Sitagliptin for Reducing Inflammation and Immune Activation

ACTG A5346 is a phase II, randomized, double-blinded, placebo-controlled, trial of
sitagliptin 100 mg vs. placebo for 16 weeks followed by a 4-week post-intervention follow-up.
A5346 studied whether sitagliptin reduced plasma concentrations of sCD14 in HIV-infected men
and women ≥18 years of age who were on suppressive ART with HIV-1 RNA below the limit of
quantification at screening and for at least the prior 48 weeks. Participants were randomized
1:1 to Sitagliptin arm vs. Placebo arm, and were stratified by screening CD4 count (100-350
vs. >350 cells/mm^3) and statin use (on statins vs. not on statins).

Inclusion Criteria:

- Documented HIV-1 infection.

- Currently on an antiretroviral regimen consisting of at least 2 NRTIs and either a
protease inhibitor boosted with low dose ritonavir, an integrase inhibitor, or an
NNRTI. (Other ART regimens may be acceptable. Sites must consult the protocol team for
approval)

- Currently on continuous ART for ≥48 weeks prior to study entry with no interruption
longer than 7 consecutive days during that period.

- Plasma HIV-1 RNA levels below 75 copies/mL for at least 48 weeks prior to study entry.
The participant must have a minimum of two values in the last 48 weeks obtained >30
days apart, with the most recent value obtained within 90 days prior to entry. (Single
determinations that are between the assay quantification limit and 500 copies/mL
(i.e., "blips") are allowed as long as the preceding and subsequent determinations are
below the level of quantification).

- CD4+ cell count ≥100 cells/mm^3 obtained within 90 days prior to study entry.

- The following laboratory values obtained within 90 days prior to entry.

- Absolute neutrophil count (ANC) ≥750/mm^3

- Hemoglobin ≥8.0 g/dL

- Platelet count ≥50,000/mm^3

- Calculated creatinine clearance (CrCl) ≥60 mL/min as estimated by the
Cockroft-Gault formula NOTE: Calculation for the Cockcroft-Gault equation is
available at https://www.fstrf.org/apps/cfmx/apps/common/Portal/index.cfm

- Aspartate aminotransferase (AST) (SGOT) ≤5 x upper limit of normal (ULN).

- alanine aminotransferase (ALT) (SGPT) ≤5 x ULN.

- alkaline phosphatase ≤5 x ULN.

- Total bilirubin ≤2.5 x ULN (if the participant is receiving atazanavir, a total
bilirubin of ≤5 x ULN is acceptable).

- Hemoglobin A1C ≤6.5%

- For females of reproductive potential, adequate contraception.

- Karnofsky performance score ≥70 within 90 days prior to entry.

- Ability and willingness of participant or legal guardian/representative to provide
informed consent.

- Participants on statin therapy must be stable on the same dose for at least the prior
12 weeks with no anticipated change in statin or dose during the intervention.

Exclusion Criteria:

- Change in the ART regimen within the 12 weeks prior to study entry, or
anticipated/intended modification of ART during the study period.

- Two or more HIV-1 RNA determinations >200 copies/mL within the 48 week period prior to
study entry.

- History of clinical pancreatitis or diabetes mellitus diagnosed by a medical provider.

- Acute or chronic liver disease with evidence of cirrhosis or portal hypertension.

- Chronic hepatitis C (defined as HCV antibody positive and HCV RNA detectable).

- History of chronic hepatitis B (defined as surface antibody negative, surface antigen
positive, and/or HBV DNA detectable).

- Use of any immunomodulator, HIV vaccine, investigational therapy, or anti-TNF
therapies within 90 days prior to study entry.

- Active malignancy with expected need for systemic chemotherapy or radiation therapy
during the study period.

- Use of human growth hormone, tesamorelin, testosterone or anabolic steroids within 90
days prior to study entry (except chronic, stable, replacement dosages in men with
diagnosed hypogonadism is allowed).

- Pregnant or breastfeeding.

- Use of any anti-diabetic medication or GLP-1 analogues within the 12 weeks prior to
study entry.

- Current diagnosis of congestive heart failure.

- Known allergy/sensitivity or any hypersensitivity to components of the study drug or
its formulation.

- 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 requiring systemic treatment and/or hospitalization within 90
days prior to entry.