Assessing and improving the quality of guideline-adherent hepatitis B virus care in people with HIV: A cross-sectional study.

The increasing use of non-tenofovir containing antiretroviral regimens calls for renewed attention to the prevention and management of hepatitis B virus (HBV) in people with HIV (PWH). We retrospectively assessed adherence to HBV guidelines, including complete HBV screening in PWH. In people with HIV/HBV co-infection, this included HBV therapy, screening for hepatitis delta virus (HDV) and on-therapy virologic response monitoring. HIV/HBV co-infection in PWH was defined as the presence of hepatitis B surface antigen (HBsAg) at the last measurement before study entry or detectable HBV-DNA for ≥6 months. After assessment, missing laboratory tests were performed to optimize HBV monitoring and screening for co-infections. Of all PWH under follow-up, 1484/1633 (90.9%) were adequately screened for HBV. After performing missing screening tests, 466 of 1618 PWH with complete screening results (28.8%) were non-immune for HBV infection. Fifty-one (3.2%) with HIV/HBV co-infection were identified. HBV treatment was adequate in 51/51 (100%). Screening for hepatitis A, C and delta virus antibodies and fibrosis was performed in 51/51 (100%), 49/51 (96.1%), 17/51 (35.3%) and 38/51 (74.5%). Annual HBV-DNA or HBsAg monitoring was done in 18/51 (35.3%) and hepatocellular carcinoma (HCC) surveillance in 2/9 (22.2%) of those indicated. Additional testing in those with missing data identified 4/34 (11.8%) persons with HDV antibodies and 3/30 (10%) with HBsAg seroclearance. Our study demonstrates the feasibility and added value of evaluating HBV care components and performing missing laboratory tests, identifying a large number of HBV vaccination candidates and HDV antibody screening, HBsAg monitoring and HCC surveillance as key areas for improvement.

REtrieval And cure of Chronic Hepatitis C (REACH): Results of micro-elimination in the Utrecht province.

BACKGROUND: The Netherlands is one of the six European countries considered on track to eliminate hepatitis C virus by 2030. To achieve this goal, continuous efforts have to be put into designing efficient case-finding strategies, including the retrieval of previously diagnosed hepatitis C virus-infected who are lost to follow-up. AIMS: To trace and treat all lost to follow-up hepatitis C virus patients in the Utrecht region and create an efficient retrieval strategy that can be used in future (national) retrieval initiatives. METHODS: Positive hepatitis C virus diagnostic tests (anti-hepatitis C virus IgG or hepatitis C virus-RNA) from the laboratory of all four hospitals and one central laboratory for primary care diagnostics in the province of Utrecht from 2001 to 2015 were linked to clinical records. Untreated patients with available contact information were deemed eligible for retrieval and invited for reevaluation with (virology) blood tests, fibroscan measurement and possible direct-acting antiviral therapy. MAIN RESULTS: After screening all hepatitis C virus diagnostics, 1913 chronic hepatitis C virus-infected were identified of which 14.1% (n = 269) were invited back into care. Overall, 17.4% was traced with the highest yield (28.3%) in those who lived in the Utrecht province. Through renewed patient assessments, 42 chronic hepatitis C virus infections were re-identified (76% with a history of intravenous drug use, 24% with Metavir F3-F4). Until now, 59% has either scheduled or initiated direct-acting antiviral therapy. CONCLUSION: The retrieval of previously diagnosed hepatitis C virus patients through screening of laboratory diagnostics from the past is feasible and should be pursued for further control and reduction of hepatitis C virus infection. Retrieval is most successful when performed regionally. LAY SUMMARY: To completely eliminate chronic hepatitis C virus (HCV) infection and prevent complications, undiagnosed and also previously diagnosed but lost to follow-up (LFU) HCV patients have to be brought (back) into care for therapy. Retrieval of LFU HCV patients through screening of laboratory diagnostics from the past is feasible and most successful when performed regionally.

Kinetics of Meningococcal Serogroup C-Specific Functional Antibody Levels Up to 15 Years after a Single Immunization with a Meningococcal Serogroup C Conjugate Vaccine during Adolescence.

