Induction/Simplification With Atazanavir + Ritonavir + Abacavir/Lamivudine Fixed-Dose Combination In HIV-1 Infection

Study Overview
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Brief Summary
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This study was designed to test the efficacy, safety, tolerability and durability of the antiviral response between atazanavir (ATV) + ritonavir (/r) + abacavir/lamivudine(ABC/3TC) Fixed dose combination (FDC) each administered once daily (QD) for 36 weeks followed by randomization to either a simplification regimen of ATV or continuation of ATV +/r for an additional 48 weeks, each in combination with ABC/3TC in antiretroviral (ART)-naive, HIV-1 infected, HLA-B*5701 negative subjects. All subjects who complete the 84-week study will be eligible to enter the treatment extension phase and continue for an additional 60 weeks. The purpose of this extension is to obtain longer term treatment data in subjects who have completed the 84-week study.

Detailed Description
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Safety and Efficacy of an Initial Regimen of Atazanavir (ATV) + Ritonavir (/r) + the Abacavir/Lamivudine Fixed-Dose Combination Tablet (ABC/3TC FDC) for 36 weeks followed by Simplification to Atazanavir with ABC/3TC FDC or Maintenance of the Initial Regimen for an Additional 48 weeks in Antiretroviral-Naive HIV-1 Infected HLA-B*5701 Negative Subjects followed by an Optional 60-Week Treatment Extension Phase

Official Title
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See Detailed Description

Conditions
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Infection, Human Immunodeficiency Virus I, HIV Infection

Intervention / Treatment
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* Drug: Abacavir (ABC)/lamivudine (3TC) + atazanavir (ATV) + ritonavir (/r)
* Drug: Abacavir (ABC)/lamivudine (3TC) + atazanavir (ATV)


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: Subject is ≥ 18 years of age and has documented evidence of HIV-1 infection. (A female is eligible to enter and participate in this study if she is of: non child-bearing potential, child bearing potential with a negative pregnancy test and agrees to approved contraception methods, or agreement for complete abstinence.) Subject is antiretroviral-naïve (defined as having ≤14 days of prior therapy with any NRTI and no prior therapy with either a PI or NNRTI). Subject has plasma HIV-1 RNA ≥ 1,000 copies/mL by Roche COBAS AMPLICOR™ (Version 1.5) method at screening (if no other documentation of HIV infection is available, a positive result here may serve as documentation of HIV infection for this study). Subject is willing and able to understand and provide written informed consent prior to participation in this study. Exclusion criteria: Subject is HLA-B*5701 positive. Subject testing positive for Hepatitis B or both Hepatitis B and Hepatitis C at screening (+ HbsAg) Genotyping results performed at the screening indicate that the subject has any of the following mutations at the reverse transcriptase (RT) enzyme: K65R, L74V, or Y115F, or a combination of two or more thymidine analog mutations (M41L, D67N, K70R, K219Q or E) that include changes at either L210 or T215, or ≥ 3 of the following protease mutations associated with atazanavir resistance: D30, V32, M36, M46, I47, G48, I50, I54, A71, G73, V77, V82, I84, N88, and L90. Women who are pregnant or breastfeeding. Subject has an active or acute CDC Clinical Category C event at screening. Treatment for the acute event must have been completed at least 30 days prior to screening. Subject is, in the opinion of the investigator, unable to complete the 84-week dosing period and protocol evaluations and assessments. Subject has ongoing clinically relevant pancreatitis or clinically relevant hepatitis at screening. Presence of a newly diagnosed HIV-related opportunistic infection or any medical condition requiring acute therapy at the time of enrollment. Subject suffers from a serious medical condition, such as diabetes, congestive heart failure, cardiomyopathy or other cardiac dysfunction (including known, clinically significant cardiac conduction system disease, severe first degree atrioventricular block [PR interval > 