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What are the most promising treatments for Covid-19?

Which drugs have shown the most promising results against the new coronavirus, and which are being tried in Italy? Susan Levenstein, an American doctor in Rome, reviews the latest scientific evidence.

Published: 6 April 2020 16:27 CEST
Updated: 14 April 2020 09:02 CEST

What are the most promising treatments for Covid-19?

Medical staff handle samples at a microbiology laboratory in Varese, northern Italy. Photo: Miguel Medina/AFP

Scientists across the globe are scrambling to find a pharmacological fix for Covid-19. There’s been so much confusion, and so much ballyhooing of false leads, that I decided to take a careful look at the candidate medications, with help from authoritative and up-to-date sources.

Here’s what I’ve found.

The drugs that are mostly hype:

Chloroquine

Some American doctors are hoarding this ancient antimalarial and its cousin, hydroxychloroquine (Plaquenil), for themselves and their families. Hydroxychloroquine is now in such short supply that patients who really need it, for autoimmune diseases such as lupus and Sjögren’s syndrome, can’t fill their prescriptions, in Italy – where many are convincing their pharmacists to give them a supply without a prescription “just in case” – as well as in the USA. A few poor fools are killing themselves by self-dosing with fish bowl cleaner made from chloroquine phosphate.

They’re all convinced we have found the magic bullet. How come?

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First of all, there’s US President Donald Trump swearing “It’s going to be great,” while the director of the National Institute of Allergy and Infectious Diseases tries to hold him back.

Second, the drug does inhibit the novel coronavirus in test tubes.

Third, hydroxychloroquine is already approved for use in other diseases, so it can be prescribed off-label immediately by any doctor for any disease.

Believe it or not, that’s just about all there is on the positive side. In research on actual Covid-19 patients the results for hydroxychloroquine have been pretty much a wash.

Studies in China were rumoured to have found it effective, but for a long time the original research reports weren’t available. When Western physicians finally managed to see them a week ago, the drug turned out to have done no better than a placebo.

The most-cited Western study of hydroxychloroquine, in France, made a splash by claiming that 20 patients treated with hydroxychloroquine cleared the coronavirus in their noses faster than 16 patients who received standard treatment alone.

There are serious problems with this study, though, even beyond the tiny number of patients. The French researchers, it turns out, had started out giving hydroxychloroquine not to 20 patients but to 26, and the patients who received the drug actually did worse than those receiving standard treatment: three of them needed to be transferred to the intensive care unit and a fourth died. (Two others dropped out voluntarily.) No control patient had these outcomes.

In Italy the health authorities have authorized physicians to try these drugs in Covid-19 patients, while warning that they are unproven and potentially toxic; about half of hospitalized patients in Italy have been receiving one or the other.

One expert has commented: “Researchers have tried this drug on virus after virus, and it never works out in humans.”

Existing antiviral drugs

Lopinavir plus ritonavir (Kaletra): This two-drug combination used in HIV patients performed dismally among Chinese patients with mild-to-moderate disease, but some Italian centres are prescribing it nonetheless.
Umifenovir: Used in Russia for the flu, it was tried in China for Covid-19 but similarly flopped.
Oseltamivir (Tamiflu): This widely-used influenza drug has been tried in China and is undergoing some “Why not?” clinical trials, but there is no reason to expect it to be effective.
Baloxavir: A brand-new anti-influenza drug set to begin clinical trials in China soon, but with little hope.
Niclosamide (Yomesan): A deworming medicine that was found long ago to have some effect against the SARS virus in test tubes but never went on to clinical trials.

Corticosteroids (dexamethasone, methylprednisolone…)

Steroids have been used for years as a kind of hail-Mary pass in patients with uncontrollable bacterial infection (septic shock), so it is reasonable to try them in end-stage Covid-19.

One Chinese study of methylprednisolone suggested a positive effect in desperately ill patients, and a similar study is underway in Italy.

The international expert consensus, however, is that corticosteroids are more likely to do harm than good.

Azithromycin (Zitromax)

This anti-bacterial (not antiviral) antibiotic is sometimes used to counter bacterial superinfection in serious viral illness, and has been given to some Covid-19 patients in combination with hydroxychloroquine.

It is known to be safe, but there is no evidence it has any benefit, and some suggestion it may do harm.

Other medications

A panoply of drugs already in use for other diseases are currently under study in Covid-19 patients on theoretical grounds, with no evidence and little hope of a clinical effect: nitric oxide (an inhaled agent used for acute respiratory distress syndrome), vitamin C, sirolimus (another kind of immunosuppressant), and losartan (an anti-hypertensive drug that many experts fear may make Covid-19 worse instead of better).

The most promising treatments so far:

Remdesivir

This investigational antiviral, effective against a variety of coronavirus diseases, is considered by many experts to be the most promising antiviral for Covid-19 and is already undergoing numerous trials.

It has been used in northern Italian hospitals for weeks, when they can obtain it, and five Italian centres are currently participating in clinical trials.

