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1.  Efficacy of Neonatal HBV Vaccination on Liver Cancer and Other Liver Diseases over 30-Year Follow-up of the Qidong Hepatitis B Intervention Study: A Cluster Randomized Controlled Trial 
PLoS Medicine  2014;11(12):e1001774.
In a 30-year follow-up of the Qidong Hepatitis B Intervention Study, Yawei Zhang and colleagues examine the effects of neonatal vaccination on liver diseases.
Please see later in the article for the Editors' Summary
Background
Neonatal hepatitis B vaccination has been implemented worldwide to prevent hepatitis B virus (HBV) infections. Its long-term protective efficacy on primary liver cancer (PLC) and other liver diseases has not been fully examined.
Methods and Findings
The Qidong Hepatitis B Intervention Study, a population-based, cluster randomized, controlled trial between 1985 and 1990 in Qidong, China, included 39,292 newborns who were randomly assigned to the vaccination group in which 38,366 participants completed the HBV vaccination series and 34,441 newborns who were randomly assigned to the control group in which the participants received neither a vaccine nor a placebo. However, 23,368 (67.8%) participants in the control group received catch-up vaccination at age 10–14 years. By December 2013, a total of 3,895 (10.2%) in the vaccination group and 3,898 (11.3%) in the control group were lost to follow-up. Information on PLC incidence and liver disease mortality were collected through linkage of all remaining cohort members to a well-established population-based tumor registry until December 31, 2013. Two cross-sectional surveys on HBV surface antigen (HBsAg) seroprevalence were conducted in 1996–2000 and 2008–2012. The participation rates of the two surveys were 57.5% (21,770) and 50.7% (17,204) in the vaccination group and 36.3% (12,184) and 58.6% (17,395) in the control group, respectively. Using intention-to-treat analysis, we found that the incidence rate of PLC and the mortality rates of severe end-stage liver diseases and infant fulminant hepatitis were significantly lower in the vaccination group than the control group with efficacies of 84% (95% CI 23%–97%), 70% (95% CI 15%–89%), and 69% (95% CI 34%–85%), respectively. The estimated efficacy of catch-up vaccination on HBsAg seroprevalence in early adulthood was 21% (95% CI 10%–30%), substantially weaker than that of the neonatal vaccination (72%, 95% CI 68%–75%). Receiving a booster at age 10–14 years decreased HBsAg seroprevalence if participants were born to HBsAg-positive mothers (hazard ratio [HR] = 0.68, 95% CI 0.47–0.97). Limitations to consider in interpreting the study results include the small number of individuals with PLC, participants lost to follow-up, and the large proportion of participants who did not provide serum samples at follow-up.
Conclusions
Neonatal HBV vaccination was found to significantly decrease HBsAg seroprevalence in childhood through young adulthood and subsequently reduce the risk of PLC and other liver diseases in young adults in rural China. The findings underscore the importance of neonatal HBV vaccination. Our results also suggest that an adolescence booster should be considered in individuals born to HBsAg-positive mothers and who have completed the HBV neonatal vaccination series.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Hepatitis B is a life-threatening liver infection caused by the hepatitis B virus (HBV). HBV, which is transmitted through contact with the blood or other bodily fluids of an infected person, can cause both acute (short-term) and chronic (long-term) liver infections. Acute infections rarely cause any symptoms and more than 90% of adults who become infected with HBV (usually through sexual intercourse with an infected partner or through the use of contaminated needles) are virus-free within 6 months. However, in sub-Saharan Africa, East Asia, and other regions where HBV infection is common, HBV is usually transmitted from mother to child at birth or between individuals during early childhood and, unfortunately, most infants who are infected with HBV during the first year of life and many children who are infected before the age of 6 years develop a chronic HBV infection. Such infections can cause liver cancer, liver cirrhosis (scarring of the liver), and other fatal liver diseases. In addition, HBV infection around the time of birth can cause infant fulminant hepatitis, a rare but frequently fatal condition.
Why Was This Study Done?
HBV infections kill about 780,000 people worldwide annually but can be prevented by neonatal vaccination—immunization against HBV at birth. A vaccine against HBV became available in 1982 and many countries now include HBV vaccination at birth followed by additional vaccine doses during early childhood in their national vaccination programs. But, although HBV vaccination has greatly reduced the rate of chronic HBV infection, the protective efficacy of neonatal HBV vaccination against liver diseases has not been fully examined. Here, the researchers investigate how well neonatal HBV vaccination protects against primary liver cancer and other liver diseases by undertaking a 30-year follow-up of the Qidong Hepatitis B intervention Study (QHBIS). This cluster randomized controlled trial of neonatal HBV vaccination was conducted between 1983 and 1990 in Qidong County, a rural area in China with a high incidence of HBV-related primary liver cancer and other liver diseases. A cluster randomized controlled trial compares outcomes in groups of people (towns in this study) chosen at random to receive an intervention or a control treatment (here, vaccination or no vaccination; this study design was ethically acceptable during the 1980s when HBV vaccination was unavailable in rural China but would be unethical nowadays).
What Did the Researchers Do and Find?
The QHBIS assigned nearly 80,000 newborns to receive either a full course of HBV vaccinations (the vaccination group) or no vaccination (the control group); two-thirds of the control group participants received a catch-up vaccination at age 10–14 years. The researchers obtained data on how many trial participants developed primary liver cancer or died from a liver disease during the follow-up period from a population-based tumor registry. They also obtained information on HBsAg seroprevalence—the presence of HBsAg (an HBV surface protein) in the blood of the participants, an indicator of current HBV infection—from surveys undertaken in1996–2000 and 2008–2012. The researchers estimate that the protective efficacy of vaccination was 84% for primary liver cancer (vaccination reduced the incidence of liver cancer by 84%), 70% for death from liver diseases, and 69% for the incidence of infant fulminant hepatitis. Overall, the efficacy of catch-up vaccination on HBsAg seroprevalence in early adulthood was weak compared with neonatal vaccination (21% versus 72%). Notably, receiving a booster vaccination at age 10–14 years decreased HBsAg seroprevalence among participants who were born to HBsAg-positive mothers.
What Do These Findings Mean?
The small number of cases of primary liver cancer and other liver diseases observed during the 30-year follow-up, the length of follow-up, and the availability of incomplete data on seroprevalence all limit the accuracy of these findings. Nevertheless, these findings indicate that neonatal HBV vaccination greatly reduced HBsAg seroprevalence (an indicator of current HBV infection) in childhood and young adulthood and subsequently reduced the risk of liver cancer and other liver diseases in young adults. These findings therefore support the importance of neonatal HBV vaccination. In addition, they suggest that booster vaccination during adolescence might consolidate the efficacy of neonatal vaccination among individuals who were born to HBsAg-positive mothers, a suggestion that needs to be confirmed in randomized controlled trials before booster vaccines are introduced into vaccination programs.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001774.
The World Health Organization provides a fact sheet about hepatitis B (available in several languages) and information about hepatitis B vaccination
The World Hepatitis Alliance (an international not-for-profit, non-governmental organization) provides information about viral hepatitis, including some personal stories about hepatitis B from Bangladesh, Pakistan, the Philippines, and Malawi
The UK National Health Service Choices website provides information about hepatitis B
The not-for-profit British Liver Trust provides information about hepatitis B, including Hepatitis B: PATH B, an interactive educational resource designed to improve the lives of people living with chronic hepatitis B
MedlinePlus provides links to other resources about hepatitis B (in English and Spanish)
Information about the Qidong Hepatitis B intervention Study is available
Chinese Center for Disease Control and Prevention provides links about hepatitis B prevention in Chinese
doi:10.1371/journal.pmed.1001774
PMCID: PMC4280122  PMID: 25549238
2.  Efficacy of HBV Vaccination in Various Stages of Chronic Kidney Disease: Is Earlier Better? 
Hepatitis Monthly  2011;11(10):816-820.
Background
Despite improvement in hepatitis B infection prevention through national vaccination programs, implementation of compulsory and thorough blood donor screening, and reduction of transfusion numbers due to erythropoietin administration,hepatitis B remains a major concern in hemodialysis (HD) centers [1]. Compared to aresponse rate of over 90% in the normal population, only 50 to 60% of those with endstage renal disease (ESRD) achieve protective antibody levels following immunization against hepatitis B [2][3]. Various strategies have been developed to overcome the low seroconversion rate in ESRD patients, including co-administering zinc, gamma-interferon,thymopentin, interleukin-2, and levamisole as immunostimulants or adjuvants [3][4],changing the injection mode (intradermal versus intramuscular), or doubling the vaccine dose [5].
Objectives
Previous studies demonstrated that renal failure patients benefit from HBV vaccination; however, not all studies have demonstrated this. Therefore, we compared the rates of seroconversion (hepatitis B surface antibody [HBsAb] titer > 10 IU/mL) in patients at various stages of chronic kidney disease (CKD) (estimated glomerular filtration rate [eGFR] < 60 mL/min/1.73 m2) who received HBV vaccination.
Patients and Methods
A total of 167 patients in 3 different stages of CKD were vaccinated against HBV. Each patient received the vaccine according to a standardized vaccination schedule consisting of 40 μg of the recombinant vaccine “Engerix” at 0, 1, and 6 months.Eight to 12 weeks after the last dose of vaccination, anti-HBsAb levels were measured.
Results
Mean age and eGFR were 57.4 ± 16.5 years and 26.7 ± 14.7 mL/min/1.73 m2, respectively.The overall seroconversion rate was 78%. Although a significant correlation between HBsAb titer and eGFR (r = 0.265, P = 0.001) was observed, in the multivariate analysis using age, CKD stage, diabetes mellitus, and gender as independent variables,the degree of renal function did not significantly contribute to seroconversion. In contrast,higher age (> 60 years) showed a significant negative correlation to seroconversion (odds ratio = 0.22; P = 0.004).
