Monotherapy with either dolutegravir or raltegravir fails to durably suppress HIV viraemia in humanized mice

• Published in: Journal of antimicrobial chemotherapy 2017-09, Vol.72 (9), p.2570-2573
• Main Authors: Heredia, Alonso, Hassounah, Said, Medina-Moreno, Sandra, Zapata, Juan C, Le, Nhut M, Han, Yingshan, Foulke, Jr, James S, Davis, Charles, Bryant, Joseph, Redfield, Robert R, Wainberg, Mark A
• Format: Article
• Language: English
• Subjects: Animals; Anti-HIV Agents - therapeutic use; Genotype; Heterocyclic Compounds, 3-Ring - therapeutic use; HIV Infections - drug therapy; HIV Infections - virology; HIV Integrase Inhibitors - therapeutic use; HIV-1 - drug effects; HIV-1 - genetics; Humans; Mice; Mice, Transgenic; Mutation; Original Research; Raltegravir Potassium - therapeutic use; RNA, Viral - blood; Viremia - drug therapy; Viremia - virology; Virus Replication - drug effects
• ISSN: 0305-7453; 1460-2091
• DOI: 10.1093/jac/dkx195

To compare the effectiveness of HIV integrase inhibitor monotherapy between raltegravir and dolutegravir as an approach to simplify therapy. We evaluated and compared the efficacy of 20 week monotherapy with dolutegravir or raltegravir in humanized mice (HSC-NSG) infected with HIVBaL. Plasma HIV RNA was measured by quantitative RT-PCR (limit of detection of 150 copies/45 μL of plasma) and drug levels by LC-MS/MS. Escape viruses were genotyped and analysed for replication capacity and drug susceptibility in tissue culture. Drug-untreated control mice maintained constant viraemia throughout the study. Virus isolates from these mice were susceptible to both raltegravir (EC50 of 1000 nM) and dolutegravir (EC50 of 550 nM), and replicated to levels similar to those of control viruses in PBMCs. Monotherapy with either raltegravir or dolutegravir does not consistently maintain HIV suppression, suggesting that dual therapy may be required in simplification strategies.