Immunogenicity and reactogenicity of a combined hepatitis A/B candidate vaccine: first results

Abstract: We evaluated immunogenicity and reactogenicity of an inactivated, combined hepatitis A/B candidate vaccine in 50 seronegative volunteers. Each volunteer received a total of three doses of vaccine (720 EIU HAV and 20 μg HBs antigen) according to a 0, 1 and 6 month vaccination schedule. One month after the first injection, the seroconversion rate was 90% (45/50) for anti-HAV and 28% (14/50) for anti-HBs, respectively. After the booster dose, at month 7, the seroconversion rate was as high as 100% (49/49) for anti-HAV and 94% (46/49) for anti-HBs. The geometric mean titres increased with each dose of vaccine administered. Mild, and mostly local side effects were reported in 54% of the volunteers after the first injection and in less than 10% after the third injection. Our results show that this inactivated, candidate hepatitis A/B vaccine is highly immunogenic and well-tolerated.     

The long-term efficacy of plasma-derived hepatitis B vaccine in babies born to carrier mothers

summary.  The long-term efficacy of a childhood hepatitis B vaccination programme was evaluated. A total of 112 newborn babies of hepatitis B carrier mothers were given hepatitis B immune globulin (HBIG) and a 10-μg three-dose regimen of plasma-derived vaccine administered at a conventional (0, 1, 6 months), delayed (2, 3, 8 months) or accelerated (0, 1, 2 months) schedule. The vaccinees were followed up to determine their anti-HBs status over a 16-year period. Upon completion of the vaccination schedules, 92.6% developed antibody against surface antigen (anti-HBs) seroconverion, the rate of which fell to 33.3% at year 16. The three schedules were equally effective in preventing chronic infection, with a protective efficacy of 88.9% from hepatitis B surface antigen (HBsAg) carriage, compared with historical control. Vaccinees on the delayed schedule had a slightly higher seroconversion rate over years, and were better able to maintain an anti-HBs level of ≥ 100 iu/L. Overall, a quarter demonstrated evidence of exposure to the virus, being positive for antibody against core antigen or HBsAg, or mounting a rise in anti-HBs during the follow-up period. We conclude that a three-dose hepatitis B vaccination regimen is generally effective in protecting newborns of hepatitis B carrier mothers from infection and chronic carriage. Booster is not needed even after 16 years of monitoring.     

Immunogenicity, reactogenicity and adherence to a combined hepatitis A and B vaccine in illicit drug users

AIMS: The use of illegal drugs is associated with an increase in infective risk for the hepatitis viruses, against which the vaccination of drug users (DUs) is recommended unanimously. The aim of the study was to determine tolerability, adherence and immune response of a combined vaccine providing dual protection against hepatitis A virus (HAV) and hepatitis B virus (HBV). METHODS: The vaccine was administered to 38 DU, attending three public health centres for drug users in northern Italy, with a three-dose schedule (at 0, 1 and 6 months). The vaccine was well tolerated: only one adverse reaction (fever) was recorded after the 110 doses administered (0.9%). The vaccine schedule was completed successfully in 35 cases (92.1%). At month 8, in 34 subjects (89.5%) antibody response was evaluated: all showed seroprotection for HAV and in 33 subjects (97.1%) for HBV. CONCLUSIONS: The vaccine, studied for the first time in DUs, proved to be safe, well accepted and immunogenic; anti-HAV response was 1272 mIU/ml and 1726 mIU/ml for anti-HBV, titres lower than reported in literature for the general population. This study suggests that DUs who are HAV/HBV-negative could be vaccinated with combined vaccine.     

Outcome of hepatitis B and C virus‐associated hepatocellular carcinoma occurring after renal transplantation

