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AIDS:
doi: 10.1097/QAD.0b013e32835cee6e
Clinical Science

Week 96 efficacy and safety of rilpivirine in treatment-naive, HIV-1 patients in two Phase III randomized trials

Cohen, Calvin J.a; Molina, Jean-Michelb; Cassetti, Isabelc; Chetchotisakd, Ploenchand; Lazzarin, Adrianoe; Orkin, Chloef; Rhame, Frankg; Stellbrink, Hans-Jürgenh; Li, Taishengi; Crauwels, Hertaj; Rimsky, Laurencej; Vanveggel, Simonj; Williams, Peterj; Boven, Katiak; on behalf of the ECHO, THRIVE study groups

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Author Information

aCommunity Research Initiative of New England, Boston, Massachusetts, USA

bDepartment of Infectious Diseases, Saint-Louis Hospital, University of Paris Diderot, Paris 7, Paris, France

cHelios Salud, Buenos Aires, Argentina

dFaculty of Medicine, Khon Kaen University, Khon Kaen, Thailand

eVita-Salute,San Raffaele University, Milan, Italy

fBarts and the London NHS Trust, London, UK

gAbbott Northwestern Hospital, Minneapolis, Minnesota, USA

hICH Study Center, Hamburg, Germany

iDepartment of Infectious Diseases, Peking Union Medical College Hospital, Beijing, China

jJanssen Infectious Diseases BVBA, Beerse, Belgium

kJanssen Research and Development, LLC, Titusville, New Jersey, USA.

Correspondence to Calvin J. Cohen, Community Research Initiative of New England, Boston, MA 02215, USA. Tel: +1 617 502 1740; fax: +1 617 502 1701; e-mail: ccohen@crine.org

Received 15 June, 2012

Revised 16 November, 2012

Accepted 22 November, 2012

Meetings at which parts of the data have been presented: Cohen CJ, Molina JM, Cassetti I, et al. Pooled Week 96 efficacy, resistance and safety results from the double-blind randomised, Phase III trials comparing rilpivirine (RPV,TMC278) versus efavirenz (EFV) in treatment-naïve, HIV-1-infected adults. 6th International AIDS Society Conference on HIV Pathogenesis, Treatment and Prevention, Rome, Italy 17–20 July 2011. Poster TULBPE032. (Also presented as an encore at EACS 2011 and BHIVA 2012). Rimsky L, Van Eygen V, Vingerhoets J, et al. Week 96 resistance analysis of the rilpivirine (RPV, TMC278) Phase III trials in treatment-naïve HIV-infected adults. 19th Conference on Retroviruses and Opportunistic Infections, Seattle, WA, USA, March 5–8, 2012. Poster 708. Cohen C, Molina J-M, Jayaweera D, et al. Relationship between combination of baseline viral load and CD4 cell count, and Week 48 or 96 responses to rilpivirine (RPV) or efavirenz (EFV) in treatment-naïve HIV-1-infected adults: pooled analysis from the Phase III ECHO and THRIVE trials. 19th Conference on Retroviruses and Opportunistic Infections, Seattle, WA, USA, March 5–8, 2012. Poster 626. Bloch M, Crane LR, Reynes J, et al. Safety and efficacy outcomes by N(t)RTI background regimen over 96 weeks in treatment-naïve HIV-1-infected patients treated with rilpivirine or efavirenz in the Phase III ECHO and THRIVE trials. 49th Annual Meeting of the Infectious Diseases Society of America and the HIV Medicine Association, Boston, MA, USA, October 20–23 2011. Poster 408. Martorell C, Mayer CA, Ribera E, et al. Week 96 safety and efficacy by gender and race subgroups in treatment-naïve HIV-1-infected patients in the Phase III ECHO and THRIVE trials. 49th Annual Meeting of the Infectious Diseases Society of America and the HIV Medicine Association, Boston, MA, USA, October 20–23 2011. Poster 404.

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

Background: In the week 48 primary analysis of ECHO and THRIVE, rilpivirine demonstrated noninferior efficacy and more favourable tolerability versus efavirenz in treatment-naive, HIV-1-infected adults. Pooled 96-week results are presented.

Methods: Patients (N = 1368) received rilpivirine 25 mg once-daily (q.d.) or efavirenz 600 mg q.d., with two background nucleoside/nucleotide reverse transcriptase inhibitors, in two randomized, double-blind, double-dummy Phase III trials.

