RESUMO
Chronic HBV infection results in >1 million deaths per year from cirrhosis and liver cancer. No known cure for chronic HBV exists, due in part to the continued presence of transcriptionally active DNA in the nucleus that is not directly targeted by current antiviral therapies. A coordinated approach is urgently needed to advance an HBV cure worldwide, such as those established in the HIV field. We propose the establishment of an International Coalition to Eliminate Hepatitis B Virus (ICE-HBV) to facilitate the formation of international working groups on HBV virology, immunology, innovative tools and clinical trials: to promote awareness and education as well as to drive changes in government policy and ensure funds are channelled to HBV cure research and drug development. With the ICE-HBV in place, it should be possible to enable a HBV cure within the next decade.
Assuntos
Antivirais/uso terapêutico , Saúde Global , Hepatite B Crônica/tratamento farmacológico , Hepatite B Crônica/prevenção & controle , Cooperação Internacional , Ensaios Clínicos como Assunto/economia , Descoberta de Drogas/economia , Descoberta de Drogas/organização & administração , Política de Saúde , Promoção da Saúde/economia , Promoção da Saúde/organização & administração , Hepatite B Crônica/imunologia , Hepatite B Crônica/virologia , Humanos , Apoio à Pesquisa como AssuntoAssuntos
Controle de Doenças Transmissíveis/economia , Controle de Doenças Transmissíveis/métodos , Saúde Global , Hepatite Viral Humana/epidemiologia , Adolescente , Adulto , Financiamento de Capital , Criança , Pré-Escolar , Feminino , Infecções por HIV/economia , Infecções por HIV/epidemiologia , Infecções por HIV/prevenção & controle , Hepatite Viral Humana/economia , Hepatite Viral Humana/prevenção & controle , Humanos , Lactente , Malária/economia , Malária/epidemiologia , Malária/prevenção & controle , Masculino , Pessoa de Meia-Idade , Prevalência , Tuberculose/economia , Tuberculose/epidemiologia , Tuberculose/prevenção & controle , Adulto JovemRESUMO
BACKGROUND: Genotype (gt)6 HCV is common amongst HCV-positive populations of the Asia-Pacific region but cell culture models for this gt have only recently been developed. Boceprevir (SCH503034) is a clinically available inhibitor of the HCV NS3 protein. We investigated the efficacy of boceprevir for inhibiting replication of a chimeric gt1b replicon encoding a gt6a NS3 protease and defined the development of mutations in the protease when boceprevir treatment was applied. METHODS: We constructed a chimeric gt1b subgenomic replicon encoding a gt6 NS3 protease (NS3p) sequence (gt6NS3p_gt1b). The boceprevir EC50 value against replication of this replicon was determined using quantitative reverse transcriptase PCR. Next-generation sequencing was used to identify nucleotide changes associated with boceprevir resistance. The replication capacities of chimeric replicons containing mutations associated with boceprevir resistance were determined by colony formation efficiency assays. RESULTS: The boceprevir EC50 value for the gt6NS3p_gt1b replicon was 535 ±79 nM. Boceprevir-resistant gt6NS3p_gt1b replicon cell lines could be selected and they demonstrated drug-associated amino acid changes that have previously been reported in other HCV gts. Interestingly, no mutations were observed at A156, a position defined for boceprevir resistance in gt1 NS3p, while mutation at N122, which is rarely reported in boceprevir-resistant gt1 proteases, was frequently observed. Re-introduction of these mutations into the chimeric replicon altered their replication capacity, ranging from complete abolishment of replication (A156T) to increasing replication capacity (V36A, N122S). This report provides the first characterization of gt6 HCV resistance to boceprevir. CONCLUSIONS: A chimeric HCV replicon encoding gt6 NS3 protease is sensitive to boceprevir and develops drug-resistant mutations at amino acid sites previously reported for other gts. Mutation at N122 also appears to be associated with boceprevir resistance in the gt6 NS3 protease.
