appendix b informed consent and
d. risks related to the

The following risks are part of the transplant process and not connected to any one medication or the transplanted donor cells.  
− **Bleeding:** Platelets help your blood to clot. Your platelets will be low until the new bone marrow grows and, as a result, bleeding may occur. This can be minor bleeding, such as nosebleeds or bruising, but more serious, life-threatening bleeding in the lungs and brain can occur if the platelet count remains low. Usually, there is success in preventing major bleeding problems with transfusions of platelets. However, some patients may not respond well to transfused platelets and may be at serious risk for bleeding.  
− **Veno-Occlusive Disease (VOD):** This can occur as a result of high dose chemotherapy, radiation therapy and/or medications used to prevent GVHD. VOD causes severe damage to the liver. Symptoms include jaundice (yellowing of the skin and eyes), weight gain, and extra fluid build-up in the abdominal cavity and other parts of the body. It can often be managed successfully, and completely resolve. However, complications can arise that may be fatal.  
− **Mouth Sores and Diarrhea:** The large doses of chemotherapy and radiation cause irritation in the lining of the mouth and intestines. This can result in painful mouth sores and diarrhea. If you have severe mouth sores you will be given medicine to help control the pain. If your mouth sores are severe you may not be able to eat normally until the sores are healed. Mouth sores get better when the white blood count starts to rise, and engraftment occurs.  
− **Capillary Leak Syndrome:** This may occur as a result of chemotherapy and radiation therapy. The blood vessels may become 'leaky' and fluid enters the abdominal cavity, lungs, and other tissues. You may gain water weight and not go to the bathroom as often as you normally do. Capillary leak syndrome can be difficult to manage if extra fluid enters the lungs and causes difficulty breathing, and can be life-threatening. You may die if there is continued fluid collection in the lungs.  
− **Unexpected Organ Damage and Other Side Effects:** It is possible you may experience unexpected, life-threatening heart, lung, kidney, or liver damage as a result of the transplant. Occasionally, the high doses of chemotherapy and radiation cause severe lung damage that cannot always be treated. If this happens, you may need to use oxygen or even a respirator. The lung damage may get worse and be lifethreatening. Rarely, multi-organ failure (such as lung and kidney failure) may occur, which is often fatal.  
− **Late Effects:** You may experience side effects that occur several months to many years after your transplant. You may experience poor function of the thyroid gland, requiring you to take thyroid medication. As a result of radiation, cataracts may occur earlier in life compared to a person who had not had a transplant. If you develop cataracts (cloudiness in the eyes) they may require treatment. It is rare, but your kidneys could be affected, causing anemia (low red blood cell count) or high blood pressure. There is also a risk you may develop a second cancer as a result of the chemotherapy, radiation and/or underlying disease. If secondary cancers occur they generally do not occur until 10 to 15 years after the transplant. The long-term effects upon heart, lung, and brain are unknown.  
− **Fluid Build-up:** You will receive intravenous fluids during the transplant process and your body may have trouble eliminating this fluid.
appendix b informed consent and
e additional side effects for

Most of the risks in this Consent Form can happen to all patients undergoing transplant, but some, such as risk of infection or organ damage, may be different in patients with HIV. There is a risk that a temporary stop to antiretroviral treatment could lead to HIV resistance to the medications you are taking. Your HIV viral load will be monitored by your doctor and if HIV resistance were to develop, alternate antiretroviral therapy may be needed. Many of the medications used for HIV will react with important medications to reduce the complications of the transplant (HCT). These reactions may require frequent blood checks to make sure the amount of medications in the blood are correct. It is possible those medications interactions will result in complications.
appendix b informed consent and
f enfuvirtide

Enfuvirtide may be given to you by your doctor if you are unable to take your pills for your HIV therapy if your doctor feels it is best for you. The following risks are associated with enfuvirtide:
- Injection site reactions: Almost all people have skin reactions at the site where enfuvirtide is injected. Reactions may include: itching, swelling, redness, pain or tenderness, hardened skin, bumps. Most reactions are mild. Occasionally they may be severe or rarely associated with infections or collection of thick liquid (abscess) at the injection site. Individuals receiving bone marrow transplant may have more serious reactions to enfuvirtide because of low blood platelets.  
- Lung infection (pneumonia). You should contact your healthcare provider right away if you have a cough, fever, or trouble breathing.  
- Serious allergic reactions. Symptoms may include: trouble breathing, fever, nausea, vomiting, chills, shakes, skin rash, blood in your urine, swelling in your feet, dizziness, severe muscle weakness starting in your feet and quickly moving to your upper body (Guillain-Barre syndrome). Contact your healthcare provider right away if you get any of these allergic reaction symptoms and do not take any more enfuvirtide. Enfuvirtide should not be restarted if your doctor thinks that you had an allergic reaction that was related to enfuvirtide.  
- Numbness and tingling of the hands and feet - Difficulty sleeping
- Depression, or anxiety
- Decreased appetite
- Sinus infections and other infections in other places, including the skin (herpes), and the blood (sepsis)
- Swollen glands (lymphadenopathy)
- Muscle pain - Constipation
appendix b informed consent and
g infections

You will need to take several antibiotics to prevent infection. You will also be watched carefully for any infections while you are being treated for HIV related Leukemia or Lymphoma. Tell your doctors right away if you get a fever, chills, cough or any other symptoms that might be a sign of an infection. Infections may be bad enough to cause death.
appendix b informed consent and
h reproductive risks

Risk to the unborn: The treatments in this study have NOT been proven to be safe at any stage of pregnancy. Therefore, if you are pregnant or nursing, you are not eligible for this study. Women who have the potential of becoming pregnant must use some form of effective birth control while receiving chemotherapy and GVHD prophylaxis. Effective birth control is defined as the following:
1) Refraining from all acts of vaginal intercourse (ABSTINENCE) 2) Consistent use of birth control pills 3) Injected birth control methods (Depro-Provera, Norplant) 4) Tubal sterilization or male partner who has undergone a vasectomy  
5) Placement of an IUD (intrauterine device) 6) Use, with every act of intercourse, of a diaphragm with contraceptive jelly and/or condoms with contraceptive foam.
Sterility and future childbearing potential for men and women: Chemotherapy and/or irradiation may affect your ability to have children. Male patients may become sterile (unable to produce sperm) and should discuss with their doctor regarding sperm banking prior to transplantation. Female patients who have attained puberty may find that their menstrual cycle becomes irregular or stops permanently. However, this DOES NOT MEAN THAT YOU CANNOT BECOME PREGNANT, and you must use some effective method of birth control during transplant and afterwards until you are off GVHD prophylaxis. Damage to reproductive tissue may result in infertility (inability to have children). It is not known if the damage could result in birth defects. You should discuss risks and options in detail with your doctor before entering this study.
appendix b informed consent and
i unforeseen risks

New risks might appear at any time during the study that are different from the risks listed in this Consent Form. We will promptly tell you of any new information that may affect your decision to participate.
appendix b informed consent and
j other treatments or medications

Some medicines react with each other, and it is important that you tell the study doctor or staff about any other drugs, treatments, or medicines you are taking. This includes nonprescription medications, vitamins and herbal treatments.  
It is also important that you tell the study staff about any changes to these medications during your participation in the study.  
For more information about risks and side effects, ask your study doctor.
appendix b informed consent and
8. possible benefits

Taking part in this study may or may not make your health better. The information from this study will help doctors learn more about transplant as a treatment for people with a blood cancer and HIV. This information could help future people with HIV who may need a transplant.
appendix b informed consent and
9. new information available during

During this research study, the study doctors may learn about new information about the study drug or the risks and benefits of the study. If this happens, they will tell you about the new information. The new information may mean that you can no longer participate in the study, or that you may not want to continue in the study. If this happens, the study doctor will stop your participation in the study and will offer you all available care to suit your needs and medical conditions.
appendix b informed consent and
10. privacy confidentiality and use

Your confidentiality is one of our main concerns. We will do our best to make sure that the personal information in your medical record is kept private. However, we cannot guarantee total privacy. We may give out your personal information if required by law. If information from this study is published or presented at scientific meetings, your name and other personal information will not be used. Information about your transplant from your original medical records may be seen or sent to national and international transplant registries, including:
- The Center for International Blood and Marrow Transplant Research (CIBMTR)  
- The National Marrow Donor Program (NMDP)
- The Food and Drug Administration (FDA)
- The National Institutes of Health (NIH), which include the National Heart, Lung, and Blood Institute (NHLBI) and the National Cancer Institute (NCI)
- Data and Coordinating Center of the Blood and Marrow Transplant Clinical Trials Network
(BMT CTN)
- Other authorized study organizations.
We will not identify you by name in any publications or reports that come from these organizations or groups. Information that does not include personally identifiable information about this clinical trial has been or will be submitted, at the appropriate and required time, to the government-operated clinical trial registry data bank, which contains registration, results, and other information about registered clinical trials. This data bank can be accessed by you and the general public at www.ClinicalTrials.gov. Federal law requires clinical trial information for certain clinical trials to be submitted to the data bank.
appendix b informed consent and
11. ending your participation

Being in this study is voluntary. You can choose to not be in this study, or leave this study at any time. If you choose not to take part or leave this study, your regular medical care will not be affected in any way. This includes standard care for your blood cancer and HIV. Tell your doctor if you are thinking about stopping or decide to stop. He or she will tell you how to stop safely. The study doctor or the study sponsor may stop the study at any time, and we may ask you to leave the study. We may ask you to leave the study if you do not follow directions or if you suffer from side effects of the treatment. If we ask you to leave the study, the reasons will be discussed with you. Possible reasons to end your participation in this study include:
- You do not meet the study requirements.  
- You need a medical treatment not allowed in this study.  
- The study doctor decides that it would be harmful to you to stay in the study. - You are having serious side effects. - You become pregnant.  
- You cannot keep appointments or take study drugs as directed.  
- The study is stopped for any reason.
If you decide to leave this study after taking the study treatment, or are asked to leave by your doctor for medical reason, you will need to come back to the doctor's office for tests for your safety. Even if you leave the study, the information collected from your participation will be included in the study evaluation, unless you specifically ask that it not be included.
appendix b informed consent and
12. physical injury as a

It is important that you tell your doctor, __________________ *[investigator's name(s)]* or study staff if you feel that you have been injured because of taking part in this study. You can tell the doctor in person or call him/her at __________________ *[telephone number]*. You will get medical treatment if you are injured as a result of taking part in this study. You and/or your health plan will be charged for this treatment. The study will not pay for medical treatment. In case of injury resulting from this study, you do not lose any of your legal rights to seek payment by signing this form.
appendix b informed consent and
13. compensation or payment

You will not be paid for your participation in the research study. You will not get compensation or reimbursement for any extra expenses (travel, meals, etc.) you may have through your participation on this trial.
appendix b informed consent and
14. costs and reimbursements

Most of the visits for this research study are standard medical care for patients undergoing allogeneic transplants and will be billed to your insurance company. You and/or your health plan/insurance company will need to pay for some or all of the costs of standard treatment in this study.  
You or your insurance will not be charged for optional blood samples for research on this study. For more information on clinical trials and insurance coverage, you can visit the National Cancer Institute's Web site at http://cancer.gov/clinicaltrials/understanding/insurance-coverage. You can print a copy of the "Clinical Trials and Insurance Coverage" information from this Web site. Another way to get the information is to call 1-800-4-CANCER (1-800-422-6237) and ask them to send you a free copy.
appendix b informed consent and
15. ethical review

The ethical aspects of this research study have been reviewed and approved by [name of IRB].
appendix b informed consent and
16. further information

If you need more information about this study, or if you have problems while you are participating in this study, you can contact the study doctor or his/her staff. They can be reached at the telephone numbers listed here: [Insert name and contact details]
appendix b informed consent and
17. independent contact

If you wish to speak to someone not directly involved in the study, or if you have any complaints about any aspect of the project, the way it is being conducted or any questions about your rights as a research participant, then you may contact: [Insert appropriate contact details] For questions about your rights while taking part in this study, call the __________[name of center] Institutional Review Board (a group of people who review the research to protect your rights) at __________________ *(telephone number).*
appendix b informed consent and
18. ccr5 donor screening

Human Immunodeficiency Virus (HIV) uses a protein called CCR5 as a way to get inside of cells. A few people are naturally able to block HIV infection because their body does not make the CCR5 protein. As a result, HIV does not have a way to enter their cells and cause an infection. Proteins are in every cell in our body and help keep the blood, skin and other parts of our bodies healthy. Every protein is made by a specific kind of gene. Every person has 2 copies of the gene that makes the CCR5 protein. One copy is from their mother and the other copy is from their father. Some people have changes to their genes that make the CCR5 protein. Another word for changes to a gene is mutation. Changes to the CCR5 gene means the body can't make the CCR5 protein. People who have 2 copies of the CCR5 gene mutation are called CCR5delta32homozygotes and they are naturally able to block HIV infection. Very few people in the world have mutations to both copies of their CCR5 gene. If you are Caucasian with a family background from northern Europe, the chance is about 1 out of 100 people in finding a matched donor with 2 copies of the CCR5 gene mutation. If you do not have a northern European background, the chance is very, very small that you would find a donor who has 2 copies of the CCR5 gene mutation. In one case, a person with 2 copies of the CCR5 gene mutation donated their blood-making cells for a transplant in a patient who had HIV and a blood cancer. Now the patient does not have any signs of HIV and does not need drugs to treat his HIV. We do not know if this will happen again, even if a donor has the CCR5 gene mutation Besides the possible benefit of blocking HIV infection, some risks may come with a donor who has the CCR5 mutations. Research has shown that people with 2 copies of the CCR5 gene mutation may not fight off infections from West Nile virus (WNV) very well. WNV spreads through mosquito bites. Serious cases of WNV can cause a brain infection.  
In addition to doing the standard tests to make sure a donor is a good match for you, we will also test possible donors to see if they have the CCR5 gene mutations. This testing will not slow down our search for your donor. We will let you know if we find a donor and if that donor has the CCR5 mutations. At that point, you and your doctor will need to decide if you want to use a donor with or without the CCR5 mutations.
appendix b informed consent and
blood samples for research (optional)

