Após anos de debates, o teste de detecção de ácidos nucleicos (NAT) para HIV e HCV na triagem de sangue foi implementado de forma obrigatória no Brasil em 2013, e HBV, em 2016. Um dos motivos citados sobre o atraso em sua implementação foi o custo elevado que seria adicionado à sorologia e, até o momento, uma ampla avaliação econômica em saúde (AES) a respeito de sua eficiência no país não está disponível. Diversos artigos já demonstraram que a razão incremental de custo-utilidade (ICUR) do NAT em relação à sorologia varia de 0,21 a 8,84 milhões de dólares americanos (US$) para cada QALY ganho. Esta grande variação dá-se, principalmente, por diferenças entre a idade média dos receptores de sangue (RS), incidência/prevalência dos vírus entre os doadores de sangue (DS), custo dos testes e tratamentos médicos, cobertura da vacina contra o HBV e sensibilidade do teste utilizado. Assim, faz-se necessária uma avaliação abrangente desta tecnologia e sua efetividade para o cenário brasileiro. Objetivos: Realizar uma revisão sistemática (RevS) de estudos econômicos completos sobre o uso do NAT para HIV, HCV e/ou HBV no mundo; realizar a AES sobre o NAT sob a perspectiva pública brasileira; caracterizar as doações de sangue em janela imunológica no país. Métodos: Metodologia Cochrane de RevS das bases de dados Medline, Embase, LILACS, CRD, BVS ECO, Google Scholar e IDEAS; questionário aplicado aos bancos de sangue e modelo econômico on-line da International Society of Blood Transfusion (ISBT) para cálculo da ICUR do \"NAT em mini-pool de seis amostras individuais\" (MP6) versus \"testes sorológicos\" (SR) no Brasil. Resultados: Quatorze estudos de dezesseis diferentes países foram avaliados. O NAT apresentou a maior relevância nos países de baixa renda, onde há as maiores prevalências e incidências virais, menores taxas de doadores de repetição (DR) e RS mais jovens. A maioria dos estudos concluiu que o NAT, independente do vírus analisado, não é custo-efetivo. As principais diferenças entre as características dos estudos foram relacionadas aos custos médicos e idade dos RS. O maior desvio dos padrões de uma RevS foram: não incluir o racional para definição dos desfechos e o modelo utilizado e não ter claro o conflito de interesse dos autores; para esta AES, o MP6 versus SR apresentou um ICUR de US$ 231.630,00/QALY, ou seja, 26,2 vezes o PIB per capita nacional) e um ICER de US$ 330.790,00/Ano de vida ganho (AVG). A análise de sensibilidade univariada do modelo demonstrou que somente a taxa de desconto, idade do RS, custo do NAT e epidemiologia dos vírus alteraram de forma significativa o ICUR obtido, variando desde US$ 76.957,00/QALY a US$ 933.311,00/QALY; a maioria dos casos de janela imunológica no Brasil são jovens, média de 29 anos, do sexo masculino, com pelo menos o ensino médio completo e mesmo com a obrigatoriedade do Anti-HBc no Brasil, o NAT-HBV é o que apresentou o maior rendimento. Conclusões: Os jovens, principalmente, ainda buscam os bancos de sangue como locais de testagem após comportamento de risco e é de extrema importância a revisão do custo real e completo do teste NAT no Brasil para ampla abordagem da tecnologia nacional incorporada e, se necessário, revisar a forma e modelo de reembolso da mesma e permitir a defesa do bem-estar da população e do bem público. / After years of discussion, nucleic acid (NAT) testing in the blood screening for HIV and HCV was implemented in Brazil in 2013 and HBV in 2016. One of the reasons cited for the delay in its implementation was the high cost that would be added to serology screening and a comprehensive economic assessment of its efficiency in the country is not yet available. Several articles have already shown that the incremental cost-utility ratio (ICUR) of NAT versus serology ranges from 0.21 to 8.84 million American dollars (US$) for each QALY gained. This large variation is mainly due to differences between the mean age of the blood recipient, viruses\' incidence / prevalence among donor population, cost of medical tests and treatments, HBV vaccine coverage, and sensitivity of the test used. Thus, a comprehensive evaluation of this technology and its effectiveness under the perspective of the Brazilian public health system (SUS) is needed. Objectives: Development of a systematic review (RevS) of complete economic studies about the use of NAT for HIV, HCV and / or HBV in the world. Conduct an economic evaluation of NAT under SUS perspective; characterize Brazilian blood donations in the serology \"window period\". Methods: Cochrane RevS Methodology of the Medline, Embase, LILACS, CRD, CRD ECO, Google Scholar and IDEAS databases; Questionnaire applied to blood banks and online economic model from the International Society of Blood Transfusion (ISBT) to calculate the ICUR for \"NAT in mini-pool of six individual samples\" (MP6) versus \"Serology Tests\" (SR) in Brazil. Results: Fourteen studies from sixteen different countries were assessed. NAT was most relevant in low-income countries, where there are the highest prevalences and viral incidences, lower rates of repeat donors and younger recipients of blood (RS). Most of the studies concluded that NAT, regardless of the virus evaluated, is not cost-effective. Differences in the characteristics of the studies were related to the costs and age of RS. The major deviations from RevS standards were: not including the rationale for selecting the outcomes and the model used and not being clear about the authors\' conflict of interest; MP6 vs SR showed an ICUR of US$ 231.630,00/QALY, 26,2 times Brazilian GND per capita) and an ICER of US$ 330.790,00/Life year gained (AVG). The univariate sensitivity analysis of the model demonstrated that only changes on discount rate, NAT cost, RS age and viruses\' epidemiology significantly altered the ICUR in a range between US$ 76.957,00/QALY and US$ 933.311,00/QALY; Most RS window period cases in Brazil are young, average of 29 years old, male, with at least high school education completed and even with the requirement of Anti-HBc in Brazil, NAT-HBV is the one that presented the highest yield. Conclusions: Young people, mainly, still seek blood banks as testing sites, especially after a risk behavior. It is extremely important to reveal the real and complete cost of the Brazilian NAT to fully evaluate its efficiency and, if needed, reassess its current reimbursement model, allowing the wellbeing defense of the population and public interest.

