Current COVID-19 therapeutic recommendations for oral antiviral therapy rely on a stage-based framework established during the first pandemic waves, restricting treatment to patients presenting within five days of symptom onset who do not require supplemental oxygen, whereas corticosteroids are recommended for hospitalized patients requiring supplemental oxygen. Although this strategy remains supported by randomized evidence, the biological and clinical landscape of COVID-19 has profoundly evolved with widespread hybrid immunity, Omicron sublineages, and an older and immunocompromised hospitalized population. We propose that oral antiviral eligibility, primarily in the context of nirmatrelvir/ritonavir, should progressively move beyond an oxygen-centered eligibility algorithm toward an integrated clinical assessment including symptom duration, host characteristics, pulmonary involvement on chest CT, virological burden (when available), and oxygen requirement. Importantly, this perspective does not challenge early antiviral initiation within the approved therapeutic window. Rather, it argues that future studies should determine whether a more integrated patient selection strategy can optimize the use of oral antiviral therapy in contemporary COVID-19 caused by Omicron sublineages.

Human cytomegalovirus (HCMV) is a major pathogen affecting immunocompromised individuals. Current antiviral drugs target the mid-to-late stages of viral replication but are limited by toxicity and drug resistance. The IE1 protein serves as a key early regulator of HCMV replication; however, it has long been considered undruggable due to the lack of conventional drug-binding sites. In this study, by integrating molecular docking-based virtual screening with in-vitro surface plasmon resonance (SPR) validation, we discovered for the first time that the HIV protease inhibitor ritonavir may bind to the IE1 protein. Further experiments demonstrated that ritonavir significantly reduces IE1 protein levels in a time- and dose-dependent manner without affecting its mRNA expression. Mechanistic investigations revealed that ritonavir promotes selective degradation of IE1 through activation of the ubiquitin-proteasome pathway. Functional assays confirmed that ritonavir effectively inhibits HCMV replication, markedly reducing viral DNA loads and the production of infectious viral particles. Notably, ritonavir exhibited synergistic antiviral effects when combined with the first-line drug ganciclovir (GCV). In summary, this study successfully repurposes the approved drug ritonavir as a regulator of IE1 protein expression, demonstrating not only its anti-HCMV activity and synergistic effects with GCV but also providing a new therapeutic strategy for HCMV infection.

Background: Ritonavir (RTV), an HIV-1 (human immunodeficiency virus-1) protease inhibitor, has low aqueous solubility and poor oral bioavailability, requiring large amounts of excipients that result in bulky dosage forms and poor patient compliance. We aimed to develop an RTV-loaded polymeric micelle formulation with high drug loading capacity that improves aqueous solubility, reduces the excipient burden and associated excipient-related adverse effects, and remains stable after lyophilization without a cryoprotectant. Methods: RTV-loaded micelles were prepared from the amphiphilic block copolymer poly(ethylene glycol)-block-poly(ε-caprolactone) (PEG-b-PCL) by thin-film hydration. Particle size and the polydispersity index (PDI) were measured by dynamic light scattering and encapsulation efficiency and drug content by HPLC, before and after lyophilization. The drug-to-excipient ratio was compared with the commercial product (Norvir[®]), and pharmacokinetics were evaluated in male Sprague-Dawley rats after single oral administration. Results: Micelles showed a mean particle size of 25.9 ± 0.09 nm, a PDI of 0.224 ± 0.008, and an encapsulation efficiency of 98.9 ± 1.54%, with particle size and drug content retained after lyophilization and reconstitution without any cryoprotectant. Drug content reached 27.3% (w/w) versus 12.5% for the commercial product, a 2.6-fold reduction in excipients per unit dose. In rats, the micelle formulation showed pharmacokinetic parameters comparable to those of the Norvir[®] suspension (Cmax, 2243.9 ± 1226.4 vs. 2106.1 ± 835.9 ng/mL; AUClast, 6695.3 ± 2162.6 vs. 8178.2 ± 2892.1 h·ng/mL; Tmax, 0.9 ± 0.6 vs. 1.5 ± 0.5 h), with no significant differences. Conclusions: The PEG-b-PCL micelle achieved high RTV loading, substantially reduced excipients, and provided oral exposure comparable to the commercial product, supporting its potential as an alternative oral delivery system.

