baloxavir – ETIDIoH

Development of cycling #probe based real-time #PCR methodology for #influenza A viruses possessing the #PA/I38T amino acid #substitution associated with reduced #baloxavir susceptibility (Antiviral Res., abstract)

[Source: Antiviral Research, full page: (LINK). Abstract, edited.]

Antiviral Research | Available online 10 February 2021, 105036 | In Press, Journal Pre-proof

Development of cycling probe based real-time PCR methodology for influenza A viruses possessing the PA/I38T amino acid substitution associated with reduced baloxavir susceptibility

Hidekazu Osada a,b, Irina Chon a, Wint Wint Phyu a, Keita Wagatsuma a, Nobuo Nagata c, Takashi Kawashim a,d, Isamu Sato e, Tadashi Saito f, Naoki Kodo g, Hironori Masaki h, Norichika Asoh i, Yoshiko Tuchihashi i, Yutaka Shirahige j, Yasuhiko Ono k, Yasushi Shimada l, Hirotsune Hamabata m, Kousuke Saito a, Reiko Saito a,b

a Division of International Health (Public Health), Graduate School of Medical and Dental Sciences, Niigata University, Niigata, Niigata, Japan; b Infectious Diseases Research Center of Niigata University in Myanmar, Yangon, Yangon Region, Myanmar; c Hiraoka-Kohen Pediatric Clinic, Sapporo, Hokkaido, Japan; d Kawashima Clinic, Shibukawa, Gunma, Japan; e Yoiko-no-Syounika Sato Pediatric Clinic, Niigata, Niigata, Japan; f Pediatric Department, Tako Central Hospital, Katori, Chiba, Japan; g Kodo Pediatric Clinic, Uji, Kyoto, Japan; h Masaki Respiratory Medicine Clinic, Nagasaki, Nagasaki, Japan; i Juzenkai Hospital, Nagasaki, Nagasaki, Japan; j Shirahige Clinic, Nagasaki, Nagasaki, Japan; k Ono Pediatric Clinic, Isahaya, Nagasaki, Japan; l Shimada Children′s Clinic, Kamiamakusa, Kumamoto, Japan; m Awase Daiichi Clinic, Okinawa, Okinawa, Japan

Received 15 May 2020, Revised 4 February 2021, Accepted 6 February 2021, Available online 10 February 2021.

DOI: https://doi.org/10.1016/j.antiviral.2021.105036

Highlights

We established cycling probe Real-time PCR systems to detect influenza A viruses with PA/I38T.
Pre-treatment prevalence of the PA/I38T mutant virus was 0.0% (0/129) for A(H1N1)pdm09 and 1.7% (4/229) for A/H3N2.
A(H3N2) PA/I38T viruses may be transmitted among humans in closed environments.

Abstract

Baloxavir marboxil has been used for influenza treatment since March 2018 in Japan. After baloxavir treatment, the most frequently detected substitution is Ile38Thr in polymerase acidic protein (PA/I38T), and this substitution reduces baloxavir susceptibility in influenza A viruses. To rapidly investigate the frequency of PA/I38T in influenza A(H1N1)pdm09 and A(H3N2) viruses in clinical samples, we established a rapid real-time system to detect single nucleotide polymorphisms in PA, using cycling probe real-time PCR. We designed two sets of probes that were labeled with either 6-carboxyfluorescein (FAM) or 6-carboxy-X-rhodamine (ROX) to identify PA/I38 (wild type strain) or PA/I38T, respectively. The established cycling probe real-time PCR system showed a dynamic linear range of 101 to 106 copies with high sensitivity in plasmid DNA controls. This real-time PCR system discriminated between PA/I38T and wild type viruses well. During the 2018/19 season, 377 influenza A-positive clinical samples were collected in Japan before antiviral treatment. Using our cycling probe real-time PCR system, we detected no (0/129, 0.0%) influenza A(H1N1)pdm09 viruses with PA/I38T substitutions and four A(H3N2) (4/229, 1.7%) with PA/I38T substitution prior to treatment. In addition, we found PA/I38T variant in siblings who did not received baloxavir treatment during an infection caused by A(H3N2) that afflicted the entire family. Although human-to-human transmission of PA/I38T variant may have occurred in a closed environment, the prevalence of this variant in influenza A viruses was still limited. Our cycling probe-PCR system is thus useful for antiviral surveillance of influenza A viruses possessing PA/I38T.

Keywords: influenza virus – baloxavir marboxil – PA/I38T substitution – cycling probe real-time PCR – antiviral susceptibility

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Keywords: Seasonal Influenza; H1N1pdm09; H3N2; Antivirals; Drugs Resistance; Baloxavir.

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Efficacy of a cap-dependent #endonuclease #inhibitor and #neuraminidase inhibitors against #H7N9 highly pathogenic #avian #influenza virus causing severe viral #pneumonia in cynomolgus #macaques (Antimicrob Agents Chemother., abstract)

[Source: Antimicrobial Agents and Chemotherapy, full page: (LINK). Abstract, edited.]

