Quantification of serum markers of hepatitis B (HBV) and Delta virus (HDV) infections in patients with chronic HDV infection

The interplay between hepatitis B (HBV) and delta (HDV) viruses is complex and not always characterized during chronic HDV infection. We assessed the clinical usefulness of new quantitative assays for HBV and HDV serum markers in a retrospective cross‐sectional study. Sera obtained from 122 HDV genotype 1 and HBV genotype D coinfected, anti‐HIV‐negative patients (71 males; median age 49.8 [21.7‐66.9] years), recruited consecutively in two geographical areas (Italy 69 patients, Romania 53 patients) with different HBV and HDV epidemiology, were tested for HBsAg, HBV‐DNA, HBcrAg, total anti‐HBc, HDV‐RNA, IgM and total anti‐HDV using quantitative assays. Cirrhosis, which showed comparable prevalence in the two cohorts, was diagnosed in 97 of 122 (79.5%) patients. At multivariate analysis, cirrhosis was associated with lower total anti‐HBc/IgM anti‐HDV ratio (OR 0.990, 95% CI 0.981‐0.999, P = .038), whereas disease activity was associated with higher total anti‐HDV (OR 10.105, 95% CI 1.671‐61.107, P = .012) and HDV‐RNA levels (OR 2.366, 95% CI 1.456‐3.844, P = .001). HDV‐RNA serum levels showed a positive correlation with HBV‐DNA (ρ = 0.276, P = .005), HBsAg (ρ = 0.404, P < .001) and HBcrAg (ρ = 0.332, P < .001). The combined quantitative profiling of HBV and HDV serum markers identifies specific patterns associated with activity and stage of chronic hepatitis D (CHD). HDV pathogenicity depends on the underlying active HBV infection in spite of the inhibition of its replication. HDV‐RNA, IgM anti‐HDV, total anti‐HDV, total anti‐HBc, HBsAg and HBcrAg serum levels qualify for prospective studies to predict progressive CHD and identify candidates to antiviral therapy.     

Hepatitis delta virus propagation enabled by hepatitis C virus—Scientifically intriguing,but is it relevant to clinical practice?

In vitro cell culture experiments and animal models have demonstrated that hepatitis delta virus (HDV) can theoretically propagate being enveloped by human pathogenic viruses other than hepatitis B virus (HBV), namely hepatitis C virus (HCV) and dengue virus. However, the clinical relevance of these findings and whether HDV replication occurs in real‐world hepatitis B surface antigen (HBsAg)–negative HCV patient cohorts remain unknown. To this aim, we analysed 323 HCV‐RNA–positive and HBsAg‐negative sera for the presence of HDV‐RNA and anti‐HDV antibodies (anti‐HDV). All 323 (100%) samples were negative for HDV‐RNA. Interestingly, 8/316 samples tested positive for anti‐HDV. The HBV serology of these eight patients showed a positive result for HBV core antibodies (anti‐HBc) indicating a seroconversion of an acute HBV infection in the past. None of the anti‐HBc–negative patients were positive for anti‐HDV. Our results indicate a distinctly low probability of replicative HDV infection in HCV mono‐infected patients in Germany. Current German clinical guidelines rightly recommend performing HDV screening only in HBsAg‐positive patients. However, larger studies on this subject should be performed in regions that are endemic for chronic HBV/HDV as well as HCV infections.     

Occult Hepatitis B Virus Infection in Japanese Chronic Hemodialysis Patients

We investigated the prevalence of occult hepatitis B virus (HBV) infection in Japanese chronic hemodialysis patients. Hemodialysis patients (n = 1041) were screened for occult HBV. The presence of hepatitis B surface antigen (HBsAg), hepatitis B surface antibody, and hepatitis B core antibody (anti‐HBc) was determined by various chemiluminescent immunoassays. HBV‐DNA was quantified in patients positive for anti‐HBc using quantitative real‐time polymerase chain reaction. Among the 1041 patients, six (0.6%) were HBsAg‐positive and 218 (20.9%) were anti‐HBc‐positive. All HBsAg‐positive patients also tested positive for the presence of HBV DNA. Of 212 HBsAg‐negative and anti‐HBc‐positive patients, three were positive for HBV DNA. Our study showed that the prevalence of occult HBV infection in chronic hemodialysis patients from eastern Japan was 0.3%.     

