Hepatitis B virus lymphotropism: emerging details and challenges

Impact of Occult Hepatitis B Virus Infection or Hepatitis B Virus DNA Integration on Efficacy of Chronic Hepatitis C Treatment With Peginterferon and Ribavirin

The role of hepatitis B virus integrations in the pathogenesis of human hepatocellular carcinoma

Hepatitis B virus (HBV) is one of the most important causes of end-stage liver disease, including cirrhosis and hepatocellular carcinoma worldwide.1 Taiwan is known to be hyperendemic for HBV infection. Although the implementation of nationwide universal hepatitis B vaccination program since 1984 significantly decreased the prevalence of chronic HBV infection from 10.9% to 0.5% in children,2 the prevalence of seropositivity of hepatitis B surface antigen (HBsAg) in adults was still up to 13.7% in 2002.3 In addition to HBV, Taiwan is also threatened by other hepatitis viruses, including hepatitis A, C, D, and E viruses. Thus, patients with chronic HBV infection coinfected or superinfected with other hepatitis viruses are not uncommon. Among these viral hepatitis, hepatitis C virus (HCV) coinfection in HBV carriers is most common in Asia. Previous studies revealed that patients with HBV and HCV coinfection have a greater risk of developing cirrhosis and hepatocellular carcinoma, leading to a poorer outcome than those with HBV or HCV monoinfection.4 However, little is known about the clinical manifestations and long-term outcomes of HBV carriers with hepatitis A virus (HAV) and hepatitis D virus (HDV) coinfection or superinfection. In this issue of the Advances in Digestive Medicine, Wu et al investigated whether prior exposure of HAV or HDV was associated with adverse long-term outcomes in patients with chronic HBV infection.5 Compared with HBV carriers without exposure to HAV or HDV, the risk of advanced liver disease increased by more than 10 times in patients with seropositivity of anti-HAV or anti-HDV. Their findings confirmed that the superinfection of other hepatitis virus in patients with chronic HBV infection will aggravate the underlying liver disease. However, several issues were worthy of discussion. First, HAV is one of the most common etiologies of acute hepatitis worldwide.6 Because of poor sanitation and inadequate hygiene, the prevalence of HAV infection was high and most individuals infected with HAV in childhood before 1990 in Taiwan. The annual incidence of HAV infection dramatically decreased after improving sanitation conditions and providing HAV vaccination for high-risk children since 1995.7 Since then, the seroprevalence of anti-HAV continued to decline in Taiwan. The age-stratified seroprevalence of anti-HAV was lower than 5% in the younger population.8 In the current study of Wu et al, the anti-HAV seropositive rates were quite low in inactive carriers younger than 60 years old. The most worrisome thing is that the risk of a sudden outbreak of HAV infection in patients with chronic HBV infection may increase in the future. To avoid severe clinical course of HAV superinfection, HAV vaccination is recommended for patients with chronic HBV infection and seronegativity of anti-HAV.9 Second, HDV is a defective RNA virus, and HDV infection occurs only when HBV exists. The prevalence of anti-HDV was 4.4% in patients with chronic HBV infection.10 However, the risk of HDV coinfection or superinfection was potentially higher in special populations of HBV carriers, such as injected drug users, individuals with human immunodeficiency virus infection, and commercial sex workers.11 Thus, it is important to accurately estimate the prevalence of anti-HDV in HBV endemic areas. Until now, only a small number of patients with chronic HBV infection were tested anti-HDV by in-house assays. The lack of commercial kits for the detection of anti-HDV leads to an underestimation of the prevalence of anti-HDV. An anti-HDV enzyme-linked immunosorbent assay with high sensitivity and specificity has been approved in Taiwan since 2018.12 The use of commercially available reagents will increase HDV awareness among physicians as well as increase the identification of HDV infection in patients with chronic HBV infection. Although anti-HDV screening increases after the existing commercial kit, the detection of HDV RNA to confirm active chronic hepatitis D is still an unmet need in general practice. In a long-term follow-up of 2850 patients with chronic hepatitis B receiving nucleos(t)ides analogs treatment, the seropositive rate of anti-HDV and HDV RNA was 2.7% and 0.9%, respectively.13 During a follow-up of 3.5 years, spontaneous HDV RNA clearance rate was very low: only 4.3 per 100 person-years. Jang et al further investigated the impact of HDV coinfection on the treatment effect of nucleos(t)ides analogs in patients with chronic hepatitis B. HDV RNA seropositivity was the significant risk factor of persistently abnormal serum level of alanine aminotransferase (odds ratio: 30.00, 95% confidence interval: 3.28-274.05, P = .003) among patients reached undetectable HBV DNA after nucleos(t)ides analogs therapy.14 Recently, a large cohort study revealed that persistent HDV RNA viremia was a strong risk factor of cirrhosis in patients with HBV and HDV coinfection. During a median follow-up of 8 years, 30% of patients with persistent HDV RNA viremia developed cirrhosis compared with 0% of those with seronegative HDV RNA (P = .002).15 Although durable, long-term suppression of HBV DNA reduces HBV-related hepatitis activity in the era of antiviral therapy, the persistent HDV RNA viremia will contribute to continuing hepatic inflammation and lead to poor outcomes in patients with HBV and HDV coinfection. Therefore, HDV RNA assay is a desperate need for the detection and monitoring of serum HDV RNA in HBV carriers with or without antiviral therapy. In summary, the prevalence of anti-HAV antibody is getting lower and lower among younger generation who have not received HAV vaccine. It is important to prevent HAV superinfection by HAV vaccination in patients with chronic HBV infection. On the other hand, there is currently no HDV vaccine to prevent HDV superinfection in patients with chronic HBV infection. The prevalence of chronic HDV infection is not rare in HBV endemic areas. Except interferon was used for treatment of chronic hepatitis D, several drugs such as HBV/HDV entry inhibitor, HBsAg secretion inhibitor, and farnesyl-transferase inhibitor reached promising results in early-phase clinical trials.16 In combination with the successful prevention of HBV infection by HBV vaccination and significant advances in anti-HDV therapies, elimination of HDV will be achievable in the foreseeable future. The author declares no conflict of interest.

