Assessment of hepatitis B virus infection and interhost cellular responses using intrahepatic cholangiocyte organoids.

The intrahepatic cholangiocyte organoids (ICOs) model was evaluated for host differences in hepatitis B virus (HBV) infection, cellular responses, antiviral and immunomodulator responses. Twelve ICOs generated from liver resections and biopsies were assessed for metabolic markers and functional HBV entry receptor expression throughout differentiation. Structural changes relevant to HBV infection were characterized using histology, confocal, and electron microscopy examinations. Optimal ICO culture conditions for HBV infection using HepAD38 (genotype D) and plasma-derived HBV (genotype B and C) were described. HBV infection was confirmed using HBcAg immunostaining, qRT-PCR (RNA, covalently closed circular DNA [cccDNA], extracellular DNA) and ELISA (HBsAg and HBeAg). Drug response to antiviral and immunosuppressive agent, and cellular responses (interferon-stimulated genes [ISG]) to interferon-α and viral mimic (PolyI:C) were assessed. ICOs underwent metabolic and structural remodeling following differentiation. Optimal HBV infection was achieved in well-differentiated ICOs using spinoculation, with time and donor-dependent increase in HBV RNA, cccDNA, extracellular DNA, HBeAg and HBsAg. Donor-dependent drug responsiveness to entry inhibitor and JAK inhibitor was observed. Despite having a robust ISG response to interferon-α and PolyI:C, HBV infection in ICOs did not upregulate ISGs. Human ICOs support HBV infection and replication with donor-dependent variation in viral dynamics and cellular responses. These features can be utilized for the development of personalized drug testing platform for antivirals.

Cost-Effectiveness of Tenofovir Alafenamide for Treatment of Chronic Hepatitis B in Canada.

BACKGROUND/AIM: Tenofovir alafenamide (TAF) has been approved for treating chronic hepatitis B (CHB) due to a proposed better safety profile in comparison with current therapies. We evaluated the cost effectiveness of TAF and other available treatment options for hepatitis B envelope antigen (HBeAg)-positive and HBeAg-negative CHB patients from a Canadian provincial Ministry of Health perspective. METHODS: A state-transition model based on the published literature was developed to compare treatment strategies involving entecavir (ETV), tenofovir disoproxil fumarate (TDF), and TAF. It adopted a lifetime time horizon. Outcomes measured were predicted number of liver-related deaths, costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs). RESULTS: For HBeAg-positive patients, TAF followed by ETV generated an additional 0.16 QALYs/person at an additional cost of Can$14,836.18 with an ICER of Can$94,142.71/QALY compared with TDF followed by ETV. Of the iterations, 28.7% showed that it is the optimal strategy with a Can$50,000 willingness-to-pay threshold. For HBeAg-negative patients, ETV followed by TAF would prevent an additional 13 liver-related deaths per 1000 CHB patients compared with TDF, followed by ETV. It generated an additional 0.13 QALYs/person at an additional cost of Can$59,776.53 with an ICER of Can$461,162.21/QALY compared with TDF, followed by ETV. TAF-containing strategies are unlikely to be a rational choice in either case. The results were sensitive to the HBeAg seroconversion rates and viral suppression rates of the treatments. CONCLUSIONS: Our analysis suggests that TAF is not cost effective at its current cost. A 33.4% reduction in price would be required to make it cost effective for HBeAg-positive patients with a Can$50,000 willingness-to-pay threshold.

First line nucleos(t)ide analog monotherapy is more cost-effective than combination strategies in hepatitis B e antigen-positive chronic hepatitis B patients in China.

BACKGROUND: Nucleos(t)ide analog (NA) in combination with peginterferon (PegIFN) therapy in patients with hepatitis B e antigen (HBeAg)-positive chronic hepatitis B (CHB) shows better effectiveness than NA monotherapy in hepatitis B surface antigen loss, termed "functional cure," based on previous published studies. However, it is not known which strategy is more cost-effective on functional cure. The aim of this study was to analyze the cost-effectiveness of first-line monotherapies and combination strategies in HBeAg-positive CHB patients in China from a social perspective. METHODS: A Markov model was developed with functional cure and other five states including CHB, compensated cirrhosis, decompensated cirrhosis, hepatocellular carcinoma, and death to assess the cost-effectiveness of seven representative treatment strategies. Entecavir (ETV) monotherapy and tenofovir disoproxil fumarate (TDF) monotherapy served as comparators, respectively. RESULTS: In the two base-case analysis, compared with ETV, ETV generated the highest costs with $44,210 and the highest quality-adjusted life-years (QALYs) with 16.78 years. Compared with TDF, treating CHB patients with ETV and NA - PegIFN strategies increased costs by $7639 and $6129, respectively, gaining incremental QALYs by 2.20 years and 1.66 years, respectively. The incremental cost-effectiveness ratios were $3472/QALY and $3692/QALY, respectively, which were less than one-time gross domestic product per capita. One-way sensitivity analysis and probabilistic sensitivity analyses showed the robustness of the results. CONCLUSION: Among seven treatment strategies, first-line NA monotherapy may be more cost-effective than combination strategies in HBeAg-positive CHB patients in China.

