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BMS-Reyataz Study in Treatment in Naive Subjects to Compare the Efficacy and Safety Between Boosted Reyataz and Kaletra When in Combination With Fixed Dose Truvada

Primary Purpose

HIV Infections

Status

Completed

Phase

Phase 3

Locations

International

Study Type

Interventional

Intervention

ATV

RTV

Tenofovi-Emtricitabine (TDF/FTC) tablet

LPV

About this trial

This is an interventional treatment trial for HIV Infections focused on measuring HIV, Treatment Naive

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: HIV RNA ≥5000 c/ml Exclusion Criteria: Any antiretroviral therapy within 30 days prior to screening; Women of Childbearing potential (WOCBP) unwilling or unable to use an acceptable method to avoid pregnancy for the entire study and for up to 8 weeks after the study; WOCBP using a prohibited contraceptive method WOCBP who are pregnant or breastfeeding; Women with a positive pregnancy test on enrollment or prior to study drug administration; Presence of a newly diagnosed HIV-Related opportunistic infection or any medical condition requiring acute therapy at the time of enrollment; Suspected primary (acute) HIV infection; Prior antiviral therapy (>30 days of NRTI and/or >7 days of non-nucleoside reverse transcriptase inhibitor (NNRTI) or PI therapies) or any antiretroviral therapy within 30 days prior to screening; some exceptions are allowed for ARV therapy in use for Mother-to-child transmission; Participants with Cushing's syndrome; Untreated hypothyroidism or hyperthyroidism. A participant who is euthyroid on a stable replacement dose of thyroid hormone is acceptable provided the thyroid stimulating hormone (TSH) performed within 30 days of screening is within normal drug range; Recent therapy with agents with significant systemic myelosuppressive, neurotoxic, pancreatotoxic, hepatotoxic or cytotoxic potential within 3 months of study start or expected need for such therapy at the time of enrollment; or therapy with methadone or ribavirin/interferons or treatment with neurotoxic drugs or drugs that affect CYP3A4; Participants with obstructive liver disease; Active alcohol or substance use sufficient, in the Investigator's opinion, to prevent adequate compliance with study therapy or to increase the risk of developing pancreatitis or chemical hepatitis; Proven or suspected acute hepatitis in the 30 days prior to study entry; Intractable diarrhea (≥6 loose stools/day for at least 7 consecutive days) within 30 days prior to study entry; Inability to swallow capsules; Active peripheral neuropathy; Presence of cardiomyopathy (due to any cause) or any significant cardiovascular disease, such as unstable ischemic heart disease; Known, clinically significant cardiac conduction system disease. Baseline laboratory values measured within 2 weeks prior to initiating study drugs as follows: calculated creatine clearance <60 mL/min as estimated by the Cockcroft-Gault equation; total serum lipase ≥ 1.4 times the upper limit of normal; liver enzymes (AST, ALT) ≥ 5 times the upper limit of normal; total serum bilirubin ≥ 1.5 times the upper limit of normal. Hypersensitivity to any component of the formulation of study drug; Prohibited therapies; Any other clinical conditions or prior therapy that, in the opinion of the Investigator, would make the participant unsuitable for study or unable to comply with the dosing requirements; Prisoners or participants who are compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric or physical (e.g., infectious disease) illness must not be enrolled into this study.

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Arm Label

Atazanavir (ATV) + Ritonovir (RTV)

Lopinavir (LPV) + RTV

Arm Description

Participants were administered an oral dose of ATV 300 mg and RTV 100 mg once daily along with food on a background of fixed dose combination TDF 300 mg plus FTC 200 mg (TDF/FTC) once daily. Doses of ATV and RTV were taken 24 hours apart at the same time as the background TDF/FTC, up to 96 Weeks.

Participants were administered an oral dose of LPV 400 mg and RTV 100 mg once daily along with food on a background of fixed dose combination TDF 300 mg plus FTC 200 mg (TDF/FTC) once daily. Doses of LPV and RTV were taken 24 hours apart at the same time as the background TDF/FTC, up to 96 Weeks.

Outcomes

Primary Outcome Measures

Number of Participants With Human-immunodeficiency Virus- Ribonucleic Acid (HIV-RNA) < 50 Copies (c)/mL at Week 48

HIV RNA < 50 c/mL is the most stringent measure of viral suppression (lowest threshold of assay) and indicates that a participant responded to treatment.

Maximum Plasma Concentration (Cmax) of ATV/RTV and LPV/RTV in the Presence of an Antiretroviral (ARV) Regimen Including TDF at Week 4

Cmax was derived from plasma concentration versus time data.

Area Under the Concentration-time Curve, in One Dosing Interval [AUC(TAU)] of ATV/RTV and LPV/RTV in the Presence of an ARV Regimen Including TDF at Week 4

AUC(TAU) was derived from the plasma concentration versus time data. It was calculated from time 0 to 12 hours for LPV and RTV in the LPV/RTV regimen, 0-24 hours for ATV and RTV in the ATV/RTV regimen, and 0-24 hours for tenofovir in both regimens at Week 4.

Minimum Plasma Concentration (Cmin) of ATV/RTV and LPV/RTV in the Presence of an ARV Regimen Including TDF at Week 4

Cmin was derived from the plasma concentration versus time data.

