RHIV A Pilot Study Refractory or Intolerant to Highly Active Antiretroviral Therapy (HAART)

Rationale for the Use of ECP with UVADEX in Patients with HIV-1 Infection

Studies have demonstrated that psoralen and ultraviolet A light inactivate HIV virus in
vitro. Edelson, et al, showed that extracorporeal photochemotherapy (ECP) with psoralen
primarily targets the CD4+ cell, the population predominately affected by HIV-1 infection.
It is postulated that the re-infusion of the ECP treated cell fraction, free virus,
cell-associated virus along with whole cells, cell fragments, and soluble antigens, may
serve to engender a specific HIV immune response.

A twenty-patient study using ECP with psoralen was conducted by Bisaccia, et al. In this
study, patients were HIV positive by enzyme linked immunosorbent assay and these positive
results were confirmed by Western blot test. Patients were staged as Walter Reed class WR3
to WR5. Extracorporeal photoimmune therapy was administered on two consecutive days on a
monthly basis for 6-29 months. This study reported that CD4 counts declined more slowly
than historical controls. Walter Reed classification improved in 55% (11/20), was stable in
35% (7/20) and declined in 10% (2/20) of the patients treated in this study.

One measure in the "in vivo" evaluation of T-cell function is provided by skin reactivity to
recall antigens (DTH). A lack of this response has been associated with progression of HIV
disease. In the Bisaccia study, skin reactivity to recall antigens (DTH) improved in 55%
(11/20) patients, were stable in 35% (7/20), progressed to anergy in 5% (1/20). One patient
was initially anergic and remained anergic post-treatment. Following treatment with ECP,
60% (9/15), displayed normal skin test responses, whereas the baseline examinations had been
normal in only 5% (1/19). In addition, 21% (4/19) of patients showed a partial skin test
response. Only 10% (2/20) of patients developed a new opportunistic infection. This
included the patient initially anergic and who remained anergic and the patient who
progressed to anergy post-ECP treatment.

DESCRIPTION OF THE UVAR® XTSÔ PHOTOPHERESIS SYSTEM

Photopheresis (or extracorporeal photoimmune therapy [ECP]) is a process developed by
THERAKOS, Inc., a Johnson and Johnson Company. During the process of ECP, whole blood is
drawn from the patient over several cycles, centrifuged and separated into the components of
plasma, white cells (or buffy coat), and red blood cells. A portion of the white cells and
the plasma are saved in a separate compartment. The remaining plasma and red blood cells
are immediately returned to the patient.

The saved buffy coat (white blood cells) and plasma are inoculated with the photosensitizing
agent UVADEX. Photoactivation begins when the suspension is exposed to a prescribed amount
of ultraviolet-A light. After photoactivation is complete, the treated suspension is
returned to the patient.

Photopheresis performed using the UVAR XTS is a continuous process. During the entire
therapy, the patient remains connected to the photopheresis instrument. The duration of time
between completion of the buffy coat collection and reinfusion of the light-activated buffy
coat is approximately 30 minutes.

Inclusion Criteria:

- HIV-1 positive by ELISA assay and confirmed by Western blot

- Patients must be refractory or intolerant to HAART. Refractory HIV patients are
defined as those patients meeting the following criteria:

- Resistance to all major groups of active agents (non-nucleotide reverse
transcriptase inhibitors [NNRTIs], nucleotide reverse transcriptase inhibitors
[NRTIs], and protease inhibitors [PIs]);

- Not achieving < 400 copies/mL by 24 weeks or < 50 copies/mL by 48 weeks of
therapy; or

- Documentation of resistance mutations by genotype testing; or

- Failure to increase CD4+ cells > 25 cells/mm3 above baseline after one year of
therapy.

- HIV RNA >= 3,000 copies/mL by PCR analysis

- CD4 count > 75 cells/mm3

- No new antiretroviral agents may be added during the pre-study evaluation, treatment,
or follow-up periods.

- Life expectancy > 6 months

- Able to give informed consent and comply with all study visits, procedures, and the
ECP treatment schedule

- Ages between 18 and 70

- Females of childbearing potential may not be lactating and must be human chorionic
gonadotropin (HCG) negative at study entry and agree to use acceptable methods of
birth control (hormonal, intrauterine device, and spermicide and barrier) throughout
the study period.

- Minimum body weight of 88 lbs (40kg)

- May not have current photosensitive diseases such as systemic lupus erythematosus
(SLE) or porphyria

- Adequate hematological function with an absolute neutrophil count of >= 500/mm and a
platelet count of >= 50,000/mm.

Exclusion Criteria:

- Established history of heparin or psoralen allergy

- Patients with aphakia because of significantly increased risk of retinal damage due
to absence of lenses. Patients with lens implants are acceptable for inclusion.

- Current participation (within 30 days) in a clinical trial examining the safety
and/or efficacy of anti-retroviral agent(s)

- Patients with any other major illness (e.g. malignancy, renal failure, severe cardiac
disease, severe neurologic disease) that either might preclude completion of the
study or bias efficacy assessments.

- Patients who cannot or may not tolerate the extracorporeal volume required during the
procedure, for reasons such as severe cardiovascular disease, i.e. history of
congestive heart failure or severe anemia (hemoglobin < 90 g/L)

- Patients with a photosensitive disease, such as porphyria or systemic lupus
erythematosus. Special care must be taken in the treatment of patients who require
medications (either topically or systemically) during the course of the study with
photosensitizing potential, such as phenothiazine, tetracyclines, sulfonamides, some
non-steroidal anti-inflammatory drugs (NSAIDs) or chlorothiazide. Patients who must
take photosensitizing drugs during the study will not receive them within 24 hours
of each scheduled treatment.