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JAIDS Journal of Acquired Immune Deficiency Syndromes:
doi: 10.1097/QAI.0b013e318298469c
Brief Report: Clinical Science

A Randomized Phase 3 Study Comparing Once-Daily Elvitegravir With Twice-Daily Raltegravir in Treatment-Experienced Subjects With HIV-1 infection: 96-Week Results

Elion, Richard MD*; Molina, Jean-Michel MD; Ramón Arribas López, José MD; Cooper, David MD§; Maggiolo, Franco MD; Wilkins, Edmund MD; Conway, Brian MD#; Liu, Ya-Pei PhD**; Margot, Nicolas MS**; Rhee, Martin MD**; Chuck, Steven L. MD**; Szwarcberg, Javier MD, MPH**; for the Study 145 Team

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Author Information

*Whitman-Walker Health, Washington, DC;

Hospital Saint-Louis, APHP, University of Sorbonne Paris Cité, Paris 7, INSERM U941, France;

Hospital Universitario La Paz, IdiPAZ, Servicio de Medicina Interna, Unidad VIH, Madrid, Spain;

§Kirby Institute, University of New South Wales, Sydney, Australia;

Ospedali Riuniti di Bergamo, Bergamo, Italy;

North Manchester General Hospital, Manchester, United Kingdom;

#Vancouver ID Research & Care Centre, Vancouver, Canada; and

**Gilead Sciences, Inc., Foster City, CA.

Correspondence to: Richard Elion, MD, Whitman-Walker Health, Washington, DC, (e-mail: relion@whitman-walker.org).

Suported by Gilead Sciences, Inc.

Presented at 6th IAS Conference on HIV Pathogenesis, July 17–20, 2011, Rome, Italy.

R. E., has received research grant support from Gilead and consulting fees as an advisory board member for Gilead; J-M. M., has received research grant support from Merck and consulting fees as an advisory board member for Merck, Gilead, BMS, and Janssen; J. R. A. L., has received research grant support from Gilead, BMS, and MSD and consulting fees as an advisory board member for Janssen, Abbott, and Gilead; D. C., has received research grant support from Merck and Gilead and consulting fees as an advisory board member for Merck and Gilead; F. M., has received research grant support from GSK, Gilead, and BMS and consulting fees as an advisory board member for Boeheringer, BMS, Gilead, GSK, Tibotec, and MSD; E. W., has received consulting fees as an advisory board member for ViiV, Gilead, BMS, MSD, Janssen, and Abbott; B. C., has received research grant support from Gilead and consulting fees as an advisory board member for Gilead; Y-P. L., N. M., M. R., S. L. C., and J. S., are employed by Gilead Sciences.

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Abstract

Abstract: This 96-week, double-blind, active-controlled, phase 3 study, randomized subjects to elvitegravir once daily or raltegravir twice daily with a fully active, ritonavir-boosted protease inhibitor plus a third agent. The proportion of subjects randomized to elvitegravir that achieved and maintained HIV-1 RNA < 50 copies/mL through week 96 was 47.6% (167/351) compared with 45.0% (158/351) for raltegravir with a treatment difference of 2.6% (95% confidence interval: 4.6% to 9.9%). Both regimens were well tolerated, with comparable rates of adverse events and laboratory abnormalities through week 96. Once-daily elvitegravir was noninferior to twice-daily raltegravir, showed durable long-term efficacy, and was well tolerated in HIV+ treatment-experienced patients.

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INTRODUCTION

Elvitegravir (EVG) is a potent inhibitor of HIV type 1 integrase1–3 and is ideally suited for once-daily administration when boosted.4 EVG can be given once daily, which may allow for a simplified regimen by reducing pill burden, which may lead to improved adherence and patient outcomes.

This phase 3, randomized, double-blind, active-controlled study (N = 724) compared EVG and raltegravir (RAL), each given with a ritonavir-boosted protease inhibitor (PI) and a third agent; noninferiority was demonstrated at week 48.5 The study continued blinded through 96 weeks, and this manuscript reports the long-term safety and durability of virologic response.

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METHODS

Study Design

Study GS-US-183-0145 (NCT00708162) has been described in detail previously.5 This prospective, randomized, double-blind, double-dummy, noninferiority phase 3 study compared once daily EVG with twice daily RAL, each administered with a background regimen. The study continued blinded through 96 weeks.

