Clinical trial NCT01295515
Conditions: HIV Infection
Keywords: HIV Replication Antiretroviral Interferon Reservoirs
Sponsor: National Cancer Institute (NCI)
Start date: 2011-02-11; Completion date: 2017-05-31
Enrollment: 7 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
Background:

* Antiretroviral therapy (ART) has been able to improve the lifespan of individuals infected with human immunodeficiency virus type 1 (HIV-1), but ART requires continuous treatment that has substantial consequences on quality of life. Recent research is attempting to determine whether this persistent infection stems from a low-level infection where new cells are continually infected with HIV, or from cells that live for a long time after infection. ART is very active against the virus in new cells, but has no effect on long-lived cells that are already infected with HIV-1 at the start of ART. As a result, new strategies may be necessary to reduce or eradicate these 'reservoir' cells.
* Interferon is a natural substance made by the body to combat virus infections, and can be made as an injectable drug known as PEGINTRON. Researchers are interested in determining whether PEGINTRON therapy will also reduce the residual low levels of HIV in patients who are already taking ART.

Objectives:

\- To evaluate the effectiveness of PEGINTRON injections on HIV levels in participants currently undergoing antiretroviral therapy.

Eligibility:

\- Individuals at least 18 years of age who have been diagnosed with HIV, are currently undergoing antiretroviral therapy, and have maintained HIV virus blood counts that are not detectable by current commercial tests for at least 12 months before the start of the study.

Design:

* This study will involve separate screening and treatment processes.
* Participants will be screened with a physical examination and medical history, including blood and urine samples. The screening analysis to determine study eligibility will take several weeks. Participants will have apheresis to provide sufficient numbers of blood cells for evaluation by the study researchers.
* Eligible participants will begin a 4-week course of PEGINTRON injections using the standard dose of PEGINTRON that is approved for treatment of chronic hepatitis C. Participants will have weekly injections and have frequent blood tests to measure HIV virus levels.
* Participants who experience problems in maintaining safe numbers of white blood cells during the study may receive injections of filgrastim to increase their white blood cell count.
* After the 4 weeks of treatment, participants will return for additional blood tests on study days 28, 35, 42, 49, 56, and 84, and Weeks 16, 24, 36, and 48 (i.e., through the end of 1 year after the start of the study).

Detailed description:
As a result of combination antiretroviral therapy (ART), morbidity and mortality from acquired immunodeficiency syndrome has declined significantly in the past 15 years, at least in developed countries. Human immunodeficiency virus type 1 (HIV-1) infected individuals now live longer, but must undergo continuous therapy that has substantial consequences on quality of life.

ART suppresses HIV-1 viremia below the limits of detection in current commercial assays (c. 50 copies/mL plasma), but HIV viremia persists even after prolonged suppressive therapy. The origin of this residual viremia is yet not clear, but data suggest that production from long lived HIV infected cells may contribute to viremia.

Antiretrovirals are extremely active against replicating cells, and can thus successfully stop viral replication, but have no effect on long-lived viral reservoirs of cells already infected with HIV-1 at the time antiretroviral therapy is initiated. As a result, new strategies are necessary to reduce or eradicate long-lived reservoirs.

Interferon alpha is a natural cytokine with antiviral activity. Prior to the introduction of antiretroviral therapy, several studies demonstrated modest effect of interferon alpha in HIV-1 viremia in active cycles of infection in infected individuals. Interferon alpha was also effective in vitro in decreasing virus production from cells chronically infected with HIV-1. With the introduction of potent antiretroviral therapy, interferon was not developed as a direct anti-HIV drug. Interferon alpha is relatively effective in therapy of hepatitis C virus (HCV) infection, and has been used in HIV-1/HCV coinfected individuals. Kottilil and coworkers in the Laboratory of Immunoregulation National Institute of Allergy and Infectious Diseases (NIAID) have shown a decrease in HIV-1 ribonucleic acid (RNA) levels in HCV coinfected participants treated with pegylated interferon alpha and ribavirin. In stored samples from that study, we conducted a retrospective trial on samples from participants with HIV-1 RNA levels of \<50 copies/mL, showing a further reduction in residual viremia using an ultrasensitive Single Copy Assay (SCA) developed in our laboratory. As such the effects of interferon on HIV viremia and cell associated HIV RNA are of growing interest.

In this protocol we will conduct a prospective, non-randomized, single arm, pilot study to investigate the effect of pegylated interferon alpha 2b on HIV-1 RNA levels as an additional drug in participants undergoing suppressive antiretroviral therapy with viral RNA levels suppressed to less than 50 copies/mL plasma. As patients may have levels of HIV RNA that are lower than our limit of detection, we will also investigate levels of HIV nucleic acid species in cells as well. We will determine whether interferon alpha therapy will reduce residual viremia or cell associated HIV RNA in participants on suppressive ART, which will expand our understanding of persistent low-level viremia and the pathogenesis of HIV in infected individuals.

Arms: arm 1: Interferon treatment The intervention is administration of Pegylated Interferon Alpha 2b (PEGINTRON) weekly for four weeks
Interventions: intervention 1: Pegylated Interferon Alpha 2b (PEGINTRON)
Intervention descriptions: intervention 1: pegylated preparation of interferon alpha 2b

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: 
11-I-0057 
PRINCIPAL INVESTIGATORS: Frank Maldarelli, M.D. 
 
 
STUDY TITLE: 
Effect of Interferon Alpha 2b Intensification on HIV-1 Residual Viremia in Individuals Suppressed 
on Antiretroviral Therapy 
 
 
Continuing Review Approved by the IRB on 06/15/15 
Amendment Approved by the IRB on 05/18/15 (D) 
 
 
 
Date Posted to Web:  06/24/15 
Screening 
 
 
 
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 (2) 
 
 
 
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 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 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 NIH, or with family, friends, or your personal physician or other 
health professional. 
 
Purpose of this Study 
You are invited to participate in this study because you have HIV infection and have viral loads that are suppressed 
below the limit of detection on antiretroviral therapy (ARVs). The therapy you are taking for HIV is effective in 
controlling but not curing the HIV infection. Low levels of HIV are present even when the viral load is measured below 
the limit of detection for virus (<50 copies RNA/mL plasma). The source of the small amount of HIV is unknown. It may 
come from a low-level infection, where new cells are continually infected with HIV. It is also possible that the virus is 
coming from cells that live for a long time after infection. We would like to learn more about the origin of residual HIV, 
because it will help us to understand the virus infection. We are interested in finding out whether antiviral agents other 
than the ARVs can affect the level of residual HIV in the blood. In this study we are investigating whether interferon 
alpha (Interferon, PEGINTRON, pegylated interferon alpha 2b) will affect the level of HIV viremia in individuals 


 
  
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: 
11-I-0057 
CONTINUATION:  page  2  of  6  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
suppressed on antiretroviral therapy. Interferon is a natural substance made by the body to combat viral infections. 
Interferon can also be made as an injectable drug, called pegylated interferon alpha 2b (PEGINTRON®), which has 
been approved by the FDA for use in hepatitis C infection including in patients with HIV infection. In several earlier 
studies of HIV infected individuals who were not on any antiretroviral therapy, PEGINTRON® was shown to reduce the 
level of HIV in the blood. We are doing the present study to learn whether PEGINTRON® therapy will also reduce the 
residual low levels of HIV in patients who are already taking antiretroviral therapy. In this study participants will receive 
weekly PEGINTRON injections for 4 weeks using the standard dose of PEGINTRON that is approved by the FDA for 
chronic Hepatitis C. During the study we will measure the levels of HIV in the blood using sensitive tests that can detect 
as little as 1 copy of HIV RNA in 3 milliliters of blood (about 6/10 of a teaspoon). After the 4 weeks of PEGINTRON®, 
we will obtain additional blood samples for a total of 1 year. Participants will also undergo apheresis before the first 
dose and after the last dose of PEGINTRON; apheresis is a procedure in which we obtain white blood cells.  We plan to 
study 10 individuals. 
 
 
Enrollment in the study is a two step process. In the first step, a screening analysis is performed during which we will 
perform a clinical evaluation and obtain blood samples to study. Based on this analysis, which will take several weeks, 
we will learn whether you are eligible for the study. If you are eligible, we will proceed to the second step of enrollment, 
when you will actually begin treatment with interferon for 4 weeks. 
 
Eligibility for Study 
In order for us to determine whether it would be appropriate for you to participate in this study, we will need to perform 
an initial evaluation to better understand the status of your HIV.  This will consist of 
• 
A visit to our clinic 
• 
A history and physical examination 
• 
Routine laboratory studies; pregnancy test if you are a woman of child-bearing potential 
• 
Blood to measure the amount of HIV virus in the blood using standard testing and ultralow viral load test 
• 
Blood specimens for storage 
• 
Participants considering getting a vaccine, including the seasonal influenza (flu) shot, should discuss this 
with the study team prior to getting vaccinated. 
Women of childbearing age will have a pregnancy test within 2 weeks prior to and another one on the day of the first 
dose of PEGINTRON. You should not get pregnant while participating in this study and must practice 2 different methods 
of contraception during this time. If you are pregnant, you cannot be in the study because we do not know how the study 
will affect the unborn fetus. If you are not pregnant, you will be asked to use methods of birth control during the study. 
Women must also not be breastfeeding while taking PEGINTRON®.  
 
This initial screening visit will take about 4 hours. The screening test results will help to determine if you’re likely to be 
eligible to continue in the screening process. Some people may not be able to join the study because of scientific or health 
reasons found during the screening visit(s). The final eligibility for the study will be determined after a complete 
assessment by a doctor that is usually done after the screening visit, and after we have spent enough time with you 
discussing the protocol that you understand the risks and possible benefits. If you should not become eligible, we will 
inform you and explain to you why you are not eligible for this study. 
 
If the results of your evaluation indicate that you are eligible for PEGINTRON therapy we will discuss the full protocol and 
provide an additional consent form for your consideration. At that time, we will describe the study procedures in detail.  


 
  
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: 
11-I-0057 
CONTINUATION:  page  3  of  6  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
 
Benefits 
There is no direct benefit to participation in the screening or in participating in the study itself. You will receive 
information about your health from the screening tests and physical examination. In the future, your participation may 
help us learn more about the causes, treatment, or prevention of HIV disease, immune dysfunction and/or related 
diseases. The information we obtain may help us to improve our understanding of HIV infection. We will perform the 
standard HIV viral load test, and also perform a sensitive research test for HIV. Although the research test can detect at 
low levels (1 copy/mL), this new viral load test is not approved by the FDA, and the information we obtain will not be 
used in making any clinical decisions regarding your care. 
 
Risks 
The risks from screening for this study are from the risks of blood drawing. Blood drawing is generally very well tolerated. 
Occasionally, pain from needle stick, bruising, or bleeding may take place; rarely fainting may occur. The amount of blood 
drawn will be within the limits allowed for adult subjects by the NIH Clinical Center (Medical Administrative Policy 95-9: 
Guidelines for Limits of Blood Drawn for Research Purposes in the Clinical Center). If you are eligible and choose to enroll 
in the study, there are additional risks from apheresis, from the PEGINTRON therapy, and from the combination of 
PEGINTRON with antiretrovirals and other therapy. We will describe those additional risks in detail if you elect to enroll. 
Blood samples obtained from the screening process will be stored and studied, whether you are eligible and elect to 
participate in the study or not. The potential risks of maintaining your specimens and of the studies we will perform with 
them are described below. 
 
REASONS FOR REMOVING YOU FROM THE STUDY WITHOUT YOUR CONSENT  
You may be removed from the study without your consent for the following reasons:  
• 
The NIH doctor feels that staying in the study is harmful to you  
• 
You don't keep your appointments  
• 
The study is cancelled or stopped 
 
Cost 
There will be no charge to you or your health insurance company for any of the costs which are directly related to this 
study. However, the costs of any other medical care outside of this study during this period will be your responsibility. 
 
Alternatives 
This study provides no benefit and the alternative to participating is not participating 
 
New Findings 
The results of the screening tests will be discussed with you and you will be told of any new information learned during 
the screening that may influence your general care 
 
Remuneration  
You will be reimbursed for your time and inconvenience in participating in the screening process according to standard 
NIH guidelines, $40.00 for each visit. 
 
Stored Samples and Future Research 
We may take extra blood and tissue samples and store them for future research. These samples will help us learn more 
about HIV or related conditions. In general, the research tests we perform are not like routine medical tests, and may not 
relate directly to your medical care, so we may not put future test results in your medical record. However, if you wish, 


 
  
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: 
11-I-0057 
CONTINUATION:  page  4  of  6  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
someone on the study team will discuss the test results with you. We will not share these test results with your private 
doctor unless you ask us to do so. By agreeing to participate in this study, you do not waive any rights that you have 
regarding access to and disclosure of your records. For further information on those rights, please contact Dr. Maldarelli 
(PI) at 301-435-8019. 
 
Labeling of Stored Samples 
We will label your stored samples with a code that only the study team can link to you. We will keep any information that 
can be traced back to you private to the extent permitted by law. 
 
