Atazanavir (BMS-232632) in Combination With Ritonavir or Saquinavir, and Lopinavir/Ritonavir, Each With Tenofovir and a Nucleoside in Subjects With HIV

Phase 3

Completed

Conditions: HIV Infections

Interventions: Drug: Atazanavir + ritonavir + tenofovir + nucleoside
Drug: Atazanavir + saquinavir + tenofovir + nucleoside
Drug: Lopinavir/ritonavir + tenofovir + nucleoside

Registration Number: NCT00035932

Lead Sponsor: Bristol-Myers Squibb

Brief Summary: The purpose of this study is to learn how well atazanavir (ATV) works in combination with ritonavir (RTV) or saquinavir (SQV) with tenofovir (TDF) and a nucleoside to reduce the viral load of treatment experienced subjects with human immunodeficiency virus (HIV). There is a comparison arm with lopinavir (LPV)/RTV and TDF and a nucleoside.

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 571

Inclusion Criteria

Virologic failure to 2 or more highly active antiretroviral therapy (HAART) regimens that, in total, have included at least one drug from all approved classes protease inhibitors, non-nucleoside reverse transcriptase inhibitors, nucleoside reverse transcriptase inhibitors (PI, NNRTI, NRTI):
1. Currently on a failing HAART regimen with 2 qualifying plasma viral load measurements (hospital/clinic value within 4 weeks of screening with viral load equivalent to =>1,000 c/mL on the Roche Amplicor[TM] and central lab measurements of =>1,000 c/mL (Roche Amplicor[TM]) within 4 weeks of randomization
2. Cluster of Differentiation 4 (CD4) cell count =>50 cells/mm3 obtained within 4 weeks prior to randomization
=>16 years of age (or minimum age as determined by local regulations or as legal requirements dictate);
History of prior virologic response to at least one HAART regimen, defined as a 1.0 log10 decline or a decline in viral load to <400 c/mL by Roche Amplicor or <500 c/mL by Chiron Quantiplex branched DNA (bDNA) assay
Both females of child bearing potential and males must utilize effective barrier contraception to reduce transmission of sexually transmitted disease, including human immunodeficiency virus (HIV). Other contraception in addition to barrier methods is permitted; interaction between atazanavir and oral contraceptives has not been studied.
Subjects must be able to provide written informed consent;
Subjects should be available for follow-up for a period of at least 48 weeks
Baseline laboratory values measured within 2 weeks prior to initiating study drugs as follows:
1. serum creatine <1.5 times the upper limit of normal (ULN)
2. total serum lipase <1.4 times the ULN
3. liver enzymes alanine aminotransferase (AST), aspartate aminotransferase (ALT) <3 times the ULN
4. total serum bilirubin <1.5 times the ULN

Exclusion Criteria

Prior use (=>3 days) of atazanavir, TVF or LPV/RTV; if history of SQV, then must be phenotypically sensitive
the current failing antiretroviral regimen must have been administered for at least eight weeks at he initiation of screening and must not include both a PI and NNRTI
Presence of a newly diagnosed HIV-related opportunistic infection or any medical requiring acute therapy at the time of enrollment
Proven or suspected acute hepatitis in the 30 days prior to study entry. Subjects with chronic hepatitis are eligible provided that their liver function enzymes (ALT/AST) are <3 x ULN
Previous therapy with agents with significant systemic myelosuppressive, neurotoxic, pancreatoxic, hepatoxic or cytotoxic potential within 3 months of study start or the expected need for such therapy at the time of enrollment of therapy with methadone or ribavirin/interferons or treatment with neurotoxic drugs or drugs that affect Cytochrome P450 3A4 (CYP3A4).
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
Intractable diarrhea (=> 6 loose stools/day for at least 7 days consecutive days) within 30 days prior to study entry
Pregnancy or breast-feeding
History of hemophilia
Presence of cardiomyopathy
Any one of the following:
1. Heart rate-corrected QT (QTc) interval >450 msec on the screening electrocardiogram (EKG)
2. Heart rate <40 beats per minute (bpm)
3. Pause length >3 seconds seen on EKG
4. Clinical symptoms potentially related to heart block
5. Third degree heart block
History of acute or chronic pancreatitis
If choosing 2'-3' dideoxyinosine (ddI) or 2',3'-didehydro-3'-deoxythymidine (d4T) as the NRTI: History or signs and symptoms of bilateral peripheral neuropathy => Grade 2 at the time of screening
Inability to tolerate oral medications
Any other clinical conditions or prior therapy that, in the opinion of the Investigator, would make the subject unsuitable for study or unable to comply with the dosing requirements.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
I	Atazanavir + ritonavir + tenofovir + nucleoside	ATV 300 mg + RTV 100 mg + TDF 300 mg + nucleoside of choice ATV , RTV, and TDF once daily, nucleoside per label 48 Weeks and then for as long as subject is in need of therapy through study
II	Atazanavir + saquinavir + tenofovir + nucleoside	ATV 400 mg + SQV 1200 mg + TDF 300 mg + nucleoside of choice ATV, SQV, and TDF once daily, nucleoside per label 48 Weeks and then for as long as subject is in need of therapy through study
III	Lopinavir/ritonavir + tenofovir + nucleoside	LPV/RTV 400/100 mg + TDF 300 mg + nucleoside of choice LPV/RTV twice daily, TDF once daily, nucleoside per label 48 Weeks and then for as long as subject is in need of therapy through study