Efficacy of a cap-dependent endonuclease inhibitor and neuraminidase inhibitors against H7N9 highly pathogenic avian influenza virus causing severe viral pneumonia in cynomolgus macaques

Saori Suzuki, Cong Thanh Nguyen, Ayako Ogata-Nakahara, Akihiro Shibata, Hiroyuki Osaka, Hirohito Ishigaki, Masatoshi Okamatsu, Yoshihiro Sakoda, Hiroshi Kida, Kazumasa Ogasawara, Yasushi Itoh

DOI: 10.1128/AAC.01825-20

ABSTRACT

H7N9 highly pathogenic avian influenza virus (HPAIV) infection in a human was first reported in 2017. A/duck/Japan/AQ-HE29-22/2017 (H7N9) (Dk/HE29-22) found in imported duck meat at an airport in Japan possessed hemagglutinin with a multi-basic cleavage site, indicating high pathogenicity in chickens as in the case of other H7 HPAIVs. In the present study, we examined the pathogenicity of Dk/HE29-22 and the effectiveness of a cap-dependent endonuclease inhibitor (baloxavir) and neuraminidase inhibitors (oseltamivir and zanamivir) against infection with this strain in a macaque model (n = 3 for each group). All of the macaques infected with Dk/HE29-22 showed severe signs of disease and pneumonia even after the virus had disappeared from lung samples. Virus titers in macaques treated with baloxavir were significantly lower than those in the other treated groups. After infection, levels of IFN-α and IFN-β in the blood of macaques in the baloxavir group were the highest among the groups, whereas levels of TNF-α and IL-13 were slightly increased in the untreated group. In addition, immune checkpoint proteins including PD-1 and TIGIT were expressed at high levels in the untreated group, especially in one macaque that showed severe signs of disease, indicating that negative feedback responses against vigorous inflammation may contribute to disease progression. In the group treated with baloxavir, the percentages of PD-1, CTLA-4, and TIGIT-positive T lymphocytes were lower than those in the untreated group, indicating that reduction in virus titers may prevent expression of immune checkpoint molecules from downregulation of T cell responses.

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Keywords: Avian Influenza; H7N9; Antivirals; Baloxavir; Oseltamivir; Zanamivir; Animal models.

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Duration of #fever and #symptoms in #children after #treatment with #baloxavir marboxil and #oseltamivir during the 2018-2019 season and detection of variant #influenza A viruses with #PA subunit substitutions (Antiviral Res., abstract)

[Source: Antiviral Research, full page: (LINK). Abstract, edited.]

Antiviral Research | Available online 25 September 2020, 104951 | In Press, Journal Pre-proof | Research paper

Duration of fever and symptoms in children after treatment with baloxavir marboxil and oseltamivir during the 2018-2019 season and detection of variant influenza A viruses with polymerase acidic subunit substitutions

Reiko Saito a, Hidekazu Osada a, Keita Wagatsuma a, Irina Chon a, Isamu Sato b, Takashi Kawashima c, Tadashi Saito d, Naoki Kodo e, Yasuhiko Ono f, Yasushi Shimada g, Wint Wint Phyu a, Yugo Shobugawa a

a Division of International Health (Public Health), Graduate School of Medical and Dental Sciences, Niigata University, Niigata City, Japan; b Yoiko Pediatric Clinic, Niigata City, Japan; c Kawashima Internal Medicine Clinic, Shibukawa City, Japan; d Pediatric Department, Tako Central Hospital, Tako Town, Japan; e Kodo Pediatric Clinic, Uji City, Japan; f Ono Pediatric Clinic, Isahaya City, Japan; g Shimada Pediatric Clinic, Kamiamakusa City, Japan

Received 1 December 2019, Revised 19 September 2020, Accepted 22 September 2020, Available online 25 September 2020.

DOI: https://doi.org/10.1016/j.antiviral.2020.104951

Highlights

Fever duration did not differ between the baloxavir and oseltamivir treated groups.
Pre-treatment prevalence of the PA/I38T substituted virus was 1.2% for A/H3N2.
Post-treatment prevalence of PA variants was 12.5% (A/H1N1pdm09) and 14.1% (A/H3N2) based on all cases.
Frequency increased with denominator based on PCR-positives on second visit, 57.1% for A/H1N1pdm09 and 33.3% for A/H3N2.
Fever and symptom duration did not differ between the treatment-emerged PA variants and non-substituted virus infections.