Time to Reach Maximum Observed Plasma Concentration (Tmax) of ATV/RTV and LPV/RTV in the Presence of an ARV Regimen Including TDF at Week 4

Tmax was derived from the plasma concentration versus time data.

Terminal Elimination Half-life (T-half) of ATV/RTV and LPV/RTV in the Presence of an ARV Regimen Including TDF at Week 4

T-half was derived from the plasma concentration versus time data.

Protein Binding Adjusted Effective Concentration (EC-90) of ATV and LPV When Dosed With RTV at Week 4

EC90/50=concentration of drug inducing 90%/50% of its maximal response. Protein binding adjusted EC90 for ATV and LPV were derived from phenotypically measured individual EC50 values at baseline using the following formula: Protein binding adjusted EC90 (ng/mL) = scale factor × molecular weight of the free base × EC50 micrometer(μM)/ unbound fraction (fu). Scale factor relates EC50 to EC90 (value of 3 and 2 for ATV and LPV, respectively); fu: estimated unbound fraction of ATV and LPV in vivo (0.14 and 0.02 for ATV and LPV respectively).

Inhibitory Quotient (IQ) of ATV and LPV When Dosed With RTV at Week 4

IQ defined as Cmin at week 4 divided by protein binding adjusted EC90 values for the respective protease inhibitor (ATV or LPV) derived from individual participant clinical isolates.

Cmax of RTV at Week 4

Cmax was derived from plasma concentration versus time data.

AUC (0-24) of RTV at Week 4

AUC (0-24) was derived from plasma concentration versus time data. It was estimated as 2 times the AUC(TAU) based on 12-hour PK.

Cmin of RTV at Week 4

Cmin was derived from plasma concentration versus time data.

Cmax of Tenofovir at Week 4

Cmax was derived from plasma concentration versus time data.

Cmin of Tenofovir at Week 4

Cmin was derived from plasma concentration versus time data.

AUC (TAU) of Tenofovir at Week 4

AUC (TAU) was derived from plasma concentration versus time data.It was calculated from time 0-24 hours for tenofovir in LPV/RPV and ATV/RTV regimen at Week 4.

Mean Change From Baseline in Trunk-to-Limb Fat Ratio as Measured by Dual Energy X-ray Absorptiometry (DEXA) at Week 96

Mean changes from baseline in trunk-to-limb fat ratio as measured by DEXA, an x-ray scan used to measure bone mineral density. Clinical improvement is associated with a decrease in values.

Number of Participants With Single Nucleotide Polymorphisms (SNPs) Included in Genotype-Phenotype Analysis

19 genes of interest were selected from previous results or literature, and 34 SNPs were genotyped. Phenotype-Genotype analysis was performed using 31 of the SNPs. The genotypes of each SNP were further classified as either a minor allele carrier (MAC) group composed of heterozygous and rare homozygous genotypes, or wild type [WT, common homozygous].

Mean Change From Baseline in Fasting Non-High Density Lipoprotein (HDL) Cholesterol Associated With RETN_097

The change-from-baseline was defined as the difference between the averages of post-treatment time points (Weeks 48 and 96) and baseline. Association analysis for each SNP was performed using a minor allele carrier (MAC) composed of heterozygous and rare homozygous genotypes, and wild type (WT, common homozygous). False discovery rate (FDR)-adjusted (adj) p-values were calculated for each phenotype-genotype pair.

Mean Change From Baseline in Fasting Triglycerides Associated With RETN_097

The change-from-baseline was defined as the difference between the averages of post-treatment time points (Weeks 48 and 96) and baseline. Association analysis for each SNP was performed using a minor allele carrier (MAC) composed of heterozygous and rare homozygous genotypes, and wild type (WT, common homozygous). False discovery rate (FDR)-adjusted p-values were calculated for each phenotype-genotype pair.

Mean Change From Baseline in Fasting Triglycerides Associated With RETN_2265

The change-from-baseline was defined as the difference between the averages of post-treatment time points (Weeks 48 and 96) and baseline. Association analysis for each SNP was performed using a minor allele carrier (MAC) composed of heterozygous and rare homozygous genotypes, and wild type (WT, common homozygous). False discovery rate (FDR)-adjusted p-values were calculated for each phenotype-genotype pair.

Mean Change From Baseline in Fasting Triglycerides Associated With RETN_598

The change-from-baseline was defined as the difference between the averages of post-treatment time points (Weeks 48 and 96) and baseline. Association analysis for each SNP was performed using a minor allele carrier (MAC) composed of heterozygous and rare homozygous genotypes, and wild type (WT, common homozygous). False discovery rate (FDR)-adjusted p-values were calculated for each phenotype-genotype pair.

Mean Change From Baseline in Fasting Triglycerides Associated With APOE_C130R

The change-from-baseline was defined as the difference between the averages of post-treatment time points (Weeks 48 and 96) and baseline. Association analysis for each SNP was performed using a minor allele carrier (MAC) composed of heterozygous and rare homozygous genotypes, and wild type (WT, common homozygous). False discovery rate (FDR)-adjusted p-values were calculated for each phenotype-genotype pair.

Mean Change From Baseline in Fasting Triglycerides Associated With RETN_734

The change-from-baseline was defined as the difference between the averages of post-treatment time points (Weeks 48 and 96) and baseline. Association analysis for each SNP was performed using a minor allele carrier (MAC) composed of heterozygous and rare homozygous genotypes, and wild type (WT, common homozygous). False discovery rate (FDR)-adjusted p-values were calculated for each phenotype-genotype pair.

