Bone Health in Aging HIV Infected Women

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.

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)

Eligibility Criteria:
Inclusion Criteria:

1. Biological female aged 40-60
2. Documented HIV-1 infection
3. Peri-menopausal ( as documented by history).
4. Signed Informed Consent Form and willing to comply with the protocol.
5. Receiving a cART regimen containing a ritonavir boosted PI (darunavir, atazanavir, lopinavir,) or an NNRTI (efavirenz, nevirapine or rilpivirine) or an integrase inhibitor (dolutegravir or raltegravir or elvitegravir) in combination with TDF-FTC for \> 24 weeks.
6. Stable viral suppression (plasma HIV-RNA\<50 copies/mL for \> 24 weeks). Single viral blip \<500/ml allowed if re-suppresses.
7. If of childbearing potential, is using effective birth control methods and is willing to continue during the trial.
8. Women will be assessed for vitamin D and calcium dietary intake; if inadequate for age, supplements will be recommended.

Exclusion Criteria:

1. HIV-2
2. High 10-year fracture risk at baseline ( \> 20%) based on country specific FRAX
3. Current treatment with active bone medications- bisphosphonates, denosumab, calcitonin, raloxifene, teriparatide, strontium
4. Current use of systemic steroids ( inhaled steroids permitted) or chemotherapeutic agents
5. Acute viral hepatitis
6. Chronic hepatitis C with liver transaminases \>5 x ULN or expected to require treatment for hepatitis C during the trial period.
7. Any investigational ARV within 30 days.
8. Dialysis or renal insufficiency (creatinine clearance \< 50ml/min)
9. History of decompensated liver disease (AST or ALT≥5x the upper limit of normal (ULN) or ALT ≥ 3 x ULN and bilirubin ≥ 1.5 x ULN with \> 35% direct bilirubin), or the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices.
10. Pregnant or breastfeeding
11. Screening blood result with any grade 3/4 toxicity according to Division of AIDS (DAIDS) grading scale, except: asymptomatic grade 3 amylase, creatinine phosphokinase, or lipid elevation.
12. Any condition (including illicit drug use or alcohol abuse) or lab results which, in the investigator's opinion, interfere with assessments or completion of the trial.