HIV-1 Infection
Conditions
Keywords
HIV, HIV-1, Antiretroviral Treatment-Naïve
Brief summary
The purpose of the study was to evaluate the safety and efficacy of the emtricitabine (FTC)/rilpivirine (RPV)/tenofovir disoproxil fumarate (TDF) single-tablet regimen (STR) compared with the efavirenz (EFV)/FTC/TDF STR in HIV-1 infected adults who had not previously received treatment with antiretroviral medications. Participants were randomized in a 1:1 ratio to receive one of the study treatments. Randomization was stratified by HIV-1 RNA level (≤ 100,000 copies/mL or \> 100,000 copies/mL) at screening. A treatment duration of 96 weeks was planned, with the option for subjects in FTC/RPV/TDF STR arm to receive treatment following the Week 96 visit until FTC/RPV/TDF STR is commercially available or until Gilead Sciences elects to terminate development in that country.
Interventions
DRUGFTC/RPV/TDF
Emtricitabine (FTC) 200 mg/rilpivirine (RPV) 25 mg/tenofovir disoproxil fumarate (TDF) 300 mg single-tablet regimen administered orally once daily with a meal
DRUGEFV/FTC/TDF
Efavirenz (EFV) 600 mg/FTC 200 mg/TDF 300 mg single-tablet regimen administered orally once daily on an empty stomach, preferably at bedtime
Sponsors
Gilead Sciences
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Ability to understand and sign a written informed consent form * Plasma HIV-1 RNA levels ≥ 2,500 copies/mL at screening * No prior use of any approved or experimental anti-HIV drug for any length of time * Screening genotype report showing sensitivity to EFV, FTC, TDF, and lack of the RPV mutations K101E/P, E138A/G/K/Q/R, Y181C/I/V, and H221Y * Normal ECG * Hepatic transaminases (alanine aminotransferase \[ALT\] and aspartate aminotransferase \[AST\]) ≤ 5 x the upper limit of the normal range (ULN) * Total bilirubin ≤ 1.5 mg/dL, or normal direct bilirubin * Adequate hematologic function * Serum amylase ≤ 5 x ULN (participants with serum amylase \> 5 x ULN remained eligible if serum lipase was ≤ 5 x ULN) * Adequate renal function * Males and Females of childbearing potential must have agreed to utilize highly effective contraception methods (two separate forms of contraception, one of which must be an effective barrier method, or be non-heterosexually active, practice sexual abstinence or have a vasectomized partner) from screening throughout the duration of study period and for 12 weeks following the last dose of study drug. * Adult (≥ 18 years) males or non-pregnant females
Exclusion criteria
* A new AIDS-defining condition diagnosed within the 30 days prior to screening * Females who were breastfeeding * Positive serum pregnancy test (female of childbearing potential) * Proven or suspected acute hepatitis in the 30 days prior to study entry * Subjects receiving drug treatment for hepatitis C, or subjects who were anticipated to receive treatment for hepatitis C during the course of the study * Subjects experiencing decompensated cirrhosis * Had an implanted defibrillator or pacemaker * Current alcohol or substance abuse * A history of malignancy within the past 5 years or ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell carcinoma, or resected, non-invasive cutaneous squamous carcinoma * Active, serious infections requiring parenteral antibiotic or antifungal therapy within 30 days prior to baseline * Receiving ongoing therapy or anticipated to need to initiate drugs or herbal/natural supplements during the study that are contraindicated or not recommended for use, including drugs not to be used with FTC, EFV, RPV, or TDF; or subjects with known allergies to the excipients of the FTC/RPV/TDF or EFV/FTC/TDF single-tablet regimens * Participation in any other clinical trial without prior approval from the sponsor was prohibited while participating in this trial. * Had been treated with immunosuppressant therapies or chemotherapeutic agents within 3 months of study screening, or expected to receive these agents or systemic steroids for immunosuppression during the study (eg, corticosteroids, immunoglobulins, and other immune-based or cytokine-based therapies) * Had any other clinical condition or prior therapy that, in the opinion of the Investigator, would have made the participant unsuitable for the study or unable to comply with the dosing requirements
