Clinical effectiveness of nirmatrelvir plus ritonavir in patients with COVID‐19 and substance use disorders based on real‐world data

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Abstract

This study assessed the clinical efficacy of nirmatrelvir plus ritonavir (NMV‐r) in treating patients with coronavirus disease‐2019 (COVID‐19) and substance use disorders (SUDs). This study included two cohorts: the first examined patients with SUDs, with and without a prescription for NMV‐r, while the second compared patients prescribed with NMV‐r, with and without a diagnosis of SUDs. SUDs were defined using ICD‐10 codes, related to SUDs, including alcohol, cannabis, cocaine, opioid, and tobacco use disorders (TUD). Patients with underlying SUDs and COVID‐19 were identified using the TriNetX network. We used 1:1 propensity score matching to create balanced groups. The primary outcome of interest was the composite outcome of all‐cause hospitalization or death within 30 days. Propensity score matching yielded two matched groups of 10 601 patients each. The results showed that the use of NMV‐r was associated with a lower risk of hospitalization or death, 30 days after COVID‐19 diagnosis (hazard ratio (HR), 0.640; 95% confidence interval (CI): 0.543–0.754), as well as a lower risk of all‐cause hospitalization (HR, 0.699; 95% CI: 0.592–0.826) and all‐cause death (HR, 0.084; 95% CI: 0.026–0.273). However, patients with SUDs had a higher risk of hospitalized or death within 30 days of COVID‐19 diagnosis than those without SUDs, even with the use of NMV‐r (HR, 1.783; 95% CI: 1.399–2.271). The study also found that patients with SUDs had a higher prevalence of comorbidities and adverse socioeconomic determinants of health than those without SUDs. Subgroup analysis showed that the benefits of NMV‐r were consistent across most subgroups with different characteristics, including age (patients aged ≥60 years [HR, 0.507; 95% CI: 0.402–0.640]), sex (women [HR, 0.636; 95% CI: 0.517–0.783] and men [HR, 0.480; 95% CI: 0.373–0.618]), vaccine status (vaccinated <2 doses [HR, 0.514; 95% CI: 0.435–0.608]), SUD subtypes (alcohol use disorder [HR, 0.711; 95% CI: 0.511– 0.988], TUD [HR, 0.666; 95% CI: 0.555–0.800]) and Omicron wave (HR, 0.624; 95% CI: 0.536–0.726). Our findings indicate that NMV‐r could reduce all‐cause hospitalization and death in the treatment of COVID‐19 among patients with SUDs and support the use of NMV‐r for treating patients with SUDs and COVID‐19.

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6-month neurological and psychiatric outcomes in 236 379 survivors of COVID-19: a retrospective cohort study using electronic health records

Maxime Taquet, John R Geddes, Masud Husain … (2021)