Assuntos
Farmacorresistência Viral/genética , Genótipo , Hepacivirus/genética , Hepatite C/virologia , Mutação , Prolina/análogos & derivados , Replicon , Proteínas não Estruturais Virais/genética , Substituição de Aminoácidos , Antivirais/química , Antivirais/farmacologia , Antivirais/uso terapêutico , Linhagem Celular Tumoral , Hepatite C/tratamento farmacológico , Humanos , Testes de Sensibilidade Microbiana , Modelos Moleculares , Conformação Molecular , Prolina/química , Prolina/farmacologia , Prolina/uso terapêutico , Recombinação Genética , Proteínas não Estruturais Virais/química , Replicação ViralAssuntos
Vacinas contra Hepatite A/uso terapêutico , Vírus da Hepatite A/imunologia , Hepatite A/prevenção & controle , Havaiano Nativo ou Outro Ilhéu do Pacífico , População Rural , Vacinação/estatística & dados numéricos , Vacinas de Produtos Inativados/uso terapêutico , Pré-Escolar , Feminino , Necessidades e Demandas de Serviços de Saúde , Hepatite A/etnologia , Humanos , Lactente , Masculino , Northern Territory/epidemiologia , Vigilância da População , Prevalência , Estudos SoroepidemiológicosRESUMO
BACKGROUND & AIMS: The World Health Organisation (WHO) Prevention & Control of Viral Hepatitis Infection: Framework for Global Action offers a global vision for the prevention and control of viral hepatitis. In October 2012, the Coalition to Eradicate Viral Hepatitis in Asia Pacific (CEVHAP) organised the North Asia Workshop on Viral Hepatitis in Taipei to discuss how to implement the WHO Framework in the North Asia region. This paper presents outcomes from this workshop. METHODS: Twenty-eight representatives from local liver associations, patient organisations, and centres of excellence in Hong Kong, Japan, Korea, and Taiwan participated in the workshop. FINDINGS: Priority areas for action were described along the four axes of the WHO Framework: (1) awareness, advocacy and resources; (2) evidence and data; (3) prevention of transmission; and (4) screening and treatment. Priorities included: axis 1: greater public and professional awareness, particularly among primary care physicians and local advocacy networks. Axis 2: better economic data and identifying barriers to screening and treatment uptake. Axis 3: monitoring of vaccination outcomes and targeted harm reduction strategies. Axis 4: strengthening links between hospitals and primary care providers, and secure funding of screening and treatment, including for hepatocellular carcinoma. CONCLUSIONS: The WHO Framework provides an opportunity to develop comprehensive and cohesive policies in North Asia and the broader region. A partnership between clinical specialists, primary care physicians, policy makers, and people with or at risk of viral hepatitis is essential in shaping future policies.
Assuntos
Hepatite Viral Humana/epidemiologia , Formulação de Políticas , Organização Mundial da Saúde , Antivirais/uso terapêutico , Ásia Setentrional/epidemiologia , Hepatite Viral Humana/tratamento farmacológico , Hepatite Viral Humana/prevenção & controle , Humanos , Fatores de Risco , Vacinas Virais/uso terapêuticoRESUMO
BACKGROUND: Hepatic Flare (HF) after initiation of highly active antiretroviral therapy (HAART) in HIV-HBV coinfected individuals is well recognized but prospective data on predictors and subsequent outcome are limited. METHODS: The Tenofovir in HIV-HBV coinfection study was a randomized clinical trial of HBV-active HAART including lamivudine and/or tenofovir in antiretroviral naïve HIV-HBV individuals in Thailand. RESULTS: Early HF (EHF) was defined as ALT > 5 × ULN during the first 12 weeks. EHF was observed in 8 (22%) of individuals at a median of 56 days. 6/8 EHF cases were asymptomatic and resolved with HAART continuation, however one subject with underlying cirrhosis died following rapid hepatic decompensation. EHF was significantly associated with higher baseline ALT (79 IU/L vs 36 IU/L non-EHF, p = 0.008) and HBV DNA (9.9 log10 c/ml vs 8.4 log10 c/ml non EHF, p = 0.009), and subsequent serological change. HBeAg loss occurred in 75% of EHF cases versus 22% in non-EHF (p = 0.04), and HBsAg loss in 25% of EHF cases versus 4% of non-EHF (p = 0.053). CONCLUSION: EHF after HBV active HAART initiation was frequently observed in this population. Timing of EHF, association with elevated ALT and HBV DNA and high rate of seroconversion are all consistent with immune restoration as the likely underlying process. CLINICAL TRIAL NUMBER: NCT00192595.