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1.  Hepatitis B virus infection in a cohort of HIV infected blood donors and AIDS patients in Sichuan, China 
Background
Co-infections of HBV and HIV are frequent due to similar routes of transmission. In that transmission through blood is an important route for both HBV and HIV, evaluation of the prevalence of HBV in HIV infected blood donors may be important for transfusion safety. In addition, because the epidemiological characteristics of HBV in HIV infected patients and blood donors may differ from each other, understanding of it could be significant for therapy and prevention of HBV in HIV infected adults. However, data reported on these in Chinese people remains limited.
Methods
614 HIV confirmed positive samples were collected from blood donors and patients and were screened for HBsAg and HBV DNA. The samples screened reactive for HBsAg or positive for HBV DNA were tested for the other serological markers of HBV including anti-HBs, HBeAg, anti-HBe and anti-HBc. For the samples tested positive for HBV DNA, the S region of HBV was amplified by nested PCR and the HBV genotypes were determined.
Results
HBV coinfections were found in 12.9% (79/614) HIV infected individuals including 42/417(10.1%) blood donors and 37/197 (18.8%) AIDS patients. In the HBsAg positive individuals, 80.0% were HBeAg negative in which 10.0% were HBV DNA negative and 38.3% with HBV DNA lower than 2000 IU/ml. The average HBV DNA levels were lower in donors than in patients. In the HBV DNA positive populations, HBV genotypes B, A and C accounted for 48.1%, 22.8% and 8.86% respectively. Mutations related to the failure of HBsAg detection were found in 2 of the 4 HBsAg-/HBV DNA + subjects.
Conclusions
High prevalence of HBV in HIV infected individuals was found in this study. Hence, we recommend routine testing of HBV for patients newly diagnosed with HIV/AIDS in China. Some HIV-HBV co-infected patients remain undiagnosed if only conventional serological markers for HBV are used and it’s important to detect HBV DNA for HIV infected patients. HBV DNA levels were relatively low in HBeAg negative patients, thus this serologic marker may be useful in prioritizing patients on their need for HBV treatment in settings in which HBV DNA is not available.
doi:10.1186/1479-5876-12-164
PMCID: PMC4067527  PMID: 24923206
HIV; HBV; Blood donors; AIDS patients
2.  Complete Genome Sequence and Phylogenetic Relatedness of Hepatitis B Virus Isolates in Papua, Indonesia▿ †  
Journal of Clinical Microbiology  2009;47(6):1842-1847.
Each hepatitis B virus (HBV) genotype and subgenotype is associated with a particular geographic distribution, ethnicity, and anthropological history. Our previous study showed the novel HBV subgenotypes C6 (HBV/C6) and D6 (HBV/D6), based on the S gene sequences of isolates in Papua, Indonesia. The present study investigated the complete genome sequence of 22 strains from Papua and subjected them to molecular evolutionary analysis. A phylogenetic analysis revealed that 9 out of 22 strains were classified as HBV/C6, 3 strains as HBV/D6, and 9 strains as HBV/B3. A particular strain positioned between HBV/B3 and HBV/B5 remained unclassifiable into any known subgenotypes. This strain showed high homology with HBV/C5 from the Philippines in the core region and was thought to have undergone genetic recombination with HBV/C5. Further studies are needed to determine whether this strain belongs to a new subgenotype of HBV/B. Based on the amino acid alignment, HBV/C6 has subgenotype specific variations (G18V and V47M) in the S region. HBV/C6 strains were more closely related in terms of evolutionary distance to strains from the east Asia and Pacific regions than those found in southeast Asia. HBV/D6 strains were most closely related to strains from the Western countries (HBV/D3) rather than those from Asia and Papua New Guinea. In conclusion, we have confirmed by complete sequence analysis that two novel HBV subgenotypes, HBV/C6 and HBV/D6, are prevalent in Papua, Indonesia.
doi:10.1128/JCM.02328-08
PMCID: PMC2697109  PMID: 19386834
3.  Predominance of precore mutations and clinical significance of basal core promoter mutations in chronic hepatitis B virus infection in Indonesia 
Biomedical Reports  2013;1(4):522-528.
Chronic hepatitis B virus (HBV) infection is a major health problem worldwide, with a particularly high prevalence in the Asian-Pacific region. During chronic hepatitis B virus (HBV) infection, mutations commonly occur in the basal core promoter (BCP) and precore (PC) regions of HBV, affecting HBeAg expression, particularly following HBeAg serocon-version. Mutations in the B- and T-cell epitopes of the HBV core have also been observed during disease progression. The clinical significance of HBV genome variability has been demonstrated, however the results are a subject of controversy. Considering the characteristics of the virus associated with geographical location, the profiles of BCP, PC and core mutations and their clinical implications in patients with chronic HBV infection in Surabaya, Indonesia, were investigated. The BCP, PC and core mutations and HBV genotypes were detected by direct sequencing. The HBeAg/anti-HBe status and HBV DNA levels were also assessed. This study enrolled 10 patients with chronic HBV infection (UC) from Dr Soetomo General Hospital and Indonesian Red Cross, Surabaya, East Java, Indonesia, 10 patients with chronic hepatitis B and liver cirrhosis (LC) and 4 patients with chronic hepatitis B and hepatocellular carcinoma (HCC) from Dr Soetomo General Hospital. The PC mutation A1896 was predominant in all the groups (60–100%), together with the PC variant T1858, which was associated with HBV genotype B. The number of detected core mutations (Thr/Ser130) was higher in HCC patients (50%). However, the BCP mutations T1762/A1764 were predominant in LC patients (50–60%). The LC and HCC patients carried HBV isolates with additional mutations, at least at BCP or PC, mainly following HBeAg seroconversion. In the majority of anti-HBe-positive samples, the BCP T1762/A1764 mutations were associated with a high viral load, regardless of the PC 1896 status. In conclusion, the PC mutations were found to be predominant in all the groups. However, the BCP mutations were mainly detected in the LC group and may be considered as a critical indicator of a poor clinical outcome.
doi:10.3892/br.2013.106
PMCID: PMC3917060  PMID: 24648979
hepatitis B virus; precore mutations; basal core promoter mutations; core mutations; chronic hepatitis B virus infection
4.  Genetic variability in the precore and core promoter regions of hepatitis B virus strains in Karachi 
BMC Gastroenterology  2006;6:20.