Factors associated with isolated anti‐hepatitis B core antibody in HIV‐positive patients: impact of compromised immunity

Summary. In regions that are hyperendemic for chronic hepatitis B virus (HBV) infection, prevalence of and risk factors associated with isolated anti‐hepatitis B core antibody (anti‐HBc) in HIV‐positive patients are less well described. HIV‐positive patients who were tested for hepatitis B surface antigen (HBsAg), anti‐hepatitis B surface antibody (anti‐HBs) and anti‐HBc at designated hospitals for HIV care in Taiwan were included for analysis. HBV DNA was detected by real‐time polymerase chain reaction in patients with and without isolated anti‐HBc. Of 2351 HIV‐positive patients, 450 (19.1%) were HBsAg positive, 411 (17.5%) were anti‐HBc positive alone and 963 (41.0%) for both anti‐HBs and anti‐HBc. Compared with patients who were positive for both anti‐HBs and anti‐HBc, patients with isolated anti‐HBc were older, less likely to have anti‐hepatitis C virus antibody (anti‐HCV), had lower CD4 lymphocyte counts and higher plasma HIV RNA loads. Older age (adjusted odds ratio, 1.029; 95% confidence interval, 1.015–1.043) and CD4 <100 cells/μL (adjusted odds ratio, 1.524; 95% confidence interval, 1.025–2.265) were independently associated with isolated anti‐HBc by logistic regression, while presence of anti‐HCV and injecting drug use were not. HBV DNA was detectable in 8.3% of 277 patients with isolated anti‐HBc and 14.3% of 56 patients with both anti‐HBs and anti‐HBc (P = 0.160). In a country hyperendemic for HBV infection, HIV‐positive patients at older age and with CD4 <100 cells/μL were more likely to have isolated anti‐HBc, suggesting that compromised immunity plays a role in the presence of this marker.     

De novo hepatitis B virus infection in hepatocellular carcinoma following eradication of hepatitis C virus by interferon therapy

Epidemiological studies have revealed that hepatocellular carcinoma (HCC) is still observed in hepatitis C virus (HCV)‐positive patients with a sustained response to interferon (IFN) treatment, although a substantial decrease in the incidence of hepatocellular carcinoma (HCC) has been achieved in those patients. Why HCC develops in patients who have a complete clearance of HCV remains unclear. Here, we provided evidence of latent hepatitis B virus (HBV) infection in an initially HCV‐positive chronic hepatitis patient who developed HCC after the complete eradication of HCV by IFN therapy. Although he was initially negative for anti‐hepatitis B surface antigen (HBsAg) or circulating HBV DNA but positive for anti‐hepatitis B core antigen (anti‐HBc) in his sera, he developed HBsAg and HBV DNA during the course of the management of a series of cancers. HBV DNA was detectable in the liver tissues before HBV reactivation and the viral sequences derived from his anti‐HBc‐positive liver showed 100% homology to that from the serum after HBsAg appearance. These findings indicates that HCV‐positive individuals who are positive for anti‐HBc in the absence of HBsAg could have latent HBV infection in their liver tissues and intrahepatic HBV infection may play a pivotal role in the development of HCC after the IFN‐mediated eradication of HCV.     