Abstract

We conducted a prospective, multicenter, non-randomized observational study to assess the duration of fever and symptoms of influenza A/H1N1pdm09 and A/H3N2 infected children < 19 years old treated with either baloxavir or oseltamivir. Additionally, these symptoms were investigated in association with pre- and post-baloxavir treatment-emergent polymerase acidic unit (PA) variants as compared to non-substituted viruses. Following receipt of informed consent, baloxavir was administered to 102 influenza A patients, and oseltamivir to 52 patients during the 2018–2019 influenza season in Japan. The average age was higher in the baloxavir treatment group compared to the oseltamivir treatment group (10.6 ± 2.7 versus 6.9 ± 2.9 years old, p<0.01). The duration of fever and symptoms in baloxavir-treated A/H1N1pdm09 and A/H3N2-infected children did not differ from those in oseltamivir-treated groups (median 22.0, 11.8, 23.0, and 21.0 hours, and median 114.5, 121.0, 123.0, and 122.0 hours, respectively). One (1.2%) of 83 A/H3N2 patients possessed a PA/I38T substituted virus prior to treatment. The frequency of PA variants in post-treatment samples obtained 2-11 days after beginning of baloxavir was 12.5% (4/32) for A/H1N1pdm09 and 14.1% (9/64) for A/H3N2 when the total number of cases was used as the denominator, however, were 57.1% (4/7) and 33.3% (9/27) when PCR-positive cases at the time of second sampling was used as the denominator. The most frequent PA substitution was I38T (9), with E23K (1), I38K (1), I38M (1), and PA/I38S (1) also observed. The duration of fever and overall symptoms did not differ significantly following baloxavir treatment in individuals with PA variant viruses, non-substituted virus, or in those that were PCR negative at the second sampling (median 20, 24 and 11 hours, and median 121, 115 and 121 hours, respectively). Rebound of viral RNA load was observed in 13.5% (2/13) of PA variants but it was not associated with recurrence of fever and symptoms. Hence, prolonged fever or symptoms were not observed in children treated with baloxavir following emergence of PA variants, however, further studies are needed to evaluate the clinical impact of PA variants.

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Keywords: Seasonal Influenza; H1N1pdm09; H3N2; Pediatrics; Antivirals; Drugs Resistance; Baloxavir; Oseltamivir.

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Detection of #baloxavir #resistant #influenza A viruses using next generation sequencing and pyrosequencing methods (Antiviral Res., abstract)

[Source: Antiviral Research, full page: (LINK). Abstract, edited.]

Antiviral Research | Available online 14 August 2020, 104906 | In Press, Journal Pre-proof | Research paper

Detection of baloxavir resistant influenza A viruses using next generation sequencing and pyrosequencing methods

Mira C. Patel a, Vasiliy P. Mishin a, Juan A. De La Cruz a,b, Anton Chesnokov a, Ha T. Nguyen a,b, Malania M. Wilson a, John Barnes a, Rebecca J.G. Kondor a, David E. Wentworth a, Larisa V. Gubareva a

a Influenza Division, National Center for Immunization and Respiratory Diseases, Centers of Disease Control and Prevention, Atlanta, Georgia, USA; b Battelle Memorial Institute, Atlanta, Georgia, USA

Received 22 May 2020, Revised 15 July 2020, Accepted 5 August 2020, Available online 14 August 2020.

DOI: https://doi.org/10.1016/j.antiviral.2020.104906

Highlights

Pyrosequencing assay was optimized to improve detection of baloxavir resistant influenza A viruses in mixtures.
Detection of PA-38 variants in virus mixtures of both subtypes was improved by using customized nucleotide dispensation.
Pyrosequencing and NGS data were comparable, except for lysine at PA-38 that was detected by NGS but not by pyrosequencing.
Attempts to recover virus carrying lysine at PA-38 were unsuccessful, raising the rare possibility of an NGS artifact.
Pyrosequencing provides an important addition to genotypic methods that can be used for baloxavir susceptibility testing.

Abstract

Baloxavir, a new antiviral drug targeting cap-dependent endonuclease activity of polymerase acidic (PA) protein of influenza viruses, is now approved in multiple countries. Several substitutions at isoleucine 38 in PA protein (e.g., PA-I38T) have been associated with decreased baloxavir susceptibility in vitro and in vivo. In recent years, next generation sequencing (NGS) analysis and pyrosequencing have been used by CDC and U.S. Public Health Laboratories to monitor drug susceptibility of influenza viruses. Here we described an improved pyrosequencing assay for detecting influenza A viruses carrying substitutions at PA-38. Cyclic and customized orders of nucleotide dispensation were evaluated, and pyrosequencing results were compared to those generated using NGS. Our data showed that the customized nucleotide dispensation has improved the pyrosequencing assay performance in identification of double mixtures (e.g., PA-38I/T); however, identification of PA-38 variants in triple mixtures remains a challenge. While NGS analysis indicated the presence of PA-I38K in one clinical specimen and isolate, our attempts to detect this mutation by pyrosequencing or recover the virus carrying PA-I38K in cell culture were unsuccessful, raising a possibility of a rarely occurring sequencing error. Overall, pyrosequencing provides a convenient means to detect baloxavir resistant influenza viruses when NGS is unavailable or a faster turnaround time is required.

Funding source: This study was supported by the Influenza Division of Centers for Disease Control and Prevention (CDC). The study does not reflect the official position of the CDC but personal opinions of authors.

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Keywords: Seasonal Influenza; Influenza A; Antivirals; Baloxavir; Drugs Resistance.

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#Baloxavir Marboxil for #Prophylaxis against #Influenza in #Household Contacts (N Engl J Med., abstract)

[Source: The New England Journal of Medicine, full page: (LINK). Abstract, edited.]

Baloxavir Marboxil for Prophylaxis against Influenza in Household Contacts

Hideyuki Ikematsu, M.D., Frederick G. Hayden, M.D., Keiko Kawaguchi, M.S., Masahiro Kinoshita, M.Pharm., Menno D. de Jong, M.D., Nelson Lee, M.D., Satoru Takashima, M.S., Takeshi Noshi, M.S., Kenji Tsuchiya, M.S., and Takeki Uehara, Ph.D.

