The primary objective was met, with RPV/FTC/TDF demonstrating noninferior efficacy to EFV/FTC/TDF (85.8 vs. 81.6%, respectively) based on Snapshot analysis of virologic suppression (HIV-1 RNA <50 copies/ml) at week 48 (difference 4.1%, 95% CI −1.1 to 9.2%, P = 0.12; Table 2). TLOVR analysis showed virologic response of 85.3% (336/394) in the RPV/FTC/TDF arm and 79.6% (312/392) in the EFV/FTC/TDF arm (difference 5.9%, 95% CI 0.6–11.2%, P = 0.03). The mean change from baseline to week 48 in CD4+ cell count was +200 cells/μl with RPV/FTC/TDF and +191 cells/μl with EFV/FTC/TDF (P = 0.34). The mean study drug adherence by pill count per visit through week 48 was high in both arms (96.7% in the RPV/FTC/TDF arm and 96.1% in the EFV/FTC/TDF arm).
For participants with baseline HIV-1 RNA 100 000 copies/ml or less, a statistically significant difference in virologic suppression favoring RPV/FTC/TDF was demonstrated: 88.8% (231/260) RPV/FTC/TDF vs. 81.6% (204/250) EFV/FTC/TDF at week 48 (difference 7.2%, 95% CI 1.1–13.4%, P = 0.02). For participants with baseline HIV-1 RNA more than 100 000 copies/ml, virologic suppression rates of RPV/FTC/TDF were noninferior to EFV/FTC/TDF, 79.9% (107/134) vs. 81.7% (116/142), respectively (difference −1.8%, 95% CI −11.1 to 7.5%, P = 0.70). Post-hoc analyses of participants with baseline HIV-1 RNA more than 100 000 and up to 500 000 copies/ml demonstrated virologic suppression rates at week 48 of 82.7% (81/98) in the RPV/FTC/TDF arm vs. 82.1% (96/117) in the EFV/FTC/TDF arm (difference 0.6%, 95% CI −9.6 to 10.8%, P = 0.909). For those with baseline HIV-1 RNA more than 500 000 copies/ml, virologic suppression was achieved in 72.2% (26/36) of participants in the RPV/FTC/TDF arm vs. 80.0% (20/25) in the EFV/FTC/TDF arm (difference −7.8%, 95% CI −29.2 to 13.7%, P = 0.49).
Virologic failure rates by Snapshot algorithm in the overall study population at week 48 (Table 2) were 8.1% (32/394) in the RPV/FTC/TDF arm and 5.6% (22/392) in the EFV/FTC/TDF arm (difference 2.7%, 95% CI −0.9 to 6.2%, P = 0.13). The virologic failure rate for participants with baseline HIV-1 RNA 100 000 copies/ml or less was 5.0% (13/260) in the RPV/FTC/TDF arm and 3.2% (8/250) in the EFV/FTC/TDF arm (difference 1.8%; 95% CI −1.6 to 5.2%, P = 0.31). For participants with baseline HIV-1 RNA more than 100 000 copies/ml, the virologic failure rate in the RPV/FTC/TDF arm was 14.2% (19/134) vs. 9.9% (14/142) in the EFV/FTC/TDF arm (difference 4.3%; 95% CI −3.4 to 12.0%, P = 0.27). In post-hoc analyses, the virologic failure rate for participants with a baseline HIV-1 RNA more than 100 000 and up to 500 000 copies/ml was 10.2% (10/98) vs. 8.5% (10/117) in the RPV/FTC/TDF and EFV/FTC/TDF arms, respectively (difference 1.7%; 95% CI −6.2 to 9.5%, P = 0.678) and for participants with a baseline HIV-1 RNA more than 500 000 copies/ml, it was 25.0% (9/36) vs. 16.0% (4/25), respectively (difference 9%, 95% CI −11.2 to 29.2%, P = 0.40).
