Evaluating the Use of Pitavastatin to Reduce the Risk of Cardiovascular Disease in HIV-Infected Adults

Currently, there are few strategies to prevent CVD in HIV-infected people, even though they
are at high risk for developing CVD. Statin medications are used to lower cholesterol and may
be effective at reducing the risk of CVD in people infected with HIV. The purpose of this
study is to evaluate the use of pitavastatin to reduce the risk of CVD in adults infected
with HIV who are on ART.

This study will enroll adults infected with HIV who are on any ART regimen (ART is not
provided by the study) for at least 6 months before study entry considered low-to-moderate
risk using the 2013 American College of Cardiology (ACC)/American Heart Association (AHA)
guideline thresholds for recommended statin initiation. Total study duration will be
approximately 84 months from the time the first participant is enrolled.

Participants will be randomly assigned to receive 4 mg of pitavastatin or placebo once a day
for the entire time they are enrolled in the study. Study visits will occur at study entry
(Day 0) and Months 1 and 4. Starting at Month 4, study visits will occur every 4 months for
the rest of the study. Depending on when participants enroll, they will be in the study for a
total of 3 to 7 years. Study visits will include medical and medication history reviews,
physical examinations, blood collections, assessments and questionnaires, urine collections
(for some participants), and an electrocardiogram (ECG) (at study entry only).

Some participants will have the option of enrolling in a substudy (Effects of Pitavastatin on
Coronary Artery Disease and Inflammatory Biomarkers: Mechanistic Substudy of REPRIEVE
[A5333s]). The substudy will evaluate the effect of pitavastatin on the progression of
non-calcified coronary atherosclerotic plaque (NCP) and inflammatory biomarkers in adults
infected with HIV. Participants in the substudy will attend study visits at study entry and
Months 4 and 24. The visits will include questionnaires and assessments, a blood collection,
and a coronary computed tomography angiography (CCTA). NOTE: The Mechanistic Substudy of
REPRIEVE (A5333s) closed to accrual on 02/06/18.

Participants enrolled in REPRIEVE from select study sites, including international sites,
through December, 2017, are included in the REPRIEVE Kidney Function Objectives Cohort to
evaluate the effects of pitavastatin on parameters of kidney function in the setting of HIV
infection. The analyses will also include an assessment of high risk groups and mechanisms
driving kidney function decline in the setting of HIV infection.

Women and men enrolled in REPRIEVE after February, 2016 are included in an observational
cohort (REPRIEVE Women's Objectives Cohort) facilitating assessment of sex-specific
mechanisms of CVD risk and risk reduction among adults with HIV. This effort also includes an
evidence-based recruitment campaign to enhance women's participation in REPRIEVE.

Inclusion Criteria:

- HIV-1 infected individuals

- Combination antiretroviral therapy (ART) for at least 180 days prior to study entry

- CD4+ cell count greater than 100 cells/mm^3

- Acceptable screening laboratories including a:

- Fasting low-density lipoprotein (LDL) cholesterol as follows: If ASCVD risk score
is less than 7.5%, LDL cholesterol must be less than 190 mg/dL. If ASCVD risk
score is greater than or equal to 7.5% and less than or equal to 10%, LDL must be
less than 160 mg/dL. If ASCVD risk score is greater than 10% and less than or
equal to 15%, LDL must be less than 130 mg/dL. NOTE: If LDL is less than 70
mg/dL, participant is eligible regardless of 10-year ASCVD risk score in line
with the ACC/AHA 2013 Prevention Guidelines.

- Fasting triglycerides less than 500 mg/dL

- Hemoglobin greater than or equal to 8 g/dL for female participants and greater
than or equal to 9 g/dL for male participants

- Glomerular filtration rate (GFR) greater than or equal to 60 mL/min/1.73m^2 or
creatinine clearance (CrCl) greater than or equal to 60 mL/min

- Alanine aminotransferase (ALT) less than or equal to 2.5 x the upper limit of
normal (ULN)

- For persons with known chronic active hepatitis B or C, calculated fibrosis 4 score
(FIB-4) must be less than or equal to 3.25

- Men and women 40 to 75 years of age

- Ability and willingness of participant or legal representative to provide written
informed consent

Exclusion Criteria:

- Clinical ASCVD, as defined by 2013 American College of Cardiology (ACC)/American Heart
Association (AHA) guidelines, including a previous diagnosis of any of the following:

- Acute myocardial infarction (AMI)

- Acute coronary syndromes

- Stable or unstable angina

- Coronary or other arterial revascularization

- Stroke

- Transient ischemic attack (TIA)

- Peripheral arterial disease presumed to be of atherosclerotic origin

- Current diabetes mellitus if LDL is greater than or equal to 70 mg/dL

- 10-year ASCVD risk score estimated by Pooled Cohort Equations greater than 15%

- Active cancer within 12 months prior to study entry.

- NOTE: Exceptions:

- Successfully treated non-melanomatous skin cancer

- Kaposi sarcoma without visceral organ involvement

- Known decompensated cirrhosis

- History of myositis or myopathy with active disease in the 180 days prior to study
entry

- Known untreated symptomatic thyroid disease

- History of allergy or severe adverse reaction to statins

- Use of specific immunosuppressants or immunomodulatory agents including but not
limited to tacrolimus, sirolimus, rapamycin, mycophenolate, cyclosporine, tumor
necrosis factor (TNF)-alpha blockers or antagonists, azathioprine, interferon, growth
factors, or intravenous immunoglobulin (IVIG) in the 30 days prior to study entry.
NOTE: Use of oral prednisone less than or equal to 10 mg/day or equivalent dosage is
allowed.

- Current use of erythromycin, colchicine, or rifampin

- Use of any statin drugs, gemfibrozil, or PCSK9 inhibitors in the 90 days prior to
study entry

- Current use of an investigational new drug that would be contraindicated

- Serious illness or trauma requiring systemic treatment or hospitalization in the 30
days prior to study entry

- Current pregnancy or breastfeeding

- Alcohol or drug use that, in the opinion of the site investigator, would interfere
with completion of study procedures

- Other medical, psychiatric, or psychological condition that, in the opinion of the
site investigator, would interfere with completion of study procedures and or
adherence to study drug