Conditions: HIV
Keywords: Viremia Statin HIV Replication Cholesterol Lipid Raft HIV Infection HIV Positive
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 24
Healthy volunteers: no

Brief summary:
This study will examine the effects of atorvastatin, a statin (drug that lowers cholesterol) on the human immunodeficiency virus (HIV). If not treated, HIV infection causes an incurable, progressive deficiency in the immune system that leads to death, usually from disease that takes advantage of weakened immunity. Previous studies, however, have suggested that if the amount of cholesterol in infected cells is reduced, multiplication of HIV is also reduced. In this study, researchers will examine the HIV viral loads, that is, amount of the virus in the blood. They will evaluate the composition of the strain of the virus that patients carry (HIV genotype), response of the immune system to the virus, and how genes may determine the way in which the drug may or may not work against the strain of virus. Researchers plan to enroll 22 participants, anticipating a study to last 30 weeks for each participant.

Patients ages 18 or older with HIV infection, who are not pregnant or breastfeeding, who do not have a known allergy to atorvastatin use, and who have not had a serious illness or infection that required hospitalization within the 30 days before entering the study may be eligible for this study. They will be assigned to random groups: one that to receive atorvastatin and the other to receive a placebo, which has no effect on cholesterol or ability of the HIV infection to multiply. Patients will remain in their groups and treatments for 8 weeks. At the completion of 8 weeks, no matter the study group, all patients will be required to discontinue all study-related medications for 4 weeks. After that period, the study assignments will be switched, so that those previously taking the placebo will take atorvastatin, and vice versa. The study will proceed for another 8 weeks, followed by a period of stopping study-related medications and patients being observed for 4 weeks. Throughout the study, patients will have regularly scheduled visits at the clinic. At those visits there will be collection of blood samples, assessments of symptoms, physical examinations, and questionnaires to complete. Blood tests may require fasting beforehand, and blood samples will be used in standard tests, including those regarding the liver, kidneys, muscles, blood cells, and pregnancy status. Specialized blood tests will determine viral load, effects of the drug on the immune cells, and genetic influence on the drug's effectiveness.

Detailed description:
This protocol is a randomized, double blind, placebo controlled trial designed to study the effects of the lipid lowering statin, atorvastatin on HIV-1 viremia.

Untreated HIV-1 infection results in an incurable, progressive immunodeficiency and death, usually from opportunistic infections. Combination antiretroviral therapy (ARV) has been successful in suppressing HIV replication and reducing morbidity and mortality. Long term ARV therapy is associated with the development of HIV-1 drug resistance, and significant adverse side effects including metabolic and cardiovascular complications. Prolonged therapy with certain antiretrovirals is associated with increased risk of cardiovascular disease and a number of dyslipidemic syndromes, including increased levels of cholesterol, LDL, and triglycerides in peripheral blood. New therapeutic strategies to suppress HIV-1 infection are essential.

Previously, in vitro studies suggested that exposure to cholesterol-lowering statins results in decreases in HIV-1 replication. The mechanisms of inhibition remain uncertain, but possibilities include disrupting membrane trafficking or cytoskeletal processes necessary for intracellular transport of viral proteins, or altering cellular activation state necessary for viral gene expression. Initial in vivo studies of the effects of statins on HIV-1 have been largely anecdotal in nature and have yielded conflicting results. Although statin therapy is commonly used in HIV-1 infection, adverse effects from the combination of antiretrovirals and statins are possible. A more thorough understanding of the effects of statins on HIV-1 replication is essential to determine the potential therapeutic effect and to investigate the risks and benefits of this approach in vivo.

We plan to conduct a double blind randomized placebo controlled trial, with a cross over design, to study the effects of atorvastatin in 22 HIV-infected patients not currently taking antiretroviral therapy. Patients will be randomized to receive either placebo or atorvastatin 80mg for 8 weeks. After a 4-week wash out period patients on the atorvastatin arm will crossover to placebo and, vice versa patients in the placebo arm will cross over to atorvastatin for an additional 8 weeks. Upon completion of study medications all patients will be followed for 4 weeks. Each arm will have a minimum of 11 patients each. The primary outcome measure in this study is the effect of lipid lowering agents on HIV-1 RNA levels; additional secondary outcome measures include effects of lipid lowering agents on lipid profile, markers of inflammation and immune activation and investigations of host and viral genetic factors.

Arms:
arm 1: Patients were randomized to receive Atorvastatin first for 8 weeks, followed by 4 weeks wash out, and then cross over to placebo for 8 weeks. arm 2: Patients were randomized to receive placebo first for 8 weeks, followed by 4 weeks wash out, and then cross over to 80 mg atorvastatin daily for 8 weeks.

Interventions: intervention 1: Atorvastatin intervention 2: Placebo
Intervention descriptions: intervention 1: 80 mg atorvastatin oral daily intervention 2: patients will be administered placebo

Protocol document:
ICF_002.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: 
06-I-0197 
 
PRINCIPAL INVESTIGATOR:   
 
 
STUDY TITLE: 
A Randomized Placebo Controlled Trial of Atorvastatin in HIV Positive Patients Not on 
Antiretroviral medications with the Specific Aims of Studying the Effects of Atorvastatin on HIV 
Viral Load and Immune Activation Markers 
 
 
Continuing Review Approved by the IRB on 4/14/08 
Amendment Approved by the IRB on 03/20/08 (G) 
Date Posted to Web: 05/06/08  
Screening 
 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY 
 
•   Adult Patient or    •   Parent, for Minor Patient 
 
NIH-2514-1 (4-97) 
 
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 the Study 
 
HIV, the virus that causes AIDS, grows in the immune cells of the body. Recent research has shown that for the HIV to 
multiply (replicate), it has to use some of the normal cell machinery. One of the pathways the virus uses to multiply 
requires cholesterol (a kind of fat in the body). Laboratory research has indicated that if the amount of cholesterol in 
infected cells is reduced, HIV replication is also decreased. These experiments have been done only in the laboratory and 
it is not known whether reducing cholesterol in people infected with HIV will also reduce HIV replication.  In this study we 
plan to investigate whether the use of cholesterol lowering drugs called statins will reduce HIV replication and lower the 
level of HIV in the blood “viral load”. We are studying the effects of one statin called atorvastatin (Lipitor), which has been 
approved by the Food and Drug Administration (FDA) for treatment of persons with hyperlipidemia (elevated lipids in the 
blood). Atorvastatin is not an approved treatment for HIV infection, and should not be considered a therapy for HIV; even 


 
 
  
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: 
06-I-0197 
CONTINUATION:  page  2  of  10  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
if it does decrease HIV viral loads (the amount of the HIV virus in your blood), it is unlikely that atorvastatin alone will 
control HIV.  Atorvastatin is approved by the FDA for the treatment of hypercholesterolemia and is available for use 
outside this study.  However, atorvastatin is not FDA approved for treatment of HIV infection.  As you are likely to have 
normal cholesterol you may not receive any benefit from taking atorvastatin.  The desire to take atorvastatin should not 
be a reason for you to volunteer to take part in this study. 
 
Study Procedures 
 
You will first come to the clinic for a screening visit, after signing this screening consent you will undergo testing to 
determine whether or not you qualify for the study. Testing at this visit will include blood and urine tests.You will be 
required to come fasting for the tests, as eating prior to testing may result in changes to your cholesterol (fat in the 
blood).  Tests will include standard tests to study the health of your liver, kidney, muscle and blood and a pregnancy test. 
You will undergo specialized tests to determine if you are infected with the hepatitis B or C virus, tests to determine the 
amount of HIV virus in your blood “HIV viral load” and also tests to measure your immune cells “CD4 count”.  You will be 
required to come fasting for this visit because we will check the level of lipids in your blood, which can change if you are 
not fasting.  You will also undergo a clinical assessment and a physical exam at this visit. 
 
If you are eligible for the study phase of the protocol based on the results of testing done at your screening visit and if 
you desire to enroll in the protocol you will enter the study phase.  In the study phase, you will sign a new consent that 
details the procedures of the study.  Briefly, you will be randomly assigned (by chance, like the flip of a coin) to one of 
two study groups.  One study group will be asked to take atorvastatin, a medicine that reduces cholesterol and may 
affect the ability of your virus to multiply.  The other study group will take a placebo (something like a sugar pill) that 
should have no affect either on the level of your cholesterol or the ability of your virus to multiply.  Once you have been 
assigned to the study groups, you will remain in your assigned groups/treatments for 8 weeks.  Upon completion of 8 
weeks, regardless of the study group you were assigned to, you will be required to discontinue all study related 
medications for 4 weeks. There may be  some circumstances where we may extend this off drug period to a total of 6 
weeks. For instance, if you require the influenza vaccination, which can sometimes affect HIV-1 viral RNA levels, we will 
administer the standard inactivated vaccine at the beginning of the off drug period, followed by  six week wash out.  At 
the end of this period, you will be asked to switch your study assignments i.e. if you were on the placebo pill you will 
switch to the study drug atorvastatin and vice versa if you were on the study drug atorvastatin you will switch to the 
placebo pill.  You will complete an additional 8 weeks on this assigned study treatment; after this you will stop all study 
related treatment and be observed for an additional 4 weeks. 
 
Study Population 
 
We plan to enroll 22 subjects for this study and the anticipated duration on study for each subject is 24weeks. We will 
screen as many patients as required to enroll 22 patients onto this study. 
 
Summary of Entry Criteria 
 
To participate in the study you must:  
• Be greater than 18 years of age  
 
• Be infected with the HIV-1 virus  
 


 
 
  
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: 
06-I-0197 
CONTINUATION:  page  3  of  10  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
• Off all antiretroviral therapy (ART) “medicines taken to control the virus multiplication” for greater than three 
months prior to study entry. While off ART you must have a stable viral load ” amount of virus in your blood” 
• Be willing to use two methods of contraception during the study period. Adequate methods of birth control 
include: condoms, male or female, with or without a spermicide; diaphragm or cervical cap with spermicide; 
intrauterine device; any of the methods that require a prescription (such as contraceptive pills or patch, 
Norplant, Depo-Provera, and others) or a male partner who has previously undergone a vasectomy, 
  
• If you had been taking ART in the past and are currently not on any medication, there must be no evidence 
that when you were taking these medications, these medications were not working against your strain of the 
virus what we refer to as “resistance”. 
 
 
• Be willing to have blood drawn 
 
 
• Have no known allergy or contraindication to atorvastatin use 
 
• Have the ability to understand and willingness to sign the informed consent 
 
• Be willing to have blood stored for future testing including tests that will study your genes and the genetics of 
the virus 
 
 
• Have a CD4 cell count (a measure of your immune cells) greater than 350 cells/ml 
 
• Have three viral loads that average greater than 1000 copies/ml within a 4 week period. 
 
• Have near normal total cholesterol “ a kind of fat in the body” (i.e lower than 240mg/dl) and an LDL 
cholesterol “a kind of fat in the body “ lower than 130mg/dl 
 
• Have near normal results for tests that test the health of your kidney, pancreas, liver, blood and muscles  
 
• Have a negative pregnancy test and not be breast feeding prior to taking the study drug 
 
• Not be on any other medication to lower your cholesterol 
 
• Let your doctor know if you are on any herbal medications or supplements 
To Participate in the Study You Must Not  
• 
Be actively using any recreational drugs or alcohol as this might interfere with your ability to participate in the 
study 
 
• 
Have had a serious illness or opportunistic infections “illnesses that occur in people with a weakened 
immunity” that required hospitalizations in the 30 days prior to entry into the study 
 
• 
Have evidence of any cancer or opportunistic illness that will require treatment during the study period except 
some forms of skin cancers 


 
 
  
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: 
06-I-0197 
CONTINUATION:  page  4  of  10  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
 
• 
Allergy to the study medication “atorvastatin” or any of its components 
 
• 
Have had a history of myositis or rhabdomyolysis (diseases that results in muscle injury or swelling 
“inflammation”) with use of any statins 
 
• 
Have had a history of  diseases of the muscle such as poly or dermatomyositis (these are diseases of the 
muscle that results in swelling “inflammation” of the muscle) 
 
• 
Be on any medications that do not mix “interactions” with the study drug.  Please see the attached listing, if 
you are on any of these drugs please let your physician know. 
  
• 
Use St.Johns wort, as this can increase the amount of study drug in your body. 
 
• 
Use grape fruit or grape fruit juice, as this can increase the levels of study drug in your body 
 
• 
Be on any medication that might affect your immune response  
 
• 
Have a low LDL cholesterol ( a kind of fat in the body) that is lower than 40 mg/dl 
 
• 
Have had any vaccines within 6 weeks of entry into the study. 
 
Withdrawal From the Protocol 
 
You may choose to withdraw from the protocol at any time. We may choose to withdraw you from the protocol at any 
time if we think it is not in your best interest to continue on the protocol, or if you fail to comply with the requirements of 
the protocol or if the Data Safety Monitoring Board (DSMB) “a panel of independent investigators” who will review the 
data after we accrue 50 % of the patients” decides to stop the protocol. If the protocol is terminated for unanticipated 
reasons subjects will be withdrawn from the study. If you need to start antiretroviral therapy, you will be withdrawn from 
the study and referred to your primary physician. Any decision to start antiretroviral therapy will be done in consultation 
with your primary physician. If you need to start antiretroviral therapy you should do so after you have discontinued 
atorvastatin for at least one week. You may also be withdrawn from the study if blood tests that measure your liver 
functions are greater than 3 times the upper limit of normal on two successive measurements. 
 
Duration of Study 
 
The study will take 24 weeks to complete once you have been assigned to one or the other group 


 
 
  
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: 
06-I-0197 
CONTINUATION:  page  5  of  10  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
Risks/Discomforts/Monitoring 
Risks 
The possible risks and discomforts from screening for this study are the risks from the blood drawing and the risks from 
sample storage.  The risks associated include bleeding, bruising, and fainting.  To minimize risk, patients will have their 
blood taken in the sitting position and will be monitored for 10 minutes after the procedure. 
 
If you are eligible to participate in the study phase of the protocol, there are additional risks from the study medication 
and from reductions in your cholesterol, and we will discuss those risks in an additional consent at the time you start 
the study phase. 
 
