Effect of Atorvastatin on Subclinical Atherosclerosis in Virally-suppressed HIV-infected Patients With CMV Seropositivity: a Randomized Double-blind Placebo-controlled Trial
Phase: NA
Conditions: CMV
Sponsor: Dr Cipto Mangunkusumo General Hospital

 
 
PROTOCOL 
 
 
 
 
 
 
 
 
STUDY TITLE: 
Effect of atorvastatin on subclinical atherosclerosis in virally-suppressed HIV-
infected patients with CMV seropositivity: a randomized double-blind 
placebo-controlled trial 
 
 
 
 
 
Principal Investigator: 
Evy Yunihastuti, MD, PhD 
Faculty of Medicine Universitas Indonesia/Cipto Mangunkusumo Hospital 
Jl Diponegoro No 71 
Jakarta, Indonesia 10320 
+62-811-996058 
evy.yunihastuti@gmail.com 
evy.yuniastuti@ui.ac.id 
 
 
 
 
 
 
 
 
Confidentiality Statement:  
This document is confidential and is to be distributed for review only to investigators, 
potential investigators, consultants, study staff, and applicable independent ethics 
committees or institutional review boards. The contents of this document shall not be 
disclosed to others without written authorization from INA-RESPOND. 
 
 
 
 
 
 
Version: 1.4 
August, 5th, 2019 

 
 

 
 
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TABLE OF CONTENTS 
 
TABLE OF CONTENTS.................................................................................................................... 2 
LIST OF ABBREVIATIONS .............................................................................................................. 4 
PROTOCOL SUMMARY ................................................................................................................. 5 
1. 
INTRODUCTION .................................................................................................................... 9 
1.1. 
Background ................................................................................................................ 9 
1.2. 
Rationale .................................................................................................................. 11 
2. 
OBJECTIVES ......................................................................................................................... 11 
2.1. 
Primary Objective .................................................................................................... 11 
2.2. 
Secondary Objective ................................................................................................ 11 
3. 
STUDY BENEFIT ................................................................................................................... 11 
3.1. 
Potential Benefit(s) .................................................................................................. 12 
METHODS ................................................................................................................................... 13 
3.2. 
Study Plan ................................................................................................................ 13 
3.3. 
Study Design............................................................................................................. 14 
3.4. 
Study Sites and Duration.......................................................................................... 14 
3.5. 
Population and Sample Size ..................................................................................... 14 
3.6. 
Eligibility Criteria ...................................................................................................... 14 
3.6.1. 
Inclusion Criteria .................................................................................................... 14 
3.6.2. 
Exclusion Criteria.................................................................................................... 14 
3.7. 
Co-enrollment Criteria ............................................................................................. 15 
3.8. 
Study Instruments .................................................................................................... 15 
3.9. 
Strategies for Recruitment and Retention ............................................................... 15 
3.10. 
Participant Retention ............................................................................................... 15 
3.11. 
Study Intervention (if applicable) ............................................................................ 15 
3.12. 
Intervention Assignment Procedures ...................................................................... 15 
3.12.1. 
Randomization Procedures ................................................................................ 15 
3.12.2. 
Masking Procedures ........................................................................................... 15 
3.13. 
Study Schedule and Procedures .............................................................................. 16 
3.13.1. 
Screening ............................................................................................................ 16 
3.13.2. 
Baseline and Enrollment .................................................................................... 16 
3.13.3. 
Follow Up Visit(s) ................................................................................................ 16 
3.13.4. 
Other visit ........................................................................................................... 16 
3.13.5. 
End of Study Visit ............................................................................................... 16 
4. 
SPECIMENS (REPOSITORY, USAGE, LOSS & DESTRUCTION) ............................................... 17 
4.1. 
Biohazard Containment ........................................................................................... 17 
4.2. 
Specimen Preparation, Handling, Storage and Shipping ......................................... 17 
4.3. 
Total Blood Volume ................................................................................................. 17 
5. 
DATA MANAGEMENT, STATISTICAL CONSIDERATION & ANALYSIS PLAN .......................... 17 
5.1. 
Data Management ................................................................................................... 17 
5.2. 
Statistical Consideration & Analysis Plan ................................................................. 17 
6. 
RESEARCH MONITORING .................................................................................................... 18 
6.1. 
Protocol Deviation ................................................................................................... 18 
6.2. 
Non-Compliance ...................................................................................................... 18 
7. 
ASSESSMENT OF SAFETY..................................................................................................... 18 
7.1. 
Adverse Events ......................................................................................................... 18 

 
 
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7.2. 
Serious Adverse Events ............................................................................................ 18 
7.3. 
Unanticipated Problem ............................................................................................ 19 
7.4. 
IRB Reporting ........................................................................................................... 19 
7.5. 
Expedited Reporting to the NIHRD IRB .................................................................... 19 
7.6. 
Annual Reporting to the IRB .................................................................................... 19 
8. 
HUMAN SUBJECTS PROTECTIONS ...................................................................................... 19 
8.1. 
Ethical Review .......................................................................................................... 19 
8.2. 
Potential Risks and Benefit to the Participant ......................................................... 20 
8.2.1. 
Potential Risks ........................................................................................................ 20 
8.2.2. 
Potential Benefit(s) ................................................................................................ 20 
8.3. 
Participant Compensation ....................................................................................... 20 
8.4. 
Vulnerable Participants or Special Population ........................................................ 20 
8.5. 
Informed Consent .................................................................................................... 20 
8.6. 
Participant Privacy and Confidentiality.................................................................... 21 
8.7. 
Post-Trial Access ......................................................... Error! Bookmark not defined. 
9. 
RESEARCH TEAM ................................................................................................................. 21 
12. 
REFERENCES ........................................................................................................... 22 
APPENDIX A. SCHEDULE OF EVENTS .......................................................................................... 24 
APPENDIX B. OPERATIONAL DEFINITION ..................................................................................... 26 
APPENDIX C. IMPLEMENTING ARRANGEMENT ............................. Error! Bookmark not defined. 
 

 
 
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LIST OF ABBREVIATIONS 
 
ART 
Antiretroviral Therapy 
Co-PI 
Co- Principal Investigator 
GCP 
Good Clinical Practice 
ICF 
Informed Consent Form 
MPR 
Medication Possession Ratio 
PI 
Principal Investigator 
 

 
 
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PROTOCOL SUMMARY 
 
Full Title 
Effect of atorvastatin on subclinical atherosclerosis in virally-
supressed HIV-infected patients with CMV seropositivity: a 
randomized double-blind placebo-controlled trial 
Protocol registration 
number 
 
