Clinical trial NCT02815566
Conditions: Osteoporosis HIV Menopause
Keywords: kidney, antiretroviral agent, tenofovir, osteoporosis, women
Sponsor: University Health Network, Toronto
Start date: 2017-09-12; Completion date: 2021-02-25
Enrollment: 34 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

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)

Arms: arm 1: Open label tenofovir-alafenamide (25/10mg)-emtricitabine (200mg) tablet once daily by mouth for 96 weeks arm 2: 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
Interventions: intervention 1: tenofovir-alafenamide-emtricitabine intervention 2: tenofovir-emtricitabine
Intervention descriptions: intervention 1: comparison of tenofovir-emtricitabine and tenofovir-alafenamide-emtricitabine on bone mineral density intervention 2: comparison of tenofovir-emtricitabine and tenofovir-alafenamide-emtricitabine on bone mineral density

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
Protocol IN-CA-311-3963/CTN 299: Version 5.0 Date: March 19, 2019 
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Study Title: 
BonE health in ageING Women: Improvement or prevention of changes in Bone Mineral 
Density by Switching Antiretroviral Agents.  Is there an optimal time to intervene?  
Protocol #: IN-CA-311-3963/CTN 299  
 
 
   
 
Protocol Version: V 5.0 
Date of protocol: March 19, 2019 
Sponsor-Principal Investigator: Dr. Sharon Walmsley, University Health Network 
Funding: Gilead Sciences and CIHR Canadian HIV Trials Network 
Clinical Trials.gov Identifier:  NCT02815566 
 
Principal Investigators: 
Dr. Sharon Walmsley 
13EN room 214; 200 Elizabeth Street 
Toronto, Ontario, Canada, M5G2C4 
T: 416-340-5077 
F: 416-340-9105 
Email: sharon.walmsley@uhn.ca 
 
Giovanni Guaraldi, MD 
Department of Medical and Surgical Sciences for Children & Adults 
University of Modena and Reggio Emilia 
Largo del Pozzo ,71 
41124 Modena, Italy 
T: +39 059 422 5318 
Mail: giovanni.guaraldi@unimore.it 
 


 
 
 
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Medical Monitor: 
Dr. Mona Loutfy 
Women and HIV Research Program 
Women's College Research Institute 
76 Grenville Street, Room 6403 
Toronto, ON  
T: 416-351-3732 ext. 2784 
F: 416-351-3746 
 
 
 


 
 
 
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GCP Statement 
This clinical study will be conducted in accordance with applicable Health Canada regulations, 
International Conference on Harmonisation (ICH) guidelines on current Good Clinical Practice 
(GCP), and the Declaration of Helsinki. 
 
Confidentiality Statement 
This clinical study protocol contains information which is of a confidential, trade-secret or 
proprietary nature. The protocol is for the use of Dr. Sharon Walmsley and her designated 
representatives participating in the investigational trial. It is not to be disclosed to any other 
person or party without the prior written approval of Dr. Sharon Walmsley 
 
 
 
 
APPROVED 
Sponsor-Investigator 
Dr. Sharon Walmsley 
Signature 
 
Date 
 
 
 
 


 
 
 
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INVESTIGATOR AGREEMENT 
 
Protocol Title:  BonE health in ageING women: Improvement or prevention of changes in Bone 
Mineral Density by Switching Antiretroviral Agents. Is there an optimal time to intervene? 
Protocol No.: IN-CA-311-3963/CTN 299 
Date: March 19, 2019 
This clinical study will be conducted in accordance with applicable Health Canada, European 
Medicines Agency (EMA) regulations, ICH guidelines on current GCP, and the Declaration of 
Helsinki. 
 
I confirm that I have read and understand this protocol and I agree to conduct this clinical study 
in accordance with the design and specific provisions of the protocol, with the exception of a 
change intended to eliminate an immediate hazard to participants. Any deviation from the study 
protocol will be documented in the case report form. 
 
I agree to promptly report to the applicable ethics boards any changes in the research activity and 
all unanticipated problems involving risks to human participants or others. Additionally, I will 
not make any changes in the research without prior ethics and sponsor approval, except where 
necessary to ensure the safety of study participants. 
 
 
 
 
 
 
 
 
Name  
Signature 
 
Date (dd-mmm-yyyy) 
  


 
 
 
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Schematic of Study Design  
 
 Biological female aged 40- 60 
 Documented HIV-1 infection 
Peri-menopausal or within 10 years of 
menopause 
Signed informed consent form and willing 
to comply with protocol 
 cART regimen containing ritonavir boosted 
PI or NNRTI or an II in combination with TDF-
FTC for > 24 weeks 
Stable viral suppression (HIV-RNA <50 
copies/ml) for > 24 weeks 
 If of childbearing potential, using effective 
birth control methods and willing to continue 
during trial 
Assessed for vitamin D and calcium dietary 
intake; if inadequate for age, supplements 
recommended 
 
 HIV-2 
 High 10-yr fracture risk at baseline 
 Current treatment with active bone 
medications 
 Current use of systematic steroids 
 Acute viral hepatitis 
 Chronic HCV or expected to require HCV 
treatment during trial period 
 Any investigational ARV within 30 days 
 Dialysis or renal insufficiency 
 History of decompensated liver disease or 
presence of ascites, encephalopathy, 
coagulopathy, hypoalbuminemia, esophageal 
or gastric varices 
 Pregnant or breastfeeding 
 Screening blood result with any grade 3/4 
Immediate switch from TDF/FTC to 
TAF/FTC 
TDF/FTC 
Switch to 
TAF/FTC 
1:
Primary Endpoint: Comparison of % 
change from baseline in BMD at spine at 
week 48  
Screening 
W0 
W48 
W96 


 
 
 
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ABBREVIATIONS AND DEFINITIONS 
Acronym / Abbreviation 
Definition 
AE 
ARV 
BMD 
CaMos 
cART 
Adverse Event 
Antiretroviral 
Bone Mineral Density 
Canadian Multicentre Osteoporosis Study 
Combination antiretroviral therapy 
DAIDS 
Division of Aids (table for grading severity of adverse events) 
DXA 
Dual Energy X-ray Absorptiometry 
F/TAF or TAF/FTC 
FTC 
FRAX® 
HATS 
HCV 
HIV 
HRpQCT 
IATA 
Tenofovir alafenamide – coformulated with Emtricitabine 
Emtricitabine 
Algorithm for calculating fracture risk 
HIV Adherence Treatment Scale 
Hepatitis C virus 
Human immunodeficiency virus 
High-resolution peripheral quantitative computed tomography 
International Air Transportation Association 
ICJME 
International Committee of Medical Journal Editors 
NNRTI 
PI 
Non-nucleoside reverse transcriptase inhibitor 
Protease Inhibitor 
RCT 
SAE 
SPPB 
TAF 
TBS 
TDF 
TDF/FTC 
Randomized Controlled Trial 
Serious Adverse Event 
Short performance physical battery 
Tenofovir alafenamide 
Trabecular bone score 
Tenofovir disoproxil 
Tenofovir disoproxil/ emtricitabine 
VAS 
Visual Analogue Scale 
 
 
 


 
 
 
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Table of Contents 
 
1.0 
BACKGROUND AND SCIENTIFIC RATIONALE.................................................................................... 10 
1.1 
Introduction ................................................................................................................................. 10 
1.2 
Study agent .................................................................................................................................. 10 
1.3  
Rationale for this Study ............................................................................................................... 11 
1.4 
Potential risks and benefits to participants ................................................................................. 12 
2.0 
STUDY SYNOPSIS .............................................................................................................................. 14 
3.0 
STUDY HYPOTHESIS ......................................................................................................................... 15 
4.0 
STUDY OBJECTIVES .......................................................................................................................... 15 
4.1 
Primary objectives: ...................................................................................................................... 15 
4.2.  
Hypothesis generating objectives:............................................................................................... 15 
5.0 
STUDY DESIGN ................................................................................................................................. 15 
5.1 
Study population: ........................................................................................................................ 15 
5.2 
Intervention: ................................................................................................................................ 15 
5.3 
Randomization ............................................................................................................................. 15 
5.4 
Primary endpoint: ........................................................................................................................ 16 
5.5 
Secondary endpoints ................................................................................................................... 16 
5.6 
Justification of Endpoints: ........................................................................................................... 16 
6.0 
ELIGIBILITY CRITERIA ........................................................................................................................ 18 
6.1 
Inclusion Criteria .......................................................................................................................... 18 
6.2 
Exclusion Criteria ......................................................................................................................... 19 
7.0 
STUDY EVALUATIONS AND PROCEDURES ....................................................................................... 20 
7.1 
Clinical Evaluations ...................................................................................................................... 20 
7.2 
Participant Identification Number Assignment ........................................................................... 21 
7.3 
Imaging ........................................................................................................................................ 21 
7.4 
Laboratory Evaluations ................................................................................................................ 21 
7.5 
Stored Research Samples ............................................................................................................ 21 
7.6 
Adherence .................................................................................................................................... 22 
7.7 
Questionnaires (in Appendix) ...................................................................................................... 22 


 
 
 
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7.8 
Transportation of Laboratory Samples ........................................................................................ 22 
8.0 
STUDY VISITS .................................................................................................................................... 22 
8.1 
Screening visit: ............................................................................................................................. 22 
8.2 
Baseline Visit for Participants ...................................................................................................... 23 
8.3 
Follow-up Visits for Participants .................................................................................................. 24 
8.4 
Final Study Visit (Week 96 +/- 14 days) ....................................................................................... 25 
8.5 
Early Termination......................................................................................................................... 25 
8.6 
Re-contact of Participants after Study Termination .................................................................... 25 
8.7 Schedule of Procedures ..................................................................................................................... 26 
9.0. STUDY DRUG ......................................................................................................................................... 29 
9.1  Study Drug Accountability ................................................................................................................ 29 
10. 
EARLY TERMINATION ....................................................................................................................... 30 
11. 
ASSESSMENT OF SAFETY .................................................................................................................. 30 
11.1 
Adverse Events (AEs) ................................................................................................................... 30 
11.2 
Recording/ Documentation of AEs .............................................................................................. 30 
11.3 
Serious Adverse Events (SAEs) ..................................................................................................... 31 
11.4 
AE/SAE Grading, Relationship Assignment and Reporting Procedures....................................... 31 
11.4.1  
AE/SAE Grading .................................................................................................................... 31 
11.4.2  
Relationship Assessment ..................................................................................................... 32 
11.4.3 
 SAE Reporting Procedures .................................................................................................. 32 
11.5 
AEs/SAEs monitoring ................................................................................................................... 33 
11.6 
Toxicities/ Adverse Event Management ...................................................................................... 33 
11.7 
Management of HIV Virologic failure. ......................................................................................... 34 
11.8 
Pregnancy Management .............................................................................................................. 34 
11.9 
Action to be taken if pregnancy occurs ....................................................................................... 34 
11.10  
Pregnancy Reporting ............................................................................................................... 34 
12. 
TRIAL MANAGEMENT ...................................................................................................................... 35 
12.1 
Local Coordination ....................................................................................................................... 35 
12.2 
Central Coordination ................................................................................................................... 35 
12.3 
Communication............................................................................................................................ 35 
13.0 
DETAILS OF STATISTICAL ANALYSIS ................................................................................................. 35 


 
 
