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). On May 31, these numbers have increased to 1844, 926 and 126.

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”. Of note, this has not changed during recent weeks. There is no agent that shows a decreased mortality.

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
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
  Immune modulation

Passive immunization

Interferon, Anakinra

Convalescent plasma, monoclonal antibodies

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 was shown in the Ebola trial. Remdesivir is currently being tested in several RCTs in > 1,000 patients with both mild-to-moderate and with severe COVID-19 disease. Remdesivir is also among four treatment options being 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 4-9 days. The key trials are listed here:

  • Compassionate Use Program: this was a fragmentary case series (Grein 2020) on some patients (only 53/61 patients were analyzed) with various disease severity. Some improved, some didn’t: random noise. We believe, for a number of reasons, that this case series published in the New England Journal of Medicine is a cautionary tale for “science in a hurry”, arousing false expectations. It might have been preferable to postpone the publication.
  • NCT04257656: This multicentre trial was conducted between Feb 6 and March 12 at ten hospitals in Hubei (Wang 2020). A total of 237 patients with pneumonia, oxygen saturation of 94% or lower on room air and within 12 days of symptom onset were randomized to receive 10 days of single infusions or placebo. Clinical improvement was defined as the number of days to the point of a decline of two levels on a six-point clinical scale (from 1 = discharged to 6 = death) or discharged alive from hospital, whichever came first. Patients were 65 years old (IQR 56–71), more male (56%) and many were co-treated with lopinavir (28%) and corticosteroids. The trial did not attain the predetermined sample size because the outbreak was brought under control in China. However, remdesivir was not associated with a difference in time to clinical improvement (hazard ratio 1.23, 95% CI 0.87–1.75). Clinical improvement rates were 27% versus 23% at day 14 and 65% versus 58% at day 28. Day 28 mortality was 14% versus 13%. Of note, the viral load decreased similarly in both groups. Some patients with remdesivir had dosing prematurely stopped due to adverse events (12% versus 5%, mainly gastrointestinal symptoms and increases of liver enzymes). The positive message from this trial is that time to recovery was “numerically” shorter in the remdesivir group than the control group, particularly in those treated within 10 days of symptom onset.
  • SIMPLE 1: in this randomized, open-label, Phase III trial in 397 hospitalized patients with severe COVID-19 and not requiring IMV, clinical improvement at day 14 was 64% with 5 days remdesivir and 54% with 10 days (Goldman 2020). After adjustment for (significant) baseline imbalances in disease severity, outcomes were similar. The most common adverse events were nausea (9%), worsening respiratory failure (8%), elevated ALT level (7%), and constipation (7%). Because the trial lacked a placebo control, it was not a test of efficacy for remdesivir. An expansion phase will enroll an additional 5,600 (!) patients around the world.
  • ACTT (Adaptive COVID-19 Treatment Trial): The conclusion of this double-blinded Phase III study that randomized 1,063 COVID-19 patients throughout the world to the drug or to placebo, was remarkably short: “Remdesivir was superior to placebo in shortening the time to recovery in adults hospitalized with Covid-19 and evidence of lower respiratory tract infection” (Beigel 2020). Median recovery time was 11 versus 15 days. The benefit was most apparent in patients with a baseline ordinal score of 5 (requiring oxygen but not high-flow oxygen). In patients requiring mechanical ventilation or ECMO, there was no effect at all (although the numbers were low). Gender, ethnicity, age or symptom duration had no impact. The Kaplan-Meier estimates of mortality by 14 days were 7.1% and somewhat (not significantly) lower with remdesivir compared to 11.9% with placebo (hazard ratio for death, 0.70; 95% CI, 0.47 to 1.04). These results are preliminary. The full analysis of the entire trial population is expected to be published soon.

