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Jun BG, Park EJ, Lee WC, Jang JY, Jeong SW, Kim YD, Cheon GJ, Cho YS, Lee SH, Kim HS, Lee YN, Kim SG, Kim YS, Kim BS. Platelet count is associated with sustained virological response rates in treatments for chronic hepatitis C. Korean J Intern Med 2019; 34. [PMID: 29529840 PMCID: PMC6718746 DOI: 10.3904/kjim.2017.322] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND/AIMS This study was conducted to clarify the sustained virological response (SVR) prediction ability of baseline and treatment-related factors in patients with chronic hepatitis C virus (HCV) infection. METHODS This retrospective study collected data at four tertiary referral hospitals between June 2004 and July 2012. Out of 476 patients, 330 treatment-naïve patients with chronic HCV infection were recruited. Pegylated interferon α-2a/- 2b plus ribavirin was administered for either 24 or 48 weeks depending on the HCV genotype. The baseline and treatment-related predictive factors of SVR were evaluated by analyzing data measured before treatment (i.e., baseline) and during treatment. RESULTS SVR rates for genotypes 1 and 2 were 63% (97/154) and 79.5% (140/176), respectively (p = 0.001). Multivariate analysis for baseline factors revealed that young age (p = 0.009), genotype 2 (p = 0.001), HCV RNA level of < 800,000 IU/mL (p < 0.001), and a baseline platelet count of > 150 × 103 /µL (p < 0.001) were significant SVR predictors, regardless of the genotype. In particular, predictive accuracy for achievement of SVR was 87.3% for a baseline platelet count of > 150 × 103 /µL. In multivariate analysis for treatment-related factors, SVR was associated with achievement of a rapid virological response (RVR; p < 0.001), treatment adherence of ≥ 80/80/80 (p < 0.001). CONCLUSION Young age, genotype 2, low HCV RNA level, RVR, and treatment adherence were significantly associated with SVR. In addition, platelet count was an independent predictive factor for SVR. Therefore, platelet count could be used to develop individualized treatment regimens and to optimize treatment outcomes in patients with chronic HCV infection.
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Affiliation(s)
- Baek Gyu Jun
- Department of Internal Medicine, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung, Korea
| | - Eui Ju Park
- Institute for Digestive Research, Digestive Disease Center, Department of Internal Medicine, Soonchunhyang University Seoul Hospital, Seoul, Korea
| | - Woong Cheul Lee
- Institute for Digestive Research, Digestive Disease Center, Department of Internal Medicine, Soonchunhyang University Seoul Hospital, Seoul, Korea
| | - Jae Young Jang
- Institute for Digestive Research, Digestive Disease Center, Department of Internal Medicine, Soonchunhyang University Seoul Hospital, Seoul, Korea
- Correspondence to Jae Young Jang, M.D. Institute for Digestive Research, Digestive Disease Center, Department of Internal Medicine, Soonchunhyang University Seoul Hospital, 59 Daesagwan-ro, Yongsan- gu, Seoul 04401, Korea Tel: +82-2-709-9202 Fax: +82-2-709-9696 E-mail:
| | - Soung Won Jeong
- Institute for Digestive Research, Digestive Disease Center, Department of Internal Medicine, Soonchunhyang University Seoul Hospital, Seoul, Korea
| | - Young Don Kim
- Department of Internal Medicine, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung, Korea
| | - Gab Jin Cheon
- Department of Internal Medicine, Gangneung Asan Hospital, University of Ulsan College of Medicine, Gangneung, Korea
| | - Young Sin Cho
- Institute for Digestive Research, Digestive Disease Center, Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea
| | - Sae Hwan Lee
- Institute for Digestive Research, Digestive Disease Center, Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea
| | - Hong Soo Kim
- Institute for Digestive Research, Digestive Disease Center, Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea
| | - Yun Nah Lee
- Institute for Digestive Research, Digestive Disease Center, Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Korea
| | - Sang Gyune Kim
- Institute for Digestive Research, Digestive Disease Center, Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Korea
| | - Young Seok Kim
- Institute for Digestive Research, Digestive Disease Center, Department of Internal Medicine, Soonchunhyang University Bucheon Hospital, Bucheon, Korea
| | - Boo Sung Kim
- Institute for Digestive Research, Digestive Disease Center, Department of Internal Medicine, Soonchunhyang University Seoul Hospital, Seoul, Korea
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Liu B, Yang JX, Yan L, Zhuang H, Li T. Novel HBV recombinants between genotypes B and C in 3'-terminal reverse transcriptase (RT) sequences are associated with enhanced viral DNA load, higher RT point mutation rates and place of birth among Chinese patients. INFECTION GENETICS AND EVOLUTION 2017; 57:26-35. [PMID: 29111272 DOI: 10.1016/j.meegid.2017.10.023] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/30/2017] [Revised: 10/25/2017] [Accepted: 10/26/2017] [Indexed: 12/13/2022]
Abstract
