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JAIDS Journal of Acquired Immune Deficiency Syndromes:
doi: 10.1097/QAI.0000000000000057
Letters to the Editor

A Randomized, Double-Blind Comparison of Single-Tablet Regimen Elvitegravir/Cobicistat/Emtricitabine/Tenofovir DF Versus Single-Tablet Regimen Efavirenz/Emtricitabine/Tenofovir DF for Initial Treatment of HIV-1 Infection: Analysis of Week 144 Results

Wohl, David A. MD*; Cohen, Calvin MD, MSc; Gallant, Joel E. MD, MPH; Mills, Anthony MD§; Sax, Paul E. MD; DeJesus, Edwin MD; Zolopa, Andrew MD#; 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**

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*Division of Infectious Diseases, University of North Carolina, Chapel Hill, NC

Community Research Initiative of New England, Boston, MA

Southwest Care Center, Santa Fe, NM

§Anthony Mills MD Inc, Los Angeles, CA

Division of Infectious Diseases, Brigham and Women's Hospital, Harvard Medical School, Boston, MA

Orlando Immunology Center, Orlando, FL

#Division of Infectious Diseases and Geographic Medicine, Stanford University, Palo Alto, CA

**Gilead Sciences, Foster City, CA

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site (www.jaids.com).

Presented at the Interscience Conference on Antimicrobial Agents and Chemotherapy, September 10–13, 2013, Denver, CO and at the 14th European AIDS Conference, October 16–19, 2013, Brussels, Belgium.

D.A.W., C.C., J.E.G., A.M., P.E.S., E.D.J., and A.Z. are all principal investigators. H.C.L., A.P., K.L.W., A.K.C., M.S.R., and J.S. 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 article.

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.

D.A.W. has received research support from Gilead Sciences and Merck and consulting fees from Gilead Sciences and Janssen Therapeutics. C.C. has received research support from Bristol-Myers Squibb, Gilead Sciences, Janssen Therapeutics, and Merck, and consulting fees from Bristol-Myers Squibb, Gilead Sciences, Janssen Therapeutics, Merck, and Tobira. J.E.G. has received research support from Gilead Sciences, and consulting fees from Bristol-Myers Squibb, Gilead Sciences, Janssen Therapeutics, and Merck. P.E.S. has received research support from Bristol-Myers Squibb, Gilead Sciences, and GlaxoSmithKline, and consulting fees from AbbVie Laboratories, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Janssen Therapeutics, and Merck. A.M. has received research support from Boehringer Ingelheim, Gilead Sciences, GlaxoSmithKline, Janssen Therapeutics, Kowa, Merck, Pfizer, Tobira, and ViiV, and consulting fees from Bristol-Myers Squibb, Gilead Sciences, Janssen Therapeutics, and Merck. E.D.J. has received research support from Achillion, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Hoffman LaRoche Laboratories, Idenix, Janssen Therapeutics, Merck, Novelos, Pfizer, Sangamo, Serono, Taimed, Tobira, Vertex; and consulting fees from Bristol-Myers Squibb, Gilead Sciences, Janssen, and Vertex. A.Z. has received research support from Gilead Sciences, and consulting fees from Bristol-Myers Squibb, Janssen Therapeutics, and Gilead Sciences.

To the Editors:

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INTRODUCTION

The first integrase inhibitor-based single-tablet regimen combines elvitegravir (an integrase inhibitor), cobicistat (a pharmacoenhancer), emtricitabine (FTC), and tenofovir DF (TDF) (EVG/COBI/FTC/TDF). In 2 phase 3 randomized trials, EVG/COBI/FTC/TDF demonstrated noninferior efficacy at week 48 to efavirenz (EFV)/FTC/TDF (study 102) and to ritonavir-boosted atazanavir ATV + RTV + FTC/TDF (study 103) with durable efficacy through week 96.1–4 We present week 144 data from study 102.

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METHODS

A full description of the methods has been published.1 A brief description is provided below.