What comes next? Several additional trials are ongoing. Some have been suspended such as NCT04252664, a trial in adults with mild and moderate COVID-19, as during the last few weeks no eligible patients could be recruited. The second SIMPLE trial, NCT04292730 (GS-US-540-5774) is probably the most interesting study, evaluating the efficacy of two remdesivir regimens compared to standard of care in 600 patients with moderate COVID-19, with respect to clinical status assessed by a 7-point ordinal scale on day 11. Estimated study completion date is May 2020. INSERM in France has initiated a study evaluating remdesivir and other potential treatments, using a master protocol (SOLIDARITY) developed by WHO. This study (NCT04315948) is a multi-centre, adaptive, randomized, open clinical trial of the safety and efficacy of treatments of COVID-19 in hospitalized adults. Adults hospitalized for severe COVID-19 will be randomized to one of 4 treatment arms, including standard of care, remdesivir, lopinavir/r plus interferon ß-1a and hydroxychloroquine.

In the meantime, EMA’s human medicines committee (CHMP) has started a ‘rolling review’ of data. This speeds up the assessment of a promising investigational medicine during a public health emergency but does not imply that its benefits outweigh its risks. The EUA allows for the distribution and emergency use of remdesivir only for the treatment of COVID-19; remdesivir remains an investigational drug and has not been approved by FDA. The fact sheet for health care providers is found here: FDA 2020.

Favipiravir

Favipiravir is another broad antiviral RdRp inhibitor that has been approved for influenza in Japan (but was never brought to the market) 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). 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). ncluding foetal abnormalities in pregnant women

Clinical data: Uncontrolled data (Cai 2020) and 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. On May 26, the Japanse government postponed approving, after an interim analysis covering 40 patients by a third-party organization stated that it was “too soon to evaluate effectiveness”.

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 May 31).

Protease inhibitors

Lopinavir

This HIV protease inhibitor (PI) is thought to inhibit the 3-chymotrypsin-like protease of coronaviruses. Lopinavir/r is administered orally. To achieve appropriate plasma levels, it has to be boosted with another HIV PI called ritonavir (usually indicated by “/r”: 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).

From the beginning of the pandemic, lopinavir/r has been widely used in clinical practice, despite the lack of any evidence (Chen 2020). For example, of all patients in the remdesivir trial NCT04257656, 18% were on lopinavir/r at baseline (Wang 2020). Clinical data: In an early retrospective study on 280 cases, early initiation of lopinavir/r and/or ribavirin showed some benefits (Wu 2020). However, in a small study from Singapore study, lopinavir/r did not affect SARS-CoV-2 clearance in nasal swabs (Young 2020). There are two randomized clinical trials (RCT) published to date:

  • The first open-lable RCT in 199 adults hospitalized with severe COVID-19 did not find any clinical benefit with lopinavir/r treatment beyond standard care in patients receiving the drug 10 to 17 days after onset of illness (Cao 2020). The percentages of patients with detectable viral RNA at various time points were similar, suggesting no discernible effect on viral shedding.
  • A Phase 2, multicentre, open-label RCT from Hong Kong randomized 127 patients with mild-to-moderate COVID-19 (median 5 days from symptom onset) to receive lopinavir/r only or a triple combination consisting lopinavir/r, ribavirin and interferon (Hung 2020). The results indicate that the triple combination can be beneficial when started early (see below, interferon). As there was no lopinavir/r-free control group, this trial does not prove lopinavir/r efficacy.

At least two studies suggested that lopinavir pharmacokinetics in COVID-19 patients may differ from those seen in HIV-infected patients. In both studies, very high concentrations were observed, exceeding those in HIV-infected patients by 2-3 fold (Schoergenhofer 2020, Gregoire 2020). However, concentrations of protein-unbound lopinavir achieved by current HIV dosing is probably still too low for inhibiting SARS-CoV-2 replication. The EC50 for HIV is much lower than for SARS-CoV-2. It remains to be seen whether these levels will be sufficient for (earlier) treatment of mild cases or as post-exposure prophylaxis. More than 30 clinical trials are ongoing. Lopinavir/r will be tested in WHO’s huge SOLIDARITY trial.

Other PIs

For another HIV PI, 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.” There is no evidence from both cell experiments or clinical observations that the drug has any prophylactic effect (De Meyer 2020, Härter 2020).

