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

Bristol-Myers Squibb (BMS)

Status and phase: Completed; Phase 3

Conditions: HIV Infections

Treatments: Drug: Atazanavir + saquinavir + tenofovir + nucleoside; Drug: Atazanavir + ritonavir + tenofovir + nucleoside; Drug: Lopinavir/ritonavir + tenofovir + nucleoside

Study type: Interventional

Funder types: Industry

Identifiers

NCT00035932

AI424-045

Details and patient eligibility

About

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.

Enrollment: 571 patients

Sex: All

Ages: 16+ years old

Volunteers: No Healthy Volunteers

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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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571 participants in 3 patient groups

I

Active Comparator group

Description:

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

Treatment:

Drug: Atazanavir + ritonavir + tenofovir + nucleoside

II

Active Comparator group

Description:

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

Treatment:

Drug: Atazanavir + saquinavir + tenofovir + nucleoside

III

Active Comparator group

Description:

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

Treatment:

Drug: Lopinavir/ritonavir + tenofovir + nucleoside