No Improvement of Hepatitis B Vaccination Response in Patients Dialysed with a Polymethylmethacrylate Membrane Compared to High-Flux Polysulfone: Results of the HEPADIAL Study.

BACKGROUND: An altered immune response and decreased vaccine response are observed in patients with chronic renal failure. A preliminary study of 15 non-immunised patients, despite appropriate previous hepatitis B vaccination, showed a 60% seroconversion rate after 3 months of dialysis with a polymethylmethacrylate (PMMA) membrane. This response was associated with circulating soluble CD40 (CD40s) decrease, a natural inhibitor of the humoral immune response. The aim of the study is to confirm these results in a randomised study. METHODS: We conducted a multicentre randomised intention-to-treat superiority clinical trial comparing polysulfone and a PMMA membrane in 2 parallel patient groups. The primary end point was the vaccine response rate, as defined by an anti-HBs antibodies titre of >10 IU/L, 1 month after the last vaccination with a double dose of Engerix B20®, performed at weeks 12, 16, 20, and 36. RESULTS: Twenty-five patients were randomised and included in an intention-to-treat analysis. They were dialysed on polysulfone (n = 11) or PMMA (n = 14) for 40 weeks. Fifty percent of the PMMA patients versus 54.5% of the polysulfone patients achieved seroconversion (p = 1.00). The median anti-HBs antibody titre in responders at week 40 was 496 (92-750) versus 395 (43-572) UI/mL for PMMA and polysulfone, respectively (p = 0.46). The median CD40s titre at week 12 was 306 (193-448) versus 491 (281-515) pg/mL (p = 0.21). The CD40s median variation between week 0 and week 12 was 5 (-105 to 90) versus 64 (-63 to 123) pg/mL (p = 0.55). The CD40s level at week 12 in non-responders was slightly inferior to that of the responders: median 193 (168-331) versus 413 (281-512) pg/mL (p = 0.08). CONCLUSION: We did not observe a better vaccine response with the PMMA membrane compared to high-flux polysulfone. The PMMA membrane did not decrease the CD40s more than the polysulfone membrane probably because the titre was previously low in the 2 groups.

Okuda lecture: Challenges of hepatitis B in the era of antiviral therapy.

Nucleos(t)ide analogs (NAs) are effective, safe, and convenient antiviral therapy to suppress replication of hepatitis B virus, which can be translated into improved long-term outcome of chronic hepatitis B patients. The current recommended first-line NAs, namely, entecavir and tenofovir, are largely free from problems of drug resistance. Nonetheless, there are still a few challenges in the era of NA. First, the risk of hepatocellular carcinoma can only be reduced but not eliminated, particularly among cirrhotic patients. For cirrhotic patients who have persistent low-level viremia on NA, that is, partial responders, the risk of hepatocellular carcinoma is higher than those with complete viral suppression. The best strategy to manage partial responders to entecavir or tenofovir is uncertain. Second, immune-tolerant patients are very difficult to treat with NA. A significant proportion of immune-tolerant patients will have detectable viremia despite a few years of continuous NA treatment, and the rate of hepatitis B e-antigen seroconversion is very low. Third, most patients need long-term treatment as NA cannot eliminate covalently closed circular DNA in the hepatocytes. Some patients can consider stop NA according to treatment guidelines, but viral and clinical relapses often occur after treatment cessation. There is no concrete consensus on when one should stop NA in a hepatitis B e-antigen-negative patient among different treatment guidelines. New biomarkers such as hepatitis B surface antigen level can be used to select patients to stop NA, but the data are still preliminary.

Applications of Gold Nanoparticles in Nanomedicine: Recent Advances in Vaccines.

Nowadays, gold is used in (nano-)medicine, usually in the form of nanoparticles, due to the solid proofs given of its therapeutic effects on several diseases. Gold also plays an important role in the vaccine field as an adjuvant and a carrier, reducing toxicity, enhancing immunogenic activity, and providing stability in storage. An even brighter golden future is expected for gold applications in this area.

HIV and co-infections.