Adolescent vaccination is now considered the key factor for offering direct protection against meningococcal disease but also for reducing carriage and transmission and, in this way, establishing herd protection. This study estimated age-dependent patterns in functional meningococcal serogroup C (MenC) antibody kinetics after primary MenC conjugate (MenCC) vaccination in adolescents. Serum samples (n = 1,676) were drawn from 2006 to 2011 from individuals aged 9 to 18 years at the time of primary MenCC vaccination in 2002. Functional antibody levels were measured with a serum bactericidal antibody assay (SBA) using rabbit complement. SBA titers gradually declined with time. Up to 9 years after primary vaccination, SBA titers were estimated to be higher in individuals who were aged 13 to 18 years at priming than in those who were aged 9 to 10 years at priming. Based on a linear mixed model, the higher functional antibody levels with age seem to be due to the achievement of higher peak levels upon vaccination rather than to lower rates of decline. It is estimated that 35 to 50% of individuals who received a single primary MenCC vaccination at an age of 9 to 18 years in 2002 will still have sufficient protective antibody levels 15 years later. Using a linear mixed model based on cohort data for a single dated serum sample per person, we were able to estimate the level of protection against MenC up to 15 years after a single vaccination. The current study shows that analysis of antibody kinetics can be done using cross-sectional serology data and is therefore relevant for future serosurveillance studies.

The hepatitis C virus nonstructural protein 3 Q80K polymorphism is frequently detected and transmitted among HIV-infected MSM in the Netherlands.

OBJECTIVES: The Q80K polymorphism is a naturally occurring resistance-associated variant in the hepatitis C virus (HCV) nonstructural protein 3 (NS3) region and is likely transmissible between hosts. This study describes the Q80K origin and prevalence among HCV risk groups in the Netherlands and examines whether Q80K is linked to specific transmission networks. DESIGN AND METHODS: Stored blood samples from HCV genotype 1a-infected patients were used for PCR and sequencing to reconstruct the NS3 maximum likelihood phylogeny. The most recent common ancestor was estimated with a coalescent-based model within a Bayesian statistical framework. RESULTS: Study participants (n = 150) were either MSM (39%), people who inject drugs (17%), or patients with other (15%) or unknown/unreported (29%) risk behavior. Overall 45% was coinfected with HIV. Q80K was present in 36% (95% confidence interval 28-44%) of patients throughout the sample collection period (2000-2015) and was most prevalent in MSM (52%, 95% confidence interval 38-65%). Five MSM-specific transmission clusters were identified, of which three exclusively contained sequences with Q80K. The HCV-1a most recent common ancestor in the Netherlands was estimated in 1914 (95% higher posterior density 1879-1944) and Q80K originated in 1957 (95% higher posterior density 1942-1970) within HCV-1a clade I. All Q80K lineages could be traced back to this single origin. CONCLUSION: Q80K is a highly stable and transmissible resistance-associated variant and was present in a large part of Dutch HIV-coinfected MSM. The introduction and expansion of Q80K variants in this key population suggest a founder effect, potentially jeopardizing future treatment with simeprevir.

Resistance-associated polymorphisms in Dutch hepatitis C genotype 1a patients with and without HIV infection.

UNLABELLED:  Background and aim. Resistance-associated variants (RAVs) on the NS3 region of the hepatitis C virus (HCV) may be relevant for antiviral therapy, but data in human immunodeficiency virus (HIV) coinfected patients are scarce. We assessed frequencies of NS3 RAVs in patients infected with HCV genotype 1a with or without HIV coinfection. MATERIAL AND METHODS: HCV NS3 amino acids 1-181 were sequenced by the Sanger method and analyzed for RAVs. RAVs and their distribution between HCV genotype 1a clade I and II viruses were compared between HIV-infected versus HIV-uninfected patients. RESULTS: 148 samples were available (n = 68 HIV and n = 80 non-HIV). Relative frequency of clade I and clade II was significantly different between HIV (85% and 15%) and non-HIV groups (49% and 51%). Overall, HIV infected patients exhibited significantly lower prevalence of RAVs than HIV-uninfected patients (62% vs. 79%, p = 0.03). However, Q80K prevalence was significantly higher in HIV-infected subjects (50% vs. 24%, p = 0.001), whereas prevalence of S122D/G/N/S (2% vs. 16%, p = 0.002) and N174G/N/S (10% vs. 55%, p < 0.0001) polymorphisms were significantly lower. Q80K was found exclusively in clade I viruses. S122 (3% vs. 22%, p=0.001) and N174 (13% vs. 75%, p<0.0001) polymorphisms had significantly lower prevalence in clade I than clade II viruses. CONCLUSIONS: In the Netherlands, prevalence of clade I viruses and Q80K was significantly higher in HCV genotype 1a infected patients with HIV coinfection than in those without HIV coinfection. Prevalence of N174 and S122 polymorphisms was significantly higher in clade II than clade I viruses.