Introdução: A hepatite C é um grande problema de saúde pública e sua prevalência global está estimada em torno de 3%. O risco de transmissão do VHC via fluído seminal é muito discutida tanto na área de reprodução assistida como em estudos sobre o fator de risco da hepatite C ser ou não uma DST. Foram investigados e analisados 23 pacientes sabidamente infectados pelo VHC. Objetivos: 1.Estabelecer uma técnica para detectar a ausência ou presença do vírus da Hepatite C no sêmen de pacientes infectados; 2.Comparar técnicas de manuseio das amostras de sêmen, procurando diminuir a quantidade de inibidores presentes nas amostras; 3.Comparar técnicas de PCR e detecção do vírus da Hepatite C nas amostras de sêmen, procurando aumentar a sensibilidade dos testes. Métodos: Na primeira fase do estudo foram recrutados 20 pacientes (13 preencheram os critérios de inclusão). Amostras de sêmen e soro foram coletadas. As amostras de sêmen foram processadas com o auxílio do Percoll 90% e 45%. Foi analisada a presença do HCVRNA em soro pelo método Amplicor Roche, teste qualitativo. Se positivas, as amostras de sangue foram genotipadas e as amostras de sêmen foram extraídas, pelo mesmo método, e a PCR executada. Na segunda fase do estudo 23 pacientes foram selecionados, sendo alguns reconvocados da primeira fase (20 preencheram os critérios de inclusão). Amostras de sêmen e soro foram coletadas. As amostras de sêmen foram processadas através de diluições seriadas. Foi analisada a presença do HCV-RNA em soro e sêmen pelo método Amplicor Roche, teste qualitativo e por PCR em Tempo-real. Os dados epidemiológicos e os genótipos foram analisados, assim como os resultados da detecção do soro. Sêmen e frações realizadas pelas 2 (duas) técnicas de processamento estabelecidas foram comparados e analisados. Resultados: Dos 23 pacientes selecionados, a média de idade foi de 40,7 anos, com mediana de 45 anos. O tempo médio de descoberta da infecção pelo VHC foi de 7,15 anos. Dez pacientes (37,1%) não possuíam epidemiologia aparente, oito pacientes (29,6%) adquiriram a infecção pelo VHC através da utilização de drogas injetáveis e/ou inalatórias; seis (22,2%) por transfusão sanguínea; dois (7,4%) apresentaram histórico de transfusão sanguínea e uso de drogas e um (3,7%) relatou ser profissional da saúde. O genótipo 3a foi encontrado em 40,7% dos pacientes, seguido pelo 1a com 26%, 1b com 14,8%, 2b em 11,1% e 1a/1b em 7,4%. Das amostras processadas pelo Percoll, 86,5% apresentaram resultados inibidos, enquanto que nas amostras processadas pela diluição seriada e amplificadas através do PCR convencional, apenas 25,62% das amostras apresentou inibição, 65% não foram detectadas e 9,38% das amostras apresentou positividade. Nas amostras processadas pela diluição seriada na PCR em Tempo-real, 95% das amostras não foram detectadas e somente 5% apresentou positividade. Conclusão: Na tentativa de driblar os inibidores presentes nas amostras de sêmen, o procedimento de diluições seriadas mostrou maior eficácia quando comparado com o processamento através do gradiente descontínuo de concentração. Contudo, a grande quantidade de não detectados mostrou que a carga viral pode ter sido diluída, gerando a necessidade da utilização de técnicas mais sensíveis. Não foi observada diferença significativa entre os resultados da PCR convencional e Tempo-real. Porém o aumento na quantidade dos resultados negativos pode ser conseqüência da ausência de um controle interno nas reações da PCR em Tempo-real. / Introduction: Hepatitis C vírus is a huge problem for public health, and its global prevalence is estimated around 3%. Its transmission by seminal fluid is still in discussion in several fields, such as assisted reproduction and in studies about risk factors, whether the hepatitis C virus is an STD (sexually transmitted disease) or not. Twenty-three patients were investigated. Objectives: 1.Establish a technique to detect the presence or absence of the HCV in semen from chronically infected patients; 2.Compare semen samples handling techniques, in order to decrease the amount of inhibitors on the samples; 3.Compare different PCR and detection techniques for the HCV in semen samples, in order to increase the sensibility of the test. Methods: On the first phase 20 patients were selected (13 filled the inclusion criterion). Semen and serum samples were collected. The semen samples were processed with the help of Percoll® 90% and 45%. The presence of the RNA-HCV were analyzed in serum with Amplicor Roche method, qualitative test. When positive, the serum samples were genotyped and the semen samples were extracted, by the same method, and the PCR was done. On the second phase 23 patients were selected, some of them were old patients from the first phase (20 filled the inclusion criterion). Semen and serum samples were collected. The semen samples were processed through a dilution series. The presence of HCV-RNA was analised by Amplicor Roche, qualitative test and by PCR in Real-time. The epidemiological data and genotypes were analised. Resultados: From the 23 patients selected the mean age was 40,7 years, mean 45 years. The mean time of Discovery was 7,15 years. Ten patients (37,1%) didn´t present any apparent epidemiology, eight patients (29,6%) contracted HCV through injection and inhalatory drug use; six patients (22,2%) through blood transfusion; two patients (7,4%) had history of drug use and blood transfusion and one patient (3,7%) who was a health professional. Genotype 3a was found in 40,7% of the patients, followed by 1a with 26% of the patients, 1b with 14,8%, 2b with 11,1% e 1a/1b in 7,4% of the patients. The samples processed with Percoll, 86,5% presented inhibited results. Whereas on the samples that were processed with dilution series and amplified on the conventional PCR only 25,62% presented inhibited results, 65% were undetected and 9,38% were positive. On the samples processed with dilution series on the Real-time PCR 95% were undetected and only 5% were positive. Conclusion: On the attempt of decreasing the amount of inhibitors found on the semen samples, the procedure of dilution series showed us more efficient results when compared to the Percoll procedure. However, the great amount of undetected showed that the viral load might have being diluted, leading us to the necessity of a more sensitive technique. There was no significant difference between the results of the conventional PCR and the Real-time. These increase on the undetected results may be a consequence of the absence of a internal control on the PCR reactions.

