Complex interactions between microRNAs and hepatitis B/C viruses

MicroRNAs(miRNAs) are a class of small noncoding RNAs that post-transcriptionally regulate the expression of many target genes via mRNA degradation or translation inhibition. Many studies have shown that miRNAs are involved in the modulation of gene expression and replication of hepatitis B virus(HBV) and hepatitis C virus(HCV) and play a pivotal role in host-virus interactions. Increasing evidence also demonstrates that viral infection leads to alteration of the miRNA expression profile in hepatic tissues or circulation. The deregulated miRNAs participate in hepatocellular carcinoma(HCC)initiation and progression by functioning as oncogenes or tumor suppressor genes by targeting various genes involved in cancer-related signaling pathways. The distinct expression pattern of miRNAs may be a useful marker for the diagnosis and prognosis of virus-related diseases considering the limitation of currently used biomarkers. Moreover, the role of deregulated miRNA in host-virus interactions and HCC development suggested that miRNAs may serve as therapeutic targets or astools. In this review, we summarize the recent findings about the deregulation and the role of miRNAs during HBV/HCV infection and HCC development, and we discuss the possible mechanism of action of miRNAs in the pathogenesis of virus-related diseases. Furthermore, we discuss the potential of using miRNAs as markers for diagnosis and prognosis as well as therapeutic targets and drugs.

Characterization of hepatitis B virus X gene quasispecies complexity in mono-infection and hepatitis delta virus superinfection

Hepatitis delta virus(HDV) seems to strongly suppress hepatitis B virus(HBV)replication, although little is known about the mechanism of this interaction. Both these viruses show a dynamic distribution of mutants, resulting in viral quasispecies. Next-generation sequencing is a viable approach for analyzing the composition of these mutant spectra. As the regulatory hepatitis B X protein(HBx) is essential for HBV replication, determination of HBV X gene(HBX)quasispecies complexity in HBV/HDV infection compared to HBV monoinfection may provide information on the interactions between these two viruses.AIM To compare HBV quasispecies complexity in the HBX 5' region between chronic hepatitis delta(CHD) and chronic HBV mono-infected patients.METHODS Twenty-four untreated patients were included: 7/24(29.2%) with HBeAgnegative chronic HBV infection(CI, previously termed inactive carriers), 8/24(33.3%) with HBeAg-negative chronic hepatitis B(CHB) and 9/24(37.5%) with CHD. A serum sample from each patient was first tested for HBV DNA levels.The HBX 5' region [nucleotides(nt) 1255-1611] was then PCR-amplified for subsequent next-generation sequencing(MiSeq, Illumina, United States). HBV quasispecies complexity in the region analyzed was evaluated using incidencebased indices(number of haplotypes and number of mutations), abundancebased indices(Hill numbers of order 1 and 2), and functional indices(mutation frequency and nucleotide diversity). We also evaluated the pattern of nucleotide changes to investigate which of them could be the cause of the quasispecies complexity.RESULTS CHB patients showed higher median HBV-DNA levels [5.4 logIU/mL,interquartile range(IQR) 3.5-7.9] than CHD(3.4 logIU/mL, IQR 3-7.6)(P = n.s.)or CI(3.2 logIU/mL, IQR 2.3-3.5)(P < 0.01) patients. The incidence and abundance indices indicated that HBV quasispecies complexity was significantly greater in CI than CHB. A similar trend was observed in CHD patients, although only Hill numbers of order 2 showed statistically significant differences(CHB2.81, IQR 1.11-4.57 vs CHD 8.87, 6.56-11.18, P = 0.038). There were no significant differences in the functional indices, but CI and CHD patients also showed a trend towards greater complexity than CHB. No differences were found for any HBV quasispecies complexity indices between CHD and CI patients. G-to-A and C-to-T nucleotide changes, characteristic of APOBEC3 G, were higher in CHD and CI than in CHB in genotype A haplotypes, but not in genotype D. The proportion of nt G-to-A vs A-to-G changes and C-to-T vs T-to-C changes in genotype A and D haplotypes in CHD patients showed no significant differences. In CHB and CI the results of these comparisons were dependent on HBV genotype.CONCLUSION The lower-replication CHD and CI groups show a trend to higher quasispecies complexity than the higher-replication CHB group. The mechanisms associated with this greater complexity require elucidation.