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Study Design and Patients

This study was conducted in North America and was approved by Institutional Review Boards at all sites. Participants were HIV-1–infected treatment-naive adults aged ≥18 years with HIV-1 RNA of ≥5000 copies per milliliter. An estimated glomerular filtration rate of ≥70 mL/min and susceptibility of the virus to EFV, FTC, and TDF by genotype were required. Eligible patients were randomized (1:1) to receive either EVG/COBI/FTC/TDF (150/150/200/300 mg) or EFV/FTC/TDF (600/200/300 mg) once daily with matching placebo tablets.

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Procedures

After week 48, study visits occurred every 12 weeks until week 144. Prespecified adverse events (AEs) were rash and neuropsychiatric events. In patients taking study drugs who had confirmed virological failure (had <1 log10 reduction from baseline and ≥50 copies/mL in HIV-1 RNA by week 8, at any visit a virological rebound of >1 log10 HIV-1 RNA from the nadir or HIV-1 RNA ≥400 copies/mL after achieving <50 copies/mL) or had HIV-1 RNA of ≥400 copies per milliliter at week 48, 96, 144, or last visit, genotyping and phenotyping assays were performed on the confirmatory sample (Monogram Biosciences, South San Francisco, CA). Study drug could be continued at the investigator's discretion, if no resistance was detected. Adherence was assessed by pill count at every visit except week 2 visit.

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Statistical Analysis

The primary end point was the proportion in the intention-to-treat population with HIV-1 RNA of <50 copies per milliliter at week 48 with a prespecified noninferiority margin of 12% per FDA-defined snapshot analysis.1 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 on subgroups. Other end points were HIV-1 RNA of <50 copies per milliliter when treating missing as failure, and change in CD4 cell count from baseline. This study is registered with ClinicalTrials.gov, number NCT01095796.

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RESULTS

Of 917 screened patients, 707 were randomized, and 700 treated (EVG/COBI/FTC/TDF 348 vs EFV/FTC/TDF 352). Baseline characteristics, efficacy, and safety through week 48 and 96 have been reported previously.1,2 The rate of study drug discontinuation through week 144 was lower in the EVG/COBI/FTC/TDF than in the EFV/FTC/TDF group [64 (18.4%) vs 81 (23.0%)]. After week 96, 11 EVG/COBI/FTC/TDF versus 20 EFV/FTC/TDF patients discontinued study drug; reasons included death (1 vs 0), lack of efficacy (2 vs 2), AEs (4 vs 2), and others (loss to follow-up, withdrawal of consent, and noncompliance) (4 vs 16).

Virological success was maintained in both groups at high rates through week 144: 80.2% (279/348) versus 75.3% (265/352), difference +4.9% (95% CI: −1.3% to 11.1%) (see Figure S1, SDC, http://links.lww.com/QAI/A484, which illustrates the efficacy results at week 48, 96, and 144). Results using missing = failure (intention to treat) at week 144 were similar: 82.2% versus 78.1% (difference: +4.1%, 95% CI: −1.9% to 10.0%). CD4 cell counts (per cubic millimeter) continued to increase from baseline (EVG/COBI/FTC/TDF + 321 versus EFV/FTC/TDF + 300).

In patients with baseline HIV-1 RNA of less than or equal to and greater than 100,000 copies per milliliter, virological success in the EVG/COBI/FTC/TDF and EFV/FTC/TDF groups was 81.7% versus 74.2% (difference: +7.6%, 95% CI: 0.1% to 15.1%) and 77.1% versus 77.6% (difference: −0.5%, 95% CI: −11.2% to 10.3%), respectively. In patients with baseline CD4 cell counts of less than or equal to and greater than 350 cells per cubic millimeter, virological success was 75.5% in the EVG/COBI/FTC/TDF group versus 76.2% in the EFV/FTC/TDF group (difference: −0.8%, 95% CI: −10.5% to 9.0%) and 83.9% versus 74.6% (difference: +9.2%, 95% CI: 1.3% to 17.2%), respectively. In addition, the efficacy of EVG/COBI/FTC/TDF relative to EFV/FTC/TDF was consistent across prespecified subgroups of age, sex, race, and adherence (see Figure S2, SDC, http://links.lww.com/QAI/A484, which illustrates the efficacy results by subgroup).

