A Prospective Longitudinal Cohort Study to Determine the Incidence of HIV-associated Non-AIDS Conditions in Newly Diagnosed HIV-infected Individuals Initiating Integrase Inhibitor-based and Other Anti-retroviral Regimens
Conditions: HIV, Metabolic Syndrome, Osteopenia, Osteoporosis, Vitamin D Deficiency, Renal Impairment, Liver Fibroses
Sponsor: Chinese University of Hong Kong

HANA Study Protocol_V5 dated 5 Jun 2020 
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A prospective longitudinal cohort study to determine the incidence of HIV-associated non-
AIDS conditions in newly diagnosed HIV-infected individuals initiating integrase inhibitor-
based and other anti-retroviral regimens 
 
Background 
Integrase strand transfer inhibitor (INSTI) based–therapy is currently the recommended 
antiretroviral regimen in most guidelines.1-3 Efficacy in terms of virological suppression of 
INSTI-based regimens was either superior or non-inferior to other comparators in clinical 
trials performed in both treatment naïve and experienced individuals.4-6 Moreover, unlike 
other classes of anti-retroviral agents, transmitted drug resistance was uncommon even after 
years of introduction of INSTI on a population level, potentially allowing this class of drug to 
remain as recommended first-line treatment in the future.7 
 
Previous clinical trials comparing INSTIs and other anti-retroviral regimens in treatment-naïve 
individuals consistently showed lower discontinuation rates secondary to adverse 
reactions.4,8,9 For treatment-experienced individuals, switching from non-nucleotide reverse 
transcriptase inhibitor (NNRTI) or protease inhibitor (PI)-containing to an INSTI-containing 
regimen often resulted in better lipid profiles6 as well as tolerability and patient satisfaction.5 
INSTIs have been shown to improve blood pressure control in those with underlying 
hypertension receiving anti-hypertensive treatment.10 INSTI also had lesser decline in bone 
loss when compared to protease inhibitors.11 On the other hand, integrase inhibitors have 
been reported to be the cause of metabolic complications,12 and neuropsychiatric adverse 
reactions.13 Transient drop in renal function6 and other renal complications in individuals 
taking some INSTIs had also been reported.14 
 
Currently, with the availability of very effective anti-retroviral agents as well as aging of the 
HIV-infected population, management of HIV-infected individuals should also include the 
assessment, prevention and management of multiple HIV-associated non-AIDS conditions 
(HANA) that are known to be more prevalent in HIV-infected individuals.15 In Asia, many of 
these conditions, like diabetes,16 dyslipidemia,17 lipodystrophy,17 osteopenia and 
osteoporosis,18 chronic kidney disease,19 and fatty liver disease and liver fibrosis,20 and retinal 
diseases21,22 were prevalent in HIV-infected individuals. Most of these studies, however, were 
performed in individuals taking older anti-retroviral agents. Whether the increase of INSTI use 
in the region is associated with lower incidence of development of HANA is currently unknown. 
Moreover, clinical trials of anti-retroviral therapy seldom included older individuals with 
multiple co-morbid illnesses.4 Currently available real world data on clinical use of INSTI 
seldom included HANA in their evaluation.14, 23, 24 Longitudinal real world data in Asia 
evaluating the incidence of various HANA after initiation of different anti-retroviral regimens 
are also limited, despite these conditions cause significant burden of disease in the Asian 
population.15  
 
The understanding of incidence of various HANA conditions in relation to the class of anti-
retroviral drugs used will potentially aid to improve outcomes in the aging HIV-infected 
population by optimizing their anti-retroviral regimen. As data on HANA in the Asian/Chinese 
HIV-infected population is currently lacking, results of studies performed in Hong Kong which 
mainly comprises of predominantly Chinese and other Southeast/South Asian HIV-infected 

HANA Study Protocol_V5 dated 5 Jun 2020 
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individuals, would likely benefit other HIV-infected populations in China, Taiwan and other 
surrounding Asian countries.  
 
This study, therefore, aims to evaluate the incidence of various HANA conditions in a cohort 
of newly diagnosed HIV-infected individuals in Hong Kong initiating anti-retroviral treatment. 
The incidence of various HANA conditions will be evaluated for those receiving INSTI versus 
other non-INSTI-based regimens. 
 
