Rilpivirine (RPV, TMC278, EDURANT) is a nonnucleoside reverse transcriptase inhibitor (NNRTI), approved in several countries worldwide including in the USA and Europe for use in treatment-naive HIV-1-infected patients in combination with other antiretrovirals [1,2]. A single-tablet regimen of RPV with tenofovir disoproxil fumarate (TDF) and emtricitabine (FTC) [Complera (USA); Eviplera (EU)] has also been approved [3,4]. These approvals were based on the primary 48-week pooled analysis of the phase III Efficacy Comparison in treatment-naive HIV-infected subjects Of TMC278 (ECHO) and TMC278 against HIV, in a once-daily RegImen Vs. Efavirenz (THRIVE) trials [5–7]. The approval of RPV and Complera/Eviplera in several countries is for treatment-naive patients with a viral load 100 000 copies/ml or less [1–4]. The US prescribing information states that more RPV-treated patients with viral load more than 100 000 copies/ml at the start of therapy experienced virological failure compared to patients with viral load less than 100 000 copies/ml .
In the primary, 48-week preplanned pooled analysis for the overall ECHO/THRIVE study population, RPV demonstrated noninferior antiviral efficacy compared to efavirenz (EFV), with response rates of 84 and 82%, respectively [viral load <50 copies/ml; intent-to-treat, time-to-loss of virological response (ITT-TLOVR)] . RPV was associated with a higher virological failure rate (9 vs. 5%, respectively) and more emerging nucleoside/tide reverse transcriptase inhibitor (N(t)RTI) resistance-associated mutations (RAMs) than EFV but with lower incidences of discontinuations due to adverse events or deaths (2 vs. 7%, respectively) and more favorable tolerability than EFV . Although not observed with the newer integrase inhibitors elvitegravir and dolutegravir [8,9], in several previous trials of different antiretroviral drugs [10–16], high baseline viral load resulted in lower responses, higher virological failure, and the development of resistance in both treatment groups. However, in ECHO/THRIVE, the influence of baseline viral load on the rate of virological failure was more apparent with RPV than EFV . In view of these data and the RPV prescribing information [1,2], the present analysis, conducted at the primary 48-week time point, compares the efficacy, virology, and safety of RPV with that of EFV in the subset of ECHO/THRIVE patients who had baseline viral load 100 000 copies/ml or less, one of the predefined stratification groups. A stratified analysis by baseline viral load was predefined in the study protocol.
Patient population and study design
ECHO (TMC278-C209, NCT00540449) and THRIVE (TMC278-C215, NCT00543725) were phase III randomized, double-blind, double-dummy, active-controlled, international trials. The trial design and methodology have been reported in detail elsewhere [5,6].
In brief, principal inclusion criteria were treatment-naive, HIV-1-infected adults with baseline viral load at least 5000 copies/ml and confirmed viral sensitivity to the background N(t)RTIs, as assessed using the vircoTYPE HIV-1 assay (Janssen Diagnostics, Beerse, Belgium). Exclusion criteria included documented presence of 39 possible NNRTI RAMs; the list was designed to exclude the possibility of a reduced response to EFV and RPV and was compiled from existing literature as well as the combination of in-vitro and in-vivo data demonstrating the association of each of these RAMs with EFV or RPV resistance .
Patients were randomized 1 : 1 to RPV 25 mg once daily (q.d.), given with EFV placebo q.d., or EFV 600 mg q.d., given with RPV placebo q.d. In ECHO, patients received a fixed N(t)RTI background regimen of TDF and FTC. In THRIVE, patients received an N(t)RTI background regimen based on the investigator's choice of TDF/FTC, zidovudine (ZDV)/lamivudine (3TC), or abacavir (ABC)/3TC. Treatment allocation was stratified by screening viral load, with three strata: 100 000 copies/ml or less; more than 100 000 copies/ml to 500 000 copies/ml or less; and more than 500 000 copies/ml, and by background regimen in THRIVE.
