In-vivo selection of the mutation F121Y in a patient failing raltegravir containing salvage regimen

Abstract

Raltegravir is an integrase inhibitor (INI) licensed for clinical use and other INI are in advanced stage of development. Different resistance mutations in HIV integrase from patients using these antiretroviral drugs have been described and G148H/R/K, N155H and less frequently Y143C/H/R are considered major resistant mutations to raltegravir. Both Stanford Database and Geno2Pheno list F121Y as conferring intermediate resistance "in vitro" both to raltegravir and elvitegravir. We report for the first time the "in vivo" selection F121Y and evolution to Y143R in a 31years old male clade B HIV-1 infected patient failing a raltegravir-containing salvage regimen. Plasma samples nine months prior to raltegravir (RAL-Naïve) and at weeks 32, 40 and 88 after RAL-containing regimen were analyzed. Antiretroviral susceptibility was evaluated at Stanford and Geno2Pheno from sequences obtained with RT-PCR. After a Viral load at week 12 below 50 copies/mL, viremia raised at week 20 to 4.5log10. The emergence of F121Y was observed at week 32 and 40, alongside with L74I, T97A, Q137H and V151I. At week 88 F121Y was no longer detected, L74I and T97A were maintained and Y143R emerged. F121Y might be an alternative pathway to Y143R. Changing of RAL-containing regimen upon the identification of F121Y might avoid the evolution of raltegravir resistance.

Lack of impact of pre-existing T97A HIV-1 integrase mutation on integrase strand transfer inhibitor resistance and treatment outcome

“…Since T97A has been associated with INSTI resistance in patients experiencing virologic failure on EVG or RAL [ 25 , 85 – 89 ], we sought to address the concern of whether this naturally occurring integrase polymorphism could change the current paradigm for supplemental integrase genotyping prior to INSTI-based therapy. Our analyses showed that only 1 of 18 patients with pre-existing T97A who enrolled on INSTI-based therapy experienced virologic failure.…”

“…As a secondary INSTI RAM, T97A further reduces INSTI susceptibility and/or rescues viral fitness in association with Y143C/R [ 41 , 47 , 82 ], Q148H+G140S [ 83 ], or N155H [ 67 , 73 , 84 ]. In rare cases, T97A has also been selected alone (i.e., in the absence of primary INSTI RAMs) by RAL [ 85 – 88 ] and EVG [ 25 , 89 ], which led us to previously consider T97A alone as a special case of primary INSTI RAM that requires additional integrase mutations ( Fig 1 ) [ 25 , 45 , 89 ]. Indeed, while T97A alone confers low-level to no effect on EVG and RAL susceptibility, respectively [ 45 , 50 ], additional integrase polymorphism(s) such as V72I, L74M, and/or G163R may serve a role to further reduce INSTI susceptibility before or during INSTI-based treatment [ 86 – 88 ].…”

Raltegravir-Induced Adaptations of the HIV-1 Integrase: Analysis of Structure, Variability, and Mutation Co-occurrence

“…The residue 92, may show the mutation E92Q that was shown to reduce RAL susceptibility (Jones et al, 2009; Kobayashi et al, 2011). While mutation F121Y, in spite of being rarely selected in vivo (Cavalcanti et al, 2012), is capable of lowering RAL efficacy (Kobayashi et al, 2008; Shimura et al, 2008). Both positions 92 and 121 are found in VG1.…”

“…Also, the VG1 position 157, which may have the mutation E157Q, does not appear to influence the INSTI therapy but is selected in treated patients (Charpentier et al, 2018). In VG1 two resistance-related positions (114 and 121) had zero entropy in both datasets, probably because the resistance mutation H114Y is rare (Goethals et al, 2008), and F121Y is rarely selected in vivo by RAL (Cavalcanti et al, 2012). Moreover, the VG1 resistance-related positions 51, 66, 95, 114, 121, 128, 142 and 149 showed entropies between zero and 0.1 in both datasets, showing a minimal degree of variability in the datasets of treated and non-treated patients.…”