Kidney transplant recipients (KTR) are subjected to immunosuppressive therapy that can enhance hepatitis B and C virus replication, leading to cirrhosis and hepatocellular carcinoma (HCC). The aim of this study was to assess the prevalence and outcome of HCC in KTR. Case‐control study. Patients with chronic HBV and/or HCV infection who underwent kidney transplantation between 1976 and 2011 and subsequently developed HCC were compared to a control group of patients with chronic HBV and/or HCV infection, matched for gender and age at HCC diagnosis, who did not receive kidney transplantation. Among 2944 KTR, 330 had hepatitis B and/or C. Fourteen developed HCC, a period prevalence of 4.2%. Age at HCC diagnosis was 52.6 ± 6.5 years (53.5 ± 5.7 in controls, P=.76). Time between transplantation and HCC diagnosis was 16.7 ± 2.7 years. Six HCCs were related to HBV, six to HCV and two to co‐infection with HBV and HCV. Immunosuppressive therapy was comparable in HBV, HCV and HBV+HCV patients. At diagnosis, 71% of patients met Milan criteria (65% in the control group, P=.4). Alpha‐fetoprotein levels, tumour characteristics and treatment modalities were comparable between both groups. Patient survival 2 years after HCC diagnosis was 28% in KTR, compared to 68% in controls (P=.024). Survival after HCC diagnosis is significantly worse in KTR compared to nontransplanted patients with HBV and/or HCV. Prevention is crucial and should be based on viral eradication/suppression before or after transplantation.     

儿童接种乙肝疫苗后乙肝表面抗体滴度的影响因素分析

目的　分析乙型肝炎（乙肝）表面抗体阴性的儿童加强免疫后抗体滴度的影响因素。方法　选取2017年1—12月期间海南省妇幼保健院乙肝疫苗免疫后乙肝表面抗体阴性的84名儿童作为研究对象,比较1～3岁及4～7岁儿童的抗体滴度,并分析低免疫或无免疫反应的相关因素。结果　1～3岁儿童抗体滴度显著高于4～7岁儿童（P＜0.05）。30例（35.71%）儿童接种乙肝疫苗后呈低免疫反应,无患儿出现无免疫反应。Logistic多因素分析显示：年龄≥4岁是接种疫苗后低免疫反应的危险因素,母乳喂养时间越长、体质量百分位数越大、血清总蛋白越高,低免疫反应发生率越低。结论　年龄是儿童乙肝疫苗接种后抗体滴度的主要影响因素,母乳喂养及营养状态亦对免疫反应产生影响。     

Prevention of viral hepatitis (B and C) reassessed

As hepatitis B and C viruses share modes of transmission, their combined occurrence is not uncommon, particularly in areas where both viruses are endemic and in individuals at high-risk of parenteral infection. Both viral hepatitis infections form an important global public health problem, responsible for over half a billion chronic infections worldwide.Their distinctive characteristics impact upon their epidemiology and transmission, and the success of the different prevention strategies.For several decades safe and effective vaccines have been available to prevent HBV infection. Universal vaccination is the cornerstone of global HBV control. Despite major success, vaccine uptake is hampered, and increasing efforts are required to eliminate acute and chronic hepatitis B. Unlike hepatitis C and HIV, HBV has not captured sufficient attention from policymakers, advocacy groups or the general public: a major challenge for the future.Although progress has been made in the development of an HCV vaccine, short-term successes are not expected. Even without a vaccine, successes can be reported in the field of hepatitis C due to e.g. implementation of universal precaution measures in health-care settings, screening of blood and blood products, and identification and counselling of infected people. Despite significant efforts, HCV transmission in injecting drug users is increasing.

• despite the availability and widespread use of effective hepatitis B vaccines, efforts are required to optimise uptake of the vaccine in universal and risk group immunisation programs

• because the development of a hepatitis C vaccine has not yet been successful, prevention and control measures are the major challenge to all those involved in public health

• screening for HBV and/or HCV should be followed by adequate management of positive patients, including counselling, referral, and possible treatment if available

• nosocomial transmission of viral hepatitis can and should be prevented by reinforcing and maintaining blood donor selection and screening procedures, strict adherence to universal safety measures in health-care settings, and thorough evaluation and communication of nosocomial infections

• immigrants should be socially fully integrated, including access to health services, to control the epidemic spread of imported infections

• the HBV and HCV epidemic among IDUs needs to be controlled by continuous educational programs for the general public and health professionals, accessible substance abuse treatment and rehabilitation programs (including outreach to homeless and socially excluded users), implementation/reinforcement of harm-reduction programs, HBV testing and vaccination of non-immune IDUs, and HCV testing and treatment in correctional facilities

• the possibility and benefits of HCV treatment should be established; adequate treatment can reduce the reservoir of chronic carriers, thereby diminishing transmission

• to make sure that HBV vaccination does not lose its place on the agenda of governments, agencies, and international organizations, as a consequence of its success so far and the interest in other vaccine-preventable diseases

• to further investigate the long-term protection after HBV vaccination and the role of cell-mediated immunity

• to assess the impact of HBIG in perinatal transmission and its possible effect on the immune response later in life

• to measure the impact of globalisation and international migration on the incidence of new hepatitis B cases

• to better understand the role of HBV genotypes in transmission, natural history and treatment

• to continue research on the treatment of (acute) HBV cases

• to improve/optimise HBV surveillance and to quantify the impact of HBV mutants.

