Coronavirus disease (COVID-19) is an infectious disease caused by the SARS-CoV-2 virus. It sparked a global pandemic that started in March 2020, and lasted for three years. According to the latest data from the World Health Organization (WHO), as of October 18, 2023, there have been 771,407,825 confirmed cases of COVID-19, resulting in 6,972,152 reported deaths worldwide. [1]. The clinical manifestations of COVID-19 vary from a completely asymptomatic course, through mild cold-like symptoms, to severe hypoxia, respiratory and multi-organ failure, and even death [2]. After the alpha, beta, gamma, and delta variants of the SARS-CoV-2 virus, the latest subvariant EG.5, known today as omicron and its subvariants, became a new worldwide —and soon dominating—threat affecting not only older individuals with underlying health conditions, but also the general population [3].
The SARS-CoV-2 virus comprises four distinct structural proteins: spike glycoproteins (S), small envelope glycoproteins (E), membrane glycoproteins (M), and nucleocapsid (N), in addition to several accessory proteins [4]. Among these, the S-protein plays a pivotal role by facilitating the attachment of the viral particle to the angiotensin-converting enzyme 2 (ACE2) receptor on host cells, enabling viral entry. Its significance as a potential target for vaccine development became evident early on, making it a prime candidate for preventing infection. Today, vaccines developed in this manner, are widely recognized within the scientific community as the foremost and most effective tool in the battle against the COVID-19 pandemic [5].
Apart from vaccines, a multitude of new drugs aimed at combatting COVID-19 have been explored or authorized since the onset of the pandemic. Unfortunately, several of these investigations, including those of antimalarials, antiparasitics, azalides, and the like, did not yield the desired results. However, some substances have demonstrated significant efficacy. Among them are remdesivir, favipiravir, molnupiravir, monoclonal antibodies like bamlanivimab, and, most recently, the combination of nirmatrelvir with ritonavir found in the pharmaceutical product Paxlovid®.
In October 2020, the FDA granted approval for the first COVID-19 treatment, the antiviral drug Veklury (remdesivir), for usage in adult and pediatric patients aged 12 and older who required hospitalization due to COVID-19. The administration of Veklury (remdesivir) was restricted to hospital settings or healthcare facilities capable of delivering acute comparable to inpatient hospital care [6]. In January 2022, this treatment was expanded to include its use for outpatients with mild-to-moderate COVID-19 [7].
The administration of molnupiravir, an inhibitor of RNA-dependent RNA polymerase, led to a notable decrease in hospitalization and mortality when compared to a placebo in a phase III trial involving non-hospitalized adults with mild to moderate infections who had at least one risk factor. However, this positive outcome is tempered by the concerning potential for molnupiravir to induce mutations in human DNA and expedite the development of new viral variants [8]. Regrettably, the efficacy of monoclonal antibodies wanes in the face of emerging viral variants. Within the spectrum of pharmacotherapeutic options for managing COVID-19, the nirmatrelvir + ritonavir combination (marketed as Paxlovid® in the Czech Republic), particularly due to its oral administration method, holds significant promise, especially in the current context of the ongoing pandemic.
Nirmatrelvir (PF-07321332) is an antiviral drug designed for oral administration, primarily targeting the 3-chymotrypsin-like cysteine protease (Mpro) enzyme of the SARS-CoV-2 virus [8]. Mpro is an appealing antiviral target due to its main role in the viral replication cycle, particularly in processing viral polyproteins into functional units. Furthermore, its high specificity ensures a minimal risk of off-target effects within human cells [9]. Nirmatrelvir has exhibited potent inhibition of Mpro activity and viral replication across a wide spectrum of coronaviruses in vitro. In a mouse model, oral administration of the drug resulted in significantly reduced SARS-CoV-2 titers in the lungs compared to the placebo [8].
