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To investigate whether hepatitis B surface antigen (HBsAg) and hepatitis B core-related antigen (HBcrAg) levels are useful to identify inactive carriers among HBeAg-negative patients infected by different hepatitis B virus (HBV) genotypes.In all, 202 consecutive HBeAg-negative patients with chronic hepatitis B, 135 inactive carriers and 67 with HBV activity, were prospectively followed for 1 year.In HBeAg-negative patients, HBsAg levels differed across the different genotypes (p0.001). The highest levels were observed in genotypes F or H (4.2 ± 0.6 logIU/mL), followed by genotype E (3.4 ± 1.1 logIU/mL), genotype A (3.4 ± 0.8 logIU/mL), and the lowest in genotype D (2.7 ± 1.1 logIU/mL). Variations in HBsAg levels were similar in inactive carriers and patients with HBV activity. HBsAg3 logIU/mL showed good performance for identifying genotype D inactive carriers: 76% of genotype D inactive carriers met this cut-off versus ≤31% for genotypes A, E, F or H. However, in patients with genotype A, HBsAg levels ≤3.7 logIU/mL better classified inactive carriers. The combination of a single measurement of HBcrAg ≤3 logU/mL plus HBV DNA ≤2000 IU/mL yielded a positive predictive value and diagnostic accuracy85% in all HBV genotypes, except genotype H or F, with values of 62.5% and 72.7%, respectively, for the two parameters.HBsAg levels varied across genotypes in HBeAg-negative patients. HBsAg levels3 logIU/mL were only useful for identifying genotype D inactive carriers. A single HBcrAg measurement ≤3 logU/mL plus HBV DNA ≤2000 IU/mL was highly accurate for identifying inactive carriers, regardless of their HBV genotype.

Recent studies have shown that antiviral treatment discontinuation is safe and associated with virologic remission in HBeAg-negative patients. However, the period of viral suppression and follow-up in these studies was relatively short.To investigate whether continuous viral suppression with tenofovir disoproxil fumarate for more than 7 years is associated with HBsAg loss and sustained response after treatment discontinuation and receiving a full course of hepatitis B vaccination.Patients with HBeAg-negative chronic HBV infection and more than 7 years of persistent viral suppression with tenofovir therapy were selected for treatment discontinuation and HBV vaccination. Follow-up with monthly ALT, HBV-DNA, and HBsAg determinations lasted 72 weeks. In patients with viral relapse, the viral quasispecies in the overlapping reverse transcriptase and small surface protein regions was analysed by ultra-deep pyrosequencing.Eight of 17 HBeAg-negative patients accepted tenofovir discontinuation: 5 patients achieved sustained response (persistent HBV-DNA levels2000IU/mL and normal ALT) despite an initial virologic relapse, one lost HBsAg, and two needed re-treatment. All patients with an on-treatment HBsAg level decline5000IU/mL achieved sustained response. Patients with HBsAg level100IU/mL during an ALT flare after antiviral discontinuation achieved sustained response. Significant changes were seen in the composition of the HBV quasispecies, and half the patients showed changes in HBV genotype.Even though the majority of patients presented an initial relapse with selection of HBV variants, most achieved sustained response. Changes in HBsAg levels on and off treatment may be useful for predicting the likelihood of virologic remission.

Aims To investigate an optimal long-term prophylactic strategy for prevention of hepatitis B virus (HBV) recurrence after liver transplantation, we conducted a randomized study of 29 transplant recipients receiving a short course of hepatitis B immune globulin (HBIg) + lamivudine (LAM), followed by randomization to long-term prophylaxis with LAM with or without HBIg. Methods The efficacy and safety, and impact on survival and HBV recurrence of these 2 prophylactic regimens were compared over a mean period of 10 years. In patients with viral recurrence, the HBV quasispecies in the surface/polymerase region were studied by ultra-deep pyrosequencing (UDPS). Results The 10-year survival rate was 76% and was not affected by the type of prophylaxis. Four patients had hepatitis B surface antigen (HBsAg) recurrence within the first 48 months after orthotopic liver transplantation (OLT). HBsAg-positive and -negative patients showed similar mean survival times, with no differences between the 2 regimens. Low HBV DNA levels were transiently detected in 32% of HBsAg-negative patients. UDPS showed major changes after OLT in the HBV quasispecies of patients with viral recurrence, which may be explained by a “bottleneck” effect of OLT together with prophylactic therapy. Conclusion Long-term survival after OLT in end-stage chronic hepatitis B patients was good with both prophylactic strategies. However, low, transient HBV DNA levels were detected even in the absence of HBsAg, showing the importance of continuing HBV prophylaxis.

