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Background: There is a dearth of research on the factors linked with adverse events (AEs) associated with nirmatrelvir/ritonavir (NMVr) and molnupiravir (MOL), particularly in the elderly. Therefore, this study aimed to investigate self-reported AEs and identify factors associated with the occurrence of AEs following NMVr or MOL treatment among survey participants aged 60 years or older in South Korea., Methods: This nationwide survey was conducted through in-person interviews using structured questionnaires, from July 24 to August 31, 2023. Eligible participants included individuals aged 60 years or older who had been diagnosed with coronavirus disease 2019 (COVID-19) and received NMVr or MOL. The study outcomes included self-reported demographic, lifestyle, and health characteristics associated with the occurrence of AEs. Multivariate logistic regression analysis was used to estimate the adjusted odds ratio (aOR) and 95% confidence interval (CI) of each characteristic in participants with and without AEs., Results: Of the 520 participants, 123 (23.7%) experienced at least one AE with oral COVID-19 treatment: 21.0% (96/458) for NMVr and 43.5% (27/62) for MOL. None of the participants reported any serious AEs. Increased odds of AE occurrence were observed in participants treated with MOL compared to those treated with NMVr (aOR, 3.05; 95% CI, 1.67-5.57), a history of two or more compared to one COVID-19 diagnosis (1.93; 1.03-3.62), and self-reported health status as "Unhealthy" compared to "Healthy" (2.65; 1.31-5.36)., Conclusion: No AEs required further evaluation to change treatment strategies in elderly patients on NMVr or MOL. Several factors, including the use of MOL, history of COVID-19, and reported health status, were associated with an increased incidence of AEs. Both treatments may still be useful choices for patients with non-severe COVID-19 aged 60 years or older. However, close monitoring of unidentified potential harm and further investigation of the factors associated with the occurrence of AEs are needed., Competing Interests: Ju-Young Shin received grants from the Korea Institute of Drug Safety and Risk Management. Other authors have no potential conflicts of interest to disclose., (© 2024 The Korean Academy of Medical Sciences.)

This retrospective cross-sectional study aims to evaluate the safety, tolerability, and adherence of patients prescribed Nirmatrelvir-ritonavir (Paxlovid) in outpatient settings, focusing on its use in managing category 2 COVID-19 patients across three primary healthcare clinics in Selangor, Malaysia. Data were collected from the Paxlovid pharmacy registry and medical records at Klinik Kesihatan Seksyen 7, Klinik Kesihatan Seksyen 19, and Klinik Kesihatan Kelana Jaya between April 1, 2022, and November 30, 2022. This study analysed data from 415 category 2 COVID-19 patients aged ≥ 18 years. The primary and secondary outcomes included the assessment of patient demographics, Paxlovid dosing, current medication, changes in drug regimen, adherence, and adverse drug reactions (ADR). Pharmacists follow-ups were conducted on days 3 and 5 post-medication initiation. The majority (79.5%) of the cohort experienced ADR, predominantly dysgeusia, diarrhoea, body ache, vomiting, and nausea. Despite this, the ADRs were generally well-tolerated, with no severe impacts reported. High adherence was observed, with 96.9% of patients completing the 5-day regimen. The primary reasons for non-adherence included adverse effect intolerability, dosing ambiguity, forgetfulness, concerns about ADR, and perceived health improvement. Notable medications interacting with Paxlovid were simvastatin, amlodipine, and atorvastatin, and 21.7% of 23 concurrent medications were found not to comply with the recommended interventions by the University of Liverpool COVID-19 Drug Interaction database. Paxlovid demonstrates a high level of safety and tolerability in outpatient COVID-19 patients, with optimal adherence observed. This study underscores the vital role of healthcare professionals in managing Paxlovid within primary healthcare and highlights the need for broader research and direct patient involvement to enhance treatment strategies against COVID-19., (© 2024. The Author(s).)

The study was to evaluate the clinical outcomes of azvudine versus nirmatrelvir-ritonavir against omicron strains of coronavirus disease 2019 infections and determine their comparative effectiveness. This retrospective study included 716 patients who received nirmatrelvir-ritonavir (NR group) or azvudine (FNC group) at Peking Union Medical College Hospital between 1 November 2022 and 27 February 2023. Patients in the FNC group (n = 304) were younger, exhibited less severe symptoms, started antiviral therapy later, received corticosteroids more frequently, and used tocilizumab less frequently than patients in the NR group (n = 412). Within 28 d of therapy, 40 (9.7%) and 20 (6.6%) deaths were in the NR and FNC groups, respectively. No differences were observed between drugs and mortality rates (odds ratio [OR] 0.78, 95% CI 0.40-1.5, P = 0.45), clinical improvement (OR 0.79, 95% CI 0.79-1.3, P = 0.38), and clinical progression (OR 1.0, 95% CI 0.58-1.8, P = 0.96). More patients in the NR group experienced platelet decline than those in the FNC group (17.6% vs. 8.9%, P = 0.034). This study indicated that the effectiveness and safety of azvudine were comparable to those of nirmatrelvir-ritonavir., (© 2024. The Author(s).)

Background: Studies have established the short-term efficacy of nirmatrelvir-ritonavir in managing COVID-19, yet its effect on post-COVID-19 condition, especially in patients admitted to hospital, remains understudied. This study aimed to examine the effect of nirmatrelvir-ritonavir on post-COVID-19 condition among patients admitted to hospital in Hong Kong., Methods: This retrospective cohort study used real-world, territory-wide inpatient records, vaccination records, and confirmed COVID-19 case data from the Hong Kong Hospital Authority and Department of Health, The Government of the Hong Kong Special Administrative Region. Patients aged 18 years and older who tested positive for SARS-CoV-2 between March 11, 2022, and Oct 10, 2023, and who were admitted to hospital with COVID-19 were included. The treatment group included patients prescribed nirmatrelvir-ritonavir within 5 days of symptom onset, excluding those prescribed molnupiravir within 21 days, and the control group had no exposure to either nirmatrelvir-ritonavir or molnupiravir. The outcomes were post-acute inpatient death and 13 sequelae (congestive heart failure, atrial fibrillation, coronary artery disease, deep vein thrombosis, chronic pulmonary disease, acute respiratory distress syndrome, interstitial lung disease, seizure, anxiety, post-traumatic stress disorder, end-stage renal disease, acute kidney injury, and pancreatitis). These outcomes were evaluated starting at 21 days after the positive RT-PCR date in each respective cohort constructed for the outcome. Standardised mortality ratio weights were applied to balance covariates, and Cox proportional hazards regression was used to investigate the relationship between nirmatrelvir-ritonavir and outcomes., Findings: 136 973 patients were screened for inclusion, among whom 50 055 were eligible and included in the analysis (24 873 [49·7%] were female and 25 182 [50·3%] were male). 15 242 patients were prescribed nirmatrelvir-ritonavir during acute COVID-19 and 23 756 patients were included in the control group; 11 057 patients did not meet our definition for the exposed and unexposed groups. Patients were followed up for a median of 393 days (IQR 317-489). In the nirmatrelvir-ritonavir group compared with the control group, there was a significantly lower hazard of post-acute inpatient death (hazard ratio 0·62 [95% CI 0·57-0·68]; p<0·0001), congestive heart failure (0·70 [0·58-0·85]; p=0·0002), atrial fibrillation (0·63 [0·52-0·76]; p<0·0001), coronary artery disease (0·71 [0·59-0·85]; p=0·0002), chronic pulmonary disease (0·68 [0·54-0·86]; p=0·0011), acute respiratory distress syndrome (0·71 [0·58-0·86]; p=0·0007), interstitial lung disease (0·17 [0·04-0·75]; p=0·020), and end-stage renal disease (0·37 [0·18-0·74]; p=0·0049). There was no evidence indicating difference between the groups in deep vein thrombosis, seizure, anxiety, post-traumatic stress disorder, acute kidney injury, and pancreatitis., Interpretation: This study showed extended benefits of nirmatrelvir-ritonavir for reducing the risk of post-acute inpatient death as well as cardiovascular and respiratory complications among patients admitted to hospital with COVID-19. Further research is essential to uncover the underlying mechanisms responsible for these observed negative associations and to devise effective strategies for preventing the onset of post-acute sequelae., Funding: Health and Medical Research Fund, Research Grants Council theme-based research schemes, and Research Grants Council Collaborative Research Fund., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

APV20002 was a multicenter, international, open-label study that began in 2003 investigating the pharmacokinetics, efficacy, and safety of ritonavir-boosted fosamprenavir (FPV/r) oral solution (OS) in combination with nucleoside reverse transcriptase inhibitor-based antiretroviral therapy (ART) in participants living with HIV-1 aged 4 weeks to <2 years with a primary endpoint at Week 48 (48W). Participants in APV20002 could continue in the study post-48W until FPV OS was locally available in their countries. Children were required to discontinue after reaching >39 kg or if FPV OS had no clinical benefit. Fifty-nine participants were enrolled; 5/59 received a single FPV OS visit for pharmacokinetic determinations. Most (38/54; 70%) were antiretroviral experienced; 39/59 participants had >48 weeks on treatment, 4/39 of whom discontinued after 48 weeks due to an adverse event (AE). At 48W, 88% of participants had HIV-1 RNA <400 copies/mL by Observed analysis; the proportion with HIV-1 RNA <400 copies/mL remained high (84%-100%) through Week 684. The median CD4 + cell count was 1,235 cells/mm 3 [ n = 51] at baseline, 1,690 cells/mm 3 ( n = 41) at Week 48, and 1,280 cells/mm 3 ( n = 21) at Week 180. From baseline to Week 684, 54/59 (92%) participants had ≥1 treatment-emergent AE regardless of causality; 42/59 (71%) had a treatment-emergent grade 2-4 AE, predominantly maximum toxicity: grade 2; 21/59 (36%) and 21/59 (36%) had severe or grade 3/4 AEs. From baseline to Week 684, 14/54 (26%) participants met virologic failure (VF) criteria, 9/14 before 48W. HIV from 1/9 VFs through 48W developed treatment-emergent reduced susceptibility to FPV and 1/9 to lamivudine/emtricitabine. Post-48W, 4/5 participants with VF had phenotype results; all were still susceptible to all study drugs at VF. In conclusion, FPV OS-based ART was efficacious and generally well tolerated in this long-running pediatric study through 684 weeks of treatment, with a safety profile consistent with experience in adults and older children.

