Porter, Danielle P. PhD; Kulkarni, Rima BS; Fralich, Todd MD; Miller, Michael D. PhD; White, Kirsten L. PhD
Single-tablet regimens (STRs) represent substantial improvements in the treatment of HIV infection by providing all the components of an antiretroviral (ARV) therapy regimen in a single pill that is dosed once daily, thereby allowing for simpler and more convenient treatment. The use of simplified regimens, such as STRs, may result in increased adherence, improved quality of life, fewer ARV-related toxicities associated with long-term use, and a lower risk of virological failure (VF).1 There are currently 3 STRs approved by the US Food and Drug Administration (FDA) for initial therapy in ARV-naive HIV-1–infected adults: efavirenz (EFV)/emtricitabine (FTC)/tenofovir disoproxil fumarate (TDF) (Atripla), rilpivirine (RPV)/FTC/TDF (Complera/Eviplera), and elvitegravir/cobicistat/FTC/TDF (Stribild).
The Single-Tablet Regimen (STaR) study (GS-US-264-0110) is a randomized, open-label, 96-week study designed to directly compare the safety and efficacy of the two STRs RPV/FTC/TDF and EFV/FTC/TDF in treatment-naive HIV-1–infected adults. STaR is the first randomized study where all enrolled subjects are taking a complete regimen consisting of one pill once-daily without additional placebo pills. Furthermore, STaR is the first study to evaluate the use of the RPV/FTC/TDF STR in a treatment-naive population. The primary endpoint of noninferiority for the proportion of subjects achieving HIV-1 RNA <50 copies/mL at week 48 for RPV/FTC/TDF versus EFV/FTC/TDF was met, with response rates of 85.8% versus 81.6%, respectively [4.1% treatment difference; 95% confidence interval (CI): −1.1% to 9.2%]. In addition, the proportion of subjects with baseline viral load ≤100,000 copies/mL that achieved HIV-1 RNA <50 copies/mL at week 48 was significantly greater for RPV/FTC/TDF (88.8%) than EFV/FTC/TDF (81.6%) (P = 0.021; 7.2% treatment difference; 95% CI: 1.1% to 13.4%), consistent with studies of other RPV-containing regimens.2,3 Among subjects with baseline viral load >100,000 copies/mL, RPV/FTC/TDF was noninferior to EFV/FTC/TDF at week 48 with 79.9% and 81.7% of subjects achieving HIV-1 RNA <50 copies/mL, respectively (−1.8% treatment difference; 95% CI: −11.1% to 7.5%).
The components of each of these STRs have previously been evaluated in the phase 3 studies ECHO and THRIVE. RPV demonstrated noninferior efficacy and improved safety and tolerability compared with EFV in these studies, with lower incidences of treatment-related adverse events leading to discontinuation.4–6 However, there was an increase in VFs and VFs that developed resistance in subjects with high baseline viral load treated with RPV compared with those treated with EFV.7
Here, the genotypic and phenotypic characterization of emergent resistance in subjects with VF or early discontinuation in the STaR study through week 48 is reported. Analyses of baseline resistance mutations were also conducted to determine the effect of pre-existing nucleoside reverse transcriptase inhibitor (NRTI)– and nonnucleoside reverse transcriptase inhibitor (NNRTI)–associated mutations on treatment response to both study regimens.
MATERIALS AND METHODS
STaR Study Design
STaR (GS-US-264-0110; clinicaltrials.gov identifier: NCT01309243) is a phase 3b, randomized, open-label, multicenter, international, 96-week study evaluating the safety, and efficacy of the RPV/FTC/TDF STR compared to the EFV/FTC/TDF STR in treatment-naive HIV-1–infected subjects. Subjects were randomized 1:1 to RPV/FTC/TDF or EFV/FTC/TDF. Eligibility criteria included screening HIV-1 RNA ≥2500 copies/mL, no prior ARV therapy, genotypic sensitivity to EFV, FTC, tenofovir (TFV), and lack of the RPV mutations K101E/P, E138A/G/K/Q/R, Y181C/I/V, and H221Y. Randomization was stratified by screening HIV-1 RNA (≤100,000 or >100,000 copies/mL). The primary endpoint was the proportion of subjects with HIV-1 RNA of <50 copies/mL at week 48 as determined by the FDA snapshot algorithm (12% prespecified noninferiority margin).
