Conditions: HIV Infections
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 148
Healthy volunteers: yes

Brief summary:
Truvada (emtricitabine/tenofovir disoproxil fumarate, or FTC/TDF) is a type of antiretroviral (ARV) medicine that is commonly used to treat HIV. Truvada is also used as pre-exposure prophylaxis (PrEP) to prevent HIV infection in HIV-negative adults. The purpose of this study is to evaluate the acceptability, safety, and use of daily Truvada PrEP as part of a comprehensive HIV prevention package in healthy, HIV-uninfected adolescents 15 to 19 years of age.

Detailed description:
Truvada PrEP is an approach used to protect HIV-uninfected adults against possible infection with HIV. The approach involves taking Truvada every day to prevent HIV infection in case the person is exposed to HIV (for example, through sex with an HIV-infected person). The purpose of this study is to evaluate the acceptability, safety, and use of daily Truvada PrEP as part of a comprehensive HIV prevention package in healthy, HIV-uninfected adolescents 15 to 19 years old. In addition to Truvada PrEP, the HIV prevention package will include HIV testing, management of sexually transmitted infections (STIs), risk reduction counseling, access to condoms, post-exposure prophylaxis (PEP), and circumcision counseling and referral for male participants.

The study will enroll 150 healthy, HIV-uninfected adolescents 15 to 19 years of age. The study will last for 12 months (52 weeks) and involve scheduled clinic visits at study entry (Week 0) and Weeks 4, 8, 12, 24, 36, 48, and 52.

For the first 12 weeks of the study, all participants will be provided with a supply of Truvada tablets to take once daily as part of the comprehensive HIV prevention package. At Weeks 12, 24, 36, and 48, participants will be offered the following options: to continue with the full HIV prevention package plus Truvada PrEP, to stop Truvada PrEP and continue with rest of the HIV prevention package, or to re-start Truvada PrEP if previously stopped. After Week 12 of the study, Truvada tablets will be given only to those participants who decide to take PrEP and who do not have any medical reasons not to do so. Regardless whether they choose to use Truvada PrEP after Week 12, all study participants will be followed through Week 52 of the study.

All study visits will include blood collection, counseling before and after HIV testing, urine collection for pregnancy testing (female participants only), completion of a sexual risk behavior questionnaire, receipt of a supply of condoms, contraceptive counseling, a medical history review, and disclosure of available test results. Select study visits may include a physical exam, blood and urine collection, testing and treatment of STIs, adherence counseling, and an acceptability assessment. Between Months 11 and 12 of the study, some participants will be randomly selected to participate in focus groups to discuss their experiences while taking Truvada PrEP.

Arms:
arm 1: All participants will take Truvada, once daily by mouth for the first 12 weeks of the study. After Week 12 of the study, only participants who indicate a willingness to use Truvada PrEP and who do not have any medical reasons not to do so will continue to receive the Truvada tablets through Week 52.

Interventions: intervention 1: Truvada
Intervention descriptions: intervention 1: Fixed-dose combination tablet containing 200 mg of FTC plus 300 mg of TDF, taken once daily by mouth.

Protocol document:
ICF_002.pdf: 
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LEGAL GUARDIAN CONSENT FORM 
LEGAL GUARDIAN CONSENT FORM FOR SCREENING AND ENROLMENT  
 
Study Title: A Demonstration Open Label Study to Assess the Acceptability and 
Use  of Truvada Pre-exposure Prophylaxis in Healthy, HIV-Uninfected 
Adolescents, 15-19 Years of Age. 
 
 
 
 
Study Number: DAIDS ES ID 11931 
 
 
Study Sponsor: Desmond Tutu HIV Foundation 
 
  
Principal Investigator 
Prof Linda-Gail Bekker 
Site Address 
Desmond Tutu HIV Foundation  
 
 
 
Guinea Fowl Road 
 
Masiphumelele 
 
 
Site Telephone Number  
021 785 5454 
 
To the potential participant: This consent form may contain words that you do 
not understand. To help you understand these words we have included simpler 
words in brackets after complex ones. Please ask the study doctor or the study staff 
to explain any words or information that you do not clearly understand. You may 
take home an unsigned copy of this consent form to think about or discuss with 
family or friends before making your decision. 
 
INTRODUCTION 
The Desmond Tutu HIV Foundation is doing a study of young people and a 
medication called Truvada, and you and your child are being invited to take part. 


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Before agreeing to be screened for enrolment into the study, it is important that 
you read and understand the following explanation of the purpose (reason for) 
of the study, the study procedures (what will happen during the study), benefits, 
risks, and you and your child’s right to withdraw from the study at any time. 
This form has information to help you decide if you want your child to 
participate. If you decide for your child to take part you will sign this form 
because your child is younger than 18 years. Your child will also need to sign a 
form. If your child turns 18 while she/he is participating in the study she/he will 
sign another form because she/he will be able to consent without your 
permission.  
ABOUT THE STUDY 
South African adolescents are at risk for HIV infection. Rates of HIV infection, 
mostly through sexual transmission, among adolescents are increasing rapidly.  
Therefore, prevention methods to lower HIV risk among adolescents are 
urgently needed.   
 
This is part of a bigger project called The CHAMPS (Choices for HIV Adolescent 
Methods of Prevention in South Africa) project. In this project we are assessing 
whether an HIV prevention “menu” can be developed for adolescents in South 
Africa. What we mean by this is that it may mean that people can apply different 
prevention tools to their lives, e.g. Condoms as well as PrEP. The CHAMPS project 
is comprised of three pilot studies rolled out as a series of small, focused, 
interrelated protocols and will help us understand how your child may choose to 
use various prevention tools when they know what  tools are on offer.  
 
The purpose of this research study is to find out whether adolescents will use the 
medication called Truvada as an HIV prevention tool.  Truvada is a type of 
antiretroviral (ARV) medication that is commonly used to treat HIV when used in 
combination with another drug. Truvada is not effective when used alone in the 
treatment of HIV infection in HIV positive individuals. Truvada is now also being 
tested as a pre-exposure prophylaxis or PrEP. PrEP is an experimental approach 


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that uses ARVs to prevent HIV infection in HIV-negative people—it is used by 
HIV negative persons to protect them against possible infection with HIV. 
 
We do not know the effects of PrEP in adolescents between the ages of 15 and 19 
years, and we do not know if it protects adolescents from getting HIV.   Because 
of this, the South African Medicines Control Council (MCC) has not yet approved 
Truvada for preventing HIV infection in adolescents. The MCC however, has 
given permission for a study to be conducted to establish how safe it is for 
adolescents to use Truvada and whether they would find it acceptable to use the 
medication as instructed.  
 
A number of studies have been conducted to show that Truvada is safe in HIV 
uninfected men and women over 18 years of age. Four studies, whose results 
were announced in 2010, 2011 and 2013, showed that HIV infection among adult 
men and women can be prevented by taking Truvada daily. These adult studies 
involved adult males and females, men who have sex with men (in South Africa) 
and sero-discordant couples (where one partner is HIV positive and the other is 
HIV negative) as well as people who inject drugs. Adult studies have shown that 
even though the risk of HIV was reduced, HIV infections still occurred. We do not 
know whether it is safe yet nor can we say whether it can stop some HIV 
infections in adolescents between the ages of 15 and 19 years. 
 
We will enroll 75 adolescents aged 15 to 19 years at the Masiphumelele Clinic in 
Cape Town and 75 adolescents at the Perinatal HIV Research Unit (PHRU) site 
which is based in Kliptown, located near Soweto, close to Johannesburg. We want 
to answer several questions during the study: 
 Will adolescents use the study medication (Truvada) in the way in which 
they have been told to take it? 
 What helps young people adhere to, or keep taking, the study medication?  
 How do young people’s relationships, attitudes, and sexual behaviour 
change over time, while taking this medication? 


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 Is the study medication (Truvada) safe for young people 15-19 years old? 
 
To see if your child can join this study, there are a number of screening 
procedures we need to do. These include: 
 Interview questions 
 Urine tests 
 Blood tests 
 Physical examination 
Your child  can not participate in this study if they are: 
 HIV positive 
 Hepatitis B positive 
 Currently taking part in another HIV prevention study that involves 
medication 
 (For females) Pregnant or planning on becoming pregnant or 
breastfeeding 
 Has a job or other obligations that would require long absences from the 
area (> 4 weeks at a time) 
SCREENING PROCEDURES 
In order to find out if  your child is eligible to participate in the study, you and 
your child will be asked to consent to some screening tests, once they are fully 
explained to both of you. These tests may take more than one visit and may take 
1-2 hours to complete.  All screening tests must be done within 40 days.   If all 
tests are not done within 40 days, and you and your child still want to find out if 
your child is eligible for the study, you will both have to be re-consented and 
your child must begin the screening tests again.  
 
The following procedures will occur at the screening visit: 
 
 An identification number will be assigned to your child. 
 


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 Your child will be counseled about HIV before having an HIV test.  We will 
take some blood from your child’s finger (about a drop) for the HIV test. 
Your child will be told their result as soon as it is available at this visit.  
Your child will talk with the study staff about the meaning of their result 
and how they feel about it.   
 
 If the test shows that your child has HIV, they cannot continue with the 
screening nor take part in the study.  Your child will receive counseling 
and referral for HIV care and treatment.  Your child will be encouraged to 
share their results with an adult whom they trust. If their test results 
show that your child does not have HIV, they may continue with the 
screening.  
 A trained medical staff member will conduct a full physical examination of 
your child. 
 Your child will also need to answer questions about themself, which will 
include where they live, their health and medical history, and personal 
questions about their relationships and sexual behaviour. Your child 
cannot take part in this study if they are not sexually active. You will 
therefore be aware that your child is sexually active if they do take part. 
 If your child is female, the study doctor and/or study nurse will ask your 
child to give some urine for a pregnancy test. Your daughter will be 
required to take a low dose hormonal birth control (the pill or injection) 
during the study, which we will provide.  She can receive information 
about contraception and access to contraceptives without your consent, 
and we will counsel her to practice safer sex. If she is pregnant, she 
cannot take part in the study. We will not tell you but will encourage her 
to tell an adult she can trust. We will counsel her about her options in 
relation to her pregnancy. 


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 We will take one tube, about 5 mls (about 1 teaspoon) of blood with a 
needle from your child’s arm to check how well their kidneys and liver 
are working as well as checking their general health.  
 We will take two tubes, about 10 mls (about 2 teaspoons) of blood to 
check for Hepatitis B infection.  Hepatitis B is a virus that causes 
inflammation of the liver. This infection is spread in a similar way as the 
HIV virus, that is, from mother to child, through contaminated blood, and 
in some cases through sexual transmission. Tenofovir, one of the active 
ingredients in the study medication, can be used to treat both Hepatitis B 
and HIV. The blood will be sent to a laboratory for testing and your child 
will be provided with their test results. If we find that your child has 
Hepatitis B infection, they may not participate in the study. Your child will 
receive appropriate counselling and referrals. If we find that your child 
does not have Hepatitis B infection, the study staff will vaccinate your 
child (give your child three separate injections) that will prevent this 
disease in the future. 
 
 Your child will be tested for, and counseled about, other infections that 
may be passed on to them during sex, including herpes (HSV-2), 
chlamydia, and gonorrhea, which are  sexually transmitted infections 
(STIs).  If your child is having health problems that may be due to these 
infections, we will help them get the appropriate medical care.  
o Chlamydia, and gonorrhea are bacterial infections. If a person 
takes medicines, they will go away completely. We will test your 
child for chlamydia and gonorrhea at screening, at Month 3, and at 
their final study visit. 
o Herpes is a virus which may cause painful sores in the genital area. 
However, herpes may cause no symptoms at all. If painful sores 
from herpes arise, they can be treated with medicine. The herpes 


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virus always stays with a person and may be spread to their sexual 
partners. We will test your child for herpes at screening, month 3  
and at their final study visit. If you child has sores, we will help 
them get medicine to help the sores go away. 
 Your child will be asked about medications they are currently taking, 
previous medical problems they may have had, and will have a physical 
examination. Your child should be open with their study doctor or study 
nurse regarding their health history, since by not disclosing all the 
information about their health, they may put themselves at risk by 
participating in this study. They will be given appropriate feedback and 
access to care, should these procedures reveal important information 
about their health. 
 If all the tests show that your child is eligible to participate in the study, we 
will explain the study to you and your child again and check that you both 
are still willing for your child to continue in the study and answer any 
questions you have. 
 Your child may be given a vaccine injection to protect against Hepatitis B, 
if they have not been previously vaccinated.  
 If you and your child are in agreement and decide for your child to be 
enrolled in the study, you will be asked to sign this document to confirm 
your understanding of and participation in the study.  You will be given a 
copy of this Guardian Consent Form for Screening and Enrolment Version 
3.0 dated 24 July 2015 to keep. 
 After reading this document, the study doctor and/or study nurse will  
ask your child to complete a short quiz in order to make sure that you 
understand what you have consented to for enrolment. If your child gets 
enough of the answers right, your child will be able to continue with 
enrolment. Your child has three chances for this. If after three chances 
your child has still not got enough answers right, your child will not be 


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able to continue in the study. This is to make sure that you are making an 
informed decision about taking part.    
 Both you and your child need to be in agreement in order for your child to 
be enrolled.   Your child will also be asked to read or will have an 
information form read to them.   If they agree, they will be asked to sign a 
copy and will be given a copy to take home. You will also need to 
complete the test to ensure that you understand what you are consenting 
to when your child takes part in the study. 
 Even though you must give consent for your child to be enrolled in the 
study, your child will be giving their own assent to take part and will 
consent independently for tests that we will perform and treatment  that 
she/he may receive during the study. We will tell you more about these 
tests in the next sections. 
 Your child’s decision to continue in the study or to withdraw will not 
affect your child’s regular care or harm your child’s relationship with the 
study doctor and/or study nurse. 
ENROLMENT VISIT 
This visit may take about 3 hours to complete. In addition to the above 
procedures, the following will happen: 
 
Study staff will provide your child with any test results received since the 
screening visit(s). 
 
Study staff will ask your child to provide information on their health 
history and any medical events that have taken place since the screening 
visit. 
 
Study staff will take some blood from your child’s finger (about a drop) 
for the HIV test. Your child will be told their result as soon as it is 
available at this visit. Your child will receive pre- and post-test counseling, 
which will include risk reduction counseling.  


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 
Female participants will be asked to give some urine at each visit for a 
pregnancy test. Study staff will talk with your child about her choices and 
will ask about her use of contraception at each study visit.  
 
Your child will also need to answer personal questions about their 
relationships, attitudes, and sexual behaviour. 
 
Study staff will ask your child to update the information on where you live 
and on how they can keep in contact with you and your child. 
 
We will provide your child with enough condoms until the next study visit 
and discuss how to use them and how your child can protect 
himself/herself from becoming infected with HIV.  
 
Your child may be given a vaccine injection to protect against Hepatitis B, 
if they have not been previously vaccinated.  
 
Your child will be asked to take the study medication “Truvada” – one pill 
every day of the week for the next month. They will be given enough pills 
for 30 days. 
 
Your child will be counseled about the need for adherence.Throughout 
the study your child will also have blood taken to test how much Truvada 
there actually is in your child’s blood. This result will be available at the 
next study visit. Your child will be asked whether he/she wishes to 
receive this result or whether they prefer to be counseled without this 
result. Research staff will give the results and counsel your child 
accordingly. Those who choose not to get these results will still receive 
standard counseling on how and why they should take the pills.  
FOLLOW-UP VISITS  
Your child will complete monthly follow-up visits (approximately every 30 days) 
during the first three months of the study, after he/she enrols. These follow-up 
visits will take about 60 to 90 minutes and the following will occur: 
 


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 Study staff will take some blood from your child’s finger (about a drop) 
for the HIV test. Your child will be told their result as soon as it is 
available at this visit.  Your child will talk with the study staff about the 
meaning of their result and how they feel about it.  Your child will receive 
pre- and post-test counseling, which will include risk reduction 
counseling.  
 Female participants will be asked to give some urine at each visit for a 
pregnancy test. If your daughter becomes pregnant, it is necessary that 
she stops using the medication.   Study staff will talk with your child about 
her choices and will ask about her use of contraception at each study visit. 
 Your child will also need to answer personal questions about their 
relationships, attitudes, and sexual behaviour. 
 Study staff will ask your child to update the information on where they 
live and on how staff can keep in contact with both of you. 
 We will provide your child with enough condoms until the next study visit 
and discuss how to use them and how they can protect themselves from 
becoming infected with HIV.  
 Should your child have any symptoms that cause concern, they will be 
asked to have a physical examination. Every 3 months, your child will 
receive a full physical examination. 
 Your child will be given study medication (Truvada) and asked to take a 
pill a day every day until the next scheduled visit. They will be re-issued 
with medication at every scheduled visit for 3 months.  
 Study staff will ask your child about how well they have taken the 
medication and any side effects or difficulties that may have occurred.  
 Study staff will also collect some blood, approximately 5 mls (1 teaspoon) 
from your child to check their general health and to determine the 
amount of study medication in their blood. Results from some of these 


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blood tests will be given to participants who wish to hear these results, in 
order for the research team to understand if that affects their usage of the 
study medication.   
FOLLOW-UP VISITS (MONTHS 4-12) 
At the 3-month visit, your child will be offered study medication, but will be 
allowed to choose whether they prefer to continue with it or stop it. It is your 
child’s choice whether or not to take this medication. Your child may decide that 
they do not want to take study medication, or your child may choose to take the 
study medication at a later time. Your child will be asked about their choice 
every 3 months by the study staff.  
If your child chooses not to take the study medication at any time, your child can 
still remain in the study and will be asked to attend all visits.  
At the end of month 3, your child will begin 3 monthly visits, approximately 
every 90 days for the remaining 9 months.  
Participants will receive blood tests throughout the study that measure the 
amount of study medication in their blood. These tests are called Dried Blood 
Spots and involve pricking your child’s vein, taking a small amount of their blood, 
and drying a blood spot on a special piece of paper. These tests will occur at all 
study visits, and at the next visit , your child will be shown the result of the test if 
they wish to receive this – it is their choice. Either way, they will be counseled 
about the use of the Truvada pills. 
For study participants who agree to take the study medication, the following 
procedures will also be conducted during follow up visits during Month 4-12: 
 Study staff will take some blood from your child’s finger (about a drop) 
for the HIV test. Your child will be told their result as soon as it is 
available at this visit.  Your child will talk with the study staff about the 
meaning of their  result and how they feel about it.  Your child will receive 
pre- and post-test counseling, which will include risk reduction 
counseling.  


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 Your child will have urine testing  
 Female participants will be asked to give some urine at each visit for a 
pregnancy test. If your child becomes pregnant, it is necessary that she 
stops using the medication.   Study staff will talk with her about her 
choices and will ask about her use of contraception at each study visit. 
 Your child will also need to answer personal questions about their 
relationships, attitudes, and sexual behaviour. 
 Study staff will ask your child to update the information on where they 
live and on how they can keep in contact with your child. 
 Your child will be given enough study medication until the next study visit 
and instructed about how to take it. 
 We will remind your child to use their study medication daily by SMS (if 
they choose to receive it) and ask your child if they are experiencing any 
problems using the medication. 
 Your child must bring back all unused study medication to the study staff.  
 We will provide your child with enough condoms until the next study visit 
and discuss how to use them and how your child can protect themselves 
from becoming infected with HIV.  
 Should your child have any symptoms that cause concern, they will be 
asked to have a physical examination. For the rest of the study, your child 
will receive a full physical examination every 3  months. 
 Study staff will also collect some blood, approximately 5 mls (1 teaspoon) 
to check your child’s general health and to determine the amount of study 
medication in their blood. Results from some of these blood tests will be 
given to those who wish, in order for the research team to understand if 
that affects their usage of the study medication.   


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 Every three months, your child will be asked by a study staff member 
again about whether or not h/she wishes to take the study medication. 
Your child can either stop or start the study medication at these visits.  
 At each adherence counseling session your child will be asked whether 
they wish to receive blood drug level results. This is voluntary. We will 
ask your child why he/she has made the choice they do.  
 Your child will be asked about any social harms or benefits they have 
experienced as a result of participating in the study. 
SECOND FINAL STUDY VISIT 
These procedures will also be done at an early discontinuation visit 
 Your child’s second final study visit will be at Month 12 (Week 48). 
 Study staff will take some blood from your child’s finger (about a drop) 
for the HIV test. You child will be told their result as soon as it is available 
at this visit.  
 Urine testing in your child will be performed.  
 Female participants will be asked to give some urine at each visit for a 
pregnancy test.  
 Study staff will test your child for herpes (HSV-2), chlamydia, and 
gonorrhea. 
 Study staff will ask your child personal questions about their 
relationships, attitudes, sexual behavior, and opinions about the study 
medication. 
 Study staff will also collect some blood, approximately 5 mls (1 teaspoon) 
to check your child’s general health and to determine the amount of study 
medication in their blood. 
FINAL STUDY VISIT (week 52) 


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 Study staff will ask your child some personal questions about your child’s 
relationships, attitudes, sexual behavior and opinions about the study 
medication. 
 All final and outstanding blood results will be returned. 
FOCUS GROUPS 
 Between Month 11 and 12, some participants will be randomly selected to 
attend a focus discussion group about their experiences with taking the 
medication, their likes, dislikes, where they would like to access it if it is 
licensed and how they think they would use it.  Your child may be asked 
to participate. This is voluntary – your child may decline. 
LEAVING THE STUDY 
Tell us if you or your child decides to leave the study or if your child stops taking 
the medication. 
You and/or your child are free to leave/withdraw consent from the study at any 
time and for any reason. Your child’s care at this clinic and their legal rights will 
not be affected, but it is important for you to let us know.  
We will ask your child to come back to the clinic one last time. We may ask to 
take some blood and urine samples. We will also ask about any personal 
problems or benefits your child has experienced from being in the study and ask 
them to complete a questionnaire about why they want to leave the study. 
IF YOUR CHILD BECOMES INFECTED WITH HIV DURING THIS STUDY  
It is important to identify people with HIV early so that they can get the services 
that they need. 
If the HIV test result is positive, your child will receive counseling from study 
staff. They will be encouraged to share their test results with an adult they trust. 
This does not have to be their parent/legal guardian. Your child will also be 
referred for appropriate care and support services in the community.   Your child 
may be asked to join other studies that may be going on at this study clinic. 


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Following another pretest information session, a blood sample for CD4 count will 
be obtained. These tests will provide the doctor with more information about 
their health, immunity, and the nature of the disease. When your child returns to 
the clinic for the next interim visit, results of the CD4 count will be discussed and 
a referral letter to a Primary Health Care facility will be prepared. Your child will 
be followed up for one year beyond sero-conversion and will have a CD4 at 3 
monthly intervals to ensure that initial care is well-managed.  
If your child becomes infected with HIV during this study, and this has been 
confirmed with the procedures described above, your child will be told to stop 
using the study medication because we are not sure about the effects of the study 
medication in HIV infected people. Your child will be invited to continue with the 
remainder of the study visits, and will be supported with disclosure to a trusted 
adult. A genotype test will be performed on the HIV Virus from your child’s blood 
to help with management. 
AT ANY TIME DURING THE STUDY 
Your child will be asked to tell the study staff about medical problems your child 
may have during the study. You or your child can also contact the study staff 
between regular visits to report these problems.  The study staff will examine 
your child as needed and will either provide or refer your child for medical care 
that they may need. 
If your child is having health problems that may be caused by infections passed 
during sex, they will be given a physical examination.  Your child will get 
treatment for curable infections passed on to them during sex if they need it.   If 
your child has any infections that their partner may also have, they  can bring 
him or her to the trial site  for treatment that may be needed.  This will be at no 
cost to them or their partner.  
Your child can have extra counseling and testing for HIV if needed between 
regular visits.   If they wish, their partner can have HIV counseling and testing 
with them.   


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Your child or the study staff may request an interim study visit at any time. 
During this study your child may also be asked to participate in other sub-studies 
(studies related to this one).  Your child does not have to participate in any sub-
studies if they do not want to.   You and your child will be given aseparate 
consent to sign for each sub-study that they wish to participate in. 
While your child is in this study, we ask that they please: 
 
Do not share their study medication with anyone else or use study 
medication that doesn’t belong to them. 
 
Do not participate in any other study involving other HIV prevention 
medication - this is important for their  own safety: 
o If your child uses other study medication from different studies at 
the same time and then has a problem that requires medical 
attention, we will not know which medication has caused the 
problem. 
o If your child is using study medication from different studies at the 
same time, we cannot assess which study medication is working.   
 
Remember that the medication that we are testing has not been proven 
for safety in adolescents and we do not know if it can prevent HIV 
infection, so it is important that your child continues to use male and 
female condoms, and engages in other safer sex behaviours. 
CONTACT  
Once you and your child join the study, it is very important for us to stay in touch 
with you and find out how you and your child are doing.   We will ask for your 
name, address, phone number, and other contact information at your child’s first 
study visit.   We also will ask for the names and contact information of people 
whom we may contact if we cannot reach you.  
We will ask your child to update this information at each study visit. We will use 
your contact information to remind your child of scheduled study visits.  If your 


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child misses a visit, we may call you with your permission or send letters or visit 
your home to find you and your child.  We will also try to reach you through the 
contact people that you list for us.   If we talk to these people, we will not tell 
them why we are trying to reach your child. 
 
 


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RISKS AND/OR DISCOMFORTS OF STUDY PARTICIPATION 
Risks of blood draws: 
In this study, we will take some blood samples. Blood draws can cause bruising, 
pain, fainting, soreness, redness, swelling, itching, and (rarely) infection where 
the needle was put in. 
Personal problems/discrimination: 
Some participants report personal problems or discrimination because of being 
in a study. This could happen to your child. Family or friends may worry, get 
upset or angry, or assume that your child is infected with HIV and treat them 
badly as a result. If you or your child has bad things happen because of the study, 
please tell us. We will try to help. 
Embarrassment/anxiety:  
Your child may feel embarrassed when we ask personal questions about 
relationships, attitudes, and sex. Your child may feel nervous or scared waiting 
for their study test results. Your child could feel worried if their test results show 
that they are infected with HIV, herpes, chlamydia or gonorrhoea. If they are 
feeling this way, we will try to help her / him feel better. 
Risks of someone finding out your personal information: 
We will protect you and your child’s personal information. The risk of someone 
seeing your child’s personal information, when they should not have done so, is 
very low. However, if that happened, you both could feel upset and embarrassed. 
Someone could use the information to treat you and your child badly. We can tell 
you more about how we will protect your personal information if you would like 
it.  
Side effects from the study medication: 
Your child may have side effects from taking the study medication.  The most 
common risks and side effects from the study drug include dizziness, fatigue, 
difficulty sleeping, depression, strange dreams, diarrhea, nausea (upset 


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stomach), vomiting, headache, rash and gas.  Skin discoloration (small spots or 
freckles) may also occur.   
 
Less common but more serious risks may include: 
 Liver problems 
 Kidney problems 
 Inflammation of the pancreas 
 Anemia (low red blood cells) 
 Lactic acidosis (a buildup of a chemical called lactate in the body that can 
cause symptoms of unexplained weight loss, stomach discomfort, nausea, 
vomiting, fatigue, cramps, muscle pain, weakness and shortness of 
breath) 
 Lipodystrophy (changes in fat distribution in your body such as an 
increase in fat around the waist, back of the neck and breast areas, and 
thinning of the face, legs and arms) 
 Metabolic disorders (changes to lipid and sugar levels in your blood) 
 Changes in bone mineral density (thinning bones). This may be made 
worse if your child is also using injectable hormonal methods of family 
planning, e.g. nur isterate IMI.   
 Allergic reactions (symptoms may include fever, rash, upset stomach, 
vomiting, loose or watery stools, abdominal pain, achiness, shortness of 
breath, a general feeling of illness or a potentially serious swelling of the 
face, lips, and/or tongue; 
 If your child is infected with hepatitis B virus, flare-ups of this infection 
may occur. We will minimise this risk by screening your child for 
Hepatitis B and vaccinating them if they are not yet vaccinated or 
infected.  


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 Resistance: if your child becomes infected with HIV and is taking Truvada, 
there is a risk that the HIV virus in your child’s blood may change its make 
up and become resistant to this antiretroviral medication. This means 
your child would not be able to use this medication for treatment of their 
HIV. We will try to minimise this risk by making sure your child is not HIV 
infected when s/he starts the treatment and also by testing her / him for 
HIV frequently.  
 The study medication is investigational (experimental) and there may be 
other risks or side effects which are unforeseen or unknown. You or your 
child should immediately contact the study doctor or study nurse if any 
side effects occur throughout their participation in this study. 
We will try to minimize any side effects and/or risks to your child’s safety 
and well-being. Tests will be done to carefully monitor your child’s physical 
and mental health, including their kidney and liver functioning. The study 
doctor or study nurse will ask your child about any side effects they have 
experienced at every visit and a full physical exam will be conducted as 
needed or every 3 months. Your child will be provided with information 
about how to prevent HIV and will have access to counseling, support, and 
other social and health-related services as needed.  
EARLY TERMINATION/DISCONTINUATION 
There are some situations where we would need to stop your child from taking 
Truvada. These are as follows:  
 Toxicity related to Truvada  
 Your child needs to take medication that cannot be taken while they are 
taking Truvada  
 Your child becomes HIV infected 
 Your child is pregnant/breastfeeding  
 Your child has completed the study   


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 Your child has requested to stop taking Truvada 
 Any conditions or clinical reasons that will threaten your child’s safety 
and well-being 
There are certain situations where we may discontinue your child’s participation 
in the study. These are as follows:  
 We are unable to contact your child after a number of attempts 
 Your child is repeatedly not taking Truvada as prescribed 
 Your child is pregnant/breastfeeding 
 Your child requests to be withdrawn from the study 
 You no longer thinks the study is in your child’s best interests 
 Your child is judged by the Site Investigator to be at significant risk of 
failing to comply with the provisions of the protocol as to cause harm to 
him/herself or seriously interfere with the validity of study results 
 At the discretion of the Independent Ethics Committee, Medicines Control 
Council, Site Investigator, or pharmaceutical supporter. 
 DAIDS, NIAID, the Office of Human Research Protection (OHRP), and the 
FDA as regulatory entities may also discontinue the study at their 
discretion. 
BENEFITS OF STUDY PARTICIPATION 
 We will give your child condoms and show them how to use them, and 
counsel them on how to prevent HIV, and provide them with referrals for 
male circumcision, Post Exposure Prophylaxis or PEP (a medication that 
someone can take after they might have been exposed to HIV), and 
reminders that STI treatment may assist in the prevention of HIV.  
 Your child will have physical examinations and some lab tests over the 
course of the study. This may help them to identify health problems that 
they did not know about. If we find medical problems during these 


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procedures, we will provide your child with treatment if it is provided at 
this clinic or we will refer your child to another clinic or services.  
 Your child will get counseling and testing for HIV and if they are infected 
with HIV, they will be referred for medical care, counseling, and other 
services available to them. 
 Your child will receive treatment if they show any symptoms of STIs. 
 You and your child’s participation in this study will contribute to medical 
knowledge that may help prevent other adolescents from developing HIV. 
PREGNANCY AND CONTRACEPTION (For female participants only) 
The risks of the study medication to an unborn baby are not known.    Adolescent 
girls who are pregnant or breastfeeding may not participate in this study.   
Adolescent girls who become pregnant during the study will remain in the study 
but will be instructed to stop using the study medication while they are 
pregnant.   Your child must confirm that they are not pregnant now, and that 
they do not intend to become pregnant during the study. If your child suspects 
that they have become pregnant during this research study they must notify the 
study doctor or study nurse immediately.  
ALTERNATIVE TREATMENT/METHODS FOR HIV PREVENTION 
There are no medications proven to prevent HIV infection in adolescents 
although medical male circumcision has been shown to reduce infection in young 
men as young as 15 years. The only known way to prevent HIV infection during 
sex is to use a condom every time you have sex. Treating STI’s may also help.   It 
may also help to give someone post-exposure prophylaxis after they might have 
been exposed to HIV.  That is, if there is a chance that they might have been 
infected with HIV e.g. during rape, they can be treated afterwards with 
medication.  In order for PEP to work, it needs to be taken within 72 hours of 
becoming exposed. 
There may also be other research studies that are testing ways to prevent HIV 
infection in this area that your child may be eligible for.   However, if your child 


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agrees to participate in an alternative study on HIV prevention that involves an 
experimental study medication, your child will not be eligible for participation in 
this study. 
RIGHTS AS A PARTICIPANT IN THIS STUDY 
Your child’s participation in this study is entirely voluntary and your child can 
refuse to participate, or stop at any time, without stating any reason.  Your child’s 
withdrawal will not affect their access to other medical care. If you or your child 
chooses to withdraw from this study, your child does not waive any of their legal 
rights as a patient or a research participant at this site. You and your child will be 
informed of any trial related new information in case it may impact your 
willingness for your child to participate. 
COSTS AND REIMBURSEMENT FOR STUDY PARTICIPATION 
You and your child will not be paid for taking part in this study.  However the 
study specific visits, study medication and laboratory tests related to this study 
will be at no extra cost to you or your child. Your child will however be 
reimbursed to cover the costs of transport to and from the clinic and to 
compensate them for time spent at the clinic. This will be R50 per visit.   We will 
not be able to reimburse your child for visits that are not part of the regular visit 
schedule.  
INSURANCE  
The sponsor has taken out insurance from SHA in the event of a trial-related 
injury, i.e. harm suffered as a result of participation in the trial. The sponsor 
agrees to pay all reasonable medical expenses in accordance with the Association 
of the British Pharmaceutical Guidelines (ABPI) in the event of an injury or side-
effect resulting directly from your child’s participation in the trial. The ABPI 
guidelines recommend that the sponsor of the study should pay, without you 
having to prove that the sponsor is at fault, for any injury resulting from your 
child getting the study medication or from other procedures carried out in 
accordance with the protocol for this study. The sponsor will not be liable for any 


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loss, injuries and/or harm that your child may sustain where the loss is caused 
by the use of unauthorized medicine or substances during the study; any injury 
that results from your child not following the protocol requirements or the 
instructions that the study doctor may give your child; any injury that arises 
from any action or lack of action to deal adequately with a side effect or reaction 
to the study medication; an injury that results from negligence on your child’s 
part. By agreeing to participate in this study, you do not give up your right to 
claim compensation for injury where you can prove negligence. In particular, 
your right to pursue such a claim in a South African court in terms of South 
African law must be ensured. 
You must notify the study doctor or nurse immediately of any complications, side 
effects and/or injuries during the study and the nature of the expenses to be 
covered.  Contact information is provided below. 
The insurance does not cover and the study will not pay for:  
 Medical treatment of other injuries or illnesses. 
 Injury caused by not following the research protocol 
 Per DAIDS policy DWD-POL-CL-02.00, the US NIH does not have a mechanism 
to provide direct compensation for research-related injury. 
CONFIDENTIALITY 
We will do our best to protect your child’s private information. Your child’s 
study records will be kept secure. We use a code number in place of your child’s 
name on most records. We will not share your child’s name unless someone 
working on or reviewing the study needs to know it. This may include the 
research staff, ethics committee members, members of the MCC, FDA, study 
sponsor (NIAID), and other related agencies.  
We will keep the information listed below, private and will not share this 
information with you:  


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 Your child’s attitudes towards sexual behaviour and reasons for staying in 
the study. 
 Your child’s answers to questions about sexual behaviour and whether 
they are having sex. 
 Any birth control information we talk about and your child’s access to 
contraceptives if they choose. 
 The results of tests (including pregnancy and STIs) and treatment that 
your child has consented to without the help of an adult. 
To protect your child from harm, we will encourage them to tell a trusted adult 
(not necessarily their parents/legal guardian) about certain situations. We will 
help and support them when they tell others about these difficult situations: 
 If they become pregnant or have a termination of pregnancy.  
 If they have a positive HIV test result.  
Also, the law requires us to tell authorities if your child is being sexually or 
physically abused. The law also requires us to report sexual offenses like rape to 
the authorities. We will tell your child if we are going to inform the authorities. 
Furthermore, if your child is in a relationship with someone who is very much 
older than s/he and who seems to be using your child in an unfair way, the study 
staff will give your child support and help. They will encourage your child to talk 
to a trusted adult, so  that they might help your child deal with this situation. 
WHO HAS REVIEWED THE STUDY 
These screening and enrolment procedures are part of an overall study.   We sent 
the protocol for the whole study to the University of Cape Town Human Research 
Ethics Committee. This is an independent committee established to help protect 
the rights of research participants at the Desmond Tutu HIV Foundation research 
sites.   
We also sent it to the South African Medicines Control Council.    Both these 
institutes have given their approval for us to run the study. 


