Evolution Of Hepatitis Research Articles

Acute Hepatitis C: Current Status and Future Perspectives

The hepatitis C virus (HCV) infection continues to represent a significant public health threat and is a leading cause of liver cirrhosis, liver cancer, and liver-related mortality. The World Health Organization (WHO) has set a goal for 2030: to eliminate HCV infection as a public health threat by reducing new HCV infections by 90% and mortality by 65%. The early phase of HCV infection represents a pivotal point in the evolution of hepatitis C. Despite a favourable course in the majority of patients, approximately 50–70% of individuals with recently acquired hepatitis C will develop a chronic infection, defined as the persistence of viremia for a period exceeding six months. The diagnosis and treatment of a recent HCV infection should facilitate engagement in multidisciplinary care, prevent the development and complications of chronic liver disease, and reduce ongoing transmission in key populations. Therefore, early treatment in the early phase of infection compared with deferring treatment until the chronic infection remains a valid approach in the era of direct antiviral agents (DAAs). This approach is supported by a cost-effectiveness analysis. The aim of this review is to synthesise the existing knowledge on the early phase of hepatitis C virus infection, with a particular focus on the current risk factors, natural history, therapeutic management, and future perspectives.

Evolution of hepatitis B virus polymerase and surface genes in patients receiving finite antiviral therapy.

Hepatitis B virus (HBV) reactivation could develop after withdrawal following a finite course of nucleoside analog (NA) therapy, leading to virological and clinical relapses. The genetic heterogeneity in the HBV surface and polymerase genes during finite NA therapy has not been carefully studied. Seven chronic HBV-infected patients experiencing relapses following entecavir (ETV; n=5; Patients 1 to 5) or tenofovir disoproxil fumarate (TDF; n=2; Patients 6 and 7) withdrawal were included. Sera obtained before treatment and at relapses were retrieved and submitted for DNA extraction and amplicon-specific deep sequencing. ETV-treated patients had a longer time-to-relapse than that of TDF-treated patients (P=0.0357). No drug-resistance related polymerase mutation was detected during relapses, except for a low percentage (1.4%) of rtM204I mutation in Patient 1. Two surface truncation mutations (sW216*; 40.9% and sW182*; 4.7%) detected before treatment in two TDF-treated patients (Patients 6 and 7, respectively) were overtaken by the wild types during subsequent drug-withdrawal-related relapses. The simultaneous presence of sG44E (T-cell epitope) and sE164G (B-cell epitope) mutations was associated with failure of HBV e antigen (HBeAg) seroclearance in ETV-treated patients. In conclusion, HBV genome continues to evolve during the courses of finite antiviral therapies. Pre-existing surface truncation mutations can be overtaken by the wild types after relapses. The sG44E/sE164G mutations are associated with failure of HBeAg seroclearance.

Mathematical Modelling and Numerical Simulation of Hepatitis B Viral Infection: The Case of Burkina Faso

Hepatitis is a viral infection that can cause inflammation of the liver and lead to severe liver damage and even death. The study of hepatitis in Burkina Faso is crucial for several reasons. Indeed, understanding the epidemiology of hepatitis in Burkina Faso can help develop effective prevention and control strategies, and its study can contribute to a better understanding of the global burden of the disease and the development of effective interventions in other parts of the world. To this aim, a new differential susceptibility and infectivity mathematical model of Hepatitis B transmission was developed in order to simulate the potential spread of the Hepatitis B virus in the population of Burkina Faso. Once the mathematical model is presented, the existence and uniqueness of non-negative solutions are proved. The model has a globally asymptotically stable disease-free equilibrium when the basic reproduction number R01 and a globally asymptotically stable endemic equilibrium when R0 > 1. The global asymptotic stability of the disease-free equilibrium has been studied using the Castillo Chavez method [5]. The Lyapunov function and the LaSalle invariance principle are used to prove the global asymptotic stability of the endemic equilibrium [26, 4, 18]. To simulate the proposed model, a Matlab numerical code has been developed. Numerical simulations are performed using data of Burkina Faso. The obtained numerical results confirm analytical results as well as the evolution of hepatitis B in Burkina Faso.