Background
Hepatitis B virus (HBV) genotypes have distinct geographic distribution. Moreover, much genetic variability has been described in the precore (PC) and basal core promoter (BCP) regions of the HBV genome. The local prevalence of HBV genotypes and mutations has not been well studied. The aim of the present study is to determine the prevalence of HBV genotypes and mutations in the PC and BCP region in HBV strains in Karachi.
Methods
A total of 109 chronic hepatitis B patients with detectable HBV DNA by a PCR assay were enrolled in the study. Sera were tested for HBeAg, anti-HBe antibody and liver profile. HBV genotypes and mutations in the PC and BCP regions were detected by INNO-LiPA line-probe assays.
Results
Of the 109 patients investigated, 38 (35%) were HBeAg positive while 71 (65%) were HBeAg negative. Genotype D was present in 100% of the patients. Two patients had co-infection with genotype A. There was no significant difference in the baseline characteristics, mean ALT levels, and presence of clinical cirrhosis in patients with HBeAg positive or negative strains with or without PC and BCP mutations. Of the 38 HBeAg positive patients, 9 (24%) had PC and BCP mutations. In the HBeAg negative patient group, mutations were detected in 44 (62%) of the strains investigated. More than one mutation was common, seen in 26 (37%) patients with HBeAg negative disease and 6 (16%) patients with HBeAg positive disease. Twelve (17%) HBeAg negative patients had dual T1762 and A1764 mutations. None of the HBeAg positive patients had T1762 mutation. Mutations were undetectable in 27 (38%) of patients with HBeAg negative disease.
Conclusion
Our study shows that type D is the main HBV genotype in Karachi, Pakistan. Significant numbers of patients infected with this genotype have PC and BCP variants. Mutations at more than one site are common. Patients harboring these mutants do not differ significantly in their clinical presentation from patients having wild type infection.
doi:10.1186/1471-230X-6-20
PMCID: PMC1544342  PMID: 16863587
5.  High prevalence of hepatitis B virus genotype C/C1 in the Minangkabau ethnic group in Indonesia 
Virology Journal  2013;10:27.
Background
The Minangkabau is one of the major ethnic groups in Indonesia. Previous studies with a limited number of samples have shown a different prevalence of HBV/C in the Minangkabau compared to the Indonesian population in general. The aim of this study was to assess the HBV genotype distribution pattern and the prevalence of pre-S, T1753V and A1762T/G1764A mutations among the Minangkabau HBV carriers. The samples were collected from Padang, West Sumatera and from western Java. Mixed primers for specific genotypes were used to determine the HBV genotype. Pre-S or S genes were amplified, sequenced and aligned with reference sequences from GenBank to derive a phylogenetic tree for subgenotyping. Pre-S genes were also analyzed for mutations. The basal core promoter (BCP) region was amplified and directly sequenced to analyze T1753V and A1762T/G1764A mutations.
Results
The predominant HBV genotype among the Minangkabau HBV carriers (n=117) was C (72.6%) followed by B (24.8%) and co-infection with B and C (2.6%). The prevalence of pre-S mutations, including both the pre-S deletion and pre-S2 start codon mutation, was 41.0%, and the T1753V and A1762T/G1764A mutations were found in 51.9% and 71.2% respectively. HBV/C1 was the predominant HBV subgenotype in the Minangkabau HBV carriers, and was found in 66.2%, followed by B3, B7, C8, B2, B9, C2, and C10 (18.3%, 7.0%, 2.8%, 1.4%, 1.4%, 1.4%, and 1.4% respectively). From samples that were found to be co-infected with HBV B and C, two samples were successfully cloned and subgenotyped, including one with mixed subgenotypes of B3 and C1, and another one with mixed subgenotypes of B7, C1, putative intergenotypic of B/A, and C/A. Furthermore, three samples from donors of non-Minangkabau ethnicity from Padang were found to be infected with an intragenotypic recombination form, including a putative recombinant of B8/B3 and B9/B7.
Conclusion
HBV/C with subgenotype C1 was the predominant HBV genotype among HBV carriers of Minangkabau ethnicity. The prevalence of pre-S, A1762T/G1764A, and T1753V mutations was higher among the Minangkabau compared to Indonesian HBV carriers in general.
doi:10.1186/1743-422X-10-27
PMCID: PMC3583810  PMID: 23336976
HBV genotype; Pre-S mutation; BCP mutation; Minangkabau
6.  A Novel Complex A/C/G Intergenotypic Recombinant of Hepatitis B Virus Isolated in Southern China 
PLoS ONE  2014;9(1):e84005.
Hepatitis B virus (HBV) genotypes and subgenotypes may vary in geographical distribution and virological features. Previous investigations, including ours, showed that HBV genotypes B and C were respectively predominant in South and North China, while genotypes A and D were infrequently detected and genotype G was not found. In this study, a novel A/C/G intergenotype was identified in patients with chronic HBV infection in Guilin, a city in southern China. Initial phylogenetic analysis based on the S gene suggested the HBV recombinant to be genotype G. However, extended genotyping based on the entire HBV genome indicated it to be an A/C/G intergenotype with a closer relation to genotype C. Breakpoint analysis using the SIMPLOT program revealed that the recombinant had a recombination with a arrangement of genotypes A, G, A and C fragments. Compared with the HBV recombinants harboring one or two genotype G fragments found in Asian countries, this Guilin recombinant was highly similar to the Vietnam (98–99%) and Long An recombinants (96–99%), but had a relatively low similarity to the Thailand one (89%). Unlike those with the typical genotype G of HBV, the patients with the Guilin recombinant were seropositive for HBeAg. Moreover, a relatively high HBV DNA viral load (>2×106 IU/ml) was detected in the patients, and the analysis of viral replication capacity showed that the Guilin recombinant strains had a competent replication capacity similar to genotypes B and C strains. These findings can aid in not only the clarification of the phylogenetic origin of the HBV recombinants with the genotype G fragment found in Asian countries, but also the understanding of the virological properties of these complicated HBV recombinants.
doi:10.1371/journal.pone.0084005
PMCID: PMC3901648  PMID: 24475029
7.  Risk factors for acute hepatitis B and its progression to chronic hepatitis in Shanghai, China 
Gut  2008;57(12):1713-1720.
Background and aims:
The major risk factors for acute hepatitis B (AHB) in China and the viral factors determining the progression from acute to chronic hepatitis B remain largely unknown.