Mean Change From Baseline in Fasting Plasminogen Activator Inhibitor (PAI)-1 Associated With APOE_R176C

The change-from-baseline was defined as the difference between the averages of post-treatment time points (Weeks 48 and 96) and baseline. Association analysis for each SNP was performed using a minor allele carrier (MAC) composed of heterozygous and rare homozygous genotypes, and wild type (WT, common homozygous). False discovery rate (FDR)-adjusted p-values were calculated for each phenotype-genotype pair.

Mean Change From Baseline in Fasting Tumor Necrosis Factor (TNF)-Alpha Associated With IL6_5309

The change-from-baseline was defined as the difference between the averages of post-treatment time points (Weeks 48 and 96) and baseline. Association analysis for each SNP was performed using a minor allele carrier (MAC) composed of heterozygous and rare homozygous genotypes, and wild type (WT, common homozygous). False discovery rate (FDR)-adjusted p-values were calculated for each phenotype-genotype pair.

Mean Change From Baseline in Fasting Tumor Necrosis Factor (TNF)-Alpha Asssociated With RS11030679

The change-from-baseline was defined as the difference between the averages of post-treatment time points (Weeks 48 and 96) and baseline. Association analysis for each SNP was performed using a minor allele carrier (MAC) composed of heterozygous and rare homozygous genotypes, and wild type (WT, common homozygous). False discovery rate (FDR)-adjusted p-values were calculated for each phenotype-genotype pair.

Mean Change From Baseline in Subcutaneous Adipose Tissue (SAT)-To-Trunk Adipose Tissue (TAT) Ratio Associated With CCDC122_5980

The change-from-baseline was defined as the difference between the averages of post-treatment time points (Weeks 48 and 96) and baseline. Association analysis for each SNP was performed using a minor allele carrier (MAC) composed of heterozygous and rare homozygous genotypes, and wild type (WT, common homozygous). False discovery rate (FDR)-adjusted p-values were calculated for each phenotype-genotype pair. SAT and TAT were measured by computed tomography (CT).

Mean Change From Baseline in Visceral Adipose Tissue (VAT) Associated With BRUNOL_1842

The change-from-baseline was defined as the difference between the averages of post-treatment time points (Weeks 48 and 96) and baseline. Association analysis for each SNP was performed using a minor allele carrier (MAC) composed of heterozygous and rare homozygous genotypes, and wild type (WT, common homozygous). False discovery rate (FDR)-adjusted p-values were calculated for each phenotype-genotype pair. VAT was measured by computed tomography (CT).

Mean Change From Baseline in VAT Associated With RETN_730

The change-from-baseline was defined as the difference between the averages of post-treatment time points (Weeks 48 and 96) and baseline. Association analysis for each SNP was performed using a minor allele carrier (MAC) composed of heterozygous and rare homozygous genotypes, and wild type (WT, common homozygous). False discovery rate (FDR)-adjusted p-values were calculated for each phenotype-genotype pair. VAT was measured by computed tomography (CT).

Mean Change From Baseline in VAT-to-TAT Ratio Associated With CCDA122_5980

The change-from-baseline was defined as the difference between the averages of post-treatment time points (Weeks 48 and 96) and baseline. Association analysis for each SNP was performed using a minor allele carrier (MAC) composed of heterozygous and rare homozygous genotypes, and wild type (WT, common homozygous). False discovery rate (FDR)-adjusted p-values were calculated for each phenotype-genotype pair. VAT and TAT were measured by computed tomography (CT).

Secondary Outcome Measures

Number of Participants With HIV RNA < 400 c/mL at Week 48

HIV RNA < 400 c/mL is a less stringent measure of viral suppression (highest threshold of assay) and indicates that a participant responded to treatment.

Number of Participants With Confirmed Plasma HIV RNA < 400 c/mL at Week 48 (Defined by the Food and Drug Administration [FDA] Time to Loss of Virologic Response [TLOVR] Algorithm)

TLOVR defines responders at Week 48 as participants with confirmed HIV RNA <400 c/mL through Week 48 without intervening virologic rebound or treatment discontinuation. Virologic rebound is defined as confirmed on-treatment HIV RNA <400 c/mL or last on-treatment HIV RNA <400 c/mL followed by discontinuation. Participants are considered failures in this analysis if they experienced virologic rebound at or before Week 48, discontinued before Week 48, never responded by Week 48, never received study therapy or had missing HIV RNA at Week 48 and beyond.

Reduction of log10 HIV RNA Levels From Baseline to Week 48

Changes from baseline in log10 HIV RNA levels were calculated.

Mean Change From Baseline in Cluster of Differentiation 4 (CD4) Cell Count at Week 48

Mean change from baseline in CD4 cell counts was determined.