No data are available about the amount of hepatitis B virus (HBV) genomes in liver of patients with chronic HBV infection. The aim of this study was to quantify the intrahepatic HBV DNA in hepatitis B surface antigen (HBsAg)-positive patients with either active or suppressed viral replication and in HBsAg-negative subjects with occult HBV infection. We optimized the Roche "Amplicor HBV Monitor" kit for quantifying liver HBV DNA and analyzed hepatic DNA extracts and serum samples from 19 HBs-Ag-positive and 43 HBsAg-negative individuals. Eight of the HBsAg carriers had active HBV replication, and for 3 of them we analyzed samples obtained before and at the end of 1 year of lamivudine treatment. Five hepatitis Delta virus (HDV) coinfected patients and 6 healthy HBsAg carriers had inhibited HBV activity. Among the HBsAg-negative subjects 21 had occult HBV infection and 22 had no evidence of HBV infection. The median of HBV genomes per microgram of liver DNA milliliter of serum was 34,500 to 2,620,000 in patients with active viral replication, 20,000 to 3,900, 000 before and 10,000 to 2,800 at the end of therapy in lamivudine-treated individuals, 9,800 to 600 in HDV-infected individuals, and 7,450 to 17,400 in healthy HBsAg carriers. These data indicate that cases with suppressed HBV activity, despite the very low levels of viremia, maintain a relatively high amount of intrahepatic viral genomes. This virus reservoir is likely involved in HBV reactivation, which is usually observed after stopping lamivudine treatment. Finally, the analysis of cases with occult HBV infection showed that the assay we used was able to specifically detect and quantify as few as 100 copies of viral genomes per microgram of liver DNA.