Evolution of Hepatitis B Virus Infection Under Antiviral Treatment in Children in the Registry of the Clinical Hospital of Infectious Diseases Constanta

Abstract Hepatitis B virus infection is one of the most common diseases diagnosed and treated in infectious disease hospitals around the world, with about 5% of the world’s population infected with this virus. In 2020, 21 cases of acute hepatitis B were registered in Romania and no case of perinatal transmission or chronic hepatitis B, the maximum incidence rate in women was among those aged between 45 and 54 years, and in men between 20 and 24 years. This study is a retrospective on the response to antiviral treatment of children with hepatitis B, which is on the records of the Clinical Hospital for Infectious Diseases between 2010 and 2021. Although the treatment was good and the disease is practically non-clinical, ongoing biochemical and imaging monitoring is required to detect a possible increase in HBV-DNA levels, as well as to prevent liver damage and complications. In the case of patients in our group, Entecavir had a beneficial effect, due to the fact that HBV-DNA became undetectable in 7 of the 9 patients, and the values of transaminases were within normal limits.

Recent molecular evolution of hepatitis B virus genotype F in Latin America.

The evolution of hepatitis B virus genotype F (HBV-F) in Latin America is not completely understood. The aim of this study was to evaluate the molecular evolution of HBV-F in Latin America by comparing 224 whole-genome sequences. Bayesian coalescent analysis was performed to estimate the time to the most recent common ancestor. Four main clades were found, dating from between 1245 and 1730. In addition, four subclades were identified, dating to between 1705 and 1801. The overall effective population size of HBV-F grew in the 18th century and showed an initial expansion outward from Venezuela to other countries from Latin America. Although HBV-F originated thousands of years ago, circulating strains of HBV-F appear to have spread in recent centuries, particularly in the 18th and 19th centuries. The new molecular data provide valuable information for characterizing the evolution of Native American HBV-F in recent centuries.

THU423 - Evolution of hepatitis C virus genotype 1a vs 1b distribution reflects profound changes in HCV epidemiology in Germany - analysis of 17,093 patients from five consecutive registries including the German hepatitis C-registry (DHC-R)

THU423 - Evolution of hepatitis C virus genotype 1a vs 1b distribution reflects profound changes in HCV epidemiology in Germany - analysis of 17,093 patients from five consecutive registries including the German hepatitis C-registry (DHC-R)

Long-term evolution of hepatitis B virus genotype F: Strong association between viral diversification and the prehistoric settlement of Central and South America.

The genotype F (HBV-F) is an autochthonous Native American strain of the hepatitis B virus. In this study, we reconstruct the HBV-F long-term evolution under a hypothesis of co-divergence with humans in Central and South America, since their entry into the region 14.5-16 thousand years ago. The Bayesian phylogeographic reconstruction supported a virus-host co-expansion; however, two evolutionary scenarios would have been present. Whereas subgenotype F1 spreads along a Pacific coastal route and would have evolved associated with Central American and Andean cultures from the west of the continent, subgenotypes F2-F6 spread along the Atlantic coastline and inner pathways associated with communities inhabiting the tropical forest lowlands. Then, we propose a model for HBV-F evolution in which the selection of differential biological characteristics in these two main groups would be related to their evolution in host populations with different genetic backgrounds and dissimilar demographic conditions.

Evolution of Hepatitis B Virus Receptor NTCP Reveals Differential Pathogenicities and Species Specificities of Hepadnaviruses in Primates, Rodents, and Bats.

