Selection dynamics of HCV genotype 3 resistance-associated substitutions under direct-acting antiviral therapy pressure

ABSTRACT The chronic hepatitis C (CHC) treatment is currently based on the use of direct-acting antivirals (DAAs), and patients infected with hepatitis C virus genotype 3 (GT3) have emerged as a more difficult-to-cure population. The NS5A inhibitor daclatasvir (DCV) and sofosbuvir (SOF), an NS5B viral polymerase inhibitor, are among the drugs that compose more effective and safer treatment regimens. The virus genetic variability is related to resistance-associated substitutions (RASs) that adversely impact DAAs effectiveness. The aims of this study were to analyze the association of NS5A and NS5B RASs and other clinical factors with DAAs regimens effectiveness in patients with GT3 CHC infection. This was a prospective cohort study performed in a Brazilian university hospital. Individuals older than 18 years with GT3 CHC treated with SOF + DCV ± ribavirin (RBV) or SOF + peginterferon (PEG) + RBV were included. Blood samples were collected at baseline and post-treatment. A total of 121 patients were included. Sustained virological response rates were 87.6% for the SOF + DCV ± RBV group and 80.0% for the SOF + PEG + RBV arm. Cirrhosis, prior treatment with interferon/PEG + RBV, and baseline NS5A RAS were associated with higher risk of treatment failure. The NS5A analysis suggested that A30K, Y93H, and RAS at site 62 were related to failure. Interestingly, a likely compensatory effect was shown between A30K and A62T. Emergence of Y93H was always associated with RAS at position 62. The RASs dynamics comprehension is an important tool to indicate more effective treatment for GT3 patients.

Cost-effectiveness analysis is a mandatory strategy for health systems: evidence from a study involving therapies for hepatitis C / Análise de custo-efetividade é uma estratégia essencial para os sistemas de saúde: as evidências de um estudo sobre terapias para hepatite C / El análisis de coste-efectividad es una estrategia esencial para los sistemas de salud: evidencias de un estudio sobre terapias para hepatitis C

Abstract: Cost-effectiveness analysis is essential in health decision making. Several countries use it as synthesis of evidence to incorporate health technologies. The protease inhibitors (PI) boceprevir (BOC) and telaprevir (TVR) are indicated for chronic hepatitis C treatment and were incorporated in guidelines worldwide. Pre-marketing clinical trials showed higher sustained virological response rates in relation to previous therapies, but the incorporation of PIs generated a significant financial impact. The aim of this study was to discuss the relevance of cost-effectiveness analysis through a study that involved the inclusion of PIs in a clinical protocol. The analysis was part of a real-life study that included patients infected with hepatitis C virus genotype 1 treated in a tertiary university hospital in Brazil. Triple therapies (TT) with ribavirin (RBV), peginterferon α-2a (Peg-INF α-2a) and BOC or TVR were compared to dual therapy with RBV and Peg-INF α-2a. Sensitivity analysis of the cost-effectiveness ratio indicated an 88.2% chance of TTs presenting a higher cost per cure. The incremental cost-effectiveness ratios (ICER) exceeded the Brazilian gross domestic product (GDP) per capita by three times in all proposed scenarios. The sensitivity of ICER showed an 88.4% chance of TT not being cost-effective. The impact of PI incorporation was negative and the conduct about this could have been different if a previous cost-effectiveness analysis had been conducted.

Resumo: A análise de custo-efetividade tem sido essencial para a tomada de decisões em saúde. Diversos países utilizam esse tipo de análise como síntese das evidências para incorporar as tecnologias em saúde. Os inibidores de protease (IPs) boceprevir (BOC) e telaprevir (TVR) são indicados para o tratamento da hepatite C crônica e foram incorporados nas diretrizes internacionais. Os ensaios clínicos pré-marketing demonstraram taxas mais altas de resposta virológica sustentada em relação às terapias anteriores, mas a incorporação dos IPs gerou um impacto financeiro significativo. O estudo teve como objetivo discutir a relevância da análise de custo-efetividade, através de um estudo que envolveu a inclusão de IPs em um protocolo clínico. A análise fez parte de um estudo de vida real que incluiu pacientes com infecção pelo vírus da hepatite C, genótipo 1, tratados em um hospital universitário terciário no Brasil. As terapias triplas (TTs) com ribavirina (RBV), peg-interferon α-2a (Peg-INF α-2a) e BOC ou TVR foram comparadas às terapias duplas com RBV e Peg-INF α-2a. A análise de sensibilidade da custo-efetividade indicou odds de 88,2% de TTs apresentarem custo mais elevado por paciente curado. Em todos os cenários propostos, as razões de custo-efetividade incremental (ICERs) superaram em três vezes o produto interno bruto (PIB) per capita brasileiro. A sensibilidade da ICER mostrou probabilidade de 88,4% das TTs não serem custo-efetivas. O impacto da incorporação dos IPs foi negativo, e a conduta teria sido diferente se tivesse sido realizada uma análise prévia de custo-efetividade.