Patients with cancer with hepatitis B virus (HBV) or hepatitis C virus (HCV) infection are excluded from many cancer clinical trials of immune checkpoint inhibitors (ICIs). Therefore, data are limited regarding the management of HBV and HCV infections in patients with cancer treated with ICIs. To address this gap, we reviewed the literature on management of HBV and HCV infections in patients with cancer receiving ICIs. We searched MEDLINE and PubMed for all original research articles, case reports, and systematic reviews published in English between Jul 2013 and Jul 2023 on patients with cancer with HBV or HCV infection receiving ICIs. We found 28 studies (three prospective clinical trials, seven retrospective cohort studies, nine retrospective case series, and nine case reports) that evaluated the safety of ICI therapy in patients with HBV infection and cancer. The overall rate of HBV reactivation was 1.4% (38/2799), and no HBV-related deaths were reported. The frequency of HBV reactivation in patients with chronic and past HBV infections was 2% (35/1667) and 0.3% (3/1132), respectively. The risk of HBV reactivation was significantly higher among patients with chronic HBV infection not receiving antiviral prophylaxis than among those receiving antivirals (17% vs 1%, p < 0.05). Based on high-quality evidence, for patients with chronic HBV infection, antiviral prophylaxis is recommended before ICI therapy initiation. For patients with past HBV infection, monitoring and on-demand antiviral treatment are sufficient. We found 11 studies (five clinical trials, five retrospective studies, and one prospective observational study) that evaluated the safety of ICI therapy in patients with HCV infection and cancer. The overall rate of HCV reactivation was 0.5% (2/387), and no HCV-related deaths were reported. HCV reactivation occurs primarily in patients receiving immunosuppressants for ICI-related toxic effects. ICIs are safe for HCV-infected patients with solid tumors. Chronic HBV or HCV infection should not be considered a contraindication for ICI therapy. Specific risk assessment, monitoring, and management strategies are necessary to reduce the risk of ICI-related liver injury in patients with cancer and chronic HBV or HCV infection.

The incidence of hepatitis B virus (HBV) infection in dialysis populations has declined over recent decades, largely because of improvements in infection control and widespread implementation of HBV vaccination. Regardless, outbreaks of infection continue to occur in dialysis units, and prevalence rates remain unacceptably high. For a variety of reasons, dialysis patients are at increased risk of acquiring HBV. They also demonstrate different disease manifestations compared with healthy individuals and are more likely to progress to chronic carriage. This paper will review the epidemiology, modes of transmission and diagnosis of HBV in this population. Prevention and treatment will be discussed, with a specific focus on strategies to improve vaccination response, new therapeutic options and selection of patients for therapy.

Introduction: Hepatitis B virus (HBV) infection is a major global health problem, causing chronic hepatitis, cirrhosis, hepatocellular carcinoma (HCC) and other chronic liver diseases. HBV infection is endemic in many parts of Kingdom of Saudi Arabia. Occult HBV infection (OBI) is a challenging clinical problem characterized by the absence of Hepatitis B surface Antigen (HBsAg) and low viral DNA load. Aims: This study aim is to investigate an epidemiological survey for the prevalence of OBI among Saudi healthy general population and two of most common HBV infection risks, hemodialysis and HIV patients in Riyadh Regional Laboratory. Methods: Three groups of samples were tested. 5025 blood samples healthy group were collected from Saudi citizens for pre-marriage screening testing. Second group is comprised of 658 adult patients with end-stage renal disease undergoing regular hemodialysis. Third group is comprised from 479 patients who had been previously confirmed for HIV infection. Results: Of 5025 healthy people enrolled into the study, 212 (4.2%) seropositive for HBsAg and/or anti HBc. Of them, 114/212 (53.8%) resolved infection with detectable anti-HBs (>10 mIU/mL), and 58/212 (27.36 %) had active HBV infection with detectable HBsAg. While, 40/212 (18.9%) were defined as OBI and HBV DNA was detected in two OBI patients. In 658 hemodialysis (HD) patients, 196 (27.96%) seropositive for HBsAg and/or anti-HBc. Of them 122/196 (66.3%) resolved infection with detectable anti-HBs (>10 mIU/mL), and 17/196 (9.24%) with active HBV infection with detectable HBsAg. OBI only detected in 32/196 (17.4%), HBV DNA was detected in 3 patients. Lastly, in 479 HIV patients, 152 seropositive for HBsAg and/or anti HBc. Of them 11/152 (7.23%) had active HBV infection with detectable HBsAg and 78 (51.3%) resolved infection with detectable anti-HBs (>10 mIU/mL). OBI detected in 63/152 (41.4%) and only 6 patients showed HBV DNA was detected. There were no statistically significant differences in the OBI prevalence between healthy population and HD prevalence while showed significance difference in HIV OBI prevalence compared to healthy group. Conclusions: this study proof that OBI is frequently encountered among healthy and high risk group individuals in Saudi Arabia and more support should be provided for the vaccination especially of high-risk groups, such as HIV and HD patients.

