
The management of coronavirus disease 2019 (COVID-19) continues to evolve as new therapies become available and new virus variants emerge. A recently published meta-analysis, including data from over 166,000 patients, examined the efficacy of antivirals in mild to moderate COVID-19. The analysis provides insights into the effectiveness of therapies in reducing hospital admissions.
This study ranked the following from most to least effective in reducing hospital admission:
- Nirmatrelvir + ritonavir (ORSC 0.15 (95% CI 0.07 to 0.32)) – moderate certainty
- Remdesivir (ORSC 0.25 (95% CI 0.07 to 0.77)) – moderate certainty
- Systemic corticosteroids (ORSC 0.43 (95% CI 0.20 to 0.90)) – low certainty
- Molnupiravir (ORSC 0.66 (95% CI 0.44 to 0.92)) – low certainty
Abbreviations: ORSC, odds ratio compared with standard care; CI, credible interval
The study authors concluded that nirmatrelvir + ritonavir and remdesivir probably reduce admission to hospital, while systemic corticosteroids and molnupiravir may reduce admission to hospital. Evidence to support a mortality benefit for these agents compared to standard care is inconsistent.
Choice of therapy
The National COVID-19 Clinical Evidence Taskforce provides information on the management of COVID-19 in the Australian context. While this resource is no longer being updated, it will remain online until it no longer reflects the evidence or recommended practice.
Antivirals that target the virus that causes COVID-19 are intended to reduce the risk of severe illness and are prescribed to patients with risk factors for developing serious complications.
Risk factors for disease progression include:
- Older age (> 65 years, or > 50 years for Aboriginal and Torres Strait Islander people);
- Diabetes requiring medication;
- Obesity (BMI >30 kg/m2);
- Renal failure;
- Cardiovascular disease, including hypertension;
- Respiratory compromise, including COPD, asthma requiring steroids, or bronchiectasis; and
- Immunocompromising conditions (i.e. primary or acquired immunodeficiency or immunosuppressive therapy).
Where antivirals are considered necessary, treatment should be initiated as soon as possible after symptom onset.
Nirmatrelvir + ritonavir (Paxlovid®)
Paxlovid® is the preferred oral treatment for COVID-19, unless contraindications are present. This product contains nirmatrelvir tablets co-packaged with ritonavir tablets.
Nirmatrelvir inhibits the main protease of the SARS‑CoV‑2 virus, preventing viral replication. Ritonavir is included to increase nirmatrelvir levels by inhibiting its metabolism.
The approved indication is:
- COVID-19 in adults ≥18 years who do not require initiation of supplemental oxygen due to COVID-19 and are at increased risk of progression to hospitalisation or death.
Administration
The recommended dosage is 300 mg nirmatrelvir (two 150 mg tablets) with 100 mg ritonavir (one 100 mg tablet). These tablets should be taken together every 12 hours for five days. Failure to correctly take nirmatrelvir with ritonavir will result in subtherapeutic plasma levels of nirmatrelvir.
No dose adjustment is required for mild renal impairment (eGFR 60 to < 90 mL/min/1.73m2). For patients with moderate impairment (eGFR 30 to < 60 mL/min/1.73m2), the nirmatrelvir dose should be reduced to 150 mg (taken with ritonavir 100 mg) every 12 hours for 5 days. Paxlovid® is currently contraindicated in severe renal impairment as data for appropriate dosing is not yet available. Its use is also contraindicated in severe hepatic impairment, although no dose adjustment is required in mild to moderate hepatic impairment.
It is recommended that the tablets be swallowed whole without regards to food. However, studies suggest that administering nirmatrelvir + ritonavir as an oral suspension does not alter its pharmacokinetic parameters. The guidelines advise that nirmatrelvir + ritonavir tablets can be crushed or split and mixed with food or liquid, where necessary. Alternatively, they may be administered via a nasogastric tube, as indicated.
Adverse effects
Common adverse effects include taste disturbance, headache, diarrhoea, and nausea.
Nirmatrelvir and ritonavir are both metabolised by CYP3A4, and this contributes to many clinically significant drug interactions. Coadministration with medicines that induce this enzyme may reduce the concentration and efficacy of the antiviral. Use with strong CYP3A4 inducers is contraindicated as this may be associated with loss of virologic response and potential resistance. Paxlovid® may also increase the levels of medications that are metabolised by CYP3A. Use is contraindicated with medicines that are highly dependent on CYP3A for clearance and for which elevated levels may result in serious or life-threatening events.
