THERAPIES FOR COVID-19
1. Introduction
Pandemicia has specifically sought not to comment on medical
or treatment matters, as while we are scientists, we have no particular medical expertise except to read and
review the published medical papers and media releases. However, we have been
intermittently asked to pass comment on alternative COVID therapies when people
have sought to protect themselves from the global pandemic in ways they find
acceptable. Here we summarise the available evidence on the various remedies for
Covid-19.
Viruses have been relatively immune to any kind of direct
treatment, because they are tiny and reproduce inside cells. A few viruses such
as HIV/AIDS, herpes simplex and influenza are responsive to antiviral
medicines, but the major weapon in the medical arsenal has been vaccines, which
stimulate the body’s own immune system to fight the virus. Vaccines have wiped
out truly major scourges– smallpox and polio in humans, rinderpest in cattle - and
they have reduced the impact of measles, influenza and pneumonia. Vaccination has been described as having “made the greatest contribution to global health of
any human intervention apart from the introduction of clean water and
sanitation”.
When there is no
available vaccine for a disease, or the death rate after vaccination remains excessive, it is
clearly beneficial to try to develop alternative treatments to assist
sufferers and to reduce mortality. In the face of the unknown, such as the COVID-19
pandemic, “putting all one’s eggs in one basket” is better avoided by having a
range of medical responses. Alternative treatments can assist patients who for
one reason or another cannot or will not be vaccinated, who cannot afford
vaccination, or who are waiting for scarce vaccine supplies - or in "breakthrough" cases where vaccinated people catch the disease.
The lack of any real treatment for Covid-19 initially led sufferers and their doctors to try almost anything. One "alternative treatment" after another was put forward - some outlandish, many harmless, a few possibly useful. A Wikipedia article on unproven methods against Covid-19 lists dozens of crank, fraudulent, religious, traditional, herbal, "repurposed drugs"and other unfounded claims. The most infamous of these was the recommendation by President Trump at a briefing in April 2020 that the antimalarial hydroxychloroquine was a Covid cure-all, while adding that injecting disinfectant and employing ultraviolet light might be useful.
The only treatments that might possibly have merit are ones that
- have the broad support of the medical fraternity,
- have evidence from large well-designed studies, or
- have been employed successfully on a wide scale.
2. Repurposing drugs for treatment of COVID--19
No
intervention should be assumed to be efficacious. Even drugs initially
supported by evidence of effectiveness may later prove to be more harmful than
beneficial. BMJ editorial, 8 April 2020.
A number of existing medications and drugs do have multiple uses, because they interfere with specific chemical pathways that might be used by all kinds of diseases and parasites. The drugs may kill organisms or viruses, block their replication or prevent them entering cells. They might be "repurposed" for treating Covid-19. The very high cost in both money and time of establishing the effectiveness and safety of new drugs to the satisfaction of medical authorities initially made the re-purposing of existing drugs to new uses seem very attractive – since in many cases they were already approved for human use and were known not to have dangerous side-effects.
The USA has about 70 per cent of the global drug market, and it is extremely influential in setting standards. The steps in introducing a repurposed drug in the USA under emergency circumstances are:
- Test it in vitro to see if it has the desired effect in the test tube;
- Run small trials to see if the drug works in the field (or run animal studies if appropriate);
- Run full scale blind random trials meeting ethical standards and which use experimental designs and control groups;
- Seek an Emergency Use Authorisation (EUA) from the Food and Drug Administration (FDA). This authorises unapproved medical products to be used in an emergency to diagnose, treat, or prevent serious conditions when there are no alternatives.
- Cautiously introduce the drug, looking for successes and unintended effects.
- Apply for full approval. This involves onerous conditions and elaborate documentation, and typically takes 6-7 years.
In the present emergency, approval procedures have been very considerably abbreviated. In the rushed environment of early Covid research, emergency acceptance of drugs that had not passed protocols and later turned out to be ineffective was undertaken – as we shall see in several examples.