Preventing Infection-Associated Cancer: From Bench to Hillside

Background and Aims Haemodialysis (HD) patients are highly susceptible to blood borne virus infections and prevention strategies include surveillance, segregation, vaccination and strict implementation of standard precautions. As per new guidelines it is mandatory for all HD patients to be tested for hepatitis B core antibody at the beginning of renal replacement therapy. In the present study we sought to determine the prevalence of core antibody positivity and occult HBV infection as evidenced by viraemia in hepatitis B surface antigen (HBsAg) negative patients on maintenance haemodialysis. Method All HD patients (aged≥ 18 years) who were dialyzing in 2019 were included in this cross-sectional study. Retrospective data based on one-off screening for hepatitis B core antibody total (anti-HBc) for all HBsAg negative patients (study population) carried out between May and Oct 2019 was used for analysis. Information was gathered on HBsAg, anti-HBc antibody, surface antibody (anti-HBs) and Hepatitis B virus (HBV) DNA. All anti-HBc antibody positive patients were tested for HBV DNA using quantitative PCR assay. Patients were classified as immune (anti-HBs &amp;gt;10 IU/L) and non-immune (anti-HBs ≤10 IU/L) based on surface antibody levels. Demographic data were compared using Chi square test for categorical variables and Independent T test/Mann Whitney U test for continuous variables between the patients with and without HBV core antibody. Baseline characteristics were compared between the immune and non-immune groups using Chi square test and Independent T test/Mann Whitney U test as appropriate. Results A total of 3704 HBsAg negative HD patients (mean age 63.5±11.3 years, 56.1% male, 57.7% Chinese, 65.4% diabetic and mean vintage of 5.8±5.4 years) were included in the study after exclusion of 147 patients (3.8%) who had chronic HBV infection from the entire HD cohort of 3851 patients. 895 (24.2%) showed evidence of past HBV infection (anti-HBc positive but HBsAg negative) with only 3 (0.1%) patients having detectable HBV DNA. The HBV core antibody positive patients were predominantly elderly, Chinese, males and with high medical dependency compared to the patients without HBV core antibodies (p&amp;lt;0.001). There were no statistically significant differences in diabetic status and dialysis vintage between the patients with and without HBV core antibody. 3202 (86.4%) patients were immune following vaccination (anti-HBs &amp;gt;10 IU/L). The non-immune patients (13.5%) were more likely to be diabetic, with high medical dependency and lower vintage compared to immune patients (p&amp;lt;0.001). Age, race and gender did not differ significantly between the immune and non-immune patients. Conclusion The prevalence of hepatitis B core antibody positivity was 24.2% in our large racially diverse haemodialysis cohort but the presence of occult HBV was low (0.1%). Elderly Chinese males with high comorbidity and poor functional status were more likely to have evidence of past HBV infection. Occult HBV infection has implications in policy development for the prevention of HBV infection in dialysis centres.

The molecular basis of the failed immune response in chronic HBV: Therapeutic implications

