Clinical trial NCT02556333
Conditions: HIV
Keywords: TAF F/TAF antiretroviral therapy TDF directly observed therapy
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Start date: 2015-09-16; Completion date: 2016-08-16
Enrollment: 1 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Background:

HIV attacks the immune system. Antiretroviral therapy (ART) is a combination of drugs used for treating HIV infection. For some people, ART drugs stop working against their HIV. Researchers want to see if a different form of the drug tenofovir (an ART drug currently approved by the FDA), combined with another drug, may help people whose HIV is resistant to ART. This combination pill is called F/TAF

Objective:

To study the safety and efficacy of the drug F/TAF, when used with other ART, for people whose HIV infection has been hard to control with available medicines.

Eligibility:

People age 14 years and older who have HIV infection and are enrolled in the DOTCOM (14-I-0009) protocol.

Design:

Participants will be screened with physical exam, medical history, and blood and urine tests.

Participants will stay in the hospital for at least 10 days. For the first 9 days, they will take F/TAF by mouth along with their usual ART drugs.

In the hospital, they will repeat the screening tests.

Participants will have a DEXA scan, an x-ray that measures calcium and other minerals in the bones. Participants will lie on a soft table while the scanner passes over the lower spine and hips.

Participants will get a supply of F/TAF and some new ART drugs to take at home.

Participants will have follow-up visits in 1, 2, 4, 8, and 12 weeks. After the 12-week visit, they will come back about every 3 months for about 1 year.

At these visits, participants will repeat the screening tests. They will discuss any problems taking their ART drugs. They may have another DEXA scan.

Detailed description:
Despite the success of antiretroviral therapy (ART), a subset of HIV-1-infected patients have uncontrolled viremia, multiple drug class resistance, and limited treatment options. Tenofovir disoproxil fumarate (TDF) forms part of most ART regimens, however its long-term use is associated with renal tubulopathy and reduced bone mineral density. Viral mutations (eg, K65R, multiple thymidine analog mutations (TAMs) can confer resistance or reduced susceptibility to TDF.

Tenofovir alafenamide (TAF) is an investigational oral prodrug of tenofovir. When compared to TDF, TAF demonstrated lower plasma tenofovir concentrations and more potent antiviral activity at approximately one-tenth of the dose. TAF has the advantage of reduced tenofovir exposure to the renal tubules and bone, potentially resulting in fewer kidney and bone effects. As with TDF, TAF has potent activities against hepatitis B virus (HBV), and may be a treatment option for patients with HIV/HBV co-infections. Phase 2 trials have demonstrated the non-inferiority of TAF to TDF in treating HIV-1 infection in ART-naive patients. Smaller reductions in bone mineral density were measured with TAF than TDF. The most common adverse events were nausea and diarrhea.

This single-arm, single-site, open-label trial will explore the safety and efficacy of TAF in a fixed combination with emtricitabine (FTC) (F/TAF, Gilead Sciences Inc.) as part of a salvage antiretroviral regimen for HIV-1-infected adults and adolescents (greater than or equal to 14 years) who experienced virologic failure. The study will recruit patients who have failed TDF-containing regimens or cannot take TDF (due to resistance mutations or risk of renal injury) and for whom abacavir/lamivudine (ABC/3TC) is not an optimal alternative. Eligible patients will begin 9 days of inpatient directly observed therapy (DOT) with F/TAF plus their pre-enrollment background regimen. On Day 10, patients will switch to F/TAF plus OBT while waiting for the results of Day 10 HIV RNA results. Patients with an HIV RNA decline of \<0.5 log10 from Day 1 to Day 10 will discontinue F/TAF, end their study participation, and continue OBT (with TDF/FTC or ABC/3TC in place of F/TAF, as appropriate) under the 14-I-0009 protocol. Patients with a greater than or equal to 0.5 log10 decline in HIV RNA will continue on F/TAF + OBT for 48 weeks, with periodic outpatient assessments of adherence, safety, renal function, bone mineral density, HIV RNA, and CD4 T cell counts. Switching of one or more drugs in an ART regimen due to inadequate viral response will require inpatient DOT under 14-I-0009.

Arms: arm 1: Emtricitabine 200mg/tenofovir alafenamide 25mg (FTC/TAF) tablet to be given orally once daily to be added to a failing regimen for 10 days. If HIV RNA decline by \>= 0.5 log copies/mL, patient will continue on FTC/TAF with a new antiretroviral regimen for 48 weeks. If \< 0.5 log copies/mL decline, patient will be taken off FTC/TAF.
Interventions: intervention 1: FTC/TAF
Intervention descriptions: intervention 1: Tenofovir alafenamide (TAF) is an investigational oral prodrug of tenofovir. This trial will explore the safety and efficacy of TAF in a fixed combination with emtricitabine (FTC) (F/TAF, Gilead Sciences Inc.) as part of a salvage antiretroviral regimen for HIV-1-infected adults and adolescents (greater than or equal to 14 years) who experienced virologic failure.

Protocol documents:
ICF_000.pdf: 
 
 
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
   MEDICAL RECORD 
               •  Adult Patient or     •  Parent, for Minor Patient 
 
 
INSTITUTE:  
National Institute of Allergy and Infectious Diseases 
 
 
 
STUDY NUMBER: 
15-I-0201 
PRINCIPAL INVESTIGATOR:  Alice K. Pau, PharmD 
 
 
STUDY TITLE:  
Safety and Efficacy of Emtricitabine/Tenofovir Alafenamide as Part of Salvage Antiretroviral 
Regimens in Patients with Uncontrolled Viremia and Drug-resistant HIV Infection  
 
 
Initial Review Approved by the IRB on 09/02/15  
 
 
Date Posted to Web: 09/18/15 
Standard 
 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY 
 
•   Adult Patient or    •   Parent, for Minor Patient 
 
NIH-2514-1 (07-09) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent (1) 
 
 
INTRODUCTION 
 
We invite you to take part in a research study at the National Institutes of Health (NIH). 
 
First, we want you to know that: 
 
 
Taking part in NIH research is entirely voluntary. 
 
 
You may choose not to take part, or you may withdraw from the study at any time. In either case, you will not 
lose any benefits to which you are otherwise entitled. However, to receive care at the NIH, you must be taking 
part in a study or be under evaluation for study participation. 
 
 
You may receive no benefit from taking part. The research may give us knowledge that may help other people in 
the future. 
 
Second, some people have personal, religious, or ethical beliefs that may limit the kinds of medical or research treatments 
they would want to receive (such as blood transfusions). If you have such beliefs, please discuss them with your NIH 
doctors or research team before you agree to join the study. 
 
Now, we will describe this research study. Before you decide to take part, please take as much time as you need to ask 
any questions and discuss this study with anyone at the NIH, or with family, friends, your personal physician, or other 
health professional. If you are signing for a child (younger than 18 years), then “you” refers to your child throughout this 
document. 
 
PURPOSE OF THE STUDY 
 
You are invited to join this study because your HIV infection has been difficult to control with available medicines. 
  
Antiretroviral therapy (ART) refers to a combination of drugs that are used for treating HIV infection. When ART drugs no 
longer work against the HIV virus, the HIV is said to have become “resistant” to the drugs. The HIV infection in your body 
may be resistant to many ART drugs. One drug that is often used to treat individuals with HIV infection is called tenofovir 
disoproxil fumerate or TDF. Some people have HIV infections that are resistant to TDF. Others cannot take TDF because 
they have kidney problems and taking TDF could cause damage to their kidneys. 
 
In this study, we are testing a different form of tenofovir that may work with people whose HIV is resistant to TDF; it also 


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
15-I-0201 
CONTINUATION:  page  2  of  7  pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY (Continuation Sheet) 
 
• Adult Patient or   • Parent, for Minor Patient 
 
NIH-2514-1 (07-09) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
may be less damaging to kidneys. This new ART drug is called tenofovir alafenamide, or TAF. It is made by a drug 
company called Gilead Sciences. Currently, TAF is being studied in research trials for people with HIV or hepatitis B virus 
(HBV) infection. TAF is not approved by the Food and Drug Administration (FDA) outside of research studies. For this 
study, the FDA has allowed us to provide TAF in a combination pill with another ART drug called emtricitabine to people 
whose HIV infection cannot be successfully treated with other ART drugs. Emtricitabine has been approved by the FDA 
and is widely used for treating HIV infection. The combination pill is also called F/TAF.   
 
We are inviting up to 20 volunteers to participate in this study. In addition to F/TAF, you will be prescribed other ART 
drugs that are FDA-approved. These drugs will be prescribed to you under the “DOTCOM” study (14-I-0009), in which 
you have already enrolled. We will evaluate your response to this ART combination and watch for side effects. If F/TAF 
works well for you, we will do our best to continue providing this drug to you until it is approved by the FDA and available 
in pharmacies. 
 
 
STUDY SCHEDULE 
 
Screening visit 
If you agree to participate in this study, we will check your health with the following tests performed at the NIH: 
• 
Physical exam with medical and social history 
• 
Blood draws to check your HIV viral load and your health, and to see if you have hepatitis B infection 
• 
Urine sample collection for kidney tests 
• 
Pregnancy test (for women of childbearing potential) 
 
If the results of these screening tests show that you are eligible for this study, your study team will construct a new ART 
combination that contains F/TAF with some new ART drugs, with or without some ART drugs that you are already 
receiving.  
 
Hospital stay 
You will be hospitalized at the NIH Clinical Center for at least 10 days. For the first 9 days, you will take F/TAF along with 
your usual ART drugs. On the 10th day, we will give you a supply of F/TAF and some new ART drugs so you can take 
them at home. If you are able to stay in the hospital longer, you may choose to stay for 12 to 15 days. 
On your first day in the hospital, we will do the following: 
• 
Physical exam with medical and social history 
• 
Blood draw to check your health and your HIV viral load (and your HBV viral load if you also have HBV infection) 
• 
Urine sample collection for kidney tests 
• 
Pregnancy test (for women of childbearing potential) 
• 
Bone mineral density test (called a DEXA scan) – this can be done before, or within the first week of your stay 
 
While you are in the hospital, we will draw blood from your arm approximately every other day to monitor your HIV 
infection. You will take ART drugs including F/TAF every day. We will tell you the schedule. It is important that you take 
your drugs on time every day. When it is time to take your ART drugs, you will need to ask a nurse to bring them to you. 
If 2 hours have passed and you still haven’t asked for your ART drugs, then the study nurse will automatically bring them. 
This will happen each day that you are in the hospital. We will help you to manage side effects if you experience them. 
We will ask you about problems you have had taking your ART drugs in the past and discuss ways to help. This is called 
adherence counseling. 


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
15-I-0201 
CONTINUATION:  page  3  of  7  pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY (Continuation Sheet) 
 
• Adult Patient or   • Parent, for Minor Patient 
 
NIH-2514-1 (07-09) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
Follow-up visits 
If you leave the hospital on Day 10, the results of your viral load tests will be available a few days later. If the tests show 
that F/TAF is not working for you, you will need to return to the NIH sometime between Day 12 and Day 15. You will be 
prescribed an ART regimen that does not include F/TAF and your participation in this study will be over. You may 
continue to participate in the DOTCOM (14-I-0009) study. 
 
If F/TAF is working for you, you will take F/TAF plus your new ART drugs at home for as long as you are in the study. 
After your hospital stay, you will return to the NIH in 1, 2, 4, 8, and 12 weeks for follow-up visits. After your 12-week 
visit, you will come back about every three months. Follow-up visits will last about 2-4 hours and will include the 
following: 
• 
Physical exam with medical and social history 
• 
Adherence counseling 
• 
Blood draw to check your health and your HIV infection 
• 
Urine sample collection for kidney tests 
• 
Pregnancy test (for women of childbearing potential) 
• 
DEXA scan (at two follow-up visits only) 
 
If you do not have a good response to the ART, the study team may design a new combination for you. You may have to 
come back to the NIH so that we can change one or more of your ART drugs. Even if the new combination does not 
include F/TAF, you will still be followed under this protocol. 
 
After about 1 year, you will be finished with this study. We expect F/TAF to be available as a prescription drug by this 
time. If it isn’t, and if it is still under development by Gilead, we will invite you to continue participating in this study. 
 
Unscheduled visits 
You should return to the NIH as needed if you have any problems. Blood may be drawn at these unscheduled visits. 
 
 
STUDY PROCEDURES AND RISKS 
 
Study drug (F/TAF): We will provide you with emtricitabine 200mg/tenofovir alafenamide 25mg oral tablets. You will 
take one tablet per day. You will also receive other ART drugs prescribed for you. 
 
The most common side effects associated with F/TAF are headache, diarrhea and nausea. Less common side effects are 
vomiting, fatigue, rash, stomach pain, indigestion and gas. F/TAF must be stopped if your blood tests show too much acid 
in the blood (lactic acidosis) – this side effect is rare. If you also have HBV infection, it’s possible that F/TAF can cause the 
hepatitis infection to worsen at first. If you stop taking this study medication without other therapy your hepatitis B 
infection can also worsen.  Your doctor will follow your HBV status and liver function closely. There may be other side 
effects from F/TAF that we do not know about yet. You will be followed closely and treated for side effects as necessary. 
F/TAF has been given experimentally to more than 1,000 patients with HIV infection. Some of these patients had kidney 
problems or hepatitis B infection before they started taking F/TAF. Most patients who took F/TAF in these studies were 
able to tolerate the drug and to manage their HIV infection. One pregnant woman taking F/TAF had a miscarriage and 
her doctor thought it could be related to F/TAF. There have not been enough studies in pregnant women to know if all 
HIV drugs are safe to take during pregnancy. Therefore, you will not be allowed to begin this study if you are pregnant. If 
you are able to become pregnant, then you must agree not to have sex or to use contraception when you begin the 


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
15-I-0201 
CONTINUATION:  page  4  of  7  pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY (Continuation Sheet) 
 
• Adult Patient or   • Parent, for Minor Patient 
 
NIH-2514-1 (07-09) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
study. Because of the risks of HIV transmission to the newborn, serious drug reactions, and the development of viral drug 
resistance in the newborn, mothers should not breastfeed while being treated with F/TAF. 
 
It is important that you tell the study team about any medicines or supplements you have been taking. While you are 
taking F/TAF, you must avoid the following drugs and supplements: carbamazepine, oxcarbazepine, phenobarbital, 
phenytoin, rifabutin, rifampin, rifapentine, bisphosphonate, St. John’s wort, echinacea, milk thistle, sho-saiko-to, and 
probenecid. 
 