Conclousions
CKD patients of advanced age should be vaccinated against HBV. Although higher eGFR was not associated with improved seroconversion, the persistence of seroconversion was not evaluated; future studies should be conducted to develop recommendations for earlier or later vaccination.
doi:10.5812/kowsar.1735143X.751
PMCID: PMC3234577  PMID: 22224080
3.  Improving Hepatitis B Vaccine Efficacy in End-Stage Renal Diseases Patients and Role of Adjuvants 
ISRN Gastroenterology  2012;2012:960413.
Hepatitis B virus (HBV) infection is a serious global health problem.The prevalence of viral hepatitis is higher in dialysis patients than in the general population because of the opportunity for exposure during the dialysis procedure. Immunization is the most effective way to prevent transmission of hepatitis B virus (HBV) and hence the development of acute or chronic hepatitis B. It is well established that patients with end-stage renal disease including dialysis-dependent patients, have an impaired immune response to hepatitis B vaccine. End stage renal diseases (ESRD) patients have lower seroconversion rates compared with the subjects with intact renal function. Moreover, even after the completion of vaccination schedule anti-hepatitis B (anti-HBs) titers of responder dialysis, patients are low and decline logarithmically with time. The impaired efficacy of HBV vaccine in patients with ESRD has been attributed to numerous factors such as immune compromise because of uremia and some other factors. One approach to improve the immunogenicity of existing HBV vaccines is adjuvantation, and it's very important to find more effective adjutants for improving HBV vaccine efficacy. In this paper we have a brief review on recently known new ways for improving HBV vaccine efficacy.
doi:10.5402/2012/960413
PMCID: PMC3458294  PMID: 23029621
4.  Levamisole Usage as an Adjuvant to Hepatitis B Vaccine in Hemodialysis Patients, Yes or No? 
Nephro-urology monthly  2012;5(1):673-678.
Background
Hepatitis B virus (HBV) infection is much more common in hemodialysis patients than the general population. These patients have an impaired immune response to HBV vaccination; to that end there are certain studies that have evaluated levamisole as an immunomodulator agent improving HBV vaccination response rate in hemodialysis patients.
Objectives
In the current review, we have assembled all of the results to determine whether lavamisole is of value as an adjuvant to HBV vaccination in hemodialysis patients.
Materials and Methods
Science Direct (Elsevier), ProQuest, Springer, MD Consult, BMJ Journals, Pubmed and Wiley were searched for levamisole application to HBV vaccination in hemodialysis patients. All studies revealed a seroconversion response level between levamisole plus HBV vaccine versus HBV vaccine alone.
Results
From 10 relevant studies, 5 studies fulfilled our inclusion criteria. Three of them suggested the significant benefit of adding levamisole to the HBV vaccine to increase augment seroprotection level in hemodialysis patients. Another study reported a decrease in seroprotection level and another study showed no significant difference caused by levamisole administration.
Conclusions
Due to the limited number of studies evaluated, it is challenging to perform a definite decision about routinely administering levamisole in addition to the HBV vaccine for all hemodialysis patients. However, it does seem reasonable to recommend administration of levamisole for impaired immune response patients.
doi:10.5812/numonthly.3985
PMCID: PMC3614321  PMID: 23577329
Hepatitis B; Vaccination; Hemodialysis Units, Hospital
5.  A cost-effectiveness analysis of hepatitis B vaccine in predialysis patients. 
Health Services Research  1993;28(1):97-121.
OBJECTIVE. Our objective was to assess the cost effectiveness of hepatitis B vaccine in predialysis patients. DATA SOURCES. Costs were calculated from estimated rates of health services use and unit costs of resource use. Efficacy data were based on probability estimates from the medical literature and included vaccination response rates, anticipated hepatitis B virus (HBV) infection rates, and outcomes from HBV. STUDY DESIGN. Costs and effectiveness of HBV vaccination was modeled with a decision tree constructed to analyze three vaccination strategies for patients with renal insufficiency: vaccine given prior to dialysis, vaccine given at time of dialysis, and no vaccine. Sensitivity analyses were performed to assess the effect of varying important clinical and cost variables. DATA COLLECTION/EXTRACTION METHODS. All analyses were based on efficacy and cost estimates derived from the medical literature. Analyses were conducted with the aid of SMLTREE software. PRINCIPAL FINDINGS. The number of patients requiring vaccination per case of HBV prevented was higher for dialysis patients (625 vaccinees/case prevented) than for predialysis patients (434 vaccinees/case prevented). The cost-effectiveness ratios were $25,313/case of HBV prevented for vaccination at the time of dialysis and $31,111 for the predialysis vaccine. When a higher HBV infection rate (based on clinical trial data) was substituted in the analysis, the cost effectiveness of a predialysis vaccination strategy improved to $856 per case prevented. Results were sensitive to the cost of the vaccine and the incidence of HBV infection in dialysis patients. For the predialysis strategy to become cost saving, the price of the vaccine would have to decrease from $114 to $1.50, or the incidence of infection would have to increase from 0.6 percent to 38 percent, holding all other variables constant. CONCLUSIONS. Additional HBV infection can be prevented by immunizing predialysis patients, but the cost is high. Decisions concerning vaccination policy should be influenced by local prevalence of HBV infection.
PMCID: PMC1069923  PMID: 8463111
6.  A Cross-Sectional Study on Anti Hepatitis B Immune Status in Vaccinated Healthcare Workers in the West Pomeranian Region of Poland 
Hepatitis Monthly  2012;12(3):185-189.
Background
Hepatitis B vaccination, recommended for medical staff, has a non-response rate of 5% to 32%. In Poland, there is no standardized postvaccination protocol to verify immunity.
Objectives
To determine the fraction of those who have been vaccinated against HBV (with a complete course followed/not followed by a booster) but not checked for serological evidence of hepatitis B immunity and to detect anti-HBs levels in this group by anonymous cross-sectional sero-survey.
Patients and Methods
Surgical/gynecological staff from 16 randomly selected hospitals in West Pomerania, Poland, were surveyed between July 2010-January 2011. EIA system version 3.0 was used to detect anti-HBs.
Results
Of 488 participants (439 females, median age 42 years) who were previously vaccinated (1-21 years ago), anti-HBs status was not determined after HBV vaccination in 361 individuals (74.0%; 95% CI: 69.9-77.7%), 5% (18/361) of whom had an anti-HBs titer of 0.0 mIU/ml (12/18 who were given booster doses developed anti-HBs > 10 mIU/ml) and 7.2% (26/361) of whom had an anti-HBs titer of 0.1-10 mIU/ml. The multivariate logistic regression model revealed that working in a teaching hospital was associated with lower odds of not being checked for anti-HBs after HBV vaccination (OR 0.22, 95% CI: 0.14-0.35; P = 0.0001).
Conclusions
The lack of a strict post-HBV vaccination policy to confirm immunity results in the majority of surgical/gynecological staff not checking their anti-HBs levels after HBV immunization. It is unknown whether the absence of current serological evidence of hepatitis B immunity can be attributed to non-response, the waning of vaccine-induced immunity, or preserved anamnestic response. The lack of a booster vaccination response in a fraction of subjects suggests that they are non-responders. Strict post-vaccination testing to document immunity remains the key practice to detect non-responders among medical staff.
doi:10.5812/hepatmon.850
PMCID: PMC3339418  PMID: 22550526
Medical Staff; Hepatitis B Virus; Vaccination; Testing
7.  Hepatitis B Vaccination in Chronic Kidney Disease: Review of Evidence in Non-Dialyzed Patients 
Hepatitis Monthly  2012;12(11):e7359.
Context
Hepatitis B vaccination of hemodialysis patients is performed all over the world. There are also recommendations from world health organizations to vaccinate patients with chronic kidney disease (CKD) prior dialysis commencement, but the implementation of a hepatitis B vaccination program is less common and not well organized.
Evidence Acquisition
This review article summarizes data indicating why, when and how to vaccinate CKD patients before they start renal replacement therapy. Publication for this review was bringing into being from PubMed.
Results
There is an agreement in the nephrological societies and among clinicians and scientists that CKD patients should be vaccinated in early stages of their disease, because a higher glomerular filtration rate is more likely to be associated with the responsiveness to vaccination. Schedules of vaccination and optimal vaccine doses are still being investigated. Differences in data with respect to these problems may result from comparisons of various vaccine doses and vaccination schedules without reference to one gold standard, variations in patients` clinical status and glomerular filtration rate, and also the small groups of the affected patients make statistical analysis non-conclusive. A titer of antibodies to surface antigen of hepatitis B virus (anti-HBs) > 10 IU/L or ≥ 10 IU/L is commonly considered as a marker of seroconversion to anti-HBs positivity after vaccination in both non-dialyzed and dialyzed patients. In advanced CKD, vaccine–induced serconversion rate is seldom observed in more than 90% of vaccinees. Various strategies have been utilized in order to increase vaccine-induced seroconversion rate in patients with advanced CKD. Changing the injection mode, the use of adjuvants and immunostimulants to improve the immunogenicity of existing recombinant hepatitis B vaccines, introduction of mammalian-cell derived pre-S/S HBV vaccines (third-generation vaccines) were tried in order to improve the immunization rate.
Conclusions
There are a substantial number of non-responders to the hepatitis B vaccine among CKD patients. Therefore, successful prevention of hepatitis B virus transmission and spread will only be attained when hepatitis B vaccination is applied together with full implementation of appropriate infection control procedures.
doi:10.5812/hepatmon.7359
PMCID: PMC3546461  PMID: 23326280
Vaccination; Hepatitis B Virus; Kidney Disease
8.  Hepatitis A and hepatitis B vaccination responses in persons with chronic hepatitis C infections: A review of the evidence and current recommendations 
In persons with chronic hepatitis C virus (HCV) infections, superinfection by hepatitis A virus (HAV) or hepatitis B virus (HBV) can cause serious complications, including fulminating hepatitis or increased severity of hepatitis. Therefore, it is important to adequately protect persons with chronic HCV infections by immunization. Suboptimal response to vaccines has been reported in patients with chronic liver disease. The present article reviews HAV and HBV vaccine responses reported in the literature when administered to individuals with chronic HCV infection, and reviews current national and international recommendations.
