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AIDS:
doi: 10.1097/QAD.0000000000000169
Clinical Science

Week 48 results from a randomized clinical trial of rilpivirine/emtricitabine/tenofovir disoproxil fumarate vs. efavirenz/emtricitabine/tenofovir disoproxil fumarate in treatment-naive HIV-1-infected adults

Cohen, Calvina; Wohl, Davidb; Arribas, Jose R.c; Henry, Keithd; Van Lunzen, Jane; Bloch, Markf; Towner, Williamg; Wilkins, Edmundh; Ebrahimi, Ramini; Porter, Daniellei; White, Kirsteni; Walker, Ivani; Chuck, Susani; De-Oertel, Shampai; Fralich, Toddi

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Author Information

aCommunity Research Initiative of New England, Boston, Massachusetts

bUniversity of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

cHospital La Paz, Madrid, Spain

dHIV Program Hennepin County Medical Center, Minneapolis, Minnesota, USA

eUniversity Medical Center Hamburg-Eppendorf, Hamburg, Germany

fHoldsworth House Medical Practice, Darlinghurst, New South Wales, Australia

gDepartment of Infectious Disease, Kaiser Los Angeles Medical Center, Los Angeles, California, USA

hNorth Manchester General Hospital, Manchester, UK

iGilead Sciences, Foster City, California, USA.

Correspondence to Todd Fralich, MD, 333 Lakeside Drive, Foster City, CA 94404, USA. Tel: +1 650 524 3000; e-mail: todd.fralich@gilead.com

Received 15 August, 2013

Revised 28 November, 2013

Accepted 28 November, 2013

Meetings at which parts of the data have been presented: Cohen C, Wohl D, J Arribas J, et al. STaR Study: single tablet regimen emtricitabine/rilpivirine/tenofovir DF is noninferior to efavirenz/emtricitabine/tenofovir DF in ART-naive adults; 11–15 November 2012; Glasgow, UK [abstract 0425].

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 Website (http://www.AIDSonline.com).

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Abstract

Objectives: To compare the safety and efficacy of the two single-tablet regimens (STRs), rilpivirine/emtricitabine/tenofovir disoproxil fumarate (RPV/FTC/TDF) and efavirenz/emtricitabine/tenofovir DF (EFV/FTC/TDF), in HIV-1-infected, treatment-naive adults.

Design: This is a phase 3b, randomized, open-label, multicenter, international, 96-week study.

Methods: Participants were randomized 1 : 1 to receive either RPV/FTC/TDF or EFV/FTC/TDF. The primary endpoint was the proportion of participants with HIV-1 RNA less than 50 copies/ml at week 48 by the Snapshot algorithm.

Results: A total of 786 participants were randomized. RPV/FTC/TDF was noninferior to EFV/FTC/TDF (85.8 vs. 81.6%) at week 48 for HIV-1 RNA less than 50 copies/ml [difference 4.1%, 95% confidence interval (CI) −1.1 to 9.2%]. A statistically significant difference in efficacy favoring RPV/FTC/TDF was demonstrated for participants with baseline HIV-1 RNA 100 000 copies/ml or less [(n = 510) 88.8% RPV/FTC/TDF vs. 81.6% EFV/FTC/TDF (difference 7.2%, 95% CI 1.1–13.4%)]. In participants with baseline HIV-1 RNA more than 100 000 copies/ml (n = 276), RPV/FTC/TDF demonstrated noninferior efficacy compared with EFV/FTC/TDF (79.9 vs. 81.7%, respectively, difference −1.8%, 95% CI −11.1 to 7.5%). In the RPV/FTC/TDF arm, more virologic failure was observed as baseline HIV-1 RNA levels increased. There were more participants with emergent resistance in the RPV/FTC/TDF arm than in the EFV/FTC/TDF arm (4 vs. 1%, respectively). There were fewer discontinuations because of adverse events with RPV/FTC/TDF (2.5%) than with EFV/FTC/TDF (8.7%).