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We are following ethical guidelines when we run this study. These are the South 
African Department of Health Clinical Trial Guidelines 2006, and DOH (2004) 
and ICH/GCP Guidelines and the Declaration of Helsinki (last updated October 
2013). These guidelines recommend ways to protect the welfare of research 
participants. Please ask us for a copy of these guidelines if you would like to see 
them.  
The study doctor does not have any financial or personal interests with this 
organisation that may bias his/her actions. 
If you want any information regarding your or your child’s rights as a research 
participant, or complaints regarding this research study, you may contact 
Professor Marc Blockman at the University of Cape Town Human Research 
Ethics Committee, which is an independent Committee established to help 
protect the rights of research participants on telephone number 021 406 6338. 
After you have consulted with the study doctor and/or Ethics Committee and if 
they have not provided you with answers to your satisfaction, you should write 
to the South African Medicines Control Council (MCC) at: 
The Registrar 
South African Medicines Control Council 
Department of Health 
Private Bag X828 
PRETORIA 
0001 
Fax: 012 395 9201 
Email: gouwsj@health.gov.za and mogobm@health.gov.za  
EMERGENCY CONTACT  
If your child requires emergency care, or if hospitalisation is required at any time 
during the study or up to 30 days after taking the last dose of study medication, 


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please tell the treating doctor that your child is/was enrolled in this research 
study and that your child’s study doctor and/or study nurse must be informed. 
If you or your child has questions or problems at any time during your 
participation in this study, use the following important contacts. 
If you have questions about this study or want to leave this study, contact 
Cleopatra Jaars 021 785 5454. 
If your child has any symptoms that you think may be related to this study, 
contact Katherine Gill 021 785 3121. 
If you have questions about your rights as a research participant, or problems or 
concerns about how you are being treated in this study, contact Linda-Gail 
Bekker at 021 650 6959 . 
 
INFORMED CONSENT/SIGNATURES 
You will be given a signed copy of this Guardian Consent Form for Screening and 
Enrolment Version 3.0 dated 24 July 2015 to keep. 
 
 I confirm that I have received and read or have had read to me and 
understood this Guardian Consent Form for Screening and Enrolment 
Version 3.0 dated 24 July 2015 for this research study and have had the 
opportunity to discuss the study and ask questions.   My questions have 
been answered to my satisfaction and I have had time to decide whether I 
wish my child to take part. 
 □ 
 I understand that sections of any of my child’s medical notes may be 
looked at by responsible individuals associated with the study, study 
monitors, or from Regulatory Authorities where it is relevant to my child 
taking part in this research study.   I give permission for these individuals 
to have access to my child’s records.  
□ 


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 I understand that my child’s participation is voluntary and that s/he is 
free to withdraw at any time without giving any reason, without her / his 
medical care or legal rights being affected. 
□ 
 I agree to my data and the results of the study being published and 
submitted to Desmond Tutu HIV Foundation’s offices, the US National 
Institutes of Health/Division of AIDS, and the South African Medicines 
Control Council 
 I give permission for my child’s personal doctor about my child’s 
participation in the study, if applicable 
 I authorise the collection, transfer and processing of my child’s study 
data. 
□ 
* FOR ANY IMPARTIAL WITNESS 
I have received and read this Guardian Consent Form for Screening and 
Enrolment Version 3.0 24 July 2015 and any other written information provided 
to the participant. 
□ 
I have attended all verbal discussions between the investigator/study 
coordinator or designee and participant about the study. 
 □ 
By signing, I attest that the information provided was accurately explained to 
and apparently understood by the participant and that informed consent was 
freely given. 
□ 
 
Printed Name of Guardian 
 


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________________________________________  
 
 
_____________________ 
Guardian Signature  
 
 
 
 
Date and time 
OR 
 
Participant thumbprint 
 
 
 
 
 
____________________
 
 
 
 
 
* Printed Name of Witness 
 
_______________________________________  
_____________________ 
* Signature of Witness 
 
 
Date and time 
 
* Printed Name of Person Conducting Consent 
(If other than Investigator) 
 
________________________________________  
 
 
_____________________ 
Signature of Person Conducting Consent  
 
Date and time 
(If other than Investigator)  
 
 
Printed Name of Investigator 
 
_______________________________________  
 
 
_____________________ 
Signature of Investigator 
 
 
 
 
Date and time 
 


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I hereby verify that consent was obtained from the above mentioned person.  
The participant’s guardian has been informed about the risks and the benefits of 
this study, understands the risks and benefits and gave consent for their child to 
participate without coercion, undue influence or inappropriate incentives. 
 
 

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Page 1 of 141 
CHAMPS:  CHOICES FOR ADOLESCENT PREVENTION METHODS FOR SOUTH AFRICA 
 
 
 
 
 
Pilot study B: “PlusPills” 
A Demonstration Open Label Study to Assess the Acceptability and Use of Truvada Pre-exposure 
Prophylaxis in Healthy, HIV-Uninfected Adolescents, 15-19 Years of Age. 
 
Sponsored by: 
Desmond Tutu HIV Foundation 
University of Cape Town. 
 
US Regulatory Sponsor: 
Division of AIDS (DAIDS), United States (US) National Institute of Allergy and Infectious Diseases 
(NIAID) and US National Institutes of Health (NIH) 
 
Grant #:  
Award 1R01AI094586 
 
DAIDS Protocol #:  DAIDS ES ID 11931 
Under IND. 
Version 1.0 
LoA # 1: 29 December 2016 
 
 


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Page 2 of 141 
TABLE OF CONTENTS 
Table of Contents ................................................................................................................... 2 
List of Abbreviations ....................................................................................................................... 5 
Investigator Signature Page ............................................................................................................ 7 
Protocol Summary .......................................................................................................................... 8 
1 Key Roles and Contact Information ........................................................................................... 14 
2 Background ................................................................................................................................ 20 
 
2.1 HIV Prevalence and Adolescents ................................................................................... 18 
 
2.2 HIV Prevalence and Adolescents in South Africa........................................................... 20 
 
2.3 CHAMPS: Choices for HIV Adolescent Methods of Prevention in South Africa ............ 19 
 
2.4 Oral Pre-Exposure Prophylaxis (PrEP) as an HIV Prevention Intervention .................... 21 
 
2.5 Study Hypothesis and Rationale .................................................................................... 21 
 
2.6 Study Product ................................................................................................................ 28 
3 Objectives ................................................................................................................................... 42 
 
3.1 Primary Objectives ......................................................................................................... 42 
 
3.2 Secondary Objectives .................................................................................................... 42 
 
3.3 Exploratory Objectives ................................................................................................... 42 
4 Study Design ............................................................................................................................... 44 
 
4.1 Identification of Study Design........................................................................................ 44 
 
4.2 Summary of Major Endpoints ........................................................................................ 46 
 
4.3 Description of Study Population .................................................................................... 48 
 
4.4 Time to Complete Enrollment ....................................................................................... 49 
 
4.5 Expected Duration of Participation ............................................................................... 49 
 
4.6 Study Sites ...................................................................................................................... 49 
5 Study Population ........................................................................................................................ 51 
 
5.1 Selection of Study Population........................................................................................ 51 
 
5.2 Inclusion Criteria ............................................................................................................ 51 
 
5.3 Exclusion Criteria ........................................................................................................... 51 


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5.4 Strategies for Recruitment ............................................................................................ 52 
 
5.5 Strategies for Retention ................................................................................................. 53 
 
5.6 Co-enrollment Guidelines .............................................................................................. 53 
6 Study Product ............................................................................................................................. 54 
 
6.1 Regimen ......................................................................................................................... 54 
 
6.2 FTC/TDF Formulation ..................................................................................................... 54 
 
6.3 Study Product Supply and Accountability ..................................................................... 54 
 
6.4 Study Product Adherence Assessment .......................................................................... 55 
 
6.5 Concomitant Medications and Procedures ................................................................... 55 
7 Study Procedures ....................................................................................................................... 57 
 
7.1 Screening Visit................................................................................................................ 57 
 
7.2 Enrollment Visit ............................................................................................................. 58 
 
7.3 Follow Up Visits (For weeks 4, 8, 12) ............................................................................. 59 
     7.4  Follow Up Visits (After Week 13 and Up to Week 48; Visit at 24, 36, 48)…………………..61 
 
7.5 Interim Visits .................................................................................................................. 64 
 
7.6 Final study visit (week 52) or Termination Visit (and at the time of any permanent study 
product termination or study product discontinuation) .......................................................... 65 
 
7.7 Clinical Evaluations and Procedures .............................................................................. 65 
 
7.8 Laboratory Evaluations and Procedures ........................................................................ 66 
 
7.9 Behavioural Evaluations and Procedures……………………………………………………………………67  
 
 7.10 Procedures for Participants Who Temporarily Hold or Discontinue Study Product .. 68 
 
7.11 Specimen Preparation, Handling and Collection ......................................................... 70 
 
7.12 Biohazardous Waste………………………………………………………………………………………………..70 
Table 1  Schedule of events………………………………………………………………………………………………….71 
8 Assessment of Safety ................................................................................................................. 76 
 
8.1 Adverse Event Procedures and Reporting Requirements ............................................. 77 
 
8.2 Expedited Adverse Events (EAE) .................................................................................... 79 
 
8.3 Local Regulatory Requirements ..................................................................................... 79 
9 Clinical Management ................................................................................................................. 81 
 
9.1Toxicity Management ..................................................................................................... 81 


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9.2 Hepatitis B Infection ...................................................................................................... 87 
 
9.3 Pregnancy ...................................................................................................................... 87 
 
9.4 Criteria for Early Termination ........................................................................................ 87 
 
9.5 Treatment for Sexually Transmitted Infections ............................................................. 88 
9.6 Management of HIV Infection 
 
 
 
 
         
 
        88 
 
9.7 Criteria for Discontinuation ........................................................................................... 88 
10 Statistical Considerations ......................................................................................................... 90 
 
10.1 Overview and Summary of Design .............................................................................. 90 
 
10.2 Study Endpoints ........................................................................................................... 90 
 
10.3 Study Hypothesis ......................................................................................................... 92 
 
10.4 Sample Size Considerations ......................................................................................... 92 
 
10.5 Data and Safety Monitoring and Review ..................................................................... 93 
10.6 Data Analysis Plan  
 
 
 
 
 
 
 
       94 
11Data Handling and Record Keeping ........................................................................................ 100 
 
11.1 Data Management Responsibilties ............................................................................ 100 
 
11.2 Source Documents and Access to Source Data ......................................................... 100 
 
11.3 Quality Control and Quality Assurance ..................................................................... 100 
12 Clinical Site Monitoring .......................................................................................................... 101 
13 Human Subject Protections ................................................................................................... 102 
 
13.1 Independent Ethics Committee and Regulatory Approval ........................................ 102 
 
13.2 DAIDS Protocol Review .............................................................................................. 102 
 
13.3 Risk/Benefit Statement .............................................................................................. 103 
 
13.4 Informed Consent and Assent Process ...................................................................... 107 
 
13.5 Participant Confidentiality ......................................................................................... 108 
 
13.6 Compensation ............................................................................................................ 110 
 
13.7 Study Discontinuation ................................................................................................ 110 
14 Ethical Considerations ............................................................................................................ 111 
15 Publication Policy ................................................................................................................... 116 
16 Appendices ............................................................................................................................. 117 


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LIST OF ABBREVIATIONS 
AE 
 
Adverse Event 
AIDS 
 
Acquired Immune Deficiency Syndrome 
CRF 
 
Case Report Form 
CRO 
 
Contract Research Organization 
DAIDS Division of AIDS 
DBS 
 
Dried Blood Spot 
DTHF  
Desmond Tutu HIV Foundation 
DSMB  
Data Safety Monitoring Board (DSMB) 
FDA 
 
Food and Drug Administration 
FTC 
 
Emtricitabine  
GCP 
 
Good Clinical Practice  
HCT 
 
HIV Counseling and Testing 
HIV 
 
Human Immunodeficiency Virus 
IB 
 
Investigator’s Brochure 
ICF 
 
Informed Consent Form 
ICH 
 
International Conference on Harmonization 
IEC 
 
Independent Ethics Committee 
MCC 
 
Medicine Control Council 
N 
 
Number (typically refers to participants) 
NIAID  
National Institute of Allergy and Infectious Diseases 
NIH 
 
National Institutes of Health 
PEP 
 
Post-Exposure Prophylaxis 
PrEP 
 
Pre-Exposure Prophylaxis 
PI 
 
Principal Investigator 
QA 
 
Quality Assurance 
QC 
 
Quality Control 
SAE 
 
Serious Adverse Event 


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SMC 
 
Safety Monitoring Committee 
SOP 
 
Standard Operating Procedure 
TDF 
 
Tenofovir Disoproxil Fumarate 
 
 
 


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INVESTIGATOR SIGNATURE PAGE 
 
Version 2.0 
 
Sponsored by: 
Desmond Tutu HIV Foundation 
 
 
The signature below constitutes the approval of this protocol and the attachments, and provides 
the necessary assurances that this study will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality, and according to all applicable legal and 
regulatory requirements and regulations as well as ICH and SA GCP guidelines. 
 
I, as the Principal Investigator, agree to conduct this study in full accordance with the provisions of 
this protocol. Publication of the results of this study will be governed by DTHF policies.  
 
I have read and understand the information in this protocol and will ensure that all associates, 
colleagues, and employees assisting in the conduct of the study are informed about the obligations 
incurred by their contribution to the study. 
 
Principal Investigator: 
 
Signed: 
 
Date: 
 
 
Name: 
 
Title: 
 
 
 
 
 


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PROTOCOL SUMMARY 
Purpose: 
To assess the Acceptability, safety and use of daily oral PrEP (FTC/TDF or 
Truvada®) in healthy, HIV-uninfected adolescents, 15-19 years of age 
Primary objective 
1. To evaluate the Acceptability and Use of a daily regimen of oral 
PrEP (FTC/TDF), as a component of a comprehensive HIV 
prevention package [with HIV testing, STI management, risk 
reduction counseling, access to condoms, PEP, counseling and 
referral for male circumcision (for boys)], for adolescents 
between 15 and 19 years of age. 
2. To evaluate the safety of a daily regimen of oral PrEP (FTC/TDF), 
as a component of a comprehensive HIV prevention package 
[with HIV testing, STI management, risk reduction counseling, 
access to condoms, PEP, counseling and referral for male 
circumcision (for boys)], for adolescents between 15 and 19 
years of age. 


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Secondary objective 
1. To evaluate adherence to a daily regimen of oral PrEP (FTC/TDF), 
as a component of a comprehensive HIV prevention package for 
adolescents between 15 and 19 years of age.  
2. To evaluate change in sexual activity, perceptions of sexual risk, 
risk compensation, and health behaviours, including condom 
use, in adolescents, between 15 and 19 years of age, who take a 
daily regimen of oral PrEP (FTC/TDF) over a 12 month period. 
3. To assess study participants’ and their partners’ perceptions on 
key issues associated with oral PrEP (FTC/TDF), including 
adherence barriers, adherence facilitators, and general product 
knowledge, as part of a comprehensive HIV prevention package 
[with HIV testing, STI management, risk reduction counseling, 
access to condoms, PEP, counseling and referral for male 
circumcision(for boys)]. 
4. To assess HIV incidence in study participants during the course 
of study participation 
 
Exploratory 
objectives 
1. To explore the utility of Dried Blood Spot (DBS) and the impact 
of biofeedback of results as an adherence enhancing strategy, 
among HIV-negative adolescents, between 15 and 19 years of 
age 
2. To explore the relationship between daily PrEP usage and sexual 
practices and behavior in adolescents.  


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Design 
The study is designed as an open-label, single arm  cohort study, to 
evaluate the Accetability, safety  and Use of daily oral PrEP (FTC/TDF) in 
150 adolescents (approximately 75 participants at each site), ages 15-19 
years, their adherence to study product, and any changes in their sexual 
and health behaviors over a 12-month (52 week) period. All participants 
will complete an initial (12 week) 3- month period, during which they 
will receive PrEP as part of a combination prevention package. At all 
subsequent visits, participants will be offered the opportunity to hear 
real-time feedback of drug level data as part of their adherence 
counseling or they may choose to have adherence counseling without 
the feedback of drug level data. The decision about feedback as well as 
self reported adherence will be captured via interviewer administed 
questionnaires at each follow up visit. At the first 3 month (week 12) 
visit and 3 monthly (weeks 24, 36, 48) intervals thereafter participants 
will be offered the following options:  full package + PrEP, stop PrEP and 
continue with rest of package or alternatively re-start PrEP if previously 
stopped.  This will occur during protocol-specified study visits. 
Participants will be followed regardless of PrEP usage for a total of 12 
months (52weeks).  PrEP may be stopped at any other clinic visit but 
recommencement can only occur at a scheduled visit when all medical 
criteria are met including a negative HIV test. Adherence counselling 
will be offered at every visit with options to have drug level feedback or 
not as part of this counselling.  
Study site 
The study will be conducted at The Desmond Tutu HIV Foundation 
research site in Masiphumelele, Cape Town and the Perinatal HIV 
Research Unit (PHRU) site in Soweto, near Johannesburg. 
Study drugs 
FTC/TDF or Truvada® is a 200mg/300mg fixed dose combination tablet 
containing emtricitabine (FTC) and tenofovir disoproxil fumarate (TDF). 
Study population 
Healthy, HIV-uninfected adolescents, 15 and 19 years of age 
Number of 
participants 
150 enrolled participants (approximately 75 participants at each site) 


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Treatment Regimen 
Participants will be provided with a supply of FTC/TDF tablets, taken 
orally, once daily for first 3 months. Thereafter, these tablets will only be 
supplied to those who indicate willingness to take PrEP and who do not 
have a clinical contraindication to do so.  
Study Duration 
Participants will be scheduled to participate in the study for 12 months or 
52 weeks.  
Accrual will require approximately 4 months (16 weeks).   
Duration of 
participation 
Each participant will be scheduled to receive study product for 52 weeks.  
Primary endpoints 
 
Acceptability 
o The proportion of participants who report willingness to 
use the study regimen, take up PrEP and remain on PrEP 
as part of a comprehensive prevention package.  
o Assessment of acceptabiltiy as per questionnaire 
administered at study end.  
 
Use 
o Number of adolescents who continue to use PrEP after 
the initial 3 month period.  
o The total time on PrEP for each adolescent and for the 
cohort as a whole by self report. 
Safety 
o Grades 2, 3, and 4 clinical and laboratory adverse events; 
 
 
 


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Secondary 
endpoints 
Adherence: 
 
Adherence to daily regimens of oral PrEP as evidenced by the use of  
self-report, pill counts, and proportion of participants on FTC/TDF who 
have detectable drug levels, in those participants who have indicated 
willingness to take PrEP and who have had tablets administered   
o Proportion of doses that are taken as instructed.  
o Proportion of blood samples with detectable drug levels  
o Proportion of adolescents with detectable drug levels 
who report using PrEP 
o Proportion of scheduled HIV testing appointments 
missed, in relation to individual characteristics (age, sex, 
number of partners, use of other prevention methods) 
and the characteristics of the product. 
 
Sexual Behavior 
o Reported number of steady and casual sex partners, 
condom use (and change after introduction of study 
product), substance use prior to or during sex, as 
evidenced by participant responses to interviewer-
administered questionnaires and focus groups. 
HIV Incidence  
HIV infection, as measured by seroconversion of study participants 
during the approximate 12 months (52 weeks) of follow-up. 
 
 


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Exploratory 
endpoints 
 
 
Impact on adherence of drug (FTC/TDF) levels as measured in Dried 
Blood Spot/Plasma given as biofeedback  
o Number of counselling opportunities in which drug level 
feedback is requested vs total number of counseling 
events 
o Number and nature of participants who request drug 
level feedback. 
o Correlation between self reported adherence and drug 
levels at each visit for each participant  
o Correlation between self reported adherence and drug 
levels at each visit in the study overall. 
o  Proportion and number of participants whose 
adherence ito study product improves when receiving 
the results of DBS/Plasma compared to those who do not 
receive feedback of results as measured by endpoints 
above.  
Relationship between daily PrEP usage and sexual practices and 
behavior in adolescents 
o Sexual behavior data obtained using a questionnaire and 
focus group.  
 
 


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1 KEY ROLES AND CONTACT INFORMATION 
Project Leader/Principal Investigator 
Name: Linda-Gail Bekker, MBChB, PhD 
Organization: Desmond Tutu HIV Centre 
Address:        University of Cape Town  
                        Werner and Beit Building North  
                        Anzio Road, Mowbray  
                        Cape Town 7925 
Tel: + 27 21 406 6970 
Mobile: +27 83 266 2876 
Fax:      +27 21 650 6963 
E-mail: Linda-gail.bekker@hiv-
research.org.za 
Project Director 
Name: Katherine Gill 
Organization: Desmond Tutu HIV Foundation 
Address:          Guinea Fowl Road  
                          Masiphumelele  
                          7975     
Tel: +27 21 7853121 
Mobile: +27 829290991 
Fax: +27 650 6963 
E-mail: Katherine.gill@hiv-
research.org.za 
Project Study Co-ordinator 
 
Name: Tanya Pidwell 
Organization: Desmond Tutu HIV Centre 
Address:        Guinea Fowl Road 
                        Masiphumelele  
                          7975     
Tel: +27 21785 5186 
Mobile: +27 82 725 5159  
Fax:  +27 650 6963 
E-mail: Tanya.pidwell@hiv-
research.org.za  
Project Socio-Behaviorist 
 
Name:  Laura Myers 
Organization:  Desmond Tutu HIV Centre  
Address:        University of Cape Town 
                        Werner and Biet Building North 
                        Anzio Road, Mowbray 
                        Cape Town 7925         
Tel:  
Mobile:  
Fax: +27 650 6963 
E-mail: Laura.Myers@hiv-
research.org.za 
Project Co-investigator 
 


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Name: Landon Myer 
Organization: School of Public Health and Family 
                          Medicine 
Address:      University of Cape Town 
                      Faculty of Health Sciences 
                      Infectious Disease Epidemiology Unit 
                      Anzio Road, Mowbray 
                      Cape Town 7925  
Tel: +27 21 406 6661 
E-mail: landon.myer@uct.ac.za 
Project Statistician 
 
Name: Maia Lesosky 
Organization: Biostatistician and Senior Lecturer 
                          Department of Medicine 
                          University of Cape Town 
Address:       J47-25, Old Main Bld 
                      Groote Schuur Hospital  
                      University of Cape Town 
Tel: +27 21 406 6891 
E-mail: maia.lesosky@uct.ac.za 
Ethico-Legal Advisors 
 
Name: Cathy Slack 
Organization: HIV AIDS Vaccines Ethics Group             
Address:      University of KwaZulu Natal 
                      School of Psychology  
                      Private Bag XO1 
                      Scottsville 
                      Pietermaritzburg  
Tel: +27 33 260 5751 
Mobile: +27 823765597 
E-mail: slackca@ukzn.ac.za 
Name: Ann Strode 
Organization: HIV AIDS Vaccines Ethics Group  
Address:       University of KwaZulu Natal 
                      School of Psychology  
                      Private Bag XO1 
                      Scottsville 
                      Pietermaritzburg 
Tel: +27 33 260 5731 
Mobile: +27 825733920 
E-mail: strode@ukzn.ac.za 


CHAMPS PrEP LoA#1 dated 29 December 2016  
 
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Consultants 
 
Name: Heather Jaspan 
Organization: Division of Immunology 
Address:      University of Cape Town 
                      Werner and Biet Building North 
                      Anzio Road, Mowbray 
                      Cape Town 7925  
E-mail: hbjaspan@gmail.com 
Name: Sybil Hosek 
Organization: Stroger Hospital of Cook County 
Address:       Department of Psychiatry 
                       Stroger Hospital of Cook County 
                       900 W Polk Street, #854 
                       Chicago, IL 60612 
                       USA 
Tel: +1 312 864-8030 
E-mail: sybilhosek@gmail.com 
Name: Leigh Johnson 
Organization: Desmond Tutu HIV Foundation 
Address:      University of Cape Town 
                      Werner and Biet Building North 
                      Anzio Road, Mowbray 
                      Cape Town 7925  
Email: leigh.johnson@uct.ac.za 
Name: Anne Schley 
Organization: Abela Consulting 
Address:        Bluebell Glen Farm 
                       Wellington 7654 
Tel: +27 21 873 6613 
Mobile: + 27 794017546 
Fax: +27 86 574 0982 
E-mail: anne@abelaconsulting.com 
PHRU Site Principal Investigator 
 
Name: Glenda Gray 
Organization:  Perinatal HIV Research Unit 
Address:         9th Floor  
                        New Nurses Home 
                        Baragwanath Hospital 
                        Soweto   
Tel: +27 11 989 9703 
E-mail: gray@pixie.co.za 


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DAIDS Medical Officer 
 
Name:             Hans Spiegel 
Organization:  KGS-DAIDS/PSP/ NIAID/NIH 
Address:       5601 Fishers Lane 
                       Room 8B51A 
                       Rockville, MD 20852 
Tel: +240-292-4633 
 
E-mail: hans.spiegel@nih.gov 
 
 


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2 
BACKGROUND 
2.1 
HIV PREVALENCE AND ADOLESCENTS  
 
Young people remain at the centre of the HIV/AIDS epidemic in terms of rates of infection, 
vulnerability, impact, and potential for change. In 2008, young people accounted for 40% of all new 
HIV infections in 15-49 year olds. Almost 3000 young people are infected with HIV each day. One 
third of women who are living with HIV are between 15 and 24 years of age. More than 4.3 million 
young people worldwide are believed to be living with HIV, and a majority of them are unaware of 
their HIV status (UNAIDS, 2009). 
 
2.2 
HIV PREVALENCE AND ADOLESCENTS IN SOUTH AFRICA 
 
South Africa has one of the highest HIV prevalences in the world, with an estimated 17% of the 
population aged 15-49 infected (Shisana O, et al 2009, 2014). As in other African countries, 
HIV incidence rates in South African women peak in the 15-24 age group, while HIV incidence rates 
in men tend to be higher in slightly older age groups. (Hallett T, et al 2010, Rehle T, et al 2010) Our 
best modelling estimates suggest that in South Africa an estimated 36% of all heterosexual 
transmission of HIV occurs in the 15-24 age group, and that this proportion is substantially higher 
(up to 45%) among women (Johnson L, et al 2009). From this it is clear that young people, and 
young women especially, are a key target in preventing the spread of HIV at the population level.  
 
South African adolescents are at risk for HIV infection for a number of reasons. Behavioural 
research indicates that sexual activity is initiated at an early age in South African (mean age of 14.6 
years), and that young people have multiple partners and use condoms less consistently compared 
to older age groups. For example, research conducted among high school students in Cape Town 
demonstrated that initiation of sexual activity for many youth begins as early as age 13 (13% among 
girls and 31% among boys). A substantial proportion (14% of girls and 26% of boys) at the average 
age of 13 years reported that they intended to have sexual intercourse in the next 6 months 
(Matthews C, et al 2009). More than half of South Africans aged 15–24 years, have had sex by age 
18 (Shisana o et al 2005,2014h). Once sexually active, adolescents engage in sexual behaviour that 
continues to place them at risk.  In a review of unsafe sexual behaviour among South African youth, 


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50 to 60% reported not using condoms (Eaton L, et al 2003). Findings from a national survey 
indicated a high incidence of multiple concurrent partners in adolescents (Pettifor et al; 2004) and 
this is often related to a history of substance use and early sexual experience (Mpofu E, et al 2006). 
Transgenerational and transactional sex have both been shown to be frequent behaviours among 
South African youth and both are associated with HIV.  
 
Adolescents are a diverse population and given their unique psychosocial, cognitive, physiological, 
and neurological developmental issues, they urgently require targeted, innovative, and responsive 
HIV prevention technologies and products that address these needs and help them to adopt health 
behaviours. 
 
2.3 
CHAMPS: CHOICES FOR HIV ADOLESCENT METHODS OF PREVENTION IN SOUTH AFRICA 
 
Since HIV made its debut almost 30 years ago, much has been learnt about prevention of the 
disease. Knowledge about HIV transmission, safer sex practices, pre-and post-exposure prophylaxis, 
male circumcision, the role of key interventions to prevent HIV transmission from mother-to-child, 
harm reduction initiatives for people who use drugs and rights-based approaches have dramatically 
altered the prevention landscape. 
 
Presently, however, there is no single intervention that protects all susceptible individuals against 
HIV. Currently available and anticipated prevention methods, both biomedical and behavioural, will 
only provide a degree of protection. Additionally, research in sub-Saharan Africa, which has 
previously emphasized a “one size fits all” approach to behavioural prevention strategies, and has 
generally assumed that prevention interventions of demonstrated efficacy and acceptability in 
adults will be easily generalizable to adolescents. 
 
In the context of this emerging evidence for efficacy and adaptability of various HIV prevention 
options and their appropriateness for adolescents, the CHAMPS (Choices for HIV Adolescent 
Methods of Prevention in South Africa) project will address this gap through a novel approach to 
combining different HIV prevention strategies 
Into an optimized prevention ‘menu’ for adolescents, from which young women and men at risk of 


CHAMPS PrEP LoA#1 dated 29 December 2016  
 
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HIV infection may choose a particular combination of strategies to meet their specific needs and 
circumstances. The negative results from the randomized placebo controlled trials of VOICE (MTN 
003) and FEMPREP conducted among African women in which low levels of study product was 
found in participants samples have made the conduct of the CHAMPS studies more compelling than 
ever: it may be that small open label studies that are able to interrogate reasons why individuals 
may be interested in PrEP as a prevention intervention but then discontinue medication when no 
longer desirable as well as whether the role of choice and mode of administration may have an 
impact in overall effectiveness.  
 
The CHAMPS project will be comprised of three pilot studies rolled out as a series of small, focused, 
interrelated protocols. Each study will examine specific questions or research gaps related to 
adolescents (ages 15-19 years old) and one of the following HIV prevention strategies:  
1. Modes of PrEP administration “Uchoose”,  
2. Pre-exposure prophylaxis- (PrEP) “Pills plus”,  
3. Male circumcision “Macho”.  
Each of the study protocols will submitted for ethical and regulatory approval separately. 
 
The findings from the three pilot studies will feed into a fourth, separately proposed study that will 
examine adolescents’ decision making, the efficacy of a ‘menu’ approach for HIV prevention 
options, and the impact of messaging about each option on the adolescents’ selection. This will 
have a large social marketing component: “iChoose”.  
 
Results from all four studies will be used to inform epidemiological modeling and costing exercises 
in order to inform how an HIV prevention ‘menu’ should be constructed and promoted among 
young people for maximum benefit. The first modeling analysis will focus on the effect of the 
specific prevention package on HIV incidence in adolescents participating in a trial setting, over the 
duration of the trial. The second modeling analysis will focus on the impact of the prevention 
package on HIV incidence in the general population over the longer term, taking into account the 
extent to which adolescents interact with the adult population and the extent to which adherence 
to the intervention is sustained as adolescents enter into adulthood. Both modeling exercises will 
attempt to assess which components of the intervention package have the greatest impact and 


CHAMPS PrEP LoA#1 dated 29 December 2016  
 
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which components are relatively cost-effective, in order to inform the selection of interventions 
that are evaluated in efficacy trials. 
 
2.4 
ORAL PRE-EXPOSURE PROPHYLAXIS (PREP) AS AN HIV PREVENTION INTERVENTION 
For adolescents and young adults, the use of PrEP may be most useful in preventing HIV infection 
during the high-risk years of youth.  A growing body of neurobiological research and imaging 
studies suggest that adolescents may be especially prone to engage in risky behaviors, including 
sexual risk and substance abuse, due to developmental changes in the brain (Galvan et al., 2007).  
Thus, PrEP in youth may be viewed as a time-limited strategy that can bridge the developmental 
period between sexual debut and adulthood. 
 
While the potential relevance and plausibility of an oral PrEP strategy as a safe, powerful and time-
limited tool for HIV prevention among high risk people is widely acknowledged (Cohen et al, 2008), 
a number of questions regarding the use of PrEP still need to be addressed.  These issues include, 
but are not limited to, the identification of the best drug(s) and optimal dosing regimens in terms of 
efficacy, safety, adherence and cost-efficiency, designing an effective message that does not reduce 
the salience of reducing sexual risk behaviors, and the acceptability of a PrEP prevention strategy 
within different populations. Many of these issues have been or are being studied currently among 
adult population [see Section 2.6.5. For an overview]. However, there are no data for adolescents 
and young adults.  Thus, the feasibility of recruiting and retaining youth participants in a PrEP study, 
the evaluation of the acceptability of such a study among adolescents, and the evaluation of 
adherence to the PrEP regimen are all issues that need to be urgently addressed. 
 
