Safety and Efficacy of Sirolimus for HIV Reservoir Reduction in Individuals on Suppressive ART

Inclusion Criteria:

- HIV-1 infection, documented by any licensed rapid HIV test or HIV enzyme or
chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and
confirmed by a licensed Western blot or a second antibody test by a method other than
the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, plasma HIV-1 RNA viral load.

NOTE: The term "licensed" refers to a US FDA-approved kit, which is required for all
investigational new drug (IND) studies.

WHO (World Health Organization) and CDC (Centers for Disease Control and Prevention)
guidelines mandate that confirmation of the initial test result must use a test that is
different from the one used for the initial assessment. A reactive initial rapid test
should be confirmed by either another type of rapid assay or an E/CIA that is based on a
different antigen preparation and/or different test principle (eg, indirect versus
competitive), or a Western blot or a plasma HIV-1 RNA viral load.

- Currently on continuous ART for ≥24 months prior to study entry. This is defined as
continuous active therapy for the 24-month period prior to study entry with no
treatment interruption longer than 5 consecutive days and a total duration off
treatment of no more than 7 days in the 90 days prior to study entry.

- CD4+ cell count ≥400 cells/mm3 obtained within 60 days prior to study entry at any US
laboratory that has a CLIA certification or its equivalent, or at any network-approved
non-US laboratory that operates in accordance with Good Clinical Laboratory Practices
(GCLP) and participates in appropriate external quality assurance programs.

- Plasma HIV-1 RNA below the level of quantification (eg, <20, <40, <50, or <75
copies/mL depending on the assay) for ≥24 months by any US laboratory that has a CLIA
certification or its equivalent, or at any network-approved non-US laboratory that
operates in accordance with GCLP and participates in appropriate external quality
assurance programs. Participants must have at least one documented HIV-1 RNA below the
level of quantification obtained 12-24 months prior to screening and one HIV-1 RNA
less than the level of quantification obtained within 12 months prior to the screening
HIV-1 RNA.

NOTE:

- One month = 30 days.

- Plasma HIV-1 RNA measurements above the limit of quantification but <200 copies/mL in
the 24 months prior to screening are allowed if directly followed by HIV-1 RNA below
assay limit, but none in the 6 months prior to screening.

- Plasma HIV-1 RNA level of <40 copies/mL obtained by the Abbott real time assay or
<20 copies/mL by the Roche COBAS TaqMan HIV-1 Test, Version 2.0 assay within 60
days prior to study entry at any laboratory that has a CLIA certification or its
equivalent.

- For females of reproductive potential (defined as women who have not been
postmenopausal for at least 24 consecutive months or documentation that the woman
has undergone hysterectomy, bilateral oophorectomy, or salpingectomy), negative
serum or urine pregnancy test within 48 hours prior to study entry.

NOTE: Patient-reported history is acceptable documentation of hysterectomy and bilateral
oophorectomy, tubal ligation, tubal micro-inserts, vasectomy, and menopause.

- Females of reproductive potential who are participating in sexual activity that could
lead to pregnancy must agree to initiate effective contraceptives before sirolimus
therapy, continue use during sirolimus therapy, and maintain use for at least 12 weeks
after sirolimus therapy has been stopped.

Female subjects and/or their male partners MUST agree to use appropriately at least one of
the following:

- Condoms (male or female) with or without a spermicidal agent

- Diaphragm or cervical cap with spermicide

- Intrauterine device (IUD)

- Tubal ligation

- Hormone-based contraceptive

NOTE:

- Sexual activity with an infertile partner is not sexual activity that can lead to
pregnancy.

- Females on hormone-based contraceptives at study entry must have been on the same
method for at least 90 days prior to study entry.

- Ability and willingness of subject or legal guardian/representative to provide
informed consent.

- Laboratory evaluations obtained within 60 days prior to entry by any US
laboratory that has a CLIA certification or its equivalent, or at any
network-approved non-US laboratory that operates in accordance with GCP and
participates in appropriate external quality assurance programs.