Future Studies 
Other investigators may want to study your stored samples. If so, the NIH study team may send your samples to them, 
(along with the coded label). The study team may also share information such as your gender, age, health history, or 
ethnicity. In some cases, an Institutional Review Board (IRB) will review new research proposals that would like to use 
your samples. The IRB is a committee that oversees medical research studies to protect volunteers’ rights and welfare. 
Investigators will use your samples only for research. We will not sell them. Future research that uses your samples may 
lead to new products, but you will not receive payment for these products. Some future studies may need health 
information (such as smoking history or present health status) that we don’t already have. If so, the NIH study team will 
contact you for this information. 
 
Risks 
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.  
 
Benefits 
In general, future research that uses your samples will not help you, but it may help us learn what causes HIV or related 
immunodeficiency conditions. This research may also help us learn how to prevent or treat the condition. 
 
Making Your Choice 
If you agree to participate in this study, you agree to let us store your samples for future research. You also agree that 
we can contact you again in the future. No matter what you decide, you may still participate in other studies at NIH. 
However, your refusal to let us store your samples may lead to your withdrawal from this specific study. Even if you agree 
now to let us store your samples, you can change your mind later. If you do, please contact us and say that you do not 
want us to use your samples for future research. 
 
Genetic Testing 
Some of the blood drawn from you as part of this study will be used for genetic tests, including HLA tests, which is a 
genetic test of markers of the immune system. Genetic tests can help researchers study how health or illness is passed on 
to you by your parents or from you to your children. HLA is usually used to match bone marrow or organ transplants. For 
research, HLA testing might be used to try to identify factors associated with the progression of disease or related 
conditions. In addition, determining HLA type is necessary to be able to perform certain research studies. Some HLA types 
have been associated with an increased risk of certain diseases like arthritis and other rheumatologic problems. However, 
simply having those HLA types doesn’t mean you will develop these diseases. 
 
Some things to consider in thinking about whether or not to participate in these genetic studies include the possible 
effects on your emotional well being. In other words, how might you feel about yourself and your life if you learn 
information about risks that could affect your own health or that of your children? There may be no treatment for certain 


 
  
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: 
11-I-0057 
CONTINUATION:  page  5  of  6  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
conditions and this may cause some individuals to feel anxious, depressed, or stressed. Additional genetics counseling and 
advice is available from the National Institutes of Health to help you understand the nature and implications of findings 
about you and your family. 
 
Also, relationships with other family members may be affected by finding out risks they have but did not want to know. 
An example would be if your children, brothers, or sisters find out they have risks for health problems because of 
information found out about you. 
 
Genetic testing can also be used to determine if people are directly related. These tests can reveal that a person’s 
biological parents are someone other than their legal parents. If these facts were not known previously they could be 
troubling to learn.   It is our policy to not discuss such information unless it has direct medical or reproductive implications 
for you or your family. By agreeing to participate in this study, you do not waive any rights that you may have regarding 
access to and disclosure of your records. For further information on those rights, please contact Dr. Maldarelli, principal 
investigator. 
 
Any genetic information collected or discovered about you or your family will be confidential. Records containing this 
information will be kept on password-protected computer systems and in locked and secured quarters within the Clinical 
Center. We will not release any information about you or your family to relatives, any insurance company, employer, or 
your primary care physician without your written permission. Some genetic information, such as the name of your 
diagnosis, will be in your medical record. An insurance company or an employer could interpret this to be a pre-existing 
condition to deny benefits or coverage. Although we are committed to confidentiality, a court could still subpoena your 
medical records. All of these issues should be carefully considered before joining the study. Genetic counselors are 
available to discuss these issues in greater detail to help you and your family think about the possible effects. There may 
be a risk that genetic information obtained as a result of participation in research could be misused for discriminatory 
purposes. However, state and federal laws provide some protections against genetic discrimination. Researchers who will 
have access to genetic information about you will take measures to maintain the confidentiality of your genetic 
information. 
 
HIV Testing 
As part of this study, we will test you for infection with the human immunodeficiency virus (HIV), the virus that causes 
AIDS. If you are infected with HIV you will be able to participate in this study. We will tell you what the results mean, how 
to find care, how to avoid infecting others, how we report newly diagnosed HIV infection, and the importance of informing 
your partners at possible risk because of your HIV infection. 
 
Conflicts of Interest 
The National Institutes of Health reviews NIH staff researchers at least yearly for conflicts of interest. The following link 
contains details on this process http://ethics.od.nih.gov/forms/Protocol-Review-Guide.pdf. You may ask your research 
team for additional information or a copy of the Protocol Review Guide. This protocol may have investigators who are not 
NIH employees. Non-NIH investigators are expected to adhere to the principles of the Protocol Review 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: 
11-I-0057 
CONTINUATION:  page  6  of  6  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. 
 
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, Dr. Frank Maldarelli, Building 10, 
Room, 5A06, Telephone301.435.8019. 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 JUNE 15, 2015 THROUGH JUNE 14, 2016.  
 
 
 
  
 
 
  
 
Signature of Investigator 
Date 
 
 
 
Print Name 
Signature of Witness 
Date 
 
 
 
Print Name 
 

ICF_001.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: 
11-I-0057 
PRINCIPAL INVESTIGATORS: Frank Maldarelli, M.D. 
 
 
STUDY TITLE: 
Effect of Interferon Alpha 2b Intensification on HIV-1 Residual Viremia in Individuals Suppressed 
on Antiretroviral Therapy 
 
 
Continuing Review Approved by the IRB on 06/15/15 
Amendment Approved by the IRB on 05/18/15 (D) 
 
 
 
Date Posted to Web:  06/24/15 
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 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 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 NIH, or with family, friends, or your personal physician or other 
health professional.
 
Purpose of this Study 
You are invited to participate in this study because you have HIV infection and the amount of HIV virus in your blood is 
suppressed below the limit of detection on antiretroviral therapy (ARVs). The therapy you are taking for HIV is effective 
in controlling but not curing the HIV infection. Low levels of HIV are present even when the amount of HIV virus in your 
blood is measured below the limit of detection for virus (<50 copies RNA/mL plasma). The source of the small amount 
of HIV is unknown. It may come from a low-level infection, where new cells are continually infected with HIV. It is also 
possible that the virus is coming from cells that live for a long time after infection. We would like to learn more about 
the origin of residual HIV, because it will help us to understand the virus infection. We are interested in finding out 
whether antiviral agents other than the ARVs can affect the level of residual HIV in the blood. In this study we are 
investigating whether interferon alpha/Pegintron/Pegylated interferon alpha 2b will affect the level of HIV virus in the 
blood of individuals whose virus is suppressed on antiretroviral therapy. Interferon is a natural substance made by 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: 
11-I-0057 
CONTINUATION:  page  2  of  6  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
 
body to combat viral infections. Interferon can also be made as an injectable drug, called pegylated interferon alpha 2b 
(PEGINTRON®), which has been approved by the FDA for use in hepatitis C infection. In several earlier studies of HIV 
infected individuals who were not on any antiretroviral therapy, PEGINTRON® was shown to reduce the level of HIV in 
the blood. We are doing the present study to learn whether PEGINTRON® therapy will also reduce the residual low 
levels of HIV in patients who are already taking antiretroviral therapy. In this study, participants will receive weekly 
PEGINTRON injections for 4 weeks using the standard dose of PEGINTRON that is approved by the FDA for hepatitis C 
infection. During the study, we will measure the levels of HIV in the blood using sensitive tests that can detect as little 
as 1 copy of HIV RNA in 3 milliliters of blood (about 6/10 of a teaspoon). After the 4 weeks of PEGINTRON®, we will 
obtain additional blood samples for a total of 1 year. We plan to study 10 individuals.  
 
Eligibility to Take Part in this for Study 
 
In order for us to determine whether it would be appropriate for you to participate in this study, we performed an initial 
evaluation to better understand the status of your HIV. This consisted of 
• 
A visit to our clinic 
• 
A history and physical examination 
• 
Routine laboratory studies; pregnancy test if you are a woman of child-bearing potential 
• 
Blood to measure the amount of HIV virus present using standard testing and ultralow viral load test 
• 
Blood specimens for storage 
• 
Participants who are considering getting a vaccine, including the seasonal influenza (flu) shot, should 
notify the study team. 
Women of childbearing age will have a pregnancy test within 2 weeks prior to and another one on the day of the first 
dose of interferon. You should not get pregnant while participating in this study and should practice 2 different methods 
of contraception during this time. If you are pregnant, you cannot be in the study because we do not know how the study 
will affect the unborn fetus. If you are not pregnant, you will be asked to use 2 methods of birth control during the study.  
 
Study Procedures 
If the results of your evaluation indicate that you are eligible for PEGINTRON therapy and you decide to participate, you 
will return to enroll in the protocol. On the day you enroll, we will do another test to determine the amount of HIV virus in 
your blood, you will have two apheresis, and receive an eye examination. Apheresis is a procedure in which we obtain 
white blood cells. During apheresis, blood is removed through a needle in the vein of one arm, spun in a machine which 
permits separation of the desired blood component (usually white blood cells and plasma), and then the remainder is re-
infused either through the same needle or through a needle in a vein in the other arm. An anticoagulant (a medication to 
prevent blood from clotting) is usually added to the blood while in the machine to prevent it from clotting during this 
processing. You will then come back to the clinic to begin a schedule of 4 weekly PEGINTRON injections (Days 0, 7, 14, 
and 21).  The PEGINTRON injections will be given subcutaneously (small injection under the skin similar to an insulin 
shot).At each of these visits, you will see your case manager to review how you are feeling, and you will have blood taken 
for safety laboratory studies. If all remains well, you will receive your next injection of PEGINTRON®. If there are any 
abnormalities noted in the examinations, then we may delay the PEGINTRON injections. One side effect of PEGINTRON is 
to cause decreases in germ fighting white blood cells. If we find concerning decreases in white blood cell numbers, we 
will not give you PEGINTRON on your visit, but we will give you a medication called Filgrastim/GCSF/Neupogen to 
increase the white blood cell count. We will also schedule an additional visit to check that the Filgrastim is working.  
 
Following completion of PEGINTRON therapy, you will return for additional blood tests on Days 28, 35, 42, 49, 56, 84, 
and Weeks 16, 24, 36, and 48; there is some flexibility about the exact days of sampling. Following the last visit at Week 


 
  
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: 
11-I-0057 
CONTINUATION:  page  3  of  6  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
 
48, your participation will be over. Antiretroviral medications will be provided by the protocol during this study. We plan to 
study a total of 10 patients for this study. 
 
Benefits 
There is no direct benefit to participation in this study. You will receive information about your health from the screening 
tests and physical examination. In the future, your participation may help us learn more about the causes, treatment, or 
prevention of HIV disease, immune dysfunction, and/or related diseases. The information we obtain may help us to 
improve our understanding of HIV infection. The viral load test we are using in this study has not been as extensively 
studied compared to commercial viral load tests, and the information we obtain will not be used in making any clinical 
decisions regarding your care. 
 
Risks 
The risks from this study are from blood drawing and apheresis from the PEGINTRON therapy, from the combination of 
PEGINTRON with antiretrovirals and other therapy you may be taking, and the risk of medications such as Filgrastim, 
which may be given during the study. Blood drawing is generally very well tolerated. Occasionally, pain from needle stick, 
bruising, or bleeding may take place; rarely fainting or infection may occur. The amount of blood drawn will be within the 
limits allowed for adult subjects by the NIH Clinical Center (Medical Administrative Policy 95-9: Guidelines for Limits of 
Blood Drawn for Research Purposes in the Clinical Center). Like standard blood drawing from veins in your arm, apheresis 
is occasionally associated with local bleeding and bruising at the site of needle insertion. Lightheadedness can also occur, 
and people faint on rare occasions. 
 
Risks of Interferon Alpha 2b (PEGINTRON®) 
PEGINTRON® is a synthetic form of interferon alpha 2b, a natural substance made by the body in response to infections. 
PEGINTRON® has been approved by the FDA for use in individuals, including those with HIV, and to treat infection of the 
liver with the hepatitis C virus. PEGINTRON® has not been approved by the FDA to treat HIV alone.  In this study, we 
will be using the standard dose of PEGINTRON® approved by the FDA for treating hepatitis C including individuals with 
HIV infection. There are a number of side effects that you may experience from the PEGINTRON® injections. In many 
patients, PEGINTRON may cause feelings similar to the flu, including fatigue (>50% of participants), fever (22%), muscle 
aches (54%), headache (56%), insomnia (23%). Gastrointestinal effects such as abdominal discomfort (15%), decreased 
appetite (22%), diarrhea (18%), indigestion (6%), nausea (26%), vomiting (7%), and dry mouth (6%) have been 
reported. Joint pain (23%) and dizziness (12%) have been reported. PEGINTRON® may cause changes in your mood. 
Depressive feelings occur in about one-third of individuals receiving PEGINTRON®; rarely, depressive symptoms have 
included suicidal thoughts and extremely rarely suicide has been reported. Our study will use PEGINTRON® for a short 
period (4 injections during 3 weeks) and we will monitor you very closely during the study for these changes in your 
mood. Infrequently, aggressive behavior, agitation, nervousness, or anxiety has been reported. There are also rare 
occurrences of autoimmune disorders, infections, eye, and vascular disorders associated with PEGINTRON® use. 
PEGINTRON has been reported to cause a problem with the retina in the eye, which is usually transient and completely 
resolves with continued treatment; all participants on this study will have eye examinations to monitor for this side effect. 
Other side effects associated with subcutaneous injection include pain and inflammation at the site of injection, cough 
(8%), shortness of breath (4%), or inflammation of the throat or sinuses (5-13 %). Other side effects have occurred 
infrequently as well. 
 
