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    Clinical Trial Results:
    Bisphosphonate Therapy with Zoledronic acid or Tenofovir Switching to Improve Low Bone Mineral Density in HIV-Infected Adults

    Summary
    EudraCT number
    		 2013-003359-39
    Trial protocol
    		 ES  
    Global end of trial date
    26 Mar 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Jun 2025
    First version publication date
    29 Jun 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ZEST
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Australian and New Zealand Clinical Trials Registr: ACTRN12612000776808
    Sponsors
    Sponsor organisation name
    Fundació Clínic per a la Recerca Biomèdica
    Sponsor organisation address
    Villarroel, 170, Barcelona, Spain, 08036
    Public contact
    Dr. Joan Albert Arnaiz, CTU (Clinical Trials Department), 34 93 227 57 07, jaarnaiz@clinic.cat
    Scientific contact
    Dr. Esteban Martínez, Fundació Clínic per a la Recerca Biomèdica, 34 93 227 57 07, estebanm@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
    22 May 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Jan 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Mar 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To compare the effects of zoledronic acid 5 mg IV yearly to switching from tenofovir to another antiretroviral drug on lumbar spine BMD (primary endpoint) over 2 years.
    Protection of trial subjects
    Participants were protected through ethics approval, informed consent, strict eligibility criteria, regular safety monitoring, and oversight by an independent Data Safety Monitoring Board.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 Jul 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy, Scientific research
    Long term follow-up duration
    		 24 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Australia: 57
    Country: Number of subjects enrolled
    Spain: 28
    Worldwide total number of subjects
    85
    EEA total number of subjects
    28
    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)
    85
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Number of subjects assessed for eligibility: 112 Number of subjects excluded prior to assignment: 25 (Reason: Did not meet inclusion/exclusion criteria – 22 subjects, Reason: Declined to participate – 3 subjects). Number of subjects assigned to trial groups: 87

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 TDF Switch
    Arm description
    		 Participants discontinued tenofovir disoproxil fumarate (TDF) and switched to another antiretroviral drug (most commonly abacavir or raltegravir), without receiving zoledronic acid. All participants also received calcium and vitamin D supplementation as needed.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Tenofovir disoproxil fumarate (TDF) switch strategy
    Investigational medicinal product code
    Other name
    TDF switch, antirretroviral switch, ARV switch
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants will switch from tenofovir disoproxil fumarate (TDF) to another potent antiretroviral drug, selected by the study physician based on prior treatment history and tolerability. The switch options include abacavir, raltegravir, or a boosted protease inhibitor. The selected antiretroviral will be administered orally, at least once daily, for the duration of the study (2 years). No bisphosphonate will be administered in this arm.

    Arm title
    		 Zoledronic acid
    Arm description
    		 Participants received intravenous zoledronic acid 5 mg at baseline and at month 12, while continuing their tenofovir disoproxil fumarate (TDF)-based antiretroviral therapy. All participants also received calcium and vitamin D supplementation as needed.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Zoledronic acid
    Investigational medicinal product code
    Other name
    Aclasta
    Pharmaceutical forms
    Solution for infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    Dosage: 5 mg of zoledronic acid once a year. Administered as a single intravenous infusion.

    Number of subjects in period 1
    		TDF Switch Zoledronic acid
    Started
    42
    43
    Completed
    38
    37
    Not completed
    4
    6
         TDF reintroduced via NG tube after injury
    1
    -
         Ceased TDF
    -
    3
         Adverse event, non-fatal
    3
    -
         Lost to follow-up
    -
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    TDF Switch
    Reporting group description
    		 Participants discontinued tenofovir disoproxil fumarate (TDF) and switched to another antiretroviral drug (most commonly abacavir or raltegravir), without receiving zoledronic acid. All participants also received calcium and vitamin D supplementation as needed.

    Reporting group title
    Zoledronic acid
    Reporting group description
    		 Participants received intravenous zoledronic acid 5 mg at baseline and at month 12, while continuing their tenofovir disoproxil fumarate (TDF)-based antiretroviral therapy. All participants also received calcium and vitamin D supplementation as needed.