Benefits 
 
You will not benefit from taking part in this study, but the information we learn may help us with the management of HIV 
positive patients in the future.  This includes the availability of a drug that is frequently used in the management of some 
of the complications of drugs currently used to control the virus and may have the potential to control the quantity of 
virus and affect the immune response in HIV positive patients.  
 
Compensation 
 
To compensate for your time and inconvenience of this screening visit, you will be paid $70.00 
 
Alternatives to Participation 
 
This study provides no direct benefits to participants.  You are in no way obligated to continue in the protocol even if you 
are eligible.  The alternative to participation is not to enroll.  
 
Additional Information 
 
There will be no cost to you for study medications, clinic visits, examinations or laboratory and test procedures that are 
part of this study and that are obtained at the NIH. Medical costs of other treatment outside this study and outside of the 
NIH will not be the responsibility of the NIH. The NIH will provide only study-related medical care, and medical care and 
medications not directly related to the study must continue to be provided by your personal physician. We will be sending 
letters regarding your study participation and your care to your doctor routinely and as needed, and we will also use the 
fax and the phone to relay information to your doctor that he or she should know to best care for you.  We will not ask 
your permission for each of these contacts.  We will contact the physician you have named as your doctor, but you may 
give us a different physician to contact instead at any time.  Once your participation in this study is completed, you will 
not be eligible for continuing care at NIH, unless you are eligible for another study at the NIH, but your doctors at NIH will 
be glad to provide telephone consultation to your own doctor on request.  During the study, you will be told about any 
research that relates to your study, especially any findings from the study itself. 


 
 
  
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: 
06-I-0197 
CONTINUATION:  page  6  of  10  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
Genetic Testing 
 
Some of the blood drawn from you as part of this study will be used for genetic tests.  Genetic tests can help researchers 
study how health or illness is passed on to you by your parents or from you to your children.  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 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.  
Some of the blood drawn from you as part of this study may be used for a test for HLA type, which is a genetic test of 
markers of the immune system.  It 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 HIV 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.  
 
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.  Medical 
records containing this information will be kept under lock and key.  We will not release any information about you or your 
family to relatives, any insurance company, or employer unless you sign a release requesting us to do so.  Genetic 
information can be requested and obtained when a person applies for health insurance or a job and has signed a release. 
 
Stored Samples and Future Research 
 
Blood left over from this study will be stored.  These stored samples will help us learn more about HIV, immune deficiency  
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, 
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. 
 
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. 


 
 
  
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: 
06-I-0197 
CONTINUATION:  page  7  of  10  pages 
 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
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 a 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 only use your samples 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.   
 
Benefits 
 
In general, future research that uses your samples will not help you, but it may help us learn what causes AIDS, immune 
deficiency, or related conditions.  This research may also help us learn how to prevent or treat the condition. 
 
Risks 
 
The greatest risk is that someone may take information from your medical records without your permission.  The chances 
of this happening are very low.  If this information becomes available, you may face discrimination when you apply for 
insurance or a job.  You may also have similar problems if you share the information yourself or let us release your 
medical records. 
 
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. 
 


MEDICAL RECORD
INCLUSION OF HIV TESTING IN CONSENT TO
PARTICIPATE IN A CLINICAL RESEARCH STUDY
 
 
 
CONTINUATION:  page  8  of  10  pages 
 
 
PATIENT IDENTIFICATION 
INCLUSION OF HIV TESTING IN CONSENT TO 
 
PARTICIPATE IN A CLINICAL RESEARCH STUDY 
 
NIH-2514-3 (5-02) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
 
As part of your participation in this study, it will be necessary to test your blood for the presence of antibodies to the 
Human Immunodeficiency Virus (HIV), the virus that causes Acquired Immune Deficiency Syndrome (AIDS).  In order to 
perform the test, a small amount of blood (approximately 2 teaspoons) will be withdrawn from one of your arms with a 
needle.  You may experience some slight discomfort at the needle entry site and there may be some bruising.  In 
addition, there is a very small risk of you fainting or of infection at the needle entry site.  If your test results are found 
to be positive, or if you are otherwise diagnosed as having AIDS, you should be aware of the following Clinical Center 
HIV Testing Policy: 
 
 
1. 
Your physician will notify you promptly of the HIV test results. 
 
 
2. 
Your physician and/or the Clinical Center HIV counselor will offer you, and any current and/or ongoing 
sexual partner(s) (spouses are generally considered to be current or ongoing sexual partners) or needle-sharing 
partner(s) you identify, information on the meaning of the test results and how to prevent the spread of the 
infection. 
 
 
3. 
Because the virus may be transmitted in several ways, it is important that you inform sexual and/or 
needle-sharing partner(s) that any, or all, of them may have been exposed to the HIV virus and encourage 
them to be tested.  If you request it, staff at the Clinical Center will assist you in notifying your partner(s) and 
arrange counseling for them through an HIV counselor. 
 
 
4. 
The results of your HIV test and/or documentation of the diagnosis of AIDS will become a part of your 
Clinical Center medical record and, as such, will be protected from unauthorized disclosure by the Federal 
Privacy Act of 1974.  In general, access to your medical record will be restricted to those health care 
professionals directly involved in your care or in the conduct of ongoing biomedical research, and information is 
not usually released to other third parties without your permission or that of your designated representative.  
However, there are some particular routine uses of such information of which you should be aware. 
 
a.  If you are unwilling or unable to notify your partner(s), the Clinical Center is responsible for 
attempting to contact and inform them of their possible exposure to the virus.  Reasonable attempts 
will be made to protect your identity including withholding your name when notifying any partner(s) of 
their possible exposure.  Some notification or counseling of current and/or ongoing partners may be 
carried out through arrangements with, or referral to, local public health agencies. 
 
b.  A summary of your care at the Clinical Center will be sent to the physician who referred you here for 
treatment. 
 
c.  The Clinical Center may report certain communicable diseases, such as HIV infection, to appropriate 
State and Federal government agencies. 
 
i. 
For Clinical Center patients who are Maryland residents, the Clinical Center reports by “Patient 
Unique Identifier Number” (rather than by name) newly obtained HIV-positive results from its 
laboratory to the Maryland Department of Health and Mental Hygiene.  Patient Unique Identifier 
Number is:  last four digits of social security number, birth month, birth day, birth year, race and 
gender. 
 


MEDICAL RECORD
INCLUSION OF HIV TESTING IN CONSENT TO
PARTICIPATE IN A CLINICAL RESEARCH STUDY
 
 
 
CONTINUATION:  page  9  of  10  pages 
 
 
PATIENT IDENTIFICATION 
INCLUSION OF HIV TESTING IN CONSENT TO 
 
PARTICIPATE IN A CLINICAL RESEARCH STUDY 
 
NIH-2514-3 (5-02) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
 
ii. 
For Clinical Center patients who are Maryland residents, the Clinical Center reports by name new 
cases of AIDS to the Maryland Department of Health and Mental Hygiene. 
 
iii. 
For Clinical Center patients who are not Maryland residents, the Clinical Center 
reports HIV-positive results and/or AIDS to the patient’s primary care/referring physician. 
 
If you have any questions regarding the HIV testing or the information provided above, you are encouraged to discuss 
them with your physician and/or a Clinical Center HIV counselor:  (301) 496-2381. 
 


 
  
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
   MEDICAL RECORD 
•  Adult Patient or    •  Parent, for Minor Patient 
 
STUDY NUMBER: 
06-I-0197 
CONTINUATION:  page  10  of  10  pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY (Continuation Sheet) 
 
•  Adult Patient or   •  Parent, for Minor Patient 
 
NIH-2514-1 (5-98) 
 
P.A.: 09-25-0099 
 
 
FAX TO:  (301) 480-3126 
 
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 other authorized 
people. 
 
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. 
 
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, Frank Maldarelli, M.D. 
Building: 10, Room 12S245, Telephone: (301) 435-8019. Other investigators you may call are Rose McConnell (301) 
443-5643.  
 
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 
Signature of Parent(s)/Guardian 
Date 
 
 
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 
 
 
 
THIS CONSENT DOCUMENT HAS BEEN APPROVED FOR USE  
FROM APRIL 14, 2008 THROUGH APRIL 13, 2009. 
 
 
 
  
 
 
  
 
Signature of Investigator 
Date 
Signature of Witness 
Date 
 
 

Prot_SAP_000.pdf: 
Version 5.2 
September 20, 2007 
A RANDOMIZED PLACEBO CONTROLLED TRIAL OF ATORVASTATIN IN HIV 
POSITIVE PATIENTS NOT ON ANTIRETROVIRAL MEDICATIONS WITH THE 
SPECIFIC AIMS OF STUDYING THE EFFECTS OF ATORVASTATIN ON HIV 
VIRAL LOAD AND IMMUNE ACTIVATION MARKERS 
 
 
 
 
Sponsored by:  National Institute of Allergy and Infectious Diseases 
 
NON-IND Protocol  
Version 5.2 
 
Principal Investigator: 
Anuradha Ganesan (NNMC) 
 
Associate Investigators:  
Frank Maldarelli, Timothy Whitman (NNMC), Catherine Decker (NNMC), Nancy Crum-
Cianflone (NMCSD), Mary Bavaro (NMCSD) 
 
Research Study Coordinator:  
Sean McCarthy (NNMC) 
Carolyn Brandt (NMCSD) 
 


Version 5.2 
September 20, 2007 
 
2
TABLE OF CONTENTS 
 
 
Page 
SITES PARTICIPATING IN THE MAIN STUDY....................................................................... 4 
1.0       PRECIS............................................................................................................................... 5 
2.0 
BACKGROUND............................................................................................................7-11 
2.1 
HIV structure and replication...................................................................................7 
2.2 
Potential antiretroviral targets..................................................................................8 
2.3       Host and viral factors in HIV assembly, budding and release..............................8,9 
 
2.4 
Statins and their putative effects on viral replication and T cell activation……...10 
2.5 
Statin effects on HIV-1 RNA levels in vivo...........................................................10   
3.0 
OBJECTIVES....................................................................................................................12  
Primary objective...............................................................................................................12 
Secondary objective...........................................................................................................12 
4.0   
STUDY DESIGN…………………………………………………………………….12, 13 
5.0 
SELECTION AND ENROLLMENT OF SUBJECTS................................................ 13-20 
5.1 
Inclusion Criteria ...................................................................................................13 
5.2 
Exclusion Criteria ..................................................................................................15 
5.3 
Study Enrollment Procedure overview............................................................…. 16 
5.3.1 Prerandomization evaluations................................................................................17 
5.3.2 Randomization scheme..........................................................................................17 
5.3.3 Study entry……………………………………………………………………….18 
5.3.4    On study evaluations………………………………………………………......... 18 
5.3.5    Post treatment evaluation………………………………………………………...19 
5.4      Criteria for withdrawal……………………………………………………............20 
5.5  
Breaking the blind………………………………………………………………..22 
5.6 
Criteria for stopping enrollment………………………………………………….22 
6.0 
STUDY TREATMENT............................................................................................... 22-24 
6.1 
Atorvastatin............................................................................................................22 


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3
6.2 
Product Supply, Distribution, and Pharmacy.........................................................24 
6.3 
Drug Storage..........................................................................................................24 
6.4 
Accountability of drugs..........................................................................................24 
 
7.0 
STATISTICAL CONSIDERATIONS…..………………………………………….........25 
8.0 
DATA COLLECTION AND MONITORING AND ADVERSE EXPERIENCE 
REPORTING…………………………………………………………………………27-30 
8.1  
Adverse and serious adverse reporting ..................................................................27 
8.1.1 Definition...............................................................................................................27 
8.1.2 Reporting................................................................................................................27 
8.2 
Protocol monitoring and DSMB............................................................................29 
 
8.3       Data and Safety Monitoring Plan………………………………………………...30 
 
8.4       Data Management Plan…………………………………………………………..30 
 
 
9.0 
HUMAN SUBJECTS………………………………………………...………………31-34 
9.1 
Benefits ..................................................................................................................31 
9.2  
Risks.......................................................................................................................31 
9.2.1 Medication associated risk…………………………………………………….....31 
 
9.2.2 Risks associated with hypercholesterolemia……………………………………..32 
 
9.2.3     Risks associated with phlebotomy………………………………………………33 
 
9.3 
Confidentiality…………………………………………………………………...33 
9.4 
Study discontinuation…………………………………………………………….33 
9.5       Sample Storage…………………………………………………………………..33 
 10.0    REFERENCES……………………………………………………………………….35-37 
 
APPENDICES  
 
APPENDIX I: DAIDS Toxicity Tables  
           APPENDIX I.A:  CPK Toxicity Criteria 
APPENDIX II:  Drug interactions with atorvastatin 


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4
APPENDIX III:  Package insert for atorvastatin 
APPENDIX IV:  Piper Fatigue Scale  
APPENDIX V: Becks Depression Inventory 
 
 
SITES PARTICIPATING IN THE MAIN STUDY 
National Institutes of Health 
National Naval Medical Center 
Naval Medical Center San-Diego 
 
 
 
 
 
 
 
 
 


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5
1.0 PRECIS 
This protocol is a randomized, double blind, placebo controlled trial designed to study the 
effects of the lipid lowering statin, atorvastatin on HIV-1 viremia. 
Untreated HIV-1 infection results in an incurable, progressive immunodeficiency and 
death, usually from opportunistic infections. Combination antiretroviral therapy (ARV) has been 
successful in suppressing HIV replication and reducing morbidity and mortality. [1] Long term 
ARV therapy is associated with the development of HIV-1 drug resistance, and significant 
adverse side effects including metabolic and cardiovascular complications. [2] Prolonged therapy 
with certain antiretrovirals is associated with increased risk of cardiovascular disease and a 
number of dyslipidemic syndromes, including increased levels of cholesterol, LDL, and 
triglycerides in peripheral blood. [3] New therapeutic strategies to suppress HIV-1 infection are 
essential. 
 Previously, in vitro studies suggested that exposure to cholesterol-lowering statins results 
in decreases in HIV-1 replication.[4, 5] The mechanisms of inhibition remain uncertain, but 
possibilities include disrupting membrane trafficking or cytoskeletal processes necessary for 
intracellular transport of viral proteins, or altering cellular activation state necessary for viral 
gene expression.[4-8]  Initial in vivo studies of the effects of statins on HIV-1 have been largely 
anecdotal in nature and have yielded conflicting results. [9-12] Although statin therapy is 
commonly used in HIV-1 infection, adverse effects from the combination of antiretrovirals and 
statins are possible.[13] A more thorough understanding of the effects of statins on HIV-1 
replication is essential to determine the potential therapeutic effect and to investigate the risks 
and benefits of this approach in vivo. 
We plan to conduct a double blind randomized placebo controlled trial, with a cross over 
design, to study the effects of atorvastatin in 22 HIV-infected patients not currently taking 
antiretroviral therapy. Patients will be randomized to receive either placebo or atorvastatin 80mg 
for 8 weeks. After a 4 week wash out period patients on the atorvastatin arm will crossover to 
placebo and vice versa patients in the placebo arm will cross over to atorvastatin for an 
additional 8 weeks. Upon completion of study medications all patients will be followed for 4 
weeks. Each arm will have a minimum of 11 patients each. The primary outcome measure in this 
study is the effect of lipid lowering agents on HIV-1 RNA levels; additional secondary outcome 


Version 5.2 
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measures include effects of lipid lowering agents on lipid profile, markers of inflammation and 
immune activation and investigations of host and viral genetic factors.  


