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.

Efficacy of entecavir and tenofovir in chronic hepatitis B under treatment in the public health system in southern Brazil

There are about 350 million hepatitis B virus (HBV) carriers worldwide and chronic HBV is considered a major public health problem. The objective of the present study was to assess the effectiveness of the nucleos(t)ide analogues tenofovir (TDF) and entecavir (ETV) in the treatment of chronic HBV. A cross-sectional study was carried out from March-December 2013, including all patients with chronic HBV, over 18 years of age, undergoing therapy through the public health system in southern Brazil. Only the data relating to the first treatments performed with TDF or ETV were considered. Retreatment, co-infection, transplanted or immunosuppressed patients were excluded. Six hundred and forty patients were evaluated, of which 336 (52.5%) received TDF and 165 (25.8%) ETV. The other 139 (21.7%) used various combinations of nucleos(t)ide analogues and were excluded. The negativation of viral load was observed in 87.3% and 78.8% and the negativation of hepatitis B e antigen was achieved in 79% and 72% of those treated with ETV or TDF, respectively. Negativation of hepatitis B surface antigen was not observed. There was no occurrence of adverse effects. This is a real-life study demonstrating that long-term treatment with ETV and TDF is both safe and effective.

Simultaneous quantitation of serum HBV DNA and HBeAg can distinguish between slow and fast viral responses to antiviral therapy in patients with chronic hepatitis B / A quantificação simultânea do DNA VHB e do AgHBe séricos podem distinguir entre resposta viral lenta e rápida à terapêutica anti-viral em pacientes com hepatite crônica B

BACKGROUND: The quantitation of serum HBeAg is not commonly used to monitor viral response to therapy in chronic hepatitis B. METHODS: In this study, 21 patients receiving varying therapies were followed and their viral response monitored by concomitant viral load and HBeAg quantitation in order to study the meaning and the kinetics of both parameters. RESULTS: It was possible to distinguish between three different patterns of viral response. The first was characterized by a simultaneous decrease in serum HBV DNA and HBeAg. The second pattern was characterized by a decrease in serum HBeAg but persistent detection of HBV DNA. The third pattern was characterized by undetectable HBV DNA with persistent HBeAg positivity, which points to a non-response (Pattern III-B) except when HBeAg levels showed a slow but steady drop, characterizing a "slow responder" patient (Pattern III-A). CONCLUSIONS: The first pattern is compatible with a viral response. A long-term HBeAg seropositivity with a slow and persistent decrease (Pattern III-A) is also compatible with a viral response and calls for a prolongation of anti-viral treatment.

INTRODUÇÃO: A quantificação do AgHBe sérico não é habitualmente utilizada para monitorizar a resposta viral ao tratamento da hepatite crônica B. MÉTODOS: Neste estudo, 21 pacientes sob tratamento com diferentes terapias foram acompanhados e a resposta viral monitorizada pela quantificação concomitante da carga viral e do AgHBe a fim de investigar o significado e a cinética de ambos os parâmetros. RESULTADOS: Distinguiram-se três diferentes padrões de resposta viral. O primeiro caracterizou-se pela redução simultânea do HBV DNA e AgHBe séricos. O segundo padrão caracterizou-se por uma redução do AgHBe porém com detecção persistente do HBV DNA. O terceiro padrão caracterizou-se por HBV DNA indetectável com positividade persistente do AgHBe, sugerindo ausência de resposta (Padrão III-B), exceto quando os níveis de AgHBe mostraram uma queda lenta porém persistente, caracterizando um "respondedor lento" (Padrão III-A). CONCLUSÕES: O primeiro padrão é compatível com resposta viral. Uma seropositividade prolongada do AgHBe porém com uma redução lenta e persistente (Padrão III-A) é também compatível com resposta viral, sugerindo o prolongamento do tratamento anti-viral.

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.

