Bone Health in Aging HIV Infected Women
Condition: Osteoporosis; HIV; Menopause
MeSH terms: Osteoporosis
Study type: Interventional
Phase: Phase 4

Summary: 
      Design: Open-label randomised multicenter international strategic trial of older women on
      combination antiretroviral therapy (cART) containing tenofovir-emtricitabine (TDF/FTC) with
      HIV RNA suppression for > 6 months to : 1. Immediate switch of TDF/FTC to tenofovir
      alafenamide-emtricitabine (TAF/FTC) while continuing the third antiretroviral agent.; 2.
      Delayed switch; with switch of TDF/FTC to TAF/FTC at 48 weeks while continuing the third
      agent. Follow up of all subjects to 96 weeks.

      Subject Population: The anticipated sample size is 128 HIV infected women aged 45-55 years
      (peri or early post menopause). .

      Primary endpoint: Percentage change from baseline bone mineral density (BMD) at the lumbar
      spine at weeks 48 and 96.

      Secondary Endpoints: BMD change at hip, trabecular bone score, estimated bone strength by
      high resolution peripheral quantitative computerized tomography (HR-pQCT), muscle quality,
      geriatric assessment; biomarkers of bone, immune activation and inflammation; HIV viral
      suppression; safety, lipid and renal function, cardiovascular risk scores at weeks 48 and 96.

      Expected Outcomes: To determine if a switch from TDF/FTC to TAF?FTC improves BMD to a degree
      correlating with a decreased risk of fragility fracture in aging HIV infected women.
      Secondary outcomes will assess bone strength using new imaging modalities, timing of switch,
      and renal health. This data will be used by health policy makers and providers to determine
      the proper use of TAF/FTC in the aging HIV population.
    

Detailed description: 
      A Randomized controlled clinical trial (RCT) of immediate vs delayed switch from TDF/FTC to
      TAF/FTC to define the impact of switching ARV on BMD in different stages of the aging
      trajectory in HIV infected women. Included is a geriatric assessment based on the
      conceptualization of health transition across menopause.

      Study Hypothesis: The primary hypothesis is that switching from TDF/FTC will improve BMD to a
      degree that correlates with a lower fracture risk in aging HIV+ women. We will further
      explore our theory that the impact is greater in those in the early stages of menopause and
      in those who also receive a protease inhibitor (PI) as the third antiretroviral agent (ARV).

      Primary objectives: To determine if: 1. Switching HIV+ women on TDF/FTC to TAF/FTC increases
      BMD at the spine at 48 weeks relative to those who continue TDF/FTC 2. To determine if any
      observed improvements continue or stabilize in the year after switch.

      Hypothesis generating objectives: To determine if the effect of switching from TDF/FTC to
      TAF/FTC on BMD varies by stage of menopause and by third ARV.

      Study design: This study is double blind placebo controlled randomised, 1:1, multicentre
      strategic trial. Patients will be randomised to immediate vs delayed switch, with
      randomization allocation arranged to minimize differences between treatment group with
      respect to stage of menopause (peri- menopause vs early post menopause) and site. Study
      population: HIV positive women who are in the peri-menopausal period or those within 10 years
      post menopause to capture those with greatest risk of BMD loss. As menopause typically occurs
      earlier in HIV + women we include those aged 45-55 years. They must be on a cART regimen
      containing TDF/FTC with HIV RNA <50 c/ml for at least 6 months.

      Intervention:

        1. Immediate switch of TDF/FTC to TAF/FTC while maintaining the third ARV agent.

        2. Delayed switch of TDF/FTC to TAF/FTC at 48 weeks while maintaining the third ARV agent.

      Randomization: A computer-generated randomization list will be prepared prior to study onset
      by a statistician unassociated with the study. Randomization will be stratified by study
      centre.

      Primary endpoint: Comparison of the immediate vs delayed group in the % change from baseline
      in BMD at the lumbar spine at week 48 and 96.

      Secondary endpoints: Will compare changes between the immediate and delayed group from data
      collected at screening or baseline and weeks 48 and 96.

        -  change from baseline in BMD at hip Changes in Bone architecture as determined by
           Trabecular bone scan (TBS) and HRpQCT (high resolution peripheral quantitative
           computerized tomography) (Toronto site) Changes in 10 year fracture risk determined by
           country specific FRAX® (fracture risk assessment) calculator

        -  with HIV-1 RNA <50 c/ml Change from baseline in geriatric functional measures: frailty,
           performance and balance Change from baseline in muscle quality: Sarcopenia - grip
           strength measured by a Dynamometer Change from baseline in lipid values and Framingham
           cardiovascular risk scores Changes in renal tubular and glomerular function: GFR
           (glomerular filtration rate), Creatinine, urine albumin /creatinine and
           protein/creatinine, glucosuria Safety (clinical and laboratory adverse events) Changes
           in biomarkers of inflammation, coagulation and bone metabolism Tolerability (EuroQoL
           questionnaire)
    

Intervention name(s): tenofovir-alafenamide-emtricitabine; tenofovir-emtricitabine
Intervention type(s): Drug; Drug
Intervention description(s): comparison of tenofovir-emtricitabine and tenofovir-alafenamide-emtricitabine on bone mineral density; comparison of tenofovir-emtricitabine and tenofovir-alafenamide-emtricitabine on bone mineral density
Other intervention name(s): Descovy; Truvada
Intervention MeSH terms: Tenofovir; Emtricitabine
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary purpose: Treatment
Keywords: kidney, antiretroviral agent, tenofovir, osteoporosis, women