Conclusion: In treatment-naive participants, RPV/FTC/TDF demonstrated noninferior efficacy and improved tolerability compared with EFV/FTC/TDF, as well as a statistically significant difference in efficacy for participants with baseline HIV-1 RNA 100 000 copies/ml or less at week 48.

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Introduction

Antiretroviral therapy (ART) selection for the treatment of HIV-1 is determined not only by potency, but also by dosing convenience and tolerability, which can influence treatment adherence [1,2]. Single-tablet regimens (STRs) taken once daily facilitate adherence by minimizing pill burden and number of daily doses and eliminate the potential for selective adherence.

Both rilpivirine/emtricitabine/tenofovir disoproxil fumarate (RPV/FTC/TDF) and efavirenz/emtricitabine/tenofovir DF (EFV/FTC/TDF) are nonnucleoside reverse transcriptase inhibitor (NNRTI)-based STRs approved for initial therapy of HIV-1 infection. The efficacy and safety of RPV was previously examined in the ECHO (Efficacy Comparison in Treatment-naive, HIV-infected Subjects of TMC278 and Efavirenz) [3,4] and THRIVE (TMC278 against HIV, in a once-daily regimen versus efavirenz) [4,5] studies. These were phase 3, randomized, double-blind, double-dummy, active-controlled noninferiority trials, in which participants received an NNRTI-based regimen including either once-daily RPV or EFV, taken with two nucleoside reverse transcriptase inhibitors (NRTIs). These trial designs required twice-daily dosing with multipill regimens and different food requirements [3–7]. The trials showed that the RPV-based regimen was noninferior in terms of efficacy and had a more favorable safety and tolerability profile. However, there were higher rates of virologic failure with resistance to RPV and the NRTIs, lamivudine and FTC, compared with EFV-based regimens, particularly for participants with baseline HIV-1 RNA more than 100 000 copies/ml [3–5,8]. To what extent the results of the ECHO and THRIVE studies were driven by the pill burden and food requirements required for the double-blinded, double-dummy design is unclear. Therefore, the Single Tablet Regimen (STaR) study was undertaken as the first head-to-head comparison of the efficacy, safety, and tolerability of the STRs RPV/FTC/TDF and EFV/FTC/TDF in circumstances that reflect the way they are used in clinical practice, which is one pill, once a day.

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Methods

Study design

STaR (GS-US-264–0110) is a phase 3b, randomized, multicenter, international, open-label, 96-week, noninferiority (12% margin) clinical trial comparing the safety and efficacy of two STRs in ART-naive, HIV-1-infected patients. The primary endpoint is the proportion of participants with HIV-1 RNA less than 50 copies/ml at week 48 by the Snapshot algorithm [9,10]. The secondary endpoint is change from baseline in CD4+ cell count using last observation carried forward (LOCF) analysis. Additional analyses include efficacy stratified by pretreatment HIV-1 RNA 100 000 or less or more than 100 000 copies/ml; efficacy measured by time to loss of virologic response (TLOVR); treatment-emergent adverse events in the US Efavirenz Package Insert [11]; and change in fasting lipid parameters [total cholesterol (TC), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and triglycerides].

Results were classified as virologic failure in the Snapshot algorithm if a participant's HIV-1 RNA was at least 50 copies/ml at week 48, or the participant had discontinued study drug prior to week 48 due to lack of efficacy per the investigator's assessment, or reasons other than adverse event or death and the last on-study drug HIV-1 RNA was at least 50 copies/ml. In contrast, for TLOVR analysis, results were classified as virologic failure if there was virologic rebound (defined as follows: at any visit after achieving HIV-1 RNA less than 50 copies/ml, a rebound to at least 50 copies/ml, which is subsequently confirmed at the following visit, or at any visit a more than 1 log10 increase in HIV-1 RNA from the nadir, which is subsequently confirmed at the following visit), if the participant was never suppressed through week 48, or if drug was discontinued due to lack of efficacy.