Mumps-specific cross-neutralization by MMR vaccine-induced antibodies predicts protection against mumps virus infection.

BACKGROUND: Similar to other recent mumps genotype G outbreaks worldwide, most mumps patients during the recent mumps genotype G outbreaks in the Netherlands had received 2 doses of measles, mumps and rubella (MMR) vaccine during childhood. Here, we investigate the capacity of vaccine-induced antibodies to neutralize wild type mumps virus strains, including mumps virus genotype G. METHODS: In this study, we tested 105 pre-outbreak serum samples from students who had received 2 MMR vaccine doses and who had no mumps virus infection (n=76), symptomatic mumps virus infection (n=10) or asymptomatic mumps virus infection (n=19) during the mumps outbreaks. In all samples, mumps-specific IgG concentrations were measured by multiplex immunoassay and neutralization titers were measured against the Jeryl Lynn vaccine strain and against wild type genotype G and genotype D mumps virus strains. RESULTS: The correlation between mumps-specific IgG concentrations and neutralization titers against Jeryl Lynn was poor, which suggests that IgG concentrations do not adequately represent immunological protection against mumps virus infection by antibody neutralization. Pre-outbreak neutralization titers in infected persons were significantly lower against genotype G than against the vaccine strain. Furthermore, antibody neutralization of wild type mumps virus genotype G and genotype D was significantly reduced in pre-outbreak samples from infected persons as compared with non-infected persons. No statistically significant difference was found for the vaccine strain. The sensitivity/specificity ratio was largest for neutralization of the genotype G strain as compared with the genotype D strain and the vaccine strain. CONCLUSIONS: The reduced neutralization of wild type mumps virus strains in MMR vaccinated persons prior to infection indicates that pre-outbreak mumps virus neutralization is partly strain-specific and that neutralization differs between infected and non-infected persons. Therefore, we recommend the use of wild type mumps virus neutralization assays as preferred tool for surveillance of protection against mumps virus infection.

Effects of prophylactic and therapeutic paracetamol treatment during vaccination on hepatitis B antibody levels in adults: two open-label, randomized controlled trials.

UNLABELLED: Worldwide, paracetamol is administered as a remedy for complaints that occur after vaccination. Recently published results indicate that paracetamol inhibits the vaccination response in infants when given prior to vaccination. The goal of this study was to establish whether paracetamol exerts similar effects in young adults. In addition, the effect of timing of paracetamol intake was investigated. In two randomized, controlled, open-label studies 496 healthy young adults were randomly assigned to three groups. The study groups received paracetamol for 24 hours starting at the time of (prophylactic use) - or 6 hours after (therapeutic use) the primary (0 month) and first booster (1 month) hepatitis B vaccination. The control group received no paracetamol. None of the participants used paracetamol around the second booster (6 months) vaccination. Anti-HBs levels were measured prior to and one month after the second booster vaccination on ADVIA Centaur XP. One month after the second booster vaccination, the anti-HBs level in the prophylactic paracetamol group was significantly lower (p = 0.048) than the level in the control group (4257 mIU/mL vs. 5768 mIU/mL). The anti-HBs level in the therapeutic paracetamol group (4958 mIU/mL) was not different (p = 0.34) from the level in the control group. Only prophylactic paracetamol treatment, and not therapeutic treatment, during vaccination has a negative influence on the antibody concentration after hepatitis B vaccination in adults. These findings prompt to consider therapeutic instead of prophylactic treatment to ensure maximal vaccination efficacy and retain the possibility to treat pain and fever after vaccination. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN03576945.