Current measures of health literacy have been criticized on a number of grounds, including use of a limited range of content, development on small and atypical patient groups, and poor psychometric characteristics. In this paper, we report the development and preliminary validation of a new computer-administered and -scored health literacy measure addressing these limitations. Items in the measure reflect a wide range of content related to health promotion and maintenance as well as care for diseases. The development process has focused on creating a measure that will be useful in both Spanish and English, while not requiring substantial time for clinician training and individual administration and scoring. The items incorporate several formats, including questions based on brief videos, which allow for the assessment of listening comprehension and the skills related to obtaining information on the Internet. In this paper, we report the interim analyses detailing the initial development and pilot testing of the items (phase 1 of the project) in groups of Spanish and English speakers. We then describe phase 2, which included a second round of testing of the items, in new groups of Spanish and English speakers, and evaluation of the new measure’s reliability and validity in relation to other measures. Data are presented that show that four scales (general health literacy, numeracy, conceptual knowledge, and listening comprehension), developed through a process of item and factor analyses, have significant relations to existing measures of health literacy., Video abstract

Objectives This study aimed to characterize the chronically infected general hepatitis C virus (HCV) population in Barcelona using a highly sensitive subtyping method that can identify the 67 recognized HCV subtypes and diagnose mixed infection by various genotypes/subtypes in a single individual. The resulting information has implications for selecting optimal direct-acting antiviral (DAA) treatment for each patient and establishing public healthcare policies in our setting. Methods Consecutive HCV patients (treatment-naive or interferon-based failures) attending Vall d'Hebron Hospital outpatient clinics from February 2015 to May 2016 ( N =1473) were included in the study. Patient samples were characterized using HCV subtyping by next-generation ultra-deep pyrosequencing. Results The following genotypes (G) were found: G1 (1126/1473 (76.4%)), G4 (145/1473 (9.8%)), G3 (135/1473 (9.2%)), G2 (51/1473 (3.5%)), and G5 (1/1473 (0.1%)). Twenty-two subtypes were seen: 1b (790/1473 (53.6%)), 1a (332/1473 (22.5%)), 3a (133/1473 (9.0%)), 4d (105/1473 (7.1%)), 4a (29/1473 (2.0%)), and 2c (25/1473 (1.7%)), with 16 low-prevalence subtypes accounting for the remaining 3.0% (44/1473). There was a worrisome 1.0% (15/1473) of mixed infections. G2 (51/1473 (3.5%)) showed a high level of heterogeneity. Analyses by age groups showed a predominance of G1b over G1a (428/506 (84.6%) vs. 24/506 (4.7%)) in patients born before 1950 ( N =506/1473), and similar percentages of these subtypes in those born between 1951 and 1975 ( N =834/1473) (315/834, 37.8% vs. 266/834, 31.9%) and after 1976 ( N =133/1473) (47/133, 35.3% vs. 42/133, 31.6%). Conclusions Subtype distribution showed a higher level of heterogeneity than was expected, particularly for G2. Prevalence of mixed infections was around 1%. HCV subtype distribution related to patient age group suggested that patients born from 1936 to 1975 in our setting should undergo screening for the infection. Next-generation sequencing enabled better classification of candidates for DAA-based treatment.

The specific drugs available for chronic hepatitis B infection include standard and pegylated IFN-α, and nucleoside/nucleotide analogs that directly inhibit the reverse transcriptase. The main goal of current hepatitis B virus therapy is to achieve sustained suppression of viral replication to prevent the development of chronic liver disease, but favorable long-term tolerability and resistance profiles are also desirable. This article reviews the chemistry and the mechanisms of action of tenofovir disoproxil fumarate, but it also focuses on the related clinical trails designed to date, in which clinical efficacy has been analyzed attending to HBe antigen status. In addition, studies including patients that have been previously treated with lamivudine or adefovir are discussed.

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 158months. 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.

Aliment Pharmacol Ther 2010; 32: 97–104 Summary Background Some patients continue to have detectable HBV-DNA levels with liver disease progression after hepatitis B e antigen (HBeAg) loss. It is important to identify these patients, candidates for long-term treatment. Aims To evaluate hepatitis B virus (HBV) genotype and the main mutations in the basic core promoter (BCP, A1762T/G1764A) and precore (G1896A) sequences as markers of persistent HBV-DNA after HBeAg loss. Methods We analysed 60 serum samples from 20 Caucasian, HBeAg-positive, chronic hepatitis B patients, who lost HBeAg and were followed-up longitudinally. HBV genotype and precore and BCP mutations were determined before, at the time of, and after HBeAg loss. Results After HBeAg loss, eight (40%) patients continued to have undetectable HBV-DNA and 12 (60%) had persistent HBV-DNA (median level 4.7 log10 copies/mL). The presence of BCP mutations prior to therapy was the only variable associated with persistently detectable viraemia (P = 0.017). Four patients with genotype A and no mutations in the BCP region experienced hepatitis B surface antigen (HBsAg) loss after a mean period of 35 months from baseline. Conclusions Main BCP mutations in HBeAg-positive patients are useful markers to identify patients who will not have sustained virological suppression after HBeAg loss and therapy discontinuation and could benefit from long-term treatment.