Methods:
Epidemiological studies within a population-based surveillance for AHB in adults were performed in Shanghai, China, including 294 patients, 588 matched controls and 572 family members of the patients.
Results:
Invasive medical procedures, household contact with hepatitis B virus (HBV) carriers, body care and beauty treatments, and lack of HBV vaccination were independently associated with AHB. Among those risks, pedicure in bath centres emerged. Sixty-eight of 128 patients with AHB were genotyped including 33 with HBV B2 and 35 with HBV C2. Twenty-five (8.50%) of the 294 patients, including 20 with HBV C2 and 5 with HBV B2 (p = 0.013), progressed to chronic infection. Multivariate analysis showed that HBV C2 was independently associated with chronicification of AHB. Patients with HBV B2 were younger and there was a higher proportion of women than those with HBV C2. The prevalence of HBV B2 was higher in the patients than in neighbourhood chronic carriers. The chronic carriers with HBV B2 showed higher viral loads, higher hepatitis B e antigen (HBeAg) seropositivity, and with higher proportion in men than those with HBV C2, implying that sexual contact plays a role in the transmission of HBV B2. Phylogenetic analysis showed that HBV C2 was frequently involved in transmissions within households.
Conclusions:
Despite lower viral load and HBeAg status in the chronic carriers, HBV C2 was more prone to causing chronic infection than was HBV B2.
doi:10.1136/gut.2008.157149
PMCID: PMC2582333  PMID: 18755887
8.  Prevalence and Predictors of Hepatitis B Virus Co-infection in a United States Cohort of Hepatitis C Virus-infected Patients 
Hepatology (Baltimore, Md.)  2013;58(2):538-545.
Background and Aim
There is sparse epidemiologic data on co-infection of hepatitis B (HBV) and hepatitis C (HCV) in the United States. Therefore, the aim of this study was to determine the prevalence and predictors of HBV co-infection in a large United States population of HCV patients.
Methods
We used the National Veterans Affairs HCV Clinical Case Registry to identify patients tested for HCV during 1997–2005. Patients were categorized based on HCV exposure (any two +HCV tests or one test with a diagnostic code), HCV infection (+RNA or genotype), HBV exposure (any +HBV test, excluding +HBsAb only) and HBV infection (+HBsAg, HBV DNA, or HBeAg). The prevalence of HBV exposure among patients with HCV exposure and that of HBV infection among patients with HCV infection were determined. Multivariable logistic regression evaluated potential demographic and clinical predictors of HBV co-infection.
Results
Among 168,239 patients with HCV exposure, 58,415 patients had HBV exposure for a prevalence of 34.7% (95% CI 34.5–35.0). Among 102,971 patients with HCV infection, 1,431 patients had HBV co-infection for a prevalence of 1.4% (95% CI 1.3–1.5). Independent associations with HBV co-infection compared with HCV mono-infection were age ≤ 50 years, male sex, positive HIV status, history of hemophilia, sickle cell anemia or thalassemia, history of blood transfusion, cocaine and other drug use; there was decreased risk in patients of Hispanic ethnicity.
Conclusions
This is the largest cohort study in the United States on the prevalence of HBV co-infection in HCV patients. Among veterans with HCV, exposure to HBV is common (~35%), but HBV co-infection is relatively low (1.4%). Several possible risk factors were identified.
doi:10.1002/hep.26400
PMCID: PMC3729715  PMID: 23505059
Epidemiology; Risk factors; HBV; HCV; Viral hepatitis
9.  Clinical and Virological Characteristics of Hepatitis B Virus Subgenotypes Ba, C1, and C2 in China▿  
Journal of Clinical Microbiology  2007;45(5):1491-1496.
Hepatitis B virus (HBV) subgenotypes Ba, C1 (Cs), and C2 (Ce) are the most prevalent HBV variants in China. To investigate the virological characteristics of these subgenotypes and their clinical implications, we enrolled a cohort of 211 patients in the Guangdong Province of China, including 132 with chronic hepatitis B virus infection (CH), 32 with liver cirrhosis (LC), and 47 with hepatocellular carcinoma (HCC) according to clinical examination, liver function test, and ultrasonograph results. Overall, HBV Ba was found in 51.2% (108/211), HBV C1 in 33.6% (71/211), and HBV C2 in 15.2% (32/211) of the cases. The distribution of HBV genotype C was greater among patients in the LC and HCC groups than among patients in the CH group, while the distribution of HBV genotype B was greater among the CH patients than among the LC and HCC patients. No significant differences in clinical features were found among patients with HBV Ba, C1, and C2. Virologically, HBV C1 had the strongest association with the A1762T G1764A double mutation, while the mutation at position 1896 resulting in A (1896A) was uncommon. In contrast, HBV Ba had the highest frequency of 1896A but the lowest of A1762T G1764A, and HBV C2 had intermediate frequencies of these mutations. Mutations of 1653T and 1753V were specifically associated with HBV C2 and C1, respectively. Multivariate analyses showed that the 1653T, 1753V, and A1762T G1764A mutations and patient age significantly increased the risk of HCC development. In conclusion, HBV Ba, C1, and C2 have different mutation patterns in the enhancer II/core promoter/precore region. Therefore, genotyping and detecting the 1653T and 1753V mutations, in addition to the A1762T G1764A double mutation, might have important clinical implications as predictive risk factors for hepatocarcinogenesis.
doi:10.1128/JCM.02157-06
PMCID: PMC1865908  PMID: 17376881
10.  Molecular Characterization of HBV Strains Circulating among the Treatment-Naive HIV/HBV Co-Infected Patients of Eastern India 
PLoS ONE  2014;9(2):e90432.