Results: At week 96, response rate (% confirmed viral load <50 copies/ml; intent-to-treat, time-to-loss-of-virologic response) was 78% in both groups. Responses were similar for both treatments by background regimen, sex, race, and in patients with more than 95% adherence (M-MASRI) or baseline viral load 100 000 copies/ml or less. Responses were lower and virologic failure higher for rilpivirine versus efavirenz in patients with 95% or less adherence or baseline viral load more than 100 000 copies/ml. Beyond week 48, the incidence of virologic failure was comparable (3 versus 2%) between treatment groups, rilpivirine resistance-associated mutations were consistent with those observed in year 1, there were few adverse events in both groups and no new safety concerns. Over 96 weeks, discontinuations due to adverse events (4 versus 9%), treatment-related grade 2–4 adverse events (17 versus 33%), rash (4 versus 15%), dizziness (8 versus 27%) and abnormal dreams/nightmares (8 versus 13%), and grade 2–4 lipid abnormalities were lower with rilpivirine than efavirenz. Only 2 and 4% of patients in the rilpivirine and efavirenz treatment groups, respectively, reported at least possibly treatment-related grade 2–4 adverse events during the second year of treatment.

Conclusions: Rilpivirine 25 mg q.d. and efavirenz 600 mg q.d. had comparable responses at week 96. Rilpivirine had more virologic failures but improved tolerability versus efavirenz. The majority of virologic failures occurred in the first 48 weeks.

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Introduction

Guidelines for the management of patients infected with human immunodeficiency virus type-1 (HIV-1) recommend the early commencement of antiretroviral therapy [1–3]. The nonnucleoside reverse transcriptase inhibitor (NNRTI), efavirenz (EFV), in combination with the nucleoside/nucleotide reverse transcriptase inhibitors (N[t]RTIs), emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF), is recommended in several treatment guidelines as a preferred first-line option for treatment naive, HIV-1-infected adults [1–3]. However, EFV is associated with side effects, including rash, elevation of lipid levels and neuropsychiatric symptoms [4–7]. Such toxicities are important because poor tolerability currently represents the most common reason for switching an initial antiretroviral regimen [8–11].

Rilpivirine (RPV; TMC278; EDURANT, Janssen Pharmaceuticals, County Cork, Ireland) is an NNRTI, recently licensed by the US FDA, European Medicines Agency and other countries to treat HIV-1 infection in antiretroviral treatment-naive adult patients [12,13]. In addition, a single-tablet regimen [COMPLERA (US) EVIPLERA (EU), Gilead Sciences], consisting of RPV combined with FTC/TDF, has also recently been approved [14,15]. The approval of RPV was based on the findings of the primary 48-week pooled analysis of two large Phase III trials: ECHO (Efficacy Comparison in treatment-naïve, HIV-infected patients Of TMC278 and efavirenz) and THRIVE (TMC278 against HIV, in a once-daily RegImen Versus Efavirenz) [16]. These studies evaluated the efficacy and tolerability of RPV 25 mg once-daily (q.d.) versus EFV 600 mg q.d., both administered in combination with an N(t)RTI background regimen in treatment naive, HIV-1-infected adults. The week 48 primary analysis of each trial demonstrated noninferior antiviral efficacy of RPV compared with EFV [17,18]. Pooled confirmed response rates [intent-to-treat, time-to-loss-of-virologic response (ITT-TLOVR)] were 84% with RPV and 82% with EFV [16]. Rilpivirine had a more favourable tolerability profile compared with EFV [16–18]. There was a higher incidence of virologic failure on RPV than EFV, which was more apparent in patients with sub-optimal adherence and/or a baseline viral load more than 100 000 copies/ml [16,19].

In this article, we present the findings of a preplanned analysis of pooled ECHO/THRIVE efficacy, virology and safety data in patients who reached week 96, which was the final study endpoint, or discontinued earlier. The main objectives of this analysis were to evaluate the durability of virologic suppression, as well as the longer term safety and tolerability profile of RPV compared with EFV.

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Methods

Detailed methodology for the ECHO (TMC278-C209, NCT00540449) and THRIVE (TMC278-C215, NCT00543725) trials has been previously reported [17,18]. ECHO and THRIVE were randomized, double-blind, active-controlled Phase III trials with nearly identical design allowing for the preplanned analysis of pooled trial data. Baseline characteristics and demographics were comparable between the two trials [17,18]. Treatment-naive, HIV-1-infected adults were enrolled (ECHO: 28 May 2008 to 2 March 2009; THRIVE: 23 June 2008 to 26 February 2009) who had baseline viral load at least 5000 HIV-1 RNA copies/ml and confirmed viral sensitivity to the background N(t)RTIs (VircoTYPE HIV-1 assay). Patients were not enrolled if they had documented genotypic evidence of NNRTI resistance-associated mutations (RAMs) as described previously [17,18,20]. In both studies, patients were randomized 1 : 1 to receive either RPV 25 mg q.d. and EFV placebo q.d. or EFV 600 mg q.d. and RPV placebo q.d., in addition to a fixed background N(t)RTI regimen. RPV/RPV placebo was recommended to be taken with a meal, preferably breakfast, whereas EFV/EFV placebo was recommended to be taken on an empty stomach at bedtime. In ECHO, patients received FTC/TDF, whereas in THRIVE patients received an investigator-selected background regimen of FTC/TDF, zidovudine (ZDV)/lamivudine (3TC), or abacavir (ABC)/3TC [17,18]. Randomization was stratified by screening viral load (≤100 000 copies/ml, >100 000 to ≤500 000 copies/ml, and >500 000 copies/ml) and background regimen (for THRIVE only).