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Statistical and Resistance Analyses

The primary endpoint was the proportion of modified intent to treat (mITT) subjects with HIV RNA < 50 copies/mL at week 48 using the FDA-defined time to loss of virologic response (TLOVR) algorithm.6 Prespecified secondary endpoints included the proportions of mITT subjects with HIV RNA < 50 copies/mL through week 96 by TLOVR, and the FDA-defined snapshot algorithm7 through weeks 48 and 96. Subjects who switched background regimen before achieving confirmed suppression were counted as failures. Efficacy was also assessed using missing = failure (HIV RNA treated as ≥50 copies/mL) and missing = excluded analyses.

Safety data through the time of the week 96 data analysis from all subjects who received at least 1 dose of study drug (safety population) were analyzed and included in this report. Incidence rates of adverse events (AEs) and laboratory abnormalities were compared using the Fisher exact test.

HIV-1 genotyping and phenotyping (Monogram Biosciences, South San Francisco, CA) was performed on blood samples obtained at screening for all patients and for subjects with a suboptimal virologic response, virologic rebound, or HIV RNA levels ≥ 400 copies/mL on their last visit before discontinuing study drugs.

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RESULTS

All week 96 visits were completed by October 31, 2011. Baseline demographics and subject characteristics have been detailed previously5 and were balanced between the 2 groups. Darunavir was the most widely used PI (58% EVG and 59% RAL subjects), and the second background agent was usually a nucleoside reverse transcriptase inhibitor (NRTI) (tenofovir disoproxil fumarate [TDF]-containing 72.4% EVG and 67.2% RAL). Nearly two thirds of subjects had baseline mutations to 2 or more classes of agents.5 From weeks 48 to 96, an additional 33 and 29 subjects discontinued study drug in the EVG and RAL group, respectively. In the EVG group, most of the discontinuations were because of nonadherence (n = 10), followed by withdrawal of consent (n = 9). In the RAL group, most of the discontinuations were because of lost to follow-up (n = 6), followed by lack of efficacy, nonadherence, and withdrew consent (n = 5 for each category).

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Efficacy

Using the prespecified TLOVR algorithm, the proportions of mITT subjects in the EVG and RAL groups, which achieved and maintained an HIV RNA < 50 copies/mL, was 59.0% (207/351) and 57.8% (203/351) through week 48 and 47.6% and 45.0% through week 96, respectively, with a treatment difference at week 96 of 2.6% [95% confidence interval: 4.6% to 9.9%]. Lower efficacy was seen in subjects without resistance at baseline of 33.3% (21/63) for EVG and 40.4% (23/57) for RAL through week 96 (Fig. 1).

Figure 1
Figure 1
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The increase in the number of patients classified as treatment failures in either group between week 48 and week 96 was primarily driven by combined reasons other than virologic failure. Between week 48 and week 96, virologic failure occurred in 15 (4.3%) and 22 (6.3%), discontinued study drug due to an AE or death in 3 (0.9%) and 5 (1.4%), and discontinuation of study drug for other reasons in 22 (6.3%) and 18 (5.1%) for subjects in the EVG and RAL group, respectively.

Among per protocol subjects, efficacy at week 96 (TLOVR) was higher than in the mITT population, with 69.1% (163/236) in the EVG group, compared with 67.8% (154/227) on RAL.

Analyses of efficacy at week 96 imputing missing as failure (M = F) and missing as excluded (M = E) revealed higher and comparable rates of virologic efficacy of 53.6% and 56.4% and 79.0% and 83.2% for each of the analysis, respectively.

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Resistance

Eighty-seven EVG group subjects and 93 RAL group subjects were evaluated for genotypic drug resistance. Through week 96, emergent integrase-resistance mutations were detected in 6.6% (23/351) of all EVG (none after week 48) and 7.4% (26/351) for all RAL (an additional 7% after week 48). Most subjects who met criteria for virology resistance analyses did not develop new resistance mutations (had the same resistance mutations at baseline).

