Treatment

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By Christian Hoffmann

The number of people infected with SARS-CoV-2 is increasing rapidly. Because up to 5-10% can have a severe, potentially life-threatening course, there is an urgent need for effective drugs. No proven effective therapy for this virus currently exists. The time in this pandemic is too short for the development of new, specific agents; a vaccine will also be a long time coming. Thus, existing antivirals or immune modulators with known safety profiles will gain traction as the fastest route to fight COVID-19. Those compounds that have already been tested in other indications now have priority, in particular those that have been shown to be effective in other beta-coronaviruses such as SARS and MERS.

Many current suggestions have emerged from animal models, cell lines or even virtual screening models. While some approaches have at least some evidence for clinical benefit, for others this remains highly speculative. A brief look at ClinicalTrials.gov may illustrate the intensive research efforts that are underway: on April 18, the platform listed 657 studies, with 284 recruiting, among them 121 in Phase III randomized clinical trials (RCTs, assessed on April 19).

Several very different therapeutic approaches are in the treatment pipeline for COVID-19: antiviral compounds that inhibit enzyme systems, those inhibiting the entry of SARS-CoV-2 into the cell and, finally, immunomodulators that are supposed to reduce the cytokine storm and associated pulmonary damage that is seen in severe case. In an interim guidance, the WHO stated on March 13, that “there is no current evidence to recommend any specific anti-COVID-19 treatment” and that use of investigational therapeutics “should be done under ethically approved, randomized, controlled trials” (WHO 2020).

However, performing clinical trials remains challenging during a public health crisis (Rome 2020) and enrolling patients in clinical trials will not be possible everywhere. For these, this chapter may support in decision-making. The following agents will be discussed here:

1. Inhibitors of viral RNA synthesis  
  RdRp Inhibitors Remdesivir, Favipiravir
(and Ribavirin, Sofosbuvir)
  Protease Inhibitors Lopinavir/r (and Darunavir)
2. Antiviral Entry Inhibitors  
  TMPRSS2 Inhibitors Camostat
   Fusion Inhibitors Umifenovir
  Others Hydroxy/chloroquine,
Oseltamivir, Baricitinib
3. Immunomodulators and
other immune therapies
 
  Corticosteroids  
  IL-6 targeting therapies Tocilizumab, Siltuximab
  Passive immunization Convalescent plasma

Inhibitors of the viral RNA synthesis

SARS-CoV-2 is a single-stranded RNA beta-coronavirus. Potential targets are some non-structural proteins such as protease, RNA-dependent RNA polymerase (RdRp) and helicase, but also accessory proteins. Coronaviruses do not use reverse transcriptase. There is only a total of 82% genetic identity between SARS-CoV and SARS-CoV-2. However, the strikingly high genetic homology for one of the key enzymes, the RdRp which reaches around 96% (Morse 2020), suggests that substances effective for SARS may also be effective for COVID-19.

RdRp inhibitors

Remdesivir

Remdesivir (RDV) is a nucleotide analogue and the prodrug of an adenosine C nucleoside which incorporates into nascent viral RNA chains, resulting in premature termination. From WHO, remdesivir has been ranked as the most promising candidate for the treatment of COVID-19. In vitro experiments have shown that remdesivir has a broad anti-CoV activity by inhibiting RdRp in airway epithelial cell cultures, even at submicromolar concentrations (Sheahan 2017). This RdRp inhibition also applies to SARS-CoV-2 (Wang 2020). The substance is very similar to tenofovir alafenamide, another nucleotide analogue used in HIV therapy. Remdesivir was originally developed by Gilead Sciences for the treatment of the Ebola virus but was subsequently abandoned, after disappointing results in a large randomized clinical trial (Mulangu 2019). Experimental data from mouse models showed better prophylactic and therapeutic efficacy in MERS than a combination of lopinavir/ritonavir (see below) and interferon beta. Remdesivir improved lung function and reduced viral load and pulmonary damage (Sheahan 2020). Resistance to remdesivir in SARS was generated in cell cultures, but was difficult to select and seemingly impaired viral fitness and virulence (Agostini 2018). The same is seen with MERS viruses (Cockrell 2016). Animal models suggest that a once-daily infusion of 10 mg/kg remdesivir may be sufficient for treatment; pharmacokinetic data for humans are still lacking. Gilead is currently “in the process” of opening expanded access programs in Europe (refer to gilead.com). In the US, this program is already in place.