Background/Aims The frequency of mixed hepatitis B virus (HBV) genotypes in chronic HBV (CHB) and genotype changes during natural disease evolution and as a result of antiviral therapy were investigated. Methods Serum samples from 103 CHB patients were included in a cross-sectional study. Longitudinal study of HBV genotypes was performed in 22 patients, 17 of them under antiviral therapy (lamivudine and/or adefovir). HBV genotyping was done by the INNO-LiPA HBV assay. Results Genotypes observed in the cross-sectional study: A 32% of cases, D 42%, C 2%, F 2%, and mixed genotypes 22% (mainly A/D, followed by A/G). Genotype G was found in 7% of patients, always combined with other genotypes. In the longitudinal study, genotype changes were observed only in treated patients (9 cases). Genotype A strains were positively selected in 6 of them, mainly as mixed A/D. In 6 patients, selection coincided with a decrease in HBV-DNA levels. Conclusions A high frequency of mixed HBV genotypes was observed in our setting. Selection of genotype A strains during treatment is likely an indication that sensitivity to therapy differs between genotypes A and D. The absence of changes in untreated patients suggests that HBV genotype is stable without external factors.

BACKGROUND Acute and chronic hepatitis E have been associated with high mortality and development of cirrhosis, particularly in solid-organ recipients and patients infected by human immunodeficiency virus. However, data regarding the epidemiology of hepatitis E in special populations is still limited. AIMS Investigate seroprevalence and possible factors associated with HEV infection in a large cohort of immunosuppressed patients. METHODS Cross-sectional study testing IgG anti-HEV in serum samples from 1373 consecutive individuals: 332 liver-transplant, 296 kidney-transplant, 6 dual organ recipients, 301 non-transplanted patients with chronic liver disease, 238 HIV-infected patients and 200 healthy controls. RESULTS IgG anti-HEV was detected in 3.5% controls, 3.7% kidney recipients, 7.4% liver transplant without cirrhosis and 32.1% patients who developed post-transplant cirrhosis (p

SUMMARY. Hepatitis delta is considered the most severe form of viral hepatitis, but variables associated with disease progression are poorly defined. This study aimed to identify risk factors associated with worse clinical outcome in patients with hepatitis delta and to develop a clinical score to determine their risk of experiencing liverrelated morbidity or mortality. We followed 75 HBsAg– anti-HDV-positive patients with hepatitis delta for up to 16 years (median 5 years). The baseline-event-anticipation score (BEA score) was developed based on variables associated with the development of liver-related clinical complications. Age, region of origin, presence of cirrhosis, albumin, INR, hyperbilirubinemia and thrombocytopenia were all associated with the development of an event in the training cohort. The BEA score included age, sex, region of origin, bilirubin, platelets and INR. Points were allocated according to hazard ratios, and three risk groups were defined: BEA-A mild risk, BEA-B moderate risk and BEA-C high risk. Hazard ratios of BEA-B and BEA-C patients for liver-related clinical endpoints were 9.01 and 25.27 vs BEA-A with an area under curve of the receiving operating characteristic curve of 0.88. The accuracy of the BEA score was confirmed in two independent validation cohorts followed in Barcelona (n = 77) and D€ (n = 62). Delta hepatitis is associated with a very severe long-term outcome. The BEA score is easy to apply and predicts with a very high accuracy the development of liver-related complications in patients with hepatitis delta.