Inclusion in the RAP required at least 8 weeks of treatment on study drug and HIV-1 RNA at least 400 copies/ml at the time of analysis, as this is the minimum viral concentration needed for the PhenoSense GT assay. The RAP consisted of 20 participants in the RPV/FTC/TDF arm and seven participants in the EFV/FTC/TDF arm (Table 3). There were 12 participants in the RPV/FTC/TDF arm and 16 in the EFV/FTC/TDF arm who were virologic failures at week 48, but were not included in the RAP because they did not meet the 400 copies/ml threshold or had been treated less than 8 weeks. In the RPV/FTC/TDF arm, 4% (17 of 394 treated patients; 85% of RAP) had emergent key primary NNRTI and/or NRTI resistance-associated mutations [(NNRTI-R): Y181C/I (n = 8), E138K/Q (n = 6), K101E (n = 5); (NRTI-R): M184V/I (n = 15), K65R/N (n
= 3)]. Of these 17 RPV/FTC/TDF-treated participants, 16 had both RPV and FTC resistance-associated substitutions. Fifteen isolates had cross-resistance to another NNRTI, but eight of these remained phenotypically susceptible to EFV. In the EFV/FTC/TDF arm, 1% (three of 392 treated patients; 43% of RAP) had emergent resistance [NNRT-R: K103N (n = 1), G190E/Q (n = 1), and Y188L (n
= 1); NRTI-R: M184I (n = 1)]. Results of post-hoc analysis of resistance development by baseline HIV-1 RNA strata are presented in Table 3.
In the safety analysis population, 7.4% of participants in the RPV/FTC/TDF arm and 13.8% in the EFV/FTC/TDF arm experienced grade 3 or 4 treatment-emergent adverse events through week 48. Of these, 1.8 and 4.8%, respectively, were considered related to study drug. A prespecified safety analysis evaluating adverse events of all grades that are common to the US Efavirenz Package Insert  showed significantly fewer nervous system and psychiatric adverse events in the RPV/FTC/TDF arm (Table 4). The most common nervous system events were dizziness (6.6% RPV/FTC/TDF vs. 22.2% EFV/FTC/TDF), insomnia (9.6 to 14.0%) somnolence (2.5 vs. 6.9%), and headache (12.4 vs. 13.5%). The most common psychiatric events in the RPV/FTC/TDF vs. the EFV/FTC/TDF arms were abnormal dreams (5.8 vs. 24.5%), depression (6.6 vs. 8.9%), and anxiety (5.1 vs. 8.4%). The difference in rates of rash events (17.3 vs. 21.2%) was not significant (P = 0.17).
Study drug discontinuation due to adverse events occurred in 2.5% (10/394) of participants in the RPV/FTC/TDF arm and 8.7% (34/392) in the EFV/FTC/TDF arm (P <0.001). There were 12 different adverse events that led to the 10 discontinuations in the RPV/FTC/TDF arm. They fell into different categories and no single adverse event led to discontinuation in more than one participant in this arm. See SDC (Table S3, http://links.lww.com/QAD/A467). In the EFV/FTC/TDF arm, the most common adverse events that led to discontinuations included 18 due to psychiatric disorders, seven due to nervous system disorders and seven due to skin and subcutaneous tissue disorders. There were two deaths in the EFV/FTC/TDF arm; one was a suicide and one due to sepsis. Neither was considered related to study drug by the investigators. There were no deaths in the RPV/FTC/TDF arm.
Grade 3 or 4 laboratory abnormalities occurred in 17.3% of participants in the RPV/FTC/TDF arm and 16.2% of participants in the EFV/FTC/TDF arm. See SDC (Safety).