Resumen: El análisis de coste-efectividad ha sido esencial para la toma de decisiones en salud. Diversos países utilizan este tipo de análisis como síntesis de evidencias para incorporar tecnologías en salud. Los inhibidores de proteasa (IPs) boceprevir (BOC) y telaprevir (TVR) se indican para el tratamiento de la hepatitis C crónica y fueron incorporados en directrices internacionales. Los ensayos clínicos pre-marketing demostraron tasas más altas de respuesta virológica sostenida, respecto a las terapias anteriores, pero la incorporación de los IPs generó un impacto financiero significativo. El objetivo del estudio fue discutir la relevancia del análisis de coste-efectividad, a través de un estudio que implicó la inclusión de IPs en un protocolo clínico. El análisis formó parte de un estudio de vida real que incluyó a pacientes con infección por el virus de la hepatitis C, genotipo 1, tratados en un hospital universitario terciario en Brasil. Las terapias triples (TTs) con ribavirina (RBV), peg-interferon α-2a (Peg-INF α-2a) y BOC o TVR se compararon con las terapias dobles con RBV y Peg-INF α-2a. El análisis de sensibilidad del coste-efectividad indicó odds de 88,2% de que las TTs presentaran un coste más elevado por paciente curado. En todos los escenarios propuestos, las razones de coste-efectividad incremental (ICERs) superaron tres veces el producto interno bruto (PIB) per cápita brasileño. La sensibilidad de la ICER mostró una probabilidad de que un 88,4% de las TTs no eran costo-efectivas. El impacto de la incorporación de los IPs fue negativo, y el resultado habría sido diferente si se hubiese realizado un análisis previo de coste-efectividad.

First-wave protease inhibitors for hepatitis C genotype 1 treatment: a real-life experience in Brazilian patients

Abstract INTRODUCTION: Licensed for chronic hepatitis C treatment in 2011, the protease inhibitors (PIs) telaprevir (TVR) and boceprevir (BOC), which have high sustained viral responses (SVR), ushered a new era characterized by the development of direct-action drugs against the hepatitis C virus (HCV). The aim of this study was to analyze the effectiveness and safety of BOC and TVR administered with pegylated interferon and ribavirin and to share the experience of a Brazilian reference center. METHODS: A retrospective descriptive study was conducted in patients with HCV genotype 1 infection who started treatment between July 2013 and December 2015. Data were collected using a computerized system. RESULTS: A total of 115 subjects were included, of which 58 (50.4 %) had liver cirrhosis and 103 (89.6 %) used TVR. The overall SVR rate was 61.7 % (62.1 % for TVR and 58.3 % for BOC). The presence of cirrhosis was associated with a lower SVR rate, whereas patients who relapsed after prior therapy had a greater chance of showing SVR than did non-responders. The incidence of adverse drug reactions (ADRs) was high. Almost all patients (~100 %) presented with hematologic events. Furthermore, treatment had to be discontinued in 15 subjects (13 %) due to severe ADRs. CONCLUSIONS: In conclusion, the SVR rates in our study were lower than those reported in pre-marketing studies but were comparable to real-life data. ADRs, particularly hematological ADRs, were more common compared to those in previous studies and resulted in a high rate of treatment discontinuity.

Basal core promoter and precore mutations among hepatitis B virus circulating in Brazil and its association with severe forms of hepatic diseases

BACKGROUND In Brazil, few studies have investigated the prevalence of infection with the precore (PC) and basal core promoter (BCP) mutants of the hepatitis B virus (HBV). OBJECTIVES This study aimed to analyse the frequency of PC and BCP mutations among patients infected with HBV and to evaluate the association between the variants and advanced hepatic disease. METHODS A total of 161 patients infected with HBV were studied. To identify PC and BCP mutations, a 501-bp fragment of HBV DNA was amplified and sequenced. FINDINGS PC and BCP regions from HBV strains were successfully amplified and sequenced in 129 and 118 cases, respectively. PC and BCP mutations were detected in 61.0% and 80.6% of the cases, respectively. The A1762T/G1764A variant was identified in 36.7% of the patients with grade 1 and 2 liver fibrosis (29/79) and in 81.8% of the patients with grade 3 and 4 liver fibrosis (9/11) (p < 0.01); in 76.9% of the patients with cirrhosis (10/13) and in 38.1% of the patients without cirrhosis (40/105) (p = 0.01); and in 77.8% of the patients with hepatocellular carcinoma (HCC) (7/9) and in 39.4% of the patients without HCC (43/109) (p = 0.03). MAIN CONCLUSIONS A high prevalence of HBV PC and BCP mutants was found. The A1762T/G1764A variant was independently associated with advanced forms of liver fibrosis, hepatic cirrhosis, and HCC.