DEXA scan: This is an x-ray that measures how much calcium and other types of minerals are in the bones of your lower 
spine and hips. TDF may increase the risk of bone fracture in some patients; we do not know if TAF will also have this 
effect. The DEXA scan helps to predict your risk of having a bone fracture in the future. For the scan, you will lie on a soft 
table while the scanner passes over your lower spine and hip. This will take about 5-10 minutes, and it is painless. 
 
The main risk from an x-ray is the increased lifetime risk of cancer due to radiation exposure. This radiation exposure is 
not necessary for your medical care and is for research purposes only. The amount of radiation you will be exposed to 
from the 3 scans planned for this study is 0.00024 rem for adults or 0.00012 rem for children (<18 years). This is below 
the limits set for research participants by the NIH Radiation Safety Committee, which are 5 rem for adults and 0.5 rem for 
children. For comparison, the average person in the United States receives a radiation exposure of 0.3 rem per year from 
natural background sources, such as the sun, outer space, and the earth’s air and soil. Therefore, the dose that you will 
receive from this research study is much less than the amount you would normally receive in a year from these natural 
sources. If you would like more information about radiation and examples of exposure levels from other sources, you may 
ask for a copy of the pamphlet “An Introduction to Radiation for NIH Research Subjects”. 
 
A fetus is more sensitive to radiation than adults or children. Women of childbearing potential will have a pregnancy test 
before each DEXA scan. If you are pregnant, you will not have the DEXA scan. 
 
Physical exam with medical and social history: You will undergo a physical exam. We will ask you questions about 
how you are feeling, if you’ve had any recent illness, and about the medications you are taking now and have taken in 
the past, including non-prescription drugs. We may also ask you questions about your social life, such as whether you 
drink alcohol or use recreational drugs, and whether you are sexually active. 
 
Blood draw: Blood will be collected to measure your HIV viral load, blood cell counts, and to see if your liver and 
kidneys are working well. Some blood will be used to test for hepatitis, and to see if your HIV has resistance to ART drugs 
(genetic testing of the virus). Blood may also be used for genetic testing. The total amount of blood drawn for research 
purposes will be within the limits allowed by the NIH Clinical Center. The risks related to drawing blood from a vein in 
your arm include pain, bruising, lightheadedness, fainting and, rarely, infection at the site where the needle entered your 
arm. 
 
Hospital stay: You may become bored or restless during your hospital stay. You will have access to game rooms, 
television, wireless internet access, a patient library, and a fitness center. You may receive visitors. You may request a 
pass to leave the hospital during the day. 
 
 
 


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
15-I-0201 
CONTINUATION:  page  5  of  7  pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY (Continuation Sheet) 
 
• Adult Patient or   • Parent, for Minor Patient 
 
NIH-2514-1 (07-09) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
BENEFITS 
 
You may benefit from taking the study drug and the new ART combination, as well as from the care you will receive 
during the study. However, there is no guarantee that the study drug and the new ART combination will manage your 
HIV infection. Your participation may help us better understand how to treat HIV infection in the future.  
 
 
ALTERNATIVES TO PARTICIPATION 
 
You can choose not to participate in this study. This decision will not affect any ongoing care or evaluations you may be 
receiving at the NIH. Your eligibility to participate in other research studies at the NIH will not be affected by your 
decision to enroll or not enroll in this study. 
 
 
WITHDRAWAL FROM THE STUDY 
 
You can stop participating in this study at any time. The decision to no longer participate in this study will in no way 
affect your ability to receive care at the Clinical Center or to participate in other NIH studies. You may be removed from 
the study without your consent if you miss your scheduled appointments, refuse to follow the study procedures, or if the 
study doctor believes that continuing the study drug would be harmful for you. 
 
You should not stop taking your study drugs without first talking to a member of the study team. If you stop 
taking the study drugs early, we will ask you to return to the NIH for monthly safety tests for about 3 months after you 
stop. If you don’t want to return to the NIH, we will ask you to follow up with your primary care doctor. 
 
 
COMPENSATION 
 
You will not be paid for participating in this study. 
 
 
COSTS TO YOU FOR YOUR PARTICIPATION 
 
There will be no charge to you or your health insurance company for any of the tests, procedures, or medications that are 
directly related to this study. We will provide you with ART drugs throughout the study. If TAF is available for sale at the 
end of the study, you may be able to obtain it through the DOTCOM protocol. After you have finished participating in this 
study and in the DOTCOM protocol, you will be asked to obtain your ART drugs from sources other than NIH Clinical 
Center. Our social worker can assist you with this as necessary. 
 
 
NEW FINDINGS 
 
Any new findings discovered during this study that are considered relevant to your health or to your decision to continue 
participation will be discussed with you. 
 
 


 
  
CONTINUATION SHEET for either: 
  MEDICAL RECORD 
NIH 2514-1, Consent to Participate in A Clinical Research Study 
 
NIH 2514-2, Minor Patient’s Assent to Participate In A Clinical Research Study 
 
STUDY NUMBER: 
15-I-0201 
CONTINUATION:  page  6  of  7  pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY (Continuation Sheet) 
 
• Adult Patient or   • Parent, for Minor Patient 
 
NIH-2514-1 (07-09) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
STORED SAMPLES AND FUTURE RESEARCH 
 
If you agree to participate in this study, you also agree to let us store some of your blood samples for future research to 
help us learn more about treating HIV infection. The samples will be labeled with a code that only the study team can link 
to you. Any information that can be traced back to you will be kept as private as possible. If you change your mind and 
decide you do not want us to store your samples, please contact us. We will do our best to comply with your request but 
cannot guarantee that we will always be able to destroy all of your samples. 
 
Your coded samples might be sent to other investigators for their research. Other information, such as your sex, age, 
health history, or ethnicity might also be shared. Your samples will not be sold, and you will not be paid for any products 
that result from this research. Future studies may require health information about you, such as your present health 
status, which we might not already have. If so, our study team may contact you. Future research that uses your samples 
will not help you, but it may help us learn more about HIV. In general, the research tests performed in this study are not 
like routine medical tests, and they may not relate directly to your medical care. The greatest risk of allowing us to store 
your samples will be an unplanned release of your identification from the samples due to release of this information from 
the stored sample database. The chances of this happening are very low. 
 
Genetic testing: Your stored blood samples may be used to conduct genetic tests in the future. These tests would help 
us to better understand how genes may contribute to HIV drug resistance. Genetic tests can provide a lot of detailed 
information about a person’s genes. However, we often do not know what this information means, so we may not have 
anything to tell you about the results. If we were to find a genetic testing result that we thought was urgent to deal with 
because of your health, we would confirm the result and then tell you about it. We expect this sort of situation to be very 
unlikely. Genetic tests done in a research lab from your stored blood samples will not become part of your medical record. 
Any genetic information collected from or discovered about you will be kept confidential. 
 
Some of the blood drawn from you during this study will be used to test for HLA type, which is a genetic test for markers 
of the immune system (body system that fights off disease). Some people with a particular kind of HLA gene have a bad 
reaction to the ART drug abacavir. We will do the HLA test to find out if we can prescribe abacavir to you. Results from 
the HLA test will become part of your medical record at the NIH. Medical records containing this information are kept in a 
secure place.  
 
 
CONFLICTS OF INTEREST 
 
The National Institutes of Health reviews NIH staff researchers at least yearly for conflicts of interest. You may ask your 
research team for additional information or for a copy of the “Guide to Avoiding Financial and Non-Financial Conflicts or 
Perceived Conflicts of Interest in Clinical Research at NIH”. This protocol may have investigators who are not NIH 
employees. Non-NIH investigators are expected to adhere to the principles of the Guide but are not required to report 
their personal financial holdings to the NIH.
 
 


 
  
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
   MEDICAL RECORD 
•  Adult Patient or    •  Parent, for Minor Patient 
 
STUDY NUMBER: 
15-I-0201 
CONTINUATION:  page  7  of  7  pages 
 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY (Continuation Sheet) 
 
•  Adult Patient or   •  Parent, for Minor Patient 
 
NIH-2514-1 (07-09) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent 
 
OTHER PERTINENT INFORMATION 
1. Confidentiality.  When results of an NIH research study are reported in medical journals or at scientific meetings, 
the people who take part are not named and identified.  In most cases, the NIH will not release any information about 
your research involvement without your written permission.  However, if you sign a release of information form, for 
example, for an insurance company, the NIH will give the insurance company information from your medical record.  This 
information might affect (either favorably or unfavorably) the willingness of the insurance company to sell you insurance. 
 
The Federal Privacy Act protects the confidentiality of your NIH medical records.  However, you should know that the Act 
allows release of some information from your medical record without your permission, for example, if it is required by the 
Food and Drug Administration (FDA), members of Congress, law enforcement officials, or authorized hospital 
accreditation organizations. 
 
2. Policy Regarding Research-Related Injuries.  The Clinical Center will provide short-term medical care for any 
injury resulting from your participation in research here.  In general, no long-term medical care or financial compensation 
for research-related injuries will be provided by the National Institutes of Health, the Clinical Center, or the Federal 
Government.  However, you have the right to pursue legal remedy if you believe that your injury justifies such action. 
 
3. Payments.  The amount of payment to research volunteers is guided by the National Institutes of Health policies.  In 
general, patients are not paid for taking part in research studies at the National Institutes of Health. Reimbursement of 
travel and subsistence will be offered consistent with NIH guidelines. For this protocol, the compensation plan is outlined 
above. 
 
4. Problems or Questions.  If you have any problems or questions about this study, or about your rights as a 
research participant, or about any research-related injury, contact the Principal Investigator Alice Pau, PharmD, Building 
10, Room 11C103, telephone: 301-451-3740; or the study coordinator, Alexander Ober, BSN, telephone: 301-435-7912. 
 
You may also call the Clinical Center Patient Representative at (301) 496-2626. 
 
5. Consent Document.  Please keep a copy of this document in case you want to read it again. 
 
COMPLETE APPROPRIATE ITEM(S) BELOW: 
 
A. Adult Patient’s Consent 
B. Parent’s Permission for Minor Patient 
I have read the explanation about this study and have been given the 
opportunity to discuss it and to ask questions.  I hereby consent to take 
part in this study. 
I have read the explanation about this study and have been given the 
opportunity to discuss it and to ask questions.  I hereby give permission 
for my child to take part in this study.   
(Attach NIH 2514-2, Minor’s Assent, if applicable.) 
 
  
 
 
  
 
Signature of Adult Patient/Legal Representative 
Date 
 
 
 
Print Name 
Signature of Parent(s)/Guardian 
Date 
 
 
 
Print Name 
C. Child’s Verbal Assent (If Applicable) 
The information in the above consent was described to my child and my child agrees to participate in the study. 
 
 
 
  
 
 
 
 
Signature of Parent(s)/Guardian 
Date 
 
Print Name 
THIS CONSENT DOCUMENT HAS BEEN APPROVED FOR USE  
FROM SEPTEMBER 2, 2015 THROUGH SEPTEMBER 1, 2016.  
 
 
 
  
 
 
  
 
Signature of Investigator 
Date 
 
 
 
Print Name 
Signature of Witness 
Date 
 
 
 
Print Name 
 
 

Prot_SAP_002.pdf: 
 
1 
 
Safety and Efficacy of Emtricitabine/Tenofovir Alafenamide as Part of Salvage 
Antiretroviral Regimens in Patients with Uncontrolled Viremia and Drug-Resistant HIV 
Infection  
 
 
 
Protocol Number: 
 
 
TBD 
 
Version Number: 
 
 
1.2 
 
Date:  
 
 
 
August 31, 2015 
 
Principal Investigator:  
 
Alice K. Pau, PharmD 
 
Medical Advisory Investigator: 
H. Clifford Lane, MD 
 
Investigational New  
Drug (IND) #:   
 
 
126570 
 
IND Sponsor: 
Office of Clinical Research Policy and Regulatory 
Operations (OCRPRO), Division of Clinical Research 
(DCR), National Institute of Allergy and Infectious Diseases 
(NIAID), National Institutes of Health (NIH) 
 
Pharmaceutical Support  
Provided by:   
 
 
Gilead Sciences Inc. 
 
Sponsor Medical Monitor (SMM): 
H. Preston Holley, MD, FACP 
 
 
 
 


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Study Staff Roster 
 
Principal Investigator:  
 
Alice K. Pau, PharmD 
Intramural Clinical Management and Operations Branch 
(ICMOB)/DCR/NIAID 
10 Center Drive, Room 11C103 
Bethesda, MD 20892  
 
 
 
 
 
Phone: 301-451-3740  
 
 
 
 
 
Email: apau@niaid.nih.gov 
 
Medical Advisory/ 
Accountable Investigator: 
 
H. Clifford Lane, MD 
Laboratory of Immunoregulation (LIR)/NIAID 
Phone: 301-496-7196 
Email: clane@niaid.nih.gov 
 
Associate Investigators: 
 
Frank Maldarelli, MD, PhD 
Host Virus Interaction Branch/National Cancer Institute (NCI) 
Phone: 301-435-8019 
Email: fmalli@mail.nih.gov 
 
Maura Manion, MD 
LIR/NIAID 
Phone: 301-496-7196 
Email:  Maura.manion@niaid.nih.gov 
 
JoAnn Mican, MD 
ICMOB/DCR/NIAID 
Phone: 301-402-1326   
Email:  jmican@niaid.nih.gov 
 
James Mikula, Pharm.D. 
Leidos Biomedical Research, Inc. 
In support of NIAID 
Phone: 301-451-1426 
Email: james.mikula@nih.gov 
 
Irini Sereti, MD, MHS 
LIR/NIAID 
Phone: 301-496-5533 
Email: isereti@niaid.nih.gov 
 
Study Coordinator: 
 
    
Alexander Ober, RN, BSN 
 
 
 
 
 
LIR/NIAID 
Phone: 301-435-7912 
Email: obera@mail.nih.gov 
 


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Study Assistant: 
 
 
Lucila Suarez, BA 
ICMOB/DCR/NIAID 
Phone: 301-827-0086 
Email: lucila.suarez@nih.gov 
 
Statistician:  
Michael Proschan, PhD 
Biostatistics Research Branch/DCR/NIAID 
Phone: 240-669-5245 
Email: proscham@mail.nih.gov 
 
Sponsor Medical Monitor: 
 
H. Preston Holley, MD, FACP 
 
 
 
 
 
Medical Monitor 
 
 
 
 
 
Leidos Biomedical Research, Inc. 
 