Clinical data: Safety has been shown in the Ebola trial. Remdesivir is currently being tested in several randomized phase III RCTs in >1,000 patients with both mild-to-moderate and with severe COVID-19 disease. These studies recruiting patients in China and several European countries are planned to be completed by the end of April 2020. Remdesivir is among four treatment options which are tested in the large WHO SOLIDARITY RCT (see below). In the phase III studies on COVID-19, an initial dose of 200 mg is started on day 1, similar to the Ebola studies, followed by 100 mg for another 9 days.

There are some case reports on critically ill patients, improving rapidly after intravenous treatment with remdesivir (Holshue 2020, Hillaker 2020). On April 10, the New England Journal of Medicine published data on the first 53 patients who were treated with 10 days of remdesivir on a compassionate use basis (Grein 2020). These results gained a lot of media attraction as the authors offered an optimistic view on remdesivir. Although viral data were not available, they concluded with a clinical “improvement in 68%” (36/53) and a “noteworthy” low mortality of 13%, seemingly lower than seen in a RCT on lopinavir/r (Cao 2020). The authors also emphasize repeatedly the severity of disease in their patients, as many required ventilation – more than in the lopinavir/r trial. However, for several reasons we feel that this report is a cautionary tale for rushing science. In the absence of primary end points and viral data, this fragmentary report may arouse false expectations. For more details, see www.CovidReference.com/remdesivir.

Favipiravir

Favipiravir is another broad antiviral RdRp inhibitor that has been approved for influenza A and B in Japan and other countries (Shiraki 2020). Favipiravir is converted into an active form intracellularly and recognized as a substrate by the viral RNA polymerase, acting like a chain terminator and thus inhibiting RNA polymerase activity (Delang 2018). In an in vitro study, this compound showed no strong activity against a clinical isolate of SARS-CoV-2 (Wang 2020). On February 14, however, a press release with promising results was published in Shenzhen (PR Favipiravir 2020). In the absence of scientific data, favipiravir has been granted five-year approval in China under the trade name Favilavir® (in Europe: Avigan®). A loading dose of 2400 mg BID is recommended, following a maintenance dose of 1200-1800 mg QD. Potential drug-drug interactions (DDIs) have to be considered. As the parent drug undergoes metabolism in the liver mainly by aldehyde oxidase (AO), potent AO inhibitors such as cimetidine, amlodipine, or amitriptyline are expected to cause relevant DDIs (review: Du 2020).

Clinical data: Preliminary results (press release) on encouraging results in 340 COVID-19 patients were reported from Wuhan and Shenzhen. With favipiravir, patients showed shorter periods of fever (2.5 versus 4.2 days), faster viral clearance (4 versus 11 days) and improvement in radiological findings (Bryner 2020). A first open-label randomized trial (RCT) was posted on March 26 (Chen 2020). This RCT was conducted in 3 hospitals from China, comparing arbidol and favipiravir in 236 patients with COVID-19 pneumonia. Primary outcome was the 7-day clinical recovery rate (recovery of fever, respiratory rate, oxygen saturation and cough relief). In “ordinary” COVID-19 patients (not critical), recovery rates were 56% with arbidol (n=111) and 71% (n=98) with favipiravir (p=0.02), which was well tolerated, except for some elevated serum uric acid levels. However, it remains unclear whether these striking results are credible. In the whole study population, no difference was evident. Many cases were not confirmed by PCR. There were also imbalances between subgroups of “ordinary” patients.

Other RdRp inhibitors

Some other compounds inhibiting RdRp have been discussed. Ribavirin is a guanosine analogue and RNA synthesis inhibitor that was used for many years for hepatitis C infection and is also thought to inhibit RdRp (Elfiky 2020). In SARS and MERS, ribavirin was mostly combined with lopinavir/ritonavir or interferon; however, a clinical effect has never been shown (Arabi 2017). Ribavirin is now available generically. Its use is limited by considerable side effects, especially anemia. Sofosbuvir is a polymerase inhibitor which is also used as a direct-acting agent in hepatitis C. It is usually very well tolerated. Modelling studies have shown that sofosbuvir could also inhibit RdRp by competing with physiological nucleotides for RdRp active site (Elfiky 2020). Sofosbuvir could be combined with HCV PIs. Among these, the fixed antiviral combinations with ledipasvir or velpatasvir could be particularly attractive as they may inhibit the both RdRp and protrease of SARS-CoV-2 (Chen 2020). Studies are planned but not yet officially registered (assessed April 17).