Compositional changes of PBL population in patients with chronic hepatitis B virus infection

In this report we have analysed the peripheral blood lymphocyte of several patients with chronic hepatitis B virus infection with flow cytometry. Based on the presence and absence of the HBeAb, patients were divided into two groups. In both, all the patients were HBsAg positive with normal range of serum alanine aminotranferase (23.9 +/- 17.8). We have found that the immunophenotypic profiles of patients were different from healthy donors with significant decrease in CD(3)(+) T cells, specially CD(8)(+) T cells and a significant increase in the CD(19)(+) B cells. The differences were seen in other subset of T cells (CD(4)(+)) or NK cells (CD(56)(+)/CD(16)(+)) and HLA-DR markers were not significant. When the phenotypic profiles of both groups were compared with each other, such changes were more dominant in group II, with HBeAb positive than in group I, with HBeAb negative. Also, we have seen a correlation between the increase of CD(19)(+) B cells and the decrease of CD CD(3)(+) T cells. No such correlation was observed with other cells.

Detección y caracterización de mutantes pre-core del virus de la hepatitis B (HBV) en pacientes cronicamente infectados / Detection and characterization of precore mutant of hepatitis B virus (HBV) in chronically infected patients

La infección por el virurs de la Hepatitis B (HBV) es causa importante de morbi-mortalidad en el mundo, hallándose asociada con afecciones hepáticas graves tales como cirrosis y/o carcinoma hepatocelular primario (HCC). Entre los diversos factores que influyen en la severidad del daño hepático pueden señalarse, la emergencia de mutantes pre-core (HBeAg defectuosa), la heterogeneidad genética del virus y del hospedador y la competencia del sistema inmune. En particular la presencia de mutantes pre-core en portadores crónicos se asocia, además, con una baja respuesta a la terapia con interferón alfa. En este trabajo presentamos evidencias de la presencia de dichas mutantes en pacientes cronicamente infectados HBeAg negativos (HB Agi positivo) en la Argentina. Al suero de estos pacientes se les extrajo el ADN viral que fue amplificado por PCR y caracterizado por análisis con enzimas de restricción. Finalmente uno de estos sueros fue secuenciado en la región pre-core evidenciando la presencia de mutaciones en los codones 15 y 28 de dicha región característicos de estas mutantes

Aspectos inmunológicos e inmunogenéticos de la hepatitis B. Evolución histórica

The most common cause of viral hepatitis in USA is the hepatitis B virus, and since 1983 is more common than hepatitis A. In 1980 a serum derived hepatitis B vaccine was evaluated and introduced to clinical practice. The fear of HIV transmission leads to the development in 1984 of a recombinant vaccine produced in the yeast Saccharomyces cerevisae through DNA recombinant technics. Both vaccines have been proved effective and safe, with seroconversion in 85-96 percent of homosexual males and 96-98 percent of healthy adults. Several recent studies have shown that 5-10 percent of healthy adults fail to respond to the vaccine, even after additional dosages. The mechanism for this lack of Anti-HBs response has been extensively studied by several groups and associated to the major histocompatibility antigens in relationships with T lymphocytes responses to specific antigens. Recent studies have demonstrated that the lack of response to the HBsAg is due to a mechanism of peripheral restriction previously shown by Crave, Alpert et al, and not related to gene suppression nor through CD8T+ cells. The absence of response is secondary to the macrophage-antigen interaction and CD4T+ cells and is also multifactorial. Studies in caucasian populations have shown that poor responders to hepatitis B vaccines have certain haplotypes such as: B8, Dr7, Dr3, Dr7, Dr4 and Dr7+B8. Alpert et al have shown for the first time in humans that persons homozygous for extended haplotype HLA B8-DR3-SCO1, have a poor response to a HBsAg and is recessive. Only one haplotype is sufficient to have an adequate Anti-HBs response. Sasasuki et al, in contrast have shown that Japanese haplotype HLA-BW54-DR4-DRW53 and DQW3 is associated to poor response to HBsAg, and is dominant, they also suggest that lack of response depends of an immunosupresion gene through CD8 cells. Finally our results suggest that no responders have a specific defect located to the level of helper T Cells stimulation, and its not mediated through immunosupresion through CD8T cells.

