( 2749 Reads)|
There is an understandable keen interest in potential treatments because of the increased risk of death from COVID-19 compared to other infectious diseases. The public and news media are looking to scientists to find remedies, and any drug that shows promise gives rise to intense publicity. Finding and testing effective treatments is a complicated and time-consuming business. Many journalists and the public at large do not have the necessary training to judge the validity of studies published in the literature or the background to evaluate appropriate controls, randomization, and all the other subtle nuances that go into a well-designed drug trial. This inexperience can lead to misinterpretation and overhyping of preliminary results. It doesn't help that some physicians who run these trials do not design good experiments. The skillset for being a doctor, where you are trying to diagnose what is wrong and treat illness effectively, is very different than that of a scientist doing research. It's not that doctors can't be great scientists, many are. It's just that being a great doctor doesn't automatically mean you have an inclination for research.
The efficacy of potential drugs against the SARS-CoV-2 virus are often first tested against the virus in cell culture. It is possible to grow human cells in special liquids that will support their growth. Scientists then expose the cells to the virus and then observe the life cycle of infection in the presence and absence of test drugs. If a drug slows or stops the progress of SARS-CoV-2, it merits further study.
Testing of SARS-CoV-2 in animal models is often the next step. Scientists are rapidly evaluating several animal models to see if they can support the growth of SARS-CoV-2. Potential animals include mice, rats, hamsters, and monkeys. The news that cats can be infected and develop observable disease makes them another possible model. Because of the urgency of finding effective treatments, some drugs will move directly into human trials.
Just because a drug can stop a viral infection in the test tube does not mean that it will do the same thing in an animal model or a human. The drug may be toxic to humans at the level needed to affect the virus. Side effects from the drug may also be too severe to allow its use. Also, the drug may not be absorbed by human patients and will not make its way to sites of infection in the body. These are just some of the reasons a promising drug in the lab may not be effective when administered to a human.
With these caveats, this section explores what drugs have made it to clinical trials and what the future might hold. Treatments for COVID-19 are a moving target, and this section highlights the most recently reported results. As more information becomes available, this section may become out of date.
The case of hydroxychloroquine is a perfect example of what can happen in the process of a drug trial. Chloroquine and hydroxychloroquine have antiviral properties. In late January, Wang et al. reported that initial cell culture experiments demonstrated an inhibitory effect of chloroquine against SARS-CoV-2 at dosages appropriate for humans. Because of their findings, the authors recommended drug trials in patients should begin immediately.
On March 20th, Gautret et al. reported clinical trials with hydroxychloroquine with or without azithromycin. After six days of treatment, 15% of control patients had cleared the virus, while 70% of patients taking hydroxychloroquine were virus-free. When combined with azithromycin, all patients had cleared SARS-CoV-2 by day 5. There were several problems with this study. First, the sample size was small, enrolling only 36 patients. Second, the patients were not randomly assigned to each group, and they were not balanced by age, pre-existing conditions, sex, and other variables that are known to influence outcomes. Finally, the test was open-label, meaning patients and doctors knew who was getting treated with a drug and who was not. Still, the treatment showed promise and warranted further investigation.
A second clinical trial at about the same time by Chen et al. appeared to support the use of hydroxychloroquine. Patients were assigned randomly to a test or control group, the control group received a placebo, and both the attending doctors and patients were unaware of the group assignments. After five days, the test group's fever disappeared 2.2 days earlier, coughing ended sooner, and chest CT scans showed that 80% of the patients had improved compared to 52% in the control group. The main criticism of this study was that it was small, having only 62 patients, but again, further investigation was warranted given the significant, positive results.
On May 11th Rosenberg et al. published a study looking at the success of treatment with hydroxychloroquine with or without azithromycin. In contrast to earlier work, this was a large study of 1428 patients. In their work, the scientists looked at mortality in patients and found no significant benefit of treating them with these drugs. One drawback of this study was its observational design. Instead of assigning patients as they entered for treatment, this study only collected the records afterward. There was no opportunity to assign patients to control and test groups randomly. The study did suffer from flaws because those in the test group were more likely to be male, have cardiovascular disease, or diabetes. All of these are known to result in worse outcomes. Also, the patients and doctors knew they were receiving treatment. However, if hydroxychloroquine and azithromycin were having a profound effect, it should have been picked up in this study.
