Infección crónica por virus de hepatitis B. Instituto de Gastroenterología de Cuba, 2016-2018 / Chronic hepatitis B virus infection. Institute of Gastroenterology, Havana, Cuba; 2016-2018

Introducción: La efectividad del programa nacional de inmunización ha impactado en la reducción de la incidencia del virus de la hepatitis B en Cuba; sin embargo, no es despreciable la cantidad de pacientes infectados crónicos, que por esta causa, se detectan en la práctica asistencial, aunque insuficientes los estudios epidemiológicos que los caracterizan. Objetivo: Describir las principales características clínicas, biomoleculares e inmunológicas de los pacientes con VHB crónica atendidos en el Instituto de Gastroenterología de Cuba. Materiales y métodos: 97 pacientes que tenían al menos un historial de 6 meses de infección crónica con VHB fueron reclutados en la propia institución desde enero 2016 hasta enero 2018. Se realizaron análisis estadísticos descriptivos para las características clínicas, estudios bioquímicos, virológicos, grado de dureza hepática (medido por elastografía transitoria) y terapia antiviral. Resultados: Todos los pacientes completaron el seguimiento; 61,9 por ciento eran varones y la mediana (rango) de edad fue de 46 (18-84) años. La media de tiempo desde el diagnóstico de la infección fue de 11,7 ± 8,9 años. El 61,9 por ciento tenían enfermedad inactiva sin fibrosis hepática o fibrosis ligera. Solamente el 2 por ciento eran negativos para el antígeno de superficie de la hepatitis B con el DNA cuantificable del VHB, el 81,4 por ciento tenían carga viral detectable y el 85,5 por ciento recibieron uno o más tratamientos antivirales, principalmente los análogos del nucleótido/sido. Conclusiones: Los pacientes con la infección crónica del VHB estudiados, en su mayoría se encuentran en fase inactiva de su enfermedad, sin evidencia significativa de daño hepático, con niveles detectables de viremia y han recibido algún tratamiento antiviral(AU)

Introduction: The effectiveness of the national immunization program has impacted on the reduction of the incidence of hepatitis B virus (HBV) infection in Cuba; however, the number of chronically infected patients is not negligible. These patients are diagnosed in the clinical practice, although the epidemiological studies that indicate the presence of the disease are insufficient. Objective: To describe the main clinical, biomolecular and immunological characteristics of patients with chronic hepatitis B virus infection treated at the National Institute of Gastroenterology, Havana, Cuba. Materials and methods: A total of 97 patients who had at least a 6-month history of chronic HBV infection were recruited at the above mentioned institution from January 2016 to January 2018. Descriptive statistical analyzes were performed to identify the clinical characteristics. Biochemical and virological studies, analysis of both liver stiffness values measured by transient elastography and use of antiviral therapy were also carried out. Results: All patients completed the follow-up. It was observed that 61,9 percent of them were male and the median (range) age was 46 (18-84) years. The mean time since the diagnosis of the infection was 11.7 ± 8,9 years. Inactive disease without liver fibrosis or light fibrosis was present in 61,9 percent. Only 2 percent were negative for hepatitis B surface antigen with quantitative analysis of HBV DNA; also, 81,4 percent of patients had detectable viral load and 85,5 percent received one or more antiviral treatments, mainly nucleotide analogues. Conclusions: The patients with chronic HBV infection studied are mostly in the inactive phase of their disease, without significant evidence of liver damage and detectable levels of viremia. All of them have received some antiviral treatment(AU)

Recomendaciones en el tratamiento actual de la infección crónica por el virus de la hepatitis B / Current recommendations for the treatment of chronic hepatitis B infection

La infección crónica por el virus de la hepatitis B (VHB) se considera un problema de salud pública mundial. Se estima que al menos dos mil millones de personas han estado expuestas al VHB, y a pesar de una vacuna efectiva, 300 millones de personas están infectadas crónicamente a nivel mundial. Aunque el virus no es directamente citopático, la infección puede desencadenar cirrosis hepática y aun, carcinoma hepatocelular (CHC). El ADN circular cerrado covalentemente (ADNccc) en el núcleo de los hepatocitos y la incapacidad del sistema inmunitario para eliminar la infección crónica por el virus son los mecanismos más importantes de la infección por VHB. Las diferentes entidades, como la Asociación Europea para el Estudio del Hígado (EASL) y la Asociación Americana para el Estudio de las Enfermedades Hepáticas (AASLD), ponen a disposición las pautas para el manejo de esta enfermedad. A pesar de los avances en el tratamiento de la infección crónica por el VHB, en particular con el desarrollo de los análogos de los nucleótidos/ nucleósidos, quedan aún muchos interrogantes. Las investigaciones continúan para el desarrollo de nuevas opciones de tratamiento enfocadas principalmente en evitar que la suspensión de la terapia conlleve a un incremento de la carga viral, con el consecuente aumento del riesgo de progresión de la enfermedad hepática, y un eventual CHC.