PEGINTRON® may cause decreases in neutrophils, a kind of germ-fighting white blood cell. We will be monitoring your 
blood counts frequently for this side effect. If your white blood cell count declines to a level that raises concern, we will 
give you a medication called Filgrastim that increases white blood cell counts, and we will not give you PEGINTRON® 
until after your white blood cell count returns to a normal range. 


 
  
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: 
11-I-0057 
CONTINUATION:  page  4  of  6  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
 
 
PEGINTRON® has been associated with temporary decreases in CD4 cell numbers measured in the blood; it is likely that 
this apparent decrease is not the result of a direct toxic effect of PEGINTRON on CD4 cells. Instead it is more likely that 
PEGINTRON® causes the cells to reside in the tissues and not to circulate in the bloodstream. These changes in CD4 
counts are temporary, and have not been associated with infectious complications; we plan to monitor CD4 cells during 
the study. 
 
Risks of the Combination of Interferon Alpha 2b (PEGINTRON) and Antiretrovirals 
We will monitor you closely for any potential drug interactions between PEGINTRON ® and other medications you may 
be taking. PEGINTRON ® has been commonly and safely used with antiretroviral medications. 
 
Risks of Filgrastim (Granulocyte Colony Stimulating Factor, GCSF, Neupogen®) 
If PEGINTRON causes too great a reduction in your neutrophil white blood cells, then we will give you Filgrastim.. 
Granulocyte colony stimulating factor (GCSF, Filgrastim) is a natural substance made by the body that stimulates the 
bone marrow to increase the number of neutrophils. Filgrastim is a synthetic form of GCSF that is FDA approved to 
increase neutrophils in individuals with severely low white blood cell counts, such as those with advanced HIV infection, 
individuals who have severe blood disorders, or individuals with fever and low white blood cell counts, such as those with 
cancer who are receiving chemotherapy. Filgrastim is an injectable medication that is commonly used, is generally very 
safe, and has been given to people with HIV infection including individuals receiving PEGINTRON. The most common side 
effect of Filgrastim is mild or moderate bone pain. Infrequently, Filgrastim can cause allergic symptoms, rash or injection 
site reactions, headache, nosebleeds, fever, nausea, and occasionally vomiting. Temporary increases in alkaline 
phosphatase, a blood test that is a marker of liver function have also occurred, but such changes have not been 
associated with disorders of the liver. Rarely, Filgrastim was associated with shortness of breath, which may be due to a 
respiratory distress syndrome, or a capillary leak syndrome of lungs. In very rare cases, rupture of the spleen has 
occurred. We will be monitoring you closely during this study to see if you will need Filgrastim and for the side effects of 
Filgrastim. 
 
Apheresis 
Apheresis is a procedure during which blood is taken from a vein in your arm. A special machine removes the white blood 
cells that are present in the blood specimen, and then returns all of the other blood components to you (via a vein in your 
arm). Thus, the only cells removed from your body by the apheresis procedure are white blood cells. Apheresis allows us 
to obtain sufficient numbers of lymphocytes to perform special studies. 
 
The risks associated with apheresis procedures are primarily those of inserting an intravenous line (a catheter placed into 
a vein) and include discomfort at the site, occasionally bruising under the skin where the needle was placed, a tingling 
sensation during the procedure that can usually be relieved by chewing a calcium-containing antacid such as Tums®, the 
rare possibility of introducing infection, and possible fainting. Mild allergic reactions, including eye tearing, coughing, 
sneezing, itching, flushing, and hives may occur during apheresis and are caused by the chemicals used to sterilize the 
plastic collection kits. If you experience these symptoms, the donor room staff will give antihistamines, such as Benadryl, 
to you. The intravenous line infusing a saline solution will be kept in place during the manual apheresis procedure. Other 
uncommon side effects of the procedure include anxiety, chills, pain, and lightheadedness. There may also be a slightly 
increased bleeding tendency for a few hours after the procedure due to the temporary presence of the anticoagulant. In 
addition, on very rare occasions (less than 1 in every 1,000 times), malfunction of the leukapheresis machine can result in 
its failure to return all of your blood cells to you. In this case, the maximum amount of blood loss experienced is less than 
450 milliliters (1 pint). Trained medical personnel who are equipped to deal with any of these potential problems are 
always on hand during the procedure. In addition, there are theoretical risks from re-infusion of the blood after 


 
  
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: 
11-I-0057 
CONTINUATION:  page  5  of  6  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
 
processing by the machine such as infection or an adverse reaction to the blood components. However, these risks must 
be exceedingly rare if they occur, since they have not been seen in many thousands of volunteers who have undergone 
this or similar procedures to date. Rarely the performance of frequent apheresis procedures over a short period of time 
can result in a drop in total lymphocyte counts, including the absolute CD4+ T cell count, or a drop in the platelet count 
(platelets are the blood cells that help your blood to clot). The extent or duration of the drop in these counts may be 
unpredictable and vary from person to person, although we plan to monitor your counts during participation so that this is 
less likely to occur. The short or long-term risks associated with these drops are also unknown, although possibly could be 
more serious in those individuals whose baseline counts are already below the normal range as a result of HIV-1 infection 
or other medical conditions. Based upon your CD4 cell count or other medical conditions, we may limit the number of 
times that you are eligible to undergo apheresis over a set period of time, and may require that these or other safety 
blood studies be performed and checked periodically during the time that you are enrolled on this protocol. 
 
REASONS FOR REMOVING YOU FROM THE STUDY WITHOUT YOUR CONSENT  
You may be removed from the study without your consent for the following reasons:  
• 
The NIH doctor feels that staying in the study is harmful to you 
• 
You don't keep your appointments 
• 
The study is cancelled or stopped 
 
Cost 
There will be no charge to you or your health insurance company for any of the costs which are directly related to this 
study. However, the costs of any other medical care outside of this study during this period will be your responsibility. 
 
Alternatives 
This study provides no benefit and the alternative to participating is not participating 
 
New Findings 
You will be told of any new information learned during the study that might cause you to change your mind about staying 
in the study. At the end of the study, you will be told when the overall results of the study may be available. 
 
Remuneration 
There is monetary compensation for time, inconvenience, and for certain procedures. You will receive payment at the end 
of the study; you will receive $40 for each visit, and $100 for the apheresis. As a result, you can receive up to $760 for 
the entire study.  
 
Conflicts of Interest 
The National Institutes of Health reviews NIH staff researchers at least yearly for conflicts of interest. The following link 
contains details on this process http://ethics.od.nih.gov/forms/Protocol-Review-Guide.pdf. You may ask your research 
team for additional information or a copy of the Protocol Review Guide. This protocol may have investigators who are not 
NIH employees. Non-NIH investigators are expected to adhere to the principles of the Protocol Review 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: 
11-I-0057 
CONTINUATION:  page  6  of  6  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. 
 
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, Dr. Frank Maldarelli, Building 10, 
Room, 5A06, Telephone301.435.8019. 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 JUNE 15, 2015 THROUGH JUNE 14, 2016.  
 
 
 
  
 
 
  
 
Signature of Investigator 
Date 
 
 
 
Print Name 
Signature of Witness 
Date 
 
 
 
Print Name 
 

Prot_SAP_002.pdf: 
 
 
Effect of Interferon Alpha 2b Intensification on HIV-1 Residual 
Viremia in Individuals Suppressed on Antiretroviral Therapy 
 
 
 
Short Title: Potential for Interferon Therapy in HIV-infected and ARV- suppressed 
Participants (PITHA) 
 
 
 
 
 
 
 
Principal Investigators: Frank Maldarelli, NCI 
Deborah McMahon, U of Pittsburgh 
 
 
 
 
 
 
 
 
 
Collaborating Investigators:  
 
Ann Wiegand 
 
Mary Kearney 
 
John Coffin 
 
John Mellors 
 
Research Contact: Jennifer Bell 
 
 
Version 5.0: March 31, 2015 
 
 


 
 
 
TABLE OF CONTENTS 
 
 
 
TABLE OF ABBREVIATIONS ........................................................................................................... 3 
Précis ................................................................................................................................................... 5 
1 Introduction ................................................................................................................................ 6 
2 Objectives .................................................................................................................................... 9 
2.1 
Primary Objective ............................................................................................................................ 9 
2.2 
Secondary Objectives ...................................................................................................................... 9 
3 Study Overview ........................................................................................................................ 10 
3.1 
Specific Aims ................................................................................................................................... 10 
3.2 
Study Design and Methods .......................................................................................................... 10 
3.2.1 
Study Population .................................................................................................................................................. 10 
3.2.2 
End Points ................................................................................................................................................................ 11 
3.2.3 
Sample Size .............................................................................................................................................................. 11 
3.2.4 
Safety Analyses ...................................................................................................................................................... 11 
4 Subject Selection...................................................................................................................... 11 
4.1 
Inclusion Criteria ........................................................................................................................... 11 
4.2 
Exclusion Criteria .......................................................................................................................... 13 
5 Schedule of Visits and Procedures...................................................................................... 13 
5.1 
Screening (Days -58 to -28) ........................................................................................................ 14 
5.2 
Pre-entry Visit 1 (Day-27 to Day -1) ......................................................................................... 14 
5.3 
Pre-Entry Visit 2: Leukapheresis Visits (Day -14 to Day -1, Day 28) ............................... 15 
5.4 
Entry (Day 0)................................................................................................................................... 15 
5.5 
Intensification Phase: Visit 1 (Day 7), Visit 2 (Day 14), Visit 3 (Day 21) ........................ 15 
5.6 
Early Post-Intensification Phase: Visit 4 (Day 28) ............................................................... 16 
5.7 
Late Post-Intensification Phase: (Visits 5 to 9) ..................................................................... 16 
5.8 
Long-term Follow-up: Week 16 (Visit 10) .............................................................................. 16 
5.9 
Weeks 24 and 36 (Visits 11 and 12) ......................................................................................... 17 
5.10 
Week 48 (Final Visit, Study Discontinuation Visit) ........................................................... 17 
5.11 
Window Periods for Study Visits ............................................................................................ 17 
6 Concomitant Medications ..................................................................................................... 17 
7 Study Drug Administration .................................................................................................. 18 
7.1 
Drugs and Dosing .......................................................................................................................... 18 
7.2 
Monitoring Parameters ............................................................................................................... 18 
7.3 
Dose Modifications/Toxicities ................................................................................................... 18 
8 Management of Toxicities to Study Drug .......................................................................... 18 
8.1 
Grade 4 Toxicities.......................................................................................................................... 18 
8.2 
Toxicity Management ................................................................................................................... 18 
8.3 
Criteria for Study Permanent Drug Discontinuation........................................................... 19 
9 Laboratory Studies.................................................................................................................. 19 


 
IFN-alpha2b for HIV on ARV (PITHA), Version 5.0 
 
April 15, 2015 
 
 
3 
 
 
9.1 
Serum Chemistry and Hematology Profiles ........................................................................... 19 
9.2 
Plasma HIV RNA Levels ................................................................................................................ 20 
9.3 
Pharmacokinetics of Pegylated Interferon ............................................................................ 21 
9.4 
Peripheral Blood Mononuclear Cells Storage ........................................................................ 20 
9.5 
CD4 Counts ...................................................................................................................................... 20 
10 Statistical Considerations ................................................................................................... 20 
11 Sample Size Estimation ....................................................................................................... 21 
12 Hazards/Discomforts/Risks .............................................................................................. 22 
12.1 
Study Drugs and Procedures ................................................................................................... 22 
12.1.1 
Pegylated Interferon Alpha 2b ................................................................................................................... 22 
12.1.2 
Granulocyte Colony Stimulating Factor ................................................................................................. 23 
12.1.3 
Potential for Previously Unrecognized Drug Interactions ........................................................... 24 
12.1.4 
Potential for Adverse Effects from Leukapheresis .......................................................................... 24 
12.1.5 
Risks of Phlebotomy ........................................................................................................................................ 24 
12.2 
Human Subject Protections ...................................................................................................... 24 
13 Study Recruitment ................................................................................................................ 24 
13.1 
Gender, Ethnicity, and Race Consideration ......................................................................... 25 
13.2 
Children and Pregnant Women ............................................................................................... 25 
14 Benefits/Compensation/Alternatives............................................................................. 25 
15 Evaluation of Safety .............................................................................................................. 26 
Recording/Documentation ................................................................................................................... 26 
15.1 
Protocol-specific Adverse Events ........................................................................................... 26 
15.1.1 
Definitions of Adverse Events..................................................................................................................... 26 
15.1.2 
Adverse Event Reporting .............................................................................................................................. 28 
Expedited Reporting to the NIAID IRB...................................................................................................................... 28 
15.1.2.2 Waiver of Reporting Anticipated Protocol Deviations, Expected non-UP AEs and 
Deaths ........................................................................................................................................................................................ 28 
15.1.2.4         Type and Duration of the Follow-up of Subjects after Adverse Events ........... 29 
16 Monitoring .............................................................................................................................. 29 
16.1 
Stored Samples and Future Research .................................................................................... 29 
16.2 
Data Management Plan.............................................................................................................. 29 
17 Anonymity and Confidentiality ......................................................................................... 30 
18 References .............................................................................................................................. 31 
 ............................................................................................................................................................. 35 
 Appendix 2: Toxicity Severity Scale ......................................................................................... 36 
 
TABLE OF ABBREVIATIONS 
AIDS 
Acquired immunodeficiency Syndrome 
ART 
Antiretroviral therapy 
BDS 
Beck Depression Inventory Score 
DHHS 
Department of Health and Human Services 
FDA 
Food and Drug Administration 


 
IFN-alpha2b for HIV on ARV (PITHA), Version 5.0 
 
April 15, 2015 
 
 
4 
 
 
G-CSF 
Granulocyte colony stimulating factor 
HCV 
Hepatitis C virus 
HIV-1 
Human immunodeficiency virus type 1 
HRPP 
Human Research Protection Program 
IRB 
Institutional Review Board 
INF 
Interferon 
NCI 
National Cancer Institute 
NIAID 
National Institute of Allergy and Infectious Diseases 
NIH 
National Institutes of Health 
NNRTI 
Non-nucleoside reverse transcriptase inhibitor 
PBMC 
Peripheral blood mononuclear cells 
PEG 
Polyethylene glycol 
PEG-INTRON 
Pegylated interferon alpha 2b 
PI 
Principal investigator 
PrI 
Protease inhibitor 
SCA 
Single copy assay (viral RNA) 
 
 


 
IFN-alpha2b for HIV on ARV (PITHA), Version 5.0 
 
April 15, 2015 
 
 
5 
 
 
Précis  
As a result of combination antiretroviral therapy (ART), morbidity and mortality 
from acquired immunodeficiency syndrome has declined significantly in the past 15 
years, at least in developed countries. Human immunodeficiency virus type 1 (HIV-
1) infected individuals now live longer, but must undergo continuous therapy that 
has substantial consequences on quality of life.  
 