The present analysis includes only patients from ECHO and THRIVE who had a baseline viral load 100 000 copies/ml or less.
Efficacy and virology analyses
The primary objective of both studies was to test for noninferiority in confirmed overall response (viral load <50 copies/ml) of RPV vs. EFV at week 48 using an ITT-TLOVR imputation algorithm and noninferiority margins of 12% [lower limit of two-sided 95% confidence intervals (CIs)] and of 10% . Any patient experiencing treatment failure was considered a virological failure for the ITT-TLOVR analysis (VFeff) if they had a confirmed response before week 48 with confirmed rebound at or before week 48 (rebounders) or had no confirmed response before week 48 (never suppressed). All other premature discontinuations (due to adverse events or other reasons) were considered treatment failures.
Any patient experiencing treatment failure was considered a virological failure for the resistance analyses (VFres), regardless of time of failure and/or discontinuation reason, provided they met either of the criteria: first achieved two consecutive viral load values less than 50 copies/ml followed by two consecutive (or single, when last available) viral load values at least 50 copies/ml (rebounder) or never achieved two consecutive viral load values less than 50 copies/ml and had an increase in viral load at least 0.5 log10 copies/ml above the nadir (never suppressed). Genotypes were determined using vircoTYPE for virologically failing patients. Data described below are based on a list of 48 NNRTI RAMs (including any NNRTI RAMs that have been shown to contribute to resistance to NNRTIs) , and the International AIDS Society-USA N(t)RTI RAMs list . Phenotypic resistance was assessed using Antivirogram (Janssen Diagnostics) to determine fold change in median effective concentration required to induce a 50% inhibitory effect (EC50). Biological cut-off values were used to denote resistance: 3.7 for RPV; 3.3 for EFV, 3.2 for etravirine (ETR), and 6.6 for nevirapine (NVP) .
Evaluation of safety
Safety and tolerability were assessed throughout the trial. Adverse events were monitored from screening onwards and at each study visit throughout the trial, and were coded using the Medical Dictionary for Regulatory Activities (MedDRA, 11.0), with severity determined according to the Division of AIDS grading scale . Laboratory parameters and changes in plasma lipids were also assessed.
The Short-Form 36 version two (SF-36v2) health survey questionnaire was used for assessing patient-reported outcomes. The preference-based utility index, SF-6D, was determined from the SF-36v2.
In addition to the primary ITT-TLOVR efficacy analysis, a per-protocol analysis was conducted to investigate the impact of exclusion of patients with major protocol violations and to confirm the results of the ITT population. A non-VFres-censored analysis was performed on the primary efficacy parameter (<50 copies/ml TLOVR), whereby all patients who discontinued prematurely and were not considered VFres were censored at the time of discontinuation, that is, excluded for later time points. Differences in response (viral load <50 copies/ml) between treatment groups at week 48 were calculated and 95% CIs were derived using normal approximation of binomial distribution.
The test for noninferiority was based on virological response rates at week 48 estimated by a logistic regression model which included treatment, background regimen, and trial as factors, with data adjusted for baseline viral load as a continuous variable.
For the overall pooled population, Fisher's exact test (5% significance level) was used for a preplanned comparison of adverse events, for which a significant difference had been recorded in the phase IIb trial . Testing was for any adverse event, any grade 2–4 adverse event, any neuropsychiatric adverse event of interest (all grades and grade 2–4), any psychiatric adverse event of interest (all grades and grade 2–4), any neurologic adverse event of interest (all grades and grade 2–4), any rash (grouped term; all grades and grade 2–4), and any single preferred terms (or the planned psychiatric event of interest grouped term, ‘abnormal dreams/nightmares’) with an incidence of more than 10% overall in either treatment group, both regardless of relationship to study medication and at least possibly related to study medication. These comparisons were also made within the current analysis of the subset of patients with baseline viral load 100 000 copies/ml or less. Differences in lipid changes from baseline between treatment groups were compared using the nonparametric Wilcoxon rank-sum test.