PI(s)o (Researchers) 
Evy Yunihastuti, Clinical Immunology Consultant 
Co-PI(s) (Researchers) 
- 
Riwanti Estiasari, Neuroinfection Consultant 
- 
Chyntia Olivia Maurine Jasirwan, Hepatology 
consultant 
- 
RR Dyah Purnamasari Sulistianingsih, Metabolic 
Endocrinology Consultant 
- 
Lusiani Rusdi, Cardiology Consultant 
- 
Sally Aman Nasution, Cardiology Consultant 
- 
Endah Ayu Tri Wulandari, Oral Medicine Specialist 
Background and rationale 
Persistent 
immune 
activation 
and 
inflammation 
in 
virologically suppressed HIV-infection are linked to excess 
cardiovascular risk and other non-communicable diseases.  
Cytomegalovirus 
(CMV) 
seropositivity 
is 
common 
in 
Indonesian people, including HIV-infected patients. However, 
treatment of CMV infection is not accessible for most 
patients. 
Periodic asymptomatic CMV-reactive patients in HIV infected 
patients over a life time may contribute to non-AIDS defining 
morbidity, including cardiovascular disease, neurocognitive 
impairment, cancer and renal disease. Despite undetectable 
levels of HIV and CMV in plasma, these patients continue to 
have increased levels of biomarkers and immune activations.  
Statin administration is supposed to reduce subclinical 
atherosclerosis by decreasing LDL cholesterol levels, possibly 
via lipid-independent anti-inflammatory effect. Its pleiotropic 
properties also adding beneficial effect against CMV infection.  
We plan to study atorvastatin in virally- suppressed HIV-
infected patients on stable ART with CMV seropositive and 
statin-naïve to evaluate the subclinical atherosclerosis 
changes assessed by carotid intima media thickness (CIMT)  
Primary Study objectives 
To compare the effect of 48 weeks of 20 mg daily atorvastatin 
versus placebo on changes CIMT in virally supressed HIV 
patients with CMV seropositivity 
Secondary Study 
Objectives 
1) To evaluate the interaction between baseline CMV 
copy number and effect of atorvastatin on CIMT 
changes 
2) To evaluate the effect of 48 weeks of 20 mg daily 

 
 
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atorvastatin versus placebo on fasted lipid changes in 
virally supressed HIV patients with CMV seropositivity  
3) To evaluate the effect of 48 weeks of 20 mg daily 
atorvastatin versus placebo on of brachial artery flow 
mediated vasodilatation (FMD) in virally supressed HIV 
patients with CMV seropositivity  
4) To evaluate the effect of 48 weeks of 20 mg daily 
atorvastatin versus placebo on liver fibrosis and 
steatosis changes in virally supressed HIV patients with 
CMV seropositivity  
5) To evaluate the effect of 48 weeks of 20 mg daily 
atorvastatin versus placebo on neurocognitive changes 
in virally supressed HIV patients with CMV 
seropositivity  
6) To evaluate the effect of 48 weeks of 20 mg daily 
atorvastatin versus placebo on several immune 
activation biomarkers (sCD14, VCAM, ICAM, hsCRP, 
and β2M) changes in virally supressed HIV patients 
with CMV seropositivity 
7) To evaluate the effect of 48 weeks of 20 mg daily 
atorvastatin versus placebo on oral periodontitis score 
changes in virally supressed HIV patients with CMV 
seropositivity  
8) To evaluate the interaction between baseline CMV 
copy number and effect of atorvastatin on FMD, 
neurocognitive function, liver fibrosis and steatosis, 
lipid profile, and immune activation biomarkers 
changes in 48 weeks 
Participant population 
HIV-positive patients on ART will be recruited from the HIV 
Integrated Care Unit, Cipto Mangunkusumo Hospital, Jakarta. 
Each participant must meet eligibility criteria as defined 
below in order to be enrolled in the study. 
Inclusion criteria: 
1. Ages between 20 to 45 years old 
2. Using stable ART at least 1 year 
3. Positive IgG CMV 
4. Viral load HIV RNA <50 copies / ml 
Exclusion criteria: 
1. Undergoing hepatitis C DAA therapy 
2. Decompensated cirrhosis or acute liver failure 
3. History of coronary artery disease 
4. Diabetes mellitus 
5. History of of brain infection, epilepsy, stroke 
6. History of rhabdomyolysis or myopathy 
7. Pregnant or breastfeeding 
8. Severe depression 
9. Using statin therapy in the past 6 weeks 

 
 
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10. History of statin hypersensitivity 
11. Framingham Risk Score above 10% within LDL ≥130 
12. Framingham Risk Score under 10% within LDL ≥160 
13. Out of Periodontitis Index (Upper right molars, top 
series, upper left molars, lower right molars, 
bottom series, lower left molars) 
 
Drop out criteria:  
1. Becomes pregnant during this study 
2. Stop using ART> 1 month 
3. Stop or refuse to continue to use atorvastatin 
during this study  
4. Not willing to continue as participant in this study 
Participating sites 
HIV Integrated Care Unit, Tertiary Hospital Cipto 
Mangunkusumo 
Study Design  
This study using double blind randomized, placebo-controlled 
clinical trial. Subject chosen by consecutive methods.  
Study Scheme or 
Intervention 
Eligible subjects will be randomized to receive an atorvastatin 
or placebo with a ratio of 1: 1. Atorvastatin 20 mg or identical 
placebo capsules will be given orally for 48 weeks.  
Schedule of Procedures/ 
Evaluations 
1. The participants who meet the inclusion and exclusion 
criterias (except viral load, anti-CMV, and Framingham 
score criterias) get an explanation of the purpose, 
method of the study, the rights to stop or refuse to 
take part during in the study. And each participant 
gives their sign to ICF. 
2. Viral load, IgG anti-CMV, fasted lipid profile, fasting 
glucose and insuline to define Framingham score will 
be done as screening process. 
3. Participants with CMV seropositivity, undetectable 
viral load, and Framingham risk score >10% LDL <130 
or Framingham risk score <10% LDL <160 will continue 
the study process.  
4. Participants will be asked to fast for 10 hours before 
taking 12 mL of venous blood: for examination of 
blood glucose, ALT, CMV DNA, and sCD14, VCAM, 
ICAM, hsCRP, β2M, and transient elastography with 
CAP. CIMT, FMD, neurocognitive examination, and 
Community Periodontal Index will be done within a 
week before taking study drugs. 
5. Participants will be randomized to get atorvastatin 
therapy or placebo. While using study drugs, 
participants continue their ART and other standard of 
cares. 
6. Study drugs will be dispensed monthly along with ART 
refill and the pharmacist records the remaining 

 
 
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medication. 
7. At week 24, blood collection procedures and 
neurocognitive 
examination 
procedures 
will 
be 
repeated. 
8. At week 48, blood collection procedures, CIMT, FMD, 
transient elastography with CAP, neurocognitive 
examination, and community periodontal index 
procedures will be repeated. 
Study Duration 
The study will be conducted from April, 2019 to April, 2021. 
Predicted accrual period: 4 months 
Enrollment of the first study participant to enrollment of last 
participant schedule on four months in the first year. 
Primary Endpoint(s) 
The mean or median CIMT changes of virally supressed HIV 
patients with CMV seropositivity in atorvastatin group versus 
placebo group between baseline and week 48 
Secondary endpoints 
- 
Magnitude of change in effect of atorvastatin on CIMT 
associated with baseline CMV copy number 
- 
The mean or median changes of fasted lipid between 
baseline and week 24, week 24 and week 48  
- 
The mean or median changes of brachial artery flow 
mediated vasodilatation (FMD) between baseline and 
week 48  
- 
The mean or median changes of liver fibrosis and steatosis 
in atorvastatin and placebo group between baseline and 
week 48 
- 
The mean or median changes of sCD14, VCAM, ICAM, CRP, 
and β2M in atorvastatin and placebo group lipid between 
baseline and week 24, week 24 and week 48 
- 
The mean or median changes of neurocognitive function 
in atorvastatin and placebo group lipid between baseline 
and week 24, week 24 and week 48 
- 
The mean or median changes of oral periodontitis score in 
atorvastatin and placebo group between baseline and 
week 48 
- 
Magnitude of change in effect of atorvastatin on FMD, 
neurocognitive function, liver fibrosis and steatosis, lipid 
profile, and immune activation biomarkers associated 
with baseline CMV copy number 
 