RESULTS
Persons with chronic HCV respond well to HAV vaccine, but studies exploring HBV vaccine efficacy in this population have equivocal results. Vaccine schedules and participant characteristics differ among studies, and most do not adjust for confounders. Some studies found no difference in HBV vaccine response between patients with chronic HCV and controls. However, HBV vaccine response was generally reduced in those with cirrhosis and HCV genotype 1. Organizations recommend HAV and HBV vaccines for persons with chronic HCV, but do not suggest alterations in schedule or dose.
RECOMMENDATIONS
Because HAV vaccine response is good and routine laboratory testing may not detect lower levels of vaccine-induced anti-HAV, the standard HAV vaccine schedule is recommended without postimmunization testing. HBV vaccine should be administered early in the course of chronic HCV infection because response may be lower in patients with cirrhosis. Reflex testing of anti-HCV reactive sera for anti-HAV and hepatitis B surface antibody can facilitate appropriate follow-up and timely immunization. Determination of postimmunization hepatitis B surface antibody, especially in patients with cirrhosis or genotype 1, will allow HBV vaccine boosters to be offered.
PMCID: PMC2605862  PMID: 19352452
Hepatitis A virus; Hepatitis B virus; Hepatitis C virus; Immunization; Vaccine efficacy
9.  Association of the interleukin-12 polymorphic variants with the development of antibodies to surface antigen of hepatitis B virus in hemodialysis patients in response to vaccination or infection 
Molecular Biology Reports  2013;40(12):6899-6911.
Cytokines, involved in the T-helper 1 system, play a role in the regulation of hepatitis B virus (HBV) clearance and the immune response to HBV antigens during natural infection or planned vaccination. Our aim was to examine whether the polymorphic variants of IL-12 are equally associated with development of antibodies to HBV surface antigen (anti-HBs) in hemodialysis (HD) patients in the case of HBV vaccination or HBV infection. The IL-12A rs568408 and IL-12B rs3212227 polymorphisms were analyzed in relation to anti-HBs development in 602 HD patients with negative antibodies to HBV core antigen (anti-HBc) who were hepatitis B vaccinated (group I) as well as in 237 anti-HBc positive HD patients who were infected with HBV in the past (group II). In group I, 199 patients did not develop an anti-HBs titre >10 IU/L (subgroup Ia), whereas in group II, 55 patients did not develop an anti-HBs titre >10 IU/L (subgroup IIa). Patients of groups I and II that developed an anti-HBs >10 IU/L were included into subgroups Ib and IIb, respectively. In hepatitis B vaccinated HD patients, development of a protective anti-HBs titre was positively associated with vintage of renal replacement therapy (RRT), chronic glomerulonephritis as a cause of RRT, and GA rs 568408 IL-12A (OR 1.6, 95 % CI 1.0–2.5, P = 0.035), but a frequency distribution of this genotype between responders and non-responders was not significant when the Bonferroni correction was applied. In HBV infected HD patients, anti-HBs development was positively associated with AC rs3212227 IL-12B (OR 8.0, 95 % CI 2.6–24.9, P < 0.001), whereas HBsAg positivity, AA rs3212227 IL-12B (OR 0.3, 95 % CI 0.1–0.7, P = 0.007), and CC rs3212227 IL-12B (OR 0.1, 95 % CI 0.03–0.6, P = 0.011) were negative predictors of positive anti-HBs phenotype. When the Bonferroni correction was applied, if appropriate, these associations remained significant. In HD patients, the studied IL-12 polymorphic variants seem to be associated with the anti-HBs phenotype (a) with borderline significance for IL-12A in hepatitis B vaccinated patients, and (b) significantly for IL-12B in patients who underwent natural HBV infection.
doi:10.1007/s11033-013-2809-7
PMCID: PMC3835950  PMID: 24158609
Anti-HBs; Gene polymorphism; Hemodialysis; Infection; Interleukin-12; Vaccination
10.  Positive hepatitis B surface antigen tests due to recent vaccination: a persistent problem 
Background
Hepatitis B virus (HBV) is a common cause of viral hepatitis with significant health complications including cirrhosis and hepatocellular carcinoma. Assays for hepatitis B surface antigen (HBsAg) are the most frequently used tests to detect HBV infection. Vaccination for HBV can produce transiently detectable levels of HBsAg in patients. However, the time course and duration of this effect is unclear. The objective of this retrospective study was to clarify the frequency and duration of transient HBsAg positivity following vaccination against HBV.
Methods
The electronic medical record at an academic tertiary care medical center was searched to identify all orders for HBsAg within a 17 month time period. Detailed chart review was performed to identify all patients who were administered HBV vaccine within 180 days prior to HBsAg testing and also to ascertain likely cause of weakly positive (grayzone) results.
Results
During the 17 month study period, 11,719 HBsAg tests were ordered on 9,930 patients. There were 34 tests performed on 34 patients who received HBV vaccine 14 days or less prior to HBsAg testing. Of these 34 patients, 11 had grayzone results for HBsAg that could be attributed to recent vaccination. Ten of the 11 patients were renal dialysis patients who were receiving HBsAg testing as part of routine and ongoing monitoring. Beyond 14 days, there were no reactive or grayzone HBsAg tests that could be attributed to recent HBV vaccination. HBsAg results reached a peak COI two to three days following vaccination before decaying. Further analysis of all the grayzone results within the 17 month study period (43 results out of 11,719 tests) revealed that only 4 of 43 were the result of true HBV infection as verified by confirmatory testing.
Conclusions
Our study confirms that transient HBsAg positivity can occur in patients following HBV vaccination. The results suggest this positivity is unlikely to persist beyond 14 days post-vaccination. Our study also demonstrates that weakly positive HBsAg results often do not reflect actual HBV infection, underscoring the importance of confirmatory testing. This study also emphasizes that vaccination-induced HBsAg positives occur most commonly in hemodialysis patients.
doi:10.1186/1472-6890-12-15
PMCID: PMC3515481  PMID: 23006828
False positive reactions; Hepatitis; Hepatitis B surface antigens; Public health; Renal dialysis; Vaccination
11.  Hepatitis B Vaccination and Risk of Hepatitis B Infection in HIV-Infected Individuals 
AIDS (London, England)  2010;24(4):545-555.
Objective
To assess the association of HBV vaccination with risk of HBV infection among HIV-infected patients and HBV infection risk factors among vaccinees.
Design
Observational cohort study
Methods
Participants enrolled from 1986 through 2004, unvaccinated and serologically negative for HBV infection at the time of HIV diagnosis, were followed longitudinally through 2007 for the occurrence of HBV infection. Risk factors for HBV infection were evaluated using time to event methods, including Kaplan-Meier survival curves and Cox proportional hazards models.
Results
During 11,632 person-years of follow-up, the rate of HBV infection was 2.01 (95% CI 1.75–2.27) /100 person-years. Receipt of at least one dose of vaccine was not associated with reduced risk of HBV (unadjusted HR 0.86, 95% CI 0.7–1.1; adjusted HR 1.08, 95% CI 0.8–1.4). Receipt of three or more doses of vaccine was also not associated with reduced risk (HR 0.96; 95% CI 0.56–1.64). Among 409 vaccinees with HBsAb <10 IU/L, 46 (11.2%) developed HBV infection compared to 11 of 217 (5.1%) vaccinees with HBsAb ≥10 IU/L (HR 0.51; 95% CI 0.3–1.0). In participants with initial HBsAb <10 IU/L, 16/46 (35%) infections were chronic, compared to 0/11 in those with initial HBsAb ≥10 IU/L (p=0.02).
Conclusion
Overall, HBV vaccination was not associated with reduced risk of HBV infection in our cohort of HIV-infected individuals. However, the small subset of vaccinees with a positive vaccine response may have had reduced HBV infection risk, including chronic disease. Improvements in vaccine delivery and immunogenicity are needed to increase HBV vaccine effectiveness in HIV-infected patients.
doi:10.1097/QAD.0b013e32832cd99e
PMCID: PMC2831117  PMID: 19487908
Hepatitis B virus; hepatitis B vaccine; human immunodeficiency virus; vaccination; immunization
12.  Long-Term Persistence of Seroprotection by Hepatitis B Vaccination in Healthcare Workers of Southern Italy 
Hepatitis Monthly  2012;12(9):e6025.
Background
The impact of hepatitis B virus (HBV) vaccination campaigns on HBV epidemiology needs to be evaluated, in order to assess the long-term immunity offered by vaccines against HBV.
Objectives
To evaluate the current status of anti-HBV vaccine coverage among healthcare workers (HCWs) in Southern Italy, and to determine the long-term persistence of antibodies to hepatitis B surface antigens (anti-HBs) in such a cohort of subjects.
Patients and Methods
A longitudinal, retrospective seroepidemiological survey was conducted among 451 HCWs, who were working at or visiting, the Occupational Health Department of a city hospital, in Catania, Italy, between January 1976 and December 2010.
Results
At the 30-year follow-up (mean follow-up 10.15 ± 5.96 years, range 0.74-30), 261 HCWs had detectable anti-HBs titers indicating a persistence of seroprotection of 89.4% (out of 292 anti-HBs positive results, three months after vaccination). An inadequate vaccination schedule was the strongest predictor of antibody loss during follow-up (OR = 8.37 95% CI: 5.41-12.95, P < 0.001). A Kaplan-Maier survival curve revealed that the persistence of anti-HBs 30 years after vaccination, was 92.2% for high responders, while it was only 27.3% for low responders (P = 0.001).
Conclusions
A good level of seroprotection persisted in 57.9% of the subjects after 30 years. Factors related to this immunization status confirmed the importance of vaccinating HCWs early in their careers and ensuring an adequate vaccination schedule. However, with particular reference to the low rate of hepatitis B vaccine coverage among HCWs in Southern Italy, the implementation of a new educational intervention as part of an active vaccination program is needed.
doi:10.5812/hepatmon.6025
PMCID: PMC3475028  PMID: 23087756
Hepatitis B Virus; Vaccines; Health Personnel; Vaccination
13.  Live, Attenuated Influenza A H5N1 Candidate Vaccines Provide Broad Cross-Protection in Mice and Ferrets 
PLoS Medicine  2006;3(9):e360.
