Multidrug-resistant mutations to antiviral and antibody therapy in an immunocompromised patient infected with SARS-CoV-2

Yosuke Hirotsu; Hiroaki Kobayashi; Yumiko Kakizaki; Akitoshi Saito; Toshiharu Tsutsui; Makoto Kawaguchi; Sou Shimamura; Kouki Hata; Syunya Hanawa; Jun Toyama; Yoshihiro Miyashita; Masao Omata

doi:10.1016/j.medj.2023.08.001

Multidrug-resistant mutations to antiviral and antibody therapy in an immunocompromised patient infected with SARS-CoV-2

Med. 2023 Nov 10;4(11):813-824.e4. doi: 10.1016/j.medj.2023.08.001. Epub 2023 Sep 7.

Affiliations

¹ Genome Analysis Center, Yamanashi Central Hospital, 1-1-1 Fujimi, Kofu, Yamanashi, Japan. Electronic address: hirotsu-bdyu@ych.pref.yamanashi.jp.
² Lung Cancer and Respiratory Disease Center, Yamanashi Central Hospital, 1-1-1 Fujimi, Kofu, Yamanashi, Japan.
³ Department of Radiology, Yamanashi Central Hospital, 1-1-1 Fujimi, Kofu, Yamanashi, Japan.
⁴ Department of Gastroenterology, Yamanashi Central Hospital, 1-1-1 Fujimi, Kofu, Yamanashi, Japan; The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, Japan.

PMID: 37683636
DOI: 10.1016/j.medj.2023.08.001

Abstract

Background: Antiviral and antibody therapies for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are being recommended for high-risk patients, but the potential for the development of multidrug-resistant mutations in immunocompromised patients is unclear.

Methods: To investigate the treatment course in cases of prolonged viral shedding in an immunocompromised patient with SARS-CoV-2 infection, we conducted longitudinal measurements of laboratory tests, chest computed tomography (CT) image evaluations, antibody titers, and antigen levels in nasopharyngeal swabs. Furthermore, we performed whole-genome sequencing and digital PCR analysis to examine the mechanisms of drug resistance.

Findings: We present a case of a 65-year-old man with a history of malignant lymphoma who was treated with multiple antiviral and antibody therapies, including sotrovimab, remdesivir, paxlovid (nirmatrelvir/ritonavir), and molnupiravir. Initially, viral antigen levels decreased after treatments. However, after the virus rebounded, the patient showed no virologic response. The viral genome analysis revealed a single Omicron subvariant (BA.1.1), which evolved within the host during the disease progression. The viruses had acquired multiple resistance mutations to nirmatrelvir (3 chymotrypsin-like protease [3CLpro] E166 A/V), sotrovimab (spike P337L and E340K), and remdesivir (RNA-dependent RNA polymerase [RdRp] V166L).

Conclusions: Our results indicate that viruses with multidrug-resistant mutations and survival fitness persist in the infected subpopulation after drug selection pressure.

Funding: This study was supported by the JSPS KAKENHI Early-Career Scientists 18K16292 (Y.H.), Grant-in-Aid for Scientific Research (B) 20H03668 and 23H02955 (Y.H.), the YASUDA Medical Foundation (Y.H.), the Uehara Memorial Foundation (Y.H.), the Takeda Science Foundation (Y.H.), and Kato Memorial Bioscience Foundation (Y.H.).

Keywords: 3CLpro; RdRp; SARS-CoV-2; Translation to patients; immunocompromised; mutation; nirmatrelvir; remdesivir; resistance; sotrovimab; spike.

Publication types

Case Reports
Research Support, Non-U.S. Gov't

MeSH terms

Aged
Antiviral Agents / therapeutic use
COVID-19*
Humans
Immunocompromised Host
Male
Mutation
SARS-CoV-2* / genetics

Substances

nirmatrelvir and ritonavir drug combination
Antiviral Agents