The Kampala Women's Bone Study
Condition: Bone Demineralization; Hypoestrogenism; Subclinical Kidney Injury; Bone Microarchitecture
MeSH terms: Bone Demineralization, Pathologic
Study type: Interventional
Phase: Phase 4

Summary: 
      The primary objective of this study is to address critical safety questions with concurrent
      TDF-based PrEP and DMPA use. We hypothesize that young women using TDF-based PrEP and DMPA
      will have lower bone acquisition and altered bone metabolism. Bone mineral metabolism is in
      part regulated by the kidney, and we hypothesize that bone effects from concurrent PrEP and
      DMPA use will be driven by subclinical kidney injury, a known side effect of TDF, as well as
      DMPA-induced hypoestrogenism. To investigate our hypothesis, we will enroll a prospective
      cohort of approximately 500 HIV-uninfected women ages 16-25 years in Kampala, Uganda who have
      substantial HIV risk and are initiating DMPA or barrier method contraception. Over a 24-month
      period, we will offer TDF-based PrEP. We will use state-of-the-art radiologic, biochemical,
      and epidemiologic methods to test the hypothesis that concurrent TDF-based PrEP and DMPA use
      results in compounding adverse effects on bone health.
    

Detailed description: 
      The proposed research will investigate the hypothesis that TDF-based PrEP and DMPA initiated
      concurrently by HIV-uninfected women will enhance each other's effects on bone metabolism.
      The investigators will conduct an open-label prospective study of approximately 500
      HIV-uninfected women at substantial risk for HIV-infection who are newly initiating DMPA or
      using condoms as their only contraceptive in Kampala, Uganda. The investigators will offer
      PrEP to all of these women and determine the joint effect of PrEP and DMPA on changes in bone
      mass (Aim 1), bone turnover, subclinical kidney injury, and hypoestrogenism (Aim 2), and
      conduct mediation analysis to assess the contribution of each pathway to overall losses in
      bone mass (Aim 3).

        1. The investigators will assess whether young women using TDF-based PrEP and DMPA
           concurrently attain lower peak bone mass over a 24-month period and have evidence of
           disrupted microarchitecture, relative to women using either agent singly or neither
           agent The investigators will use dual energy x-ray absorptiometry (DXA) scans to measure
           BMD annually at 3 anatomical sites (lumbar spine, total hip, and wrist). Additionally,
           the investigators will derive the trabecular bone score (TBS), an index of lumbar spine
           trabecular microarchitecture.

        2. The investigators will investigate whether young women concurrently using TDF-based PrEP
           and DMPA experience: 1) higher rates of bone turnover, a direct precursor to bone loss
           and 2) subclinical kidney injury and hypoestrogenism, markers of two mechanistic
           pathways between TDF and DMPA use and bone mass

      At baseline and 24 months, the investigators will measure:

        1. Markers of bone formation and resorption (e.g. NTX, P1NP, serum intact parathyroid
           hormone, total and bioavailable 25-OH-vitamin D)

        2. Markers of kidney function (phosphate, glucose, creatinine, total protein, albumin) and

        3. Markers of estrogen (serum estradiol, sex hormone binding protein, and the occurrence of
           amenorrhea) Hypothesis: Relative to women using DMPA only and PrEP only, women
           concurrently using TDF-based PrEP and DMPA will have increased bone turnover markers and
           PTH. In addition, women concurrently using TDF-based PrEP and DMPA will have more
           frequent subclinical kidney injury (relative to women without tenofovir exposure) and
           reduced serum estrogen (relative to women without DMPA exposure).

      3. Using mediation analysis, the investigators will identify the degree to which the pathways
      through subclinical kidney injury and hypoestrogenism account for changes in bone density
      among women concurrently using TDF-based PrEP and DMPA The investigators will conduct
      mediation analysis to determine the degree to which changes in the pathways through
      subclinical kidney injury, hypoestrogenism and the combination of these pathways account for
      changes in bone density.