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. At least five trials are ongoing. A Phase III study in the UK (named SPIKE1) in patients who exhibit symptoms but do not require hospitalization was announced at the end of May. Another Phase II study is underway in Denmark. A German study (CLOCC trial) which has been planned to start in June, comparing camostat and hydroxychloroquine, will have to deal with the disappointing results of HCQ (see below).

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. Another retrospective study on 45 patients from a non-intensive care unit in Jinyintan, China failed to show any clinical benefit (Lian 2020). 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. Hydroxychloroquine is approved for malaria and certain autoimmune diseases and is also better tolerated. Some lab experiments had suggested that HCQ and CQ might have some antiviral effects against SARS-CoV-2, due to an increase in the endosomal pH value, which disrupts the virus-cell fusion and some post-entry steps (Wang 2020, Yao 2020). An early enthusiastic mini-review stated that “results from more than 100 patients” showed that chloroquine phosphate would be able to alleviate the course of the disease (Gao 2020). Other experts, however, raised doubts (Touret 2020). A benefit of chloroquine would be the first positive signal, after decades of unsuccessfully studies conducted in a huge number of acute viral diseases. On March 17, a preliminary report from Marseille, France appeared to show some benefit in a small non-randomized study on 36 patients (Gautret 2020). Although this work lacked essential standards of data generation and interpretation (Kim 2020), someone’s swanky tweet on March 21 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”, attracted world-wide attention and led to ten thousands of uncontrolled treatments. Moreover, many patients turned away from clinical trials of other therapies that would require them to give up chloroquine treatments. This has already prompted serious delays in trial enrolment, muddled efforts to interpret data and endangered clinical research (Ledford 2020). Some countries stockpiled CQ and HCQ, resulting in a shortage of these medications for those that need them for approved clinical indications. Only a few weeks later, we are now facing an overwhelming amount of data strongly arguing against any use of both HCQ and CQ.

Clinical data: There are no large RCT, comparing HCQ or CQ with placebo as treatment. However, growing data indicates that there is only low efficacy. If there is any. Some key studies arguing against HCQ during recent weeks

  • In an observational study from New York City (Geleris 2020) of 1,376 consecutive hospitalized patients, 811 received HCQ (60% received also azithromycin). After adjusting for several confounders (HCQ patients were more severely ill at baseline), there was no significant association between HCQ use and intubation or death.
  • Another retrospective cohort of 1,438 patients from 25 hospitals in the New York metropolitan region looked at 1,438 patients (Rosenberg 2020). In adjusted Cox models, compared with patients receiving neither drug, there were no significant differences in mortality for patients receiving HCQ + azithromycin, HCQ alone, or azithromycin alone. Cardiac arrest was significantly more likely seen with HCQ + azithromycin (adjusted OR 2.13).
  • A randomized, Phase IIb clinical trial in Brazil allocated severe COVID-19 patients to receive high-dosage CQ (600 mg BID for 10 days) or low-dosage CQ (450 mg BID on day 1, QD for 4 days). The DSMB terminated the trial after 81/440 individuals had been enrolled (Borba 2020). By day 13 of enrolment, 6/40 patients (15%) in the low-dose group had died, compared with 16/41 (39%) in the high-dose group. Viral RNA was detected in 78% and 76%, respectively.
  • In a retrospective study of 251 patients receiving HCQ plus azithromycin, extreme new QTc prolongation to > 500 ms, a known marker of high risk for torsade de pointes, had developed in 23% (Chorin 2020).
  • In 150 patients with mainly persistent mild to moderate COVID-19, the probability of negative PCR conversion by 28 was 85.4% with HCQ, similar to that in the standard of care group (81.3%) (Tang W 2020). Adverse events were recorded more frequently with HCQ (30% vs 9%, mainly diarrhea).
  • Free plasma HCQ concentration achieved with HCQ doses tolerable for humans are probably too low to have any antiviral effects (Fan 2020).
  • HCQ does not work as a prophylaxis. In total, 821 asymptomatic participants were randomized to receive hydroxychloroquine or placebo within 4 days after exposure (88% with a high-risk exposure). Incidence of confirmed SARS-CoV-2 was 11.8% with CQ and 14.3% with placebo. Side effects were more common with hydroxychloroquine than with placebo (40.1% vs. 16.8%), but no serious adverse reactions were reported (Boulware 2020).

