Abstract: This ongoing, randomized, double-blind, active-controlled phase 3 international trial demonstrated the noninferior efficacy of elvitegravir/cobicistat/emtricitabine/tenofovir DF (EVG/COBI/FTC/TDF) compared with atazanavir boosted by ritonavir (ATV/RTV) plus emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) at 48 weeks. Here, we report the week 96 results. Of 708 treated subjects, virological success (Food and Drug Administration snapshot) was maintained at week 96 with EVG/COBI/FTC/TDF and ATV/RTV + FTC/TDF (83% vs 82%, difference 1.1%, 95% confidence interval −4.5% to 6.7%). Study drug discontinuations due to adverse events were low (4% vs 6%). Median increases from baseline in serum Cr (mg/dL) in EVG/COBI/FTC/TDF vs ATV/RTV + FTC/TDF at week 96 (0.12 vs 0.08) were similar to those at week 48 (0.12 vs 0.08). EVG/COBI/FTC/TDF showed similar mean decreases (%) in bone mineral density from baseline vs ATV/RTV + FTC/TDF (hip: −3.16 vs −4.19, P = 0.069; spine: −1.96 vs −3.54, P = 0.049). Overall, week 96 results support durable efficacy and safety of EVG/COBI/FTC/TDF in HIV-1–infected patients.
*Department of Medicine I, University of Bonn, Bonn, Germany;
†Orlando Immunology Center, Orlando, FL;
‡Department of Infectious Diseases, Hennepin County Medical Center, Minneapolis, MN;
§Department of Infectious Diseases, Hopital Saint-Louis, AP-HP and University of Paris Sorbonne Cité, INSERM U941, Paris, France;
‖Therapeutic Concepts, Houston, TX;
¶Gilead Sciences, Foster City, CA.
Correspondence to: Jürgen K. Rockstroh, MD, Department of Medicine I, University of Bonn, Sigmund-Freud-Str. 25, Bonn 53127, Germany (e-mail: email@example.com).
Supported by Gilead Sciences.
Portions of this study were presented at the 11th International Congress on Drug Therapy in HIV Infection, November 11–15, 2012, Glasgow, United Kingdom.
J.K.R. has received lecture fees and advisory board honoraria from Abbott, Bristol-Myers Squibb, Gilead Sciences, Boehringer Ingelheim, GlaxoSmithKline, ViiV, Tibotec, Janssen, Merck and Pfizer. E.DJ. has received research grant support from Abbott Laboratories, Achillion Pharmaceuticals, Avexa, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Hoffmann 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. K.H. has received research grant support from Gilead Sciences, GlaxoSmithKline, US Centers for Disease Control, and the US National Institutes of Health; consulting fees as an advisory board member for Gilead Sciences. J-M.M. has acted as a consultant, participated in advisory boards, has received speaker fees, and has been an investigator for clinical trials for Abbott, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Merck, Tibotec, and ViiV Healthcare. J.G. has received research grant support from Abbott Laboratories, Boehringer Ingelheim, Gilead Sciences, GlaxoSmithKline, Janssen, and receives consulting fees from Abbott Laboratories and Boehringer Ingelheim. S.R., X.W., A.P., M.A., A.K.C., M.W.F., and J.S. are employees of Gilead Sciences.
Received October 24, 2012
Accepted January 04, 2013
A new single-tablet regimen that combines elvitegravir, cobicistat, emtricitabine, and tenofovir DF (EVG/COBI/FTC/TDF) is the first once-daily regimen that combines an integrase strand transfer inhibitor with the preferred backbone of FTC and TDF. At 48 weeks, this formulation demonstrated potent antiretroviral efficacy and favorable safety and tolerability in 2 phase 3 studies, GS-US-236-0102 and GS-US-236-0103, when administered to HIV-1–infected antiretroviral treatment-naive adults, supporting regulatory approval of EVG/COBI/FTC/TDF in the United States and Canada1,2and has been recommended by DHHS as an alternative regimen for treatment-naive patients.3 In GS-US-236-0103, the EVG/COBI/FTC/TDF group had statistically lower increases in fasting triglycerides and a lower percentage of subjects experienced alanine aminotransferase, aspartate aminotransferase, or bilirubin elevations, compared with the ATV/RTV + FTC/TDF group. Increases in serum creatinine were seen in both groups, with a median change from baseline at week 48 of 0.12 mg/dL in the EVG/COBI/FTC/TDF compared with 0.08 mg/dL in the ATV/RTV + FTC/TDF group, reflecting a known effect of cobicistat and ritonavir on serum creatinine secretion.4 Here, we present the week 96 efficacy and safety results of study GS-US-236-0103.
