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    Clinical Trial Results:
    Immune reconstitution in severely immunosuppressed antiretroviral-naive HIV-1?infected patients (<100 CD4+ T cells/?L) taking antiretroviral regimens based on dolutegravir or ritonavir-boosted darunavir (the AdvanZ-4 Trial).

    Summary
    EudraCT number
    		 2014-002281-70
    Trial protocol
    		 ES  
    Global end of trial date
    28 Jul 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Oct 2026
    First version publication date
    21 Oct 2026
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    2014-002281-70
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02337322
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Fundacio Recerca Clinic Barcelona - Institut d’Investigacions Biomediques August Pi i Sunyer (FRCB-IDIBAPS)
    Sponsor organisation address
    C/ Villarroel 170, Barcelona, Spain,
    Public contact
    Judit Pich, CTU Clinic (Clinical Trial Unit), jpich@recerca.clinic.cat
    Scientific contact
    Judit Pich, CTU Clinic (Clinical Trial Unit), jpich@recerca.clinic.cat
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    28 Jul 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Jul 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Jul 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    -Compare the change in the absolute number of CD4 in peripheral blood to 48 to 96 weeks of initiating treatment.
    Protection of trial subjects
    All subjects provided written informed consent before participation. The study protocol was approved by the Institutional Review Boards/Ethics Committees of all participating centres and by the Spanish Regulatory Authorities (AEMPS). The trial was conducted in accordance with the Declaration of Helsinki and applicable data protection regulations. Patient safety was monitored throughout the study, including adverse event and serious adverse event reporting procedures, predefined treatment discontinuation criteria, pregnancy reporting, and regular safety assessments.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Dec 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Spain: 104
    Worldwide total number of subjects
    104
    EEA total number of subjects
    104
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    104
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 149 subjects were screened for eligibility between December 2014 and July 2018. Eligible participants were antiretroviral-naïve HIV-1 infected adults with CD4+ cell counts <100 cells/µL. Subjects were excluded if they did not meet inclusion/exclusion criteria, including positive HLA-B*5701 status or a confirmatory CD4+ count >100 cells/µ

    Pre-assignment
    Screening details
    		 A total of 149 subjects were screened for participation. Forty-five subjects were excluded during screening and were not randomised. A total of 104 eligible subjects were randomised into the study.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Open-label trial. Participants and investigators were aware of treatment allocation after enrolment. Randomization was centralized and computer-generated (1:1), stratified by AIDS diagnosis. Investigators remained blinded only until patient inclusion/allocation. No blinding of participants, treating physicians, outcome assessors, or data collection procedures was reported.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 DTG arm
    Arm description
    		 Participants randomized to receive once-daily dolutegravir-based triple antiretroviral therapy consisting of dolutegravir 50 mg, abacavir 600 mg, and lamivudine 300 mg (Triumeq®) for the treatment of antiretroviral-naïve adults with advanced HIV-1 infection and CD4+ cell counts <100 cells/μL.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Triumeq
    Investigational medicinal product code
    Other name
    Dolutegravir/Abacavir/Lamivudine, DTG/ABC/3TC
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Triumeq: 300mg 3TC/LAmivudina + 600mg ABC/Abacavir + 50mg DGT/Doultegrvir 1 tablet once per day.

    Arm title
    		 DRV/c arm
    Arm description
    		 Participants randomized to receive once-daily darunavir/ritonavir-based triple antiretroviral therapy consisting of darunavir 800 mg plus ritonavir 100 mg, combined with abacavir 600 mg and lamivudine 300 mg. Participants enrolled after the protocol amendment received darunavir/cobicistat (Rezolsta®) instead of darunavir/ritonavir.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Rezolsta
    Investigational medicinal product code
    Other name
    Darunavir/Cobicistat, DRV/c
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Rezolsta:Darunavir 800 mg/Cobicistat 150 mg (Rezolsta®), one film-coated tablet orally once daily.

    Investigational medicinal product name
    Kivexa
    Investigational medicinal product code
    Other name
    Abacavir/Lamivudine, ABC/3TC
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Abacavir 600 mg/Lamivudine 300 mg (Kivexa®), one film-coated tablet orally once daily.

    Number of subjects in period 1
    		DTG arm DRV/c arm
    Started
    52
    52
    Completed
    48
    37
    Not completed
    4
    15
         Adverse event, serious fatal
    -
    1
         Virologic failure
    1
    -
         Adverse event, non-fatal
    -
    5
         New AIDS event / disease progression
    -
    1
         Randomised but did not receive allocated treatment
    -
    3
         Lost to follow-up
    1
    2
         New AIDS events
    2
    -
         Lack of efficacy
    -
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    DTG arm
    Reporting group description
    		 Participants randomized to receive once-daily dolutegravir-based triple antiretroviral therapy consisting of dolutegravir 50 mg, abacavir 600 mg, and lamivudine 300 mg (Triumeq®) for the treatment of antiretroviral-naïve adults with advanced HIV-1 infection and CD4+ cell counts <100 cells/μL.