2.5 
STUDY HYPOTHESIS AND RATIONALE 
 
This study aims to assess the acceptability, and use, primarily, as well as adherence, and safety of 
daily oral PrEP (FTC/TDF) for HIV-1 prevention, among 150 male and female adolescent participants 
at two sites (with approximately 75 participants at each site), ranging in ages between 15 and 19 
years old. Willing participants will be asked after consent and enrollment to take daily oral PrEP for 
3 months. After this period they will be asked to say whether they would like to continue or 
discontinue oral PrEP as part of a prevention package whilst continuing follow up. This question will 


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be posed at the following 2 three monthly intervals (Month 6 (24 weeks) and month 9 (36 weeks) 
until a full 12 months of follow up are complete. Participants will be encouraged to remain on the 
full prevention package including PrEP but will also be informed that should they wish to stop PrEP 
they can be followed without PrEP usage. They will be offered PrEP as part of the full package at 
the next 3-month visit. All participants will complete a questionnaire that will explore choices 
around use/non-use of PrEP at these visits and will also complete a short acceptability 
questionnaire. In addition for those who self report PrEP usage, adherence will be assessed.  
The rationale for this study design is based on some of the feedback received from the VOICE and 
FEMPREP studies. Women in these studies reported high PrEP usage, remained in study and yet 
drug levels indicated very poor PrEP usage (Marazzo et al CROI 2013). Some rationale for this has 
been that PrEP acceptability was low, but with a keen perception among participants that study 
participation hinged on pill adherence. Thus, despite information that drug levels would be 
assessed, participants chose to report pill usage falsely. By making it very clear that trial 
participation does NOT hinge on PrEP usage (other than the first 3 months) we hope that we will 
get a more accurate assessment of real PrEP usage. We also hope that if participants really want to 
be taking PrEP, that adherence to product will persist. Other open label studies such as iPrEx OLE 
suggest this may be the case. By designing the study with an “opt out” arm we hope that we will 
create an authentic comparator group for participants taking oral PrEP (FTC/TDF) persistently and 
adherently, in order to assess any significant differences in adolescents taking oral PrEP (FTC/TDF) 
versus those who choose NOT to do so. We recognize that these may include demographic 
differences but may also include perceptions of risk, sexual activity, etc. In addition, we hope that 
this will give us a true sense of pill usage among this population- data that is currently unknown and 
required in order to more accurately model the impact of this intervention in this age group.  
Both groups will be treated equally, except for administration of TDF/FTC therapy to those who 
select to include PrEP in their prevention package.  
It was felt by the protocol team that the question of use and acceptability would best be answered 
by employing an open label design, The three month initial phase will mean that everyone will at 
least be exposed to 3 months of PrEP usage.  
Adherence to medication can be measured in different ways depending on the condition and the 


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medication in question. Besides usual patient self report of doses correctly taken, adherence may 
be calculated by performing pill counts on pill returns, or else symptoms may be monitored or drug 
levels in blood or urine measured. In HIV treatment, plasma viral load is measured to ensure 
appropriate response to therapy but is also used in practice as a measure of adherence. In the 
latter case, viral load suppression or not may be used during counseling to probe whether a patient 
has been adherent to antiretrovirals or not. Up until recently, the use of antiretrovirals as 
prophylaxis for HIV prevention has been difficult to monitor but increasingly more laboratories are 
setting up assays to measure drug levels in plasma, cells and even in dried blood spots. To date, this 
data has been used to confirm or refute self-reported adherence in prevention trials. In this 
protocol, we would like to explore the feasibility of drug levels of TDF/FTC derived from DBS to 
enhance adherence counseling. Drug levels will be performed real time during the study. 
Participants who have indicated PrEP usage and who return to the study site will be asked about 
their adherence. They will be asked to grade their adherence on a scale since the last visit. They will 
also be asked specific questions about missed doses as well as barriers and facilitators to 
adherence. They will then be asked whether they wish to have their drug levels disclosed to them. 
If they choose yes, they will be told the level and motivational counseling will be structured around 
this result. Should they choose NOT to have the level disclosed to them, they will be asked to give a 
reason and to guess what they think it may be. This data will be recorded on a CRF.  
All participants will be offered motivational adherence counselling on their return visit as long as 
they are taking PrEP (this will apply should they stop and restart PrEP during the course of the 
study). Participants at each visit will also be asked whether they wish to receive feedback of plasma 
drug levels, in order to explore the impact of this intervention on adherence. Participants who 
choose on a follow up visit to NOT receive their blood drug levels will still receive the standard 
adherence counselling during their study visit. In participants who have opted NOT to take PrEP 
they will be followed up as usual with risk reduction counseling, but without additional PrEP 
adherence counseling. A safety team will also review blood drug levels and in a case where 
excessively high blood levels are reported, staff will be informed to investigate possible pill 
overusage. This information WILL be relayed to the site staff regardless of randomisation to ensure 
follow up with participants on possible drug over-use. In addition, drug levels will be available to 
site staff regardless of whether participants choose to hear the results of not. Counselors will be 
trained in motivational counseling and will also be trained on how to use the drug levels during 


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counseling if participants request this.  
 
Dried Blood Spot sampling is an easy and inexpensive way of collecting, shipping and storing blood 
samples. It represents an alternative to the body fluid based method (plasma, liquid blood or 
serum). As a microsampling technique, it has gained increasing importance since this method offers 
strong advantages compared to the conventional collection and analysis of blood or plasma 
samples. These advantages include the need for remarkably lower blood volumes and easier 
shipping and storage, at ambient temperatures. This leads to a simplification of the blood collection 
process and a reduction of the costs involved. In addition, it offers the possibility of both cellular 
and non-cellular drug levels which may indicate more consistent adherence (in the case of cellular 
drug levels) than recent drug levels (non-cellular).  This negates the need for large amounts of 
blood collection, cellular extraction and special storage required in order to assay peripheral blood 
mononuclear cells.  These samples will be collected along with the plasma samples for drug levels, 
and stored. 
 
DBS analysis for TDF drug levels has now been sufficiently validated such that concurrent plasma 
levels are not required (Castillo-Mancilla et al 2013). DBS cellular assays are still being validated and 
so whilst these tests will be done later, for the purposes of this proposal, the equivalent non-
cellular assay will be done on the DBS in order to provide real time feedback to the randomised 
participants within the next monthly visit. The DBS will be from venous (as to capillary) blood which 
is currently validated.  
 
We hypothesize that oral, daily PrEP (FTC/TDF) will be acceptable and used  by HIV-negative 
adolescents, 15-19 years of age and in those who opt to use PrEP, PrEP adherence will be enhanced 
through client centered, motivational adherence counselling that includes feedback about blood 
drug levels. 
 
The study will focus on adolescents in South Africa, where HIV prevalence among youth is high but 
involvement in HIV prevention clinical studies has been low. The study’s outcomes will contribute 
to important prior and current research and will ultimately help build an innovative menu of 
prevention approaches for adolescents that allows for developmental variation and cultural 


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sensitivity. 
 
Recent findings show both safety and efficacy of PrEP in adult populations (including men and 
transgender women who have sex with men; discordant heterosexual couples, and uninfected 
heterosexual men and women). [See section 2.6.5: Studies of Tenofovir and PrEP in Human 
Participants]. In addition, the iPrEx OLE study enrolled youth to receive PrEP and two adoelscents 
studies, ATN 110 and 113 are currently enrolling young MSM aged 15-22years in the USA. 
 
Given the scarcity of data for PrEP and adolescents and as gaps in our knowledge persist, the 
integration of adolescents into HIV biomedical research is critical for the following reasons: 
 
 Outcomes from research involving adolescents may strengthen capacity to create 
efficacious country-level heath policies and prevention programmes that are truly 
responsive to the needs of this population.    
 
 Research suggests that any prevention strategy would be well targeted to young people at 
the time of sexual debut in order to reduce the steep increase in incidence rates seen in 
youth shortly thereafter. Sexual debut in South Africa occurs at a mean age of 14.6 years. To 
this end, a number of research agencies, researchers, and the US Food and Drug 
Administration advise that adolescents are included in safety studies as soon as safety and 
efficacy of a prevention strategy has been shown in adult populations. It is further 
recommended in these and other related documents that this be done in a stepwise fashion 
with gradual roll down in age (US Food and Drug Administration; 2006).  
 
 Due to the distinct physical, social, emotional, and cognitive differences between adults and 
adolescents, it is necessary to test safety and acceptability of interventions in the population 
in question and not merely extrapolate from adults. It cannot be assumed that results of 
adult HIV prevention trials will fully apply to this younger age group. 
 
 Lastly, it seems both timely and necessary to conduct related research in the South African 
context, where the greatest burden of adolescent HIV incidence and prevalence is felt.  


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2.6  
STUDY PRODUCTS 
 
2.6.1 
FTC/TDF (emtricitabine, tenofovir disoproxil fumarate)  
FTC/TDF or Truvada® is a fixed-dose combination of emtricitabine or FTC (5-fluoro-1-(2R,5S)-
[2-(hydroxymethyl)-1,3-oxatholan-5-yl]cytosine) and tenofovir or TDF (9-[(R)-
2[[bis[[(isopropoxycarbonyl)oxy]methoxy]phosphinyl]methoxy]propyl]adenine fumarate), 
hereafter referred to as FTC /TDF.  FTC and TDF are reverse transcriptase inhibitors that 
have been licensed for the treatment of HIV-1 infection in adults and pediatric patients, 12 
years and older (Truvada, GILEAD Sciences 2011) by the U.S. Food and Drug Administration 
(FDA) and, in 18 years and older, by the  Medicines Control Council (MCC) in South Africa. 
Additionally, an application for PrEP licensure approval has recently been submitted to the 
Food and Drug Administration (FDA), and in January 2012, the FDA has approved Viread® 
(tenofovir disoproxil fumarate) in combination with other antiretroviral agents for the 
treatment of HIV-1 infection in pediatric patients ages 2-12 (Viread, Gilead Sciences 2013) 
and FTC is approved for use in children 3 months and older  (Emtriva, Gilead Sciences 2012). 
 
2.6.2 Choice or product.  
TDF and FTC have demonstrated outstanding safety and efficacy in human clinical trials 
(CDC 2011).  TDF has characteristics that make it suitable for evaluation as a 
chemoprophylaxis agent.  These characteristics include: prolonged intracellular half-life that 
allows once-a-day dosing, high levels of tolerability, potent antiviral effects, and selection of 
drug-resistant variants that have mutations associated with diminished viral replication 
capacity.  There are more than 3 million patient years of experience with Tenofovir based 
products worldwide. It is also the most tested antiviral agent for purposes of HIV 
prophylaxis and is currently FDA (USA) approved for this purpose in MSM and at risk 
heterosexual individuals.  
 
2.6.3 Strength of Study Product  
Co-formulation of FTC and TDF has been approved by the FDA and MCC for use for 
treatment of HIV-1 infection, in combination with other antiretroviral drugs. This once daily 


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film-coated tablet contains the active ingredients of 200 mg of FTC and 300 mg of TDF, 
which is the FDA’s recommended dose of Truvada for treating HIV-infected adults and 
adolescents 12 years and older. Further information on Truvada® is available in the current 
package insert. 
 
2.6.4 
Animal Studies of Tenofovir and PrEP 
 
Much of the interest in PrEP stems from studies using TDF in rhesus monkeys.  In the first 
studies investigators injected macaque monkeys with large doses of simian-human 
immunodeficiency virus (SHIV) containing roughly 1000 times the viral load equivalent of 
that in human semen during acute HIV infections.  The macaques were given subcutaneous 
injections of TDF once daily for 4 weeks starting either 48 hours before, 4 hours after, or 48 
hours after intravenous challenge with SIV.  All 10 control animals had established viremia 
within 3 weeks, while the 15 macaques that received TDF prior to viral challenge remained 
SIV-uninfected for 56 weeks.  
 
A subsequent study examined use of TDF to prevent SIV transmission via weekly rectal 
exposure of SHIV in doses that were about five times higher than the amount of HIV 
ribonucleic acid (RNA) in human semen during acute HIV infection (Subbarao et al., 2006).  
Twelve male macaques were included in the study – four received once-daily oral TDF, four 
received once-weekly oral TDF, and four control animals received no TDF.  Macaques 
receiving once-daily TDF became infected after a median of six weeks, while those receiving 
the drug once weekly became infected after a median of seven weeks.  One monkey 
receiving daily TDF remained uninfected after all 14 SHIV exposures.  The control animals 
not receiving TDF became infected after receiving a median of 1.5 virus inoculations (i.e., 
between weeks 1 and 2).  
  
Another study used the same low-dose challenge model to evaluate the efficacy of TDF 
combined with another drug, FTC (Garcia-Lerma et al., 2006).  Six macaques received once-
daily injections of TDF and FTC while six animals served as controls.  Four controls became 
infected after four challenges (5/6 controls were infected by the 10th challenge) while none 


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of the recipients of TDF/FTC became infected even after 14 challenges.  The results were 
highly statistically significant. Just released results from a continuation of this study 
investigated the use of PrEP to prevent rectal HIV transmission in macaques.  Results 
showed that macaques in any of the four treatment groups were less likely to become 
infected than those in the comparison condition.  In particular, all of the macaques that 
received the TDF/FTC combination were protected from infection (Garcia-Lerma et al., 
2008). 
 
The most recently published PrEP study in animals investigated vaginal transmission of HIV 
in humanized bone marrow liver thymic (BLT) mice.  This study, using TDF/FTC, found that 
PrEP using ARVs was highly effective for preventing vaginal HIV transmission.  The authors 
report that none (0%) of the BLT mice that received PrEP became infected after inoculation 
with HIV as compared to 88% of BLT mice that did not receive PrEP.  Thus, BLT mice 
pretreated with ARVs were resistant to intravaginal HIV infection (Denton et al., 2008).  
Finally, a paper presented at the 2008 International AIDS Society conference reported on 
the efficacy of a TDF/FTC topical gel applied vaginally in macaques.  All macaques receiving 
the gel had complete protection against multiple exposures (Parikh et al., 2009). 
 
Two abstracts presented at the 2009 Conference on Retroviruses and Opportunistic 
Infections (CROI) showed additional promising results for PrEP in animal studies.  Dobard 
and colleagues (2012) demonstrated that both TDF and FTC/TDF offered complete 
protection against SHIV among macaques after repeated vaginal exposure.  Garcia-Lerma 
and colleagues (2009) presented data that showed protection against HIV in macaques who 
received FTC/TDF intermittently.  These animal studies suggest that FTC/TDF as PrEP does 
not need daily dosing and that there are several highly protective intermittent PrEP 
modalities (Cong M-E, et al 2011). 
 
2.6.5 
Studies of Tenofovir and PrEP in Human Participants 
These and other encouraging animal studies have prompted investigators to initiate 
multiple clinical studies of PrEP, which have provided further data on its safety and efficacy. 
A summary of completed and ongoing PrEP studies is contained in Table 1 below. 


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Table 1. Completed and Ongoing Studies of Oral PrEP 
 
 
 
 
Results from iPrEx study, released in 2010, showed that in men and transgender women 
who have sex with men, taking a daily TDF or TDF/FTC reduced the risk of acquiring HIV. A 
total of 2499 HIV-seronegative men or transgender women who have sex with men were 
randomly assigned to receive FTC/TDF or placebo once daily. Ten participants were found to 
have been infected with HIV at enrollment, and 100 became infected during follow-up (36 in 
the FTC–TDF group and 64 in the placebo group), indicating a 44% reduction in the 
incidence of HIV (95% confidence interval, 15 to 63; P=0.005) (Grant RM, et al 2010). 
An open-label extension or “rollover” of the iPrEx study will provide TDF/FTC for 72 weeks 
to all HIV-negative iPrEx participants who wish to wish to enroll. The goal of the study is to 
get information on how to improve adherence, and whether people are more likely to take 
the pill now that it has shown partial efficacy in preventing HIV infection. It will also provide 
additional safety data. Participants who became HIV-positive during the iPrEx study or 
between the study and the start of the rollover study will also be eligible to join the study 
for follow-up. This study began in early 2011 and plans to report its findings in early 2013. In 


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addition to collecting longer-term data on PrEP efficacy and safety, iPrEx OLE’s site, Project 
PrEPare Chicago, will explore the acceptability and feasibility of a PrEP trial among YMSM in 
the area. Approximately 99 YMSM between the ages of 18 and 22 years inclusive will be 
recruited for participation in this study.  An additional 15-20 youth age 16 and 17 years will 
be recruited for the focus groups. 
Another success occurred when results were announced in 2011 by the Partners PrEP study, 
which demonstrated that HIV infection among discordant heterosexual couples can be 
prevented by taking oral PrEP daily. Through May 31, 2011, a total of 78 HIV infections 
occurred in the study: 18 among those assigned TDF, 13 among those assigned to FTC/TDF, 
and 47 among those assigned placebo. Thus, those who received TDF had an average of 62% 
fewer HIV infections (95% CI 34 to 78%, p=0.0003) and those who received FTC/TDF had 
73% fewer HIV infections (95% CI 49 to 85%, p<0.0001) than those who received placebo. 
(Baeten J, et al 2012) Additionally, PrEP was found to be safe: the rate of serious medical 
events was similar for those assigned to TDF, FTC/TDF, and placebo. Pregnancy rates were 
similar across the three arms and there was no evidence that TDF or FTC/TDF was 
associated with pregnancy complications. Adherence to the daily PrEP medication was very 
high – more than 97% of dispensed doses of the study medications were taken. More than 
95% of participants were retained in study follow-up. The Partners PrEP Study is continuing: 
those receiving TDF and FTC/TDF PrEP will continue on those medications and those 
receiving placebo will start TDF or FTC/TDF PrEP. 
 
A recent sub analysis (Celum C, et al, 2013) of the Partners PrEP data showed that point 
efficacy in higher risk (higher incidence) participants (including women <30 years)  was still 
77% (Truvada) and 72% (Tenofovir)  albeit with wide confidence intervals.  
Whilst other sub group analyses have shown reasons for concern around adherence to daily 
PrEP regimens in younger participants, these same studies have confirmed high rates of HIV 
acquisition in this same age group.  
 
Additionally, the CDC TDF2 study in Botswana found that a once-daily tablet of TDF/FTC 
reduced the risk of acquiring HIV infection by roughly 63% among uninfected heterosexual 
men and women in the study. Overall, a total of 1,219 HIV-uninfected heterosexual male 


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and female participants (aged 18-39) in Botswana were enrolled in the TDF2 study and 
randomly assigned to take a daily TDF/FTC pill or a placebo pill.  Three participants were 
determined to be HIV-infected at the time of enrollment, and 16 of the participants 
randomized never began study medication.  Those individuals were excluded from these 
analyses, which include data on the remaining 1,200 participants who were HIV-negative at 
the time of enrollment and began study medication (54.7 percent male, 45.3 percent 
female). In the primary analysis, among the 601 participants who received TDF/FTC, there 
were nine who became infected with HIV during the study.  Among the 599 individuals who 
received a placebo, 24 became infected with HIV during the study, translating into a 
statistically significant overall reduction in risk of 62.6 percent (Baeten J, et  al. 2012). 
 
However, despite this recent groundbreaking efficacy data, other studies have 
demonstrated different results. FEM-PrEP, a Phase III trial designed to assess the safety and 
effectiveness of a daily oral dose of TDF/FTC for HIV prevention among women in sub-
Saharan Africa, was stopped in April 2011, following a scheduled interim review of study 
data. The trial's Independent Data Monitoring Committee advised that the study would be 
highly unlikely to demonstrate TDF/FTC effectiveness in preventing HIV infection in the 
study population, even if it continued to its originally planned conclusion. However, no 
safety issues were reported. 
 
The VOICE Study – Vaginal and Oral Interventions to Control the Epidemic – was designed to 
evaluate the safety and effectiveness of two ARV-based approaches for preventing sexual 
transmission of HIV in 5,029 women from Uganda, South Africa and Zimbabwe, as well as 
determining which of these types of administration women were more likely to follow: 
applying vaginal gel daily or taking an ARV tablet once a day.The pill options included 
Tenofovir or Truvada and both the gel and pill arms were placebo controlled.  In September 
2011, an interim review of VOICE determined that it was not possible to show whether oral 
TDF tablets were any better than a placebo for preventing HIV in the women assigned to 
that study group. The Data Safety Monitoring Board (DSMB) therefore recommended that 
the women randomized to the oral TDF tablet group discontinue their use of the study 
product. This recommendation at the time did not apply to the women in the groups using 


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either the TDF gel or oral TDF/FTC tablets, or the corresponding placebos, and as a result, 
the DSMB recommended that these four study groups continue in VOICE. In November 
2011, an additional interim review of safety and efficacy data led the DSMB to recommend 
discontinuation of the vaginal gel arm. However, on both occasions the DSMB did not raise 
any safety issues. The oral Truvada arm and placebo pills arms continued, but in March 
2013, .researchers announced that none of the interventions tested—daily oral tenofovir, 
daily oral TDF/FTC (Truvada), and daily 1% vaginal tenofovir gel—provided additional 
protection against HIV in the study, likely because few of the women in the trial used the 
products as directed. This low adherence explains the lack of benefit and is consistent with 
data from other trials that found a correlation between higher levels of adherence and 
protection from HIV. 
Results from VOICE provide an urgent reminder that products must meet the needs of the 
people using them. While disappointing, the results lend new urgency to understanding the 
needs and desires of women who need HIV protection and also direction to the search for 
additional safe and effective HIV prevention options for women.There is now an even more 
critical need to explore why VOICE, FEM-PrEP and the other PrEP trials had seemingly 
different findings. PrEP has been shown to be efficacious in three clinical trials (Partners 
PrEP, TDF2 and Global iPrEx) and has been licensed for prevention in MSM and 
heterosexuals by the FDA.  On the other hand, two clinical trials (FemPrEP and VOICE) have 
shown no efficacy of PrEP and this has been shown to be due to low uptake and usage of 
study product. In addition to differences in adherence to the study product, there may have 
been important differences in the study populations related to sexual activity, other sexually 
transmitted infections or levels of inflammation that can affect HIV susceptibility. It is 
increasingly accepted however, that product usage has been the greatest driving force in 
differences in efficacy in these clinical trials.  
 
These studies also highlight the key role of CHAMPS in providing currently unavailable data 
on the feasibility of, acceptability of, and, most significantly, adherence to PrEP in other at-
risk populations, such as adolescents. Given that PrEP is a novel prevention method shown 
to be efficacious that is immediately available, it is urgent to understand in carefully 
designed open label studies which individuals may take PrEP, under which circumstances 


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and what the barriers and faciltators to uptake and consistent adherence may be.  
 
2.6.6 
Studies of FTC and TDF in Children and Adolescents  
A review of the current published literature on the feasibility and acceptability of biomedical 
prevention strategy use in adolescents revealed no single study of PrEP’s utility, feasibility, 
or acceptability, targeting an adolescent sample less than 18 years, globally. While data is 
emerging on the use of PrEP in youth aged 18 to 22 years in the USA (Hosek et al; 2013), this 
may not be applicable to a younger African population. 
Happily, ATN 110 and 113 are currently underway and are demonstration projects of 
Truvada as PrEP in young MSM in the USA. Age group here is 15-24 years. Encouragingly, 
regulators have approved proxy parental consent waiver in MSM <18 years of age (personal 
communication: S Hosek, B Kappiogannis).  
 
Data supporting the adolescent indication for FTC/TDF PrEP or Truvada is based on studies 
of the individual components of FTC and TDF. Available data from Gilead Sciences suggest 
that both TDF and FTC are relatively well-tolerated in adolescents, with safety and 
pharmacologic profiles similar to those observed in adults. 
 
The safety and efficacy of FTC or EMTRIVA in adolescents is supported in three open-label, 
non-randomized clinical studies. FTC was administered to 169 HIV-1 infected treatment-
naive and experienced (defined as virologically suppressed on a lamivudine [3TC] containing 
regimen for which FTC was substituted for 3TC) participants between 3 months and 21 years 
of age (mean age 7.8 years). Participants received once-daily EMTRIVA oral solution (6 
mg/kg to a maximum of 240 mg/day) or EMTRIVA capsules (a single 200 mg capsule once 
daily) in combination with at least two other antiretroviral agents. Through 48 weeks of 
therapy, the overall proportion of participants who achieved and sustained an HIV-1 RNA 
<400 copies/mL was 86%, and <50 copies/mL was 73%. 
 
Assessment of adverse reactions is based on data from Study 203, an open label, 
uncontrolled study of 116 HIV-1-infected pediatric and adolescent participants who received 
FTC through 48 weeks. The adverse reaction profile observed during these clinical trials was 


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consistent to that of adult clinical trial participants, with the exception of the occurrence of 
anemia and higher frequency of hyperpigmentation in adolescents and children.  
 
The safety of TDF or VIREAD in adolescent and paediatric participants, aged 2 to less than 18 
years, is supported by data from two randomized trials (Studies 352 and 321) in 184 HIV-1 
infected participants, who received treatment with VIREAD or placebo/active comparator, 
in combination with other antiretrovirals, for 48 weeks.  
 
In Study 352, 92 treatment-experienced participants, 2 to less than 12 years of age, with 
stable, virologic suppression on stavudine (d4T)- or zidovudine (AZT)-containing regimen 
were randomized to either replace d4T or AZT with VIREAD (N = 44) or continue their 
original regimen (N = 48) for 48 weeks. Five additional participants over the age of 12 were 
enrolled and randomized, but were not included in the efficacy analysis. After 48 weeks, all 
eligible participants were allowed to continue in the study receiving open-label VIREAD. At 
Week 48, 89% of subjects in the VIREAD treatment group and 90% of subjects in the d4T or 
AZT treatment group had HIV-1 RNA concentrations <400 copies/ml. The adverse reactions 
observed in participants were also consistent with those observed in clinical trials in adults, 
including those related to lumbar spine bone mineral density and bone turnover. 
 
In Study 321, 87 treatment-experienced participants 12 to less than 18 years of age were 
treated with VIREAD (N=45) or placebo (N=42) in combination with an optimized 
background regimen (OBR) for 48 weeks. The mean baseline CD4 cell count was 374 
cells/mm3 and the mean baseline plasma HIV-1 RNA was 4.6 log10 copies/mL. At baseline, 
90% of subjects harbored NRTI resistance-associated substitutions in their HIV-1 isolates. 
Overall, the trial failed to show a difference in virologic response between the VIREAD and 
placebo treatment groups. However, these data taken together, suggest that the 
pharmacokinetic profile of TDF in participants 2 to less than 18 years of age (at the 
recommended doses) is similar to that found to be safe and effective in adult clinical trials. 
Clinical safety issues and adverse reactions identified in these trials are consistent with 
those observed in adult clinical trials, such as bone mineral density, renal toxicity, and 
gastrointestinal side effects.  


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Overall, these data suggest that there are similar potential safety concerns for FTC and TDF 
in both adolescent and adult populations. However, the long-term safety of PrEP for 
prevention in adolescents is unknown. More research is urgently needed to improve on the 
existing safety and efficacy profiles of these drugs, both individually and in combination. 
Substantial work is also required to measure the effect of knowledge of PrEP efficacy on risk 
behavior and adherence of adolescents. 
 
2.6.7 
Concerns and Potential Risks Regarding Use of PrEP 
Several concerns regarding the use of PrEP remain and warrant further discussion.  
 
Truvada in HIV+ populations 
Among HIV infected populations, antiretroviral medication-associated alterations in 
metabolic systems such as dyslipidemia, fat redistribution, and insulin resistance, 
cardiovascular disease, lower bone mineral density, osteopenia, osteroporosis and renal 
disease have been shown. However, there are some favorable safety data on Truvada® that 
have allowed licensure for use in HIV-infected youth down to age 12 years. 
 
Adverse Drug Events: The risk of adverse drug events resulting from chronic ART in 
uninfected individuals must be evaluated.  Most current PrEP trials use TDF with or without 
FTC.  These agents were chosen as a result of promising data from animal studies as well as 
the overall low rate of toxicity associated with these agents. TDF is associated with low-level 
side effects including nausea, vomiting, and loss of appetite.  Side effects associated with 
FTC/TDF include diarrhea, nausea, fatigue, headache and rash (CDC, 2011).  There have also 
been reports of impaired kidney function and bone density reduction among HIV-positive 
individuals on these medications, which were mostly reversed when the person stopped 
taking the drug (CDC, 2011). Liu and colleagues (Liu A, et al. 2011) studied a subsample of 
US iPrEx participants (n=200) and found a 1.1% net decrease in mean BMD in the TDF vs 
pre-treatment or placebo group at the femoral neck (95% CI 0.4 to 1.9%, p = 0.004) and a 
0.8% net decline at the total hip (95%CI 0.3 to 1.3%, p = 0.003). These declines in BMD in the 
TDF group were most prominent during the first 12 to 15 months of treatment. The authors 


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conclude that TDF use resulted in a small but statistically significant decline in BMD at the 
total hip and femoral neck in HIV-negative men participating in a PrEP trial (Liu et al., 2011). 
 
The iPrEx trial found that daily use of PrEP with FTC/TDF was safe and generally well 
tolerated, with no difference in adverse events between study drug and placebo arms 
(Grant et al., 2010). There were no differences between groups in laboratory abnormalities 
related to liver function, pancreatitis, electrolytes, glucose, phosphate and CBC. Nausea was 
the most common side effect. Data on markers of bone turnover, renal tubular toxicity, and 
parathyroid hormone concentrations have not yet been reported on iPrEx participants. 
 
Both TDF and FTC are highly active against hepatitis B virus (HBV) and are recommended as 
part of the ART regimens in HIV/HBV co-infected individuals. However, HBV exacerbations 
(or increases in HBV load and abnormalities of liver function indicating liver damage) have 
been reported after stopping TDF, adefovir (a nucleotide similar to TDF) or 3TC (closely 
related to FTC) in approximately 20% of persons with chronic active hepatitis B (Lim SG, et 
al. 2002). The frequency of exacerbations of hepatitis B in persons starting antiviral drugs 
with normal or near normal liver function tests is not known, and may be lower than has 
been observed in clinical trials of persons with active HBV disease. In HBeAg-positive and 
HBeAg-negative studies in participants with compensated liver disease at baseline, the 
exacerbations associated with discontinuing antiviral drugs were not generally accompanied 
by hepatic decompensation.   
 
Viral Resistance: A third area of concern is the risk of viral resistance in individuals who 
become HIV-infected despite the use of PrEP.  Results on viral resistance among non-human 
primates exposed to TFV have been mixed (Atchison, 2008; Johnson, 2006).  In treatment 
settings with HIV-infected individuals, appearance of the K65R mutation associated with TFV 
resistance is infrequent.  Atchison and colleagues (2008) report that there was no evidence 
of mutations in an adherent research participant who seroconverted after one month of 
daily TDF exposure.  The authors suggest that preventative use of antivirals, as opposed to 
treatment use, may not engender drug resistance because the viral populations being 
inhibited are too small to readily generate resistant mutants.  In addition, recent studies 


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have suggested that ARV-resistant HIV strains may be less readily transmissible (Turner et 
al., 2004; Yerly et al., 2004), which could diminish concerns regarding resistance among 
people using ARVs for prevention (Gay et al., 2008).  In response to community concerns 
about the risk of resistance from PrEP studies in Cameroon, Smith and colleagues (Smith, et 
al 2006) performed mathematical modeling of 600 participants receiving prophylaxis in the 
Botswana TFV study, which revealed that less than 1 percent of the predicted 
seroconverters would acquire or develop a TFV-resistant strain.  
 
Finally, a case study published recently reports on a patient treated with PrEP for repeated 
high-risk exposures who subsequently seroconverted.  This patient demonstrated TDF/FTC 
susceptible HIV, low post-seroconversion HIV RNA levels, and slow kinetics of 
seroconversion.  Thus, drug resistance to TFV did not occur and the clinical course of HIV 
may have been attenuated (Prada et al., 2010). 
 
Because PrEP is not triple combination therapy, the concern about PrEP participants who 
may sero-convert then develop drug resistance has been raised. Results from the iPrEx trial 
demonstrate very little drug resistance, with no-one developing resistance to tenofovir. 
Three cases of FTC-resistant infections occurred in iPrEx participants who were already 
newly HIV-infected at enrollment. No drug resistance was observed among those who 
became infected during the study (Grant et al., 2010). In the TDF2 trial, two cases of drug 
resistance emerged. One participant in the active drug arm with unrecognized acute wild-
type HIV infection at enrollment demonstrated high levels of K65R, M184V and A62V. One 
participant in the placebo group showed K65R only in very low levels (<1%) (Thigpen et al., 
2011). 
 
Non-Adherence:  It is important to closely assess whether individuals at risk for HIV 
infection will be willing and able to maintain consistent use of a daily medication regimen 
that is used for prevention and thus, not treating an illness they have.  Additionally, close 
monitoring of adherence is necessary to be certain that a PrEP study is evaluating PrEP 
rather than PEP.  Results of medication adherence from the Peterson and colleagues 
(Peterson, et al. 2007) PrEP study demonstrated adherence rates of approximately 74% 


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across sites.  The most commonly noted reasons for missing medications included missed or 
late clinic visits and pregnancy, for which participants were taken off the study drug.  
Preliminary results from the Bangkok PrEP study show participant adherence rates of 92% in 
the week prior to study visit (Choopanya et al., 2013). According to investigators in the 
Partners PrEP study, participants achieved adherence levels of 99% during an average four-
month period during the two-year study (Haberer et al., 2011). However, both iPrEx, 
CAPRISA 004 and VOICE data demonstrate the bias of self-report in over-reporting 
adherence. In the iPrEx trial, non-adherence to study medication was strongly associated 
with infection risk with only 9% of those newly infected having detectable drug in their 
blood (Grant et al., 2010), despite high levels of self-reported adherence. Thus, optimizing 
adherence and its measurement is critical for interpretation of efficacy data and 
implementation planning (Buchbinder & Liu, 2011). Recent thinking has described 3 phases 
to adherence: initial uptake, persistence or continued usage and finally quality of the 
adherence to sustained use in terms of numbers of prescribed doses taken (Bangsberg DR, 
et al 2001). This proposal aims to investigate all 3 aspects of adherence: uptake, persistent 
use and quality of adherence. Use of drug levels real time is explored as a way to enhance 
the ongoing quality of medication adherence over time.  
 