- White blood cell (WBC) ≥3000/mm3

- Platelet count ≥125,000/mm3

- ANC >1300/mm3

- Aspartate aminotransferase (AST) <1.25 x ULN

- Alanine aminotransferase (ALT) <1.25 x ULN

- Calculated creatinine clearance (CrCl) ≥60 mL/min as estimated by the Cockcroft-Gault
equation:

For men, (140 - age in years) x (body weight in kg) ÷ (serum creatinine in mg/dL x 72) =
CrCl (mL/min)*

- For women, multiply the result by 0.85 = CrCl (mL/min) NOTE: A program to assist in
calculations is available on the DMC website at: http://www.fstrf.org/ACTG/ccc.html

- Fasting or non-fasting triglyceride level ≤350 mg/dL

- Fasting or non-fasting LDL <160 mg/dL

- Urine protein to urine creatinine ratio ≤1 gram from random urine collection

Exclusion Criteria:

- Serious illness requiring systemic treatment and/or hospitalization until subject
either completes therapy or is clinically stable on therapy in the opinion of the site
investigator for at least 30 days prior to study entry.

- Documentation of any CDC Category C AIDS-indicator condition or oropharyngeal
candidiasis (thrush) within 90 days prior to study entry.
(http://www.cdc.gov/mmwr/preview/mmwrhtml/00018871.htm)

- Intended modification of ART during the study.

- Latent tuberculosis (TB) infection defined as a positive PPD ≥5 mm or positive
interferon-gamma release assay (IGRA) at any time in the past or evidence of latent TB
on the screening chest x-ray without subsequent INH or equivalent antibiotic
prophylaxis.

NOTE: Prophylaxis must have been completed at least 48 weeks prior to study entry.

- TB disease within 48 weeks prior to study entry requiring treatment. Subjects with a
history of active TB must have completed treatment at least 48 weeks prior to study
entry.

- History of or current (within 90 days prior to study entry) active hepatitis B (HBV)
infection defined as positive HBV surface antigen test or positive HBV DNA in subjects
with isolated HBcAb positivity.

- HCV RNA-positive within 90 days prior to study entry.

NOTE: Subjects who are HCV antibody negative within 90 days prior to study entry are
eligible for the study. Those who are not taking HCV therapy and who are HCV
antibody-positive but HCV RNA negative within 90 days prior to study entry are eligible for
the study.

- Previously diagnosed myelodysplasia syndrome.

- History of lymphoproliferative disease prior to study entry.

- Clinically significant lung disease on the screening chest x-ray that, in the opinion
of the site investigator, places the subject at increased risk of lung toxicity (eg,
history of pulmonary fibrosis, interstitial lung disease, or pulmonary
lymphoproliferative disease).

- Any prior or current diagnosis of solid tumor or hematologic malignancies, including
localized skin cancers with or without evidence of metastasis.

- History of congestive heart failure as defined by physician documentation in the
medical record at any time prior to screening that required medication for heart
failure, or that required medical management within 2 years prior to study entry.

- Detectable Epstein-Barr virus (EBV) in blood by polymerase chain reaction (PCR) within
90 days prior to study entry at any US laboratory that has a CLIA certification or its
equivalent.

- Active infection other than HIV that required receipt of systemic antibiotic therapy
by intravenous infusion within 90 days prior to study entry.

- Life-threatening fungal infection that in the opinion of the site investigator
requires treatment within 48 weeks prior to study entry.

- Herpes-zoster or varicella-zoster viral infection requiring treatment within 90 days
prior to study entry or currently on suppressive therapy.

- History of major hypersensitivity reaction to macrolide drugs including angioedema,
anaphylaxis, drug-induced dermatitis, or hypersensitivity vasculitis.

- Currently pregnant or breastfeeding, or planning to become pregnant prior to or during
the study.

- Use of immunomodulators (eg, interleukins, interferons, and cyclosporine), HIV
vaccine, systemic cytotoxic chemotherapy, or investigational therapy within 90 days
prior to study entry.

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

- Vaccination (eg, pneumococcal polysaccharide/influenza vaccine) within 14 days prior
to study entry.

NOTE: If subjects receive influenza vaccination for routine clinical care during or prior
to the screening visit, they may be rescreened 14 days after vaccination.

- On a PI-based ART or cobicistat-boosted regimen within 90 days prior to study entry or
plans to change to a PI-based or cobicistat-boosted regimen during the study.

NOTE: Prior PI-based or cobicistat-boosted regimens are allowed.

- Anal or perianal administration of anti-HPV therapies (eg, imiquimod, 5FU, veregen)
for 90 days prior to study entry or plans to initiate anti-HPV therapies during the
study.