 
 
 
 
 
 
Clinical Safety Office 
5705 Industry Lane 
Frederick, MD 21704 
 
 
 
 
 
Phone: 301-228-4005 
 
 
 
 
 
Fax: 301-846-6224 
 
 
 
 
 
Email: Preston.Holley@fnlcr.nih.gov 
 
 
 
 
 
 
CSO email: rchspsafety@mail.nih.gov 
 
Institutional Review Board (IRB): 
NCI IRB 
9030 Old Georgetown Road 
Bethesda, MD 20892-8200 
Tel: 301-496-6375 
Fax: 301-480-0106 
Email: nciirbadmin@mail.nih.gov 
 
 


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Table of Contents 
 
Précis ............................................................................................................................................ 10 
1 
Background Information and Scientific Rationale ................................................................ 11 
2 
Study Objectives ................................................................................................................... 13 
3 
Study Design ......................................................................................................................... 14 
4 
Study Population ................................................................................................................... 15 
5 
Study Agent/Interventions ..................................................................................................... 17 
6 
Study Schedule ..................................................................................................................... 18 
7 
Study Procedures/Evaluations.............................................................................................. 21 
8 
Potential Risks and Benefits ................................................................................................. 24 
9 
Research Use of Stored Human Samples, Specimens or Data .......................................... 26 
10 
Assessment of Safety ........................................................................................................... 26 


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10.7.2.1 
Discontinuation of Study Agent ....................................................................... 32 
11 
Clinical Monitoring Structure ................................................................................................. 34 
12 
Statistical Considerations ..................................................................................................... 34 
13 
Ethics/Protection of Human Subjects ................................................................................... 35 
14 
Data Handling and Record Keeping ..................................................................................... 36 
Appendix A: Scientific References ............................................................................................... 38 
Appendix B. Schedule of Procedures ........................................................................................... 40 
 


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List of Abbreviations 
ABC 
 
 
Abacavir 
ABC/3TC 
 
Abacavir/lamivudine 
AE 
 
 
Adverse Event/Adverse Experience 
AIDS 
 
 
Acquired Immunodeficiency Syndrome 
ALT 
 
 
Alanine Aminotransferase 
Anti-HBc  
 
Antibody to Hepatitis B Core Antigen  
Anti-HBs 
 
Antibody to Hepatitis B Surface Antigen  
AR 
 
 
Adverse Reaction 
ART 
 
 
Antiretroviral therapy 
ARV 
 
 
Antiretroviral 
AUC 
 
 
Area under the concentration-time curve 
CBC 
 
 
Complete Blood Count 
CC 
 
 
Clinical Center 
CD4 
 
 
Cluster of Differentiation 4 
CrCl 
 
 
Creatinine Clearance 
CRIS 
 
 
Clinical Research Information System 
CRIMSON 
 
Clinical Research Information Management System of NIAID 
CSO 
 
 
Clinical Safety Office 
DCR 
 
 
Division of Clinical Research 
DEXA  
 
Dual X-ray Absorptiometry 
DOT 
 
 
Directly Observed Therapy 
DOTCOM 
 
NCI Protocol #14-I-0009 concerning treatment-resistant HIV-1 infection 
E/C/F  
 
Elvitegravir/cobicistat/emtricitabine 
eGFR  
 
Estimated glomerular filtration rate 
eGFRCG 
 
Estimated glomerular filtration rate by Cockcroft-Gault Equation 
EIND 
 
 
Emergency Investigational New Drug 
ELISA  
 
Enzyme-Linked Immunosorbent Assay 
FDA 
 
 
Food and Drug Administration 
F/TAF  
 
Emtricitabine 200 mg/tenofovir alafenamide 25 mg 
FTC/TDF 
 
Emtricitabine 200 mg/tenofovir disoproxil fumarate 300 mg 
HBeAg  
 
Hepatitis B ‘e’ Antigen 
HBsAg  
 
Hepatitis B Surface Antigen 
HBV  
 
 
Hepatitis B Virus  
HCV 
 
 
Hepatitis C Virus  
HIV-1  
 
Human Immunodeficiency Virus Type 1 
HLA 
 
 
Human Leukocyte Antigen 
HRPP  
 
Human Research Protection Program 
ICMOB  
 
Intramural Clinical Management and Operations Branch 
IND 
 
 
Investigational New Drug 
INR 
 
 
International normalized ratio  
IRB 
 
 
Institutional Review Board 
iRIS 
 
 
Integrated Research Information System 
LIR 
 
 
Laboratory of Immunoregulation 
NCI 
 
 
National Cancer Institute 
NIAID  
 
National Institute of Allergy and Infectious Diseases  
NIH 
 
 
National Institutes of Health 
NRTI 
 
 
Nucleos(t)ide Reverse Transcriptase Inhibitor 


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OBT 
 
 
Optimized background therapy 
OCRPRO  
 
Office of Clinical Research Policy and Regulatory Operations 
PBMC  
 
Peripheral Blood Mononuclear Cell 
PI 
 
 
Principal Investigator 
RBP 
 
 
Retinol-binding Protein 
RNA 
 
 
Ribonucleic Acid 
RT 
 
 
Reverse Transcriptase 
SCr 
 
 
Serum Creatinine 
SAE 
 
 
Serious Adverse Event/Serious Adverse Experience 
SAR 
 
 
Suspected Adverse Reaction 
SERF  
 
Safety Expedited Report Form 
SMM 
 
 
Sponsor Medical Monitor 
SRCP  
 
Safety Review and Communications Plan 
SUSAR  
 
Serious and Unexpected Suspected Adverse Reaction 
TAF 
 
 
Tenofovir alafenamide 
TAM 
 
 
Thymidine analog resistance mutation 
TDF 
 
 
Tenofovir disoproxil fumarate 
TFV 
 
 
Tenofovir 
TFV-DP 
 
Tenofovir diphosphate 
UP 
 
 
Unanticipated Problem 
UPnonAE 
 
Unanticipated Problem That Is Not an Adverse Event 


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Protocol Summary 
 
Full Title: 
Safety and efficacy of emtricitabine/tenofovir alafenamide as part 
of salvage antiretroviral regimens in patients with uncontrolled 
viremia and drug-resistant HIV infection 
Short Title: 
 
 
TAF 
Clinical Phase: 
 
2 
IND Sponsor: 
OCRPRO/DCR/NIAID/NIH 
Conducted by: 
ICMOB/DCR and LIR/Division of Intramural Research 
Principal Investigator: 
Alice K. Pau, PharmD 
Sample Size: 
N = 20 
Accrual Ceiling: 
N = 25 
Study Population: 
Adults and adolescents (≥14 years) with human immunodeficiency 
virus-1 (HIV-1) infection who experienced virologic failure while on 
a second or greater antiretroviral therapy (ART) regimen and for 
whom tenofovir disoproxil fumerate (TDF) is not a good option 
(due to genotypic resistance mutations or risk of renal injury) and 
for whom abacavir/lamivudine (ABC/3TC) is not an optimal 
alternative (due to human leukocyte antigen [HLA]-B*5701 allele, 
resistance mutations or hepatitis B virus [HBV] co-infection). 
 
Accrual Period: 
2 years or until Food and Drug Administration (FDA) approval of 
the study agent 
Study Duration: 
Start Date: September 1, 2015 
End Date: August 31, 2018 
Length of individual participation: 52 weeks 
Study Design: 
Single-arm, single site, open-label study 
Study Agent: 
F/TAF fixed-dose combination (emtricitabine 200 mg/tenofovir 
alafenamide 25 mg) 
Intervention description: 
Patients will be hospitalized to receive directly observed therapy 
(DOT) with F/TAF (in place of F/TDF or ABC/3TC, if applicable) 
plus their pre-enrollment ART regimen for 9 days. On Day 10, 
patients will switch to F/TAF plus an optimized background 
therapy (OBT) while waiting for the report of the result of Day 10 
HIV RNA.. Patients with a ≥0.5 log10 decline in HIV RNA from Day 
1 to Day 10 will continue F/TAF + OBT for 48 weeks. Patients with 
an HIV RNA decline of <0.5 log10 will discontinue F/TAF and their 
study participation will end. They will continue OBT (with TDF/FTC 


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or ABC/3TC in place of F/TAF, as appropriate) under protocol 14-
I-0009. 
Primary Objective: 
•  To explore the safety and efficacy of F/TAF as part of a salvage  
antiretroviral regimen for patients who experienced virologic failure 
Secondary Objective: 
•  To use stored blood samples for future research related to HIV 
and drug resistance 
Study Endpoints: 
•  Percent of patients with HIV RNA ≥ 0.5 log10 copies/mL decline 
on Day 10 of DOT with F/TAF plus a failing regimen 
• Change in log HIV RNA from Day 1 to Day 10 of DOT with 
F/TAF plus a failing regimen 
The following Study Endpoints are for patients with ≥ 0.5 log10 
copies/mL decline in HIV RNA from Day 1 to Day 10: 
• HIV RNA at 1, 2, 4, 8, 12, 24, 36, and 48 weeks after starting 
F/TAF + OBT as compared to baseline 
• For HBV co-infected patients, HBV DNA 1, 2, 4, 8, 12, 24, 36, 
and 48 weeks after starting F/TAF + OBT as compared to 
baseline 
• Renal function assessment at  1, 2, 4, 8, 12, 24, 36, and 48  
weeks after starting F/TAF + OBT as compared to baseline: 
o Serum measurements: creatinine, cystatin C, phosphorus, 
and estimated glomerular filtration rate (eGFR) 
o Urine measurements: creatinine, phosphorus, glucose, and 
solute-to-creatinine ratios for the following solutes: protein, 
albumin, beta-2-microglobulin, retinol-binding protein 
• Bone mineral density at 24 and 48 weeks after starting F/TAF + 
OBT as compared to baseline 
• Genotypic resistance testing at study time points after week 12, 
if presence of plasma viremia with HIV RNA >500 copies/mL 


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Précis 
Despite the success of antiretroviral therapy (ART), a subset of HIV-1-infected patients have 
uncontrolled viremia, multiple drug class resistance, and limited treatment options. Tenofovir 
disoproxil fumarate (TDF) forms part of most ART regimens, however its long-term use is 
associated with renal tubulopathy and reduced bone mineral density. Viral mutations (eg, K65R, 
multiple thymidine analog mutations (TAMs) can confer resistance or reduced susceptibility to 
TDF. 
 
Tenofovir alafenamide (TAF) is an investigational oral prodrug of tenofovir. When compared to 
TDF, TAF demonstrated lower plasma tenofovir concentrations and more potent antiviral activity 
at approximately one-tenth of the dose. TAF has the advantage of reduced tenofovir exposure 
to the renal tubules and bone, potentially resulting in fewer kidney and bone effects. As with 
TDF, TAF has potent activities against hepatitis B virus (HBV), and may be a treatment option 
for patients with HIV/HBV co-infections. Phase 2 trials have demonstrated the non-inferiority of 
TAF to TDF in treating HIV-1 infection in ART-naïve patients. Smaller reductions in bone 
mineral density were measured with TAF than TDF. The most common adverse events were 
nausea and diarrhea. 
 
This single-arm, single-site, open-label trial will explore the safety and efficacy of TAF in a fixed 
combination with emtricitabine (FTC) (F/TAF, Gilead Sciences Inc.) as part of a salvage 
antiretroviral regimen for HIV-1-infected adults and adolescents (≥14 years) who experienced 
virologic failure. The study will recruit patients who have failed TDF-containing regimens or 
cannot take TDF (due to resistance mutations or risk of renal injury) and for whom 
abacavir/lamivudine (ABC/3TC) is not an optimal alternative. Eligible patients will begin 9 days 
of inpatient directly observed therapy (DOT) with F/TAF plus their pre-enrollment background 
regimen. On Day 10, patients will switch to F/TAF plus OBT while waiting for the results of Day 
10 HIV RNA results. Patients with an HIV RNA decline of <0.5 log10 from Day 1 to Day 10 will 
discontinue F/TAF, end their study participation, and continue OBT (with TDF/FTC or ABC/3TC 
in place of F/TAF, as appropriate) under the 14-I-0009 protocol. Patients with a ≥0.5 log10 
decline in HIV RNA will continue on F/TAF + OBT for 48 weeks, with periodic outpatient 
assessments of adherence, safety, renal function, bone mineral density, HIV RNA, and CD4 T 
cell counts. Switching of one or more drugs in an ART regimen due to inadequate viral response 
will require inpatient DOT under 14-I-0009.  


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1 Background Information and Scientific Rationale 
 
Background information 
With the advances in ART, most HIV-infected patients who remain in care can achieve viral 
suppression with their prescribed regimens.1 Despite this success, there remains a small subset 
of patients who have uncontrolled viremia, in some cases, with multiple-drug-class resistance 
and limited treatment options.2 ART failure has been an independent risk factor of mortality in 
North America.3 
 
TDF in a fixed-dose formulation with emtricitabine (FTC) is a potent 2-nucleoside reverse 
transcriptase inhibitor (NRTI) combination that forms part of most ART regimens for treatment-
naïve as well as treatment-experienced patients. Approved by the U.S. FDA in 2003, TDF has 
demonstrated long-term antiretroviral efficacy. TDF is an oral prodrug of tenofovir (TFV), a 
nucleotide analog with activities against both HIV-1 and HBV. TFV itself has very low oral 
bioavailability. As a prodrug, oral TDF is rapidly absorbed and converts to TFV in the plasma, 
which in turn converts to TFV-diphosphate (TFV-DP) intracellularly. Long-term use of TDF, 
however, has been associated with renal tubulopathy,4,5 potential for osteomalacia,6 as well as 
increased incidence of reduced bone mineral density7 and increased fracture risk.7,8 Genotypic 
resistance to TDF has been reported, especially in the presence of the K65R mutation.9-11 
Additionally, the presence of multiple thymidine analog mutations (TAMs) can confer reduced 
susceptibility to TDF.11 
 
TAF is an investigational oral prodrug of TFV. After absorption, it remains stable in the plasma 
and achieves low plasma concentration of TFV, but it is converted from TAF to TFV and then to 
TFV-DP intracellularly, where it exerts its activity as a reverse transcriptase (RT) inhibitor. The 
GS-US-120-0104 study evaluated the pharmacokinetics and viral kinetics of 300 mg of TDF and 
various doses of TAF monotherapy for 10 days in HIV-infected subjects. Compared to TFV, TAF 
demonstrated lower plasma TFV exposures, higher peripheral blood mononuclear cell (PBMC) 
intracellular TFV-DP levels, and more potent antiviral activity at approximately one-tenth of the 
dose (Table 1).12 
 
Table 1. Pharmacokinetics and virologic responses of HIV-infected adults (n = 38) after 10 days of 
monotherapy with tenofovir (TFV) or tenofovir alafenamide (TAF)12  
 
TDF 300 mg 
TAF 8 mg 
TAF 25 mg 
TAF 40 mg 
Plasma TFV AUC 
(ng*h/mL) 
1918 
66 
268 
406 
PBMC TFV-DP AUC 
(M*h) 
3.0 
3.5 
21.4 
74.5 
Day 10 HIV RNA Δ 
(log10 copies/mL) 
-0.81 ± 0.58 
-0.98 ± 0.46 
-1.50 ± 0.41 
-1.74 ±0.19 
AUC, area under the curve; PBMC, peripheral blood mononuclear cells; TFV-DP, tenofovir diphosphate 
 
With the lower plasma TFV concentration, TAF has the advantage of reduced TFV exposure to 
the renal tubules as compared with TDF, potentially resulting a lesser degree of kidney and 


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bone effects. TAF is not a substrate for renal organic anion transporters, which may account for 
its reduced potential to cause proximal renal tubulopathy.13 The higher PBMC concentrations 
with TFV may explain the greater 10-day virologic suppression.  
 
