*Maladies Infectieuses, Brussels, Belgium
†Service de Maladies Infectieuses et Tropicales, Hospital Saint-Louis, AP-HP and University of Paris Sorbonne Cité, INSERM, Paris, France
‡Department of Infectious Diseases, Hennepin County Medical Center, Minneapolis, MN
§Therapeutic Concepts, Houston, TX
‖Department of Medicine I, University of Bonn, Bonn, Germany
¶Orlando Immunology Center, Orlando, FL
#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 11th International Congress on Drug Therapy in HIV Infection, November 11–15, 2012, Glasgow, United Kingdom.
N.C., J.-M.M., K.H., J.G., J.R., and E.D.J. are all principal investigators and enrolled at least 5 participants in this study. All authors have reviewed the results of this study and manuscript.
N.C. has received lecture fees and advisory board honoraria from Gilead, Merck, Tibotec Janssen, and ViiV Healthcare. 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.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. X.W., K.W., M.F., 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.
K.H. has received research grant support from Gilead Sciences, GlaxoSmithKline, US Centers for Disease Control, and the US National Institutes of Health and consulting fees as an advisory board member for Gilead Sciences. E.D.J. 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. J.G. has received research grant support from Abbott Laboratories, Boehringer Ingelheim, Gilead Sciences, GlaxoSmithKline, and Janssen and receives consulting fees from Abbott Laboratories and Boehringer Ingelheim.
To the Editors:
The first integrase inhibitor–based single-tablet regimen combines elvitegravir, cobicistat, emtricitabine, and tenofovir DF (EVG/COBI/FTC/TDF). In 2 phase 3 studies, EVG/COBI/FTC/TDF has demonstrated durable, noninferior efficacy and favorable safety and tolerability through 96 weeks.1,2 The week 144 efficacy and safety results of study 103 are presented here.
A full description of the study design and methods has been published.3 A brief description is provided below.
This study was conducted in Australia, Europe, North America, and Thailand and was approved by institutional review boards at all sites. Participants were HIV-1–infected, treatment-naive adults ≥18 years with HIV-1 RNA ≥5000 copies per milliliter. An estimated glomerular filtration rate ≥70 mL/min and susceptibility of the virus to atazanavir (ATV), FTC, and TDF by screening genotype were required. Eligible patients were randomized (1:1) to receive EVG/COBI/FTC/TDF (150/150/200/300 mg) or ATV (300 mg) plus RTV (100 mg) plus FTC/TDF (200/300 mg), once daily orally with food with matching placebo.
After week 48, study visits occurred every 12 weeks until week 144. The resistance analysis population consisted of patients taking study drugs who had confirmed virologic failure of <1 log10 reduction from baseline and ≥50 copies per milliliter of HIV-1 RNA by week 8 and confirmed at the next visit, or at any visit, a virologic rebound of >1 log10 HIV-1 RNA from the nadir or confirmed HIV-1 RNA ≥400 copies per milliliter after achieving <50 copies per milliliter or had a single visit with HIV-1 RNA ≥400 copies per milliliter at week 48, 96, or 144 or last visit; protease, reverse transcriptase, and integrase genotyping and phenotyping assays were performed on the second, confirmatory sample if available with PhenoSense GT, PhenoSense Integrase, and GeneSeq Integrase (Monogram Biosciences, San Francisco, CA). Study drug could be continued at the investigator's discretion if no reverse transcriptase or integrase resistance was detected. Adherence was assessed by pill count at every visit except week 2 visit.
The primary end point was the proportion of patients in the intention-to-treat population with HIV-1 RNA <50 copies per milliliter at week 48 with a prespecified noninferiority margin of 12% as per Food and Drug Administration–defined snapshot analysis.3 The difference, weighted by baseline HIV-1 RNA stratum, for response rate and its 95% confidence interval (CI) were calculated based on the stratum-adjusted Mantel–Haenszel proportions. The snapshot analysis was also conducted on subgroups. Other end points were HIV-1 RNA <50 copies per milliliter at week 144 when treating missing as failure 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 normoglycemic glycosuria). In a subset of patients, dual energy x-ray absorptiometry scans of the spine and hip were done at baseline and weeks 24, 48, 96, and 144 to measure percent changes in bone mineral density (BMD). This study is registered with ClinicalTrials.gov, number NCT 01106586.
Of 715 randomized subjects, 708 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 previously.3 At week 144, study drug discontinuation rates and reasons were similar between treatment groups, with 21 of 353 (5.9%) vs 30 of 355 (8.5%) discontinuations because of AEs, 5 of 353 (1.4%) vs 1 of 355 (0.3%) because of lack of efficacy, and 42 of 353 (11.9%) vs 51 of 355 (14.4%) because of other reasons.
High rates of virologic success (HIV-1 RNA <50 copies/mL) in both groups were maintained at week 144: EVG/COBI/FTC/TDF: 77.6% (274/353) vs ATV + RTV + FTC/TDF: 74.6% (265/355) (difference: 3.1%; 95% CI: −3.2% to 9.4%) (see Figure S1, Supplemental Digital Content, http://links.lww.com/QAI/A498, which illustrates the efficacy results at weeks 48, 96, and 144). The proportion of subjects with virologic failure was similar in both groups at week 96 (6.8% vs 7.3%) and week 144 (7.9% vs 7.3%). Results using missing = failure (intention-to-treat) at week 144 were similar: 81.0% vs 78.9% (difference: 2.3%; 95% CI: −3.6% to 8.2%). Mean CD4 cell count (per cubic millimeter) increase from baseline was similar between arms: EVG/COBI/FTC/TDF, 280, vs ATV + RTV + FTC/TDF, 293.
