This study describes resistance analyses conducted over 4 years in the DRIVE-FORWARD and DRIVE-AHEAD trials (which compared doravirine-based regimens to ritonavir-boosted darunavir- and efavirenz-based regimens, respectively, among participants without known baseline RT substitutions).  Two groups were involved: (a) Initial Therapy participants (who remained on DOR for an additional 96-weeks in the open-label extension) and (2) Switch Therapy participants (who were initially randomized to the comparator regimen for 96-weeks then switched to DOR in the OLE).  In the Initial Therapy group, 83 cases of PDVF were observed and 35 met criteria for resistance testing, which was successful in 34.  In the Switch Therapy group, PDVF occurred in 26 participants between week 96 and week 192, and 6 met criteria for testing.  Of participants who discontinued treatment for reasons other than PDVF, 22 met criteria for testing, which was successful in 20.  Overall, of the 60 participants with successful testing, treatment-emergent doravirine RAMs were detected in 16 (corresponding to 1.3% of the total 1249 participants): 12/747 (1.6%) in the Initial Therapy group and 4/502 (0.8%) in the Switch Therapy group.  Most (13/16) had two or more doravirine RAMs, and specific mutations (listed in order of frequency) included: V106A/I/M/L, F227C/L/R, A98G, Y318F, H221Y, P225H, V108I, and Y188L.  Emergent NRTI RAMs were detected in 16 (11 also had doravirine mutations), most commonly M184V/I, followed by A62V, V118I, and K65R.

Following clinical trial participants out to 4 years, these results confirm that emergent resistance to doravirine is highly uncommon (both among people experiencing virologic failure on treatment but also among people who discontinue it for reasons other than virologic failure).  Most cases were observed within the first year on doravirine, and development of additional NRTI resistance was also uncommon.  Although emergent mutations observed in these trial participants were distinct from those associated with first-generation NNRTIs, in most cases participants were found to have more than one doravirine RAM, which may limit future treatment options.