2.1 Hydroxychloroquinine
Hydroxychloroquinine (HCQ)
and chloroquinine (CQ) are the modern versions of the antimalarial drug quinine.
From 1985, it has been known that these substances are active against a range of viruses. They were found to be a "potent inhibitor of SARS coronavirus" in vitro in 2005. However, there are 42 known side effects of HCQ, some fatal, and
doctors have always been cautious about prescribing the drug.
The drugs initially appeared
to show promise in the treatment of Covid-19. Chinese doctors announced some success in limited trials in March 2020. At least 80 trials of CQ
and HCQ, sometimes in combination with other drugs, were registered worldwide.
In the emergency situation of late March and early April
2020, as Covid-19 deaths soared in Europe and the USA, President Trump
advocated HCQ as a “pandemic game changer”, though it had never before been
used to treat a viral illness and there was little evidence of its efficacy. Within
days, the number of prescriptions for the drug skyrocketed. The US Food and Drug Administration
(FDA) issued an EUA on March 28 to use HCQ in Covid-19
treatment.
In May, WHO issued an advisory to suspend the use of HCQ
citing safety
issues. A clinical trial by the National Institutes of Health (NIH) ended in
June, and it “became immediately obvious HCQ did nothing” for severely ill
patients. The FDA revoked its support. A global observational
study reported that the mortality rate was higher with HCQ than without it.
In November, the
NIH formally reported that HCQ provided no clinical benefit for
hospitalized patients. WHO also reported strongly against the drug on 1 March 2021 and on 30 April
2021, citing the results of six large trials.
The Indian Council for Medical Research recommended the use of HCQ in a bulletin of March 21 2020. They complained about the early withdrawal of the drug by WHO, saying their own much lower dosage regimen worked. They advised people exposed and front-line workers to take the drug to prevent infection. As late as June 2021, they found it effective in a prophylactic study covering 12,000 health care workers, while citing the “limitations of vaccines” in a situation of extreme shortage. As with other studies outside of the mainstream however, the trial did not appear to employ blind controls, allowing the possibility that those who took the drug might be more likely to avoid infection in other ways, such as PPE, than those who did not.
2.2 Antivirals
Remdesivir (Veklury-Gilead) is a virus inhibitor arresting RNA synthesis, which was originally developed for use against Hepatitis C. It is injected, and it is high-priced at about US$2400 for a five-day course. It became the only antiviral drug recommended by the CDC, and was the first Covid medication to receive full approval by the FDA. On Nov 2020 the ACTT-1 study showed it shortened recovery times for a specific group [T1] of non-intubated hospitalised patients by about five days on average.2.3 Steroids
Methylprednisolone and dexamethasone are
corticosteroids. These steroids bind to and activate specific nuclear
receptors, resulting in altered gene expression and inhibiting cytokine
production. They are said to reduce inflammation in severe cases. Corticosteroids however have had a poor record in dealing with
pneumonia caused by influenza and SARS, resulting in worse outcomes.
Although corticosteroids do not have an EUA, they are very widely employed in the treatment of severe illness. Studies suggest a general benefit applying only to certain patients. According to the large randomised RECOVERY trial in the UK, steroids delivered a decrease in mortality for those with severe groundglass pneumonia and intubated. Steroids were also effective in mild or moderate cases. One metaanalysis of 73 studies in October showed mortality benefits for steroids, but noted the death rate for patients taking steroids as higher - cautioning against the great heterogeneity in both dosage regimens and patient conditions in the different studies. Another metastudy in December of 44 trials covering 4400 patients found reduced rates of death for hospitalised patients. The various studies confirm that it is fairly difficult to verify positive effects of corticosteroids for the seriously ill because the benefits are small and the risk of bias is high.
While WHO recommends corticosteroids for severe and critically ill patients, it does not advise their general use because of the risk of complications and adverse effects.