Please note: *This section of the informed consent form is about future research studies that* will be done using blood samples from people who are taking part in the main study described above. You may give small blood samples for these future research studies if you want to. You can still be a part of the main study even if you say 'no' to giving blood samples for future research studies. You can say "yes" or "no" to giving blood samples for future research studies. Please mark your choice at the end of this section. We would like to have one small (4 teaspoons or 17 mL) blood sample for future research. If you agree, this sample will be obtained pre-transplant. It will be kept and may be used in research to learn more about HIV, cancer and other diseases. Usually the blood can be drawn from your central venous catheter at the time of the other blood collections. If this is not possible, it will be taken from a vein. When the sample is given to investigators for research, no information about your name, address, phone number or other information that will let the researcher know who you are will be provided. The samples collected for research purposes will be sent to the AIDS and Cancer Specimen Resource Repository. The samples will be labeled with unique codes that do not contain information that could identify you. A link to this code does exist. The link is stored at the Data and Coordinating Center for the Blood and Marrow Transplant Clinical Trials Network (BMT CTN). The staff at the repository where your sample is being stored does not have a link to this code. Your research samples will continue to be stored at the ACSR Repository until they are used up for approved research. DNA from your stored blood and tissue samples and your health information might be used in genome-wide association (GWA) studies for a future project either done or supported by the National Institutes of Health (NIH). Genome-wide association studies are a way for scientists to identify genes involved in human disease. This method searches the genome for small genetic changes that are more common in people with a particular disease than in people without the disease. Each study can look at hundreds of thousands of genetic changes at the same time. Researchers use data from this type of study to find genes that may add to a person's risk of developing a certain disease. If your coded genetic and clinical information is used in such a study, the researcher is required to add the DNA test results and non-identifying information into a public research database. This public database is called the NIH Genotype and Phenotype Database and it is managed by the National Center for Biotechnology Information (NCBI). The NCBI will never have any information that would identify you, or link you to your information or research samples. A new federal law (2009), called the Genetic Information Nondiscrimination Act (GINA), generally makes it illegal for health insurance companies, group health plans, and employers of 15 or more persons to discriminate against you based on your genetic information. Health insurance companies and group health plans may not request your genetic information that we get from this research. This means that they must not use your genetic information when making decisions regarding insurability. Be aware that this new federal law will not protect you against genetic discrimination by companies that sell life insurance, disability insurance, or long-term care insurance. The research that may be done with your blood is not designed specifically to help you. It might help people who have HIV, cancer and other diseases in the future. Reports about research done with your blood will not be given to you or your doctor. These reports will not be put in your health record. The research will not have an effect on your care. Things to Think About: The choice to let us have blood samples for future research is up to you. No matter what you decide to do, it will not affect your care. If you decide now that your blood can be kept for research, you can change your mind at any time. Just contact your study doctor and let him or her know that you do not want us to use your blood sample. Then any blood that remains will no longer be used for research. In the future, people who do research on these blood samples may need to know more about your health. While the study doctor or others involved in running this study may give the researchers reports about your health, it will not give them your name, address, phone number, or any other information that will let the researchers know who you are. Sometimes blood is used for genetic research (about diseases that are passed on in families). Even if your blood is used for this kind of research, the results will not be put in your health records. Your blood will be used only for research and will not be sold. The research done with your blood may help to develop new products in the future.  
Benefits: The benefits of research using blood include learning more about what causes HIV,
cancer and other diseases, how to prevent them, and how to treat them. Risks: The greatest risk to you is the release of information from your health records. We will do our best to make sure that your personal information will be kept private. The chance that this information will be given to someone else is very small. Making Your Choice: Please read each sentence below and think about your choice. After reading each sentence, please indicate your choice below. If you have any questions, please talk to your doctor or nurse, or call our research review board at ___________________.  
No matter what you decide to do, it will not affect your care.
appendix b informed consent and
statement of consent

The purpose of storing blood samples, the procedures involved, and the risks and benefits have been explained to me. I have asked all the questions I have at this time and I have been told whom to contact if I have more questions. I have been told that I will be given a signed copy of this consent form to keep. I understand that I do not have to allow the use of my blood and for research. If I decide to not let you store research samples now or in the future, it will not affect my medical care in any way. I voluntarily agree that a blood sample may be collected and that my blood and related information can be stored indefinitely by the BMT CTN and/or AIDS and Cancer Specimen Resource Repository for research to learn about, prevent, or treat health problems. I also understand that my DNA and health information may or may not be used in genome-wide association studies.  
❑ I do agree to give a blood sample for research.  
❑ I do not agree to give a blood sample for research.
Signature Date  
  
⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧ ⬧
appendix b informed consent and
health insurance portability and accountability

As a research participant, I authorize the Principal Investigators and the researcher's staff to use and disclose my individual health information for the purpose of conducting the research study: Allogeneic Hematopoietic Cell Transplant for Hematological Cancers and Myelodysplastic Syndromes in HIV-Infected Individuals
appendix b informed consent and
b. individual health information to

My individual health information that may be used or disclosed to do this research includes:
- Demographic information (for example: date of birth, sex, weight). - Medical history (for example: diagnosis, complications with prior treatment).  
- Findings from physical exams. - Laboratory test results obtained at the time of work up and after transplant (for example:
blood tests, biopsy results).
appendix b informed consent and
c. parties who may disclose

The researcher and the researcher's staff may collect my individual health information from: [List hospitals, clinics or providers from which health care information can be *requested*].  
D. **Parties Who May Receive or Use My Individual Health Information**:
The individual health information disclosed by parties listed in item c and information disclosed by me during the course of the research may be received and used by the following parties: Principal Investigator and the researcher's staff Dr. Joseph Alvarnas, Co-Principal Investigator Dr. Richard Ambinder, Co-Principal Investigator
appendix b informed consent and
study sponsors

- National Heart, Lung, and Blood Institute (NHLBI) and the National Cancer Institute
(NCI), both of the National Institutes of Health (NIH),  
- Blood and Marrow Transplant Clinical Trials Network (BMT CTN), Data and Coordinating Center
- U.S. government agencies that are responsible for overseeing research such as the Food and Drug Administration (FDA) and the Office of Human Research Protections (OHRP)
- U.S. government agencies that are responsible for overseeing public health concerns such as the Centers for Disease Control (CDC) and federal, state and local health departments.  
E. **Right to Refuse to Sign this Authorization**:
I do not have to sign this Authorization. If I decide not to sign the Authorization, I will not be allowed to participate in this study or receive any treatment related to research that is provided through the study.  
My decision not to sign this authorization will not affect any other treatment, payment, or enrollment in health plans or eligibility for benefits.
appendix b informed consent and
f. right to revoke

I can change my mind and withdraw this authorization at any time by sending a written notice to the Principal Investigator to inform the researcher of my decision. If I withdraw this authorization, the researcher may only use and disclose the protected health information already collected for this research study. No further health information about me will be collected by or disclosed to the researcher for this study.
appendix b informed consent and
g. potential for re-disclosure

My individual health information disclosed under this authorization may be subject to redisclosure outside the research study and no longer protected.  
Examples include potential disclosures for law enforcement purposes, mandated reporting or abuse or neglect, judicial proceedings, health oversight activities and public health measures.
appendix b informed consent and
h. this authorization does not

I have read and understood this Consent Form. The nature and purpose of the research study has been explained to me.  
- I have had the chance to ask questions, and understand the answers I have been given. I
understand that I may ask questions at any time during the study.  
- I freely agree to be a participant in the study.  
- I understand that I may not directly benefit from taking part in the study.
- I understand that, while information gained during the study may be published, I will not be identified and my personal results will stay confidential.  
- I have had the chance to discuss my participation in this research study with a family member or friend.  
- I understand that I can leave this study at any time, and doing so will not affect my current care or prevent me from receiving future treatment.  
- I understand that I will be given a copy of this signed consent form.  
  
  
| Participant Name   | Date   |
|--------------------|--------|
| Signature          | Date   |  
I certify that I have provided a verbal explanation of the details of the research study, including the procedures and risks. I believe the participant has understood the information provided.  
| Name of Counseling Physician      | Date   |      |
|-----------------------------------|--------|------|
|                                   |        |      |
| Signature of Counseling Physician |        | Date |
appendix b informed consent and
pediatric assent to participate in

Study Title: Allogeneic Hematopoietic Cell Transplant for Hematological Cancers and Myelodysplastic Syndromes in HIV-Infected Individuals Protocol: BMT CTN 0903 (AMC 080)
appendix b informed consent and
a. why am i here?

We are inviting you to join our study because you have HIV (human immunodeficiency virus) and you need a transplant to treat your blood cancer.
appendix b informed consent and
b. why are you doing

We are doing this study because we want to learn how well hematopoietic cell transplant treats blood cancers in people like you who have HIV. The kind of transplant we would do for you would use blood or bone marrow from another person who matches you. This is called an allogeneic transplant. This form gives you information to help you decide if you want to be in this study. You should read this form and ask any questions you have before agreeing to be in the study. It is up to you to decide if you want to be in the study.
appendix b informed consent and
c. what will happen to

Your doctor will check to see if you have a type matched donor for your transplant. You will have several tests to see if it is okay for you to be on this study.
appendix b informed consent and
before the transplant

You will have several tests done to check your organ function. These tests will check your heart, lungs, and brain. Most of these tests are X-rays or scans, questions, or blood tests. The doctors will look at the results of all these tests to make sure that it is okay for you to have a transplant. You will also need to have several tests for research. We will ask if we can take some blood from you up to 4 times (10-47 mL or about 2-13 teaspoons) with a very small needle. Eight weeks before your transplant, we will also ask to take more blood from you (about 36 teaspoons) only if the HIV in your body does not show up in a standard test.
appendix b informed consent and
preparation for the transplant

Before the transplant, you will need to receive medicines so that your body can accept the new bone marrow cells. This is called a 'conditioning regimen.' You will receive chemotherapy medicine before your transplant. Chemotherapy is a combination of strong drugs that work to destroy your cancer cells and get your body ready for transplant. Post-transplant follow-up and care: After the transplant you will continue to get medicines to help the donor cells grow. These drugs will also help lower the chance of getting graft-versus-host disease (GVHD). GVHD is a complication that happens when the donor's cells attack your body. You will receive one or more medicines to prevent GVHD. You will continue to receive these drugs for at least six months after the transplant. You will be in the hospital for about four weeks after your transplant. You will be allowed to go home from the hospital when your doctor feels it is safe. After you go home you will need to return to visit your doctors so they can check your recovery. Your doctors will need to check your blood and bone marrow after the transplant to make sure the new blood cells are growing in your body. Your doctors will also do blood tests and other tests to make sure your organs are working well. The study team will also check in with you weekly to see if you missed any HIV medicines or certain medicines used as part of the transplant. This study will last for 2 years and we will watch you carefully for side effects, fevers, infections and other problems. You will also need to have several tests for research. We will take some blood from you up to 7 times (about 2-14 teaspoons each time) with a very small needle. Also, 13 months after your transplant, we will ask to take more blood from you (about 36 teaspoons) only if the HIV in your body still does not show up in a standard test.
appendix b informed consent and
optional test for future research

Between 1 and 3 weeks prior to your transplant, we will ask your permission to take some more blood (about 6 teaspoons of blood) from you to use for future research. You don't have to be in this research. If you don't want to give blood samples for future research you can still be in the other parts of the study. Your care will not be changed if you decide not to give these blood samples for research purposes. Please mark your choice below (check only one box):
❑ I do agree to give a blood sample for research.  
❑ I do not agree to give a blood sample for research.
appendix b informed consent and
d. will it hurt?

