HIV-1
Conditions
Keywords
Double-blind, comparative, trial, maraviroc, versus, emtricitabine/tenofovir, both with darunavir/ritonavir, antiretroviral-naive, Ccr5 tropic, Hiv 1, patients.
Brief summary
The purpose of this study is to assess whether maraviroc administered once daily is non-inferior to emtricitabine/tenofovir also administered once daily each in combination with darunavir/ritonavir in the treatment of antiretroviral-naive patients as evaluated at Week 48 of treatment.
Detailed description
The study was terminated on October 8, 2013 following a preliminary review of the Week 48 primary efficacy data by the study's external independent Data Monitoring Committee (DMC). The DMC assessed the data as demonstrating significant differences between the treatment arms in virologic responses and failures. The DMC recommended and the Sponsor concurred that the study be terminated because of the inferior efficacy of the Maraviroc arm as compared to the comparator arm (Emtricitabine/Tenofovir).
Interventions
DRUGMaraviroc
Maraviroc tablet 150 mg once daily for 96 weeks.
Emtricitabine/tenofovir tablet 200/300 mg once daily for 96 weeks.
DRUGdarunavir/ritonavir 800/100 mg
darunavir/ritonavir 800/100 mg
DRUGplacebo for emtricitabine/tenofovir
placebo for emtricitabine/tenofovir
placebo for maraviroc
Sponsors
Pfizer
ViiV Healthcare
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Plasma HIV-1 RNA equal to or greater than 1,000 copies/mL measured at the Screening Visit. * CD4 count equal to or greater than 100 cells/mm3 at Screening. * Have only R5 HIV 1 at Screening as verified by a randomized tropism assay.
Exclusion criteria
* Prior treatment with any other HIV antiretroviral therapy for more than 14 days at any time. * Any evidence of genotypic/phenotypic resistance to darunavir, tenofovir, and emtricitabine. * CXCR4 using virus detected using randomized tropism determination or repeated failure to obtain an interpretable tropism result.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Plasma HIV-1 RNA <50 Copies/mL. | Week 48 | The proportion of participants who achieved HIV-1 RNA \<50 copies/mL at week 48 was assessed according to Food and Drug Administration's (FDA's) Missing, Switch, Discontinuation'=Failure (MSDF) Snapshot algorithm. The algorithm used the plasma HIV-1 RNA in the Week 48 visit window, followed the virology-first principle and considers a participant who has a missing plasma HIV-1 RNA, or switches to prohibited ARV regimen or discontinues from the study or study drug for any reason, or dies, as a failure. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Grade 3 or 4 AEs | Week 96 | Number of participants with grade 3 or 4 AEs are presented here. |
| Number of Participants Who Discontinued Due to AEs | Week 96 | Number of participants who discontinued due to AEs are reported here. Three participants (two from the MVC+DRV/r arm and one from the FTC/TDF+DRV/r arm) were not considered as discontinued due to AE because other reasons for discontinuation were prioritized for these participants. |
| Number of Treatment-related AEs | Week 96 | Number of treatment-related AEs are presented here. |
| Number of Participants With Treatment-emergent Serious Adverse Events | Week 96 | Total number of participants with treatment-emergent serious adverse events are reported |
| Number of Participants With Abnormal Laboratory Values | Week 96 | Number of participants with laboratory abnormalities are reported |
| Severity of Abnormal Laboratory Values | Week 96 | Number of participants who had clinically significant laboratory abnormalities of Grade 3 and Grade 4 according to DAIDS. Abnormality incidence of highest grade was reported for a labcode for each individual participant. |
| The Relationship Between the Proportion of Participants With Plasma HIV-1 RNA <50 Copies/mL at the Week 48 and the Screening Tropism Test (Genotype Test or ESTA). | Week 48 | The relationship of the proportion of participants achieving HIV-1 RNA \<50 copies/mL at Week 48 with the screening tropism test for the MVC containing regimen was analyzed. Virologic response for a participant at Week 48 was derived using the FDA's Snapshot MSDF algorithm. Difference in proportions of patients with plasma HIV-1 RNA \<50 copies/mL at week 48 between the maraviroc and the emtricitabine/tenofovir treatment arms, with two-sided 95% confidence interval, among patients who are R5 by genotype (including some who were originally randomized to ESTA and are R5 by genotype upon retesting), were calculated via the Maximum Likelihood method. The estimate was adjusted for the screening plasma HIV RNA level (\<100,000 vs. ≥100,000) copies/mL via the Mantel Haenszel (MH) method. |
| Virologic Outcomes at Week 48 Using Protocol-Defined Treatment Failure (PDTF). | Week 48 | Per the protocol participants who meet the following criteria were regarded as PDTFs requiring a confirmatory plasma HIV-1 RNA determination: • Decrease in plasma HIV-1 RNA \<1 log10 from baseline after Week 4 unless plasma HIV-1 RNA is \<50 copies/mL, or • Plasma HIV-1 RNA \>1.0 log10 above the nadir value after Week 4 where the nadir is the lowest plasma HIV-1 RNA concentration, or • Plasma HIV-1 RNA ≥50 copies/mL at any time after Week 24, or • Plasma HIV-1 RNA ≥50 copies/mL after suppression to \<50 copies/mL on two consecutive visits, or • Decrease in plasma HIV-1 RNA ≤2 log10 from baseline on or after Week 12 unless plasma HIV-1 RNA is \<400 copies/mL. Decrease in plasma HIV-1 RNA ≤2 log10 from baseline on or after Week 12 unless plasma HIV-1 RNA is \<50 copies/mL (before August 30 2012) or \<400 copies/mL (after August 30 2012). |
| Tropism Change Between Screening or Baseline and PDTF | Week 48 | For participants meeting the PDTF criteria, tropism was assessed using the original randomized and alternate assays (ie, both genotype testing and ESTA). Data reported here corresponds to the timepoint at or after PDTF. |
| Number of Participants With Viral Resistance to Maraviroc (Maraviroc Treated Participants Only) in Participants Meeting PDTF Criteria. | Week 48 | For participants meeting the PDTF criteria, viral resistance to maraviroc for maraviroc treated participants was assessed in patients with R5 virus at failure. The resistance level is calculated by reference to a laboratory strain of virus that is analyzed in parallel with the clinical isolate to identify 50% inhibitory concentrations (IC50). The maximal percent inhibition is the percent inhibition that is achieved in a titration of the drug at high concentrations when the addition of more drug does not result in increased inhibition. Maximal percent inhibition is obtained in the same way as the titration for IC50, but the key measure is of the plateau height of percent inhibition, where increased concentration of maraviroc does not result in additional inhibition. This is consistent with the virus developing some ability to use maraviroc-bound CCR5 for entry. A significant change in IC50 is not required for this mechanism. |
| Number of Participants With Resistance to Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTI), Non-nucleoside Reverse Transcriptase Inhibitors (NNRTI), and Protease Inhibitors (PI) in Participants Meeting PDTF Criteria | Week 48 | For participants meeting the PDTF criteria, viral resistance (both genotypic and phenotypic) to NRTI, NNRTI, and PI's were assessed at Baseline and on-treatment. The assessment was performed using the overall (i.e. net) susceptibility score provided using the PhenoSense GT assay. The number of participants with successful assessments were 15/17 for the MVC+DRV/r arm and 3/3 for the FTC/TDF+DRV/r arm. |
| Frequency of Adverse Events (AE). | Week 96 | Number of participants with treatment-emergent non serious AEs |
| Percent Change From Baseline in Immune Cell Function at Week 48: Lymphocyte Activation Marker CD4 (%) | Baseline, Week 48 | The differences in the magnitude of changes in CD4+ from Baseline through Week 48 for maraviroc versus emtricitabine/tenofovir were compared. |