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7
2.0 BACKGROUND 
2.1 HIV structure and replication 
HIV-1 is a member of the lentivirus family of retroviruses, a group of enveloped RNA 
viruses that replicate via a DNA intermediate.   The HIV genome is composed of genes that code 
for structural components, enzymes necessary for viral replication, as well as regulatory and 
accessory proteins.  Steps in HIV-1 replication depicted in figure 1 include viral binding and 
interaction with chemokine receptors (1), membrane fusion, (2) viral uncoating (3) and reverse 
transcription of viral RNA (4). The pre-integration complex is then transported to the nucleus 
where viral DNA integrates into the host cell chromosome (5) followed by viral RNA synthesis 
(6).  The later steps include translation of viral mRNA into viral proteins, virion processing, 
assembly, (7) maturation followed by budding and release (8).  
 
 
Figure 1 - Schematic representation of HIV-1 replication (adapted from the article by 
Peterlin and Trono [14])
2
3
4
5
6
7
8
1


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2.2- Potential antiretroviral targets  
Initially, antiretroviral therapy was concentrated exclusively on viral targets and focused 
on available inhibitors of viral enzymes reverse transcriptase and protease (Steps 4, and 7, 
respectively) or the viral fusion reaction (Step 1). Newer approaches include targeting 
interactions between host and viral factors, including inhibiting virion binding  to susceptible 
cells with HIV-1 coreceptor inhibitors.[15]   HIV populations in vivo are genetically diverse, and 
one effect of drug therapy is selection of viral mutants that are resistant to antiretrovirals. 
Emergence of drug resistance is one of the most critical factors limiting long term suppression of 
HIV replication.  New therapeutic strategies to limit HIV replication are essential. One such 
approach is to target cellular processes that are essential for virus replication in such a way that 
virus replication is inhibited without causing critical damage to cellular functions. In one 
potential example of this approach, several investigators have reported that statin therapy may 
inhibit  HIV-1 replication in vitro, either by interfering with intracellular transport or cellular 
activation pathways, resulting in marked reductions in HIV replication without significant 
cellular injury.[4-8] In vivo data evaluating this approach are lacking, and we propose to 
investigate the effects of statin therapy on HIV-1 replication in chronically infected individuals. 
2.3 Host and viral factors in HIV assembly, budding and release 
HIV virion maturation is a complex process requiring interactions between the host and 
the virus. One critical step in virus replication, virion assembly, requires specific host virion 
interactions. Virion components are transported to the cell surface using specific lipid “rafts”, 
cholesterol-rich cellular micro domains and bud through cell membranes by co-opting the 
multivesicular body (MVB) process that normally functions to recycle plasma membrane 
components.[16] [17] Transport via rafts is a highly specialized process that requires specific 
protein protein interactions; for HIV-1 transport is thought to involve both cellular and viral gene 
products. 
Host pathways involved in transport and budding include a series of membrane- protein 
complexes which bind target proteins and ensure targeting to specific intracellular locations. A 
number of cellular proteins have been identified that participate in intracellular trafficking, 
including TSG101, a lipid raft constituent, which binds specific protein domains ensuring 
transport.  


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HIV-1 viral genes involved in transport are products of the HIV-1 gag gene. Gag is 
synthesized as a polypeptide precursor molecule composed of several proteins including Matrix 
(p17), Nucleocapsid (p7), Capsid (p24), p6, p1, p2 and a spacer protein. Expression of gag 
proteins appears sufficient for the assembly and release of non-infectious virion like particles. 
[18-20] The gag precursor, referred to as pr55gag, is composed of several domains that play 
specific roles in viral assembly and release. These domains include the membrane binding 
domain that directs virus to the membrane (M), the multimerization domain that promotes gag -
gag multimerization (I) and the late domain (L) that is involved in viral budding. [21]   A 
specific HIV-1 Gag protein, denoted p6, may provide a critical link between cellular machinery 
and virion component. P6 has a specific proline-threonine-alanine-proline (PTAP) domain that is 
thought to define the L domain and interact directly with cellular protein TSG101. [22, 23] The 
P6-TSG101 interact may represent the docking mechanism by which virion components are 
loaded onto lipid rafts. Notably, in vitro investigations studying the effects of mutations in p6 
resulted in marked decreases in HIV-1 production.[24] Similarly, depletion and overexpression 
of cellular TSG 101 inhibits viral budding.[25, 26] Recently Carrington et al investigated the 
hypothesis that TSG101 may have naturally occurring variants in the human population, and that 
these variants may influence circulating levels of HIV-1.  Interestingly, TSG 101 polymorphisms 
in this study appeared to have a strong association with disease progression over time 
(Carrington M, in preparation).  In addition, analysis of genetic polymorphisms in the Swiss 
Cohort, a large natural history study of HIV-1 infected patients in Europe revealed an association 
between TSG101 genotype and disease progression .[27]  These data suggest that interactions 
between TSG 101 and HIV may have significant clinical consequences. The virion transport 
mechanism using lipid rafts may represent an attractive therapeutic target. In addition to proteins 
such as TSG101, lipid rafts contain large amounts of cholesterol.  Disruption of lipid rafts by 
depleting cellular cholesterol using either methyl beta cyclodextrin or the statin simvastatin 
results in marked reduction in HIV virion production. Furthermore the virion particles produced 
are not as infectious as wild type virus.[4] This suggests that lipid rafts play a critical role in 
HIV-1 replication and may be potential therapeutic targets for control of HIV viral replication.  
 
 


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2.4- Statins and their putative effects on viral replication and T cell activation 
Disruption of lipid rafts may not be the only mechanism by which statins might alter viral 
replication. Statin drugs are competitive inhibitors of the enzyme HMG CoA reductase. This 
enzyme catalyzes the conversion of HMG CoA (3-hydroxy 3 methylglutaryl-coenzymeA) to 
mevalonate, the rate limiting step in cholesterol synthesis. By limiting synthesis of mevalonate, 
statins inhibit the synthesis of not just cholesterol but also of non–steroidal isoprenoid 
derivatives. Non-steroidal isoprenoid compounds are involved in the post-translational 
modification of several cell proteins including the Rho and Rac GTPases.  
The Rho family of GTPases, this family includes Rac GTPases, control actin 
cytoskeleton remodeling in response to stimuli.[28] HIV entry into cells is an actin dependent 
process.[6] It is believed that interactions between HIV env, CD4, and its co receptors activate 
Rac-1 GTPase. This stimulates actin filament reorganization, which is needed for HIV fusion.[7] 
By blocking mevalonate synthesis, statins prevent the functioning of Rho GTPases and actin 
cytoskeleton remodeling. [29] Recently published data suggest that by targeting the function of 
Rho GTPases statins inhibit HIV-infection of SCID mice grafted with adult human PBMCs.[11]  
T cell activation plays an important role in HIV progression. Depletion of CD4 positive 
cells during HIV infection is not merely a consequence of direct infection of these cells. T cell 
activation leads to T cell proliferation T cell depletion and ensuing immunosupression. [30] 
Statins alter T cell activation and may affect disease progression in HIV infected patients.  
Statins may affect T cell activation via several mechanisms including altering MHC II 
expression and lipid rafts disruption. T cell receptors localize within lipid rafts and disruption of 
lipid rafts leads to altered T cell activation. [31]  [32]  
2.5 Statin effects on HIV-1 RNA levels in vivo   
In vivo data on statin use in HIV infection is limited.  In a study of 6 early stage (CDC 
stage A1), ARV naïve patients with stable viral loads, treated with lovastatin, plasma viral load 
decreased with statin use. The reductions in viral load in this group of patients were between 0.2 
and 1.3 log10 copies. Viral loads done 12 weeks after Lovastatin discontinuation demonstrated a 
viral rebound, with 5 of the 6 patients demonstrating a change in their set point. This study was 
non-randomized and did not study viral RNA levels in patients not treated with statins[11]. In a 
recent report, we reported analysis of patients treated with 40 mg Pravastatin as part of a study of 


Version 5.2 
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11
endothelial function. Seven patients in this study had detectable viremia allowing the authors to 
analyze the effects of Pravastatin 40 mg on viral load. 3/7 patients had a decrease in viral load 
while 4/7 had increases. We concluded that there appeared to be no significant effect of statin 
therapy on HIV-1 viral RNA levels in this group. Interestingly, however, 3/7 patients had 
rebound in viral load after discontinuation of Pravastatin.[12] Two additional studies have also 
failed to show any effect of statin therapy on HIV-1 viral RNA levels.  In a retrospective study 
patients who started “first line HAART’ were compared with those who started ‘first line 
HAART” and were at some point thereafter started on statins.  In this study the 2 groups did not 
differ in the number of patients who had viral rebound after initial suppression to less than 500 
copies/ml or blips (defined in this study as a decline in viral load to <500 copies followed by a 
rebound to greater than 500 copies/ml and then a fall to <500 copies).[10]  Finally, chronically 
infected patients who had discontinued antiviral therapy for 12 weeks were studied by examining 
the effects of Simvastatin (80mg) on HIV-1 RNA. No decreases in viral RNA were detected after  
4, 8 and 12 weeks.[9] The results of this study are difficult to interpret given the missing data 
points.  
There may be numerous reasons for the inconsistent effect of statin exposure on HIV-1 
viral RNA levels; statins may be effective with certain strains of HIV-1 or with specific 
combinations of TSG101/p6 genotypes. Effects may not be manifest or may be blunted in 
patients with elevated cholesterol levels at baseline, where statin induced decreases may not 
sufficiently decrease intracellular cholesterol levels sufficiently to affect HIV replication. The 
lack of a rigorous study design for most of these studies may introduce sufficient bias to prevent 
clear cut results.  
The 3 statins tested thus far in vivo models are pravastatin, lovastatin and simvastatin. 
Pravastatin is the only statin that does not have significant drug- drug interactions in HIV 
positive patients on antiretrovirals. However, pravastatin use is associated with modest decreases 
in serum cholesterol, as the decreases in serum cholesterol seen with pravastatin use may not be 
sufficient to result in lipid raft disruptions necessary to demonstrate any significant antiviral 
effects.  Both simvastatin and lovastatin use is associated with significant decreases in serum 
cholesterol but both drugs are contraindicated with other antiretrovirals. Atorvastatin use is 
associated with significant reductions in serum cholesterol, and several reports suggest that the 


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12
use of atorvastatin while theoretically contraindicated with antiretrovirals is safe and well 
tolerated. Given this we chose to study atorvastatin for its antiviral effects. 
 
To further define the effects of statins on HIV viremia and to study virus host interactions 
in the context of statin use we have designed a randomized placebo controlled cross over study 
of atorvastatin use in HIV positive patients. In this study the effects of cholesterol reduction on 
HIV-1 viremia, T cell activation, and metabolic parameters in HIV positive patients will be 
explored. Furthermore viral and host genetic factors as it relates to response or lack of response 
to statins will also be explored.  
 
3.0 OBJECTIVES 
3.1 Primary objective 
The primary objective of this study is to compare the changes in HIV-1 viral load during 
the atorvastatin phase with the changes in viral load in the placebo phase. 
3.2 Secondary objectives 
• To compare the changes in the expression of immune activation markers between the 
placebo phase and the atorvastatin phase. 
• To investigate HIV-1 and TSG 101 phenotypes among enrollees   
• To investigate the changes in the metabolic profile between the placebo and the 
atorvastatin phase 
• To investigate the safety profile of atorvastatin in HIV positive patients not on 
antiretroviral therapy 
• To compare the subjective and objective evaluation of fatigue during the atorvastatin and 
placebo phase 
 
4.0 STUDY DESIGN  
Study design 
 This study utilizes a case cross over design to investigate the effects of atorvastatin on 
HIV viral load, immune activation markers and metabolic profile. Figure 2 is a diagrammatic 
representation of the study design. A double blind strategy was chosen for the design of this trial. 
In general statin therapy is associated with a number of side effects, some of which, including 


Version 5.2 
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13
fatigue and muscle aches may be highly subjective or multifactorial in origin. If statins do show 
an antiviral effect, then their use will be balanced by well described adverse effects. We wish to 
evaluate such adverse effects in detail in patients enrolled in the trial, and feel double blind 
approach is the most rigorous and objective. 
HIV positive patients, who have been off anti-retroviral medications for a minimum of 3 
months and with no documented evidence of resistance, will be recruited for this study.  Each 
subject will have 3 baseline viral loads and will be randomized to receive either 80 mg of 
atorvastatin or placebo for 8 weeks. Following this, there will be a 4 week wash out phase. Upon 
completion of the wash out phase patients who were initially on the atorvastatin arm will switch 
to the placebo arm, while patients who started in the placebo arm will switch to atorvastatin to 
complete an additional 8 weeks.  All patients will be followed for 4 more weeks upon 
completion of study medications. The study design is schematically represented in Figure 2. 
Atorvastatin 80
Placebo
Wash out
Atorvastatin 80
Placebo
0
8
12
20 
24
Figure 2 - Graphical representation of the study design (time represented
in weeks)
Follow up
 
5.0 SELECTION AND ENROLLMENT OF SUBJECTS 
5.1 Inclusion Criteria 
 
Establish with patient prior to Informed Consent: 
• Adults 18 years of age or older 
• HIV-1 infection, as documented by a licensed ELISA test kit and confirmed by a 
Western blot assay at any time point prior to study entry or at study entry ( May do 
after informed consent if no test results are available). 


