COVID-19

Background: Olgotrelvir is an oral antiviral with dual mechanisms of action targeting severe acute respiratory syndrome coronavirus 2 main protease (i.e., Mpro) and human cathepsin L. It has potential to serve as a single-agent treatment of coronavirus disease 2019 (Covid-19).

Methods: We conducted a phase 3, double-blind, randomized, placebo-controlled trial to evaluate the efficacy and safety of olgotrelvir in 1212 nonhospitalized adult participants with mild to moderate Covid-19, irrespective of risk factors, who were randomly assigned to receive orally either 600 mg of olgotrelvir or placebo twice daily for 5 days. The primary and key secondary end points were time to sustained recovery of a panel of 11 Covid-19-related symptoms and the viral ribonucleic acid (RNA) load. The safety end point was incidence of treatment-emergent adverse events.

Results: The baseline characteristics of 1212 participants were similar in the two groups. In the modified intention-to-treat population (567 patients in the placebo group and 558 in the olgotrelvir group), the median time to symptom recovery was 205 hours in the olgotrelvir group versus 264 hours in the placebo group (hazard ratio, 1.29; 95% confidence interval [CI], 1.13 to 1.46; P<0.001). The least squares mean (95% CI) changes of viral RNA load from baseline were -2.20 (-2.59 to -1.81) log10 copies/ml in olgotrelvir-treated participants and -1.40 (-1.79 to -1.01) in participants receiving placebo at day 4. Skin rash (3.3%) and nausea (1.5%) were more frequent in the olgotrelvir group than in the placebo group; there were no treatment-related serious adverse events, and no deaths were reported.

Conclusions: Olgotrelvir as a single-agent treatment significantly improved symptom recovery. Adverse effects were not dose limiting. (Funded by Sorrento Therapeutics, a parent company of ACEA Therapeutics; ClinicalTrials.gov number, NCT05716425.).

A 43-year-old woman presented with a 1-year history of recurring symptoms of sudden onset of fatigue, palpitations, dyspnea, chest pain, lightheadedness, and nausea that were associated with standing and resolved with sitting. These symptoms began 1 month after mild COVID-19 infection. At presentation, while supine, blood pressure (BP) was 123/70 mm Hg and heart rate (HR) was 90/min; while seated, BP was 120/80 and HR was 93/min; after standing for 1 minute, BP was 124/80 and HR was 119/min. Physical examination results were normal. Oxygen saturation was 98% at rest while breathing room air. She had no oxygen desaturation during a 6-minute walk test but walked only 282 m (45% predicted). Complete blood cell count, morning cortisol, and thyrotropin blood levels were normal. Electrocardiogram (ECG), chest computed tomography, pulmonary function testing, methacholine challenge, bronchoscopy, echocardiography, and cardiac catheterization findings were normal. During tilt table testing, the patient experienced lightheadedness and nausea when moved from horizontal to the upright position. Results of the tilt table test are shown in the Table and Figure.

Question: What outcomes are associated with ritonavir-boosted nirmatrelvir or molnupiravir use for outpatient treatment of SARS-CoV-2 Omicron subvariants, particularly BQ.1.1 and XBB.1.5, in high-risk individuals?

Findings: In a cohort study of 68 867 patients who received a diagnosis of COVID-19 at Cleveland Clinic from April 1, 2022, to February 20, 2023, and who were at high risk of progressing to severe COVID-19, both nirmatrelvir and molnupiravir use were significantly associated with reductions in hospitalization and death. The association was observed across subgroups defined by age, race and ethnicity, date of diagnosis, vaccination status, previous infection status, and coexisting conditions.

Meaning: These findings suggest that both nirmatrelvir and molnupiravir can be used to treat nonhospitalized patients who are at high risk of progressing to severe COVID-19.

Importance Estimates of the rate of waning of vaccine effectiveness (VE) against COVID-19 are key to assess population levels of protection and future needs for booster doses to face the resurgence of epidemic waves.

Objective To quantify the progressive waning of VE associated with the Delta and Omicron variants of SARS-CoV-2 by number of received doses.

Data Sources PubMed and Web of Science were searched from the databases’ inception to October 19, 2022, as well as reference lists of eligible articles. Preprints were included.

Study Selection Selected studies for this systematic review and meta-analysis were original articles reporting estimates of VE over time against laboratory-confirmed SARS-CoV-2 infection and symptomatic disease.

Data Extraction and Synthesis Estimates of VE at different time points from vaccination were retrieved from original studies. A secondary data analysis was performed to project VE at any time from last dose administration, improving the comparability across different studies and between the 2 considered variants. Pooled estimates were obtained from random-effects meta-analysis.

Main Outcomes and Measures Outcomes were VE against laboratory-confirmed Omicron or Delta infection and symptomatic disease and half-life and waning rate associated with vaccine-induced protection.

Results A total of 799 original articles and 149 reviews published in peer-reviewed journals and 35 preprints were identified. Of these, 40 studies were included in the analysis. Pooled estimates of VE of a primary vaccination cycle against laboratory-confirmed Omicron infection and symptomatic disease were both lower than 20% at 6 months from last dose administration. Booster doses restored VE to levels comparable to those acquired soon after the administration of the primary cycle. However, 9 months after booster administration, VE against Omicron was lower than 30% against laboratory-confirmed infection and symptomatic disease. The half-life of VE against symptomatic infection was estimated to be 87 days (95% CI, 67-129 days) for Omicron compared with 316 days (95% CI, 240-470 days) for Delta. Similar waning rates of VE were found for different age segments of the population.

Conclusions and Relevance These findings suggest that the effectiveness of COVID-19 vaccines against laboratory-confirmed Omicron or Delta infection and symptomatic disease rapidly wanes over time after the primary vaccination cycle and booster dose. These results can inform the design of appropriate targets and timing for future vaccination programs.