Behavioral Disinhibition: Some have raised the concern that individuals may increase risk-
taking behaviors if they believe that PrEP will prevent HIV transmission – this is called 
“behavioral disinhibition.”  These concerns have been addressed to some degree in a 
previous (Peterson et al., 2007) PrEP study.  Regarding sexual risk behaviors, the mean 
number of sexual partners during the previous month dropped from 21 partners at 
screening to 14 partners at follow-up.  Condom use actually increased from 52% at 
screening to 92% at 3, 6, & 9-month visits and 95% at the 12-month visit (Guest et al., 2008; 
Peterson et al., 2007).  In the Bangkok study of IDUs, injection risk behavior also decreased, 
with 14% of participants reporting needle sharing before enrollment and 4% of participants 
reporting needle sharing at 12-month follow-up (Choopanya et al., 2013).  Two completed 
studies of PEP have also examined the data for evidence of behavioral disinhibition (Martin 
et al., 2004; Schechter et al., 2004).  Both studies reported no associated increase in risk 
behaviors among PEP users.  Furthermore, the majority of participants in both studies 


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reported a significant decrease in sexual risk behaviors as compared to baseline. It is 
understood however, that this phenomenon should be monitored in adolescent 
populations.  
 
Concerns regarding the use of PrEP, while valid, must be weighed against the risks 
associated with continued high infection rates in higher-risk communities such as 
adolescents.  We have carefully designed this study to evaluate the specific protocol 
components that would be necessary in a future effectiveness study of PrEP among youth 
and to evaluate the aforementioned concerns regarding behavioral disinhibition and 
medication adherence. While the proposed study is not designed to determine the efficacy 
of PrEP, this developmental work will provide important data regarding promising strategies 
for introducing new HIV-prevention interventions into adolescent populations. 


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3 
OBJECTIVES 
3.1 
PRIMARY OBJECTIVES 
 To evaluate the acceptability, safety and use of a daily regimen of oral PrEP (FTC/TDF), as a 
component of a comprehensive HIV prevention package [with HIV testing, STI management, 
risk reduction counseling, access to condoms, PEP, counseling and referral for male 
circumcision (for boys)], for adolescents between 15 and 19 years of age. 
 
3.2 
SECONDARY OBJECTIVES 
 To evaluate adherence to a daily regimen of oral PrEP (FTC/TDF), as a component of a 
comprehensive HIV prevention package for adolescents between 15 and 19 years of age.  
 To evaluate change in sexual activity, perceptions of sexual risk, risk compensation, and 
health behaviours, including condom use, in adolescents, between 15 and 19 years of 
age, who take a daily regimen of oral PrEP (FTC/TDF) over a 12 month period. 
 To assess study participants’ and their partners’ perceptions on key issues associated 
with oral PrEP (FTC/TDF), including adherence barriers, adherence facilitiators, and 
general product knoweldge, as part of a comprehensive HIV prevention package [with 
HIV testing, STI management, risk reduction counseling, access to condoms, PEP, 
counseling and referral for male circumcision(for boys)]. 
 Incidence of HIV infection, as measured by seroconversion of study participants during 
the approximate 12 months (52 weeks) of follow-up. 
 
3.3   
EXPLORATORY OBJECTIVES 
 To explore the utility of Dried Blood Spot (DBS)/Plasma drug levels and the impact of 
biofeedback of results as an adherence enhancing strategy among HIV-negative adolescents 
between 15 and 19 years of age 
 To explore the relationship between daily PrEP usage and sexual practices and behavior in 
adolescents. 


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4 
STUDY DESIGN 
4.1 
IDENTIFICATION OF STUDY DESIGN 
We propose an open-label phase II cohort study, to evaluate the acceptability, safety and use of, 
daily oral PrEP (FTC/TDF) in 150 HIV-negative adolescents at two sites (approximately 75 
participants at each site), ages 15-19 years, as well as adherence to medication in participants who 
choose to have biofeedback of drug levels versus those who choose not to and any changes in their 
sexual and health behaviors over a 12-month (52 week) period. Enrolled participants will be 
stratified by gender (33% Male: 66% Female). Out of the 75 participants at each site, approximately 
25 adolescent males and 50 adolescent females will be enrolled. This oversampling of women is to 
account for the fact that although oral PrEP is relevant to both genders, young women are more 
vulnerable to HIV acquistion in South Africa. 
 
After a period of community engagement and general education about prevention packages 
including PrEP, participants will be invited to screen for this study. Those who are considered 
eligible will be asked to return for an enrollment visit. At enrollment, all participants who still wish 
to take part will be asked to take PrEP as part of a comprehensive prevention package for at least 3 
months (12 weeks). During the first 3 months (12 weeks), participants will attend monthly (4 
weekly) clinic visits for adherence counselling, trouble shooting, HIV testing and dried blood spot/ 
plasma drug level sampling.  
Researchers will use dried blood / plasma drug level sampling, combined with the reporting of 
results to individuals by the next visit, as an adherence enhancing strategy for those participants 
who elect to receive this information during adherence counselling at follow up visits. Those 
participants who agree to it, will receive blood drug level results during personal counseling in 
month 2 and 3 (weeks 8 and 12). Those who choose not to get this information will receive 
standard motivational adherence counseling during their study visits. Study staff will explore 
through standard questionnaires the reasons for not receiving drug level data. 
Participants will be asked at the 3-month visit whether they would like to continue PrEP for a 
further 3 months. Those who opt out will continue to be followed in all aspects of the study except 
for distribution of Truvada pills. All participants will receive a brief questionnaire to explore reasons 


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for continuing or stopping PrEP. A short acceptability questionnaire will also be administered. This 
opportunity to “opt out” or “opt back in” will occur at 3 monthly visits until Week 36. Followup will 
continue until week 48. Those who opt out at a 3 monthly visit will be asked whether they wish to 
restart at the next 3 monthly visit. Participants will also be advised that they may “opt out” of PrEP 
in their prevention package at any scheduled visit or at any time in consultation with clinic staff. 
They will be expected to return all study product and will not be issued TDF/FTC. They may “opt 
back in” on a subsequent study visit if all eligibility criteria are met and after a negative HIV test is 
obtained. At each study follow up visit, participants will be asked to grade their adherence on a 
visual scale, they will also be asked whether they wish to receive drug levels and their response and 
reasons for this will be captured. They will then receive motivational adherence counseling with or 
without drug levels depending on their choice at the time.  Monthly scheduled visits will occur until 
month 3, thereafter scheduled visits will be 3 monthly.  
Whilst every effort will be made to encourage adherence to PrEP in the first 3 months, poor 
adherence during those months will NOT preclude participation after 3 months. Every effort will be 
made to ascertain level of use and reasons for less than optimal use.  
Additionally, two focus groups will be conducted at each site during the study period. The first 
focus group will be conducted prior to study initiation (within 3-4 weeks) with as yet non-enrolled 
participants from the community setting (n= 6-8). This size is recommended when conducting focus 
groups on non-commercial topics (Krueger, R.A and Casey, M.A (2008). Focus groups: a practical 
guide for applied research. London: Sage Publications Ltd). This first group will address a number of 
questions including adolescents’ attitudes towards and knowledge of PrEP, in particular, adolescent 
perceptions of taking drugs previously reserved for HIV treatment as a form of prevention; what 
some of the barriers and facilitators of PrEP use may be, where they would like to access these 
drugs outside of the research setting ; whether taking PrEP might identified individuals as high-risk 
and therefore stigmatise them; whether enhanced protection against HIV infection provided by 
PrEP might lead to sexual disinhibition or risk compensation; whether adolescents will still use 
condoms in order to protect against other STI’s; and what factors might impact on adherence. This 
will be seen as perceptions (and identify misperceptions) in agroup of as yet uninitiated and 
perhaps uninformed  youth.This data will be gathered and used for the “social marketing objective 
of CHAMPS-SA, to inform some of the issues that must be considered when creating demand for 


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youth PrEP. The data will NOT be used to inform the protocol nor will any changes to protocol be 
made based on this. Parental/ guardian consent and adolescent assent will be obtained for all focus 
group participants. These FG participants (aged 15-19 years) will be actively recruited from the 
potential pool of participants for the cohort study.  
 
The second focus group will be conducted in two groups with enrolled participants (n= 6-8 in each 
separate group) at each site, to be scheduled in the last four weeks of study follow up. It will 
address a number of questions including participants’ attitudes towards PrEP, in particular, their 
experience taking and general acceptability of the drug; where they would like to access these 
drugs in the future; whether taking PrEP resulted in identification of individuals as high-risk and 
stigmatization; whether enhanced protection against HIV infection provided by PrEP led to sexual 
disinhibition or risk compensation; whether participants still used condoms in order to protect 
against other STI’s; and what factors (such as appearance changes as a result of drug side-effects) 
impacted on adherence. In addition, they will be asked what the impact of real time (whilst this 
does not mean on the day of testing, it is used to denote during the study at the next visit) drug 
levels were in terms of adherence counseling and how they felt about receiving these results at 
study visits. This data will inform the nature of design of PrEP roll oput for youth in the future. 
Parental/ guardian consent and adolescent assent will be obtained for all focus group participants. 
In order to ensure a good spread of FG participants, the follow up cohort will be divided into 2 
groups: those who chose PrEP and were adherent at least 80% of the follow up time and those who 
did not choose PrEP or were adherent <50% of the time. 6-8 participants will be randomly selected 
from each group and then invited to participate in the 2 FGs. The data from these focus groups may 
be reviewed by Research Ethics Committee members, Data Safety Monitoring Committee members 
and the sponsors (NIAID), FDA and/or MCC.  
 
4.2 
SUMMARY OF MAJOR ENDPOINTS 
 
Primary endpoints:  
Acceptability 
o The proportion of participants who report willingness to use the study regimen, take 
up PrEP and remain on PrEP as part of a comprehensive prevention package.  


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o Assessment of acceptabiltiy as per questionnaire administered at study end.  
Use 
o Number of adolescents who continue to use PrEP (as indicated by DBS/ plasma 
levels) after the initial 3 month period   
o The total time on PrEP for each adolescent (as indicated by DBS/plasma levels) and 
for the cohort as a whole in those individuals who indicated PrEP use by self report 
at the beginning of each 3 month period. 
Safety 
o Grades 2, 3, and 4 clinical and laboratory adverse events; 
 
Secondary endpoints:   
Adherence: 
o Adherence to daily regimens of oral PrEP as evidenced by the use self-report, pill 
counts, and proportion of participants on FTC/TDF who have detectable drug levels. 
Proportion of blood samples with detectable drug levels  
o Proportion of adolescents with detectable drug levels who report using PrEP 
o Proportion of doses that are taken as instructed.  
Sexual and other Behaviors 
o Reported number of steady and casual sex partners, condom use (and change after 
introduction of study product), substance use prior to or during sex, as evidenced by 
participant responses to interviewer-administered questionnaires and focus groups. 
o Proportion of scheduled HIV testing appointments missed, in relation to individual 
characteristics (age, sex, number of partners, use of other prevention methods) and 
the characteristics of the product. 
HIV infection,  
o as measured by seroconversion of study participants during the approximate 
12 months of follow-up. 
 


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Exploratory endpoints:   
 
Impact on adherence of providing information on drug (FTC/TDF) levels (as measured in Dried 
Blood Spot/Plasma) given as feedback during counseling sessions.  
o Number of counselling opportunities in which drug level feedback is requested vs 
total number of counseling events 
o Number and nature of participants who request drug level feedback. 
o Correlation between self reported adherence and drug levels at each visit for each 
participant  
o Correlation between self reported adherence and drug levels at each visit in the 
study overall. 
o  Proportion and number of participants whose adherence ito study product 
improves when receiving the results of DBS/Plasma compared to those who do not 
receive feedback of results as measured by endpoints above.  
o Relationship between daily PrEP usage and sexual practives and behavior in 
adolescents  
o Sexual Behaviour Data obtained using a questionnaire and focus groups. 
o  
4.3 
DESCRIPTION OF STUDY POPULATION 
The study population will consist of 150 healthy, HIV-negative adolescents, between the ages of 15 
and 19 years, who will be enrolled with consent of a parent or guardian and meet the criteria in 
Section 5. To achieve balance in baseline characteristics, stratified randomization will be used. A 
total of 75 participants will be enrolled at each study site, consisting of 30 adolescent males and 45 
adolescent females.  
 
All participants will be offered study product and followed for the first 3 months. At the 3-month 
visit, all participants will be asked whether they wish to continue with study product. At every 
subsequent three monthly scheduled visit until month 9, participants will be asked by a study staff 
member again about their choice regarding the study product. Participants will be offered the 
option to continue, stop or re-start the study product at these visits as long as no contra-


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inducations to PrEP usage and their HIV test is negative.  
Participants can opt out of the prescribed study product regimen at any time, but these participants 
will be asked to report to the study site, return all medication and still attend scheduled visits. 
Follow up period is 12 months in all. 
 
4.4 
TIME TO COMPLETE ENROLLMENT 
The maximum allowable time between screening and enrolment per participant is 40 days. 
Following enrollment into the study, each participant will be followed for a total of 12 months. 
Time to complete total enrollment of participants is expected to be completed within 8 months. 
4.5 
EXPECTED DURATION OF PARTICIPATION 
All participants will complete 12 months (52 weeks) of study duration in total.  
4.6 
STUDY SITES 
There are two proposed study sites. The first is a site managed by Desmond Tutu HIV Foundation 
(DTHF) at the Institute of Infectious Disease and Molecular Medicine, University of Cape Town. The 
DTHF site in Masiphumelele is approximately 20km south of Cape Town where DTHF has been 
working since 1999. Several cross-sectional and cohort studies focusing on adolescents have been 
successfully conducted in this under resourced community of 22 000 people. In 2005, DTHF 
demonstrated that the mean HIV prevalence in the 11-19 yr old was 11%; and the HIV prevalence 
was 5% in the local high school (the adult HIV prevalence is 26%). Sexual risk assessment suggests 
that young people in this community practice a range of high risk HIV behaviors. The site has a long-
established relationship with community stakeholders, highly experienced study staff, a youth 
center offering peer-focused activities as well as sexual and reproductive health services, and an 
active adolescent CAB. 
 
The Perinatal HIV Research Unit (PHRU) site is based in in Soweto, near Johannesburg. Soweto is a 
sprawling collection of formal and less formal townships around 40 kilometres from Johannesburg 
in Gauteng. It has a population of approx 1 000 000, and an unemployment rate of over 60%. The 
HIV prevalence of Soweto is approximately 11%, with adolescent prevalence of 2%.  
 


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Both sites have worked together with the South Africa AIDS Vaccine Initiative (SAAVI) and the HIV 
AIDS Vaccine Ethics Group (HAVEG) to develop resources that ensure that the current ethico-legal 
framework for adolescent involvement in vaccine studies is implemented, and both sites also have 
well-established adolescent community advisory boards. 
 


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5 
STUDY POPULATION 
5.1 
SELECTION OF STUDY POPULATION 
The inclusion and exclusion criteria in Sections 5.2 and 5.3 will be used by study staff to ensure the 
appropriate selection of study participants. 
5.2 
INCLUSION CRITERIA 
Participants must meet all of the following criteria to be eligible for inclusion in the study: 
1. Age 15 to 19 years (inclusive) at screening, verified per study site SOPs 
2. Able and willing to provide written informed consent/ assent (age dependant) to be 
screened for and to take part in the study 
3. Have a guardian who is able and willing to provide written informed consent for their child 
to be screened for and to take part in the study 
4. Able and willing to provide adequate locator information, as defined in site SOPs 
5. HIV-uninfected based on testing performed by study staff at screening and enrollment 
6. Sexually active, as defined as a minimum of one act of (penile vaginal)sexual intercourse in 
the last 12 months, per self-report 
7. (For female participants) Negative pregnancy test at screening and enrollment and per 
participant report, does not intend to become pregnant in the next 12 months 
8. (For female participants) Using an effective method of contraception at enrolment, and 
intending to use an effective method for the study duration; effective methods include low 
dose oral, implant or injectable hormonal methods.  
9. Does not report intention to relocate out of the study area during the course of the study 
10. Does not have job or other obligations that would require long absences from the area (> 4 
weeks at a time) 
11. Willing to undergo all study-required procedures 
12. At screening and enrollment, agrees not to participate in other research studies involving 
drugs or medical devices for the next 12 months 
 


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5.3 
EXCLUSION CRITERIA 
Participants who meet any of the following criteria, at baseline, are excluded from the study: 
 
As determined by the Site Investigator, any significant uncontrolled, active or chronic 
disease process such as but not limited to diabetes, hypertension, and other diseases 
involving the cardiovascular, pulmonary, gastrointestinal, genitourinary, musculoskeletal, 
and central nervous systems 
 
Confirmed > Grade 2 hypophosphatemia 
 
Presence of serious psychiatric symptoms (e.g., active hallucinations) 
 
Visibly distraught at the time of consent (e.g., suicidal, homicidal, exhibiting violent 
behavior) 
 
Intoxicated or under the influence of alcohol or other drugs at the time of consent 
 
Acute or chronic hepatitis B infection (i.e. if hepatitis B surface antigen positive) 
 
Hep B seronegative and refuses vaccination.  
 
Renal dysfunction (Creatinine Clearance < 75 ml/min);  
(Use Cockroft-Gault equation: 
 
Male      
(140−𝑎𝑔𝑒)∗  𝑊𝑒𝑖𝑔ℎ𝑡(𝐾𝑔)
𝑆𝑒𝑟𝑢𝑚 𝐶𝑟𝑒𝑎𝑡𝑖𝑛𝑖𝑛𝑒 (𝑚𝑔 𝑝𝑒𝑟 𝑑𝑙)∗72   = ml/min 
Female    
(140−𝑎𝑔𝑒)∗  𝑊𝑒𝑖𝑔ℎ𝑡(𝐾𝑔)
𝑆𝑒𝑟𝑢𝑚 𝐶𝑟𝑒𝑎𝑡𝑖𝑛𝑖𝑛𝑒 (𝑚𝑔 𝑝𝑒𝑟 𝑑𝑙)∗72   = ml/min * 0.85 
 
Serum Creatinine conversion Factors  
Creatinine (mg/dl) = Creatinine (µmol)/ 88.4 
Creatinine (mg/dl) = Creatinine (mmol)/ 88.4 *1000 
 
 
Urine dipstick for protein and glucose, excluding 1+ or greater 
 
Any history of bone fractures not explained by trauma 
 
Any Grade > 2 toxicity on screening tests and assessments 
 
Concurrent participation in an HIV vaccine study or other investigational drug study 
 
Known allergy/sensitivity to the study drug or its components 
 
Use of disallowed medications (see section 6.5) 
 


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Note: Otherwise eligible participants with an exclusionary test result may be re- tested during the 
screening process. If a participant is re-tested and a non- exclusionary result is documented within 
40 days of providing informed consent for screening, the participant may be enrolled. 
 
5.4 
STRATEGIES FOR RECRUITMENT  
Adolescents will be recruited through community outreach, by targeting schools, youth groups, 
sport clubs, taxi ranks, and other points of convergence in the community. In addition, local HCT 
centres and primary health care clinics will be targeted. Well-established relationships with 
community stakeholders exist at both proposed study locations and these will be capitalised on.  
 
DTHF’s adolescent CAB has also assisted researchers in developing strategies to enhance 
adolescent participation in studies. The Future Fighters have assisted with the development of 
many stakeholder engagement initiatives, aimed at strengthening recruitment and retention 
mechanisms, including drama, poetry, rap, song, and dance performances in their local settings. 
Media is also widely incorporated into their recruitment strategies, including MXIT, Facebook and 
other social networks.  
5.5 
STRATEGIES FOR RETENTION 
Given the study sites’ previous experience with the South African Studies on HIV in Adolescents 
(SASHA) Project, funded by the EDCTP, the study staff have an in-depth understanding of youth 
friendly health services, age-appropriate counseling techniques, and adolescent-specific 
recruitment and retention strategies. Attempts will also be made to engage adolescent participants 
in a number of activities, including pairing participants with one another to offer support and 
encouragement to complete the study, where adolescents are willing to do so. 
 
Other mechanisms that will be used during the study, to ensure maximum retention, such as: 
 
Collection of detailed locator information at the study screening visits, and active review 
and updating of this information at each subsequent visit 
 
Use of visit reminder strategies (these have been tried and tested by this adolescent 
community and are acceptable) 


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 
Follow-up on missed visits 
 
Mobilization of trained outreach workers to assist with follow up 
 
Regular communication with the study community at large to increase awareness of HIV 
and explain the purpose of HIV prevention research in adolescent populations and the 
importance of completing research study visits 
5.6  
CO-ENROLLMENT GUIDELINES 
Co-enrollment in other research studies, which do not involve investigational agents or active study 
products or medical devices, is permitted. 


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6 
STUDY PRODUCT 
6.1 
REGIMEN 
The regimen for enrolled study participants who choose to receive the study product during the 12 
months of follow up is a FTC/TDF (Truvada®) tablet taken orally, once daily. For any missed doses, 
participants will be instructed to take the next scheduled dose.  
6. 2 
FTC/TDF FORMULATION   
FTC/TDF or Truvada® is a 200mg/300mg fixed dose combination tablet containing emtricitabine 
(FTC) and tenofovir disoproxil fumarate (TDF).  FTC is a synthetic nucleoside analogue of cytidine. 
(See Section 2.4: Study Products). One FTC/TDF tablet contains 200 mg FTC plus 300 mg of TDF. 
FTC/TDF should be stored at 25°C. Excursions are permitted between 15°C and 30°C. 
6.3 
STUDY PRODUCT SUPPLY AND ACCOUNTABILITY 
FTC/TDF tablets will be supplied by Gilead Sciences (Foster City, CA, USA).  FTC/TDF tablets (30 
tablets per bottle) are packaged in bottles with a child-resistant screw cap.  In addition to the 
tablets, each bottle contains a silica gel desiccant to protect the product from humidity and 
polyester packing material that cushions it during handling and shipping.  Gilead will prepare 
bottles of study agent that are each labeled with the active agents and the expiry date.  
 
6.3.1 
Pharmacy Facilities and Drug Dispensing 
A pharmacist will be responsible for dispensing the drug to each study participant. Only 
participants with negative HIV test results, will be dispensed the study drug.  At enrollment, 
participants who take study medication will receive a prescription that will include the 
participant ID. Detailed instructions for receipt, handling, storage, dispensing, 
accountability, retrieval of unused study products from participants will be provided in site-
specific SOPs and South Africa’s Good Pharmacy Practice Guidelines.  
 
6.3.2 
Retrieval of Unused Study Drug 
The study pharmacist will document all product returns and store any unused study product 


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in a designated area of the pharmacy. At the end of the study, any unused product will be 
destroyed, per GCP guidelines and instructions received by Gilead Sciences.  
6.4 
STUDY PRODUCT ADHERENCE ASSESSMENT 
Adherence to study product will be measured by the use of self-report, pill counts, and proportion 
of participants on FTC/TDF who have detectable drug levels.  
 
Comprehensive and age-appropriate study product adherence counseling will be provided to all 
study participants who receive study product, at every visit (until week 48,) to help ensure high 
rates of study product use. Counseling will address such topics as personal barriers and facilitators 
to using PrEP, remembering to use the study product daily, reminders to contact study staff with 
questions about study product use, and not to distribute or share their study products to other 
people. The current client centered counseling methodology applied by both sites for the FACTS 
001 study (both sites are involved in this adult microbicide study) is being adapted for adolescent 
appropriateness and will be applied in this study. This will also be adapted to include or not include 
(depending on participant choice) the incorporation of drug level data back to the participant. It is 
envisaged that the adaptation will include modifications around daily use vs BAT24 (regimen in 
FACTS001), Oral PrEP vs topical and a youth centered approach vs an adult approach. It will have all 
the elements of being client centered, with emphasis on finding barriers and facilitators of 
adherence in a non-judgemental approach.  
For the participants who select biofeedback during counseling, results from blood plasma or dried 
blood spots, which indicate their drug levels, will be fed back to participants at scheduled follow up 
visits. Participants may choose differently at each feedback session. In cases where drug levels 
indicate overuse study staff will be informed to intervene.  
6.5  
CONCOMITANT MEDICATIONS AND PROCEDURES 
With the exception of medications listed as prohibited (see below, this section), enrolled study 
participants may use concomitant medications during study participation.  All concomitant 
medications, including prescribed and over-the-counter Preparations, vitamins and nutritional 
supplements, recreational drugs, and herbal Preparations reported within the 70 days prior to 
study enrollment and throughout the course of the study will be recorded on the Case Report 


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Forms (CRF) designated for that purpose.  Medications used for the treatment of AEs that occur 
during study participation also will be recorded on applicable study case report forms. 
Should participants report use of any of the following medications, they will be required to 
discontinue use of study drug: interleukin therapy, medications with significant nephrotoxic 
potential (including but not limited to amphotericin B, aminoglycosides, cidofovir, foscarnet and 
systemic chemotherapy), and medications that may inhibit or compete for elimination via active 
renal tubular secretion (including but not limited to probenecid). In addition, if a participant 
requests post-exposure prophylaxis (PEP) for HIV exposure, they will be referred to a health care 
provider for evaluation. If a participant starts ARV therapy for PEP, they should hold study 
medications until completion of the course of PEP. 
 


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7 
STUDY PROCEDURES 
An overview of the study visits and evaluations schedule is presented in Table 1: Schedule of Study 
Visits and Procedures. 
 
Scheduled visits for participants include the following; 
 Screening  
 Enrollment 
 Follow up Visits (initial product use period: Weeks 4-12; visits at wk 4,8,12) 
 Follow-up Visits (optional product use period: Weeks 13- 48; visits at wk 24,36,48) 
 Final Study Visit (week 52) 
7.1 
SCREENING VISIT 
Screening procedures may take place up to 40 days prior to a participant’s enrollment. It is 
expected that, in most cases, all required screening procedures would be completed at one visit. 
However multiple visits may be conducted within this time period to complete all required 
screening procedures, if necessary. Written informed consent for screening is obtained before any 
screening procedures are initiated. For participants who do not meet the eligibility criteria, 
screening is discontinued once ineligibility is determined. If HIV-infection is identified as the reason 
for ineligibility, counseling and referral to appropriate treatment site will be performed. 
 
Screening procedures are as follows: 
 Administrative/Behavioural Procedures 
o Obtain written informed consent for enrollment, from participant and his/her parent 
or guardian 
o Assessment of understanding for informed consent form 
o Identification number assignment 
o Locator information 
o HIV pre-and post-test counseling, inlcuding risk reduction counselling 
o Provision of condoms 
o Schedule next visit (if applicable) 


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o Reimbursement. 
 
 Clinical Procedures 
o Medical eligibility information 
o Medical history 
o Physical exam, including Tanner staging  
o Syndromic treatment for STI, if clinically indicated  
o Offer of STI testing and treatment for participant and partner(s) if indicated 
o Ascertainment of current contraceptive method and contraceptive counseling  
o Contraceptive counselling and provision of contraception as appropriate 
o Blood collection  
o Hep B vaccination if non-immune by serologic testing. (This will be given at 0,1 and 6 
months; Wks 0,4, 24)  
 
 Laboratory Procedures 
o HIV serology  
o Hepatitis B surface antibody and antigen testing (test results will be given to 
participants approximately one week after the test and vaccination will be provided 
during screening window) 
o Herpes (HSV-2), and a swab  
o Gonorrhea and Chlamydia  * 
o Urine dip stick  
o Aspartate aminotransferase/alanine aminotransferase (AST/ALT) testing 
o Serum chemistries, including creatinine, glucose, electrolytes, and lipase  
o Full Blood Count  
o Urine pregnancy testing (for females) 
* The swab will be self collected vaginal swab for girls and a urine test for boys.  
7.2 
ENROLLMENT VISIT 
Day 0 for the participant will be the day of the Enrollment Visit: 
 Administrative/Behavioural Procedures 


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o Locator information (update) 
o Review of study procedures (ongoing consent) 
o HIV pre-and post-test counseling, inlcuding risk reduction counselling 
o Provision of condoms 
o Eligibility assessment (including review of all screening documentation) 
o Baseline sexual risk behavior questionnaire (for all enrolled participants) 
o Reimbursement  
o Schedule next visit (if applicable) 
 
 Clinical Procedures 
o Review of all prior screening documentation  
o Update medical history and/or current medications, if applicable  
o Re-confirmation (by participant self-report) of medical eligibility information  
o Syndromic treatment for STI, if clinically indicated  
o Offer of STI testing and treatment for participant and partner(s) if indicated 
o Confirmation of current contraceptive method and contraceptive counseling  
o Contraceptive counselling and provision of contraception as appropriate 
o Disclosure of available test results, which must be made available to participant prior 
to administration of study product  
o Hepatitis B vaccination, if indicated 
o Update Medical History 
o Provision of study drug and instructions 
 
 Laboratory Procedures 
o Urine pregnancy testing (for females) 
o HIV rapid testing 
 At all visits 
 As clinically indicated 
  
7.3 
FOLLOW UP VISITS (FOR WEEKS 4, 8, 12) 


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All enrolled study participants will complete 4 weekly follow-up visits for the first 12 weeks, 
targeted to occur every 28 days after the participant’s study enrollment date (Day 0). Target dates 
are set based on the enrollment date, and do not change if subsequent actual visits take place 
before or after the target date. As it will not always be possible to complete monthly follow-up 
visits on the targeted dates, follow-up visits may be completed within an approximate 2-week 
window around the target date (-/+7 days from the target date). Thereafter visits will be 12 weekly 
with similar windows applying.  
 
The following procedures will be completed at each initial Follow-Up Visits; Wks 4, 8, 12: 
 Administrative/Behavioural Procedures 
o Locator information (update) 
 At all visits 
o HIV pre-and post-test counseling, including risk reducation counselling 
 At all visits 
o Social harms and/or benefits 
 At all visits 
o Sexual risk behavior questionnaire 
 At all visits 
o Acceptability questionnaire 
 At all visits 
o Provision of condoms 
 At all visits 
o Reimbursement  
 At all visits 
o Schedule next visit 
 At all scheduled visits, except Final Study Visit 
 
 Clinical Procedures 
o Contraceptive counselling and provision as appropriate 
 At all visits 
o Targeted Physical exam 


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 As clinically indicated 
o Update medical and menstrual history and/or current medications if applicable  
 At all visits 
o Record/update adverse events (AEs) applicable  
 At all visits 
o Hepatitis B vaccination, if indicated  
 At Enrollment (wk 0), month1 (Wk 4) and Month 6 (Wk 24) 
o Provision of study drug and instructions 
 At weeks 4, 8 . 
 
 Laboratory Procedures 
o HIV rapid testing 
 At all visits 
 As clinically indicated 
o STI testing 
 Herpes (HSV-2),  
 Chlamydia and Gonorrhea testing (wk 12 only) 
o Urine dip stick testing 
 Every 3 months; At wk 12 only 
o Aspartate aminotransferase/alanine aminotransferase (AST/ALT) testing 
 Every 3 months; at wk 12 only 
o Serum chemistries, including creatinine, glucose, electrolytes, and lipase 
 Every 3 months, at wk 12 only 
o Full blood count  testing 
 Every 3 months; at wk 12 only 
o Haematocrit testing  
 Weeks 4 and 8 
o Urine pregnancy testing (for females) 
 At all visits 
o Contraceptive counseling  
 At all visits  


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o TDF/FTC drug levels via venous blood sampling and preparation of dried blood spots 
for storage. 
 At all visits, Wks 4, 8 and 12.  
7.4 
FOLLOW UP VISITS (AFTER WEEK 13 AND UP TO WEEK 48; VISITS AT 24, 36, 48) 
For the initial product usage lead-in period (Weeks 4-12), study participants will be asked to adhere 
to the study product. After the 12 week lead in period, participants will be asked at subsequent 12 
weekly visits whether they wish to continue PrEP, stop PrEP or restart PrEP as part of their 
prevention package (Week 12, 24 and 36). All participants regardless of product usage will be 
followed for the duration of the study. Participants will be advised to make these decisions at 
scheduled study visits. Reasons for decision will be enquired upon and recorded in CRFs. 
Participants will also however be told they can contact study site at any time and also when they 
should with-hold PrEP for medical reasons.  
Participants will complete scheduled 4 weekly follow-up visits until week 12. Thereafter, all visits 
will be 12 weekly regardless of PrEP addition to the prevention package or not. Target dates are set 
based on the enrollment date, and do not change if subsequent actual visits take place before or 
after the target date. 
 
As it will not always be possible to complete follow-up visits on the targeted dates, follow-up visits 
may be completed within an approximate 2-week window around the target date (-/+7days from 
the target date). 
 