Protease inhibitors

Lopinavir

Some HIV protease inhibitors (PI) such as lopinavir and darunavir are thought to inhibit the 3-chymotrypsin-like protease of coronaviruses. Both are administered orally. To achieve appropriate plasma levels, these PIs have to be boosted with another HIV PI called ritonavir (usually indicated by “/r”: lopinavir/r and darunavir/r). For lopinavir/r, at least two case-control studies on SARS (Chan 2003, Chu 2004) and one prophylactic study on MERS (Park 2019) have indicated a beneficial effect, but the evidence remains poor. A small substudy indicated that SARS-CoV viral load seems to decrease more quickly with lopinavir than without (Chu 2004). However, all studies were small and non-randomized. It therefore remained unclear, whether all prognostic factors were matched appropriately. As with all HIV PIs, one should be always aware of drug-drug interactions. Ritonavir is a strong pharmacoenhancer. For example, tacrolimus has to be reduced by 10-100 fold to maintain concentration within the therapeutical range. In a case report, a woman with kidney transplantation was treated with lopinavir/r for COVID-19 while receiving full dose tacrolimus. Levels went incredibly high and were still above the therapeutical range 9 days after stopping both lopinavir/r and tacrolimus (Bartiromo 2020).

Clinical data: Lopinavir/r was used in many patients in China at the beginning of the outbreak (Chen 2020). A sharp decline has been seen in individual cases (Lim 2020, Liu 2020, Wang 2020). However, in a small study from Singapore study, lopinavir/r showed no effect on SARS-CoV-2 clearance in nasal swabs (Young 2020). In addition, the first randomized open-lable trial in 199 adults hospitalized with severe COVID-19 did not find any clinical benefit with lopinavir/r treatment beyond standard care (Cao 2020) in patients receiving the drug 10 to 17 days after onset of illness. The percentages of patients with detectable viral RNA at various time points were similar, suggesting no discernible effect on viral shedding. Although PK data is lacking, it seems to be possible that concentrations of protein-unbound lopinavir achieved by current HIV dosing is too low for inhibiting viral replication. It remains to be seen whether levels will be sufficient for (earlier) treatment of mild cases or as post-exposure prophylaxis. There is one retrospective study on 280 cases in which early initiation of lopinavir/r and/or ribavirin showed some benefits (Wu 2020). Lopinavir/r will be tested in WHO’s huge SOLIDARITY trial.

Darunavir

For the other HIV PI, darunavir, there are also press releases on antiviral effects in cell cultures (PR 2020). In HIV infection, darunavir is more effective than lopinavir which led to speculations about an effect in COVID-19. However, the manufacturer Janssen-Cilag published a letter to the European Medical Agency on March 13, pointing out that “based on preliminary, unpublished results from a previously reported in vitro experiment, it is not likely darunavir will have significant activity against SARS-CoV-2 when administered at the approved safe and efficacious dose for the treatment of HIV-1 infection.” In vitro there was no antiviral activity against a clinical isolate at clinically relevant concentrations (EC50 >100 μM).

Clinical data: None. However, we have seen at least 4 HIV-infected patients developing COVID-19 while on darunavir. Nevertheless, a large study (CQ4COV19) with 3,040 participants was started on March 18 in Spain for darunavir and is still ongoing (assessed April 14). Patients with mild symptoms are treated with darunavir/ritonavir and chloroquine immediately after a positive SARS-CoV-2 test.

Other PIs

It is hoped that the recently published pharmacokinetic characterization of crystal structure of the main protease SARS-CoV-2 may lead to the design of optimized protease inhibitors (Zhang 2020). Virtual drug screening to identify new drug leads that target protease which plays a pivotal role in mediating viral replication and transcription, have already identified several compounds. Six compounds inhibited M(pro) with IC50 values ranging from 0.67 to 21.4 muM, among them with disulfiram and carmofur (a pyrimidine analogue used as an antineoplastic agent) two approved drugs (Jin 2020).