The main conclusion of a recent review was that “there is insufficient and often conflicting evidence on the benefits and harms of using hydroxychloroquine or chloroquine to treat COVID-19. As such, it is impossible to determine the balance of benefits to harms”. There are no assessments of hydroxychloroquine or chloroquine for prophylaxis against COVID-19 (Hernandez 2020). No. 45 may continue to take it, but for other patients, there is no rationale outside of clinical trials.

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, among them a huge trial (ACTT-II), comparing baricitinib and remdesivir to remdesivir alone in more than 1,000 patients.

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

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. Numerous 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. 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. However, convincing clinical data is pending for most strategies.

Interferon

The interferon (IFN) response constitutes the major first line of defense against viruses. This complex host defense strategy can, with accurate understanding of its biology, be translated into safe and effective antiviral therapies. In a recent comprehensive review, the recent progress in our understanding of both type I and type III IFN-mediated innate antiviral responses against human coronaviruses is described (Park 2020).

In patients with coronaviruses such as MERS, however, 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 COVID-19 treatment guidelines.

Clinical data: A Phase 2, multicentre, open-label RCT from Hong Kong randomized 127 patients with mild-to-moderate COVID-19 (median 5 days from symptom onset) to receive lopinavir/r only or a triple combination consisting lopinavir/r, ribavirin and interferon (Hung 2020). This trial indicates that the triple combination can be beneficial when started early. Combination therapy was given only in patients with less than 7 days from symptom onset and consisted of lopinavir/r, ribavirin (400 mg BID), and interferon beta-1b (1-3 doses of 8 Mio IE per week). Combination therapy led to a significantly shorter median time to negative results in nasopharyngeal swab (7 versus 12 days, p = 0·001) and other specimens. Clinical improvement was significantly better, with a shorter time to complete alleviation of symptoms and a shorter hospital stay. Of note, all differences were driven by the 76 patients who started treatment less than 7 days after onset of symptoms. In these patients, it seems that interferon made the difference. Up to now, this is the only larger RCT showing a virological response of a specific drug regimen.

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). One group, after reviewing 213 patients, postulated that an early short course of methylprednisolone in patients with moderate to severe COVID-19 may reduce escalation of care and improved clinical outcomes (Fadel 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).

Famotidine

Famotidine is a histamine-2 receptor antagonist that suppresses gastric acid production. It has an excellent safety profile. Initially it was thought to inhibit the 3-chymotrypsin-like protease (3CLpro), but it seems to act rather as an immune modulator, via its antagonism or inverse-agonism of histamine signalling. A retrospective study looked at 1,620 patients, including 84 patients (5.1%) who received different doses of famotidine within 24 hours of hospital admission (Freedberg 2020). After adjusting for baseline patient characteristics, use of famotidine remained independently associated with risk for death or intubation (adjusted hazard ratio 0.42, 95% CI 0.21-0.85) and this remained unchanged after careful propensity score matching to further balance the co-variables. Of note, there was no protective effect associated with use of PPIs. The maximum plasma ferritin value during the hospitalization was lower with famotidine, indicating that the drug blocks viral replication and reduces cytokine storm. Randomized clincial trials are underway.

Cytokine Blockers

The hypothesis that quelling the cytokine storm with anti-inflammatory therapies directed at reducing interleukin-6 (IL-6), IL-1, or even tumour necrosis factor TNF alpha, might be beneficial has led to several ongoing trials. It is suggestive that interleukin blocking strategies might improve the hyperinflammatory state seen in severe COVID-19. A recent review on this strategy, however, was less enthusiastic and urged caution (Remy 2020). Past attempts to block the cytokine storm associated with other microbial infections and with sepsis have not been successful and, in some cases, have worsened outcomes. Moreover, there is concern that suppressing the innate and adaptive immune system to address increased cytokine concentrations, could enable unfettered viral replication, suppress adaptive immunity, and delay recovery processes. There is growing recognition that potent immunosuppressive mechanisms are also prevalent in such patients. Following, we will briefly discuss the evidence on cytokine blockers.