Distribution of HBV subgenotypes in Ribeirão Preto, Southeastern Brazil: a region with history of intense Italian immigration

Abstract Hepatitis B virus (HBV) is distributed worldwide, with geographical variations regarding prevalence of the different genotypes. The aim of this study was to determine the HBV genotypes and subgenotypes circulating in Southeast Brazil and compare the genetic sequences found with HBV sequences previously described in the world. Sequences from 166 chronic HBV carriers were analyzed using the fragment constituted by 1306 base pairs comprising surface and polymerase regions of the HBV genome. The sequences obtained were submitted to phylogenetic analysis. HBV subgenotypes A1, A2, D1-D4, F2a, and F4 were found. HBV genotype D was the most frequent, found in 99 patients (58.4%). Within this group, subgenotype D3 was the most prevalent, in 73 patients (42.9%). HBV genotype A was identified in 58 (36%) patients, subgenotype A1, in 48 (29.8%) subjects. Genotype F was identified in 9 (5.4%). According to the phylogenetic analysis, the sequences found were grouped with sequences from Europe, Asia and Middle East (subgenotypes D1, D2, D3) and sequences from Latin America and Africa (subgenotype A1). HBV D3 grouped in different clusters inside D3 clade, several of them with sequences isolated in Italy. We also identified eight families whose relatives were infected with the same HBV subgenotype, most with high similarity between sequences. In conclusion, the distribution of the HBV sequences obtained interweaved with sequences from other continents, corresponding to regions from where many immigrants came to this region, in accordance to the hypothesis that the HBV detected over there were brought during the colonization times.

Epidemiological study of hepatitis B and C in a municipality with rural characteristics: Cássia dos Coqueiros, State of São Paulo, Brazil

Abstract: INTRODUCTION: Hepatitis B and C viral infections remain an important cause of global morbidity and mortality. Studies have been conducted in population groups of large cities, leaving gaps in the knowledge regarding the situation in small municipalities. We aimed to measure the prevalence of hepatitis B and C markers and presence of infection-associated factors. METHODS: All inhabitants of Cássia dos Coqueiros aged ≥18 years who agreed to participate in the research were included. We collected blood as well as information via a questionnaire between March 2011 and December 2013. Univariate and multivariate analyses were conducted. RESULTS: Among the 1,001 participants, 41 (4.1%) participants had a serological profile of hepatitis B viral exposure, and only one (0.1%) participant was considered a virus carrier. The frequency of isolated antibody to hepatitis B virus surface antigen (anti-HBs) markers was 17.8% for the overall population. In the multivariate analysis, hepatitis B virus (HBV) infection was associated with age, birth outside the State of São Paulo, history of hepatitis, ≥2 sexual partners in the last 6 months, and tattoos. Four (0.4%) participants had a serological profile of hepatitis C viral exposure. However, after confirmation using viral ribonucleic acid (RNA) evaluation, only one (0.1%) individual remained positive. CONCLUSIONS: The positivity rates for hepatitis B and C were low, despite greater sexual freedom and the recent emergence of illicit drugs, as observed by the health personnel working in Cássia dos Coqueiros.

Addition of n-butyl cyanoacrylate to classic transarterial chemoembolization may improve the radiological response in patients with hepatocellular carcinoma

OBJECTIVE: Transarterial chemoembolization is the treatment of choice for intermediate-stage hepatocellular carcinoma. However, there are no clear data supporting transarterial chemoembolization vs . transarterial embolization or regarding the best chemotherapeutic agent, which may suggest a preponderant role of ischemia over chemotherapeutic action. This study sought to evaluate the radiological response and outcome of transarterial chemoembolization modified by n-butyl cyanoacrylate addition compared to conventional transarterial chemoembolization in hepatocellular carcinoma patients. MATERIALS AND METHODS: A retrospective review identified forty-seven patients who underwent modified chemoembolization and thirty-three who underwent conventional chemoembolization between June 2006 and December 2011. The radiological response was reassessed using the modified Response Evaluation Criteria in Solid Tumors. The sustained complete response, time to progression and overall survival rates were also analyzed. RESULTS: Complete response rates were significantly higher in patients who had undergone modified chemoembolization compared to those who had undergone conventional treatment (61.7% and 24.3%, respectively; p <0.001). The rate of sustained complete response was significantly higher in the modified chemoembolization group compared to the conventional chemoembolization group (median of 236 and 37 days, respectively; p <0.001). Time to progression was significantly higher in the modified chemoembolization group compared to the conventional chemoembolization group (median of 424 and 201 days, respectively; p =0.042). Overall survival rates revealed no difference between patients who received modified chemoembolization and conventional chemoembolization (median of 483 and 399 days, respectively; p =0.316). CONCLUSION: Transarterial chemoembolization modified by n-butyl cyanoacrylate addition was superior to conventional transarterial chemoembolization in terms of the radiological response in the first imaging control. Although the sustained complete response and time to progression rates were higher for the modified chemoembolization group, no differences in overall survival rates were observed.