ART suppresses HIV-1 viremia below the limits of detection in current commercial 
assays (c. 50 copies/mL plasma)., but HIV viremia persists even after prolonged 
suppressive therapy. The origin of this residual viremia is yet not clear, but data 
suggest that production from long lived HIV infected cells may contribute to 
viremia.  Antiretrovirals are extremely active against replicating cells, and can thus 
successfully stop viral replication, but have no effect on long-lived viral reservoirs of 
cells already infected with HIV-1 at the time antiretroviral therapy is initiated. As a 
result, new strategies are necessary to reduce or eradicate long-lived reservoirs.  
Interferon alpha is a natural cytokine with antiviral activity. Prior to the introduction 
of antiretroviral therapy, several studies demonstrated modest effect of interferon 
alpha in HIV-1 viremia in active cycles of infection in infected individuals. Interferon 
alpha was also effective in vitro in decreasing virus production from cells chronically 
infected with HIV-1. With the introduction of potent antiretroviral therapy, 
interferon was not developed as a direct anti-HIV drug. Interferon alpha is relatively 
effective in therapy of hepatitis C virus (HCV) infection, and has been used in HIV-
1/HCV coinfected individuals. Kottilil and coworkers in the Laboratory of 
Immunoregulation NIAID have shown a decrease in HIV-1 RNA levels in HCV 
coinfected participants treated with pegylated interferon alpha and ribavirin. In 
stored samples from that study, we conducted a retrospective trial on samples from 
participants with HIV-1 RNA levels of <50 copies/mL, showing a further reduction in 
residual viremia using an ultrasensitive Single Copy Assay (SCA) developed in our 
laboratory. As such the effects of interferon on HIV viremia and cell associated HIV 
RNA are of growing interest.  
In this protocol we will conduct a prospective, non-randomized, single arm, pilot 
study to investigate the effect of pegylated interferon alpha 2b on HIV-1 RNA levels 
as an additional drug in participants undergoing suppressive antiretroviral therapy 
with viral RNA levels suppressed to less than 50 copies/mL plasma. As patients may 
have levels of HIV RNA that are lower than our limit of detection, we will also 
investigate levels of HIV nucleic acid species in cells as well We will determine 
whether interferon alpha therapy will reduce residual viremia or cell associated HIV 
RNA in participants on suppressive ART, which will expand our understanding of 
persistent low-level viremia and the pathogenesis of HIV in infected individuals. 
 
 


 
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6 
 
 
1 
Introduction 
The human immunodeficiency virus type 1 (HIV-1) is responsible for the 
development of acquired immunodeficiency syndrome (AIDS) that results in 
progressive immune system deterioration and death. Therapy treating HIV 
(antiretroviral therapy or ART) by inhibiting viral replication and allowing immune 
restoration, has dramatically reduced AIDS-related mortality, but is not curative 
(Palella, Delaney et al. 1998, Egger, May et al. 2002). After introduction of ART, 
viral RNA levels in the blood decline significantly. The decay of HIV-1 replication in 
the presence of an effective ARV follows a biphasic pathway (Shen and Siliciano 
2008): a first rapid decay of the cells that produce >90% of plasma virus is 
followed by a second slower decline in viremia. Several studies have demonstrated 
that virus declines in plasma because new rounds of virus replication are 
interrupted by ART and because the cells producing virus die. As a result, the 
decline in viremia reflects the death rate of virus-infected cells. The first phase of 
decline in viremia involves mostly activated CD4+ T lymphocytes that have a very 
short life, surviving only about 1 day; the second phase involves mostly infected 
macrophages and partially activated CD4+ lymphocytes that have an half life of 
about 2 weeks.  
 
Decline in viremia is measured by commercially available assays that measure HIV-
1 RNA. The current limit of plasma HIV-1-RNA detection is 50 copies/mL, and this is 
the threshold that international guidelines use as the gold standard for therapy 
efficacy (Clumeck, Pozniak et al. 2008, DHHS 2008). Using ultrasensitive HIV-1 
RNA assays, with sensitivity of HIV-1-RNA down to 1 copy/mL, it is possible to 
detect persistent HIV-1 viremia even in participants undergoing successful 
treatment for prolonged periods with ARV (Di Mascio, Dornadula et al. 2003, 
Maldarelli, Palmer et al. 2007). In participants who have undergone an effective 
ARV regimen for 7 years, we showed an additional third and a fourth phase of viral 
decay in these participants.  
 
The set point of residual viremia is predicted by the pre-therapy HIV-1 RNA level; 
participants with pre-therapy HIV-1 RNA levels greater than 100,000 copies/mL had 
persistent detectable HIV-1 RNA levels over time (Palmer, Maldarelli et al. 2008). 
The origin of this residual viremia is uncertain. One possible source is an ongoing 
replication of viral strains spreading infection to uninfected cells (Zhang, 
Ramratnam et al. 1999, Havlir, Strain et al. 2003). Ongoing replication may occur if 
drug therapy does not completely inhibit virus replication, or if virus replication 
takes place in anatomic sanctuary sites in the body where antiretroviral drugs do 
not penetrate. Alternatively, HIV-1 may be produced from viral genomes integrated 
in cells from long-lived HIV-1 reservoirs (Palmer, Maldarelli et al. 2008, Shen and 
Siliciano 2008). Antiretroviral intensification studies revealed no decrease in HIV 
RNA levels after introduction of an additional potent antiretroviral(Dinoso, Kim et al. 
2009, McMahon, Jones et al. 2010, Besson, McMahon et al. 2012), suggesting 
ongoing replication was not the source of persistent HIV present during therapy. 
Increases in 2LTR circles in some patients suggest that low level replication events 
may occur in some patients (Buzon, Massanella et al. 2010, Hatano, Hayes et al. 
2011, Hatano, Strain et al. 2013). These data suggest that although replication 
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is chronic viral production from long-lived cells, and strategies other than 
conventional antiretroviral therapy are needed to eradicate HIV-1 from infected 
individuals. In order to investigate the nature of the HIV-1 reservoir we plan to use 
the intensification strategy with novel antiretroviral therapy.  
 
One possible candidate in this strategy is the antiviral immune modulator interferon 
alpha (INF). Interferon alphas (interferon-alpha 2a and 2b) are a class of 
compounds known for their antiviral, immune-activating and immune-suppressing 
properties (Tilg 1997, Patel and McHutchison 2001, Tilg and Kaser 2004, Stetson 
and Medzhitov 2006). The addition of polyethylene glycol (PEG) to interferon 
increases its half-life in the body. PEG-Interferon alpha 2b, administered with 
ribavirin, is Food and Drug Administration (FDA)-approved for the treatment of 
chronic hepatitis C. Several clinical trials have shown its efficacy (especially in 
association with ribavirin) against HCV (Lindsay, Trepo et al. 2001, Manns, 
McHutchison et al. 2001). In addition, interferon alpha 2b is FDA-approved for the 
treatment of: hairy cell leukemia, malignant melanoma, follicular lymphoma, 
condylomata acuminata, AIDS- related Kaposi sarcoma, and chronic hepatitis B and 
C. In vitro studies conducted with HCV-infected cell-culture systems showed that 
INF exerts its activity by inducing a non-virus-specific antiviral state within the cell 
by activating a number of INF-responsive genes (Sen 2001, Bekisz, Schmeisser et 
al. 2004, Jiang, Guo et al. 2008). Exogenous administration of INF has a similar 
inducing effect, leading to a rapid reduction of HCV-RNA levels (Guo, Bichko et al. 
2001, Zhu, Zhao et al. 2003). Treatment with INF 2b or its pegylated form and 
ribavirin resulted in a successful clearance of hepatitis C in infected participants 
(Lindsay, Trepo et al. 2001, Manns, McHutchison et al. 2001), and the level of 
expression of genes related to INF response, immune cell signaling, defense 
response, and cell death has been associated with treatment outcome (Lempicki, 
Polis et al. 2006).  
 
With respect to HIV, INF has shown antiviral activity both in vitro (Ho, Hartshorn et 
al. 1985) and in vivo (Lane, Kovacs et al. 1988, Hatzakis, Gargalianos et al. 2001). 
The major activity of INF against HIV is thought to be the inhibition of the release 
of progeny virions from host-infected cells (Poli, Orenstein et al. 1989, Gottlinger, 
Dorfman et al. 1991). This anti- HIV-1 activity is opposed by the viral protein Vpu 
(Gottlinger, Dorfman et al. 1993) and recently the cell protein that mediates viral 
retention was identified as an INF-induced protein, Bst-317 or tetherin (Neil, Zang 
et al. 2008). In addition it is known that retroviral restriction factors such as 
APOBEC3G and TRIM5a are INF INF-regulated genes and their induction might also 
play a role in INF antiviral activity (Goff 2004). A number of in vitro studies 
suggested that the effects of interferon were modest (2-8 fold reductions in viral 
RNA) but interestingly, the combination of interferon and early antiretrovirals, such 
as AZT, was markedly synergistic (Hartshorn, Vogt et al. 1987), including in vitro 
models of cells chronically infected with HIV-1. These results are particularly 
intriguing because in cultures of chronically infected cells, the majority of the cells 
produce HIV-1 from integrated proviruses, and there is little spreading infection; as 
a result, AZT has minimal or no direct antiviral effect, and interferon may have 
been the most potent antiviral in these experiments (Poli, Orenstein et al. 1989). 
Experiments with HIV-1 production from chronically infected cells may represent a 


 
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useful model for participants suppressed on antiretroviral therapy as experiments 
suggest the majority of the detectable virus is produced from cells with integrated 
proviruses. Although interferon has been studied in active spreading infections, 
little data are available from participants who are already suppressed on ARV.  
 
