Newer oral antivirals for COVID-19: Are they the real game changer?

The unprecedented increase in COVID-19 cases globally following the emergence of novel variants such as Delta and Omicron has led to a focus on the concept of “Hit early, Hit hard” to prevent the progression of mild/moderate illness by accelerating viral clearance into a more severe one. Remdesivir, the only FDA approved antiviral against COVID-19, has its own limitations necessitating hospital visit. Similarly, monoclonal antibodies are plagued by its high cost, limited availability and need for a hospital-based administration. Owing to the urgent need for treatment of critically ill COVID-19 patients, research on drugs for use in the outpatient setting has understandably lagged behind. Given it seems likely that COVID-19 will become endemic, research should focus on identifying safe, affordable, and globally accessible oral drugs for treatment. This letter tends to address the rationale, unmet need, scientific evidence and the associated controversies surrounding the novel oral antiviral therapies in COVID-19 treatment.

Molnupiravir acts by replacing cytidine and uridine triphosphates with either Adenine or Guanine forms, eventually causing lethal mutagenesis and inhibition of viral propagation.¹ This drug was recently licensed in the United Kingdom and subsequently received United States Food and Drug Administration (FDA) emergency use authorization (EUA) for use in mild to moderate COVID-19 cases with risk factors for progression to severe illness based on the MOVe-OUT study (Table 1 ). Subsequent approval by the Drug Controller of India (CDSCO) coupled by ​​Merck's decision to expand global access to Molnupiravir through generics manufacturers led to widespread availability in Indian markets during the recent surge of Omicron. This overambitious use of the drug can have disastrous consequences. In fact, the FDA issued a warning that Molnupiravir is unsafe in pregnancy due to potential embryo-foetal toxicity, and in children due to potential cartilage and bone toxicity demonstrated in host animal cell culture assay.² Since Molnupiravir induces errors in the viral RNA, another concern is emergence of newer variants, especially if there is underdosing or premature termination of therapy. Another major concern is the theoretical risk of mutagenesis as was shown in Chinese hamster ovary cells.² However, extensive studies in-vivo whole animal mutagenicity assays (Pig-a mutagenicity assay and Big Blue [cII locus] transgenic rodent assay) have failed to reveal any distinct mutagenicity.³ This calls for rational use of Molnupiravir only on the advice of a registered medical practitioner (symptomatic patients with risk for progression to severe illness).

Table 1.

Summary of Newer Oral Antivirals for COVID-19 with the evidence.