For the virology analysis, statistical comparisons between the two treatment groups were all performed at 5% significance level without multiplicity correction using Fisher's exact test.
Treatment group differences in change-from-baseline in SF-36v2 scores at week 48 were tested using separate univariate analysis of covariance (ANCOVA) models for each score.
Patient disposition and baseline characteristics
Of the overall ECHO/THRIVE population (N = 1368), a total of 698 patients had baseline viral load 100 000 copies/ml or less; 368/686 (54%) and 330/682 (48%) patients in the RPV and EFV treatment groups, respectively. Of these, at the time of the week 48 analysis, 90% of RPV patients and 85% of EFV patients remained on study (Fig. 1). The most common reason for study discontinuation, as reported by the investigator, was the occurrence of adverse events, followed by reaching a virological endpoint (Fig. 1).
Baseline demographic parameters and disease characteristics were broadly similar between treatment groups (Table 1). Hepatitis B/C co-infection occurred at a slightly higher incidence in the EFV group (P = 0.02 vs. RPV). The use of each background N(t)RTI regimen was well balanced between the treatment groups in THRIVE and in the pooled dataset, most patients (78% in each group) received TDF/FTC.
A high proportion of patients in both the RPV (90%) and EFV (84%) groups achieved a response (<50 copies/ml, ITT-TLOVR) at week 48 (Table 2). The difference of 6.6% in response rate between RPV and EFV was significant (95% CI 1.6–11.5%), and was consistent between the two studies [ECHO: difference 6.1% (95% CI −1.1 to 13.3%)/THRIVE: difference 7.1% (95% CI 0.2–13.9%)]. The per-protocol analysis also demonstrated a significantly higher response rate for RPV compared with EFV [92 vs. 84%; difference 7.6% (95% CI 2.7–12.5%)]. However, in the TLOVR non-VFres-censored population, response rates were the same for RPV and EFV [332/350 (95%) vs. 276/290 (95%); difference 0.3% (95% CI −3.7 to 3.1%)], reflecting a similar rate of virological failures but a higher proportion of other discontinuations (mainly due to adverse events) in the EFV group than in the RPV group.
In the logistic regression analysis, the difference in response between the RPV and EFV groups for the pooled data was 7.2% (95% CI 1.5–12.9%). The lower limit of the 95% CI of the difference between treatment groups was well above −12 and −10%, so noninferiority of RPV compared to EFV was established at both margins.
A greater increase in the mean absolute imputed CD4+ cell count from baseline to week 48 was observed for RPV [+185 (95% CI 172–199) cells/μl] compared with EFV [+161 (95% CI 145–176) cells/μl], which was statistically significant (P = 0.0256; ANCOVA).
Virological failure and development of resistance
In the population with viral load 100 000 copies/ml or less, 5% of patients in each treatment group were classified as virological failures (VFres) (Table 3). In the RPV group, the proportions of VFres patients who were rebounders [47% (9/19)] and never suppressed [53% (10/19)] were similar, whereas in the EFV group more VFres patients [75% (12/16)] were rebounders.
Paired genotypic data were available for 16 of 19 RPV and 12 of 16 EFV VFres patients at failure. An identical proportion (50%) of the VFres patients with genotypic data in each treatment subgroup developed at least one RAM in the reverse transcriptase gene (Table 3): RPV, eight of 16 (50%) vs. EFV, six of 12 (50%). A comparable proportion of RPV and EFV VFres patients had at least one treatment-emergent NNRTI RAM [6/16 (38%) vs. 5/12 (42%), respectively; P = 1.0] (Table 3). There was a numerically higher proportion of VFres patients with treatment-emergent N(t)RTI RAMs in the RPV group [7/16 (44%)] than in the EFV group [2/12 (17%); P = 0.2232 (Table 3)]. Two patients had phenotypic resistance to RPV, with one having NNRTI RAMs and cross-resistance to EFV and ETR. All six patients with phenotypic resistance to EFV (five with NNRTI RAMs) were also cross-resistant to NVP, whereas none were cross-resistant to RPV or ETR.
