Integrase and Maraviroc Intensification in Neurocognitive Dysfunction (InMIND)

HIV-infected people often have cognitive dysfunction (HIV-associated neurocognitive disorder,
or HAND), which includes asymptomatic neurocognitive impairment (ANI), mild neurocognitive
disorder (MND), and HIV-associated dementia (HAD), even if they are on ART and have
undetectable viral loads. In this study, researchers will evaluate the effectiveness of
adding MVC and DTG to the current ART regimen of HIV-infected people with undetectable (<50
copies/mL) plasma HIV-1 RNA who have mild to moderate neurocognitive impairment and who have
been on stable ART for at least 6 months prior to study entry. The purpose of this study is
to evaluate if the addition of MVC and DTG to participants' existing ART regimens will
improve participants' neurocognitive performance.

Participants will be randomly assigned to one of three arms. All participants will remain on
their existing ART regimens; they will take their assigned study drugs in addition to their
ART regimen. Participants in Arm A will receive placebo for MVC and placebo for DTG.
Participants in Arm B will receive DTG and placebo for MVC. Participants in Arm C will
receive MVC and DTG. Study visits will occur at entry and Weeks 2, 4, 12, 24, 48, 72, and 96.
Visits may include physical examinations, blood collection, neurocognitive testing, pregnancy
testing, and questionnaires. Some participants may have an optional lumbar puncture
procedure. Participants will have to return for refills of study drugs on Weeks 36, 60, and
84.

Inclusion Criteria:

- HIV-1 infection, documented by:

- a 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 or plasma HIV-1 RNA viral load. NOTE: The term
"licensed" refers to a United States Food and Drug Administration (FDA)-approved
kit, which is required for all IND studies, or for sites located in countries
other than the United States, a kit that has been certified or licensed by an
oversight body within that country and validated internally. Non-US sites are
encouraged to use US FDA-approved methods for 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. OR

- Documentation of HIV diagnosis in the medical record by a healthcare provider.

- On current ART for at least 6 months prior to study entry with no interruption in
treatment of greater than or equal to 7 consecutive days. Note: The following ART
changes are allowed:

- Tenofovir disoproxil fumarate (TDF) to tenofovir alafenamide fumarate
(TAF)/TAF-containing fixed-dose combination regimens

- Ritonavir (RTV) to cobicistat (COBI)/COBI-containing fixed-dose combination
regimens

- No plans to change ART while on study. Note: The following planned ART changes are
allowed:

- TDF to TAF/TAF-containing fixed-dose combination regimens

- RTV to COBI/COBI-containing fixed-dose combination regimens

- HIV-1 plasma RNA less than 50 copies/mL obtained within 90 days prior to study entry
by any FDA-approved assay at any United States laboratory that has a Clinical
Laboratory Improvement Amendments (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.

- No more than one HIV-1 plasma RNA greater than or equal to 50 and less than 200
copies/mL (only one "blip") in the past 6 months with a subsequent HIV-1 plasma RNA
less than 50 copies/mL. NOTE: There should be no plasma HIV-1 RNA greater than 200
copies/mL within the 6 months prior to study entry.

- HAND diagnosis (ANI, MND, or HAD) within 60 days prior to study entry. HAND is defined
as at least mild impairment on neurocognitive testing (more than one standard
deviation below appropriate normative data in two domains of functioning) and no
severely confounding factors.

- Screening laboratory values obtained within 60 days prior to study 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 GCLP and participates in
appropriate external quality assurance programs:

- Absolute neutrophil count (ANC) greater than or equal to 500/mm^3

- Hemoglobin greater than or equal to 7.5 g/dL

- Platelet count greater than or equal to 40,000/mm^3

- Creatinine less than or equal to 2.0 x upper limit of normal (ULN)

- Aspartate transaminase (AST) less than or equal to 5 x ULN

- Alanine transaminase (ALT) less than 3 x ULN

- Alkaline phosphatase less than or equal to 5 x ULN

- Total bilirubin less than 1.5 x ULN. NOTE: If the potential participant is taking
an indinavir (IDV)- or atazanavir (ATV)-containing regimen at the time of
screening, total bilirubin less than or equal to 5 x ULN is acceptable.

