Social and environmental factors of high-altitude regions, such as the Tibetan Plateau, are proposed to protect inhabitants against SARS-CoV-2 infection. 1Song P. Han H. Feng H. et al. High Altitude Alleviates COVID-19 Transmission Risks and Environmental Factors: Evidence from China.,2Segovia-Juarez J. Castagnetto JM Gonzales GF High altitude reduces the COVID-19 infection rate but not the fatality rate. However, once infected, high-altitude dwellers may suffer more severe respiratory stress due to the combined effect of hypobaric hypoxia and hypoxemia induced by SARS-CoV-2.2Segovia-Juarez J. Castagnetto JM Gonzales GF High altitude it reduces the infection rate of COVID-19 but not the fatality rate. Access to comprehensive medical care and therapeutic options are often limited in high-altitude regions, making available oral antivirals, such as nirmatrelvir-ritonavir, essential for high-altitude dwellers with COVID-19.3 Dal-Re R. Becker SL Bottieau E. Holm S. Availability of oral antivirals against SARS-CoV-2 infection and the requirement for an ethical prescribing approach.Nirmatrelvir-ritonavir reduces viral load by inhibiting the main protease of SARS-CoV-2, effectively preventing the assembly of new virions. the treatment of COVID-19. A caveat to this strategy is the requirement for early treatment, typically within 5 days of symptom onset, which is challenging in high-altitude regions with limited drug distribution and testing capabilities. Chronic hypoxia may also alter the infection pattern of SARS-CoV-2 by reducing ACE2 expression in lung epithelial cells, which could make nirmatrelvir-ritonavir less effective in high-altitude dwellers.5Wing PAC Keeley TP Zhuang X. et al. Hypoxic and pharmacologically activated HIF inhibits SARS-CoV-2 infection of lung epithelial cells.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 subvariant BA.2.76 (appendix p 2). Hospital procedures, including viral testing, symptom control, and treatments, were detailed in the Methods (appendix p 7–9). Most cases had mild or no symptoms, and all cases survived the infection. Booster status was not associated with peak viral load or viral clearance probably due to decreased immunity and high immunological 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 worse demographics and clinical features (appendix p 9), upper respiratory viral loads declined more rapidly among nirmatrelvir-ritonavir recipients with a geometric mean falling below the detection threshold 1 day earlier than treatment. control group (Fig. 1A). Viral clearance ratios at day 10 from virus positive were 62.9% and 36.4% (odds ratio 2.96, 95% CI 1.75–4.83) in the nirmatrelvir-ritonavir groups and control, respectively (Fig. 1B). Cox regression for time to viral clearance estimated the hazard ratio for nirmatrelvir-ritonavir vs. control at 2.43 (95% CI: 1.83–3.23) after adjusting for confounding factors ( Fig. 1C). Of note, viral rebound was observed in 10.1% and 9.8% of patients in the nirmatrelvir-ritonavir and control groups, respectively.
Figure 1Nirmatrelvir-ritonavir treatment on viral dynamics of SARS-CoV-2 in the upper respiratory tract. (A) Dynamics of viral load in the upper respiratory tract of individuals infected with SARS-CoV-2 treated with or without nimatrelvir-ritonavir. Time zero corresponds to the time when a patient first tested positive for SARS-CoV-2 infection. Points and error bars represent geometric means and 95% confidence intervals (CI). The horizontal dashed line indicates the detection limit of the qRT-PCR assay (100 copies/ml). The sample number at each data point is listed below the graph. (B.) Cumulative event plots of time to viral clearance by nirmatrelvir-ritonavir treatment status. Hazard ratios (HRs) and CI were estimated using the Cox proportional hazards model after adjusting for the confounding factors listed in panel C. (C.) Forest plots showing Cox proportional hazard model analysis of the indicated factors with time to viral clearance as the dependent variable (n = 314). The adjusted HR of each factor is expressed on the logarithmic axis. Squares and error bars represent the HR and 95% CI. Directional trends are labeled below the X axis.
Stratification by high-altitude status or ethnicity showed a comparable association of nirmatrelvir-ritonavir with early viral clearance in each group (appendix p 4-5), indicating that neither physiological nor genetic adaptation to the high-altitude environment could interfere with the 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 for females), suggesting a possible sex-associated mechanism regulating viral clearance. therapeutic efficacy of nirmatrelvir-ritonavir (appendix p 6-7). Booster vaccination was also associated with a higher adjusted risk ratio of nirmatrelvir-ritonavir for viral clearance (3.50 vs 1.87 for non-booster vaccinated subjects), supporting a possible synergy or mutual dependence between nirmatrelvir-ritonavir and vaccine-induced immunity (appendix p 6-7). ), which might be unique in high-altitude settings.6Wong CKH Au ICH Lau KTK Lau EHY Cowling BJ Leung GM Real-world efficacy of molnupiravir and nirmatrelvir plus ritonavir against mortality, hospitalization, and in-hospital outcomes in living outpatients in the community patients with confirmed SARS-CoV-2 infection during the omicron wave in Hong Kong: an observational study. Among subjects with comorbidities, nirmatrelvir-ritonavir was associated with a 50% (9/18 days), 61% (12.5/20.5), and 33% (5/15) reduction in median viral positive duration in all subjects and subgroups of hypertension or diabetes, respectively (appendix p 8). However, some of these stratified analyzes were underpowered due to limited sample sizes and the results should be interpreted with caution.
Our data provided preliminary evidence that nirmatrelvir-ritonavir remained effective in accelerating omicron viral clearance in high-altitude settings, and highlighted the importance of availability and timely prescription of nirmatrelvir-ritonavir in regions with limited medical resources. However, further studies are needed to evaluate the protective effect of nirmatrelvir-ritonavir against severe COVID-19 in high-altitude regions.
Role of the funding source
This study did not receive funding.
Collaborators
AL and XZ contributed equally. AL, XZ and XR summarized the case information and did clinical investigations; LT did statistical analysis; DH and YZ interpreted the clinical findings; PH conceived of the study, analyzed the data, and wrote the manuscript. No author was prevented from accessing the study data, and they accept responsibility for submitting it for publication. All authors read and approve the final manuscript.
Declaration of interests
The authors declare not to have any interest conflicts.
Appendix A. supplementary data
References
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High altitude reduces the infection rate of COVID-19 but not the fatality rate.
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Posted: December 24, 2022
Accepted: December 11, 2022
Received in revised form: December 5, 2022
Received: October 13, 2022
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DOI: https://doi.org/10.1016/j.lanwpc.2022.100671
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