OBJETIVO: Analisar a sintomatologia climatérica, a função hepática e a hemostasia das pacientes com hepatite crônica pelo vírus C, durante o uso da terapia hormonal. METODOLOGIA: As pacientes foram divididas em dois grupos: Grupo TH (Grupo caso) - 25 pacientes com terapia hormonal transdérmica (50mcg de estradiol e 170 mcg de noretisterona/dia) por 9 meses, e Grupo NT (Grupo controle) - 25 pacientes sem terapia hormonal, ambos com sintomas climatéricos. A menopausa foi confirmada pela dosagem do FSH, LH e estradiol, e a hepatite C foi diagnosticada pela sorologia, PCR (reação em cadeia de polimerase) e biópsia hepática (grau histológico variando de I-IV). Os dois grupos foram avaliados no mês 0, 1,4,7 e 9; sendo a sintomatologia climatérica mensurada através do Índice Menopausal de Kupperman, a função hepática e a hemostasia pelos exames: alanina aminotransferase, aspartato aminotransferase, gama glutamiltransferase, fosfatase alcalina, bilirrubinas, albumina, tempo de protrombina, fator V, fibrinogênio e plaquetas. ANÁLISE ESTATÍSTICA: realizada através do teste t de Student, teste de Mann Whitney e análises de variâncias com medidas repetidas com dois fatores. Após a realização das análises de variâncias, para os efeitos estatisticamente significantes foram realizadas comparações múltiplas através de contrastes ou do método de Dunnett. RESULTADOS: A média da idade das pacientes foi de 53,72 e a da menopausa foi de 47,3 anos. Os escores médios dos sintomas vasomotores, fraqueza, palpitação e a somatória dos valores atribuídos ao índice menopausal de Kupperman sofreram alteração no comportamento ao longo do tempo (p<0,05). Os valores da fosfatase alcalina apresentaram alteração no comportamento ao longo do tempo (p<0,05), entretanto, as demais medidas da função hepática e hemostasia, não apresentaram diferença entre os grupos. CONCLUSÕES: Houve melhora da sintomatologia climatérica. Não houve alteração na hemostasia e na função hepática, exceção feita à fosfatase alcalina que apresentou melhora significativa no Grupo TH a partir do 4º mês; portanto, houve melhora na qualidade de vida, sem interferência na função hepática e na hemostasia. / OBJECTIVE: To analize climacteric symptoms, liver function, hemostasis in patients with chronic viral hepatitis C, during hormone therapy. DESIGN: Patients were divided in two groups: Group TH (Case Group) - 25 patients on transdermal hormone therapy (50mcg of estradiol and 170 mcg of norethisterone/day) for 9 months, and Group NT (Control Group) - 25 hormone-untreated patients, both with climacteric symptoms. Menopause was confirmed by measuring FSH, LH and estradiol, and hepatitis C was diagnosed by serology, PCR (Polymerase Chain Reaction) and liver biopsy (histological type stages I to IV). Both groups were evaluated in the months 0, 1, 4, 7 and 9; and the climacteric symptoms measured by using Kupperman menopausal index, liver function and hemostasis by the following laboratory tests: alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma glutamyl transferase, alkaline phosphatase, bilirubin, albumin, prothrombin time (PT), factor V, fibrinogen and platelets. STATISTICAL ANALYSIS: Student\'s t test, Mann-Whitney test and two-factor analysis of variance with repeated measures were applied. After analysis of variance, multi-factor analysis of variance was applied for the statistically significant effects using contrasts or Dunnett?s test. RESULTS: The mean age of patients was 53.72 and the mean age of menopause was 47.3 years. The total mean scores for vasomotor symptoms, fatigue, palpitations and the sum of the values attributed to Kupperman menopausal index do change throughout time (p<0.05). Levels of alkaline phosphatase show alteration throughout time (p<0.05), although, other measures for liver function and hemostasis present no mean difference between the groups. CONCLUSION: There was an improvement in climacteric symptoms. No change was found in hemostasis levels or liver function. However, alkaline phosphatase levels significantly improved in Group TH starting in month 4; therefore, an increase in quality of life was observed.