0.26 seconds], second or third-degree atrioventricular block), which in the opinion of the investigator would compromise the safety of the subject. Subject has pre-existing mental, physical, or substance abuse disorder, which in the opinion of the investigator would interfere with the subject's ability to comply with the dosing schedule and protocol evaluations and assessments. Subject has a history of inflammatory bowel disease or malignancy, intestinal ischemia, malabsorption, or other gastrointestinal dysfunction, which may interfere with drug absorption or render the subject unable to take oral medication. Subject requires treatment with foscarnet, hydroxyurea or other agents with documented activity against HIV-1 in vitro within 28 days of study administration. Subject requires treatment with immunomodulating agents (such as systemic corticosteroids, interleukins, vaccines, or interferons) within 28 days prior to screening, or subject had received an HIV-1 immunotherapeutic vaccine within 90 days prior to screening. Subjects using inhaled corticosteroids are eligible for enrollment. Creatinine clearance <50 mL/min via the Cockroft-Gault method [Cockroft, 1976]. 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. Hypersensitivity to any component of the study drugs. Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >5 times the upper limit of normal (ULN). Total bilirubin > 1.5 times the upper limit of normal (ULN). Subject has any acute laboratory abnormality at screening, which, in the opinion of the investigator, would preclude the subject's participation in the study of an investigational compound. Any grade 4 laboratory abnormality would exclude a subject from study participation. Subject requires treatment with radiation therapy or cytotoxic chemotherapeutic agents within 28 days prior to screening, or has an anticipated need for these agents within the study period. Enrolled in one or more investigational drug protocols, which may have impacted HIV-1 RNA suppression. Prisoners or subjects 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. Subjects requiring concomitant administration of proton pump inhibitors. Subjects who require treatment with the prohibited medications within 28 days of commencement of investigational product, or an anticipated need during the study. Eligibility Criteria for Treatment Extension Phase: -Subjects will be eligible to continue in the treatment extension phase (Weeks 84 to 144) if they have successfully completed the 84-week study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Other: Simplification<br>Atazanavir (ATV) 400 mg QD + abacavir (ABC) 600 mg/lamivudine (3TC) 300 mg fixed dose combination (FDC) QD for 48 weeks followed by optional treatment extension for 60 weeks on the same regimen. | Drug: Abacavir (ABC)/lamivudine (3TC) + atazanavir (ATV)<br>* Abacavir (ABC)/lamivudine (3TC) FDC + atazanavir (ATV) + ritonavir (/r) for 36 weeks followed by ABC/3TC + ATV for 48wks followed by optional treatment extension for 60 weeks on the same regimen<br>|
| Other: Continuation<br>Atazanavir (ATV) 300 mg QD + ritonavir (/r) 100 mg QD + abacavir (ABC) 600mg/lamivuidine (3TC )300 mg FDC QD for 48 weeks followed by optional treatment extension for 60 weeks on the same regimen. | Drug: Abacavir (ABC)/lamivudine (3TC) + atazanavir (ATV) + ritonavir (/r)<br>* Abacavir (ABC)/lamivudine (3TC) FDC + atazanavir (ATV)+ ritoanvir (/r) for 36weeks followed by ABC/3TC + ATV + /r for 48wks followed by optional treatment extension for 60 weeks on the same regimen<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants (PAR) Who Achieved Plasma HIV-1 RNA <50 Copies (c) /Milliliter (ml) at the Week 84 Visit | The percentage of PAR with HIV-1 RNA virus <50 c/ml determined from a blood sample drawn at Week 84 was tabulated by treatment arm with stratification by baseline HIV-1 RNA (<100,000 c/ml and >=100,000 c/ml). Per TLOVR algorithm, responders were PAR with confirmed viral load <50 c/ml who had not met any non-responder criterion. Non-responders were PAR who never achieved confirmed HIV RNA <50 c/ml, prematurely discontinued study or study medication for any reason, had confirmed rebound to at least 50 c/ml, or had an unconfirmed HIV RNA of at least 50 c/ml at last visit. | Week 84 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Age at Baseline of Participants Randomized to Treatment for the 48-Week Randomized Phase | The mean age of participants randomized to treatment in the Randomized Phase was calculated at Baseline. | Baseline of Randomized Phase | 