 
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13.1. 
Sample size considerations ...................................................................................................... 35 
13.2 
Primary analysis: .......................................................................................................................... 36 
13.3  
Secondary analyses: ................................................................................................................. 36 
15. 
ETHICS AND PROTECTION OF HUMAN PARTICIPANTS .................................................................... 38 
15.1 
ICH Guidance E6:.......................................................................................................................... 38 
15.2 
Research Ethics Board/ Institutional Review Board .................................................................... 38 
15.3 
Informed consent process ........................................................................................................... 38 
15.4 
Subject confidentiality ................................................................................................................. 38 
15.5 
Early Termination of the Protocol ............................................................................................... 39 
15.6 
Record Retention ......................................................................................................................... 39 
16.0 
PROTOCOL DEVIATIONS .................................................................................................................. 39 
17.0 
STUDY CONDUCT AND MONITORING.............................................................................................. 39 
18.0 
 MANAGEMENT RESPONSIBILITIES .................................................................................................. 40 
19.0 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA DOCUMENTS ............................................ 40 
20. 
DISCLOSURE AND PUBLICATION POLICY ......................................................................................... 40 
21. 
STUDY TEAM ROLES AND RESPONSIBILITIES ................................................................................... 41 
22. REFERENCES ........................................................................................................................................... 43 
23.  APPENDIX A-Methodology………………………………………………………………………………………………………………47 
 
 
 
 


 
 
 
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1.0 
BACKGROUND AND SCIENTIFIC RATIONALE 
1.1 
Introduction 
With health advances from combination antiretroviral therapy (cART) management of comorbid 
illness is now a major focus of research and clinical care of HIV infected persons.1,2. 
Osteoporosis is a systemic skeletal disease with an increase in bone fragility and susceptibility to 
fracture3. HIV independently contributes to low bone mineral density (BMD) through viral, 
immune, inflammatory and ART-related effects on bone metabolism.4, 5  
The Canadian Multicentre Osteoporosis Study (CaMos) estimates the prevalence of osteoporosis 
at the lumbar spine in the general population of women > age 50 to be 12.1%.6  The most serious 
manifestation is a fragility fracture, defined as a fracture occurring spontaneously or following 
minor trauma. The consequences of fracture include increased mortality, morbidity, 
institutionalization and economic costs. There is a  25% risk of death in the year following a hip 
fracture  with  excess risk continuing into the second year.7The HIV population is aging with > 
50% now over 50 years.  Osteoporosis is higher in HIV relative to the general population, is 
greater in severity and increases with age.8, 9  
Although greater BMD losses are seen with initiation of cART including tenofovir (TDF) 
relative to other antiretroviral agents10-2, the co-formulation of TDF/FTC (emtricitabine) is the 
preferred NRTI backbone for most cART regimens and hence the majority of HIV patients are 
exposed to TDF, often for many years.13 Greater BMD losses are seen when cART is initiated 
with this agent, possibly due to a form of immune reconstitution syndrome14.  Further BMD loss 
occurs with continued use likely due to an effect on osteoclastic activity10. Cohort studies have 
observed an increased fracture risk with use of this agent especially with age. 15,16 The relative 
importance of low BMD to clinical care differs significantly between countries and regions, 
based on factors such as the population at risk, access to adequate screening resources and 
physicians’ knowledge.17 There are no guidelines as to whether BMD should be monitored 
differently in HIV than the general population, whether HIV alone is an independent factor to be 
used in fracture risk assessment nor whether TDF should be discontinued if osteoporosis 
develops on therapy.10 In many situations, it is not safe to stop TDF for risk of loss of HIV 
control. 
1.2 
Study agent   
As a prodrug, tenofovir disoproxil fumarate is initially metabolised to tenofovir, which is 
subsequently metabolised in cells to tenofovir-diphosphate. Although intracellular tenofovir-
diphosphate is responsible for the drug's antiviral activity, higher circulating plasma levels of 
tenofovir have been associated with an increased risk of both renal and bone toxicity. A novel 
tenofovir prodrug tenofovir alafenamide results in roughly four times higher intracellular 
concentrations of the active metabolite tenofovir-diphosphate compared with tenofovir 
disoproxil fumarate, allowing for much lower doses of tenofovir alafenamide versus tenofovir 
disoproxil fumarate. Because of tenofovir alafenamide's reduced dose and the improved stability, 


 
 
 
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plasma exposure of tenofovir is 90% lower with tenofovir alafenamide than with tenofovir 
disoproxil fumarate, which is believed to reduce the risk of renal and bone toxicity.18 Initial 
licencing studies compared a co-formulation of TDF/FTC with an integrase inhibitor elvitegravir 
boosted by cobicistat (Stribild) to a similar co-formulation of elvitegravir, cobicistat and 
TAF/FTC19. The non -inferior viral suppression rates, CD4 count increases, rate and spectrum of 
adverse events, and resistance profiles with failure led to the approval of the latter as Genvoya20, 
recently in use in Canada. Of note, Initiation of cART with TAF/FTC was shown to cause 
statistically significant lesser BMD losses, and smaller declines in glomerular renal function than 
TDF/FTC 19. The lower serum level is thought the reason for potential less bone and renal 
toxicity.  
Subsequent studies that evaluated a switch from TDF/FTC to TAF/FTC in HIV infected persons 
with viral suppression, the absence of viral resistance and with a variety of third cART agents 
were associated with a small but statistically significant increase in BMD21-3 in largely younger 
male populations. Although BMD assessment with dual energy x-ray absorptiometry (DXA) is 
well established for the diagnosis of osteoporosis and for fracture risk assessment in 
postmenopausal women it is not validated in young men.14 Therefore it remains uncertain 
whether these changes will be clinically relevant. 
1.3  
Rationale for this Study 
TAF (co-formulated with FTC) as a fixed tablet regimen is recently licenced in Canada24 and 
Europe. It will be unclear for treating physicians and policy makers whether all HIV+ who 
require TDF/FTC should be switched to TAF/FTC. It is anticipated that the cost will be similar 
to the current price for TDF/FTC (approximately $1000 CAN per month), however generic 
TDF/FTC will soon be available and will be considerably cheaper. Statistically significant 
increases in BMD that are not linked to clinical outcomes will be insufficient to guide that 
decision. 
Given sample size considerations and time to fracture endpoints, clinical validation studies are 
not possible.  Further, it is unknown whether BMD can be improved in aging HIV+ women 
through cART switching. Demonstrating changes in BMD that correlate with fracture risk in a 
population of older HIV infected women in whom BMD data is validated with fracture risk will 
provide better evidence.  To better understand the potential impact, in this study we also include 
new bone imaging modalities – trabecular bone score 25and HR-pQCT26 that collect further 
information about bone microarchitecture and bone strength to more fully understand changes in 
bone health. There is emerging evidence that changes detected by these new imaging modalities 
are independently associated with fracture risk. In previous work we showed an excess of 
fragility fractures in HIV infected women despite similar BMD scores.27 suggesting that other 
parameters are important to evaluate risk. Since women experience sharp declines in BMD 
during menopause, the potential for improved bone health through adjustment of HIV therapy 
may reduce future health burdens associated with osteoporosis 


 
 
 
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1.4 
Potential risks and benefits to participants 
Tenofovir alafenamide as an individual agent has been administered to more than 40 HIV-positive 
participants in two separate studies. In study GS-US-120-1101, participants received higher doses 
of TAF (50 mg and 150 mg) than the TAF dose in this study. Side effects that were seen in more 
than two participants were headache, nausea, and gas (flatulence). In study GS-US-120-0104, 
adverse events observed in more than two participants were nausea and fatigue. One serious 
adverse event of chest pain was reported, but not considered related to study drugs.28  
In addition, F/TAF has been given to over 3000 HIV infected participants in switching studies21-3.  
In these trials, there was no new toxicity observed relative to TDF/FTC and less than 1 % had to 
discontinue medication secondary to adverse events.  The most frequently described adverse 
events occurring in more than 5% of persons included headache, diarrhea, nasal congestion, and 
fatigue. 
A study in dogs detected eye problems (posterior uveitis- inflammation in the back of the eye) in 
some dogs when TAF was given at the highest doses.  There have not been cases of uveitis related 
to TAF in clinical studies. 28  
TAF is a drug similar to Tenofovir disoproxil fumarate (TDF), Viread®, an approved medication 
by the FDA for the treatment of HIV and hepatitis B infection29. The side effects for TAF are 
expected to be similar to Viread®.  The side effects for Viread® are listed below. 
Tenofovir DF (TDF, Viread®) 
Tenofovir DF has been studied in more than 12,000 HIV-infected adults for as long as 480 weeks 
in some patients. Common potential side effects identified in patients who received at least 
one dose of tenofovir DF 300 mg include diarrhea, nausea, vomiting, flatulence (intestinal gas), 
and dizziness.  Those side effects were often mild or moderate in severity, and did not lead to 
discontinuation of tenofovir DF.29  
 
In addition to side effects reported from clinical trials the following side effects have also been 
identified after tenofovir DF was approved by the FDA and Health Canada in HIV-infected 
patients treated with combination therapy that has included tenofovir DF and other anti-HIV drugs. 
Because post marketing (after regulatory licensing) reactions are reported voluntarily from a 
patient population of uncertain size, it is not always possible to reliably estimate how frequently 
these side effects occurred, or establish a causal relationship to tenofovir DF. The side effects 
which have been reported with tenofovir DF when taken with other anti-HIV drugs include:   
• allergic reaction  
• rash 
• abdominal pain 
• pancreatitis  
• shortness of breath 
• weakness 
• abnormalities of hepatic 
(liver) function and 
hepatitis (inflammation 
of liver). 


 
 
 
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Cases of lactic acidosis, hepatosteatosis, including fatal cases, were reported in HIV-infected 
patients treated with anti-retroviral agents similar to tenofovir DF. The symptoms of lactic acidosis 
include:  
• weakness 
• nausea 
• unexpected and uncommon abdominal 
pain 
• vomiting 
 
Symptoms of liver problems include: 
• yellowing of the skin or 
whites of the eyes 
• light 
colored 
bowel 
movements 
• loss of appetite 
• dark urine 
• nausea 
• lower abdominal pain 
 
Cases of kidney damage have been reported in patients taking tenofovir DF who already have 
atherosclerosis, or specific kidney disease, and patients who, while receiving tenofovir DF, were 
also taking medications that may cause damage to the kidneys. Kidney damage has also been 
reported in patients without any of these factors.   In addition, continuous or sudden kidney failure, 
abnormal kidney function, inflammation of the kidneys, protein in the urine, excessive urination, 
nephrogenic diabetes insipidus, and increased creatinine have also been reported in patients taking 
tenofovir DF. 
Bone toxicity, including a decrease in bone mineral density was seen in animals following 
treatment with tenofovir DF. Decreases in bone mineral density have been seen in humans. The 
risk of bone fractures associated with these types of changes is unknown. 
Because these events have been reported voluntarily from a population of unknown size, estimates 
of frequency cannot be made. 
Emtricitabine (FTC, Emtriva®)30 
The most common adverse reactions seen in greater than or equal to 10% of patients treated with 
FTC include: 
• headache 
• depression 
• weakness 
• diarrhea 
• trouble sleeping 
• increased cough 
• nausea 
• abnormal dreams 
• runny nose 
• fatigue 
• rash 
 
• dizziness 
• abdominal pain 
 
Other common side effects seen more than 1% and less than 10% with emtricitabine include: pain, 
weakness, vomiting, indigestion, changes in skin color primarily on the palms and/or soles, 
increased triglycerides, increased bilirubin, increased blood glucose, allergic reaction, increased 
liver enzymes , increased pancreatic enzymes and low white blood cell count.   


 
 
 
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Rare cases of lactic acidosis, and hepatosteatosis were reported in HIV-infected patients treated 
with anti-HIV medications similar to emtricitabine.  
Allergic Reaction Risks 
As with taking any drug, there is a risk of allergic reaction.  
Blood Draws 
Drawing blood from a vein may cause local pain, bruising, occasional light-headedness, fainting, 
and very rarely, infection at the site of the blood draw. 
DXA 
Decreases in bone mineral density have been observed in HIV-infected patients10. An X-Ray called 
dual energy X-ray absorptiometry, or a DXA scan, will be performed on spine and hip to measure 
changes in bone mineral density. The radiation exposure is lower than with a chest x-ray. The 
DXA scans are considered, in general, less harmful than a standard x-ray31  
 
HRpQCT 
This scan provides different types of information about bone strength and structure. Measurements 
are done on one forearm and one ankle and are performed when seated in a chair. This exposes 
participants to a small amount of radiation similar to that of the DXA scan31.  This test will only 
be available at selected participating sites. 
 
