Renal Effect of Stribild or Other Tenofovir DF-containing Regimens Compared to Ritonavir-boosted Atazanavir Plus Abacavir/Lamivudine in Antiretroviral Treatment-naive HIV-1 Infected Adults

• STB (Drug), also known as Stribild®: 150/150/200/300 mg fixed dose combination (FDC) tablet administered orally once daily with food
• TVD (Drug), also known as Truvada®: 200/300 mg FDC tablet administered orally once daily with food
• ATR (Drug), also known as Atripla®: 600/200/300 mg FDC tablet administered orally once daily on an empty stomach at bedtime
• RTV (Drug), also known as Norvir®: 100 mg tablet administered orally once daily with food
• ATV (Drug), also known as Reyataz®: 300 mg capsule administered orally once daily with food
• ABC/3TC (Drug), also known as Kivexa®: 600/300 mg FDC tablet administered orally once daily with food
• Iohexol (Drug), also known as Omnipaque™: 1500 mg solution administered intravenously at baseline, and at Weeks 4, 8, 16, and 24

Primary outcomes

• Actual Glomerular Filtration Rate (aGFR) Using Iohexol Plasma Clearance (CLiohexol) at Week 24 [Week 24]
• Estimated GFR (eGFR) Calculated by Cockcroft-Gault Formula at Week 24 [Week 24]: GFR is a measure of the rate at which blood is filtered by the kidney. Cockcroft-Gault is an equation (calculation) used to estimate GFR based on serum creatinine, weight, and gender. eGFR = (140 - age) * (mass in kg) * (0.85 if female) divided by 72 * serum creatinine in mg/dL
• Estimated GFR Calculated by Modification of Diet in Renal Disease (MDRD) Formula at Week 24 [Week 24]: MDRD is an equation (calculation) used to estimate GFR in participants with impaired renal function based on serum creatinine, age, race, and gender. eGFR (mL/min/1.73 m\^2) = 186 * (Scr)\^-1.154 * (Age)\^(-0.203) * (0.742 if female) * (1.212 if black). Scr = serum creatinine in mg/dL