Development of resistance to one or more components of the regimens was infrequent. Through week 144, 49 patients met criteria for resistance testing (21 EVG/COBI/FTC/TDF vs 28 EFV/FTC/TDF). Overall, resistance mutations emerged in 10 of 21 patients in the EVG/COBI/FTC/TDF group; 9 patients in the integrase gene (primarily E92Q) and all 10 patients in reverse transcriptase (6 with M184V/I, and 4 with M184V/I and K65R). In the EVG/COBI/FTC/TDF group, no patient developed resistance after week 96. In the EFV/FTC/TDF group, resistance mutations in reverse transcriptase emerged in 14 of 28 patients; the most common resistance mutation was K103N (n = 13) with M184V/I (n = 1) or with M184V/I and K65R (n = 3).

The overall safety findings in both groups were consistent with those through week 96. One EVG/COBI/FTC/TDF patient died after week 96 due to upper gastrointestinal bleeding not considered by the site investigator to be related to study drug. Rates of study drug discontinuation due to AEs were similar [EVG/COBI/FTC/TDF 21 (6.0%) vs EFV/FTC/TDF 26 (7.4%)]. No patient discontinued study drug due to proximal renal tubulopathy (PRT) after week 48. One patient discontinued EVG/COBI/FTC/TDF after week 96 due to an isolated increase in serum creatinine (grade 1), which was present since week 32, without PRT; serum creatinine improved after study drug discontinuation. The rates of prespecified neuropsychiatric events continued to be lower in the EVG/COBI/FTC/TDF group (50.9% vs 67.9%, P < 0.001). Prespecified rash events also occurred less frequently in EVG/COBI/FTC/TDF group (24.7% vs 31.8%, P = 0.044). The common AEs and those leading to study drug discontinuation through weeks 96 and 144 are shown in Table 1.

Table 1
Table 1
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The median changes (interquartile range) (mg/dL) from baseline in serum creatinine at week 144 in both groups [EVG/COBI/FTC/TDF +0.14 (0.05–0.24) vs EFV/FTC/TDF +0.01 (−0.07 to 0.09)] were similar to those observed at week 48. In the EVG/COBI/FTC/TDF group, median increases (mg/dL) in total (16 vs 20, P = 0.007), low-density lipoprotein (12 vs 18, P = 0.007), and high-density lipoprotein cholesterol at week 144 were smaller (6 vs 9, P = 0.021) than those in the EFV/FTC/TDF group, and increases in triglycerides were similar to those in the EFV/FTC/TDF group (2 vs 2); changes in total cholesterol to HDL ratio were similar (−0.3 vs −0.3).

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DISCUSSION

In this randomized trial, EVG/COBI/FTC/TDF demonstrated noninferior efficacy to EFV/FTC/TDF at the primary end point of week 48 and at the longer-term secondary end point of week 144. Among patients with high baseline viral load (>100,000 copies/mL) and in those with low CD4 (<350 cells/mm3), the response rates in the EVG/COBI/FTC/TDF group were high and similar to those in the EFV/FTC/TDF group. The emergence of drug resistance was infrequent and decreased over time during the study; no patient in the EVG/COBI/FTC/TDF group versus 4 patients in the EFVFTC/TDF group developed resistance after week 96.

While cross-study comparisons should be undertaken cautiously, the 144-week response rates observed with EVG/COBI/FTC/TDF (80.2%) in this study were similar to or somewhat higher than those in previous studies of integrase inhibitor–containing regimens in treatment-naive patients. For example, the 156-week response rates (HIV-1 RNA <50 copies/mL by noncompleter = failure) in the STARTMRK study, which compared raltegravir versus EFV in combination with FTC/TDF, were 75% versus 68%.5 More recently, in the SPRING-2 study, which compared dolutegravir versus raltegravir in combination with 2 NRTIs (either abacavir/lamivudine or FTC/TDF), 96-week response rates (HIV-1 RNA <50 copies per milliliter by snapshot) were 81% versus 76%.6