The resistance analysis population (RAP) included isolates from individuals with HIV-1 RNA at least 400 copies/ml (limit of detection of PhenoSense GT assay; Monogram Biosciences, South San Francisco, California, USA) and either suboptimal virologic response (less than 1 log10 decrease in HIV-1 RNA from baseline at week 8 and confirmed at the subsequent visit) or confirmed virologic rebound (defined above). In addition, isolates from individuals who were on study drugs, had not been analyzed previously, and had HIV-1 RNA of at least 400 copies/ml at week 48 or their last study visit (at or after week 8) were also included in the RAP. Genotypic and phenotypic testing were done for reverse transcriptase and protease with the PhenoSense GT assay (Monogram Biosciences), using the confirmatory sample [12].

Participants signed a written consent prior to initiation of study procedures. Key eligibility criteria are as follows: HIV-1-infected adult (≥18 years of age); HIV-1 RNA more than 2500 copies/ml at screening (determined using the Roche COBAS AMPLICOR Monitor Version 1.5 Ultra PCR-based assay; Covance Central Laboratories; Indianapolis, Indiana, USA); no prior use of any anti-HIV drug for any length of time; genotype report showing sensitivity to EFV, FTC, and TDF, and absence of the RPV resistance mutations known at the time of study conduct, that is, K101E/P, E138A/G/K/Q/R, Y181C/I/V, and H221Y (GeneSeq; Monogram Biosciences); estimated glomerular filtration rate (eGFR) of at least 50 ml/min according to the Cockcroft–Gault formula. Use of proton pump inhibitors was not allowed during the treatment period. See Supplemental Digital Content (SDC, http://links.lww.com/QAD/A467; Expanded Methods) for additional inclusion and exclusion criteria and excluded medications.

Randomization was stratified by HIV-1 RNA level at screening: 100 000 or less or more than 100 000 copies/ml. Participants were randomized 1 : 1, using an Interactive Voice/Web Response System at the baseline visit, in an open-label design to receive either RPV/FTC/TDF, taken orally once daily with a meal consisting of at least 500 kcal, or EFV/FTC/TDF, taken orally once daily on an empty stomach, preferably at bedtime. Each tablet of RPV/FTC/TDF contains 25 mg RPV, 200 mg FTC, and 300 mg TDF. Each tablet of EFV/FTC/TDF contains 600 mg EFV, 200 mg FTC, and 300 mg TDF. All study medications were provided by the sponsor.

Participants were enrolled from 121 clinical and research study centers in Australia, Austria, Belgium, Canada, France, Germany, Portugal, Puerto Rico, Spain, Switzerland, the United Kingdom, and the United States. The study was performed in accordance with recognized international scientific and ethical standards and was conducted from March 2011 through July 2013.

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Statistical analyses

The planned sample size was 700 participants. This was based on the expectation that the lower limit of the observed one-sided 97.5% confidence interval (CI) or the difference in response rates would be greater than −12% with more than 95% power when the proportion of responders in both treatment groups for the primary endpoint (HIV-1 RNA <50 copies/ml at week 48 by Snapshot analysis) is 80%. The difference between treatment groups and its 95% CI are calculated based on the stratum-adjusted Mantel–Haenszel proportions.

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Assessments

Participants returned for study visits at weeks 4, 8, 12, and 16, then every 8 weeks through week 48, and then every 12 weeks through week 96. Laboratory analyses (hematology, chemistry, and urinalysis), HIV-1 RNA, CD4+ cell count, pill counts of returned study drug, and complete or symptom-directed physical examinations were performed at screening, baseline, and all subsequent study visits.

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Results

All participants were treatment-naive at study entry. The full data analysis and safety analysis sets included participants who were randomized and received at least one dose of study drug (394 RPV/FTC/TDF, 392 EFV/FTC/TDF; Fig. 1). Demographics and baseline characteristics were similar in the two arms (Table 1).