Introduction: In May 2022, the Centers for Disease Control and Prevention disseminated an alert advising that "a few" persons with Nirmatrelvir/ritonavir (NM/R)-associated rebound of COVID-19 infection had been identified. Three case reports appearing as pre-print postings described the first cases. Analyses in March 2023 by NM/R's manufacturer and the Food and Drug Administration (FDA) reported no association between NM/R and COVID-19 rebound in a large phase 3 randomized clinical trial. Our study evaluated if social media databases or electronically disseminated new articles might provide insights related to the putative new toxicity, NM/R-associated COVID-19 rebound., Methods: Information on NM/R-associated COVID-19 rebound cases was abstracted from preprint postings of non-peer-reviewed manuscripts, social media websites, electronically disseminated print and television media reports, a new FDA adverse event database for drugs that received Emergency Use Approval, and news articles in scientific journals., Results: Thirty-five persons experienced presumed or documented NM/R-associated COVID-19 rebound, based on information described in preprint services (n = 27), Twitter postings and related news articles (n = 7), and news articles without related Twitter reports (n = 1). These reports included information on dates of initial COVID-19 illness and rebound onset, COVID-19 testing, vaccine status, presentation, and outcome. A new FDA safety database identified 12,500 possible cases of this toxicity, but the quality of these data was poor. Preprint postings preceded peer-reviewed publications describing the same cases by four months. Social media websites including Instagram, Reddit, YouTube, the Center for Disease Control and Prevention's (CDC) Health Alert Network, CDC Twitter, and Facebook did not provide clinically meaningful information on individual cases., Conclusion: Preprint services and Twitter facilitated identification of the largest case series of NM/R-associated COVID-19 rebound. The cases were reported in non-peer-reviewed media several weeks prior to the first peer-reviewed electronically disseminated publication of one person with this diagnosis., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Bennett et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Objectives: To describe the management of haematological patients experiencing prolonged SARS-CoV-2 viral shedding, as the optimal management strategy for this condition remains undetermined., Methods: We conducted a retrospective evaluation of our prospectively followed cohort of haematological patients treated with remdesivir for more than 10 days. Starting January 2023, upon COVID-19 diagnosis, the treatment strategy was based on symptoms and PCR cycle threshold (Ct) as follows: (i) when Ct was 25 or less or if the patient had symptoms, a course of remdesivir for at least 10 days, nirmatrelvir/ritonavir for 5 days (whenever possible) and convalescent plasma was administered; and (ii) when the patient was asymptomatic and had a PCR Ct of more than 25, when possible, a course of 5 days of nirmatrelvir/ritonavir was administered. The patient was considered to have achieved viral clearance and, thus, remdesivir was stopped, in either of these cases: (i) PCR negativity, or (ii) subgenomic RNA negativity., Results: From January to November 2023, 18 patients benefited from a safe extended remdesivir administration, resulting in detection of SARS-CoV-2 viral clearance in a median time of 3.5 weeks (IQR 2.6-3.9) (min-max 1.6-8.0). No clinical or biological side effects were detected. No patient died or needed further treatment for their COVID-19 episode., Conclusions: The extended course of remdesivir, combined with other active therapies for COVID-19 infection, was well tolerated. Cure and virus negativity were obtained in all these high-risk patients., (© The Author(s) 2024. Published by Oxford University Press on behalf of British Society for Antimicrobial Chemotherapy. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Ritonavir (RTV), which is used in combination with nilmatrelvir (NMV) to treat coronavirus disease 2019 (COVID-19), inhibits cytochrome P450 (CYP) 3A, thereby increasing blood tacrolimus (TAC) levels through a drug-drug interaction (DDI). We experienced a case in which a DDI between the two drugs led to markedly increased blood TAC levels, resulting in vasospastic angina (VSA) and acute kidney injury (AKI). Rifampicin (RFP) was administered to induce CYP3A and promote TAC metabolism. A 60-year-old man with dermatomyositis who was taking 3 mg/day TAC contracted COVID-19. The patient started oral NMV/RTV therapy, and he was admitted to the hospital after 4 days because of chest pain and AKI. On day 5, his blood TAC level increased markedly to 119.8 ng/mL. RFP 600 mg was administered once daily for 3 days, and his blood TAC level decreased to the therapeutic range of 9.6 ng/mL on day 9, leading to AKI improvement. Transient complete atrioventricular block and nonsustained ventricular tachycardia were present during chest pain. In the coronary spasm provocation test, complete occlusion was observed in the right coronary artery, leading to a diagnosis of VSA. VSA and AKI are possible side effects of high blood TAC levels caused by DDI, and attention should be paid to cardiovascular side effects such as VSA and AKI associated with increased blood levels of TAC when it is used together with NMV/RTV. When blood levels of TAC increase, oral RFP can rapidly decrease TAC blood levels and potentially reduce its toxicity., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Background : Several studies have examined INR fluctuations using pharmacokinetic (PK) models or post-hoc INR values after completing nirmatrelvir/ritonavir, but further study of the effects of the drug interaction with warfarin during treatment is necessary. Case Summary : Nirmatrelvir/ritonavir is largely utilized in the outpatient setting so data regarding INR trends in hospitalized patients on warfarin is limited. However, many who receive nirmatrelvir/ritonavir outpatient experience difficulty with presenting to clinic for INR checks due to feeling acutely ill along with isolation precautions. We present the case of a patient receiving warfarin and utilizing home INR testing for monitoring. After diagnosis of coronavirus disease of 2019 (COVID-19), she was started on nirmatrelvir/ritonavir on day five after testing positive. Most recent INR prior to the start of therapy was 2.7 and had been stable on the same dose for months prior to infection. On day two of nirmatrelvir/ritonavir, her INR rose to 4.0 on home point of care INR testing. Despite reducing her dose of warfarin by 15%, her INR remained supratherapeutic the day after completing nirmatrelvir/ritonavir (4.0) and for several checks after. One month after completion of therapy, her INR returned to therapeutic levels. Practice Implications : While PK models and case series have hypothesized both potential increases or decreases in INR with the nirmatrelvir/ritonavir and warfarin interaction, COVID-19 infection itself can cause several pharmacodynamic changes which can increase INR, including decreased appetite and, in severe cases, organ dysfunction. This case provides real-world insight into the drug interaction between nirmatrelvir/ritonavir and the drug-disease state interaction between warfarin and COVID-19., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

GST-HG171 is a potent, broad-spectrum, orally bioavailable small-molecule 3C-like (3CL) protease inhibitor that was recently approved for treating mild to moderate coronavirus disease 2019 patients in China. Since cytochrome P450 (CYP) enzymes, primarily CYP3A, are the main metabolic enzymes of GST-HG171, hepatic impairment may affect its pharmacokinetic (PK) profile. Aiming to guide clinical dosing for patients with hepatic impairment, this study, using a non-randomized, open-label, single-dose design, assessed the impact of hepatic impairment on the PK, safety, and tolerability of GST-HG171. Patients with mild and moderate hepatic impairment along with healthy subjects were enrolled ( n = 8 each), receiving a single oral dose of 150 mg GST-HG171, with concurrent administration of 100 mg ritonavir to sustain CYP3A inhibition before and after GST-HG171 administration (-12, 0, 12, and 24 hours). Compared to subjects with normal hepatic function, the geometric least-squares mean ratios (90% confidence intervals) for GST-HG171's maximum plasma concentration ( C max ), area under the concentration-time curve up to the last quantifiable time (AUC 0- t ), and area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC 0-∞ ) in subjects with mild hepatic impairment were 1.14 (0.99, 1.31), 1.07 (0.88, 1.30), and 1.07 (0.88, 1.29), respectively. For moderate hepatic impairment, the ratios were 0.87 (0.70, 1.07), 0.82 (0.61, 1.10), and 0.82 (0.61, 1.10), respectively. Hepatic impairment did not significantly alter GST-HG171's peak time ( T max ) and elimination half-life ( T 1/2 ). GST-HG171 exhibited good safety and tolerability in the study. Taken together, mild to moderate hepatic impairment minimally impacted GST-HG171 exposure, suggesting no need to adjust GST-HG171 dosage for patients with mild to moderate hepatic impairment in the clinic.Clinical TrialsRegistered at ClinicalTrials.gov (NCT06106113)., Competing Interests: The authors declare no conflict of interest.