Risk factors for hepatitis C virus transmission in the municipality of Catanduva, State of São Paulo: a case-control study

Introduction Hepatitis C virus (HCV) is primarily transmitted via contact with the blood of infected patients, although the form of contact has not been identified for a significant percentage of carriers. The present study evaluated possible risk factors for HCV transmission in a medium-sized town located in the northwest region of the State of São Paulo. Methods This was a case-control study, with the case group consisting of 190 chronic HCV carriers older than 18 years residing in the municipality of Catanduva. The control group also consisted of 190 individuals with HCV-negative serology. The groups were paired (1:1) for gender, age range (± five years), and place of residence. The same structured questionnaire was applied to all subjects, who gave written informed consent to participate in the study. The data were statistically analyzed using crude and adjusted logistic regression, and the results were expressed as odds ratios with a 95% confidence interval. Results The demographic profiles of the groups indicated a predominance of males (68.9%) and mean ages of 47.1 years (case group) and 47.3 years (control group). After adjusting for conditional regression, the following factors were found to represent risks for HCV: history of sexually transmitted disease (STD) and blood transfusion; accidents with syringes and/or needles; tattoos; and the use of non-injectable drugs and injectable medications. Conclusions The transmission of HCV via the blood route has been well characterized. Other forms of contact with human blood and/or secretions are likely to transmit the virus, although with a lower frequency of occurrence. .

Clinical, demographic and epidemiological characteristics of patients with hepatitis B followed at a university hospital in southeastern Brazil: predominance of HBeAg negative cases / Características clínicas, demográficas e epidemiológicas dos pacientes com hepatite B em seguimento em hospital universitário no sudeste do Brasil: predominância de casos HBeAg negativos

INTRODUCTION: Hepatitis B is common in Brazil, although there are regional differences regarding the degree of endemicity, the most frequent forms of transmission and the presence of different evolutive stages of chronic disease. The present study aimed to determine the clinical, demographic and epidemiological characteristics of patients chronically infected with hepatitis B virus (HBV) residing in the Ribeirão Preto region, southeastern Brazil. METHODS: A total of 529 medical records of individuals with HBV monoinfection were reviewed. RESULTS: More than 60 percent of the subjects were males, with a mean age of 38 years-old. The HBeAg-negative serological pattern was verified in 84.4 percent of the patients, among whom the risk of vertical/intrafamily transmission was 43.2 percent (p = 0.02). The consumption of alcohol in amounts exceeding 20g a day was observed in 21.3 percent of the subjects and was more frequent among men (33 percent) (p < 0.001). Among patients with cirrhosis, 54.1 percent were alcohol abusers (p = 0.04), all of them males. The presence of cirrhosis was more frequent in the HBeAg-positive group (24.4 percent) than in the HBeAg-negative group (10.2 percent) (p < 0.001). CONCLUSIONS: High proportions of HBV-infected subjects with an HBeAg-negative pattern were observed, with a higher risk of vertical/intrafamily transmission. Alcohol abuse was associated with male subjects and with cirrhosis of the liver in this group. A tendency toward an increase in the number of HBeAg-negative cases was observed over time.

INTRODUÇÃO: No Brasil, a hepatite B é comum. No entanto, há diferenças regionais no que diz respeito ao grau de endemicidade, as formas de transmissão mais encontradas e a presença dos diferentes estágios evolutivos da doença crônica. O objetivo deste trabalho foi o de conhecer características clínicas, demográficas e epidemiológicas de pacientes cronicamente infectados pelo vírus da hepatite B (HBV), residentes na região de Ribeirão Preto, no sudeste do Brasil. MÉTODOS: Foi realizada a análise retrospectiva de 529 prontuários de indivíduos com monoinfecção pelo HBV. RESULTADOS: Mais de 60 por cento eram masculinos, a média de idade foi de 38 anos. O padrão sorológico HBeAg negativo foi encontrado em 84,4 por cento dos pacientes, entre os quais o risco para transmissão vertical/intrafamiliar foi de 43,2 por cento (p = 0,02). Verificou-se uso de álcool em quantidades maiores que 20g ao dia em 21,3 por cento dos indivíduos, sendo mais frequente entre os homens (33 por cento) (p < 0,001). Entre os pacientes com cirrose, 54,1 por cento faziam uso abusivo de bebidas alcoólicas (p = 0,04), sendo todos estes do gênero masculino. A presença de cirrose foi maior no grupo HBeAg positivo (24,4 por cento) que no grupo HBeAg negativo (10,2 por cento) (p < 0,001). CONCLUSÕES: Observaram-se elevadas proporções de indivíduos com infecção pelo HBV com padrão sorológico HBeAg negativo, entre os quais houve maior risco para a transmissão vertical/intrafamiliar. O uso abusivo de álcool esteve associado a indivíduos do sexo masculino e, neste grupo, à cirrose hepática. Observou-se tendência ao aumento no número de casos HBeAg negativo ao longo do tempo.

Long-term follow-up of patients with chronic hepatitis C with sustained virologic response to interferon