Human hepatitis B virus (HBV) is a global health problem, affecting more than 250 million people worldwide. HBV-like viruses, named orthohepadnaviruses, also naturally infect nonhuman primates, rodents, and bats, but their pathogenicity and evolutionary history are unclear. Here, we determined the evolutionary history of the HBV receptors NTCP and GPC5 over millions of years of primate, rodent, and bat evolution. We use this as a proxy to understand the pathogenicity of orthohepadnaviruses in mammalian hosts and to determine the implications for species specificity. We found that NTCP, but not GPC5, has evolved under positive selection in primates (27 species), rodents (18 species), and bats (21 species) although at distinct residues. Notably, the positively selected codons map to the HBV-binding sites in primate NTCP, suggesting past genetic "arms races" with pathogenic orthohepadnaviruses. In rodents, the positively selected codons fall outside and within the presumed HBV-binding sites, which may contribute to the restricted circulation of rodent orthohepadnaviruses. In contrast, the presumed HBV-binding motifs in bat NTCP are conserved, and none of the positively selected codons map to this region. This suggests that orthohepadnaviruses may bind to different surfaces in bat NTCP. Alternatively, the patterns may reflect adaptive changes associated with metabolism rather than pathogens. Overall, our findings further point to NTCP as a naturally occurring genetic barrier for cross-species transmissions in primates, which may contribute to the narrow host range of HBV. In contrast, this constraint seems less important in bats, which may correspond to greater orthohepadnavirus circulation and diversity.IMPORTANCE Chronic infection with hepatitis B virus (HBV) is a major cause of liver disease and cancer in humans. Mammalian HBV-like viruses are also found in nonhuman primates, rodents, and bats. As for most viruses, HBV requires a successful interaction with a host receptor for replication. Cellular receptors are thus key determinants of host susceptibility as well as specificity. One hallmark of pathogenic virus-host relationships is the reciprocal evolution of host receptor and viral envelope proteins, as a result of their antagonistic interaction over time. The dynamics of these so-called "evolutionary arms races" can leave signatures of adaptive selection, which in turn reveal the evolutionary history of the virus-host interaction as well as viral pathogenicity and the genetic determinants of species specificity. Here, we show how HBV-like viruses have shaped the evolutionary history of their mammalian host receptor, as a result of their ancient pathogenicity, and decipher the genetic determinants of cross-species transmissions.

Obesity: A neurobiological approach

A huge outbreak in the men-having-sex-with-men (MSM) has hit Europe during the years 2016–2018. Outbreak control has been hampered by vaccine shortages in many countries, and to minimize their impact, reduction of antigen doses has been implemented. However, these measures may have consequences on the evolution of hepatitis A virus (HAV), leading to the emergence of antigenic variants. Cases in vaccinated MSM patients have been detected in Barcelona, opening the possibility to study HAV evolution under immune pressure.We performed deep-sequencing analysis of ten overlapping fragments covering the complete capsid coding region of HAV. A total of 14578255 reads were obtained and used for the analysis of virus evolution in vaccinated versus non-vaccinated patients. We estimated maximum and minimum mutation frequencies, and Shannon entropy in the quasispecies of each patient. Non-synonymous (NSyn) mutations affecting residues exposed in the capsid surface were located, with respect to epitopes, using the recently described crystal structure of HAV, as an indication of its potential role in escaping to the effect of vaccines.HAV evolution at the quasispecies level, in non-vaccinated and vaccinated patients, revealed higher diversity in epitope-coding regions of the vaccinated group. Although amino acid replacements occurring in and around the epitopes were observed in both groups, their abundance was significantly higher in the quasispecies of vaccinated patients, indicating ongoing processes of fixation.Our data suggest positive selection of antigenic variants in some vaccinated patients, raising concerns for new vaccination polices directed to the MSM group.

Evidence for positive selection of hepatitis A virus antigenic variants in vaccinated men-having-sex-with men patients: Implications for immunization policies.

BackgroundA huge outbreak in the men-having-sex-with-men (MSM) has hit Europe during the years 2016–2018. Outbreak control has been hampered by vaccine shortages in many countries, and to minimize their impact, reduction of antigen doses has been implemented. However, these measures may have consequences on the evolution of hepatitis A virus (HAV), leading to the emergence of antigenic variants. Cases in vaccinated MSM patients have been detected in Barcelona, opening the possibility to study HAV evolution under immune pressure.MethodsWe performed deep-sequencing analysis of ten overlapping fragments covering the complete capsid coding region of HAV. A total of 14578255 reads were obtained and used for the analysis of virus evolution in vaccinated versus non-vaccinated patients. We estimated maximum and minimum mutation frequencies, and Shannon entropy in the quasispecies of each patient. Non-synonymous (NSyn) mutations affecting residues exposed in the capsid surface were located, with respect to epitopes, using the recently described crystal structure of HAV, as an indication of its potential role in escaping to the effect of vaccines.FindingsHAV evolution at the quasispecies level, in non-vaccinated and vaccinated patients, revealed higher diversity in epitope-coding regions of the vaccinated group. Although amino acid replacements occurring in and around the epitopes were observed in both groups, their abundance was significantly higher in the quasispecies of vaccinated patients, indicating ongoing processes of fixation.InterpretationOur data suggest positive selection of antigenic variants in some vaccinated patients, raising concerns for new vaccination polices directed to the MSM group.

