Osteoporosis, HIV, Menopause
Conditions
Keywords
kidney, antiretroviral agent, tenofovir, osteoporosis, women
Brief 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)
Interventions
DRUGtenofovir-alafenamide-emtricitabine
comparison of tenofovir-emtricitabine and tenofovir-alafenamide-emtricitabine on bone mineral density
comparison of tenofovir-emtricitabine and tenofovir-alafenamide-emtricitabine on bone mineral density
Sponsors
University of Modena and Reggio Emilia
San Raffaele University Hospital, Italy
Gilead Sciences
CIHR Canadian HIV Trials Network
University Health Network, Toronto
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
FEMALE
Age
40 Years to 60 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change in Bone Mineral Density From Baseline at the Lumbar Spine | Baseline, 48 weeks and 96 weeks | The outcome measures presented are descriptive as enrollment in the clinical trial did not reach the target number of subjects needed to achieve target power and was insufficient to produce statistically reliable results. There are limited results at the week 48 timepoint due to the COVID pandemic. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| % Change in Bone Mineral Density From Baseline at the Femoral Neck | Baseline, 48 weeks and 96 weeks | The outcome measures presented are descriptive as enrollment in the clinical trial did not reach the target number of subjects needed to achieve target power and was insufficient to produce statistically reliable results. There are limited results at the week 48 timepoint due to the COVID pandemic. |
Countries
Canada, Italy
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Immediate Switch Open label tenofovir-alafenamide (25/10mg)-emtricitabine (200mg) tablet once daily by mouth for 96 weeks
tenofovir-alafenamide-emtricitabine: comparison of tenofovir-emtricitabine and tenofovir-alafenamide-emtricitabine on bone mineral density | 19 |
| Delayed Switch Open-label tenofovir (300mg)-emtricitabine (200mg) tablet once daily by mouth for 48 weeks followed by open label tenofovir-alafenamide (25/10mg)-emtricitabine (200mg) tablet once daily by mouth for an additional 48 weeks
tenofovir-emtricitabine: comparison of tenofovir-emtricitabine and tenofovir-alafenamide-emtricitabine on bone mineral density | 15 |
| Total | 34 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
| Overall Study | Lost to Follow-up | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Total | Immediate Switch | Delayed Switch |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 34 Participants | 19 Participants | 15 Participants |
| Age, Continuous | 50.6 years STANDARD_DEVIATION 3.3 | 52.0 years STANDARD_DEVIATION 3.1 | 48.8 years STANDARD_DEVIATION 2.9 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 20 Participants | 10 Participants | 10 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) White | 13 Participants | 8 Participants | 5 Participants |
| Region of Enrollment Canada | 24 Participants | 13 Participants | 11 Participants |
| Region of Enrollment Italy | 10 Participants | 6 Participants | 4 Participants |
| Sex: Female, Male Female | 34 Participants | 19 Participants | 15 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 19 | 0 / 15 | 0 / 15 |
| other Total, other adverse events | 0 / 19 | 0 / 15 | 0 / 15 |
| serious Total, serious adverse events | 2 / 19 | 0 / 15 | 0 / 15 |
Outcome results
Primary
Percent Change in Bone Mineral Density From Baseline at the Lumbar Spine
The outcome measures presented are descriptive as enrollment in the clinical trial did not reach the target number of subjects needed to achieve target power and was insufficient to produce statistically reliable results. There are limited results at the week 48 timepoint due to the COVID pandemic.
Time frame: Baseline, 48 weeks and 96 weeks
Population: Thirty-four women enrolled: 19 in the immediate and 15 in the delayed switch arm between Sept 2017 and April 2019; 30 completed the 96-week protocol. The study closed to follow up March 2021. Two participants in the delayed arm inadvertently switched to TAF at baseline and one participant in the delayed arm remained on TDF for the entire 96 weeks.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Immediate Switch | Percent Change in Bone Mineral Density From Baseline at the Lumbar Spine | 48 weeks | 1.97 Percent Change |
| Immediate Switch | Percent Change in Bone Mineral Density From Baseline at the Lumbar Spine | 96 weeks | 2.33 Percent Change |
| Delayed Switch | Percent Change in Bone Mineral Density From Baseline at the Lumbar Spine | 48 weeks | -2.32 Percent Change |
| Delayed Switch | Percent Change in Bone Mineral Density From Baseline at the Lumbar Spine | 96 weeks | 0.7 Percent Change |
Secondary
% Change in Bone Mineral Density From Baseline at the Femoral Neck
The outcome measures presented are descriptive as enrollment in the clinical trial did not reach the target number of subjects needed to achieve target power and was insufficient to produce statistically reliable results. There are limited results at the week 48 timepoint due to the COVID pandemic.
Time frame: Baseline, 48 weeks and 96 weeks
Population: Thirty-four women enrolled: 19 in the immediate and 15 in the delayed switch arm between Sept 2017 and April 2019; 30 completed the 96-week protocol. The study closed to follow up March 2021. Two participants in the delayed arm inadvertently switched to TAF at baseline and one participant in the delayed arm remained on TDF for the entire 96 weeks.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Immediate Switch | % Change in Bone Mineral Density From Baseline at the Femoral Neck | 48 weeks | 1.46 Percent Change |
| Immediate Switch | % Change in Bone Mineral Density From Baseline at the Femoral Neck | 96 weeks | 2.33 Percent Change |
| Delayed Switch | % Change in Bone Mineral Density From Baseline at the Femoral Neck | 48 weeks | 0.22 Percent Change |
| Delayed Switch | % Change in Bone Mineral Density From Baseline at the Femoral Neck | 96 weeks | 0.70 Percent Change |