Donor screening for hepatitis B virus infection in a cell and tissue bank

Abstract: Background and objectives. Hepatitis B virus (HBV) has been transmitted by tissue transplantation. In order to reduce the risk of HBV transmission, testing for antibody to HBV core antigen (anti‐HBc) is used in addition to testing for hepatitis B surface antigen (HBsAg) in many blood centers and tissue banks. Design and methods. We retrospectively analyzed the results of HBV assays in tissue donors. All tissue donors were tested for HBsAg and anti‐HBc. All anti‐HBc positive sera were tested for the antibody to HBsAg (anti‐HBs). From July 2006, an HBV nucleic acid testing (NAT) assay was also performed. Results. A total of 6855 tissue donors from January 1999 till July 2007 were tested for HBV assays: 4756 women and 2099 men. Positive HBsAg was found in 23 (0.36%) living donors, while no multiorgan or cord blood (CB) donor was found to be positive for HBsAg. Positive anti‐HBc was found in 80 multiorgan donors (12.94%), 599 living donors (17.84%), and 103 CB donors (3.57%) (P<0.005), while isolated anti‐HBc was found in 12 multiorgan (1.94%), in 126 living tissue donors (3.75%), and in 8 CB donors (0.28%). A total of 1310 donors were analyzed for single‐sample DNA HBV NAT assay. Discussion. We consider that anti‐HBc and NAT assays must both still be performed in addition to HBsAg assay for HBV screening in tissue donors. All these tests will be useful in order to define an algorithm for safe and efficient management of the tissue bank.     

Evidence of protection against clinical and chronic hepatitis B infection 20 years after infant vaccination in a high endemicity region

Summary. Vaccination against hepatitis B virus (HBV) immediately after birth prevents neonatal infection by vertical transmission from HBV carrier mothers. There is an ongoing debate whether infant vaccination is sufficient to protect against infection when exposed to HBV later in life. We studied 222 Thai infants born to HBsAg ?/+ and HBeAg ?/+ mothers who were vaccinated with recombinant hepatitis B vaccine at 0‐1‐2‐12 months of age. A subset of 100 subjects received a booster dose at age 5 years. Blood samples collected yearly for 20 years were examined for anti‐HBs antibodies and serological markers of hepatitis B infection (anti‐HBc, HBsAg, and in selected cases HBeAg, anti‐HBe, HBV DNA). During the 20‐year follow‐up, no subject acquired new chronic HBV infection or clinical hepatitis B disease. During the first decade, possible subclinical breakthrough HBV infection (anti‐HBc seroconversion) was only observed in subjects born to HBsAg +/HBeAg + mothers (6/49 [12.2%]). During the second decade, breakthrough HBV infections were detected in all groups (18/140 [12.8%]). Increases in anti‐HBs concentrations that were unrelated to additional HBV vaccination or infection were detected in approximately 10% of subjects in each decade. Primary infant vaccination with a recombinant hepatitis B vaccine confers long‐term protection against clinical disease and new chronic hepatitis B infection despite confirmed hepatitis B exposure. ( http://www.clinicaltrials.gov NCT00240500 and NCT00456625)     

T‐ and B‐cell responses and previous exposure to hepatitis B virus in ‘anti‐HBc alone’ patients

A serologic response to hepatitis B virus (HBV) defined as ‘anti‐HBc alone’ is commonly observed, but its significance remains unclear. This study aimed to define the relationship between ‘anti‐HBc alone’ serostatus and HBV infection, including HBV‐specific T‐ and B‐cell memory responses. We enrolled 31 ‘anti‐HBc alone’ patients. Total HBV DNA and cccDNA were tested by nested polymerase chain reaction (PCR) analysis in liver samples from 22 ‘anti‐HBc alone’ patients vs controls (chronic or resolved HBV infection), followed by HBsAg/HBcAg immunohistochemical (IHC) staining. IFN‐γ secretion by HBV‐specific T cells was compared in individuals who were ‘anti‐HBc alone’ (n = 27), resolved HBV (n = 21), chronic HBV (n = 24) and 12 healthy controls using enzyme‐linked immunospot (ELISpot) assays. An HBsAg‐IgG B‐cell ELISpot assay was performed in ‘anti‐HBc alone’ patients before and after one dose of recombinant HBsAg vaccine. The majority (23/31, 74.2%) of the ‘anti‐HBc alone’ individuals were co‐infected with HCV. Infrequent intrahepatic total HBV DNA (2/22, 9.1%) and cccDNA (1/22, 4.5%) were detected in biopsies; HBsAg and HBcAg IHC staining was negative. HBV‐specific T‐cell responses were similar between ‘anti‐HBc alone’ individuals and HBV resolvers. Circulating HBV‐memory B‐cell responses were detected in all ‘anti‐HBc alone’ individuals, consistent with an HBsAg‐specific memory pool. After one HBV vaccine dose, increased anti‐HBs antibody levels were observed, accompanied by an expansion of HBsAg‐specific memory B cells (P = 0.0226). ‘Anti‐HBc alone’ individuals showed HBV‐specific T‐cell and memory B‐cell responses typical of previous viral exposure and protective memory, suggesting a resolved infection.     