Objective To investigate the differences of expression and activation of natural killer (NK) cell G2D (NKG2D) in patients with different immune status of chronic hepatitis B virus (HBV) infection, and to explore the significance of NKG2D-mediated immune injury in HBV infection. Methods Fifteen chronic HBV carriers (immune tolerance), 15 chronic hepatitis B (CHB, immune activation) patients, 15 HBV-related acute/subacute-on-chronic liver failure (HBV-ACLF, immune over-activation) patients were enro1led in this study from January 2010 to December 2011 in the Third Hospital of Hebei Medical University. The frequencies of NK cells and NKG2D+ NK cells in peripheral blood mononuclear cells (PBMC) were detected by flow cytometry. The NKG2D mRNA expressions were measured by real-time fluorescent quantitative polymerase chain reaction. Localization and hemi-quantitative analysis of NKG2D+ cells in liver tissue were performed by immunohistochemistry staining. Concentrations of serum interferon(IFN)-γ, tumor necrosis factor(TNF)-α, perforin and granzyme B were quantified by enzyme 1inked immunosorbent assay (ELISA). Normally distributed continuous variables were analyzed using one-way analysis of variance (ANOVA), followed by Student-Newman-Keuls q test for evaluating variances between each two groups. For non-normally distributed data or heterogeneity of variance, differences between groups were analyzed using nonparametric Kruskal-Wallis H test, followed by Nemenyi test for pairwise comparisons. Pearson chi-square test was used to analyze categorical variables. Results The percentages of NK cells in PBMC were (13.58±3.24)% in healthy controls, (5.42±2.18)% in chronic HBV carriers, (7.92±2.85)% in HBV-ACLF group and (8.43±2.92)% in CHB group.The percentage of NK cells in PBMCs was lower in each chronic HBV-infected group compared with healthy controls (F=22.04, P<0.05). The frequency of NKG2D+ NK cells in HBV-ACLF group (18.92±5.85)% was the highest, followed by CHB group (12.85±3.39)%, healthy controls (8.45±2.86)%, and chronic HBV carriers (3.36±1.05%), with the statistically significant differences between each two groups (H=46.09, P<0.01). Intrahepatic NKG2D mRNA expression and NKG2D+ cells density were highest in HBV-ACLF group (6.58±1.86 and 30.69±6.67, respectively), followed by CHB group (3.25±0.95 and 17.36±4.13, respectively) and chronic HBV carriers (0.69±0.20 and 3.16±1.24, respectively), with the statistically significant differences between each two groups (H=52.10 and 52.73 respectively, both P<0.01). The similar patterns were observed in serum IFN-γ, TNF-α, perforin and granzyme B concentrations. Conclusions NKG2D expresses variously in patients with different immune status of chronic HBV infection. Activation of NKG2D may take part in the immune pathogenesis of chronic HBV infection. Key words: Killer cells, natural; NKG2D; Hepatitis B virus; Hepatitis B, chronic; Acute-on-chronic liver failure

