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 Calvin Cohena, David Wohlb, Jose R. Arribasc, Keith Henryd, Jan Van Lunzene, Mark Blochf, William Townerg, Edmund Wilkinsh, Ramin Ebrahimii, Danielle Porteri, Kirsten Whitei, Ivan Walkeri, Susan Chucki, Shampa De-Oerteli and Todd Fralichi 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 ¼ 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 ¼ 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. ß 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
AIDS 2014, 28:989–997 Keywords: antiretroviral therapy, efavirenz, HIV-1, rilpivirine, single-tablet regimens, treatment-naive a
Community 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, and 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: [email protected] Received: 15 August 2013; revised: 28 November 2013; accepted: 28 November 2013. DOI:10.1097/QAD.0000000000000169
ISSN 0269-9370 Q 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
989
990
AIDS
2014, Vol 28 No 7
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, HIVinfected 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, activecontrolled 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.
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-1infected 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 CD4þ 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), lowdensity 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 antiHIV 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
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Rilpivirine/emtricitabine/tenofovir DF Cohen et al.
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.
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 500 000 copies/ml, n (%)
RPV/FTC/TDF (n ¼ 394) 37 366 266 98 59 396 4.8
(29, 45) (93%) (68%) (25%) (15%) (180) (0.7)
260 (66%) 98 (25%) 36 (9%)
EFV/FTC/TDF (n ¼ 392) 35 364 262 94 75 385 4.8
(28, 45) (93%) (67%) (24%) (19%) (187) (0.6)
250 (64%) 117 (30%) 25 (6%)
EFV/FTC/TDF, efavirenz/emtricitabine/tenofovir disoproxil fumarate; RPV/FTC/TDF, rilpivirine/emtricitabine/tenofovir disoproxil fumarate.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Rilpivirine/emtricitabine/tenofovir DF Cohen et al. Table 2. Snapshot analysis: virologic outcomes at week 48, full analysis set. RPV/FTC/TDF (n ¼ 394) Virologic success at week 48 HIV-1 RNA 5% of participants in either armb). Type of adverse event Nervous system events, n (%) Dizziness, n (%) Insomnia, n (%) Somnolence, n (%) Headache, n (%) Psychiatric events, n (%) Abnormal dreams, n (%) Depression, n (%) Anxiety, n (%) Rash events, n (%) Folliculitis, n (%) Rash (preferred term)c, n (%)
RPV/FTC/TDF (n ¼ 394) 117 26 38 10 49 62 23 26 20 68 21 24
EFV/FTC/TDF (n ¼ 392)
(29.7%) (6.6%) (9.6%) (2.5%) (12.4%) (15.7%) (5.8%) (6.6%) (5.1%) (17.3%) (5.3%) (6.1%)
198 87 55 27 53 147 96 35 33 83 4 47
(50.5%) (22.2%) (14.0%) (6.9%) (13.5%) (37.5%) (24.5%) (8.9%) (8.4%) (21.2%) (1.0%) (12.0%)
P value
AIDS 2014, 28:989–997 Keywords: antiretroviral therapy, efavirenz, HIV-1, rilpivirine, single-tablet regimens, treatment-naive a
Community 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, and 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: [email protected] Received: 15 August 2013; revised: 28 November 2013; accepted: 28 November 2013. DOI:10.1097/QAD.0000000000000169
ISSN 0269-9370 Q 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
989
990
AIDS
2014, Vol 28 No 7
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, HIVinfected 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, activecontrolled 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.
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-1infected 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 CD4þ 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), lowdensity 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 antiHIV 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
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Rilpivirine/emtricitabine/tenofovir DF Cohen et al.
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.
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 500 000 copies/ml, n (%)
RPV/FTC/TDF (n ¼ 394) 37 366 266 98 59 396 4.8
(29, 45) (93%) (68%) (25%) (15%) (180) (0.7)
260 (66%) 98 (25%) 36 (9%)
EFV/FTC/TDF (n ¼ 392) 35 364 262 94 75 385 4.8
(28, 45) (93%) (67%) (24%) (19%) (187) (0.6)
250 (64%) 117 (30%) 25 (6%)
EFV/FTC/TDF, efavirenz/emtricitabine/tenofovir disoproxil fumarate; RPV/FTC/TDF, rilpivirine/emtricitabine/tenofovir disoproxil fumarate.
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Rilpivirine/emtricitabine/tenofovir DF Cohen et al. Table 2. Snapshot analysis: virologic outcomes at week 48, full analysis set. RPV/FTC/TDF (n ¼ 394) Virologic success at week 48 HIV-1 RNA 5% of participants in either armb). Type of adverse event Nervous system events, n (%) Dizziness, n (%) Insomnia, n (%) Somnolence, n (%) Headache, n (%) Psychiatric events, n (%) Abnormal dreams, n (%) Depression, n (%) Anxiety, n (%) Rash events, n (%) Folliculitis, n (%) Rash (preferred term)c, n (%)
RPV/FTC/TDF (n ¼ 394) 117 26 38 10 49 62 23 26 20 68 21 24
EFV/FTC/TDF (n ¼ 392)
(29.7%) (6.6%) (9.6%) (2.5%) (12.4%) (15.7%) (5.8%) (6.6%) (5.1%) (17.3%) (5.3%) (6.1%)
198 87 55 27 53 147 96 35 33 83 4 47
(50.5%) (22.2%) (14.0%) (6.9%) (13.5%) (37.5%) (24.5%) (8.9%) (8.4%) (21.2%) (1.0%) (12.0%)
P value
