The role of oral antivirals in COVID-19 treatment: Who, when, and how?

Though most countries have eased pandemic restrictions, there is no room for complacency in managing COVID-19, which continues to cause significant morbidity and mortality.

At a recent symposium, esteemed experts Dr Roger Paredes, Head of Department of Infectious Diseases at the Hospital Universitari Germans Trias i Pujol, Badalona, Catalonia, Spain, and Dr Nicola Petrosillo, Head of the Infection Prevention and Control and Infectious Disease Service at University Hospital Campus Bio-Medico, Rome, Italy, gave global perspectives on the continuing unmet needs in the COVID-19 outpatient landscape and discussed the role of antiviral treatment options in patients at risk of progressing to severe COVID-19. Dr Petrick Periyasamy, Head of Infectious Diseases Unit, Medical Department, UKM Medical Centre, Kuala Lumpur, Malaysia, chaired the session.

COVID-19 challenges and unmet needs
Although nearly 70 percent of the world’s population has received at least one dose of COVID-19 vaccine, COVID-19 remains an enduring health issue. [https://ourworldindata. org/covid-vaccinations?country=OWID_WRL]

“Repeated waves of COVID-19 infection have led to excess death as well as debilitation caused by long COVID,” lamented Petrosillo. “According to recent WHO estimates, global excess mortality due to COVID-19 likely exceeded 3 million in 2020. [www.who.int/data/stories/the-true-death-toll-of-covid-19-estimating-global-excess-mortality] Even when the virus results in mild or moderate disease, patients may suffer persistent symptoms,’’ he added. A study estimated that 80 percent of patients infected with SARS-CoV-2 developed one or more long-term symptoms, such as fatigue, headache, attention disorder, and dyspnoea. [Sci Rep 2021;11:16144]

Current challenges include the emergence of new variants of concern (VOCs), stalling vaccination rates and low uptake of boosters, waning immunity, breakthrough infections, and continued transmission. [Vaccines 2021;9:160-424; Nature 2023;613:7]

COVID-19 management strategies have evolved over time, with vaccinations forming the mainstay of management (Figure 1). “Vaccinations are effective in reducing the severity of the disease, but less so in preventing transmissions. COVID-19 disproportionately affects the elderly and those with comorbidities; these patients account for the majority of hospitalizations and deaths. Therefore, outpatient treatment of COVID-19 patients at high-risk of severe disease is an important strategy to reduce adverse patient outcomes,” pointed out Petrosillo.

Identify and prioritize people at risk for severe disease
In late 2022, the WHO launched a COVID-19 strategy which emphasizes the need for early case detection and primary care access to oral antivirals for vulnerable patients. [https://rb.gy/bl3ypf] “These vulnerable patients, including those who are unvaccinated, are at higher risks of becoming severely ill from COVID-19,” said Paredes. “Risk factors include older age, pregnancy or recent pregnancy, presence of comorbidities or disability, and being a member of a racial/ethnic minority due to health and social inequalities. Hypertension and diabetes are the most prevalent comorbidities among individuals with COVID-19 requiring hospitalization.” [COVID-19 People with Certain Medical Conditions. www.cdc.gov/coronavirus/2019-ncov/need-extra-precautions/people-with-medical-conditions.html; JAMA 2020;323:2052-2059]

“High-risk patients can quickly progress to severe disease, underscoring the need for rapid therapeutic intervention. [Int J Environ Res Public Health 2021;18:7212; J Heart Lung Transplant 2020;39:405-407] Effective and early COVID-19 treatments will not only prevent hospitalization and chronic sequelae but will also help to curb disease transmission. Consequently, the strain on medical systems and healthcare workers will be reduced,” Petrosillo emphasized.

COVID-19 antiviral treatment options
“Treatment of COVID-19 depends on the stage and severity of disease (Figure 2). As viral replication is most rapid soon after symptom onset, antiviral medications (eg, monoclonal antibodies (mAbs) and protease inhibitors) are most effective when used early. Later stages of the disease are characterized by inflammation and coagulopathy; in this stage, anti-inflammatory medications and immunomodulators may be more effective than antiviral agents,” explained Petrosillo. [New Engl J Med 2020;383:1757-1766]

He elaborated that mAbs are designed to block the virus’ spike protein attachment and have been shown to reduce hospitalization when administered in the early stages of COVID-19. However, efficacy is lacking against certain SARS-CoV-2 variants, such as the Omicron BA.2, which have extensively mutated spike proteins. [Nature 2022;602:676-681]

Protease inhibitors, such as nirmatrelvir, prevent the formation of proteins involved in viral replication. [ACS Cent Sci 2020;6:672-683] Data have indicated that nirmatrelvir maintains in vitro efficacy against predominating SARS-CoV-2 VOCs, including Alpha, Beta, Gamma, Delta, Lambda, Mu, and Omicron. [New Engl J Med 2022;386:1475-1477]

However, Petrosillo cautioned that the use of convalescent plasma is not efficient and not recommended as a standard of care. [N Engl J Med 2022; 386:1753-1754]

Role of nirmatrelvir/ritonavir in the COVID-19 paradigm
“Nirmatrelvir is an oral covalent 3CL protease inhibitor of SARS-CoV-2, while ritonavir, at a low dose, works to inhibit cytochrome P450 3A4, thus increasing the bioavailability of nirmatrelvir. Nirmatrelvir/ritonavir combination is approved for COVID-19 treatment in adults who do not require supplemental oxygen and who are at increased risk for progressing to severe COVID-19,” said Paredes.

Presenting the clinical trial evidence, Paredes recalled that the EPIC-HR phase II/III trial demonstrated that in unvaccinated, nonhospitalized individuals, treatment with nirmatrelvir/ritonavir can decrease progression to severe disease. A relative risk reduction of 88.9 percent in COVID-19-related hospitalization or death from any cause was observed among patients commencing treatment ≤3 days from symptom onset. Treatment with nirmatrelvir/ritonavir was associated with a reduction in SARS-CoV-2 viral load at Day 5, by a factor of 10, compared with placebo. Notably, nirmatrelvir/ritonavir treatment was well-tolerated, with fewer serious adverse events and adverse events leading to treatment discontinuation, relative to placebo. [N Engl J Med 2022;386:1397-1408]

“Early intervention with nirmatrelvir/ritonavir in high-risk, nonhospitalized adults with symptomatic COVID-19 can significantly lower the risk of progression to severe disease, without evident safety concerns,” Paredes concluded.