Chronic hepatitis B virus (HBV) infection is considered a global public health problem. It is estimated that at least two billion people have been exposed to HBV, and despite an effective vaccine, 300 million people are chronically infected worldwide. Although the virus is not directly cytopathic, the infection can trigger liver cirrhosis and even hepatocellular carcinoma (HCC). Covalently closed circular DNA (cccDNA) in the nucleus of hepatocytes and the inability of the immune system to eliminate chronic virus infection are the most important mechanisms of chronic HBV infection. Different entities, such as the European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Diseases (AASLD), provide guidelines for the management of this disease. Despite advances in the treatment of chronic HBV infection, including the development of nucleotide and nucleoside analogs, many questions remain. Research continues for the development of new treatment options focused mainly on avoiding a relapse on viral load after therapy discontinuation, with an increased risk of liver disease progression, and an eventual CHC.

The effectiveness of the national hepatitis B vaccination program 25 years after its introduction in Iran: a historical cohort study

ABSTRACT Introduction: Hepatitis B virus (HBV) is responsible for one of the most common human viral infections. An estimated 257 million people are living with chronic HBV infection worldwide, and mortality has reached 900,000 deaths in recent years. In 2001, the World Health Organization reported a prevalence of chronic hepatitis B infection in Iran between 2-7%. Objective: To assess the effect of the national HBV mass vaccination program after 25 years. Methods: A retrospective cohort study was conducted in vaccinated and unvaccinated people according to the year of birth. Blood samples were obtained from each enrolled person and data about demographic variables, and medical and vaccination history were collected using a standardized questionnaire. Persons were considered uninfected if they were negative for both HBsAg and anti-HBc. Also, Vaccine effectiveness was measured by calculating the risk of disease among vaccinated and unvaccinated persons and defining the percentage risk reduction of infection in the vaccinated group. Results: A total of 2720 persons were interviewed. The rate of HBV breakthrough infection among the vaccinated group was significantly lower than in unvaccinated group. One hundred ninety-four cases with positive HBV markers of infection were identified. The risk ratio of HBV infection was 0.71, 95% CI: 0.54-0.94 (vaccinated/unvaccinated). The estimated vaccination effectiveness against Hepatitis B infection was 29% (95% CI: 6%-46%). Conclusions: Iran has successfully combined hepatitis B vaccination into regular immunization programs. The WHO goal of reducing HBsAg prevalence to an equivalent of 1% by 2020 has been reached. With respect to vaccination effectiveness and low prevalence of the disease in the country, catch-up hepatitis B vaccination programs for adolescents can guarantee the immunity of the population.

Predictors of HBeAg seroconversion after long-term nucleos(t)ide analogues treatment for chronic hepatitis B: a multicenter study in real clinical setting

ABSTRACT Aims: To evaluate the HBeAg seroconversion rate in real clinical setting and explore its predictors in long-term nucleos(t)ide analogues (NAs) treatment for chronic hepatitis B (CHB). Methods: 251 patients were recruited from January 2001 to September 2009 in four hospitals in Hebei province, China, for this retrospective study. Clinical and laboratory data before and after treatment with lamivudine (LAM, 100 mg daily), adefovir (ADV, 10 mg daily), telbivudine (LDT, 600 mg daily), entecavir (ETV, 0.5 mg daily), and LAM/ADV combination were compared among three groups according to treatment outcomes: synchronous HBeAg loss and HBeAg seroconversion, anti-HBe development after treatment, and no anti-HBe. Adherence was also evaluated. Results: In real clinical setting, cumulative HBeAg seroconversion rates were 14.3%, 32.7%, 43.0%, 46.9%, and 50.5% after 1, 2, 3, 5, and 8 years, respectively. 45 patients (17.9%) were non-adherent. Adherence (p < 0.001, Hazard Ratio (HR) = 2.203), elevated alanine aminotransferase (ALT) levels (p < 0.001, HR = 2.049), and non-vertical transmission (p = 0.006, HR = 1.656) were predictors of HBeAg seroconversion. Conclusion: Adherence, elevated ALT, and non-vertical transmission are predictors of HBeAg seroconversion in CHB patients treated with NAs.

