HIV, HIV Infections
Conditions
Keywords
HIV, HIV-1 Infected, Treatment Experienced, Treatment Naive
Brief summary
The primary objective of this study is to evaluate the effect of elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) fixed-dose combination (FDC) tablet on renal parameters at Week 24 in treatment-naive and treatment-experienced HIV-positive, adults with mild to moderate renal impairment.
Interventions
DRUGE/C/F/TAF
E/C/F/TAF (150/150/200/10 mg) FDC tablet administered orally once daily with food
Sponsors
Gilead Sciences
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: Cohort 1 (treatment-experienced switch) * Must not have a history of known resistance to elvitegravir (EVG), tenofovir disoproxil fumarate (TDF), or emtricitabine (FTC) * Plasma HIV-1 RNA concentrations (at least two measurements) at undetectable levels (according to the local assay being used) in the 6 months preceding the screening visit and have HIV-1 RNA \< 50 copies/mL at screening * Estimated glomerular filtration rate (GFR) 30-69 mL/min according to the Cockcroft-Gault formula for creatinine clearance, using actual weight * May be currently enrolled in Gilead studies GS-US-236-0102, GS-US-236-0103, and GS-US-216-0114, but will be eligible to enroll only after the Week 144 visit for that study is complete; or currently receiving Stribild® (STB) or atazanavir (ATV)/cobicistat (COBI) + Truvada (TVD) in Gilead studies GS-US-236-0104 or GS-US-216-0105, but will be eligible to enroll only after the Week 48 visit for that study is complete. Cohort 2 (treatment-naive) * Plasma HIV-1 RNA levels ≥ 1,000 copies/mL at screening * Screening genotype report provided by Gilead Sciences must show sensitivity to EVG, FTC, and TDF * No prior use of any approved or investigational antiretroviral drug for any length of time, except the use for pre-exposure prophylaxis (PrEP), or post-exposure prophylaxis (PEP), up to 6 months prior to screening * Estimated GFR 30-69 mL/min according to the Cockcroft Gault formula for creatinine clearance, using actual weight All Cohorts: All individuals must meet all of the following inclusion criteria to be eligible for participation in this study: * The ability to understand and sign a written informed consent form, which must be obtained prior to initiation of study procedures * CD4+ count of ≥ 50 cells/μL * Stable renal function: serum creatinine measurements to be taken at least once (within three months of screening) * Cause of underlying chronic kidney disease (eg hypertension, diabetes) stable, without change in medical management, for 3 months prior to baseline * Normal electrocardiogram (ECG) * Hepatic transaminases (AST and ALT) ≤ 5 x upper limit of normal (ULN) * Total bilirubin ≤ 1.5 mg/dL, or normal direct bilirubin * Adequate hematologic function * Serum amylase ≤ 5 x ULN * Females of childbearing potential must agree 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) from screening throughout the duration of study treatment and for 30 days following the last dose of study drug * Females who utilize hormonal contraceptive as one of their birth control methods must have used the same method for at least three months prior to study dosing * Males must agree to utilize a highly effective method of contraception during heterosexual intercourse throughout the study period and for 30 days following discontinuation of investigational medicinal product. A highly effective method of contraception is defined as two separate forms of contraception, one of which must be an effective barrier method, or males must be non-heterosexually active, or practice sexual abstinence Key
Exclusion criteria
* A new AIDS-defining condition (excluding CD4 cell count and percentage criteria) diagnosed within the 30 days prior to screening,with the exception of the first two bullet points * Hepatitis C virus (HCV) antibody positive. Individuals who are HCV positive, but have a documented negative HCV RNA, are eligible * Hepatitis B surface antigen (HBVsAg) positive * Individuals receiving drug treatment for Hepatitis C, or individuals who are anticipated to receive treatment for Hepatitis C during the course of the study * Individuals experiencing decompensated cirrhosis (eg, ascites, encephalopathy, etc.) * Females who are breastfeeding * Positive serum pregnancy test * Have an implanted defibrillator or pacemaker * Current alcohol or substance use judged by the Investigator to potentially interfere with study compliance * 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 (other than HIV-1 infection) requiring parenteral antibiotic or antifungal therapy within 30 days prior to baseline * Individuals on hemodialysis, other forms of renal replacement therapy, or on treatment for underlying kidney diseases (including prednisolone and dexamethasone) * Individuals receiving ongoing therapy with any medications not to be used with EVG, COBI, FTC, or TAF or individuals with any known allergies to the excipients of E/C/F/TAF Note: Other protocol defined Inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in the Estimated Glomerular Filtration Rate Calculated by the Cockcroft-Gault Formula (eGFR_CG) at Week 24 | Baseline; Week 24 | eGFR is a measurement of the kidney's ability to filter blood. |
| Change From Baseline in eGFR Calculated by the Chronic Kidney Disease Epidemiology Collaboration Method Based on Cystatin C (eGFR_CKD-EPI,cysC) at Week 24 | Baseline; Week 24 | eGFR is a measurement of the kidney's ability to filter blood. The eGFR\_CKD-EPI,cysC method is adjusted for age and sex. |