BACKGROUND AND AIM: The durability of the sustained virologic response (SVR) in patients with chronic hepatitis C after treatment and the ideal follow-up time for these patients remains undefined. The objective of the study was to evaluate the durability of the virologic response in patients with chronic hepatitis C followed up for at least 12 months after SVR at HCFMRP-USP. METHODS: The study was conducted on 174 patients with chronic hepatitis C treated with different antiviral regimens who had achieved SVR. Qualitative serum HCV-RNA was determined by the commercial kit (COBAS AMPLICOR HCV, v2.0). RESULTS: There was predominance of male (73 percent) with a mean age of 45.6 ± 10 years. Liver cirrhosis was present in 16.1 percent of the study subjects. Mean follow-up time after SVR was 47 months (12-156 months). Twenty-two patients received monotherapy with interferon; 94 received interferon plus ribavirin, and 58 received pegylated interferon plus ribavirin. A total of 134 patients (77.0 percent) received one treatment course, 29 (16.7 percent) received two courses, and 11 (6.3 percent) received three courses. The distribution of HCV genotypes was: genotype 1 (40.2 percent), genotype 3 (40.8 percent) and genotype 2 (10.3 percent). Genotype was undetermined in 8.7 percent of cases. None of the 174 patients had recurrence of HCV infection. Two cirrhotic patients developed hepatocellular carcinoma (HCC) during follow-up. CONCLUSIONS: Among patients with SVR there was no recurrence of HCV infection or evidence of liver disease progression in any patient followed up for a mean of 47 months after SVR, except for patients with advanced hepatic disease before treatment, who may develop HCC despite SVR. Therefore, one can assume that SVR is associated with long term good prognosis.

Hepatitis B virus genotyping among chronic hepatitis B patients with resistance to treatment with lamivudine in the City of Ribeirão Preto, State of São Paulo / Genotipagem do vírus da hepatite B de pacientes crônicos com resistência ao tratamento com lamivudina na Cidade de Ribeirão Preto, Estado de São Paulo

INTRODUCTION: Lamivudine is a nucleoside analogue that is used clinically for treating chronic hepatitis B infection. However, the main problem with prolonged use of lamivudine is the development of viral resistance to the treatment. Mutations in the YMDD motif of the hepatitis B virus DNA polymerase gene have been associated with resistance to drug therapy. So far, there have not been many studies in Brazil reporting on genotype-dependent development of resistance to lamivudine. Thus, the aim of the present study was to determine the possible correlation between a certain genotype and increased development of resistance to lamivudine among chronic hepatitis B patients. METHODS: HBV DNA in samples from 50 patients under lamivudine treatment was amplified by means of conventional PCR. Samples were collected at Hospital das Clínicas, FMRP-USP. The products were then sequenced and phylogenetic analysis was performed. RESULTS: Phylogenetic analysis revealed that 29 (58 percent) patients were infected with genotype D, 20 (40 percent) with genotype A and one (2 percent) with genotype F. Mutations in the YMDD motif occurred in 20 percent of the patients with genotype A and 27.6 percent of the patients with genotype D. CONCLUSIONS: Despite the small number of samples, our results indicated that mutations in the YMDD motif were 1.38 times more frequent in genotype D than in genotype A.

INTRODUÇÃO: Lamivudina é um análogo de nucleosídeo clinicamente utilizado para o tratamento da infecção crônica pela hepatite B. Entretanto, o principal problema do uso prolongado da lamivudina é o desenvolvimento de resistência viral ao tratamento. Mutações no motivo YMDD no gene da DNA polimerase do vírus da hepatite B estão associados com a resistência a terapia medicamentosa. Até o presente momento, não há muitos estudos no Brasil que descrevem o desenvolvimento genótipo-dependente da resistência à lamivudina. Assim, o intuito do trabalho aqui descrito foi determinar a possível correlação entre um determinado genótipo e o desenvolvimento aumentado da resistência à lamivudina em pacientes com hepatite B crônica. MÉTODOS: O HBV DNA foi amplificado por PCR convencional a partir de 50 amostras coletadas de pacientes submetidos ao tratamento com lamivudina no Hospital das Clínicas- FMRP- USP. Posteriormente, os produtos foram seqüenciados e a análise filogenética foi realizada. RESULTADOS: A análise filogenética mostrou que 29 (58 por cento) pacientes foram infectados com o genótipo D, 20 (40 por cento) com o genótipo A e 1 (2 por cento) com o genótipo F. Mutações no motivo YMDD ocorreu em 20 por cento dos pacientes com genótipo A e 27,6 por cento em pacientes do genótipo D. CONCLUSÕES: Apesar do baixo número de amostras, nossos resultados indicaram que mutações no motivo YMDD são 1,38 X mais frequentes no genótipo D em relação ao genótipo A.

Hepatitis C among former athletes: association with the use of injectable stimulants in the past

This study was performed with the purpose of testing the hypothesis that the high prevalence of hepatitis C among former athletes is associated with their past use of injectable stimulants. The study involved the participation of 208 former professional and amateur soccer and basketball players from the region of Ribeirão Preto, Brazil, who answered a questionnaire regarding their exposure to risk factors, including the use of injectable stimulants in the time they were engaged in sporting activities. ELISA tests were used to detect infection by the hepatitis C virus, and confirmed with PCR and genotyping for the positive cases. It was observed that the former use of injectable stimulants was a practice disseminated among the participants (24.5 percent), reaching 50.8 percent in the professionals. The overall prevalence for hepatitis C was 7.2 percent, with values of 11 percent among professionals and 5.5 percent among amateurs. In both categories, the presence of infection was markedly higher among those who admitted past use of injectable stimulants when compared to those who denied such practice (36 percent and 0.8 percent among amateurs; 21.9 percent and 0 percent among professionals, respectively). Multivariate analysis showed that the use of those substances was the only variable associated with the risk of hepatitis C. This confirms previous observations, performed with reduced sample sizes and without comparison groups, which indicated that the use of injectable vitamins was a risk factor of hepatitis C among former athletes.

