Assessing Antiviral Therapies for COVID-19

Introduction

The outbreak of the novel Covid-19 in December 2019 has a global health emergency just four months since its outbreak in the Chinese city of Wuhan. As a result of many phylogenetic studies on the virus around the world, it has come out that the virus has a significant resemblance to the severe acute respiratory coronavirus 1 syndrome commonly referred to as SARS-CoV-1 hence resulting to its naming as SARS-CoV-2 Syndrome(1). For students studying biomedical science, navigating through challenges like viral outbreaks and their implications, especially when it comes to research and dissertation writing. If you require expert guidance and support, consider biomedical science dissertation help to ensure your research is comprehensive and well-structured.

The study conducted by Cao et al (2) at the very early stages of the infection around the world and even in China, had the intention to dissect the various mechanisms capable of ensuring that infected patients were well managed as there is no specific therapeutic and pharmaceutic drug or treatment to defeat the virus (3). Cao et al were canvassing whether anti-viral drugs, specifically those used in the management of patients with HIV 1, would help to curtail the rapid pathophysiology of the disease in a patient and reduce the fatality rate of the virus as it has been suggested in other studies (4).

Although the trial was done in understandably stringent circumstances considering the global stigma due to the virus, the outcome which tends to favour the use of lopinavir-enhanced ritonavir (LPV-RTV) has serious deficiencies and gives room for critic of the accuracy of the randomized controlled trial conducted in Wuhan. This paper offers to critic the outcomes of the trial as well as offer better mechanisms to test these anti-viral drugs for their efficacy to combat this global pandemic. It first looks at the mechanism of LPV-RTV in combating viral infection. Then it digests the methodology of the trials and concludes with the critique of the outcomes of the trial. This paper will then suggest advanced RCT designs which may be relied in furtherance of LPV-RTV trials on the novel Covid-19.

The Mechanism of lopinavir-ritonavir

Initially ritonavir used to be administered without lopinavir but the effectiveness of either being used separately was greatly reduced although the effectiveness of lopinavir on the HIV 1 virus was more than double the effect of RTV (5). When the combination of lopinavir with smaller dose of RTV was used, their effectiveness in combating HIV 1 virus improved (6).

The HIV 1 protease enzyme ensures that the virus completes its essential lifecycle and replicate within the body by attaching to the peptide bonds of the viral cell (7). Thus the lopinavir-ritonavir drug upon assimilation into the body it inhibits the protease enzyme thus reducing or curtailing the replication of the virus-infected cells within the body. Thus Ciao et al believed that the mechanism of the lopinavir-ritonavir drug would have a similar effect on the novel Covid-19 virus thus reducing the instances of severity on patients.

However, the oral administration of lopinavir-ritonavir is associated with development of severe gastrointestinal complications such as vomiting on patients. It is also associated with caused abnormalities in the body’s metabolism and causing irregular fat deposition thus having an adverse effect on patients with hypercholesterolemia (8, 9).

Clarity of the Clinical Question

Whereas the novel Covid-19 virus’ features were yet to be fully understood at the time of starting the trials, the aim or the hypothetical conclusion desired was vague as it failed to take into consideration the dynamic effect of lopinavir-ritonavir drugs on human beings. The trial ought to have had a targeted patient population depending on the already known side effects of lopinavir-ritonavir (9). Whereas there was an outright elimination of pregnant patients, this still left a large portion of classified persons who are at risk of adverse effects of lopinavir-ritonavir. For example, as the metabolism of lopinavir-ritonavir is usually through the liver, patients with hepatic disorder are generally at greater risk of suffering adverse side effects of the drug (10, 11).

Moreover, the intended goal to assess the impact of lopinavir-ritonavir on novel-Covid-19 patients over the standard care treatment offered was not specific as to tell the specifically desired impact of lopinavir-ritonavir on the virus as compared to standard treatment. Although the outcomes are obviously expected for any trial on Covid-19, which is basically to reduce severity and fatality rate, there was no deliberate attempt to select a classified study population or have a specific outcome in the response of the patient to the trial. This is contrary to scholarly suggestions that patient and assay blinding ought to consider only the suitable candidates for the trial (12). The suitability of patients for this kind of a trial would also inform the concentration levels of lopinavir-ritonavir necessary for novel Covid-19 patients. Even for Lopez-Cortes et al (13) who conducted a trial of lopinavir-ritonavir drug on HIV-infected patients, the viral load levels very much informed the ineligibility of patients with HIV-RNA viral load of > 50 copies/ml for the trial.