 
 
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1. INTRODUCTION 
1.1. 
Background 
HIV continues to be a major public health issue. In Indonesia, from January to March 
2017 there were 10,376 people infected with HIV (PLWH). The highest percentage(87.2%) 
was in the productive-aged grup (age 18 - 49 years).1,2 Antiretroviral therapy (ART) has 
contributed to significant reduction in morbidity and mortality of HIV patients, as evidenced 
by reducing AIDS-related deaths from 2.3 million in 2005 to 1.6 million in 2016.3 Free ART 
program conducted in Indonesia since 2004 had an impact on declining mortality of PLWH 
from 2.72% in 2013 to 1.22% at the end of 2014.4 Decreased morbidity and mortality due to 
AIDS is accompanied by an increase of non-communicable diseases (NCD) in PLWH.  
Based on 10 years observational research, 10% of deaths in PLWH caused by 
cardiovascular disease, even 3 out of 4 PLWHAs had a low risk of the disease in the 
beginning of the observation.5 Increasing other NCD diseases, such as diabetes, 
neurocognitive disorder, chronic liver disease, chronic kidney disease, low bone mineral 
density, and other inflammatory related diseases, are associated with chronic immune and 
inflammatory activation that is still ongoing even in the state of viral suppression 
(undetectable viral load). Several antiretroviral drugs also increase to the worsening of these 
condition. 
Cytomegalovirus (CMV) seropositivity is common in Indonesian people, including 
HIV-infected patients. In 2012, prevalence of CMV infection in pre-marital woman is 78,9%. 
In 2017, prevalence of CMV seropositivity is 98,23%.6,7 However, treatment of CMV 
infection is not accessible for most patients. Periodic asymptomatic CMV-reactive patients 
in HIV infected patients over a life time may contribute to non-AIDS defining morbidity, 
including cardiovascular disease, neurocognitive impairment, cancer and renal disease.8 
Despite undetectable levels of HIV and CMV in plasma, these patients continue to have 
increased levels of biomarkers and immune activations.9 
Atherosclerosis precedes cardiovascular events and has a prolonged asymptomatic 
phase during which the course of the disease can be modified by lifestyle modifications and 
treatment. The age of initiation and the rate of progression of atherosclerosis vary markedly 
among individuals and have been difficult to predict with traditional cardiovascular risk 
assessment models. Therefore, individuals with subclinical atherosclerosis should preferably 
be identified at an early stage, so that the primary prevention measures can be initiated. 
Early identification of subclinical atherosclerosis in individuals at low-to intermediate 
cardiovascular risk has been challenging.8 There are several markers of subclinical 
atherosclerosis including Carotid Intima-Media Thickness (CIMT), Coronary Artery Calcium 
Score (CACS), Ankle-Brachial Index (ABI), and Flow-Mediated Dilatation (FMD).10 
As a surrogate marker for subclinical atherosclerosis, CIMT evaluation is a non-
invasive examination using B-mode ultrasonography which relatively reproducible, easy and 
safely performed to detect early stages of atherosclerosis and is accepted as one of the best 
methods for evaluation of arterial wall structure.  There are several factors affecting 
changes on CIMT including traditional risk factors such as age, sex, dyslipidemia, diabetes 
mellitus, etc and also novel risk factors including hereditary, certain genotypic indices, 
anthropometric parameters, rheumatoid arthritis, immunologic and inflamatory cytokines, 
yet socioecomonic position (SEP) and job stress.  
Recent years, systemic inflammation and immune activation have gained attention 
as an emerged factors of atherosclerosis. HIV is one of the common risk factor of 
atherosclerosis. The direct correlation between CIMT and atherosclerosis among HIV-

 
 
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positive patients had been established in several studies. A prospective study of 307 
patients (179 HIV positive and 128 HIV negative) found that despite HIV supression, lipid and 
hypertension control, HIV-positive patients have a disproportionately greater CIMT than 
HIV-negative comparators.11 That facts parallel with one of  our study  which revealed that 
cIMT rose slightly in ART-naïve patients 12 months after commencing ART.12 Cross-sectional 
study of 1183 HIV-infected patients compared with 297 HIV-uninfected patients from 
showed after multivariable adjustment for demographic characteristics and traditional 
cardiovascular risk factors, HIV infection was independently associated with subclinical 
atherosclerosis measured by cIMT.13 Cohort study from 1563 HIV-infected patients 
compared to 584 HIV-uninfected Patients patient showed cIMT among middle-aged (30-49 
years and older adult (50 – 75 years) that were similar to or lower than those in HIV-
unifected participants. In contrast among those aged 6-29 years HIV infection was 
associated with higher cIMT.14 
While HIV replication has been considered the major trigger of the immune system, 
persistent inflamation and immune activation have also found in patients receiving affective 
antiretroviral therapy (ART). Therefore, additional causes may elicit immune activation and 
might be involved in the accelerated course of atherosclerosis disease in virologically 
controlled HIV-infected patient. In HIV-infected patients, a relationship with subclinical 
atherosclerosis has been reported for CMV and herpes simplex virus type-2 (HSV-2). In HIV-
infected patient, CMV antibody titers have been related to decreased artery distensibilty 
and carotid lesion in women, but no association was found with the CIMT measurement.15  
Statins are inhibitors of hydroxyl-3-methylglutaryl coenzyme A which were first 
extracted from Pythim sp, Penicillium sp, and Aspergillus sp. Initially, the target of statin 
therapy was to reduce cholesterol levels. Recent studies shown that the use of statin also 
associated with decrease other atherogenic lipid particles, such as oxidized LDL and 
phospholipase associated with lipoprotein.16 Statins remain key to primary and secondary 
CVD prevention; they improve endothelial function, slow the progression of atherosclerosis 
and stabilize atherosclerotic plaque. In the HIV population, decreased oxidized LDL is 
independently associated with a decrease in important markers of subclinical 
atherosclerosis, such as coronary plaque and carotid intima media thickness. The dual 
mechanism of statin use reduces LDL cholesterol, modifies inflammatory responses, 
antioxidant effects, antithrombic effects (clotting processes), and effects of removal of 
blood vessel plaques, thereby preventing cholesterol build-up and muscle proliferation.17 
Treating dyslipidemia with statin has been challenging in people with HIV due to potential 
drug interaction between statin and antiretroviral drug due to competing cytochrome P450. 
A study comparing comparing pitavastatin and pravastatin in patients using protease 
inhibitor shown higher virological failure in pravastatin group. Therefore, guideline 
recommend pitavastatin as a preferred drug in the treatment of dyslipidemia in PLWH.18 
However pitavastatin is expensive as it is not available in generic formulation. Atorvastatin, 
another moderate intensity statin is available in generic formulation and widely used in 
Indonesia. This drug has no interaction with all antiretroviral drugs use in Indonesia. 
Seropositivity to cytomegalovirus (CMV) may jointly predict increased mortality rate in 
patients with coronary heart disease (coronary heart disease). Statin therapy reduced lipid 
level and also has anti-inflamatory effect. Study showed statin reduce mortality rate among 
CMV-infected patients with CAD.19 In Vitro study demonstrated Statins has a broad anti-
cytomegalovirus activity. All statins dose-dependently reduced CMV titers in human aortic 
endothelial cells. These findings provide new insight into benefical effects of statins.20 

