BACKGROUND: Molnupiravir and nirmatrelvir-ritonavir are orally administered pharmacotherapies for mild to moderate COVID-19. However, the effectiveness of these drugs among very old (≥80 years), hospitalised patients remains unclear, limiting the risk-benefit assessment of these antivirals in this specific group. This study investigates the effectiveness of these antivirals in reducing mortality among this group of hospitalised patients with COVID-19.
METHODS: Using a territory-wide public healthcare database in Hong Kong, a target trial emulation study was conducted with data from 13 642 eligible participants for the molnupiravir trial and 9553 for the nirmatrelvir-ritonavir trial. The primary outcome was all-cause mortality. Immortal time and confounding bias was minimised using cloning-censoring-weighting approach. Mortality odds ratios were estimated by pooled logistic regression after adjusting confounding biases by stabilised inverse probability weights.
RESULTS: Both molnupiravir (HR: 0.895, 95% CI: 0.826-0.970) and nirmatrelvir-ritonavir (HR: 0.804, 95% CI: 0.678-0.955) demonstrated moderate mortality risk reduction among oldest-old hospitalised patients. No significant interaction was observed between oral antiviral treatment and vaccination status. The 28-day risk of mortality was lower in initiators than non-initiators for both molnupiravir (risk difference: -1.09%, 95% CI: -2.29, 0.11) and nirmatrelvir-ritonavir (risk difference: -1.71%, 95% CI: -3.30, -0.16) trials. The effectiveness of these medications was observed regardless of the patients\' prior vaccination status.
CONCLUSIONS: Molnupiravir and nirmatrelvir-ritonavir are moderately effective in reducing mortality risk among hospitalised oldest-old patients with COVID-19, regardless of their vaccination status.

Despite the potential of neutralizing antibodies in the management of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), clinical research on its efficacy in Chinese patients remains limited. This study is aimed at investigating the therapeutic effect of combination of antiviral therapy with neutralizing monoclonal antibodies for recurrent persistent SARS-CoV-2 pneumonia in patients with lymphoma complicated by B cell depletion. A prospective study was conducted on Chinese patients who were treated with antiviral nirmatrelvir/ritonavir therapy and the neutralizing antibody tixagevimab-cilgavimab (tix-cil). The primary outcome was the rate of recurrent SARS-CoV-2 infection. Five patients with lymphoma experienced recurrent SARS-CoV-2 pneumonia and received tix-cil treatment. All patients had a history of CD20 monoclonal antibody use within the year preceding SARS-CoV-2 infection, and two patients also had a history of Bruton\'s tyrosine kinase (BTK) inhibitor use. These patients had notably low lymphocyte counts and exhibited near depletion of B cells. All five patients tested negative for serum SARS-CoV-2 IgG and IgM antibodies. None of the patients developed reinfection with SARS-CoV-2 pneumonia after antiviral and tix-cil treatment during the 6-month follow-up period. In conclusion, the administration of antiviral and SARS-CoV-2-neutralizing antibodies showed encouraging therapeutic efficacy against SARS-CoV-2 pneumonia in patients with lymphoma complicated by B cell depletion, along with the potential preventive effect of neutralizing antibodies for up to 6 months.

Patients with Hematological Malignancies (HM) are at a high risk of mortality from Coronavirus disease 2019 (COVID-19). The available antivirals were different between China and other countries. In China, azvudine was obtained for emergency use to treat adult COVID-19 patients with moderate symptoms in July 2022. While nirmatrelvir-ritonavir was well-known and used in many countries. The purpose of the present study was to assess whether there was any difference in the efficacy and safety of the two drugs.
This study was a prospective observational study of patients with HM who developed COVID-19. Patients were divided into three treatment groups: nirmatrelvir-ritonavir, azvudine, and observation. Treatment outcomes, first nucleic acid test negative time, hospitalization time, and the conversion rate of mild or moderate disease to severe disease were recorded.
First nucleic acid test negative time (23.5 days vs. 34 days, p = 0.015), hospitalization time (p = 0.015), and conversion rate (31.8 % vs. 8 %, p = 0.046) were statistically different between the nirmatrelvir-ritonavir and observation groups. First nucleic acid test negative time (20 days vs. 34 days, p = 0.009) and hospitalization time (p = 0.026) were statistically different between the azvudine and observation groups. ECOG score and liver disease were significantly associated with the conversion rate from mild or moderate disease to severe disease using multivariate analysis (p < 0.05).
The authors found no significant differences existed in outcome measures between patients with HM and COVID-19 who were treated with nirmatrelvir-ritonavir or azvudine.

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 (Cmax), area under the concentration-time curve up to the last quantifiable time (AUC0-t), and area under the plasma concentration-time curve from time 0 extrapolated to infinity (AUC0-∞) 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 (Tmax) and elimination half-life (T1/2). 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).

