Interferon Alpha 2b Intensification in HIV-Positive Individuals on Antiretroviral Therapy

As a result of combination antiretroviral therapy (ART), morbidity and mortality from
acquired immunodeficiency syndrome has declined significantly in the past 15 years, at least
in developed countries. Human immunodeficiency virus type 1 (HIV-1) infected individuals now
live longer, but must undergo continuous therapy that has substantial consequences on quality
of life.

ART suppresses HIV-1 viremia below the limits of detection in current commercial assays (c.
50 copies/mL plasma)., but HIV viremia persists even after prolonged suppressive therapy. The
origin of this residual viremia is yet not clear, but data suggest that production from long
lived HIV infected cells may contribute to viremia.

Antiretrovirals are extremely active against replicating cells, and can thus successfully
stop viral replication, but have no effect on long-lived viral reservoirs of cells already
infected with HIV-1 at the time antiretroviral therapy is initiated. As a result, new
strategies are necessary to reduce or eradicate long-lived reservoirs.

Interferon alpha is a natural cytokine with antiviral activity. Prior to the introduction of
antiretroviral therapy, several studies demonstrated modest effect of interferon alpha in
HIV-1 viremia in active cycles of infection in infected individuals. Interferon alpha was
also effective in vitro in decreasing virus production from cells chronically infected with
HIV-1. With the introduction of potent antiretroviral therapy, interferon was not developed
as a direct anti-HIV drug. Interferon alpha is relatively effective in therapy of hepatitis C
virus (HCV) infection, and has been used in HIV-1/HCV coinfected individuals. Kottilil and
coworkers in the Laboratory of Immunoregulation NIAID have shown a decrease in HIV-1 RNA
levels in HCV coinfected participants treated with pegylated interferon alpha and ribavirin.
In stored samples from that study, we conducted a retrospective trial on samples from
participants with HIV-1 RNA levels of <50 copies/mL, showing a further reduction in residual
viremia using an ultrasensitive Single Copy Assay (SCA) developed in our laboratory. As such
the effects of interferon on HIV viremia and cell associated HIV RNA are of growing interest.

In this protocol we will conduct a prospective, non-randomized, single arm, pilot study to
investigate the effect of pegylated interferon alpha 2b on HIV-1 RNA levels as an additional
drug in participants undergoing suppressive antiretroviral therapy with viral RNA levels
suppressed to less than 50 copies/mL plasma. As patients may have levels of HIV RNA that are
lower than our limit of detection, we will also investigate levels of HIV nucleic acid
species in cells as well. We will determine whether interferon alpha therapy will reduce
residual viremia or cell associated HIV RNA in participants on suppressive ART, which will
expand our understanding of persistent low-level viremia and the pathogenesis of HIV in
infected individuals.

- INCLUSION CRITERIA:

To be eligible for study participation, a volunteer must satisfy all of the following
inclusion criteria:

1. Age greater than or equal to 18 years.

2. Documentation of HIV-1 infection by any licensed ELISA test and confirmed by a Western
Blot.

3. Receiving a DHHS-approved ARV regimen.

4. Level of cell-associated HIV RNA greater than or equal to 5 copies/million peripheral
blood mononuclear cells (PBMC) done at screening visit 1.

5. HIV-1 RNA levels less than detectable by current commercial means (e.g., Roche
Amplicor, b-DNA test) for a minimum of 12 months prior to screening at all time
points, and with at least 2 measurements in this 12 month window.

6. CD4 greater than or equal to 300 cells/mm(3) at pre-entry visit within 14 days prior
to enrollment.

7. Ability to sign informed consent and willingness to comply with the study requirements
and clinic policies.

8. No evidence of viral hepatitis co-infection as assessed by Hepatitis C antibody, HCV
RNA, and hepatitis B surface antigen; determinations at pre-entry visit within 28 days
prior to enrollment.

9. No history of or evidence of autoimmune hepatitis or other autoimmune disorders at
screening, or Antinuclear antibody (ANA > 3 times upper limit of normal.

10. Laboratory values at pre-entry visit within 14 days prior to enrollment:

- Alkaline phosphatase <2.0 times upper limit of normal

- Alanine transaminase (ALT) <2.0 times upper limit of normal

- Total bilirubin < 2.5 mg/dL (< 40 mg/dL if on Atazanavir)

- Creatinine clearance greater than or equal to 60 mL/min as estimated by the
Cockcroft-Gault equation

- Neutrophil count greater than or equal 1500 cells/mm(3)

- Platelets greater than or equal to 150,000/ mm(3)

- Hemoglobin greater than or equal to 12.0 mg/dL for men and >11.0 g/dL for women

- Fasting glucose < 126 mg/dL

11. No history or evidence of significant clinical depression at screening that in the
opinion of the investigator would affect the ability of the patient to participate in
the study, or which would constitute a threat for his/her health in case of relapse
upon INF treatment. The Beck Depression Inventory score must be less than or equal to
13 at pre-entry visit.

12. No history of INF/PEG-INF therapy.

13. If capable of pregnancy: use of effective contraception during study: effective
contraception methods include abstinence, surgical sterilization of either partner,
barrier methods such as diaphragm, condom, cap or sponge, or use of hormonal
contraception with an anti-HIV regimen that will not alter metabolism of hormonal
contraception.

14. Participants must have primary medical care outside this protocol: participants will
have to provide Primary Care Doctor s contact information.

EXCLUSION CRITERIA:

A volunteer will be ineligible to participate in this study if any of the following
criteria are met:

1. History of neoplastic disease requiring cytotoxic therapy including hydroxyurea.

2. Use of long-term systemic corticosteroids, immunosuppressive agents, or cytotoxic
agents within 60 days prior to enrollment.

3. Any vaccination within 30 days prior to enrollment. Individuals interested in
participating who require vaccination will delay screening until 30 day period is
completed.

4. Concurrent therapy with investigational cytokines including IL-2 or IL-12 during the
course of the study. Prior administration of cytokines is not an exclusion criterion;
at least 4 months from most recent cycle of IL-2 or IL-12 is required.

5. Any febrile illness (>38 degrees C) in the 3 weeks prior to enrollment or any acute
therapy for a serious infection completed within 30 days prior to enrollment.

6. Current pregnancy or lactation, history of pregnancy in the last 4 months.

7. Preexisting autoimmune disorders including inflammatory bowel diseases, psoriasis,
idiopathic thrombocytopenic purpura, lupus erythematous, autoimmune hemolytic anemia,
scleroderma, severe psoriasis, rheumatoid arthritis, and optic neuritis.

8. History of severe retinopathy or evidence of severe retinopathy judged by pre-entry
ophthalmologic examination.

9. Known allergy/sensitivity to study drug or its formulation.

10. History of seizure disorders or current anticonvulsant use.

11. Any history of medical conditions associated with chronic liver disease (genetic
hemochromatosis, alcoholic liver disease, toxin exposures, and autoimmune hepatitis)
or documented cirrhosis due to any cause.

12. History of pulmonary disease associated with functional limitation.

13. Documented history of thyroid disease.

14. Active drug or alcohol use or dependence, which in the opinion of the investigator,
would interfere with complying with the study requirements.

15. Known hypersensitivity to Escherichia coli-derived products such as filgrastim.

16. Any systemic illness that will make it unlikely that the subject will be able to
return for the required study visits.

17. History of, or any condition that in the opinion of the investigator would interfere
with the conduct of the study, or it would not be in the best interest of the subject
to enroll in this study.