| Percentage of Participants Who Achieved Plasma HIV-1 RNA <50 c/ml at the Week 36 Visit | The percentage of PAR with HIV-1 RNA virus <50 c/ml from a Week 36 blood sample was tabulated. Per TLOVR algorithm, responders were PAR with confirmed viral load <50 c/ml who had not met any non-responder criterion. Non-responders were PAR who never achieved confirmed HIV RNA <50 c/ml, prematurely discontinued (DC) study or study medication (any reason), had confirmed rebound to >=50 c/ml, or had an unconfirmed HIV RNA >=50 c/ml at last visit. ITT-E observed analysis (Obs): all observed data. ITT-E M/D=F analysis: PAR with missing data/data collected after study medication DC were failures. | Week 36 | 
| Percentage of Participants Who Achieved Plasma HIV-1 RNA <50 c/ml at the Week 84 Visit | A blood sample was drawn to determine the amount of HIV-1 RNA virus in c/ml at Week 84. The percentage of participants with HIV-1 RNA <50 c/ml at Week 84 was tabulated. The secondary analysis methods were: Observed (Obs; uses all visits with data in the analysis period), and missing/discontinuation=failure (M/D=F) analyses. M/D=F: participants with missing data or data collected after study medication DC were considered failures. | Week 84 | 
| Percentage of Participants Who Achieved Plasma HIV-1 RNA <50 c/ml at the Week 144 Visit | Percentage of PAR with HIV-1 RNA <50 c/ml at Week 144 was tabulated; stratified by baseline HIV-1 RNA (<100,000 and >=100,000 c/ml). Per TLOVR algorithm, responders were PAR with confirmed (CF) HIV RNA <50 c/ml who had not met any non-responder (NR) criterion. NR were PAR who never achieved CF HIV RNA <50 c/ml, prematurely discontinued (DC) study or study medication (Med), had CF rebound to >=50 c/ml, or had an unconfirmed HIV RNA >=50 c/ml at last visit. Observed analysis (Obs): all observed data. M/D=F analysis: PAR with missing data/data collected after study Med DC were failures. | Week 144 | 
| Percentage of Participants Who Achieved Plasma HIV-1 RNA <400 c/ml at the Week 36 Visit | The percentage of PAR with HIV-1 RNA virus <400 c/ml from a Week 36 blood sample was tabulated. Per TLOVR algorithm, responders were PAR with confirmed (CF) HIV RNA <400 c/ml who had not met any non-responder criterion. Non-responders were PAR who never achieved CF HIV RNA <400 c/ml, prematurely discontinued (DC) study or study medication (Med; any reason), had CF rebound to >=400 c/ml, or had an unconfirmed HIV RNA >=400 c/ml at last visit. ITT-E observed analysis (Obs): all observed data. ITT-E M/D=F analysis: PAR with missing data/data collected after study Med DC were failures. | Week 36 | 
| Percentage of Participants Who Achieved HIV-1 RNA <400 c/ml at the Week 84 Visit | Percentage of PAR with HIV-1 RNA <400 c/ml at Week 84 was tabulated; stratified by baseline HIV-1 RNA (<100,000 and >=100,000 c/ml). Per TLOVR algorithm, responders were PAR with confirmed (CF) HIV-RNA <400 c/ml who had not met any non-responder (NR) criterion. NR were PAR who never achieved CF HIV RNA <400 c/ml, prematurely discontinued (DC) study or study medication (Med), had CF rebound to >=400 c/ml, or had an unconfirmed HIV RNA >=400 c/ml at last visit. Observed analysis (Obs): all observed data. M/D=F analysis: PAR with missing data/data collected after study Med DC were failures. | Week 84 | 
| Percentage of Participants Who Achieved HIV-1 RNA <400 c/ml at the Week 144 Visit | Percentage of PAR with HIV-1 RNA <400 c/ml at Week 144 was tabulated; stratified by baseline HIV-1 RNA (<100,000 and >=100,000 c/ml). Per TLOVR algorithm, responders were PAR with confirmed (CF) HIV-RNA <400 c/ml who had not met any non-responder (NR) criterion. NR were PAR who never achieved CF HIV RNA <400 c/ml, prematurely discontinued (DC) study or study medication (Med), had CF rebound to >=400 c/ml, or had an unconfirmed HIV RNA >=400 c/ml at last visit. Observed analysis (Obs): all observed data. M/D=F analysis: PAR with missing data/data collected after study Med DC were failures. | Week 144 | 