Mumps serum antibody levels before and after an outbreak to assess infection and immunity in vaccinated students.

BACKGROUND: Since 2009, various mumps outbreaks have occurred in the Netherlands, affecting mostly young adults vaccinated against mumps. In this retrospective study, we estimated attack rates for symptomatic and asymptomatic mumps virus infection based on mumps-specific immunoglobulin (Ig)G concentrations in paired blood samples obtained before and after the mumps outbreaks, collected in 2 university cities. We aimed to identify a serological correlate of immune protection and risk factors for mumps virus infection. METHODS: Mumps-specific IgG levels were measured by Luminex technology in paired pre- and post-outbreak samples from students from Leiden (n = 135) and Utrecht (n = 619). Persons with a 4-fold increase in mumps IgG concentrations or mumps IgG concentrations >1500 RU/mL were assumed to have had a mumps virus infection. RESULTS: Attack rates for symptomatic and asymptomatic mumps virus infection were 2.0% and 3.8%, respectively. Pre-outbreak mumps-specific IgG concentrations were lower among cases than among noncases (P = .005) despite vaccination history, but no serological cutoff for immune protection could be established. Mumps among housemates was significantly associated with serological evidence for mumps virus infection (odds ratio, 7.25 [95% confidence interval, 3.20-16.40]; P < .001). CONCLUSIONS: Symptomatic and asymptomatic mumps virus infections in vaccinated persons can be identified by retrospective assessment of mumps-specific IgG antibodies in blood samples.

Measuring ribavirin concentrations during the earliest stages of antiviral therapy for hepatitis C: potential relevance for treatment outcome.

BACKGROUND: Correlations between ribavirin (RBV) concentrations and sustained virological response (SVR) to hepatitis C virus treatment have been demonstrated previously. As steady state is reached after several weeks of RBV treatment, dose modifications based on steady-state levels can only be applied relatively late in treatment, possibly too late to influence SVR rates. The authors aimed to determine whether measurement of early concentrations is useful to predict optimal steady-state RBV concentrations. METHODS: In 61 treatment-naive genotype 1/4 patients RBV concentrations were determined in samples collected after 1, 2, 4, 8, 12, and 24 weeks of therapy. RBV concentrations were compared between responders and nonresponders; Receiver Operating Characteristic analyses were conducted to find optimal cut-off values to predict week 8 concentrations from earlier measurements. RESULTS: Median week 8 RBV concentrations were significantly higher in patients with SVR compared with those without: 3.4 (interquartile range 2.4-3.9) versus 2.6 (interquartile range 2.0-3.5) mg/L (P < 0.05). RBV concentration at week 8 was an independent predictor of SVR [adjusted odds ratio 2.3 (95% confidence interval: 1.1-4.9; P = 0.03)]. The optimal cut-off value of week 8 RBV concentration to predict SVR was 2.20 mg/L [sensitivity 87%, specificity 40%, positive predictive value 64%, negative predictive value 71%]. Optimal cut-off values at weeks 1, 2, or 4 to predict an RBV concentration ≥2.20 mg/L at week 8 were 0.92, 1.29, and 1.67 mg/L, respectively, with positive predictive values and negative predictive values ranging from 88% to 91% and 71% to 86%, respectively. CONCLUSIONS: RBV concentrations in the earliest stages of antiviral therapy predict therapeutic steady-state concentrations, allowing timely dose adjustments with potential implications for treatment outcome.

A genome-wide association study of hepatitis B vaccine response in an Indonesian population reveals multiple independent risk variants in the HLA region.

We performed a two-stage genome-wide association study (GWAS) of antibody titer in 3614 hepatitis B vaccine recipients from Indonesia's Riau Archipelago, leading to the identification of at least three independent signals within the human leukocyte antigen (HLA) complex. These appear to implicate HLA-DR [rs3135363; P= 6.53 × 10(-22); odds ratio (OR) = 1.53, 95% confidence interval (CI) = 1.35-1.74]; HLA-DP, previously associated with the risk of chronic hepatitis B infection (rs9277535; P= 2.91 × 10(-12); OR = 0.72, 95% CI = 0.63-0.81); and a gene rich HLA Class III interval (rs9267665; P = 1.24 × 10(-17); OR = 2.05, CI = 1.64-2.57). The substantial overlap of these variants and those identified by GWAS of chronic hepatitis B infection confirms vaccine response as a model for infection, while suggesting that the vaccine is least effective in those most at risk of lifelong infection, following exposure to the virus.

