Viruses, Vol. 15, Pages 71: Impact of Early SARS-CoV-2 Antiviral Therapy on Disease Progression

1. IntroductionAt the end of December 2019, several cases of an unknown respiratory syndrome were reported in Wuhan (Hubei Province, China). On 9 January 2020, Severe Acute Respiratory Syndrome – Coronavirus 2 (SARS-CoV2), the causative agent of the novel Chinese respiratory syndrome, was finally identified [1,2,3].The estimated cumulative incidence of SARS-CoV-2 infection cases is half a billion globally, with more than six million deaths caused by COVID-19. To date, 23 million cases with more than 178 thousand deaths have been recorded in Italy [4].The most prevalent symptoms of COVID-19 are fever, cough, and dyspnoea; a low proportion complain of gastrointestinal symptoms, anosmia, dysgeusia, headache, and skin lesions [5,6,7,8,9,10]. However, the disease can progress to life-threatening systemic inflammation, respiratory failure, and multiorgan dysfunction [11,12]. At the end of 2020, mRNA vaccines were distributed worldwide and showed high efficacy and safety in disease prevention [13,14,15,16]. Concomitantly, several therapies are available for hospitalised patients with moderate or severe COVID-19 [17,18,19,20]. Three early SARS-CoV-2 antiviral therapies are currently available in Italy. Molnupiravir and remdesivir are inhibitors of SARS-CoV-2 polymerases, while nirmatrelvir/ritonavir(r) inhibits the main protease (Mpro) [21,22,23]. To date, real-life data about the use and efficacy of these treatments are limited in the literature [24,25].

The aim of the present study was to evaluate the effectiveness of antivirals and monoclonal antibodies in preventing disease progression.

2. Materials and Methods

An observational, retrospective study was conducted at an Italian university hospital (University of Sassari, Sassari) between 1 January and 31 July 2022. Inclusion criteria were: (i) age ≥ 18 years; (ii) diagnosis of SARS-CoV-2 infection by Polymerase Chain Reaction (PCR) or third-generation antigenic tests; (iii) exclusion of respiratory failure (PaO2/FiO2 > 300). All people included in the study were evaluated in the emergency room, or in wards for those who had a hospital infection.

We collected information on medical history, vaccination status, computer tomography (CT) findings, symptoms at admission, and therapies.

2.1. Treatment Prescription

Antiviral treatments (molnupiravir, nirmatrelvir/ritonavir, and remdesivir) and monoclonal antibodies (casirivimab/imdevimab and sotrovimab) were prescribed in accordance with the recommendations of the Italian Drug Agency. Criteria for their prescription were: recent symptom onset (≤5 days for molnupiravir and nirmatrelvir/ritonavir, ≤7 days for remdesivir and monoclonal antibodies), no need for oxygen supplementation, and high risk of disease progression for the presence of at least one of the following chronic diseases: (i) obesity (body mass index > 30); (ii) diabetes mellitus with organ damage or hemoglobin A1c > 7.5%; (iii) kidney failure; (iv) severe lung disease; (v) severe cardiovascular disease; (vi) immune deficiency; (vii) cancer. Contraindications included (i) estimated glomerular filtration rate (eGFR) <30 ml/min/1.73 m2 (only for nirmatrelvir/ritonavir and remdesivir); (ii) pregnancy; (iii) advanced chronic liver disease. In addition, males had to accept the use of condoms for at least three months if their partner was fertile, while fertile females had to accept the use of condoms for at least four days from the end of treatment.

Regarding treatment choice, when more than one was eligible, the choice was at the discretion of the attending physician. The choice was driven by drug–drug interactions (DDI), severe renal impairment, the necessity of hospital admission, the ability to swallow, and patient frailty.

2.2. Outcomes

The effectiveness and safety of antiviral treatments and monoclonal antibodies to decrease the risk of disease progression (i.e., administration of oxygen, non-invasive ventilation, and death) were evaluated.

Furthermore, predictors of disease progression were investigated.

2.3. Statistical Analysis

Quantitative variables were summarised with medians and 25th−75th percentiles (interquartile range), whereas qualitative ones with absolute and relative (percentages) frequencies. The Shapiro–Wilk test was used to assess the normality of quantitative data. The Mann–Whitney test evaluated subgroup differences for quantitative variables. Pearson’s χ2 or Fisher’s exact tests were used to assess differences for qualitative variables. Logistic regression analysis was performed to identify factors associated with disease progression. A two-tailed p-value less than 0.05 was considered statistically significant. All statistical analyses were performed with STATA version 17 (StatsCorp, TX, USA).

3. ResultsBetween January 1 and July 31, 1581 people were evaluated. Of these, 220 (13.9%) were not enrolled because of missing data. Of the remainder, 216/1361 (15.9%) had moderate/severe acute respiratory distress syndrome (ARDS) with a PaO2/FiO2 Figure 1).Overall, 1145 people were enrolled in the study. The median (IQR) age was 74 (62–83) years, with 417 (36.4%) people > 80 years; 336 (29.3%) developed severe disease needing oxygen supplementation (Table 1).