Antiviral entry inhibitors

Most coronaviruses attach to cellular receptors by their spike (S) protein. Within a few weeks, several groups have elucidated the entry of SARS-CoV-2 into the target cell (Hoffmann 2020, Zhou 2020). Similar to SARS-CoV, SARS-CoV-2 uses angiotensin-converting enzyme 2 (ACE2) as a key receptor, a surface protein that is found in various organs and on lung AT2 alveolar epithelial cells. The affinity for this ACE-2 receptor appears to be higher with SARS-CoV-2 than with other coronaviruses. The hypothesis that ACE inhibitors promote severe COVID-19 courses through increased expression of the ACE2 receptor remains unproven (see clinical chapter).

Camostat

In addition to binding to the ACE2 receptor, priming or cleavage of the spike protein is also necessary for viral entry, enabling the fusion of viral and cellular membranes. SARS-CoV-2 uses the cellular protease transmembrane protease serine 2 (TMPRSS2). Compounds inhibiting this protease may therefore inhibit viral entry (Kawase 2012). The TMPRSS2 inhibitor camostat, which was approved in Japan for the treatment of chronic pancreatitis (trade name: Foipan®), may block the cellular entry of the SARS-CoV-2 virus (Hoffmann 2020).

Clinical data: pending. Phase II studies are underway (Denmark). Another study (CLOCC trial) is planned for June in Germany, comparing camostat and hydroxychloroquine.

Umifenovir

Umifenovir (Arbidol®) is a broad-spectrum antiviral drug which is approved as a membrane fusion inhibitor in Russia and China for the prophylaxis and treatment of influenza. Chinese guidelines recommend it for COVID-19, according to a Chinese press release it is able to inhibit the replication of SARS-CoV-2 in low concentrations of 10-30 μM (PR 2020).

Clinical data: In a small retrospective and uncontrolled study in mild to moderate COVID-19 cases, 16 patients who were treated with oral umifenovir 200 mg TID and lopinavir/r were compared with 17 patients who had received lopinavir/r as monotherapy for 5–21 days (Deng 2020). At day 7 (day 14), in the combination group, SARS-CoV-2 nasopharyngeal specimens became negative in 75% (94%), compared to 35% (53%) with lopinavir/r monotherapy. Chest CT scans were improving for 69% versus 29%, respectively. Similar results were seen in another retrospective analysis (Zhu 2020). However, a clear explanation for this remarkable benefit was not provided. There is a preliminary report of a randomized study indicating a weaker effect of umifenovir compared to favipiravir (Chen 2020).

Hydroxychloroquine (HCQ) and Chloroquine (CQ)

Chloroquine is used for prevention and treatment of malaria and is effective (but not approved) as an anti-inflammatory agent for rheumatoid arthritis and lupus erythematosus. The potential broadly antiviral effect is due to an increase in the endosomal pH value, which disrupts the virus-cell fusion. The glycosylation of cellular receptors of SARS-CoV is also disturbed (Savarino 2003, Vincent 2005, Yan 2013). In SARS-CoV-2 infection, chloroquine may possibly also inhibit post-entry steps (Wang 2020). In addition to the antiviral effect, anti-inflammatory effects could also be beneficial in COVID-19 pneumonia. A Chinese consensus paper dated March 12 recommended chloroquine for patients with both mild and severe pneumonia (EC 2020). Hydroxychloroquine may be more effective than chloroquine (Yao 2020); it is approved for malaria and certain autoimmune diseases and is also better tolerated. According to in vitro data, hydrochloroquine is recommended in a loading dose of 400 mg twice daily, followed by maintenance therapy of 200 mg twice daily (Yao 2020).

An early mini-review stated that “results from more than 100 patients” showed that chloroquine phosphate would be able to alleviate and shorten the course of the disease (Gao 2020). Other experts have raised considerable doubts (Touret 2020). A benefit of chloroquine would be the first positive signal, after decades and hundreds of unsuccessfully studies conducted in a huge number of acute viral diseases. There are also experts arguing that CQ/HCQ could not only be useless but even harmful, as it was seen for Chikungunya virus infection which may be explained by a delay in immune adaptive response (Guastalegname 2020). In cell and animal studies, the effects on other viruses such as avian influenza, Epstein-Barr, or Zika have been variable (Ferner 2020). Precautions for HCQ also include QTc >500 msec and several diseases such as myasthenia gravis, epilepsy etc. Wide use of these drugs will expose patients to rare but potentially fatal harms, including serious cutaneous adverse reactions, fulminant hepatic failure, and ventricular arrhythmias (especially when prescribed with azithromycin).

