Low prevalence of nirmatrelvir-ritonavir resistance-associated mutations in SARS-CoV-2 lineages from Botswana

Abstract

Abstract Background We evaluated naturally occurring nirmatrelvir-ritonavir (NTV/r) resistance-associated mutations (RAMs)among SARS-CoV-2 strains from Botswana, a country with no NTV/r use to date, in order to recommend the usage of the agent for high-risk patients with COVID-19. Methods We conducted a retrospective analysis using 5254 complete SARS-CoV-2 sequences from Botswana (September 2020–September 2023). We evaluated the mutational landscape of the SARS-CoV-2 3-Chymotrypsin-like protease (3CLpro) relative to the highlighted list of RAMs provided by FDA emergency use authorization in 2023. Results The sequenced 5254 samples included Beta VOC (N = 323), Delta VOC (N = 1314), and Omicron VOC (N = 3354). Overall, 77.8% of the sequences exhibited at least one polymorphism within 76/306 amino acid positions in the nsp5 gene. NTV/rRAMs were identified in 34/5254 (0.65%, 95%CI:.43%–.87%), and occurred at five distinct positions. Amongst the NTV/r RAMS detected, A191 V was the most prevalent (24/34; 70.6%). Notably, T21I mutation had a prevalence of 20.6% (7/34) and co-existed with either K90R (n = 3) polymorphism in Beta sequences with RAMs or P132H (n = 3) polymorphism for Omicron sequences with RAMs. Other NTV/r RAMs detected include P108S with prevalence of 5.88% (2/34) and L50F prevalence of 2.94% (1/34).NTV/r RAMs were significantly higher (P < .001) in Delta (24/35) compared to either Beta (4/34) or Omicron (6/34) sequences. Conclusions The frequency of NTV/r RAMs in Botswana was low. Higher rates were observed in Delta VOC variants compared to in Omicron and Beta VOC. As NTV/r use expands globally, continuous surveillance for drug-resistant variants is essential, given the RAMs identified in our study.