How can a drug seem to show promise in some studies, and then not have any success in others? It has to do with the design of the study, uncontrolled confounding variables, and the number of participants. First, knowledge of the patient and the doctor to your treatment can have a powerful effect. If you believe you are getting something useful, you will feel better, at least for a while. Your attending physician may also have an unconscious bias because they know you are in the treatment group. This bias is what is called the placebo effect. A well-designed study will blind participants to their group assignment to neutralize this phenomenon. Second, a control group is necessary for any quality research, and it needs to have identical conditions to the test group, except for the drug under study. Third, balancing the overall health of the individuals in each group is also essential. For example, if the control group has more patients with pre-existing conditions, they will likely have poorer outcomes. Finally, the number of patients in the study has to be large enough that it is possible to see statistical differences between each group. All of the early studies had significant design flaws, and so did the last one, but it was the best of the bunch. If hydroxychloroquine has substantial clinical benefit, it should have shown up in this last large study.
Unfortunately, the politicization by the president and his detractors of the legitimate research on hydroxychloroquine is unhelpful. There is indeed no strong evidence for the use of hydroxychloroquine for the treat of COVID-19. However, the comments by detractors of the president who, in my opinion, are exaggerating the risks of taking hydroxychloroquine are equally misinformed. The drug does indeed have serious side effects, and recent studies have demonstrated that the risks, including heart abnormalities, heart failure, and death, outweigh any benefit. These side effects are rare, and hydroxychloroquine has been used for decades to treat malaria and lupus. In any case, no one should be taking the drug unless under the supervision of a physician.
Remdesivir is another drug that showed promise in that first initial study by Wang et al. cited above. Several clinical trials around the globe have tested the success of remdesivir against Sars-CoV-2 infection. As with hydroxychloroquine, some studies suggest positive effects, but in most cases, poor experimental design makes them hard to interpret.
A report by Antinori et al. is an excellent example. Physicians are desperate to try anything that might help. Patients are given drugs without including control groups. In the face of a deadly illness such as COVID-19, using control groups is fraught with ethical problems. If a drug turns out to be effective, harm was done to those who died in the control group. However, the absence of a control group makes it difficult to determine the efficacy of any treatment. The results of the study show that only 38.9% of those in the ICU had improved, while 44% died. However, this is better than reports from Northwell Health in New York, where 88% of patients on mechanical ventilation had died.
A notable finding from Antinori's research was the large number of patients who experience liver or kidney damage, causing 22.8% of them to drop the treatment. Several other studies have shown potential beneficial effects of remdesivir but suffer from the same design flaws.
As of this writing (mid-May, 2020), there have been no large clinical trials containing a control group, that test remdesivir. Dr. Anthony Fauci did comment on a large clinical trial of remdesivir during a photo opportunity at the White House. Preliminary data was showing that the drug shortened the time to recovery by 31%. The study was published on May 22nd and did show a shortened time to recovery. Treatment with remdesivir did decrease the fatality rate but did not eliminate it, with 7.1% dying in the test group vs. 11.9% in the placebo group. We need to keep searching for better treatments. A notable problem with all of these trials is the use of the drug long after the infection begins (often seven days), and frequently in critically ill patients. Other antivirals are known to work best if used early in infection. We will know more when the study is published, peer-reviewed, and analyzed by the scientific community, but until then, the jury is still out on remdesivir.
Jeon et al. had previously tested 3,000 available drugs against SARS-CoV, this is the original SARS virus, not SARS-CoV-2. They reasoned since the viruses have a 76% sequence identity, the two viruses should react in a similar fashion to these drugs. An additional 13 drugs were added at the suggestion of infectious disease experts to the 35 identified by the screening of SARS-CoV. Of the 48 drugs evaluated, 24 of them showed promise. Two FDA-approved drugs were of the most interest since they could more rapidly be brought to use in humans. Niclosamide, a drug originally developed against worms, had very potent antiviral activity, inhibiting SARS-CoV-2 at concentrations 40 times lower than remdesivir. However, niclosamide has very poor adsorption. It may be possible to change its structure or the drug formulation to improve this limitation.