| Change From Baseline in eGFR Calculated by the CKD-EPI Method Based on Serum Creatinine (eGFR_CKD-EPI,Creatinine) at Week 24 | Baseline; Week 24 | eGFR is a measurement of the kidney's ability to filter blood. The eGFR\_CKD-EPI,creatinine method is adjusted for age, race, and sex. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Retinol Binding Protein (RBP) to Creatinine Ratio (μg/g) at Weeks 24, 48, 96, and 144 | Baseline; Weeks 24, 48, 96, and 144 | Urine RBP is a renal biomarker which is used to evaluate drug-induced kidney injury. |
| Percent Change From Baseline in Urine Beta-2-microglobulin to Creatinine Ratio (μg/g) at Weeks 24, 48, 96, and 144 | Baseline; Weeks 24, 48, 96, and 144 | Urine beta-2-microglobulin is a renal biomarker which is used to evaluate drug-induced kidney injury. |
| Percentage of Participants Experiencing Adverse Events or Graded Laboratory Abnormalities | Baseline up to Week 240 plus 30 days | Adverse events (AEs) and graded laboratory abnormalities occurring during the E/C/F/TAF treatment period were summarized across the participant population. A participant was counted once if they had a qualifying event. |
| Percentage of Participants Achieving HIV-1 RNA < 50 Copies/mL at Weeks 24, 48, 96, and 144 | Weeks 24, 48, 96, and 144 | The percentage of participants achieving HIV-1 RNA \< 50 Copies/mL at Weeks 24, 48, 96, and 144 was analyzed using the snapshot algorithm, which defines a patient's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status. |
| Pharmacokinetic (PK) Parameter: Cmax of TAF | Predose, and 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, and 24 hours postdose | Cmax is defined as the maximum concentration of drug. Blood draws for this outcome may have been at the Week 2, 4, or 8 visit. |
| PK Parameter: Tmax of TAF | Predose, and 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, and 24 hours postdose | Tmax is defined as the time of Cmax. Blood draws for this outcome may have been at the Week 2, 4, or 8 visit. |
| PK Parameter: Clast of TAF | Predose, and 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, and 24 hours postdose | Clast is defined as the last observable concentration of drug. Blood draws for this outcome may have been at the Week 2, 4, or 8 visit. |
| Change From Baseline in Actual GFR (aGFR) of E/C/F/TAF for Participants Enrolled in the PK/PD Substudy | Baseline; Week 2, 4, or 8; Week 24 | aGFR was directly measured using iohexol plasma clearance (CLiohexol). |
| PK Parameter: λz of TAF | Predose, and 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, and 24 hours postdose | λz is defined as the terminal elimination rate constant. Blood draws for this outcome may have been at the Week 2, 4, or 8 visit. |
| PK Parameter: AUCtau of TAF | Predose, and 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, and 24 hours postdose | AUCtau is defined as the concentration of drug over time (area under the plasma concentration versus time curve over the dosing interval). Blood draws for this outcome may have been at the Week 2, 4, or 8 visit. |
| PK Parameter: t1/2 of TAF | Predose, and 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, and 24 hours postdose | t1/2 is defined as the estimate of the terminal elimination half-life of the drug. Blood draws for this outcome may have been at the Week 2, 4, or 8 visit. |
| PK Parameter: AUCtau of Tenofovir Diphosphate (TFV-DP) in Peripheral Blood Mononuclear Cell (PBMC) for Participants Enrolled in PK/PD Sub-study | Predose, and 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, and 24 hours postdose | TFV-DP is an active phosphorylated metabolite of tenofovir alafenamide. AUCtau is defined as the concentration of drug over time (area under the plasma concentration versus time curve over the dosing interval). Blood draws for this outcome may have been at the Week 2, 4, or 8 visit. |
| Change From Baseline in the eGFR_CG at Weeks 48, 96, and 144 | Baseline; Weeks 48, 96, and 144 | eGFR is a measurement of the kidney's ability to filter blood. |
| Change From Baseline in eGFR_CKD-EPI,cysC at Weeks 48, 96, and 144 | Baseline; Weeks 48, 96, and 144 | eGFR is a measurement of the kidney's ability to filter blood. The eGFR\_CKD-EPI,cysC method is adjusted for age and sex. |
| Change From Baseline in eGFR_CKD-EPI,Creatinine at Weeks 48, 96, and 144 | Baseline; Weeks 48, 96, and 144 | eGFR is a measurement of the kidney's ability to filter blood. The eGFR\_CKD-EPI,creatinine method is adjusted for age, race, and sex. |
| PK Parameter: Tlast of TAF | Predose, and 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, and 24 hours postdose | Tlast is defined as the time of Clast. Blood draws for this outcome may have been at the Week 2, 4, or 8 visit. |
| Percent Change From Baseline in C-type Collagen Sequence (CTX) at Weeks 24 and 48 | Baseline; Weeks 24 and 48 | CTX is a biomarker of bone turnover. |
| Percent Change From Baseline in Procollagen Type 1 N-terminal Propeptide (P1NP) at Weeks 24 and 48 | Baseline; Weeks 24 and 48 | P1NP is a biomarker of bone turnover. |
Countries
Australia, Dominican Republic, France, Mexico, Netherlands, Spain, Thailand, United Kingdom, United States
Participant flow
Recruitment details
Participants were enrolled at study sites in North America, Australia, Asia, and Europe. The first participant was screened on 27 March 2013. The last study visit occurred on 18 July 2018.
