COVID-19: Drug Therapy

Therapy goals

Symptom relief
Treat complications and respiratory insufficiency (inadequate breathing resulting in inadequate gas exchange).
Prevent the spread of infection

Therapy recommendations

Treat according to the current guideline for “suspected nCoV infection of adult and pediatric patients with severe acute respiratory infection (SARI) in hospital” [guidelines: WHO].
Symptomatic therapy: including acid-base balance and electrolytes (blood salts) balance.
Antiviral therapy: a specific antiviral therapy is currently not yet available (see below “Further notes / Possible therapy).
Corticosteroids:
- Dexamethasone (6 mg/d i.v. or p.o. for 10 days): steroid treatment may reduce the risk of death in patients with severe COVID-19 (meta-analysis).
Thromboprophylaxis
- Low-molecular-weight heparins (LMWH) in prophylactic doses in all patients hospitalized for COVID-19 (because of microthrombosis in the pulmonary vasculature) [Guidelines: 2].Anticoagulants may lead to better survival in COVID-19 patients: mechanically ventilated patients showed a mortality of 29.1%, versus 62.7% in the mechanically ventilated patients without anticoagulation. Significance: retrospective analysis of patient data.Similarly, COVID-19 patients on anticoagulation showed a significant decrease in intubation and death. Here, prophylactic anticoagulation with subcutaneous low-molecular-weight heparin (NMH) was sufficient.In pregnancy:All pregnant women with suspected or confirmed COVID-19 disease should receive low-molecular-weight heparin. Prophylaxis should be continued for at least ten days after discharge.
Cytokine-release syndrome (CRS).
- Anakinra (interleukin-1 receptor antagonist) positively affected “cytokine storm” in COVID-19 patients on high-dose intravenous therapy: the difference in survival of 90% in the anakinra group versus 56% on standard treatment was statistically significant.
- Glucocorticoids (see below).
Concomitant diseases
- Viral-related fulminant myocarditis (inflammation of the heart muscle): glucocorticoids and immunoglobulins.
- Superinfection: antibiosis (antibiotic therapy).
Intensive medical treatment (see below “Further therapy”).