The following procedures will be completed at each Follow-Up Visit (wks 24, 36, 48): 
 Administrative/Behavioural Procedures 
o Locator information (update) 
 At all visits 
o HIV pre-and post-test counseling, including risk reducation counselling 
 At all visits 
o Social harms and/or benefits 
 At all visits 
o Sexual risk behavior questionnaire 


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 At all visits 
o Provision of condoms 
 At all visits 
o Provision of study drug (for participants who choose to receive study product) 
 at visits Wk 12, 24, 36 . 
o Acceptability assessment  
 at visits Wk 12, 24, 36, 48. 
o Adherence Counselling (if participant is on study product) 
 at visits Wk 12, 24, 36, 48 (week 48 visit will be feedback on last 3 months 
only since no more product will be offered). 
o Feedback of plasma drug level/DBS results (to participants on study product who 
agree to receive this information at the time of adherence counseling.)  
 At visits Wk 12, 24, 36, 48. 
o Adherence assessment (including pill counts) and counselling (for participants who 
choose to receive study product) 
 At visits Wk 12, 24, 36, 48 
o Study drug supplies and instructions/counseling (for participants who choose to 
receive study product) 
 At all visits where study product is administered week 12, 24, 36 
o Reimbursement  
 At all visits 
o Schedule next visit 
 At all scheduled visits, except Final Study Visit 
 
 Clinical Procedures 
o Contraceptive counselling and provision as appropriate 
 At all visits 
o Physical exam 
 At week 48  
 As clinically indicated 
o Update medical and menstrual history and/or current medications if applicable  


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 At all visits 
o Record/update adverse events (AEs) applicable  
 At all visits 
 
 Laboratory Procedures 
o HIV rapid testing 
 At all visits 
 As clinically indicated at unscheduled visits (reported exposures) 
o STI testing 
 Herpes (HSV-2), 
 Chlamydia, and Gonorrhea testing (0, 12, and 48 weeks) 
o Urine dip stick testing 
 Every 12, 24, 36, 48 weeks  
o Aspartate aminotransferase/alanine aminotransferase (AST/ALT) testing 
 Every 12, 24, 36, 48  weeks  
o Serum chemistries, including creatinine, glucose, electrolytes, and lipase 
 Every 12, 24, 36, 48 weeks  
o Full Blood Count  testing 
 Every 12, 24, 36, 48 weeks 
o Urine pregnancy testing (for females) 
 At all visits 
o Contraceptive counseling  
 At all visits 
o Measurement of study drug levels by Plasma/DBS  
  At 12, 24, 36, 48 weeks. 
7.5 
INTERIM VISITS 
Participants may make interim contacts and unscheduled visits at their request, or as deemed 
necessary by the Site Investigator or designee, at any time during the study. All interim contacts 
and unscheduled visits will be documented in the participant’s study file. When an interim contact 
or unscheduled visit occurs in response to AEs, a study clinician will clinically assess the reported 


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event and provide, or refer the participant for, appropriate medical care. Study participants will be 
instructed to contact their study clinic in the event of any AE. Participants will also be instructed to 
seek immediate emergency care (even from other providers) if they consider they require it. The AE 
will be reported on the appropriate CRF. 
Some examples of reasons for an interim visit are: 
 To report an AE; 
 To get more condoms or study product; 
 To address any contraceptive needs; 
 To ask questions of study staff; 
 To discuss problems with study adherence; 
 To perform an interim examination (e.g., follow-up on an AE or participant request); and 
 To provide lab results not available at the last follow-up visit. 
If a participant is contacted when s/he missed a visit, staff will try to obtain her reasons for missing 
a visit. This information may be used to try to improve overall retention in the study. 
7.6 
FINAL STUDY VISIT (WEEK 52) OR TERMINATION VISIT (AND AT THE TIME OF ANY 
PERMANENT STUDY PRODUCT TERMINATION OR STUDY PRODUCT DISCONTINUATION) 
Participants who reach week 52 will follow procedures included in the table of study procedures on 
page 72.   This  includes provision of any outstanding test results and final interviews. In addition a 
DBS/ plasma will be performed for drug levels at the final study visit. 
 
Participants who have chosen to discontinue the product prior to the routine protocol-required 
withdrawal at Week 52 should continue routine follow-up visits. All protocol-required interviews 
and procedures, besides study product administration and drug levels, should be continued until 
Final Study Visit. 
 
If a participant discontinues study product following instruction from the Investigator or wishes to 
withdraw permanently from the study, visit procedures as per week 48 will be conducted. The 
participant will then return for a final study visit (week 52) if possible.  
 
The following procedures will be completed the final visit (wk 52 the final visit): 


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 Administrative/Behavioural Procedures 
o Locator information (update) 
 At all visits 
o HIV pre-and post-test counseling, including risk reducation counselling 
 At all visits 
o Social harms and/or benefits 
 At all visits 
o Sexual risk behavior questionnaire 
 At all visits 
o Provision of condoms 
 At all visits. 
o Acceptability assessment  
 Wk 52. 
o Feedback of plasma drug level/DBS results (to participants on study product who 
agree to receive this information at the time of adherence counseling.)  
 At visits Wk 12, 24, 36, 48. 
o Reimbursement  
 At all visits 
 
 Clinical Procedures 
o Contraceptive counselling and provision as appropriate 
 At all visits 
o Physical exam 
 As clinically indicated 
o Update medical and menstrual history and/or current medications if applicable  
 At all visits 
o Record/update adverse events (AEs) applicable  
 At all visits 
 
 Laboratory Procedures 
o HIV rapid testing 


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 At all visits 
o Aspartate aminotransferase/alanine aminotransferase (AST/ALT) testing 
 Wk 52 
o Serum chemistries, including creatinine, glucose, electrolytes, and lipase 
 Wk 52 
o Urine pregnancy testing (for females) 
 At all visits 
o Contraceptive counseling  
 At all visits 
o Measurement of study drug levels by DBS for those participants on study prouct up 
to and including wk36 
  Wk 52 
 
7.7 CLINICAL EVALUATIONS AND PROCEDURES  
Full physical exams will be performed at screening and week 48 and targeted exams will be 
performed at other study visits as required.  Clinical symptoms will be systematically assessed in a 
structured medical history at screening and enrollment (wk 0), Wks 4, 8, 12  and then every 12 
weeks for the length of the trial. 
 
Full physical exams include the following assessments:  
Vital signs:  
 Oral temperature  
 Blood pressure  
 Pulse  
 Respirations  
 
Measurements of:  
 Weight  
 Height  
 


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Clinical assessments of: 
 
 Head and eyes  
 Ears, nose, and throat  
 Neck  
 Lymph nodes  
 Heart  
 Lungs  
 Abdomen  
 Extremities 
 Neurological  
 Skin  
 Breasts  
 Tanner stage 
 
Additional assessments may be performed at the discretion of the examining clinician in response 
to symptoms or illnesses present at the time of the exam. 
7.8 LABORATORY EVALUATIONS AND PROCEDURES  
Laboratory evaluations will include the following:  
 Hepatitis B surface antigen and antibody testing  
o At Screening  
 
 Urine pregnancy test  
o At every visit 
 
 HIV serology 
o At every visit 
 
 HSV-2 serology 
o At screening, Week 12, 48 
 Chlamydia, and Gonorrhea. 


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o At screening, Week 12, 48 
 
 Serum chemistries, creatinine only 
o Week 52 
 
 AST, ALT  
o Screening, Week 12, 24, 36, 48 and 52 
 
 Full Blood Count  
o Screening, Week 12, 24, 36, 48 
  
 Haematocrit  
o Week 4, 8, 52  
 
 DBS / Plasma drug level sampling 
o Week 4, 8, 12, 24,  
o Week 36, 48, for those who remain on study product 
o Week 52, Plasma only for those who remain on study product 
 Urine dip stick  
o Screening, Week 12, 24, 36, 48 
 
The location of laboratory evaluations will depend on laboratory capacity. 
7.9 BEHAVIOURAL EVALUATIONS AND PROCEDURES  
Using interviewer administered questionnaires the following behaviors of participants will be 
recorded and assessed over the 52 weeks of study participation at scheduled study visits:  
 Study product adherence, with measures of barriers and facilitators of adherence (for focus 
group with enrolled participants who receive study product), including a visual scale. 
 Product acceptability 
 Sexual activity  


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 Condom use, including frequency of condom use when having sex and condom use at last 
sex  
 Willingness to have real time drug level data and reasons for or against.  
 Estimation of drug levels if not willing to have data shared.  
 
All focus groups will be conducted by a study staff member, who will be trained by an expert socio-
behavioural researcher. Focus groups will address a number of questions including adolescents’ 
attitudes towards PrEP; adolescent perceptions of taking drugs previously reserved for HIV 
treatment as a form of prevention; where they would like to access these drugs; whether taking 
PrEP might identify individuals as high-risk and therefore stigmatise them; whether enhanced 
protection against HIV infection provided by PrEP might lead to sexual disinhibition or risk 
compensation; whether adolescents will/do still use condoms in order to protect against other 
STI’s; what factors (e.g. appearance changes as a result of drug side-effects) might/do impact on 
adherence; where adolescents would like to access the drugs. They will also examine willingness to 
have drug levels shared and impact of hearing actual drug levels during counseling.  
 
Parental/ guardian consent and adolescent assent will be obtained for all focus group participants 
(see Appendices 16.3 and 16.4). 
7.10 
PROCEDURES FOR PARTICIPANTS WHO TEMPORARILY HOLD OR DISCONTINUE STUDY 
PRODUCT 
7.10.1 
Participants Who Become Infected with HIV 
 
If a participant becomes HIV-infected at any time after enrolment into the study, the study product 
will be immediately terminated (if applicable) and the protocol-specified visit schedule will be 
followed, for participants who choose to be maintained in the study. In addition, extra interim visits 
will be added to their schedule for psychosocial support, if needed. These visits will occur in 
addition to study visits, although they can be combined with regularly-scheduled study visits. 
 
If a participant tests positive on two rapid HIV antibody rapid tests, they will be considered HIV-
infected and will receive post-test counseling on these results. Participants with an indeterminate 


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HIV test result will be asked to provide a blood sample for ELISA testing, to confirm whether they 
are HIV-infected.  
 
Participants will be allowed as much time and given as much support as they need to cope with the 
positive result. The counselor disclosing the result will encourage the participant to identify a 
trusted adult (not necessarily the parent/ guardian) that they would like to disclose to. If necessary, 
this adult will be called into the clinic to help support the participant [see Section 16.5 for more 
detail, including the HIV testing algorithm]. 
 
The participant will also be given a referral letter for counseling and support in the community. The 
participant will also be reassured that they can return to the clinic at any time during clinic hours 
for support. Clinic staff will make telephone contact with the service to which they are referring the 
participant. 
 
If both rapids are positive blood will be sent for confirmatory viral load testing. When these results 
are available the participant will be recalled and following another pretest information session, a 
blood sample for CD4 count as well as resistance and genotype testing will be obtained. The 
participant will be followed up at the study site for the duration of the study, and will receive a CD4 
count at 3-monthly intervals and psychosocial support for disclosure, to ensure that initial care and 
counselling is well-managed. After the Final Study Visit, the research team will link the participant 
into long-term HIV care and treatment at one of the existing local health facilities.  
 
7.10.2 
Participants Who Become Pregnant 
 
If a female participant becomes pregnant after enrolment into the study, the study product will be 
immediately terminated, the protocol-specified visit schedule will be followed (for participants who 
choose to be maintained in follow-up), and the participant will be followed until delivery. The 
participant will be counseled about available options and appropriate referrals will be made 
depending on the participants’ choice. Participants will also be encouraged to disclose their 
pregnancy results to a trusted adult (not necessarily the parent/ guardian) [See Section 9.3 for 
more details]. 


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7.10.3 
Management of Hepatitis B  
Hepatitis B surface antigen and antibody testing will be conducted at screening for all potential 
participants. All adolescents who are not immune will be vaccinated for hepatitis B prior to 
enrollment. Participants will receive their first dose when they receive their results during the 
screening window, followed by another dose after 30 days (ideally at enrolment). The final dose will 
occur at approximately 6 months after the first dose, once they are enrolled and participating in the 
study. Potential participants with positive HepBsAg results will be referred for care and treatment 
of active infection and cannot be enrolled.  
 
If symptoms or signs of clinical hepatitis are present in a participant during the course of the study, 
the Site Investigator or designee will temporarily hold oral study product and test the participant 
for hepatitis (including HBsAg plus any other testing indicated by the local standard of care). If 
hepatitis B infection is confirmed, the participant will be referred for appropriate care. 
 
7.10.4 
Participants Who Temporarily Hold or Discontinue Product Use (Initiated by 
Participant) 
 
For participants who independently choose to discontinue use of the study product (either 
temporarily or permanently), the protocol-specified visit schedule will be followed (for participants 
who choose to be maintained in follow-up), with the exception of administration of study product.  
7.11 
SPECIMEN PREPARATION, HANDLING AND COLLECTION 
Each study site will subscribe to the standards of good clinical laboratory practices (GCLP) and site-
specific SOPs for proper collection, processing, labeling, transport, and storage of specimens at the 
local laboratory. All left over samples after testing, will be destroyed. 
7.12 
BIOHAZARDOUS WASTE 
The Principal Investigator will ensure that biohazardous waste will be contained according to 
institutional, transportation/carrier, and all applicable regulations.  
 


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Table1: Schedule of Study Visits and Procedures 
Nb. Screening visit (up to -4 weeks); Enrollment (0 weeks); Final visit (52 weeks). 
Visit week 
Prior 
Screening 
Enrolment 4 
8 
12 
24 
36 
48 
Final 
52 
Obtain written informed consent for screening and 
enrolment, from participant and his/her guardian 
X 
  
 
 
 
 
 
 
 
Assessment of understanding for ICF 
X 
  
 
 
 
 
 
 
 
Identification number assignment 
 X 
 
 
 
 
 
 
 
Locator information 
X 
X 
X 
X 
X 
X 
X 
X 
X 
HIV pre-and post-test counselling 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Eligibility assessment (including review of all screening 
documentation) 
 X 
 
 
 
 
 
 
 
Sexual risk behavior questionnaire 
X 
X 
X 
X 
X 
X 
X 
X 
Acceptability questionnaire 
X 
X 
X 
X 
X 
X 
X 
Adherence assessment and counselling 
X 
X 
X 
X 
X 
X 
 
Feedback of DBS or plasma results to those who agree 
to this.  
X 
X 
X 
X* 
X* 
X* 
  
Provision of condoms, condom counselling and rest of 
prevention package (bar PrEP) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study product supplies and instructions 
*Only to those who indicate willingness to use. 
X 
X 
X 
X* 
X* 
X* 
 


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Visit week 
Prior 
Screening 
Enrolment 4 
8 
12 
24 
36 
48 
Final 
52 
Reimbursement  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Schedule next visit (if applicable) 
X 
X 
X 
X 
X 
X 
X 
X 
* 
Focus group (including assent/consent) 
X 
X 
Obtain/update medical history 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Conduct physical exam 
Incl TS at enrollment and week 48 
X 
* 
* 
* 
*  
*  
*  
X 
* 
Disclose available test results 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Provide or refer for contraception 
X  
X 
X  
X 
X 
X  
X  
X 
* 
Contraceptive counseling 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Record/update AEs including social harms/benefits 
 
X 
X 
X 
X 
X 
X 
X 
X 
Treat or prescribe treatment  
Syndromic treatment for STIs 
* 
* 
* 
* 
* 
* 
* 
* 
* 
Hepatitis B sAb/sAg testing  
X 
  
Hepatitis B vaccination 
* 
* 
  
  
* 
HIV serology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Herpes (HSV-2)  
X 
  
  
X 
X  
  
Chlamydia, and Gonorrhea testing.  
Females low vaginal self-swab 
Males Urine 
X 
 
 
 
X 
 
 
X 
 
Serum chemistries 
X 
  
  
X 
X 
X 
X 
Creatinine Clearance 
 
 
 
 
 
 
 
X 
ALT/AST serology 
X 
  
  
X 
X 
X 
X 
X 
Haematocrit  
  
X 
X 
  
  
X 
Full Blood count  
X 
  
  
X 
X 
X 
X 
  
Measurement of study drug levels (DBS and plasma 
for drug levels 
X 
X 
X 
X # 
X # 
X # 
X # 
Measurement of study drug levels by DBS only 
 
 
 
 
 
 
X # 


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Visit week 
Prior 
Screening 
Enrolment 4 
8 
12 
24 
36 
48 
Final 
52 
Urine pregnancy testing 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine dip stick testing 
X 
  
  
X 
X 
X 
X 
  
Adherence counseling  
  
X 
X 
X 
X 
X 
* IF clinically indicated, per local standard X = 
Mandatory # = on PrEP 
  
  
  
  
  
  
  
 
 
 


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8 
ASSESSMENT OF SAFETY 
The Principal Investigator, site investigators and designated clinical staff are responsible for 
continuous and close safety monitoring of all study participants and for alerting the Safety 
Monitoring Committee (see Section 10.5), if unexpected safety concerns arise. Study sites will have 
written procedures for ensuring prompt reporting to the local Independent Ethics Committees, of any 
unanticipated problems involving risks to study participants or others. Safety of the adolescent 
participants in this study are of paramount concern.  
• Primary safety monitoring and safeguarding of individual study participants is the responsibility of 
study staff, under the direction of the IoR. The IoR and designated study staff also are 
responsible for submitting case report forms to the SMC and EAE reports to the DAIDS RSC, 
such that relevant safety data are available in a timely manner for other study-specific safety 
monitoring procedures, as follows:  
• The DAIDS RSC, DAIDS RAB Safety Specialist, and DAIDS PSB Medical Officers will review all EAE 
Forms received for PlusPills and follow up on these reports with site staff, the Protocol Team, 
and drug regulatory authorities when indicated.  
• The PSRT will routinely review safety data reports and will meet approximately once per month or 
as needed via conference call to discuss cumulative study safety data and any potential safety 
concerns.  
• The Study Monitoring Committee (SMC) also will periodically review study data with a focus on 
performance indicators such as participant accrual and retention, protocol adherence, and 
data quality. While site staff is not typically involved in these reviews, site staff should be 
aware that the SMC might make recommendations to DAIDS and/or the protocol team that 
could affect the study and sites in significant ways. These decisions are based on a detailed 
review of the available study data and careful consideration of ongoing participant safety and 
study viability.  
 
This section presents information related to adverse event (AE) reporting and participant safety 
monitoring in Plus Pills. Please also refer the following resources relevant to AE assessment and 
reporting:  
o DAIDS Table for Grading Adult and Pediatric Adverse Events (Toxicity Table), version 
2.0 dated Nov 2014  
o Manual for Expedited Reporting of Adverse Events to DAIDS, Version 2 (DAIDS EAE 
Manual), dated January 2010  
o DAERS Reference Guide for Site Reporters and Study 


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Physicians  
o Package Insert for Emtricitabine/Tenofovir Disoproxil Fumarate  (Truvada)  
o Package Insert for Emtricitabine  
o Package Insert for Tenofovir Disoproxil Fumarate  
8.1 
ADVERSE EVENT PROCEDURES AND REPORTING REQUIREMENTS 
An Adverse Event (AE) is defined as any untoward medical occurrence in a study participant, from the 
time of enrollment through when s/he terminates from the study; it does not necessarily have a 
causal relationship with the study product. As such, an AE can be an unfavorable or unintended sign 
(including an abnormal laboratory finding, for example), symptom or disease temporally associated 
with the use of a study product, whether or not considered related to the product. This definition is 
applied to all participants beginning from the time of enrollment. 
 
Study site staff will document in source documents and the appropriate AE Log CRF all AEs reported 
by or observed in enrolled study participants regardless of severity and presumed relationship to 
study product. The severity of clinical symptoms will be scored using the DAIDS Table for Grading the 
Severity of Adult and Pediatric AEs, Version 2.0 Dated Nov 2014.  The Investigator or designee must 
determine the severity of the AE and document it on the appropriate CRF (AE Form). Each adverse 
event that the participant reports will be graded for severity according to the DAIDS grading scale. 
If not on the grading scale then the following scale will be applied: 
 Mild: participant was able to perform all normal activities. 
 Moderate: the participant had to discontinue some activities due to the adverse event. 
 Severe: the participant was incapacitated by the adverse event and unable to perform 
normal activities.  
 Life-threatening participant experienced extreme limitation in activity, significant assistance 
required; significant medical intervention / therapy required, hospitalisation or hospice - care 
probable. 
An AE does not include: 
 Pre-existing diseases or conditions present or detected prior to start of study intervention 
that do not worsen. 


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 Medical or surgical procedures (e.g. surgery, endoscopy, tooth extraction, transfusion); the 
condition that leads to the procedure is an adverse event. 
 Situations where an untoward medical occurrence has not occurred (e.g. hospitalization for 
elective surgery, social and/or convenience admissions). 
 
All AEs will be captured regardless of the association or otherwise to the study intervention and 
reported on the AE CRF in accordance with study specific procedures.  All AE reports will contain at 
least the date the AE occurred, a brief description of the event, the relationship to study intervention, 
the action taken, the outcome, date resolved, and the severity of the event.  
Suspected, Unexpected Serious Adverse Reactions (SUSARS) will also be reported after the protcol-
defined AE reporting period, if the study staff become aware of these at any time. 
Requirements, definitions and methods for expedited reporting of Adverse Events (AEs) are outlined 
in Version 2.0 of the DAIDS EAE Manual, which is available on the RSC website at http://rsc.tech-
res.com/safetyandpharmacovigilance.   
The DAIDS Adverse Experience Reporting System (DAERS), an internet-based reporting system, must 
be used for expedited AE reporting to DAIDS. In the event of system outages or technical difficulties, 
expedited AEs may be submitted via the DAIDS EAE Form. For questions about DAERS, please contact 
DAIDS-ES at DAIDS-ESSupport@niaid.nih.gov. Site queries may also be sent from within the DAERS 
application itself. 
Where DAERS has not been implemented, sites will submit expedited AEs by documenting the 
information on the current DAIDS EAE Form. This form is available on the RSC website: 
http://rsc.tech-res.com/safetyandpharmacovigilance/.  For questions about expedited reporting, 
please contact DAIDS RSC DAIDSRSCSafetyOffice@tech-res.com. 
Designated study staff will submit AE information and any other relevant safety information to the 
local Ethics Committee(s) in accordance with EC requirements. 
Reporting Requirements for this Study 
 The SAE Reporting Category, as defined in Version 2.0 of the DAIDS EAE Manual, will be 
used for this study. 
 The study agents for which expedited reporting are required are: Tenofovir and 
Emtracitabine as a single combined formulation known as TRUVADA.   


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 AEs and SAEs will be reported throughout the period of trial follow up.  
 
8.1.1 
Social Harms Reporting 
 
The study site teams will monitor for and track unanticipated problems related to study 
procedures and/or to participation in the study, until participants’ time of termination from 
the study. Study site staff will provide clinically appropriate treatment and/or referrals should 
any such problems occur. 
8.2 
EXPEDITED ADVERSE EVENTS (EAE) 
The expedited AE reporting period for this study is as per the EAE manual, from study enrollment 
until study completion or discontinuation of the subject from study participation for any reason. 
After the protocol-defined AE reporting period, unless otherwise noted, only SUSARs as defined in 
version 2.0 of the EAE manual will be reported to DAIDS if the study staff become aware of the 
events on a passive basis (from publicly available information). 
All unexpected SAEs related to the study product observed in the clinical trial will be reported to 
the FDA in accordance with 21 CFR 312.32 (IND Safety Reports). 
FOR FURTHER DETAILS SEE APPENDIX 16.9 
8.3 
LOCAL REGULATORY REQUIREMENTS 
In addition to submitting EAE information to the DAIDS Safety Office through the Regulatory Support 
Center (RSC), the investigators will submit AE information in accordance with local regulatory 
agencies’ or other local authorities’ requirements. 
8.3 (i) Serious Adverse Events (SAEs) are defined by the ICH E2A definition, as described in Version 2 
(January 2010) of the DAIDS EAE Manual, section 2.1, Seriousness. An SAE is any untoward medical 
occurrence following any exposure to the study agent that: 
• Results in death,  
• Is life-threatening, (The term “life-threatening” refers to an event in which the patient was at 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.)  


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• Requires inpatient hospitalization or prolongation of existing hospitalization, (Per ICH SAE 
definition, hospitalization itself is not an AE, but is an outcome of the event.)  
The following types of hospitalization do not require expedited reporting to DAIDS: 
• Any admission unrelated to an AE (e.g., for labor/delivery, cosmetic surgery, administrative or 
social admission for temporary placement for lack of a place to sleep),  
• Protocol-specified admission (e.g., for a procedure required by protocol), or  
• Admission for diagnosis or therapy of a condition that existed before receipt of study agent(s) and 
has not increased in severity or frequency as judged by the clinical investigator. (NOTE: A new 
AIDS-defining event in a subject already known to be HIV-infected would be considered an 
increase in severity of a pre-existing condition [HIV infection] and would therefore be 
reportable.)  Results in persistent or significant disability/incapacity,  Is a congenital 
anomaly/birth defect,  
• Clinically insignificant physical findings at birth, including those regarded as normal variants, do not 
meet reporting criteria. If a clinically significant anomaly is reported, all other findings 
(including those of no individual significance) should be included in the same report. For 
example, an isolated finding of polydactyly (extra fingers or toes) or Mongolian spot in an 
infant with no other findings would not be reported as an SAE, but polydactyly or Mongolian 
spot occurring with a major cardiac defect would be reported and included in the SAE report.  
• Information about congenital anomalies can be found on the Centers for Disease Control and 
Prevention (CDC) website: http://www.cdc.gov/ncbddd/bd/monitoring.htm – Guidelines for 
Conducting Birth Defects Surveillance, National Birth Defects Prevention Network (NBDPN), 
Appendix 3.1. Direct link to document: www.nbdpn.org/current/resources/sgm/appendix3- 
1.pdf. This website listing should not restrict the reporting of anomalies that the site 
investigator deems important for the sponsor to know.  Is an important medical event that 
may not be immediately life- threatening or result in death or hospitalization but may 
jeopardize the patient or may require intervention to prevent one of the other outcomes 
listed in the definition above. Examples include the following: intensive treatment in an 
emergency room or at home for allergic bronchospasm; blood dyscrasias or convulsions that 
do not result in hospitalization; development of drug dependency or drug abuse; etc.  
  


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9           CLINICAL MANAGEMENT 
9.1 
TOXICITY MANAGEMENT 
Full physical exams will be performed at screening and week 48. Targeted physical exams will be 
performed at other visits as needed. Clinical symptoms will be systematically assessed in a structured 
medical history at screening and enrollment, monthly for three months, and then every 12 weeks for 
the remaining length of the trial (Months 5-12).  
In general, all participants who develop a Grade 1 or 2 AE, regardless of relatedness to the study 
product, may continue use of the study drug per protocol. 
 
Grade 3:  Study drug use should be temporarily discontinued in consultation with the PSRT in 
Participants, who develop a Grade 3 AE or toxicity that is not specifically addressed below regardless 
of study product relatedness.  In general, and unless otherwise decided in consultation with the PSRT, 
the investigator should re-evaluate the participant at least weekly for up to 2 weeks (or for 2 weeks 
following the receipt of the results for lab toxicities) to document resolution of toxicity to less than 
Grade 2.  The study drug should be permanently discontinued if improvement to severity ≤ Grade 2 
cannot be documented within 4 weeks of receipt of the initial result.  If study drug use is resumed 
and the same Grade 3 AE recurs at any time, the IoR/designee must hold product use and consult the 
PSRT for further guidance on frequency of reevaluation or progression to permanent discontinuation 
of the study drug.  
 
For all Grade 4 laboratory-identified or clinical toxicities, the study product will be withheld.  
Laboratory toxicity will be promptly confirmed by repeating the test on an additional specimen, 
preferably within seven days.  If Grade 4 toxicity is also present on repeat testing of additional 
specimen and is considered to be related to study medication, the study product will be permanently 
discontinued.  Study product may be resumed after resolution to Grade 1 of any Grade 4 laboratory 
toxicity or clinical event considered to be not related to study product based on the judgment of the 
Site Investigator after consultation with the PSRT. If the toxicity recurs to Grade 3 or higher after 
study product is restarted, the study product will be permanently discontinued.   
Participants will be asked to report AEs at every study visit. Clinical AEs will be evaluated by the 
investigator or designee who has clinical qualifications. Any Grade 3 and 4 clinical AEs will be referred 


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to a Site Investigator at the time of the visit.  A back-up coverage schedule will be developed and 
posted to assure that a study physician or nurse is available at all times. 
 
In addition to the informal safety monitoring done by the Site Investigator and study clinician, the 
Protocol Safety and Review Team (PSRT) will conduct interim reviews of safety data and study 
conduct. These reviews will take place approximately every month, or as needed. Any 
discontinuation and potential resumption of study product will be managed in consultation with the 
PSRT (see section 10.5 for additional detail). 
 
9.1.1 Nausea, Vomiting, and Diarrhea 
Participants with Grade 1 or 2 nausea, vomiting, or diarrhea may be treated 
symptomatically with hydration, oral antiemetic therapies or antiemetic 
suppositories at the discretion of the site investigator or designated clinical staff. The site 
investigator should order any clinically relevant laboratory analyses (per judgment of the site 
investigator/or designee). Participants should be reminded to take study drug with food. 
Participants with Grade ≥ 3 nausea, vomiting, or diarrhea, for which an alternative etiology is 
not established, must discontinue the study drug temporarily until grade 2 or lower and be 
treated symptomatically. Should condition(s) not improve to Grade <2 within 7 days, the site 
investigator/designee should consult the PSRT for guidance on continuing the temporary 
discontinuation or progressing to permanent discontinuation of study drug. Repeat episodes 
of these events will be handled independently, and the instruction above will be followed for 
each event. 
 
9.1.2 
Management of ALT/AST Elevations 
 
All study participants will either be immune to HBV at study entry, or will receive HBV 
vaccination. Therefore, HBV infection is not likely to be a cause of AST/ALT elevations. 
Careful assessments should be done to rule out the use of alcohol, lactic acidosis syndrome, 
non-study medication-related drug toxicity, herbal medications/supplements, or viral 
hepatitis as the cause of elevation in AST or ALT of any grade. The participant must be 
carefully assessed for any symptoms or signs of hepatotoxicity, including fatigue, malaise, 


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anorexia and nausea, jaundice, acholic stools, right upper quadrant pain, or hepatomegaly. If 
the AST/ALT elevation is considered most likely to be due to concomitant illness or 
medication, standard management, including discontinuation of the likely causative agent, if 
possible, should be undertaken. If symptoms or signs of clinical hepatitis are present, study 
drug must be held or discontinued. 
 
Grade 1 transaminase elevation: 
For study participants with less than Grade 1 AST and ALT at study entry, an 
 increase to Grade 1 AST or ALT even in an asymptomatic participant may be of concern. AST 
and ALT must be repeated as soon as possible (at most within 1 week of the receipt of the 
results). Study drug may be continued while repeating AST and ALT at the discretion of the 
investigator provided the participant is asymptomatic. Should the repeat AST and ALT testing 
indicate a continuation of Grade 1, the PSRT should be immediately consulted. In the case of 
symptomatic participants, study drug will be held temporarily, and management (including 
resumption of study drug) should be arranged in consultation with the PSRT. 
 
Grade 2 transaminase elevation:  
Participants should have AST/ALT re-checked as soon as possible (at most within 1 week of 
the receipt of the results) and then be followed weekly until levels are Grade < 1. The 
frequency of follow up may be altered at the discretion of the site investigator following 
consultation with the PSRT. Study drug may continue at the discretion of the investigator 
provided the participant is asymptomatic. In the case of symptomatic participants, study drug 
will be held temporarily, and management (including resumption of study drug) should be 
arranged in consultation with the PSRT. 
 
Grade 3 transaminase elevation:  
Study drug should be temporarily held for any Grade 3 AST or ALT. Participants should have 
AST/ALT re-checked as soon as possible (at most within 1 week of the receipt of the results). 
Participants should then be followed weekly until levels are Grade < 1. Resumption of study 
drug should be arranged in consultation with the PSRT. 
 


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Grade 4 transaminase elevation:  
Study product should be permanently discontinued for any Grade 4 AST and/or ALT. 
Appropriate care and management of the participant will be ensured.  
 
If the investigator has determined in consultation with the PSRT that the case has stabilized, it 
may be possible to decrease the frequency of follow-up laboratory testing in addition to 
resumption of study drug. 
 
9.1.3 
Management of Creatinine Clearance 
After enrollment, if the calculated creatinine clearance is less than <75ml/min, the study 
product should be temporarily held and confirmed within one week of the receipt of the 
results, and the PSRT should be consulted. If the creatinine is confirmed to be <75ml/min, the 
study product must be permanently discontinued.  
 
9.1.4 
Management of Hypophosphatemia 
Grades 1 and 2 hypophosphatemia: 
The phosphate should be repeated within 2 weeks of the receipt of any initially abnormal 
results. Supplemental phosphate should be given with phosphate-rich food or fluid with or 
without neutral phosphate solution. Other causes of phosphate loss should be evaluated. 
Unless other temporary study drug hold requirements apply, study drug need not be held. 
 
Grade 3 hypophosphatemia: 
The phosphate should be repeated within 1 week of receipt of any initially abnormal results, 
and should be accompanied by serum creatinine testing and urine dipstick for 
protein/glucose. Supplemental phosphate should be given with phosphate-rich food or fluid 
with or without neutral phosphate solution, and other causes of low phosphate should be 
investigated. Participants with any of the following results (of tests accompanying the repeat 
phosphate test) will have study drug held: 
• Proteinuria >2+ 
• Glycosuria >2+ 


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• Creatinine > ULN 
• Creatinine clearance <LLN 
 
Participants may continue study drug provided that: 
• Study drug hold is not otherwise indicated (e.g., due to the results of creatinine, 
creatinine clearance, urine protein, and/or urine glucose) 
• Phosphate levels will be retested approximately weekly until return to <Grade 2, unless 
other retesting schedule has been advised by the PSRT 
 
Grade 4 hypophosphatemia: 
The phosphate should be repeated within 1 week of the receipt of any initially 
abnormal results, and should be accompanied by serum creatinine testing and urine dipstick 
for protein/glucose. Supplemental phosphate should be given with phosphate-rich food or 
fluid with or without neutral phosphate solution. Other causes of low phosphate should be 
investigated. 
Participants will have study drug held, and the PSRT must be immediately 
contacted. Phosphate levels will be retested approximately weekly until return to <Grade 2, 
unless another retesting scheduled has been advised by the PSRT. 
 
Participants may resume study drug, provided that: 
• Study drug hold is not otherwise indicated (e.g., due to the results of serum 
creatinine, creatinine clearance, urine protein, and/or urine glucose) 
• The phosphate level has returned to <Grade 2 
• A request to resume study drug is approved by the PSRT 
 
PSRT notification should occur for any result >Grade 2 for protein or glucose 
measured by urine dipstick performed at the time of confirmatory draw for a phosphate level. 
 
 
9.1.5 
Proteinuria 
Proteinuria will be assessed by urine dipstick. A finding of 1+ proteinuria should be confirmed 


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with a second urine dipstick performed no earlier than one week. Proteinuria of 2+ or greater 
does not need to be confirmed at a separate visit. The site investigator/designee should 
temporarily hold study drug in the following circumstances: 
• Detection of 3+ or greater proteinuria at any visit. Study drug should be held regardless of 
serum creatinine or phosphorus results obtained at the time of proteinuria detection. Urine 
dipstick testing and serum creatinine and phosphate should then be performed monthly for at 
least three months. 
 
• Detection of 2+ proteinuria. Study drug should be held until results of serum 
creatinine results obtained at the time of proteinuria detection are available. Study drug hold 
should continue if hold criteria outlined for serum creatinine are met. If neither value meets 
criteria for study product hold, study drug should be resumed. 
 
• Detection of 1+ proteinuria confirmed on two separate visits. Study drug should be held 
only if serum creatinine or phosphorus results obtained at the time of detection of proteinuria 
meet hold criteria. 
 
 
9.1.6 
Glycosuria 
Glycosuria will be assessed by urine dipstick. A finding of 1+ glycosuria should be confirmed 
with a second urine dipstick performed no earlier than one week but no later than 2 weeks 
after detection of the first 1+ glycosuria. Glycosuria of 2+ or greater does not need to be 
confirmed at a separate visit.  
 