Pre-assignment details
380 participants were screened.
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 (Treatment-experienced) E/C/F/TAF (150/150/200/10 mg) FDC tablet administered orally once daily with food for up to 240 weeks in ART-experienced participants | 242 |
| Cohort 2 (Treatment-naive) E/C/F/TAF (150/150/200/10 mg) FDC tablet administered orally once daily with food for up to 188 weeks in ART-naive participants | 6 |
| Total | 248 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 7 | 0 |
| Overall Study | Death | 3 | 0 |
| Overall Study | Enrolled but Not Treated | 4 | 0 |
| Overall Study | Investigator's Discretion | 4 | 0 |
| Overall Study | Lost to Follow-up | 7 | 0 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Withdrew Consent | 5 | 0 |
Baseline characteristics
| Characteristic | Total | Cohort 2 (Treatment-naive) | Cohort 1 (Treatment-experienced) |
|---|---|---|---|
| Age, Continuous | 58 years STANDARD_DEVIATION 9.8 | 55 years STANDARD_DEVIATION 7.1 | 58 years STANDARD_DEVIATION 9.9 |
| Race/Ethnicity, Customized Ethnicity Hispanic or Latino | 32 Participants | 1 Participants | 31 Participants |
| Race/Ethnicity, Customized Ethnicity Not Hispanic or Latino | 214 Participants | 5 Participants | 209 Participants |
| Race/Ethnicity, Customized Ethnicity Not Permitted | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Race American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Race Asian | 35 Participants | 1 Participants | 34 Participants |
| Race/Ethnicity, Customized Race Black or African American | 47 Participants | 3 Participants | 44 Participants |
| Race/Ethnicity, Customized Race Native Hawaiian or Pacific Islander | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Race Not Permitted | 2 Participants | 0 Participants | 2 Participants |
| Race/Ethnicity, Customized Race Other | 7 Participants | 0 Participants | 7 Participants |
| Race/Ethnicity, Customized Race White | 154 Participants | 2 Participants | 152 Participants |
| Region of Enrollment Australia | 12 Participants | 0 Participants | 12 Participants |
| Region of Enrollment Dominican Republic | 6 Participants | 0 Participants | 6 Participants |
| Region of Enrollment France | 6 Participants | 0 Participants | 6 Participants |
| Region of Enrollment Mexico | 2 Participants | 0 Participants | 2 Participants |
| Region of Enrollment Netherlands | 2 Participants | 0 Participants | 2 Participants |
| Region of Enrollment Spain | 13 Participants | 0 Participants | 13 Participants |
| Region of Enrollment Thailand | 31 Participants | 1 Participants | 30 Participants |
| Region of Enrollment United Kingdom | 5 Participants | 0 Participants | 5 Participants |
| Region of Enrollment United States | 171 Participants | 5 Participants | 166 Participants |
| Sex: Female, Male Female | 50 Participants | 0 Participants | 50 Participants |
| Sex: Female, Male Male | 198 Participants | 6 Participants | 192 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 195 / 242 | 5 / 6 |
| serious Total, serious adverse events | 55 / 242 | 1 / 6 |
Outcome results
Primary
Change From Baseline in eGFR Calculated by the Chronic Kidney Disease Epidemiology Collaboration Method Based on Cystatin C (eGFR_CKD-EPI,cysC) at Week 24
eGFR is a measurement of the kidney's ability to filter blood. The eGFR\_CKD-EPI,cysC method is adjusted for age and sex.
Time frame: Baseline; Week 24
Population: Participants in the Safety Analysis Set with available data at the respective time point were analyzed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort 1 (Treatment-experienced) | Change From Baseline in eGFR Calculated by the Chronic Kidney Disease Epidemiology Collaboration Method Based on Cystatin C (eGFR_CKD-EPI,cysC) at Week 24 | Baseline | 69.7 mL/min/1.73 m^2 |
| Cohort 1 (Treatment-experienced) | Change From Baseline in eGFR Calculated by the Chronic Kidney Disease Epidemiology Collaboration Method Based on Cystatin C (eGFR_CKD-EPI,cysC) at Week 24 | Change at Week 24 | 3.8 mL/min/1.73 m^2 |
| Cohort 2 (Treatment-naive) | Change From Baseline in eGFR Calculated by the Chronic Kidney Disease Epidemiology Collaboration Method Based on Cystatin C (eGFR_CKD-EPI,cysC) at Week 24 | Baseline | 70.2 mL/min/1.73 m^2 |
| Cohort 2 (Treatment-naive) | Change From Baseline in eGFR Calculated by the Chronic Kidney Disease Epidemiology Collaboration Method Based on Cystatin C (eGFR_CKD-EPI,cysC) at Week 24 | Change at Week 24 | 3.9 mL/min/1.73 m^2 |
Primary
Change From Baseline in eGFR Calculated by the CKD-EPI Method Based on Serum Creatinine (eGFR_CKD-EPI,Creatinine) at Week 24
eGFR is a measurement of the kidney's ability to filter blood. The eGFR\_CKD-EPI,creatinine method is adjusted for age, race, and sex.