Anakinra

Anakinra is an FDA-approved treatment for rheumatoid arthritis and neonatal onset multisystem inflammatory disease. It is a recombinant human IL-1 receptor antagonist that prevents the binding of IL-1 and blocks signal transduction. Anakinra is thought to abrogate the dysfunctional immune response in hyperinflammatory COVID-19 and is currently being investigated in clinical trials.

Clinical data: Some case series have reported on encouraging results.

  • A study from Paris, comparing 52 “consecutive” patients treated with anakinra with 44 historical patients. Admission to the ICU for invasive mechanical ventilation or death occurred in 25% of patients in the anakinra group and 73% of patients in the historical group. The treatment effect of anakinra remained significant in the multivariate analysis. Controlled trials are needed.
  • A retrospective cohort study at the San Raffaele Hospital in Milan, Italy, including 29 patients with moderate-to-severe ARDS and hyperinflammation (serum C-reactive protein, CRP ≥ 100 mg/L) who were managed with non-invasive ventilation and HCQ and lopinavir/r (Cavalli 2020). At 21 days, treatment with high-dose anakinra was associated with reductions in CRP and progressive improvements in respiratory function in 21/29 (72%) patients.
  • Another small case series of critically ill patients with secondary hemophagocytic lymphohistocytosis (sHLH) characterized by pancytopenia, hyper-coagulation, acute kidney injury and hepatobiliary dysfunction. At the end of treatment, ICU patients had less need for vasopressors and significantly improved respiratory function. Although 3/8 patients died, the mortality was lower than historical series of patients with sHLH in sepsis (Dimipoulos 2020).
  • Clinical improvement in three patients with acute leukaemia and confirmed or suspected COVID-19 pneumonia with a life-threatening hyperinflammatory syndrome (Day 2020).

Tocilizumab

Tocilizumab (TCZ) 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 TCZ 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). 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 of May 31, 46 trials at clinicaltrials.gov were listed, among them 14 Phase III studies) as well as for sarilumab (Kevzara®), another IL-6 receptor antagonist.

Clinical data: Some uncontrolled case series exist, many showing rapid relief of respiratory symptoms in some patients, as well as a resolution of fever and reduction in CRP following TCZ administration.

  • 62 consecutive patients admitted to the Montichiari Hospital (Italy) with COVID-19 related pneumonia and respiratory failure (but not needing mechanical ventilation) received tocilizumab when the drug became available on March 12 (Capra 2020). Patients were compared with 23 “control” patients admitted before March 13th who were prescribed the standard therapy (HCQ, lopinavir/r). Patients receiving TCZ showed significantly greater survival rate, even after adjusting for baseline clinical characteristics. Only two out of 62 patients of the TCZ group and 11 out of 23 in the control group died. The respiratory function resulted improved in 64.8% of the observations in tocilizumab patients who were still hospitalized, whereas 100% of controls worsened and needed mechanical ventilation.
  • Among 58 patients who received TCZ at a center in Barcelona, 8 (14%) died. Almost all (98%) received intravenous pulse therapy with steroids. There was a trend towards lower mortality when steroids were given before TCZ (Campins 2020).
  • In a risk-adjusted Cox regression analysis of 31 hyperglycemic and 47 normoglycemic patients with severe COVID-19, TCZ in hyperglycemic patients failed to attenuate the risk of severe outcomes as it did in normoglycemic patients (Marfella 2020).
  • Off-label use in 45 patients (most requiring high-flow oxygen supplementation or invasive ventilation) from Milan (Morena 2020). 14 died (27%). From baseline to day 7 after TCZ, however, a dramatic drop of body temperature and CRP value with a significant increase in lymphocyte count was seen (Morena 2020).