| Absolute Change From Baseline in Immune Cell Function at Week 48: Lymphocyte Marker Cluster of Differentiation 8 (CD8, Cell/mm^3) | Baseline, Week 48 | The differences in the magnitude of changes in CD8+ cell counts from baseline through Week 48 for maraviroc versus emtricitabine/tenofovir were compared. |
| Percent Change From Baseline in Immune Cell Function at Week 48: Lymphocyte Activation Marker CD8 (%) | Baseline, Week 48 | The differences in the magnitude of changes in CD8+ cell counts from Baseline through Week 48 for maraviroc versus emtricitabine/tenofovir were compared. |
| Absolute Change in CD4+/CD8+ Ratio From Baseline to Week 48 | Baseline, Week 48 | The differences in the magnitude of changes in CD4+/CD8+ ratio from Baseline through Weeks 48 for maraviroc versus emtricitabine/tenofovir were compared. |
| Changes in Peripheral Fat Distribution Using Dual Energy X-ray Absorptiometry [DEXA] Scan From Baseline and at Week 48. | Week 48 | A sub-study was conducted in which the participants underwent whole-body DEXA scans to evaluate peripheral fat tissue estimates for left and right arms and legs and truncal fat mass and truncal lean mass. Truncal abdominal fat were estimated from the DEXA scan field set on the torso. The effects on estimates of fat mass and lean mass were addressed by providing LSMs of change from baseline. |
| Changes in Trunk to Limb Fat Distribution Using DEXA Scan From Baseline and at Week 48 | Week 48 | A sub-study was conducted in which the participants underwent whole-body DEXA scans to evaluate peripheral fat tissue estimates for left and right arms and legs and truncal fat mass and truncal lean mass. Truncal abdominal fat were estimated from the DEXA scan field set on the torso. The effects on estimates of fat mass and lean mass were addressed by providing LSMs of change from baseline. |
| Changes in Bone Mineral Density (Using DEXA Scan and Serum Markers) From Baseline and at Week 48 - Total Hip BMD | Week 48 | Bone mineral density was evaluated by DEXA scan in a subset of participants who consented to these evaluations. The effects on BMD were addressed by providing LSMs of change from baseline bone mineral density of the lumbar spine (L1-L4), left total hip and femoral neck as measured by the DEXA scan. |
| Changes in Bone Mineral Density (Using DEXA Scan and Serum Markers) From Baseline and at Week 48 - Femoral Neck BMD | Week 48 | Bone mineral density was evaluated by DEXA scan in a subset of participants who consented to these evaluations. The effects on BMD were addressed by providing LSMs of change from Baseline bone mineral density femoral neck as measured by the DEXA scan. |
| Changes in Bone Mineral Density (Using DEXA Scan and Serum Markers) From Baseline and at Week 48 - AP Lumbar Spine (L1 - L4) BMD | Week 48 | Bone mineral density was evaluated by DEXA scan in a subset of participants who consented to these evaluations. The effects on BMD were addressed by providing LSMs of change from baseline bone mineral density of the lumbar spine (L1-L4) as measured by the DEXA scan. |
| Change in Bone Turnover Markers From Baseline and at Week 48 - Blood Osteocalcin | Week 48 | Bone turnover marker, osteocalcin, was collected in the subset of participants participating in the DEXA scan sub-study. |
| Change in Bone Turnover Markers From Baseline and at Week 48 - Type 1 Collagen Peptide (CTX-1) | Week 48 | Bone turnover marker, C-telopeptide of type 1 collagen (CTx), was collected in the subset of participants participating in the DEXA scan sub-study. |
| Absolute Change From Baseline in Immune Cell Function at Week 48: Lymphocyte Marker Cluster of Differentiation 4 (CD4, Cell/mm^3) | Baseline, Week 48 | The differences in the magnitude of changes in CD4+ at Baseline and at Week 48 for maraviroc versus emtricitabine/tenofovir were compared. |
Countries
Australia, Austria, Belgium, Canada, Denmark, Finland, France, Germany, Hungary, Italy, Netherlands, Poland, Portugal, Puerto Rico, Spain, Sweden, Switzerland, United Kingdom, United States
Participant flow
Recruitment details
Overall, 1423 participants were screened and 813 participants randomized in the study. A total of 797 participants were treated (396 were treated in the maraviroc + darunavir/ritonavir \[MVC+DRV/r\] group and 401 in the emtricitabine/tenofovir + darunavir/ritonavir \[FTC/TDF+DRV/r\] group). The study was conducted in 138 sites in 18 countries.
Pre-assignment details
Participants were randomized to undergo either genotype testing or enhanced Trofile assay (ESTA) in a 1:1 ratio. Among participants who were identified as being infected with R5 tropic HIV-1 by either testing methods, 813 were randomized in a 1:1 ratio to receive 96-week treatment either in the MVC+DRV/r arm or in the FTC/TDF+DRV/r arm.
Participants by arm
| Arm | Count |
|---|---|
| MVC+DRV/r Participants infected with R5 HIV-1 received oral tablets of Maraviroc 150 mg once daily plus darunavir/ritonavir 800/100 mg once daily plus placebo for emtricitabine/tenofovir once daily. | 396 |
| FTC/TDF+DRV/r Participants infected with R5 HIV-1 received oral tablets of emtricitabine/tenofovir 200/300 mg once daily plus darunavir/ritonavir 800/100 mg once daily plus placebo for maraviroc once daily. | 401 |
| Total | 797 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 22 | 23 |
| Overall Study | Insufficient clinical response | 48 | 11 |
| Overall Study | Lost to Follow-up | 17 | 16 |
| Overall Study | Medication error without associated AE | 0 | 1 |
| Overall Study | No longer willing to participate | 9 | 12 |
| Overall Study | Other reasons | 6 | 8 |
| Overall Study | Protocol Violation | 4 | 1 |
| Overall Study | Study terminated by sponsor | 254 | 285 |
| Overall Study | Withdrawn due to pregnancy | 1 | 2 |
Baseline characteristics
| Characteristic | MVC+DRV/r | FTC/TDF+DRV/r | Total |
|---|---|---|---|
| Age, Continuous | 37.9 Years STANDARD_DEVIATION 10.9 | 36.2 Years STANDARD_DEVIATION 10.9 | 37.1 Years STANDARD_DEVIATION 10.9 |
| Sex: Female, Male Female | 36 Participants | 34 Participants | 70 Participants |
| Sex: Female, Male Male | 360 Participants | 367 Participants | 727 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 257 / 396 | 285 / 401 |
| serious Total, serious adverse events | 41 / 396 | 40 / 401 |
Outcome results
Primary
Percentage of Participants With Plasma HIV-1 RNA <50 Copies/mL.
The proportion of participants who achieved HIV-1 RNA \<50 copies/mL at week 48 was assessed according to Food and Drug Administration's (FDA's) Missing, Switch, Discontinuation'=Failure (MSDF) Snapshot algorithm. The algorithm used the plasma HIV-1 RNA in the Week 48 visit window, followed the virology-first principle and considers a participant who has a missing plasma HIV-1 RNA, or switches to prohibited ARV regimen or discontinues from the study or study drug for any reason, or dies, as a failure.
Time frame: Week 48
Population: The Full Analysis Set (FAS) consisted of all randomized participants who received at least one dose of the study drug. The missing value was imputed per FDA's MSDF Snapshot algorithm as described under Outcome Measure Description above.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MVC+DRV/r | Percentage of Participants With Plasma HIV-1 RNA <50 Copies/mL. | 77.3 Percentage of participants |
| FTC/TDF+DRV/r | Percentage of Participants With Plasma HIV-1 RNA <50 Copies/mL. | 86.8 Percentage of participants |
Comparison: The difference in the percentages between the maraviroc and the emtricitabine/tenofovir treatment arms and the 2-sided 95% confidence interval for the difference was provided using the stratum-adjusted Mantel-Haenszel (MH) method over the two assays and the screening plasma HIV-1 RNA levels (\>=100,000 copies/mL or \<100,000 copies/mL). The sample size was chosen to yield a power of ≥90%. The 95% CIs and mean difference (final values) are presented as percentages above.95% CI: [-14.83, -4.24]
Secondary
Absolute Change From Baseline in Immune Cell Function at Week 48: Lymphocyte Marker Cluster of Differentiation 4 (CD4, Cell/mm^3)
The differences in the magnitude of changes in CD4+ at Baseline and at Week 48 for maraviroc versus emtricitabine/tenofovir were compared.