As hepatites são as causas mais comuns de cirrose hepática e carcinoma hepatocelular (HCC) no mundo, sendo as infecções por Vírus da Hepatite B (HBV) e Vírus da Hepatite C (HCV) consideradas aquelas de maior importância como problemas de saúde pública, devido ao grande número de indivíduos atingidos (cerca de 350 milhões com hepatite B crônica e 170 milhões com HCV). No Brasil, avaliações realizadas nas últimas décadas sugerem que a endemicidade da hepatite B na região amazônica não tem decaído, com o agravante da precariedade do acesso aos cuidados de saúde nessa região. Assim, este estudo tem por objetivo avaliar o tratamento dispensado aos pacientes com hepatites virais B e C no Amapá, que faz parte da Amazônia Legal, para que seja possível conhecer a situação da saúde publica dessa localidade. A coleta de dados foi realizada em um centro de referência que centraliza o atendimento aos pacientes portadores de hepatite B e C, por meio de instrumento de coleta de dados previamente validado e aprovado pelo Comitê de Ética em Pesquisa da Faculdade de Ciências Farmacêuticas de Ribeirão Preto, Universidade de São Paulo (CEPFCFRP/USP), entre 1º de julho de 2007 e 30 de junho de 2009, e o programa estatístico EPI INFO, versão 3.5.1, foi utilizado para o lançamento e análise dos dados coletados. Foram incluídos 123 pacientes suspeitos ou portadores de hepatites virais B e/ou C, com idade média de 48,3 anos e 85,4% dos indivíduos entre 30 e 69 anos de idade, sendo 55,3% do sexo masculino, 61,0% casados, 82,1% residentes em Macapá, e 39,0% encaminhados por detecção de suspeita através de exames de rotina/pré-operatório ou pelo HEMOAP. Somando-se monoinfecções e coinfecções, 66,4% e 33,6% eram de pacientes infectados por HCV e HBV, respectivamente, sendo que os crônicos eram 61,0%. O acompanhamento clínico/ambulatorial desses pacientes foi inferior a 6 meses em 52% dos casos, e 40,0% apresentavam algum grau de severidade da doença, mas em 28,6% e 65,1% desses pacientes houve ausência de exames de ultrassonografia abdominal e determinação de níveis de aminotransferases, respectivamente. O genótipo para HCV só foi determinado em 30,6% dos casos de HCV e houve falha de notificação no SINAN em 25,2% dos pacientes do estudo. Três (7,0%) portadores de HBV e 16 (18,8%) de HCV receberam tratamento farmacológico específico, entretanto, outros seis pacientes com HBV e 19 com HCV apresentavam um critério de inclusão no tratamento, mas não foram tratados por ausência de exames de monitoramento. Na avaliação dos protocolos clínicos brasileiros para tratamento de HBV e HCV em relação aos internacionais, os primeiros se mostraram adequados e atualizados, entretanto, as falhas em seu seguimento pelas unidades de saúde que integram a rede assistencial para pacientes com HBV e HCV resultaram em deficiências nos serviços oferecidos, possivelmente decorrentes de treinamentos e capacitações insuficientes, ausência serviços de maior complexidade, e também devido isolamento natural da região. Diante dessas evidências, verifica-se a necessidade de ações governamentais no combate às hepatites virais mais abrangentes e que alcancem essa região. / Hepatitis are the most common cause for cirrhosis and hepatocelullar carcinoma (HCC) in the worldwide, and infections by the Hepatitis B Virus (HBV) and Hepatitis C Virus (HCV) are considered the most importance as public health problems, due to the large number of affected individuals (about 350 millions with chronic hepatitis B and 170 millions with HCV). In Brazil, evaluations made in the last decades suggest that the endemicity in Amazon area has not decreased, with the worsen situation of uncertain access to the health care in this location. Therefore, this research has the purpose to evaluate the treatment delivered to the patients infected by hepatitis virus B and C in Amapa, which belongs to the Legal Amazon, due to become possible to know the public health situation in this location. The data collection was placed in a reference center which concentrates the attendance to the hepatitis B and C carriers, using a data collection instrument previously validated and approved by the Ethics Committee in Research of the College of Pharmaceuticals Sciences of Ribeirão Preto, University of São Paulo (CEP-FCFRP/USP), between July 1st 2007 and June 30th 2009, in addition, the statistical software EPI INFO, version 3.5.1, was used to register and analyze the collected data. The 123 included individuals were suspected to have the infection or hepatitis B and/or C carriers, mean age of 48.3 years and 85.4% of these individuals were aged between 30 and 69 years old, 55.3% were men, 61.0% of them were married, 82.1% were resident in Macapa, and 39.0% of them were forwarded to the reference center due to detection of the infection by the routine exams / before surgery or by the HEMOAP, the blood bank. By the total of monoinfections and coinfections, 66.4% and 33.6% were patients infected by HCV and HBV, respectively, and the chronic patients were 61.0%. The clinical/ambulatorial follow-up of these patients were less than 6 months in 52.0% from the total, and 40.0% showed some severity grade due to the disease, however, 28.6% and 65.1 of these patients were lack of abdominal ultrasonography and aminotransferases determination exams, respectively. The genotype for HCV were determinate only in 30.6% of HCV infections and there were in SINAN notification failure in 25.2% of patients of study. Three (7.0%) HBV carriers and 16 (18.8%) HCV carriers receipt specific pharmacological treatment, nevertheless, others six HBV patients and 19 HCV patients had at least one criteria of inclusion in the treatment, but they were not treated because of monitoring exams absence. In the evaluation of Brazilian clinical protocol to HBV and HCV in regard to the international ones, those ones showed to be appropriates and updated, however, the failures in their following by the health units that integrate the assistance network to the HBV and HCV infected patients had outcomes in lack of offered services, probably due to insufficient training and qualification of the professionals, lack of more complex services, and also due to natural isolation of this area. Because of these evidences, it verifies the need of more including and reaching government actions to fight the viral hepatitis in this location.