Abstract

BACKGROUND

Baloxavir marboxil (baloxavir) is a polymerase acidic protein (PA) endonuclease inhibitor with clinical efficacy in the treatment of uncomplicated influenza, including in outpatients at increased risk for complications. The postexposure prophylactic efficacy of baloxavir in the household setting is unclear.

METHODS

We conducted a multicenter, double-blind, randomized, placebo-controlled trial to evaluate the postexposure prophylactic efficacy of baloxavir in household contacts of index patients with confirmed influenza during the 2018–2019 season in Japan. The participants were assigned in a 1:1 ratio to receive either a single dose of baloxavir or placebo. The primary end point was clinical influenza, as confirmed by reverse-transcriptase–polymerase-chain-reaction testing, over a period of 10 days. The occurrence of baloxavir-selected PA substitutions associated with reduced susceptibility was assessed.

RESULTS

A total of 752 household contacts of 545 index patients were randomly assigned to receive baloxavir or placebo. Among the index patients, 95.6% had influenza A virus infection, 73.6% were younger than 12 years of age, and 52.7% received baloxavir. Among the participants who could be evaluated (374 in the baloxavir group and 375 in the placebo group), the percentage in whom clinical influenza developed was significantly lower in the baloxavir group than in the placebo group (1.9% vs. 13.6%) (adjusted risk ratio, 0.14; 95% confidence interval [CI], 0.06 to 0.30; P<0.001). Baloxavir was effective in high-risk, pediatric, and unvaccinated subgroups of participants. The risk of influenza infection, regardless of symptoms, was lower with baloxavir than with placebo (adjusted risk ratio, 0.43; 95% CI, 0.32 to 0.58). The incidence of adverse events was similar in the two groups (22.2% in the baloxavir group and 20.5% in the placebo group). In the baloxavir group, the viral PA substitutions I38T/M or E23K were detected in 10 (2.7%) and 5 (1.3%) participants, respectively. No transmission of these variants from baloxavir-treated index patients to participants in the placebo group was detected; however, several instances of transmission to participants in the baloxavir group could not be ruled out.

CONCLUSIONS

Single-dose baloxavir showed significant postexposure prophylactic efficacy in preventing influenza in household contacts of patients with influenza. (Funded by Shionogi; Japan Primary Registries Network number, JapicCTI-184180.)

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Keywords: Seasonal Influenza; Antivirals; Baloxavir.

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Successful #Treatment With #Baloxavir Marboxil of a Patient With #Peramivir #Resistant #Influenza A / #H3N2 With a Dual E119D/R292K Substitution After Allogeneic Hematopoietic Cell #Transplantation: A Case Report (BMC Infect Dis., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

BMC Infect Dis. 2020 Jul 6;20(1):478. doi: 10.1186/s12879-020-05205-1.

Successful Treatment With Baloxavir Marboxil of a Patient With Peramivir-Resistant Influenza A/H3N2 With a Dual E119D/R292K Substitution After Allogeneic Hematopoietic Cell Transplantation: A Case Report

Naonori Harada 1, Wataru Shibata 2 3, Hideo Koh 4, Emi Takashita 5, Seiichiro Fujisaki 5, Hiroshi Okamura 1, Satoru Nanno 1, Koichi Yamada 2 3, Hirohisa Nakamae 1, Masayuki Hino 1, Hiroshi Kakeya 2 3

Affiliations: 1 Hematology, Graduate School of Medicine, Osaka City University, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan. 2 Department of Infection Control Science, Graduate School of Medicine, Osaka City University, Osaka, Japan. 3 Research Center for Infectious Disease Sciences (RCIDS), Graduate School of Medicine, Osaka City University, Osaka, Japan. 4 Hematology, Graduate School of Medicine, Osaka City University, 1-4-3 Asahi-machi, Abeno-ku, Osaka, 545-8585, Japan. hide_koh@med.osaka-cu.ac.jp. 5 Influenza Virus Research Center, National Institute of Infectious Diseases, Tokyo, Japan.

PMID: 32631240 DOI: 10.1186/s12879-020-05205-1

Abstract

Background:

Extended use of oseltamivir in an immunocompromised host could reportedly induce neuraminidase gene mutation possibly leading to oseltamivir-resistant influenza A/H3N2 virus. To our knowledge, no report is available on the clinical course of a severely immunocompromised patient with a dual E119D/R292K neuraminidase mutated-influenza A/H3N2 during the administration of peramivir.

Case presentation:

A 49-year-old male patient was admitted for second allogeneic hematopoietic cell transplantation for active acute leukemia. The patient received 5 mg prednisolone and 75 mg cyclosporine and had severe lymphopenia (70/μL). At the time of hospitalization, the patient was diagnosed with upper tract influenza A virus infection, and oseltamivir treatment was initiated immediately. However, the patient was intolerant to oseltamivir. The following day, treatment was changed to peramivir. Despite a total period of neuraminidase-inhibitor administration of 16 days, the symptoms and viral shedding continued. Changing to baloxavir marboxil resolved the symptoms, and the influenza diagnostic test became negative. Subsequently, sequence analysis of the nasopharyngeal specimen revealed the dual E119D/R292K neuraminidase mutant influenza A/H3N2.

