Pilot Study of Diflunisal in HIV-infected Adults
Pilot Study of Diflunisal in HIV-infected Adults
Diflunisal is an anti-inflammatory drug (like ASA or ibuprofen) that has been used as a
 painkiller for 20 years. Recent research shows that it may have an anti-HIV effect in the
 laboratory. Approximately 20 HIV-infected adults who are not receiving antiretroviral therapy
 will be given diflunisal by mouth twice daily for 4 weeks, at a dose that has been shown to
 be safe when used to treat pain. Subjects will be monitored closely for safety and will have
 frequent blood tests during the study to see if the drug has any effect on the level of HIV
 in their blood.
Following informed consent, potential subjects will undergo a screening visit to determine
 study eligibility. Within 2 weeks of screening, they will undergo a Day 1 visit for blood
 testing. At the Day 8 visit on the following Monday, after study visit procedures have been
 completed, they will commence taking diflunisal 500 mg twice daily by mouth for 4 weeks (Days
 8-36, study treatment period), during which they will be seen once a week for blood tests.
 Following the last dose of diflunisal which will be taken on the morning of Day 36, they will
 be seen for blood tests after 1 week off the study drug (Days 43, washout phase), and again
 for a final visit after 2 weeks off study drug, on Day 50.

 Subjects will be instructed to take diflunisal 500 mg by mouth in two doses approximately 12
 hours apart (+ or - 1 hour), with or without food. A 2-week supply will be dispensed on Days
 8 and 22. Study medication bottles (empty or not) will be returned to the clinic on Days 22
 and 36. Pill counts will be performed to assess adherence. Adherence will further be
 evaluated by measuring diflunisal drug levels in plasma samples collected weekly starting at
 the baseline visit, and assayed at the end of the study.

 After the subject has provided informed consent, a screening visit will be performed
 including a complete medical history and record of concomitant medications to determine study
 eligibility. Complete physical exam, CBC, platelet count, serum creatinine and estimated GFR,
 serum potassium, AST, ALT, total bilirubin, CD4 cell count, and pregnancy test for women of
 child-bearing potential will be performed at the screening visit and repeated at the final
 study visit. At each study visit, blood will be drawn for HIV RNA, and a serum sample will be
 collected and stored for measurement of C-reactive protein (CRP), d-dimer, and possibly other
 inflammatory biomarkers. Plasma (for diflunisal drug level measurement) and peripheral blood
 mononuclear cells (PBMC's) will be collected and stored weekly from the baseline visit to Day
 50. PBMC's will be frozen and shipped in batches to Eric Verdin, MD at the Gladstone
 Institute of Virology and Immunology (1650 Owens St San Francisco, CA 94158, USA) for
 analysis of T cell subsets (naïve, memory CD4 and CD8 T cells) and levels of protein
 acetylation (histone or other) as a surrogate marker of drug activity. Adverse events and
 concomitant medications will be recorded at the baseline visit and updated weekly.

 After completion of the final study visit, subjects will be compensated for their time in the
 amount of $500. Subjects who need to discontinue the study early, e.g. due to significant
 clinical or laboratory adverse events related to the study drug, will receive the full
 stipend at the end of their participation in the study. Subjects who choose to withdraw from
 the study early or who are withdrawn for study noncompliance will not be eligible to receive
 the stipend. Subjects who require ongoing reimbursement for travel expenses to enable them to
 attend study visits will receive advances on their stipend upon providing receipts for
 parking, etc.
Inclusion Criteria:

 1. Adult men and women aged 19 years or over

 2. HIV positive by ELISA and Western blot, at least 3 months prior to screening

 3. No antiretroviral therapy within 3 months prior to screening

 4. Plasma HIV RNA (viral load) > 2,500 copies/mL at screening

 5. Current CD4 cell count >350 cells/mm3 at screening

 6. Adequate renal function as demonstrated by eGFR >60 mL/min. at screening

 Exclusion Criteria:

 1. Pregnancy or breast-feeding

 2. Any HIV-associated symptom or condition (e.g. nephropathy) for which standard
 antiretroviral therapy is indicated immediately

 3. History of peptic ulcer and/or gastrointestinal bleeding

 4. Allergy to ASA, other salicylates, or NSAIDs

 5. Currently receiving treatment with an ACE inhibitor, ASA, anticoagulants, antacids
 containing aluminum hydroxide, cyclosporine, diuretics, systemic glucocorticoids,
 lithium, methotrexate, or other NSAIDs

 6. Significant hepatic impairment or active liver disease - screening AST, ALT, or
 bilirubin >2.5x upper limit of normal (ULN)

 7. Hyperkalemia - screening serum potassium >5.5 mmol/L

 8. Anemia - screening hemoglobin <85 g/L