Protecting High-Risk Populations: The Role of Specific Antivirals in Preventing Severe Outcomes

The rationale of the study published in The Lancet Infectious Diseases is twofold: the prevention of serious forms remains a priority in vulnerable subjects, while the reduction in severity makes “hard” criteria rare and not very informative. In an open-label randomized platform conducted in Thailand and Laos in low-risk adults symptomatic for less than 4 days, ensitrelvir and nirmatrelvir-ritonavir for 5 days were compared to no treatment.

Between March 2023 and April 2024, 604 patients were concomitantly randomized (ensitrelvir n=202, nirmatrelvir-ritonavir n=207, control n=195). The primary endpoint, the modeled oropharyngeal viral clearance rate (D0–D5), shows a median half-life of 5.9 h [IQR 4,0–8,6] sous ensitrelvir, 5,2 h [3,8–6,6] under nirmatrelvir/ritonavir, versus 11.6 h [8,1–14,5] without treatment.

Ensitrelvir accelerates clearance by 82% (ICr 61–104) vs. no treatment and is 16% slower (5–25) than nirmatrelvir-ritonavir. In individual meta-analysis of the “small molecule” arms of the platform (n=1157), these two antivirals provide the most marked in vivo antiviral effects.

Accelerate oropharyngeal viral clearance

No major clinical differences are observed in the evolution of symptoms, which are expected to be uncommon in this low-risk population. Virological rebounds remain rare and comparable: 7% (15/207) under nirmatrelvir-ritonavir versus 5% (10/202) under ensitrelvir (p=0.45). Tolerance distinguishes the 2 options: more than a quarter of patients taking nirmatrelvir-ritonavir report bothersome dysgeusia; this effect is not found with ensitrelvir.

On a practical level, ensitrelvir offers daily dosing and the absence of the need for “boosting” with ritonavir, with inhibition of CYP3A4, less than ritonavir but exposing it to common contraindications in polymedicated subjects. The question of availability and cost, determining for outpatient access, remains central for both molecules, with registration of ensitrelvir currently limited to a few countries.

Measure what matters today

The open-label, phase 2, adaptive, block-randomized trial included adults aged 18–60 years, low risk, with repeated oropharyngeal samples (4 on D0, then 2/d from D1 to D7, then D10 and D14) and hierarchical Bayesian modeling of log10 viral densities to estimate an individual clearance rate. This strategy favors an antiviral response biomarker validated at the start of the pandemic, transposing the evaluation of effectiveness to realistic numbers when hospitalizations and deaths have become rare. The limits are explicit: absence of direct evaluation of the prevention of serious forms, population restricted geographically and in age/risk, low power for rebounds and clinical events, impossibility of inferring the benefit in the very elderly or immunocompromised. Nevertheless, the consistency of the internal meta-analysis strengthens the comparative estimation of antiviral effects.

According to the authors, the data support the use of ensitrelvir as an alternative when nirmatrelvir/ritonavir is contraindicated (interactions, tolerance) or difficult to access, in particular thanks to a once-daily regimen. In fragile patients, clinical translation must be confirmed by targeted studies on severe criteria, optimization of treatment windows, and exploration of combinations/sequential strategies, including in the face of new variants and other respiratory viruses. In the short term, integrating a systematic evaluation of interactions (CYP3A4) and access routes in the city determines the real impact of these antivirals. In a context of a disease that has become milder in the general population but still at risk in the vulnerable, a pharmacometric approach focused on viral kinetics makes it possible to compare antivirals without resorting to excessive numbers of people.

What are the key considerations when determining the appropriate antiviral prophylaxis strategy for immunocompromised individuals?

Understanding Vulnerability & Antiviral Prophylaxis

Certain populations are disproportionately affected by viral infections, facing a higher risk of severe illness, hospitalization, and even death. These high-risk populations include the elderly, immunocompromised individuals (those with HIV/AIDS, undergoing chemotherapy, or with autoimmune diseases), people with chronic conditions like heart disease or diabetes, and pregnant women. Antiviral prophylaxis,the use of antiviral medications before exposure to a virus or shortly after,plays a crucial role in mitigating these risks. This isn’t simply about treating illness; it’s about preventing it from becoming severe.