Virologic Failure Definition and Primary Resistance Analysis Population
Subjects with HIV-1 RNA of ≥400 copies/mL who were on study drugs and experienced either virologic nonresponse (VN) or virologic rebound (VR), as defined below, were considered to have VF and were included in the primary resistance analysis population (RAP). Virologic nonresponse was assessed at week 8 and was defined as having HIV-1 RNA ≥50 copies/mL and <1 log10 reduction from baseline at the week 8 visit, which was confirmed at the subsequent visit. Virologic rebound was defined as having 2 consecutive visits with HIV-1 RNA ≥50 copies/mL after achieving HIV-1 RNA <50 copies/mL, or as having 2 consecutive visits with >1 log10 increase in HIV-1 RNA from nadir. The sample from the confirmation visit (if available) was analyzed for resistance development. In addition, subjects who were on study drugs, had not been analyzed previously, and had HIV-1 RNA ≥400 copies/mL at week 48 or their last visit (at or after week 8) were also analyzed for resistance.
Viral load (HIV-1 RNA copies/mL) was assessed at screening, every visit during the treatment period, and at the final/early study drug discontinuation visit using COBAS AMPLICOR Monitor Version 1.5 (Roche Diagnostics, Basel, Switzerland).
At screening, pre-existing resistance in the protease (PR) and reverse transcriptase (RT) portion of the pol gene was assessed by genotype (population sequencing) using the GeneSeq assay (Monogram Biosciences, South San Francisco, CA). This assay also determines the HIV-1 subtype. These screening data were used for baseline resistance analyses. For postbaseline resistance analyses of subjects in the RAP, PR/RT genotyping (population sequencing) and phenotyping were performed using the PhenoSense GT assay (Monogram Biosciences).8 Retrospective baseline PR/RT phenotypes were determined for those subjects in the RAP. The PhenoSense GT assay included genotypic and phenotypic data relevant to all currently approved NRTIs, NNRTIs, and protease inhibitors (PIs).
Secondary Resistance Analyses
Secondary resistance analyses consisted of isolates from subjects not previously analyzed for resistance who discontinued early with any postbaseline HIV-1 RNA ≥400 copies before week 8, and isolates from subjects at VF or discontinuation with HIV-1 RNA 50-399 copies/mL at any postbaseline time point while on study drugs through week 48. The PhenoSense GT assay was used to analyze these samples.
Where appropriate, Fisher's exact test was used to calculate 2-sided P values.
Baseline Genotypic Analyses
Among the 786 enrolled subjects in the intent-to-treat (ITT) analysis set, all subject isolates showed genotypic sensitivity to FTC, TFV, EFV, and RPV at their screening visit as required by the enrollment criteria. Consistent with these enrollment criteria, no subject had a viral isolate with K65R or M184V/I at study entry. One subject in each treatment arm had E138A in their HIV, which was allowed at the beginning of screening but was subsequently not allowed. No other subject isolates had the NNRTI-associated mutations K103N, L100I, K101E/P, E138G/K/R/Q, V179L, Y181C/I/V, Y188C/H/L, G190A/E/S, H221Y, P225H, or M230L. Other primary NNRTI and NRTI resistance mutations were observed in 12.7% and 8.3% of isolates, respectively (Table 1). The most common pre-existing NRTI- or NNRTI-associated mutations were V179D/I/T, V90I, and V118I in RT. Primary PI resistance mutations were observed in 2.5% of subject isolates, most commonly M46I/L and L90M in PR.
