RESUMO
Sofosbuvir/ledipasvir (SOF/LDV) is the first all-oral ribavirin-free treatment approved for chronic hepatitis C virus (HCV) genotype 6, offering a safe and highly efficacious treatment option. Large studies evaluating real-world outcomes of this regimen are lacking. We aim to evaluate real-world treatment outcomes for HCV genotype 6. A retrospective cohort study evaluated 65 adults (age ≥18) with chronic HCV genotype 6 treated with SOF/LDV without ribavirin at a community gastroenterology clinic in the United States from November 2014 to May 2016. Rates of undetectable virus at week 4 on treatment, at end of treatment (EOT) and SVR12 were stratified by the presence of cirrhosis and prior treatment (treatment naïve vs treatment experienced). Among 65 patients with chronic HCV genotype 6 treated with SOF/LDV (52.3% male, mean age 66.3 years [SD 9.7], 41.5% cirrhosis and 15.4% treatment experienced), 97.3% had undetectable virus at week 4 on treatment, 96.9% had undetectable virus at EOT and 95.3% achieved SVR12. SVR12 was 100% in females vs 91.2% in males, P=.096, and 92.3% in patients with cirrhosis vs 97.4% in those without cirrhosis, P=.347. Resistance testing of treatment failures was attempted but unsuccessful due to lack of conforming primers to define the possible resistance mutations. Among the largest U.S. community-based real-world cohort of Asian chronic HCV genotype 6 patients treated with all-oral SOF/LDV without ribavirin, SVR12 was similar to SVR12 reported in clinical trials, confirming the safety and effectiveness of this regimen and validating current HCV genotype 6 treatment guideline recommendations.
Assuntos
Antivirais/uso terapêutico , Benzimidazóis/uso terapêutico , Fluorenos/uso terapêutico , Genótipo , Hepacivirus/classificação , Hepacivirus/genética , Hepatite C Crônica/tratamento farmacológico , Sofosbuvir/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Asiático , Feminino , Hepacivirus/isolamento & purificação , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resposta Viral Sustentada , Resultado do Tratamento , Estados Unidos , Adulto JovemRESUMO
Community-based real-world outcomes on effectiveness of antiviral therapies for chronic hepatitis B virus (CHB) in Asians are limited. Whether hepatitis B surface antigen (HBsAg) loss correlates with undetectable virus and alanine aminotransferase (ALT) normalization on treatment or what predicts risk of seroreversion or detectable virus after stopping therapy is unclear. We aim to evaluate rates and predictors of HBsAg loss, seroconversion, ALT normalization and undetectable HBV DNA, including HBsAg seroreversion or re-emergence of HBV DNA among Asian CHB patients. We retrospectively evaluated 1072 CHB adults on antiviral therapy at two community gastroenterology clinics from 1997 to 2015. Rates of HBsAg loss, ALT normalization, achieving undetectable HBV DNA and developing surface antibody (anti-HBs) were stratified by HBeAg status. Following HBsAg loss, HBsAg seroreversion or re-emergence of detectable HBV DNA was analysed. With median treatment of 76.7 months, the overall rate of HBsAg loss was 4.58%, with similar HBsAg loss rates between HBeAg-positive and HBeAg-negative patients (4.44% vs 4.71%, P=.85) in a predominantly Asian population (98.1%). Among HBsAg loss patients, 33.3% developed anti-HBs, 95.8% achieved undetectable virus and 66.0% normalized ALT. No significant baseline or on-treatment predictors of HBsAg loss were observed. While six patients who achieved HBsAg loss had seroreversion with re-emergence of HBsAg positivity, viral load remained undetectable, demonstrating the sustainability of viral suppression. Among a large community-based real-world cohort of Asian CHB patients treated with antiviral therapy, rate of HBsAg loss was 4.58%. Despite only 33.3% of HBsAg loss patients achieving anti-HBs, nearly all patients achieved sustained undetectable virus.