When you have your blood taken with a needle, it may feel like a pinch. It will hurt for a minute and sometimes the place where the needle went might be red and sore. You might get a little bruise where the blood was taken but it goes away in a few days.
appendix b informed consent and
e. what are the risks

The drugs may cause a skin rash, hair loss, nausea and vomiting, diarrhea and infections. Your blood counts will fall and you may get fevers, infections or start bleeding. You may also get mouth sores. These are temporary and you will feel better as your new bone marrow grows. Since you will not be able to fight infections while your new bone marrow is growing back, you may need to get antibiotics. You may also need to get blood transfusions since your new bone marrow will not be making new blood cells right away. Even with medicines to prevent it, you may get GVHD. This can cause skin rash, vomiting, diarrhea, stomach pain, lung and liver problems, swelling of the hands and feet, dry eyes, stiff joints, and tiredness. These problems are usually mild but can become very serious and prolonged. Medicines are given to prevent GVHD during and after transplant. If GVHD occurs even after taking these medicines, other medicines will need to be started and hospital stays may be necessary. The medicines used to treat GVHD also have side effects. They can cause tiredness, depression, sleep problems and mood swings. They can also make you get severe infections very easily. Your doctors will do their best to make you feel better and keep you safe. Often this may require many hospital stays. However, it is important to understand that there is a small risk (about a 1 in 10 chance) that you may die as a result of one or more of the complications of unrelated donor transplantation.
appendix b informed consent and
f. will the study help

You may or may not benefit from taking part in this study.
appendix b informed consent and
g. what if i have

You can ask us any questions that you have about the study. If you forget to ask a question and think of it later, you can call me [*insert office number*]. You can also ask your question the next time you see me. You can call the study office at any time to ask questions about the study.
appendix b informed consent and
h. do i have to

It is up to you if you want to participate in this research study. If you don't want to be in the study, you can tell us and your parent or guardian. Your doctor will not be upset or angry if you don't want to join. You can say yes now and change your mind at any time. If you leave the study you can still get medical care from your doctor and transplant center. You will be told about new information or changes in the study that may affect your health or your willingness to continue in the study.
appendix b informed consent and
i. can the doctor who

You can be taken off the study (with or without your consent) for any of the following reasons:
- You need a medical treatment not allowed in this study  
- The investigator decides that continuing in the study would be harmful to you
- You become pregnant and the study participation could be harmful to the fetus
- The study is cancelled by the Food and Drug Administration (FDA) or the National Institutes of Health (NIH)
appendix b informed consent and
j. will my medical information

We will do our best to make sure that the personal information in your medical record be kept private. However, we cannot guarantee total privacy. Your personal information may be given out if required by law. If information from this study is published or presented at scientific meetings, your name and other personal information will not be used. You will receive a copy of this form. If you need more information about this study, ask the study doctor.  
*************************************************
appendix b informed consent and
minor's assent

I have read the information in this consent form and have had the study explained to me. My questions have been answered to my satisfaction. I agree to participate in the study.  
______________________________________________ _____________  
  
Certification of Counseling Healthcare Professional I certify that the nature and purpose, the potential benefits, and possible risks associated with participation in this study have been explained to the above individual and that any questions about this information have been answered.  
______________________________________________ _____________
Counseling Healthcare Professional Date
appendix c laboratory procedures appendix
1. microbial translocation markers characterization

HCT-related risk factors for infection (time to engraftment, degree of mucositis, duration of neutropenia) and HIV-related (CD4, VL, HAART resistance) risk factors will be investigated. Specimens will be collected to allow the analysis of the relationship of microbial translocation markers to febrile neutropenia and infectious outcomes.
appendix c laboratory procedures appendix
background

Recent observations that persons with chronic HIV-1 infection and AIDS demonstrate increased microbial translocation (MT) from the gut compared to uninfected persons may be related to the massive depletion of intestinal CD4+ lymphocytes within weeks of HIV-1 acquisition (1). Our group also recently demonstrated that microbial translocation in HIVHCV co-infection was strongly associated with more rapid progression of liver cirrhosis. A
key finding was that serum endotoxin (LPS) level, a marker of microbial translocation, was higher in patients with more advanced fibrosis (2). The detection of microbial translocation in peripheral blood likely underestimates the higher quantities of microbial products that enter the portal venous circulation with resulting sequelae in the liver. Previous studies have shown that HIV+ recipients of autologous stem cell transplant are at risk for early hepatic veno-occlusive disease (VOD) (3). VOD is a condition that is characterized by endothelial cell injury in the hepatic sinusoids leading to sinusoidal thrombosis and occlusion. LPS is known to have a procoagulant effect by inducing gene expression of several inflammatory mediators including the procoagulant protein, tissue factor (4). Therefore, a high level of circulating MT markers (such as LPS) at the time of transplant could be a risk factor for development of early hepatic VOD. Moreover, monitoring serum levels temporally to explore associations with liver associated morbidity including VOD, may provide insights into defining risk factors for VOD. The long-term goal of this approach is to provide a rational basis for targeted antimicrobial therapy to reduce microbial translocation in patients at higher risk of developing VOD.
appendix c laboratory procedures appendix
hypothesis

We hypothesize that increased microbial translocation in HIV infected recipients of induction chemotherapy may increase the risk for development of veno-occlusive disease after autologous or allogeneic stem cell transplant.
appendix c laboratory procedures appendix
study objectives

We propose testing archived sera for microbial translocation markers from HIV-infected persons who have received allogeneic stem cell transplant. Microbial translocation marker levels will then be correlated with clinical outcome (hyperbilirubinemia, development of VOD, death) as patients are followed longitudinally.
appendix c laboratory procedures appendix
study design

Clinical data that will be obtained at baseline will include age, gender, race, HCV RNA
levels, HIV RNA levels, CD4+ lymphocyte count, AST, ALT, total bilirubin, antibiotic usage within the prior 6 weeks, antiretroviral therapy, MELD score, and a history of liverrelated complications.
appendix c laboratory procedures appendix
microbial translocation measurements

Markers of microbial translocation that will be tested include plasma LPS, LPS-binding protein (LBP), soluble CD14 (sCD14), and the polyclonal IgM antibody directed toward the LPS core polysaccharide (EndoCAb IgM). LPS testing will be done using the *Limulus* Amebocyte Lysate (LAL) assay (Lonza), while LBP (Cell Sciences), sCD14 (R&D
Systems), and EndoCAb IgM (Hycult Biotechnology) assays are all standard plate-based ELISA tests. Microbial translocation markers will be log-transformed to normalize the data, as has been done previously. Values of the LAL assay < 10 pg/mL are considered below the linear range of the assay and will be considered 5 pg/mL (mean of 0 and 10 pg/mL) for standard calculations.
appendix c laboratory procedures appendix
statistical components

Association between outcome (hyperbilirubinemia, VOD, and death) at Days 7, 14 and 100 post-transplant and level of microbial translocation markers will be determined by nonparametric Mann-Whitney tests comparing the distribution of prior microbial translocation markers between patients with vs. without each outcome.
appendix c laboratory procedures appendix
samples required pre-transplant

A 10 mL peripheral blood sample will be collected in an EDTA containing Vacutainer tube 1 week prior to conditioning as well as on Day -3 of the conditioning regimen.
appendix c laboratory procedures appendix
post-transplant

A 10 mL peripheral blood sample will be collected in an EDTA containing Vacutainer tube will be collected at Days 7, 14, and 100 post-transplant.
appendix c laboratory procedures appendix
samples shipment

Transplant centers will ship whole blood tube by priority overnight FedEx on the day of collection to the project laboratory for processing and microbial translocation marker testing.
appendix c laboratory procedures appendix
references

1. J. M. Brenchley et al., *Nature Medicine* 12, 1365-1371 (2006).  
2. A. Balagopal et al., *Gastroenterology* 135, 226-233 (2008).  
3. T Spitzer et al., *Biol of Blood and Marrow Transpl.* 14, 59-66 (2008). 4. Luyendik et al., *J Immunol.* 180, 4218-4226 (2008).
appendix c laboratory procedures appendix
2. hiv single copy pcr

The effect of marrow ablative and reduced intensity chemotherapy on the HIV reservoir is not known, but the model of AIDS-related malignancies treatment does provide an opportunity to define changes which are associated with HCT. In the current study, we propose to characterize the HIV infection during and after such treatment of hematological malignancies and Myelodysplastic syndromes, by measurement of HIV load including the use of an assay which measures HIV at less than 1 copy per milliliter. In patients with no detectable viral load by standard clinical assays, this assay regularly detects low copy number viral RNA. This RNA is believed to be released from latency compartments established in hematopoietic cells.
appendix c laboratory procedures appendix
hypothesis

We hypothesize that treatment of AIDS-related malignancies using dose-intense or cytotoxic reduced-intensity therapy in patients will result in a substantial reduction in the size of the HIV reservoirs and thus in this very low level viremia. This study will represent the first application of this single copy PCR technique to such conditioning therapies with allogeneic hematopoietic stem cell transplant—although the approach has been used multi-institutional studies of antiretroviral therapies.
appendix c laboratory procedures appendix
hiv cellular reservoir analysis &

In patients with undetectable viral load as measured in conventional assays, there is persistent viremia that can be measured at single copy/ml by specialized PCR analysis. This viremia may reflect virus being released by the decay of latently infected cells or possibly ongoing viral replication. Therapies that impact on the latently infected reservoir might be expected to change the viremia if it mainly reflected the decay of latently infected cells. Pre-transplant conditioning therapies may kill cells that constitute the latency reservoir and thus might thus be expected to impact on the reservoir and the very low level viremia that can be assessed by this assay.
appendix c laboratory procedures appendix
sample requirements latent hiv cellular

Once the patient is consented and enrolled on the trial, a peripheral blood sample will be collected at approximately 8 weeks prior to initiation of ablative therapy for only those patients that have documented undetectable plasma HIV-1 by standard assay. A 180 mL peripheral blood sample will be collected and placed in to eighteen (18) 10 mL EDTA containing, lavender-top Vacutainer tubes. Post-transplant A peripheral blood collection will be scheduled sometime after 12 months post-transplant, typically at 13 months post-HCT, for only those patients that are found to have undetectable plasma HIV-1 RNA by the standard assay performed at the clinical site on the 12 months sample. A 180 mL peripheral blood sample will be collected and placed in to eighteen (18) 10 mL EDTA containing, lavender-top Vacutainer tubes.
appendix c laboratory procedures appendix
sample shipment

Transplant centers will ship whole blood tubes by priority overnight FedEx on the day of collection to the project laboratory for processing and testing.
appendix c laboratory procedures appendix
single-copy hiv assays (plasma &

A 30 mL peripheral blood sample will be collected in EDTA containing Vacutainer tubes 1-3 weeks and 1 week prior to initiation of ablative therapy.
appendix c laboratory procedures appendix
post-transplant

A 30 mL peripheral blood sample will be collected in EDTA containing Vacutainer tubes on Day 100, and at 6, 12, and 24 months post-transplant.
appendix c laboratory procedures appendix
sample processing and shipment

Transplant centers will ship whole blood tubes by priority overnight FedEx on the day of collection to the BMT CTN 0903-specific Central Processing Laboratory for sample plasma and PBMC aliquot processing and temporary sample storage. Available sample aliquots will be periodically shipped to the designated project laboratory for testing.
appendix c laboratory procedures appendix
3. immune reconstitution assays (research)

Little is known about immune reconstitution following allogeneic hematopoietic cell transplantation to treat patients with hematologic malignancies in patients with HIV infection. Multiple variables including adaptive immune dysfunction and chronic viral infections raise the possibility that HIV+ patients will encounter more infectious complications compared to HIVindividuals following hematopoietic cell transplantation. It will therefore, be critical to perform correlative laboratory investigations examining adaptive and innate immune surveillance in this very unique setting. The use of multiparametric flow cytometry to identify specific adaptive and innate immune cell subsets, and use of available pathogen-specific epitopes should allow us to characterize the dynamics of immune reconstitution and identify first responses against HIV and other common pathogens post-ASCT.
appendix c laboratory procedures appendix
hypothesis