The severity of glycosuria is graded using the same grading scale as for proteinuria. The site 
investigator/designee should temporarily hold study drug in the following circumstances: 
• Detection of 3+ or greater glycosuria at any visit. Study drug should be held regardless of 
serum creatinine or phosphorus results obtained at the time of proteinuria detection. Urine 
dipstick testing and serum creatinine and phosphorus should then be performed monthly for 
at least three months. 
 


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• Detection of 2+ glycosuria. Study drug should be held until results of serum 
creatinine and phosphorus results obtained at the time of glycosuria detection 
are available. Study drug hold should continue if hold criteria outlined for 
serum creatinine and/or phosphorus are met. If neither of these values meets criteria for 
study drug hold, study drug should be resumed. 
 
• Detection of 1+ glycosuria confirmed on two separate visits. Study drug should be held only 
if serum creatinine or phosphorus results obtained at the time of detection of glycosuria meet 
hold criteria. 
9.2 
HEPATITIS B INFECTION 
Adolescents who test positive for Hepatitis B surface antigen (HBsAg) during screening, or 
demonstrate signs or symptoms of Hepatitis B during the study, will be will be referred for 
appropriate care. If Ag positive at screening, participants are ineligible for study participation. All 
HBsAB sero-negative adolescents who have no history of previous vaccination, will be vaccinated, 
during the screening period, 30 days after the initial injection (ideally at enrollment), and then again 
after 24 weeks. It is important to note that participants who are Hep B infected may incur a “Hep B 
viral flare” on cessation of TDF/FTC therapy. This should be monitored for and appropriately 
managed should it occur.  
9.3 
PREGNANCY 
All participants will be provided with male and/or female condoms. As participants will be required to 
be sexually active in order to enroll in the study, females will be required to use condoms as well as 
take low dose, combination oral or injectable hormonal contraception, in addition to receiving 
contraceptive counseling throughout the duration of study participation. Pregnancy testing is 
performed at all study visits and participants are encouraged to report all signs or symptoms of 
pregnancy to study staff. The Site Investigator or designee will discontinue drug permanently, 
counsel any participant who becomes pregnant regarding possible risks to the fetus according to site 
SOPs. The Site Investigator/designee also will refer the participant to all applicable services; however, 
sites will not be responsible for paying for pregnancy-related care.  Youth-friendly sexual 
reproductive health services are available free of charge at care facilities in site surrounds. A 


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participant who is pregnant will continue to be followed until the pregnancy outcome is ascertained 
but will not receive any study product. 
9.4 
CRITERIA FOR EARLY TERMINATION 
Participants may voluntarily withdraw from the study for any reason at any time. The 
Principal Investigators may withdraw participants to protect their safety, and/or if participants are 
unable or unwilling to comply with study procedures. 
9.5 
TREATMENT FOR SEXUALLY TRANSMITTED INFECTIONS 
Participants will be tested for HSV-2, chlamydia, and gonorrhea during screening, week 12 and at 
week 48.. All participants will receive screening and treatment for STIs throughout the study and 
their identified partners will be managed using syndromic management of STIs according to South 
African STI guidelines.  
9.6 
MANAGEMENT OF HIV INFECTION 
Refer to Section 7.10.1 for specific study procedures regarding participants who become infected 
with HIV at any time during the study. 
9.7 
CRITERIA FOR DISCONTINUATION 
The criteria for permanent discontinuation of further study product for an individual participant are:  
 Product-related toxicity (see Section 9.1)  
 Requirement for prohibited concomitant medications  
 HIV infection 
 Pregnancy/lactation  
 Completion of study as defined in the protocol  
 Request by participant to terminate study product 
 Any conditions or clinical reasons that will threaten safety and well-being of participant 
 
The criteria for premature discontinuation of further study participation for an individual participant 
are:  


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 Lost to follow up as per site SOP 
 Participant repeatedly non-compliant with study product as prescribed 
 Pregnancy/lactation 
 Request by participant to withdraw from study 
 Request of the primary guardian or caregiver if s/he thinks the study is no longer in the best 
interest of the participant 
 Participant judged by the Site Investigator to be at significant risk of failing to comply with the 
provisions of the protocol as to cause harm to self or seriously interfere with the validity of 
study results 
 At the discretion of the Independent Ethics Committee, Medicine Control Council, Site 
Investigator, or pharmaceutical supporter. 
 DAIDS, NIAID, the Office of Human Research Protection (OHRP), and the FDA as regulatory 
entities may also discontinue the study at their discretion. 


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10 
STATISTICAL CONSIDERATIONS 
10.1 
OVERVIEW AND SUMMARY OF DESIGN 
The study is designed as an open-label phase 2 demonstration project, to evaluate the acceptability, 
safety, feasibility, as well as the adherence to daily oral PrEP (FTC/TDF) for HIV-1 prevention, among 
150 male and female adolescent participants at two sites (with approximately 75 participants at each 
site), ranging in ages between 15 and 19 years old, over a 12 month period. The study will also 
investigate the uptake and utility of feedback to the participants real time about drug levels obtained 
from dried blood spots/plasma during adherence counselling. 
10.2 
STUDY ENDPOINTS  
Primary Acceptability/Use Endpoints:  
Consistent with the primary study objective to evaluate the acceptability and use of daily oral PrEP 
(FTC/TDF) in HIV-negative adolescents, ages 15-19 years, the following primary safety endpoints will 
be assessed: 
o The proportion of participants who report willingness to use the study regimen, take 
up PrEP and remain on PrEP as part of a comprehensive prevention package.  
o An acceptability questionnaire will be administered at the final study visit to assess the 
delivery of PrEP and the content of the study visits, including the user-friendliness of 
the medication regimen (including an assessment of side effects), the delivery format, 
the dosing strategy, and the clinic visit schedule. 
o Number of adolescents recruited, enrolled, and retained in the study. 
Primary Safety Endpoint: 
 
o Grades 2, 3, and 4 clinical and laboratory adverse events; 
Secondary Endpoints: 
Consistent with the secondary study objectives to evaluate the adherence and sexual behaviour of 
daily oral PrEP (FTC/TDF) in HIV-negative adolescents, ages 15-19 years, the following endpoint will 
be assessed: 


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Adherence Endpoint:  
 Adherence to daily regimens of oral PrEP as evidenced by self-report, pill counts, and 
proportion of participants assigned to FTC/TDF who have detectable drug levels. 
o Proportion of doses that are taken as instructed. 
 
Sexual behaviour 
o Reported number of steady and casual sex partners, condom use (and change after 
introduction of study product), substance use prior to or during sex, as evidenced by 
participant responses to interviewer-administered questionnaires and focus group. 
o Proportion of scheduled HIV testing appointments that are missed, in relation to 
individual characteristics (age, sex, number of partners, use of other prevention 
methods) and the characteristics of the product. 
Consistent with the exploratory objective to assess the HIV incidence in study participants during the 
course of study participation, the following endpoint will be assessed: 
 HIV infection, as measured by seroconversion of study participants during the 
approximate 12 months of follow-up 
 
Exploratory Endpoints:   
o Consistent with the exploratory study objective to explore the feasibility of 
biofeedback of  Blood Spot results as an adherence enhancing strategy in 150 HIV-
negative adolescents, ages 15-19 years, the following exploratory endpoints will be 
assessed: 
 Proportion and number of participants who are tested using DBS and 
received results of DBS compared to participants who are tested using 
DBS but do not receive biofeedback of results. 
 Number of counselling opportunities in which drug level feedback is 
requested vs total number of counseling events 
 Number and nature of participants who request drug level feedback . 
 Correlation between self reported adherence and drug levels at each 
visit for each participant  
 Correlation between self reported adherence and drug levels at each 


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visit in the study overall. 
  Proportion and number of participants whose adherence ito study 
product improves when receiving the results of DBS compared to those 
who do not receive feedback of results as measured by endpoints 
above. 
Consistent with the exploratory study objective to investigate the relationship between daily 
PrEP usage and sexual practices and behavior in adolescents, the following exploratory 
endpoints will be assessed 
             Sexual behaviour data obtained using questionnaires and a focus group.  
10.3  STUDY HYPOTHESIS  
The DTHF protocol and research teams hypothesize that oral once daily PrEP (TDF/FTC) will be 
acceptable and utilized safely by healthy adolescents, between the ages of 15-19 years.  
10.4 
SAMPLE SIZE CONSIDERATIONS 
The sample size calculation is based on the ability to detect the measure the primary objectives 
(acceptability and use) in the participant population. The table below shows the precision (as 95% 
confidence limits) provided by various sample sizes in detecting the occurrence of acceptability 
endpoints (with a frequency non- uptake and use varying from 5%-20%). 
 
Acceptability will be measured by proportion of youth who take up PrEP and remain on PrEP as part 
of a comprehensive prevention package. Also they will complete an acceptability questionnaire. 
 
 
Precision * 
 
 
Frequency 
n=100 
n=135 
n=170 
5% 
1.6; 11.2 
2.1; 10.4 
2.4; 9.8 
10% 
4.9; 17.6 
5.7; 16.8 
6.4; 16.2 
15% 
8.6; 23.5 
9.9; 22.8 
10.7; 22.2 
20% 
12.7; 29.1 
14.2; 28.6 
15.3; 28.1 
* Asymptotic (exact) binomial 95% confidence limits 
 


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Based on these calculations, we anticipate that 135 participants, rounded up to 150 participants to 
account for premature censoring (due to loss to follow-up and/or withdrawal of consent, estimated 
at maximum 10%) will be required to detect non-acceptabiltiy endpoints that occur in 10% of 
subjects with approximately 5% precision. 
10.5 
DATA AND SAFETY MONITORING AND REVIEW 
In addition to the informal safety monitoring done by the Site Investigator and study clinician, DTHF 
will convene an independent Protocol Safety Review Team (PSRT). The roles of the PSRT are: 
 
 
To conduct interim reviews of primary safety data as well as study conduct and progress, 
including rates of participant accrual, retention, rates of adherence to study product and 
protocol, as well as HIV rates. These reviews will take place approximately every month, or as 
needed. The PSRT may recommend early termination of the study or modification when there 
is clear evidence of harm towards participants.  The PSRT will make a recommendation to the 
SMC for immediate review of data.   
 
 To respond to queries from site staff on eligibility determination and conditions for exclusion 
from initial drug dosing.   
 
 To consider and rapidly respond to queries from study staff regarding study drug dosing 
discontinuation or resumption following occurrence of toxicities as outlined in Section 9 of 
the study protocol.  Additionally, when a site reports any condition that results in study drug 
being held with resumption pending PSRT consultation, the PSRT will be convened via 
conference call to make a final determination (unless this is done via email in the interim).   
 
 To respond to queries from the study team when information is needed to guide clinical data 
management and safety reporting.  The Principal Investigator is designated as the point 
person for queries, and will consult with other PSRT members as needed. 
 
In addition, the Safety Monitoring Committee (SMC) will conduct interim reviews of safety data as 
well as study conduct and progress, including rates of participant accrual. Retention, rates of 


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adherence to study product and protocol, as well as HIV rates. These reviews will take place 
approximately every 3 months, or as needed. The SMC may recommend early termination of the 
study or modification when there is clear evidence of harm towards participants. Should the SMC or 
the PSRT detect evidence of harm such that the recommendation for halting or modifying the study is 
made, then this will be communicated to the PI, The protocol team and the DAIDS prevention 
division. The IRB and MCC will also be informed of the discontinuation of the study and/or the 
modification and reasons for modification of the study. All further enrollment, and study activities 
other than safety follow up will be put on hold. Participants, guardians and CABS will be notified as 
soon as possible after next steps are identified.  
10.6 
DATA ANALYSIS PLAN 
A customized data entry and management system will be implemented for the project in Microsoft 
Access. Data will be analysed using the statistical programme STATA (Stata Corporation, College 
Station, Texas, USA). Simple descriptive statistics including frequency distributions will be used to 
assist in data cleaning and summarization.  
 
The analysis plan for each of the study objectives (per 10.2 above) is detailed below. (Note that 
throughout the analysis, all statistical tests will be 2-sided using an alpha of 0.05.) 
 
Endpoints:  
A. PRIMARY 
1. Primary: Use  
Number of adolescents who continue to use PrEP after the initial 3 month period and the total time 
on PrEP for each adolescent and for the cohort as a whole. 
Analysis: 
Proportions of participants (a) willing to use and (b) taking up PrEP will be described with point 
estimates and exact 95% confidence intervals. “Remaining on PrEP” will be defined as any self-
reported use of PrEP at each study interval (regardless of adherence) over the 9-month follow-up 
period, as a binary outcome. The first 3-month “use” will be 100% for all 150 participants. We will use 
product-limit methods to examine ‘survival’ proportions for participants remaining on PrEP, 
accounting for censoring due to loss to follow-up. We will (i) examine the reasons for discontinuation 


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and (ii) examine the baseline and/or pre-LTF characteristics of those LTF, and compare to those 
retained, in order to understand the possible associations between LTF and adherence and/or sexual 
risk taking. While our preliminary analyses will presume this censoring is uninformative, we will 
include analyses that assume LTF are non-adherent. Our intention is to (i) examine the reasons for 
discontinuation and (ii) examine the baseline and/or pre-LTF characteristics of those LTF, and 
compare to those retained, in order to understand the possible associations between LTF and 
adherence and/or sexual risk taking. While our preliminary analyses will presume this censoring is 
uninformative, we will include analyses that assume LTF are non-adherent. In subsidiary analyses for 
this primary endpoint, we will also examine the factors associated with PrEP willingness, uptake and 
“remaining on PrEP” using standard methods (including chi-square and exact tests for the 
comparisons of proportions, and log-rank tests for the comparison of ‘survival’ curves in product-limit 
analysis). 
2. Primary: Acceptability 
An acceptability questionnaire will be administered 3 monthly to assess reasons for continuing, 
stopping or restarting PrEP.  A further questionnaire will be administered at the final study visit to 
assess the delivery of PrEP and the content of the study visits, including the user-friendliness of the 
medication regimen (including an assessment of side effects), the delivery format, the dosing 
strategy, and the clinic visit schedule. 
Analysis Plan:  
This acceptability questionnaire will contain both binary items as well as continuous (interval) 
measures from Likert-type items. Analysis of data from this questionnaire will begin with standard 
descriptive statistics for each item, overall and by key participant subgroups (a priori, these will be 
based on participant age, gender, sexual activity during the study and PrEP adherence during the 
study). We will compare responses to acceptability items using standard methods, including chi-
square and exact tests; Student’s t- and rank-sum tests, replaced by analysis of variance or u-tests for 
global comparisons across polytomous groupings. 
3. Primary: Safety 
Grades 2, 3, and 4 clinical and laboratory adverse events 
Analysis:  
This analysis will be based on descriptive statistics. 
 


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B. Secondary Endpoints:  
1. Secondary: Adherence  
Adherence to daily regimens of oral PrEP as evidenced by the use self-report, pill counts, and 
proportion of participants on FTC/TDF who have detectable drug levels.  
Proportion of doses that are taken as instructed.  
Proportion of blood samples with detectable drug levels  
Proportion of adolescents with detectable drug levels who report using PrEP 
Analysis Plan: 
There are 3 different measures of PrEP adherence that will be used for the primary adherence 
endpoint: Participant self-report, pill count results, and detectable drug levels. While the 
distributions of each of these measures may vary, a priori we anticipate that analysis of each of these 
3 measures will use two different binary metrics from data at each study visit: (i) perfect adherence 
(defined as adherence data that do not suggest any missed doses, e.g., pill count data consistent with 
daily dosing, or no missed doses detected on self-report); and, (ii) effective adherence (defined as 
adherence levels that are consistent with protection against HIV exposure based on available data 
from PrEP efficacy trials, e.g., >85% doses taken, from pill count, or self-report; or therapeutic drug 
levels on biological assays). Note that drug levels will be used in analyses of effective adherence only. 
Analyses of adherence data will be based on the binary constructs of perfect and effective adherence 
as well as continuous measures of the proportion of PrEP doses taken; both the binary and 
continuous constructs will be analysed at each study visit (repeated measures) and in the overall 
study period (through aggregation of measures from each study visit). 
The analysis for this primary endpoint is largely descriptive, with the estimates of adherence and 
their 95% confidence intervals reported for different adherence measures for the cohort overall as 
well as a priori subgroupings by age, gender and sexual activity during the study. Subsidiary analyses 
will develop models to examine the predictors of adherence within the cohort; given the sample size, 
such analyses will have limited statistical power and should be considered exploratory. For repeated 
measures of adherence from each study visit, we will use a generalized linear modelling approach 
that includes fixed effects (e.g., participant characteristics) and random effects (e.g., characteristics of 
study visits). Following the GLLAMM routine in Stata, this will include mixed-effects linear models (for 
continuous measures of adherence) with maximum-likelihood extensions to binary adherence 
endpoints. (Skrondal A, Rabe-Hesketh S. Generalized latent variable modeling: multilevel, 


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longitudinal and structural equation models. Boca Raton: Chapman and Hall, 2004.) 
This approach converges with that of generalized estimating equations based on the Huber-White 
sandwich variance estimator. 
2a. Secondary:  Sexual Activity  
Reported number of steady and casual sex partners, condom use (and change after introduction of 
study product), substance use prior to or during sex, as evidenced by participant responses to 
interviewer-administered questionnaires  
Analysis plan:  
The key analysis question for this secondary endpoint is whether different measures of sexual risk 
change with the availability and/or uptake of PrEP (in the initial 3-month mandatory study follow-up 
period) compared to periods “off-Prep”. The measures of sexual risk include continuous measures 
(number of sexual partners) as well as binary measures (casual sex partners yes/no, substance use 
prior to sex, consistent condom use during sex). All measures are visit-specific, with a maximum of 12 
measures during the study, per participant. In analysis, we will first use graphical approaches to 
display the proportions of participants reporting binary sexual risk behaviours (or means of 
continuous measures) at each study visit over the 12-month period. Following this, we will use 
repeated measures methods (as described above) for both binary and continuous dependent 
variables, with PrEP access treated as a binary variable distinguishing visits in on vs. off PrEP phases; 
in the first instance, these models will not include other covariates.   
2b. Proportion of scheduled HIV testing appointments that are missed, in relation to individual 
characteristics (age, sex, number of partners, use of other prevention methods) and the 
characteristics of the product. 
Analysis: 
“Missed appointments” will be defined as participants being >7 days late for a visit scheduled on a 
28-day cycle. This measure will be analysed as a binary variable following the repeated measures 
approaches described above. 
3. Secondary:  HIV Incidence  
HIV infection, as measured by seroconversion of study participants during the approximate 12 
months of follow-up  
Analysis:  
The incidence of HIV will be described using person-time (rates per 100 person years of observation) 


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and product-limit (survival proportion) approaches. For both methods, the date of seroconversion 
will be the midpoint of the interval between the last negative and first positive HIV test. For 
participants lost to follow-up, the date of censoring will be one day after the last visit attended. 
 
C. Exploratory Endpoints: 
1. Exploratory:  Dried Blood Spot/plasma biofeedback  
Correlation of self reported adherence and presence of drug levels in participants who are tested 
using plasma drug levels or DBS and received results compared to participants who are tested using 
plasma/DBS but do not receive biofeedback of results.  
Analysis: 
These data will be described as proportions at each study visit; while we will calculate differences in 
proportions attending between participant who do and do not receive biofeedback results, no formal 
statistical tests will be used for this exploratory endpoint. 
2.Exploratory: Sexual behaviour by coital diaries  
Sexual behaviour data obtained using a questionnaires and focus group.  
Analysis:  
Data from questionnaires will be compared to self-reported sexual behaviour on a per participant 
and per visit basis. While this endpoint is exploratory, we anticipate using the distributions of the 
observed data to defined post-hoc boundaries of acceptable agreement, and then use this to 
estimate the proportion of participants with acceptable versus unacceptable agreement at each visit, 
and overall during the study.  
 
Analysis of Focus Group data: 
All focus groups and interviews will be transcribed and then analysed using Framework Analysis 
(Ritchie and Lewis; 2003). This approach was developed in the 1980’s by researchers at the UK 
National Centre for Social Research and has been used extensively for applied or policy relevant 
qualitative research (Pope et al; 2000). It uses an analytical framework to organize data according to 
key themes, concepts and emergent categories in grids or matrices. This method facilitates both 
between case and within case analysis to look for patterns and connections. It provides a systematic, 
consistent and transparent approach to handling data that also enables analysis to go beyond 
description to interpretation where appropriate. In addition, it facilitates the linking of findings with 


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those of quantitative research, which will be relevant in comparing, contrasting and enhancing 
findings collected quantitatively in this study, in particular on PrEP acceptability and adherence. In 
addition, this triangulation of methods (qualitative and quantitative) has been advocated as an 
approach to increase the validity of findings (Mays and Pope; 2000, Shenton; 2004). 
 
Up to three researchers experienced in qualitative data analysis will form the data analysis team and 
all will be trained on the process of Framework analysis to ensure a consistent approach to analysis. 
The initial coding framework will be developed and agreed on by the team after coding of half the 
transcripts at each time point. However, as this is an iterative process, the framework may be 
amended as coding of the second transcript ensues. Any amendments will be discussed and agreed 
upon by the team. Each transcript will be coded by two researchers and assessed for consistency in 
coding. Inconsistencies between two coders will be brought to the data analysis team and discussed 
until agreement is reached. 
 


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11 
DATA HANDLING AND RECORD KEEPING 
11.1 
DATA MANAGEMENT RESPONSIBILTIES 
Data collection is the responsibility of the research site staff under the supervision of the Site 
Investigator.  
Case Report Forms (CRFs) will be developed by a multidisciplinary team of study staff members. 
11.2 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA 
Each participant will be allocated a study reference or participant identification number. All data will 
only be identified by this unique reference number. Data will be stored in a way in which participant 
identity is protected in a locked cupboard in a locked room on clinic premises and will be entered into 
computer by reference number only on password-protected computers. Consent forms with 
participant names and reference numbers will be kept separately from other data in a locked 
cupboard on clinic premises. Data will be stored for three years after the completion of the research, 
per DAIDS policy. Throughout this time, data held on computer will only be accessible by members of 
the research team who will have access to the computer system by way of security passwords. If the 
results of this research are published or presented, only group information will be given, not names 
of people in the study.  
 
The Site Investigator or designee will maintain, and store securely, complete, accurate and current 
study records throughout the study, in accordance with local regulations. All study-related records 
must be maintained on site for the entire period of study implementation. No study records may be 
moved to an off-site location or destroyed prior to receiving approval from DTHF and/or DAIDS. 
11.3 
QUALITY CONTROL AND QUALITY ASSURANCE 
Each site will be required to develop a robust SOP for quality control and quality assurance 
procedures.   


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12 
CLINICAL SITE MONITORING 
Regular study monitoring will be conducted internally by DTHF or outsourced to an external contract 
research organization (CRO).  
 
Study monitors will visit the sites to do the following: 
 Review procedures and documentation 
 Assess compliance with the study protocol, GCP guidelines, and applicable regulatory 
requirements  
 Perform source document verification to ensure the accuracy and completeness of study data 
 Assess implementation and documentation of internal site quality management procedures 
 
Site Investigators will allow study monitors to inspect site facilities and documentation (e.g., 
informed consent forms, clinic and laboratory records, other source documents, case report forms), 
as well as observe the performance of study procedures. Investigators also will allow inspection of all 
study-related documentation by authorized representatives of DAIDS and local regulatory 
authorities, if necessary.  
 
Details of the specific monitoring plan will be contained in the site-specific SOPs and will include 
information, such as who will conduct the monitoring, at what frequency monitoring will be done, 
and at what level of detail monitoring will be conducted. 
 


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13 
HUMAN SUBJECT PROTECTIONS 
See Section 14: Ethical Considerations for more information regarding this topic. 
 
13.1 
INDEPENDENT ETHICS COMMITTEE AND REGULATORY APPROVAL 
 
Prior to implementation of this protocol, and any subsequent full version amendments, each site will 
have the protocol and the protocol consent form(s) approved, as appropriate, by the local ethics 
committee and the South African Medicine Control Council. 
13.2 
DAIDS PROTOCOL REVIEW  
DTHF will submit the protocol and all required documents to the DAIDS Program Officer for review 
and approval. The RSC Human Subjects Protection (HSP) team is responsible for reviewing all 
Informed Consents (ICs) during review at the P/CSRC, Regulatory Review, and Protocol Registration. 
These include ICs for DAIDS-sponsored network and investigator-initiated protocols supported 
through DAIDS' grants. Prior to implementation of this protocol, and any subsequent full version 
amendments, each site must have the protocol and the protocol informed consent form(s) approved, 
as appropriate, by their local institutional review board (IRB)/ethics committee (EC) and any other 
applicable regulatory entity (RE). Upon receiving final approval, sites will submit all required protocol 
registration documents to the DAIDS Protocol Registration Office (DAIDS PRO) at the Regulatory 
Support Center (RSC).  The DAIDS PRO will review the submitted protocol registration packet to 
ensure that all of the required documents have been received.  Site-specific informed consent forms 
(ICFs) WILL be reviewed and approved by the DAIDS PRO and sites will receive an Initial Registration 
Notification from the DAIDS PRO that indicates successful completion of the protocol registration 
process. A copy of the Initial Registration Notification should be retained in the site's regulatory files. 
Upon receiving final IRB/EC and any other applicable RE approval(s) for an amendment, sites should 
implement the amendment immediately.  Sites are required to submit an amendment registration 
packet to the DAIDS PRO at the RSC.  The DAIDS PRO will review the submitted protocol registration 
packet to ensure that all the required documents have been received. Site-specific ICF(s) WILL NOT 
be reviewed and approved by the DAIDS PRO and sites will receive an Amendment Registration 


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Notification when the DAIDS PRO receives a complete registration packet. A copy of the Amendment 
Registration Notification should be retained in the site's regulatory files. 
For additional information on the protocol registration process and specific documents required for 
initial and amendment registrations, refer to the current version of the DAIDS Protocol Registration 
Manual. 
This protocol has also been submitted to the US Food and Drug Administration (FDA) as this study will 
be conducted under a US Investigational New Drug Application (IND). Implementation of this 
protocol must comply with US FDA and Office for Human Research Protection (OHRP). 
13.3 
RISK/BENEFIT STATEMENT 
The administration of the study product carries more than minimal risk to participants but holds out 
the prospect of direct benefit, based on the adult data available. These risks will be reduced as far as 
possible by extensive monitoring of participant health and well-being as well as provision of a 
comprehensive package of HIV prevention options, counseling, and psychosocial support. In South 
African ethical guidelines for child research, the following is permissible, that the research involved 
more than minimal risk but provides possible benefit for the child participants, and the degree of risk 
must be justified by the potential benefit (DOH, 2004, px) and the research interventions present 
more than minimal risk but hold out the prospect of direct benefit for the participant, and the risks 
must be justified by the anticipated benefit (DOH, 2006, px).  
 
Risks 
No new or unexpected side effects are observed with the FTC 200 mg/TDF 300 mg combination 
tablet versus when each drug is given separately.  
 
The most common risks and side effects from the study drug include headache, dizziness, fatigue, 
difficulty sleeping, depression, abnormal dreams, diarrhea, nausea (upset stomach), vomiting, 
headache, rash, gas, and skin darkening of the palms and/or soles. 
 
Less common but more serious risks may include: 
 Liver problems 


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 Inflammation of the pancreas 
 Anemia  
  Lactic acidosis (a buildup of a chemical called lactate in the body that can cause symptoms of 
unexplained weight loss, stomach discomfort, nausea, vomiting, fatigue, cramps, muscle pain, 
weakness and shortness of breath) 
 Lipodystrophy--changes in fat distribution in your body such as an increase in fat around the 
waist, back of the neck and breast areas, and thinning of the face, legs and arms—but unlikely 
with short term use 
 Decreased kidney function 
 Metabolic disorders  
 Changes in bone mineral density  
 Allergic reactions (symptoms may include fever, rash, upset stomach, vomiting, loose or 
watery stools, abdominal pain, achiness, shortness of breath, a general feeling of illness or a 
potentially serious swelling of the face, lips, and/or tongue) 
 
No controlled human studies of FTC among pregnant women have been conducted. No data on 
excretion of FTC/TDF in human breast milk have been reported.  
 
Protection against risks 
Side effects: Monitoring for kidney function loss will be done frequently during the course of the 
study such that problems will be detected early and study drug withheld. Serum chemistries and full 
blood countwill be monitored for other possible side effects. Persons with abdominal or other 
symptoms thought to be due to study drug may have drug held. Monitoring for depression will occur 
at every visit. 
 
As all participants will be required to be sexually active in order to enroll in the study, All partipants 
will be required to use condoms and will receive risk reduction counselling, which will include 
education about safer sex and condom provision. However, female participants will be required to 
use condoms as well as a low dose, combination contraception, in addition to receiving contraceptive 
counseling throughout the duration of study participation. As a result, the risks to pregnancy will be 
limited in this study.  Study participants will be counseled that study drug should not be shared with 


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any individual.   
Sexual disinhibition: Risk reduction counselling and condom provision will be performed at every 
visit.  
 
Social harms: Adolescents will have access to psychosocial support and counseling services provided. 
Should additional support be required for some participants due to study-related harms, referrals will 
be made to community-based services as needed. 
 
Benefits 
This research protocol contains interventions and procedures that at least hold out the prospect of 
benefit for adolescent participants. While there are some procedures which are unlikely to hold out 
the prospect of benefit and for which the intention is to generate knowledge (e.g. questionnaire 
administration), this protocol does contain several elements that hold out the prospect of a health-
related benefit for those taking part.  
 
An increased awareness of HIV and decreased or altered risk behaviour due to risk reduction 
counseling and regular testing may benefit participants.  
 
All participants will receive a comprehensive HIV prevention package, which includes: 
 Risk reduction counselling 
 Free condoms and condom counselling  
 Screening and treatment for STIs (syndromic management of STIs). 
 Counselling & referral for other HIV prevention interventions (e.g., male circumcision and Post 
Exposure Prophylaxis), as per national policies 
 
Participants will also have access to a package of sexual and reproductive health care, including STI 
syndromic treatment (see above), regular pregnancy testing and if necessary, counseling and 
contraceptive counseling and access. 
 
Adolescents will have regular monitoring for general health and receive appropriate management for 
identified conditions through appropriate referrals, and this may be of benefit to them. 


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Adolescents will have access to psychosocial support through the counseling services provided at all 
sites. Should additional support be required for whatever reason (e.g. social harm), appropriate 
referrals will be made to community-based services.  
 
Participants and others may benefit in the future from information learned from this study. 
Participants may appreciate the opportunity to contribute to the field of HIV prevention research. 
Information learned in this study may lead to the development of safe and effective interventions to 
prevent HIV transmission.  
 
Taken together, in a country with a significant adolescent HIV epidemic and within a context of 
frequently inadequate and inaccessible primary health care for youth, the presence of study 
interventions and procedures that hold out the prospect of benefit can be argued to be in the `best 
interests' of the individual adolescent trial participants. While none of the enrolled participants will 
be in ill health, many of these participants may be susceptible to acquiring certain health conditions. 
It is at the very least not against the best interests of the individual child participants to take part in a 
study that comprises several procedures and interventions that hold out the prospect of benefit. 
Moreover, given the high rate of HIV incidence in South African youth, it is in the best interests of 
adolescents as a class to have access to a formulation of PrEP which has been appropriately tested 
for safety, dosage, and acceptability amongst adolescents thus providing adolescents with a potential 
biomedical HIV prevention option. 
 
In terms of South African guidelines for child research (see 13.3 above) the risks of procedures/ 
interventions that hold out the prospect of direct benefit can exceed minimal risk however the risks 
must be justified by the anticipated benefits (the risk-benefit ratio). In terms of South African 
guidelines, the risks of procedures/ interventions that do not hold out the prospect of direct benefit 
must represent a minor increase over minimal risk and be justified by anticipated knowledge to be 
generated (the risk-knowledge ratio). This study protocol has attempted to identify which study 
components do, and do not, hold out the prospect of benefit, and has attempted to reduce risks of all 
components to an acceptable minimum, and to ensure that risk-benefit/ knowledge ratios are 
satisfied. 


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13.4 
INFORMED CONSENT AND ASSENT PROCESS 
Parental/ guardian consent and adolescent assent for both screening and study enrollment will be 
obtained prior to screening. For participants that are eligible for the study, a private informed 
assent/consent session will be held with each individual potential participant and their guardian, 
during which the study will be explained in an age-appropriate way. The assent/consent process will 
include a thorough review of any other current knowledge of the safety and protective effects of 
FTC/TDF pre-exposure prophylaxis.   
 
The informed consent and assent forms will include information about the study and individual 
request for consent of participants’ guardians and assent of the participants to participate in the 
study.  
 
Each study site is responsible for developing study informed consent and assent forms for local 
use,and translating these forms into local languages (if needed). 
 
It will be emphasized that participation is voluntary and that participants are free to withdraw from 
the study at any stage without any disadvantage to them.  
 
The informed consent and assent process will cover all elements of informed consent required by 
research regulations. In addition, the process specifically will address the following topics: 
 The need to practice safer sex behaviors. 
 The importance of adherence to the study drugs, visits, and procedures schedule.  
 The potential risks of study participation (and what to do if such risks are experienced). 
 The potential social harms associated with study participation (and what to do if such harms 
are experienced). 
 The potential benefits of study participation.  
 The right to withdraw from the trial at any time 
 Confidentiality and the limits of confidentiality. 
 
The potential participant and guardian should be given sufficient time and necessary information to 
consider the benefits and risks of involving the participant in the clinical trial.  


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An assessment of understanding will be conducted at screening to ensure that guardian consent and 
participant assent are informed.  
 
The name of investigators(s) who are responsible for conducting the study and direct contact details 
(telephone, address, e-mail) will be given to all participants and their guardians. 
 
Adolescents can consent independently to some procedures in the study--that is they should consent 
independently to:  
 
 Terminations of pregnancy at any age. However, study staff members will advise adolescents 
to “consult with their parents, guardian, family members or friends” before the termination. 
 HIV testing  
 Medical treatment, including STI and HIV treatment  
 Contraceptives access and contraceptive advice and information, including emergency 
contraceptives  
 
For further details on the development of this latter recommendation, please see Appendix 16.10: 
Selected Ethical-Legal Norms in Child and Adolescent HIV Prevention Research in South Africa: 
Consent, Confidentiality and Mandatory Reporting. 
13.5 
PARTICIPANT CONFIDENTIALITY 
Participant confidentiality is strictly held in trust by the participating investigators, their staff, and the 
pharmaceutical sponsor(s). Every effort will be made to maintain participants’ confidentiality. All data 
will be identified only by a unique participant number and kept in confidential files. All study 
documentation including questionnaires and informed consents will be kept in locked cupboards. 
Consent documents will be kept separately from questionnaires. No individual identifying 
information will be collected or disclosed in reports, publications, or presentations. See Section 14: 
Ethical Considerations for more information regarding the topic of privacy. 
 