Time frame: Baseline; Week 24
Population: Participants in the Safety Analysis Set with available data at the respective time point were analyzed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort 1 (Treatment-experienced) | Change From Baseline in eGFR Calculated by the CKD-EPI Method Based on Serum Creatinine (eGFR_CKD-EPI,Creatinine) at Week 24 | Baseline | 54.1 mL/min/1.73 m^2 |
| Cohort 1 (Treatment-experienced) | Change From Baseline in eGFR Calculated by the CKD-EPI Method Based on Serum Creatinine (eGFR_CKD-EPI,Creatinine) at Week 24 | Change at Week 24 | -1.8 mL/min/1.73 m^2 |
| Cohort 2 (Treatment-naive) | Change From Baseline in eGFR Calculated by the CKD-EPI Method Based on Serum Creatinine (eGFR_CKD-EPI,Creatinine) at Week 24 | Baseline | 54.4 mL/min/1.73 m^2 |
| Cohort 2 (Treatment-naive) | Change From Baseline in eGFR Calculated by the CKD-EPI Method Based on Serum Creatinine (eGFR_CKD-EPI,Creatinine) at Week 24 | Change at Week 24 | -2.6 mL/min/1.73 m^2 |
Primary
Change From Baseline in the Estimated Glomerular Filtration Rate Calculated by the Cockcroft-Gault Formula (eGFR_CG) at Week 24
eGFR is a measurement of the kidney's ability to filter blood.
Time frame: Baseline; Week 24
Population: Participants in the Safety Analysis Set (enrolled and received at least 1 dose of study drug) with available data at the respective time point were analyzed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort 1 (Treatment-experienced) | Change From Baseline in the Estimated Glomerular Filtration Rate Calculated by the Cockcroft-Gault Formula (eGFR_CG) at Week 24 | Baseline | 55.6 mL/min |
| Cohort 1 (Treatment-experienced) | Change From Baseline in the Estimated Glomerular Filtration Rate Calculated by the Cockcroft-Gault Formula (eGFR_CG) at Week 24 | Change at Week 24 | -0.4 mL/min |
| Cohort 2 (Treatment-naive) | Change From Baseline in the Estimated Glomerular Filtration Rate Calculated by the Cockcroft-Gault Formula (eGFR_CG) at Week 24 | Baseline | 60.2 mL/min |
| Cohort 2 (Treatment-naive) | Change From Baseline in the Estimated Glomerular Filtration Rate Calculated by the Cockcroft-Gault Formula (eGFR_CG) at Week 24 | Change at Week 24 | -0.3 mL/min |
Secondary
Change From Baseline in Actual GFR (aGFR) of E/C/F/TAF for Participants Enrolled in the PK/PD Substudy
aGFR was directly measured using iohexol plasma clearance (CLiohexol).
Time frame: Baseline; Week 2, 4, or 8; Week 24
Population: Participants in the Pharmacodynamic (PD) Substudy Analysis Set (enrolled in the pharmacokinetic (PK)/PD substudy, received at least 1 dose of study drug, and had baseline and at least 1 postbaseline assessment for aGFR assessed by CLiohexol) with available data at the respective time point were analyzed.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Cohort 1 (Treatment-experienced) | Change From Baseline in Actual GFR (aGFR) of E/C/F/TAF for Participants Enrolled in the PK/PD Substudy | Baseline | 60.1 mL/min | Standard Deviation 19.06 |
| Cohort 1 (Treatment-experienced) | Change From Baseline in Actual GFR (aGFR) of E/C/F/TAF for Participants Enrolled in the PK/PD Substudy | Change at Week 2, 4, or 8 | -0.6 mL/min | Standard Deviation 8.45 |
| Cohort 1 (Treatment-experienced) | Change From Baseline in Actual GFR (aGFR) of E/C/F/TAF for Participants Enrolled in the PK/PD Substudy | Change at Week 24 | 1.4 mL/min | Standard Deviation 9.91 |
Comparison: Comparison is made between the baseline value and the value from the Week 2, 4, or 8 visit and presented as a geometric least squares mean (GLSM) ratio with 90% confidence interval (CI). Postbaseline value and baseline value were used as test and reference, respectively.90% CI: [93.71, 104.46]
Comparison: Comparison is made between the baseline value and the value from the Week 24 visit and presented as a GLSM ratio with 90% CI. Week 24 value and baseline value were used as test and reference, respectively.90% CI: [97.11, 108.53]
Secondary
Change From Baseline in eGFR_CKD-EPI,Creatinine at Weeks 48, 96, and 144
eGFR is a measurement of the kidney's ability to filter blood. The eGFR\_CKD-EPI,creatinine method is adjusted for age, race, and sex.