 
 
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1.2. 
Rationale 
Non-communicable diseases that are rapidly developing among HIV-positive with 
stable ART, including cardiovascular disease. Atorvastatin administration supposed to have a 
positive effect on the reduction of subclinical atherosclerosis assessed by the thickness of 
the carotid artery intima media. The use of atorvastatin, a cheap and widely accessible drug 
in Indonesia, has not been specifically studied in term of improving cardiovascular disorder 
in HIV-infected patients under ART.  
 
2. OBJECTIVES 
2.1. 
Primary Objective 
 
To compare the effect of 48 weeks of 20 mg daily atorvastatin versus placebo on changes 
CIMT in virally supressed HIV patients with CMV seropositivity 
 
2.2. 
Secondary Objective 
1. To evaluate the interaction between baseline CMV copy number and effect of 
atorvastatin on CIMT changes 
2. To evaluate the effect of 48 weeks of 20 mg daily atorvastatin versus placebo on 
fasted lipid changes in virally supressed HIV patients with CMV seropositivity  
3. To evaluate the effect of 48 weeks of 20 mg daily atorvastatin versus placebo on of 
brachial artery flow mediated vasodilatation (FMD) in virally supressed HIV patients 
with CMV seropositivity  
4. To evaluate the effect of 48 weeks of 20 mg daily atorvastatin versus placebo on liver 
fibrosis and steatosis changes in virally supressed HIV patients with CMV 
seropositivity  
5. To evaluate the effect of 48 weeks of 20 mg daily atorvastatin versus placebo on 
neurocognitive changes in virally supressed HIV patients with CMV seropositivity 
6. To evaluate the effect of 48 weeks of 20 mg daily atorvastatin versus placebo on 
several immune activation biomarkers (sCD14, VCAM, ICAM, hsCRP, and β2M) 
changes in virally supressed HIV patients with CMV seropositivity 
7. To evaluate the effect of 48 weeks of 20 mg daily atorvastatin versus placebo on oral 
periodontitis score changes in virally supressed HIV patients with CMV seropositivity   
8. To evaluate the interaction between baseline CMV copy number and effect of 
atorvastatin on FMD, neurocognitive function, liver fibrosis and steatosis, lipid 
profile, and immune activation biomarkers changes in 48 weeks 
 
3. STUDY ENDPOINTS 
3.1. 
Primary endpoint 
The mean or median CIMT changes of virally supressed HIV patients with CMV seropositivity 
in atorvastatin group versus placebo group between baseline and week 48 
 
3.2. 
Secondary endpoints 
1. Magnitude of change in effect of atorvastatin on CIMT associated with baseline CMV 
copy number 
2. The mean or median changes of fasted lipid between baseline and week 24, week 24 
and week 48  

 
 
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3. The mean or median changes of brachial artery flow mediated vasodilatation (FMD) 
between baseline and week 48  
4. The mean or median changes of liver fibrosis and steatosis in atorvastatin and placebo 
group between baseline and week 48 
5. The mean or median changes of sCD14, VCAM, ICAM, CRP, and β2M in atorvastatin and 
placebo group lipid between baseline and week 24, week 24 and week 48 
6. The mean or median changes of neurocognitive function in atorvastatin and placebo 
group lipid between baseline and week 24, week 24 and week 48 
7. The mean or median changes of oral periodontitis score in atorvastatin and placebo 
group between baseline and week 48 
8. Magnitude of change in effect of atorvastatin on FMD, neurocognitive function, liver 
fibrosis and steatosis, lipid profile, and immune activation biomarkers associated with 
baseline CMV copy number 
 
4. STUDY BENEFIT 
4.1. 
Potential Benefit(s) 
There are some potential benefits to those individuals who use atorvastatin such as 
lowering lipid level, but this will not be available for those who got placebo. However, 
society will gain general knowledge that will improve care of similar cases. 
 

 
 
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METHODS 
4.2. 
Study Plan 
 
HIV-positive patients who meet the eligible criteria get an explanation of the purpose, method of 
the study, the rights to stop or refuse to take part during in the study. . 
Subjects will be categorized use double blind randomized clinical  trial 
into statin groups and placebo groups with a ratio of 1: 1 (40 subjects 
per group).  
Subjects will undergo CIMT examination, FMD, transient elastography with CAP, neurocognitive examination, blood 
sample collection, Semi Food-Frequency Questioner, lifestyle, dietary education, and community periodontal index 
atorvastatin group 
placebo group 
Monthly adherence 
evaluation & pill refill 
Monthly adherence 
evaluation & pill refill 
Neurocognitive examination, 
IQ5D assessment, body 
composition measure, and 
blood sample collection 
Neurocognitive examination, 
IQ5D assessment, body 
composition measure, and 
blood sample collection 
CIMT examination, transient 
elastography with CAP, 
neurocognitive examination, 
Semi Food-Frequency 
Questioner, blood sample 
collection, and community 
periodontal index 
CIMT examination, transient 
elastography with CAP, 
neurocognitive examination, 
Semi Food-Frequency 
Questioner, blood sample 
collection, and community 
periodontal index 
Screening: viral load, anti-CMV, lipid profile, 
Framingham score 
Week 24th 
Week 48th 
Eligible subject 
Not-Eligible 
Subject 

 
 
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4.3. 
Study Design 
 
This study used a double-blind randomized placebo-controlled trial design. 
Participants who met the inclusion and exclusion criteria were randomized into atorvastatin 
groups and placebo groups with a ratio of 1: 1 (40 subjects per group). Randomization using 
a computer program based on randomization of permutation blocks with block 4 sizes 
carried out by statistical analysts. Then the code is given to pharmacists who involved in the 
study. Researchers, doctors, and participants did not know the results of randomization. 
 
4.4. 
Study Sites and Duration 
 
The study will conduct during 2019-2020 at HIV Integrated Care Unit and Integrated 
Cardiovascular Care Cipto Mangunkusumo Hospital, Jakarta. 
 
4.5. 
Population and Sample Size 
Target population is HIV-positive patient on stable ART routinely controlled in HIV 
Integrated Care Unit Cipto Mangunkusumo Hospital, Jakarta.  
Assuming that the effect size is 0.1, standard deviation is 0.12, and the use of 2 
sample t-test, the sample size needed for 90% power and 5% significant level is 32 per arm. 
With additional 20% drop, each arm (placebo and control group) will need 40 participants.  
 