We hypothesize that quantitative and qualitative differences in adaptive and innate immune reconstitution will correlate with clinical outcome in HIV+ patients who undergo allogeneic hematopoietic cell transplantation.  Improved understanding of immune reconstitution in this very unique setting will lead to advances in the management of HIV+ patients with cancer and lead to novel approaches to improve long term survival of these patients.
appendix c laboratory procedures appendix
study design immunophenotypic evaluation of

time point study has been performed to evaluate reconstitution of adaptive immunity in HIV+ patients treated with peripheral blood hematopoietic cell transplantation.  Examining the nature of adaptive and innate immune reconstitution will involve use of a multi panel flow cytometric assay to track changes in naïve, memory, activated and regulatory T cell subsets. Specifically, these studies will involve a detailed in vivo analysis of early, mid, early-late and late activation of B and T lymphocytes and characterization of T cell subsets including naïve, memory, Th1, Th2 and T regulatory cells.  In addition we will evaluate maturation status of NK cells and their activation status.  Multiparametric flow analysis will be performed on fresh peripheral blood samples collected at 60, 180 and 365 days post stem cell infusion.  
| Table 1 Multicolor T Cell Panel   | Table 2 Multicolor NK Cell Panel   |          |          |       |           |                                        |       |       |        |      |          |
|-----------------------------------|------------------------------------|----------|----------|-------|-----------|----------------------------------------|-------|-------|--------|------|----------|
| FITC                              | PE                                 | ED       | PC5      | PC7   | Condition | Flow Cytometric 5-color antigen panels |       |       |        |      |          |
| CD3                               | CD56+                              | CD19     | CD45     | CD13  | Viability | 7-AAD                                  |       |       |        |      |          |
| gate purity                       | CD16                               |          |          |       |           |                                        |       |       |        |      |          |
| Activation                        | HLA DR                             | CD69     | CD3      | CD134 | CD45      | NK cell                                | CD45  | CD3-  | CD158- | CD69 | CD56+CD1 |
| Med activation                    | C8                                 | CD49a    | CD4      | CD3   | CD45      | activation                             | PC7   | FITC  | PE     | ECD  | 6-PC5    |
| Naïve/memory                      | LAMP-1                             |          |          |       |           |                                        |       |       |        |      |          |
| CD45RA                            | CD27                               | CD45RO   | CD4      | CD8   | NK cell   | NKG2A                                  |       |       |        |      |          |
| CD45                              | CD107a+                            | CD3      | CD58+CD1 |       |           |                                        |       |       |        |      |          |
| clls                              | granulation                        | PC7      | CD107b   | CD159 | ED        | 6-PC5                                  |       |       |        |      |          |
| PE                                |                                    |          |          |       |           |                                        |       |       |        |      |          |
| Naïve/memory                      | status                             | FITC     |          |       |           |                                        |       |       |        |      |          |
| CD45RA                            | CD29                               | CD45RO   | CD4      | CD8   | NK cell   | LAMP-3                                 | NKG2D |       |        |      |          |
| CD45-                             | CD3                                | CD56+CD1 |          |       |           |                                        |       |       |        |      |          |
| TH1/Th2                           | CD193                              | CD294    | CD4      | CXCR3 | CD45      | granulation                            | CD63  | CD314 |        |      |          |
| PC7                               | FITC                               | ED       | 8-PC5    |       |           |                                        |       |       |        |      |          |
| Th1/Th2                           | CD193                              | CD294    | CD4      | CD45  | CR4       | PE                                     |       |       |        |      |          |
| T regulatory cells                | CD8                                | CD127    | CD4      | CD25  | CD45      | CD117-                                 |       |       |        |      |          |
| NK Cell                           | CD45                               | CR       | CD16     | CD56- |           |                                        |       |       |        |      |          |
| TCR α/β and g/d                   | TCR Y8                             | TCR αβ   | CD45     | CD3   | PC7       | FITC                                   | ECD   | PC7   |        |      |          |
| maturity status                   |                                    |          |          |       |           |                                        |       |       |        |      |          |  
Samples of ACD (yellow top) and EDTA (lavender top) anticoagulant containing blood will be received at the project laboratory within 24h following collection and processed immediately upon receipt in the clinical flow cytometry laboratory.  Prior to staining, all samples will be analyzed for viability using 7AAD method.  Only samples with mononuclear cell viability > 90% will be considered acceptable for further analysis.  Viability of >95% is achieved in ACD tubes stored at room temperature for up to 48 hours.  All samples will be stained using a PrepPlus2 automated staining system (Beckman Coulter) utilizing a five color whole blood staining technique with panels of directly conjugated monoclonal antibodies (see Tables 1 and 2)
used in quantities that have been predetermined and standardized in our flow cytometric laboratory.  Following 30 minutes of incubation at room temperature in the dark, red cells will be lysed using a Q-prep instrument and Coulter Lyse reagent according to manufacturer's recommendations.  Samples will be analyzed on FC500 flow cytometer equipped with CXP
software version 2.1 (all equipment and reagents by Beckman Coulter).  Multiparametric analysis will be performed with a gating strategy based on CD45 staining and light side scatter characteristics that allow adequate separation of lymphocyte, monocyte and myeloid cell populations. Detailed immunophenotypic characterization of the lymphocyte gate will be performed using Prism plot algorithm (Beckman Coulter). The results will be reported as percent of lymphocyte gate and as percent of total leukocytes analyzed. The results will also be reported as an absolute number of specific cell subset types per microliter of whole blood. Absolute cell number will be calculated based on duel platform method using percent of lymphocytes expressing specific immunophenotypic profile (derived from prism plot) and absolute number of lymphocytes derived from analysis of each whole blood sample using ActDIFF hematology analyzer (Beckman Coulter).
appendix c laboratory procedures appendix
functional evaluation of adaptive immune

adaptive cellular immunity by tracking responsiveness to viral recall antigens. We will follow responsiveness to HIV as well as common viral pathogens like CMV and EBV. Studies will use pools of overlapping 15-18mer peptides from full-length viral proteins (JPT Technologies) encoded by CMV (pp65), EBV (BZLF1) and HIV (gag). Aliquots of frozen PBMCs will be thawed and enumerated. 1x106 PBMCs will be cultured in the presence of individual viral pooled peptide preparations (or actin control pooled peptides, 1ug/ml final concentration) in the presence or absence of agonistic anti CD28 monoclonal antibody to control for costimulatory signals and provide an optimal condition for evaluation of responsiveness. Following overnight incubation (in presence of brefeldin A golgi plug reagent), a multi color flow cytometric evaluation will identify CD3/CD8 subsets that costain with IFN or CD107a (degranulation marker). Separate controls with 7AAD will evaluate PBMC viability. 1 x 105 CD3+ events will be collected using a FC500 flow cytometer and percentage of CD3/CD8+ T cells staining positive for IFN and or CD107a will be determined. Outcome of these bioassays will be correlated with immunophenotypic and clinical patient data.
appendix c laboratory procedures appendix
functional evaluation of innate immune

studies will examine natural killer (NK) cell responsiveness to cytokines and to FcRIIIa signaling. NK cell responsiveness assays will be performed on purified NK cells that will be isolated via rosette-sep immuno selection kits. To test cytokine responsiveness, 1x105 NK cells will be incubated overnight in standard culture medium (supplemented with human AB serum)
in interleukin 2 (IL-2 10nM) +/- IL-12 (10ng/ml). To evaluate FcRIIIa responsiveness, 2 methods will be employed: (i) Immobilized IgG in presence or absence of IL12; and (ii) anti FcRIIIa monoclonal antibody treatment +/- IL12. For FcgRIIIa signaling studies, 96-well flatbottom plates will be coated with 100 g/mL huIgG in cold PBS overnight at 4°C, washed with cold PBS, and then plated with immune cells (2 x 105cells/well) +/- 10 ng/mL IL-12 (or saline control). At 24 and 48 hours cell-free culture supernatants will be harvested and analyzed for levels of IFN- by enzyme-linked immunosorbent assay (ELISA; R&D Systems, Minneapolis, MN). NK cells will be checked for viability following the overnight pretreatment period and again at the conclusion of the experiment. The readout for the assay will be IFN- measured by ELISA or intracellular IFN and CD107a expression determined by flow cytometry (as in adaptive immune reconstitution studies) at 24 and 48 hrs. FcRIIIa responsiveness can also be tested via use of anti FcRIIIa mAb (clone 3G8) to cross link receptors +/- IL12 and IFN and CD107a detected via flow cytometry. Positive controls will include PBMCs collected from immune-competent individuals, purified NK cells from immune-competent individuals incubated with IL2 + IL12, IL-15 + IL-18 and IL-15 + IL-21. We will correlate the outcome of these biologic studies with immunophenotypic studies examining NK cell subsets and clinical patient data. Correlative Evaluation of Immune Reconstitution Studies: Immunophenotypic and functional immune reconstitution studies will produce quantitative and qualitative data that can be compared to multiple clinical and laboratory outcomes in this unique setting. Specifically:  
1) Clinical outcome: Recovery of specific T and NK cell subsets and functional immune responsiveness in the above assays can be compared to (a) documented infections post transplant (bacterial, fungal, viral) CR; (b) lymphoma disease free survival; (c) overall survival.  
2) Laboratory comparisons: immunophenotypic and functional immune reconstitution can be compared to the following laboratory correlates, such as: chronic viral infection/reactivation (EBV, CMV, HIV).
appendix c laboratory procedures appendix
statistical components

Immune reconstitution results will be summarized at each post-transplant time point using descriptive statistics. Individual T, B and NK cell subsets identified by flow cytometry will be reported as percent of total mononuclear cells and as absolute cell numbers per microliter of peripheral blood. Statistical evaluation of functional studies evaluating adaptive and innate immune reconstitution will be reported as percentage of mononuclear cell subsets staining positive for IFN or granzyme B relative to control conditions. Two sided T tests will be employed for evaluation of statistical significance with p<0.05 considered significant.
appendix c laboratory procedures appendix
samples required

A total of 37 mL peripheral blood will be collected and placed into (1) four 8.5 mL-fill, ACD Vacutainer tubes (yellow top) tubes containing ACD anticoagulant solution, and (2) one 3 mL EDTA containing (lavender) Vacutainer tube 8 weeks, and 6 and 12 months post-transplant. Sample shipment: Transplant centers will ship whole blood tubes by priority overnight FedEx on the day of collection to the project laboratory for immediate processing for flow cytometry and for procurement of viable cells for functional immunology assays. Project Laboratory Sample Processing & Testing: Upon arrival, mononuclear cell count in whole blood will be determined and, depending on absolute mononuclear cell count, 1 - 2 tubes will be immediately processed for flow cytometry immunophenotyping panels. PBMC will be cryopreserved for innate and adaptive functional studies that will be performed in batch at a later date.
appendix c laboratory procedures appendix
4. optional research sample for

Patients consenting to provide research samples to be submitted to The AIDS and Cancer Specimen Resource Repository for future undefined testing will have an additional baseline peripheral blood sample collected.
appendix c laboratory procedures appendix
samples required

A 17 mL peripheral blood sample will be collected in two 8.5 mL-fill Vacutainer blood tubes (yellow) containing ACD solution A anticoagulant. Samples will be collected 1-3 weeks prior to initiation of ablative therapy.
appendix c laboratory procedures appendix
sample shipment

Transplant centers will ship whole blood tubes by priority overnight FedEx on the day of collection to the Aids Cancer Research Specimen Repository (ACSR) Repository for sample aliquot processing and sample storage.
appendix c laboratory procedures appendix
table c-1 collection and shipping