As one of the major global public health concerns, hepatitis B virus (HBV) can be divided into at least eight genotypes, which may be related to disease severity and treatment response. We previously demonstrated that genotypes B and C HBV, with distinct geographical distribution in China, had divergent genotype-dependent amino acid polymorphisms and variations in reverse transcriptase (RT) gene region, a target of antiviral therapy using nucleos(t)ide analogues. Recently recombination between HBV genotypes B and C was reported to occur in the RT region. However, their frequency and clinical significance is poorly understood. Here full-length HBV RT sequences from 201 Chinese chronic hepatitis B (CHB) patients were amplified and sequenced, among which 31.34% (63/201) were genotype B whereas 68.66% (138/201) genotype C. Although no intergenotypic recombination was detected among C-genotype HBV, 38.10% (24/63) of B-genotype HBV had recombination with genotype C in the 3'-terminal RT sequences. The patients with B/C intergenotypic recombinants had significantly (P<0.05) higher serum HBV DNA level than the "pure" B-genotype cohort did. Moreover, the B/C intergenotypic recombinants were prone to more substitutions at several specific residues in the RT region than genotype B or C. Besides, unlike their parental genotypes, the recombinant HBV appeared to display an altered geographic distribution feature in China. Our findings provide novel insight into the virological, clinical and epidemiological features of new HBV B/C intergenotypic recombinants at the 3' end of RT sequences among Chinese CHB patients. The highly complex genetic background of the novel recombinant HBV carrying new mutations affecting RT protein may contribute to an enhanced heterogeneity in treatment response or prognosis among CHB patients.
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Affiliation(s)
- Baoming Liu
- Department of Microbiology and Center of Infectious Diseases, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China; Department of Microbiology, Immunology and Biochemistry, University of Tennessee Health Science Center, Memphis, TN, USA.
| | - Jing-Xian Yang
- Department of Microbiology and Center of Infectious Diseases, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Ling Yan
- Department of Microbiology and Center of Infectious Diseases, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Hui Zhuang
- Department of Microbiology and Center of Infectious Diseases, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China
| | - Tong Li
- Department of Microbiology and Center of Infectious Diseases, School of Basic Medical Sciences, Peking University Health Science Center, Beijing, China.
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Leung NWY, Herrmann E, Lau GKK, Chan HLY, So TMK, Zeuzem S, Dong Y, Trylesinski A, Naoumov NV. Early Viral Kinetics with Telbivudine, Tenofovir or Combination of Both in Immunotolerant Patients with Hepatitis B e Antigen-Positive Chronic Hepatitis B. Infect Dis Ther 2014; 3:191-202. [PMID: 25228496 PMCID: PMC4269624 DOI: 10.1007/s40121-014-0039-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2014] [Indexed: 01/05/2023] Open
Abstract
Introduction Viral kinetics has proved useful in understanding antiviral potency, determining antiviral profiles and optimizing treatment strategy. Methods This was a randomized, open-label study comparing the viral kinetics in 46 hepatitis B e antigen-positive patients during 12-week treatment with telbivudine monotherapy, tenofovir monotherapy or the combination of telbivudine plus tenofovir. A standard biphasic mathematical model was used to compare hepatitis B virus (HBV) DNA decay parameters. Results Forty-six patients received telbivudine (n = 16), tenofovir (n = 14) or telbivudine plus tenofovir (n = 16). From baseline to Week 12, the mean (SD) reduction in HBV DNA levels was not significantly different between treatment groups: −3.9 (0.9) log10 copies/mL in telbivudine group, −4.2 (0.7) log10 copies/mL in tenofovir group, and −4.4 (1.0) log10 copies/mL in combination group. No significant difference was observed among the three groups for viral clearance rate per day (0.97, 1.02, and 0.88, respectively) or for infected cell loss rate per day (0.04, 0.05, and 0.05, respectively). Antiviral efficiency in blocking viral production was similar in the monotherapy groups (median; 99.7% in telbivudine group and 99.4% in tenofovir group), but was slightly better and more homogeneous in the combination treatment group than in the monotherapy groups: mean (SD), 99.1% (0.8%) and 98.8% (1.6%), respectively (Wald–Wolfowitz test; P = 0.038). All treatments were well tolerated and no serious adverse event was reported during the study. Of the 46 patients in the safety population, 23 experienced adverse events. Most of the adverse events were not suspected to be related to the study drug by the investigators. Conclusion Monotherapy with telbivudine or tenofovir showed similar antiviral effectiveness in HBV DNA reduction and viral kinetics of HBV DNA decay. Efficiency in blocking viral production was slightly improved in the combination treatment group compared to the monotherapy groups. Electronic supplementary material The online version of this article (doi:10.1007/s40121-014-0039-5) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Nancy W Y Leung
- , 1501 Melbourne Plaza, 33 Queen's Road Central, Hong Kong S.A.R., China.