The HIV-1 subtype was determined by the screening genotype. Most subjects had HIV-1 subtype B (726/786, 92.4%). Other subtypes present were subtypes C (10/786, 1.3%), AE (6/786, 0.8%), AG (6/786, 0.8%), A1 (5/786, 0.6%), G (5/786, 0.6%), D (2/786, 0.3%), A (1/786, 0.1%), F1 (1/786, 0.1%), F2 (1/786, 0.1%), and “complex” mixtures of subtypes (22/786, 2.8%). One subject did not have data for the HIV-1 subtype. All isolates that developed resistance at week 48 had HIV-1 subtype B except for 1 that had a complex subtype.
Genotypic and Phenotypic Resistance Development in the Overall Study Population at Week 48
Of the 786 randomized and treated subjects, a total of 27 subjects met the criteria for inclusion in the primary RAP (27/786, 3.4%). Isolates from a total of 20/394 (5.1%) and 7/392 (1.8%) subjects were analyzed in the RPV/FTC/TDF and EFV/FTC/TDF arms, respectively, with postbaseline genotypic and phenotypic data for PR and RT available for all subjects (Table 2).
In the RPV/FTC/TDF arm, of the 20 subjects with isolates analyzed for resistance development, 17 (17/394, 4.3% of ITT; 17/20, 85% of RAP) had emergent resistance to a study drug. Sixteen of these had emergent NNRTI resistance mutations, most commonly Y181C/I (n = 8), E138K/Q (n = 6), V90I (n = 6), and K101E (n = 5), and most had multiple NNRTI resistance mutations. Isolates from 16 subjects developed NRTI resistance mutations, most commonly M184V/I (n = 15), K65R/N (n = 3), and K219E (n = 3). The remaining 3 subject isolates in the RPV/FTC/TDF arm lacked emergent resistance mutations in RT and remained phenotypically susceptible to all drugs in the regimen.
Within the RPV/FTC/TDF arm, 16 of 17 isolates with any emergent resistance developed both NNRTI and NRTI genotypic or phenotypic resistance (Tables 3 and 4). All isolates with reduced susceptibility to RPV had primary NNRTI resistance mutations. Among the 16 isolates that had reduced susceptibility to RPV (mean of 17-fold compared with wild-type), most also showed reduced susceptibility to 1 or more of the other NNRTIs: 15 to etravirine, 12 to nevirapine, and 7 to EFV. One isolate had reduced susceptibility to RPV without reduced susceptibility to any other NNRTIs. Isolates with genotypic and/or phenotypic resistance to FTC showed a mean of 90-fold reduced susceptibility to FTC compared with wild-type. All subject isolates with an M184V/I substitution showed reduced susceptibility to FTC and lamivudine. One isolate had phenotypic resistance to FTC and lamivudine but did not have any NRTI-associated resistance mutations by population sequencing. One additional isolate developed phenotypic resistance to FTC and lamivudine with K65R, a mixture of a 1 amino acid deletion and wild-type at T69 (T69T/del), and K219K/E; this isolate also showed reduced susceptibility to TFV. All other isolates remained phenotypically susceptible to TFV. All isolates had full sensitivity to all approved PIs except for 1 that had pre-existing PI resistance that did not progress.
In the EFV/FTC/TDF arm, of the 7 subjects with isolates analyzed for resistance development, 3 (3/392, 0.8% of ITT; 3/7, 43% of RAP) had emergent resistance to a study drug. All 3 developed NNRTI resistance mutations (1 each of K103N, Y188L, and G190E/Q). One of these also developed M184I. The remaining 4 subject isolates in the EFV/FTC/TDF arm lacked emergent resistance mutations and remained phenotypically susceptible to all drugs in the regimen.
Within the EFV/FTC/TDF arm, isolates with phenotypic resistance to EFV had a mean of 75-fold reduced susceptibility to EFV. Among the 3 isolates that had reduced susceptibility to EFV, all also showed reduced susceptibility to 1 or more of the other NNRTIs: 3 to nevirapine and 1 to RPV. All remained susceptible to etravirine. The isolate with M184I in RT had reduced susceptibility to FTC and lamivudine. All isolates remained susceptible to TFV and had full sensitivity to all approved PIs at VF.