Despite significant reductions in morbidity and mortality secondary to availability of effective combination anti-retroviral therapy (cART), human immunodeficiency virus (HIV) infection still accounts for 1.5 million deaths annually. The majority of deaths occur in sub-Saharan Africa where rates of opportunistic co-infections are disproportionately high. In this review, we discuss the immunopathogenesis of five common infections that cause significant morbidity in HIV-infected patients globally. These include co-infection with Mycobacterium tuberculosis, Cryptococcus neoformans, hepatitis B virus, hepatitis C virus, and Plasmodium falciparum. Specifically, we review the natural history of each co-infection in the setting of HIV, the specific immune defects induced by HIV, the effects of cART on the immune response to the co-infection, the pathogenesis of immune restoration disease (IRD) associated with each infection, and advances in the areas of prevention of each co-infection via vaccination. Finally, we discuss the opportunities and gaps in knowledge for future research.

Hepatitis B: Working Towards a Cure.

First-line oral therapies for hepatitis B are effective at viral suppression, and treatment can lead to biochemical improvement and histologic regression. Unfortunately, recommended endpoints of treatment such as HBeAg loss and seroconversion may not be durable, with high rates of seroreversion, requiring monitoring, and unfortunately, low rates of  HBsAg loss/seroconversion. Additionally, meeting these endpoints requires years or even indefinite administration, leading to concerns regarding cost, side effects, and high rates of nonadherence. This article will review defined endpoints of therapy and their durability, the risks of long-term therapy, and the evolving new therapies aimed at a viral cure.

[Risk Management of HBV Reactivation: Construction of Check System].

In recent years, reactivation of HBV in patients receiving cancer chemotherapy or immunosuppressive therapy has been a problem. Generally, HBV-DNA levels are elevated prior to HBsAg concentration, and then hepatic dysfunction is observed in the process of hepatitis by HBV reactivation. Therefore, the monitoring of HBV-DNA is useful for the prediction of hepatic dysfunction, and nucleoside/nucleoside analogue (NA) administration is able to prevent this HBV reactivation. According to these facts, "Guidelines for the Prevention of HBV Reactivation in Patients Receiving Immunosuppressive Therapy or Chemotherapy", 2009 (revised as "JSH Guidelines for the Management of Hepatitis B Virus Infection", 2013) is established, and the diagnostic algorithm of HBsAg, anti-HBc, anti-HBs, and HBV-DNA has relevant descriptions. Combination therapy with rituximab and steroid for malignant lymphoma has a high risk of leading to fulminant hepatitis and, consequently, the guidelines are widely followed in such cases. We introduced the improvement of electronic medical recording and ordering systems in collaboration with hepatologists, and such a system has been widely used. Although the monitoring of HBV-DNA levels is required every 1-3 months, the guidelines are not followed strictly in cases such as rheumatoid disease and solid tumors only with chemotherapy or steroid treatment. Since a DNA assay is complicated and expensive, cost-effective, time-saving, and highly sensitive/specific measurements are required as well. Therefore, Lumipulse HBsAg-HQ (CLIA method) with high sensitivity is expected to be used for the monitoring of HBV reactivation.

[Reactivation of Hepatitis B Virus and Guidelines for Its Prevention].

Since the discovery of hepatitis B virus (HBV) as Australia antigen by Dr. Baruch Blumberg in 1964, significant advances have been made in understanding the pathophysiology of HBV infection, and in developing therapy for infected patients. Today, the progression of chronic hepatitis B to cirrhosis or hepatocellular carcinoma can be prevented using nucleic acid analogs. HBV is thought to be eliminated from patients with acute hepatitis B after they are cured. However, a 1996 study showed that cured hepatitis B patients were positive for HBV DNA and the HBV-specific cytotoxic T-cell response approximately 5 years after acute infection. These results indicate that HBV persists in the livers of patients who have been cured of acute HBV infection. HBV can be activated in chronic hepatitis B patients following steroid treatment. Recent clinical reports described cases of malignant lymphoma with fulminant hepatitis B arising during or after immunosuppressive regimens, such as R-CHOP therapy. Prior to immunosuppressive treatment, such patients are negative for HBs antigen and/or positive for HBs antibody, indicative of previous HBV infection. Sixteen cases of fulminant hepatitis B due to HBV reactivation in previously HBV-infected patients were collected between 2004 and 2009, and all of them had fatal prognoses despite treatment with nucleic acid analogs. Hence, guidelines for the prevention of HBV reactivation in immunosuppressive therapy were originally formulated by the Intractable Hepatobiliary Disease Study Group in 2009, and recently updated by the Japanese Society of Hepatology in 2013. The usefulness of these guidelines has been confirmed by several research groups. Dissemination and further improvement of the guidelines are necessary to prevent HBV reactivation in various types of patient receiving immunosuppressive or anti-cancer treatments.

