Long-Acting Cabotegravir Plus VRC01LS for Viral Suppression in Adults Living With HIV-1

This study will assess the safety, tolerability, pharmacokinetics, and antiviral activity of
long-acting cabotegravir (CAB LA) plus the broadly neutralizing monoclonal antibody,
VRC-HIVMAB080-00-AB (VRC01LS), in adults living with HIV-1 with suppressed plasma viremia.

The study will be conducted in three steps. At Step 1 entry, all participants will
discontinue their current antiretroviral therapy (ART) regimen except for nucleoside reverse
transcriptase inhibitors (NRTIs), and initiate oral CAB.

During Step 1, participants tolerating oral CAB plus their current two NRTIs, and displaying
viral suppression (HIV-1 RNA <50 copies/mL), will register to Step 2. At entry into Step 2,
eligible participants will stop their oral CAB and NRTIs and will receive a VRC01LS infusion
plus CAB LA injection. After entry in Step 2, participants will receive CAB LA every 4 weeks
through Week 44 plus VRC01LS every 12 weeks through Week 36.

At the last visit in Step 2 (Week 48), or at premature study treatment discontinuation, all
participants who received any CAB LA or VRC01LS will enter Step 3 and switch to standard of
care (SOC) oral ART for 48 weeks.

Participants will attend a number of study visits throughout the study. Study visits may
include a physical examination, clinical assessment, pregnancy testing, and blood and urine
collection. Participants will remain in the study for approximately 101 weeks, including
approximately 5 weeks in Step 1, 48 weeks in Step 2, followed by 48 weeks in Step 3.

Step 1 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 Food and Drug Administration
(FDA)-approved kit, which is required for all IND studies.

- World Health Organization (WHO) and Centers for Disease Control and Prevention
(CDC) 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 (e.g., indirect versus competitive), or a Western blot or a plasma
HIV-1 RNA viral load.

- Clinically stable for at least 8 weeks prior to study entry on a three-drug ART
regimen that includes a boosted protease inhibitor, a nonnucleoside reverse
transcriptase inhibitor (NNRTI), or an integrase inhibitor, plus two NRTIs, with no
history of a switch due to virologic failure.

- NOTE: Previous switches for reasons other than virologic failure prior to
screening are allowed.

- Screening CD4+ cell count greater than or equal to 350 cells/mm^3 obtained within 60
days prior to study entry at any US laboratory that has a Clinical Laboratory
Improvement Amendments (CLIA) certification or its equivalent.

- All available HIV-1 RNA measurements must be less than 50 copies/mL within the 2 years
prior to study entry except as allowed by the note below.

- NOTE: A single plasma HIV-1 RNA greater than or equal to 50 copies/mL but less
than 200 copies/mL is allowed if followed by a subsequent HIV-1 RNA value below
50 copies/mL.

- Participants must have at least two documented HIV-1 RNA less than 50 copies/mL within
12 months prior to study entry.

- NOTE: The HIV-1 RNA level obtained at the screening visit can be used as the
second measurement, but must meet the requirements of screening plasma HIV-1 RNA
criterion below.

- Screening plasma HIV-1 RNA less than 40 copies/mL by any FDA-approved assay with
minimum limit of detection of 40 copies/mL or lower obtained within 60 days prior to
study entry by any US laboratory that has a CLIA certification or its equivalent.

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

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

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

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

- Calculated creatinine clearance (Cockcroft-Gault formula) greater than or equal
to 50 mL/min

- Aspartate aminotransferase (AST) (SGOT) less than or equal to 2.0 x ULN

- Alanine aminotransferase (ALT) (SGPT) less than or equal to 2.0 x ULN

- For females of reproductive potential, negative serum or urine pregnancy test within
48 hours prior to entry by any clinic or laboratory that has a CLIA certification or
its equivalent, or is using a point of care (POC)/CLIA-waived test.

- NOTE A: Reproductive potential is defined as girls who have reached menarche and
women who have had menses within the prior 12 months, and have not undergone
surgical sterilization. If no menses for a year or longer, the
follicle-stimulating hormone (FSH) should be less than or equal to 40 IU/mL to be
considered of reproductive potential. If an FSH is not available, and they have
not had menses in 24 or more consecutive months, they would be considered not to
be of reproductive potential. Women who have undergone surgical sterilization
(e.g., hysterectomy, bilateral oophorectomy, tubal micro-inserts, tubal ligation
or salpingectomy) are considered not to be of reproductive potential.

