Phase IIB Pilot of Atazanavir + Raltegravir (SPARTAN)

• Number of Nonresponders at Week 8 [ Time Frame: At Week 8 from Baseline ] [ Designated as safety issue: No ]
  Participants were classified as nonresponders if they had an HIV RNA level ≥400 copies/mL and a decrease from baseline <2 log10 copies/mL.
• Number of Participants With HIV RNA Levels <50 Copies/mL at Weeks 48 and 96 [ Time Frame: At Weeks 48 and 96 from Baseline ] [ Designated as safety issue: No ]
  Participant HIV RNA level was determined at Weeks 48 and 96 using the Roche Amplicor® Ultrasensitive Assay Version 1. VR-OC=Virologic response-observed cases.
• Number of Participants With HIV RNA Levels <400 Copies/mL at Week 24 [ Time Frame: At Week 24 from Baseline ] [ Designated as safety issue: No ]
  NC=F: noncompleter=failure; NC=M: noncompleter=missing; VR-OC: virologic response-observed
• Number of Participants With HIV RNA Levels <400 Copies/mL at Week 48 [ Time Frame: At Week 48 from Baseline ] [ Designated as safety issue: No ]
• Number of Participants With HIV RNA Levels <400 Copies/mL at Week 96 [ Time Frame: At Week 96 from Baseline ] [ Designated as safety issue: No ]
• Mean Change From Baseline in Absolute Cluster of Differentiation 4 Cell Count [ Time Frame: From Baseline to Weeks 2, 4, 8, 12, 16, 20, and 24 ] [ Designated as safety issue: No ]
• Number of Participants With Adverse Events (AEs), Serious Adverse Events (SAEs), Death as Outcome, AEs Leading to Discontinuation, SAEs Leading to Discontinuation [ Time Frame: Week 1 to Week 96, continuously ] [ Designated as safety issue: Yes ]
  AE=any new untoward medical occurrence or worsening of a preexisting medical condition that does not necessarily have a causal relationship with this treatment. SAE=any untoward medical occurrence that at any dose results in death, is life-threatening, requires inpatient hospitalization or causes prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, results in drug dependency or drug abuse, or is an important medical event.
• Baseline and Mean Change From Baseline in Total Cholesterol Levels [ Time Frame: From Baseline to Week 24 and Week 48 ] [ Designated as safety issue: No ]
  The mean change from baseline in participant fasting lipids was determined using fasting serum samples.
• Mean Change From Baseline in Total Bilirubin Level [ Time Frame: From Baseline to Week 24 and Week 48 ] [ Designated as safety issue: Yes ]
• Mean Change From Baseline in Electrocardiogram Findings [ Time Frame: From Baseline to Week 24 ] [ Designated as safety issue: Yes ]
  The incidence of QRS wave widening and QT and PR prolongation on participant electrocardiogram findings were evaluated at study Week 24.
• Atazanavir Maximum Observed Plasma Concentration (Cmax) in 1 Dosing Interval [ Time Frame: At Week 2 from Baseline ] [ Designated as safety issue: No ]
  Serial blood samples were collected over a 12-hour period after the morning dose at Week 2.
• Raltegravir Cmax in 1 Dosing Interval [ Time Frame: At Week 2 from Baseline ] [ Designated as safety issue: No ]
  Serial blood samples were collected over a 12-hour period after the morning dose at Week 2.
• Atazanavir Time of Maximum Observed Plasma Concentration (Tmax) [ Time Frame: At Week 2 from Baseline ] [ Designated as safety issue: No ]
  Serial blood samples were collected over a 12-hour period after the morning dose at Week 2.
• Raltegravir Tmax [ Time Frame: At Week 2 from Baseline ] [ Designated as safety issue: No ]
  Serial blood samples were collected over a 12-hour period after the morning dose at Week 2.
• Atazanavir Trough Plasma Concentration (Cmin) 12 Hours Postdose [ Time Frame: At Week 2 from Baseline ] [ Designated as safety issue: No ]
• Raltegravir Cmin 12 Hours Postdose [ Time Frame: At Week 2 from Baseline ] [ Designated as safety issue: No ]
• Atazanavir Cmin Prior to the Morning Dose [ Time Frame: At Week 2 from Baseline ] [ Designated as safety issue: No ]
• Raltegravir Cmin Prior to the Morning Dose [ Time Frame: At Week 2 from Baseline ] [ Designated as safety issue: No ]
• Atazanavir Area Under the Concentration Curve From Time 0 to 12 Hours (AUC [0-12h]) in 1 Dosing Interval [ Time Frame: At Week 2 from Baseline ] [ Designated as safety issue: No ]