Assuntos
Antivirais/uso terapêutico , Antígenos de Superfície da Hepatite B/sangue , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/virologia , Resposta Viral Sustentada , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alanina Transaminase/sangue , Ásia , DNA Viral/sangue , Feminino , Anticorpos Anti-Hepatite B , Hepatite B Crônica/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Soroconversão , Resultado do Tratamento , Carga Viral , Adulto JovemRESUMO
Early identification of chronic hepatitis B is important for optimal disease management and prevention of transmission. Cost and lack of access to commercial hepatitis B surface antigen (HBsAg) immunoassays can compromise the effectiveness of HBV screening in resource-limited settings and among marginalized populations. High-quality point-of-care (POC) testing may improve HBV diagnosis in these situations. Currently available POC HBsAg assays are often limited in sensitivity. We evaluated the NanoSign(®) HBs POC chromatographic immunoassay for its ability to detect HBsAg of different genotypes and with substitutions in the 'a' determinant. Thirty-seven serum samples from patients with HBV infection, covering HBV genotypes A-G, were assessed for HBsAg titre with the Roche Elecsys HBsAg II quantification assay and with the POC assay. The POC assay reliably detected HBsAg at a concentration of at least 50 IU/mL for all genotypes, and at lower concentrations for some genotypes. Eight samples with substitutions in the HBV 'a' determinant were reliably detected after a 1/100 dilution. The POC strips were used to screen serum samples from 297 individuals at risk for HBV in local clinical settings (health fairs and outreach events) in parallel with commercial laboratory HBsAg testing (Quest Diagnostics EIA). POC testing was 73.7% sensitive and 97.8% specific for detection of HBsAg. Although the POC test demonstrated high sensitivity over a range of genotypes, false negatives were frequent in a clinical setting. Nevertheless, the POC assay offers advantages for testing in both developed and resource-limited countries due to its low cost (0.50$) and immediately available results.
Assuntos
Cromatografia de Afinidade/métodos , Testes Diagnósticos de Rotina/métodos , Antígenos de Superfície da Hepatite B/sangue , Hepatite B Crônica/diagnóstico , Sistemas Automatizados de Assistência Junto ao Leito , Reações Falso-Negativas , Genótipo , Vírus da Hepatite B/genética , Humanos , Masculino , Pessoa de Meia-Idade , Sensibilidade e EspecificidadeRESUMO
Although chronic hepatitis B (CHB) affects approximately 2 million United States residents, there is no systematic screening of at-risk individuals, and most remain unaware of their hepatitis B virus (HBV) infection. Unmonitored and untreated, CHB results in a 25-30% risk of death from liver cancer and/or cirrhosis, inflicting an increasing healthcare burden in high-prevalence regions. Despite high prevalence in immigrant Asians and Pacific Islanders, among whom CHB is a leading cause of death, community and healthcare provider awareness remains low. Because safe and effective vaccines and effective antiviral treatments exist, there is an urgent need for integrated programmes that identify, follow and treat people with existing CHB, while vaccinating the susceptible. We describe an extant San Francisco programme that integrates culturally targeted, population-based, HBV screening, vaccination or reassurance, management and research. After screening over 3000 at-risk individuals, we here review our operational and practical experience and describe a simple, rationally designed model that could be successfully used to greatly improve the current approach to hepatitis B while ultimately reducing the related healthcare costs, especially in the high-risk populations, which are currently underserved.
Assuntos
Hepatite B/epidemiologia , Hepatite B/prevenção & controle , Hepatite B/diagnóstico , Hepatite B/tratamento farmacológico , Vacinas contra Hepatite B/administração & dosagem , Humanos , Programas de Rastreamento/métodos , São Francisco/epidemiologia , Vacinação/métodosRESUMO
Chronic infection with the hepatitis B virus (HBV) is a major risk factor for development of end-stage liver disease, including cirrhosis, liver failure and primary liver cancer. There are now seven antiviral agents approved by the United States Food and Drug Administration (FDA) for the management of chronic HBV infection. Despite the fact that there are between 1.4 and 2 million chronic HBV infections in the United States, fewer than 50,000 people per year receive prescriptions for HBV antiviral medications. This report discusses possible explanations for the disparity between the number of people who are chronically infected and the number of people who receive treatment. Explanations for this incongruence include the potentially large number of infected persons who are unscreened and thus remain undiagnosed, and lack of access, including insurance, education and referral to appropriate medical care, particularly for disproportionately infected populations.
