Clinical trial NCT02212379
Conditions: HIV-1 Infection
Keywords: Raltegravir Etravirine aged, 45 and over Viral load Efficacy Safety
Sponsor: ANRS, Emerging Infectious Diseases
Start date: 2015-01-01; Completion date: 2018-04-01
Enrollment: 170 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This multicenter, international, non randomized (single arm), open, phase II trial aims to evaluate the capacity of the dual combination raltegravir/etravirine to maintain virological success in virologically suppressed HIV-1 infected patients, of at least 45 years of age, switching from a boosted PI-containing regimen. Patients will be followed for 96 weeks. The primary endpoint was the proportion of participants with virological success at 48 weeks. Virological success is defined as the absence of 2 consecutive plasma viral load \>50 copies/mL within 2 to 4 weeks apart. The study was designed to show an efficacy \>90%, assuming a success rate \>95%, with a power of 80% and a 5%type-1 error. A total of 160 individuals was required to achieve the objective. The principal secondary endpoint is the proportion of patients in therapeutic success up to week 48 and 96.

Detailed description:

Arms: arm 1: None
Interventions: intervention 1: raltegravir and etravirine
Intervention descriptions: intervention 1: Raltegravir (RAL, ISENTRESS®) 400 mg tablets will be administered as one 400 mg oral tablet PO twice daily (800 mg per day) after a meal.

Etravirine (ETR, INTELENCE®) 200 mg tablets will be administered as one 200 mg oral tablet PO twice daily (400 mg per day) after a meal.

Protocol documents:
ICF_001.pdf: 
ANRS 163 ETRAL Trial  
  
 
 
  
  
ANRS 163 ETRAL Trial 
  
Information notice  
  
Non-comparative phase II pilot trial to evaluate the ability of a combination of 
raltegravir + etravirine to maintain virological success in HIV-1-infected patients of 
at least 45 years of age with a plasma viral load of less than 50 copies/mL on 
antiretroviral therapy including a boosted protease inhibitor. 
 
  
Version 2.0, dated 03/18/2015, approved by the CPP on 05/15/2015  
  
  
Coordinating Investigator:   
Prof. Christine Katlama, Pitié-Salpêtrière Hospital, Paris.   
Scientific Director:  
Prof. Jacques Reynes, Montpellier University Hospital.  
    
  
Trial Sponsor:   
  
National Institute of Health and Medical Research - National Agency for Research on AIDS and 
Viral Hepatitis (Inserm - ANRS) 101 rue de Tolbiac, Paris 75013.  
 
- This notice is designed to help you decide whether or not to participate in the trial described below. 
- You are free to answer yes or no to the question asked: do you want to participate in the trial? 
- You have the right to take as much time as you need to think about it, to discuss this trial and to ask 
anyone you want whatever you want to know about it. 
- If you do not wish to participate, you will still continue to receive the best possible care 
- You can change your mind at any time and ask to withdraw from the trial. You will continue to benefit 
from the best care that your doctor can offer you. We ask only that you inform your doctor of your 
decision as soon as possible. 
 


ANRS 163 ETRAL Trial  
  
  
 
  
  
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The words underlined in the text are explained in the glossary.  
 
Glossary 
 
    Biobank: A bank of biological samples kept for research purposes. 
 Data: Information collected as part of the trial.  
 Right of access: The right to see the data concerning you.  
 Anonymized data: Your name and surname are removed from all medical records and replaced with a code. Only the 
doctor and people with a right of access to the medical data are aware of the link between your identity and this code.  
Right of opposition: The right to oppose the transmission of your data by the investigating doctor to the sponsor. The 
exercise of this right terminates your participation in the trial. 
Right of rectification: The right to request that the correction of your data in the event of an error. 
Samples: Samples taken from people participating in the trial (e.g. blood, cells, etc.). In general, the samples are 
stored in a Biobank centralized at the ANRS.  
 Consent form: A document in which you declare that you have read the terms of participation in the trial and give 
your consent to participate. 
 Coordinating investigator: The doctor supervising the running of the trial at the various participating centers.  
 Investigating doctor of the trial (or investigator): The doctor following you in the framework of the trial. He/she may 
be your regular doctor, or another doctor involved in the trial. 
 Bone densitometry: A painless radiological examination measuring the mineral content of the bone, and the 
percentage of fat and lean mass in the limbs and trunk. 
 Pre-inclusion: The time point at which all conditions are met for your participation in the trial.  
 Sponsor: The organization legally and financially responsible for the trial. 
 Substudy: A study carried out only on some of the people participating in the trial. 
 Adipose tissue: A tissue that contains fat.  
 Integrase inhibitor: A molecule that blocks a viral enzyme, integrase, which allows the virus to enter the cell’s 
nucleus to multiply. 
 Non-nucleoside reverse transcriptase inhibitor: A molecule that blocks a viral enzyme, reverse transcriptase, the 
role of which is to convert the viral genome into DNA that can integrate into the genome of the host cell. 
 
In this notice you will find:  
 
  
1. The objectives of the trial 
4 
2. The conditions for participation in the trial 
Erreur ! Signet non défini. 
3. A schema for the trial 
Erreur ! Signet non défini. 
4. The trial treatments 
5 


ANRS 163 ETRAL Trial  
  
  
 
  
  
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5. Sexuality, contraception, and pregnancy 
6 
6. What are the constraints linked to participation in this trial? 
6 
7. The progress and timetable of the trial 
Erreur ! Signet non défini. 
8. Expected benefits and possible risks 
9 
9. Monitoring 
Erreur ! Signet non défini. 
10. Alternatives 
9 
11. What will happen at the end of the trial 
9 
12. What are your rights? 
9 
13. Information about the fate of your samples at the end of the trial 
11 
 
  
You will find a consent form on the last page: this signed document attests to your willingness to participate in 
the trial and contains the contact details of the investigating doctor of the trial, whom you can contact if 
necessary.  
  
To whom it may concern,  
  
The investigating doctor of the ANRS 163 ETRAL trial would like to invite you to participate in this trial.  
You have been on antiretroviral therapy including at least one boosted protease inhibition for the treatment of HIV 
infection for at least six months. This treatment makes it possible to control your viral load, that is, it prevents the 
multiplication of the virus in the blood (resulting in what we call an "undetectable plasma viral load"). This treatment also 
increases the number of CD4 cells in the blood, improves survival, and slows disease progression. 
Despite the considerable clinical progress achieved in patients whose virus is under control, vascular (angina pectoris or 
myocardial infarction), lipid (increases in cholesterol and triglyceride levels), renal (a decrease in the filtration rate of the 
kidney), or bone (decrease in bone density) complications may emerge over time. They are related to the persistent 
inflammation due to HIV, and to certain molecules used in antiretroviral treatments, such as, nucleoside or nucleotide 
analogs (tenofovir (Viréad®, Truvada®) or abacavir (Ziagen®, Kivexa®)) and protease inhibitors (atazanavir (Réyataz®), 
darunavir (Prézista®) lopinavir / r (Kalétra®)). The frequency of these events also increases with age and increasing 
patient life expectancy. Today, almost 40% of patients treated in French hospitals at least 50 years old. A comparison 
between HIV-positive and HIV-negative patients has shown that the frequency of complications is higher in HIV-positive 
patients and that these complications occur earlier. 
Some of the most recent classes of antiretroviral therapy or drugs are both effective against HIV and have little effect on 
lipid balance, bones, or adipose tissue. 
 
We are inviting you to participate in a trial evaluating a new strategy combining two powerful antiretroviral drugs that are 
well known and have been marketed for several years: 
-  
Raltegravir (or Isentress®), which has been available since 2008, belongs to the new class of integrase inhibitors 
(integrase allows the virus to enter the nucleus of the cell to multiply). 
-  
Etravirine (or Intelence®), which belongs to the second generation of non-nucleoside reverse transcriptase 
inhibitors, blocks a viral enzyme, reverse transcriptase, which converts the viral genome into DNA capable of integrating 
into the genome of the host cell (see the Trial treatments section). 
 
 


ANRS 163 ETRAL Trial  
  
  
 
  
  
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1. Objectives of the trial  
 
The objective of the trial is to determine whether this new combination of two antiretroviral molecules — raltegravir 
(Isentress®) and etravirine (Intelence®) — makes it possible to maintain an undetectable HIV viral load while reducing 
potential side effects, such as cardiovascular, bone, kidney, or adipose tissue distribution disorders. 
This trial includes two substudies to evaluate the following parameters: 
- The DXA substudy: changes in the distribution of adipose tissue in the body and in bone mineral density. This substudy 
will involve a painless radiological examination for measuring the mineral content of the bone, and the percentage of fat 
and lean mass in the limbs and trunk, which will be performed at regular intervals (day (D) 0, week (W) 48, W96) for 80 
participants. 
- The semen substudy: measurements of HIV RNA viral load and the residual concentrations of raltegravir (Isentress®) 
and etravirine (Intelence®) in a sample of sperm fluid collected at W48 from 20 male participants. 
 
2. The conditions for participation in the trial 
 
If you decide to participate in this trial, a first visit, the "pre-inclusion visit", will take place 2 to 4 weeks before the 
start of the trial. During this visit, the doctor will assess your state of health: clinical examination, weight, height; 
blood and urine samples will also be collected. Your doctor will ask you about your medical history, to check that 
you are eligible to participate in the trial. 
 
The principal conditions for participation in this trial are as follows. You must:   
- Be at least 45 years old 
- Be infected with HIV-1 
- Have been on stable antiretroviral treatment for at least six months 
- Have a CD4 lymphocyte count above 200/mm3  
- Have had an undetectable viral load (i.e. less than 50 copies/mL) for at least 24 months 
- Have never been treated with raltegravir (Isentress®) and etravirine (Intelence®) 
-Not take prohibited drugs during the trial (see the list in the Trial treatments section) 
- Accept the constraints imposed by the trial (see the paragraph What are the constraints linked to participation in 
the trial? section) 
- Be affiliated to or be a beneficiary of a social security regime (State Medical Aid or AME is not a social security    
regime) 
- Have signed the consent form: this form must be signed before any examination (e.g. blood test, scan, etc.) is 
carried out as part of the trial 
- Not participate in another trial at the same time as this one 
The following situations are incompatible with participation in the trial:  
- Being pregnant or breastfeeding 
- Having chronic hepatitis B or C (treated during the 24 months of the trial) 
- Anti-hypercholesterolemia and/or anti-diabetic treatment initiated in the 3 months preceding your participation in the 
trial 


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If, after checking these conditions, the investigator decides that you cannot participate in this trial, he/she will decide, 
with you, which treatment is best suited to your situation.
 
3. Schema for the trial 
 
Once the eligibility criteria have been verified, you can start the trial. 
    
All participants will replace their usual antiretroviral therapy with raltegravir (Isentress®) plus etravirine 
(Intelence®). 
    Therefore, all trial participants will receive the same treatment: raltegravir (Isentress®) and etravirine 
(Intelence®). 
    The duration of participation in the trial is 96 weeks (approximately two years). 
    The maximum total duration of the trial is estimated at four years, including the time required to include all the 
trial participants. 
     We to include 160 participants from several hospitals in France and Spain. 
 
4. Trial treatments  
 
Raltegravir (Isentress®): what you should know  
Raltegravir (Isentress®), developed by the Merck Sharp & Dohme Ltd laboratory, has been marketed in France since 
January 2008. 
Raltegravir (Isentress®) blocks the action of an enzyme (protein) called "integrase". It is produced in the form of tablets 
and must be taken at a dose of 1 tablet twice daily (i.e. 2 tablets per day). 
The tolerance of raltegravir (Isentress®) is generally good. However, like most treatments, it can cause certain adverse 
effects, the main ones being: 
- Diarrhea, nausea (feeling sick) and headache (may affect more than 1 in 10 people) 
- Insomnia (difficulty sleeping), dizziness, bloating, stomachache, flatulence (gas), vomiting, rash, weakness, fatigue 
(may affect 1 to 10 users in 100) 
- Contact your doctor immediately if you develop a cutaneous (skin) reaction. Skin reactions and life-threatening 
severe allergic reactions have been reported in some people receiving this medicine. 
- Inform your doctor if you have a history of depression or psychiatric illness. Depression, including suicidal 
thoughts and behavior, has been reported in some people taking this medication, especially those with a history of 
depression or psychiatric illness. 
 
 
Etravirine (Intelence®): what you should know 
Etravirine (Intelence®), developed by Janssen Cilag Laboratories, has been marketed in France since August 2008.  
It is produced in the form of tablets and must be taken at a dose of 1 tablet twice daily (i.e. 2 tablets per day). 
Etravirine is a non-nucleotide reverse transcriptase inhibitor. 
Tolerance to etravirine is generally good, but like most treatments, it can have certain adverse effects, the main ones 
being: 
- Skin rashes that are usually mild to moderate. However, a very serious and potentially life-threatening rash has been 
reported in rare cases. It is therefore important that you contact your doctor immediately if you develop a rash. 
- Nausea, stomach problems (diarrhea, stomachache, indigestion), headache, dizziness, tiredness (may affect less than 
1 in 10 people). 


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- Risk of myocardial infarction (frequency: less than 1 in 10 people). 
 
Doses of raltegravir (Isentress®) and etravirine (Intelence®):  
The table below specifies the dose and number of doses of the treatments that you will take as part of this trial: 
 
Who?  
Medicine  
Form  
Morning Evening
How to take it  
All participants  
Raltegravir 400 mg 
(Isentress®),  
Pink oval tablets 
1  
1  
After a meal  
Etravirine 200 mg 
(Intelence®),  
White oval tablets  
1  
1  
After a meal  
If you want more information about these treatments, do not hesitate to talk to your doctor. 
 
Tell your doctor before taking other medicines during the trial:  
It is important to tell your doctor about the medicines that you take or wish to take (with or without a prescription) during 
the trial. 
The following drugs are formally contraindicated and must not be taken in combination with the trial treatments 
because they may interact with or limit the efficacy of the anti-HIV treatments: 
 
• Antiplatelet agents: Clopidogrel (Plavix®), prasugrel (Effient®), ticagrelor (Brilique®), ticlopidine (Ticlid®), 
flurbiprofene (Antadys® - Cebutid®).  
• Anti-infection agents: Rifampicine (Rifampicine® - Rifadin® - RofactMC - Rifater®), rifapentine (Priftin®).  
• Certain herbal medicines containing St. John's Wort.  
• Anti-epileptic agents: Carbamazepine (Tegretol®), phenobarbital, phenytoine (Dilantin®).  
• Other drugs: Avanafil (Stendra™), triazolam (Halcion®).  
If you have any questions about these medicines, do not hesitate to talk to your doctor.
 
5. Sexuality, contraception, and pregnancy 
 
It is very important to use a condom during sex, because treatment for HIV does not always prevent the transmission of 
HIV and other sexually transmitted infections. 
Raltegravir (Isentress®) and etravirine (Intelence®) have not been evaluated in pregnant women. Their effects on the 
unborn child are not known. It is therefore important not to take any risks and not to become pregnant during the trial. 
You should discuss the contraceptive method best suited to your situation with your doctor. If you, nevertheless, discover 
that you are pregnant during the trial, you should immediately tell your doctor. 
 
6. What are the constraints linked to participation in the trial?   
 
During this trial, medical examinations will be slightly more frequent than during your usual follow-up. You should expect: 
• 
A pre-inclusion visit and 10 follow-up visits during the two years of participation.   
• 
Blood tests at each visit and questionnaires to be completed at certain visits. 


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If you agree to take part in one or both of the two proposed substudies, you must also be available for the examinations 
or blood tests for these substudies: bone densitometry (a painless radiological examination that measures the mineral 
content of bone and the percentages of fat and lean mass in the limbs and trunk) and sperm collection. 
For your safety and for the success of the trial, it is important to follow the visit schedule as closely as possible. Given the 
importance of keeping to the timetable for the trial, the medical team in charge of your follow-up in the trial will do their 
utmost to facilitate this. You will be in contact with the clinical research team of your center, who will give you your 
schedule and all the telephone numbers that might prove useful for the smooth running of your participation. If you 
cannot come for a consultation or provide a sample, remember to tell your doctor. 
Your agreement to participate in this trial implies that you accept the constraints imposed by the scheduled examinations. 
Do not hesitate to ask the investigating doctor all the necessary questions on this subject. If you wish, he/she can give 
you information about your follow-up in the trial at each consultation. 
 
7. The progress and timetable of the trial 
 
If you agree to participate in the trial, you will sign a consent form before the first examination related to the trial. You will 
have a total of 11 visits spread over the two years of your participation in the trial: 
"Pre-inclusion" visit: the investigating doctor will ask you about your medical history and perform a clinical 
examination and blood tests to make sure that you can participate in the trial. 
  
If all the conditions for participation are met: 
Visit D0: corresponds to the first dose of raltegravir (Isentress®) and etravirine (Intelence®). This visit 
takes place 2 to 4 weeks after the pre-inclusion visit. 
There will be 9 other visits: W2, W4, W12, W24, W36, W48, W64, W80, and W96 (see the trial calendar). 
 
During these visits, the investigating doctor will take blood samples for routine blood tests, such as blood sugar, the 
measurement of viral load (measurement of the amount of virus in the blood), or counts of CD4 lymphocytes. Other 
blood samples will be used to carry out more specific blood tests, such as determinations of the amount of the trial drugs 
in your blood. 
Some samples/blood samples will be analyzed immediately, and others will be kept for analysis at the end of the trial. 
You will be asked for a urine sample at visits W-6/W-4, W4, W12, W24, W48, W80, and W96, to check for protein or 
glucose (sugar) in your urine, these substances normally being present in only very small amounts. 
Blood samples for storage will be sent to the French Blood Establishment (EFS) in Beynost (France) to constitute a 
biobank. Each sample will be labeled and numbered anonymously (your name will not be indicated). 
The samples from the biobank can be used for additional studies. If these additional studies involve genetic testing, 
you will be asked for consent for such testing. 
You can specify in your consent that you do not wish your samples to be kept in the biobank for use in future 
research. 
 
Substudies 
If you are volunteering for the DXA substudy, to evaluate changes in the distribution of fat in your body and changes in 
bone mineral density, bone densitometry will be performed on D0 and at W48 and W96 (80 participants). 
Patients wishing to participate in the semen substudy, which aims to measure the viral load of HIV and the residual 
concentration of raltegravir (Isentress®) and etravirine (Intelence®) in sperm fluid, will provide a sperm sample at W48 
(20 participants). 
 


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The questionnaires and self-administered questionnaires to be completed during the trial  
- “Quality of life” and “compliance” self-administered questionnaires: These are anonymized questionnaires, on paper, 
that you will complete on your own. At no time will we be able to intervene your responses. The self-administered 
"compliance" questionnaire will tell us whether you are taking your treatments as prescribed by your doctor. If this is not 
the case, your doctor will try to understand why and work with you to try to find a solution. 
  
  
 
 
 
 
  
Trial Calendar  
  
Pre-
inclusion*  
(W-6/W-4 
to  
W-2)  
D:  
Start of 
treatment  
W2  
W4  
W12  
W24  
W36  
W48  
W64  
W80  
W96  
In case of 
virological 
failure 
Signature of consent form 
  
  
  
  
  
  
  
  
  
  
  
  
Clinical examination 
  
  
  
  
  
  
  
  
  
  
  
  
Quality of life self-
administered 
questionnaires  
  
  
  
  
  
  
  
  
  
  
  
  
Compliance questionnaire 
  
  
  
  
  
  
  
  
  
  
  
  
Come to the consultation 
after a period of at least 
12 h without eating  
  
  
  
  
  
  
  
  
  
  
  
  
Pregnancy test (1)  
  
  
  
  
  
  
  
  
  
  
  
  
Urine sample  
  
  
  
  
  
  
  
  
  
  
  
  
DXA /  
Bone densitometry 
(substudy) 
  
  
  
  
  
  
  
  
  
  
  
  
Sperm sample          
(substudy)  
  
  
  
  
  
  
  
  
  
  
  
  
Amount of blood for the 
ETRAL trial (without 
storage in the biobank) 
29 mL  (7 
tubes)  
22 mL   
  
(6 tubes)  
0 mL  
19 mL  
(5 
tubes) 
22 mL  
(6 
tubes) 
25 mL  
(7 
tubes) 
7 mL  
(1 
tubes) 
25mL 
(7 
tubes)  
7 mL  
(1 
tubes)  
16 mL  
(4 
tubes)  
25 mL 
(7 
tubes) 
14 mL 
  
 (2 tubes) 
Additional blood for the 
biobank  
0 mL  
45 mL  
  
(7 tubes)   
21 mL  
(3 
tubes)  
21 mL  
(3 
tubes) 
21 mL  
(3 
tubes)   
21 mL  
(3 
tubes)  
21 mL 
(3 
tubes) 
45 mL 
(7 
tubes)  
21 mL  
(3 
tubes)  
21 mL  
(3 
tubes)  
45 mL 
(7 
tubes) 
7 mL (1 
tubes)  
Total amount of blood 
collected 
(mL)  
29 mL (7 
tubes)  
67 mL  
(13 tubes)  
21 mL  
(3 
tubes)  
40 mL 
(8 
tubes) 
43 mL 
(9 
tubes) 
46 mL 
(10 
tubes) 
28 mL 
(4 
tubes) 
70 mL 
(14 
tubes)  
28 mL  
(4 
tubes)  
37 mL  
(7 
tubes)  
70 mL 
(14 
tubes)  
21 mL (3 
tubes)  
*Pre-inclusion: takes place 2 to 4 weeks before the start of treatment. W: week 
(1) The pregnancy test is carried out only for women of childbearing age at W-6/W-4 and then at subsequent visits if pregnancy is suspected. 
 
  
  


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8. Expected benefits and possible risks 
 
Expected benefits  
- The antiretroviral drugs that you will receive as part of the ANRS 163 ETRAL trial have shown, separately, to have 
virological efficacy, with raltegravir (Isentress®) having a lesser effect on lipid profile and bones. 
You will benefit from participation if the trial shows that the raltegravir (Isentress®) + etravirine (Intelence®) combination 
controls viral replication, is well tolerated, and reduces the frequency of complications associated with HIV infection and 
your previous treatment. 
 
- You will benefit from more frequent monitoring and more detailed examinations. 
- You will be involved in research, the results of which may be of benefit to other people. 
 
Possible risks  
- Raltegravir (Isentress®) and etravirine (Intelence®) can cause known (as described in the Trial treatments section)      
or unknown adverse effects. 
- The trial treatment should control viral replication and ireduce the complications of HIV infection and your previous 
treatment. However, there is a risk of replication. You will be monitored closely to detect any rise in HIV viral load. 
- Blood tests may cause bruising at site of puncture, on the day of the examination and on the following two to three 
days. 
 
9. Monitoring 
 
During the trial if, for example, your health deteriorates and other treatments are preferable, or if justified by adverse 
effects, you can decide, with your doctor, to stop the trial treatment at any time, while continuing your monitoring. 
Throughout the trial, scientific committees will monitor the study for adverse effects or failures of raltegravir (Isentress®) 
and etravirine (Intelence®). These committees ensure the safety of those involved in the trial and oversee the running of 
the trial. If necessary, for safety reasons, for example, they can decide to end the trial or to modify the way in which it is 
performed. 
 
10. Alternatives  
 
You should know that your participation in the trial is free and voluntary. You can decide to refuse to participate in the 
trial and remain on your current treatment. Your decision to agree or refuse to participate in this trial will not change the 
quality of your medical care. 
 
11. What will happen at the end of the trial?   
 


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Raltegravir (Isentress®) and etravirine (Intelence®) are already sold in France. If the final results of the trial are 
conclusive, your doctor may wish to consider continuing with this combination. At the end of the trial, participants will be 
able to discuss their results and their experience of participation in the trial. 
The overall results of the trial will be communicated to the participants after the trial has ended. 
 
12. What are your rights?  
 
Do not forget that you can:  
- Take as long as you need to think before deciding to participate in this trial 
- Leave the trial at any time, without giving a reason, by simply telling your doctor 
- Find out about your health 
- Be informed of any serious events occurring during the trial 
- Be informed of your results and of the overall results of the trial 
- Check and correct data concerning you 
- Oppose the transmission of data concerning you  
- Obtain compensation in the event of harm 
 
Your data:  
As part of the trial in which you are being asked to participate by the National Agency for Research on AIDS and Viral 
Hepatitis (ANRS), your personal data will be processed as part of the analysis of the results of the trial with respect to its 
objectives, which have been presented to you. 
To this end, the medical data concerning you and the data relating to your lifestyle, and, insofar as these data are 
necessary for the trial, your ethnic origins, and sex life, will be transmitted to the sponsor of the trial or to individuals or 
companies acting on the sponsor’s behalf, in France or abroad. 
These data will be identified by a code number. These data may also be transmitted to French or foreign health 
authorities (Medicines Agency, etc.) or to other ANRS partners, under conditions of confidentiality. 
In accordance with the provisions of the law relating to data processing and freedoms, you have the right of access and 
rectification. You also have the right to oppose the transmission of data covered by professional secrecy that may be 
used in the context of this trial and be processed. The exercise of this right will terminate your participation in the trial. 
You can also access all of your medical data directly or through a doctor of your choice, in accordance with the 
provisions of article L 1111-7 of the French Public Health Code. 
If you have any questions about these rights, you can contact the doctor following you during the trial. If desired, 
information about the trial and your participation will be shared with your general practitioner. 
This trial received was approved by the Personal Protection Committee (CPP) on 04/16/2014 and authorized by the 
ANSM on 04/04/2014. 
The sponsor of this trial, Inserm-ANRS, has taken out civil liability insurance in the event of harm, in accordance with the 
provisions of the French Public Health Code, with HDI Gerling (Tours opus 12, 77 Esplanade de la Défense 92914 
PARIS LA DEFENSE) . 
The French Public Health Code also guarantees compensation to anyone suffering harm due to participation in research. 
 
 
 
 
 
 


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13. 
Information about the fate of your samples at the end of the trial 
 
  
  
To whom it may concern,  
  
  
As specified in the information notice specific to the ANRS 163 ETRAL trial, in which you are invited to 
participate, blood samples, urine samples, and (possibly) a semen sample will be taken. 
If the blood and semen samples are not completely used up at the end of this trial, they may be used for 
scientific research on HIV unless you object. 
The remaining samples: 
 
• 
Will be stored at the EFS (French Blood Establishment - Beynost site), under the control of its 
logistics management, on behalf of the ANRS, and under the scientific responsibility of the 
common service 10-US019 of Inserm (Paul Brousse Hospital, Villejuif) 
• 
May be supplied free of charge, and under certain conditions, to other national or international 
private or public research groups, under conditions guaranteeing the confidentiality of your data  
• 
May not, in any case, be used for the examination of genetic characteristics without new written 
consent from you. 
 
You may freely, and at any time, object to this further use for research purposes, by contacting 
the investigating doctor of the trial. 
Your decision will have no consequences for your participation in the ANRS 163 ETRAL trial or your 
medical care. 
Name, address, and contact details. 
 
 .......................................................................................................................................................   
  
 .......................................................................................................................................................   ............
...........................................................................................................................................   
  
 
In accordance with the law, no remuneration can be paid to you. 
The transferred samples cannot be sold. 


ANRS 163 ETRAL Trial  
  
  
 
  
  
Page 12 of 11  
For sample management, the EFS uses a computer file authorized by the French National Commission 
for Data Protection (CNIL). This file contains anonymized data for the identification of samples. 
 
 


ANRS 163 ETRAL Trial                          Consent Form                             
└─┴─┘└─┴─┴─┘└─┴─┴─┘└─┴─┴─┴─┘  
 Country         Center No.    Patient No.         Letter code 
 
    
Version 2.0 of 03/18/2015, approved by the CPP on 05/15/2015  
Sponsor: Inserm-ANRS                  Coordinating investigator: Prof. Christine Katlama   
Ms, Mr 
(first and last name)  
 
I certify: having received information notice version 2.0 dated 03/18/2015, that I have had the opportunity to ask all the 
questions I wished on the nature, objectives, potential risks, and constraints relating to my participation in this trial, 
 and that I have had sufficient time to reflect between receiving this information and giving my consent. 
I understand the constraints (more frequent visits, numerous blood samples) and the benefits linked to my participation in 
this trial, which will last approximately 2 years. 
I understand that I am free to discontinue my participation in this trial at any time, without having to explain why, but I will 
do my best to inform the doctor. This will not affect the quality of my subsequent care. 
I have been reassured that the decisions that are necessary for my health will be made at all times, in accordance with 
the state of knowledge on HIV. 
I have noted that blood samples and a semen sample (if I participate in the semen substudy) will be taken during the trial 
and stored anonymously. They will make it possible to carry out the planned analyses for this trial. 
I accept that the data recorded during this trial will be collected, processed, and computerized. I understand that the right 
of access laid down in the modified law of January 6, 1978 relating to data processing, files, and freedoms, can be 
exercised at any time, through the doctor following me in the trial, and that I can exercise my right of rectification and 
opposition. 
I accept that the scientists involved in this trial, and the individuals authorized by the health authorities in France and 
abroad, may have access to the information, under strict conditions of confidentiality. 
My consent in no way relieves the organizers of the trial of their responsibilities. I retain all my statutory rights. 
At the end of the trial, I may be informed of the overall results through the investigating doctor of the trial. 
I have been informed by the explanatory notice that my blood and/or semen samples may be used at the end of the trial 
for other research on HIV infection, unless I oppose this. 
 
    I authorize the storage of my blood samples for             I oppose the storage of my blood samples for         
future research.  
 
 
 
 
 
future research.  
They will be destroyed at the end of the trial. 
I agree to participate in the DXA substudy "Distribution of fat mass and bone mineral density" 
 
I agree to participate in the seminal sub-study "Measurement of RNA-HIV viral load in semen"  
 
   I authorize the storage of my sperm samples for           I oppose the storage of my sperm samples for     
further research. 
 
 
 
 
 
future research.  
They will be destroyed at the end of the trial. 
I freely agree to participate in this test under the conditions 
specified in the information notice 
           
 Date └─┴─┘└─┴─┘└─┴─┴─┴─┘  
  
  
Participant’s signature  
I, the undersigned, Dr/Pr ……………………………………..  certify that I have communicated to the participant all the 
useful information relating to this trial, that I have answered his questions and obtained his consent.  
 Date└─┴─┘└─┴─┘└─┴─┴─┴─┘  


ANRS 163 ETRAL Trial                          Consent Form                             
└─┴─┘└─┴─┴─┘└─┴─┴─┘└─┴─┴─┴─┘  
 Country         Center No.    Patient No.         Letter code 
 
Write or place a label  
    
Name of the unit:  
Address:  
Telephone:   
Doctor’s signature 
INVESTIGATOR COPY (a copy is made for the sponsor) 
  
1/1  
 
 


ANRS 163 ETRAL Trial                          Consent Form                             
└─┴─┘└─┴─┴─┘└─┴─┴─┘└─┴─┴─┴─┘  
 Country         Center No.    Patient No.         Letter code 
 
    
Version 2.0 dated 03/18/2015, approved by the CPP on 05/15/2015  
Sponsor: Inserm-ANRS                  Coordinating investigator: Prof. Christine Katlama  
Ms, Mr (first 
and 
last name)  
I certify:  
having received information notice version 2.0 dated 03/18/2015, that I have had the opportunity to ask all the 
questions I wished on the nature, objectives, potential risks, and constraints relating to my participation in this trial, 
 and that I have had sufficient time to reflect between receiving this information and giving my consent. 
I understand the constraints (more frequent visits, numerous blood samples) and the benefits linked to my participation in 
this trial, which will last approximately 2 years. 
I understand that I am free to discontinue my participation in this trial at any time, without having to explain why, but I will 
do my best to inform the doctor. This will not affect the quality of my subsequent care. 
I have been reassured that the decisions that are necessary for my health will be made at all times, in accordance with 
the state of knowledge on HIV. 
I have noted that blood samples and a semen sample (if I participate in the semen substudy) will be taken during the trial 
and stored anonymously. They will make it possible to carry out the planned analyses for this trial. 
I accept that the data recorded during this trial will be collected, processed, and computerized. I understand that the right 
of access laid down in the modified law of January 6, 1978 relating to data processing, files, and freedoms, can be 
exercised at any time, through the doctor following me in the trial, and that I can exercise my right of rectification and 
opposition. 
I accept that the scientists involved in this trial, and the individuals authorized by the health authorities in France and 
abroad, may have access to the information, under strict conditions of confidentiality. 
My consent in no way relieves the organizers of the trial of their responsibilities. I retain all my statutory rights. 
At the end of the trial, I may be informed of the overall results through the investigating doctor of the trial. 
I have been informed by the explanatory notice that my blood and/or semen samples may be used at the end of the trial 
for other research on HIV infection, unless I oppose this. 
 
    I authorize the storage of my blood samples for             I oppose the storage of my blood samples for         
future research.  
 
 
 
 
 
future research.  
They will be destroyed at the end of the trial. 
I agree to participate in the DXA substudy "Distribution of fat mass and bone mineral density" 
 
I agree to participate in the seminal sub-study "Measurement of RNA-HIV viral load in semen"  
 
   I authorize the storage of my sperm samples for           I oppose the storage of my sperm samples for     
further research. 
 
 
 
 
 
future research.  
They will be destroyed at the end of the trial. 
  
 I freely agree to participate in this trial under the conditions   
specified in the information notice 
           
Date └─┴─┘└─┴─┘└─┴─┴─┴─┘  
  
  
Participant’s signature  
  


ANRS 163 ETRAL Trial                          Consent Form                             
└─┴─┘└─┴─┴─┘└─┴─┴─┘└─┴─┴─┴─┘  
 Country         Center No.    Patient No.         Letter code 
 
I, the undersigned, Dr/Pr ……………………………………..  
certify that I have communicated to the participant all the useful information relating to this trial, that I have answered 
his/her questions and obtained his/her consent.  
  
Date └─┴─┘└─┴─┘└─┴─┴─┴─┘  
Write or place a label  
    
Name of the unit:  
Address:  
Telephone:   
Doctor’s signature  
CMG Inserm UMR S 1136 COPY 
 
 


ANRS 163 ETRAL Trial                          Consent Form                             
└─┴─┘└─┴─┴─┘└─┴─┴─┘└─┴─┴─┴─┘  
 Country         Center No.    Patient No.         Letter code 
 
    
Version 2.0 dated 03/18/2015, approved by the CPP on 05/15/2015  
Sponsor: Inserm-ANRS                  Coordinating investigator: Prof. Christine Katlama   
Ms, Mr 
(first and last name)  
  
I certify:  
having received information notice version 2.0 dated 03/18/2015, that I have had the opportunity to ask all the 
questions I wished on the nature, objectives, potential risks, and constraints relating to my participation in this trial, 
 and that I have had sufficient time to reflect between receiving this information and giving my consent. 
I understand the constraints (more frequent visits, numerous blood samples) and the benefits linked to my participation in 
this trial, which will last approximately 2 years. 
I understand that I am free to discontinue my participation in this trial at any time, without having to explain why, but I will 
do my best to inform the doctor. This will not affect the quality of my subsequent care. 
I have been reassured that the decisions that are necessary for my health will be made at all times, in accordance with 
the state of knowledge on HIV. 
I have noted that blood samples and a semen sample (if I participate in the semen substudy) will be taken during the trial 
and stored anonymously. They will make it possible to carry out the planned analyses for this trial. 
I accept that the data recorded during this trial will be collected, processed, and computerized. I understand that the right 
of access laid down in the modified law of January 6, 1978 relating to data processing, files, and freedoms, can be 
exercised at any time, through the doctor following me in the trial, and that I can exercise my right of rectification and 
opposition. 
I accept that the scientists involved in this trial, and the individuals authorized by the health authorities in France and 
abroad, may have access to the information, under strict conditions of confidentiality. 
My consent in no way relieves the organizers of the trial of their responsibilities. I retain all my statutory rights. 
At the end of the trial, I may be informed of the overall results through the investigating doctor of the trial. 
I have been informed by the explanatory notice that my blood and/or semen samples may be used at the end of the trial 
for other research on HIV infection, unless I oppose this. 
   J’autorise la conservation de mes échantillons      Je 
* 
 
 
 
 
I authorize the storage of my blood samples for             I oppose the storage of my blood samples for           
future research.  
 
 
 
 
 
future research.  
They will be destroyed at the end of the trial. 
I agree to participate in the DXA substudy "Distribution of fat mass and bone mineral density" 
 
I agree to participate in the semen substudy "Measurement of HIV-RNA viral load in semen"  
 
    I authorize the storage of my sperm samples for           I oppose the storage of my sperm samples for     
further research. 
 
 
 
 
 
future research.  
They will be destroyed at the end of the trial. 
 
 I freely agree to participate in this trial under the conditions 
   specified in the information notice  
 
Date└─┴─┘└─┴─┘└─┴─┴─┴─┘  
           
  
Participant’s signature  


ANRS 163 ETRAL Trial                          Consent Form                             
└─┴─┘└─┴─┴─┘└─┴─┴─┘└─┴─┴─┴─┘  
 Country         Center No.    Patient No.         Letter code 
 
  
  
I, the undersigned, Dr/Prof. ……………………………………..  
certify that I have communicated to the participant all the useful information relating to this trial, that I have answered 
his/her questions and obtained his/her consent.  
  
Date └─┴─┘└─┴─┘└─┴─┴─┴─┘  
Write or place a label  
    
Name of the unit:  
Address:  
Telephone:   
Doctor’s signature  
  
PATIENT’S COPY (attached to the notice) 

Prot_SAP_ICF_000.pdf: 
ANRS 163 - ETRAL  
Version n° 3.0 dated 19/01/2018 
 
1  
 
 
CLINICAL TRIAL PROTOCOL 
      REGARDING A DRUG HUMAN USE 
 
 
      ANRS 163 ETRAL 
 
 
 
A non-comparative phase II trial evaluating the capacity of the dual combination 
raltegravir/etravirine to maintain virological success in HIV-1 infected patients of at 
least 45 years of age with an HIV-RNA plasma viremia below 50 copies/mL 
under a current boosted protease inhibitor containing regimen. 
 
Version n°3.0 dated 19/01/2018 
 
EudraCT number: 2014-000828-24 
Number of registration in http://clinicaltrials.gov/: NCT 02212379 
Approved by the CPP Ethics Committee on 06/03/2018 
Authorized by ANSM on 27/04/2015 
 
Sponsor: 
Institut National de la Santé et de la Recherche Médicale – Agence nationale de 
recherches sur le sida et les hépatites virales (Inserm - ANRS) 
101 rue de Tolbiac 
75013 Paris 
France 
Tél. : + 33 (0)1 53 94 60 00 - Fax : + 33 (0)1 53 94 60 01 
 
Coordinating investigator: 
Pr Christine Katlama 
Service des Maladies Infectieuses et 
Tropicales  
Groupe Hospitalier Pitié-Salpêtrière, Paris 
France 
: + 33 (0)1 42 16 01 42 
: christine.katlama@psl.aphp.fr 
 
Scientific director: 
Pr Jacques Reynes 
Département des Maladies Infectieuses et 
Tropicales 
Hôpital Gui de Chauliac, CHU de Montpellier 
France 
: + 33 (0)4 67 33 72 20 
: j-reynes@chu-montpellier.fr 
 
 
 
 
 
 
 
Methodology centre: 
 
Dominique Costagliola 
Inserm UMR S 1136 Université Pierre et 
Marie Curie 
Epidémiologie, stratégies thérapeutiques et 
virologie cliniques dans l’infection à VIH 
56 Bd Vincent Auriol, BP 335,  
75625 Paris Cedex 13 
France 
: + 33 (0)1 42 16 42 82 
:dominique.costagliola@ccde.chups.jussieu.fr  
 
Confidentiality clause 
This document contains information that is the property of the Sponsor and which are 
entrusted in confidence to be considered by you, your team, members of the Ethics 
Committee and the Competent Authority concerned. The information contained in this 
document shall not be communicated to third parties without the prior written consent of the 
sponsor of the trial, except as necessary to obtain informed consent from people who could 
lending for trial. 


ANRS 163 - ETRAL  
Version n° 3.0 dated 19/01/2018 
 
2  
 


ANRS 163 - ETRAL  
Version n° 3.0 dated 19/01/2018 
 
3  
 
 
TABLE OF CONTENTS 
 
TABLE OF PROTOCOL VERSIONS ......................................................................................................6 
LIST OF ABBREVIATIONS .....................................................................................................................7 
MAIN CORRESPONDENTS ....................................................................................................................9 
1 
STUDY SYNOPSIS .................................................................................................................................... 11 
2 
RESUME DE L’ESSAI .............................................................................................................................. 16 
3 
STUDY DESIGN ........................................................................................................................................ 21 
4 
SCHEDULE OF ASSESSMENTS ............................................................................................................ 22 
5  
BACKGROUND / RATIONALE .............................................................................................................. 23 
5.1 BACKGROUND ............................................................................................................................................. 23 
5.2 POTENTIAL LONG-TERM COMPLICATIONS OF CURRENT ANTIRETROVIRAL TREATMENTS ............................. 23 
5.2.1 Cardiovascular risk ............................................................................................................................ 23 
5.2.2 Bone toxicity ....................................................................................................................................... 23 
5.2.3 Renal toxicity ...................................................................................................................................... 24 
5.3 AN AGING HIV-POPULATION AT RISK OF CUMULATING DRUG TOXICITY AND CO-MORBIDITIES ................... 24 
5.4 RALTEGRAVIR AND ETRAVIRINE: BENEFITS AND ADVANTAGES IN TERMS OF TOXICITY ............................... 25 
5.4.1 Raltegravir (RAL) ............................................................................................................................... 25 
5.4.2 Etravirine (ETR) ................................................................................................................................. 25 
5.5 RALTEGRAVIR AND ETRAVIRINE DUAL COMBINATION AS SWITCH ALTERNATIVE IN VIROLOGICALLY 
SUPRESSED HIV-INFECTED PATIENTS ................................................................................................................ 26 
5.5.1 Viral efficacy ....................................................................................................................................... 26 
5.5.2 Pharmacologic interactions between raltegravir and etravirine ....................................................... 26 
5.6 TRIAL HYPOTHESIS ...................................................................................................................................... 27 
6 
OBJECTIVES ............................................................................................................................................. 27 
6.1 PRINCIPAL OBJECTIVE .................................................................................................................................. 27 
6.2 SECONDARY OBJECTIVES ............................................................................................................................ 27 
6.2.1 Biological efficacy .............................................................................................................................. 27 
6.2.2 Tolerability and Metabolic Impact ..................................................................................................... 27 
7 
EXPERIMENTAL DESIGN ..................................................................................................................... 28 
7.1 MAIN STUDY ................................................................................................................................................ 28 
7.2 SUB-STUDIES ............................................................................................................................................... 28 
7.2.1 DXA-scan ............................................................................................................................................ 28 
7.2.2 Seminal sub-study ............................................................................................................................... 28 
7.3 STUDY DESIGN ............................................................................................................................................ 30 
7.4 ESTIMATED STUDY DURATION ..................................................................................................................... 31 
8 
ELIGIBILITY CRITERIA ........................................................................................................................ 31 
8.1 INCLUSION CRITERIA ................................................................................................................................... 31 
8.2 NON-INCLUSION CRITERIA ........................................................................................................................... 31 
9 
STUDY ENDPOINTS ................................................................................................................................ 32 
9.1 PRIMARY ENDPOINT .................................................................................................................................... 32 
9.2 SECONDARY ENDPOINTS.............................................................................................................................. 32 
10.  DRUGS MANAGEMENT ......................................................................................................................... 33 
10.1 STUDY DRUG ............................................................................................................................................. 33 
10.2 STUDY DRUG CIRCUIT ................................................................................................................................ 33 
10.2.1 Study drug: delivery .......................................................................................................................... 33 
10.2.2 Study drug: packaging ..................................................................................................................... 33 
10.2.3 Study drug: labeling ......................................................................................................................... 33 
10.2.4 Study drug: dispatching and dispensiation ...................................................................................... 33 
10.2.5 Study drug: return and destruction .................................................................................................. 34 


ANRS 163 - ETRAL  
Version n° 3.0 dated 19/01/2018 
 
4  
 
10.3 CONCOMITANT TREATMENTS ..................................................................................................................... 34 
10.3.1 Interations and dose recommendations with other medicinal products concomitant .................... 35 
10.3.2 Drugs That Should Not Be Used With Antiretroviral Agents as etravirine and raltegravir .......... 36 
11 
STUDY ASSESSMENTS AND CONDUCT ............................................................................................ 37 
11.1 SCHEDULE OF ASSESSMENTS ...................................................................................................................... 37 
11.2 STUDY PARTICIPATION .............................................................................................................................. 38 
11.2.1 Information ....................................................................................................................................... 38 
11.2.2 Obtaining consent ............................................................................................................................. 38 
11.2.3 Patient identification ........................................................................................................................ 38 
11.3 SCREENING VISIT (W -6/W-4) .................................................................................................................... 38 
11.4 DAY 0 VISIT (INCLUSION) ........................................................................................................................... 39 
11.5 FOLLOW-UP VISITS ..................................................................................................................................... 39 
11.5.1 Visits W2 to W80 ............................................................................................................................... 40 
11.5.2 Last visit of follow-up ....................................................................................................................... 41 
11.6 STUDY END ................................................................................................................................................ 42 
11.7 PREMATURE AND DEFINITIVE STOP OF THE STUDY TREATMENT ................................................................. 42 
11.8 LOST TO FOLLOW-UP ................................................................................................................................. 42 
11.9 WITHDRAWAL OF THE CONSENT AND GIVING UP ....................................................................................... 42 
11.9.1 Consent withdrawal .......................................................................................................................... 42 
11.9.2 Giving up ........................................................................................................................................... 43 
11.10 PROTOCOL DEVIATIONS ........................................................................................................................... 43 
11.11 TRIAL-SPECIFIC RULES FOR TREATMENT MANAGEMENT .......................................................................... 43 
11.11.1 Virological failure .......................................................................................................................... 43 
11.11.2 Potential risks of study drug and the research and management guidelines ............................... 43 
11.11.3 Management of lipid metabolism impairment ............................................................................... 44 
11.11.4 Management of glycaemia impairment ......................................................................................... 44 
11.11.5 Management of pregnancy ............................................................................................................. 44 
12 
BIOLOGICAL SAMPLES AND STORAGE .......................................................................................... 44 
12.1 SCHEDULE OF SAMPLE’S COLLECTION ....................................................................................................... 45 
12.2 BLOOD SAMPLES PREPARATION FOR HIV-DNA QUANTIFICATION AND PLASMA STORAGE ........................ 47 
12.3 EVALUATED PARAMETERS ......................................................................................................................... 47 
12.3.1 Evaluation of the glucid and lipid metabolism ................................................................................ 47 
12.3.2 Evaluation of the cardiovascular risk .............................................................................................. 47 
12.3.3. Evaluation of the HIV reservoir in the blood ................................................................................. 48 
12.3.4. Minimal concentrations of ARVs in the plasma ............................................................................. 48 
12.4 CENTRALIZATION OF SAMPLES IN INSERM-ANRS BIOBANK ..................................................................... 48 
12.4.1 Centralization at site Beynost (France) ........................................................................................... 48 
12.4.2 Samples access .................................................................................................................................. 48 
13 
TRIAL SAFETY ......................................................................................................................................... 49 
13.1 DEFINITIONS .............................................................................................................................................. 49 
13.1.1 Adverse Event (AE) .......................................................................................................................... 49 
13.1.2 Adverse Reaction (AR) ..................................................................................................................... 49 
13.1.3 Serious Adverse Event (SAE) or Serious Adverse Reaction (SAR) ................................................ 49 
13.1.4 Suspected Unexpected Serious Adverse Reaction (SUSAR) ........................................................... 49 
13.1.5 New fact ............................................................................................................................................ 49 
13.2 RESPONSIBILITIES OF THE INVESTIGATOR .................................................................................................. 50 
13.2.1 AE notification ................................................................................................................................. 50 
13.2.2 SAE notification ............................................................................................................................... 50 
13.2.3 SAE evaluation ................................................................................................................................. 51 
13.2.4 Pregnancy notification ..................................................................................................................... 52 
13.3 RESPONSIBILITIES OF THE SPONSOR ........................................................................................................... 53 
13.3.1 Recording and assessment of SAE ................................................................................................... 53 
13.3.2 Reporting of safety data to the national competent authority and the Ethics Committee .............. 54 
14 
TRIAL SURVEY ........................................................................................................................................ 55 
14.1 SCIENTIFIC COMMITTEE (SC) .................................................................................................................... 55 
14.1.1 Composition ...................................................................................................................................... 55 
14.1.2 Frequency of meetings ..................................................................................................................... 55 
14.1.3 Role ................................................................................................................................................... 55 


