Background:
Drug resistance is a major hurdle in the treatment of people living with HIV-2 (PLWH-2). The limited number of therapeutic options combined with the rapid selection of mutations can lead to therapeutic dead ends. Lenacapavir (LEN) is the first capsid inhibitor, with in vitro activity against both HIV-1 and HIV-2. It has been approved for PLWH-1 with multi-drug resistant viruses but its genetic barrier is low and several drug-resistance associated mutations (DRAMs) have been reported.
Methods:
French PLWH-2 with multi-drug resistant viruses had access to LEN through a compassionate use program. LEN was initiated along with an optimized background regimen (OBR). Plasma viral loads were measured throughout follow-up, and capsid genotyping was performed at time of virological failure using an in-house PCR assay, followed by high-throughput sequencing. Capsid sequences were compared with viral sequences obtained prior to LEN initiation to identify potential DRAMs.
Results:
A total of 8 PLWH-2 (4 female) initiated a treatment with LEN and an OBR. The genotypic susceptibility score (GSS) of the OBR was equal to, or below, two for all patients. Plasma viral loads at time of initiation were detectable in 6/8 patients (median: 3,830 copies/mL, range: 665-60,450). Three additional PLWH-2 achieved virological suppression within two to three months after initiating LEN+OBR. Capsid genotyping was performed on the first positive plasma viral load (median pVL: 1,600 copies/mL, range: 260-7,210). Capsid mutations were observed in six PLWH-2: five N73D mutations and one double mutation (Q66H+R69K) (Table). In addition to the N73D mutation, an A76V mutation emerged in the viruses of two patients at 11 and 17 months after initiation of LEN. Two patients (#7 and #8) had persistently high plasma viral loads but their viruses did not select any capsid mutations. Of note, the patient with the highest GSS (#4) had adherence issues, resulting in a functional monotherapy of LEN for several weeks.
Conclusions:
We report the rapid selection of capsid mutations in PLWH-2 failing a LEN-containing regimen. These mutations occurred at positions close to those previously reported in HIV-1. Additional data on the impact of these mutations on the phenotypic susceptibility to LEN are needed. This preliminary study underscores the low genetic barrier to resistance of LEN, especially when the GSS of the optimized background regimen is low, and the need to use it along with therapeutic drug monitoring and therapeutic education.