Updated CDC recommendations for the management of hepatitis B virus-infected health-care providers and students.

This report updates the 1991 CDC recommendations for the management of hepatitis B virus (HBV)-infected health-care providers and students to reduce risk for transmitting HBV to patients during the conduct of exposure-prone invasive procedures (CDC. Recommendations for preventing transmission of human immunodeficiency virus and hepatitis B virus to patients during exposure-prone invasive procedures. MMWR 1991;40[No. RR-8]). This update reflects changes in the epidemiology of HBV infection in the United States and advances in the medical management of chronic HBV infection and policy directives issued by health authorities since 1991. The primary goal of this report is to promote patient safety while providing risk management and practice guidance to HBV-infected health-care providers and students, particularly those performing exposure-prone procedures such as certain types of surgery. Because percutaneous injuries sustained by health-care personnel during certain surgical, obstetrical, and dental procedures provide a potential route of HBV transmission to patients as well as providers, this report emphasizes prevention of operator injuries and blood exposures during exposure-prone surgical, obstetrical, and dental procedures. These updated recommendations reaffirm the 1991 CDC recommendation that HBV infection alone should not disqualify infected persons from the practice or study of surgery, dentistry, medicine, or allied health fields. The previous recommendations have been updated to include the following changes: no prenotification of patients of a health-care provider's or student's HBV status; use of HBV DNA serum levels rather than hepatitis B e-antigen status to monitor infectivity; and, for those health-care professionals requiring oversight, specific suggestions for composition of expert review panels and threshold value of serum HBV DNA considered "safe" for practice (<1,000 IU/ml). These recommendations also explicitly address the issue of medical and dental students who are discovered to have chronic HBV infection. For most chronically HBV-infected providers and students who conform to current standards for infection control, HBV infection status alone does not require any curtailing of their practices or supervised learning experiences. These updated recommendations outline the criteria for safe clinical practice of HBV-infected providers and students that can be used by the appropriate occupational or student health authorities to develop their own institutional policies. These recommendations also can be used by an institutional expert panel that monitors providers who perform exposure-prone procedures.

Tenofovir disoproxil fumarate for the treatment of chronic hepatitis B infection.

This paper presents a summary of the evidence review group (ERG) report into the clinical effectiveness and cost-effectiveness of tenofovir disoproxil fumarate for the treatment of chronic hepatitis B, in accordance with the licensed indication, based upon the evidence submission from Gilead to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal process. The submitted clinical evidence included two international randomised controlled trials (RCTs) comparing tenofovir with adefovir, and a mixed treatment comparison (MTC) using Bayesian methodology to compare tenofovir with other nucleos(t)ide analogues using direct and indirect RCT evidence. There were no statistically significant differences between tenofovir and adefovir in overall adverse events although, in hepatitis B 'e' antigen (HBeAg)-positive patients, there was a higher incidence of mild nausea in the tenofovir treatment group. The primary outcome, 'complete response', was a composite end point defined as histology response and hepatitis B virus DNA below 400 copies/ml. For both HBeAg-positive and HBeAg-negative patients, a significantly greater proportion had a complete response after 48 weeks with tenofovir than with adefovir. There was no statistically significant difference in histological response in either group of patients compared with adefovir. The MTC could only generate results for HBeAg positive nucleos(t)ide naive patients as there was insufficient evidence for other subgroups. The probability of achieving undetectable HBV DNA with tenofovir was found to be significantly higher than that for all other treatments considered in the analysis at the 0.05 level. The analysis demonstrated that there is a 98% probability that tenofovir is the most potent nucleos(t)ide in terms of this outcome. The manufacturer's submission concluded that tenofovir is a cost-effective option as first-line treatment. For HBeAg-positive patients, tenofovir followed by lamivudine has an incremental cost-effective ratio (ICER) of 9940 pounds per quality-adjusted life-year (QALY) gained, compared with lamivudine followed by tenofovir. A more appropriate treatment strategy of tenofovir followed by tenofovir plus lamivudine has an ICER of 13,619 pounds per QALY gained, compared with lamivudine followed by tenofovir. For HBeAg-negative patients, tenofovir followed by lamivudine has an ICER of 9811 pounds per QALY gained, compared with best supportive care. A more clinically appropriate treatment strategy of tenofovir followed by tenofovir plus lamivudine has an ICER of 13,854 pounds per QALY gained, compared with tenofovir followed by lamivudine. The ERG uncovered a number of errors in the submission and these ICERs approximately doubled when the analysis was corrected and reran. The guidance issued by NICE on 22 July 2009 states that tenofovir disoproxil, within its marketing authorization is recommended as an option for the treatment of people with chronic HBe-Ag-positive or HBe-Ag-negative hepatitis B in whom antiviral treatment is indicated.