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

- Female participants of reproductive potential, who are participating in sexual
activity that could lead to pregnancy, must agree to use an effective form of
contraception from 30 days prior to the first dose of study medication, while
receiving the study drugs, and for 30 days after stopping oral medications, or
the duration specified in the product label if receiving study drugs not supplied
by the study, or for 52 weeks after last dose of CAB LA or VRC01LS. Acceptable
methods of contraception include:

- Contraceptive subdermal implant

- Intrauterine device or intrauterine system

- Combined estrogen and progestogen oral contraceptive

- Injectable progestogen

- Contraceptive vaginal ring

- Percutaneous contraceptive patches

- Women who are not of reproductive potential are eligible to start study drugs
without requiring the use of contraceptives. Refer to above criterion for
definition of female who is not of reproductive potential.

- NOTE: All participants in the study should be counseled on safer sexual practices
including the use and benefit/risk of effective barrier methods (e.g., male
condom) and on the risk of HIV transmission to an uninfected partner.

- Men and women aged greater than or equal to 18 years.

- Ability and willingness of participant to provide written informed consent.

- Negative HBsAg results obtained within 60 days prior to study entry.

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

- Susceptibility to VRC01LS based on IC50 less than or equal to 1.0 µg/mL using the
Monogram Phenosense Assay on sample obtained at the screening visit.

- Adequate venous access in at least one arm.

- Willingness to continue current two NRTIs and have continued access to NRTIs in Step
1.

- NOTE: NRTIs will not be provided by the study. Participants without continued
access to NRTIs will be provided reimbursement for these drugs by the study.

- Willingness to not actively engage in the conception process for the duration of the
study.

Step 1 Exclusion Criteria

- Any 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 prior to 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 prior to study entry.

- Vaccinations within 7 days prior to study entry.

- NOTE: Participants are encouraged to get routine vaccinations, such as seasonal
influenza vaccine outside this window. If vaccination occurs within 7 days prior
to study entry, the entry visit should be postponed for at least 7 days after the
vaccination.

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

- Personal or known family history of prolonged QT syndrome or a clinically significant
finding on the screening electrocardiogram (ECG).

- Unstable liver disease (as defined by the presence of ascites, encephalopathy,
coagulopathy, hypoalbuminemia, esophageal or gastric varices, or persistent jaundice),
known biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic
gallstones).

- Moderate or severe hepatic impairment (Class B or C) as determined by Child-Pugh
classification.

- History of seizures or treatment for seizures within the past 2 years prior to study
entry.

- NOTE: For candidates with a remote (greater than 2 year) history of seizure,
consult the A5357 protocol core team for eligibility determination.

Step 2 Inclusion Criteria

- HIV-1 RNA less than 50 copies/mL at week 4 (Step 1), or HIV-1 RNA of 50-199 copies/mL
at week 4 followed by HIV-1 RNA less than 50 copies/mL at week 5 (Step 1).

- Females of reproductive potential must have a negative serum or urine pregnancy test
obtained within 48 hours prior to Step 2 registration.

- NOTE: Refer to the criteria above for definition of reproductive potential and
acceptable documentation.

- Female participant agrees to continue to use an effective form of contraception (see
criterion above) while on study, and for 52 weeks after last dose of CAB LA or
VRC01LS.

- Willingness to not actively engage in the conception process for the duration of the
study.

Step 2 Exclusion Criteria

- Discontinuation or temporary hold of oral CAB for greater than 7 consecutive days for
any reason during Step 1.

- Discontinuation or temporary hold of NRTIs for greater than 7 consecutive days for any
reason during Step 1.

- Grade 3 or 4 adverse event thought to be related to oral CAB during Step 1 according
to the site investigator.

- Vaccination (e.g., influenza) within 7 days prior to the Step 2 registration.

- NOTE: Vaccination should also be avoided when possible within 7 days of the week
44 and week 48 visits.

- Currently breastfeeding or pregnant.

- Any greater than or equal to Grade 2 ALT (greater than 2.5 times ULN) that developed
during Step 1.

Step 3 Inclusion Criterion

- Received any CAB LA or VRC01LS during Step 2.

- NOTE: Participants who prematurely discontinue study treatment for any reason in
Step 2 remain eligible for Step 3.

Step 3 Exclusion Criterion

- There are no exclusion criteria to Step 3.