Molecular evolution and genomics of hepatitis B virus subgenotype C2 strain predominant in the chronic patients in Bangladesh.

Evolution of hepatitis B virus (HBV) is a mystery and caused mainly by genomic mutations as well as recombination. Viral evolution may be responsible for increasing disease severity and render resistance to the existing treatment processes. HBV/C2 strain is associated with chronicity, which may progress to the liver cirrhosis and hepatocellular carcinoma. Furthermore, HBV/C2 strain is highly prevalent in the chronic hepatitis B patients in Bangladesh. Hence, the molecular evolution of that strain and its disease pattern need to be uncovered. Herein, the purpose of this study is to determine the potential mutations of HBV complete genome sequences isolated in Bangladesh and the molecular evolution of HBV/C2 strain. Mutation analysis of the total 57 complete genome sequences of HBV in Bangladesh revealed that 42.11%, 12.28%, 7.02% and 3.51% of the strains were vaccine resistant, HBsAg detection escape, HBV immunoglobulin escape, multi-drug resistant respectively. Furthermore, of the vaccine resistant strains, 16.67% were observed resistant to both vaccine, HBsAg detection and immunoglobulin escape. Bayesian skyline analysis with 462 HBV/C2 strains from 2000 to 2017 revealed the evolution of the strain was in nineteenth century with two rapid sharp increases in the genetic diversity at the end of the twentieth century and then a sudden decrease in the early twenty-first century as observed in C and X gene analysis. This study may help researchers and clinicians to get a better knowledge about the emergence and evolution of HBV/C2 strain that may help to find a proper treatment strategy against hepatitis B.

Shorter hepatitis B immunoglobulin administration is not associated to hepatitis B virus recurrence when receiving combined prophylaxis after liver transplantation.

The combination of hepatitis B immunoglobulin and a nucleos(t)ide analogues has markedly reduced the rate of hepatitis B virus recurrence after liver transplantation; however, the optimal duration of hepatitis B immunoglobulin has not been clarified. This lack of consensus perpetuates the use of different strategies. The aim of this study was to evaluate the risk factors associated to hepatitis B virus recurrence after liver transplantation in a large cohort of patients under different hepatitis B immunoglobulin regimens. Retrospective multicentre analysis of hepatitis B virus-related liver transplantation recipients receiving combined prophylaxis (hepatitis B immunoglobulin + nucleos(t)ide analogues). The strategy of short-term hepatitis B immunoglobulin was compared to lifelong administration. Hepatitis B virus recurrence was defined as positive HBsAg after liver transplantation. Three hundred and thirty-eight patients were analysed. After a median follow-up period of 72months, 37 patients (11%) developed hepatitis B virus recurrence. Hepatocellular carcinoma recurrence and lamivudine resistance after liver transplantation were the only factors independently associated to hepatitis B virus recurrence (HR 5.4 [2.3-12] and 9.3 [4.2-20] respectively P<.001). HBsAg reappearance after hepatitis B virus recurrence was transient (16 patients), persistent (15) or alternant (6). The hepatitis B immunoglobulin regimen did not have an impact on the rate or evolution of hepatitis B virus recurrence. Overall, patient survival was good and not influenced by hepatitis B virus recurrence (82% at 5years). Fulminant liver failure, hepatitis C coinfection or hepatocellular carcinoma at liver transplantation were independent risk factors for lower survival. Liver transplantation is an effective treatment for hepatitis B virus-related liver disease. Since the introduction of combined prophylaxis the rate of hepatitis B virus recurrence is very low. However, lifelong hepatitis B immunoglobulin administration does not seem necessary to reduce hepatitis B virus recurrence.

Deciphering the Origin and Evolution of Hepatitis B Viruses by Means of a Family of Non-enveloped Fish Viruses

SummaryHepatitis B viruses (HBVs), which are enveloped viruses with reverse-transcribed DNA genomes, constitute the family Hepadnaviridae. An outstanding feature of HBVs is their streamlined genome organization with extensive gene overlap. Remarkably, the ∼1,100 bp open reading frame (ORF) encoding the envelope proteins is fully nested within the ORF of the viral replicase P. Here, we report the discovery of a diversified family of fish viruses, designated nackednaviruses, which lack the envelope protein gene, but otherwise exhibit key characteristics of HBVs including genome replication via protein-primed reverse-transcription and utilization of structurally related capsids. Phylogenetic reconstruction indicates that these two virus families separated more than 400 million years ago before the rise of tetrapods. We show that HBVs are of ancient origin, descending from non-enveloped progenitors in fishes. Their envelope protein gene emerged de novo, leading to a major transition in viral lifestyle, followed by co-evolution with their hosts over geologic eras.