Hepatitis B virus (HBV) is a hepatotropic double-stranded DNA virus which can cause hepatitis and cirrhosis; the World Health Organisation (WHO) estimates around 250 million people to be affected worldwide. It is highly endemic in the Western Pacific area and Southeast Asia and Africa, while the prevalence in the United States and Europe is lower.1 The virus is also considered oncogenic and is associated with an increased risk of cancers such as hepatocellular carcinoma and biliary cancer.2 In addition, epidemiological studies have documented an increased risk of developing lymphoid neoplasms, in particular B-cell non-Hodgkin lymphoma (NHL).3, 4 Among those with NHL, the strongest association seems to be with diffuse large B-cell lymphoma (DLBCL).5 HbsAg-positive DLBCL patients are younger and present with a more aggressive disease and a worse outcome in comparison to negative cases.6, 7 From a biological point of view, an increased mutation load has been reported, with a peculiar set of mutated genes which might be related to the by the activities of APOBEC and activation-induced cytidine deaminase (AID).7 For HbsAg-positive patients, the clinical and therapeutic approach is well standardised; on the contrary, in the case of patients with occult HBV infection (OBI), the strategy is not so adequately delineated.8 The European Association for the Study of the Liver clarified the classification of the HBV infection by recognising four phases, and the Taormina workshop on OBI categorised seropositive OBI (anti-HBc and/or anti-HBs-positive) or seronegative OBI (anti-HBc and anti-HBs-negative).9 The prevention of HBV reactivation during anti-CD20 antibody treatment for DLBCL is important in the areas where HBV is endemic. According to recent recommendations,10 HBsAg-positive patients with haematological malignancies and those undergoing haematopoietic stem cell transplantation (HSCT) should receive third-generation antiviral therapy as prophylaxis, while anti-HBc-positive lymphoma patients and those receiving HSCT should receive antiviral prophylaxis. Recently, the risk of HBV reactivation was assessed in DLBCL and indolent B-cell NHL patients with resolved HBV infection (HbsAg-negative, anti-HBc-positive) who received anti-CD20 antibodies (obinutuzumab or rituximab) combined with chemotherapy in the phase 3 GOYA and GALLIUM studies.11 In this setting, DNA monitoring-guided preemptive nucleos(t)ide analogue treatment (NAT) could prevent HBV-related hepatitis; antiviral prophylaxis was also active and it has been suggested as appropriate for high-risk subjects. In this issue of the British Journal of Haematology, researchers from Taiwan report a population-based study focused on the impact of antiviral prophylaxis for DLBCL patients with HBV infection. They describe 3702 adult patients with DLBCL from the Taiwan Cancer Registry, diagnosed and treated between 2011 and 2015 (2912 HBsAg-negative patients, 711 carriers receiving antiviral prophylaxis and 70 carriers not receiving prophylaxis): patients receiving prophylaxis were younger and nearly 70% received entecavir. The median overall survival of HBV-negative patients and patients receiving prophylaxis was similar, although it was shorter in the cohort not receiving prophylaxis. In a multivariate analysis, the HBV status and antiviral prophylaxis were independent prognostic factors. Although the underlying mechanism leading to a specific patient’s outcome is unclear, literature offers a different insight to support this finding. First, on the basis of accumulating data concerning the role of HCV eradication in haematological response,12 some researchers suggested that HBV therapy could also positively impact on the natural history of the lymphoproliferative disorder. With this in mind, several studies were designed13, 14 in order to evaluate the actual impact of HBV status and antiviral prophylaxis on the outcome of HBV-infected NHL patients, but no instances of a haematological response were reported after antiviral treatment alone. Despite the strong rationale that links HBV infection to lymphomagenesis, there are still unexplored areas and the model of chronic antigenic stimulation proposed for HCV-related NHL does not seem to be applicable for HBV-related NHL.15 An important issue is also the role of the tumour microenvironment: Wilcox et al. showed that the absolute monocyte count (AMC) and absolute lymphocyte count (ALC) at diagnosis were surrogate markers which were able to predict survival and identify high-risk patients in DLBCL.16 Interestingly, the incidence of low ALC tended to be higher in the HBsAg-positive patients compared with the HBsAg-negative patients.17 Yan et al. also showed lower levels of peripheral lymphocyte-to-monocyte ratios in HBV-infected patients with DLBCL, compared with non-HBV-infected patients.18 In conclusion, the development of an algorithm of screening, diagnosis and treatment shared world-wide should be an important tool in order to avoid reactivation of HBV replication. The impact of antiviral prophylaxis on the natural history of lymphoma and its underlying mechanisms in patients with active HBV infection should be evaluated with further studies to open up opportunities for a more tailored approach. LA received advisory honoraria from Bayer, Celgene, Gilead, Roche, Sandoz, Verastem and research support from Gilead; RB received advisory and speaker’s bureau honoraria from Gilead, AbbVie and MSD. RB: advisory board and speaker for AbbVie, Gilead, MSD.