Primary Outcome Measures

Name	Time	Method
Mean Change From Baseline in HIV Ribonucleic Acid (RNA) at Week 24	Baseline, Week 24
Mean Change From Baseline in HIV RNA at Week 48	Baseline, Week 48
Mean Change From Baseline in HIV RNA at Week 96	Baseline, Week 96

Secondary Outcome Measures

Name	Time	Method
Participants Achieving Virologic Half Log Suppression (LOQ = 400 c/mL) at Week 48, (Overall and by PI Sensitivity)	Baseline, Week 48	Number of participants with a \>=0.5 log10 decrease in HIV RNA from baseline or HIV RNA \< 400 c/mL at Week 48, by their baseline phenotypic sensitivity to their randomized PI.
Participants Achieving Virologic Half Log Suppression (LOQ = 400 c/mL) at Week 96	Baseline, Week 96	Number of participants with a \>=0.5 log10 decrease in HIV RNA from baseline or HIV RNA \< 400 c/mL at Week 96.
Mean Change From Baseline in HIV RNA at Week 2	Baseline, Week 2
Participants Achieving Virologic Half Log Suppression (Limit of Quantification [LOQ] = 400 c/mL) at Week 24 (Overall and by Protease Inhibitor [PI] Sensitivity)	Baseline, Week 24	Number of participants with a \>=0.5 log10 decrease in HIV RNA from baseline or HIV RNA \< 400 c/mL at Week 24, by their baseline phenotypic sensitivity to their randomized PI.
Participants Achieving Virologic Half Log Suppression (LOQ = 50 c/mL) at Week 24	Week 24
Participants Achieving Virologic Half Log Suppression (LOQ = 50 c/mL) at Week 24, by PI Sensitivity	Baseline, Week 24	Number of participants with a \>=0.5 log10 decrease in HIV RNA from baseline or HIV RNA \< 50 c/mL at Week 24, by their baseline phenotypic sensitivity to their randomized PI.
Participants Achieving Virologic Half Log Suppression (LOQ = 50 c/mL) at Week 48	Week 48
Participants Achieving Virologic Half Log Suppression (LOQ = 50 c/mL) at Week 48, by PI Sensitivity	Baseline, Week 48	Number of participants with a \>=0.5 log10 decrease in HIV RNA from baseline or HIV RNA \< 50 c/mL at Week 48, by their baseline phenotypic sensitivity to their randomized PI.
Participants Achieving Virologic Half Log Suppression (LOQ = 50 c/mL) at Week 96	Week 96
Participants Achieving Treatment Response (LOQ = 400 c/mL) Without Prior Failure at Week 24	Week 24	Treatment Response = confirmed suppression to LOQ (400 c/mL). The Algorithm for Treatment Response Without Prior Failure (TRPWF) = participants staying in response at the analysis timepoint without having an intervening, confirmed rebound.
Participants Achieving Treatment Response (LOQ = 400 c/mL) Without Prior Failure at Week 48	Week 48	Treatment Response = confirmed suppression to LOQ (400 c/mL). The Algorithm for Treatment Response Without Prior Failure (TRPWF) = participants staying in response at the analysis timepoint without having an intervening, confirmed rebound.
Participants Achieving Treatment Response (LOQ = 400 c/mL) Without Prior Failure at Week 96	Week 96	Treatment Response = confirmed suppression to LOQ (400 c/mL). The Algorithm for Treatment Response Without Prior Failure (TRPWF) = participants staying in response at the analysis timepoint without having an intervening, confirmed rebound.
Participants Achieving Treatment Response (LOQ = 50 c/mL) Without Prior Failure at Week 24	Week 24	Treatment Response = confirmed suppression to LOQ (50 c/mL). The Algorithm for Treatment Response Without Prior Failure (TRPWF) = participants staying in response at the analysis timepoint without having an intervening, confirmed rebound.
Participants Achieving Treatment Response (LOQ = 50 c/mL) Without Prior Failure at Week 48	Week 48	Treatment Response = confirmed suppression to LOQ (50 c/mL). The Algorithm for Treatment Response Without Prior Failure (TRPWF) = participants staying in response at the analysis timepoint without having an intervening, confirmed rebound.
Participants Achieving Treatment Response (LOQ = 50 c/mL) Without Prior Failure at Week 96	Week 96	Treatment Response = confirmed suppression to LOQ (50 c/mL). The Algorithm for Treatment Response Without Prior Failure (TRPWF) = participants staying in response at the analysis timepoint without having an intervening, confirmed rebound.
