Background

Despite non-nucleoside reverse transcriptase inhibitor (NNRTI) cross-resistance, doravirine (DOR) maintains in vitro activity to some multidrug-resistant HIV strains. Our aim was to explore virological outcomes of DOR-based regimens in people with 4-class drug-resistant HIV (4DR-PWH).

 

Methods

Retrospective, cohort study on antiretroviral treatment (ART)-experienced PWH with resistance to nucleoside reverse transcriptase inhibitors (NRTIs), NNRTIs, protease inhibitors (PIs), and integrase strand transfer inhibitors (INSTIs) from the PRESTIGIO Registry, who started a DOR-based regimen. Baseline (BL) was defined as the date of initiation of DOR.

The primary outcomes were virological suppression [(VS) defined as ≥1 viral load (VL) <50 copies/mL] in 4DR-PWH with BL viremia ≥50 copies/mL and virological failure [(VF) defined as ≥2 consecutive VLs ≥50 copies/mL or ≥1 VL ≥1000 copies/mL] in individuals with BL viremia <50 copies/mL.

The cumulative incidence function was used to estimate cumulative probabilities of VS in 4DR-PWH with BL viremia ≥50 copies/mL and of VF in 4DR-PWH with BL viremia <50 copies/mL, considering as competing risks those who discontinued DOR; follow-up accrued from BL to the VS or VF, the last available VL, or the date of DOR discontinuation, whichever occurred first. Other changes in regimen without DOR discontinuation were allowed.

Descriptions by median (interquartile range) or frequency (percentage).

 

Results

Overall, 29 viremic and 23 suppressed 4DR-PWH initiated a DOR-based regimen and were evaluated (Table 1).

After a median follow-up of 1.0 (0.3-1.7) years, 17/29 (58.6%) 4DR-PWH with BL VL ≥50 copies/mL achieved VS; overall genotypic susceptibility score (GSS) [VS: 2 (2-3); non-VS: 3 (2-3.3); p=0.324] and DOR-specific GSS [VS: 1 in 10/17 (58.8%); non-VS: 1 in 3/12 (25%); p=0.237) were not associated with VS. Cumulative probabilities of VS reported in Figure 1A. Interestingly, only 3/17 (17.6%) had a new VF after undetectability, and 2 of them (66.7%) regained VS on DOR.

After a median follow-up of 1.8 (0.6-3.3) years, 4/23 (17.4%) 4DR-PWH with BL VL <50 copies/mL had VF; not overall GSS [VF: 1.5 (1.3-2); non-VF: 2 (2-3); p=0.136] but only DOR-specific GSS [VF: 1 in 0/4 (0%); non-VF: 1 in 14/19 (73.7%); p=0.009] was associated with VF. Cumulative probabilities of VF reported in Figure 1B. Of the 4 individuals with VF, 3 (75%) regained undetectability on DOR.

Reasons for DOR discontinuation reported in Table 2.

Three individuals (all unsuppressed at BL) appeared to have selected new resistance-associated mutations: all to DOR, 2 also to background therapy.

 

Conclusions

In our cohort of 4DR-PWH, DOR-based regimens showed good virological efficacy, even as rescue therapy for uncontrolled viremia. DOR should be considered in the design of new regimens for heavily treatment-experienced individuals with multidrug resistance