No influence of haemodialysis on interferon production in the QuantiFERON-TB Gold-In-Tube test.

BACKGROUND: Immunodeficiency in end-stage renal disease (ESRD) can be aggravated by haemodialysis (HD). This results in an increased incidence of reactivation of tuberculosis (TB) in HD patients. The tuberculin skin test to detect a latent TB infection (LTBI) has its limitations in these patients because of a high rate of false negative results due to anergy of T cells. Data on the influence of HD on the performance of interferon-gamma release assays are limited. The aim of this study was to determine the effect of HD on the performance of the QuantiFERON-TB Gold (QFT-G) assay in ESRD patients before, during and after the HD session. METHODS: In HD patients older than 18 years without immunosuppressive medication or other immunocompromising conditions, the QFT-G assay was performed just before starting HD, 30 minutes after start and immediately after the finish of the HD session. RESULTS: Twenty patients were included. No statistically significant differences were found in interferon-gamma production in the nil- and antigen tubes between pre-HD, during and after HD. In 1 patient the predialysis result was indeterminate (one of 60 samples, 1.67%). In all 3 patients with a history of LTBI, the QFT-G test tube results were positive at all time points. In the other 16 patients, all test tubes showed negative results. CONCLUSIONS: The QFT-G assay could be a useful test for the evaluation of the immunological response against Mycobacterium tuberculosis in HD patients. The time point of blood sampling does not seem to affect the interpretation of test results.

Suboptimal endogenous erythropoietin response in chronic hepatitis C patients during ribavirin and PEG interferon treatment.

BACKGROUND: During the treatment of hepatitis C, anaemia may necessitate pegylated-interferon and ribavirin dose reductions with reduced sustained viral response rates. Although erythropoietic growth factors are frequently used to improve anaemia, it is controversial whether endogenous erythropoietic response is insufficient under these circumstances. We aimed to identify risk factors for more pronounced anaemia and to evaluate endogenous erythropoietic response during antiviral therapy. METHODS: One hundred and forty-five naive chronic hepatitis C patients on pegylated-interferon-ribavirin treatment were evaluated for haemoglobin, haematocrit, serum ribavirin and erythropoietin levels. RESULTS: About 99% of patients developed anaemia, with maximal decrease in haemoglobin of 2.5 ± 1.0 mmol/l (range 0.3-5.5 mmol/l). Older age, lower baseline creatinine clearance, higher baseline haemoglobin, more pronounced haemoglobin decrease after 2 weeks and higher week 24 serum ribavirin concentrations were independent risk factors for more pronounced anaemia. Serum erythropoietin levels increased from median 12 IU/l (range 4-63 IU/l) at baseline to 41 IU/l (range 12-683 IU/l) after 12 weeks of therapy and to 43 IU/l (range 7-3238 IU/l) at week 24 (P<0.001). Erythropoietin levels at baseline, week 12 and week 24 negatively correlated with haematocrit. The erythropoietic response to anaemia in our study population was significantly different from the normal human response to anaemia. CONCLUSION: Older age, lower baseline creatinine clearance, higher baseline haemoglobin, more pronounced haemoglobin decrease after 2 weeks and higher week 24 serum ribavirin concentrations were independent risk factors for more pronounced anaemia during antiviral therapy. Endogenous erythropoietin production is suboptimal during antiviral therapy, supporting use of erythropoietic growth factors.

Intradermal hepatitis B vaccination in non-responders after topical application of imiquimod (Aldara).