2.4 Tocilizumab (Actemra)
This monoclonal antibody does not target Covid-19, but reduces inflammation in severely ill patients undergoing corticosteroid treatment. It received an EUA by FDA on June 24 2021, after four clinical trials showed it reduced mortality and length of hospital stay - particularly the RECOVERY and IMPACTA trials. Mortality was still high in the first trial (over 30% among 4116 severely ill patients).
2.5 Baricitinib
Baracitinib (Olumiant-Lilly) is used to treat rheumatoid arthritis, and it is expensive. It blocks the action of Janus kinase enzymes which cause inflammation. It showed positive results for the seriously ill in both the ACCT and COV-BARRIER trials, and was well-tolerated. The latter trial showed a profound improvement in mortality rates of about 5 absolute percentage points,the first medication to do so. It received an EUA to be used in combination with remdesivir on 19 November,
2.6 Ivermectin
It has been claimed by a very vocal minority that Ivermectin results in substantial improvements in both Covid-19 prophylaxis and disease severity. There is no widely accepted proof or disproof of its effectiveness. Matters have become so heated that both for and against sides have selectively quoted studies and made unsupported assertions.
Because of the violence of the arguments, the claims by adherents that ivermectin can replace vaccines, and some self-administered overdoses, social media have banned discussion of the drug and doctors have been prevented from prescribing it. The “Invermectin wars” are discussed in more detail in a separate paper.
2.7 Other
Famotidine (zantac) is a common reflux medicine. Administered to a high dose, it is said to reduce Covid intubation and mortality, though subsequent studies have been unable to find a mechanism where this might occur.
Fluvoxamine This cheap, popular anti-depressant has antiviral properties. The TOGETHER blind trial in Brazil gave 750 risky patients 100mg twice daily for ten days. It found 11% were hospitalised compared with 16% given the placebo, and deaths were significantly reduced, The results are not spectacular, but may be useful.
Emetine, an ipecac-based antiprotozoal and emetic
drug, was found by Indian doctors to be “effective
against Covid-19”. It has been shown to inhibit
viral replication in vitro.
Convalescent plasma is blood derived from recovered patients. It received an EUA in August 2020 for high risk outpatients, but was later shown to have no value.
The WHO Solidarity-plus worldwide trial for promising drugs continued
in August 2021, A panel chose the drugs artesunate, imatinib and infliximab
as promising candidates.
- Artesunate is a strong antimalarial with anti-inflammatory properties
- Iminatib is used to treat some cancers, and it is said to reduce pulmonary capillary leak
- Infliximab is a monoclonal antibody used to treat diseases of the immune system. It resists broad-spectrum inflammation, and is tolerated well by elderly people.
3. Drugs built for purpose
A number of major drug companies have plunged into the opportunity to develop new purpose-built drugs. The first efforts have been monoclonal antibodies, These are effectively artificial vaccines, in that they directly infuse patients with high levels of artificial antibodies designed to mimic the body's immune system. They may be provided as a cocktail to avoid "mutational escape" - where if a virus version develops immunity to one element of the cocktail, it will not evade the other.
3.1 Bamlanivimab/etesevimab
On 9 November, the FDA issued an EUA to the drug giant Eli Lilly and Co for the use of bamlanivimab for "people with mild to moderate Covid-19 with a high risk of progressing to severe disease". Some 8% to 15% of Covid patients are in this class.
The efficacy of the drug was determined from a randomised double-blind Phase 3 clinical trial of 1175 health workers and residents of facilities, conducted between August to November 2020, which took Covid infection rates as target. The trial found that 8.5% taking the drug became infected with Covid-19 compared with 15.2% taking a placebo. Side effects were very similar in both groups (but with such a small sample, rare side effects would not appear).
Thus bamlanivimab was accepted by FDA before the trial concluded. It was priced at US$1250 per vial - a cost very much higher than any vaccine, with a lower effectiveness, and with no guarantee of benefits for severely ill patients.
On April 16 2021, FDA revoked the EUA for bamlanivimab used alone, stating variants resistant to the drug had now risen. Because there were no testing technologies available to test patients for viral variants prior to start of treatment with monoclonal antibodies, a high failure rate was expected.