Conclusions:

In a highly immunocompromised host, clinicians should take care when peramivir is used for extended periods to treat influenza virus A/H3N2 infection as this could potentially leading to a dual E119D/R292K substitution in neuraminidase protein. Baloxavir marboxil may be one of the agents that can be used to treat this type of mutated influenza virus infection.

Keywords: Allogeneic hematopoietic cell transplantation; Baloxavir marboxil; Dual E119D/R292K substitution; Immunocompromised host; Influenza A/H3N2; Neuraminidase mutation; Peramivir resistance.

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Keywords: Seasonal Influenza; Antivirals; Drugs Resistance; Hematology; H3N2; Cancer; Immunosuppression; Peramivir; Baloxavir.

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#Influenza #H1N1pdm09 virus exhibiting reduced #susceptibility to #baloxavir due to a PA E23K #substitution detected from a #child without baloxavir #treatment (Antiviral Res., abstract)

[Source: Antiviral Research, full page: (LINK). Abstract, edited.]

Antiviral Research | Available online 20 June 2020, 104828 | In Press, Journal Pre-proof | Short Communication

Influenza A(H1N1)pdm09 virus exhibiting reduced susceptibility to baloxavir due to a PA E23K substitution detected from a child without baloxavir treatment

Emi Takashita 1, Takashi Abe 2, Hiroko Morita 1, Shiho Nagata 1, Seiichiro Fujisaki 1, Hideka Miura 1, Masayuki Shirakura 1, Noriko Kishida 1, Kazuya Nakamura 1, Tomoko Kuwahara 1, KeikoMitamura 3, Masataka Ichikawa 4, Masahiko Yamazaki 5, Shinji Watanabe 1, Hideki Hasegawa 1, The Influenza Virus Surveillance Group of Japan, Rika Komagome 6, Asami Ohnishi 7, Rika Tsutsui 8, Masaki Takahashi 9, MieSasaki 10, Shiho Tamura 11, Chihiro Shibata 12, Kenichi Komabayashi 13, Nozomi Saito 14, Aoi Saito 15, Fuminori Mizukoshi 16, Akira Wakatsuki 17, Hiroyuki Tsukagoshi 18, Noriko Suzuki 19, Yuka Uno 20, Noriko Oitate 21, Wakako Nishikawa 22, Mami Nagashima 23, Sumi Watanabe 24, Chiharu Kawakami 25, Hideaki Shimizu 26, Hazime Amano 27, Satoko Kanazawa 28, Kaori Watanabe 29, Kazunari Yamamoto 30, Tetsuya Yoneda 31, Sachiko Nakamura 32, Kaori Sato 33, Masayuki Oonuma 34, Michiko Takeuchi 35, ErinaTanaka 36, Masahiro Nishioka 37, Yusuke Sato 38, Yukiko Sakai 39, Takaharu Maehata 40, Toshihiko Furuta 41, Yoshihiro Yasui 42, Takuya Yano 43, Asa Tanino 44, Sachi Hirata 45, Akiko Nagasao 46, Satoshi Hiroi 47, Hideyuki Kubo 47, Fumika Okayama 48, Tomohiro Oshibe 49, Ai Mori 50, Ryutaro Murayama 51, Shoko Chiba 52, Yuki Matsui 53, Yuko Kiguchi 54, Koji Takeuchi 55, Tetsuo Mita 56, Kayoko Nomiya 57, Yukie Shimazu 58, Yoshiki Fujii 59, Shoichi Toda 60, Yumiko Kawakami 61, Yukari Terajima 62, Mayumi Yamashita 63, Tomiyo Takahashi 64, Yuki Ashizuka 65, Chinami Wasano 66, Takashi Kimura 67, Sanae Moroishi 68, Miho Urakawa 69, Takashi Sakai 70, Kaori Nishizawa 71, Toru Hayashi 72, Yu Matsuura 73, Yuka Hamada 74, Yumani Kuba 75