TAF is a poor substrate of cytochrome P450 (CYP) enzymes, and is not an inducer or inhibitor 
of these enzymes. Thus, drugs metabolized by these enzymes are not expected to influence the 
pharmacokinetics of TAF, and TAF will not affect the pharmacokinetics of CYP substrates. TAF 
is a substrate for the intestinal efflux transporters P-glycoprotein (Pgp) and breast cancer 
resistance protein (BCRP), and the hepatic update transporters organic anion transporting 
polypeptides (OATP) 1B1 and 1B3, thus, TAF exposures may be affected by inhibitors or 
inducers of the intestinal transporters, and inhibitors or genetic polymorphisms of OATPs. 
Systemic exposure of TAF can be increased by cobicistat (165% increase) and ritonavir-
boosted atazanavir (91% increase).11 
 
In a phase 2 trial of ART-naïve HIV-1 infected patients randomized 2:1 to TAF or TDF, both in 
combination with elvitegravir/cobicistat/emtricitabine (E/C/F), 87.5% of 112 subjects in the TAF 
arm and 89.7% of 58 subjects in the TDF arm achieved HIV RNA < 50 copies/mL at week 24 (p 
= 0.48).14 In a pooled analysis of 2 treatment trials comparing E/C/F/TAF and E/C/F/TDF, 92.4% 
and 90.4% reported virologic success at week 48, demonstrating non-inferiority of TAF to TDF 
treatment.15 In the intensive pharmacokinetic analysis in a subset of 26 patients, TFV plasma 
exposure (area under the plasma concentration curve [AUCtau]) was 91% lower in the TAF arm 
than the TDF arm, whereas the intracellular TDF-DP levels in PBMCs were 5.3-fold higher in 
the TAF arm. The most common adverse events (AEs) were nausea and diarrhea, with nausea 
reported in 15% and 17% of patients treatment with TAF and TDF, respectively.16 Significantly 
smaller reductions in bone mineral density in both the hip and spine were seen in the TAF group 
compared to the TDF group at week 48, as measured by dual energy X-ray absorptiometry 
(DEXA) scan.14  
 
Median change in serum creatinine did not differ between the two arms (0.07 mg/dL vs. 0.10 
mg/dL increase in the TAF and TDF arms, respectively) and stabilized at week 4 of therapy. As 
all study participants received cobicistat, a pharmacokinetic enhancer that has been associated 
with inhibition of tubular secretion of creatinine,17 it is difficult to attribute the serum creatinine 
changes to TAF or TDF in this study. In pooled analysis of renal safety from various ART-naïve 
treatment studies, overall, there is less change in serum creatinine, eGFR, and less proteinuria 
in the TAF-treated compared to TDF-treated patients.15 The pharmacokinetics of TAF 25 mg 
was compared between subjects with severe renal impairment (eGFR 15-29 mL/min) and 
matched healthy controls (eGFR > 90 mL/min). No difference in TAF exposure was observed, 
TFV concentrations were comparable to or below that seen in healthy volunteers with normal 
renal function prescribed TDF 300 mg dose.15  
 
As with TDF, TAF has potent activities against HBV, and is therefore a treatment option for 
patients with HIV/HBV co-infections. When subjects with chronic hepatitis B were randomized 
(1:1:1:1:1) to daily doses of TDF 300 mg or TAF 8, 25, 40 or 120 mg, all 5 groups showed 
similar declines in HBV RNA at 4 weeks. No grade 3 or 4 adverse events were reported.18 


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Currently, a combination product of TAF/emtricitabine (F/TAF) (Gilead Sciences, Inc., Foster 
City, CA) is undergoing phase 3 clinical trials as a 2-NRTI backbone for antiretroviral regimens, 
as a treatment for HBV mono-infection (NCT01940471, NCT01940341) and as a treatment for 
HIV/HBV co-infection (NCT02071082 – in combination with elvitegravir and cobicistat). A new 
drug application (NDA) for F/TAF has recently been submitted to the FDA for approval, but it is 
anticipated that the product will not be commercially available until late spring 2016. NDAs for 
fixed-dose formulations of E/c/F/TAF 10mg, rilpivirine/F/TAF 25mg and darunavir/c/F/TAF 10mg 
are currently under evaluation at the FDA.. 
 
Rationale 
The DOTCOM protocol (14-I-0009) aims to characterize and manage patients who experience 
virologic failure despite being on a second or greater regimen. Most if not all of such patients 
have been receiving FTC/TDF as part of their regimens for many years. Of the 5 subjects 
enrolled in DOTCOM thus far, 3 have extensive multiple-drug-class resistance, including the 
presence of several viral mutations that confer resistance to TDF by genotypic testing. In all 3 
cases, phenotypic testing demonstrated partial sensitivity to TDF. Despite the reduced 
susceptibility, we chose to maintain FTC/TDF in the salvage regimen in the hope of attaining a 
partial antiviral effect. One of the 3 patients received F/TAF through an Emergency 
Investigational New Drug (EIND) protocol (14-I-9950) due to repeated episodes of acute kidney 
injury (peaked serum creatinine 4.4 mg/dL) after receiving TDF. After 24 weeks of treatment 
with an F/TAF containing regimen, this patient’s renal function remains stable (last serum 
creatinine [SCr] = 1.36 mg/dL), with viral suppression (HIV RNA < 40 copies/mL). In a 4th 
subject, who has HBV co-infection, despite susceptibility to TFV, TDF was discontinued due to 
chronic kidney disease (last SCr = 2.22 mg/dL, eGFR = 36 mL/min). This patient is currently 
receiving a regimen including ABC/3TC as the NRTI backbone, despite the presence of the 
M184V mutation, which reduces susceptibility to ABC. 
 
To date, there are few data on the efficacy of TAF in HIV-infected patients who harbor multiple-
drug-class-resistant HIV, and who have reduced susceptibility to TFV in genotype or phenotype 
resistance testing. In these cases, FTC/TDF is often maintained as part of the salvage regimen 
despite the potential for resistance. Given the higher intracellular concentration of TFV-DP after 
administration of TAF as compared to TDF, we propose to replace FTC/TDF with F/TAF in 
salvage ART regimens of selected patients.  In our study, a fixed dose combination of F 
200mg/TAF 25mg will be used, regardless of antiretroviral drugs to be used in the OBT. The 
25mg dose is used as it has been found to have potent antiviral activities in the ARV naïve 
populations, and as even at higher doses, TAF achieves significantly lower plasma TFV 
concentration and thus less systemic toxicities expected as compared to TDF 300mg dose. 
2 Study Objectives 
 
Primary Objective 
To explore the safety and efficacy of F/TAF as part of a salvage antiretroviral regimen for 
patients who experienced virologic failure. 


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Secondary Objective 
To use stored blood samples for future research related to HIV and drug resistance 
3 Study Design 
 
Description of study design 
This is a single-arm, single site, open-label trial of F/TAF to be prescribed in place of FTC/TDF 
or ABC/3TC in combination with a selected OBT. OBT will be comprised of antiretroviral agents 
and designed based on prior ART history and drug tolerance, responses to therapy, and current 
and, if available, cumulative genotypic and/or phenotypic testing results. 
 
To be eligible for enrollment, patients must be enrolled in the DOTCOM protocol where they will 
be admitted to the NIH Clinical Center (CC) to receive 7 days of their pre-enrollment ART 
regimen as self-guided DOT to confirm the lack of or suboptimal virologic efficacy of that 
regimen. Then, if eligible for and after signing the consent to this protocol, patients will begin 9 
days of DOT with F/TAF in addition to their failing regimen. On Day 10 they will switch to F/TAF 
plus OBT while awaiting the results of the Day 10 HIV RNA. Most patients will be discharged on 
Day 10 with instructions to take F/TAF+OBT at home. Those patients who are able to remain 
hospitalized will be administered F/TAF+OBT as inpatient DOT until Day 12-15. 
 
On Day 12-15, the Day 10 HIV RNA results will be reviewed by the study team. Patients with a 
≥0.5 log10 decline in HIV RNA (from Day 1 to Day 10) will continue F/TAF plus OBT for 48 
weeks. The Day 10 HIV RNA results may be shared with these patients by phone. Patients with 
an HIV RNA decline of <0.5 log10 will be asked to return to the NIH on Day 12-15 for a regimen 
change. They will discontinue F/TAF and their study participation will end. They will continue 
OBT (with TDF/FTC or ABC/3TC, as appropriate) under the DOTCOM protocol. 
 
Patients who continue F/TAF during the 48 weeks of study will return for periodic outpatient 
assessments of adherence, safety, HIV RNA, and CD4 cell counts as outlined in Section 6. ART 
regimen changes due to inadequate viral response will require an additional 7 days inpatient 
DOT. After Week 48, if F/TAF is approved by the FDA, the patient will receive it through 
commercial source. If F/TAF has not yet received FDA approval, the patient will remain on this 
protocol to be followed every 3 months until F/TAF receives approval (or drug development is 
discontinued). 
 
 
 
Study endpoints 
• 
Percent  of patients with ≥ 0.5 log10 decline in HIV RNA on Day 10 of DOT with F/TAF 
plus a failing regimen 
• 
Change in log10 HIV RNA  from Day 1 to Day 10 of DOT with F/TAF plus a failing regimen 
For patients with ≥0.5 log10 copies/mL decline in HIV RNA from Day 1 to Day 10:  


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• 
HIV RNA at 1, 2, 4, 8, 12, 24, 36, and 48 weeks after starting F/TAF + OBT as compared 
to baseline 
• 
For HBV co-infected patients, HBV DNA at 1, 2, 4, 8, 12,  24, 36, and 48 weeks after 
starting F/TAF + OBT as compared to baseline 
• 
Renal function assessment 1, 2, 4, 8, 12, 24, 36, and 48 weeks after starting F/TAF + 
OBT as compared to baseline: 
o Serum measurements: creatinine, cystatin C, phosphorus 
o Urine measurements: creatinine, phosphorus, glucose, and solute-to-creatinine ratios 
for the following solutes: protein, albumin, beta-2-microglobulin, retinol-binding protein 
(RBP) 
• 
Bone mineral density at 24 and 48 weeks after starting F/TAF + OBT as compared to 
baseline 
• 
Genotypic resistance testing at study time points after week 12, if presence of plasma 
viremia with HIV RNA >500 copies/mL 
4 Study Population 
 
Rationale for Subject Selection 
Patients who will be enrolled in this study represent a population of HIV-1-infected individuals 
who fail to achieve sustained viral suppression despite the use of current antiretroviral drugs. 
For patients with NRTI including TDF resistance mutations or where TDF (eg, renal tubulopathy, 
reduced bone mineral density) and/or to abacavir/lamivudine (eg, HLA-B*5701) are not optimal 
options, F/TAF may represent a new treatment option. 
 
Recruitment Plan 
Patients will be recruited from those enrolled in the DOTCOM protocol as well as locally and 
nationally through existing contacts with HIV primary care providers and clinics. 
 
Subject Inclusion Criteria 
1. Age ≥14 years 
2. Documented HIV-1 infection (written documentation of positive standard ELISA or rapid HIV-
1/HIV-2 antibody test with confirmatory Western Blot, or documentation of repeated HIV RNA 
of > 1,000 copies/mL) 
3. Concurrent enrollment in the DOTCOM (14-I-0009) protocol 
4. For females of childbearing potential, willingness to use effective contraception for the 
duration of the study  
5. Willingness to be hospitalized for 10-15 days (with potential for day passes) 
6. Willingness to have blood samples stored for future research that may include genetic testing 
7. Multiple ART failure as defined by at least one of the following criteria: 
5a. HIV RNA > 1000 copies/mL and documented virologic failure on at least 1 prior ART 
regimen and at least 2 consecutive HIV RNA plasma measurements of > 1,000 


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copies/mL, including the last documented value, while on the currently prescribed 
ART regimen for at least 6 months; or 
5b. Documented extensive resistance to at least 3 antiretroviral (ARV) drug classes, and 
persistent plasma viremia (HIV RNA > 1,000 copies/mL for > 6 months) despite 
multiple regimen changes. The patient may be enrolled even if they have been 
prescribed their current regimens for less than 6 months.*  
8. Where neither TDF nor ABC are optimal NRTI options as defined by at least one of the 
following criteria: 
7a. Presence of the M184V mutation plus TDF-associated resistance mutations based 
on genotypic/phenotypic testing, specifically K65R alone, or with TAMs (such as 41L, 
67N, 70R, 210W, 215Y/F, or 219Q/E) with or without other NRTI-associated 
mutations; or 
7b. FTC/TDF is not considered an option due to impaired renal function (eGFR by 
Cockroft-Gault equation [eGFRCG]=30-60 mL/min), or risk of renal impairment 
because of conditions such as uncontrolled hypertension, diabetes mellitus, or 
history of renal toxicity while receiving a TDF-based regimen; and  
      where ABC/3TC is contraindicated (ie, presence of HLA B*5701 allele or history of 
hypersensitivity reaction to ABC), or is a suboptimal option (eg, presence of ABC-
associated resistance mutation(s) or in patients with HBV co-infection). 
 
