Identifying and Treating Non-Severe COVID-19 in Non-Hospitalised Patients at Risk of Severe COVID-19

Background

With the emergence and global expansion of the SARS CoV-2 omicron variant of concern, COVID-19 continues to be a significant burden on health systems. Omicron sublineages have been shown to escape vaccine-elicited and therapeutic monoclonal neutralizing antibodies, resulting in effective immune evasion and an increased risk of progression to severe disease, especially among patients with suboptimal antibody responses following vaccination or infection.^[1,2] Progression from non-severe COVID-19 to severe and critical disease (Box 1) is associated with several risk factors—older age being a vital risk factor associated with COVID-19 mortality and severity.^[3,4] Comorbidities such as asthma, obesity, chronic lung disease, diabetes, cerebrovascular disease, chronic kidney disease, as well as cancer are all strongly associated with severe disease.^[3,4] Further commonly considered factors related to risk of progression include immunocompromised status, smoking and pregnancy.^[3,4] In pregnant women, additional risk factors include being aged ≥30 years, overweight or obesity, and mixed ethnicity.^[5]

The use of therapeutic monoclonal antibodies to reduce the risk of progression to severe disease is limited as omicron sublineages BA.2.12.1, BA.4, and BA.5 escape all approved monoclonal antibodies except one.^[2] None of the major international guidelines recommend the use of monoclonal antibodies in patients with non-severe disease at risk of progression to severe COVID-19.^[6,7] Therefore the use of early antiviral treatment options for populations at risk of severe COVID-19 is of key clinical importance.

Antiviral Agents for Treating SARS CoV-2 Infected Patients with Non-Severe Disease at Risk of Progression

Three antiviral treatment options—nirmatrelvir/ritonavir,^[8] remdesivir,^[9] and molnupiravir^[10] are early therapeutic interventions for SARS CoV-2 infected patients not requiring oxygen support who are at risk of progression to severe COVID-19. It should be noted that all three antivirals are subject to additional monitoring. Remdesivir^[9] and molnupiravir^[10] are a direct-acting nucleoside analogues inhibiting coronavirus RNA-dependent RNA polymerase (RdRp). Nirmatrelvir acts as an irreversible inhibitor of SARS-CoV-2 Mpro cysteine protease and is co-formulated with ritonavir, a strong cytochrome CYP 3A4 P450 inhibitor.^[8] As these antivirals target genes that are conserved between SARS-CoV-2 variants, these therapies retain antiviral activity against current circulating variants, including omicron sublineages.^[11,12] Three placebo-controlled randomised clinical trials (RCT) assessed safety and efficacy of nirmatrelvir/ritonavir,^[13] remdesivir^[14] and molnupiravir^[15] in non-hospitalised unvaccinated patients with confirmed SARS-CoV-2 infection and with at least one risk factor for disease progression.

A phase 2/3 double-blind RCT (EPIC-HR) investigated a 5-day course of nirmatrelvir/ritonavir, administered within 5 days of symptom onset.^[13] The study found nirmatrelvir/ritonavir reduced the incidence of hospitalisation or death by day 28 compared with placebo (0.77% versus 6.31%), translating to a relative risk reduction of 87.8%.^[13] Gastrointestinal adverse events such as dysgeusia (5.6% versus 0.3%) and diarrhoea (1.3% versus 1.6%) were more common with nirmatrelvir/ritonavir than placebo.^[13]

The phase-3 double-blind PINETREE study evaluated a 3-day course of remdesivir given within 7 days of symptom onset.^[14] Similar to EPIC-HR, the primary endpoint was hospitalisation or all-cause mortality by day 28, which was 0.7% in the remdesivir group compared with 5.3% in the placebo group (hazard ratio (HR) 0.13, 95% CI 0.03 to 0.59), translating to an 87% lower risk of hospitalisation or death with remdesivir compared to placebo.^[14] Among remdesivir-treated patients there were similar reductions in the hazard ratios for age ≥60 years, male sex, or comorbidities such as diabetes, obesity and hypertension.^[14] It should be noted however, that the PINETREE study was conducted before the emergence of the delta variant, and no detailed variant data is provided in the study report. The most common adverse event among patients receiving remdesivir was nausea observed in 10.8% of patients.^[14]

The phase-3 double-blind trial MOVe-OUT analysed a 5-day course of molnupiravir, with treatment initiated within 5 days of the onset of symptoms.^[15]  The study was conducted in the setting of multiple circulating variants of concern including delta (58%), gamma (11%) and mu (20%). Risk of hospitalisation or death at day 29 was lower with molnupiravir than placebo (6.8% versus 9.7%; difference -3.0 percentage points, 95% CI, -5.9 to -0.1)].^[15] This translates to approximately a 31% reduction in the rate of hospitalisations and deaths by day 29. Molnupiravir was associated with a shorter time to recovery from anosmia (HR 1.20, 95% CI 1.01 to 1.43) and fatigue (HR 1.15, 95% CI 1.01 to 1.31).^[15] The most frequent adverse events associated with molnupiravir were diarrhoea (1.7%), nausea (1.4%), and dizziness (1.0%).^[15]