Fig. 1
Fig. 1
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Table 1
Table 1
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Efficacy

The primary objective was met, with RPV/FTC/TDF demonstrating noninferior efficacy to EFV/FTC/TDF (85.8 vs. 81.6%, respectively) based on Snapshot analysis of virologic suppression (HIV-1 RNA <50 copies/ml) at week 48 (difference 4.1%, 95% CI −1.1 to 9.2%, P = 0.12; Table 2). TLOVR analysis showed virologic response of 85.3% (336/394) in the RPV/FTC/TDF arm and 79.6% (312/392) in the EFV/FTC/TDF arm (difference 5.9%, 95% CI 0.6–11.2%, P = 0.03). The mean change from baseline to week 48 in CD4+ cell count was +200 cells/μl with RPV/FTC/TDF and +191 cells/μl with EFV/FTC/TDF (P = 0.34). The mean study drug adherence by pill count per visit through week 48 was high in both arms (96.7% in the RPV/FTC/TDF arm and 96.1% in the EFV/FTC/TDF arm).

Table 2
Table 2
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For participants with baseline HIV-1 RNA 100 000 copies/ml or less, a statistically significant difference in virologic suppression favoring RPV/FTC/TDF was demonstrated: 88.8% (231/260) RPV/FTC/TDF vs. 81.6% (204/250) EFV/FTC/TDF at week 48 (difference 7.2%, 95% CI 1.1–13.4%, P = 0.02). For participants with baseline HIV-1 RNA more than 100 000 copies/ml, virologic suppression rates of RPV/FTC/TDF were noninferior to EFV/FTC/TDF, 79.9% (107/134) vs. 81.7% (116/142), respectively (difference −1.8%, 95% CI −11.1 to 7.5%, P = 0.70). Post-hoc analyses of participants with baseline HIV-1 RNA more than 100 000 and up to 500 000 copies/ml demonstrated virologic suppression rates at week 48 of 82.7% (81/98) in the RPV/FTC/TDF arm vs. 82.1% (96/117) in the EFV/FTC/TDF arm (difference 0.6%, 95% CI −9.6 to 10.8%, P = 0.909). For those with baseline HIV-1 RNA more than 500 000 copies/ml, virologic suppression was achieved in 72.2% (26/36) of participants in the RPV/FTC/TDF arm vs. 80.0% (20/25) in the EFV/FTC/TDF arm (difference −7.8%, 95% CI −29.2 to 13.7%, P = 0.49).

Virologic failure rates by Snapshot algorithm in the overall study population at week 48 (Table 2) were 8.1% (32/394) in the RPV/FTC/TDF arm and 5.6% (22/392) in the EFV/FTC/TDF arm (difference 2.7%, 95% CI −0.9 to 6.2%, P = 0.13). The virologic failure rate for participants with baseline HIV-1 RNA 100 000 copies/ml or less was 5.0% (13/260) in the RPV/FTC/TDF arm and 3.2% (8/250) in the EFV/FTC/TDF arm (difference 1.8%; 95% CI −1.6 to 5.2%, P = 0.31). For participants with baseline HIV-1 RNA more than 100 000 copies/ml, the virologic failure rate in the RPV/FTC/TDF arm was 14.2% (19/134) vs. 9.9% (14/142) in the EFV/FTC/TDF arm (difference 4.3%; 95% CI −3.4 to 12.0%, P = 0.27). In post-hoc analyses, the virologic failure rate for participants with a baseline HIV-1 RNA more than 100 000 and up to 500 000 copies/ml was 10.2% (10/98) vs. 8.5% (10/117) in the RPV/FTC/TDF and EFV/FTC/TDF arms, respectively (difference 1.7%; 95% CI −6.2 to 9.5%, P = 0.678) and for participants with a baseline HIV-1 RNA more than 500 000 copies/ml, it was 25.0% (9/36) vs. 16.0% (4/25), respectively (difference 9%, 95% CI −11.2 to 29.2%, P = 0.40).