Hepatitis B and C Testing Risks 
Participants will be tested for Hepatitis C and B at the screening visit, if not previously recorded. 
The results of these tests, if active, must be reported to the local health authority, such as Public 
Health.  
2.0 
STUDY SYNOPSIS 
This is 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. The study will be conducted in five  
Canadian (University Health Network, Vancouver Infectious Diseases Centre, Centre Hospitalier 
de l'Université Laval, McGill University Health Centre, Hamilton Health Sciences Centre,  and 
two Italian centres  (Modena metabolic clinic and Milan clinic) by HIV physicians with interest 
and expertise in women’s issues in HIV care. The Maple Leaf medical clinic in Toronto will 
refer all their participants to the UHN site for study procedures. 


 
 
 
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3.0 
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 ARV. 
4.0 
STUDY OBJECTIVES 
4.1 
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. 
4.2.  
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. 
5.0 
STUDY DESIGN 
This study is open-label 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 groups with respect to country.  
5.1 
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 40 - 60 years.32  They must be on a cART 
regimen containing TDF/FTC with HIV RNA <50 c/ml for at least 6 months. 
5.2 
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.  
5.3 
Randomization 
A computer-generated randomization list will be prepared prior to study onset by a  
statistician/programmer at the CIHR Canadian HIV Trials Network.  Randomization will be 
stratified by country. Site coordinators will each be given a personal code through which they 


 
 
 
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can access the web randomization system.  When a site coordinator has identified an eligible, 
consenting participant, s/he will access the web page, register the participant and indicate non-
nominal information linked to the participant. The computer will record date and time of the 
transaction, the participant information and allocation, which will be issued to the coordinator. 
5.4 
Primary endpoint:  
Comparison of the immediate vs delayed group in the % change from baseline in BMD at the 
lumbar spine at week 48.   
5.5 
Secondary endpoints  
We 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 lumbar spine at 96 weeks  
% change from baseline in BMD at hip at 48 weeks 
% change from baseline in BMD at hip at 96 weeks 
Changes in Bone architecture as determined by Trabecular bone scan (TBS)25 and 
HRpQCT 26    
 
Changes in 10 year fracture risk determined by country specific FRAX calculator33 
% with undetectable viral load HIV-1 RNA as per current assays. (This may be < 50/ml, 
< 40/ml or viral load not detected) 
Change from baseline in geriatric functional measures: frailty, performance and balance  
Change from baseline in muscle quality:  Sarcopenia – grip strength measured by a 
Dynamometer and fat free mass measure (from the DXA) 
 
Change from baseline in lipid values and Framingham cardiovascular risk scores  
Changes in renal tubular and glomerular function: eGFR, Cr, urine alb/cr and protein/cr, 
glucosuria  
 
Safety (clinical and laboratory adverse events)  
 
Changes in biomarkers of inflammation, coagulation and bone metabolism  
Tolerability (EuroQoL questionnaire)  
5.6 
Justification of Endpoints: 
Primary Endpoint: BMD assessment with dual energy x-ray absorptiometry (DXA) is well 
established for the diagnosis of osteoporosis and for fracture risk assessment in postmenopausal 
women7. For BMD measurements to be clinically useful, they are expressed in comparison with 


 
 
 
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established normative databases. BMD is expressed as a numerical value (g/cm2). Change in 
BMD is considered a valid intermediate end point for efficacy of fracture risk reduction7. To 
inform the site and timing of the primary endpoint, data from studies of biphosphonates (a major 
therapy for osteoporosis) was used in which the increase in BMD is greatest at the lumbar spine, 
with one half of the gain of BMD achieved within 6–12 months followed by a lower increase 
over subsequent years34 
Secondary Endpoints: New imaging modalities are increasingly incorporated into studies of 
osteoporosis to gain more detailed information on bone strength.  
Trabecular bone score (TBS) is a recently-developed analytical tool that performs novel 
measurements on lumbar spine DXA images, and captures data relating to trabecular 
microarchitecture25. Low TBS is consistently associated with an increase in both prevalent and 
incident fractures that is partly independent of both clinical risk factors and BMD. TBS has 
predictive value for fracture independent of probabilities using the FRAX® algorithm.33  
High-resolution peripheral quantitative computed tomography (HRpQCT) is a new method 
that can determine both bone geometric parameters (such as cortical thickness, trabecular 
thickness, trabecular separation and trabecular number) and BMD (such as total, cortical and 
trabecular volumetric BMD).This technology offers a non-invasive method to gain unique 
insights into bone microarchitecture that are not obtainable using routine DEXA and can provide 
additional 3-dimensional information about bone architecture that is associated with fracture, 
even among those with similar DXA results.26  Given  limited availability it will only be 
performed at selected participating sites. 
As BMD does not add details on overall function or provide data on clinical outcomes, we 
include a broader geriatric assessment of study participants including:  
1. Sarcopenia with a combined definition of fat free mass measure (from the DXA) and muscle 
grip strength obtained with a handheld dynamometer35  
2. Frailty measured with some components from a Frailty Index. 
3. Short performance physical battery test (SPPB) to assess balance, and walking speed 37 
4. Fall frequency, assessed using self-administered questionnaire validated in the 2008 National 
Health Interview Survey Dizziness and Balance Supplement.38  
Increasingly biomarkers are studied with the goal to identify surrogate markers for use in 
interventional studies where clinical endpoints are less frequent.   Many of the comorbidities 
seen with aging in HIV may be a consequence of persistent immune activation and inflammation 
despite control of HIV replication.  Therefore we propose to collect samples to enable further 
analysis of putative biomarkers to be correlated with BMD changes.4, 39-41 


 
 
 
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1. Biomarkers of bone formation and resorption- to include - C-terminal cross-linked 
telopeptide of type I collagen (CTX) procollagen 1 N terminal extension peptide (P1NP) , 
vitamin D, Ca 41 
2. Biomarkers of immune activation and inflammation which could include- (CD38+CD8+ 
and CD4+T cells), inflammatory cytokines (IL-1b, IL-6, MCP-1, TNF), endothelial activation 
(sICAM-1, sVCAM-1) and the acute phase reactant hsCRP. 39-40We are currently conducting a 
systematic review of the published literature to inform the optimal measures...  Panels of the 
most appropriate measures will be conducted at study end. 
The second major reported toxicity of TDF is renal insufficiency 42-3.   As improvements are 
reported with TAF, measures of renal glomerular and tubular function are included as 
secondary outcomes.  TDF has a more favourable lipid profile than TAF, and we will also assess 
lipid parameters and cardiovascular risk scores. 
6.0 
ELIGIBILITY CRITERIA 
6.1 
Inclusion Criteria – all criteria must be met 
1. 
Biological female aged 40 – 60   
2. 
Documented HIV-1 infection by means of any one of the following: 
i. Documentation of HIV diagnosis in the medical record by a licensed 
health care provider;  
 
ii. OR HIV-1 RNA detection by a licensed HIV-1 RNA assay 
demonstrating >1000 RNA copies/mL; 
 
iii. OR any licensed HIV screening antibody and/or HIV 
antibody/antigen combination assay confirmed by a second licensed 
HIV assay such as a HIV-1 Western blot confirmation or HIV rapid 
Multispot antibody differentiation assay. 
 
3. 
Peri-menopausal or within 10 years of menopause (based on history) 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, raltegravir or elvitegravir) in combination with TDF-FTC for > 24 weeks.   
i. Participants on a single tablet regimen containing TDF/FTC are able to 
participate as long as they meet the virologic suppression criteria. 
1.  For those who are on elvitegravir/cobicistat/tenofovir disoproxil 
fumarate/emtricitabine (EVG/c/TDF/FTC), they will either remain on 
their current regimen or switch to elvitegravir/cobicistat/tenofovir 
alafenamide/emtricitabine (EVG/c/F/TAF). 


 
 
 
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2. For those who are on rilpivirine/tenofovir disoproxil 
fumarate/emtricitabine (RPV/TDF/FTC), they will either remain 
on RPV/TDF/FTC or switch to rilpivirine/tenofovir 
alfenomide/emtricitabine (RPV/F/TAF). 
3. For those on other single tablet regimens, if no component needs to 
be changed they will need to switch to TDF/FTC and the third 
agent in the STR as separate tablets prior to randomization. If the 
third agent needs to be changed they will need to switch to 
TDF/FTC plus the new third agent and show continued evidence of 
viral suppression for one month prior to randomization. For 
example: those on atripla would need to switch to TDF/FTC plus 
efavirenz and be randomized immediately or switch to TDF/FTC 
plus dolutegravir and remain suppressed for one month before 
randomization. 
ii. Those who are on more than 3 agents are eligible provided they meet these 
criteria. 
6. 
Stable viral suppression (plasma HIV-RNA<50 copies/mL for > 24weeks). Single viral 
blip <500 copies/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. 
 
6.2 
Exclusion Criteria - if any are present the participant cannot be included  
1. 
HIV-2 
2. 
High 10-year fracture risk at screening ( > 20%) based on country specific FRAX 
3. 
Current treatment with active bone medications- bisphosphonates, denosumab, 
calcitonin, raloxifene, teriparatide, stontrium 
4. 
Current use of systemic steroids (inhaled steroids permitted) or chemotherapeutic 
agents 
5. 
Acute viral hepatitis   
6. 
Chronic hepatitis C with AST and/or ALT >5 x ULN or expected to require HCV 
treatment 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  


 
 
 
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11. 
Screening blood result with any grade 3/4 toxicity according to Division of AIDS 
(DAIDS) grading scale, except: asymptomatic grade 3 amylase, CPK, 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.  
7.0 
STUDY EVALUATIONS AND PROCEDURES 
7.1 
Clinical Evaluations 
Once a candidate for screening has been identified, study details will be carefully 
discussed with the potential participant. The participant will be asked to read and sign the 
approved informed consent form prior to any assessments being performed. 
Medical history, documented HIV test results, and demographic information will be 
obtained at the screening visit. Data will be collected on age, race, HIV risk factor, 
smoking history, exercise habits, prior fractures, calcium and vitamin D intake, illicit 
drug use, alcohol, steroid use, ARV history, past medical illness, medications, menstrual 
history, obstetrical history, weight, body mass index. The FRAX calculator will be used 
to estimate 10 year fracture risk. 
Routine investigations will include viral load, CD4, haematology, biochemistry, lipids, 
endocrinology, renal monitoring. These are investigations that are typically performed as 
part of standard of care at 3 month intervals and will not be done specifically for study 
purposes but the data will be collected and recorded. Hepatitis B and C status will be 
recorded. 
A complete physical exam, including vital signs will also be performed at the screening 
visit.  A brief physical exam, including vital signs, will be performed as per site local 
practices at subsequent visits. Information pertaining to medication review, and adverse 
events will be collected as indicated in Table 1 (Appendix A). 
Information regarding the antiretroviral regimens including time of starting ART and 
type of drugs will be recorded. While on the study, ART switching, adherence to ART or 
stopping ART for any reasons will also be documented. 
Sarcopenia will be determined with a combined definition of fat free mass measure (from 
the DXA) and muscle grip strength obtained with dynamometer 
Short performance physical battery test (SPPB) will be performed to assess walking 
speed and balance. 