At week 144, the 95% CI for the treatment difference in virologic success in the subgroup analysis contained 0 for all subgroups suggesting no treatment difference according to age, sex, race, baseline HIV-1 RNA level, and baseline CD4 cell count, except for the study drug adherence rate, where subjects with ≥95% adherence had a treatment difference of 6.8% (95% CI: 0.1% to 13.6%), favoring EVG/COBI/FTC/TDF (see Figure S2, Supplemental Digital Content, http://links.lww.com/QAI/A498, which illustrates the subgroup efficacy results at week 144).
Development of resistance to 1 or more components of the EVG/COBI/FTC/TDF regimen was infrequent. Cumulatively, 8 (2.3%) subjects in the EVG/COBI/FTC/TDF group failed with emergent resistance mutations vs 2 (0.6%) subjects in the ATV + RTV + FTC/TDF group through week 144. In the EVG/COBI/FTC/TDF group, emergent resistance through week 144 was comprised of T66I (n = 1), E92Q (n = 2), Q148R (n = 2), N155H (n = 2), and T97A (n = 1) in integrase and M184V/I (n = 7) and K65R (n = 1) in reverse transcriptase. In the ATV + RTV + FTC/TDF group, 2 patients had emergent M184V/I in reverse transcriptase.
The overall safety findings through week 144 were generally consistent with those observed through week 96. Through week 144, 21 subjects (5.9%) discontinued study drug because of an AE in EVG/COBI/FTC/TDF and 30 subjects (8.5%) in ATV + RTV + FTC/TDF. From weeks 96 to 144, 6 and 9 additional subjects from each group, respectively, discontinued study drug because of AE. Rates of study drug discontinuation because of renal events remained low and similar through week 144 [5 (1.4%) vs 8 (2.3%)], including 2 subjects in EVG/COBI/FTC/TDF group and 6 subjects in the ATV + RTV + FTC/TDF group since week 96. There were no cases of PRT among EVG/COBI/FTC/TDF subjects and 3 cases among ATV + RTV + FTC/TDF subjects. Through 144 weeks, fractures occurred in 10 EVG/COBI/FTC/TDF subjects (2.8%) vs 19 ATV + RTV + FTC/TDF subjects (5.4%) (P = 0.13). All fractures in the EVG/COBI/FTC/TDF group were trauma related; 2 subjects in the ATV + RTV + FTC/TDF group had nontraumatic fracture (one with bilateral calcaneous fracture and the other with vertebral fracture found on baseline dual energy x-ray absorptiometry scan).
Serious AEs were reported for a similar percentage of subjects in the EVG/COBI/FTC/TDF group (14.4%) and in the ATV + RTV + FTC/TDF group (16.6%). Frequent AEs reported at weeks 96 and 144 and those leading to study drug discontinuation are presented in Table 1.
At week 144, the median change from baseline fasting triglycerides was numerically higher but not significant: 9 mg/dL [interquartile range (IQR), −22 to 40] vs 12 mg/dL (IQR, −18 to 56) (P = 0.24). There were no significant treatment differences in change from baseline through week 144 in median fasting low-density lipoprotein cholesterol, fasting high-density lipoprotein cholesterol, or fasting total cholesterol to fasting high-density lipoprotein cholesterol ratio.
Renal laboratory assessments showed changes consistent with COBI's expected effect on estimated glomerular filtration rate, which were seen as early as weeks 2–4, plateaus around weeks 18–24, and remains stable through week 144. Median increases from baseline in serum creatinine at week 144 was similar to week 96 in EVG/COBI/FTC/TDF (0.12 mg/dL; IQR, 0.03–0.20) vs ATV + RTV + FTC/TDF (0.08 mg/dL; IQR, 0–0.17) groups.
At week 144, the mean percent decrease from baseline in spine BMD was −1.43% in the EVG/COBI/FTC/TDF group and −3.68% in the ATV + RTV + FTC/TDF group (P = 0.018) and the mean percent decrease from baseline in hip BMD was −2.83% in the EVG/COBI/FTC/TDF group and −3.77% in the ATV + RTV + FTC/TDF group (P = 0.23).
In this multinational randomized controlled trial, EVG/COBI/FTC/TDF demonstrated high and durable efficacy through 144 weeks in HIV-1–infected, antiretroviral treatment–naive subjects. Durable virologic suppression was consistent across subgroups using multiple sensitivity efficacy analyses. Immunologic benefit continued in both groups, as evidenced by increases from baseline in CD4 cell counts. A low number (2.3%) of patients who received EVG/COBI/FTC/TDF developed resistance, a rate similar to other first-line regimens.4–8
No new safety concern emerged after week 96. Both the EVG/COBI/FTC/TDF and ATV + RTV + FTC/TDF regimens continued to be well tolerated in this study through week 144, as demonstrated by the low percentages of subjects with serious AEs and subjects who discontinued study drug because of 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 since week 96. No EVG/COBI/FTC/TDF patients developed PRT at any time in this study, whereas 3 cases were reported after week 96 in the ATV + RTV + FTC/TDF arm. Changes from baseline in serum creatinine were seen as early as week 2 and remained stable after week 24 through week 144, consistent with the inhibitory effect of COBI on renal tubular secretion of creatinine. BMD at week 144 showed similar or smaller mean percent decreases from baseline in the EVG/COBI/FTC/TDF group compared with the ATV + RTV + FTC/TDF group.
In summary, these results demonstrate durable efficacy for EVG/COBI/FTC/TDF, no new renal safety signal, and a longer term safety profile that is differentiated from ATV + RTV + FTC/TDF. These findings, along with those of study 102, support the use of EVG/COBI/FTC/TDF as an important first-line treatment option for 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.
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