• Raltegravir AUC (0-12h) in 1 Dosing Interval [ Time Frame: At Week 2 from Baseline ] [ Designated as safety issue: No ]
• Atazanavir Area Under the Concentration Curve From Time 0 to 24 Hours (AUC [0-24h]) in 1 Dosing Interval [ Time Frame: At Week 2 from Baseline ] [ Designated as safety issue: No ]
  AUC (0-24h) was estimated by multiplying AUC (0-12h) by 2.
• Atazanavir Individual Inhibitory Quotient (IQ) [ Time Frame: At Week 2 from Baseline ] [ Designated as safety issue: No ]
  Individual IQ was defined at Cmin at Week 2 divided by the protein binding adjusted EC90 (ie, the drug concentration observed to inhibit virion production by 90% in a cell-based assay) values for Atazanavir that were derived from individual participant clinical isolates.
• Atazanavir Terminal Elimination Half Life [ Time Frame: At Week 2 from Baseline ] [ Designated as safety issue: No ]
• Raltegravir Terminal Elimination Half Life [ Time Frame: At Week 2 from Baseline ] [ Designated as safety issue: No ]
• Number of Participants With Hematology Laboratory Test Results With Worst Toxicity of Grades 1 to 4 Among All Treated Participants [ Time Frame: While on treatment from Baseline through Week 96 ] [ Designated as safety issue: Yes ]
  ULN=upper limit of normal. Hematocrit(%) Grade (Gr) 1: ≥28.5-<31; Gr 2: ≥24-<28.5; Gr 3: ≥19.5-<24; Gr 4: <19.5. Hemoglobin (g/dL) Gr 1: 9.5-11; Gr 2: 8-9.4; Gr 3: 6.5-7.9; Gr 4: <6.5. Platelets (/mm^3) Gr 1: 75,000-99,000; Gr 2: 50,000-74,999; Gr 3: 20,000-49,999; Gr 4: <20,000. White Blood Cells (/mm^3) Gr 1: >2500-4000; Gr 2: >1000-<2500; Gr 3: >800-<1000; Gr 4: <800. . Prothrombin time (seconds) Gr 1: 1.01-1.25*ULN; Gr 2: 1.26-1.5*ULN; Gr 3: 1.51-3*ULN; Gr 4: >3*ULN.
• Number of Participants With Blood Chemistry Laboratory Test Results With Worst Toxicity of Grades 1 to 4 [ Time Frame: While on treatment from Baseline through Week 96 ] [ Designated as safety issue: Yes ]
  Blood urea nitrogen Gr 1:1.25-2.5*ULN;Gr 2:2.6-5.0*ULN; Gr 3:5.1-10*ULN; Gr 4:>10*ULN. Creatinine (mg/dL) Gr 1: 1.1-1.5 *ULN; Gr 2: 1.6-3*ULN: Gr 3: 3.1-6*ULN; Gr 4: >6*ULN. Hypercarbia (meq/L)Gr 1: 33-36; Gr 2:37-40; Gr 3: 41-45; Gr 4:>45. Hypocarbia (meq/L)Gr 1:19-21; Gr 2: 15-18; Gr 3: 10-14; Gr 4:<10. Hypercalcemia (mg/dL)Gr 1:10.6-11.5;Gr 2:11.6-12.5; Gr 3:12.6-13.5;Gr 4: >13.5. Hypocalcemia (mg/dL)Gr 1: 8.4-7.8;Gr 2:7.7-7; Gr 3:6.9-6.1; Gr 4: <6.1.Hyperchloremia(meq/L)Gr 1:113-116; Gr 2:117-120; Gr 3:121-125; Gr 4: >125.Hypochloremia(meq/L)Gr 1: 90-93; Gr 2: 85-89; Gr 3:80-84; Gr 4:<80.
• Number of Participants With Blood Chemistry Laboratory Test Results With Worst Toxicity of Grades 1 to 4 (Continued) [ Time Frame: While on treatment from Baseline through Week 96 ] [ Designated as safety issue: Yes ]
  Hyperkalemia(meq/L) Gr 1: 5.6-6; Gr 2: 6.1-6.5; Gr 3: 6.6-7; Gr4: >7. Hypokalemia(meq/L) Gr 1: 3-3.4; Gr 2: 2.5-2.9; Gr 3: 2-2.4; Gr 4:<2. Hypernatremia (meq/L) Gr 1: 148-150; Gr 2: 151-157; Gr 3: 148-165; Gr 4: >165. Hyponatremia (meq/L) Gr 1: 130-132; Gr 2: 123-129; Gr 3: 116-122; Gr 4: >115.Hyperglycemia(mg/dL)Gr 1: 116-160; Gr 2: 161-250; Gr 3: 251-500; Gr 4: >500. Hypoglycemia(mg/dL)Gr 1: 55-64; Gr 2: 40-54; Gr 3:30-39;Gr 4:<30.Creatine kinase (IU/L) Gr 1: >ULN-1.5*ULN; Gr 2: 1.5-3*ULN; Gr 3: >3-6*ULN; Gr 4: >6.0*ULN. Albumin (g/dL) Gr 1: <LLN-30; Gr 2: <30-20; Gr 3&4: <20.
• Number of Participants With Enzyme and Urine Laboratory Test Results With Worst Toxicity of Grades 1 to 4 [ Time Frame: While on treatment from Baseline through Week 96 ] [ Designated as safety issue: Yes ]
  AST/SGOT=Aspartate aminotransferase/serum glutamate oxaloacetate transaminase; ALT/SGPT=Alanine transaminase/serum glutamic pyruvic transaminase. Bilirubin (mg/dL)Gr 1: 1.1-1.5*ULN;Gr 2:1.6-2.5*ULN;Gr3:2.6-5*ULN;Gr4:>5*ULN.AST/SGOT(U/L)Gr 1:1.25-2.5*ULN;Gr 2: 2.6-5*ULN;Gr 3:5.1-10*ULN;Gr4:>10*ULN.ALT/SGPT (U/L)Gr 1:1.25-2.5*ULN;Gr 2:1.4-2.09*ULN;Gr 3:5.1-10*ULN;Gr4:>10*ULN. Lipase(U/L)Gr 1:1.1-1.39*ULN;Gr 2:>1.5-2*ULN;Gr 3:2.5-5;Gr 4:5*ULN.Proteinuria(g/24 hr loss)Gr 1:1+or <1;Gr 2:2-3+or>1-2; Gr 3:4+or>2-3.5;Gr4:>3.5.Creatine kinase(IU/L)Gr1:2-3*ULN;Gr 2:3.1-5*ULN;Gr 3:5.1-10*ULN;Gr4:>10*ULN.

