EXPERT REACTION: WHO COVID-19 trial finds remdesivir, hydroxychloroquine, lopinavir and interferon don't save lives

The WHO today released the results of a multicentre clinical trial of four different repurposed antiviral drugs in hospitalised COVID-19 patients. In 405 hospitals in 30 countries, a total of 7,178 adults were treated with Remdesivir (2750 people), or Hydroxychloroquine (954), or Lopinavir (1,141) or Interferon β1a alone (1412) or interferon β1a + Lopinavir (651) and compared to a combined 408 patients with no treatment.

Their conclusion was that “…(these) regimens appeared to have little or no effect on hospitalised COVID-19, as indicated by overall mortality, initiation of ventilation and duration of hospital stay.”

However, I would urge caution before abandoning one of the body’s premier family of antiviral compounds, because of the design of this SOLIDARITY trial. Firstly, the route of administration might not be ideal. The interferon β1a was mostly delivered subcutaneously, which is not the best way to deliver interferon β1a to the lungs and is known to be less efficient than intravenous or inhaled. The latter is being trialled. Secondly, about half of the patients received corticosteroids at the same time and these are known to block interferon responses. Thirdly, recent papers have indicated that certain patients might not be responsive to Interferon since they produce antibodies to IFN or have mutations in interferon response pathways.  Fourth, interferon β1a may not be the ideal type to use (there are 20 different ones with different characteristics).

The stage of disease will also affect the efficacy of an interferon’s antiviral properties. The earlier it is given, the better chance it has of limiting damage from the virus. In the natural course of infection, several types of interferon out of the available repertoire of 20 different types are produced rapidly to limit local infection. Strategic identification of the patients to treat, their concurrent medications, the type of interferon to use and its mode and timing of delivery may yet see these premier antiviral cytokines be used to good effect in the multipronged approach to treating infection with SARS CoV2.

No surprises - all the most hyped COVID-19 drugs don't work when subjected to the rigorous controlled SOLIDARITY trial.

Let's globally remove all ability of politicians to interfere in the drug and vaccine approval process once and for all.

Otherwise we are back to the era of snake oil salesmen. Hydroxychloroquine was always a highly dubious claim and remdesivir negative data begs the question of how it got expedited FDA approval and whether that should be now withdrawn.

I have read the interim findings of the SOLIDARITY trial and am concerned that the conclusions made identify all the trial drugs as ineffective. I have several reservations about the trial design. Notably, at entry into the trial, some patients required oxygen and others mechanical ventilation. Given that all the emerging evidence points to interferon treatment being effective at the early, viral phase of COVID-19, treatment when patients are in the pulmonary or hyper inflammatory phases of Covid-19, ie later in disease, would likely be ineffective.

Close scrutiny of the data in the MedRxiv preprint shows that this was a heterogeneous patient population at different phases of COVID-19. Until such time as all the data are scrutinized to evaluate the different subgroups of patients, their phase of disease and their rate of viral clearance, it is premature to dismiss some of these repurposed drugs as ‘ineffective’ and to suggest they should not be evaluated further.

Again, case in point, several peer reviewed publications have shown that in controlled trials interferon-alpha and interferon-beta treatments are effective in terms of accelerated viral clearance. Interim findings of the Synairgen trial of inhaled interferon-beta for COVID-19 identified a significant advantage and therapeutic benefit: patients had a 79 percent lower risk of developing severe disease and were more than twice as likely to recover from COVID-19 than those on placebo. Trial design is absolutely critical to permit the correct interpretation.

This study provides high quality evidence indicating that Remdesivir, Hydroxychloroquine, Lopinavir and Interferon regimens appear to have little or no effect on hospitalized COVID-19. The study focussed on three health outcomes, these being; mortality, initiation of ventilation and hospitalization duration. And on none of these was there a benefit found when on any of these regimens.

Despite the early hope for these therapies, as we gather more, better quality evidence, it is clear that we should be moving our attention to other potential treatments for COVID-19.

The publication of the Solidarity trial results (in non-peer-reviewed form) underscores just how difficult it has been to find anti-viral drugs that are effective against SARS-CoV-2. This is a large pragmatic randomised trial that studied the impact of several anti-viral drugs (remdesivir, lopinavir/ritonavir, hydroxychloroquine and interferon) on death rates at 28 days after treatment commenced.

In summary, no drug had a significant impact on mortality, need for mechanical ventilation or time to discharge. The trial did not use a placebo arm, but observer bias in adjudicating mortality is unlikely. In the case of remdesivir, the results are particularly disappointing. Previous trials (including Recovery and ACTT-1) have shown shortened recovery times with remdesivir and a signal that early mortality (at 14 to 15 days) might be reduced. The Solidarity Trial did not measure time to recovery, so that benefit remains unchallenged, but the new results seem to eliminate the possibility of a reduction in mortality.