Change From Baseline in CD4 Cell Count at Week 24	Baseline, Week 24
Change From Baseline in CD4 Cell Count at Week 48	Baseline, Week 48
Change From Baseline in CD4 Cell Count at Week 96	Baseline, Week 96
Correlation of ATV Minimum Plasma Concentration (Cmin), Inhibitory Quotient (IQ), and Number of Protease Inhibitor (PI) Mutations at Baseline With HIV RNA Change From Baseline at Week 24	Baseline, Week 24	Pearson correlations of the Cmin (trough plasma concentration), IQ (the ratio of Cmin of ATV to HIV IC50), and Number of baseline PI Mutations with HIV RNA change from baseline at Week 24 were explored.
Correlation of ATV Minimum Plasma Concentration (Cmin), Inhibitory Quotient (IQ), and Number of Protease Inhibitor (PI) Mutations at Baseline With HIV RNA Change From Baseline at Week 48	Baseline, Week 48	Pearson correlations of the Cmin (trough plasma concentration), IQ (the ratio of Cmin of ATV to HIV IC50), and Number of baseline PI Mutations with HIV RNA change from baseline at Week 48 were explored.
Correlation of ATV Minimum Plasma Concentration (Cmin) Inhibitory Quotient (IQ), and Number of PI Mutations at Baseline and CD4 Cell Count Change From Baseline at Week 24	Baseline, Week 24	Pearson correlations of the Cmin (trough plasma concentration), IQ (the ratio of Cmin of ATV to HIV IC50), and Number of baseline PI Mutations with CD4 cell count change from baseline at Week 24 were explored.
Correlation of ATV Minimum Plasma Concentration (Cmin) Inhibitory Quotient (IQ), and Number of PI Mutations at Baseline and CD4 Cell Count Change From Baseline at Week 48	Baseline, Week 48	Pearson correlations of the Cmin (trough plasma concentration), IQ (the ratio of Cmin of ATV to HIV IC50), and Number of baseline PI Mutations with CD4 cell count change from baseline at Week 48 were explored.
Lipid Mean Percent Change From Baseline at Week 24	Baseline, Week 24	Mean percent change in total cholesterol, high density lipoprotein (HDL) cholesterol, fasting low density lipoprotein (LDL) cholesterol, and fasting triglycerides.
Lipid Mean Percent Change From Baseline at Week 48	Week 48	Mean percent change in total cholesterol, high density lipoprotein (HDL) cholesterol, fasting low density lipoprotein (LDL) cholesterol, and fasting triglycerides.
Lipid Mean Percent Change From Baseline at Week 96, Observed Values	Week 96	Mean percent change in total cholesterol, high density lipoprotein (HDL) cholesterol, fasting low density lipoprotein (LDL) cholesterol, and fasting triglycerides.
Deaths, Serious Adverse Events (SAEs), and Adverse Events (AEs) Through Week 48	From Enrollment through Week 48	AE=any new untoward medical occurrence/worsening of a pre-existing medical condition regardless of causal relationship. SAE=any untoward medical occurrence at any dose that: results in death; is life-threatening; requires/prolongs inpatient hospitalization; results in persistent/significant disability; is cancer; is congenital anomaly/birth defect; results in drug dependency/abuse; is an important medical event.
Most Common AEs and AEs of Interest Through Week 48	From Enrollment to Week 48	Prespecified AEs of interest included jaundice, ocular icterus, and hyperbilirubinemia.
Fasting Glucose Mean Change From Baseline at Week 24	Baseline, Week 24
Fasting Glucose Mean Change From Baseline at Week 48	Week 48
Grade 3/4 Laboratory Abnormalities Through Week 48	From Enrollment to Week 48	Common Terminology Criteria for Adverse Events v3.0 (CTCAE) Grades:1=Mild, 2=Moderate, 3=Severe, 4=Life-threatening/disabling, 5=Death. Abnormal values: absolute neutrophil count: ≥500 to \<750/mm3 (grade 3), \<500/mm3 (grade 4); platelets: 20,000-49,999/mm3 (grade 3), \<20,000/mm3 or diffuse petechiae (grade 4); alanine transaminase (ALT): 5.1-10 x upper limit of normal (ULN; grade 3), \>10 x ULN (grade 4); aspartate transaminase (AST): 5.1-10 x ULN (grade 3), \>10 x ULN (grade 4); bilirubin: 2.6-5 x ULN (grade 3), \>5 x ULN (grade 4).