Background: Nirmatrelvir/Ritonavir is an orally administered anti-SARS-Cov-2 drug used in mild-to-moderate COVID-19 patients. Our retrospective cohort study aims to evaluate the efficacy and safety of Nirmatrelvir/Ritonavir in severe hospitalized patients with Omicron infection, as well as in patients at high risk for progression to critical illness in real-world settings. Methods: A total of 350 patients received Nirmatrelvir/Ritonavir while 350 matched controls did not. Patients with confirmed COVID-19 were administered Nirmatrelvir 300 mg and Ritonavir 100 mg orally twice a day for 5 days, with the medication initiated on the first day after admission. The primary endpoint of the study was a composite outcome of hospitalization or death from any cause within 28 days. Secondary endpoints included the occurrence of adverse events and the evaluation of serum levels of IL-6 and viral load. Results: We documented the mortality risk from any cause within 28 days, viral load, serum IL-6 levels, and adverse events. Nirmatrelvir/Ritonavir reduced the 28-day risk of all-cause mortality by 86% ( P  = .011, hazard ratio (HR) = 0.14, 95% confidence interval (CI) = 0.03, 0.64). At baseline, the serum level of IL-6 was significantly higher in the antiviral treatment group compared to the control group ( P  < .001), but no significant difference ( P  = .990) was found between the two groups at discharge. In CKD patients undergoing hemodialysis, no significant worsening of renal function was observed in the Nirmatrelvir/Ritonavir treatment group compared to the control group. Conclusion: Nirmatrelvir/Ritonavir may reduce the 28-day risk of all-cause mortality in critically ill patients with COVID-19 and in patients at high risk for critical disease progression., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Clinical trials of treatments for coronavirus disease 2019 (Covid-19) have not shown a significant benefit of postexposure prophylaxis., Methods: We conducted a phase 2-3 double-blind trial to assess the efficacy and safety of nirmatrelvir-ritonavir in asymptomatic, rapid antigen test-negative adults who had been exposed to a household contact with Covid-19 within 96 hours before randomization. The participants were randomly assigned in a 1:1:1 ratio to receive nirmatrelvir-ritonavir (300 mg of nirmatrelvir and 100 mg of ritonavir) every 12 hours for 5 days or for 10 days or matching placebo for 5 or 10 days. The primary end point was the development of symptomatic SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) infection, confirmed on reverse-transcriptase-polymerase-chain-reaction (RT-PCR) or rapid antigen testing, through 14 days in participants who had a negative RT-PCR test at baseline., Results: A total of 2736 participants were randomly assigned to a trial group - 921 to the 5-day nirmatrelvir-ritonavir group, 917 to the 10-day nirmatrelvir-ritonavir group, and 898 to the placebo group. Symptomatic, confirmed SARS-CoV-2 infection developed by day 14 in 2.6% of the participants in the 5-day nirmatrelvir-ritonavir group, 2.4% of those in the 10-day nirmatrelvir-ritonavir group, and 3.9% of those in the placebo group. In each nirmatrelvir-ritonavir group, the percentage of participants in whom symptomatic, confirmed SARS-CoV-2 infection developed did not differ significantly from that in the placebo group, with risk reductions relative to placebo of 29.8% (95% confidence interval [CI], -16.7 to 57.8; P = 0.17) in the 5-day nirmatrelvir-ritonavir group and 35.5% (95% CI, -11.5 to 62.7; P = 0.12) in the 10-day nirmatrelvir-ritonavir group. The incidence of adverse events was similar across the trial groups, with dysgeusia being the most frequently reported adverse event (in 5.9% and 6.8% of the participants in the 5-day and 10-day nirmatrelvir-ritonavir groups, respectively, and in 0.7% of those in the placebo group)., Conclusions: In this placebo-controlled trial, postexposure prophylaxis with nirmatrelvir-ritonavir for 5 or 10 days did not significantly reduce the risk of symptomatic SARS-CoV-2 infection. (Funded by Pfizer; ClinicalTrials.gov number, NCT05047601.)., (Copyright © 2024 Massachusetts Medical Society.)

Background: This study aims to compare the effectiveness and safety of nirmatrelvir/ritonavir (Paxlovid) and sotrovimab for coronavirus disease 2019 (COVID-19)., Methods: A search was conducted on PubMed, Cochrane Library, and Web of Science to explore relevant studies from January 2021 to November 2023. The risk of bias in the included studies was assessed using the Cochrane Collaboration's tool. Data analysis was conducted using the Comprehensive Meta-Analysis software (version 3.0)., Results: Fifteen retrospective studies involving 13, 306 patients were included. The meta-analysis revealed no significant difference between the nirmatrelvir/ritonavir and sotrovimab groups in terms of mortality rate (odds ratio [OR] = 0.62, 95% confidence interval [CI]: 0.28 to 1.38), hospitalization rate (OR = 0.76, 95% CI: 0.48 to 1.22), death or hospitalization rate (OR = 0.75, 95% CI: 0.51 to 1.10), and intensive unit care admission (OR = 1.97, 95% CI: 0.38 to 10.07). In terms of safety, nirmatrelvir/ritonavir was associated with a higher incidence of adverse events (OR = 3.44, 95% CI: 1.29 to 9.17)., Conclusions: The meta-analysis showed that nirmatrelvir/ritonavir and sotrovimab have similar effectiveness in treating COVID-19 patients. However, the certainty of evidence supporting these findings is low. High-quality research is needed to better compare these interventions in COVID-19.

This systematic review and meta-analysis aimed to compare the effectiveness and safety of azvudine versus nirmatrelvir/ritonavir (Paxlovid) in treating coronavirus disease 2019 (COVID-19). The researchers conducted searches on PubMed, Cochrane Library, Web of Science, medRxiv, and Google Scholar until January 2024. The Cochrane risk of bias tool was utilised to evaluate the quality of the included studies, and data analysis was performed using Comprehensive Meta-Analysis software. Thirteen studies, including 4949 patients, were analysed. The meta-analysis results showed no significant difference between the azvudine and Paxlovid groups in terms of mortality rate (odds rate [OR] = 0.84, 95% confidence interval [CI]: 0.59-1.21), negative polymerase chain reaction (PCR) conversion time (standard mean difference [SMD] = 1.52, 95% CI: -1.07-4.11), and hospital stay (SMD = -0.39, 95% CI: -1.12-0.33). However, a significant difference was observed between the two groups in terms of intensive care unit admission (OR = 0.42, 95% CI: 0.23-0.75) and the need for mechanical ventilation (OR = 0.61, 95% CI: 0.44-0.86) in favour of azvudine. The incidence of adverse events in the azvudine group was significantly lower (OR = 0.66, 95% CI: 0.43-0.99). The certainty of evidence was rated as low and moderate. Azvudine and Paxlovid demonstrated similar effectiveness in reducing mortality rates, negative PCR conversion time and hospital stay. However, azvudine showed better effectiveness in improving other outcomes. Regarding the level of certainty of evidence, further research is needed to validate or challenge these results., (© 2024 John Wiley & Sons Ltd.)

Immunocompromised patients with hematologic malignancies, particularly those treated with anti-CD20 antibodies such as rituximab and obinutuzumab, are known to be at risk of prolonged infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Prolonged administration or combination therapy with antiviral medications reportedly yields favorable outcomes in these patients. However, knowledge regarding the adverse events associated with such therapeutic approaches is limited. Herein, we report a case of acute acalculous cholecystitis (AAC) following extended administration of nirmatrelvir/ritonavir (NMV/r) in a 68-year-old Japanese man with persistent SARS-CoV-2 infection. The patient had received obinutuzumab and bendamustine for follicular lymphoma and was diagnosed with coronavirus disease 2019 (COVID-19) approximately one year after treatment initiation with these drugs. Subsequently, he was admitted to a different hospital, where he received antiviral drugs, monoclonal antibodies, and steroids. Despite these interventions, the patient relapsed and was subsequently transferred to our hospital due to persistent SARS-CoV-2 infection. Remdesivir administration was ineffective, leading to the initiation of extended NMV/r therapy. One week later, he exhibited elevated gamma-glutamyl transpeptidase (GGT) levels, and one month later, he developed AAC. Cholecystitis was successfully resolved via percutaneous transhepatic gallbladder drainage and administration of antibiotics. We speculate that extended NMV/r administration, in addition to COVID-19, may have contributed to the elevated GGT and AAC. During treatment of persistent SARS-CoV-2 infection with extended NMV/r therapy, patients should be carefully monitored for the appearance of findings suggestive of biliary stasis and the development of AAC., Competing Interests: Declaration of competing interest None., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Background/aim: Reports regarding the association of remdesivir use for the treatment of Coronavirus disease 2019 (COVID-19) with the development of acute kidney injury (AKI) are inconsistent, and the associations between the use of other antivirals and AKI remain unclear. Therefore, this study investigated whether the use of antiviral drugs for the treatment of COVID-19 is a risk factor for the development of AKI., Patients and Methods: This study analyzed 176,197 reports submitted to the Japanese Adverse Event Reporting Database between 2020 and 2022. Reporting odds ratios (RORs) and 95% confidence intervals (95%CIs) for AKI that were associated with the use of antiviral drugs in patients with COVID-19 were calculated after adjusting for potential confounders., Results: Overall, 5,879 of the reports analyzed were associated with AKI. Signs of AKI were detected with the use of remdesivir [crude ROR (cROR)=2.45; 95%CI=1.91-3.14] and nirmatrelvir/ritonavir (cROR=6.07; 95%CI=4.06-9.06). These results were maintained even after adjusting for potential confounders [remdesivir: adjusted ROR (aROR)=2.18; 95%CI=1.69-2.80, nirmatrelvir/ritonavir: aROR=5.24; 95%CI=3.48-7.90]. However, when analyzing data stratified by reporting year, the association between remdesivir and AKI appeared to diminish over time and was not sustained., Conclusion: Nirmatrelvir/ritonavir use may be associated with developing AKI. This knowledge may be useful in helping patients with COVID-19 avoid AKI complications., (Copyright © 2024, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Sanhan Huashi granules (SHG) demonstrated therapeutic effects against coronavirus disease 2019 (COVID-19) in observational studies. In order to compare the effectiveness and safety of SHG and nirmatrelvir-ritonavir in treating adults with mild-to-moderate COVID-19, we conducted a randomized, active-controlled, open-label, multi-center trial conducted between February and July in 2023. The patients were randomized in a 1:1 ratio to the SHG group and the nirmatrelvir-ritonavir group. A total of 400 participants were randomized, among which 200 participants ultimately received SHG and 198 received nirmatrelvir-ritonavir. The primary outcome was time to sustained clinical recovery through day 28. SHG significantly shortened the median time to sustained clinical recovery compared to nirmatrelvir-ritonavir (6.0 (95% CI, 5.0 to 6.0) vs. 8.0 (95% CI, 6.0 to 9.0) d; P = 0.001), particularly for individual symptoms including fever, sore throat, cough and fatigue. No participants in either group died and incidence of severe COVID-19 showed no difference between two groups. Participants who received nirmatrelvir-ritonavir demonstrated a higher rate of virus clearance on day 5 compared to those received SHG (46.4% (95% CI, 39.1 to 53.7) vs. 65.6% (95% CI, 58.3 to 72.4); P < 0.001). Most adverse events were mild in both groups. In summary, SHG was superior to nirmatrelvir-ritonavir in shortening the time to sustained clinical recovery in participants with mild-to-moderate COVID-19, despite a lower virus clearance rate observed after 5 d of treatment (Chinese Clinical Trial Registry Identifier: ChiCTR2300067872)., (Copyright © 2024 Science China Press. Published by Elsevier B.V. All rights reserved.)