Temporal trend of hepatitis B surface mutations in the post-immunization period: 9 years of surveillance (2005\u20132013) in eastern China

Limited information is available about the temporal trend in the prevalence and evolution of hepatitis B virus (HBV) S-gene mutations in the post-immunization era in China. From 2005 to 2013, 1077 hepatitis B cases under 15 years of age reported through Chinese National Notifiable Disease Reporting System (NNDRS) were successfully sequenced of S-gene in Shandong province, China. A total of 97 (9.01%) cases had amino acid (aa) substitution in the “α” determinant of HBsAg. The yearly prevalence from 2005 to 2013 maintained at a relatively stable level, and showed no significant change (P > 0.05). Multivariate logistic regression analysis demonstrated that the prevalence of “α” mutations was independently associated with the maternal HBsAg status (P < 0.05), and not with surveillance year and hepatitis B vaccination (P > 0.05). The hottest mutation position was aa126 (I126S/N and T126A, 29.63%), and aa 145 (G145R/A, 25.93%). Mutated residue 126 tended to occur less frequent, while that of residue 145 was more frequent with increasing year. Our data showed that there was no increase in the frequency of HBV “α” mutations over time during the post-immunization period. However, long-term vaccination might enhance the change of HBV mutational pattern, and G145 mutation was becoming dominant.

Deep sequencing analysis of quasispecies in the HBV pre-S region and its association with hepatocellular carcinoma.

The association between the evolution of hepatitis B virus (HBV) quasispecies and the development of hepatocellular carcinoma (HCC) is unknown. We used deep sequencing to examine the dynamics of HBV quasispecies and their relationship to HCC development. Thirty-two chronic hepatitis B (CHB) patients with HCC (HCC group) and 32 matched CHB patients without HCC (controls) were recruited. Fourteen patients from each group had serial sera available up to 9years before the time of the present study. Deep sequencing of the HBV pre-S regions was performed. HBV quasispecies complexity, diversity, and intrapatient prevalence of pre-S deletions/mutations were analyzed. Compared with control patients, HCC patients had a significant greater quasispecies complexity (p=0.04 at the nucleotide level), greater diversity (p=0.004 and 0.009 at the nucleotide level and the amino acid level respectively), and a trend of greater complexity at the amino acid level (p=0.065). HCC patients had a higher intrapatient prevalence of pre-S deletions and point mutations (at codons 4, 27, and 167) compared with the control patients (all p<0.05). Longitudinal observation in the sera of 14 HCC patients showed that quasispecies complexity (p=0.027 and 0.024 at the nucleotide level and the amino acid level respectively) and diversity (p=0.035 and 0.031 at the nucleotide level and the amino acid level respectively) increased as the disease progressed to HCC. Increased HBV quasispecies complexity and diversity in the pre-S region, probably reflecting enhanced virus-host interplay, was associated with disease progression from CHB to HCC.

Evolution of hepatitis B serological markers in HIV coinfected patients: a case study.