Identifying High-Risk Groups: A Closer look

* Age: Immune function naturally declines with age (immunosenescence), making older adults more susceptible.

* Immunocompromise: Conditions or treatments suppressing the immune system severely limit the body’s ability to fight off infection. This includes organ transplant recipients on immunosuppressants.

* Chronic Diseases: Underlying health issues can exacerbate the effects of viral infections. Chronic lung disease, heart failure, and diabetes are notably concerning.

* Pregnancy: Physiological changes during pregnancy can alter immune responses, increasing vulnerability to certain viruses like influenza and COVID-19.

* Healthcare Workers: Frequent exposure to pathogens puts healthcare professionals at elevated risk.

Specific Antivirals & Their Applications

The choice of antiviral depends heavily on the specific virus and the individual’s risk factors. Here’s a breakdown of key antivirals and their roles in protecting vulnerable groups:

Influenza: Neuraminidase Inhibitors & Beyond

For influenza, neuraminidase inhibitors (like oseltamivir – Tamiflu – and zanamivir – Relenza) are the mainstay of prophylaxis. They work by preventing the virus from spreading within the body.

* Prophylactic Use: Recommended for close contacts of individuals with confirmed influenza, particularly in nursing homes or long-term care facilities.

* Timing is Critical: Antivirals are most effective when started within 48 hours of symptom onset, but prophylactic use before exposure is also valuable.

* Baloxavir marboxil (Xofluza): A newer option offering a single-dose regimen, showing promise in reducing influenza severity, though it’s prophylactic use is still evolving.

Respiratory Syncytial Virus (RSV): Palivizumab & Nirsevimab

RSV is a significant threat to infants and young children, as well as older adults.

* Palivizumab (Synagis): A monoclonal antibody traditionally used for passive immunization in high-risk infants (premature babies, those with congenital heart disease, or chronic lung disease). administered monthly during RSV season.

* Nirsevimab (Beyfortus): A newer long-acting monoclonal antibody offering broader protection against RSV for infants, administered as a single dose. This represents a significant advancement in RSV prevention.

* Importance of Vaccination: While not an antiviral, maternal RSV vaccination during pregnancy provides passive immunity to the newborn.

Herpesviruses: Acyclovir, valacyclovir & Famciclovir

Herpesviruses (HSV-1, HSV-2, VZV – causing chickenpox and shingles) can cause severe complications in immunocompromised individuals.

* Acyclovir, Valacyclovir, and Famciclovir: These antivirals suppress viral replication, preventing outbreaks and reducing the risk of complications like encephalitis or disseminated herpes.

* Prophylaxis for Transplant Recipients: Often used long-term in organ transplant recipients to prevent CMV (cytomegalovirus) infection, a major cause of morbidity and mortality.

* Shingles Prevention: Valacyclovir can be used prophylactically in immunocompromised patients to prevent herpes zoster (shingles).

COVID-19: Paxlovid & Remdesivir

The COVID-19 pandemic highlighted the importance of antiviral interventions.

* Paxlovid (nirmatrelvir/ritonavir): An oral antiviral significantly reducing the risk of hospitalization and death in high-risk individuals when administered early in the course of infection. Early treatment is paramount.

* Remdesivir: An intravenous antiviral used for hospitalized patients with severe COVID-19, and sometimes considered for non-hospitalized high-risk individuals.

* Evolving Variants: Ongoing monitoring of viral variants is crucial to ensure antiviral effectiveness.

Benefits of Antiviral Prophylaxis

* Reduced Severity of Illness: Even if infection occurs, antivirals can lessen the severity of symptoms.

* Lower Hospitalization Rates: Prophylaxis can prevent the need for hospitalization, freeing up healthcare resources.

* Decreased Mortality: In vulnerable populations, antivirals can significantly reduce the risk of death.

* Improved Quality of Life: Preventing severe illness allows individuals to maintain their daily activities and overall well-being.

* Public Health Impact: reducing transmission through prophylactic use contributes to broader community protection.

Practical Tips & Considerations

* Vaccination First: Vaccination remains the primary defense against many viral infections. Antivirals are often used in addition to vaccination, not as a replacement.

* Early Intervention: The sooner an antiviral