3.2 REGEN-COV,
On 21 November, the FDA issued an EUA for a cocktail of two more anti-spike monoclonal anti-bodies to be used by high-risk patients, the combination casirivimab/imdevimab (REGEN-COV or Ronapreve).
The EUA was based on a trial funded by Regeneron Pharmaceuticals, enrolling only 275 patients. In 2017 Regeneron had fortuitously cut a deal with the Biomedical Advanced Research and Development Authority to fund 80% of development costs on new antibody treatments. It was awarded an Operation Warp Speed $450m contract in July 2020 to develop and manufacture its cocktail. The intention was to provide up to a million doses of the drug to the public for free.
When President Trump caught the virus in October 2020, he was given the cocktail through a compassionate use request. Regeneron filed for an EUA that same day.
A retrospective real-world study of 1392 patients at the Mayo Clinic from December showed a significant reduction in all-cause hospitalisation - from 4.8% to 1.6% after 28 days. This "clinical outcomes study was convincing", with many older and high risk patients (an interesting side outcome was that due to improved patient care at Mayo Clinic, hospitalisation of untreated patents had fallen from 11.4% in the first six months of the pandemic to 4.8%, due to improved outpatient care). These results encouraged the Infectious Diseases Society of America and the US National Institutes of Health to endorse the product.
Like the previous cocktail 3.1, ronapreve is also injected and is regarded as having an efficiency against hospitalisation of 70%. In the USA it costs only $9.50 a dose
On 8 October 2021, REGEN-COV was also authorised for post-exposure high-risk patients, noting it was not a substitute for vaccination.
3.3 Sotrovimab
Sotrovimab VIR-7831 from GlaxoSmithKline is a third monoclonal antibody treatment, also supported by interim data from a single trial. It is given by intravenous infusion and costs over $2000 a dose.
The COMET-ICE Phase 3 trial of sotrovimab began in September 2020. It was an outpatients study of 583 mild-to-moderate cases with risk factors for disease progression to serious illness. The report of this study appeared in May 2021 and has yet to be peer-reviewed. The drug was said to reduce hospitalisation by 85% (with a wide confidence limit), and there were no obvious safety concerns. All five patients who proceeded to intensive care received the placebo. There was no consideration of efficacy versus the more infectious later variants, or the possibility of mutational escape - issues which had led bamlanivimab's ETA to be revoked.
The drug was approved immediately for emergency use by the FDA, then surprisingly by the Europe Medicines Agency the TGA in Australia on 20 August. and in Japan on 27 September.
Sotrovimab is the first medicine approved by TGA for its stockpile since remdesvir. The Australian government bought a token 7700 doses ahead of TGA approval, apparently trying to "get ahead of the curve". Sotrovimab has been given to patients-at-risk in Sydney for three weeks, apparently with good results. It is said to be the "first drug for which there is really good evidence that it can actually keep people out of hospital", though the actual evidence is not yet so impressive.
3.4 Response to monoclonal antibodies
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| Repurposed Barnstorm Theatre in Florida |
Monoclonal treatments are like a safety net 10 feet below a steep cliff while the vaccines are like a large fence preventing someone from falling in the first place.
Initially, monoclonal antibodies received little publicity. However, in the last few months the numbers of doses of monoclonal antibodies supplied have turned out to be far short of demand, particularly in areas where vaccine resistance is highest. Seven states in the Deep South have been using most of the national supply. With shortages developing, the Biden government has taken over distribution and ordered 1.4 million doses.
One might have thought that drugs which mimicked vaccines and which required injection or infusion just like vaccines would also have been rejected by anti-vaxx groups. In practice however, many people have been asking for monoclonal antibodies instead of vaccine.
3.5 New-generation antivirals
In January, the drug major Merck announced it would discontinue vaccine development in favour of several promising therapeutic candidates. On 1 October 2021, Merck announced that its new tablet molnupiravir (MK4482) was the first orally administered substance for patients at risk of progression to severe disease. It is an antiviral designed to introduce errors into the genetic code of the disease.
