A5288/MULTI-OCTAVE: Management Using Latest Technologies to Optimize Combination Therapy After Viral Failure
Condition: HIV-1 Infection
Intervention: Darunavir; Etravirine; Emtricitabine/tenofovir disoproxil fumarate; Raltegravir; Second line ART regimens - based on a boosted protease inhibitor (bPI) plus two nucleoside analogues (NRTIs); Study provided drugs according to patient resistance profile (DRV, ETR, RTV, FTC/TDF) + any in country available drug as applicable & available; SOC adherence versus SOC+CPI adherence
Intervention description: Participants were administered darunavir orally as one 600 mg tablet twice a day (1200 mg per day) with food (taken with Ritonavir 100 mg twice a day [200 mg per day]); Patients were administered Etravirine orally as two 100 mg tablets or one 200 mg tablet twice a day (400 mg per day) following a meal.; Patients were administered FTC/TDF orally as one fixed dose combination tablet (FTC 200 mg/TDF 300 mg) once daily, with or without food.; Participants were administered Raltegravir orally as one 400 mg tablet twice daily (800 mg per day), with or without food; LPV/r and ATV/r were the preferred bPIs for second-line ART. TDF + (3TC or FTC) or AZT + 3TC were the most frequent NRTI backbones. Cohort A did not include any of the new drugs; therefore, it is distinct from Cohorts B, C, and D.; For Cohort D, in many situations a participant received the same regimen that patients are getting in Cohorts B and C if that was the best combination that can be obtained according to his/her resistance profile and drug availability (as for many countries there were no further drug options beyond the available study drugs).; not participating in the adherence randomization; OR
randomized to SOC adherence; OR
randomized to SOC+CPI adherence.
Intervention MeSH terms: Tenofovir; Emtricitabine; Raltegravir Potassium; Emtricitabine, Tenofovir Disoproxil Fumarate Drug Combination; Darunavir; Etravirine; HIV Protease Inhibitors; Protease Inhibitors
Phase: Phase 4
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 545.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      The study was done to:

        -  test a strategy of using a resistance test to choose anti-HIV drugs

        -  see how well combinations of new anti-HIV drugs work to lower HIV infection

        -  see if taking new anti-HIV drugs together is safe and tolerable

        -  see if text messages improve people's anti-HIV drug-taking behavior (only at sites
           participating in the adherence study)

        -  in people taking certain combinations of anti-HIV drugs with an anti-TB drug, compare
           how these drugs act in the body

        -  to see how people do after they stop having frequent clinic visits as part of a research
           study
    

Eligibility criteria:

        Inclusion Criteria for Step 1:

          -  HIV-1 infection, documented by any licensed rapid HIV test or HIV enzyme or
             chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and
             confirmed by a licensed Western blot or a second antibody test by a method other than
             the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, plasma HIV-1 RNA VL.

          -  Any previous combination of ARV treatment at any time with at least one regimen that
             contained one NNRTI and two NRTIs which was replaced with a PI-based regimen because
             of virologic, immunologic, or clinical treatment failure, or because of toxicity.

        NOTE: All potential participants with prior RAL exposure were assigned to either Cohort A
        or Cohort D.

          -  At screening, receipt of a PI-based regimen with no regimen change for a minimum of 24
             weeks prior to screening.

          -  Confirmation of VF of current second-line PI-based ART. NOTE A: Failure of the current
             second-line regimen was defined as two consecutive measurements of plasma HIV-1 RNA
             ≥1000 copies/mL obtained at least 1 day apart while on the current PI-based regimen.
             "Current PI-based regimen" and "current regimen" were understood to be the regimen
             described (ie, the regimen that the candidate was taking when the first VF sample was
             drawn plus only those modifications allowed).