Seroprevalence and Molecular Biodiversity of Hepatitis B and Delta Virus Infections in the Republic of Congo

Hepatitis B virus (HBV) infection is a major public health problem in the world. In Congo, studies on the prevalence of HBV infection are common but HDV infection is rare. Objective: Contribute to improve the management and prevention of HBV and HDV infections. Patients and Methods: This was a descriptive and cross-sectional study conducted from January to August 2016 in the health services of the various departments of Congo and at the national public health laboratory in Brazzaville. All patients with HBsAg surface antigen who were at least 18 years old and who consented to the study were included. The HBs antigen was first tested by a rapid test then confirmed by ELISA. All HBsAg positive patients were subsequently subjected to a second ELISA test for Delta antibody. The techniques of extraction and conventional and specific gene amplification were carried out on plasma for the identification of the genotypes of the two viruses. The data analysis was done with EpiInfo V7 software. The proportions were compared using the Chi-square test or the Fisher test at the significance level of 5%. Results: 1618 subjects were included, of whom 180 were positive for HBsAg, a frequency of 11.12%. The sex ratio (M/F) was 0.77%, the mean age was 40.2 ± 15.6 years with extremes ranging from 18 to 88 years. Of the 180 HBsAg positive, 22 were anti-VHD positive, a frequency of 12.22%. HBV DNA was amplified in 83.8% (151/180), HDV RNA in 63.6% (14/22). For HBV, three genotypes were identified: E (46.9%), A (43.7%) and D (9.4%), however for VHD three genotypes D1, D5, D8 were identified. Conclusion: Co-infection of hepatitis B and Delta viruses is common in Congo. The management and prevention of hepatitis B must take into account the reality of this co-infection.

Hepatitis B virus and hepatitis C virus dual infection

Hepatitis B virus(HBV)and hepatitis C virus(HCV)share common mode of transmission and both are able to induce a chronic infection.Dual HBV/HCV chronic coinfection is a fairly frequent occurrence,especially in high endemic areas and among individuals at high risk of parenterally transmitted infections.The intracellular interplay between HBV and HCV has not yet been sufficiently clarified,also due to the lack of a proper in vitro cellular model.Longitudinal evaluation of serum HBV DNA and HCV RNA amounts has revealed that complex virological profiles may be present in coinfected patients.Dual HBV/HCV infection has been associated to a severe course of the liver disease and to a high risk of developing hepatocellular carcinoma.Despite the clinical importance,solid evidence and clear guidelines for treatment of this special population are still lacking.This review summarizes the available data on the virological and clinical features as well as the therapeutic options of the dual HBV/HCV infection,and highlights the aspects that need to be better clarified.

MicroRNAs may solve the mystery of chronic hepatitis B virus infection

Hepatitis B virus(HBV)infection is a global public health problem that causes persistent liver diseases such as chronic hepatitis,cirrhosis,and hepatocellular carcinoma.A large amount of people die annually from HBV infection.However,the pathogenesises of the HBV-related diseases are ill defined and the therapeutic strategies for the diseases are less than optimum.The recently discovered microRNAs(miRNAs)are tiny noncoding RNAs that regulate gene expression primarily at the post-transcriptional level by binding to mRNAs.miRNAs contribute to a variety of physiological and pathological processes.A number of miRNAs have been found to play a pivotal role in the host-virus interaction including host-HBV interaction.Numerous studies have indicated that HBV infection could change the cellular miRNA expression patterns and different stages of HBV associated disease have displayed distinctive miRNA profiles.Furthermore,the differential expressed miRNAs have been found involved in the progression of HBV-related diseases,for instance some miRNAs are involved in liver tumorigenesis and tumor metastasis.Studies have also shown that the circulating miRNA in serum or plasma might be a very useful biomarker for the diagnosis and prognosis of HBV-related diseases.In addition,miRNA-based therapy strategies have attracted increasing attention,indicating a promising future in the treatment of HBV-related diseases.