Purpose: Nirmatrelvir/ritonavir is one of few options for outpatient treatment of COVID-19, but its use has been limited in transplant recipients due to significant drug interactions with immunosuppressants. Tacrolimus toxicity is possible when the drug is coadministered with nirmatrelvir/ritonavir and may require urgent reduction of tacrolimus levels. This case series describes the use of phenytoin for enzyme induction in 5 adult solid organ transplant recipients with supratherapeutic tacrolimus levels resulting from coadministration with nirmatrelvir/ritonavir., Summary: Solid organ transplant recipients are at high risk for complications related to COVID-19. Outpatient treatment options are limited, and therapeutic drug monitoring is complex in patients requiring quarantine. The 5 solid organ transplant recipients described herein were initiated on nirmatrelvir/ritonavir in the outpatient setting and subsequently presented with supratherapeutic tacrolimus concentrations greater than 59 ng/mL and developed signs and symptoms of tacrolimus toxicity. In all patients, nirmatrelvir/ritonavir and tacrolimus were discontinued, and oral phenytoin (200-400 mg/day) was given for 2 to 4 days. Tacrolimus was resumed once tacrolimus levels decreased to appropriate levels., Conclusion: These observations demonstrate that metabolism induction using phenytoin may be a useful strategy in the setting of supratherapeutic tacrolimus levels resulting from concomitant administration with nirmatrelvir/ritonavir., (© American Society of Health-System Pharmacists 2024. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: Due to the low number of individuals with HIV-2, no randomised trials of HIV-2 treatment have ever been done. We hypothesised that a non-comparative study describing the outcomes of several antiretroviral therapy (ART) regimens in parallel groups would improve understanding of how differences between HIV-1 and HIV-2 might lead to different therapeutic approaches., Methods: This pilot, phase 2, non-comparative, open-label, randomised controlled trial was done in Burkina Faso, Côte d'Ivoire, Senegal, and Togo. Adults with HIV-2 who were ART naive with CD4 counts of 200 cells per μL or greater were randomly assigned 1:1:1 to one of three treatment groups. A computer-generated sequentially numbered block randomisation list stratified by country was used for online allocation to the next available treatment group. In all groups, tenofovir disoproxil fumarate (henceforth tenofovir) was dosed at 245 mg once daily with either emtricitabine at 200 mg once daily or lamivudine at 300 mg once daily. The triple nucleoside reverse transcriptase inhibitor (NRTI) group received zidovudine at 250 mg twice daily. The ritonavir-boosted lopinavir group received lopinavir at 400 mg twice daily boosted with ritonavir at 100 mg twice daily. The raltegravir group received raltegravir at 400 mg twice daily. The primary outcome was the rate of treatment success at week 96, defined as an absence of serious morbidity event during follow-up, plasma HIV-2 RNA less than 50 copies per mL at week 96, and a substantial increase in CD4 cells between baseline and week 96. This trial is registered at ClinicalTrials.gov, NCT02150993, and is closed to new participants., Findings: Between Jan 26, 2016, and June 29, 2017, 210 participants were randomly assigned to treatment groups. Five participants died during the 96 weeks of follow-up (triple NRTI group, n=2; ritonavir-boosted lopinavir group, n=2; and raltegravir group, n=1), eight had a serious morbidity event (triple NRTI group, n=4; ritonavir-boosted lopinavir group, n=3; and raltegravir group, n=1), 17 had plasma HIV-2 RNA of 50 copies per mL or greater at least once (triple NRTI group, n=11; ritonavir-boosted lopinavir group, n=4; and raltegravir group, n=2), 32 (all in the triple NRTI group) switched to another ART regimen, and 18 permanently discontinued ART (triple NRTI group, n=5; ritonavir-boosted lopinavir group, n=7; and raltegravir group, n=6). The Data Safety Monitoring Board recommended premature termination of the triple NRTI regimen for safety reasons. The overall treatment success rate was 57% (95% CI 47-66) in the ritonavir-boosted lopinavir group and 59% (49-68) in the raltegravir group., Interpretation: The raltegravir and ritonavir-boosted lopinavir regimens were efficient and safe in adults with HIV-2. Both regimens could be compared in future phase 3 trials. The results of this pilot study suggest a trend towards better virological and immunological efficacy in the raltegravir-based regimen., Funding: ANRS MIE., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

(1) Background: Geriatric patients are at high risk of complications of Coronavirus disease-2019 (COVID-19) and are good candidates for antiviral drugs. (2) Methods: A retrospective study of electronic health records (EHRs) aiming to describe antiviral (nirmatrelvir and ritonavir (nirmatrelvir/r) or remdesivir) use, drug-drug interactions (DDIs) and adverse drug reactions (ADRs) in elderly patients (75 and over), hospitalized with mild-to-moderate COVID-19 between July 2022 and June 2023. (3) Results: Out of 491 patients (mean age: 86.9 years), 180 (36.7%) received nirmatrelvir/r, 78 (15.9%) received remdesivir, and 233 (47.4%) received no antiviral therapy. No association was found between the choice of antiviral and the demographic or medical data. No serious ADR was observed. Nirmatrelvir/r dosage adjustment was inadequate in 65% of patients with renal impairment. In total, 128 patients (71%) on nirmatrelvir/r had potential pharmacokinetic DDIs, with 43 resulting in a possibly related ADR. In the remdesivir group, pharmacodynamic DDIs were more frequent, with QTc prolongation risk in 56 patients (72%). Only 20 patients underwent follow-up ECG, revealing QTc prolongation in 4. (4) Conclusions: There is an underutilization of antivirals despite their justified indications. Nirmatrelvir/r dosage was rarely adjusted to renal function. Dose adjustments and closer monitoring are needed due to the high risk of drug interactions.

Background: Critical drug-drug interactions (DDI) and hepatotoxicity complicate concurrent use of rifampicin and protease inhibitors. We investigated whether dose escalation of atazanavir/ritonavir could safely overcome the DDI with rifampicin., Methods: DERIVE (NCT04121195, EDCTP) was a dose-escalation trial in people with human immunodeficiency virus (HIV) on atazanavir/ritonavir-based antiretroviral therapy (ART) in Uganda. Four intensive pharmacokinetic (PK) visits were performed: PK1 300/100 mg OD (baseline); PK2 300/100 mg OD with rifampicin 600 mg; PK3 300/100 mg twice a day (BID) with rifampicin 600 mg OD; PK4 300/100 mg BID with rifampicin 1200 mg OD. Dolutegravir 50 mg BID throughout the study period ensured participants remained protected from subtherapeutic atazanavir concentrations. The data were interpreted with noncompartmental analysis. The target minimum concentration was atazanavir's protein-adjusted IC90 (PA-IC90), 0.014 mg/L., Results: We enrolled 26 participants (23 female) with median (range) age 44 (28-61) years and weight 67 (50-75) kg. Compared with PK1, atazanavir Ctau, and AUC were significantly reduced at PK2 by 96% and 85%, respectively. The escalation to BID dosing (PK3) reduced this difference in Ctau, and AUC24 to 18% lower and 8% higher, respectively. Comparable exposures were maintained with double doses of rifampicin. Lowest Ctau during PK1, PK3, and PK4 were 12.7-, 4.8-, and 8.6-fold higher than PA-IC90, respectively, whereas 65% of PK2 Ctau were below the limit of quantification (0.03 mg/L), hence likely below PA-IC90. No participant developed significant elevation of liver enzymes, reported a serious adverse event (SAE) or experienced rebound viraemia., Conclusions: Twice daily atazanavir/ritonavir during rifampicin co-administration was well tolerated and achieved plasma concentrations above the target., Clinical Trials Registration: NCT04121195. Registered on 09 October 2019, https://clinicaltrials.gov/ct2/show/NCT04121195., Competing Interests: Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Study Aim: ModraDoc006, an oral formulation of docetaxel, is co-administered with the cytochrome P450-3A4 and P-glycoprotein inhibitor, ritonavir (r): ModraDoc006/r. The preliminary efficacy and safety of oral ModraDoc006/r was evaluated in a global randomized phase II trial and compared to the current standard chemotherapy regimen of intravenous (i.v.) docetaxel and prednisone., Methods: 103 mCRPC patients, chemotherapy-naïve with/without abiraterone and/or enzalutamide pretreated, with adequate organ function and evaluable disease per RECIST v1.1 and PCWG3 guidelines were randomized 1:1 into two cohorts. In Cohort 1, 49 patients received docetaxel 75 mg/m 2 i.v. every 3 weeks (Q3W). In Cohort 2, 52 patients received ModraDoc006/r; 21 patients with a starting dose of ModraDoc006 30 mg with ritonavir 200 mg in the morning and ModraDoc006 20 mg with ritonavir 100 mg in the evening (30-20/200-100 mg) bi-daily-once-weekly (BIDW) on Days 1, 8, and 15 of a 21-day cycle. To alleviate tolerability, the starting dose was amended to ModraDoc006/r 20-20/200-100 mg in another 31 patients. All patients received prednisone 10 mg daily. Primary endpoint was rPFS., Results: There was no significant difference in rPFS between the 2 arms (p = 0.1465). Median rPFS was 9.5 months and 11.1 months (95% CI) for ModraDoc006/r and i.v. docetaxel, respectively. Partial response was noted in 44.1% and 38.7% measurable disease patients, and 50% decline of PSA was seen in 23 (50%) and 26 (56.5%) evaluable cases treated with ModraDoc006/r and i.v. docetaxel, respectively. The safety profile of ModraDoc006/r 20-20/200-100 mg dose was significantly better than i.v. docetaxel, with mild (mostly Grade 1) gastrointestinal toxicities, no hematologic adverse events, and neuropathy and alopecia incidence of 11.5% and 25%, respectively., Conclusions: ModraDoc006/r potentially represents a widely applicable, convenient, effective, and better tolerated oral taxane therapy option for mCRPC. Further investigation of ModraDoc006/r in a large randomized trial is warranted., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Modra Pharmaceuticals BV was founded as a spin-off company of the Netherlands Cancer Institute, enabling the further clinical development of novel oral taxane formulations, after their pharmaceutical and preclinical development in the Netherlands Cancer Institute. Marianne Keessen is a full-time employee of Modra Pharmaceuticals BV. The other authors declare no relevant conflict of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Study of liquid lopinavir/ritonavir (LPV/r) in young infants has been limited by concerns for its safety in neonates., Methods: International Maternal Pediatric Adolescent AIDS Clinical Trials Network P1106 was a phase IV, prospective, trial evaluating the safety and pharmacokinetics of antiretroviral medications administered according to local guidelines to South African preterm and term infants <3 months of age. Safety evaluation through 24-week follow-up included clinical, cardiac and laboratory assessments. Pharmacokinetic data from P1106 were combined with data from International Maternal Pediatric Adolescent AIDS Clinical Trials Network studies P1030 and P1083 in a population pharmacokinetics model used to simulate LPV exposures with a weight-band dosing regimen in infants through age 6 months., Results: Safety and pharmacokinetics results were similar in 13/28 (46%) infants initiating LPV/r <42 weeks postmenstrual age (PMA) and in those starting ≥42 weeks PMA. LPV/r was started at a median (range) age of 47 (13-121) days. No grade 3 or higher adverse events were considered treatment related. Modeling and simulation predicted that for infants with gestational age ≥27 weeks who receive the weight-band dosing regimen, 82.6% will achieve LPV trough concentration above the target trough concentration of 1.0 µg/mL and 56.6% would exceed the observed adult lower limit of LPV exposure of 55.9 µg·h/mL through age 6 months., Conclusions: LPV/r oral solution was safely initiated in a relatively small sample size of infants ≥34 weeks PMA and >2 weeks of life. No serious drug-related safety signal was observed; however, adrenal function assessments were not performed. Weight-band dosing regimen in infants with gestational age ≥27 weeks is predicted to result in LPV exposures equivalent to those observed in other pediatric studies., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Coronavirus disease 2019 (COVID-19) infection in lung transplant recipients can be lethal owing to the use of immunosuppressants. Antiviral agents may be administered to these patients. Co-packaged nirmatrelvir-ritonavir is a new agent currently being used in combination., Case Presentation: In this report, we present a case of a 64-year-old woman, a lung transplant recipient, who experienced hyponatremia and showed a high serum tacrolimus concentration following the administration of the co-packaged nirmatrelvir-ritonavir combination., Conclusion: Although the nirmatrelvir-ritonavir and tacrolimus combination is not contraindicated, other treatment strategies should be considered first, if available, and the dose of tacrolimus should be reduced when using the nirmatrelvir-ritonavir combination. In cases where combination therapy is necessary, serum tacrolimus levels should be closely monitored in lung transplant recipients. Documentation of more such reports is important to identify drug interactions between nirmatrelvir-ritonavir and other agents, with the aim of preventing severe adverse effects., (© 2024. The Author(s).)