    Reporting group values
    		 TDF Switch Zoledronic acid Total
    Number of subjects
    		 42 43 85
    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
        arithmetic mean (standard deviation)
    		 51 ( 12 ) 49 ( 11 ) -
    Gender categorical
    Units: Subjects
        Male
    		 42 40 82
        Female
    		 0 3 3
    Lumbar spine BMD (L1–L4)
    Bone mineral density at the lumbar spine measured by DXA at baseline.
    Units: g/cm²
        median (inter-quartile range (Q1-Q3))
    		 1.01 (0.88 to 1.11) 0.97 (0.85 to 1.10) -

    End points

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    End points reporting groups
    Reporting group title
    TDF Switch
    Reporting group description
    		 Participants discontinued tenofovir disoproxil fumarate (TDF) and switched to another antiretroviral drug (most commonly abacavir or raltegravir), without receiving zoledronic acid. All participants also received calcium and vitamin D supplementation as needed.

    Reporting group title
    Zoledronic acid
    Reporting group description
    		 Participants received intravenous zoledronic acid 5 mg at baseline and at month 12, while continuing their tenofovir disoproxil fumarate (TDF)-based antiretroviral therapy. All participants also received calcium and vitamin D supplementation as needed.

    Primary: Change in lumbar spine bone mineral density (BMD)

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    End point title
    		 Change in lumbar spine bone mineral density (BMD)
    End point description
    End point type
    Primary
    End point timeframe
    24 months
    End point values
    		 TDF Switch Zoledronic acid
    Number of subjects analysed
    42
    43
    Units: g/cm2
        arithmetic mean (standard deviation)
    2.9 ( 4.5 )
    7.4 ( 4.3 )
    Statistical analysis title
    		 Lumbar spine BMD change at 24 months
    Comparison groups
    TDF Switch v Zoledronic acid
    Number of subjects included in analysis
    85
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    4.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 2.6
         upper limit
    		 6.3

    Secondary: Osteoporosis

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    End point title
    		 Osteoporosis
    End point description
    Incidence of osteoporosis (T-score <-2.5 at hip or spine)
    End point type
    Secondary
    End point timeframe
    24 months
    End point values
    		 TDF Switch Zoledronic acid
    Number of subjects analysed
    42
    43
    Units: Subjects
    6
    4
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the time of signing the informed consent until 30 days after the participant's final study involvement (defined as the last dose of investigational product or the last study visit, whichever occurs later).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    TDF Switch
    Reporting group description
    		 Participants discontinued tenofovir disoproxil fumarate (TDF) and switched to another antiretroviral drug (most commonly abacavir or raltegravir), without receiving zoledronic acid. All participants also received calcium and vitamin D supplementation as needed.

    Reporting group title
    Zoledronic acid
    Reporting group description
    		 Participants received intravenous zoledronic acid 5 mg at baseline and at month 12, while continuing their tenofovir disoproxil fumarate (TDF)-based antiretroviral therapy. All participants also received calcium and vitamin D supplementation as needed.

    Serious adverse events
    		 TDF Switch Zoledronic acid
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 42 (14.29%)
    8 / 43 (18.60%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    General disorders and administration site conditions
    Not related to study treatment
    Additional description: The specific System Organ Class and Event Terms were not detailed in the publication. None of the SAEs were considered related to the study treatment. One death occurred in the zoledronic acid group, unrelated to treatment.
         subjects affected / exposed
    6 / 42 (14.29%)
    8 / 43 (18.60%)
         occurrences causally related to treatment / all
    0 / 10
    0 / 9
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 TDF Switch Zoledronic acid
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    33 / 42 (78.57%)
    37 / 43 (86.05%)
    General disorders and administration site conditions
    Not specified
    Additional description: Most non-serious adverse events were not considered related to study treatment. Related events: 14 in zoledronic acid group, 22 in TDF-switch group.
         subjects affected / exposed
    33 / 42 (78.57%)
    37 / 43 (86.05%)
         occurrences all number
    163
    114

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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 population was predominantly male and Caucasian, limiting generalizability. Results reflect 24-month follow-up; longer-term effects remain unknown.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/29927785
    http://www.ncbi.nlm.nih.gov/pubmed/31361922
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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