Chen Pj

Asian-Pacific clinical practice guidelines on the management of hepatitis B: a 2015 update

Worldwide, some 240 million people have chronic hepatitis B virus (HBV), with the highest rates of infection in Africa and Asia. Our understanding of the natural history of HBV infection and the potential for therapy of the resultant disease is continuously improving. New data have become available since the previous APASL guidelines for management of HBV infection were published in 2012. The objective of this manuscript is to update the recommendations for the optimal management of chronic HBV infection. The 2015 guidelines were developed by a panel of Asian experts chosen by the APASL. The clinical practice guidelines are based on evidence from existing publications or, if evidence was unavailable, on the experts’ personal experience and opinion after deliberations. Manuscripts and abstracts of important meetings published through January 2015 have been evaluated. This guideline covers the full spectrum of care of patients infected with hepatitis B, including new terminology, natural history, screening, vaccination, counseling, diagnosis, assessment of the stage of liver disease, the indications, timing, choice and duration of single or combination of antiviral drugs, screening for HCC, management in special situations like childhood, pregnancy, coinfections, renal impairment and pre- and post-liver transplant, and policy guidelines. However, areas of uncertainty still exist, and clinicians, patients, and public health authorities must therefore continue to make choices on the basis of the evolving evidence. The final clinical practice guidelines and recommendations are presented here, along with the relevant background information.

Acute exacerbations of chronic type B hepatitis are accompanied by increased T cell responses to hepatitis B core and e antigens. Implications for hepatitis B e antigen seroconversion.

T cell proliferative responses to hepatitis B virus-encoded envelope antigen (S + preS2 + preS1), recombinant core antigen (HBcAg), and natural hepatitis B e antigen (HBeAg) were examined in 22 HBeAg-positive patients with chronic type B hepatitis and 17 healthy hepatitis B surface antigen (HBsAg) carriers. The results showed that HBeAg-positive patients had (a) higher levels of T cell responses to HBcAg/HBeAg than those of healthy HBsAg carriers (P less than 0.001 and P less than 0.01, respectively); (b) a further increase in these T cell responses during acute exacerbations (P less than 0.05 and P less than 0.05, respectively); (c) subsidence in the T cell responses to HBcAg/HBeAg after recovery from acute exacerbations and HBeAg seroconversion, whereas the responses would persist at high levels if the patients did not enter a clinical remission; and (d) low levels of T cell responses to S + preS2 + preS1 either before or after HBeAg seroconversion. The appearance of increasing T cell responses to HBcAg/HBeAg usually occurred in the early phase of acute exacerbations. These findings imply that HBcAg/HBeAg-specific T cells play an important role in the exacerbations of chronic hepatitis B and in HBeAg seroconversion. HBcAg/HBeAg-specific precursor T cell frequencies were serially studied in selected cases by limiting dilution assay. Elevation (two- to fourfold) of HBcAg/HBeAg-specific precursor T cell frequencies contributed to the increase of HBcAg/HBeAg-specific T cell proliferation during acute exacerbations.

Hepatitis B virus X protein enhances androgen receptor-responsive gene expression depending on androgen level

Persistent hepatitis B virus (HBV) infection is a major risk of hepatocellular carcinoma (HCC). One intriguing feature of HBV-related HCC is the male predominance, with a male to female ratio of 5–7:1. This dominance has been attributed to the elevated androgen level and the enhanced androgen receptor (AR)-mediated activity in the host. How HBV infection and AR signaling modulate HCC is unknown. We investigated whether the HBV nonstructural protein, X protein (HBx) could cooperate with the AR signaling pathway to enhance carcinogenesis. We found that HBx increased the anchorage-independent colony-formation potency of AR in a nontransformed mouse hepatocyte cell line. We also found that HBx functioned as a positive transcriptional coregulator to increase AR-mediated transcriptional activity. This transcription enhancement was increased in the presence of androgen in a concentration-responsive manner, thus explaining a more prominent effect in males. HBx did not physically associate with ligand-bound AR in the nucleus, and it likely augmented AR activity by increasing the phosphorylation of AR through HBx-mediated activation of the c-Src kinase signaling pathway. Our study documents HBx as a previously undescribed class of noncellular positive coregulators for AR. The results reveal a mechanism for the vulnerability of males to microbial infections and the subsequent development of cancer.

Androgen pathway stimulates microRNA-216a transcription to suppress the tumor suppressor in lung cancer-1 gene in early hepatocarcinogenesis.