Transplant patients face an elevated risk of coronavirus disease 2019 (COVID-19) morbidity and mortality and commonly encounter renal dysfunction. Nirmatrelvir is primarily excreted through the kidneys. The dosage of nirmatrelvir/ritonavir (NR) needs to be adjusted according to the degree of renal function impairment. Nevertheless, NR is not recommended for patients with severe renal impairment (estimated glomerular filtration rate < 30 mL/min) due to a dearth of associated research. In this study, we focus on kidney transplant patients and document and analyze the experiences of using NR in individuals with severe kidney dysfunction. This was a retrospective multicenter study that included transplant recipients hospitalized for COVID-19 in five major tertiary hospitals in China from December 2022 to June 2023. The outcomes consisted of the disease progression rate by day 28, individual disease progression events, safety outcomes, information on adverse events (AEs), and the blood drug concentrations of immunosuppressants. Data were presented with descriptive statistics. All analyses were performed using SPSS version 22. In total, 40 patients were included in the analysis. Considering the potential interaction between drugs, all patients temporarily discontinued their immunosuppressants during the NR treatment. None of the 32 moderate patients experienced disease progression. However, among the eight patients with critical COVID-19, unfortunately, two of them died. During the medication period, four patients experienced a total of six AEs associated with NR. None of them experienced AEs with a maximum grade of ≥3. Blood drug concentrations of immunosuppressants were monitored in 22 of 40 patients, and the blood drug concentrations of immunosuppressants did not show a significant increase, but some patients experienced lower blood drug concentrations. Our findings supported the use of NR therapy for the treatment of COVID-19 in transplant patients with severe renal insufficiency. A modified dose of NR was well-tolerated., Competing Interests: The authors declare no conflict of interest.

Objective: The aim of the study was to evaluate the safety profile of nirmatrelvir-ritonavir (NMV-r) in real clinical practice and to analyse the clinical relevance of drug-drug interactions in the development of adverse events., Methods: Observational, retrospective study in which safety data of patients treated with NMV-r between April and July 2022 in an outpatient setting were evaluated. The duration of follow-up was 28 days and the number of adverse reactions reported, as well as whether they were managed on an outpatient basis or required health care, and the presence of renal and hepatic function impairment were assessed. Concomitant treatment was reviewed, identifying theoretical drug-drug interactions (TDDIs) whose severity was defined using the Lexi-interact classification., Results: The study included 146 patients. 82 (56.16%) were women, whose median age was 65 years (22-95). the number of TDDIs detected and maintained during treatment with NMV-r was 164, with the percentage of patients with at least 1 interaction being 62.33%. The median number of TDDIs per patient was 1 (0-5). At least 1 adverse event (AE) was reported in 18 patients (11.84%). 11 AEs were potentially related to any TDDI. 7 patients required contact with hospital assistance for AE management. 8 patients had impaired renal function and 2 had impaired liver function at 28 days. The main groups of drugs implicated in the occurrence of an AE were oral anticoagulants and calcium antagonists., Conclusions: Our results show a high number of TDDIs detected were detected between NMV-r and other drugs. This study provides greater knowledge of the drugs involved in such interactions and their potential relationship with the occurrence of adverse events., Competing Interests: Conflicts of interest None declared., (Copyright © 2023 Sociedad Española de Farmacia Hospitalaria (S.E.F.H). Publicado por Elsevier España, S.L.U. All rights reserved.)

Objective: The aim of the study was to evaluate the safety profile of nirmatrelvir-ritonavir (NMV-r) in real clinical practice and to analyze the clinical relevance of drug-drug interactions in the development of adverse events., Methods: Observational, retrospective study in which safety data of patients treated with NMV-r between April and July 2022 in an outpatient setting were evaluated. The duration of follow-up was 28 days and the number of adverse reactions reported, as well as whether they were managed on an outpatient basis or required health care, and the presence of renal and hepatic function impairment were assessed. Concomitant treatment was reviewed, identifying theoretical drug-drug interactions (TDDIs) whose severity was defined using the Lexi-interact classification., Results: The study included 146 patients, 82 (56,16%) were women, whose median age was 65 years (22-95). The number of TDDIs detected and maintained during treatment with NMV-r was 164, with the percentage of patients with at least one interaction being 62,33%. The median number of TDDIs per patient was 1 (0-5). At least 1 adverse event (AE) was reported in 18 patients (11,84%). Eleven AEs were potentially related to any TDDI. Seven patients required contact with hospital assistance for AE management. Eight patients had impaired renal function and 2 had impaired liver function at 28 days. The main groups of drugs implicated in the occurrence of an AE were oral anticoagulants and calcium antagonists., Conclusions: Our results show a high number of TDDIs detected were detected between NMV-r and other drugs. This study provides greater knowledge of the drugs involved in such interactions and their potential relationship with the occurrence of adverse events., (Copyright © 2023 Sociedad Española de Farmacia Hospitalaria (S.E.F.H). Publicado por Elsevier España, S.L.U. All rights reserved.)

Background: Over the past 2 years of the several strategies recommended to help fight COVID-19, nirmatrelvir/ritonavir is a novel drug shown in the EPIC-HR phase 2 to 3 clinical trial to lower COVID-19-related death or hospitalization at day 28 when compared with placebo., Objective: Our study's aim was to explore the reported adverse events (AEs) associated with nirmatrelvir/ritonavir use for COVID-19., Method: We conducted a retrospective analysis using the FDA Adverse Event Reporting System (FAERS) database for AEs, listing nirmatrelvir/ritonavir as the primary drug between January and June 2022. The primary outcome was the incidence of reported AEs associated with nirmatrelvir/ritonavir. The OpenFDA database was queried using Python 3.10 to collect the AEs and Stata 17 was used to analyze the database. Adverse events were analyzed by associated medication, with "Covid-19" excluded., Results: A total of 8098 reports were identified between January and June 2022. Most reported complaints in the AE system were COVID-19 and disease recurrence. The most common symptomatic AEs were dysgeusia, diarrhea, cough, fatigue, and headache. Event rates significantly rose between April and May. Disease recurrence and dysgeusia were the most commonly reported complaints for the top 8 concomitant drugs identified. Cardiac arrest, tremor, akathisia, and death were reported in 1, 3, 67, and 5 cases, respectively., Conclusions and Relevance: This is the first retrospective study done on reported AEs associated with nirmatrelvir/ritonavir use for COVID-19. COVID-19 and disease recurrence were the most reported AEs. Further monitoring of the FAERS database is warranted to periodically reassess the safety profile of this medication., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Simnotrelvir is an oral 3-chymotrypsin-like protease inhibitor that has been found to have in vitro activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and potential efficacy in a phase 1B trial., Methods: In this phase 2-3, double-blind, randomized, placebo-controlled trial, we assigned patients who had mild-to-moderate coronavirus disease 2019 (Covid-19) and onset of symptoms within the past 3 days in a 1:1 ratio to receive 750 mg of simnotrelvir plus 100 mg of ritonavir or placebo twice daily for 5 days. The primary efficacy end point was the time to sustained resolution of symptoms, defined as the absence of 11 Covid-19-related symptoms for 2 consecutive days. Safety and changes in viral load were also assessed., Results: A total of 1208 patients were enrolled at 35 sites in China; 603 were assigned to receive simnotrelvir and 605 to receive placebo. Among patients in the modified intention-to-treat population who received the first dose of trial drug or placebo within 72 hours after symptom onset, the time to sustained resolution of Covid-19 symptoms was significantly shorter in the simnotrelvir group than in the placebo group (180.1 hours [95% confidence interval {CI}, 162.1 to 201.6] vs. 216.0 hours [95% CI, 203.4 to 228.1]; median difference, -35.8 hours [95% CI, -60.1 to -12.4]; P = 0.006 by Peto-Prentice test). On day 5, the decrease in viral load from baseline was greater in the simnotrelvir group than in the placebo group (mean difference [±SE], -1.51±0.14 log 10 copies per milliliter; 95% CI, -1.79 to -1.24). The incidence of adverse events during treatment was higher in the simnotrelvir group than in the placebo group (29.0% vs. 21.6%). Most adverse events were mild or moderate., Conclusions: Early administration of simnotrelvir plus ritonavir shortened the time to the resolution of symptoms among adult patients with Covid-19, without evident safety concerns. (Funded by Jiangsu Simcere Pharmaceutical; ClinicalTrials.gov number, NCT05506176.)., (Copyright © 2024 Massachusetts Medical Society.)