    Reporting group title
    DRV/c arm
    Reporting group description
    		 Participants randomized to receive once-daily darunavir/ritonavir-based triple antiretroviral therapy consisting of darunavir 800 mg plus ritonavir 100 mg, combined with abacavir 600 mg and lamivudine 300 mg. Participants enrolled after the protocol amendment received darunavir/cobicistat (Rezolsta®) instead of darunavir/ritonavir.

    Reporting group values
    		 DTG arm DRV/c arm Total
    Number of subjects
    		 52 52 104
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0
        Newborns (0-27 days)
    		 0
        Infants and toddlers (28 days-23 months)
    		 0
        Children (2-11 years)
    		 0
        Adolescents (12-17 years)
    		 0
        Adults (18-64 years)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 40 (30 to 48.5) 42 (34.5 to 47) -
    Gender categorical
    Units: Subjects
        Female
    		 8 6 14
        Male
    		 44 46 90

    End points

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    End points reporting groups
    Reporting group title
    DTG arm
    Reporting group description
    		 Participants randomized to receive once-daily dolutegravir-based triple antiretroviral therapy consisting of dolutegravir 50 mg, abacavir 600 mg, and lamivudine 300 mg (Triumeq®) for the treatment of antiretroviral-naïve adults with advanced HIV-1 infection and CD4+ cell counts <100 cells/μL.

    Reporting group title
    DRV/c arm
    Reporting group description
    		 Participants randomized to receive once-daily darunavir/ritonavir-based triple antiretroviral therapy consisting of darunavir 800 mg plus ritonavir 100 mg, combined with abacavir 600 mg and lamivudine 300 mg. Participants enrolled after the protocol amendment received darunavir/cobicistat (Rezolsta®) instead of darunavir/ritonavir.

    Primary: Change in the absolute number of CD4+ cells in peripherial blood 48 weeks after treatment start

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    End point title
    		 Change in the absolute number of CD4+ cells in peripherial blood 48 weeks after treatment start
    End point description
    End point type
    Primary
    End point timeframe
    48 weeks
    End point values
    		 DTG arm DRV/c arm
    Number of subjects analysed
    52
    49
    Units: cells/microlitre
        median (inter-quartile range (Q1-Q3))
    206.5 (154.4 to 2310.5)
    180.0 (89.4 to 314.0)
    Statistical analysis title
    		 Comparison of change in CD4+ cell count at Week 48
    Statistical analysis description
    Comparison of the change from baseline in absolute CD4+ cell count in peripheral blood at Week 48 between the DTG and DRV/r arms in the modified intention-to-treat population.
    Comparison groups
    DTG arm v DRV/c arm
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4299
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    48 weeks
    Adverse event reporting additional description
    Adverse events were assessed throughout the 48-week treatment period in all patients who received at least one dose of study treatment (safety population).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    DTG arm
    Reporting group description
    		 Participants randomized to receive once-daily dolutegravir-based triple antiretroviral therapy consisting of dolutegravir 50 mg, abacavir 600 mg, and lamivudine 300 mg (Triumeq®) for the treatment of antiretroviral-naïve adults with advanced HIV-1 infection and CD4+ cell counts <100 cells/μL.

    Reporting group title
    DRV/c arm
    Reporting group description
    		 Participants randomized to receive once-daily darunavir/ritonavir-based triple antiretroviral therapy consisting of darunavir 800 mg plus ritonavir 100 mg, combined with abacavir 600 mg and lamivudine 300 mg. Participants enrolled after the protocol amendment received darunavir/cobicistat (Rezolsta®) instead of darunavir/ritonavir.

    Serious adverse events
    		 DTG arm DRV/c arm
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 52 (23.08%)
    11 / 51 (21.57%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    1
    General disorders and administration site conditions
    Total SAEs
    Additional description: Reported serious adverse events included severe allergic reactions, neurocognitive/behavioural disorders, pharmacokinetic interactions with anti-tuberculosis medication, and one sudden cardiovascular death.
         subjects affected / exposed
    12 / 52 (23.08%)
    11 / 51 (21.57%)
         occurrences causally related to treatment / all
    0 / 19
    5 / 18
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 DTG arm DRV/c arm
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 52 (23.08%)
    10 / 51 (19.61%)
    General disorders and administration site conditions
    Any AE Grade 3 and 4
         subjects affected / exposed
    12 / 52 (23.08%)
    10 / 51 (19.61%)
         occurrences all number
    12
    10

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 May 2016
    Substantial Modification Number 2: Harmonisation of microbiome sampling procedures, addition of DEXA assessments as a secondary objective, extension of the randomisation period by 12 months, and inclusion of CMV testing (IgG, IgM, PCR and QuantiFERON) as secondary objectives.
    15 Jun 2018
    Substantial Modification Number 3: Modification of Arm B treatment regimen, inclusion of interim efficacy analyses, and extension of the recruitment period.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The open-label design may have contributed to treatment discontinuation decisions, particularly in the DRV/r arm. Additionally, the sample size was relatively small.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/41083105
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