For both studies, the primary objective was to demonstrate noninferiority (with a maximum allowable difference of 12%, in line with other studies [21] and FDA guidelines [22]) in confirmed overall response with RPV versus EFV at week 48 (ITT-TLOVR). Secondary objectives included the durability of antiviral activity, treatment adherence as measured by the Modified Medication Adherence Self-Report Inventory (M-MASRI), CD4+ cell count changes, genotypic and phenotypic characteristics of the virologic failures, and safety and tolerability.

Virologic failure was determined in both the efficacy according to ITT-TLOVR at the week 96 timepoint (VFeff) and resistance (VFres) analyses. The resistance analysis included all patients in the database (ITT population) with signs of virologic failure regardless of the time of failure (on, before or after week 96) or reason for discontinuation. In both analyses, virologic failures were sub-classified as ‘rebounders’ (two consecutive viral load <50 copies/ml before week 96 followed by two consecutive viral load ≥50 copies/ml at or before week 96, or in the resistance analysis only, a single viral load value ≥50 copies/ml, if it was the last available); or ‘never suppressed’ [defined as never having had two consecutive viral loads less than 50 copies/ml before week 96 (efficacy analysis) or never having had two consecutive viral loads <50 copies/ml and an increase in viral load ≥0.5 log10 copies/ml above the nadir before week 96 (resistance analysis)]. Resistance and genotype/phenotype were analyzed in the sample confirming the virologic failure. Viral phenotypic and genotypic assessments were performed by Janssen Diagnostics BVBA (Beerse, Belgium), by means of the Antivirogram and VircoTYPE HIV-1 assays, respectively. Clinical isolates were considered drug resistant if the fold-change was above the biological cut-off [3.3 (EFV); 6.0 (nevirapine [NVP]); 3.7 (RPV)] or the lower clinical cut-off for etravirine (ETR; 3.2) [19].

The main outcome analysis was performed on the entire ITT population, which included all randomized patients who received at least one dose of study medication. Per protocol (PP; as ITT but excluding major protocol violators) and ITT-TLOVR non-VF censored (excluding patients who did not reach week 96 for reasons other than VFres) population analyses were also performed. An ITT outcome analysis using the FDA snapshot approach was also conducted using the last viral load value in the week 96 window (90–103 weeks) [23].

In the preplanned analysis of mean change in absolute CD4+ cell count from baseline, both observed and imputed data, in which premature discontinuations were assigned the baseline value (noncompleter equalled failure), are presented. For other missing values, a last observation carried forward approach was used.

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Results

Patient disposition and baseline characteristics

The baseline patient demographic and disease characteristics were well balanced between the treatment groups [17,18] (Supplementary table, http://links.lww.com/QAD/A289). The proportions of patients receiving each N(t)RTI background regimen were well balanced between treatment groups (FTC/TDF 80%; ZDV/3TC 15%; ABC/3TC 5%).

Of 1368 patients originally randomized in the two trials, 132 of 686 patients in the RPV group (19%) and 137 of 682 patients in the EFV group (20%) had discontinued treatment by 96 weeks, with 38 and 25 patients in these two groups, respectively, discontinuing the trials after the week 48 analysis (Fig. 1). Over 96 weeks, the most common reasons for discontinuation, as indicated by the investigator, were reaching a virologic endpoint (8 and 3% of patients in the RPV and EFV groups, respectively) and adverse events (4 and 9%, respectively).

Fig. 1
Fig. 1
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Efficacy analyses

The response rate (proportion of patients with viral load <50 copies/ml; ITT-TLOVR algorithm) at week 96 was 78% (532/686 patients) in the RPV group and 78% (529/682 patients) in the EFV group [difference (95% confidence interval [CI]): 0.0% (−4.4 to 4.4%)] (Table 1). The model-adjusted responses (including covariate baseline log10 plasma viral load, background N[t]RTI regimen, and study as factors) [difference (95% CI): −0.4% (−4.6 to 3.8%)], and the PP-TLOVR and ITT-snapshot responses were all similar to the ITT-TLOVR responses (Table 1). In the ITT-TLOVR non-VFres-censored population, response rates were lower with RPV than with EFV (Table 1). There were no notable differences between the RPV and EFV groups regarding the percentage of overall responders over time (Fig. 2a). In addition, compared with EFV, RPV was associated with fewer discontinuations for adverse events and other reasons (Table 1).