In the pre-ART era, INF clinical trials showed a degree of efficacy in reducing viral 
replication, p24 production, and slowing progression to AIDS (de Wit, Schattenkerk 
et al. 1988, Lane, Davey et al. 1990, Berglund, Engman et al. 1991). After 
development of combination ARV, however, INF was not developed as an 
antiretroviral, due to lower antiviral efficacy, inconvenient route of administration, 
and adverse affects (Lane, Davey et al. 1990, Dusheiko 1997). Recently, several 
groups have shown a substantial HIV RNA reduction in participants treated with the 
pegylated form of interferon alpha (PEG-INF) as part of chronic hepatitis C therapy 
(Torriani, Ribeiro et al. 2003, Talal, Shata et al. 2004, Neumann, Polis et al. 2007). 
In addition, Asmuth and colleagues recently studied the effect of pegylated 
interferon alpha on HIV viral load in HBV/HCV seronegative HIV-1-infected 
participants who were not receiving antiretroviral therapy. HIV-1 viremia declined 
by a mean 0.77 log10 copies/mL over 12 weeks (Asmuth D 2009).  
The mechanism of interferon effect on HIV viremia is uncertain. There is a 
substantial literature regarding the effects of interferon in retroviruses in vitro, and 
in HIV in particular(Pitha 2011). Interferon may induce expression of a number of 
innate immune responses, which have direct effects on a number of distinct steps in 
virus replication. Induction of the cellular gene APOBEC 3G and 3F can result in 
hypermutation of the HIV genome during reverse transcription(Goila-Gaur and 
Strebel 2008). Induction of the gene tetherin results in retention of HIV on the 
surface of infected cells and decreases in production of extracellular HIV 
virions(Perez-Caballero, Zang et al. 2009). The effects of interferon may be 
manifest as a decrease in peripheral viremia, and a corresponding accumulation of  
HIV RNA intracellularly  
 
Much of the information available regarding the effects of interferon in HIV 
infection has been obtained in patients co-infected with HCV. We performed a 
retrospective analysis of HIV-1 RNA levels in plasma stored from HIV-1/HCV 
coinfected participants enrolled in NIH clinical trials for chronic hepatitis C 
treatment. We selected participants undergoing antiretroviral therapy with HIV-1 
viral RNA suppressed to <50 copies/mL, and used only samples that were obtained 
within 4 months of initiating therapy. Plasma HIV-1 RNA from 5/6 participants 
undergoing interferon/ribavirin therapy was decreased in 5/6 participants. In this 
retrospective pilot study, we could not distinguish whether the decrease in viremia 
resulted from therapy with interferon or ribavirin, or the combination. Prior clinical 
studies have indicated no evidence of anti-HIV-1 activity of ribavirin, suggesting 
that interferon may represent the active agent responsible for this result. Although 
the number of participants is small, these findings suggest that INF might decrease 
HIV-1 RNA levels in participants undergoing a successful ARV regimen.  
There are limited data on the in vivo effects of interferon alone in individuals 
undergoing antiretroviral therapy. Montaner et al., studied the effects of pegylated 
interferon on plasma HIV RNA in individuals undergoing antiretroviral therapy who 
underwent a structured ART interruption(Azzoni, Foulkes et al. 2013). Decreases in 
cell associated HIV DNA were detected in a subset of patients; no differences in 


 
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plasma HIV levels  were detected (using an assay with a 4-5 copy limit of detection 
,approximately 30 fold higher than the single copy assay. Differences in levels of 
cell associated DNA were detected, but no studies of intracellular HIV RNA were 
performed(Azzoni, Foulkes et al. 2013).Recently intracellular HIV RNA may be 
recognized by intracellular toll like receptors,which are themselves induced by 
interferon. As such the effects of interferon on cell associated HIV RNA are of 
growing interest. Recently we have developed digital droplet methods to quantify 
HIV RNA levels in infected cells, including levels of unspliced, spliced, and short 
(tat- ) transcripts, which may be synthesized in latently infected cells not producing 
full length HIV RNA.  In combination with single genome sequencing, these 
approaches will be useful in investigating the effects of interferon alpha in HIV 
infected individuals, including determining overall levels of cell associated RNA, 
numbers of cells producing HIV RNA, and phylogenetic analysis of HIV RNA 
sequences in plasma and cells. This advance will permit us to investigate the effects 
of interferon in patients with and without detectable levels of HIV RNA in plasma; 
patients with levels of HIV RNA below levels of single copy detection are still be 
detectable by measurements of HIV RNA . 
In the present protocol, we will investigate the effects of interferon alpha 2b 
in reducing low level HIV viremia. We plan to conduct a non-randomized, open-
label, single arm, pilot clinical trial of participants with viremia suppressed on 
antiretroviral therapy to investigate whether the addition of interferon alpha 2b 
therapy for 1 month (1.5 µg/kg interferon alpha 2b subcutaneously weekly for a 
total of 4 doses) results in changes in HIV-1 RNA levels in plasma or in peripheral 
blood lymphocytes. For the purposes of this pilot study, we will study 10 patients 
with suppressed viremia. Previously, we have obtained useful information regarding 
the effects of PI, NNRTI, and raltegravir intensification on HIV-1 viremia using this 
sample size. In the study planned here, we will perform gene expression studies to 
characterize the cellular response to interferon therapy in HIV infection. We will 
investigate potential correlations between expression of interferon-inducible genes 
and response. We will be particularly interested in the relationship between the 
interferon responsive gene, tetherin (Perez-Caballero, Zang et al. 2009), and the 
response to interferon. 
 
 
2 
Objectives 
2.1 Primary Objective 
This is a non-randomized, single arm pilot study of 10 participants to investigate 
the effect of interferon alpha on HIV-1 production in plasma and peripheral blood 
lymphocytes from HIV-infected individuals with HIV-1 RNA levels below the limit of 
detection in commercial assays. 
 
2.2 Secondary Objectives 
The secondary objectives of this study are the following: 
1. Investigate HIV-1 genetic variation in individuals undergoing interferon 
therapy.  


 
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2. Investigate the safety and tolerability of PEG INF 2b in HIV-1 infected 
individuals taking FDA-approved antiretrovirals in combinations 
recommended by Department of Health and Human Services (DHHS) 
guidelines. 
 
This study will allow us to elucidate the relationship between the viral decay in 
response to treatment intensification in HIV-infected individuals with residual 
viremia on antiretroviral therapy. This information will provide further clarifications 
on the origin of residual viremia and could provide clues to the eradication of HIV-1 
infection. 
 
This is a 48-week study to evaluate the effect of administering interferon alpha 2b 
to individuals in with viral RNA levels <50 c/ml undergoing antiretroviral therapy. 
Individuals entered into the study will viral RNA and PBMC sampling determinations 
prior to interferon intensification. During the second phase of the study, they will 
receive pegylated interferon alpha 2b (PEG-INTRON) at a dose of 1.5 µg/kg 
subcutaneously once weekly for 4 weeks starting at Study Entry, then at Visits 1, 2, 
and 3, for a total of 4 doses. During the interferon intensification phase, 
participants will continue to receive their standard of care HIV regimen. Following 
completion of the interferon dosing, participants will be monitored through 48 
weeks and will remain on their standard HIV regimen. During all phases, 
participants will be assessed for viremia using standard and single copy viral load 
assays. In addition, CD4 and CD8 counts as well as interferon levels will be 
measured.  
 
3 
Study Overview 
3.1 Specific Aims 
The goal of this study is to investigate the ability of pegylated interferon alpha 2b to 
reduce residual viremia or cell associated HIV RNA in HIV-infected individuals who 
are receiving antiretroviral therapy. Viral RNA load will be measured using the 
sensitive single RNA copy per milliliter assay. 
 
We will also delineate the safety and toxicity profiles of pegylated interferon alpha 
2b when co-administered with antiretroviral therapy in HIV-1 infected individuals. 
 
3.2 Study Design and Methods 
3.2.1 Study Population 
Ten evaluable HIV-1 chronically infected individuals with viremia suppressed to 
below the limit of detection, on antiretroviral therapy will be enrolled in this trial. 
Individuals with CD4 counts greater than or equal to 300 cells/µL at screening will 
be eligible to participate. We plan to conduct this study at the National Institute of 
Allergy and Infectious Diseases (NIAID)/CCMD Clinic at the National Institutes of 
Health (NIH) Clinical Center, and at the AIDS Clinical Trials Unit, Division of 
Infectious Diseases, University of Pittsburgh (active enrollment at Pittsburgh was 
completed in 2014).  


 
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3.2.2 End Points 
Unless unacceptable drug-related toxicities emerge (see Appendix 2), clinical 
contraindications unrelated to drug therapy develop that compromise the health or 
safety of study participants, or one of the specific criteria for withdrawal from the 
study is met, all participants will be treated for 4 weeks. Participants will be 
followed through Week 48. 
 
3.2.2.1 
Primary End Points 
We will compare viral RNA levels in blood and peripheral blood lymphocytes drawn 
before, during, and after intensification, including comparison of absolute values of 
viremia, as well as changes in viremia and area under the curve analyses to detect 
whether increases or decreases of viremia occurred as a function of interferon 
therapy. Standard analyses will be included. 
 
3.2.2.2 
Secondary End Points 
In participants with detectable and amplifiable virus, HIV-1 genetic sequencing will 
be performed to determine whether interferon therapy results in differences in 
population structure during the 4-week intensification period. HIV RNA and DNA 
levels will be investigated using quantitative PCR approaches, including digital 
droplet PCR. The safety and tolerability of single agent interferon will be assessed 
through standard clinical management. 
 
3.2.3 Sample Size  
As described below (see Statistical Considerations) we expect that 10 participants 
completing the study will be necessary to yield useful clinical information. In order 
to enroll 10 participants for this study, we will be screening up to 65 individuals. 
Any dropouts and non-adherent participants will be replaced. 
 
3.2.4 Safety Analyses 
All safety data including adverse events, deaths, vital signs, physical examinations, 
discontinuations from study drug, and clinical laboratory measurements 
(hematology, serum chemistry, and urinalysis) will be listed and summarized, using 
the mean, standard deviations, and percentiles for continuous variables and 
frequencies and percentages for categorical variables. Any notable values will be 
flagged. Any comparisons with respect to safety parameters from baseline will be 
made using the same procedures described above for endpoint analyses. 
 
4 
Subject Selection 
4.1 Inclusion Criteria 
To be eligible for study participation, a volunteer must satisfy all of the following 
inclusion criteria: 


 
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1. Age >18 years. 
2. Documentation of HIV-1 infection by any licensed ELISA test and confirmed 
by a Western Blot. 
3. Receiving a DHHS-approved ARV regimen,. 
4. Level of cell-associated HIV RNA ≥ 5 copies/million peripheral blood 
mononuclear cells (PBMC) done at screening visit 1 
5. HIV-1 RNA levels less than detectable by current commercial means (e.g., 
Roche Amplicor, b-DNA test) for a minimum of 12 months prior to screening 
at all time points, and with at least 2 measurements in this 12 month 
window. 
 
6. CD4 >300 cells/mm3 at pre-entry visit within 14 days prior to enrollment. 
7. Ability to sign informed consent and willingness to comply with the study 
requirements and clinic policies. 
8. No evidence of viral hepatitis co-infection as assessed by Hepatitis C 
antibody, HCV RNA, and hepatitis B surface antigen; determinations at pre-
entry visit within 28 days prior to enrollment. 
9. No history of or evidence of autoimmune hepatitis or other autoimmune 
disorders at screening, or antinuclear antibody (ANA > 3x upper limit of 
normal. 
10. Laboratory values at pre-entry visit within 14 days prior to enrollment:  
• 
Alkaline phosphatase <2.0 times upper limit of normal 
• 
Alanine transaminase (ALT) <2.0 times upper limit of normal 
• 
Total bilirubin <2.5 mg/dL (< 40 mg/dL if on Atazanavir) 
• 
Creatinine clearance >60 mL/min as estimated by the Cockcroft-Gault 
equation 
• 
Neutrophil count >1500 cells/mm3 
• 
Platelets >150,000/ mm3 
• 
Hemoglobin >12.0 mg/dL for men and >11.0 g/dL for women 
• 
Fasting glucose <126 mg/dL 
11. No history or evidence of significant clinical depression at screening that in 
the opinion of the investigator would affect the ability of the patient to 
participate in the study, or which would constitute a threat for his/her health 
in case of relapse upon INF treatment. The Beck Depression Inventory score 
must be £13 at pre-entry visit. 
12. No history of INF/PEG-INF therapy. 
13. If capable of pregnancy: use of effective contraception during study: 
effective contraception methods include abstinence, surgical sterilization of 
either partner, barrier methods such as diaphragm, condom, cap or sponge, 
or use of hormonal contraception with an anti-HIV regimen that will not alter 
metabolism of hormonal contraception. 
14. Participants must have primary medical care outside this protocol: 
participants will have to provide Primary Care Doctor’s contact information. 
 


 
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4.2 Exclusion Criteria 
A volunteer will be ineligible to participate in this study if any of the following 
criteria are met: 
 
1. History of neoplastic disease requiring cytotoxic therapy including 
hydroxyurea. 
2. Use of long-term systemic corticosteroids, immunosuppressive agents, or 
cytotoxic agents within 60 days prior to enrollment. 
3. Any vaccination within 30 days prior to enrollment. Individuals interested in 
participating who require vaccination will delay screening until 30-day period 
is completed. 
4. Concurrent therapy with investigational cytokines including IL-2 or IL-12 
during the course of the study. Prior administration of cytokines is not an 
exclusion criterion; at least 4 months from most recent cycle of IL-2 or IL-12 
is required. 
5. Any febrile illness (>38oC) in the 3 weeks prior to enrollment or any acute 
therapy for a serious infection completed within 30 days prior to enrollment. 
6. Current pregnancy or lactation, history of pregnancy in the last 4 months. 
7. Preexisting autoimmune disorders including inflammatory bowel diseases, 
psoriasis, idiopathic thrombocytopenic purpura, lupus erythematous, 
autoimmune hemolytic anemia, scleroderma, severe psoriasis, rheumatoid 
arthritis, and optic neuritis. 
8. History of severe retinopathy or evidence of severe retinopathy judged by 
pre-entry ophthalmologic examination. 
9. Known allergy/sensitivity to study drug or its formulation. 
10. History of seizure disorders or current anticonvulsant use. 
11. Any history of medical conditions associated with chronic liver disease 
(genetic hemochromatosis, alcoholic liver disease, toxin exposures, and 
autoimmune hepatitis) or documented cirrhosis due to any cause. 
12. History of pulmonary disease associated with functional limitation. 
13. Documented history of thyroid disease. 
14. Active drug or alcohol use or dependence, which in the opinion of the 
investigator, would interfere with complying with the study requirements. 
15. Known hypersensitivity to Escherichia coli-derived products such as 
filgrastim. 
16. Any systemic illness that will make it unlikely that the subject will be able to 
return for the required study visits. 
17. History of, or any condition that in the opinion of the investigator would 
interfere with the conduct of the study, or it would not be in the best interest 
of the subject to enroll in this study. 
 