Whereas fasting lipid levels remained relatively unchanged from baseline to week 48 in the RPV/FTC/TDF arm, there were significantly higher increases in fasting TC, LDL, triglycerides, and HDL in the EFV/FTC/TDF arm (P
<0.001 for all comparisons between treatment arms using analysis of variance), though the change in TC:HDL was −0.2 in both arms. Categorical analyses of fasting lipids showed similar trends, with more participants in less desirable categories at week 48 in the EFV/FTC/TDF arm for TC, LDL, and triglycerides compared with the RPV/FTC/TDF arm (P <0.001 for each), in which distribution across categories was relatively unchanged from baseline. See SDC (Figures S1-S3, http://links.lww.com/QAD/A467) for additional details on fasting lipids.
The change from baseline to week 48 in eGFR using the Cockcroft–Gault formula based on actual weight was −5.4 ml/min in the RPV/FTC/TDF arm, compared with +4.6 ml/min in the EFV/FTC/TDF arm (P <0.001). The decrease in eGFR in the RPV/FTC/TDF arm was observed at week 4 (first on-treatment assessment) and eGFR was stable thereafter. In contrast, the increase in eGFR in the EFV/FTC/TDF was gradual over the 48-week study. There was one discontinuation in each arm due to a renal event; in both cases, the renal event was renal failure, which resolved after study drug discontinuation. See SDC for additional details on eGFR (Figure S4, http://links.lww.com/QAD/A467) and the discontinuations due to renal failure.
STaR is the first head-to-head comparison of the efficacy and safety of the two STRs, RPV/FTC/TDF and EFV/FTC/TDF, in treatment-naive individuals. Overall, RPV/FTC/TDF was noninferior to EFV/FTC/TDF for virologic suppression and was better tolerated. The greater number of discontinuations due to adverse events in the EFV/FTC/TDF arm, consistent with similar studies [3–5,11], may have influenced virologic success in the Snapshot analysis. Both treatment arms achieved high rates of virologic suppression at week 48 and similar mean CD4+ cell count increases.
In an a priori planned analysis of efficacy stratified by baseline HIV-1 RNA at 100 000 copies/ml, there was a statistically significant difference favoring RPV/FTC/TDF for individuals with HIV-1 RNA 100 000 copies/ml or less (88.8% RFV/FTC/TDF vs. 81.6% EFV/FTC/TDF); RPV/FTC/TDF was noninferior for the more than 100 000 copies/ml stratum (79.9 vs. 81.7%, respectively). This may be due to the fact that for the HIV-1 RNA 100 000 copies/ml or less stratum, there was a higher rate of discontinuations for reasons other than virologic failure in the EFV/FTC/TDF arm. See SDC (Table S1, http://links.lww.com/QAD/A467).
Similar trends in efficacy results were seen in the ECHO and THRIVE studies [3–5], which utilized three different strata for baseline viral load analyses. The results raised concerns about virologic efficacy in the higher viral load strata; therefore, a post-hoc analysis was undertaken in STaR to explore these strata in more detail. In this study, participants with a baseline HIV-1 RNA more than 100 000 and up to 500 000 copies/ml demonstrated similar rates of suppression between the two arms (82.7% RPV/FTC/TDF vs. 82.1% EFV/FTC/TDF). However, for participants with HIV-1 RNA more than 500 000 copies/ml, the virologic response was higher in the EFV/FTC/TDF arm (72.2% RPV/FTC/TDF vs. 80.0% EFV/FTC/TDF). It is difficult to draw conclusions about differences in efficacy in the strata of baseline HIV-1 RNA more than 100 000 copies/ml because the data are based on a small number of participants, especially in the more than 500 000 copies/ml stratum, and the study was not powered to look at differences within strata. However, these data are consistent with previous studies [3–5] and suggest that the response rate to RPV/FTC/TDF may be lower compared with EFV/FTC/TDF for patients with very high HIV-1 RNA levels at treatment initiation.
