COVID-19 Treatment Update: April 20, 2020
So far hydroxychloroquine and Kaletra have not delivered but there are some glimmers of hope from remdesivir…
As of today, there are 406 studies relating to COVID-19 registered on clinicaltrials.gov. Of those, 114 are recruiting, active or completed clinical trials (not counting eight vaccine trials). These studies are testing the safety and effectiveness of a number of drugs, including immune modulators (42), chloroquine (32), anti-virals (27), cell therapies (6), convalescent plasma (4) and others. Nearly all are still in progress but in the last two weeks, the results of a few trials have been published in scientific journals or uploaded to pre-print servers (posted online before peer-review), so let’s take a look at those.
Chloroquine/hydroxychloroquine
As discussed previously, chloroquine (CQ) and a related drug hydroxychloroquine (HCQ) have gotten a lot of attention as potential COVID-19 treatments due to their ability to block viruses from infecting cells in vitro (in a dish) and to suppress the immune system (which would be useful in the case of an immune overreaction to SARS-CoV-2). Unfortunately, the first few HCQ trials had some serious flaws and even the best trial demonstrated minimal improvement in the HCQ-treated group (symptoms went away one day sooner). But research into CQ/HCQ has continued nonetheless, so let’s take a look at the latest clinical trial data. It’s important to note that the following HCQ studies have not yet been peer-reviewed (i.e. vetted by experts).
First we have an open-label (i.e. not blinded) randomized controlled trial from Shanghai, China that tested the safety and efficacy of high dose HCQ (800–1200 mg/day for 2–3 weeks). The researchers randomized 150 patients into either the control or HCQ group and monitored viral RNA, symptoms and blood chemistry. They found no difference in viral RNA levels or symptoms between the two groups at any point in the treatment period. However the authors mentioned that when they removed patients who received other anti-viral medications they did see faster symptom alleviation in the HCQ group. It’s unclear why some patients received anti-viral drugs on top of the standard of care and HCQ, as they probably should have been excluded from the start. The researchers also reported faster normalization of C-reactive protein (CRP) (meaning reduced inflammation) and recovery of baseline lymphocytopenia (meaning a normal number of immune cells in the blood). However they measured a lot of laboratory parameters (21 in fact) so it’s not surprising that two might show a statistical difference between the groups. The more things you measure, the more likely it is that you’ll find something, but it doesn’t mean it’s true or relevant. The multiple comparisons problem is a known issue in statistics but the authors did not account for it in their data. Nevertheless, lymphocytopenia is a biomarker of poor prognosis for COVID-19 and high CRP is associated with cytokine release syndrome, which is the immune system’s overreaction to a pathogen. So there are some hints here that perhaps HCQ is useful for modulating the immune system for these patients, if not viral control. However, the researchers noted that there were significantly more adverse events (side effects) in the HCQ group, which leads us to our next trial…
A double-blinded, randomized trial in Brazil tested the safety and effectiveness of high dose (1200mg/day for 10 days) or low dose (900mg/day for 5 days) CQ plus ceftriaxone and azithromycin (two antibiotics). The high dose CQ arm had to be ended early however due to cardiac issues and a trend toward higher fatality. The researchers are continuing the trial with low dose CQ, but by design there is no control arm so it’s probably not going to be very definitive. One thing to keep in mind is that CQ is known to have worse side effects than HCQ, and HCQ is more commonly used in the US.
Finally there is a retrospective study out of France that assessed low dose (600mg/day) HCQ. The researchers analyzed existing clinical data for 181 COVID-19 patients in four French hospitals. They found no difference in ICU admission between the HCQ and control groups (20.2% and 22.1%, respectively), no difference in progression to acute respiratory syndrome (ARDS) (27.4% vs 24.1%) and no difference in the number of deaths (2.8% vs 4.6%). A few patients (9.5%) in the HCQ arm had to stop taking the drug due to cardiac side effects. So unfortunately, we have another study that does not look good for HCQ.
Nonetheless, today Novartis announced it will conduct a randomized, double-blind, controlled trial of HCQ for COVID-19. The US Department of Defense is also moving forward with a randomized, double-blind controlled HCQ trial to test the drug in a prophylactic (preventative) context.
