Several drugs have been analyzed to determine their efficacy against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) since the first few cases of SARS-CoV-2 pneumonia were diagnosed in December 2019 in Wuhan1. The results of such analyses have been rather disheartening as most of the drugs tested did not prove effective2-4. The only drugs that have so far been shown to reduce mortality in patients with severe SARS-CoV-2 pneumonia are dexamethasone5 and, more recently, tocilizumab6.

Remdesivir is a prodrug of an adenosine nucleotide that is metabolized within the host cells into its active adenosine triphosphate analog form, which inhibits the virus’ RNA polymerase. Remdesivir has demonstrated in vitro antiviral activity against SARS-CoV-27. It has also achieved a shorter time-to-recovery (TTR) vs. placebo8, with one study even reporting a reduction in 14-day mortality, which was not maintained at 28 days8-10.

Since the end of June 2020, Spanish hospitals have been able to use remdesivir as a compassionate treatment through the Spanish Drug Agency (AEMPS)'s expanded access program. Treatments under the program require AEMPS’ authorization which is granted on the basis of a series of clinical criteria that have evolved with time11.

The purpose of this study is to describe the efficacy and safety of remdesivir in patients with severe SARS-CoV-2 pneumonia hospitalized in the Moisès Broggi Hospital.

During the study period, 111 patients were administered remdesivir in our hospital. None of the applications filed by our hospital under the expanded access program was rejected by the AEMPS.

The subjects’ baseline characteristics are shown in table 1. Median age was 56.8 years [43.6-67.8] and 81 (73%) subjects were male. Mean score on the age-adjusted Charlson index was 1 [0-4]. A total of 51 patients (45.9%) presented obesity (BMI > 30 kg/m2). The most common comorbidities were hypertension [27 patients (24.3%)] and diabetes [25 patients (22.5%)]. At the time of initiation of remdesivir, 97 patients (874%) required low-flow oxygen therapy (score 5 on the ordinal scale), 8 patients (7.2%) required HFO or VMNI (score 6), 5 patients (4.5%) required IMV (score 7) and only one patient (0.9%) did not need oxygen therapy (score 4). As regards concomitant treatments, 88 patients (79.3%) received dexamethasone and 15 (13.5%) tocilizumab.

The data on treatment and its efficacy are presented in table 2. Median length of treatment was 5 days [5-5]. Remdesivir had to be discontinued in 10 patients for the following reasons: clinical deterioration (8 cases), hepatic toxicity (2 cases) and death of the patient (1 case). Mean time from symptoms's onset to initiation of remdesivir was 6 days [4-8], with 76 patients (68.5%) started on remdesivir within the first 7 days from symptoms's onset. Figure 1 shows the distribution of patients according to the time of initiation of remdesivir. Once treatment was initiated, 29 patients (26.1%) required admission to the ICU and 20 patients (18%) required initiation of IMV. Median TTR among patients who received the treatment was 9 days [6-14] and 7 patients (6.3%) had died at 28 days’ follow-up.

Figure 1.

Distribution of patients according to time from onset of symptoms to initiation of treatment with remdesivir.

(0,06MB).

The patients who died were significantly older (median of 69.8 years [52.1-85.3] vs. 54.9 years [42.9-66.2] of age, p = 0.024) and presented with more comorbidities (median Charlson index of 3 [1-6] vs. 1 [0-3]), although this difference did not reach statistical significance (p = 0.0667).

No significant differences in mortality were found when comparing patients who received dexamethasone with those who did not; 7 of the 88 (8%) who received dexamethasone died vs. 0 of the 23 (0%) who did not (p = 0.1623). Nor were any mortality-related statistically significant differences found between patients who received tocilizumab and those who did not: one of the 14 (6.7%) patients on tocilizumab died vs. 6 of the 96 patients (6.3%) who were not on the drug (p = 0.9508).

As regards adverse events, 51 patients (46%) presented with higher-than-normal AST and/or ALT concentrations. Elevations were mild in 37 cases (33%) (grade 1 on the CTCAE scale), moderate in 10 cases (9%) (grade 2 on the CTCAE scale) and severe in 4 cases (4%) (grade 3). No patients presented with a grade 4 alteration. The initial mean AST value was 52.8 U/l (SD 34.8) and the final mean value was 64.7 U/l (SD 58.9), with the difference between final and initial mean AST values not reaching statistical significance (11.9 U/L, 95% CI: -2 to 25.9, p = 0.0928). A statistically significant difference of 45.2 U/L (95% CI: 26.4 to 64.0. p < 0.0001) was however found between initial and final mean values for ALT (55.2 U/L, SD 56.7 vs. 100.4 U/L, SD 85.1). Changes in AST and/or ALT could not be determined in 13 patients (11%) because of the lack of follow-up data.

This study reports on the clinical results of remdesivir in patients with severe SARS-CoV-2 pneumonia in real-world clinical practice with respect to AEMPS’ access criteria.

TTR in our study was 9 days. This contrasts with the findings of Wang et al.9, who reported a TTR of 21 days, which was similar to that in patients on in the placebo group. This difference can be explained by several factors. For a start, mean time from onset of symptoms to initiation of treatment in Wang et al. was 11 days, whereas in our study it was nearly half (6 days). According to these authors, earlier administration of treatment could result in a more efficient inhibition of viral replication, as shown in some animal studies16. Secondly, Wang et al.'s definition of the TTR parameter was different. Finally, patients included in that study were older (65 years or older) and exhibited a higher incidence of hypertension (46%) than patients in this study. Age, hypertension, diabetes and obesity are, among others, negative prognostic factors for patients with SARS-CoV-2 pneumonia17-19.