ABSTRACTOBJECTIVE To describe the evolution of serological markers among HIV and hepatitis B coinfected patients, with emphasis on evaluating the reactivation or seroreversion of these markers.METHODS The study population consisted of patients met in an AIDS Outpatient Clinic in São Paulo State, Brazil. We included in the analysis all HIV-infected and who underwent at least two positive hepatitis B surface antigen serological testing during clinical follow up, with tests taken six months apart. Patients were tested with commercial kits available for hepatitis B serological markers by microparticle enzyme immunoassay. Clinical variables were collected: age, sex, CD4+ T-cell count, HIV viral load, alanine aminotransferase level, exposure to antiretroviral drugs including lamivudine and/or tenofovir.RESULTS Among 2,242 HIV positive patients, we identified 105 (4.7%) patients with chronic hepatitis B. Follow up time for these patients varied from six months to 20.5 years. All patients underwent antiretroviral therapy during follow-up. Among patients with chronic hepatitis B, 58% were hepatitis B “e” antigen positive at the first assessment. Clearance of hepatitis B surface antigen occurred in 15% (16/105) of patients with chronic hepatitis B, and 50% (8/16) of these patients presented subsequent reactivation or seroreversion of hepatitis B surface antigen. Among hepatitis B “e” antigen positive patients, 57% (35/61) presented clearance of this serologic marker. During clinical follow up, 28.5% (10/35) of those who initially cleared hepatitis B “e” antigen presented seroreversion or reactivation of this marker.CONCLUSIONS Among HIV coinfected patients under antiretroviral therapy, changes of HBV serological markers were frequently observed. These results suggest that frequent monitoring of these serum markers should be recommended.

Evolution of hepatitis C virus in HIV coinfected patients under antiretroviral therapy

Five patients (P) were followed-up for an average of 7.73years after highly active antiretroviral therapy (HAART) initiation. Patients' immune and virological status were determined by periodical CD4+T-cell counts and HIV and HCV viral load. HCV populations were studied using longitudinal high throughput sequence data obtained in parallel by virological and immunological parameters. Two patients (P7, P28) with sub-optimal responses to HAART presented HCV viral loads significantly higher than those recorded for two patients (P1, P18) that achieved good responses to HAART. Interestingly, HCV populations from P7 and P28 displayed a stable phylogenetic structure, whereas HCV populations from P1 and P18showeda significant increase in their phylogenetic structure, followed by a decrease after achieving acceptable CD4+T-cell counts (>500 cell/μl). The fifth patient (P25) presented high HCV viral loads, preserved CD4+T-cell counts from baseline and all along the follow-up, and displayed a constant viral phylogenetic structure. These results strongly suggest that HAART-induced immune recovery induces a decrease in HCV viral load and an increase in the HCV population phylogenetic structure likely reflecting the virus diversification in response to the afresh immune response. The relatively low HCV viral load observed in the HAART responder patients suggests that once HCV is adapted it reaches a maximum number of haplotypes higher than that achieved during the initial stages of the immune response as inferred from the two recovering patients. Future studies using larger number of patients are needed to corroborate these hypotheses.

Public health impact of Infanrix hexa™ (DTPa-HBV-IPV/Hib) reimbursement: A study programme in France. Part 1: Evolution of hepatitis B vaccine coverage rates in infants aged less than 27 months, in the general population – the PopCorn study

BackgroundReimbursement of the hexavalent vaccine (Infanrix hexa™) comprising the DTPa-IPV-Hib components and the hepatitis B valence in a single vaccine was decided in March 2008 in France. The impact of its reimbursement on the hepatitis B vaccine coverage rate was assessed in a study conducted in the general population prior to and after implementation of the reimbursement policy. MethodsThe PopCorn study (NCT01782794) was a national, cross-sectional and repeated study, with four assessment periods over 3 years, from 2009 to 2012, to assess the hepatitis B vaccine coverage in 12- to 15- and 24- to 27-month-old children, vaccinated between 2007 and 2011 and selected by the quota sampling method. Face-to-face interviews were conducted at their homes and vaccination status was collected using their child's health record. Parents were also interviewed on their perceptions and acceptance of hepatitis B vaccination. Three indicators were calculated to assess hepatitis B vaccination coverage: proportions of infants with at least one dose before 6 months of age, with at least two doses before 6 months of age and with a complete schedule at 24 months of age. ResultsA total of 4903 children were enrolled in the study. An overall significant increase (P-value [P<0.05]) of the three indicators of interest over the four periods of time was observed for both age groups. The proportion of children receiving hepatitis B vaccination before 6 months increased from 21% at baseline (before vaccine reimbursement) to almost 75% at the last assessment period in 2012. More than 60% of 24- to 27-month-old children received a complete schedule in 2012 compared to 33% at baseline. No significant increases in the proportions of parents “favourable” and “moderately in favour” of hepatitis B vaccination were observed across the four evaluation periods (respectively, 17–22% and 48–50%, P=0.09). ConclusionThe rapid increase of hepatitis B vaccination coverage suggests a significant change in hepatitis B vaccination practice related to the hexavalent vaccine's reimbursement. This change was observed in a context of stability regarding parents’ perceptions and acceptance of hepatitis B vaccination and of coverage rates for other infant vaccinations.

