Susceptibility of Drug Resistant Hepatitis B Virus Mutants to Besifovir
Currently, interferon alpha and nucleos(t)ide analogues (NAs) are clinically available to treat hepatitis B virus (HBV) infection. Several NAs, including lamivudine (LMV), adefovir (ADV), entecavir (ETV) and tenofovir (TDF or TAF) have been approved and administered to chronic hepatitis B (CHB) pati...
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MDPI AG
2022-07-01
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| Online Access: | https://www.mdpi.com/2227-9059/10/7/1637 |
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| author | Juhee Won Ah Ram Lee Mehrangiz Dezhbord Da Rae Lee Seong Ho Kim Jong Chul Kim Soree Park Nayeon Kim Byengjune Jae Kyun-Hwan Kim |
| author_facet | Juhee Won Ah Ram Lee Mehrangiz Dezhbord Da Rae Lee Seong Ho Kim Jong Chul Kim Soree Park Nayeon Kim Byengjune Jae Kyun-Hwan Kim |
| author_sort | Juhee Won |
| collection | DOAJ |
| description | Currently, interferon alpha and nucleos(t)ide analogues (NAs) are clinically available to treat hepatitis B virus (HBV) infection. Several NAs, including lamivudine (LMV), adefovir (ADV), entecavir (ETV) and tenofovir (TDF or TAF) have been approved and administered to chronic hepatitis B (CHB) patients. NAs inhibit HBV DNA synthesis by targeting the reverse transcriptase (RT) domain of HBV polymerase. Several mutations in the RT domain which lead to drug resistance against NAs have been reported, even for TDF and TAF which are highly potent with very low resistance rate. Besifovir (BFV) is a new antiviral dGMP analogue able to be used as a new NA drug for the control of CHB infection. Drug resistance to BFV is not well known due to its shorter duration of clinical use. Recently, we reported that rtL180M (M) and rtM204V (V) mutations, already resistant to LMV, are associated with BFV resistance. However, the susceptibility to BFV of previously known HBV mutants resistant to various drugs has not been studied. To investigate this, we performed in vitro drug susceptibility assays using natural and artificial mutants that are associated with resistance to LMV, ADV, ETV or TDF. As a result, LMV-resistant mutants were not susceptible to BFV and ETV-resistant clones showed partial resistance against BFV as well. However, ADV-resistant mutants were highly sensitive to BFV. In case of tenofovir-resistant mutations, the HBV mutants harboring primary mutations to tenofovir resistance were susceptible to BFV. Therefore, our study revealed that BSV may serve as an alternative drug for patients with ADV-, ETV-, TDF- or TAF-resistance. |
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| last_indexed | 2024-03-09T10:22:12Z |
| publishDate | 2022-07-01 |
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| series | Biomedicines |
| spelling | doaj.art-62566b7b06f44274bc675d39f58ed72d2023-12-01T21:56:08ZengMDPI AGBiomedicines2227-90592022-07-01107163710.3390/biomedicines10071637Susceptibility of Drug Resistant Hepatitis B Virus Mutants to BesifovirJuhee Won0Ah Ram Lee1Mehrangiz Dezhbord2Da Rae Lee3Seong Ho Kim4Jong Chul Kim5Soree Park6Nayeon Kim7Byengjune Jae8Kyun-Hwan Kim9Department of Pharmacology, School of Medicine, Konkuk University, Seoul 05029, KoreaDepartment of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon 16419, KoreaDepartment of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon 16419, KoreaDepartment of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon 16419, KoreaDepartment of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon 16419, KoreaDepartment of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon 16419, KoreaDepartment of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon 16419, KoreaDepartment of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon 16419, KoreaDepartment of Pharmacology, School of Medicine, Konkuk University, Seoul 05029, KoreaDepartment of Precision Medicine, School of Medicine, Sungkyunkwan University, Suwon 16419, KoreaCurrently, interferon alpha and nucleos(t)ide analogues (NAs) are clinically available to treat hepatitis B virus (HBV) infection. Several NAs, including lamivudine (LMV), adefovir (ADV), entecavir (ETV) and tenofovir (TDF or TAF) have been approved and administered to chronic hepatitis B (CHB) patients. NAs inhibit HBV DNA synthesis by targeting the reverse transcriptase (RT) domain of HBV polymerase. Several mutations in the RT domain which lead to drug resistance against NAs have been reported, even for TDF and TAF which are highly potent with very low resistance rate. Besifovir (BFV) is a new antiviral dGMP analogue able to be used as a new NA drug for the control of CHB infection. Drug resistance to BFV is not well known due to its shorter duration of clinical use. Recently, we reported that rtL180M (M) and rtM204V (V) mutations, already resistant to LMV, are associated with BFV resistance. However, the susceptibility to BFV of previously known HBV mutants resistant to various drugs has not been studied. To investigate this, we performed in vitro drug susceptibility assays using natural and artificial mutants that are associated with resistance to LMV, ADV, ETV or TDF. As a result, LMV-resistant mutants were not susceptible to BFV and ETV-resistant clones showed partial resistance against BFV as well. However, ADV-resistant mutants were highly sensitive to BFV. In case of tenofovir-resistant mutations, the HBV mutants harboring primary mutations to tenofovir resistance were susceptible to BFV. Therefore, our study revealed that BSV may serve as an alternative drug for patients with ADV-, ETV-, TDF- or TAF-resistance.https://www.mdpi.com/2227-9059/10/7/1637hepatitis B virusbesifovirreverse transcriptionnucleos(t)ide analoguedrug resistance |
| spellingShingle | Juhee Won Ah Ram Lee Mehrangiz Dezhbord Da Rae Lee Seong Ho Kim Jong Chul Kim Soree Park Nayeon Kim Byengjune Jae Kyun-Hwan Kim Susceptibility of Drug Resistant Hepatitis B Virus Mutants to Besifovir Biomedicines hepatitis B virus besifovir reverse transcription nucleos(t)ide analogue drug resistance |
| title | Susceptibility of Drug Resistant Hepatitis B Virus Mutants to Besifovir |
| title_full | Susceptibility of Drug Resistant Hepatitis B Virus Mutants to Besifovir |
| title_fullStr | Susceptibility of Drug Resistant Hepatitis B Virus Mutants to Besifovir |
| title_full_unstemmed | Susceptibility of Drug Resistant Hepatitis B Virus Mutants to Besifovir |
| title_short | Susceptibility of Drug Resistant Hepatitis B Virus Mutants to Besifovir |
| title_sort | susceptibility of drug resistant hepatitis b virus mutants to besifovir |
| topic | hepatitis B virus besifovir reverse transcription nucleos(t)ide analogue drug resistance |
| url | https://www.mdpi.com/2227-9059/10/7/1637 |
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