HCV virological response during treatment of chronic hepatitis C is associated with liver histological Improvement in patients with HCV/HIV co-infection

Liver histological improvement after treatment for chronic hepatitis C in patients co-infected with human immunodeficiency virus-1 (HIV-1) has been described. Paired liver biopsies in twenty six HCV/HIV co-infected patients were compared to determine factors possibly associated with histological improvement. The patients were submitted to a liver biopsy before treatment for hepatitis C and 25 months after the end of treatment. Fragments of the liver biopsy obtained before and after treatment were compared regarding the following parameters: histological activity index (HAI) and degree of fibrosis (Knodell); intensity of collagen deposits (Sirius Red staining) and degree of stellate cell activation (alpha-smooth muscle actin labeling). The ratios of the post and pre-treatment variables were related through logistic regression to body mass index (BMI), alcohol ingestion, HCV genotype, HCV viremia, presence of hepatic iron and pre-treatment hepatic steatosis. A negative RNA test in the 24th week of treatment was associated with improvement in fibrosis, collagen deposits and stellate cell numbers. The other variables analyzed did not correlate to an improvement in hepatic histology after hepatitis C treatment. Reduction in HCV viremia during treatment may result in reduced hepatic fibrosis even in patients without a sustained virological response.

Autoimmune hemolytic anemia in HCV/HIV coinfected patients during treatment with pegylated alpha-2a interferon plus ribavirin

Two cases of autoimmune hemolytic anemia that occurred during the treatment of chronic hepatitis C with pegylated alpha-2a interferon and ribavirin, in HIV coinfected patients, are presented and described. The late occurrence (after six months of therapy) of this severe hemolytic anemia leads to the recommendation that hemoglobin levels should be monitored throughout the treatment period, even among patients who presented stable hemoglobin levels in the preceding months.

São apresentados e discutidos dois casos de anemia hemolítica auto-imune que ocorreram durante o tratamento da hepatite crônica pelo vírus C, com interferon peguilado alfa 2a e ribavirina, em pacientes co-infectados pelo HIV. A ocorrência de anemia hemolítica grave em etapa tardia, após o sexto mês da terapêutica, recomenda que o controle dos níveis de hemoglobina deva ser feito durante todo o período do tratamento , mesmo nos pacientes que apresentam níveis estáveis de hemoglobina nos meses precedentes.

Hepatitis B among female sex workers in Ribeirão Preto - São Paulo, Brazil

OBJECTIVE: To estimate the prevalence of hepatitis B markers and to study the risk factors for this disease among female sex workers in the city of Ribeirão Preto, Brazil. METHODS: A questionnaire was given to 449 female sex workers in order to obtain information about demographic, socioeconomic and behavioral variables. Blood samples were collected and analyzed by immunoenzymatic techniques for detection of HBsAg, anti-HBs, anti-HBc and anti-HCV markers. RESULTS: The mean age of participants was 23 years, varying from 13 to 64 years. A high spatial mobility was observed, with 47.9 percent of participants residing in places out of the region of Ribeirão Preto or in other Brazilian states. Complete absence of previous vaccine against hepatitis B was referred by 98.2 percent. Overall, the presence of any hepatitis B marker was observed in 106 participants (prevalence of 23.6 percent; 95 percent CI: 19.7 27.5), with 84 positive for anti-HBs (18.7 percent), 100 for anti-HBc (22.3 percent), and only 3 for HBsAg (0.7 percent). The logistic regression analysis showed association between hepatitis B markers and the following co-variables: residence in Ribeirão Preto, age, low socioeconomic level, consumption of crack, intercourse with HIV-infected individuals, history of previous hepatitis, intercourse with a case of hepatitis, and positivity for hepatitis C. CONCLUSIONS: Ribeirão Preto's female sex workers present several risk factors for hepatitis B and almost absence of previous specific vaccination, making it necessary to emphasize this low-cost preventive measure, preferably through the use of a mobile team, taking the vaccine to their places of work.