Table 1-a Treatment ...
Table 1-a Treatment ...
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Fig. 2
Fig. 2
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In preplanned analyses, suboptimal adherence (M-MASRI adherence ≤95%) and higher baseline viral load (>100 000 copies/ml) were associated with lower responses and increased VFeff rates in both treatment groups (Table 1). However, the influence of higher baseline viral load and suboptimal adherence on these virologic outcomes was more apparent with RPV than with EFV. There was a 4.4% difference in response between treatment groups for patients with baseline viral load more than 100 000 to 500 000 copies/ml or less; this difference in response was 8.3% in patients with baseline viral load more than 500 000 copies/ml. Of patients with available M-MASRI data, 86% (552/639) in the RPV group and 83% (499/599) in the EFV group reported more than 95% adherence. Response rates were high and similar between treatment groups in the subgroup of patients reporting more than 95% adherence. Lower baseline CD4+ cell counts were also associated with decreased response rates in both treatment groups (Table 1). As there were few patients in the subgroups with suboptimal adherence or low baseline CD4+ cell count, these data should be interpreted with caution.

Table 1-b Treatment ...
Table 1-b Treatment ...
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Given that week 48 ECHO and THRIVE data showed that adherence was the most important predictor of response, and baseline viral load was a more important predictor than baseline CD4+ cell count [24], a post-hoc analysis was conducted to investigate ITT-TLOVR outcome stratified by both adherence and baseline viral load. The lowest responses and highest VFeff rates were observed in the small number of patients who had a baseline viral load more than 100 000 copies/ml and M-MASRI adherence 95% or less (Table 1). The lower response rate for RPV than EFV in this small patient subgroup was due in some part to differences in VFeff, but also to the higher rate of discontinuations for reasons other than adverse events (e.g. lost to follow-up, withdrawal of consent, etc.) in the RPV group. The highest responses and lowest VFeff rates, which were the same in each treatment group, were observed in patients who had a baseline viral load 100 000 copies/ml or less and M-MASRI adherence more than 95%.

Overall, responses by background N(t)RTI regimen, sex, and race at week 96 were similar for RPV and EFV. In the RPV group, response rates among patients receiving FTC/TDF, ZDV/3TC and ABC/3TC were 77 (N= 550), 81 (N= 101) and 77% (N= 35), respectively [versus 77 (N= 546), 77 (N= 103) and 85% (N= 33), respectively, for EFV]. Response rates were also similar in men and women for both treatment groups [men: RPV 79% (N= 518) versus EFV 77% (N= 519); women: 74% (N= 168) versus 78% (N= 163), respectively]. Response rates were lower for both RPV and EFV in Black patients [64% for RPV (N= 165) and 71% for EFV (N= 156)] than in Asians [90% (N= 78) and 91% (N= 97), respectively] and White patients [80% (N= 420) and 77% (N= 410), respectively].

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Change in CD4+ cell count

The mean CD4+ cell count rose in both treatment groups over the 96-week treatment period. The mean (95% CI) change in CD4+ cell count from baseline to week 96 in the RPV treatment group was 228 cells/μl (215–240 cells/μl; N= 685), compared with 219 cells/μl (206–233 cells/μl; N= 682) in the EFV group (Fig. 2b). Corresponding mean (95% CI) changes from baseline in observed CD4+ cell counts were 275 (264–287; N= 555) and 271 (258–285; N= 543) cells/μl, respectively.

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VFres and development of resistance

In the week 96 analysis, proportions of VFres were 14% (N= 96) with RPV and 8% (N= 52) with EFV (Table 2). During the first 48 weeks, there had been a higher incidence of VFres in the RPV group (more never-suppressed than rebounders) than in the EFV group (Table 2). However, the incidence of VFres between weeks 48–96 was comparable in the two groups (Table 2), with only one never-suppressed patient in each group.

Table 2
Table 2
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At failure, in RPV and EFV VFres with available genotypes (N′ = 86 and N′ = 42, respectively), NNRTI RAMs [20] emerged at similar rates (53 and 48%, respectively) (Table 2). N(t)RTI RAMs [25], however, emerged more frequently in RPV than EFV VFres (56 versus 26%, respectively). The most frequently emerging NNRTI and N(t)RTI RAMs were E138K and M184I, respectively, in RPV VFres (Table 2). E138K never emerged alone, but always in combination with other NNRTI RAMs and/or N(t)RTI RAMs, most commonly with M184I/V. E138K and M184I comprised 44% (19/43) of RPV VFres having at least one treatment-emergent NNRTI RAM and at least one treatment-emergent N(t)RTI RAM. The median RPV fold-change of this combination in absence of other RAMs was 6.45 (N = 6), with five of six having an RPV fold-change more than 3.7. Other treatment-emergent NNRTI RAMs occurring in at least 2 RPV VFres patients were V90I, L100I, K101E, E138Q, V179I, Y181C, V189I, H221Y and F227C. Other treatment-emergent N(t)RTI RAMs occurring in at least 2 RPV VFres patients were A62 V, K65R, Y115F, K219E and M184 V. The most frequently emerging NNRTI and N(t)RTI RAMs in EFV VFres were K103N and M184 V, respectively, and were observed in combination in eight of 42 (19%) EFV VFres. Other treatment-emergent NNRTI RAMs occurring in at least two EFV VFres patients were K101E, V106 M, V108I and Y188C, and treatment-emergent N(t)RTI RAMs occurring in at least two EFV VFres patients were K65R and M184I. In both groups, fewer NNRTI and N(t)RTI RAMs newly emerged during weeks 48–96 than during the first 48 weeks of therapy (Table 2). A detailed analysis of pooled week 96 virology will be described separately.