Time frame: Baseline; Weeks 48, 96, and 144
Population: Participants in the Safety Analysis Set with available data at the respective time point were analyzed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort 1 (Treatment-experienced) | Change From Baseline in eGFR_CKD-EPI,Creatinine at Weeks 48, 96, and 144 | Baseline | 54.1 mL/min/1.73 m^2 |
| Cohort 1 (Treatment-experienced) | Change From Baseline in eGFR_CKD-EPI,Creatinine at Weeks 48, 96, and 144 | Change at Week 48 | -1.7 mL/min/1.73 m^2 |
| Cohort 1 (Treatment-experienced) | Change From Baseline in eGFR_CKD-EPI,Creatinine at Weeks 48, 96, and 144 | Change at Week 96 | 0.1 mL/min/1.73 m^2 |
| Cohort 1 (Treatment-experienced) | Change From Baseline in eGFR_CKD-EPI,Creatinine at Weeks 48, 96, and 144 | Change at Week 144 | 1.7 mL/min/1.73 m^2 |
| Cohort 2 (Treatment-naive) | Change From Baseline in eGFR_CKD-EPI,Creatinine at Weeks 48, 96, and 144 | Change at Week 144 | 0.9 mL/min/1.73 m^2 |
| Cohort 2 (Treatment-naive) | Change From Baseline in eGFR_CKD-EPI,Creatinine at Weeks 48, 96, and 144 | Baseline | 54.4 mL/min/1.73 m^2 |
| Cohort 2 (Treatment-naive) | Change From Baseline in eGFR_CKD-EPI,Creatinine at Weeks 48, 96, and 144 | Change at Week 96 | -3.1 mL/min/1.73 m^2 |
| Cohort 2 (Treatment-naive) | Change From Baseline in eGFR_CKD-EPI,Creatinine at Weeks 48, 96, and 144 | Change at Week 48 | -3.0 mL/min/1.73 m^2 |
Secondary
Change From Baseline in eGFR_CKD-EPI,cysC at Weeks 48, 96, and 144
eGFR is a measurement of the kidney's ability to filter blood. The eGFR\_CKD-EPI,cysC method is adjusted for age and sex.
Time frame: Baseline; Weeks 48, 96, and 144
Population: Participants in the Safety Analysis Set with available data at the respective time point were analyzed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort 1 (Treatment-experienced) | Change From Baseline in eGFR_CKD-EPI,cysC at Weeks 48, 96, and 144 | Baseline | 69.7 mL/min/1.73 m^2 |
| Cohort 1 (Treatment-experienced) | Change From Baseline in eGFR_CKD-EPI,cysC at Weeks 48, 96, and 144 | Change at Week 48 | 1.7 mL/min/1.73 m^2 |
| Cohort 1 (Treatment-experienced) | Change From Baseline in eGFR_CKD-EPI,cysC at Weeks 48, 96, and 144 | Change at Week 96 | 3.2 mL/min/1.73 m^2 |
| Cohort 1 (Treatment-experienced) | Change From Baseline in eGFR_CKD-EPI,cysC at Weeks 48, 96, and 144 | Change at Week 144 | 3.1 mL/min/1.73 m^2 |
| Cohort 2 (Treatment-naive) | Change From Baseline in eGFR_CKD-EPI,cysC at Weeks 48, 96, and 144 | Change at Week 144 | 3.5 mL/min/1.73 m^2 |
| Cohort 2 (Treatment-naive) | Change From Baseline in eGFR_CKD-EPI,cysC at Weeks 48, 96, and 144 | Baseline | 70.2 mL/min/1.73 m^2 |
| Cohort 2 (Treatment-naive) | Change From Baseline in eGFR_CKD-EPI,cysC at Weeks 48, 96, and 144 | Change at Week 96 | 5.6 mL/min/1.73 m^2 |
| Cohort 2 (Treatment-naive) | Change From Baseline in eGFR_CKD-EPI,cysC at Weeks 48, 96, and 144 | Change at Week 48 | 7.3 mL/min/1.73 m^2 |
Secondary
Change From Baseline in the eGFR_CG at Weeks 48, 96, and 144
eGFR is a measurement of the kidney's ability to filter blood.
Time frame: Baseline; Weeks 48, 96, and 144
Population: Participants in the Safety Analysis Set with available data at the respective time point were analyzed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort 1 (Treatment-experienced) | Change From Baseline in the eGFR_CG at Weeks 48, 96, and 144 | Baseline | 55.6 mL/min |
| Cohort 1 (Treatment-experienced) | Change From Baseline in the eGFR_CG at Weeks 48, 96, and 144 | Change at Week 48 | -0.6 mL/min |
| Cohort 1 (Treatment-experienced) | Change From Baseline in the eGFR_CG at Weeks 48, 96, and 144 | Change at Week 96 | 0.6 mL/min |
| Cohort 1 (Treatment-experienced) | Change From Baseline in the eGFR_CG at Weeks 48, 96, and 144 | Change at Week 144 | 1.5 mL/min |
| Cohort 2 (Treatment-naive) | Change From Baseline in the eGFR_CG at Weeks 48, 96, and 144 | Change at Week 144 | 7.0 mL/min |
| Cohort 2 (Treatment-naive) | Change From Baseline in the eGFR_CG at Weeks 48, 96, and 144 | Baseline | 60.2 mL/min |
| Cohort 2 (Treatment-naive) | Change From Baseline in the eGFR_CG at Weeks 48, 96, and 144 | Change at Week 96 | -1.9 mL/min |
| Cohort 2 (Treatment-naive) | Change From Baseline in the eGFR_CG at Weeks 48, 96, and 144 | Change at Week 48 | -0.6 mL/min |
Secondary
Percentage of Participants Achieving HIV-1 RNA < 50 Copies/mL at Weeks 24, 48, 96, and 144
The percentage of participants achieving HIV-1 RNA \< 50 Copies/mL at Weeks 24, 48, 96, and 144 was analyzed using the snapshot algorithm, which defines a patient's virologic response status using only the viral load at the predefined time point within an allowed window of time, along with study drug discontinuation status.