Beigel et al.8 reported a TTR of 10 days with statistically significant differences with respect to subjects treated with placebo where TTR was 15 days. Those authors used the same TTR definition as in this study, which means that their data is comparable to the one obtained here. The subgroup analysis of this study resulted in a TTR for patients on low-flow oxygen therapy of 7 days. It is important to note that in our study almost 90% of the patients required low-flow oxygen therapy at the time on initiation of remdesivir. Although our results are similar to Beigel et al.‘s (median TTR was 9 days), it must be considered that the incidence of hypertension and diabetes in that study was considerably higher (50.7% and 30.6% respectively) that in our population. In contrast, the incidence of obesity was similar (45.4%) in both studies. These considerations, added to the fact that few of our patients received IMV as initial treatment, could indicate that our population had less severe initial SARS-CoV-2 pneumonia than Beigel et al.‘s8 and, for that reason, it would be expected to find a shorter TTR in our study.

Twenty-eight-day mortality was 6.3% in our population. This rate is lower than that reported for patients treated with remdesivir in Beigel et al.8 (11.4%), Wang et al.9 (14%) or the SOLIDARITY trial4 (11%), none of which were able to demonstrate a reduction in mortality with respect to the control group. Beigel et al.'s8 subgroup analysis found a 4% 28-day mortality in patients on initial low-flow oxygen therapy (score 5 on the CTCAE scale) who received remdesivir, with statistically significant differences with respect to placebo, which should be confirmed by randomized clinical trials20. This mortality rate is similar and rightfully comparable to the one found in this study (6.3%) as most of our patients exhibited the same profile at the initiation of treatment. Nonetheless, patients in our study were initiated on remdesivir earlier than those in Beigel et al.8, had a lower incidence of hypertension and diabetes, and mostly received dexamethasone. It is therefore difficult to claim that remdesivir had a beneficial effect on mortality in our study given that the variable could have been affected by all the factors mentioned.

As regards the potential effect of dexamethasone on the results of our cohort, although no statistically significant mortality differences were found between the patients treated with dexamethasone and those who were not, the numerical difference was certainly striking (8 vs. 0 deaths, respectively). This might be explained by the fact that our hospital's clinical protocol only recommended dexamethasone to be administered to patients with SpO2 ≤ 94% from the seventh day following the onset of symptoms. These are therefore more severely ill patients than those who do not receive dexamethasone. Regarding the potential effect of tocilizumab, only 14 patients (13%) in our cohort were treated with tocilizumab. Although no significant differences were found between patients who received tocilizumab and those who did not, it is not possible to draw any conclusions in this respect given the low number of patients treated with this drug.

García-Vidal et al.21 recently published real world results of the use of remdesivir in 123 COVID-19 patients in a third-level hospital in Spain. The authors found similar mortality results among patients treated with remdesivir as those reported in this study (4.1% vs. 6.3%, respectively), However, ICU admissions and the need of IMV were higher in our cohort (26.1% vs. 19.5% and 18% vs. 7.3%, respectively). Patients in that study exhibited similar baseline characteristics as those in presented here in terms of median age (58 years) and median time of initiation of remdesivir (7 days from symptoms’ onset). However, patients in the García-Vidal et al. presented more comorbidity than those in this study.

According to the SEMI-COVID-19 Register22 mortality among people between 50 and 69 years (which was the majority age group patients in this study belonged to) stood between 4.7% and 10.5% during the first wave of the pandemic. Although the proportion of patients receiving remdesivir in the register was low (0.5%), the mortality data reported is similar to that in this study. This is in correspondence with the evidence published to date, which indicates that remdesivir has not as yet been able to demonstrate an ability to reduce 28-day mortality in patients with SARS-CoV-2 pneumonia8-10,20.

As regard the treatment's toxicity, nearly half of the patients exhibited increased transaminase levels, although only 4% presented grade 3 toxicity. This is in line with the findings of Beigel et al8, where elevation of AST occurred in 3.4% of patients and that of ALT in 2.3%. As the authors state in the appendix to the study, these elevations resulted mainly from grade 3 or 4 adverse events. Although the ALT elevation observed in this cohort was statistically significant, it must be taken into consideration that in spite of the time relation existing between initiation of remdesivir and the appearance of hypertransaminasemia, SARS-CoV-2 infection can cause elevated transaminase levels due to liver inflammation.

No other adverse events were observed that could help establish the toxicity profile of remdesivir treatment. This could have been due to the retrospective nature of the study, which could have led to an underestimation of adverse events.

The main strength of this study is that it closely reflects real-world clinical practice in Spain. However, it does present a few limitations. Firstly, it is a retrospective observational study with no control group, which precludes the establishment of a direct cause-effect relationship between the intervention carried out and the results obtained. Secondly, the fact that the criteria for accessing remdesivir changed during the course of the study made it impossible to divide the patient sample into different subgroups and analyze the effect the treatment had on each of them. In spite of that, the majority of patients were receiving low-flow oxygen therapy which, according to some authors8, could be the group of patients deriving the greatest benefit from remdesivir. This hypothetical benefit should be demonstrated in future clinical trials that focus exclusively on those patients20.

In conclusion, treatment with remdesivir in our hospital yields similar results to those published for patients with low-flow oxygen therapy both in terms of TTR and 28-day mortality.

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No conflict of interests.