Virologic failure rates were numerically similar between the two arms for the overall study population (8.1% RPV/FTC/TDF vs. 5.6% EFV/FTC/TDF), as well as in the strata with baseline HIV-1 RNA 100 000 copies/ml or less (5.0 vs. 3.2%) and more than 100 000 and up to 500 000 copies/ml (10.2 vs. 8.5%). The results in the baseline HIV-1 RNA more than 100 000 and up to 500 000 copies/ml stratum of numerically similar virologic efficacy and virologic failure rates suggest that longer term evaluation may inform the potential utility of RPV/FTC/TDF in this subset of patients. Although there was a small sample size (n = 61) in the baseline HIV-1 RNA more than 500 000 copies/ml stratum, the higher virologic failure rates observed (25.0% in the RPV/FTC/TDF arm vs. 16.0% in the EFV/FTC/TDF arm), confirm decreased efficacy in this stratum.
More individuals in the RPV/FTC/TDF arm than in the EFV/FTC/TDF arm met the criteria for inclusion in the RAP, which required HIV-1 RNA at least 400 copies/ml for analysis due to limitations of the assay. A greater proportion of patients in the RPV/FTC/TDF arm developed primary emergent NRTI or NNRTI resistance mutations to at least one regimen component. The M184V/I substitution emerged most frequently in the RPV/FTC/TDF arm, commonly in combination with the E138K and/or Y181C/I substitutions in HIV-1 reverse transcriptase. In addition, the TDF-associated resistance substitutions K65R/N emerged in three patients in the RPV/FTC/TDF arm. Cross-resistance to another NNRTI was common. This pattern of NRTI and NNRTI mutations is similar to previous clinical trials of RPV-containing treatment regimens except that Y181C/I was more frequently observed than E138K/Q in this study .
In individuals with baseline HIV-1 RNA 100 000 copies/ml or less, the proportion of individuals with emergent resistance was similar between arms, whereas the development of resistance to at least one regimen component occurred more frequently with RPV/FTC/TDF among individuals with baseline HIV-1 RNA more than 100 000 and up to 500 000 copies/ml and more than 500 000 copies/ml. Notably, there were more individuals with very high baseline viral load (>500 000 copies/ml) in the RPV/FTC/TDF arm than in the EFV/FTC/TDF arm, potentially contributing to the increased number of individuals with resistance development in this group.
Collectively, these data about patterns of virologic suppression, virologic failure, and resistance development among the higher and lower strata baseline HIV-1 RNA may be an important consideration when initiating treatment in ART-naive patients.
RPV/FTC/TDF was better tolerated than EFV/FTC/TDF, with significantly fewer discontinuations due to adverse events (2.5 vs. 8.7%, respectively) as well as fewer grade 3 or 4 adverse events in the RPV/FTC/TDF arm (7.4 vs. 13.8%, respectively) through week 48. Evaluation of specific adverse events that are listed in the US Efavirenz Package Insert  found significantly lower rates of nervous system and psychiatric adverse events in patients treated with RPV/FTC/TDF than those with EFV/FTC/TDF, with the differences primarily due to dizziness and abnormal dreams. These data suggest RPV/FTC/TDF has a more favorable neuropsychiatric tolerability profile than EFV/FTC/TDF.
The STRs evaluated in this study differed in the changes in fasting lipid subsets at week 48 and this may have clinical relevance for some patients. In the RPV/FTC/TDF arm, there was little change from baseline in fasting lipids. In contrast, there were greater changes in these parameters in the EFV/FTC/TDF arm, including increases in TC, LDL, and triglycerides with concomitant shifts to less optimal NCEP categories. Because of the greater improvement in HDL in the EFV/FTC/TDF arm, the net change in the TC : HDL ratio was −0.2 for both arms. RPV/FTC/TDF demonstrates minimal impact on fasting TC, LDL, and triglycerides, which may be a consideration for some patients.
There was a statistically significant difference in the change from baseline in eGFR favoring EFV/FTC/TDF. The decrease of 5.4 ml/min seen in the RPV/FTC/TDF occurred within the first 4 weeks of treatment and is consistent with the known effect of RPV on the inhibition of tubular secretion of creatinine .
