title: Short Communication: Comparative Evaluation of Coformulated Injectable Combination Antiretroviral Therapy Regimens in Simian Immunodeficiency Virus-Infected Rhesus Macaques.
abstract: The use of nonhuman primate (NHP) models to study persistent residual virus and viral eradication strategies in combination antiretroviral therapy (cART)-treated individuals requires regimens that effectively suppress SIV replication to clinically relevant levels in macaques. We developed and evaluated two novel cART regimens in SIVmac239-infected rhesus macaques: (1) a "triple regimen" containing the nucleo(s/t)ide reverse transcriptase inhibitors emtricitabine (FTC) and tenofovir disoproxil fumarate [TDF, prodrug of tenofovir (TFV, PMPA)] with the integrase strand transfer inhibitor dolutegravir (DTG) (n = 3), or (2) a "quad regimen" containing the same three drugs plus the protease inhibitor darunavir (DRV) (n = 3), with each regimen coformulated for convenient administration by a single daily subcutaneous injection. Plasma drug concentrations were consistent across animals within the triple and quad regimen-treated groups, although DTG levels were lower in the quad regimen animals. Time to achieve plasma viral loads stably <30 viral RNA copies/ml ranged from 12 to 20 weeks of treatment between animals, and viral loads <30 viral RNA copies/ml plasma were maintained through 40 weeks of follow-up on cART. Notably, although we show virologic suppression and development of viral resistance in a separate cohort of SIV-infected animals treated with oral DRV monotherapy, the addition of DRV in the quad regimen did not confer an apparent virologic benefit during early treatment, hence the quad regimen-treated animals were switched to the triple regimen after 4 weeks. This coformulated triple cART regimen can be safely, conveniently, and sustainably administered to durably suppress SIV replication to clinically relevant levels in rhesus macaques.
authors.affiliation: 1 AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research , Frederick, Maryland.
authors.forename: Gregory Q
authors.initials: GQ
authors.lastname: Del Prete
authors.affiliation: 2 Laboratory Animal Sciences Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research , Frederick, Maryland.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Smedley
authors.affiliation: 2 Laboratory Animal Sciences Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research , Frederick, Maryland.
authors.forename: Rhonda
authors.initials: R
authors.lastname: Macallister
authors.affiliation: 3 Gilead Sciences , Foster City, California.
authors.forename: Gregg S
authors.initials: GS
authors.lastname: Jones
authors.affiliation: 3 Gilead Sciences , Foster City, California.
authors.forename: Bei
authors.initials: B
authors.lastname: Li
authors.affiliation: 3 Gilead Sciences , Foster City, California.
authors.forename: Jillian
authors.initials: J
authors.lastname: Hattersley
authors.affiliation: 3 Gilead Sciences , Foster City, California.
authors.forename: Jim
authors.initials: J
authors.lastname: Zheng
authors.affiliation: 1 AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research , Frederick, Maryland.
authors.forename: Michael
authors.initials: M
authors.lastname: Piatak
authors.affiliation: 1 AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research , Frederick, Maryland.
authors.forename: Brandon F
authors.initials: BF
authors.lastname: Keele
authors.affiliation: 3 Gilead Sciences , Foster City, California.
authors.forename: Joseph
authors.initials: J
authors.lastname: Hesselgesser
authors.affiliation: 3 Gilead Sciences , Foster City, California.
authors.forename: Romas
authors.initials: R
authors.lastname: Geleziunas
authors.affiliation: 1 AIDS and Cancer Virus Program, Leidos Biomedical Research, Inc., Frederick National Laboratory for Cancer Research , Frederick, Maryland.
authors.forename: Jeffrey D
authors.initials: JD
authors.lastname: Lifson
mesh_terms: D000818:Animals; D044966:Anti-Retroviral Agents / Q000493:pharmacokinetics / Q000627:therapeutic use*; D023241:Antiretroviral Therapy, Highly Active; D004338:Drug Combinations; D024882:Drug Resistance, Viral; D000068679:Emtricitabine / Q000493:pharmacokinetics / Q000627:therapeutic use; D019428:HIV Integrase Inhibitors / Q000627:therapeutic use; D006575:Heterocyclic Compounds, 3-Ring / Q000493:pharmacokinetics / Q000627:therapeutic use; D008253:Macaca mulatta; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D018894:Reverse Transcriptase Inhibitors / Q000627:therapeutic use; D016097:Simian Acquired Immunodeficiency Syndrome / Q000188:drug therapy* / Q000821:virology; D015302:Simian Immunodeficiency Virus / Q000187:drug effects*; D000068698:Tenofovir / Q000493:pharmacokinetics / Q000627:therapeutic use; D016896:Treatment Outcome; D019562:Viral Load / Q000187:drug effects*; D000099226:Dolutegravir
chemical_list: D044966:Anti-Retroviral Agents; D004338:Drug Combinations; D000068679:Emtricitabine; D019428:HIV Integrase Inhibitors; D006575:Heterocyclic Compounds, 3-Ring; D010078:Oxazines; D010879:Piperazines; D011728:Pyridones; D018894:Reverse Transcriptase Inhibitors; D000068698:Tenofovir; D000099226:Dolutegravir