8%). High rates of virologic success in both groups were maintained at week 96 as follows: 84.2% (293/348) vs 81.5% (287/352), difference: +2.7% (95% CI: −2.9% to 8.3%) (Fig. 1). Results of virologic outcome using other efficacy endpoints at week 96 were similar as follows: Snapshot (per protocol), EVG/COBI/FTC/TDF: 96.9% vs EFV/FTC/TDF: 96.3% (difference: +0.7%, 95% CI: −2.4% to 3.7%); time to loss of virologic response (intent-to-treat), 79.3 vs 77.3% (difference: +2.1%, 95% CI: −4.0% to 8.2%); missing = failure (intent-to-treat), 86.2% vs 83.2% (difference: +3.0%, 95% CI: −2.4% to 8.3%). CD4 cell counts per cubic millimeter continued to increase comparably in both groups between week 48 and 96: week 48, EVG/COBI/FTC/TDF +239 vs EFV/FTC/TDF +206 (P = 0.009); week 96, +295 vs +273 (P = 0.19).
The efficacy of EVG/COBI/FTC/TDF relative to EFV/FTC/TDF was consistent across prespecified subgroups. In patients with baseline HIV-1 RNA ≤100,000 copies per milliliter and >100,000 copies per milliliter, virologic success were EVG/COBI/FTC/TDF 85.7% vs EFV/FTC/TDF 80.9% (difference:+ 4.7%, 95% CI: −2.0% to 11.5%) and 81.4% vs 82.8% (difference: −1.4%, 95% CI: −11.2% to 8.4%). In patients with CD4 cell count ≤350 cells per cubic millimeter and >350 cells per cubic millimeter, virologic success were EVG/COBI/FTC/TDF 80.0% vs EFV/FTC/TDF 80.3% (difference: −0.3%, 95% CI: −9.4% to 8.8%) and 87.6% vs 82.4% (difference: +5.1%, 95% CI: −2.0% to 12.2%). In patients with adherence <95% and ≥95%, virologic success were EVG/COBI/FTC/TDF 74.4% vs EFV/FTC/TDF 62.8% (difference: 11.1%, 95% CI: −2.5% to 24.8%) and 88.3% vs 88.6% (difference: −0.3%, 95% CI: −5.9% to 5.3%).
Development of resistance to 1 or more components of the regimens was infrequent through week 96. Forty patients met virologic criteria for resistance testing [EVG/COBI/FTC/TDF 17 (4.9%) vs EFV/FTC/TDF 23 (6.5%)]. Ten of 17 EVG/COBI/FTC/TDF patients had emergent resistance mutations. Nine of the 10 patients had integrase resistance mutations (primarily E92Q). All 10 patients had NRTI resistance mutations (6 with M184V/I alone, and 4 with M184V/I and K65R). Ten of 23 EFV/FTC/TDF patients had emergent resistance mutations; the most common resistance mutation was K103N mutation (9 patients) with or without the combination of M184V/I and K65R (3 patients). Only 2 patients in each group developed resistance mutations after the first 48 weeks and no new resistance patterns or unique mutations emerged between weeks 48 and 96.
The overall safety findings were consistent with those observed at week 48. No patients died after week 48. The number of patients who discontinued study drug due to AE through week 96 was similar [EVG/COBI/FTC/TDF 17 (4.9%) vs EFV/FTC/TDF 24 (6.8%)]; 4 (intentional overdose/suicidal behavior, abnormal GFR, Burkitt lymphoma, and renal failure) and 6 (intracardiac mass, abnormal feeling, fatigue, hepatitis C, depression, and insomnia) additional patients from each group discontinued study drug due to AEs after week 48.