ANRS 163 - ETRAL  
Version n° 3.0 dated 19/01/2018 
 
5  
 
14.2 DATA SAFETY MONITORING BOARD (DSMB) ........................................................................................... 55 
14.2.1 Composition ...................................................................................................................................... 55 
14.2.2 Frequency of meetings ..................................................................................................................... 56 
14.2.3 Role ................................................................................................................................................... 56 
14.3 METHODOLOGY AND STUDY MANAGEMENT CENTRE (CMG INSERM UMR S 1136) ................................. 56 
14.3.1 Composition ...................................................................................................................................... 56 
14.3.2 Role ................................................................................................................................................... 56 
15 
CONTROL AND DATA MANAGEMENT ............................................................................................. 57 
15.1 DATA TRANSFER TO CMG INSERM UMR S 1136 ...................................................................................... 57 
15.2 DATA CONTROL ......................................................................................................................................... 57 
15.2.1 Electronic control of the data ........................................................................................................... 57 
15.2.2 Data control in the clinical site ........................................................................................................ 57 
15.2.3 Participants in charge of study monitoring .............................................................................................. 58 
15.2.4 Monitoring of the trial .................................................................................................................................. 58 
15.3 AUDITING .................................................................................................................................................. 58 
16 
STATISTICAL CONSIDERATIONS ...................................................................................................... 58 
16.1 PATIENTS SAMPLE CALCULATION .............................................................................................................. 58 
16.2 STATISTICAL ANALYSIS ............................................................................................................................. 59 
16.2.1 Criteria for evaluation ...................................................................................................................... 59 
16.2.2 Statistical methods ............................................................................................................................ 59 
16.2.3 Statistical analysis plan .................................................................................................................... 59 
16.2.4 Software programs used ................................................................................................................... 60 
17 
PUBLICATION .......................................................................................................................................... 60 
18 
ETHICS AND REGULATORY ISSUES ................................................................................................. 60 
18.1 ETHICAL AND REGULATORY ASPECTS ........................................................................................................ 60 
18.2 PARTICIPANT CONSENT (CF. INFORMATION NOTE AND CONSENT) .............................................................. 60 
18.3 DATA CONFIDENTIALITY ............................................................................................................................ 61 
18.4 DATA COLLECTION .................................................................................................................................... 61 
18.5 AMENDMENT POLICY ................................................................................................................................. 61 
18.6 INSURANCE ................................................................................................................................................ 62 
18.7 REDACTION OF THE FINAL REPORT............................................................................................................. 62 
18.8 ARCHIVING ................................................................................................................................................ 62 
19 
DATA ACCESS .......................................................................................................................................... 64 
20 
INVESTIGATOR DUTIES ....................................................................................................................... 64 
21 
REFERENCES BIBLIOGRAPHY ........................................................................................................... 65 
APPENDICES ..................................................................................................................................................... 69 
APPENDICES A ................................................................................................................................................... 69 
APPENDIX A1:  ETHICAL COMMITTEE OR INSTITUTIONAL REVIEW BOARD APPROVAL 
APPENDIX A2: NATIONAL COMPETENT AUTHORITIES AUTHORIZATION 
APPENDIX A3: INSURANCE 
APPENDIX A4: DECLARATION OF HELSINKI (VERSION 2013)  
APPENDIX A5: INFORMATION AND CONSENT (IN FRENCH)  
APPENDIX A6: ANRS SCALE TO GRADE THE SEVERITY OF ADVERSE EVENTS IN ADULTS 
APPENDIX A7: RECOMMENDATIONS FOR BLOOD PRESSURE MEASUREMENT IN HUMANS AND EXPERIMENTAL 
ANIMALS  
APPENDICES B (SEPARATE APPENDICES)  
APPENDIX B1: INVESTIGATOR’S SITES 


ANRS 163 - ETRAL  
Version n° 3.0 dated 19/01/2018 
 
6  
 
TABLE OF PROTOCOL VERSIONS: 
 
Version n° 
Date 
Amending n° 
Main changes 
1.0 
07/03/2014 
 
 
2.0 
18/03/2015 
1 
Modification of a inclusion criteria, 
modification of the timeframe between 
the screening and the D0 and minor 
updates 
3.0 
19/01/2018 
2 
Addition of a secondary objective and 
a secondary endpoint  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


ANRS 163 - ETRAL  
Version n° 3.0 dated 19/01/2018 
 
7  
 
List of abbreviations 
 
AE 
 
 
Adverse Event 
ALT 
 
 
Alanine Aminotransferase 
ANRS  
 
Agence nationale de  recherches sur le sida et les  
 
 
 
hépatites virales 
ANSM  
 
Agence Nationale de Sécurité du Médicament et des produits de 
 
 
 
 
santé (France) 
AR 
 
 
Adverse Reaction 
ART 
 
 
Antiretroviral Therapy 
 
ARV 
 
 
Antiretroviral 
 
AST 
 
 
Aspartate Aminotransferase 
 
AUC 
 
 
Area Under the Curve 
 
BID 
 
 
bis in die (twice daily) 
 
BMD 
 
 
Bone Mineral Density 
 
BPH 
 
 
Benign Prostatic Hyperplasia 
 
Cmin 
 
 
Minimal Drug Concentration 
 
CAD 
 
 
Coronary Artery Disease 
 
CCB 
 
 
Calcium-Channel Blocker 
 
CKD-EPI 
 
Chronic Kidney Disease Epidemiology Collaboration  
 
 
 
 
 
Calculator 
 
CI 
 
 
Confidence Interval 
 
CIOMS  
 
Council for International Organizations of Medical  
 
 
 
 
 
Sciences 
 
CMG 
 
 
Methodology and study Management Center 
 
CPK 
 
 
Creatine Phospho-Kinase 
CPP 
 
 
Comité de Protection des Personnes (France) 
CRA 
 
 
Clinical Research Associate 
CRP 
 
 
C-Reactive Protein 
DNA 
 
 
Deoxyribonucleic Acid 
DSMB  
 
Data Safety Monitoring Board 
DXA 
 
 
Dual-energy X-Ray Absorptiometry 
ECG 
 
 
Electrocardiogram 
eCRF  
 
electronic Case Report Form 
EDTA  
 
Ethylene Di-Amine Tetra-Acetate 
EFV 
 
 
Efavirenz 
EFS 
 
 
Etablissement Français du Sang 
EOT 
 
 
End Of Treatment 
ETR 
 
 
Etravirine 
FHDH  
 
French Hospital Database on HIV 
FTC 
 
 
Emtricitabine 
 
GCP 
 
 
Good Clinical Practice 
 
GFR 
 
 
Glomerular Filtration Rate 
 
GMP 
 
 
Good Manufacturing Practice 
 
HBV 
 
 
Hepatitis B Virus 
 
β HCG  
 
β Human Chorionic Gonadotrophin 
 
HCV 
 
 
Hepatitis C Virus 
 
HDL 
 
 
High Density Lipoprotein 
 
HIV 
 
 
Human Immunodeficiency Virus 
 
hsCRP  
 
high-sensitivity C-Reactive Protein 
 
ICF 
 
 
Informed Consent Form 
 
ICH 
 
 
International Conference on Harmonization 
 
IEC 
 
 
Independent Ethics Committee 
 
IL-6 
 
 
Interleukin-6 
 
IL-6us  
 
Interleukin-6 Ultra-Sensitive 
 
IP-10 
 
 
Interferon gamma induced Protein 10 
 
IMP 
 
 
Investigational Medical Product 
 
INSERM 
 
Institut National de la Santé et de la Recherche Médicale 
 
IQR 
 
 
Inter-Quartile Range 
 
IRB 
 
 
Institutional Review Board 
 
ITT 
 
 
Intent to Treat 
 
LDL 
 
 
Low Density Lipoprotein 


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8  
 
 
LPV 
 
 
Lopinavir 
 
LSN 
 
 
French translation of Upper Limit of Normal 
 
MI 
 
 
Myocardial Infarction 
 
NNRTI  
 
Non-Nucleosidic Reverse Transcriptase Inhibitor 
 
NRTI 
 
 
Nucleosidic Reverse Transcriptase Inhibitor 
 
OR 
 
 
Odd Ratio 
PCR 
 
 
Polymerase Chain Reaction 
 
PI 
 
 
Protease Inhibitor 
 
PI/r 
 
 
Protease Inhibitor Ritonavir-boosted 
 
PO 
 
 
per os 
 
PY 
 
 
Person-Year 
 
RAL 
 
 
Raltegravir 
 
RNA 
 
 
Ribonucleic Acid 
RH 
 
 
Relative Hazard  
RSI 
 
 
Reference Safety Information 
 
SAE 
 
 
Serious Adverse Event 
 
SC 
 
 
Scientific Committee 
 
sCD14  
 
Cluster of Differentiation 14soluble form 
 
sCD163 
 
Haemoglobin Scavenger Receptor soluble form 
SOP 
 
 
Standard Operating Procedure 
 
SUSAR  
 
Suspected Unexpected Serious Adverse Reaction 
SmPC   
 
Summary of the Product Characteristics 
 
TDF 
 
 
Tenofovir 
 
TNF 
 
 
Tumor Necrosis Factor 
 
UDP 
 
 
Uridine Diphosphate 
 
UGT 
 
 
Uridyl Glucoronosyl Transferase  
 
ULN 
 
 
Upper Limit of Normal 
 
VL 
 
 
Viral Load 
 
WOCBP 
 
Women of Childbearing Potential 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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9  
 
 
MAIN CORRESPONDENTS 
 
 
Clinical Coordination 
 
Coordinating Investigator 
Inserm UMR S 1136 and Université Pierre 
et Marie Curie 
Pr Christine KATLAMA 
Service des Maladies Infectieuses et Tropicales, 
Groupe Hospitalier Pitié-Salpêtrière, Paris, France 
: + 33 (0)1 42 16 01 42 
: christine.katlama@psl.aphp.fr 
 
Scientific director 
 
Pr Jacques REYNES 
Département des Maladies Infectieuses et 
Tropicales, Hôpital Gui de Chauliac, 
CHU de Montpellier, France 
: + 33 (0)4 67 33 72 20 
: j-reynes@chu-montpellier.fr 
 
Co Investigator 
Inserm UMR S 1136 and Université Pierre et 
Marie Curie 
Dr Marc-Antoine VALANTIN 
Service des Maladies Infectieuses et Tropicales, 
Groupe Hospitalier Pitié-Salpêtrière, Paris, France 
: + 33 (0)1 42 16 01 71 
: marc-antoine.valantin@psl.aphp.fr 
 
Principal Investigator in Spain 
 
Dr Esteban MARTINEZ 
Medicine Infectious Diseases Unit Hospital Clínic  
IDIBAPS University of Barcelona  
08036 Barcelona, Spain 
: +34 93 227 55 74 
: estebanm@clinic.ub.es  
Virology Coordination 
Service de Virologie – Inserm UMR S 1136 and Université Pierre et Marie Curie 
Groupe Hospitalier Pitié-Salpêtrière 
 
Pr Vincent CALVEZ 
: + 33 (0)1 42 17 74 16 
: vincent.calvez@psl.aphp.fr 
 
Dr Anne-Geneviève MARCELIN 
: + 33 (0)1 42 17 74 16 
: anne-genevieve.marcelin@psl.aphp.fr 
 
Dr Cathia SOULIE 
: +33  (0)1 42 17 58 42 
: cathia.soulie@psl.aphp.fr 
 
Immunology Coordination 
CDR Saint-Antoine INSERM Unité 938 
Faculté de Médecine et Université Pierre et 
Marie Curie 
site Saint-Antoine 
DXA Coordination 
Hôpital Cochin  
Service de rhumatologie 
 
 
Pr Jacqueline CAPEAU 
: + 33 (0)1 40 01 13 32 
: jacqueline.capeau@inserm.fr 
 
 
Dr Sami KOLTA 
: + 33 (0)1 58 41 25 84 
: sami.kolta@cch.aphp.fr 
 
Pharmacology Coordination 
Laboratoire de Pharmacologie Clinique – 
Hôpital Bichat-Claude Bernard 
 
Dr Gilles PEYTAVIN 
: + 33 (0)1 40.25.80.04 
: gilles.peytavin@bch.aphp.fr 
 


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10  
 
 
Methodology centre: 
CMG Inserm UMR S 1136 and Université Pierre et Marie Curie 
Epidémiologie, stratégies thérapeutiques et virologie cliniques dans l’infection à VIH 
56 Bd Vincent Auriol, BP 335,  
75625 Paris Cedex 13, France 
: + 33 (0)1 42 16 42 72 - Fax: 01 42 16 42 61 
 
 
Methodology coordination: 
 
Dominique COSTAGLIOLA 
: + 33 (0)1 42 16 42 82 
Fax: + 33 (0)1 42 16 42 61 
: dcostagliola@ccde.chups.jussieu.fr 
 
Lambert ASSOUMOU 
: + 33 (0)1 42 16 42 80 
Fax: + 33 (0)1 42 16 42 61 
: klassoumou@ccde.chups.jussieu.fr 
 
 
Project Manager / Clinical Trial Monitors:
 
Lydie BENIGUEL (Project Manager) 
: + 33 (0)1 42 16 42 68 
Fax: + 33 (0)1 42 16 42 67 
: lbeniguel@ccde.chups.jussieu.fr 
 
Josiane AKO 
: + 33 (0)1 42 16 42 92 
Fax: + 33 (0)1 42 16 42 61 
: josiane.ako@iplesp.upmc.fr 
 
Jérémy LAFABLE 
: + 33 (0)1 42 16 42 55 
Fax: + 33 (0) 1 42 16 42 67 
: jlafable@iplesp.upmc.fr  
 
Statistician: 
 
Clément GUIHENEUF 
: + 33 (0)1 42 16 42 94 
Fax: + 33 (0)1 42 16 42 61 
: clement.guiheneuf@iplesp.upmc.fr 
 
 
Data Manager: 
 
Serge RODRIGUES 
: + 33 (0)1 42 16 42 63 
Fax: + 33 (0) 1 42 16 42 61 
: srodrigues@ccde.chups.jussieu.fr 
 
 
Sponsor: 
Institut national de la santé et de la recherche médicale - Agence nationale de  
recherches sur le sida et les hépatites virales (Inserm-ANRS) 
101, rue de Tolbiac. 75013 Paris - France 
: + 33 (0)1 53 94 60 00 - Fax: + 33 (0)1 53 94 60 02 
 
 
ANRS Project Manager: 
 
Fanny CARDON 
: + 33 (0)1 44 23 60 36 
: fanny.cardon@anrs.fr 
 
 
 
 
Clinical research safety office: 
 
Dr Alpha DIALLO, Head of office 
: + 33 (0)1 53 94 60 45 
 
Séverine GIBOWSKI  
Clinical research safety officer 
: + 33 (0)1 53 94 60 08 
Fax: + 33 (0)1 53 94 60 02 
: ec.vigilance@anrs.fr 
 
Secretariat: : + 33 (0)1 53 94 80 96


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Version n° 3.0 dated 1 
11  
 
1 
STUDY SYNOPSIS  
Version n° 3.0 dated 19/01/2018 
EudraCT N°: 2014-000828-24 
 
Title of Study 
A non-comparative phase II trial evaluating the capacity of the dual combination 
raltegravir/etravirine to maintain virological success in HIV-1 infected patients of 
at least 45 years of age with an HIV-RNA plasma viremia below 50 copies/mL 
under a current boosted protease inhibitor containing regimen. 
Short title 
ANRS 163 ETRAL 
Sponsor 
French National Institute for Health and Medical Research - French national 
agency for research on AIDS and viral hepatitis (Inserm-ANRS) 
Coordinating 
investigator 
Pr Christine Katlama 
Service des Maladies Infectieuses et Tropicales, 
Groupe Hospitalier Pitié-Salpêtrière, Paris, France 
Scientific director 
Pr Jacques Reynes 
Département des Maladies Infectieuses et Tropicales, 
Hôpital Gui de Chauliac, CHU de Montpellier, France 
Participating 
countries 
France / Spain 
Objectives 
Principal objective 
 
To evaluate over 48 weeks of treatment the capacity to maintain virological 
success defined as the absence of 2 consecutive plasma viral loads (VL) > 50 
copies/mL within 2 to 4 weeks of a dual raltegravir/etravirine regimen in HIV-1 
infected patients, of at least 45 years of age, with suppressed plasma viremia 
switching from a boosted PI-containing regimen. 
 
Secondary Objectives  
To evaluate the: 
 Biological efficacy 
- 
To assess the proportion of patients in therapeutic success up to week 48 
and week 96.  
- 
To assess the proportion of patients with virological success (plasma HIV-
RNA ≤ 50 copies/mL) up to week 96. 
- 
To assess the proportion of patients with an interruption of therapeutic 
strategy. 
- 
To assess the proportion of patients with low grade virological failure (HIV-
RNA plasma VL between 51 and 200 copies/mL) and the proportion of 
patients with high grade of virological failure defined as HIV-RNA > 200 
copies/mL at time of virological failure. 
- 
Time limit to virological failure.  
- 
HIV genotypic resistance profile, in plasma, in case of virological failure 
- 
To determine the factors associated with virological rebound (plasma HIV-
RNA > 50 copies/mL). 
- 
Evolution of total cell-associated HIV-DNA from D0 to W48 and W96. 
- 
Evolution of CD4+, CD8+ T cells counts and CD4/CD8 ratio at each time 
point from D0. 
 
 Tolerability and Metabolic Impact 
- 
Incidence of clinical and biological adverse effects.  
- 
Incidence of clinical and biological adverse events (grade 3 or 4). 
- 
Modification 
of 
metabolic 
parameters 
(fasting 
triglycerides, 
total 
cholesterol, HDL-cholesterol, LDL-cholesterol and fasting glycemia). 
- 
Evolution of the calibrated Framingham risk score and of the SCORE risk 
equation including HDL cholesterol (from the European Cardiovascular 
Society) from D0 to W48 and W96. 
- 
Evolution of renal function evaluated using proteinuria and the CKD-EPI 
(Chronic Kidney Disease Epidemiology Collaboration Calculator) formula 
to estimate the Glomerular Filtration Rate (GFR) from D0 to W96. 


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- 
Modification of peripheral and central body fat distribution at W48 and W96 
compared to D0 measured by DXA scan (Dual-energy X-Ray 
Absorptiometry) (DXA scan sub-study, 80 patients). 
- 
Evolution of bone mineral density measured by DXA scans at W48 and 
W96 compared to D0 (DXA scan sub-study, 80 patients).  
- 
To assess HIV-RNA viral load and Cmin (Minimal Drug Concentration) of 
raltegravir and etravirine at W48 in human male genital compartment 
(semen sub-study, 20 patients). 
- 
Evolution of the inflammation markers (IL-6hs, sCD14, sCD163, D-Dimers, 
IP-10, IgG, CRPus and insulin on frozen plasma aliquots from D0 to W48, 
and W96. 
- 
Evaluation of health-related quality of life with a self-assessment 
questionnaire at D0, W48, W96 and of the compliance with a self-
assessment questionnaire at W-6/W-4, W48, W96. 
- 
 
 Evaluation of the evolution of the cardio-vascular disease-related 
markers in women according to their ovarian reserve and their 
menopausal status 
- 
Evolution of the ovarian reserve from D0 to W48 measured by AMH on 
frozen aliquots 
- 
Evolution of the level of MCP1/CCL2 from D0 to W48 on frozen samples 
- 
Evaluation of the metabolic/inflammatory profile according to sex at 
inclusion and its evolution up to week 48 
- 
Evaluation of metabolic profile, inflammatory, innate immune activation 
markers in women according to their status regarding ovarian reserve and 
menopausal status at inclusion and its evolution up to week 48 
 
Methodology 
Multicenter non-comparative phase II trial evaluating the capacity of the dual 
combination raltegravir/etravirine to maintain virological success defined as the 
absence of 2 consecutive plasma viral loads (VL) > 50 copies/mL within 2 to 4 
weeks in virologically suppressed HIV-1 infected patients, of at least 45 years of 
age, switching from a boosted PI-containing regimen. 
Estimated 
enrolment 
By including 160 individuals and considering the strategy to be acceptable if at 
least 152 individuals maintain virological success, we will have a 95 % 
probability to discard a combination for which efficacy is smaller than 90 % and 
we will select with a power of 80 % a strategy for which the efficacy is above or 
equal to 95 %. 
 


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13  
 
 
Study endpoints 
Primary endpoint Proportion of patients remaining, at week 48 on virological 
success defined as the absence of 2 consecutive HIV-RNA plasma VL > 50 
copies/mL within 2 to 4 weeks interval. 
 
Secondary endpoints 
 Biological efficacy 
- 
Percentage of patients remaining in therapeutic success up to week 48 
and week 96 defined as the absence of virological failure and the absence 
of treatment interruption due to adverse event judged by DSMB as related 
to the trial treatment or procedure. 
- 
Percentage of patients in virological success (plasma HIV-RNA ≤ 50 
copies/mL) up to week 96. 
- 
Percentage of patients with trial treatment interruption.  
- 
Percentage of patients with plasma HIV-RNA VL between 51 and 200 
copies/mL and percentage of patients with plasma HIVRNA VL > 200 
copies/mL at time of virological failure. 
- 
Median time of virological failure (time limit between the date of the trial 
treatment initiation and the date of virological failure).  
- 
Percentage of patients with RAL and/or ETR resistance mutations in case 
of virological failure and percentage of patients with resistant viruses to all 
study drug’s class in case of virological failure. 
- 
Factors associated with the occurrence of plasma HIV-RNA VL> 50 
copies/mL (genotype history, pre-cART VL,  plasma drug concentration 
(etravirine, raltegravir) at the virological rebound, viral reservoir measured 
by HIV-DNA at D0 and adherence assessed with a self-questionnaire). 
- 
Evolution of total cell-associated HIV-DNA from D0 to W48 and W96. 
- 
Evolution of CD4+, CD8+ T cells counts and CD4/CD8 ratio at each time 
point from D0. 
 
 Tolerability and Metabolic Impact 
- 
Percentage of patients with at least one serious adverse event as judged 
by DSMB as related to the trial treatment or to the trial strategy. 
- 
Percentage of patients with grade 3 or grade 4 clinical or biological 
adverse events.  
- 
Evolution of metabolic parameters (fasting triglycerides, total cholesterol, 
HDL-cholesterol, LDL-cholesterol and fasting glycemia). 
- 
Evolution of the calibrated Framingham risk score and of the SCORE risk 
equation including HDL cholesterol (from the European Cardiovascular 
Society) from D0 to W48 and W96. 
- 
Evolution of renal function measured using proteinuria and the CKD-EPI 
(Chronic Kidney Disease Epidemiology Collaboration Calculator) formula 
to estimate the Glomerular Filtration Rate (GFR) from D0 to W96. 
- 
Evolution of limb lean, limb fat, visceral adipose tissue (VAT) and 
subcutaneous adipose tissue (SAT), measured by DXA scan (Dual-energy 
X-Ray Absorptiometry), from D0 to W48 and W96 (DXA scan sub-study, 
80 patients). 
- 
Evolution of bone mineral density measured by DXA scans from D0, to 
W48 and W96 (DXA scan sub-study, 80 patients).  
- 
HIV-RNA viral load and Cmin (Minimal  Drug Concentration) of raltegravir 
and etravirine in seminal fluid at W48 (seminal sub-study, 20 patients). 
- 
Evolution of the inflammation markers (IL-6hs, sCD14, sCD163, D-Dimers, 
IP-10, IgG, CRPus and insulin) on frozen plasma aliquots from D0 to W48, 
and W96. 
- 
Evaluation of health-related quality of life with a self-assessment 
questionnaire from D0 to W48, and W96 and of the compliance with a self-
assessment questionnaire at W-6/W-4, W48, and W96. 
 
 Evaluation of metabolic impact according to the ovarian reserve 
and menopausal status 
 
 


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14  
 
 
Evolution of the AMH and MCP1/CCL2 levels on frozen samples 
between D0 and W48 
 
Comparison of metabolic (total cholesterol, LDL-cholesterol, HDL-
cholesterol, triglycerides, non-HDL-cholesterol and triglyceride/HDL-
cholesterol), inflammatory and innate immune activation (IL-6hs, 
sCD14, sCD163, D-Dimers, IP-10, IgG, CRPus and insulin), fat 
distribution and bone markers measured by DEXA scan between 
men and women at D0 et comparison of their evolution at W48 
 
Comparaison of the metabolic/inflammatory profile in women 
according to their ovarian reserve and menopausal status at D0 and 
its evolution up to week 48 
Eligibility criteria 
Inclusion criteria 
- 
Documented HIV-1 infection. 
- 
Age ≥ 45 years. 
- 
Naïve to integrase inhibitor and etravirine.  
- 
At least 6 months of stable antiretroviral therapy (ART) including a boosted 
protease inhibitor, whatever the number of combined drugs.  
- 
HIV-RNA plasma VL ≤ 50 copies/mL during the last 24 months prior to 
screening visit (W-6/W-4), documented by at least 4 time-points with no 
more than one blip in HIV-RNA plasma viral load between 51 and 200 
copies/mL. 
- 
HIV-RNA plasma VL ≤ 50 copies/mL at screening visit (W-6/W-4). 
- 
A genotype is available (on amplified DNA at W-6/W-4 Visit and/or on RNA 
in the medical history of the patient) and shows a virus sensitive to ETR 
OR no genotype is available (amplification failure on DNA at W-6/W-4 Visit 
and no genotype in the medical history of the patient), there are no 
virological failure on NNRTI in the medical history. 
- 
CD4+ lymphocytes > 200 cells/mm3. 
- 
Creatinine < 2.5 x ULN. 
- 
CPK (Creatine Phospho Kinase) < 6 ULN. 
- 
AST (Aspartate Aminotransferase), ALT (Alanine Aminotransferase) < 5 
ULN. 
- 
Hemoglobin > 10 g/dL. 
- 
Platelets > 100 000/mm3. 
- 
Negative urinary pregnancy test and use of efficient contraception for 
women of childbearing potential.  
- 
For French participants only: subject enrolled in or a beneficiary of a Social 
Security programme (State Medical Aid or AME is not a Social Security 
programme), article L1121-11 of the Public heatlh code... 
- 
Patients with a coverage from a social health. 
- 
Signed informed consent.  
 
Non-inclusion criteria 
- 
Previous exposure to raltegravir or etravirine. 
- 
Presence of any documented integrase inhibitor mutation on DNA 
genotype at W-6/W-4 and/or on RNA in the medical history of the patient. 
- 
Positive hepatitis B HBsAg or Positive HBc Ac and negative HBs Ac. 
- 
HIV-2 infection. 
- 
Active viral hepatitis C requiring a specific treatment during the 24 months 
of the trial.  
- 
Patient with a history of non-compliance or irregular follow-up.  
- 
Initiation of a concomitant anti-hypercholesterolemia (e.g. statins) or anti-
diabetic treatment within the last 3 months prior the screening visit (W-
6/W-4). 
- 
Patient using: Clopidogrel (Plavix®), Prasugrel (Effient®), Ticagrelor 
(Brilinta®), Ticlopidine (Ticlid®), Flurbiprofen (Antadys® - Cebutid®), 
Rifampin (Rifampicin® - Rifadin® - RofactMC - Rifater®), Rifapentine 
(Priftin®), St John’s wort, Carbamazepine (Tegretol®), Phenobarbital, 
Phenytoin (Dilantin®),Avanafil (Stendra™), Triazolam (Halcion®). 
- 
Concomitant treatment using interferon, interleukins or any other immune-
therapy or chemotherapy.  
- 
Concomitant prophylactic or curative treatment for an opportunistic 
infection.  


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- 
All conditions (use of alcohol, drugs, etc.) judged by the investigator to 
possibly interfere with trial protocol compliance, adherence and/or trial 
treatment tolerance. 
- 
Subjects under "sauvegarde de justice" (judicial protection due to 
temporarily and slightly diminished mental or physical faculties), or under 
legal guardianship. 
- 
Subjects participating in another clinical trial evaluating different therapies 
and including an exclusion period that is still in force during the screening 
phase. 
- 
Pregnant women or breastfeeding women. 
Intervention 
In patients who had signed informed consent and fulfilled all eligibility criteria at 
screening (W-6/W-4) will be prescribed a switch to the dual raltegravir (400 mg 
BID - bis in die-) plus etravirine (200 mg BID) regimen: 
- 
Raltegravir 400 mg tablets will be administered as one 400 mg oral 
tablet PO (per os) twice daily (800 mg per day), after a meal 
- 
Etravirine 200 mg tablets will be administered as one 200 mg oral tablet 
PO twice daily (400 mg per day) after a meal 
Substudies 
(for 
French centres) 
- 
DXA sub-study: 80 patients 
- 
Seminal sub-study: 20 patients (centres located in the region of Ile-de-
France (neighbourhood of Paris))  
Estimated 
trial 
duration 
 
- 
Inclusion duration:  
 
 
 
18 months 
- 
Maximum 
trial 
duration 
per 
patient:  
 
 
- 
Primary endpoint and analysis: 
End of the trial: 
 
24 months (4 weeks for screening, 
96 weeks of trial treatment and 2 
weeks post-treatment interruption 
for safety reasons) 
30 months after trial initiation 
6 months after the last visit of the 
last patient 
 
- 
Trial duration:   
- 
Expected trial initiation:  
3.5 to 4 years 
1st trimester 2015 
 
Sample size 
- 
160 patients  
 
 
 
 
 
 
 
 
 
 


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2 
RESUME DE L’ESSAI  
Version n° 3.0 du 19/01/2018 
EudraCT N°: 2014-000828-24 
 
Titre de l’essai 
 
Essai pilote de phase II non comparatif évaluant la capacité de la combinaison 
raltégravir+étravirine à maintenir le succès virologique chez des patients 
infectés par le VIH-1, âgés d’au moins 45 ans, avec une charge virale 
plasmatique inférieure à 50 copies/mL sous un traitement antirétroviral 
comportant un inhibiteur de protéase boosté 
Titre abrégé 
ANRS 163 ETRAL 
Promoteur 
Institut National de la Santé et de la Recherche Médicale - Agence nationale de 
recherches sur le sida et les hépatites virales (Inserm-ANRS) 
Investigateur 
coordonnateur 
Pr Christine Katlama 
Service des Maladies Infectieuses et Tropicales, 
Groupe Hospitalier Pitié-Salpêtrière, Paris, France 
Responsable 
scientifique 
Pr Jacques Reynes 
Département des Maladies Infectieuses et Tropicales, 
Hôpital Gui de Chauliac, CHU de Montpellier, France 
Pays participants   France, Espagne 
Objectifs 
Objectif principal 
Evaluer la capacité d’une bithérapie associant raltégravir/étravirine à maintenir 
le succès virologique jusqu’à S48 défini par l’absence de 2 charges virales (CV) 
plasmatiques consécutives >50 copies/mL mesurées dans un intervalle de 2 à 4 
semaines maximum, chez des patients infectés par le VIH-1, âgés d’au moins 
45 ans et actuellement sous traitement antirétroviral efficace comportant un 
inhibiteur de protéase boosté.  
 
Objectifs secondaires  
 Efficacité biologique 
- 
Evaluer la proportion de patients en succès thérapeutique jusqu'à S48 et 
S96.  
- 
Evaluer la proportion de patients en succès virologique (ARN-VIH≤50 
copies/mL) jusqu’à S96. 
- 
Evaluer la proportion de patients ayant arrêté la stratégie thérapeutique. 
- 
Evaluer la proportion de patients en échec virologique de bas grade (ARN-
VIH entre 51 et 200 copies/mL) et la proportion de patients en échec 
virologique de haut grade (ARN-VIH >200 copies/mL) au moment de 
l'échec virologique. 
- 
Délai de survenue de l’échec virologique. 
- 
Profil de résistance génotypique dans le plasma en cas d’échec 
virologique. 
- 
Identifier les facteurs associés au rebond virologique (ARN-VIH>50 
copies/mL). 
- 
Evolution de l’ADN-VIH total dans les cellules de J0, à S48 et à S96. 
- 
Evolution des cellules lymphocytaire T CD4+ et T CD8+ et le rapport 
CD4/CD8 à tous les points de mesure par rapport à J0. 
 
 Tolérance et impact métabolique 
- 
Incidence des effets indésirables cliniques et biologiques. 
- 
Incidence des évènements indésirables cliniques ou biologiques de grade 
3 ou 4.  
- 
Modification des paramètres métaboliques mesurés à jeun (triglycérides, 
cholestérol total, HDL-cholestérol, LDL- cholestérol et glycémie). 
- 
Evolution du score de risque de Framingham calibré et du score de risque 
de la Société européenne de cardiologie issu d’une équation incluant le 
HDL-cholestérol (de la Société européenne de cardiologie) de J0 à S48 et 
S96. 
- 
Evolution de la fonction rénale mesurée par la protéinurie et la formule 
CKD–EPI 
(Chronic 
Kidney 
Disease 
Epidemiology 
Collaboration 


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17  
 
Calculator) de J0 à S96. 
- 
Modification de la répartition du tissu adipeux des membres et du tronc, à 
S48 et S96 par rapport à J0 mesurée par DXA scan (sous-étude DXA 
scan, 80 patients). 
- 
Evolution de la densité minérale osseuse évaluée par DXA scan à S48 et 
S96 par rapport à J0 (sous-étude DXA scan, 80 patients). 
- 
Evaluation de la charge virale VIH et de la concentration minimale du  et 
de l'étravirine au sein du compartiment génital masculin à S48 (sous-étude 
séminale, 20 patients). 
- 
Evaluation des marqueurs inflammatoires (IL-6hs, sCD14, sCD163, D-
Dimère, IP-10, IgG, CRPus, insuline) mesurés sur plasma congelés de J0, 
à S48 et S96. 
- 
Évaluation de la qualité de vie par auto-questionnaires à J0, S48 et S96 et 
de l’observance par auto-questionnaires à S-6/S-4, S48 et S96. 
 
 Evaluation de l’évolution des marqueurs de maladies cardio-vasculaires 
chez des femmes selon leur reserve ovarienne et leur status 
ménopausique 
- 
Evolution de la réserve ovarienne de J0 à S48 par mesure de l’AMH 
(Hormone anti-mullërienne) sur des échantillons congelés. 
- 
Evolution du taux de MCP1/CCL2 de J0 à S48 sur échantillons congelés. 
- 
Evaluation des profils métabolique/inflammatoire selon le sexe à l’inclusion 
et jusqu’à S48. 
- 
Evaluation des profils métaboliques, des marqueurs inflammatoires et 
d’activation de l’immunité innée chez les femmes selon leur réserve 
ovarienne et le statis ménopausique à l’inclusion et jusqu’à S48 
 
Méthodologie 
Essai multicentrique, non comparatif, pilote de phase II, évaluant la capacité de 
l’association  raltégravir et étravirine à maintenir le succès virologique, défini par 
l’absence de 2 charges virales (CV) plasmatiques consécutives > 50 copies/mL  
dans un intervalle de 2 à 4 semaines, chez des patients infectés par le VIH, 
âgés d’au moins 45 ans et recevant actuellement une thérapie antirétrovirale 
efficace comportant un inhibiteur de protéase boosté. 
Nombre de sujets 
prévus 
En incluant 160 sujets et en considérant la stratégie comme acceptable si on 
observe au moins 152 patients en succès virologique, on écartera avec une 
probabilité de 95% les stratégies d’efficacité inférieure à 90% et on 
sélectionnera avec une probabilité de 80% celles dont l’efficacité est supérieure 
ou égale à 95%. 
Critères  
de jugement 
Critère principal  
Proportion de patients en succès virologique jusqu’à S48 défini par l'absence de 
2 CV ARN-VIH > 50 copies/mL mesurées dans un intervalle de 2 à 4 semaines 
maximum. 
 
Les critères secondaires 
 
 Efficacité biologique 
- 
Pourcentage de patients ayant maintenu le succès thérapeutique jusqu'à 
S48 et S96 défini par l'absence d'échec virologique (i.e. 2 CV consécutives 
>50 copies/mL mesurées dans un intervalle de 2 à 4 semaines maximum) et 
par l’absence d’arrêt du traitement de l’essai dû à la survenue d’un 
événement indésirable jugé par le comité indépendant de surveillance (CIS) 
comme lié au traitement ou à la stratégie de l’essai. 
- 
Pourcentage de patients en succès virologique (ARN-VIH ≤50 copies/mL) 
jusqu’à S96. 
- 
Pourcentage de patients ayant arrêté le traitement de l'essai. 
- 
Pourcentage de patients ayant une charge virale ARN-VIH entre 51 et 200 
copies/mL et le pourcentage de patients ayant une charge virale ARN VIH 
>200 copies / mL au moment de l'échec virologique. 
- 
Délai médian entre la date de l'initiation du traitement de l'essai et la perte 
du succès virologique. 
- 
Pourcentage de patients avec des virus présentant des mutations de 
résistance au traitement de l’essai en cas d'échec virologique et 
pourcentage de patients avec des virus résistants à toutes les molécules de 


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la classe thérapeutique en cas d'échec virologique. 
- 
Recherche de facteurs associés à la survenue d’une charge virale >50 
copies/mL (historique des génotypes, charge virale pré-thérapeutique 
concentration plasmatique des médicaments de l’essai (étravirine, 
raltégravir) mesurée au rebond virologique, le réservoir viral mesuré par 
l'ADN-VIH à D0 et l’observance mesurée par auto-questionnaire). 
- 
Evolution de l’ADN-VIH total dans les cellules de J0, à S48 et à S96. 
- 
Evolution des cellules lymphocytaire T CD4+ et T CD8+ et le rapport 
CD4/CD8 à tous les points de mesure par rapport à J0. 
 
 Tolérance et impact métabolique 
- 
Pourcentage de patients présentant au moins un événement indésirable 
grave jugé par le CIS comme liés au traitement ou à la stratégie de l’essai. 
- 
Pourcentage de patients ayant eu des événements indésirables cliniques ou 
biologiques de grade 3 ou 4. 
- 
Evolution des paramètres métaboliques mesurés à jeun (triglycérides, 
cholestérol total, HDL-cholestérol, LDL-cholestérol et glycémie). 
- 
Evolution du score de risque de Framingham calibré et du score de risque 
de la Société européenne de cardiologie issue d’une équation incluant le 
HDL-cholestérol de J0 à S48 et S96. 
- 
Evolution de la fonction rénale mesurée par la protéinurie et la formule 
CKD–EPI (Chronic Kidney Disease Epidemiology Collaboration Calculator) 
de J0 à S96. 
- 
Evolution de la masse maigre et de la masse grasse dans les membres et 
du tissu adipeux sous-cutané et péri-viscéral au tronc, mesurés par DXA 
Scan de J0 à S48 et S96 (sous-étude DXA scan réalisée sur 80 patients). 
- 
Evolution de la densité minérale osseuse mesurée par DXA scan de J0, S48 
et S96 (sous-étude DXA scan réalisée sur 80 patients).  
- 
Charge virale VIH et concentration minimale du raltégravir et l'étravirine 
dans le sperme à S48 (sous-étude séminale réalisée sur 20 patients). 
- 
Evolution des marqueurs inflammatoire (IL-6hs, sCD14, sCD163, D-Dimère, 
IP-10, IgG, CRPus, insuline) mesurés sur du plasma congelé de J0, S48 et 
S96. 
- 
Evolution de la qualité de vie à J0, S48, S96 et de l’observance par auto-
questionnaires à S-6/S-4, S48 et S96. 
 
 Evaluation de l’impact métabolique selon la réserve ovarienne et le 
status ménopausique 
- 
Evolution des taux d’AMH (hormone anti-mullërienne) et de MCP1/CCL2 sur 
échantillons congelés entre J0 et S48 
- 
Comparaison des profils métaboliques (cholesterol total, LDL-cholestérol, 
HDL-cholestérol, triglycérides, non-HDL cholestérol et triglycérides/HDL-
cholestérol), des marqueurs d’activation inflammatoires et de l’immunité 
innée (IL-6hs, sCD14, sCD163, D-Dimers, IP-10, IgG, CRPus et insuline), de 
la distribution des graisses et des marqueurs osseux mesurés par DEXA 
entre les hommes et les femmes à J0 et comparaison de leur évolution 
jusqu’à S48. 
- 
Evaluation des profils métaboliques/inflammatoires chez les femmes et leur 
évolution jusqu’à S48 selon leur réserve ovarienne et leur status 
ménopausique 
 
Critères 
d’éligibilité 
Critères d’inclusion 
- 
Infection par le VIH-1. 
- 
Age ≥ 45 ans. 
- 
Naïf d’inhibiteur d’intégrase et d’étravirine. 
- 
Au moins 6 mois de traitement antirétroviral stable (ARV) incluant un 
inhibiteur de protéase boosté, quel que soit le nombre d’ARVs 
combinés. 
- 
ARN-VIH ≤ 50 copies/mL au cours des 24 derniers mois précédant la 
visite de screening (S-6/S-4), documenté par au moins 4 mesures avec 
autorisation d’un seul blip entre 51 et 200 copies/mL. 
- 
ARN-VIH ≤ 50 copies/mL à la visite de pré-inclusion (S-6/S-4). 
- 
Un génotype est disponible (sur ADN amplifié à S-6/S-4, et/ou sur ARN 


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dans l’historique du patient), montrant un virus pleinement sensible à 
l’étravirine 
OU 
en 
l’absence 
de 
génotype 
disponible 
(échec 
d’amplification sur ADN à S-6/S-4 et pas de génotype sur ARN dans 
l’historique du patient), il n’y a pas d’antécédent d’échec aux 
INNTI.Lymphocytes T CD4 + > 200 cellules/mm3. 
- 
Créatinine < 2,5 x limites supérieures normales (LSN). 
- 
CPK (créatine-phosphokinase) < 6 (LSN). 
- 
ASAT, ALAT < 5 x LSN. 
- 
Hémoglobine > 10 g/dL. 
- 
Plaquettes >100 000 /mm3. 
- 
Test de grossesse urinaire négatif pour les femmes en âge de procréer 
et utilisation d’une méthode de contraception efficace. 
- 
Pour les  participants français uniquement : personne affiliée ou 
bénéficiaire d’un régime de sécurité sociale (article L1121-11 du Code 
de la Santé Publique)  (l’Aide Médicale d’Etat ou AME n’est pas un 
régime de sécurité sociale). 
- 
Patient affilié à un régime d'assurance- santé. 
- 
Signature d’un consentement libre et éclairé. 
 