 
 
 
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7.2 
Participant Identification Number Assignment 
Participant Identification (ID) numbers will be assigned sequentially to each participant 
who is eligible to participate in the study. Participants who are not eligible for the study 
will not be assigned a Participant ID Number. The Participant ID Number will consist of 
a three digit centre number and a three digit number according to chronological order of 
entry at each centre. Details for assigning Participant ID Numbers will be provided in the 
Operations Manual. Log(s) should be completed by each site to capture all participants 
who have consented and who have been assigned a participant identification number. If a 
patient discontinues from the study the Participant ID Number will not be reused. 
The Participant ID Numbers will be used for identification of participants in the source 
documentation, CRFs, and laboratory samples. This will ensure that participant data and 
laboratory samples leaving the study sites will be identified and tracked. 
7.3 
Imaging 
Participants will complete DXA scans at the local site. Specific software will be used to 
calculate the trabecular bone score at selected sites.  Participants enrolled at selected 
participating sites will undergo HRpQCT.  
7.4 
Laboratory Evaluations  
Blood samples will be obtained for clinical laboratory evaluations on the days specified 
in Table 1 (Appendix A). Routine investigations will include HIV viral load, CD4 cell 
counts, complete blood count (CBC) with differential and measurements of hepatic 
(AST, ALT, ALP, GGT, bilirubin, albumin) and renal function (creatinine, GFR, 
urinalysis, urine albumin, Ur albumin/Cr, and Ur Protein/cr), urine and serum phosphate), 
calcium, glucose and lipid profiles ( triglyceride, LDL, HDL, TC/HDL). These are 
investigations that are typically performed as part of standard of care at 3 month intervals 
and will not be done for study purposes but the data will be collected and recorded. 
Plasma HIV RNA levels will be measured at local laboratories with a lower limit of 
detection as per current assays. (This may be < 50/ml, < 40/ml or viral load not detected). 
Clinical laboratory evaluations for hematology, biochemistry, CD4/CD8, viral load and 
serology will be performed at site local laboratories as per local practices.  
7.5 
Stored Research Samples 
Blood samples will be aliquoted, frozen and stored in order to perform biomarker testing 
at a later date. As this field is rapidly evolving, not all tests are currently known or 
developed but the frozen samples will be used only for HIV research purposes and testing 
related to this study. The samples will not be made available to any commercial 
enterprise. Stored samples will be identified only by a code number and will be destroyed 
after 10 years. 


 
 
 
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7.6 
Adherence  
For self-reports of adherence will use the Visual Analogue Scale44 (VAS last week and/or 
last month) which measures item ratings by participants in percentile terms from 0 to 
100% and using a descriptor, for subjective perception of adherence in the last day, week, 
two weeks, and month. We will also collect self-reported adherence with the HIV 
Adherence Treatment Scale (HATS)45. We will corroborate self-reported measure with 
objective outcome measurements such as returned pill counts. 
7.7 
Questionnaires (in Appendix) 
English and Italian questionnaires  
Frailty measured with some components from Frailty Phenotype  
Quality of life using the EuroQoL EQ-5D 46 
Fall frequency, assessed using self-administered questionnaire validated in the 2008 
National Health Interview Survey Dizziness and Balance Supplement47 
7.8 
Transportation of Laboratory Samples 
Stored samples for biomarkers will be transported from all sites to the UHN laboratory of 
Dr Rupert Kaul. Details for sample shipment will be provided in the laboratory manual. 
All shipments will be prepared by qualified individuals ensuring that all shipments are 
packed and shipped according to IATA regulations for the shipment of infectious and 
dangerous goods. 
All samples will be clearly labelled and must be accompanied with a copy of a shipment 
list. Prior to shipment of samples, the sites will notify the laboratory regarding the date of 
shipment to ensure receipt of the shipment. 
8.0 
STUDY VISITS 
8.1 
Screening visit:  
The screening visit is anticipated to require 1-2 hours of the participant’s time. 
During this visit the following will take place: 
• 
Informed Consent 
• 
Assign Participant ID Number 
• 
Demographic Information 
• 
Medical History 
• 
Physical Exam 


 
 
 
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• 
Calcium and Vitamin D intake assessment 
• 
FRAX Score determined by country specific FRAX calculator 
• 
Framingham Cardiovascular Risk Score 
• 
Vital Signs including height, weight and determination of BMI 
• 
HIV Viral load (within 1 month of screening date) 
• 
Serum Pregnancy test and FSH (if post-menopausal) 
• 
Hepatitis B and C (only if not previously tested) 
• 
Hematology and biochemistry: CBC with differential and liver profile 
(AST, ALT, serum creatinine, Urinalysis, GFR, Urine albumin/creatinine, 
urine protein/creatinine) (within 1 month of screening date) 
• 
Medication Review 
• 
Review of Eligibility Criteria 
•       Dexa scan will be scheduled before baseline visit. (Dexa scan should be 
completed prior to Randomization.). 
8.2 
Baseline Visit for Participants  
Day 1- Week 0 (no more than 30 days after screening visit date) 
This visit must occur within 30 days of the screening visit. (Note: If baseline visit 
is within 2 weeks of screening labwork, then available screening lab results may 
be used and duplicate lab work need not be recollected).  This visit is anticipated 
to require 2 hours of the participant’s time. A baseline visit should be scheduled if 
the eligibility criteria met, at which the following events will take place: 
• 
Confirmation that eligibility criteria have been met 
•       Confirm Dexa Scan has been completed.  
• 
Urine Pregnancy test (if premenopausal) 
• 
Randomization 
• 
Targeted Physical Exam 
• 
Vital Signs 
•       Framingham Cardiovascular Risk Score 
• 
Hematology and biochemistry: CBC with differential and liver profile 
(AST, ALT), serum creatinine, calcium, phosphate, Urinalysis, GFR, 


 
 
 
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Urine albumin/creatinine, urine protein/creatinine, lipids- cholesterol, 
LDL, HDL, TG, glucose) 
• 
CD4/CD8 
• 
HIV Viral Load 
• 
Research Blood Sample 
• 
Study Drug dispensation 
• 
Questionnaires: all questionnaires/adherence scales should be completed 
to include, quality of life, frailty, and falls 
• 
Medication review  
•       Trabecular bone score (TBS) will be determined from the screening DXA 
at selected participating sites 
 
•       Participants at selected participating sites will have HRpQCT  scan  
 
•       Grip strength with the dynamometer 
 
•       Tests of balance and gait - balance tests, gait speed, chair stand  
 
8.3 
Follow-up Visits for Participants 
These will occur at weeks 4, 12, 24, 36, 48, 52, 60, 72, 84 and 96.   At weeks 4, 
12, 24, 36, 52, 60, 72, and 84, the participants will have routine investigations as 
per the study site, and will complete targeted physical exams. Complete physical 
exams, labwork as outlined in the schedule of Assessments on pages 25 – 26, and 
FSH (if premenopausal) will be required at weeks 48 and 96. Adverse events will 
be captured at each study visit as will any changes in clinical conditions or 
medications.  Pill counts of returned study drug except week 52 will also be 
captured. The accepted windows around study visits are +/- 7 days.  The 
procedures will last about 60 minutes. 
If they agree, participants will continue to be followed even if they decide to stop 
the study medication 
At weeks 48 and 96 all participants will complete the study imaging, collection of 
plasma specimens for marker banking, quality of life questionnaires, FRAX score 
as determined by country specific FRAX calculator, Framingham cardiovascular 
risk score, and geriatric measures as above. The additional procedures will last 


 
 
 
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approximately 30 minutes plus imaging time. The imaging is to be scheduled 
within 4 weeks of these visit dates. 
Drug dispensation will be done every 3 months during the regular visits at W0, 
12, W24, W36, W48, W60, W72, and 84. At week 48, all participants will receive 
open label TAF/FTC.   
8.4 
Final Study Visit (Week 96 +/- 14 days) 
The duration of the study is 2 years per participant. Participants will be recruited 
during the first year of the study and will be followed for 96 weeks. The final visit 
will be the participant’s last follow-up visit and the following assessments will 
take place: 
• Complete Physical Exam 
• Vital Signs 
• Hematology and biochemistry: CBC with differential and liver profile 
(AST, ALT), serum creatinine, calcium, phosphate, Urinalysis, GFR, 
Urine albumin/creatinine, urine protein/creatinine, lipids- cholesterol, 
LDL, HDL, TG, glucose. CD4/CD8 
• Urine pregnancy test and FSH (if premenopausal) 
• HIV Viral Load 
• Research Blood Sample 
• 
Questionnaires- quality of life, adherence, falls, balance  
• 
Frax Score determined by country specific FRAX calculator 
• 
Framingham Cardiovascular Risk Score 
•  
• Medication review: ART and Other Concomitant Medications 
• Imaging as per study site: DXA, TBS, HRpQCT 
• Geriatric assessment, with questionnaires (frailty, quality of life, 
balance, falls), dynamometer, performance walking test. 
To collect any information on potential adverse event reaction, patients will be 
called 4 weeks after their last visit at 96 weeks +/- 7 days. 
8.5 
Early Termination 
If a participant withdraws from the study early, documentation for reason of early 
termination is required. Investigations will be completed as per final visit. 
8.6 
Re-contact of Participants after Study Termination 
Study results will be made known to the site investigators. As per site practices 
and IRB/REB requirements, site investigators will be responsible for 
disseminating the information to participants who participated in the study. 


 
 
 
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8.7  
Schedule of Procedures  
 
Study Weeks 
 
 
 
 
W0 
W4 
W12 
W24 
W36 
W48 
W52 
W60 
W72 
W84 
W96/End 
of Study 
W100 
Study Visits 
Screening 
 (-30 days) 
 
Baseline 
(screening 
+ 30 days 
 
 
 
 
 
 
 
 
 
 
 
Visit Duration 
1-2 hours 
2 hours 
1 hour 
1 hour 
1 hour 
1 hour 
1-2 hours 
1 hour 
1 hour 
1 hour 
1 hour 
1-2 hours 
Phone call 
Informed Consent Form 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Assign Subject ID number 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
FRAX and Framingham Score 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam1 
Signs/ Symptoms 
X (complete) 
X 
X 
X 
X 
X 
X (complete) 
X 
X 
X 
X 
X (complete)  
Vital Signs including height, 
weight and determination of 
BMI 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Pregnancy test (if 
premenopausal), FSH 
X2 
X 
X 
X 
X 
X 
X2 
X 
X 
X 
X 
X2 
 
 HIV viral load 3 
X 
X3 
X3 
X 
X 
X 
X3 
X3 
X 
X 
X 
X3 
 
CD4/CD8 count3 
 
X3 
 
X 
X 
X 
X3 
X 
X 
X 
X 
X3 
 
Hematology and 
biochemistry: CBC with 
differential and liver profile 
(AST, ALT, serum creatinine, 
calcium, phosphate,  
Urinalysis, GFR, Urine 
albumin/creatinine)3 
*X 
X3 
X 
X 
X 
X 
X3 
X 
X 
X 
X 
X3 
 
HBsAg, anti-HBcAb, HBsAb, 
HCV antibody4 
X4 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
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Study Weeks 
 
 
 
 
W0 
W4 
W12 
W24 
W36 
W48 
W52 
W60 
W72 
W84 
W96/End 
of Study 
W100 
Fasting glucose/cholesterol3 
 
X3 
 
 
 
 
X3 
 
 
 
 
X3 
 
Research blood sample 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
Study Drug dispensation 
 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
Study Drug Accountability 
(pill counts) 
 
 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
Questionnaires/assessments 
(calcium & vitamin D5,  
quality of life, adherence,  
frailty, falls, balance) 
X5 
X 
 
 
 
 
X 
 
 
 
 
X 
 
Concomitant Medication 
review 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Dexa scan6  
X6 
 
 
 
 
 
X 
 
 
 