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The comparative crystallizability and polymorphic selectivity of ritonavir, a novel protease inhibitor for the treatment of acquired immune-deficiency syndrome, as a function of solvent selection are examined through an integrated and self-consistent experimental and computational molecular modeling study. Recrystallization at high supersaturation by rapid cooling at 283.15 K is found to produce the metastable \"disappeared\" polymorphic form I from acetone, ethyl acetate, acetonitrile, and toluene solutions in contrast to ethanol which produces the stable form II. Concomitant crystallization of the other known solid forms is not found under these conditions. Isothermal crystallization studies using turbidometric detection based upon classical nucleation theory reveal that, for an equal induction time, the required driving force needed to initiate solution nucleation decreases with solubility in the order of ethanol, acetone, acetonitrile, ethyl acetate, and toluene consistent with the expected desolvation behavior predicted from the calculated solute solvation free energies. Molecular dynamics simulations of the molecular and intermolecular chemistry reveal the presence of conformational interplay between intramolecular and intermolecular interactions within the solution phase. These encompass the solvent-dependent formation of intramolecular O-H...O hydrogen bonding between the hydroxyl and carbamate groups coupled with differing conformations of the hydroxyl\'s shielding phenyl groups. These conformational preferences and their relative interaction propensities, as a function of solvent selection, may play a rate-limiting role in the crystallization behavior by not only inhibiting to different degrees the nucleation process but also restricting the assembly of the optimal intermolecular hydrogen bonding network needed for the formation of the stable form II polymorph.

BACKGROUND: There is an urgent need for therapeutic strategies for inpatients with severe or critical COVID-19. The evaluation of the clinical benefits of nirmatrelvir and ritonavir (Nmr/r) for these patients beyond five days of symptom onset is insufficient.
METHODS: A new propensity score-matched cohort was constructed by using multicenter data from 6695 adult inpatients with COVID-19 from December 2022 to February 2023 in China after the epidemic control measures were lifted across the country. The severity of disease of the inpatients was based on the tenth trial edition of the Guidelines on the Diagnosis and Treatment of COVID-19 in China. The symptom onset of 1870 enrolled severe or critical inpatients was beyond five days, and they received either Nmr/r plus standard treatment or only standard care. The ratio of patients whose SOFA score improved more than 2 points, crucial respiratory endpoints, changes in inflammatory markers, safety on the seventh day following the initiation of Nmr/r treatment, and length of hospital stay were evaluated.
RESULTS: In the Nmr/r group, on Day 7, the number of patients with an improvement in SOFA score ≥ 2 was much greater than that in the standard treatment group (P = 0.024) without a significant decrease in glomerular filtration rate (P = 0.815). Additionally, the rate of new intubation was lower (P = 0.004) and the no intubation days were higher (P = 0.003) in the first 7 days in the Nmr/r group. Other clinical benefits were limited.
CONCLUSIONS: Our study may provide new insight that inpatients with severe or critical COVID-19 beyond five days of symptom onset benefit from Nmr/r. Future studies, particularly randomized controlled trials, are necessary to verify the above findings.

PAXLOVID™ (Co-packaging of Nirmatrelvir with Ritonavir) has been approved for the treatment of Coronavirus Disease 2019 (COVID-19). The goal of the experiment was to create an accurate and straightforward analytical method using ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) to simultaneously quantify nirmatrelvir and ritonavir in rat plasma, and to investigate the pharmacokinetic profiles of these drugs in rats. After protein precipitation using acetonitrile, nirmatrelvir, ritonavir, and the internal standard (IS) lopinavir were separated using ultra performance liquid chromatography (UPLC). This separation was achieved with a mobile phase composed of acetonitrile and an aqueous solution of 0.1% formic acid, using a reversed-phase column with a binary gradient elution. Using multiple reaction monitoring (MRM) technology, the analytes were detected in the positive electrospray ionization mode. Favorable linearity was observed in the calibration range of 2.0-10000 ng/mL for nirmatrelvir and 1.0-5000 ng/mL for ritonavir, respectively, within plasma samples. The lower limits of quantification (LLOQ) attained were 2.0 ng/mL for nirmatrelvir and 1.0 ng/mL for ritonavir, respectively. Both drugs demonstrated inter-day and intra-day precision below 15%, with accuracies ranging from -7.6% to 13.2%. Analytes were extracted with recoveries higher than 90.7% and without significant matrix effects. Likewise, the stability was found to meet the requirements of the analytical method under different conditions. This UPLC-MS/MS method, characterized by enabling accurate and precise quantification of nirmatrelvir and ritonavir in plasma, was effectively utilized for in vivo pharmacokinetic studies in rats.

Currently there is a lack of randomized trial data examining the use of the antiviral nirmatrelvir/ritonavir in paediatric patients with SARS-CoV-2 infection. This target trial emulation study aims to address this gap by evaluating the use of nirmatrelvir/ritonavir in non-hospitalized paediatric patients aged 12-17 years with SARS-CoV-2 Omicron variant infection. Among paediatric patients diagnosed between 16th March 2022 and 5th February 2023, exposure was defined as outpatient nirmatrelvir/ritonavir treatment within 5 days of symptom onset or COVID-19 diagnosis. Primary outcome was 28 day all-cause mortality or all-cause hospitalization, while secondary outcomes were 28 day in-hospital disease progression, 28 day COVID-19-specific hospitalization, multisystem inflammatory syndrome in children (MIS-C), acute liver injury, acute renal failure, and acute respiratory distress syndrome. Overall, 49,378 eligible paediatric patients were included. Nirmatrelvir/ritonavir treatment was associated with reduced 28 day all-cause hospitalization (absolute risk reduction = 0.23%, 95%CI = 0.19%-0.31%; relative risk = 0.66, 95%CI = 0.56-0.71). No events of mortality, in-hospital disease progression, or adverse clinical outcomes were observed among nirmatrelvir/ritonavir users. The findings confirmed the effectiveness of nirmatrelvir/ritonavir in reducing all-cause hospitalization risk among non-hospitalized pediatric patients with SARS-CoV-2 Omicron variant infection.