Treatment-emergent NNRTI RAMs observed exclusively in RPV VFres patients were as follows: V90I, L100I, E138K, and V179I. K103N was observed exclusively in EFV VFres patients (Table 3). The K101E mutation was observed in both RPV and EFV VFres patients. The N(t)RTI RAM M184V was observed in both RPV and EFV VFres patients, whereas M184I was only seen in the RPV VFres patients. Overall, the most common reverse transcriptase mutations in those RPV VFres patients with emergent reverse transcriptase mutations were E138K [5/6 (83%)] and M184I [6/7 (86%)], usually observed in combination.
Safety and tolerability
At the time of the week 48 analysis, median treatment exposure in both treatment groups was 56 weeks (Table 4). Most adverse events were grade 1 or 2 in severity, with grade 3 or 4 adverse events reported in 12% (n = 43) and 18% (n = 58) of patients in the RPV and EFV groups, respectively. The incidence of treatment-related (as determined by the investigator) grade 2–4 adverse events was significantly lower in the RPV group than in the EFV group (Table 4). The most common treatment-related grade 2–4 adverse events at least possibly related to treatment (excluding laboratory abnormalities) occurring in at least 2% of patients in either group were rash, dizziness, abnormal dreams/nightmares, nausea, headache, and insomnia (Table 4).
Permanent discontinuation from study due to adverse events occurred in 4% of RPV patients vs. 6% of EFV patients (Table 4). Reasons for discontinuation varied, and no single adverse event or serious adverse event (SAE) accounted for discontinuation in at least 1% of patients in either treatment group. SAEs occurred in 5% of RPV-treated patients and 7% of EFV patients. SAEs considered to be at least possibly related to treatment occurred at low incidence (approximately 1%) in both treatment groups. No deaths occurred in the RPV group during the 48-week study period. One death (due to grade 4 dysentery) occurring in the EFV group was considered by the investigator not to be related to treatment.
Adverse events of interest
The incidence of both rash and treatment-related neurological adverse events of interest was significantly lower for RPV than for EFV (Table 4). The incidence of rash was highest in the first 4 weeks, with few new rash events occurring thereafter. The incidence of treatment-related psychiatric adverse events of interest was 16% for RPV vs. 21% for EFV (P = 0.0776) (Table 4). Treatment-related hepatic adverse events of interest were reported in a low and comparable proportion of patients in each treatment group [RPV: 5 patients (1%) vs. EFV 7 patients (2%)].
The most frequently reported treatment-emergent laboratory abnormalities of grade 2–4 in the RPV group were hypophosphatemia and increased pancreatic amylase (Table 4). In the EFV group, the most frequent grade ≥2 treatment-emergent laboratory abnormalities were increased fasted low-density lipoprotein (LDL) cholesterol and increased fasted total cholesterol (Table 4).
Renal changes over time
Mean serum creatinine levels showed a small increase on RPV treatment over time, from a 0.05 mg/dl increase at the first on-treatment assessment to a 0.09 mg/dl increase at week 48. This increase appears to be related to altered tubular secretion of creatinine rather than a change in renal function . In the EFV group, mean serum creatinine levels fluctuated around the baseline levels over time.
Lipid changes over time
In the RPV group, mean total cholesterol, LDL cholesterol, and triglyceride levels all decreased from baseline over the first few weeks and then remained stable over time, and mean high-density lipoprotein (HDL) cholesterol increased from baseline. Levels of all these lipids increased from baseline over time in the EFV group, and the increase in HDL cholesterol was greater than in the RPV group (Suppl. Fig., http://links.lww.com/QAD/A303). The difference between treatment groups at week 48 was statistically significant for all four lipid parameters (P < 0.0001). There was no significant difference between treatment groups in the total cholesterol/HDL cholesterol ratio at week 48.