5 
Schedule of Visits and Procedures 
Participants will be seen in the NIAID/CCM Clinic at the NIH Clinical Center, NIH (PI: 
Frank Maldarelli, MD) OR at the AIDS Clinical Trials Unit, Division of Infectious 
Diseases, University of Pittsburgh (PI: Deborah McMahon, MD; active enrollment at 
Pittsburgh was completed in 2014). We plan to enroll a total of 10 completed 


 
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participants for this study.  Any dropouts and non-adherent participants will be 
replaced. 
 
5.1 Screening (Days -58 to -28) 
Screening will consist of HIV-1 RNA level and if < 50 copies/mL by standard assay 
and have detectable PBMC-associated HIV RNA  ≥ 5 copies/million cells will 
continue with screening. If > 50 copies/mL, the subject will not undergo further 
screening assessments.  
 
Screening for the protocol will be completed within 4 weeks prior to the study 
enrollment. During screening visit the protocol design will be reviewed, and 
informed consent will be obtained prior to any study-related screening procedures. 
The subject will then be given the consent document to read. Consent forms may 
be sent to the subject for review prior to the screening visit. The site investigator 
will review the study with the subject and answer any questions the subject may 
have about the study design, interferon, or study procedures. After the subject has 
read this information, there will be further opportunity for discussion with one of 
the investigators.  Potential participants will sign consent prior to any study-related 
procedures. Once consented, eligibility will be assessed.  
 
 
5.2 Pre-entry Visit 1 (Day-27 to Day -1)    
When eligibility evaluation is complete, the subject will return for further 
assessments and the standard consent will be administered. The subject’s medical 
history will be reviewed and a physical examination will be performed, including 
weight and vital signs. Concomitant medications will be documented. The 
assessments are summarized in Appendix 1, and include:  
• 
Complete physical examination, including vital signs 
• 
Beck Depression Inventory Scoring (BDS) 
• 
Complete blood count with differential, platelet count 
• 
Serum chemistries (sodium, potassium, chloride, carbon dioxide, creatinine, 
urea nitrogen, alkaline phosphatase) 
• 
Creatinine clearance (Cockcroft-Gault method) 
• 
Fasting blood glucose 
• 
TSH, free T4 
• 
Urine pregnancy test (women of childbearing age) 
• 
Antinuclear antibody (ANA) 
• 
Urinalysis 
• 
Amylase 
• 
ALT, bilirubin 
• 
Hepatitis B surface antigen, hepatitis B surface antibody, hepatitis C antibody 
and hepatitis C viral RNA level (HCV PCR) 
• 
CD4 count 
• 
Ophthalmology examination (dilated funduscopic examination) 
• 
Single copy assay for HIV-1 RNA 
• 
HIV-1 RNA standard assay 


 
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• 
HIV-1 ELISA/Western Blot (if documentation not available) 
 
5.3 Pre-Entry Visit 2: Leukapheresis Visits (Day -14 to Day -1, Day 28) 
Once the subject has been found to meet the eligibility criteria, the subject will 
return for leukapheresis for the purposes of peripheral blood lymphocyte (PBL) 
storage for use in future virologic and immunologic studies. Leukapheresis, will be 
scheduled to occur at Pre-Entry 2 and during Visit 4 (Day 28). 
 
5.4 Entry (Day 0) 
Participants will have laboratory safety assessments performed and receive their 
first dose of PEG-IFN. Administration of pegylated interferon will be performed by 
trained personnel. Vital signs will be obtained, concomitant medications 
documented, and a targeted physical examination will be performed based upon 
any signs or symptoms that the subject has experienced since the last visit. 
Assessments are detailed in Appendix 1 and include: 
• 
Beck Depression Inventory score 
• 
Complete blood count with differential, platelet count 
• 
Serum chemistries (sodium, potassium, chloride, carbon dioxide, creatinine, 
urea nitrogen, alkaline phosphatase) 
• 
Urine pregnancy test (women of childbearing age) prior to interferon 
administration 
• 
ALT, Bilirubin 
• 
Creatinine clearance (Cockcroft-Gault method) 
• 
CD4 count 
• 
Single copy assay for HIV-1 RNA 
• 
HIV-1 RNA standard assay 
• 
Interferon level (baseline) 
• 
PBMCs for storage 
 
5.5 Intensification Phase: Visit 1 (Day 7), Visit 2 (Day 14), Visit 3 (Day 
21) 
Participants will have laboratory safety assessments performed and receive their 
subsequent doses of PEG-IFN. Vital signs will be obtained and concomitant 
medications documented. Administration of interferon will be performed by study 
personnel. Dosing will be based on body weight obtained during initial evaluation. 
The last PEG-IFN administration will be on Day 21 (Visit 3). A targeted physical 
examination will be performed based upon any signs or symptoms that the subject 
has experienced since the last visit. Assessments are detailed in Appendix 1 and 
include: 
• 
Beck Depression Inventory score 
• 
Complete blood count with differential, platelet count (STAT, prior to 
interferon administration) 
• 
Serum chemistries (sodium, potassium, chloride, carbon dioxide, creatinine, 
urea nitrogen, alkaline phosphatase) 
• 
Creatinine clearance (Cockcroft-Gault method) 


 
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• 
Urine pregnancy test (women of childbearing age) prior to drug 
administration 
• 
ALT, Bilirubin 
• 
Single copy assay of HIV-1 RNA 
• 
HIV-1 RNA standard assay 
• 
Interferon level 
 
5.6 Early Post-Intensification Phase: Visit 4 (Day 28) 
Participants will have laboratory safety assessments performed. Vital signs will be 
obtained and concomitant medications documented. A targeted physical 
examination will be performed based upon any signs or symptoms that the subject 
has experienced since the last visit. Assessments are detailed in Appendix 1 and 
include: 
• 
Beck Depression Inventory score 
• 
Complete blood count with differential, platelet count  
• 
Serum chemistries (sodium, potassium, chloride, carbon dioxide, creatinine, 
urea nitrogen, alkaline phosphatase) 
• 
Creatinine clearance (Cockcroft-Gault method) 
• 
ALT, Bilirubin 
• 
CD4 count 
• 
Single copy assay of HIV-1 RNA 
• 
HIV-1 RNA standard assay 
• 
Interferon level 
• 
PBMCs for storage 
• 
Leukapheresis 
 
5.7 Late Post-Intensification Phase: (Visits 5 to 9) 
Participants will return for visits at Days 35, 42, 49, and 56 during the pegylated 
interferon post-intensification phase. The Assessments are detailed in Appendix 1 
and include: 
• 
Beck Depression Inventory score 
• 
Complete blood count with differential, platelet count  
• 
Serum chemistries (sodium, potassium, chloride, carbon dioxide, creatinine, 
urea nitrogen, alkaline phosphatase) 
• 
Creatinine clearance (Cockcroft-Gault method) 
• 
ALT, bilirubin  
• 
Single copy assay for HIV-1 RNA 
• 
HIV-1 RNA standard assay 
• 
CD4 count (Visits 8 and 9) 
 
5.8 Long-term Follow-up: Week 16 (Visit 10) 
The following determinations will be assessed at the Week 16 visit: 
• 
Beck Depression Inventory score 
• 
Complete blood count with differential, platelet count  


 
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• 
Serum chemistries (sodium, potassium, chloride, carbon dioxide, creatinine, 
urea nitrogen, alkaline phosphatase)  
• 
Creatinine clearance (Cockcroft-Gault method) 
• 
ALT, bilirubin  
• 
Single copy assay for HIV-1 RNA and assays for cell associated HIV 
• 
HIV-1 RNA standard assay 
 
5.9 Weeks 24 and 36 (Visits 11 and 12) 
The following determinations will be assessed at the Week 24 and Week 36 visits: 
• 
HIV-1 RNA standard assay 
• 
Single copy assay for HIV-1 RNA and assays for cell associated HIV 
 
5.10 Week 48 (Final Visit, Study Discontinuation Visit) 
The following determinations will be assessed at the Week 48 or Study 
Discontinuation visit: 
• 
Beck Depression Inventory score 
• 
Complete blood count with differential, platelet count  
• 
Serum chemistries (sodium, potassium, chloride, carbon dioxide, creatinine, 
urea nitrogen, alkaline phosphatase)  
• 
Creatinine clearance (Cockcroft-Gault method) 
• 
ALT, bilirubin  
• 
Single copy assay for HIV-1 RNA and assays for cell associated HIV 
• 
HIV-1 RNA standard assay 
• 
CD4 count 
• 
PBMC 
 
5.11 Window Periods for Study Visits 
The following variable scheduling is permitted for study visits: 
Days -58 to 14: ±1 day  
Days 21 to 49: ±2 days  
Days 56 to 84: ±5 days  
Weeks 16 to 48: ±14 days  
 
6 
Concomitant Medications 
All concomitant medications will be documented at each study visit. 
 
Concomitant administration of immunomodulatory treatments (including steroids, 
radiation, IL-2, and anti-neoplastic agents) is not allowed during the course of this 
trial. Other investigational drugs are excluded. No vaccinations are allowed during 
the study period from 30 days  prior to the time of signing consent to the end of  
the four week interferon therapy period.  
.  
 


 
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7 
Study Drug Administration 
7.1 Drugs and Dosing 
All participants will receive pegylated interferon alpha 2b at the dose of 1.5 µg/kg 
subcutaneously every week for 4 doses. Dosing will be determined at Entry, and 
Visits 1, 2, and 3 based on subject's body weight obtained at the time of 
enrollment. Administration of study medication will be performed by study 
personnel. Antiretroviral therapy will be continued throughout the study. 
 
7.2 Monitoring Parameters 
The Schedule of Events is found in Appendix 1. Participants will be closely 
monitored for clinical and laboratory evidence of adverse events associated with the 
study drug or medical complications. 
 
7.3 Dose Modifications/Toxicities 
A complete blood count with differential (done STAT) will be reviewed before PEG-
INF administration at visits 0, 1, 2, and 3. Participants experiencing an adverse 
event Grade £2 may continue at their current dose. No interferon dose 
modifications will be made in the study but additional visits or monitoring will be 
permitted to evaluate participants. Toxicity will be evaluated using the Division of 
AIDS Table for Grading Adults Adverse Events:  
(http://rcc.tech-res.com/safetyandpharmacovigilance/ ).  
 
8 
Management of Toxicities to Study Drug 
8.1 Grade 4 Toxicities 
Participants with life threatening or Grade 4 adverse events thought to be possibly, 
probably, or definitely related to study treatment will discontinue study treatment 
and remain on study follow-up and undergo additional visits and therapy as needed 
for toxicity management. Grade 4 neutropenia determinations will be repeated with 
duplicate samples to document that neutropenia is present. 
 
8.2 Toxicity Management  
Specific expected toxicities lower than grade 4 will be managed as follows: 
 
Adverse Event Action 
Neutropenia 
Participants who experience Grade 3 neutropenia will receive 
filgrastim at 300 µg subcutaneously up to 3 times a week. Absolute 
neutrophil counts will be monitored until return to subject’s 
baseline or <Grade 1. Patient will be asked to return in 1-3 days for 
evaluation. If grade 3 neutropenia has resolved, patient will return 
2-3 days later for repeat evaluation. If grade 3 neutropenia has not 
resolved at the day 1-3 visit, additional G-CSF will be administered 


 
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and the patient will return daily for evaluation and additional G-CSF 
as medically indicated until resolved.  Filgrastim will be 
discontinued at this time. Interferon will be continued for Grade 3 
neutropenia. 
CD4 cell count If the CD4 count declines to <14%, pneumocystis prophylaxis will 
be offered until the percentage of CD4 cells increases to ≥14%.  
Depression 
If a BDS score of 14-19 is reported, assessment by the site 
investigator will be scheduled before the next dose of study drug. If 
a BDS score of 20-28 is reported, a psychiatric evaluation is 
required before the next dose of study drug. If a BDS score is >29 
or suicidal ideation is reported, participants will permanently 
discontinue study drug and undergo prompt psychiatric evaluation.  
 
 
8.3 
Criteria for Study Permanent Drug Discontinuation 
In addition to the criteria for stopping the study drug, the following will constitute 
criteria for discontinuation of study drug: 
 
1. Development of life-threatening infection or malignancy. 
2. Grade 3 or higher neutropenia. 
3. Development of clinical depression (see Section 8.5). 
4. Acquisition of hepatitis A, B, or C. 
5. Pregnancy. 
6. If subject’s CD4 cell percent remains <14% (see Section 8.2). 
7. If it is felt by the site’s principal investigator that further participation in the 
study is no longer in the best interest of the subject. 
8. Development of a medical condition, that in the opinion of the investigator, it 
is in the subject’s best interest to discontinue study treatment even if criteria 
requiring drug discontinuation have not been met. 
9. In addition, participants may be withdrawn from the study for: 
a. Withdrawal of consent 
b. Non-compliance with study visits or study treatment; subject misses a 
dose of study drug for reasons other than toxicity 
c. Termination by sponsor 
 
9 
Laboratory Studies 
9.1 Serum Chemistry and Hematology Profiles 
Routine safety laboratory tests (Appendix 1) will be performed to monitor clinical 
status and detect potential drug-related toxicities. Safety tests will be performed at 
each site’s laboratory. During the intensification phase of the study, results of 
safety tests will be reviewed by the site investigator at each visit before PEG-
Interferon administration. 
 