| SAMPLE COLLECTION,                                                                                                                                          |                                                                                                                                                                                                                                                                                                                         |                                                                                                    |                |                                                                                                                                                                                                                                                                                                                                     |
|-------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------|----------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| PROCESSING AND STORAGE  REQUIREMENTS                                                                                                                        | SAMPLE                                                                                                                                                                                                                                                                                                                  |                                                                                                    |                |                                                                                                                                                                                                                                                                                                                                     |
| COLLECTION TIME                                                                                                                                             | SHIPPING SPECIFICATIONS                                                                                                                                                                                                                                                                                                 |                                                                                                    |                |                                                                                                                                                                                                                                                                                                                                     |
| POINTS                                                                                                                                                      |                                                                                                                                                                                                                                                                                                                         |                                                                                                    |                |                                                                                                                                                                                                                                                                                                                                     |
| RESEARCH                                                                                                                                                    | RESEARCH                                                                                                                                                                                                                                                                                                                | TYPE OF                                                                                            |                |                                                                                                                                                                                                                                                                                                                                     |
| TOPIC                                                                                                                                                       | SAMPLE                                                                                                                                                                                                                                                                                                                  | SAMPLE                                                                                             | Pre-transplant | Peripheral blood tubes will be shipped at ambient  temperature on the day of collection, to the  Project Laboratory by priority overnight FED EX  delivery for processing and research testing.  Guidelines for specimen handling and shipment to  the Project Laboratory is detailed in the BMT  CTN 0903 Laboratory Sample Guide. |
| 10 mL peripheral  blood sample  collected in an  EDTA containing,  lavender-top  Vacutainer tube.                                                           |                                                                                                                                                                                                                                                                                                                         |                                                                                                    |                |                                                                                                                                                                                                                                                                                                                                     |
| Optimizing                                                                                                                                                  |                                                                                                                                                                                                                                                                                                                         |                                                                                                    |                |                                                                                                                                                                                                                                                                                                                                     |
| Diagnostics and  Preventative Care  for Infections                                                                                                          | Gently mix blood with EDTA by inverting  the tube 8-10 times. Store at room  temperature while preparing to ship to  project laboratory.                                                                                                                                                                                | Within 1 week prior to conditioning and Day -3  of conditioning Post-transplant Days 7, 14 and 100 |                |                                                                                                                                                                                                                                                                                                                                     |
| Microbial Translocation  Markers                                                                                                                            | Pre-transplant                                                                                                                                                                                                                                                                                                          |                                                                                                    |                |                                                                                                                                                                                                                                                                                                                                     |
| 30 mL peripheral  blood sample  collected in three 10 mL EDTA  containing,  lavender-top  Vacutainer tubes.                                                 | Peripheral blood tubes will be shipped at ambient  temperature on the day of collection, to the BMT  CTN 0903-specific Central Processing Laboratory by priority overnight FED EX delivery for plasma  and PBMC processing, temporary storage and batched distribution directly to the project  laboratory for testing. |                                                                                                    |                |                                                                                                                                                                                                                                                                                                                                     |
| Within 1-3 weeks prior to  initiation of conditioning Within 1 week prior to  initiation of conditioning  Post-transplant Day 100, and 6, 12 and  24 months |                                                                                                                                                                                                                                                                                                                         |                                                                                                    |                |                                                                                                                                                                                                                                                                                                                                     |
| Characterization  of HIV Infection  and Latent HIV  Reservoirs                                                                                              | Gently mix blood with EDTA by inverting  the tubes 8-10 times. Store at room  temperature while preparing to ship to  central sample processing laboratory.                                                                                                                                                             |                                                                                                    |                |                                                                                                                                                                                                                                                                                                                                     |
| HIV                                                                                                                                                         |                                                                                                                                                                                                                                                                                                                         |                                                                                                    |                |                                                                                                                                                                                                                                                                                                                                     |
| Single-Copy PCR (Plasma & PBMC)                                                                                                                             |                                                                                                                                                                                                                                                                                                                         |                                                                                                    |                |                                                                                                                                                                                                                                                                                                                                     |  
| SAMPLE COLLECTION,                                                                                                         |                                                                                                                                                                                                                                                                                                                                     |                                                                                                                                                                                                                                                                                                                                     |                                    |
|----------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------|
| PROCESSING AND STORAGE  REQUIREMENTS                                                                                       | SAMPLE                                                                                                                                                                                                                                                                                                                              |                                                                                                                                                                                                                                                                                                                                     |                                    |
| COLLECTION TIME                                                                                                            | SHIPPING SPECIFICATIONS                                                                                                                                                                                                                                                                                                             |                                                                                                                                                                                                                                                                                                                                     |                                    |
| POINTS                                                                                                                     |                                                                                                                                                                                                                                                                                                                                     |                                                                                                                                                                                                                                                                                                                                     |                                    |
| RESEARCH                                                                                                                   | RESEARCH                                                                                                                                                                                                                                                                                                                            | TYPE OF                                                                                                                                                                                                                                                                                                                             |                                    |
| TOPIC                                                                                                                      | SAMPLE                                                                                                                                                                                                                                                                                                                              | SAMPLE                                                                                                                                                                                                                                                                                                                              | Pre-transplant Once the patient is |
| consented and enrolled on  the trial, sample will be  collected at  approximately 8 weeks  prior to initiation of  ablative therapy for only  those patients that have  documented undetectable  plasma HIV-1 by  standard assay. Post-transplant Will be scheduled  sometime at 13 months post-transplant, for only  those patients that are  found to have  undetectable plasma HIV1 RNA by the standard  assay performed at the  clinical site on the 12  month sample.                                                                                                                            |                                                                                                                                                                                                                                                                                                                                     |                                                                                                                                                                                                                                                                                                                                     |                                    |
| 180 mL peripheral  blood sample  collected in  18-10 mL EDTA  containing,  lavender-top  Vacutainer tubes.                 | Peripheral blood tubes will be shipped at ambient  temperature on the day of collection, to the  Project Laboratory by priority overnight FED EX  delivery for processing and research testing.  Guidelines for specimen handling and shipment  to the Project Laboratory is detailed in the BMT  CTN 0903 Laboratory Sample Guide. |                                                                                                                                                                                                                                                                                                                                     |                                    |
| Characterization  of HIV Infection and Latent HIV  Reservoirs                                                              | Gently mix blood with the EDTA                                                                                                                                                                                                                                                                                                      |                                                                                                                                                                                                                                                                                                                                     |                                    |
| anticoagulant by inverting the tube 8-10  times. Store at room temperature while  preparing to ship to project laboratory. |                                                                                                                                                                                                                                                                                                                                     |                                                                                                                                                                                                                                                                                                                                     |                                    |
| Latent HIV Reservoir  Measurements                                                                                         | 37 mL peripheral  blood sample will  be collected in four  8.5 mL-fill ACD  solution (yellow  top) containing  Vacutainer tubes  and one 3 mL  Vacutainer tube  (lavender)  containing EDTA.                                                                                                                                        | Peripheral blood tubes will be shipped at ambient  temperature on the day of collection, to the  Project Laboratory by priority overnight FED EX  delivery for processing and research testing.  Guidelines for specimen handling and shipment  to the Project Laboratory is detailed in the BMT  CTN 0903 Laboratory Sample Guide. |                                    |
| T/NK                                                                                                                       |                                                                                                                                                                                                                                                                                                                                     |                                                                                                                                                                                                                                                                                                                                     |                                    |
| Immunophenotyping,  Innate Immune  Function, Adaptive  Immune Function,                                                    | Gently mix blood with the ACD                                                                                                                                                                                                                                                                                                       |                                                                                                                                                                                                                                                                                                                                     |                                    |
| anticoagulant by inverting the tube 8-10  times. Store at room temperature while  preparing to ship to project laboratory  |                                                                                                                                                                                                                                                                                                                                     |                                                                                                                                                                                                                                                                                                                                     |                                    |
| Immune                                                                                                                     |                                                                                                                                                                                                                                                                                                                                     |                                                                                                                                                                                                                                                                                                                                     |                                    |
| Reconstitution  Studies                                                                                                    | Post-transplant                                                                                                                                                                                                                                                                                                                     |                                                                                                                                                                                                                                                                                                                                     |                                    |
| 8 weeks, and 6 and 12  months post-transplant                                                                              |                                                                                                                                                                                                                                                                                                                                     |                                                                                                                                                                                                                                                                                                                                     |                                    |  
| SAMPLE COLLECTION,                       |                                                                                                                                                 |                |                                                                                                                                                                                                                                                                                                                                                            |
|------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------|----------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| PROCESSING AND STORAGE  REQUIREMENTS     | SAMPLE                                                                                                                                          |                |                                                                                                                                                                                                                                                                                                                                                            |
| COLLECTION TIME                          | SHIPPING SPECIFICATIONS                                                                                                                         |                |                                                                                                                                                                                                                                                                                                                                                            |
| POINTS                                   |                                                                                                                                                 |                |                                                                                                                                                                                                                                                                                                                                                            |
| RESEARCH                                 | RESEARCH                                                                                                                                        | TYPE OF        |                                                                                                                                                                                                                                                                                                                                                            |
| TOPIC                                    | SAMPLE                                                                                                                                          | SAMPLE         | Peripheral blood tubes will be shipped at ambient  temperature on the day of collection, to the Aids  Cancer Research Specimen Repository by priority  overnight FED EX delivery for processing and  research testing. Guidelines for specimen  handling and shipment to the Project Laboratory  is detailed in the BMT CTN 0903 Laboratory  Sample Guide. |
| 17 mL peripheral  blood sample  collected in  2-8.5 mL ACD  containing, yellowtop Vacutainer  tubes.                                          |                                                                                                                                                 |                |                                                                                                                                                                                                                                                                                                                                                            |
| (Optional)                               |                                                                                                                                                 |                |                                                                                                                                                                                                                                                                                                                                                            |
| Investigational  Future Research  Sample | Gently mix blood with ACD by inverting  the tube 8-10 times. Store at room  temperature while preparing to ship to the  ACSR Sample Repository. | Pre-transplant |                                                                                                                                                                                                                                                                                                                                                            |
| Undefined Future  Research               | 1-3 weeks prior to  ablative therapy                                                                                                            |                |                                                                                                                                                                                                                                                                                                                                                            |
appendix d treatment review committee
treatment review committee

The treating institution will review patients with the Treatment Review Committee prior to the initiation of transplant therapy by a five member review panel composed of experts in HIV drug resistance, HIV care, pharmacology, transplant infectious diseases and oncology.  
Recommendations for transplant are based on data contained in the patient registration and pretransplant forms, as well as in supporting documentation, which includes the following:
− Current Diagnosis
− Past Medical History
− Prior ARV History
− Documented ARV Drug Toxicities
− Drug Allergies
− History of HLA B57 Antigen Testing, if available − Current Creatinine and Liver Function Tests − Past and Recent HIV Drug Resistance Test Results, if applicable − Current ARV Drug Regimen − Current Concomitant Medications The Committee will review available past and current HIV-1 genotype results for patients with detectable viremia so as to exclude patients with multi-drug resistant HIV-1 who are unlikely to achieve viral suppression on alternate antiretroviral therapy. The Committee will also advise with regard to various drug interactions anticipated during the course of transplantation. The Treatment Review Committee will include well-qualified investigators from the University of Pittsburgh and Johns Hopkins University and other institutions as appropriate. Review materials will be sent to the panel four weeks prior to initiation of transplant therapy to allow sufficient time for implementation of recommendations for the antiretroviral regimen.
appendix e suggested prophylaxis
appendix e suggested prophylaxis

Infectious prophylaxis for HIV patients undergoing HCT will include prophylaxis for:
1. Bacteria: In keeping with the BMT CTN MOP and local institutional standards.  
2. *Pneumocystis Jiroveci* Pneumonia: Prophylaxis will be administered until CD4 counts are >200 and for a minimum of 6 months. Several effective regimens are available. Patient tolerance (nausea, allergic reaction, G6PD or other considerations) may contraindicate a particular regimen. Choices in order of preference are: 1) TMP/SMX 1 DS daily; 2) TMP/SMX 1 SS daily; 3) Dapsone 100 mg daily (may be decreased to 50 mg daily if given in combination with pyrimethamine as described below for toxoplasmosis prophylaxis; 4) Atovaquone 1500 mg daily; and, 5) Aerosolized or IV pentamidine monthly, or per institutional standard.  
3. Toxoplasmosis: Patients on TMP/SMX do not require additional prophylaxis. If toxoplasma IgG is positive and TMP/SMX cannot be used patients should be prophylaxed for at least 3 months after HCT and until CD4>100. This prophylaxis may be either: 1) dapsone 50 mg po daily and pyrimethamine 50 mg/week and leucovorin 25 mg/week or 2) atovaquone 1500 mg daily plus pyrimethamine 25 mg/day plus leucovorin 10 mg/day. Since all medications for toxoplasmosis prophylaxis are oral, and some patients may be unable to take po medications in the peri-transplant period, PCR for toxoplasmosis should be checked at least weekly whenever prophylaxis must be held in toxoplasma IgG positive patients for more than a week and the CD4 count is less than 100.  
4. Fungi: Anti-fungal prophylaxis will be per local institutional practice. It is noted that in histoplasma endemic areas (Midwest and Puerto Rico) antifungal prophylaxis is standard for CD4 <150 and would be appropriate for at least 3 months after HCT and until CD4>150. (See Appendix F for detailed interactions with antiretroviral medications.)
5. HSV/VZV: One of the following regimens should be used for 12 months after HCT, or per institutional standard, unless the patient remains on immunosuppressive Acyclovir 400 - 800 mg bid, valaciclovir 500 mg bid, or famciclovir 500 mg po bid.  
6. M. Avium Complex (MAC): If CD4 less than 50, Azithromycin suggested at 1200 mg q week or 600 mg twice weekly.  
7. Hepatitis:
a. Patients with positive hepatitis B surface antigen should be evaluated for viral DNA replication (viral load) by a quantitative PCR method before enrolling the patient on the study.
b. Lamivudine or newer generation of anti-hepatitis B agents, like tenofovir, should be started in those with detectable Hepatitis B viral load according to institutional preferences. The goal of the treatment should be achieving undetectable (<500 copies/ml) viral load status.  
c. Patients should be maintained on anti-Hepatitis B treatment throughout chemotherapy, throughout the transplant, and at least 12 months after the transplant.  
d. Patients with hepatitis-C infection may be enrolled on the trial providing the above Hepatic criteria are met. Anti-hepatitis C treatment with ribavirin and interferon alpha is recommended but not required to be eligible for the study.  
e. Liver biopsy must be performed in patients with Hepatitis-B or C infections if the severity assessment of liver disease based on Child-Turcotte-Pugh (CTP) classification indicates all of the following criteria; Serum bilirubin > 2, serum albumin < 3.5, and INR > 1.7 f. Patients with no pathologic evidence of irreversible chronic liver disease such as bridging necrosis and/or significant fibrosis can be eligible for the study.
appendix f pharmacokinetic drug-drug interactions
appendix f