Clinical data: On March 17, a preliminary report from Marseille, France (Gautret 2020) appeared to show some benefit in a small non-randomized trial on 36 patients. Patients who refused treatment or had an exclusion criteria, served as controls. At day 6, 70% were virologically cured (100% when azithromycin was added) as assessed by nasopharyngeal swabs, compared to 13% in the control group. After reviewing these data, several methodological issues have raised doubts on validity of the data. It became evident that essential standards of data generation and interpretation were seen to be lacking (Kim 2020). However, someone’s swanky tweet claiming that the combination of HCQ and azithromycin has “a real chance to be one of the biggest game changers in the history of medicine” (March 21), has attracted world-wide attention. On March 31, a careful review of the risks of HCQ was published, showing how pretentious dissemination of overpromised data may cause severe harm (Yazdany 2020). A small randomized trial from China on 30 patients failed to show any clinical or virological benefit (Chen 2020). However, hydroxychloroquine is currently tested in several trials, including WHO’s SOLIDARITY trial. Optimal dosing still remains unclear. Ongoing clinical trials use different dosing regimens. In a PK study on 13 critically ill patients with COVID-19, a dosing regimen of 200 mg three times daily dosing was inappropriate to reach a supposed target blood level of 1-2 mg/L. Authors proposed 800 mg once daily on day 1, followed by 200 mg twice daily for 7 days (Perinel 2020). However, further PK studies are needed.

Others

Baricitinib (Olumiant®) is a Janus-associated kinase (JAK) inhibitor approved for rheumatoid arthritis. Using virtual screening algorithms, baricitinib was identified as a substance that could inhibit ACE2-mediated endocytosis (Stebbing 2020). Like other JAK inhibitors such as fedratinib or ruxolitinib, signaling inhibition may also reduce the effects of the increased cytokine levels that are frequently seen in patients with COVID-19. There is some evidence that baricitinib could be the optimal agent in this group (Richardson 2020). Other experts have argued that the drug would be not an ideal option due the fact that baricitinib causes lymphocytopenia, neutropenia and viral reactivation (Praveen 2020). However, several studies are underway in Italy and the US.

Oseltamivir (Tamiflu®) is a neuraminidase inhibitor that is also approved for the treatment and prophylaxis of influenza in many countries. Like lopinavir, oseltamivir has been widely used for the current outbreak in China (Guan 2020). Initiation may be crucial immediately after the onset of symptoms. Oseltamivir is best indicated for accompanying influenza coinfection, which has been seen as quite common in MERS patients at around 30% (Bleibtreu 2018). There is no valid data for COVID-19. It is more than questionable whether there is a direct effect in influenza-negative patients with COVID-19 pneumonia. SARS-CoV-2 does not require neuramidases to enter target cells.

Immunomodulators and other immune therapies

While antiviral drugs are most likely to prevent mild COVID-19 cases from becoming severe, adjuvant strategies will be particularly necessary in severe cases. Coronavirus infections may induce excessive and aberrant, ultimately ineffective host immune responses that are associated with severe lung damage (Channappanavar 2017). Similar to SARS and MERS, some patients with COVID-19 develop acute respiratory distress syndrome (ARDS), often associated with a cytokine storm (Mehta 2020). This is characterized by increased plasma concentrations of various interleukins, chemokines and inflammatory proteins.

Various host-specific therapies aim to limit the immense damage caused by the dysregulation of pro-inflammatory cytokine and chemokine reactions (Zumla 2020). Immunosuppressants, interleukin-1 blocking agents such as anakinra or JAK-2 inhibitors are also an option (Mehta 2020). These therapies may potentially act synergistically when combined with antivirals. Several marketed drugs are discussed, including those for lowering cholesterol, for diabetes, arthritis, epilepsy and cancer, but also antibiotics. They are said to modulate autophagy, promote other immune effector mechanisms and the production of antimicrobial peptides. However, clinical data is pending for most strategies.