A full description of the study design and methods has been published previously.2 Briefly, GS-US-236-0103 is an ongoing phase 3 study being conducted in Australia, Europe, North America, and Thailand in accordance with the Declaration of Helsinki and was reviewed and approved by central or site-specific review boards or ethics committees. Participants are adults infected with HIV-1 with no previous use of antiretroviral drugs, an estimated glomerular filtration rate ≥ 70 mL/min, and susceptibility to atazanavir, emtricitabine, and tenofovir DF at screening. Positive hepatitis B surface antigen or hepatitis C antibody was allowed.
Eligible patients were randomized in a 1:1 ratio, stratified by HIV-1 RNA (≤100,000 or >100,000 copies/mL), to receive EVG/COBI/FTC/TDF (150/150/200/300 mg) or ATV/RTV (300/100 mg) plus FTC/TDF (200/300 mg), once daily orally with food. Patients also received placebo matching the alternative treatment, totaling 4 pills once per day per subject. After week 48, study visits occurred every 12 weeks until week 96. The study is scheduled to continue to 192 weeks.
The primary end point was the proportion of patients in the intention-to-treat population with viral suppression (HIV-1 RNA <50 copies/mL) at week 48 according to snapshot analysis as defined by the US Food and Drug Administration. Other end points included treatment differences by subgroup, achievement, and maintenance of HIV-1 RNA <50 copies/mL (based on the Food and Drug Administration –defined TLOVR algorithm), proportion of patients with HIV-1 RNA <50 copies/mL when treating missing as failure and missing as excluded, change in HIV-1 RNA from baseline, and change in CD4 cell count from baseline. Proximal renal tubulopathy (PRT) events were identified through investigator-reported adverse event (AE) and/or renal laboratory parameters (increases serum creatinine, hypophosphatemia, proteinuria, or glycosuria). In a subset of patients, dual-energy x-ray absorptiometry scans of the spine and hip were done at baseline, week 24, 48, and 96 to measure percent changes in bone mineral density.
The primary end point was assessed noninferiority of EVG/COBI/FTC/TDF compared with ATV/RTV + FTC/TDF with 95% confidence interval (CI) and with a prespecified noninferiority margin of 12%. In the snapshot analysis, participants with HIV-1 RNA <50 copies/mL between days 631 and 714 (week 96 window) were classified as successes. Participants with HIV-1 RNA ≥50 copies/mL or with missing HIV-1 RNA data (ie, participants discontinued study drug or participants missed HIV-1 RNA assessment but on study drug) for the week 96 analysis window were classed as failures. The difference, weighted by baseline HIV-1 RNA stratum, for response rate and its 95% CI were calculated on the basis of stratum-adjusted Mantel–Haenszel proportions. This study is registered with ClinicalTrials.gov, number NCT 01106586.
A total of 715 subjects were randomized; 708 of these subjects received at least 1 dose of study drug (353 in the EVG/COBI/FTC/TDF group and 355 in the ATV/RTV + FTC/TDF group). Baseline demographic and disease characteristics have been described elsewhere.2 At 96 weeks, study drug discontinuation rates and reasons for discontinuation were similar between treatment groups: 49/353 (14%) in the EVG/COBI/FTC/TDF group vs 55/355 (15%) in the ATV/RTV + FTC/TDF group.