Assuntos
Antivirais/uso terapêutico , Disparidades em Assistência à Saúde , Hepatite B Crônica/tratamento farmacológico , Doença Hepática Terminal/diagnóstico , Doença Hepática Terminal/tratamento farmacológico , Vírus da Hepatite B , Hepatite B Crônica/diagnóstico , Humanos , Estados Unidos , VacinaçãoRESUMO
This retrospective analysis was conducted to describe the characteristics of nucleoside-naïve hepatitis B e antigen (HBeAg)-positive patients with chronic hepatitis B, who achieved hepatitis B surface antigen (HBsAg) loss during entecavir or lamivudine therapy. HBeAg-positive adults with chronic hepatitis B, elevated serum alanine aminotransferase, and compensated liver disease were randomized to double-blind treatment for up to 96 weeks with entecavir 0.5 mg/day or lamivudine 100 mg/day. HBsAg and hepatitis B virus (HBV) DNA were measured at regular intervals during and off-treatment follow-up. Through a maximum duration of 96 weeks on-treatment and 24 weeks off-treatment, HBsAg loss was confirmed in 18/354 (5.1%) patients treated with entecavir and 10/355 (2.8%) patients treated with lamivudine. Among the 28 patients with confirmed HBsAg loss, 27 (96%) achieved HBV DNA <300 copies/mL, and 27 (96%) achieved confirmed HBeAg loss. All entecavir recipients with HBsAg loss had HBV DNA <300 copies/mL. Caucasian patients, and those infected with HBV genotype A or D, were significantly more likely to lose HBsAg. This retrospective analysis of data from a randomized, global phase three trial shows that confirmed loss of HBsAg occurred in 5% of nucleoside-naïve HBeAg-positive patients treated with entecavir, and that HBsAg loss is associated with sustained off-treatment suppression of HBV DNA.
Assuntos
Antivirais/uso terapêutico , Guanina/análogos & derivados , Antígenos de Superfície da Hepatite B/sangue , Antígenos E da Hepatite B/sangue , Hepatite B Crônica/tratamento farmacológico , Lamivudina/uso terapêutico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alanina Transaminase/sangue , DNA Viral/sangue , Método Duplo-Cego , Feminino , Guanina/uso terapêutico , Vírus da Hepatite B/isolamento & purificação , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do Tratamento , Carga Viral , Adulto JovemRESUMO
Entecavir is a potent inhibitor of hepatitis B virus (HBV) polymerase. The efficacy and safety of entecavir in nucleoside-naïve patients with hepatitis B virus e antigen (HBeAg)-positive chronic hepatitis B was established in a large, international, double-dummy study (ETV-022) where patients were randomized to entecavir 0.5 mg/day (n = 354) or lamivudine 100 mg/day (n = 355) once daily. ETV-022 had a 52-week blinded treatment phase, followed by an extended blinded treatment phase for up to 44 additional weeks (96 weeks total). Treatment was discontinued for patients achieving a protocol-defined response as determined by patient management criteria that intended to test the possibility of finite therapy, which has not previously been studied for entecavir or other anti-HBV agents in a large trial. Early results from this study have been previously presented/published separately. This paper compiles the results of up to 2 years of treatment for protocol-defined responders, virologic responders and nonresponders. For responders who discontinued therapy (per protocol), 24-week off-treatment evaluation is presented to provide a more 'complete picture' of what clinicians can expect when treating nucleoside-naïve HBeAg-positive patients with chronic hepatitis B. For patients who discontinued therapy because of nonresponse (nonresponders) and subsequently entered the rollover study ETV-901, follow-up results, including resistance profile, are provided.