In the RPV group, SF-36v2 scores improved from baseline to week 48 across all domains. Improvements were also observed in the EFV group, with the exception of the role limitations due to physical health score. This score is a measure of the limitations in usual role activities due to physical health. The change from baseline at week 48 was significantly higher (demonstrating improvement) for RPV vs. EFV for the mental health summary component score (3.128 vs. 1.343, respectively; P = 0.022) and the preference-based SF-6D utility index (0.045 vs. 0.016, respectively; P = 0.020).
In the subset of patients in ECHO and THRIVE who had baseline viral load 100 000 copies/ml or less, RPV-treated patients demonstrated a significantly higher virological response rate, a greater mean increase in CD4+ cell count, and a more favorable tolerability profile than those receiving EFV. There were comparable rates of virologic failure and overall proportions of emergent RAMs in the reverse transcriptase gene between the two groups. There was a consistency across the individual trials in reaching noninferiority of RPV compared with EFV and the actual treatment difference observed for this subset of patients.
Response rates in this analysis of patients with baseline viral load 100 000 copies/ml or less were considerably higher for RPV than in the subset with baseline viral load more than 100 000 copies/ml (90 vs. 77%, respectively), which differs from the comparable rates for EFV of 84 vs. 81%, respectively . These results for RPV are consistent with a lower response rate observed in patients with baseline viral loads more than 100 000 copies/ml in several other antiretroviral trials [10–16] but differ from the results from phase III trials of the newer integrase inhibitors elvitegravir and dolutegravir [8,9] and from results for EFV from the current analysis, which show that virological response is not greatly influenced by baseline viral load .
In patients with baseline viral load 100 000 copies/ml or less, the rate of VFres was the same for both RPV and EFV (5% of patients). As such, the ITT-TLOVR non-VFres-censored analysis showed the response was noninferior with RPV compared to EFV. A similar proportion of RPV and EFV VFres patients developed treatment-emergent NNRTI RAMs, although there was a greater variety of NNRTI RAMs per VFres in RPV patients (V90I, L100I, K101E, E138K, and V179I) than in the EFV VFres patients (K103N and K101E). Treatment-emergent N(t)RTI RAMs were proportionally more common in RPV VFres patients than in EFV VFres patients. The difference between treatments was, however, not statistically significant, and the clinical implications of this finding have not yet been elucidated. The most common treatment-emergent NNRTI and N(t)RTI RAMs in RPV VFres patients were E138K and M184I, usually occurring in combination. In contrast, K103N and M184V were the most common treatment-emergent RAMs in EFV VFres patients. These results are consistent with observations from the overall trial population [5–7,20]. In RPV VFres patients, co-presence of E138K and M184I resulted in resistance to RPV. These data were confirmed by in-vitro studies of RPV site-directed mutants showing that the combination of E138K + M184I was associated with a greater loss of susceptibility to RPV than E138K alone [20,23]. The clinical implications of the presence of E138K are not yet fully understood as one in-vitro study showed that M184I improves the fitness of E138K-containing isolates [24,25], whereas another demonstrated that the combination of E138K and M184I imposed a higher fitness cost to the virus . Currently, the prevalence of E138K in routine clinical practice is less than 1% .
Cross-resistance to EFV and ETR occurred in patients failing RPV, whereas those failing EFV were cross-resistant to NVP and remained susceptible to RPV and ETR. However, these observations are based on small patient numbers. Furthermore, the pattern of cross-resistance differed according to baseline viral load; RPV cross-resistance to ETR and EFV was less common at baseline viral load 100 000 copies/ml or less than at high baseline viral load . Nonetheless, taken together with the role for E138K in ETR resistance , these results suggest that it is likely ETR will not retain its activity after RPV virological failure. Any use of an ETR-based regimen in those patients should not be recommended .