Inclusion in the RAP required at least 8 weeks of treatment on study drug and HIV-1 RNA at least 400 copies/ml at the time of analysis, as this is the minimum viral concentration needed for the PhenoSense GT assay. The RAP consisted of 20 participants in the RPV/FTC/TDF arm and seven participants in the EFV/FTC/TDF arm (Table 3). There were 12 participants in the RPV/FTC/TDF arm and 16 in the EFV/FTC/TDF arm who were virologic failures at week 48, but were not included in the RAP because they did not meet the 400 copies/ml threshold or had been treated less than 8 weeks. In the RPV/FTC/TDF arm, 4% (17 of 394 treated patients; 85% of RAP) had emergent key primary NNRTI and/or NRTI resistance-associated mutations [(NNRTI-R): Y181C/I (n = 8), E138K/Q (n = 6), K101E (n = 5); (NRTI-R): M184V/I (n = 15), K65R/N (n= 3)]. Of these 17 RPV/FTC/TDF-treated participants, 16 had both RPV and FTC resistance-associated substitutions. Fifteen isolates had cross-resistance to another NNRTI, but eight of these remained phenotypically susceptible to EFV. In the EFV/FTC/TDF arm, 1% (three of 392 treated patients; 43% of RAP) had emergent resistance [NNRT-R: K103N (n = 1), G190E/Q (n = 1), and Y188L (n= 1); NRTI-R: M184I (n = 1)]. Results of post-hoc analysis of resistance development by baseline HIV-1 RNA strata are presented in Table 3.

Table 3
Table 3
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Safety

In the safety analysis population, 7.4% of participants in the RPV/FTC/TDF arm and 13.8% in the EFV/FTC/TDF arm experienced grade 3 or 4 treatment-emergent adverse events through week 48. Of these, 1.8 and 4.8%, respectively, were considered related to study drug. A prespecified safety analysis evaluating adverse events of all grades that are common to the US Efavirenz Package Insert [11] showed significantly fewer nervous system and psychiatric adverse events in the RPV/FTC/TDF arm (Table 4). The most common nervous system events were dizziness (6.6% RPV/FTC/TDF vs. 22.2% EFV/FTC/TDF), insomnia (9.6 to 14.0%) somnolence (2.5 vs. 6.9%), and headache (12.4 vs. 13.5%). The most common psychiatric events in the RPV/FTC/TDF vs. the EFV/FTC/TDF arms were abnormal dreams (5.8 vs. 24.5%), depression (6.6 vs. 8.9%), and anxiety (5.1 vs. 8.4%). The difference in rates of rash events (17.3 vs. 21.2%) was not significant (P = 0.17).

Table 4
Table 4
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Study drug discontinuation due to adverse events occurred in 2.5% (10/394) of participants in the RPV/FTC/TDF arm and 8.7% (34/392) in the EFV/FTC/TDF arm (P <0.001). There were 12 different adverse events that led to the 10 discontinuations in the RPV/FTC/TDF arm. They fell into different categories and no single adverse event led to discontinuation in more than one participant in this arm. See SDC (Table S3, http://links.lww.com/QAD/A467). In the EFV/FTC/TDF arm, the most common adverse events that led to discontinuations included 18 due to psychiatric disorders, seven due to nervous system disorders and seven due to skin and subcutaneous tissue disorders. There were two deaths in the EFV/FTC/TDF arm; one was a suicide and one due to sepsis. Neither was considered related to study drug by the investigators. There were no deaths in the RPV/FTC/TDF arm.

Grade 3 or 4 laboratory abnormalities occurred in 17.3% of participants in the RPV/FTC/TDF arm and 16.2% of participants in the EFV/FTC/TDF arm. See SDC (Safety).