Deregulation of microRNAs (miRNAs) is common in advanced human hepatocellular carcinoma (HCC); however, the ones involved in early carcinogenesis have not yet been investigated. By examining the expression of 22 HCC‐related miRNAs between precancerous and cancerous liver tissues, we found miR‐216a and miR‐224 were significantly up‐regulated, starting from the precancerous stage. Furthermore, the elevation of miR‐216a was mainly identified in male patients. To study this gender difference, we demonstrated that pri‐miR‐216a is activated transcriptionally by the androgen pathway in a ligand‐dependent manner and is further enhanced by the hepatitis B virus X protein. The transcription initiation site for pri‐miR‐216a was delineated, and one putative androgen‐responsive element site was identified within its promoter region. Mutation of this site abolished the elevation of pri‐miR‐216a by the androgen pathway. One target of miR‐216a was shown to be the tumor suppressor in lung cancer‐1 gene (TSLC1) messenger RNA (mRNA) through the three target sites at its 3′ untranslated region. Finally, the androgen receptor level increased in male liver tissues during hepatocarcinogenesis, starting from the precancerous stage, with a concomitant elevation of miR‐216a but a decrease of TSLC1. Conclusion: The current study discovered the up‐regulation of miRNA‐216a by the androgen pathway and a subsequent suppression of TSLC1 as a new mechanism for the androgen pathway in early hepatocarcinogenesis. (HEPATOLOGY 2012)

Amplification of GB virus‐C/hepatitis G virus RNA with primers from different regions of the viral genome

GB virus‐C/hepatitis G virus (GBV‐C/HGV) is a newly identified RNA virus. The aim of the study was to compare three primer pairs from the 5′ untranslated region (5′UTR), envelope region 2 (E 2) and nonstructural region 3 (NS 3) of GBV‐C/HGV genome for their ability to detect GBV‐C/HGV RNA by polymerase chain reaction (PCR) assays. By using PCR with primers from different regions of the viral genome, serum GBV‐C/HGV RNA was assayed in 200 at‐risk individuals. The sensitivity of this assay was assessed by a titration experiment, and nucleotide sequences of the amplified products were determined directly. Of 200 serum samples, 43 (21.5%) were positive for GBV‐C/HGV RNA with at least one of the primer pairs. The positive rates by 5′UTR, NS 3, and E 2 primers were 100%, 98%, and 84%, respectively, and the sensitivity of PCR assays using 5′UTR primers was 10 to 100 times more likely to detect GBV‐C/HGV RNA than that of NS 3 and E 2 primers. The average homology of amplified targets to the prototype HGV genome was 89%, 80%, and 85% and the similarity between each amplified target was up to 100%, 90%, and 92% in the 5′UTR, E 2, and NS 3 regions, respectively. Therefore, the 5′UTR of GBV‐C/HGV genome is highly conserved and primers deduced from this region can provide a sensitive and specific PCR assay for GBV‐C/HGV RNA. J. Med. Virol. 51:284–289, 1997.

Molecular Epidemiology of Hepatitis B Viral Serotypes and Genotypes in Taiwan

Subtypes of hepatitis B virus (HBV) have specific geographic distributions and can serve as epidemiological markers. The relationship of HBV serotypes and genotypes in Taiwan and their correlation with the domiciles of origin in 122 patients with chronic HBV infection were investigated. The serotype of HBV was determined by comparing the surface gene encoding amino acids 22-148 of the major surface protein with published sequences. Genotyping of HBV was performed by polymerase chain reaction-restriction fragment length polymorphism. Serotype adw accounted for 70% (85/122) of all HBVs, with the remaining belonging to serotype adr. All adr HBVs were genotype C, regardless of the patients domicile. Of the 85 adw HBVs, 69 (81%) were genotype B, 10 (12%) were genotype C, 5 (6%) were genotype F and only 1 (1%) was genotype A. In the 31 patients originating from mainland China, the prevalence of adr/genotype C was higher than in the 91 Taiwanese patients (15/31 vs. 22/91; p < 0.05). The distribution of the HBV serotypes and genotypes was not significantly different between 17 patients born in Taiwan (6 adw/genotype B, 2 adw/genotype C, 1 adw/genotype F and 8 adr/genotype C) and 14 patients born in mainland China (5 adw/genotype B, 2 adw/genotype C and 7 adr/genotype C). Our results indicate that in Taiwan, most HBVs of serotype adw are genotype B, and all HBVs of serotype adr are genotype C. Patients with origins in mainland China have a higher proportion of serotype adr/genotype C infection.

