genotypic resistance profile of hepatitis b virus hbv in a large cohort of nucleos t ide CORD-Papers-2021-10-25 (Version 1)

Title: Genotypic resistance profile of hepatitis B virus (HBV) in a large cohort of nucleos(t)ide analogueexperienced Chinese patients with chronic HBV infection
Abstract: Summary. The study investigated the hepatitis B virus (HBV) genotypic resistance profile in 1803 nucleos(t)ide analogue (NA)experienced Chinese patients with chronic HBV infection. Serum HBV DNA was extracted, and the reverse transcriptase region was analysed by a highsensitive direct PCR sequencing and verified by clonal sequencing if necessary. Drugresistant mutations were detected in 560 of the 1803 patients, including 214 of 490 patients who received lamivudine (LAM), 35 of 428 patients who received adefovir (ADV), five of 18 patients who received telbivudine and 306 of 794 patients who received various sequential/combined NA therapies. ADVresistant mutations were detected in 36 of 381 patients who received LAM and then switchedto ADV in contrast to one of 82 patients who received ADV addon LAM. Entecavir (ETV)resistant mutations were detected not only in LAM and ETVtreated patients but also in LAMtreated ETVnave patients. Double mutations rtM204I and rtL180M were detected more frequently in genotype C than in genotype B virus, and patients infected with this mutant had higher alanine transaminase levels than those infected with mutant containing the rtM204I substitution alone. Multidrugresistant HBV strains were identified in eight patients, including two novel strains with mutational patterns rtL180M + A181V + S202G + M204V + N236T and rtL180M + S202G + M204V + N236T. The results provide new information on HBV genotypic resistance profiles in a large cohort of Chinese patients with chronic HBV infection and may have important clinical implication for HBV drug resistance management in China.
Published: 9/6/2010
Journal: J Viral Hepat
DOI: 10.1111/j.1365-2893.2010.01360.x
DOI_URL: http://doi.org/10.1111/j.1365-2893.2010.01360.x
Author Name: Liu, Y
Author link: https://covid19-data.nist.gov/pid/rest/local/author/liu_y
Author Name: Wang, C
Author link: https://covid19-data.nist.gov/pid/rest/local/author/wang_c
Author Name: Zhong, Y
Author link: https://covid19-data.nist.gov/pid/rest/local/author/zhong_y
Author Name: Li, X
Author link: https://covid19-data.nist.gov/pid/rest/local/author/li_x
Author Name: Dai, J
Author link: https://covid19-data.nist.gov/pid/rest/local/author/dai_j
Author Name: Ren, X
Author link: https://covid19-data.nist.gov/pid/rest/local/author/ren_x
Author Name: Xu, Z
Author link: https://covid19-data.nist.gov/pid/rest/local/author/xu_z
Author Name: Li, L
Author link: https://covid19-data.nist.gov/pid/rest/local/author/li_l
Author Name: Yao, Z
Author link: https://covid19-data.nist.gov/pid/rest/local/author/yao_z
Author Name: Ji, D
Author link: https://covid19-data.nist.gov/pid/rest/local/author/ji_d
Author Name: Wang, L
Author link: https://covid19-data.nist.gov/pid/rest/local/author/wang_l
Author Name: Zhang, L
Author link: https://covid19-data.nist.gov/pid/rest/local/author/zhang_l
Author Name: Wong, V W S
Author link: https://covid19-data.nist.gov/pid/rest/local/author/wong_v_w_s
Author Name: Zoulim, F
Author link: https://covid19-data.nist.gov/pid/rest/local/author/zoulim_f
Author Name: Xu, D
Author link: https://covid19-data.nist.gov/pid/rest/local/author/xu_d
sha: 0f9c43aca920761d4e91a8e9a859a50a9408534c
license: no-cc
license_url: [no creative commons license associated]
source_x: Medline; PMC
source_x_url: https://www.medline.com/https://www.ncbi.nlm.nih.gov/pubmed/
pubmed_id: 21392168
pubmed_id_url: https://www.ncbi.nlm.nih.gov/pubmed/21392168
pmcid: PMC7167191
pmcid_url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7167191
url: https://doi.org/10.1111/j.1365-2893.2010.01360.x https://www.ncbi.nlm.nih.gov/pubmed/21392168/
has_full_text: TRUE