Background
Recent outbreaks of highly pathogenic influenza A H5N1 viruses in humans and avian species that began in Asia and have spread to other continents underscore an urgent need to develop vaccines that would protect the human population in the event of a pandemic.
Methods and Findings
Live, attenuated candidate vaccines possessing genes encoding a modified H5 hemagglutinin (HA) and a wild-type (wt) N1 neuraminidase from influenza A H5N1 viruses isolated in Hong Kong and Vietnam in 1997, 2003, and 2004, and remaining gene segments derived from the cold-adapted (ca) influenza A vaccine donor strain, influenza A/Ann Arbor/6/60 ca (H2N2), were generated by reverse genetics. The H5N1 ca vaccine viruses required trypsin for efficient growth in vitro, as predicted by the modification engineered in the gene encoding the HA, and possessed the temperature-sensitive and attenuation phenotypes specified by the internal protein genes of the ca vaccine donor strain. More importantly, the candidate vaccines were immunogenic in mice. Four weeks after receiving a single dose of 106 50% tissue culture infectious doses of intranasally administered vaccines, mice were fully protected from lethality following challenge with homologous and antigenically distinct heterologous wt H5N1 viruses from different genetic sublineages (clades 1, 2, and 3) that were isolated in Asia between 1997 and 2005. Four weeks after receiving two doses of the vaccines, mice and ferrets were fully protected against pulmonary replication of homologous and heterologous wt H5N1 viruses.
Conclusions
The promising findings in these preclinical studies of safety, immunogenicity, and efficacy of the H5N1 ca vaccines against antigenically diverse H5N1 vaccines provide support for their careful evaluation in Phase 1 clinical trials in humans.
Promising preclinical results on safety, immunogenicity, and efficacy against diverse H5N1 strains provide support for careful evaluation of live, attenuated H5N1 vaccines in clinical trials in humans.
Editors' Summary
Background.
Influenza A viruses are classified into subtypes according to two of the proteins from the virus surface, the hemagglutinin (HA) and neuraminidase (NA) proteins, each of which occurs naturally in several different versions. For example, the global epidemic (pandemic) of 1918–1919 was caused by an influenza virus containing subtype 1 hemagglutinin and subtype 1 neuraminidase (H1N1), the 1957–1958 pandemic involved an H2N2 virus, and the 1969 pandemic, H3N2. Since 1997, several serious outbreaks of H5N1 infection have occurred in poultry and in humans, raising concerns that H5N1 “bird flu” may cause the next human influenza pandemic. Although human-to-human transmission of H5N1 viruses appears limited, mortality rates in human outbreaks of the disease have been alarmingly high—approximately 50%. A protective vaccine against H5N1 influenza might not only benefit regions where transmission from poultry to humans occurs, but could conceivably avert global catastrophe in the event that H5N1 evolves such that human-to-human spread becomes more frequent.
Why Was This Study Done?
Several approaches are in progress to develop vaccines against H5N1 viruses. To date, the products that have been tested in humans have not been very effective in producing a strong immune response. To be optimal for human use, a vaccine would have to be very safe, remain stable in storage, and provide protection against influenza caused by naturally occurring H5N1 viruses that are not precisely identical to the ones used to make the vaccine. This study was done to develop a new H5N1 vaccine and to test it in animals.
What Did the Researchers Do and Find?
The researchers developed vaccines using three artificially constructed, weakened forms of the H5N1 influenza virus. The three vaccine viruses were constructed using flu virus proteins other than HA and NA from an artificially weakened (attenuated) strain of influenza. These were combined in laboratory-grown cells with HA and NA proteins from H5N1 viruses isolated from human cases during three different years: 2004, 2003, and 1997. They grew larger quantities of the resulting viruses in hen's eggs, and tested the vaccines in chickens, ferrets, and mice.
In tests of safety, the study found that, unlike the natural viruses from which they were derived, the vaccine strains did not cause death when injected into the bloodstream of chickens, and did not even cause infection when given through the birds' breathing passages. Similarly, while the natural viruses were lethal in mice at various doses, the vaccine strains did not cause death even at the highest dose. In ferrets, infection with the vaccine strains was limited to the upper respiratory tract, while the natural viruses spread to the lungs and other organs.
In tests of protection, all mice that had received any of the three vaccines survived following infection with any of the natural viruses (so-called viral challenge), while unvaccinated mice died following viral challenge. This occurred even though standard blood tests could not detect a strong immune responses following a single dose of vaccine. Challenge virus was detected in the lungs of the immunized mice, but at lower levels than in the unvaccinated mice. Mice given two doses of a vaccine showed stronger immunity on blood tests, and almost complete protection from respiratory infection following challenge. In addition, mice and ferrets that had received two doses of vaccine were protected against challenge with H5N1 strains from more recent outbreaks in Asia that differed substantially from the strains that were used for the vaccine.
What Do These Findings Mean?
This study shows that it is possible to create a live, attenuated vaccine based on a single H5N1 virus that can provide protection (in mice and ferrets, at least) against different H5N1 viruses that emerge years later. Attenuated influenza virus vaccines of this sort are unlikely to be useful to protect fowl because they do not infect or induce an immune response in chickens. However, while the safety and protection found in small animals are encouraging, it is not possible to know without human testing whether a vaccine that protects mice and ferrets will work in humans, or how this type of vaccine may compare with others being developed for use in humans against H5N1 influenza. Tests of one of the vaccines in human volunteers in carefully conducted clinical trials are currently under way.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030360.
WHO Influenza Pandemic Preparedness page
US Department of Health and Human Services Avian and Pandemic flu information site
Wikipedia entry on H5N1 (note: Wikipedia is a free Internet encyclopedia that anyone can edit)
CDC Avian Influenza Web page
doi:10.1371/journal.pmed.0030360
PMCID: PMC1564176  PMID: 16968127
14.  An Assessment of Survival among Korean Elderly Patients Initiating Dialysis: A National Population-Based Study 
PLoS ONE  2014;9(1):e86776.
Background
Although the proportion of the elderly patients with incident end-stage renal disease (ESRD) patients has been increasing in Korea, there has been a lack of information on outcomes of dialysis treatment. This study aimed to assess the survival rate and to elucidate predictors for all-cause mortality among elderly Korean patients initiating dialysis.
Methods
We analyzed 11,301 patients (6,138 men) aged 65 years or older who had initiated dialysis from 2005 to 2008 and had followed up (median, 37.8 months; range, 3–84 months). Baseline demographics, comorbidities and mortality data were obtained using the database from the Health Insurance Review & Assessment Service.
Results
The unadjusted 5-year survival rate was 37.6% for all elderly dialysis patients, and the rate decreased with increasing age categories; 45.9% (65∼69), 37.5% (70∼74), 28.4% (75∼79), 24.1% (80∼84), and 13.7% (≥85 years). The multivariate Cox proportional hazard model revealed that age, sex, dialysis modality, the type of insurance, and comorbidities such as diabetes mellitus, myocardial infarction, congestive heart failure, peripheral vascular disease, cerebrovascular disease, dementia, chronic pulmonary disease, hemiparesis, liver disease, and any malignancy were independent predictors for mortality. In addition, survival rate was significantly higher in patients on hemodialysis compared to patients on peritoneal dialysis during the whole follow-up period in the intention-to-treat analysis.
Conclusions
Survival rate was significantly associated with age, sex, and various comorbidities in Korean elderly patients initiating dialysis. The results of our study can help to provide relevant guidance on the individualization strategy in elderly ESRD patients requiring dialysis.
doi:10.1371/journal.pone.0086776
PMCID: PMC3899356  PMID: 24466236
15.  The Effect of Universal Influenza Immunization on Mortality and Health Care Use 
PLoS Medicine  2008;5(10):e211.
Background
In 2000, Ontario, Canada, initiated a universal influenza immunization program (UIIP) to provide free influenza vaccines for the entire population aged 6 mo or older. Influenza immunization increased more rapidly in younger age groups in Ontario compared to other Canadian provinces, which all maintained targeted immunization programs. We evaluated the effect of Ontario's UIIP on influenza-associated mortality, hospitalizations, emergency department (ED) use, and visits to doctors' offices.
Methods and Findings
Mortality and hospitalization data from 1997 to 2004 for all ten Canadian provinces were obtained from national datasets. Physician billing claims for visits to EDs and doctors' offices were obtained from provincial administrative datasets for four provinces with comprehensive data. Since outcomes coded as influenza are known to underestimate the true burden of influenza, we studied more broadly defined conditions. Hospitalizations, ED use, doctors' office visits for pneumonia and influenza, and all-cause mortality from 1997 to 2004 were modelled using Poisson regression, controlling for age, sex, province, influenza surveillance data, and temporal trends, and used to estimate the expected baseline outcome rates in the absence of influenza activity. The primary outcome was then defined as influenza-associated events, or the difference between the observed events and the expected baseline events. Changes in influenza-associated outcome rates before and after UIIP introduction in Ontario were compared to the corresponding changes in other provinces. After UIIP introduction, influenza-associated mortality decreased more in Ontario (relative rate [RR] = 0.26) than in other provinces (RR = 0.43) (ratio of RRs = 0.61, p = 0.002). Similar differences between Ontario and other provinces were observed for influenza-associated hospitalizations (RR = 0.25 versus 0.44, ratio of RRs = 0.58, p < 0.001), ED use (RR = 0.31 versus 0.69, ratio of RRs = 0.45, p < 0.001), and doctors' office visits (RR = 0.21 versus 0.52, ratio of RRs = 0.41, p < 0.001). Sensitivity analyses were carried out to assess consistency, specificity, and the presence of a dose-response relationship. Limitations of this study include the ecological study design, the nonspecific outcomes, difficulty in modeling baseline events, data quality and availability, and the inability to control for potentially important confounders.