4.6. 
Eligibility Criteria 
4.6.1. Inclusion Criteria 
1. Age between 20 to 45 years old 
2. Using stable ART at least 1 year 
3. positive CMV IgG  
4. Viral load HIV RNA <50 copies / ml 
4.6.2. Exclusion Criteria 
1. Undergoing for Hepatitis C DAA Therapy 
2. Decompensated cirrhosis or acute liver failure 
3. History of coronary artery disease 
4. Diabetes mellitus 
5. History of of brain infection, epilepsy, stroke 
6. History of rhabdomyolysis or myopathy 
7. Pregnant or breastfeeding 
8. Severe depression 
9. Using statin therapy in the past 6 weeks 
10. History of statin hypersensitivity 
11. Framingham Risk Score above 10% within LDL ≥130 
12. Framingham Risk Score under 10% within LDL ≥160 
13. Out of Periodontitis Index (Upper right molars, top series, upper left molars, lower 
right molars, bottom series, lower left molars) 
4.6.3 Drop Out Criteria 
1. Pregnant during this study 
2. Stop using ART> 1 month 
3. Stop or refuse to use atorvastatin during this study  
4. Not willing to continue as participant in this study 
 
 

 
 
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4.7. 
Co-enrollment Criteria 
HIV-positive patients who include into this study are still permitted to follow other 
observational studies as participants. However, patients who participate in this study are 
not permitted to take other interventional studies. Sticker affixed in participant’s medical 
record as required by hospital policy will ensure that participant is not under other 
interventional study. 
4.8. 
Study Instruments 
Instruments used in this study included an ICF, demographic form contains medical 
record and essential information of each participant, CIMT examination form, blood 
collection and sample storage form, adherence form. A paper based forms that will be 
transferred to electronic format. 
 
4.9. 
Strategies for Recruitment  
Potential subjects as participants in this study are all adult patients who meet the eligible 
criteria and under antiretroviral therapy at HIV Integrated Care Unit Cipto Mangunkusumo 
Hospital. These patients regularly control once for each two or a month(s) but antiretroviral 
drugs be refilled monthly. A promotion poster will be placed in the clinic area during the 
enrollment period. 
 
4.10. Participant Retention 
To enhance participant retention, all participant will be monitored by research assistant 
using phone once every two weeks. In addition, a reminder of the next schedule visit will be 
sent a week before.   
 
4.11. Study Intervention  
4.11.1. Study drug and dosage:  
- 
Atorvastatin 20 mg tablets in generic form 
- 
The placebo tablets will be prepared by Cipto Mangunkusumo hospital pharmacist, were 
composed of starch and were similar to atorvastatin tablets in size, shape, and colour.  
4.11.2. Treatment administration: 
The administration of study drug is home-based participant self-administration. The 
participants will get the medication after randomization process (week – 0) at least 1 week 
after. The participants will get supply every month along with the refill of antiretroviral 
drugs. The drug and placebo tablets will be administered to patients by a staff member who 
are privy to the treatment. In the end of every month, each participant should return the 
unused pills every month. All prescriptions will use hospital Electronic Medical Record 
system. 
4.11.3. Drug interaction: 
During this study, each participant is not allowed to use cyclosporin, fenofibrate, and rice 
yeast herbal supplements. 
4.12. Intervention Assignment Procedures 
4.12.1. Randomization Procedures 
Research assistant will do randomization for each participant using computerized statistic 
application. 
4.12.2. Masking Procedures 
Study pharmacist will make code (A and B) for atorvastatin and placebo, then save the code 
in safe place. Pharmacist will record each subject as participant received A or B intervention. 

 
 
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Patients, managing doctor, researcher, and those assessing outcomes would not know what 
type of drug given. The code will only be opened when a participant having adverse event 
that require identification of study drug, ie drug allergy and acute coronary syndrome. 
 
4.13. Study Schedule and Procedures 
Each participant will be followed for one year after start using study drug. 
4.13.1. Screening 
Patients meeting the initial screening criteria will be test for HIV RNA (viral load), anti-CMV 
and fasting lipid profile: 
 Age between 20 to 45 years old 
 Using ART at least 1 year 
 Not under hepatitis C therapy 
 No history of coronary artery disease, brain infection, epilepsy, stroke 
 No diabetes mellitus 
 Not pregnant or breastfeeding 
 Not severe depression (using mini ICD10) 
 Not using statin therapy 
4.13.2. Baseline and Enrollment 
Subjects with undetectable HIV-RNA, positive anti-CMV, having Framingham Risk 
Score above 10% with LDL < 130 or under 10% with LDL <160 will undergo thorough medical 
history and anthropometric examination as the initial data. Venous blood sample will be 
collected for fasting blood glucose, ALT, CMV DNA, hsCRP, sCD14, VCAM, ICAM, and β2M 
examinations. CIMT, transient elastography with CAP, neurocognitive function, and 
community periodontal index procedure will be done within a week before taking study 
drugs. CIMT and FMD evaluation will be done by trained cardiologist using B mode 
ultrasonography. Transient elastography with CAP will be done by trained cardiologist 
Fibroscan (Echosens) device. A trained neurologist will do neurocognitive evaluation using 
trail making test (TMT) A and TMT B (attention and executive function), digit symbol 
(processing speed), brief visuospatial memory test revised (visual and visuospatial memory), 
and California verbal making test (verbal memory). 
4.13.3. Follow Up Visit(s) 
Patient will be seen for regular clinical follow up as standard of care in the clinic 
(monthly/ bimonthly). Follow up visit will include clinical and laboratory procedure as 
presented in table study schedule (appendix). 
At week 24, blood collection procedures and neurocognitive examination procedures 
will be repeated. At week 48, blood collection procedures, CIMT, FMD, transient 
elastography with CAP, neurocognitive examination, and community periodontal index 
procedures will be repeated. 
4.13.4. Other visit 
 
Other visit or investigations (or referral to other clinical specialists) may be 
requested as clinically indicated. These include side effect encountered and other treatment 
related issue.  
4.13.5. End of Study Visit 
In the end of study (week 48), a total drug consumption adherence will be assessed 
using Medication Possession Ratio (MPR) method.  

 
 
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5. SPECIMENS (REPOSITORY, USAGE, LOSS & DESTRUCTION) 
5.1. 
Biohazard Containment 
This study using a blood samples which will be analyzed by laboratory analysis. So, that will 
increase the risk of infection for laboratory analysis. 
 
5.2. 
Specimen Preparation, Handling, Storage and Shipping 
Before a blood sample collection, the subject is required to fasting minimum 8-10 hours. 
Blood glucose, lipid profile, IgG anti-CMV, ALT, and viral load will be checked at the time in 
hospital laboratory service. For other evaluation, the blood sample will be inserted into a 
tube with EDTA preservative and will be centrifuged to become plasma. Then, the plasma 
will be aliquoted into several tubes and will be saved in -80˚C refrigerator. 
 