Evolution of hepatitis B serological markers in HIV coinfected patients: a case study

ABSTRACT OBJECTIVE To describe the evolution of serological markers among HIV and hepatitis B coinfected patients, with emphasis on evaluating the reactivation or seroreversion of these markers. METHODS The study population consisted of patients met in an AIDS Outpatient Clinic in São Paulo State, Brazil. We included in the analysis all HIV-infected and who underwent at least two positive hepatitis B surface antigen serological testing during clinical follow up, with tests taken six months apart. Patients were tested with commercial kits available for hepatitis B serological markers by microparticle enzyme immunoassay. Clinical variables were collected: age, sex, CD4+ T-cell count, HIV viral load, alanine aminotransferase level, exposure to antiretroviral drugs including lamivudine and/or tenofovir. RESULTS Among 2,242 HIV positive patients, we identified 105 (4.7%) patients with chronic hepatitis B. Follow up time for these patients varied from six months to 20.5 years. All patients underwent antiretroviral therapy during follow-up. Among patients with chronic hepatitis B, 58% were hepatitis B “e” antigen positive at the first assessment. Clearance of hepatitis B surface antigen occurred in 15% (16/105) of patients with chronic hepatitis B, and 50% (8/16) of these patients presented subsequent reactivation or seroreversion of hepatitis B surface antigen. Among hepatitis B “e” antigen positive patients, 57% (35/61) presented clearance of this serologic marker. During clinical follow up, 28.5% (10/35) of those who initially cleared hepatitis B “e” antigen presented seroreversion or reactivation of this marker. CONCLUSIONS Among HIV coinfected patients under antiretroviral therapy, changes of HBV serological markers were frequently observed. These results suggest that frequent monitoring of these serum markers should be recommended.

Mutations in the S gene and in the overlapping reverse transcriptase region in chronic hepatitis B Chinese patients with coexistence of HBsAg and anti-HBs

Abstract Background The mechanism underlying the coexistence of hepatitis B surface antigen and antibodies to HBsAg in chronic hepatitis B patients remains unknown. Aims This research aimed to determine the clinical and virological features of the rare pattern. Methods A total of 32 chronic hepatitis B patients infected by HBV genotype C were included: 15 carrying both HBsAg and anti-HBs (group I) and 17 solely positive for HBsAg (group II). S gene and reverse transcriptase region sequences were amplified, sequenced and compared with the reference sequences. Results The amino acid variability within major hydrophilic region, especially the “a” determinant region, and within reverse transcriptase for regions overlapping the major hydrophilic region in group I is significantly higher than those in group II. Mutation sI126S/T within the “a” determinant was the most frequent change, and only patients from group I had the sQ129R, sG130N, sF134I, sG145R amino acid changes, which are known to alter immunogenicity. Conclusions In chronic patients, the concurrent HBsAg/anti-HBs serological profile is associated with an increased aa variability in several key areas of HBV genome. Additional research on these genetic mutants are needed to clarify their biological significance for viral persistence.

Characteristics of an outpatient chronic hepatitis B virus infection cohort / Caracterização de uma coorte ambulatorial de pacientes com infecção por vírus da hepatite B crônica

