Treating COVID-19: As widely-available steroid dexamethasone raises hopes, a look at other potential treatments in trials already
So far there are no approved treatments for the coronavirus infection which has claimed more than 443,000 lives globally and 9,900 in India alone
A study led by Oxford University which claims that low cost widely available steroid drug dexamethasone can improve chances of survival among severely-ill hospitalized COVID-19 patients has raised hopes even as cases are surging, particularly in South Asia and Americas.
This becomes particularly significant as so far there are no approved vaccinations or treatments for the coronavirus infection, which has claimed over 4,44,000 lives globally and 9,900 in India alone.
Based on clinical trials with large sample size, the researchers estimated that the drug would prevent one death for every eight patients treated while on breathing machines and one for every 25 patients on extra oxygen alone.
According to an Associated Press report, the British government immediately authorized the drug's use across the United Kingdom for coronavirus patients like those who did well in the study. Even the US's top infectious disease expert Dr Anthony Fauci called it a significant development among treatments currently available.
However, experts have taken a cautious approach, suggesting that the full details of the study need to be studied to gauge who the drug might benefit and to what extent. The researchers have confirmed that they will publish the details soon.
Meanwhile, the World Health Organisation continues research under its Solidarity trials on four other treatment options – Remdesivir, Lopinavir/Ritonavir and Interferon beta-1a.
Chloroquine and hydroxychloroquine
An early, errant research study published in a widely-respected British journal the Lancet, that was later retracted, spurred one of the earliest whispers of a promising treatment for COVID-19 – hydroxychloroquine. The drug, best known for its use in treating malaria, is now out of consideration for COVID-19 by most major organizations.
The WHO claims to have 'temporarily paused' the hydroxychloroquine trial due to concerns over the safe use of the drug.
The United States' Food and Drug Administration (FDA) has also revoked the emergency authorization of the anti-malarial drug stating that its unproven benefits "do not outweigh the known and potential risks."
In April, just four weeks after granting the EUA, the FDA issued a warning about reports of serious arrhythmias in patients with COVID-19 treated with either drug, especially when prescribed along with the antibacterial azithromycin and similar medicines that are under a class of 'QT-prolonging' medications.
The UK's RECOVERY trial – a massive undertaking of 11,000+ test cases – also carried out a study on the anti-inflammatory drug dexamethasone. They stopped enrolling participants for the hydroxychloroquine arm of its trial on 5 June, after it had found "there is no beneficial effect of hydroxychloroquine in patients hospitalized with COVID-19" – be it mortality, duration of stay at the hospital, or other outcomes.
Peter Horby, a professor at the University of Oxford, and Chief Investigator for the Trial, told Oxford press, "Hydroxychloroquine and chloroquine have received a lot of attention and have been used very widely to treat COVID-19 patients despite the absence of any good evidence. The RECOVERY Trial has shown that hydroxychloroquine is not an effective treatment in patients hospitalised with COVID-19. Although it is disappointing that this treatment has been shown to be ineffective, it does allow us to focus care and research on more promising drugs.”
In India, the health ministry has recommended the use of antiviral drug Remdesivir in moderate stage of COVID-19 but approval for the manufacturing and sale of the drug is still pending from the Drug Controller General of India (DCGI). In recently published guidelines on critical management, India has also backtracked from its earlier stance on hydroxychloroquine, saying the anti-malarial drug should be used in the early course of the disease and not in critically-ill COVID-19 patients.
In light of the withdrawal of the Emergency Use Authorization (EUA) to hydroxychloroquine and chloroquine, Remdesivir remains the only drug with EUA in the US.
Among the more promising candidates emerging right now is Remdesivir, Gilead Sciences Inc’s anti-viral drug. Remdesivir has approved for emergency usage in South Korea, Japan, India, and Singapore already, and is currently in multiple clinical trials to treat COVID-19.
Israel on Tuesday joined these countries in granting approval to the usage of the drug for treating coronavirus patients, as per a recent Reuters report.
The anti-viral drug Remdesivir had been similarly trialled during the Ebola outbreak in 2014-2016. Gilead Sciences, the company that manufactures the drug, came out with the results of its phase three Remdesivir trials on 29 April, reporting that patients in the study who received Remdesivir within 10 days of COVID-19 symptoms onset had improved outcomes.
According to a press release issued Gilead, by day 14 of treatment, 62 percent of patients treated early in their infection were able to be discharged from the hospital. This contrasts, albeit not starkly, with 49 percent of patients who were treated later on in the disease progression.
An unrelated trial by US’s National Institute of Health (NIH) on 1063 patients, which was begun in February, suggested that patients who received Remdesivir recovered 31 percent faster than those who received the placebo.
Remdesivir, Reuters reported, offers the most benefit for COVID-19 patients who need extra oxygen but do not require mechanical ventilation. That said, researchers have pointed to the "high mortality despite the use of Remdesivir," suggesting that that drug was likely to be more effective in combination with other treatments for COVID-19.