5.3. 
Total Blood Volume 
Subjects who are willing to take this part in this study will take maximum 12 mL of venous 
blood sample in each visit (see appendix). 
 
6. DATA MANAGEMENT, STATISTICAL CONSIDERATION & ANALYSIS PLAN 
6.1. 
Data Management 
Data management will be managed in HIV Integrated Care Unit, Cipto Mangunkusumo 
Hospital.   
a. 
Specific Case Report Forms (CRF) will be created prior to study 
b. 
A study-specific, relational electronic database will be created to house the 
anonymized study data by statistical analyst and saved by research team. 
c. 
Prior to patient recruitment and data collection, all research team will receive training 
in study procedures.  
 
All research team will have overall responsibility for maintaining the study CRFs. 
Corrections to the paper CRF documents must be made by striking through the incorrect 
entry with a single line (taking care not to obliterate or render the original entry illegible) 
and entering the correct information adjacent to the incorrect entry. Corrections to paper 
CRFs must be initialed and dated by the person making the correction. The researchers are 
responsible for maintaining accurate, complete and up-to-date records. These forms are to 
be completed on an on-going basis during the course of the study. 
6.2. 
Statistical Consideration & Analysis Plan  
Subjects will be analyzed in the group to which they were randomized, regardless of the 
treatment received. 
6.2.1. Analysis of primary endpoints 
T test will be used to compare the mean CIMT changes of virally supressed HIV patients with 
CMV seropositivity in atorvastatin group versus placebo group between baseline and week 
48. 
6.2.2. Analysis of secondary endpoints 
- 
Linear regression with interaction will be used to assess magnitude of change in effect of 
atorvastatin on CIMT associated with baseline CMV copy number 
- 
For other continuous endpoints, a 2 sample T-test 
6.2.3 Missing data plan 
We will compare subject characteristics in the drop out with remaining participants. If there 
is no different of the characteristic, we assume that the missing is at random. 
 

 
 
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7. RESEARCH MONITORING 
Study will be monitored by Faculty of Medicine Universitas Indonesia CRO.  
7.1. 
Record Retention 
Research records for all study subjects including CRFs, laboratory and other investigations 
data/results are to be maintained by the investigator in secure storage for five (5) years. 
These records are to be maintained in compliance with all designated IRBs requirements.  
It is the investigator’s responsibility to retain copies of these study records until notified in 
that they can be destroyed.  
 
6.2 Protocol Deviation 
Protocol Deviation is defined as any change, divergence, or departure from the IRB approved study 
procedures in the research protocol. Protocol deviations are designated as serious or non-serious and 
further characterized as: 
1. 
Those that occur because a member of the research team deviates from the protocol. 
2. 
Those that are identified before they occur, but cannot be prevented. 
3. 
Those that are discovered after they occur 
Serious Protocol Deviation is a deviation that meets the definition of a Serious Adverse Event or 
compromises the safety, welfare or rights of participants or others. 
7.2. 
Non-Compliance 
Non-compliance is defined as the failure to comply with applicable IRB requirements, or regulatory 
requirements for the protection of human participants. Non-compliance is further characterized as 
1. 
Serious: Non-compliance that 
 Increases risks, or causes harm, to participants 
 Decreases potential benefits to participants 
 Compromises the integrity of the NIH-HRPP 
 Invalidates the study data 
2. 
Continuing: Non-compliance that is recurring 
3. 
Minor: Non-compliance that, is neither serious nor continuing. 
8. ASSESSMENT OF SAFETY 
8.1. 
Adverse Events 
Side effects that can occur in this study are the subjects feels pain at the site of injection for 
venous blood sample collection, and in some rarely case is a hematoma and dermatitis in 
the site of injection for venous blood sample.  
Patients will be asked about signs and symptoms of atorvastatin toxicity. If any signs or 
symptoms are reported, patients will undergo clinical and laboratory evaluation to 
determine if the study drugs need to be stopped. 
Stopping criterias: 
- 
ALT level rise above 10-fold upper normal limit or persist in being above 5-fold elevated 
or are associated with symptoms of liver failure 
- 
Creatine kinase rise 10-fold upper normal limit in patients with clinically rhabdomyolisis 
- 
Severe drug allergic reactions, such as Stevens Johnson syndrome, toxic epidermal 
necrolysis 
 
8.2. 
Serious Adverse Events 
A serious adverse event (SAE) is defined as any adverse event that results in the following 
 results in death;  
 is life-threatening (places the participant at immediate risk of death from the event as it 
occurred); 

 
 
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 or based upon appropriate medical judgement, may jeopardize the participant’s health 
and may require medical or surgical intervention to prevent one of the other outcomes 
listed in this definition. 
All SAE will be collected on a specific SAE form and reported to the Faculty of Medicine 
Universitas Indonesia IRB within a week of occurrence.  
The management of AE will be according to best clinical practices at the judgment of the 
researcher at occurence.  
 
8.3. 
Unanticipated Problem 
An unanticipated problem (UP) is defined as any incident, experience, or outcome that is:  
1. Unexpected in terms of nature, severity, or frequency in relation to:  
 the research risks that are described in the research protocol and informed consent 
document or other study documents; and  
 the characteristics of the participant population being studied; and  
2. Related or possibly related to the participation in the research; and  
3. Places participants or others at a greater risk of harm (including physical, psychological, 
economic, or social harm) than was previously known or recognized or is an SAE.   
 
8.4. 
IRB Reporting 
8.5. 
 Expedited Reporting to the NIHRD IRB 
Unanticipated Problems, Serious Adverse Events, Serious Deviations, and Serious or 
Continuing Non-Compliance will be reported within 7 calendar days of investigator 
awareness to the IRB, regardless of expectedness. 
8.6. 
Annual Reporting to the IRB 
The following items will be reported to the IRB in summary at the time of Continuing 
Review: 
 All deaths  
 Summary of AEs, SAEs 
 Serious and non-serious unanticipated problems 
 Serious and Non-Serious Protocol deviations  
 Serious, continuing, and minor non-compliance 
 Any trends or events which in the opinion of the investigator should be reported 
 
9. HUMAN SUBJECTS PROTECTIONS 
9.1. 
Ethical Review 
Prior to the protocol implementation, protocol, ICF, CRF, and any written information to be 
provided to participants for this study will be submitted for approval to the appropriate IRB. 
Any change to the protocol and ICF will only be implemented after approval from the IRB. 
Records of the IRB review and approval of all the documents pertaining to the study will be 
kept on file by the site investigator and will be made available for inspection at any time 
during the study. Continuing reviews, including a study progress report will be submitted 
according to the requirement of the appropriate IRB, but not less than once a year at a 
minimum. 
 