Preferred Antiretroviral Regimens for Patients Undergoing Allogeneic Hematopoietic Cell Transplant Tier 1: Raltegravir (INSTI) based therapy (no interruption of therapy is required) Tier 2: NNRTI based therapy (interruption of therapy may be required, see Table F-1)
Tier 3: Boosted-PI based therapy (interruption of therapy may be required, see Table F1)
Summary of Antiretroviral Agents and Drug-Drug Interactions 1. **Protease Inhibitors [PI]** (amprenavir, atazanavir, darunavir, fosamprenavir, indinavir, lopinavir/ritonavir, nelfinavir, ritonavir, saquinavir, tipranavir)
a. Dosing i. All protease inhibitors (except nelfinavir) are typically given in combination with ritonavir to reach optimal pharmacokinetic targets b. Toxicity i. All protease inhibitors can cause gastrointestinal intolerance, hyperglycemia, lipohypertrophy, osteonecrosis, hepatotoxicity and hyperlipidemia.  
c. Metabolism i. Protease inhibitors are metabolized hepatically via cytochrome P450 coenzymes, especially CYP3A4 d. Drug Interactions i. When given in combination with ritonavir, all protease inhibitors are potent CYP3A4 inhibitors ii. Ritonavir 1. Substrate for CYP1A2 (minor), 2B6 (minor), 2D6 (major), 3A4
(major)
2. Inhibits CYP 2C8 (strong), 2C9 (weak), 2C19 (weak), 2D6
(strong), 2E1 (weak), 3A4 (strong)
3. Induces CYP1A2 (weak), 2C8 (weak), 2C9 (weak), 3A4 (weak)
2. **Non-Nucleoside Reverse Transcriptase Inhibitors [NNRTI]** (delavirdine, efavirenz, nevirapine, etravirine)
a. Dosing i. Efavirenz is the preferred agent in this class, nevirapine should be used with caution due to toxicity b. Toxicity i. Class adverse effects include, rash, hepatotoxicity and gastrointestinal intolerance c. Metabolism i. NNRTIs are metabolized hepatically via cytochrome P450 co-enzymes d. Drug Interactions i. All NNRTIs induce CYP3A4 (etravirine > efavirenz > nevirapine)
ii. Efavirenz 1. Substrate for CYP3A4 (major), 2B6 (major) 2. Inhibits CYP2C9 (moderate), 2C19 (moderate), 3A4 (moderate) 3. Induces CYP2B6 (weak), 3A4 (strong)
appendix f pharmacokinetic drug-drug interactions
3. nucleoside reverse transcriptase inhibitors

lamivudine, stavudine, tenofovir, zidovudine)
a. Dosing i. Zidovudine (AZT) should not be used in patients receiving hematopoietic cell transplantation b. Toxicity i. Adverse effects of the class include lactic acidosis, peripheral neuropathy and hepatic steatosis c. Metabolism i. Not extensively metabolized, eliminated renally (except abacavir)
d. Drug Interactions i. None of the NRTIs are metabolized via CYP450 co-enzymes ii. Avoid additive toxicities
appendix f pharmacokinetic drug-drug interactions
4. other agents

a. Raltegravir (INSTI): Preferred agent due to excellent tolerability and lack of drugdrug interactions b. Maraviroc: Substrate of CYP3A4, but does not induce or inhibit the metabolism of other agents c. Enfuvirtide: No clinically relevant drug interactions, reserved for salvage therapy only  
| Conditioning                                                                     | Metabolism                                                                                                                                                                                                   | Interaction Potential*   |                                                    |
|----------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------|----------------------------------------------------|
| Regimen                                                                          | (Primary Site)                                                                                                                                                                                               | (Predicted Effect)       | Recommendation/Evidence                            |
| Flu/Bu  - Fludarabine - Busulfan                                                 | Fludarabine (Liver):  - Rapid  dephosphorylation to 2- fluoro-ara-A, then  phosphorylated to 2- fluoro-ara-ATP  intracellularly                                                                              | High                     | Raltegravir-Based: May continue HAART as tolerated |
| Concomitant administration of ritonavirboosted PIs may increase the levels of  busulfan.                                                                                  | NNRTI-Based: May continue HAART as tolerated PI-Based: Regimens including ritonavir should be  discontinued a minimum of 48 hours prior to the  administration of myeloablative regimens containing busulfan |                          |                                                    |
| NNRTIs may decrease levels of busulfan.                                          | Antiretroviral therapy should not be resumed until, at least, 48  hours after the last dose of busulfan and once the patient is  able to consistently tolerate oral medications                              |                          |                                                    |
| Busulfan (Liver): - Metabolized hepatically;  substrate of CYP3A4                | Strength of evidence: LOW                                                                                                                                                                                    | RIC with Flu/Bu has been given to one patient who was  concomitantly receiving unboosted atazanavir and two  patients receiving efavirenz (1) Flu/TBI was given successfully with concomitant efavirenzbased HAART in two patients (2)                          |                                                    |
| Flu/Mel  - Fludarabine - Melphalan                                               | Fludarabine (Liver):  - Rapid  dephosphorylation to 2- fluoro-ara-A, then  phosphorylated to 2- fluoro-ara-ATP  intracellularly                                                                              | Low                      | Raltegravir-Based: May continue HAART as tolerated |
| The effects of ritonavir-boosted PIs on  levels of fludarabine are unknown.      | NNRTI-Based: May continue HAART as tolerated PI-Based: The potential for interactions with ritonavirboosted PIs or NNRTIs is low. Antiretroviral therapy should  only be continued if the benefits clearly outweigh the risks.                                                                                                                                                                                                              |                          |                                                    |
| Efavirenz has been given in combination  with fludarabine.                       |                                                                                                                                                                                                              |                          |                                                    |
| Melphalan (Blood): - Chemical hydrolysis in  the plasma to inactive  metabolites | Flu/Mel has been given successfully as a reduced-intensity  conditioning regimen in a patient on lopinavir/ritonavir,  tenofovir, and lamivudine (3)                                                         |                          |                                                    |
| Strength of evidence: MODERATE                                                   | Flu/TBI was given successfully with concomitant efavirenzbased HAART in two patients (2)                                                                                                                                                                                                              |                          |                                                    |
appendix f pharmacokinetic drug-drug interactions
table f-1 summary of antiretroviral

| Conditioning                                                                                                                                                                                                                                                                                                                                                                      | Metabolism                                                                                                                                                                                                                                                                                                                                                         | Interaction Potential*                                                                                                                                           |                         |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------|
| Regimen                                                                                                                                                                                                                                                                                                                                                                           | (Primary Site)                                                                                                                                                                                                                                                                                                                                                     | (Predicted Effect)                                                                                                                                               | Recommendation/Evidence |
| Cy/TBI - Cyclophospha mide - Total Body  Irradiation                                                                                                                                                                                                                                                                                                                              | High                                                                                                                                                                                                                                                                                                                                                               | Raltegravir-Based: May continue HAART as tolerated                                                                                                               |                         |
| Cyclophosphamide  (Liver):  - Prodrug is converted by  hepatic microsomal  enzymes to the active  form. The activation  pathway involves  CYP2B6, CYP2C9 and  CYP3A4 isoenzymes. - Substrate for CYP2A6  (minor), 2B6 (major),  2C8/9 (minor), 2C19  (minor), 3A4 (major) - Inhibits CYP3A4  (weak) - Induces CYP2B6  (weak), 2C8/9 (weak) - Active metabolites  include acrolein | Concomitant administration of ritonavir  may increase the levels of busulfan.                                                                                                                                                                                                                                                                                      | NNRTI-Based: Regimens including NNRTIs should be used  with caution and frequent monitoring due to the increase in  toxic metabolites caused by CYP450 induction |                         |
| Complex interactions exist between  ritonavir and cyclophosphamide or                                                                                                                                                                                                                                                                                                             |                                                                                                                                                                                                                                                                                                                                                                    |                                                                                                                                                                  |                         |
| acrolein. Cyclophosphamide levels may be  increased when combined with protease  inhibitors, but the active metabolites may  be decreased.                                                                                                                                                                                                                                        | PI-Based: Regimens including ritonavir should be  discontinued a minimum of 48 hours prior to the  administration of myeloablative regimens containing  cyclophosphamide. Antiretroviral therapy should not be resumed until, at least, 72  hours after the last dose of cyclophosphamide and once the  patient is able to consistently tolerate oral medications. |                                                                                                                                                                  |                         |
| NNRTIs may increase levels of acrolein  through CYP induction. Other CYP  inducers like phenytoin have been shown  to increase the AUC of active metabolites  by 50%. Strength of evidence: LOW                                                                                                                                                                                   |                                                                                                                                                                                                                                                                                                                                                                    |                                                                                                                                                                  |                         |
| *Combinations have not been studied and the interaction potential has been predicted based on the metabolic pathways of each agent.                                                                                                                                                                                                                                               |                                                                                                                                                                                                                                                                                                                                                                    |                                                                                                                                                                  |                         |  
*Combinations have not been studied and the interaction potential has been predicted based on the metabolic pathways of each agent. RIC = Reduced intensity conditioning  
| Antiretroviral                                      |                                                                                                                                                                                                                                                                    |                                                                                                                                                              |                                                                                                                                                                                         |
|-----------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Study                                               | Conditioning Regimen                                                                                                                                                                                                                                               | Regimen                                                                                                                                                      | Interactions/Toxicity                                                                                                                                                                   |
| Krishnan (6)                                        | - Only 9/20 patients tolerated ARV throughout transplantation - 19/20 had abnormal LFTs - ARV resumed by 2 months after ASCT in most - 10/17 survivors required a change in ARV due to virologic failure - One patient died of regimen-related toxicity at Day +22 |                                                                                                                                                              |                                                                                                                                                                                         |
| Spitzer (7)                                         | BCNU, VP-16, Cy (n=17)                                                                                                                                                                                                                                             | *PI-based (n=15)                                                                                                                                             |                                                                                                                                                                                         |
| ASCT, n=20                                          | or                                                                                                                                                                                                                                                                 | NNRTI-based (n=5)                                                                                                                                            |                                                                                                                                                                                         |
| TBI, VP-16, Cy (n=3) Dose-reduced Bu, Cy            |                                                                                                                                                                                                                                                                    |                                                                                                                                                              |                                                                                                                                                                                         |
| Bu: 14 mg/kg (PO) or 11.2  mg/kg (IV) Cy: 120 mg/kg | *PI-based (n=20) (Ritonavir and AZT  not included)                                                                                                                                                                                                                 | - One patient died of regimen-related toxicity at Day +33 (VOD) - No grade III or IV nausea or vomiting - Number of patients who discontinued ARV is unknown |                                                                                                                                                                                         |
| ASCT, n=20 Re (8)                                   | BEAM                                                                                                                                                                                                                                                               | *NA                                                                                                                                                          | - 7/10 patients had gastrointestinal toxicity and 2/10 had hepatic toxicity - 3/10 patients stopped ARV after BEAM due to toxicity                                                      |
| ASCT, n=10 Balsalobre (9)                           | BEAM and variants (n=65)                                                                                                                                                                                                                                           | NA                                                                                                                                                           | - HAART continued in 95% of patients, but withdrawn in 22.5% - Of the patients who discontinued HAART, mucositis was the most common  reason                                            |
| ASCT, n=68                                          | TBI based regimens (n=3)                                                                                                                                                                                                                                           |                                                                                                                                                              |                                                                                                                                                                                         |
| Serrano (10)                                        | BEAM (n=10)                                                                                                                                                                                                                                                        | *NNRTI-based  (n=8)                                                                                                                                          | - No patients died from treatment related complications - No apparent interference between HAART and conditioning regimens was  observed - No patients were concomitantly receiving AZT |
| ASCT, n=11                                          | or                                                                                                                                                                                                                                                                 | PI-based (n=2)                                                                                                                                               |                                                                                                                                                                                         |
| BEAC (n=1)                                          |                                                                                                                                                                                                                                                                    |                                                                                                                                                              |                                                                                                                                                                                         |
| *HAART continued through conditioning.              |                                                                                                                                                                                                                                                                    |                                                                                                                                                              |                                                                                                                                                                                         |
appendix f pharmacokinetic drug-drug interactions
table f-2 experience with drug-drug

*HAART continued through conditioning.  
ASCT = Autologous Stem-Cell Transplantation; AZT = Zidovudine
appendix f pharmacokinetic drug-drug interactions
references

1. Hamadani M, Devine SM. Reduced-Intensity Conditioning Allogeneic Stem Cell Transplantation In HIV Patients With Hematologic Malignancies: Yes, We Can. Blood. 2009;114(12):2564-6.  
2. Woolfrey AE, Malhotra U, Harrington RD, Mcnevin J, Manley TJ, Riddell SR, et al.  
Generation Of HIV-1-Specific CD8+ Cell Responses Following Allogeneic Hematopoietic Cell Transplantation. Blood. 2008;112(8):3484-7. PMCID: 2569185.  
3. Bryant A, Milliken S. Successful Reduced-Intensity Conditioning Allogeneic HSCT For HIV-Related Primary Effusion Lymphoma. Biol Blood Marrow Transplant. 2008;14(5):601-2.  
4. Gupta V, Tomblyn M, Pedersen TL, Atkins HL, Battiwalla M, Gress RE, et al. Allogeneic Hematopoietic Cell Transplantation in Human Immunodeficiency Virus-Positive Patients With Hematologic Disorders: A Report From The Center For International Blood and Marrow Transplant Research. Biol Blood Marrow Transplant. 2009;15(7):864-71.  
5. Polizzotto MN, Skinner M, Cole-Sinclair MF, Opat SS, Spencer A, Avery S. Allo-SCT F
for Hematological Malignancies in the Setting of HIV. Bone Marrow Transplant. 2009.  
6. Krishnan A, Molina A, Zaia J, Smith D, Vasquez D, Kogut N, et al. Durable Remissions with Autologous Stem Cell Transplantation for High-Risk HIV-Associated Lymphomas. Blood. 2005;105(2):874-8.  
7. Spitzer TR, Ambinder RF, Lee JY, Kaplan LD, Wachsman W, Straus DJ, et al. DoseReduced Busulfan, Cyclophosphamide, and Autologous Stem Cell Transplantation for Human Immunodeficiency Virus-Associated Lymphoma: Aids Malignancy Consortium Study 020. Biol Blood Marrow Transplant. 2008;14(1):59-66.  
8. Re A, Cattaneo C, Michieli M, Casari S, Spina M, Rupolo M, et al. High-Dose Therapy and Autologous Peripheral-Blood Stem-Cell Transplantation as Salvage Treatment for HIV-Associated Lymphoma in Patients Receiving Highly Active Antiretroviral Therapy. J Clin Oncol. 2003;21(23):4423-7.  
9. Balsalobre P, Diez-Martin JL, Re A, Michieli M, Ribera JM, Canals C, et al. Autologous Stem-Cell Transplantation in Patients With HIV-Related Lymphoma. J Clin Oncol. 2009;27(13):2192-8.  
10. Serrano D, Carrion R, Balsalobre P, Miralles P, Berenguer J, Buno I, et al. HIV-Associated Lymphoma Successfully Treated with Peripheral Blood Stem Cell Transplantation. Exp Hematol. 2005;33(4):487-94.
table f-3 pharmacokinetic interactions for
references