BACKGROUND: Five to ten percent of immunocompetent persons fail to develop a protective immune response to hepatitis B vaccination, and are defined non-responders (NR). We investigated the immune response to intradermal hepatitis B vaccination after pre-treatment of the skin with the TLR7 agonist imiquimod. METHODS: Twenty-one non-responders (anti-HBs <10 IU/l after at least 6 intramuscular hepatitis B vaccinations) were randomly assigned to the control group (N=11) or the experimental group (N=10). Participants in both groups received 3 intradermal (ID) vaccinations with 5 microg HBsAg (0.125 mL) at 0, 1 and 6 months. In the experimental group, the dermal site of injection was pre-treated with 250 mg imiquimod ointment. Anti-HBs antibodies were determined at 0, 1, 2, 6 and 7 months. RESULTS: In both study groups, 70% of the participants developed a protective immune response (anti-HBs >or=10 IU/l), after the 3rd intradermal vaccination. CONCLUSION: The application of imiquimod on the skin prior to intradermal vaccination did not enhance the humoral response to hepatitis B vaccine. However, irrespective of imiquimod application, 70% of the NR who had not responded to 6 previous intramuscular vaccinations, developed a protective immune response with high affinity antibodies after 3 ID hepatitis B vaccinations with 5 microg HBsAg.

Influence of alpha-1 antitrypsin heterozygosity on treatment efficacy of HCV combination therapy.

BACKGROUND: The role of heterozygosity for alpha-1 antitrypsin (A1AT) alleles in patients with chronic hepatitis C virus (HCV) is unclear. There is limited evidence to suggest that there is an increased prevalence of heterozygous A1AT carriers in HCV, but it is unclear how this affects treatment success. AIM: To investigate the (i) prevalence of A1AT heterozygosity among two HCV cohorts and (ii) its effect on treatment outcome. METHODS: We performed a retrospective cohort study using two different cohorts. Cohort 1 consisted of 678 German HCV patients, 507 of them were treated for HCV with standard therapy. Cohort 2 consisted of 370 Dutch HCV patients of which 252 were part of a clinical trial (treatment with amantadine or placebo, in combination with pegylated interferon alpha-2b and ribavirin) whereas 37 HCV patients received standard therapy. We analyzed A1AT status using direct sequencing of the A1AT gene (cohort 1) or isoelectric focusing of serum (cohort 2). In addition, we measured A1AT serum levels (cohort 2). RESULTS: In total, we included 1048 HCV patients; 986 (94%) were wildtype [protease inhibitor (Pi) MM], whereas 61 (6%) were heterozygous for a mutant A1AT allele (41 Pi MS, 20 Pi MZ). Mean A1AT serum levels (370 patients) were lower in A1AT heterozygous patients (1.68 vs. 1.36 g/l), (P<0.05) compared with wildtypes. Sustained viral response (SVR) after treatment was equal between the wildtypes and heterozygotes (54 vs. 56%). CONCLUSION: We found a heterozygosity rate of 0.06, in line with healthy controls in other studies. Serum A1AT levels from A1AT heterozygous HCV patients are significantly lower compared with wildtype patients, although they do not discriminate on an individual level. Finally, SVR in A1AT wildtypes was not different from SVR in A1AT heterozygotes.

No beneficial effects of amantadine in treatment of chronic hepatitis C patients.

BACKGROUND: Benefit of adding amantadine to antiviral therapy for hepatitis C is controversial. AIMS: We aimed to examine whether such policy enhances sustained viral response in treatment-naïve patients. METHODS: 297 naïve hepatitis C patients were randomized for treatment with amantadine 200mg or placebo, combined with weight-based ribavirin and 12-day high-dose interferon alpha-2b induction therapy, followed by PEG-interferon alpha-2b (1.5 microg/kg/week up to 26 weeks and thereafter, 1.0 microg/kg/week until week 52). Treatment was discontinued if hepatitis C virus (HCV) RNA was positive at week 24. RESULTS: 49% of patients were (former) drug users. Genotype 1 occurred in 45%, high viral load in 70% and severe fibrosis/cirrhosis in 32%, without differences between amantadine or placebo groups. 90 patients prematurely discontinued treatment, mainly because of grade 3 or 4 toxicity. Intention-to-treat analysis revealed sustained viral response in 47% and 51% of amantadine and placebo groups (p=0.49). Amantadine did not enhance sustained viral response in patients with genotype 1 or high viral load nor did it improve primary non-response, breakthrough or relapse rates. Genotype non-1 and lower pre-treatment gamma GT levels were independent predictors for sustained viral response. CONCLUSION: Adding amantadine to antiviral therapy of previously untreated chronic hepatitis C patients has no beneficial effects.