Drug/Trial	Trial/design/participants	Inclusion/Exclusion Criteria	Dose and Duration	Outcomes	Current status
Molnupiravir	MOVe-OUT4 (NCT04575597) Phase 2–3, double-blind, parallel-group, RCT; n = 1433	Inclusion: Adults with mild-moderate COVID-19 with symptoms ≤ 5 days and at least one risk factor for development of severe illness (age >60 years; active cancer; CKD; COPD; obesity, serious heart conditions; diabetes mellitus) Exclusion: (a) Need for hospitalization in next 48 h, (b) dialysis/EGFR<30 ml/min/ 1.73 m2, (c) pregnancy, (d) unwillingness to use contraception during and for at least 4 days post therapy, (e) severe neutropenia, (f) platelet count <100,000/ml, (g) SARS-CoV-2 vaccination	800 mg twice a day for 5 days vs placebo	Risk of hospitalization or death through day 29: lower with molnupiravir (7.3%) vs placebo (14.1%) (P = 0.001) Time-to-event analysis: rate of hospitalization or death through day 29: 31% lower with molnupiravir than placebo Greater decrease from baseline in viral RNA compared to placebo at Day 5 and 10	EUA from FDA; UK and CDSCO (India) based on this trial IDSA guideline panel8: In ambulatory patients (≥18 years) with mild to moderate COVID-19 at high risk for progression to severe disease and no other treatment options: Molnupiravir initiated within 5 days of symptom onset rather than no Molnupiravir. (Conditional recommendation, Low certainty of evidence)
Molnupiravir	MOVe-IN9 (NCT04575584) Phase 2/3, double-blind, placebo-controlled, RCT; n = 304)	Inclusion: Hospitalized adults (>18 years) with laboratory confirmed mild, moderate, or severe COVID-19 and symptom onset < 10 days Exclusion: critical COVID-19 (NIV/IMV/ECMO); dialysis or EGFR< 30 ml/min/1.73 m2, (c) pregnancy, (d) unwillingness to use contraception during therapy and for at least 4 days post therapy	Four arms; Molnupiravir 200 mg, 400 mg, 800 mg or placebo twice daily for 5 days	Higher deaths in Molnupiravir 200 mg, 400 mg, and 800 mg: 4 (5.5%), 8 (11%), and 3 (4.2%) vs 2 (2.7%) in placebo group Interim analysis: clinical benefits unlikely to be significant in hospitalized patients	Study Prematurely discontinued
Paxlovid	EPIC—HR10 (NCT04960202) Phase 2/3, double-blind, placebo-controlled, RCT; n = 2246	Inclusion: Adults with mild-moderate COVID-19 with symptoms ≤ 5 days and at least one characteristic or underlying medical condition associated with an increased risk of developing severe illness from COVID-19 Exclusion: (a) Need for hospitalization for COVID-19 (b) dialysis/ moderate-severe renal impairment (c) pregnancy/breastfeeding, (d) Use of any medications or substances that are highly dependent on CYP3A4 for clearance or are strong inducers of CYP3A4, (e) HIV infection with viral load > 400 copies/ml, (f) active liver disease, (g) received or is expected to receive convalescent COVID-19 plasma/ COVID-19 vaccine	Dose of 300 mg (two 150 mg tablets) of Nirmatrelvir with one 100 mg tablet of Ritonavir, BD X 5 days	Primary endpoint: Reduced risk of hospitalization/death by 89% compared to placebo within 3 days of symptom onset and by 88% compared to placebo within 5 days of symptom onset (P<0.0001) Relative risk reduction: 94% in patients >65 years of age No deaths in Paxlovid arm as compared to 12 (1.2%) deaths in placebo arm Secondary endpoint: Reduced viral load by approximately 10-fold relative to placebo	EUA from FDA based on this trial IDSA guideline panel8: Ambulatory patients with mild-to-moderate COVID-19 at high risk for disease progression - IDSA suggests Paxlovid within 5 days of symptom onset rather than no Paxlovid (Conditional recommendation, low certainty of evidence)
Paxlovid	EPIC-SR10 (NCT05011513) Phase 2/3, double-blind, placebo-controlled, RCT; n = 673	Inclusion: Mild to moderate COVID-19 with symptoms ≤ 5 days and were (a) either unvaccinated adults at standard risk (low risk of hospitalization or death) or (b) vaccinated adults with one or more risk factors for progressing to severe illness from COVID-19 Exclusion: (a) Need for hospitalization for COVID-19 (b) dialysis/ moderate-severe renal impairment (c) pregnancy/breastfeeding, (d) Use of any medications or substances that are highly dependent on CYP3A4 for clearance or are strong inducers of CYP3A4, (e) HIV infection with viral load>400 copies/ml, (f) active liver disease, (g) received or is expected to receive convalescent COVID-19 plasma (h) received or is expected to receive any COVID-19 vaccine except for individuals with high risk conditions	Dose of 300 mg (two 150 mg tablets) Nirmatrelvir with one 100 mg tablet of ritonavir BD X 5 days	Primary endpoint: Self-reported, sustained alleviation of all symptoms for four consecutive days as compared to placebo not met Secondary endpoint: 70% reduction in hospitalization and no deaths in treatment arm vs placebo Reduced viral load by approximately 10-fold relative to placebo	Failed to meet its primary end point
Favipiravir	CTRI/2020/05/0,251,146 Phase 3, open-label, parallel-arm, RCT; n = 150	Inclusion: Adults (18–75 years) with (a) mild-moderate COVID-19 and (b) agreement to use effective contraception during and for ≥7 days following the last dose, and (c) negative pregnancy test for females of child bearing age Exclusion: severe COVID-19 infection, (b) asthma/COPD/CLD /CKD, (c) gout or hyperuricemia, (d) prolonged QT, (e) severely Left Ventricular dysfunction (Ejection Fraction <30%)	Oral Favipiravir (1800 mg BD loading dose on day 1; 800 mg BD maintenance dose) + standard care for up to 14 days vs standard care alone (control arm)	Primary endpoint: Median time to cessation of viral shedding: Favipiravir - 5 days vs standard care - 7 days; P = 0.129 Median time to clinical cure: Favipiravir −3 days vs standard care - 5 days; P = 0.030	Failed to meet its primary end point Significant improvement in time to clinical cure

