Immune Reconstitution Syndrome in HIV-Infected Patients Taking Antiretroviral Therapy

A cohort observational study evaluating the predictors, incidence, clinical presentation and
immunopathogenesis of Immune Reconstitution Syndrome (IRIS) in human immunodeficiency virus
(HIV-1) infected patients with CD4 Count less than or equal to 100 cells/microL who are
initiating antiretroviral therapy.

Immune reconstitution syndrome (IRIS) is a clinical syndrome that has been described in HIV
infected patients after initiation of highly active anti-retroviral therapy (HAART), and is
characterized by paradoxical acute worsening of an underlying opportunistic infection or
AIDS-defining illness. There is no widely accepted syndromic definition, the pathogenesis of
the syndrome is unclear and there is no specific therapy. The syndrome is more common in
patients with low CD4+ T cell counts (less than 50 cells/microL) and in those with certain
underlying infections (e.g. mycobacterial or cryptococcal infection) and is typically
observed when there is evidence of response to HAART and while patients are still at risk for
other opportunistic infections (OIs) or AIDS defining illnesses (e.g. pneumocystis jirovecii
pneumonia or cytomegalovirus [CMV] retinitis). The incidence of IRIS varies depending on the
studied population and is very frequent in developing countries creating significant
diagnostic and therapeutic challenges as well as utilization of limited health resources.

DESIGN: International observational cohort study. Participants will be evaluated at baseline
and followed according to the protocol follow up schedule after initiation of antiretroviral
therapy for a total of two years. Acute symptoms that may be representing manifestations of
IRIS will also be evaluated at additional acute care visits if necessary.

DURATION: Enrollment is ongoing. Each volunteer will be followed for at least two years.
Total duration of the study will be approximately 8 years (including the optional extension
phase in US).

SAMPLE SIZE: Approximately 600 patients will be enrolled, 200 in Kenya, 100 in Thailand and
300 in US. (enrollment is US will continue until approximately the other sites are full).
Based on the incidence of IRIS in patients with low CD4 counts (approximately 20-40 percent),
we anticipate strong power (approximately 90 percent) to identify baseline factors predictive
of IRIS.

POPULATION: HIV-l-infected men and women, age greater than or equal to 18 years,
antiretroviral therapy (ART)-naive with CD4+ T cell counts less than or equal to 100
cells/mm(3). Participants will be recruited and followed at three sites: the broader
Washington DC, Kericho, Kenya and Bangkok, Thailand areas.

REGIMEN: Participants will be initiated on ART according to the clinical standard of care. If
an OI or other AIDS defining illness is identified prior to or during screening or at any
point during the study, they will also be treated according to standard of care.

- INCLUSION CRITERIA:

1. For the National Institutes of Health (NIH)/US site: HIV-1 infection, as
documented by OraQuick rapid test using venipuncture whole blood, or fingerstick
whole blood done at screening; or by reactive enzyme-linked immunosorbent assay
(ELISA) and Western Blot as determined by NIH Clinical Pathology Laboratory or
Leidos Biomedical Research, Inc. Monitoring Laboratory. HIV infection as
determined by an outside Clinical Laboratory Improvement Amendments
(CLIA)-approved laboratory facility" will be accepted for enrollment and verified
by a standard HIV-1 ELISA with Western Blot at NIH.

For Keny Medical Research Institute/Walter Reed Project Clinical Research Center
(KEMRI/WRP CRC)/Kenya site: HIV-1 infection will initially be diagnosed based
upon two, serial rapid HIV tests according to Kenya Ministry of Health (MOH)
guidelines. Volunteers entering this study will have HIV infection confirmed by
two serial rapid HIV test in accordance with Kenya MOH guidelines and testing
algorithm followed by a confirmation with a Western Blot using FDA approved-kits.
Samples from participants with discrepant results (between the results from other
institution and KEMRI/WRP-CRC laboratory) and/or indeterminate/negative Western
Blot will be subjected to a nucleic acid assay i.e. DNA or RNA PCR. For Thailand,
HIV-1 screening and confirmatory testing will be based on 3, HIV tests according
to the Thai Ministry of Public Health guidelines. The subjects will initially be
tested with a chemiluminescent microparticle immunoassay (CMIA) method that
detects both HIV antigen and antibody. Confirmatory testing of HIV reactive
samples by two different antibody detection methods will follow. Positive results
by all three methods confirm HIV diagnosis. Discrepancy between the tests will
require a nucleic acid detection method to confirm HIV diagnosis.

2. No previous treatment with potent combination anti-retroviral therapy (ART),
defined as any protease inhibitor (PI)-based or non-nucleoside reverse
transcriptase inhibitor (NNRTI)-based regimen, or even triple nucleoside reverse
transcriptase inhibitors (NRTI)-based regimen, consisting of at least three
antiretroviral drugs (including a boosted PI with NNRTI combination). Patients
with limited use of ART (less than 12 weeks duration) more than 24 weeks before
screening will be eligible for study participation.

3. Screening CD4+ cell count less than or equal to 100 cells/mm(3). * Note: CD4 <
100 cells/microL from an outside or the site s laboratory within 8 weeks prior to
screening can be accepted as the screening value.

4. Residence within the wider Washington D.C. area (approximately within a 120-mile
radius from the NIH Bethesda campus) for the National Institutes of Health/US
site and residents of the Kericho District Hospital catchment area, an
approximate 93-mile (150 kilometers) radius, for the KEMRI/WRP CRC/Kenya site.
Residence within the Bangkok Metropolitan area and nearby provinces are allowed
to participate (approximately 120-mile radius from each of the clinical sites)

5. Men and women age greater than or equal to 18 years.

6. Ability and willingness of subject or legal guardian/representative to understand
study requirements and give informed consent.

7. Be willing to allow storage of blood or tissue samples for future research. (For
Thailand: storage of blood or tissue samples is an optional procedure and
therefore not a inclusion criteria)

8. Be willing to have HLA testing. (For Thailand: HLA testing is an optional
procedure and therefore not an inclusion criteria)

9. For the NIH/US site: Participants should have a primary care physician or will
need to agree to find one during the first 24-48 weeks on study. For the
KEMRI/WRP/Kenya site: Participants must be enrolled in the Kericho District
Hospital HIV Clinic. For the two Thailand clinical sites: participants must be
enrolled in the HIV clinic at either of the sites.

EXCLUSION CRITERIA:

1. Active drug or alcohol use or dependence that, in the opinion of the investigator,
would interfere with adherence to study requirements.

2. Pregnancy will be an exclusion criterion for study entry given the intense nature of
the protocol regarding blood draws, diagnostic testing, and follow-up.