Time frame: Baseline, Week 48
Population: The FAS consisted of all randomized participants who received at least one dose of the study drug. Missing values were imputed using LOCF approach. Baseline was calculated as the average of all the pre-dose measurements excluding the screening value. If all pre-dose values were missing, screening value was considered as the baseline.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MVC+DRV/r | Absolute Change From Baseline in Immune Cell Function at Week 48: Lymphocyte Marker Cluster of Differentiation 4 (CD4, Cell/mm^3) | Baseline (n=396, 401) | 382.0 cell/mm^3 | Standard Deviation 173.4 |
| MVC+DRV/r | Absolute Change From Baseline in Immune Cell Function at Week 48: Lymphocyte Marker Cluster of Differentiation 4 (CD4, Cell/mm^3) | Week 48 (n=394, 396) | 576.9 cell/mm^3 | Standard Deviation 226 |
| MVC+DRV/r | Absolute Change From Baseline in Immune Cell Function at Week 48: Lymphocyte Marker Cluster of Differentiation 4 (CD4, Cell/mm^3) | Change from Baseline at Week 48 (n=394, 396) | 194.9 cell/mm^3 | Standard Deviation 175.5 |
| FTC/TDF+DRV/r | Absolute Change From Baseline in Immune Cell Function at Week 48: Lymphocyte Marker Cluster of Differentiation 4 (CD4, Cell/mm^3) | Baseline (n=396, 401) | 379.5 cell/mm^3 | Standard Deviation 170.9 |
| FTC/TDF+DRV/r | Absolute Change From Baseline in Immune Cell Function at Week 48: Lymphocyte Marker Cluster of Differentiation 4 (CD4, Cell/mm^3) | Week 48 (n=394, 396) | 574.6 cell/mm^3 | Standard Deviation 232.1 |
| FTC/TDF+DRV/r | Absolute Change From Baseline in Immune Cell Function at Week 48: Lymphocyte Marker Cluster of Differentiation 4 (CD4, Cell/mm^3) | Change from Baseline at Week 48 (n=394, 396) | 194.2 cell/mm^3 | Standard Deviation 175.8 |
Comparison: Results were from an ANCOVA model with change from Baseline as the response variable and the following fixed effect model terms: Treatment group, Screening plasma HIV RNA concentration, Screening Tropism Assay, Baseline value of the response variable.p-value: 0.97595% CI: [-24.4, 23.6]ANCOVA
Secondary
Absolute Change From Baseline in Immune Cell Function at Week 48: Lymphocyte Marker Cluster of Differentiation 8 (CD8, Cell/mm^3)
The differences in the magnitude of changes in CD8+ cell counts from baseline through Week 48 for maraviroc versus emtricitabine/tenofovir were compared.
Time frame: Baseline, Week 48
Population: The FAS consisted of all randomized participants who received at least one dose of the study drug. Missing values were imputed using LOCF approach. Baseline was calculated as the average of all the pre-dose measurements excluding the screening value. If all pre-dose values were missing, screening value was considered as the baseline.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MVC+DRV/r | Absolute Change From Baseline in Immune Cell Function at Week 48: Lymphocyte Marker Cluster of Differentiation 8 (CD8, Cell/mm^3) | Baseline (n=396, 401) | 954.4 cell/mm^3 | Standard Deviation 502.1 |
| MVC+DRV/r | Absolute Change From Baseline in Immune Cell Function at Week 48: Lymphocyte Marker Cluster of Differentiation 8 (CD8, Cell/mm^3) | Week 48 (n=394, 396) | 900.0 cell/mm^3 | Standard Deviation 508.3 |
| MVC+DRV/r | Absolute Change From Baseline in Immune Cell Function at Week 48: Lymphocyte Marker Cluster of Differentiation 8 (CD8, Cell/mm^3) | Change from Baseline at Week 48 (n=394, 396) | -49.9 cell/mm^3 | Standard Deviation 410.7 |
| FTC/TDF+DRV/r | Absolute Change From Baseline in Immune Cell Function at Week 48: Lymphocyte Marker Cluster of Differentiation 8 (CD8, Cell/mm^3) | Baseline (n=396, 401) | 914.5 cell/mm^3 | Standard Deviation 473 |
| FTC/TDF+DRV/r | Absolute Change From Baseline in Immune Cell Function at Week 48: Lymphocyte Marker Cluster of Differentiation 8 (CD8, Cell/mm^3) | Week 48 (n=394, 396) | 751.1 cell/mm^3 | Standard Deviation 386.7 |
| FTC/TDF+DRV/r | Absolute Change From Baseline in Immune Cell Function at Week 48: Lymphocyte Marker Cluster of Differentiation 8 (CD8, Cell/mm^3) | Change from Baseline at Week 48 (n=394, 396) | -157.9 cell/mm^3 | Standard Deviation 444 |
Comparison: Results were from ANCOVA model with change from baseline as the response variable and the following fixed effect model terms: Treatment group, Screening plasma HIV RNA concentration, Screening Tropism Assay, Baseline value of the response variable.p-value: <0.000195% CI: [76.5, 178.8]ANCOVA
Secondary
Absolute Change in CD4+/CD8+ Ratio From Baseline to Week 48
The differences in the magnitude of changes in CD4+/CD8+ ratio from Baseline through Weeks 48 for maraviroc versus emtricitabine/tenofovir were compared.
Time frame: Baseline, Week 48
Population: The FAS consisted of all randomized participants who received at least one dose of the study drug. Missing values were imputed using LOCF approach. Baseline was calculated as the average of all the pre-dose measurements excluding the screening value. If all pre-dose values were missing, screening value was considered as the baseline.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MVC+DRV/r | Absolute Change in CD4+/CD8+ Ratio From Baseline to Week 48 | Baseline (n=396, 401) | 0.47 Ratio | Standard Deviation 0.24 |
| MVC+DRV/r | Absolute Change in CD4+/CD8+ Ratio From Baseline to Week 48 | Week 48 (n=394, 396) | 0.75 Ratio | Standard Deviation 0.34 |
| MVC+DRV/r | Absolute Change in CD4+/CD8+ Ratio From Baseline to Week 48 | Change from Baseline at Week 48 (n=394, 396) | 0.28 Ratio | Standard Deviation 0.22 |
| FTC/TDF+DRV/r | Absolute Change in CD4+/CD8+ Ratio From Baseline to Week 48 | Baseline (n=396, 401) | 0.48 Ratio | Standard Deviation 0.25 |
| FTC/TDF+DRV/r | Absolute Change in CD4+/CD8+ Ratio From Baseline to Week 48 | Week 48 (n=394, 396) | 0.87 Ratio | Standard Deviation 0.45 |
| FTC/TDF+DRV/r | Absolute Change in CD4+/CD8+ Ratio From Baseline to Week 48 | Change from Baseline at Week 48 (n=394, 396) | 0.39 Ratio | Standard Deviation 0.34 |
Comparison: Results are from an ANCOVA model with change from Baseline as the response variable and the following fixed effect model terms: Treatment group, Screening plasma HIV RNA concentration, Screening Tropism Assay, Baseline value of the response variable.p-value: <0.000195% CI: [-0.15, -0.07]ANCOVA
Secondary
Change in Bone Turnover Markers From Baseline and at Week 48 - Blood Osteocalcin
Bone turnover marker, osteocalcin, was collected in the subset of participants participating in the DEXA scan sub-study.
Time frame: Week 48
Population: Safety Analysis Set was the same as the FAS consisting of all randomized participants who received at least one dose of the study drug but analyzed as realized for tropism assay and treatment. Missing values were imputed using LOCF approach.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MVC+DRV/r | Change in Bone Turnover Markers From Baseline and at Week 48 - Blood Osteocalcin | 5.61 ng/mL | Standard Deviation 8.02 |
| FTC/TDF+DRV/r | Change in Bone Turnover Markers From Baseline and at Week 48 - Blood Osteocalcin | 6.77 ng/mL | Standard Deviation 8.31 |
Comparison: Results are from ANCOVA model with change from Baseline as the response variable and the following fixed effect model terms: treatment group, age, race, Screening BMI, and Baseline value of the response variable. Treatment differences are estimated using LS means with factor levels weighted according to overall analysis population proportions.p-value: 0.172295% CI: [-5.17, 0.94]ANCOVA
Secondary
Change in Bone Turnover Markers From Baseline and at Week 48 - Type 1 Collagen Peptide (CTX-1)
Bone turnover marker, C-telopeptide of type 1 collagen (CTx), was collected in the subset of participants participating in the DEXA scan sub-study.