Two patients (<1%) discontinued EVG/COBI/FTC/TDF due to renal events after week 48. Neither patients had laboratory findings of proximal tubulopathy, such as hypophosphatemia, normoglycemic glycosuria, or proteinuria; both patients had elevation in serum creatinine consistent with inhibition of tubular creatinine secretion by COBI. The median changes (interquartile range) (mg/dL) in serum creatinine at week 96 in both groups [EVG/COBI/FTC/TDF 0.13 (0.05 to 0.22) vs EFV/FTC/TDF 0.01 (−0.07 to 0.09)] were similar to those observed at week 48 [0.14 (0.06 to 0.22) vs 0.01 (−0.06 to 0.09)]. The corresponding changes (mL/min) in eGFR at week 96 were EVG/COBI/FTC/TDF −13.8 (−22.8 to −3.7) vs EFV/FTC/TDF −0.8 (−11.4 to 9.3).
The most frequent AEs at weeks 48 and 96 are shown in Table 1. There were only minimal increases in the frequency of most AEs in both groups since week 48. Nausea was more frequent in the EVG/COBI/FTC/TDF (21.8% vs 15.1%) consistent with the finding at week 48; however, only a few patients from each group reported new nausea since week 48 [4 (1.1%) vs 5 (1.4%)], none of whom discontinued study drug due to nausea. The most frequent AEs leading to study drug discontinuation are also shown in Table 1.
The rates of prespecified neuropsychiatric events continued to be lower in EVG/COBI/FTC/TDF group (46.6% vs 65.9%, P < 0.001); only small numbers of additional patients (13 vs 12) in each group reported these AEs after week 48. Study drug discontinuation due to these events occurred in EVG/COBI/FTC/TDF: 0.9% vs EFV/FTC/TDF: 2.8%. Prespecified rash events also occurred less frequently in EVG/COBI/FTC/TDF group (21.3% vs 30.7%, P = 0.006); study drug discontinuation due to these events occurred in 0% vs 1.1%. Prespecified bone fracture events did not differ between the 2 groups (EVG/COBI/FTC/TDF 2.9% vs EFV/FTC/TDF 2.3%, P = 0.64); a small number of patients in each group had bone fractures after week 48 (4 vs 2).
In this randomized controlled trial, EVG/COBI/FTC/TDF demonstrated noninferior efficacy to EFV/FTC/TDF at week 48 and continued to achieve high rates of virologic suppression at week 96.
The response rates in our study are consistent with a previous study of integrase inhibitor in treatment-naïve patients, which compared raltegravir vs EFV in combination with FTC/TDF (81% vs 79% with HIV-1 RNA <50 copies per milliliter (noncompleter = failure) at week 96.5
For both groups, the emergence of drug resistance was very infrequent during the second 48 weeks (2 patients in each group). The patterns of resistance mutations in both groups were similar to those reported in the first 48 weeks. The integrase and reverse transcriptase resistance results in our study are comparable to results of other trials in treatment-naive patients.5,6
It was reassuring that no new or unexpected safety concerns emerged between weeks 48 and 96. Both regimens were well tolerated with infrequent study drug discontinuation due to AEs. EVG/COBI/FTC/TDF demonstrated an improved safety profile compared to EFV/FTC/TDF with regard to neuropsychiatric and rash events, which are associated with EFV. Although nausea occurred more frequently in EVG/COBI/FTC/TDF group, it rarely led to study drug discontinuation and mostly occurred in the first month; only a few patients had new nausea events after week 48 (5 vs 3).