Analysis of Resistance Development in Subjects With Baseline Viral Load ≤100,000 Copies/mL
In subjects with baseline viral load ≤100,000 copies/mL, the proportion of subjects with isolates that developed resistance was low and similar between arms [5/260 (1.9%) for RPV/FTC/TDF and 2/250 (0.8%) for EFV/FTC/TDF] (P = 0.45; Table 2). Most of these subjects experienced VR after having achieved HIV-1 RNA <50 copies/mL (4/5 RPV/FTC/TDF; 1/2 EFV/FTC/TDF). Table 3 provides details of genotypic and phenotypic resistance development for all subjects with baseline viral load ≤100,000 copies/mL.
In the RPV/FTC/TDF arm, 4 of the 5 subjects with baseline viral load ≤100,000 copies/mL that developed resistance had isolates with emergent NNRTI resistance mutations, most commonly Y181C (n = 2) and M230I/L (n = 2), and had baseline CD4 cell counts of ≤200 cells per microliter (Table 3). All 5 subjects had isolates that developed NRTI resistance mutations, most commonly M184V/I (n = 5) and K65R/N (n = 2). Among these same isolates, 4 of 5 subjects had virus that developed both NNRTI and NRTI genotypic or phenotypic resistance. Isolates with genotypic resistance to RPV showed a mean of 32-fold reduced susceptibility to RPV compared with wild-type. The 4 isolates with reduced susceptibility to RPV also showed reduced susceptibility to the other NNRTIs etravirine, nevirapine, and efavirenz. All isolates had M184V/I with reduced susceptibility to FTC (mean of 100-fold) and lamivudine, but remained phenotypically susceptible to TFV and all approved PR inhibitors.
In the EFV/FTC/TDF arm, both subjects with baseline viral load ≤100,000 copies/mL that developed resistance had isolates with emergent NNRTI resistance mutations (K103N or Y188L). These isolates had reduced phenotypic susceptibility to EFV (mean of 63-fold) and nevirapine, but remained susceptible to rilpivirine in 1 of 2 cases. Both isolates remained susceptible to etravirine, FTC, TFV, and all approved PR inhibitors.
Analysis of Resistance Development in Subjects With Baseline Viral Load >100,000 Copies/mL
In subjects with baseline viral load >100,000 copies/mL, the number of subjects with isolates that developed resistance was 12/134 (9.0%) for RPV/FTC/TDF and 1/142 (0.7%) for EFV/FTC/TDF (P = 0.001; Table 2). Most of these subjects were nonresponders or rebounders that never suppressed to HIV-1 RNA <50 copies/mL (9/12 RPV/FTC/TDF; 1/1 EFV/FTC/TDF). Table 4 provides details of genotypic and phenotypic resistance development for subjects with baseline viral load >100,000 copies/mL. Of note, within this group, the proportion of subjects with emergent resistant isolates and very high baseline viral load >500,000 copies/mL was 7/36 (19.4%) in the RPV/FTC/TDF arm and 1/25 (4%) in the EFV/FTC/TDF arm (P = 0.13).
In the RPV/FTC/TDF arm, of the 12 subjects with baseline viral load >100,000 copies/mL who had isolates with emergent resistance to a study drug, all 12 had NNRTI resistance mutations, most commonly Y181C/I (n = 6), E138K/Q (n = 6), V90I (n = 6), and K101E (n = 4). Eleven of these 12 isolates developed NRTI resistance mutations, most commonly M184V/I (n = 10) and K219E (n = 2). All 12 isolates developed both NNRTI and NRTI genotypic or phenotypic resistance. The 12 isolates with primary RPV mutations had reduced susceptibility to RPV (mean 13-fold compared with wild-type) and most also showed reduced susceptibility to 1 or more of the other NNRTIs: 11 to etravirine, 8 to nevirapine, and 3 to EFV. One had reduced susceptibility to RPV without reduced susceptibility to any other NNRTIs. Isolates that developed genotypic and/or phenotypic resistance to FTC showed a mean of 85-fold reduced susceptibility compared with wild-type.