Time frame: Week 48
Population: Safety Analysis Set was the same as the FAS consisting of all randomized participants who received at least one dose of the study drug but analyzed as realized for tropism assay and treatment. Missing values were imputed using LOCF approach.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MVC+DRV/r | Change in Bone Turnover Markers From Baseline and at Week 48 - Type 1 Collagen Peptide (CTX-1) | 121.13 pg/mL | Standard Deviation 243.03 |
| FTC/TDF+DRV/r | Change in Bone Turnover Markers From Baseline and at Week 48 - Type 1 Collagen Peptide (CTX-1) | 223.52 pg/mL | Standard Deviation 293.03 |
Comparison: Results are from an ANCOVA model with change from Baseline as the response variable and the following fixed effect model terms: treatment group, age, race, Screening BMI, Baseline value of the response variable. Treatment differences are estimated using LS means with factor levels weighted according to overall analysis population proportions.p-value: 0.007195% CI: [-218.34, -35.23]ANCOVA
Secondary
Changes in Bone Mineral Density (Using DEXA Scan and Serum Markers) From Baseline and at Week 48 - AP Lumbar Spine (L1 - L4) BMD
Bone mineral density was evaluated by DEXA scan in a subset of participants who consented to these evaluations. The effects on BMD were addressed by providing LSMs of change from baseline bone mineral density of the lumbar spine (L1-L4) as measured by the DEXA scan.
Time frame: Week 48
Population: Safety Analysis Set was the same as the FAS consisting of all randomized participants who received at least one dose of the study drug but analyzed as realized for tropism assay and treatment. Missing values were imputed using LOCF approach.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MVC+DRV/r | Changes in Bone Mineral Density (Using DEXA Scan and Serum Markers) From Baseline and at Week 48 - AP Lumbar Spine (L1 - L4) BMD | -0.020 g/cm^2 | Standard Error 0.006 |
| FTC/TDF+DRV/r | Changes in Bone Mineral Density (Using DEXA Scan and Serum Markers) From Baseline and at Week 48 - AP Lumbar Spine (L1 - L4) BMD | -0.025 g/cm^2 | Standard Error 0.006 |
Comparison: Results are from ANCOVA model with change from Baseline as the response variable and the following fixed effect model terms: treatment group, age, race, Screening BMI, and Baseline value of the response variable. Treatment differences are estimated using LS means with factor levels weighted according to overall analysis population proportions.p-value: 0.418895% CI: [-0.007, 0.018]ANCOVA
Secondary
Changes in Bone Mineral Density (Using DEXA Scan and Serum Markers) From Baseline and at Week 48 - Femoral Neck BMD
Bone mineral density was evaluated by DEXA scan in a subset of participants who consented to these evaluations. The effects on BMD were addressed by providing LSMs of change from Baseline bone mineral density femoral neck as measured by the DEXA scan.
Time frame: Week 48
Population: Safety Analysis Set was the same as the FAS consisting of all randomized participants who received at least one dose of the study drug but analyzed as realized for tropism assay and treatment. Missing values were imputed using LOCF approach.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MVC+DRV/r | Changes in Bone Mineral Density (Using DEXA Scan and Serum Markers) From Baseline and at Week 48 - Femoral Neck BMD | -0.021 g/cm^2 | Standard Error 0.007 |
| FTC/TDF+DRV/r | Changes in Bone Mineral Density (Using DEXA Scan and Serum Markers) From Baseline and at Week 48 - Femoral Neck BMD | -0.029 g/cm^2 | Standard Error 0.007 |
Comparison: Results are from ANCOVA model with change from Baseline as the response variable and the following fixed effect model terms: treatment group, age, race, Screening BMI, and Baseline value of the response variable. Treatment differences are estimated using LS means with factor levels weighted according to overall analysis population proportions.p-value: 0.227395% CI: [-0.005, 0.022]ANCOVA
Secondary
Changes in Bone Mineral Density (Using DEXA Scan and Serum Markers) From Baseline and at Week 48 - Total Hip BMD
Bone mineral density was evaluated by DEXA scan in a subset of participants who consented to these evaluations. The effects on BMD were addressed by providing LSMs of change from baseline bone mineral density of the lumbar spine (L1-L4), left total hip and femoral neck as measured by the DEXA scan.
Time frame: Week 48
Population: Safety Analysis Set was the same as the FAS consisting of all randomized participants who received at least one dose of the study drug but analyzed as realized for tropism assay and treatment. Missing values were imputed using LOCF approach.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MVC+DRV/r | Changes in Bone Mineral Density (Using DEXA Scan and Serum Markers) From Baseline and at Week 48 - Total Hip BMD | -0.014 g/cm^2 | Standard Error 0.005 |
| FTC/TDF+DRV/r | Changes in Bone Mineral Density (Using DEXA Scan and Serum Markers) From Baseline and at Week 48 - Total Hip BMD | -0.028 g/cm^2 | Standard Error 0.005 |
Comparison: Results are from ANCOVA model with change from Baseline as the response variable and the following fixed effect model terms: treatment group, age, race, Screening BMI, and Baseline value of the response variable. Treatment differences are estimated using LS means with factor levels weighted according to overall analysis population proportions.p-value: 0.004395% CI: [0.004, 0.023]ANCOVA
Secondary
Changes in Peripheral Fat Distribution Using Dual Energy X-ray Absorptiometry [DEXA] Scan From Baseline and at Week 48.
A sub-study was conducted in which the participants underwent whole-body DEXA scans to evaluate peripheral fat tissue estimates for left and right arms and legs and truncal fat mass and truncal lean mass. Truncal abdominal fat were estimated from the DEXA scan field set on the torso. The effects on estimates of fat mass and lean mass were addressed by providing LSMs of change from baseline.
Time frame: Week 48
Population: Safety Analysis Set was the same as the FAS consisting of all randomized participants who received at least one dose of the study drug but analyzed as realized for tropism assay and treatment. Missing values were imputed using LOCF approach.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MVC+DRV/r | Changes in Peripheral Fat Distribution Using Dual Energy X-ray Absorptiometry [DEXA] Scan From Baseline and at Week 48. | -181.6 gram | Standard Error 569.8 |
| FTC/TDF+DRV/r | Changes in Peripheral Fat Distribution Using Dual Energy X-ray Absorptiometry [DEXA] Scan From Baseline and at Week 48. | -257.5 gram | Standard Error 556.9 |
Comparison: Results are from ANCOVA model with change from Baseline as the response variable and the following fixed effect model terms: treatment group, age, race, Screening BMI, and Baseline value of the response variable. Treatment differences are estimated using LS means with factor levels weighted according to overall analysis population proportions.p-value: 0.837995% CI: [-658.181, 809.903]ANCOVA
Secondary
Changes in Trunk to Limb Fat Distribution Using DEXA Scan From Baseline and at Week 48
A sub-study was conducted in which the participants underwent whole-body DEXA scans to evaluate peripheral fat tissue estimates for left and right arms and legs and truncal fat mass and truncal lean mass. Truncal abdominal fat were estimated from the DEXA scan field set on the torso. The effects on estimates of fat mass and lean mass were addressed by providing LSMs of change from baseline.
Time frame: Week 48
Population: Safety Analysis Set was the same as the FAS consisting of all randomized participants who received at least one dose of the study drug but analyzed as realized for tropism assay and treatment. Missing values were imputed using LOCF approach.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| MVC+DRV/r | Changes in Trunk to Limb Fat Distribution Using DEXA Scan From Baseline and at Week 48 | 0.017 ratio | Standard Error 0.048 |
| FTC/TDF+DRV/r | Changes in Trunk to Limb Fat Distribution Using DEXA Scan From Baseline and at Week 48 | -0.014 ratio | Standard Error 0.048 |
Comparison: Results are from ANCOVA model with change from Baseline as the response variable and the following fixed effect model terms: treatment group, age, race, Screening BMI, and Baseline value of the response variable. Treatment differences are estimated using LS means with factor levels weighted according to overall analysis population proportions.p-value: 0.337695% CI: [-0.033, 0.094]ANCOVA
Secondary
Frequency of Adverse Events (AE).