Background HCV is a major cause of morbidity and mortality in HIV-coinfected patients. Several observational studies have suggested that HCV response to pegylated interferon and ribavirin is lower in HIV-coinfected patients treated with abacavir. It has been postulated that abacavir could compete with ribavirin to be phosphorylated, leading to a reduction in the active form of the drug (triphosphorylated ribavirin). Here, we studied the effect of abacavir, tenofovir or lamivudine addition on the suppressive activity of ribavirin in an HCV RNA replicon system. Methods We used the human hepatoma HuH-7 cell clone 9B containing the HCV genotype 1b replicon I389/ NS3-3’. Cells were treated for 24 h with ribavirin (0, 10 and 50 μM) plus abacavir, tenofovir or lamivudine at doses of 0, 10 and 50 μM and HCV RNA production was quantified by real-time PCR in triplicate assays. Results were expressed as mean ±sd of the HCV RNA produced per cell (log10 IU/cell). Means were compared using the Student's t-test. Results Ribavirin treatment produced a dose-dependent suppression of HCV RNA production by the replicon system. Combination of ribavirin and interferon resulted in an additive antiviral activity. The addition of abacavir did not modify the suppressive activity of ribavirin on the replicon HCV RNA expression. Similar results were obtained when ribavirin was used in combination with tenofovir or lamivudine. Conclusions In a subgenomic HCV RNA replicon system, the antiviral effect of ribavirin was not modified by the addition of abacavir, tenofovir or lamivudine.

Background & Aims This study presents a real-time reverse-transcription PCR (rt-RT-PCR) assay for hepatitis delta virus (HDV) RNA quantification, designed to clarify the interplay between HDV and hepatitis B virus (HBV) in chronic infection. Methods Serum HDV-RNA and HBV-DNA were analysed by rt-RT-PCR in a cross-sectional study of 37 untreated chronic HDV patients, 25 of whom were also longitudinally studied. Results In the cross-sectional study, both viruses were active in 15 (40.5%) patients and inactive in 4 (10.8%); HDV alone was active in 12 (32.4%) and HBV in 6 (16.2%). The longitudinal study showed seven replication profiles, with considerable fluctuating activity of one or both viruses, including alternating predominance. In 20% of cases, longitudinal HBV/HDV viral loads differed from cross-sectional results, indicating a risk of misinterpreting HBV/HDV interactions when assessing a single determination. Fluctuating HBV replication only increased in the presence of fluctuating HDV activity. HBsAg levels, stable in HBV single infection, fluctuated in HDV chronic infection. The results of both the cross-sectional and longitudinal study call into question the major suppressor effect of HDV over HBV, revealing an important role of HBV. Conclusions Longitudinal evaluation of viremia shows a complex interaction between HBV and HDV and is essential to understand the pathophysiology of chronic HDV infection.

Backgrounds/Aims Hepatitis B virus (HBV) reactivation following treatment with rituximab has been reported in patients with either HBsAg-positive, or HBsAg-negative and anti-HBc positive infection. Patients with severe reactivation often have a fatal outcome despite treatment with lamivudine. The use of entecavir has not been reported in patients with severe HBV reactivation. Methods We present a case of a HBsAg-negative patient diagnosed with chronic lymphocytic leukemia who received a chemotherapeutic regimen that included rituximab, who subsequently presented with severe HBV reactivation with ascites, jaundice and coagulopathy and was treated with entecavir. A review of the literature and underlying HBV associated mutations are discussed. Results Entecavir produced a rapid and sustained suppression of HBV that was associated with rapid clinical improvement without any side effects. Conclusion Entecavir is an efficacious and safe treatment for severe HBV reactivation.

Serious adverse events (SAEs) 33 (32.4%) Premature discontinuation 33 (32.4%) Due to SAEs 10 (9.8%) Discontinuing patient care 3 (2.9%) Virological failure 20 (10.6%) Death Septic shock, Multi-organ failure secondary to pneumonia 2 (1.96%) Dose modification (PegIFN) 8 (7.8%) Infection Grade 3–4 5 (4.9%) Hepatic decompensation (Grade 3/4) 4 (3.9%) Anaemia Hg

Background HBV variants rtA181V/T, rtN236T and rtI233V, which confer resistance to adefovir dipivoxil (ADV), are not detected in many non-responding patients. Virological characteristics useful for predicting response have not been clearly elucidated. We determined pre-treatment virological markers to predict non-response and possible emergence of new variants during therapy. Methods This longitudinal study included 41 patients with chronic hepatitis B virus (HBV) infection receiving ADV monotherapy or ADV plus lamivudine (3TC). A fragment of HBV polymerase including catalytic domains was analysed for ADV-resistant variants. Results Complete virological response (CVR; HBV DNA10 copies/ml) was observed in 15 (36.6%) patients and partial virological response (PVR; HBV DNA10 copies/ml) in 23 (56.1%) patients. On multivariate analyses, hepatitis B e antigen (HBeAg) status was independently associated with CVR (hazard ratio [HR]=0.27, P=0.002) and PVR (HR=0.21, PConclusions Virological pretreatment characteristics (HBeAg, viral genotype and rtL217R polymorphism) are potentially associated with ADV response. HBV polymerase structural modelling has provided a hypothesis to explain the molecular mechanism for ADV resistance associated with rtR217.