Lymphocyte Infusions for the Treatment of HIV-Infected Patients Failing Anti-HIV Therapy
Lymphocyte Infusions for the Treatment of HIV-Infected Patients Failing Anti-HIV Therapy
Some HIV-infected individuals have a white blood cell marker known as HLA-B*57 that appears
 to help control the progress of the disease; however, not all who have the HLA-B*57 marker
 are able to control the infection. This study will examine the effects of giving white blood
 cells with HLA-B*57 from an individual who controls HIV infection to an individual who cannot
 control HIV infection, as a form of HIV treatment. All candidates will be screened with a
 medical history, physical examination, and blood and urine tests.

 Both donor and recipient volunteers must be HIV-positive individuals 18 years of age or older
 who have the HLA-B*57 marker and are receiving care. Donor candidates must have positive HIV
 antibody tests for at least seven years with a recent CD4 cell count greater than 400
 cells/mm?, HIV viral load less than 50 copies/mL, and no previous HIV viral load greater than
 1,000 copies/mL. Recipient candidates must have positive HIV antibody tests with a recent CD4
 cell count less than 400 cells/mm? and HIV viral load greater than 10,000 copies/mL, and must
 have failed at least two prior combination antiretroviral regimes and are willing to receive
 or resume combination antiretroviral therapy. Donor volunteers will be excluded if they have
 taken certain antiretrovirals drugs, have a medical history of cancer or of other blood-borne
 illnesses, or have other medical conditions that might interfere with the study. Recipient
 volunteers will be excluded if they have a medical history of malignant cancer or other
 medical conditions that might possibly interfere with the study.

 Donors will undergo apheresis to separate white blood cells from circulating blood before the
 red blood cells and plasma are returned to the bloodstream. The procedure will take up to
 five hours, and donors will be required to return for additional tests. Donors may be asked
 to return for further white blood cell donations, a maximum of six procedures per year.

 Recipients will undergo apheresis to obtain stem cells for possible use in the study, and
 will be admitted to an NIH Clinical Center inpatient unit to receive an infusion of white
 blood cells and undergo a series of blood tests both before and after the infusion. The
 infusion process will take two hours. After being discharged, recipients will be asked to
 return to the Clinical Center for monitoring and follow-up tests, and may receive further
 infusions.
Improvements in human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS)
 treatments in the United States have made the disease in many cases a chronic illness.
 However, many individuals have failed multiple lines of standard therapy, and thus,
 development of new modes of salvage treatment is crucial. Restriction of viral replication,
 mediated by CD8+ cells, appears to play an important role in control of HIV replication. A
 subset of individuals, many of whom possess human leukocyte antigen (HLA) B*57 exhibit
 restriction of HIV type 1 viral replication to less than 50 copies/mL, presumably by a
 mechanism that is CD8+ T-cell mediated, and become elite long-term non-progressors (LTNP),
 who have no evidence of progressive immunodeficiency and no development of opportunistic
 complications during many years of follow-up. Other individuals, including those with
 HLA-B*57 show no evidence of control of HIV replication, and without antiretroviral therapy
 will develop progressive immunodeficiency and HIV-related opportunistic complications. In
 this exploratory study, we are investigating a novel cell transfer strategy: up to 3 patients
 with HIV infection have failed at least 2 standard regimens of antiretroviral therapy, have a
 CD4+ count under 200 cells/mm (3), and a plasma HIV viral load of greater than 10,000
 copies/mL, will be administered 10 (10) peripheral blood mononuclear cells obtained by
 lymphapheresis from an "elite" LTNP matched to the recipient on at least one HLA-B allele. Up
 to 70 patients may be enrolled for screening to identify 3 donors and 3 recipients. Up to 3
 infusions may be administered per patient, with each infusion occurring no more frequently
 than every 3 months. The primary endpoints will be the safety of the infusions and the
 survival of donor cells in the recipient. Changes in the recipient s CD4+ and CD8+ cell
 number, other immune parameters, and plasma HIV viral load will also be monitored closely for
 evidence of anti-HIV activity.
-  INCLUSION CRITERIA RECIPIENT:

 Under this protocol, cell recipients must fulfill all of the following characteristics and
 conditions:

 Greater than or equal to 18 years old

 Ability to sign informed consent

 For women of child-bearing potential, negative result on a serum or urine pregnancy test;
 in addition, men and women of childbearing potential must agree to practice abstinence or
 use two methods of birth control/contraception (condoms, diaphragm or cervical cap with
 spermicide, IUD, or hormonal-based contraception) for at least 4 weeks after each cell
 infusion

 Willingness to comply with study requirements and procedures including storage of blood for
 possible future use to study HIV/AIDS, related diseases, or the immune system

 Willingness to permit HLA testing

 Hematocrit greater than or equal to 27 percent, platelets greater than or equal to
 25,000/mm (3)

 No significant underlying cardiac, renal, or hepatic disease (Creatinine less than 2.0
 mg/dL; aspartate aminotransferase (AST) and alanine aminotransferase (ALT) less than 150
 U/mL)

 HIV infection must be confirmed by ELISA and a confirmatory test (e.g. western blot if not
 previously documented, and patients must be under the care of a primary care physician.

 Viral load greater than 10,000 copies/mL on available optimized combination antiretroviral
 therapy, to include at least 3 drugs, one of which is a non-nucleoside reverse
 transcriptase inhibitor (NNRTI), integrase inhibitor, or protease inhibitor. Patients not
 on combination antiretroviral therapy will be eligible, but must be willing to resume
 combination antiretroviral therapy and to have had a viral load greater than 10,000
 copies/mL after at least 2 weeks of therapy.

