Short Communication: Comparative Evaluation of Coformulated Injectable Combination Antiretroviral Therapy Regimens in Simian Immunodeficiency Virus-Infected Rhesus Macaques

• Published in: AIDS research and human retroviruses Vol. 32; no. 2; p. 163
• Main Authors: Del Prete, Gregory Q, Smedley, Jeremy, Macallister, Rhonda, Jones, Gregg S, Li, Bei, Hattersley, Jillian, Zheng, Jim, Piatak, Jr, Michael, Keele, Brandon F, Hesselgesser, Joseph, Geleziunas, Romas, Lifson, Jeffrey D
• Format: Journal Article
• Language: English
• Published: United States 01-02-2016
• Subjects: Animals; Anti-Retroviral Agents - pharmacokinetics; Anti-Retroviral Agents - therapeutic use; Antiretroviral Therapy, Highly Active; Drug Combinations; Drug Resistance, Viral; Emtricitabine - pharmacokinetics; Emtricitabine - therapeutic use; Heterocyclic Compounds, 3-Ring - pharmacokinetics; Heterocyclic Compounds, 3-Ring - therapeutic use; HIV Integrase Inhibitors - therapeutic use; Macaca mulatta; Reverse Transcriptase Inhibitors - therapeutic use; Simian Acquired Immunodeficiency Syndrome - drug therapy; Simian Acquired Immunodeficiency Syndrome - virology; Simian Immunodeficiency Virus - drug effects; Tenofovir - pharmacokinetics; Tenofovir - therapeutic use; Treatment Outcome; Viral Load - drug effects
• ISSN: 1931-8405
• DOI: 10.1089/aid.2015.0130

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.