Conclusions
Compared to targeted programs in other provinces, introduction of universal vaccination in Ontario in 2000 was associated with relative reductions in influenza-associated mortality and health care use. The results of this large-scale natural experiment suggest that universal vaccination may be an effective public health measure for reducing the annual burden of influenza.
Comparing influenza-related mortality and health care use between Ontario and other Canadian provinces, Jeffrey Kwong and colleagues find evidence that Ontario's universal vaccination program has reduced the burden of influenza.
Editors' Summary
Background.
Seasonal outbreaks (epidemics) of influenza—a viral disease of the nose, throat, and airways—affect millions of people and kill about 500,000 individuals every year. These epidemics occur because of “antigenic drift”: small but frequent changes in the viral proteins to which the human immune system responds mean that an immune response produced one year by exposure to an influenza virus provides only partial protection against influenza the next year. Immunization can boost this natural immunity and reduce a person's chances of catching influenza. That is, an injection of killed influenza viruses can be used to prime the immune system so that it responds quickly and efficiently when exposed to live virus. However, because of antigenic drift, for influenza immunization to be effective, it has to be repeated annually with a vaccine that contains the major circulating strains of the influenza virus.
Why Was This Study Done?
Public-health organizations recommend targeted vaccination programs, so that elderly people, infants, and chronically ill individuals—the people most likely to die from pneumonia and other complications of influenza—receive annual influenza vaccination. Some experts argue, however, that universal vaccination might provide populations with better protection from influenza, both directly by increasing the number of vaccinated people and indirectly through “herd immunity,” which occurs when a high proportion of the population is immune to an infectious disease, so that even unvaccinated people are unlikely to become infected (because infected people rarely come into contact with susceptible people). In this study, the researchers compare the effects of the world's first free universal influenza immunization program (UIIP), which started in 2000 in the Canadian province of Ontario, on influenza-associated deaths and health care use with the effects of targeted vaccine programs on the same outcomes elsewhere in Canada.
What Did the Researchers Do and Find?
Using national records, the researchers collected data on influenza vaccination, on all deaths, and on hospitalizations for pneumonia and influenza in all Canadian provinces between 1997 and 2004. They also collected data on emergency department and doctors' office visits for pneumonia and influenza for Ontario, Quebec, Alberta, and Manitoba. They then used a mathematical model to estimate the baseline rates for these outcomes in the absence of influenza activity, and from these calculated weekly rates for deaths and health care use specifically resulting from influenza. In 1996–1997, 18% of the population was vaccinated against influenza in Ontario whereas in the other provinces combined the vaccination rate was 13%. On average, since 2000—the year in which UIIP was introduced in Ontario—vaccination rates have risen to 38% and 24% in Ontario and the other provinces, respectively. Since the introduction of UIIP, the researchers report, influenza-associated deaths have decreased by 74% in Ontario but by only 57% in the other provinces combined. Influenza-associated use of health care facilities has also decreased more in Ontario than in the other provinces over the same period.
What Do These Findings Mean?
These findings are limited by some aspects of the study design. For example, they depend on the accuracy of the assumptions made when calculating events due specifically to influenza, and on the availability and accuracy of vaccination and clinical outcome data. In addition, it is possible that influenza-associated deaths and health care use may have decreased more in Ontario than in the other Canadian provinces because of some unrecognized health care changes specific to Ontario but unrelated to the introduction of universal influenza vaccination. Nevertheless, these findings indicate that, compared to the targeted vaccination programs in the other Canadian provinces, the Ontarian UIIP is associated with reductions in influenza-associated deaths and health care use, particularly in people younger than 65 years old. This effect is seen at a level of vaccination unlikely to produce herd immunity so might be more marked if the uptake of vaccination could be further increased. Thus, although it is possible that Canada is a special case, these findings suggest that universal influenza vaccination might be an effective way to reduce the global burden of influenza.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0050211.
Read the related PLoSMedicine Perspective by Cécile Viboud and Mark Miller
A related PLoSMedicine Research Article by Carline van den Dool and colleagues is also available
The Ontario Ministry of Health provides information on its universal influenza immunization program (in English and French)
The World Health Organization provides information on influenza and on influenza vaccines (in several languages)
The US Centers for Disease Control and Prevention provide information for patients and professionals on all aspects of influenza (in English and Spanish)
MedlinePlus provides a list of links to other information about influenza (in English and Spanish)
The UK National Health Service provides information about the science of immunization, including a simple explanatory animation of immunity
doi:10.1371/journal.pmed.0050211
PMCID: PMC2573914  PMID: 18959473
16.  Herpes Zoster Vaccine Effectiveness against Incident Herpes Zoster and Post-herpetic Neuralgia in an Older US Population: A Cohort Study 
PLoS Medicine  2013;10(4):e1001420.
Sinead Marie Langan and colleagues studied a cohort of more than 750,000 individuals over the age of 65 years to assess whether herpes zoster vaccine is effective against incident zoster and post-herpetic neuralgia in an older population.
Background
Herpes zoster is common and has serious consequences, notably post-herpetic neuralgia (PHN). Vaccine efficacy against incident zoster and PHN has been demonstrated in clinical trials, but effectiveness has not been studied in unselected general populations unrestricted by region, full health insurance coverage, or immune status. Our objective was to assess zoster vaccine effectiveness (VE) against incident zoster and PHN in a general population-based setting.
Methods and Findings
A cohort study of 766,330 fully eligible individuals aged ≥65 years was undertaken in a 5% random sample of Medicare who received and did not receive zoster vaccination between 1st January 2007 and 31st December 2009.
Incidence rates and hazard ratios for zoster and PHN were determined in vaccinated and unvaccinated individuals. Analyses were adjusted for age, gender, race, low income, immunosuppression, and important comorbidities associated with zoster, and then stratified by immunosuppression status. Adjusted hazard ratios were estimated using time-updated Cox proportional hazards models.
Vaccine uptake was low (3.9%) particularly among black people (0.3%) and those with evidence of low income (0.6%). 13,112 US Medicare beneficiaries developed incident zoster; the overall zoster incidence rate was 10.0 (9.8–10.2) per 1,000 person-years in the unvaccinated group and 5.4 (95% CI 4.6–6.4) per 1,000 person-years in vaccinees, giving an adjusted VE against incident zoster of 0.48 (95% CI 0.39–0.56). In immunosuppressed individuals, VE against zoster was 0.37 (95% CI 0.06–0.58). VE against PHN was 0.59 (95% CI 0.21–0.79).
Conclusions
Vaccine uptake was low with variation in specific patient groups. In a general population cohort of older individuals, zoster vaccination was associated with reduction in incident zoster, including among those with immunosuppression. Importantly, this study demonstrates that zoster vaccination is associated with a reduction in PHN.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Chickenpox is an extremely common childhood infectious disease that is caused by the herpes varicella-zoster virus. Children usually recover quickly from chickenpox, but dormant varicella-zoster virus persists throughout life inside the nervous system. The dormant virus causes no symptoms but if it becomes reactivated, it causes shingles (zoster), a painful skin rash. Anyone who has had chickenpox can develop shingles but shingles is most common and most severe in 60–80-year-old people. Indeed, about half of people who live to 85 will have an episode of shingles. Early signs of shingles include burning or shooting pain and tingling or itching. Blister-like sores, which last from 1–14 days, then develop in a region of one side of the body or on one side of the face. The pain of shingles can be debilitating and can continue after the rash disappears—“post-herpetic neuralgia,” which can last for months to years, greatly reduces the quality of life. There is no cure for shingles but early treatment with antivirals may help to prevent lingering pain by inhibiting viral replication.
Why Was This Study Done?
Shingles vaccination can prevent shingles or lessen its effects. In clinical trials, vaccination reduced the incidence of shingles (the proportion of a population who develop shingles in a year) and the incidence of post-herpetic neuralgia, and vaccination against shingles is now recommended in the US for everyone over the age of 60 except individuals with a weakened immune system (for example, people with HIV/AIDS). However, these clinical trials determined the vaccine's efficacy in selected populations under controlled conditions. How effective is the vaccine in unselected populations in routine clinical use? In this cohort study, the researchers assess zoster (shingles) vaccine effectiveness against incident shingles and post-herpetic neuralgia in an unselected population of older individuals in the US. A cohort study follows a group of individuals who differ with respect to specific factors (in this study, vaccination against shingles) to determine how these factors affect the rates of specific outcomes (shingles and post-herpetic neuralgia).
What Did the Researchers Do and Find?
The researchers undertook their cohort study in 766,330 randomly chosen Medicare beneficiaries aged 65 years or more. Medicare is a US government health insurance scheme that mainly helps to pay the health care costs of people aged 65 or older. The researchers used Medicare administrative data to identify which cohort members received zoster vaccination between January 2007 and December 2009 and which developed incident shingles (defined as a first diagnosis of shingles combined with the use of antivirals) or post-herpetic neuralgia (defined as a code for post-herpetic neuralgia, non-specific neuralgia, or a second diagnostic code for shingles 90 days after the first diagnosis combined with a prescription for pain relief, an anticonvulsant, or an antidepressant). Vaccine uptake was low in this unselected study population—only 3.9% of the participants were vaccinated. The vaccination rate was particularly low among black people (0.6% of person-time) and among people with a low income (0.3%). About 13,000 participants developed incident shingles. The shingles incidence rate was 10.0 per 1,000 person-years among unvaccinated participants and 5.4 per 1,000 person-years among vaccinated participants. Vaccine effectiveness against incident shingles was 48%. That is, vaccination reduced the incidence of shingles by 48% (in other words, approximately half as many vaccinated individuals developed shingles as those who were not vaccinated). Vaccine effectiveness against incident shingles among immunosuppressed individuals was lower (37%). Finally, vaccine effectiveness against post-herpetic neuralgia was 59%.
What Do These Findings Mean?