Potential impact of long-term nucleoside therapy on the mortality and morbidity of active chronic hepatitis B.

UNLABELLED: The potential impact of long-term antiviral therapy on the burden of chronic hepatitis B has hardly been documented. The aim of this study was to estimate the effects of prolonged antiviral therapy and antiviral resistance on the mortality and morbidity of active chronic hepatitis B patients. A population cohort of chronic hepatitis B patients in the Netherlands was constructed and stratified according to 10-year age groups, prevalence of hepatitis B surface antigen, hepatitis B virus DNA level, alanine aminotransferase level, hepatitis B e antigen status, and presence of cirrhosis. A Markov model was created to mathematically simulate the cohort's progression through a finite series of health states. The analysis was performed on the basis of four scenarios: natural history, long-term therapy with a high-resistance profile drug without or with salvage, and therapy with a low-resistance profile drug. It has been estimated that there were 64,000 people (0.4%) suffering from chronic hepatitis B infection in the Netherlands in 2005, with 6521 (10%) of them having high viremia and elevated alanine aminotransferase levels. Within a 20-year period, 1725 (26%) of the 6521 patients in the active chronic hepatitis B cohort will die because of liver-related causes. Of the 5685 without cirrhosis at entry, 1671 (29%) will develop cirrhosis. Of those 836 with cirrhosis at entry, 619 (74%) will die within a 20-year period. If this active chronic hepatitis B cohort is fully detected and treated, mortality related to liver disease can be reduced by 80% if a low-resistance profile drug is chosen from the start. The effect is due to both the reduction in complications of cirrhosis and the prevention of the development of cirrhosis. CONCLUSION: Long-term antiviral therapy with a strategy that minimizes or controls resistance will have a major preventive effect on liver-related mortality and morbidity.

Current status of nucleoside antivirals in chronic hepatitis B.

Chronic hepatitis B is a serious disease both worldwide and in the United States. There are two types of drugs available to treat chronic hepatitis B virus (HBV) infection: interferons that boost the immune system, and antiviral or nucleoside analogues that are designed to interfere with HBV DNA to prevent its replication. This review focuses on nucleoside antivirals, namely lamivudine, entecavir and telbivudine, which are widely prescribed for patients with the disease, particularly lamivudine. Additionally, current Food and Drug Administration-approved nucleoside antivirals for hepatitis B will be briefly highlighted. Comparisons are performed based on previous clinical trials from primary sources. Treatments with entecavir and telbivudine are compared with lamivudine treatment in regard to pharmacotherapy, resistance and cost-effectiveness. Outcomes varied depending on each trial, but the main findings were more favorable for entecavir and telbivudine treatments than for lamivudine treatment. It was concluded that entecavir treatment is associated with better outcomes than lamivudine in the three aspects studied. Similarly, telbivudine showed more improvements than lamivudine in all three areas. Concomitant pharmacotherapy, especially in lamivudine-refractory patients, demonstrated significant improvement in the management of chronic hepatitis B. Furthermore, the availability of hepatitis B vaccines should enable us to prevent the occurrence of the disease.

[Evaluation of 5 kinds of China-made enzyme immunoassay kits for antibody to hepatitis B virus e antigen detection].

OBJECTIVE: The aim of this study is to select a better one from five EIA kits made in China for the serological detection of anti-HBe in a national hepatitis B survey. METHODS: Top 5 kinds of kits on the best seller list of China-made anti-HBe EIA detection were selected and each was detected the anti-HBe panel (66 positive and 88 negative) 5 times. The co/s ratio of each test was recorded and transformed by log(co/s+1). ICC and CV, the reliability indices and AUC, pAUC and Se(PR=e), the validity indices were calculated and compared between every two kits. RESULTS: The indices of ICC and CV of the 5 kinds of kits arranged in the same order of A, E, C, D and B, from the best to the worst. For ICC, there were significantly different between every two of them (Bootstrap method, P < 0.05), except for between kit C and E. The magnitude ofAUCs were from 0.969 to 0.996; the orders of pAUC and Se(FPR=e) indices was C, E, D, A, B, and C, D, E, B, A respectively; both the indices of kit C were significantly higher than others (Bootstrap method, P < 0.05). CONCLUSION: All the 5 kinds of kits are excellent and kit C is the best.