I. **Tacrolimus**
a. Standard Dose i. IV: 0.03 mg/kg every 24 hours as a continuous IV infusion to begin 3 days prior to transplant (based on IBW)
ii. PO: 0.12 mg/kg/day divided into 2 doses (Convert to oral administration when patient is able to tolerate)
b. Target Trough Level i. 5 - 15 ng/mL  
| Concomitant Medication                                                                                                                                                                                                    | Effect on Tacrolimus                                                                                                                                                                                                                                                                                                                                                                        | Mechanism                                                      | Recommendation   |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------|------------------|
| Protease Inhibitors (boosted) - Atazanavir/ritonavir (ATZ/r) - Fosamprenavir/ritonavir (fAPV/r) - Indinavir/ritonavir (IND/r) - Lopinavir/ritonavir (LPV/r) - Saquinavir/ritonavir (SQV/r) - Tipranavir/ritonavir (TPV/r) | Hold tacrolimus upon initiation of ARV and monitor trough  levels daily Based on level: - < 5 ng/mL: Administer 1 mg (PO) or 0.25 mg (IV)* - 5-15 ng/mL: Administer 0.5 mg (PO) or 0.125 mg (IV)* - >15 ng/mL: HOLD tacrolimus until next level Once dosing is stable, tacrolimus levels may be monitored  according to local guidelines. Most patients are maintained on  0.5 - 1 mg/week. |                                                                |                  |
| Protease Inhibitors (unboosted) - Atazanavir (ATZ) - Nelfinavir (NFV)                                                                                                                                                     | ↑↑↑ Tacrolimus Levels 1-9                                                                                                                                                                                                                                                                                                                                                                   | Potent inhibition of  CYP3A4 and Pglycoprotein                                                                |                  |
| May result in severe and                                                                                                                                                                                                  |                                                                                                                                                                                                                                                                                                                                                                                             |                                                                |                  |
| prolonged tacrolimus toxicity. ↑↑ Tacrolimus Levels 2, 6-7, 10- 11                                                                                                                                                        | Strong inhibition of                                                                                                                                                                                                                                                                                                                                                                        | Hold tacrolimus upon initiation of ARV and monitor trough      |                  |
| CYP3A4                                                                                                                                                                                                                    | levels daily Based on level: - < 5 ng/mL: Administer 1 mg (PO) or 0.25 mg (IV)* - 5-15 ng/mL: Administer 0.5 mg (PO) or 0.125 mg (IV)* - >15 ng/mL: HOLD tacrolimus until next level Once dosing is stable, tacrolimus levels may be monitored  according to local guidelines.                                                                                                              |                                                                |                  |
| NNRTIs - Efavirenz (EFV) - Nevirapine (NVP)                                                                                                                                                                               | May result in severe and                                                                                                                                                                                                                                                                                                                                                                    |                                                                |                  |
| prolonged tacrolimus toxicity. ↓ Tacrolimus Levels 6                                                                                                                                                                      | Strong induction of                                                                                                                                                                                                                                                                                                                                                                         | Continue tacrolimus at the same dose and monitor trough levels |                  |
| CYP3A4                                                                                                                                                                                                                    | daily. Based on level: - < 5 ng/mL: Increase tacrolimus daily dose by 25% - 5-15 ng/mL: No adjustment  - >15 ng/mL: Decrease tacrolimus daily dose by 25% Full induction effects may take up to two weeks.                                                                                                                                                                                  | Daily                                                          |                  |
| tacrolimus doses are substantially increased for most patients  with co-administration of NNRTIs. Efavirenz is a more potent  inducer of CYP3A4 than is nevirapine.                                                       |                                                                                                                                                                                                                                                                                                                                                                                             |                                                                |                  |  
| Concomitant Medication                                                                                                                         | Effect on Tacrolimus   | Mechanism                                        | Recommendation                                                                                                                                                                                                                                                                                   |              |
|------------------------------------------------------------------------------------------------------------------------------------------------|------------------------|--------------------------------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------|
| NNRTIs                                                                                                                                         | ↓↓ Tacrolimus Levels   | Potent induction of                              | Concomitant use of etravirine and tacrolimus should be                                                                                                                                                                                                                                           |              |
| -                                                                                                                                              | Etravirine (ETV)       | (Thoeretical)                                    | CYP3A4                                                                                                                                                                                                                                                                                           | discouraged. |
| NRTIs - Abacavir (ABC) - Didanosine (ddI) - Emtricitabine (FTC) - Lamivudine (3TC) - Stavudine (d4T) - Tenofovir (TDF) - Zidovudine (AZT, ZDV) | None 12                | N/A                                              | No adjustments necessary. Monitor tacrolimus trough levels 2-3 times/week. Frequent monitoring of renal function is required for those  patients on tenofovir due to the increased risk of nephrotoxicity. For patients with renal impairment, adjust NRTI doses according  to local guidelines. |              |
| Integrase Inhibitor                                                                                                                            | None                   | N/A                                              | No adjustments necessary.                                                                                                                                                                                                                                                                        |              |
| -                                                                                                                                              | Raltegravir (RLV)      | Monitor tacrolimus trough levels 2-3 times/week. Raltegravir based regimens may be preferred over PI- or NNRTIbased regimens as it is primarily metabolized via glucuronidation  and not by CYP3A4.                                                  |                                                                                                                                                                                                                                                                                                  |              |
| Fusion Inhibitor                                                                                                                               | None                   | N/A                                              | No adjustments necessary.                                                                                                                                                                                                                                                                        |              |
| -                                                                                                                                              | Enfuvirtide (ENF, T20) | Monitor tacrolimus trough levels 2-3 times/week. |                                                                                                                                                                                                                                                                                                  |              |
| CCR5 Antagonist                                                                                                                                | None                   | N/A                                              | No adjustments necessary.                                                                                                                                                                                                                                                                        |              |
| -                                                                                                                                              | Maraviroc (MVC)        | Monitor tacrolimus trough levels 2-3 times/week. |                                                                                                                                                                                                                                                                                                  |              |
| *To be administered in a one-time dose in response to the observed level.                                                                      |                        |                                                  |                                                                                                                                                                                                                                                                                                  |              |
table f-3 pharmacokinetic interactions for
ii. sirolimus

a. Standard Dose i. PO: 12 mg once on Day -3, then 4 mg daily as a single dose (administer on an empty stomach)
b. Target Trough Level i. 3 - 12 ng/mL  
| Concomitant Medication                                                                                                                                                                                                    | Effect on Sirolimus                                                                                                                                                                                                               | Mechanism                                                       | Recommendation                                                                                                                                                                                                                                                                                           |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Protease Inhibitors (boosted) - Atazanavir/ritonavir (ATZ/r) - Fosamprenavir/ritonavir (fAPV/r) - Indinavir/ritonavir (IND/r) - Lopinavir/ritonavir (LPV/r) - Saquinavir/ritonavir (SQV/r) - Tipranavir/ritonavir (TPV/r) | ↑↑↑ Sirolimus Levels 3, 8                                                                                                                                                                                                         | Potent inhibition of  CYP3A4 and Pglycoprotein                                                                 | Hold sirolimus upon initiation of ARV and monitor trough levels  daily Based on level: - < 3 ng/mL: Administer 0.4 mg (PO)  - 3 - 12 ng/mL: Administer 0.3 mg (PO) - >12 ng/mL: HOLD sirolimus until next level Once dosing is stable, sirolimus levels may be monitored  according to local guidelines. |
| May result in severe and                                                                                                                                                                                                  |                                                                                                                                                                                                                                   |                                                                 |                                                                                                                                                                                                                                                                                                          |
| prolonged sirolimus toxicity. ↑↑ Sirolimus Levels 13                                                                                                                                                                      |                                                                                                                                                                                                                                   |                                                                 |                                                                                                                                                                                                                                                                                                          |
| Protease Inhibitors (unboosted) - Atazanavir (ATZ) - Nelfinavir (NFV)                                                                                                                                                     | Strong inhibition of                                                                                                                                                                                                              | Hold sirolimus upon initiation of ARV and monitor trough levels |                                                                                                                                                                                                                                                                                                          |
| CYP3A4                                                                                                                                                                                                                    | daily                                                                                                                                                                                                                             |                                                                 |                                                                                                                                                                                                                                                                                                          |
| May result in severe and                                                                                                                                                                                                  |                                                                                                                                                                                                                                   |                                                                 |                                                                                                                                                                                                                                                                                                          |
| prolonged sirolimus toxicity.                                                                                                                                                                                             | Based on level: - < 3 ng/mL: Administer 0.4 mg (PO)  - 3 - 12 ng/mL: Administer 0.3 mg (PO) - >12 ng/mL: HOLD sirolimus until next level Once dosing is stable, sirolimus levels may be monitored  according to local guidelines. |                                                                 |                                                                                                                                                                                                                                                                                                          |
| NNRTIs - Efavirenz (EFV) - Nevirapine (NVP)                                                                                                                                                                               | ↓ Sirolimus Levels                                                                                                                                                                                                                | Strong induction of                                             | Continue sirolimus at the same dose and monitor trough levels                                                                                                                                                                                                                                            |
| CYP3A4                                                                                                                                                                                                                    | daily. Based on level: - < 3 ng/mL: Increase sirolimus daily dose by 25% - 3 - 12 ng/mL: No adjustment  - >12 ng/mL: Decrease sirolimus daily dose by 25% Full induction effects may take up to two weeks. Daily sirolimus  doses are substantially increased for most patients with coadministration of NNRTIs. Efavirenz is a more potent inducer of  CYP3A4 than is nevirapine.                                                                                                                                                                                                                                   |                                                                 |                                                                                                                                                                                                                                                                                                          |  
| Concomitant Medication                                                                                                                         | Effect on Sirolimus     | Mechanism                                       | Recommendation                                                                                                                                                                                                                                                                                  |              |
|------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------|-------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------|
| NNRTIs                                                                                                                                         | ↓↓ Sirolimus Levels     | Potent induction of                             | Concomitant use of etravirine and sirolimus should be                                                                                                                                                                                                                                           |              |
| -                                                                                                                                              | Etravirine (ETV)        | (Thoeretical)                                   | CYP3A4                                                                                                                                                                                                                                                                                          | discouraged. |
| NRTIs - Abacavir (ABC) - Didanosine (ddI) - Emtricitabine (FTC) - Lamivudine (3TC) - Stavudine (d4T) - Tenofovir (TDF) - Zidovudine (AZT, ZDV) | None                    | N/A                                             | No adjustments necessary. Monitor sirolimus trough levels 2-3 times/week. Frequent monitoring of renal function is required for those  patients on tenofovir due to the increased risk of nephrotoxicity. For patients with renal impairment, adjust NRTI doses according  to local guidelines. |              |
| Integrase Inhibitor                                                                                                                            | None                    | N/A                                             | No adjustments necessary.                                                                                                                                                                                                                                                                       |              |
| -                                                                                                                                              | Raltegravir (RLV)       | Monitor sirolimus trough levels 2-3 times/week. Raltegravir based regimens may be preferred over PI- or NNRTIbased regimens as it is primarily metabolized via glucuronidation  and not by CYP3A4.                                                 |                                                                                                                                                                                                                                                                                                 |              |
| Fusion Inhibitor                                                                                                                               | None                    | N/A                                             | No adjustments necessary.                                                                                                                                                                                                                                                                       |              |
| -                                                                                                                                              | Enfuviritide (ENF, T20) | Monitor sirolimus trough levels 2-3 times/week. |                                                                                                                                                                                                                                                                                                 |              |
| CCR5 Antagonist                                                                                                                                | None                    | N/A                                             | No adjustments necessary.                                                                                                                                                                                                                                                                       |              |
| -                                                                                                                                              | Maraviroc (MVC)         | Monitor sirolimus trough levels 2-3 times/week. |                                                                                                                                                                                                                                                                                                 |              |
table f-3 pharmacokinetic interactions for
iii.cyclophosphamide

