| Purpose: |
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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....
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| Study Summary: |
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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.
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| Criteria: |
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- 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 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 200 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 western blot if not previously on record, and
patients must be under the care of a primary care physician.
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 greater than 1,000 copies/mL.
HIV infection for greater than or equal to 7 years.
Minimum wt of 110 lbs
From 1980 through 1996, did not spend time that adds up to three (3) months or more in the
United Kingdom.
From 1980 to the present, did not spend time that adds up to five (5) years or more in
Europe.
From 1980 to the present, did not receive a blood transfusion in the United Kingdom.
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
Ever being on antiretroviral therapy other than one or two nucleotide reverse
transcriptase inhibitor (NRTI) drugs; no NRTI therapy during the previous year
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.
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