Critères de non-inclusion 
- 
Patient ayant déjà reçu du raltégravir ou de l’étravirine. 
- 
Présence de mutations de résistance aux inhibiteurs d’intégrase 
documentée par la séquence génotypique extraite de l’ADN à W-6/W-4 
et/ou sur l’ARN dans l’histoire médicale du patient 
- 
Antigène HBs positif ou présence de l'anticorps anti-HBc positif et 
anticorps HBs négatif 
- 
Infection par le VIH-2. 
- 
Hépatite virale C active nécessitant un traitement spécifique au cours 
des 24 mois de l'essai. 
- 
Patient ayant des antécédents d’inobservance ou de suivi irrégulier. 
- 
Initiation d’un traitement anti-hypercholestérolémie (par exemple : 
statines) ou d’un traitement anti- diabétique dans les 3 mois précédant 
la visite de pré-inclusion (S-6/S-4). 
- 
Patient traité par clopidogrel (Plavix®),prasugrel (Effient®), Ticagrelor 
(Brilique®), Ticlopidine (Ticlid®), Flurbiprofène (Antadys® - Cebutid®), 
Rifampine (Rifampicine® - Rifadin® - RofactMC - Rifater®), Rifapentine 
(Priftin®), Millepertuis, Carbamazepine (Tegretol®), Phénobarbital, 
Phénytoïne (Dilantin®), Avanafil (Stendra™), Triazolam (Halcion®). 
- 
Patient traité par interféron, interleukines ou toute autre immuno- 
thérapie ou chimiothérapie. 
- 
Traitement concomitant prophylactique ou curatif d'une infection 
opportuniste. 
- 
Toutes conditions (consommation d'alcool, de drogues, etc) jugées par 
l'investigateur comme pouvant interférer avec le respect du protocole de 
l'essai, l'observance et/ou la tolérance du traitement de l’essai. 
- 
Personnes placées sous sauvegarde de justice, sous tutelle ou 
curatelle. 
- 
Personnes participants à une autre recherche évaluant d’autres 
traitements en investigation comprenant une période d’exclusion 
toujours en cours à la pré-inclusion. 
- 
Femmes enceintes ou allaitantes. 
Intervention 
Chez les patients ayant signé un consentement éclairé et remplissant tous les 
critères d’éligibilité au moment de la pré-inclusion (S-6/S-4) sera prescrit une 
bithérapie associant le raltégravir (400 mg) et l'étravirine (200 mg): 
- 
Le raltégravir en comprimés de 400 mg sera administré par voie orale 
deux fois par jour (soit 800 mg par jour) après un repas 
- 
L'étravirine en comprimés de 200 mg sera administré par voie orale 
deux fois par jour (soit 400 mg par jour) après un repas 
Sous-études 
(pour les centres 
français) 
- 
Sous-étude DXA: 80 patients 
- 
Sous-étude séminale: 20 patients (seulement centres d’Ile de France)  
Calendrier/ 
- 
Durée d’inclusion:  
 
 
18 mois 


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Echéancier 
prévisionnel 
- 
Durée de participation maximale 
par patient: 
 
 
 
 
- 
Critère d’évaluation et analyse 
primaire:   
- 
Fin de l’essai: 
24 mois (4 semaines de screening, 
96 semaines de traitement de 
l’essai et 2 semaines après la fin 
de traitement pour des raisons de 
sécurité) 
 
30 mois après le début de l’essai 
 
6 mois après la dernière visite du 
dernier patient 
- 
Durée de l’essai:  
 
- 
Date 
de 
début 
de 
l’essai 
prévisionnelle:   
3.5 à 4 ans 
1er trimester 2015 
 
 
Nombre de sujets 
- 
160 participants  


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3 
STUDY DESIGN   
 
 
 
 


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4 
SCHEDULE OF ASSESSMENTS 
 
 
 
 
W-
6/W-
4 
D0 
W2
W4 
W12 W24 W36
W48 
W64 W80 
W96 
EOT
Informed Consent Signature 
X 
 
 
 
 
 
 
 
 
 
 
Review eligibility criteria 
X 
X 
 
 
 
 
 
 
 
 
 
Collection of adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Quality of life, felt symptoms 
 
X 
 
 
 
 
 
X 
 
 
X 
X 
Adherence evaluation 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
Clinical exam  
(blood pressure, heart rate, body 
temperature, weight and targeted 
physical examination) 
X1 
X2,3,4
X 
X 
X 
X 
X 
X2,3,4 
X 
X 
X2, 3, 4
X2 
HBV/HCV serology  
X 
 
 
 
 
 
 
 
 
 
 
 
Urinary pregnancy test 
If positive:  HCG5 
X 
X6 
X6 
X6 
X6 
X6 
X6 
X6 
X6 
X6 
X6 
X6 
HIV-RNA plasma Viral Load7 
X 
X 
 
X8 
X8 
X8 
X8 
X8 
X8 
X8 
X8 
X8 
CD4/CD8 Lymphocytes 
X 
X 
 
 
X 
X 
 
X 
 
X 
X 
X 
Whole blood cells count 
X 
 
 
 
 
X 
 
X 
 
X 
X 
X 
Creatinine, AST, ALT, CPK, 
bilirubin, urine analysis9 
X 
 
 
X 
X 
X 
 
X 
 
X 
X 
X 
Lipid profile10, fasting glycemia 
 
X 
 
X 
X 
 
X 
 
 
X 
X 
Genotypic resistance on blood 
DNA  
X 
 
 
 
 
 
 
 
 
 
 
DXA-Scan sub-study11 
 
X 
 
 
 
 
X 
 
 
X 
 
Seminal sub-study12 
 
 
 
 
 
 
X 
 
 
 
 
Study drug prescription 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Sample bank13 
Plasma bank: minimal plasma ARV 
concentration, virological analysis 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Whole blood bank:Total cell-
associated HIV-DNA 
 
X 
 
 
 
 
X 
 
 
X 
X 
Plasma and serum 
bank:Immunologic analysis of 
inflammation markers14 
 
X 
 
 
 
 
X 
 
 
X 
X 
 
1 Electrocardiogram (ECG) 
2 Anthropometric measurements (abdominal and waist circumference) 
3 Cardiovasculor risk factors: arterial hypertension, tobacco, alcohol abuse, physical activity, diabetes 
4 Measurement of the systolic blood pressure at D0 W48 W96 according to the recommendations (Pickering et al. 
Circulation 2005, in Appendix A7) 
5 Only for women of childbearing potential 
6 Only in case of suspicion 
7 Plasma viral loads using a routine technique with a positivity threshold of maximum 50 copies/mL 
8 If HIV-RNA plasma viral loads > 50 copies/mL an additional blood collection have to be performed, within an 
interval of two to four weeks, to confirm the virological rebound. If the virological failure is confirmed, a resistance 
genotype and a dosage of ARV drugs concentration in plasma will be performed on the second HIV-RNA plasma 
VL test. A plasma bank should also be done 
9 Urine analysis: proteinuria, albuminuria, creatininuria, glycosuria 
10 Lipid profile: fasting triglycerides, total cholesterol, HDL-cholesterol, LDL-cholesterol 
11 DXA-scan sub-study: evolution of the Bone Mineral Density (BMD) and of the body fat distribution in 80 patients  
12 Seminal sub-study in 20 patients. The HIV-RNA viral load and the RAL/ETR Cmin will be measured 
13 Refer to paragraph 12 
14 Immunological analysis of inflammation markers might be performed on frozen plasma aliquots. Markers of 
interest are: IL-6hs, sCD14, sCD163, D-Dimers, IP-10, IgG, CRPus and insulin  


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5  
BACKGROUND / RATIONALE  
5.1 
 Background 
The objective of antiretroviral therapy (ART) is the maintenance of HIV viral suppression, the optimal condition to 
prevent disease progression, to optimize immune restoration, to prevent the development of viral resistance and to 
reduce viral transmission [1]. Antiretroviral therapy has to be maintained long life over decades in the absence of 
strategies for HIV cure. This is why the long-term cumulative toxicity of ARV drugs is a major issue. Indeed as a 
consequence of potent ART strategies, in 2011 over 88% of patients on ART in the French Hospital database 
(ANRS CO4 FHDH) (Prise en charge médicale des personnes vivant avec le VIH, Recommandations du groupe 
d’experts, Rapport 2013, sous la direction du Pr Philippe Morlat et sous l’égide du CNS et de l’ANRS. La 
documentation française, 2013) have achieved viral suppression with HIV-RNA plasma viral load < 50 copies/mL 
and nearly 60% have CD4 > 500/mm3. As a consequence of massive reduction of mortality and morbidity related 
to HIV, infected patients are aging with 40% of patients over 50 years of age in the ANRS CO4 FHDH.  
The current standard-of-care for antiretroviral therapy consists in a triple drug combination (ART) with 2 
nucleoside reverse transcriptase inhibitors (NRTIs) plus either a non-nucleoside reverse transcriptase inhibitor 
(NNRTI), a protease inhibitor (PI), or an integrase inhibitor. NRTIs and PIs have been associated to cumulative 
long-term toxicity such as bone and renal disorders related to tenofovir and increased cardio-vascular risk with PIs 
[2-3]. In general population, aging is associated with well-known comorbidities such as bone demineralization, 
increased incidence of cardio or cerebrovascular disease, diabetes, renal dysfunction. HIV infected patients are at 
a greater risk for such abnormalities. Alternative strategies are needed, which must address the following 
questions: how to maintain the control of HIV viral replication while minimizing the occurrence of long-term clinical 
and metabolic complications.  
5.2 
 Potential long-term complications of current antiretroviral 
treatments 
5.2.1 Cardiovascular risk 
The recent years have highlighted the cumulative toxicities of long-term exposure to antiretroviral drugs. 
Cardiovascular disease is one of the most common comorbidities in the aging HIV-infected population [4-5]. 
Coronary artery disease (CAD) results from a combination of increasing age, traditional risk factor such as 
smoking, toxicity from long-term ART [6], and potentially related to HIV immune activation.  
The French Hospital Database on HIV (ANRS CO4 FHDH) included over 80 000 patients followed over several 
years and measured the incidence of non-HIV related events. As early as 2003, ANRS CO4 FHDH showed that 
the risk of myocardial infarction (MI) was higher in HIV-infected patients exposed to PI than in the general 
population and dependent of cumulative exposure [7]. More recently ANRS CO4 FHDH showed that cumulative 
exposure to PI was associated with an increased risk of MI, and that the link to abacavir could not be considered 
causal [8]. We also showed a higher risk of MI in HIV infected patients than in the general population and the 
influence of both HIV replication and immunological status (CD4 nadir, current CD8 count) on the risk of MI, 
independently of traditional risk factors and exposure to antiretroviral drugs [9]. Exposure to PI was associated 
with a higher risk of MI [relative hazard (RH), 2.56; 95% confidence interval (CI), 1.03–6.34]. The expected 
incidence in the French general male population was 10.8/10 000 PY (Person-Year). The standardized morbidity 
ratios relative to the French general male population was 0.8 (95% CI, 0.5–1.3) for men exposed to PI for < 18 
months, 1.5 (95% CI, 0.8–2.5) for men exposed for 18–29 months and 2.9 (95% CI, 1.5–5.0) for men exposed for 
> 30 months [8, 10]. 
Most of boosted PIs and the NNRTI efavirenz are associated to an increase in triglycerides and total cholesterol 
plasma levels [11]. In the ANRS CO8 APROCO COPILOTE cohort about 30% of patients developed 
hypertriglyceridemia. Prevalence of lipodystrophy and metabolic alterations and these alterations appear as early 
as 12 months after the initiation of PI therapy [12].  
5.2.2 Bone toxicity 
The prevalence of osteopenia and osteoporosis in HIV-infected individuals is higher in HIV-infected compared with 
HIV-negative individuals ranging, from 23 to 65% for osteopenia and from 3 to 22% for osteoporosis according to 
the studies [13-16] with, as consequence, a higher prevalence of patients with fracture (p < 0.0001) [17].  
Several antiretroviral drugs have been shown to increase risk of bone demineralization [18-19]. Current exposure 
to tenofovir is associated with a higher risk of osteopenia and osteoporosis (OR(Odd Ratio)=1.59, p=0.0343 and 


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OR=2.20, p =0.0541, respectively) and a higher risk of low BMD (β= -33.35; p=0.0211). Tenofovir-containing 
antiretroviral regimens induce larger decrease in spine and hip bone mineral density when compared with 
abacavir-containing regimens [20]. Tenofovir induces renal phosphate and calcium losses leading to 
compensatory resorption of bone (osteoporosis) and mineralization defects in regenerating bone (osteomalacia) 
[21]. Long exposure to protease inhibitors has been associated with a higher risk of osteopenia, with borderline 
statistical significance (OR=1.05 per year of exposure, p=0.0560). HIV-infected patients have a lower bone 
mineral density (BMD) than the general population of the same age [13, 17, 22] and several studies have shown 
that there is an increased risk of fractures in HIV-infected individuals compared to the general population of same 
sex and age [17, 22-26]. The lowest BMD is mainly associated with a lower body mass index (BMI) [22-25] while 
HIV itself and its consequences may also contribute to the increased prevalence of osteopenia, osteoporosis and 
fracture in the HIV-infected population [13, 17, 24-28]. Data from randomized clinical trials have shown that BMD 
decreases when initiating antiretroviral treatment and this decrease is greater with some treatments [29-32]. 
Indeed, BMD decrease is more important with tenofovir than with other nucleoside reverse transcriptase 
analogues [33], and with protease inhibitors [18, 20, 29, 32, 34]. Moreover, when stopping antiretroviral treatment 
the BMD increases [35]. In addition, HIV-negative men participating in a trial examining the effects of tenofovir for 
pre-exposure prophylaxis experienced a small but significant decrease in BMD when taking the medication [36]. In 
a recent study, cumulative exposure to tenofovir and to boosted PIs was shown increasing the risk of fracture in 
hip, spine and wrist [37]. However, another study did not support these findings, but it first offer was belonging to a 
pharmaceuticals company [38]. 
5.2.3 Renal toxicity 
Tenofovir is currently the most widely used antiretroviral drug. Globally, clinical trials have suggested that renal 
toxicity related to tenofovir is low (approximately 1%) in selected populations from clinical studies. However, 
observational cohort studies have suggested that this risk was higher with rates varying from approximately 2% 
[39-43].  
In a systematic review and meta-analysis whereas over time with longer exposure to antiretroviral drugs [3] the 
overall relative risk of renal disease was 3.87 (95% CI: 2.85-6.85) in HIV-infected patients compared to HIV-
uninfected in ART treated patients. 0.54 (95% CI: 0.29-0.99) compared to naïve patients and 1.56 (95% CI: 0.83-
2.93) in patients treated with tenofovir compared to patients without tenofovir. 
In the DAD study not only tenofovir but also abacavir, lopinavir and atazanavir were associated to high risk [44].  
The use of strategies that could minimize renal toxicity has to be investigated particularly in senior HIV infected 
population. 
5.3 
 An aging HIV-population at risk of cumulating drug toxicity and 
co-morbidities 
Increased risk for drug-drug interactions: a cause of concern in the elderly. 
Aging increases polypharmacy prescriptions for treatment and prevention of comorbidities such as cardio-vascular 
disease, hypertension or diabetes. One major issue is the risk for drug-drug interactions in elderly ART treated 
HIV infected patients due to the common CYP450 cytochrome pathway, shared by ARV drug and drug for 
comorbidities. 
Calcium channel blockers (CCBs) are metabolized via CYP3A4; as a result, all boosted protease inhibitors may 
increase CCB serum concentrations and can potentially prolong the PR interval and augment hypotensive effect 
[45]. Diltiazem is massively increased with unboosted PI such as atazanavir resulting in PR prolongation and first-
degree atrioventricular block and has to be reduced. On the contrary, efavirenz, etravirine and nevirapine have the 
potential to decrease CCB serum concentrations and dose adjustment of CCB at steady state may be needed 
[45]. Digoxin concentration is increased by 86% with ritonavir co-administration) [46].  
Furthermore many antiarrhythmic medications are CYP450 3A4 substrates. Use of amiodarone, bepridil, 
flecainide, propafenone and quinidine is contraindicated with ritonavir boosted protease inhibitors (PI/r) due to the 
potential risk of exacerbating cardiac arrhythmias [45]. The use of disopyramide, dofetilide, lidocaine, mexiletine 
and procainamide with PI/r should be approached with caution due to the potential risk of significantly increasing 
antiarrhythmic serum concentrations [45]. 
Significant drug-drug interactions between warfarin, protease inhibitors and NNRTIs may further increase the risk 
of significant haemorrhage. Induction properties of nevirapine and lopinavir/ritonavir at steady state resulting in 
increased warfarin requirements have been reported [47]. 
Significant drug-drug interactions between antiretrovirals and anti-hyperlipidemic agents have been reported in 
different publications [48-49]. PI/r can significantly increase simvastatin and lovastatin concentrations. Co-


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administrations of these 3-hydroxy-3-methyl-glutaryl-CoA reductase inhibitors are not recommended due to the 
potential for rhabdomyolysis.  
Monitoring concentration of these drugs is not easy in routine practice. Given these drug-drug interactions with 
potential severe clinical consequences, it is key to investigate alternative ART strategies with different 
metabolization pathways, such as raltegravir. 
5.4 
 Raltegravir and etravirine: benefits and advantages in terms of 
toxicity 
5.4.1 Raltegravir (RAL) 
Raltegravir (RAL, Isentress® MK-0518), was the first approved integrase inhibitor in 2008 in treatment naïve and 
experienced HIV infected individuals.  
 In the STARTMRK study, the proportion of treatment-naive patients who achieved virological suppression in 
the raltegravir arm was 86.1% at 48 weeks, non-inferior to a TDF (Tenofovir) /FTC (Emtricitabine)/EFV 
(Efavirenz). Importantly this efficacy rate was maintained over 5 years with a trend towards superiority over 
efavirenz mainly due to a better tolerability on long term [50]. More recently, raltegravir was compared to 
dolutegravir, a new integrase inhibitor currently in development, in treatment naïve patients in the SPRING 2 study 
which displays one of the highest efficacy rate with 85% and 88% of viral suppression (< 50 copies/mL at W48), 
respectively [51]. 
 
 Raltegravir is characterized by an excellent tolerability profile.  
In all randomized clinical trials, the safety and the tolerability of raltegravir were excellent and the rate of side 
effects has been low [52]. The most common adverse events reported were: headache, other nervous system 
effects and gastrointestinal events and the majority were mild and transient in nature.  
The most important superiority in terms of long-term tolerability is the metabolic profile of raltegravir. Raltegravir is 
a drug with an excellent metabolic profile [53-54]. In patients initiating ART with raltegravir in the STARTMRK trial, 
there were no significant changes from baseline in fasting total cholesterol, LDL-cholesterol, HDL-cholesterol, and 
triglyceride levels. There was a trend toward a greater decrease from baseline in the total cholesterol:HDL-
cholesterol ratio for raltegravir (−0.20) than efavirenz (+0.04) recipients (p=0.06) in a previously treatment-naive 
population [55].  
 
Switch studies  
The SPIRAL and SWITCHMRK [56-57] trials also demonstrated advantages in terms of toxicity and tolerance after 
raltegravir initiation. Switching to raltegravir was associated with significant decreases in plasma lipids and total-to-
HDL cholesterol ratio relative to continuing lopinavir/r (median decrease of triglyceride, 41% to 43% reduction from 
baseline at 12 weeks) [57]. The SPIRAL-LIP sub-study examined changes in body composition in 86 treatment-
experienced patients switching from protease inhibitors to raltegravir [58]. After 48 weeks, total and visceral 
abdominal fat tissue remained stable contrasting with an increase in those maintaining protease inhibitors. Bone 
mineral density (BMD) increased with raltegravir, but no significant change occurred in those remaining on 
protease inhibitors. Furthermore, switching from IP/r to raltegravir induced a significant change in several 
cardiovascular markers, an improved lipid profile and a significant decrease in several biomarkers like hsCRP 
(high-sensitivity C-Reactive Protein), osteoprotegerin, IL-6 (Interleukin-6), TNF-α (Tumor Necrosis Factor-α), 
insulin and D-dimers [59].  
5.4.2 Etravirine (ETR) 
- 
Etravirine (ETR, Intelence®,TMC125) is a second-generation NNRTI with activity against both wild-type 
HIV-1 and NNRTI-resistant virus [60]. Efficacy of ETR has been demonstrated in treatment-naive [61] and 
experienced patients [62-63]. Etravirine remains fully active on virus harbouring the single K103N mutation, one of 
the most prevalent mutations in patients who had failed with all NNRTI generations.  
- 
In the double blind, placebo-controlled SENSE trial, 157 treatment-naive patients were randomized 1:1 
to 400 mg of etravirine once daily (n=79) or 600 mg of efavirenz once daily (n=78) plus two nucleoside analogues 
(either abacavir/lamivudine, zidovudine/lamivudine or tenofovir/emtricitabine) for 48 weeks. In the efavirenz arm, 
there was larger increase in high-density lipoprotein (HDL) (p=0.004), low-density lipoprotein (LDL) (p=0.005), 


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total cholesterol (p<0.0001) and triglycerides (p=0.03) compared with the etravirine arm. Also, there were fewer 
grade 3/4 elevations in total cholesterol, LDL and triglycerides in the etravirine versus the efavirenz arm [64]. 
 
5.5 
 Raltegravir and etravirine dual combination as switch alternative 
in virologically supressed HIV-infected patients 
5.5.1 Viral efficacy 
 
A pilot observational study in 18 patients with suppressed HIV-RNA plasma viral load (VL<200 copies/mL), 
switching from a standard regimen to a raltegravir/etravirine combination has shown an intent-to-treat efficacy rate 
of 94.4% (n=17/18, 95% CI 74.2, 99%) at 6 months and 83.3% (n=15/18, 95% CI 60.7, 94.1%) at 12 months [65]. 
In per-protocol analysis, the efficacy at 12 months was 100% (n=15/15, 95% CI 80.6, 100%). No tolerability-
related treatment discontinuation was recorded. In 15 patients, the lipid profile was available before and after 
switch which showed a median decrease in cholesterol of -0.2 mmol/L (IQR (:Inter-Quartile Range )-0.86, -0.05) 
and of -0.4 mmol/L (IQR -0.9, 0.2) in triglyceride levels [65]. 
 
We then evaluated in an observational study 91 patients with plasma VL < 50 copies/mL who had been 
switched from an NRTI, PI or NNRTI-based regimen to a dual raltegravir/etravirine therapy.  
Among the 91 patients included, 65 have already completed 6 months of follow-up and 48 have completed 12 
months of follow-up. At 6 and 12 months respectively, 89.2% (54/55) and 92.3% (36/39) patients under RAL/ETR 
had an HIV-RNA plasma VL <50 copies/mL. Five cases of virological failure, defined as 2 consecutive plasma 
VLs > 50 copies/mL, occurred after a median (IQR) treatment duration of 7 months (IQR, 6-16).  
All 5 patients had been previously exposed to NNRTIs and 4/5 patients had previously replicated under an NNRTI 
containing regimen. Two of these 4 patients showed pre-existing mutations conferring resistance to ETR at the 
time of raltegravir/etravirine initiation (K103N and Y181C in both cases).  
These data underlines the need of ensuring the absence of mutations impacting ETR prior to switch, as RAL 
functional mono-therapy is hazardous in terms of virological suppression and resistance. 
In conclusion, clinical experience concerning the virological safety and tolerability to raltegravir/etravirine 
combination is encouraging and emphasises the need for further investigation in a clinical trial. 
5.5.2 Pharmacologic interactions between raltegravir and etravirine 
 
Interactions involving both raltegravir and etravirine are well documented. Raltegravir is metabolised through 
glucuronidation by UDP (Uridine Diphosphate)-glucuronosyltransferase 1A1 (UGT1A1) and has a low potential for 
drug-drug interactions and does not interfere with the hepatic cytochrome P450-3A4 such as most of the NNRTIs 
and PIs. Raltegravir is known to interact with atazanavir, an inhibitor of UGT1A1, increasing the plasma 
concentrations of raltegravir by 40%.   
 
Etravirine is a substrate of CYP2C19, CYP2C9 and CYP3A4. It moderately inhibits CYP2C19 and CYP2C9 
and strongly induces CYP3A4. Etravirine specific interactions are listed in paragraph 10.3. 
There is minimal interaction to be expected between etravirine and raltegravir. Etravirine, an inducer of UGT1A1, 
reduced raltegravir C12 by 34% and AUC (Area Under the Curve) by 10% when given concomitantly in healthy 
volunteers considered as not clinically relevant [66]. No dose modification is recommended in light of these 
findings. A retrospective study performed on a pharmacological database between 2011-2012, including 867 
patients (of whom 166 were under a RAL/ETR therapy) with 1208 RAL C12h samples collected, found no 
significant PK interaction between RAL and ETR [67]. 
 
In the ANRS 163 ETRAL trial a sample bank will be constituted in order to monitor raltegravir and etravirine 
plasma concentrations. At specific points these concentrations will be analysed in correlation with trial end-points. 


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5.6 
 Trial hypothesis 
Given the potency of raltegravir and etravirine, and although our limited clinical experience, we bring the 
hypothesis that a dual RAL/ETR regimen will be able to maintain the viral suppression if the two drugs are fully 
sensitive namely in patients naïve to both raltegravir and etravirine without any mutation that might impair drug’s 
efficacy. 
The second hypothesis is that, in a patient population with long-term ART, of at least 45 years of age, the switch to 
dual raltegravir/etravirine therapy should limit the long-term toxicity induced by NRTI and PI drugs, in particular 
cardiovascular, bone and renal diseases, without derogating from the key principle of sustained virological control. 
ANRS 163 ETRAL trial should assess: 
 
The virological safety of raltegravir/etravirine association. 
 
The impact of the discontinuation of NRTIs, PIs on the distribution of adipose tissue, bone mineral 
density, metabolic parameters and seminal HIV-RNA viral load. 
6 
OBJECTIVES 
6.1 
 Principal objective 
To evaluate over 48 weeks of treatment the capacity to maintain virological success defined as the absence of 2 
consecutive plasma viral loads (VL) > 50 copies/mL within 2 to 4 weeks of a dual raltegravir/etravirine regimen in 
HIV-1 infected patients, of at least 45 years of age, with suppressed plasma viremia switching from a boosted PI-
containing regimen. 
6.2 
 Secondary Objectives 
6.2.1 Biological efficacy 
 To assess the proportion of patients in therapeutic success up to week 48 and week 96  
 To assess the proportion of patients with virological success (plasma HIV-RNA ≤ 50 copies/mL) up to week 
96 
 To assess the proportion of patients with an interruption of therapeutic strategy 
 To assess the proportion of patients with low grade virological failure (HIV-RNA plasma VL between 51 and 
200 copies/mL) and the proportion of patients with high grade of virological failure defined as HIV-RNA 
>200 copies/mL at time of virological failure 
 Time limit to virological failure  
 HIV genotypic resistance profile, in plasma, in case of virological failure 
 To determine the factors associated with virological rebound (plasma HIV-RNA > 50 copies/mL) 
 Evolution of total cell-associated HIV-DNA from D0 to W48 and W96 
 Evolution of CD4+, CD8+ T cells counts and CD4/CD8 ratio at each time point from D0 
6.2.2 Tolerability and Metabolic Impact 
 Incidence of clinical and biological adverse effects  
 Incidence of clinical and biological adverse events (grade 3 or 4) 
 Modification of metabolic parameters (fasting triglycerides, total cholesterol, HDL-cholesterol, LDL-
cholesterol and fasting glycemia) 
 Evolution of the calibrated Framingham risk score and of the SCORE risk equation including HDL 
cholesterol (from the European Cardiovascular Society) from D0 to W48 and W96 
 Evolution of renal function evaluated using proteinuria and the CKD-EPI (Chronic Kidney Disease 
Epidemiology Collaboration Calculator) formula to estimate the Glomerular Filtration Rate (GFR) from D0 
to W96 
 Modification of peripheral and central body fat distribution, at W48 and W96 compared to D0 measured by 
DXA scan (Dual-energy X-Ray Absorptiometry) (DXA scan sub-study, 80 patients) 
 Evolution of bone mineral density measured by DXA scans at  W48 and W96 compared to D0 (DXA sub-
study, 80 patients)  
 To assess HIV-RNA viral load and Cmin (Minimal Drug Concentration) of raltegravir and etravirine at W48 
in human male genital compartment (Semen sub-study, 20 patients) 
 Evolution of the inflammation markers (IL-6hs, sCD14, sCD163, D-Dimers, IP-10, IgG, CRPus and insulin 
on frozen plasma aliquots from D0 to W48, and W96  


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 Evaluation of health-related quality of life with a self-assessment questionnaire at D0, W48, W96 and of the 
compliance with a self-assessment questionnaire at W-6/W-4, W48, W96 
 
6.2.3 Evaluation of the evolution of the cardio-vascular disease-related markers in women according 
to their ovarian reserve and their menopausal status 
 
Evolution of the ovarian reserve from D0 to W48 measured by AMH on frozen aliquots 
 
Evolution of the level of MCP1/CCL2 from D0 to W48 on frozen samples 
 
Evaluation of the metabolic/inflammatory profile according to sex at inclusion and its evolution up to 
week 48 
 
Evaluation of metabolic profile, inflammatory, innate immune activation markers in women according to 
their status regarding ovarian reserve and menopausal status at inclusion and its evolution up to week 
48 
 
7 
EXPERIMENTAL DESIGN 
7.1 
 Main study 
ANRS 163 ETRAL is a multicentre non-comparative phase II trial evaluating, in fully suppressed HIV-1-infected 
patients, of at least 45 years of age, with a suppressed viremia, the capacity of a dual raltegravir/etravirine 
antiretroviral regimen to maintain the virological success defined as two consecutive HIV-RNA plasma viral loads 
> 50 copies/mL within 2 to 4 weeks. Eligible patients must be under a stable PI-containing ARV regimen for at 
least 6 months and they must be fully suppressed within the 24 months prior the screening visit (W-6/W-4), as 
confirmed by 4 documented viral loads (e.g. 2 measurements per year during the past 24 months and not more 
than 1 HIV-RNA plasma viral load between 51 and 200 copies/mL). 
All PI-containing baseline ARV regimens are eligible except those containing raltegravir and/or etravirine. 
At Day 0, patients eligible according all criteria detailed in paragraph 8 will be switched to the dual raltegravir (400 
mg BID) plus etravirine (200 mg BID) regimen. 
Any SAE considered by the investigator and/or the sponsor as potentially related to the trial treatments will be 
reviewed and evaluated by DSMB. 
For all patients, during the 96 first weeks of the trial, a summary of the virological data including HIV-RNA viral 
loads and virus strains genotypes will be regularly submitted to the DSMB for review.  
The immunologic analysis of the evolution of the inflammation markers will be performed on frozen plasma 
aliquots from whole blood samples collected at specific time points: D0, W48, and W96. The markers of interest 
are: IL-6hs, sCD14, sCD163, D-Dimers, IP-10, IgG, CRPus and insulin.  
7.2 
 Sub-studies 
7.2.1 DXA-scan 
After signing a sub-study-specific informed consent form, 80 patients will be included in the DXA-scan sub-study 
assessing the evolution of bone mineral density (BMD) and of body fat distribution, and evaluating the potential 
impact of the dual raltegravir/etravirine regimen on these two parameters.  
DXA-scans will be performed locally in all participating French sites at D0, W48 and W96 with a time limit up to 7 
days before the date of D0 visit and with a time limit up to 10 days before and after the visit date of W48 and W96. 
The acquired images will be electronically transferred to a central review facility for final evaluation. 
7.2.2 Seminal sub-study 
This sub-study will be proposed to 20 male patients of the centres located in the region of Ile-de-France 
(neighbourhood of Paris) to evaluate at W48 the potential suppressive effect of the dual raltegravir/etravirine 
regimen on the HIV-RNA seminal viral load; and the minimal concentrations (Cmin) of RAL and ETR in the 
seminal fluid. 
Total sperm samples will be collected at home the day of the patient visit using the dedicated container delivered 
by the investigator during the previous visit and then transferred to the participating site within the 6 hours 
following sample collection.  
 


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Collected samples will be directly carried by the participant to “Service des maladies infectieuses”, department of 
the Pitié-Salpêtriere site. 
 
 
 
 
7.2.3 Women substudy 
 
This study will include all women recruited in the ETRAL trial. It will use frozen samples already collected and 
stored at Tenon Hospital, department of Biochemistry and Hormonology, for additional essays of Anti-Müllerian 
Hormone and CCL2/MCP1. Il will also use information on menopausal status already collected in the database.  
 


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7.3 
 Study Design 
 


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 7.4 Estimated Study duration 
Inclusion duration:  
 
 
        
18 months 
Maximum trial duration per patient: 
 
24 months (4 weeks for screening, 96 weeks of trial  
 
 
 
 
 
 
treatment and 2 weeks post-treatment interruption for safety  
 
 
 
 
 
reasons) 
Primary endpoint and analysis:   
 
30 months after trial initiation 
End of the trial: 
 
 
 
6 months after the last visit of the last patient 
Trial duration:  
 
 
        
3.5 to 4 years 
Expected trial initiation:  
 
 
 
1st trimester 2015 
8 
ELIGIBILITY CRITERIA 
 8.1 Inclusion criteria 
 Documented HIV-1 infection 
 Age ≥ 45 years 
 Naïve to integrase inhibitor and etravirine  
 At least 6 months of stable antiretroviral therapy (ART) including a boosted protease inhibitor, whatever the 
number of combined drugs  
 HIV-RNA plasma VL ≤ 50 copies/mL during the last 24 months prior to screening visit (W-6/W-4), 
documented by at least 4 time-points with no more than one blip in HIV-RNA plasma viral load between 
51 and 200 copies/mL 
 HIV-RNA plasma VL ≤ 50 copies/mL at screening visit (W-6/W-4) 
 A genotype is available (on amplified DNA at W-6/W-4 Visit and/or on RNA in the medical history of the 
patient) and shows a virus sensitive to ETR OR no genotype is available (amplification failure on DNA at 
W-6/W-4 Visit and no genotype in the medical history of the patient), there are no virological failure on 
NNRTI in the medical history 
 CD4+ lymphocytes > 200 cells/mm3 
 Creatinine < 2.5 x ULN 
 CPK (Creatine Phospho Kinase) < 6 ULN 
 AST (Aspartate Aminotransferase), ALT (Alanine Aminotransferase) < 5 ULN 
 Hemoglobin > 10 g/dL 
 Platelets > 100 000/mm3 
 Negative urinary pregnancy test and use of efficient contraception for women of childbearing potential  
 For French participants only : subject enrolled in or a beneficiary of a Social Security programme (State 
Medical Aid or AME is not a Social Security programme), article L1121-11 of the Public heatlh code.)  
 Patients with a coverage  from a social healthSigned informed consent 
 8.2 Non-inclusion criteria  
 Previous exposure to raltegravir or etravirine 
 Presence of any documented integrase inhibitor mutation on DNA genotype at W-6/W-4 and/or on RNA in 
the medical history of the patient. 
 Positive hepatitis B HBsAg or Positive HBc Ac and negative HBs Ac 
 HIV-2 infection 
 Active viral hepatitis C requiring a specific treatment during the 24 months of the trial  
 Patient with a history of non-compliance or irregular follow-up  
 Initiation of a concomitant anti-hypercholesterolemia (e.g. statins) or anti-diabetic treatment within the last 3 
months prior the screening visit (W-6/W-4) 
 Patient using: clopidogrel (Plavix®), prasugrel (Effient®), Ticagrelor (Brilinta®), Ticlopidine (Ticlid®), 
Flurbiprofen (Antadys® - Cebutid®), Rifampin (Rifampicin® - Rifadin® - RofactMC - Rifater®), Rifapentine 
(Priftin®), St John’s wort, Carbamazepine (Tegretol®), Phenobarbital, Phenytoin (Dilantin®), Avanafil 
(Stendra™), Triazolam (Halcion®). 
 Concomitant treatment using interferon, interleukins or any other immune-therapy or chemotherapy  
 Concomitant prophylactic or curative treatment for an opportunistic infection  
 All conditions (use of alcohol, drugs, etc.) judged by the investigator to possibly interfere with trial protocol 
compliance, adherence and/or trial treatment tolerance 
 Subjects under "sauvegarde de justice" (judicial protection due to temporarily and slightly diminished mental 
or physical faculties), or under legal guardianship 


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 Subjects participating in another clinical trial evaluating different therapies and including an exclusion period 
that is still in force during the screening phase 
 Pregnant women or breastfeeding women 
 
9 
STUDY ENDPOINTS 
 9.1 Primary Endpoint  
Proportion of patients remaining, at week 48, on virological success defined as the absence of 2 consecutive HIV-
RNA plasma VL > 50 copies/mL within 2 to 4 weeks. 
 9.2 Secondary Endpoints  
Biological efficacy   
 Percentage of patients remaining in therapeutic success up to week 48 and week 96 defined as the 
absence of virological failure and the absence of treatment interruption due to adverse event judged by 
DSMB as related to the trial treatment or procedure 
 Percentage of patients in virological success (plasma HIV-RNA ≤ 50 copies/mL) up to week 96 
 Percentage of patients with trial treatment interruption  
 Percentage of patients with plasma HIV-RNA VL between 51 and 200 copies/mL and percentage of patients 
with plasma HIVRNA VL ˃ 200 copies/mL at time of virological failure 
 Median time of virological failure (time limit between the date of the study treatment initiation and the date of 
virological failure)  
 Percentage of patients with RAL and/or ETR resistance mutations in case of virological failure and 
percentage of patients with resistant viruses to all study drug’s class in case of virological failure 
 Factors associated with the occurrence of plasma HIV-RNA VL> 50 copies/mL (genotype history, pre-cART 
VL, plasma drug concentration (etravirine, raltegravir) at the virological rebound, viral reservoir measured 
by HIV-DNA at D0 and adherence assessed with a self-questionnaire) 
 Evolution of total cell-associated HIV-DNA from D0 to W48 and W96 
 Evolution of CD4+, CD8+ T cells counts and CD4/CD8 ratio at each time point from D0 
 
Tolerability and Metabolic Impact 
 Percentage of patients with at least one serious adverse event as judged by DSMB as related to the trial 
treatment or to the trial strategy 
 Percentage of patients with grade 3 or grade 4 clinical and biological adverse events  
 Evolution of metabolic parameters (fasting triglycerides, total cholesterol, HDL-cholesterol, LDL-cholesterol 
and fasting glycemia) 
 Evolution of the calibrated Framingham risk score and of the SCORE risk equation including HDL 
cholesterol (from the European Cardiovascular Society) from D0 to W48 and W96 
 Evolution of renal function measured using proteinuria and the CKD-EPI (Chronic Kidney Disease 
Epidemiology Collaboration Calculator) formula to estimate the Glomerular Filtration Rate (GFR) from D0 
to W96 
 Evolution of limb lean, limb fat, visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT)., 
measured by DXA scan (Dual-energy X-Ray Absorptiometry), from D0 to W48 and W96 (DXA scan sub-
study, 80 patients) 
 Evolution of bone mineral density measured by DXA scans from D0, to W48 and W96 (DXA scan sub-
study, 80 patients)  
 HIV-RNA viral load and Cmin (Minimal Drug Concentration) of raltegravir and etravirine in seminal fluid at 
W48 (Seminal sub-study, 20 patients) 
 Evolution of the inflammation markers (IL-6hs, sCD14, sCD163, D-Dimers, IP-10, IgG, CRPus and insulin) 
on frozen plasma aliquots from D0 to W48, and W96  
 Evaluation of health-related quality of life with a self-assessment questionnaire from D0 to W48, and W96 
and of the compliance with a self-assessment questionnaire at W-6/W-4, W48, and W96 
  
Evaluation of metabolic impact according to the ovarian reserve and menopausal status 
 
between D0 and W48 
 
Comparison of metabolic (total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, non-HDL-
cholesterol and triglyceride/HDL-cholesterol), inflammatory and innate immune activation (IL-6hs, 


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sCD14, sCD163, D-Dimers, IP-10, IgG, CRPus and insulin), fat distribution and bone markers 
measured by DEXA scan between men and women at D0 et comparison of their evolution at W48 
 
Comparaison of the metabolic/inflammatory profile in women according to their ovarian reserve and 
menopausal status at D0 and its evolution up to week 48 
10. 
DRUGS MANAGEMENT 
 10.1 Study drug 
The investigational ARV regimen is defined as raltegravir (RAL, Isentress®) plus etravirine (ETR, Intelence®).  
Raltegravir 400 mg tablets will be administered as one 400 mg oral tablet PO twice daily (800 mg per day) after a 
meal.  
Etravirine 200 mg tablets will be administered as one 200 mg oral tablet PO twice daily (400 mg per day) after a 
meal. 
The reference documents for raltegravir and etravirine, follow the recommendations clearly stated in the summary 
of product characteristics of the respective drugs. 
 10.2 Study drug circuit 
10.2.1 Study drug: delivery 
The sponsor is in charge of providing raltegravir and etravirine in association with Merck Sharp & Dohme Ltd and 
Janssen Cilag Pty Ltd. The Sponsor will contract a specific partner, to manage the trial drugs provided to the 
patients.  
 
Study drug order to pharmaceutical firms will be done by the sponsor in collaboration with the CMG Inserm UMR 
S 1136 and the pharmacy of study sites. 
 
The service provider of the trial drug, also called a pharmaceutical provider in this study protocol, will be 
responsible to receipt study drugs delivered by the pharmaceutical firms, store, and label both raltegravir and 
etravirine according to GCP (Good Clinical Practice) requirements and to deliver the study drugs ready to use to 
the pharmacy of the clinical centres. The service provider will also regularly perform quality controls according to 
GMP (Good Manufacturing Practice) requirements. 
10.2.2 Study drug: packaging  
Merck Sharp & Dohme Ltd will provide raltegravir in the form of commercial supply Isentress® and Janssen will 
provide etravirine in the form of commercial supply Intelence®.  
Raltegravir (RAL, Isentress®) 400 mg tablets and etravirine (ETR, Intelence®) 200 mg tablets will be packed in 
their original and respective boxes/bottles. 
10.2.3 Study drug: labeling 
The sponsor will provide trial specifications to the service provider in charge of drugs labeling within the respect of 
the Good Manufacturing Practices (according to article 26 to 30 of annex 13 of the European Good Manufacturing 
Practices of 2009).  
The study drug’s label will be in agreement with European regulatory requirements (according to article 26 to 30 of 
annex 13 of the European Good Manufacturing Practices of 2009). 
10.2.4 Study drug: dispatching and dispensiation 
Study drug dispatching 
Pharmaceutical companies will ship the study drugs to the pharmaceutical provider in charge of the delivery to the 
pharmacy of the clinical centres. Pharmaceutical firms will provide the trial medication to the pharmaceutical 
provider in several batches which will be defined in the contract.   
The CMG Inserm UMR S 1136 will inform the study drug service provider or every patient’s inclusion. 


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A theoretical calendar for every patient’s visit will be provided by the CMG Inserm UMR S 1136 to the 
pharmaceutical provider. This will be realized once the D0 visit is done and the data of the D0 visit are reported 
into the eCRF by the investigator of the clinical centre.  
 
Study drug: dispensation 
Raltegravir and etravirine, will be dispensed by the pharmacist of the trial site upon receipt of a prescription 
specific to ARNS 163 ETRAL trial filled and signed by the investigator at the name of the patient. 
Delivery of raltegravir and etravirine to the patient will occur at the pharmacy on the trial site and have to be 
dispensed in their original containers.  In most cases, one bottle will include enough for one month of therapy. 
The patient should return the empty boxes of treatment at each time of delivery in order to measure the 
adherence. 
 
Pharmacists of trial sites will be in charge of  
 Receiving trial medication; 
 keeping trial medications in a locked secure storage facility, only accessible to authorized staff; 
 A trial medication inventory will be maintained, including materials received and dispensed to patients; 
 At the conclusion or termination of the trial, the pharmacist agrees to conduct a final drug supply inventory 
and to record this on a Drug Accountability Form; 
 Deliveries are documented; 
 Trial medications are adequately stored; 
 Records should include dates, quantities and the unique code numbers assigned to the investigational 
drugs and the trial subjects. 
10.2.5 Study drug: return and destruction 
Before IMP(s) (Investigational Medical Product) is returned to or destroyed, documentation of the delivery, use, 
and destruction or return of unused, used or partially used packages of IMP(s) has to be kept by the pharmacist. 
Accountability will include documentation (on a study-specific accountability log) of the numbers of tablets 
dispensed by the pharmacist, as well as the amount of medication, which is not used and returned. The 
accountability log will be checked by the Sponsor’s study monitor. 
Upon completion or termination of the trial, all unused and/or partially used study drugs must be returned to the 
service provider of the study drug 
All study drugs returned to the service provider must be accompanied by appropriate documentation and be 
clearly identified by protocol number and trial site number on the outermost shipping container. Returned supplies 
should be in the original containers (eg patient kits). The assigned study monitor should facilitate the return of 
unused and/or partially used study drugs. 
If the study drug is authorized to be destroyed at the site by the Sponsor, it is the pharmacist’s responsibility to 
ensure that arrangements have been made for the disposal. Written authorization should be issued by the 
Sponsor, procedures for proper disposal should be established according to applicable regulations, guidelines and 
procedures, and appropriate records of the disposal/study drug destruction should be documented and forwarded 
to the Sponsor. 
 10.3 Concomitant treatments 
 
Interactions with Other Drugs 
Potential drug-drug and/or drug-food interactions should be taken into consideration when selecting an antiretroviral 
(ARV) regimen. A thorough review of concomitant medications can help in designing a regimen that minimizes 
undesirable interactions. In addition, the potential for drug interactions should be assessed when any new drug 
(including over-the-counter agents), is added to an existing ARV combination. Most drug interactions with ARV 
drugs are mediated through inhibition or induction of hepatic drug metabolism. 
 
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) 
All NNRTIs are metabolized in the liver by cytochrome P450 (CYP) 3A isoenzymes. In addition, efavirenz (EFV) and 
nevirapine (NVP) are substrates of CYP2B6 enzymes, and etravirine (ETR) is a substrate of CYP2C9 and 2C19 
enzymes. Concomitantly administered drugs that induce or inhibit these enzymes can alter NNRTI drug 
concentrations, resulting in virologic failure or adverse effects. All NNRTIs, except rilpivirine (RPV), induce or inhibit 
CYP isoenzymes. EFV acts as a mixed inducer and inhibitor, but like NVP, it primarily induces CYP3A and 2B6 


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enzymes. ETR also induces CYP3A but inhibits CYP2C9 and 2C19 enzymes. The inducing effects of NNRTIs can 
result in sub-therapeutic concentrations of concomitantly administered drugs that are metabolized by CYP enzymes. 
Examples of such interacting medications include azole antifungals, rifamycins, benzodiazepines, hepatitis C virus 
(HCV) protease inhibitors, HMG-CoA reductase inhibitors (statins), and methadone.  
 
Integrase Strand Transfer Inhibitors (INSTIs) 
Raltegravir (RAL) is primarily eliminated by glucuronidation mediated by the uridine diphosphate (UDP)- 
glucuronosyltransferase (UGT) 1A1 enzymes. Strong inducers of UGT1A1 enzymes (e.g., rifampin) can significantly 
reduce the concentration of RAL. Raltegravir does not appear to affect CYP or UGT enzymes or P-glycoprotein-
mediated transport. 
 
Drug Interactions between Non-Nucleoside Reverse Transcriptase Inhibitors/ Integrase Inhibitors and Other Drugs 
(Last updated February 12, 2013; last reviewed February 12, 2013) (Guidelines for the Use of Antiretroviral Agents 
in HIV-1-Infected Adults and Adolescents - Downloaded from http://aidsinfo.nih.gov/guidelines on 2/16/2014) 
 
10.3.1 Interations and dose recommendations with other medicinal products concomitant 
 
Drug 
Class/Name 
Etravirine (ETR) 
or raltegravir 
(RAL) 
Effect on NNRTI or INI or 
Concomitant Drug 
Concentrations 
Dosing Recommendations and Clinical 
Comments 
Anticoagulant 
Warfarin 
Etravirine 
↑ warfarin possible 
No dosage adjustment necessary; use 
with caution. 
Consider monitoring International 
Normalized Ratio (INR) level. 
Antifungals, 
Voriconazole 
Etravirine 
voriconazole AUC ↑ 14% 
ETR AUC ↑ 36% 
No dosage adjustment necessary; use 
with caution. 
Consider monitoring voriconazole level. 
Antimycobacterials 
Clarithromycin 
Etravirine 
clarithromycin AUC ↓ 39% 
ETR AUC ↑ 42% 
Consider alternative agent, such as 
azithromycin, for MAC prophylaxis and 
treatment. 
Rifabutin 
Etravirine 
rifabutin and metabolite AUC ↓ 
17% 
ETR AUC ↓ 37% 
If ETR is used with an RTV-boosted PI, 
rifabutin should not be co-administered. 
Dose: rifabutin 300 mg once daily if ETR is 
not coadministered with an RTV-boosted 
PI. 
Benzodiazepines 
Alprazolam 
Etravirine 
No data 
Monitor for therapeutic effectiveness of 
alprazolam. 
Diazepam 
Etravirine 
↑ diazepam possible 
Decreased dose of diazepam may be 
necessary. 
Midazolam 
Etravirine 
Significant ↑ midazolam expected 
Do not co-administer with oral midazolam. 
Parenteral midazolam can be used with 
caution as a single dose and can be given 
in a monitored situation for procedural 
sedation. 
Cardiac Medications 
Antiarythmic 
medications  
Etravirine 
↓ antiarythmic medications 
possible 
No dosage adjustment necessary; use 
with caution. 
Dihydropyridine 
calcium channel 
blockers (CCBs) 
Etravirine 
↓ CCBs possible 
Titrate CCB dose based on clinical 
response. 
Diltiazem 
Verapamil 
Etravirine 
diltiazem AUC ↓ 69% 
↓ verapamil possible 
Titrate diltiazem or verapamil dose based 
on clinical response. 
Digoxin 
Etravirine 
Digoxin AUC  ↑ 18% 
No dosage adjustment necessary; use 
with caution. 
Corticosteroids 
Dexamethasone 
Etravirine 
↓ ETR possible 
Consider alternative corticosteroid for 
long-term use. If dexamethasone is used 
with NNRTI, monitor virologic response. 
HMG-CoA Reductase Inhibitors 
Atorvastatin 
Etravirine 
atorvastatin AUC ↓ 32%–43% 
Adjust atorvastatin according to lipid 
responses, not to exceed the maximum 
recommended dose. 
Fluvastatin 
Etravirine 
↑ fluvastatin possible 
Dose adjustments for fluvastatin may be 
necessary. 
Lovastatin 
Simvastatin 
Etravirine 
↓ lovastatin possible 
↓ simvastatin possible 
Adjust lovastatin or simvastatin dose 
according to lipid responses, not to exceed 
the maximum recommended dose. If ETR 


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or NVP used with RTV-boosted PI, 
simvastatin and lovastatin should be 
avoided. 
Immunosuppressants 
Cyclosporine 
Sirolimus 
Tacrolimus 
Etravirine 
↓ immunosuppressant possible 
Increase in immunosuppressant dose may 
be necessary. 
Therapeutic drug monitoring of 
immunosuppressant is recommended. 
Consult with specialist as necessary. 
Phosphodiesterase Type 5 (PDE5) Inhibitors 
Sildenafil 
Etravirine 
sildenafil AUC ↓ 57% 
May need to increase sildenafil dose 
based on clinical effect. 
Tadalafil 
Etravirine 
↓ tadalafil possible 
May need to increase tadalafil dose based 
on clinical effect. 
Vardenafil 
Etravirine 
↓ vardenafil possible 
May need to increase vardenafil dose 
based on clinical effect. 
 