Occupational blood exposure accidents in the Netherlands.

BACKGROUND: To make proper evaluation of prevention policies possible, data on the incidence and associated medical costs of occupational blood exposure accidents in the Netherlands are needed. METHODS: Descriptive analysis of blood exposure accidents and risk estimates for occupational groups. Costs of handling accidents were calculated. RESULTS: Each year, an estimated 13,000-15,000 blood exposure accidents are reported in the Netherlands, 95% in occupational settings. Hepatitis B (HBV) vaccination is offered free of charge only to people in risk groups, the seroprevalence of HBV, hepatitis C (HCV) and human immunodeficiency virus (HIV) is low and few infections are related to blood exposure accidents. High-risk accidents occur mainly in hospitals. In nursing homes and home care settings, the majority of the accidents are low-risk. Limited data are available about occurrence of accidents in other occupational groups. Associated medical costs from occupational blood exposure accidents are mainly determined by the initial risk management. CONCLUSIONS: Accidents must be managed effectively to prevent infection and reduce anxiety in injured employees. While strategies to reduce HCV and HIV infection should be primarily aimed at reducing the occurrence of high-risk accidents, vaccination can prevent HBV infection and cut the costs of handling low-risk accidents. The implementation of vaccination strategies, safe working policies and the proper use of safe equipment should be monitored better.

[Management and treatment of pregnant women with hepatitis B]. / Beleid en behandeling bij zwangeren met hepatitis B.

Every year about 800 chronic hepatitis B infections are identified in the Netherlands as result of the nationwide pregnancy screening. About one-third of these are newly discovered infections. In recent years there has been a marked increase in treatment options for chronic hepatitis B infection using antiviral drugs. Pregnant women can now be treated as well. A pregnant woman with a low viral load does not require immediate treatment, as due to the passive immunisation and active vaccination of the newborn the chances of infection due to perinatal transmission are negligible. Treatment of the mother can therefore be postponed until after the birth. However, when the pregnant woman has a high viral load (>10(9) copies/ml in serum), perinatal transmission can still occur despite vaccination of the newborn. In these women, antiviral treatment in the last trimester of the pregnancy should be considered. At present, experience of treating HBV-infected pregnant women has only been gained with lamivudine. It appears that the quantity of circulating virus decreases due to the treatment. Treatment should always be supervised by a gastroenterologist or an infectiologist. Detection, referral and treatment of the mother and child are described in several guidelines that have recently been updated and harmonized with each other. These include a practice guideline from the Dutch College of General Practitioners, a guideline from the Centre for Infectious Disease Control of the National Institute for Public Health and the Environment, and a guideline from the Netherlands Society of Gastroenterology.

Long-term persistence of T cell memory to HBsAg after hepatitis B vaccination.

AIM: To determine if the T cell memory to HBsAg can persist for a long time after hepatitis B (HB) vaccination. METHODS: Thirty one vaccine recipients who were healthcare workers (18 females and 13 males aged 34-58 years) from Utrecht University Hospital, Netherlands, and had previously received a standard course of vaccination for hepatitis B were investigated and another 9 unvaccinated healthy volunteers from the same hospital were used as the control. Blood samples were taken just before the experiment to test serum anti-HBs levels and the subjects were classified into different groups according to their serum titers of anti-HBs and vaccination history. Their peripheral blood mononuclear cells (PBMC) were isolated from freshly heparinized venous blood and the proliferative response of T lymphocytes to the recombinant hepatitis B surface antigen (HBsAg) was investigated. RESULTS: Positive serum anti-HBs was found in 61.3% (19/31) vaccine recipients and a significant in vitro lymphocyte proliferative response to recombinant HBsAg was observed in all the vaccinees with positive anti-HBs. Serum anti-HBs level < or =10 IU/L was found in 38.7% (12/31) subjects. In this study, we specially focused on lymphocyte proliferative response to recombinant HBsAg in those vaccine recipients with serum anti-HBsAg less than 10 IU/L. Most of them had received a standard course of vaccination about 10 years before. T lymphocyte proliferative response was found positive in 7 of the 12 vaccine recipients. These results confirmed that HBsAg-specific memory T cells remained detectable in the circulation for a long time after vaccination, even when serum anti-HBs level had been undetectable. CONCLUSION: The T cell memory to HBsAg can persist for at least 10 years after HB vaccination. Further booster injection is not necessary in healthy responders to HB vaccine.