Treatment Emergent Resistance in Isolates From Participants With Virologic Failure at Week 48

Participants with virologic failure are those who never suppressed (HIV RNA <400 c/mL) and were on study through Week 48, or who rebounded to HIV RNA >= 400 c/mL and those who discontinued due to insufficient viral load response. IAS=International AIDS Society, PI=protease inhibitor, RTI=reverse transcription inhibitor, TAMS=Thymidine Analogue-Associated Mutations, NRTI=non-nucleotide reverse transcriptase inhibitor, M184V= Methionine-to-valine mutation at position 184 (in reverse transcription [RT] gene), FC=fold change

Number of Participants Who Died, Experienced Other Serious Adverse Events (SAEs), Experienced Adverse Events (AEs) and Experienced AEs Leading to Discontinuation Through Week 48

AEs:new,untoward medical occurrences/worsening of pre-existing medical condition,drug-related or not.SAEs:any AE that:resulted in death;was life threatening;resulted in a persistent or significant disability/incapacity;resulted in/prolonged an existing in-patient hospitalization; was a congenital anomaly/birth defect; was cancer;or overdose.Discontinuation from study was due either to an AE or was conducted at the investigator's discretion.AEs represented here include SAEs, which are not included in the AE count represented in the AE xml upload section. As such, these numbers may not match.

Number of Participants With Laboratory Abnormalities in Hematology Through Week 48: Hemoglobin, Hematocrit, Platelet Count, International Normalized Ratio (INR), Neutrophils, Prothrombin Time (PT) and White Blood Cells (WBC)

Hematology abnormalities were graded per modified World Health Organization (WHO) criteria (Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = very severe). Grade 3 and 4 criteria were: Hemoglobin: Grade 3: 6.5-7.9 g/dL, Grade 4: <6.5 g/dL; Hematocrit: Grade 3: >=19.5 - 24%, Grade 4: <19.5%; platelet count: Grade 3: 20,000- 49, 999/ mm^3, Grade 4: <20,000/mm^3; INR: Grade 3 Absolute Neutrophil Count (ANC): Grade 3: >= 500 - <750/mm^3, Grade 4: <500/mm^3; PT: Grade 3: 1.51 - 3.0*ULN, Grade 4: >3*ULN; WBC: Grade 3: >=800 to <1000/mm^3, Grade 4: <80/mm^3.

Number of Participants With Laboratory Abnormalities in Serum Enzymes Levels Through Week 48

Laboratory measurements marked as abnormal, as per modified WHO criteria (Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = very severe). Grade 3 and 4 criteria in serum enzymes were: Creatine phosphokinase (CPK): Grade 3: 5.1 - 10.0 * upper limit of normal (ULN), Grade 4: >10* ULN; Lipase: Grade 3: 2.10 - 5.0* ULN, Grade 4: 5.0* ULN.

Number of Participants With Laboratory Abnormalities in Liver Function Test Through Week 48

Liver function tests abnormalities were graded as per modified WHO criteria (Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = very severe), while albumin was graded as per National Cancer Institute's Common Terminology Criteria for Adverse Events (NCI-CTCAE). Grade 3 and 4 criteria were: alanine aminotransferase (ALT), aspartate aminotransferase(AST), alkaline phosphatase: Grade 3: 5.1- 10*ULN, Grade 4: >10*ULN; direct and total bilirubin: Grade 3: 2.6- 5*ULN, Grade 4: >5*ULN, Albumin: Grade 3: <2g/dL.

Number of Participants With Laboratory Abnormalities in Renal Function Test Through Week 48

Renal function test abnormalities were graded as per modified WHO criteria (Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = very severe). Grade 3 and 4 criteria were: Blood urea nitrogen (BUN): Grade 3: 5.1- 10*ULN, Grade 4: >10*ULN; Creatinine: Grade 3: 3.1 - 6*ULN, Grade 4: >6*ULN; low phosphorous (hypophosphatemia): Grade 3: 1.0- 1.4 mg/dL, Grade 4: <1.0mg/dL; high uric acid (hyperuricemia): Grade 3: 12.1 - 15.0 mg/dL, Grade 4: >15.0 mg/dL.

Number of Participants With Laboratory Abnormalities in Electrolytes Through Week 48

Serum electrolytes abnormalities,graded per modified WHOcriteria.Ranges were:hypercarbia:Grade3:41-45milliequivalents(meq)/L,Grade4:>45meq/L;hypocarbia:Grade3:10-14 meq/L,Grade4:<10 meq/L;hypercalcemia:Grade3:12.6 - 13.5 mg/dL,Grade 4:>13.5 mg/dL;hypocalcemia:6.1-6.9mg/dL,Grade4:<6.1mg/dL;hyperchloremia:Grade 3: 121-125 meq/L,Grade4:>125meq/L;hypochloremia:Grade 3:80-84 meq/L,Grade4:<80meq/L;hyperkalemia:Grade3:6.6-7.0meq/L,Grade4:>7.0meq/L;hypokalemia:Grade3:2.0-2.4 meq/L,Grade4:<2.0meq/L;hypernatremia:Grade3:158-165 meq/L,Grade4:>165meq/L;hyponatremia:Grade 3:116-122 meq/L,Grade 4:115 meq/L.

Number of Participants With Laboratory Abnormalities in Urinalysis Through Week 48

Laboratory measurements marked as abnormal, per modified WHO criteria (Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = very severe), at any study time point. The following Grade 3 and 4 definitions specify the criteria for MAs in urinalysis: Proteinuria: Grade 3: 4= or >2-3.5 g loss/day, Grade 4: >3.5 g loss/day.

Number of Participants With Laboratory Abnormalities in Fasting Lipids Through Week 48

Laboratory measurements marked as abnormal, as per National Cholesterol Education Program (NCEP)- Adult Treatment Panel (ATP)-III guided categories. The following definitions specify the criteria for MAs in fasting lipids: Total cholesterol: Grade 3: 240 - 300 mg/dL, Grade 4: >=240 mg/dL, triglycerides: Grade 3: 200 - <500 mg/dL, Grade 4: >=500 mg/dL.