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

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 relatively 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. Other issues that have to be addressed in clinical practice (Kupferschmidt 2020) are plasma supply (may become a challenge), consistency (concentration differs) and rare but relevant risks (transfusion-related acute lung injury, in which transferred antibodies damage pulmonary blood vessels, or transfusion-associated circulatory overload).

Clinical data: Up to now, no larger controlled clinical trials in COVID-19 have been published. There are small case series:

  • In 5 critically ill patients with COVID-19 and ARDS, administration of convalescent plasma 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.
  • In 25 patients with severe and/or life-threatening COVID-19 disease enrolled at Houston, convalescent plasma was safe. By day 14 post-transfusion, 19 (76%) patients had at least a 1-point improvement in clinical status and 11 were discharged (Salazar 2020).
  • Don’t be too late: Of 6 patients with respiratory failure receiving convalescent plasma at a median of 21 days after first detection of viral shedding, all tested RNA negative by 3 days after infusion. However, 5 eventually died (Zeng 2020).

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 and controlled studies.

Monoclonal antibodies

As long as all other therapies fail or have only modest effects, monoclonal neutralizing antibodies are the hope for the near future. There is no doubt that antibodies with high and broad neutralizing capacity, many of them directed to the receptor binding domain (RBD) of SARS-CoV-2, are promising candidates for prophylactic and therapeutic treatment. On the other hand, these antibodies also have to go through all phases of clinical trial testing programs, which will take time. Safety and tolerability in particular is an important issue. The production of larger quantities is also likely to cause problems. No antibody has been tested in humans to date. However, some are very promising. Key papers:

  • The first report of a human monoclonal antibody that neutralizes SARS-CoV-2 (Wang 2020). 47D11 binds a conserved epitope on the spike RBD explaining its ability to cross-neutralize SARS-CoV and SARS-CoV-2, using a mechanism that is independent of receptor-binding inhibition. This antibody could be useful for development of antigen detection tests and serological assays targeting SARS-CoV-2.
  • Fantastic study identifying 14 potent neutralizing antibodies by high-throughput single B cell RNA-sequencing from 60 convalescent patients (Cao 2020). The most potent one, BD-368-2, exhibited an IC50 of 15 ng/mL against SARS-CoV-2. This antibody displayed strong therapeutic and prophylactic efficacy in mice, the epitope overlaps with the ACE2 binding site. Time to go into the clinic!
  • Isolation and characterization of 206 RBD-specific monoclonal antibodies derived from single B cells of eight SARS-CoV-2 infected individuals. Some antibodies showed potent anti-SARS-CoV-2 neutralization activity that correlates with their competitive capacity with ACE2 for RBD binding (Ju 2020).
  • Four human-origin monoclonal antibodies were isolated from a convalescent patient, all of which display neutralization abilities. B38 and H4 blocked the binding between virus S-protein RBD and cellular receptor ACE2. A competition assay indicates their different epitopes on the RBD. In a mouse model, both antibodies reduced virus titers in infected lungs. The RBD-B38 complex structure revealed that most residues on the epitope overlap with the RBD-ACE2 binding interface, explaining the blocking effect and neutralizing capacity (Wu 2020).

Outlook

It is hoped 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. Guidelines do not help, especially those concluding that evidence is insufficient and that “all patients should be treated in controlled randomized trials”. Moreover, on the day of their publication, many guidelines are outdated. However, after reviewing all these studies until May 31, we would recommend reviewing the following treatment options, considering the severity of the disease:

Hospital, severe COVID-19

  • In the clinic, use remdesivir if available and as soon as possible
  • In patients with severe COVID-19, consider tocilizumab, anakinra and corticosteroids (short)

Outpatient, mild to moderate COVID-18

  • Daily infusions of remdesivir are not feasible (and will not be approved)
  • HCQ and CQ should no longer be used (too many side effects)
  • Lopinavir is still an (useless) option, but interactions and gastrointestinal side effects have to be considered
  • Famotidin: why not? Potential harm seems to be limited
  • Interferon may work, if given early (optimal usage is unclear)

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