Number of participants with treatment-emergent non serious AEs
Time frame: Week 96
Population: Safety Analysis Set was the same as the FAS consisting of all randomized participants who received at least one dose of the study drug but analyzed as realized for tropism assay and treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MVC+DRV/r | Frequency of Adverse Events (AE). | 360 participants |
| FTC/TDF+DRV/r | Frequency of Adverse Events (AE). | 365 participants |
Secondary
Number of Participants Who Discontinued Due to AEs
Number of participants who discontinued due to AEs are reported here. Three participants (two from the MVC+DRV/r arm and one from the FTC/TDF+DRV/r arm) were not considered as discontinued due to AE because other reasons for discontinuation were prioritized for these participants.
Time frame: Week 96
Population: Safety Analysis Set was the same as the FAS consisting of all randomized participants who received at least one dose of the study drug but analyzed as realized for tropism assay and treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MVC+DRV/r | Number of Participants Who Discontinued Due to AEs | 22 participants |
| FTC/TDF+DRV/r | Number of Participants Who Discontinued Due to AEs | 23 participants |
Secondary
Number of Participants With Abnormal Laboratory Values
Number of participants with laboratory abnormalities are reported
Time frame: Week 96
Population: Safety Analysis Set was the same as the FAS consisting of all randomized participants who received at least one dose of the study drug but analyzed as realized for tropism assay and treatment. One participant was not analyzed for laboratory data as the collection date for all lab data was less than the first active therapy date.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MVC+DRV/r | Number of Participants With Abnormal Laboratory Values | Normal Baseline | 210 participants |
| MVC+DRV/r | Number of Participants With Abnormal Laboratory Values | Abnormal Baseline | 111 participants |
| FTC/TDF+DRV/r | Number of Participants With Abnormal Laboratory Values | Normal Baseline | 205 participants |
| FTC/TDF+DRV/r | Number of Participants With Abnormal Laboratory Values | Abnormal Baseline | 101 participants |
Secondary
Number of Participants With Grade 3 or 4 AEs
Number of participants with grade 3 or 4 AEs are presented here.
Time frame: Week 96
Population: Safety Analysis Set was the same as the FAS consisting of all randomized participants who received at least one dose of the study drug but analyzed as realized for tropism assay and treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MVC+DRV/r | Number of Participants With Grade 3 or 4 AEs | 65 participants |
| FTC/TDF+DRV/r | Number of Participants With Grade 3 or 4 AEs | 71 participants |
Secondary
Number of Participants With Resistance to Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTI), Non-nucleoside Reverse Transcriptase Inhibitors (NNRTI), and Protease Inhibitors (PI) in Participants Meeting PDTF Criteria
For participants meeting the PDTF criteria, viral resistance (both genotypic and phenotypic) to NRTI, NNRTI, and PI's were assessed at Baseline and on-treatment. The assessment was performed using the overall (i.e. net) susceptibility score provided using the PhenoSense GT assay. The number of participants with successful assessments were 15/17 for the MVC+DRV/r arm and 3/3 for the FTC/TDF+DRV/r arm.
Time frame: Week 48
Population: The FAS consisted of all randomized participants who received at least one dose of the study drug. The assessment was performed using the overall (ie. net) susceptibility score provided using the PhenoSense GT assay. The number of participants with successful assessments were 15 for the MVC+DRV/r arm and 3 for the FTC/TDF+DRV/r arm.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MVC+DRV/r | Number of Participants With Resistance to Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTI), Non-nucleoside Reverse Transcriptase Inhibitors (NNRTI), and Protease Inhibitors (PI) in Participants Meeting PDTF Criteria | NRTI - All (Baseline, n=15, 3) | 0 participants |
| MVC+DRV/r | Number of Participants With Resistance to Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTI), Non-nucleoside Reverse Transcriptase Inhibitors (NNRTI), and Protease Inhibitors (PI) in Participants Meeting PDTF Criteria | NNRTI Delavirdine (Baseline, n=15, 3) | 1 participants |
| MVC+DRV/r | Number of Participants With Resistance to Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTI), Non-nucleoside Reverse Transcriptase Inhibitors (NNRTI), and Protease Inhibitors (PI) in Participants Meeting PDTF Criteria | NNRTI Nevirapine (Baseline, n=15, 3) | 1 participants |
| MVC+DRV/r | Number of Participants With Resistance to Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTI), Non-nucleoside Reverse Transcriptase Inhibitors (NNRTI), and Protease Inhibitors (PI) in Participants Meeting PDTF Criteria | NNRTI Efavirenz (Baseline, n=15, 3) | 1 participants |
| MVC+DRV/r | Number of Participants With Resistance to Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTI), Non-nucleoside Reverse Transcriptase Inhibitors (NNRTI), and Protease Inhibitors (PI) in Participants Meeting PDTF Criteria | PRI - All (Baseline, n=15, 3) | 0 participants |
| MVC+DRV/r | Number of Participants With Resistance to Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTI), Non-nucleoside Reverse Transcriptase Inhibitors (NNRTI), and Protease Inhibitors (PI) in Participants Meeting PDTF Criteria | NRTI - All (PDTF, n=15, 3) | 0 participants |
| MVC+DRV/r | Number of Participants With Resistance to Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTI), Non-nucleoside Reverse Transcriptase Inhibitors (NNRTI), and Protease Inhibitors (PI) in Participants Meeting PDTF Criteria | NNRTI Delavirdine (PDTF, n=15, 3) | 1 participants |
| MVC+DRV/r | Number of Participants With Resistance to Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTI), Non-nucleoside Reverse Transcriptase Inhibitors (NNRTI), and Protease Inhibitors (PI) in Participants Meeting PDTF Criteria | NNRTI Nevirapine (PDTF, n=15, 3) | 1 participants |
| MVC+DRV/r | Number of Participants With Resistance to Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTI), Non-nucleoside Reverse Transcriptase Inhibitors (NNRTI), and Protease Inhibitors (PI) in Participants Meeting PDTF Criteria | NNRTI Efavirenz (PDTF, n=15, 3) | 1 participants |
| MVC+DRV/r | Number of Participants With Resistance to Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTI), Non-nucleoside Reverse Transcriptase Inhibitors (NNRTI), and Protease Inhibitors (PI) in Participants Meeting PDTF Criteria | PRI - All (PDTF, n=15, 3) | 0 participants |
| FTC/TDF+DRV/r | Number of Participants With Resistance to Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTI), Non-nucleoside Reverse Transcriptase Inhibitors (NNRTI), and Protease Inhibitors (PI) in Participants Meeting PDTF Criteria | NNRTI Nevirapine (PDTF, n=15, 3) | 0 participants |
| FTC/TDF+DRV/r | Number of Participants With Resistance to Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTI), Non-nucleoside Reverse Transcriptase Inhibitors (NNRTI), and Protease Inhibitors (PI) in Participants Meeting PDTF Criteria | NRTI - All (Baseline, n=15, 3) | 0 participants |
| FTC/TDF+DRV/r | Number of Participants With Resistance to Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTI), Non-nucleoside Reverse Transcriptase Inhibitors (NNRTI), and Protease Inhibitors (PI) in Participants Meeting PDTF Criteria | NRTI - All (PDTF, n=15, 3) | 0 participants |
| FTC/TDF+DRV/r | Number of Participants With Resistance to Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTI), Non-nucleoside Reverse Transcriptase Inhibitors (NNRTI), and Protease Inhibitors (PI) in Participants Meeting PDTF Criteria | NNRTI Delavirdine (Baseline, n=15, 3) | 0 participants |
| FTC/TDF+DRV/r | Number of Participants With Resistance to Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTI), Non-nucleoside Reverse Transcriptase Inhibitors (NNRTI), and Protease Inhibitors (PI) in Participants Meeting PDTF Criteria | PRI - All (PDTF, n=15, 3) | 0 participants |
| FTC/TDF+DRV/r | Number of Participants With Resistance to Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTI), Non-nucleoside Reverse Transcriptase Inhibitors (NNRTI), and Protease Inhibitors (PI) in Participants Meeting PDTF Criteria | NNRTI Nevirapine (Baseline, n=15, 3) | 0 participants |
| FTC/TDF+DRV/r | Number of Participants With Resistance to Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTI), Non-nucleoside Reverse Transcriptase Inhibitors (NNRTI), and Protease Inhibitors (PI) in Participants Meeting PDTF Criteria | NNRTI Delavirdine (PDTF, n=15, 3) | 0 participants |
| FTC/TDF+DRV/r | Number of Participants With Resistance to Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTI), Non-nucleoside Reverse Transcriptase Inhibitors (NNRTI), and Protease Inhibitors (PI) in Participants Meeting PDTF Criteria | NNRTI Efavirenz (Baseline, n=15, 3) | 0 participants |
| FTC/TDF+DRV/r | Number of Participants With Resistance to Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTI), Non-nucleoside Reverse Transcriptase Inhibitors (NNRTI), and Protease Inhibitors (PI) in Participants Meeting PDTF Criteria | NNRTI Efavirenz (PDTF, n=15, 3) | 0 participants |
| FTC/TDF+DRV/r | Number of Participants With Resistance to Nucleoside/Nucleotide Reverse Transcriptase Inhibitors (NRTI), Non-nucleoside Reverse Transcriptase Inhibitors (NNRTI), and Protease Inhibitors (PI) in Participants Meeting PDTF Criteria | PRI - All (Baseline, n=15, 3) | 0 participants |
Secondary
Number of Participants With Treatment-emergent Serious Adverse Events
Total number of participants with treatment-emergent serious adverse events are reported
Time frame: Week 96
Population: Safety Analysis Set was the same as the FAS consisting of all randomized participants who received at least one dose of the study drug but analyzed as realized for tropism assay and treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MVC+DRV/r | Number of Participants With Treatment-emergent Serious Adverse Events | 41 participants |
| FTC/TDF+DRV/r | Number of Participants With Treatment-emergent Serious Adverse Events | 40 participants |
Secondary
Number of Participants With Viral Resistance to Maraviroc (Maraviroc Treated Participants Only) in Participants Meeting PDTF Criteria.