RPV was generally better tolerated than EFV with a significantly lower incidence of treatment-related adverse events (both any grade and grade 2–4), and treatment-related rash and neurological adverse events [5–7]. The incidence of psychiatric adverse events was numerically lower in the RPV group than in the EFV group. There were clinically meaningful improvements in the change from baseline at week 48 in the SF-36 mental health summary component score and the SF-6D utility score in both treatment groups, with statistically significant differences in favor of RPV compared with EFV. Also consistent with the findings for the overall population, RPV was associated with significantly smaller mean changes from baseline than EFV in total cholesterol, LDL cholesterol, HDL cholesterol, and triglyceride levels [5–7], with no difference between groups in total cholesterol/HDL cholesterol ratio. Changes in creatinine in the RPV subgroup are not likely to be clinically relevant, as they appear to be due to altered tubular secretion of creatinine rather than actual changes in renal function . As shown in THRIVE, glomerular filtration rate calculated using cystatin C increased in both the RPV and EFV treatment groups, but the increases were not clinically relevant in either treatment group .
A limitation for this analysis is the statistical comparisons of frequency of adverse events of interest between treatment groups, which were preplanned for the overall population rather than the subset with baseline viral load 100 000 copies/ml or less. Also, it should be noted that, although baseline characteristics were generally well balanced between groups, the EFV group contained a higher proportion of HIV-infected patients with hepatitis B and/or C co-infection.
This analysis demonstrates that RPV represents a valuable treatment option for HIV-1-infected antiretroviral treatment-naive adults with viral load 100 000 copies/ml or less, given its noninferior efficacy and superior clinical and laboratory safety profile compared with EFV, although treatment-emergent N(t)RTI RAMs were more common in RPV VFres patients. The clinical implications of the RPV resistance findings remain to be elucidated.
The authors thank the patients and their families for their participation and support during the trials, as well as the investigators, trial center staff and trial coordinators from each center, and Janssen trial personnel. Both trials were designed and conducted by Janssen, the trials’ sponsor, and developer of rilpivirine. 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 article: Ines Adriaenssen, David Anderson, Christiane Moecklinghoff, Peter Williams and Eric Wong.
All authors substantially contributed to the studies’ conception, design, and performance. J-M.M., and N.C. participated in recruiting significant numbers of patients and reported data for those patients. K.R., L.R., S.V., and M.S. 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.
Conflicts of interest
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, Bristol-Myers Squibb, Abbott Laboratories, Boehringer Ingelheim (BI), and Merck, Sharp & Dohme (MSD). N.C. has participated as an expert or investigator for Abbott Laboratories, BI, Gilead Sciences, GlaxoSmithKline (GSK), MSD, Pfizer, Roche, and Janssen. K.R., L.R., S.V., and M.S. are Janssen employees.
Meetings at which parts of the data have been presented: Cohen C, Molina JM, Cahn P, Clotet B, Fourie J, Grinsztejn B, et al. Pooled week 48 efficacy and safety results from ECHO and THRIVE, two double-blind, randomised, phase III trials comparing TMC278 vs. EFV in treatment-naïve, HIV-1-infected patients. 18th International AIDS Conference, Vienna, Austria, 18–23 July 2010. Abstract THLBB206; Cohen C, Molina JM, Cahn P, Clotet B, Fourie J, Grinsztejn B et al. Pooled week 48 safety and efficacy results from the ECHO and THRIVE Phase III trials comparing TMC278 vs EFV in treatment-naïve HIV-1-infected patients. 10th International Congress on Drug Therapy in HIV Infection, Glasgow, UK, 7–11 November 2010. Abstract O432; Rimsky L, Vingerhoets J, Van Eygen V, Eron J, Clotet B, Vanveggel S, et al. Genotypic and phenotypic characterization of HIV-1 isolates obtained from patients failing rilpivirine (RPV, TMC278) in the Phase III studies ECHO and THRIVE: 48 week analysis. 20th International Workshop on HIV & Hepatitis Virus Drug Resistance and Curative Strategies, Los Cabos, Mexico, June 7–11 2011. Antivir Ther 2011; 16 (Suppl 1): A17. Some efficacy and virology data have also been published in part in: Cohen CJ, Molina JM, Cahn P, Clotet B, Fourie J, Grinsztejn B, et al. Efficacy and safety of rilpivirine (TMC278) versus efavirenz at 48 weeks in treatment-naive HIV-1-infected patients: pooled results from the phase 3 double-blind randomized ECHO and THRIVE Trials. J Acquir Immune Defic Syndr 2012; 60(1): 33–42; Rimsky L, Vingerhoets J, Van Eygen V, Eron J, Clotet B, Hoogstoel A, et al. Genotypic and phenotypic characterization of HIV-1 isolates obtained from patients on rilpivirine therapy experiencing virologic failure in the phase 3 ECHO and THRIVE studies: 48-week analysis. J Acquir Immune Defic Syndr 2012; 59(1): 39–46.