Number of Participants With Laboratory Abnormalities in Fasting Glucose Through Week 48

Laboratory measurements marked as abnormal, per modified WHO criteria (Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = very severe), at any study time point. The following Grade 3 and 4 definitions specify the criteria for MAs in fasting glucose: hypoglycemia: Grade 3: 30-39 mg/dL, Grade 4: <30 mg/dL; hyperglycemia: 251-500 mg/dL, Grade 4: >500 mg/dL.

Mean Change in Weight From Baseline at Week 48

Mean change in body weight from baseline was determined.

Mean Change in Body Mass Index (BMI) in Participants at Week 48

Mean change in BMI from baseline at Week 48 was determined.

Mean Change in Fasting Lipid at Week 48

Mean change from baseline in fasting lipids, for fasting total cholesterol, LDL cholesterol, HDL cholesterol, non-HDL cholesterol, and triglycerides at Week 48 were determined.

Mean Change in Fasting Glucose at Week 48

Mean change from baseline in fasting glucose at Week 48.

Mean Change in Fasting Insulin at Week 48

Mean change from baseline in fasting insulin at Week 48.

Mean Change From Baseline in Quality of Life as Measured by the Medical Outcomes Survey - Human Immunodeficiency Virus (MOS-HIV) at Week 24

Medical Outcomes Study HIV Health Survey (MOS-HIV) is developed to assess a patient's health and functional status associated with HIV infection. The MOS-HIV questionnaire is applied to participants with adequate linguistic skills. The subscale and summary scores range from 0-100 with a higher score indicating better health.

Mean Change From Baseline in Quality of Life as Measured by the Medical Outcomes Survey - Human Immunodeficiency Virus (MOS-HIV) at Week 48

MOS-HIV is developed to assess a participant's health and functional status associated with HIV infection. The questionnaire is applied to participants with adequate linguistic skills and consists of 35 items. The questionnaire derives an overall health score and 10 subscale scores (health transitions, pain, physical functioning, role functioning, social functioning, cognitive functioning, mental health, energy/fatigue, health distress and quality of life).The subscale and summary scores range from 0-100 with a higher score indicating better health.

Mean Change From Baseline (BL) in Quality of Life as Measured by the Impact of Gastro-intestinal Toxicity at Week 4 (IBS-QoL)

The IBS-QoL questionnaire has 34 items and an overall score and 8 subscale scores: dysphoria,interference with activity,body image,health worry, food avoidance,social reaction,sexual, and relationships. Overall and subscores transformed to a 0-100 scale (0=lowest score, 100=highest possible score). Scores between these values represent the percentage of the total possible score achieved. Higher scores=better IBS-related QoL. A 14-point change from BL in IBS-QoL score in women with moderate to severe functional bowel disorders is a minimally important difference based on pain and satisfaction.

Mean Change From Baseline in Quality of Life as Measured by the Impact of Gastro-intestinal Toxicity at Week 12 (IBS-QoL)

Mean Change From Baseline in Quality of Life as Measured by the Impact of Gastro-intestinal Toxicity at Week 24 Using the Irritable Bowel Syndrome Quality of Life (IBS-QoL)

Number of Participants Who Adhered to Regimen as Measured by Multicenter AIDS Cohort Study Adherence Questionnaire (MACS) at Week 48

The MACS adherence questionnaire asks patients how many medication doses they missed during the previous day, 2 days, 3 days and 4 days. Adherence to regimen was defined as taking 100% of medicine (all doses and numbers of pills as prescribed for each medicine). This strict adherence cut-off was based on the guidelines stating that anything less than excellent adherence may result in a virus breakthrough and development of resistance.

Number of Participants With HIV RNA < 50 c/mL) at Week 96

HIV RNA < 50 c/mL is the most stringent measure of viral suppression (lowest threshold of assay) and indicates that a participant has responded to treatment.

Number of Participants With HIV RNA < 400 c/mL) at Week 96

HIV RNA <400 c/mL is a less stringent measure of viral suppression (highest threshold of assay) and indicates that a participant has responded to treatment.

Reduction of log10 HIV RNA Levels From Baseline at Week 96

Changes from baseline in log10 HIV RNA levels were calculated.

Mean Change From Baseline in CD4 Cell Count at Week 96

Mean change from baseline in CD4 count among treated participants was determined.

Number of Participants Who Died, Experienced Other Serious Adverse Events (SAEs), Experienced Adverse Events (AEs) and Experienced Events Leading to Discontinuation Through Week 96

Mean Changes in Fasting Lipids at Week 96

Mean change from baseline in fasting lipids at Week 96 was determined.

Mean Changes in Fasting Glucose at Week 96

Mean change from baseline in fasting glucose at Week 96 was determined.

Mean Changes in Fasting Insulin at Week 96

Mean change from baseline in fasting insulin at Week 96.