Objectives 
• 
To determine the incidence of HANA conditions in newly diagnosed HIV-infected 
individuals initiating integrase inhibitor-based and other anti-retroviral regimens in 
an Asian population 
• 
To evaluate the risk factors associated with developing each HANA condition 
• 
To set up an electronic platform for systematic collection of clinical data and 
establishment of a clinical decision tool for clinical risk prediction and improvement 
in clinical management 
 
Clinical hypotheses 
Individuals initiating integrase inhibitor-based anti-retroviral regimens will develop lower 
incidence of HANA. 
 
Study design 
This is a prospective, longitudinal, cohort study. 400 newly diagnosed HIV-infected individuals 
attending HIV clinics in Hong Kong will be recruited. Clinical assessment, and laboratory and 
imaging studies will be performed at baseline prior to initiation of anti-retroviral regimen, 
than annually thereafter for 5 years. Choice of anti-retroviral regimen will be decided by the 
in-charge HIV physician. Incidence of development of various HANA conditions will be 
determined for those initiated INSTI-based regimens and other anti-retroviral regimens. An 
electronic platform will be used to formulate risk prediction for various clinical outcomes, and 
serve as a clinical decision support tool. 
 
Subjects and sampling 
a. Study population 
All newly diagnosed HIV-infected individuals naïve to ART meeting inclusion criteria, who 
attend the government HIV clinic, which is the largest HIV clinic in Hong Kong, will be 
invited to participate in this study. Subjects will also be referred by non-governmental 
organizations providing support to HIV-infected individuals at the time of diagnosis. 
b. Inclusion criteria: 
1. 
Confirmed HIV infection by HIV antibody or RNA test  
2. 
Age ≥18 years old 
3. 
Anti-retroviral treatment naïve,  within 6 months of initiation of anti-retroviral drugs, 
or switching ART regimens within 24 months 
4. 
Agree to initiate anti-retroviral therapy (ART) as determined by in-charge HIV 
physician 
c. Exclusion criteria: 
1. 
Pregnancy 
2. 
Refusal to consent 

HANA Study Protocol_V5 dated 5 Jun 2020 
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Data collection and investigations 
a. Eligible subjects will attend Infectious Diseases clinic at the Prince of Wales Hospital for 
assessment. 
The first study visit will be scheduled before or within four weeks of initiation of ART. Annual 
visits will be scheduled thereafter for 5 years. During each study visit, demographic and 
clinical data will be collected. Physical examination will be performed. Blood and urine tests 
will be done at fasting state. Imaging, including ultrasonography of carotid arteries, DEXA scan 
and fibroscan, will be performed. Stool samples will be collected for microbiota study.  
b. Clinical data 
A structured standardized research tool will be used to collect demographic and clinical 
data: 
1. 
Age, gender, smoking status, alcohol consumption, exercise 
2. 
Co-morbid illnesses, including history or new diagnoses of hepatitis B and C, 
diabetes, dyslipidemia, hypertension, metabolic syndrome, and cardiovascular 
diseases, as well as all comorbidities included in the Charlson comorbidity score 
3. 
Date of HIV diagnosis, latest CD4 counts, latest HIV viral load 
4. 
Medication history, including anti-retroviral drugs and other medications 
c. Physical examination and anthropometric measurements 
1. 
Body weight and height, and body mass index 
2. 
Hip and waist circumferences 
3. 
Blood pressure 
4. 
For subjects aged ≥50 years old, assessment of frailty, including hand grip strength, 
balance tests, 6-metre walking speed, will be performed  
5. 
Neurocognitive assessment 
i. 
International HIV dementia scale 
https://www.hiv.uw.edu/page/mental-health-screening/ihds25 
ii. 
Montreal Cognitive Assessment  
iii. 
Symbol digit modality test (SDMT) 
iv. 
Action fluency: ask the patient to say as many things that people do in 1 minute 
v. 
Cogstate platform neurocognitive tests 
vi. 
DASS 21 for screening of mood 
vii. 
Lawton Instrumental Activities of Daily Living 
6. 
Quality of life assessment 
i. 
EQ-5D-5L questionnaire 
7. 
Lung function test 
i. 
FEV1 and FVC will be performed in smokers. 
d. Blood tests: 
The following blood tests will be performed after an  8-hour fast: 
1. 
Glucose, insulin, HbA1c 
2. 
Total cholesterol, LDL cholesterol, HDL cholesterol, triglyceride, apolipoprotein A 
and apolipoprotein E 
3. 
Complete blood count, creatinine, urate, calcium, phosphate, urea, ferritin 
4. 
Testosterone, estradiol, luteinizing hormone, follicle-stimulating hormone, free 
thyroxine, thyrotropin, growth hormone, cortisol 
5. 
25(OH) vitamin D, parathyroid hormone, calcium, alkaline phosphatase 
6. 
Alanine aminotransferase (ALT), aspartate aminotransferase (AST), platelet count, 