OBJETIVOS: Estimar a prevalência de marcadores de hepatite B e estudar os fatores de risco para esta doença entre mulheres profissionais do sexo na cidade de Ribeirão Preto, Brasil. MÉTODOS: Foi aplicado um questionário a 449 mulheres profissionais do sexo, com a finalidade de levantar informações demográficas, socioeconômicas e comportamentais. Amostras de sangue das participantes foram analisadas através de técnicas imunoenzimáticas, para detecção dos marcadores HBsAg, anti-HBs e anti-HBc. RESULTADOS: A idade média das participantes foi 23 anos, variando de 13 a 64 anos. Uma elevada mobilidade espacial foi verificada, com 47,9 por cento delas residindo em locais fora da região de Ribeirão Preto ou em outros estados brasileiros. Completa ausência de vacinação prévia contra hepatite B foi referida por 98,2 por cento. No total, observou-se presença de qualquer marcador de hepatite B em 106 participantes (prevalência de 23,6 por cento; IC95 por cento: 19,7 27,5), com 84 positivos para anti-HBs (18,7 por cento), 100 para anti-HBc (22,3 por cento) e apenas 3 para HBsAg (0,7 por cento). A análise por regressão logística evidenciou associação entre marcadores de hepatite B e as seguintes co-variáveis: idade, baixo nível socioeconômico, consumo de crack, relações sexuais com indivíduos infectados pelo HIV, história de hepatite prévia, relações sexuais com pessoas portadoras de hepatite e positividade para hepatite C. CONCLUSÕES: As profissionais do sexo em Ribeirão Preto apresentam diversos fatores de risco para hepatite B e quase total ausência de vacinação prévia específica, tornando necessários esforços concentrados na aplicação dessa medida de baixo custo, preferencialmente através do uso de equipes móveis que levem a vacina até os seus locais de trabalho.

Liver transplantation: expectation with MELD score for liver allocation in Brazil / Transplante hepático: expectativas com escore MELD para alocação de fígado no Brasil

Liver transplantation represents the most effective therapy for patients suffering from chronic end-stage liver disease. Until very recently, in Brazil, liver allocation was based on the Child-Turcotte-Pugh score and the waiting list followed a chronological criterion. In February 2002 the Model for End-stage Liver Disease (MELD) score was adopted for the allocation of donor livers in the US. After that change, an increased number of patients with more severe liver disease was observed, although there was no difference in 1-year patient and graft survival. A reduction in waiting-list mortality was also observed. In Brazil, the MELD score was adopted on May 31st, 2006. Good results are expected regarding the new criterion for allocation.

O transplante de fígado representa o tratamento mais eficiente disponível no momento para pacientes com doença hepática crônica terminal. Em fevereiro de 2002 o escore - Model for End-stage Liver Disease (MELD), o qual determina a gravidade da doença com estimativa de mortalidade em três meses, foi implantado para alocação de doadores de fígado nos Estados Unidos. Conseqüentemente foi observado um maior número de pacientes graves transplantados, com redução de mortalidade na lista de espera e não houve diferença de sobrevida em um ano de paciente e enxerto. Até recentemente no Brasil a alocação de órgãos era baseada no critério cronológico de acordo com a inclusão em lista de espera para transplante de fígado, doador cadáver. Há poucos dias (31 de maio de 2006), foi publicada a portaria que institui o critério de gravidade para alocação de fígado. Expectativas quanto aos resultados e o impacto dessa mudança na realidade brasileira são aguardados.

Hepatitis C: a challenge to hepatologists and to the liver transplantation team / Hepatite C: um desafio aos hepatologistas e à equipe de transplante de fígado

Hepatitis C is the main cause of cirrhosis and hepatocellular carcinoma and the leading indication of liver transplantation. The aim of this article was to review specific epidemiological, clinical and therapeutic aspects of hepatitis C and theirs implication for the hepatologists belonging to liver transplantation services. These specific aspects were reviewed in the literature mainly using Medline. Data regarding the epidemiological, clinical and therapeutic aspects of hepatitis C are discussed, with emphasis on their consequences for the liver transplantation team. Hepatitis C is a challenge for hepatologists and for the liver transplantation team. The burden we observe today is the late consequence of infection that occurred in the past. Measures for early recognition of complications of liver disease are recommended. HCV treatment should always be performed before liver transplantation if possible, but if not, HCV recurrence should be recognized and treated early after transplantation.

O objetivo deste artigo foi revisar aspectos epidemiológicos, clínicos e terapêuticos da hepatite C e suas implicações para a equipe de transplante de fígado. Esses aspectos específicos foram revisados na literatura usando principalmente o Medline.Dados relativos a aspectos epidemiológicos, clínicos e terapêuticos da hepatite C foram discutidos com ênfase nas suas conseqüências para a equipe de transplante de fígado. A hepatite C é um desafio para hepatologistas e para a equipe de transplante de fígado. A epidemia que observamos atualmente é a conseqüência tardia da infecção que ocorreu no passado. São recomendadas medidas para o reconhecimento precoce das complicações da infecção. Recomenda-se que o tratamento da hepatite C deve ser feito sempre que possível e de preferência, antes do transplante, mas se isso não for possível, esforços devem ser feitos para o reconhecimento precoce da reinfecção e instituição do tratamento.

Liver cirrhosis and hepatic stellate cells / Cirrose hepática e células estreladas do figado

The cirrhosis represents the final stage of several chronic hepatic diseases and it is characterized by the presence of fibrosis and morphologic conversion from the normal hepatic architecture into structurally abnormal nodules. In the evolution of the disease there is loss of the normal vascular relationship and portal hypertension. There are also regenerative hepatocelular alterations that become more prominent with the progression of the disease. The liver transplantation continues to be the only therapeutic option in cases of disease in terminal phase. The hepatic stellate cells (HSC) are perisinusoidal cells that store vitamin A and produce growth factors, citocins, prostaglandins and other bioactive substances. They can suffer an activation process that convert them to cells with a phenotype similar to myofibroblasts. When activated, they present increased capacity of proliferation, mobility, contractility and synthesis of collagen and other components of extracelular matrix. They possess cytoplasmic processes adhered to sinusoids and can affect the sinusoidal blood flow. HSC are important in pathogenesis of fibrosis and portal hypertension.