For participants meeting the PDTF criteria, viral resistance to maraviroc for maraviroc treated participants was assessed in patients with R5 virus at failure. The resistance level is calculated by reference to a laboratory strain of virus that is analyzed in parallel with the clinical isolate to identify 50% inhibitory concentrations (IC50). The maximal percent inhibition is the percent inhibition that is achieved in a titration of the drug at high concentrations when the addition of more drug does not result in increased inhibition. Maximal percent inhibition is obtained in the same way as the titration for IC50, but the key measure is of the plateau height of percent inhibition, where increased concentration of maraviroc does not result in additional inhibition. This is consistent with the virus developing some ability to use maraviroc-bound CCR5 for entry. A significant change in IC50 is not required for this mechanism.
Time frame: Week 48
Population: The FAS consisted of all randomized participants who received at least one dose of the study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MVC+DRV/r | Number of Participants With Viral Resistance to Maraviroc (Maraviroc Treated Participants Only) in Participants Meeting PDTF Criteria. | Results reported | 12 participants |
| MVC+DRV/r | Number of Participants With Viral Resistance to Maraviroc (Maraviroc Treated Participants Only) in Participants Meeting PDTF Criteria. | Not eligible for analysis (non-R5 tropism) | 1 participants |
| MVC+DRV/r | Number of Participants With Viral Resistance to Maraviroc (Maraviroc Treated Participants Only) in Participants Meeting PDTF Criteria. | Maximal percent inhibition <95% | 0 participants |
| MVC+DRV/r | Number of Participants With Viral Resistance to Maraviroc (Maraviroc Treated Participants Only) in Participants Meeting PDTF Criteria. | Eligible for analysis (R5 virus using ESTA) | 12 participants |
| MVC+DRV/r | Number of Participants With Viral Resistance to Maraviroc (Maraviroc Treated Participants Only) in Participants Meeting PDTF Criteria. | IC50 FC ≥3.0 | 0 participants |
| MVC+DRV/r | Number of Participants With Viral Resistance to Maraviroc (Maraviroc Treated Participants Only) in Participants Meeting PDTF Criteria. | Not eligible for analysis (failed tropism test) | 4 participants |
| FTC/TDF+DRV/r | Number of Participants With Viral Resistance to Maraviroc (Maraviroc Treated Participants Only) in Participants Meeting PDTF Criteria. | IC50 FC ≥3.0 | 0 participants |
| FTC/TDF+DRV/r | Number of Participants With Viral Resistance to Maraviroc (Maraviroc Treated Participants Only) in Participants Meeting PDTF Criteria. | Not eligible for analysis (failed tropism test) | 1 participants |
| FTC/TDF+DRV/r | Number of Participants With Viral Resistance to Maraviroc (Maraviroc Treated Participants Only) in Participants Meeting PDTF Criteria. | Eligible for analysis (R5 virus using ESTA) | 1 participants |
| FTC/TDF+DRV/r | Number of Participants With Viral Resistance to Maraviroc (Maraviroc Treated Participants Only) in Participants Meeting PDTF Criteria. | Results reported | 1 participants |
| FTC/TDF+DRV/r | Number of Participants With Viral Resistance to Maraviroc (Maraviroc Treated Participants Only) in Participants Meeting PDTF Criteria. | Maximal percent inhibition <95% | 0 participants |
| FTC/TDF+DRV/r | Number of Participants With Viral Resistance to Maraviroc (Maraviroc Treated Participants Only) in Participants Meeting PDTF Criteria. | Not eligible for analysis (non-R5 tropism) | 1 participants |
Secondary
Number of Treatment-related AEs
Number of treatment-related AEs are presented here.
Time frame: Week 96
Population: Safety Analysis Set was the same as the FAS consisting of all randomized participants who received at least one dose of the study drug but analyzed as realized for tropism assay and treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| MVC+DRV/r | Number of Treatment-related AEs | 316 events |
| FTC/TDF+DRV/r | Number of Treatment-related AEs | 361 events |
Secondary
Percent Change From Baseline in Immune Cell Function at Week 48: Lymphocyte Activation Marker CD4 (%)
The differences in the magnitude of changes in CD4+ from Baseline through Week 48 for maraviroc versus emtricitabine/tenofovir were compared.
Time frame: Baseline, Week 48
Population: The FAS consisted of all randomized participants who received at least one dose of the study drug. Missing values were imputed using LOCF approach. Baseline was calculated as the average of all the pre-dose measurements excluding the screening value. If all pre-dose values were missing, screening value was considered as the baseline.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MVC+DRV/r | Percent Change From Baseline in Immune Cell Function at Week 48: Lymphocyte Activation Marker CD4 (%) | Baseline (n=396, 401) | 24.2 Percentage of lymphocytes | Standard Deviation 7.9 |
| MVC+DRV/r | Percent Change From Baseline in Immune Cell Function at Week 48: Lymphocyte Activation Marker CD4 (%) | Week 48 (n=394, 396) | 31.3 Percentage of lymphocytes | Standard Deviation 8.3 |
| MVC+DRV/r | Percent Change From Baseline in Immune Cell Function at Week 48: Lymphocyte Activation Marker CD4 (%) | Change from Baseline at Week 48 (n=394, 396) | 7.0 Percentage of lymphocytes | Standard Deviation 5.7 |
| FTC/TDF+DRV/r | Percent Change From Baseline in Immune Cell Function at Week 48: Lymphocyte Activation Marker CD4 (%) | Baseline (n=396, 401) | 24.5 Percentage of lymphocytes | Standard Deviation 8.2 |
| FTC/TDF+DRV/r | Percent Change From Baseline in Immune Cell Function at Week 48: Lymphocyte Activation Marker CD4 (%) | Week 48 (n=394, 396) | 33.7 Percentage of lymphocytes | Standard Deviation 8.6 |
| FTC/TDF+DRV/r | Percent Change From Baseline in Immune Cell Function at Week 48: Lymphocyte Activation Marker CD4 (%) | Change from Baseline at Week 48 (n=394, 396) | 9.2 Percentage of lymphocytes | Standard Deviation 6 |
Comparison: Results were from ANCOVA model with change from Baseline as the response variable and the following fixed effect model terms: Treatment group, Screening plasma HIV RNA concentration, Screening Tropism Assay, Baseline value of the response variable.p-value: <0.000195% CI: [-3.1, -1.5]ANCOVA
Secondary
Percent Change From Baseline in Immune Cell Function at Week 48: Lymphocyte Activation Marker CD8 (%)
The differences in the magnitude of changes in CD8+ cell counts from Baseline through Week 48 for maraviroc versus emtricitabine/tenofovir were compared.