RCT- randomised control trial, CKD- chronic kidney disease, COPD- chronic obstructive pulmonary disease, EGFR- estimated glomerular filtration rate, RNA- ribonucleic acid, EUA- emergency use authorization, FDA- Food and Drug Administration, UK- United Kingdom, CDSCO- Central Drugs Standard Control organisation, NIV- Non-invasive ventilation, IMV- invasive mechanical ventilation, ECMO- Extracorporeal membrane oxygenation, IDSA- Infectious Diseases Society of America, CLD- chronic liver disease.

Paxlovid, another oral antiviral drug is a combination of protease inhibitors Nirmatrelvir and Ritonavir. Nirmatrelvir, an orally active main protease (Mpro) inhibitor, limits the activity of viral proteases thereby preventing viral replication. It is co-administered with Ritonavir which by virtue of its inhibitory effects on cytochrome P450 slows down the metabolism of Nirmatrelvir thus increasing its bioavailability. This novel antiviral recently received an EUA from the FDA for use in non-hospitalised adults with mild to moderate COVID-19 infection and with pre-specified risk factors for disease progression. This was based on the findings of the EPIC—HR trial⁴ among non-hospitalized symptomatic adults (n = 2246) where Paxlovid significantly reduced risk of hospitalization or death as compared to placebo (Table 1). Additionally, Paxlovid led to a ten-fold reduction in viral load, a finding consistently seen in-vitro studies with effectiveness even against Delta and Omicron variants. Similarly, the drug was also found effective in mild to moderate COVID-19 patients at low risk of hospitalization/death (EPIC-SR trial; Table 1). Concerns regarding use of Paxlovid include its cost, multiple drug interactions with CYP3A enzyme inducers/inhibitors, emergence of HIV drug resistance in individuals with uncontrolled/undiagnosed HIV-1 infection and need for dose modification in moderate renal dysfunction.

Favipiravir is an inhibitor of the viral RNA-dependent RNA polymerase. The rapid viral clearance, higher clinical recovery rate, and availability as an oral drug with a proven safety profile made it a promising therapy for COVID-19. The Drug Controller of India (CDSCO) did provide an EUA⁵ for favipiravir with a consent form and multiple state governments included it in their treatment cocktail, however evidence for objective benefit is still lacking. Open-label studies reported initial promising results; however, the cost of therapy and pill burden were major limitations.⁶

To conclude, COVID-19 spread across the globe in pandemic proportions and caused huge morbidity and mortality. The sudden spurt in cases led to widespread fear, exhaustion of health-care resources and multiple treatment regimens in India⁷; evidence-based treatment approach for treatment could hardly be realised. However, till evidence for efficacy and safety is generated, indiscriminate use of any drug should be discouraged. The concept of primum non nocere must never be forgotten.

Author's statements- Contributors

SK, PI, NM involved in Conceptualization, literature search, writing the original draft of manuscript, literature search, planning, conduct and editing. SK, PI, NM, PS involved in review and editing. All the authors have read and agreed with the submitted manuscript.

Declaration of competing interest

The authors decleared that they have no known competing finacial interest or presonal relationship that could have appeared to influance the work reported in this paper.