Hepatitis D outbreak among children in a hepatitis B hyper‐endemic settlement in Greenland

Summary. Hepatitis B virus (HBV) infection is endemic in Greenland with 5–10% of the population being HBsAg‐positive (chronic carriers). Surprisingly, despite of the high prevalence of HBV infection, acute and chronic hepatitis B, liver cirrhosis and primary hepatocellular carcinoma appear much less frequently than expected. The reasons for the low frequencies are unknown, but as a consequence implementation of a childhood HBV vaccination programme, though debated for years, has never been instituted. We describe an outbreak of hepatitis D (HDV) infection among children in a hepatitis B hyper‐endemic settlement of 133 inhabitants on the west coast of Greenland. In 2006 a total of 27% of the inhabitants were HBsAg‐positive (chronic carriers) and 83% were HBcAb‐positive (previously exposed). Forty‐six percent of the HBsAg‐positive persons were below 20 years of age. On follow‐up 1 year later a total of 68% of the HBsAg‐positive persons were HDV‐IgG positive. Five children, who were HBsAg‐positive in 2006, had HDV‐seroconverted from 2006 to 2007, indicating a HDV‐super‐infection. Most of the HDV‐IgG positive children had markedly elevated liver enzymes. In the multivariate analysis, among the HBV and HDV markers, presence of HDV‐IgG was most strongly associated with elevation of liver enzymes. In conclusion, the HBV‐HDV super‐infection and presumed HDV outbreak in this settlement challenges the notion that HBV infection may not be as harmless in Greenland as previously anticipated. The findings strongly suggest that HBV vaccination should be included in the child‐immunization program in Greenland.     

High prevalence and diversity of hepatitis B and hepatitis delta virus in Gabon

Although central Africa is classified as having a high endemicity of hepatitis B virus (HBV) and hepatitis D virus (HDV) infection, there is paucity of prevalence studies. For the first time on a country‐wide level in Central Africa, we show in Gabon an overall 7.4% prevalence of Hepatitis B surface antigen (HBsAg) and that more than 25% of the HBsAg‐positive population are infected by HDV. Although HBV prevalence did not differ significantly between provinces, there is a north‐south split in the distribution of HDV seroprevalence, with the highest rates (>66.0%) correlating with the presence of specific ethnic groups in the northeastern provinces. Genotyping revealed high genetic diversity of the HBV and HDV strains circulating in Gabon, including many restricted to this region of the globe. This work confirmed that high exposure to HBV and HDV infection reported in selected regions of Gabon holds true across the whole country.     

Clinical, biochemical, immunological and virological profiles of, and differential diagnosis between, patients with acute hepatitis B and chronic hepatitis B with acute flare