Keywords Extracted from Text Content: hepatitis B virus rtM204I Serum HBV DNA LAM-and rtL180M telbivudine ADVresistant alanine transaminase adefovir LAM nucleos(t)ide rtL180M + A181V lamivudine HBV Entecavir ADV LAM-treated ETV-naïve patients patients Madison, WI hepatitis rtM250 rtI233V serum ALT rtM204V + L180M ± V173L ETV-naïve patients LdT. nucleoside DNA LdT CHB-LC rtM204I + L180M CHB patient [7] telbivudine ± rtL217R rtV173L HBeAg rt204 HBeAg/anti-HBe SP6 hepatocellular carcinoma rt180 [9] [10] [11] 5¢-AGG Nonoptimal rt173 UP3 rtA181V dATP tenofovir MDR rtL180M ± V173L LAM switching-to LdT tube Serum samples rtL180M entecavir ETV rtV214A ÔnewÕ SARS coronavirus rtN236T LAM Ôgold IFN GQ402162 HBV DNA Serum ALT Red rtM204I HBsAg/anti-HBs UP4 anti-HBc rtQ215S Blue rtA181T LAM-resistant anti-HBV NA people nucleotide nucleos(t)ide hepatic inflammation HBV ADV-R LAMresistant ALT MDR strains · 10 5 amino acid rtM250I/L/ V rtA194T ADV GAA GAC AGC [13] [14] [15] [16] HBV DNA HBsAg rt80 Hepatitis B virus LAM-and/or Taq DNA polymerase serum HBV DNA HCC 1225-bp-long rtL80I LAM-experienced · 10 3 GQ402161 CHB-LC patients · 10 4 rtL180M + M204V rt250 lamivudine LAM switching-to ADV ‡100 ‡2000 liver rtM204I + L180M ± V173L lamivudine- LAM [20] hepatitis B virus LAM-R alanine transaminase adefovir rtL180M + A181V · 10 6 NA rtM204I/V rtN236T + A181T rtM204V DOWN1 rtV84M Fosun Pharmaceutical Co. rt84 rtM204I/V. patients rtA181T/S TDF LAM-R/ETV-R rtS202C/G/I B line YMDD manufacturerÕs
Extracted Text Content in Record: First 5000 Characters:The study investigated the hepatitis B virus (HBV) genotypic resistance profile in 1803 nucleos(t)ide analogue (NA)-experienced Chinese patients with chronic HBV infection. Serum HBV DNA was extracted, and the reverse transcriptase region was analysed by a high-sensitive direct PCR sequencing and verified by clonal sequencing if necessary. Drug-resistant mutations were detected in 560 of the 1803 patients, including 214 of 490 patients who received lamivudine (LAM), 35 of 428 patients who received adefovir (ADV), five of 18 patients who received telbivudine and 306 of 794 patients who received various sequential/combined NA therapies. ADVresistant mutations were detected in 36 of 381 patients who received LAM and then switched-to ADV in contrast to one of 82 patients who received ADV add-on LAM. Entecavir (ETV)-resistant mutations were detected not only in LAM-and ETV-treated patients but also in LAM-treated ETV-naïve patients. Double mutations rtM204I and rtL180M were detected more frequently in genotype C than in genotype B virus, and patients infected with this mutant had higher alanine transaminase levels than those infected with mutant containing the rtM204I substitution alone. Multidrug-resistant HBV strains were identified in eight patients, including two novel strains with mutational patterns rtL180M + A181V + S202G + M204V + N236T and rtL180M + S202G + M204V + N236T. The results provide new information on HBV genotypic resistance profiles in a large cohort of Chinese patients with chronic HBV infection and may have important clinical implication for HBV drug resistance management in China. Hepatitis B virus (HBV) chronic infection afflicts about 350 million people worldwide, of whom 93 million live in China [1, 2] . Morbidity and mortality in chronic hepatitis B (CHB) are linked to persistent viral replication and evolution to CHB-related liver cirrhosis (CHB-LC) or hepatocellular carcinoma (HCC) [3] . In China, four nucleos(t)ide analogues (NA), i.e. lamivudine (LAM), adefovir (ADV), entecavir (ETV) and telbivudine (LdT) are currently approved for the treatment of HBV infection, whilst recently developed tenofovir (TDF) is still unavailable. Treatment of CHB and CHB-LC is aimed at suppressing viral replication to the lowest possible level, and thereby halting the progression of liver disease. However, viral resistance is the main drawback of long-term antiviral therapy [4] [5] [6] . Suboptimal treatment regimens and drug-resistant viral infection can increase the incidence of drug resistance and may favour the selection of multidrugresistant (MDR) HBV [7, 8] . The resistance mutations are located in the reverse transcriptase (RT) region of the HBV polymerase gene. The rtM204I and rtM204V are classic LAM-resistant mutations and often coexist with compensatory mutations (rtV173L and rtL180M) [9] [10] [11] . The rtN236T and rtA181V are two well-recognized ADV-resistant mutations [12, 13] , and some purported mutations such as