 
 
 

 
 
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9.2. 
Potential Risks and Benefit to the Participant 
9.2.1. Potential Risks 
Subjects can feel less comfortable and pain in blood sampling. Other complications which 
may arise are the occurrence of phlebitis (infection in the place of needle puncture) and 
hematoma (bruising at the place of needle puncture). To reduce discomfort in each subject, 
blood sampling will be carried out by experienced staff. Furthermore, researchers will 
guarantee the confidentiality of data from research subjects. The community periodontal 
index procedures might cause little bleeding. 
The possibility of getting side effect related to atorvastatin can also make subject less 
comfortable. Common reactions include headache, difficulty sleeping, muscle aches, muscle 
tenderness, or muscle weakness, nausea, vomiting, diarrhea, bloating and constipation. 
Serious reactions might include severe liver toxicity, tendon rupture, severe allergic reaction 
and rhabdomyolisis. 
 
9.2.2. Potential Benefit(s) 
Subject will get various diagnostic tests which covered by this study. For those in 
atorvastatin arm, additional benefit such as decreasing cholesterol levels, might also 
possible. Information gained from this study may improve future treatment of similar patients. 
 
9.3. 
Participant Compensation 
The study will cover the costs of the tests used in this research, for those that are not free 
of charge to participants within the standard of care. Study participants will receive 
financial support for transportation to and from sites on visits days, as well as for time 
consented for the study procedures once per study-procedures from beginning to end per 
subject.  
The management of AE will be using participant’s national health insurance and will be 
based on best clinical practices.  For this reason, researchers will provide treatment 
recommendations for each subject of research. 
 
9.4. 
Vulnerable Participants or Special Population 
No vulnerable participant will be included in this study among all special populations.  
 
9.5. 
Informed Consent 
A written informed consent to participation will be obtained from each participant.  
The consent form will describe the purpose of the study, the study procedures and the risks 
and benefits of participation, in accordance with all applicable regulations. Consent will also 
include mention of the recording of all relevant clinical and para-clinical data obtained as 
part of participation in the study.   
The consent form will be in the appropriate language(s) of the country. Literate patients will 
document their provision of informed consent by signing and dating the informed consent 
forms. Non-literate patients will be asked to mark their informed consent forms (with 
thumb print) in the presence of a literate third party witness who will also sign the consent 
as a witness.  
Signed consents must remain in each study participant’s study file. The informed consent 
procedure will be documented in the patient’s medical records. A copy of the signed 
consent must be provided to the study participant. 
 

 
 
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9.6. 
Participant Privacy and Confidentiality 
Private identity of each participant will be saved privately. Name, domain, and others 
private identity will not mention in publication, report, public media, and others. 
Researchers will replace the identity of each participant using codes. Each file only can be 
accessed by researchers, pharmacist, and analyst. This study is voluntary based. Each 
participant may decide at any time and for any reason withdraw from participation in the 
study. Any such decision will not affect the standard of care that patient in the hospital. 
Researcher may also at any time at discontinue subjects from receiving treatment or 
participating in the study, for their benefit and well-being. Information related to treatment 
or study follow up interruption will be documented in the study CRF.  
 
 
8. RESEARCH TEAM 
 
Name 
Role 
Institution & Contact Information 
Evy Yunihastuti 
PI 
Allergic-Immunology Consultant, HIV 
Integrated Care Unit, Cipto Mangunkusumo 
Hospital 
Chyntia Olivia Maurine 
Jasirwan 
Co-PI 
Hepatobiliary Consultant, Cipto 
Mangunkusumo Hospital 
RR Dyah Purnamasari 
Sulistianingsih 
 
Co-PI 
Metabolic-Endocrine Consultant, Cipto 
Mangunkusumo Hospital 
Riwanti Estiasari,  
 
Co-PI 
Neuro-Infection Consultant, Department of 
Neurology, Cipto Mangunkusumo Hospital 
Lusiani Siregar, Internist, 
Cardiology Consultant 
 
Co-PI 
Cardiovascular Consultant, Department of 
Internal Medicine, Cipto Mangunkusumo 
Hospital 
Sally Aman Nasution, 
Internist, Cardiology 
Consultant 
Co-PI 
Cardiovascular Consultant, Department of 
Internal Medicine, Cipto Mangunkusumo 
Hospital 
Endah Ayu Tri Wulandari, 
Oral Medicine Specialist 
Co-PI 
Oral Medicine Specialist, Departemen of 
Dentistry, Cipto Mangunkusumo Hospital 
 
 
 
 
 
 
 
 

 
 
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12. 
REFERENCES 
1. World Health Organization. Number of people living with HIV estimates by WHO region 
[Internet]. 
 
[updated 
2016; 
cited 
2018 
Dec 
20]. 
Available 
from: 
http://apps.who.int/gho/data/view.main.22100WHO?lang=en 
2. Ministry of Health RI. The progress report of HIV AIDS and sexually transmitted 
infections (PIMS) in the first quarter of 2017 [Internet]. [updated 2017; cited 2018 Dec 
20]. 
Available 
from: 
http://siha.depkes.go.id/portal/files_upload/Laporan_HIV_AIDS_tw_1_2017_rev.pdf 
3. Marcolina S. Statin use and cognitive effects: not a brain drain [Internet]. [updated 2015; 
cited 2018 Dec 20]. Available from: http://reliasmedia.com/articles/135948-statin-use-n-
cognitive-effects-note-a-brain-drain. 
4. Disease Control and Environmental Health General Directorate. Action plan for disease 
control and environmental health programs in 2015-2019 [Internet]. [updated 2015; 
cited 
2018 
Dec 
20]. 
Available 
from: 
http://depkes.go.id/resourcecs/download/RAP%20Unit20Utama%202015-
2019/5.%20Ditjen%20P2P.pdf 
5. Chastain DB, Kayl RS, Daniel MR. Evidence-based review of statin use in patients with 
HIV on antiretroviral theraphy. J Clin Transl Endocrinol. 2017;8:6-14.  
6. Noviar G, Ritchie NK, Bela B, Soedarmono YSM. Prevalensi antibody IgG dan DNA 
cytomegalovirus pada darah donor di unit transfuse darah provinsi DKI Jakarta. JHECDs. 
2017;3(5):28-35. 
7. Gugun AM. Prevalensi seropositive IgM/IgG cytomegalovirus pada populasi wanita pra-
nikah dengan riwayat konsumsi makan lesehan. Mutiara Medika. 2012;12(2):124-31. 
8. Lederman MM, Funderburg NT, Sekaly RP.  Residual immune dysregulation syndrome in 
treated HIV infection. Adv Immunol. 2013;119:51-83. 
9. Barrett L, Fowke KR, Grant MD. Cytomegalovirus, aging, and HIV: a perfect storm. AIDS 
Rev. 2012;14(3):159-67. 
10. Papageorgiou N, Briasoulis A, Androulakis E, Tousoulis E. Imaging subclinical 
atherosclerosis: where do we stand? Curr cardiol Rev. 2017;13(1):47-53.  
11. Hsu R, Patton K, Liang J, Okabe R, Aberg J, Fineberg N. Independent Predictors of Carotid 
Intimal Thickness Differ Between HIV+ and HIV- Patients with Respect to Traditional 
Cardiac Risk Factors, Risk Calculators, Lipid Subfractions, and Inflammatory Markers. 
Paper presented at: 7th International AIDS Conference on HIV Pathogenesis, Treatment, 
and Prevention. Kuala Lumpur, Malaysia July 3, 2013) 
12. Karim B, Wijaya IP, Rahmaniyah R, Ariyanto I, Waters S, Estiasari R, et al. Factors 
affecting affect cardiovascular health in Indonesian HIV patients beginning ART. AIDS Res 
Ther. 2017;14(52):1-7 
13. Grunfel C, Delaney J, Wanke C, Currier J, Scherzer R, Biggs M, et al. Preclinical 
atherosclerosis due to HIV infection: carotid intima-medial thickness measurements 
from FRAM study. Wolters Kluwer Health. 2009;23:1841–9. 
14. Hanna D, Guo M, Buzkova P, Miller T, Post W, Stein J, et al. HIV infection and carotid 
artery intima—media thickness: pooled analysis across 5 cohorts of the NHLBI HIV-CVD 
collaborative. Oxf J Leg Stud. 2016;63(2):249-56. 
15. Masia M, Robledano C, Tabla V, Antequera P, Lopez N, Gutierrez F. Increased carotid 
intima-media thickness associated with antibody responses to varicella-zoster virus and 
cytomegalovirus in hiv-infected patients. PLoS ONE. 2013;8(5):1-6. 