• good surveillance data for HCV are absent in many regions of the world, and consequently there are gaps in our understanding of incidence, risk factors, transmission, and disease progression

• improvements in assays and/or testing algorithms for hepatitis C are required to optimise surveillance data

• development of hepatitis C vaccines is needed

• more insight into HCV immunology and cross-protection is required

• there is a need to measure the impact of globalisation and international migration on the incidence of new hepatitis B and C cases

Occult hepatitis B in renal transplant patients

BACKGROUND: Occult hepatitis B (HB) is characterized by the presence of HBV-DNA in patients who do not have HB surface antigen (HBsAg) detectable in sera, and is frequently described in patients with hepatitis C virus (HCV) infection. These viral liver diseases are common and may have a negative impact on the survival of renal transplant patients, especially if they are both present. In this study we aimed to evaluate the prevalence of occult HB in renal transplant patients either with or without HCV infection. PATIENTS AND METHODS: In a cross-sectional survey 101 HbsAg-negative renal transplant patients were evaluated; 51 were anti-HCV positive. Sera were analyzed for the presence of the S and core genes of the HBV-DNA by a nested polymerase chain reaction technique. Markers of HBV infection and liver function tests were also analyzed. RESULTS: The core gene was identified in 1 HCV-infected patient and 1 anti-HCV-negative patient who also presented the S gene (prevalence: 2% and 1% for each gene, respectively). HCV-infected patients had longer pre-transplant dialysis time (50.8 +/- 34.6 vs. 32.0 +/- 20.9; P < 0.001). Liver function tests were also increased in the HCV-infected group: alanine aminotransferase (P < 0.001), aspartate aminotransferase (P < 0.05), gamma-glutamyl transpeptidase (P<0.02), and alkaline phosphatase (P < 0.04). Multivariate analysis revealed that HCV infection was the only determinant of the altered results of the liver function tests. CONCLUSION: We found that occult HB is a condition present in our population of renal transplant patients and that HCV infection does not seem to be associated with occult HB infection in this setting.     

Economic evaluation of the societal costs of hepatitis B in South Korea

BACKGROUND AND AIMS: Hepatitis B (HBV) infection remains a major public health problem in South Korea, and accounts for considerable morbidity and mortality. At present, very little is known about the cost of HBV to the South Korean health-care system and society. The present study was therefore conducted to estimate the total annual cost of HBV infection in South Korea for a given year (1997). METHODS: The study was conducted from the South Korean societal perspective, taking into account the direct and indirect costs of HBV vaccination programs (prevention costs), and those related to the treatment of acute and chronic hepatitis, cirrhosis and liver cancer (disease costs). Several assumptions were made in arriving to actual cost estimates. RESULTS: The total societal cost of HBV in 1997 was 1078.3 billion Won ($US 959.7 million), 142.3 billion Won or 13.2% being attributable to prevention costs and 225.4 billion Won or 20.9% being attributable to indirect costs of HBV-related diseases. The total cost (direct plus indirect) associated with HBV-related diseases to the South Korean society was 936.1 billion Won ($US 833.1 million), of which 45.3% was attributable to cirrhosis-related costs. In terms of disease-related direct costs alone (710.5 billion Won or $US 632.3 million), the estimated annual spending per patient was 1.37 million Won ($US 1219). The direct costs of the HBV disease (prevention and disease treatment, amounting to 782.2 billion Won or $US 696.2 million) is equivalent to 3.2% of the national health-care expenditure for 1997. CONCLUSIONS: This study confirms that HBV is a significant cost burden to the South Korean society, and in the absence of an effective cure reinforces the importance of continued disease prevention via vaccination.     