Time frame: Weeks 24, 48, 96, and 144
Population: Full Analysis Set included participants who were enrolled and received at least 1 dose of study drug.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 (Treatment-experienced) | Percentage of Participants Achieving HIV-1 RNA < 50 Copies/mL at Weeks 24, 48, 96, and 144 | Week 24 | 95.0 percentage of participants |
| Cohort 1 (Treatment-experienced) | Percentage of Participants Achieving HIV-1 RNA < 50 Copies/mL at Weeks 24, 48, 96, and 144 | Week 48 | 93.0 percentage of participants |
| Cohort 1 (Treatment-experienced) | Percentage of Participants Achieving HIV-1 RNA < 50 Copies/mL at Weeks 24, 48, 96, and 144 | Week 96 | 88.4 percentage of participants |
| Cohort 1 (Treatment-experienced) | Percentage of Participants Achieving HIV-1 RNA < 50 Copies/mL at Weeks 24, 48, 96, and 144 | Week 144 | 81.4 percentage of participants |
| Cohort 2 (Treatment-naive) | Percentage of Participants Achieving HIV-1 RNA < 50 Copies/mL at Weeks 24, 48, 96, and 144 | Week 144 | 100.0 percentage of participants |
| Cohort 2 (Treatment-naive) | Percentage of Participants Achieving HIV-1 RNA < 50 Copies/mL at Weeks 24, 48, 96, and 144 | Week 24 | 83.3 percentage of participants |
| Cohort 2 (Treatment-naive) | Percentage of Participants Achieving HIV-1 RNA < 50 Copies/mL at Weeks 24, 48, 96, and 144 | Week 96 | 100.0 percentage of participants |
| Cohort 2 (Treatment-naive) | Percentage of Participants Achieving HIV-1 RNA < 50 Copies/mL at Weeks 24, 48, 96, and 144 | Week 48 | 100.0 percentage of participants |
Secondary
Percentage of Participants Experiencing Adverse Events or Graded Laboratory Abnormalities
Adverse events (AEs) and graded laboratory abnormalities occurring during the E/C/F/TAF treatment period were summarized across the participant population. A participant was counted once if they had a qualifying event.
Time frame: Baseline up to Week 240 plus 30 days
Population: Participants in the Safety Analysis Set were analyzed.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 (Treatment-experienced) | Percentage of Participants Experiencing Adverse Events or Graded Laboratory Abnormalities | Grade 3 or 4 AE | 22.3 percentage of participants |
| Cohort 1 (Treatment-experienced) | Percentage of Participants Experiencing Adverse Events or Graded Laboratory Abnormalities | Serious AE | 22.7 percentage of participants |
| Cohort 1 (Treatment-experienced) | Percentage of Participants Experiencing Adverse Events or Graded Laboratory Abnormalities | AE leading to drug discontinuation | 5.0 percentage of participants |
| Cohort 1 (Treatment-experienced) | Percentage of Participants Experiencing Adverse Events or Graded Laboratory Abnormalities | Grade 3 or 4 laboratory abnormality | 42.6 percentage of participants |
| Cohort 1 (Treatment-experienced) | Percentage of Participants Experiencing Adverse Events or Graded Laboratory Abnormalities | Any AE | 95.5 percentage of participants |
| Cohort 2 (Treatment-naive) | Percentage of Participants Experiencing Adverse Events or Graded Laboratory Abnormalities | Grade 3 or 4 laboratory abnormality | 66.7 percentage of participants |
| Cohort 2 (Treatment-naive) | Percentage of Participants Experiencing Adverse Events or Graded Laboratory Abnormalities | Any AE | 100.0 percentage of participants |
| Cohort 2 (Treatment-naive) | Percentage of Participants Experiencing Adverse Events or Graded Laboratory Abnormalities | Grade 3 or 4 AE | 16.7 percentage of participants |
| Cohort 2 (Treatment-naive) | Percentage of Participants Experiencing Adverse Events or Graded Laboratory Abnormalities | AE leading to drug discontinuation | 0 percentage of participants |
| Cohort 2 (Treatment-naive) | Percentage of Participants Experiencing Adverse Events or Graded Laboratory Abnormalities | Serious AE | 16.7 percentage of participants |
Secondary
Percent Change From Baseline in C-type Collagen Sequence (CTX) at Weeks 24 and 48
CTX is a biomarker of bone turnover.
Time frame: Baseline; Weeks 24 and 48
Population: Participants in the Safety Analysis Set with available data at the respective time point were analyzed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort 1 (Treatment-experienced) | Percent Change From Baseline in C-type Collagen Sequence (CTX) at Weeks 24 and 48 | Change at Week 24 | -3.9 percentage change |
| Cohort 1 (Treatment-experienced) | Percent Change From Baseline in C-type Collagen Sequence (CTX) at Weeks 24 and 48 | Change at Week 48 | -2.2 percentage change |
| Cohort 2 (Treatment-naive) | Percent Change From Baseline in C-type Collagen Sequence (CTX) at Weeks 24 and 48 | Change at Week 24 | 16.9 percentage change |
| Cohort 2 (Treatment-naive) | Percent Change From Baseline in C-type Collagen Sequence (CTX) at Weeks 24 and 48 | Change at Week 48 | 0.0 percentage change |
Secondary
Percent Change From Baseline in Procollagen Type 1 N-terminal Propeptide (P1NP) at Weeks 24 and 48
P1NP is a biomarker of bone turnover.