Whereas fasting lipid levels remained relatively unchanged from baseline to week 48 in the RPV/FTC/TDF arm, there were significantly higher increases in fasting TC, LDL, triglycerides, and HDL in the EFV/FTC/TDF arm (P<0.001 for all comparisons between treatment arms using analysis of variance), though the change in TC:HDL was −0.2 in both arms. Categorical analyses of fasting lipids showed similar trends, with more participants in less desirable categories at week 48 in the EFV/FTC/TDF arm for TC, LDL, and triglycerides compared with the RPV/FTC/TDF arm (P <0.001 for each), in which distribution across categories was relatively unchanged from baseline. See SDC (Figures S1-S3, http://links.lww.com/QAD/A467) for additional details on fasting lipids.

The change from baseline to week 48 in eGFR using the Cockcroft–Gault formula based on actual weight was −5.4 ml/min in the RPV/FTC/TDF arm, compared with +4.6 ml/min in the EFV/FTC/TDF arm (P <0.001). The decrease in eGFR in the RPV/FTC/TDF arm was observed at week 4 (first on-treatment assessment) and eGFR was stable thereafter. In contrast, the increase in eGFR in the EFV/FTC/TDF was gradual over the 48-week study. There was one discontinuation in each arm due to a renal event; in both cases, the renal event was renal failure, which resolved after study drug discontinuation. See SDC for additional details on eGFR (Figure S4, http://links.lww.com/QAD/A467) and the discontinuations due to renal failure.

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Discussion

STaR is the first head-to-head comparison of the efficacy and safety of the two STRs, RPV/FTC/TDF and EFV/FTC/TDF, in treatment-naive individuals. Overall, RPV/FTC/TDF was noninferior to EFV/FTC/TDF for virologic suppression and was better tolerated. The greater number of discontinuations due to adverse events in the EFV/FTC/TDF arm, consistent with similar studies [3–5,11], may have influenced virologic success in the Snapshot analysis. Both treatment arms achieved high rates of virologic suppression at week 48 and similar mean CD4+ cell count increases.

In an a priori planned analysis of efficacy stratified by baseline HIV-1 RNA at 100 000 copies/ml, there was a statistically significant difference favoring RPV/FTC/TDF for individuals with HIV-1 RNA 100 000 copies/ml or less (88.8% RFV/FTC/TDF vs. 81.6% EFV/FTC/TDF); RPV/FTC/TDF was noninferior for the more than 100 000 copies/ml stratum (79.9 vs. 81.7%, respectively). This may be due to the fact that for the HIV-1 RNA 100 000 copies/ml or less stratum, there was a higher rate of discontinuations for reasons other than virologic failure in the EFV/FTC/TDF arm. See SDC (Table S1, http://links.lww.com/QAD/A467).

Similar trends in efficacy results were seen in the ECHO and THRIVE studies [3–5], which utilized three different strata for baseline viral load analyses. The results raised concerns about virologic efficacy in the higher viral load strata; therefore, a post-hoc analysis was undertaken in STaR to explore these strata in more detail. In this study, participants with a baseline HIV-1 RNA more than 100 000 and up to 500 000 copies/ml demonstrated similar rates of suppression between the two arms (82.7% RPV/FTC/TDF vs. 82.1% EFV/FTC/TDF). However, for participants with HIV-1 RNA more than 500 000 copies/ml, the virologic response was higher in the EFV/FTC/TDF arm (72.2% RPV/FTC/TDF vs. 80.0% EFV/FTC/TDF). It is difficult to draw conclusions about differences in efficacy in the strata of baseline HIV-1 RNA more than 100 000 copies/ml because the data are based on a small number of participants, especially in the more than 500 000 copies/ml stratum, and the study was not powered to look at differences within strata. However, these data are consistent with previous studies [3–5] and suggest that the response rate to RPV/FTC/TDF may be lower compared with EFV/FTC/TDF for patients with very high HIV-1 RNA levels at treatment initiation.