Secondary outcomes

• Percentage of Participants Experiencing Treatment-Emergent Graded Laboratory Abnormality: Urine Glucose (by Dipstick) [Up to 24 weeks plus 30 days]
• Percentage of Participants Experiencing Treatment-Emergent Graded Laboratory Abnormality: Serum Glucose (Fasting) [Up to 24 weeks plus 30 days]
• Percentage Change From Baseline in Urine Albumin to Creatinine Ratio (mg/g) at Week 24 [Baseline; Week 24]
• Percentage Change From Baseline in Urine Protein to Creatinine Ratio (mg/g) at Week 24 [Baseline; Week 24]
• Percentage Change From Baseline in Urine β2-microglobulin to Creatinine Ratio (µg/g) at Week 24 [Baseline; Week 24]
• Percentage Change From Baseline in Urine Retinol Binding Protein (RBP) to Creatinine Ratio (µg/g) at Week 24 [Baseline; Week 24]
• Pharmacokinetic (PK) Parameter: Cmax for COBI [Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24]: Cmax is defined as the maximum observed concentration of drug in plasma.
• PK Parameter: Tmax for COBI [Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24]: Tmax is defined as the time of Cmax.
• PK Parameter: Clast for COBI [Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24]: Clast is defined as the last observable concentration of drug.
• PK Parameter: Tlast for COBI [Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24]: * Tlast is defined as the time of Clast. * Plasma samples for PK analysis were collected out to 10 hours postdose, and the predose concentration was used as a surrogate for the 24 hour concentration for PK parameter generation.
• PK Parameter: Ctau for COBI [Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24]: Ctau is defined as the observed drug concentration at the end of the dosing interval.
• PK Parameter: λz for COBI [Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24]: λz is defined as the terminal elimination rate constant.
• PK Parameter: AUCtau for COBI [Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24]: AUCtau is defined as the concentration of drug over time (area under the plasma concentration versus time curve over the dosing interval).
• PK Parameter: t1/2 for COBI [Predose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24]: t1/2 is defined as the estimate of the terminal elimination half-life of the drug.
• PK Parameter: Cmax for RTV [Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24]
• PK Parameter: Tmax for RTV [Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24]
• PK Parameter: Clast for RTV [Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24]
• PK Parameter: Tlast for RTV [Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24]: Plasma samples for PK analysis were collected out to 10 hours postdose, and the predose concentration was used as a surrogate for the 24 hour concentration for PK parameter generation.
• PK Parameter: Ctau for RTV [Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24]
• PK Parameter: AUCtau for RTV [Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24]
• PK Parameter: λz for RTV [Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24]
• PK Parameter: t1/2 for RTV [Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24]
• PK Parameter: Cmax for TFV [Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24]
• PK Parameter: Tmax for TFV [Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24]
• PK Parameter: Clast for TFV [Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24]
• PK Parameter: Tlast for TFV [Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24]: Plasma samples for PK analysis were collected out to 10 hours postdose, and the predose concentration was used as a surrogate for the 24 hour concentration for PK parameter generation.
• PK Parameter: Ctau for TFV [Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24]
• PK Parameter: λz for TFV [Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24]
• PK Parameter: AUCtau for TFV [Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24]
• PK Parameter: t1/2 for TFV [Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" at Weeks 4, 8, 16, and 24]
• PK Parameter: AUCinf for Iohexol [Pre-dose, 0, 0.5, 1, 2, 3, 4, 5, 6, and 10 hours post "time zero" on Day 1 and Weeks 4, 8, 16, and 24]: AUC inf is defined as the concentration of drug extrapolated to infinite time (area under the plasma concentration versus time curve extrapolated to infinite time).
• Percentage of Participants With HIV-1 RNA < 50 Copies/mL Week 24 as Determined by Snapshot Algorithm [Week 24]
• Change From Baseline in Cluster of Differentiation 4 Positive (CD4+) Cell Count at Week 24 [Baseline; Week 24]
• Percentage of Participants Experiencing Adverse Events (AEs) [Up to the last dose date plus 30 days (Up to 24 weeks plus 30 days)]: Incidences of adverse events and laboratory abnormalities will be summarized.
• Percentage of Participants Experiencing Treatment Emergent (TE) Grade 3 or 4 Laboratory Abnormalities [Up to the last dose date plus 30 days (Up to 24 weeks plus 30 days)]: Graded laboratory abnormalities were defined as values that increased at least one toxicity grade from predose at any postdose up to the last dose date of study drug plus 30 days. The most severe graded abnormality from all tests was counted for each participant.

Sex: All, ages: 18 Years to 55 Years

Key Inclusion Criteria:

* Treatment naïve
* Plasma HIV-1 RNA levels ≥ 5,000 copies/mL at Screening
* CD4 cell count > 200 cells/µL
* Screening genotype report provided by the site must show sensitivity to FTC, TDF, EFV, ABC, 3TC, ATV and absence of study drug resistance mutations that include K65R, K70E and M184V in RT
* Estimated GFR ≥ 70 mL/min
* Hepatic transaminases (aspartate aminotransferase \[AST\] and alanine aminotransferase \[ALT\]) ≤ 5 × upper limit of normal (ULN)
* Total bilirubin ≤ 1.5 mg/dL (≤ 26 umol/L), or normal direct bilirubin
* Adequate hematologic function (absolute neutrophil count ≥ 1,000/mm\^3; platelets ≥ 50,000/mm\^3; hemoglobin ≥ 8.5 g/dL)
* Serum amylase ≤ 5 × ULN (individuals with serum amylase > 5 × ULN will remain eligible if serum lipase is ≤ 5 × ULN)
* Normal electrocardiogram (ECG) or not clinically significant if abnormal ECG
* Not pregnant or non-lactating females of non-childbearing potential. Or females with childbearing potential who agree to utilize highly effective contraception methods or be non-heterosexually active or practice sexual abstinence from screening throughout the duration of study treatment and for 90 days if taking EFV/FTC/TDF or for 30 days for all other study drugs following the last study drug dose
* Males who agree to utilize a highly effective method of contraception during heterosexual intercourse or be non-heterosexually active, or practice sexual abstinence from first dose throughout the study period and for 90 days if taking EFV/FTC/TDF or for 30 days for all other study drugs following the last study drug dose. Males who agree to refrain from sperm donation from first dose until at least 90 days if taking EFV/FTC/TDF or for 30 days for all other study drugs following the last study drug dose
* Body mass index (BMI) of 19 ≤ BMI ≤ 30 kg/m\^2 and body weight ≥ 40 kg
* Life expectancy ≥ 1 year