Time frame: Baseline; Weeks 24 and 48
Population: Participants in the Safety Analysis Set with available data at the respective time point were analyzed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort 1 (Treatment-experienced) | Percent Change From Baseline in Procollagen Type 1 N-terminal Propeptide (P1NP) at Weeks 24 and 48 | Change at Week 24 | -12.98 percentage change |
| Cohort 1 (Treatment-experienced) | Percent Change From Baseline in Procollagen Type 1 N-terminal Propeptide (P1NP) at Weeks 24 and 48 | Change at Week 48 | -25.29 percentage change |
| Cohort 2 (Treatment-naive) | Percent Change From Baseline in Procollagen Type 1 N-terminal Propeptide (P1NP) at Weeks 24 and 48 | Change at Week 24 | 6.44 percentage change |
| Cohort 2 (Treatment-naive) | Percent Change From Baseline in Procollagen Type 1 N-terminal Propeptide (P1NP) at Weeks 24 and 48 | Change at Week 48 | 2.27 percentage change |
Secondary
Percent Change From Baseline in Retinol Binding Protein (RBP) to Creatinine Ratio (μg/g) at Weeks 24, 48, 96, and 144
Urine RBP is a renal biomarker which is used to evaluate drug-induced kidney injury.
Time frame: Baseline; Weeks 24, 48, 96, and 144
Population: Participants in the Safety Analysis Set with available data at the respective time point were analyzed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort 1 (Treatment-experienced) | Percent Change From Baseline in Retinol Binding Protein (RBP) to Creatinine Ratio (μg/g) at Weeks 24, 48, 96, and 144 | Change at Week 24 | -56.2 percentage change |
| Cohort 1 (Treatment-experienced) | Percent Change From Baseline in Retinol Binding Protein (RBP) to Creatinine Ratio (μg/g) at Weeks 24, 48, 96, and 144 | Change at Week 48 | -68.9 percentage change |
| Cohort 1 (Treatment-experienced) | Percent Change From Baseline in Retinol Binding Protein (RBP) to Creatinine Ratio (μg/g) at Weeks 24, 48, 96, and 144 | Change at Week 96 | -64.1 percentage change |
| Cohort 1 (Treatment-experienced) | Percent Change From Baseline in Retinol Binding Protein (RBP) to Creatinine Ratio (μg/g) at Weeks 24, 48, 96, and 144 | Change at Week 144 | -63.8 percentage change |
| Cohort 2 (Treatment-naive) | Percent Change From Baseline in Retinol Binding Protein (RBP) to Creatinine Ratio (μg/g) at Weeks 24, 48, 96, and 144 | Change at Week 144 | -1.0 percentage change |
| Cohort 2 (Treatment-naive) | Percent Change From Baseline in Retinol Binding Protein (RBP) to Creatinine Ratio (μg/g) at Weeks 24, 48, 96, and 144 | Change at Week 24 | 68.8 percentage change |
| Cohort 2 (Treatment-naive) | Percent Change From Baseline in Retinol Binding Protein (RBP) to Creatinine Ratio (μg/g) at Weeks 24, 48, 96, and 144 | Change at Week 96 | 55.0 percentage change |
| Cohort 2 (Treatment-naive) | Percent Change From Baseline in Retinol Binding Protein (RBP) to Creatinine Ratio (μg/g) at Weeks 24, 48, 96, and 144 | Change at Week 48 | 47.8 percentage change |
Secondary
Percent Change From Baseline in Urine Beta-2-microglobulin to Creatinine Ratio (μg/g) at Weeks 24, 48, 96, and 144
Urine beta-2-microglobulin is a renal biomarker which is used to evaluate drug-induced kidney injury.