 
Subject Exclusion Criteria 
1. Severe renal impairment (eGFRCG <30 mL/min) 
2. Acute medical illness stemming from a significant co-morbidity (eg, malignancy requiring 
chemotherapy, treatment of an acute opportunistic infection or acute renal failture). 
Enrollment may be deferred up to 3 months to allow a condition to resolve or stabilize. 
3. Pregnancy; however if a patient becomes pregnant while enrolled in the protocol, she may 
continue participation throughout her pregnancy. 
4. Breastfeeding 
5. Concomitant use of one of the following medications: carbamazepine, oxcarbazepine, 
phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, bisphosphonate, St. John’s wort, 
echinacea, milk thistle, sho-saiko-to, and probenecid. 
6. Any illness or condition that, in the investigator’s opinion, may substantially increase the risk 
of participation in the study, or compromise the scientific objectives. 
 
 
Justification for Exclusion of Children and Pregnant Women (Special 
Populations)  
Exclusion of children:  There are limited data regarding dosing and efficacy of F/TAF in 
subjects younger than 12 years. Since the DOTCOM protocol enrolls subjects >14 years and 
we aim to have patients co-enroll in this protocol, age 14 will be used as the cutoff.  
 
Exclusion of pregnant women: No adequate and well-controlled studies of F/TAF or its 
components have been conducted in pregnant women. Patients who enroll in the protocol may 


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experience a delay between study screening and an ART regimen change, during which 
uncontrolled viremia could increase the risk of HIV transmission to the fetus. Therefore, we do 
not think it is in the best interest of pregnant women and their unborn children to join this 
protocol.  
 
Patients who become pregnant while enrolled may continue participation and continue F/TAF 
throughout pregnancy. Protocol-specified DEXA scan will be postponed until after delivery. 
Animal studies do not indicate direct or indirect harmful effects of TAF or FTC with respect to 
pregnancy, embryonal and fetal development, partition, or post-natal development. F/TDF is 
currently recommended in the United States as one of the preferred 2-NRTI for pregnant 
women for their treatment and for preventing mother-to-child transmission.10 All women who 
become pregnant during this study will be followed until after delivery. 
 
Exclusions of breastfeeding women: Women with uncontrolled viremia are discouraged from 
breastfeeding due to the potential for HIV transmission. In addition, emtricitabine and tenofovir  
(when used in TDF) are both excreted in breast milk and the risks in newborns are unknown.  
5 Study Agent/Interventions  
 
Disposition and Dispensation  
F/TAF along with all co-administered ARV drugs will be distributed via the NIH CC Pharmacy 
according to standard pharmacy procedures. During the DOT period, all agents will be 
dispensed from the NIH CC Pharmacy to the inpatient nursing unit. 
 
Formulation, Packaging and Labeling 
FTC 200 mg/TAF 25 mg tablets are rectangular-shaped, film-coated blue tablets labeled with 
“225”. The formulation is packaged as 30 tablets in white bottles with child-resistant screw caps. 
Each bottle will be individually labeled with, dosing instructions, recommended storage 
conditions, the name and address of the manufacturer, Investigational Use Statement (“Caution: 
New Drug – Limited by Federal [USA] law to Investigational Use”) and that the agent should be 
kept out of reach of children.  
 
Storage and Stability 
F/TAF tablets must be stored at a room temperature of 25 °C (77 °F); excursions are permitted 
between 15 °C and 30 °C (59 °F and 86 °F). To ensure stability, the tablets should be 
dispensed only in the bottles in which they are supplied. 
 
Preparation, Administration and Dosage 
 
Dosing and administration 
F/TAF will be orally self-administered as one tablet daily without regard to food. This dose is for 
adults and pediatric patients ≥12 years and weighing ≥35 kg. No dose adjustment is required for 
elderly patients. No dose adjustment is required for adults with mild to moderate renal 
impairment (eGFRCG ≥30 mL/min). See Section 7.1 for management of patients whose eGFRCG 
falls below 30 mL/min while on therapy. 


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Subject access to F/TAF at study closure 
F/TAF is expected to become a licensed drug in 2016. In the event that F/TAF has not been 
licensed before the end of a subject’s study participation, Gilead will continue to provide F/TAF 
until FDA approval or until development of F/TAF is discontinued by Gilead.  
 
Assessment of Subject Compliance with Study Agent 
Treatment adherence will be assessed at baseline and during follow-up visits using patient 
recall of doses missed in the past week, or since last clinic visit, and patient interviews. 
 
Concomitant Medications and Procedures  
All concomitant prescription medications taken during study participation will be recorded in the 
Clinical Research Information Management System of NIAID (CRIMSON). For this protocol, a 
prescription medication is defined as a medication that can be prescribed only by a properly 
authorized/licensed clinician. Medications to be reported in CRIMSON are concomitant 
prescription medications, over-the-counter medications and non-prescription medications taken 
at the time of AEs (all grades). 
 
Prohibited Medications and Procedures  
Concomitant use of any of the following medications is not allowed: carbamazepine, 
oxcarbazepine, phenobarbital, phenytoin, rifabutin, rifampin, rifapentine, bisphosphonate, St. 
John’s wort, echinacea, milk thistle, sho-saiko-to, and probenecid. 
Treatment with investigational agents other than F/TAF will be permitted only if discussed with 
and approved by the principal investigator (PI) and by Gilead Sciences. 
6 Study Schedule 
 
Screening visit (Day -28 to Day -1) 
Patients will come to the NIH CC to undergo the following procedures after signing informed 
consent. Evaluations or procedures will not be repeated if they were performed under another 
protocol within the visit window and results are available in CRIMSON or Clinical Research 
Information System (CRIS). The screening visit may occur during a DOTCOM protocol study 
visit. 
• 
Review of eligibility criteria 
• 
Physical exam and medical/social history 
• 
Medication history/adherence assessment 
• 
Urine collection for: 
o Pregnancy test (for women of childbearing potential) 
o Renal function assessments: creatinine, phosphorus, glucose, and solute-to-
creatinine ratios for the following solutes: protein, albumin, beta-2-
microglobulin, RBP 
• 
Blood draw for  
o HIV-1 serology (if no prior written documentation of HIV status is available, 
repeated documents of positive HIV RNA > 1,000 copies/mL can be used as 
documentation of HIV status) 


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o Plasma HIV RNA levels 
o CD4+ T cell count 
o Complete blood count (CBC) with differential 
o Acute care, mineral, and hepatic panels 
o Genotypic/phenotypic resistance testing (described in section 7.2) for reverse 
transcriptase, protease, and integrase genes unless already performed and 
available from CRIMSON 
o HLA B*5701 screening, unless available in CRIMSON or CRIS 
o Hepatitis serology (anti-HAV [antibody to hepatitis A virus], Hepatits B surface 
antigen (HBsAg), antibody to HBsAg [anti-HBs], and antibody to hepatitis B 
core antigen [anti-HBc] anti-HCV [antibody to Hepatitis C virus]), unless 
available in CRIMSON 
o If the subject has documented Hepatitis B surface antigen (HbsAg), HBV 
DNA and hepatitis B ‘e’ antigen (HBeAg) testing will be performed  
 
Patients who meet the criteria for this study will complete one week of inpatient DOT on their 
pre-enrollment regimen under the DOTCOM protocol. Based on screening test results and 
outcomes from participation in DOTCOM, the study team will choose an OBT for each patient. 
The ARV treatment plans will be communicated to the patients’ primary care providers.  
 
Inpatient DOT with F/TAF+failing regimen: Day 1 to Day 9(+/-1 day) 
Patients will receive F/TAF plus their pre-enrollment regimen for 9 days. If the same laboratory 
evaluations are conducted under DOTCOM within the visit window, they will not be repeated. 
Day 1: 
• 
Physical exam and medical/social history 
• 
Urine collection for: 
o Pregnancy test (for women of childbearing potential) 
o Renal function assessments: creatinine, phosphorus, glucose, and solute-to-
creatinine ratios for the following solutes: protein, albumin, beta-2-microglobulin, 
RBP 
• 
DEXA scan scheduled: scan may be conducted either before inpatient DOT or within 7 
days of the start of F/TAF. The scan will NOT be repeated during any additional weeks 
of DOT. 
• 
Blood draw for: 
o CD4+ T cell count 
o Plasma HIV RNA 
o HBV co-infected patients only: HBV DNA and serum alanine aminotransferase 
(ALT) 
o CBC with differential 
o Acute care, mineral, and hepatic panels 
o Renal function assessment: creatinine, cystatin C, phosphorus, and calculated 
eGFR 
o Storage of plasma, serum, and PBMCs 


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• 
Begin self-guided DOT of F/TAF plus pre-enrollment regimen and continue for 9 days, 
with daily AE monitoring 
Day 3 (+/- 1 day): 
• 
HIV RNA 
• 
HBV-coinfected patients only: HBV DNA 
 
Day 5 (+/- 1 day): 
• 
HIV RNA 
• 
HBV-coinfected patients only: HBV DNA and serum ALT 
• 
CBC with differential 
• 
Acute care, mineral and hepatic panels 
 
Day 8 (+/- 1 day): 
• 
HIV RNA 
• 
HBV-coinfected patients only: HBV DNA 
• 
 
Day 10 (+/- 1 day): 
• 
HIV RNA 
• 
HBV-coinfected patients only: HBV DNA 
• 
CBC with differential 
• 
Acute care, mineral and hepatic panels 
• 
Begin F/TAF plus OBT at home OR as inpatient DOT until Day 12-15 only. 
• 
In the event of intolerance of F/TAF or OBT, the patients will be asked to return to the 
NIH CC. A new treatment plan will be made in conjunction with the patients’ primary care 
team. 
 
Day 12-15 (+/-1 day): 
• 
Results of Day 10 HIV RNA will be available for evaluation. 
• 
Patients with a ≥0.5 log10 decline in HIV RNA from day 1 to day 10 will continue F/TAF + 
OBT for 48 weeks. The investigator may phone the patients to inform them of their Day 
10 HIV RNA results. 
• 
Patients with an HIV RNA decline of <0.5 log10 will return to the NIH CC and their 
results will be discussed with them. These patients will discontinue F/TAF (TDF/FTC or 
ABC/3TC may be resumed on a case-by-case basis) and will be discontinued from this 
protocol. They will continue OBT under the DOTCOM protocol. 
 
Follow-up assessments at 1, 2, 4, 8  and 12 weeks (see Appendix B for visit 
windows) after starting F/TAF+OBT (for patients continuing F/TAF) 
• 
Urine pregnancy test (for women of childbearing potential) 
• 
Urine renal function assessments: creatinine, phosphorus, glucose, and solute-to-
creatinine ratios for the following solutes: protein, albumin, beta-2-microglobulin, RBP 
• 
Physical exam and medical/social history 
• 
Medication history 


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• 
Adherence assessment and counseling 
• 
AE monitoring 
• 
Blood draw for: 
o HIV RNA 
o HBV-coinfected patients only: HBV DNA 
o CBC with differential 
o Acute care, mineral and hepatic panels  
o Serum renal function assessments: creatinine, cystatin C, phosphorus, and 
calculated eGFR 
o 12 weeks only: CD4+ T cell count 
• 
Patients with reduced HIV RNA levels during DOT but with viral rebound during post-
DOT follow-up will be managed as detailed in Section 7.1 
 
Follow-up assessments at 24, 36, and 48 weeks after starting F/TAF+OBT (+/- 2 
weeks) 
• 
Urine pregnancy test (for women of childbearing potential) 
• 
Urine renal function assessment (as detailed in 6.2) 
• 
Physical exam and medical/social history 
• 
Medication history 
• 
Adherence assessment and counseling 
• 
AE monitoring 
• 
24 and 48 weeks only: DEXA scan  
• 
Blood draw for: 
o HIV RNA 
o HBV-coinfected patients only: HBV DNA  
o CD4 T cell count 
o Acute care, mineral and hepatic panels 
o CBC with differential  
o Serum renal function assessments (as detailed in 6.3) 
o Genotypic/phenotypic resistance testing for patients with plasma HIV RNA 
> 500 copies/mL 
o Storage of plasma, serum and PBMCs 
 
Unscheduled visits 
Patients will be advised to return to the CC as needed in the event of viral rebound, drug 
intolerance, or hepatitis flare as per the PI and the study team. Additional adherence counseling 
and a repeat blood draw for clinical purposes may be done during these visits. 
7 Study Procedures/Evaluations 
 
Clinical Evaluations 
Physical exam and medical/social history including vital signs, targeted physical exam, and 
questions/discussion regarding social issues that may impact medication adherence.  
Urine collection for pregnancy and renal function tests. 