a. Standard dose24 i. 50 mg/kg IV over 1-2 hours is given on Day 3 post-transplant **(between 60 and 72 hours after marrow infusion)** and again on day 4 post-transplant (approximately 24 hours after first dose) (based on IBW)  
| Effect on                                                                                                                                                                                                                                        |                                                                                                                                                                        |                                                            |                                                                                                                                                                                                                                                                                                                |
|--------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Cyclophosphamide (Cy)                                                                                                                                                                                                                            | Mechanism                                                                                                                                                              | Recommendation                                             |                                                                                                                                                                                                                                                                                                                |
| Protease Inhibitors (boosted) - Atazanavir/ritonavir (ATZ/r) - Fosamprenavir/ritonavir (fAPV/r) - Indinavir/ritonavir (IND/r) - Lopinavir/ritonavir (LPV/r) - Saquinavir/ritonavir (SQV/r) - Tipranavir/ritonavir (TPV/r) Concomitant Medication | The conversion of Cy (a prodrug)  to its active metabolites will be  delayed, resulting in increased  levels of Cy in the serum.                                       | Inhibition of CYP3A4                                       | Conversion of Cy to its active metabolites will be delayed,  resulting in reduced efficacy of Cy. Certain metabolites may be  increased or decreased.  Hold ritonavir-boosted regimens during GVHD prophylaxis.                                                                                                |
| Protease Inhibitors (unboosted) - Atazanavir (ATZ) - Nelfinavir (NFV)                                                                                                                                                                            | The conversion of Cy (a prodrug)  to its active metabolites will be  delayed, resulting in increased  levels of Cy in the serum.                                       | Inhibition of CYP3A4                                       | Conversion of Cy to its active metabolites will be delayed,  resulting in reduced efficacy of Cy. Certain metabolites may be  increased or decreased.  The concomitant use of unboosted PIs should be used with  caution as Cy efficacy may be decreased. Consultation with  pharmacokinetic team is required. |
| NNRTIs - Efavirenz (EFV) - Nevirapine (NVP)                                                                                                                                                                                                      | Rapid conversion of Cy to its  active metabolites results in  decreased Cy concentrations and  increase levels of active  metabolites                                  | Induction of CYP3A4                                        | Dose reductions of Cy may be recommended to prevent toxicity.                                                                                                                                                                                                                                                  |
| and CYP2B6                                                                                                                                                                                                                                       | This has been shown to be effective with other CYP inducers,  such as phenytoin.25 Monitor patients closely for toxicity from active metabolites of  cyclophosphamide. |                                                            |                                                                                                                                                                                                                                                                                                                |
| NNRTIs                                                                                                                                                                                                                                           | Rapid conversion of Cy to its                                                                                                                                          |                                                            |                                                                                                                                                                                                                                                                                                                |
| -                                                                                                                                                                                                                                                | Etravirine (ETV)                                                                                                                                                       | active metabolites results in                              |                                                                                                                                                                                                                                                                                                                |
| decreased Cy concentrations and  increase levels of active  metabolites                                                                                                                                                                          | Potent induction of                                                                                                                                                    | Avoid concomitant use due to the unpredictable interaction |                                                                                                                                                                                                                                                                                                                |
| CYP3A4 and CYP2B6                                                                                                                                                                                                                                | potential.                                                                                                                                                             |                                                            |                                                                                                                                                                                                                                                                                                                |
| NRTIs - Abacavir (ABC) - Didanosine (ddI)                                                                                                                                                                                                        | None                                                                                                                                                                   | N/A                                                        | No adjustment necessary                                                                                                                                                                                                                                                                                        |  
| Effect on                                                              |                         |                |                           |
|------------------------------------------------------------------------|-------------------------|----------------|---------------------------|
| Cyclophosphamide (Cy)                                                  | Mechanism               | Recommendation |                           |
| NRTIs - Stavudine (d4T) - Zidovudine (AZT, ZDV) Concomitant Medication | None                    | N/A            | No adjustment necessary   |
| NRTIs - Lamivudine (3TC) - Emtricitabine (FTC) - Tenofovir (TDF)       | None                    | N/A            | No adjustments necessary  |
| Integrase Inhibitor                                                    | None                    | N/A            | No adjustments necessary. |
| -                                                                      | Raltegravir (RLV)       |                |                           |
| Fusion Inhibitor                                                       | None                    | N/A            | No adjustments necessary. |
| -                                                                      | Enfuviritide (ENF, T20) |                |                           |
| CCR5 Antagonist                                                        | None                    | N/A            | No adjustments necessary. |
| -                                                                      | Maraviroc (MVC)         |                |                           |  
References 1. Jain AB, Venkataramanan R, Eghtesad B, et al. Effect of coadministered lopinavir and ritonavir (Kaletra) on tacrolimus blood concentration in liver transplantation patients. Liver Transpl 2003;9:954-60.  
2. Neff GW, Bonham A, Tzakis AG, et al. Orthotopic liver transplantation in patients with human immunodeficiency virus and end-stage liver disease. Liver Transpl 2003;9:239-47.  
3. Barau C, Blouin P, Creput C, Taburet AM, Durrbach A, Furlan V. Effect of coadministered HIV-protease inhibitors on tacrolimus and sirolimus blood concentrations in a kidney transplant recipient. Fundam Clin Pharmacol 2009;23:423-5.  
4. Mertz D, Battegay M, Marzolini C, Mayr M. Drug-drug interaction in a kidney transplant recipient receiving HIV salvage therapy and tacrolimus. Am J Kidney Dis 2009;54:e1-4.  
5. Schonder KS, Shullo MA, Okusanya O. Tacrolimus and lopinavir/ritonavir interaction in liver transplantation. Ann Pharmacother 2003;37:1793-6.  
6. Jain AK, Venkataramanan R, Shapiro R, et al. The interaction between antiretroviral agents and tacrolimus in liver and kidney transplant patients. Liver Transpl 2002;8:841-5.  
7. Teicher E, Vincent I, Bonhomme-Faivre L, et al. Effect of highly active antiretroviral therapy on tacrolimus pharmacokinetics in hepatitis C
virus and HIV co-infected liver transplant recipients in the ANRS HC-08 study. Clin Pharmacokinet 2007;46:941-52.  
8. Frassetto LA, Browne M, Cheng A, et al. Immunosuppressant pharmacokinetics and dosing modifications in HIV-1 infected liver and kidney transplant recipients. Am J Transplant 2007;7:2816-20.  
9. Guaraldi G, Cocchi S, Codeluppi M, et al. Role of therapeutic drug monitoring in a patient with human immunodeficiency virus infection and end-stage liver disease undergoing orthotopic liver transplantation. Transplant Proc 2005;37:2609-10.  
10. Schvarcz R, Rudbeck G, Soderdahl G, Stahle L. Interaction between nelfinavir and tacrolimus after orthoptic liver transplantation in a patient coinfected with HIV and hepatitis C virus (HCV). Transplantation 2000;69:2194-5.  
11. Sheikh AM, Wolf DC, Lebovics E, Goldberg R, Horowitz HW. Concomitant human immunodeficiency virus protease inhibitor therapy markedly reduces tacrolimus metabolism and increases blood levels. Transplantation 1999;68:307-9.  
12. Chittick GE, Zong J, Begley JA, Alianti JR, Sorbel JJ, Blum MR. Pharmacokinetics of emtricitabine/tenofovir disoproxil fumarate and tacrolimus at steady state when administered alone or in combination. Int J Clin Pharmacol Ther 2008;46:627-36.  
13. Jain AK, Venkataramanan R, Fridell JA, et al. Nelfinavir, a protease inhibitor, increases sirolimus levels in a liver transplantation patient: a case report. Liver Transpl 2002;8:838-40.  
14. Vogel M, Voigt E, Michaelis HC, et al. Management of drug-to-drug interactions between cyclosporine A and the protease-inhibitor lopinavir/ritonavir in liver-transplanted HIV-infected patients. Liver Transpl 2004;10:939-44.  
15. Brinkman K, Huysmans F, Burger DM. Pharmacokinetic interaction between saquinavir and cyclosporine. Ann Intern Med 1998;129:914-5.  
16. Frassetto L, Baluom M, Jacobsen W, et al. Cyclosporine pharmacokinetics and dosing modifications in human immunodeficiency virusinfected liver and kidney transplant recipients. Transplantation 2005;80:13-7.  
17. Frassetto L, Thai T, Aggarwal AM, et al. Pharmacokinetic interactions between cyclosporine and protease inhibitors in HIV+ subjects. Drug Metab Pharmacokinet 2003;18:114-20.  
18. Guaraldi G, Cocchi S, Codeluppi M, et al. Pharmacokinetic interaction between Amprenavir/Ritonavir and FosAmprenavir on cyclosporine in two patients with human immunodeficiency virus infection undergoing orthotopic liver transplantation. Transplant Proc 2006;38:1138-40.  
19. Tseng A, Nguyen ME, Cardella C, Humar A, Conly J. Probable interaction between efavirenz and cyclosporine. AIDS 2002;16:505-6. 20. Wenning LA, Friedman EJ, Kost JT, et al. Lack of a significant drug interaction between raltegravir and tenofovir. Antimicrob Agents Chemother 2008;52:3253-8.  
21. Di Biagio A, Rosso R, Siccardi M, D'Avolio A, Bonora S, Viscoli C. Lack of interaction between raltegravir and cyclosporin in an HIVinfected liver transplant recipient. J Antimicrob Chemother 2009;64:874-5.  
22. Margolis DM, Kewn S, Coull JJ, et al. The addition of mycophenolate mofetil to antiretroviral therapy including abacavir is associated with depletion of intracellular deoxyguanosine triphosphate and a decrease in plasma HIV-1 RNA. J Acquir Immune Defic Syndr 2002;31:45-9.  
23. Heredia A, Margolis D, Oldach D, Hazen R, Le N, Redfield R. Abacavir in combination with the inosine monophosphate dehydrogenase
(IMPDH)-inhibitor mycophenolic acid is active against multidrug-resistant HIV-1. J Acquir Immune Defic Syndr 1999;22:406-7.  
24. Luznik L, Bolanos-Meade J, Zahurak M, et al. High-dose cyclophosphamide as single agent, short-course prophylaxis of graft-versus-host disease. Blood 2010.  
25. de Jonge ME, Huitema AD, van Dam SM, Beijnen JH, Rodenhuis S. Significant induction of cyclophosphamide and thiotepa metabolism by phenytoin. Cancer Chemother Pharmacol 2005;55:507-10.
table f-3 pharmacokinetic interactions for
table f-4 continuation of antiretroviral

| *Monitor azole drug levels routinely.                                        | Raltegravir Based  Regimen                                           | NNRTI Based Regimen                                          | Boosted PI Based Regimen    | Other                                                        |
|------------------------------------------------------------------------------|----------------------------------------------------------------------|--------------------------------------------------------------|-----------------------------|--------------------------------------------------------------|
| Antifungal Agent                                                             | ↑ voriconazole dose to 400mg  BID* ↓ efavirenz dose to 300mg  daily. | Consider alternative                                         |                             |                                                              |
| antifungal agent; monitor  voriconazole levels and                           |                                                                      |                                                              |                             |                                                              |
| increase dose based on level*                                                | Consultation recommended,  reviewed on a case by case  basis         |                                                              |                             |                                                              |
| Voriconazole                                                                 | No adjustments                                                       | Consider alternative                                         |                             |                                                              |
| antifungal agent; monitor  posaconazole levels and  increase dose as needed* | Consider alternative                                                 |                                                              |                             |                                                              |
| antifungal agent; monitor  closely for PI toxicity*                          | Consultation recommended,  reviewed on a case by case  basis         |                                                              |                             |                                                              |
| Posaconazole                                                                 | No adjustments                                                       | Consultation recommended,  reviewed on a case by case  basis |                             |                                                              |
| Fluconazole                                                                  | No adjustments                                                       | No adjustments. Monitor  closely for hepatotoxicity.         | Do not use doses >200mg/day | Consultation recommended,  reviewed on a case by case  basis |
| Echinocandins                                                                |                                                                      |                                                              |                             |                                                              |
| (Anidulafungin, Micafungin, Caspofungin)                                     | No adjustments                                                       | No adjustments                                               | No adjustments              | Consultation recommended,                                    |
| Amphotericin B and derivatives                                               | No adjustments                                                       | No adjustments                                               | No adjustments              | reviewed on a case by case  basis†                           |
table f-3 pharmacokinetic interactions for
table f-5 dose adjustments for

| *Monitor immunosuppression levels routinely.   | Tacrolimus (FK) Cyclosporine (CY)   | Sirolimus                  | Mycophenolate              | Cyclophosphamide28         |      |
|------------------------------------------------|-------------------------------------|----------------------------|----------------------------|----------------------------|------|
| Antifungal Agent                               | Avoid concomitant use (see          | No adjustments             | Avoid concomitant use (see |                            |      |
| below)                                         | below)                              |                            |                            |                            |      |
| ↓ Sirolimus dose by 90%*                       |                                     |                            |                            |                            |      |
| Voriconazole                                   | ↓ FK dose by 67%* ↓ CY dose by 50%* | Avoid concomitant use (see | No adjustments             | Avoid concomitant use (see |      |
| below)                                         | below)                              |                            |                            |                            |      |
| ↓ Sirolimus dose by 67%                        |                                     |                            |                            |                            |      |
| Posaconazole                                   | ↓ FK dose by 67%* ↓ CY dose by 25%* |                            |                            |                            |      |
| Fluconazole                                    | No adjustments*                     | No adjustments*            | No adjustments             | No adjustments             | (see |
| below)                                         |                                     |                            |                            |                            |      |
| Echinocandins                                  |                                     |                            |                            |                            |      |
| (Anidulafungin, Micafungin, Caspofungin)       | No adjustments                      | No adjustments             | No adjustments             | No adjustments             |      |
| Amphotericin B and derivatives                 | No adjustments                      | No adjustments             | No adjustments             | No adjustments             |      |