| Number of Participants Who Met the Protocol-defined Virologic Failure (PDVF) Criteria at Week 36 | The number of participants that failed to respond to therapy through 36 weeks on treatment, based on the protocol definition of virologic failure (PDVF), was tabulated. PDVF was defined as (a) failure to achieve plasma HIV-1 RNA <400 c/ml by Week 30 or (b) confirmed HIV-1 RNA rebound >=400 c/ml after achieving HIV-1 <400 c/ml. | Week 36 | 
| Number of Participants Who Met the PDVF Criteria at Week 84 | The number of participants that failed to respond to therapy from the time of treatment randomization through Week 84, based on the protocol definition of virologic failure (PDVF), was tabulated. PDVF was defined as (a) failure to achieve plasma HIV-1 RNA <400 c/ml by Week 30 or (b) confirmed HIV-1 RNA rebound >=400 c/ml after achieving HIV-1 <400 c/ml. | Week 84 | 
| Number of Participants Who Met the PDVF Criteria at Week 144 | The number of participants enrolled in the extension phase that failed to respond to therapy from Week 84 through Week 144, based on the protocol definition of virologic failure (PDVF) was tabulated,. PDVF was defined as (a) failure to achieve plasma HIV-1 RNA <400 c/ml by Week 30 or (b) confirmed HIV-1 RNA rebound >=400 c/ml after achieving HIV-1 <400 c/ml. | Week 144 | 
| Change From Baseline in HIV-1 RNA at Week 36 | Change from baseline was calculated as the Week 36 value minus the baseline value. Blood was drawn to analyze for plasma HIV viral load. | Baseline and Week 36 | 
| Change From Baseline in HIV-1 RNA at Week 84 | Change from baseline was calculated as the Week 84 value minus the baseline value. Blood was drawn to analyze for plasma HIV viral load. | Baseline and Week 84 | 
| Change From Baseline in HIV-1 RNA at Week 144 | Change from baseline was calculated as the Week 144 value minus the baseline value. Blood was drawn to analyze for plasma HIV viral load. | Baseline and Week 144 | 
| Change From Baseline in CD4+ Cell Count at Week 36 | Blood was drawn to analyze for CD4+ cell count. A CD4+ cell is a T lymphocyte that carries the CD4 antigen. Immunologic response was assessed by CD4+ counts. Change from baseline was calculated as the Week 36 value minus the baseline value. | Baseline and Week 36 | 
| Change From Baseline in CD4+ Cell Count at Week 84 | A CD4+ cell is a T lymphocyte that carries the CD4 antigen. Immunologic response was assessed by CD4+ counts. Change from baseline was calculated as the Week 84 value minus the baseline value. Blood was drawn to analyze for CD4+ cell count. | Baseline and Week 84 | 
| Change From Baseline in CD4+ Cell Count at Week 144 | A CD4+ cell is a T lymphocyte that carries the CD4 antigen. Immunologic response was assessed by CD4+ counts. Change from baseline was calculated as the Week 144 value minus the baseline value. Blood was drawn to analyze for CD4+ cell count. | Baseline and Week 144 | 
| Number of Confirmed Virologic Failure Participants With Treatment-emergent HIV Genotypic Resistance in Reverse Transcriptase and Protease From Baseline Through Week 36 | A blood sample was drawn for participants failing to respond to therapy, and the mutations present in the virus were identified. For each participant, the mutations found at the time of failure were compared with any mutations found in the blood sample at baseline. New resistance-associated mutations (defined by the International AIDS Society-USA guidelines) that developed at the time of failure were tabulated by drug class. PAR, participants; VF, virologic failure; NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; PI, protease inhibitor. | Baseline through Week 36 | 
| Number of Confirmed Virologic Failure Participants With Treatment-emergent HIV Genotypic Resistance in Reverse Transcriptase and Protease From Randomization at Week 36 Through Week 84 | A blood sample was drawn for participants failing to respond to therapy, and the mutations present in the virus were identified. For each participant, the mutations found at the time of failure were compared with any mutations found in the blood sample at baseline. New International AIDs Society-USA defined resistance mutations that developed at the time of failure were tabulated by drug class. VF, virologic failure; NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; PI, protease inhibitor. | Randomization at Week 36 through Week 84 | 
