Greater knowledge of the disease and therapeutic evidence obtained in record time have allowed us to have, one year after the emergence of SARS-CoV-2, a more or less defined pharmacological guideline. However, there is still a long way to go.
By Carla Nieto
In the early stages of the pandemic, the approach to Covid-19 was based on teamwork, with each specialty contributing the options considered most optimal. More than a year later, and after considerable trial and error, protocols are now being developed based on the available evidence regarding the drugs that have proven most effective against SARS-CoV-2 and its complications. However, the reality is that optimal disease management is still a long way off, although fortunately several lines of research are underway with promising results.
With the aim of sharing what is being achieved with these drugs, analyzing the alternatives under development and defining the pharmacological challenges that, beyond vaccines, this disease poses, Diario Médico, in collaboration with GSK, organized the Research and Development of Treatments against Covid-19 observatory, a meeting that included the participation of Eva Prats, pulmonologist from the Intermediate Respiratory Care Unit (UCRI) of the Enfermera Isabel Zendal Emergency Hospital, in Madrid; Bernardino Alcázar, pulmonologist from the High Resolution Hospital of Loja, in Granada; Alejandro Martín Quirós, from the Emergency Department of the La Paz Hospital, in Madrid, and José Ramón Paño, member of the board of directors of the Spanish Society of Infectious Diseases and Clinical Microbiology (Seimc).
“There are probably few diseases with so much evidence in such a short time, and in the case of SARS-CoV-2, the evidence has come more from what not to do than from treatments that have yielded positive results. For example, we quickly learned that chloroquine, azithromycin, and lopinavir, among others, did not have truly relevant clinical effects ,” commented Alcázar, who also pointed out that the evolution of treatments over these months has defined the currently available guidelines: corticosteroids, especially in hospitalized patients; tocilizumab, in some cases; and remdesivir, with some uncertainty, applied in the initial stages and with strict criteria. “Anything other than these drugs falls within the realm of uncertainty.”
Along the same lines, Prats recalled how the use of hydroxychloroquine, one of the most widely used drugs in the early stages of the pandemic, has been abandoned, "while, on the other hand, we now have a clear understanding of the role that dexamethasone plays and we are also beginning to position tocilizumab in some more specific cases, although still with many doubts."
Lessons learned
For Paño, one of the biggest lessons has been realizing that collaborative research, when time, effort, and money are invested, can help answer questions that were initially resolved intuitively at the beginning of the pandemic. “Initially, we were all guided by what our specialty could logically contribute, and until clinical trials were conducted, we had no evidence about the best course of action.”
Another lesson is the realization that COVID-19 affects different types of patients, and that treatment varies depending on the patient's condition, the stage of the illness, and the impact the virus has on them. “It's a dynamic process, which makes it necessary to adapt and individualize treatment. For example, we've learned that antiviral therapy is probably no longer indicated when the patient is inflamed, and the same goes for corticosteroids administered during an earlier phase. We've also learned that there are other treatments we might never have considered before, such as lymphocytes or hyperimmune plasma, which could open a new door not only for COVID-19 but also for the future of other infectious diseases,” commented Martín Quirós.
Prats emphasized the importance of Intermediate Care Units: “We have found that both high-flow therapy and CPAP significantly reduce the need for ICU admission and, therefore, improve the prognosis. The role of physiotherapy has also become clear, proving to be a fundamental tool.”
Options with evidence
In this race for evidence, one of the drugs that has yielded the best results is corticosteroids, “especially dexamethasone, an option that is well positioned, since we know who not to give it to (patients who are not excessively ill, who do not need oxygen, outpatients, etc.), while in those with significant pulmonary dysfunction or who at least need oxygen therapy, it reduces the possibility of them going to intensive care and also mortality,” said Alcázar, to which Prats added that the standardization of the use of dexamethasone is one of the examples of this multidisciplinary teamwork that has become the norm since the beginning of the pandemic.
Regarding tocilizumab, although some doubts remain due to conflicting results from different studies, the patient profile for whom it is most indicated is quite clear, as Paño explained: “In patients requiring high-flow oxygen therapy and mechanical ventilation, with significant clinical deterioration, it has been shown to significantly reduce mortality and also decrease the number of days the patient needs respiratory support. Therefore, it is currently considered a standard treatment, provided there are no contraindications. The other type of patient in whom positive results are observed is the one who does not respond adequately to standard treatment and who, although they do not reach the high-flow stage, does not progress well and remains inflamed.”