rtV84M, rtV214A, rtQ215S, rtL217R and rtI233V may reduce susceptibility to ADV, although these are still controversial [13] [14] [15] [16] . Substitutions in rtT184, rtS202 or rtM250 in conjunction with LAMresistant mutations result in ETV resistance [17] [18] [19] . Cross-resistance (usually rtM204I) also exists between LdT and LAM [20] . In addition, rtA181T seems to be an atypical substitution associated with LAM and ADV selection and may reduce the typical extent of virologic breakthrough [21] . Genotypic antiviral resistance is designated by the presence of unique nucleotide and corresponding deduced amino acid mutations in the drug target gene that have been previously demonstrated to be associated with antiviral resistance. The incidence of genotypic resistance is related to viral factors, host factors and treatment characteristics and is also affected by the methods used for detection of resistance mutations and the patient population being studied [22] . Several methods have been used for typing HBV genetic drug-resistant mutations, each with individual advantages and disadvantages [1, 22] . Direct polymerase chain reaction (PCR) sequencing is the most popular method owing to the abundant information it provides. However, it is also considered less sensitive for typing samples with low viral load (<2000 IU/mL) and minor mutant subpopulations (<20%) [22] . As more antiviral strategies become available for the treatment of CHB and CHB-LC, the risk and patterns of resistant and cross-resistant emergence are diverse. Nonoptimal strategies based on the sequential use of NA increase the development of MDR strains [23] . Knowledge on the incidence and patterns of drug-resistant mutants is valuable for clinicians and would assist clinical monitoring and management of the resistance. To date, data are largely derived from a few clinical trials and cohorts with limited drug resistance profiling. This study is intended to investigate population-based profiles of HBV genotypic resi
Keywords Extracted from PMC Text: [12, 13] HBsAg/anti‐HBs Patients adefovir wild‐type HBV rtQ215S LAM switching‐to ADV alanine transaminase INNO‐LiPA × tenofovir LAM rtM204I rtM204V LAM‐ anti‐HBV NA rt250 Madison, WI B (44.6%/55.4%vs 19.4%/80.6 rtV84M rtM204I + L180M rtM204V + L180M ± V173L 's less‐sensitive one‐tube ALT LAM [20] dATP rtL180M ± V173L rtM250I/L/V 5′‐AGG TGA AGC GAA GTG CAC AC‐3′ UP3 rtA181T/V MDR HBV strains rtN236T rtM250 ETV‐naïve patients Hepatitis B virus genotypes C CHB people Taq DNA polymerase HBeAg line NA GQ402161 rtL180M + A181V rtL180M + M204V entecavir liver B and D ≥20 serum ALT ADV add‐on rt180 rtV214A LAM‐R rtM204I + L180M ± V173L Serum amino acid rtM204I/V rt80 GQ402162 LAM switching‐to LdT rtA181T ≥100 rtA194T Coexist‐R samples YMDD rtA181V Nonoptimal 5′‐AGT CAG GAA GAC AGC Coexist‐R hepatitis telbivudine nucleotide rt173 × 106 ETV long‐term CHB‐LC HBV DNA ADV‐R LdT HBsAg Hepatitis B virus lamivudine rtV173L rt204 rtM204I/V. serum HBV DNA 54–75 CGC AGT ATG MDR tube immunoglobulin patients rtS202C/G/I HCC chi‐square tests hepatocellular carcinoma nucleos(t)ide [7] coronavirus add‐on rtA181T/S rtL80I DNA patient wild‐type HBV LdT. LdT‐resistant ≥2000 nucleoside LAM‐experienced hepatic inflammation rtL180M CHB‐LC patients rtI233V B rtL217R rtN236T + A181T ADV TDF Fosun Pharmaceutical Co. MDR strains Serum samples SP6 B, C rt84 DOWN1
Extracted PMC Text Content in Record: First 5000 Characters:Hepatitis B virus (HBV) chronic infection afflicts about 350 million people worldwide, of whom 93 million live in China [1, 2]. Morbidity and mortality in chronic hepatitis B (CHB) are linked to persistent viral replication and evolution to CHB‐related liver cirrhosis (CHB‐LC) or hepatocellular carcinoma (HCC) [3]. In China, four nucleos(t)ide analogues (NA), i.e. lamivudine (LAM), adefovir (ADV), entecavir (ETV) and telbivudine (LdT) are currently approved for the treatment of HBV infection, whilst recently developed tenofovir (TDF) is still unavailable. Treatment of CHB and CHB‐LC is aimed at suppressing viral replication to the lowest possible level, and thereby halting the progression of liver disease. However, viral resistance is the main drawback of long‐term antiviral therapy [4, 5, 