Further notes

Possible therapy:
- Acetylsalicylic acid (ASA) with “low dose” ASA (81 mg): patients required mechanical ventilation less frequently (35.7 versus 48.4%), were transferred to the intensive care unit less frequently (38.8 versus 51.0%), and the risk of death was reduced by 47% (adjusted hazard ratio 0.53; 0.31 to 0.90).
- Camostat (active ingredient from the protease inhibitor group): binding to the ACE2 receptor.
- Colchicine – accelerated recovery in patients with COVID-19 in a smaller randomized trial; authors suggest colchicine may be of benefit in patients with a severe course.
- Ivermectin (antiparasitic agent; single oral administration of 200 µg ivermectin per kilogram body weight): Active ingredient is an inhibitor of COVID-19-causing virus in vitro.
- Antidepressants (Selective Serotonin Reuptake Inhibitor (SSRI))
  - Fluoxetine belongs to the group of FIASMA (functional inhibitors of acid sphingomyelinase)): inhibits the uptake of SARS-CoV-2 viruses into cell culture as well as their further spread.
  - Adult outpatients with symptomatic COVID-19 infection on fluvoxamine (3 x 100 mg/d for 15 days) were less likely to have clinical worsening over 15 days compared with placebo in a randomized “remote” trial.The authors note that fluvoxamine, unlike other antidepressants in the SSNRI group, does not cause QT prolongation on ECG.
- Glucocorticoids:
  - Dexamethasone (6 mg/d i.v. or p.o. for 10 days) reduced mortality (death rate) in ventilated patients; this was one-third lower than with standard therapy; Number Needed to Treat (NNT) to prevent death with dexamethasone was 8 (for ventilated patients) and 25 for all COVID-19 inpatients.
  - A meta-analysis of 7 randomized trials demonstrated that treatment with glucocorticoids reduced all-cause mortality (all-cause mortality rate) by 36% in patients with severe COVID-19 infection.CONCLUSION: Glucocorticoids are part of the standard therapy for severely affected COVID-19 patients according to evidence-based criteria.
  - Note: The German Society of Pneumology and Respiratory Medicine. (DGP) advises against dexamethasone in COVID-19 patients without ventilation requirement [guidelines: DGP position paper].
- Monoclonal antibodies:
  - Initial laboratory experiments have shown that the antibody 47D11 is able to prevent infection of cells by SARS-CoV-2.
  - Acalabrutinib (monoclonal antibody; 2nd generation BTK inhibitor: class of protein kinase inhibitors or tyrosine kinase inhibitors that inhibit Bruton tyrosine kinase (BTK)) attenuated cytokine storm (potentially life-threatening immune system derailment) in an open-label study (oxygen administration was omitted in 8 of 11 patients). Cytokine storm is a common complication in patients with COVID-19.
  - Bamlanivimab (LY-CoV555) has received emergency approval; further results are awaited.
  - Ruxolitinib (monoclonal antibody; tyrosine kinase inhibitor):Ruxolitinib not only reduced ARDS-associated inflammatory blood cytokine levels such as IL-6 and acute phase protein ferritin, but was also associated with rapid respiratory and cardiac improvement and clinical stabilization. Limitation: single case!
  - Tocilizumab (monoclonal antibody; blocking interleukin-6 receptor); indication: cytokine release syndrome (CRS); phase III trial ongoing.
    - In a small retrospective study of 25 patients, tocilizumab was associated with radiographic improvement and reduced need for ventilatory support in patients with severe COVID-19.
    - Study of 179 patients treated with tocilizumab antibody: Horovitz ratio (PaO2/FiO2; oxygenation index; lung function parameter used to describe the extent of lung injury), which describes the severity of lung failure, had already decreased to 169 mmHg in patients treated with tocilizumab compared with 277 mmHg in the comparison group (patients who did not receive tocilizumab). The mortality rate (death rate) was 7% (13 patients), only 1/3 as high as in the comparison group, where 73 of 365 patients (20%) died.
  - Combination of two Regeneron monoclonal antibodies (REGN10933 and REGN10987): a randomized, double-blind trial reduced viral load by day 7; patients with progressively higher baseline viral levels had a correspondingly greater reduction in viral load on day 7 after REGN-COV2 treatment.
- Convalescent serum (plasma therapy; blood serum obtained from individuals who have survived infectious disease).
  - In a preliminary uncontrolled case series of 5 critically ill patients with confirmed 2019 coronavirus disease (COVID-19) and acute respiratory distress syndrome (ARDS), administration of convalescent serum containing neutralizing antibodies was followed by improvement in their clinical condition.
  - In a treatment series of 39 patients, they recovered more frequently; only 7 patients (18%) experienced a worsening of their clinical condition by day 14. In the control group, this worsened in 24.3% of patients.
  - Experience at one major center suggests that plasma therapy is successful only in the early phase of the disease: patients treated within 72 hours of admission to the hospital had a more than 3-fold increased chance of surviving the disease.
- Virustatics
  - Favipiravir (antiviral used for oral treatment of infections with various RNA viruses; Japanese version of remdesivir; used as a reserve agent to treat influenza):
    - Mildly ill patients: 87.8% had clinical improvement after 14 days; 5.1% of patients had died from COVID-19.
    - Moderately ill patients: improvement occurred in 84.5%; mortality (death rate) was 12.7
    - Severely ill patients: 60.3% improved; mortality rate was 31.7
    Limitation: lack of a comparison group
  - Ribavirin (guanosine analog and RNA synthesis inhibitor): likely also inhibits RdRp; same for sofosbuvir (polymerase inhibitor).
  - 14-day triple combination of 400 mg lopinavir /100 mg ritonavir (every 12 hours), 400 mg ribavirin (every 12 hours), and 3 doses of interferon beta-1b on alternate days versus lopinavir 400 mg / ritonavir 100 mg every 12 hours for 14 days. The median hospital stay in the combination group was 9 days compared with 14.5 days in the control group. A post hoc subgroup comparison of these patients showed that those who started treatment <7 days after symptom onset had better clinical and virologic outcomes.
No therapeutic success:
- Hydroxychloroquine*
  - A smaller randomized trial finds evidence of an effect in 20 patients who were mildly ill with Covic 19: patients were treated with hydroxychloroquine for 5 days. After 10 days, 14 patients (70%) were virus-free, including all patients who had also received azithromycin* . Twenty-five of 31 patients (80.6%) showed improvement at the 2nd CT scan versus 17 of 31 patients (54.8%) in the control group.
  - One clinical trial was discontinued: Very high doses of 1,200 mg/d of chloroquine resulted in clustered fatal adverse events attributable to QTC time prolongation without a decrease in viral load. Note: All patients also received ceftriaxone and azithromycin as standard of care.
  - In this observational study of patients hospitalized with covid-19, hydroxychloroquine administration (600 mg twice on day 1, then 400 mg daily for a median of 5 days) was not associated with a greatly reduced or increased risk of the composite end point of intubation or death in 1,376 patients.
  - Hydroxychloroquine without effect in WHO study.
- Lopinavir /ritonavir (inhibitors of HIV protease) did not accelerate viral elimination or reduce patient morbidity (disease incidence) and mortality (mortality) in an open-label study of critically ill COVID-19 patients at a clinic in Wuhan.In a subgroup analysis, the HIV combination lopinavir/ritonavir showed no effect in hospitalized COVID-19 patients.
- Remdesivir-a broadly antiviral nucleotide analogue that inhibits RNA-dependent RNA polymerase-and chloroquine* -an anti-inflammatory, immunomodulatory, antiparasitic, and antiviral agent in the antimalarial group-effectively inhibit novel coronavirus (SARS-CoV-2) in vitro. Contraindications (counterindications) to remdesivir: increase in transaminases (ALT) to more than 5 times the upper limit of normal ( ULN) and markedly impaired renal function.
  - A median of 18 days after the first dose is reported to have improved in 36 of 53 patients (68%). Patients who were not ventilated before starting treatment were more likely to show improvement (hazard ratio to worsening: 0.33; 95% confidence interval, 0.16 to 0.68); this was also true for patients younger than 50 years (hazard ratio: 0.29; 0.11 to 0.74). The power of the study is considered limited because no comparison group was available.
  - In a Chinese study of adult patients hospitalized for severe COVID-19, remdesivir was not associated with statistically significant clinical benefits. However, the numerical reduction in time to clinical improvement in previously treated patients requires confirmation in larger studies.
  - A double-blind, randomized, placebo-controlled trial of intravenous remdesivir in adults hospitalized with COVID-19 demonstrated that remdesivir (200 mg starting dose on day 1, followed by 100 mg daily for up to 9 additional days) was superior to placebo, reduced time to recovery (11 days versus 15 days), and decreased lower respiratory tract infections. Similarly, mortality (death rate) was significantly reduced at 14 days: 7.1% with remdesivir and 11.9% with placebo.Shortening treatment duration with remdesivir to 5 days instead of 10 days had no disadvantages in a randomized trial.
  - Remdesivir in WHO study without effect.

* Note: In patients with pre-existing cardiac disease, ventricular fibrillation with fatal outcome is possible. The drug may cause prolongation of the QT interval and associated electrical instability of the heart (long-QT syndrome).