Effect of Cenicriviroc on HIV Neurocognitive Impairment

HIV-associated neurocognitive disease (HAND), particularly in its milder form, is estimated
to occur in greater than 30% of HIV infected individuals in the era of potent antiretroviral
therapy. As even mild disease leads to functional consequences with decreased ability to live
independently, HAND is of substantial public health concern. HIV-induced immune
activation/inflammation of monocytes (MO) may be primarily responsible for the development of
HAND.

Cenicriviroc is a combined CCR5 and CCR2 chemokine co-receptor antagonist. The investigators
hypothesize that dual CCR5 and CCR2 blockade with the use of CVC will lead to measurable
reductions in MO activation and lead to cognitive improvement by decreasing HIV infection of
MO and by interrupting the trafficking of such MO into the central nervous system.

The investigators propose a single arm, 24-week trial of CVC in 24 subjects with HIV-1
infection suppressed on ART (plasma HIV RNA < 50 copies/ml) for 1 year or more with mild to
moderate cognitive impairment.

Inclusion Criteria:

- 4.2.1.1 Documentation of HIV-1 infection by an FDA approved test at any time prior to
study entry

- On ARV medication uninterrupted for > 1 year leading up to the screening period

- Screening plasma HIV RNA < 50 copies/ml within 3 months of entry

- Willingness for males and females of childbearing potential to utilize 2 effective
contraception methods (2 separate forms, one of which must be an effective barrier
method), be non-heterosexually active or have a an exclusive vasectomized partner from
screening throughout the duration of the study treatment and for 30 days following the
last dose of study drugs.

- Age 18 to 70 years

- Ability and willingness to provide written informed consent

- Mild to moderate cognitive impairment with global neuropsychological (NP) test
(NPZglobal) score of < -0.5 or a neurocognitive abnormality (<-0.5) in at least one
cognitive domain known to be typically affected by HIV OR unimpaired

- On antiretroviral (ARV) therapy consisting of nucleoside reverse transcriptase
inhibitors, atazanavir with/or without ritonavir, darunavir plus ritonavir,
dolutegravir, raltegravir or efavirenz.

Exclusion Criteria:

- Receiving or used a CCR5 antagonist within 6 months of study entry

- Plasma HIV RNA > 100 copies/ml within 6 mo. of screening

- HIV-2

- Chronic hepatitis B (positive hepatitis B surface antigen)

- Chronic hepatitis C (positive hepatitis C antibody), except with proof of viral
clearance and normal liver function tests

- Active or chronic liver disease

- Active or inadequately treated tuberculosis infection, or inadequate treatment for a
positive purified protein derivative test. Adequate treatment meets current
recommendations of the Center for Disease Control, NIH and the HIV Medicine
Association of the Infectious Diseases Society of America (IDSA) guidelines or other
Center for Disease Control recommendations if patient was treated before the current
recommendations or before coinfection with HIV.

- Prior/current diagnosis with other intracellular pathogens (Listeria monocytogenes,
Toxoplasma gondii, and Cryptococcus neoformans).

- Uncontrolled seizures

- Current or past malignancies excluding basal cell cancer and Kaposi's sarcoma (skin).

- Immunomodulator, HIV vaccine, any other vaccine, or investigational therapy within 30
days of entry.

- Requirement for acute therapy for AIDS-defining or other serious medical illnesses
within 14 days of entry.

- Other chronic illnesses including hematologic, pulmonary, autoimmune diseases and
endocrinopathies, except for stable controlled diabetes or cardiovascular disease in
the view of the investigator and stable testosterone or thyroid therapy.

- Known hypersensitivity to CVC or its excipients

- Anticipated need for prescription medication not allowed in the study. Unwilling to
stop eating grapefruit or using St. John's wort).

- Chronic use of over the counter medications unless approved by Study Investigator

- Hemoglobin < 8.5; Absolute neutrophil count < 1000; Platelet count < 100,000; serum
glutamate oxaloacetate and pyruvate transaminase > 2.5x upper limit of normal ; Lipase
> 2.0 x upper limit of normal

- Estimated creatinine clearance < 30 mL/min(Cockcroft and Gault 1979)

- Bradycardia, sinus rhythm <50 beats/min (bpm).

- Presence of any condition that would interfere with the absorption, distribution,
metabolism, or excretion of the drug

- Current active illicit substance or alcohol use or abuse which, in the judgment of the
Investigator, will interfere with the patient's ability to comply with protocol
requirements

- Pregnancy or breast-feeding

- History of moderate (Child-Pugh class B) or severe (Child-Pugh C) hepatic impairment

- Patients, who, in the opinion of the Investigator, are unable to comply with the
dosing schedule and protocol evaluation or for whom the study may not be advisable

- For MRI substudy [impaired]: Any factor that precludes MRI scan including presence of
metal or exposure to metal work (e.g. metal grinder/worker) and claustrophobia

- For MRI substudy [impaired]: Any central nervous system pathology which, in the
judgment of the investigator, will interfere with the ability to assess study change
in magnetic resonance spectroscopy

- 4.2.2.28 For lumbar puncture substudy: Thrombocytopenia or other bleeding disorders
(including ongoing anticoagulant therapy), suspected increased intracranial pressure
or spinal epidural abscess, or any other factor which would increase risk of
complications following lumbar puncture