Further Evidence for Treatment with Oral Antivirals of Non-Severe COVID-19 in Patients at Risk of Severe Disease

PANORAMIC is a large (>25,000 cases), UK-based multicentre, multi-arm, open-label RCT enrolling non-hospitalised SARS CoV-2 infected participants aged ≥50 (or ≥ 18 with comorbidities) with symptoms not exceeding 5 days.^[16] Participants are randomised to usual care or usual care plus an antiviral. Evaluation of nirmatrelvir/ritonavir is ongoing; data on molnupiravir has been reported.^[17]

The sample of molnupiravir-treated individuals was considerable (12,821 participants; 12,962 were randomised to usual care), with the majority enrolled during omicron variant dominance (from December 2021 until April 2022).^[17] The study was performed in an extensively vaccinated population (at least 99% of participants had received at least one dose of a vaccine). Due to mutagenetic potential and genotoxicity, pregnant women and participants of childbearing potential not choosing to use effective contraception were excluded.^[17]

The rate of hospitalisations and deaths was equally low among both molnupiravir-treated and usual care only arms (0.8% each), however molnupiravir was associated with shorter time to recovery—median time to recovery of 9 days, interquartile range (IQR) 5–23 days versus 15 (IQR 7–not reached).^[17] By day 7 there was also a higher proportion of SARS CoV-2 eliminations (measured in self-taken nasopharyngeal swabs) in the molnupiravir-treated group (21%) versus usual care (3%).^[17] Serious adverse events were observed in 0.4% of participants in both groups, however 1.1% of participants withdrew from the study due to adverse events.^[17] Key study outcomes related to molnupiravir use were faster recovery time, higher self-rating of wellness, shorter time to alleviation of symptoms, lower frequency of moderate/severe symptoms (including cough, shortness of breath, fatigue, loss of smell/tase), lower involvement of medical primary healthcare resources as well as reduced viral detection and viral loads.^[17]

Nirmatrelvir/ritonavir use in a non-hospital setting was analysed in a matched observational cohort study in Southern California when omicron was the dominant variant.^[18] The study included 4329 nirmatrelvir/ritonavir-treated patients matched for testing date, age, gender, care setting, status of symptoms, and vaccination history with 20,980 cases.^[18] The included population was highly vaccinated (93.3% of participants with at least two and 78.1% with at least three vaccine doses). Nirmatrelvir/ritonavir treatment administered within 5 days from the symptom onset was associated with 88.1% (95% CI 49.0 to 97.5%) and 71.9% (95% CI 25.3 to 90.0%) effectiveness in preventing all hospital admissions over 15 and 30 days, respectively.^[18] Furthermore, effectiveness in preventing hospital admissions associated with acute respiratory infection were 88.3% (95% CI 12.9 to 98.8%) and 87.3% (95% CI 18.3 to 98.5%) over 15 and 30 days, respectively.^[18] Interestingly, high efficacy in preventing hospitalisation was also observed for treatment received at any timepoint during the course of infection (although numbers of individuals initiating treatment beyond 5 days from the symptom onset was low) and was similar across vaccination history strata.^[18] The less pronounced effect related to the prevention of all-cause hospitalisation over the longer, 30-day period of observation may be related to the accumulation of non-COVID-19 hospitalisations over longer observation periods.^[18] This study confirms high efficacy of nirmatrelvir/ritonavir in the real-life settings of vaccinated individuals during omicron lineage spread.

Several real-life studies further confirmed clinical benefit of nirmatrelvir/ritonavir administration during omicron variant predominance. In a study in Israel of patients ≥65 years its use was associated with reduced hospitalisation rates (14.7 cases per 100,000 person-days compared with 58.9 cases per 100,000 person-days among untreated patients [adjusted HR, 0.27; 95% CI 0.15 to 0.49]), and reduced mortality (adjusted HR of 0.21 [95% CI 0.05 to 0.82]).^[19] Of note, no clear benefit was observed in patients aged 40–64 years.^[19] Clinical benefit related to the use of oral antivirals (both nirmatrelvir/ritonavir and molnupiravir) was also observed in large cohorts from Hong Kong.^[20,21]

Key International Guideline Recommendations on the Use of Antiviral Therapeutics

The WHO living guideline on therapeutics and COVID-19 includes all three antiviral treatments as early treatment options for patients with non-severe COVID-19 at highest risk of progression to severe disease and hospitalisation.^[6] Risk factors for disease progression are older age, immunosuppression and/or chronic diseases, plus lack of vaccination as an additional risk factor.^[6]

There is a preference for nirmatrelvir/ritonavir (strong recommendation for use), with conditional recommendations for use of molnupiravir and remdesivir.^[6] However, the guidance acknowledges that choice of drug will depend on practical issues such as administration (for example, remdesivir is an intravenous drug) and potential drug–drug interactions (DDIs).^[6] All agents should optimally be initiated within the timeline defined in the trials (within 5 days from the onset of symptoms for nirmatrelvir/ritonavir and molnupiravir, within 7 days for remdesivir). WHO advises caution for nirmatrelvir/ritonavir use among pregnant women, children and patients with possible drug–drug interactions. Given the complexity of administration, use of remdesivir should be based on the assessment of risk and benefit. Due to uncertainty about mutagenetic potential, molnupiravir should not be offered to pregnant or breastfeeding women or children, with birth control recommended for men during treatment and for at least 3 months after the last dose.^[6]