Background Neurological and psychiatric sequelae of COVID-19 have been reported, but more data are needed to adequately assess the effects of COVID-19 on brain health. We aimed to provide robust estimates of incidence rates and relative risks of neurological and psychiatric diagnoses in patients in the 6 months following a COVID-19 diagnosis. Methods For this retrospective cohort study and time-to-event analysis, we used data obtained from the TriNetX electronic health records network (with over 81 million patients). Our primary cohort comprised patients who had a COVID-19 diagnosis; one matched control cohort included patients diagnosed with influenza, and the other matched control cohort included patients diagnosed with any respiratory tract infection including influenza in the same period. Patients with a diagnosis of COVID-19 or a positive test for SARS-CoV-2 were excluded from the control cohorts. All cohorts included patients older than 10 years who had an index event on or after Jan 20, 2020, and who were still alive on Dec 13, 2020. We estimated the incidence of 14 neurological and psychiatric outcomes in the 6 months after a confirmed diagnosis of COVID-19: intracranial haemorrhage; ischaemic stroke; parkinsonism; Guillain-Barré syndrome; nerve, nerve root, and plexus disorders; myoneural junction and muscle disease; encephalitis; dementia; psychotic, mood, and anxiety disorders (grouped and separately); substance use disorder; and insomnia. Using a Cox model, we compared incidences with those in propensity score-matched cohorts of patients with influenza or other respiratory tract infections. We investigated how these estimates were affected by COVID-19 severity, as proxied by hospitalisation, intensive therapy unit (ITU) admission, and encephalopathy (delirium and related disorders). We assessed the robustness of the differences in outcomes between cohorts by repeating the analysis in different scenarios. To provide benchmarking for the incidence and risk of neurological and psychiatric sequelae, we compared our primary cohort with four cohorts of patients diagnosed in the same period with additional index events: skin infection, urolithiasis, fracture of a large bone, and pulmonary embolism. Findings Among 236 379 patients diagnosed with COVID-19, the estimated incidence of a neurological or psychiatric diagnosis in the following 6 months was 33·62% (95% CI 33·17–34·07), with 12·84% (12·36–13·33) receiving their first such diagnosis. For patients who had been admitted to an ITU, the estimated incidence of a diagnosis was 46·42% (44·78–48·09) and for a first diagnosis was 25·79% (23·50–28·25). Regarding individual diagnoses of the study outcomes, the whole COVID-19 cohort had estimated incidences of 0·56% (0·50–0·63) for intracranial haemorrhage, 2·10% (1·97–2·23) for ischaemic stroke, 0·11% (0·08–0·14) for parkinsonism, 0·67% (0·59–0·75) for dementia, 17·39% (17·04–17·74) for anxiety disorder, and 1·40% (1·30–1·51) for psychotic disorder, among others. In the group with ITU admission, estimated incidences were 2·66% (2·24–3·16) for intracranial haemorrhage, 6·92% (6·17–7·76) for ischaemic stroke, 0·26% (0·15–0·45) for parkinsonism, 1·74% (1·31–2·30) for dementia, 19·15% (17·90–20·48) for anxiety disorder, and 2·77% (2·31–3·33) for psychotic disorder. Most diagnostic categories were more common in patients who had COVID-19 than in those who had influenza (hazard ratio [HR] 1·44, 95% CI 1·40–1·47, for any diagnosis; 1·78, 1·68–1·89, for any first diagnosis) and those who had other respiratory tract infections (1·16, 1·14–1·17, for any diagnosis; 1·32, 1·27–1·36, for any first diagnosis). As with incidences, HRs were higher in patients who had more severe COVID-19 (eg, those admitted to ITU compared with those who were not: 1·58, 1·50–1·67, for any diagnosis; 2·87, 2·45–3·35, for any first diagnosis). Results were robust to various sensitivity analyses and benchmarking against the four additional index health events. Interpretation Our study provides evidence for substantial neurological and psychiatric morbidity in the 6 months after COVID-19 infection. Risks were greatest in, but not limited to, patients who had severe COVID-19. This information could help in service planning and identification of research priorities. Complementary study designs, including prospective cohorts, are needed to corroborate and explain these findings. Funding National Institute for Health Research (NIHR) Oxford Health Biomedical Research Centre.

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Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19

Jennifer Hammond, Heidi Leister-Tebbe, Annie Gardner … (2022)

Background Nirmatrelvir is an orally administered severe acute respiratory syndrome coronavirus 2 main protease (M pro ) inhibitor with potent pan–human-coronavirus activity in vitro. Methods We conducted a phase 2–3 double-blind, randomized, controlled trial in which symptomatic, unvaccinated, nonhospitalized adults at high risk for progression to severe coronavirus disease 2019 (Covid-19) were assigned in a 1:1 ratio to receive either 300 mg of nirmatrelvir plus 100 mg of ritonavir (a pharmacokinetic enhancer) or placebo every 12 hours for 5 days. Covid-19–related hospitalization or death from any cause through day 28, viral load, and safety were evaluated. Results A total of 2246 patients underwent randomization; 1120 patients received nirmatrelvir plus ritonavir (nirmatrelvir group) and 1126 received placebo (placebo group). In the planned interim analysis of patients treated within 3 days after symptom onset (modified intention-to treat population, comprising 774 of the 1361 patients in the full analysis population), the incidence of Covid-19–related hospitalization or death by day 28 was lower in the nirmatrelvir group than in the placebo group by 6.32 percentage points (95% confidence interval [CI], −9.04 to −3.59; P<0.001; relative risk reduction, 89.1%); the incidence was 0.77% (3 of 389 patients) in the nirmatrelvir group, with 0 deaths, as compared with 7.01% (27 of 385 patients) in the placebo group, with 7 deaths. Efficacy was maintained in the final analysis involving the 1379 patients in the modified intention-to-treat population, with a difference of −5.81 percentage points (95% CI, −7.78 to −3.84; P<0.001; relative risk reduction, 88.9%). All 13 deaths occurred in the placebo group. The viral load was lower with nirmaltrelvir plus ritonavir than with placebo at day 5 of treatment, with an adjusted mean difference of −0.868 log 10 copies per milliliter when treatment was initiated within 3 days after the onset of symptoms. The incidence of adverse events that emerged during the treatment period was similar in the two groups (any adverse event, 22.6% with nirmatrelvir plus ritonavir vs. 23.9% with placebo; serious adverse events, 1.6% vs. 6.6%; and adverse events leading to discontinuation of the drugs or placebo, 2.1% vs. 4.2%). Dysgeusia (5.6% vs. 0.3%) and diarrhea (3.1% vs. 1.6%) occurred more frequently with nirmatrelvir plus ritonavir than with placebo. Conclusions Treatment of symptomatic Covid-19 with nirmatrelvir plus ritonavir resulted in a risk of progression to severe Covid-19 that was 89% lower than the risk with placebo, without evident safety concerns. (Supported by Pfizer; ClinicalTrials.gov number, NCT04960202 .)