Favipiravir (Avigan)

This Japanese antiviral was originally reported to reduce recovery time and improved chest X-ray abnormalities in two trials in Wuhan and Shenzhen involving a total of 340 patients.

But that report has now been abruptly and mysteriously withdrawn by the researchers. I’m not sure what will happen to the therapeutic trials that had been started in Italy and elsewhere.

Convalescent serum

Most people who recover from infections develop antibodies that protect them from reinfection.

Products derived from their blood – either whole blood, or the antibody-rich serum that remains when you remove the red blood cells, or a more refined immunoglobulin product – can be effective drugs. For decades a century ago, before we had antibiotics, they were the mainstay of treatment for infection, and are still potentially invaluable.

Photo: Miguel Medina/AFP

Such products were the only decent drug treatment for Ebola, and there is reason to hope not only that they might keep moderate Covid-19 from deteriorating, but that small daily doses might protect people at very high risk – such as healthcare workers on the front lines – from becoming infected.

The Chinese brought some Covid-19 immune serum to Italy as part of their aid effort, and now Italy is producing its own. Teams in Mantua and Pavia have already reported encouraging results on ten patients.

Researchers have successfully rushed to develop blood tests that will be able to identify people who have antibodies against Covid-19 and therefore could usefully donate blood for this purpose.

Tocilizumab (Actemra)

This “biologic”, most often used for inflammatory diseases such as rheumatoid arthritis, has no direct action against viruses, but might help tamp down an overactive inflammatory response in the lungs of patients with Covid-19 pneumonia.

Preliminary results among 20 Chinese patients suggested improvement over several days, following one or two doses.

Unfortunately this drug can also promote tuberculosis and other serious infections, so it should only be tried in desperate cases.

Large studies are underway, including in Italy, and a similar antibody called sarilumab is also being examined.

Photo: Miguel Medina/AFP

Interferon (Avonex and others)

Interferon alpha, beta or gamma, like tocilizumab, has complex effects on the immune system, and may in addition suppress viral multiplication. Injected forms of interferon are usually prescribed for hepatitis C and multiple sclerosis, have shown promise in non-Covid-19 coronavirus disease, and are undergoing clinical trials in Europe.

Interferon is quite toxic, however, and like tocilizumab risks making patients worse rather than better.

It is hoped that an inhaled formulation of the same drug, code named SNG001, might give similar benefits with fewer side effects. It has been found to improve the recovery of asthma and chronic obstructive pulmonary disease patients with lung infections, and is set to begin testing in the United Kingdom in critically ill Covid-19 patients.

Both antiviral drugs and convalescent serum seem to be more effective early in the course of disease, while the powerful, toxic anti-inflammatory medications such as tocilizumab and inhaled beta-interferon are more appropriately used late in the disease, in severely ill patients on respirators, in the hope of warding off total body shutdown.

The ultimate solution

The real hope for social distancing and even anti-Covid-19 medications is that they will put us into a holding pattern until an effective vaccine can knock out the pandemic.

Groups in a half dozen countries, including Italy, have already developed candidate vaccines, animal studies are encouraging, and a few volunteers have received a first dose.

Most vaccine research has been proceeding in the spirit of international cooperation, starting with the Chinese researchers who rapidly sequenced the virus and shared their results.

But it will probably not be before at least the fall of 2021 that we will have developed a vaccine, proven it effective, and administer it to enough people that herd immunity will protect the uninfected.

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So for now our best bet lies in sheltering at home and other social distancing measures.

Fortunately, there’s double good news on that front. One is that social distancing measures seem to be effective even if they are less than draconian and less than constant.

And the other is that nearly four weeks after an aggressive lockdown began in northern Italy, the daily death rate has almost stopped rising and the number of Covid-19 patients in ICU is actually falling.

Susan Levenstein is an American doctor who has been practicing in Italy for the past 40 years. She is the author of Dottoressa: An American Doctor in Rome (Paul Dry Books, 2019).

A version of this article first appeared on her blog, Stethoscope on Rome. Follow her on Twitter @slevenstein.

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Public vs private: What are your healthcare options in Italy?

Italy is well-known for having one of the best healthcare systems in Europe: skilled physicians, advanced technology, and quality facilities available free of charge to every citizen.

But is that actually the case? In reality, across the country, access to quality healthcare varies widely — and since the 1990s, Italy’s world-famous public system has gradually given ground to a growing number of private providers who offer top-notch services at a top-shelf cost.

That means, when you need health services the most, navigating Italy’s system can be a complicated and potentially costly affair.

Here’s what you need to know about Italy’s public and private systems before a health crisis hits.

Your rights to care

The right to public healthcare is enshrined in Italy’s constitution, which recognizes “health as a fundamental right of the individual and the interest of the community.”

Since 1978, when Italy’s national health service (Servizio Sanitario Nazionale, or SSN) was first established, it has provided free, public health services based on the principles of universality, equality, and fairness.