 
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9.2 HIV RNA Levels 
HIV-1 RNA levels will be measured by FDA-approved standard assay (b-DNA or HIV 
RT-PCR assay) and SCA assay will be measured at screening and at each study 
visit. Samples for b-DNA testing and samples for SCA assay will be processed the 
same day and plasma will be stored at -80°C. Analysis of HIV in plasma and cells 
will be analyzed through the Clinical Retrovirology Section of the HIV Drug 
Resistance Program and the HIV Molecular Monitoring Core (Leidos).  
 
9.3 Pharmacokinetics of Pegylated Interferon 
Serum levels of pegylated interferon alpha 2b will be measured at Entry and Visits 
1, 2, 3, and 4. 
 
9.4 Peripheral Blood Mononuclear Cells Storage 
PBMCs will be collected and stored at Entry, at Visits 4, , and at the Final Visit (13), 
or in the event of early study discontinuation. Samples will be processed according 
to standard processing for cryopreservation. 
 
9.5 CD4 Counts 
CD4 counts (absolute number and percentage) will be measured at Pre-entry, 
Entry, Visits 1, 4, 8, 9 and the Final Study or Discontinuation Visit. Samples will be 
processed according to standard flow cytometry procedures.  
 
10 Statistical Considerations 
 
 
This pilot study will investigate whether pegylated interferon alpha2-b will reduce 
residual HIV-1 RNA in participants with HIV-1 viremia suppressed below detectable 
levels  as measured by commercial assays.  Two relevant questions are: 1) does 
intensification reduce viremia in a consistent way across different patients, and 2) 
are there any patients in whom intensification reduces viremia?  The first question 
is of primary interest, and it pertains to the population.  The second question 
concerns whether individual intensification responders can be identified.  It is 
possible to find no consistent pattern across patients, yet identify one or more 
patients in whom the pattern of viremia lowering over time convincingly rules out a 
flat slope for that patient.  Therefore, analyses will be directed at both population 
responses and individual responses, with the primary emphasis being on the 
former. 
 
For both population and individual analyses, one complication is that because 
patients are selected on the basis of low baseline viral loads, regression to the 
mean would cause subsequent viral loads to be somewhat larger, in the absence of 
intensification.  To account for this, we will use one baseline measurement to 
determine eligibility and another to assess changes over time.   
 


 
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The primary analysis (which is at the population level), compares the viral loads 
obtained from the pre-intensification control period to the week 4 value using a 
paired t-test.  A sensitivity analysis will use the nonparametric Wicoxon signed rank 
test to analyze these baseline to week 4 changes.  Another analysis computes the 
slope of viral load over time for each patient, and uses a 1-sample t-statistic and 
confidence interval to estimate and test whether the average slope is 0.   
 
Secondary analyses will attempt to identify individual intensification responders. 
One definition of responder is whether the patient had at least a 1-log decrease 
from baseline to 4 weeks in viral load.  Because patients with baseline viral load 
below 10 cannot achieve this, another method will compute the least squares slope 
of viral load versus time for each patient and declare patients with statistically 
significant slopes as responders.   Because the goal for this analysis is to 
summarize the response of a given individual, we treat the data as independent 
observations from that patient.  This is the same assumption made when using a 
mixed model, namely that conditioned on the random, patient-specific intercept and 
slope, the observations are independent.  For both the 1 log method and significant 
slope method of identifying individual responders, we attempt to find differences in 
baseline characteristics between responders and non-responders, though very low 
power precludes finding any of these statistically significant unless they are huge.  
Of particular interest is whether baseline viral load predicts responder status.  As 
described above, for this analysis we will use one baseline value to characterize 
baseline viral load and another for the calculation of slope to identify responder 
status.  
 
All tests will be two-sided and an alpha level of less than 0.05 will be considered 
statistically significant.  Analyses will be performed on both intent-to-treat and as 
per protocol participants. Any dropouts and non-adherent participants will be 
replaced. We do not feel that stopping criteria are necessary as this pilot study is 
not for prognosis or clinical management; there is no blinding of study treatment 
and we will be monitoring toxicities in real time. In this study, we will be studying 
participants on an ongoing basis, and no interim analysis is planned. 
 
 
11 Sample Size Estimation  
This is a pilot study of the effect of pegylated interferon on HIV-1 RNA levels in 
participants who are receiving antiretroviral therapy. To date, there is limited 
published data available, and the proportion of participants who will respond with 
decreases in HIV-1 viral RNA levels remains to be clearly defined. As described 
above, responses may be similar to those observed with PI, integrase inhibitor, or 
NNRTI intensification, where no participants have experienced a decrease in viral 
RNA levels. If so, previous sample size analyses estimating the frequency of 
suppressible participants are relevant. In the accompanying table, we estimate the 
90% confidence intervals of the probability that a participant has a detectable 
decrease in viral RNA levels (participants suppressed in the table below) after 
studying increasing numbers of participants without observing episodes of drug 
suppression. As shown here, if we study 10 participants and observe no 


 
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suppression in plasma or cell-associated HIV RNA, we have 90% confidence that 
the frequency of suppressible participants is less than 21%. For this pilot study, we 
will request a sample size of 65 participants to achieve our goal of studying 10 
participants who have ≥0.1 copies/mL HIV-1 RNA at screening.  
 
90% exact confidence intervals (using the Clopper-Pearson method) for the 
probability of being suppressible.  
  
Participants 
intensified 
Participants 
suppressed 
 90% confidence interval 
5 
0 
0,0.45 
6 
0 
0,0.39 
7 
0 
0.0.35 
8 
0 
0,0.31 
9 
0 
0,0.28 
10 
0 
0,0.26 
15 
0 
0,0.18 
20 
0 
0,0.14 
 
 
 
12 Hazards/Discomforts/Risks 
12.1 Study Drugs and Procedures 
12.1.1 
Pegylated Interferon Alpha 2b 
Interferon alpha is a cytokine with proven antiviral activity against many viruses, 
especially HCV. The exact mechanism of this antiviral activity is not known. The 
proposed mechanisms of actions for interferon alpha are:  
1. Antiviral activity through the inhibition of viral replication in infected cells 
(Sen 2001, Bekisz, Schmeisser et al. 2004, Jiang, Guo et al. 2008). With 
respect to HIV-1 specifically, INF has shown antiviral activity both in vitro 
(Ho, Hartshorn et al. 1985) and in vivo (Lane, Kovacs et al. 1988, Hatzakis, 
Gargalianos et al. 2001) studies.  
2. Immune regulatory actions increasing the ability of reticuloendothelial cells to 
clear virus through the following mechanisms (Missale, Bertoni et al. 1996, 
Gerlach, Diepolder et al. 1999, Patel and McHutchison 2001):  
a. Increase in class 1 MHC antigens and cellular adhesion molecules on 
effector cells 
b. Activation of effector cells (NK cell and macrophages) 
c. Upregulation of Th1-T helper subset  
 
In participants with cirrhosis, exacerbation of cirrhosis-related neutropenia and 
thrombocytopenia is a recognized risk associated with interferon and pegylated 
interferon. Participants with documented cirrhosis will be excluded from 


 
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participating in this study. The other recognized side effects associated with the use 
of pegylated interferon include fatigue, headaches, myalgia, fever, nausea, upper 
abdominal discomfort, depression, diarrhea, insomnia, reduced appetite, and 
dermatitis. There are also rare occurrences of autoimmune, infections, ophthalmic, 
and ischemic disorders associated with pegylated interferon use. Ophthalmologic 
complications include retinopathy, which is usually transient and completely 
resolves with continued treatment. Other side effects associated with subcutaneous 
injection include pain and inflammation at the site of injection.  
The specific adverse events listed below will be handled as specified. PEGINTRON 
will be administered in clinic by trained personnel.  Merck Inc. will be providing 
study drug PEGINTRON; other study agents will be provided through respective 
pharmacies as indicated. 
12.1.2 
Granulocyte Colony Stimulating Factor 
Endogenous granulocyte colony stimulating factor (G-CSF) is a lineage specific 
colony-stimulating factor, which is produced by monocytes, fibroblasts, and 
endothelial cells. G-CSF regulates the production of neutrophils within the bone 
marrow and affects neutrophil progenitor proliferation, differentiation, and selected 
end-cell functional activation. 
Filgrastim is a human granulocyte colony-stimulating factor (G-CSF), produced by 
Escherichia coli bacteria into which has been inserted the human granulocyte 
colony-stimulating factor gene. Filgrastim is available as a sterile, clear, colorless, 
preservative-free liquid for parenteral administration at a specific activity of 1.0 ± 
0.6 x 10 U/mg (as measured by a cell mitogenesis assay). The product is available 
in single-use vials and prefilled syringes. The single-use vials contain either 300 µg 
or 480 µg filgrastim at a fill volume of 1.0 mL or 1.6 mL, respectively. It has been 
shown to be safe and effective in accelerating the recovery of neutrophil counts 
following a variety of chemotherapy regimens. Filgrastim is contraindicated in 
patients with known hypersensitivity to E. coli-derived proteins, or any component 
of the product. Allergic-type reactions occurring on initial or subsequent treatment 
have been reported in <1 in 4000 patients treated with filgrastim. These have 
generally been characterized by systemic symptoms involving at least 2 body 
systems, most often skin (rash, urticaria, facial edema), respiratory (wheezing, 
dyspnea), and cardiovascular (hypotension, tachycardia). Some reactions occurred 
on initial exposure. Reactions tended to occur within the first 30 minutes after 
administration IV. Rapid resolution of symptoms occurred in most cases after 
administration of antihistamines, steroids, bronchodilators, and/or epinephrine. 
Symptoms recurred in more than half the patients who were rechallenged. Other 
rarely reported serious complications associated with filgrastim include splenic 
rupture, acute respiratory distress syndrome, alveolar hemorrhage and hemoptysis, 
and sickle cell crises. G-CSF will be administered in clinic b trained personnel. 
 


 
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12.1.3 
Potential for Previously Unrecognized Drug Interactions 
Interferon alpha 2b has been co-administered with antiretroviral therapy in HIV-
infected individuals without any severe toxicity. Adverse events observed in 
HIV/HCV-coinfected participants receiving treatment with PEG INF and ribavirin 
were similar to those occurring in HCV-monoinfected participants. Drug interactions 
between antiretrovirals and treatment for hepatitis C concern mostly ribavirin and 
reverse transcriptase inhibitors (Mallolas and Laguno 2008). 
 
12.1.4 
Potential for Adverse Effects from Leukapheresis 
Risks associated with leukapheresis are similar to those seen with whole blood 
transfusions. They rarely include infection (<1% of persons) and commonly include 
nausea, fainting, dizziness, bruising at the needle puncture site, blood loss, and a 
transient decrease in platelet or red blood cell counts in 10% to 25% of persons. 
Potential problems of a leukapheresis procedure when citrate is given intravenously 
as an anticoagulant rarely includes seizures in <1% of persons and commonly 
includes muscle cramping, numbness, chilling, tingling sensations, and feelings of 
anxiety. Citrate is approved by the Food and Drug Administration for this use. If 
citrate/heparin or heparin alone is used as the anticoagulant, there may be a 
transient increase in clotting time, which may lead to blood loss in very rare 
instances (<1%). There is also a small risk of technical problems with the apheresis 
machine (1:1000 phereses). 
 
12.1.5 
Risks of Phlebotomy 
The primary risks of phlebotomy include occasional bleeding or bruising of the skin 
at the site of needle puncture, and the sensation of transient lightheadedness or 
rarely, fainting or infection. The amount of blood drawn for research purposes shall 
not exceed 10.5 mL/kg or 550 mL, whichever is smaller, over any 8-week period. 
 
12.2 Human Subject Protections 
Participants will be fully counseled prior to entry into the study as to the potential 
risks of the study. Participants who, in the opinion of the study team, do not fully 
comprehend these potential risks will not routinely be offered participation in the 
study. Participants will be monitored closely during their participation in the study, 
and informed of any new information regarding the study treatment that may 
influence their willingness to continue study participation. 
 
13 Study Recruitment  
The study will be advertised and posted on the NIH web site. The University of 
Pittsburgh AIDS Clinical Trials Unit will recruit participants from its Volunteer 
Registry. IRB-approved recruitment materials will be distributed among AIDS 
service organizations and other HIV providers in the region. Both the NIH and the 
University of Pittsburgh have recently completed drug intensification studies and 
have been successful in enrolling participants willing to complete the frequent visits. 


 
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In the most recent study, we used the current viral RNA enrollment criterion (≥0.38 
copies/mL) to study raltegravir intensification; 36 participants were screened for 
the study and 10 were eligible; the remainder were excluded chiefly on the basis of 
viral RNA levels. Nevertheless, 9 of the 10 enrolled participants completed this 
study and had evaluable data that were useful in determining whether viremia 
decreased. To improve our statistical analysis, we have increased the sensitivity of 
the assay (lower limit of quantification = 0.1 copies/ml) and will use 0.1 copies/ml 
as cutoff. 
 