Hepatitis B virus/hepatitis D virus epidemiology: Changes over time and possible future influence of the SARS-CoV-2 pandemic

Hepatitis D virus(HDV)is a defective liver-tropic virus that needs the helper function of hepatitis B virus(HBV)to infect humans and replicate.HDV is transmitted sexually or by a parenteral route,in co-infection with HBV or by super-infection in HBV chronic carriers.HDV infection causes acute hepatitis that may progress to a fulminant form(7%-14%by super-infection and 2%-3%by HBV/HDV co-infection)or to chronic hepatitis(90%by HDV super-infection and 2%-5%by HBV/HDV co-infection),frequently and rapidly progressing to cirrhosis or hepatocellular carcinoma(HCC).Peg-interferon alfa the only recommended therapy,clears HDV in only 10%-20%of cases and,consequently,new treatment strategies are being explored.HDV endemicity progressively decreased over the 50 years from the identification of the virus,due to improved population lifestyles and economic levels,to the use of HBV nuclei(t)side analogues to suppress HBV replication and to the application of universal HBV vaccination programs.Further changes are expected during the severe acute respiratory syndrome coronavirus-2 pandemic,unfortunately towards increased endemicity due to the focus of healthcare towards coronavirus disease 2019 and the consequently lower possibility of screening and access to treatments,lower care for patients with severe liver diseases and a reduced impulse to the HBV vaccination policy.

Virus entry mediated by hepatitis B virus envelope proteins

Hepatitis B virus(HBV),a major cause of human liver disease worldwide,encodes three envelope proteins needed for the attachment and entry of the virus into susceptible host cells.A second virus,hepatitis delta virus,which is known to enhance liver disease in HBV infected patients,diverts the same HBV envelope proteins to achieve its own assembly and infection.In the lab,lentiviral vectors based on human immunodeficiency virus type 1 can be assembled using the HBV envelope proteins,and will similarly infect susceptible cells.This article provides a partial review and some personal reflections of how these three viruses infect and of how recipient cells become susceptible,along with some consideration of questions that remain to be answered.

Host RNA circles and the origin of hepatitis delta virus

Recent reports show that many cellular RNAs are processed to form circular species that are relatively abundant and resistant to host nucleases.In some cases,such circles actually bind host microRNAs.Such depletion of available microRNAs appears to have biological roles;for instance,in homeostasis and disease.These findings regarding host RNA circles support a speculative reappraisal of the origin and mode of replication of hepatitis delta virus,hepatitis delta virus(HDV),an agent with a small circular RNA genome;specifically,it is proposed that in hepatocytes infected with hepatitis B virus(HBV),some viral RNA species are processed to circular forms,which by a series of chance events lead to an RNA that can be both replicated by host enzymes and assembled,using HBV envelope proteins,to form particles some of which are infectious.Such a model also may provide some new insights into the potential pathogenic potential of HDV infections.In return,new insights into HDV might provide information leading to a better understanding of the roles of the host RNA circles.

Hepatitis delta virus: From infection to new therapeutic strategies

The hepatitis delta virus(HDV)is a small RNA virus that encodes a single protein and which requires the hepatitis B virus(HBV)-encoded hepatitis B surface antigen(HBsAg)for its assembly and transmission.HBV/HDV co-infections exist worldwide and show a higher prevalence among selected groups of HBV-infected populations,specifically intravenous drug users,practitioners of high-risk sexual behaviours,and patients with cirrhosis and hepatocellular carcinoma.The chronic form of HDV-related hepatitis is usually severe and rapidly progressive.Patterns of the viral infection itself,including the status of co-infection or super-infection,virus genotypes(both for HBV and HDV),and persistence of the virus’replication,influence the outcome of the accompanying and manifested liver disease.Unfortunately,disease severity is burdened by the lack of an effective cure for either virus type.For decades,the main treatment option has been interferon,administered as mono-therapy or in combination with nucleos(t)ide analogues.While its efficacy has been reported for different doses,durations and courses,only a minority of patients achieve a sustained response,which is the foundation of eventual improvement in related liver fibrosis.The need for an efficient therapeutic alternative remains.Research efforts towards this end have led to new treatment options that target specific steps in the HDV life cycle;the most promising among these are myrcludex B,which inhibits virus entry into hepatocytes,lonafarnib,which inhibits farnesylation of the viral-encoded LHDAg large hepatitis D antigen,and REP-2139,which interferes with HBsAg release and assembly.