Version 5.2 
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14
Off all ARV for ≥ three months prior to study entry, no documented evidence of viral resistance, 
and no evidence of acute HIV infection. For the purposes of this study acute HIV infection will 
be defined as presence of a detectable HIV-1 viral RNA in the presence of a non reactive HIV-1 
or HIV-2 antibody assay or an indeterminate western blot. For the purposes of this study viral 
resistance is being defined as having a genotypic or phenotypic evidence of resistance or in the 
absence of formal resistance testing clinical evidence of resistance for e.g. patients with 
persistent viremia in the face of adequate adherence 
• Willingness to use a method of contraception during the study period. Adequate 
methods of birth control include: condoms, male or female, with or without a 
spermicide; diaphragm or cervical cap with spermicide; intrauterine device; any of 
the methods that require a prescription (such as contraceptive pills or patch, Norplant, 
Depo-Provera, and others) or a male partner who has previously undergone a 
vasectomy,  
•  Willingness to have blood drawn 
• Non known allergy or contraindication to atorvastatin use 
• Ability to understand and willingness to sign the informed consent 
• Willingness to have blood stored for future phenotyping and genotyping 
After Informed Consent: 
• CD4 cell count greater than 350 cells/ml  
• 3 viral loads that average greater than 1000 copies/ml within a 4 week period. 
• The viral loads will be done using the bDNA method in the NIH laboratory and must 
be within 20% (log10bDNA of each other). 
• A fasting total cholesterol lower than 240mg/dl and a LDL cholesterol lower than 
130mg/dl 
• Liver function tests (AST or ALT) not greater than 1.5 times the upper limit of 
normal. Evidence of active hepatitis B or C will not be considered an exclusion 
criteria if the liver function tests are within normal limits. 


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15
• Creatine phosphokinase elevations (CPK) not greater than 3 times the upper limit of 
normal (ULN) on two sequential determinations and, in the opinion of the 
investigator, without clear association with exercise.  
• Laboratory values: 
 
Absolute neutrophil count (ANC) ≥ 1000/mm3. 
Hemoglobin ≥ 11.0 g/dL. 
Platelet count ≥ 100,000/mm3 
Creatinine ≤ 2 x ULN 
Serum amylase and lipase ≤ 1.25 x ULN 
• Negative serum pregnancy test at randomization 
5.2 Exclusion Criteria 
• Pregnancy or breast feeding 
• Active drug use or alcohol abuse/dependence, which in the opinion of the 
investigators will interfere with the patient’s ability to participate in the study  
• Serious illness requiring systemic treatment and/or hospitalization within 30 days of 
entry 
• Evidence of active opportunistic infections or neoplasms that require chemotherapy 
during the study period except cutaneous Kaposi Sarcoma 
• Allergy or hypersensitivity to atorvastatin or any of its components 
• History of myositis or rhabdomyolysis with use of any statins 
• History of inflammatory muscle disease such as poly or dermatomyositis 
• Concomitant use of fibric acid derivatives or other lipid lowering agents including 
patients on statins and Ezetimibe 
• Concomitant use of drugs that have significant interactions with atorvastatin.  Please 
see appendix II for a listing, 
• Concomitant use of  St.Johns wort 
• Concomitant use of Valproic acid 


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16
• Patients who are on concurrent immunomodulatory agents, including systemic 
corticosteroids will be ineligible for 3 months after completion of therapy with the 
immunomodulating agents. Topical, nasal or inhaled corticosteroids use is not an 
exclusion criteria  
• Serum LDL cholesterol less than 40 mg/dl 
• Vaccinations within 6 weeks of study entry. 
5.3 Study enrollment procedure overview 
 
 Prior to implementation of this protocol, sites must have the protocol and informed 
consent forms approved by their local institutional review board (IRB). Health care providers at 
participating institutions will identify eligible patients. At the National Naval Medical Centers all 
providers and research nurses at the Infectious Disease Clinic (IDSI) will identify eligible 
patients.  Once a candidate for study entry is identified, patients will be approached by their 
providers or research nurses about the protocol. If the candidate is interested details of the 
protocol will be reviewed with the candidate by the study PI/designee.  If the volunteer is willing 
to participate in the study, they will be provided with copies of the informed consent to review. 
After all questions, about the study and the informed consent, have been answered to the 
participant’s satisfaction, they will be asked to sign the IRB approved consent form.  
 
Volunteers enrolled at the NIH will be required to sign a screening consent to undergo 
screening laboratories for the study. Patients who satisfy inclusion criteria and are willing to 
participate in the study will be required to sign the study informed consent. Since study 
participants at NNMC receive their routine care at NNMC screening consents will not be used at 
the NNMC prior to study enrollment.  Volunteers at NNMC will be required to sign the study 
consent only. 
 
It is anticipated that most subjects will have their routine immunizations prior to signing 
informed consent. However, in the event routine vaccination is required after the subject has 
been randomized; for DOD sites (NNMC and NMCSD) we will attempt to vaccinate the 
individual after completion of the week 8 visit or at the end of the study phase of the protocol.  
For subjects vaccinated during the wash-out phase or at the end of the study the wash-out phase 


Version 5.2 
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17
or the last study visit will be extended by 2 weeks. For patients seen at the NIH site, the protocol 
will not administer routine vaccinations, with the exception of the influenza vaccination. It is 
anticipated for some patients, participation may overlap with influenza season and that influenza 
vaccination will be necessary in the event that protocol participation begins prior to but extends 
into, influenza season. For such patients, standard, inactivated influenza vaccination will be 
administered (if necessary) during the week 8 visit. For subjects vaccinated during the wash-out 
phase or at the end of the study the wash-out phase or the last study visit will be extended by 2 
weeks. Extension of both these study phases is necessary because of the effects of vaccination on 
viral kinetics.[33] 
Definitions for Schedule of Events – Timing of Evaluations 
 
5.3.1 Prerandomization evaluations 
After signing either the screening/study informed consent, patients will undergo 
screening tests. Screening will include a complete medical history and physical examination. 
Laboratory testing will include a fasting lipid profile, flow studies (FACS), routine safety labs 
which will include a liver function test and creatinine kinase assay, a hepatitis profile and viral 
load assay to establish baseline viral load. Due to the variability in the viral load assay, we will 
utilize a minimum of 3 viral load assays to establish a baseline.  All testing will need to be 
completed within a 4 week period prior to randomization. During this period, patients may come 
in for testing at their own convenience, but testing will not be done more than once within a 24 
hour period. All laboratory tests except standard safety labs will be done centrally at SAIC 
Frederick to maintain consistency. Volunteers at the NIH who satisfy the inclusion criteria and 
who continue to be interested in the protocol will be now required to sign the study consent. 
5.3.2 Randomization scheme 
Subjects will be randomized after the investigators have ascertained that the subject 
meets criteria for inclusion. Prior to randomization investigators will ensure that the patient 
understands the risks and benefits associated with the study and informed consent has been 
signed. Randomization will be done using a random number table generated by the NIH 
pharmacy department. 11 patients will be randomized to the placebo arm of the study and 11 to 
the drug arm of the study initially. The 11 patients randomized to placebo will then cross over 
after completion of 12 weeks on study (8 weeks on study treatment and 4 weeks wash out) to the 


Version 5.2 
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18
study arm and vice versa patients in the atorvastatin arm will cross over the placebo arm after 12 
weeks on study  
5.3.3 Study entry 
 
On the day patients get randomized, patients will undergo routine safety labs including 
liver function tests (LFT), creatinine phosphokinase, hematological parameters, fasting lipids 
including apolipoprotein B, hsCRP, plasma HIV viral load and a full FACS. Patients will also 
have a sample of blood stored for future phenotyping and genotyping. Patients will be required to 
answer both the Piper Fatigue Scale and the Beck Depression Inventory.  
5.3.4 On study evaluations 
Efficacy Assessments 
 
Patients will undergo HIV BDNA assays on days 7, 14, 42, 56, 84, 91, 98, 126, 140 and 
168. Patients will also undergo evaluation for immune activation markers levels specifically 
CD38 and HLA-DR expression on CD4 and CD8 cells and Ki67 will be done on days 7, 56, 84, 
91, 140 and 168. Fasting lipids, apolipoprotein and ultrasensitive hsCRP will be done at 
randomization and on day 7, 56, 84, 91, 140 and 168.  All testing other than standard safety 
testing will be done at SAIC Frederick. The Beck depression inventory and the Piper fatigue 
scale will be administered on days 56, 84, 140 and 168. 
Safety assessments 
 
Safety assessments will be done at specified study visits and will include clinical 
assessment, physical exam, medication assessment, routine chemistry and hematology, serum 
creatinine phosphokinase, liver function tests, and serum pregnancy tests. The Piper Fatigue 
Scale will be administered prior to and following each arm.  Please see table 1 for details. All 
safety labs will be done at the individual institutions. All laboratories performing study related 
tests are CLIA certified laboratories 
Genetic studies 
  
TSG 101 genotyping and HLA typing will be performed. Additional genotyping of 
specific host genes will be performed as indicated. Additional blood will be obtained as indicated 
for   storage and future use.  
 
 
 


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19
Adherence assessment 
 
Pill counts will be performed at each visit to monitor adherence to the protocol, and 
patients will be asked about adherence.  
5.3.5 Post treatment evaluations 
4 weeks after treatment discontinuation (± 1 week), patients will have repeat viral load, 
lymphocyte sub set analysis, immune activation parameters, safety labs including LFTs and 
creatinine phosphokinase. All visits will be completed on the indicated days of the protocol, for 
unforeseeable circumstances that might render the patient unable to complete the study visit on 
the designated days the patient may reschedule within a 2-5 day window except for the end of 
study visit which may be completed within a 1 week window. 
5.4 Subjects can be discontinued from the study for the following reasons: 
• Failure to comply with the protocol 
• If they develop a serious adverse event (SAE) 
• Pregnancy, if a patient becomes pregnant on study; she will stop the study drug and be 
followed as part of the study through the pregnancy including the peri-partum period to 
ensure her safety. 
• Any subject with a creatinine phosphokinase (CPK) value greater than 10 times the 
upper limit of normal (i.e grade 3 or higher), will undergo repeat testing. Repeat 
testing will be conducted at protocol specified time points (i.e. within 1-3 days of the 
initial result and also at day 7). Persistently elevated laboratory values, i.e. CPK 
measurements that remain at the same level or are higher than the initial value, on 
three consecutive determinations, despite cessation of exercise will result in study 
drug discontinuation.    
• In addition, all CPK elevations associated with grade 3 or higher symptoms or for 
significant symptoms or elevations in CPK that do not fall into either of the above 
mentioned categories; a conference call with representatives from all three 
participating sites (either the PI or their designee) will be initiated.  Decisions 
regarding study drug discontinuation for patients meeting the above listed criteria 
will be made on an individual case by case basis. The medical monitor at the sites 
will be involved in all decisions regarding study drug discontinuation. 


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20
• Patient develops liver function elevations 3 times the upper limit of normal  
• If the serum LDL cholesterol falls to less than 40mg/dl  
• Develops a grade 2 or greater allergic reaction to the medicine or develops signs and 
symptoms of an immediate hypersensitivity reaction to the medication 
• Patient needs to start antiretroviral agents using current DHHS guidelines as 
recommendations. 
• Patient develops any condition that the study investigators deem would be detrimental for 
the patient to continue on the study 
• If the patient desires to leave the study 
• Patient starts taking other lipid lowering drugs including fibric acid derivatives, bile acid 
sequestrants and niacin preparations 
• Patients will be dropped from the study if their CD4 count drops by fifty percent on two 
successive determinations, or falls below 250 cells/µl in the absence of any documented 
ongoing infections/inflammatory processes while on study 
If subjects are discontinued from the study secondary to any of the above given reasons they will 
be replaced according to the prior randomization. 


Version 5.2 
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21
 
CLINICAL AND LABORATORY EVALUATION  
• * Study consent will be signed at NNMC prior to screening and at randomization at the 
NIH 
• † In the event subject is vaccinated these visits will be extended by 2 weeks 
Table 1- Schedule of events 
Evaluation* 
Screening 
Randomization 
D7 
W1 
D14 
W2 
D42 
W6 
D56 
W8 
D84† 
W12 
D91 
W13 
D98 
W14 
D126 
W18 
D140
† 
W20 
D168 
W24 
Documentation of 
HIV 
Pos ELISA 
and 
Confirmatory 
Blot, previous 
results will be 
allowed 
 
 
 
 
 
 
 
 
 
 
 
Medical 
/Medication 
history 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nadir CD4 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical 
Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
Questionnaires 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis profile 
 
 
 
 
 
 
 
 
 
 
 
 
Fasting lipid 
profile 
 
 
 
 
 
 
 
 
 
 
 
 
Markers of 
inflammation 
 
 
 
 
 
 
 
 
 
 
 
 
Hematology 
 
 
 
 
 
 
 
 
 
 
 
 
Chemistry 
including CK 
 
 
 
 
 
 
 
 
 
 
 
 
Liver Function 
Tests 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Testing 
 
 
 
 
 
 
 
 
 
 
 
 
Full FACs 
 
 
 
 
 
 
 
 
 
 
 
 
HIV viral load 
(bdna)  
 (3 viral load 
measures will 
be used to 
establish 
baseline) 
 
 
 
 
 
 
 
 
 
 
 
Statin/placebo 
 
 
 
 
 
 
 
 
 
 
 
 
Stored 
Plasma/PBMC 
 
 
 
 
 
 
 
 
 
 
 
 
Stored Sera 
 
 
 
 
 
 
 
 
 
 
 
 


Version 5.2 
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22
5.5 Breaking the blind 
In the event of a medical emergency or in the event an off study criterion is met where 
knowledge of the treatment will affect medical management, the investigators after consulting 
with the medical monitor can break the blind. To break the blind investigators will contact the 
pharmacy department by pager and via electronic mail, as they will hold the randomization code. 
 In the rare event of such an occurrence the process will be documented in writing. If the 
DSMB decides to terminate the study, the blind will be broken and study participants and their 
primary physicians will be informed of their drug assignments.  
5.6 Criteria for Stopping Enrollment 
           Once patient enrollment is completed the study will be closed for further enrollment or if 
the DSMB decides to terminate the study prior to complete enrollment. The DSMB will meet 
after half the participants in the clinical trial have completed the study. Alternatively they will 
also convene if two study patients have grade III or higher adverse events that in the opinion of 
the investigator are definitely, possibly or probably associated with the drug. Please note: unlike 
other lab AE’s that would necessitate convening a DSMB if 2 subjects have a grade 3 or higher adverse 
event, the DSMB would convene only if the grade 3 CPK elevations are persistent. 
 