Cost-effectiveness of interferon-alpha 2b treatment for hepatitis B e antigen-positive chronic hepatitis B.

OBJECTIVE: To estimate the cost-effectiveness of interferon-alpha 2B for the treatment of patients with chronic hepatitis B infection who are positive for hepatitis B e antigen (HBeAg). DESIGN: Meta-analysis of nine randomized controlled trials and cost-effectiveness analysis, projecting the clinical and economic outcomes expected from changes in serologic markers of hepatitis B viral replication. DATA SOURCES: MEDLINE search, expert panel opinion, hospital cost data, and adjusted physician charges. PATIENTS: 552 patients with confirmed chronic hepatitis B infection who were positive for HBeAg. INTERVENTION: Interferon-alpha 2b. MEASUREMENTS: Lifetime incidence of cirrhosis and hepatocellular carcinoma; life expectancy; quality-adjusted life expectancy; and costs and marginal cost-effectiveness ratios from a societal perspective. RESULTS: Interferon-alpha 2b increases the likelihood of becoming negative for HBeAg from 9.1% to 45.6% (difference, 36.5%; 95% CI, 23.7% to 49.2%) and of becoming negative for hepatitis B surface antigen from 1.7% to 7.7% (difference, 6.0%; CI, 2.8% to 9.3%) in the first year. For a 35-year-old person with chronic hepatitis B who is HBeAg positive, our analysis suggests that interferon-alpha 2b will increase life expectancy by 3.1 years or 3.4 quality-adjusted life-years and will decrease projected lifetime costs, even if future savings are discounted; thus, interferon-alpha 2b is the dominant strategy. Even with the model biased strongly in favor of standard care, the marginal cost-effectiveness ratio of interferon did not exceed $12,000 per life-year gained. CONCLUSIONS: Interferon-alpha 2b should prolong life and lower costs for patients with chronic hepatitis B who are HBeAg positive.

Familial clustering of hepatitis B virus infections and prevention of perinatal transmission by immunization with a reduced number of doses in an area of intermediate endemicity (Tunisia).

Hepatitis B surface antigen (HBsAg) was detected in 3.3% of 7162 pregnant Tunisian women tested and HBeAg in 9.6% of the HBsAg-positive mothers. Family members of 46 of these HBsAg-positive mothers (33 husbands and 61 children aged 1-6 years) were investigated for the presence of HBV markers. HBsAg was detected in 21% of the children and 18% of the husbands. Fifty children born to HBsAg-positive mothers received hepatitis B vaccine at birth, at the age of 2-3 months and at the age of 9 months. After immunization, anti-HBs were detected in 92% of them with an anti-HBs geometric mean titre of 415 mIU ml-1. Compared with the HBsAg carrier state in older siblings, the protective efficacy was estimated to be 60%. It was 100% for infants born to HBeAg-negative mothers, but only 31% for those born to HBeAg-positive mothers. For a better efficacy, the schedule of the EPI needs to be modified to include an immunization session at 1 month of age.

Should pregnant urban south African women be screened for hepatitis B?

The prevalence of hepatitis B virus (HBV) infection in the South African urban obstetric population, which consists of white, black, coloured and Asian patients from different socio-economic, cultural and geographical backgrounds, is unknown. Routine screening performed in 3,469 urban pregnant women revealed that 42 patients were HBV surface antigen-positive (a prevalence of 1.21%). Only 2 patients (4.6%) were hepatitis B e antigen (HBeAg)-positive (0.06% of the entire cohort), whereas the remaining 40 were identified as hepatitis B e antibody-positive. Despite a significant increase in the numbers of black patients, there has not been an accompanying increase in the number of HBV carriers. Replicative infection was equally distributed among white and black pregnant women. Because the low prevalence of HBeAg results in lack of perinatal transmission and the prevention of a single case of neonatal hepatitis B infection is costly, we conclude that in South African urban hospitals, routine screening for hepatitis B is not cost-effective.

Epidemiologic assessment of interactions of hepatitis-C virus with seromarkers of hepatitis-B and -D viruses, cirrhosis and tobacco smoking in hepatocellular carcinoma.