伴有肾脏损伤及其高危风险的慢性乙型肝炎患者抗病毒治疗专家共识

正1前言(1)2015年版多个乙型肝炎防治指南推荐慢性乙型肝炎(CHB)患者在抗病毒治疗前后应监测肾脏功能相关指标。(2)对于具有肾脏损伤风险以及合并肾脏损伤的CHB患者提出了推荐治疗方案的意见和药物。2015年版亚太肝病学会(APASL)《亚太乙型肝炎临床管理指南》、2015年版中国《慢性乙型肝炎防治指南》以及2015年版世界卫生组织(WHO)《慢性乙型肝炎感染预防、管理和治     

Response to hepatitis B vaccination by liver transplant candidates

Liver transplantation (OLTx) is a procedure offered to individuals with advanced liver disease who are expected to live less than a year. Despite improvement in the care of transplant recipients, these patients are exposed to large volumes of blood and, as a result, are at risk to acquire hepatitis. Currently, the only vaccines available for the prevention of hepatitis are those that induce a response to HB_sAg. In this study, 144 patients awaiting OLTx and 15 controls were vaccinated three times, once a month, intramuscularly in the deltoid using the Merck Hepatovax plasma-derived vaccine. This schedule was continued regardless of whether or not OLTx occurred before the series was completed. For the 15 controls, the response rate was 93% and for individuals with end-stage liver disease, it ranged from 44 to 54% (P<0.004). No difference in the percentage of those developing antibody was detected between groups based upon disease indication or whether the vaccination series was completed before or after OLTx. Of the following: WBC, lymphocytes (percent and number), CD3+ cells (percent and number), CD4+ cells (percent and number), CD8+ cells (percent and number), CD4+/CD8+ ratio, and B cells (percent and number), only the absolute WBC (P<0.05) distinguished between those who did and did not develop antibody. These data suggest: (1) those with chronic liver disease respond less well to Hepatovax than do controls; (2) a rapid sequence of vaccinations is capable of producing antibody in normals and those with liver disease; (3) no difference is evident between those who completed their vaccination schedule before or after OLTx; and (4) among patients with chronic advanced liver disease, a higher total WBC is associated with an increased rate of seroconversion.     

Legend of hepatitis B vaccination: the Taiwan experience

Hepatitis B, a disease entity currently affecting more than 350 million persons worldwide, is also a serious health problem in Taiwan. Liver cirrhosis and hepatoma, which are both closely correlated with hepatitis B, are among the 10 leading causes of death in Taiwan. A mass hepatitis B vaccination program, conducted by the government of Taiwan, was started in 1984. Prior to this vaccination program, a series of viral epidemiological surveys, transmission pattern studies, and pilot immunization trials proved the clinical, economic, and strategic benefits of mass immunization, thus providing the impetus for the implementation of this mass vaccination program. The success of this program has led to a decline in hepatitis B carrier rates among children in Taiwan from 10% to <1%. Furthermore, the mortality rate of fulminant hepatitis in infants and the annual incidence of childhood hepatoma have also decreased significantly in recent years. This is one of the most remarkable success stories in the field of public health.     

Practical difficulties in the management of hepatitis B in the Asia-Pacific region

The Asia-Pacific Expert Committee on Hepatitis B Management recently reviewed the impact of hepatitis B in the region and assessed the differences and similarities observed in the practical management of the disease in individual Asia-Pacific countries. Hepatitis B is a major health concern in the Asia-Pacific region, and of all chronically infected carriers worldwide, approximately 75% are found in Asia. The disease poses a considerable burden on healthcare systems, and is likely to remain a cause of substantial morbidity and mortality for several decades. Disease prevention activities, including screening and vaccination programs, have been implemented successfully in some Asia-Pacific countries and similar measures are being established in other parts of the region. The management of hepatitis B in the Asia-Pacific varies throughout the region, with each country confronting different issues related to treatment options, disease monitoring and duration of therapy. The influence of cost, availability of diagnostic equipment, and patient awareness and compliance are of additional concern. Although guidelines such as those developed by the Asian Pacific Association for the Study of the Liver have been created to address problems encountered in the management of hepatitis B, many physicians in the region still find it difficult to make satisfactory management decisions because of the treatment choices available. This article examines the different approaches to hepatitis B management in a number of Asia-Pacific countries, and highlights the difficulties that can arise when adhering to treatment guidelines and disease prevention solutions that have proved to be successful in the region.     