Hepatitis delta virus: A fascinating and neglected pathogen

Hepatitis delta virus(HDV) is the etiologic agent of the most severe form of virus hepatitis in humans. Sharing some structural and functional properties with plant viroids, the HDV RNA contains a single open reading frame coding for the only virus protein, the Delta antigen. A number of unique features, including ribozyme activity, RNA editing, rolling-circle RNA replication, and redirection for a RNA template of host DNA-dependent RNA polymerase Ⅱ, make this small pathogen an excellent model to study virus-cell interactions and RNA biology. Treatment options for chronic hepatitis Delta are scarce and ineffective. The disease burden is perhaps largely underestimated making the search for new, specific drugs, targets, and treatment strategies an important public health challenge. In this review we address the main features of virus structure, replication, and interaction with the host. Virus pathogenicity and current treatment options are discussed in the light of recent developments.

Analysis of hepatitis B virus preS1 variability and prevalence of the rs2296651 polymorphism in a Spanish population

AIM To determine the variability/conservation of the domain of hepatitis B virus(HBV) pre S1 region that interacts with sodium-taurocholate cotransporting polypeptide(hereafter, NTCP-interacting domain) and the prevalence of the rs2296651 polymorphism(S267 F, NTCP variant) in a Spanish population. METHODS Serum samples from 246 individuals were included and divided into 3 groups: patients with chronic HBV infection(CHB)(n = 41, 73% Caucasians), patients with resolved HBV infection(n = 100, 100% Caucasians) and an HBV-uninfected control group(n = 105, 100% Caucasians). Variability/conservation of the amino acid(aa) sequences of the NTCPinteracting domain,(aa 2-48 in viral genotype D) and a highly conserved pre S1 domain associated with virion morphogenesis(aa 92-103 in viral genotype D) were analyzed by next-generation sequencing and compared in 18 CHB patients with viremia > 4 log IU/mL. The rs2296651 polymorphism was determined in all individuals in all 3 groups using an in-house real-time PCR melting curve analysis.RESULTS The HBV pre S1 NTCP-interacting domain showed a high degree of conservation among the examined viral genomes especially between aa 9 and 21(in the genotype D consensus sequence). As compared with the virion morphogenesis domain, the NTCPinteracting domain had a smaller proportion of HBV genotype-unrelated changes comprising > 1% of the quasispecies(25.5% vs 31.8%), but a larger proportion of genotype-associated viral polymorphisms(34% vs 27.3%), according to consensus sequences from Gen Bank patterns of HBV genotypes A to H. Variation/conservation in both domains depended on viral genotype, with genotype C being the most highly conserved and genotype E the most variable(limited finding, only 2 genotype E included). Of note, proline residues were highly conserved in both domains, and serine residues showed changes only to threonine or tyrosine in the virion morphogenesis domain. The rs2296651 polymorphism was not detected in any participant.CONCLUSION In our CHB population, the NTCP-interacting domain was highly conserved, particularly the proline residues and essential amino acids related with the NTCP interaction, and the prevalence of rs2296651 was low/null.

Inhibition of Hepatitis B Virus Replication and Expression in Vitro and in Vivo by the Hammerhead Ribozymes Targeted Different Sites

