Availability of oral antivirals against SARS-CoV-2 infection and the requirement for an ethical prescribing approach

Dal‐Ré, Rafael; Becker, Sören L.; Bottieau, Emmanuel; Holm, Søren

doi:10.1016/s1473-3099(22)00119-0

Cited by 56 publications

(75 citation statements)

References 22 publications

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“…Our head-to-head comparison between the two oral antivirals offers preliminary evidence confirming the prioritization of nirmatrelvir/ritonavir over molnupiravir in COVID-19 patients who do not require supplemental oxygen, whenever accessible and clinically appropriate 3,4,21 . A relatively larger reduction in all-cause mortality risk was observed with nirmatrelvir/ritonavir use in this study, in addition to its greater efficacy in preventing COVID-19-related hospitalization than molnupiravir in previous trials, and without the risk of host mutational activity 11 . Recently, an experimental study hypothesized that the efficacy of different antivirals may be influenced by their drug concentrations in the lungs of COVID-19 patients 33 .…”

Section: Discussionmentioning

confidence: 42%

“…Based on the very limited studies on the safety and efficacy of oral antivirals in COVID-19 patients, current guidelines and the medical community are now prioritizing their distribution to those who do not require supplemental oxygen, but who are at the highest risk of disease progression, i.e. who will likely benefit the most from antivirals 4,11,20,21 . Our study cohort reflected such prescription pattern in real-world clinical practice; and provided real-world evidence supporting their use in those at risk of progression to severe disease, namely the elderly with multiple pre-existing comorbidities and who had not been fully vaccinated, during a pandemic wave dominated by the Omicron variant.…”

Section: Discussionmentioning

confidence: 99%

“…Real-world evidence on the effectiveness of molnupiravir and nirmatrelvir/ritonavir in COVID-19 patients is urgently needed 11 , as well as head-to-head comparison between the two oral antivirals. This retrospective cohort study aims to evaluate the clinical and virologic outcomes associated with molnupiravir and nirmatrelvir/ritonavir use in COVID-19 patients during a community epidemic dominated by the Omicron BA.2 variant.…”

Section: Introductionmentioning

confidence: 99%

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Real-world effectiveness of early molnupiravir and nirmatrelvir/ritonavir among hospitalized, non-oxygen-dependent COVID-19 patients on admission during Hong Kong’s Omicron BA.2 wave: an observational study