6 Hokkaido Institute of Public Health; 7 Sapporo City Institute of Public Health; 8 Aomori Prefectural Public Health and Environment Center; 9 Iwate Prefectural Research Institute for Environmental Sciences and Public Health; 10 Miyagi Prefectural Institute of Public Health and Environment; 11 Sendai City Institute of Public Health; 12 Akita Prefectural Research Center for Public Health and Environment; 13 Yamagata Prefectural Institute of Public Health; 14 Fukushima Prefectural Institute of Public Health; 15 Ibaraki Prefectural Institute of Public Health; 16 Tochigi Prefectural Institute of Public Health and Environmental Sciences; 17 Utsunomiya City Institute of Public Health and Environment Science; 18 Gunma Prefectural Institute of Public Health and Environmental Sciences; 19 Saitama Institute of Public Health; 20 Saitama City Institute of Health Science and Research; 21 Chiba Prefectural Institute of Public Health; 22 Chiba City Institute of Health and Environment; 23 Tokyo Metropolitan Institute of Public Health; 24 Kanagawa Prefectural Institute of Public Health; 25 Yokohama City Institute of Public Health; 26 Kawasaki City Institute of Public Health; 27 Yokosuka Institute of Public Health; 28 Sagamihara City Institute of Public Health; 29 Niigata Prefectural Institute of Public Health and Environmental Sciences; 30 Niigata City Institute of Public Health and Environment; 31 Toyama Institute of Health; 32 Ishikawa Prefectural Institute of Public Health and Environmental Science; 33 Fukui Prefectural Institute of Public Health and Environmental Science; 34 Yamanashi Institute for Public Health; 35 Nagano Environmental Conservation Research Institute; 36 Nagano City Health Center; 37
Gifu Prefectural Research Institute for Health and Environmental Sciences; 38 Gifu Municipal Institute of Public Health; 39 Shizuoka Institute of Environment and Hygiene; 40 Shizuoka City Institute of Environmental Sciences and Public Health; 41 Hamamatsu City Health Environment Research Center; 42 Aichi Prefectural Institute of Public Health; 43 Mie Prefecture Health and Environment Research Institute; 44 Shiga Prefectural Institute of Public Health; 45 Kyoto Prefectural Institute of Public Health and Environment; 46 Kyoto City Institute of Health and Environmental Sciences; 47 Osaka Institute of Public Health; 48 Sakai City Institute of Public Health; 49 Hyogo Prefectural Institute of Public Health Science; 50 Kobe Institute of Health; 51 Amagasaki City Institute of Public Health; 52 Nara Prefecture Institute of Health; 53 Wakayama Prefectural Research Center of Environment and Public Health; 54 Wakayama City Institute of Public Health; 55 Tottori Prefectural Institute of Public Health and Environmental Science; 56 Shimane Prefectural Institute of Public Health and Environmental Science; 57 Okayama Prefectural Institute for Environmental Science and Public Health; 58 Hiroshima Prefectural Technology Research Institute; 59 Hiroshima City Institute of Public Health; 60 Yamaguchi Prefectural Institute of Public Health and Environment; 61 Tokushima Prefectural Public Health, Pharmaceutical and Environmental Sciences Center; 62 Kagawa Prefectural Research Institute for Environmental Sciences and Public Health; 63 Ehime Prefecture Institute of Public Health and Environmental Science; 64 Kochi Public Health and Environmental Science Research Institute; 65 Fukuoka Institute of Health and Environmental Sciences; 66 Fukuoka City Institute of Health and Environment; 67 Kitakyushu City Institute of Health and Environmental Sciences; 68 Saga Prefectural Institute of Public Health and Pharmaceutical Research; 69 Nagasaki Prefectural Institute for Environment Research and Public Health; 70 Kumamoto Prefectural Institute of Public-Health and Environmental Science; 71 Kumamoto City Environmental Research Center; 72 Oita Prefectural Institute of Health and Environment; 73 Miyazaki Prefectural Institute for Public Health and Environment; 74 Kagoshima Prefectural Institute for Environmental Research and Public Health; 75 Okinawa Prefectural Institute of Health and Environment; 1 Influenza Virus Research Center, National Institute of Infectious Diseases, Gakuen 4-7-1, Musashimurayama, Tokyo, 208-0011, Japan; 2 Abe Children’s Clinic, Minowa 2-15-22, Kohoku, Yokohama, Kanagawa, 223-0051, Japan; 3 Eiju General Hospital, Higashi Ueno 2-23-16, Taito, Tokyo, 110-8645, Japan; 4 Ichikawa Children’s Clinic, Higashi Odake 1544-3, Isehara, Kanagawa, 259-1133, Japan; 5 Zama Children’s Clinic, Tatsuno Dai 2-20-24, Zama, Kanagawa, 252-0023, Japan

Received 18 February 2020, Revised 14 May 2020, Accepted 28 May 2020, Available online 20 June 2020.

DOI: https://doi.org/10.1016/j.antiviral.2020.104828

Highlights

Influenza A(H1N1)pdm09 virus carrying a PA E23K substitution was detected.
The PA E23K mutant virus showed reduced baloxavir susceptibility.
The PA E23K mutant virus was isolated from a child without baloxavir treatment.
Possible transmission of the PA E23K mutant virus among humans is suggested.
Baloxavir susceptibility monitoring of influenza viruses is essential.

Abstract

Human-to-human transmission of PA I38 mutant influenza A(H3N2) viruses with reduced baloxavir susceptibility has been reported in Japan. In December 2019, we detected a PA E23K mutant A(H1N1)pdm09 virus from a child without baloxavir treatment. The PA E23K mutant virus exhibited reduced baloxavir susceptibility but remained susceptible to neuraminidase inhibitors. Epidemiological data suggest possible transmission of this PA E23K mutant virus among humans, although its growth capability relative to that of the wild-type virus was reduced. Therefore, baloxavir susceptibility monitoring of influenza viruses is essential.

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Keywords: Influenza A; Antivirals; Drugs Resistance; Baloxavir; Oseltamivir; Pediatrics; Japan.

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The #Antiviral Effects of #Baloxavir Marboxil Against #Influenza A Virus Infection in #Ferrets (Influenza Other Respir Viruses, abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Influenza Other Respir Viruses. 2020 Jun 13. doi: 10.1111/irv.12760. Online ahead of print.