A second candidate was ciclesonide that was effective at concentrations 2.6 times lower than remdesivir. Ciclesonide is an inhaled corticosteroid used to treat asthma and allergic reactions. A case study was recently published that showed dramatic reversals of disease course within two days of starting treatment with ciclesonide. It appears that the steroid has a direct antiviral activity and also suppresses the potentially deadly inflammation reaction that kills patients. The case studies show promise, but these are not controlled drug trials. The drug has immediately gone into clinical trials and results should be available soon.
A key step in the replication of coronaviruses involves some of their proteins being acted upon by cyclophylins. These enzymes change the structure of the target protein and are involved in proper protein folding. Alisporivir is a drug that is a known potent inhibitor of cyclophilins and is currently in stage 3 clinical trials for treating hepatitis C viral infection. This drug is known to also have activity against SARS-CoV and MERS-CoV. Softic et al. tested the activity of alisporivir against SARS-CoV-2. Alisporivir had antiviral activity in cell culture experiments against SAR-CoV-2 that was comparable to chloroquine and there was no damage observed to host cells at lethal concentrations for the virus. Alisporivir is known to be safe for use in humans, has demonstrated antiviral activity against a number of viruses, including SARS-CoV-2. Having already passed safety trials during investigations of its use in hepatitis C treatment should accelerate trials of its effectiveness against SARS-CoV-2. Clinical trials for alisporivir are warranted.
Hung et. al may have found a powerful weapon against SARS-CoV-2. A study of a known candidate drug (GC376) used to treat feline infectious peritonitis virus, is showing potent inhibition of SARS-CoV-2. The drug is an M protease inhibitor. These proteases are common in RNA viruses. It is a great target for drugs because humans don't make polyprotein proteases. GC376 has potent activity against the M protein, inhibiting it at nanomolar concentrations (That is one-billionth of a gram per liter of water). In viral replication assays using human Vero cells, it had a half-maximum effective concentration (IC50) of 0.91 µM. In comparison, remdesivir has an IC50 of 11.41. That is about one part per billion, so it is working at very small concentrations. The drug is under investigation to treat feline infectious peritonitis virus in cats, where it has been demonstrated to cure this fatal disease. It is well tolerated in cats, where the drug was well tolerated at a dose of 10 mg/kg/dose, which was enough to raise the concentrations of the drug in plasma to 2 µM, well above its potential effective concentration. This drug is in early stages and no clinical trials of its use are ongoing.
There are a number of promising drugs for the treatment of COVID-19 in the midst of clinical trials. It is probable that at least some of them will turn out to be effective treatments against the disease. I think the most effective treatments will stop viral replication and also suppress the cytokine storm that causes to the immune system to overreact and damages organs and tissues. It is a testament to how far science and medicine have advanced that within six months of this pandemic emerging, we are on the verge of effective treatments.
Convalescent plasma therapy (CPT) is not a new idea. There are well-documented cases of using it to treat Spanish influenza in 1917-18, SARS in 2003, 2009 influenza, and other viral infections. Antibodies present in the plasma limit virus reproduction and tag the virus for elimination by the immune system. There is no approved drug or vaccine for COVID-19, and therefore it is a good candidate for CPT. As of May of 2020, five reports describe the use of CPT to treat COVID-19 infection.
Most of the patients in these studies were gravely ill, with 78% in the ICU, and 50% being on mechanical ventilation. CPT was well tolerated by all patients with no significant adverse events. Almost all patients given CPT showed clinical signs of improvement, including the normalization of body temperature, improved lung function, and weaning from ventilation. All 27 patients in the reports survived.
Due to the administration of other drugs and the lack of control groups, it is difficult to confidently say that CPT was the cause of recovery. However, other examples of treatments with the drugs used in these studies, but not CPT, did not show such a high recovery rate. Clearly, CPT has promise, and a larger, controlled investigation is needed as soon as possible to assess the benefits of CPT.