Na prática hemoterápica em todo mundo, a triagem e o diagnóstico da infecção pelo HCV continua sendo um desafio. Desta forma, considerando as variáveis genéticas do vírus da Hepatite C e as variáveis populacionais de cada região, o conhecimento mais profundo da realidade da epidemiologia molecular do vírus da Hepatite C na população de doadores de sangue em regiões específicas se torna cada vez mais imprescindível. Desta forma, este estudo visou realizar a caracterização sorológica e molecular da infecção pelo Vírus da Hepatite C (HCV) em doadores de sangue do Estado do Amazonas a fim de subsidiar conhecimentos para interpretação dos diferentes perfis laboratoriais e clínicos, além de contribuir para o conhecimento das rotas de transmissão e da epidemiologia da infecção do Amazonas. Foram estudados 154 doadores de sangue do Estado do Amazonas com sorologia repetidamente reativa para anti-HCV. Foram realizados testes sorológicos por ELISA e Imunoblot, testes de detecção de RNA viral plasmático por Nested PCR, determinação da carga viral e genotipagem do vírus por sequenciamento. O estudo foi realizado no período de setembro de 2005 a abril de 2007 quando o índice de descarte por anti-HCV reativo foi de 0,37%. Foi observado que 50% dos casos de Imunoblot indeterminado apresentaram positividade no Nested PCR indicando a presença de RNA plasmático. A carga viral baixa foi um fator limitante para a determinação do genótipo viral pelo método de sequenciamento de algumas amostras. A freqüência de casos presumidos de clearance viral plasmático na amostra estudada foi de 18,8%. O genótipo mais prevalente do HCV nos doadores do Estado do Amazonas foi o genótipo 1 (87,5%) seguido do genótipo 3 (12,5%). Considerando as nuances da história natural da Hepatite C e os diversos momentos clínicos que os doadores possam se encontrar devem ser adotadas mudanças de condutas do acompanhamento dos doadores sororeativos para anti-HCV no banco de sangue do Amazonas e no fluxograma de diagnóstico da infecção. / The screening and diagnostic of HCV infection continue to be a challenge on the hemotherapic practice because the unique characteristics of each population and the molecular variability of the virus. The aim of this study was to characterize the serologic and molecular profile of 154 anti-HCV+ Amazon blood donors from the Amazon Hematology and Hemoterapy Foundation. Screening for anti HCV antibody was performed using ELISA and recombinant Imunoblot assay. Seropositive samples were assessed further with Nested PCR, viral load and genotyping techniques. In the study period, 2005-2007 the anti-HCV discard rate was 0,37%. We observed that 50% of the indeterminate Immunoblot cases showed HCV RNA presence in plasma by Nested PCR. The most prevalent genotype between subjects of this study was genotype 1 (87,5%), followed by genotype 3 (12,5%). The presumed plasma clearance frequency was 18,8%. The low viral load was a determinant critical factor to the genotype determination in some samples. Considering the different stages of the HCV natural infection different conducts may be adopted with inclusion of molecular testes as the first option for confirmation to the follow up of the positive anti-HCV blood donors in the Amazon blood bank and in the algorithm of the infection diagnostic, saving resources and providing a better counseling for the reactive donors.

alpha-Interferon (alpha IFN) ist derzeit die Grundlage jeder Behandlung der chronischen Hepatitis C. Zu den unerwünschten Effekten von alpha-IFN gehört die Entwicklung psychiatrischer Nebenwirkungen, die sich häufig als Depressivität äussern. Deren Häufigkeit, Schweregrad und Behandlungsbedarf wurden jedoch bisher nur unzureichend erforscht. 66 Patienten mit chronischer Hepatitis C wurden in einer Pilotstudie mit alpha-IFN als Monotherapie (3x3 MU/ Woche) oder in Kombination mit Ribavirin (1000-1200 mg/ Woche) behandelt. Sämtliche Patienten wurden vor, während und nach der Therapie hinsichtlich ihrer Depressivität beurteilt. Dies geschah sowohl im persönlichen Gespräch als auch mit Hilfe der Selbstbeurteilungsinstrumente ADS (Allgemeine Depressions Skala) und BDI (Beck Depressions Inventar). Die Ausgangsdepressivität der Hepatitispatienten entsprach dem gesunden Eichkollektiv. Im Gesamtdurchschnitt stieg die Depressivität innerhalb der ersten drei Behandlungsmonate um 5,15 (+/-8,94) Punkte auf der ADS und um 3,85 (+/-6,94) Punkte im BDI an. Weniger als ein Drittel der Patienten erlebte keine Zunahme der Depressivität. Patienten, die vor Therapiebeginn eine geringe Depressivität aufwiesen, beschrieben eine stärkere Zunahme depressiver Symptome als Patienten, die initial als depressiv beurteilt wurden. Letztere blieben während des Therapieverlaufs jedoch weiterhin depressiver als die anfangs nicht-depressiven Patienten. Vier Patienten wurden wegen schwerster depressiver Nebenwirkungen stationär psychiatrisch behandelt. Es wurde kein signifikanter Zusammenhang zwischen Ausgangsdepressivität und Behandlungserfolg festgestellt. Um stark gefährdete Patienten frühzeitig zu erkennen, wird vorgeschlagen, sowohl ADS als auch BDI vor und während der Therapie zu verwenden. Anhand eines ADS-Grenzwertes von > 17 vor und >= 30 während der Behandlung konnten 75% derjenigen Patienten, die im Verlauf der Therapie mit alpha-IFN schwerste depressive Symptome entwickelten, identifiziert werden. / Interferon-alpha (alpha-IFN) is presently the mainstay of the treatment of chronic hepatitis C. Side effects include a range of psychiatric symptoms, most frequently the development of depressive symptoms. Their incidence, severity and necessity for therapeutic intervention has not yet been sufficiently studied. 66 patients with chronic hepatitis C were enrolled in a pilot study and treated with either alpha-IFN alone (3x3 MU/ week) or in combination with Ribavirin (1000-1200 mg/ week). All patients went through repeated evaluations concerning their depressive symptoms before, during, and after treatment. Apart from individual interviews with the psychosomatic staff, the psychometric instruments used were the ADS (Allgemeine Depressions Skala, the German version of the Center for Epidemiological Studies Depression Scale, CES-D) and the BDI (Beck Depression Inventory). The initial depression score of the hepatitis C patients was comparable to that of a healthy population. On average, depression scores increased by 5,15 points (+/-8,94) on the ADS and 3,85 points (+/-6,94) on the BDI during the first 3 months of treatment. Less than a third of all patients did not show an increase of depressive symptoms. Patients with an initially low depression score experienced a greater increase of depressive symptoms than patients initially diagnosed as depressive. Nevertheless, the latter patients remained more depressive throughout the study period. Four patients developed severe depressions that necessitated admission to a psychiatric clinic. There was no significant correlation between the initial depression score and the treatment response. In order to recognize those patients at high risk for the development of severe depressions at an early stage, the author proposes the use of ADS and BDI both before and during treatment with alpha-IFN. Using a cut-off score of more than 17 points on the ADS before, and >=30 points during treatment, 75% of all patients developing severe depressions during treatment with alpha-IFN could be identified.