Of the 81 RPV VFres with phenotypic resistance data at failure, 35 were phenotypically resistant to RPV. Of these 35, 16 (46%) were phenotypically cross-resistant to NVP, 30 (86%) to EFV, and 32 (91%) to ETR. For EFV, of 41 VFres with phenotypic resistance data at the time of failure, 17 were phenotypically resistant to EFV. Of these 17, 15 (88%) were phenotypically cross-resistant to NVP, one (6%) to ETR and none (0%) to RPV.

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Safety and tolerability

Table 3 summarizes the tolerability data for RPV and EFV over a median 104 weeks of treatment in each group. The safety data were comparable in the two Phase III trials, with similar incidences in the two trials of adverse events, at least grade two adverse events at least possibly related to study treatment, serious adverse events, adverse events leading to discontinuation, and adverse events of interest. This longer term analysis of the pooled data revealed only small increases in the incidence of adverse events in these categories compared with the week 48 analysis. The safety and tolerability profiles of the two study drugs were similar during the second year of treatment. Additionally, no new safety concerns arose in either treatment group after week 48.

Table 3
Table 3
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There were comparable overall incidences of serious adverse events with RPV (9%) and EFV (10%) in the pooled week 96 analysis (Table 3). Eight patients (1%) in each group had serious adverse events at least possibly related to study drug, an increase of one patient in the RPV group and two patients in the EFV group compared with week 48 analysis. Compared with week 48, there were no additional deaths in the RPV group and two additional deaths in the EFV group. In total, there was one death and six deaths in the RPV and EFV groups, respectively, but none were considered to be related to study medication.

There was a significantly lower incidence of grade 2–4 adverse events at least possibly related to study treatment with RPV versus EFV (17 versus 33%, respectively) in the week 96 analysis. Only 2 and 4% of patients in the RPV and EFV treatment groups, respectively, reported at least possibly treatment-related grade 2–4 adverse events during the second year of treatment (Table 3). Adverse events leading to discontinuation were also less frequent in the RPV group than in the EFV group (4 versus 9%, respectively) in the week 96 analysis. The most common adverse events leading to discontinuation (regardless of causality) in the week 96 analysis were any rash [RPV 0.1% (N= 1), EFV 1.8% (N= 12)] and depression [RPV 0.4% (N= 3), EFV 0.6% (N= 4)]. During weeks 48–96, the incidence of discontinuations due to adverse events was similar in the two treatment groups. Five patients in the RPV group discontinued due to eight adverse events [pulmonary tuberculosis (N = 2), suicide attempt (N = 1), bone tuberculosis (N = 1), hepatitis B (N = 1), hepatotoxicity (N = 1), mycobacterium avium complex infection (N = 1) and depression (N = 1)] and seven patients in the EFV group discontinued [as a result of hepatitis A (N = 1), hepatitis C (N = 1), meningococcal sepsis (N = 1), increased hepatic enzymes (N = 1), asphyxia (N = 1) and pregnancy (N = 2)].

Regarding adverse events of interest (in ≥10% of patients in either group) at least possibly related to study treatment (any grade), the incidences of any rash, neurologic adverse events, including dizziness, and psychiatric adverse events, including abnormal dreams/nightmares, were significantly lower in the RPV group than in the EFV group (Table 3). Most rashes, neurologic adverse events, and psychiatric adverse events occurred during the first 4 weeks of treatment and were transient. All of these adverse events were rare (occurring in ≤1% of patients) in either group during the second year of treatment. The majority of rashes were grade 1–2 in severity and there were no reported grade 4 events. Most neurologic and psychiatric adverse events were grade 1. There were fewer discontinuations due to neurologic adverse events (one patient in the RPV group versus six in the EFV group) and psychiatric adverse events (11 versus 15 patients, respectively) with RPV than with EFV.

