Reducing Proviral HIV DNA With Interferon-a

Our long-term goal is to evaluate the effect of pegylated interferon (peg-IFN) α as an
anti-HIV reservoir immunotherapy that could potentiate eradication strategies against HIV.

The present study is a 3-arm randomized clinical trial (RCT). The aim of this study is to
determine whether a 20-week treatment course with 1μg/kg/week of pegylated interferon alpha 2
b (peg-IFN-α2b) will reduce the levels of HIV-1 proviral DNA levels in circulating PBMC and
mucosa-associated lymphoid tissue (MALT) in HIV-infected individuals receiving long-term ART.

In addition, we will study if a 4-week interruption of ART is necessary to observe any change
in proviral DNA levels.

In our previous study (NCT00594880) with a different form of Interferon alpha (peg-IFN-α2a),
we observed a reduction in proviral DNA in peripheral blood cells in 50% of the patients.
However, we did not measure the levels in MALT, and we could not determine whether or not an
interruption of ART was necessary. The present study will address these questions.

We will also seek to determine the biological mechanisms (such as an increase in Natural
Killer cell cytotoxicity) that mediate the antiviral effects of peg-IFN-α.

Inclusion criteria

- 18-65 years of age

- Body weight ≥ 125 and ≤ 300 lbs

- Confirmed diagnosis of HIV-1 infection by western blot or by a documented HIV-1 viral
load at screening.

- Currently receiving ART and on ART for ≥ 1 year

- VL < 50 copies/ml for ≥ 1 year, with at least 2 measurements in the previous year. 1
viral "blip" with VL< 400 copies/ml allowed if 1 or more measurements of < 50
copies/ml are available no more than 3 months before and 3 months after the "blip"
without change in ART

- HIV viral load of <50 copies/ml at screening.

- CD4 >450 cells/µL at screening.

- a negative electrocardiogram (EKG, see section 7.4) for: a) men >45 years or women >
55 years of age b) younger subjects of either sex with two risk factors for coronary
artery disease [smoking, hypertension (BP >140/90 or on antihypertensive medications),
low HDL (<40 mg/dl), family history of premature CHD (<55 yrs males/<65 females, c)
subjects with a Framingham score > 15% (men) or 10% (women)

Exclusion criteria Current or prior medications

- Confirmed clinical history of developing resistance to ART regimens that resulted in
treatment changes

- Receiving didanosine as part of the participant's ART regimen at the time of screening

- Ongoing treatment with Isoniazid, Pyrazinamide, Rifabutin, Rifampicin, Ganciclovir,
Valgancyclovir, Oxymetholone, Thalidomide or Theophylline.

- Ongoing treatment with anticoagulants

- Use of any investigational drug within 30 days prior to screening

- History or current use of immunomodulatory therapy for over 2 weeks during the 6
months prior to enrollment, including, but not limited to: IFN-α or γ (recombinant or
pegylated), systemic corticosteroids (inhaled steroids allowed at the discretion of
the Investigator); systemic cancer chemotherapy/irradiation; cyclosporin; tacrolimus
(FK-506); OKT-3; any Interleukin, including IL-2; cyclophosphamide; methotrexate; IVIG
(gamma globulin); G/M-CSF; hydroxyurea; thalidomide; pentoxifylline; thymopentin;
thymosin; dithiocarbonate; polyribonucloside.

- History of adverse or allergic reactions to any type-1 interferon (e.g. IFN-α2a,
IFN-α2b, IFN-β)

Current or prior clinical conditions

- History of severe depression, including history of suicidal ideation or attempt, or
ongoing moderate depression determined by PHQ-9 at screening

- Type I diabetes mellitus, or type II diabetes mellitus that is not controlled with
oral agents and/or insulin (i.e.: subjects with a history of diabetes mellitus and
HA1C of > 9 in the last 3 months or at screening).

- Prior diagnosis of multiple sclerosis or other neurodegenerative disorders

- Significant co-existing lab abnormalities including: a) Anemia (Hgb <9.1 mg/dl men,
<8.9 mg/dl women); b) Ongoing coagulopathy/clotting disorder; c) WBC <2000 cells/µl;
d) Absolute neutrophil count (ANC) <1200 cells/ µl; e) Platelet count <60,000 cells/
µl; f) Liver disease (AST/ALT > 2.5x OR total bilirubin > 1.5x upper limits of norm
(ULN), (if not receiving atazanavir) or direct bilirubin > 0.6 (if receiving
atazanavir); g) Pancreatic disease (amylase : > 1.5 ULN, lipase > 1.5 ULN,
triglycerides > 750 mg/dl); h Renal disease (creatinine > 2x ULN or creatinine
clearance <60mg/dl (by Crockoff-Gault)

- Chronic HCV infection (HCV viremia), or HBV Ag positive and/ or HBV viremia (Notice:
subjects with prior HCV infection with a documented sustained virologic response with
treatment finishing >1 year prior to screening are eligible for enrollment).

- Liver cirrhosis or hepatic decompensation with Child Pugh score > 6

- History of major organ transplantation with an existing functional graft.

- Evidence of OI or other active infectious diseases or active malignancies

- Active Autoimmune diseases, including autoimmune hepatitis

- History of retinopathy or clinically significant ophthalmologic disease on eye exam
performed within 60 days prior to initiation of IFN

- Significant EKG abnormalities (see section 7.4)

Other conditions

- Pregnancy or breastfeeding

- A planned pregnancy during study participation

- Lack of one of three strategies for birth control during study participation: a)
Barrier contraceptives (male or female condoms with or without a spermicidal agent,
diaphragm or cervical cap with spermicidal); b) Non-hormonal Intrauterine Devices
(IUDs); c) Hormonal-based, including hormonal IUDs, in combination with barrier
contraceptives.

- Body weight < 125 lbs or > 300 lbs

- Other conditions, such as active drug/alcohol abuse or dependence,that in the opinion
of the Investigator would interfere with study compliance.