Purpose: Long-term human immunodeficiency virus (HIV)-infected patients are considered at higher risk for osteoporosis. Among the various causes that lead these patients to lower bone health, there is the use of antiretroviral drugs (ARVs), especially protease inhibitors (PI), such as ritonavir (RTV). In this context, emerge the potential benefits of LED therapy, whose effects on bone cells are currently being extensively studied, showing a modulation in cell differentiation. However, it remains unclear if photobiostimulation might interfere with RTV effects on osteoblast differentiation., Methods: In the present study, we investigated the effects of red LED (625 nm) irradiation (15 mW/cm 2 , 0.2 J/cm 2 , and 8 mW/cm 2 , 0.12 J/cm 2 ) on osteoblast cell line MC3T3-E1 treated with RTV (2.5, 5, and 10 μg/mL)., Results: Our results indicated that red LED irradiation was able to reverse, or at least minimize, the deleterious effects of RTV on the osteoblasts. Neither the ARV treatments 5 and 10 μg/mL (104.4% and 95.01%) nor the LED protocols (100.3% and 105.7%) statistically altered cell viability, assessed by the MTT assay. Also, the alkaline phosphatase activity and mineralization showed a decrease in osteoblast activity followed by ARV exposure (39.3-73%), which was attenuated by LED in more than 70% with statistical significance (p < 0.05)., Conclusion: In conclusion, photobiostimulation with red LED at 625 nm was associated with improved beneficial biological effects as a potential inducer of osteogenic activity on RTV-affected cells. This is the first study that investigated the benefits of red LED irradiation over ARV-treated in vitro osteoblasts., (© 2024. The Author(s), under exclusive licence to Springer-Verlag London Ltd., part of Springer Nature.)

Introduction: Nirmatrelvir-ritonavir (NMV-r) and molnupiravir (MOL) were developed as out-patient anti-viral for mild COVID-19. There was limited data on their role in treating COVID-19 for hospitalized patients, especially among adult patients who are unvaccinated and had chronic respiratory diseases., Methods: A territory-wide retrospective study was conducted in Hong Kong to compare the efficacy of NMV-r and MOL against COVID-19 in unvaccinated adult patients with asthma, chronic obstructive pulmonary disease, bronchiectasis and interstitial lung diseases presenting with moderate COVID-19 from 16th February 2022 to 15th March 2023., Results: A total of 1354 patients were included, 738 received NMV-r and 616 received MOL. NMV-r was more effective in reducing 90-day mortality with adjusted hazard ratios (aHR) of 0.508 (95% confidence interval [CI] = 0.314-0.822, p = 0.006). Patients who received NMV-r also had significantly shorter length of stay (LOS) than those receiving MOL, with median LOS of 4 (Interquartile range [IQR] = 2-7) for NMV-r and 6 (IQR = 3-10) for MOL (p-value < 0.001). There was no statistically significant difference in the development of respiratory failure and severe respiratory failure in the two groups., Discussion: NMV-r was more effective than MOL among unvaccinated adults with chronic respiratory diseases who were hospitalized for moderate COVID-19 without hypoxaemia on admission., Competing Interests: All authors report no conflicts of interest in this work., (© 2024 Kwok et al.)

Background: Remdesivir, molnupiravir, and nirmatrelvir/ritonavir are three antiviral agents approved by FDA emergency authorization for treating mild to moderate symptomatic COVID-19 adult outpatients at high risk for hospitalization and death., Objectives: To compare the efficacy and safety of these antivirals based on updated published RCT and real-world data., Study Design: This systematic review followed the preferred reporting items for systematic reviews and meta-analysis framework guidelines. We searched all publications up to January 2023. RRs and 95% CIs for death, hospitalization, and adverse events were calculated., Results: Six RCTs and seven cohort studies were included, with 1,456,523 participants, of whom 50,979 were treated with antivirals. Remdesivir was associated with the lowest probability of hospitalization and death compared to nirmatrelvir/ritonavir and molnupiravir (P-scores 0.99 and 0.90, respectively, for remdesivir, 0.64 and 0.55, respectively for nirmatrelvir/ritonavir, and 0.26 and 0.49, respectively for molnupiravir). Based on indirect comparisons, remdesivir was associated with a statistically significant decreased risk for hospitalization compared to molnupiravir (RR 0.09; 95% CI 0.02-0.40) and to nirmatrelvir/ritonavir (RR 0.11; 95% CI 0.03-0.73). No statistically significant difference was found between antivirals in the mortality risk reduction and the risk for side effects., Conclusions: This is the most comprehensive network meta-analysis integrating RCTs and real-world data. In our indirect comparison, remdesivir was associated with the highest efficacy in preventing hospitalization among high risk symptomatic COVID-19 outpatients, compared to nirmatrelvir/ritonavir and molnupiravir. This finding supports current guidelines, and may have importance when deciding which antiviral to use, together with other important factors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objectives: HIV-induced chronic inflammation, immune activation and combination antiretroviral therapy (cART) are linked with adverse metabolic changes known to cause cardiovascular adversities. This study evaluates the prevalence of lipodystrophy, and metabolic syndrome (MetS), and analyses risk factors in HIV-infected Ethiopians taking cART., Methods: A multicentre cross-sectional study was conducted at tertiary-level hospitals. Eligible participants attending the HIV clinics were enrolled. Sociodemographic, anthropometric, clinical, HIV treatment variables, lipid profile, fasting blood glucose level, risk factors and components of MetS, also lipodystrophy, were studied. Data were analysed by SPSS statistical package V.25 with descriptive and analytical statistics. For multivariable analysis of risk factors, a logistic regression model was used. Results were presented in frequency and percentages, mean±SD, or median+IQR. Statistical significance was taken as p<0.05., Results: Among 518 studied participants, two-thirds were females, and the mean age of the study population was 45 years (SD=11). The mean duration of cART was 10 years (SD=4). Median CD4 count was 460 cells/mm 3 . The prevalence of MetS according to the Adult Treatment Panel III (2005) criteria was 37.6%. In multivariable analysis, independent risk factors for MetS were age >45 years (aHR 1.8, 95% CI 1.2 to 2.4), female sex (aHR 1.8, 95% CI 1.1 to 2.8), body mass index (BMI) > 25 kg/m 2 (aHR 2.7, 95% CI 1.8 to 4.1), efavirenz-based cART (aHR 2.8, 95% CI 1.6 to 4.8) and lopinavir/ritonavir-based cART (aHR 3.7, 95% CI 1.0 to 13.3). The prevalence of lipodystrophy was 23.6%. Prior exposure to a stavudine-containing regimen was independently associated with lipodystrophy (aHR 3.1, 95% CI 1.6 to 6.1)., Conclusion: Our study revealed 38% of the participants had MetS indicating considerable cardiovascular disease (CVD) risks. Independent risk factors for MetS were BMI≥25 kg/m 2 , efavirenz and lopinavir/ritonavir-based cART, female sex and age ≥45 years. In addition to prevention, CVD risk stratification and management will reduce morbidity and mortality in people with HIV infection., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ.)

Regimens containing darunavir are one of the first one with two drugs that demonstrated good efficacy as a simplification strategy. We wanted to describe the characteristics of patients followed in our center on a dual therapy regimen containing darunavir evaluating the metabolic aspects during follow-ups. We collected data from 208 patients switching to lamivudine plus darunavir with either ritonavir or cobicistat between 2010 and 2019. In all patients we found an increase in low-density lipoprotein (LDL), with no rising in creatinine, total cholesterol, or triglycerides. Twenty-five patients reached 120 weeks of follow-up. In these patients, no significant metabolic changes were described without concomitant treatment with drugs for dyslipidemia. These regimens seem to be more tolerable in metabolic profile compared with the data concerning three-drug therapies, leading only to a slight increase in LDL. The main reason for discontinuation was for a single-tablet therapy. None of the patients started treatment for dyslipidemia.

Background and Purpose: The COVID-19 pandemic, caused by severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2), rapidly spread across the globe. Tremendous efforts have been mobilized to create effective antiviral treatment options to reduce the burden of the disease. This article summarizes the available knowledge about the antiviral drugs against SARS-CoV-2 from a neurologist's perspective., Methods: We summarize neurological aspects of antiviral compounds against SARS-CoV-2 with full, conditional, or previous marketing authorization by the European Medicines Agency (EMA)., Results: Nirmatrelvir/ritonavir targets the SARS-CoV-2 3c-like protease using combinatorial chemistry. Nirmatrelvir/ritonavir levels are affected by medications metabolized by or inducing CYP3A4, including those used in neurological diseases. Dysgeusia with a bitter or metallic taste is a common side effect of nirmatrelvir/ritonavir. Molnupiravir is a nucleotide analog developed to inhibit the replication of viruses. No clinically significant interactions with other drugs have been identified, and no specific considerations for people with neurological comorbidity are required. In the meantime, inconsistent results from clinical trials regarding efficacy have led to the withdrawal of marketing authorization by the EMA. Remdesivir is a viral RNA polymerase inhibitor and interferes with the production of viral RNA. The most common side effect in patients with COVID-19 is nausea. Remdesivir is a substrate for CYP3A4., Conclusions: Neurological side effects and drug interactions must be considered for antiviral compounds against SARS-CoV-2. Further studies are required to better evaluate their efficacy and adverse events in patients with concomitant neurological diseases. Moreover, evidence from real-world studies will complement the current knowledge., (© 2023 European Academy of Neurology.)