Objective To develop an effective and specific medicine targeting hepatitis B virus(HBV) pregenome. Based on the identified accessible target sites for hammerhead ribozyme in our previous researches, a recombinant hepatitis delta virus(HDV) ribozyme was chosen and used to demonstrate the effective cleavage in vitro and in vivo. Methods Three hammerhead ribozymes for potential target sites(S, X and C genes) and co-expression plasmid(pTr-dB, pTdδ-dB, pTrX-dB and pTrC-dB) as well as four HDV-ribozyme chimera constructs with HBV(pTdXX, pTdXC, pTdSX and pTdSC) were severally chosen to validate the inhibition of the replication and expression of HBV. The co-expression plasmids(pTdδ and pTr-Db) in physiological saline were hydrodynamically injected to mice by tail vein. Results Compared with the group injected with pTr-dB in Huh-7 cell, hepatitis B surface antigen(HBsAg) was reduced by 31% in the group injected with pTdδ-dB, by 54%, 26%, 72% and 97% in the group injected with recombinant-ribozymes pTdSX, pTdSC, pTdXC and pTdXX, respectively. The inhibiting effects of endogenous ribozymes RzX and RzC on the HBsAg expression were 66% and 57%, respectively. Compared with the positive control, the amount of HBsAg was decreased in mice injected with pTdXX through tail vein by 88% and 96% on the second day and the third day, respectively. HBsAg was undetectable on the 6th day and could not primitively be detected on the 9th day in the sera from all mice. HBV DNA was not detected in the sera of BALB/c mice injected with pTdXX-dB, pTrX-dB or replicating-defective plasmid pHBV, while HBV DNA replication in control group could be detected on the 6th day. While HBcAg could not be detected in liver tissues of mice injected with plasmid pTdXX-dB on the 3rd day. Conclusions Encoding regions of HBV S, C and X gene were the effective cleavage sites for hammerhead ribozyme in vitro and in vivo, which provides basis for further construction of therapeutic recombinant HDV and the development of targeting antiviral gene therapy.

Hepatitis B and D viruses replication interference: Influence of hepatitis B genotype

AIM: To study the hepatitis B virus(HBV) and hepatitis D virus(HDV) replication interferences in patients with chronic hepatitis delta infected with different HBV genotypes.METHODS: We conducted a transversal study including 68 chronic hepatitis delta(CHD)(37 HIVpositive) patients and a control group of 49 chronic hepatitis B(CHB)(22 HIV-positive) patients. In addition, a dynamic follow-up was performed in 16 CHD patients. In all the samples, the surface antigen of hepatitis B(HBs Ag) serum titers were analyzed with the Monolisa HBs Ag Ultra system(Bio-Rad), using as quantification standard a serial dilution curve of an international HBs Ag standard. Serum HBV-DNA titers were analyzed using the Roche Cobas Taq Man(Roche, Barcelona, Spain), and the serum HDV-RNA using an in-house real-time q RT-PCR method, with Taq Man probes. HBV genotype was determined with the line immunoassay Li PA HBV genotyping system(Innogenetics, Ghent, Belgium). In those patients negative for Li PA assay, a nested PCR method of complete HBs Ag coding region, followed by sequence analysis was applied.RESULTS: No differences in the HBV-DNA levels were found in CHB patients infected with different HBV genotypes. However, in CHD patients the HBV-DNA levels were lower in those infected with HBV-A than in those with HBV-D, both in HIV negative [median(IQR): 1.25(1.00-1.35) vs 2.95(2.07-3.93) log10(copies/m L), P = 0.013] and HIV positive patients [2.63(1.24-2.69) vs 7.25(4.61-7.55) log10(copies/m L), P < 0.001]. This was confirmed in the dynamic study of the HBV/HDV patients. These differences induce an under-estimation of HBV-A incidence in patients with CHD analyzed with Li PA assay. Finally, the HBs Ag titers reflected no significant differences in CHD patients infected with HBV-A or D.CONCLUSION: Viral replication interference between HBV and HDV is HBV-genotype dependent, and more evident in patients infected with HBV-genotype A, than with HBV-D or E.