These findings show that shingles vaccine uptake is low among elderly people in the US and varies between different patient groups. They show that shingles vaccination is effective against incident shingles in a general population of older individuals, including those who are immunosuppressed, and suggest that shingles vaccination is effective against post-herpetic neuralgia. However, because these findings rely on administrative data, their accuracy may be affected by misclassification of vaccination and of outcomes. Moreover, because shingles vaccination was not randomized, the vaccinated individuals might have shared other characteristics that were actually responsible for their lower incidence of shingles and/or post-herpetic neuralgia compared to unvaccinated individuals. Despite these limitations, these findings provide useful information for policy makers in countries that are currently considering the introduction of shingles vaccination into routine practice. Moreover, they highlight the need to increase shingles vaccination among elderly individuals in the US, the section of the population at the highest risk of post-herpetic neuralgia.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/ 10.1371/journal.pmed.1001420.
The US Centers for Disease Control and Prevention have detailed information about all aspects of shingles (zoster), including information on vaccination for the public and for health care professionals, and a personal story about shingles
The NIH Senior Health website includes information on shingles and a video describing a personal experience of shingles
The UK National Health Service Choices also provides information about all aspects of shingles and a personal story
MedlinePlus provides links to other resources about shingles (in English and Spanish)
The British Association of Dermatologists website has an information leaflet on shingles
The New Zealand Dermatological Society website has a leaflet on shingles
doi:10.1371/journal.pmed.1001420
PMCID: PMC3621740  PMID: 23585738
17.  Hepatitis B Screening and Vaccination Strategies for Newly Arrived Adult Canadian Immigrants and Refugees: A Cost-Effectiveness Analysis  
PLoS ONE  2013;8(10):e78548.
Background
Immigrants have increased mortality from hepatocellular carcinoma as compared to the host populations, primarily due to undetected chronic hepatitis B virus (HBV) infection. Despite this, there are no systematic programs in most immigrant-receiving countries to screen for chronic HBV infection and immigrants are not routinely offered HBV vaccination outside of the universal childhood vaccination program.
Methods and findings
A cost-effective analysis was performed to compare four HBV screening and vaccination strategies with no intervention in a hypothetical cohort of newly-arriving adult Canadian immigrants. The strategies considered were a) universal vaccination, b) screening for prior immunity and vaccination, c) chronic HBV screening and treatment, and d) combined screening for chronic HBV and prior immunity, treatment and vaccination. The analysis was performed from a societal perspective, using a Markov model. Seroprevalence estimates, annual transition probabilities, health-care costs (in Canadian dollars), and utilities were obtained from the published literature. Acute HBV infection, mortality from chronic HBV, quality-adjusted life years (QALYs), and costs were modeled over the lifetime of the cohort of immigrants. Costs and QALYs were discounted at a rate of 3% per year. Screening for chronic HBV infection, and offering treatment if indicated, was found to be the most cost-effective intervention and was estimated to cost $40,880 per additional QALY gained, relative to no intervention. This strategy was most cost-effective for immigrants < 55 years of age and would cost < $50,000 per additional QALY gained for immigrants from areas where HBV seroprevalence is ≥ 3%. Strategies that included HBV vaccination were either prohibitively expensive or dominated by the chronic HBV screening strategy.
Conclusions
Screening for chronic HBV infection from regions where most Canadian immigrants originate, except for Latin America and the Middle East, was found to be reasonably cost-effective and has the potential to reduce HBV-associated morbidity and mortality.
doi:10.1371/journal.pone.0078548
PMCID: PMC3799697  PMID: 24205255
18.  Hepatitis B and C infection in haemodialysis patients in Libya: prevalence, incidence and risk factors 
BMC Infectious Diseases  2012;12:265.
Background
Patients receiving maintenance haemodialysis (HD) are at higher risk for acquiring Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) infections than the general population. Strict infection control measures are essential to prevent nosocomial transmission. We aimed to investigate the incidence and prevalence of HBV and HCV infection in the HD population of Libya as well as risk factors for infection.
Methods
All adult patients receiving maintenance HD (n=2382) in Libyan dialysis centres (n=39) were studied between May 2009 and October 2010. Testing for Hepatitis B surface antigen (HBsAg) and anti-HCV antibodies was performed at initiation of dialysis and every 3–6 months thereafter. Patients who were sero-negative for HBV and HCV (n=1160) were followed up for 1 year to detect sero-conversions.
Results
Participant median age was 49 years and 58% were male. 831 patients (34.9%) were sero-positive for HBV and/or HCV (anti-HCV positive 31.1%; HBsAg positive 2.6%; both positive 1.2%). Of the sero-positive patients 4.7% were known to be infected before the initiation of HD. The prevalence of HBV±HCV infection varied widely between HD centres from 0% to 75.9%. Sero-positive patients were younger, had longer time on dialysis and more previous blood transfusions. Prospective follow-up revealed an incidence of sero-conversion of 7.7% during 1 year (7.1% HCV; 0.6% HBV). Wide variation in rates of newly acquired infections was observed between dialysis centres. All new HBV cases were referred from centres already treating HBV infected patients. New HCV infections were reported in most centres but the rate of HCV sero-conversion varied widely from 1.5% to 31%. Duration of dialysis, history of previous renal transplant and history of receiving HD in another centre in Libya were significantly associated with sero-conversion.
Conclusion
Patients on maintenance HD in Libya have a high incidence and prevalence of HCV infection and lower rates of HBV infection. The factors associated with HBV and HCV infection are highly suggestive of nosocomial transmission within HD units. Urgent action is required to improve infection control measures in HD centres and to reduce dependence on blood transfusions for the treatment of anaemia.
doi:10.1186/1471-2334-12-265
PMCID: PMC3507892  PMID: 23082935
Haemodialysis; Hepatitis B; Hepatitis C; Incidence; Libya; Nosocomial infection; Prevalence
19.  Lack of implementation of Hepatitis B Virus (HBV) vaccination policy in household contacts of HBV carriers in Italy 
Background
In Italy, HBV vaccination is recommended and offered free of charge through the National Health Service to selected population groups – e.g., family members of an HBsAg carrier, healthcare workers, newborns and those who were 12-years old in 1991. However, a significant proportion of cases of acute hepatitis B still occur in Italy among persons who should have been vaccinated. We analysed HBV sero-prevalence data of two vaccination target populations (people born after 1980 and household contacts of an HBV carrier) living in a southern Italian area in order to evaluate HBV vaccine coverage and its possible determinants.
Methods
Between 2003 and 2006, we carried out a cross-sectional, population-based, sero-epidemiological survey on HBV infection on 4496 randomly selected individuals (aged 20 years or more) from the general population of the province of Naples. Sera were tested for antibodies to hepatitis B core antigen (anti-HBc) and to hepatitis B surface antigen (anti-HBsAg) by commercial immunoassays. Prevalence of past or current HBV infection and of HBV vaccination-induced immunity was calculated in two vaccination target populations. To analyze the association of epidemiological and socioeconomic characteristics with HBV vaccination of household contacts, we calculated crude and multiple logistic regression (MLR) odds ratio (OR).
Results
Prevalence of HBV vaccine-induced immunity (anti-HBs alone) was much lower among household contacts (25%) than among those who had been targeted for universal adolescent vaccination (81.6%). Male sex, older age, unemployment and lower education levels were associated to lower immunization rates.
Conclusion
Understanding the different uptake of hepatitis B vaccination in these populations may provide useful information for optimizing vaccination campaigns in other contexts. Our data clearly demonstrated the need of improving the uptake of vaccination for household contacts of HBV carriers.
doi:10.1186/1471-2334-9-86
PMCID: PMC2702368  PMID: 19500412
20.  The Relationship Between Erythropoietin Resistance and Antibody Response to Hepatitis B Vaccine in Hemodialysis Patients 
Nephro-urology Monthly  2013;5(3):806-812.
Background
Seroconversion following Hepatitis B virus (HBV) vaccine in hemodialysis (HD) patients has been shown to be suboptimal. Nutritional and immunological factors were shown to influence the seroconversion related to HBV vaccination in HD patients. Resistance to erythropoiesis stimulating agents (ESA) for correction of anemia has also been shown to be associated with nutrition and inflammation in these patients.
Objectives
The aim of the current study was to analyze the relationship between anti-HBs response and erythropoietin (EPO) resistance in HD patients.
Patients and Methods
Demographics, clinical characteristics, laboratory parameters and the data about vaccination status were obtained from dialysis charts and vaccination registries retrospectively. To calculate the EPO resistance ESA hypo responsiveness index (EHRI) was used. The EHRI was calculated through deviding the weekly dose of EPO by per kilogram of body weight divided by the hemoglobin level. Patients were divided into non-seroconversion (anti-HBs titers were < 10 IU/L) and seroconversion groups (anti-HBs titers were ≥ 10 IU/L) after completion of the four-dose vaccination schedule.
Results
In total 97 patients were enrolled. For the entire group, stepwise linear regression analysis revealed that square root transformed anti-HBs levels were independently associated with age (P = 0.016), blood urea nitrogen (P = 0.019), high sensitive C-Reactive Protein (P = 0.009), and square root transformed EHRI (P = 0.019). Logistic regression analysis have also demonstrated that blood urea nitrogen (P = 0.002), creatinine (P = 0.046), albumin (P = 0.01) and square root transformed EHRI (P = 0.011) were independently related to seroconversion.
Conclusions
EPO resistance was negatively associated with anti-HBs levels and seroconversion. More studies are needed to highlight the underlying mechanisms regarding EPO resistance and response to HBV vaccination in HD patients.
doi:10.5812/numonthly.8919
PMCID: PMC3830906  PMID: 24282790
Erythropoietin; Hepatitis B; Renal Dialysis; Vaccines
21.  Long-Term Survival and Dialysis Dependency Following Acute Kidney Injury in Intensive Care: Extended Follow-up of a Randomized Controlled Trial 
PLoS Medicine  2014;11(2):e1001601.
Martin Gallagher and colleagues examine the long-term outcomes of renal replacement therapy (RRT) dosing in patients with acute kidney injury randomized to normal vs. augmented RRT.