Through week 96, a similar percentage of subjects in each group developed new mutations in the reverse transcriptase: NRTI, 2.6% (9/351) and 3.4% (12/351); non-NRTI, 3.4% (12/351) and 2.3% (8/351); and protease, 1.4% (5/351) and 1.4% (5/351), for EVG and RAL, respectively. Most treatment emergent integrase strand-transfer inhibitor mutations occurred in isolation and were not accompanied by new primary mutations in the NRTI, non-NRTI, or PI genes.

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Safety

Through week 96, adherence to ≥90% of study drug was 78.3% for EVG and 65.3% for RAL.

For EVG and the RAL groups, the incidences of AEs attributed to study drug through week 96 were similar at 23.7% and 20.4%; rates of grades 3–4 AEs attributed to study drugs were low and similar at 2.3% and 3.1%; study drug-related serious AEs occurred in 1.1% and 2% subjects, respectively. Changes in estimated glomerular filtration rate from baseline to week 96 were similar between groups with a median change of −10.8 mL/min for EVG and −11.7 mL/min for RAL.

AEs of grades 2–4 that occurred in at least 5% subjects are presented in Table 1. Although more subjects (P = 0.02) on EVG reported diarrhea through week 96, most of these events occurred in the first 48 weeks of the trial, with only 3 subjects (0.8%) on EVG and 2 subjects (0.6%) on RAL reporting new onset or worsening diarrhea between week 48 and week 96. No subject discontinued study drug because of diarrhea, and most were self-limited, with low and comparable use of antidiarrheal agents through week 96 in 17.8% and 13.7% on each group respectively.

Table 1
Table 1
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Through week 96, 11 EVG subjects (3.1%) and 15 RAL subjects (4.2%) discontinued study drugs because of AE. Reasons for discontinuation in more than 1 subject were nausea and vomiting in 3 EVG subjects and hepatitis in 2 RAL subjects.

Three subjects randomized to EVG died: 2 deaths before week 48 and 1 death after (end-stage liver disease caused by hepatitis C, intestinal perforation, and cardiac failure). In the RAL group, 9 subjects died: 8 deaths before week 48 and 1 death after (hemolytic anemia, cardiac arrest, possible coronary event, choking, heroin overdose, cardiomegaly with mitral valve prolapse, automobile accident, non-Hodgkin lymphoma, and Hodgkin lymphoma with sepsis).

Laboratory test abnormalities observed through week 96 were also similar between the EVG and RAL treatment groups, except for alanine transaminase (ALT) and aspartate transaminase (AST) elevations. More subjects randomized to RAL (19/352 or 5.4%) had grades 3–4 elevations in ALT than subjects randomized to EVG (6/349 or 1.7%) (P = 0.013). Eight RAL subjects reported grade 4 ALT elevations compared with none in the EVG group (P = 0.008). Except for 1 subject, all the ALT abnormalities occurred in the first 48 weeks. Similarly, more subjects randomized to RAL (21/352 or 6.0%) had grades 3–4 elevations in AST than subjects randomized to EVG (8/349 or 2.3%) (P = 0.021). Seven of those RAL subjects experienced a grade 4 AST elevations compared with none in the EVG group (P = 0.015). Among subjects with grades 3–4 treatment emergent ALT and/or AST elevations, coinfection with hepatitis B or C virus was reported at baseline in 41.6% EVG- and 45.8% RAL-treated subjects. A low number of hepatitis B or C virus acute infections occurred on study (1.7% for RAL and 0% for EVG).

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DISCUSSION

Week 96 data from this phase 3 study demonstrate that EVG given in combination with a ritonavir-boosted PI and a third antiretroviral agent had durable efficacy and was well tolerated in treatment-experienced subjects. Rates of virologic suppression were comparable for EVG and RAL through 96 weeks. The percentage of subjects with HIV RNA < 50 copies/mL declined from week 485 to week 96 in both groups, from 59% to 48% for EVG and from 58% to 45% for RAL; this decline was driven primarily by nonvirologic failure study drug discontinuations (TLOVR analysis). The durability of efficacy through 96 weeks in subjects who adhered to study drug decreased less relative to week 485 in both arms (from 74% to 69% for EVG and from 74% to 68% for RAL group). To put these results in context, the M = F response rates of 54% and 56% for EVG and RAL at week 96 are comparable with the 57% response rate (noncompleters equal failure) reported for RAL in the BENCHMRK studies.7