 
X 
 
Trabecular bone score 
determined from DXA 
(participating sites) 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
HRQCT scan (participating 
sites) 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
Grip strength with 
dynamometer 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
Test of balance and gait-
balance tests, gait speed, 
chair stand 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
Capture adverse events or 
changes in clinical 
conditions/medications 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1 Targeted physical exam except at Screening, Weeks 48 and 96/end of study 
2 Serum pregnancy and FSH for all participants at screening. Urine pregnancy at all other visits, and FSH at Weeks 48 and 96/end of study for pre-menopausal women only 


 
 
 
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3 Screening lab results may be within 1 month of screening visit.  Lab collection and results as per site Standard of Care, except at Weeks 0, 48 and 96 (end of study) where lab 
collection and results are required. Repeat viral load and safety assessments should be done at Weeks 4 and 52. 
4 HBV and HCV status to be tested at screening only if NOT previously done 
5 Calcium & Vitamin D assessment should be done at Screening. All other questionnaires at Weeks 0, 48 & 96/end of study 
6 Baseline Dexa Scan should be completed prior to baseline visit 


 
 
 
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9.0. STUDY DRUG 
Participants will take a single tablet of FTC/TDF (300/200mg) or FTC/TAF (200/10 mg) if the 
third agent is a ritonavir boosted protease inhibitor, or 200mg/25 mg if the third antiretroviral 
agent is an NNRTI, raltegravir or dolutegravir) 24 once daily orally with the recommended dose 
of the co-administered third agent. For those previously on EVG/c/TDF/FTC or RPV/TDF/FTC, 
you will continue to receive EVG/c/TDF/FTC or RPV/TDF/FTC, or switch to EVG/c/F/TAF or 
RPV/F/TAF.  
After 48 weeks all participants will take a single tablet of FTC/TAF (200mg/10 mg if the third 
agent is a ritonavir boosted protease inhibitor or 200mg/25 mg if the third agent is an NNRTI, 
raltegravir or dolutegravir), EVG/c/F/TAF, or RPV/F/TAF once daily.  
Study drug will be donated by Gilead. Study drug will be packaged in bottles containing 30 
tablets, silica gel desiccant and polyester packing material. Each bottle will be enclosed with a 
polypropylene screw cap. To ensure stability the drug should not be stored in any other container 
than that supplied. The study drug bottles will be labelled to meet all the applicable requirements 
of the EU guidelines to good manufacturing practice, Health Canada and the US food and drug 
administration. The bottles should be stored at a controlled room temperature of 25C (77F) with 
excursions permitted to between 15C and 30C).  Storage conditions will be specified on the 
labels. 
Until dispensed to participants, all bottles of study drug will be stored in a securely locked area, 
accessible only to authorized study personnel. 
The third ARV agent of the participants pre-existing regimen should be taken and stored 
according to the approved product labeling for each particular component. 
9.1 Study Drug Accountability 
The investigator at each site is responsible to ensure adequate accountability of all used and 
unused study products. The investigator or designated central pharmacy will acknowledge 
receipt of the study drugs from Gilead after reviewing the shipment’s content and condition.  
Study sites will acknowledge receipt of study drugs from the UHN Central Pharmacy after 
reviewing the contents and condition of the shipment. The investigator or designee will be 
responsible for maintaining an accurate inventory of the dates and quantities of all study drugs 
received, dispensed and returned. Each dose of the study drug administered by the qualified 
study centre personnel will be accurately recorded on logs which indicate the date and quantity 
of all doses dispensed.  These logs will be available for inspection by study monitors.  Study 
medication supplies must be accounted for by the study monitor prior to destruction or return. 


 
 
 
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10. 
EARLY TERMINATION 
Participation in the study will be terminated early if: the participant refuses further treatment 
and/or follow-up evaluations; the study staff or participant’s medical provider determines that 
further participation in the study would be detrimental to the participant’s health or well-being; 
the participant is non-compliant with the study requirements in a manner that is either 
detrimental to her health or interferes with the validity of the study results; the patient has viral 
failure and requires an alternative antiretroviral regimen ( the viral load that requires a change in 
therapy will be at discretion of the investigator), or the sponsor terminates the study.  
11. 
ASSESSMENT OF SAFETY 
11.1 Adverse Events (AEs) 
Adverse events (AEs) are defined as any untoward medical occurrence in a participant that does 
not necessarily have a causal relationship with the study medication/intervention. An AE can 
therefore be any unfavourable and unintended sign (including abnormal laboratory finding), 
symptom, or disease temporally associated with the use of study drug/intervention, whether or 
not it is related to the medication/intervention. 
Toxicities will be graded on a 4-point scale according to standard guidelines outlined in the 
“Division of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events” 
48[Appendix C]. In general, grade 1 and 2 events will not be considered adverse events, but 
details should be documented in the source documents. Fractures will be considered and captured 
as an adverse event regardless of grading. 
Stable chronic conditions which are present prior to clinical study entry and do not worsen are 
not considered adverse events and will be accounted for in the participant’s medical history. 
Participants who have an adverse event should be followed and treated by the site Investigator 
until the abnormal parameter or symptom has resolved or stabilized. It is up to the clinician to 
determine that the AE is either resolved or that is has reached a stable state, after which no 
further follow-up is necessary. There should also be source documentation to support this 
determination. 
Rates of adverse events, serious adverse events and hospitalisations will be compared between 
the two arms. Specific attention will be paid to HIV RNA (see below), CD4 cell counts, and 
metabolic parameters such as fasting glucose, and lipid profiles. 
The most common adverse reactions of moderate to severe intensity and incidence ≥2% in those 
receiving TAF are headache, fatigue, nasal congestion and diarrhea. 
11.2 Recording/ Documentation of AEs 
At each contact with the participant, information regarding adverse events will be elicited by 
appropriate questioning and examinations, and will be recorded immediately on a source 


 
 
 
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document (e.g., progress notes, laboratory reports, survey tools, and data collection tools). The 
start date, stop date, severity of each reportable event, and the PI’s judgment of the AE’s 
relationship to the study medication/intervention will also be recorded in the case report form 
(CRF). 
11.3 Serious Adverse Events (SAEs) 
A Serious Adverse Event is defined as an AE meeting one of the following: 
• 
Death during the period of protocol-defined surveillance 
• 
Life Threatening Event (immediate risk of death at the time of the event) 
• 
In-patient hospitalization or prolongation of existing hospitalization during the period of 
protocol-defined surveillance 
• 
Results in congenital anomaly or birth defect 
• 
Results in a persistent or significant disability/incapacity 
• 
Any other important medical event that may not result in one of the above outcomes may 
be considered a serious adverse event when: based upon appropriate medical judgment, the event 
may jeopardize the participant, and may require medical or surgical intervention to prevent one 
of the outcomes listed above. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias, or convulsions 
that do not result in in-patient hospitalization, or the development of drug dependency or drug 
abuse or any event of possible drug-induced liver injury with hyperbilirubinemia defined as 
ALT>3xULN and bilirubin >2xULN (>35% direct)  
Any AE that occurs between baseline and 30 days following the last study visit at Week 96 (or at 
the time of early discontinuation of the participant from the study for any reason) is to be 
recorded in the source documentation (patient will be called). Surveillance for AEs will end at 30 
days following Week 96. If an SAE is ongoing at the time a participant discontinues/completes 
the trial the SAE will be followed until the Investigator agrees that the event is satisfactorily 
resolved, becomes chronic, or that no further follow-up is required. 
11.4 AE/SAE Grading, Relationship Assignment and Reporting Procedures 
11.4.1  AE/SAE Grading  
The intensity (severity) of each adverse/serious event will be graded according to the toxicity 
table and toxicity guidelines provided by the Division of AIDS (DAIDS) Table for Grading the 
Severity of Adult and Pediatric Adverse Events.  The DAIDS Table will be provided with the 
Operations Manual. 


 
 
 
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11.4.2  Relationship Assessment 
For all collected AEs (including SAEs), the clinician who examines and evaluates the participant 
will determine the AE’s causality based on temporal relationship and his/her clinical judgment. 
The degree of certainty about causality will be graded using the categories below: 
Definitely Related: There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test 
result, occurs in a plausible time relationship to drug administration and cannot be explained by 
concurrent disease or other drugs or chemicals. The response to withdrawal of the drug (de-
challenge) should be clinically plausible. The event must be pharmacologically or 
phenomenologically definitive, with use of a satisfactory re-challenge procedure if necessary. 
Probably Related: There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely. The clinical event, including an abnormal laboratory test result, occurs within 
a reasonable time sequence to administration of the drug, is unlikely to be attributed to 
concurrent disease or other drugs or chemicals, and follows a clinically reasonable response on 
withdrawal (de-challenge). Re-challenge information is not required to fulfill this definition. 
Possibly Related: There is some evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time after administration of the trial medication). However, the 
influence of other factors may have contributed to the event (e.g., the participant’s clinical 
condition, other concomitant events). Although an adverse drug event may rate only as “possibly 
related” soon after discovery, it can be flagged as requiring more information and later be 
upgraded to “probably related” or “definitely related”, as appropriate. 
Unlikely: A clinical event, including an abnormal laboratory test result, whose temporal 
relationship to drug administration makes a causal relationship improbable (e.g., the event did 
not occur within a reasonable time after administration of the trial medication) and in which 
other drugs or chemicals or underlying disease provides plausible explanations (e.g., the 
participant’s clinical condition, other concomitant treatments). 
Not related: The AE is completely independent of study drug administration, and/or evidence 
exists that the event is definitely related to another etiology. There must be an alternative, 
definitive etiology documented by the clinician. 
11.4.3  
SAE Reporting Procedures 
The Investigator or designee must report any SAE occurring in a patient receiving study drug to 
the Sponsor within 24 hours, even if the SAE is not drug-related. This should be done by 
telephone and by sending a faxed or emailed copy of the Serious Adverse Event form plus other 
supporting documentation, as required. 
SAEs will be reported to: 
Immunodeficiency Clinic 


 
 
 
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University Health Network 
Attention: Rosemarie Clarke, Research Nurse Manager 
Phone: 416-340-4800 ext. 6723 or 416-340-5077  
Fax:  416-340-9105 
E-mail: rosemarie.clarke@uhn.ca 
All additional follow-up evaluations must also be reported as soon as possible in the same 
manner. All SAEs will be followed until the Investigator agrees that the event is satisfactorily 
resolved, becomes chronic, or that no further follow-up is required. 
The Sponsor or designee will be responsible for notifying the relevant authorities of any 
reportable SAE as outlined in the Canadian Food and Drug Regulations and ICH Guidelines.  
The Sponsor will also ensure that other participating Investigators are notified of any SAEs. The 
Investigator is responsible for ensuring that their local Research Ethics Board (REB) is notified 
of any SAEs. 
11.5 AEs/SAEs monitoring 
Any AE/SAE that occurs between baseline and the time the participant departs the study at the 
end of the final follow-up visit (or at the time of early discontinuation of the participant from the 
study for any reason) will be captured and recorded in the source documentation. At each contact 
with the participant, the investigator (or designate) must seek information on adverse events by 
specific questioning and, as appropriate, by examination.  
Adverse events that had previously been reported by the study participant will also be reassessed 
for duration, intensity and possible reoccurrence. Assessment of safety will include clinical 
observation and monitoring of routine hematology and biochemistry. 
Surveillance for AEs will end 30 days post Week 96 (or at the time of early discontinuation of 
the participant from the study for any reason). If an SAE is ongoing at the time a participant 
discontinues/completes the study, the SAE will be followed up until the Investigator agrees that 
the event is satisfactorily resolved, becomes chronic, or that no further follow-up is required. 
11.6 Toxicities/ Adverse Event Management  
In the event of a discontinuation of TAF/FTC for suspected renal impairment, or other clinically 
significant chemistry elevations, participants should not restart TDF/FTC or TAF/FTC due to the 
risk of a recurrent reaction; such participants should be withdrawn from study and seek/be 
reviewed for alternative antiretroviral therapy. If they agree, participants will continue to be 
followed for the duration of the study. 


