Fostemsavir resistance in clinical context: a narrative review

Abstract

Fostemsavir, a prodrug of the first-in-class gp120-directed attachment inhibitor temsavir, is indicated in combination with other antiretrovirals for the treatment of multidrug-resistant HIV-1 in adults who are heavily treatment-experienced (HTE). Temsavir binds to HIV-1 gp120, close to the CD4 binding site, preventing the initial interaction of HIV-1 with CD4 on the host cell. Amino acid substitutions at four positions in gp120 have been identified as important determinants of viral susceptibility to temsavir (S375H/I/M/N/T/Y, M426L/P, M434I/K, M475I), with a fifth position (T202E) recently described. For most currently circulating group M HIV-1 subtypes, the prevalence of these resistance-associated polymorphisms (RAPs) is low. As with many other antiretrovirals, the impact of RAPs is modified by other changes in the target molecule. Different regions of gp120 interact to modify the temsavir binding pocket, with multiple amino acids playing a role in determining susceptibility. Extensive variability of HIV-1 gp120 means the susceptibility of clinical isolates to temsavir is also highly variable. Importantly, in vitro measurement of the susceptibility of clinical isolates to temsavir does not necessarily capture the range of susceptibilities of the heterogeneous mix of viruses generally present in each isolate. Due to these factors and limited phenotypic clinical data, thus far, no relevant phenotypic cutoff or genotypic algorithms have been derived that reliably predict response to fostemsavir-based therapy in individuals who are HTE; therefore, pre-treatment temsavir resistance testing may be of limited benefit. In the phase III BRIGHTE study, re-suppression after virologic failure was observed in some participants despite treatment-emergent genotypic and/or phenotypic evidence of reduced temsavir susceptibility, and substantial CD4+ T-cell count increases occurred even among participants with HIV-1 RNA ⩾40 copies/mL at Week 240. Clinical management of people who are HTE and experience virologic failure during treatment with fostemsavir-based regimens requires an individualized approach with consideration of potential benefits beyond virologic suppression.

Keywords: fostemsavir; heavily treatment-experienced; multidrug resistance.

Figure 1.

Chemical structures of (a) fostemsavir and (b) temsavir and homology models of (c) CD4 (protein data bank code 2NXY), in brown, and (d) temsavir (protein data bank code 5U7O), in magenta, bound to wild-type HIV-1 JR-FL gp120, in green, with annotation to show key amino acid positions. Models illustrate the distinct CD4 and temsavir binding sites on opposite sides of the β20-21 loop (in blue).^,,

Figure 2.

Variability of in vitro susceptibility to temsavir among individual clones from the same clinical isolate population with the same key amino acid substitutions. Clinical isolates were derived from participants at baseline in the phase IIa fostemsavir clinical study. Source: Adapted from Zhou et al. FC-IC₅₀, fold change in temsavir IC₅₀ in a cell–cell fusion assay between wild-type reference virus and test virus; IC₅₀, half-maximal inhibitory concentration.

Figure 3.

Variability of in vitro susceptibility to temsavir among different clinical isolates of HIV-1 (N = 208 biologically independent viral strains) grouped by (a) identity of the polymorphic residue at position 375 of gp120 and (b) virus subtype. Horizontal lines indicate median IC₅₀, dotted line indicates maximum detectable IC₅₀, % coverage indicates percentage of tested isolates with measurable IC₅₀ within detectable range. Source: Adapted from Prévost et al., with permission under a Creative Commons Attribution 4.0 International License. IC₅₀, half-maximal inhibitory concentration.

Figure 4.

Range of temsavir susceptibility observed within subtypes. Viruses with >5 isolates grouped by subtype. Horizontal solid lines indicate geometric mean. Symbols on dotted horizontal line had IC₅₀s above the highest concentration tested. Source: Adapted from Gartland et al. IC₅₀, half-maximal inhibitory concentration.