麻豆传媒

An investigational oral antiviral drug eased bronchiolitis and was safe for children 2 years and younger hospitalized with respiratory syncytial virus (RSV) infection, according to a phase III trial in China.

From baseline to day 3, the RSV F protein inhibitor ziresovir resulted in a 30% greater decrease in the Wang bronchiolitis clinical score compared with placebo (-3.4 vs -2.7 points; difference -0.8 points, 95% CI -1.3 to -0.3). The proportion of children with a reduction of at least 75% on the 0-12 scale at day 3 also favored the ziresovir group (OR 2.73, 95% CI 1.14-6.54).

Additionally, nasopharyngeal RSV viral load reduction from baseline at day 5 was significantly greater in the ziresovir group than the placebo group (difference -0.6 log₁₀ copies/mL, 95% CI -1.1 to -0.2), Xin Ni, MD, PhD, of the Beijing Children's Hospital, and colleagues reported in the .

No safety concerns were identified, according to the study authors, with adverse events occurring in 16% of the infants and young children randomized to ziresovir versus 13% of those allocated to placebo.

"These initial findings warrant further evaluation in an international, phase 3 trial of ziresovir treatment for RSV infection," wrote Ni and co-authors.

A key caveat to the so-called AIRFLO trial, which involved children ages 1 to 24 months, is that the Wang bronchiolitis clinical score has not been fully validated for use in studies of RSV infection. The question is whether improvement by this scale can be translated to clinical improvement, Edward Walsh, MD, of the University of Rochester in New York, commented in an .

The scale rates the severity of lower respiratory tract infection signs and symptoms, including wheezing, respiratory rate, retraction of respiratory muscles, and general condition as subscores on a scale of 0 to 3 (most severe).

It remains to be seen whether changes in the bronchiolitis score correlate with important outcomes such as earlier hospital discharge or fewer ICU admissions, Walsh pointed out.

Moreover, in AIRFLO, the median time from symptom onset to first ziresovir dose was 4 days, "a time when the viral load is already declining," Walsh noted. However, severity of illness in RSV infection appears to be driven by early virus-induced inflammation, not by viral load, so earlier treatment with ziresovir in the outpatient setting, "especially in the youngest infants or those with prematurity, who are at the highest risk for hospitalization," could prove more effective, he commented.

One implication of early treatment with ziresovir would be the potential to benefit children 2 to 5 years of age with underlying high-risk conditions as well as infants with RSV presenting at emergency departments, Walsh noted.

Also, the positive results of AIRFLO "may portend clinical benefits in persons with severe immunosuppression, a group in dire need of an effective RSV antiviral agent," he posited.

Current strategies to prevent severe RSV disease in infants include maternal vaccination with the RSV prefusion F vaccine (Abrysvo) or the monoclonal antibody nirsevimab (Beyfortus) for infants and some children at high risk for severe disease.

Ni's group reported that the present study results were consistent across subgroups at high risk for adverse outcomes -- namely those with a baseline bronchiolitis score of at least 8 and those 6 months of age or younger.

The AIRFLO trial had been conducted in over two dozen Chinese hospitals. It was designed with two parts: the first evaluating safety and pharmacokinetics, and the second assessing efficacy.

Investigators had 164 patients randomized to ziresovir and 80 to placebo in the intention-to-treat population, the cohort counting all participants with RSV-confirmed infection who received at least one dose of ziresovir or placebo. The larger safety population, including all patients receiving at least one of their assigned treatments, included 200 children in the ziresovir group and 102 assigned placebo.

Between study arms, most participants were boys, 61% to 62% were 6 months of age or younger, and about 90% were of the Han Chinese ethnic group. Demographic characteristics were well balanced, according to the authors.

Dosing of ziresovir or placebo was 10 mg for children weighing 2.5 to 5 kg, 20 mg for those weighing 5 to 10 kg, and 40 mg for those weighing more than 10 to 20 kg. Participants received ziresovir or placebo every 12 hours for 5 days.

Ni's group reported that the mean Wang bronchiolitis clinical score at baseline was approximately 6.6 to 6.9 across treatment and placebo groups. Over 70% of all participants had bronchodilator use within 2 days before the first dose of ziresovir or placebo and about 40% to 44% received supplemental oxygen or noninvasive positive-pressure ventilation at baseline. No participants were admitted to the ICU during the treatment period.

The most common adverse events related to treatment with ziresovir were diarrhea, elevated liver-enzymes, rash, and thrombocytosis. In the ziresovir group, 3% of participants had adverse events leading to treatment discontinuation, including grade 2 or 3 rash, grade 3 thrombocytopenia, grade 4 anomalous pulmonary venous connection, and grade 2 pneumonia.

Evidence of resistance-associated mutations were found in 9% of treated patients during follow-up. However, researchers observed no correlation between resistance mutations and viral rebound.

Ni and colleagues pointed out that the trial was conducted exclusively in China and results may not be applicable to other patient populations or clinical practices outside of that country.

Comment