Background and Aim: In areas with high or intermediate endemicity for chronic hepatitis B virus (HBV) infection, it is difficult to distinguish acute hepatitis B (AHB) from chronic hepatitis B with an acute flare (CHB‐AF) in patients whose prior history of HBV infection has been unknown. The present study aimed to screen laboratory parameters other than immunoglobulin M antibody to hepatitis B core antigen (IgM anti‐HBc) to discriminate between the two conditions. Methods: A retrospective and prospective study was conducted in patients first presenting clinically as HBV‐related acute hepatitis to sort out acute self‐limited hepatitis B (ASL‐HB). Then, clinical and laboratory profiles were compared between patients with ASL‐HB and CHB‐AF. Parameters closely associated with ASL‐HB were chosen to evaluate sensitivity, specificity, accuracy, positive predictive values and negative predictive values for diagnosing AHB. Results: There were significant differences between patients with ASL‐HB and CHB‐AF in relation to clinical and laboratory aspects, with many outstanding differences in levels of serum HBV‐DNA, hepatitis B e antigen (HBeAg) and alpha‐fetoprotein (AFP) as well as IgM anti‐HBc. In particular, there was a greater difference between the two groups in low levels of HBeAg (ratio of the optical density of the sample to the cut‐off value [S/CO] <20) than in negativity for HBeAg (42.7% and 13.5% vs 49.3% and 45.9%). 1:10 000 IgM anti‐HBc had a sensitivity and specificity of 96.2% and 93.1%, respectively, for predicting ASL‐HB. Combining it with AFP, HBeAg or HBV‐DNA could improve diagnostic power. A combination of IgM anti‐HBc, HBV‐DNA and HBeAg had a predictive value of 98.9% and a negative predictive value of 100.0%, similar to that of a combination of IgM anti‐HBc and HBV‐DNA. Adding AFP to the combinations of IgM anti‐HBc and HBV‐DNA or HBeAg could further heighten the positive predictive value. The positive predictive value and negative predictive value of the combination of IgM anti‐HBc, HBV‐DNA and AFP were both 100.0%. Conclusions: (i) There are significant differences with respect to clinical, biochemical, immunological and virological aspects between ASL‐HB and CHB‐AF. (ii) Of several diagnostic combinations, IgM anti‐HBc jointing HBV‐DNA is most effective and most practicable in distinguishing ASL‐HB from CHB‐AF. (iii) A low HBeAg level is more useful than negative HBeAg in differential diagnosis between ASL‐HB and CHB‐AF. (iv) In those patients with a high level of IgM anti‐HBc, serum AFP level >10× upper reference limit could rule out a probability of ASL‐HB.     

Clinical outcome of acute and chronic hepatitis delta over time: a long‐term follow‐up study

Summary. Long‐term changes in the frequency and outcome of hepatitis delta virus (HDV) infection have seldom been analysed. This retrospective, longitudinal study includes 398 consecutive hepatitis B surface antigen (HBsAg)‐positive patients with anti‐HDV antibodies who attended our institution between 1983 and 2008. At enrolment, 182 patients had acute and 216 chronic hepatitis. Patients were grouped into two periods. Those who attended between 1983 and 1995 and those between 1996 and 2008. The former group was significantly younger, mainly intravenous drugs users, and had a greater incidence of acute HDV and HIV and HCV coinfection. Patients with acute HBV/HDV coinfection cleared both infections in 90% of cases, while all patients with HDV superinfection evolved to chronic disease. One hundred and fifty‐eight patients with chronic HDV were followed for a median period of 158 months. Seventy‐two per cent of the patients remained stable, 18% had hepatic decompensation, 3% developed hepatocellular carcinoma, and 8% cleared HBsAg. Liver‐related death was observed in 13% of patients and mainly occurred in patients from the first period (P = 0.012). These results indicate an outbreak of HDV at the end of the 1980s and the beginning of the 1990s, with a large number of acute HDV cases affecting predominately young, male intravenous drug users. Currently, patients with chronic HDV disease are older, and factors associated with worse prognosis include the presence of cirrhosis and age at the time of diagnosis.     