Background: Elevations in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were reported as adverse events of nirmatrelvir/ritonavir users in the EPIC-HR trial., Aim: To quantify the risk and severity of acute liver injury (ALI) associated with nirmatrelvir/ritonavir use., Methods: This self-controlled case-series study was conducted using electronic medical records of patients with confirmed diagnosis of SARS-CoV-2 infection between 26th February 2022 and 12th February 2023 in Hong Kong., Results: Among 2 409 848 patients with SARS-CoV-2 infection during the study period, 153 853 were prescribed with nirmatrelvir/ritonavir, of whom 834 (.5%) had incident ALI (moderate: 30.5%; moderate to severe: 18.9%; severe or fatal: 5.8%). Compared with the non-exposure period, risk of ALI increased significantly during the pre-exposure period (IRR = 38.13, 95% CI = 29.29-49.62) and remained elevated during the five-day nirmatrelvir/ritonavir treatment (IRR = 20.75, 95% CI = 17.06-25.25) and during wash-out period (IRR = 16.27, 95% CI = 13.23-20.01). Compared to the pre-exposure period, risk of ALI was not increased during the five-day nirmatrelvir/ritonavir treatment period (IRR = .54, 95% CI = .43-.70). Compared to 5469 non-nirmatrelvir/ritonavir users with incident ALI, nirmatrelvir/ritonavir users had less severe ALI by the severity index (p < .001) and peak INR (1.7 vs. 2.3; p < .001). ALI cases with nirmatrelvir/ritonavir use had lower risk of all-cause death (29.1% vs. 39.1%; OR = .64; p < .001) and no increase in risk of liver decompensation (1.0% vs. 1.3%; OR = .62; p = .230) compared to non-users., Conclusion: The risk of ALI associated with nirmatrelvir/ritonavir treatment for COVID-19 was elevated in the pre-exposure period, but not following nirmatrelvir/ritonavir initiation. ALI following nirmatrelvir/ritonavir treatment were mostly mild and less severe than ALI events in non-nirmatrelvir/ritonavir users., (© 2023 The Authors. Liver International published by John Wiley & Sons Ltd.)

Study Objective: To estimate the prevalence of potential moderate to severe drug-drug interactions (DDIs) involving nirmatrelvir/ritonavir, identify interacting medications, and evaluate risk factors associated with potential DDIs., Design: Cross-sectional study., Data Source: Electronic health records from the National COVID Cohort Collaborative Enclave, one of the largest COVID-19 data resources in the United States., Patients: Outpatients aged ≥18 years and started nirmatrelvir/ritonavir between December 23, 2021 and March 31, 2022., Intervention: Nirmatrelvir/ritonavir., Measurements: The outcome is potential moderate to severe DDIs, defined as starting interacting medications reported by National Institutes of Health 30 days before or 10 days after starting nirmatrelvir/ritonavir., Main Results: Of 3214 outpatients who started nirmatrelvir/ritonavir, the mean age was 56.8 ± 17.1 years, 39.5% were male, and 65.8% were non-Hispanic white. Overall, 521 (16.2%) were potentially exposed to at least one moderate to severe DDI, most commonly to atorvastatin (19.2% of all DDIs), hydrocodone (14.0%), or oxycodone (14.0%). After adjustment for covariates, potential DDIs were more likely among individuals who were older (odds ratio [OR] 1.16 per 10-year increase, 95% confidence interval [CI] 1.08-1.25), male (OR 1.36, CI 1.09-1.71), smokers (OR 1.38, CI 1.10-1.73), on more co-medications (OR 1.35, CI 1.31-1.39), and with a history of solid organ transplant (OR 3.63, CI 2.05-6.45)., Conclusions: One in six of individuals receiving nirmatrelvir/ritonavir were at risk of a potential moderate or severe DDI, underscoring the importance of clinical and pharmacy systems to mitigate such risks., (© 2023 Pharmacotherapy Publications, Inc.)

Background: Nirmatrelvir-ritonavir is currently not recommended in patients with an estimated glomerular filtration rate (eGFR) <30 mL/minute/1.73 m2., Methods: To determine the safety profile and clinical and virological outcomes of nirmatrelvir-ritonavir use at a modified dosage in adults with chronic kidney disease (CKD), a prospective, single-arm, interventional trial recruited patients with eGFR <30 mL/minute/1.73 m2 and on dialysis. Primary outcomes included safety profile, adverse/serious adverse events, and events leading to drug discontinuation. Disease symptoms, virological outcomes by serial severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral polymerase chain reaction (PCR) tests, rapid antigen tests, and virological and symptomatic rebound were also recorded., Results: Fifty-nine (69.4%) of the 85 participants had stage 5 CKD and were on dialysis. Eighty (94.1%) completed the full treatment course; 9.4% and 5.9% had adverse and serious adverse events, and these were comparable between those with eGFR < or >30 mL/minute/1.73 m2. The viral load significantly decreased on days 5, 15, and 30 (P < .001 for all), and the reduction was consistent in the subgroup with eGFR <30 mL/minute/1.73 m2. Ten patients had virological rebound, which was transient and asymptomatic., Conclusions: Among patients with CKD, a modified dose of nirmatrelvir-ritonavir is a well-tolerated therapy in mild COVID-19 as it can effectively suppress the SARS-CoV-2 viral load with a favorable safety profile. Virological and symptomatic rebound, although transient with low infectivity, may occur after treatment. Nirmatrelvir-ritonavir should be considered for use in patients with CKD, including stage 5 CKD on dialysis. Clinical Trials Registration. Clinical Trials.gov; identifier: NCT05624840., Competing Interests: Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

This project aims to explore the repercussions of ritonavir on both the drug kinetics of clonidine in rats and clonidine metabolism in liver micro somes. Eighteen healthy male laboratory rats were haphazardly placed into groups: Group A, the control, Group B, got 20mg/kg ritonavir and Group C, got 180 mg/kg ritonavir. Ritonavir was administered to the rats by oral gavage and 30 minutes later, clonidine at 0.25mg/kg was administered for once. Moreover, rat and human liver micro somes, along with recombinant human CYP2D6*1, were used to study the inhibition effect of ritonavir on clonidine in vitro. The concentrations of clonidine and its metabolite were determined by the UPLC-MS/MS. The area under the curve (AUC) of clonidine increased (P<0.01) and clearance (CL) decreased significantly (P<0.01), after co-administration with 180mg/kg ritonavir. The half-maximal inhibitory concentration (IC 50 ) of ritonavir was 11.48μmol/L in rat liver micro somes, 3.52μmol/L in human liver micro somes and 18.04μmol/L in CYP2D6*1. Our findings demonstrate that ritonavir exhibited an inhibitory effect on clonidine metabolism in vitro and in vivo. It suggests that concurrent use of clonidine with ritonavir required close monitoring of the clonidine plasma concentration to alert drug adverse reactions.

Background: Huashi Baidu granule (HSBD) and Paxlovid (Nirmatrelvir-Ritonavir) are antiviral Chinese patent medicine and western medicine specially developed for treating coronavirus disease 2019 (COVID-19). Their efficacy and safety in treating COVID-19 are still under investigated., Purpose: To assess and compare the efficacy and safety of HSBD, Paxlovid, and the combination in treating high-risk patients infected with SARS-CoV-2 Omicron., Study Design: The study was a prospective single-center, open-label, randomized, controlled clinical trial conducted from April 18 to June 5, 2022. (ClinicalTrial.gov registration number: ChiCTR2200059390) METHODS: 312 severe patients aged 18 years and older infected with SARS-CoV-2 Omicron from Shuguang Hospital in Shanghai were randomly allocated to HSBD monotherapy (orally 137 g twice daily for 7 days, n = 105), Paxlovid monotherapy (orally 300 mg of Nirmatrelvir plus 100 mg of Ritonavir every 12 h for 5 days, n = 103), or combination therapy (n = 104). The primary outcome was SARS-CoV-2 nucleic acid negative conversion within 7-day treatment. The secondary outcome included hospital discharging conditions, severe conversion of symptom, and adverse events., Results: Of 312 participants, 85 (82%) of 104 in combination therapy, 71 (68%) of 105 in HSBD monotherapy, and 73 (71%) of 103 in Paxlovid monotherapy had a primary outcome event. The hazard ratios of primary outcome were 1.37 (95% CI 1.03 - 1.84, p = 0.012) for combination versus HSBD, 1.28 (0.98-1.69, p = 0.043) for combination versus Paxlovid, and 0.88 (0.66-1.18, p = 0.33) for HSBD versus Paxlovid. There was no statistical difference of efficacy between HSBD and Paxlovid, while combination therapy exhibited more effective than either alone. For secondary outcomes, the hospital discharging rates within 7 days exhibited the significant increase in combination therapy than in HSBD or Paxlovid monotherapy (71% (74/104) vs 55% (58/105) vs 52% (54/103), p < 0.05). The risk of severe conversion of symptom showed no statistical significance among three interventions (1% (1/104) vs 3% (3/105) vs 3% (3/103), p > 0.05). No severe adverse events occurred among combination therapy and monotherapies in the trial., Conclusion: For patients with severe COVID-19, HSBD exhibits similar efficacy to Paxlovid, while combination therapy is more likely to increase the curative efficacy of Omicron variant than monotherapies, with few serious adverse events., Competing Interests: Declaration of Competing Interest None, (Copyright © 2023. Published by Elsevier GmbH.)

