P-I1 Monotherapy with integrase inhibitors does not maintain viral suppression in humanized mice with chronic HIV infection

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Introduction and Methods:Simplification of current triple ART to dual ART or monotherapy may suffice to maintain HIV suppression while sparing drug toxicities. 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 qRT-PCR (limit of detection of 150 copies/40 μL plasma) and drug levels by LC/MS/MS. Escape viruses were genotyped and analyzed for replication capacity and drug susceptibility in tissue culture.Results:Drug untreated control mice maintained constant viremia throughout the study. Virus isolates from these mice were susceptible to both raltegravir (EC50 <8 nM) and dolutegravir (EC50 <1 nM). Mice treated with raltegravir or dolutegravir had plasma drug levels comparable to those in humans. Monotherapy with raltegravir initially suppressed HIV viremia, but failed to maintain suppression in 4/4 mice. Viruses from raltegravir failing mice had the G140S and Q148H/K substitutions, and were resistant to both raltegravir (EC50 values of >100 nM) and dolutegravir (EC50 values ranging 8.8–13.3 nM) in drug susceptibility assays using human PBMCs. Monotherapy with dolutegravir suppressed viremia in 5/5 of mice, but viremia rebounded in one animal after 12 weeks of treatment. The virus from this mouse had mutations E138K, G140S, Q148H, N155H and S230R, was highly resistant to both raltegravir (EC50 >1000 nM) and dolutegravir (EC50 of 550 nM), and replicated to high levels in PBMCs.Discussion:Raltegravir or dolutegravir monotherapy does not ultimately maintain HIV suppression in humanized mice, suggesting that dual therapy will most likely be required for simplification of ART treatment. Eleven (OR = 10.93) & 7 (OR = 6.53) times more likely respectively, to have HIV negative infants compared to prophylaxis regimen.Conclusion:HAART prior to and during pregnancy is associated with an increased likelihood of achieving a favorable EID result.

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