6]. Suboptimal treatment regimens and drug‐resistant viral infection can increase the incidence of drug resistance and may favour the selection of multidrug‐resistant (MDR) HBV [7, 8]. The resistance mutations are located in the reverse transcriptase (RT) region of the HBV polymerase gene. The rtM204I and rtM204V are classic LAM‐resistant mutations and often coexist with compensatory mutations (rtV173L and rtL180M) [9, 10, 11]. The rtN236T and rtA181V are two well‐recognized ADV‐resistant mutations [12, 13], and some purported mutations such as rtV84M, rtV214A, rtQ215S, rtL217R and rtI233V may reduce susceptibility to ADV, although these are still controversial [13, 14, 15, 16]. Substitutions in rtT184, rtS202 or rtM250 in conjunction with LAM‐resistant mutations result in ETV resistance [17, 18, 19]. Cross‐resistance (usually rtM204I) also exists between LdT and LAM [20]. In addition, rtA181T seems to be an atypical substitution associated with LAM and ADV selection and may reduce the typical extent of virologic breakthrough [21]. Genotypic antiviral resistance is designated by the presence of unique nucleotide and corresponding deduced amino acid mutations in the drug target gene that have been previously demonstrated to be associated with antiviral resistance. The incidence of genotypic resistance is related to viral factors, host factors and treatment characteristics and is also affected by the methods used for detection of resistance mutations and the patient population being studied [22]. Several methods have been used for typing HBV genetic drug‐resistant mutations, each with individual advantages and disadvantages [1, 22]. Direct polymerase chain reaction (PCR) sequencing is the most popular method owing to the abundant information it provides. However, it is also considered less sensitive for typing samples with low viral load (<2000 IU/mL) and minor mutant subpopulations (<20%) [22]. As more antiviral strategies become available for the treatment of CHB and CHB‐LC, the risk and patterns of resistant and cross‐resistant emergence are diverse. Nonoptimal strategies based on the sequential use of NA increase the development of MDR strains [23]. Knowledge on the incidence and patterns of drug‐resistant mutants is valuable for clinicians and would assist clinical monitoring and management of the resistance. To date, data are largely derived from a few clinical trials and cohorts with limited drug resistance profiling. This study is intended to investigate population‐based profiles of HBV genotypic resistance in Chinese patients, with an improved direct PCR sequencing assay. Serum samples were collected from 1803 CHB and CHB‐LC patients who visited Beijing 302 Hospital during July 2007–March 2009. The standard for diagnoses of CHB and CHB‐LC was based on the Chinese Management Scheme of Diagnostic and Therapy Criteria of Viral Hepatitis [24] and have been described elsewhere [25, 26]. The male/female ratio was 1524/279. Average age was 37.2 ± 13.6 years. At the time of sampling for HBV genotyping, all patients were HBsAg positive, and 1203 (66.7%) patients were HBeAg positive. The median (Q1, Q3) of the alanine transaminase (ALT) level was 38 (24, 70) U/L; and the median (Q1, Q3) of the HBV DNA level was 2.8 × 104 (1.7 × 103, 7.5 × 105) IU/mL. All patients had received anti‐HBV NA (LAM, ADV, ETV and LdT) monotherapy, combination or sequential therapy for a minimum of 3 months. Written informed consents for the analysis were obtained from every patient. The study was approved by the ethics committee of Beijing 302 Hospital. Serum ALT, HBsAg/anti‐HBs, HBeAg/anti‐HBe, anti‐HBc and other biochemical and serological markers, as well as HBV DNA level were routinely measured or detected in the Central Clinical Laboratory of the Beijing 302 Hospital. HBV DNA level was determined by real‐time quantitative PCR (qPCR) (Fosun Pharmaceutical Co., Ltd., Shanghai, China) with a lower detection limit of 100 IU/mL (≈500 copies/mL). Hepatitis B virus gene fragment (nt 54–1278) encompassing the complete RT gene was amplified by nested PCR. The sense and antisense primers for the first‐round PCR were 5′‐AGT CAG GAA GAC AGC CTA CTC C‐3′ (
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