Virologic failure rates were numerically similar between the two arms for the overall study population (8.1% RPV/FTC/TDF vs. 5.6% EFV/FTC/TDF), as well as in the strata with baseline HIV-1 RNA 100 000 copies/ml or less (5.0 vs. 3.2%) and more than 100 000 and up to 500 000 copies/ml (10.2 vs. 8.5%). The results in the baseline HIV-1 RNA more than 100 000 and up to 500 000 copies/ml stratum of numerically similar virologic efficacy and virologic failure rates suggest that longer term evaluation may inform the potential utility of RPV/FTC/TDF in this subset of patients. Although there was a small sample size (n = 61) in the baseline HIV-1 RNA more than 500 000 copies/ml stratum, the higher virologic failure rates observed (25.0% in the RPV/FTC/TDF arm vs. 16.0% in the EFV/FTC/TDF arm), confirm decreased efficacy in this stratum.

More individuals in the RPV/FTC/TDF arm than in the EFV/FTC/TDF arm met the criteria for inclusion in the RAP, which required HIV-1 RNA at least 400 copies/ml for analysis due to limitations of the assay. A greater proportion of patients in the RPV/FTC/TDF arm developed primary emergent NRTI or NNRTI resistance mutations to at least one regimen component. The M184V/I substitution emerged most frequently in the RPV/FTC/TDF arm, commonly in combination with the E138K and/or Y181C/I substitutions in HIV-1 reverse transcriptase. In addition, the TDF-associated resistance substitutions K65R/N emerged in three patients in the RPV/FTC/TDF arm. Cross-resistance to another NNRTI was common. This pattern of NRTI and NNRTI mutations is similar to previous clinical trials of RPV-containing treatment regimens except that Y181C/I was more frequently observed than E138K/Q in this study [8].

In individuals with baseline HIV-1 RNA 100 000 copies/ml or less, the proportion of individuals with emergent resistance was similar between arms, whereas the development of resistance to at least one regimen component occurred more frequently with RPV/FTC/TDF among individuals with baseline HIV-1 RNA more than 100 000 and up to 500 000 copies/ml and more than 500 000 copies/ml. Notably, there were more individuals with very high baseline viral load (>500 000 copies/ml) in the RPV/FTC/TDF arm than in the EFV/FTC/TDF arm, potentially contributing to the increased number of individuals with resistance development in this group.

Collectively, these data about patterns of virologic suppression, virologic failure, and resistance development among the higher and lower strata baseline HIV-1 RNA may be an important consideration when initiating treatment in ART-naive patients.

RPV/FTC/TDF was better tolerated than EFV/FTC/TDF, with significantly fewer discontinuations due to adverse events (2.5 vs. 8.7%, respectively) as well as fewer grade 3 or 4 adverse events in the RPV/FTC/TDF arm (7.4 vs. 13.8%, respectively) through week 48. Evaluation of specific adverse events that are listed in the US Efavirenz Package Insert [11] found significantly lower rates of nervous system and psychiatric adverse events in patients treated with RPV/FTC/TDF than those with EFV/FTC/TDF, with the differences primarily due to dizziness and abnormal dreams. These data suggest RPV/FTC/TDF has a more favorable neuropsychiatric tolerability profile than EFV/FTC/TDF.

The STRs evaluated in this study differed in the changes in fasting lipid subsets at week 48 and this may have clinical relevance for some patients. In the RPV/FTC/TDF arm, there was little change from baseline in fasting lipids. In contrast, there were greater changes in these parameters in the EFV/FTC/TDF arm, including increases in TC, LDL, and triglycerides with concomitant shifts to less optimal NCEP categories. Because of the greater improvement in HDL in the EFV/FTC/TDF arm, the net change in the TC : HDL ratio was −0.2 for both arms. RPV/FTC/TDF demonstrates minimal impact on fasting TC, LDL, and triglycerides, which may be a consideration for some patients.

There was a statistically significant difference in the change from baseline in eGFR favoring EFV/FTC/TDF. The decrease of 5.4 ml/min seen in the RPV/FTC/TDF occurred within the first 4 weeks of treatment and is consistent with the known effect of RPV on the inhibition of tubular secretion of creatinine [13].