      Over a 24-month period, the investigators will follow women quarterly with HIV rapid testing,
      PrEP adherence counseling and refills, DMPA injections, and provision of other contraceptives
      as desired. At enrollment and quarterly visits, the investigators will assess physical
      activity, sexual behavior, and menstrual cycle characteristics. Annually, the investigators
      will conduct physical exams and anthropometric readings. Sexually transmitted infections will
      be routinely assessed syndromically, according to national guidelines. Women will be
      encouraged to consider their HIV risk and fertility desires at every visit and counseled
      about contraception and PrEP accordingly. Dual energy x-ray absorptiometry (DXA) scans will
      be performed at baseline and annually thereafter. Blood and urine samples will be obtained
      quarterly, aliquoted, and archived at minus 80o Celsius.

      DXA and TBS assessments:

      DXA scans will be conducted at study enrollment (within 1 week of contraceptive initiation),
      12, and 24 months after enrollment. DXA is the clinical standard for measuring BMD. It is
      painless and non-invasive. Women will be exposed to a relatively low level of radiation which
      is <1/10 the dose of a standard chest x-ray, and less than a day's exposure to natural
      radiation. BMD by DXA of the hip and spine is generally considered the most reliable way to
      classify osteoporosis, assess changes in BMD, and predict fracture risk. The investigators
      will measure areal BMD of the lumbar spine (L1-4), hip, and wrist, and body composition
      (total and % fat and lean mass) using a DXA machine. For the TBS analysis, no additional
      image acquisition is required. TBS will be performed as a re-analysis of the lumbar spine
      taken as part of the standard DXA procedure with specialized software.

      Contraceptive provision:

      Women will initiate contraception at the study clinic or a family planning clinic, as they
      are seeking services. Throughout study follow up, the study will assume responsibility for
      contraceptive provision, including DMPA injections, and care of all other methods desired by
      women. The staff at the IDI-Kasangati research clinic have extensive experience with the
      provision of contraception and contraceptive counseling during previous HIV prevention
      studies.

      PrEP provision and adherence monitoring

      Co-formulated emtricitabine FTC/TDF will be provided as PrEP by the study. PrEP counseling
      and provision will follow WHO guidelines, or Ugandan clinical guidelines when they are
      available. The investigators will measure adherence using three different methods:

        1. Pill counts will be conducted by the pharmacist during study visits to determine the
           percentage of expected pills that were used

        2. Real time monitoring will be conducted using an electronic monitoring system that
           captures a date-time stamp each time the pill container is opened

        3. The primary circulating form of TDF, tenofovir (TFV), will be quantified in blood
           archives from 1) a random sample of up to 15% of women who initiate PrEP to characterize
           the adherence in the cohort overall and 2) a targeted group of women who have no BMD
           change and women who experience a fracture.

      Laboratory processing to measure markers of bone turnover, subclinical kidney injury, and
      hypoestrogenism.

      Using state-of-the-art assay techniques on archival samples, the investigators will measure
      1) established markers of bone turnover and bone health, 2) markers of subclinical kidney
      injury, and 3) markers of hypoestrogenism. Archived samples will be batch-analyzed.
    

Intervention name(s): FTC/TDF and DMPA; FTC/TDF; DMPA; Neither DMPA nor FTC/TDF
Intervention type(s): Combination Product; Drug; Drug; Other
Intervention description(s): The primary analysis will be separate comparisons of the annualized rates of change in BMD and TBS of the spine and hip between women using PrEP and DMPA concurrently versus women using DMPA only (comparison 1), women using PrEP only (comparison 2), and women using neither (comparison 3). Analyses will account for baseline BMD.; The primary analysis will be separate comparisons of the annualized rates of change in BMD and TBS of the spine and hip between women using PrEP and DMPA concurrently versus women using DMPA only (comparison 1), women using PrEP only (comparison 2), and women using neither (comparison 3). Analyses will account for baseline BMD.; The primary analysis will be separate comparisons of the annualized rates of change in BMD and TBS of the spine and hip between women using PrEP and DMPA concurrently versus women using DMPA only (comparison 1), women using PrEP only (comparison 2), and women using neither (comparison 3). Analyses will account for baseline BMD.; The primary analysis will be separate comparisons of the annualized rates of change in BMD and TBS of the spine and hip between women using PrEP and DMPA concurrently versus women using DMPA only (comparison 1), women using PrEP only (comparison 2), and women using neither (comparison 3). Analyses will account for baseline BMD.
Allocation: Non-Randomized
Intervention model: Factorial Assignment
Masking: None (Open Label)
Primary purpose: Diagnostic