Comparative Efficacy and Safety Study of Dolutegravir and Lopinavir/Ritonavir in Second-line Treatment
Condition: HIV Infections
MeSH terms: HIV Infections
Intervention: DTG; LPV/RTV; Two NRTIs
Intervention description: DTG is supplied as 50 mg tablets; LPV/RTV is supplied as the LPV/RTV oral tablet, which contains 200 mg of LPV and 50 mg of RTV; Investigators will choose a dual NRTI background regimen for each subject . In consultation with the medical monitor, 3TC may be added as a third NRTI to a dual-NRTI background regimen in subjects with chronic HBV infection and evidence of HIV resistance to 3TC
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 627.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: integrase inhibitor; non-inferiority; dolutegravir; lopinavir/ritonavir; second-line treatment; HIV-1; antiretroviral therapy-experienced

Summary:

      For treatment of human immunodeficiency virus type 1(HIV-1), publicly funded programmes tend
      to follow World Health Organization (WHO) guidelines to use a non-nucleoside reverse
      transcriptase inhibitor (NNRTI) combined with two nucleoside reverse transcriptase inhibitors
      (NRTIs) for first-line antiretroviral therapy (ART); however, there is a need for further
      data on the best treatment options for people with HIV-1 who have virological failure with
      this first-line regimen. The number of patients failing on their first-line regimen is
      increasing thereby requiring a switch to second-line treatment to reduce accumulation of
      drug-resistance mutations, disease progression, HIV transmission, and death. WHO guidelines
      recommend second-line antiretroviral therapy for adults consisting of two NRTIs + a
      ritonavir-boosted protease inhibitor (PI); atazanavir (ATV) plus ritonavir (RTV) or lopinavir
      (LPV)/RTV are the preferred boosted PI options. This study is conducted to demonstrate
      non-inferior antiviral activity at 48 weeks of a dolutegravir (DTG) containing regimen
      compared to a WHO-recommended standard of care regimen for second line treatment, LPV/RTV +
      two NRTIs, in HIV-1 infected patients failing first line therapy. This study comprises of a
      Screening Phase (approximately 28 to 42 days), a Randomized Phase (Day 1 to Week 48 plus a
      4-week treatment extension), and a Continuation Phase. Approximately 612 subjects will be
      randomized 1:1 to receive DTG 50 milligram (mg) once daily or LPV/RTV (800/200 mg once daily
      or 400/100 mg twice daily, in accordance with investigator decision and local label), each
      added to an investigator selected background regimen of two NRTIs at least one of which needs
      to be fully active based on viral resistance testing at Screening. Subjects randomized to the
      LPV/RTV arm will either (i) continue receiving LPV/RTV and complete the study after the
      4-week treatment extension at Week 52, or (ii) switch to the DTG arm prior to study
      completion at Week 52 and continue to have access to DTG in the Continuation Phase. Subjects
      randomized to receive DTG who successfully complete 52 weeks of treatment and subjects
      originally randomized to receive LPV/RTV but switched to DTG prior to Week 52 will continue
      to have access to DTG until it is either locally approved and commercial supplies are
      available to patients or the patient no longer derives clinical benefit, or the patient meets
      a protocol-defined reason for discontinuation.
    

Eligibility criteria:

        Inclusion Criteria:

          -  HIV-1 infected subjects >=18 years of age.

          -  A female subject may be eligible to enter and participate in the study if she:

        is of non-childbearing potential defined as either post-menopausal (12 months of
        spontaneous amenorrhea and >=45 years of age) or physically incapable of becoming pregnant
        with documented tubal ligation, hysterectomy, or bilateral oophorectomy or, is of
        child-bearing potential, with a negative pregnancy test at both Screening and Day 1 and
        agrees to use one of the protocol-defined methods of contraception to avoid pregnancy
        throughout the study and for at least 2 weeks after discontinuation of all study
        medication.

          -  HIV-1 infection as documented by HIV-1 RNA >=400 c/mL at Screening.

          -  Subject has been on a first-line treatment regimen consisting of an NNRTI plus two
             NRTIs for at least 6 months and is currently experiencing virologic failure to this
             first-line regimen defined as two consecutive (>=7 days apart) HIV-1 RNA results of
             >=400 c/mL.

          -  Subjects must receive at least one fully active agent within the dual-NRTI background
             regimen for second line treatment. Fully active is defined by the Screening genotypic
             resistance report of the central laboratory (or a laboratory contracted by the central
             laboratory) showing no evidence of full or of partial resistance for a given NRTI
             which will be taken on study.

          -  Subject is PI-naïve and Integrase inhibitor (INI)-naïve, defined as no prior or
             current exposure to any PI or INI.

          -  Subject or the subject's legal representative is willing and able to understand and
             provide signed and dated written informed consent prior to screening.

        Exclusion Criteria:

          -  Women who are breastfeeding.

          -  Any evidence of an active Centers for Disease Control and Prevention (CDC) Category C
             disease Exceptions include cutaneous Kaposi's sarcoma not requiring systemic therapy
             and historic or current CD4+ cell levels <200 cells per cubic millimeter

          -  Subjects with severe hepatic impairment (Class C) as determined by Child-Pugh
             classification

          -  Unstable liver disease (as defined by the presence of ascites, encephalopathy,
             coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, or persistent
             jaundice), cirrhosis, known biliary abnormalities (with the exception of Gilbert's
             syndrome or asymptomatic gallstones).

          -  Anticipated need for hepatitis C virus (HCV) therapy during the Randomized Phase of
             the study.

          -  History or presence of allergy or intolerance to the study drugs or their components
             or drugs of their class.

          -  Ongoing malignancy other than cutaneous Kaposi's sarcoma, basal cell carcinoma, or
             resected, non-invasive cutaneous squamous cell carcinoma, or cervical intraepithelial
             neoplasia; other localized malignancies require agreement between the investigator and
             the Study medical monitor for inclusion of the subject.

          -  Subjects who in the investigator's judgment, poses a significant suicidality risk.
             Recent history of suicidal behavior and/or suicidal ideation may be considered as
             evidence of serious suicide risk.

          -  Treatment with an HIV-1 immunotherapeutic vaccine within 90 days of Screening.

          -  Treatment with any of the following agents within 28 days of Screening: radiation
             therapy, cytotoxic chemotherapeutic agents, systemically administered
             immunomodulators.

          -  Treatment with any agent, other than licensed ART as allowed above with documented
             activity against HIV-1 in vitro/vivo within 28 days of first dose of IP. The exception
             is use of entecavir, in appropriate clinical situations, for treatment of hepatitis B
             [e.g. prior intolerance to Tenofovir (TDF), viral resistance to lamivudine (3TC) /
             Emtricitabine (FTC)] after discussion and agreement between the investigator and the
             medical monitor.

          -  Exposure to an experimental drug or experimental vaccine within either 28 days, 5
             half-lives of the test agent, or twice the duration of the biological effect of the
             test agent, whichever is longer, prior to the first dose of IP.

          -  Any evidence of primary viral resistance to PIs or INIs based on the presence of any
             major resistance-associated mutation.

          -  The subject's virus does not yield results using genotype at Screening (assay data is
             essential for eligibility determination).

          -  Any verified Grade 4 laboratory abnormality, with the exception of Grade 4
             triglycerides. A single repeat test is allowed during the Screening period to verify a
             result.

          -  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.

          -  Alanine aminotransferase (ALT) >=5 times the upper limit of normal (ULN) or ALT
             >=3xULN and bilirubin >=1.5xULN (with >35% direct bilirubin)