The Antiviral Effects of Baloxavir Marboxil Against Influenza A Virus Infection in Ferrets

Mitsutaka Kitano 1, Takanobu Matsuzaki 1, Ryoko Oka 1, Kaoru Baba 2, Takahiro Noda 2, Yuki Yoshida 1, Kenji Sato 1, Kohei Kiyota 1, Tohru Mizutare 1, Ryu Yoshida 1, Akihiko Sato 1, Hiroshi Kamimori 1, Takao Shishido 1, Akira Naito 1

Affiliations: 1 Shionogi & Co., Ltd., Toyonaka, Japan. 2 Shionogi TechnoAdvance Research, Co., Ltd., Toyonaka, Japan.

PMID: 32533654 DOI: 10.1111/irv.12760

Abstract

Background:

Baloxavir marboxil (BXM), the oral prodrug of baloxavir acid (BXA), greatly reduces virus titers as well as influenza symptoms of uncomplicated influenza in patients.

Objectives:

To investigate the pharmacokinetic profiles of BXA and its efficacy against influenza A virus infection in ferrets.

Methods:

Ferrets were dosed orally with BXM (10 and 30 mg/kg twice daily for 1 day), oseltamivir phosphate (OSP) (5 mg/kg twice daily for 2 days) or vehicle to measure the antiviral effects of BXM and OSP. The pharmacokinetic parameters of BXA was determined after single oral dosing of BXM.

Results:

The maximum plasma concentrations of BXA were observed at 1.50 and 2.00 hours with the two BXM doses, which then declined with an elimination half-life of 6.91 and 4.44 hours, respectively. BXM at both doses remained detectable in the plasma in ferrets, which may be due to higher stability in liver microsomes. BXM (10 and 30 mg/kg twice daily) treatment at Day 1 post-infection (p.i.) reduced virus titers by ≥3 log10 of the 50% tissue culture infective doses by Day 2, which was significantly different compared with vehicle or OSP. Body temperature drops over time were significantly greater with BXM than with vehicle or OSP. Significant reduction in virus titers was also demonstrated when BXM was administrated after symptom onset at Day 2 p.i. compared with vehicle and OSP, although body temperature changes largely overlapped between Day 2 and Day 4.

Conclusions:

The results highlight the rapid antiviral action of BXM with post-exposure prophylaxis or therapeutic dosing in ferrets and offer support for further research on prevention of influenza virus infection and transmission.

Keywords: baloxavir marboxil; ferrets; influenza A virus; pharmacodynamics; pharmacokinetics.

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Keywords: Influenza A; Antivirals; Baloxavir; Oseltamivir; Animal models.

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#Baloxavir Marboxil Single-dose #Treatment in #Influenza-infected #Children: A Randomized, Double-blind, Active Controlled Phase 3 Safety and Efficacy Trial (miniSTONE-2) (Pediatr Infect Dis J., abstract)

[Source: US National Library of Medicine, full page: (LINK). Abstract, edited.]

Pediatr Infect Dis J. 2020 Jun 5. doi: 10.1097/INF.0000000000002747. Online ahead of print.

Baloxavir Marboxil Single-dose Treatment in Influenza-infected Children: A Randomized, Double-blind, Active Controlled Phase 3 Safety and Efficacy Trial (miniSTONE-2)

Jeffrey Baker 1, Stanley L Block 2, Balpreet Matharu 3, Laura Burleigh Macutkiewicz 3, Steffen Wildum 4, Sophie Dimonaco 3, Neil Collinson 3, Barry Clinch 3, Pedro A Piedra 5

Affiliations: 1 From the Clinical Research Prime, Idaho Falls, Idaho. 2 Kentucky Pediatric and Adult Research Inc., Bardstown, Kentucky. 3 F. Hoffmann-La Roche Ltd, Welwyn Garden City, Hertfordshire, United Kingdom. 4 F. Hoffmann-La Roche Ltd, Basel, Switzerland. 5 Baylor College of Medicine, Houston, Texas.

PMID: 32516282 DOI: 10.1097/INF.0000000000002747

Abstract

Background:

Baloxavir marboxil (baloxavir) is a novel, cap-dependent endonuclease inhibitor that has previously demonstrated efficacy in the treatment of influenza in adults and adolescents. We assessed the safety and efficacy of baloxavir in otherwise healthy children with acute influenza.

Methods:

MiniSTONE-2 (Clinicaltrials.gov: NCT03629184) was a double-blind, randomized, active controlled trial enrolling children 1-<12 years old with a clinical diagnosis of influenza. Children were randomized 2:1 to receive either a single dose of oral baloxavir or oral oseltamivir twice daily for 5 days. The primary endpoint was incidence, severity and timing of adverse events (AEs); efficacy was a secondary endpoint.