 
10.3.2 Drugs That Should Not Be Used With Antiretroviral Agents as etravirine and raltegravir 
 
Trade names 
DCI 
Metabolic pathway 
Effects on drug levels 
Platelet Aggregation Inhibitors 
Plavix® 
Clopidogrel 
A prodrug, active metabolite 
CYP2C19 
Increased activity of 
Clopidogrel, risk of 
overdose 
Effient® 
Prasugrel 
A prodrug, active metabolite 
CYP3A4, 
CYP2B6, 2C9/19 
Increased activity of 
Prasugrel, risk of overdose 
Brilinta® 
Ticagrelor 
Active parent compound 
CYP3A4/5 
Decreased activity of 
Ticagrelor, risk of 
inefficiency 
Ticlid® 
Ticlopidine 
Active parent compound 
CYP1A2, 2C19, 2D6 +active 
metabolite CYP2B6  
Decreased activity of 
Ticlopidine, risk of 
inefficiency 
Antadys®  
Cebutid® 
 
Flurbiprofen 
Active parent compound 
CYP2C9,UGT (Isozyme) 
 
Possible decrease activity 
of Flurbiprofen, risk of 
inefficiency 
Anti 
mycobacterials 
Rifampicin® 
Rifadin®  
RofactMC  
Rifater® 
 
Rifampin 
/ 
Rifampin reduces plasma 
levels of etravirine and 
Raltegravir. 
 Priftin® 
Rifapentine 
/ 
Rifapentine reduces 
plasma levels of Etravirine 
Herbs 
Millepertuis 
St John’s wort 
/ 
St John’s wort reduces 
plasma levels of Etravirine 
Anticonvulsa
nt 
Tegretol® 
Carbamazepine 
/ 
Carbazamepine, 
phenobarbital and 
phenytoin are expected to 
decrease plasma 
concentrations of 
Etravirine. 
 
Phenobarbital 
/ 
Dilantin® 
Phenytoin 
/ 
Others 
Stendra™ 
Avanafil 
/ 
Co-administration is not 
recommended 
Halcion® 
Triazolam 
/ 
Significant increased 
triazolam expected 
 
 
 
 
 


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11 STUDY ASSESSMENTS AND CONDUCT 
 11.1 Schedule of assessments  
 
 
 
W-
6/W-
4 
D0 
W2
W4 
W12 W24 W36
W48 
W64 W80 W96 
EOT
Informed Consent Signature 
X 
 
 
 
 
 
 
 
 
 
 
Review eligibility criteria 
X 
X 
 
 
 
 
 
 
 
 
 
Collection of adverse events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Quality of life, felt symptoms 
 
X 
 
 
 
 
 
X 
 
 
X 
X 
Adherence evaluation 
X 
 
 
 
 
 
 
X 
 
 
X 
X 
Clinical exam  
(blood pressure, heart rate, body 
temperature, weight and targeted 
physical examination) 
X1 
X2,3,4
X 
X 
X 
X 
X 
X2,3,4
X 
X 
X2, 3, 4
X2 
HBV/HCV serology  
X 
 
 
 
 
 
 
 
 
 
 
 
Urinary pregnancy test  
If positive:  HCG5 
X 
X6 
X6 
X6 
X6 
X6 
X6 
X6 
X6 
X6 
X6 
X6 
HIV-RNA plasma Viral Load7 
X 
X 
 
X8 
X8 
X8 
X8 
X8 
X8 
X8 
X8 
X8 
CD4/CD8 Lymphocytes 
X 
X 
 
 
X 
X 
 
X 
 
X 
X 
X 
Whole blood cells count 
X 
 
 
 
 
X 
 
X 
 
X 
X 
X 
Creatinine, AST, ALT, CPK, 
bilirubin, urine analysis9 
X 
 
 
X 
X 
X 
 
X 
 
X 
X 
X 
Lipid profile10, fasting glycemia 
 
X 
 
X 
X 
 
X 
 
 
X 
X 
Genotypic resistance on blood 
DNA 
X 
 
 
 
 
 
 
 
 
 
 
DXA-Scan sub-study11 
 
X 
 
 
 
 
X 
 
 
X 
 
Seminal sub-study12 
 
 
 
 
 
 
X 
 
 
 
 
Study drug prescription 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Sample bank13 
Plasma bank:minimal plasma ARV 
concentration, virological analysis 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Whole blood bank:Total cell-
associated HIV-DNA 
 
X 
 
 
 
 
X 
 
 
X 
X 
Plasma and serum 
bank:Immunologic analysis of 
inflammation markers14 
 
X 
 
 
 
 
X 
 
 
X 
X 
 
1 Electrocardiogram (ECG)  
2 Anthropometric measurements (abdominal and waist circumference) 
3 Cardiovasculor risk factors: arterial hypertension, tobacco, alcohol abuse, physical activity, diabetes 
4 Measurement of the systolic blood pressure at D0 W48 W96 according to the recommendations (Pickering et al. Circulation 
2005, in Appendix A7) 
5 Only for women of childbearing potential 
6 Only in case of suspicion 
7 Plasma viral loads using a routine technique with a positivity threshold of maximum 50 copies/mL 
8 If HIV-RNA plasma viral loads > 50 copies/mL an additional blood collection have to be performed, within an interval of two to 
four weeks, to confirm the virological rebound. If the virological failure is confirmed, a resistance genotype and a dosage of ARV 
drugs concentration in plasma will be performed on the second HIV-RNA plasma VL test. A plasma bank should also be done 
9 Urine analysis: proteinuria, albuminuria, creatininuria, glycosuria 
10 Lipid profile: fasting triglycerides, total cholesterol, HDL-cholesterol, LDL-cholesterol 
11 DXA-scan sub-study: evolution of the Bone Mineral Density (BMD) and of the body fat distribution in 80 patients  
12 Seminal sub-study in 20 patients. The HIV-RNA viral load and the RAL/ETR Cmin will be measured 
13 Refer to paragraph 12 
14 Immunological analysis of inflammation markers might be performed on frozen plasma aliquots. Markers of interest are: IL-
6hs, sCD14, sCD163, D-Dimers, IP-10, IgG, CRPus and insulin  


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 11.2 Study participation 
11.2.1 Information 
No examinations will be carried out before the patient concerned gave his/her written informed consent. Before 
any study-related trial procedures, the investigator will: 
- Explain the nature, purpose and potential risks of the trial in which patients volunteer to participate and answer 
all questions regarding this trial,  
- Inform patients that their participation is voluntary and that they may withdraw consent to participate at any time 
without giving any reason; if patients decide not to participate or withdraw from the trial, it will not affect the 
standard care they will receive to treat their disease, 
- Provide to patients the informed consent form in their own language. The patients will be given sufficient time to 
consider before consenting, 
The investigator(s) has both ethical and legal responsibility to ensure that each patient being considered for 
inclusion in this trial is given a full explanation of the protocol. 
11.2.2 Obtaining consent  
Once the appropriate essential information has been provided to the patient and fully explained by the investigator 
(or a qualified designee) and it is felt that the patient understands the implications of participating, the IRB 
(Institutional Review Board)/IEC-approved written informed consent form shall be signed and dated by both the 
patient and the person obtaining consent (investigator or designee), and by any other parties required by the 
IRB/IEC. The patient shall be given a copy of the signed informed consent form; the original shall be kept on file 
by the investigator. All of the above mentioned activities must be completed prior to the patient’s participating in 
the trial.  
After obtaining the informed consent form signed and personally dated by the patients, the investigator must 
attribute a trial identification code to any patient who has accepted to participate into the trial (see procedure 
described below). 
The inclusion and non-inclusion criteria after signature of the written informed consent must be checked. 
Patients that fail screening may be re-screened while keeping their previous identification code. 
11.2.3 Patient identification  
The investigator will assign an identification code to the patient according to the following procedure. 
The patient identification code is composed of: 
- Two letters for the country: FR for France, ES for Spain 
- The centre number (3 digits) 
- The patient order of entry in the trial in this centre (3 digits) 
- A four letter code randomly generated and be provided to any participant centres by the CMG Inserm UMR S 
1136 before starting the trial 
For example, for a patient, screened in France, in centre 060, and screened for inclusion at the second position in 
this centre with letter code of FRSD, the patient identification code will be: FR-060-002-FRSD. 
 11.3 Screening visit (W -6/W-4) 
This visit will be performed between 4 and  6 weeks before the beginning of trial treatment (RAL/ETR) at D0 Visit.  
During this visit, the investigator: 
 Collects the fully informed patient’s consent,  
 Collects the following patient characteristics (Birth date, Sex, Origin and HIV transmission group) and 
patient’s lifestyle (tobacco, drugs and alcohol), 
 Collects current/previous ART,  


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 Interviews the patient to collect the medical history, the potential concomitant pathologies and concomitants 
treatments, 
 Evaluates the patient’s adherence using self-questionnaires 
 Performs an extensive and detailed anamnesis of the patient’s immunovirologic history including a complete 
chronological list of the viral strains genotypes allowing the exclusion of any virological failure under NNRTI 
treatment. In addition, the investigator has to perform prior to inclusion a Genotypic resistance on blood DNA 
showing its full sensibility to ETR and RAL, 
 Performs a clinical examination: blood pressure, heart rate, body temperature, targeted physical 
examination,weight, and height. An ECG will be performed to exclude any concomitant condition that might 
jeopardize patient’s safety and participation, 
 Performs urinary pregnancy test for women of childbearing potential, 
 Collects urine sample for urine analysis: proteinuria, albuminuria, creatininuria, glycosuria, 
 Collects blood samples for the following biological exams: 
- 
Whole blood cells counts 
- 
HIV-RNA plasma viral load 
- Genotypic resistance on blood DNA 
- 
CD4/CD8 lymphocytes count 
- 
Creatinine, CPK, AST, ALT and bilirubin dosages 
- 
HBV and HCV serologies  
- 
ßHCG for women of childbearing potential with positive urinary test 
A copy of the biological exams with an anonymized copy of the Patient’s Informed Consent Form will be faxed by 
the investigator to CMG Inserm UMR S 1136 in order for them to validate the inclusion. 
The investigator will schedule the D0 visit and the DXA scan of D0 visit (for patients participating in the DXA sub-
study). DXA scan might be performed with a time limit up to 7 days before the date of D0 visit. 
 
11.4 Day 0 visit (inclusion) 
The designated D0 Visit (Day 0) is the date planned for the first prescription and, a fortiori, the first administration 
of trial treatment (RAL/ETR). 
During this visit, the investigator: 
 Realizes a clinical examination (blood pressure, heart rate, body temperature, targeted physical examination, 
weight) and anthropometric measurements (specific circumferences: abdomen (perimeter at the umbilicus) 
and hips (bi-trochanterian perimeter)). Cardiovascular risk factors (arterial hypertension, tobacco, alcohol 
abuse, physical activity, diabetes) and the measurement of the systolic blood pressure (refer to appendix 7) 
will be recorded.  
 Checks the presence of intercurrent pathologies and the treatments intake 
 Evaluates the patient’s quality of life and felt symptoms using self-questionnaires 
 Performs urinary pregnancy test for women of childbearing potential, in case of suspicion 
 Collects blood samples for the following biological exams: 
- 
HIV-RNA plasma viral load 
- 
CD4/CD8 lymphocytes count 
- 
Lipids (fasting triglycerides, total cholesterol, HDL-Cholesterol, and LDL-cholesterol) and 
fasting glycemia 
- 
Sample bank (plasma,serum and whole blood bank)  
 DXA-Scan will be performed for patients participating in this sub-study (DXA scan might be performed up to 7 
days before D0 visit). 
A copy of the biological exams will be faxed by the investigator to CMG Inserm UMR S 1136. 
The investigator will give the first prescription of trial treatment (RAL/ETR) and schedule the W2 visit.  
11.5 Follow-up visits 
After the D0 visit, 9 visits are scheduled in the clinical centres, W2, W4, W12, W24, W36, W48, W64, W80 and 
W96 or End of treatment (EOT). EOT visit will be performed in case of giving up or premature stop of trial 


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treatment. Assessments and procedures will be performed according to schedules reported in the table (schedule 
of assessment). A copy of all biological exams will be faxed by the investigator to CMG Inserm UMR S 1136. 
11.5.1 Visits W2 to W80 
- 
W2 Visit: the investigator will realize a clinical examination (blood pressure, heart rate, body temperature, 
targeted physical examination, weight), check the presence of intercurrent pathologies and the treatments 
intake. Urinary pregnancy test for women of childbearing potential will be performed, in case of suspicion. 
Blood samples will be collected for sample bank (plasma bank). 
The investigator will schedule the W4 visit. 
 
- 
W4 Visit: the investigator will realize a clinical examination (blood pressure, heart rate, body temperature, 
targeted physical examination, weight), check the presence of intercurrent pathologies and the treatments 
intake. Urinary pregnancy test for women of childbearing potential will be performed, in case of suspicion. 
Plasma HIV-1 RNA viral load, Creatinine, CPK, AST, ALT and bilirubin dosages will be realized in the local 
laboratory. Blood samples will be collected for sample bank (plasma bank). Urine sample for proteinuria, 
albuminuria, creatininuria, glycosuria analysis (in the local laboratory) will be collected. 
The investigator will give the prescription of trial treatment (RAL/ETR) and schedule the W12 visit. 
 
- 
W12 Visit: the investigator will realize a clinical examination (blood pressure, heart rate, body temperature, 
targeted physical examination, weight), check the presence of intercurrent pathologies and the treatments 
intake. Urinary pregnancy test for women of childbearing potential will be performed, in case of suspicion. 
Plasma HIV-1 RNA viral load, CD4/CD8 count, metabolic parameters (fasting triglycerides, total cholesterol, 
HDL-Cholesterol, and LDL-cholesterol), fasting glycemia, Creatinine, CPK, AST, ALT and bilirubin dosages 
will be realized in the local laboratory. Urine sample for proteinuria, albuminuria, creatininuria, glycosuria 
analysis (in the local laboratory) will be collected. Blood samples will be collected for sample bank (plasma 
bank). 
The investigator will give the prescription of trial treatment (RAL/ETR) and schedule the W24 visit. 
 
- W24 Visit: the investigator will realize a clinical examination (blood pressure, heart rate, body temperature, 
targeted physical examination, weight), check the presence of intercurrent pathologies and the treatments 
intake. Urinary pregnancy test for women of childbearing potential will be performed, in case of suspicion. 
Plasma HIV-1 RNA viral load, CD4/CD8 count, whole blood cells count, metabolic parameters (fasting 
triglycerides, total cholesterol, HDL-Cholesterol, and LDL-cholesterol), fasting glycemia, Creatinine, CPK, 
AST, ALT, bilirubin dosages and urine analysis (proteinuria, albuminuria, creatininuria, glycosuria) will be 
realized in the local laboratory. Blood samples will be collected for sample bank (plasma bank). The 
investigator will give the prescription of trial treatment (RAL/ETR) and schedule the W36 visit. 
 
- 
W36 Visit: the investigator will realize a clinical examination (blood pressure, heart rate, body temperature, 
targeted physical examination, weight), check the presence of intercurrent pathologies and the treatments 
intake. Urinary pregnancy test for women of childbearing potential will be performed, in case of suspicion. 
Plasma HIV-1 RNA viral load will be realized in the local laboratory. Blood samples will be collected for 
sample bank (plasma bank).  
The investigator will give the prescription of trial treatment (RAL/ETR), schedule the W48 visit and the DXA 
scan (for patients participating in the DXA sub-study). DXA scan might be performed with a time limit up to 
10 days before and after the visit date of W48. 
The investigator will deliver the dedicated container for patients participating in the seminal sub-study to 
collect the sperm within the 6 hours prior the W48 visit. 
 
- 
W48 Visit: the investigator will realize a clinical examination (blood pressure, heart rate, body temperature, 
targeted physical examination, weight) check the presence of intercurrent pathologies and the treatments 
intake. Anthropometric measurements (specific circumferences: abdomen (perimeter at the umbilicus) and 
hips (bi-trochanterian perimeter)),cardiovascular risk factors (arterial hypertensions, tobacco, alcohol abuse, 
physical activity, diabetes), measurement of the systolic blood pressure (refer to appendix 7) will be 
recorded . Urinary pregnancy test for women of childbearing potential will be performed, in case of 
suspicion. Plasma HIV-1 RNA viral load, CD4/CD8 count, whole blood cells count, metabolic parameters 
(fasting triglycerides, total cholesterol, HDL-Cholesterol, and LDL-cholesterol), fasting glycemia, Creatinine, 
CPK, AST, ALT, bilirubin dosages, urine analysis (proteinuria, albuminuria, creatininuria, glycosuria) will be 
realized in the local laboratory. Blood samples will be collected for sample bank (plasma, serum and whole 


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blood bank), The patient’s quality of life, felt symptoms, and adherence will be collected using self-
questionnaires. 
 
Patients participating to the DXA-Scan sub-study will perform their second scans. DXA scan might be 
performed with a time limit up to 10 days before and after the visit date of W48. 
At W48, patients participating to the seminal sub-study will bring the total sperm sample collected within the 
6 hours prior the visit using the dedicated container delivered by the investigator at W36. 
 
The investigator will give the prescription of trial treatment (RAL/ETR) and schedule the W64 visit. 
 
- 
W64 Visit: the investigator will realize a clinical examination (blood pressure, heart rate, body temperature, 
targeted physical examination, weight), check the presence of intercurrent pathologies and the treatments 
intake. Urinary pregnancy test for women of childbearing potential will be performed, in case of suspicion. 
Plasma HIV-1 RNA viral will be realized in the local laboratory. Blood samples will be collected for sample 
bank (plasma bank). 
The investigator will give the prescription of trial treatment (RAL/ETR) and schedule the W80 visit. 
 
-    W80 Visit: the investigator will realize a clinical examination (blood pressure, heart rate, body temperature, 
targeted physical examination, weight), check the presence of intercurrent pathologies and the treatments 
intake. Urinary pregnancy test for women of childbearing potential will be performed, in case of suspicion. 
Plasma HIV-1 RNA viral load, CD4/CD8 count, whole blood cells count, Creatinine, CPK, AST, ALT, 
bilirubin dosages and urine analysis (proteinuria, albuminuria, creatininuria, glycosuria) will be realized in 
the local laboratory. Blood samples will be collected for sample bank (plasma bank).  
The investigator will give the prescription of trial treatment (RAL/ETR), schedule the W96 visit and the DXA 
scan (for patients participating in the DXA sub-study). DXA scan might be performed with a time limit up to 
10 days before and after the visit date of W96. 
11.5.2 Last visit of follow-up 
The last visit of follow-up for each patient will be the week 96 visit if the patient completes the trial or the EOT visit 
in case of giving up or premature stop. Patients who stop the trial treatment will continue to be followed according 
to the trial calendar until the week 96. 
- 
W96 Visit: the investigator will realize a clinical examination (blood pressure, heart rate, body temperature, 
targeted physical examination, weight), anthropometric measurements (specific circumferences: abdomen 
(perimeter at the umbilicus) and hips (bi-trochanterian perimeter), check the presence of intercurrent 
pathologies and the treatments intake. Cardiovascular risk factors (arterial hypertensions, tobacco, alcohol 
abuse, physical activity, diabetes) and the measurement of the systolic blood pressure (refer to appendix 7) 
will be recorded. Urinary pregnancy test for women of childbearing potential will be performed, in case of 
suspicion. Plasma HIV-1 RNA viral load, CD4/CD8 count, whole blood cells count, metabolic parameters 
(fasting triglycerides, total cholesterol, HDL-Cholesterol, and LDL-cholesterol), fasting glycemia, Creatinine, 
CPK, AST, ALT, bilirubin dosages, urine analysis (proteinuria, albuminuria, creatininuria, glycosuria) will be 
realized in the local laboratory. Blood samples will be collected for sample bank (plasma, serum and whole 
blood bank). The patient’s quality of life, felt  
symptoms and adherence will be collected using self-
questionnaires. 
Patients participating to the DXA-Scan sub-study will perform their third scans. DXA scan might be 
performed with a time limit up to 10 days before and after the visit date of W96. 
 
- EOT Visit (End of treatment): this visit will be realized only in case of giving up or premature stop of trial 
treatment.  
At this visit, the investigator will realize a clinical examination (blood pressure, heart rate, body temperature, 
targeted 
physical 
examination, 
weight), 
anthropometric 
measurements 
(abdominal 
and 
waist 
circumference),check the presence of intercurrent pathologies and the treatments intake. Urinary pregnancy 
test for women of childbearing potential will be performed, in case of suspicion. Plasma HIV-1 RNA viral, 
CD4/CD8 count, whole blood cells count, metabolic parameters (fasting triglycerides, total cholesterol, HDL-
Cholesterol, and LDL-cholesterol), fasting glycemia, Creatinine, CPK, AST, ALT, bilirubin dosages, and 
urine analysis (proteinuria, albuminuria, creatininuria, glycosuria) will be realized in the local laboratory. 
Blood samples will be collected for sample bank (plasma, serum and whole blood bank). 
The patient’s quality of life, felt symptoms and adherence will be collected using self-questionnaires. 


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 11.6 Study end 
The end of the trial occurs when the last patient still being followed realizes the week 96 visit, abandons or 
withdraws consent plus 6 months. At the end of the trial (six months after the last visit of the last patient), for each 
participant, according to the trial results, the investigator will decide to maintain or change the trial treatment. The 
patients will be followed with the best clinical practices. In case of premature stop of the trial, the investigator will 
follow the scientific committee recommendation. All patients will be informed of the trial results. 
 11.7 Premature and definitive stop of the study treatment 
“Stop of treatment” is when the patient is not taking RAL and/or ETR. 
All patients who discontinue trial medication will be followed up and requested to attend for trial visits up 
until week 96, even if they stop taking trial medication. 
Reasons of a premature stop can be: 
- 
Wish of the patient, 
- 
Intolerance or occurrence of an adverse event, 
- 
New or worsening of an intercurrent pathology, 
- 
Death of the patient, 
- 
Virological failure defined as two successive HIV-RNA plasma viral loads > 50 copies/mL within 2 to 4 
weeks, 
- 
Pregnancy, 
- 
All medical event that induce an interruption of the treatment, 
- 
Major violation of the protocol, 
- 
Non- adherence of the treatment resulting in danger for the health of the patient, 
- 
Necessity for the patient to be treated by a non-authorized treatment in the protocol, 
- 
Motivated investigator’s decision for any other reason than those listed above. 
 
“Premature stop” is considered as a deviation to the protocol if it is not due to a reason cited above. Any event 
resulting in premature stop should be reported within the two working days of the decision to discontinue in the 
eCRF using the dedicated form. The reason and date of the treatment discontinuation will have to be documented. 
The CMG project manager will receive an automatic alert email. Patients who stop the trial treatment will continue 
to be followed according to the trial calendar.  
The investigator must collect the information for the primary end points at the time of the premature stop of trial 
treatment (EOT visit). 
 11.8 Lost to follow-up 
A patient is considered lost to follow-up when he/she is not coming to more than 2 consecutives visits of the 
protocol. Three documented attempts should be made to contact the patient via telephone and one registered 
letter (letter which requires signature upon receipt) should be sent to the patient prior to assigning the patient as 
lost to follow-up. Patients who cannot be contacted on or before the last scheduled visit prior to the week 96 and 
who do not have a known reason for discontinuation (eg, withdrew consent, giving up, etc.) will be classified as 
“lost to follow-up”.  
The CMG UMR S 1136 should be informed as soon as possible using the dedicated form in the eCRF. The CMG 
project manager will receive an automatic alert email.  
 11.9 Withdrawal of the consent and giving up 
Patients who want to giving up or withdraw their consent as they are allowed to do at any time, are no more 
followed in the context of the protocol but will be followed with the best clinical practices. 
11.9.1 Consent withdrawal 
In case of a withdrawal of the consent, the investigator must inform the CMG UMR S 1136 to have the procedure 
to follow. The patient’s data will be removed  (from the date of the consent’s withdrawal) from the database 
according to the law (loi n°78-17 du 6 janvier 1978 modifiée, article 38) and the biological samples will be 
destroyed.  
Any consent withdrawal has to be confirmed to the Methodology Centre by using the dedicated form in the eCRF 
within the two working days, and date of withdrawal. 
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11.9.2 Giving up 
Patients give up the trial when they refuse to continue the follow-up of the trial. The investigator must identify the 
reason and collect the information for the primary end points at the time of the giving up (EOT visit). The CMG 
UMR S 1136 should be informed within the two working days using the dedicated form in the eCRF. The reason 
and date of discontinuation have to be documented. The CMG project manager will receive an automatic alert 
email. 
They will be followed with the best clinical practices. 
11.10 Protocol deviations 
According to Good Clinical Practises sponsor and investigators should not use systems of prospectively approving 
protocol deviations, in order to effectively widen the scope of a protocol. 
 
Protocol deviations have to be fully argumented and documented. Are defined as major protocol deviations the 
following violations related to: regulatory aspects of the research, eligibility criteria, the primary evaluation criteria, 
the investigational treatment. The whole protocol deviations will be listed and submitted to both Trial Scientific 
Committee, Data Safety Monitoring Board and to the sponsor. According to the deviation, the end of participation 
of the patient concerned may be considered 
11.11 Trial-specific rules for treatment management  
11.11.1 Virological failure 
A virological failure is defined as two consecutive HIV-RNA plasma viral loads > 50 copies/mL within an interval of 
two to four weeks. During the course of the trial, the onset of an HIV-RNA plasma VL > 50 copies/mL will 
automatically conduct to schedule an additional blood collection within an interval of two to four weeks o confirm 
the rebound of the HIV-RNA plasma VL. If the virological failure is confirmed, a resistance genotype and a dosage 
of ARV drugs concentration in plasma will be performed on the second HIV-RNA plasma VL test A plasma bank 
should also be done.  
  
 
If the HIV-RNA plasma VL rebound is not confirmed by the second test, the trial treatment will be 
maintained without any specific adaptation. 
 
If the HIV-RNA plasma VL rebound is confirmed by the second test the baseline ARV regimen will 
be immediately reintroduced. If needed, treatment will be subsequently adapted according 
resistance genotype. 
 
 
 
 
 
11.11.2 Potential risks of study drug and the research and management guidelines 
In case of grade 3/4 intolerance related to raltegravir and/or etravirine, one or both drugs should be interrupted 
and the baseline ARV regimen might be reintroduced once the event is resolved or once the related clinical and/or 
biological symptoms are enough improved. 
No raltegravir and/or etravirine dosage adaptation will be authorized. Upon investigator’s opinion, an additional 
clinical visit might be scheduled within 2 to 4 weeks following the onset of the event to control the symptoms 
evolution. 
In case of raltegravir and/or etravirine treatment related grade 1/2 adverse event, a symptomatic treatment can be 
proposed.    
Particular attention to the following symptoms (see below), related to raltegravir and/or etravirine, will be 
requested. In case of grade 3/4 (please refer to Appendix A6 for a definition) suspected treatment will be 
discontinued: 
- Skin reaction and severe hypersensitivity (such as: Stevens-Johnson syndrome, erythema multiforme (EM) 
- Psychiatric effects (such as: depression, suicide attempt, suicidal behavior and suicidal thoughts) 
- Metabolism disorder (such as: diabetes,hyperglycemia, hyperlipidemia) 
- Heart conditions (such as: myocardial infarction) 
In order to ensure real-time virological safety for patients included, the Data Safety 
Monitoring Board will be informed every time 2 virological failures are confirmed by two 
consecutive plasma viral load tests > 50 copies/mL within 2 to 4weeks. (see 10.2.2) 


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11.11.3 Management of lipid metabolism impairment 
In case of mild increase of the lipid parameters, a dietary regime will be proposed. Concomitant lipid-lowering 
treatments with fibrates or statins are needed. They will have to be prescribed according the guidelines, taking into 
account the potential interactions with cytochrome P450 based enzymes.  
11.11.4 Management of glycaemia impairment  
In case of onset of hyperglycaemia or diabetes, an appropriate treatment should be proposed with a dietary 
regime, physical exercise and anti-diabetic drugs if needed. 
11.11.5 Management of pregnancy 
In case of suspicion of pregnancy during the trial, a pregnancy test should be performed immediately. Pregnancy 
must be notified to the sponsor and the methodology centre (see section 13.2.4). 
If a female participant becomes pregnant, all study drugs that are not recommended during pregnancy based on 
the latest SmPC (Summary of the Product Characteristics) must be discontinued. Women should receive 
regimens that are authorised during pregnancy. 
12 BIOLOGICAL SAMPLES AND STORAGE 
 


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12.1 Schedule of sample’s collection 
 
 
 
W-
6/W-
4 
D0 
W2 
W4 
W12 
W24 
W36 
W48 
W64 
W80 
W96 
EOT 
In case of 
virological 
failure 
Volume 
collected  
Aliquots to be 
prepared 
Location of sample’s analysis 
HBV/HCV serology  
√ 
 
 
 
 
 
 
 
 
 
 
 
 
2 tubes of 3mL 
According to 
the local 
virology 
laboratory 
procedures 
Local virology laboratory 
Genotypic resistance 
on blood DNA  
√ 
 
 
 
 
 
 
 
 
 
 
 
 
1 tube of 7mL 
HIV-RNA plasma Viral 
Load 
√ 
√ 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
1 tube of 7mL 
Urinary pregnancy test If 
positive:  HCG
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
/ 
Urine analysis 
√ 
 
 
√ 
√ 
√ 
 
√ 
 
√ 
√ 
√ 
 
/ 
Whole blood cells count 
√ 
 
 
 
 
√ 
 
√ 
 
√ 
√ 
√ 
 
1 tube of 3mL 
CD4/CD8 Lymphocytes 
√ 
√ 
 
 
√ 
√ 
 
√ 
 
√ 
√ 
√ 
 
1 tube of 3mL 
Creatinine, AST, ALT, 
CPK, 
Bilirubin 
√ 
 
 
√ 
√ 
√ 
 
√ 
 
√ 
√ 
√ 
 
1 tube of 3mL 
Lipid profilefasting 
glyceemia 
 
√ 
 
√ 
√ 
√ 
 
√ 
 
 
√ 
√ 
 
3 tubes of 3mL 
Concentrations of ARVs in
Plasma/ Genotypic 
resistance on blood RNA 
 
 
 
 
 
 
 
 
 
 
 
 
√ 
2 EDTA tubes of 
7mL 
3-4 aliquots of 
1.2mL of EDTA 
plasma 
Seminal sub-study 
 
 
 
 
 
 
 
√ 
 
 
 
 
 
/ 
Pr 
Vincent 
CALVEZ/ 
Dr 
Anne-
Geneviève MARCELIN,  
Service de Virologie - 
Groupe Hospitalier Pitié-Salpêtrière 
Sample bank centralized and stored at Biobank 
Plasma bank 
 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
3 EDTA tubes of 
7mL 
6-7 aliquots of 
1.2mL of EDTA 
plasma 
1 aliquot of 1.2 mL to measure ARVs 
concentration in Plasma  
Dr Gilles PEYTAVIN, 
Laboratoire de Pharmacologie 
Clinique - Hôpital Bichat-C. Bernard 
Concentrations of ARVs in
Plasma/ Genotypic 
resistance on blood RNA  
 
 
 
 
 
 
 
 
 
 
 
 
√ 
1 EDTA tube of 
7mL 
3-4 aliquots of 
1mL EDTA 
plasma 
Dr Gilles PEYTAVIN  and Pr Vincent 
CALVEZ/ Dr Anne-Geneviève 
MARCELIN,  
Laboratoire de Pharmacologie 
Clinique - Hôpital Bichat-C.Bernard 
Service de Virologie -Groupe 
Hospitalier Pitié-Salpêtrière 
Immunologic analysis of 
inflammation markers 
 
√ 
 
 
 
 
 
√ 
 
 
√ 
√ 
 
1 EDTA tube of 
7mL  
3-4 aliquots of 
1mL EDTA 
plasma 
Pr Jacqueline CAPEAU,  
CDR Saint-Antoine  
Faculté de Médecine et Université 
Pierre et Marie Curiesite Saint-Antoine 
 
1 citrate tube of 
5mL 
2 aliquots of 
1mL citrate 
plasma 
1 dry tube of 
5mL 
2-3 aliquots of 
1mL of serum 
Total cell-associated HIV- 
DNA quantification 
 
√ 
 
 
 
 
 
√ 
 
 
√ 
√ 
 
1 EDTA tube of 
7mL 
3 aliquots of 
2mL of whole 
blood sample 
Pr 
Vincent 
CALVEZ/ 
Dr 
Anne-
Geneviève MARCELIN,  
Service de Virologie - 
Groupe Hospitalier Pitié-Salpêtrière 
Total blood volume 
29 
67 
21 
40 
43 
46 
28 
70 
28 
37 
70 
53 
21 
 
 
 


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12.2 Blood samples preparation for HIV-DNA quantification and 
plasma storage  
 
The blood samples collected during the patients’ visits as defined above will be transferred to the virology 
laboratories of the participating sites using EDTA (Ethylene Di-Amine Tetra-Acetate) tubes (3,4,5 tubes of 7 
mL according to the visit) with an additional citrate and dry tube (1 tube of 5 mL each) according to the visit.  
A trial-specific form inside the eCRF will ensure the traceability of the collected samples from the clinical 
site to the virology laboratory mentioning: 
 Patient’s name 
 Patient’s identification code 
 Site’s number 
 Date and number of the patient’s visit 
Plasma and serum bank preparation and storage: 
 At each time point, 6-7 plasma aliquots of 1,2 mL (EDTA tube) will be precisely measured. Additional 
3-4 plasma aliquots of 1 mL (EDTA tube), 2 aliquots of 1mL (citrate tube), 2-3 aliquots of 1mL of 
serum (dry tube), depending the visit, will be prepared. 
 The plasma aliquots will be stored in 2 mL NUNC- vials  
 The vials will be identified using anonymized labels mentioning only patients’ identification codes, sites 
numbers, number and dates of each visits 
 Prepared samples will be cryopreserved at -80°C 
Preparation of whole blood samples for total cell-associated HIV-DNA quantification: 
 Whole blood samples will be slowly and gently blended for homogeneity  
 3 whole blood aliquots of 2mL will be precisely measured 
 The plasma aliquots will be stored in 2 mL NUNC vials  
 The vials will be identified using anonymized labels mentioning only patients’ identification codes, sites 
numbers, number and dates of each visits 
 Prepared samples will be cryopreserved at -80°C 
12.3 Evaluated parameters  
12.3.1 Evaluation of the glucid and lipid metabolism  
 
The evolution of the glucid and lipid metabolism will be evaluated by measuring the fasting glycemia, 
triglycerides, total-cholesterol, LDL-cholesterol and HDL-cholesterol. At visit at which these parameters 
will be measured, the median values and the proportion of patients above the upper normal will be 
reported and analyzed.  
12.3.2 Evaluation of the cardiovascular risk 
For all included patients, the cardiovascular risk will be evaluated at Day 0, week 48 and week 96 using 
the Framingham equation adapted for France and the SCORE equation proposed by the European 
Society of Cardiology for countries with a low risk of cardiovascular event. The variables needed for the 
equations are: Age, sex, blood pressure, tobacco, total- and HDL-cholesterol, and diabetic defined by the 
fasting glycemia value or any anti-diabetic treatment. This evaluation supposes a standardization of the 
blood pressure measurements between the participating sites. The measurements have to be performed 
according to the “Recommendations for Blood Pressure Measurements in Humans and Experimented 
Animals” (Pickering et al. Circulation 2005).  
 


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12.3.3. Evaluation of the HIV reservoir in the blood 
The quantification of total cell-associated HIV-DNA will be performed using the consensual real-time PCR 
method developed and implemented by the ANRS AC11 Quantification Group (limit of detection: 5 HIV-
DNA copies/150 000 cells).  
12.3.4. Minimal concentrations of ARVs in the plasma  
At each visit, for all patients, a specific blood sample will be drawn and frozen to measure the minimal 
concentrations of all antiretroviral drugs including raltegravir and etravirine. The precise date and hour of 
each blood collection will be strictly reported in the eCRF. The minimal concentrations of ARVs will be 
measuredin case of virological failure in local laboratory and at the end of the study (plasma bank). 
 
 
12.4 Centralization of samples in Inserm-ANRS Biobank 
12.4.1 Centralization at CRB CHU Bordeaux-Pellegrin (France) 
Blood samples are collected at the trial site. The trial site is responsible for cytopreservation, separation 
and storage of all samples collected at the trial site as prescribed by the protocol. 
The samples which have to be transported to central laboratories or to a central biobank, are stored at 
the trial site until shipment. The handling and shipment of these samples is detailed in a separate 
document (trial specific SOP (Standard Operating Procedure)). Blood samples will be centralized in the 
Biobank at CRB (CHU Bordeaux-Pellegrin, France). 
All laboratories involved shall use the human materials sampled in the trial only in accordance with the 
agreed protocol, the international Good Clinical Practice principles as laid down by the ICH Harmonised. 
Tripartite Guidelines for Good Clinical Practice (ICH GCP), the EU Clinical Study Directive and relevant 
other legislation or regulatory requirements as may be required in the country. 
The CMG project manager shall supply trial sites with guidance on handling and storage of the materials, 
and other related relevant information. 
All proposals for additional laboratory assessments that are not specified in this protocol must be 
submitted to the Study Steering Committee and approved prior to their implementation. 
12.4.2 Samples access 
Samples centralized at CRB should exclusively be used to: 
• confirm the results obtained during the research authorized by the Scientific Committee, 
• perform studies already planned according to the protocol, 
• further studies  not initially foreseen in the protocol and in accordance with procedures established by the 
Scientific Committee. For studies outside the field of investigation specified in the participants' information 
consent, an Ethics Committee approval and if appropriate, a new consent will be required. 
These samples will be used according to procedures set up by INSERM SC10-US019. Before extraction 
of samples for analysis, sampling, recipients and deadlines will have been decided by the Scientific 
Committee. 
At the end of the trial, six months after the last visit of the last participant, biological samples will be 
included in the Inserm-ANRS biobank, authorized for their total or partial transfer for scientific use, except 
in case of disagreement by each participant. Samples will no longer be available to the the scientific 
committee, but remain under the responsibility of the Inserm-ANRS. Strict adherence to the participants' 
rights to refuse further use of this biobank is guaranteed. 
 


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13 TRIAL SAFETY 
13.1 Definitions 
13.1.1 Adverse Event (AE) 
Any untoward medical occurrence in a patient or a clinical trial subject administered a medicinal product 
and which does not necessarily have a causal relationship with the treatment or the research. 
13.1.2 Adverse Reaction (AR) 
All untoward and unintended responses to an investigational medicinal product related to any dose 
administered or to the research (e.g. trial procedures, trial treatments). 
13.1.3 Serious Adverse Event (SAE) or Serious Adverse Reaction (SAR) 
Any untoward medical occurrence or effect that at any dose: 
- results in death; 
- is life-threatening (means that the subject was at immediate risk of death at the time of the event; it does 
not refer to an event which hypothetically might have caused death if it were more severe); 
- requires hospitalization or prolongation of existing hospitalization; 
- results in persistent or significant disability or incapacity; 
- is a congenital anomaly or birth defect; 
- is a grade 3 or 4 clinical or biological adverse event; 
- is an important medical event that, when based upon appropriate medical judgment may jeopardize the 
subject and may require medical or surgical intervention to prevent one of the outcomes listed above in 
the definition for a serious adverse event; 
Examples of such events include allergic bronchospasm requiring intensive treatment at an emergency 
room or at home, blood dyscrasias, convulsions those do not result in inpatient hospitalization, 
development of drug dependency or drug abuse, or suspected transmission of an infectious agent via a 
medicinal product… 
 
EXCEPTIONS: SAE not requiring immediate reporting to the sponsor 
• Hospitalizations or prolongation of existing hospitalizations that are not considered as serious: 
 
- outpatient care: the patient has been formally admitted to a hospital for medical reasons with no 
seriousness criteria (described above) and does not require overnight hospitalization; 
 
- elective or previously scheduled surgery or medical treatment; 
 
- hospitalization for social or administrative reasons; 
 
- pre-specified trial hospitalization for observation. 
 
• Pre-existing biological abnormalities or diseases or conditions present or detected prior to start of study 
drug administration that do not worsen. 
13.1.4 Suspected Unexpected Serious Adverse Reaction (SUSAR) 
An adverse reaction, the nature, the outcome or severity of which is not consistent with the applicable 
product Reference Safety Information (Summary of the Product Characteristics, SmPC, for the study 
drugs) or the applicable trial procedures information noted in the protocol. 
13.1.5 New fact 
Any safety data that could modify significantly the evaluation of the benefit/risk ratio of the study drug or 
the clinical trial, likely to affect the safety of participants or that could modify the study drug 
administration, the trial documentation or the conduct of the trial. 
Examples: a serious adverse event which could be associated with the trial procedures and which could 
modify the conduct of the trial, a significant hazard to the subject population such as lack of efficacy of an 
investigational medicinal product used for the treatment of a life-threatening disease, recommendations 
of the DSMB, if any, where relevant for the safety of subjects. 


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13.2 Responsibilities of the investigator 
13.2.1 AE notification 
Grade 1 and 2 clinical and biological events and all other AE/AR have to be reported in corresponding 
sheet of the eCRF (AE form) with the intensity and causal relationship, except those detected prior to 
start of study drug administration. If a clinical or biological event is present at inclusion, only its 
aggravation will be notified. 
13.2.2 SAE notification 
 What needs to be notified? 
The investigator has to notify to the sponsor all Serious Adverse Events (SAE) except those that the 
protocol identifies as not requiring immediate reporting (see section 13.1.3). 
 
The investigator should collect all relevant documentation related to the SAE/SAR (e.g. hospitalization 
report, laboratories results…) and send it to the sponsor, without omitting to make it anonymous and note 
the identification number of the participant in the trial. 
 
The investigator must follow the participant until clinical recovery is complete and laboratory results have 
returned to normal or baseline, or until the event has stabilized. Follow-up should continue after 
completion of protocol treatment if requested. 
 Reporting time frames 
SAE requiring reporting and all relevant documentation related to these SAE have to be sent by the 
investigator to the sponsor, immediately, and no later than 24 hours after being made aware of it. 
 
 
The investigator ensures that all relevant information is forwarded to the sponsor within 8 days after the 
initial notification. 
 
All SAE must be reported since the subject signed the informed consent to the clinical trial and during the 
follow-up scheduled by the trial. 
Serious adverse events occurring to a subject after the treatment of that subject has ended should be 
reported to the sponsor if the investigator becomes aware of them. The investigator does not need to 
actively monitor subjects for adverse events once the trial has ended, unless provided otherwise in the 
protocol. 
 How to report? 
The initial report should be notified as a detailed, written report, using "SAE initial notification form". 
The initial report must include the minimum information following: the identifiable coded subject, the 
identifiable reporter, one suspect medicinal product and one AE. 
 
The initial report shall be followed by complementary detailed, written reports using "SAE complementary 
notification form". 
 
Notification via eCRF: 
All SAE/SAR should be recorded in corresponding form of the eCRF. 
When the eCRF SAE notification form is completed, dated and signed by the investigator, an automatic 
email is sent immediately to the Inserm-ANRS Clinical research safety office and to the Clinical project 
manager of the CMG Inserm UMR S 1136. 
 
Backup circuit when eCRF is unavailable: 
The investigator must report all SAE/SAR using the CRF SAE printed form to the CMG Inserm UMR S 
1136, by fax: + 33 (0)1 42 16 42 61 (67) or by email: lbeniguel@ccde.chups.jussieu.fr, 
mesteban@ccde.chups.jussieu.fr, nessouf@ccde.chups.jussieu.fr 


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Then the CMG Inserm UMR S 1136 will send, within one business day, the CRF SAE printed form to the 
Inserm-ANRS Clinical research safety office, by fax: + 33 (0)1 53 94 60 02 or by email: 
pharmacovigilance@anrs.fr. 
If an SAE is declared by paper circuit, it is the responsibility of the site to re-enter the form in the eCRF. 
 
Relevant documentation related to the SAE (e.g. hospitalization report, laboratories results…): 
The investigator sends all relevant anonymised documentation related to the SAE to the CMG Inserm 
UMR 
S 
1136, 
by 
fax: 
+ 
33 
(0)1 
42 
16 
42 
61 
(67) 
or 
by 
email: 
lprely@ccde.chups.jussieu.fr/staibi@ccde.chups.jussieu.fr 
Then the CMG Inserm UMR S 1136 will send, immediately, all documentation to the Inserm-ANRS 
Clinical research safety office, by fax: + 33  53 94 60 02 or by email: pharmacovigilance@anrs.fr. 
13.2.3 SAE evaluation 
The adverse event 
The investigator should assess, if possible, the diagnosis of all SAE/SAR. Diagnosis, or if not available, 
syndrome should be reported whenever possible. 
Date of “event onset” on SAE notification form should be earlier (or the same day) than date of 
seriousness. 
When medical or surgical procedures (e.g.: surgery, endoscopy, tooth extraction, transfusion) occurred; 
the condition that leads to the procedure should be notified. 
 
The severity 
The severity (i.e. intensity) of all AEs/ARs (serious and non-serious) should be graded using the 
appropriate table "ANRS scale to grade the severity of adverse events in adults, Version 1.0, November, 
2008" (see appendix A6) and reported by the investigator in the corresponding form of the eCRF. 
 
The seriousness 
The judgment as to whether the event is serious is usually made by the reporting investigator (see 
section 13.1.3 for serious criteria). 
Deaths must be reported for subjects as the outcome of an adverse event and not as an adverse event 
itself if the cause is known. If the cause is unknown, the death should be reported as “unknown cause of 
death”. 
 