The incidence of any grade 2−4 treatment-emergent laboratory abnormality was 46% with RPV and 58% with EFV (Table 3). The incidences of grade 2−4 treatment-emergent total cholesterol, LDL-cholesterol, aspartate aminotransferase and alanine aminotransferase elevations were lower with RPV than with EFV. There were small increases from baseline in median (interquartile range) serum creatinine levels in both treatment groups at week 96. In the RPV group, median increase was 0.1 mg/dl (range 0.03–0.2 mg/dl), whereas in the EFV group it was 0.01 mg/dl (−0.02 to 0.1 mg/dl). There appeared to be some effect of the backbone regimen, the largest increase being seen in the FTC/TDF subgroups (RPV median increase 0.1 mg/dl, EFV 0.03 mg/dl) and the smallest changes in the ZDV/3TC subgroups (RPV 0.06 mg/dl, EFV −0.05 mg/dl). One RPV patient had a grade 3 increase in creatinine levels (occurring at week 84) and one EFV patient had a grade 4 increase (occurring at week 12), neither of which were related to the NNRTIs. The RPV patient discontinued the trial at week 84 based on ‘investigator decision’ with a grade 2 creatinine increase. The EFV patient completed the trial with a week 96 creatinine of 71 μmol/l (grade 0). There were no discontinuations due to renal adverse events. Following a small decrease in mean basal cortisol levels during the first 12 weeks of therapy in both treatment groups (with a greater decrease in the RPV group), levels remained stable in both groups over the last 48 weeks of treatment [mean change from baseline to week 96: RPV −19.11 (−30.85 to −7.37) nmol/l and EFV: −0.56 (−13.29 to 12.17) nmol/l]. There were no discontinuations due to adrenal insufficiency.

Rilpivirine was associated with minimal changes from baseline in mean total cholesterol [0.12 (0.06–0.18) mmol/l], LDL-cholesterol [0.03 (−0.02 to 0.08) mmol/l] and triglycerides [−0.07 (−0.15 to 0.005) mmol/l], and a small increase in HDL-cholesterol [0.11 (0.09–0.13) mmol/l] through 96 weeks of treatment, whereas EFV treatment resulted in increases in all four lipid parameters [0.74 (0.66–0.82) mmol/l, 0.37 (0.31–0.43) mmol/l, 0.14 (0.04–0.25) mmol/l and 0.29 (0.26–0.31) mmol/l, respectively]. For all four parameters, the differences between RPV and EFV were statistically significant at week 96 (all P < 0.0001; nonparametric Wilcoxon rank-sum test, preplanned analysis). There was, however, no significant difference in total cholesterol/HDL-cholesterol ratio between the two treatment groups (P = 0.17).

There were no consistent or clinically relevant changes in vital signs with RPV treatment. The corrected QT (QTc) interval increased over time in both groups up to week 48, remaining stable thereafter. The mean change from baseline at week 96 in QTc interval was similar between the RPV and EFV treatment groups (+12.4 and +13.6 ms, respectively). Incidences of any QT prolongation-related adverse event (regardless of relationship to study medication) were 0.6% (RPV) and 2.6% (EFV). Symptomatic QT prolongation-related adverse events included syncope (RPV 0.1%, EFV 0.9%) and loss of consciousness (RPV 0.1%, EFV 0%).

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Discussion

This pooled analysis of the ECHO/THRIVE trial data demonstrated sustained virologic suppression with RPV over 2 years of treatment, with identical overall response rates at 96 weeks for RPV and EFV (78%, ITT-TLOVR). Response rates at week 96 in both treatment groups declined only slightly compared with the values reported for the primary week 48 analysis (84% with RPV, 82% with EFV). The week 96 response rates with RPV and EFV reported in this analysis also compare favorably to those that have been reported in previous trials in treatment-naive patients that have included EFV in the treatment regimen [26–30]. Similar response rates for RPV and EFV were seen at week 96 in the snapshot and ITT-TLOVR PP analyses, indicating the robustness of the results. Consistent with the higher virologic failure rate for RPV, the non-VFres censored analysis showed a lower response rate with RPV than with EFV. Differences in overall virologic failure, which mainly occurred in the first year, were observed between the two Phase III trials, such that the difference between EFV and RPV was greater in ECHO than in THRIVE [17,18] and the reasons for these differences remain unclear.