Assuntos
Antivirais , Guanina/análogos & derivados , Antígenos E da Hepatite B/sangue , Hepatite B Crônica/tratamento farmacológico , Lamivudina , Antivirais/administração & dosagem , Antivirais/efeitos adversos , Antivirais/farmacologia , Antivirais/uso terapêutico , DNA Viral/sangue , Relação Dose-Resposta a Droga , Método Duplo-Cego , Farmacorresistência Viral , Guanina/administração & dosagem , Guanina/efeitos adversos , Guanina/farmacologia , Guanina/uso terapêutico , Vírus da Hepatite B/efeitos dos fármacos , Hepatite B Crônica/virologia , Humanos , Lamivudina/administração & dosagem , Lamivudina/efeitos adversos , Lamivudina/farmacologia , Lamivudina/uso terapêutico , Testes de Sensibilidade Microbiana , Fatores de Tempo , Resultado do TratamentoRESUMO
The diagnosis and management of autoimmune hepatitis continues to evolve as new diagnostic tests and new therapies are added to the armamentarium. Also encouraging are the advances in the understanding of the human immune system and its involvement in the origin and course of auto immune diseases in general and in the variants of autoimmune liver disease. Promising changes are expected in the next few years as new medications become available to the practicing hepatologist. New immune tests may allow therapies to be customized to patients, and antiviral therapies may also eventually be used in the management of this autoimmune liver diseases.
Assuntos
Doenças Autoimunes , Hepatopatias , Anti-Inflamatórios/uso terapêutico , Doenças Autoimunes/classificação , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/tratamento farmacológico , Azatioprina/uso terapêutico , Colagogos e Coleréticos/uso terapêutico , Colangite Esclerosante/diagnóstico , Colangite Esclerosante/tratamento farmacológico , Colangite Esclerosante/imunologia , Hepatite Autoimune/diagnóstico , Hepatite Autoimune/tratamento farmacológico , Humanos , Imunossupressores/uso terapêutico , Cirrose Hepática Biliar/diagnóstico , Cirrose Hepática Biliar/tratamento farmacológico , Cirrose Hepática Biliar/imunologia , Hepatopatias/diagnóstico , Hepatopatias/tratamento farmacológico , Hepatopatias/imunologia , Transplante de Fígado , Prednisona/uso terapêutico , Prognóstico , Ácido Ursodesoxicólico/uso terapêuticoRESUMO
The detection of antibody to the hepatitis C virus C100-3 antigen from the nonstructural region (NS3/NS4) of the viral genome was the first useful marker developed to detect past or potentially active infection with the hepatitis C virus. A systematic epitope survey of the nonstructural region has uncovered other immunogenic antigens. In order to assess the possible diagnostic utility of these antigens, their reactivity against a limited panel of sera from patients with chronic liver disease due to hepatitis C virus and other etiologies was tested. Antibody assays were performed using an immunoblot plaque assay and an enzyme-linked immunosorbent assay (ELISA). In a study of 16 C100-3-reactive individuals, all 16 patients were reactive using the plaque assay for the NS3 3' (409-1-1) and NS3 5' (C33u). In this same group of patients, antibodies by ELISA were reactive to NS3 3' in 12 of 16 patients (75%), NS3 5' in 15 of 16 patients (93%), and a capsid antigen (NC450) in 14 of 16 patients. In a group of five patients who were diagnosed with cryptogenic liver disease (C100-3 negative), 4 of 5 patients were reactive for antibody to all of the above epitopes. In a survey of 23 patients with other forms of chronic liver disease (nonviral liver disease, hepatitis B, alcoholic liver disease, cholestatic liver disease, and autoimmune hepatitis), only 1 of 23 patients was reactive for antibody to the C100-3 and 4 of 23 patients were reactive for antibodies to structural and nonstructural regions of the virus.(ABSTRACT TRUNCATED AT 250 WORDS)
Assuntos
Antígenos Virais/imunologia , Ensaio de Imunoadsorção Enzimática , Epitopos/imunologia , Hepacivirus/imunologia , Anticorpos Anti-Hepatite/imunologia , Hepatite C/diagnóstico , Immunoblotting , Proteínas não Estruturais Virais/imunologia , Ensaio de Placa Viral , Doença Aguda , Adulto , Sequência de Aminoácidos , Sequência de Bases , Biomarcadores , Capsídeo/imunologia , Criança , Feminino , Hepatite C/imunologia , Hepatite C/microbiologia , Anticorpos Anti-Hepatite C , Humanos , Hepatopatias/sangue , Hepatopatias/imunologia , Masculino , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , Parceiros SexuaisRESUMO
Hepatitis B virus (HBV) has been classified into six genotypes designated A-F by sequence divergence in the entire genome exceeding 8%. Very recently, the seventh genotype was reported and named genotype G. HBV genotype G is distinct from genomes of the other six genotypes in that it possesses an insertion of 36 nucleotides in the core gene, and has been found so far in France and the United States. A method for determining HBV genotype G was developed by polymerase chain reaction (PCR) with primers deduced from the 36-nucleotide (nt) insertion in five isolates of HBV genotype G the sequences of which have been deposited in DNA databases. The validity of this method, for specifically detecting HBV genotype G, was verified on a panel consisting of 142 HBV isolates of six major genotypes and four of genotype G. A total of 540 sera containing HBV in Japan covering symptom free carriers and patients with a spectrum of chronic liver disease were tested by this method, but not a single HBV genotype G sample was found. A possible method for serological determination of hepatitis B surface antigen of genotype G is suggested, without amplification or sequencing nucleotides, which would expand epidemiological and clinical researches on HBV genotype G.
