Nirmatrelvir-ritonavir treatment on SARS-CoV-2 viral dynamics in high altitude habitants

Social and environmental factors of high-altitude regions such as the Tibet plateau are proposed to protect habitants against SARS-CoV-2 infection.1Song P. Han H. Feng H. et al.High altitude Relieves transmission risks of COVID-19 through meteorological and environmental factors: evidence from China.Environ Res. 2022; 212113214Google Scholar,2Segovia-Juarez J. Castagnetto J.M. Gonzales G.F. High altitude reduces infection rate of COVID-19 but not case-fatality rate.Respir Physiol Neurobiol. 2020; 281103494Google Scholar However, once infected, high altitude habitants may suffer more severe respiratory stress due to the compounding effect of hypobaric hypoxia and SARS-CoV-2-induced hypoxemia.2Segovia-Juarez J. Castagnetto J.M. Gonzales G.F. High altitude reduces infection rate of COVID-19 but not case-fatality rate.Respir Physiol Neurobiol. 2020; 281103494Google Scholar Access to comprehensive medical care and therapeutic options are often limited in high-altitude regions, making orally available antivirals such as nirmatrelvir-ritonavir essential for high altitude habitants with COVID-19.3Dal-Re R. Becker S.L. Bottieau E. Holm S. Availability of oral antivirals against SARS-CoV-2 infection and the requirement for an ethical prescribing approach.Lancet Infect Dis. 2022; 22: e231-e238Google Scholar Nirmatrelvir-ritonavir reduces viral load by inhibiting the main protease of SARS-CoV-2, which effectively prevents assembly of new virions.4Owen D.R. Allerton C.M.N. Anderson A.S. et al.An oral SARS-CoV-2 M(pro) inhibitor clinical candidate for the treatment of COVID-19.Science. 2021; 374: 1586-1593Google Scholar A caveat of this strategy is the requirement of early treatment, normally within 5 days after symptom onset, which is challenging in high-altitude regions with limited testing and drug distribution capacities. Chronic hypoxia may also alter the infection pattern of SARS-CoV-2 by reducing ACE2 expression in lung epithelial cells, which could render nirmatrelvir-ritonavir less effective in high altitude habitants.5Wing P.A.C. Keeley T.P. Zhuang X. et al.Hypoxic and pharmacological activation of HIF inhibits SARS-CoV-2 infection of lung epithelial cells.Cell Rep. 2021; 35109020Google Scholar Here, we analyzed a cohort of 314 hospitalized COVID-19 cases in Nyingchi city of the Tibet Autonomous Region of China (alt. 3100 m), who were infected by the omicron BA.2.76 subvariant (appendix p 2). In-hospital procedures including viral testing, symptom monitoring, and treatments were detailed in the Methods (appendix p 7–9). Most cases had mild or no symptoms, and all cases survived the infection. Boost vaccination status was not associated with peak viral load or viral clearance likely due to wanning immunity and high immune evasiveness of omicron (appendix p 3). 89 cases with indications were prescribed nirmatrelvir-ritonavir at a median of 2 (IQR 1–2) days after viral positive. Despite of worse demographic and clinical characteristics (appendix p 9), viral loads in upper respiratory tracts decreased faster among nirmatrelvir-ritonavir recipients with geometric mean dropped below detection threshold 1 day earlier than control group (Fig. 1A). Proportions of viral clearance at day 10 since viral positive were 62.9% and 36.4% (odds ratio 2.96, 95% CI 1.75–4.83) in nirmatrelvir-ritonavir and control groups, respectively (Fig. 1B). Cox regression for time to viral clearance estimated the hazard ratio of nirmatrelvir-ritonavir vs control as 2.43 (95% CI 1.83–3.23) after adjusting for confounders (Fig. 1C). Of note, viral rebound was observed in 10.1% and 9.8% patients in nirmatrelvir-ritonavir and control groups, respectively. Stratification by high-altitude habitant status or ethnicity showed comparable association of nirmatrelvir-ritonavir with early viral clearance in every group (appendix p 4–5), indicating that neither physiological nor genetic adaptation to high-altitude environment might interfere with therapeutic mechanisms of nirmatrelvir-ritonavir. In contrast, the adjusted hazard ratio of nirmatrelvir-ritonavir for viral clearance was higher among male subjects (3.16 vs 1.93 of females), indicating potential sex-associated mechanism regulating the therapeutic efficacy of nirmatrelvir-ritonavir (appendix p 6–7). Booster vaccination was also associated with higher adjusted hazard ratio of nirmatrelvir-ritonavir for viral clearance (3.50 vs 1.87 of subjects not booster vaccinated), supporting a possible synergy or mutual dependence between nirmatrelvir-ritonavir and vaccine-elicited immunity (appendix p 6–7), which might be unique in high-altitude settings.6Wong C.K.H. Au I.C.H. Lau K.T.K. Lau E.H.Y. Cowling B.J. Leung G.M. Real-world effectiveness of molnupiravir and nirmatrelvir plus ritonavir against mortality, hospitalisation, and in-hospital outcomes among community-dwelling, ambulatory patients with confirmed SARS-CoV-2 infection during the omicron wave in Hong Kong: an observational study.Lancet. 2022; 400: 1213-1222Google Scholar Among subjects with comorbidities, nirmatrelvir-ritonavir was associated with 50% (9/18 days), 61% (12.5/20.5), and 33% (5/15) reduction of median viral positive duration in all subjects and hypertension or diabetes subgroups, respectively (appendix p 8). However, some of these stratified analyses had insufficient statistical power due to limited sample sizes and results should be interpreted with caution. Our data provided preliminary evidence that nirmatrelvir-ritonavir remained effective in accelerating omicron viral clearance at high-altitude settings, and highlighted the importance of nirmatrelvir-ritonavir availability and timely prescription in regions with limited medical resources. Nonetheless, further studies are needed to assess the protective effect of nirmatrelvir-ritonavir against severe COVID-19 in high-altitude regions. This study received no funding.