Acquirement and disappearance of HBsAg and anti‐HCV in an aged population: a follow‐up study in an endemic township

Background: HBsAg and anti‐hepatitis C virus (anti‐HCV) are stable markers and widely used. The seroconversion and seroclearance of HBsAg and anti‐HCV are important for disease control and prognosis of diseases. Aims: To investigate acquirement and disappearance of HBsAg and anti‐HCV in an endemic area. Methods: Seven years after a community screening, 1002 of 2909 residents of Tzukuan Township were recruited. HBsAg, anti‐HCV and alanine transaminase (ALT) were checked in all who participated and hepatitis B virus (HBV) DNA, anti‐HBs, anti‐HBc, HCV RNA, anti‐HDV and upper abdominal ultrasonography were studied in different groups. Results: There were 461 male and 541 female residents with a mean age of 66.7±8.6 years. No new HBsAg carrier was noted and the HBsAg clearance rate was 1.58% per year. One of the 17 cases with HBsAg clearance had positive HBV DNA, three had ALT elevation, two had cirrhosis and seven had anti‐HBs seroconversion. Quantitative of HBsAg and HBV DNA were concordant and 78.1% subjects had low levels of titration. Anti‐HBc alone contributed to 32.1% and was prominent in old age and the anti‐HCV‐positive group. The anti‐HCV seroconversion rate was only 0.74% per year and household transmission was the only risk factor. Only 37.5% of cases with anti‐HCV seroconversion had HCV viraemia and the anti‐HCV seroreversion rate was 0.63% per year. The anti‐HDV seroconversion rate was 0.72% per year and no subject showed anti‐HDV clearance. Conclusions: Much higher rates of HBsAg seroclearance, anti‐HCV seroreversion and anti‐HBc alone were noted in this endemic area and no subject showed anti‐HDV clearance.     

Clinical and histological impact of previous hepatitis B virus infection in patients with chronic hepatitis C

Background: Recent reports suggest that hepatitis C virus (HCV) carriers with serological markers of prior hepatitis B virus (HBV) infection have more advanced liver fibrosis, irrespective of HBV‐DNA detection. Aims: We sought to assess the prevalence and impact of previous HBV infection in patients with HCV chronic infection. Methods: This cross‐sectional study included hepatitis B surface antigen‐ and human immunodeficiency virus‐negative subjects with positive HCV‐RNA. All patients had prior parenteral exposure as the probable source of HCV infection. Serum samples were tested for HBV‐DNA using a commercial assay. The METAVIR system was used for histological analysis. Results: One‐hundred and eleven patients were evaluated. Thirty‐one out of 111 patients (28%) tested positive for antihepatitis B core antigen (anti‐HBc). HBV‐DNA was not detected in any sample. Anti‐HBc‐positive patients showed higher histological grading, staging and a higher fibrosis progression rate. By multivariate analysis, anti‐HBc‐positivity was predictive of moderate to severe activity [odds ratio (OR)=3.532; P=0.032] and significant hepatic fibrosis (OR=3.364; P=0.017). After approximately 20 years of infection, advanced liver fibrosis (F3/F4) can be expected in 13% of anti‐HBc‐negative subjects who acquired HCV before the age of 30 and in 57% of those anti‐HBc‐positive patients who were infected by HCV after 30 years of age (P<0.001). Conclusion: Previous HBV infection is common among HCV carriers and may exert a negative impact on the natural history of HCV infection, independently of the presence of significant HBV replication.     

Fatal outcome of a hepatitis B virus transfusion‐transmitted infection

Background and Objectives In 2008, hepatitis B virus (HBV) DNA testing was not yet mandatory for the screening of blood donations in Switzerland. At that time, HBsAg was the only specific mandatory marker for HBV. The importance of high sensitivity for HBV NAT screening is shown. Materials and Methods Donor and recipient of a transfusion‐transmitted HBV infection were followed up. Multiple samples were tested for HBV serological and molecular markers. Results At donation, the donor appeared healthy, HBsAg was negative and had a normal ALAT level. Ten weeks later, clinical symptoms suggested acute HBV infection as was confirmed with positive HBsAg, HBeAg, anti‐HBc IgG, anti‐HBc IgM and anti‐HBe. The archived sample from the original donation was negative for anti‐HBc, but positive for HBV DNA (17 IU/ml). A recipient transfused with the red cell concentrate was HBV DNA positive (3100 IU/ml) 3 months post‐transfusion. After five months, HBsAg, HBeAg, anti‐HBc and HBV DNA (1·1 × 10¹¹ IU/ml) were positive. Two weeks later, the patient died from complications associated with HBV infection and his underlying bone marrow disease. Conclusions The present case illustrates the importance of introducing highly sensitive HBV NAT screening strategy to prevent possible HBV transfusion‐transmitted infections from donors with low viral load.     