HANA Study Protocol_V5 dated 5 Jun 2020 
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bilirubin, albumin 
7. 
Adiponectin, leptin 
8. 
Quantitative immunoglobulins, serum paraproteins 
9. 
sCD14, hsCRP, IL-6, D-dimer, sVCAM-1, sICAM, TNF-a 
10. HBsAg, anti-HBc, anti-HCV antibody 
11. Cytokeratin-18 fragments using M30-Apoptosense ELISA kit (PEVIVA, Bromma, 
Sweden) as a marker for steatohepatitis 
e. Spot urine tests for: 
1. 
Phosphate, urate, creatinine 
2. 
Retinol-binding protein (RBP), β2 microglobulin 
3. 
Protein and albumin 
f. Ultrasonography of carotid arteries 
1. 
Carotid IMT (cIMT) will be measured to provide estimates on atherosclerosis extent 
and progression.26 B-mode ultrasound examinations will be performed with Vivid 
E9 (GE Healthcare, Milwaukee, WI, USA) with a 11 MHz scanning frequency linear 
transducer. All scans will be performed by an experienced physician after a 
predetermined, standardized scanning protocol for the posterior wall of right and 
left carotid arteries using images of the far wall of the distal 10mm of the common 
carotid arteries. The reported cIMT value represents the mean of measurements at 
both left and right carotid arteries. A carotid plaque will be considered to be present 
when cIMT was >1.2 mm at any site. 
g. Dual energy absorptiometry (DEXA) scan: 
1. 
Site-specific bone DEXA will be performed using a Hologic QDR 4500A fan beam 
densitometer (Hologic, Inc., Bedford, MA) to measure hip and lumbar spine (from 
L1 to L4) bone mineral density (BMD) and lumbar spine trabecular bone score. 
2. 
Whole body DEXA will be performed to measure total body fat, lean body mass, and 
regional fat in arms, legs, and trunk (in grams). In measuring trunk fat, a line of 
delineation will be drawn between the head of the humerus and the glenoid fossa 
of the scapula to separate the upper limb from the trunk, and the leg consists of the 
parts of the body between the inferior border of the ischial tuberosity to the most 
distal tip of the toes.  
h. Fibroscan 
1. 
Liver stiffness measurement by transient elastography will be performed. Ten 
successful acquisitions will be performed on each subject. The median value 
represents the liver elastic modulus. Liver stiffness will be expressed in kiloPascal 
(kPa). Liver stiffness measurements will be considered valid only if 10 successful 
acquisitions are obtained, and the interquartile range (IQR) to median ratio of the 
10 acquisitions is <0.3. Only valid liver stiffness measurements were included in the 
analyses involving liver stiffness.20  
2. 
Controlled attenuation parameter (CAP) will be used to measure liver ultrasonic 
attenuation, for determination of hepatic steatosis. CAP will be computed only 
when the associated liver stiffness measurement is valid and using the same signals 
as the one used to measure liver stiffness. The final CAP value is the median of 
individual CAP values and will be expressed in dB/m.27 
i. Automated retinal image analysis 
1. 
Digital fundus photographs will be acquired by a trained technician using a Canon 
CR2 AF non-mydriatic retinal camera of both eyes (Canon). Retinal vessel 