| | - Eva Herrmann
- Johann Wolfgang Goethe University Frankfurt Department of Medicine, Institute of Biostatistics and Mathematical Modeling, Theodor-Stern-Kai 7, Frankfurt am Main, Germany
| | - George K K Lau
- The Institute of Translational Hepatology, Beijing 302 Hospital, Beijing, China
| | - Henry L Y Chan
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong S.A.R., China
| | - Tokutei M K So
- Department of Medicine and Geriatrics, Princess Margaret Hospital, Hong Kong S.A.R., China
| | - Stefan Zeuzem
- Klinikum der Johann Wolfgang Goethe-Universitaet, Frankfurt am Main, Germany
| | - Yu Dong
- Novartis Pharma AG, Basel, Switzerland
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Sayan M, Cavdar C, Dogan C. Naturally occurring polymerase and surface gene variants of hepatitis B virus in Turkish hemodialysis patients with chronic hepatitis B. Jpn J Infect Dis 2013. [PMID: 23183201 DOI: 10.7883/yoken.65.495] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
The aim of this study was to assess the frequencies and patterns of naturally occurring genotypic resistance to nucleos(t)ide analogues (NUCs) and typical hepatitis B surface antigen (HBsAg) amino acid substitutions in naive hemodialysis (HD) patients with chronic hepatitis B. In order to achieve this, the genotypic resistance to NUCs and HBsAg amino acid substitutions were classified into primary/compensatory resistance mutation and antiviral drug-associated potential vaccine-escape mutation (ADAPVEM)/typical HBsAg amino acid substitution, respectively. Direct sequencing of polymerase (pol) gene of hepatitis B virus (HBV) was performed on DNA samples obtained from 248 HBsAg-positive Turkish patients. Overall, 38% (n = 94) of HBsAg-positive HD patients had detectable HBV DNA in their serum. Naturally occurring primary and compensatory resistance mutations to NUCs were detected in 30% (n = 28) and 52% (n = 49) of HD patients, respectively. However, 6 types of ADAPVEMs and 48 types of typical HBsAg amino acid substitutions were found in 10.6% (n = 10) and 46% (n = 43) of the HD patients, respectively. Our study suggests that every HD patient diagnosed with chronic hepatitis B, who is a potential candidate for NUCs treatment, should also be monitored for the baseline pol gene sequence changes before the initial treatment, for a more effective management of future treatment options. Further, a relatively higher frequency of ADAPVEMs variants needs to be addressed as a public health problem.
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Affiliation(s)
- Murat Sayan
- PCR Unit, Clinical Laboratory, Faculty of Medicine, University of Kocaeli, Kocaeli, Turkey. sayanmurat＠hotmail.com
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Molecular epidemiological study of hepatitis B virus in blood donors from five Chinese blood centers. Arch Virol 2012; 157:1699-707. [PMID: 22669316 PMCID: PMC3431469 DOI: 10.1007/s00705-012-1331-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2012] [Accepted: 03/29/2012] [Indexed: 12/18/2022]
Abstract
Although the genetic variability of hepatitis B virus (HBV) in HBV-infected patients has been extensively studied, reports on genotypes, subtypes and mutations in the S region of HBV strains from Chinese blood donors are limited. In this study, 245 blood samples from HBsAg-positive blood donors were collected from five geographically diverse blood centers in China. The S region of HBV was amplified, and the HBV genotype and subtype were determined. The amino acid sequences of the S region were aligned, and mutations related to the failure of immunization and HBsAg detection were determined. Of the 245 samples, 228 (93 %) were genotyped successfully. We found that genotypes B, C, D and A accounted for 58.8 %, 21.9 %, 6.6 % and 3.95 % of the isolates, respectively. The distribution of HBV antigen subtypes was as follows: adw (67.6 %), adr (23.3 %) and ayw (8.7 %). Mutations were present in 39 (17.1 %) of 228 samples in the major hydrophilic region (MHR) of the S region. This study demonstrated that HBV genotype/subtype B/adw was the most frequent strain circulating in HBV-infected Chinese blood donors, followed by C/adr. The occurrence of MHR mutants in HBV-infected blood donors and the potential failure to detect some of them in collected units poses a threat to transfusion safety.
