2′-Deoxy-4′-C-ethynyl-2-halo-adenosines active against drug-resistant human immunodeficiency virus type 1 variants

HIV pre-exposure prophylaxis for women and infants prevents vaginal and oral HIV transmission in a preclinical model of HIV infection

“…Therefore, future studies may be needed to examine the emergence of 4 ′ -ethynyl-2-fluoro-2 ′ -deoxyadenosine resistance upon extended 4 ′ -ethynyl-2-fluoro-2 ′ -deoxyadenosine administration in the context of HIV infection. Nonetheless, our results combined with those of others demonstrating 4 ′ -ethynyl-2-fluoro-2 ′ -deoxyadenosine's high genetic barrier to resistance 20 indicate that the risk of developing 4 ′ -ethynyl-2-fluoro-2 ′ -deoxyadenosine-resistant HIV strains in vivo is lower compared with nevirapine, the current first-line ARV for PrEP in infants.…”

“…Sequence analysis also revealed that although 4 ′ -ethynyl-2-fluoro-2 ′ -deoxyadenosine treatment continued for six additional days after HIV-1 JR-CSF exposure, no RT mutations associated with 4 ′ -ethynyl-2-fluoro-2 ′ -deoxyadenosine resistance emerged (Figure 3d). 20 Analysis of CD4+ T cell levels in peripheral blood longitudinally and in tissues at necropsy also revealed that CD4+ T cell levels were significantly higher in protected 4 ′ -ethynyl-2-fluoro-2 ′ -deoxyadenosine-treated mice ( Figure S2). Collectively these data demonstrate that oral 4 ′ -ethynyl-2-fluoro-2 ′ -deoxyadenosine PrEP significantly reduced oral HIV transmission following multiple high-dose oral HIV challenges with relevant T/F viruses (P¼0.0031) (Figure 3e).…”

“…16,17 Importantly, 4 ′ -ethynyl-2-fluoro-2 ′ -deoxyadenosine exhibits low cytotoxicity due to nearly negligible incorporation into human mitochondrial DNA by DNA polymerase g. 14,18,19 Furthermore, 4 ′ -ethynyl-2-fluoro-2 ′ -deoxyadenosine retains significant potency against a broad range of clinically important drug-resistant isolates, including HIV strains containing the K65R RT mutation, which is associated with resistance to tenofovir, an ARV included in all PrEP regimens evaluated in women to date. 18,20 Studies on the in vivo protective efficacy of 4 ′ -ethynyl-2-fluoro-2 ′ -deoxyadenosine PrEP are very limited 21 and it is currently not known if 4 ′ -ethynyl-2-fluoro-2 ′ -deoxyadenosine PrEP can prevent vaginal or oral HIV transmission of clinically relevant HIV-1 strains. In this study, we utilized bone marrow/liver/thymus (BLT) humanized mice 22 -28 individually bioengineered from NOD/ SCID/gc 2/2 (NSG) immunodeficient mice, as a preclinical in vivo model to evaluate the efficacy of 4 ′ -ethynyl-2-fluoro-2 ′ -deoxyadenosine PrEP to prevent vaginal and oral HIV transmission following multiple high-dose challenges with relevant transmitted/ founder (T/F) viruses.…”

Structural basis of HIV inhibition by translocation-defective RT inhibitor 4′-ethynyl-2-fluoro-2′-deoxyadenosine (EFdA)

“…1). EFdA blocks HIV replication in peripheral blood mononuclear cells (PBMCs) at picomolar concentrations, making it orders of magnitude more potent than current clinical anti-HIV NRTIs (6)(7)(8). Recent phase I clinical data with EFdA (also known as MK-8591) demonstrate that it is well tolerated in healthy adult subjects (9).…”

“…Recent phase I clinical data with EFdA (also known as MK-8591) demonstrate that it is well tolerated in healthy adult subjects (9). Moreover, it has exceptionally favorable pharmacokinetic properties and an unusually long intracellular half-life compared with other NRTIs, mainly due to its resistance to degradation by adenosine deaminase (6,(9)(10)(11)(12). Hence, it is targeted for use as a single 10-mg dose for >7 d (9).…”