For further details on the development of the following recommendations please see Appendix 


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16.10: Selected Ethical-Legal Norms in Child and Adolescent HIV Prevention Research in South 
Africa: Consent, Confidentiality and Mandatory Reporting1 
             
It is recommended that: 
 STI results, HIV, and pregnancy test results are given to the adolescents and not their parents 
 Adolescents who acquire conditions with long-term physical and emotional complications will 
require on-going support, and therefore, it is in their best interests to disclose changes in their 
health status to a trusted adult within a reasonable timeframe. Accordingly, adolescents who 
become HIV positive or pregnant ought to be required to identify and disclose this 
information to a trusted adult (not necessarily the parent or guardian). 
 Young adolescents (between the age of 15 and 16 or below the age of consent to sex), who 
are infected with an STI, will also be asked to disclose this information to a trusted adult. 
 With older adolescents (16-19 years), the results of the sexual risk assessment not be given to 
their parents.  
 With younger adolescents (15-16 years), parents may legally receive this information but they 
will be asked to agree not to be informed, given that safeguards like counseling and access to 
services are built in to the trial. 
 
It is further recommended that:  
 If participants are being sexually abused, deliberately neglected, or abused in a manner 
causing physical injury, then, because of their age, certain persons (e.g. medical practitioners, 
nurses, workers at youth care centers) will be required by law to report this abuse or neglect 
to designated child protection organizations, the provincial department of social development 
or police officials (s110 of the Children’s Act, 2010). Some study staff members may fall into 
these designated categories and be obliged to report.  
 Where sexual offenses are being committed against children (including rape and commercial 
sex work) then site staff should comply with laws requiring them to report to the South 
African Police Service (the Criminal Law, Sexual Offences and Related Matters Amendment 
Act, No. 32 of 2007). 
                                            
 


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 The circumstances in which adolescent information will be kept private should be stipulated 
in the consent and assent forms, to enable parents and participants to have a good 
understanding of the privacy norms and what results parents will or will not have access to. 
Based on this understanding, children or their parents may or may not agree to enrolment.  
 More specifically, a parent or legal guardian who is providing consent will need to understand 
that he or she will not receive feedback from site staff regarding the participant’s risk 
behavior, contraceptive usage, STI or HIV results, or pregnancy results; however, the 
participant will be asked to disclose to a trusted adult in the event of a positive HIV result, or 
pregnancy result, and will receive appropriate support services. Parents and legal guardians 
will also need to understand that they themselves may not be informed directly by site staff, 
in the event that a report must be made by law to an authority. It is possible that some 
parents or guardians may exercise their right to refuse enrolment on these grounds. 
Participants will need to understand that their parents and guardians will not be informed 
about their risk behavior, HIV, STI, or pregnancy results, but that there are instances where 
site staff will be required by law to make reports (for example, in instances of abuse). It is 
possible that participants may exercise their right to refuse enrolment on these grounds. 
 Note: DAIDS, IRB/ECs, OHRP, FDA, NIAID, MCC, other government or regulatory agencies will 
have access to the subject’s record.   
13.6 
COMPENSATION 
Participants may receive monetary remuneration at the end of each scheduled visits in the amount 
that will be reviewed and approved by the Independent Ethics Committees at each site and approved 
by the local CABs.  
In addition, a light snack and refreshment may be provided at each study visit. 
13.7 
STUDY DISCONTINUATION 
The study may be discontinued at any time by DTHF, DAIDS, NIAID, the pharmaceutical supporter(s) 
or designee, the MCC, the Independent Ethics Committees, the Office of Human Research Protection 
(OHRP), and the FDA or other government and regulatory agencies as part of their duties to ensure 
that study participants are protected. 


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14 
ETHICAL CONSIDERATIONS 
This study will be approved by DAIDS, Independent Ethics Committees, and South Africa’s Medicines 
Control Council prior to implementation. This study will be conducted according to the protocol as 
well as ICH and South African Good Clinical Practices. 
 
Community participation: Prior to study enrolment, key youth organizations will be educated about 
the study and their concerns and inputs solicited. Community structures like the adolescent CAB will 
be included to ensure that community views and perspectives are appropriately canvassed. In 
addition, CABS will be engaged to advise on informed consent procedures and forms, recruitment 
procedures, and retention of participants in the study. Organizations that serve and medically treat 
adolescents will be engaged to ensure that adolescent needs are met. 
 
Selection of participants aged 15-19 years. Although the age of lawful consent to sex in South Africa 
is 16 years, there is abundant evidence that South African adolescents are sexually-active at a 
significantly earlier age, as discussed in Section 1. It is therefore imperative that prevention 
interventions (ranging from behaviour change to biomedical intervention) acknowledge this and 
engage with those under 16 years. Risk reduction counselling (see below for further details) will be 
provided at every opportunity, as part of the HIV pre- and post- test counselling process.  
 
Study procedures and risk minimization: When adolescents are enrolled in this study, they will 
undergo an assessment of understanding; medical history and targeted physical exam; pregnancy 
testing and pregnancy counseling and prevention; HIV testing; risk behavior assessment and risk 
reduction; and PrEP administration and acceptability assessment. It is possible that adolescents, if 
they choose to take product, may increase their sexual risk behavior because of expectations of 
protection against HIV. Sexual risk will be carefully monitored and risk reduction counseling provided. 
In order to minimize the possible impact of risk compensation, counseling will emphasize high levels 
of personal risk (Cassell et al; 2006). STI (including HIV) and pregnancy testing may be stressful, but 
quality counseling and access to services as required will offset this risk.  
 
Section 71C of South Africa’s new National Health Act requires ministerial consent for so-called “non 


CHAMPS PrEP LoA#1 dated 29 December 2016  
 
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therapeutic research” (NTR). Although there is no current definition in law for NTR, ethical guidelines 
do distinguish between research that does (and does not) hold out the prospect of benefit for the 
child-participant. 
 
According to the South African ethical framework, clinical trial interventions that will not hold out the 
prospect of direct benefit must be limited to minimal risk or a  "minor increase over” minimal risk. 
However, interventions that hold out the prospect of direct benefit are not expressly capped, but the 
risks must be minimized and reasonable in relation to potential benefits (DOH GCP 2006; DOH, 2004). 
Study-related risks will be reduced as far as possible by extensive monitoring of participant health 
and well-being as well as provision of a comprehensive package of HIV prevention options, 
counseling, and psychosocial support. (See Section 13.3 for Risk/Benefit Statement). 
 
Consent for study enrolment: In accordance with South African guidelines for clinical trials and 
general research, consent for enrolment will be sought from a parent or legal guardian (DOH, GCP, 
2006; DOH, 2004).  
 
Disclosure of sexual activity to parents: It is recognized that disclosure of information regarding 
sexual activity may be problematic for adolescents and/or parents and where required, mediation 
and facilitation of adolescent disclosure of sexual activity will take place. Effective ways of doing this 
will be negotiated and developed with adolescents, and will be documented for future clinical 
practice. 
 
Mandatory Reporting: It is recommended that all abuse and neglect be reported to the relevant 
authorities and will be managed per site-specific SOPs. It is also recommended that sexual offenses 
involving children be reported to the relevant authorities, including rape and commercial sex work.  
 
However, certain types of sexual offenses will not be reported, more specifically underage sex or 
sexual activity that appears ‘consensual’ in nature and non-exploitative in nature. If participants, 
aged 15 years, report being sexually involved with older adolescent partners (with more than a 2 
year-age gap), study staff will not report the partner unless the sex/activity is clearly exploitative and 
after further investigation and assessment by the trial site team. Site staff will consider the age 


CHAMPS PrEP LoA#1 dated 29 December 2016  
 
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differential as well as other aspects of the relationship. 
 
In all instances of under-age sex, adolescents will be ensured of access to appropriate services (eg. 
contraceptive services, risk reduction counseling).  
Ethical review: In addition to review by South Africa’s Medicine Control Council (MCC) and relevant 
local research Ethics Committees, an adolescent community advisory board will be asked to make 
inputs into appropriate aspects of the study implementation.  
 
Schooling: Study participation will not interfere with school attendance; clinic hours will fall outside 
of core school hours. 
 
Standard of prevention: HIV Counselling and Testing (HCT) has been promoted as an effective tool 
for the reduction of risk of HIV infection. A study in Kenya reported positive risk behaviour changes 
up to 6 months after voluntary counselling and testing (VCT), including fewer sexual partners, 
increased condom use as well as fewer reported symptoms of sexually transmitted infections (Arthur 
et al; 2007). A further study in Zambia found sustained (although imperfect) condom use in 
discordant couples after VCT (Allen et al; 2003). Pre and post HIV test counseling, including risk 
reduction counseling (tailored to adolescents), will therefore be performed at every visit. Trained and 
qualified study personnel will provide age –appropriate pre-HIV test, risk reduction and post HIV test 
counseling at each visit, according to the site standard operating procedures (SOPs) [see Appendix 
16.5 for HIV Pre/Post Test Counseling Procedures and Appendix 16.6. for Risk Reduction Counseling 
Procedures]. Study sites will document their counseling policies and procedures prior to study 
implementation for purposes of staff training, quality assessment, and study monitoring. The 
counseling process will include information on HIV, safer sex practices, and risk reduction. The 
objective of counseling is to ensure that study participants have sufficient knowledge about HIV 
infection to understand what the test is for, the implications of a positive or negative result and the 
care available for HIV infection locally. In addition, risk reduction counseling, safe sex practices and 
methods of avoidance of transmission will be discussed with all participants regardless of their HIV 
test results. The content of risk reduction counseling will include facilitating participants to work on 
reducing their risk through modification of specific risk behaviours identified by the adolescents and 
counselors. This approach is based on psychological constructs identified as significant in facilitating 


CHAMPS PrEP LoA#1 dated 29 December 2016  
 
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behaviour change, and will include enabling participants to assess the costs and benefits of their risk 
behaviour/s, setting behavioural goals, identifying barriers to goal fulfillment and developing 
confidence to fulfill goals. Adolescent participants will be invited to bring their sexual partner/s to the 
clinic for risk reduction counseling and/or HCT if they wish. 
 Adolescents will also have access to post-exposure prophylaxis. Male adolescents will be provided 
with information on the benefits of circumcision. 
HSV-2, chlamydia, and gonorrhea will be tested for and treated (as needed) during study screening, 
Month 3, and at the last study visit. Other STIs will be treated syndromically. 
All adolescents taking part in the study will have access to male and female condoms and 
combination, low-dose oral contraception will be provided. 
 
Standard of care: As above, the adolescent will be given HIV pre and post test counseling support 
(see Appendix 16.5 for HIV Pre/Post Test Counseling Procedures), including risk-reduction counseling 
(see Apppendix 16.6. for Risk Reduction Counseling Procedures) and support for disclosure to a 
responsible adult.  
 
Any seroconversions that occur will be referred to the local health facility, and the necessary 
assistance provided to remove barriers to treatment access. See Section 7.8.1 for complete overview 
of study procedures for HIV-infected participants. 
 
Health benefits: [see Benefits Section, under 13.3]  
 
Social harms monitoring:  At every visit, social impact questions will be included in the assessments 
to determine whether study participation is having a negative psycho-social impact. In addition to 
documenting social harm events, participants’ experience of the event will be elicited as well as their 
perception of its severity and any resolution strategies they may have adopted (Milford et al; 2007). 
Where necessary, counseling services will provide support and in addition, other ways of moderating 
social harm will be developed and documented. This information will inform a protocol for future use 
in delivering adolescent services and in conducting adolescent prevention research in South Africa. 
 
Results dissemination plan: Study results will be communicated back to participants and community 


CHAMPS PrEP LoA#1 dated 29 December 2016  
 
Page 113 of 141 
representatives through DTHF’s established infrastructure (adolescent and adult CABs), as well as 
through participant information sheets that summarize the key findings from the study (to those 
participants expressing desire to be informed). Results may be published or presented at conferences 
to make information available to a wider community. 


CHAMPS PrEP LoA#1 dated 29 December 2016  
 
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15 
PUBLICATION POLICY 
DAIDS and DTHF policies will govern publication of the results of this study. Any presentation, 
abstract, or manuscript will be submitted to DTHF and DAIDS for review prior to submission. 
 
 


Guardian consent focus group V1.0  6 May 2014 
1
16 
APPENDICES 


 
1
16.5 
HIV PRE/POST-TEST COUNSELING PROCEDURES   (INCLUDING HIV TESTING 
ALGORITHM) 
 
HIV Counseling Procedures 
 
For HIV testing within the study, where the consent for study participation includes HIV 
testing, written consent for each individual HIV test within the study need not be obtained, 
however verbal consent should be confirmed.  Pre and post test counseling is always 
performed. 
 
Pretest counseling: 
a) The counseling staff deliver pre-test counseling, which includes: 
 
An explanation of the test, and the window of infection with a negative test; 
 
Basic information on HIV transmission and prevention 
 The significance of the potential test result 
 A reminder that although their test result is confidential, should the result be 
positive, staff will encourage the adolescent to share their result with a trusted 
adult 
 Discussion regarding who the participant might share their result with if positive 
 An explanation that a participant may be infectious even if their test result is 
negative. 
 
b) The staff member evaluates the psychological stability of the participant and the 
possible impact of testing positive at the pre-test visit. 
 
Post-test counseling: 
a) If the result is negative, the counseling staff: 
 
Discusses protection during the window period of a negative test; and 
 
Discusses HIV test intervals, as appropriate. 
 
Provides risk reduction counseling (see below) 


 
2
 
b) If the result is indeterminate, the counseling staff discusses its significance with the 
participant. A repeat test is performed. 
 
c) If the participant’s result is positive, a second rapid test is performed. If this is 
positive, blood is drawn for a confirmatory laboratory test and a CD4 count. If the 
second rapid test result is negative, a confirmatory laboratory test should also be 
performed.  
        
d) If a positive result is confirmed: 
 
The counseling staff/study physician shares the participant’s result with them in 
a sensitive and neutral manner, allowing them time for the information to be 
understood and absorbed 
 
The counseling staff/study physician discusses the difference between HIV and 
AIDS, treatment options, transmission issues, and the risks and benefits of 
partner notification, as well as the risks and benefits of notifying a trusted adult 
and how this might be done.  
 
If this occurs at screening, the counseling staff/study physician explains to the 
participant that inclusion in study is not possible and refers the participant to a 
service provider/ clinic for further evaluation, management and support.  
 
If a participant tests positive at any other visit, they can remain in the study and 
complete all study activities as planned including continuing to receive the 
vaccine (if they have consented to receive it). Further visits for psychosocial 
support and clinical management should be planned with the participant, per 
site-specific procedures. 
 
Personalized referral to services for long term clinical management, and follow-
up to ensure adolescent attendance should take place 
 
Details of any community support groups and other relevant organizations 
should be passed on to the participant  


 
3
16.6 HIV Algorithm for Screening and Enrolment 
 


 
4
16.7 HIV Algorithm for Follow-up visits
                                                                                                                    Both rapids 
                                                                                                                       Negative  
 
One/both rapids reactive  
                          Positive  
Negative  
HIV rapid tests  
HIV seronegative  
If acute HIV infection 
suspected perform HIV RNA  
Possible HIV infection  
Inform Site PI and protocol Chair  
HIV RNA  
Repeat HIV RNA  within 2 weeks  to 
confirm HIV infection  
Consult  
Protocol Chair  
2nd Confirmatory Test  
Positive – Confirmed HIV- Infected  inform Protocol Chair  
Indeterminate/ Negative  - Consult with Protocol Chair for next steps 
 


 
5
 


 
1
16.8  RISK REDUCTION COUNSELING PROCEDURES 
 
Risk Assessment 
a) The counseling staff member assesses the individual’s risk factors for acquiring infection, 
including: 
 
Sexual activity  
 
Type of sex (vaginal, anal, oral) 
 
Reasons for being in a sexual relationship 
 
Number of sex partners (casual and steady) and sexual activities 
 
Sex with someone known to be HIV positive 
 
Sex with someone more than 2 years older or younger 
 
Sharing needles or having sex with someone who shares needles 
 
History of STI’s and having sex with someone who has a history of STI’s, 
especially genital lesions; 
 
Sex in exchange for drugs, money or other inducements 
 
Use of substances (e.g. alcohol) in connection with sexual activities 
 
Condom use 
 
b) Included in the risk assessment, should be an assessment of the participant’s knowledge 
of modes of HIV transmission and the impact of risk taking behaviors. Basic information on 
HIV transmission and prevention; this should focus on, but not be limited to, areas identified 
during risk assessment where knowledge was incomplete 
 
c) The counseling is focused on the participant’s individual risk factors and situation. 
 
d) The counseling staff member and participant set manageable goals for risk reduction. 
 
e) At each visit, the counseling staff member and the participant reassess the participant’s 
behavior and risk factors, and if necessary, adjust the goals. 
 


 
2
Risk reduction counseling for those who are HIV positive 
Where participants have just learnt of their HIV-positive status, their immediate concerns 
may not be regarding risk reduction. It may be more appropriate to provide in depth risk 
reduction counseling (as above) at further visits.  
 
Nonetheless, it is important to convey to adolescents that they are most infectious in the 
first few months after becoming HIV infected and should therefore take steps to protect 
others. In addition, they may be more susceptible to other STIs and it is therefore important 
that they protect themselves. This information at least should be communicated at the 
same visit where they learn of their HIV-positive status.  


16. 9 
Expedited Adverse Event Reporting Requirements for Pluspills: 
 
 
1.“Life-threatening” refers to an event in which the patient was at risk of death at the time of the event. It does NOT refer to an event that 
hypothetically might have caused death if it were more severe. 
2 Per the ICH SAE definition, hospitalization is NOT an adverse event (AE), but is an outcome of the event. DO NOT REPORT: Any admission 
unrelated to an AE (e.g., for standard labor/delivery, cosmetic surgery, administrative or social admission for temporary placement for lack 
of a place to sleep); protocol-specified admission (e.g., for a procedure required by protocol); admission for diagnosis or therapy of a 
condition that existed before receipt of study agent(s) and has not increased in severity or frequency as judged by the clinical investigator. 
(NOTE: A new AIDS-defining event in a subject already known to be HIV-infected would be considered an increase in severity of a pre-
existing condition [HIV infection] and would be reportable.) 
3 Clinically insignificant physical findings at birth, including those regarded as normal variants, do NOT meet reporting criteria. If a clinically 
significant anomaly is reported, all findings (including those of no individual significance) should be included in the same report. For 
example, do NOT report an isolated finding of polydactyly (extra fingers or toes) or Mongolian spot in an infant. But if either finding 
occurred with a major cardiac defect, report all findings in the SAE Report. 
4 Please ensure that any other protocol-specific reporting requirements are met. 
Contact Information for the DAIDS Safety Office: Website: http://rsc.tech‐res.com ‐ Email: 
DAIDSRSCSafetyOffice@tech‐res.com 
Office Phone: 1‐800‐537‐9979 (U.S. only) or +‐301‐897‐1709 – Fax: 1‐800‐275‐7619 (U.S. only) or +1‐
301‐897‐ 1710 (Office Phone and Fax are accessible 24 hours per day)  
Mailing Address: DAIDS Safety Office 6500 Rock Spring Drive, Suite 650, Bethesda, MD 20817 
Reporting Adverse Events in an Expedited Manner 
The timeframe for expedited reporting of individual AEs begins when the clinical research 
site recognizes that an event meets SAE criteria for expedited reporting to DAIDS. The day 
that the site becomes aware of the event is considered Day 1. Clinical research sites must 
submit AEs to the DAIDS Safety Office immediately, and no later than 3 reporting days after 
the site becomes aware of an event that meets criteria for expedited reporting. 
“Reporting days” are those that count toward the 3-day timeline provided for reporting of 
EAEs to DAIDS. The criteria used to determine reporting days are as follows: 


2 
 
• A reporting day starts at 12:00 AM (midnight) and ends at 11:59 PM local time.  
• A day is counted as a reporting day regardless of the time of day that awareness occurred. 
The day a site indicates that site personnel became aware of an EAE that meets 
reporting criteria shall count as day 1 (even if it is 23:00) if that day occurs on a 
reporting day (i.e., Monday through Friday). If that day occurs on a non-reporting 
day (i.e., Saturday or Sunday), then the next reporting day shall count as day 1.  
• Monday through Friday count as reporting days.  
• Saturday and Sunday are not considered reporting days.  
• Any holiday (U.S. or in-country/local) that occurs on a Monday through Friday counts as a 
reporting day. The figure above details EAE reporting requirements. For each 
PlusPills participant, the EAE reporting period begins with study enrollment (Day 0), 
and ends with the participant’s termination visit. All EAEs should be reported to the 
DAIDS Regulatory Support Center (RSC) using the internet- based DAIDS Adverse 
Experience Reporting System (DAERS).  
 The process of EAE reporting via DAERS involves a designated “Study Reporter” creating an 
electronic EAE report and a designated “Study Physician” reviewing the EAE report, signing 
the EAE report with an electronic signature, and submitting the EAE report to the DAIDS 
RSC. If an EAE report is not completed and submitted within three reporting days of site 
awareness of the EAE, an explanation must be entered in DAERS before the report can be 
submitted. 
DAERS also may be used to modify or update an EAE report or to withdraw an EAE report 
that was submitted in error. 
DAERS incorporates a report printing function that should be used to print all EAE reports —
including modifications and updates — for filing in participant study notebooks. Automated 
email messages confirming submission of EAE reports also should be printed and filed with 
the print- out of the associated EAE report. 
In the event that DAERS cannot be accessed (e.g., due to poor internet connectivity), paper-
based EAE reporting should be used, per instructions provided in the Manual for Expedited 
Reporting of Adverse Events to DAIDS. Completed paper EAE Forms may be faxed or digitally 
scanned and emailed to the DAIDS RSC via email. The EAE Form and form completion 
instructions are available on the DAIDS RSC web site (http://rsc.tech-res.com). Contact 
details for submission of EAE Forms to the RSC are provided in the Manual for Expedited 
Reporting of Adverse Events to DAIDS. 
IMPORTANT: Sites must submit an AE CRF to DAIDS along with any SAE/EAE. The following 
data points must be exactly the same on both the AE Log submitted to EAE Report 
submitted to DAERS: 
• Participant ID  


3 
 
• Onset Date  
• Severity of event  
• Relationship to study product  
• Adverse Event Term (Diagnosis)  
It is important to remember that if the site updates any of these data points on one 
document that same change must be made on the other. 


4 
 
16.10 : SELECTED ETHICAL-LEGAL NORMS IN CHILD AND ADOLESCENT HIV PREVENTION 
RESEARCH IN SOUTH AFRICA: CONSENT, CONFIDENTIALITY AND MANDATORY REPORTING 
[revised] 
 
Suggested citation: Strode, A. & Slack, C. (2013). Selected ethical-legal norms in child and adolescent HIV 
prevention research: Consent, confidentiality and mandatory reporting [revised]. NIH, Desmond Tutu HIV 
Foundation (DTHF) and European and Developing Countries Clinical Trials Partnership (EDCTP): 2013.  
 
Comments to Catherine Slack (slackca@ukzn.ac.za) or Ann Strode (strodea@ukzn.ac.za) at the HIV AIDS 
Vaccines Ethics Group (HAVEG), University of KwaZulu-Natal (UKZN) South Africa 
http://www.saavi.org.za/haveg.htm  
 
Updated 4 June 2013 
 
INTRODUCTION 
The HIV AIDS Vaccines Ethics Group (HAVEG) at the University of KwaZulu-Natal (UKZN) was  funded through 
the European and Developing Countries Clinical Trials Partnership (EDCTP) to develop resources on the ethical-
legal framework for researchers and research ethics committees (RECs) working with adolescent HIV 
prevention trials. This memo was originally designed to assist and guide researchers working on the South 
African Studies on HIV in Adolescents (SASHA) project. The aim of the SASHA study was to build stakeholder 
capacity for adolescent prevention trials. The memo has been revised, updated and adapted to assist other 
protocol developers and protocol reviewers by identifying key ethical-legal issues in adolescent HIV prevention 
trials and describing the legal obligations relating thereto. Current funding to update this resource is received 
from the National Institutes of Health via the Desmond Tutu HIV Foundation (DTHF).  
 
Key legal complexities in HIV prevention research with adolescents include:   
 
Who consents for trial enrolment? Who consents to the health-related interventions in the trial? 
 
What components of the trial should adolescents enjoy confidentiality for? 
 
What disclosures are likely to trigger reporting obligations? 
 
What should researchers do to intervene to assist adolescents when key problems are picked up? 
 
Based on the current ethical-legal framework, this memo has identified nine key norms which should 
apply to adolescent HIV prevention trials. These are:  
 


5 
 
1. 
A parent or legal guardian (LG) should provide consent for adolescents to take part in prevention 
trials; 
2. 
Adolescents should consent independently to key trial components, even though their parents/ 
LGs will provide consent to enrolment in the trial; 
3. 
Adolescents should enjoy confidentiality for key trial components;   
4. 
Adolescents’ right to confidentiality can be limited and adolescents could be asked to disclose to 
otherwise confidential information to a trusted adult in certain instances; 
5. 
Parent s/ LGs and adolescent should understand what information will or will not be made 
available to parents/ LGs;  
6. 
If adolescents are being abused, neglected or maltreated, this should be reported to authorities and 
adolescents should be assisted; 
7. 
If adolescents are engaged in underage sexual relationships that are consensual but exploitative, this 
should be reported to the authorities and the adolescents should be assisted; 
8. 
There is no legal obligation to report other offenses but adolescents should be assisted; and 
9. 
Parents/ LGs and adolescents should consent to confidentiality limits posed by reporting to 
authorities. 
 
These are each discussed in more detail below: 
 
1: A parent or legal guardian (LG) must provide consent for adolescents to 
take part in prevention trials 
1. 
The first norm is that a parent or LG must provide consent for trial enrolment. 
 
2. 
How was this established? Currently, there is no clear legal standard specifying when children 
can independently consent to research, however, there are ethical norms. The Department of 
Health’s GCP (2006) guidelines1 provide that children cannot consent on their own to clinical 
trials and that consent must be obtained from a parent or a LG. The National Health Research 
Ethics Council guidelines (2004)2 allow that adolescents can only consent unassisted to minimal 
risk research (where research risks are approximate to those of the child’s everyday life). Clinical 
trials are generally held to present a higher standard of risk than this, therefore, consent from a 
parent or LG must be secured.   
 
3. 
Parents or LGs must consent to adolescent enrolment only when they understand the 
implications for their children and themselves. Some of the norms relating to the manner in 
which the trial will be run (described in more detail below) may be unacceptable to a parent, for 
example, the protocol may provide that parents will not necessarily be told that their child is 
pregnant or that their child elected to have the pregnancy terminated with the assistance of 
researchers. Therefore, in such situations parents or LGs may refuse to enrol their child in the 


6 
 
trial. Adolescents themselves must provide assent to participation. Some norms may be also 
unacceptable to an adolescent, for example, the obligation to disclose HIV status to a trusted 
adult if they test positive. Therefore, adolescents may also refuse to enrol in the study. 
 
4. 
In the future, if Section 71 of the National Health Act3 is implemented, parental/legal guardian 
consent will be a legal requirement for all health research (trial and non-trial). This change in the 
law will have very few repercussions in the clinical trial environment, where stakeholders are 
generally used to this requirement. However, repercussions will be felt by social scientists. In 
addition, should s71 be implemented then children will be required to “consent” rather than 
assent alongside their parent if they have “sufficient understanding”. 
 
2: Adolescents should consent independently to key trial components, even 
though their parents or LGs will provide consent to trial enrolment  
 
1. 
The second norm is that even where a parent or LG provides consent for enrolment, adolescents 
should consent independently to certain trial components.   
 
2. 
How was this norm established? According to various statutes, adolescents can consent 
independently to a number of health-related interventions, such as:  
a. 
Terminations of Pregnancy at any age (s 5, Choice of Termination of Pregnancy Act, No. 92 of 
1996)4.  However the  Act  requires providers to advise adolescents to “consult with their 
parents, guardian, family members or friends” before the termination (s 5, Choice of Termination 
of Pregnancy Act)4 
b. 
HIV testing from the age of 12 (s 130, Children’s Act, No. 38 of 2010)5 and even children below 
12 can consent independently to such testing if they have “sufficient capacity” 
c. 
Medical treatment from the age of 12, including STI and HIV treatment provided the child has 
“sufficient maturity”. In other words the child should be 12  and have the mental capacity to 
understand the benefits, risks, social and other implications of the treatment; and (s 129, 
Children’s Act No. 38 of 2010)6 
d. 
Contraceptives and contraceptive advice, including emergency contraceptives from the age of 
12 (s 134, Children’s Act, No. 38 of 2010)7 
e. 
Circumcision at the age of 168. If boys are below the age of 16, then consent must be obtained 
from their parent or legal guardian. The Act also requires that boys below 16 can only be 
circumcised for ‘religious’ or ‘medical reasons on the recommendation of a medical practitioner’ 
whereas those above 16 may undergo circumcision for any reason. Boys over 16 must receive 
counselling prior to the circumcision, and they have the right to refuse circumcision. (s12 (8) and 
s12(9-10) of the Children’s Act No. 38 of 2005 


7 
 
f. 
Surgical operations at the age of 12 provided he/she (i) has ‘sufficient maturity and has the 
mental capacity to understand the benefits, risks, social and other implications of the surgical 
operation’, and (ii) is assisted by a parent or guardian. (See section 129(3) of the Children’s Act 
No. 38 of 2005). 
 
3. 
Another factor that is relevant to consent by adolescents within HIV prevention trials is the age at 
which they can lawfully engage in sex. This is set at 16 in the Sexual Offences Act (s 15, Criminal 
Law (Sexual Offences and Related Matters) Amendment Act, No, 32 of 2007). See section 7 for 
more detail.  
 
4. 
Currently in prevention trials this means that: 
a. 
Adolescents, who need to be tested for pregnancy regularly as part of a prevention trial, can give 
their own consent for pregnancy tests from the age of 12  and could receive a TOP at any age with 
their own consent, provided they have the capacity to consent; 
b. 
Adolescents, who need to be tested for HIV regularly as part of the study, can give their own 
consent for these HIV tests from 12; 
c. 
Adolescents, who need to be tested regularly for STIs, can give consent on their own from 12 for 
STI testing and treatment, if required, provided they meet the capacity requirements (which 
could vary according the medical condition or procedure); and 
d. 
Adolescents wanting access to male or female condoms or other forms of contraceptives or 
contraceptive advice could receive these on their own from the age of 12. 
 
3: Adolescents should enjoy confidentiality for key trial components  
1. 
The third norm is that adolescents should enjoy confidentiality for key trial components. How 
was this norm established?  
 
2. 
Firstly, adolescents have the right to confidentiality for the range of health-related interventions 
that they have consented to independently.  That is:  
a. 
Adolescent TPs of 12 years and older (and not their parents) should receive HIV test results; 
b. 
Adolescents of 12 (who have capacity) and older (and not their parents) should get the results of 
STI tests; 
c. 
Adolescent TPs of 12 years and older should enjoy confidentiality for access to contraceptives; 
d. 
Adolescent TPs (and not their parents) should get results of pregnancy tests and/ or enjoy 
confidentiality for TOPs. 
 
3. 
Secondly, adolescents have a right to privacy if there is an expectation of privacy that society 
regards as reasonable.  Where the law is silent on whether a right to privacy exists, one can use 
the “legitimate expectation test” to establish if something should be kept private. 


8 
 
 
a. 
It can be argued that adolescents who are 16 years and older have the right to confidentiality 
regarding their sexual risk data. That is, older adolescents (and not their parents) should get the 
results of sexual risk assessments. This is on the grounds that older adolescents would have an 
expectation of privacy (which most would hold as reasonable) because adolescents can lawfully 
consent to sex at 16. For adolescents who are under 16, the above rationale may not hold, 
however, parents can agree not to be informed on the grounds that safeguards (such as 
counseling and access to services) will be built in to the trial. 
 
4: Adolescents’ right to confidentiality can be limited and adolescents could 
be asked to disclose otherwise confidential information to a trusted adult in 
certain instances  
 
1. 
The fourth norm is that even though adolescents have rights to confidentiality, these rights can 
be limited.  
 
2. 
How was this norm established? In law, a child’s right to confidentiality regarding their health 
status can be limited where this is in their “best interests” (s 13(1)(d), Children’s Act). In ethics, 
respect for emerging autonomy can be balanced by the need to minimize harms and promote 
welfare. In law, South African courts have generally held that the best interests of children 
require a wide range of factors to be considered in decision-making, including those which 
promote a child’s physical, moral, emotional and spiritual welfare.9 This means decision-makers 
must evaluate, weigh and balance these competing factors. They must also take into account the 
child’s wishes. 
 
3. 
In prevention trials, adolescents, who acquire conditions or a health status with long-term 
complications that need on-going support, should be asked to disclose to a trusted adult within a 
reasonable time-frame, because this is in their best interests. For example, maintaining 
confidentiality regarding a child’s HIV status or their pregnancy may not be in their best interests 
as these are chronic, long-term conditions that require specialist treatment and emotional 
support.  
 
5: Parents/ LGs and adolescents should understand what information will or 
will not be made available to parents/ LGs 
 


9 
 
1. 
The fifth norm is that both parties must understand what information will be kept confidential 
and what will be disclosed to another party.  
 
2. 
How was this norm established? In law, consent is valid only if it is based on a full appreciation of 
information that most people would consider very important to know. In ethics, consent is only 
meaningful if it is based on a full understanding of the personal implications of research 
participation. In prevention trials, it is possible that the parent/ guardian may refuse enrolment 
when they understand these matters, or the child may refuse to take part. 
 
6: If adolescents are being abused or neglected, this should be reported to 
authorities and adolescents should be assisted   
 
1. 
The sixth norm is that adolescents’ right to confidentiality is expressly limited where they are 
being abused or neglected, or are identified as being in need of care and protection.  
 
2. 
How was this norm established? In terms of s 110 of the Children’s Act (2010)10 there is a broad 
range of persons who must report any child that has been sexually abused, deliberately neglected 
or abused in a manner causing physical injury.   
 
3. 
The category of persons who must report such abuses includes medical practitioners, nurses, 
psychologists, social service professionals, social workers and members of staff or volunteer 
workers at a drop-in centres or child and youth care centres.  
 