[Are the Japanese guidelines for the management of hepatitis B virus reactivation being properly implemented ?].

Hepatitis B virus(HBV)reactivation has been reported as a fatal complication following systemic chemotherapy or other immunosuppressive therapies. The Japanese Guidelines for HBV reactivation were published in 2009. Despite the publication of these guidelines, there have been some reports of fulminant hepatitis B. Therefore, it was suggested that the guidelines were not yet been widely implemented. We investigated whether the guidelines had been implemented in our hospital. After the evaluation, it was determined that 89%of HBV cases were screened for the HBV surface antigen(HBs-Ag). Additionally, the screening for HBV surface antibody(HBs-Ab)and HBV core antibody(HBc-Ab)should be performed in cases negative for HBs-Ag, which was performed in only 17% of HBs-Ag-negative cases. It was concluded that the guidelines had not been implemented in our hospital. Therefore, we conducted educational activities to promote the implementation of the guidelines. Screening tests were performed in all 270 HBV cases between January and June 2013. Two antigen-positive carriers were identified. The rate of HBs-Ag-negative and/or HBc antibody -positive cases was 20.3%. Of these, 76.4%were tested using a DNA quantitative test, but DNA quantification did not increase in any case. HBV reactivation is expected to increase due to the development of new drugs and the use of diverse regimens. All physicians who perform immunotherapy and chemotherapy should immediately participate in educational activities.

Hepatitis B virus reactivation in a juvenile rheumatoid arthritis patient under treatment and its successful management: a complicated case.

Juvenile rheumatoid arthritis is a common chronic inflammatory disease in the childhood and it can differentiate rarely into spondiloarthropaties. It is one of the important causes of chronic pain and disability. Some of the drugs used for the treatment have immunosupressive activity. One of the serious side-effects of immunosupressive treatment is activation of opportunistic pathogens. Hepatitis B virus (HBV) is one of these pathogens, and the rate of carriers in the population is considerably high. It can cause liver damage and death if reactivated. Thus, the management of oppotunistic pathogens becomes a complex issue when treating rheumatic diseases with immunosupressive drugs. In this case report, we present a juvenile rheumatoid arthritis patient whose liver enzymes raised while he was under treatment and afterwards HBV reactivation was determined as the cause. When reactivation was detected, we started controlled antiviral therapy. We achieved successful clinical and laboratory results after adding biological agents to the treatment. Careful evaluation of the patients who have indication for immunosuppressive agents and regular follow-up in case of infection may be protective from severe morbidity and/or mortality.

A case of refractory cutaneous polyarteritis nodosa in a patient with hepatitis B carrier status successfully treated with tumor necrosis factor alpha blockade.

We describe a patient with refractory cutaneous polyarteritis nodosa (CPAN) with hepatitis B virus (HBV) carrier status who was successfully treated with tumor necrosis factor alpha (TNF-α) blockade, using etanercept, and we review 5 similar cases. We administered etanercept because of the occurrence of repeated flares despite aggressive therapy. C-reactive protein normalization; prednisolone dose-sparing; and absence of any adverse events, including HBV reactivation with nucleotide analogue administration, or renal dysfunction, have been achieved for 8 months. TNF-α blockade should be considered for intractable CPAN.

Combined DTP-HBV-HIB vaccine versus separately administered DTP-HBV and HIB vaccines for primary prevention of diphtheria, tetanus, pertussis, hepatitis B and Haemophilus influenzae B (HIB).