Key Exclusion Criteria:

* HLA-B*5701 allele positive
* A new AIDS-defining condition diagnosed within the 30 days prior to screening
* Hepatitis B surface antigen (HBsAg) positive
* Hepatitis C virus (HCV) antibody positive and HCV RNA detectable
* Individuals experiencing decompensated cirrhosis
* Females who are breastfeeding
* Positive serum pregnancy test
* Have an implanted defibrillator or pacemaker
* Current alcohol or substance that could potentially interfere with study compliance
* A history of malignancy within the past 5 years (prior to screening) or ongoing malignancy other than cutaneous Kaposi's sarcoma (KS), basal cell carcinoma, or resected, non-invasive cutaneous squamous carcinoma. Individuals with cutaneous KS are eligible, but must not have received any systemic therapy for KS within 30 days of Day 1 Visit and must not be anticipated to require systemic therapy during the study
* Active, serious infections (other than HIV-1 infection) requiring parenteral antibiotic or antifungal therapy within 30 days prior to Day 1 Visit

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Participant flow

Outcome results

• Actual Glomerular Filtration Rate (aGFR) Using Iohexol Plasma Clearance (CLiohexol) at Week 24 (Primary), Mean, mL/min: STB + Iohexol 103.6 +/- 23.28; TVD + ATV/r + Iohexol 104.9 +/- 27.16; ATR + Iohexol 111.1 +/- 23.23; ABC/3TC + ATV/r + Iohexol 101.0 +/- 27.01
• Estimated GFR (eGFR) Calculated by Cockcroft-Gault Formula at Week 24 (Primary), Mean, mL/min: STB + Iohexol 116.9 +/- 17.06; TVD + ATV/r + Iohexol 122.4 +/- 31.71; ATR + Iohexol 120.0 +/- 20.52; ABC/3TC + ATV/r + Iohexol 123.0 +/- 25.74
• Estimated GFR Calculated by Modification of Diet in Renal Disease (MDRD) Formula at Week 24 (Primary), Mean, mL/min/1.73m^2: STB + Iohexol 99.3 +/- 17.07; TVD + ATV/r + Iohexol 110.2 +/- 23.98; ATR + Iohexol 109.2 +/- 20.90; ABC/3TC + ATV/r + Iohexol 104.9 +/- 12.59
• Percentage of Participants Experiencing Treatment-Emergent Graded Laboratory Abnormality: Urine Glucose (by Dipstick) (Secondary), Count of participants, Participants: STB + Iohexol 0; TVD + ATV/r + Iohexol 0; ATR + Iohexol 0; ABC/3TC + ATV/r + Iohexol 0
• Percentage of Participants Experiencing Treatment-Emergent Graded Laboratory Abnormality: Serum Glucose (Fasting) (Secondary), Number, percentage of participants: STB + Iohexol 11.8; TVD + ATV/r + Iohexol 12.5; ATR + Iohexol 20.0; ABC/3TC + ATV/r + Iohexol 0
• Percentage Change From Baseline in Urine Albumin to Creatinine Ratio (mg/g) at Week 24 (Secondary), Median, percentage change: STB + Iohexol 0.0 (-23.6 to 50.0); TVD + ATV/r + Iohexol -18.3 (-57.1 to 50.0); ATR + Iohexol 50.0 (-25.0 to 100.0); ABC/3TC + ATV/r + Iohexol -16.7 (-37.5 to 0.0)