This thesis examines cancer and mortality rates among people diagnosed with hepatitis B (HBV) and C (HCV) infection in New South Wales (NSW) from 1990 through 2002, by linking hepatitis notifications with the NSW Central Cancer Registry (CCR) and National Death Index. Of the 39101 HBV, 75834 HCV and 2604 HBV/HCV co-infection notifications included 1052, 1761 and 85 were linked to cancer notifications and 1233, 4008 and 186 were linked to death notifications respectively. Of 2072 hepatocellular carcinoma (HCC) notifications to the CCR 323, 267 and 85 were linked to HBV, HCV and HBV/HCV co-infection notifications. Incidence of HCC was 6.5, 4.0 and 5.9 per 1000 person years for HBV, HCV and HBV/HCV co-infected groups. Risk of HCC in those diagnosed with hepatitis was 20 to 30 times greater than the standard population. There was a marginally statistically significant increased risk of immunoproliferative malignancies associated with HCV infection (SIR=5.6 95% CI 1.8 ???17.5). Risk of death for those with hepatitis was significantly greater, 1.5 to 5 fold, than the general population with the greatest risk among those with HBV/HCV co-infection. The primary cause of HBV deaths was liver related, particularly HCC, whereas in the HCV groups drug related deaths were most frequent. Among people with HCV, risk of dying from drug related causes was significantly greater than from liver related causes (p=0.012), with the greatest increased risk in females age 15- 24 years (SMR 56.9, 95%CI 39.2???79.9). Median age at diagnosis of HCC varied markedly by country of birth and hepatitis group: HBV 66, 63 and 57years ; HCV 51, 68 and 71 years; unlinked 69, 70 and 64 years for Australian, European, and Asian-born groups, respectively (P<0.0001 for all groups). While the risk of cancer, particularly HCC, is elevated among people with HBV and HCV infection, the absolute risk remains low. Young people with HCV face a higher mortality risk from continued drug use than from liver damage related to their HCV infection. The influence of IDU in the epidemiology of HCC in New South Wales was possibly reflected in the varying distributions of age and country of birth.

published_or_final_version / Medicine / Master / Doctor of Medicine

No description available.

Glomerulonephritis as an extra hepatic manifestation of chronic HBV infection has now been well documented [1,2,3,4,5]. HBV-associated nephropathy has been described in areas of both high and low endemicity [6]. In Africa HBV-associated nephropathy has been reported from the southern, central and northern regions [7,8,9,10,11]. In the southern African continent the prevalence of HBV-associated nephropathy appears to be higher than the rest of the continent [12]. In KwaZulu/Natal, South Africa, the prevalence of hepatitis B surface antigenaemia (HbsAg) in urban, rural and institutionalised children was reported to be 6.3%, 18.5% and 35.4% and the HBV exposure rates, as shown by the presence of any marker of HBV infection, 19.5%, 65.1% and 70.1% respectively amongst black children [13]. Prior experience of nephrotic syndrome (NS) and its association with HBV in black children, already published in a series of reports, showed HBV-associated nephropathy to be the commonest form of nephrotic syndrome among black patients in KwaZulu/Natal; membranous nephropathy (MN) being the commonest histological type reported [7,14]. The only other large series of HBV-associated nephropathy in southern Africa was from Cape Town of a large cohort of children, mainly of mixed ancestory (coloured), with a small number of black children [8]. There have been no other large studies of this condition amongst black children in Africa. We therefore undertook a series of studies to delineate the spectrum of this disease in black children with regard to the following: clinical presentation, laboratory findings, natural history, biosocial background, genetics (using HLA Class I and II antigens) as well as the impact of treatment and prevention by immunisation. We commenced these studies by reviewing our 20-year experience of 636 children with NS in Durban, South Africa for the period 1976- - 1995. Three hundred and six (48.2%) were blacks, 307 (48.2%) Indians and 23 (3.6%) were a mixed group (coloured); 91 (14.3%) could not be categorised and were excluded from the analysis. In black children, membranous nephropathy accounted for 43% of all cases of NS; 86.2% of these 306 children were associated with hepatitis B virus antigens [15]. This contrasts with the 2% - 5% prevalence of idiopathic membranous nephropathy reported in western countries [16]. We then proceeded to document the clinical features of this disease in black children. One hundred and thirty-three children with NS positive for HBV carriage were studied. In 70 patients the histological type was membranous; 46 of these 70 patients were followed up for a mean of 3.4 years (range 1-11). Spontaneous elimination of both HBsAg and HBeAg occurred in 10 (21.7%) of the 46 patients; 16 (34.8%) cleared HBeAg alone. Co-existing liver disease occurred in 18 (25.7%); hypocomplementaemia (low C3 and C4) in 22 (47.8%) and 5 (10.9%) of these 46 children respectively. Sixty-five (92.9%) of the 70 patients had normal renal function; 1(1.4%) impaired renal function; 3 (4.3%) chronic renal insufficiency and 1(1.4%) end stage renal disease at last hospital visit. Twelve (17.1%) of the 70 patients were in remission; all having cleared HBeAg. HBVMN was clinically indistinguishable from 24 children with idiopathic MN although biochemical characteristics were different. There were 23 patients with histological lesions other than MN. Forty patients with clinical, biochemical and serological findings similar to those with HBVMN and the other histological types, were unbiopsied. This report delineates the natural history of HBV infection in black South African children with NS, the majority of whom have MN. Disease remission in HBVMN parallels elimination of HBV antigens, particularly HBeAg. Comparison of HBVMN with idiopathic MN revealed clinically indistinguishable characteristics but unexplained biochemical