Over the last 2 decades, successful public health interventions have altered the epidemiology of viral hepatitis in the United States. Vaccination of children and adolescents has reduced the incidence of hepatitis A virus (HAV) and hepatitis B virus (HBV) infections to historic lows. American Indians/Alaskan Natives, a population whose HBV rate was once 5 times that of other racial/ethnic populations, now has the lowest (0.5 cases per 100 000).1–3 Since the adoption in 1991 of a strategy to eliminate HBV transmission, HBV vaccination of infants, children, and adolescents has largely contributed to an 81% decline in new cases of HBV, and infant HBV vaccination is now on par with that of other vaccines in the childhood schedule. (1,2,4,5) With more than 90% of pregnant women screened for HBV infection and postexposure prophylaxis 85% to 95% effective in preventing mother-to-child HBV transmission at delivery, substantial progress has been made in the prevention of perinatal HBV infections.4 In the absence of a vaccine to prevent HCV, the advent of laboratory testing in 1992 to protect the nation’s blood supply and prevention efforts to reduce risk behaviors among injection drug users (IDUs) have led to a 78% decline in new HCV infections.1,2,6 Health care–related transmission of HBV and HCV is now rare thanks to widespread vaccination of health care workers and the adoption of universal infection control procedures.7 Although these prevention successes are remarkable, challenges remain. Despite the existence of risk-based vaccination recommendations, HAV and HBV infections remain common.3,5 In 2006, an estimated 32000 persons were infected with HAV, with risks highest among international travelers, individuals in close contact with infected persons, men who have sex with men, and IDUs; food-borne outbreaks also continue to be reported.2 Of an estimated 46000 new HBV infections in 2006, more than 80% were attributable to injection drug use and high-risk sexual activity.2,5 Children continue to be infected at birth. Of approximately 24000 infants born to HBV-infected women annually, only about one quarter complete case management and are tested for infection or susceptibility (CDC, unpublished data, 2007). In 2006, a total of 86 perinatal HBV cases were reported to the CDC, but testing and reporting are incomplete; thus, the true number of perinatal HBV cases per year is likely 10 to 20 times higher. Approximately half of persons with chronic HBV in the United States are Asian Americans (CDC, unpublished data, 2006). HBV-related liver cancer is a leading cause of cancer deaths in this population.8 Although the incidence of HBV infection in the United States is declining, the prevalence of chronic HBV is sustained by immigration from HBV-endemic countries in Asia, Africa, and Eastern Europe; each year, an estimated 40000 persons with chronic HBV immigrate to the United States from these countries.5 In 2006, approximately 20000 persons were infected with HCV.2 Injection drug use was responsible for most of these new cases, and at least one third of IDUs are HCV infected.9 Despite the decline in the number of new infections, the number of persons with chronic viral hepatitis is over 4 million, including 3.2 million chronic HCV infections and 800 000 to 1.4 million chronic HBV infections (CDC, unpublished data, 2006).10 Chronic viral hepatitis is a major cause of morbidity responsible for approximately two thirds of chronic liver disease and conservatively 9000 deaths per year. 11,12 Mortality from HCV is expected to rise as the HCV-infected population ages, extending their years of living with the infection and increasing their risk of liver cirrhosis and cancer.13 Cofactors such as HIV infection and alcohol use accelerate the progression of HCV; approximately 25% of the 1 million persons infected with HIV are co-infected with HCV.6 Finally, cases of health care–associated HBV and HCV transmission continue to occur. The changing epidemiology of viral hepatitis reveals both gaps in the delivery of proven interventions and new opportunities to reduce the health consequences of chronic disease. The Centers for Disease Control and Prevention (CDC) has identified new priorities to improve current programs and develop new prevention goals.

At present, hepatitis B virus surface antigen (HBsAg) is the only mandatory index of hepatitis B virus (HBV) infection for blood donor in China. Because of undetected screening sometimes, occult HBV infection (OBI) of blood donors can affect blood safety. The incidence of OBI in blood donors is different in different countries or regions, ranging from 0.000 2% to 0.111%. OBI prevalence is relatively high in HBV high prevalence countries and regions. HBV can be transmitted to blood recipients from blood components of OBI blood donors. HBV transmission rate is high in OBI blood donors with hepatitis B core antibody (anti-HBc) positive, while low in those with hepatitis B surface antibody (anti-HBs) positive. The HBV infectivity of OBI blood donors is related to the amount of blood plasma, viral load and immune status of the recipients. In order to reduce the risk of HBV transmission by OBI blood donors, nucleic acid testing can be used while improving the detection sensitivity of HBsAg. The number of blood donors' blood samples for nucleic acid testing can be reduced, and anti-HBc screening can be used in HBV low endemic area. The authors intend to summarize the correlation between OBI blood donation and HBV infection after blood transfusion, and further explore the effects of blood components from OBI donors on blood recipients. This review aims to reveal impact of OBI on the safety of blood transfusion. Key words: Occult hepatitis B virus infection; Blood donors; Hepatitis B virus transmission; Safety of blood transfusion

Genetic variability of hepatitis B virus and response to antiviral treatments: Searching for a bigger picture