ABSTRACT Objective: To characterize a chronic hepatitis B cohort based on initial and follow-up clinical evaluations. Methods: A retrospective and descriptive analysis of clinical and laboratory data from chronic HBsAg adult carriers, without HIV, unexposed to treatment, with at least two outpatient visits, between February 2006 and November 2012. Fisher´s exact test, χ², Wilcoxon, Spearman, multiple comparisons and Kappa tests were applied, the level of significance adopted was 5%, with a 95% confidence interval. Results: 175 patients with mean age of 42.95±12.53 years were included: 93 (53.1%) were men, 152 (86.9%) were negative for hepatitis B e-antigen (HBeAg), 3 (1.7%) had hepatitis C coinfection, 15 (8.6%) had cirrhosis, and 2 (1.1%) had hepatocellular carcinoma. Genotype A predominated. Sixty-six patients (37.7%) had active hepatitis, 6 (3.4%) presented immune tolerance, and 38 (21.7%) were inactive carriers. Exacerbations and/or viral breakthrough were detected in 16 patients (9.1%). In 32 patients (18.3%), hepatitis B virus DNA remained persistently elevated and alanine aminotransferase levels were normal, whereas in 17 (9.7%), there was low hepatitis B virus DNA and alterated alanine aminotransferase. If only initial alanine aminotransferase and hepatitis B virus DNA values were considered, 15 cases of active hepatitis would not have been detected. Advanced fibrosis was more common in HBeAg-positive patients, and it was significantly associated with transaminases, hepatitis B virus DNA, and age. Conclusion: Many patients had active hepatitis, but almost 25%, who were HBeAg non-reactive, were only identified because of combined analyses of the hepatitis B virus DNA and transaminases levels, sometimes associated with histological data, after clinical follow-up. .

RESUMO Objetivo: Caracterizar uma coorte de pacientes com hepatite B crônica, segundo parâmetros iniciais e evolutivos. Métodos: Análise retrospectiva e descritiva dos dados clínicos e laboratoriais de portadores crônicos adultos do HBsAg, sem HIV, virgens de tratamento, com ao menos duas consultas ambulatoriais entre fevereiro de 2006 a novembro de 2012. Empregaram-se os testes exato de Fisher, χ², Wilcoxon, Spearman, Kappa e comparações múltiplas, o nível de significância estatística adotado foi de 5% e intervalo de confiança de 95%. Resultados: Foram incluídos 175 pacientes com média de idade de 42,95±12,53 anos, 93 (53,1%) do sexo masculino, 152 (86,9%) não reagentes para o antígeno e (HBeAg), 3 (1,7%) coinfectados com hepatite C, 15 (8,6%) cirróticos e 2 (1,1%) com carcinoma hepatocelular. Predominou o genótipo A. Constataram-se hepatite ativa em 66 pacientes (37,7%), imunotolerância em 6 (3,4%), estado de portador inativo em 38 (21,7%), exacerbações e/ou escapes virais em 16 (9,1%). Em 32 (18,3%), havia DNA viral persistentemente elevado e alanina aminotransferase normal; em 17 (9,7%), carga viral constantemente baixa e alanina aminotransferase alterada. Se fossem considerados apenas transaminases e DNA viral iniciais, 15 casos de hepatite ativa não teriam sido evidenciados. Fibrose avançada foi mais prevalente em HBeAg reagentes e associou-se direta e significativamente ao DNA do vírus da hepatite, idade e transaminases. Conclusão: Grande parte dos pacientes apresentou hepatite ativa. Porém, aproximadamente um quarto (todos pertencentes ao grupo HBeAg não reagente) foram identificados somente em função da análise conjunta das mensurações sequenciais de DNA do vírus da hepatite e transaminases, por vezes aliada a dados histológicos, após seguimento. .

Hepatitis B Surface Antigen Quantification across Different Phases of Chronic Hepatitis B Virus Infection Using an Immunoradiometric Assay

BACKGROUND/AIMS: Quantification of hepatitis B surface antigen (HBsAg) is an emerging serologic test and may be useful for identifying treatment strategies for chronic hepatitis B (CHB). This study aimed to evaluate HBsAg titers during the natural course of CHB and identify correlations between HBsAg titers and hepatitis B virus (HBV) DNA concentrations across different CHB phases measured using an immunoradiometric assay (IRMA). METHODS: CHB phases were defined on the basis of HBV DNA concentrations, the presence of hepatitis B e antigen/antibody (HBeAg/Ab) and serum alanine aminotransferase levels. Serum HBsAg titers and paired HBV DNA concentrations in the different phases of CHB were compared using 627 serum samples. RESULTS: Mean HBsAg titers were significantly higher in the immunotolerant (IT) phase and immunoreactive (IR) HBeAg-positive phase than in the low-replicative (LR) and HBeAg-negative CHB (ENH) states. The correlation between HBsAg titers and HBV DNA concentrations was modest in the IT (n=36, r=0.804, p<0.001) and IR (n=48, r=0.773, p<0.001) phases, and it was poor in the LR state (n=116, r=0.289, p=0.002); however, no significant correlation was observed in the ENH state (n=67, r=0.146, p=0.237) or in the oral nucleos(t)ide analogue-treated group (n=267). CONCLUSIONS: HBsAg quantification using IRMA might be useful for discriminating different CHB phases and different stages of chronic liver disease.