2. EDURANT (rilpivirine) tablets. Summary of product characteristics. Janssen-Cilag; December 2012. http://http://www.medicines.org.uk
/EMC/medicine/25490/SPC/Edurant+25+mg/ [Accessed 8 January 2013].
3. Prescribing information for COMPLERA (emtricitabine/rilpivirine/tenofovir disoproxil fumarate) tablets. Gilead Sciences; August 2012. http://www.gilead.com/pdf/complera_pi.pdf
. [Accessed 8 January 2013].
5. Molina J-M, Cahn P, Grinsztejn B, Lazzarin A, Mills A, Saag M, et al. Rilpivirine versus efavirenz with tenofovir and emtricitabine in treatment-naive adults infected with HIV-1 (ECHO): a phase 3 randomised double-blind active-controlled trial
6. Cohen CJ, Andrade-Villanueva J, Clotet B, Fourie J, Johnson MA, Ruxrungtham K, et al. Rilpivirine versus efavirenz with two background nucleoside or nucleotide reverse transcriptase inhibitors in treatment-naive adults infected with HIV-1 (THRIVE): a phase 3, randomised, noninferiority trial
7. Cohen C, Molina JM, Cahn P, Clotet B, Fourie J, Grinsztejn B, et al. Efficacy and safety of rilpivirine (TMC278) versus efavirenz at 48 weeks in treatment-naïve, HIV-1-infected patients: pooled results from the phase 3 double-blind, randomized ECHO and THRIVE trials
. J Acquir Immune Defic Syndr
8. Sax PE, DeJesus E, Mills A, Zolopa A, Cohen C, Wohl D, et al. Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir versus co-formulated efavirenz, emtricitabine, and tenofovir for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3 trial, analysis of results after 48 weeks
9. Walmsley S, Antela A, Clumeck N, et al.Dolutegravir (DTG; S/GSK1349572) + abacavir/lamivudine once daily statistically superior to tenofovir/emtricitabine/efavirenz: 48-week results – SINGLE (ING114467)
. 52nd Interscience Conference on Antimicrobials and Chemotherapy
; San Francisco, CA; 9–12 September 2012. Abstract H-556b.