Number of Participants With Laboratory Abnormalities in Hematology: Hemoglobin, Hematocrit, Platelet Count, INR, Neutrophils, PT and WBC Through Week 96

Hematology abnormalities were graded per modified WHO criteria (Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = very severe). Grade 3 and 4 criteria were: Hemoglobin: Grade 3: 6.5-7.9 g/dL, Grade 4: <6.5 g/dL; Hematocrit: Grade 3: >=19.5 - 24%, Grade 4: <19.5%; platelet count: Grade 3: 20,000- 49, 999/ mm^3, Grade 4: <20,000/mm^3; INR: Grade 3 Absolute Neutrophil Count (ANC): Grade 3: >= 500 - <750/mm^3, Grade 4: <500/mm^3; PT: Grade 3: 1.51 - 3.0*ULN, Grade 4: >3*ULN; WBC: Grade 3: >=800 to <1000/mm^3, Grade 4: <80/mm^3.

Number of Participants With Laboratory Abnormalities in Serum Enzyme Levels Through Week 96

Laboratory measurements marked as abnormal, as per modified WHO criteria (Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = very severe). Grade 3 and 4 criteria in serum enzymes were: CPK: Grade 3: 5.1 - 10.0 * ULN, Grade 4: >10* ULN; Lipase: Grade 3: 2.10 - 5.0* ULN, Grade 4: 5.0* ULN.

Number of Participants With Laboratory Abnormalities in Liver Function Test Through Week 96

Liver function tests abnormalities were graded as per modified WHO criteria (Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = very severe), while albumin was graded as per NCI-CTCAE. Grade 3 and 4 criteria were: ALT, AST, alkaline phosphatase: Grade 3: 5.1- 10*ULN, Grade 4: >10*ULN; direct and total bilirubin: Grade 3: 2.6- 5*ULN, Grade 4: >5*ULN, Albumin: Grade 3: <2g/dL.

Number of Participants With Laboratory Abnormalities in Renal Function Test Through Week 96

Renal function test abnormalities were graded as per modified WHO criteria (Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = very severe). Grade 3 and 4 criteria were: BUN: Grade 3: 5.1- 10*ULN, Grade 4: >10*ULN; Creatinine: Grade 3: 3.1 - 6*ULN, Grade 4: >6*ULN; low phosphorous (hypophosphatemia): Grade 3: 1.0- 1.4 mg/dL, Grade 4: <1.0mg/dL; high uric acid (hyperuricemia): Grade 3: 12.1 - 15.0 mg/dL, Grade 4: >15.0 mg/dL.

Number of Participants With Laboratory Abnormalities in Electrolytes Level Through Week 96

Number of Participants With Laboratory Abnormalities in Fasting Lipids Level Through Week 96

Laboratory measurements marked as abnormal, as per NCEP-ATP-III guided categories. The following definitions specify the criteria for MAs in fasting lipids: Total cholesterol: Grade 3: 240 - 300 mg/dL, Grade 4: >=240 mg/dL, triglycerides: Grade 3: 200 - <500 mg/dL, Grade 4: >=500 mg/dL.

Number of Participants With Laboratory Abnormalities in Fasting Glucose Levels Through Week 96

Laboratory measurements marked as abnormal, per modified WHO criteria (Grade 1 = mild, Grade 2 = moderate, Grade 3 = severe, Grade 4 = very severe), at any study time point. The following Grade 3 and 4 definitions specify the criteria for MAs in fasting glucose: hypoglycemia: Grade 3: 30-39 mg/dL, Grade 4: <30 mg/dL; hyperglycemia: 251-500 mg/dL, Grade 4: >500 mg/dL.

Number of Participants With Laboratory Abnormalities in Urinalysis Through Week 96

Number of Participants With Virologic Failure Showing Treatment Emergent Resistance Through Week 96

Virologic failure participants defined as participants who were never suppressed (HIV RNA < 400 c/mL) and on study through Week 48, or who rebounded to HIV RNA ≥ 400 c/mL, and those who discontinued due to insufficient viral load response using CVR (NC=F). IAS-USA=International AIDS Society-United States of America, PI=protease inhibitor, RTI=reverse transcription inhibitor, TAMS=Thymidine Analogue-Associated Mutations, NRTI=non-nucleotide reverse transcriptase inhibitor, M184/V= Methionine-to-valine mutation at position 184 (in reverse transcription [RT] gene), FC=fold change

Mean Change From Baseline in Trunk-to-limb Fat Ratio Measured by DEXA at Week 48

Mean changes from baseline in trunk-to-limb fat ratio as measured by DEXA, an x-ray scan used to measure bone mineral density. Clinical improvement was associated with a decrease in values.

Mean Percent Changes From Baseline in Limb, Trunk and Total Body Fat Measured by DEXA at Week 48

The mean percent change from baseline in limb, trunk and total body fat was measured by DEXA. Limb fat: a physical sign of lipoatrophy, clinical improvement in limb fat is associated with a decrease in values. Trunk fat: a physical sign of lipohypertrophy, clinical improvement in trunk fat is associated with a decrease in values. Total body fat: association of many factors like trunk fat, limb fat, weight etc. Clinical improvement in total body fat cannot be predicted based solely an increase or decrease of these values.

Mean Percent Changes From Baseline in Limb, Trunk and Total Body Fat Measured by DEXA at Week 96

The mean percent change from baseline in limb, trunk and total body fat was measured by DEXA. Limb fat: a physical sign of lipoatrophy, clinical improvement in limb fat is associated with a decrease in values. Trunk fat: physical sign of lipohypertrophy, clinical improvement in trunk fat is associated with a decrease in values. Total body fat: association of many factors like trunk fat, limb fat, weight etc. Clinical improvement in total body fat cannot be predicted based solely an increase or decrease of these values.