Please see later in the article for the Editors' Summary
Background
The incidence of acute kidney injury (AKI) is increasing globally and it is much more common than end-stage kidney disease. AKI is associated with high mortality and cost of hospitalisation. Studies of treatments to reduce this high mortality have used differing renal replacement therapy (RRT) modalities and have not shown improvement in the short term. The reported long-term outcomes of AKI are variable and the effect of differing RRT modalities upon them is not clear. We used the prolonged follow-up of a large clinical trial to prospectively examine the long-term outcomes and effect of RRT dosing in patients with AKI.
Methods and Findings
We extended the follow-up of participants in the Randomised Evaluation of Normal vs. Augmented Levels of RRT (RENAL) study from 90 days to 4 years after randomization. Primary and secondary outcomes were mortality and requirement for maintenance dialysis, respectively, assessed in 1,464 (97%) patients at a median of 43.9 months (interquartile range [IQR] 30.0–48.6 months) post randomization. A total of 468/743 (63%) and 444/721 (62%) patients died in the lower and higher intensity groups, respectively (risk ratio [RR] 1.04, 95% CI 0.96–1.12, p = 0.49). Amongst survivors to day 90, 21 of 411 (5.1%) and 23 of 399 (5.8%) in the respective groups were treated with maintenance dialysis (RR 1.12, 95% CI 0.63–2.00, p = 0.69). The prevalence of albuminuria among survivors was 40% and 44%, respectively (p = 0.48). Quality of life was not different between the two treatment groups. The generalizability of these findings to other populations with AKI requires further exploration.
Conclusions
Patients with AKI requiring RRT in intensive care have high long-term mortality but few require maintenance dialysis. Long-term survivors have a heavy burden of proteinuria. Increased intensity of RRT does not reduce mortality or subsequent treatment with dialysis.
Trial registration
www.ClinicalTrials.gov NCT00221013
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Throughout life, the kidneys perform the essential task of filtering waste products (from the normal breakdown of tissues and from food) and excess water from the blood to make urine. Chronic kidney disease (caused, for example, by diabetes) gradually destroys the kidneys' filtration units (the nephrons), eventually leading to life-threatening end-stage kidney disease. However, the kidneys can also stop working suddenly because of injury, infection, or poisoning. Acute kidney injury (AKI) is much more common than end-stage kidney disease and its incidence is increasing worldwide. In the US, for example, the number of hospitalizations that included an AKI diagnosis rose from 4,000 in 1996 to 23,000 in 2008. Moreover, nearly half of patients with AKI will die shortly after the condition develops. Symptoms of AKI include changes in urination, swollen feet and ankles, and tiredness. Treatments for AKI aim to prevent fluid and waste build up in the body and treat the underlying cause (e.g., severe infection or dehydration) while allowing the kidneys time to recover. In some patients, it is sufficient to limit the fluid intake and to reduce waste build-up by eating a diet that is low in protein, salt, and potassium. Other patients need renal replacement therapy (RRT), life-supporting treatments such as hemodialysis and hemofiltration, two processes that clean the blood by filtering it outside the body.
Why Was This Study Done?
The long-term outcomes of AKI (specifically, death and chronic kidney disease) and the effects of different RRT modalities on these outcomes are unclear. A recent controlled trial that randomly assigned patients with AKI who were managed in intensive care units (ICUs) to receive two different intensities of continuous hemodiafiltration (a combination of hemodialysis and hemofiltration) found no difference in all-cause mortality (death) at 90 days. Here, the researchers extend the follow-up of this trial (the Randomized Evaluation of Normal vs. Augmented Levels of renal replacement therapy [RENAL] study) to investigate longer-term mortality, the variables that predict mortality, treatment with long-term dialysis (an indicator of chronic kidney disease), and functional outcomes in patients with AKI treated with different intensities of continuous RRT.
What Did the Researchers Do and Find?
For the Prolonged Outcomes Study of RENAL (POST-RENAL), the researchers extended the follow-up of the RENAL participants up to 4 years. Over an average follow-up of 43.9 months, 63% of patients in the lower intensity treatment group died compared to 62% of patients in the higher intensity group. Overall, a third of patients who survived to 90 days died during the extended follow-up. Among the survivors to day 90, 5.1% and 5.8% of patients in the lower and higher intensity groups, respectively, were treated with maintenance dialysis during the extended follow-up. Among survivors who consented to analysis, 40% and 44% of patients in the lower and higher intensity groups, respectively, had albuminuria (protein in the urine, an indicator of kidney damage). Patients in both groups had a similar quality life (determined through telephone interviews). Finally, increasing age, APACHE III score (a scoring system that predicts the survival of patients in ICU), and serum creatinine level (an indicator of kidney function) at randomization were all predictors of long-term mortality.
What Do These Findings Mean?
These findings indicate that patients with AKI in ICUs who require RRT have a high long-term mortality. They show that few survivors require maintenance dialysis for chronic kidney disease but that there is a substantial rate of albuminuria among survivors despite relative preservation of kidney function. The findings also suggest that the intensity of RRT has no significant effect on mortality or the need for dialysis. Because these findings were obtained in a randomized controlled trial, they may not be generalizable to other patient populations. Moreover, although data on mortality and maintenance dialysis were available for all the trial participants, clinical and biochemical outcomes were only available for some participants and may not be representative of all the participants. Despite these study limitations, these findings suggest that survivors of AKI may be at a high risk of death or of developing chronic kidney disease. Survivors of AKI are, therefore, at high risk of further illness and long-term albuminuria reduction strategies may offer a therapeutic intervention for this group of patients.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001601.
The US National Kidney and Urologic Diseases Information Clearinghouse provides information about the kidneys and about all aspects of kidney disease and its treatment; the US National Kidney Disease Education Program provides resources to help improve the understanding, detection, and management of kidney disease (in English and Spanish)
The Mayo Clinic provides information for patients about acute kidney injury
Wikipedia has a page on acute kidney injury (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The not-for-profit UK National Kidney Federation provides support and information for patients with kidney disease and for their carers, including a link to a video about acute kidney injury
World Kidney Day, a joint initiative between the International Society of Nephrology and the International Federation of Kidney Foundations (IFKF), aims to raise awareness about kidneys and kidney disease; its website provides information about acute kidney injury
The MedlinePlus Encyclopedia has a pages about acute kidney failure and about renal dialysis
The UK National Institute for Health and Care Excellence (NICE) recently published new guidelines on the treatment of acute kidney injury; a clinical practice guideline for acute kidney injury produced by KDIGO (a not-for-profit organization that aims to improve the care and outcomes of kidney disease patients worldwide through the development and implementation of global clinical practice guidelines) is available; the Acute Kidney Injury app provides a fast and simple way to explore guidelines on the diagnosis, prevention, and management of AKI
doi:10.1371/journal.pmed.1001601
PMCID: PMC3921111  PMID: 24523666
22.  Frequency of Adverse Events after Vaccination with Different Vaccinia Strains 
PLoS Medicine  2006;3(8):e272.
Background
Large quantities of smallpox vaccine have been stockpiled to protect entire nations against a possible reintroduction of smallpox. Planning for an appropriate use of these stockpiled vaccines in response to a smallpox outbreak requires a rational assessment of the risks of vaccination-related adverse events, compared to the risk of contracting an infection. Although considerable effort has been made to understand the dynamics of smallpox transmission in modern societies, little attention has been paid to estimating the frequency of adverse events due to smallpox vaccination. Studies exploring the consequences of smallpox vaccination strategies have commonly used a frequency of approximately one death per million vaccinations, which is based on a study of vaccination with the New York City Board of Health (NYCBH) strain of vaccinia virus. However, a multitude of historical studies of smallpox vaccination with other vaccinia strains suggest that there are strain-related differences in the frequency of adverse events after vaccination. Because many countries have stockpiled vaccine based on the Lister strain of vaccinia virus, a quantitative evaluation of the adverse effects of such vaccines is essential for emergency response planning. We conducted a systematic review and statistical analysis of historical data concerning vaccination against smallpox with different strains of vaccinia virus.
Methods and Findings
We analyzed historical vaccination data extracted from the literature. We extracted data on the frequency of postvaccinal encephalitis and death with respect to vaccinia strain and age of vaccinees. Using a hierarchical Bayesian approach for meta-analysis, we estimated the expected frequencies of postvaccinal encephalitis and death with respect to age at vaccination for smallpox vaccines based on the NYCBH and Lister vaccinia strains. We found large heterogeneity between findings from different studies and a time-period effect that showed decreasing incidences of adverse events over several decades. To estimate death rates, we then restricted our analysis to more-recent studies. We estimated that vaccination with the NYCBH strain leads to an average of 1.4 deaths per million vaccinations (95% credible interval, 0–6) and that vaccination with Lister vaccine leads to an average of 8.4 deaths per million vaccinations (95% credible interval, 0–31). We combined age-dependent estimates of the frequency of death after vaccination and revaccination with demographic data to obtain estimates of the expected number of deaths in present societies due to vaccination with the NYCBH and Lister vaccinia strains.
Conclusions
Previous analyses of smallpox vaccination policies, which rely on the commonly assumed value of one death per million vaccinations, may give serious underestimates of the number of deaths resulting from vaccination. Moreover, because there are large, strain-dependent differences in the frequency of adverse events due to smallpox vaccination, it is difficult to extrapolate from predictions for the NYCBH-derived vaccines (stockpiled in countries such as the US) to predictions for the Lister-derived vaccines (stockpiled in countries such as Germany). In planning for an effective response to a possible smallpox outbreak, public-health decision makers should reconsider their strategies of when to opt for ring vaccination and when to opt for mass vaccination.
Analysis of historical data for adverse events suggests that the commonly assumed number of one death per million vaccinations is inaccurate. Large differences between different vaccinia strains used should be taken into account when mass vaccinations are considered.
Editors' Summary
Background.