Corticosteroids

Corticosteroids are often used, especially in severe cases. In the largest uncontrolled cohort study to date of 1,099 patients with COVID-19, a total of 19% were treated with corticosteroids, in severe cases almost half of all patients (Guan 2020). However, according to current WHO guidelines, steroids are not recommended outside clinical trials.

A systematic review of several observational SARS studies (Stockman 2006) yielded no benefit and various side effects (avascular necrosis, psychosis, diabetes). However, the use of corticosteroids COVID-19 is still very controversial (Russell 2020, Shang 2020). In a retrospective study of 401 patients with SARS, it was found that low doses reduce mortality and are able to shorten the length of hospital stay for critically ill patients, without causing secondary infection and/or other complications (Chen 2006).

In another retrospective study involving a total of 201 COVID-19 patients, methylprednisolone reduced mortality in patients with ARDS (Wu 2020). On the other hand, there is strong evidence of a delayed viral clearance (Ling 2020), which has also been observed with SARS (Stockman 2006). In a consensus statement by the Chinese Thoracic Society on February 8, corticosteroids should only be used with caution, after careful consideration, at low doses (≤ 0.5–1 mg/kg methylprednisolone or equivalent per day) and, last but not least, as short as possible (≤ 7 Days) (Zhao 2020).

Tocilizumab

Tocilizumab is a monoclonal antibody that targets the interleukin-6 receptor. Tocilizumab (RoActemra® or Actemra®) is used for rheumatic arthritis and has a good safety profile. There is no doubt that tocilizumab should be reserved for patients with severe disease who have failed other therapies. However, some case reports have suggested that IL-6-blocking treatment given for chronic autoimmune diseases may even prevent the development of severe COVID-19 (Mihai 2020).

Clinical data: Some case reports exist. Three patients showed rapid relief of respiratory symptoms, resolution of fever and reduction in CRP following tocilizumab administration (Di Giambenedetto 2020). One uncontrolled, retrospective study has been published (not yet peer reviewed), showing encouraging results in 91% of 21 patients with severe COVID-19 and elevated IL-6 levels, as measured by improved respiratory function, rapid defervescence and successful discharge (Xu 2020). The initial dose should be 4-8 mg/kg, with the recommended dosage being 400 mg (infusion over more than 1 hour). Controlled trials are underway as well as for sarilumab (Kevzara®), another IL-6 receptor antagonist.

Siltuximab

Siltuximab (Sylvant®) is another anti-IL-6-blocking agent. However, this chimeric monoclonal antibody targets interleukin-6 directly and not the receptor. Siltuximab has been approved for idiopathic multicentric Castleman’s disease (iMCD). In these patients it is well tolerated.

Clinical data: First results of a pilot trial in Italy (“SISCO trial”) have shown encouraging results. According to interim interim data, presented on April 2 from the first 21 patients treated with siltuximab and followed for up to seven days, one-third (33%) of patients experienced a clinical improvement with a reduced need for oxygen support and 43% of patients saw their condition stabilise, indicated by no clinically relevant changes (McKee 2020).

Passive immunization (antibodies)

A meta-analysis of observational studies on passive immunotherapy for SARS and severe influenza indicates a decrease in mortality, but the studies were commonly of low or very low quality and lacked control groups (Mair-Jenkins 2015). In MERS, fresh frozen convalescent plasma or immunoglobulin from recovered patients have been discussed (Zumla 2015, Arabi 2017). Recovered SARS patients develop a neutralizing antibody response against the viral spike protein (Liu 2006). Preliminary data indicate that this response also extends to SARS-CoV-2 (Hoffmann 2020), but the effect on SARS-CoV-2 was somewhat weaker. Others have argued that human convalescent serum could be an option for prevention and treatment of COVID-19 disease to be rapidly available when there are sufficient numbers of people who have recovered and can donate immunoglobulin-containing serum (Casadevall 2020). Recently, an overview on current evidence of benefit, regulatory considerations, logistical work flow (recruitment of donors etc) and proposed clinical trials has been published (Bloch 2020). Passive immune therapy appears to be safe. However, an unintended consequence of receiving convalescent plasma or globulins may be that recipients won’t develop their own immunity, putting them at risk for reinfection.