Time frame: Baseline; Weeks 24, 48, 96, and 144
Population: Participants in the Safety Analysis Set with available data at the respective time point were analyzed.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Cohort 1 (Treatment-experienced) | Percent Change From Baseline in Urine Beta-2-microglobulin to Creatinine Ratio (μg/g) at Weeks 24, 48, 96, and 144 | Change at Week 24 | -70.7 percentage change |
| Cohort 1 (Treatment-experienced) | Percent Change From Baseline in Urine Beta-2-microglobulin to Creatinine Ratio (μg/g) at Weeks 24, 48, 96, and 144 | Change at Week 48 | -76.5 percentage change |
| Cohort 1 (Treatment-experienced) | Percent Change From Baseline in Urine Beta-2-microglobulin to Creatinine Ratio (μg/g) at Weeks 24, 48, 96, and 144 | Change at Week 96 | -83.6 percentage change |
| Cohort 1 (Treatment-experienced) | Percent Change From Baseline in Urine Beta-2-microglobulin to Creatinine Ratio (μg/g) at Weeks 24, 48, 96, and 144 | Change at Week 144 | -81.9 percentage change |
| Cohort 2 (Treatment-naive) | Percent Change From Baseline in Urine Beta-2-microglobulin to Creatinine Ratio (μg/g) at Weeks 24, 48, 96, and 144 | Change at Week 144 | -3.6 percentage change |
| Cohort 2 (Treatment-naive) | Percent Change From Baseline in Urine Beta-2-microglobulin to Creatinine Ratio (μg/g) at Weeks 24, 48, 96, and 144 | Change at Week 24 | -19.5 percentage change |
| Cohort 2 (Treatment-naive) | Percent Change From Baseline in Urine Beta-2-microglobulin to Creatinine Ratio (μg/g) at Weeks 24, 48, 96, and 144 | Change at Week 96 | -45.9 percentage change |
| Cohort 2 (Treatment-naive) | Percent Change From Baseline in Urine Beta-2-microglobulin to Creatinine Ratio (μg/g) at Weeks 24, 48, 96, and 144 | Change at Week 48 | -59.2 percentage change |
Secondary
Pharmacokinetic (PK) Parameter: Cmax of TAF
Cmax is defined as the maximum concentration of drug. Blood draws for this outcome may have been at the Week 2, 4, or 8 visit.
Time frame: Predose, and 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, and 24 hours postdose
Population: Participants in the PK Substudy Analysis Set (enrolled in the PK/PD substudy, received at least 1 dose of study drug, and for whom steady-state PK parameters were available) with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 (Treatment-experienced) | Pharmacokinetic (PK) Parameter: Cmax of TAF | 269.8 ng/mL | Standard Deviation 180.77 |
Secondary
PK Parameter: AUCtau of TAF
AUCtau is defined as the concentration of drug over time (area under the plasma concentration versus time curve over the dosing interval). Blood draws for this outcome may have been at the Week 2, 4, or 8 visit.
Time frame: Predose, and 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, and 24 hours postdose
Population: Participants in the PK Substudy Analysis Set with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 (Treatment-experienced) | PK Parameter: AUCtau of TAF | 368.4 ng*h/mL | Standard Deviation 631.2 |
Secondary
PK Parameter: AUCtau of Tenofovir Diphosphate (TFV-DP) in Peripheral Blood Mononuclear Cell (PBMC) for Participants Enrolled in PK/PD Sub-study
TFV-DP is an active phosphorylated metabolite of tenofovir alafenamide. AUCtau is defined as the concentration of drug over time (area under the plasma concentration versus time curve over the dosing interval). Blood draws for this outcome may have been at the Week 2, 4, or 8 visit.
Time frame: Predose, and 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, and 24 hours postdose
Population: Participants who were enrolled in the PK/PD substudy, received at least 1 dose of study drug, and for whom the steady-state PK parameter (AUCtau) of TFV-DP was evaluable were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 (Treatment-experienced) | PK Parameter: AUCtau of Tenofovir Diphosphate (TFV-DP) in Peripheral Blood Mononuclear Cell (PBMC) for Participants Enrolled in PK/PD Sub-study | 50.6 µmol*h/L | Standard Deviation 55.75 |
Secondary
PK Parameter: Clast of TAF
Clast is defined as the last observable concentration of drug. Blood draws for this outcome may have been at the Week 2, 4, or 8 visit.
Time frame: Predose, and 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, and 24 hours postdose
Population: Participants in the PK Substudy Analysis Set with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 (Treatment-experienced) | PK Parameter: Clast of TAF | 7.6 ng/mL | Standard Deviation 25.73 |
Secondary
PK Parameter: t1/2 of TAF
t1/2 is defined as the estimate of the terminal elimination half-life of the drug. Blood draws for this outcome may have been at the Week 2, 4, or 8 visit.
Time frame: Predose, and 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, and 24 hours postdose
Population: Participants in the PK Substudy Analysis Set with available data were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 (Treatment-experienced) | PK Parameter: t1/2 of TAF | 0.43 hours |
Secondary
PK Parameter: Tlast of TAF
Tlast is defined as the time of Clast. Blood draws for this outcome may have been at the Week 2, 4, or 8 visit.
Time frame: Predose, and 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, and 24 hours postdose
Population: Participants in the PK Substudy Analysis Set with available data were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 (Treatment-experienced) | PK Parameter: Tlast of TAF | 4.45 hours |
Secondary
PK Parameter: Tmax of TAF
Tmax is defined as the time of Cmax. Blood draws for this outcome may have been at the Week 2, 4, or 8 visit.
Time frame: Predose, and 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, and 24 hours postdose
Population: Participants in the PK Substudy Analysis Set with available data were analyzed.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1 (Treatment-experienced) | PK Parameter: Tmax of TAF | 0.97 hours |
Secondary
PK Parameter: λz of TAF
λz is defined as the terminal elimination rate constant. Blood draws for this outcome may have been at the Week 2, 4, or 8 visit.
Time frame: Predose, and 5 minutes, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 5, 8, and 24 hours postdose
Population: Participants in the PK Substudy Analysis Set with available data were analyzed.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 (Treatment-experienced) | PK Parameter: λz of TAF | 1.764 1/hour | Standard Deviation 1.4521 |