Ensitrelvir: The Japanese Antiviral Against COVID-19 and Its Potential Role in Long COVID Research

Arnaud Pontin (Image : News-medical.net)

A somewhat unusual situation has emerged following the recent development of a new drug manufactured in Japan, known as ensitrelvir.

Ensitrelvir is an antiviral medication for COVID-19, marketed under the brand name Xocova. It was developed by Shionogi, a Japanese pharmaceutical company.

Its mechanism of action is similar to that of Paxlovid, as it inhibits a key enzyme required for SARS-CoV-2 replication, known as the main protease (Mpro or 3CLpro). By blocking viral replication, it reduces both viral load and the risk of infection.

This drug is particularly noteworthy because it is the first oral antiviral to demonstrate significant efficacy in preventing symptomatic COVID-19 following recent exposure to an infected individual. In a phase 3 clinical trial, the risk of developing symptomatic COVID was reduced by approximately 67% compared with placebo.

The most common side effects include headache, diarrhea, and cough, generally mild.

Ensitrelvir has also attracted growing attention in long COVID research, although current evidence remains preliminary and it is not yet approved for this indication.

The somewhat paradoxical issue is that the drug must be administered within the first three days following exposure to a person infected with COVID-19, at a time when access to rapid COVID testing has significantly decreased in many regions.

This raises practical questions about how prescriptions can be justified or guided in the absence of confirmed testing.

This is one of the broader criticisms surrounding the use of COVID-19 antivirals in a context where rapid testing is less available and routine screening has declined.

The usefulness of ensitrelvir therefore depends heavily on clinical context.

For individuals who develop sudden symptoms consistent with COVID-19 after a known exposure (for example, a household contact or colleague), physicians may sometimes rely on a clinical diagnosis without requiring a positive test.

In some countries, the drug is also considered for post-exposure prophylaxis, meaning it may be used after close contact with an infected person, even before symptoms appear.

In higher-risk patients, clinicians may be more inclined to initiate treatment quickly when there is strong clinical suspicion.

However, in practice, the lack of widely available diagnostic testing complicates the use of such treatment strategies. COVID-19 antivirals are most effective when administered early, typically within the first days of infection. Without rapid confirmation, it becomes more difficult to identify appropriate candidates and to avoid unnecessary treatment of other respiratory infections such as influenza, RSV, or rhinoviruses.

Beyond acute infection, interest in ensitrelvir for long COVID is based on a still-unproven hypothesis: in some patients, viral remnants or low-level SARS-CoV-2 persistence may continue to stimulate the immune system for months after the initial infection.

If confirmed, an antiviral like ensitrelvir could potentially help eliminate residual viral material and reduce persistent symptoms such as chronic fatigue, brain fog, concentration difficulties, or shortness of breath.

However, caution is warranted. Long COVID is likely a multifactorial condition that cannot be explained by a single mechanism.

To date, clinical evidence remains limited. Several trials are currently evaluating ensitrelvir and other antivirals in patients with long COVID, but there is still no solid proof of efficacy. Early results are interesting, but not yet sufficient to recommend routine use for this indication.

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Japanese COVID-19 Antiviral Raises New Questions About Rapid Testing Access and Long COVID

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