Prevention of cytomegalovirus disease in recipients of allogeneic stem cell transplants.

The main risk factors for cytomegalovirus (CMV) disease in recipients of allogeneic stem cell transplants (SCT) are recipient CMV seropositivity and acute graft-versus-host disease. Currently, two antiviral strategies, prophylactic or preemptive antiviral treatment, are used for prevention of CMV disease. Preemptive treatment is most favorable when short-term (14-day) treatment is applied. Several methods are available for monitoring of CMV reactivation. PCR-based CMV DNA detection assays are the most sensitive methods; however, the clinical benefit of this high sensitivity is unclear. Even more, there is lack of clarity whether PCR tests can better be performed with plasma, whole blood, or peripheral blood leukocyte samples. Recovery of a CMV-specific CD8(+) cytotoxic-T-lymphocyte (CTL) response is necessary for preventing CMV reactivation and disease. Reconstitution of absolute CMV-specific CTL counts to values above 10 x 10(6) to 20 x 10(6) CTLs/liter is associated with protection from CMV disease. In the near future, preemptive therapy might be withheld in patients with CMV reactivation who are shown to have adequate CMV-specific cytotoxic T-cell levels. Antiviral therapy with (val)acyclovir has been studied only as prophylactic treatment for prevention of CMV infection. High-dose oral valacyclovir is more effective than acyclovir when used in addition to preemptive treatment of CMV reactivation with ganciclovir or foscarnet. Three antiviral drugs have been tested for preemptive therapy of CMV reactivation and/or treatment of CMV disease. Although intravenous ganciclovir is considered the drug of choice, foscarnet has similar efficacy and less toxicity, especially hematologic toxicity. Cidofovir has not been tested extensively, but so far the results are disappointing. Oral valganciclovir for preemptive treatment of SCT recipients is currently being studied. In addition to antiviral therapy, adoptive immunotherapy with CMV-specific cytotoxic T cells as prophylactic or preemptive therapy is a very elegant strategy; however, generation of these cells is expensive and time-consuming, and therefore the therapy is not available at every transplantation center. Magnetic selection of CMV-specific CD8(+) T cells from peripheral blood by using HLA class I-peptide tetramers may be very promising, making this strategy more accessible.

Transmission profile of hepatitis B virus infection in the Batam region, Indonesia. Evidence for a predominantly horizontal transmission profile.

The aim of this study was to describe the distribution of hepatitis B virus markers among the autochthonous and immigrant multicultural populations of Riau province, Indonesia, in order to define the groups at risk and their infrastructure. This investigation was part of a large hepatitis B vaccination study. A total of 9701 healthy individuals, aged 5 years or older and living in the urbanised area of Batam, near Singapore, and on the surrounding islands were included. Socio-epidemiological data were collected, blood was drawn, and sera were tested for antibodies to hepatitis B core (anti-HBc) and surface antigen (anti-HBs). Anti-HBc-positive sera were tested against hepatitis B surface antigen (HBsAg). All tests comprised immunoassays from Roche (Germany) using Elecsys 2010. Complete data were available from 9314 subjects. The results showed relatively low prevalences of anti-HBc (a marker of a previous hepatitis B infection) and HBsAg in the 5-year-old chiLdren (5.8 and 1.9%, respectively) that increased continuously with increasing age. High anti-HBs levels (>1000 IU/L) were found in all age cohorts, indicating a lifelong threat of active hepatitis B infection. In conclusion, the transmission profile of hepatitis B appeared to be mainly horizontal (person-to-person) in the highly endemic region studied. Vertical transmission was less than 5%. The horizontal transmission routes included non-sexual activities of life since children <10 years of age also showed considerable infection rates. The results underline the need for catch-up hepatitis B vaccination programs for children and adults.