In practice, this all means that all Italian citizens and most legal Italian residents have a right to access public healthcare free of charge, most of the time.

If you are resident in Italy for reasons of work, family reunification, asylum, or medical care, it is mandatory that you are registered with the public health insurance system. This means applying for your tessera sanitaria or health card after your residency paperwork is complete.

See our guide to who can register for national healthcare, plus more information about applying for (and renewing) your tessera sanitaria here.

If you are resident in Italy for other reasons — for example, to study at a university — you can still opt to enroll, for an annual fee.

Italy also recognizes health insurance provided by any EU country without a tessera sanitaria — you can show your European health card (EHIC). You are required to swap it for an Italian card if you’re in the country for more than six months.

Italy has also made international agreements with a handful of countries to recognize their state insurance as well — these include Australia, Argentina, Brazil, Bosnia-Herzegovina, Serbia, Macedonia, Montenegro, Monaco, and Tunisia. Talk to your local Italian embassy if you’re from one of these countries to get the documentation you need.

The public system

But, in reality, what does your tessera sanitaria get you?

First and foremost, it covers all emergency care. If you need an ambulance ride or a stop by the pronto soccorso (emergency room), this will be provided free of charge.

You will also be assigned a general practice doctor from a list in your region, who will be your first point of contact for any non-emergency care. Many of these doctors are also specialists in a particular field of health, though not all will be comfortable working in English.

In practice, though, these physicians are often massively oversubscribed, counting thousands of patients under their care. Wait times for an appointment can often be lengthy, if you can even get through to their booking line. If you don’t like your doctor, you can only change them once per year, by applying again to your local health authority.

Italy’s healthcare system is said to be among the best in the world, but stark regional imbalances persist. Photo by Miguel MEDINA / AFP

If you require any non-emergency care — blood tests, a specialist exam, or certain prescriptions — you will need to receive a referral from this doctor. This takes the form of a paper ricevuta, a card specifying the services you need with a barcode that will be scanned by the specialist in question.

You won’t have a choice in what specialist you are referred to, and you will likely face a lengthy wait for these services, which are often performed at the local hospital.

Not all of these services will be completely free. Even with a health card, you will be required to make copayments for some specialist visits and exams.

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For example, if your doctor orders full blood work — a procedure that involves more than a dozen different laboratory tests — you may pay as much as €100 in copayments or more, as the public system will only cover up to eight tests at any one time.

You will also need to make nominal copayments on certain prescription drugs. In theory, these fees are subject to certain maximums and should be geared to your household income. Dental care is free for children under 16, but only emergencies are covered for everyone else.

It’s important to know that, because Italy’s health system is managed by regional authorities, access to care varies greatly across the country. A 2015 report by the OECD found “profound regional differences” indicating many in the south of the country were not receiving timely access to preventative medicine.

Today, while many cities in northern Italy are known for their world-beating medical facilities, they are also often plagued by long wait times, partly because southern residents frequently travel north for care.

The private option

These concerns have given rise to an expanding market for private healthcare in Italy, which offers the chance to skip the line — at a cost.

Private providers can offer specialist services without a referral from your general practitioner, and often have much shorter wait times: a week or two, as opposed to several months.

Though they are discouraged from doing so, you may find your general practitioner advising you to seek out private care to avoid a long wait. This is particularly true for services like ultrasounds, for which there is a long delay.

See our complete guide to healthcare options during pregnancy in Italy.

It’s worth noting that these private practices do not necessarily offer better facilities than their public competitors. Some operate out of the same hospital facilities as their public counterparts.

The Policlinico A. Gemelli Hospital in Rome. Italy’s capital is home to several highly-rated hospitals and clinics, but some residents still travel north in search of better or faster treatment. (Photo by Filippo MONTEFORTE / AFP)

Their services can also be very costly. A single appointment can cost anywhere from €60 to €150 or more, and any follow-up exams or prescriptions will not be covered by the public system.

Though most Italians still pay these costs out-of-pocket, there are a number of private health insurance plans that can help spare you the financial headache.

At their most basic, these policies, known as polizze salute, cover emergency care and little else. Policies like these are sometimes a requirement for residency applications, and usually cost just a few hundred euro per year.

If you’re looking to supplement public health care with access to private specialists, however, expect to pay €100 per month or more. For this, you can expect perks like private rooms during hospital stays or cover for home care after discharge.

To apply, you’ll need to undergo a medical checkup and declare any previous conditions. These policies are usually subject to age limits and some common chronic conditions, like diabetes, may be uninsurable.

Unlike American policies, insurers usually require that you pay up front, and will reimburse you only when you provide the proper paperwork. In some regions, where accredited private hospitals provide private care, your company may have a relationship that allows for direct billing.

Ultimately, the decision to go with private care comes down to a cost-benefit analysis: how long are you willing to wait — and how much would you pay to skip the queue?

If you would like to share your own experiences of using Italy’s public or private healthcare services, please leave a comment below or get in touch by email.

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