Dating the origin of hepatitis B virus reveals higher substitution rate and adaptation on the branch leading to F/H genotypes.

The evolution of hepatitis B virus (HBV), particularly its origins and evolutionary timescale, has been the subject of debate. Three major scenarios have been proposed, variously placing the origin of HBV in humans and great apes from some million years to only a few thousand years ago (ka). To compare these scenarios, we analyzed 105 full-length HBV genome sequences from all major genotypes sampled globally. We found a high correlation between the demographic histories of HBV and humans, as well as coincidence in the times of origin of specific subgenotypes with human migrations giving rise to their host indigenous populations. Together with phylogenetic evidence, this suggests that HBV has co-expanded with modern humans. Based on the co-expansion, we conducted a Bayesian dating analysis to estimate a precise evolutionary timescale for HBV. Five calibrations were used at the origins of F/H genotypes, D4, C3 and B6 from respective indigenous populations in the Pacific and Arctic and A5 from Haiti. The estimated time for the origin of HBV was 34.1ka (95% highest posterior density interval 27.6-41.3ka), coinciding with the dispersal of modern non-African humans. Our study, the first to use full-length HBV sequences, places a precise timescale on the HBV epidemic and also shows that the "branching paradox" of the more divergent genotypes F/H from Amerindians is due to an accelerated substitution rate, probably driven by positive selection. This may explain previously observed differences in the natural history of HBV between genotypes F1 and A2, B1, and D.

Association between IL7R polymorphisms and severe liver disease in HIV/HCV coinfected patients: a cross-sectional study.

BackgroundInterleukin-7 (IL-7) is a critical factor for T cell development and for maintaining and restoring homeostasis of mature T cells. Polymorphisms at α-chain of the IL-7 receptor (IL7R or CD127) gene are related to evolution of HIV-infection, but there are no data concerning the evolution of hepatitis C virus (HCV) infection. The aim of this study was to analyze the association between IL7R polymorphisms and severe liver disease in HCV/HIV coinfected patients.MethodsWe performed a cross-sectional study in 220 naïve patients who underwent a liver biopsy. IL7R polymorphisms (rs6897932, rs987106 and rs3194051) were genotyped using the GoldenGate® assay. The outcome variables were: (a) liver biopsy: advanced fibrosis (F ≥ 3), severe activity grade (A3); (b) non-invasive indexes: advanced fibrosis (APRI ≥1.5 and FIB-4 ≥3.25). Logistic regression analysis was used to investigate the association between IL7R polymorphisms and outcome variables. This test gives the differences between groups and the odds ratio (OR) for liver disease.ResultsPatients with rs6897932 CC genotype had higher likelihood of having A3 than patients with rs6897932 CT/TT (adjusted odds ratio (aOR) = 4.16; p = 0.026). Patients with rs987106 TT genotype had higher odds of having F ≥ 3 (aOR = 3.09; p = 0.009) than rs987106 AA/AT carriers. Finally, patients with rs3194051 AA genotype had higher odds of having severe liver fibrosis (F ≥ 3; APRI ≥1.5, and FIB4 ≥3.25) than patients with rs3194051 AG/GG genotype [aOR = 2.73 (p = 0.010); aOR = 2.52 (p = 0.029); and aOR = 4.01 (p = 0.027); respectively]. The CTA haplotype (comprised of rs6897932, rs987106, and rs3194051) carriers had higher odds of having F ≥ 3 (aOR = 1.85; p = 0.012), APRI ≥1.5 (aOR = 1.94; p = 0.023), and FIB4 ≥3.25 (aOR = 2.47; p = 0.024). Conversely, the CAG haplotype carriers had lower odds of having F ≥ 3 (aOR = 0.48; p = 0.011), APRI ≥1.5 (aOR = 0.48; p = 0.029), and FIB4 ≥3.25 (aOR = 0.29; p = 0.010).ConclusionsThe presence of IL7R polymorphisms seems to be related to severe liver disease in HIV/HCV coinfected patients, because patients with unfavorable IL7R genotypes (rs6897932 CC, rs987106 TT, and rs3194051AA) had a worse prognosis of CHC.