Many questions around its usefulness as a COVID-19 treatment still remain, as studies conducted prior to Gilead’s phase 3, including one trial in China’s Hubei, didn't throw up very encouraging results.
Another drug under consideration is Lopinavir-Ritonavir, currently used to control HIV infection, and prevent its progression in patients into full-blown AIDS. According to WHO, while there are indications from laboratory experiments that this combination may be effective against COVID-19, studies done so far in COVID-19 patients have shown inconclusive results.
A trial conducted in Wuhan between January and February 2020 and published in the New England Journal of Medicine, studied 199 severely-ill patients – 99 of whom were administered the drug combination, while 100 were given standard care. They found that the combination neither accelerated clinical improvement, nor reduced mortality or viral load in treated patients.
A research review carried out by Oxford University in April flagged the need to conduct more randomized clinical trials to ascertain the efficacy and safety of the drug combination. "At present, there is insufficient evidence to recommend the use of LPVr for COVID-19 outside of research studies," it concluded.
As per a report in the Strait Times , a study conducted by Singapore researchers using Artificial Intelligence (AI) suggested that Lopinavir and Ritonavir in combination with Remdesivir could be six-and-a-half times more effective at treating patients compared with just Remdesivir. This drug combination came out as the most effective from among 5,30,000 other drug combinations. A major drawback here is that the study is neither peer-reviewed, nor backed by wider animal or clinical trials.
Another study published in The Lancet found that triple antiviral therapy – combining beta-1b interferon, lopinavir–ritonavir, and ribavirin – was more effective than lopinavir–ritonavir alone. This was recommended by the study to alleviate symptoms and shorten the duration of viral shedding and hospital stay in patients with mild to moderate COVID-19 cases. The effectiveness of this tripe antiviral therapy is yet to be established through large scale, rigorous clinical trials.
While the studies above seem to point towards the use of lopinavir-ritonavir in combination with other drugs, no evidence or proof of its efficacy has been found so far, making it an inaccessible option.
Another drug under consideration in WHO's global Solidarity trial is Interferon beta-1a – a licensed autoimmune drug used in treating multiple sclerosis.
A review published in Science Direct explores the argument for using Interferon beta-1a (IFNβ1) as a broad antiviral drug currently in clinical trials to treat MERS-CoV. The review says, "IFNβ1 may account for a safe and easy-to-upscale treatment against COVID-19 in early stages of infection. Similar treatments had a mixed efficiency against MERS-CoV and SARS-CoV viruses, but in vitro studies suggest that SARS-CoV-2 could be substantially more sensitive to IFN-I than other coronaviruses."
It also suggests that the safety of this auto-immune drug has been established, making it a worthwhile candidate for clinical evaluation in COVID-19 patients.
As elaborated in an earlier article on Firstpost, the journal Medicinenet notes that there is some hesitance in testing the drug, despite it being included in the WHO trial. This, because IFNβ1 was reported to have severe side-effects in patients when it was originally trialled for treating Hepatitis C. In the best cases, clinicians saw a 30 percent cure rate in treating Hep C with interferon, but the side effects were severe – drop in white blood cell levels, liver problems, patients would become suicidal or fall into deep depressions.
Giving interferon-based treatment to severely-ill patients or those on ventilator support could be catastrophic for more than one reasons, Medicinenet adds, since interferon ramps up the immune system and causes flu-like symptoms to get worse before they get better. This isn't something clinicians can afford to risk with coronavirus, which presents similar symptoms to the flu, and could aggravate an already-severe infection.
The Indian Council of Medical Research (ICMR) has permitted the use of tocilizumab in clinical management of COVID-19 in India, under certain conditions. The revised clinical management protocol states "Tocilizumab (Off Label) may be considered in patients with moderate disease with progressively increasing oxygen requirements, and in mechanically ventilated patients not improving despite the use of steroids. Long-term safety data in COVID-19 remains largely unknown."
It also lists certain special considerations to be factored in – like ruling out active infections, and Tuberculosis – before its use, and close monitoring for secondary infections and neutropenia after use.
However, it must be noted that tocilizumab is not an anti-viral drug, but an anti-inflammatory one. Though this anti-inflammatory treatment isn't part of WHO's Solidarity trials, it is being tested among other promising drugs in Britain's over 11,000-strong RECOVERY trials.
A paper from China had, in April, argued that tocilizumab could provide some relief to severe patients by calming the inflammatory storm whipped up when the immune system goes into overdrive to fight a viral infection. By short-circuiting the chain reaction that creates this storm in the first place, the researchers claim the potential to reduce mortality in COVID-19 patients. The "inspiring clinical results" they presented, however, are a drop in temperature to normal and improved respiratory function in a set of 21 patients, which isn't a large enough number to turn heads in the midst of a raging pandemic.