Correlation between hepatitis B surface antigen titers and HBV DNA levels

To assess the correlation between serum HBsAg titers and hepatitis B virus [HBV] DNA levels in patients with hepatitis B envelop antigen-negative [HBeAg -ve] HBV genotype-D [HBV/D] infection. A total of 106 treatment- na‹ve, HBeAg -ve HBV/D patients were included; 78 in the inactive carrier [IC] state and 28 in the active hepatitis [AH] stage. HBV DNA load and HBsAg titers were tested using TaqMan real-time polymerase chain reaction [PCR] and automated chemiluminescent microparticle immunoassay, respectively. The median [range] log10 HbsAg titer was significantly lower in the IC group compared with AH group, 3.09 [-1 to -4.4] versus 3.68 [-0.77 to 5.09] IU/mL, respectively; P < 0.001. The suggested cutoff value of HBsAg titer to differentiate between the two groups was 3.79 log10 IU/mL. In addition, there was a significant positive correlation between HBsAg and HBV DNA levels in the whole cohort, AH, and IC groups [r = 0.6, P < 0.0001; r = 0.591, P = 0.001; and r = 0.243, P = 0.032, respectively]. Serum HBsAg titers may correlate with HBV DNA in treatment-na‹ve HBeAg -ve HBV/D patients, and supports the use of HBsAg levels in clinical practice as a predictor of serum HBV DNA levels.

Precore and Core Promoter Mutations of the Hepatitis B Virus Gene in Chronic Genotype C -Infected Children

The precore (G1896A) and core promoter (A1762T, G1764A) mutations of the hepatitis B virus gene are known to be associated with changes in immunologic phase or the progression to complicated liver disease in adults. We analyzed these mutations in chronically HBV-infected children. Serum was collected from 37 children with chronic HBV infection from March 2005 to September 2008. HBV DNA extraction and nested PCR were followed by sequencing of the PCR products. The children were 6.7 +/- 4.6 yr old. All of 37 children had HBV genotype C. Of the cohort, 31 (83.8%) were HBeAg-positive and 6 (16.2%) were HBeAg-negative; the former group comprised 18 (48.6%) who were in the immune-tolerance phase (ITP) and 13 (35.2%) in the immune-clearance phase (ICP). Most of the patients had HBV DNA levels of > 1.0 x 10(8) copies/mL. In the ITP group, only 1 (5.5%) had core promoter mutations, and none had the precore mutation. In the ICP group, only 2 (15.4%) had core promoter mutations; the remaining 6 patients had HBV DNA levels of < 2.0 x 10(3) copies/mL and no core promoter/precore mutations. The very low incidence of the precore/core promoter gene mutation, in children, suggests that these mutations may be the result of life-long chronic HBV infection.

Actualización en manejo de la Hepatitis B / Update on hepatitis B management

La infección por virus de la Hepatitis B (VHB) constituye un grave problema de salud. Aproximadamente un cuarto de la población mundial presenta evidencia serológica de infección pasada o presente por VHB y 350 millones de personas presentan la infección en forma crónica. La infección por VHB se asocia con 500.000 muertes al año causadas por hepatitis, cirrosis y carcinoma hepatocelular. Chile es considerado un país con baja prevalencia de infección por VHB (menor que 1 por ciento) en que la mayoría de los casos se adquieren en la adultez, contrariamente a lo que ocurre en países de Asia y África, donde la infección crónica por VHB es muy común (5-18 por ciento) y donde esta enfermedad es adquirida generalmente en el período perinatal o durante la infancia. La historia natural de la infección crónica por VHB es variable y fluctúa desde estado de portadores inactivos de HBs Ag a una hepatitis crónica menos progresiva, que potencialmente puede evolucionar a cirrosis y hepatocarcinoma. Programas efectivos de vacunación contra la infección por VHB disminuirán la incidencia de nuevas infecciones por VHB y la carga de enfermedad en las próximas décadas. Los pacientes con infección crónica por VHB deben ser correctamente evaluados para decidir si requerirán o no terapia antiviral. Pacientes adultos con infección crónica por VHB con una carga viral de, mayor 104 copias/ml (mayor que 2.000 UI/mL), con niveles anormales de alanina aminotransferasa (ALT) y evidencia de actividad necroinflamatoria en la biopsia hepática son candidatos para tratamiento antiviral. Actualmente se encuentran disponibles siete drogas para el tratamiento de la hepatitis B crónica: interferón-α convencional, lamivudina, adefovir dipivoxil, interferón pegilado α 2a y 2b, entecavir, telbivudina y tenofovir. Los análogos de nucleósidos/nucleótidos orales actualmente disponibles son muy potentes y pueden producir altas tasas de respuesta virológica, con una alta barrera genética a...

