Open Label, Pilot Study of Darunavir Boosted by Cobicistat in Combination With Rilpivirine to Treat HIV+ Naïve Subjects

This is a Phase IV, 48-week, open-label, pilot study in 30 ARV-naïve patients examining the safety, viral response, and tolerability of darunavir/cobicistat in combination with rilpivirine once daily for the treatment of HIV in treatment-naïve patients.

Thirty subjects meeting the inclusion criteria for study will be selected at a single site. All 30 subjects will receive darunavir/cobicistat 800/150mg in combination with rilpivirine 25 mg once daily at study onset and will be followed for 48 weeks after starting study medications. Virologic failure will be defined as failure to achieve HIV-1 RNA <50 copies/mL by week 24 of therapy, or in patients with baseline HIV-1 RNA >100,000 copies/mL, failure to achieve 1 log10 reduction in HIV-1 RNA by week 24. Confirmed virologic failure will be defined as two consecutive HIV RNA levels ≥50 copies/mL after suppression to <50 copies/mL for two consecutive measurements. Patients with confirmed virologic failure will be discontinued from the study and switched to a new antiretroviral treatment regimen.

Patients who have decided to initiate treatment after consultation with their physician and after careful review of the Department of Health and Human Services (DHHS) guidelines for treatment will be considered for enrollment as research subjects. Individuals considered for enrollment providing informed consent (See Appendix A) will be screened and, if eligible, enrolled in the study. Adherence to study regimen and symptoms of hypersensitivity reactions will be monitored by self-report at each study visit. Adherence will be assessed using the standard ACTG Adherence Questionnaire II (See Appendix B), either over the telephone or during a clinic visit. Those patients reporting problems with adherence will be counseled and monitored closely every 4 weeks at clinic visits with phone consultation bi-weekly until adherence improves. If despite counseling, adherence is not maintained, patients will be discontinued from the study due to increased risk of drug resistance. AEs will be monitored closely to determine if appropriate management affects tolerability and adherence, i.e., prescribing anti-emetic or anti-diarrhea medications for nausea and diarrhea, respectively. Patients will be counseled on the importance of adherence at every study visit.

Hematology, blood chemistry, liver function tests, virologic and immunologic measurements will be obtained at baseline (week 0), weeks 4, 12, 24, 36, and 48. In addition to blood chemistry evaluations, fasting blood samples will be obtained at baseline and weeks 24 and 48 for triglycerides, total cholesterol, direct HDL cholesterol and LDL cholesterol. Pancreatic amylase and serum lipase levels will be determined if serum amylase results are >2x ULN (see Section 5.4.2 Laboratory Evaluations).

In a subset of 12 subjects at their baseline and with at least 24 weeks exposure to darunavir and rilpivirine a lumbar puncture will be performed to obtain a sample of CSF for viral load, cell count and darunavir and rilpivirine concentration.

Adherence counseling will be performed after each HIV-1 RNA measurement of >400 copies/mL. New combination therapy for HIV will be initiated upon evidence of developing resistance in the face of virologic failure.

Samples for flow cytometry (including but not limited to absolute and percent CD4+ and CD8+ cell counts) and HIV RNA levels will be obtained at each study visit. The Roche Amplicor 1.5v (LOQ= 50 copies/mL) will be used until the patient has achieved an HIV RNA level < 50 copies/mL at which time the HIV RNA PCR (LOQ=50 copies/mL) assay will be used. It is noted that no testing outside of what is specified in this protocol, will be conducted without additional written informed consent.

LabCorps of America Monogram Phenosense GT will be performed in all patients at baseline and for all patients with confirmed virologic failure (two consecutive HIV RNA levels ≥400 copies/mL after suppression to <400 copies/mL for two consecutive measurements). Due to test reliability, HIV RNA must be ≥1000 copies/mL in order to obtain genotype. In patients with HIV RNA >500 but <1,000 copies/mL, testing may be unsuccessful but will be up to the discretion of the investigator. Genotypes will be utilized for use in clinical management.12subjects at their baseline and with at least 24 weeks exposure to darunavir and rilpivirine will have a sample of CSF for viral load, cell count and darunavir and rilpivirine concentration to be performed by LabCorps of America and by the University of California, San Diego, CA

Assessment of facial lipoatrophy, central adiposity, breast hypertrophy, dorsal fat pad ("buffalo hump"), multiple lipomas, and Cushingoid appearance without Cushing's disease will be performed by physician assessment and self-report at baseline, weeks 24, 48, and at premature discontinuation.

Patients who develop a study drug-related Grade 1 or 2 AE or clinical laboratory abnormality may elect to continue study medications. Patients who develop a study drug-related Grade 3 AE or clinical laboratory abnormality, with the exception of hyperglycemia, hypertriglyceridemia, hypercholesterolemia, or Grade 3 AST/ALT elevations, may interrupt the offending study medication(s) based on the discretion of the investigator. If only rilpivirine is determined to be the most likely most likely cause, darunavir/cobicistat may be continued for one additional week due to the long half-life of rilpivirine (~40 hours) to prevent functional monotherapy. Patients who develop a study drug-related Grade 4 AE or clinical laboratory abnormality, with the exception of hyperglycemia, hypertriglyceridemia, hypercholesterolemia, should interrupt all study medication, regardless of half-life. Upon resolution of the AE or clinical laboratory abnormality to within one grade level (not to exceed Grade 2) of the patient's baseline level, the patient may resume study drug dosing under the guidance of the investigator. Refer to Section 5 for more detailed information on toxicity management.