The causality 
The investigator must assess the causality of all AEs/ARs (serious and non-serious) in relation to the 
study drug, concomitant medication and the research (e.g. trial procedures). 
 
All SAE for which the investigator or the sponsor considers that a causal relationship is a reasonable 
possibility are considered as suspected SAR. 
 
The relationship of an adverse event to treatment will be assessed as follows: 
Relationship 
Description 
Event 
type 
Definitely 
There is a plausible time relationship between the study drug administration 
and the (S)AE. 
The (S)AE cannot be explained by another cause (concurrent disease, other 
drug or chemicals). 
Dechallange (the event responds to withdrawal of the study drug), if 
performed, is positive. 
Rechallange (the event recurs with readministration of the study drug), if 
feasible, is positive. 
The (S)AE shows a pattern consistent with previous knowledge of the 
medication or medication class. 
 
(S)AR 
Probable 
There is a reasonable time relationship between the study drug 
administration and the (S)AE. 
The event responds to dechallenge. 
Rechallenge is not required. 
The (S)AE is more likely explained by the study drug than by another cause 
(S)AR 


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(concurrent disease, other drug or chemicals). 
 
Possible 
There is a reasonable time relationship between the study drug 
administration and the (S)AE. 
The (S)AE could also be explained by another cause (concurrent disease, 
other drug or chemicals). 
Dechallenge is lacking or unclear. 
 
(S)AR 
Unlikely 
There is an improbable time relationship to study drug administration. 
Other drugs, chemicals or underlying disease provide plausible explanations. 
 
(S)AE 
Unrelated 
There is an incompatible time relationship to study drug administration. 
There is another obvious cause of the (S)AE. 
 
(S)AE 
 
 
The expectedness 
Assessment on expectedness is usually done by the sponsor. 
The expectedness of a SAR is assessed in the light of the RSI (SmPC of study drug). 
 
The adverse event outcome 
The adverse event outcome at the time of reporting should be provided on the initial SAE notification 
form. 
Any change in the initial outcome (e.g. resolved, back to previous status, worsening…) should be 
reported using complementary reporting form(s). As long as the adverse event is not resolved, any new 
worsening will be reported using complementary forms of the corresponding initial SAE. 
13.2.4 Pregnancy notification 
Women of childbearing potential (WOCBP) who are sexually active and not sterile must use an effective 
method of birth control during the course of the trial, in a manner such that risk of failure is minimized. Any 
single method of birth control, including vasectomy and tubal ligation, may fail, leading to pregnancy. 
Before enrolling women of childbearing potential in this clinical trial, investigators must review guidelines 
about trial participation for WOCBP. The topics should generally include: 
 
General information 
 
Informed consent form 
 
Pregnancy prevention information 
 
Drug interactions with hormonal contraceptives 
 
Contraceptives in current use 
 
Guidelines for the follow-up of a reported pregnancy. 
Prior to trial enrolment, WOCBP must be advised of the importance of avoiding pregnancy during trial 
participation and the potential risk factors for an unintentional pregnancy. The patient must sign an 
informed consent form stating that the above-mentioned risk factors and the consequences were discussed 
with her. 
During the trial, all WOCBP should be instructed to contact the investigator immediately if they suspect they 
might be pregnant (eg, missed or late menstrual cycle). 
 
The investigator has to notify to the sponsor, immediately and no later than 48 hours after being made 
aware of it, any pregnancy and its outcome, concerning either the enrolled woman or the wife of an 
enrolled man. 
If pregnancy concerns the wife of enrolled man, the investigator must obtain her consent for information 
on pregnancy. 
 
The initial report should be notified as a detailed, written report, using the "Initial pregnancy notification 
form" and specifying estimated date of delivery, obstetrician contact and name of maternity hospital. 
 
The investigator has to follow the subject until the end of the pregnancy (including perinatal and neonatal 
outcome) or its interruption and to notify the outcome to the sponsor using the “Final pregnancy 
notification form”. 


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The investigator will report to the sponsor any safety data occurring to infants if he becomes aware of them, 
for a minimum of six months. 
Follow-up of pregnant participant continues until the end of the trial. 
Any exceptions, related to the indication of maternal treatment, should be discussed between the 
investigator, the coordinating investigator, the sponsor and if necessary a specialist in terato-vigilance. 
 
 
Warning: 
• 
The medical surveillance of the women and their children should be reinforced: a particular 
attention must be given on serious pathology occurring during pregnancy abnormalities. A SAE initial 
report form should be filled if any anomaly or birth defect is detected. 
• 
All voluntary interruption of pregnancy, therapeutic interruption of pregnancy or miscarriage 
needed a hospitalization is considered as a SAE/SAR and should be notify as mentioned in section 
13.2.2. SAE notification. 
 
Notification via eCRF: 
All pregnancies should be recorded in corresponding form of the eCRF. 
When the eCRF pregnancy notification form is completed, dated and signed by the investigator, an 
automatic email is sent immediately to the Inserm-ANRS Clinical research safety office and to the Clinical 
project manager of the CMG Inserm UMR S 1136. 
 
Backup circuit when eCRF is unavailable: 
The investigator must report all pregnancy using the CRF pregnancy printed form to the CMG Inserm 
UMR 
S 
1136, 
by 
fax: 
+ 
33 
(0)1 
42 
16 
42 
61 
(67) 
or 
by 
email: 
lprely@ccde.chups.jussieu.fr/staibi@ccde.chups.jussieu.fr 
Then the CMG Inserm UMR S 1136 will send, within one business day, the CRF pregnancy printed form 
to the Inserm-ANRS Clinical research safety office, by fax: + 33 (0)153 94 60 02 or by email: 
pharmacovigilance@anrs.fr. 
If an SAE is declared by paper circuit, it is the responsibility of the site to re-enter the form in the eCRF. 
 
 
13.3 Responsibilities of the sponsor 
13.3.1 Recording and assessment of SAE 
The sponsor shall keep detailed records of all SAE which are reported to him by investigators. 
 
The sponsor is also responsible for the assessment of the causality of the SAE in relation to the study 
drug, concomitant medication (e.g. drug-drug interaction) and the research. 
 
In the absence of information on causality from the reporting investigator, the sponsor should consult the 
reporting investigator and encourage him to express an opinion on this aspect. 
 
The causality assessment given by the investigator should not be downgraded by the sponsor. If the 
sponsor disagrees with the investigator’s causality assessment, the opinion of both the investigator and 
the sponsor should be provided in the report to the national competent authority and the Ethics 
Committee. 
 
All SAE for which the investigator or the sponsor considers that a causal relationship is a reasonable 
possibility are considered as suspected SAR. 
 
The expectedness of the SAR shall be determined by the sponsor. 
The sponsor assesses if the SAE is expected or not using the applicable Reference Safety Information 
(Summary of the Product Characteristics, SmPC, of study drug). 
If information on expectedness has been made available by the reporting investigator, this should be 
taken into consideration by the sponsor. 


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13.3.2 Reporting of safety data to the national competent authority and the Ethics 
Committee 
 SUSAR reporting 
All Suspected Unexpected Adverse Reactions (SUSARs) have to be reported, within the legal timeframe, 
by the Inserm-ANRS Clinical research safety office to the national competent authority of the Member 
State concerned, directly or indirectly through EudraVigilance Clinical Trial Module (EVCTM): 
- direct reporting: the sponsor reports the SUSAR directly as an individual case safety report (ICSR) to 
the national competent authority of the relevant Member State; 
- indirect reporting: the sponsor reports the SUSAR as an ICSR through EVCTM to the national 
competent authority of the relevant Member State. 
 
The Inserm-ANRS Clinical research safety office should also report to the concerned Ethics Committee, 
all SUSAR occurred in the territory of that Member State. 
 
The timelines for expedited initial reporting (day 0) starts as soon as the information containing the 
minimum reporting criteria has been received by the sponsor. 
For fatal and life-threatening SUSAR, the sponsor should report at least the minimum information as 
soon as possible and in any case no later than 7 calendar days after being made aware of the case. 
Relevant complementary information should be collected and notified within 8 extra-days. 
SUSAR which are not fatal and not life-threatening are to be reported within 15 calendar days. 
 New fact reporting 
The sponsor should inform the national competent authority and the Ethics Committee of safety data that 
may be relevant in terms of subject safety, or safety issues which might alter the current benefit-risk 
assessment of the trial immediately and no later than 15 calendar days after being made aware of it. 
When a new fact likely to affect the safety of subjects occurs in the trial, the sponsor must implement 
urgent safety measures. 
 Annual safety reporting 
Once a year throughout the clinical trial, the sponsor should submit to the national competent authority 
and the concerned Ethics Committee, an annual safety report, the Development Safety Update Report 
(DSUR - guideline ICH Topic E2F). 
 
The DSUR should be submitted no later than 60 calendar days from the date of the sponsor's first 
authorization to conduct the clinical trial in any country. 
 
The RSI in effect at the start of the reporting period serves as RSI during the reporting period. The DSUR 
should clearly indicate the version number and date of the applicable RSI used for this purpose. If there 
are significant changes to the RSI during the reporting period, they should be listed in the DSUR. Despite 
the change to the RSI, the RSI in effect at the start of the reporting period serves as RSI during the 
reporting period. 
 
The DSUR is prepared in collaboration between the Inserm-ANRS Clinical research safety office and the 
Clinical project manager of the CMG Inserm UMR S 1136, and includes: 
- 
a line-listing of all suspected serious adverse reactions which have occurred over this period 
(expected and unexpected SAR); 
- 
a cumulative summary tabulation of the all expected and unexpected SAR by System Organ Class 
(SOC) name; 
- 
a cumulative summary tabulation of all SAE by SOC name; 
- 
a line-listing of deaths; 
- 
DSMB opinion and Steering committee report; 
- 
a concise, critical analysis of the subjects' safety. 
 
The DSUR may be submitted to the coordinating investigator for approval. 
 


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14 TRIAL SURVEY 
14.1 Scientific Committee (SC) 
14.1.1 Composition 
The Scientific Committee will be composed of the following members: 
 
-voting members: Pr Christine Katlama (President), Jacques Reynes, Dr Marc-Antoine Valantin, 
Dominique Costagliola, Pr Jacqueline Capeau, Dr Sami Kolta, Pr Vincent Calvez, Dr Anne-Geneviève 
Marcelin, Cathia Soulié, Gilles Peytavin, Lambert Assoumou, Lydie Béniguel, Dr Esteban Martinez, 
Ventzislava Petrov-Sanchez. 
 
- Non-voting members: Clément Guiheneuf, Alpha Diallo or Séverine Gibowski (Representatives of 
the Inserm-ANRS Clinical research safety office), Fanny Cardon, Josiane Ako, Jérémy Lafable and 
representatives of Pharmaceutical firms (Merck Sharp & Dohme and Janssen pharmaceutica NV). 
 
14.1.2 Frequency of meetings 
The first meeting of the Scientific Committee should be organized prior to the start of the research, and if 
possible before initiating regulatory procedures to validate all scientific, ethical and logistical aspects of the 
trial. The subsequent meetings are scheduled twice a year until the end of the research according to the 
specificities and the progress of the project. Extraordinary meetings may be decided by the chairperson of 
the Scientific Committee upon request from the Sponsor, or from one or several members of the Scientific 
Committee. The request motivated in writing shall be diffused for information to all members of the 
Scientific Committee.  
14.1.3 Role 
The Scientific Committee's missions are:  
- approval of DSMB composition, 
- to ask theCMG for information regarding the progress of the research project, any potential issue and 
available results, 
- to ensure compliance with ethics requirements, 
- to perform the scientific follow-up of the research: maintain the relevance of the research objectives and 
the permanent validity of the methods implemented to meet them, 
- to make all important decisions at the demand of the Coordinating Investigator or the DSMB regarding the 
good conduct of the research in compliance with the protocol, any procedure specific to the research and 
Good Clinical Practices, 
- to decide on all relevant modification of the protocol required to achieve the research project (including 
recruitment facilitating measures, protocol amendments before regulatory submissions, addition or closure 
of participating sites), 
- to provide information to all investigators and other participants in the research, 
- to ensure that rules related to data and biological samples access are followed, 
- to ensure that rules related to the communication and publication of research results are fulfilled. 
Meeting minutes are drafted following each meeting by the CMG Inserm UMR S 1136, together with the 
president of the Scientific Committee (at least an exhaustive list of the issues discussed and the decisions 
made as well as the list of the points raised). The minutes are submitted for review and modifications to the 
members of the Scientific Committee present at the meeting. The minutes are then validated by the 
president of the Scientific Committee. It is then distributed to the Scientific Committee members and to the 
persons invited to the meeting, as well as to the Head of the relevant Inserm-ANRS HIV clinical research 
department, to the Head of the Inserm-ANRS Clinical research safety office. The minutes are definitely 
adopted at the beginning of the following meeting of the Scientific Committee. 
 
14.2 Data Safety Monitoring Board (DSMB) 
14.2.1 Composition 
The DSMB will consist of Isabelle Charreau (statistician, Inserm SC10 - US019, Villejuif, France), Dr. 
Laurence Bocket (clinician and virologist, Centre Hospitalier Régional Universitaire de Lille, France), Dr. 


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Cédric Arvieux, (clinician, Unité de Maladies Infectieuses CHU de Rennes, France), Dr. David Rey 
(clinician, Hôpitaux Universitaires de Strasbourg, France), and one representative of the TRT-5 (French 
organization focused on HIV clinical research and HIV treatment).  
 
14.2.2 Frequency of meetings 
The first DSMB meeting will occur: 
 
Within the first three months following the first patient inclusion. 
 
In order to ensure real-time virological safety for patients included, the Data Safety Monitoring Board will 
be convoked every time 2 virological failures are confirmed by two consecutive plasma viral load tests > 
50 copies/mL within 2 to 4 weeks.  
 
Then, during the course of the trial, the frequency of the DSMB meetings will have to meet at least once 
a year. At any time, an extraordinary meeting might be required upon the advice of the Scientific 
Committee, of the Sponsor, of the Coordinating Investigator, of the Centre of Methodology or by any 
investigator. 
 
Additionally, whenever deemed necessary, DSMB expert members or the sponsor can request an 
additional meeting to discuss specific issues. 
14.2.3 Role 
The role of the DSMB is to review the progress of the trial and the accumulating data to detect evidence of 
early safety issues for the enrolled subjects. The DSMB will give recommendation regarding modification to 
the ongoing conduct of the trial. 
The DSMB will monitor the virological safety. Every 2 episodes of virological failures, a complete report will 
be sent to the DSMB for review. 
The DSMB will review and validate any adverse event leading to the trial treatment discontinuation in order 
to establish whether the adverse event is related to the trial treatment or procedure. This evaluation should 
not downgrade the causality assessment given by the investigator and the sponsor. 
 
Recommendation regarding trial termination should be done if eight virological failures occur or if a high 
level of adverse events leading trial treatment discontinuation was judged by the DSMB as related to trial 
treatment. The DSMB will report its recommendations to the sponsor and the Scientific Committee, for 
taking a decision about trial termination.  
14.3 Methodology and study management Centre (CMG Inserm UMR 
S 1136) 
A methodology and study management centre (CMG Inserm UMR S 1136) will be assigned by the sponsor 
in order to ensure good clinical practices. 
14.3.1 Composition 
The members will be chosen among the participating researchers in the current trial and include at least, 
the following members: 
Methodologists: Dominique COSTAGLIOLA and Lambert ASSOUMOU 
Project Manager / Clinical Trial Monitors: Lydie BENIGUEL, Josiane AKO and Jérémy LAFABLE 
Statistician: Clément GUIHENEUF 
14.3.2 Role 
CMG Inserm UMR S 1136 is located in Paris. His objective is to ensure the quality of the trial and to 
discuss and analyze all the relevant clinical and scientific aspects. 


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The CMG Inserm UMR S 1136 prepares the implementation of the research, coordinates the logistics, data 
management and statistical analysis. 
The CMG Inserm UMR S 1136 is responsible for the quality of data and computer databases. 
It prepares the research status and files for the pooled analysis for the Scientific Committee. It informs the 
Scientific Committee of the conduct of the research, prepares the general meetings of investigators' 
meetings. 
15 
CONTROL AND DATA MANAGEMENT 
The CMG Inserm UMR S 1136 will be responsible for the data management of the trial. It will be 
responsible to design and develop an eCRF for data management. The Clinsight software will be used for 
the management of the data. The eCRF will be developed from the model of the exercise book of 
observation made by the UMR S 1136 and validated by the Coordinating Investigator and the sponsor. 
Access to the eCRF will be limited to the trial participants. A specific profile will be assigned to the 
participants according to their role in the trial. An identifier and password will be provided to the participants 
by the CMG Inserm UMR S 1136 (must be changed at the first connection). 
15.1 Data transfer to CMG Inserm UMR S 1136 
The site principal investigator will be responsible for the completion of the eCRF according to SOP. eCRF 
will be completed according to the source records by the investigator or an appointed representing. Data 
will be recorded onto the eCRF, which will provide the majority of source data for the trial. There will be 
some additional source data in the clinical notes, such as medical history related to eligibility, dates of 
visits, results of pregnancy tests, and details of clinical management (description of adverse events and 
concomitant medication). 
Data will be collected and validated under the responsibility of the principal investigator of each site. 
Staff at the clinical centres will be responsible for: 
 
Entering relevant information in the clinical notes, and holding a record for each participant which 
includes the eCRF. 
 
The accurate completion of the eCRF. 
 
The prompt return of the copy of biological results (CD4, Viral load, biological results of the 
screening visit, reports for specific diagnosis of primary endpoint infections as specified in the eCRF) 
to CMG Inserm UMR S 1136. 
 
Notification of SAEs in the eCRF as soon as they become aware of the event. 
 
At the end of the trial every eCRF pages must be filled, locked by the investigator or its representative, 
monitored by the project manager of CMG Inserm UMR S 1136 and signed by the investigator who 
followed the patient.  
 
Every data for each patient will be printed in PDF and stored onto a CD (Compact Disc) and given to the 
principal investigator of the site by the CMG Inserm UMR S 1136. 
15.2 Data control 
15.2.1 Electronic control of the data 
The data manager or their deputy will review all data entered in the eCRF, as they arise. Queries raised will 
be directed to the investigators at the relevant clinical site using the dedicate tool of the eCRF or during a 
monitoring visit. Prior to analysis, the safety data will be checked, AEs validated and data extracted in order 
for the trial statisticians to run the analysis and prepare the tables. 
15.2.2 Data control in the clinical site 
Before starting the trial, the CMG Inserm UMR S 1136 will establish the monitoring plan that will be sent to 
the trial sponsor (Inserm-ANRS). The monitoring plan may be amended during the trial based on the 
dynamic of inclusions. 


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15.2.3 Participants in charge of study monitoring 
Monitoring will be done by the CMG project manager from CMG Inserm UMR S 1136 mandated by the 
sponsor in accordance with the regulations and recommendations of Good Clinical Practice. At any time, 
the CRA or project manager in charge of the trial can be contacted for any questions regarding the protocol 
and its practical application. 
15.2.4 Monitoring of the trial 
An investigator meeting with at least one representative in each participating centre will be held before 
starting the trial. Staff from CMG Inserm UMR S 1136 in charge of trial monitoring will visit the clinical 
centres. The first visit will be to open the centre. This opening visit will be held before any screening in the 
centre. During this visit, the CMG project manager will give to investigators all documents needed for 
starting the trial: Protocol, Manual for the use eCRF, and all procedures. Participants (clinical centres and 
laboratories members) in each centre must be present during the opening visit. 
All monitoring visits will be done in the centres with at least one patient included and will take place 
according to the monitoring plan established by the CMG Inserm UMR S 1136. The first monitoring visit will 
take place within the first three months after the first inclusion in the centre. 
 the CMG Inserm UMR S 1136 projet manager in charge of the monitoring is responsible for to validate 
data entered in the eCRF against the clinical records. The site principal investigator and participants, by 
giving consent, agree that the CMG Inserm UMR S 1136 may consult and/or copy source records (clinical 
notes and laboratory values) in order to do this. Such information will be treated as strictly confidential and 
will in no circumstances be made publicly available. The monitoring will adhere to ICH GCP guidelines. 
The volume of data that will be collected allows us to plan only a control of 100% of the baseline data and 
100% of the data used as endpoints in 100% of patients.  
However, particular attention will be paid to the following data: 
- Signed consent 
- Documentation of any existing conditions or past conditions relevant to eligibility 
- Dates of visits 
- Laboratory results 
- Grade 3 or 4 AEs and any events leading to trial treatment discontinuation 
- Date of trial treatment discontinuation, date of giving up, and date of consent withdrawal  
A Closing visit will take place in each of the centres in which at least one patient has been selected at the 
end of the trial. 
 
15.3 Auditing 
An audit can be performed at any time by persons representing the sponsor and independent from the 
research. Its objectives are to ensure the quality and follow-up of the research, data consistency and local 
regulations in force. 
The sponsor’s as well as the investigational products’ suppliers’ Quality Assurance Units (or 
representatives) may conduct audits at the trial site(s). Audits will include, but are not limited to, drug 
supply, presence of required documents, the informed consent process, and comparison of eCRFs with 
source documents. The investigator agrees to participate with audits conducted at a reasonable time in a 
reasonable manner. 
Regulatory authorities worldwide may also inspect the investigator during or after the trial. The investigator 
should contact the sponsor immediately if this occurs, and must fully cooperate with the inspections 
conducted at a reasonable time in a reasonable manner. 
16 STATISTICAL CONSIDERATIONS 
16.1 Patients sample calculation 
ANRS 163 ETRAL is a non-comparative phase II trial evaluating in HIV-1-infected patients, of at least 45 
years of age, switching from a virologically suppressive boosted PI-containing regimen the capacity of a 
dual raltegravir/etravirine regimen to maintain the virological success as defined by the absence of 2 
consecutive HIV-RNA plasma VL > 50 copies/mL within 2 to 4 weeks.  
Raltegravir/etravirine will be considered acceptable if the percentage of patients in virological success at 
week 48 is significantly above 90 %.  
Assuming a 95 % virological success rate, by including 160 individuals and considering the strategy to be 
acceptable if no more than 8 individuals have virological failure; we will have a 95 % probability to discard a 


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combination for which efficacy is smaller than 90 % and we will select with a power of 80 % the strategy for 
which the efficacy is above or equal to 95 %. 
16.2 Statistical analysis  
16.2.1 Criteria for evaluation  
All enrolled patients receiving at least one day of trial treatment will be included in the intent-to-treat (ITT) 
population. Patients who withdrew their consent will be excluded in the ITT population. The per-protocol 
population will include all patients from the ITT population except those who did not fulfil the inclusion 
criteria or discontinued trial treatment without virologic failure or adverse event as judged by the DSMB as 
related to trial treatment or procedure. 
16.2.2 Statistical methods 
The primary endpoint is the virological success up to week 48 defined by the absence of 2 consecutive 
HIV-RNA plasma VL > 50 copies/mL within 2 to 4 weeks.  
The therapeutic success is defined by the absence of virological failure and the absence of treatment 
interruption due to adverse event judged by DSMB as related to the trial treatment or procedure up to week 
96. 
In particular:  
 
Patients with 2 or more consecutive missing HIV-1 RNA plasma viral load values or lost to follow 
up will be considered as patients with treatment failure (failing patients). 
 
Patients who discontinue the treatment due to adverse event judged by DSMB as related to the 
trial treatment or procedure will be considered as failing patients. 
 
Patients who discontinued the treatment due to adverse event judged by DSMB as NOT related 
to the trial treatment or procedure will not be considered as failing patients. 
 
Patients who gave up will not be considered as failing patients. 
 
Patients who discontinued the trial treatment for any reason other than a virological failure or 
adverse event judged by DSMB as related to the trial treatment will not be considered as failing 
patients. 
 
Patients with a missing HIV-1 RNA value between 2 documented HIV-1 RNA plasma viral loads 
≤ 50 copies/mL will not be considered as failing patients.  
Analysis of the primary endpoint will be performed on both ITT and per protocol populations. The 95% two-
sided confidence interval of the percentage of patients in therapeutic success will be calculated and 
raltegravir/etravirine will be considered as an acceptable strategy if the lower bound is greater than 90%. 
 
The changes in continuous endpoints will be compared in the ITT population (LOCF of other imputation 
method to be defined in the statistical analysis plan) using a two-sided non-parametric paired Wilcoxon test 
with a 5 % type I error. We will use percentage and 95 % two-sided confidence interval to describe the 
qualitative endpoints, their change over time will be tested a McNemar test with a 5 % type I error.  
The adverse events leading to a trial treatment discontinuation and the number of patients who 
discontinued the trial treatment, as well as the number and nature of grade 3 and 4 adverse events will be 
described.  
16.2.3 Statistical analysis plan 
The number of included patients and the flowchart of the trial will be presented. 
The baseline patients’ eligibility and characteristics of the ITT population will be described. Quantitative 
variables will be described by their means, standard deviations, medians, IQR, minimums and maximums. 
For qualitative variables, figures and percentages per class will be presented or method will be given. All 
protocol deviations and their reasons will be described.  
A detailed statistical analysis plan will be written prior to any analysis of the trial results. 


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16.2.4 Software programs used 
The analyzes are performed with the software <SAS® /logiciel SPSS®/logiciel STATA® > (version n° 9.4 
and later versions). 
17 PUBLICATION 
The results of the trial (positive or negative) must be made publicly available. The President of the Scientific 
Committee (Pr Christine Katlama) is responsible for publication of the trial results.  
All publications shall include a list of participants (the investigators mentioned above), and if there are 
named authors, these should include the main persons responsible for the trial including the Study 
coordinator (Christine Katlama, Jacques Reynes) and the Methodology and Study Management 
Coordinator (Dominique Costagliola) and its results.  
If there are no named authors (i.e. group authorship) then a writing committee is identified that would 
usually include these people.  
The principles of generally accepted specifications for authorship shall be followed in the appointing of 
authors and co-authors. All contributors to a specific publication (abstracts or original studies) have a true 
opportunity for full evaluation of the final text before submission to a scientific meeting or an editor.  
Inserm-ANRS will review any abstract, poster, communication or publication written on this trial. 
The results from different centres are analysed together and published as soon as possible. Individual 
clinicians must not publish data concerning their patients that are directly relevant to questions posed by 
the trial until the report of the overall results of the trial has been published. 
The trial identifier that has been allocated to this trial (ANRS 163 ETRAL), as well as the name of the 
sponsor, Inserm – ANRS, should be attached to any publications resulting from this trial. 
The sponsor agrees to include in all scientific publication-type communications and in all submissions to 
scientific conferences or to the media the following type of notice: “Trial conducted with the support of 
Merck and Janssen”. 
The members of the Scientific Committee and DSMB are to be listed with their affiliations in the 
Acknowledgements/Appendix of the main publication. 
Any publication has to be reviewed by ANRS 163 ETRAL Scientific Committee. 
18 ETHICS AND REGULATORY ISSUES 
18.1 Ethical and regulatory aspects 
Before the initiation of this trial, regulatory approval by the National Competent Authorities and local Ethical 
Committees or Institutional Review Boards is obtained for conduct of the trial (see appendices A2 and A3). 
The trial only starts after written approval from an Independent Ethics Committee (IEC) or Institutional 
Review Board (IRB) that operates according to ICH GCP guidelines. The written IEC/IRB approval and the 
names and qualifications of members of the IEC/IRB must be made available to the legal sponsor before 
the trial can start. The sponsor or its delegate is, together with the investigator, responsible for submission 
to and communication with the IEC/IRB as well as for obtaining approval of all subsequent major changes, 
in compliance with local law. 
The investigator should conduct the trial in in accordance with this protocol, the declaration of Helsinki 
(version 2013) and the ICH GCP guidelines. . 
18.2 Participant consent (cf. information note and consent) 
Each participant’s consent to participate in the trial should be obtained after a full explanation has been 
given about the trial. The right of the patient to refuse to participate in the trial without giving reasons must 
be respected. The patient must remain free to withdraw at any time from the protocol and follow-up without 
giving reasons and without prejudicing his/her further care. 
Consent from the patient participating to the trial has to be signed BEFORE any related trial procedures. If 
consent is given, the patient and the investigator write both their name in all letters and date and sign. 
The consent form will consist of three sheets. 
The first sheet will be kept by the investigator for at least 15 years. 
The second sheet on which the names and signature of the patient are hidden will be faxed to CMG Inserm 
UMR S 1136 at the screening date. 
The last sheet attached to the information note is intended to the patient. If the patient refuses to take his 
copy, the investigator must report this information in the eCRF and in the patient's source document. The 
patient's consent must be sealed in an individual envelope signed by the principal investigator or its 


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representative and must be kept in the investigator's document ANRS 163 - ETRAL Version n° 1.0 dated 
10/03/2014appendix A5. 
For any amendment to the Protocol that modifies the care of the participant, a new information note must 
be given to the participant and a new consent form must be collected based on the same procedure 
described above. 
18.3 Data confidentiality  
Individual subject medical information, obtained as result of this trial is considered confidential and 
disclosure to third parties is prohibited. Such medical information may be given to the subject’s physician or 
to other appropriate medical personnel responsible for the subject’s well being. 
Data generated as a result of this trial are anonymised and are to be available for inspection on request by 
the participating physicians, the sponsor’s monitor, the IEC/IRB and the regulatory health authorities, 
including external site audits and inspections. 
During the trial, data that will be collected for any patients in the trial must never clearly mentioned any 
information (names, address, etc...) which could allow to identify him easily. For this reason, each patient 
will be assigned an identification code in the trial (cf patient identification). 
18.4 Data collection 
During each patient visit to the clinic/hospital, a clinician participating in the trial will record progress notes 
to document all significant observations. At a minimum, these notes will contain: 
 
Documentation of the informed consent process, including any revised consents; 
 
Demographic data (date of birth, sex, ethnic group); 
 
Details related to the inclusion criteria; 
 
Medical history and physical examination details; 
 
The date of the visit and the corresponding Visit or Day in the trial schedule; 
 
General subject status remarks, including any significant medical findings. The severity, 
frequency, and duration of any adverse experiences and the investigator’s assessment of 
relationship to study drug must also be recorded; 
 
Any changes in concomitant medications or dosages; 
 
Results of relevant examinations; 
 
Laboratory print-outs; 
 
A general reference to the procedures completed; 
 
Information from the trial progress and other source documents have to be promptly entered into the eCRF 
for each patient. The reported information in the eCRF and the name of the person who completed the 
eCRF will be automatically stored and dated. 
Any information changes in the eCRF will be saved with the name of the person who made the correction 
to assure a data tracking. 
 
18.5 Amendment policy 
The investigator will not make any changes to this protocol without prior written consent from the sponsor 
and subsequent approval by the IRB/IEC.  
Any permanent change to the protocol, whether it be an overall change or a change for specific trial 
centre(s), must be handled as a protocol amendment. Any amendment to the protocol that appears 
indicated as the trial progresses will be fully discussed by the investigator(s) and the sponsor. 
A “substantial amendment” is defined as an amendment to the terms of the IEC/IRB application, or to the 
protocol     or any other supporting documentation, that is likely to affect to a significant degree: 
 
- 
the safety or physical or mental integrity of the subjects of the trial, 
 
- 
the scientific value of the trial, 
 
- 
the conduct or management of the trial, or 
 
- 
the quality or safety of any intervention used in the trial. 
 
 If agreement is reached regarding the need for an amendment, it will be written by the sponsor. The 
written amendment must be submitted to the chairman of the IRB/IEC identified with this responsibility.  
Except for “non-substantial amendments”, investigators must await IRB/IEC approval of protocol 
amendments before implementing the change(s).  


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Non-substantial amendments are only notified to the accredited IEC/IRB and competent authority, and are 
recorded and filed by the sponsor. 
Examples of non-substantial amendments are typing errors and administrative changes like changes in 
names, telephone numbers and other contact details of involved persons mentioned in the submitted trial 
documentation. 
 
 
When, in the judgment of the chairman of the local IRB/IEC, the investigators and/or the sponsor, the 
amendment to the protocol substantially alters the trial design and/or increases the potential risk to the 
subject, the currently approved written informed consent will require similar modification. In such cases, 
repeat informed consent will be obtained from subjects enrolled in the trial before expecting continued 
participation. 
18.6 Insurance 
Inserm-ANRS will provide insurance (HDI Gerling, tours opus 12, 77 Esplanade de la Défense 92914 
PARIS LA DEFENSE) for individual patient’s for the period of the trial (see Appendix A3) from France and 
Spain and covering its civil liability in conformance with applicable legal and regulatory requirements. 
Each clinical centre will be responsible for ensuring that cover is in place for harm due to clinical negligence 
caused by their employees to a trial participant. 
18.7 Redaction of the final report 
The final report of the research and its summary will be prepared by the CMG Inserm UMR S 1136, the 
sponsor Inserm-ANRS and the coordinating investigator. 
These documents should be prepared in accordance with the recommendations of the International 
Conference on Harmonization (International Conference for Harmonization - ICH Topic E3 - Structure and 
Content of Clinical Study Reports CPMP/ICH/137/95). 
The final report should be established within the year following the end of the trial and will be addressed to 
the competent authorities by the sponsor (Inserm - ANRS). 
18.8 Archiving 
The trial documentation includes the following documents: 
- Trial protocol (and amendments) 
- Subject Information documents (including Informed Consent) 
- SAE report forms 
- eCRF 
- Questionnaires 
- Investigator’s File 
- Trial contracts 
 
In order to start the trial, the investigator is required to have the following documentation available: 
- Signed investigator statement for this protocol, 
- Signed trial contracts, 
- IEC approval letter, stating the sponsor’s name, trial number, as well as all documents reviewed and should 
include a list of members present at the meeting, 
- Recent CVs of investigators and sub investigators (signed and dated), 
- Signature sheet, documenting delegation of tasks and names and initials of the investigator team, 
- Regulatory approval, 
- Laboratory normal ranges and quality certificates and/or accreditations. 
 
At the end of the trial every eCRF pages must be filled, locked by the investigator or its representative, 
monitored by the CMG Inserm UMR S 1136 project manager and signed by the investigator who followed 
the patient.  
Every data for each patient will be printed in PDF and stored onto a CD (Compact Disc) and given to the 
principal investigator of the site by the CMG Inserm UMR S 1136. 
The investigator archives all trial data (subject ID code list, source data, CD storing the eCRF, and 
Investigator File) and relevant correspondence in a secure location. These documents are to be kept on file 
for at least 15 years after completion of the trial or another time period as specified by local laws. 
Consents for the sponsor will be sealed in an inviolable envelope signed by the principal investigator or its 
representative. 
On each consent form will be reported the patient anonymous code. 


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After this 15 years' period, trial documents can be discarded by the trial site after sponsor's written 
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19 DATA ACCESS 
All material collected under the protocol, that is to say, the research data and biological samples is placed 
at the beginning of the research under the responsibility of the CMG Inserm UMR S 1136. It remains under 
its responsibility throughout the research and beyond in case of research data, after dissolution of the 
Scientific Committee, unless otherwise decided by the sponsor. 
20 INVESTIGATOR DUTIES 
In accordance with good clinical practices and to ensure the quality of research, each 
investigator will: 
- Respect the rights of participants and ensure their safety and well-being, 
- Ensure that the whole team and himself remain available, 
- Ensure that its recruitment possibilities are compatible with the conduct of research, 
- Take responsibility for organizing the technical structures for the implementation of circuits 
specific research (consultations, samples) and archiving of documents during the duration of the research 
and for fifteen (15) years after the end of the research, 
- Collect and store the written consent of the participants in a safe place, 
- Ensure compliance with the protocol and to ensure the quality of data in the eCRF: Biological results should 
be submitted to the CMG UMR S 1136 within a maximum of ten (10) days after the visit of the participant, 
- Immediately inform the CMG UMR S 1136 if serious adverse events occur during the research, as 
described in the protocol (see chapter safety) 
- Allow regular monitoring of research by a representative of the CMG Inserm UMR S 1136 and access to 
the source documents for validation of data reported in the eCRFs. 
At any time, the CMG Inserm UMR S 1136 project manager or coordinating investigator can be contacted 
for any questions regarding the protocol, its application in practice or actions to take with certain events, 
- Accept any audit of research by the sponsor directly or with his authorization by other organizations, 
- Accept the inspection of research by health authorities. 
 
 


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APPENDICES 
 Appendices A 
Appendix A1:  Ethical Committee or Institutional Review Board 
Approval 
Appendix A2: National Competent Authorities authorization 
Appendix A3: Insurance 
Appendix A4: Declaration of Helsinki (Version 2013) 
Appendix A5: Information and consent (in french) 
Appendix A6: ANRS scale to grade the severity of adverse events in 
adults 
Appendix A7: Recommendations for blood pressure measurement in 
humans and experimental animals 
Appendix A8: Women substudy 
 
 Appendices B (separate appendices) 
Appendix B1: Investigator’s sites  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Appendix A1:  Ethical Committee or Institutional Review Board 
Approval 
 


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Appendix A2: National Competent Authorities authorization 
 
 
 


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Appendix A3: Insurance 
 
 
 


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Appendix A4: Declaration of Helsinki (Version 2013) 
WMA Declaration of Helsinki  
Ethical Principles for Medical Research 
Involving Human Subjects 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964 
and amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
52nd WMA General Assembly, Edinburgh, Scotland, October 2000  
53rd WMA General Assembly, Washington DC, USA, October 2002 (Note of Clarification 
added) 
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification added) 
59th WMA General Assembly, Seoul, Republic of Korea, October 2008 
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
4.1.1 Preamble 
1.         The World Medical Association (WMA) has developed the Declaration of Helsinki 
as a statement of ethical principles for medical research involving human subjects, 
including research on identifiable human material and data. 
            The Declaration is intended to be read as a whole and each of its constituent 
paragraphs should be applied with consideration of all other relevant paragraphs. 
2.         Consistent with the mandate of the WMA, the Declaration is addressed primarily to 
physicians. The WMA encourages others who are involved in medical research involving 
human subjects to adopt these principles.  
4.1.2 General Principles 
3.         The Declaration of Geneva of the WMA binds the physician with the words, “The 
health of my patient will be my first consideration,” and the International Code of Medical 
Ethics declares that, “A physician shall act in the patient's best interest when providing 
medical care.” 
4.         It is the duty of the physician to promote and safeguard the health, well-being and 
rights of patients, including those who are involved in medical research. The physician's 
knowledge and conscience are dedicated to the fulfilment of this duty. 
5.         Medical progress is based on research that ultimately must include studies 
involving human subjects. 
6.         The primary purpose of medical research involving human subjects is to 
understand the causes, development and effects of diseases and improve preventive, 


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diagnostic and therapeutic interventions (methods, procedures and treatments). Even the 
best proven interventions must be evaluated continually through research for their safety, 
effectiveness, efficiency, accessibility and quality. 
7.         Medical research is subject to ethical standards that promote and ensure respect 
for all human subjects and protect their health and rights. 
8.         While the primary purpose of medical research is to generate new knowledge, this 
goal can never take precedence over the rights and interests of individual research 
subjects. 
9.         It is the duty of physicians who are involved in medical research to protect the life, 
health, dignity, integrity, right to self-determination, privacy, and confidentiality of personal 
information of research subjects. The responsibility for the protection of research subjects 
must always rest with the physician or other health care professionals and never with the 
research subjects, even though they have given consent. 
10.       Physicians must consider the ethical, legal and regulatory norms and standards for 
research involving human subjects in their own countries as well as applicable 
international norms and standards. No national or international ethical, legal or regulatory 
requirement should reduce or eliminate any of the protections for research subjects set 
forth in this Declaration. 
11.       Medical research should be conducted in a manner that minimises possible harm 
to the environment. 
12.       Medical research involving human subjects must be conducted only by individuals 
with the appropriate ethics and scientific education, training and qualifications. Research 
on patients or healthy volunteers requires the supervision of a competent and 
appropriately qualified physician or other health care professional. 
13.       Groups that are underrepresented in medical research should be provided 
appropriate access to participation in research. 
14.       Physicians who combine medical research with medical care should involve their 
patients in research only to the extent that this is justified by its potential preventive, 
diagnostic or therapeutic value and if the physician has good reason to believe that 
participation in the research study will not adversely affect the health of the patients who 
serve as research subjects. 
15.       Appropriate compensation and treatment for subjects who are harmed as a result 
of participating in research must be ensured. 
4.1.3 Risks, Burdens and Benefits  
16.       In medical practice and in medical research, most interventions involve risks and 
burdens. 
           Medical research involving human subjects may only be conducted if the 
importance of the objective outweighs the risks and burdens to the research subjects. 
17.       All medical research involving human subjects must be preceded by careful 
assessment of predictable risks and burdens to the individuals and groups involved in the 
research in comparison with foreseeable benefits to them and to other individuals or 
groups affected by the condition under investigation. 


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           Measures to minimise the risks must be implemented. The risks must be 
continuously monitored, assessed and documented by the researcher.  
18.       Physicians may not be involved in a research study involving human subjects 
unless they are confident that the risks have been adequately assessed and can be 
satisfactorily managed. 
           When the risks are found to outweigh the potential benefits or when there is 
conclusive proof of definitive outcomes, physicians must assess whether to continue, 
modify or immediately stop the study.            
4.1.4 Vulnerable Groups and Individuals 
19.       Some groups and individuals are particularly vulnerable and may have an 
increased likelihood of being wronged or of incurring additional harm. 
           All vulnerable groups and individuals should receive specifically considered 
protection. 
20.       Medical research with a vulnerable group is only justified if the research is 
responsive to the health needs or priorities of this group and the research cannot be 
carried out in a non-vulnerable group. In addition, this group should stand to benefit from 
the knowledge, practices or interventions that result from the research. 
4.1.5 Scientific Requirements and Research Protocols  
21.       Medical research involving human subjects must conform to generally accepted 
scientific principles, be based on a thorough knowledge of the scientific literature, other 
relevant sources of information, and adequate laboratory and, as appropriate, animal 
experimentation. The welfare of animals used for research must be respected. 
22.       The design and performance of each research study involving human subjects 
must be clearly described and justified in a research protocol. 
           The protocol should contain a statement of the ethical considerations involved and 
should indicate how the principles in this Declaration have been addressed. The protocol 
should include information regarding funding, sponsors, institutional affiliations, potential 
conflicts of interest, incentives for subjects and information regarding provisions for 
treating and/or compensating subjects who are harmed as a consequence of participation 
in the research study. 
           In clinical trials, the protocol must also describe appropriate arrangements for post-
trial provisions. 
4.1.6 Research Ethics Committees 
23.       The research protocol must be submitted for consideration, comment, guidance 
and approval to the concerned research ethics committee before the study begins. This 
committee must be transparent in its functioning, must be independent of the researcher, 
the sponsor and any other undue influence and must be duly qualified. It must take into 
consideration the laws and regulations of the country or countries in which the research is 
to be performed as well as applicable international norms and standards but these must 
not be allowed to reduce or eliminate any of the protections for research subjects set forth 
in this Declaration.  


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80  
 
           The committee must have the right to monitor ongoing studies. The researcher 
must provide monitoring information to the committee, especially information about any 
serious adverse events. No amendment to the protocol may be made without 
consideration and approval by the committee. After the end of the study, the researchers 
must submit a final report to the committee containing a summary of the study’s findings 
and conclusions.  
4.1.7 Privacy and Confidentiality  
24.       Every precaution must be taken to protect the privacy of research subjects and the 
confidentiality of their personal information. 
4.1.8 Informed Consent  
25.       Participation by individuals capable of giving informed consent as subjects in 
medical research must be voluntary. Although it may be appropriate to consult family 
members or community leaders, no individual capable of giving informed consent may be 
enrolled in a research study unless he or she freely agrees. 
26.       In medical research involving human subjects capable of giving informed consent, 
each potential subject must be adequately informed of the aims, methods, sources of 
funding, any possible conflicts of interest, institutional affiliations of the researcher, the 
anticipated benefits and potential risks of the study and the discomfort it may entail, post-
study provisions and any other relevant aspects of the study. The potential subject must 
be informed of the right to refuse to participate in the study or to withdraw consent to 
participate at any time without reprisal. Special attention should be given to the specific 
information needs of individual potential subjects as well as to the methods used to deliver 
the information. 
           After ensuring that the potential subject has understood the information, the 
physician or another appropriately qualified individual must then seek the potential 
subject’s freely-given informed consent, preferably in writing. If the consent cannot be 
expressed in writing, the non-written consent must be formally documented and 
witnessed.       
           All medical research subjects should be given the option of being informed about 
the general outcome and results of the study. 
27.       When seeking informed consent for participation in a research study the physician 
must be particularly cautious if the potential subject is in a dependent relationship with the 
physician or may consent under duress. In such situations the informed consent must be 
sought by an appropriately qualified individual who is completely independent of this 
relationship. 
28.       For a potential research subject who is incapable of giving informed consent, the 
physician must seek informed consent from the legally authorised representative. These 
individuals must not be included in a research study that has no likelihood of benefit for 
them unless it is intended to promote the health of the group represented by the potential 
subject, the research cannot instead be performed with persons capable of providing 
informed consent, and the research entails only minimal risk and minimal burden. 
29.       When a potential research subject who is deemed incapable of giving informed 
consent is able to give assent to decisions about participation in research, the physician 


ANRS 163 - ETRAL  
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81  
 
must seek that assent in addition to the consent of the legally authorised representative. 
The potential subject’s dissent should be respected. 
30.       Research involving subjects who are physically or mentally incapable of giving 
consent, for example, unconscious patients, may be done only if the physical or mental 
condition that prevents giving informed consent is a necessary characteristic of the 
research  group. In such circumstances the physician must seek informed consent from 
the legally authorised representative. If no such representative is available and if the 
research cannot be delayed, the study may proceed without informed consent provided 
that the specific reasons for involving subjects with a condition that renders them unable to 
give informed consent have been stated in the research protocol and the study has been 
approved by a research ethics committee. Consent to remain in the research must be 
obtained as soon as possible from the subject or a legally authorised representative. 
31.       The physician must fully inform the patient which aspects of their care are related 
to the research. The refusal of a patient to participate in a study or the patient’s decision to 
withdraw from the study must never adversely affect the patient-physician relationship. 
32.       For medical research using identifiable human material or data, such as research 
on material or data contained in biobanks or similar repositories, physicians must seek 
informed consent for its collection, storage and/or reuse. There may be exceptional 
situations where consent would be impossible or impracticable to obtain for such research. 
In such situations the research may be done only after consideration and approval of a 
research ethics committee. 
4.1.9 Use of Placebo 
33.       The benefits, risks, burdens and effectiveness of a new intervention must be tested 
against those of the best proven intervention(s), except in the following circumstances: 
           Where no proven intervention exists, the use of placebo, or no intervention, is 
acceptable; or 
           Where for compelling and scientifically sound methodological reasons the use of 
any intervention less effective than the best proven one, the use of placebo, or no 
intervention is necessary to determine the efficacy or safety of an intervention  
           and the patients who receive any intervention less effective than the best proven 
one, placebo, or no intervention will not be subject to additional risks of serious or 
irreversible harm as a result of not receiving the best proven intervention.  
           Extreme care must be taken to avoid abuse of this option. 
4.1.10 Post-Trial Provisions 
34.       In advance of a clinical trial, sponsors, researchers and host country governments 
should make provisions for post-trial access for all participants who still need an 
intervention identified as beneficial in the trial. This information must also be disclosed to 
participants during the informed consent process. 
4.1.11 Research Registration and Publication and Dissemination of 
Results 
35.       Every research study involving human subjects must be registered in a publicly 
accessible database before recruitment of the first subject. 


