Viral Infections


Table 1: Indications for Antiviral Therapy Antiviral Recommended


Severe, complicated, or progressive illness Hospitalisation


High risk for complications • Age <2 years or >65 years • Pulmonary, cardiovascular, renal, hepatic, haematological, neurological, metabolic conditions (including diabetes), immunosuppression, pregnant or post-partum state, age <19 on long-term aspirin therapy, Alaskan Natives, Native Americans, body mass index >40, residents of chronic-care facilities


Antiviral Treatment Considered


Any previously healthy, non-high-risk, symptomatic outpatient with confirmed or suspected influenza based upon clinical judgment, if treatment can be initiated within 48 hours of illness onset


Table 2: Drug Resistance by Genetic Mutation Mutation


Resistance Conferred


H274Y/H275Y (NA gene) Confers resistance to oseltamivir with cross resistance to peramivir; widespread in seasonal H1N1 (pre-2009), seen in isolated cases of 2009 H1N1 and H5N1


S31N (M2 gene) Q136K (NA gene)


Confers resistance to adamantanes; seen in virtually all H3N2 and 2009 H1N1 isolates


Confers resistance to zanamivir; very rare; cross-resistance to peramivir


Table 3: Vaccine Type, Dose and Age Indication Vaccine Type


Standard trivalent inactivated injectable vaccine (45 µg) Live-attenuated trivalent nasal spray vaccine (FluMist™) High-dose trivalent inactivated injectable vaccine (FluZone High Dose™, 180 µg)


Intradermal trivalent inactivated injectable vaccine (Fluzone intradermal, 27 µg)


The Antiviral Agents The Adamantanes


Amantadine and rimantidine, members of the adamantane class of antiviral drugs, which block the function of the influenza M2 protein, have largely been supplanted because of the near-universal resistance of H3N2 and 2009 H1N1 to this class of agents. Moreover, adamantanes have no activity against influenza B.11


Neuraminidase Inhibitors


There are two neuraminidase inhibitors available in the US (oseltamivir and zanamivir) and two additional agents are available in Japan (peramivir and laninamivir).12


Neuraminidase inhibitors are active against


both influenza A and B and are the mainstay of treatment for influenza. The main limitation with both oseltamivir and zanamivir are their modes of delivery. Oseltamivir is available only in an oral formulation while zanamivir is available solely via the inhalational route.13


(at a reduced dose).15 However, in severe cases longer treatment


duration and higher administered dosages have been advocated, sometimes guided by the duration of influenza PCR/culture positivity.16


Ribavirin


Used in the treatment of hepatitis C and respiratory synctial virus (RSV) – two other RNA viral diseases – the nucleoside analogue ribavirin is known to have activity against influenza A and B and was once submitted for FDA approval for that indication. Robust studies detailing its efficacy are lacking, however it has been used for influenza treatment in its oral, inhalational and intravenous (via an investigational drug application) forms for influenza. Its side-effect profile (haemolytic anaemia and teratogenicity) will likely preclude its widespread use.17


Combination Therapy


Although it has not been studied in randomised controlled trials, dual therapy with agents from both the adamantane and neuraminidase inhibitor class has been used successfully and advocated in cases with the highly fatal H5N1 avian influenza strains.18


More recent data


A triple-combination pill containing amantadine, ribavirin and oseltamivir is also under development.20


using both oseltamivir and zanamivir have not shown benefit for dual use.19


Age Indication All ages


Ages 2–49 Age >65


Ages 18–64


Influenza Antiviral Resistance as a Distinct Discipline As has become apparent with HIV, resistance testing and understanding of genotypic implications for treatment decisions can become very complex. Influenza’s myriad subspecies, clades, and subtypes make it difficult for healthcare providers to keep abreast of which drug is best for which virus. One hundred per cent oseltamivir resistance in H1N1 isolates with 100 % adamantane sensitivity juxtaposed with the opposite scenario in H3N2 – the situation pre-2009 H1N1 – is difficult for clinicians to comprehend and consequently can have a deleterious effect on prescribing practices. Use of resistance testing, similar to the paradigm of HIV, is needed.21


Of the many mutations that can confer


resistance to antiviral agents in influenza, three antiviral mutations in influenza merit close study by clinicians (see Table 2).22,23


Neuraminidase Inhibitor Resistance Explained Neuraminidase inhibitors are all derived from a parent compound known as 2-deoxy-2,3-didehydro-N-acetylneuraminic acid (DANA), which binds avidly to the viral neuraminidase active site. Oseltamivir includes two modifications from the DANA structure that require an active site conformation change for binding. This area is a site of resistance mutations (e.g. H275Y). Zanamivir has one modification from the DANA structure and is, therefore, less susceptible to resistance, while peramivir cross-resistance occurs in oseltamivir-resistant viruses because peramivir and oseltamivir are similar in structure.24


Influenza Vaccination is Now Universally Recommended


Because of these


limitations, during the 2009 H1N1 pandemic, an intravenous formulation of peramivir was used via an Emergency Use Authorization (EUA) from the US Food and Drug Administration (FDA).14 zanamivir was available via ‘compassionate use’.


Additionally, intravenous


Four Formulations of Influenza Vaccine are Available


The duration of treatment with neuraminidase inhibitors is generally five days for treatment and seven days after exposure for prophylaxis


116


There are currently four different unadjuvanted vaccines available in the US (see Table 3).27,28


The live-attenuated vaccine has shown greater EUROPEAN INFECTIOUS DISEASE


For the upcoming season, influenza vaccine is now recommended for all age groups greater than six months. Prior season vaccination rates have varied, with the most recent season showing a median uptake rate of approximately 40 % for the seasonal vaccine and 24 % for the 2009 monovalent H1N1 vaccine.25,26


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