The noninferior efficacy of EVG/COBI/FTC/TDF to ATV/RTV + FTC/TDF at week 48 was confirmed (margin: 12%) using the week 96 dataset (89.5% vs 87.0%, difference +2.7%, 95% CI −2.1% to 7.5%). High rates of virological success (HIV-1 RNA <50 copies/mL) in both groups were maintained at week 96: EVG/COBI/FTC/TDF 83.3% (294/353) vs ATV/RTV + FTC/TDF 82.3% (292/355), difference 1.1% (95% CI: −4.5% to 6.7%) (Fig. 1). The proportion of subjects with virological failure was similar in both groups at week 48 (5.4% vs 5.1%) and week 96 (6.8% vs 7.3%). Reasons for virological failure and lack of virological data in the week 96 analysis were balanced between the treatment groups. Other efficacy end points showed similar results: TLOVR, 81.3% vs 77.5% (difference: 4.0%, 95% CI: −2.0% to 9.9%), missing = failure, 86.7% vs 85.4% (difference: 1.4%, 95% CI: −3.8% to 6.5%), and per protocol, 97.0% vs 96.3% (difference: 0.8%, 95% CI: −2.2% to 3.8%). The recovery of CD4 cell count persisted through week 96, with mean (SD) increases from baseline of 256 cells/mm3 in the EVG/COBI/FTC/TDF group and 261 cells/mm3 in the ATR/RTV + FTC/TDF group. At week 96 based, the 95% CI contained 0 for all subgroups suggesting no treatment difference according to age, sex, race, baseline HIV-1 RNA level, baseline CD4 cell count, or study drug adherence rate. However, in the subgroup of female subjects (n = 68, 9.6%), the small number contributed to a wide CI. Median adherence to active study drug, as measured by pill count, was similar in the both groups (97.4% vs 97.3%).
Development of resistance to one or more component of the EVG/COBI/FTC/TDF regimen was infrequent. Overall, 6 (1.7%) subjects in the EVG/COBI/FTC/TDF group failed with emergent resistance mutations vs no subjects in the ATV/RTV + FTC/TDF group. Of the 6 subjects with resistance to EVG/COBI/FTC/TDF, 5 occurred during the first 48 weeks and 1 occurred during the second 48 weeks of treatment,2 which failed with M184V but no integrase resistance.
The overall safety findings at 96 weeks were generally consistent with those observed at week 48. Through week 96, 36 subjects discontinued study drug due to an AE [15 subjects (4.2%) in EVG/COBI/FTC/TDF; 21 subjects (5.9%) in ATV/RTV + FTC/TDF]; 2 and 3 additional subjects from each group, respectively, discontinued study drug due to AE since week 48. Rates of study drug discontinuation due to renal events remained low and similar through week 96 [3 (0.8%) vs 2 (0.6%)], including 1 subject in each group since week 48. Neither subject had evidence of PRT. Through 96 weeks, fractures occurred in 4 EVG/COBI/FTC/TDF subjects (1.1%) vs 14 ATV/RTV + FTC/TDF subjects (3.9%), P = 0.029; since week 48, 1 additional subject in the EVG/COBI/FTC/TDF group and 8 additional subjects in the ATV/RTV + FTC/TDF group developed fracture. The majority of fractures was due to traumatic injury, with nontraumatic fractures reported in 3 subjects, all in the ATV/RTV + FTC/TDF arm.
Serious AEs were reported for a slightly lower percentage of subjects in the EVG/COBI/FTC/TDF group than in the ATV/RTV + FTC/TDF group (EVG/COBI/FTC/TDF = 9.6%, 34 subjects; ATV/RTV + FTC/TDF = 14.1%, 50 subjects). Frequent AEs reported at week 48 and week 96 are presented in Table 1. There were small increases in the rates of most AEs in both groups since week 48. Differences of >5% included ocular icterus, reported in 51 ATV/RTV + FTC/TDF patients (14.4%) vs 2 EVG/COBI/FTC/TDF patients (0.6%); diarrhea, reported in 111 ATV/RTV + FTC/TDF patients (31.3%) vs 88 EVG/COBI/FTC/TDF patients (24.9%); and back pain, reported in 41 EVG/COBI/FTC/TDF patients (11.6%) vs 19 ATV/RTV + FTC/TDF patients (5.4%).