In the EFV/FTC/TDF arm, the isolate from the subject with baseline viral load >100,000 copies/mL that had emergent resistance to a study drug developed the NNRTI resistance mutation G190E/Q and reduced susceptibility to EFV (>101-fold) with cross-resistance to nevirapine, but remained susceptible to all of the other NNRTIs. This isolate also developed the M184I substitution in RT and reduced susceptibility to FTC (>80-fold) and lamivudine.
Analysis of Baseline Mutations and Treatment Response
Subjects with pre-existing NNRTI-, NRTI-, and PI-associated resistance mutations in their HIV that were not excluded at study entry had virological responses by FDA snapshot outcome that were generally similar to the responses observed for the overall study population at week 48 (Table 5). Both subjects with pre-existing E138A in their HIV screening genotype (1 in each arm) achieved and maintained virologic suppression through week 48. The presence of the NNRTI substitutions V90I, V106I, V108I, V179D/I/T, and V189I at baseline was associated with comparable response rates to the overall population, consistent with previous RPV studies.9 Moreover, there was no apparent effect of primary PI-associated resistance mutations or the NRTI-associated resistance mutations permitted at study entry (eg, M41L, D67N, V118I, L210W, K219Q/R).
Secondary Resistance Analyses
In addition to the 27 subjects in the primary RAP, 9 subjects (2 RPV/FTC/TDF and 7 EFV/FTC/TDF) who discontinued before week 8 with HIV-1 RNA ≥400 copies/mL were also analyzed for resistance development. All subjects had data available, and no isolates developed genotypic or phenotypic resistance to study drugs.
Twenty-one additional subjects (9 RPV/FTC/TDF and 12 EFV/FTC/TDF) with failure or postbaseline discontinuation samples with HIV-1 RNA 50–399 copies/mL were analyzed for resistance with data available for 3/9 isolates in the RPV/FTC/TDF arm and 4/12 isolates in the EFV/FTC/TDF arm. One isolate in each arm showed development of an NNRTI polymorphic site mutation (RPV/FTC/TDF: V106I; EFV/FTC/TDF: V179V/I) in the absence of other primary NNRTI resistance mutations and without reduced susceptibility to study drugs.
STaR is the first trial to evaluate the use of the RPV/FTC/TDF STR in treatment-naive subjects as well as the first randomized study where all subjects are taking a complete one pill once-daily regimen without additional placebo pills. Week 48 safety and efficacy results demonstrated that RPV/FTC/TDF was noninferior to EFV/FTC/TDF for virological suppression with an improved tolerability profile. The overall rate of resistance development in both arms of the STaR study was low (4.3% RPV/FTC/TDF; 0.8% EFV/FTC/TDF) and comparable with that seen in other recent studies,10,11 and was lower than in previous phase 3 studies conducted using the components of these two regimens (8.0% RPV + FTC/TDF; 3.1% EFV + FTC/TDF).12
Overall, resistance development to at least one regimen component occurred more frequently with RPV/FTC/TDF than EFV/FTC/TDF through week 48. More subjects in the RPV/FTC/TDF arm met the criteria for inclusion in the RAP and a greater proportion developed isolates with primary emergent NRTI and NNRTI resistance mutations and/or reduced susceptibility to at least one regimen component. Within the RPV/FTC/TDF arm, 16 of 17 isolates with any emergent resistance developed both NRTI and NNRTI genotypic and/or phenotypic resistance. This pattern of NRTI and NNRTI mutations is consistent with that previously observed in clinical trials of RPV-containing treatment regimens.7
The proportion of subjects with emergent resistance in their HIV was low (<2%) and similar between arms among subjects with baseline HIV-1 RNA ≤100,000 copies/mL, while resistance development occurred more frequently among RPV/FTC/TDF-treated subjects with baseline viral load >100,000 copies/mL and was primarily driven by subjects with very high baseline viral load >500,000 copies/mL. Notably, there were more subjects with very high baseline viral load (>500,000 copies/mL) in the RPV/FTC/TDF arm (n = 36) than in the EFV/FTC/TDF arm (n = 25), potentially contributing to the increased number of subject isolates with resistance development in this group. Higher baseline viral load correlated with a higher rate of resistance development, as observed in the phase 3 studies of RPV.4–7