differences [14]. Little is understood of the biosocial context in which HBV-associated nephropathy (particularly MN) develops. In the next two studies we evaluated HBV status and proteinuria in family members and household contacts of index children with HBVMN to test the hypothesis that HBV carriage and asymptomatic proteinuria are closely linked and may be causally associated. In the first of these two studies, thirty-one black children with biopsy-proven HBVMN were the index cases. One hundred and fifty-two family members and 43 black household contacts were the subjects of this study. We assessed HBV carrier status by testing for HBV antigens and antibodies using enzyme-linked immunosorbent assays (ELISA) and for HBV DNA by using slot-blot hybridisation and nested polymerase chain reaction. Sequencing of the precore HBV region of HBV was done in a subset of both index cases and subjects. Proteinuria was assessed by measuring the urinary protein: creatinine ratio. Seventy-two (37%) of the 197 family members and household contacts were HBV carriers, and 53 (27%) had a protein: creatinine ratio greater than the physiological limit (protein: creatinine ratio <0.2). Abnormal proteinuria was defined by a protein: creatinine ratio 0.2. Continuous data was compared using analysis of variance. Categorical data were compared using Chi-square test or Fisher’s exact test where appropriate. A probability of <0.05 was considered significant. The frequency of abnormal proteinuria was not significantly different in those with [22 (30.5%) of 72] or without [33 (32%) of 104] HBV carriage. This lack of association remained when carriers were classified into those who were HBsAg positive only and those with active viral replication (HBsAg and/or HBeAg and/or HBV DNA; p = 0.01). Family members were more predisposed to HBV carriage than household contacts, but abnormal proteinuria was present with equal frequency (p = 0.48). Age had a significant impact on proteinuria, with children less than five years being more likely to have abnormal proteinuria (p = 0.008). The prevalence of abnormal proteinuria in family members and household contacts of the index cases was more than in community-based controls. The 10 index HBVMN cases and 14 family members and household contacts that were tested all had HBV of genotype A. The results suggest that the family members and household contacts of children with HBVMN are at very high risk of HBV carriage; they also have asymptomatic proteinuria at a significantly higher rate than community-based controls. The HBV carrier status was not associated with proteinuria. This lack of association was a finding supported by peak prevalences of proteinuria in those under five years but no corresponding peak of HBV carriage. Proteinuria may indicate glomerular basement membrane dysfunction. Environmental and social factors may underpin development of these two disorders, but are insufficient to account for the index cases of HBVMN. The emergence of children with HBVMN from such households additionally depends on unidentified and possibly genetic factors [17]. In the second study of the biosocial background in which the HBV carrier-state with MN develops, we used the same subjects. One hundred and twenty-three unrelated individuals from the communities of the index cases, negative for HBV, served as controls. In this study, proteinuria was assessed using sodium dodecyl sulphate polyacrylamide gel electrophoresis (SDS-PAGE) and protein: creatinine ratios. Patterns of proteinuria on SDS-PAGE were classified as glomerular, tubular or mixed; IgG and haptoglobulin were suggestive of MN. Seventy-two (36.9%) of the 195 family members and household contacts were HBV carriers; 21 (29.2%) of these carriers had evidence of proteinuria using SDS-PAGE. Twenty-eight (41.2%) of the sixty-eight members of the study group who were HBV negative and 26.8% of the controls also showed proteinuria on SDS-PAGE. This lack of association between HBV carriage and proteinuria remained when controlled for gender and family relationship. Also, HBV was not protective against the development of proteinuria. Age was associated directly with a glomerular pattern of proteinuria (p = 0.007). Those having a pattern of proteinuria suggestive of MN were more likely to have an abnormal protein: creatinine ratio (p = 0.001). Ten (59%) subjects with a membranous pattern of proteinuria and 19 (47.5%) with a non-membranous pattern of proteinuria had microscopic haematuria. Such a pattern of proteinuria was not significantly different between subjects and community based controls (8.7% vs. 6.5%, p = 0.5). Environmental exposures in these subjects may be responsible for the proteinuria, which probably reflects underlying glomerular basement membrane damage. Discordance between the HBV carrier-state and patterns of proteinuria in the study group suggest that interaction between specifically vulnerable individuals and HBV group suggest HBV and MN may not be causally related or that it reflects exceptional interaction between specifically vulnerable individuals and HBV [18]. From the above two studies we inferred that the pathogenetic mechanisms by which individuals with chronic HBV infection develop MN are probably dependent on interactions between viral, host and environmental factors; some evidence suggests a genetic predisposition. We therefore undertook another two studies to explore HLA associations in black children with HBVMN. In the first of these two studies, thirty black children, age range 2 to 16 years, with biospy-proven HBVMN, were the subjects of this study. HLA A, B and C antigens were determined using a two-stage lymphocytotoxic test. HLA DRB1* and DQB1* typing was done using sequence-specific primers. HLA class I and II antigen frequencies of the study subjects were compared to controls that were randomly chosen healthy blood donors from the same population. HLA DQB1*0603 was increased in patients with HBVMN compared to controls (chi-square 13.65, RR 4.3). DRB1*07 and DQB1*02 were increased in frequency in the study subjects but failed to reach statistical