A retrospective review in the Journal of Medical Virology studied another small sample (25 patients) with severe COVID-19, where tocilizumab was linked to lower inflammatory markers, improvement in radiological scans, and lower dependence on ventilator support. This study, too, had severe limitations, not the least of which is that a randomised clinical trial is needed to validate the results of a drug. Such trials appear to be underway, the biggest of them being Oxford's RECOVERY, with their results still awaited.
Convalescent Plasma Therapy
The ICMR, in a revised treatment protocol issued on the Ministry of Family, Health and Welfare website, said that convalescent plasma (Off Label) may be considered in patients that have moderate COVID-19 symptoms who aren't improving despite the use of steroids (oxygen requirement is progressively increasing). This form of therapy is also among the treatments in the UK's RECOVERY trials. It has generated much interest in India, where clinical trials are underway.
Convalescent plasma therapy involves the use of antibody-rich plasma collected from recovered COVID-19 patients, which is injected into recovering patients to help them stave off the infection. This technique was previously used during the SARS and MERS outbreaks (which were also caused by viruses in the same family as the coronavirus SARS-CoV-2 that causes COVID).
However, as per an AP report, the claim that recipients of the blood plasma were less likely to die of the infection isn't backed by rigorous research.
While news reports in India of successful use of this therapy has stoked hopes and demand, doctors are warning relatives and patients to not hold out hope for a perceived silver bullet. Doctors also say that finding suitable donors could be a challenge.
Globally, too, the evidence for staving off the infection has not been conclusive. Hospitals in the hard-hit Chinese city of Wuhan were comparing severely-ill patients randomly assigned to receive plasma or regular care, but ran out of new patients when the virus waned. With only half of the 200 planned patients enrolled, more plasma recipients survived but researchers couldn’t tell if it was a real difference or coincidence, according to a report in the Journal of the American Medical Association last week.
Apart from medical benefits in treatment, the risks and side effects of this therapy are also debated. Convalescent plasma seems to be safe to use, the AP report quotes Dr Michael Joyner of the Mayo Clinic as saying. However, as an earlier Firstpost article reports, the risks include transfusion-related acute lung injury (TRALI) – which can cause breathing difficulty/respiratory failure, transfusion-associated circulatory overload (TACO) – which can cause heart failure symptoms, allergic reactions or life-threatening anaphylactic shock, risk of infection from other pathogens in the donor's plasma or acquired during processing, fever, graft vs host disease, hemolysis or breakdown of red blood cells in the recipient, among other complications.
Nevertheless, a confirmation on its efficacy in treating COVID-19 is awaited from various clinical trials underway in India and overseas.
Use of Azithromycin, a common antibacterial drug, for mild and moderate COVID-19 cases has been rolled back in India by the Health Ministry, as per an India Today report. Azithromycin, while an antibacterial drug, is was thought to be effective against the Zika virus and Ebola.
While initial studies had suggested that azithromycin had a synergistic effect with other antimalarial drugs in reducing the virus load and bringing about clinical improvement, there are growing concerns about its usage, according to Down to Earth (DTE) report. A study conducted in France on 11 patients showed there was no rapid anti-viral clearance or clinical benefits in patients with severe infection.
A WHO database had, in late May, flagged concerns over the use of azithromycin, particularly in combination with hydroxychloroquine, in the journal Diagnostic and Interventional Cardiology. The researchers noted that, "reports of potentially lethal acute cardiac pro-arrhythmogenic effects have been described mainly with azithromycin, but also with hydroxychloroquine. Their combination yielded an even stronger signal."
Additionally, the DTE report also draws attention to the phenomenon of antimicrobial resistance that may result from increased use of antibiotics, which will only make matters worse in the long-term – considering the uncertainty surrounding COVID-19 treatment is unlikely to clear anytime soon.
In addition to the above, there are many clinical trials world over that are currently underway to study the effect of the following drugs in COVID-19 patients with moderate to serious symptoms.
Merimepodib/Remdesivir – this combo has been found to suppress the SARS-CoV-2 virus that causes COVID-19, and together cut viral replication to "undetectable levels" at low concentrations.
Duvelisib – could quell hyperactive immune system, reduce pulmonary inflammation, and limit viral persistence
Favipiravir – oral antiviral approved for the treatment of influenza in Japan
Levilimab – a fully human antibody acting against the interleukin-6 receptor
Methylprednisolone – corticosteroid medication used to suppress the immune system and decrease inflammation
Danoprevir+Ritonavir – the antiviral combo is used to treat Hepatitis C. Ritonavir also acts as a HIV inhibitor.
Sarilumab – a human monoclonal antibody against the interleukin-6 receptor, used to treat rheumatoid arthritis
Baricitinib – a rheumatoid arthritis treatment drug manufactured by Eli Lilly that interferes with inflammatory processes in the immune system that cause symptoms of RA.
Infliximab – a monoclonal antibody used to treat a range of autoimmune diseases including Crohn's disease, ulcerative colitis, rheumatoid arthritis, psoriasis, among others
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