Some of the other results in the new report are unsurprising. Hydroxychloroquine once again was found to be ineffective and surely must now be abandoned even by its strongest advocates. Lopinavir and Ritonavir are effective drugs in HIV but have been consistently found to be ineffective in COVID-19. There is no clear case for their continuation. Finally, there has been some hope for interferon in inhaled form in a small study that showed improved recovery times but subcutaneous injection in this new trial had no effect on mortality.

Although in summary the results of the Solidarity Trial are disappointing, they underscore, yet again, the need to rapidly perform rigorous randomised trials of candidate treatments during the epidemic.

These findings highlight again the crucial importance of proper randomised controlled trials, rather than 'compassionate use' or other random use of medications. The results of SOLIDARITY are consistent with results to date from the other two large pragmatic trials (RECOVERY and REMAP-CAP) confirming no substantial benefit from a variety of 'repurposed' agents, which had been proposed after small or observational trials.

To date the only agents with any robust data showing benefit are the corticosteroids (dexamethasone or methylprednisolone). It is now time to stop spending resources studying these drugs and to move on to robust, well designed trials of new agents, including preparations of antibodies which have yet to be properly evaluated.

The WHO SOLIDARITY trial is a well-designed study, involving 11,266 adults hospitalised due to COVID-19 in 405 hospitals, where patients were randomly allocated to one of four repurposed antiviral drugs that were thought to potentially provide some benefit in patients with this infection. The study drugs were remdesivir, hydroxychloroquine, lopinavir (fixed-dose combination with ritonavir) and interferon-β1a (with and without lopinavir). Patients were not allocated study drugs equally, presumably due to local availability of the treatment options, with those treated with remdesivir having the highest number of included patients at 2750 compared to 954 receiving hydroxychloroquine.

Despite reportedly good compliance, the findings that are available in preprint (i.e. not yet published in a peer reviewed journal) were that no study drug reduced thjree important indicators of drug efficacy namely mortality, initiation of ventilation or duration of hospitalisation. These findings were described as consistent with meta analyses of mortality in all major trials.

This means that despite some reports of benefit and ongoing debate with all of these therapies, this large high-quality study adds to mounting evidence suggesting that these drugs have little or no effect on patients hospitalised with COVID-19. Notwithstanding these results, I suspect studies will continue with at least some if not all these drugs to see if there is potentially an effect, perhaps on different populations or subgroups and particularly until more efficacious therapeutic options become available.

Today, the World Health Organization posted on the preprint server MedRxiv their highly anticipated results for a large clinical trial called SOLIDARITY on repurposed drugs for patients hospitalised with COVID-19.

The SOLIDARITY trial is a large randomised controlled clinical trial involving 30 countries, 405 hospitals across the world and over 11,000 COVID-19 patients. Four repurposed drugs (hydroxychloroquine, remdesivir, lopinavir and interferon beta) were evaluated against standard of care for their efficacy in reducing the mortality at 28 days post treatment and mechanical ventilation.

The results show compellingly that all these treatments have little to no effect on mortality at 28 days or on technical ventilation. Together this confirms the results from previous clinical trials, such as the RECOVERY trial in UK for hydroxychloroquine or lopinavir, but also provides additional evidence that remdesivir treatment is partially effective in low risk patients but hazardous for high risk patients. Plus a disappointing result for the interferon beta trial.

Overall this indicates there is no silver bullet treatment against COVID-19 and the preventive measures such as social distancing, wearing masks or implementing a large number of tests for contact tracing are by far the most efficacious measures for COVID-19.

Whilst the study findings were negative, this is an incredibly important study for patients with COVID-19.  Knowing which drugs do not work is important so that ineffective therapies are not given to patients. This allows more effective therapies such as dexamethasone or newer experimental drugs to be evaluated.

The study findings have been shown in other studies, but importantly there were a large number of patients from different ethnicities included in the current clinical trial, which makes these findings impactful.

The World Health Organisation has published the results of the SOLIDARITY trial conducted at multiple centres in 11,266 adults hospitalised with COVID-19 infections. Study drugs were remdesivir, hydroxychloroquine, lopinavir in a fixed-dose combination with ritonavir, and interferon-β.  None of the drugs showed any benefit in reducing deaths, time to initiation of ventilation or the duration of hospitalisation.

The results are disappointing particularly from the perspective of remdesivir, which has shown promising effects in other trials. Experience with influenza antivirals has shown that treatment needs to be started within 48 hours of the first symptoms for a benefit to be seen. Participants in the SOLIDARITY COVID-19 trial may have had symptoms for several days before being hospitalized and this could well reduce the chance of seeing any benefit.