4. 
Reports must be made to designated child protection organisations, the provincial department of 
social development or police officials. While all research staff are not expressly included in this list, 
some members of the team will fall into these designated categories and are obliged to report.  
 
5. 
Even if staff do not fall within a designated category obliging them to report, the Act also states that 
any person who, on reasonable grounds, believes that a child is in need of care and protection may 
report that belief to the provincial department of social development, a designated child protection 
organisation or a police official. 
 
6. 
In addition, researchers should assist children by referring them for various kinds of support. 
Assistance could involve encouraging adolescents to reach out for all forms of adult support, 
including their reaching out to their parents, where this seems helpful.  
 
7. 
Trial sites could partner with professional organisations to assist them to make determinations of 
abuse or neglect. 


10 
 
 
7: If adolescents are engaged in underage sexual relationships that are 
consensual but exploitative, this should be reported to the authorities and 
the adolescents should be assisted 
 
1. 
The seventh norm is that adolescents’ right to confidentiality may be expressly limited in certain 
circumstances, such as when certain sexual offences are being committed.   
 
2. 
How was this norm established? In ethics, respect for emerging autonomy can be balanced by the need 
to minimize harms and promote welfare. In law, the Criminal Law [Sexual Offences and Related 
Matters] Amendment Act, No. 32 of 200711 requires any person who is aware of a sexual offence having 
been committed against a child to report this to the South African Police Service (SAPS).  
 
3. 
This memo recommends that all instances the sexual offences of rape and commercial sex work should 
be reported to SAPS. In terms of rape, it is important to note that all sex (even if it is ‘consensual’) with 
persons under the age of 12 is rape in terms of the Sexual Offences Act. Therefore, even if a child 
participant discloses ‘consensual’ sex under 12, this will have to be reported as statutory rape.  
 
4. 
According to the Sexual Offences Act (s 15, Criminal Law [Sexual Offences and Related Matters] 
Amendment Act, No, 32 of 2007) it is a sexual offence for an adult (older than 18 years) to have 
consensual sex/sexual activity with a child between the ages of 12 – 15 years. This is still the case.   
 
5. 
Recently, the High Court declared certain sections of the Sexual Offences Act - which criminalized 
consensual sex between children (12 - 15 years) - to be unconstitutional. Resultantly it is no longer a 
sexual offence if both parties to the consensual sex/sexual activity are between 12-15 years. In addition, 
the court held that it is no longer a sexual offence if children between 16 -17 years have sex with 
children between 12-15 years if there is two year age gap or less between the older and younger child. 
This means that certain instances of consensual sex/sexual activity are no longer illegal.  The Sexual 
Offences Act has thus (to some degree) become more aligned with the principles articulated in the 
Children’s Act (2005) which expressly allows sexually active children under the age of 16 years to access 
services such as contraceptive advice and methods, HIV testing, and medical treatment.   
 
6. 
This also means that where there is a large age gap between those in the sexual relationship or where 
one party is an adult (over 18), the older person is committing a sexual offence and the law requires 
that reporting to the police take place.  
 


11 
 
7. 
However, we have proposed a more nuanced approach:  
i. 
When adolescent participants (12-15) report that they are sexually involved with persons 18 years 
and older, site staff should be aware that this is a reportable offence. However, the partner, if 
known, should not be reported unless that sex/activity is clearly exploitative. This is because 
adolescent participants themselves (between the ages of 12 and 15) are not committing a crime 
by having under-age, consensual sex and because reporting – where relationships are not 
exploitative - is not in their best interests as it will drag young persons into the criminal justice 
system requiring them to give evidence in court and face possible negative consequences from 
their partner who faces a criminal record and being entered onto the Sexual Offences Register. 
ii. 
When younger adolescent participants (12 -15) report being sexually involved with older 
adolescent partners (with more than a 2 year-age gap) site staff should be aware that this is a 
reportable offence. However, the partner, if known should not be reported unless the sex/activity 
is clearly exploitative; after an assessment by the trial site team. 
iii. 
When older adolescent participants (16/17) report that they are sexually involved with younger 
children (with more than a 2 year age gap) site staff should be aware that this is a reportable 
offence. However, the adolescent participant should not be reported unless the sex/activity is 
clearly exploitative, in order words, after an assessment by the trial site team. 
iv. 
The determination of whether the sex/ sexual activity is exploitative should be made by a multi-
disciplinary team who consider whether the ability of the adolescent to consent to the sexual 
activity has been compromised by factors such as coercion, violence or a lack of power.   
 
8. 
This approach can also be defended on ethical grounds that harmful activities (such as non-consensual 
or exploitative sex) are reported, but that non-harmful activities (consensual and non-exploitative sex) 
are not reported because this is unlikely to protect children, may erode trust in adult or authority 
figures and may decrease the veracity of disclosures children make to research staff – impeding the 
ability to steer them to appropriate services.  
 
9. 
This approach requires trial sites to undertake an assessment of exploitation. Site staff should consider 
the age differential as well as other aspects of the relationship such as where one party assumes an 
unfair level of benefit relative to another party. There is no easy formula for this assessment.  
 
10. 
This approach should be discussed with Research Ethics Committees involved in oversight of the 
prevention trial. 
 
11. 
Sites may wish to partner with professional organisations to assist them to make such determinations.  
 


12 
 
12. 
If adolescents are aware that certain categories of sexual activity, including ‘exploitative’ sex, may be 
reported to authorities, they may elect not to disclose this to site staff. 
 
8: There is no legal obligation to report other offenses but adolescents should 
be assisted 
 
1. 
The eighth norm is that where adolescents are acting in a way that contravenes other laws, there 
may be no legal obligation to report this, but there is an ethical responsibility to assist. Again, such 
assistance could involve encouraging adolescents to reach out for forms of adult support, including 
their reaching out to their parents where this seems helpful. 
 
2. 
How was this norm established? The South African Schools Act (1996)12 requires all children 
between the ages of 7 – 15 to attend school. The Basic Conditions of Employment Act (1997)13 
asserts that it is illegal for children under the age of 15 to work, or those between the ages of 15 
and 18 to perform unsuitable work (work that places their well-being, education, physical or 
mental health, or spiritual, moral or social development at risk). 
 
3. 
Currently, in HIV prevention trials:  
a. 
A researcher is not under a legal obligation to report truancy from school to any authority. 
However given that parents are required to ensure that children under 15 attend school and 
they may be unaware that their child is not attending, researchers may wish to inform parents 
of under 15 year-olds of truancy, so that parents can act to fulfil their duty. Children should 
also get assistance, advice and appropriate referrals. Trial attendance should not interfere 
with the school attendance. 
b. 
A researcher is not under a legal obligation to report child labour or inappropriate work. 
There may however be an ethical obligation to act in the best interests of the child by 
providing assistance, advice and appropriate referrals. 
c. 
A researcher is not under a legal obligation to report information regarding a child participant 
who has committed, or is committing, crimes (e,g., abusing substances, committing theft). 
However, where a child, involved in a criminal offense, is being exploited, this should be 
reported to the police or other relevant authorities because this amounts to ill-treatment (e.g. 
where a child is being forced to sell drugs by an adult). However, in the instance of criminal 
activity, researchers should intervene through advice and appropriate referrals.  
d. 
A researcher is not under a legal obligation to take further steps when a research participant 
informs the researcher of a third party, who has been the “victim” of a crime or has 
“committed” a crime. However, they may be under an ethical duty if a child is in clear and 
imminent danger, for example from a violent and abusive parent. In such a case they should 


13 
 
assist the child research participant to report this information to the local police or social 
workers for further investigation.  
 
9: Parents/ LGs and adolescents should consent to confidentiality limits 
posed by reporting to authorities  
 
1. 
The last norm is that both parties (parent and adolescent) must understand what information will 
be kept confidential and what will be disclosed to authorities.    
 
2. 
How was this norm established? In law, consent is valid only if it based on a full appreciation of 
information most people would consider very important to know. In ethics discourse, consent is 
only meaningful if it is based on a full understanding of the personal implications of research 
participation. 
 
3. 
In prevention trials, it should be explained to parents that the researchers are not necessarily 
required by law to tell parents if a report is made to authorities. However, each case will be 
approached on a individual basis with the best interests of the child being the basis for deciding 
whether parents should be informed by researchers.  
 
4. 
In all instances, the adolescent will receive assistance, support and appropriate referrals.  
 
5. 
It is possible that the parent/guardian may refuse enrolment when they understand these matters, 
or the child may refuse to take part. 
 
CONCLUSION 
 
1. 
Ethical-legal norms for adolescent HIV prevention trials should be understood by, and acceptable 
to, key stakeholders such as participating communities. Where high levels of objection to trials are 
anticipated, it may not be feasible to run such trials. It may be helpful to research the acceptability 
of such norms among participating communities.  
 
2. 
It may also be helpful for researchers implementing such norms in prevention trials to monitor 
“events” such as mandatory reports to authorities and direct disclosures to parents to estimate 
frequency and impact. 
 


14 
 
3. 
In the long run, success of adolescent prevention trials will, in part, involve identifying and 
partnering with range of adolescent service organisations around sites, to assist researchers to 
implement their responsibilities. 
 
Comments to Catherine Slack (slackca@ukzn.ac.za) or Ann Strode (strodea@ukzn.ac.za) 
 
Acknowledgements & disclaimer 
This memo was made possible by funding from the European and Developing Countries Clinical Trials 
Partnership (EDCTP) to the HIV AIDS Vaccines Ethics Group (HAVEG). The views expressed herein are 
not necessarily the views of EDCTP. Thanks to Jennifer Koen and Jacintha Toohey for edits to the 
document, as well as to Melissa Wallace and Agnes Ronan.  
 
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3  Section 71 of the National Health Act No. 61 of 2003 
4  Section 5 of the Choice on Termination of Pregnancy Act No. 92 of 1996 
5  Section 130 of the Children’s Act No. 38 of 2005 
6  Section  129 of the Children’s Act No. 38 of 2005 
7  Section 134 of the Children’s Act No. 38 of 2005 
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SAP_001.pdf: 
CHAMPS:  Choices For Adolescent Prevention Methods for SOUTH AFRICA 
Pilot study B: “PlusPills” 
A Demonstration Open Label Study to Assess the Acceptability and Use of Truvada Pre-exposure Prophylaxis in 
Healthy, HIV-Uninfected Adolescents, 15-19 Years of Age. 
 
CHAMPS PrEP LoA#1 dated 29 December 2016 
Statistical Analysis Plan 
Page 1 of 14 
 
STATISTICAL ANALYSIS PLAN 
OVERVIEW AND SUMMARY OF DESIGN 
The study is designed as an open-label phase 2 demonstration project, to evaluate the 
acceptability, safety, feasibility, as well as the adherence to daily oral PrEP (FTC/TDF) for 
HIV-1 prevention, among 150 male and female adolescent participants at two sites (with 
approximately 75 participants at each site), ranging in ages between 15 and 19 years old, 
over a 12 month period. The study will also investigate the uptake and utility of feedback to 
the participants real time about drug levels obtained from dried blood spots/plasma during 
adherence counselling. 
STUDY ENDPOINTS  
Primary Acceptability/Use Endpoints:  
Consistent with the primary study objective to evaluate the acceptability and use of daily 
oral PrEP (FTC/TDF) in HIV-negative adolescents, ages 15-19 years, the following primary 
safety endpoints will be assessed: 
o The proportion of participants who report willingness to use the study 
regimen, take up PrEP and remain on PrEP as part of a comprehensive 
prevention package.  
o An acceptability questionnaire will be administered at the final study visit to 
assess the delivery of PrEP and the content of the study visits, including the 
user-friendliness of the medication regimen (including an assessment of side 
effects), the delivery format, the dosing strategy, and the clinic visit schedule. 
o Number of adolescents recruited, enrolled, and retained in the study. 
Primary Safety Endpoint: 
 


CHAMPS:  Choices For Adolescent Prevention Methods for SOUTH AFRICA 
Pilot study B: “PlusPills” 
A Demonstration Open Label Study to Assess the Acceptability and Use of Truvada Pre-exposure Prophylaxis in 
Healthy, HIV-Uninfected Adolescents, 15-19 Years of Age. 
 
CHAMPS PrEP LoA#1 dated 29 December 2016 
Statistical Analysis Plan 
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o Grades 2, 3, and 4 clinical and laboratory adverse events; 
Secondary Endpoints: 
Consistent with the secondary study objectives to evaluate the adherence and sexual 
behaviour of daily oral PrEP (FTC/TDF) in HIV-negative adolescents, ages 15-19 years, the 
following endpoint will be assessed: 
Adherence Endpoint:  
 Adherence to daily regimens of oral PrEP as evidenced by self-report, pill counts, and 
proportion of participants assigned to FTC/TDF who have detectable drug levels. 
o Proportion of doses that are taken as instructed. 
 
Sexual behaviour 
o Reported number of steady and casual sex partners, condom use (and change 
after introduction of study product), substance use prior to or during sex, as 
evidenced by participant responses to interviewer-administered 
questionnaires and focus group. 
o Proportion of scheduled HIV testing appointments that are missed, in relation 
to individual characteristics (age, sex, number of partners, use of other 
prevention methods) and the characteristics of the product. 
Consistent with the exploratory objective to assess the HIV incidence in study participants 
during the course of study participation, the following endpoint will be assessed: 
 HIV infection, as measured by seroconversion of study participants 
during the approximate 12 months of follow-up 
 
Exploratory Endpoints:   
o Consistent with the exploratory study objective to explore the feasibility of 
biofeedback of  Blood Spot results as an adherence enhancing strategy in 150 


CHAMPS:  Choices For Adolescent Prevention Methods for SOUTH AFRICA 
Pilot study B: “PlusPills” 
A Demonstration Open Label Study to Assess the Acceptability and Use of Truvada Pre-exposure Prophylaxis in 
Healthy, HIV-Uninfected Adolescents, 15-19 Years of Age. 
 
CHAMPS PrEP LoA#1 dated 29 December 2016 
Statistical Analysis Plan 
Page 3 of 14 
 
HIV-negative adolescents, ages 15-19 years, the following exploratory 
endpoints will be assessed: 
 Proportion and number of participants who are tested using 
DBS and received results of DBS compared to participants who 
are tested using DBS but do not receive biofeedback of results. 
 Number of counselling opportunities in which drug level 
feedback is requested vs total number of counseling events 
 Number and nature of participants who request drug level 
feedback . 
 Correlation between self reported adherence and drug levels 
at each visit for each participant  
 Correlation between self reported adherence and drug levels 
at each visit in the study overall. 
  Proportion and number of participants whose adherence ito 
study product improves when receiving the results of DBS 
compared to those who do not receive feedback of results as 
measured by endpoints above. 
Consistent with the exploratory study objective to investigate the relationship 
between daily PrEP usage and sexual practices and behavior in adolescents, the 
following exploratory endpoints will be assessed 
             Sexual behaviour data obtained using questionnaires and a focus group.  
STUDY HYPOTHESIS  
The DTHF protocol and research teams hypothesize that oral once daily PrEP (TDF/FTC) will 
be acceptable and utilized safely by healthy adolescents, between the ages of 15-19 years.  
SAMPLE SIZE CONSIDERATIONS 
The sample size calculation is based on the ability to detect the measure the primary 


CHAMPS:  Choices For Adolescent Prevention Methods for SOUTH AFRICA 
Pilot study B: “PlusPills” 
A Demonstration Open Label Study to Assess the Acceptability and Use of Truvada Pre-exposure Prophylaxis in 
Healthy, HIV-Uninfected Adolescents, 15-19 Years of Age. 
 
CHAMPS PrEP LoA#1 dated 29 December 2016 
Statistical Analysis Plan 
Page 4 of 14 
 
objectives (acceptability and use) in the participant population. The table below shows the 
precision (as 95% confidence limits) provided by various sample sizes in detecting the 
occurrence of acceptability endpoints (with a frequency non- uptake and use varying from 
5%-20%). 
 
Acceptability will be measured by proportion of youth who take up PrEP and remain on PrEP 
as part of a comprehensive prevention package. Also they will complete an acceptability 
questionnaire. 
 
 
Precision * 
 
 
Frequency 
n=100 
n=135 
n=170 
5% 
1.6; 11.2 
2.1; 10.4 
2.4; 9.8 
10% 
4.9; 17.6 
5.7; 16.8 
6.4; 16.2 
15% 
8.6; 23.5 
9.9; 22.8 
10.7; 22.2 
20% 
12.7; 29.1 
14.2; 28.6 
15.3; 28.1 
* Asymptotic (exact) binomial 95% confidence limits 
 
Based on these calculations, we anticipate that 135 participants, rounded up to 150 
participants to account for premature censoring (due to loss to follow-up and/or withdrawal 
of consent, estimated at maximum 10%) will be required to detect non-acceptabiltiy 
endpoints that occur in 10% of subjects with approximately 5% precision. 
DATA AND SAFETY MONITORING AND REVIEW 
In addition to the informal safety monitoring done by the Site Investigator and study 
clinician, DTHF will convene an independent Protocol Safety Review Team (PSRT). The roles 
of the PSRT are: 
 


CHAMPS:  Choices For Adolescent Prevention Methods for SOUTH AFRICA 
Pilot study B: “PlusPills” 
A Demonstration Open Label Study to Assess the Acceptability and Use of Truvada Pre-exposure Prophylaxis in 
Healthy, HIV-Uninfected Adolescents, 15-19 Years of Age. 
 
CHAMPS PrEP LoA#1 dated 29 December 2016 
Statistical Analysis Plan 
Page 5 of 14 
 
 
To conduct interim reviews of primary safety data as well as study conduct and 
progress, including rates of participant accrual, retention, rates of adherence to 
study product and protocol, as well as HIV rates. These reviews will take place 
approximately every month, or as needed. The PSRT may recommend early 
termination of the study or modification when there is clear evidence of harm 
towards participants.  The PSRT will make a recommendation to the SMC for 
immediate review of data.   
 
 To respond to queries from site staff on eligibility determination and conditions for 
exclusion from initial drug dosing.   
 
 To consider and rapidly respond to queries from study staff regarding study drug 
dosing discontinuation or resumption following occurrence of toxicities as outlined 
in Section 9 of the study protocol.  Additionally, when a site reports any condition 
that results in study drug being held with resumption pending PSRT consultation, the 
PSRT will be convened via conference call to make a final determination (unless this 
is done via email in the interim).   
 
 To respond to queries from the study team when information is needed to guide 
clinical data management and safety reporting.  The Principal Investigator is 
designated as the point person for queries, and will consult with other PSRT 
members as needed. 
 
In addition, the Safety Monitoring Committee (SMC) will conduct interim reviews of safety 
data as well as study conduct and progress, including rates of participant accrual. Retention, 
rates of adherence to study product and protocol, as well as HIV rates. These reviews will 
take place approximately every 3 months, or as needed. The SMC may recommend early 
termination of the study or modification when there is clear evidence of harm towards 


CHAMPS:  Choices For Adolescent Prevention Methods for SOUTH AFRICA 
Pilot study B: “PlusPills” 
A Demonstration Open Label Study to Assess the Acceptability and Use of Truvada Pre-exposure Prophylaxis in 
Healthy, HIV-Uninfected Adolescents, 15-19 Years of Age. 
 
CHAMPS PrEP LoA#1 dated 29 December 2016 
Statistical Analysis Plan 
Page 6 of 14 
 
participants. Should the SMC or the PSRT detect evidence of harm such that the 
recommendation for halting or modifying the study is made, then this will be communicated 
to the PI, The protocol team and the DAIDS prevention division. The IRB and MCC will also 
be informed of the discontinuation of the study and/or the modification and reasons for 
modification of the study. All further enrollment, and study activities other than safety 
follow up will be put on hold. Participants, guardians and CABS will be notified as soon as 
possible after next steps are identified.  
DATA ANALYSIS PLAN 
A customized data entry and management system will be implemented for the project in 
Microsoft Access. Data will be analysed using the statistical programme STATA (Stata 
Corporation, College Station, Texas, USA). Simple descriptive statistics including frequency 
distributions will be used to assist in data cleaning and summarization.  
 
The analysis plan for each of the study objectives (per 10.2 above) is detailed below. (Note 
that throughout the analysis, all statistical tests will be 2-sided using an alpha of 0.05.) 
 
Endpoints:  
A. PRIMARY 
1. Primary: Use  
Number of adolescents who continue to use PrEP after the initial 3 month period and the 
total time on PrEP for each adolescent and for the cohort as a whole. 
Analysis: 
Proportions of participants (a) willing to use and (b) taking up PrEP will be described with 
point estimates and exact 95% confidence intervals. “Remaining on PrEP” will be defined as 
any self-reported use of PrEP at each study interval (regardless of adherence) over the 9-
month follow-up period, as a binary outcome. The first 3-month “use” will be 100% for all 
150 participants. We will use product-limit methods to examine ‘survival’ proportions for 


CHAMPS:  Choices For Adolescent Prevention Methods for SOUTH AFRICA 
Pilot study B: “PlusPills” 
A Demonstration Open Label Study to Assess the Acceptability and Use of Truvada Pre-exposure Prophylaxis in 
Healthy, HIV-Uninfected Adolescents, 15-19 Years of Age. 
 
CHAMPS PrEP LoA#1 dated 29 December 2016 
Statistical Analysis Plan 
Page 7 of 14 
 
participants remaining on PrEP, accounting for censoring due to loss to follow-up. We will (i) 
examine the reasons for discontinuation and (ii) examine the baseline and/or pre-LTF 
characteristics of those LTF, and compare to those retained, in order to understand the 
possible associations between LTF and adherence and/or sexual risk taking. While our 
preliminary analyses will presume this censoring is uninformative, we will include analyses 
that assume LTF are non-adherent. Our intention is to (i) examine the reasons for 
discontinuation and (ii) examine the baseline and/or pre-LTF characteristics of those LTF, 
and compare to those retained, in order to understand the possible associations between 
LTF and adherence and/or sexual risk taking. While our preliminary analyses will presume 
this censoring is uninformative, we will include analyses that assume LTF are non-adherent. 
In subsidiary analyses for this primary endpoint, we will also examine the factors associated 
with PrEP willingness, uptake and “remaining on PrEP” using standard methods (including 
chi-square and exact tests for the comparisons of proportions, and log-rank tests for the 
comparison of ‘survival’ curves in product-limit analysis). 
2. Primary: Acceptability 
An acceptability questionnaire will be administered 3 monthly to assess reasons for 
continuing, stopping or restarting PrEP.  A further questionnaire will be administered at the 
final study visit to assess the delivery of PrEP and the content of the study visits, including 
the user-friendliness of the medication regimen (including an assessment of side effects), 
the delivery format, the dosing strategy, and the clinic visit schedule. 
Analysis Plan:  
This acceptability questionnaire will contain both binary items as well as continuous 
(interval) measures from Likert-type items. Analysis of data from this questionnaire will 
begin with standard descriptive statistics for each item, overall and by key participant 
subgroups (a priori, these will be based on participant age, gender, sexual activity during the 
study and PrEP adherence during the study). We will compare responses to acceptability 
items using standard methods, including chi-square and exact tests; Student’s t- and rank-


CHAMPS:  Choices For Adolescent Prevention Methods for SOUTH AFRICA 
Pilot study B: “PlusPills” 
A Demonstration Open Label Study to Assess the Acceptability and Use of Truvada Pre-exposure Prophylaxis in 
Healthy, HIV-Uninfected Adolescents, 15-19 Years of Age. 
 
CHAMPS PrEP LoA#1 dated 29 December 2016 
Statistical Analysis Plan 
Page 8 of 14 
 
sum tests, replaced by analysis of variance or u-tests for global comparisons across 
polytomous groupings. 
3. Primary: Safety 
Grades 2, 3, and 4 clinical and laboratory adverse events 
Analysis:  
This analysis will be based on descriptive statistics. 
 
B. Secondary Endpoints:  
1. Secondary: Adherence  
Adherence to daily regimens of oral PrEP as evidenced by the use self-report, pill counts, 
and proportion of participants on FTC/TDF who have detectable drug levels.  
Proportion of doses that are taken as instructed.  
Proportion of blood samples with detectable drug levels  
Proportion of adolescents with detectable drug levels who report using PrEP 
Analysis Plan: 
There are 3 different measures of PrEP adherence that will be used for the primary 
adherence endpoint: Participant self-report, pill count results, and detectable drug levels. 
While the distributions of each of these measures may vary, a priori we anticipate that 
analysis of each of these 3 measures will use two different binary metrics from data at each 
study visit: (i) perfect adherence (defined as adherence data that do not suggest any missed 
doses, e.g., pill count data consistent with daily dosing, or no missed doses detected on self-
report); and, (ii) effective adherence (defined as adherence levels that are consistent with 
protection against HIV exposure based on available data from PrEP efficacy trials, e.g., >85% 
doses taken, from pill count, or self-report; or therapeutic drug levels on biological assays). 
Note that drug levels will be used in analyses of effective adherence only. 
Analyses of adherence data will be based on the binary constructs of perfect and effective 
adherence as well as continuous measures of the proportion of PrEP doses taken; both the 


CHAMPS:  Choices For Adolescent Prevention Methods for SOUTH AFRICA 
Pilot study B: “PlusPills” 
A Demonstration Open Label Study to Assess the Acceptability and Use of Truvada Pre-exposure Prophylaxis in 
Healthy, HIV-Uninfected Adolescents, 15-19 Years of Age. 
 
CHAMPS PrEP LoA#1 dated 29 December 2016 
Statistical Analysis Plan 
Page 9 of 14 
 
binary and continuous constructs will be analysed at each study visit (repeated measures) 
and in the overall study period (through aggregation of measures from each study visit). 
The analysis for this primary endpoint is largely descriptive, with the estimates of adherence 
and their 95% confidence intervals reported for different adherence measures for the 
cohort overall as well as a priori subgroupings by age, gender and sexual activity during the 
study. Subsidiary analyses will develop models to examine the predictors of adherence 
within the cohort; given the sample size, such analyses will have limited statistical power 
and should be considered exploratory. For repeated measures of adherence from each 
study visit, we will use a generalized linear modelling approach that includes fixed effects 
(e.g., participant characteristics) and random effects (e.g., characteristics of study visits). 
Following the GLLAMM routine in Stata, this will include mixed-effects linear models (for 
continuous measures of adherence) with maximum-likelihood extensions to binary 
adherence endpoints. (Skrondal A, Rabe-Hesketh S. Generalized latent variable modeling: 
multilevel, longitudinal and structural equation models. Boca Raton: Chapman and Hall, 
2004.) 
This approach converges with that of generalized estimating equations based on the Huber-
White sandwich variance estimator. 
2a. Secondary:  Sexual Activity  
Reported number of steady and casual sex partners, condom use (and change after 
introduction of study product), substance use prior to or during sex, as evidenced by 
participant responses to interviewer-administered questionnaires  
Analysis plan:  
The key analysis question for this secondary endpoint is whether different measures of 
sexual risk change with the availability and/or uptake of PrEP (in the initial 3-month 
mandatory study follow-up period) compared to periods “off-Prep”. The measures of sexual 
risk include continuous measures (number of sexual partners) as well as binary measures 
(casual sex partners yes/no, substance use prior to sex, consistent condom use during sex). 
All measures are visit-specific, with a maximum of 12 measures during the study, per 


CHAMPS:  Choices For Adolescent Prevention Methods for SOUTH AFRICA 
Pilot study B: “PlusPills” 
A Demonstration Open Label Study to Assess the Acceptability and Use of Truvada Pre-exposure Prophylaxis in 
Healthy, HIV-Uninfected Adolescents, 15-19 Years of Age. 
 
CHAMPS PrEP LoA#1 dated 29 December 2016 
Statistical Analysis Plan 
Page 10 of 14 
 
participant. In analysis, we will first use graphical approaches to display the proportions of 
participants reporting binary sexual risk behaviours (or means of continuous measures) at 
each study visit over the 12-month period. Following this, we will use repeated measures 
methods (as described above) for both binary and continuous dependent variables, with 
PrEP access treated as a binary variable distinguishing visits in on vs. off PrEP phases; in the 
first instance, these models will not include other covariates.   
2b. Proportion of scheduled HIV testing appointments that are missed, in relation to 
individual characteristics (age, sex, number of partners, use of other prevention methods) 
and the characteristics of the product. 
Analysis: 
“Missed appointments” will be defined as participants being >7 days late for a visit 
scheduled on a 28-day cycle. This measure will be analysed as a binary variable following the 
repeated measures approaches described above. 
3. Secondary:  HIV Incidence  
HIV infection, as measured by seroconversion of study participants during the approximate 
12 months of follow-up  
Analysis:  
The incidence of HIV will be described using person-time (rates per 100 person years of 
observation) and product-limit (survival proportion) approaches. For both methods, the 
date of seroconversion will be the midpoint of the interval between the last negative and 
first positive HIV test. For participants lost to follow-up, the date of censoring will be one 
day after the last visit attended. 
 
C. Exploratory Endpoints: 
1. Exploratory:  Dried Blood Spot/plasma biofeedback  
Correlation of self reported adherence and presence of drug levels in participants who are 
tested using plasma drug levels or DBS and received results compared to participants who 
are tested using plasma/DBS but do not receive biofeedback of results.  


CHAMPS:  Choices For Adolescent Prevention Methods for SOUTH AFRICA 
Pilot study B: “PlusPills” 
A Demonstration Open Label Study to Assess the Acceptability and Use of Truvada Pre-exposure Prophylaxis in 
Healthy, HIV-Uninfected Adolescents, 15-19 Years of Age. 
 
CHAMPS PrEP LoA#1 dated 29 December 2016 
Statistical Analysis Plan 
Page 11 of 14 
 
Analysis: 
These data will be described as proportions at each study visit; while we will calculate 
differences in proportions attending between participant who do and do not receive 
biofeedback results, no formal statistical tests will be used for this exploratory endpoint. 
2.Exploratory: Sexual behaviour by coital diaries  
Sexual behaviour data obtained using a questionnaires and focus group.  
Analysis:  
Data from questionnaires will be compared to self-reported sexual behaviour on a per 
participant and per visit basis. While this endpoint is exploratory, we anticipate using the 
distributions of the observed data to defined post-hoc boundaries of acceptable agreement, 
and then use this to estimate the proportion of participants with acceptable versus 
unacceptable agreement at each visit, and overall during the study.  
 
Analysis of Focus Group data: 
All focus groups and interviews will be transcribed and then analysed using Framework 
Analysis (Ritchie and Lewis; 2003). This approach was developed in the 1980’s by 
researchers at the UK National Centre for Social Research and has been used extensively for 
applied or policy relevant qualitative research (Pope et al; 2000). It uses an analytical 
framework to organize data according to key themes, concepts and emergent categories in 
grids or matrices. This method facilitates both between case and within case analysis to look 
for patterns and connections. It provides a systematic, consistent and transparent approach 
to handling data that also enables analysis to go beyond description to interpretation where 
appropriate. In addition, it facilitates the linking of findings with those of quantitative 
research, which will be relevant in comparing, contrasting and enhancing findings collected 
quantitatively in this study, in particular on PrEP acceptability and adherence. In addition, 
this triangulation of methods (qualitative and quantitative) has been advocated as an 
approach to increase the validity of findings (Mays and Pope; 2000, Shenton; 2004). 
 


CHAMPS:  Choices For Adolescent Prevention Methods for SOUTH AFRICA 
Pilot study B: “PlusPills” 
A Demonstration Open Label Study to Assess the Acceptability and Use of Truvada Pre-exposure Prophylaxis in 
Healthy, HIV-Uninfected Adolescents, 15-19 Years of Age. 
 
CHAMPS PrEP LoA#1 dated 29 December 2016 
Statistical Analysis Plan 
Page 12 of 14 
 
Up to three researchers experienced in qualitative data analysis will form the data analysis 
team and all will be trained on the process of Framework analysis to ensure a consistent 
approach to analysis. The initial coding framework will be developed and agreed on by the 
team after coding of half the transcripts at each time point. However, as this is an iterative 
process, the framework may be amended as coding of the second transcript ensues. Any 
amendments will be discussed and agreed upon by the team. Each transcript will be coded 
by two researchers and assessed for consistency in coding. Inconsistencies between two 
coders will be brought to the data analysis team and discussed until agreement is reached. 
 


CHAMPS:  Choices For Adolescent Prevention Methods for SOUTH AFRICA 
Pilot study B: “PlusPills” 
A Demonstration Open Label Study to Assess the Acceptability and Use of Truvada Pre-exposure Prophylaxis in 
Healthy, HIV-Uninfected Adolescents, 15-19 Years of Age. 
 
CHAMPS PrEP LoA#1 dated 29 December 2016 
Statistical Analysis Plan 
Page 13 of 14 
 
DATA HANDLING AND RECORD KEEPING 
DATA MANAGEMENT RESPONSIBILITIES 
Data collection is the responsibility of the research site staff under the supervision of the 
Site Investigator.  
Case Report Forms (CRFs) will be developed by a multidisciplinary team of study staff 
members. 
SOURCE DOCUMENTS AND ACCESS TO SOURCE DATA 
Each participant will be allocated a study reference or participant identification number. All 
data will only be identified by this unique reference number. Data will be stored in a way in 
which participant identity is protected in a locked cupboard in a locked room on clinic 
premises and will be entered into computer by reference number only on password-
protected computers. Consent forms with participant names and reference numbers will be 
kept separately from other data in a locked cupboard on clinic premises. Data will be stored 
for three years after the completion of the research, per DAIDS policy. Throughout this time, 
data held on computer will only be accessible by members of the research team who will 
have access to the computer system by way of security passwords. If the results of this 
research are published or presented, only group information will be given, not names of 
people in the study.  
 
The Site Investigator or designee will maintain, and store securely, complete, accurate and 
current study records throughout the study, in accordance with local regulations. All study-
related records must be maintained on site for the entire period of study implementation. 
No study records may be moved to an off-site location or destroyed prior to receiving 
approval from DTHF and/or DAIDS. 


CHAMPS:  Choices For Adolescent Prevention Methods for SOUTH AFRICA 
Pilot study B: “PlusPills” 
A Demonstration Open Label Study to Assess the Acceptability and Use of Truvada Pre-exposure Prophylaxis in 
Healthy, HIV-Uninfected Adolescents, 15-19 Years of Age. 
 
CHAMPS PrEP LoA#1 dated 29 December 2016 
Statistical Analysis Plan 
Page 14 of 14 
 
QUALITY CONTROL AND QUALITY ASSURANCE 
Each site will be required to develop a robust SOP for quality control and quality assurance 
procedures.