HANA Study Protocol_V5 dated 5 Jun 2020 
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measurements will be made. ARIA-stroke risk score will be calculated. 
j. Risk prediction 
1. 
Cardiovascular 
i. 
10-year risk of developing atherosclerotic cardiovascular disease will be 
calculated based on the Pooled Cohort ASCVD Risk Equations.28 
ii. 
Cardiovascular disease risk will be calculated using the DAD cohort risk 
prediction 
equation 
http://www.hivpv.org/Home/Tools/tabid/91/ctl/ExamView/mid/500/eid/0/li
d/0/Default.aspx  
2. 
Renal disease  
i. 
Risk of developing chronic kidney disease will be calculated based on the 
following risk scores: 
ii. 
DAD risk prediction https://www.chip.dk/Tools-Standards/Clinical-risk-scores29 
iii. 
UCSF risk prediction http://hivinsite.ucsf.edu/InSite?page=md-calculator30 
3. 
Osteoporosis/fracture 
i. 
10-year risk of fracture will be calculated using WHO Fracture Risk Assessment 
Tool (FRAX) score: http://www.shef.ac.uk/FRAX/  
4. 
Cognitive impairment 
i. 
HIV international dementia scale ≤10 
5. 
Mood 
i. 
Depression score >9, anxiety score >7, or stress score >14 according to DASS 21 
assessment 
 
Outcome measures 
HANA conditions will be defined as follows: 
a. Cardiovascular diseases 
1. 
Diagnosis of coronary heart disease, cerebrovascular disease, or peripheral artery 
disease by physician supported by relevant imaging results 
2. 
Subclinical atherosclerosis 
i. 
Presence of plaques on carotid arteries 
ii. 
cIMT greater than 75th percentile of population 
b. Diabetes and pre-DM 
1. 
DM will be defined by fasting glucose ≥ 7.0 mmol/L, or HbA1c ≥6.5%.31  
2. 
Pre-DM will be defined by fasting glucose 5.6-6.9 mmol/L, or HbA1c 5.7-6.4% 32 
3. 
Insulin resistance will be defined by HOMA-insulin resistance (fasting insulin 
(μU/ml)/22.5*(glucose (mmol/l)) >2.5 33 
c. Hypertension 
1. 
Systolic blood pressure ≥130mmHg, or diastolic blood pressure ≥80mmHg34  
d. Metabolic syndrome 
1. 
Metabolic syndrome will be defined according to ethnic-specific criteria by the 
International Diabetes Federation, as any three of the following: (1) central obesity 
(waist circumference ≥90cm in men and ≥80cm in women); (2) triglycerides 
>1.7mmol/l; (3) reduced HDL cholesterol (<1.03mmol/l in men and <1.29mmol/l in 
women); (4) blood pressure ≥130/85mm Hg; and (5) fasting plasma glucose 
≥5.6mmol/l; or receiving treatment for the above metabolic abnormalities.35 
e. Obesity 
1. 
Overweight will be defined as BMI >23 kg/m2 36 

HANA Study Protocol_V5 dated 5 Jun 2020 
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2. 
Obesity will be defined as BMI >26 kg/m2 36 
f. Fatty liver and liver fibrosis 
1. 
Fatty liver will be expressed as CAP in dB/m, and hepatic steatosis grading will be 
defined as mild if CAP is 248-267 dB/m, moderate if 268-279 dB/m, and severe if 
≥280 dB/m37   
2. 
Liver stiffness will be expressed in kiloPascal (kPa). LS>9.6-11.5kPa will be 
considered as advanced fibrosis, and LS>11.5kPa as cirrhosis38  
g. Renal disease 
1. 
Glomerular filtration rate (GFR) will be calculated using the 2009 CKD-EPI creatinine 
equation. Renal impairment will be defined as GFR <90 ml/min, and albuminuria 
will be defined as urine albumin/Creatinine ratio ≥30mg/g, according to KDIGO 
2012 clinical practice guideline.39  
2. 
Kidney tubular dysfunction will be defined by:40  
i. 
Fractional tubular resorption of phosphate {1- [(urine phosphate  x serum 
Cr)/(urine Cr x serum phosphate)]}x100 of <82%; 
ii. 
Fractional excretion of uric acid {[(urine uric acid x serum Cr)/(urine Cr x serum 
uric acid)] x 100} of >15%; 
iii. 
β2-microglobulin:creatinine > 1000 μg/g Cr; or 
iv. 
RBP:creatinine >17μg/mmol Cr 
h. Osteopenia and osteoporosis 
1. 
Osteoporosis is defined, according to World Health Organization criteria, as BMD T-
score of ≤2.5 at the hip or spine in men ≥50 years old and post-menopausal women, 
or Z-score of ≤2.0 in men younger than 50 years old and pre-menopausal women.41 
2. 
Osteopenia is defined as a T-score between 1 and 2.49.41 
i. Chronic obstructive airway disease 
1. 
FEV1/FVC <0.7  
j. Frailty and sarcopenia in those aged 50 and above 
1. 
Frailty is defined by Frailty phenotype measurement, according to Fried definition42 
k. Sarcopenia is defined as appendicular lean mass (kg)/height2(m2) < 2 standard deviations 
below the mean for young healthy adults (cut-offs were < 7.26 kg/m2 for men and < 5.45 
kg/m2 for women)43 
l. Retinal vasculopathy 
1. 
Presence of HIV retinopathy, retinal vein occlusions and retinal artery occlusions  
 