Background: In this study, we aimed to compare the effectiveness and adverse reactions of nirmatrelvir/ritonavir and molnupiravir in high-risk outpatients with coronavirus disease 2019 (COVID-19)., Methods: This multicenter prospective observational study evaluated the rate of hospitalization, death, and adverse events within 28 days of oral antiviral agent prescription (molnupiravir, n = 240; nirmatrelvir/ritonavir, n = 240) to 480 nonhospitalized adult patients with COVID-19 from August 2, 2022 to March 31, 2023., Results: Patients receiving molnupiravir had a higher prevalence of comorbidities (85.8% vs. 70.4%; P < 0.001) and a higher Charlson comorbidity index (2.8 ± 1.4 vs. 2.5 ± 1.5; P = 0.009) than those receiving nirmatrelvir/ritonavir. Three patients required hospitalization (nirmatrelvir/ritonavir group, n = 1 [0.4%]; molnupiravir group, n = 2 [0.8%]; P = 1.000). Nirmatrelvir/ritonavir was associated with a higher risk of adverse events than molnupiravir (odds ratio [OR], 1.96; 95% confidence interval [CI], 1.27-3.03), especially for patients aged 65 years and older (OR, 3.04; 95% CI, 1.71-5.39). The severity of adverse events in both groups was mild to moderate and improved after discontinuation of medication. In the molnupiravir group, age ≥ 65 years (OR, 0.43 95% CI, 0.22-0.86) and appropriate vaccination (OR, 0.37; 95% CI, 0.15-0.91) reduced the occurrence of adverse events., Conclusion: The rates of hospitalization and death were low and not significantly different between high-risk patients who received either nirmatrelvir/ritonavir or molnupiravir. Although adverse events were more frequent with nirmatrelvir/ritonavir than with molnupiravir, none were severe. Nirmatrelvir/ritonavir can be safely used to treat COVID-19, while molnupiravir could be considered as an alternative treatment option for high-risk groups., Competing Interests: The authors have no potential conflicts of interest to disclose., (© 2023 The Korean Academy of Medical Sciences.)

Competing Interests: Competing interests: None declared.

We report the first published case of a drug induced liver injury (DILI) presumed secondary to a drug-drug interaction between ritonavir and levonorgestrel progestogen-only emergency contraception (POEC). Our patient is a 25-year-old female living with human immunodeficiency virus (HIV), taking antiretroviral therapy (ART) containing tenofovir alafenamide/emtricitabine and darunavir/ritonavir. She was found to have elevated transaminases at a routine clinic appointment consistent with hepatocellular DILI. Further investigation found the most likely cause of this was a drug-drug interaction (DDI) between the ritonavir component of her ART and recent use of levonorgestrel POEC 3 days earlier. Evidence suggests that ritonavir increases levonorgestrel exposure, yet our patient received double the usual dose as per dispensing guidance at the time. We review the pharmacokinetics of ritonavir-levonorgestrel DDIs and highlight the need for consistent guidelines on this topic., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Aims: The objective of this study was to evaluate the effects of a strong cytochrome P450 family (CYP) 3A4 inhibitor (itraconazole) and inducer (carbamazepine) on the pharmacokinetics and safety of nirmatrelvir/ritonavir., Methods: Pharmacokinetics were measured in two phase 1, open-label, fixed-sequence studies in healthy adults. During Period 1, oral nirmatrelvir/ritonavir 300 mg/100 mg twice daily was administered alone; during Period 2, it was administered with itraconazole or carbamazepine. Nirmatrelvir/ritonavir was administered as repeated doses or one dose in the itraconazole and carbamazepine studies, respectively. Nirmatrelvir and ritonavir plasma concentrations and adverse event (AE) rates in both periods were analysed., Results: Each study included 12 participants. Following administration of nirmatrelvir/ritonavir with itraconazole (Test) or alone (Reference), test/reference ratios of the adjusted geometric means (90% CIs) for nirmatrelvir AUC tau and C max were 138.82% (129.25%, 149.11%) and 118.57% (112.50%, 124.97%), respectively. After administration of nirmatrelvir/ritonavir with carbamazepine (Test) or alone (Reference), test/reference ratios (90% CIs) of the adjusted geometric means for nirmatrelvir AUC inf and C max were 44.50% (33.77%, 58.65%) and 56.82% (47.04%, 68.62%), respectively. Nirmatrelvir/ritonavir was generally safe when administered with or without itraconazole or carbamazepine. No serious or severe AEs were reported., Conclusions: Coadministration of a strong CYP3A4 inhibitor with a strong CYP3A inhibitor used for pharmacokinetic enhancement (i.e., ritonavir) resulted in small increases in plasma nirmatrelvir exposure, whereas coadministration of a strong inducer substantially decreased systemic nirmatrelvir and ritonavir exposures suggesting a contraindication in the label with CYP3A4 strong inducers. Administration of nirmatrelvir/ritonavir alone or with itraconazole or carbamazepine was generally safe., (© 2023 British Pharmacological Society.)

Our study is aimed to access the efficacy and safety outcomes for coronavirus disease 2019 (COVID-19) patients treated with Paxlovid. According to inclusion and exclusion criteria, databases were used to retrieve articles from 1 January 2020 to 1 January 2023. Article screening, quality evaluation and data extraction were completed and cross-checked. The meta-analysis and trial sequential analysis (TSA) were conducted using RevMan, StataMP, and TSA software. A total of 42 original articles were included. Overall meta-analysis results showed that for death, hospitalisation, death or hospitalisation, emergency department (ED) visit, intensive care unit (ICU) admission, and extra oxygen requirement outcomes, every odds ratio (OR) was <1 and p < 0.05. For rebound outcome, the OR was >1 and p > 0.05. For adverse events (AEs) outcome, the OR was >1 and p < 0.05. In conclusion, Paxlovid effectively reduced the risks of death, hospitalisation, death or hospitalisation, ED visit, ICU admission, and extra oxygen requirement. There was no significant statistical difference considering rebound, but people should pay attention to possible AEs. However, for rebound and AEs outcomes, observations in certain subgroups suggested conclusions contrary to the overall meta-analysis. Trial sequential analysis indicated these two outcomes have a risk of false negative or false positive conclusions, so additional original studies are needed for further validation., (© 2023 John Wiley & Sons Ltd.)

Introduction: In the context of COVID-19 pandemic, a national pharmacovigilance survey was set up in March 2020. The purpose of this survey was to ensure continuous monitoring of adverse drug reactions (ADRs) in patients with COVID-19, not only related to the drugs used in this indication but also related to all drugs administered to these patients or suspected of having promoted the infection., Material and Methods: This descriptive study was based on data extracted from the French Pharmacovigilance Database from 1 January 2020 to 30 September 2021. Misuse was also analysed through the MESANGE project. The ADRs were classified according to three groups: "drugs used to treat COVID-19", "other drugs administered to COVID-19 positive patients" and "drugs suspected of having promoted COVID-19". The data were also presented according to 2 periods (period one was from January to June 2020 and period two from July 2020 onwards)., Results: Among 2189 included cases, 67.1% were serious. Cases were mainly related to "other drugs administrated to COVID-19 positive patients" (58.5%) followed by "drugs used to treat COVID-19" (33.7%) and "drugs suspected of having promoted COVID-19" (7.8%). Drugs used to treat COVID-19 and their main safety profile were different depending on the period: mostly hydroxychloroquine (51%) with heart injury and lopinavir/ritonavir (42%) with liver injury for the first period, and dexamethasone (46%) with hyperglycemia and tocilizumab (28%) with liver injury for the second period. The drugs suspected of worsening COVID-19 differed in both periods especially for non-steroidal anti-inflammatory drugs mainly reported in period 1 (41.5% versus 8.2% in period 2). Other immunosuppressive drugs were in the majority in the second period (85.7%), with mainly methotrexate (15.3%), anti-CD20 (15.3%) and anti-TNF alpha (10.5%). No confirmed safety signal was identified among other drugs administered to patients with COVID-19. The profile of ADRs and suspected drugs was similar between the 2 periods. The study of misuse in outpatient settings identified in both periods mainly hydroxychloroquine, azithromycin, ivermectin and zinc±vitamin C., Discussion: This survey, based on real-time pharmacological and medical assessment of ADRs and weekly meetings in a specific national committee, made it possible to identify relevant safety signals which contribute to patient care with no delay. The main safety signal highlighted was serious cardiac damage under hydroxychloroquine, alone or combined with azithromycin and also with lopinavir/ritonavir. This signal has contributed to the evolution of the recommendations for these 2 drugs. The methodology of this survey has been taken over and is still going on for the pharmacovigilance monitoring of vaccines against COVID-19, for monoclonal antibodies used against COVID-19 and also for Paxlovid® (nirmatrelvir/ritonavir) which benefit from dedicated surveys., (Copyright © 2023 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)

Introduction: Nirmatrelvir/ritonavir (Paxlovid®) is currently one of the few therapeutic options for coronavirus disease 2019 (COVID-19) curative treatment in non-oxygen-requiring adult patients at-high risk of progressing to severe disease. This recently approved boosted antiviral therapy presents a significant risk of drug-drug interactions (DDI). As part of the enhanced surveillance program in France for COVID-19 drugs and vaccines, the French national pharmacovigilance database (BNPV [base nationale de pharmacovigilance]) was queried in order to better characterize the drug safety profile, with a special focus on DDI. The aim of the study was to describe the adverse drug reactions reported through the BNPV., Method: All nirmatrelvir/ritonavir reports validated in the BNPV from the first authorization in France (January, 20th 2022) to December, 3rd 2022 (date of the query) were considered. An analysis of the scientific literature (PubMed®) and from the WHO pharmacovigilance database (Vigibase) was also performed., Results: Over this period (11 months), 228 reports (40% of serious reports) were registered with a sex ratio of 1.9 female/1 male and a mean age of 66 years old. DDI reports account for more than 13% of reports (n=30) and were mainly related to immunosuppressive drugs overexposure (n=16). A total of 10/228 reports with fatal outcomes were reported in complex clinical settings. The main reported unexpected adverse drug reaction (ADRs) were high blood pressure (n=7), confusion (n=5), acute kidney injuries (AKI, n=7) and various skin reactions (n=22). Apart from situations of disease recurrence (not found in this analysis), data from Pubmed® and Vigibase also reported the above-mentioned events of interest., Conclusion: Overall, this analysis shows that nirmatrelvir/ritonavir safety profile was conform to current summary of product characteristics (SmPC). The main concern was the risk of DDI. Therefore, SmPC and expert recommendations should be systematically consulted before initiation of this antiviral, which is particularly indicated in polypharmacy patients. A case-by-case multidisciplinary approach including a clinical pharmacologist is required in these complex situations. Blood pressure elevation, confusion, cutaneous reactions and AKIs were the main unexpected ADRs of interest to follow, but need to be confirmed with a qualitative approach over time and new reports., (Copyright © 2023 Société française de pharmacologie et de thérapeutique. Published by Elsevier Masson SAS. All rights reserved.)