Median Changes From Baseline at Week 96 in VAT-to-TAT, VAT-to-SAT and, Trunk-to-limb Fat Ratio Measured by Computed Tomography (CT)/DEXA

Mean Percent Changes From Baseline in Bone Mineral Density (BMD) Measured by DEXA at Week 48

Mean percent change from baseline in BMD of arms, legs, trunk and total body was measured using DEXA, an X-ray scan technique.

Mean Percent Changes From Baseline in BMD Measured by DEXA at Week 96

Mean percent change from baseline in BMD of arms, legs, trunk and total body was measured using DEXA, an X-ray scan technique.

Mean Change From Baseline in Body Weight at Week 96

Mean change from baseline in weight at Week 96

Mean Change From Baseline in Body Weight at Week 48

Mean change from baseline in body weight at Week 48 was determined.

Mean Change From Baseline in BMI at Week 96

Mean Change From Baseline in Waist Circumference at Week 96

Mean change From baseline in waist circumference at Week 96 was determined.

Mean Change From Baseline in Waist Circumference at Week 48

Mean change from baseline in waist circumference at Week 48 was determined.

Mean Change From Baseline in Waist-to-hip-ratio at Week 96

Mean change from baseline in waist-to-hip-ratio at Week 96 was determined.

Mean Change From Baseline in BMI at Week 48

Mean change from baseline in BMI at Week 48 was determined.

Mean Change From Baseline in Waist-to-hip-ratio at Week 48

Mean change from baseline in waist-to-hip-ratio at Week 48 was determined.

Percentage of Participants With Lipoatrophy at Week 96

Lipoatrophy, redistribution of body fat was defined as >= 20% decrease in limb fat. The percentage of participants with lipoatrophy from baseline was determined.

Mean Changes From Baseline in Body Weight at Week 96

Mean change in body weight from baseline was determined.

Mean Change From Baseline in BMI at Week 96

Mean change From baseline in BMI at Week 96 was determined.

Full Information

NCT ID

NCT00272779

First Posted

January 5, 2006

Last Updated

April 7, 2011

Sponsor

Bristol-Myers Squibb

1. Study Identification

Unique Protocol Identification Number

NCT00272779

Brief Title

BMS-Reyataz Study in Treatment in Naive Subjects to Compare the Efficacy and Safety Between Boosted Reyataz and Kaletra When in Combination With Fixed Dose Truvada

Official Title

A 96 Week Study Comparing the Antiviral Efficacy and Safety of Atazanavir/Ritonavir With Lopinavir/Ritonavir, Each in Combination With Fixed Dose Tenofovir-Emtricitabine in HIV-1 Infected Treatment in Naive Subjects

Study Type

Interventional

2. Study Status

Record Verification Date

April 2011

Overall Recruitment Status

Completed

Study Start Date

November 2005 (undefined)

Primary Completion Date

June 2007 (Actual)

Study Completion Date

October 2008 (Actual)

3. Sponsor/Collaborators

Name of the Sponsor

Bristol-Myers Squibb

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

The purpose of this study is to evaluate the safety, tolerability and antiviral effects of atazanavir (ATV) plus ritonavir (RTV) versus a combination drug of lopinavir (LPV) plus RTV. A combination drug containing tenofovir (TDF) and emtricitabine (FTC) will also be taken by participants in both arms.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

HIV Infections

Keywords

HIV, Treatment Naive

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

1057 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Atazanavir (ATV) + Ritonovir (RTV)

Arm Type

Active Comparator

Arm Description

Arm Title

Lopinavir (LPV) + RTV

Arm Type

Active Comparator

Arm Description

Intervention Type

Drug

Intervention Name(s)

ATV

Other Intervention Name(s)

Atazanavir, Reyataz, BMS-232632

Intervention Description

300mg Oral capsules for 96 weeks

Intervention Type

Drug

Intervention Name(s)

RTV

Intervention Description

100mg Oral Capsules for 96 weeks

Intervention Type

Drug

Intervention Name(s)

Tenofovi-Emtricitabine (TDF/FTC) tablet

Intervention Description

One tablet with 300 mg - 200 mg once a day for 96 weeks.

Intervention Type

Drug

Intervention Name(s)

LPV

Intervention Description

400 mg (3 133mg capsules) BID for 96 weeks

Primary Outcome Measure Information:

Title

Number of Participants With Human-immunodeficiency Virus- Ribonucleic Acid (HIV-RNA) < 50 Copies (c)/mL at Week 48

Description

HIV RNA < 50 c/mL is the most stringent measure of viral suppression (lowest threshold of assay) and indicates that a participant responded to treatment.

Time Frame

Baseline (Day 1) and Week 48

Title

Maximum Plasma Concentration (Cmax) of ATV/RTV and LPV/RTV in the Presence of an Antiretroviral (ARV) Regimen Including TDF at Week 4

Description

Cmax was derived from plasma concentration versus time data.

Time Frame

Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 Hrs post dosing with ATV/RTV and TDF all given every day (QD) and at predose, 1, 2, 3, 4, 6, 8, 12 Hrs post dosing with LPV/RTV given twice daily (BID) and TDF given QD.