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48 | Week 48 | The percentage of participants with HIV-1 RNA \< 50 copies/mL at Week 48 was analyzed using the US FDA snapshot algorithm. The snapshot algorithm defines a patient's virologic response status using only the viral load at the predefined time point within an allowed window of time. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Fasting Low-density Lipoprotein (LDL) Cholesterol at Week 48 | Baseline to Week 48 | — |
| Change From Baseline in Fasting Triglycerides at Week 48 | Baseline to Week 48 | — |
| Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 96 | Baseline to Week 96 | The percentage of participants with HIV-1 RNA \< 50 copies/mL at Week 96 was analyzed using the US FDA snapshot algorithm. |
| Change From Baseline in CD4 Cell Count at Week 48 | Baseline to Week 48 | — |
| Change From Baseline in Fasting High-density Lipoprotein (HDL) Cholesterol at Week 48 | Baseline to Week 48 | — |
| Change From Baseline in Fasting Total Cholesterol at Week 48 | Baseline to Week 48 | — |
| Development of HIV-1 Drug Resistance Through Week 96, All Participants | Baseline to Week 96 | Participants who experienced either suboptimal virologic response or virologic rebound were considered to have virologic failure and were analyzed for resistance. Suboptimal virologic response 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 ≥ 400 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 their nadir. In addition, subjects who were on study drugs, had not been analyzed previously, and who had HIV-1 RNA ≥ 400 copies/mL at Week 48, Week 96, or their last visit (at or after Week 8) were also analyzed for resistance at their last visit. Subsequent to the first resistance testing, subjects experiencing repeated confirmed virologic failure were assessed for resistance retesting on a case-by-case basis. |
| Development of HIV-1 Drug Resistance Through Week 96, Participants With Viral Resistance | Baseline to Week 96 | Resistance Analysis Set: participants with either suboptimal virologic response or virologic rebound were considered to have virologic failure and were analyzed. Suboptimal virologic response 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 ≥ 400 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 their nadir. In addition, subjects who were on study drugs, had not been analyzed previously, and who had HIV-1 RNA ≥ 400 copies/mL at Week 48, Week 96, or their last visit (at or after Week 8) were also analyzed for resistance at their last visit. Subsequent to the first resistance testing, subjects experiencing repeated confirmed virologic failure were assessed for resistance retesting on a case-by-case basis. |
| Change From Baseline in CD4 Cell Count at Week 96 | Baseline to Week 96 | — |
Countries
Australia, Austria, Belgium, Canada, France, Germany, Italy, Netherlands, Portugal, Puerto Rico, Spain, Switzerland, United Kingdom, United States
Participant flow
Recruitment details
Subjects were enrolled in a total of 121 study sites in North America, Europe, and Australia. The first participant was screened on 23 February 2011. The last participant observation was on 03 February 2014.