For thousands of years, smallpox was one of the world's most-feared diseases. This contagious disease, caused by the variola virus, historically killed about 30 percent of the people it infected. Over the centuries, it probably killed more people than all other infectious diseases combined, but it was also the first disease to be prevented by vaccination. In 1796, the English physician Edward Jenner rubbed pus from the spots of a milkmaid with cowpox into scratches on a young boy's arm; according to folklore, people who caught cowpox, a related but mild disease of cows, were protected against smallpox. Six weeks later, after a mild bout of cowpox, when the boy was challenged with pus from a smallpox patient, he did not develop smallpox. This vaccination procedure was later refined so that people were inoculated with pure preparations of live vaccinia virus, which is closely related to the smallpox and cowpox viruses, and by 1979 a global vaccination campaign had totally eradicated the disease.
Why Was This Study Done?
Smallpox vaccination has some adverse effects. In particular, vaccinia virus occasionally infects the brain. This so-called post-vaccination encephalitis can cause permanent brain damage and, it has been estimated, kills one vaccinee in every million. Consequently, as smallpox became rarer, the dangers of vaccination began to outweigh its benefits. Routine smallpox vaccination stopped in the US in 1972, and in 1980 the World Health Organization recommended that all countries stop vaccination. Now, however, there are fears that smallpox may be used for bioterrorism. If this did happen, exposed individuals and their contacts, possibly even whole populations, would have to be vaccinated as quickly as possible (very few people now have strong immunity to smallpox). Many countries have stockpiles of smallpox vaccines for this eventuality, but these contain different vaccinia virus strains. In this study, the researchers examined historical data to discover whether these strains differ in their potential to cause encephalitis and death. This information should help public-health officials plan their vaccination strategies in response to a bioterrorism attack with smallpox.
What Did the Researchers Do and Find?
The researchers collected data from published studies on smallpox vaccination and adverse events from several countries from the late 1950s onwards. They then used these data to extrapolate how often the different vaccinia strains might cause encephalitis and death if they were used today in vaccination programs. They estimate that vaccinating with the New York City Board of Health (NYCBH) strain, which is stockpiled in the US, might cause 2.9 cases of post-vaccination encephalitis and 1.4 deaths per million vaccinated individuals. In contrast, the Lister strain, which is stockpiled in many European countries, might cause 26.2 cases of post-vaccination encephalitis and 2.5 deaths per million vaccinees. For both strains, vaccination of children younger than 1 year old would cause the highest death rate, and individuals being re-vaccinated would be less likely to die than those being vaccinated for the first time. Finally, the researchers use their figures to estimate that about ten people would die if mass vaccination with the NYCBH strain were used in the Netherlands (population 16 million), whereas 55 people would die if the Lister strain were used.
What Do These Findings Mean?
The data used in this study are of variable quality, so the figures calculated by the researchers are only estimates. For instance, given the scatter of the original data, mass vaccination in the Netherlands with the Lister strain might cause anywhere between seven and nearly 200 deaths. However, the study clearly suggests that more serious adverse events would occur after vaccination with the Lister strain than after vaccination with the NYCBH strain. It also indicates that even in the US, where the NYCBH vaccine strain is stockpiled, previous analyses of the effects of vaccination in response to a bioterrorist attack have probably underestimated how many people might die from post-vaccination encephalitis. Public-health decision makers should incorporate these new estimates into their planning for a smallpox outbreak. These increased estimates of adverse events after vaccination might, for example, make mass vaccination with the Lister strain of vaccinia virus less acceptable. Instead, public-health officials might decide to rely on vaccination of only the people directly exposed to released smallpox virus and their close contacts (ring vaccination) to contain a smallpox outbreak.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0030272.
World Health Organization, information on smallpox and preparedness in the event of a smallpox outbreak
MedlinePlus encyclopedia entry on smallpox
US National Institute of Allergy and Infectious Diseases, patient fact sheet on smallpox
US Centers for Disease Control and Prevention, information for patients and professionals on smallpox
Wikipedia page on smallpox (note that Wikipedia is a free online encyclopedia that anyone can edit)
Wellcome Library MedHist, links to information on the history of smallpox vaccination
doi:10.1371/journal.pmed.0030272
PMCID: PMC1551910  PMID: 16933957
23.  The Epidemiology of Hepatitis B Virus Infection in a U.S. Cohort of HIV-Infected Individuals During the Last 20 Years 
Background
The epidemiologic trends of hepatitis B virus (HBV) infection in HIV-infected patients over the last twenty years are largely unknown.
Methods
Prevalence and risk factors for HBV infection overall, at the time of HIV infection, and following HIV infection were examined in an ongoing observational HIV cohort study. Risk factors for HBV infection at the time of HIV diagnosis were evaluated using logistic regression, and risk for incident HBV infection following HIV diagnosis was evaluated using Cox proportional hazards models.
Results
Of the 2769 evaluable participants, 1078 (39%) had HBV infection, of which 117 (11%) had chronic HBV. The yearly cross-sectional prevalence of HBV infection decreased from a peak of 49% in 1995 to 36% in 2008 (p<0.001). HBV prevalence at the time of HIV diagnosis decreased between 1989 and 2008 from 34% to 9% (p<0.001). The incidence of HBV infection following HIV diagnosis decreased from 4.0/100 person-years in the pre-HAART era to 1.1/100 person-years in the HAART era (p<0.001), but has remained unchanged from 2000 through 2008 (p=0.49), with over 20% of incident HBV infections having chronic HBV. Decreased risk of HBV infection following HIV diagnosis was associated with higher CD4 cell counts and the use of HBV-active HAART. Receipt of ≥1 dose of HBV vaccine was not associated with reduced risk of HBV infection after HIV diagnosis.
Conclusions
While the burden of HBV infection overall is slowly decreasing among HIV-infected individuals, the persistent rate of HBV infection following HIV diagnosis raises concern that more effective prevention strategies may be needed to significantly reduce HBV infections in this patient population.
doi:10.1086/649885
PMCID: PMC2805765  PMID: 20047484
Hepatitis B Virus; Human Immunodeficiency Virus; Sexually Transmitted Infections; Highly Active Antiretroviral Therapy; Hepatitis B Vaccine
24.  Hepatitis B virus vaccination booster does not provide additional protection in adolescents: a cross-sectional school-based study 
BMC Public Health  2014;14(1):991.
Background
Current consensus does not support the use of a universal booster of hepatitis B virus (HBV) vaccine because there is an anamnestic response in almost all children 15 years after universal infant HBV vaccination. We aimed to provide a booster strategy among adolescents as a result of their changes in lifestyle and sexual activity.
Methods
This study comprised a series of cross-sectional serological surveys of HBV markers in four age groups between 2004 and 2012. The seropositivity rates of hepatitis B surface antigen (HBsAg) and its reciprocal antibody (anti-HBs) for each age group were collected. There were two parts to this study; age-specific HBV seroepidemiology and subgroup analysis, including effects of different vaccine types, booster response for immunogenicity at 15 years of age, and longitudinal follow-up to identify possible additional protection by HBV booster.
Results
Within the study period, data on serum anti-HBs and HBsAg in a total of 6950 students from four age groups were collected. The overall anti-HBs and HBsAg seropositivity rates were 44.3% and 1.2%, respectively. The anti-HBs seropositivity rate in the plasma-derived subgroup was significantly higher in both 15- and 18-year age groups. Overall response rate in the double-seronegative recipients at 15 years of age was 92.5% at 6 weeks following one recombinant HBV booster dose. Among the 24 recipients showing anti-HBs seroconversion at 6 weeks after booster, seven subjects (29.2%) had lost their anti-HBs seropositivity again within 3 years. Increased seropositivity rates and titers of anti-HBs did not provide additional protective effects among subjects comprehensively vaccinated against HBV in infancy.
Conclusions
HBV booster strategy at 15 years of age was the main contributor to the unique age-related phenomenon of anti-HBs seropositivity rate and titer. No increase in HBsAg seropositivity rates within different age groups was observed. Vaccination with plasma-derived HBV vaccines in infancy provided higher anti-HBs seropositivity at 15–18 years of age. Overall booster response rate was 92.5% and indicated that intact immunogenicity persisted at least 15 years after primary HBV vaccination in infancy. Booster vaccination of HBV did not confer additional protection against HBsAg carriage in our study.
doi:10.1186/1471-2458-14-991
PMCID: PMC4246462  PMID: 25248369
HBV booster; Adolescents; Anamnestic response; Infant HBV vaccination
25.  The evaluation of Tetanus-diphtheria (Td) vaccine impacts on immune response to hepatitis B (HB) vaccine in non-responder dialysis patients* 
BACKGROUND:
The Hepatitis B (HB) vaccine response in hemodialysis patients is less than healthy individuals. Different strategies have been taken into account to improve the response rate. This study aimed to evaluate the effect of tetanus and diphtheria (Td) vaccine as an adjuvant therapy to HB vaccination.
METHODS:
Sixty three end-stage renal disease patients were recruited on dialysis that were older than 18 years and had passed at least 3 doses of HB vaccination schedule, and had HBS antibody (Ab) with titer less than 10 IU/L. The patients were divided into two groups; A (30 patients) and B (33 patients). Both of the groups received a 3-dose HB vaccination schedule of 40 μ g intramuscularly in the left deltoid muscle at 0, 1 and 6 months. Group A also received Td vaccine intramuscularly simultaneous with the first dose of HB vaccine. HBS Ab was measured in periods of 1 and 6 months after completion of the vaccination.
RESULTS:
One month after completion of the vaccination, group A had better but not significant response rate (96%) than group B (83.9%) (p > 0.05); in addition, after 6 month there was no difference between the two groups (87.5% vs. 83.3%) (p > 0.05). Patients with HCV infection had lower response rate than patients who did not have HCV infection (33.3% vs. 92.5%) (p < 0.05). Age had negative effect on immune response to HB vaccination (r = -0.339; p = 0.005).
CONCLUSIONS:
The use of Td vaccine concurrent with HB vaccination may increase the response rate in non-responder individuals; however, it seems it does not have any role in the persistence of immune response. Age and HCV infection negatively affected the response to HB vaccination in dialysis patients.
PMCID: PMC3214370  PMID: 22091281
Hemodialysis; Peritoneal Dialysis; Hepatitis B Vaccine; Tetanus-Diphtheria Vaccine

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