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Phlebotomy: Blood will be collected for routine serologic, hematologic, and clinical chemistry 
evaluations as listed Section 6. 
Adherence assessment and counseling: Medication adherence will be assessed by a clinical 
pharmacist or other member of the study staff via patient interview or patient recall of doses 
missed in the past week, or since the last clinic visit.  
Management of subjects with reduced HIV RNA levels during DOT and viral rebound 
during the post-DOT follow-up: For this study, since the enrolled patients are heavily 
treatment-experienced, virologic failure is defined as either (1) confirmed HIV RNA rebound to 
>200 copies/mL after viral suppression with F/TAF + OBT; or (2) failure to have a >1 log10HIV 
RNA decline at week 24. For patients with extensive treatment experience, multiple drug-class 
resistance, and less than 2-3 fully active antiretroviral drugs in the regimen, maximal 
suppression may not be feasible, thus, virologic success may have to be defined on a case-by-
case basis. In general, it has been shown that even partial viral suppression (eg, > 1-2 log 
reduction in HIV RNA copies/mL) with a stable CD4 cell count can provide clinical benefit. In the 
event of viral rebound during the post-DOT period, we will begin with adherence assessment 
and counseling. Genotype +/- phenotype resistance testing may be performed to identify 
emergence of new resistance-associated mutations or changes in phenotypic susceptibility to 
the ART regimen. Unless factors can be identified that would indicate that a change in the 
treatment regimen might be successful (ie, treatment-related AEs), we will keep patients on their 
respective regimens and continue to follow them while emphasizing the importance of 
adherence.  
Management of HBV co-infected subjects: Due to the risk of hepatitis flare upon initation and 
discontinuation of F/TAF, HBV-coinfected patients will be monitored for clinical signs of hepatitis 
and changes in laboratory measures of HBV DNA and serum ALT. Patients will be informed to 
contact the study team with any new symptoms compatible with hepatitis. Adherence 
counseling will discourage patients from abruptly stopping their F/TAF regimen. Subjects with 
HIV/HBV coinfections who discontinue F/TAF will be monitored (with clinical and laboratory 
assessments) at least monthly for up to 3 months after stopping treatment either by the study 
team or by their primary care physician.The study team will work with the subjects’ primary care 
physician to identify commercially available HBV treatment for subjects who discontinue F/TAF. 
For the purpose of this protocol, hepatitis flare is defined as confirmed serum ALT increase to 2 
times Day 1 value and >5x the upper limit of normal, with or without associated symptoms. If 
serum ALT measures indicate hepatitis flare, other liver-associated parameters, including total 
bilirubin and international normalized ratio (INR) will be assessed. Efforts will be made to 
identify other causes of serum transaminase elevation, including a review of other concomitant 
medications and history of recent alcohol use. Viral hepatitis serology (HAV IgM, HCV RNA, and 
HBV DNA) will also be done. On a case-by-case basis, if the total bilirubin is greater than 2 
times the Day 1 value and INR is >0.5 above the Day 1 value (provided if both are >ULN), the 
study team in consultation with Gilead will determine whether to continue F/TAF and monitor 
ALT weekly until it returns to Day 1 value, or if it is necessary to discontinue F/TAF portion of 
the regimen. 


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Management of Potential Nephrotoxicity: Any patient whose eGFR falls below 30 mL/min 
must have serum creatinine and cystatin C  repeated within 3 business days. eGFR by CKD-
EPI (cystatin C) should be calculated.19 Any subject who have an eGFRCG <30 mL/min and also 
experience >20% reductionfrom baseline in eGFR by CKD-EPI (cystatin C) or who have clinical 
and/or laboratory evidence of acute renal failure will be discussed with the SMM and may 
discontinue from F/TAF if deemed appropriate. For subjects with eGFRCG in whom F/TAF has 
not been discontinued and considered to have stable renal function per Principal Investigator 
and/or SMM, it is not mandatory to repeat eGFR assessments within 3 days, and can be 
monitored per protocol. 
 
Research Evaluations 
Inpatient self-guided DOT: Patients will be admitted to the CC for 10-15 days to assess the 
change in HIV RNA while receiving an ART regimen by DOT. Patients will be instructed to 
request the antiretroviral drugs from the nursing staff at a pre-arranged time reflecting their 
home medication schedule. If patients do not request to have their antiretroviral drugs 
administered within 2 hours of the scheduled time, the nursing staff will automatically administer 
the drugs to them 2 hours after the scheduled time. The nursing staff will monitor patients as 
they take each dose and document the time of administration. A self-guided DOT plan will be 
established by the study team in conjunction with the patients and their parent(s)/guardian(s) for 
adolescents ages 14-18 (exception will be given to emancipated adolescents). 
Bone mineral density test: A DEXA scan of the lumbar vertebrae and hip will be performed to 
generate mean bone mineral density scores. Subjects who become pregnant during study 
participation will not have DEXA scans. 
Urinary RBP: Urine samples will be stored and will later be shipped to Gilead Sciences Inc. or a 
designated contract laboratory for assessment of urinary RBP. 
PBMCs, plasma, and serum storage: For investigations related to HIV treatment failure, viral 
resistance, immunologic responses, and subsequent responses to therapy. 
HIV genotypic and phenotypic resistance testing: Genotypic testing will be done using 
genotype testing and Genotypic resistance testing will be performed using Trugene HIV-1 at 
baseline in the Viral Isolation Laboratory, Clinical Services Program, Frederick National 
Laboratory for Cancer Research. Phenotypic assay will be performed at Monogram Sciences 
using the PhenoSense assay. In the event that a patient is found to have rebound viremia after 
the initial virologic response, or has persistent viremia despite a new antiretroviral regimen, 
stored plasma samples may be used to perform the HIV genotypic resistance testing. If 
phenotypic resistance testing is deemed necessary, a stored sample will be sent to a 
commercial laboratory from the repository. 
 
Specimen Preparation, Handling, and Shipping 
All clinical care and research blood specimens will be handled according to NIAID and NIH CC 
standard procedures. Urine samples for RBP will be stored in Frederick and then batched and 
shipped to Gilead Sciences or a contract laboratory. 


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8 Potential Risks and Benefits 
 
Potential Risks 
F/TAF: TAF has been given experimentally to more than 1,000 subjects, including individuals 
with both HIV infection and renal insufficiency. Single and multiple doses of the F/TAF 
combination or FTC+TAF were generally well tolerated in healthy subjects. Most AEs were mild 
in severity and considered unrelated to the study drug. A serious adverse event (SAE) of 
spontaneous abortion was reported during one study and was considered related to the drug by 
the investigator. The most commonly reported AEs were headache, diarrhea, nausea and upper 
respiratory tract infection, with ≥10% of subjects experiencing one or more of these events. 
Vomiting, abdominal pain, dyspepsia, flatulence, rash, and fatigue were less common (≥1% and 
<10%). 
Older NRTIs such as didanosine, stavudine and didanosine had been associated with 
mitochondrial toxicities manifested as lactic acidosis and severe hepatomegaly with steatosis. 
These events are seldom reported with newer NRTIs such as ABC or TDF, and has not been 
reported with F/TAF to date. Treatment with F/TAF should be suspended in patients who 
develop clinical or laboratory findings suggestive of lactic acidosis. Upon initiation of effective 
ART, patients with severe immunodeficiency have experienced immune reconstitution 
syndrome manifesting as inflammatory reactions such as cytomegalovirus retinitis, generalized 
and/or focal mycobacterial infections, or Pneumocystis jiroveci pneumonia.  
F/TAF in HIV/HBV co-infected subjects: Hepatitis flare, defined as an abrupt rise in serum 
ALT to >5 times upper limit of normal may occur after initiation or discontinuation of HBV 
treatment, or may occur spontaneously. The clinical presentation varies from asymptomatic to 
acute hepatitis to hepatic decompensation. Patients with positive HBeAg are at higher risk of 
flares.20  In a study of a TDF-containing regimen as treatment for chronic hepatitis B-
monoinfected patients, 6% of 426 subjects had hepatitis flare, nearly all in the first 2 months of 
treatment.21 In HIV/HBV co-infected patients who are typically treated with nucleo(t)side therapy 
active against both HBV and HIV, immune reconstitution from HIV viral suppression may also 
lead to hepatitis flare. In one study, hepatitis flare was reported in 1 of 10 patients who received 
a combination of lamivudine and TDF and in 2 of 10 patients who received TDF alone.22  
 
HBV-coinfected subjects who experience hepatitis flare or who discontinue F/TAF will be 
managed as described in Section 7.1. 
 
Bone mineral density test (DEXA scan): The total amount of radiation exposure from 3 DEXA 
scans is 0.00024 rem for adults or 0.00012 rem for children (<18 years). The radiation exposure 
in this study is below the limits set for research subjects by the NIH Radiation Safety 
Committee. These limits are 5 rem per year for adults and 0.5 rem per year for children. There 
is no direct evidence that radiation exposure at this level is harmful, but, as with all radiation 
exposure, there may be a very slight increase in the risk of cancer. The average person in the 
United States receives a radiation exposure of 0.3 rem per year from natural sources, such as 
the sun, outer space, and the earth's air and soil. A copy of the pamphlet, “An Introduction to 
Radiation for NIH Research Subjects”, will be provided to patients upon request. If a subject 


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becomes pregnant during enrollment, protocol-specified DEXA scan will be postponed until after 
delivery. 
 
Phlebotomy: The risks associated with phlebotomy include discomfort, bruising, local 
hematoma formation and, on rare occasions, lightheadedness, fainting, and infection at the 
puncture site. The amount of blood drawn for research purposes will be within the limits allowed 
for adult and pediatric subjects at the NIH CC (Medical Administrative Policy 95-9: Guidelines 
for Limits of Blood Drawn for Research Purposes in the Clinical Center: http://cc-
internal.cc.nih.gov/policies/PDF/M95-9.pdf). 
 
HLA typing and other genetic testing: Some HLA types have been associated with an 
increased risk of certain diseases like arthritis and other rheumatologic disorders, or a faster 
progression to AIDS. The presence of the HLA B*5701 allele has been associated with 
hypersensitivity reactions to abacavir, an HIV NRTI.23 Results from this test will guide the team 
regarding whether or not abacavir can be prescribed to a specific patient. Results from the HLA 
typing will become part of each patient’s medical record at the NIH. Medical records containing 
this information are maintained in a secure place.  
 
Other genetic testing may be performed on stored samples in the future to identify genetic 
components related to HIV-1 pathogenesis and virologic failure. Results from genetic testing 
may have psychological implications for patients, such as revelations about future health risks, 
incurable conditions, and/or information contradictory to stated biological relationships. Genetic 
counseling and advice is available from the NIH to help patients understand the implications of 
these findings, if necessary. All information relating to the participant’s genetic testing will be 
stored and maintained in a secure database (CRIMSON).  
 
Following the genetic testing, data will be shared in a controlled-access public database in 
accordance with NIH guidelines, for other investigators to benefit from the information (eg, the 
Database of Genotypes and Phenotypes or dbGaP). However, no personal, identifiable 
information will be shared in this process, as the results will only be shared with a code.  
 
Inpatient admission for DOT: Patients may become bored and restless during their inpatient 
stay. Patients will have access to game rooms, television, wireless internet access, patient 
library, and a fitness center. They may receive visitors and request a pass to leave during the 
day. 
 
Potential Benefits 
There is no guarantee that patients will benefit from participating in this study. Along with F/TAF, 
patients will receive an individualized ART plan designed to achieve optimal HIV suppression. If 
sustained viral suppression can be achieved, it may prevent further disease progression or 
further emergence of new resistance associated mutations. 


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9 Research Use of Stored Human Samples, Specimens or Data 
Intended use: PBMCs, serum, and plasma samples, and data collected under this protocol 
may be used to further study the pathogenesis of HIV infection, including virologic and 
immunologic studies in this population. HLA testing will be performed at baseline, unless such 
testing results are available from participation in other NIAID studies. Other genetic testing may 
be performed from stored samples for research purposes only. For any other research or 
experimental treatments done under this or other protocols, IRB permission will be obtained. 
In the future, other investigators (both at the NIH and outside) may wish to study the samples 
and/or data. In that case, IRB approval must be sought prior to any sharing of samples and/or 
data. Any clinical information shared about the sample would similarly require prior IRB 
approval. 
Storage: Access to stored samples will be limited using a locked room or a locked freezer. 
Samples and data will be stored using codes assigned by the investigators. Data will be kept in 
password-protected computers. Only investigators will have access to the samples and data.  
Tracking: Samples will be tracked utilizing the repository operated by Leidos Biomedical 
Research, Inc. Data will be stored and maintained in the CRIMSON database. 
Disposition at the completion of the protocol: At the completion of the protocol (termination), 
samples and data will either be destroyed, or after IRB approval, transferred to another existing 
protocol.  
• 
In the future, other investigators (both at NIH and outside) may wish to study these samples 
and/or data. In that case, IRB approval must be sought prior to sharing any coded samples 
and/or data. Any clinical information shared about the sample would similarly require prior 
IRB approval.  
• 
At the completion of the protocol (termination), samples and data will either be destroyed, or 
after IRB approval, transferred to another existing protocol.  
 
Reporting the loss or destruction of samples/specimens/data to the IRB: 
• 
Any loss or unanticipated destruction of the samples or data (for example, due to freezer 
malfunction) that meets the NIH Intramural protocol violation definition or results in a 
violation that compromises the scientific integrity of the data collected for the study will be 
reported to the NCI IRB.  
• 
Additionally, subjects may decide at any point not to have their samples stored. In that case, 
the PI will destroy all known remaining samples and report what was done to the subject 
and the IRB. This decision will affect the subject’s participation in this protocol, but it may not 
affect participation in other protocols at the NIH.  
10 Assessment of Safety 
 
Definitions  
Adverse Event: An AE is any untoward or unfavorable medical occurrence in a human subject, 
including any abnormal sign (eg, abnormal physical exam or laboratory finding), symptom, or 


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disease, temporally associated with the subject’s participation in the research, whether or not 
considered related to the research. 
 
Adverse Reaction (AR): An AE that is caused by an investigational agent (drug or biologic). 
 
Suspected Adverse Reaction (SAR): An AE for which there is a reasonable possibility that the 
investigational agent caused the AE. ‘Reasonable possibility’ means that there is evidence to 
suggest a causal relationship between the drug and the AE. An SAR implies a lesser degree of 
certainty about causality than AR, which implies a high degree of certainty. 
 
Serious Adverse Event: An SAE is an AE that results in one or more of the following outcomes: 
• 
death 
• 
a life threatening event (places the subject at immediate risk of death from the event as it 
occurred)  
• 
an inpatient hospitalization (other than protocol specified DOT) or prolongation of an existing 
hospitalization 
• 
a persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions 
• 
a congenital anomaly/birth defect 
• 
a medically important event* 
 
* Medical and scientific judgment should be exercised in deciding events that may not be 
immediately life threatening or result in death or hospitalization but may jeopardize the subject 
or may require intervention to prevent one of the other outcomes listed above.  
 
Unexpected Adverse Event: An AE is unexpected if it is not listed in the Investigator’s 
Brochure or Package Insert (for marketed products) or is not listed at the specificity or severity 
that has been observed. It is the responsibility of the IND Sponsor to make this determination. 
 
Serious and Unexpected Suspected Adverse Reaction (SUSAR): A SUSAR is a SAR that is 
both Serious and Unexpected. 
 
Unanticipated Problem (UP): A UP is any event, incident, experience, or outcome that is 
 
1.  unexpected in terms of nature, severity, or frequency in relation to 
a. the research risks that are described in the IRB-approved research protocol and 
informed consent document; Investigator’s Brochure or other study documents; and 
b. the characteristics of the subject population being studied; and 
2. possibly, probably, or definitely related to participation in the research; and 
3. places subjects or others at a greater risk of harm (including physical, psychological, 
economic, or social harm) than was previously known or recognized. (Per the IND Sponsor, 
an AE with a serious outcome will be considered increased risk.) 
 