Previously we reported that the exposure to hepatitis B virus (HBV) infection serves as a major threat among the treatment naive HIV infected population of eastern India. Hence, molecular characterization of these strains is of utmost importance in order to identify clinically significant HBV mutations. A total of 85 treatment naive HIV/HBV co-infected participants were included of whom the complete basal core promoter/precore region, the core and the whole envelope gene could be successfully sequenced for 59, 57 and 39 isolates respectively. Following phylogenetic analysis, it was found that HBV/D was the predominant genotype with HBV/D2 (38.5%) being the most prevalent subgenotype followed by HBV/A1. The major mutations affecting HBeAg expression includes the A1762T/G1764A (13.6%), G1896A (22%) and G1862T mutation (33.9%) which was predominantly associated with HBV/A1. Moreover, the prevalence of G1896A was considerably high among the HBeAg negative HIV/HBV co-infected subjects compared to HBV mono-infection. The main amino acid substitutions within the MHC class II restricted T-cell epitope of HBcAg includes the T12S (15.8%) and T67N (12.3%) mutation and the V27I (10.5%) mutation in the MHC class I restricted T-cell epitope. PreS1/S2 deletion was detected in 3 isolates with all harboring the BCP double mutation. Furthermore, the frequently occurring mutations in the major hydrophilic loop of the S gene include the T125M, A128V and M133I/L. Therefore, this study is the first from India to report useful information on the molecular heterogeneity of the HBV strains circulating among the treatment naive HIV/HBV co-infected population and is thus clinically relevant.
doi:10.1371/journal.pone.0090432
PMCID: PMC3938687  PMID: 24587360
11.  High prevalence of the B2+C2 subgenotype mixture in patients with chronic hepatitis B in Eastern China 
Acta Pharmacologica Sinica  2012;33(10):1271-1276.
Aim:
To investigate the prevalence of hepatitis B virus (HBV) genotype mixtures among patients with chronic hepatitis B (CHB) in Eastern China.
Methods:
A total of 4908 chronic HBV patients from Eastern China were enrolled. HBV genotypes and subgenotypes were determined using a multiplex PCR technique. Serum viral loads and hepatitis B e antigen (HBeAg) levels detected using real-time fluorescent quantitative PCR and ELISA assay, respectively. The presence of precore/basic core promoter (PC/BCP) mutations was examined with PCR and direct sequencing of the amplified products.
Results:
HBV genotypes B, C, D, B+C, and B+D were found in 19.21%, 64.75%, 1.49%, 13.63%, and 0.92% of the patients, respectively. In 669 patients with the genotype mixture B+C, the subgenotypes B2+C2 and B2+C1 accounted for 68.13% and 31.87%, respectively, no other subgenotypes were identified. HBV B+C was more frequent in the patients with moderate CHB than in patients with mild CHB. In patients with moderate CHB, the subgenotype mixture B2+C2 was lower than B2+C1 (51.97% vs 63.38%), while the opposite situation was found in patients with severe CHB (22.15% vs 15.49%). The highest average viral load was found in patients with the genotype B+C mixture. The prevalence of HBV B2+C2 increased in patients from 50 to 59 years of age and was significantly different from the proportion of patients in the same age group with genotype B (23.2% vs 15.2%). A double mutation (G1896A) in the PC was significantly more common in subgenotype B2+C2 than in subgenotype B2+C1.
Conclusion:
The HBV B2+C2 subgenotype was prevalent in CH patients with a high HBV replication status and correlated with a more severe course of the disease.
doi:10.1038/aps.2012.78
PMCID: PMC4002708  PMID: 22941290
liver disease; chronic hepatitis; hepatitis B virus; genotype mixture; subgenotype; mutation; Eastern China
12.  Hepatitis B virus genotypes and precore and core mutants in UAE patients 
Virology Journal  2010;7:160.
Background
Knowledge of the HBV genotype with which a patient is infected is crucial information for a physician to have when planning clinical treatment for that patient. Previous studies have suggested that there are possible differences in the pathogenicity and therapeutic response of different HBV genotypes. However, the prevalence of the various HBV genotypes and Precore and Core mutations is unknown in the UAE. Therefore, we sought to determine the prevalence of the different HBV genotypes in the UAE population.
Methodology/Principal Findings
A total of 88 HBsAg-positive patients were included in the study.
A method for genotyping and subtyping HBV by partial HBsAg gene sequencing using primers that are complementary to all known genotypes was used. Precore and core region of these viruses were also sequenced in 88 patients.
HBV genotype D was the most prevalent (79.5%) genotype identified in our study population, followed by genotypes A (18.2%) and C (2.3%). The following subtypes were isolated: ayw2 (80.7%), adw2 (14.8%), and adw (2.3%). The HBV-DNA viral load was higher in HBeAg-positive patients than it was in patients who were HBeAg-negative. Precore mutants were found in 51 (58.0%) of 88 patients. Mutations in the basal core promotor were found in 22 (25.3%) of 88 patients.
Conclusion/Significance
HBV infection is a major health problem in the UAE, and while genotypes B and C are the most prevalent HBV genotypes in the Asian population, our study reveals that genotype D is the predominant genotype that is present in the UAE. More patients were HBeAg-negative than were HBeAg-positive in our study sample, which could be due to the duration of infection of the included patients. Additionally, the viral loads of the HBeAg-positive patients were higher those of the HBeAg-negative patients. Analysis of nucleotide 1858 showed presence of thymine in all patients with genotypes C, and D and in a few patients with genotypes A. This nucleotide was closely related to the presence of precore mutants. Mutations in the basal core promoter were found in 22 of 88 (25.3%) samples. These mutations were more frequent in patients infected with genotype A (37.5%) and not found in patients infected with genotype C.
doi:10.1186/1743-422X-7-160
PMCID: PMC2913959  PMID: 20633273
13.  A Rare HBV Subgenotype D4 with Unique Genomic Signatures Identified in North-Eastern India –An Emerging Clinical Challenge? 
PLoS ONE  2014;9(10):e109425.
Background/Aims
HBV has been classified into ten genotypes (A–J) and multiple subgenotypes, some of which strongly influence disease outcome and their distribution also correlate with human migration. HBV infection is highly prevalent in India and its diverse population provides an excellent opportunity to study the distinctiveness of HBV, its evolution and disease biology in variegated ethnic groups. The North-East India, having international frontiers on three sides, is one of the most ethnically and linguistically diverse region of the country. Given the paucity of information on molecular epidemiology of HBV in this region, the study aimed to carry out an in-depth genetic characterization of HBV prevailing in North-East state of Tripura.
Methods
From sera of chronically HBV infected patients biochemical/serological tests, HBV DNA quantification, PCR-amplification, sequencing of PreS/S or full-length HBV genomes were done. HBV genotype/subgenotype determination and sequence variability were assessed by MEGA5-software. The evolutionary divergence times of different HBV subgenotypes were estimated by DNAMLK/PHYLIP program while jpHMM method was used to detect any recombination event in HBV genomes.