Hepatitis B virus (HBV) infection constitutes a serious health problem, with approximately one-fourth of the world population having serological evidence of past or present infection by HBV and 350 million people being chronically infected. HBV infection is associated to 500,000 deaths per year caused by hepatitis, cirrhosis, and hepatocellular carcinoma. Chile is considered a country with a low prevalence of HVB infection (less than 1 percent) where most cases are acquired in adulthood, as opposed to countries in Asia and Africa, where chronic HBV infection is very common (5-18 percent) and where this disease is usually acquired perinatally or during childhood. The natural history of HBV chronic infection is variable, ranging from an inactive HBsAg carrier state to a more or less progressive chronic hepatitis, potentially evolving to cirrhosis and hepatocarcinoma. Effective vaccination programs against HBV infection will decrease the incidence of new HVB infections and the burden of disease in the next few decades. Patients with chronic HVB infection need to be correctly evaluated to decide whether or not they will require antiviral therapy. Adult patients with chronic HVB infection with a viral load of more than 104 copies/ml (more than 2,000 IU/mL), with abnormal ALT levels and evidence of necroinfl ammatory activity on liver biopsy are candidates for antiviral treatment. Seven drugs are currently available for the treatment of chronic hepatitis B (CHB): conventional interferon-α, lamivudine, adefovir dipivoxil, pegylated interferon α-2a and 2b, entecavir, telbivudine and tenofovir. Currently available oral nucleotide analogues are very potent and can induce high rates of virological response, with a high genetic barrier to resistance in the majority of patients (entecavir and tenofovir).

Situación actual de la hepatitis B en Chile / Present situation of hepatitis B in Chile

Background: Hepatitis B virus infection generates carriers and 8 percent will evolve to a chronic phase. Aim: To perform a compilation of studies on hepatitis B in Chile and other sources of information to estímate the impact of this disease in our country. Material and methods: Published and unpublished evidence about the infection, in the general population and risk groups in our country, was compiled and reviewed critically. Informal interviews to experts, revisión of the mandatory notification book of the Ministry of Health and collection of data from laboratories that study hepatitis B virus, were also carried out. Results: The seroprevalence of chronic carriers in blood donors is nearly O.3 percent. Among risk groups such as health care personnel, the figure is O.7 percent, among homosexuals 29 percent, among HIV positive patients 30 percent, among sexual workers 2 percent and among children with chronic hemodialysis, 9 percent. Prevalence rate according to notified cases in 2004 was 1.8 x 100,000 habitants. Detection of viral hepatitis B surface antigen in ¡aboratories occurs in 0.2 percent of donors and 1.396 of non donors. Conclusions: The seroprevalence of hepatitis B virus, the lack of notification, and the introduction of hepatitis B vaccine to our Regular Program of Immunizations, are arguments to develop in Chile a hepatitis B and C surveillance system.

Increased in vivo immunological potency of HB-110, a novel therapeutic HBV DNA vaccine, by electroporation

Pulse-induced permeabilization of cellular membranes, generally referred to as electroporation (EP), has been used for years as a tool to increase macromolecule uptake in tissues, including nucleic acids, for gene therapeutic applications, and this technique has been shown to result in improved immunogenicity. In this study, we assessed the utility of EP as a tool to improve the efficacy of HB-110, a novel therapeutic DNA vaccine against chronic hepatitis B, now in phase 1 of clinical study in South Korea. The potency of HB-110 in mice was shown to be improved by EP. The rapid onset of antigen expression and higher magnitude of humoral and cellular responses in electric pulse-treated mice revealed that EP may enable a substantial reduction in the dosage of DNA vaccine required to elicit a response similar in magnitude to that achievable via conventional administration. This study also showed that EP-based vaccination at 4-week-intervals elicited a cellular immune response which was about two-fold higher than the response elicited by conventional vaccination at 2-week intervals. These results may provide a rationale to reduce the clinical dose and increase the interval between the doses in the multidose vaccination schedule. Electric pulsing also elicited a more balanced immune response against four antigens expressed by HB-110: S, preS, Core, and Pol.