Time frame: Baseline, Week 48
Population: The FAS consisted of all randomized participants who received at least one dose of the study drug. Missing values were imputed using LOCF approach. Baseline was calculated as the average of all the pre-dose measurements excluding the screening value. If all pre-dose values were missing, screening value was considered as the baseline.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| MVC+DRV/r | Percent Change From Baseline in Immune Cell Function at Week 48: Lymphocyte Activation Marker CD8 (%) | Baseline (n=396, 401) | 57.0 Percentage of lymphocytes | Standard Deviation 10.7 |
| MVC+DRV/r | Percent Change From Baseline in Immune Cell Function at Week 48: Lymphocyte Activation Marker CD8 (%) | Week 48 (n=394, 396) | 46.0 Percentage of lymphocytes | Standard Deviation 10.4 |
| MVC+DRV/r | Percent Change From Baseline in Immune Cell Function at Week 48: Lymphocyte Activation Marker CD8 (%) | Change from Baseline at Week 48 (n=394, 396) | -10.9 Percentage of lymphocytes | Standard Deviation 7.2 |
| FTC/TDF+DRV/r | Percent Change From Baseline in Immune Cell Function at Week 48: Lymphocyte Activation Marker CD8 (%) | Baseline (n=396, 401) | 55.8 Percentage of lymphocytes | Standard Deviation 10.5 |
| FTC/TDF+DRV/r | Percent Change From Baseline in Immune Cell Function at Week 48: Lymphocyte Activation Marker CD8 (%) | Week 48 (n=394, 396) | 43.0 Percentage of lymphocytes | Standard Deviation 10.2 |
| FTC/TDF+DRV/r | Percent Change From Baseline in Immune Cell Function at Week 48: Lymphocyte Activation Marker CD8 (%) | Change from Baseline at Week 48 (n=394, 396) | -12.6 Percentage of lymphocytes | Standard Deviation 8.1 |
Comparison: Results were from ANCOVA model with change from Baseline as the response variable and the following fixed effect model terms: Treatment group, Screening plasma HIV RNA concentration, Screening Tropism Assay, Baseline value of the response variable.p-value: <0.000195% CI: [1.1, 3.1]ANCOVA
Secondary
Severity of Abnormal Laboratory Values
Number of participants who had clinically significant laboratory abnormalities of Grade 3 and Grade 4 according to DAIDS. Abnormality incidence of highest grade was reported for a labcode for each individual participant.
Time frame: Week 96
Population: Safety Analysis Set was the same as the FAS consisting of all randomized participants who received at least one dose of the study drug but analyzed as realized for tropism assay and treatment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MVC+DRV/r | Severity of Abnormal Laboratory Values | LDL Cholesterol (n=396, 400) | 50 participants |
| MVC+DRV/r | Severity of Abnormal Laboratory Values | Alanine Aminotransferase (ALT) (n=396, 400) | 9 participants |
| MVC+DRV/r | Severity of Abnormal Laboratory Values | Alkaline Phosphatase (n=396, 400) | 1 participants |
| MVC+DRV/r | Severity of Abnormal Laboratory Values | Amylase (n=396, 400) | 5 participants |
| MVC+DRV/r | Severity of Abnormal Laboratory Values | Aspartate Aminotransferase (AST) (n=396, 400) | 11 participants |
| MVC+DRV/r | Severity of Abnormal Laboratory Values | Blood Urea Nitrogen (BUN) (n=396, 400) | 3 participants |
| MVC+DRV/r | Severity of Abnormal Laboratory Values | Calcium (n=396, 400) | 7 participants |
| MVC+DRV/r | Severity of Abnormal Laboratory Values | Creatine Kinase (n=396, 400) | 18 participants |
| MVC+DRV/r | Severity of Abnormal Laboratory Values | Hemoglobin (n=396, 400) | 4 participants |
| MVC+DRV/r | Severity of Abnormal Laboratory Values | Lipase (n=116, 122) | 3 participants |
| MVC+DRV/r | Severity of Abnormal Laboratory Values | Lymphocytes (Abs) (n=396, 400) | 2 participants |
| MVC+DRV/r | Severity of Abnormal Laboratory Values | Phosphate (n=396, 400) | 5 participants |
| MVC+DRV/r | Severity of Abnormal Laboratory Values | Platelets (n=396, 400) | 5 participants |
| MVC+DRV/r | Severity of Abnormal Laboratory Values | Potassium (n=396, 400) | 3 participants |
| MVC+DRV/r | Severity of Abnormal Laboratory Values | Sodium (n=396, 400) | 2 participants |
| MVC+DRV/r | Severity of Abnormal Laboratory Values | Total Bilirubin (n=396, 400) | 3 participants |
| MVC+DRV/r | Severity of Abnormal Laboratory Values | Total Neutrophils (Abs) (n=396, 400) | 6 participants |
| MVC+DRV/r | Severity of Abnormal Laboratory Values | Triglycerides (n=396, 400) | 4 participants |
| MVC+DRV/r | Severity of Abnormal Laboratory Values | Uric Acid (n=396, 400) | 0 participants |
| MVC+DRV/r | Severity of Abnormal Laboratory Values | White Blood Cell Count (n=396, 400) | 1 participants |
| MVC+DRV/r | Severity of Abnormal Laboratory Values | Creatinine (n=396, 400) | 0 participants |
| FTC/TDF+DRV/r | Severity of Abnormal Laboratory Values | Lymphocytes (Abs) (n=396, 400) | 2 participants |
| FTC/TDF+DRV/r | Severity of Abnormal Laboratory Values | LDL Cholesterol (n=396, 400) | 24 participants |
| FTC/TDF+DRV/r | Severity of Abnormal Laboratory Values | Uric Acid (n=396, 400) | 2 participants |
| FTC/TDF+DRV/r | Severity of Abnormal Laboratory Values | Alanine Aminotransferase (ALT) (n=396, 400) | 6 participants |
| FTC/TDF+DRV/r | Severity of Abnormal Laboratory Values | Phosphate (n=396, 400) | 12 participants |
| FTC/TDF+DRV/r | Severity of Abnormal Laboratory Values | Alkaline Phosphatase (n=396, 400) | 0 participants |
| FTC/TDF+DRV/r | Severity of Abnormal Laboratory Values | Total Neutrophils (Abs) (n=396, 400) | 2 participants |
| FTC/TDF+DRV/r | Severity of Abnormal Laboratory Values | Amylase (n=396, 400) | 13 participants |
| FTC/TDF+DRV/r | Severity of Abnormal Laboratory Values | Platelets (n=396, 400) | 1 participants |
| FTC/TDF+DRV/r | Severity of Abnormal Laboratory Values | Aspartate Aminotransferase (AST) (n=396, 400) | 7 participants |
| FTC/TDF+DRV/r | Severity of Abnormal Laboratory Values | Creatinine (n=396, 400) | 1 participants |
| FTC/TDF+DRV/r | Severity of Abnormal Laboratory Values | Blood Urea Nitrogen (BUN) (n=396, 400) | 5 participants |
| FTC/TDF+DRV/r | Severity of Abnormal Laboratory Values | Potassium (n=396, 400) | 2 participants |
| FTC/TDF+DRV/r | Severity of Abnormal Laboratory Values | Calcium (n=396, 400) | 10 participants |
| FTC/TDF+DRV/r | Severity of Abnormal Laboratory Values | Triglycerides (n=396, 400) | 6 participants |
| FTC/TDF+DRV/r | Severity of Abnormal Laboratory Values | Creatine Kinase (n=396, 400) | 22 participants |
| FTC/TDF+DRV/r | Severity of Abnormal Laboratory Values | Sodium (n=396, 400) | 0 participants |
| FTC/TDF+DRV/r | Severity of Abnormal Laboratory Values | Hemoglobin (n=396, 400) | 2 participants |
| FTC/TDF+DRV/r | Severity of Abnormal Laboratory Values | White Blood Cell Count (n=396, 400) | 0 participants |
| FTC/TDF+DRV/r | Severity of Abnormal Laboratory Values | Lipase (n=116, 122) | 10 participants |
| FTC/TDF+DRV/r | Severity of Abnormal Laboratory Values | Total Bilirubin (n=396, 400) | 1 participants |
Secondary
The Relationship Between the Proportion of Participants With Plasma HIV-1 RNA <50 Copies/mL at the Week 48 and the Screening Tropism Test (Genotype Test or ESTA).
