Molecular characterization of hepatitis B virus (HBV) in African children living in Australia identifies genotypes and variants associated with poor clinical outcome
Migration from sub-Saharan Africa is contributing to the rising incidence of chronic hepatitis B (CHB) infection and its complications in Australia. African CHB is associated with unique genotypes, such as E and A1, which are associated with reduced vaccine efficacy and early-onset hepatocellular carcinoma, respectively, although the prevalence of these genotypes outside Africa is poorly described. Treatment-naïve children of African origin with CHB were recruited at the Royal Children’s Hospital Melbourne. Population-based sequencing of the complete HBV genome, or the clinically relevant basal core promoter (BCP)/precore (PC) region, was performed, and the HBV genotype/subgenotype assigned by phylogenetic analysis. HBV was characterized in serum from 67 children, median age 12.5 years. HBV genotype E was most frequent (70 %), with genotype D [25 %; subgenotypes D6 (formerly D7)/D3/D2)] and subgenotype A1 (5 %) also being identified. Despite their young age, over 50 % of the children were HBeAg-negative and had seroconverted to anti-HBe, with this being associated with canonical BCP/PC mutations in the majority of cases. The profile of HBV in African children living in Australia was characterized by early HBeAg seroconversion and infection with HBV variants associated with poor clinical outcome, as well as genotypes previously associated with reduced vaccine efficacy or rapid progression to liver cancer. These findings have important ramifications for patient monitoring and treatment guidelines in the Australian paediatric setting.
StanawayJD, FlaxmanAD, NaghaviM, FitzmauriceC, VosT et al. The global burden of viral hepatitis from 1990 to 2013: findings from the Global Burden of Disease Study 2013. Lancet2016; 388:1081–1088 [View Article][PubMed]
MacLachlanJH, AllardN, TowellV, CowieBC. The burden of chronic hepatitis B virus infection in Australia, 2011. Aust N Z J Public Health2013; 37:416–422 [View Article][PubMed]
KramvisA, KewMC. Epidemiology of hepatitis B virus in Africa, its genotypes and clinical associations of genotypes. Hepatol Res2007; 37:S9–S19 [View Article][PubMed]
SchweitzerA, HornJ, MikolajczykRT, KrauseG, OttJJ. Estimations of worldwide prevalence of chronic hepatitis B virus infection: a systematic review of data published between 1965 and 2013. Lancet2015; 386:1546–1555 [View Article][PubMed]
MartinJA, MakDB. Changing faces: a review of infectious disease screening of refugees by the Migrant Health Unit, Western Australia in 2003 and 2004. Med J Aust2006; 185:607–610[PubMed]
ReinDB, LesesneSB, O'FallonA, WeinbaumCM. Prevalence of hepatitis B surface antigen among refugees entering the United States between 2006 and 2008. Hepatology2010; 51:431–434 [View Article][PubMed]
TiongAC, PatelMS, GardinerJ, RyanR, LintonKS et al. Health issues in newly arrived African refugees attending general practice clinics in Melbourne. Med J Aust2006; 185:602–606[PubMed]
LadhaniSN, FloodJS, AmirthalingamG, Mieli-VerganiG, BansalS et al. Epidemiology and clinical features of childhood chronic hepatitis B infection diagnosed in England. Pediatr Infect Dis J2014; 33:130–135 [View Article][PubMed]
CroaghCM, DesmondPV, BellSJ. Genotypes and viral variants in chronic hepatitis B: a review of epidemiology and clinical relevance. World J Hepatol2015; 7:289–303 [View Article][PubMed]
TatematsuK, TanakaY, KurbanovF, SugauchiF, ManoS et al. A genetic variant of hepatitis B virus divergent from known human and ape genotypes isolated from a Japanese patient and provisionally assigned to new genotype J. J Virol2009; 83:10538–10547 [View Article][PubMed]
KewMC, KramvisA, YuMC, ArakawaK, HodkinsonJ. Increased hepatocarcinogenic potential of hepatitis B virus genotype A in Bantu-speaking sub-saharan Africans. J Med Virol2005; 75:513–521 [View Article][PubMed]
GopalakrishnanD, KeyterM, ShenoyKT, LeenaKB, ThayumanavanL et al. Hepatitis B virus subgenotype A1 predominates in liver disease patients from Kerala, India. World J Gastroenterol2013; 19:9294–9306 [View Article][PubMed]
MuldersMN, VenardV, NjayouM, EdorhAP, Bola OyefoluAO et al. Low genetic diversity despite hyperendemicity of hepatitis B virus genotype E throughout West Africa. J Infect Dis2004; 190:400–408 [View Article][PubMed]
AbushadyEA, GameelMM, KlenaJD, AhmedSF, Abdel-WahabKS et al. HBV vaccine efficacy and detection and genotyping of vaccineé asymptomatic breakthrough HBV infection in Egypt. World J Hepatol2011; 3:147–156 [View Article][PubMed]
European Association for the Study of the Liver EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol2017; 67:370–398 [View Article][PubMed]
ThurnheerMC, EdwardsR, SchulzTR, YuenL, LittlejohnM et al. Genotypic profiles of hepatitis B in African immigrants and their clinical relevance. J Med Virol2017; 89:1000–1007 [View Article]