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Sayan M, Akhan SC. Antiviral drug-associated potential vaccine-escape hepatitis B virus mutants in Turkish patients with chronic hepatitis B. Int J Infect Dis 2011; 15:e722-6. [PMID: 21784687 DOI: 10.1016/j.ijid.2011.05.019] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2011] [Revised: 05/13/2011] [Accepted: 05/30/2011] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND The hepatitis B virus (HBV) polymerase (pol) gene completely overlaps with the envelope (S) gene. Mutations in the pol gene of HBV, either from selection of primary or secondary resistance mutations, typically result in changes in the overlapping hepatitis B surface antigen (HBsAg). Recent studies have conferred a new acronym to these HBV pol/S gene overlap mutants: ADAPVEMs, for antiviral drug-associated potential vaccine-escape mutants. The present study aimed to assess the prevalence and pattern of ADAPVEMs in Turkish patients with chronic hepatitis B (CHB). METHODS The investigation was conducted between March 2007 and July 2010 and involved a total of 442 patients. These patients were in the following phases of HBV infection: immune tolerant (n=50), immune reactive (n=37), inactive carrier (n=90), HBeAg-negative CHB (n=217), and HBsAg-negative (n=12), or were hemodialysis patients (n=36). One hundred eighty-six patients were receiving nucleos(t)ide analogue (NUC) therapy and 256 patients had treatment-naïve CHB. RESULTS Seven types of ADAPVEM were detected in the total CHB patients: rtM204V/sI195M, rtM204I/sW196S, rtM204I/sW196L, rtV173L/sE164D, rtA181T/sW172*, rtA181T/sW172L, and rtA181V/sL173F. The ADAPVEMs were associated with lamivudine, telbivudine, and adefovir. The prevalence of ADAPVEMs in all CHB patients was found to be 10% (46/442). The difference in the prevalence of ADAPVEMs across the different CHB clinical phases was not significant (Pearson Chi-square, p=0.112). The prevalence of ADAPVEMs was 24% (44/186) in those undergoing NUC therapy and 0.7% (2/256) in the treatment-naïve group; this difference was significant (Pearson Chi-square, p=0.00). CONCLUSIONS We determined the prevalence and pattern of ADAPVEMs in Turkish patients in the different phases of CHB. Preferred drugs in Turkey, such as lamivudine, have the potential to cause the emergence of ADAPVEMs, with the possibility that these will spread to both individuals immunized with the hepatitis B vaccine and nonimmunized individuals. ADAPVEMs should be monitored in infected and treated patients and their public health risks assessed.
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Affiliation(s)
- M Sayan
- Clinical Laboratory, PCR Unit, Faculty of Medicine, University of Kocaeli, 41380 İzmit-Kocaeli, Turkey.
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Khaled IAEA, Mahmoud OM, Saleh AF, Bioumie EE. Prevalence of HBV genotypes among Egyptian hepatitis patients. Mol Biol Rep 2010; 38:4353-7. [PMID: 21181276 DOI: 10.1007/s11033-010-0562-8] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2010] [Accepted: 11/17/2010] [Indexed: 12/15/2022]
Abstract
Phylogenetic analysis has led to the classification of hepatitis B virus into eight genotypes, designated A to H. The genotypes have differences in biological properties and show heterogeneity in their global distribution. These attributes of the genotypes may account not only for differences in the prevalence of hepatitis B virus mutants in various geographic regions, but also makes them responsible for differences in the clinical outcome and response to antiviral treatment in different population groups. Africa is one of the highly endemic regions of HBV with five genotypes (A-E) identified. Almost all patients in the Mediterranean area are infected with genotype D. However, there is little information of genotype distribution in Egypt. A total of 140 Egyptian patients with hepatitis B surface antigen (HBsAg) positive were enrolled in this study. Of the 140 patients, only 100 patients were HBV DNA positive and only these were included in the study. They were classified into 20 patients with acute hepatitis (AH), 75 patients with chronic active hepatitis (CAH) and 5 patients with hepatocellular carcinoma (HCC). HBV genotypes were determined using INNO-LiPA methodology which is based on the reversed hybridization principle. This study showed that genotype D constituted 87% of the total infections (75 CAH cases, 7 AH cases and 5 HCC cases). The other 13% showed mixed infections of D/F. These findings show that the most prevalent genotype in Egypt is genotype D especially in CAH and HCC patients while the mixed type D/F is only encountered in AH.
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Affiliation(s)
- Iman A El Aziz Khaled
- Haematology & Blood Bank, Haematology & Blood Bank Theodor Bilharz Research Institute (TBRI), Cairo, Egypt.