13.1 Gender, Ethnicity, and Race Consideration 
Participants will not be excluded based on race, gender, or ethnicity. It is hoped 
that the racial and ethnic character of the participants in this study will reflect, as 
closely as possible, the demographics of the HIV epidemic in the United States. The 
NIAID has an outreach program to medically underserved minority participants in 
order to improve their access to clinical trials. The University of Pittsburgh’s AIDS 
Clinical Trials Unit makes a concerted effort to provide access to AIDS clinical trials 
for women and minorities. 
 
13.2 Children and Pregnant Women 
This study will be limited to adults 18 years of age and older. Insufficient data are 
available to evaluate the safety and efficacy of pegylated interferon in the pediatric 
population. In addition, this study is a no benefit study and would not be applicable 
to pediatric populations. The risks of pegylated interferon alpha 2b treatment 
during pregnancy have not been evaluated. Therefore, pregnant or nursing women 
will be excluded from this study. Any woman of childbearing potential must have a 
negative pregnancy test at screening, baseline, and prior to each dose of pegylated 
interferon and also agree to use two accepted methods of contraception throughout 
the study.  
 
 
14 Benefits/Compensation/Alternatives 
Financial compensation will be provided to study participants as outlined below. 
Participants will receive remuneration for the immediate costs associated with their 
study-related expenses like travel expenses, lodging, etc., as provided by the 
National Institutes of Health. 
 
Participants will be financially compensated according to the NIH Normal Volunteer 
Guidelines proportionate to the inconvenience of the procedures necessary to 
obtain the samples. The compensation schedule is as follows:  
Day 0 to Week 24: $40 at each visit  
Leukapheresis: $100 each 
 
The University of Pittsburgh AIDS Clinical Trials Unit will provide compensation for 
travel based on zip code and distance from the University. 
 


 
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This is a no benefit study; the alternative is not to participate. By participating in 
this study, participants may contribute to our understanding of persistent HIV 
viremia in individuals receiving potent antiretroviral therapy. 
 
15 Evaluation of Safety 
All enrolled participants who have received any study drugs will be evaluated for 
safety. Safety will be assessed by physical examination, vital signs, hematology, 
chemistry, urinalysis, and assessment of AEs. The severity of signs, symptoms, and 
AEs will be determined by using the Toxicity Severity Scale (Appendix 2). 
Recording/Documentation 
At each contact with the subject, information regarding adverse events will be elicited 
by appropriate questioning and examinations. All events, both expected/unexpected 
and related/unrelated will be recorded on a source document. Source documents will 
include: progress notes, laboratory reports, consult notes, phone call summaries, 
survey tools and data collection tools. Source documents will be reviewed in a timely 
manner by the research team. All reportable adverse events that are identified will 
be recorded in CRIMSON, or the appropriate case report form (CRF), or source 
document. The start date, the stop date, the severity of each reportable event, and 
the PI’s judgment of the AEs relationship and expectedness to the study 
agent/intervention will also be recorded in CRIMSON, or on the appropriate CRF, or 
source document. 
 
 
15.1 Protocol-specific Adverse Events  
15.1.1 
Definitions of Adverse Events 
Adverse Event: Any untoward or unfavorable medical occurrence in a human 
subject, that includes any abnormal sign (e.g. abnormal physical exam or 
laboratory finding), symptom, or disease, temporally associated with the subject’s 
participation in the research, whether or not considered related to the research. 
 
Serious adverse event: Any adverse event that 
• results in death; 
• is life-threatening (places the subject at immediate risk of death from the event as 
it occurred); 
• results in inpatient hospitalization or prolongation of existing hospitalization; 
• results in a persistent or significant incapacity; 
• results in a congenital anomaly/birth defect; or 
• based upon appropriate medical judgment, may jeopardize the subject’s health 
and may require medical or surgical intervention to prevent one of the other 
outcomes listed in this definition. (examples of such events include allergic 
bronchospasm requiring intensive treatment in the emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse) 
 


 
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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 Serious 
Adverse Event or compromises the safety, welfare or rights of subjects or others. 
 
Non-compliance: The failure to comply with applicable NIH 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. 
Unanticipated Problem (UP): Any incident, experience, or outcome that meets all 
three of the following criteria would be considered a serious UP:  
 
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 
2. related or possibly related to participation in the research 
3. suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized. 
 
Unanticipated problem that is not an Adverse Event (UPnonAE): An unanticipated 
problem that does not fit the definition of an adverse event, 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.  These events may 
involve a greater risk of social or economic harm to subjects or others rather than 
physical/psychological harm. Such events would be considered a non-serious UP. 
Examples of a UPnonAE include a breach of confidentiality, accidental destruction of 
study records, or unaccounted-for study drug. 
 


 
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15.1.2 
Adverse Event Reporting 
Expected adverse events are those listed in the package inserts for Pegintron. 
Adverse events will be graded according to the Division of AIDS Table for Grading 
Adults Adverse Events (http://rcc.tech-res.com/safetyandpharmacovigilance/ , 
Appendix 2), assessed for severity (mild/moderate/severe), expectedness 
(expected/unexpected), and relatedness to study drug (definitely, probably, 
possibly, unlikely, or unrelated). All adverse events will be recorded in the study 
database. Serious adverse events will be reported to the participating IRBs and the 
FDA. Adverse events that do not meet guidelines for expedited reporting will be 
included with each continuing review. 
 
15.1.2.1 
 
Expedited Reporting to the NIAID IRB 
 
Serious and non-serious Unanticipated Problems, deaths, serious deviations, and 
serious or continuing non-compliance will be reported within 7 calendar days of 
investigator awareness. Serious Adverse Events that are possibly, probably, or 
definitely related to the research will be reported to the NIAID IRB within 7 calendar 
days of investigator’s awareness, regardless of expectedness. 
15.1.2.2 Waiver of Reporting Anticipated Protocol Deviations, Expected 
non-UP AEs and Deaths   
Anticipated deviations in the conduct of the protocol will not be reported to the IRB 
unless they occur at a rate greater than anticipated by the study team. Expected 
adverse events will not be reported to the IRB unless they occur at a rate greater 
than that known to occur in HIV infection.  If the rate of these events exceeds the 
rate expected by the study team, the events will be classified and reported as 
though they are unanticipated problems. Deaths related to the natural history of 
HIV infection will be reported at the time of continuing review. 
 
15.1.2.2 
Annual Reporting 
The following items will be reported to the NIAID IRB in summary at the time of 
Continuing Review: 
 
- 
Serious and non-serious unanticipated problems  
- 
Expected serious adverse events that are possibly, probably, or definitely 
related to the research 
- 
Serious adverse events that are not related to the research 
- 
All adverse events, except expected AEs and deaths granted a waiver of 
reporting.  
- 
Serious and Non-Serious Protocol deviations  
- 
Serious, continuing, and minor non-compliance 
- 
Any trends or events which in the opinion of the investigator should be 
reported 
- 
Protocol specific reporting as applicable 


 
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- 
 
15.1.2.3 
Reporting of Pregnancy  
Pregnancy that occurs during the course of the protocol will be reported within 7 
days of the investigator’s awareness 
15.1.2.4         Type and Duration of the Follow-up of Subjects after Adverse 
Events 
Serious adverse events will be followed until resolution; Some adverse events resulting 
that do not resolve completely will be followed until stable.  Pregnancy will be followed 
until 3 months after delivery, miscarriage, or termination. 
 
16 Monitoring 
This is an open-label treatment protocol. Monitoring will be performed by the site 
investigators. The NIAID and the University of Pittsburgh Institutional Review 
Boards will review the study at least annually. Because of the nature of the study, 
we plan to constitute a Data Safety Monitoring Board (DSMB) at the NIH to review 
the study progress and safety at least annually.  This function will be provided 
through NIAID DSMB, although the group will be functioning as a safety monitoring 
committee. 
 
The NIAID Intramural DSMB is constituted to review the safety data of Intramural 
NIAID clinical studies that require DSMB oversight, and consists of experts in 
infectious diseases, biostatistics, and clinical trials. The DSMB will meet at least 
once a year to review the completeness of the study data collected, the adherence 
to the protocol, and PI’s review summaries to evaluate safety, study conduct, and 
scientific validity and integrity of the study. Other reviews may occur as needed if 
other safety issues arise. 
 
The initial review will occur prior to opening the study to enrollment. 
16.1 Stored Samples and Future Research 
Extra blood samples will be stored using a code number that only the study team 
can trace back to the subject.  These samples will be stored for other investigators 
who may want to pursue additional research using these stored samples. If so, the 
NIH study team may send these samples to them, along with the coded number 
label. Once the protocol is terminated and data analysis is completed remaining 
samples will be maintained for future research by appropriate transfer to other 
protocols for ongoing human subjects protection oversight; requesting the use of 
stored samples may be submitted to the IRB for approval if the intended use is not 
covered by original consent. Any loss or destruction of stored samples will require 
written IRB notification.  
 
16.2 Data Management Plan 
All research data and results will be carefully recorded using data collection forms 
that will be saved and allow for continuous access. Further, all collected data will be 
entered and saved to a password-protected computer spreadsheet (Microsoft 


 
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ExcelTM) for analysis and review. The investigator is responsible for assuring that 
the data collected is complete, accurate and recorded in a timely manner.  Source 
documentation should support the data collected on the CRF and must be signed 
and dated by the person recording and/or reviewing the data.  All data will be 
annotated and indexed, including all notebooks and computerized information, to 
facilitate detailed review of data. All data, even those of experiments not directly 
leading to publication, will be treated comparably. All research data will be made 
available to scientific collaborators and supervisors for immediate review, consistent 
with requirements of confidentiality.   All research data, including the primary 
experimental results, will be retained for a minimum of 5 years to allow for analysis 
and repetition by others of published material resulting from the data.  
 
Demographic information and laboratory results will be collected using case report 
forms and then transcribed into an electronic database on an ongoing basis as 
participants are enrolled. At the NIH site, data will be stored in the CRIMSON 
database.  Other experimental data, including HIV viral load results and IFN drug 
levels, will be analyzed and reported in batches. Standard laboratory results will be 
accessed by the site investigators and the study coordinators. All results, whether 
recorded on paper or electronically, will be maintained using only the subject's 
numeric code for identification. Data collection and quality assurance will be 
performed primarily by the site investigators and study coordinators. 
 
Data management, including the decision to publish, will be the responsibility of the 
Co-Principal Investigators. After publication, all research data that form the basis of 
that communication will be made available promptly and completely to responsible 
scientists seeking further information. Exceptions include those requests that would 
infringe on confidentiality of clinical data or if unique materials were obtained under 
agreements that preclude their dissemination. 
 
17 Anonymity and Confidentiality 
As each subject is consented and then enrolled, he or she will be allocated a unique 
study number. To ensure subject confidentiality, these numeric codes will substitute 
for personal identifiers on all paper documents, computer records, and blood 
sample vials. The information obtained during the conduct of this clinical study is 
confidential, and disclosure to third parties other than those noted is prohibited. 
The results of the research study may be published, but subject’s names or 
identities will not be revealed. Records will remain confidential. To maintain 
confidentiality, the Principal Investigators will keep records with personal identifiers 
in double-locked cabinets and the results of tests will be coded to prevent 
association with subject names. It is expected that this data will be reported in 
scientific journals and scientific meetings. Confidentiality of participants will be 
maintained in all forms of reporting. Participants will be informed in general terms 
of the results as soon as practical.  
 
 


 
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Visit
Screen
Pre-Ent 1
Pre-Ent 2
Entry
1
2
3
4
5
6
7
8
9
10
11
12
Final Visit*
Day/Wk
D-58 to -28
D-27 to -1
D-14 to -1
D0
D7
D14
D21
D28
D35
D42
D49
D56
D84
W16
W24
W36
W48
Consent
x
x
Physical
x
x
Vital signs
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Tar. Phys.
x
x
x
x
Med Hx
x
Con meds
x
x
BDS
x
x
x
x
x
x
x
x
x
x
x
x
x
Psy Eval
**
**
C/D/Pl
x
x
x
x
x
x
x
x
x
x
x
x
x
Chem*
x
x
x
x
x
x
x
x
x
x
x
x
x
FBS 
X
ALT,Bili
x
x
x
x
x
x
x
x
x
x
x
x
x
Amylase
x
Creat Cl
x
x
x
x
x
x
x
x
x
TSH/FT4
x
UA
x
Preg
x
x
x
x
x
ELISA/WB**
x
ANA
x
Hep B SA
x
HepB Sab
x
HepC Ab
x
HepC VL
x
CD4+
x
x
x
x
x
x
HIV RNA
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
SCA
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Eye exam
x
PBMC 
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Apheresis
x
x
IFN admin
x
x
x
x
IFN level
x
x
x
x
x
*Chem&includes&Creatinine,&lytes,&BUN,&Alk&phos
&&&&&&&&&&&&&&**
* If not available 
&


 
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Appendix 2: Toxicity Severity Scale 
The toxicity grading scale for this protocol is the “Table for Grading the Severity of Adult and Pediatric 
Adverse Events; Version 1.0 - December 2004 (Clarification dated August 2009).”    
 
It can be found at: 
http://rcc.tech-res.com/safetyandpharmacovigilance/