Results
HBV genotypes D (89.5%), C (6.6%) and A (3.9%) were detected among chronic carriers. While all HBV/A and HBV/C isolates belonged to subgenotype-A1 and C1 respectively, five subgenotypes of HBV/D (D1–D5) were identified including the first detection of rare D4. These non-recombinant Indian D4 (IndD4) formed a distinct phylogenetic clade, had 2.7% nucleotide divergence and recent evolutionary radiation than other global D4. Ten unique amino acids and 9 novel nucleotide substitutions were identified as IndD4 signatures. All IndD4 carried T120 and R129 in ORF-S that may cause immune/vaccine/diagnostic escape and N128 in ORF-P, implicated as compensatory Lamivudine resistance mutation.
Conclusions
IndD4 has potential to undermine vaccination programs or anti-viral therapy and its introduction to North-East India is believed to be linked with the settlement of ancient Tibeto-Burman migrants from East-Asia.
doi:10.1371/journal.pone.0109425
PMCID: PMC4190083  PMID: 25295865
14.  Serolological Profile Among HBsAg-Positive Infections in Southeast China: A Community-Based Study 
Hepatitis Monthly  2013;13(1):e7604.
Background
Hepatitis B virus (HBV) infection has remained a significant public health problem. Generating a large-scale, community-based profile of HBV infection in China is essential to prevention of the disease.
Objectives
The current study was designed to investigate HBV-infected individuals at the community level and determine the age distribution, hepatitis B e antigen (HBeAg) positivity and its related risk factors, relationship among serological markers.
Patients and Methods
A cross-sectional, community-based survey was carried out without age restriction, in 12 communities of two counties. The study population was selected by random multistage cluster sampling. Serological samples and demographic information were collected from 8439 HB surface antigen (HBsAg)-positive individuals.
Results
The constituent ratio of individuals with HBsAg-positive infections was lowest among persons aged < 20 years (0.4%) and the highest among persons aged 40-49 years (33.2%). The HBeAg-positive rate among infected individuals was 18.5%, and the constituent ratio decreased with increasing of age. The HBeAg-positive rate in males (21.9%) was significantly higher than in females (14.7%), and was higher among coastland inhabitants (22.9%) than among plains inhabitants (12.9%). Among the 1561 HBeAg-positive individuals, 91.0% were HBV DNA-positive. However, of the 6878 HBeAg-negative individuals, only 45.4% were HBV DNA-positive, and the HBeAg-positive rate was significantly different at different levels of HBV DNA expression. The proportion of detectable HBV DNA levels was significantly higher in individuals with elevated ALT, compared to those with normal ALT, regardless of HBeAg-positivity.
Conclusions
The HBV prevalence remained high in the > 20 age group. The positivity of HBeAg was related to age, region, and sex. Testing HBeAg and serum ALT levels were effective ways to assess HBV infectiousness in community-level hospitals in China.
doi:10.5812/hepatmon.7604
PMCID: PMC3589882  PMID: 23483608
China; Hepatitis B; Hepatitis B e Antigens; Residence Characteristics; Serologic Tests
15.  High Endemicity and Low Molecular Diversity of Hepatitis B Virus Infections in Pregnant Women in a Rural District of North Cameroon 
PLoS ONE  2013;8(11):e80346.
Background
A program, supported by the GEMHEP (Groupe d'étude Moléculaire des Hépatites), was established in 2007 in the sanitary district of Tokombéré, to prevent perinatal transmission of hepatitis B virus (HBV). It comprises screening for HBV surface antigen (HBsAg) in all pregnant women and vaccinating the newborn if tests are positive.
Methods/Principal Findings
1276 women were enrolled in the study after providing informed consent. Demographic data and blood samples were available for 1267 of the enrolled patients. HBsAg was determined locally using a rapid test (Vikia HBsAg, Biomerieux). Tests for HBV and HDV virological markers (HBeAg, anti-HDV antibodies (Ab), HBV-DNA, HDV-RNA, HBV and HDV genotypes) were performed on the confirmed HBsAg-positive samples in the virology unit of the Angers University Hospital (France). HBsAg was found in 259 of the 1267 pregnant women (20.4%) between January 2009 and April 2010, of whom 59 were HBeAg-positive (22.7%) with high levels of HBV-DNA. Anti-HDV Ab were found in 19 (7.3%) of the HBsAg-positive women. The prevalence rates of HBsAg and HDV were not age-dependent whereas HBeAg carriers were statistically younger than non carriers. Basal core promoter (BCP) and precore (PC) mutations and genotypes were determined by sequencing. Of 120 amplified sequences, 119 belonged to HBV genotype E (HBV/E) and the 9 HDV strains belonged to HDV clade 1. In the PC region, 83/228 patients (36.4%) harbored a G1896A mutant or mixed phenotype virus. In the BCP region, the double mutation A1762T/G1764A and the G1757A substitution were detected respectively in 26/228 patients (11.4%) and 189/228 patients (82.8%).
Conclusions
Our results confirm the high prevalence and low molecular diversity of HBV in Far Northern Cameroon; more than 20% of the infected women were highly viremic, suggesting a high rate of HBV perinatal transmission and supporting the WHO recommendation to vaccinate at birth against hepatitis B.
doi:10.1371/journal.pone.0080346
PMCID: PMC3827216  PMID: 24265811
16.  Phylogenetic, Virological, and Clinical Characteristics of Genotype C Hepatitis B Virus with TCC at Codon 15 of the Precore Region 
Journal of Clinical Microbiology  2006;44(3):681-687.