SarinSK, KumarM, LauGK, AbbasZ, ChanHL et al. Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update. Hepatol Int2016; 10:1–98 [View Article][PubMed]
TerraultNA, BzowejNH, ChangKM, HwangJP, JonasMM. et al. AASLD guidelines for treatment of chronic hepatitis B. Hepatology2016; 63:261–283 [View Article][PubMed]
JimenezG, AlexG, PaxtonG, ConnellTG, HardikarW. B alert: hepatitis B virus infection in children in Victoria. J Paediatr Child Health2013; 49:E213E216 [View Article][PubMed]
Abdou ChekaraouM, BrichlerS, MansourW, Le GalF, GarbaA et al. A novel hepatitis B virus (HBV) subgenotype D (D8) strain, resulting from recombination between genotypes D and E, is circulating in Niger along with HBV/E strains. J Gen Virol2010; 91:1609–1620 [View Article][PubMed]
van der SandeMA, WaightPA, MendyM, ZamanS, KayeS et al. Long-term protection against HBV chronic carriage of Gambian adolescents vaccinated in infancy and immune response in HBV booster trial in adolescence. PLoS One2007; 2:e753 [View Article][PubMed]
PaxtonGA, RiceJ, DavieG, CarapetisJR, SkullSA. East African immigrant children in Australia have poor immunisation coverage. J Paediatr Child Health2011; 47:888–892 [View Article][PubMed]
ChenCY, CrowtherC, KewMC, KramvisA. A valine to phenylalanine mutation in the precore region of hepatitis B virus causes intracellular retention and impaired secretion of HBe-antigen. Hepatol Res2008; 38:580–592 [View Article][PubMed]
MahgoubS, CandottiD, El EkiabyM, AllainJP. Hepatitis B virus (HBV) infection and recombination between HBV genotypes D and E in asymptomatic blood donors from Khartoum, Sudan. J Clin Microbiol2011; 49:298–306 [View Article][PubMed]
YousifM, MudawiH, BakhietS, GlebeD, KramvisA. Molecular characterization of hepatitis B virus in liver disease patients and asymptomatic carriers of the virus in Sudan. BMC Infect Dis2013; 13:328 [View Article][PubMed]
HannachiN, FredjNB, BahriO, ThibaultV, FerjaniA et al. Molecular analysis of HBV genotypes and subgenotypes in the Central-East region of Tunisia. Virol J2010; 7:302 [View Article][PubMed]
MeldalBH, MoulaNM, BarnesIH, BoukefK, AllainJP. A novel hepatitis B virus subgenotype, D7, in Tunisian blood donors. J Gen Virol2009; 90:1622–1628 [View Article][PubMed]
Rodríguez LayLA, CorredorMB, VillalbaMC, FrómetaSS, WongMS et al. Genetic Diversity of the hepatitis B virus strains in Cuba: absence of West-African genotypes despite the transatlantic slave trade. PLoS One2015; 10:e0125052 [View Article][PubMed]
KarthigesuVD, AllisonLM, FergusonM, HowardCR. A hepatitis B virus variant found in the sera of immunised children induces a conformational change in the HBsAg "a" determinant. J Med Virol1999; 58:346–352 [View Article][PubMed]
MathetVL, CuestasML, RuizV, MinassianML, RiveroC et al. Detection of hepatitis B virus (HBV) genotype E carried-even in the presence of high titers of anti-HBs antibodies-by an Argentinean patient of African descent who had received vaccination against HBV. J Clin Microbiol2006; 44:3435–3439 [View Article][PubMed]
BaylissJ, YuenL, RosenbergG, WongD, LittlejohnM et al. Deep sequencing shows that HBV basal core promoter and precore variants reduce the likelihood of HBsAg loss following tenofovir disoproxil fumarate therapy in HBeAg-positive chronic hepatitis B. Gut2016
BoglioneL, CusatoJ, CaritiG, di PerriG, D'AvolioA. The E genotype of hepatitis B: clinical and virological characteristics, and response to interferon. J Infect2014; 69:81–87 [View Article][PubMed]
SozziV, WalshR, LittlejohnM, ColledgeD, JacksonK et al. In vitro studies show that sequence variability contributes to marked variation in hepatitis B virus replication, protein expression, and function observed across genotypes. J Virol2016; 90:10054–10064 [View Article][PubMed]
FriedMW, PiratvisuthT, LauGK, MarcellinP, ChowWC et al. HBeAg and hepatitis B virus DNA as outcome predictors during therapy with peginterferon alfa-2a for HBeAg-positive chronic hepatitis B. Hepatology2008; 47:428–434 [View Article][PubMed]
GüntherS, LiBC, MiskaS, KrügerDH, MeiselH et al. A novel method for efficient amplification of whole hepatitis B virus genomes permits rapid functional analysis and reveals deletion mutants in immunosuppressed patients. J Virol1995; 69:5437–5444[PubMed]
YuenLK, AyresA, LittlejohnM, ColledgeD, EdgelyA et al. SeqHepB: a sequence analysis program and relational database system for chronic hepatitis B. Antiviral Res2007; 75:64–74 [View Article][PubMed]
HallTA. BioEdit: a user-friendly biological sequence alignment editor and analysis program for Windows 95/98/NT. Nucleic Acids Symposium Series1999; 41:95–98
LoleKS, BollingerRC, ParanjapeRS, GadkariD, KulkarniSS et al. Full-length human immunodeficiency virus type 1 genomes from subtype C-infected seroconverters in India, with evidence of intersubtype recombination. J Virol1999; 73:152–160[PubMed]
Molecular characterization of hepatitis B virus (HBV) in African children living in Australia identifies genotypes and variants associated with poor clinical outcome