Life cycle and pathogenesis of hepatitis D virus:A review

Hepatitis D virus(HDV) is a defective RNA virus which requires the help of hepatitis B virus(HBV) virus for its replication and assembly of new virions. HDV genome contains only one actively transcribed open reading frame which encodes for two isoforms of hepatitis delta antigen. Post-translational modifications of small and large delta antigens(S-HDAg and L-HDAg) involving phosphorylation and isoprenylation respectively con- fer these antigens their specific properties. S-HDAg is required for the initiation of the viral genome replica- tion, whereas L-HDAg serves as a principal inhibitor of replication and is essential for the assembly of new virion particles. Immune mediation has usually been implicated in HDV-associated liver damage. The patho- genesis of HDV mainly involves interferon-α signaling inhibition, HDV-specific T-lymphocyte activation and cytokine responses, and tumor necrosis factor-alpha and nuclear factor kappa B signaling. Due to limited protein coding capacity, HDV makes use of host cel- lular proteins to accomplish their life cycle processes, including transcription, replication, post-transcriptional and translational modifications. This intimate host- pathogen interaction significantly alters cell proteome and is associated with an augmented expression of pro-inflammatory, growth and anti-apoptotic factorswhich explains severe necroinflammation and increased cell survival and an early progression to hepatocellular carcinoma in HDV patients. The understanding of the process of viral replication, HBV-HDV interactions, and etio-pathogenesis of the severe course of HDV infection is helpful in identifying the potential therapeutic targets in the virus life cycle for the prophylaxis and treatment of HDV infection and complications.

Epidemiology of acute and chronic hepatitis B and delta over the last 5 decades in Italy

The spread of hepatitis B virus(HBV)infection has gradually decreased in Italy in the last 5 decades as shown by the steady reduction in the incidence rates of acute hepatitis B,from 10/100000 inhabitants in1984 to 0.85/100000 in 2012,and by the reduced prevalence of hepatitis B surface antigen(HBsAg)-positive cases among chronic hepatitis patients with different etiologies,from 60%in 1975 to about 10%in 2001.The prevalence of HBsAg chronic carriers in the general population also decreased from nearly 3%in the 1980s to 1%in 2010.Linked to HBV by its characteristics of defective virus,the hepatitis delta virus(HDV)has shown a similar epidemiological impact on the Italian population over time.The incidence of acute HDV infection decreased from 3.2/100000 inhabitants in 1987 to 0.8/100000 in 2010 and the prevalence of HDV infection in HBsAg chronic carriers decreased from24%in 1990 to 8.5%in 2006.Before the beneficial effects of HBV mass vaccination introduced in 1991,the decreased endemicity of HBV and HDV infection in Italy paralleled the improvement in screening blood donations,the higher standard of living and impressive reduction in the birth rate associated with a marked reduction in the family size.A further contribution to the decline in HBV and HDV infections most probably came from the media campaigns to prevent the spread of human immunodeficiency virus infection by focusing the attention of the general population on the same routes of transmission of viral infections such as unsafe sexual intercourse and parenteral exposures of different kinds.

Hepatitis D virus and liver transplantation: Indications and outcomes

Hepatitis D virus(HDV)is a dependent virus that relies on hepatitis B virus for its replication and transmission.Chronic hepatitis D is a severe form of viral hepatitis that can result in end stage liver disease.Currently,pegylated interferon alpha is the only approved therapy for chronic HDV infection and is associated with significant side effects.Liver transplantation(LT)is the only treatment option for patients with end-stage liver disease,hepatocellular carcinoma,or fulminant hepatitis due to coinfection with HDV.As LT for HDV and hepatitis B virus coinfection is uncommon in the United States,most data on the long-term impact of LT on HDV are from international centers.In this review,we discuss the indications and results of LT with treatment options in HDV patients.

"Defective" mutations of hepatitis D viruses in chronic hepatitis D patients

AIM: To verify whether 'defective' mutations existed in hepatitis D virus (HDV).METHODS: Hepatitis delta antigen (HDAg)-codingsequences were amplified using Pfu DNA polymerases with proof-reading activities from sera of five patients with chronic hepatitis D. Multiple colonies were sequenced for each patient. Pfu analyzed a total of 270 HDV clones.Three representative defective HDV clones were constructed in expression plasmids and transfected into a human hepatoma cell line. Cellular proteins were extracted and analyzed by Western blot.RESULTS: Four of five cases (80%) showed defective HDV genomes in their sera. The percentage of defective genomes was 3.7% (10/270). The majority (90%) of the defective mutations were insertions or deletions that resulted in frameshift and abnormal stop translation of the HDAg. The predicted mutated HDAg ranged from 45amino acids to ＞214 amino acids in length. Various domains of HDAg associated with viral replication or packaging were affected in different HDV isolates. Western blot analysis showed defected HDAg in predicted positions.CONCLUSION: 'Defective' viruses do exist in chronic HDV infected patients, but represented as minor strains. The clinical significance of the 'defected' HDV needs further study to evaluate.