Wong

Lau

et al. 2022

Preprint

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SummaryBackgroundReal-world evidence on the effectiveness of oral antivirals in mild-to-moderate COVID-19 patients is urgently needed. This retrospective cohort study aims to evaluate the clinical and virologic outcomes associated with molnupiravir and nirmatrelvir/ritonavir use in COVID-19 patients during a pandemic wave dominated by the Omicron BA.2 variant.MethodsWe analyzed data from a territory-wide retrospective cohort of hospitalized patients with confirmed diagnosis of SARS-CoV-2 infection from 26th February 2022 to 26th April 2022 in Hong Kong. Oral antiviral users were matched with controls using propensity-score matching in a ratio of 1:4. Study outcomes were a composite outcome of disease progression (all-cause mortality, initiation of invasive mechanical ventilation [IMV], or intensive care unit admission) and their individual outcomes, and lower viral load of cycle threshold (Ct) value ≥30 cycles. Hazard ratios (HR) of event outcomes were estimated using Cox regression models.ResultsAmong 40,776 hospitalized patients with SARS-CoV-2 infection over a mean follow-up of 41.3 days with 925,713 person-days, 2,359 and 1,000 patients not initially requiring oxygen therapy were initiated with molnupiravir and nirmatrelvir/ritonavir, respectively. The crude incidence rates of all-cause mortality and IMV were 22.24 and 1.06 events per 10,000 person-days among molnupiravir users, 11.04 and 1.75 events per 10,000 person-days among nirmatrelvir/ritonavir users. Oral antiviral use was associated with a significantly lower risk of the composite outcome of disease progression (molnupiravir: HR=0.53, 95%CI=0.46-0.62, p<0.001; nirmatrelvir/ritonavir: HR=0.33, 95%CI=0.24-0.46, p<0.001) than non-use, which was consistently observed for all-cause mortality (molnupiravir: HR=0.55, 95%CI=0.47-0.63, p<0.001; nirmatrelvir/ritonavir: HR=0.32, 95%CI=0.23-0.45, p<0.001). Molnupiravir users had lower risks of IMV (HR=0.31, 95%CI=0.16-0.61, p<0.001). Time to achieving lower viral load was significantly shorter among oral antiviral users than matched controls (molnupiravir: HR=1.21, 95%CI=1.07-1.37, p=0.002; nirmatrelvir/ritonavir: HR=1.25, 95%CI=1.04-1.50, p=0.015). Amongst survivors, nirmatrelvir/ritonavir had shorter length of hospital stay (−0.70 days, 95%CI=-1.37 to -0.04, p=0.039) than matched controls. Head-to-head comparison of molnupiravir and nirmatrelvir/ritonavir reported higher risk of mortality (HR=1.53 95%CI=1.01-2.31, p=0.047) and longer length of hospital stay (0.83 days, 95%CI=0.07-1.58, p=0.032) for molnupiravir users.ConclusionsAgainst Omicron BA.2, initiation of novel oral antiviral treatment in hospitalized patients not requiring any oxygen therapy was associated with lower risks of disease progression and all-cause mortality, in addition to achieving low viral load faster.FundingHealth and Medical Research Fund, Food and Health BureauResearch in contextEvidence before this studyThe medical and research community are actively exploring the use of oral antivirals in COVID-19 patients to lower their risks of hospitalization and death, and to reduce the burden on healthcare systems. We searched Scopus and PubMed for studies until 13 May 2022 using the search terms “SARS-CoV-2 OR COVID-19” AND “molnupiravir OR Lagevrio OR EIDD-2801” OR “nirmatrelvir OR Paxlovid OR PF-07321332”. Major studies examining the safety and efficacy of molnupiravir include MOVe-IN and MOVe-OUT trials conducted in hospitalized and non-hospitalized COVID-19 patients, respectively. Clinical evidence for the use of ritonavir-boosted nirmatrelvir came from the EPIC-HR trial conducted among non-hospitalized adults with COVID-19. While no clinical benefits have been observed with molnupiravir use in the inpatient setting among patients with moderate-to-severe COVID-19, early initiation of molnupiravir or nirmatrelvir/ritonavir within 5 days of symptom onset in non-hospitalized patients with mild-to-moderate COVID-19 and risk factors for progression to severe disease has been associated with relative risk reduction of hospitalization or death by 30% and 88%, respectively. Notably, these clinical trials were conducted prior to the prevalence of Omicron variant, and the efficacy of oral antivirals against this current variant of concern can only be inferred from experimental evidence to date. Real-world evidence of oral antiviral use in patients with SARS-CoV-2 infection of Omicron variant is lacking.Added value of this studyTo the best of our knowledge, this is the first real-world study exploring the clinical use of oral antivirals during a pandemic wave dominated by SARS-CoV-2 Omicron variant. We conducted a territory-wide, retrospective cohort study to examine the effectiveness of molnupiravir and nirmatrelvir/ritonavir in COVID-19 patients who did not require supplemental oxygen on admission in Hong Kong. Early initiation of oral antivirals within 2 days of admission was associated with significantly lower risks of disease progression and all-cause mortality, in addition to achieving low viral load faster than their respective matched controls. Molnupiravir use was also associated with a significantly lower risk of requiring invasive mechanical ventilation than non-use. Furthermore, our head-to-head comparison suggested a relatively larger reduction in mortality risk with nirmatrelvir/ritonavir than molnupiravir use.Implications of all the available evidenceCurrent guidelines are now prioritizing the distribution of oral antivirals to those who do not require supplemental oxygen, but who are at the highest risk of disease progression. Our study cohort reflected such prescription pattern in real-world clinical practice. The antiviral effect and mortality benefit observed in this patient cohort support the use of oral antivirals in COVID-19 patients who do not require supplemental oxygen on admission during a pandemic wave of Omicron variant. Our findings also support the prioritization of nirmatrelvir/ritonavir over molnupiravir use in COVID-19 patients whenever accessible and clinically appropriate, in view of the former’s substantial mortality benefit. Ongoing research will inform the safety and effectiveness of oral antivirals in specific patient populations (by vaccination status and viral variants), drug combinations, and different healthcare settings.