6.0 STUDY TREATMENT 
STUDY DRUG 
6.1 Atorvastatin  
Metabolism and mechanism of action 
Atorvastatin calcium belongs to a group of lipid lowering agents referred to as statins. 
Atorvastatin is a selective competitive inhibitor of the enzyme 3 hydroxy-3methylglutaryl 
coenzyme A (HMG CoA reductase).  This enzyme catalyzes the conversion of HMG CoA to 
mevalonic acid, the rate- limiting step in cholesterol biosynthesis. This class of drugs have been 
utilized in both the primary and the secondary prevention of coronary artery disease (CAD) [34] 
[35] [36]. 
Atorvastatin is orally administered and is well tolerated. Atorvastatin is metabolized by 
the cytochrome P450 3A4 system to ortho and para hydroxylated metabolites. Atorvastatin and 
its metabolites are primarily hepatically excreted [37]. The metabolism of atorvastatin may be 
influenced by CYP 3A4 inducers and inhibitors. 


Version 5.2 
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23
Adverse effects of Atorvastatin 
The most common side effects associated with atorvastatin use are gastrointestinal. In 
clinical trials the following events were reported as per the package insert in greater than 2% of 
the cases: chest pain, nausea, bronchitis, rhinitis, arthritis, insomnia and dizziness, urinary tract 
infection and peripheral edema.  
Atorvastatin and effects on liver enzymes 
Persistent elevations in liver enzyme to 3 times the ULN have been reported in 0.2-2.3% 
of patients studied on clinical trials of atorvastatin. Upon discontinuation of the drug these 
elevations are reversible. Fatal liver injury has been reported with atorvastatin use [38]. Overall it 
appears that fatal liver injury is a rare event in patients using statins. Liver function abnormalities 
associated with atorvastatin use are seen at all doses. However, the incidence of these 
abnormalities is greater with higher doses of the drug. 
In a recently reported study of secondary prevention of CAD, 10,001 patients were 
randomized to receive either10 or 80 mg of atorvastatin. In this study persistent elevation in liver 
enzymes were seen in less than 1% of all patients, however the incidence was significantly 
higher in the 80 mg subgroup (1.2% vs 0.2%). [39]  
The package insert states that the use of atorvastatin is not recommended in patients with 
active liver disease. Serial monitoring of liver function tests prior to start of drug, 6 to 12 weeks 
after and semi annually thereafter is advised by the drug manufacturers. More stringent 
monitoring at shorter intervals will be done as part of this protocol. 
Atorvastatin and myopathy 
Myalgia and rhabdomyolysis have been reported with atorvastatin use. In the ASCOT 
study there was a single case of non-fatal rhabdomyolysis among 5168 patients randomized to 
atorvastatin. [40]  In a study of secondary prevention of CAD, among 10,000 patients 
randomized to receive either 10 or 80 mg of atorvastatin there were 5 cases of 
rhabdomyolysis.[39]  While rhabdomyolysis is a complication of atorvastatin it appears 
relatively rare.  
The risk of myopathy is increased when atorvastatin is used in conjunction with azole 
antifungals, erythromycin, clarithromycin, niacin, fibric acid derivatives or cyclosporine [37]. 
Patients who use fibric acid derivatives, niacin and cyclosporine will not be enrolled into the 


Version 5.2 
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24
study. Patients who start azoles or erythromycin or clarithromycin while on study will be 
monitored closely for signs and symptoms of myopathy, patients on these drugs at the time of 
enrollment will not be eligible for this study until completion of therapy with these agents. 
In addition the risk of myopathy is increased with the concomitant use of grape fruit juice 
and atorvastatin.  These interactions are mediated via the cytochrome p 450 system; grape fruit 
juice is an inhibitor of this system [41] While on study patient will be advised to avoid grape 
fruit juice and grape fruit. 
To reduce risk to our study patients we will monitor liver function (LFT) and creatinine 
phosphokinase (CPK) at baseline and as indicated in the schedule of events. Patients will also be 
questioned about myalgia or weakness at each visit. Presence of any of these symptoms will 
require complete evaluation as judged suitable by their health care provider. Patients who 
participate in this study will be asked to refrain from vigorous exercise regimens for the study 
period. Vigorous exercise is known to increase CPK levels and may cause patients to be 
unnecessarily excluded /withdrawn from the study. 
• Pregnancy and breast feeding are contraindications for atorvastatin use; atorvastatin is 
classified as a pregnancy category X drug. Pregnant or nursing women will not be 
enrolled in this study and patients will be required to use reliable methods of 
contraception to be enrolled in this study. If a patient becomes pregnant on study, she will 
be asked to stop taking study drug and will be followed through her pregnancy and the 
peripartum period.  
6.2 Product Supply, Distribution, and Pharmacy 
Both drugs (i.e. atorvastatin and Placebo) will be formulated by the NIH PDS and will be 
supplied to both the sites. Both placebo and drug will be identical in appearance. They will be 
packaged and labeled with the study number, and will have a space where the subjects initial and 
randomization number will be entered. 
6.3 Drug Storage 
Both drugs and placebo can be stored at room temperature in a locked storage area. 
6.4 Accountability of drugs 
  
Some drug records will be maintained centrally by the NIH PDS such as shipping 
records. The individual sites will also maintain drug records locally such as drug dispensing and 


Version 5.2 
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25
accountability records. Drugs will be dispensed to the sites by NIH PDS. Patients will be 
required to pick up medications per visit schedule. 
 
7.0 STATISTICAL CONSIDERATION 
 
This is a double blind randomized crossover placebo controlled trial of statin use in HIV 
positive patients with the specific aim of studying the effect of statins on HIV viral load.  22 
chronically infected HIV positive patients will be randomized to either atorvastatin 80 mg 
followed by placebo or placebo followed by atorvastatin (11 per sequence).  After 8 weeks of 
treatment and another 4 weeks washout period, patients in the placebo arm will receive 
atorvastatin 80mg, whereas patients in the atorvastatin arm will be followed on placebo for 
another 8 weeks.  Table 2 displays the treatment sequence for the two groups.   
 
 
 
 
 
 
 
Table 2 
 
The effect of lipid lowering agents on HIV-1 RNA levels will be evaluated at the end of 7 
weeks and at the end of 19 weeks. The primary goal of this study is to assess the treatment effect 
by assuming that the carry-over effect is negligible. The primary strength of this cross-over trial 
is increased efficiency because each patient serves as his or her own control, and the within-
subject variability is usually less than the between-subject variability. As a result, the sample size 
for a cross-over trial will be lower than that for a comparable parallel group design. There is a 
possible drawback of this design, however, if the carry-over effect cannot be ignored.  
   
Based on historical data we estimate the standard deviation of the log10 viral load as.74 
and the correlation coefficient of log10 viral loads before and after treatment as 0.83.  To be 
conservative, a correlation coefficient of 0.75 is used in our calculation. The paired t-test is used 
 
(Week 0-7) 
Week 8-11 
 
(Week 12-19) 
Atorvastatin 80mg 
Washout 
Placebo 
Placebo 
Washout 
Atorvastatin  80mg 


Version 5.2 
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26
for power calculation.  A trial of 20 subjects has a power of 77% (with type I error 0.05) for 
detecting a 1/3 log10 drop in viral load with atorvastatin.   Power to detect a change of 0.4 or 0.5 
in log10 viral load based on 10 patients per sequence is 90% and 98% respectively. Thus we 
have excellent power to detect at least .4 log10 viral load difference by the treatment and 
reasonable power to detect a 1/3 log10 viral load difference. Due to the possible loss to follow-
up (10%), 11 patients will be accrued in each sequence.   
At the end of this study, the paired t-test will be used to test this hypothesis.  If the 
underlying distribution is clearly not close to a normal, then the sign-rank Wilcoxon test will be 
used instead.  
Secondary Objectives for Statistical Consideration 
1- To study the difference in the expression of immune activation markers (i.e HLA DR 
CD38 and Ki67 expression both percentage and number on CD4+ and CD8+ cells) between the 
end of 7 weeks and the end of 19 weeks in the placebo and atorvastatin sequence. All 
comparisons of changes between the end of 7 weeks and the end of 19 weeks, i.e. the difference 
between months 19 and 7 or months 7 and 19 will be conducted by using the paired t-test if the 
measurements are continuous. McNemar statistic will be used for the changes of discrete 
markers.  
 Because of the randomization, the baseline measurements (at beginning of this trial) in 
placebo and atorvastatin sequences should have the same distribution. This information can be 
incorporated into an additional statistical analysis, called analysis of covariance ANCOVA.  A 
linear mixed effects model can be used to analyze the difference between the change of viral 
loads evaluated at the beginning of this trial and at the end of the 7th week, and at the end of 11th 
week and 19th week in atorvastatin and placebo sequence and placebo and atorvastatin sequence.  
The difference of viral load at the end of 11th week in two treatment sequences can be used to 
assess whether there is a treatment carryover effect.  
Additional analyses will be conducted to assess whether there is any effect of drug on 
change viral load, beyond that predicted by the change in LDL.   
Finally the correlation between reductions in serum cholesterol and HIV viral load in 
treatment arm will be assessed by using Spearman's correlation coefficient statistics.  


Version 5.2 
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27
 
8.0 DATA COLLECTION AND MONITORING AND ADVERSE EXPERIENCE 
REPORTING 
8.1 Adverse and Serious Adverse Experience (SAE) reporting 
8.1.1 Definition 
An adverse event is defined as “undesired and unintended, though not unexpected, result 
of therapy or intervention”. 
An adverse event may also be defined as any “unfavorable and unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of an experimental medical treatment or procedure, regardless of whether it is considered 
related to the medical treatment or procedure. These include both anticipated and unanticipated 
risk”.A serious adverse event (SAE) is one “that results in death, is life threatening or results in 
inpatient hospitalization or prolongs the existing hospitalization, results in a persistent or 
significant disability of incapacity, or results in congenital anomaly / birth defect”.  A serious 
adverse event may not be immediately life threatening or result in death or hospitalization but 
may jeopardize the patient/study participant or may require intervention to prevent one of the 
other outcomes listed above.”  
8.1.2 Reporting 
All adverse events regardless of treatment group or relationship to the drug will need to 
be reported to the necessary IRB as per their requirements. As reporting requirements are 
somewhat different at NIAID and NNMC we will follow reporting requirements at both 
institutions. 
All SAE will be reported within 24 hours of when the investigator learns of this event. to 
both the NIAID and the NNMC IRB. In addition to the above listed event any event that in the 
investigators judgment is serious even if it does not meet the above criteria will be reported as 
such. 
Adverse events will be graded as per the attached toxicity table in Appendix 1. For toxicities 
not listed in the table, grading will be based on the schema provided below 
• 
Grade 1: Transient or mild discomfort; no limitation in activity; no medical 
intervention/therapy required. 


Version 5.2 
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28
• Grade 2: Mild to moderate limitation in activity - some assistance may be needed; no or 
minimal medical intervention/therapy required. 
• Grade 3: Marked limitation in activity, some assistance usually required; medical 
intervention/therapy required hospitalization possible. 
• Grade 4: Extreme limitation in activity, significant assistance required; significant 
medical intervention/therapy required hospitalization or hospice care. 
 
Adverse events will also be assessed for their relation to study medications and 
procedures.  
Patients coming to the NIH clinical center often travel long distances and are hospitalized for 
procedures that are routinely done as outpatients at other hospitals. Such elective hospitalizations 
will not be reported as a SAE or an AE. 
For all AEs, the clinician who examines and evaluates the subject will determine the 
adverse event’s causality based upon the temporal relationship to administration of the study 
agent, the pharmacology of the study agent, and his/her clinical judgment.  Terms to describe the 
degree of causality between the study agent and an event will be definitely, probably, possibly, 
unlikely related or not related.   The best estimate at the time of reporting of the causal 
relationship between the experimental intervention and an adverse event and the degree of 
certainty about causality will be graded as follows:   
Definitely Related: The adverse event and administration of study agent are related in 
time, and a direct association can be demonstrated (e.g., disappears or decreases with reduction 
in dose or cessation of drug/investigational product and recurs with re-exposure). 
 
Probably Related: The adverse event and administration of study agent are reasonably 
related in time and/or follows a known pattern of response, and the adverse event is more likely 
explained by study agent than other causes. 
      
Possibly Related: The adverse event and administration of study agent are reasonably 
related in time and/or follows a known pattern of response, and the adverse event can be 
explained equally well by causes other than study agent (e.g., could readily have been produced 
by the subject’s clinical state or could have been due to environmental or other interventions). 
   
Unlikely Related: A potential relationship between study agent and the adverse event 
could exist (i.e., the possibility cannot be excluded), but the adverse event is most likely 


Version 5.2 
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29
explained by causes other than the study agent (e.g., could readily have been produced by the 
subject’s clinical state or could have been due to environmental or other interventions).                            
 