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82  
 
36.       Researchers, authors, sponsors, editors and publishers all have ethical obligations 
with regard to the publication and dissemination of the results of research. Researchers 
have a duty to make publicly available the results of their research on human subjects and 
are accountable for the completeness and accuracy of their reports. All parties should 
adhere to accepted guidelines for ethical reporting. Negative and inconclusive as well as 
positive results must be published or otherwise made publicly available. Sources of 
funding, institutional affiliations and conflicts of interest must be declared in the publication. 
Reports of research not in accordance with the principles of this Declaration should not be 
accepted for publication. 
4.1.12 Unproven Interventions in Clinical Practice 
37.       In the treatment of an individual patient, where proven interventions do not exist or 
other known interventions have been ineffective, the physician, after seeking expert 
advice, with informed consent from the patient or a legally authorised representative, may 
use an unproven intervention if in the physician's judgement it offers hope of saving life, re-
establishing health or alleviating suffering. This intervention should subsequently be made 
the object of research, designed to evaluate its safety and efficacy. In all cases, new 
information must be recorded and, where appropriate, made publicly available.


ANRS 163 ETRAL Trial 
ANRS 163 ETRAL Trial
Information notice 
Non-comparative phase II pilot trial to evaluate the ability of a combination of 
raltegravir + etravirine to maintain virological success in HIV-1-infected patients of 
at least 45 years of age with a plasma viral load of less than 50 copies/mL on 
antiretroviral therapy including a boosted protease inhibitor. 
Version 2.0, dated 03/18/2015, approved by the CPP on 05/15/2015 
Coordinating Investigator:   
Prof. Christine Katlama, Pitié-Salpêtrière Hospital, Paris. 
Scientific Director:  
Prof. Jacques Reynes, Montpellier University Hospital. 
Trial Sponsor: 
National Institute of Health and Medical Research - National Agency for Research on AIDS and 
Viral Hepatitis (Inserm - ANRS) 101 rue de Tolbiac, Paris 75013.  
- This notice is designed to help you decide whether or not to participate in the trial described below.
- You are free to answer yes or no to the question asked: do you want to participate in the trial?
- You have the right to take as much time as you need to think about it, to discuss this trial and to ask
anyone you want whatever you want to know about it.
- If you do not wish to participate, you will still continue to receive the best possible care
- You can change your mind at any time and ask to withdraw from the trial. You will continue to benefit
from the best care that your doctor can offer you. We ask only that you inform your doctor of your
decision as soon as possible.
Appendix A5: Information and consent


ANRS 163 ETRAL Trial  
  
  
 
  
  
Page 2 of 11  
 
 
  
  
Page 1 of 11  
The words underlined in the text are explained in the glossary.  
 
Glossary 
 
    Biobank: A bank of biological samples kept for research purposes. 
 Data: Information collected as part of the trial.  
 Right of access: The right to see the data concerning you.  
 Anonymized data: Your name and surname are removed from all medical records and replaced with a code. Only the 
doctor and people with a right of access to the medical data are aware of the link between your identity and this code.  
Right of opposition: The right to oppose the transmission of your data by the investigating doctor to the sponsor. The 
exercise of this right terminates your participation in the trial. 
Right of rectification: The right to request that the correction of your data in the event of an error. 
Samples: Samples taken from people participating in the trial (e.g. blood, cells, etc.). In general, the samples are 
stored in a Biobank centralized at the ANRS.  
 Consent form: A document in which you declare that you have read the terms of participation in the trial and give 
your consent to participate. 
 Coordinating investigator: The doctor supervising the running of the trial at the various participating centers.  
 Investigating doctor of the trial (or investigator): The doctor following you in the framework of the trial. He/she may 
be your regular doctor, or another doctor involved in the trial. 
 Bone densitometry: A painless radiological examination measuring the mineral content of the bone, and the 
percentage of fat and lean mass in the limbs and trunk. 
 Pre-inclusion: The time point at which all conditions are met for your participation in the trial.  
 Sponsor: The organization legally and financially responsible for the trial. 
 Substudy: A study carried out only on some of the people participating in the trial. 
 Adipose tissue: A tissue that contains fat.  
 Integrase inhibitor: A molecule that blocks a viral enzyme, integrase, which allows the virus to enter the cell’s 
nucleus to multiply. 
 Non-nucleoside reverse transcriptase inhibitor: A molecule that blocks a viral enzyme, reverse transcriptase, the 
role of which is to convert the viral genome into DNA that can integrate into the genome of the host cell. 
 
In this notice you will find:  
 
  
1. 
Objectives of the trial 
4 
2. 
The conditions for participation in the trial 
4 
3. 
Schema for the trial 
5 
4. 
Trial treatments 
5 


ANRS 163 ETRAL Trial  
  
  
 
  
  
Page 3 of 11  
5. 
Sexuality, contraception, and pregnancy 
6 
6. 
What are the constraints linked to participation in the trial? 
6 
7. 
The progress and timetable of the trial 
7 
8. 
Expected benefits and possible risks 
9 
9. 
Monitoring 
9 
10. 
Alternatives 
9 
11. 
What will happen at the end of the trial? 
10 
12. 
What are your rights? 
10 
13. 
Information about the fate of your samples at the end of the trial 
 10 
 
  
You will find a consent form on the last page: this signed document attests to your willingness to participate in 
the trial and contains the contact details of the investigating doctor of the trial, whom you can contact if 
necessary.  
  
To whom it may concern,  
  
The investigating doctor of the ANRS 163 ETRAL trial would like to invite you to participate in this trial.  
You have been on antiretroviral therapy including at least one boosted protease inhibition for the treatment of HIV 
infection for at least six months. This treatment makes it possible to control your viral load, that is, it prevents the 
multiplication of the virus in the blood (resulting in what we call an "undetectable plasma viral load"). This treatment also 
increases the number of CD4 cells in the blood, improves survival, and slows disease progression. 
Despite the considerable clinical progress achieved in patients whose virus is under control, vascular (angina pectoris or 
myocardial infarction), lipid (increases in cholesterol and triglyceride levels), renal (a decrease in the filtration rate of the 
kidney), or bone (decrease in bone density) complications may emerge over time. They are related to the persistent 
inflammation due to HIV, and to certain molecules used in antiretroviral treatments, such as, nucleoside or nucleotide 
analogs (tenofovir (Viréad®, Truvada®) or abacavir (Ziagen®, Kivexa®)) and protease inhibitors (atazanavir (Réyataz®), 
darunavir (Prézista®) lopinavir / r (Kalétra®)). The frequency of these events also increases with age and increasing 
patient life expectancy. Today, almost 40% of patients treated in French hospitals at least 50 years old. A comparison 
between HIV-positive and HIV-negative patients has shown that the frequency of complications is higher in HIV-positive 
patients and that these complications occur earlier. 
Some of the most recent classes of antiretroviral therapy or drugs are both effective against HIV and have little effect on 
lipid balance, bones, or adipose tissue. 
 
We are inviting you to participate in a trial evaluating a new strategy combining two powerful antiretroviral drugs that are 
well known and have been marketed for several years: 
-  
Raltegravir (or Isentress®), which has been available since 2008, belongs to the new class of integrase inhibitors 
(integrase allows the virus to enter the nucleus of the cell to multiply). 
-  
Etravirine (or Intelence®), which belongs to the second generation of non-nucleoside reverse transcriptase 
inhibitors, blocks a viral enzyme, reverse transcriptase, which converts the viral genome into DNA capable of integrating 
into the genome of the host cell (see the Trial treatments section). 
 
 


ANRS 163 ETRAL Trial  
  
  
 
  
  
Page 4 of 11  
 
1. Objectives of the trial  
 
The objective of the trial is to determine whether this new combination of two antiretroviral molecules — raltegravir 
(Isentress®) and etravirine (Intelence®) — makes it possible to maintain an undetectable HIV viral load while reducing 
potential side effects, such as cardiovascular, bone, kidney, or adipose tissue distribution disorders. 
This trial includes two substudies to evaluate the following parameters: 
- The DXA substudy: changes in the distribution of adipose tissue in the body and in bone mineral density. This substudy 
will involve a painless radiological examination for measuring the mineral content of the bone, and the percentage of fat 
and lean mass in the limbs and trunk, which will be performed at regular intervals (day (D) 0, week (W) 48, W96) for 80 
participants. 
- The semen substudy: measurements of HIV RNA viral load and the residual concentrations of raltegravir (Isentress®) 
and etravirine (Intelence®) in a sample of sperm fluid collected at W48 from 20 male participants. 
 
2. The conditions for participation in the trial 
 
If you decide to participate in this trial, a first visit, the "pre-inclusion visit", will take place 2 to 4 weeks before the 
start of the trial. During this visit, the doctor will assess your state of health: clinical examination, weight, height; 
blood and urine samples will also be collected. Your doctor will ask you about your medical history, to check that 
you are eligible to participate in the trial. 
 
The principal conditions for participation in this trial are as follows. You must:   
- Be at least 45 years old 
- Be infected with HIV-1 
- Have been on stable antiretroviral treatment for at least six months 
- Have a CD4 lymphocyte count above 200/mm3  
- Have had an undetectable viral load (i.e. less than 50 copies/mL) for at least 24 months 
- Have never been treated with raltegravir (Isentress®) and etravirine (Intelence®) 
-Not take prohibited drugs during the trial (see the list in the Trial treatments section) 
- Accept the constraints imposed by the trial (see the paragraph What are the constraints linked to participation in 
the trial? section) 
- Be affiliated to or be a beneficiary of a social security regime (State Medical Aid or AME is not a social security    
regime) 
- Have signed the consent form: this form must be signed before any examination (e.g. blood test, scan, etc.) is 
carried out as part of the trial 
- Not participate in another trial at the same time as this one 
The following situations are incompatible with participation in the trial:  
- Being pregnant or breastfeeding 
- Having chronic hepatitis B or C (treated during the 24 months of the trial) 
- Anti-hypercholesterolemia and/or anti-diabetic treatment initiated in the 3 months preceding your participation in the 
trial 


ANRS 163 ETRAL Trial  
  
  
 
  
  
Page 5 of 11  
If, after checking these conditions, the investigator decides that you cannot participate in this trial, he/she will decide, 
with you, which treatment is best suited to your situation.
 
3. Schema for the trial 
 
Once the eligibility criteria have been verified, you can start the trial. 
    
All participants will replace their usual antiretroviral therapy with raltegravir (Isentress®) plus etravirine 
(Intelence®). 
    Therefore, all trial participants will receive the same treatment: raltegravir (Isentress®) and etravirine 
(Intelence®). 
    The duration of participation in the trial is 96 weeks (approximately two years). 
    The maximum total duration of the trial is estimated at four years, including the time required to include all the 
trial participants. 
     We to include 160 participants from several hospitals in France and Spain. 
 
4. Trial treatments  
 
Raltegravir (Isentress®): what you should know  
Raltegravir (Isentress®), developed by the Merck Sharp & Dohme Ltd laboratory, has been marketed in France since 
January 2008. 
Raltegravir (Isentress®) blocks the action of an enzyme (protein) called "integrase". It is produced in the form of tablets 
and must be taken at a dose of 1 tablet twice daily (i.e. 2 tablets per day). 
The tolerance of raltegravir (Isentress®) is generally good. However, like most treatments, it can cause certain adverse 
effects, the main ones being: 
- Diarrhea, nausea (feeling sick) and headache (may affect more than 1 in 10 people) 
- Insomnia (difficulty sleeping), dizziness, bloating, stomachache, flatulence (gas), vomiting, rash, weakness, fatigue 
(may affect 1 to 10 users in 100) 
- Contact your doctor immediately if you develop a cutaneous (skin) reaction. Skin reactions and life-threatening 
severe allergic reactions have been reported in some people receiving this medicine. 
- Inform your doctor if you have a history of depression or psychiatric illness. Depression, including suicidal 
thoughts and behavior, has been reported in some people taking this medication, especially those with a history of 
depression or psychiatric illness. 
 
 
Etravirine (Intelence®): what you should know 
Etravirine (Intelence®), developed by Janssen Cilag Laboratories, has been marketed in France since August 2008.  
It is produced in the form of tablets and must be taken at a dose of 1 tablet twice daily (i.e. 2 tablets per day). 
Etravirine is a non-nucleotide reverse transcriptase inhibitor. 
Tolerance to etravirine is generally good, but like most treatments, it can have certain adverse effects, the main ones 
being: 
- Skin rashes that are usually mild to moderate. However, a very serious and potentially life-threatening rash has been 
reported in rare cases. It is therefore important that you contact your doctor immediately if you develop a rash. 
- Nausea, stomach problems (diarrhea, stomachache, indigestion), headache, dizziness, tiredness (may affect less than 
1 in 10 people). 


ANRS 163 ETRAL Trial  
  
  
 
  
  
Page 6 of 11  
- Risk of myocardial infarction (frequency: less than 1 in 10 people). 
 
Doses of raltegravir (Isentress®) and etravirine (Intelence®):  
The table below specifies the dose and number of doses of the treatments that you will take as part of this trial: 
 
Who?  
Medicine  
Form  
Morning Evening 
How to take it  
All participants  
Raltegravir 400 mg 
(Isentress®),  
Pink oval tablets 
1  
1  
After a meal  
Etravirine 200 mg 
(Intelence®),  
White oval tablets  
1  
1  
After a meal  
If you want more information about these treatments, do not hesitate to talk to your doctor. 
 
Tell your doctor before taking other medicines during the trial:  
It is important to tell your doctor about the medicines that you take or wish to take (with or without a prescription) during 
the trial. 
The following drugs are formally contraindicated and must not be taken in combination with the trial treatments 
because they may interact with or limit the efficacy of the anti-HIV treatments: 
 
• Antiplatelet agents: Clopidogrel (Plavix®), prasugrel (Effient®), ticagrelor (Brilique®), ticlopidine (Ticlid®), 
flurbiprofene (Antadys® - Cebutid®).  
• Anti-infection agents: Rifampicine (Rifampicine® - Rifadin® - RofactMC - Rifater®), rifapentine (Priftin®).  
• Certain herbal medicines containing St. John's Wort.  
• Anti-epileptic agents: Carbamazepine (Tegretol®), phenobarbital, phenytoine (Dilantin®).  
• Other drugs: Avanafil (Stendra™), triazolam (Halcion®).  
If you have any questions about these medicines, do not hesitate to talk to your doctor.
 
5. Sexuality, contraception, and pregnancy 
 
It is very important to use a condom during sex, because treatment for HIV does not always prevent the transmission of 
HIV and other sexually transmitted infections. 
Raltegravir (Isentress®) and etravirine (Intelence®) have not been evaluated in pregnant women. Their effects on the 
unborn child are not known. It is therefore important not to take any risks and not to become pregnant during the trial. 
You should discuss the contraceptive method best suited to your situation with your doctor. If you, nevertheless, discover 
that you are pregnant during the trial, you should immediately tell your doctor. 
 
6. What are the constraints linked to participation in the trial?   
 
During this trial, medical examinations will be slightly more frequent than during your usual follow-up. You should expect: 
• 
A pre-inclusion visit and 10 follow-up visits during the two years of participation.   
• 
Blood tests at each visit and questionnaires to be completed at certain visits. 


ANRS 163 ETRAL Trial  
  
  
 
  
  
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If you agree to take part in one or both of the two proposed substudies, you must also be available for the examinations 
or blood tests for these substudies: bone densitometry (a painless radiological examination that measures the mineral 
content of bone and the percentages of fat and lean mass in the limbs and trunk) and sperm collection. 
For your safety and for the success of the trial, it is important to follow the visit schedule as closely as possible. Given the 
importance of keeping to the timetable for the trial, the medical team in charge of your follow-up in the trial will do their 
utmost to facilitate this. You will be in contact with the clinical research team of your center, who will give you your 
schedule and all the telephone numbers that might prove useful for the smooth running of your participation. If you 
cannot come for a consultation or provide a sample, remember to tell your doctor. 
Your agreement to participate in this trial implies that you accept the constraints imposed by the scheduled examinations. 
Do not hesitate to ask the investigating doctor all the necessary questions on this subject. If you wish, he/she can give 
you information about your follow-up in the trial at each consultation. 
 
7. The progress and timetable of the trial 
 
If you agree to participate in the trial, you will sign a consent form before the first examination related to the trial. You will 
have a total of 11 visits spread over the two years of your participation in the trial: 
"Pre-inclusion" visit: the investigating doctor will ask you about your medical history and perform a clinical 
examination and blood tests to make sure that you can participate in the trial. 
  
If all the conditions for participation are met: 
Visit D0: corresponds to the first dose of raltegravir (Isentress®) and etravirine (Intelence®). This visit 
takes place 2 to 4 weeks after the pre-inclusion visit. 
There will be 9 other visits: W2, W4, W12, W24, W36, W48, W64, W80, and W96 (see the trial calendar). 
 
During these visits, the investigating doctor will take blood samples for routine blood tests, such as blood sugar, the 
measurement of viral load (measurement of the amount of virus in the blood), or counts of CD4 lymphocytes. Other 
blood samples will be used to carry out more specific blood tests, such as determinations of the amount of the trial drugs 
in your blood. 
Some samples/blood samples will be analyzed immediately, and others will be kept for analysis at the end of the trial. 
You will be asked for a urine sample at visits W-6/W-4, W4, W12, W24, W48, W80, and W96, to check for protein or 
glucose (sugar) in your urine, these substances normally being present in only very small amounts. 
Blood samples for storage will be sent to the French Blood Establishment (EFS) in Beynost (France) to constitute a 
biobank. Each sample will be labeled and numbered anonymously (your name will not be indicated). 
The samples from the biobank can be used for additional studies. If these additional studies involve genetic testing, 
you will be asked for consent for such testing. 
You can specify in your consent that you do not wish your samples to be kept in the biobank for use in future 
research. 
 
Substudies 
If you are volunteering for the DXA substudy, to evaluate changes in the distribution of fat in your body and changes in 
bone mineral density, bone densitometry will be performed on D0 and at W48 and W96 (80 participants). 
Patients wishing to participate in the semen substudy, which aims to measure the viral load of HIV and the residual 
concentration of raltegravir (Isentress®) and etravirine (Intelence®) in sperm fluid, will provide a sperm sample at W48 
(20 participants). 
 


ANRS 163 ETRAL Trial  
  
  
 
  
  
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The questionnaires and self-administered questionnaires to be completed during the trial  
- “Quality of life” and “compliance” self-administered questionnaires: These are anonymized questionnaires, on paper, 
that you will complete on your own. At no time will we be able to intervene your responses. The self-administered 
"compliance" questionnaire will tell us whether you are taking your treatments as prescribed by your doctor. If this is not 
the case, your doctor will try to understand why and work with you to try to find a solution. 
  
  
  
  
  
  
  
  
 
 
 
 
 
  
Trial Calendar  
  
Pre-
inclusion*  
(W-6/W-4 
to  
W-2)  
D:  
Start of 
treatment  
W2  
W4  
W12  
W24  
W36  
W48  
W64  
W80  
W96  
In case of 
virological 
failure 
Signature of consent form 
  
  
  
  
  
  
  
  
  
  
  
  
Clinical examination 
  
  
  
  
  
  
  
  
  
  
  
  
Quality of life self-
administered 
questionnaires  
  
  
  
  
  
  
  
  
  
  
  
  
Compliance questionnaire 
  
  
  
  
  
  
  
  
  
  
  
  
Come to the consultation 
after a period of at least 
12 h without eating  
  
  
  
  
  
  
  
  
  
  
  
  
Pregnancy test (1)  
  
  
  
  
  
  
  
  
  
  
  
  
Urine sample  
  
  
  
  
  
  
  
  
  
  
  
  
DXA /  
Bone densitometry 
(substudy) 
  
  
  
  
  
  
  
  
  
  
  
  
Sperm sample          
(substudy)  
  
  
  
  
  
  
  
  
  
  
  
  
Amount of blood for the 
ETRAL trial (without 
storage in the biobank) 
29 mL  (7 
tubes)  
22 mL   
  
(6 tubes)  
0 mL  
19 mL  
(5 
tubes)  
22 mL  
(6 
tubes)  
25 mL  
(7 
tubes)  
7 mL  
(1 
tubes)  
25mL  
(7 
tubes)  
7 mL  
(1 
tubes)  
16 mL  
(4 
tubes)  
25 mL  
(7 
tubes)  
14 mL  
  
 (2 tubes)  


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Additional blood for the 
biobank  
0 mL  
45 mL  
  
(7 tubes)   
21 mL  
(3 
tubes)  
21 mL  
(3 
tubes)  
21 mL  
(3 
tubes)    
21 mL  
(3 
tubes)   
21 mL  
(3 
tubes)  
45 mL  
(7 
tubes)  
21 mL  
(3 
tubes)  
21 mL  
(3 
tubes)  
45 mL  
(7 
tubes)  
7 mL (1 
tubes)  
Total amount of blood 
collected 
(mL)  
29 mL (7 
tubes)  
67 mL  
(13 tubes)  
21 mL  
(3 
tubes)  
40 mL  
(8 
tubes)  
43 mL  
(9 
tubes)  
46 mL  
(10 
tubes)  
28 mL  
(4 
tubes)  
70 mL  
(14 
tubes)  
28 mL  
(4 
tubes)  
37 mL  
(7 
tubes)  
70 mL  
(14 
tubes)   
21 mL (3 
tubes)  
*Pre-inclusion: takes place 2 to 4 weeks before the start of treatment. W: week 
(1) The pregnancy test is carried out only for women of childbearing age at W-6/W-4 and then at subsequent visits if pregnancy is suspected. 
 
  
  
 
8. Expected benefits and possible risks 
 
Expected benefits  
- The antiretroviral drugs that you will receive as part of the ANRS 163 ETRAL trial have shown, separately, to have 
virological efficacy, with raltegravir (Isentress®) having a lesser effect on lipid profile and bones. 
You will benefit from participation if the trial shows that the raltegravir (Isentress®) + etravirine (Intelence®) combination 
controls viral replication, is well tolerated, and reduces the frequency of complications associated with HIV infection and 
your previous treatment. 
 
- You will benefit from more frequent monitoring and more detailed examinations. 
- You will be involved in research, the results of which may be of benefit to other people. 
 
Possible risks  
- Raltegravir (Isentress®) and etravirine (Intelence®) can cause known (as described in the Trial treatments section)      
or unknown adverse effects. 
- The trial treatment should control viral replication and ireduce the complications of HIV infection and your previous 
treatment. However, there is a risk of replication. You will be monitored closely to detect any rise in HIV viral load. 
- Blood tests may cause bruising at site of puncture, on the day of the examination and on the following two to three 
days. 
 
9. Monitoring 
 
During the trial if, for example, your health deteriorates and other treatments are preferable, or if justified by adverse 
effects, you can decide, with your doctor, to stop the trial treatment at any time, while continuing your monitoring. 
Throughout the trial, scientific committees will monitor the study for adverse effects or failures of raltegravir (Isentress®) 
and etravirine (Intelence®). These committees ensure the safety of those involved in the trial and oversee the running of 
the trial. If necessary, for safety reasons, for example, they can decide to end the trial or to modify the way in which it is 
performed. 
 
10. Alternatives  
 
You should know that your participation in the trial is free and voluntary. You can decide to refuse to participate in the 
trial and remain on your current treatment. Your decision to agree or refuse to participate in this trial will not change the 
quality of your medical care. 
 


ANRS 163 ETRAL Trial  
  
  
 
  
  
Page 10 of 11  
11. What will happen at the end of the trial?   
 
Raltegravir (Isentress®) and etravirine (Intelence®) are already sold in France. If the final results of the trial are 
conclusive, your doctor may wish to consider continuing with this combination. At the end of the trial, participants will be 
able to discuss their results and their experience of participation in the trial. 
The overall results of the trial will be communicated to the participants after the trial has ended. 
 
12. What are your rights?  
 
Do not forget that you can:  
- Take as long as you need to think before deciding to participate in this trial 
- Leave the trial at any time, without giving a reason, by simply telling your doctor 
- Find out about your health 
- Be informed of any serious events occurring during the trial 
- Be informed of your results and of the overall results of the trial 
- Check and correct data concerning you 
- Oppose the transmission of data concerning you  
- Obtain compensation in the event of harm 
 
Your data:  
As part of the trial in which you are being asked to participate by the National Agency for Research on AIDS and Viral 
Hepatitis (ANRS), your personal data will be processed as part of the analysis of the results of the trial with respect to its 
objectives, which have been presented to you. 
To this end, the medical data concerning you and the data relating to your lifestyle, and, insofar as these data are 
necessary for the trial, your ethnic origins, and sex life, will be transmitted to the sponsor of the trial or to individuals or 
companies acting on the sponsor’s behalf, in France or abroad. 
These data will be identified by a code number. These data may also be transmitted to French or foreign health 
authorities (Medicines Agency, etc.) or to other ANRS partners, under conditions of confidentiality. 
In accordance with the provisions of the law relating to data processing and freedoms, you have the right of access and 
rectification. You also have the right to oppose the transmission of data covered by professional secrecy that may be 
used in the context of this trial and be processed. The exercise of this right will terminate your participation in the trial. 
You can also access all of your medical data directly or through a doctor of your choice, in accordance with the 
provisions of article L 1111-7 of the French Public Health Code. 
If you have any questions about these rights, you can contact the doctor following you during the trial. If desired, 
information about the trial and your participation will be shared with your general practitioner. 
This trial received was approved by the Personal Protection Committee (CPP) on 04/16/2014 and authorized by the 
ANSM on 04/04/2014. 
The sponsor of this trial, Inserm-ANRS, has taken out civil liability insurance in the event of harm, in accordance with the 
provisions of the French Public Health Code, with HDI Gerling (Tours opus 12, 77 Esplanade de la Défense 92914 
PARIS LA DEFENSE) . 
The French Public Health Code also guarantees compensation to anyone suffering harm due to participation in research. 
 
13. 
Information about the fate of your samples at the end of the trial 
 
  


ANRS 163 ETRAL Trial  
  
  
 
  
  
Page 11 of 11  
  
To whom it may concern,  
  
  
As specified in the information notice specific to the ANRS 163 ETRAL trial, in which you are invited to 
participate, blood samples, urine samples, and (possibly) a semen sample will be taken. 
If the blood and semen samples are not completely used up at the end of this trial, they may be used for 
scientific research on HIV unless you object. 
The remaining samples: 
 
• 
Will be stored at the EFS (French Blood Establishment - Beynost site), under the control of its 
logistics management, on behalf of the ANRS, and under the scientific responsibility of the 
common service 10-US019 of Inserm (Paul Brousse Hospital, Villejuif) 
• 
May be supplied free of charge, and under certain conditions, to other national or international 
private or public research groups, under conditions guaranteeing the confidentiality of your data  
• 
May not, in any case, be used for the examination of genetic characteristics without new written 
consent from you. 
 
You may freely, and at any time, object to this further use for research purposes, by contacting 
the investigating doctor of the trial. 
Your decision will have no consequences for your participation in the ANRS 163 ETRAL trial or your 
medical care. 
Name, address, and contact details. 
 
 .......................................................................................................................................................   
  
 .......................................................................................................................................................   ............
...........................................................................................................................................   
  
 
In accordance with the law, no remuneration can be paid to you. 
The transferred samples cannot be sold. 
For sample management, the EFS uses a computer file authorized by the French National Commission 
for Data Protection (CNIL). This file contains anonymized data for the identification of samples. 
 
 


ANRS 163 ETRAL Trial                          Consent Form                             
└─┴─┘└─┴─┴─┘└─┴─┴─┘└─┴─┴─┴─┘  
                                                                                                                                                         Country         Center No.    Patient No.         Letter 
code 
 
    
Version 2.0 of 03/18/2015, approved by the CPP on 05/15/2015  
Sponsor: Inserm-ANRS                  Coordinating investigator: Prof. Christine Katlama   
Ms, Mr 
(first and last name)  
  
I certify:  
having received information notice version 2.0 dated 03/18/2015, that I have had the opportunity to ask all the 
questions I wished on the nature, objectives, potential risks, and constraints relating to my participation in this trial, 
 and that I have had sufficient time to reflect between receiving this information and giving my consent. 
 
I understand the constraints (more frequent visits, numerous blood samples) and the benefits linked to my participation in 
this trial, which will last approximately 2 years. 
I understand that I am free to discontinue my participation in this trial at any time, without having to explain why, but I will 
do my best to inform the doctor. This will not affect the quality of my subsequent care. 
I have been reassured that the decisions that are necessary for my health will be made at all times, in accordance with 
the state of knowledge on HIV. 
I have noted that blood samples and a semen sample (if I participate in the semen substudy) will be taken during the trial 
and stored anonymously. They will make it possible to carry out the planned analyses for this trial. 
I accept that the data recorded during this trial will be collected, processed, and computerized. I understand that the right 
of access laid down in the modified law of January 6, 1978 relating to data processing, files, and freedoms, can be 
exercised at any time, through the doctor following me in the trial, and that I can exercise my right of rectification and 
opposition. 
I accept that the scientists involved in this trial, and the individuals authorized by the health authorities in France and 
abroad, may have access to the information, under strict conditions of confidentiality. 
My consent in no way relieves the organizers of the trial of their responsibilities. I retain all my statutory rights. 
At the end of the trial, I may be informed of the overall results through the investigating doctor of the trial. 
I have been informed by the explanatory notice that my blood and/or semen samples may be used at the end of the trial 
for other research on HIV infection, unless I oppose this. 
 
    I authorize the storage of my blood samples for             I oppose the storage of my blood samples for         
future research.  
 
 
 
 
 
future research.  
They will be destroyed at the end of the trial. 
I agree to participate in the DXA substudy "Distribution of fat mass and bone mineral density" 
 
I agree to participate in the seminal sub-study "Measurement of RNA-HIV viral load in semen"  
 
    I authorize the storage of my sperm samples for           I oppose the storage of my sperm samples for     
further research. 
 
 
 
 
 
future research.  
They will be destroyed at the end of the trial. 
  
I freely agree to participate in this test under the conditions   
specified in the information notice 
           
 Date └─┴─┘└─┴─┘└─┴─┴─┴─┘  
  
  
Participant’s signature  
  


ANRS 163 ETRAL Trial                          Consent Form                             
└─┴─┘└─┴─┴─┘└─┴─┴─┘└─┴─┴─┴─┘  
                                                                                                                                                         Country         Center No.    Patient No.         Letter 
code 
 
I, the undersigned, Dr/Pr ……………………………………..  
certify that I have communicated to the participant all the useful information relating to this trial, that I have answered his 
questions and obtained his consent.  
  
Date└─┴─┘└─┴─┘└─┴─┴─┴─┘  
Write or place a label  
    
Name of the unit:  
Address:  
Telephone:   
Doctor’s signature 
INVESTIGATOR COPY (a copy is made for the sponsor) 
  
1/1  
    
Version 2.0 dated 03/18/2015, approved by the CPP on 05/15/2015  
Sponsor: Inserm-ANRS                  Coordinating investigator: Prof. Christine Katlama  
Ms, Mr (first and last name)  
  
I certify:  
having received information notice version 2.0 dated 03/18/2015, that I have had the opportunity to ask all the 
questions I wished on the nature, objectives, potential risks, and constraints relating to my participation in this trial, 
 and that I have had sufficient time to reflect between receiving this information and giving my consent. 
 
I understand the constraints (more frequent visits, numerous blood samples) and the benefits linked to my participation in 
this trial, which will last approximately 2 years. 
I understand that I am free to discontinue my participation in this trial at any time, without having to explain why, but I will 
do my best to inform the doctor. This will not affect the quality of my subsequent care. 
I have been reassured that the decisions that are necessary for my health will be made at all times, in accordance with 
the state of knowledge on HIV. 
I have noted that blood samples and a semen sample (if I participate in the semen substudy) will be taken during the trial 
and stored anonymously. They will make it possible to carry out the planned analyses for this trial. 
I accept that the data recorded during this trial will be collected, processed, and computerized. I understand that the right 
of access laid down in the modified law of January 6, 1978 relating to data processing, files, and freedoms, can be 
exercised at any time, through the doctor following me in the trial, and that I can exercise my right of rectification and 
opposition. 
I accept that the scientists involved in this trial, and the individuals authorized by the health authorities in France and 
abroad, may have access to the information, under strict conditions of confidentiality. 
My consent in no way relieves the organizers of the trial of their responsibilities. I retain all my statutory rights. 
At the end of the trial, I may be informed of the overall results through the investigating doctor of the trial. 
I have been informed by the explanatory notice that my blood and/or semen samples may be used at the end of the trial 
for other research on HIV infection, unless I oppose this. 
 
    I authorize the storage of my blood samples for             I oppose the storage of my blood samples for         
future research.  
 
 
 
 
 
future research.  
They will be destroyed at the end of the trial. 


ANRS 163 ETRAL Trial                          Consent Form                             
└─┴─┘└─┴─┴─┘└─┴─┴─┘└─┴─┴─┴─┘  
                                                                                                                                                         Country         Center No.    Patient No.         Letter 
code 
 
I agree to participate in the DXA substudy "Distribution of fat mass and bone mineral density" 
 
I agree to participate in the seminal sub-study "Measurement of RNA-HIV viral load in semen"  
 
    I authorize the storage of my sperm samples for           I oppose the storage of my sperm samples for     
further research. 
 
 
 
 
 
future research.  
They will be destroyed at the end of the trial. 
  
I freely agree to participate in this trial under the conditions   
specified in the information notice 
           
Date └─┴─┘└─┴─┘└─┴─┴─┴─┘  
  
  
Participant’s signature  
 
  
I, the undersigned, Dr/Pr ……………………………………..  
certify that I have communicated to the participant all the useful information relating to this trial, that I have answered 
his/her questions and obtained his/her consent.  
  
Date └─┴─┘└─┴─┘└─┴─┴─┴─┘  
Write or place a label  
    
Name of the unit:  
Address:  
Telephone:   
Doctor’s signature  
CMG Inserm UMR S 1136 COPY 
    
Version 2.0 dated 03/18/2015, approved by the CPP on 05/15/2015  
Sponsor: Inserm-ANRS                  Coordinating investigator: Prof. Christine Katlama   
Ms, Mr 
(first and last name)  
  
I certify:  
having received information notice version 2.0 dated 03/18/2015, that I have had the opportunity to ask all the 
questions I wished on the nature, objectives, potential risks, and constraints relating to my participation in this trial, 
 and that I have had sufficient time to reflect between receiving this information and giving my consent. 
 
I understand the constraints (more frequent visits, numerous blood samples) and the benefits linked to my participation in 
this trial, which will last approximately 2 years. 
I understand that I am free to discontinue my participation in this trial at any time, without having to explain why, but I will 
do my best to inform the doctor. This will not affect the quality of my subsequent care. 
I have been reassured that the decisions that are necessary for my health will be made at all times, in accordance with 
the state of knowledge on HIV. 
I have noted that blood samples and a semen sample (if I participate in the semen substudy) will be taken during the trial 
and stored anonymously. They will make it possible to carry out the planned analyses for this trial. 
I accept that the data recorded during this trial will be collected, processed, and computerized. I understand that the right 
of access laid down in the modified law of January 6, 1978 relating to data processing, files, and freedoms, can be 
exercised at any time, through the doctor following me in the trial, and that I can exercise my right of rectification and 
opposition. 


ANRS 163 ETRAL Trial                          Consent Form                             
└─┴─┘└─┴─┴─┘└─┴─┴─┘└─┴─┴─┴─┘  
                                                                                                                                                         Country         Center No.    Patient No.         Letter 
code 
 
I accept that the scientists involved in this trial, and the individuals authorized by the health authorities in France and 
abroad, may have access to the information, under strict conditions of confidentiality. 
My consent in no way relieves the organizers of the trial of their responsibilities. I retain all my statutory rights. 
At the end of the trial, I may be informed of the overall results through the investigating doctor of the trial. 
I have been informed by the explanatory notice that my blood and/or semen samples may be used at the end of the trial 
for other research on HIV infection, unless I oppose this. 
 
    J’autorise la conservation de mes échantillons      Je 
* 
 
 
 
 
I authorize the storage of my blood samples for             I oppose the storage of my blood samples for           
future research.  
 
 
 
 
 
future research.  
They will be destroyed at the end of the trial. 
I agree to participate in the DXA substudy "Distribution of fat mass and bone mineral density" 
 
I agree to participate in the semen substudy "Measurement of HIV-RNA viral load in semen"  
 
    I authorize the storage of my sperm samples for           I oppose the storage of my sperm samples for     
further research. 
 
 
 
 
 
future research.  
They will be destroyed at the end of the trial. 
 
 
 I freely agree to participate in this trial under the conditions 
   specified in the information notice  
 
Date└─┴─┘└─┴─┘└─┴─┴─┴─┘  
           
  
  
Participant’s signature  
  
I, the undersigned, Dr/Prof. ……………………………………..  
certify that I have communicated to the participant all the useful information relating to this trial, that I have answered 
his/her questions and obtained his/her consent.  
  
Date └─┴─┘└─┴─┘└─┴─┴─┴─┘  
Write or place a label  
    
Name of the unit:  
Address:  
Telephone:   
Doctor’s signature  
  
PATIENT’S COPY (attached to the notice) 


 
90  
 
 
Appendix A6: ANRS scale to grade the severity of adverse events in 
adults 
 
 
A.N.R.S 
 
ANRS scale to grade the severity of adverse events in adults 
 
Version n° 1.0    4 November 2008 
 
This severity scale is a working guide intended to harmonise evaluation and grading practices for 
symptomatology in ANRS biomedical research protocols. 
 
In practice, the items evaluated are grouped according to the system taking the form of a non-
exhaustive symptomatic table (and not a classification of pathologies). Our choices focus on the 
most frequently observed clinical and biological signs or those whose monitoring is essential to 
ensure the protection of the subjects participating in the research. 
 
For abnormalities NOT found elsewhere on the Table, refer to the scale below to estimate grade of 
severity: 
 
 
GRADE 1 
Mild 
Mild or transient discomfort, without limitation of normal daily 
activities; no medical intervention or corrective treatment required. 
 
GRADE 2 
Moderate 
Mild to moderate limitation of normal daily activities; minimal medical 
intervention or corrective treatment required. 
 
GRADE 3 
Severe 
Marked limitation of normal daily activities; medical intervention and 
corrective treatment required, possible hospitalisation. 
GRADE 4 
Life-threatening 
Severe limitation of normal daily activities; medical intervention and 
corrective treatment required, almost always in a hospital setting. 
 
Abbreviations used in the table: 
ULN 
: Upper Limit of Normal 
RBC 
: Red Blood Cells 
FEV1  
: Forced Expiratory Volume in one second  
EMG 
: Electromyogram 
Prothrombin Time (%) 
: Corresponds to Quick time (sec) 
aPTT 
: activated Partial Thromboplastin Time 
 
This document is the exclusive property of the ANRS and must not be modified or published 
without the authors’ prior consent. Any use is subject to prior consent from the ANRS. Any 
questions should be addressed to pharmacovigilance@anrs.fr. 
Please note that this scale was devised for use in HIV, HCV or HBV related pathologies.              
 
 
 
 
 
 
 
 
 
 


 
91  
 
 
ANRS scale to grade the severity of adverse events in adults (version n° 1.0      4 November 2008) 
 
GRADES 
GRADE 1 
Mild 
GRADE 2 
Moderate 
GRADE 3 
Severe 
GRADE 4 
Life-threatening 
HAEMATOLOGY 
1 
Haemoglobin (g/dl) 
8.0 – 9.4  
7.0 – 7.99 
6.5 – 6.99 
< 6.5 
2 
Leucocytes (/mm3) 
3 000 – 3 900 
2 000 – 2 999 
1 000 – 1 999 
< 1 000 
3 
Neutrophils (/mm3) 
1 000 – 1 500 
750 – 999 
500 – 749 
< 500 
4 
Platelets (/mm3) 
75 000 – 99 000 
50 000 – 74 999 
20 000 – 49 999 
<20 000 or generalized 
petechiae 
5 
Prothrombin Time (%) 
/ 
45 – ≤ 70 
20 – < 45 
< 20 
6 
aPTT 
1.0 – 1.66 x ULN 
> 1.66 – 2.33 x ULN 
> 2.33 – 3.0 x ULN 
> 3.0 x ULN 
BIOCHEMISTRY 
Hepatic and pancreatic biochemistry 
7 
AST (SGOT) (UI/l) 
1.25 – 2.50 x ULN 
> 2.50 – 5.0 x ULN 
> 5.00 – 10.0 x ULN 
> 10.0 x ULN 
8 
ALT (SGPT) (UI/l) 
1.25 – 2.50 x ULN 
> 2.50 – 5.0 x ULN 
> 5.00 – 10.0 x ULN 
> 10.0 x ULN 
9 
GAMMA GT (UI/l) 
1.25 – 2.50 x ULN 
> 2.50 – 5.0 x ULN 
> 5.00 – 10.0 x ULN 
> 10.0 x ULN 
10 
Alkaline phosphatase (UI/l) 
1.25 – 2.50 x ULN 
> 2.50 – 5.0 x ULN 
> 5.00 – 10.0 x ULN 
> 10.0 x ULN 
11 
Hyperbilirubinaemia (µmol/l) 
1.25 – 2.50 x ULN 
> 2.50 – 5.0 x ULN 
> 5.00 – 10.0 x ULN 
> 10.0x ULN 
12 
Amylasaemia (UI/l) /  
Lipasaemia (UI/l)/ 
Pancreatitis 
≥1.25 – 2.50 x ULN 
> 2.50 – 5.0 x ULN 
> 3.0 x ULN with acute 
abdominal pain and/or 
imaging indicating acute 
pancreatitis. 
> 3.0 x ULN  
with abdominal pain and 
signs of shock. 
13 
CPK (UI/l) 
1.25 – 2.50 x ULN 
> 2.50 – 5.0 x ULN 
> 5.00 – 10.0 x ULN  
> 10.0 x ULN 
Lipid status 
14 
Hypertriglyceridaemia (mmol/l) 
/ 
4.50 – 8.59 
8.60 – 13.70 
> 13.70 
15 
Hypercholesterolaemia (mmol/l) 
>ULN –7.75 
>7.75 – 10.34 
>10.34 – 12.92 
>12.92 
 


 
92  
 
 
ANRS scale to grade the severity of adverse events in adults (version n° 1.0      4 November 2008) 
 
GRADES 
GRADE 1 
Mild 
GRADE 2 
Moderate 
GRADE 3 
Severe 
GRADE 4 
Life-threatening 
Electrolytes / Evaluation of renal function / Metabolism 
16 
Hyponatraemia (mEq/l) 
130 – 135 
123 – 129 
116 – 122 
<116 
17 
Hypernatraemia (mEq/l) 
146 – 150 
151 – 157 
158 – 165 
>165 
18 
Hypokalaemia (mEq/l) 
3.2 – 3.4 
2.8 – 3.1 
2.5 – 2.7 
<2.5 
19 
Hyperkalaemia (mEq/l) 
5.6 – 6.0 
6.1 – 6.5 
6.6 – 7.0 
>7.0 
20 
Bicarbonate (mEq/l or mmol/l) 
20.0 – 24.0 
15.0 – 19.99 
10.0 – 14.99  
< 10.0  
21 
Creatininaemia (µmol/l) 
1.0 – 1.50 x ULN 
> 1.50 – 3.0 x ULN 
> 3.0 – 6.0 x ULN 
6.0 x ULN or dialysis required 
22 
Blood Urea Nitrogen (UI/l) 
1.25 – 2.5 x ULN 
2.6 – 5.0 x ULN 
5.1 – 10 x ULN 
> 10 x ULN 
23 
Hypocalcaemia (mmol/l) 
1.95 – 2.10 
1.75 – 1.94 
1.50 – 1.74 
< 1.50 
24 
Hypercalcaemia (mmol/l) 
2.65 – 2.87 
2.88 – 3.13 
3.14 – 3.38 
> 3.38 
25 
Hypophosphataemia (mg/dl) 
2.0 – 2.4 
1.5 – 1.9 
1.0 – 1.4 
<1.0 
26 
Hyperuricaemia (µmol/l) 
1.25 – 2.0 x ULN 
> 2.0 – 5.0 x ULN 
> 5.0 – 10.0 x ULN 
> 10.0 x ULN 
27 
Hypoglycaemia (mmol/l) 
3.1 – 3.6 
2.2 – 3.0 
1.7 – 2.1 
< 1.7 
28 
Hyperglycaemia (mmol/l) 
6.1 – 7.0 
> 7.0 – 16.5 
> 16.5 without ketosis. 
See diabetes 
Item no. 52 (grade 4) 
29 
Hyperlactataemia (mmol/l)  
(venous blood sample) 
2.0 – 2.99* 
3.0 – 3.99** 
4.0 – 4.99** 
≥ 5.0*** 
Urinalysis 
30 
Proteinuria (dipstick) 
+ 
++ 
≥ +++ 
Nephrotic syndrome 
31 
Haematuria. 
≥ 80 RBC/µl  
(dipstick). 
≥ 200 RBC/µl 
(dipstick). 
Macroscopic with or without 
clots. 
Obstructive or requiring a 
blood transfusion. 
* 
Lactataemia – GRADE 1: a confirmatory test is necessary within 8 to 10 days 
 
** 
Lactataemia – GRADE 2, 3: a confirmatory test is necessary within 24 hours. 
*** 
Lactataemia – GRADE 4: a confirmation test is necessary immediately. 