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Section: Discussionmentioning

confidence: 42%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Real-world effectiveness of early molnupiravir and nirmatrelvir/ritonavir among hospitalized, non-oxygen-dependent COVID-19 patients on admission during Hong Kong’s Omicron BA.2 wave: an observational study

Wong

Lau

et al. 2022

Preprint

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“… [1] However, most of these therapies are limited by their high cost and parenteral administration that needs to be performed in an in-hospital setting by trained medical staff to avoid adverse effects. [ 1 , 2 ] Thus, there is an urgent need for effective oral agents, especially in non-hospitalized patients. Molnupiravir, an oral RdRp inhibitor exhibiting advantageous pharmacokinetics, has recently attracted attention due to its ability to inhibit viral replication, reduce viral load rapidly and cause fast recovery.…”

mentioning

confidence: 99%

“…The current treatment plan for non-hospitalized COVID-19 patients involves remdesivir and monoclonal antibodies like sotrovimab; however, these treatments require complex parenteral administration and are expensive. [2] Molnupiravir, being oral and also effective against newer COVID-19 variants, [8] is more practical and convenient for administration in ambulatory patients fulfilling the unmet need for safe and effective oral drugs in this population. [9] The huge reduction in the risk of mortality observed in our meta-analysis is highly encouraging.…”

mentioning

confidence: 99%

Efficacy and safety of molnupiravir for COVID-19 patients

Fatima

Azeem

Saeed

et al. 2022

European Journal of Internal Medicine

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Nirmatrelvir and ritonavir combination against COVID‐19 caused by omicron BA.2.2 in the elderly: A single‐center large observational study

Chen,

Li,

Xing

et al. 2024

Immunity Inflam & Disease

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BackgroundSince coronavirus 2019 (COVID‐19) swept the world, a variety of novel therapeutic and prevention strategies have been developed, among which nirmatrelvir–ritonavir is highly recommended. We intended to assess the effectiveness and safety of nirmatrelvir–ritonavir in the elderly mild‐to‐moderate COVID‐19 population caused by the omicron BA.2.2 variant in real‐world settings.MethodsAn observational study was conducted retrospectively to review the outcomes of mild‐to‐moderate COVID‐19 patients admitted between April 26 and June 30, 2022. Patients' baseline characteristics were collected and assessed. Participants in the intervention group were administered nirmatrelvir–ritonavir in addition to standard care, whereas those in the control group only received standard care. The primary outcome was the duration between the initial positive reverse‐transcription polymerase chain reaction (RT‐PCR) test and the subsequent conversion to a negative result.ResultsThe analysis included 324 patients who were administered nirmatrelvir–ritonavir and an equal number of control patients. The patient characteristics in both groups were evenly matched. The average duration from the initial positive RT‐PCR to negative conversion was similar in both groups (16.2 ± 5.0 vs. 16.1 ± 6.3 days, p = .83). Control patients exhibited slower conversion in comparison to patients who received nirmatrelvir–ritonavir treatment within 10 days of symptom onset.ConclusionsThese findings suggest that administering nirmatrelvir–ritonavir within 10 days of symptom onset could potentially reduce the time it takes for SARS‐CoV‐2‐infected patients to negative RT‐PCR results, thereby expanding the current usage guidelines for nirmatrelvir–ritonavir.

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Availability of oral antivirals against SARS-CoV-2 infection and the requirement for an ethical prescribing approach

Cited by 56 publications

References 22 publications

Real-world effectiveness of early molnupiravir and nirmatrelvir/ritonavir among hospitalized, non-oxygen-dependent COVID-19 patients on admission during Hong Kong’s Omicron BA.2 wave: an observational study

Real-world effectiveness of early molnupiravir and nirmatrelvir/ritonavir among hospitalized, non-oxygen-dependent COVID-19 patients on admission during Hong Kong’s Omicron BA.2 wave: an observational study

Efficacy and safety of molnupiravir for COVID-19 patients

Nirmatrelvir and ritonavir combination against COVID‐19 caused by omicron BA.2.2 in the elderly: A single‐center large observational study

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