 
Not Related: Adverse event is clearly due to extraneous causes (e.g., underlying disease, 
environment) or exposure to the investigational product has not occurred. Such events MUST 
have an alternative, definitive etiology documented in the patient’s medical record.  
Therefore, a suspected adverse drug/investigational product reaction would be one that is 
categorized as definitely, probably, possibly, and unlikely related to a study drug/ investigational 
product”. 
Please see attached appendix for the toxicity table.  All adverse event reporting will end 4 
weeks after the end of the study treatment.Any new toxicities not previously reported will be 
submitted to Med-Watch. 
As the study is being done at both the NIAID and at the NNMC reporting requirements 
for both sites will be followed these include reporting all SAE within 24 hours after becoming 
aware of a subject death or a potentially life threatening serious adverse event. This will meet the 
reporting requirements of both the NIAID and the NNMC IRB, as the NIAID requires reporting 
within 7 days and the NNMC requires reporting within 24 hours of knowledge of death or 
potentially life threatening SAE. A completed NIAID IRB serious adverse event report will be 
submitted to the NIAID IRB within 15 days after becoming aware of an inpatient hospitalization 
(other than elective), a persistent or significant disability/incapacity, or a congenital 
anomaly/birth defect. Investigators will report within 15 days any other event or condition 
regardless of grade, which in their judgment represents an event reportable to the IRB. All other 
serious adverse events will be reported to the NIAID IRB at the time of the annual review. In 
addition a summary of all adverse events will be reported to the NIAID IRB with submission of 
a request for continuing review.  
8.2 Protocol monitoring and DSMB 
  
Day to day protocol management will be provided by the PI at the NIH and by the 
sponsors of the study at NNMC.  As this is a randomized placebo controlled trial, a DSMB will 
monitor the progress of the trial. The DSMB will be constituted through the NIAID. The DSMB 
will evaluate data after enrollment and completion of study by 50% of the study patients. 


Version 5.2 
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30
             The trial will be conducted in compliance with this protocol, International Conference on 
Harmonization Good Clinical Practices (ICH/GCP) and all applicable regulatory requirements.  
Monitors under contract to the NIAID will visit the clinical research site(s) to monitor all aspects 
of the study in accordance with the appropriate regulations. The objectives of a monitoring visit 
will be: 1) to verify the prompt reporting of all data points, including reporting SAEs, checking 
availability of signed informed consents; 2) to compare individual subject records and the source 
documents (supporting data, laboratory specimen records and medical records to include 
physician progress notes, nurse’ notes, subjects’ hospital charts); 3) to ensure protection of study 
subjects, compliance with the protocol, and accuracy and completeness of records.  The monitors 
also will inspect the clinical site regulatory files to ensure that regulatory requirements are being 
followed.  During the monitoring visits, the investigator (and/or designee) and other study 
personnel will be available to discuss the study progress and monitoring visit findings.  The 
investigator (and/or designee) will make study documents (e.g., consent forms) and pertinent 
hospital, CRFs or clinical records readily available for inspection by the local IRB, the site 
monitors, and the NIAID staff for confirmation of the study data 
8.3 Data and Safety Monitoring Plan.  
Day to day protocol management will be provided by the PI at the NIH and by the 
sponsors of the study at NNMC.  As this is a randomized placebo controlled trial, a DSMB will 
monitor the progress of the trial. The DSMB will be constituted through NIAID. The DSMB will 
evaluate data after 50% of the study patients have completed study. 
8.4 Data management plan  
 
“Study data will be collected and maintained on standardized Case Report Forms (CRF).  
The study investigators will be responsible for assuring that the data collected is complete, 
accurate, and recorded in a timely manner.  Source documentation (the point of initial recording 
of a piece of data) should support the data collected on the case report form, and be signed and 
dated by the person recording and/or reviewing the data.  Source documents include all 
recordings of observations or notations of clinical activities and all reports and records necessary 
for the evaluation and reconstruction of the clinical trial.  Source documents include, but are not 
limited to, the patient medical records, laboratory reports, ECG tracings, x-rays, radiologist 
reports, patient diaries, biopsy reports, ultrasound photographs, patient progress notes, pharmacy 


Version 5.2 
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31
records and any other similar reports or records of procedures performed during the subject’s 
participation in the protocol.  Data for CRFs will be collected during patient visits, phone calls 
with subjects and health care providers, patient diaries and abstracted from the medical record.  It 
is not acceptable for the CRF to be the only record of the patient participation in the study.  This 
is to ensure that anyone who would access the patient medical record has adequate knowledge 
that the patient is participating in a clinical trial.” 
 
9.0 HUMAN SUBJECTS 
Institutional Review Board (IRB) Review and Informed Consent   
 
The protocol and any subsequent changes and the informed consent will be reviewed by 
the IRB before initiation of the study. The informed consent will explain the study, the 
procedures and the risks and benefits associated with the study. The study participants will be 
provided copies of the informed consent for review, any questions that he/she may have about 
the study will be answered prior to the final signing of the informed consent. A copy of the 
consent form will be given to the subject and the informed consent process will be documented. 
 HIV infection in pediatric patients may represent a somewhat different disease; with 
greater contributions from lymphoid organs such as thymus. We do not know whether children 
and adults will represent a uniform group mechanistically, and we propose to study adults (≥ 
18y). As we obtain additional information, we may consider a pediatric study, although children 
with HIV infection are no longer seen at NIH and such studies would be carried out in 
collaboration.  
9.1 Benefit  
 There is no immediate benefit to the patient. However, a potential benefit may be a 
reduction in their viral load and temporary improvement in their lipid profile.  
9.2 Risks 
9.2.1 Medication associated risk 
Atorvastatin 
Per the package insert the following warnings are associated with atorvastatin use 
Liver dysfunction-“persistent elevations (>3 times the upper limit of normal (ULN) occurring 
on 2 or more occasions) in serum transaminases occurred in 0.7% of patients who received 


Version 5.2 
September 20, 2007 
 
32
atorvastatin in clinical trials. The incidence of these abnormalities was 0.2%, 0.2%, 0.6% and 
2.3% for 10, 20, 40 and 80 mg respectively.” Dose reduction, interruption or discontinuation of 
atorvastatin resulted in reversal of these abnormalities. 
Skeletal muscle- “rare cases of rhabdomyolysis with acute renal failure secondary to 
myoglobinuria have been reported with atorvastatin use and with drugs in this class”   
The following events have also been reported among patients in clinical trial of 
atorvastatin at a frequency greater than 2% this include chest pain, nausea, bronchitis, rhinitis, 
insomnia, dizziness, arthritis, urinary tract infection, peripheral edema. [42] 
For events that were noted in less than 2% of the cases please refer to package insert appendix 2 
9.2.2 Risks Associated with Hypocholesterolemia 
Animal studies 
As per the package insert a single female dog treated for 3 months with atorvastatin at a 
dose of 120mg/kg/day, which would result in an exposure that is 16 times that seen in humans, 
resulted in brain hemorrhage in the dog. Another female dog treated with escalating doses of 
atorvastatin to a max of 280mg/kg/day suffered optic nerve vacuolation and brain hemorrhage. 
In animal studies treatment with HMG CoA reductase inhibitors has resulted in 
neurotoxicity. In normocholesterolemic dogs given doses of 180 mg/kg/day of lovastatin, this 
dose is 180 times the normal therapeutic dose in humans, there was evidence of neurotoxicity in 
37% of the animals. These dogs demonstrated a hemorrhagic encephalopathy. [43]  
In a recent study designed to study the effects on coronary outcomes of lowering LDL 
cholesterol to less than 100 mg/dl in patients with established coronary artery disease, 10,001 
patients with established CAD were randomized to receive either atorvastatin 10 or 80 mg. The 
median follow up in this study was 4.9 years. The mean LDL cholesterol achieved in the 
atorvastatin 80 mg sub group was 77 mg/dl in this study. The authors of this study concluded that 
there was no difference in reported adverse effects in those with LDL cholesterol less than 70 
mg/dl.[39] The results of this study seemed to suggest that the reductions in LDL cholesterol 
achieved in this population were well tolerated. However, not much is known about the effects of 
temporary reductions in cholesterol and LDL in normo-cholesterolemic HIV positive patients.  
Given the above animal data we will follow all patients on study and four weeks after 


Version 5.2 
September 20, 2007 
 
33
discontinuing placebo/statin for possible CNS and optic toxicities by targeted history and 
physicals and laboratory testing as necessary. 
There have been case reports of CNS side effects with statin use. These include reports of 
memory loss, irritability and polyneuropathy. [44-46] These associations have however, not been 
borne out in large clinical trials. 
9.2.3 Risks Associated with Phlebotomy 
Risks include bleeding, bruising, infection and syncope (fainting). Fainting and 
complications thereof are rare but well recognized complications of phlebotomy. To minimize 
risk, patients will undergo phlebotomy in the sitting position and will be monitored for 10 
minutes after the procedure. 
9.3. Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records that leave the site 
will be identified by coded number only, to maintain subject confidentiality. The link to the 
patient will be maintained at the site in a locked cabinet. All computer entry will be done with 
coded numbers only. Clinical information will not be released without written permission of the 
subject, except as necessary for monitoring by IRB, the FDA, the NIAID, the OHRP, the 
pharmaceutical supporter(s), or the supporter’s designee. At the completion of the study the link 
will be destroyed and the remaining samples will be stored without any link.  
9.4 Study Discontinuation 
The study may be discontinued at any time by the IRB, the NIAID, the FDA, or other 
government agencies as part of their duties to ensure that research subjects are protected 
9.5 Sample Storage 
This section describes the storage and use of samples in this study. 
 
Samples and data collected under this protocol may be used to study _HIV infection, 
immune disorders and interactions of HIV and host immune metabolic and genetic factors. 
Genetic testing will be performed. Access to research samples will be limited using a locked 
room or a locked freezer or both.  Samples and data will be stored using codes assigned by the 


Version 5.2 
September 20, 2007 
 
34
investigators or their designees.  Data will be kept in password-protected computers.  Only 
investigators or their designees will have access to the samples and data.  Samples obtained at 
NIH will be tracked in the Crimson system. Samples will be stored and tracked utilizing the NCI 
FCRF REPOSITORY operated by SAIC FREDERICK. In the future, other investigators (both at 
NIH and NNMC) may wish to study these samples and/or data.  In that case, IRB approval must 
be sought prior to any sharing of samples.  Any clinical information shared about the sample 
with or without patient identifiers would similarly require prior IRB approval. At the completion 
of the protocol ( at termination), samples and data will either be destroyed, or after IRB approval, 
transferred to another existing protocol or a repository.  
 
The NIH Intramural Protocol Violation definition related to loss of or destruction of 
samples (for example, due to freezer malfunction) will be followed in reporting to the IRB: The 
violation compromises the scientific integrity of the data collected for the study. 
 
Any loss or unanticipated destruction of samples (for example, due to freezer 
malfunction) or data (for example, misplacing a printout of data with identifiers) that 
compromises the scientific integrity of the study will be reported to the IRB. 
 
Additionally, subjects may decide at any point not to have their samples stored.  In this 
case, the principal investigator will destroy all known remaining samples and report what was 
done to both the subject and to the IRB.  This decision may not affect the subject’s participation 
in this protocol or any other protocols at NIH. 
 
 


Version 5.2 
September 20, 2007 
 
35
10.0 REFERENCES 
1. 
Palella FJ, Jr., Delaney KM, Moorman AC, Loveless MO, Fuhrer J, Satten GA, et al. 
Declining morbidity and mortality among patients with advanced human 
immunodeficiency virus infection. HIV Outpatient Study Investigators. N Engl J 
Med 1998,338:853-860. 
2. 
Carr A, Cooper DA. Adverse effects of antiretroviral therapy. Lancet 2000,356:1423-
1430. 
3. 
Carr A, Samaras K, Thorisdottir A, Kaufmann GR, Chisholm DJ, Cooper DA. Diagnosis, 
prediction, and natural course of HIV-1 protease-inhibitor-associated 
lipodystrophy, hyperlipidaemia, and diabetes mellitus: a cohort study. Lancet 
1999,353:2093-2099. 
4. 
Ono A, Freed EO. Plasma membrane rafts play a critical role in HIV-1 assembly and 
release. Proc Natl Acad Sci U S A 2001,98:13925-13930. 
5. 
Giguere JF, Tremblay MJ. Statin compounds reduce human immunodeficiency virus 
type 1 replication by preventing the interaction between virion-associated host 
intercellular adhesion molecule 1 and its natural cell surface ligand LFA-1. J Virol 
2004,78:12062-12065. 
6. 
Iyengar S, Hildreth JE, Schwartz DH. Actin-dependent receptor colocalization 
required for human immunodeficiency virus entry into host cells. J Virol 
1998,72:5251-5255. 
7. 
Pontow SE, Heyden NV, Wei S, Ratner L. Actin cytoskeletal reorganizations and 
coreceptor-mediated activation of rac during human immunodeficiency virus-
induced cell fusion. J Virol 2004,78:7138-7147. 
8. 
Popik W, Alce TM, Au WC. Human immunodeficiency virus type 1 uses lipid raft-
colocalized CD4 and chemokine receptors for productive entry into CD4(+) T cells. 
J Virol 2002,76:4709-4722. 
9. 
Moncunill G, Negredo E, Bosch L, Vilarrasa J, Witvrouw M, Llano A, et al. Evaluation 
of the anti-HIV activity of statins. Aids 2005,19:1697-1700. 
10. 
Waters L, Stebbing J, Jones R, Mandalia S, Bower M, Stefanovic M, et al. The effect of 
statins on HIV rebound and blips. J Acquir Immune Defic Syndr 2005,39:637-638. 
11. 
del Real G, Jimenez-Baranda S, Mira E, Lacalle RA, Lucas P, Gomez-Mouton C, et al. 
Statins inhibit HIV-1 infection by down-regulating Rho activity. J Exp Med 
2004,200:541-547. 
12. 
Sklar PA, Masur H, Grubb JR, Voell J, Witek J, Ono A, et al. Pravastatin does not have 
a consistent antiviral effect in chronically HIV-infected individuals on antiretroviral 
therapy. Aids 2005,19:1109-1111. 
13. 
Penzak SR, Chuck SK, Stajich GV. Safety and efficacy of HMG-CoA reductase 
inhibitors for treatment of hyperlipidemia in patients with HIV infection. 
Pharmacotherapy 2000,20:1066-1071. 
14. 
Peterlin BM, Trono D. Hide, shield and strike back: how HIV-infected cells avoid 
immune eradication. Nat Rev Immunol 2003,3:97-107. 
15. 
Reeves JD, Piefer AJ. Emerging drug targets for antiretroviral therapy. Drugs 
2005,65:1747-1766. 
16. 
Simons K, Ikonen E. Functional rafts in cell membranes. Nature 1997,387:569-572. 