Molecular and clinical aspects of hepatitis D virus infections

Hepatitis D virus(HDV) is a defective virus with circular, single-stranded genomic RNA which needs hepatitis B virus(HBV) as a helper virus for virion assembly and infectivity. HDV virions are composed of a circular shape HDV RNA and two types of viral proteins, small and large HDAgs, surrounded by HBV surface antigen(HBs Ag). The RNA polymerase Ⅱ from infected hepatocytes is responsible for synthesizing RNAs with positive and negative polarities for HDV, as the virus does not code any enzyme to replicate its genome. HDV occurs as co-infection or super-infection in up to 5% of HBs Ag carriers. A recent multi-center study highlighted that pegylated interferon α-2a(PEG-IFN) is currently the only treatment option for delta hepatitis. Nucleotide/nucleoside analogues, which are effective against HBV, have no relevant effects on HDV. However, additional clinical trials combining PEG-IFN and tenofovir are currently ongoing. The molecular interactions between HDV and HBV are incompletely understood. Despite fluctuating patterns of HBV viral load in the presence of HDV in patients, several observations indicate that HDV has suppressive effects on HBV replication, and even in triple infections with HDV, HBV and HCV, replication of both concomitant viruses can be reduced. Additional molecular virology studies are warranted to clarify how HDV interacts with the helper virus and which key cellular pathways are used by both viruses. Further clinical trials are underway to optimize treatment strategies for delta hepatitis.

Challenge of hepatitis C in Egypt and hepatitis B in Mauritania

Egypt has one of the highest prevalence rates of hepatitis C virus(HCV) in the world,mostly with genotype 4 that is highly associated with severe fibrosis. As a consequence,hepatocellular carcinoma has become the leading cause of cancer in this country. Mauritania is a highly endemic area for hepatitis B virus(HBV). HBV and HCV could both be iatrogenically transmitted through infected blood products,infected needles,and medical equipment improperly sterilized. Adequate and efficient healthcare and public health measures with good surveillance programs,access for screening,prevention strategies,and successful treatment are needed to halt the spread of these diseases. Herein,we have reviewed the epidemiology,modes of transmission,predisposing factors,and novel treatment modalities of these viruses. We have proposed practices and interventions to decrease the risk of transmission of HCV and HBV in the affected countries,including strict adherence to standard precautions in the healthcare setting,rigorous education and training of patients and healthcare providers,universal screening of blood donors,use of safetyengineered devices,proper sterilization of medical equipment,hepatitis B vaccination,as well as effective direct-acting antiviral agents for the treatment of HCV.

MicroRNAs as Important Players in Host-hepatitis B Virus Interactions

Hepatitis B virus (HBV) infection,a major public health problem,causes acute and chronic hepatitis that is often complicated by liver cirrhosis and hepatocellular carcinoma.The pathogenic mechanisms of HBV-related liver disease are not well understood,and the current licensed therapies are not effective in permanently clearing virus from the circulation.In recent years,the role of micro-ribonucleic acids (miRNAs) in HBV infection has attracted great interest.Cellular miRNAs can influence HBV replication directly by binding to HBV transcripts and indirectly by targeting cellular factors relevant to the HBV life cycle.They are also involved in the regulation of cellular genes and signaling pathways that have critical roles in HBV pathogenesis.HBV infection,in turn,can trigger changes in cellular miRNA expression that are associated with distinctive miRNA expression profiles depending on the phase of liver disease.These alterations in miRNA expression have been linked to disease progression and hepatocarcinogenesis.We provide here an up to date review regarding the field of miRNAs and HBV interplay and highlight the potential utility of miRNAs as diagnostic biomarkers and therapeutic targets for the management of HBV-related liver disease.