Lopinavir/Ritonavir (Kaletra)
Lopinavir and ritonavir are anti-viral drugs that are FDA-approved for treating HIV. Lopinavir targets an enzyme encoded in the HIV genome and ritonavir helps prevent lopinavir from being metabolized too quickly. Together, these drugs are sold under the brand name Kaletra. Kaletra hasn’t been tested against SARS-CoV-2 in vitro, but it was tested in a clinical trial during the first SARS epidemic. It was an open-label trial with no control group but when combined with another anti-viral drug called ribavirin, Kaletra seemed to reduce the risk of ARDS and viral load. So it made sense to try this drug combination for SARS-CoV-2, and this time it was an open-label, randomized, controlled trial with 199 patients. The researchers tested whether Kaletra could reduce the time to clinical improvement and/or hospital discharge as well as viral load. Unfortunately they did not find a difference between the Kaletra and control groups for any of these criteria. They noted that on average patients didn’t start treatment until 13 days after symptom onset so it’s possible that treatment was started too late. But when the authors looked only at the subset of patients who started treatment earlier, they still didn’t see a difference between the two groups.
An exploratory randomized, controlled study was performed at Guangzhou Eighth’s People’s Hospital to test the effects of Kaletra as well as a flu medication called arbidol, which will be discussed further in the next section. They enrolled 86 patients with mild illness and no signs of pneumonia (35 for Kaletra, 34 for arbidol, 17 controls). The researchers primarily wanted to know if either drug could reduce viral load by 21 days but they also monitored clinical symptoms. All groups averaged about 9 days for a negative viral PCR test and there were no significant differences in clinical improvement between groups. So at this point, Kaletra does not look very promising.
Remdesivir is an anti-viral drug developed by Gilead to specifically target viral RNA polymerase, which makes copies of the viral RNA genome and therefore is necessary for viral replication. The drug has anti-viral activity in vitro against HIV, Ebola, and both SARS-CoV viruses, and preliminary results from a study in Ebola patients looked promising and established that it was safe for humans. So a few clinical trials for remdesivir in COVID-19 were initiated. Unfortunately, two remdesivir trials in China were stopped early due to a lack of COVID-19 patients. This is a common problem for infectious diseases like this… once it’s under control, resources (patients, money, motivation) dry up. However a compassionate use study being performed by the drug’s manufacturer was recently published. Compassionate use means that doctors could ask Gilead for the drug to try it on very sick COVID-19 patients as a last resort. It’s not really a trial because there is no standardization of treatment, no criteria for patient selection (other than being extremely ill), no blinding and no control group, so it’s difficult to interpret the data. All we can do is try to compare the clinical outcomes of remdesivir-treated patients to historical controls. We ask, “how do patients with similar characteristics (age, sex, pre-existing conditions, severity of illness) usually do?” The compassionate use study includes data from 61 patients in the US, Canada, Europe and Japan. A majority of the patients (57%) were on ventilators and 8% were receiving extracorporeal membrane oxygenation (ECMO) at the start of the trial, so these are very sick people. They received a 10-day course of intravenous remdesivir and 57% of the ventilated patients were healthy enough to be extubated by the 18-day follow-up, while 13% of patients died. For comparison, the authors noted that 22% of patients died in the Kaletra trial and they were generally healthier at the start. There are currently five ongoing trials for remdesivir registered at clinicaltrials.gov so hopefully we will find out soon whether it is truly effective against COVID-19.
What’s next?
This is not a comprehensive list of COVID-19 trials but they represent some of the most highly anticipated drugs. There are more anti-virals being tested — for example there were a couple of pre-prints on favipiravir (similar to remdesivir) and arbidol (flu medication). And there are a ton of clinical trials in progress looking at immune modulators like tocilizumab, which tamps down the immune system and could be useful for patients who are experiencing cytokine storm (a potentially deadly immune overreaction). There are also calls for plasma donations from recovered COVID-19 patients. Convalescent plasma was used during the Spanish flu epidemic 100 years ago to transfer antibodies against the virus from the recovered directly to the sick and it has shown some promise already for COVID-19 patients. Watch this space for more updates in the coming weeks!