BACKGROUND: Advantages to combining childhood vaccines include reducing the number of visits, injections and patient discomfort, increasing compliance and optimising prevention. The World Health Organization (WHO) recommends that routine infant immunisation programmes include a vaccination against Haemophilus influenzae (H. influenzae) type B (HIB) in the combined diphtheria-tetanus-pertussis (DTP)-hepatitis B virus (HBV) vaccination. The effectiveness and safety of the combined vaccine should be carefully and systematically assessed to ensure its acceptability by the community. OBJECTIVES: To compare the effectiveness of combined DTP-HBV-HIB vaccines versus combined DTP-HBV and separate HIB vaccinations. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2011, Issue 4), which contains the Cochrane Acute Respiratory Infections Group's Specialised Register, MEDLINE (January 1966 to week 1, November 2011), EMBASE (January 1990 to November 2011) and www.clinicaltrials.gov (up to April 2011). SELECTION CRITERIA: Randomised controlled trials (RCTs) or quasi-RCTs comparing vaccination with any combined DTP-HBV-HIB vaccine, with or without three types of inactivated polio virus (IPV) or concomitant oral polio vaccine (OPV) in any dose, preparation or time schedule, compared with separate vaccines or placebo, administered to infants up to two years old. DATA COLLECTION AND ANALYSIS: Two review authors independently inspected references identified by the searches and evaluated them against the inclusion criteria, extracted data and assessed the methodological quality of included trials. MAIN RESULTS: Data for the primary outcome (prevention of disease) were lacking. We performed a meta-analysis to pool the results of 20 studies with 5874 participants in an immunogenicity analysis and 5232 participants in the reactogenicity analysis. There were no data on clinical outcomes for the primary outcome (prevention of disease) and all studies used immunogenicity and reactogenicity (adverse events). The number of vaccine doses differed significantly between the studies. Heterogeneous interventions, study location, healthcare environment and combining research across disparate geographical locations, may have lead to bias. The risk of bias was unclear across most of the included studies. Comparisons found little heterogeneity. In two immunological responses the combined vaccine achieved lower responses than the separate vaccines for HIB and tetanus. No significant differences in immunogenicity were found for pertussis, diphtheria, polio and hepatitis B. Serious adverse events were comparable with mainly hospitalisation and acute bronchiolitis cases. Minor adverse events such as pain and redness were more common in children given the combined vaccine. Overall, the direction shown by the results is in favour of the DTPw (diptheria-tetanus-whole cell pertussis)-HBV-HIB vaccine rather than the DTPa (diptheria-tetanus-acellular pertussis)-HBV-HIB vaccine when compared to the separate vaccines (size of effect: risk ratio (RR) 1.43; 95% confidence interval (CI) 0.98 to 2.10, for 5269 participants). AUTHORS' CONCLUSIONS: We could not conclude that the immune responses elicited by the combined vaccine were different from or equivalent to the separate vaccines. There was significantly less immunological response for HIB and tetanus and more local reactions in the combined injections. However, these differences rely mostly on one study each. Studies did not use an intention-to-treat (ITT) analysis and we were uncertain about the risk of bias in many of the studies. These results are therefore inconclusive. Studies addressing clinical end points whenever possible, using correct methodology and a large enough sample size should be conducted.

[Anti-hepatitis B surface antigen titres in vaccinated dentistry students at Damascus University].

Dental practice carries considerable danger for acquiring bloodborne pathogens such as hepatitis B virus (HBV). Vaccination against this virus is an important approach to reducing the infection. Post-vaccination test to confirm the seroconversion is important also. Over the period 1 March-31 May 2010, we assessed the efficacy of HBV vaccination among 91 fourth-year dental students at Damascus University, who were vaccinated under the mandatory Faculty of Dentistry programme. Anti-HBsAg antibody titres were determined in the blood samples using an enzyme immunoassay to measure; > or = 10 IU/mm was considered an adequate response titer. Seven of the 91 dentistry students (7.7%) had anti-HBs antibody titre < 10 mlU/mL. The frequency of unresponsiveness was significantly higherwith smoking (P = 0.012) and alcohol consumption (P = 0.014). Anti-HBs test should be included in routine immunization services of the School of Dentistry at Damascus University.