A cirrose representa o estágio final de diversas doenças hepáticas crônicas e é caracterizada pela presença de fibrose e conversão da arquitetura hepática normal em nódulos estruturalmente anormais. Na evolução da doença ocorre perda da relação vascular normal e hipertensão portal. Há também alterações regenerativas hepatocelulares que se tornam mais proeminentes com a progressão da doença. O transplante hepático permanece como a única opção terapêutica nos casos de doença em fase terminal. As células estreladas hepáticas (CEH) são células perisinusoidais que armazenam vitamina A e produzem fatores de crescimento, citocinas, prostaglandinas e outras substâncias bioativas. Podem sofrer um processo de ativação para um fenótipo semelhante a miofibroblastos. Quando ativadas apresentam maior capacidade de proliferação, motilidade, contractilidade, síntese de colágeno e componentes da matriz extracelular. Possuem processos citoplasmáticos aderidos aos sinusóides e podem afetar o fluxo sangüíneo sinusoidal. As CEH são importantes na patogênese da fibrose e hipertensão portal.

Chronic liver disease prevention strategies and liver transplantation / Estratégias de prevenção da doença hepática crônica e transplante de fígado

Chronic liver disease is a considerable burden on society, being one of the three main causes of death in certain regions of Africa and Asia. Liver transplant is the only treatment option for cirrhosis, which is the end stage of many chronic liver diseases. This article reviews the preventable causes of cirrhosis and the preventive strategies which could be implemented in order to avoid the catastrophic consequences of cirrhosis. With small variations around the world, 70 to 80 percent of the end stage liver diseases are caused by excessive alcohol consumption and by viral hepatitis, both of which are potentially preventable. Excessive alcohol consumption has important public health consequences because of its involvement not only with cirrhosis, but also with motor vehicle accidents, unemployment, domestic violence etc. Among the viral causes, Hepatitis Virus B and C have the greatest impact on public health. Effective vaccine is available for Hepatitis Virus B and must be put in use. While a vaccine for Hepatitis Virus C is awaited, effective preventive strategies should be undertaken to avoid the preventable cases of end stage liver disease.

As doenças hepáticas crônicas estão entre as três principais causas de morte na Africa e Asia.O transplante de fígado é o único tratamento curativo para esta doença hepática de caráter terminal.O presente artigo tem como objetivo apresentar as causas passíveis de prevenção de cirrose e as estratégias que podem ser utilizadas no sentido de preveni-las. Com pequenas variações ao redor do mundo, 70 a 80 por cento das doenças hepáticas terminais são causadas por consumo excessivo de álcool e por hepatites virais que são doenças passíveis de prevenção.O consumo excessivo de álcool é importante problema de saúde pública, pois envolve violência doméstica, acidentes de trânsito, além da possível evolução para cirrose e suas conseqüências. Entre as causas virais as hepatites pelo vírus B e C têm o maior impacto na saúde pública. Para a hepatite B já há vacinas disponíveis. Enquanto a vacina para a hepatite C é ainda aguardada, estratégias efetivas de prevenção devem ser efetuadas com o objetivo precípuo de se evitar, por conseqüência, casos de hepatopatias crônicas desta natureza.

Quantitation of HCV RNA in liver of patients with chronic hepatits C

Background/Aims - Liver HCV RNA has been quantitated in few studies and the feasibility and the role of this parameter in the evaluation of patients with chronic HCV hepatitis still warant study. Our aim was to determine the concentrations of HCV RNA in the liver of cronic HCV patients and the correlate the results with serum viral load. We also studied the relation of leves of HCV RNA in the liver with serum aminotransferase levels and with the presence of cirrhosis. Methods-Twenty patients (14 males, aged 28 to 61 years) were studied. Twelve were infected by HCV type 1, six by type 3 and one by type 5. Percutaneos liver biopsy samples were obtained from 14 patients, and the remaider from liver explant in patients undergoing OLT. Twelve had chronic hepatitis and eight cirrhosis.HCV RNA levels were determined by bDNA. Results- HCV RNA levels below the detection limit were found in one liver and in five serum samples. HCV RNA ( mean +/- SD) was 2.1x10 8 +/- 2.2x10 8 Eq/gm in the liver and 94x10 5 +/- 93x10 5 Eq/gL in serum, with a significantly correlation between these values (r=0.89; P<0.0001). Serum HCV RNA levels were significantly lower (P=0.001) in cirrhotic than in chronic hepatitis patients, while the groups did not differ in liver HCV RNA levels. No correlation was observed between liver or serum HCV RNA and serum ALT or AST. Conclusions- Quantitation of HCV RNA is possible even en small liver samples. Although averange levels are more than one log higher than those observed in serum, hepatic concentrations correlate with those observed in serum. The application of this technology to monitoring antiviral therapy and understanding the pathogenesis of the disease remains to be determined.