As in the week 48 analysis [16], response rates in both treatment groups were affected by patients’ adherence to study treatment and by baseline viral load, with suboptimal adherence (≤95% adherence by M-MASRI) and higher baseline viral load (>100 000 copies/ml) associated with lower responses and a higher VFeff rate in both treatment groups (Table 1). These factors, however, appeared to exert a greater influence for RPV than for EFV on reducing response rates and increasing VFeff. The trend for a lower proportion of discontinuations for adverse events/deaths for RPV than for EFV was maintained irrespective of adherence and also for patients with baseline viral load ≤100 000 copies/ml or >100 000 to ≤500 000 copies/ml, although there was a comparable proportion of discontinuations for adverse events/deaths in each treatment group for patients with baseline viral load >500 000 copies/ml. The treatment difference in terms of discontinuations for adverse events/death was 9 and 1%, respectively, in the >100 000 to ≤500 000 copies/ml and >500 000 copies/ml baseline viral load strata. As the difference in VFeff between treatment groups was the same (10%) for patients in these baseline viral load strata, the difference in response between treatment groups was 4.4% for patients with baseline viral load >100 000 to ≤500 000 copies/ml and 8.3% for patients with baseline viral load >500 000 copies/ml. The effect of high viral load on virologic failure with RPV is described in the United States prescribing information [12]. In Europe, RPV is indicated for antiretroviral treatment-naive adults with a viral load ≤100 000 copies/ml or less [13]. As expected, response rates in both treatment groups were also reduced in patients with lower baseline CD4+ cell counts. Again, although this parameter appeared to exert a greater effect on the efficacy of RPV than EFV, the small sizes of some of the subgroups should be noted. The effect of CD4+ cell count on treatment response was largely, but not completely explained by the effect of baseline viral load. Response rates were similar with RPV and EFV irrespective of background regimen, sex and race. Response rates were lowest in Black patients in both treatment groups and highest in Asian patients, consistent with findings in the week 48 analysis [16].

Although at week 48 the overall VFres rate was higher with RPV (11%) than with EFV (5%), the incidence of VFres between weeks 48 and 96 was low and comparable in the two groups (3 versus 2%, respectively). As described, the likelihood of RPV VFres and treatment-emergent RAMs is greater among patients with baseline viral load more than 100 000 copies/ml, although the resistance profile of RPV (i.e. type of RAMs) is independent of baseline viral load [19]. A similar proportion of VFres developed NNRTI RAMs between groups, but more VFres developed N(t)RTI RAMs in the RPV group. As reported previously [16], the most prevalent NNRTI RAM in RPV VFres was E138K and in EFV VFres was K103N. The most prevalent N(t)RTI RAMs in the RPV and EFV VFres were M184I and M184 V, respectively. In RPV VFres patients, E138K never emerged in isolation, always occurring with other NNRTI RAMs and/or N(t)RTI RAMs [19], most commonly with M184I/V. This suggests a role for the combination of E138K with M184I/V in RPV resistance, which is supported by in-vitro phenotypic analyses of HIV-1 site-directed mutants [19,31,32]. E138K in combination with M184I was shown to be associated with greater resistance to RPV compared with E138K alone, and to affect viral fitness [32–34]. Further, the presence of M184I and M184 V are associated with reduced susceptibility to 3TC and FTC [35]. Following virologic failure when RAMs are detected, the EACS guidelines recommend to avoid N(t)RTIs if multiple N(t)RTI resistance is demonstrated, but to consider continuation of 3TC or FTC even if there are documented M184I/V RAMs [3].

Of the 81 RPV VFres with phenotypic resistance data at the time of failure, 35 were phenotypically resistant to RPV and of these, most were cross-resistant to EFV and ETR. These data suggest that ETR will not retain activity in patients who developed resistance to RPV, although clinical data are currently lacking. In contrast, both ETR and RPV appear to retain activity in most virologic failures treated with EFV who develop resistance to EFV. Nonetheless, clinical responses with ETR and RPV could be affected. For example, in a randomized, open-label Phase IIb trial (TMC125-C227; NCT00225303), NNRTI-resistant, protease inhibitor-naive HIV-1-infected patients had lower virologic responses when treated with ETR versus a protease inhibitor, when each were given in combination with two N(t)RTIs [36]. As such, ETR is not indicated for use in combination with only N(t)RTIs in patients who have experienced virologic failure on an NNRTI- and N(t)RTI-containing regimen [37,38].

In the overall week 96 analysis, there were lower incidences of grades 2–4 adverse events, rash, dizziness and abnormal dreams/nightmares (any grade) at least possibly related to study treatment, discontinuations due to adverse events (mainly rash and depression), and of grade 2−4 lipid abnormalities in the RPV group than in the EFV group as reported previously at week 48 [16–18]. Most of these adverse events were reported during the first 48 weeks of treatment. No new safety concerns were identified in either treatment group beyond 48 weeks of treatment. Reports of additional adverse events were sparse and incidences of grades 2–4 adverse events, rash, dizziness and abnormal dreams/nightmares, and discontinuations due to adverse events were comparable between the two treatment groups during weeks 48–96. With regard to the observed changes in lipids, 2 years of RPV treatment had minimal effect. There were significantly smaller increases from baseline in total cholesterol and LDL-cholesterol compared with EFV, and a negligible decrease in triglycerides compared with an increase in the EFV group. However, there was a greater increase from baseline in levels of HDL-cholesterol in the EFV group, with no change in total cholesterol/HDL-cholesterol ratio between groups. There were no new safety concerns relating to laboratory parameters in either treatment group. The reported small, early-onset increase in serum creatinine levels in the RPV group is likely related to changes in the renal tubular disposition of creatinine rather than any renal toxicity, as cystatin C measurements in THRIVE showed that RPV did not decrease the glomerular filtration rate [17]. In an in-vitro test, RPV showed inhibition of the organic cation transporter, the active transporter of creatinine in the proximal renal tubule (Janssen, data on file). As such, these changes in serum creatinine are not considered to be clinically relevant.