A difference in fasting metabolic assessments was observed between treatment groups at 96 weeks. Median change from baseline fasting total cholesterol was higher in the EVG/COBI/FTC/TDF group vs the ATV/RTV + FTC/TDF group: at week 48, 10 [interquartile range (IQR), 26 to 29] mg/dL vs 8 (IQR, −12 to 30) mg/dL (P = 0.30), and at week 96, 14 (IQR, −3 to 31) mg/dL vs 8 (IQR, −12 to 30) mg/dL (P = 0.046). A greater median change from baseline fasting triglycerides was observed in the ATV/RTV + FTC/TDF group: at week 48, 8 (IQR, −20 to 37) mg/dL vs 23 (IQR, −11 to 59) mg/dL (P = 0.006), and at week 96, 5 (IQR, −22 to 37) mg/dL vs 16 (IQR, −13 to 52) mg/dL (P = 0.012). There were no significant changes from baseline through week 96 in median values for fasting low-density lipoprotein cholesterol, fasting high-density lipoprotein cholesterol, or fasting total cholesterol to fasting high-density lipoprotein cholesterol ratio in either treatment group.
Renal laboratory assessments showed changes consistent with COBI's expected effect on estimated glomerular filtration rate, which were seen as early as week 2–4, and appears to stabilize after week 24 through week 96. Median increases from baseline in serum Cr [mg/dL (IQR)] in EVG/COBI/FTC/TDF vs ATV/RTV + FTC/TDF at week 96 [0.12 (0.04–0.19) vs 0.08 (0.00–0.16) mg/dL] (P ≤ 0.001) were similar to those at week 48 [0.12 (0.06–0.21) vs 0.08 (0.01–0.17) mg/dL] (P ≤ 0.001).
At week 96, the mean percentage decrease from baseline in spine bone mineral density (BMD) was −1.96% in the EVG/COBI/FTC/TDF group and −3.54% in the ATV/RTV + FTC/TDF group (P = 0.049), and the mean percentage decrease from baseline in hip BMD was −3.16% in the EVG/COBI/FTC/TDF group and −4.19% in the ATV/RTV + FTC/TDF group (P = 0.069).
In this international randomized controlled trial, EVG/COBI/FTC/TDF administered once daily in HIV-1–infected, antiretroviral treatment-naive subjects demonstrated high rates of viral suppression through 96 weeks. This finding was robust, using multiple efficacy analyses and was consistent across subgroups. We previously reported that EVG/COBI/FTC/TDF was noninferior to ATV/RTV + FTC/TDF through week 48,2 and now confirm that result in analyses using the week 96 dataset. Immunologic benefit continued in both groups, as evidenced by increases from baseline in CD4 cell counts.
Overall, our study demonstrated high rates of viral suppression compared to published 96 week data with other first-line regimens.5,6 Data in female subjects and subjects with CD4 counts less than 50 cells per milliliter are limited.
The number of patients who received EVG/COBI/FTC/TDF and developed resistance was low (1.7%) and similar to other first-line regimens.6–10 The absence of development of drug resistance in patients with virological failure taking ATV/RTV + FTC/TDF is characteristic of protease-inhibitor-based regimens.11
No new safety concern emerged between week 48 and week 96. Both the EVG/COBI/FTC/TDF and ATV/RTV + FTC/TDF regimens continued to be well tolerated in this study through week 96, as demonstrated by the low percentages of subjects with serious AEs, mostly mild or moderate AEs, and a low percentage of subjects who discontinued study drug due an AE. The renal safety profile of EVG/COBI/FTC/TDF was consistent with that of TDF, with renal events leading to study drug discontinuation occurring infrequently (<1%). No patients developed PRT through 96 weeks. Changes from baseline in serum creatinine were seen as early as week 2 and did not progress from week 48 through week 96, consistent with the inhibitory effect of COBI on renal tubular secretion of creatinine. BMD at week 96 showed similar mean percentage decreases from baseline in the EVG/COBI/FTC/TDF group compared with the ATV/RTV + FTC/TDF group.
At week 96, EVG/COBI/FTC/TDF demonstrated high rates of virological suppression with low rates of resistance and a differentiated tolerability profile relative to ATV/RTV + FTC/TDF. These results support the efficacy, tolerability, and safety of EVG/COBI/FTC/TDF in HIV-1–infected patients through 96 weeks. The study continues blinded, allowing for long-term efficacy and safety assessments.
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. J.R., E.D.J., K.H., J-M.M., and J.G. are all principal investigators and enrolled at least 5 participants in this study. S.R., X.W., A.P., M.A., A.C., M. F., 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 manuscript.
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