          -  CD4+ T-cell count result from a specimen drawn within 103 days prior to study entry

          -  Laboratory values obtained within 30 days prior to study entry:

               -  Absolute neutrophil count (ANC) ≥ 500/mm^3

               -  Hemoglobin ≥7.5 g/dL

               -  Platelet count ≥40,000/mm^3

               -  Creatinine ≤2 X upper limit of normal (ULN)

               -  Aspartate aminotransferase (AST), serum glutamic oxaloacetic transaminase (SGOT),
                  alanine aminotransferase (ALT), serum glutamic pyruvic transaminase (SGPT), and
                  alkaline phosphatase ≤5 x ULN

               -  Total bilirubin ≤2.5 x ULN

               -  Creatinine clearance (CrCl) >30 mL/min, either measured or estimated by
                  Cockcroft-Gault equation

               -  Hepatitis B panel that includes HbsAB, HBcAB, and HBsAG or only HBsAG, with
                  plasma stored for later anti-HBs and anti-HBc.

        NOTE A: Candidates who were eligible for cohort B and who were positive for active
        hepatitis B infection were assigned to sub-cohort B3 at registration/randomization.

        NOTE B: Candidates with CrCl <60 mL/min who were also positive for active hepatitis B
        infection were not eligible.

          -  Females of reproductive potential (women who have not been post-menopausal for at
             least 24 consecutive months, ie, who have had menses within the preceding 24 months,
             or women who have not undergone surgical sterilization, hysterectomy or bilateral
             salpingectomy or bilateral oophorectomy or tubal ligation) must have had a negative
             serum or urine pregnancy test prior to the submission of the screening genotype
             testing sample and again within 48 hours prior to randomization or registration.

          -  Female participants of reproductive potential must have agreed not to participate in
             the conception process (ie, active attempt to become pregnant, in vitro
             fertilization), and if participating in sexual activity that could lead to pregnancy,
             the female participant must have used at least one reliable form of contraceptive.
             Female participants must have continued to use contraceptives while receiving study
             treatment and for 6 weeks after stopping study treatment.

        Acceptable forms of contraceptives included:

          -  Condoms (male or female) with or without a spermicidal agent

          -  Diaphragm or cervical cap with spermicide

          -  Intrauterine device (IUD)

          -  Hormonal contraception

        Female participants who were not of reproductive potential or whose male partner(s) had
        documented azoospermia) were not required to use contraceptives. Any statement of
        self-reported sterility or that of her partner's must have been entered in the source
        documents.

        NOTE: Acceptable documentation of lack of reproductive potential was oral or written
        documentation from the participant.

          -  Karnofsky performance score >/= 70 within 30 days prior to study entry.

          -  Ability and willingness of potential participant to provide informed consent.

          -  Willingness of potential participant to adhere to protocol requirements, especially
             with respect to treatment assignment and ability to obtain non-study provided ART, if
             needed.

          -  Ability to take oral study medications.

          -  No intention of permanent relocation that would preclude attending Step 1 and 2 study
             follow-up visits.

          -  Availability of a successful, interpretable resistance genotype report from a
             DAIDS-approved regional genotyping facility from testing performed on a plasma sample
             that was collected during screening (ie, at or after the date that a sample is
             collected to confirm HIV-1 virologic failure) and which was shipped to a regional
             resistance testing laboratory once documentation of two screening plasma HIV-1 RNA
             values ≥1000 copies/mL were available.

          -  Identification of a cohort assignment and ARV regimen for use on study, selected from
             the recommended options provided by the site investigator, and reviewed and approved
             by the A5288 Clinical Management Committee (CMC).

        Exclusion Criteria for Step 1:

          -  Pregnancy or breast-feeding.

          -  Known allergy/sensitivity or any hypersensitivity to components of study drugs or
             their formulation.

          -  Active drug or alcohol use or dependence that, in the opinion of the site
             investigator, would have interfered with adherence to study requirements.

          -  Serious illness requiring systemic treatment and/or hospitalization until candidate
             either completes therapy or was clinically stable on therapy, in the opinion of the
             site investigator, for at least 7 days prior to study entry.

          -  Concurrent illness or condition that would compromise the ability to take study
             medication, follow the protocol, or that would make participation not in the best
             interest of the participant, per the site investigator.

          -  Requirement for taking any of the prohibited medications with the selected ARV study
             regimen, or within 14 days prior to study entry.

        NOTE: Study candidates should not have discontinued any component of their ART during
        screening. The 14-day restriction on prohibited medications did not apply to ARVs.

          -  Active tuberculosis (TB) or rifampin exposure less than 2 weeks prior to study entry.

          -  Any exposure to darunavir or etravirine.