The present analysis of the pooled ECHO/THRIVE 96 week study data provides data on the long-term efficacy and tolerability of RPV-based treatment. A limitation of the Phase III studies is that their double-blind, double dummy design (oral doses taken twice daily, rather than once daily as in clinical practice) may have adversely affected patient adherence. Thus, the study findings may not reflect the outcome that may be observed with once-daily dosing and only one pill per day. In this regard, a study (NCT01309243; GS-US-264-0110), now underway, will evaluate the safety and efficacy of the single-tablet regimen of RPV and FTC/TDF [COMPLERA (US)/EVIPLERA (EU)] compared with the single-tablet regimen of EFV and FTC/TDF (ATRIPLA) in treatment-naive adults. Also, the recommendation for patients to take rilpivirine (or matching placebo) with a meal might not have been followed in all cases, resulting in a lower exposure of RPV.

In conclusion, this pooled analysis of the ECHO/THRIVE 96-week study data demonstrated that RPV was efficacious and well tolerated over 2 years in a large and diverse group of treatment-naive adults. Thus, RPV is a convenient, well tolerated option for first-line therapy of HIV-1 infected patients.

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Acknowledgements

The authors thank the patients and their families for their participation and support during the trials, as well as the investigators, trial centre staff and trial coordinators from each centre, and Janssen trial personnel. Both trials were designed and conducted by Janssen, the trials’ sponsor and developer of RPV. The authors received medical writing support and assistance in coordinating and collating author contributions from Ian Woolveridge (Gardiner-Caldwell Communications Ltd, Macclesfield, UK), funded by Janssen. Finally, the authors would like to thank the following people from the Janssen R&D team for their input into this manuscript: Guy De La Rosa, Ines Adriaenssen, David Anderson, Christiane Moecklinghoff, Kati Vandermeulen and Marita Stevens.

Author contributions: all authors substantially contributed to the studies’ conception, design, and performance. C.J.C., J.M.M., I.C., P.C., A.L., C.O., F.R., H.J.S., T.L. all participated in recruiting significant numbers of patients and reported data for those patients. H.C., L.R., S.V., P.W., K.B. all had a significant involvement in the data analyses. All authors were involved in the development of the primary manuscript, interpretation of data, have read and approved the final version, and have met the criteria for authorship as established by the ICMJE.

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Conflicts of interest

The following are potential conflicts of interest to declare: C.J.C. has received research funding from Janssen, Gilead Sciences, Bristol-Myers Squibb (BMS), Merck, Sharp & Dohme (MSD), Tobira and ViiV Healthcare, and he is on advisory boards for Gilead Sciences, Janssen, MSD, Tobira, and BMS. 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 Janssen, ViiV Healthcare, Gilead Sciences, BMS, Abbott Laboratories, Boehringer Ingelheim (BI) and MSD. I.C. has received consulting, lecture fees, and grant support from BMS, ViiV Healthcare, Janssen and Gilead Sciences. P.C. has received speaker honoraria and/or has been an investigator for clinical trials for Janssen, BMS, Abbott Laboratories, MSD and Gilead Sciences. A.L. has acted as a consultant, participated in advisory boards, speaker bureaus and has been an investigator in clinical trials for Abbott Laboratories, BMS, BI, Gilead Sciences, MSD, Janssen, Pfizer, ViiV Healthcare, GlaxoSmithKline (GSK) and Roche. C.O. has served as a speaker and received honoraria from Janssen, BMS, BI, GSK, Gilead Sciences, ViiV Healthcare and Abbott Laboratories. F.R. has served as a consultant or study investigator or on an advisory board for BI, Janssen, GSK/ViiV Healthcare, MSD and Gilead Sciences. H.J.S. has received reimbursement or fees for attending a symposium, speaking at or chairing a symposium, performing research, or consulting from BMS, Roche, Janssen, GSK, Gilead Sciences, Abbott Laboratories, Pfizer, MSD, and BI. T.L. declares no conflict of interest. H.C., L.R., S.V., P.W. and K.B. are full-time employees of Janssen.

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Keywords:

efavirenz; HIV-1; rilpivirine; treatment naive

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