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36
17. 
Morita E, Sundquist WI. Retrovirus budding. Annu Rev Cell Dev Biol 2004,20:395-425. 
18. 
Gheysen D, Jacobs E, de Foresta F, Thiriart C, Francotte M, Thines D, De Wilde M. 
Assembly and release of HIV-1 precursor Pr55gag virus-like particles from 
recombinant baculovirus-infected insect cells. Cell 1989,59:103-112. 
19. 
Karacostas V, Nagashima K, Gonda MA, Moss B. Human immunodeficiency virus-
like particles produced by a vaccinia virus expression vector. Proc Natl Acad Sci U S 
A 1989,86:8964-8967. 
20. 
Shioda T, Shibuta H. Production of human immunodeficiency virus (HIV)-like 
particles from cells infected with recombinant vaccinia viruses carrying the gag 
gene of HIV. Virology 1990,175:139-148. 
21. 
Freed EO. HIV-1 gag proteins: diverse functions in the virus life cycle. Virology 
1998,251:1-15. 
22. 
VerPlank L, Bouamr F, LaGrassa TJ, Agresta B, Kikonyogo A, Leis J, Carter CA. 
Tsg101, a homologue of ubiquitin-conjugating (E2) enzymes, binds the L domain in 
HIV type 1 Pr55(Gag). Proc Natl Acad Sci U S A 2001,98:7724-7729. 
23. 
Huang M, Orenstein JM, Martin MA, Freed EO. p6Gag is required for particle 
production from full-length human immunodeficiency virus type 1 molecular clones 
expressing protease. J Virol 1995,69:6810-6818. 
24. 
Demirov DG, Orenstein JM, Freed EO. The late domain of human immunodeficiency 
virus type 1 p6 promotes virus release in a cell type-dependent manner. J Virol 
2002,76:105-117. 
25. 
Garrus JE, von Schwedler UK, Pornillos OW, Morham SG, Zavitz KH, Wang HE, et al. 
Tsg101 and the vacuolar protein sorting pathway are essential for HIV-1 budding. 
Cell 2001,107:55-65. 
26. 
Demirov DG, Ono A, Orenstein JM, Freed EO. Overexpression of the N-terminal 
domain of TSG101 inhibits HIV-1 budding by blocking late domain function. Proc 
Natl Acad Sci U S A 2002,99:955-960. 
27. 
Bleiber G, May M, Martinez R, Meylan P, Ott J, Beckmann JS, Telenti A. Use of a 
combined ex vivo/in vivo population approach for screening of human genes 
involved in the human immunodeficiency virus type 1 life cycle for variants 
influencing disease progression. J Virol 2005,79:12674-12680. 
28. 
Hall A. Rho GTPases and the actin cytoskeleton. Science 1998,279:509-514. 
29. 
Fenton RG, Kung HF, Longo DL, Smith MR. Regulation of intracellular actin 
polymerization by prenylated cellular proteins. J Cell Biol 1992,117:347-356. 
30. 
Gougeon ML. Apoptosis as an HIV strategy to escape immune attack. Nat Rev 
Immunol 2003,3:392-404. 
31. 
Janes PW, Ley SC, Magee AI. Aggregation of lipid rafts accompanies signaling via 
the T cell antigen receptor. J Cell Biol 1999,147:447-461. 
32. 
Drake DR, 3rd, Braciale TJ. Cutting edge: lipid raft integrity affects the efficiency of 
MHC class I tetramer binding and cell surface TCR arrangement on CD8+ T cells. J 
Immunol 2001,166:7009-7013. 
33. 
Stanley SK, Ostrowski MA, Justement JS, Gantt K, Hedayati S, Mannix M, et al. Effect 
of immunization with a common recall antigen on viral expression in patients 
infected with human immunodeficiency virus type 1. N Engl J Med 1996,334:1222-
1230. 


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37
34. 
Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA, Livingstone SJ, et al. 
Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in 
the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised 
placebo-controlled trial. Lancet 2004,364:685-696. 
35. 
Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, MacFarlane PW, et al. 
Prevention of coronary heart disease with pravastatin in men with 
hypercholesterolemia. West of Scotland Coronary Prevention Study Group. N Engl 
J Med 1995,333:1301-1307. 
36. 
Randomised trial of cholesterol lowering in 4444 patients with coronary heart 
disease: the Scandinavian Simvastatin Survival Study (4S). Lancet 1994,344:1383-
1389. 
37. 
Lennernas H. Clinical pharmacokinetics of atorvastatin. Clin Pharmacokinet 
2003,42:1141-1160. 
38. 
Perger L, Kohler M, Fattinger K, Flury R, Meier PJ, Pauli-Magnus C. Fatal liver failure 
with atorvastatin. J Hepatol 2003,39:1095-1097. 
39. 
Larosa JC, Grundy SM, Waters DD, Shear C, Barter P, Fruchart JC, et al. Intensive 
Lipid Lowering with Atorvastatin in Patients with Stable Coronary Disease. N Engl 
J Med 2005. 
40. 
Sever PS, Dahlof B, Poulter NR, Wedel H, Beevers G, Caulfield M, et al. Prevention of 
coronary and stroke events with atorvastatin in hypertensive patients who have 
average or lower-than-average cholesterol concentrations, in the Anglo-
Scandinavian Cardiac Outcomes Trial--Lipid Lowering Arm (ASCOT-LLA): a 
multicentre randomised controlled trial. Lancet 2003,361:1149-1158. 
41. 
Bailey DG, Dresser GK. Interactions between grapefruit juice and cardiovascular 
drugs. Am J Cardiovasc Drugs 2004,4:281-297. 
42. 
Merck. Lipitor (Atorvastatin calcium). In. 
43. 
Berry PH, MacDonald JS, Alberts AW, Molon-Noblot S, Chen JS, Lo CY, et al. Brain 
and optic system pathology in hypocholesterolemic dogs treated with a competitive 
inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase. Am J Pathol 
1988,132:427-443. 
44. 
Wagstaff LR, Mitton MW, Arvik BM, Doraiswamy PM. Statin-associated memory 
loss: analysis of 60 case reports and review of the literature. Pharmacotherapy 
2003,23:871-880. 
45. 
Golomb BA, Kane T, Dimsdale JE. Severe irritability associated with statin 
cholesterol-lowering drugs. Qjm 2004,97:229-235. 
46. 
Gaist D, Jeppesen U, Andersen M, Garcia Rodriguez LA, Hallas J, Sindrup SH. Statins 
and risk of polyneuropathy: a case-control study. Neurology 2002,58:1333-1337. 
 
 

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: 
06-I-0197 
PRINCIPAL INVESTIGATOR:  Frank Maldarelli, M.D.   
 
 
STUDY TITLE: 
A Randomized Placebo Controlled Trial of Atorvastatin in HIV Positive Patients Not on 
Antiretroviral medications with the Specific Aims of Studying the Effects of Atorvastatin on HIV 
Viral Load and Immune Activation Markers 
 
 
Continuing Review Approved by the IRB on 4/14/08 
Amendment Approved by the IRB on 03/20/08 (G) 
Date Posted to Web: 05/06/08 
Standard 
 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY 
 
•   Adult Patient or    •   Parent, for Minor Patient 
 
NIH-2514-1 (4-97) 
 
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 the Study 
 
HIV, the virus that causes AIDS, grows in the immune cells of the body.  Recent research has shown that for the HIV to 
multiply (replicate), it has to use some of the normal cell machinery.  One of the pathways the virus uses to multiply 
requires cholesterol (a kind of fat in the blood).  Laboratory research has indicated that if the amount of cholesterol in 
infected cells is reduced, HIV replication is also decreased.  These experiments have been done only in the laboratory and 
it is not known whether reducing cholesterol in people infected with HIV will also reduce HIV replication.  In this study we 
plan to investigate whether the use of cholesterol lowering drugs called statins will reduce HIV replication and lower the 
level of HIV in the blood. We are studying the effects of one statin called atorvastatin (Lipitor), which has been approved 
by the Food and Drug Administration (FDA) for treatment of persons with hyperlipidemia (elevated lipids in the blood). 
Atorvastatin is not an approved treatment for HIV infection, and should not be considered a therapy for HIV; even if it  


 
 
  
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: 
06-I-0197 
CONTINUATION:  page  2  of  11  pages 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
does decrease HIV viral loads (the amount of the HIV virus in your blood), it is unlikely that atorvastatin alone will control 
HIV.  Atorvastatin is approved by the FDA for the treatment of hypercholesterolemia and is available for use outside this 
study.  However, atorvastatin is not FDA approved for treatment of HIV infection.  As you are likely to have normal 
cholesterol you may not receive any benefit from taking atorvastatin.  The desire to take atorvastatin should not be a 
reason for you to volunteer to take part in this study. 
 
The primary purpose of this research study is to study the effect of this drug on HIV viral load. As part of this study we 
will be looking at: 
• 
The amount of HIV virus in your blood (HIV viral load).  
• 
The composition of the strain of HIV virus that you carry (HIV genotype). 
• 
The response of your immune system to the virus.    
• 
Some of your genes that may determine the way this drug may or not work against your strain of the virus. 
 
Study Procedures 
 
You have already come to the clinic for a screening visit, and have undergone testing to determine whether or not you 
qualify for the study. Based on your screening visit, you are eligible for the protocol and are invited to enroll in the study 
phase. In the study phase, you will be randomly assigned (by chance, like the flip of a coin) to one of two study groups. 
One study group will be asked to take atorvastatin, a medicine that reduces cholesterol and may affect the ability of your 
virus to multiply. The other study group will take a placebo (something like a sugar pill) that should have no affect either 
on the level of your cholesterol or the ability of your virus to multiply.  Neither you nor your doctor will know whether you 
will be in the drug or to the placebo pill group.  Once you have been assigned to either the drug or the placebo pill 
groups, you will remain in your groups/treatments for 8 weeks. Upon completion of 8 weeks, regardless of the study 
group you were in, you will be required to discontinue all study related medications for 4 weeks. There may be  some 
circumstances where we may extend this off drug period to a total of 6 weeks. For instance, if you require the influenza 
vaccination, which can sometimes affect HIV-1 viral RNA levels, we will administer the standard inactivated vaccine at the 
beginning of the off drug period, followed by  six week wash out.  At the end of this period, you will be asked to switch 
your study assignments i.e. if you were on the placebo pill you will switch to the study drug atorvastatin and vice versa if 
you were on the study drug atorvastatin you will switch to the placebo pill.  You will complete an additional 8 weeks on 
this assigned study treatment; after this you will stop all study related treatment and be observed for an additional 4 
weeks.  
 
While on this research study you will have regularly scheduled study visits; at these visits you will have blood drawn, 
symptoms assessed, physical examinations done, and a questionnaire given at regular intervals.  You will be required to 
come fasting for these visits as we will be drawing blood to check the fats (lipids) in your blood.  This test can vary 
depending on whether you are fasting or not.  The blood will be used in standard as well as specialized tests.  The 
standard tests will include tests to determine the health of your liver, kidney, muscles, blood cells and your pregnancy 
status as applicable.  The specialized tests will include tests to determine the viral load (a measure of the amount of virus 
in your blood), study the effects of the drug on your immune cells, the genotype (tests to study the composition of your 
virus) and your own genes that might determine how the drug might, or might not work on you. 
 
The table below details the number of visits, an estimate of the time you will be required to spend at each of the visits 
and the procedures you will undergo during these visits.  The volume of blood drawn at each visit will be no more than 75 
cc (about 4 tablespoons).  This table is merely an approximation of what you can expect as a subject in this study, you 
may be required to undergo additional testing based on signs and symptoms that you may develop while on the study.  


 
 
  
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: 
06-I-0197 
CONTINUATION:  page  3  of  11  pages 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
 
Week 
0 to 4 
0 
1 
2 
6 
1
2 
1
3
1
4 
1
8 
2
0 
2
4 
Visit 
1 
2 
4 
5 
6 
7 
9 
1
0
1
1 
1
2 
1
3 
1
4 
Phase 
Screening 
Study 
Approximate time 
(hrs) 
2.
5 
3
0 
m
i
n 
3
0
 
m
i
n 
2 
4
5
 
m
i
n 
4
5
 
m
i
n 
4
5 
m
i
n 
2 
4
5
 
m
i
n
4
5 
m
i
n 
4
5 
m
i
n 
2 
1
.
5 
Procedure 
 
 
 
 
 
 
 
 
 
 
 
 
 
Consent process 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical assessment 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Questionnaire (fatigue 
scale)  
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
Physical exam 
X 
 
 
X 
 
 
 
X 
 
 
 
X 
X 
Blood draws 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Atorvastatin or 
placebo 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 


 
 
  
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: 
06-I-0197 
CONTINUATION:  page  4  of  11  pages 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
Study Population 
 
We plan to enroll 22 subjects for this study and the anticipated duration on study for each subject is 30 weeks. 
 
Summary of Entry Criteria 
 
To participate in the study you must:  
 
• 
Be greater than 18 years of age 
 
• 
Be infected with the HIV-1 virus 
 
• 
Off all Antiretroviral therapy (ART) “medicines taken to control the virus multiplication” for greater than three 
months prior to study entry.  While of ART you must have a stable viral load “amount of virus in your blood”.  
 
• 
Be willing to use a method of contraception during the study period.  Adequate methods of birth control include: 
condoms, male or female, with or without a spermicide; diaphragm or cervical cap with spermicide; intrauterine 
device; any of the methods that require a prescription (such as contraceptive pills or patch, Norplant, Depo-
Provera, and others) or a male partner who has previously undergone a vasectomy, 
  
• 
 Be willing to have blood drawn 
• 
Have no known allergy or contraindication to atorvastatin use 
 
• 
Have the ability to understand and willingness to sign the informed consent 
 
• 
Be willing to have blood stored for future testing including tests that will study your genes and the genetics of the 
virus 
 
• 
Have a CD4 cell count “a measure of your immune cells” greater than 350 cells/ml 
  
• 
Have three viral loads that average greater than 1000 copies/ml within a 4 week period. 
 
• 
Have a near normal total cholesterol “a kind of fat in the body” lower than 240mg/dl and a LDL cholesterol “a kind 
of fat in the body” lower than 130mg/dl 
 
• 
 Have near normal results for tests that test the health of your kidney, pancreas, liver, blood and muscles.  
 