A limitation of this study is that it was open-label. This design was chosen to allow for how the antiretrovirals would be given in clinical practice as STRs; however, this could introduce a bias in reported adverse events and efficacy results secondary to influence on adherence and tolerability. Additionally, although both arms of the study were well matched overall, men were overrepresented and enrollment of individuals with low baseline CD4+ cell counts, high baseline viral load, or age more than 50 years was low. This lack of heterogeneity may limit the generalizability of the results. It should be noted that in the pooled results of the ECHO and THRIVE studies, individuals with baseline CD4+ cell counts less than 50 cells/ml showed poorer response to RPV than EFV [13]. Measuring adherence by pill count also has limitations because it cannot be verified that unreturned pills were in fact consumed at the appropriate dosing interval. No therapeutic drug monitoring or pharmacokinetic analyses were undertaken to verify adherence. As the results reported here are only for 48 weeks of treatment, conclusions on safety and efficacy of long-term use are limited. Greater clarification in this regard will come with the week 96 data from this study.

The STaR study, the first to compare two STRs for the treatment of HIV-1 infection, demonstrated that RPV/FTC/TDF is noninferior to EFV/FTC/TDF at week 48. RPV/FTC/TDF was more efficacious in individuals with baseline HIV-1 RNA 100 000 copies/ml or less, performed similarly to EFV/FTC/TDF in individuals with baseline HIV-1 RNA more than 100 000 and up to 500 000 copies/ml, and was numerically worse for those with baseline HIV-1 RNA more than 500 000 copies/ml. There were more virologic failures with resistance development as the participant's baseline HIV-1 RNA increased in the RPV/FTC/TDF arm (2, 5, and 19%, respectively). After starting treatment, more patients were able to continue taking RPV/FTC/TDF than EFV/FTC/TDF due to fewer adverse events. These results suggest that for all but those with very high levels of HIV-1 RNA, RPV/FTC/TDF provides similar efficacy with better tolerability than EFV/FTC/TDF.

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Acknowledgements

The authors would like to thank Babi Das Wadwhani, Devon Chung, and the Gilead Sciences Clinical Operations group for help with study operations; Dina Saba and the Complera Project Team; Hui Wang and the biostatistics group at Gilead Sciences for help with statistical analysis; Mike Tran, Katherine Fung, and Shelu Bhatia for help with graphics; and Mary Anderson, PhD for help with article development. Most importantly, they would like to thank the study participants as well as the investigators and study staff. This study was designed, funded, conducted and data were analyzed by Gilead Sciences, Foster City, California, USA.

All authors substantially contributed to the study's conception, design, and performance. C.C., D.W., J.A., K.H., J.v.L., M.B., W.T., and E.W. all participated in recruiting significant numbers of participants and reported data for those patients. C.C., D.W., K.H., R.E., D.P., K.W., I.W., S.C., S.D.O., and T.F. all had a significant involvement in the data analyses. All authors were involved in the development of the primary article, interpretation of data, and have read and approved the final version.

This study was supported by Gilead Sciences, Foster City, California, USA.

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Conflicts of interest

C.C. has received consulting fees/honoraria and support for travel to meetings for the study from Gilead; serves on scientific advisory boards for Gilead; and has provided expert testimony for Gilead. D.W. has received grants and consulting fees/honoraria, and provisions from Gilead. J.R.A. has received consulting fees/honoraria, fees for participation in review activities, and payment for lectures from Gilead and acts as a scientific advisory board member. K.H. has received grants from Gilead. J.v.L. acts as a scientific advisory board member and steering committee member for Gilead as well as receiving payment for lectures and other meeting-related expenses. M.B. acts as a scientific advisory board member for and has received grants from Gilead. W.T. has received grants from Gilead. E.W. belongs to the Gilead speakers’ bureau. R.E., D.P., K.W., I.W., S.C., S.D.O., and T.F. are employees of and own stock in Gilead Sciences.

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References

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Keywords:

antiretroviral therapy; efavirenz; HIV-1; rilpivirine; single-tablet regimens; treatment-naive

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