10. Molina J-M, Andrade-Villanueva J, Echevarria J, Chetchotisakd P, Corral J, Neal D, et al. Once-daily atazanavir/ritonavir compared with twice-daily lopinavir/ritonavir, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naïve HIV-1-infected patients: 96-week efficacy and safety results of the CASTLE study
. J Acquir Immune Defic Syndr
11. Ortiz R, Dejesus E, Khanlou H, Voronin E, van Lunzen J, Andrade-Villanueva J, et al. Efficacy and safety of once-daily darunavir/ritonavir vs lopinavir/ritonavir in treatment naïve HIV-1-infected patients at week 48
12. Lennox JL, DeJesus E, Lazzarin A, Pollard RB, Madruga JV, Berger DS, et al. Safety and efficacy of raltegravir-based vs efavirenz-based combination therapy in treatment naïve patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial
13. Lima VD, Gill VS, Yip B, Hogg RS, Montaner JS, Harrigan PR. Increased resilience to the development of drug resistance with modern boosted protease inhibitor-based highly active antiretroviral therapy
. J Infect Dis
14. Katlama C, Haubrich R, Lalezari J, Lazzarin A, Madruga JV, Molina JM, et al. Efficacy and safety of etravirine in treatment experienced, HIV-1 patients: pooled 48 week analysis of two randomized, controlled trials
15. Taiwo B, Zheng L, Gallien S, Matining RM, Kuritzkes DR, Wilson CC, et al. Efficacy of a nucleoside-sparing regimen of darunavir/ritonavir plus raltegravir in treatment-naive HIV-1-infected patients (ACTG A5262)
16. Eron JJ Jr, Rockstroh JK, Reynes J, Andrade-Villanueva J, Ramalho-Madruga JV, Bekker LG, et al. Raltegravir once daily or twice daily in previously untreated patients with HIV-1: a randomised, active-controlled, phase 3 noninferiority trial
. Lancet Infect Dis
17. Vingerhoets J, Rimsky L, Van Eygen V, Nijs S, Vanveggel S, Boven K, et al. Screening and baseline mutations in the TMC278 phase III trials ECHO and THRIVE: prevalence and impact on virological response (abstract 41)
. Antivir Ther
2011; 16 (Suppl 1):A51.
19. Johnson VA, Brun-Vézinet F, Clotet B, Gunthard HF, Kuritzkes DR, Pillay D, et al. Update of the drug resistance mutations in HIV-1: December 2009
. Top HIV Med
20. Rimsky L, Vingerhoets J, Van Eygen V, Eron J, Clotet B, Hoogstoel A, et al. Genotypic and phenotypic characterization of HIV-1 isolates obtained from patients on rilpivirine therapy experiencing virologic failure in the phase 3 ECHO and THRIVE studies: 48-week analysis
. J Acquir Immune Defic Syndr
21. Division of Acquired Immune Deficiency Syndrome (DAIDS) table for grading the severity of adult and pediatric adverse events. Version 1; 28 December 2004. Available at: http://rsc.tech-res.com/safetyandpharmacovigilance
. [Accessed 8 January 2013].
22. Pozniak AL, Morales-Ramirez J, Katabira E, Steyn D, Lupo SH, Santoscoy M, et al. Efficacy and safety of TMC278 in antiretroviral-naive HIV-1 patients: week 96 results of a phase IIb randomized trial
23. Kulkarni R, Babaoglu K, Lansdon EB, Rimsky L, Van Eygen V, Picchio G, et al. The HIV-1 reverse transcriptase M184I mutation enhances the E138K-associated resistance to rilpivirine and decreases viral fitness
. J Acquir Immune Defic Syndr
24. Xu HT, Asahchop EL, Oliveira M, Quashie PK, Quan Y, Brenner BG, Wainberg MA. Compensation by the E138K mutation in HIV-1 reverse transcriptase for deficits in viral replication capacity and enzyme processivity associated with the M184I/V mutations
. J Virol
25. Hu Z, Kuritzkes DR. Interaction of reverse transcriptase (RT) mutations conferring resistance to lamivudine and etravirine: effects on fitness and RT activity of human immunodeficiency virus type 1
. J Virol
26. Picchio G, Vingerhoets J, Tambuyzer L, Coakley E, Haddad M, Witek J. Short communication: prevalence of susceptibility to etravirine by genotype and phenotype in samples received for routine HIV type 1 resistance testing in the United States
. AIDS Res Hum Retroviruses
27. Tambuyzer L, Nijs S, Daems B, Picchio G, Vingerhoets J. Effect of mutations at position E138 in HIV-1 reverse transcriptase on phenotypic susceptibility and virologic response to etravirine
. J Acquir Immune Defic Syndr
© 2013 Lippincott Williams & Wilkins, Inc.