Low Prevalence of Nirmatrelvir-Ritonavir Resistance-Associated Mutations in SARS-CoV-2 Lineages From Botswana

Wonderful T Choga; Ontlametse T Bareng; Natasha O Moraka; Dorcas Maruapula; Irene Gobe; Nokuthula S Ndlovu; Boitumelo J L Zuze; Patience C Motshosi; Kedumetse B Seru; Teko Matsuru; Matshwenyego Boitswarelo; Mogomotsi Matshaba; Tendani Gaolathe; Mosepele Mosepele; Joseph Makhema; Trevor J M Tamura; Jonathan Z Li; Roger Shapiro; Shahin Lockman; Simani Gaseitsiwe; Sikhulile Moyo

doi:10.1093/ofid/ofae344

Low Prevalence of Nirmatrelvir-Ritonavir Resistance-Associated Mutations in SARS-CoV-2 Lineages From Botswana

Open Forum Infect Dis. 2024 Jul 2;11(7):ofae344. doi: 10.1093/ofid/ofae344. eCollection 2024 Jul.

Authors

Wonderful T Choga^{1

2}, Ontlametse T Bareng^{1

2}, Natasha O Moraka^{1

2}, Dorcas Maruapula¹, Irene Gobe², Nokuthula S Ndlovu^{1

3}, Boitumelo J L Zuze¹, Patience C Motshosi¹, Kedumetse B Seru¹, Teko Matsuru¹, Matshwenyego Boitswarelo⁴, Mogomotsi Matshaba^{5

6}, Tendani Gaolathe^{1

7}, Mosepele Mosepele^{1

7}, Joseph Makhema^{1

8}, Trevor J M Tamura⁹, Jonathan Z Li⁹, Roger Shapiro^{1

8}, Shahin Lockman^{1

8

10}, Simani Gaseitsiwe^{1

8}, Sikhulile Moyo^{1

2

8

11

12}

Affiliations

¹ Botswana Harvard Health Partnership, Gaborone, Botswana.
² School of Applied Health Sciences, Faculty of Health Sciences, University of Botswana, Gaborone, Botswana.
³ Department of Biological Sciences and Biotechnology, Faculty of Sciences, Botswana International University of Science and Technology, Palapye, Botswana.
⁴ Department of Health Systems Management, Clinical Services, Ministry of Health Botswana, Gaborone, Botswana.
⁵ Botswana-Baylor Children's Clinical Centre of Excellence, Gaborone, Botswana.
⁶ Department of Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
⁷ Department of Internal Medicine, Faculty of Medicine, University of Botswana, Gaborone, Botswana.
⁸ Department of Immunology and Infectious Diseases, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, USA.
⁹ Division of Infectious Diseases, Brigham & Women's Hospital, Boston, Massachusetts, USA.
¹⁰ Harvard Medical School, Boston, Massachusetts, USA.
¹¹ School of Health Systems and Public Health, University of Pretoria, Pretoria, South Africa.
¹² Division of Medical Virology, Faculty of Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.

Abstract

Background: We evaluated naturally occurring nirmatrelvir-ritonavir (NTV/r) resistance-associated mutations (RAMs) among severe acute respiratory syndrome coronavirus 2 (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 coronavirus disease 2019 (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 SARS-CoV-2 3-Chymotrypsin-like protease (3CLpro) relative to the highlighted list of RAMs granted Food and Drug Administration Emergency Use Authorization in 2023.

Results: The sequenced 5254 samples included Beta variants of concerns (VOCs; n = 323), Delta VOCs (n = 1314), and Omicron VOCs (n = 3354). Overall, 77.8% of the sequences exhibited at least 1 polymorphism within 76/306 amino acid positions in the nsp5 gene. NTV/rRAMs were identified in 34/5254 (0.65%; 95% CI, 0.43%-0.87%) and occurred at 5 distinct positions. Among the NTV/r RAMS detected, A191V was the most prevalent (24/34; 70.6%). Notably, T21I mutation had a prevalence of 20.6% (7/34) and coexisted 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 included P108S, with a prevalence of 5.88% (2/34), and L50F, with a prevalence of 2.94% (1/34). NTV/r RAMs were significantly higher (P < .001) in Delta (24/35) compared with Beta (4/34) and Omicron (6/34) sequences.

Conclusions: The frequency of NTV/r RAMs in Botswana was low. Higher rates were observed in Delta VOCs compared to Omicron and Beta VOCs. As NTV/r use expands globally, continuous surveillance for drug-resistant variants is essential, given the RAMs identified in our study.

Keywords: Botswana; Paxlovid; SARS-CoV-2; nirmatrelvir-ritonavir; resistance mutations.

Abstract

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