A recently introduced enzyme immunoassay procedure for antibodies against the hepatitis-C virus (HCV) was used to test samples from 185 cases with hepatocellular carcinoma (HCC) and 432 hospital controls. The anti-HCV results were examined in conjunction with previously reported data from this study concerning hepatitis-B virus (HBV) serology, hepatitis-D virus (HDV) antibodies, presence of cirrhosis and tobacco smoking. There was evidence for interaction between HBV and HCV in the causation of HCC: as previously reported, the rate ratio (RR) linking the presence of anti-HCV to HCC among subjects positive for hepatitis-B surface antigen (HBsAg) was substantially higher than the corresponding RR among those negative for this marker; furthermore, among HCC patients positive for HBsAg, a high proportion (33/61) of those who were positive for hepatitis-Be antigen (HBeAg) or its antibody were positive for anti-HCV, whereas among HBsAg-positive controls who were also positive for HBeAg or its antibody, none was positive for anti-HCV (0/18; p less than 10(-4)). The anti-HCV-related RR for HCC was also higher among HCC patients with cirrhosis than among those without evidence of co-existing cirrhosis (RR 11.4 vs. 4.4; p = 0.06). In addition, there was some evidence of interaction between tobacco smoking and HCV in the origin of HCC; after controlling for age, sex and HBsAg status, the RR for subjects positive for anti-HCV was 6.8 among smokers but only 3.2 among non-smokers (p = 0.26). By contrast, there was no suggestion of an interaction between anti-HCV and anti-HDV, in agreement with the presumed minimal role, if any, of HDV in HCC etiology. These results support the notion that HCV is involved in the etiology of HCC by advancing, through a chronic liver disease process, carcinogenesis initiated by other factors.

Antenatal screening for hepatitis B is medically and economically effective in the prevention of vertical transmission: three years experience in a London hospital.

We describe our experience over a three-year period in the detection of antenatal patients with hepatitis B virus (HBV) carriage, and the successful prevention of vertical transmission in the infants of HBsAg-positive women. Nine of the 26 infants born to HBsAg-positive mothers were considered to be at high risk of infection. Eight of these nine remained HBsAg-negative after passive or passive/active immunization. The majority of infants tested had anti-HBs antibody titres above 10 i.u./l from the first month. In comparison with the cost of caring for patients with chronic hepatitis B infection and decompensated cirrhosis, non-selective testing of pregnant women for HBsAg is found to be cost effective.

An experimental assessment of the tampan tick Ornithodoros moubata as vector of hepatitis B virus.

Wild-caught and colonized tampan ticks, Ornithodoros moubata (Murray), were fed on hepatitis B virus (HBV)-positive blood-means in a series of four experiments. Hepatitis B surface antigen (HBsAg) persisted in nymphal and adult ticks for up to 779 days, while the epsmark antigen (HBeAg) persisted in mature nymphs up to 13 days, in adult males up to 11 days and in adult females up to 16 days. HBsAg was transmitted trans-stadially through two moults during the life cycle but transovarial transmission did not occur. The surface antigen was transmitted by two out of fifteen single ticks into 0.4 ml aliquots of HBV-negative blood, although six groups of ticks failed to transmit into 5.5 ml aliquots of blood: this antigen was not transmitted to hamsters. HBsAg was detected in samples of the ticks' coxal and rectal fluid secretions always at the infecting feed and usually at the second feed. HBeAg was only detected in one of two samples of coxal fluid collected at the infecting feed. The results as a whole indicate that no biological multiplication of virus occurs in O.moubata but that mechanical transmission from ticks to man could occur by: (i) contamination of a person when crushing infected ticks; (ii) infection by bite; (iii) contamination with coxal fluid, especially by scratching bites. This is thought to take place among the Kavango tribe in their village huts in north-eastern Namibia where infestations of infected O.moubata occur.

Assessment of infectiousness of male Malaysian blood donors.

HBeAg and anti-HBe were determined in the blood of 189 male blood donors. The incidence of HBsAg was 6.9% while that for HBeAg and anti-HBe was 1.6 and 18%, respectively. Of the 13 samples positive for HBsAg, two (15.4%) were positive for HBe while six (46.2%) were positive for anti-HBe. One specimen was negative for HBsAg but was positive for HBeAg and anti-HBe. The observations are discussed.

[Management of disease carriers]. / Gestione dei portatori.

In the present communication there are exposed the treatment modalities of health carriers. The difficulties of action depends primarily on scarcity of health education and of adequate structures and manufacturing equipment in the places of work.