Hepatitis B virus (HBV) with T-1856 of the precore region is always associated with C-1858 (i.e., TCC at nucleotides 1856 to 1858), and it is reported only in genotype C HBV isolates. We aimed to investigate the phylogenetic, virological, and clinical characteristics of HBV isolates bearing TCC at nucleotides 1856 to 1858. We have previously reported on the presence of two major subgroups in genotype C HBV, namely, HBV genotype Cs (Southeast Asia) and HBV genotype Ce (Far East). We have designed a novel 5′ nuclease technology based on the nucleotide polymorphism (C or A) at nucleotide 2733 to differentiate the two genotype C HBV subgroups. The mutations at the basal core promoter and precore regions were analyzed by direct sequencing. Among 214 genotype C HBV-infected patients, 31% had TCC, 37% had CCC, 3% had CTC, and 29% had CCT at nucleotides 1856 to 1858. All except one HBV strain with TCC at nucleotides 1856 to 1858 belonged to subgroup Cs, which has been reported only in Hong Kong; Guangzhou, China; and Vietnam. HBV with TCC at nucleotides 1856 to 1858 was associated with the G1898A mutation (64%). Patients infected with HBV harboring TCC had more liver cirrhosis than those infected with HBV harboring CCC (18% versus 5%; P = 0.008), and more of the patients infected with HBV harboring TCC were positive for HBeAg (58% versus 36%; P = 0.01) and had higher median alanine aminotransferase levels (65 IU/liter versus 49 IU/liter; P = 0.006); but similar proportions of patients infected with HBV harboring TCC and those infected with HBV harboring CCT had liver cirrhosis (18% versus 13%; P = 0.43). In summary, we report that HBV with TCC at nucleotides 1856 to 1858 of the precore region might represent a specific HBV strain associated with more aggressive liver disease than other genotype C HBV strains.
doi:10.1128/JCM.44.3.681-687.2006
PMCID: PMC1393116  PMID: 16517839
17.  Investigation of DNA Sequence in the Basal Core Promoter, Precore, and Core Regions of Hepatitis B Virus from Tunisia Shows a Shift in Genotype Prevalence 
Hepatitis Monthly  2012;12(11):e6191.
Background
In this study, we evaluated the prevalence of the most common mutations occurring in Enhancer II (EnhII), Basal Core Promoter (BCP), Precore (PC), and Core (C) regions of hepatitis B virus (HBV) genome.
Objectives
We also investigated the correlation between HBV variants, their genotypes, and patients’ HBe antigen (HBeAg: soluble shape of the capsid antigen) status.
Patients and Methods
We retrieved viral DNA from 40 serum samples of Tunisian patients positive for hepatitis B surface antigen (HBsAg) and HBV DNA, amplified the above mentioned regions using specific primers, and sequenced the corresponding PCR (polymerase chain reaction) products. For further analysis purpose, the patients were divided into two groups: Group1 including 34 HBeAg-negative patients and Group2 with 6 HBeAg-positive patients.
Results
Twenty-one patients (52.5%) showed PC G1896A mutation and 11 (27.5%) carried A1762T/G1764A double mutations. These mutations were more frequent in HBeAg-negative patients than that in HBeAg-positive ones. Indeed, 58.8% of patients bearing G1896A mutation were HBeAg-negative while 16.7% were positive. In patients bearing T1762/A1764 double mutation, 29.4% were positive and 16.7% were negative. In addition, the A1896 mutation was restricted to HBV isolates that had wild-type T1858, while C1858 was rather linked to the occurrence of T1762/A1764 mutation. Interestingly, this study revealed a high frequency of genotype E. This frequency was important as compared to that of genotype D known to be predominant in the country as delineated in previous studies.
Conclusions
Previous results supported and showed that HBV strains present in Tunisia belonging to genotype D and, to a lesser extent, to genotype E, were prone to mutations in BCP/ PC regions. This observation was more obvious in HBV isolates from asymptomatic chronic carriers (AsC). The high mutational rates observed in our study might result from a mechanism of viral escape that plays an important role in the loss of HBeAg.
doi:10.5812/hepatmon.6191
PMCID: PMC3549613  PMID: 23346148
Hepatitis B virus; Promoter Regions, Genetic; Mutations; Genotypes
18.  Influence of Hepatitis B Virus X and Core Promoter Mutations on Hepatocellular Carcinoma among Patients Infected with Subgenotype C2▿  
Journal of Clinical Microbiology  2007;45(10):3191-3197.
Hepatitis B virus (HBV) genotypes/subgenotypes and their related mutations in the HBV genome have been reported to be associated with hepatocellular carcinoma (HCC). To determine the HCC-associated mutations of the HBV genome in the entire X, core promoter, and precore/core regions, a cross-sectional control study was conducted comparing 80 Japanese patients infected with HBV C2 and suffering from HCC with 80 age-, sex-, and hepatitis B e antigen (HBeAg) status-matched patients without HCC (non-HCC group). Each HBeAg-positive group (31 with HCC; 29 without HCC) and HBeAg-negative group (49 with HCC; 51 without HCC) was also matched with respect to age and sex. The C1479, T1485, H1499, A1613, T1653, V1753, T1762/A1764, and A1896 mutations were frequent in this population. The prevalences of the T1653 mutation in the box α region and the V1753 and T1762/A1764 mutations in the basal core promoter region were significantly higher in the HCC group than in the non-HCC group (56% versus 30%, 50% versus 24%, and 91% versus 73% [P = 0.0013, P = 0.0010, and P = 0.0035, respectively]). The platelet count was significantly lower for the HCC group than for the non-HCC group (10.7 × 104 ± 5.1 × 104 versus 17.3 × 104 ± 5.1 × 104 platelets/mm3 [P < 0.0001]). Regardless of HBeAg status, the prevalence of the T1653 mutation was higher in the HCC group (52% versus 24% [P = 0.036] for HBeAg-positive patients and 59% versus 33% [P = 0.029] for HBeAg-negative patients). In the multivariate analysis, the presence of T1653, the presence of V1753, and a platelet count of ≤10 × 104/mm3 were independent predictive factors for HCC (odds ratios [95% confidence intervals], 4.37 [1.53 to 12.48], 7.98 [2.54 to 25.10], and 24.39 [8.11 to 73.33], respectively). Regardless of HBeAg status, the T1653 mutation increases the risk of HCC in Japanese patients with HBV/C2.
doi:10.1128/JCM.00411-07
PMCID: PMC2045330  PMID: 17652471
19.  Clinical and Serological Variation between Patients Infected with Different Hepatitis B Virus Genotypes 
Journal of Clinical Microbiology  2004;42(12):5837-5841.