Assuntos
Anticorpos Monoclonais/imunologia , Antígenos de Superfície da Hepatite B/imunologia , Vírus da Hepatite B/genética , Precursores de Proteínas/imunologia , Sequência de Aminoácidos , Sequência de Bases , Sequência Conservada , Primers do DNA , Ensaio de Imunoadsorção Enzimática , Epitopos , Amplificação de Genes , Triagem de Portadores Genéticos/métodos , Genótipo , Antígenos de Superfície da Hepatite B/genética , Vírus da Hepatite B/classificação , Vírus da Hepatite B/isolamento & purificação , Humanos , Japão/epidemiologia , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , Precursores de Proteínas/genética , Sensibilidade e Especificidade , Análise de Sequência de DNA , Homologia de Sequência do Ácido Nucleico , Proteínas do Envelope ViralRESUMO
Hepatitis C virus (HCV) infects over 170 million people worldwide. While interferon is currently the most used single agent therapy, this drug may result in a sustained loss of virus from the blood in only up to 15% of patients; new options for treatment are needed. With the release of ribavirin in North America and Europe, a viral clearance rate or 'cure' may be attained in up to 40% of patients. Developing successful antiviral therapy that prevents or delays the development of cirrhosis, liver failure and liver cancer as well as decreasing the demand for liver transplantation are clearly identified goals. Unfortunately, there is no complete in vitro model of HCV replication or translation. Due to the lack of an animal or cell culture model of HCV infection, in vitro translation screening systems to identify inhibitors of HCV protein translation are being evaluated by a large number of biotechnology companies. With advancing computer technology, high throughput screening processes are now possible and can be joined to specific in vitro model testing systems. Along with examining some of the information known about HCV therapy and the HCV genome, the present review discusses potential targets for new therapies and identifies therapeutic agents that are nearing clinical application.
Assuntos
Antivirais/uso terapêutico , Hepatite C Crônica/terapia , Citocinas/uso terapêutico , Humanos , Interferon alfa-2 , Interferon-alfa/uso terapêutico , Proteínas Recombinantes , Ribavirina/uso terapêutico , Replicação ViralAssuntos
Interleucina-12/biossíntese , Transplante de Fígado/imunologia , Linfócitos T Citotóxicos/imunologia , Biópsia , Diferenciação Celular , Expressão Gênica/imunologia , Rejeição de Enxerto/imunologia , Rejeição de Enxerto/patologia , Humanos , Interleucina-12/análise , Transplante de Fígado/patologia , Reação em Cadeia da Polimerase , RNA Mensageiro/biossíntese , Linfócitos T Citotóxicos/citologia , Linfócitos T Citotóxicos/patologia , Transplante HomólogoRESUMO
BACKGROUND: Several anti-viral treatments are now available for HBeAg-negative chronic hepatitis B (CHB), but the clinical and economic outcomes of potential treatment strategies and durations are unclear. AIM: To examine the clinical and economic outcomes of potential treatment strategies and durations for HBeAg-negative CHB. METHODS: We conducted a cost-utility analysis from a payer perspective over a lifetime time horizon. Disease progression probabilities, costs and quality of life data were derived from the literature. We evaluated 5-year, 10-year, lifetime and 5 on-1 off treatment durations. For each of these treatment durations, we evaluated initial therapy with entecavir, lamivudine or adefovir, with addition of adefovir or entecavir for patients who developed virological breakthrough because of resistance (12 strategies total). RESULTS: Increasing treatment duration improved quality-adjusted life-years (QALYs) and was generally cost-effective for all three drugs. However, a 5 on-1 off strategy was the most cost-effective: lifetime vs. 5 on-1 off entecavir had an ICER of $148,200/QALY. In probabilistic sensitivity analyses, entecavir 5 on-1 off was the preferred strategy over the range of commonly reimbursed cost-effectiveness thresholds. Lifetime treatment was preferred to a 5 on-1 off strategy, if treatment durability was < 10%. CONCLUSION: The results of our analysis suggest that in HBeAg-negative CHB infection, a 5 on-1 off treatment strategy with entecavir improves health outcomes in a cost-effective manner compared to alternative strategies.