• Proportions of subjects with HIV RNA <50 [ Time Frame: at Weeks 48 and 96 ] [ Designated as safety issue: No ]
• Antiretroviral activity [ Time Frame: at Weeks 24, 48, and 96 ] [ Designated as safety issue: No ]
• Safety as measured by adverse events, laboratory abnormalities and ECG findings [ Time Frame: through Weeks 24, 48, and 96 ] [ Designated as safety issue: Yes ]
• Assessment of pharmacokinetics [ Time Frame: throughout the study ] [ Designated as safety issue: No ]

The purpose of this study is to determine if the combination of atazanavir and raltegravir taken together is safe and effective in the treatment of human immunodeficiency virus (HIV).

• Drug: Atazanavir
  Capsules, Oral, 300 mg, twice daily, 96 weeks
  Other Names:

  • Reyataz
  • BMS-232632
• Drug: Raltegravir
  Tablet, Oral, 400 mg, twice daily, 96 weeks
• Drug: Atazanavir
  Capsules, Oral, 300 mg, once daily, 96 weeks
  Other Names:

  • Reyataz
  • BMS-232632
• Drug: Ritonavir
  Capsules, Oral, 100 mg, once daily, 96 weeks
• Drug: Tenofovir/Emtricitabine
  Tablet, Oral, 300-mg Tenofovir/200-mg Emtricitabine, once daily, 96 weeks
  Other Name: Truvada

• Experimental: Atazanavir + Raltegravir
  Atazanavir 300 mg twice daily + Raltegravir 400 mg twice daily
  Interventions:

  • Drug: Atazanavir
  • Drug: Raltegravir
• Active Comparator: Atazanavir + Ritonavir + Tenofovir /Emtricitabine
  Atazanavir, 300 mg once daily, + Ritonavir, 100 mg once daily, + Tenofovir 300 mg/Emtricitabine, 200 mg once daily
  Interventions:

  • Drug: Atazanavir
  • Drug: Ritonavir
  • Drug: Tenofovir/Emtricitabine

Inclusion Criteria:

• Human Immunodeficiency Virus (HIV)-1 positive status
• HIV ribonucleic acid (RNA) level >=5000 copies/mL
• Antiretroviral treatment-naive
• Absolute Cluster of Differentiation 4 (CD4) cell count meeting 1 of the following criteria:
• <350 cells/mm^3

• Screening CD4 >=350 and <=500 cells/mm^3 ONLY if at least 1 of the following conditions apply:

  • Screening HIV RNA level >100,000 copies/mL, or
  • CD4 decline >50-100 cells/mm^3/year, or
  • Age >=55 years
• Any CD4 cell count, if participant has a history of an acquired immune deficiency syndrome-defining illness
• Medically stable

Exclusion Criteria:

• Screening HIV genotype showing resistance to any component of the study regimen (Atazanavir, Raltegravir, Tenofovir/Emtricitabine)
• Hepatitis B or hepatitis C coinfection
• History of or current cardiac disease
• Electrocardiogram findings:
• PR Interval >260 msec (severe 1st degree atrioventricular block)
• QRS Interval >120 msec