Hepatitis B virus (HBV) has eight genotypes which have distinct geographical distributions. Studies comparing differences in the clinical outcomes of infections caused by strains with genotype-related variations in the HBV genome have largely compared genotypes B and C and genotypes A and D but not all four genotypes. The present study included 196 HBV-infected patients attending an infectious diseases outpatient clinic in Sweden. The age and geographic origin, liver function, HBeAg and anti-HBe status, and the presence or absence of HBV DNA were analyzed for each patient. HBV DNA was detected in 144 patients, and the HBV genotype and the core promoter and precore sequences were determined for the isolates from 101 of these patients. Among the patients who might be considered most likely to be nonviremic, namely, anti-HBe-positive HBV carriers with normal alanine aminotransferase (ALT) levels, 65% had detectable HBV DNA and were thus viremic. Among the viremic patients, HBeAg-positive patients were more likely to have elevated ALT levels than anti-HBe-positive patients. HBV genotypes A to F were represented in the study, and their distributions coincided accurately with the origin of the patient. A significantly higher number of genotype D-infected patients were anti-HBe positive and had elevated ALT levels (42% of genotype D-infected patients but 0% of patients infected with genotypes B and C). Genotype D strains with mutations in the core promoter and precore regions were significantly correlated with elevated ALT levels in the patients. The differences were not age related. Therefore, in this large-scale cross-sectional study, genotype D appears to be associated with more active disease.
doi:10.1128/JCM.42.12.5837-5841.2004
PMCID: PMC535251  PMID: 15583320
20.  Strong Association between Genotype F and Hepatitis B Virus (HBV) e Antigen-Negative Variants among HBV-Infected Argentinean Blood Donors 
Journal of Clinical Microbiology  2004;42(11):5015-5021.
A number of reports have indicated an increased risk of cirrhosis and hepatocellular carcinoma in hepatitis B virus (HBV)-infected individuals carrying HBV e antigen (HBeAg)-negative variants. Although distinct core promoter and precore mutations distributed according to geographical locality and viral genotype have been reported, epidemiological data from South America are still scarce. The prevalences of HBV genotypes and core promoter and precore polymorphisms in 75 HBeAg-negative Argentinean blood donors were surveyed. The observed frequencies of HBV genotypes were 64.0% for genotype F, 17.3% each for genotypes A and D, and 1.3% for genotype C. Genotype F strains were widely distributed and significantly more prevalent in the northern region of the country (P < 0.001). An overall high proportion of a stop codon mutation (UAG) at precore codon 28 (66.7%) was observed. Wild-type codon 28 (UGG) was present in 29.3% of the samples, and the remaining 4.0% of samples had mixed variants. The combination of A at nucleotide (nt) 1762 and G at nt 1764 of the core promoter was found in 58.7% of the samples. The variant profiles—T at nt 1762 and A at nt 1764 or A at nt 1762 and A at nt 1764—were detected in 28.0 and 1.3% of the samples, respectively. The observed core promoter polymorphisms could not be related to the ratio of HBeAg to anti-HBeAg antibody, HBV genotype, or precore codon 28 status. Nevertheless, a clear association of genotype F and a precore stop codon mutation was found (P < 0.05). In conclusion, HBV genotype F and mutant codon 28 strains predominated and were strongly associated in a geographically broad Argentinean blood donor population.
doi:10.1128/JCM.42.11.5015-5021.2004
PMCID: PMC525202  PMID: 15528689
21.  Hepatitis B Virus of Genotype B with or without Recombination with Genotype C over the Precore Region plus the Core Gene 
Journal of Virology  2002;76(12):5985-5992.
The entire nucleotide sequences of 70 hepatitis B virus (HBV) isolates of genotype B (HBV/B), including 38 newly determined and 32 retrieved from the international DNA database (DDBJ/EMBL/GenBank), were compared phylogenetically. Two subgroups of HBV/B were identified based on sequence divergence in the precore region plus the core gene, one with the recombination with genotype C and the other without it. The analysis over the entire genome of HBV/B by the SimPlot program located the recombination with genotype C in the precore region plus the core gene spanning nucleotide positions from 1740 to 1838 to 2443 to 2485. Within this genomic area, HBV/B strains with the recombination had higher nucleotide and amino acid homology to genotype C than those without the recombination (96.9 versus 91.1% in nucleotides and 97.0 versus 92.9% in amino acids). There were 29 HBV/B strains without the recombination, and they were all recovered from carriers in Japan. The remaining 41 HBV/B isolates having the recombination with genotype C were from carriers in China (12 strains), Hong Kong (3 strains), Indonesia (4 strains), Japan (3 strains), Taiwan (4 strains), Thailand (3 strains), and Vietnam (12 strains). Due to the frequency of the distribution of HBV/B without the recombination (29 of 32 isolates, or 91%) and the fact that it was exclusive to Japan, it was provisionally classified into the Bj (j standing for Japan) subgroup, and HBV/B with the recombination was classified into the Ba (a for Asia) subgroup. Virological differences between HBV/Bj and HBV/Ba may be reflected in the severity of clinical disease in the patients infected with HBV of genotype B, which seems to be under strong geographic influences in Asia.
doi:10.1128/JVI.76.12.5985-5992.2002
PMCID: PMC136227  PMID: 12021331
22.  Distribution of hepatitis B virus genotypes: Phylogenetic analysis and virological characteristics of Genotype C circulating among HBV carriers in Kolkata, Eastern India 
AIM: To evaluate the genotype distribution of hepatitis B virus (HBV) in Eastern India and to clarify the phylogenetic origin and virological characteristics of the recently identified genotype C in this region.
METHODS: Genotype determination, T1762/A1764 mutation in the basal core promoter (BCP) and A1896 mutation in the precore region of 230 subjects were determined by restriction fragment length polymorphism method (RFLP) and the result was confirmed by direct sequencing.
RESULTS: The predominant genotypes D (HBV/D) and A (HBV/A) were detected in 131/230 (57%) and 57/230 (25%) samples. In addition, genotype C (HBV/C) was detected in 42/230 (18%) isolates. Surface gene region was sequenced from 45 isolates (27 HBV/C, 9 HBV/A and 9 HBV/D). Phylogenetic analysis revealed that all of the HBV/C sequences clustered with South East Asian subgenotype (HBV/Cs). The sequence data showed remarkable similarity with a Thai strain (AF068756) (99.5% ± 0.4% nucleotide identities) in 90% of the genotype C strains analyzed. T1762/A1764 mutation in BCP region, associated with high ALT was significantly higher in HBeAg negative isolates than HBeAg positive isolates. Frequency of A1896 mutation leading to HBeAg negativity was low.