Assuntos
Adenina/análogos & derivados , Antivirais/uso terapêutico , Guanina/análogos & derivados , Hepatite B Crônica/tratamento farmacológico , Organofosfonatos/uso terapêutico , Adenina/economia , Adenina/uso terapêutico , Antivirais/economia , Análise Custo-Benefício , Métodos Epidemiológicos , Guanina/economia , Guanina/uso terapêutico , Antígenos E da Hepatite B/metabolismo , Hepatite B Crônica/economia , Humanos , Lamivudina/economia , Lamivudina/uso terapêutico , Organofosfonatos/economiaRESUMO
Hepatitis B virus (HBV) remains a serious health threat in many parts of the world. Although its prevalence is lower in the Americas than in Asia, Africa and the Middle East, it is responsible for significant morbidity and mortality in North, Central and South America. There is a nonuniform pattern of distribution throughout this region, with HBV prevalence related to geographical, social and cultural factors that predispose certain individuals to infection. This report details the incidence, modes of viral transmission of hepatitis B in the Americas and clinical course of disease in different regions of the Americas. Additionally, the implications for management focusing on issues predominant in high-risk populations are presented.
Assuntos
Hepatite B Crônica/epidemiologia , América/epidemiologia , Ensaios Clínicos como Assunto , Hepatite B Crônica/terapia , Hepatite B Crônica/transmissão , HumanosRESUMO
Standards of treatment for patients who are infected with the hepatitis C virus have been developed from national and international consensus conferences, from extensive clinical experience with various regimens, from exhaustive literature reviews, and from opinion leaders in the general medical community. From 1987 until very recently, the standard of treatment for non-A, non-B hepatitis, later defined as hepatitis C, had consisted of alpha interferon monotherapy administered for up to 18 to 24 months. Alpha interferon has been used in a variety of regimens with varying success for the initial treatment of chronic hepatitis C, for the retreatment of patients who have relapsed after responding to interferon, and for the retreatment of alpha interferon nonresponders. Treatment standards have evolved as new agents have become available for use in our treatment armamentarium. The current treatment standards, as well as recommendations for the treatment of specific HCV subgroups, are reviewed.
Assuntos
Antivirais/uso terapêutico , Hepatite C Crônica/terapia , Interferon-alfa/uso terapêutico , Guias de Prática Clínica como Assunto , Ribavirina/uso terapêutico , Quimioterapia Combinada , Hepacivirus/efeitos dos fármacos , Hepacivirus/genética , Hepatite C Crônica/virologia , Humanos , Interferon alfa-2 , RNA Viral/análise , RNA Viral/efeitos dos fármacos , Proteínas Recombinantes , Resultado do TratamentoRESUMO
Chronic hepatitis B infection is the most important cause of cirrhosis and hepatocellular carcinoma worldwide. Interferon-alpha has been shown to be effective in approximately one third of patients, and response seems to be sustained in long-term follow-up studies in Western countries. New treatments using lamivudine and other nucleoside analogues such as famciclovir, lobucavir, and adfovir showed promising results although sustained suppression of viral replication is unusual after discontinuation of therapy. The results of recent clinical studies using these nucleoside analogues are discussed in detail in this review. Other important issues such as drug resistance and the role of combination therapy are also addressed.