 
 
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16. Hemkens LG, Bucher HC. HIV infection and cardiovascular disease. Eur Heart J. 
2014;35(21):1373-81. 
17. Eckard AR, Grace AM. The role of statins in the setting of HIV infection. Curr HIV/AIDS 
Repp. 2015;12(3):305-12. 
18. Aberg JA, Sponseller CA, Ward DJ, Kryzhanovski VA, Campbell SA, Thompson MA. 
Pitavastatin versus pravastatin in adults with HIV-1 infection and dyslipidaemia 
(INTREPID): 12 week and 52 week results of a phase 4, multicentre, randomised, double-
blind, superiority trial. Lancet HIV. 2017;4(7): e284-94 
19. Benjamin D, Muhleistein J, Carlquist J, Tami L, Madsen T, Hart N, et al. Seropositivity and 
high c-reactive protein in reducing mortality among patient with angiographically 
significant coronary disease. American Heart Asociation. 2003;107:258-263 
20. Ponroy N, Traveira A, Mueller NJ, Milliard AL. Statins demonstrate a broad anti-
cytomegalovirus activity in vitro ganciclovir-susceptible and resistant strains. J Med Virol. 
2015;87(1):141-53. 
 

 
 
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APPENDIX A. SCHEDULE OF EVENTS 
{Schedule of Events diagram or table, must match with section 4.12} 
Study flowchart and schedule 
 
Screening 
Randomization 
(visit 0) 
Week 24 
(visit 1) 
Week 48 
(visit 2) 
Extra Visit 
Clinical assessment 
Informed 
consent 
V 
 
 
 
 
Review 
eligibility 
V 
V 
 
 
V 
Physical 
examination 
 
V 
V 
V 
V* 
CIMT 
examination 
(puasa 4 jam), 
pemeriksaan 
1-3 menit 
 
V 
 
V 
 
Transient 
elastography 
and CAP 
 
v 
 
v 
 
Neurocognitive 
examination 
 
V 
V 
V 
 
Community 
Periodontal 
Index 
 
V 
 
V 
 
Lab assessment 
Viral load 
V 
 
 
 
 
Lipid profile 
V 
 
V 
V 
 
IgG Anti-CMV 
V 
 
 
 
 
CBC 
 
V 
 
 
 
ALT 
 
V 
 
 
V* 
Creatinin 
 
V 
 
 
 
CK 
 
 
 
 
V* 
Fasting blood 
glucose and 
insulin 
 
V 
V 
V 
 
DPL 
V* 
 
 
 
 
LED 
V* 
 
 
 
 
Store sample 
Serum 
 
V 
V 
V 
 
Other Assessment 
Depression 
assessment 
v 
 
 
 
 
*According to patient’s symptom.  
 

 
 
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Blood volume collection 
 
Type 
Blood 
collected 
screening randomization 
Week 
24 
Week 
48 
Extravisit 
1 
Viral 
load 
Plasma 
3 mL 
3 mL 
 
 
 
 
Lipid 
profile 
Serum 
2 mL 
2 mL 
 
2 mL 
2 mL 
 
Fasting 
blood 
glucose 
Serum 
1 mL 
1 mL 
 
1 mL 
1 mL 
 
IgG Anti-
CMV 
Serum 
1 mL 
1 mL 
 
 
 
 
Complete 
blood 
count 
Plasma 
EDTA 
3 mL 
 
3 mL 
 
 
 
ALT, 
Creatine 
Plasma 
EDTA 
1 mL 
 
1 mL 
 
 
1 mL 
CK 
Plasma 
EDTA 
1 mL 
 
1 mL 
 
 
1 mL 
Storage 
sample 
plasma 
6 mL 
5 mL 
6 mL 
9 mL 
9 mL 
 
TOTAL 
volume 
 
 
12 mL 
12 mL 
12 mL 
12 mL 
2 mL 

 
 
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APPENDIX B. OPERATIONAL DEFINITION 
{Operational definition table, please describe the main variables and how to measure them.} 
Variable 
Operational Definition 
Measurement 
CIMT changes 
Numerical changes  (in 
millimeter) between 
baseline and 48 weeks 
CIMT 
Common Carotid Artery (CCA) intima media thickness 
measured by using B mode imaging system, equipped with a 
linear array transducer > 7 MHz with minimal compression 
(<10:1) and footprint of at least 3 cm 
(https://www.escardio.org/Journals/E-Journal-of-Cardiology-
Practice/Volume-13/Intima-media-thickness-Appropriate-
evaluation-and-proper-measurement-described) 
FMD changes 
Numerical changes (in 
percentage) between 
baseline and 48 weeks 
FMD 
Using a high-resolution ultrasound linear array transducer, 
longitudinal images of the right brachial artery (mostly 3-15 
cm above the elbow) were recorded at the baseline and for 3 
minutes after cuff deflation following suprasystolic 
compression (50 mmHg over the systolic blood pressure) of 
the right forearm for 5 minutes. 
https://www.jstage.jst.go.jp/article/ihj/advpub/0/advpub_17-
013/_pdf; EHJ 2010. 2854-61 Assesment of atherosclerosis : 
the rolw of FMD 
Liver fibrosis 
change 
Numerical changes (in 
KPa) between baseline 
and 48 weeks 
The measurement of liver stiffness which uses the velocity of 
shear waves that travel through the liver using the Fibroscan 
(Echosens) device  
Liver steatosis 
change 
Numerical changes (in 
dB/m) between 
baseline and 48 weeks 
The measurement of steatosis using the Fibroscan (Echosens) 
equipped with CAP software. dB/m 
 

 
 
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APPENDIX C. BUDGET 
 
Items 
Cost 
Personnel 
Research assistant, pharmacist and 
laboratory assistant 
184.000.000 (IDR) 
Research cost 
Study drug, laboratory, CIMT and TE 
examination, patient transportation 
647.240.000 (IDR) 
Direct cost 
Ethical committee approval, stationary, 
communication, publication 
81.000.000 (IDR) 
TOTAL 
 
912.000.000 (IDR)