Emerging treatments

Baloxavir marboxil

Baloxavir marboxil is a cap-dependent endonuclease inhibitor that inhibits influenza virus polymerase and, therefore, has a different mode of action to the neuraminidase inhibitors. It is approved in the US for the treatment of acute, uncomplicated influenza in people 12 years of age and older, and has also been approved in other countries. Inhibition of replication of avian A(H7N9) viruses has been demonstrated in vitro and in vivo,[175] but there are no data on efficacy in infected humans and no data on dosing or efficacy of baloxavir marboxil for treatment of hospitalised patients with seasonal influenza. Using baloxavir marboxil alone as a first-line therapy for A(H7N9) patients is not recommended. Markers of resistance to baloxavir marboxil emerged in 9.7% to 23.4% of participants in clinical trials of baloxavir marboxil for the early treatment of outpatients with seasonal influenza.[176][177][178][179] A cap-dependent endonuclease inhibitor in combination with a neuraminidase inhibitor, with or without ribavirin, should be given only in the context of a controlled clinical research study.

M2 inhibitors

Giving M2 inhibitors (amantadine or rimantadine) alone as a first-line therapy is not recommended. Virus isolates from humans demonstrate inherent resistance to M2 inhibitors. M2 inhibitors have been used in combination with other antivirals (with possible synergistic action) to treat influenza A virus infections in experimental settings only. An M2 inhibitor in combination with a neuraminidase inhibitor, with or without ribavirin, should be given only in the context of a clinical research study.

Convalescent plasma

There is only one published case report of uncontrolled treatment and no clinical trials of convalescent plasma for treatment of Asian lineage A(H7N9) virus infection. In January 2015, a 45-year-old male patient with respiratory failure and confirmed Asian lineage A(H7N9) virus infection was treated with oseltamivir. Convalescent plasma collected from an H7N9 patient who had recovered from A(H7N9) virus infection 9 months earlier was added for treatment, with associated resolution of A(H7N9) virus shedding and full recovery.[180] In June 2006, a 31-year-old male patient with highly pathogenic avian influenza (HPAI) A(H5N1) virus infection was treated with convalescent plasma that was obtained from a patient who had recovered from A(H5N1) illness earlier that year. HPAI A(H5N1) viral load from respiratory specimens decreased after 3 doses of convalescent plasma, with undetectable levels within 32 hours.[181] Two other HPAI A(H5N1) virus-infected patients who received convalescent plasma from a recovered A(H5N1) case or an A(H5N1) vaccine recipient have been reported.[182] A clinical trial assessing the use of A(H5N1) vaccine to generate levels of antibodies sufficient for use as convalescent plasma therapy has been completed.[183] Twenty-three patients received high antibody-titre convalescent plasma as part of a prospective cohort study of 93 patients with severe influenza A(H1N1)pdm09 virus infection. Mortality in the treatment group was significantly lower than in the non-treatment group (20.0% vs. 54.8%; p = 0.01). Reductions in respiratory tract viral load and serum cytokines were also seen.[184] Convalescent plasma therapy is experimental and not yet approved for clinical use in the treatment of illness caused by any influenza virus.

Intravenous neuraminidase inhibitors

Parenteral formulations of neuraminidase inhibitors have been developed and may be of use for specific clinical circumstances. Intravenous peramivir[185][186][187] is licensed in the US for early treatment of uncomplicated seasonal influenza in people aged 2 years and older, and is also approved in Japan, Europe, and the Republic of Korea. Common resistance mutations in seasonal influenza viruses that confer resistance to oseltamivir typically confer resistance to peramivir as well; oseltamivir-resistance mutations in Asian lineage A(H7N9) virus infection may also confer resistance to peramivir. Intravenous zanamivir was approved for the treatment of patients 6 months of age and older with complicated and potentially life-threatening influenza in Europe in 2019, but is not approved in the US. One study of intravenous zanamivir versus oral oseltamivir for treatment of seasonal influenza in hospitalised patients did not demonstrate superiority.[188] During and after the 2009-10 H1N1 influenza pandemic, intravenous zanamivir was provided internationally by the manufacturer through a compassionate-use programme for patients with seasonal influenza who met specific prescribing criteria, but it is no longer available in the US. Although some oseltamivir-resistant influenza A viruses remain sensitive to zanamivir, some mutations can confer reduced susceptibility or resistance to zanamivir, in addition to oseltamivir and peramivir. A(H7N9) viruses resistant to all neuraminidase inhibitors have emerged during the treatment of some H7N9 patients in China.[37][52] Multiple mutations can also occur; specialist antiviral susceptibility testing is recommended. The World Health Organization (WHO) recommends that treatment with intravenous neuraminidase inhibitors should be used in accordance with relevant emergency-use provisions.[142]

Laninamivir

Laninamivir is a new inhaled neuraminidase inhibitor that was approved in Japan for use against seasonal influenza. It is chemically similar to zanamivir, and is converted into its active form in the lungs where higher concentrations of the drug persist, permitting treatment of seasonal influenza with a single drug dose. Asian lineage A(H7N9) virus isolates appear to be sensitive to laninamivir in vitro.[99] Little is known about the clinical efficacy of laninamivir against Asian lineage A(H7N9) virus infection, and it is not currently recommended for this purpose.[189]

Favipiravir

Favipiravir is a new oral agent that has been approved in Japan for treatment of novel or re-emerging influenza virus infections in adults (limited to cases in which other anti-influenza virus drugs are ineffective or not sufficiently effective). The mechanism of action is inhibition of the RNA polymerase of influenza viruses.[190] Although in-vitro data have demonstrated inhibition of Asian lineage A(H7N9) low-pathogenic avian influenza (LPAI) viruses by favipiravir, informative clinical data on the use of favipiravir in the treatment of A(H7N9) virus infection or severe seasonal influenza are lacking.

Ribavirin

Although not licensed for the treatment of influenza in most countries, ribavirin has been demonstrated to increase efficacy of oseltamivir against some A(H5N1) viruses in mouse models.[191] However, studies of severe acute respiratory syndrome (SARS) coronavirus-infected patients treated with ribavirin have found strong associations between high-dose therapy and progressive haemolytic anaemia.[192] A WHO panel concluded that there is insufficient data on either its efficacy or safety to recommend its use for the treatment of influenza.[142] This conclusion may be extended to the treatment of A(H7N9) virus infection. Combination therapy using ribavirin with an M2 inhibitors and a neuraminidase inhibitor should be restricted to a clinical trial setting.

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