There is also no absolute certainty regarding remdesivir, “the only antiviral that has shown some clinical effect, although the effects would be very modest. There is evidence that it reduces the length of hospital stay, but apparently it has no impact on mortality, and we have doubts about in which cases it should be used and whether the criteria established by the Ministry for its use are the most appropriate, this being an aspect in which we need more research,” Alcázar pointed out.
Define recipients
In addition to defining a standard treatment, the research effort to find new drugs is allowing for a more precise understanding of which type of patient or stage of the disease benefits most from the different options. In the case of monoclonal antibodies, which are not yet used routinely, Alcázar points out that they are currently at an impasse, given that there is data suggesting a reduction of up to 85 percent in the risk of hospitalization and mortality, but these data come from clinical trials that must be validated through scientific publication.
“Based on what we know, monoclonal antibodies, when used properly, would have their role, but within the framework of situations for which they have been approved by the FDA: patients with very mild disease and without hypoxemia; patients with moderate disease or with mild hypoxemia who have immunosuppression; and those over 55 years of age with COPD, chronic kidney disease, diabetes or obesity,” Prats noted.
Given that guidelines for these drugs recommend administering them within the first ten days of infection, and preferably within the first three, this option presents the challenge of rapid patient identification. “The key target we need to reach with these drugs is early-stage treatment, but defining the timing of administration is difficult, since the patient's decision to go to the hospital doesn't always correspond to the stage of the disease ,” explained Martín Quirós. “Now that the tsunami has passed and we have data from three waves of the pandemic in Spain, it's probably time to sit down and evaluate these profiles, regardless of age groups. We already have several different types of scores (biochemical, immunological) that allow us to identify these target patients early on,” he added.
For Paño, in addition to this early identification, the confirmation of the benefits suggested by clinical trials would imply the need to have an adequate infrastructure for their administration, "since the implementation of these therapies is very complex and, in fact, this is one of the reasons why in the US, where these drugs are available, their use is lower than expected."
Another point to consider is that monoclonal antibodies , as currently administered, require intravenous infusion, which limits their use. “It is reasonable to assume that, if their efficacy is confirmed, an intermediate step would be to evaluate their intramuscular administration, to see if this option can provide prophylaxis in a context where the entire population is not vaccinated. Once the vaccine is widely available, the role of these drugs could be reduced to specific groups with inborn errors in their immune system,” Alcázar explained.
Hyperimmune plasma
Regarding the role of antivirals, experts agreed that, with the exception of remdesivir, both research and evidence are slow and, moreover, the available results are inconclusive, but they seem to suggest that, outside of the first few days of infection, their impact is small; hence, they are not emerging as a short-to-medium-term solution.
Regarding hyperimmune plasma from donors, initial expectations have also been dampened, as there are many doubts about when to use it and the patient profile is still not clearly defined, although everything points to its greatest benefit being obtained in the initial phase of the disease, and especially in immunocompromised individuals. “Its principle is the same as that of monoclonal antibodies, but compared to them, it has the advantage of being inexhaustible, as well as inexpensive. The disadvantage is that not everyone generates the same amount of antibodies, and this variability is one of the problems that studies have encountered regarding its efficacy,” Paño commented.
In line with this, one of the ongoing research projects focuses on T lymphocytes from convalescent patients. “The approach is the same as with plasma, but using T lymphocytes from these patients, with the advantage that a large population can be treated with a small number of donations,” explained Martín Quirós.
Outpatient treatment
In addition to establishing the therapeutic approach and incorporating new drugs as evidence confirms it, the immediate challenge is the outpatient treatment of mild cases. “At this stage, especially in the developed world, the priority is no longer so much the severely ill patient, for whom we are beginning to have evidence on the best course of action, but we are completely lacking in outpatient treatment,” said Martín Quirós, an opinion shared by Alcázar, for whom the current unmet pharmacological needs lie in the treatment of patients diagnosed with active infection who are recovering at home: “ Solutions are needed that allow us to inhibit viral replication and treat the infection on an outpatient basis , avoiding hospital admission.”
And, undoubtedly, the future landscape of COVID-19 pharmacological treatment will be shaped by the emergence of new viral variants, which means considering the effectiveness of these pharmacological options against them. According to experts, little is known at present regarding the potential impact, and we must continue to monitor how the mutations progress, “but in the case of monoclonal antibodies, even if they are not effective against a particular variant, they have the advantage that others can be created, knowing that it is a safe option, something that does not occur, for example, with antivirals,” commented Bernardino Alcázar.