Because P-glycoprotein (P-gp) influences the disposition of substrate drugs, regulatory agencies recommend ascertaining the P-gp substrate status of active pharmaceutical ingredients (API's) intended for humans. Transwell-based assays using P-gp-overexpressing human cell lines are routinely used to predict the API's P-gp substrate status. Although ABCB1-1Δ-mediated P-gp deficiency contributes to serious canine adverse drug reactions, assessment of canine P-gp status is not currently recommended by regulatory agencies for canine API's. We have previously employed a competitive efflux assay to assess drugs as canine P-gp substrates as it affords some advantages over transwell assays. Our objective was to preliminarily compare results generated from these two methods using historical data for transwell assays. Eleven drugs were assessed as canine P-gp substrates by both methods, with two identified as non-P-gp substrates (erythromycin, propranolol) and nine identified as canine P-gp substrates (clarithromycin, daunorubicin, digoxin, etoposide, paclitaxel, quinidine, ritonavir, verapamil, vinblastine). Erythromycin was identified as a canine P-gp substrate by competitive efflux assay at roughly 10-fold higher concentrations than was used for transwell assays. Concordance of these methods assessing canine P-gp substrate status using historical data supports the need for head-to-head studies comparing these two methods for identifying canine P-gp substrates.

We report a case of erythema multiforme (EM) associated with atazanavir/ritonavir in a patient with HIV-1 infection. The patient was receiving tenofovir, lamivudine, and dolutegravir; however, owing to a supply chain issue, dolutegravir was substituted with atazanavir/ritonavir. The patient subsequently developed pruritic erythematous papules and plaques with characteristic target lesions over the face and a hemorrhagic crust on the lower lip, without epidermal detachment or systemic symptoms. The Naranjo probability score indicated a probable adverse drug reaction. This case highlights the importance of recognizing EM as a potential adverse reaction to atazanavir and of early drug withdrawal to prevent progression to more severe cutaneous adverse reactions, including Stevens-Johnson syndrome.

The extensive use of antiviral drugs for COVID-19 and influenza has increased their release into clinical and environmental settings, yet their potential to promote bacterial antibiotic cross-resistance remains poorly understood. Here, we investigated the antibacterial off-target effects of four clinically used anti-IFV/COV drugs-baloxavir acid (BXA), favipiravir (FAV), nirmatrelvir/ritonavir (NMV/r), and oseltamivir phosphate (OSV)-and their potential to influence bacterial stress responses and antibiotic cross-resistance in Escherichia coli, Bacillus subtilis, and Pseudomonas aeruginosa PAO1. BXA and NMV/r showed clear antibacterial off-target effects, while antiviral exposure induced rapid oxidative and metabolic stress in a drug- and species-dependent manner. Following high-dose single-drug selection, evolved populations developed distinct antibiotic cross-resistance profiles, with BXA producing the broadest effects and B. subtilis showing the most recurrent β-lactam-associated responses. Under chronic environmental mixture exposure, low-dose antivirals further promoted β-lactam resistance, again with the strongest response observed in B. subtilis, highlighting the potential risk of antiviral residues as environmental selective pressures for antibiotic resistance. Comparative transcriptomic analysis further revealed that cross-resistance did not arise from a universal resistance pathway, but from drug-specific adaptive remodeling, including transporter and metabolic responses under BXA, sporulation/biofilm-associated developmental responses under NMV/r, and a more limited response to OSV. Together, this study provides initial systematic evidence that clinically used anti-IFV/COV drugs can directly perturb bacterial physiology and promote antibiotic cross-resistance under both elevated and environmentally relevant exposure scenarios, identifying antiviral contamination as an underappreciated driver of antibiotic resistance evolution.