Results:

In total, 173 children were randomized and dosed, 115 to the baloxavir group and 58 to the oseltamivir group. Characteristics of participants were similar between treatment groups. Overall, 122 AEs were reported in 84 (48.6%) children. Incidence of AEs was similar between baloxavir and oseltamivir groups (46.1% vs. 53.4%, respectively). The most common AEs were gastrointestinal (vomiting/diarrhea) in both groups [baloxavir: 12 children (10.4%); oseltamivir: 10 children (17.2%)]. No deaths, serious AEs or hospitalizations were reported. Median time (95% confidence interval) to alleviation of signs and symptoms of influenza was similar between groups: 138.1 (116.6-163.2) hours with baloxavir versus 150.0 (115.0-165.7) hours with oseltamivir.

Conclusions:

Oral baloxavir is well tolerated and effective at alleviating symptoms in otherwise healthy children with acute influenza. Baloxavir provides a new therapeutic option with a simple oral dosing regimen.

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Keywords: Seasonal Influenza; Antivirals; Baloxavir; Pediatrics.

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Early #treatment with #baloxavir marboxil in high-risk #adolescent and #adult outpatients with uncomplicated #influenza (#CAPSTONE2)… (Lancet Infect Dis., abstract)

[Source: Lancet Infectious Diseases, full page: (LINK). Abstract, edited.]

Early treatment with baloxavir marboxil in high-risk adolescent and adult outpatients with uncomplicated influenza (CAPSTONE-2): a randomised, placebo-controlled, phase 3 trial

Prof Michael G Ison, MD, Simon Portsmouth, MD, Yuki Yoshida, MS, Takao Shishido, PhD, Melissa Mitchener, PharmD, Kenji Tsuchiya, MS, Takeki Uehara, PhD, Frederick G Hayden

Published: June 08, 2020 | DOI: https://doi.org/10.1016/S1473-3099(20)30004-9

Summary

Background

Baloxavir marboxil (hereafter baloxavir), a selective inhibitor of influenza cap-dependent endonuclease, was approved in 2018 in the USA and Japan for the treatment of uncomplicated influenza in otherwise healthy individuals aged 12 years and older. We aimed to study the efficacy of baloxavir in outpatients at high risk of developing influenza-associated complications.

Methods

We did a double-blind, placebo-controlled and oseltamivir-controlled trial in outpatients aged 12 years and older in 551 sites in 17 countries and territories. Eligible patients had clinically diagnosed influenza-like illness, at least one risk factor for influenza-associated complications (eg, age older than 65 years), and a symptom duration of less than 48 h. Patients were stratified by baseline symptom score (≤14 vs ≥15), pre-existing and worsened symptoms at onset of illness compared with pre-influenza (yes or no), region (Asia, North America and Europe, or southern hemisphere), and weight (<80 kg vs ≥80 kg), and randomly assigned (1:1:1) via an interactive web-response system to either a single weight-based dose of baloxavir (40 mg for patients weighing <80 kg and 80 mg for patients weighing ≥80 kg; baloxavir group), oseltamivir 75 mg twice daily for 5 days (oseltamivir group), or matching placebo (placebo group). All patients, investigators, study personnel, and data analysts were masked to treatment assignment until database lock. The primary endpoint was time to improvement of influenza symptoms (TTIIS) in the modified intention-to-treat population, which included all patients who received at least one dose of study drug and had RT-PCR-confirmed influenza virus infection. Safety was assessed in all patients who receved at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT02949011.

Findings

2184 patients were enrolled from Jan 11, 2017, to March 30, 2018, and randomly assigned to receive baloxavir (n=730), placebo (n=729), or oseltamivir (n=725). The modified intention-to-treat population included 1163 patients: 388 in the baloxavir group, 386 in the placebo group, and 389 in the oseltamivir group. 557 (48%) of 1163 patients had influenza A H3N2, 484 (42%) had influenza B, 80 (7%) had influenza A H1N1, 14 patients had a mixed infection, and 28 had infections with non-typable viruses. The median TTIIS was shorter in the baloxavir group (73·2 h [95% CI 67·2 to 85·1]) than in the placebo group (102·3 h [92·7 to 113·1]; difference 29·1 h [95% CI 14·6 to 42·8]; p<0·0001). The median TTIIS in the oseltamivir group was 81·0 h (95% CI 69·4 to 91·5), with a difference from the baloxavir group of 7·7 h (−7·9 to 22·7). Adverse events were reported in 183 (25%) of 730 patients in the baloxavir group, 216 (30%) of 727 in the placebo group, and 202 (28%) of 721 in the oseltamivir group. Serious adverse events were noted in five patients in the baloxavir group, nine patients in the placebo group, and eight patients in the oseltamivir group; one case each of hypertension and nausea in the placebo group and two cases of transaminase elevation in the oseltamivir group were considered to be treatment related. Polymerase acidic protein variants with Ile38Thr, Ile38Met, or Ile38Asn substitutions conferring reduced baloxavir susceptibility emerged in 15 (5%) of 290 baloxavir recipients assessed for amino acid substitutions in the virus.

Interpretation

Single-dose baloxavir has superior efficacy to placebo and similar efficacy to oseltamivir for ameliorating influenza symptoms in high-risk outpatients. The safety of baloxavir was comparable to placebo. This study supports early therapy for patients at high risk of complications of influenza to speed clinical recovery and reduce complications.

Funding

Shionogi.

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Keywords: Seasonal Influenza; Antivirals; Baloxavir.

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