Pre-assignment details
991 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| FTC/RPV/TDF FTC 200 mg/RPV 25 mg/TDF 300 mg STR administered orally once daily | 394 |
| EFV/FTC/TDF EFV 600 mg/FTC 200 mg/TDF 300 mg STR administered orally once daily | 392 |
| Total | 786 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Extension Phase | Lost to Follow-up | 6 | 0 |
| Randomized Phase Through Week 96 | Adverse Event | 12 | 43 |
| Randomized Phase Through Week 96 | Death | 0 | 1 |
| Randomized Phase Through Week 96 | Investigators Discretion | 3 | 6 |
| Randomized Phase Through Week 96 | Lack of Efficacy | 16 | 4 |
| Randomized Phase Through Week 96 | Lost to Follow-up | 23 | 22 |
| Randomized Phase Through Week 96 | Pregnancy | 2 | 0 |
| Randomized Phase Through Week 96 | Protocol Violation | 1 | 1 |
| Randomized Phase Through Week 96 | Randomized but not treated | 6 | 7 |
| Randomized Phase Through Week 96 | Subject Non-Compliance | 9 | 7 |
| Randomized Phase Through Week 96 | Withdrew Consent | 12 | 18 |
Baseline characteristics
| Characteristic | Total | FTC/RPV/TDF | EFV/FTC/TDF |
|---|---|---|---|
| Age, Continuous | 37 years STANDARD_DEVIATION 10.7 | 37 years STANDARD_DEVIATION 10.4 | 37 years STANDARD_DEVIATION 11 |
| Cluster of differentiation 4 (CD4) Cell Count | 390.5 cells/μL STANDARD_DEVIATION 183.21 | 395.7 cells/μL STANDARD_DEVIATION 179.64 | 385.2 cells/μL STANDARD_DEVIATION 186.82 |
| HIV-1 RNA | 4.8 log10 copies/mL STANDARD_DEVIATION 0.63 | 4.8 log10 copies/mL STANDARD_DEVIATION 0.65 | 4.8 log10 copies/mL STANDARD_DEVIATION 0.61 |
| HIV-1 RNA Category ≤ 100,000 copies/mL | 510 participants | 260 participants | 250 participants |
| HIV-1 RNA Category > 100,000 copies/mL | 276 participants | 134 participants | 142 participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 4 participants | 3 participants | 1 participants |
| Race/Ethnicity, Customized Asian | 21 participants | 8 participants | 13 participants |
| Race/Ethnicity, Customized Black or African Heritage | 192 participants | 98 participants | 94 participants |
| Race/Ethnicity, Customized Hispanic/Latino | 134 participants | 59 participants | 75 participants |
| Race/Ethnicity, Customized Native Hawaiian or Pacific Islander | 7 participants | 4 participants | 3 participants |
| Race/Ethnicity, Customized Non-Hispanic/Latino | 646 participants | 331 participants | 315 participants |
| Race/Ethnicity, Customized Not Permitted | 5 participants | 3 participants | 2 participants |
| Race/Ethnicity, Customized Not Reported | 1 participants | 1 participants | 0 participants |
| Race/Ethnicity, Customized Other | 32 participants | 13 participants | 19 participants |
| Race/Ethnicity, Customized White | 528 participants | 266 participants | 262 participants |
| Region of Enrollment Australia | 40 participants | 15 participants | 25 participants |
| Region of Enrollment Austria | 13 participants | 7 participants | 6 participants |
| Region of Enrollment Belgium | 9 participants | 4 participants | 5 participants |
| Region of Enrollment Canada | 48 participants | 28 participants | 20 participants |
| Region of Enrollment France | 23 participants | 16 participants | 7 participants |
| Region of Enrollment Germany | 47 participants | 25 participants | 22 participants |
| Region of Enrollment Italy | 13 participants | 10 participants | 3 participants |
| Region of Enrollment Portugal | 7 participants | 2 participants | 5 participants |
| Region of Enrollment Puerto Rico | 18 participants | 8 participants | 10 participants |
| Region of Enrollment Spain | 15 participants | 9 participants | 6 participants |
| Region of Enrollment Switzerland | 5 participants | 2 participants | 3 participants |
| Region of Enrollment United Kingdom | 20 participants | 12 participants | 8 participants |
| Region of Enrollment United States | 541 participants | 262 participants | 279 participants |
| Sex: Female, Male Female | 56 Participants | 28 Participants | 28 Participants |
| Sex: Female, Male Male | 730 Participants | 366 Participants | 364 Participants |
| Use of lipid-lowering agent No | 781 participants | 390 participants | 391 participants |
| Use of lipid-lowering agent Yes | 5 participants | 4 participants | 1 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 300 / 394 | 322 / 392 |
| serious Total, serious adverse events | 36 / 394 | 48 / 392 |
Outcome results
Primary
Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48
The percentage of participants with HIV-1 RNA \< 50 copies/mL at Week 48 was analyzed using the US FDA snapshot algorithm. The snapshot algorithm defines a patient's virologic response status using only the viral load at the predefined time point within an allowed window of time.