CONCLUSION: The present study reports the genotypic distribution and the characteristics of partial genome sequences of HBV/C isolates from Eastern India. Low genetic diversity and confinement of HBV/C in Eastern India possibly indicate a recent, limited, spread in this region. Genotype C with T1762/A1764 mutation has been reported to increase the risk for hepatocellular carcinoma; therefore genotype C carriers in Eastern India should be carefully monitored.
doi:10.3748/wjg.v12.i37.5964
PMCID: PMC4124403  PMID: 17009394
HBV genotypes; HBV/Cs, Eastern India; T1762/A1764 mutation
23.  Mutation Profiling of the Hepatitis B Virus Strains Circulating in North Indian Population 
PLoS ONE  2014;9(3):e91150.
Aims
The aim of this study was to investigate the genomic mutations in the circulating Hepatitis B virus strains causing infection in the Indian population. Further, we wanted to analyze the biological significance of these mutations in HBV mediated disease.
Methods
222 HBsAg positive patients were enrolled in the study. The genotype and mutation profile was determined for the infecting HBV isolate by sequencing overlapping fragments. These sequences were analyzed by using different tools and compared with previously available HBV sequence information. Mutation Frequency Index (MFI) for the Genes and Diagnosis group was also calculated.
Results
HBV Genotype D was found in 55% (n = 121) of the patient group and genotype A was found in 30% (n = 66) of samples. The majority (52%) of the HBV-infected individuals in the present study were HBeAg-negative in all the age groups studied. Spontaneous drug associated mutations implicated in resistance to antiviral therapy were also identified in about quarter of our patients, which is of therapeutic concern. The MFI approach used in the study indicated that Core peptide was the most conserved region in both genotypes and Surface peptide had highest mutation frequency. Few mutations in X gene (T36A and G50R) showed high frequency of association with HCC. A rare recombinant strain of HBV genotype A and D was also identified in the patient group.
Conclusions
HBV genotype D was found out to be most prevalent. More than half of the patients studied had HBeAg negative disease. Core region was found to be most conserved. Drug Associated mutations were detected in 22% of the patient group and T36A and G50R mutations in X gene were found to be associated with HCC.
doi:10.1371/journal.pone.0091150
PMCID: PMC3956465  PMID: 24637457
24.  Association of core promoter mutations of hepatitis B virus and viral load is different in HBeAg(+) and HBeAg(-) patients 
AIM: To identify the prevalence of hepatitis B e antigen (HBeAg) and to assess the association of hepatitis B virus (HBV) core promoter mutations and viral load in Indonesian patients.
METHODS: Sixty-four patients with chronic hepatitis, 65 with liver cirrhosis and 50 with hepatocellular carcinoma were included in this study. HBeAg and hepatitis B e antibody (HBeAb) tests were performed using enzyme-linked immunosorbent assay and the mutations were analyzed by sequencing. Viral load was measured by real-time polymerase chain reaction.
RESULTS: Of 179 patients, 108 (60.3%) were HBeAg(-) and 86 (79.6%) of these HBeAg(-) patients had been seroconverted. The A1896 mutation was not found in HBeAg(+) patients, however, this mutation was detected in 70.7% of HBeAg(-) patients. This mutation was frequently found when HBeAg was not expressed (87.7%), compared to that found in HBeAg seroconverted patients (65.1%). The A1899 mutation was also more prevalent in HBeAg(-) than in HBeAg(+) patients (P = 0.004). The T1762/A1764 mutation was frequently found in both HBeAg(+) and HBeAg(-) patients, however, the prevalence of this mutation did not significantly differ among the two groups (P = 0.054). In HBeAg(+) patients, the T1762/A1764 mutation was correlated with lower HBV DNA (P < 0.001). The A1899 mutation did not correlate with HBV DNA (P = 0.609). In HBeAg(-) patients, the T1762/A1764 mutation alone was not correlated with HBV DNA (P = 0.095), however, the presence of either the T1762/A1764 or A1896 mutations was associated with increased HBV DNA (P < 0.001).
CONCLUSION: The percentage of HBeAg(-) patients is high in Indonesia, and most of the HBeAg(-) patients had been seroconverted. The A1896 mutation was most likely the major cause of HBeAg loss. The T1762/A1764 mutation alone was associated with lower viral loads in HBeAg(+) patients, but not in HBeAg(-) patients.
doi:10.3748/wjg.v17.i6.708
PMCID: PMC3042648  PMID: 21390140
Hepatitis B e antibody; Hepatitis B e antigen; Hepatitis B virus; Indonesia; Precore/core promoter mutations; Viral load
25.  An overview of molecular epidemiology of hepatitis B virus (HBV) in India 
Virology Journal  2008;5:156.
Hepatitis B virus (HBV) is one of the major global public health problems. In India, HBsAg prevalence among general population ranges from 2% to 8%, placing India in intermediate HBV endemicity zone and the number of HBV carriers is estimated to be 50 million, forming the second largest global pool of chronic HBV infections. India is a vast country, comprised of multiracial communities with wide variations in ethnicity and cultural patterns, which is attributable to its geographical location, gene influx due to invasion and/or anthropological migrations in the past. Moreover, recent increase in trade, trafficking and use of illicit drugs has also considerably influenced the epidemiology of HBV, specifically in the eastern and north eastern parts of India. However, data on the molecular epidemiology of HBV in India is scanty. HBV genotypes A and D have been well documented from different parts of mainland India. Interestingly, in addition to genotypes A and D, genotype C having high nucleotide similarity with south East Asian subgenotype Cs/C1 strain, have been detected exclusively from eastern Indian HBV carriers, suggesting a recent introduction. Thus, compared to other parts of India, the molecular epidemiology of HBV is naturally distinct in eastern India. Very recently, taking the advantage of circulation of three distinct HBV genotypes within the population of eastern India, different aspects of HBV molecular epidemiology was studied that revealed very interesting results. In this study, the clinical significance of HBV genotypes, core promoter and precore mutations, possible routes of introduction of HBV genotype C in eastern India, the clinical implications of x gene variability, prevalence of the AFB1 induced p53 gene codon 249 mutation, the transmission potentiality of HBV among asymptomatic/inactive or occult HBV carriers and the genetic variability of HBV persisting in the PBL was investigated. In this manuscript, the information available on the molecular epidemiology of HBV in India has been reviewed and the results of studies among the eastern Indian population have been summarised.
doi:10.1186/1743-422X-5-156
PMCID: PMC2640379  PMID: 19099581

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