No new safety concerns emerged after week 96. Both regimens were well tolerated. No new renal safety findings were observed after week 96. No patient in the EVG/COBI/FTC/TDF group had PRT after the 48-week report, which had described 4 cases of PRT; all had onset in the first 24 weeks. One patient had a persistent grade 1 elevated serum creatinine without PRT, which led to discontinuation of EVG/COBI/FTC/TDF after week 96. In the parallel study (study 103) comparing EVG/COBI/FTC/TDF versus ATV + RTV + FTC/TDF, no case of PRT was reported in the EVG/COBI/FTC/TDF group through week 144, whereas 3 patients in the ATV + RTV + FTC/TDF group had PRT leading to study drug discontinuation after week 96.7 In the current study (study 102), the changes in serum creatinine at week 144 were similar to those observed at week 48,3 which further suggests that the initial increase in serum creatinine observed using EVG/COBI/FTC/TDF is the result of an inhibitory effect of COBI on renal tubular creatinine secretion.8 A similar effect on serum creatinine has been observed with dolutegravir and other commonly used antiretroviral agents (eg, ritonavir and rilpivirine).9–11

In summary, these results demonstrate durable efficacy of EVG/COBI/FTC/TDF along with no new renal safety signal and a longer-term safety profile that is differentiated from EFV/FTC/TDF. These findings, along with those of study 103, support the use of the EVG/COBI/FTC/TDF single-tablet regimen as an important first-line treatment option for HIV-1–infected patients.

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ACKNOWLEDGMENTS

The authors acknowledge the patients who participated in this study, as well as 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.

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REFERENCES

1. Sax PE, DeJesus E, Mills A, et al.. Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus co-formulated efavirenz, emtricitabine, and tenofovir for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3 trial, analysis of results after 48 weeks. Lancet. 2012;379:2439–2448.

2. Zolopa A, Sax PE, DeJesus E, et al.. 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. J Acquir Immune Defic Syndr. 2013;63:96–100.

3. 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.

4. Rockstroh JK, DeJesus E, Henry K, et al.. A randomized, double-blind comparison of coformulated elvitegravir/cobicistat/emtricitabine/tenofovir DF vs ritonavir-boosted atazanavir plus coformulated emtricitabine and tenofovir DF for initial treatment of HIV-1 infection: analysis of week 96 results. J Acquir Immune Defic Syndr. 2013;62:483–486.

5. Rockstroh JK, Lennox JL, Dejesus E, et al.. Long-term treatment with raltegravir or efavirenz combined with tenofovir/emtricitabine for treatment-naive human immunodeficiency virus-1-infected patients: 156-week results from STARTMRK. Clin Infect Dis. 2011;53:807–816.

6. Raffi F, Jaeger H, Motta D, et al.. Dolutegravir is non-inferior to raltegravir and shows durable response through 96 weeks: results from the SPRING-2 trial [Abstract TULBPE17]. Paper presented at: 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention; June 30–July 3, 2013; Kuala Lumpur, Malaysia.

7. Cooper D, Zolopa A, Rockstroh J, et al.. Subgroup analyses of 96-week efficacy and safety of elvitegravir/cobicistat/emtricitabine/tenofovir DF [Abstract TUPE281]. Paper presented at: 7th IAS Conference on HIV Pathogenesis, Treatment and Prevention; June 30–July 3, 2013; Kuala Lumpur, Malaysia.

8. 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.

9. Koteff J, Borland J, Chen S, et al.. A phase 1 study to evaluate the effect of dolutegravir on renal function via measurement of iohexol and para-aminohippurate clearance in healthy subjects. Br J Clin Pharmacol. 2013;75:990–996.

10. Janssen Therapeutics. Edurant (rilpivirine) US prescribing information. Available at: http://www.edurant.com/sites/default/files/EDURANT-PI.pdf. Accessed August 1, 2013.

11. Lepist EI, Murray B, Tong L, et al.. Effect of cobicistat and ritonavir on proximal renal tubular cell uptake and efflux transporters [abstract A1-1724]. Paper presented at: 51st Interscience Conference on Antimicrobial Agents and Chemotherapy; September 17–20, 2011; Chicago, IL.

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