Time frame: Week 48
Population: Full Analysis Set: participants who were randomized into the study and received at least 1 dose of study drug
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FTC/RPV/TDF | Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48 | 85.8 percentage of participants |
| EFV/FTC/TDF | Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 48 | 81.6 percentage of participants |
Comparison: The analysis was to assess the noninferiority of FTC/RPV/TDF versus EFV/FTC/TDF using a 95% confidence interval (CI) approach, with a noninferiority margin of 12% (lower bound of CI \> -12%).~700 subjects allocated 1:1 to either treatment arm was predicted to give \> 95% power when the proportion of responders in both treatment groups for the primary endpoint is 80% at Week 48.95% CI: [-1.1, 9.2]
Secondary
Change From Baseline in CD4 Cell Count at Week 48
Time frame: Baseline to Week 48
Population: Participants in the Full Analysis Set with available data were analyzed; the missing = excluded method was used in which all participants with missing data were excluded from analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| FTC/RPV/TDF | Change From Baseline in CD4 Cell Count at Week 48 | 200 cells/μL | Standard Deviation 158.6 |
| EFV/FTC/TDF | Change From Baseline in CD4 Cell Count at Week 48 | 191 cells/μL | Standard Deviation 144.3 |
p-value: 0.3495% CI: [-11, 32]ANOVA
Secondary
Change From Baseline in CD4 Cell Count at Week 96
Time frame: Baseline to Week 96
Population: Participants in the Full Analysis Set with available data were analyzed; the missing = excluded method was used in which all participants with missing data were excluded from analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| FTC/RPV/TDF | Change From Baseline in CD4 Cell Count at Week 96 | 278 cells/μL | Standard Deviation 186.6 |
| EFV/FTC/TDF | Change From Baseline in CD4 Cell Count at Week 96 | 259 cells/μL | Standard Deviation 191.4 |
p-value: 0.1795% CI: [-9, 49]ANOVA
Secondary
Change From Baseline in Fasting High-density Lipoprotein (HDL) Cholesterol at Week 48
Time frame: Baseline to Week 48
Population: Participants in the Safety Analysis Set with available data were analyzed using the missing = excluded method.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| FTC/RPV/TDF | Change From Baseline in Fasting High-density Lipoprotein (HDL) Cholesterol at Week 48 | 2 mg/dL | Standard Deviation 8.7 |
| EFV/FTC/TDF | Change From Baseline in Fasting High-density Lipoprotein (HDL) Cholesterol at Week 48 | 8 mg/dL | Standard Deviation 10.3 |
p-value: <0.001ANOVA
Secondary
Change From Baseline in Fasting Low-density Lipoprotein (LDL) Cholesterol at Week 48
Time frame: Baseline to Week 48
Population: Participants in the Safety Analysis Set with available data were analyzed using the missing = excluded method.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| FTC/RPV/TDF | Change From Baseline in Fasting Low-density Lipoprotein (LDL) Cholesterol at Week 48 | 1 mg/dL | Standard Deviation 24.4 |
| EFV/FTC/TDF | Change From Baseline in Fasting Low-density Lipoprotein (LDL) Cholesterol at Week 48 | 14 mg/dL | Standard Deviation 28.2 |
p-value: <0.001ANOVA
Secondary
Change From Baseline in Fasting Total Cholesterol at Week 48
Time frame: Baseline to Week 48
Population: Participants in the Safety Analysis Set with available data were analyzed using the missing = excluded method.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| FTC/RPV/TDF | Change From Baseline in Fasting Total Cholesterol at Week 48 | 1 mg/dL | Standard Deviation 28.1 |
| EFV/FTC/TDF | Change From Baseline in Fasting Total Cholesterol at Week 48 | 22 mg/dL | Standard Deviation 31.3 |
p-value: <0.001ANOVA
Secondary
Change From Baseline in Fasting Triglycerides at Week 48
Time frame: Baseline to Week 48
Population: Participants in the Safety Analysis Set with available data were analyzed using the missing = excluded method.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| FTC/RPV/TDF | Change From Baseline in Fasting Triglycerides at Week 48 | -8 mg/dL | Standard Deviation 68.9 |
| EFV/FTC/TDF | Change From Baseline in Fasting Triglycerides at Week 48 | 8 mg/dL | Standard Deviation 103 |
p-value: <0.001ANOVA
Secondary
Development of HIV-1 Drug Resistance Through Week 96, All Participants
Participants who experienced either suboptimal virologic response or virologic rebound were considered to have virologic failure and were analyzed for resistance. Suboptimal virologic response 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 ≥ 400 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 their nadir. In addition, subjects who were on study drugs, had not been analyzed previously, and who had HIV-1 RNA ≥ 400 copies/mL at Week 48, Week 96, or their last visit (at or after Week 8) were also analyzed for resistance at their last visit. Subsequent to the first resistance testing, subjects experiencing repeated confirmed virologic failure were assessed for resistance retesting on a case-by-case basis.
