Viral Kinetics and Resistance Development in Children Treated with Neuraminidase Inhibitors: The Influenza Resistance Information Study (IRIS)

Abstract

Background We studied the effect of age, baseline viral load, vaccination status, antiviral therapy, and emergence of drug resistance on viral shedding in children infected with influenza A or B virus. Methods Samples from children (aged ≤13 years) enrolled during the 7 years of the prospective Influenza Resistance Information Study were analyzed using polymerase chain reaction to determine the influenza virus (sub-)type, viral load, and resistance mutations. Disease severity was assessed; clinical symptoms were recorded. The association of age with viral load and viral clearance was examined by determining the area under the curve for viral RNA shedding using logistic regression and Kaplan-Meier analyses. Results A total of 2131 children infected with influenza (683, A/H1N1pdm09; 825, A/H3N2; 623, influenza B) were investigated. Age did not affect the mean baseline viral load. Children aged 1−5 years had prolonged viral RNA shedding (±1–2 days) compared with older children and up to 1.2-fold higher total viral burden. Besides, in older age (odds ratio [OR], 1.08; confidence interval [CI], 1.05–1.12), prior vaccination status (OR, 1.72; CI, 1.22–2.43) and antiviral treatment (OR, 1.74; CI, 1.43–2.12) increased the rate of viral clearance. Resistance mutations were detected in 49 children infected with influenza A virus (34, A/H1N1pdm09; 15, A/H3N2) treated with oseltamivir, most of whom were aged <5 years (n = 39). Conclusions Children aged 1−5 years had a higher total viral burden with prolonged virus shedding and had an increased risk of acquiring resistance mutations following antiviral treatment. Clinical Trials Registration NCT00884117.

Clinical impact of nosocomial infection with pandemic influenza A (H1N1) 2009 in a respiratory ward in Guangzhou

“…The patients recovered from influenza after antiviral treatment with oseltamivir. Studies have shown that prolonged shedding of the virus is associated with drug resistance (35,36). However, the common drug resistance mutation H275Y in the NA protein was not identified in the isolates in our study.…”

Clinical and virological outcomes with baloxavir compared with oseltamivir in pediatric patients aged 6 to < 12 years with influenza: an open-label, randomized, active-controlled trial protocol

“…The present study will be one of the first to assess treatment-emergent amino-acid substitutions for both PA and NA among children treated with baloxavir and oseltamivir in the same study. Several studies suggest that treatment-emergent antiviral resistance is more likely to emerge in children than in adults [ 27 , 28 , 31 , 32 ], which is of concern because of the potential risk of transmission of virus variants to close contacts [ 33 ]. The frequency of treatment-emergent PA/I38X amino-acid substitutions that are associated with reduced susceptibility to baloxavir has been shown to be more than twofold higher in children than in adults [ 27 , 28 ].…”

“…The frequency of treatment-emergent PA/I38X amino-acid substitutions that are associated with reduced susceptibility to baloxavir has been shown to be more than twofold higher in children than in adults [ 27 , 28 ]. Findings from a global 7-year surveillance study showed that treatment-emergent resistance to oseltamivir (NA/H275Y for N1 viruses and NA/R292K for N2 viruses) is highest among young children (1–5 years) compared with adults and older children or adolescents [ 31 , 32 ]. Although it has not been established why young children may be more susceptible to the emergence of antiviral treatment resistance, it is thought that influenza virus variants emerge in response to selective pressure during drug treatment, possibly as a result of the immature immune response in children, at a time when drug concentrations in plasma have started to wane [ 27 , 28 , 32 ].…”

The Importance of Vaccinating Children and Pregnant Women against Influenza Virus Infection

“…Similarly, data suggested that a high viral load and a strong cytokine response contributed to mortality in humans infected with H5N1 influenza virus [95]. One recent study demonstrated that children between one and five years of age had higher viral loads compared to older children, perhaps contributing to their increased susceptibility to influenza virus infection [96]. While these results seem to indicate that decreasing viral load would lead to improved outcomes, a recent phase III clinical trial demonstrated that transfer of sera containing high levels of anti-influenza antibody into patients with severe influenza virus infection did not lead to detectable benefit [97].…”