Background: GS-6207 is a multi-stage capsid inhibitor with picomolar activity against all major HIV-1 subtypes. In healthy volunteers, GS-6207 was well tolerated and its pharmacokinetic profile following subcutaneous administration supports dosing once every 3 months. This study evaluated in vitro resistance emergence to GS-6207.
Methods: GS-6207-resistant HIV-1 (HXB2D) variants were selected in MT-2 cells using escalating or fixed drug concentrations. Additional selections at fixed concentrations of GS-6207 and control antiretrovirals were conducted in peripheral human blood mononuclear cells (PBMCs) infected independently with 6 clinical isolates. Selected HIV-1 mutants were characterized using standard genotyping and phenotyping methods and their fitness evaluated in primary CD4+ T-lymphocytes.
Results: Dose escalation selections progressed more slowly with GS-6207 over 15 weeks than with efavirenz or elvitegravir. Early GS-6207-selected HIV-1 passages encoded N74D in capsid and showed 5.3-fold reduced susceptibility (RS) to GS-6207, whereas later passages encoded Q67H+N74D conferring >100-fold RS to GS-6207. In MT-2 cells, GS-6207 prevented viral breakthrough (VB) at 8-fold EC95 and selected for VB with N74D in 38% (3/8) of replicates at 4-fold EC95, a concentration below its anticipated clinical trough concentration. In PBMCs infected with HIV-1 clinical isolates, GS-6207 selected for VB with N74D in 8% (3/36) of samples at 8-fold EC95, a frequency superior or similar to emtricitabine (81%), rilpivirine (33%) and efavirenz (8%) at their respective human plasma-free clinical trough concentration. At 4-fold EC95, GS-6207 selected for L56I, Q67H, N74D/S, or T107N mutations alone or in distinct pairwise combinations. These HIV-1 capsid mutants showed a range of RS to GS-6207 and all but Q67H replicated poorly in primary CD4+ T-cells relative to wild-type virus. All GS-6207-selected HIV-1 variants remained fully susceptible to other antiretroviral classes. The residues at which the GS-6207-selected mutations occurred in vitro are highly conserved (94-100%) across >10,000 capsid sequences from all major HIV-1 subtypes (www.hiv.lanl.gov). In addition, deep sequencing (2% frequency cut-off) of HIV-1 isolates from >100 treatment-naive patients detected only the T107N variant (4-fold RS to GS-6207) in a single patient isolate.
Conclusions: GS-6207 exhibits a unique in vitro resistance profile that supports its further clinical development as a new long-acting agent for the treatment of HIV-1 infection.

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