The emergence of YMDD mutants precedes biochemical flare by 19 weeks in lamivudine-treated chronic hepatitis B patients: an opportunity for therapy reevaluation

Given the loss of therapeutic efficacy associated with the development of resistance to lamivudine (LMV) and the availability of new alternative treatments for chronic hepatitis B patients, early detection of viral genotypic resistance could allow the clinician to consider therapy modification before viral breakthrough and biochemical relapse occur. To this end, 28 LMV-treated patients (44 ± 12 years; 24 men), on their first therapy schedule, were monitored monthly at four Brazilian centers for the emergence of drug resistance using the reverse hybridization-based INNO-LiPA HBV DR assay and occasionally sequencing (two cases). Positive viral responses (HBV DNA clearance) after 6, 12, and 18 months of therapy were achieved by 57, 68, and 53 percent of patients, while biochemical responses (serum alanine aminotransferase normalization) were observed in 82, 82, and 53 percent of cases. All viral breakthrough cases (N = 8) were related to the emergence of YMDD variants observed in 7, 21, and 35 percent of patients at 6, 12, and 18 months, respectively. The emergence of these variants was not associated with viral genotype, HBeAg expression status, or pretreatment serum alanine aminotransferase levels. The detection of resistance-associated mutations was observed before the corresponding biochemical flare (41 ± 14 and 60 ± 15 weeks) in the same individuals. Then, if highly sensitive LMV drug resistance testing is carried out at frequent and regular intervals, the relatively long period (19 ± 2 weeks) between the emergence of viral resistance and the onset of biochemical relapse can provide clinicians with ample time to re-evaluate drug therapy.

História natural da hepatite crônica B: [revisão] / Natural history of chronic hepatitis B: [review]

Estima-se que existam 350 milhões de portadores crônicos do VHB distribuídos ao redor do mundo. Três fases de infecção crônica pelo VHB são reconhecidas: fase de imunotolerância (HBsAg e HBeAg positivos, altos títulos de HBV-DNA, ALT normal e não evidência de doença hepática ativa); fase imunoativa ou de hepatite crônica B (HBsAg e HBeAg positivos, altos títulos de HBV-DNA, ALT elevada e evidência de doença hepática ativa); fase de portador inativo do VHB ou assintomático (HBsAg no soro sem o HBeAg , títulos do HBV-DNA < 10(5) cópias p/ml, ALT normal). Hepatite crônica B é dividida em duas formas maiores: doença HBeAg positiva (VHB tipo selvagem); doença HBeAg negativa (pré-core, core promoter VHB variante). As duas formas podem evoluir para cirrose hepática, descompensação hepática e câncer hepático. A proposta deste artigo foi o de rever os principais aspectos da história natural da hepatite crônica B.

An estimated 350 million people worldwide are chronically infected with hepatitis B virus (HBV). Three phases of chronic hepatitis B virus infection is are recognized: the immune tolerant phase (HBeAg-positive, high levels of serum HBV-DNA, normal ALT, and no evidence of active liver diseases), the immune clearance phase or chronic hepatitis phase (HBeAg-positive, high levels of serum HBV-DNA, elevated ALT, and active liver disease ), and the inactive carrier state or asymptomatic phase (HBsAg-positive in serum without HBeAg, HBV-DNA levels than < 10(5) copies/mL, and normal ALT levels). Chronic hepatitis B is classified into 2 major forms: HBeAg-positive disease (wild-type HBV) and HBeAg negative disease (pre-core/core promoter HBV variant). Both forms can lead to liver cirrhosis, hepatic decompensation and liver cancer. The purpose of this article is to review the principal aspects of natural history of chronic hepatitis B.