No new renal safety findings were observed at week 96. Since week 48, 2 patients discontinued EVG/COBI/FTC/TDF due to renal events and neither had proximal tubulopathy. The rate of renal discontinuation in EVG/COBI/FTC/TDF group through week 96 (2.0%) is consistent with previous studies of regimens that contain TDF with ritonavir-boosted protease inhibitors, ranging from 0% to 2.8%.7–16 In the parallel independent study (study 103) comparing EVG/COBI/FTC/TDF vs ritonavir-boosted atazanavir (ATV/r) plus FTC/TDF, the rates of renal discontinuation through week 48 (EVG/COBI/FTC/TDF 0.3% vs ATV/r + FTC/TDF 0.3%) and week 96 (0.8% vs 0.6%) were lower than those in the current study.17,18 Changes in serum creatinine and eGFR through week 96 occurred early within few weeks, after which they stabilized with little change between weeks 48 and 96. This further supports that the increase in serum creatinine seen with the use of EVG/COBI/FTC/TDF is the effect of COBI on renal tubular creatinine secretion.19
In our study, renal safety was monitored using routine laboratory tests. All 4 patients who discontinued due to proximal tubulopathy had confirmed serum creatinine increase >0.4 mg/dL along with abnormalities consistent with proximal tubulopathy (i.e., hypophosphatemia, normoglycemic glycosuria, or proteinuria). This led to the US prescribing information of EVG/COBI/FTC/TDF (Stribild) that recommends assessing creatinine clearance, urine glucose, and urine protein before initiating EVG/COBI/FTC/TDF in all patients with close monitoring in those with a confirmed serum creatinine increase >0.4 mg/dL.20
EVG/COBI/FTC/TDF demonstrated durable efficacy through week 96 with a safety profile that is differentiated from EFV/FTC/TDF and is consistent with the week 48 report.3 These results, along with those of study 103,18 support the use of EVG/COBI/FTC/TDF as an important treatment option for treatment-naive HIV-1–infected patients.
The authors acknowledge the patients who participated in this study and the site and study management staff whose efforts made this work possible. All investigators and sites who participated in the study have been previously published.
1. US Department of Health and Human Services. Panel on antiretroviral guidelines for adults and adolescents recommends a fixed-dose combination product of elvitegravir/cobicistat/tenofovir/emtricitabine as an alternative regimen in antiretroviral treatment-naive individuals with HIV-1 infection. Available at: http://www.aidsinfo.nih.gov/contentfiles/AdultARVStatementOnEVG_COBI_TDF_FTC.pdf
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13. Smith KY, Weinberg WG, Dejesus E, et al.. Fosamprenavir or atazanavir once daily boosted with ritonavir 100 mg, plus tenofovir/emtricitabine, for the initial treatment of HIV infection: 48-week results of ALERT. AIDS Res Ther. 2008;5:5.
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15. Elion R, Cohen C, Ward D, et al.. Evaluation of efficacy, safety, pharmacokinetics, and adherence in HIV-1-infected, antiretroviral-naive patients treated with ritonavir-boosted atazanavir plus fixed-dose tenofovir DF/emtricitabine given once daily. HIV Clin Trials. 2008;9:213–224.
16. McGrath D, Zhu L, Thiry A, et al.. Renal function in treatment-naïve subjects exposed to tenofovir/emtricitabine in combination with atazanavir/ritonavir or lopinavir/ritonavir: 48-week results from the CASTLE study (BMS AI424138)[THPE0190]. Presented at: 17th International AIDS Conference; August 3-8, 2008; Mexico City, Mexico.
17. DeJesus E, Rockstroh JK, Henry K, et al.. Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate versus ritonavir-boosted atazanavir plus co-formulated emtricitabine and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet. 2012;379:2429–2438.
18. Rockstroh JK, DeJesus E, Henry K, et al.. Elvitegravir/cobicistat/emtricitabine/tenofovir DF (Quad) has durable efficacy and differentiated safety compared to atazanavir boosted by ritonavir plus emtricitabine/tenofovir DF at week 96 in treatment-naïve HIV-1 infected patients. Presented at: 11th International Congress on Drug Therapy in HIV Infection; November 11-15, 2012; Glasgow, United Kingdom.
19. German P, Liu HC, Szwarcberg J, et al.. Effect of cobicistat on glomerular filtration rate in subjects with normal and impaired renal function. J Acquir Immune Defic Syndr. 2012;61:32–40.
20. Gilead Sciences. Stribild (elvitegravir, cobicistat, emtricitabine, tenofovir disoproxil fumarate) US prescribing information. Available at: http://www.gilead.com/pdf/stribild_pi.pdf
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