Title

Area Under the Concentration-time Curve, in One Dosing Interval [AUC(TAU)] of ATV/RTV and LPV/RTV in the Presence of an ARV Regimen Including TDF at Week 4

Description

Time Frame

Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 Hrs post dosing with ATV/RTV and TDF all given QD and at predose, 1, 2, 3, 4, 6, 8, 12 Hrs post dosing with LPV/RTV given BID and TDF given QD.

Title

Minimum Plasma Concentration (Cmin) of ATV/RTV and LPV/RTV in the Presence of an ARV Regimen Including TDF at Week 4

Description

Cmin was derived from the plasma concentration versus time data.

Time Frame

Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 Hrs post dosing with ATV/RTV and TDF all given QD and at predose, 1, 2, 3, 4, 6, 8, 12 Hrs post dosing with LPV/RTV given BID and TDF given QD.

Title

Time to Reach Maximum Observed Plasma Concentration (Tmax) of ATV/RTV and LPV/RTV in the Presence of an ARV Regimen Including TDF at Week 4

Description

Tmax was derived from the plasma concentration versus time data.

Time Frame

Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 Hrs post dosing with ATV/RTV and TDF all given QD and at predose, 1, 2, 3, 4, 6, 8, 12 Hrs post dosing with LPV/RTV given BID and TDF given QD.

Title

Terminal Elimination Half-life (T-half) of ATV/RTV and LPV/RTV in the Presence of an ARV Regimen Including TDF at Week 4

Description

T-half was derived from the plasma concentration versus time data.

Time Frame

Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 Hrs post dosing with ATV/RTV and TDF all given QD and at predose, 1, 2, 3, 4, 6, 8, 12 Hrs post dosing with LPV/RTV given BID and TDF given QD.

Title

Protein Binding Adjusted Effective Concentration (EC-90) of ATV and LPV When Dosed With RTV at Week 4

Description

Time Frame

Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 Hrs post dosing with ATV/RTV and TDF all given QD and at predose, 1, 2, 3, 4, 6, 8, 12 Hrs post dosing with LPV/RTV given BID and TDF given QD.

Title

Inhibitory Quotient (IQ) of ATV and LPV When Dosed With RTV at Week 4

Description

IQ defined as Cmin at week 4 divided by protein binding adjusted EC90 values for the respective protease inhibitor (ATV or LPV) derived from individual participant clinical isolates.

Time Frame

Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 Hrs post dosing with ATV/RTV and TDF all given QD and at predose, 1, 2, 3, 4, 6, 8, 12 Hrs post dosing with LPV/RTV given BID and TDF given QD.

Title

Cmax of RTV at Week 4

Description

Cmax was derived from plasma concentration versus time data.

Time Frame

Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 Hrs post dosing with ATV/RTV and TDF all given QD and at predose, 1, 2, 3, 4, 6, 8, 12 Hrs post dosing with LPV/RTV given BID and TDF given QD.

Title

AUC (0-24) of RTV at Week 4

Description

AUC (0-24) was derived from plasma concentration versus time data. It was estimated as 2 times the AUC(TAU) based on 12-hour PK.

Time Frame

Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 Hrs post dosing with ATV/RTV and TDF all given QD and at predose, 1, 2, 3, 4, 6, 8, 12 Hrs post dosing with LPV/RTV given BID and TDF given QD.

Title

Cmin of RTV at Week 4

Description

Cmin was derived from plasma concentration versus time data.

Time Frame

Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 Hrs post dosing with ATV/RTV and TDF all given QD and at predose, 1, 2, 3, 4, 6, 8, 12 Hrs post dosing with LPV/RTV given BID and TDF given QD.

Title

Cmax of Tenofovir at Week 4

Description

Cmax was derived from plasma concentration versus time data.

Time Frame

Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 Hrs post dosing with ATV/RTV and TDF all given QD and at predose, 1, 2, 3, 4, 6, 8, 12 Hrs post dosing with LPV/RTV given BID and TDF given QD.

Title

Cmin of Tenofovir at Week 4

Description

Cmin was derived from plasma concentration versus time data.

Time Frame

Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 Hrs post dosing with ATV/RTV and TDF all given QD and at predose, 1, 2, 3, 4, 6, 8, 12 Hrs post dosing with LPV/RTV given BID and TDF given QD.

Title

AUC (TAU) of Tenofovir at Week 4

Description

AUC (TAU) was derived from plasma concentration versus time data.It was calculated from time 0-24 hours for tenofovir in LPV/RPV and ATV/RTV regimen at Week 4.

Time Frame

Predose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 12, 24 Hrs post dosing with ATV/RTV and TDF all given QD and at predose, 1, 2, 3, 4, 6, 8, 12 Hrs post dosing with LPV/RTV given BID and TDF given QD.

Title

Mean Change From Baseline in Trunk-to-Limb Fat Ratio as Measured by Dual Energy X-ray Absorptiometry (DEXA) at Week 96

Description

Mean changes from baseline in trunk-to-limb fat ratio as measured by DEXA, an x-ray scan used to measure bone mineral density. Clinical improvement is associated with a decrease in values.

Time Frame

Baseline (Day 1) and Week 96.

Title

Number of Participants With Single Nucleotide Polymorphisms (SNPs) Included in Genotype-Phenotype Analysis

Description

Time Frame

Baseline visit

Title

Mean Change From Baseline in Fasting Non-High Density Lipoprotein (HDL) Cholesterol Associated With RETN_097

Description

Time Frame