 
93  
 
 
 
ANRS scale to grade the severity of adverse events in adults (version n° 1.0      4 November 2008) 
 
GRADES 
GRADE 1 
Mild 
GRADE 2 
Moderate 
GRADE 3 
Severe 
GRADE 4 
Life-threatening 
Gastro-intestinal/hepatic/pancreatic abnormalities 
32 
Nausea. 
Transient,  
normal diet. 
Restricted diet for less than 3 
days. 
Restricted diet for more than 3 
days. 
Liquid only diet.  
Hospitalization required. 
33 
Vomiting. 
Transient:  
2 – 3 episodes / day or 
duration ≤ 1 week. 
Repeated:  
4 – 5 episodes / day or 
duration > 1 week. 
Solid/liquid vomiting for 24 h. 
Orthostatic hypotension. 
Perfusion required. 
Hospitalization for 
hypovolemic shock. 
34 
Diarrhoea. 
Transient,  
3 – 4 stools / day,  
diarrhoea ≤ 1 week. 
Persistent,  
5-7 stools / day, 
diarrhoea > 1 week.  
> 7 stools/day or requiring 
perfusion.  
Bloody stools. 
Hospitalization,  
Hypovolemic shock, 
perfusion. 
35 
Constipation. 
/ 
Moderate abdominal pain,  
78 h without stools. 
Treatment required. 
Meteorism. 
Requiring disimpaction or 
hospital treatment. 
Meteorism with vomiting or 
occlusion. 
36 
Dysphagia. 
Mild discomfort when 
swallowing. 
Difficulty in swallowing but 
food intake possible. 
Inability to swallow solids. 
Inability to swallow liquids, 
perfusion required. 
37 
Oesophagitis. 
Pyrosis occurring less than 
once a week 
Pyrosis occurring at least 
once a week but relieved by 
PPIs* 
Pyrosis occurring at least 
once a week but not relieved 
by PPIs* 
Food intolerance and vomiting 
*PPIs: proton pump inhibitors 
 
 
 
 
 


 
94  
 
 
ANRS scale to grade the severity of adverse events in adults (version n° 1.0      4 November 2008) 
 
 
GRADES 
GRADE 1 
Mild 
GRADE 2 
Moderate 
GRADE 3 
Severe 
GRADE 4 
Life-threatening 
Respiratory abnormalities 
38 
Bronchospasm. 
Transient,  
no treatment,  
FEV1 70 % - < 80 %. 
Permanent,  
Improvement under 
bronchodilation  
FEV1 50 % - < 70 %. 
Persistent under 
bronchodilation.  
FEV1 25 % - < 50 %. 
Cyanosis,  
FEV1 < 25 % 
intubation. 
39 
Dyspnoea 
Dyspnoea upon exertion. 
Dyspnoea during normal daily 
activities. 
Dyspnoea at rest. 
Dyspnoea requiring 
respiratory assistance. 
Muscular abnormalities 
40 
Myalgia 
(excluding injection site). 
Mild myalgia for less than 4 
weeks. Not requiring 
analgesic treatment. 
Presence of one of the 
following symptoms:  
1 – Mild to moderate myalgia 
for more than 4 weeks and/or 
which may require treatment 
with level 1* analgesics. 
2 – Predominance of 
difficulties upon exertion 
(difficulty in climbing stairs or 
rising from a sitting position).  
Can walk without assistance. 
Optional confirmation through 
the identification of biological 
(CPK), electromyographical 
(EMG) or histological  
(muscular biopsy) 
abnormalities. 
Presence of one of the 
following symptoms: 
 1 – Moderate to severe 
myalgia for more than 4 
weeks requiring treatment 
with level I/II* analgesics. 
2 – Assistance required for 
walking and normal daily 
activities.  
Paraclinical confirmation 
recommended (CPK, EMG 
and/or muscular biopsy). 
Presence of one of the 
following symptoms:  
1 – Severe myalgia not 
related to exertion requiring 
treatment with level II/III* 
analgesics. 
2 – Muscular weakness 
making walking impossible 
without assistance. 
3 – Acute rhabdomyolysis with 
muscular necrosis and 
oedema. 
4 – Acute rhabdomyolysis with 
electrolytic disturbances and 
renal insufficiency. 
Paraclinical confirmation 
required  
(biology, EMG and/or 
muscular biopsy). 
* Level I analgesics 
: Peripheral analgesics (paracetamol and/or salicylics or non-steroid anti-inflammatory drugs) ; 
* Level II analgesics 
: Weak opiates (codeine, dextropropoxyphene), morphinic agonists-antagonists (buprenorphine, nalbuphine) ; 
* Level III analgesics 
: Morphine. 
 


 
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GRADES 
GRADE 1 
Mild 
GRADE 2 
Moderate 
GRADE 3 
Severe 
GRADE 4 
Life-threatening 
Cardiovascular abnormalities
41 Arterial 
hypertension. 
Transient or permanent. 
Increased blood pressure ≤ 20 
mmHg and systolic BP 140-159 or 
diastolic BP 90-99.  
Permanent. 
Increased blood pressure > 20 
mmHg and systolic BP 160-179 or 
diastolic BP 100-109.  
Permanent. 
Systolic BP  180 or diastolic BP > 110 
Malignant or accelerated 
arterial hypertension.  
42 Orthostatic 
hypotension. 
Decreased systolic blood 
pressure  
≤ 20 mmHg in orthostatic 
position. No treatment. 
Decreased systolic blood pressure 
> 20 mmHg, durable but corrected 
with liquid intake per os. 
Perfusion required. 
Hypovolemic shock requiring 
hospitalization. 
43 
Ventricular 
cardiac rhythm 
disorders. 
/ 
Isolated ventricular 
extrasystoles, no treatment, 
symptomatic or asymptomatic. 
Recurrent, persistent or symptomatic 
cardiac rhythm disorders. Treatment 
required. 
Dysrhythmia requiring 
hospitalization. 
44 Prolongation of 
the QT interval. 
/ 
Man: >450 and < 500 ms 
Woman: >470 and <500 ms 
>500ms 
>500 ms with clinical 
symptoms (ventricular rhythm 
disorders, syncope, torsade de pointes) 
45 Cardiac 
ischaemia. 
/ 
Atypical pain under exploration.
Appearance of angina upon exertion, 
controlled with treatment. 
Myocardial infarction,  
unstable angina, 
preinfarction syndrome. 
46 Pericarditis. 
Chance discovery of a small 
effusion during ultrasound scan 
Moderate effusion with few 
symptoms. No treatment or 
intervention deemed necessary 
for the time being. 
Moderate or significant symptomatic 
effusion but without tamponade. Treatment 
required and hospitalization to be 
considered. 
Tamponade. 
Hospitalization and 
intervention required. 
47 Stroke. 
/ 
/ 
Transient Ischemic Attack 
(regressive focal neurological syndrome within 24 h). 
Cerebrovascular accident 
non-regressive within 24 h. 
48 
Peripheral 
arterial 
embolism. 
/ 
/ 
/ 
Peripheral arterial embolism. 
Hospitalization.  
Adapted treatment. 
49 
Deep vein 
thrombosis and/or 
pulmonary 
/ 
/ 
Deep vein thrombosis. 
Anticoagulant treatment. 
Hospitalization to be considered. 
Pulmonary embolism. Adequate 
hospitalization and treatment. 


 
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embolism. 


 
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GRADES 
GRADE 1 
Mild 
GRADE 2 
Moderate 
GRADE 3 
Severe 
GRADE 4 
Life-threatening 
Endocrine abnormalities 
50 
Hyperthyroidism. 
Infraclinical 
hyperthyroidism. Low TSH. 
Normal free T3 and T4. 
Moderate, non-complicated 
thyrotoxicosis. 
Treatment required. 
Malignant exophtalmia. 
Cardiac arrhythmia. 
Myopathy. 
Thyrotoxic crisis and/or 
cardiac insufficiency. 
51 
Hypothyroidism. 
Infraclinical 
hypothyroidism. Increased 
TSH but <12 mU/l. Normal 
free T4.  
Simple hypothyroidism without 
complications. Treatment 
required. 
Severe hypothyroidism with 
multiple clinical symptoms. 
Urgent treatment. 
Hospitalization to be 
considered. 
Myxoedematous coma. 
52 
Diabetes/hyperglycaemia. 
Moderate fasting 
hyperglycaemia between 
6.1 and 7 mmol/l. No 
immediate treatment 
required. 
Fasting glycaemia: > 7 mmol/l. 
Special diet required, possibly 
supplemented with oral 
antidiabetics. 
Fasting glycaemia:>16.5 mmol/l 
on an empty stomach, with or 
without clinical symptoms. 
Insulin therapy required. 
Ketoacidosis or 
hyperosmolarity (>27.8 
mmol/l without acidosis). 
Cutaneous abnormalities 
53 
Cutaneous and/or mucosal 
eruptions. 
Erythaema,  
Moderate pruritis. 
Extended maculopapular 
eruption, with or without pruritis.
Extended papulovesicular or 
oozing eruption. 
Palpable purpura  
(suggestive of vasculitis). 
Polymorphous erythaema. 
Small-size cutaneous or 
mucous ulcerations. 
Any blistering cutaneous 
and/or mucosal lesions (Lyell 
or  
Stevens-Johnson). 
Febrile erythrodermia, 
whether or not associated 
with other signs indicative of 
hypersensitivity. 
Cutaneous necrosis 
requiring surgical excision. 
54 
Symptoms of immediate 
hypersensitivity, with or without 
cutaneous symptoms.  
/ 
Acute localised urticaria. 
Giant urticaria,  
Quincke’s oedema. 
Anaphylactic shock. 


 
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GRADES 
GRADE 1 
Mild 
GRADE 2 
Moderate 
GRADE 3 
Severe 
GRADE 4 
Life-threatening 
Neurological abnormalities 
55 
Wakefulness / sleep 
disorders. 
Minor attention and concentration 
impairment. 
Diurnal somnolence and/or 
difficulty falling asleep and/or 
night time awakening, mental 
activity decreased, 
obnubilation. 
Sleep-wake cycle modification 
or insomnia requiring 
treatment or change in dream 
content. Obvious confusional 
syndrome with temporal 
disorientation. 
Sleep-wake cycle 
disorganisation not 
responding to treatment. 
Dreamlike confusional 
syndrome, coma and/or 
convulsion. 
56 
Psychiatric disorders.
Minor anxiety. 
Anxiety requiring treatment or 
moderate depression. 
Major anxiety or confirmed 
depressive episode requiring 
treatment. 
Acute psychosis requiring 
hospitalization, including 
suicidal ideation, manic 
state, hallucinatory delusion. 
57 
Cephalalgia. 
Intermittent, no treatment. 
Requiring level I* analgesics. 
Requiring at least level II* 
analgesics. 
Not responsive to level III* 
analgesics. 
58 
Paraesthesia. 
Paraesthesia, mild pain,  
no treatment. 
Paresthesia, permanent pain of 
moderate intensity, requiring 
level I* analgesics. 
Paraesthesia, permanent pain 
of severe intensity, requiring 
at least level II* analgesics. 
Unbearable pain resulting in 
disability, restricted activity 
despite administration of 
level III* analgesics. 
59 
Motor deficiency. 
Subjective feeling of weakness without 
objective impairment,  
no reflex changes. 
Distal motor deficiency,  
moderate functional impairment 
or reflex changes. 
Marked motor deficiency 
interfering with normal daily 
activities. 
Confined to bed or a 
wheelchair because of motor 
deficiency. 
60 
Difficulty controlling 
movement. 
Occasional clumsiness, mild 
coordination difficulties. 
Tremor or dyskinaesia or 
dysmetria, or dysarthria, 
moderate limitation of normal 
daily activities. 
Upper or lower limbs ataxia or 
abnormal movements, 
limitation of normal daily 
activities. 
Inability to stand up. Total 
dependence. 
61 
Sensory loss. 
Mild sensory loss, regardless of mode 
and distribution (focal or symmetric). 
Moderate sensory loss. 
Severe sensory loss. 
Extensive sensory loss 
involving the trunk and four 
limbs. 
* Level I analgesics 
: Peripheral analgesics (paracetamol and/or salicylics or non-steroid anti-inflammatory drugs) ; 
* Level II analgesics 
: Weak opiates (codeine, dextropropoxyphene), morphinic agonists-antagonists (buprenorphine, nalbuphine) ; 
* Level III analgesics 
: Morphine. 
 


 
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ANRS scale to grade the severity of adverse events in adults (version n° 1.0      4 November 2008) 
 
GRADES 
GRADE 1 
Mild 
GRADE 2 
Moderate 
GRADE 3 
Severe 
GRADE 4 
Life-threatening 
Miscellaneous 
62 
Fever (oral temperature, °C) 
for more than 12 h. 
37.7 – 38.9 
39 – 39.5 
39.6 – 40.5 
> 40.5  
63 
Renal colic. 
Spontaneous regression of 
symptoms.  
Pain not requiring treatment. 
Colic requiring medical 
treatment. 
Obstructive syndrome, does 
not disappear spontaneously. 
/ 
64 
Fatigue. 
Normal daily activities reduced by 
less than 25% for less than 48 h. 
Normal daily activities 
reduced by 25 – 50 % for 
more than 48 h. 
Normal daily activities 
reduced by more than 50%, 
cannot work for more than  
48 h. 
Unable to care for self. 
Assistance required for 
normal daily activities. 
65 
Arthritis / Arthralgia. 
Arthralgia. 
Arthralgia, with or without 
articular effusion or with 
moderate functional 
impairment. 
Marked arthritis with or 
without effusion or with severe 
functional impairment. 
/ 
66 
Ocular disorders. 
Conjunctival hyperaemia. 
Moderate pain.  
Conjunctivitis. 
Decreased visual acuity. 
Uveitis. 
Severe pain. Glaucoma. 
/ 
 


 
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ANRS Vaccine trials 
ANRS scale to grade the severity of adverse events in adults (version n° 1.0      4 November 2008) 
 
 
 
 
GRADES 
GRADE 1 
Mild 
GRADE 2 
Moderate 
GRADE 3 
Severe 
GRADE 4 
Life-threatening 
1 
Erythaema, oedema, nodule 
(induration). 
< 15 x 15 cm. 
≥ 15 x 15 cm. 
Ulceration or superinfection or 
superficial phlebitis. 
Skin necrosis  
2 
Pain, functional impairment. 
Mild, no limitation of 
movements. 
Pain inducing partial mobility 
impairment. 
Pain inducing functional 
impotence. 
/ 


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Appendix A7: Recommendations for blood pressure measurement in 
humans and experimental animals 
 
AHA Scientific Statement 
Circulation. 2005; 111: 697-716. 
RECOMMENDATIONS FOR BLOOD PRESSURE MEASUREMENT IN 
HUMANS AND EXPERIMENTAL ANIMALS 
Part 1: Blood Pressure Measurement in Humans: A Statement for 
Professionals From the Subcommittee of Professional and 
Public Education of the American Heart Association 
Council on High Blood Pressure Research 
Thomas G. Pickering, MD, DPhil; John E. Hall, PhD; Lawrence J. Appel, MD; Bonita E. Falkner, 
MD; John Graves, MD; Martha N. Hill, RN, PhD; Daniel W. Jones, MD; Theodore Kurtz, MD; 
Sheldon G. Sheps, MD; Edward J. Roccella, PhD, MPH 
 Abstract 
Accurate measurement of blood pressure is essential to classify individuals, to ascertain blood 
pressure– related risk, and to guide management. The auscultatory technique with a trained observer 
and mercury sphygmomanometer continues to be the method of choice for measurement in the office, 
using the first and fifth phases of the Korotkoff sounds, including in pregnant women. The use of mercury 
is declining, and alternatives are needed. Aneroid devices are suitable, but they require frequent 
calibration. Hybrid devices that use electronic transducers instead of mercury have promise. The 
oscillometric method can be used for office measurement, but only devices independently validated 
according to standard protocols should be used, and individual calibration is recommended. They have 
the advantage of being able to take multiple measurements. Proper training of observers, positioning of 
the patient, and selection of cuff size are all essential. It is increasingly recognized that office 
measurements correlate poorly with blood pressure measured in other settings, and that they can be 
supplemented by self-measured readings taken with validated devices at home. There is increasing 
evidence that home readings predict cardiovascular events and are particularly useful for monitoring the 
effects of treatment. Twenty-four-hour ambulatory monitoring gives a better prediction of risk than office 
measurements and is useful for diagnosing white-coat hypertension. There is increasing evidence that a 
failure of blood pressure to fall during the night may be associated with increased risk. In obese patients 
and children, the use of an appropriate cuff size is of paramount importance.  
Key Words: hypertension ; ambulatory monitoring ; self-measurement 


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Ten years have passed since the last version of the American Heart Association (AHA) blood pressure 
measurement recommendations, during which time there have been major changes in the ways by which blood 
pressure is measured in clinical practice and research; hence, this document is a radical revision of previous 
versions. Blood pressure determination continues to be one of the most important measurements in all of clinical 
medicine and is still one of the most inaccurately performed. Hypertension is a major risk factor for coronary heart 
disease, stroke, and renal failure, and affects approximately one-third of the American population. The latest version 
of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC) 
recommendations has drawn attention to the condition of “ prehypertension,”  that is, people with blood pressures 
at the high end of the normal range, which applies to another one-quarter of the adult population. The target blood 
pressure for patients using antihypertensive treatment has recently been lowered for those with diabetes or renal 
disease.1 Thus, it is becoming increasingly important to be able detect small differences in blood pressure.  
The gold standard for clinical blood pressure measurement has always been readings taken by a trained health 
care provider using a mercury sphygmomanometer and the Korotkoff sound technique, but there is increasing 
evidence that this procedure may lead to the misclassification of large numbers of individuals as hypertensive and 
also to a failure to diagnose blood pressure that may be normal in the clinic setting but elevated at other times in 
some individuals. There are 3 main reasons for this: (1) inaccuracies in the methods, some of which are avoidable; 
(2) the inherent variability of blood pressure; and (3) the tendency for blood pressure to increase in the presence of 
a physician (the so-called white coat effect).  
Numerous surveys have shown that physicians and other health care providers rarely follow established guidelines 
for blood pressure measurement; however, when they do, the readings correlate much more closely with more 
objective measures of blood pressure than the usual clinic readings. It is generally agreed that conventional clinic 
readings, when made correctly, are a surrogate marker for a patient’ s true blood pressure, which is conceived as 
the average level over prolonged periods of time, and which is thought to be the most important component of blood 
pressure in determining its adverse effects. Usual clinic readings give a very poor estimate of this, not only because 
of poor technique but also because they typically only consist of 1 or 2 individual measurements, and the beat-to-
beat blood pressure variability is such that a small number of readings can only give a crude estimate of the 
average level.  
There are potentially 3 measures of blood pressure that could contribute to the adverse effects of hypertension. The 
first is the average level, the second is the diurnal variation, and the third is the short-term variability. At the present 
time, the measure of blood pressure that is most clearly related to morbid events is the average level, although 
there is also evidence accumulating that suggests that hypertensive patients whose pressure remains high at night 
(nondippers) are at greater risk for cardiovascular morbidity than dippers.2 Less information is available for defining 
the clinical significance of blood pressure variability, although it has been suggested that it is a risk factor for 
cardiovascular morbidity.  
The recognition of these limitations of the traditional clinic readings has led to 2 parallel developments: first, 
increasing use of measurements made out of the clinic, which avoids the unrepresentative nature of the clinic 
setting and also allows for increased numbers of readings to be taken; and second, the increased use of automated 
devices, which are being used both in and out of the office setting. This decreased reliance on traditional readings 
has been accelerated by the fact that mercury is being banned in many countries, although there is still uncertainty 


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regarding what will replace it. The leading contenders are aneroid and oscillometric devices, both of which are being 
used with increasing frequency but have not been accepted as being as accurate as mercury.  
Epidemiology of Hypertension 
1.1.1 
Overview 
Blood pressure is a powerful, consistent, and independent risk factor for cardiovascular disease and renal disease. 
According to the National Health And Nutrition Examination Survey (NHANES), at least 65 million adult Americans, 
or nearly one-third of the US adult population, have hypertension, defined as a systolic blood pressure ≥140 mm 
Hg, diastolic blood pressure ≥90 mm Hg, and/or current use of antihypertensive medication.3 Another one-quarter 
of US adults have blood pressure in the “ prehypertension”  range, a systolic blood pressure of 120 to 139 mm Hg 
or diastolic blood pressure of 80 to 89 mm Hg, ie, a level above normal yet below the hypertensive range.4 The 
prevalence of hypertension rises progressively with age, such that more than half of all Americans aged 65 years or 
older have hypertension.  
Data from numerous observational epidemiological studies provide persuasive evidence of the direct relationship 
between blood pressure and cardiovascular disease. In a recent meta-analysis that aggregated data across 61 
prospective observational studies that together enrolled 958 074 adults,5 there were strong, direct relationships 
between average blood pressure and vascular mortality. These relationships were evident in middle-aged and 
older-aged individuals. Importantly, there was no evidence of a blood pressure threshold, that is, cardiovascular 
mortality increased progressively throughout the range of blood pressure, including the prehypertensive range. It 
has been estimated that ≈15% of blood pressure– related deaths from coronary heart disease occur in individuals 
with blood pressure in the prehypertensive range.6 
Individual trials and meta-analyses of clinical trials have conclusively documented that antihypertensive drug 
therapy reduces the risk of cardiovascular events in hypertensive individuals. Such evidence provides strong 
evidence for current efforts to identify and treat individuals with hypertension and for parallel efforts to identify 
individuals with prehypertension, who are at risk for hypertension and blood pressure– related morbidity.  
1.1.2 
Systolic, Diastolic, and Pulse Pressure 
Several dimensions of blood pressure are associated with an increased risk of vascular disease. Clinic-based 
measurements that predict vascular disease include systolic and diastolic blood pressure, as well as mean arterial 
pressure and pulse pressure. Several studies have attempted to tease apart the relative importance of these 
measurements.7,8 Despite evolving interest in pulse pressure, the best available evidence still supports the use of 
systolic and diastolic blood pressures as a means to classify individuals.  
1.1.3 
Importance of Blood Pressure Variability 
It has been suggested that blood pressure variability may be an independent risk factor for cardiovascular morbidity, 
on the grounds that biological materials are more susceptible to damage by changes of pressure than steady-state 
levels. There are many different ways of expressing blood pressure variability, ranging from beat-to-beat changes9 
to long-term changes between office visits.10 Although there have been some studies supporting a pathological role 
of increased variability,10,11 it remains unclear to what extent such adverse effects are a manifestation of more 
extensive target organ damage impairing the baroreflex regulation of blood pressure (and hence increasing blood 
pressure variability) as opposed to a direct effect of the variability itself.  


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“ Labile hypertension”  is a term that has been used in the past to describe blood pressure that is unusually 
variable, but the wider use of out-of-office monitoring has shown that lability of blood pressure is the rule rather than 
the exception.  
Classification/Subtypes of Hypertension 
1.1.4 
Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and 
Treatment of High Blood Pressure Classification  
The health risks attributable to increasing blood pressure in adults are continuous, beginning at 115/75 mm Hg.12 
Definitions have been established based on these risks and on the demonstrated net health benefits of blood 
pressure reduction. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and 
Treatment of High Blood Pressure1 (JNC 7) has continued the definition of hypertension beginning at 140/90 mm 
Hg for adults aged 18 or older. The classification is based on the average of ≥2 seated blood pressure 
measurements, properly measured with well-maintained equipment, at each of ≥2 visits to the office or clinic. 
Hypertension has been divided into stages 1 and 2, as shown in Table 1. JNC 7 has defined normal blood pressure 
as <120 and <80. The intervening levels, 120 to 139 and 80 to 89 mm Hg, are now defined as prehypertension, a 
group that has increasing health risks and from which definite hypertension progresses.  
 
 
 
Current recommendations from World Health Organizations, International Society of Hypertension, and European 
Society of Hypertension/European Society of Cardiology continue to divide stage 2 hypertension, with stage 3 
beginning at ≥180 and ≥110.13 They also refer to <120/<80 as optimal, 120 to 129/80 to 84 as normal, and 130 to 
139/85 to 89 as high normal. Classification determined by self-measurement or ambulatory assessment is provided 
in those sections of this statement.  
1.1.5 
Isolated Systolic Hypertension 
As adults age, systolic blood pressure tends to rise and diastolic tends to fall. When the average systolic blood 
pressure is ≥140 and diastolic blood pressure is <90, the patient is classified as having isolated systolic 
hypertension. The increased pulse pressure (systolic– diastolic) and systolic pressure predict risk and determine 
treatment.14 


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1.1.6 
Isolated Systolic Hypertension of the Young 
In older children and young adults, often males, the combination of rapid growth in height and very elastic arteries 
accentuates the normal amplification of the pressure wave between the aorta and brachial artery, resulting in a high 
systolic pressure in the brachial artery but normal diastolic and mean pressures. The aortic systolic pressure is 
normal, however. This can be suspected from pulse wave analysis or intra-aortic blood pressure measurements.15 
1.1.7 
Isolated Diastolic Hypertension 
More commonly seen in some younger adults, isolated diastolic hypertension is defined as a systolic pressure <140 
and a diastolic ≥90. Although diastolic pressure is generally thought to be the best predictor of risk in patients 
younger than 50,16 some prospective studies of isolated diastolic hypertension have indicated that the prognosis 
may be benign.17 This topic remains controversial, however.  
1.1.8 
White-Coat Hypertension or Isolated Office Hypertension 
In ≈15% to 20% of people with stage 1 hypertension, blood pressure may only be elevated persistently in the 
presence of a health care worker, particularly a physician. When measured elsewhere, including while at work, the 
blood pressure is not elevated. When this phenomenon is detected in patients not taking medications, it is referred 
to as white-coat hypertension (WCH). The commonly used definition is a persistently elevated average office blood 
pressure of >140/90 and an average awake ambulatory reading of <135/85 mm Hg.18 Although it can occur at any 
age, it is more common in older men and women. The phenomenon responsible for WCH is commonly referred to 
as the white coat effect and is defined as the difference between the office and daytime ambulatory blood pressure; 
it is present in the majority of hypertensive patients. Its magnitude can be reduced (but not eliminated) by the use of 
stationary oscillometric devices that automatically determine and analyze a series of blood pressures over 15 to 20 
minutes with the patient in a quiet environment in the office or clinic. Other health risk factors are often present and 
should be treated accordingly. Its prognosis is discussed further in the section on Prognostic Significance in 
Ambulatory Blood Pressure Measurement. In some patients, WCH may progress to definite sustained hypertension, 
and all need to be followed-up indefinitely with office and out-of-office measurements of blood pressure. Treatment 
with antihypertensive drugs may lower the office blood pressure but does not change the ambulatory 
measurement.19 This pattern of findings suggests that drug treatment of WCH is less beneficial than treatment of 
sustained hypertension.  
1.1.9 
Masked Hypertension or Isolated Ambulatory Hypertension 
Somewhat less frequent than WCH but more problematic to detect is the converse condition of normal blood 
pressure in the office and elevated blood pressures elsewhere, eg, at work or at home. Lifestyle can contribute to 
this, eg, alcohol, tobacco, caffeine consumption, and physical activity away from the clinic/office. Target organ 
damage is related to the more prolonged elevations in pressure away from the physician’ s office and the presence 
of such when the blood pressure is normal in the office can be a clue.20 There is also some evidence that such 
patients are at increased risk.21 
1.1.10 Pseudohypertension 
When the peripheral muscular arteries become very rigid from advanced (often calcified) arteriosclerosis, the cuff 
has to be at a higher pressure to compress them. Rarely, usually in elderly patients or those with longstanding 
diabetes or chronic renal failure, it may be very difficult to do so. The brachial or radial artery may be palpated distal 
to the fully inflated cuff in these instances (positive Osler sign). The patients may be overdosed with 


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antihypertensive medications inadvertently, resulting in orthostatic hypotension and other side effects. When 
suspected, an intra-arterial radial artery blood pressure can be obtained for verification. The Osler maneuver is not 
a reliable screen for pseudohypertension. It was present in 7.2% of 3387 persons older than 59 years screened for 
the Systolic Hypertension in the Elderly Program (SHEP) study—more common in men, those found to be 
hypertensive, and those with a history of stroke.22 However, the Osler maneuver may be positive in the absence of 
pseudohypertension in one-third of hospitalized elderly subjects.23 
1.1.11 Orthostatic or Postural Hypotension 
Orthostatic hypotension is defined as a reduction of systolic blood pressure of at least 20 mm Hg or 10 mm Hg in 
diastolic blood pressure within 3 minutes of quiet standing.15 An alternative method is to detect a similar fall during 
head-up tilt at 60 degrees. This may be asymptomatic or accompanied by symptoms of lightheadedness, faintness, 
dizziness, blurred vision, neck ache, and cognitive impairment. Factors affecting this response to posture include 
food ingestion, time of day, medications, ambient temperature, hydration, deconditioning, standing after vigorous 
exercise, and age.24,25 If chronic, the fall of blood pressure may be part of pure autonomic failure, multiple system 
atrophy, associated with Parkinsonism or a complication of diabetes, multiple myeloma, and other dysautonomias. 
Patients with autonomic failure exhibit a disabling failure of control of many autonomic functions. The major life-
limiting failure is inability to control the level of blood pressure, especially in those patients with orthostatic 
hypotension who concomitantly have supine hypertension. In these patients, there are great and swift changes in 
pressure so that the patients faint because of profound hypotension on standing and have very severe hypertension 
when supine during the night. Often the heart rate is fixed as well. The supine hypertension subjects them to life-
threatening target organ damage such as left ventricular hypertrophy, coronary heart disease, flash pulmonary 
edema, heart failure, renal failure, stroke, and sudden death (presumably caused by central apnea or cardiac 
arrhythmias).26– 28 
Blood Pressure Measurement Methods 
The auscultatory method has been the mainstay of clinical blood pressure measurement for as long as blood 
pressure has been measured but is gradually being supplanted by other techniques that are more suited to 
automated measurement.  
1.1.12 The Auscultatory Method—Mercury, Aneroid, and Hybrid Sphygmomanometers 
It is surprising that nearly 100 years after it was first discovered, and the subsequent recognition of its limited 
accuracy, the Korotkoff technique for measuring blood pressure has continued to be used without any substantial 
improvement. The brachial artery is occluded by a cuff placed around the upper arm and inflated to above systolic 
pressure. As it is gradually deflated, pulsatile blood flow is re-established and accompanied by sounds that can be 
detected by a stethoscope held over the artery just below the cuff. Traditionally, the sounds have been classified as 
5 phases: phase I, appearance of clear tapping sounds corresponding to the appearance of a palpable pulse; phase 
II, sounds become softer and longer; phase III, sounds become crisper and louder; phase IV, sounds become 
muffled and softer; and phase V, sounds disappear completely. The fifth phase is thus recorded as the last audible 
sound.  
The sounds are thought to originate from a combination of turbulent blood flow and oscillations of the arterial wall. 
There is agreement that the onset of phase I corresponds to systolic pressure but tends to underestimate the 
systolic pressure recorded by direct intra-arterial measurement.29 The disappearance of sounds (phase V) 


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corresponds to diastolic pressure but tends to occur before diastolic pressure determined by direct intra-arterial 
measurement.29 No clinical significance has been attached to phases II and III.  
The Korotkoff sound method tends to give values for systolic pressure that are lower than the true intra-arterial 
pressure, and diastolic values that are higher.30,31 The range of discrepancies is quite striking: One author 
commented that the difference between the 2 methods might be as much as 25 mm Hg in some individuals.32 There 
has been disagreement in the past as to whether phase IV or V of the Korotkoff sounds should be used for 
recording diastolic pressure, but phase IV tends to be even higher than phase V when compared against the true 
intra-arterial diastolic pressure and is more difficult to identify than phase V. There is now general consensus that 
the fifth phase should be used, except in situations in which the disappearance of sounds cannot reliably be 
determined because sounds are audible even after complete deflation of the cuff, for example, in pregnant women, 
patients with arteriovenous fistulas (eg, for hemodialysis), and aortic insufficiency.33– 35 Most of the large-scale 
clinical trials that have evaluated the benefits of treating hypertension have used the fifth phase.  
In older patients with a wide pulse pressure, the Korotkoff sounds may become inaudible between systolic and 
diastolic pressure, and reappear as cuff deflation is continued. This phenomenon is known as the auscultatory gap. 
In some cases, this may occur because of fluctuations of intra-arterial pressure and is most likely to occur in 
subjects with target organ damage.36 The auscultatory gap often can be eliminated by elevating the arm overhead 
for 30 seconds before inflating the cuff and then bringing the arm to the usual position to continue in the 
measurement. This maneuver reduces vascular volume in the limb and improves inflow to enhance the Korotkoff 
sounds. The auscultatory gap is not an issue with nonauscultatory methods.  
1.1.12.1 Mercury Sphygmomanometers  
The mercury sphygmomanometer has always been regarded as the gold standard for clinical measurement of blood 
pressure, but this situation is likely to change in the near future, as discussed. The design of mercury 
sphygmomanometers has changed little over the past 50 years, except that modern versions are less likely to spill 
mercury if dropped. In principle, there is less to go wrong with mercury sphygmomanometers than with other 
devices, and one of the unique features is that the simplicity of the design means that there is negligible difference 
in the accuracy of different brands, which certainly does not apply to any other type of manometer. However, this 
should not be any cause for complacency. One hospital survey found that 21% of devices had technical problems 
that would limit their accuracy,37 whereas another found >50% to be defective.38 The random zero 
sphygmomanometer was designed to eliminate observer bias but is no longer available.  
1.1.12.2 Aneroid Sphygmomanometers  
In these devices, the pressure is registered by a mechanical system of metal bellows that expands as the cuff 
pressure increases and a series of levers that register the pressure on a circular scale. This type of system does not 
necessarily maintain its stability over time, particularly if handled roughly. They therefore are inherently less 
accurate than mercury sphygmomanometers and require calibrating at regular intervals. Recent developments in 
the design of aneroid devices may make them less susceptible to mechanical damage when dropped. Wall-
mounted devices may be less susceptible to trauma and, hence, more accurate than mobile devices.39 
The accuracy of the manometers varies greatly from one manufacturer to another. Thus, 4 surveys conducted in 
hospitals in the past 10 years have examined the accuracy of the aneroid devices and have shown significant 


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inaccuracies ranging from 1%39,40 to 44%.37 The few studies that have been conducted with aneroid devices have 
focused on the accuracy of the pressure registering system as opposed to the degree of observer error, which is 
likely to be higher with the small dials used in many of the devices.  
1.1.12.3 Hybrid Sphygmomanometers  
Devices have been developed that combine some of the features of both electronic and auscultatory devices, and 
are referred to as “ hybrid”  sphygmomanometers. The key feature is that the mercury column is replaced by an 
electronic pressure gauge, such as are used in oscillometric devices. Blood pressure is taken in the same way as 
with a mercury or aneroid device, by an observer using a stethoscope and listening for the Korotkoff sounds. The 
cuff pressure can be displayed as a simulated mercury column, as a digital readout, or as a simulated aneroid 
display. In one version, the cuff is deflated in the normal way, and when systolic and diastolic pressure are heard a 
button next to the deflation knob is pressed, which freezes the digital display to show systolic and diastolic 
pressures. This has the potential of minimizing terminal digit preference, which is a major source of error with 
mercury and aneroid devices. The hybrid sphygmomanometer has the potential to become a replacement for 
mercury, because it combines some of the best features of both mercury and electronic devices at any rate until the 
latter become accurate enough to be used without individual validation.41 
1.1.13 The Oscillometric Technique 
This was first demonstrated by Marey in 1876,42 and it was subsequently shown that when the oscillations of 
pressure in a sphygmomanometer cuff are recorded during gradual deflation, the point of maximal oscillation 
corresponds to the mean intra-arterial pressure.43,44 The oscillations begin well above systolic pressure and 
continue below diastolic, so that systolic and diastolic pressures can only be estimated indirectly according to some 
empirically derived algorithm. One advantage of the method is that no transducer need be placed over the brachial 
artery, so that placement of the cuff is not critical. Other potential advantages of the oscillometric method for 
ambulatory monitoring are that it is less susceptible to external noise (but not to low-frequency mechanical 
vibration), and that the cuff can be removed and replaced by the patient, for example, to take a shower. The main 
problem with the technique is that the amplitude of the oscillations depends on several factors other than blood 
pressure, most importantly the stiffness of the arteries. Thus, in older people with stiff arteries and wide pulse 
pressures the mean arterial pressure may be significantly underestimated.45 The algorithms used for detecting 
systolic and diastolic pressures are different from one device to another and are not divulged by the manufacturers. 
The differences between devices has been dramatically shown by studies using simulated pressure waves, in which 
a systolic pressure of 120 mm Hg was registered as low as 110 and as high as 125 mm Hg46 by different devices. 
Another disadvantage is that such recorders do not work well during physical activity, when there may be 
considerable movement artifact. Additionally, the bladders deflate at a manufacturer-specific “ bleed rate,”  which 
assumes a regular pulse between bleed steps as part of the algorithms used to determine systolic and diastolic 
pressure.  
The oscillometric technique has been used successfully in ambulatory blood pressure monitors and home monitors. 
Comparisons of several different commercial models with intra-arterial and Korotkoff sound measurements have 
shown generally good agreement,47– 49 but the results have been better with ambulatory monitors than with the 
cheaper devices marketed for home use. Oscillometric devices are also now available for taking multiple 
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1.1.14 The Finger Cuff Method of Penaz 
This interesting method was first developed by Penaz50 and works on the principle of the “ unloaded arterial wall.”  
Arterial pulsation in a finger is detected by a photoplethysmograph under a pressure cuff. The output of the 
plethysmograph is used to drive a servo-loop, which rapidly changes the cuff pressure to keep the output constant, 
so that the artery is held in a partially opened state. The oscillations of pressure in the cuff are measured and have 
been found to resemble the intra-arterial pressure wave in most subjects. This method gives an accurate estimate 
of the changes of systolic and diastolic pressure, although both may be underestimated (or overestimated in some 
subjects) when compared with brachial artery pressures50; the cuff can be kept inflated for up to 2 hours. It is now 
commercially available as the Finometer (formerly Finapres) and Portapres recorders, and has been validated in 
several studies against intra-arterial pressures.51,52 The Portapres enables readings to be taken over 24 hours while 
the subjects are ambulatory, although it is somewhat cumbersome.53 
This method in its present form is not suited to clinical use because of its cost, inconvenience, and relative 
inaccuracy for measuring absolute levels of blood pressure. Its greatest value is for research studies assessing 
short-term changes of blood pressure and its variability. The finger blood pressure monitors that are available in 
drug stores do not use this method.  
1.1.15 Ultrasound Techniques 
Devices incorporating this technique use an ultrasound transmitter and receiver placed over the brachial artery 
under a sphygmomanometer cuff. As the cuff is deflated, the movement of the arterial wall at systolic pressure 
causes a Doppler phase shift in the reflected ultrasound, and diastolic pressure is recorded as the point at which 
diminution of arterial motion occurs.54 Another variation of this method detects the onset of blood flow, which has 
been found to be of particular value for measuring systolic pressure in infants and children.55 
In patients with very faint Korotkoff sounds (for example those with muscular atrophy), placing a Doppler probe over 
the brachial artery may help to detect the systolic pressure, and the same technique can be used for measuring the 
ankle– arm index, in which the systolic pressures in the brachial artery and the posterior tibial artery are compared 
to obtain an index of peripheral arterial disease.  
1.1.16 Tonometry 
The principle of this technique is that when an artery is partially compressed or splinted against a bone, the 
pulsations are proportional to the intra-arterial pressure. This has been developed for measurement of the blood 
pressure at the wrist, because the radial artery lies just over the radius bone.56 However, the transducer needs to be 
situated directly over the center of the artery; hence, the signal is very position-sensitive. This has been dealt with 
by using an array of transducers placed across the artery. Although the technique has been developed for beat-to-
beat monitoring of the wrist blood pressure, it requires calibration in each patient and is not suitable for routine 
clinical use.  
Another application is applanation tonometry, in which a single transducer is held manually over the radial artery to 
record the pressure waveform while systolic and diastolic pressures are measured from the brachial artery. This 
technique has been used to estimate central aortic pressure. The rationale for this is that the arterial pressure at the 
level of the aortic root is different from the brachial artery pressure, and that this difference varies according to a 
number of physiological and pathological variables. Thus, it might be expected that the aortic pressure might predict 
cardiac events more closely than the brachial artery pressure. The shape of the pressure waveform in the arterial 


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tree is determined by a combination of the incident wave and the wave reflected from the periphery. In hypertensive 
subjects and subjects with stiff arteries, the systolic pressure wave in the aorta and brachial artery is augmented by 
a late systolic peak, which can be attributed to wave reflection and which is not seen in more peripheral arteries 
such as the radial artery. Using Fourier analysis, it is possible to derive the central aortic pressure waveform from 
the radial artery trace. However, comparisons with directly recorded aortic pressure made during cardiac 
catheterization have shown considerable scatter between the estimated and true values,57 so the technique cannot 
yet be recommended for routine clinical practice.  
1.1.17 Location of Measurement—Arm, Wrist, Finger 
The standard location for blood pressure measurement is the upper arm, with the stethoscope at the elbow crease 
over the brachial artery, although there are several other sites where it can be performed. Monitors that measure 
pressure at the wrist and fingers have become popular, but it is important to realize that the systolic and diastolic 
pressures vary substantially in different parts of the arterial tree. In general, the systolic pressure increases in more 
distal arteries, whereas the diastolic pressure decreases. Mean arterial pressure falls by only 1 to 2 mm Hg between 
the aorta and peripheral arteries.58 
1.1.17.1 Wrist Monitors  
Wrist monitors have the advantages of being smaller than the arm devices and can be used in obese people, 
because the wrist diameter is little affected by obesity. A potential problem with wrist monitors is the systematic 
error introduced by the hydrostatic effect of differences in the position of the wrist relative to the heart.59 This can be 
avoided if the wrist is always at heart level when the readings are taken, but there is no way of knowing 
retrospectively whether this was performed when a series of readings are reviewed. Devices are now available that 
will only record a measurement when the monitor is held at heart level. Wrist monitors have potential but need to be 
evaluated further.60 
1.1.17.2 Finger Monitors  
Finger monitors have so far been found to be inaccurate and are not recommended.61 
1.1.18 Validation of Monitors 
All monitors in clinical use should be tested for accuracy. This involves 2 stages. First, all oscillometric automated 
monitors that provide read-outs of systolic and diastolic pressure should be subjected by independent investigators 
to formal validation protocols. The original 2 protocols that gained the widest acceptance were developed by the 
Association for the Advancement of Medical Instrumentation (AAMI) in 1987 and the British Hypertension Society 
(BHS) in 1990, with revisions to both in 1993, and to AAMI in 2002.62 These required testing of a device against 2 
trained human observers in 85 subjects, which made validation studies difficult to perform. One consequence of this 
has been that there are still many devices on the market that have never been adequately validated. More recently, 
an international group of experts who are members of the European Society of Hypertension Working Group on 
Blood Pressure Monitoring has produced an International Protocol that could replace the 2 earlier versions63 and is 
easier to perform. Briefly, it requires comparison of the device readings (4 in all) alternating with 5 mercury readings 
taken by 2 trained observers. Devices are recommended for approval if both systolic and diastolic readings taken 
are at least within 5 mm Hg of each other for at least 50% of readings.  


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It is recommended that only those devices that have passed this or similar tests should be used in practice. 
However, the fact that a device passed a validation test does not mean that it will provide accurate readings in all 
patients. There can be substantial numbers of individual subjects in whom the error is consistently >5 mm Hg with a 
device that has achieved a passing grade.64 This may be more likely to occur in elderly65 or diabetic patients.66 For 
this reason, it is recommended that each oscillometric monitor should be validated on each patient before the 
readings are accepted. No formal protocol has yet been developed for doing this, but if sequential readings are 
taken with a mercury sphygmomanometer and the device, then major inaccuracies can be detected.  
Another problem is that manufacturers may change the model number after a device has been tested without 
indicating whether the measurement algorithm has also been changed.  
With nonautomatic devices, such as mercury and aneroid monitors, it is recommended that the accuracy of the 
pressure registration mechanism be checked. In the case of mercury sphygmomanometers, this involves checking 
that the upper curve of the meniscus of the mercury column is at 0 mm Hg, that the column is free of dirt, and that it 
rises and falls freely during cuff inflation and deflation.  
Aneroid devices or other nonmercury devices should be checked by connecting the manometer to a mercury 
column or an electronic testing device with a Y-tube. The needle should rest at the zero point before the cuff is 
inflated and should register a reading that is within 4 mm Hg of the mercury column when the cuff is inflated to 
pressures of 100 and 200 mm Hg. The needle should return to zero after deflation.  
Blood Pressure Measurement in the Clinic or Office 
Accurate auscultatory office blood pressure measurement is the bedrock of the diagnosis and treatment of 
hypertension and has been the standard method used in the major epidemiologic and treatment trials of the past 50 
years. However, it is becoming increasingly clear that as it is used in everyday practice, there are major 
shortcomings. Thus, surveys of mercury devices in clinical practices have shown that there are frequently 
mechanical defects,67 and physicians rarely follow official guidelines for their use.67 Added to these is the 
phenomenon of the white coat effect, whereby the recorded blood pressure may be unrepresentative of the 
patient’ s true blood pressure.  
1.1.19 Subject Preparation 
A number of factors related to the subject can cause significant deviations in measured blood pressure. These 
include room temperature, exercise, alcohol or nicotine consumption, positioning of the arm, muscle tension, 
bladder distension, talking, and background noise.28 The patient should be asked to remove all clothing that covers 
the location of cuff placement. The individual should be comfortably seated, with the legs uncrossed, and the back 
and arm supported, such that the middle of the cuff on the upper arm is at the level of the right atrium (the mid-point 
of the sternum). Measurements made while the patient is on an examining table do not fulfill these criteria and 
should preferably be made while the patient is seated in a chair. At the initial visit, blood pressure should be 
measured in both arms. The patient should be instructed to relax as much as possible and to not talk during the 
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1.1.20 Choice of Blood Pressure Measurement Devices 
The “ gold standard”  device for office blood pressure measurement has been the mercury sphygmomanometer, 
but these are being removed from clinical practice because of environmental concerns about mercury 
contamination.68 Mercury sphygmomanometers are already banned in Veterans Administration hospitals. There is a 
role for other types of device in office use, both as a substitute for the traditional mercury readings (eg, aneroid and 
hybrid sphygmomanometers) and as supplements to them (eg, oscillometric automatic devices). However, because 
there is currently no generally accepted replacement for mercury, it is recommended that, if available, a properly 
maintained mercury sphygmomanometer be used for routine office measurements. Mercury sphygmomanometers 
are critical for evaluating the accuracy of any type of nonmercury device. Nonmercury pressurometers that use 
electronic pressure transducers with a digital read-out are available for calibrating the pressure detection systems of 
aneroid or oscillometric devices.  
1.1.21 Cuff Size 
Von Recklinghausen in 1901 recognized that Riva Rocci’ s device for determination of accurate systolic blood 
pressure by palpation had a significant flaw, its 5-cm-width cuff.69 Multiple authors have shown that the error in 
blood pressure measurement is larger when the cuff is too small relative to the patient’ s arm circumference70– 76 
than when it is too large. Previous epidemiological data from Britain77 and Ireland78 had suggested that arm 
circumferences of >34 cm were uncommon. Data from NHANES III and NHANES 2000 have shown the opposite in 
the United States. In the United States during the period from 1988 to 2000, there has been a significant increase in 
mean arm circumference and an increase in the frequency of arm circumferences of >33 cm was found because of 
increasing weight in the American population.79 This should not be surprising, because the prevalence of obesity in 
the United States has increased from 22.9% in NHANES III (1988 to 1994) to >30% in 2000.80 Similar data 
regarding the increased frequency of larger arm circumferences were also found in a study of a referral practice of 
hypertensive subjects, in which a striking 61% of 430 subjects had an arm circumference of ≥33 cm.81 Recognition 
of the increasing need for the “ large adult”  cuff, or even the thigh cuff, for accurate blood pressure measurement 
is critical, because frequently in practice only the standard adult size has been demonstrated to be available.82 More 
importantly, it has been demonstrated that the most frequent error in measuring blood pressure in the outpatient 
clinic is “ miscuffing,”  with undercuffing large arms accounting for 84% of the “ miscuffings.”
83 
The “ ideal”  cuff should have a bladder length that is 80% and a width that is at least 40% of arm circumference 
(a length-to-width ratio of 2:1). A recent study comparing intra-arterial and auscultatory blood pressure concluded 
that the error is minimized with a cuff width of 46% of the arm circumference.84 The recommended cuff sizes are:  
 
For arm circumference of 22 to 26 cm, the cuff should be “ small adult”  size: 12×22 cm 
 
For arm circumference of 27 to 34 cm, the cuff should be “ adult”  size: 16×30 cm 
 
For arm circumference of 35 to 44 cm, the cuff should be “ large adult”  size: 16×36 cm 
 
For arm circumference of 45 to 52 cm, the cuff should be “ adult thigh”  size: 16×42 cm 
The optimum ratios of width and length to arm circumference are shown for the small adult and standard adult cuffs. 
For the large adult and thigh cuffs, the ideal width ratio of 46% of arm circumference is not practical, because it 
would result in a width of 20 cm and 24 cm, respectively. These widths would give a cuff that would not be clinically 
usable for most patients, so for the larger cuffs, a less than ideal ratio of width to arm circumference must be 
accepted. The ideal ratio of length to arm circumference is maintained in all 4 cuffs.  


