Efficacy of Tenofovir Alafenamide Versus Placebo Added to a Failing Regimen Followed by Treatment With Elvitegravir/Cobicistat/Emtricitabine/Tenofovir Alafenamide Plus Atazanavir in HIV-1 Positive, Antiretroviral Treatment-Experienced Adults
Condition: HIV; HIV Infections; Acquired Immunodeficiency Syndrome
MeSH terms: HIV Infections; Acquired Immunodeficiency Syndrome; Immunologic Deficiency Syndromes
Intervention: TAF; Placebo; E/C/F/TAF; Current failing ARV regimen; ATV
Intervention description: 25 mg tablet administered orally once daily with food; Tablets to match TAF administered orally once daily with food; 150/150/200/10 mg STR administered orally once daily with food; Participants will continue taking their current ARV regimen as prescribed in Part 1.; 300 mg tablet administered orally once daily.
Intervention MeSH terms: Atazanavir Sulfate; Elvitegravir, Cobicistat, Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Part 1 (Sentinel Cohort followed by a Randomized Cohort), 14-day washout period, then Part 2
Masking: Double (Participant, Investigator)
Masking description: Part 1 Sentinel Cohort: Open-label, non-randomized Part 1 Randomized Cohort: Double-blind, randomized Part 2: Open-label, non-randomized
Enrollment: 55.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: HIV-1; HIV; Treatment-Experienced

Summary:

      The primary objective of this study is to evaluate the efficacy of tenofovir alafenamide
      (TAF) versus placebo, each administered with the existing, failing antiretroviral (ARV)
      regimen. There are 2 parts to this study: Part 1 and Part 2.

      Part 1 consists of 2 cohorts, starting with a sentinel cohort, in which participants will be
      enrolled to receive open-label TAF in addition to their current failing ARV regimen. This
      cohort will then be followed by a randomized, double-blind, cohort to compare the addition of
      TAF or placebo in HIV-1 positive adults who are failing their current ARV regimen.

      In Part 2, all participants who complete Part 1 of the study will discontinue their failing
      ARV regimen and TAF or placebo for a 14-day washout period. Following the washout period, all
      participants who received TAF in Part 1 and have a > 0.5 log10 decline in HIV-1 RNA will
      receive elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide (E/C/F/TAF) single-tablet
      regimen (STR) plus atazanavir (ATV) once daily for 48 weeks. Participants who received TAF
      who have a ≤ 0.5 log10 decline in HIV-1 RNA will be discontinued from the study and will not
      be eligible to continue into Part 2 of the study. All participants who received placebo in
      Part 1 will be eligible to participate in Part 2 regardless of their viral load change. After
      completion of Part 2, all participants will be eligible to continue to receive E/C/F/TAF plus
      ATV in the extension phase until E/C/F/TAF becomes commercially available, or until Gilead
      Sciences terminates development of E/C/F/TAF in the applicable country.
    

Eligibility criteria:

        Key Inclusion Criteria:

          -  Ability to understand and sign a written informed consent form, which must be obtained
             prior to initiation of study procedures

          -  Currently taking a failing ARV regimen

          -  Plasma HIV-1 RNA ≥ 500 copies/mL but ≤ 100,000 copies/mL at screening

          -  Normal ECG

          -  Estimated glomerular filtration rate (eGFR) ≥ 50 mL/min according to the
             Cockcroft-Gault formula for creatinine clearance

          -  Alanine aminotransferase (AST)/aspartate aminotransferase (AST) ≤ 5 × the upper limit
             of the normal range (ULN)

          -  Total bilirubin ≤ 1.5 mg/dL, or normal direct bilirubin

          -  Adequate hematologic function

          -  Serum amylase ≤ 5 × ULN

          -  Females may enter the study if it is confirmed that she is:

               -  Not pregnant or nursing

               -  Of non-childbearing potential (ie, have had a hysterectomy, both ovaries removed,
                  medically documented ovarian failure, or are postmenopausal women > 54 years of
                  age with cessation [for ≥ 12 months] of previously occurring menses), or

               -  Of childbearing potential and agrees to utilize highly effective contraception
                  methods or be non-heterosexually active or practice sexual abstinence from
                  screening throughout the duration of study treatment and for 30 days following
                  study drug dosing

                    -  Females who utilize hormonal contraceptive as one of their birth control
                       methods must have used the same method for at least three months prior to
                       study dosing.

          -  Males must agree to utilize a highly effective method of contraception during
             heterosexual intercourse or be non-heterosexually active, or practice sexual
             abstinence from first dose throughout the study period and for 30 days following the
             last study drug dose.

          -  Males must agree to refrain from sperm donation from first dose until at least 30 days
             after the last study drug dose.

        Key Exclusion Criteria:

          -  A new AIDS-defining condition diagnosed within the 30 days prior to screening

          -  Hepatitis B surface antigen (HBsAg) positive

          -  Hepatitis C antibody positive (individuals with positive hepatitis C virus (HCV)
             antibody and without detectable HCV RNA are permitted to enroll)

          -  History of integrase inhibitor use

          -  Screening or historical genotype reports shows Q151M or T69ins or more than 3 TAMs.

          -  Screening or historical genotype report shows resistance to integrase inhibitors

          -  Individuals experiencing decompensated cirrhosis

          -  Current alcohol or substance use

          -  History of malignancy within the past 5 years (prior to screening) or ongoing
             malignancy other than cutaneous Kaposi's sarcoma (KS), basal cell carcinoma, or
             resected, non-invasive cutaneous squamous carcinoma. Individuals with cutaneous KS are
             eligible, but must not have received any systemic therapy for KS within 30 days of
             Part 1, Day 1 and must not be anticipated to require systemic therapy during the
             study.

          -  Active, serious infections (other than HIV-1 infection) requiring parenteral
             antibiotic or antifungal therapy within 30 days prior to Part 1, Day 1

          -  Any other clinical condition or prior therapy that would make the individual
             unsuitable for the study or unable to comply with dosing requirements

          -  Participation in any other clinical trial (including observational trials) without
             prior approval from the sponsor is prohibited while participating in this trial

          -  Receiving ongoing therapy with any disallowed medications, including any drugs not to
             be used with elvitegravir, cobicistat, emtricitabine and tenofovir alafenamide or
             known allergies to the excipients of E/C/F/TAF STR

        Note: Other protocol defined Inclusion/Exclusion criteria may apply.