 
 
 
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11.7 Management of HIV Virologic failure. 
Virologic failure must be considered for any patient with plasma HIV RNA ≥50 c/mL at any 
time following randomization. For the purposes of clinical management in this study, virologic 
failure is defined as: 
Two consecutive plasma HIV RNA ≥50 c/mL within four weeks of the initial suspected 
virologic failure. 
Cases of confirmed virologic failure will trigger genotypic virologic resistance testing, including 
integrase resistance testing, when plasma HIV RNA >400c/mL. The virologic failure definition 
is intended for guidance and Investigators should use their discretion as to the most appropriate 
clinical management of their patients. The choice of antiretroviral therapy will be left to the 
discretion of the treating physician. In some cases, e.g. if there is no evidence of acquired 
resistance to the current regimen, treatment may be continued with increased efforts at adherence 
support. 
11.8 Pregnancy Management 
As this study is enrolling peri and post-menopausal women the risk of pregnancy is extremely 
low. 
11.9 Action to be taken if pregnancy occurs 
Any participant who becomes pregnant during the study must be immediately withdrawn from 
TAF/FTC to eliminate further exposure to the embryo/foetus.   
11.10  Pregnancy Reporting 
If pregnancy occurs during the period of protocol-defined surveillance, while it is not considered 
an adverse event or serious adverse event requires monitoring and follow up. The investigator 
must report the pregnancy information for trial participants using a pregnancy CRF. The 
pregnancy should be followed up by the investigator until delivery. To ensure participant safety, 
each pregnancy must be reported within one week of learning of its occurrence.  The pregnancy 
must be followed up to determine outcome (including premature termination) and status of 
mother and child, which must also be reported using a pregnancy outcome CRF.  Pregnancy 
complications and elective terminations for medical reasons must be reported as an AE or SAE.  
Spontaneous abortions must be reported as an SAE. 
Any SAE occurring in association with a pregnancy brought to the investigator’s attention after 
the participant has completed the study and considered by the investigator as possibly related to 
the investigational product, must be promptly reported. 
[Investigators are also encouraged to report any pregnancy that occurs during study participation 
to the Antiretroviral Pregnancy Registry. More information including copies of applicable CRFs 
and fax numbers are available at www.apregistry.com.] 


 
 
 
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12. 
TRIAL MANAGEMENT 
12.1 Local Coordination 
Each collaborating investigator will be responsible for recruiting study personnel, obtaining local 
REB/IRB approval, ensuring local clinic staff are informed about the study, and supervising 
local study activities. The study personnel at the site will be responsible for: identifying 
participants; obtaining informed consent; conducting study visits; ensuring participants have 
regular follow-up; encouraging attendance at visits; telephoning participants if visits are missed; 
and collecting participant data. A study manual will outline methods for CRF completion and 
record management. Personnel will also be trained on study procedures prior to and during the 
study. The informed consent forms and study questionnaires will be translated into Italian and 
French.   
12.2 Central Coordination 
A Project Manager will coordinate the day-to-day management of the study. A computerized 
study database will be created by an appointed Data Manager and managed at the data 
management centre at the CIHR Canadian HIV Trials Network.  Electronic CRFs will be used. 
12.3 Communication 
Regular investigator meetings will be planned by teleconference to keep study personnel 
informed of study progress, and to encourage ongoing recruitment. Brief updates will be 
provided to meet enrolment targets. The information on criteria for study participation will be 
posted on the websites of the different clinical centres.   
13.0 DETAILS OF STATISTICAL ANALYSIS 
13.1. Sample size considerations 
128 women, 64 per group, are required to detect a difference of 1% in the annual change in spine 
BMD at 48 weeks between those randomized to immediate switch to TAF/FTC vs those 
randomized to delayed switch to TAF/FTC with a two sample t test, assuming a standard 
deviation (SD) of 2%, 80% power and a significance level of .05.   The difference of 1% is 
believed to be a clinically important difference to detect. The expected rate of loss in BMD in 
peri- and post-menopausal women is 1-3% per year.     
The SD in the % change in BMD was estimated from several studies of BMD in HIV+ 
individuals.   Yin et al 49 compared longitudinal changes in BMD in pre and post-menopausal 
HIV+ and uninfected women in two separate cohorts. In the premenopausal period annual % 
decrease in BMD was not different in HIV+ and HIV- at the lumbar spine (LS) (-0.8 +/-2.1% vs 
0.4 +/-1.9%, p=.20) and remained similar after adjusting for traditional risk factors.  In the 
postmenopausal period annualized rates of bone loss adjusted for baseline BMD were higher in 
HIV+ women by 2.4 fold at the LS (-1.2 vs -0.5 %, p<.00009). In a randomized study, where 
participants were 90% men, mean age 40, switching from TDF to TAF containing regimens 


 
 
 
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showed a statistically significant increase in BMD (median(IQR) + 1.79 % (-.22%, 3.38%)vs 
0.28% loss( -2.25,1.5%), p<.001).21  Another study (85 % men, median age 49)  showed a mean 
increase in BMD of 1.5%  at 48 weeks with a switch from TDF to TAF compared to a .2% loss 
in those continuing TDF. 29A third study in persons with impaired renal function switching from 
a TDF to TAF containing regimen resulted in a mean  increase in BMD of 2.29% at the spine 
and 1.47% increase at the hip.22 
13.2 Primary analysis:   
Generalized linear mixed models (GLMM) will be used to estimate the effect of immediate vs 
delayed switch from TDF/FTC to TAF/FTC on the percent change in BMD at the spine at 48 
weeks. 
In the GLMM model of percent change in BMD at the spine, each patient shall contribute two 
data points:  the percent change in BMD at the spine at 48 weeks and the percent change in BMD 
at the spine at 96 weeks.  A variogram will be used to determine the amount of error due to 
random effects and serial correlation.  If random effects are the source of a significant amount of 
variation, terms for random intercept and random time shall be included in the model.   If serial 
correlation is determined to be the main source of error, a single parameter will be required to 
model the correlation between the week 48 and week 96 values from a single patient, since there 
will be only two BMD values per patient after enrolment. 
The model shall contain four covariates: (1) treatment arm, (2) a binary indicator for whether or 
not the data point corresponds to week 96, (3) the interaction between the treatment arm and the 
96 week indicator and (4) a binary for country (Canada vs Italy).  If sufficient woman are 
receiving hormone replacement therapy, an additional binary covariate may be included to 
capture whether or not the woman was receiving hormone replacement therapy at randomization. 
The GLMM model can be expressed as follows: 
Y = β0 + β1 treatment + β2 week 96 + β3 treatment* week 96                       (1) 
where Y is the percent change in BMD at the spine. 
The hypothesis test for the primary analysis is H0: β1 = 0, which corresponds to the primary 
hypothesis of the effect of switching from TDF to TAF on percent change in BMD at the spine at 
48 weeks. 
 
13.3  Secondary analyses:   
The secondary endpoints of greatest importance are:  the percent change in BMD at the hip at 
week 48, the percent change in BMD at the hip at week 96, and the percentage change at the 
spine at week 96. GLMM will be used to estimate the effect of immediate switch to TAF/FTC on 
these outcomes 


 
 
 
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The hypothesis test for the secondary analysis is H0: β3 = 0 in model (1) above, which 
corresponds to the secondary hypothesis of the effect of switching from TDF to TAF on percent 
change in BMD at the spine at 96 weeks. 
A similar model will be fit for the outcome of percent change in the spine. In that model, the 
hypothesis tests of H0: β1 = 0 and H0: β3 = 0 will both be of interest, corresponding to the 
secondary hypotheses of the effects of switching from TDF to TAF on percent change in BMD at 
the hip at 48 and 96 weeks, respectively. 
Interactions terms will be used to determine if the effect of switching from TDF/FTC to 
TAF/FTC on 48 week endpoints varies between peri and post–menopausal women or according 
to whether a protease inhibitor is used as the third ARV. 
Other secondary endpoints such as the change in TBS at the hip, the proportions of patients with 
viral load < 50 copies/mL and the mean eGFR at 48 and 96 weeks will be summarized over time 
by treatment group to provide preliminary information but will not be compared formally to 
avoid type 1 errors due to multiple comparisons.  
13.4. Interim analysis:  no interim analyses are planned 
13.5 
Feasibility:   The number of women on TDF/FTC aged 45-55 at UHN, MLMC, Modena 
and Milan are 48, 114, 105 and 80 respectively, for a total of 347.   We expect that 90% (n=312) 
will be eligible and of those, that 80% (n=250) women would agree to participate.  In addition 
each of the additional four Canadian sites have agreed to recruit between 5-10 participants. 
Therefore, it should thus be feasible to recruit the required 128 women within 12 months.   
13.6 
Timeline:    6 months for start- up and ethics approval, 12 months for enrollment; 24 
months for follow-up; 6 months for analysis/write-up 
13.7.  Loss to follow-up: We expect that 10% of randomized patients will drop out before 48 
weeks. Primary analyses will be conducted assuming data are missing at random. Pattern mixture 
models and selection models will be used as sensitivity analyses to determine the range of 
possible treatment effects under the assumption of not missing at random.50 
14.0 
Quality control and quality assurance 
Checks will be built into the database to alert the data manager to inconsistent data at the time of 
data entry. Site personnel will then be prompted to double-check the data. Source documentation 
will not be verified by an on-site monitor visit during the study. It is the responsibility of the 
Sponsor Investigator with the CIHR Canadian HIV Trials Network Data Management Centre to 
assure the quality of computerized data for this study. 


 
 
 
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15. 
ETHICS AND PROTECTION OF HUMAN PARTICIPANTS 
15.1 ICH Guidance E6:  
Good Clinical Practice: Consolidating Guideline/ Declaration of Helsinki.  The conduct 
of this study will conform to the International Conference for Harmonization and Good 
Clinical Practice (ICH-GCP) regulations and guidelines and the current revision of the 
Declaration of Helsinki. 
15.2 Research Ethics Board/ Institutional Review Board 
A copy of the protocol (including protocol amendments), all versions of the informed 
consents, other information to be completed by participants such as questionnaires, and 
any proposed advertising/ recruitment materials must be reviewed and approved by the 
REB/IRB of each participating centre prior to implementation of the study. The site 
investigator will be responsible for obtaining REB/IRB approval of the annual 
Continuing Review throughout the duration of the study.  The site investigator will notify 
the REB/IRB of violations from the protocol and serious adverse events.   
15.3 Informed consent process 
All participants will be given detailed oral and written information about the study. 
Consent forms describing in detail the study medications/intervention(s), study 
procedures, anticipated benefits and potential risks will be given to each participant and 
written documentation of informed consent is required prior to starting the study. 
Participants must voluntarily sign and date an informed consent document that has been 
approved by a participating centre’s REB/IRB prior to any procedures being done 
specifically for the trial. Each participant should have sufficient opportunity to discuss 
the study and consider the information in the consent process prior to agreeing to 
participate. Participants may withdraw consent at any time during the course of the trial. 
The informed consent will be signed and dated by the participant, the person who 
conducted the informed consent discussion and the investigator. The original signed 
informed consent form will be retained in the participant’s study files and a copy will be 
provided to the subject.       
15.4 Subject confidentiality 
All participant related information including the CRFs, laboratory samples, evaluation 
forms, etc. will be kept strictly confidential. All records will be kept in a secure, locked 
location and only research staff will have access to the records. Participants will be 
identified only by means of a coded number specific to each participant, and a participant 
letter code. All computerized databases will identify participants by numeric codes only, 
and will be password protected. Upon request, clinical information may be reviewed by 
or released to study monitors, auditors, or regulatory agencies.   