Unanticipated Problem that is not an Adverse Event (UPnonAE): A UP that does not fit the 
definition of an AE, but which may, in the opinion of the investigator, involve risk to the subject, 
affect others in the research study, or significantly impact the integrity of research data. Such 


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events would be considered a non-serious UP. For example, we will report occurrences of 
breaches of confidentiality, accidental destruction of study records, or unaccounted-for study 
drug. 
 
Protocol Deviation: Any change, divergence, or departure from the IRB-approved study 
procedures in a research protocol. Protocol deviations are designated as serious or non-serious 
and further characterized as 
 
1. Those that occur because a member of the research team deviates from the protocol. 
2. Those that are identified before they occur, but cannot be prevented. 
3. Those that are discovered after they occur 
 
Serious Protocol Deviation: A deviation that meets the definition of a SAE or compromises the 
safety, welfare or rights of subjects or others. 
 
Non-compliance: The failure to comply with applicable NIH Human Research Protection 
Program (HRPP) policies, IRB requirements, or regulatory requirements for the protection of 
human subjects. Non-compliance is further characterized as 
1. 
Serious: Non-compliance that 
a. Increases risks, or causes harm, to participants 
b. Decreases potential benefits to participants 
c. Compromises the integrity of the NIH-HRPP 
d. Invalidates the study data 
2. 
Continuing: Non-compliance that is recurring 
3. 
Minor: Non-compliance that is neither serious nor continuing 
 
Documenting, Recording, and Reporting Adverse Events 
All AEs occurring from the time the informed consent is signed through the final study visit will 
be documented, recorded, and reported. 
 
At each contact with the subject, information regarding AEs will be elicited by appropriate 
questioning and examinations and will be:  
• 
immediately documented in the subject’s medical record/source document, 
• 
recorded in CRIMSON, and 
• 
reported as outlined below (eg, IND Sponsor, IRB, and FDA). 
 
If a diagnosis is clinically evident (or subsequently determined), the diagnosis rather than the 
individual signs and symptoms or lab abnormalities will be recorded as the AE. 
 
A laboratory abnormality will not be reported as an AE if ALL of the following criteria are met: 
• It is no more than “Grade 1” or “Mild” per the protocol specified toxicity table (or 
investigator assessment if not listed on the table); AND 
• It does NOT require an intervention (eg, discontinuation of treatment, dose 
reduction/delay, additional assessments, or treatment); AND 
• It is assessed by the PI as NOT related to the study agent(s); AND 
• It is assessed by the PI as NOT clinically significant (eg, the abnormal value does 


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NOT suggest a disease or organ toxicity) 
 
All abnormal laboratory findings will be reviewed on a routine basis by the PI to identify potential 
safety signals. An abnormal lab not included on the toxicity table should be assessed in a 
similar fashion to the criteria above. 
 
Investigator Assessment of Adverse Events 
The Investigator will assess all AEs with respect to Seriousness (criteria listed above), 
Severity (intensity or grade), and Causality (relationship to study agent and relationship to 
research) according to the following guidelines.  
 
Severity 
The Investigator will grade the severity of each AE according to the “Division of Aids Table for 
Grading the Severity of Adult and Pediatric Adverse Events” Version 2.0, November 2014 which 
can be found at: http://rsc.tech-
res.com/Document/safetyandpharmacovigilance/DAIDS_AE_Grading_Table_v2_NOV2014.pdf 
 
Some Grade 1 lab parameters on the DAIDS Toxicity Table (Fibrinogen, Potassium (low), Uric 
Acid (males only, elevated)) fall within the NIH lab reference range for normal values. These 
normal values will not be reported as Grade 1 AEs. The Grade 1 values for these tests will be 
reported as follows: 
• 
Fibrinogen: 100-176 mg/dL 
• 
Potassium (low): 3.0-3.3 mmol/L 
• 
Uric Acid (males): 8.7-10.0 mg/dL  
 
Causality   
Causality (likelihood that the event is caused by the study agent(s)) will be assessed 
considering the factors listed under the following categories:  
 
Definitely Related 
  
• 
reasonable temporal relationship 
• 
follows a known response pattern 
• 
clear evidence to suggest a causal relationship 
• 
there is no alternative etiology 
 
Probably Related 
 
• 
reasonable temporal relationship 
• 
follows a suspected response pattern (based on similar agents) 
• 
no evidence of a more likely alternative etiology 
 
Possibly Related 
 
• 
reasonable temporal relationship 
• 
little evidence for a more likely alternative etiology 
 
Unlikely Related 
 
• 
does not have a reasonable temporal relationship  
OR 
• 
good evidence for a more likely alternative etiology 


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Not Related 
 
• 
does not have a temporal relationship 
OR 
• 
definitely due to an alternative etiology 
 
Note: Other factors (eg, dechallenge, rechallenge) should also be considered for 
each causality category when appropriate. Causality assessment is based on 
available information at the time of the assessment of the AE. The investigator may 
revise the causality assessment as additional information becomes available. 
 
Investigator Reporting Responsibilities to the Sponsor  
 
Adverse Events 
AE data will be submitted to the IND Sponsor when requested for periodic safety assessments, 
review of IND annual reports, review of IND safety reports, and preparation of final study 
reports. 
 
Serious Adverse Events 
All SAEs (regardless of relationship and whether or not they are also UPs) must be reported on 
the Safety Expedited Report Form (SERF) and sent to the Clinical Safety Office (CSO) by fax or 
e-mail attachment. Deaths and immediately life threatening SAEs must be reported to the CSO 
within 1 business day after the site becomes aware of the event. All other SAEs must be 
reported within 3 business days of site awareness.  
 
Clinical Safety Office contact information: 
 
Clinical Safety Office 
5705 Industry Lane 
Frederick, MD 21704 
 
Phone 301-846-5301 
Fax 301-846-6224 
E-mail: rchspsafety@mail.nih.gov 
 
SAEs that have not resolved by the final study visit are followed until final outcome is known. If it 
is not possible to obtain a final outcome for an SAE (eg, the subject is lost to follow-up), the 
reason a final outcome could not be obtained will be recorded by the investigator on the AE 
CRF and the SERF.  
 
SAEs that occur after the final study visit that are reported to and are assessed by the 
investigator to be possibly, probably, or definitely related to study drug must be reported to the 
CSO. 
 
Unanticipated Problems 
Unanticipated Problems that are also AEs must be reported to the CSO by fax or e-mail 
attachment no later than 7 calendar days of site awareness of the event. UPs that are not AEs 


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are not reported to the CSO. Report UPs that are also AEs to the CSO on a SERF or IRB UP 
form. 
 
Pregnancy  
All pregnancies will be reported on the Pregnancy Notification/Outcome Form to the CSO within 
1 business day of site awareness.  
 
Pregnancy outcome data (eg, delivery outcome, spontaneous or elective termination of the 
pregnancy) will be reported to the CSO within 3 business days of the site’s awareness.  
 
Although pregnancy itself is not an AE, events that meet SAE criteria during pregnancy, 
delivery, or in the neonate (eg, congenital anomaly/birth defect) are reportable on the SERF.  
 
In the event of pregnancy, the subject may continue study participation. The research subject 
will be advised to notify her obstetrician of study participation and study agent exposure. 
 
Investigator Reporting Procedures to the IRB  
 
National Cancer Institute IRB Expedited Reporting of Unanticipated Problems 
and Deaths 
The protocol PI will report to the NCI IRB: 
• 
All deaths, except deaths due to progressive disease.  
• 
All protocol deviations (except for visits outside of the protocol schedule window). 
• 
All UPs. 
• 
All serious non-compliance.  
 
Reports must be received by the NCI IRB via the Integrated Research Information System 
(iRIS) within 7 working days of the PI’s awareness of the events. 
 
National Cancer Institute IRB Requirements for Principal Investigator Reporting 
at Continuing Review 
The protocol PI will report the following to the NCI IRB: 
1. A summary of all protocol deviations in a tabular format to include the date the 
deviation occurred, a brief description of the deviation, and any corrective action. 
2. A summary of any instances of non-compliance. 
3. A tabular summary of the following AEs: 
• All Grade 2 unexpected events that are possibly, probably, or definitely related 
to the research. 
• All Grade 3 and 4 events that are possibly, probably, or definitely related to the 
research. 
• All Grade 5 events regardless of attribution. 
• All SAEs regardless of attribution.  
NOTE: Grade 1 events are not required to be reported.  


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Sponsor’s Reporting Responsibilities 
Serious and unexpected suspected adverse reactions (SUSARs) as defined in 21 CFR 312.32 
and determined by the IND Sponsor will be reported to FDA and all participating investigators as 
IND Safety Reports.  
 
The IND Sponsor will also submit an IND Annual Report of the progress of the investigation to 
the FDA as defined in 21 CFR 312.33.  
 
Pausing Rules for an Individual Subject 
Pausing is the suspension of administration of study agent to a single subject until a decision is 
made whether or not to resume administration of the study agent. 
 
The pausing criteria for a single subject in this study include any of the following:  
• 
A subject experiences an SAE that is unexpected and possibly, probably, or definitely 
related to a study agent;  
• 
A subject experiences (2) Grade 3 or greater AEs (not including total bilirubin in subjects 
taking atazanavir) that are unexpected and possibly, probably, or definitely related to a study 
agent;  
• 
Any safety issue that the site investigator determines should pause administration of a study 
agent to a single subject. 
 
The CSO, in collaboration with the PI, may also pause for an entire group if a safety concern is 
identified. 
 
Reporting a Pause  
If a pausing criteria is met, a description of the AE(s) or safety issue must be reported by the PI, 
within 1 business day, to the CSO, the IRB, and Gilead Sciences, Inc. by fax or email. 
 
Resumption of a Paused Study  
The CSO in collaboration with the PI will determine whether or not it is safe to resume 
administration of the study agent to the subject. The PI will notify the IRB and Gilead Sciences 
Inc. of the decision on resumption of the study agent. 
10.7.2.1 
Discontinuation of Study Agent 
A subject who does not resume study agent will continue to be followed for safety.  
 
Halting Rules 
Halting the study requires immediate discontinuation of study agent administered for all subjects 
and suspension of enrollment until a decision is made whether or not to continue enrollment and 
study agent administration.  
 
The halting rules are: 
• 
Two or more subjects experience the same or similar SAEs that are unexpected and are 
possibly, probably, or definitely related to the study agent  
OR 


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• 
Three or more of the same or similar AE in different subjects that are grade 3 or above and 
are unexpected and possibly, probably, or definitely related to the study agent  
OR 
• 
Any safety issue that the PI, Gilead Sciences, Inc and/or the CSO determines should halt 
the study  
 
The PI, Gilead Sciences Inc, and/or CSO will determine if the study should be halted. In 
addition, the FDA may halt the study at any time following review of any safety concerns. A local 
IRB may halt the study at their site.  
 
Reporting a Study Halt 
If a halting rule is met, a description of the AE(s) or safety issue must be reported by the PI, 
within one business day, to the CSO, the IRB, and Gilead Sciences, Inc. by fax or email.  The 
fax or email should specify in the Subject Line that a halting rule has been met with the study 
name or number. 
 
Resumption of a Halted Study 
The IND Sponsor, in collaboration with the PI will determine if it is safe to resume the study. The 
PI will notify the IRB of the decision on resumption of the study.  
 
Discontinuation of Study Agent 
Subjects who do not resume study agent will continue to be followed for safety. 
 
Withdrawal Criteria for an Individual Subject 
An individual subject will be withdrawn for any of the following:  
• 
An individual subject’s decision. (The investigator should attempt to determine the reason 
for the subject’s decision.)  
• 
Non-compliance with study procedures to the extent that it is potentially harmful to the 
subject or to the integrity of the study data. 
• 
The investigator determines that continued participation in the study would not be in the best 
interest of the subject. 
 
Replacement of Withdrawn Subjects or Subjects Who Discontinue F/TAF 
Subjects who withdraw will continue to be followed and included in safety assessments. No 
replacement of subjects will be necessary. 
 Safety Oversight 
 Safety Review and Communications Plan (SRCP) 
A Safety Review and Communication Plan (SRCP) has been developed for the protocol. The 
SRCP is an internal communications document between the PI and the CSO, which delineates 
the safety oversight responsibilities of the PI, the CSO, and other stakeholders. The SRCP also 
includes the overall plan for conducting periodic safety surveillance assessments.  


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 Sponsor Medical Monitor (SMM) 
A Medical Monitor, representing the IND Sponsor (OCRPRO), has been appointed for oversight 
of safety in this clinical study. The SMM will be responsible for performing safety assessments 
as outlined in a Safety Review and Communications Plan (SRCP).  
11 Clinical Monitoring Structure 
 
Site Monitoring Plan  
As per International Conference on Harmonization (ICH) Good Clinical Practice (GCP) 5.18 
FDA 21 CFR 312.50, if under IND, clinical protocols are required to be adequately monitored by 
the study sponsor. This study monitoring will be conducted according to the “NIAID Intramural 
Clinical Monitoring Guidelines”. Monitors under contract to the NIAID/OCRPRO will visit the 
clinical research site to monitor aspects of the study in accordance with the appropriate 
regulations and the approved protocol. The objectives of a monitoring visit will be: 1) to verify 
the existence of signed informed consent documents and documentation of the ICF process for 
each monitored subject; 2) to verify the prompt and accurate recording of all monitored data 
points, and prompt reporting of all SAEs; 3) to compare abstracted information or CRIMSON 
data abstracts with individual subjects’ records and source documents (subjects’ charts, 
laboratory analyses and test results, physicians’ progress notes, nurses’ notes, and any other 
relevant original subject information); and 4) to help ensure investigators’ are in compliance with 
the protocol. The monitors also will inspect the clinical site regulatory files to ensure that 
regulatory requirements (Office for Human Research Protections-OHRP), the FDA, and 
applicable guidelines (ICH-GCP) are being followed. During the monitoring visits, the 
investigator (and/or designee) and other study personnel will be available to discuss the study 
progress and monitoring visit. 
 
The investigator (and/or designee) will make the study documents (eg, consent forms, 
CRIMSON data abstracts, and pertinent hospital or clinical records readily available for 
inspection by the local IRB, the FDA, the site monitors, and the NIAID staff for confirmation of 
the study data.  
 