• Percentage Change From Baseline in Urine Protein to Creatinine Ratio (mg/g) at Week 24 (Secondary), Median, percentage change: STB + Iohexol 5.7 (-11.0 to 22.5); TVD + ATV/r + Iohexol 17.5 (0.0 to 45.7); ATR + Iohexol -10.5 (-41.9 to 69.8); ABC/3TC + ATV/r + Iohexol 7.1 (-24.3 to 13.3)
• Percentage Change From Baseline in Urine β2-microglobulin to Creatinine Ratio (µg/g) at Week 24 (Secondary), Median, percentage change: STB + Iohexol -5.1 (-48.2 to 22.8); TVD + ATV/r + Iohexol 197.3 (21.7 to 328.7); ATR + Iohexol -1.1 (-33.1 to 36.7); ABC/3TC + ATV/r + Iohexol -22.7 (-60.8 to -6.0)
• Percentage Change From Baseline in Urine Retinol Binding Protein (RBP) to Creatinine Ratio (µg/g) at Week 24 (Secondary), Median, percentage change: STB + Iohexol 38.1 (-1.1 to 51.1); TVD + ATV/r + Iohexol 52.2 (5.9 to 147.6); ATR + Iohexol 52.1 (-33.8 to 92.8); ABC/3TC + ATV/r + Iohexol 4.8 (-13.6 to 15.5)
• Pharmacokinetic (PK) Parameter: Cmax for COBI (Secondary), Mean, ng/mL: STB + Iohexol 1189.1 +/- 377.88
• PK Parameter: Tmax for COBI (Secondary), Median, hours: STB + Iohexol 3.3 (3.0 to 4.1)
• PK Parameter: Clast for COBI (Secondary), Mean, ng/mL: STB + Iohexol 85.0 +/- 126.69
• PK Parameter: Tlast for COBI (Secondary), Median, hours: STB + Iohexol 24.0 (24.0 to 24.0)
• PK Parameter: Ctau for COBI (Secondary), Mean, ng/mL: STB + Iohexol 59.7 +/- 113.31
• PK Parameter: λz for COBI (Secondary), Mean, 1/hour: STB + Iohexol 0.179 +/- 0.0598
• PK Parameter: AUCtau for COBI (Secondary), Mean, h*ng/mL: STB + Iohexol 9225.8 +/- 2786.60
• PK Parameter: t1/2 for COBI (Secondary), Median, hours: STB + Iohexol 3.80 (3.24 to 4.63)
• PK Parameter: Cmax for RTV (Secondary), Mean, ng/mL: TVD + ATV/r + Iohexol 1260.0 +/- 453.58; ABC/3TC + ATV/r + Iohexol 1352.1 +/- 513.74
• PK Parameter: Tmax for RTV (Secondary), Median, hours: TVD + ATV/r + Iohexol 4.0 (3.2 to 4.6); ABC/3TC + ATV/r + Iohexol 4.0 (2.1 to 4.1)
• PK Parameter: Clast for RTV (Secondary), Mean, ng/mL: TVD + ATV/r + Iohexol 59.5 +/- 57.85; ABC/3TC + ATV/r + Iohexol 61.0 +/- 56.51
• 18 more outcome measures not shown.

Adverse events

Time frame: Baseline to 30 days after last dose of study drug (up to 24 weeks plus 30 days)

Serious adverse events by term

Other adverse events by term

18 more terms not shown.

Limitations and caveats: There were no limitations affecting the analysis or results.

• Gilead Study Director, Study director, Gilead Sciences

NIH grants: 2014