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Guirgis BS, Abbas RO, Azzazy HM. Hepatitis B virus genotyping: current methods and clinical implications. Int J Infect Dis 2010; 14:e941-53. [PMID: 20674432 DOI: 10.1016/j.ijid.2010.03.020] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2008] [Revised: 03/10/2010] [Accepted: 03/11/2010] [Indexed: 02/06/2023] Open
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Early viral kinetics of telbivudine and entecavir: results of a 12-week randomized exploratory study with patients with HBeAg-positive chronic hepatitis B. Antimicrob Agents Chemother 2009; 54:1242-7. [PMID: 20028815 DOI: 10.1128/aac.01163-09] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
We characterized the early viral kinetic profiles of telbivudine and entecavir and the effects of these potent nucleoside analogs on hepatitis B virus (HBV) DNA and alanine aminotransferase levels in adults with hepatitis B e antigen-positive compensated chronic hepatitis B. Forty-four patients were enrolled in this open-label, parallel-group, multicenter study and randomized to receive telbivudine or entecavir for 12 weeks. Reductions in hepatitis B virus DNA and alanine aminotransferase levels from baseline to weeks 2, 4, 8, and 12 were assessed. Viral kinetic parameters, including viral clearance per day, loss of infected cells per day, and efficiency of inhibition of viral production, were estimated by using a biphasic mathematical model. Statistical analyses were limited to descriptive analyses. The 2 treatment groups achieved similar reductions in HBV DNA and alanine aminotransferase levels. Mean reductions in levels of hepatitis B virus DNA at week 12 were 6.6 +/- 1.6 and 6.5 +/- 1.5 log(10) copies/ml for the telbivudine- and entecavir-treated patients, respectively. There were no significant differences between groups in values for mean viral clearance per day, mean loss of infected cells per day, or efficiency of blocking viral production. The safety profiles for both medications were favorable. During the first 12 weeks of treatment, telbivudine and entecavir demonstrated similar antiviral potencies, resulting in a rapid and profound suppression of serum hepatitis B virus DNA and reduction of alanine aminotransferase levels. No differences in the effects of these 2 agents on early viral kinetics were observed. Both medications were well tolerated.
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Yoshikawa A, Gotanda Y, Suzuki Y, Tanaka M, Matsukura H, Shiraishi T, Matsubayashi K, Kon E, Suzuki K, Yugi H. Age- and gender-specific distributions of hepatitis B virus (HBV) genotypes in Japanese HBV-positive blood donors. Transfusion 2009; 49:1314-20. [PMID: 19389027 DOI: 10.1111/j.1537-2995.2009.02156.x] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
BACKGROUND There are an increasing number of reports on the hepatitis B virus (HBV) genotype distribution in acute or chronic HBV-infected patients in Japan; however, reports on the HBV genotype of blood donors are few. To compare the HBV genotypes of hepatitis B surface antigen (HBsAg)-positive blood donors with infected patients, all the HBsAg-positive donors' genotypes were determined. STUDY DESIGN AND METHODS Data on Japanese blood donors from October 2006 to September 2007 were obtained from the Japanese Red Cross database. The number of available samples was 1979, and the HBV genotypes were determined in 1887 samples. The six major genotypes of HBV (A-F) were determined by enzyme-linked immunosorbent assay. The presence of the immunoglobulin M (IgM) antibody against the HBV core antigen was determined by enzyme immunoassay among all HBsAg-positive donors. RESULTS A significant difference in the HBV genotype distribution between donors and patients was in the C/B genotype ratio. The ratios were low in blood donors (2.0-3.9) and high in patients (5.3-18.2). The genotype B ratio increases from 13.8% in teenage donors to 42.4% in those in their 50s; however; the genotype C ratio decreases from 83.1% in teenage donors to 55.1% in those in their 50s. In both IgM antibody against hepatitis B core antigen and nucleic acid test-positive donors, genotypes A and B were restricted to male donors. CONCLUSIONS The age-specific distribution of HBV genotypes in Japanese blood donors was observed in the B/C genotype ratio. The gender-specific distribution of HBV genotype A, which originated from the US or Western countries, was observed in male Japanese donors.
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Affiliation(s)
- Akira Yoshikawa
- Japanese Red Cross Saitama Blood Center, 1370-12 Takahagi, Hidaka-shi, Saitama-ken, Japan.
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Panjaworayan N, Roessner SK, Firth AE, Brown CM. HBVRegDB: annotation, comparison, detection and visualization of regulatory elements in hepatitis B virus sequences. Virol J 2007; 4:136. [PMID: 18086305 PMCID: PMC2235840 DOI: 10.1186/1743-422x-4-136] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2007] [Accepted: 12/17/2007] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND The many Hepadnaviridae sequences available have widely varied functional annotation. The genomes are very compact (approximately 3.2 kb) but contain multiple layers of functional regulatory elements in addition to coding regions. Key regions are subject to purifying selection, as mutations in these regions will produce non-functional viruses. RESULTS These genomic sequences have been organized into a structured database to facilitate research at the molecular level. HBVRegDB is a comparative genomic analysis tool with an integrated underlying sequence database. The database contains genomic sequence data from representative viruses. In addition to INSDC and RefSeq annotation, HBVRegDB also contains expert and systematically calculated annotations (e.g. promoters) and comparative genome analysis results (e.g. blastn, tblastx). It also contains analyses based on curated HBV alignments. Information about conserved regions - including primary conservation (e.g. CDS-Plotcon) and RNA secondary structure predictions (e.g. Alidot) - is integrated into the database. A large amount of data is graphically presented using the GBrowse (Generic Genome Browser) adapted for analysis of viral genomes. Flexible query access is provided based on any annotated genomic feature. Novel regulatory motifs can be found by analysing the annotated sequences. CONCLUSION HBVRegDB serves as a knowledge database and as a comparative genomic analysis tool for molecular biologists investigating HBV. It is publicly available and complementary to other viral and HBV focused datasets and tools http://hbvregdb.otago.ac.nz. The availability of multiple and highly annotated sequences of viral genomes in one database combined with comparative analysis tools facilitates detection of novel genomic elements.