A specific protocol monitoring plan will be discussed with the principal investigator and study 
staff prior to enrollment. The plan will outline the frequency of the monitoring visits based on 
factors such as the study enrollment, data collection status, and regulatory obligations.  
12 Statistical Considerations 
 
Description of the Analyses 
The primary outcome is the change in log10HIV RNAfrom baseline to day 10, analyzed using a 
one-sample t-statistic if the data are not skewed.  The estimated change will then be expressed 
in terms of a confidence interval for the percentage change from baseline.  If changes from 
baseline appear skewed, we will use a Wilcoxon signed rank test instead of a t-test. Similar 
analyses will be applied for changes from baseline in other continuous outcomes. The 


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proportion of patients with HIV RNA ≥0.5 log10 decline on day 10 will be computed, along with 
an exact 95% confidence interval using the binomial distribution.   
A secondary analysis will fit a mixed model to log10HIV RNA data across multiple time points.  
The model will include subject-specific random effects for intercepts, slopes, and quadratic 
terms. 
Power calculations are problematic because it is difficult to estimate the standard deviation of 1-
week change in log viral load for these patients.  The most similar trial was Akil et al, but their 
reported standard deviation of change was after adjusting for several factors.24  The standard 
deviation of a raw change is likely to be substantially larger than their reported value of 0.18.  If 
we assume a standard deviation of change of 0.50, a sample size of 20 participants provides 
90% and 80% power to detect changes from baseline approximately equal to 0.38 and 0.33 
logs, respectively.  These are large effects, but much smaller than those observed in Akil et al 
(2014). 
13 Ethics/Protection of Human Subjects 
 
Informed Consent Process 
Informed consent is a process where information is presented to enable persons to decide 
voluntarily whether or not to participate as a research subject. It is an ongoing conversation 
between the human research subject and the researchers, which begins before consent is given 
and continues until the end of the subject's involvement in the research. Discussions about the 
research will provide essential information about the study and include: purpose, duration, 
experimental procedures, alternatives, risks, and benefits. Subjects will be given the opportunity 
to ask questions and have their questions answered.  
 
Subjects will sign the informed consent document prior to undergoing any study procedures. 
The subjects may withdraw consent at any time throughout the course of the trial. A copy of the 
informed consent document will be given to the subjects for their records. The researcher will 
document the process of signing the consent form in the subject’s medical record. The rights 
and welfare of the subjects will be protected by emphasizing to them that the quality of their 
medical care will not be adversely affected if they decline to participate in this study.  
 
Assent or Informed Consent Process (in Case of a Minor) 
Assent forms will be used for all study subjects ≥14 years to <18 years of age who are capable 
to give their assent to participate. Parental consent will be obtained for all study subjects under 
the age of 18. Study subjects <18 years will be contacted after they have reached the age of 18 
to determine whether they wish to continue on the trial and informed consent will be obtained 
from them at that time. 
 
Non-English–Speaking Participants 
If a non-English speaking participant is unexpectedly eligible for enrollment, the participant will 
be provided with the CC Short Written Consent Form for Non-English Speaking Research 
Participants in the participant’s native language and a verbal explanation of the purpose, 
procedures and risks of the study as described in MAS Policy M77-2, NIH HRPP SOP 12 and 


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45 CFR 46.117(b)(2). The IRB-approved English consent form will serve as basis for the verbal 
explanation of the study. The investigator will obtain an interpreter unless the investigator is 
fluent in the prospective participant’s language. Preferably, the interpreter will be someone who 
is independent of the participant (ie, not a family member). Interpreters provided by the CC will 
be used whenever possible. The interpreters will translate the IRB-approved English consent 
form verbatim and facilitate discussion between the participant and investigator. 
The IRB-approved English consent form will be signed by the investigator obtaining consent and 
a witness to the oral presentation. The CC Short Written Consent Form will be signed by the 
participant and a witness who observed the presentation of information. The interpreter may 
sign the consent document as the witness and, in this case, will note “Interpreter” under the 
signature line. A copy of both signed forms will be provided to the participant to take home. 
The investigator obtaining consent will document the consent process in the participant’s 
medical record (CRIMSON), including the name of the interpreter. Further, all instances of use 
of the CC Short Written Consent Form will be reported to the IRB at the time of annual review. If 
the CC Short Written Consent Form is used three times or more for the same language, this will 
be reported to the IRB immediately. 
 
Subject Confidentiality 
All records will be kept confidential to the extent provided by federal, state, and local law. The 
study monitors and other authorized representatives of the sponsor may inspect all documents 
and records required to be maintained by the investigator, including, but not limited to, medical 
records. Records will be kept locked and all computer entry and networking programs will be 
done with coded numbers only. Clinical information will not be released without written 
permission of the subject, except as necessary for monitoring by the NCI IRB, NIAID, or Office 
for Human Research Protections. 
14 Data Handling and Record Keeping 
 
Data Capture and Management 
Study data will be maintained in CRIMSON and CRIS (Clinical Research Information System), 
and collected directly from subjects during study visits and telephone calls, or they will be 
abstracted from subjects’ medical records. Source documents include all recordings of 
observations or notations of clinical activities and all reports and records necessary to confirm 
the data abstracted for this study. Data entry into CRIMSON will be performed by authorized 
individuals. The PI is responsible for assuring that all the data collected are complete, accurate, 
and recorded in a timely manner. Any outside medical records pertinent to protocol participation 
will be uploaded into the CRIMSON repository (also known as CRIMSON Cloud). 
 
Record Retention 
The investigator is responsible for retaining all essential documents listed in the International 
Conference on Harmonization Good Clinical Practice Guidelines. Study records will be 
maintained by the PI for a minimum of 3 years or in compliance with institutional, IRB, state, and 
federal medical records retention requirements, whichever is longest. All stored records will be 
kept confidential to the extent required by federal, state, and local law. 


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Should the PI wish to assign the study records to another party and/or move them to another 
location, he/she must provide written notification of such intent to NIAID/OCRPRO with the 
name of the person who will accept responsibility for the transferred records and/or their new 
location. Destruction or relocation of research records will not proceed without written 
permission from NIAID/OCRPRO. 


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Appendix A: Scientific References 
1. 
Dombrowski JC, Kitahata MM, Van Rompaey SE, et al. High levels of antiretroviral use and 
viral suppression among persons in HIV care in the United States, 2010. Journal of acquired immune 
deficiency syndromes 2013;63:299-306. 
2. 
Paquet AC, Solberg OD, Napolitano LA, et al. A decade of HIV-1 drug resistance in the 
United States: trends and characteristics in a large protease/reverse transcriptase and co-receptor 
tropism database from 2003 to 2012. Antiviral therapy 2014;19:435-41. 
3. 
Deeks SG, Gange SJ, Kitahata MM, et al. Trends in multidrug treatment failure and 
subsequent mortality among antiretroviral therapy-experienced patients with HIV infection in North 
America. Clinical infectious diseases : an official publication of the Infectious Diseases Society of 
America 2009;49:1582-90. 
4. 
Ezinga M, Wetzels JF, Bosch ME, van der Ven AJ, Burger DM. Long-term treatment with 
tenofovir: prevalence of kidney tubular dysfunction and its association with tenofovir plasma 
concentration. Antiviral therapy 2014. 
5. 
Scherzer R, Estrella M, Li Y, et al. Association of tenofovir exposure with kidney disease risk 
in HIV infection. Aids 2012;26:867-75. 
6. 
Mateo L, Holgado S, Marinoso ML, et al. Hypophosphatemic osteomalacia induced by 
tenofovir in HIV-infected patients. Clinical rheumatology 2014. 
7. 
Calmy A, Fux CA, Norris R, et al. Low bone mineral density, renal dysfunction, and fracture 
risk in HIV infection: a cross-sectional study. The Journal of infectious diseases 2009;200:1746-54. 
8. 
Bedimo R, Maalouf NM, Zhang S, Drechsler H, Tebas P. Osteoporotic fracture risk 
associated with cumulative exposure to tenofovir and other antiretroviral agents. Aids 2012;26:825-
31. 
9. 
Wensing AM, Calvez V, Gunthard HF, et al. 2014 Update of the drug resistance mutations in 
HIV-1. Topics in antiviral medicine 2014;22:642-50. 
10. 
Wirden M, Marcelin AG, Simon A, et al. Resistance mutations before and after tenofovir 
regimen failure in HIV-1 infected patients. Journal of medical virology 2005;76:297-301. 
11. 
VIREAD - Product Information, Gilead Sciences. October 23, 2013 ed. Drugs@FDA2013. 
12. 
Ruane PJ, DeJesus E, Berger D, et al. Antiviral activity, safety, and 
pharmacokinetics/pharmacodynamics of tenofovir alafenamide as 10-day monotherapy in HIV-1-
positive adults. Journal of acquired immune deficiency syndromes 2013;63:449-55. 
13. 
Bam RA, Yant SR, Cihlar T. Tenofovir alafenamide is not a substrate for renal organic anion 
transporters (OATs) and does not exhibit OAT-dependent cytotoxicity. Antiviral therapy 2014;19:687-
92. 
14. 
Sax PE, Zolopa A, Brar I, et al. Tenofovir alafenamide vs. tenofovir disoproxil fumarate in 
single tablet regimens for initial HIV-1 therapy: a randomized phase 2 study. Journal of acquired 
immune deficiency syndromes 2014;67:52-8. 
15. 
Gilead Sciences I. Investigator's Brochure - Emtricitabine/Tenofovir Alafenamide Fixed-Dose 
Combination (F/TAF FDC)2014 19 December 2014. 
16. 
Tenofovir Alafenamide (TAF) in a Single-Tablet Regimen in Initial HIV-1 Therapy.  22nd 
Conference on Retroviruses and Opportunistic Infections. Seattle, WA2015. 
17. 
German P, Liu HC, Szwarcberg J, et al. Effect of cobicistat on glomerular filtration rate in 
subjects with normal and impaired renal function. Journal of acquired immune deficiency syndromes 
2012;61:32-40. 
18. 
Agarwal K, Fung SK, Nguyen TT, et al. Twenty-eight day safety, antiviral activity, and 
pharmacokinetics of tenofovir alafenamide for treatment of chronic hepatitis B infection. Journal of 
hepatology 2014. 
19. 
Levey AS SL, Schmid CH, Zhang YL, Castro AF 3rd, Feldman HI, Kusek JW, Eggers P, Van 
Lente F, Greene T, Coresh J; CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration). A new 
equation to estimate glomerular filtration rate. Ann Intern Med 150:604-12. 
20. 
Chang ML, Liaw YF. Hepatitis B flares in chronic hepatitis B: pathogenesis, natural course, 
and management. Journal of hepatology 2014;61:1407-17. 
21. 
Marcellin P, Heathcote EJ, Buti M, et al. Tenofovir disoproxil fumarate versus adefovir 
dipivoxil for chronic hepatitis B. The New England journal of medicine 2008;359:2442-55. 


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22. 
Crane M, Oliver B, Matthews G, et al. Immunopathogenesis of hepatic flare in HIV/hepatitis B 
virus (HBV)-coinfected individuals after the initiation of HBV-active antiretroviral therapy. The Journal 
of infectious diseases 2009;199:974-81. 
23. 
Martin AM, Nolan D, Gaudieri S, et al. Predisposition to abacavir hypersensitivity conferred 
by HLA-B*5701 and a haplotypic Hsp70-Hom variant. Proceedings of the National Academy of 
Sciences of the United States of America 2004;101:4180-5. 
24. 
Akil B, Blick G, Hagins DP, et al. Dolutegravir versus placebo in subjects harbouring HIV-1 
with integrase inhibitor resistance associated substitutions: 48-week results from VIKING-4, a 
randomized study. Antiviral therapy 2014. 


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Appendix B. Schedule of Procedures 
 
Screeningvisit 
Inpatient DOT: Day 1 to Day 10 
or Day 1 to Day 12-14 (+/-1 day)1 
Follow-up evaluations (No. of weeks after starting F/TAF plus OBT)  
Study day or week 
Day -28 to 
Day -1 
Day 
1 
Day 
3 
Day 
5 
Day 
8 
Day 
10 
Day 
12-
152 
1 week 
(+/- 2 
working 
days) 
2 
weeks 
(+/- 2 
working 
days) 
4 
weeks 
(+/- 2 
working 
days) 
8 
weeks 
(+/- 4 
working 
days) 
12 
weeks 
(+/- 1 
wk) 
24 
weeks 
(+/- 2 
wks) 
36 
weeks 
(+/- 2 
wks)  
48 
weeks 
(+/- 2 
wks) 
Procedures 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test3 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Physical exam, 
medical/social history 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Medication history 
X 
 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Adherence 
assessment/counseling 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Urine renal function 
assessments4 
 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Urinary retinol-binding 
protein (Gilead) 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
DEXA scan5 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
X 
Adverse event 
monitoring 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Evaluation of Day 10 
HIV RNA results 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
Blood evaluations 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV-1 serology6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis serology7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Genotypic +/- 
phenotypic resistance 
testing8 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 


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41 
 
HLA B*5701 
screening6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Plasma HIV RNA 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
HBV DNA9 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Hepatitis B ‘e’ antigen9 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CD4 T cell count 
X 
X 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
CBC with differential 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Acute care, mineral, 
hepatic panels 
X 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Cystatin C 
X 
X 
 
 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
1If the same laboratory evaluations are conducted under DOTCOM within the visit window, they will not be repeated. 
2Patients who do not have a ≥0.5 log10 decline in HIV RNA after 9 days of F/TAF + failing regimen will be prescribed a regimen change on Day 12-15 (to include and TDF/FTC or 
ABC/3TC instead of F/TAF, as appropriate) and their study participation will end. They will continue to be followed under the DOTCOM protocol   
3Women of childbearing potential 
4Renal function assessment: creatinine, cystatin C, phosphorus, and calculated eGFR 
5Will not be perfomed if patient is pregnant 
6Will not be repeated if available in CRIMSON database or from outside medical records, documentation of HIV RNA >1000 copies/mL x 2 can be used in place of HIV-1 serology 
7Antibody to hepatitis A (anti-HAV), hepatitis B surface antigen (HbsAg), antibody to HBsAg (anti-HBs), antibody to hepatitis B core antigen (anti-HBc), anti-HCV (antibody to HCV). 
Will not be repeated if available in CRIMSON or CRIS. 
8All patients at baseline. Patients with HIV RNA >500 copies/mL at time points after 12 weeks 
9Patients with documented HBsAg (+)