A randomised trial of 775 patients showed that 7.3% of those given molnupiravir were hospitalised after 28 days compared with 14.1% of placebo patients. Only placebo patients died. The trial was apparently so successful that Merck stopped it early, and is seeking to fast-track approval without publication of results. If it meets Merck's claims, the drug could halve hospitalisations.
Pfizer and Roche are seeking to develop similar products.
5. Conclusions
5.1 The failure to coordinate trials
5.2 The attraction of unproven methods in a time of social emergency
Any pandemic involves an element of existential dread, and the public and political leaders are prone to grasping at any solution. The typical “quack medicine” response to the unknown has been enormously magnified today by the presence of social media, so that websites that promise cures or present conspiracy theories have millions of viewers.
A major consideration that has been underlined by the pandemic is that a significant proportion of the population are not interested in formal medicine or are actually hostile to it. These people rarely see doctors, prefer naturopaths, pharmacists or lay community members to recommend treatments, believe in prevention rather than cure, and prefer to use 'holistic remedies' to self-medicate. They form a core of limited compliance with formal medicine, around whom particular-issue campaigners such as anti-vaxxers may congregate and find fertile ground.
A peculiar outcome of the authorities’ single minded drive for vaccination has been that it has welded together all kinds of libertarian and anti-vaccination groups: from the Right (seeking individual freedom from government), from the far Left (who believe that government and possibly the medical fraternity are in league with "Big Pharma") and from New Agers and "wellness influencers" seeking holistic cures.
Underlying it all has been a general feeling among the public that they are being “dudded”: in the initial stages of the pandemic, by an obvious lack of any effective medical response; and later, by contradictory pronouncements from the authorities. Anxiety about COVID-19 makes people more willing to "try anything" that might give them a sense of control of the situation, making them easy targets for scammers, conspiracy theorists, anti-vaxxers and libertarians.
Many claims that existing products help against COVID-19 have been spread through rumours online rather than by medical recommendation or conventional advertising. One of the peculiarities of the “social media” age is that it turns out a number of people take more notice of information passed to them by “people they know” than they do to “official” statements or scientific studies, which they may believe to be fabricated. This has been exaggerated by the wide variety of information coming from all sides, so that many people are unable to judge what may be correct and may grasp at straws or “alternative solutions”. The loss of respect for "the expert" that has emerged since the 1970s has been exaggerated in the information age, where many outspoken individuals think they can become their own expert.
From the government side, there has been such a diversity of public opinion that it has been difficult to maintain a consistent message that will please the majority, and there have been frequent reversals of message. Snipers such as President Trump in the USA, President Bolsonaro in Brazil, and dissident doctors have undermined the mainstream message with sometimes outlandish claims.
The presence of a very public resistance when almost complete co-operation with vaccination is required to have any real effect has caused authorities to clamp down hard on material promoting alternatives, even when these are harmless – further wedging a divide between the compliant and the non-compliant.
5.3 The approved drugs
- four or five vaccines for prophylaxis;
- three monoclonal antibody preparations for high-risk people who have been exposed or diagnosed, but do not yet require oxygen (plus one promising "morning-after pill");
- remdesivir/.baracitinib antiviral/anti-inflammatory for the hospitalised - but results are disputed;
- steroids for severely and critically ill patients.
5.4 The opportunities for further research
The pandemic is an unrivalled opportunity to conduct broad-based
antiviral research. It would be a truly missed opportunity if some of the
hundreds of billions of dollars outlaid so far on Covid prevention were not
directed to developing new treatment methods.
About all that can be agreed from the many trials conducted in difficult conditions is that it will take a very long time to work out which drugs might be effective in relieving or preventing Covid-19, and there are rarely any shortcuts.
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| Anti-mandate protesters Melbourne |
DISCLOSURE: The author and his family are fully vaccinated, have not considered any alternative treatments and strongly advise against self-medication.
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