Hepatitis D virus infection,cirrhosis and hepatocellular carcinoma in The Gambia

Hepatocellular carcinoma (HCC) incidence is high in The Gambia, and hepatitis B virus (HBV) infection is the main cause. People coinfected with HBV and hepatitis D virus (HDV) have an even greater risk of HCC and cirrhosis. Using a new HDV quantitative microarray antibody capture (Q‐MAC) assay, we evaluated the association between HDV infection and HCC or cirrhosis among participants in The Gambia Liver Cancer Study. In this case‐control study, cases had HCC (n = 312) or cirrhosis (n = 119). Controls (n = 470) had no clinical evidence of liver disease and normal serum alpha‐foetoprotein. Participants were previously tested for hepatitis B surface antigen (HBsAg); we tested HBsAg+ specimens by HDV Q‐MAC, western blot and RNA assays. We evaluated separate cut‐offs of the Q‐MAC assay for predicting anti‐HDV and RNA positivity. Q‐MAC correctly identified 29/29 subjects who were western blot‐positive (sensitivity = 100%, specificity = 99.4%) and 16/17 who were RNA‐positive (sensitivity = 94.1%, specificity = 100%). Compared to controls, cases more often had HBV monoinfection (HBsAg+/HDV RNA?; 54.1% vs 17.0%; odds ratio [OR] = 6.28; P < 0.001) or HBV‐HDV coinfection (HBsAg+/HDV RNA+; 3.9% vs 0%; P < 0.001). Risk estimates (for HCC or cirrhosis) based on HDV antibody status and adjusted for covariates (demographics, alcohol, smoking, body mass index, anti‐HCV and aflatoxin B1 exposure) yielded consistent results for both HBV monoinfection (adjusted OR = 8.29; 95% confidence interval = 5.74‐11.98) and HBV‐HDV coinfection (adjusted OR = 30.66; 95% confidence interval = 6.97‐134.95). In this Gambian population, HDV Q‐MAC had high sensitivity and specificity for both anti‐HDV and HDV RNA. HDV infection contributed to the high risk of HCC in The Gambia.     

Frequent delayed spontaneous seroclearance of hepatitis B virus after incident HBV infection among adult high‐risk groups

High rates (~25%) of developing chronic hepatitis B virus (HBV) infection (hepatitis B surface antigen (HBsAg)‐positive for > 6 months following infection) have been observed in people who use drugs (PWUD) and men who have sex with men (MSM). We aimed to estimate the frequency of delayed HBsAg seroclearance, along with its determinants, and time to delayed HBsAg seroclearance. Data were used from MSM and PWUD enrolled in the Amsterdam Cohort Studies (1985‐2002) who had anti‐hepatitis B core antibody seroconversion. Potential determinants for standard HBsAg seroclearance, delayed HBsAg seroclearance and chronic HBV were examined using multinominal logistic regression. Time to HBsAg seroclearance was estimated using Kaplan‐Meier curves. A total of 147 incident HBV infections occurred during follow‐up. On initial HBsAg testing after infection (6‐12 months), 42 (29%) were HBsAg‐positive and 105 (71%) were HBsAg‐negative (‘standard HBsAg seroclearance’). Of the 42 initially HBsAg‐positive individuals, 22 subsequently tested HBsAg‐negative (of whom 7 (31.8%) were HBV DNA positive at last visit, suggesting occult HBV). Overall, 15 became HBsAg‐negative and HBV DNA‐negative (‘delayed HBsAg seroclearance’), while 27 remained HBsAg and/or HBV DNA‐positive (‘chronic HBV’). The 5‐year cumulative probability of delayed HBsAg seroclearance was 41.6% for initially HBsAg‐positive individuals. Delayed HBsAg seroclearance and remaining chronically infected were associated with younger age and HIV/hepatitis C virus (HCV)‐co‐infection. In conclusion, delayed HBsAg seroclearance is common in these key adult populations at‐risk for HBV, while proportion developing HBV chronicity (18%) is still higher compared to the general population (~5%). Given the proportion of individuals with occult HBV infection and that HCV direct‐acting antivirals can lead to HBV reactivation, HBV DNA testing in HCV co‐infected MSM/PWUD are warranted prior to treatment initiation.     