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Yuen MF, Lai CL. Hepatitis B virus genotypes: natural history and implications for treatment. Expert Rev Gastroenterol Hepatol 2007; 1:321-8. [PMID: 19072424 DOI: 10.1586/17474124.1.2.321] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
There are eight different genotypes named A-H. Genotypes have distinct geographic distribution in different regions of the world. There exists a difference in the disease profile between different genotypes. Genotype A compared with D, and B compared with C have earlier hepatitis B e-antigen seroconversion and less severe liver disease. However, genotypes are closely linked with core promoter and precore mutations. This may have a confounding effect on the association of genotypes with disease progression. Patients with genotype A compared with D and B compared with C have a better treatment response to IFN-alpha. However, there are no differences in the treatment response and rate of emergence of drug-resistant hepatitis B virus between different genotypes to nucleoside/nucleotide analog therapy.
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Affiliation(s)
- Man-Fung Yuen
- The University of Hong Kong, Department of Medicine, Queen Mary Hospital, Pokfulam Road, Hong Kong, China.
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Alvarado-Esquivel C, Sablon E, Conde-González CJ, Juárez-Figueroa L, Ruiz-Maya L, Aguilar-Benavides S. Molecular analysis of hepatitis B virus isolates in Mexico: Predominant circulation of hepatitis B virus genotype H. World J Gastroenterol 2006; 12:6540-5. [PMID: 17072988 PMCID: PMC4100645 DOI: 10.3748/wjg.v12.i40.6540] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To determine the genotypes in Mexican hepatitis B virus (HBV) isolates and characterize their precore and core promoter mutations.
METHODS: Forty-nine HBV isolates of Mexico obtained from sera of 15 hepatitis patients, 6 hemodialysis patients, 20 men seeking HIV testing, and 8 AIDS patients were analyzed. HBV isolates were amplified by PCR, and genotyped by line probe assay (INNO-LiPA HBV Genotyping; INNOGENETICS N V, Ghent, Belgium). HBV genotype confirmation was performed by DNA sequencing part of the sAg region. Precore and core promoter mutation characterization was performed by line probe assay (INNO-LiPA HBV PreCore; INNOGENETICS N V, Ghent, Belgium).
RESULTS: Overall, HBV genotype H was found in 37 (75.5%) out of the 49 isolates studied. HBV genotypes G, A, and D were found in 5 (10.2%), 4 (8.2%), and 3 (6.1%) isolates, respectively. HBV genotype H was predominant in isolates from hemodialysis patients (100%), hepatitis patients (80%), and men seeking HIV testing (75%), and accounted for half of infections in AIDS patients (50%). Six (12.2%) out of the 49 HBV isolates showed both wild type and mutant populations at precore codon 28. These mixed wild type and precore mutant populations were observed in one HBV genotype A isolate and in all HBV genotype G isolates. A dual variant core promoter mutation was observed in 1 (2%) of the isolates, which was genotype H.
CONCLUSION: HBV genotype H is highly predominant in HBV isolates of Mexico followed by genotypes G, A and D. A low frequency of precore and core promoter mutations is observed in HBV Mexican isolates.
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Riedl P, Bertoletti A, Lopes R, Lemonnier F, Reimann J, Schirmbeck R. Distinct, Cross-Reactive Epitope Specificities of CD8 T Cell Responses Are Induced by Natural Hepatitis B Surface Antigen Variants of Different Hepatitis B Virus Genotypes. THE JOURNAL OF IMMUNOLOGY 2006; 176:4003-11. [PMID: 16547235 DOI: 10.4049/jimmunol.176.7.4003] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
We investigated the specific and cross-reactive CD8 T cell immunity to three natural variants (of different geno/serotype) of the small hepatitis B surface Ag (or S protein). The D(d)-binding variants of the S(201-209) epitope showed different immunogenicity. The loss of the consensus C-terminal (P9) anchor abrogated its immunogenicity. In contrast, a conservative (serine vs asparagine) exchange at P7 primed cross-reactive CD8 T cells that preferentially recognized the priming variant. Cross-reactive CD8 T cell responses to a variant could be primed in mice tolerant to an alternative variant of the D(d)-binding S(201-209) peptide. Loss of the C-terminal (P10) anchor in S(185-194) eliminated its immunogenicity in HLA-A*0201(A2)-transgenic mice but two conservative exchanges (leucine vs valine in P2, and leucine vs isoleucine in P6) in S(208-216) generated cross-reactive CD8 T cell responses with strong preference for the priming variant. Similar cross-reactive recognition of variant envelope epitopes were also found in S(208-216)-specific CD8 T cells from hepatitis B virus (HBV)-infected patients. Distinct CD8 T cell populations cross-reactive to natural variants of class I-restricted HBV epitopes can be primed by vaccination (of mice) or natural infection (of humans), and they may play a role in the "spontaneous remission" or the specific immunotherapy of chronic HBV infection.