Assuntos
Hepatite B Crônica/tratamento farmacológico , Inibidores da Transcriptase Reversa/uso terapêutico , Quimioterapia Combinada , Hepatite B Crônica/diagnóstico , Humanos , Interferons/efeitos adversos , Interferons/uso terapêutico , Inibidores da Transcriptase Reversa/efeitos adversos , Resultado do TratamentoRESUMO
We utilized a technique, previously used to study myocardial cells (G. A. Langer, J. S. Frank, and L. M. Nudd, 1979, Amer. J. Physiol. 237, H239-H246), to study 45Ca2+ isotope exchange kinetics in hepatocyte monolayers, cultured on scintillation disks, and perfused in a flow-through chamber. Isolated rat hepatocytes were plated directly on Primaria-coated disks impregnated with scintillation fluors which made up the walls of the perfusion chamber. Following the labeling of the cells with radioactive calcium (45Ca2+), to apparent asymptote, the washout of 45Ca2+ from the cells was measured. A large very fast turnover compartment, as well as small fast and slow turnover compartments, were identified in each experiment. Surface calcium (Ca2+) was determined by its displacement with 1 mM La3+ after asymptote had been reached during 45Ca2+ labeling (1.59 mmol Ca2+/kg dry wt). The rate constant for this compartment was faster than the washout of the chamber (greater than 3.4 min-1 with a t1/2 less than 12 s). The rate constants for the fast and slow exchangeable compartments were 0.11 min-1 (t1/2 = 6.5 min) and 0.013 min-1 (t1/2 = 56 min), respectively. The fast compartment contained 0.40 mmol Ca2+/kg dry wt and the slow compartment contained 0.27 mmol Ca2+/kg dry wt. Neither the fast nor the slow compartment was lanthanum displaceable. Release of 45Ca2+ in response to 100 microM phenylephrine, 10 nM angiotensin II, and 100-microM 2,5-ditert-butyl hydroquinone was measured during the washout phase. Ca2+ released by these compounds was determined to be 0.50 mmol 0.44, and 0.43 mmol Ca2+/kg dry cell wt, respectively. These agents had an effect only during the washout of the fast compartment. In conclusion, this novel technique of on-line measurement of 45Ca2+ exchange in hepatocyte monolayers identified three exchangeable compartments: (1) a very rapidly exchangeable surface compartment, (2) a fast "microsomal" hormone-releasable compartment, and (3) a slow, non-hormone-releasable compartment.
Assuntos
Cálcio/metabolismo , Compartimento Celular , Fígado/metabolismo , Angiotensina II/farmacologia , Animais , Células Cultivadas , Hidroquinonas/farmacologia , Cinética , Lantânio/farmacologia , Fígado/ultraestrutura , Fenilefrina/farmacologia , Ratos , Ratos EndogâmicosRESUMO
BACKGROUND/AIMS: Recurrent hepatitis B virus infection after liver transplantation performed for chronic hepatitis B with cirrhosis is influenced by a number of factors, including coinfection with the hepatitis D virus, the level of HBV replication, and administration of hepatitis B immune globulin. Another potentially important factor in modulating HBV infection after liver transplantation is the degree of immunosuppression post-transplant. We reviewed an institutional experience with liver transplantation for chronic hepatitis B and analyzed the impact of using lower doses of corticosteroids on HBV reinfection, expression of recurrent HBV disease and patient survival. METHODS: Of 17 patients undergoing liver transplantation for chronic hepatitis B, 16 patients received variable doses of hepatitis B immune globulin for up to 6 months. RESULTS: Fifteen of the 16 patients remained HBsAg-negative during hepatitis B immune globulin therapy, but ultimately 13 of the 17 patients had HBV reinfection, including 3 of 4 patients with hepatitis D virus coinfection. Long-term survival (82%) of the 17 chronic hepatitis B patients was not different from the survival (75%) of 195 patients transplanted for other indications. Three of 13 patients who were reinfected died from chronic hepatitis B with liver failure. Reinfection did not appear to be related to the pretransplant degree of viral replication. Compared to an age- and sex-matched control group, patients undergoing liver transplantation for chronic hepatitis B received less cumulative intravenous methylprednisolone and oral prednisone, but did not experience a higher rate of graft rejection. CONCLUSIONS: We postulate that use of lower doses of corticosteroids after liver transplantation for chronic hepatitis B is safe and not associated with a higher incidence of graft rejection. Moreover, low-dose maintenance prednisone therapy may modify the course of post-transplant HBV reinfection by leading to less viral replication, milder HBV-related liver disease and better patient survival.