Association of cytokine genetic polymorphism with hepatites B infection evolution in adult patients

The infection by the hepatitis B virus (HBV) has different forms of evolution, ranging from self-limited infection to chronic hepatic disease. The objective of this study was to evaluate the influence of cytokine genetic polymorphisms in the disease evolution. The patients were divided into two groups, one with chronic HBV (n = 30), and the other with self-limited infection (n = 41). The genotyping for TNF (-308), TGFB1 (+869, +915), IL-10 (1082, -819, and -592), IL-6 (-174), and IFNG (+874) was accomplished by the PCR-SSP (polymerase chain reaction with sequence specific primers technique using the One Lambda kit. Although no statistically significant differences were found between the groups, the combination of TNF -308GG and IFNG +874TA was found in a lower frequency in chronic patients than in individuals with self-limited infection (26.7 versus 46.3 percent; P = 0.079; OR = 0.40; IC95 percent = 0.14-1.11). In chronic patients with histological alterations it was not observed the genotype TGFB1+869 C/C, against 24.4 percent in the self limited infection group (100 versus 75.6 percent; P = 0.096; OR = 7.67; IC95 percent = 0.42-141.63). Further studies in other populations, and evaluation of a greater number of individuals could contribute for a better understanding of the cytokine genetic polymorphism influence in HBV infection evolution.

Lamivudina por tempo prolongado no tratamento da hepatite B crônica no estado de Mato Grosso / Long-term use of lamivudine for treating chronic hepatitis B in the State of Mato Grosso

Para avaliar resultados do tratamento da hepatite B crônica com lamivudina, 100mg ou 150mg diários, foram acompanhados 34 pacientes em um serviço em Cuiabá, Mato Grosso. Entre os 34, 21 (62 por cento), eram cirróticos e 24 (70 por cento) HBeAg positivos. Genótipo viral foi determinado em 18, sendo predominante o genótipo A (12). O acompanhamento teve mediana de 27 meses (7 a 64). Do total, 23 (67 por cento) apresentaram resposta bioquímica entre dois e 24 meses de tratamento. Dos 24 pacientes com positividade para o HBeAg, 13 (54 por cento) apresentaram negativação do HBeAg durante o acompanhamento. Entre os anti-HBe positivos, 70 por cento tiveram normalização das aminotransferases. Quatorze (41 por cento) não apresentaram resposta bioquímica ou sorológica de início ou apresentaram breakthrough. Em seis dos que não responderam, foram encontradas as mutações L180M e M204V. Quatro pacientes faleceram após pelo menos 21 meses de lamivudina e três cirróticos desenvolveram hepatocarcinoma após 24 meses. A partir do terceiro ano surgiram complicações, como hepatocarcinoma ou hemorragia digestiva. Os presentes achados sugerem que resposta precoce ao tratamento com lamivudina pode estar associada a um melhor controle da hepatite B crônica.

To assess the results from lamivudine treatment (100 mg or 150 mg) for chronic hepatitis B, 34 patients were followed at a clinic in Cuiabá, Mato Grosso, Central Brazil. Among them, 21 (62 percent) had liver cirrhosis and 24 (70 percent) were HBeAg-positive. The viral genotype was determined for 18 patients, among whom genotype A was the most prevalent (12). The median follow-up was 27 months (range from 7 to 64 months). Among the total, 23 (67 percent) presented a biochemical response after 2 to 24 months of treatment. Among the 24 HBeAg-positive subjects, 13 (54 percent) became HBeAg-negative during the follow-up. Among the anti-HBe-positive patients, 70 percent obtained normalization of aminotransferase levels. Fourteen (41 percent) did not present any initial biochemical or serological response or presented breakthrough. The L180M and M204V mutations were found in six of the non-responders. Four patients died after at least 21 months of lamivudine and three patients with liver cirrhosis developed liver cancer after 24 months. From the third year onwards, complications such as digestive system hemorrhage or liver cancer started to emerge. The present findings suggest that an early response to lamivudine treatment may be associated with better control over chronic hepatitis B.

Hepatitis B virus carrier state, with negative surface antigen serology, and non-detectable viral DNA by polymerase chain reaction

Hepatitis B virus [HBV] infection is found worldwide. Acute HBV commonly infects adults. After the resolution of the symptoms, most immunocompetent adults are able to clear the virus and become immune for life; this is identified serologically by the disappearance of the surface antigen [HBV s Ag] and the appearance of the surface antibody [anti-HBs]. In a small percentage of healthy adults, the disease might become chronic with the persistence of the HBV s Ag for more than 6 months, which might progress in the future to chronic liver disease. Herein is presented a case in which the patient after the acute stage of HBV infection, despite becoming asymptomatic and HBVsAg was no more detectable; he probably progressed to a chronic carrier of the virus

Clinical Significance and Natural History of "HBeAg Negativity" in Patients with Chronic HBV Infection / 대한간학회지

No abstract available.