Evaluating the Safety, Tolerability, and Effect of a Human Monoclonal Antibody (VRC01) on Markers of HIV Persistence in HIV-Infected Adults Receiving Antiretroviral Therapy (ART)

Monoclonal antibodies (mAbs) have been developed as treatment for a variety of conditions
including cancer, autoimmune disorders, and infections. mAbs may also be a potential
treatment for people infected with HIV. The purpose of this study was to evaluate the safety
and tolerability of an experimental human mAb, VRC-HIVMAB060-00-AB (VRC01), in HIV-infected
adults receiving ART. Study researchers will also evaluate the effect of VRC01 on the number
of infected cells containing unspliced HIV-1 transcripts in the blood in participants.

This study enrolled HIV-infected people 18 to 65 years old, who had been receiving ART for at
least 2 years and who had a CD4+ count of 200 cells/mm^3 or greater. Participants were
randomly assigned to Arm A or Arm B. Participants in Arm A received an intravenous (IV)
infusion of VRC01 at Day 0 and Week 3 and an IV infusion of placebo (normal saline) at Weeks
6 and 9. Participants in Arm B received an IV infusion of placebo (normal saline) at Day 0
and Week 3 and an IV infusion of VRC01 at Weeks 6 and 9. Participants recorded their
temperature and symptoms for 3 days after each infusion. Study visits occured at study entry
(Day 0), and Weeks 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 15, 18, and 30. Study visits
included physical examinations, clinical assessments, and blood collection.

The primary safety outcome for this study was descriptive and assessed the occurrence of
Grade ≥ 3 AEs including signs/symptoms, lab toxicities, and/or clinical events that are
possibly, probably, or definitely related to study treatment (as judged by the core team,
blinded to treatment arm) at any time from the initial dose of study treatment to the end of
study follow-up. Since this outcome is descriptive, no statistical significance testing was
performed.

Inclusion Criteria:

- HIV-1 infection, documented by any FDA-approved 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 or E/CIA tests, or by HIV-1 antigen, or plasma HIV-1 RNA assay.
More information on this criterion is available in the protocol.

- Received continuous ART for at least 2 years (defined as no interruptions longer than
14 consecutive days) and with no changes in the components of the ART for at least 90
days prior to study entry

- CD4+ cell count greater than or equal to 200 cells/mm^3 obtained within 60 days prior
to study entry in a clinical laboratory improvement amendments (CLIA)-certified
laboratory

- Plasma HIV-1 RNA below the limit of detection of the FDA-approved assays (limit of
detection: 75, 50, 40 or 20 copies/mL) for greater than or equal to 2 years on ART.
Participants must have had at least one documented HIV-1 RNA less than the limit of
detection 12-24 months prior to study entry and at least one HIV-1 RNA less than the
limit of detection within 12 months prior to study entry. All available HIV-1 RNA
measurements must have been below the assay limit of detection during the 2 years
prior to study entry except as allowed by the following note. NOTE: A single
unconfirmed plasma HIV-1 RNA greater than the limit of detection but less than 200
copies/mL within 6-24 months was allowed if followed by a subsequent value below the
limit of detection.

- Plasma HIV-1 RNA level of less than 40 copies/mL obtained by the Abbott Real-time HIV
assay (m2000) or less than 20 copies/mL obtained by the Roche COBAS Taqman HIV-1 v2.0
assay within 60 days prior to entry

- The following laboratory values obtained within 60 days prior to entry by any U.S.
laboratory that has a CLIA certification or its equivalent.

- Absolute neutrophil count (ANC) greater than or equal to 750 cells/mm^3

- Hemoglobin greater than or equal to 11.0 g/dL for men and greater than or equal
to 10.0 g/dL for women

- Platelet count greater than or equal to 100,000/mm^3

- Creatinine clearance greater than or equal to 60 mL/min estimated by the
Cockcroft-Gault equation. NOTE: A program for calculating creatinine clearance by
the Cockcroft-Gault method is available on www.fstrf.org.

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) (SGPT) less
than or equal to 2.0 times upper limit of normal (ULN)

- Hepatitis C virus (HCV) antibody negative result within 60 days prior to study entry
or, if the HCV antibody result is positive, a negative HCV RNA result within 60 days
prior to study entry

- Negative HBsAg result obtained within 60 days prior to study entry

- Ability and willingness of participant to provide informed consent

- Females of reproductive potential (women who have not been post-menopausal for at
least 24 consecutive months, i.e., who have had menses within the preceding 24 months,
or women who have not undergone surgical sterilization, specifically hysterectomy, or
bilateral oophorectomy and/or bilateral salpingectomy), needed a negative serum or
urine pregnancy test within 48 hours prior to study entry. NOTE: Acceptable
documentation of hysterectomy and bilateral oophorectomy, bilateral salpingectomy,
tubal micro-inserts, partner who has undergone vasectomy, and menopause is
participant-reported history.

- All participants must have agreed not to participate in the conception process (e.g.,
active attempt to become pregnant or to impregnate, sperm donation, in vitro
fertilization), and if participating in sexual activity that could lead to pregnancy,
the participant/partner must use at least one reliable form of contraception (condoms,
with or without a spermicidal agent; a diaphragm or cervical cap with spermicide; an
intrauterine device (IUD); or hormone-based contraceptive), while receiving study
treatment and for 12 weeks after stopping study treatment

- Documentation of the availability of the following stored samples from the screening
visit: peripheral blood mononuclear cell (PBMC) for CD4+ T-cell associated HIV-1 RNA,
DNA assay and plasma for HIV-1 SCA. Sites must receive confirmation from the
processing lab via phone, email, or fax, that specimens have been entered into the
AIDS Clinical Trials Group (ACTG) Laboratory Data Management System (LDMS).

Exclusion Criteria:

- Previous receipt of humanized or human monoclonal antibody (licensed or
investigational)

- Weight greater than 115 kg or less than 53 kg

- Acute or ongoing AIDS-defining illness within 60 days prior to study entry

- History of a severe allergic reaction with generalized urticarial, angioedema, or
anaphylaxis within 2 years of study entry

- Currently breastfeeding or pregnant

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

- Acute or serious illness that, in the opinion of the site investigator, requires
systemic treatment and/or hospitalization within 60 days prior to entry

- Use of immunomodulators (e.g., interleukins, interferons, cyclosporine), HIV vaccine,
systemic cytotoxic chemotherapy, or investigational therapy within 60 days prior to
study entry. NOTE: Participants receiving stable physiologic doses of glucocorticoids,
defined as the equivalent of prednisone less than or equal to 10 mg/day, will not be
excluded. Stable physiologic glucocorticoid doses should not be discontinued for the
duration of the study. In addition, participants receiving inhaled or topical
corticosteroids will not be excluded.

- Treatment for hepatitis C within 24 weeks of study entry

- Vaccinations within 7 days prior to the screening, pre-entry, or study entry visits.
NOTE: Participants are encouraged to get routine vaccinations, such as seasonal
influenza vaccine more than 7 days prior to screening or between screening and
pre-entry visits (outside of the 7-day window above).

- Initiation of ART during acute HIV-1 infection (as determined by the site investigator
by history and/or available medical records)