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Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients

Angélica Jayk Bernal, Monica M. Gomes da Silva, Dany Musungaie … (2021)

Abstract Background New treatments are needed to reduce the risk of progression of coronavirus disease 2019 (Covid-19). Molnupiravir is an oral, small-molecule antiviral prodrug that is active against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Methods We conducted a phase 3, double-blind, randomized, placebo-controlled trial to evaluate the efficacy and safety of treatment with molnupiravir started within 5 days after the onset of signs or symptoms in nonhospitalized, unvaccinated adults with mild-to-moderate, laboratory-confirmed Covid-19 and at least one risk factor for severe Covid-19 illness. Participants in the trial were randomly assigned to receive 800 mg of molnupiravir or placebo twice daily for 5 days. The primary efficacy end point was the incidence hospitalization or death at day 29; the incidence of adverse events was the primary safety end point. A planned interim analysis was performed when 50% of 1550 participants (target enrollment) had been followed through day 29. Results A total of 1433 participants underwent randomization; 716 were assigned to receive molnupiravir and 717 to receive placebo. With the exception of an imbalance in sex, baseline characteristics were similar in the two groups. The superiority of molnupiravir was demonstrated at the interim analysis; the risk of hospitalization for any cause or death through day 29 was lower with molnupiravir (28 of 385 participants [7.3%]) than with placebo (53 of 377 [14.1%]) (difference, −6.8 percentage points; 95% confidence interval, −11.3 to −2.4; P=0.001). In the analysis of all participants who had undergone randomization, the percentage of participants who were hospitalized or died through day 29 was lower in the molnupiravir group than in the placebo group (6.8% [48 of 709] vs. 9.7% [68 of 699]; difference, −3.0 percentage points; 95% confidence interval, −5.9 to −0.1). Results of subgroup analyses were largely consistent with these overall results; in some subgroups, such as patients with evidence of previous SARS-CoV-2 infection, those with low baseline viral load, and those with diabetes, the point estimate for the difference favored placebo. One death was reported in the molnupiravir group and 9 were reported in the placebo group through day 29. Adverse events were reported in 216 of 710 participants (30.4%) in the molnupiravir group and 231 of 701 (33.0%) in the placebo group. Conclusions Early treatment with molnupiravir reduced the risk of hospitalization or death in at-risk, unvaccinated adults with Covid-19. (Funded by Merck Sharp and Dohme; MOVe-OUT ClinicalTrials.gov number, NCT04575597.)

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Contributors

Po‐Yu Huang: (View ORCID Profile)

Jheng‐Yan Wu: (View ORCID Profile)

Ya‐Wen Tsai: (View ORCID Profile)

Chih‐Cheng Lai: (View ORCID Profile)

Journal

Title: Journal of Medical Virology

Abbreviated Title: Journal of Medical Virology

Publisher: Wiley

ISSN (Print): 0146-6615

ISSN (Electronic): 1096-9071

Publication date Created: May 2023

Publication date (Electronic): May 22 2023

Publication date (Print): May 2023

Volume: 95

Issue: 5

Affiliations

[1 ] Department of Psychiatry Chi Mei Medical Center Tainan Taiwan

[2 ] Department of Internal Medicine Chi Mei Medical Center Tainan Taiwan

[3 ] Department of Nutrition Chi Mei Medical Center Tainan Taiwan

[4 ] Center for Integrative Medicine Chi Mei Medical Center Tainan Taiwan

[5 ] Department of Health Psychology Chang Jung Christian University Tainan Taiwan

[6 ] Department of Internal Medicine, Division of Hospital Medicine Chi Mei Medical Center Tainan Taiwan

[7 ] School of Medicine, College of Medicine National Sun Yat‐sen University Kaohsiung Taiwan

Article

DOI: 10.1002/jmv.28801

PubMed ID: 37218308

SO-VID: 65d91b02-effe-4574-94e1-77fe24c7f2f9

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Clinical effectiveness of nirmatrelvir plus ritonavir in patients with COVID‐19 and substance use disorders based on real‐world data

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Most cited references 39

6-month neurological and psychiatric outcomes in 236 379 survivors of COVID-19: a retrospective cohort study using electronic health records

Oral Nirmatrelvir for High-Risk, Nonhospitalized Adults with Covid-19

Molnupiravir for Oral Treatment of Covid-19 in Nonhospitalized Patients

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