Most subjects in the RPV/FTC/TDF arm who had HIV with emergent NNRTI-associated resistance acquired multiple NNRTI mutations and complex patterns of resistance. The Y181C/I substitution emerged most frequently through week 48, always in combination with at least one other RPV-associated NNRTI resistance mutation. This pattern of resistance is slightly different than that observed in the phase 3 studies of RPV where E138K was the most frequent NNRTI substitution while Y181C/I emerged at a lower rate than E138K and only in subjects with baseline viral load >100,000 copies/mL.7 Through week 48 in the present study, no subjects with baseline viral load ≤100,000 copies/mL developed isolates with E138 substitutions and 2 developed Y181C. Among subjects with baseline viral load >100,000 copies/mL, 6 had isolates with E138K/Q and 6 had Y181C/I with 2 having substitutions at both E138 and Y181. Isolates that acquired Y181C/I had increased phenotypic resistance to RPV compared with isolates that developed E138K/Q (mean fold changes for RPV were 30-fold for isolates that included Y181C, 27-fold for Y181I, and 8-fold for E138K/Q). Differences in regimens and formulations between STaR and the phase 3 studies (ie, open-label STR vs. individual components + placebo pills) may have contributed to the variations in resistance development in these studies with the STR resulting in a moderately higher genetic barrier to resistance with less resistance development overall (8.0% for RPV + FTC/TDF vs. 4.3% for RPV/FTC/TDF).
One RPV/FTC/TDF-treated subject with baseline viral load ≤100,000 copies/mL developed the RPV-resistance associated mutation combination K103N + L100I in their HIV. While neither the K103N nor the L100I mutation confer resistance to RPV on their own (in vitro fold changes of 0.9 for each), this combination of mutations has been shown to confer 7-fold reduced susceptibility to RPV in vitro and was also observed in one subject with VF that switched to RPV/FTC/TDF from a PI-based regimen in the GS-US-264-0106 study.12–15
All 17 subject isolates that developed any resistance in the RPV/FTC/TDF arm had the M184V/I substitution and/or reduced susceptibility to FTC. Most isolates with emergent E138K developed the combination of E138K + M184I rather than E138K + M184V, as has been previously observed, a combination that increases resistance to RPV relative to E138K alone and confers resistance to FTC.7,16–18 Isolates with emergent Y181C developed the combination with M184I more frequently than M184V while all isolates with emergent Y181I also developed M184V. However, the overall number of isolates that developed Y181C/I + M184I/V was low.
Secondary resistance analyses revealed no significant additional resistance development in subjects who discontinued before week 8 or with HIV-1 RNA <400 copies/mL. Notably, the success rate for the PhenoSense GT assay was low (33%) as expected for samples with viral loads 50–399 copies/mL. Nevertheless, data from these analyses demonstrate the robustness of the protocol-defined criteria for inclusion in the primary RAP, which successfully captured all resistance development in this study.
The STRs in the STaR study demonstrated overall lower rates of resistance development in both treatment arms compared with the phase 3 studies of the individual components of these regimens. The proportion of subjects that developed resistant isolates was similar between arms in subjects with baseline viral load ≤100,000 copies/mL, but was higher in RPV/FTC/TDF-treated compared with EFV/FTC/TDF-treated subjects with baseline viral load >100,000 copies/mL. While overall trends in NNRTI and NRTI resistance in the STaR study were consistent with the earlier phase 3 studies of RPV as an individual agent, slight variations that may result from the use of the RPV/FTC/TDF STR were observed.
The authors would like to thank all of the patients and investigators who participated in the STaR study, and the Rilpivirine and Complera/Eviplera project teams for their contributions to this work.
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