The relationship of the proportion of participants achieving HIV-1 RNA \<50 copies/mL at Week 48 with the screening tropism test for the MVC containing regimen was analyzed. Virologic response for a participant at Week 48 was derived using the FDA's Snapshot MSDF algorithm. Difference in proportions of patients with plasma HIV-1 RNA \<50 copies/mL at week 48 between the maraviroc and the emtricitabine/tenofovir treatment arms, with two-sided 95% confidence interval, among patients who are R5 by genotype (including some who were originally randomized to ESTA and are R5 by genotype upon retesting), were calculated via the Maximum Likelihood method. The estimate was adjusted for the screening plasma HIV RNA level (\<100,000 vs. ≥100,000) copies/mL via the Mantel Haenszel (MH) method.
Time frame: Week 48
Population: The FAS consisted of all randomized participants who received at least one dose of the study drug.
| Arm | Measure | Value (NUMBER) | Dispersion |
|---|---|---|---|
| MVC+DRV/r | The Relationship Between the Proportion of Participants With Plasma HIV-1 RNA <50 Copies/mL at the Week 48 and the Screening Tropism Test (Genotype Test or ESTA). | 0.8047 proportion of participants | 0.0238 |
| FTC/TDF+DRV/r | The Relationship Between the Proportion of Participants With Plasma HIV-1 RNA <50 Copies/mL at the Week 48 and the Screening Tropism Test (Genotype Test or ESTA). | 0.8797 proportion of participants | 0.0187 |
Comparison: The difference in proportions of patients with plasma HIV-1 RNA \<50 copies/mL at Week 48 between the \[MVC+DRV/r\] and the \[FTC/TDF+DRV/r\] treatment arms, with two-sided 95% confidence interval, is shown for those patients who were R5 by genotype (including all who were originally randomized to ESTA and were R5 by genotype upon retesting), via the maximum likelihood (ML) method.95% CI: [-0.1343, -0.0157]
Secondary
Tropism Change Between Screening or Baseline and PDTF
For participants meeting the PDTF criteria, tropism was assessed using the original randomized and alternate assays (ie, both genotype testing and ESTA). Data reported here corresponds to the timepoint at or after PDTF.
Time frame: Week 48
Population: Number of Evaluable PDTF = Virology Analysis Population (VAP) 'Evaluability' is determined by the on-treatment viral load (≥400 copies/mL at sample time point).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MVC+DRV/r | Tropism Change Between Screening or Baseline and PDTF | R5 (Randomized Assay) | 14 participants |
| MVC+DRV/r | Tropism Change Between Screening or Baseline and PDTF | NON R5 (Randomized Assay) | 1 participants |
| MVC+DRV/r | Tropism Change Between Screening or Baseline and PDTF | NR (Randomized Assay) | 2 participants |
| MVC+DRV/r | Tropism Change Between Screening or Baseline and PDTF | R5 (Alternate Assay) | 10 participants |
| MVC+DRV/r | Tropism Change Between Screening or Baseline and PDTF | NON R5 (Alternate Assay) | 2 participants |
| MVC+DRV/r | Tropism Change Between Screening or Baseline and PDTF | NR (Alternate Assay) | 5 participants |
| FTC/TDF+DRV/r | Tropism Change Between Screening or Baseline and PDTF | NR (Alternate Assay) | 4 participants |
| FTC/TDF+DRV/r | Tropism Change Between Screening or Baseline and PDTF | R5 (Alternate Assay) | 10 participants |
| FTC/TDF+DRV/r | Tropism Change Between Screening or Baseline and PDTF | R5 (Randomized Assay) | 13 participants |
| FTC/TDF+DRV/r | Tropism Change Between Screening or Baseline and PDTF | NR (Randomized Assay) | 3 participants |
| FTC/TDF+DRV/r | Tropism Change Between Screening or Baseline and PDTF | NON R5 (Randomized Assay) | 1 participants |
| FTC/TDF+DRV/r | Tropism Change Between Screening or Baseline and PDTF | NON R5 (Alternate Assay) | 3 participants |
| FTC/TDF+DRV/r - Baseline | Tropism Change Between Screening or Baseline and PDTF | NON R5 (Randomized Assay) | 0 participants |
| FTC/TDF+DRV/r - Baseline | Tropism Change Between Screening or Baseline and PDTF | NR (Randomized Assay) | 1 participants |
| FTC/TDF+DRV/r - Baseline | Tropism Change Between Screening or Baseline and PDTF | R5 (Alternate Assay) | 3 participants |
| FTC/TDF+DRV/r - Baseline | Tropism Change Between Screening or Baseline and PDTF | NR (Alternate Assay) | 0 participants |
| FTC/TDF+DRV/r - Baseline | Tropism Change Between Screening or Baseline and PDTF | NON R5 (Alternate Assay) | 0 participants |
| FTC/TDF+DRV/r - Baseline | Tropism Change Between Screening or Baseline and PDTF | R5 (Randomized Assay) | 2 participants |
| FTC/TDF+DRV/r - Failure | Tropism Change Between Screening or Baseline and PDTF | NON R5 (Alternate Assay) | 1 participants |
| FTC/TDF+DRV/r - Failure | Tropism Change Between Screening or Baseline and PDTF | NR (Alternate Assay) | 0 participants |
| FTC/TDF+DRV/r - Failure | Tropism Change Between Screening or Baseline and PDTF | NON R5 (Randomized Assay) | 0 participants |
| FTC/TDF+DRV/r - Failure | Tropism Change Between Screening or Baseline and PDTF | R5 (Alternate Assay) | 2 participants |
| FTC/TDF+DRV/r - Failure | Tropism Change Between Screening or Baseline and PDTF | R5 (Randomized Assay) | 1 participants |
| FTC/TDF+DRV/r - Failure | Tropism Change Between Screening or Baseline and PDTF | NR (Randomized Assay) | 2 participants |
Secondary
Virologic Outcomes at Week 48 Using Protocol-Defined Treatment Failure (PDTF).
Per the protocol participants who meet the following criteria were regarded as PDTFs requiring a confirmatory plasma HIV-1 RNA determination: • Decrease in plasma HIV-1 RNA \<1 log10 from baseline after Week 4 unless plasma HIV-1 RNA is \<50 copies/mL, or • Plasma HIV-1 RNA \>1.0 log10 above the nadir value after Week 4 where the nadir is the lowest plasma HIV-1 RNA concentration, or • Plasma HIV-1 RNA ≥50 copies/mL at any time after Week 24, or • Plasma HIV-1 RNA ≥50 copies/mL after suppression to \<50 copies/mL on two consecutive visits, or • Decrease in plasma HIV-1 RNA ≤2 log10 from baseline on or after Week 12 unless plasma HIV-1 RNA is \<400 copies/mL. Decrease in plasma HIV-1 RNA ≤2 log10 from baseline on or after Week 12 unless plasma HIV-1 RNA is \<50 copies/mL (before August 30 2012) or \<400 copies/mL (after August 30 2012).
Time frame: Week 48
Population: The FAS consisted of all randomized participants who received at least one dose of the study drug. No imputation for missing values was performed for this endpoint. 'Evaluability' is determined by the on-treatment viral load (≥400 copies/mL at sample time point).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| MVC+DRV/r | Virologic Outcomes at Week 48 Using Protocol-Defined Treatment Failure (PDTF). | Confirmed PDTF | 40 Number of participants |
| MVC+DRV/r | Virologic Outcomes at Week 48 Using Protocol-Defined Treatment Failure (PDTF). | Evaluable PDTF | 17 Number of participants |
| FTC/TDF+DRV/r | Virologic Outcomes at Week 48 Using Protocol-Defined Treatment Failure (PDTF). | Confirmed PDTF | 13 Number of participants |
| FTC/TDF+DRV/r | Virologic Outcomes at Week 48 Using Protocol-Defined Treatment Failure (PDTF). | Evaluable PDTF | 3 Number of participants |