Furthermore, the study does not show that the randomly selected population were suffering from severe novel Covid-19 as the operational categories put in place ranged from mild cases to severe and even death. Thus, it becomes difficult to assess the impact of the lopinavir-ritonavir drug on persons showcasing mild symptoms of the disease and those who have developed acute symptoms of the disease.

That three patients intended for the lopinavir-ritonavir group ended up in standard treatment group, leaves this trial inaccurate and unpredictable.

Relevance of the Study design to the question

The investigators deployed randomized controlled trial mechanism to conduct the study which ideally is the most recommended for any clinical trial (14, 15). However, it is perhaps not the most effective means of studying lopinavir-ritonavir effect on the novel Covid-19 patients. Indeed, Baden et al (16) called into question the viability of running a randomized clinical trial during an outbreak of a disease informed by the Ebola outbreak in West Africa. Firstly, the diagnostic methodology deployed initially in China was the use of RT-PCR assays which have already been heavily criticised for giving many false negatives (17, 18). Therefore for patients who may have not shown severe symptoms of the virus and were later ruled out negative in the early days of the trials may heavily have affected the accuracy of the outcome given.

Secondly, the spread of the novel Covid-19 virus is at a very high pace without proper preventative measures that using randomized controlled trials would result to inaccurate data on lopinavir-ritonavir. This is particularly important as the trial was done before the curve began to rise rapidly and in the very early stages of the virus’ epidemiology (19). According to data sourced from various news outlets and government daily briefings, the total number of infected persons by 31st January 2020 was 9826 (20). Interestingly, the age distribution at that time reflects high infection rate with older people with a median age of 45 years. As the current infection rate show that younger people are increasingly becoming infected, this would have helped in streamlining the accuracy of the information so as to include the effect of lopinavir-ritonavir on younger adults and children who are also likely to suffer from severe symptoms of the novel Covid-19 virus.

Moreover, having a control group for lopinavir-ritonavir, during the outbreak, and another for the standard treatment management is unethical as it endangers the lives of patients in the former group. For this reason it was only prudent for the attending physicians to administer other medications to the patients involved in the trial. As the virus was still not yet properly studied, limiting patients from accessing alternative treatment would have endangered their lives even if this was done for a shorter period of time than anticipated. Hence this further downplays the accuracy of the results to be recorded after the trial period. Indeed as Baden and Rubin (21) connoted in their critique of this same trial, the effect of the drug would never be registered in such circumstances where the heterogeneous groups received other medication such as glucocorticoids systematically for approximately 34% of all patients involved in the trial across board.

Thus it suffices that considering the dynamic changes in relation to the infection rate; a randomized controlled trial was not the most appropriate study design for such a clinical trial unless it was modified and spread out over a long period of time.

Study Methodology

The methodology at the time of randomization was largely done in accordance with the original protocol intended to be used. The investigators recorded that 5 patients assigned to the lopinavir-ritonavir randomized group either ended up dead before administration of lopinavir-ritonavir or were moved to the control group. Moreover, the investigators cited lack of control over the involved physicians thus resulting to physicians refusing administration of the lopinavir-ritonavir for a recorded number of two patients. Whereas there were patients enrolled to the trial on the first day, more than 30 patients were admitted in due course of time as the investigators cited lack of support to their work by the authorities at the time. Furthermore, the investigators had to cut short the trial period after the patients were involved in another antiviral drug called remdesivir. Although the lack of care-giver or physician blinding is associated with minimal impact on the outcome of clinical trials, the same is difficult to assess on a trial to trial basis especially in epidemiology due to multilevel blinding involved in any trial (22)

However, the attrition rate was at a meagre 6% which resonates well with the outcome of the trial.