The interactions of ritonavir can be difficult to predict, as it inhibits and induces CYP3A4 and other CYP enzymes. It also inhibits P‑glycoprotein and is a strong inducer of UGTs (which mediate glucuronidation). A full medication history should be taken before initiating therapy, ensuring that complementary and over-the-counter products are included.
Many medications are contraindicated with Paxlovid®, including:
- Drugs that may result in serious or life-threatening reactions, e.g. amiodarone, flecainide, colchicine, simvastatin, diazepam, and sildenafil.
- Drugs that may result in loss of virologic response and potential resistance, e.g. apalutamide, carbamazepine, phenytoin, rifampicin, St John’s wort.
The product information should be consulted for comprehensive advice on drug interactions.
Molnupiravir (Lagevrio®)
Molnupiravir has provisional approval for the treatment of adults with COVID-19 who do not require initiation of oxygen due to COVID-19 and who are at increased risk for hospitalisation or death.
Molnupiravir inhibits viral replication following incorporation into viral RNA. It is less effective than nirmatrelvir + ritonavir and is not routinely recommended for the treatment of COVID-19. Molnupiravir is only recommended if an oral agent is required and the nirmatrelvir + ritonavir combination is contraindicated.
Administration
The recommended dose is 800 mg (four 200 mg capsules) taken orally every 12 hours for five days. Doses may be taken with or without food.
Adverse effects
Diarrhoea, nausea, and dizziness were the most commonly reported adverse events in clinical trials. These were of mild to moderate severity. No serious drug-related adverse events were reported.
Molnupiravir is not a substrate of any major drug metabolising enzymes or transporters and is considered unlikely to cause drug interactions.
Remdesivir (Veklury®)
Remdesivir is an intravenously administered agent that may also be considered for patients with mild to moderate disease, as well as more severe cases where ventilation is not required.
The approved indications are for the treatment of COVID-19 in:
- Adults and paediatric patients (at least 4 weeks of age and weighing at least 3 kg) who have pneumonia due to SARS-CoV-2, and who require supplemental oxygen; and
- Adults and paediatric patients (weighing at least 40 kg) who do not require supplemental oxygen and who are at high risk of progressing to severe COVID-19.
Remdesivir is metabolised to remdesivir triphosphate (an adenosine analogue). This pharmacologically active form is then incorporated into viral RNA, preventing its replication. Remdesivir is used in both outpatient and hospital settings and treatment should begin within seven days of symptom onset.
Administration:
Remdesivir is administered daily via IV infusion. For adults and patients >40kg, the usual dose is 200mg on day 1, then 100mg on subsequent days. The usual treatment duration is three days for patients who do not require supplemental oxygen, and 5-10 days for patients with pneumonia who do need supplemental oxygen.
Remdesivir is supplied as a powder for injection. The powder is reconstituted with water for injection and then further diluted with 0.9% sodium chloride. The final volume is typically 250mL, although a volume of 100mL may be used for patients with severe fluid restrictions. The infusion should run over 30-120 minutes.
Dose adjustment is not required for patients with renal impairment (including those on dialysis) or hepatic impairment.
Adverse effects
Common adverse effects include nausea, vomiting, headache, rash, increased aminotransferases, and prolonged prothrombin time (PT). While prolonged PT has been observed in clinical trials, no difference has been reported in the incidence of bleeding events compared to placebo.
Hypersensitivity reactions (including infusion-related and anaphylactic reactions) have been associated with remdesivir. Signs and symptoms may include hypotension, hypertension, tachycardia, bradycardia, hypoxia, fever, dyspnoea, wheezing, angioedema, rash, nausea, vomiting, diaphoresis, and shivering. Slower infusion rates (up to 120 minutes) may reduce the risk of these events. Remdesevir must only be administered in settings where there is immediate access to medications to treat a severe infusion or hypersensitivity reaction and access to an emergency medical response.
Table 1. Comparison of COVID-19 antiviral agents.
Drug | Route | Timing of initiation | Comments |
Remdesivir | IV | ≤7 days | 30-120 minute infusion |
Nirmatrelvir + ritonavir | Oral | ≤5 days | 1st line oral agent
Many drug interactions + contraindications |
Molnupiravir | Oral | ≤5 days | Less effective |
Summary
If an antiviral is considered appropriate for COVID-19, therapy should be promptly initiated following diagnosis. Where an oral agent is required, nirmatrelvir + ritonavir is preferred as it is more effective than molnupiravir. Remdesivir remains a valuable option for reducing the risk of hospitalisation. However, as it requires IV administration, its use in the community is limited.