A total of 389 (34.0%) patients received antiviral therapies; specifically, 242 (21.1%) received molnupiravir, 39 (3.4%) nirmatrelvir/ritonavir, and 108 (9.4%) remdesivir.

People treated with nirmatrelvir/ritonavir were younger and showed a lower comorbidity burden (Table 2). More than half of people treated with remdesivir acquired SARS-CoV-2 infection during hospitalisation. The percentage of disease progression in people treated with remdesivir was twofold higher, without significant differences.At the logistic regression analysis, an age of >50 years was associated with a higher risk of disease progression, especially for people aged 70–79 (Table 3). Dementia, haematologic cancer, and heart failure were associated with a higher risk of disease progression; the same risk existed in cases of fever or dyspnoea, ground-glass opacities or consolidation at the CT scan, and bacterial coinfections.

By comparison, receiving at least two doses of vaccine and receiving treatment with antiviral or monoclonal antibodies were associated with a lower risk of progression.

4. Discussion

Our retrospective study showed that antivirals and monoclonal antibodies were associated with a significantly lower risk of disease progression in COVID-19 patients.

Three clinical trials (MOVe-OUT, EPIC-HR, and PINETREE) demonstrated the efficacy of antivirals [21,23,26]. However, the enrolled population was different when compared with those attending inpatient and outpatient settings: median ages were 42 (MOVeOUT), 45 (EPIC-HR), and 50 (PINETREE) years, whereas in our study it was 74 years. As well, the main comorbidity was obesity, with a low prevalence of other comorbidities. On the other hand, in the PINETREE trial, they enrolled patients with a higher comorbidity burden: patients with diabetes totalled 61.4% (MOVe-OUT), and those with COPD totalled 24% in the PINETREE trial [21,23,26].

To the best of our knowledge, this is the first study to describe the efficacy of the three available antiviral drugs in a real-life scenario.

Ronza Najjar-Debbiny et al. enrolled 4,737 treated with nirmatrelvir/ritonavir. They observed that people treated with nirmatrelvir/ritonavir and those with adequate (two or more doses) SARS-CoV-2 vaccination had a lower risk of disease progression [27]. Another study by the same research group evaluated the efficacy of monlupiravir. They observed that people treated with molnupiravir had no differences in composite outcomes (severe disease or death) HR 0.83 (95%CI 0.57–1.21). However, subgroup analyses showed that monlupiravir was associated with a significant decrease in the risk of composite outcomes in older patients, females, and people with inadequate COVID-19 vaccination [28].Another Israeli study by Ronen Arbel et al. showed that Nirmatrelvir/r reduced the risk of hospitalisation due to COVID-19 only in people older than 64 (HR 0.27 [CI95%] 0.15–0.49), while being male and not having had adequate vaccination was related to a higher risk of hospitalization [22].Wong et al. published their data about nirmatrelvir/r and monlupiravir use in hospitalised patients in Hong Kong. Both monlupiravir and nirmatrelvir/r showed a beneficial impact on disease progression (HR 0.60 [95%CI 0.52–0.69] and HR 0.57 [95%CI 0.45–0.72], respectively) [25]. The same authors published another study on non-hospitalised people treated with monlupiravir or nirmatrelvir/r. Both treatments reduced mortality risk (monlupiravir HR 0.76 [95%CI 0.61–0.95] and nirmatrelvir/r HR 0.34 [0.22–0.52]) and in-hospital disease progression. By contrast, only nirmatrelvir/r was linked to reduced hospitalisation. However, a significant limitation of this study was the absence of comorbidities. In addition, the percentage of vaccinated people in the nirmatrelvir/r group was double that in the monlupiravir group [29].Other studies with small sample sizes have been conducted. Gentile et al. enrolled 257 people, of which 146 were treated with monlupiravir and 111 with nirmatrelvir/r. People treated with monlupiravir were older than people treated with nirmatrelvir/r (median age(IQR) 70 (59–79) vs. 60 (40–67), p 30].Finally, Piccicacco et al. published a paper on using early remdesivir in a real-life setting, comparing it with people treated with sotrovimab and those who had not received any treatments [31]. People treated with remdesivir or sotrovimab had a lower risk of hospitalisation and emergency department admission due to COVID-19 than those without treatments. No differences were noted between people treated with remdesivir and sotrovimab.

Our data are consistent with previous findings, confirming the benefits of early antiviral treatments on disease progression: monlupiravir had an OR of 0.11, followed by nirmatrelvir/r with 0.22 and remdesivir with 0.26. In addition, vaccination was associated with a lower risk of disease progression (OR 0.27).

It is crucial to highlight that, in all studies involving treatment with monlupiravir, patients receiving this antiviral had a higher mean age and showed a higher comorbidities burden.

Our study has some limitations. Its monocentric and retrospective nature could affect its generalizability. However, we believe it could be generalised to all countries where antiviral and monoclonal antibodies are available. Furthermore, the number of patients treated with nirmatrelvir/r is poor because of a high comorbidity burden and DDI.

However, the total sample size was large, and the data collection was complete. In addition, we reported data about the efficacy of the remdesivir three-day course, on which few data are available in the published literature.

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