 Failure or intolerance of at least two previous combination antiretroviral regimens.
 Failure will be defined as an HIV viral load greater than 400 copies/mL while taking a
 given regimen.

 Recipient must be taking appropriate prophylaxis for opportunistic infections, as per
 Public Health Service (PHS) guidelines, unless there is intolerance to available
 medications.

 Screening CD4+ cell count less than or equal to 350 cells/mm(3) obtained within 6 weeks
 prior to study entry.

 EXCLUSION CRITERIA FOR RECIPIENT:

 An individual will be ineligible to receive cells if one or more of the following
 conditions are present:

 Discordance with donor on antibody status of EBV, CMV, or HHV-8 if donor is antibody
 positive for EBV, CMV, or HHV-8.

 Malignancy requiring systemic therapy, or a history of malignancy that required myelotoxic
 chemotherapy.

 Active untreated opportunistic infection that requires systemic therapy. Patients with
 opportunistic infections who have received greater than 2 weeks of therapy will be
 eligible.

 Is pregnant or breast feeding.

 Severe psychiatric disorder that would interfere with adherence to protocol requirements.
 Individuals who have a stable psychiatric condition may be eligible.

 Current use or a history of treatment with investigational agent(s) within 3 months of
 protocol enrollment. ARVs obtained through expanded access programs are permitted.

 Current use or a history of treatment with a systemic corticosteroid, immunosuppressive, or
 cytotoxic agent within 30 days of protocol enrollment.

 Any other medical condition for which the investigator believes cell transfer may be
 contraindicated.

 Ever been diagnosed with autoimmune vasculitis.

 INCLUSION CRITERIA DONOR:

 Donor eligibility criteria as specified by the FDA will be followed, except for HIV
 testing. All donors will be HIV positive as per protocol and as described in the IND
 application. Under this protocol, cell donors must fulfill all of the following
 characteristics and conditions:

 Greater than or equal to 18 years old.

 Ability to sign informed consent.

 For women of child-bearing potential, negative result on a serum or urine pregnancy test.

 Willingness to comply with study requirements and procedures including storage of blood for
 possible future use to study HIV/AIDS, related diseases, or the immune system.

 Willingness to permit HLA testing.

 Matched to at least one HLA-B allele of the potential recipient. The

 match will be at a two-digit resolution HLA allele level of typing or higher.

 Hematocrit greater than or equal to 30 percent, platelets greater than or equal to
 100,000/mm(3), white blood cells greater than or equal to 3.0 times 10(9)/L.

 No underlying cardiac, pulmonary, renal, or hepatic disease that would preclude patient
 from undergoing apheresis.

 HIV infection must be confirmed by ELISA and a confirmatory test (e.g. western blot if not
 previously on record, and patients must be under the care of a primary care physician.

 HIV infection for greater trhan or equal to 7 years.

 For patients with a history of no or minimal (one or two nucleotide reverse transcriptase
 inhibitor (NRTI) drugs) prior antiretroviral therapy: CD4+ cell count greater than or equal
 to 400 cells/mm(3) and HIV viral load less than 50 copies/mL, with no recorded HIV viral
 load obtained after acute HIV infection greater than 2,500 copies/mL. For patients
 currently receiving antiretroviral therapy: no antiretroviral therapy for a period of at
 least 7 years prior to starting antiretroviral therapy, with CD4+ cell count greater than
 or equal to 400 cells/mm(3) and HIV viral load < 50 copies/mL at the time of initiation of
 antiretroviral therapy, and no recorded HIV viral load obtained after acute HIV infection >
 2,500 copies/mL. HIV viral loads obtained during acute HIV infection (within 6 months of
 the estimated date of seroconversion) will not be utilized for study inclusion/exclusion.

 Minimum wt of 110 lbs<TAB>

 EXCLUSION CRITERIA FOR DONOR:

 An individual will be ineligible to donate cells if one or more of the following conditions
 are present:

 Ever having been diagnosed with any AIDS-defining illnesses

 Positive results on screening test for any of the following tests: HCV enzyme immunoassay
 (EIA) repeat reactive/ recombinant immunoblot (RIBA) confirmed, HBV/HCV NAT, HTLV-I/II
 antibodies, T.cruzi antibodies, HBsAg, or serologic test for syphilis (with positive
 confirmatory treponemal-based assay), unless the patient has received adequate therapy for
 syphilis. Donors with a positive West Nile Virus NAT are deferred for 120 days.

 Is pregnant or breast feeding

 HLA homozygous donor who is haplo-identical to recipient

 History of malignancy other than basal cell carcinoma of the skin, or in situ carcinoma of
 cervix or colon

 ALT or AST greater than 2 times the upper limit of normal

 Been diagnosed with malaria

 Been diagnosed with Chagas disease

 Been diagnosed with babesiosis

 Received a dura mater (or brain covering) graft

 Been diagnosed with any neurological disease

 Relative had Creutzfeldt-Jakob disease

 Had a transplant or other medical procedure that involved being exposed to live cells,
 tissues, or organs from an animal

 Had a sexual partner or a member of the household have a transplant or other medical
 procedure that involved being exposed to live cells, tissues, or organs from an animal

 Severe psychiatric disorder that would interfere with adherence to protocol requirements.
 Individuals who have a stable psychiatric condition may be eligible.

 Current use or a history of treatment with investigational agent(s) within 3 months of
 protocol enrollment.

 Current use or a history of treatment with a systemic corticosteroid, immunosuppressive, or
 cytotoxic agent within 30 days of protocol enrollment.

 Any other medical condition for which the investigator believes apheresis may be
 contraindicated.