抗—HBs阳性不同血清学模式病毒学及临床意义分析

目的：通过对抗－HBs阳性不同血清学模式病毒学和临床意义的分析,了解抗－HBs阳性不同血清学模式特点,探讨其形成机理及抗－HBs的作用。方法：采用Abbott和PCR定量、PCR定性方法分别检测抗－HBs阳性不同血清学模式病人的HBV血清标志物和HBV DNA。结果：抗－HBs、抗－HBe、抗－HBc阳性组与其它模式组比较,其抗－HBs值显著升高（P＜0．05）;HBsAg、抗－HBs、HBeAg阳性组与其它模式组比较,其HBV DNA含量显著增高（P＜0．01）;定性检测HBV DNA阳性组与HBV DNA阴性组比较抗－HBs值,前者抗－HBs值显著降低（P＜0．05）;抗－HBs阳性不同血清学模式病人生化指标比较无显著性差异（P＞0．05）;抗－HBs阳性不同血清学模式病人比较其肝炎临床类型的构成有非常显著性差异（P＜0．005）：即抗－HBs、抗－HBe、抗－HBc阳性组主要表现为急性肝炎,HBsAg、抗－HBS、HBeAg阳性组与HBsAg、抗－HBs阳性组主要表现为慢性肝炎。结论：抗－HBs阳性时HBV处于复制水平,但并不标志HBV复制的停止,仅预示病人感染相和恢复相的动态消长过程。如抗－HBs水平不断提高,则感染相向稳定的恢复相发展。同时从肝功能损伤的程度及肝炎临床类型分析,提示抗－HBs引发的免疫效应最终使部分病人由感染相进入恢复相。     

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 in 1984 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 from 24% 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.     

Impact of comorbidities on the severity of chronic hepatitis B at presentation

AIM: To evaluate the clinical relevance of each cofactor on clinical presentation of chronic hepatitis B.METHODS: Out of 1366 hepatitis B surface antigen (HBsAg) positive subjects consecutively observed in 79 Italian hospitals, 53 (4.3%) showed as the only cofactor hepatitis D virus (HDV) infection [hepatitis B virus (HBV)/HDV group], 130 (9.5%) hepatitis C virus (HCV) (group HBV/HCV), 6 (0.4%) human immunodeficiency virus (HIV) (group HBV/HIV), 138 (10.2%) alcohol abuse (group HBV/alcohol); 109 (8.0%) subjects had at least two cofactors and 924 were in the cofactor-free (CF) group.RESULTS: Compared with patients in group CF those in group HBV/alcohol were older and more frequently had cirrhosis (P < 0.001), those in group HBV/HDV were younger (P < 0.001), more frequently resided in the south of the country and had cirrhosis (P <0.001), those in group HBV/HCV were older (P < 0.001) and more frequently had cirrhosis (P < 0.001). These cofactors were all independent predictors of liver cirrhosis in HBsAg positive patients. Multivariate analysis showed that an older age [odds ratio (OR) 1.06, 95% CI: 1.05-1.08], alcohol abuse with more than 8 drinks daily (OR 2.89, 95% CI: 1.81-4.62) and anti-HDV positivity (OR 3.48, 95% CI: 2.16-5.58) are all independently associated with liver cirrhosis. This association was found also for anti-HCV positivity in univariate analysis, but it was no longer associated (OR 1.23, 95% CI: 0.84-1.80) at multivariate analysis.CONCLUSION: Older age, HDV infection and alcohol abuse are the major determinants of severe liver disease in chronic HBV infection, while HCV replication plays a lesser role in the severity of hepatic damage.