Prospects for hepatitis B virus eradication and control of hepatocellular carcinoma

Hepatitis B virus infection is the most common cause of chronic hepatitis, liver cirrhosis and hepatocellular carcinoma worldwide. In areas hyperendemic for HBV infection, the related complications occur mostly during adulthood. However, nearly half of all primary infection in chronic carriers occurs in the perinatal period through maternal transmission, the other half arising from horizontal transmission mainly through intrafamilial spread or injection using unsterilized needles. A universal vaccination programme is better than immunization for at-risk groups. Hepatitis B vaccination should be integrated into the Expanded Programme on Immunization in children. Universal immunization against hepatitis B virus has proved to be effective in reducing the hepatitis B carrier rate to one-tenth of the prevalence before the vaccination programme in highly endemic areas, and the incidence of hepatocellular carcinoma in children has also been shown to be significantly reduced. Continued efforts to implement universal vaccination programmes worldwide will very likely reduce the incidence of hepatitis B virus-related diseases, particularly liver cirrhosis and hepatocellular carcinoma.     

肾移植患者接受 HBcAb 阳性供体时应用 HBIg预防乙肝的安全性和有效性

目的：探讨肾移植（KT）患者接受HBcAb阳性供体时应用乙肝免疫球蛋白（HBIg）预防乙肝的安全性和有效性。方法选择行同种异体KT患者69例,受体术前均无乙肝,供体均为HBsAg阴性、HBcAb-IgM阳性。将其随机分为观察组39例,KT前后应用小剂量HBIg;对照组30例不用HBIg。比较两组术后不同时间的肝肾功能及术后12、36个月乙肝发生率。结果观察组术后发生急性排斥1例。随访3～36个月,观察组术后8、12个月死于肺部感染2例,对照组术后6、24个月死于肺部感染、暴发性肝炎各1例。观察组术后12、36个月乙肝发生率分别为0、2．6％,对照组分别为10．3％、17．9％,两组比较P均＜0．05。两组术后12、24、36个月的血肌酐、总胆红素水平及24个月的肝功能异常率比较,P均＜0．05。结论 KT患者接受HBcAb-IgM阳性者的供肾时,预防性应用HBIg进行被动免疫,可有效降低乙肝发生率,改善其术后肝肾功能,延长生存时间。     

Clinical management of hepatitis B virus infection correlated with liver transplantation

BACKGROUND:As a radical cure for post-hepatitis B virus (HBV)-related liver cirrhosis and hepatocellular carcinoma,liver transplantation has been applied in many medical centers.Before the use of effective measures,hepatitis B recurrence and the existence of HBsAg(+) donors,patients with hepatitis B-related diseases are contraindicated for liver transplantation.Application of interferon,hepatitis B immunoglobulin (HBIG),and nucleotide analogues (e.g.,lamivudine) has made great progress in the clinical care ...     

Chronic hepatitis B virus in the Philippines

Multiple studies have shown a high prevalence of chronic hepatitis B (CHB) infection in the Philippines, not only in high‐risk populations but also in the general population. The most recent national study estimated HBsAg seroprevalence to be 16.7%, corresponding to an estimated 7.3 million CHB adults. The factors underlying the high prevalence of CHB and its sequelae include the inadequate use of vaccination for prevention and the lack of treatment for many Filipinos. Because without medical monitoring and treatment of CHB the risk of progression to liver failure and death is 25–30%, the ultimate medical and societal costs will be very high if the Philippines fails to properly address hepatitis B infection. It will be very important to move forward with programs that can help to ensure universal vaccination of newborns, screening and vaccination nationwide, and monitoring and treatment for CHB persons. It will also be crucial to address transmission of HBV in the health‐care setting (via contaminated needles and syringes and inadequately sterilized hospital equipment) and via injection drug use and tattooing. Because of the relatively low average per capita income and the lack of coverage by PhilHealth of outpatient visits and medications, there is an urgent need to move forward with a nationally supported program that includes education for both the general public and health‐care workers on liver disease and screening for hepatitis viruses, followed by, as appropriate, vaccination or treatment, with expanded government coverage for these for all those who could not otherwise afford it.     

Current use of hepatitis B immune globulin for prevention of de novo hepatitis B in recipients receiving anti-HBc-positive livers

Livers from donors positive for antibody against anti-HBc can potentially transmit de novo hepatitis B (DNH) to their recipients. Despite a good outcome, prophylaxis is usually offered to such recipients. There is no consensus on the standard prophylactic regimen and hence prophylaxis varies among different transplant centres. Nonetheless, hepatitis B immune globulin (HBIG) is considered the mainstay of such prophylaxis, either alone or in combination with an oral antiviral treatment. We aim to provide a concise review of the current use of HBIG in prevention of DNH. We also address a few important questions regarding HBIG use.