| Number of Confirmed Virologic Failure Participants With Treatment-emergent HIV Genotypic Resistance in Reverse Transcriptase and Protease From Week 84 Through Week 144 | A blood sample was drawn for participants failing to respond to therapy, and the mutations present in the virus were identified. For each participant, the mutations found at the time of failure were compared with any mutations found in the blood sample at baseline. New International AIDs Society-USA defined resistance mutations that developed at the time of failure were tabulated by drug class. VF, virologic failure; NRTI, nucleoside reverse transcriptase inhibitor; NNRTI, non-nucleoside reverse transcriptase inhibitor; PI, protease inhibitor. | Week 84 through Week 144 | 
| Number of Confirmed Virologic Failure Participants From Baseline Through Week 36 With Treatment-emergent Reductions in Susceptibility to Abacavir, Lamivudine, Atazanavir, or Ritonavir | A blood sample was drawn for participants failing to respond to therapy, and changes in drug susceptibility for HIV isolated from the participants for each drug used in the study were assessed. For each participant, the changes in drug susceptibility detected by phenotypic assay in virus from the sample collected at the time of failure was compared with drug susceptibility in the virus from the blood sample at baseline. PAR, participant. | Baseline through Week 36 | 
| Number of Confirmed Virologic Failure Participants From Randomization at Week 36 Through Week 84 With Treatment-emergent Reductions in HIV Susceptibility to Abacavir, Lamivudine, Atazanavir, or Ritonavir | A blood sample was drawn for participants failing to respond to therapy, and changes in drug susceptibility for HIV isolated from the participants for each drug used in the study were assessed. For each participant, the changes in drug susceptibility detected by phenotypic assay in virus from the sample collected at the time of failure was compared with drug susceptibility in the virus from the blood sample at baseline. PAR, participant. | Randomization at Week 36 through Week 84 | 
| Number of Confirmed Virologic Failure Participants From Week 84 Through Week 144 With Treatment-emergent Reductions in HIV Susceptibility to Abacavir, Lamivudine, Atazanavir, or Ritonavir | A blood sample was drawn for participants failing to respond to therapy, and changes in drug susceptibility for HIV isolated from the participants for each drug used in the study were assessed. For each participant, the changes in drug susceptibility detected by phenotypic assay in virus from the sample collected at the time of failure was compared with drug susceptibility in the virus from the blood sample at baseline. PAR, participant. | Week 84 through Week 144 | 
| Mean Percent Compliance at Week 36 | Percent compliance is defined as the total number of pills taken divided by the total number of pills prescribed. The total number of pills taken was calculated by subtracting any returned pills from the total number of pills that were dispensed to each participant during this period. Compliance was calculated for each medication in the regimen. | Week 36 | 
| Mean Percent Compliance at Week 84 | Percent compliance is defined as the total number of pills taken divided by the total number of pills prescribed. The total number of pills taken was calculated by subtracting any returned pills from the total number of pills that were dispensed to each participant during this period. Compliance was calculated for each medication in the regimen. | Week 84 | 
| Mean Percent Compliance at Week 144 | Percent compliance is defined as the total number of pills taken divided by the total number of pills prescribed. The total number of pills taken was calculated by subtracting any returned pills from the total number of pills that were dispensed to each participant during this period. Compliance was calculated for each medication in the regimen. | Week 144 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NORVIR, ARIES, EPZICOM, REYATAZ, HIV, simplification, Antiretroviral-naive