Transient impact of lenacapavir against MDR HIV-2 without other active ART

The rapid development of drug resistance to lenacapavir when used at the only active drug as part of rescue therapy against multidrug resistant HIV-2 was reported in a brief case review in CID.

Thomas Montrouge and colleagues reported on eight people enrolled in the French ANRS-MIE CO5 HIV-2 cohort who had received lenacapavir on named patient access.

Participant characteristics included 4 men and 4 women with a median age 57 (range: 36 to 66) years. All 8/8 had extensive drug resistance and were already on an individualised optimised background regimen (OBR).

The median genotypic susceptibility score (GSS) to the OBR was 1.25 (range: 0 to 2.5), with 5/8 having ≤1 fully active drug; 3/8 used ibalizumab, 2/8 maraviroc, 1/8 foscarnet.

Viral load at day 0 was detectable in 6/8 (median: 3,830 c/mL, range: 665 to 60,450) and became undetectable within 3 months in 4/6 after adding lenacapavir with 2/8 reaching <200 c/mL at month 6.

Although median viral load at month 6 was 757 c/mL (range: 117 to 3,000), by month 12 viral rebound to baseline levels was reported in all participants (to approximately 500 to >10,000 c/mL).

Median trough concentrations at month 6 after the first injection (IQR): 157 to 182 days) was 89 ng/mL (IQR: 27 to 181). Although in-vitro efficacy has been reported for lenacapavir against HIV-2, with an EC50 that is a log higher than against HIV-1, at 1 nM vs 0.1 nM, respectively, both concentrations remain significantly below the lenacapavir trough levels reported.

Lenacapavir drug resistance was reported in the 5/8 participant with the highest drug concentrations. For details resistance mutations please see the full paper.

CD4 responses were highly heterogeneous from 135 cells/mm³ (range: 0 to 360) at baseline to 185 cells/mm³ (range: 90 to 290) at month 6, with a median change of +3 cells/mm³ but a range of –110 to +130.

Importantly, the authors emphasised that the low immunological and virological responses in this study “should not preclude the use of lenacapavir in other populations with MDR HIV-2, especially if they have a higher GSS >2.0”.

comment

These results are disappointing and they show the vulnerability of lenacapavir against HIV-2 if not supported by other active HIV drugs. Even when trough levels suggested continued drug sensitivity, achieving undetectable viral load <50 c/mL was only transient.

Although not discussed in the paper, the limitations of predicting genotypic sensitivity also needs to be considered as lenacapavir responses did not closely correlate with the GSS.

Although the potency of lenacapavir might be supported in this setting by using a shorter experimental 4-monthly dosing schedule, 6/8 viral failures were reported earlier in the dosing cycle.

Montrouge T et al. Rapid selection of HIV-2 capsid mutations in salvage therapy with lenacapavir-containing regimen. Clinical Infectious Diseases, 2024;, ciae650. (31 December 2024).
https://doi.org/10.1093/cid/ciae650