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Affiliation(s)
- Petra Riedl
- Department of Internal Medicine I, University of Ulm, Germany
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Ohnuma H, Yoshikawa A, Mizoguchi H, Okamoto H. Characterization of genotype H hepatitis B virus strain identified for the first time from a Japanese blood donor by nucleic acid amplification test. J Gen Virol 2005; 86:595-599. [PMID: 15722519 DOI: 10.1099/vir.0.80732-0] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
The Japanese Red Cross has been conducting a nucleic acid amplification test (NAT) screening for hepatitis B virus (HBV), hepatitis C virus and human immunodeficiency virus 1 among blood donors since July 1 1999. The first case of HBV genotype H was found and reported in Japan. Serological markers of HBV were not detected in this NAT-positive donation. It may be that the positive donation was in the serological window period at the early stage of infection. The complete genome of 3215 nt was sequenced, and the sequence had 99.3 % homology with the strain from Los Angeles, USA (LSA2523). Here, a leucine zipper motif was found in the region of the HBV surface antigen conserved through genotypes A-H.
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Affiliation(s)
- Hitoshi Ohnuma
- Saitama Red Cross Blood Center, 1370-12, Takahagi, Hidaka, Saitama-ken 350-1213, Japan
| | - Akira Yoshikawa
- Saitama Red Cross Blood Center, 1370-12, Takahagi, Hidaka, Saitama-ken 350-1213, Japan
| | - Hideaki Mizoguchi
- Saitama Red Cross Blood Center, 1370-12, Takahagi, Hidaka, Saitama-ken 350-1213, Japan
| | - Hiroaki Okamoto
- Division of Virology, Department of Infection and Immunity, Jichi Medical School, Tochigi-ken 329-0498, Japan
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Yoshikawa A, Gotanda Y, Itabashi M, Minegishi K, Kanemitsu K, Nishioka K. Hepatitis B NAT virus-positive blood donors in the early and late stages of HBV infection: analyses of the window period and kinetics of HBV DNA. Vox Sang 2005; 88:77-86. [PMID: 15720604 DOI: 10.1111/j.1423-0410.2005.00602.x] [Citation(s) in RCA: 69] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
BACKGROUND AND OBJECTIVES The Japanese Red Cross (JRC) carries out nucleic acid amplification testing (NAT) for hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus-1 (HIV-1) by using a multiplex (MPX) reagent. Screening is undertaken on serologically negative units. In this study we characterized HBV NAT-positive donations individually and analysed the window period and kinetics of HBV DNA, during acute infection, in follow-up studies. MATERIALS AND METHODS Two hundred and seventy-seven HBV DNA-positive donations have been identified in Japan since the introduction of NAT screening of 50-donation minipools. The viral loads and genotypes of these HBV DNA-positive donations were characterized. The doubling time and half-life of HBV was estimated from the data of 123 follow-up donors. The sensitivity of the NAT system (based on 50-donation minipools) was compared with the sensitivities of the enzyme immunoassay (EIA) and the chemiluminescence immunoassay (CLIA). Samples that were CLIA negative, but with > 10(4) copies/ml of HBV DNA, were analysed by sequencing the hepatitis B surface antigen (HBsAg) region. RESULTS Out of 277 HBV NAT-positive samples, 125 (45%) were found to have an increasing viral load and 45 (16%) a decreasing viral load. Forty per cent of HBV NAT-positive samples with an increasing viral load, and 33% of those with a decreasing viral load, were negative when tested by using the CLIA. No mutations related to escape mutants were found in the samples that were CLIA negative but with HBV DNA loads of > 10(4) copies/ml. The median HBV doubling time was 2.6 days (n = 93, 1.3-15.2 days) and the half-life was 1.6 days (n = 55, 0.9-6.3 days). Some kinetic difference was observed between genotypes A and B. CONCLUSIONS HBV NAT screening detected HBV DNA in both early (the so-called serological window period) and late stages of acute HBV infection.
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Affiliation(s)
- Akira Yoshikawa
- Japanese Red Cross Saitama Blood Center, Hidaka, Saitama, Japan.