Assuntos
Corticosteroides/administração & dosagem , Hepatite B/mortalidade , Transplante de Fígado , Adulto , Idoso , Doença Crônica , Feminino , Seguimentos , Rejeição de Enxerto , Hepatite B/complicações , Hepatite B/cirurgia , Vírus da Hepatite B/fisiologia , Hepatite D/complicações , Humanos , Imunização Passiva , Imunoglobulinas/uso terapêutico , Cirrose Hepática/complicações , Cirrose Hepática/cirurgia , Masculino , Pessoa de Meia-Idade , Recidiva , Estudos Retrospectivos , Taxa de Sobrevida , Replicação ViralRESUMO
Liver transplantation for alcoholic cirrhosis remains controversial. In particular, criteria for the selection of patients who will remain recovered from alcoholism post-transplant require better definition. We analyzed the long-term predictive value of categorizing transplant referral patients with alcoholism and end-stage liver disease into risk groups for recidivism and noncompliance. Forty-seven patients with the diagnosis of alcoholism and advanced liver disease were evaluated and placed into predefined risk groups (low-, moderate-, and high-risk) for recidivism and noncompliance. No absolute period of abstinence from alcohol was required. All patients were asked to sign a contract not to drink alcohol and comply with a rehabilitation program before and after transplantation. Compliance with alcohol rehabilitation, abstinence, functional level, employment, and survival were assessed. Patients who were not compliant with the rehabilitation program or consumed alcohol were scored as failures. Thirty-one patients were ranked as low risk, and were accepted for liver transplantation; 27 patients were transplanted. Five of 31 patients (16%) drank alcohol. One patient drank before and four patients drank transiently after transplantation. Ten patients were categorized as moderate risk, and were deferred for transplantation; two patients underwent later transplantation. All 10 patients (100%) were noncompliant or drank alcohol, including two patients who drank after transplantation after a period of abstinence and rehabilitation. Six patients were ranked as high risk, and were denied liver transplantation. Five patients (83%) drank alcohol and were noncompliant. Minimum follow-up was 12 months (mean, 24 months; range, 12-41 months). The mean Karnofsky performance score was 34 before and 84 after liver transplantation. Actuarial survival of alcoholic patients undergoing transplantation was 93%. We conclude that categorization of transplant referral patients with alcoholism and liver failure into predefined risk groups for recidivism and noncompliance accurately predicts pre- and post-transplant behavior. As defined, only low-risk alcoholic patients are good candidates for liver transplantation.
Assuntos
Hepatopatias Alcoólicas/cirurgia , Transplante de Fígado , Análise Atuarial , Alcoolismo/reabilitação , Feminino , Humanos , Hepatopatias Alcoólicas/mortalidade , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Recidiva , Fatores de Risco , TemperançaRESUMO
The selection of patients with cirrhosis and the diagnosis of alcohol dependence or abuse who have a long-term high probability of abstinence after orthotopic liver transplantation (OLT) may enhance patient survival and outcomes. The aim of this study is to identify factors that would predict which patients would consume alcohol after OLT. Sixty-one patients with a history of alcohol dependence or abuse underwent OLT from June 1989 to June 1994 and were followed up monthly for a median of 6.9 years after OLT (range, 2.5 to 9.3 years). Survival analysis techniques (Cox proportional hazard model) were used to identify patients at high risk for recidivism. Recidivism occurred in 12 of 61 patients (20%) after OLT during follow-up. Noncompliance, with a relative hazard of 20.9 (95% confidence interval [CI], 5.6 to 78.3; P <.001), and personality disorder, with a relative hazard of 6.0 (95% CI, 1.9 to 18.7; P =.002), independently predicted recidivism among patients who underwent OLT. These data indicate that specific behaviors and psychiatric diagnoses can be used to select patients at high risk for drinking alcohol before and after OLT.