The high rate of administrative discontinuations through week 96 in more than a quarter of the subjects (26%) was the primary driver for the reduction in the TLOVR response rates and was larger than the rate observed in previous studies conducted in similar populations, such as BENCHMRK study. When this study was conducted, there were a number of alternative treatment options available to these patients outside of our clinical trial, which may have lead to nonadherence and non-AE discontinuations. This is particularly true for subjects without baseline resistance (18% EVG and 16% RAL), which showed lower efficacy rates and typically failed without integrase resistance,7 supporting nonadherence. It is reassuring that, in the noncompleters equal failure efficacy analyses, the response rates in both groups paralleled those reported in the BENCHMRK protocols.8

Through 96 weeks, approximately 6.6% subjects in the EVG and 7.4% subjects in the RAL treatment groups developed integrase resistance mutations. Most of these mutations occurred in isolation without accompanying primary resistance to other classes of antiretroviral agents and occurred in the first 48 weeks of the trial.

Between weeks 48 and 96, the type and incidence of AEs and laboratory abnormalities were generally similar in the 2 treatment groups. Most reports of diarrhea in EVG occurred early in the study, were mild and self-limited, and did not lead to study drug discontinuation.5 Overall, the RAL group had more grades 3–4 hepatic transaminase elevations through week 96, but these may be confounded by reports of acute hepatitis B or C virus infection during the study.

In conclusion, this study demonstrated that once-daily EVG was well tolerated and had comparable efficacy to twice-daily RAL through 96 weeks when given as part of an antiretroviral regimen. EVG, along with a ritonavir-boosted PI and a third agent, can form an effective, well-tolerated, once-daily long-term regimen for treatment-experienced HIV-infected patients.

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ACKNOWLEDGMENTS

The authors thank all study participants and investigators (a list of the study sites and investigators is published5) and Hiba Graham, PharmD, for her help in editing this report.

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REFERENCES

1. Shimura K, Kodama E, Sakagami, et al.. Broad antiretroviral activity and resistance profile of the novel human immunodeficiency virus integrase inhibitor elvitegravir (JTK-303/GS-9137). J Virol. 2008;82:764–774.

2. DeJesus E, Berger D, Markowitz M, et al.. Antiviral activity, pharmacokinetics, and dose response of the HIV-1 integrase inhibitor GS-9137 (JTK-303) in treatment-naive and treatment-experienced patients. J Acquir Immune Defic Syndr. 2006;43:1–5.

3. Zolopa AR, Berger DS, Lampiris H, et al.. Activity of elvitegravir, a once-daily integrase inhibitor, against resistant HIV type 1: results of a phase 2, randomized, controlled, dose-ranging clinical trial. J Infect Dis. 2010;20:814–822.

4. Mathias AA, West S, Hui J, et al.. Dose-response of ritonavir on hepatic CYP3A activity and elvitegravir oral exposure. Clin Pharmacol Ther. 2009;85:64–70.

5. Molina JM, Lamarca A, Andrade-Villanueva J, et al.. Efficacy and safety of once daily elvitegravir versus twice daily raltegravir in treatment-experienced patients with HIV-1 receiving a ritonavir-boosted protease inhibitor: randomised, double-blind, phase 3, non-inferiority study. Lancet Infect Dis. 2012;12:27–35.

6. Smith F, Hammerstrom T, Soon G, et al.. A meta-analysis to assess the FDA DAVP’s TLOVR algorithm in HIV submissions. Drug Inform J. 2011;45:291–300.

7. Margot NA, Rhee MS, Szwarcberg JS, et al.. Low rates of integrase resistance for elvitegravir and raltegravir through week 96 in the phase 3 clinical study GS-US-183-0145. Paper presented at: XIX International AIDS Conference; July 2012; Washington, DC.

8. Steigbigel RT, Cooper DA, Teppler H, et al.. Long-term efficacy and safety of raltegravir combined with optimized background therapy in treatment-experienced patients with drug-resistant HIV infection: week 96 results of the BENCHMRK 1 and 2 phase III trials. Clin Infect Dis. 2010;50:605–612.

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Keywords:

HIV-1; elvitegravir; safety; efficacy; raltegravir

© 2013 by Lippincott Williams & Wilkins

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