• 
Have a negative serum pregnancy test  and not be breast feeding prior to taking the study drugs 
 
To Participate in the Study You Must Not  
 
• 
Be actively using recreational drugs or alcohol, as this might affect your ability to participate in the study 
 
• 
Have had a serious illness or opportunistic infections  “illnesses that occur in people with a weakened immunity” 
that required hospitalization in the 30 days prior to study entry 


 
 
  
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: 
06-I-0197 
CONTINUATION:  page  5  of  11  pages 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
• 
Have evidence of any cancer or opportunistic illness that will require treatment during the study period except 
some kinds of skin cancer 
 
• 
Allergy to the study medication “atorvastatin” or any of its components 
 
• 
Have had a history of myositis or rhabdomyolysis (diseases that result in muscle injury or swelling “inflammation”) 
with use of any statins 
 
• 
Have had a history of  diseases of the muscle such as poly or dermatomyositis  (these are diseases of the muscle 
which result in swelling or “ inflammation” of the muscle) 
 
• 
Be on any medication that do not mix “interact” with the study drug “ atorvostatin” . Please see the attached 
listing If you are any of these medications please let your physician know. 
 
• 
Use St.Johns wort as this can increase the amount of the study drug in your body 
 
• 
Use grape fruit or grape fruit juice, as this can increase the levels of study drug in your body 
 
• 
Be on any medication that might affect your immune response 
 
• 
Have a low LDL cholesterol ( a kind of fat in your body ) that is less than 40 mg/dl 
 
• 
Have had any vaccines within 6 weeks of entry into the study 
 
Withdrawal From the Protocol 
 
You may choose to withdraw from the protocol at any time. We may choose to withdraw you from the protocol at any 
time if we think it is not in your best interest to continue on the protocol, or if you fail to comply with the requirements 
of the protocol or if the DSMB, a panel of independent investigators who will review the data after we accrue 50 % of 
the patients, decides to stop the protocol. If the protocol is terminated for unanticipated reasons you will be withdrawn 
from the study. If you need to start antiretroviral therapy, you will be withdrawn from the study and referred to your 
primary physician. Any decision to start antiretroviral therapy will be done in consultation with your primary physician. If 
you need to start antiretroviral therapy you should do so after you have discontinued atorvastatin for one week. You 
may also be withdrawn from the study if blood tests that measure your liver functions are greater than 3 times the 
upper limit of normal on two successive measurements. 
 
Duration of Study 
 
The study will take 24 weeks to complete once you have been assigned to your group. 
 
Risks/Discomforts/Monitoring 
 
Risks 
 
The possible risks and discomforts from being in this research study include risks from the study medication, from 
reductions in your cholesterol, those associated with phlebotomy (blood draw).  Each one of these risks is explained in 
detail below: 


 
 
  
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: 
06-I-0197 
CONTINUATION:  page  6  of  11  pages 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
Atorvastatin - The use of this drug in research studies (clinical trials) designed to win approval of this drug have 
demonstrated that about 2% of the population reported different side-effects such as chest pain, nausea, bronchitis 
(inflammation of the bronchus), rhinitis (similar to a runny nose), arthritis (swelling and inflammation of the joints), 
insomnia (difficulty sleeping) and dizziness, urinary tract infection and peripheral edema (swelling of your feet/leg).  In 
addition this drug has been associated with increases in liver enzymes and rarely fatal liver failure.  However, in most 
cases the liver enzymes come back to where they started (baseline) if the drug is stopped.  This drug has also been 
associated with increases in muscle enzymes, muscle pain and a complication called rhabdomyolysis.  This complication 
refers to a condition that is associated with injury to your muscles that can sometimes lead to kidney failure.  There have 
also been some cases of altered behavior, memory loss and inflammation of the nerves (peripheral neuropathy) with the 
use of this drug.  
 
While all risks to you cannot be foreseen, all attempts will be made to ensure your safety.  This will include testing your 
blood, reviewing your symptoms and doing physical examinations at regular intervals as previously described.  In addition 
a data safety monitoring board, which consists of a panel of individuals not associated with the study, will evaluate the 
data collected after half the subjects have been enrolled and completed the study.  If this board feels that this trial should 
be discontinued because it poses a risk to the participants, the trial will be discontinued. 
 
Pregnancy - Atorvastatin belongs to a class of drugs referred to as statins.  This group of drugs cannot be used during 
pregnancy as it may cause damage to the unborn baby.  To participate in this study you will be required to use two 
reliable methods of contraception at all times while you are on this study and will undergo periodic testing to confirm your 
pregnancy status.  If you become pregnant while on study you will be asked to discontinue all on study medications.  We 
will continue to follow you throughout the pregnancy and immediately after pregnancy to assess for adverse effects.  
 
Hypocholesterolemia (low cholesterol) - As your cholesterol (a kind of lipid in your blood) will be normal at the 
beginning of the study we anticipate that your cholesterol will fall during this study because the drug being used is known 
to reduce cholesterol.  Not much is known about what happens in humans when the cholesterol falls to a very low level. 
In animal studies when the cholesterol levels fall to very low levels, there are reports of damage to the brain and eyes.  
We will ensure that your cholesterol does not fall to such levels, by ensuring that a physician not associated with the 
study team, reviews your cholesterol.  If he/she feels that your cholesterol is too low (that is levels that could be 
potentially harmful) he will discuss this with the study investigators and you will be withdrawn from the study.  In addition 
all subjects will be followed for signs and symptoms and problems with your nervous system/ eyes.  
Phlebotomy (sampling of blood by needle puncture) - The risks associated include bleeding, bruising, and fainting. 
To minimize risk, patients will have their blood taken in the sitting position and will be monitored for 10 minutes after the 
procedure. 
 
Benefits 
 
You will not benefit from taking part in this study, but the information we learn may help us with the management of HIV 
positive patients in the future.  This includes the availability of a drug that is frequently used in the management of some 
of the complications of drugs currently used to control the virus and may have the potential to control the quantity of 
virus and affect the immune response in HIV positive patients.  
 
Compensation 
 
To compensate for your time and inconvenience of this protocol, you will be paid a total of $600.00 at the end of the 
study.  If you choose to leave the study before the end, you will be paid according to the amount of time you participated, 
$50 for each visit you complete.  The compensation will be provided as a lump sum at the end of your participation.  If 
you need to stop the study because of toxicity, you will be paid the total amount.  


 
 
  
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: 
06-I-0197 
CONTINUATION:  page  7  of  11  pages 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
Alternatives to Participation 
 
This study provides no direct benefits to participants.  You are in no way obligated to continue in the protocol even if you 
are eligible.  The alternative to participation is not to enroll.  
 
Additional Information 
 
There will be no cost to you for study medications, clinic visits, examinations or laboratory and test procedures that are 
part of this study and that are obtained at the NIH.  Medical costs of other treatment outside this study and outside of 
the NIH will not be the responsibility of the NIH.  The NIH will provide only study-related medical care, and medical care 
and medications not directly related to the study must continue to be provided by your personal physician.  We will be 
sending letters regarding your study participation and your care to your doctor routinely and as needed, and we will 
also use the fax and the phone to relay information to your doctor that he or she should know to best care for you. We 
will not ask your permission for each of these contacts.  We will contact the physician you have named as your doctor, 
but you may give us a different physician to contact instead at any time. Once your participation in this study is 
completed, you will not be eligible for continuing care at NIH, unless you are eligible for another study at the NIH, but 
your doctors at NIH will be glad to provide telephone consultation to your own doctor on request.  During the study, 
you will be told about any research that relates to your study, especially any findings from the study itself. 
 
Genetic Testing 
 
Some of the blood drawn from you as part of this study will be used for genetic tests.  Genetic tests can help researchers 
study how health or illness is passed on to you by your parents or from you to your children.  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 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. 
 
Some of the blood drawn from you as part of this study may be used for a test for HLA type, which is a genetic test of 
markers of the immune system.  It 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 HIV 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.  
 
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.  Medical 
records containing this information will be kept under lock and key.  We will not release any information about you or your 
family to relatives, any insurance company, or employer unless you sign a release requesting us to do so.  Genetic 
information can be requested and obtained when a person applies for health insurance or a job and has signed a release. 
 


 
 
  
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: 
06-I-0197 
CONTINUATION:  page  8  of  11  pages 
 
 
PATIENT IDENTIFICATION 
CONTINUATION SHEET for either: 
 
NIH-2514-1 (10-84) 
 
NIH-2514-2 (10-84) 
 
P.A.: 09-25-0099 
 
 
 
Stored Samples and Future Research 
 
Blood left over from this study will be stored.  These stored samples will help us learn more about HIV, immune deficiency  
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, 
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. 
 
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 a 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 only use your samples 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.   
 
Benefits 
 
In general, future research that uses your samples will not help you, but it may help us learn what causes AIDS, immune 
deficiency, or related conditions.  This research may also help us learn how to prevent or treat the condition. 
 
Risks 
 
The greatest risk is that someone may take information from your medical records without your permission.  The chances 
of this happening are very low.  If this information becomes available, you may face discrimination when you apply for 
insurance or a job.  You may also have similar problems if you share the information yourself or let us release your 
medical records. 
 
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. 
 


MEDICAL RECORD
INCLUSION OF HIV TESTING IN CONSENT TO
PARTICIPATE IN A CLINICAL RESEARCH STUDY
 
 
 
CONTINUATION:  page  9  of  11  pages 
 
 
PATIENT IDENTIFICATION 
INCLUSION OF HIV TESTING IN CONSENT TO 
 
PARTICIPATE IN A CLINICAL RESEARCH STUDY 
 
NIH-2514-3 (5-02) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
 
As part of your participation in this study, it will be necessary to test your blood for the presence of antibodies to the 
Human Immunodeficiency Virus (HIV), the virus that causes Acquired Immune Deficiency Syndrome (AIDS).  In order to 
perform the test, a small amount of blood (approximately 2 teaspoons) will be withdrawn from one of your arms with a 
needle.  You may experience some slight discomfort at the needle entry site and there may be some bruising.  In 
addition, there is a very small risk of you fainting or of infection at the needle entry site.  If your test results are found 
to be positive, or if you are otherwise diagnosed as having AIDS, you should be aware of the following Clinical Center 
HIV Testing Policy: 
 
 
1. 
Your physician will notify you promptly of the HIV test results. 
 
 
2. 
Your physician and/or the Clinical Center HIV counselor will offer you, and any current and/or ongoing 
sexual partner(s) (spouses are generally considered to be current or ongoing sexual partners) or needle-sharing 
partner(s) you identify, information on the meaning of the test results and how to prevent the spread of the 
infection. 
 
 
3. 
Because the virus may be transmitted in several ways, it is important that you inform sexual and/or 
needle-sharing partner(s) that any, or all, of them may have been exposed to the HIV virus and encourage 
them to be tested.  If you request it, staff at the Clinical Center will assist you in notifying your partner(s) and 
arrange counseling for them through an HIV counselor. 
 
 
4. 
The results of your HIV test and/or documentation of the diagnosis of AIDS will become a part of your 
Clinical Center medical record and, as such, will be protected from unauthorized disclosure by the Federal 
Privacy Act of 1974.  In general, access to your medical record will be restricted to those health care 
professionals directly involved in your care or in the conduct of ongoing biomedical research, and information is 
not usually released to other third parties without your permission or that of your designated representative.  
However, there are some particular routine uses of such information of which you should be aware. 
 
a.  If you are unwilling or unable to notify your partner(s), the Clinical Center is responsible for 
attempting to contact and inform them of their possible exposure to the virus.  Reasonable attempts 
will be made to protect your identity including withholding your name when notifying any partner(s) of 
their possible exposure.  Some notification or counseling of current and/or ongoing partners may be 
carried out through arrangements with, or referral to, local public health agencies. 
 
b.  A summary of your care at the Clinical Center will be sent to the physician who referred you here for 
treatment. 
 
c.  The Clinical Center may report certain communicable diseases, such as HIV infection, to appropriate 
State and Federal government agencies. 
 
i. 
For Clinical Center patients who are Maryland residents, the Clinical Center reports by “Patient 
Unique Identifier Number” (rather than by name) newly obtained HIV-positive results from its 
laboratory to the Maryland Department of Health and Mental Hygiene.  Patient Unique Identifier 
Number is:  last four digits of social security number, birth month, birth day, birth year, race and 
gender. 
 


MEDICAL RECORD
INCLUSION OF HIV TESTING IN CONSENT TO
PARTICIPATE IN A CLINICAL RESEARCH STUDY
 
 
 
CONTINUATION:  page  10  of  11  pages 
 
 
PATIENT IDENTIFICATION 
INCLUSION OF HIV TESTING IN CONSENT TO 
 
PARTICIPATE IN A CLINICAL RESEARCH STUDY 
 
NIH-2514-3 (5-02) 
 
P.A.: 09-25-0099 
 
File in Section 4:  Protocol Consent 
 
 
 
ii. 
For Clinical Center patients who are Maryland residents, the Clinical Center reports by name new 
cases of AIDS to the Maryland Department of Health and Mental Hygiene. 
 
iii. 
For Clinical Center patients who are not Maryland residents, the Clinical Center 
reports HIV-positive results and/or AIDS to the patient’s primary care/referring physician. 
 
If you have any questions regarding the HIV testing or the information provided above, you are encouraged to discuss 
them with your physician and/or a Clinical Center HIV counselor:  (301) 496-2381. 
 


 
  
CONSENT TO PARTICIPATE IN A CLINICAL RESEARCH STUDY 
   MEDICAL RECORD 
•  Adult Patient or    •  Parent, for Minor Patient 
 
STUDY NUMBER: 
06-I-0197 
CONTINUATION:  page  11  of  11  pages 
 
PATIENT IDENTIFICATION 
CONSENT TO PARTICIPATE IN A CLINICAL 
 
RESEARCH STUDY (Continuation Sheet) 
 
•  Adult Patient or   •  Parent, for Minor Patient 
 
NIH-2514-1 (5-98) 
 
P.A.: 09-25-0099 
 
 
FAX TO:  (301) 480-3126 
 
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 other authorized 
people. 
 
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. 
 
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, Frank Maldarelli, M.D., 
Building: 10, Room 12S245, Telephone: (301) 435-8019.  Other investigators you may call are Rose McConnell (301) 
443-5643. 
 
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 
Signature of Parent(s)/Guardian 
Date 
 
 
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 
 
 
 
THIS CONSENT DOCUMENT HAS BEEN APPROVED FOR USE  
FROM APRIL 14, 2008 THROUGH APRIL 13, 2009. 
 
 
 
  
 
 
  
 
Signature of Investigator 
Date 
Signature of Witness 
Date