Fridericia-corrected QT (QTcF) Interval and Change From Baseline by Analysis Time Point	Baseline, Week 4 predose, 2-3 hours postdose, 6-12 hours postdose, Week 12, Week 24, Week 48	The QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. The QT interval was corrected for heart rate using Fridericia's (QTcF) formula.
PR Interval and Change From Baseline by Analysis Time Point	Baseline, Week 4 predose, 2-3 hours postdose, 6-12 hours postdose, Week 12, Week 24, Week 48	The PR interval is measured from the beginning of the P wave to the beginning of the QRS complex, and reflects the time the electrical impulse takes to travel from the sinus node through the atrioventricular (AV) node and entering the ventricles. The PR interval is therefore a good estimate of AV node function.
Adherence to Regimen Though Week 48 Based on MACS the Multicenter AIDS Cohort Study (MACS) Adherence Questionnaire	Baseline, Week 24, 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. Drug-specific questions included adherence with dose and frequency. Adherence was defined as taking all doses and numbers of pills as prescribed for each medication. 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.
Mean Score of European Quality of Life-5 Dimensions (EQ-5D) Health Index Score at Baseline, Mid-Study (Week 24), and Final (Week 48)	Baseline, Week 24, Week 48	The EQ-5D is a 5-item questionnaire to assess health-related quality of life in 5 health dimensions (mobility, self-care, usual activity, pain/discomfort, anxiety/depression) are scored on a 3-level scale: no problems (1), some problems (2), extreme problems (3). Using a standard algorithm, responses are summarized into a single score, the EQ-5D Health Index Score (HIS), which ranges between 1 (representing perfect health) and 0 (representing the worst imaginable health state or death). The smallest coefficient of change is 0.03.
Mean Score of European Quality of Life-5 Dimensions (EQ-5D) Visual Analog Scale (VAS) at Baseline, Mid-Study (Week 24), and Final (Week 48)	Baseline, Week 24, Week 48	The EQ-5D has a Visual Analog Scale (VAS), which is a feeling thermometer-like scale with a range between 0 and 100. Patients are required to draw a line from a box on the VAS scale to an actual mark on the thermometer-like scale that corresponds with a number that reflects their self-assessed health status at the time they are completing the questionnaire. Higher VAS scores indicate better overall health. There is no minimum clinically important difference reported in the literature for VAS.
Number of Participants Utilizing Resources for Managing Lipid Elevation	Baseline, Week 24, Week 48	Participants' overall resource utilization for managing lipid elevation that includes the management of side effects of lipid lowering medications, such as those due to drug interactions.
Mean ATV, RTV and SQV Minimum Concentration (Cmin) Values	collected at the pre-dose time point after receiving atazanavir for at least four weeks	The minimum or "trough" concentration (Cmin) of a drug observed after its administration and just prior to the administration of a subsequent dose.
HIV IC50 at Week 24	Week 24	IC50: inhibitory concentration of drug required to reduce viral replication by 50%.
Inhibitory Quotient at Week 24	Baseline, Week 24	Inhibitory quotient is a measure of drug exposure and susceptibility in an individual. The IQ is typically calculated as the ratio of Cmin to HIV IC50.
Inhibitory Quotient at Week 48	Baseline, Week 48	Inhibitory quotient is a measure of drug exposure and susceptibility in an individual. The IQ is typically calculated as the ratio of Cmin to HIV IC50.
HIV RNA Level - Treated Subjects With Evaluable Cmins at Week 24	Baseline, Week 24	Week 24 HIV RNA level and change from baseline were summarized for treated subjects with evaluable Cmins.
HIV RNA Level - Treated Subjects With Evaluable Cmins at Week 48	Baseline, Week 48	Week 24 HIV RNA level and change from baseline were summarized for treated subjects with evaluable Cmins.