Electronic platform 
a. An electronic database will be established for systematic collection of all the above clinical 
and laboratory data, and clinical outcomes. 
b. The collected data will be used to generate risk assessment for multiple HANA conditions. 
Clinical management will be recommended according to risk assessment. 
c. A report summarizing the risk assessment and diagnosis of each HANA condition will be 
generated for each patient after each study visit. The report will be submitted to their HIV 
physicians for further clinical management. 
 
 
Study Flowchart 

HANA Study Protocol_V5 dated 5 Jun 2020 
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*During each study visit, demographic and clinical data will be collected. Physical examination will be performed. 
Blood and urine tests will be done at fasting state. Imaging, including ultrasonography of carotid arteries, DEXA 
scan and fibroscan, will be performed. Stool samples will be collected for microbiota study. 
 
Sample size calculation 
There were around 700 new HIV infections reported in Hong Kong in 2015 and 2016. Based 
on previous published data,44 the risk of developing metabolic syndrome is approximately 
20% at 96 weeks after initiation of ART, a sample size of 400 will give a 95% confidence interval 
from 16% to 24% at 96 weeks. Using the same 400 patients, we would be able to detect with 
95% confidence an odds ratio of 2 for any risk factors with respect to the incidence of 
metabolic syndrome assuming that the prevalence is 20% and we would like to have an 
estimate of the population odds ratio to within 50% of the true value (i.e. a lower bound of 
1.0 for the 95% confidence interval of the odds ratio) even after adjusted for type I error due 
to multiple risk factors.45  
 
Statistical analysis 
a. The incidence rate of each HANA defined as above will be calculated as: 
𝑖𝑛𝑐𝑖𝑑𝑒𝑛𝑐𝑒 𝑟𝑎𝑡𝑒 𝑜𝑓 𝐻𝐴𝑁𝐴 (𝑝𝑒𝑟 100 𝑝𝑒𝑟𝑠𝑜𝑛−𝑦𝑒𝑎𝑟𝑠)
= 𝑛𝑢𝑚𝑏𝑒𝑟 𝑜𝑓 𝑛𝑒𝑤 𝑑𝑖𝑎𝑔𝑛𝑜𝑠𝑖𝑠 𝑜𝑓 𝐻𝐴𝑁𝐴 𝑎𝑡 𝑒𝑛𝑑 𝑜𝑓 𝑓𝑜𝑙𝑙𝑜𝑤 𝑢𝑝
number of persons at risk ∗number of years of follow up  𝑥 100 
b. The incidence rate of each HANA will be determined for subjects started INSTI-based 
regimens and other non-INSTI-anti-retroviral regimens.   
c. Variables, including demographic, clinical, treatment-related, and laboratory parameters, 
will be evaluated for association with development of various HANA, in univariate and 
multivariate analyses. Analyses will be performed for the whole cohort, and subgroup 
analyses will be performed in those initiated INSTI-based regimens and other non-INSTI-
based regimens. 
 
Study Conduct 
This study will be conducted in accordance with Declaration of Helsinki. 
 
 
 
 
Recruitment of newly 
diagnosed HIV-infected 
individuals in Hong 
Kong
Baseline assessment 
(prior to initiation of 
ART or within 4 weeks 
of starting ART)*
1-Yr after 
initiation of 
ART*
2-Yr after 
initiation of 
ART*
3-Yr after 
initiation of 
ART*
4-Yr after 
initiation of 
ART*
5-Yr after 
initiation of 
ART*

HANA Study Protocol_V5 dated 5 Jun 2020 
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