Circulating immune complexes and cell-mediated immunity in patients with hepatitis B virus associated liver diseases

The prevalence of circulating immune complexes (CIC), their role and their relationship to cell-mediated immunity in patients with hepatitis B virus associated liver disease are still controversial. This study was designed to investigate the prevalence of CIC and their relationship to viral markers, to subsets of peripheral blood T lymphocytes and to suppressor cell activity in patients with hepatitis B virus associated liver diseases. CIC were positive in 29.3% of 41 healthy HBsAg carriers, 37.8% of 88 patients with hepatitis B virus associated liver diseases, and 15% of 41 healthy subjects by the platelet aggregation test (PAT). The prevalence of CIC in patients with acute hepatitis (40.0%) and in those with cirrhosis (61.5%) was significantly higher than in normal controls (p less than 0.05, p less than 0.005 respectively). There was no correlation between the titer of CIC and serum HBsAg titer or the status of HBeAg, and no significant decrease in the peripheral blood lymphocyte CD4/CD8 ratio in healthy HBsAg carriers (1.39 +/- 0.31) and in patients with liver diseases (1.40 +/- 0.54) compared to the normal controls (1.48 +/- 0.31). Concanavalin A induced suppressor cell activity on IgG producing cells was impaired in healthy HBsAg carriers (34.9%) (p less than 0.005) and in patients with liver diseases (25.3%) (p less than 0.0001), and this change was prominent in patients with chronic active hepatitis and cirrhosis (p less than 0.0001). And there was a significant reverse correlation between concanavalin A induced suppressor cell activity on IgG-producing cells and the titer of CIC in PAT positive patients with hepatitis B virus associated liver diseases. In conclusion, it was suggested that defective suppressor cell function may lead to an increased B cell activation and such activity may account for the presence of CIC.

Hepatitis B immunization in high risk neonates born from HBsAg positive mothers: comparison between plasma derived and recombinant DNA vaccine.

A half dose recombinant hepatitis B vaccine (HBVax II, MSD, 5 micrograms) was investigated for efficacy in the prevention of perinatal hepatitis B virus (HBV) transmission in high risk neonates born from e-antigen positive HBsAg carrier mothers as compared to the half-standard dose regimen of plasma derived hepatitis B vaccine (HBVax, MSD, 10 micrograms). Forty infants born to carrier mothers were given hepatitis B immune globulin (HBIG) 100 IU intramuscularly immediately after birth, combined with either the recombinant or plasma derived hepatitis B vaccine. The infants were randomly divided into two groups of 20 infants each. The plasma derived vaccine (10 micrograms) was given to group I, while infants in group II received the recombinant vaccine (5 micrograms) at birth, 1 and 6 months of age. There were no statistically significant differences in the efficacy and the seroconversion rate of these two combined prophylaxis regimens. The protective efficacy rate of both kinds of HBV vaccine was found to be 94.6 and 89.2 percent in group I and group II respectively. At twelve months of age, the anti-HBs seroconversion rates were 95.0 percent in group I and 84.2 percent in group II. However, the geometric mean titres in group I (179.55 mIU/ml) was significantly higher than those in group II (42.2 mIU/ml) but the anti-HBs titre was still above protective level (10 mIU/ml) in most of the infants.(ABSTRACT TRUNCATED AT 250 WORDS)

Utilidad de los marcadores serológicos en el diagnóstico y pronóstico de la hepatitis crónica por virus / Udefulness of serologic markers in the diagnosis and prognosis of chronic viral hepatitis

En este trabajo se revisan las características de las hepatitis crónicas causadas por virus B, NANB y Delta, algunos aspectos de estos virus, los diferentes tipos de enfermedad hepática crónica, los factores predisponentes para su desarrollo y se hace énfasis en la utilidad de los marcadores virales serológicos para establecer el diagnóstico etiológico. Con relación a la hepatitis crónica B se analiza el comportamiento serológico de los marcadores y su valor para definir si el virus se encuentra en fase de replicación o de integración al núcleo del hepatocito. Se discuten las posibles relaciones entre infección crónica por virus B y el desarrollo de hepatocarcinoma. Finalmente se hacen consideraciones respecto al manejo de esta enfermedad

Hepatitis viral: interpretación clínica de los antígenos y anticuerpos en el suero / Viral hepatitis: clinical interpretation of serum antigens and antibodies

Se hace una revisión de los aspectos clínicos y bioquímicos de la hepatitis viral, con énfasis en las características biológicas y epidemiológicas de los virus A, B, no A - no B (NANB) y Delta, así como de los eventos serológicos que ocurren durante la infección con estos agentes virales. Se presenta también la secuencia de aparición y comportamiento de los diversos antígenos y anticuerpos, las técnicas de laboratorio para detectarlos y su significado clínico. Finalmente, se propone una guía para el estudio y seguimiento serológico de los pacientes con hepatitis viral aguda