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Guettouche T, Hnatyszyn HJ. Chronic hepatitis B and viral genotype: the clinical significance of determining HBV genotypes. Antivir Ther 2005; 10:593-604. [PMID: 16152753 DOI: 10.1177/135965350501000501] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2025]
Abstract
The global health challenge posed by the hepatitis B virus (HBV) centres around the widespread distribution and the serious complications as a result of persistent infection with the virus. As with other chronic diseases mediated by pathogens such as human immunodeficiency virus (HIV) and hepatitis C virus (HCV), clinicians are searching for epidemiological, pathological and viral characteristics of HBV infection that may lead to more effective management of patients with chronic infection. Unlike HCV, the role of HBV genotype in disease progression, severity, response to therapy and drug resistance is still under investigation and just beginning to be clarified. This review examines the potential role of HBV genotype determination in the clinic with emphasis on how this genetic information may used to provide effective management for the treatment of patients with chronic hepatitis B.
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Affiliation(s)
- Toumy Guettouche
- Bayer Institute for Clinical Investigation, Bayer Healthcare-Diagnostics, Berkeley, CA, USA
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Lai CL, Lim SG, Brown NA, Zhou XJ, Lloyd DM, Lee YM, Yuen MF, Chao GC, Myers MW. A dose-finding study of once-daily oral telbivudine in HBeAg-positive patients with chronic hepatitis B virus infection. Hepatology 2004; 40:719-26. [PMID: 15349912 DOI: 10.1002/hep.20374] [Citation(s) in RCA: 81] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Current therapy for chronic hepatitis B is suboptimal as a result of limited durable response rates, cumulative viral resistance, and/or poor tolerability. Telbivudine has potent antiviral activity against hepatitis B virus (HBV) in vitro and in the woodchuck model and has a promising preclinical safety profile. In this first clinical study of telbivudine, safety, antiviral activity, and pharmacokinetics were assessed in 43 adults with hepatitis B e antigen-positive chronic hepatitis B. This placebo-controlled dose-escalation trial investigated 6 telbivudine daily dosing levels (25, 50, 100, 200, 400, and 800 mg/d); treatment was given for 4 weeks, with 12 weeks' follow-up. Serum HBV DNA levels were monitored via quantitative polymerase chain reaction. The results indicate that telbivudine was well tolerated at all dosing levels, with no dose-related or treatment-related clinical or laboratory adverse events. telbivudine plasma pharmacokinetics were dose-proportional within the studied dose range. Marked dose-related antiviral activity was evident, with a maximum at telbivudine doses of 400 mg/d or more. In the 800 mg/d cohort, the mean HBV DNA reduction was 3.75 log10 copies/mL at week 4, comprising a 99.98% reduction in serum viral load. Correspondingly, posttreatment return of viral load was slowest in the high-dose groups. Viral dynamic analyses suggested a high degree of efficiency of inhibition of HBV replication by telbivudine and helped refine selection of the optimal dose. In conclusion, these results support expanded clinical studies of this new agent for the treatment of hepatitis B.
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Osiowy C, Giles E. Evaluation of the INNO-LiPA HBV genotyping assay for determination of hepatitis B virus genotype. J Clin Microbiol 2004; 41:5473-7. [PMID: 14662927 PMCID: PMC308976 DOI: 10.1128/jcm.41.12.5473-5477.2003] [Citation(s) in RCA: 96] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Specific genotypes of hepatitis B virus (HBV) are increasingly recognized for their clinical significance and association with particular viral mutations. Although many HBV genotyping methods exist, there has been no standardized or commercially available method for direct molecular typing of the HBV genome. A newly available line probe assay (INNO-LiPA HBV Genotyping assay; Innogenetics N.V., Ghent, Belgium) that allows the identification of HBV genotypes A to G was assessed by comparison with pre-S1/pre-S2 sequence analysis of the isolates in 188 serum specimens. All seven genotypes were detected by the line probe assay (LiPA), and complete concordance between LiPA and sequence analysis was observed for 152 specimens (81%). LiPA was able to detect 19 mixed genotype infections not detected by amplicon sequencing, which for the most part were confirmed by cloning and sequencing of the pre-S1/pre-S2 amplicon. Four specimens had discrepant results between the two methods, and five specimens had indeterminate results by LiPA. The HBV DNA in four specimens was unable to be amplified by the nested INNO-LiPA HBV DR amplification primers; however, the HBV DNA in six specimens unable to be genotyped by sequencing was clearly genotyped by LiPA. The INNO-LiPA HBV Genotyping assay appears to be useful for the rapid genotyping of HBV, particularly for the sensitive detection of mixed genotype infections.
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Affiliation(s)
- Carla Osiowy
- Bloodborne Pathogens and Hepatitis, National Microbiology Laboratory, Canadian Science Centre for Human and Animal Health, Winnipeg, Manitoba R3E 3P6, Canada.
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