Time frame: Baseline to Week 96
Population: Full Analysis Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FTC/RPV/TDF | Development of HIV-1 Drug Resistance Through Week 96, All Participants | Baseline through Week 48 | 4.3 percentage of participants |
| FTC/RPV/TDF | Development of HIV-1 Drug Resistance Through Week 96, All Participants | Week 48 through Week 96 | 1.0 percentage of participants |
| FTC/RPV/TDF | Development of HIV-1 Drug Resistance Through Week 96, All Participants | Baseline through Week 96 | 5.3 percentage of participants |
| EFV/FTC/TDF | Development of HIV-1 Drug Resistance Through Week 96, All Participants | Baseline through Week 48 | 0.8 percentage of participants |
| EFV/FTC/TDF | Development of HIV-1 Drug Resistance Through Week 96, All Participants | Week 48 through Week 96 | 0.3 percentage of participants |
| EFV/FTC/TDF | Development of HIV-1 Drug Resistance Through Week 96, All Participants | Baseline through Week 96 | 1.0 percentage of participants |
Secondary
Development of HIV-1 Drug Resistance Through Week 96, Participants With Viral Resistance
Resistance Analysis Set: participants with either suboptimal virologic response or virologic rebound were considered to have virologic failure and were analyzed. Suboptimal virologic response 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 ≥ 400 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 their nadir. In addition, subjects who were on study drugs, had not been analyzed previously, and who had HIV-1 RNA ≥ 400 copies/mL at Week 48, Week 96, or their last visit (at or after Week 8) were also analyzed for resistance at their last visit. Subsequent to the first resistance testing, subjects experiencing repeated confirmed virologic failure were assessed for resistance retesting on a case-by-case basis.
Time frame: Baseline to Week 96
Population: Resistance Analysis Set
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FTC/RPV/TDF | Development of HIV-1 Drug Resistance Through Week 96, Participants With Viral Resistance | Baseline through Week 48 | 17 participants |
| FTC/RPV/TDF | Development of HIV-1 Drug Resistance Through Week 96, Participants With Viral Resistance | Week 48 through Week 96 | 4 participants |
| FTC/RPV/TDF | Development of HIV-1 Drug Resistance Through Week 96, Participants With Viral Resistance | Baseline through Week 96 | 21 participants |
| EFV/FTC/TDF | Development of HIV-1 Drug Resistance Through Week 96, Participants With Viral Resistance | Baseline through Week 48 | 3 participants |
| EFV/FTC/TDF | Development of HIV-1 Drug Resistance Through Week 96, Participants With Viral Resistance | Week 48 through Week 96 | 1 participants |
| EFV/FTC/TDF | Development of HIV-1 Drug Resistance Through Week 96, Participants With Viral Resistance | Baseline through Week 96 | 4 participants |
Secondary
Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 96
The percentage of participants with HIV-1 RNA \< 50 copies/mL at Week 96 was analyzed using the US FDA snapshot algorithm.
Time frame: Baseline to Week 96
Population: Full Analysis Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FTC/RPV/TDF | Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 96 | 77.9 percentage of participants |
| EFV/FTC/TDF | Percentage of Participants With HIV-1 RNA < 50 Copies/mL at Week 96 | 72.4 percentage of participants |
95% CI: [-0.6, 11.5]