significance. There was no significant difference in the frequencies of class I antigens in the study group compared to controls. This study is the first report of HLA associations in black patients with HBVMN in whom Class I and II antigens were determined using molecular methodology. It shows a high frequency of DQB1*0603 in black children with HBVMN compared to controls suggesting a possible genetic predisposition to the development of HBVMN [19]. Following our findings of an HLA Class II association in black children with HBVMN, we proceeded to determine if HLA DQB1*0603 predisposes to HBV carriage and development of abnormal proteinuria in the second study. We studied 70 family members of 14 children with HBVMN positive for HLA DQB1*0603 selected from the first study. Associations of HLA DQB1*0603 to HBV carriage and abnormal proteinuria were determined using the mean probability ratio (LOD scores). Forty-seven of the 70 (67%) family members were positive for HBV infection. Nineteen (27%) had abnormal range proteinuria. LOD scores in the study subjects with DQB1*0603 who were HBV negative vs. those with DQB1*0603 who were HBV positive was not significant (anti-log sum = 2.0559 and average 0.23). When a similar calculation was done for abnormal proteinuria, there were no significant findings (anti-log sum = 3.8587 and average 0.43). This lack of association between HLA DQB1*0603 with either HBV carriage or abnormal proteinuria in family members suggests that additional factors may play a role in predisposing children to chronic HBV carriage and the development of MN. We therefore conclude that the main effect of HLA DQB1*0603 which distinguishes HBVMN from family members is the degree of proteinuria which is a reflection of the severity of glomerular basement membrane damage in the latter [20]. In the next study we proceed to investigate the efficacy of Interferon alpha 2b (INTRON A ®) in the treatment of HBV-associated nephropathy in black children. Twenty-four black children with biopsy-proven HBV-associated nephropathy were recruited into the study during the period April 1997 to June 1999. Five defaulted treatment and were excluded from the primary analysis. IFN 2b was administered for 16 weeks. Response to treatment was defined as loss of HBeAg, decrease in proteinuria, and prevention of deterioration in renal and liver function. A control group of 20 patients was followed up for the same period. Ten (52.6%) of the treated children responded with clearance of HBeAg by 40 weeks. None cleared HBsAg. All responders showed remission of proteinuria, 90% maintained normal renal function and 1 (10%) showed improvement of renal function. HBV DNA levels decreased in this group. Nine patients did not clear HBeAg; none showed remission of proteinuria, 2 showed deterioration of renal function. Liver enzymes rose during treatment but subsequently declined irrespective of response to therapy. No serious side effects were encountered. Only 5% of controls showed spontaneous clearance of HBeAg, and none had remission of proteinuria. Black children with HBV-associated nephropathy show accelerated clearance of HBeAg with remission of proteinuria following treatment with IFN 2b. IFN 2b was well-tolerated [21]. We then went on to investigate the impact of HBV vaccination in South Africa over 6 years on HBV-associated MN. HBV vaccine has resulted in a decline in the incidence of HBV carriage and hepatocellular carcinoma in South East Asia. Vaccine efficacy in Africa has not been adequately assessed. King Edward VIII Hospital, Durban, South Africa, is the only tertiary referral centre for the province of KwaZulu/Natal for children with renal diseases. HBV vaccine was introduced into the Extended Programme on Immunisation (EPI) in April 1995; vaccine coverage rates between 1995-2001 for children for the first, second and third doses were 85.4%, 78.2% and 62.0% respectively. HBV status was determined using radioimmunoassay (1984 – 1991) or ELISA. MN was confirmed on renal biopsy. The hospital average annual incidence of HBVMN was compared pre and post-vaccination, and according to age groups. Between 1984 and 2001 there were 119 children with HBVMN; the mean age was 7 years (range 1 to 14 years) and 101(85%) were males. The average annual rate ratio (aRR) per 105 child population was 0.25. The aRR of 0.03 for the years 2000-2001, was significantly lower than the aRR of 0.22 during the pre-immunisation period (1984 – 1994) [p = 0.003; RR = 0.12 (95% CI: 0.03 – 0.5)]. The aRR in 2000-2001 for children 0 – 4 years (0.00) and 5 – 10 years (0.09) were significantly lower than in the pre-vaccination years (0.16 and 0.46, p = 0.01 and 0.02 respectively). Thus, HBV vaccine, even at low coverage for the full EPI schedule, reduced the hospital incidence of HBVMN by six years [22]. From this series of studies we concluded that prior to the introduction of the HBV vaccine into the Expanded Programme on Immunisation in Children, HBV-associated nephropathy, particularly MN was the commonest form of NS in black children. Several studies have suggested on the basis of epidemiological, clinical and immunological evidence a causal association between chronic HBV carriage and the development of nephropathy. In our present series of studies we have findings that lend further support to the causal association between HBV carriage and development of nephropathy, particularly MN, in black children. We have shown that genetic and other environmental factors may also play a role in determining the degree of proteinuria. Those children with abnormal range proteinuria less than the nephrotic range show no association with HBV carriage or genetic factors with regard to HLA linkage. The efficacy of interferon treatment in elimination of the HBV and abrogation of proteinuria following clearance of the virus (particularly the HBeAg) as well as the impact of routine HBV immunisation in preventing HBV carriage and subsequent development of nephropathy lends further support to our findings. The impact of viral load has yet to be investigated. / Thesis (Ph.D.)-University of Natal, Durban, 2002.