Clinical data: In a preliminary uncontrolled case series of 5 critically ill patients with COVID-19 and ARDS, administration of convalescent plasma containing neutralizing antibody was followed by improvement in their clinical status (Shen 2020). All 5 patients were receiving mechanical ventilation at the time of treatment and all had received antiviral agents and methylprednisolone. In another pilot study, a single dose (200 mL) of convalescent plasma was given to 10 patients (9 treated with umifenovir, 6 with methylprednisolone, 1 with remdesivir). In all 7 patients with viremia, serum SARS-CoV-2 RNA decreased to an undetectable level within 2-6 days (Duan 2020). Meanwhile, clinical symptoms and paraclinical criteria rapidly improved – within three days. On March 26, the FDA has approved the use of plasma from recovered patients to treat people who are critically ill with COVID-19 (Tanne 2020). It’s now time for larger studies.

 

Others

Interferons: In patients with MERS, interferon studies were disappointing. Despite impressive antiviral effects in cell cultures (Falzarano 2013), no convincing benefit was shown in clinical studies in combination with ribavirin (Omrani 2014, Shalhoub 2015, Arabi 2019). Nevertheless, inhalation of interferon is still recommended as an option in Chinese treatment guidelines.

Other immunomodulatory and other approaches in clinical testing include bevacizumab, brilacidin, cyclosporin, fedratinib (Wu 2020), fingolimod, lenadilomide and thalidomide, sildenafil, teicoplanin (Baron 2020), monoclonal antibodies (Shanmugaraj 2020) and many more. Cellular therapy approaches are also being discussed. However, there is no doubt that these strategies are still far away from broad clinical use.

Outlook

It is hoped that local health systems can withstand the current outbreak and that at least some of the options given in this overview will show positive results over time. It is also important that in this difficult situation, despite the immense pressure, the basic principles of drug development and research including repurposing are not abandoned.

Four different options, namely lopinavir/r, alone and in combination with interferon, remdesivir and (hydroxy) chloroquine will be tested in the SOLIDARITY study launched on March 18 by the WHO. Results of this large-scale, pragmatic trial will generate the robust data we need, to show which treatments are the most effective (Sayburn 2020).

So in the present dark times, which are the best options to offer patients? There is currently no evidence from controlled clinical trials to recommend a specific treatment for SARS-CoV-2 coronavirus infection. A task force of diverse groups of Belgian clinicians has developed “Interim Guidelines for patients suspected of/confirmed with COVID-19 in Belgium” that were published on March 24. They also refer to other Interim Guidelines, as shown in Table 1.

 

Table 1. Preliminary guidelines for COVID-19 in different countries, according to disease severity (https://epidemio.wiv-isp.be)
Disease severity Italy (Lombardia protocol) France Netherlands Belgium
Mild to moderate, no risk factors No No No No
Mild to moderate, risk factors LPV/r + (H)CQ for 5-7 days Consider LPV/r, duration depending on viral shedding Consider CQ for 5 days Consider HCQ 400 BID, then 200 mg BID for 4 days
Severe RDV + (H)CQ for 5-20 days RDV, duration depending on viral shedding CQ (600 mg, then 300 mg) for 5 days HCQ 400 BID, then 200 mg BID for 4 days
Severe,
2nd Choice
LPV/r with CQ No LPV/r for 10-14 days LPV/r for 14 days
Critical RDV + (H)CQ for 5-20 days RDV, duration depending on viral shedding RDV for 10 days + CQ for 5 days RDV
Critical,
2nd Choice
LPV/r with CQ LPV/r   HCQ (TOC within RCTs)

RDV Remdesivir, LPV/r Lopinavir/ritonavir, (H)CQ (Hydroxy) Chloroquine, TOC Tocilizumab. Risk factors: age > 65 years and/or underlying end organ dysfunction (lung, heart, liver), diabetes, CVD, COPD, hypertension

 

We predict that within months, we will shake our heads in disbelief at these recommendations but this is no reason to remain inactive today. The task of medicine is to offer the best known treatment at a given moment. At present, the best treatment is supportive care for respiratory failure and hope that some of the above mentioned drugs have a marginal benefit. Even a marginal benefit might help patients to surpass in extremis the divide between life and death.

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