The European Society of Clinical Microbiology and Infectious Diseases (ESCMID) guideline update on the treatment of patients with mild/moderate COVID-19 outlines risk factors for disease progression (Box 2) and vaccine failure (Box 3).^[7]

For patients at risk of progression the guidance recommends the use of nirmatrelvir/ritonavir and suggests the use of molnupiravir or remdesivir (conditional recommendations), for unvaccinated patients or with undetectable SARS CoV-2 RBD antibodies. For all agents, the maximum time from symptom onset to initiation of treatment is the same as in the trials and WHO guideline.^[6] For vaccinated patients at risk of vaccine failure there are conditional recommendations for the use of nirmatrelvir/ritonavir, molnupiravir and remdesivir. The ESCMID panel noted that there is insufficient data to inform recommendations about the use of nirmatrelvir/ritonavir or molnupiravir in fully vaccinated populations.^[7]

In pregnancy, the guidance advises a risk–benefit consideration of nirmatrelvir/ritonavir due to lack toxicity signal in animal tests and extensive experience related to safe ritonavir use in pregnancy among people who live with HIV.^[7] Similarly, there is a recommendation for risk–benefit assessment for remdesivir use, which was initially associated with higher rates of the pre-term delivery when used compassionately in women with severe COVID-19.^[7] This signal was not significant in a later study,^[22] however safety data for the first trimester of the pregnancy are limited.

It should be noted that all guidelines highlight issues related to the evaluation of antiviral agents only in unvaccinated patients and before the emergence of the omicron variant.

Challenges in Implementing Guideline Recommendations and Choosing Treatment

Real-life data and treatment recommendations indicate that the window for effective antiviral treatment for non-severe COVID-19 is short; treatment needs to be initiated within 5 days of initial symptoms for oral treatment (nirmatrelvir/ritonavir and molnupriavir) and within 7 days for remdesivir.

If early administration of treatment in non-hospital settings is to be scaled-up, rapid testing and patient scheduling for care needs to be achieved. Identifying patients potentially at risk is challenging. While a systematic review identified over 200 prognosis models, there are currently no validated risk prediction tools to support clinical decision making.^[23] Also, equity of treatment access needs to be considered to avoid racial and cross-country disparities—access to treatment is however largely dependent on national drug funding policies which remain unequal. Access to remdesivir in non-hospital settings is further complicated by intravenous administration, which would require the establishment of infusion hubs.

As antiviral therapeutics are of the greatest benefit to older patients and those with multimorbidities, the consideration of DDIs is of primary importance. Molnupiravir and remdesivir do not exhibit major DDI potential, however nirmatrelvir boosting with ritonavir results in multiple interactions, many potentially life-threatening or fatal, therefore thorough review of concomitant therapy as well as other supplements including herbal ones should be performed. Several dedicated support tools are available for the purpose of managing DDIs with COVID-19 drugs (Box 4).

These tools facilitate identification of medications with and without relevant interactions, including agents which may be temporarily withdrawn in clinical settings. Real-life data are reassuring in the context of the safety profile of all three antiviral treatment options, with use of nirmatrelvir/ritonavir contraindicated in patients with severe hepatic and renal impairment^[8]and remdesivir contraindicated in patients with eGFR <30 ml/min.^[9] For these patients molnupiravir remains an attractive option.^[10]

Consideration of childbearing potential and pregnancy also notably influence treatment choices. Nirmatrelvir/ritonavir and remdesivir may be administered following careful consideration of the risk–benefit profile. The uncertain mutagenic potential of molnupiravir means it is not recommended for this group.

Summary

With the evolving landscape of SARS CoV-2 variants and loss of monoclonal antibody efficacy, antiviral agents are a key treatment option for use in patients with non-severe COVID-19 at risk of developing severe disease. Data from large-scale randomised clinical trials provide a basis for clinical recommendations which generally favour use of nirmatrelvir/ritonavir due to its efficacy in preventing hospitalisations and deaths and oral route of administration. Remdesivir use, despite considerable clinical efficacy, is practically limited by the intravenous transmission route, while molnupiravir is recommended conditionally due to uncertainty about potential harms. Real-life data in the setting of predominantly circulating omicron variant indicate benefit of both nirmatrelvir/ritonavir and molnupiravir in reducing progression risk and quicker return to health and symptom alleviation. In older patients with multiple comorbidities and concomitant medications DDIs must be cautiously managed, particularly for nirmatrelvir/ritonavir, and all three antiviral drugs are subject to additional monitoring.

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Cite this: Identifying and Treating Non-Severe COVID-19 in Non-Hospitalised Patients at Risk of Severe COVID-19 - Medscape - Mar 15, 2023.