Presence of maternal anti-HBs antibodies does not influence hepatitis B vaccine response in Brazilian neonates.

Recently, it was suggested that maternal hepatitis B surface antigen antibodies (anti-HBs) acquired transplacentally could play a negative role in newborn infants' immune response to the hepatitis B vaccine. We compared the hepatitis B virus (HBV) vaccine response in infants born to mothers previously vaccinated against HBV (n = 91) to infants born to mothers who were not previously vaccinated (n = 221). All newborn infants received three intramuscular doses (10 µg) of HBV vaccine (Butang®) at 0,1 and six months. The first dose was administered at the maternity hospital within 12 h of birth. The geometric mean titres of anti-HBs were not different among newborn infants born to mothers who were anti-HBs-negative (492.7 mIU/mL) and anti-HBs-positive (578.7 mIU/mL) (p = 0.38). Eight infants did not respond to the HBV vaccine. Of them, six were born to anti-HBs-negative mothers and two were born to mothers with anti-HBs titres less than 50 mlU/mL. Despite the mother's anti-HBs-positive status, our data show a good immunogenicity of the Brazilian HBV recombinant vaccine in neonates.

[New vaccination protocol against hepatitis B for hemodialysis patients--a single-centre experience]. / Novi protokol vakcinacije pacijenata na hemodijalizi protiv hepatitisa B--iskustvo jednog centra.

UNLABELLED: Patients with end stage renal disease (ESRD) have a reduced response to vaccination against hepatitis B infection. The aim of the study has been to determine the adequacy of immune response with new protocol of vaccination against hepatitis B infection. PATIENTS AND METHODS: The study included incident hemodialysis patients since 2008 until 2011 at the Clinic of Hemodialysis of the Clinical Center of the University of Sarajevo. We started the new vaccination protocol in September 2009. New protocol implied vaccination six month before starting renal replacement therapy (RRT) and "ic" (intracutaneously) application vaccine vs. "sc" (subcutaneously) application. Vaccination was carried out for over 12 months. The follow up period lasted from 2009 to 2011. RESULTS: The study included 64 patients, men were represented with 57,81% (37), and 42,19% women (27), who were divided in two groups. The first group included patients from the period from 2008 to 2009, who have been vaccinated under the old vaccination protocol, while the second group included patients with the new protocol from September 2009 to 2011. The first group had 28 patients, mean age of patients was 55,17 +/- 11.84 and mean duration of hemodialysis was 24,65 +/- 5,32 months. The second group had 36 patients, mean age of patients was 62,79 +/- 15,88 years, and mean duration of hemodialysis was 22,16 +/- 24,53 month. Neither group of patient has been previously vaccinated, nor these had positive in serum antiHBs before vaccination in second group. Five patients received a booster dose of vaccine, after which 4 showed adequate responses to anti HbS. In the first group of patients, out of total of 28 patients, 15 patients did not respond response with the adequate anti-HbS titer at the end of vaccination. In the second group of patients, out of 36 patients 31 of them responded to the vaccination with the new protocol, which was statistically significant (p<0,005). The total percentage of patients with adequate titer of antiHBs after vaccination towards a new protocol was 97.43% and the percentage of patients who required booster dose of vaccines was 12.82%. CONCLUSION: Vaccination of patients in ESRD,six months before renal replacement therapy and intradermal application of vaccine vs. subcutaneously, improved immune response of our patients.

Increasing hepatitis B vaccination coverage of healthcare workers - global lessons for South Africa.

Healthcare workers (HCWs) are at high risk of contracting hepatitis B (HB), a severe blood-borne vaccine-preventable disease, caused by HB virus (HBV) infection. Low HB vaccine (HepB) coverage has resulted in suboptimal protection and high HBV infection rates in South African HCWs. Studies from Africa have identified cost; unavailability/lack of access to HepB; and lack of awareness/knowledge of HB and HepB, as barriers to HCW uptake. Studies from Europe show little difference in HepB coverage between countries mandating versus recommending HepB. Providing easy and sustained access to free HepB to student HCWs, together with education about HB and HepB, are recommended to create demand for HepB. Only if this fails should mandatory vaccination be considered.