- Creatinine clearance (CrCl) greater than or equal to 60 mL/min, either measured
or estimated by Cockcroft-Gault equation. NOTE: A calculator for estimating the
CrCl can be found at www.fstrf.org/ACTG/ccc.html

- Females of reproductive potential (women who have not been post-menopausal for at
least 24 consecutive months, ie, who have had menses within the preceding 24 months,
or women who have not undergone surgical sterilization, hysterectomy or bilateral
salpingectomy or bilateral oophorectomy or tubal ligation) must have a negative serum
or urine pregnancy test by any US clinic or laboratory that has a CLIA certification
or its equivalent, or is using a point of care (POC) / CLIA-waived test, or at any
network-approved non-US laboratory or clinic that operates in accordance with GCLP and
participates in appropriate external quality assurance programs within 48 hours prior
to study entry

- Females of reproductive potential must agree not to participate in the conception
process (ie, active attempt to become pregnant, in vitro fertilization), and if
participating in sexual activity that could lead to pregnancy, must use at least one
reliable form of contraception. Female participants must use contraceptives while
receiving study treatment and for 6 weeks after stopping study treatment. More
information on this criterion is available in the protocol.

- Men and women 18 years of age and older who are able to complete the
neuropsychological tests

- Ability and willingness of participant or a legally authorized representative (see
protocol for more information) to provide informed consent

- Ability and willingness to take oral study medications

Exclusion Criteria:

- Current or past medical condition(s) that in the opinion of the investigator prevents
attribution of the cause of cognitive impairment to HIV. For example:

- Major depressive disorder with psychotic features

- Traumatic Brain Injury (TBI) with a clear impact on activities of daily living

- Developmental delay, intellectual deficit, and/or severe educational disability
resulting in some dependence for activities of daily living

- Ongoing substance use disorder with significant impact on activities of daily
living. Difficult or impossible to determine whether cognitive or functional
decline is due to substance use or HIV, or both

- Evidence of intoxication or withdrawal during the screening evaluation

- Central nervous system (CNS) infections or opportunistic conditions: brain
abscess (bacterial, mycobacterial, fungal or Toxoplasma), meningitis with
persistent neurologic impairment, primary CNS lymphoma, progressive multifocal
leukoencephalopathy (PML), or another structural brain lesion with neurological
sequelae

- Other CNS conditions: non-opportunistic primary or metastatic brain tumors,
uncontrolled seizure disorder, progressive multiple sclerosis, stroke with
neurological sequelae, or dementia due to causes other than HIV (eg, Alzheimer's
disease)

- Constitutional illness (eg, persistent unexplained fever, diarrhea, significant
weight loss, disabling weakness) within 30 days of screening

- Known untreated B12 deficiency or malnutrition (body mass index [BMI] less than
18) at screening

- Evidence of current hepatitis C virus infection (HCV) (ie, HCV antibody [Ab] positive
within 90 days prior to study entry unless also shown to be plasma HCV RNA negative
within the same time period)

- Unstable and advanced liver disease (as defined by the presence of at least one of the
following: ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or
gastric varices, or persistent jaundice)

- Prior or current use of any CCR5 antagonist (such as MVC and cenicriviroc [CVC]) and
integrase inhibitor (such as RAL, DTG, and elvitegravir [EVG])

- Current use of any medication, including antiretrovirals, prohibited in the study
(refer to the A5324 protocol-specific web page [PSWP] for the prohibited medications)

- Breastfeeding

- Presence of an AIDS-defining opportunistic infection within 6 months prior to entry.
Note: Refer to the A5324 Manual of Operations (MOPS) for the list of AIDS-defining
opportunistic infections.

- Active syphilis or treatment for syphilis within 90 days prior to study entry. NOTE:
Active syphilis is defined as four-fold increase in serum rapid plasma reagin (RPR) or
venereal disease research laboratory (VDRL) tests in an individual with past syphilis,
or newly reactive serum RPR or VDRL with a reactive confirmatory test (enzyme
immunoassays [EIA] or chemiluminescent assay [CIA], T. pallidum particle agglutination
[TP-PA], or fluorescent treponemal antibody absorbed [FTA-ABS]).

- Known allergy/sensitivity or any hypersensitivity to components of study drugs or
their formulation