 
 
 
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15.5 Early Termination of the Protocol 
The REB/IRB or other government organizations, as part of their duties to ensure that 
research participants are protected may discontinue the study at any time. Regulatory 
authorities and the study Sponsor retain the authority to suspend additional enrollment for 
the entire study as applicable.  
15.6 Record Retention 
The Investigator will maintain all study records according to the ICH-GCP and applicable 
regulatory requirement(s). Records will be retained for 25 years, in accordance with 
applicable regulatory requirement(s). If the Investigator withdraws from the 
responsibility of keeping the study records, custody must be transferred to a person 
willing to accept the responsibility and the Sponsor notified. The Investigator should 
ensure that no destruction of medical records occurs without the written approval of the 
Sponsor. 
Samples collected and sent to the central laboratory will be retained for 10 years, after 
which they will be destroyed.   
16.0 PROTOCOL DEVIATIONS 
No deviations from this protocol will be permitted without the prior written approval of 
the Sponsor, except when the modification is needed to eliminate an immediate hazard or 
hazards to participants. Any deviations that may affect a participant’s treatment or 
informed consent, especially those increasing potential risks, must receive prior approval 
from the REB unless performed to remove an immediate safety risk to the participants. In 
this case it will be reported to the REB and the Sponsor immediately thereafter. Any 
departures from the protocol must be documented. 
17.0 STUDY CONDUCT AND MONITORING 
The study site agrees to allow monitors direct access to the study records and medical 
records from those participants enrolled in the clinical study as well as drug 
accountability records. Monitoring for this study will consist of data management review 
focused on erroneous data, illogical entries, and missing data and central monitoring of 
clinical and operational data reviewed for outliers and trends. On-site monitoring will be 
targeted based on results of the data management and central monitoring reviews as 
necessary.  


 
 
 
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18.0 DATA  MANAGEMENT RESPONSIBILITIES 
Instructions concerning the recording of study data on case report forms will be provided 
by the CIHR Canadian HIV Trials Network. Each study site is responsible for submitting 
the data in a timely fashion. It is the responsibility of the Data Management Centre to 
assure the quality of computerized data for this study. This role extends from protocol 
development to generation of the final study databases. 
19.0 SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA DOCUMENTS 
Each participating site must maintain appropriate medical and research records for this 
study and regulatory/ institutional requirements for the protection of confidentiality of 
study participants. The Principal Investigator is responsible for assuring that the data 
collected are complete, accurate, and recorded in a timely manner.  
Study data will be collected on study specific CRFs. Source documentation should 
support the data collected on the CRFs. Source documents include all recordings of 
observations or notations of clinical activities and all reports and records necessary for 
the evaluation and reconstruction of the clinical trial. Data for CRFs will be collected 
during participant visits, phone calls with participants and health care providers, 
completed questionnaires and abstracted from the participant’s medical records. It is not 
acceptable for the CRF to be the only record of participation in the trial. 
Clear and detailed instruction explaining CRF completion and where, when and how 
CRFs are to be sent to the data centre will be included in the study Operations Manual.    
20. 
DISCLOSURE AND PUBLICATION POLICY 
Publication of the final study report is planned. The Sponsor-Investigator (Dr. Walmsley) 
will determine authorship for each manuscript based on contributions to the study design, 
study execution, and manuscript completion. No author will be included without prior 
authorization but the intention is to be broadly inclusive of all study investigators who 
make active contributions as outlined by the ICJME criteria for authorship (Authorship 
credit should be based on 1) substantial contributions to conception and design, 
acquisition of data, or analysis and interpretation of data; 2) drafting the article or 
revising it critically for important intellectual content; and 3) final approval of the version 
to be published. Authors should meet conditions 1, 2, and 3). 
   
 
 


 
 
 
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21. 
STUDY TEAM ROLES AND RESPONSIBILITIES 
Dr. Walmsley, MD is a clinician investigator with a strong and sustained (over 25 year) track 
record in the conduct of multicentre RCT in clinic HIV management. Her interest and knowledge 
translation in the field of HIV, aging and women, and her clinical practice which includes HIV 
infected aging women on TDF will strengthen recruitment and interest in this study. She directs a 
clinical research team who will conduct this study at the Toronto site. The team has participated 
in over 150 HIV related studies and have excellent recruitment and retention records. She has 
collaborations with HIV immunologist (Dr Kaul) for completion of the inflammatory marker 
studies. 
Dr. Guaraldi, MD is a clinician investigator, with extensive expertise, interest and experience in 
HIV and women and aging. He has developed and oversees the Modena HIV Metabolic clinic 
(MHMC) data base which includes 680 HIV+ women, including 131 women who he has 
evaluated in the pre-menopausal, transition, early, and late menopausal period for a total of 1577 
person-year follow-up. Approximately 60% of these women are on TDF containing regimens. 
Analysis of this data provided the framework for this study. He has expertise in conducting 
clinical trials and will supervise the participation of subjects in Italy.  He has interest and has 
published on the aging and frailty measures that will be incorporated into this study. He will also 
supervise the development, maintenance and cleaning of the database for this study.  In order to 
ensure timely recruitment to the study, Dr Castagna, MD who has a large population of HIV 
infected woman in Milan has agreed to serve as an enrolling centre for this study. Her site will be 
supervised by Dr. Guaraldi. 
Dr. Mona Loutfy, MD is an infectious diseases and HIV clinician scientist who has many 
ongoing studies and cohorts addressing issues important to HIV infected women.  In addition to 
her clinical trial expertise she has many collaborations with the infected community in Toronto 
and a strong focus and record in KTE activities. She will refer patients to the Toronto site, assist 
in the interpretation of the data, and direct the KTE resulting from this project.  
Dr. Janet Raboud, PhD statistician holds a Chair in Biostatistics from the Ontario HIV 
Treatment Network.  She has a long history of analysis of HIV research projects and clinical 
trials many in collaboration with Dr. Walmsley. She supervises a statistical team with content 
expertise who will be responsible for the analysis of this RCT. 
Dr. Joel Singer, PhD statistician is a professor in the School of Population and Public Health at 
University of British Columbia, and has been the head of Methods and Statistics at the CIHR 
Canadian HIV Trial Network since its inception in 1990.  He has a long history as a 
methodologist in HIV clinical trials as well as in other clinical disciplines. He has also served as 
member or chair of many data and safety monitoring committees  
Dr. Angela Cheung, MD, is the head of the osteoporosis unit at the University Health Network.  
She has participated on developing the Canadian guidelines on this topic.  She has expertise in 


 
 
 
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the newer imaging modalities.  She has collaborated on previous HIV related projects with the 
team.  She will advise on the imaging, bone biomarkers and outcomes.  
All members of the team will collaborate on presentations and publications arising from this 
project. 
 
 


 
 
 
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22. REFERENCES 
1. 
Samji H, Cescon A, Hogg RS, et al; for The North American AIDS Cohort Collaboration on 
Research and Design of IeDEA.  Closing the gap: increases in life expectancy among treated 
HIV-positive individuals in the United States and Canada.  PLoS One.  2013 18;8(12):e81355. 
2. 
Antiretroviral Therapy Cohort Collaboration.  Causes of death in HIV-1-infected patients treated 
with ARV, 1996-2006: collaborative analysis of 13 HIV cohort studies.  Clin Infect Dis. 2010 
May 15;50(10):1387-96. 
3. 
Expert Insight on Osteoporosis.  WHO Criteria for Diagnosis of Osteoporosis. Retrieved from: 
http://www.4bonehealth.org/education/world-health-organization-criteria-diagnosis-
osteoporosis/.  Accessed January 30, 2016. 
4. 
Wada NI, Jacobson LP, Margolick JB,, et al.  The effect of HAART-induced HIV suppression on 
circulating markers of inflammation and immune activation.  AIDS. 2015 Feb 20;29(4):463-71. 
5. 
Tenorio AR, Zheng Y, Bosch RJ, et al.  Soluble markers of inflammation and coagulation but not 
T-cell activation predict non-AIDS-defining morbid events during suppressive ART. J Infect Dis. 
2014;210(8):1248-59. 
6. 
Tenenhouse A, Joseph L, Kreiger N, et al; for the CaMos Research Group.  Estimation of the 
prevalence of low bone density in Canadian women and men using a population-specific DXA 
reference standard:  Osteoporos Int. 2000;11(10):897-904. 
7. 
Papaioannou A, Morin S, Cheung AM, et al.  2010 clinical practice guidelines for the diagnosis 
and management of osteoporosis in Canada: summary. CMAJ. 2010 Nov 23;182(17):1864-73. 
8. 
Guaraldi G, Orlando G, Zona S, et al.  Premature age-related comorbidities among HIV-infected 
persons compared with the general population.  Clin Infect Dis. 2011 Dec;53(11):1120-6. 
9. 
Brown TT, Hoy J, Borderi M, et al.  Recommendations for evaluation and management of bone 
disease in HIV.  Clin Infect Dis. 2015 Apr 15;60(8):1242-51. 
10. Brown TT, Qaqish RB.  ARV therapy and the prevalence of osteopenia and osteoporosis: a meta-
analytic review AIDS. 2006 Nov 14;20(17):2165-74. 
11. Stellbrink HJ, Orkin C, Arribas JR, et al; for the ASSERT Study Group.  Comparison of changes 
in bone density and turnover with abacavir-lamivudine versus tenofovir-emtricitabine in HIV: 48-
week results from the ASSERT study.  Clin Infect Dis. 2010 Oct 15;51(8):963-72. 
12. Woodward CLN, Hall AM, Williams IG,et al.  Tenofovir-associated renal and bone toxicity.  
HIV Med. 2009 Sep;10(8):482-7. 
13. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of 
antiretroviral agents in HIV-1-infected adults and adolescents. Department of Health and Human 
Services. Available at http://aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf. Section 
accessed on 31/01/2016. 
14. Ofotokun I, Titanji K, Vunnava A, et al.  Antiretroviral therapy induces a rapid increase in bone 
resorption that is positively associated with the magnitude of immune reconstitution in HIV 
infection.  AIDS. 2016 Jan 28;30(3):405-14 
15. Shiau S, Broun EC, Arpadi SM, Yin MT.  Incident fractures in HIV-infected individuals: a 
systematic review and meta-analysis. AIDS. 2013 Jul 31;27(12):1949-57. 
16. Calmy A, Fux CA, Norris R, et al.  Low bone mineral density, renal dysfunction, and fracture risk 
in HIV infection: a cross-sectional study.  J Infect Dis. 2009 Dec 1;200(11):1746-54. 
17. Alvarez E, Belloso W, Boyd M, Walmsley S, et al.  Which HIV patients should be screened for 
Osteoporosis: An international perspective.  Current Opinion in HIV and AIDS.  2016.  In Press. 
18. Custodio J, Garner W, Callebaut C, et al. The pharmacokinetics of tenofovir and tenofovir 
diphosphate following administration of tenofovir alafenamide versus tenofovir disoproxil 


 
 