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In practice, bladder width is easily appreciated by the clinician but bladder length often is not, because the bladder 
is enclosed in the cuff. To further complicate the issue for clinicians, there are no standards for manufacturers of 
different sizes of blood pressure cuff. This has led to significant differences in which arm circumferences are 
accurately measured by individual manufacturers’  standard adult and large adult cuffs.  
Individual cuffs should be labeled with the ranges of arm circumferences, to which they can be correctly applied, 
preferably by having lines that show whether the cuff size is appropriate when it is wrapped around the arm. In 
patients with morbid obesity, one will encounter very large arm circumferences with short upper arm length. This 
geometry often cannot be correctly cuffed, even with the thigh cuff. In this circumstance, the clinician may measure 
blood pressure from a cuff placed on the forearm and listening for sounds over the radial artery (although this may 
overestimate systolic blood pressure)85 or use a validated wrist blood pressure monitor held at the level of the 
heart.86,87 
1.1.22 Effects of Body Position 
Blood pressure measurement is most commonly made in either the sitting or the supine position, but the 2 positions 
give different measurements. It is widely accepted that diastolic pressure measured while sitting is higher than when 
measured supine (by ≈5 mm Hg), although there is less agreement about systolic pressure.88 When the arm 
position is meticulously adjusted so that the cuff is at the level of the right atrium in both positions, the systolic 
pressure has been reported to be 8 mm Hg higher in the supine than the upright position.89 
Other considerations include the position of the back and legs. If the back is not supported (as when the patient is 
seated on an examination table as opposed to a chair), the diastolic pressure may be increased by 6 mm Hg.90 
Crossing the legs may raise systolic pressure by 2 to 8 mm Hg.91 
In the supine position, the right atrium is approximately halfway between the bed and the level of the sternum92; 
thus, if the arm is resting on the bed, it will be below heart level. For this reason, when measurements are taken in 
the supine position the arm should be supported with a pillow. In the sitting position, the right atrium level is the 
midpoint of the sternum or the fourth intercostal space.  
1.1.23 Effects of Arm Position 
The position of the arm can have a major influence when the blood pressure is measured; if the upper arm is below 
the level of the right atrium (when the arm is hanging down while in the sitting position), the readings will be too 
high. Similarly, if the arm is above the heart level, the readings will be too low. These differences can be attributed 
to the effects of hydrostatic pressure59 and may be 10 mm Hg or more,93 or 2 mm Hg for every inch above or below 
the heart level.  
Other physiological factors that may influence the blood pressure during the measurement process include muscle 
tension. If the arm is held up by the patient (as opposed to being supported by the observer), the isometric exercise 
will raise the pressure.  
1.1.24 Differences Between the 2 Arms 
Several studies have compared the blood pressure measured in both arms, mostly using the auscultatory 
technique. Almost all have reported finding differences, but there is no clear pattern; thus, the difference does not 
appear to be determined by whether the subject is right- or left-handed.94 One of the largest studies was conducted 


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in 400 subjects using simultaneous measurements with oscillometric devices, which found no systematic 
differences between the 2 arms, but 20% of subjects had differences of >10 mm Hg.94 Although these findings are 
disturbing, it is not clear to what extent the differences were consistent and reproducible, as opposed to being the 
result of inherent blood pressure variability. Nevertheless, it is recommended that blood pressure should be 
checked in both arms at the first examination. This may be helpful in detecting coarctation of the aorta and upper 
extremity arterial obstruction. When there is a consistent interarm difference, the arm with the higher pressure 
should be used. In women who have had a mastectomy, blood pressure can be measured in both arms unless 
there is lymphedema.  
1.1.25 Cuff Placement and Stethoscope 
Cuff placement must be preceded by selection of the appropriate cuff size for the subject’ s arm circumference. 
The observer must first palpate the brachial artery in the antecubital fossa and place the midline of the bladder of 
the cuff (commonly marked on the cuff by the manufacturer) so that it is over the arterial pulsation over the 
patient’ s bare upper arm. The sleeve should not be rolled up such that it has a tourniquet effect above the blood 
pressure cuff. The lower end of the cuff should be 2 to 3 cm above the antecubital fossa to allow room for 
placement of the stethoscope. However, if a cuff that leaves such space has a bladder length that does not 
sufficiently encircle the arm (at least 80%), a larger cuff should be used, recognizing that if the cuff touches the 
stethoscope, artifactual noise will be generated. The cuff is then pulled snugly around the bare upper arm. Neither 
the observer nor the patient should talk during the measurement. Phase 1 (systolic) and phase 5 (diastolic) 
Korotkoff sounds are best heard using the bell of the stethoscope over the palpated brachial artery in the 
antecubital fossa, although some studies have shown that there is little difference90,95 when using the bell or the 
diaphragm. The key to good measurement is the use of a high-quality stethoscope with short tubing, because 
inexpensive models may lack good tonal transmission properties required for accurate auscultatory measurement.  
1.1.26 Inflation/Deflation System 
Indirect blood pressure measurement requires that occlusion of the brachial artery is produced by gradual inflation 
and deflation of an appropriately sized cuff. The tubing from the device to the cuff must be of sufficient length (70 
cm or more) to allow for its function in the office setting. Successful inflation and deflation requires an airtight 
system; ongoing inspection and maintenance of the tubing for deterioration of the rubber (cracking) and the release 
valve are required. The cuff should initially be inflated to at least 30 mm Hg above the point at which the radial pulse 
disappears. The rate of deflation has a significant effect on blood pressure determination. Deflation rates >2 mm per 
second can lead to a significant underestimation of systolic and overestimation of diastolic blood pressure. 
Automated devices with a linear deflation rate may have improved accuracy over the more common circumstances 
in automated devices that have stepwise deflation. It is recommended that a deflation rate of 2 to 3 mm Hg per 
second (or per pulse when the heart rate is very slow) be used.96,97 
1.1.26.1 Important Points for Clinical Blood Pressure Measurement  
 
The patient should be seated comfortably with the back supported and the upper arm bared without 
constrictive clothing. The legs should not be crossed.  
 
The arm should be supported at heart level, and the bladder of the cuff should encircle at least 80% of the 
arm circumference. 
 
The mercury column should be deflated at 2 to 3 mm/s, and the first and last audible sounds should be 
taken as systolic and diastolic pressure. The column should be read to the nearest 2 mm Hg.  


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 
Neither the patient nor the observer should talk during the measurement. 
1.1.27 Observer 
The observer is the most critical component of accurate blood pressure measurement. For accurate blood pressure 
measurement, the observer must: (1) be properly trained in the techniques of blood pressure measurement; (2) use 
an accurate and properly maintained device; (3) recognize subject factors, such as anxiety and recent nicotine use, 
that would adversely affect blood pressure measurements; (4) position the subject appropriately; (5) select the 
correct cuff and position it correctly; and (6) perform the measurement using the auscultatory or automated 
oscillometric method and accurately record the values obtained.  
Observer error is a major limitation of the auscultatory method.98 Systematic errors lead to intra-observer and 
interobserver error. Terminal digit preference is perhaps the most common manifestation of suboptimal blood 
pressure determination. It is generally recommended that the observer should read the blood pressure to the 
nearest 2 mm Hg, but an inappropriate excess in the recording of “ zero”  as the last digit in auscultatory blood 
pressure determinations has been reported by multiple investigators in clinical and research settings.99,100 Digit bias 
or digit prejudice is particularly common when the observer recognizes a specific threshold value for blood pressure 
and, depending on the circumstances, records a pressure just above or below that number. A good example is the 
Syst-Eur Trial, which showed both increased zero preference and a significant digit bias for 148 mm Hg systolic, the 
threshold for successful treatment in that trial.95 
1.1.28 Number of Measurements 
It is well recognized that the predictive power of multiple blood pressure determinations is much greater than a 
single office reading.101 One of the potential advantages of supplementing auscultatory readings with readings taken 
by an automated device is the ability to obtain a larger number of readings. When a series of readings is taken, the 
first is typically the highest. A minimum of 2 readings should be taken at intervals of at least 1 minute, and the 
average of those readings should be used to represent the patient’ s blood pressure. If there is >5 mm Hg 
difference between the first and second readings, additional (1 or 2) readings should be obtained, and then the 
average of these multiple readings is used.  
1.1.29 Automated Methods 
Automated oscillometric blood pressure devices are increasingly being used in office blood pressure measurement, 
as well as for home and ambulatory monitoring. When they are used in the office, the readings are typically lower 
than readings taken by a physician or nurse. The potential advantages of automated measurement in the office are 
the elimination of observer error, minimizing the white coat effect, and increasing the number of readings. The main 
disadvantages are the error inherent in the oscillometric method and the fact that epidemiologic data are mostly 
based on auscultated blood pressure measures.  
Automated devices may also offer the opportunity to avoid expensive and repetitive training of health care 
professionals in auscultation, which is necessary to reduce observer errors. Their use still requires careful patient 
evaluation for caffeine or nicotine use, selection of the correct cuff size, and proper patient positioning if accurate 
blood pressures are to be obtained. Devices are now available that can take a series of sequential readings and 
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1.1.30 The White Coat Effect and the Differences Between Physician and Nurse Blood Pressure 
Measurements 
The initial epidemiological studies of hypertension and the first major hypertension treatment trial (VA Cooperative 
Study) were performed using physician blood pressure measurements.102– 104 Since that time, all the major 
hypertension treatment trials have used a nurse, “ a trained observer,”  or automated blood pressure 
measurements. In hypertensive patients (but not necessarily in normotensive patients), the blood pressure recorded 
by a physician or nurse is typically higher than the average daytime level, and this difference is commonly referred 
to as the white coat effect.  
In addition to these effects of the medical environment on blood pressure measurement, there is a recognized 
difference between blood pressure levels measured by a physician versus a nurse in the same subjects. In the 
largest study of physician– nurse blood pressure differences, it was found that a nurse recorded significantly lower 
mean systolic and diastolic pressures than a physician (by 6.3/7.9 mm Hg).105 This difference is not caused by any 
difference in technique, because when a dual-headed stethoscope is used and the physician and nurse 
simultaneously take the blood pressure, the physician– nurse difference is insignificant. In addition, the nurse-
recorded blood pressure is usually closer to the patient’ s daytime average pressure than the pressure recorded by 
the physician. Because all of the most recent treatment trials of hypertension are based on blood pressure 
measurements made by nurses or other professionals, but not by physicians, the difference in office blood pressure 
measured by physicians and nurses suggests that physician blood pressures should not be used exclusively in the 
routine management of the hypertensive subject.  
Training of Observers 
As the number and type of blood pressure measurement devices and direct-to-consumer advertising increase, more 
people are measuring blood pressure more frequently. In medical settings, physicians, nurses, nurses’  aids, 
students, and pharmacists all measure blood pressure and record the values in a patient’ s records. Outside 
medical settings, patients, family members, or lay persons also measure blood pressure. The training given to lay 
observers should be as comprehensive and similar to that recommended for health care professionals in 
ambulatory and community settings.106 With careful training even unpaid volunteers in large population surveys can 
measure blood pressure accurately.107 However, even with the newer automated devices, the accuracy of the 
readings can be optimal only if all observers are appropriately trained and retrained and conscientious about using 
appropriate techniques.  
1.1.31 Required Competencies 
Before training begins, potential observers should be assessed for physical and cognitive competencies required to 
perform the procedure. The physical requirements include the following:  
 
Vision. The observer must be able to see the dial of the manometer or the meniscus of the mercury column 
at eye level without straining or stretching, and must be able to read well enough to see the 
sphygmomanometer or digital display no further than 3 feet away.  
 
Hearing. The observer must be able to hear the appearance and disappearance of Korotkoff sounds. 
 
Eye/hand/ear coordination. This is required for the use of mercury and aneroid sphygmomanometers but 
not for the newer electronic technologies.  


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1.1.32 Training 
Traditionally, health professionals are trained in blood pressure measurement in introductory courses on physical 
assessment. They may receive a classroom lecture with a video on how to measure blood pressure, some 
laboratory skills training with demonstration and practice on fellow trainees, and mentored experience measuring 
blood pressure of patients, potential research subjects, or community volunteers. In clinical trials, standardized 
programs with audiovisual tapes that test and retest accuracy in measurement are extremely effective in training 
and retraining. In contrast, such training and retraining is not routinely required in nonresearch settings.  
Some information is available on the Internet,108 and the British Hypertension Society has a web-based video that 
can be used for the training and evaluation of observers.109 
1.1.33 Evaluation of Observers 
Pencil-and-paper questionnaires or interviews can be used to assess knowledge of the correct methodology of 
blood pressure measurement. The evaluation of observers should include an assessment of their knowledge of the 
different types of observer bias, general technique, and the interpretation of the measurements, including an 
understanding of the normal variability of blood pressure by time of day, exercise, timing of antihypertensive 
medications, etc. The observers should also know how and when to communicate blood pressure readings 
gathered at home or other settings to the health care professional responsible for the care of the patient and 
management of hypertension.  
Observers should be aware of the need to use only well-maintained and calibrated equipment, choosing a quiet 
location with adequate room temperature, correctly positioning the person having blood pressure measured, and 
ensuring that the person does not talk or move during the measurement.  
The skills of the observer should be demonstrated by assessing items such as positioning the patient, selecting the 
right size cuff, obtaining a valid and reliable measurement, recording the measurement accurately, and appropriate 
reporting of abnormal levels.  
1.1.34 Retraining 
Correct blood pressure measurement technique is difficult to maintain without careful attention to all steps in the 
protocol and retraining. The gold standard for retraining has been set by federally funded multisite clinical trials of 
hypertension care and control, in which retraining is required of all blood pressure observers every 6 months. 
Retraining requires competency in cuff selection, patient positioning, no talking, and accurate observation of the 
blood pressure level by either auditory or visual assessment. Four methods of assessment are used: audio– video 
test tapes; Y-tube– connected simultaneous readings by 2 trained observers; a written quiz; and direct observation. 
In the National Heart, Lung, and Blood Institute (NLHBI)-sponsored multisite clinical trials, a senior experienced 
person is assigned as the central trial master trainer and a master trainer is designated for each site. The central 
master trainer trains the site master trainers, and they in turn train the observers at each site. This model could be 
replicated within hospitals, ambulatory care settings, and community agencies. Retraining of all health care 
professionals is strongly recommended.  


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Blood Pressure Measurement in Other Settings 
1.1.35 Acute Care 
Blood pressure measurements in acute care settings, such as the emergency department, dialysis unit, or operating 
suite, are usually performed to judge vital signs and volume status of the patient rather than the presence or 
absence of hypertension. Oscillometric devices are widely used for this purpose and may give accurate assessment 
of mean arterial pressure, but are often inaccurate for registering systolic and diastolic pressure.110,111 Blood 
pressure values obtained in acute care settings are unlikely to be useful for decisions on chronic hypertension 
management,112 because of inadequate patient preparation, faulty equipment,82 and the impact of the acute illness 
on blood pressure. Still, high readings recorded in the emergency room do predict hypertension on subsequent 
clinic visits, to some extent,113 and warrant follow-up.  
Blood pressure measurement is also important in the prehospital setting. Multiple techniques of blood pressure 
determination in the field and ambulance and helicopter transportation environments, including auscultatory, 
oscillometric, palpation, and use of obliteration of the pulse wave on the pulse oximeter, have been used. All of 
these suffer from a high degree of error that is worse with systolic blood pressures of <90 mm Hg.114– 116 In addition, 
it has been shown that standard equipment used by emergency medical services for blood pressure determination 
is often highly unreliable.117 Determining blood pressures in prehospital settings requires a high degree of clinical 
experience and repetitive measurement. In this setting, establishment of trends in blood pressure before arriving in 
the more controlled hospital environment is more important than the absolute value of the blood pressure.  
An elevated blood pressure in the acute care setting should raise the suspicion that the patient has hypertension, 
and a referral to the outpatient setting for further evaluation is warranted. Because of the lack of precision of blood 
pressure measurement (and the impact of bed rest, acute illness, medication administration, and alteration in the 
patient’ s usual diet while in the hospital), blood pressures obtained in the acute care setting should not be used to 
judge the adequacy of blood pressure control.  
1.1.36 Public Places 
Automated blood pressure devices are commonly found in public places and represent a potential mechanism for 
increased screening for hypertension. In 1995, Whitcomb et al118 reported that because the introduction of the 
VitaStat device in 1976, >8000 devices were in use in the United States, providing >10 million measurements per 
year. The initial version was the 8000 model, which was never tested by approved protocols and which was found to 
give very inconsistent results, particularly for systolic pressure.119– 121 A later model (the 90550) has been tested in a 
community setting and has also failed to meet the BHS or AAMI criteria for accuracy.122 Other potential problems 
with these devices are that the cuff size (23×33 cm) is inadequate for patients with large arms, and that they are not 
labeled to show when or if there has been recent maintenance and revalidation of the device’ s performance. Clear 
demonstration to the user of ongoing device servicing and validation would be critical to acceptance of the devices 
for public blood pressure screening.  
Self-Measurement 
1.1.37 Types of Monitor 
When self-monitoring or home-monitoring was first used, the majority of studies used aneroid 
sphygmomanometers.123 In the past few years, automatic electronic devices have become increasingly popular. 


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The standard type of monitor for home use is now an oscillometric device that records pressure from the brachial 
artery.124 Unfortunately, only a few have been subjected to proper validation tests such as the AAMI and BHS 
protocols, and of 24 devices that have been tested by these, only 5 have passed.125 An up-to-date list of validated 
monitors is available.126 The advantages of electronic monitors have begun to be appreciated by epidemiologists,127 
who have always been greatly concerned about the accuracy of clinical blood pressure measurement and have 
paid much attention to the problems of observer error, digit preference, and the other causes of inaccuracy 
described. It has been argued that the ease of use of the electronic devices and the relative insensitivity to who is 
actually taking the reading can outweigh any inherent inaccuracy compared with the traditional sphygmomanometer 
method.127 This issue remains controversial, however.  
Electronic devices are now available that will take blood pressure from the upper arm, wrist, or finger. Although the 
use of the more distal sites may be more convenient, measurement of blood pressure from the arm (brachial artery) 
has always been the standard method and is likely to remain so for the foreseeable future. The fact that a device 
has passed the validation criteria does not guarantee accuracy in the individual patient, and it is essential that each 
device be checked on each patient before the readings are accepted as being valid (see the previous section on 
Validation of Monitors). Home-monitoring devices should be checked for accuracy every 1 to 2 years.  
1.1.38 Clinical Applications 
Home- or self-monitoring has numerous advantages over ambulatory monitoring, principal among which are that it 
is relatively cheap and provides a convenient way for monitoring blood pressure over long periods of time. There is 
some evidence that it improves both therapeutic compliance and blood pressure control.128– 130 However, technical, 
economic, and behavioral barriers have until now inhibited the widespread use of home-monitoring in clinical 
practice. Two technological developments, low-cost monitors with memory and systems for sending stored readings 
over the telephone, have the potential of overcoming these barriers.  
Unfortunately, accurate readings do not guarantee accurate reporting to the physician. In 2 separate studies, 
patients were given home monitors, but they were not told that the devices had memory. Patients were urged to 
carefully record all readings, but in both studies, more than half the subjects omitted or fabricated readings.131,132 
Devices that have memory or printouts of the readings are therefore recommended.  
It is recommended that when readings are taken, the patient should not have recently indulged in any activity such 
as exercise or eating that is likely to affect the blood pressure, and the patient should be resting quietly in a 
comfortable chair for 3 to 5 minutes with the upper arm at heart level. Three readings should be taken in 
succession, separated by at least 1 minute. The first is typically the highest, and the average should be used as the 
blood pressure reading. It is helpful to get readings in the early morning and the evening.  
1.1.39 What Is Normal Home Blood Pressure? 
Home blood pressures are consistently lower than clinic pressures in most hypertensive patients.133 Several recent 
studies have addressed the question of the level of home pressure that best corresponds to a normal clinic 
pressure of 140/90 mm Hg. The largest, the Ohasama study, proposed a level of 137/84 mm Hg as an acceptable 
upper limit for home readings134– 136 on the grounds that cardiovascular risk increases above this level. An ad hoc 
committee of the American Society of Hypertension, reviewing several studies, recommended 135/85 mm Hg as the 
upper limit of normal for home and ambulatory blood pressure.137 As with office blood pressure, a lower home blood 


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pressure goal is advisable for certain patients, including diabetic patients, pregnant women, and patients with renal 
failure.  
1.1.40 Prognostic Significance 
One factor that has held back the wider use of self-monitoring in clinical practice has been the lack of prognostic 
data. Two prospective studies, 1 from Japan134– 136 and 1 from France,21 have found that home blood pressure 
predicts morbid events better than conventional clinic measurements. There is an increasing body of evidence that 
home blood pressure may also predict target organ damage better than clinic pressure.123,138– 140 
1.1.41 Telemonitoring 
Devices are now available that have the capacity to store readings in their memory and then transmit them via the 
telephone to a central server computer, and then to the health care provider. They have the potential to improve 
patient compliance and, hence, blood pressure control.140,141 Readings taken with a telemonitoring system may 
correlate more closely than clinic readings with ambulatory blood pressure.133 
Features of different methods of BP measurement are provided in Table 2.  
 
 
Ambulatory Blood Pressure Measurement 
1.1.42 Types of Monitor 
Ambulatory blood pressure (ABP) monitoring is a noninvasive, fully automated technique in which blood pressure is 
recorded over an extended period of time, typically 24 hours. It has been used for many years as a research 
procedure and has recently been approved by Medicare for reimbursement of a single recording in patients with 
suspected WCH. The standard equipment includes a cuff, a small monitor attached to a belt, and a tube connecting 
the monitor to the cuff. Most, but not all, ABP devices use an oscillometric technique. Of the available ABP devices, 
most have undergone validation testing as recommended by the AAMI or the BHS. An up-to-date list of validated 
monitors is available.126 
During a typical ABP monitoring session, blood pressure is measured every 15 to 30 minutes over a 24-hour period 
including both awake and asleep hours, preferably on a workday. The total number of readings usually varies 
between 50 and 100. Blood pressure data are stored in the monitor and then downloaded into device-specific 
computer software. The raw data can then be synthesized into a report that provides mean values by hour and 
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pressure. The most common output used in decision-making are absolute levels of blood pressure, that is, mean 
daytime, nighttime, and 24-hour values.  
The monitors can be attached by a trained technician, who should be skilled in blood pressure measurement 
techniques (see the previous section on Blood Pressure Measurement in Other Settings). The cuff is attached to the 
nondominant upper arm, and a series of calibration readings are taken with a mercury sphygmomanometer to 
ensure that the device is giving accurate readings (within 5 mm Hg of the mercury readings). It is important to 
instruct the patient to hold the arm still by the side while the device is taking a reading. It may be helpful to ask the 
patient to keep a diary of activities, particularly when going to bed and getting up in the morning.  
1.1.43 Clinical Applications 
Although ABP could be used to monitor therapy, the most common application is diagnostic, that is, to ascertain an 
individual’ s usual level of blood pressure outside the clinic setting and thereby identify individuals with WCH. Other 
potential applications of ABP include the identification of individuals with a nondipping blood pressure pattern (eg, in 
diabetes), patients with apparently refractory hypertension but relatively little target organ damage, suspected 
autonomic neuropathy, and patients in whom there is a large discrepancy between clinic and home measurements 
of blood pressure. The Centers for Medicare and Medicaid Services has approved the use of ABP measurement for 
the diagnosis of patients with suspected WCH (documented high clinic pressures and normal pressures in other 
settings, and no evidence of target organ damage).  
A recent overview sponsored by Agency for Healthcare Research and Quality summarized available evidence on 
cross-sectional associations of ABP with subclinical outcomes and on prospective associations of ABP with clinical 
outcomes.142 In cross-sectional studies of blood pressure with left ventricular mass (22 studies) and albuminuria (6 
studies), ABP levels were directly associated with both measurements. Left ventricular mass was less in individuals 
with WCH than in those with sustained hypertension but was greater in WCH than in nonhypertensive subjects. 
Such evidence suggests that WCH is an intermediate phenotype. In each of 10 prospective studies, at least one 
dimension of ABP predicted clinical outcomes. In studies that compared the prognostic importance of ABP to clinic 
measurements, ABP was usually superior to clinic measurements. In some instances, including a recent study 
unavailable at the time of the overview,143 mean ABP levels provided additional predictive information beyond that 
of clinic measurements, confirming the seminal study by Perloff et al.144 In a few prospective studies, WCH 
predicted a reduced risk of cardiovascular disease events compared with sustained hypertension. However, data 
were inadequate to compare the risk associated with WCH to the risk associated with normotension. A nondipping 
or inverse dipping pattern predicted an increased risk of clinical outcomes. Just 2 ABP trials tested the usefulness of 
ABP to guide blood pressure management. Overall, available studies indicate that ABP monitoring can provide 
useful prognostic information.145 
1.1.44 What Is Normal ABP? 
The normal range for ABP has been established in 2 ways: first, by comparison of the ABP level that corresponds to 
a clinic pressure of 140/90 mm Hg and, second, by relating ABP to risk in prospective studies. The suggested 
values for daytime, nighttime, and 24-hour average levels are shown in Table 3.  


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1.1.45 Prognostic Significance 
Several prospective studies have documented that the average level of ABP predicts risk of morbid events better 
than clinic blood pressure.136,143,144,146– 149 In addition to mean absolute levels of ABP, certain ABP patterns may 
predict blood pressure-related complications. The patterns of greatest interest are WCH and nondipping blood 
pressure. WCH is a pattern in which clinic blood pressure is in the hypertensive range but ABP is normal or low. 
Individuals with WCH are at lower risk for blood pressure-related complications in comparison to individuals with 
sustained hypertension. An important but unresolved issue is whether the risk of cardiovascular disease in WCH 
exceeds that of nonhypertensive subjects. Using both daytime and nocturnal ABP, one can identify individuals, 
termed nondippers, who do not experience the decline in blood pressure that occurs during sleep hours. Usually, 
nighttime (asleep) blood pressure drops by 10% or more from daytime (awake) blood pressure. Individuals with a 
nondipping pattern (<10% blood pressure reduction from night to day) appear to be at increased risk for blood 
pressure-related complications compared with those with a normal dipping pattern.146,150 Other evidence suggests 
that the nighttime blood pressure may be the best predictor of risk.151 
Blood Pressure Recording in Special Situations 
1.1.46 Elderly Patients 
Elderly patients are more likely to have WCH, isolated systolic hypertension, and pseudohypertension (see the 
previous section on Pseudohypertension). Blood pressure should be measured while seated, 2 or more times at 
each visit, and the readings should be averaged. Blood pressure should also be taken in the standing position 
routinely because the elderly may have postural hypotension. Hypotension is more common in diabetic patients. It is 
frequently noticed by patients on arising in the morning, after meals, and when standing up quickly. Self-
measurements can be quite helpful when considering changes in dosage of antihypertensive medications. 
Ambulatory blood pressure monitoring, sometimes coupled with Holter recordings of ECGs, can help elucidate 
some symptoms such as episodic faintness and nocturnal dyspnea.  
1.1.47 Pulseless Syndromes 
Rarely, patients present with occlusive arterial disease in the major arteries to all 4 limbs (eg, Takayasu arteritis, 
giant cell arteritis, or atherosclerosis) so that a reliable blood pressure cannot be obtained from any limb. In this 
situation, if a carotid artery is normal, it is possible to obtain retinal artery systolic pressure and use the nomogram 
in reverse to estimate the brachial pressure (oculoplethysmography), but this procedure and the measurement of 
retinal artery pressures are not generally available. If a central intra-arterial blood pressure can be obtained, a 
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1.1.48 Arrhythmias 
When the cardiac rhythm is very irregular, the cardiac output and blood pressure varies greatly from beat to beat. 
There is considerable interobserver and intra-observer error.152 Estimating blood pressure from Korotkoff sounds is 
a guess at best; there are no generally accepted guidelines. The blood pressure should be measured several times 
and the average value used. Automated devices frequently are inaccurate for single observations in the presence of 
atrial fibrillation, for example, and should be validated in each subject before use.153 However prolonged (2 to 24 
hours) ambulatory observations do provide data similar to that in subjects with normal cardiac rhythm.154,155 
Sometimes, an intra-arterial blood pressure is necessary to get a baseline for comparison. If severe regular 
bradycardia is present (eg, 40 to 50 bpm), deflation should be slower than usual to prevent underestimation of 
systolic and overestimation of diastolic blood pressure.  
1.1.49 Obese Patients 
A longer and wider cuff is needed for adequate compression of the brachial artery in the obese patient with a very 
large upper arm (see the previous section on Cuff Size). A large cuff may also be required for a big, muscular arm 
with a prominent biceps over which a regular, nontapered cuff might not fit smoothly. In both situations, it is 
particularly important to place the center of the bladder over the brachial artery pulse. If the upper arm is relatively 
short despite the large circumference, it may be difficult to fit a standard large adult cuff over the arm. The BHS’ s 
recommendation to use a very long cuff (12×40 cm; BHS web site August 13, 2003, 
http://w3.abdn.ac.uk/BHS/booklet/special.htm) could obviate this problem. In the rare patient with an arm 
circumference >50 cm, when even a thigh cuff cannot be fitted over the arm, it is recommended that the health care 
practitioner wrap an appropriately sized cuff around the patient’ s forearm, support it at heart level, and feel for the 
appearance of the radial pulse at the wrist. Other potential methods for measuring radial artery pressure include 
listening for Korotkoff sounds over the radial artery, detecting systolic pressure with a Doppler probe, or using an 
oscillometric device to determine systolic blood pressure; diastolic blood pressure is largely overestimated by both 
methods.156 The accuracy of these methods has not been validated, but they provide at least a general estimate of 
the systolic blood pressure. The error of overestimating the pressure when measuring with a cuff that is too small for 
an obese arm can be considerable and can lead to misclassification of an individual as hypertensive and to 
unnecessary concern and therapy.  
1.1.50 Children 
Blood pressure is most conveniently measured in children by auscultation with a standard mercury 
sphygmomanometer. As with adults, the stethoscope is placed over the brachial artery pulse, proximal and medial 
to the antecubital fossa, and below the bottom edge of the cuff. The right arm is generally the preferred arm for 
blood pressure measurement for consistency and comparison with the reference tables.  
Correct blood pressure measurement in children requires the use of a cuff that is appropriate for the size of the 
child’ s upper arm.156 A technique that can be used to select a blood pressure cuff size of appropriate size is to 
select a cuff that has a bladder width that is at least 40% of the arm circumference midway between the olecranon 
and the acromion. This will usually be a cuff bladder that will cover 80% to 100% of the circumference of the arm. 
The equipment necessary to measure blood pressure in children 3 years of age through adolescence includes 
pediatric cuffs of different sizes. For newborn– premature infants, a cuff size of 4×8 cm is recommended; for 
infants, 6×12 cm; and for older children, 9×18 cm. A standard adult cuff, a large adult cuff, and a thigh cuff for leg 
blood pressure measurement and for use in children with very large arms should also be available.  


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Blood pressure measurements in children should be conducted in a quiet and comfortable environment after 3 to 5 
minutes of rest. With the exception of acute illness, the blood pressure should be measured with the child in the 
seated position with the antecubital fossa supported at heart level. It is preferable that the child has feet on the floor 
while the blood pressure is measured, rather than feet dangling from an examination table. Overinflation of the cuff 
should be avoided because of discomfort, particularly in younger children. It is useful to initially inflate the cuff while 
palpating the pulse to estimate the approximate range for the systolic pressure and then inflate the cuff to 30 mm 
Hg above this estimate when the blood pressure is auscultated. The blood pressure should be measured and 
recorded at least twice on each measurement occasion, and the average of these 2 measurements is the 
measurement for systolic and diastolic blood pressure.  
Systolic blood pressure is determined by the onset of the auscultated pulsation or first Korotkoff sound. The phase 
of the Korotkoff sounds that defines diastolic blood pressure has been somewhat controversial. The disappearance 
of Korotkoff sounds or fifth Korotkoff sound (K5, the last sound heard) is the definition of diastolic pressure in adults. 
In children, particularly preadolescents, a difference of several millimeters of mercury is frequently present between 
the fourth and fifth Korotkoff sounds.157,158 In some children, the Korotkoff sounds can be heard to 0 mm Hg, which 
has limited physiological meaning.  
Elevated blood pressure measurements in a child or adolescent must be confirmed on repeated visits before 
characterizing a child as having hypertension. Within individual children, blood pressure at high levels tends to fall 
on subsequent measurement as a result of an accommodation effect (reduction of anxiety as the circumstances 
become more familiar) and regression to the mean, a nonbiological phenomenon that derives, in part, from 
mathematical considerations. Therefore, a more precise characterization of an individual’ s blood pressure level is 
an average of multiple blood pressure measurements taken for weeks or months. A notable exception to this 
general guideline for asymptomatic generally well children would be situations in which the child is symptomatic or 
has profoundly elevated blood pressure. Children who show elevated blood pressure on repeated measurement 
should also have the blood pressure measured in the leg as a screen for coarctation of the aorta. To measure the 
blood pressure in the leg, a thigh cuff or an oversized cuff should be placed on the thigh and the blood pressure 
measured by auscultation over the popliteal fossa. If the systolic blood pressure measured in the thigh is >10 mm 
Hg lower than the systolic blood pressure measured in the arm, additional studies for coarctation should be 
performed.  
There continues to be an increase in the use of automated devices to measure blood pressure in children. These 
devices are easier to use and are becoming alternative instruments for blood pressure measurement when use of 
mercury sphygmomanometers is not permitted for ecological reasons. The most commonly used devices use 
oscillometric methods (see the previous section on The Oscillometric Technique). Situations in which the use of the 
automated devices is acceptable include blood pressure measurement in newborn and young infants in whom 
auscultation is difficult, as well as in an intensive care setting, where frequent blood pressure measurement is 
necessary. The reliability of these instruments in an ambulatory clinical setting is less clear, however.45 
The interpretation of the blood pressure measurement in children requires consideration of the child’ s age, sex, 
and height. Hypertension in children and adolescents is defined as systolic and/or diastolic blood pressure that is 
consistently equal to or greater than the 95th percentile of the blood pressure distribution. Tables are available that 
provide the systolic and diastolic blood pressure level at the 95th percentile according to age, sex, and height.159 
These tables should be consulted to determine if the blood pressure measurements are normal or elevated. 


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Children also demonstrate white coat effects, but the role of ambulatory blood pressure monitoring is less clear in 
children. Validated devices should be used, preferably in a center with experience using ABPM. Large population-
based normative data in children using ABPM are limited.160,161 
1.1.51 Pregnant Women 
Hypertension is the most common medical disorder of pregnancy and occurs in 10% to 12% of all pregnancies. The 
detection of elevated blood pressure during pregnancy is one of the major aspects of optimal antenatal care; thus, 
accurate measurement of blood pressure is essential.161 Mercury sphygmomanometry continues to be the 
recommended method for blood pressure measurement during pregnancy. Blood pressure should be obtained in 
the seated position. Measurement of blood pressure in the left lateral recumbency, on the left arm, does not differ 
substantially from blood pressure that is recorded in the sitting position. Therefore, the left lateral recumbency 
position is a reasonable alternative, particularly during labor. If the patient’ s upper arm circumference is 33 cm or 
greater, a large blood pressure cuff should be used. In the past, there had been some question as to whether the 
fourth (K4) or fifth (K5) Korotkoff sound should be used to define the diastolic blood pressure. The International 
Society for the Study of Hypertension in Pregnancy currently recommends using K5 for the measurement of 
diastolic blood pressure in pregnancy.161 When sounds are audible with the cuff deflated, K4 should be used.  
It is recognized that alternatives to mercury devices may be necessary in the future, and a small number of 
automated blood pressure recorders have been validated for use in pregnancy.162 Self-monitoring may be useful in 
evaluating blood pressure changes during pregnancy.163,164 
Summary and Recommendations 
Accurate measurement of blood pressure is essential to classify individuals, to ascertain blood pressure-
related risk, and to guide management. The objective of this report is to provide clinicians with a 
standardized set of recommendations that, if followed, should lead to accurate estimation of blood 
pressure.  
We recognize that many committees and organizations have published recommendations and that, in 
practice, blood pressure measurement remains suboptimal. In view of the consequences of inaccurate 
measurement, including both the risks of overtreatment and undertreatment, it is the opinion of the 
committee that regulatory agencies should establish standards to ensure the use of validated devices, 
routine calibration of equipment, and the training and retraining of manual observers. Because the use of 
automated devices does not eliminate all major sources of human error, the training of observers should 
be required even when automated devices are used 
Footnotes 
 
The American Heart Association makes every effort to avoid any actual or potential conflicts of interest that may arise 
as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel. 
Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing 
all such relationships that might be perceived as real or potential conflicts of interest.  
 
This statement was approved by the American Heart Association Science Advisory and Coordinating Committee on 
October 13, 2004. A single reprint is available by calling 800-242-8721 (US only) or writing the American Heart 
Association, Public Information, 7272 Greenville Ave, Dallas, TX 75231-4596. Ask for reprint No. 71-0308. To purchase 


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additional reprints: up to 999 copies, call 800-611-6083 (US only) or fax 413-665-2671; 1000 or more copies, call 410-
528-4121, fax 410-528-4264, or e-mail kgray@lww.com. To make photocopies for personal or educational use, call the 
Copyright Clearance Center, 978-750-8400.  
 
Expert peer review of AHA scientific statements is conducted at the AHA National Center. For more on AHA statement 
and guideline development, visit http://www.americanheart.org/presenter.jhtml?identifier=3023366.  
 
This is Part 1 of a 2-part Statement. Part 2 appeared in the February 2005 issue of Hypertension. Both parts were 
published online at http://hyper.ahajournals.org in December 2004.  
 
This Statement originally appeared in the January 2005 issue of Hypertension. When this document is cited, the 
American Heart Association requests the following format: Pickering TG, Hall JE, Appel LJ, Falkner BE, Graves J, Hill 
MN, Jones DW, Kurtz T, Sheps SG, Roccella EJ, Recommendations for blood pressure measurement in humans and 
experimental animals, part 1: blood pressure measurement in humans: a statement for professionals from the 
Subcommittee of Professional and Public Education of the American Heart Association Council on High Blood Pressure 
Research. Hypertension. 2005;45:142– 161.  
  
References 
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Wright JT, Jr, Roccella EJ, Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High 
Blood Pressure; National Heart, Lung, and Blood Institute; National High Blood Pressure Education Program 
Coordinating Committee. Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and 
Treatment of High Blood Pressure: the JNC 7 complete report. Hypertension. 2003; 42: 1206–1252. 
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Appendix A8: Women substudy 
 
Complementary study of the ANRS163-ETRAL trial: evaluation of the evolution of the 
cardiovascular disease-related markers in women included in the ETRAL trial according 
to their ovarian reserve as evaluated by the level of the anti-Müllerian hormone, and their 
menopausal status. 
 
Investigator Contact Information  
Jacqueline Capeau, 
Faculty of Medicine Saint-Antoine site, 27 rue chaligny 75012 Paris, FRANCE 
+33 668456988 
+33 140011432 
Jacqueline.capeau@inserm.fr 
 
Objectives & Hypotheses  
 
First objective: to evaluate, at inclusion and after a 48-week follow-up, the ovarian reserve and the 
menopausal status (by evaluating AMH, anti-Müllerian hormone as a marker of ovarian reserve and from 
the questionnaire regarding the menopausal status) and to analyze whether the metabolic/inflammatory 
/immune activation profile is different according to this status in the group of 48 women.  
 
Second objective: to analyze whether switching women towards a dual therapy raltegravir plus etravirine 
could improve cardiovascular-related markers and inflammatory/immune activation biomarkers to a 
different extent in women according to their ovarian reserve/menopausal status.  
 
Third objective: to compare in women and men from the ETRAL study (165 patients) whether metabolic, 
inflammatory, innate immune activation, fat and bone parameters were different at inclusion 
 
Fourth objective: to comparatively evaluate in women and men from the ETRAL study whether metabolic, 
inflammatory, innate immune activation, fat and bone parameters were modified differently after 1 year, 
according to sex 
 
Background & Rationale, Significance of Selected Topic & Preliminary Data 
 
HIV-infected women present an altered menopausal status and several studies have reported an early 
onset of natural menopause, which is a risk factor for bone loss and cardiovascular diseases (GA Calvet 
Am J Obstet Gynecol 2015;216:765,). In addition, HIV-infected women were found to present a 
decreased level of ovarian reserve, as evaluated by serum anti-Müllerian hormone (AMH), compared to 
seronegative women (P Santulli AIDS, 2016;30:1083). Interestingly, in HIV-infected women, AMH can be 
used to predict the menopausal transition (R Scherzer Am J Obstet Gynecol 2017;216:46).  
 
When aging, HIV-infected patients are at high risk of cardiovascular disease, in relation to personal 
factors, to the virus but also to ART, in particular to PIs (group D:A:D, NEJM 2007, S Lang Arch Int Med 
2010, L Ryom CROI 2017). Inflammation and immune activation probably play a specific role in the 
increased CVD risk observed in these patients (VA Triant JAIDS 2009, DA Duprez PLOS One 2012, T 
Kelesidis JID 2012, E Merlini PLOS One 2012).  
 
More specifically, in women, a recent study revealed that biomarkers of innate immune activation were 
increased in women with reduced ovarian reserve as evaluated by AMH. Moreover, these women have 
increased subclinical coronary atherosclerotic plaques compared to premenopausal women in whom 
AMH is measurable (SE Looby AIDS 2016;30:383).  In these women, with often perturbed menstrual 
cycles, measuring AMH is easier than measuring other female hormones since it has not to be timed to 
menstrual cycle phase. 
 


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Thus, in order to assess the cardiovascular risk in these women aging with HIV infection, it would be 
interesting to evaluate their metabolic status according to their ovarian reserve and their menopausal 
condition.  
 
Preliminary data: First results of the ETRAL trial have shown that switching middle-aged HIV-infected 
individuals with suppressed HIV viremia under a PI-containing regimen towards the dual association 
etravirine/raltegravir resulted in excellent virological efficacy. It also resulted into a marked improvement 
in lipid parameters, decreased inflammatory profile, moderate weight gain both peripheral and central 
and associated bone gain. 
In the ETRAL study, the median age was 52 years old and 48 out of 165 subjects were female (29%). To 
study the ovarian reserve/menopausal status of women included in the ETRAL trail could add important 
results regarding women infected by HIV with regard to their risk of comorbidities when aging. This could 
also be important regarding their ART strategies. 
 
 
Study Design 
This study is observational and is a sub-study of the ETRAL study, that is a phase II trial, non-
comparative, with inclusion of 165 patients from 20 clinical sites. All the samples for the patients have 
been collected and are stored in the Biomarkers Unit at Tenon hospital (Paris), where a number of 
immune activation /inflammatory /metabolic parameters have been already analyzed. 
 
We propose to comparatively evaluate in the female and male groups of the ETRAL trial whether 
metabolic, inflammatory, innate immune activation, fat and bone parameters were different at inclusion 
and whether they were modified differently after 1 year according to sex.  
 
In the group of 48 women, we propose to evaluate the ovarian reserve and the menopausal status and 
their evolution after 48 weeks by evaluating AMH (anti-Müllerian hormone as a marker of ovarian 
reserve) and from the questionnaire (menopausal status) and to separate the women into 3 groups (as in 
the paper of SE Lobby AIDS 2016).  
• 
Non-menopausal with detectable AMH level (premenopausal with measurable AMH) 
• 
Non-menopausal with undetectable AMH level (premenopausal with reduced ovarian reserve) 
• 
Menopausal with undetectable AMH level (post-menopausal). 
 
The evolution of the metabolic, inflammatory, innate immune activation, fat and bone parameters will be 
followed according to the initial values. We plan to add the dosage of MCP-1 to the AMH dosage. 
To that end, the evaluation of the AMH level will be performed in the team of B Fève (Saint-Antoine 
Research Center) by Nathalie Di Clemente, an international expert in the domain (A Pierre JCEM 2017, A 
Pierre JCEM 2016a, A Pierre JCEM 2016b). Most inflammatory and immune activation markers have 
already been evaluated. We will add the marker MCP-1/CCL2, which was shown to be of interest in this 
regard (SE Looby AIDS 2016) to be performed in the UF of JP Bastard at Tenon hospital (APHP and 
UMR_S938)  
 
Expected results 
First, we want to analyze whether the metabolic/inflammatory profile is different at inclusion between men 
and women and whether its evolution differs according to sex. 
Second, since the ovarian reserve/menopausal status could affect the cardiovascular risk, we want to 
analyze whether the metabolic/inflammatory/immune activation profile is different according to this status 
in HIV-infected women receiving PIs.  
Then we want to analyze whether switching women towards a PI-avoiding regimen comprising ART 
considered as lipid friendly and with few adverse impact of age-related comorbidities, could improve 
cardiovascular-related markers and inflammatory/immune activation biomarkers to a different extent in 
women according to their ovarian reserve/menopausal status. 
 
Study Flowchart 
April to May 2018: data analyses in the entire group of 165 patients comparing women and men 
April to June 2018: dosages of AMH and MCP-1 
June to July 2018 : data analyses of the date obtained in the woman group. 
September 2018 : redaction of the report 


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October to November 2018 : redaction of the paper 
Duration : 8 months (with the redaction of the paper) 
 
Study Procedures 
The data entry and data mining analyses will be performed by the team of L Assoumou, working within 
the Institute of Epidemiology and public Health IPLESP (UPMC Inserm UMR_S1136) directed by D 
Costagliola by using the adapted statistical tools (see below). 
The dosage of AMH will be performed by the team of N Di Clemente by using an in-house dosage 
technique 
The dosage of MCP-1 will be performed by the team of JP Bastard and S Fellahi in the biomarker unit of 
Hôpital Tenon using the ELLA system by an ELISA technique (Biotechne). 
 
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