Nirmatrelvir’s primary metabolic pathway is through the cytochrome P450 3A4 enzyme [8]. In contrast, ritonavir is primarily recognized as a protease inhibitor targeting this particular isoform. Ritonarvir was originally approved for HIV treatment. While it possesses limited intrinsic antiviral activity, its principal function is to enhance the efficacy of other protease inhibitors. Beyond its initial use against HIV protease, studies have revealed its capacity to inhibit cytochrome P450-3A4. Presently, ritonavir is under investigation for potential applications in cancer treatment due to its mechanism of action. It is also employed in combination with other medications for the treatment of Hepatitis C infection [10].
Consequently, co-administering Nirmatrelvir with a low dose (100 mg) of ritonavir increases the systemic exposure of Nirmatrelvir, thereby supporting its therapeutic effect. The first study in healthy volunteers confirmed the favorable safety profile of this combination, even at the highest dose and exposure evaluated (500 mg nirmatrelvir plus 100 mg ritonavir, twice daily for 10 days).
Based on these findings, a double-blind phase II/III EPIC-HR clinical trial was conducted in 2021, with the objective of evaluating the therapeutic impact of this specific combination in symptomatically ill, unvaccinated adults who were not hospitalized but were at a high risk of progressing to a severe form of COVID-19 [10].
The patients were randomly divided in a 1:1 ratio to receive either 300 mg of nirmatrelvir plus 100 mg of ritonavir or a placebo every 12 hours for 5 days. The primary assessment involved the need for hospitalization related to COVID-19 or death from any cause within 28 days [10].
A total of 2,246 patients were enrolled in the randomization process, with 1,120 patients receiving nirmatrelvir plus ritonavir, and 1,126 receiving the placebo. In a planned interim analysis of patients treated within 3 days of the onset of symptoms, the incidence of COVID-19-related hospitalization or death by day 28 was significantly lower in the nirmatrelvir group compared to the placebo group, with a 6.32% difference (95% CI: -9.04 to -3.59; p < 0.001). In the actively treated group of patients, no deaths were recorded, while 27 out of 385 patients (7.01%) died in the placebo group. A similar difference in efficacy was also observed in the final analysis of the study. This corresponded with the total viral load, which was lower in patients in the nirmatrelvir with ritonavir group compared to patients in the placebo group on the fifth day of treatment [10].
Nevertheless, the incidence of adverse events during the treatment period was comparable in both groups, encompassing any adverse event (22.6% with nirmatrelvir plus ritonavir vs. 23.9% with the placebo), serious adverse events (1.6% vs. 6.6%), and adverse events necessitating the discontinuation of the drug or placebo (2.1% vs. 4.2%). Certain side effects, such as dysgeusia (5.6% vs. 0.3%) and diarrhea (3.1% vs. 1.6%), occurred more frequently in the nirmatrelvir with ritonavir group [10].
The provided data vividly demonstrate that the treatment with nirmatrelvir in combination with ritonavir in the early stages of COVID-19 can fundamentally suppress the progression to severe illness and, at the same time, rapidly reduce the viral load of SARS-CoV-2. Nevertheless, there is a significant apprehension in clinical settings regarding its safety due to the potential for drug interactions, chiefly stemming from ritonavir's inhibitory impact on cytochrome P450.
Based on the results of the clinical studies conducted, and a comprehensive evaluation of the therapeutic effectiveness of different antiviral medications, the Czech Ministry of Health issued an Interdisciplinary Opinion in July 2022 concerning the utilization of antivirals for the treatment and prevention of COVID-19 progression. The opinion highlights a decrease in the relative risk of hospitalization: 30% with molnupiravir, 87% with remdesivir, and 89% with nirmatrelvir [11].
The aim of our study is to analyze data regarding the utilization and prescription of commonly administered medicinal products in specific medical fields. Our objective is to delineate the prevalent concurrent therapies among patients diagnosed with COVID-19 and the possible interaction with the treatment with Paxlovid.