 
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fumarate. 16th International Workshop on Clinical Pharmacology of HIV and Hepatitis Therapy. 
May 26-28, 2015. Washington, DC. Abstract 6. 
19. Sax PE, Wohl D, Yin MT, et al; for The GS-US-292-0104/0111 Study Team (Walmsley S, 
member).  Tenofovir alafenamide versus tenofovir disoproxil fumarate, coformulated with 
elvitegravir, cobicistat, and emtricitabine, for initial treatment of HIV-1 infection: two 
randomised, double-blind, phase 3, non-inferiority trials.  Lancet. 2015 Jun 27;385(9987):2606-
15. 
20. Gilead Canada.  (2016). Genvoya (elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide): 
Product monograph; Including Patient Medication Information.  Retrieved from 
http://www.gilead.ca/pdf/ca/genvoya_pm_english.pdf. 
21. Mills A, Arribas JR, Andrade-Villanueva J, et al; for The GS-US-292-0109 team.  Switching 
from TDF to TAF in ARV regimens for virologically suppressed adults with HIV-1: a 
randomised, active-controlled, multicentre, open-label, phase 3, non-inferiority study.  Lancet 
Infect Dis. 2016 Jan;16(1):43-52. doi: 10.1016/S1473-3099(15)00348-5. Epub 2015 Nov 2. 
22. Pozniak A, Arribas JR, Gathe J, et al for the GS-US-292-0112 Study Team.  Switching to 
Tenofovir Alafenamide, Coformulated With Elvitegravir, Cobicistat, and Emtricitabine, in HIV-
Infected Patients With Renal Impairment: 48-Week Results From a Single-Arm, Multicenter, 
Open-Label Phase 3 Study.  J Acquir Immune Defic Syndr. 2016 Apr 15;71(5):530-7. 
23. Gallant J, Daar E, Raffi F, et al.  Switching Tenofovir DF to Tenofovir Alafenamide in 
Virologically Suppressed Adults.  Presented at the 19th Conference on Retroviruses and 
Opportunistic Infections (CROI 2016).  Boston, MA.  February 22-25, 2016.  Abstract 29. 
24. Gilead.  (2015). Descovy (emtricitabine and tenofovir alafenamide): Product monograph.  
Retrieved from 
http://www.gilead.com/~/media/files/pdfs/medicines/hiv/descovy/descovy_pi.pdf?la=en. 
25. Harvey NC, Gluer CC, Binkley N, et al.  Trabecular bone score (TBS) as a new complementary 
approach for osteoporosis evaluation in clinical practice.  Bone. 2015 Sep;78:216-24. 
26. Cheung A, Adachi JD, Hanley Da, et al.  High-resolution peripheral quantitative computed 
tomography for the assessment of bone strength and structure: a review by the Canadian Bone 
Strength Working Group. Curr Osteoporos Rep. 2013 Jun;11(2):136-46. 
27. Prior JC, Burdge DR, Maan E, Milner R, Morris C, Walmsley S. Fragility fractures and bone 
mineral density in HIV positive women: a case-control population-based study.  Osteoporos Int 
2007 Oct; 18 (10):1345-53. 
28. Ruane P, DeJesus E, Berger D, et al.  GS-7340 25 mg and 40 mg demonstrate superior efficacy to 
Tenofovir 300 mg in a 10-day monotherapy study of HIV-1+ patients.  Presented at the 19th 
Conference on Retroviruses and Opportunistic Infections (CROI 2012).  Seattle, WA.  March 5-8, 
2015.  Abstract 103. 
29. Gilead Canada.  (2016). Viread (tenofovir disoproxil fumarate): Product monograph.  Retrieved 
from http://www.gilead.ca/pdf/ca/viread_pm_english.pdf. 
30. Gilead Canada.  (2016). Truvada (Emtricitabine/Tenofovir Disoproxil Fumarate): Product 
monograph.  Retrieved from http://www.gilead.ca/pdf/ca/truvada_pm_english.pdf. 
31. Damilakis J, Adams JE, Guglielmi G, and Link TM.  Radiation exposure in X-ray-based imaging 
techniques used in osteoporosis.  Eur Radiol. 2010 Nov;20(11):2707-14. doi: 10.1007/s00330-
010-1845-0. Epub 2010 Jun 1. 
32. Schoenbaum EE, Hartel D, Lo Y.  HIV infection, drug use, and onset of natural menopause. Clin 
Infect Dis. 2005 Nov 15;41(10):1517-24. Epub 2005 Oct 13.  
33. Siris ES, Baim S, Nattiv A.  Primary care use of FRAX: absolute fracture risk assessment in 
postmenopausal women and older men. Postgrad Med. 2010 Jan;122(1):82-90. 


 
 
 
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34. Liberman UA, Weiss SR, Broll J, et al for the Alendronate Phase III Osteoporosis Treatment 
Study Group.  Effect of oral alendronate on bone mineral density and the incidence of fractures in 
postmenopausal osteoporosis. N Engl J Med. 1995 Nov 30;333(22):1437-43. 
35. Cruz-Jentoft AJ, Baeyens JP, Bauer JM, et al.  Sarcopenia: European consensus on definition and 
diagnosis: Report of the European Working Group on Sarcopenia in Older People.  Age Ageing. 
2010 Jul;39(4):412-23. 
36. Jones D, Song X, Mitinitski A, Rockwood K.  Evaluation of a frailty index based on a 
comprehensive geriatric assessment in a population based study of elderly Canadians. Aging Clin 
Exp Res. 2005 Dec; 17(6):465-71. 
37. Puthoff ML.  Outcome measures in cardiopulmonary physical therapy: short physical 
performance battery.  Cardiopulm Phys Ther J. 2008 Mar;19(1):17-22. 
38. CDC: Centers for Disease Control and Prevention.  December 18, 2015.  National Health 
Interview Survey.  Retrieved from:  http://www.cdc.gov/nchs/nhis.htm.  Accessed January 30, 
2015.  
39. Kuller LH, Tracy R, Belloso W, et al.  Inflammatory and coagulation biomarkers and mortality in 
patients with HIV infection.  PLoS Med. 2008 Oct 21;5(10):e203. 
40. Boulware DR, Hullsiek KH, Puronen CE, et al.  Higher levels of CRP, D-dimer, IL-6, and 
hyaluronic acid before initiation of antiretroviral therapy (ART) are associated with increased risk 
of AIDS or death.  J Infect Dis. 2011 Jun 1;203(11):1637-46. 
41. Eastell R, Hannon RA.  Biomarkers of bone health and osteoporosis risk. Proc Nutr Soc. 2008 
May;67(2):157-62. 
42. Cooper RD, Wiebe N, Smith N, et al .  Systematic review and meta-analysis: renal safety of 
tenofovir disoproxil fumarate in HIV-infected patients.  Clin Infect Dis. 2010 Sep 1;51(5):496-
505. 
43. Wever K, van Agtmael MA, Carr A .  Incomplete reversibility of tenofovir-related renal toxicity 
in HIV-infected men. J Acquir Immune Defic Syndr. 2010 Sep;55(1):78-81. 
44. Kalichman SC, Amaral CM, Swetzes C, et al.  A simple single-item rating scale to measure 
medication adherence: further evidence for convergent validity.  J Int Assoc Physicians AIDS 
Care (Chic). 2009 Nov-Dec;8(6):367-74. 
45. Johnson MO, Neilands TB, Dilworth S, et al.  The role of self-efficacy in HIV treatment 
adherence: validation of the HIV Treatment Adherence Self-Efficacy Scale (HIV-ASES).  J 
Behav Med. 2007 Oct;30(5):359-70. Epub 2007 Jun 23. 
46. Wu AW, Hanson KA, Harding G, et al.  Responsiveness of the MOS-HIV and EQ-5D in HIV-
infected adults receiving antiretroviral therapies.  Health Qual Life Outcomes. 2013 Mar 
12;11:42. 
47. Johns Hopkins University: Baltimore Washington India Clinical Trials.  (2014). A5322: Long-
Term Follow-up of Older HIV-infected Adults in the ACTG: Addressing Issues of Aging, HIV 
Infection and Inflammation – HAILO.  ACTG A5322 Fall History Questionnaire.  Retrieved 
from: http://bwictu.jhu.edu/publications. 
48. National Institute of Allergy and Infectious Diseases: Division of AIDS (DAIDS).  (2004). 
Division of AIDS Table for grading the severity of adult and pediatric adverse events.  Retrieved 
from: 
http://www.niaid.nih.gov/labsandresources/resources/daidsclinrsrch/documents/daidsaegradingta
ble.pdf. 
49. Yin MT, Shi Q, Hoover DR, et al.  Fracture incidence in HIV-infected women: results from the 
Women's Interagency HIV Study.  AIDS. 2010 Nov 13;24(17):2679-86. 


 
 
 
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50. Molenberghs, G., et al. (2014). Handbook of missing data methodology (Chapman & Hall/CRC 
Handbook of Modern Statistical Methods). CRC Press. 
 
 


 
 
 
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22. 
APPENDIX A 
METHODOLOGY 
 
During the study visit at Baseline and at week 48 and 96 a partial assessment will be performed 
using the following outcome measurements: 
 
1. Physical Function. 
This is assessed using Short Performance Physical Battery (SPPB). This test consists of 
three components: balance, timed 4 m walk, and chair stands. The standing balance portion 
required participants to maintain a side-by-side, semi-tandem, and tandem stance for 10 
seconds, with scores ranging from 0 to 4 (maximum score) 1. 
The fastest time of two 4 m usual-pace walk attempts was used. The chair stands required 
participants to rise from a chair with arms across their chest for five repetitions.  
A score of less than 9 is highly predictive for subsequent disability and was considered low 
function, 9–11 points moderate function, and 12 points (no deficits) high function. 
The figure represents test task and score system: 
 
 
 


 
 
 
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2. SARCOPENIA 
Sarcopenia will be assessed using the following measurements and cut off:  
1. Muscle mass using DEXA 
 
2. Muscle strength using grip strength with handheld dynamometry using age- 
and gender specific cut-off reported in the table: 
 
 
3. Performance, using  SPPB (see above) with the following cut off points 
 
 


 
 
 
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3. Frailty 
 
Some components of frailty will be collected as follows: 
The study data base will also embed most variables utilized in a Frailty Index (FI) based on 
available measures of age-related health deficits. Based on studies of HIV-negative older adults, 
standard criteria were established for candidate health deficits in a FI. It was determined that each 
deficit should be associated with adverse health outcomes and with age, have a prevalence of at 
least 1%, and  
 
Unemployment  
 Self-report 
High or low BMI  
<18, 19 – 24,  or >25 kg/m2 
Abnormal white blood cell 
counts  
<4000 cells/ml 
Anemia  
If female: <10 g/dl 
If male: <12 g/dl 
Low platelets  
<150 billion/l 
Hepatitis C coinfection  
Positive 
Hepatitis B coinfection  
Hepatitis B antigen positive 
Elevated 
aspartate 
transaminase  
>31 U/l  
Elevated 
alanine 
transaminase  
>31 U/l 
Abnormal 
alkaline 
phosphatase  
<38 or >126 U/l 
Abnormal phosphorus 
<2.5 or >5.1 mg/dl 


 
 
 
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Elevated total bilirubin  
>1.10 mg/dl  
Polypharmacy  
>5 drug classes (excluding antiretroviral therapy) 
Current CD4 cell count  
<500 cells/ml 
Nadir CD4 cell count  
<200 cells/ml  
 HIV viral load  
>40 copies/ml 
CD4/CD8 cell ratio  
<1.0  
Duration of HIV infection 
>10 years 
Pre-HAART start  
Start of antiretroviral therapy before 1 January 1997 
History of AIDS  
History of CDC category C HIV disease [42] 
ART failure  
History of viral load > 1000 copes/ml while on ART  
 
 
 


 
 
 
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4. Fall Frequency  
 
The following questionnaire will be used to capture Fall Frequency
 


 
 
 
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References: 
1. 
Vasunilashorn, S. et al. Use of the Short Physical Performance Battery Score to predict loss of 
ability to walk 400 meters: analysis from the InCHIANTI study. The Journals of Gerontology Series 
A: Biological Sciences and Medical Sciences 64, 223–229 (2009). 
2. 
Fried, L. P. et al. Frailty in older adults: evidence for a phenotype. J Gerontol A Biol Sci Med Sci 56, 
M146–56 (2001).