Indeed the researchers acknowledged the lack of placebo before the randomization to carefully select perfect patients for the lopinavir-ritonavir administration. The use of placebos or general run-in periods in randomized controlled trials enables the investigator to carefully eliminate non-cooperative or unsuitable patients from the trial (23, 24) yet this could simply not happen due to the urgency of the medical treatment of the patients.

The importance of run-in periods to a randomized controlled trial is that it increases chances of similarity to normal clinical practice especially for cases where it seeks to introduce new therapeutic measures (25). Thus in this case an advanced used of run-in period would enable clinicians who would later confront this virus around the world to properly identify characteristic patients eligible for lopinavir-ritonavir therapy. Moreover, the use of poorly defined, broad eligibility denied the authors of the study opportunity to exclude patients without the desired characteristic. This is a common problem of severe infections trials (26).

Whereas the methodology during randomization was satisfactory, the run-in period was extremely deficient even though there was a low dropout rate during the trial as the attrition rate stood at 6% although it was poorly reported considering the little control the investigators had over the involved physicians.

The investigators during the trial had established a seven-stage parameter to determine whether there was clinical improvement or deterioration in a patient. The initial stage concerned those who were not hospitalized and continued with their daily routine. The second stage concerned those who were not hospitalized but were not performing their daily chores. Third stage entailed those hospitalized but without oxygen support. Fourth stage concerned those requiring supplementary oxygen. Those requiring high flow of oxygen or mechanical ventilation were categorised in the fifth stage of severity. On stage six, concerned patients facing acute respiratory distress hence put on invasive ventilation and the last stage was death.

This parameter sufficiently met the expected criteria of novel Covid-19 impact on patients in terms of severity. However, the investigators ought to have registered the ratio of patients in each stage at the time of randomization so as to generate a more accurate and specific outcome which would guide clinicians on the effect of lopinavir-ritonavir drugs to novel Covid-19 patients.

Validity of the Outcomes

Despite all the shortcomings of the study, the trial came out with a distorted positive result for the application of lopinavir-ritonavir as furtherance to the standard treatment management narrowly outdoing the use of standard treatment.

The result showed that a clinical improvement in terms of the seven-stage parameter was recorded at an average of 15 days for lopinavir-ritonavir group and 16 days for those in standard treatment. Mortality rate was 19.2% in lopinavir-ritonavir group and 25% in standard treatment group. Patients on lopinavir-ritonavir recorded 6 day stay in Intensive Care Unit compared to 11 days for those on standard treatment only. Generally lopinavir-ritonavir patients recorded edged response to the therapy compared to those on standard treatment alone.

Considering the overlying circumstances during the trial period, it cannot be said with certainty, a fact that the authors of the trial admit to, that the lopinavir-ritonavir therapy would in any way significantly reduce the severity. The lack of proper classification of the study population of patients and accurate breakdown of response to the lopinavir-ritonavir for difference classes of patients further contribute to the unreliability of this trial. The pathophysiology of the SARS-CoV 2 makes it theoretically susceptible to lopinavir-ritonavir therapy hence the trial still maintains relevance even though scientists involved in HIV 1 believe that the HIV protease inhibitors are unlikely to be active in SARS-CoV 2 because of its protease structural difference (27).

Already there are countries such as the United Kingdom that are furthering this trial in a more accurate and selective manner (28).

Conclusion

Whereas the use of lopinavir-ritonavir drugs may appear theoretically effective in fighting Covid-19, this trial is by no means a benchmark to administer these protease inhibitors. The study design and methodology were too general to make any accurate and targeted conclusions that would be used in clinical management of the novel Covid-19 disease. Further trials such as those initiated by the United Kingdom are necessary so as to ensure accuracy of any trial and its outcome. Furthermore, as the ailment period of patients is short and drastically changing, perhaps randomized controlled trial method should be done in large scale, modified or changed to other methods that allow flexibility in clinical management. As Baden and Rubin suggested, further studies should focus on having an elaborate methodology and mechanism of testing that is at per with the rate of infection of such epidemics as the novel Covid-19 disease.

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