Superinfection by homotypic virus in hepatitis C virus carriers: Studies on patients with post‐transfusion hepatitis

Although heterotypic superinfection and mixed infections of hepatitis C virus (HCV) may be possible for hepatitis flares in chronic hepatitis C, the possibility of homotypic HCV superinfection in HCV carriers with post‐transfusion hepatitis has not been explored. Six HCV carriers with post‐transfusion non‐A, non‐B hepatitis found in a prospective study of post‐transfusion hepatitis were included. Serum samples before transfusion and during hepatitis were selected to determine genotypes of HCV and nucleotide sequences of the hypervariable region (HVR). The genotypes identified before and after transfusion were concordant in all. There were four with type 1b and one each with type 2a and type 2b. Amplified nucleotide sequences of the HVR before transfusion and during hepatitis were compared in four patients, and a, >95% homology was observed in three, suggesting persistence of original viruses. In contrast, only a 51% homogeneity was seen in a given patient, suggesting a homotypic HCV superinfection. Phylogenotic tree analysis validated further these findings. This study implies that HCV carriers can be reinfected by homotypic HCV, and this may contribute to hepatitis flares in chronic hepatitis C. These findings also confirm a weak or inadequate protective immunity in HCV infection and justify protection from reinfection of HCV of patients with chronic hepatitis C.

GB virus-C/hepatitis G virus infection in prostitutes: possible role of sexual transmission.

The modes of transmission of GB virus‐C/hepatitis G virus (GBV‐C/HGV) other than by blood transfusion are largely unknown. The prevalence of GBV‐C/HGV viremia and the associated risk factors in 145 female prostitutes were examined. The seroprevalence of hepatitis B surface antigen (HBsAg), antibodies to hepatitis C virus (anti‐HCV), and GBV‐C/HGV RNA were 14%, 18%, and 11%, respectively. The demographic characteristics were similar between subjects with and without HBsAg. In contrast, those with HCV or GBV‐C/HGV infection had practised longer as prostitutes and received blood transfusion more frequently. Moreover, the prevalence of GBV‐C/HGV RNA and anti‐HCV tended to increase in parallel with the duration of prostitution. These results suggest that like HCV, sexual transmission of GBV‐C/HGV occurs and the risk increased with prolonged duration of exposure. The transmission efficiency between GBV‐C/HGV and HCV appears to be similar. J. Med. Virol. 52:381–384, 1997,

Prevalence and infectivity of hepatitis G virus and its strain variant, the GB agent, in volunteer blood donors in Taiwan.

BACKGROUND: The prevalence of hepatitis G virus (HGV) and its strain variant, the GB agent (GBV‐C) is high in non‐virus‐inactivated plasma products, but, persistent infection in recipients is relatively low. STUDY DESIGN AND METHODS: Stored samples from transfusion donors and recipients in a prospective study of posttransfusion hepatitis were tested for HGV RNA and antibody to the E2 protein (anti‐E2). RESULTS: Thirty‐two (2.1%) of the 1500 qualified donors were positive for HGV RNA. Twenty‐four persons had received a transfusion of blood from one of these 32 viremic donors. Of these 24 recipients, 3 were positive for HGV RNA before transfusion. Of the remaining 21 recipients, 8 became viremic after transfusion, while the other 13 were not infected. Four of the eight infected recipients were persistently positive for HGV RNA, while four became negative in 1 to 3 years. Three of the four patients with HGV clearance seroconverted to anti‐E2 positivity. Comparison of the viral titer, viral sequences at E2, storage period of blood donations, and clinical data in the infected and noninfected recipients revealed no significant differences. However, the noninfected recipients seemed to have a higher prevalence of anti‐E2 before transfusion. CONCLUSION: The prevalence of HGV viremia in volunteer blood donors in Taiwan is 2.1 percent, and blood from 0.6 percent of them actually causes HGV infection in the recipients. In half of infected recipients, clearance of HGV occurs. Anti‐E2 appears in most recipients whose viremia is cleared.

Effects of GB virus-C/hepatitis G virus on hepatitis B and C viremia in multiple hepatitis virus infections

SummaryWe found that patients with dual HBV and GBV-C/HGV infection had comparable serum HBV DNA positivity and mean virus concentration compared with age-matched HBV carriers, and those with triple infection had a significantly lower HBV DNA positivity. Serum HCV RNA positivity and mean virus titer were similar between HCV carriers with or without GBV-C/HGV co-infection, and those with GBV-C/HGV co-infection seemed to have a lower serum ALT level. These data suggest that GBV-C/HGV infection exerts no significant suppression on levels of chronic hepatitis B or hepatitis C viremia.