A limitation of this study is that it was open-label. This design was chosen to allow for how the antiretrovirals would be given in clinical practice as STRs; however, this could introduce a bias in reported adverse events and efficacy results secondary to influence on adherence and tolerability. Additionally, although both arms of the study were well matched overall, men were overrepresented and enrollment of individuals with low baseline CD4+ cell counts, high baseline viral load, or age more than 50 years was low. This lack of heterogeneity may limit the generalizability of the results. It should be noted that in the pooled results of the ECHO and THRIVE studies, individuals with baseline CD4+ cell counts less than 50 cells/ml showed poorer response to RPV than EFV . Measuring adherence by pill count also has limitations because it cannot be verified that unreturned pills were in fact consumed at the appropriate dosing interval. No therapeutic drug monitoring or pharmacokinetic analyses were undertaken to verify adherence. As the results reported here are only for 48 weeks of treatment, conclusions on safety and efficacy of long-term use are limited. Greater clarification in this regard will come with the week 96 data from this study.
The STaR study, the first to compare two STRs for the treatment of HIV-1 infection, demonstrated that RPV/FTC/TDF is noninferior to EFV/FTC/TDF at week 48. RPV/FTC/TDF was more efficacious in individuals with baseline HIV-1 RNA 100 000 copies/ml or less, performed similarly to EFV/FTC/TDF in individuals with baseline HIV-1 RNA more than 100 000 and up to 500 000 copies/ml, and was numerically worse for those with baseline HIV-1 RNA more than 500 000 copies/ml. There were more virologic failures with resistance development as the participant's baseline HIV-1 RNA increased in the RPV/FTC/TDF arm (2, 5, and 19%, respectively). After starting treatment, more patients were able to continue taking RPV/FTC/TDF than EFV/FTC/TDF due to fewer adverse events. These results suggest that for all but those with very high levels of HIV-1 RNA, RPV/FTC/TDF provides similar efficacy with better tolerability than EFV/FTC/TDF.
The authors would like to thank Babi Das Wadwhani, Devon Chung, and the Gilead Sciences Clinical Operations group for help with study operations; Dina Saba and the Complera Project Team; Hui Wang and the biostatistics group at Gilead Sciences for help with statistical analysis; Mike Tran, Katherine Fung, and Shelu Bhatia for help with graphics; and Mary Anderson, PhD for help with article development. Most importantly, they would like to thank the study participants as well as the investigators and study staff. This study was designed, funded, conducted and data were analyzed by Gilead Sciences, Foster City, California, USA.
All authors substantially contributed to the study's conception, design, and performance. C.C., D.W., J.A., K.H., J.v.L., M.B., W.T., and E.W. all participated in recruiting significant numbers of participants and reported data for those patients. C.C., D.W., K.H., R.E., D.P., K.W., I.W., S.C., S.D.O., and T.F. all had a significant involvement in the data analyses. All authors were involved in the development of the primary article, interpretation of data, and have read and approved the final version.
This study was supported by Gilead Sciences, Foster City, California, USA.
Conflicts of interest
C.C. has received consulting fees/honoraria and support for travel to meetings for the study from Gilead; serves on scientific advisory boards for Gilead; and has provided expert testimony for Gilead. D.W. has received grants and consulting fees/honoraria, and provisions from Gilead. J.R.A. has received consulting fees/honoraria, fees for participation in review activities, and payment for lectures from Gilead and acts as a scientific advisory board member. K.H. has received grants from Gilead. J.v.L. acts as a scientific advisory board member and steering committee member for Gilead as well as receiving payment for lectures and other meeting-related expenses. M.B. acts as a scientific advisory board member for and has received grants from Gilead. W.T. has received grants from Gilead. E.W. belongs to the Gilead speakers’ bureau. R.E., D.P., K.W., I.W., S.C., S.D.O., and T.F. are employees of and own stock in Gilead Sciences.
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Keywords:© 2014 Lippincott Williams & Wilkins, Inc.
antiretroviral therapy; efavirenz; HIV-1; rilpivirine; single-tablet regimens; treatment-naive