Rituximab (RTX)-induced B-cell depletion is associated with prolonged SARS-CoV-2 infection. We describe a case of persistent COVID-19 in a patient with rheumatoid arthritis (RA) initially misdiagnosed as cryptogenic organising pneumonia (COP), highlighting the diagnostic and management challenges in RTX-treated patients. Retreatment with a second 5-day course of nirmatrelvir/ritonavir led to rapid clinical improvement and complete radiological resolution. Persistent SARS-CoV-2 infection should be considered in RTX-treated patients with non-resolving pulmonary infiltrates, particularly when corticosteroid therapy is ineffective.

Ritonavir is excreted into milk in measurable concentration and low levels can be found in the blood of some breastfed infants. No reports of adverse reactions in breastfed infants have been reported.

To assess the efficacy and safety of each therapeutic options in the treatment of COVID-19 by assessing the evidence from existing systematic reviews and meta-analyses, and to carry out an umbrella meta-analysis of all meta-analysis studies to assess the efficacy of each drug. A comprehensive search was carried out in electronic databases for systematic reviews and meta-analyses which compared the efficacy and/or safety of therapeutic options in the treatment of COVID-19. Findings from the reviews were synthesized using tables and forest plots and the pooled estimate of effect size using the DerSimonian and Laird method was used for the updated meta-analysis. The main outcome was mortality. 285 reviews with 152 meta-analyses were included, The analysis of systematic reviews contents indicated that most reviewed drugs were as follows: chroquine/hydroxychloroquine (n = 48), tocilizumab (n = 39), remdesivir (n = 25), corticosteroids (n = 25), JAK inhibitors (n = 12), colchicine (n = 11), ivermectin (n = 8), anakinra (n = 7), favipravir (n = 7), lopinavir/ritonavir (n = 6), ACEI/ARB (n = 6), azithromycin (n = 4), sofosbuvir (n = 4), and Vitamin D (n = 4). Findings from the included reviews suggested that tocilizumab, remdesivir, corticosteroids, JAKI, anakinra, colchicine, ivermectin, and sofosbuvir decreased the rate of mortality significantly in those taking the drugs; otherwise hydroxylchroquine increased the risk of mortality significantly, while Lopinavir/Ritonavir had no benefit and ACEI and azithromycin decreased mortality rate not significantly. lower requirement for mechanical ventilation and intensive care unit admission and a shorter hospital length of stay was observed with the tocilizumab, JAKIs, anakinra, corticosteroids and sofosbuvir Only one third of the included reviews had 70% quality based on the AMSTAR scale assessment. The results of this study have the potential to be a useful tool for the translation of health evidence and for designing the decision support systems for evidence synthesis.

Porous silicates have been investigated as drug carriers to promote the solubility and in vitro dissolution of poorly water-soluble drugs, owing to their potential to adsorb drug molecules in the amorphous form within their structural cavities. This study aimed to evaluate the efficiency of bentonite (BT), Aeroperl 300 Pharma (AP), and Florite PS-200 (FR) as water-insoluble silicate drug carriers, and the polymer polyvinylpyrrolidone-vinyl acetate (PVPVA) in improving the dissolution of ritonavir (RTV). The effect of phosphatidylcholine (PC) as a water-insoluble excipient on drug dissolution was also investigated. Multiple linear regression analysis of the dissolution data was performed to identify the factors influencing dissolution, complemented by mechanistic simulations of the best-performing carrier. The in vitro dissolution rank order of carriers with a 30% drug load (DL) based on % dissolved300min was AP = FR > PVPVA = BT in the absence of PC, and AP > FR > PVPVA > BT with PC. The extent of dissolution for all formulations increased in the presence of PC, with the AP and FR formulations exceeding that of marketed formulations. High drug load did not significantly affect the dissolution profile of silicate formulations, but it reduced dissolution from PVPVA solid dispersion. In silico results showed that silicate pore size governed RTV release, with open pores forming fewer hydrogen bonds, allowing more facile RTV release. The significant improvement in RTV dissolution with AP and FR supports the use of these carriers for poorly soluble drugs as alternatives to traditional polymers, especially for formulations with high drug loads.