Reply to Abed et al

TO THE EDITOR—Abed and colleagues [1] stress the importance of rigorous evaluation of new antivirals for patients infected with influenza viruses that have developed resistance to approved antiviral drugs. They suggest that the observed shift in susceptibility to peramivir in H275Y mutants in 2009 pandemic influenza A H1N1 viruses may not be clinically significant and that controlled human trials are needed to confirm the efficacy of intravenous peramivir against H275Y mutants. We agree with Abed and colleagues that controlled clinical trials are needed to confirm the efficacy of intravenous peramivir, especially in treatment of patients infected with oseltamivir-resistant pandemic influenza A H1N1 viruses, but we also believe that case reports of clinical treatment failure and evidence of rapidly developing decreased sensitivity to neuraminidase inhibitors, including peramivir, are extremely important and should be considered when therapeutic strategies for complicated influenza infection are designed and evaluated. In their letter [1], Abed et al cite some of the intrinsic properties of peramivir as important in determining efficacy, and they review data from mouse models that showed that animals infected with a mouse-adapted influenza A H1N1 virus, A/WSN/33, engineered with the H275Y mutation, responded well to prophylactic peramivir in both single and multidose regimens. It is important to note that the phenotypic consequences of acquiring the neuraminidase H275Y mutation in influenza A H1N1 viruses are not uniform and are context dependent in relation to the overall genetic makeup of the viral strain. For example, many oseltamivir-resistant seasonal influenza A H1N1 virus strains in the past decade were also associated with a significant decrease in viral fitness, whereas most seasonal strains isolated after 2007 with the identical mutation had no evident fitness loss [2–4]. In our recent study [5], we demonstrated that H275Y-bearing 2009 pandemic influenza A H1N1 virus strains isolated from immunocompromised patients after treatment [6] also had no in vitro or in vivo fitness loss as compared with their initial neuraminidase inhibitor-sensitive viral isolates. Importantly, there was likewise no loss of transmissibility in the well-established ferret model. This viral phenotypic variability makes it difficult to extrapolate the fitness effect that mutations such as H275Y will have on one viral strain compared with another. It is also currently difficult to correlate the clinical significance of decreased sensitivity of influenza viruses to different neuraminidase inhibitors in vitro, and the currently accepted definition is based primarily on data collected on oseltamivir resistance [7]. In the 2 clinical cases we recently reported on and described above, we documented the rapid development of the H275Y mutation in patients with complicated 2009 pandemic H1N1 influenza infections. In both cases, the viruses isolated demonstrated reduced sensitivity to peramivir in vitro, and in 1 patient who received a full course of intravenous peramivir, there was no reduction in symptoms or viral shedding [6]. Although this case was an isolated example, this clinical failure of intravenous peramivir may be an indicator that peramivir might not be an optimal or effective therapy after oseltamivir failure, and this should ideally be considered when developing future clinical studies of such agents. Given that peramivir is administered parenterally, it is not an ideal prophylactic agent and is targeted for patients who require intravenous administration of the drug. These patients primarily include those who are severely ill, require hospitalization, or are unable to receive oral administration of drugs. In many cases, such individuals will be immunocompromised or will have significant underlying medical conditions that put them at high risk for complicated influenza infection. These patients pose a unique challenge to physicians, even in the absence of resistance mutations. Infection with resistant strains or development of antiviral resistance during treatment (as occurred in these 2 cases) may make treatment of such patients even more problematic. Rapidly developing neuraminidase inhibitor resistance has now been identified in cases of seasonal influenza, 2009 pandemic H1N1 influenza, and highly pathogenic avian H5N1 influenza [6, 7–10], and currently available influenza therapeutic options are clearly not adequate for treating more severely ill and high-risk individuals. The reported case [6] describing the failure of intravenous peramivir to clear viral shedding after the failure of oseltamivir treatment is instructive and should serve as a clear indicator that we need to carefully evaluate our antiviral treatment protocols, including how best to use peramivir and other new antivirals in different clinical contexts. More importantly, we need to develop new classes of drugs for treatment of influenza-induced illness in these difficult clinical situations.