Combination therapies for chronic HBV, liver disease and cancer

慢性乙型肝炎、肝病和癌症的联合疗法

• 批准号: 7628953
• 负责人: MARK A FEITELSON
• 金额: $ 35.41万
• 依托单位: TEMPLE UNIV OF THE COMMONWEALTH
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-15 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7628953
• 关键词: 2' -fluoro-5-methylarabinosyluracil; Address; Adoptive Transfer; Adverse effects; Aftercare; Animal Model; Antiviral Agents; Appearance; Biological Assay; Blood; Carrier State; Cell Line; Cells; Cessation of life; Characteristics; Chronic; Chronic Hepatitis B; Cirrhosis; Clinical; Clinical Trials; Combined Modality Therapy; Data; Development; Developmental Therapeutics Program; Disease; Disease remission; Drug Administration Routes; Drug Combinations; Drug Kinetics; Drug resistance; Extrahepatic; Future; Goals; HBV Liver Disease; HIV; Half-Life; Hepatitis; Hepatitis B; Hepatitis B Virus; Hepatocyte; Human; Immune; Immunity; In Vitro; Infection; Inflammation; Interferons; Lamivudine; Liver Cirrhosis; Liver diseases; Malignant Neoplasms; Malignant neoplasm of liver; Mediating; Modeling; Morbidity - disease rate; Mus; Nude Mice; Organ; Pathogenesis; Patients; Pharmaceutical Preparations; Polymerase; Prevention; Primary carcinoma of the liver cells; Protocols documentation; Public Health; Resolution; Risk; Risk Factors; SCID Mice; Simian B disease; South Korea; Staging; Telbivudine; Tenofovir; Testing; Tetracycline Control; Therapeutic; Toxic effect; Transgenic Organisms; Viral Antigens; Virus; Virus Diseases; Virus Replication; Work; adefovir; analog; base; design; drug resistant virus; emtricitabine; entecavir; hepatitis B virus P protein; high risk; improved; in vivo; mouse model; mutant; novel therapeutics; nucleoside analog; problem drinker; public health relevance; response; therapy development; tumor; uptake; viral DNA

DESCRIPTION (provided by applicant): There are an estimated 350 million people worldwide who are chronically infected with hepatitis B virus (HBV) and are at high risk for the development of hepatitis, cirrhosis (end stage liver disease) and hepatocellular carcinoma (HCC). Hepatitis and cirrhosis are associated with prolonged morbidity, and HCC, which appears in more than 250,000 people each year, is rapidly fatal. Given that the major risk factors for HCC are the HBV carrier state (defined as the persistence of virus or virus antigens in blood for more than 6 months) and chronic liver disease (CLD) (hepatitis and cirrhosis), the most direct way to reduce risk factors for HCC is to target the virus and/or corresponding immunity. Accordingly, the FDA has now approved interferon 1, pegylated interferon 1, lamivudine, adefovir dipivoxal, entecavir, and telbivudine. Additional drugs, such as emtricitabine, clevudine, and tenofovir, will probably be approved soon. Although these are potent drugs, they are limited by low rates of sustained response, side effects, and the emergence of drug resistance. Hence, the objective of this proposal is to devise combination therapies, following the model of HIV combination therapy development, to successfully treat long term HBV infection. To do so, the lab will assess the pharmacokinetics (PK), antiviral efficacy and toxicity of drug combinations in primary human hepatocytes and in HepG2 cells replicating wild type or selected mutants of HBV (aim 1). Favorable combinations will then be assessed in vivo in nude mouse injected with HepAD38 cells (AD38 cells replicate wild type HBV, which accumulates in the blood of these mice) in order to get a sense of what combinations and concentrations of drugs are most effective in reducing virus titer, for assessing how long virus DNA levels remain suppressed during and after treatment, and whether different combinations have a favorable PK profile in vivo (aim 2). The best combinations will then be evaluated for long term antiviral efficacy in HBV transgenic SCID mice, which stably replicate wild type HBV and develop CLD (aim 3). This work will develop combination therapies that will demonstrate a sustained antiviral effect against HBV, against HBV in HIV co-infected patients, in chronically infected alcoholics, as well as prolonged suppression of CLD. Elimination of CLD will reduce the risk of chronic HBV carriers of developing HCC. This will contribute centrally to the design of future clinical trials that will be suitable for long term treatment of chronic infections without significant side effects or the frequent development of drug resistance that limit present day therapeutics against HBV. PUBLIC HEALTH RELEVANCE There are more than 350 million people worldwide chronically infected with hepatitis B virus (HBV) and who are at risk for the development of hepatitis (inflammation of the liver), cirrhosis, and liver cancer. Millions of people each year die from liver cirrhosis. Liver cancer is among the top five most prevalent tumor types worldwide, with an estimated 1 million deaths each year. Present treatments for chronic hepatitis B use single drugs that are expensive, have side effects, and select for drug resistant viruses. Hence, new therapeutic options to treat long term virus infection and associated diseases are urgently needed. The proposed work will develop combination therapies with sustained antiviral effect against HBV and associated chronic liver disease, against HBV in HIV co-infected patients, and against HBV among chronic alcoholics. Prevention and/or elimination of chronic liver disease will reduce the risk of HBV carriers developing cirrhosis and liver cancer, thereby contributing centrally to improving public health.

描述（由申请人提供）：全球估计有3.5亿人慢性感染B型肝炎病毒（HBV），并处于肝炎、肝硬化（终末期肝病）和肝细胞癌（HCC）发展的高风险中。肝炎和肝硬化与长期发病有关，每年有超过25万人出现HCC，迅速致命。鉴于HCC的主要风险因素是HBV携带状态（定义为血液中病毒或病毒抗原持续存在超过6个月）和慢性肝病（CLD）（肝炎和肝硬化），降低HCC风险因素的最直接方法是靶向病毒和/或相应的免疫力。因此，FDA现在已经批准了干扰素1、聚乙二醇干扰素1、拉米夫定、阿德福韦酯、恩替卡韦和替比夫定。其他药物，如恩曲他滨、克来夫定和替诺福韦，可能很快就会被批准。虽然这些都是有效的药物，但它们受到持续反应率低，副作用和耐药性出现的限制。因此，本提案的目的是按照HIV联合治疗开发的模式设计联合治疗，以成功治疗长期HBV感染。为此，实验室将评估药物组合在原代人肝细胞和复制HBV野生型或选定突变体的HepG 2细胞中的药代动力学（PK）、抗病毒疗效和毒性（目的1）。然后在注射HepAD 38细胞的裸鼠中体内评估有利的组合（AD 38细胞复制野生型HBV，其在这些小鼠的血液中积累），以了解什么样的药物组合和浓度在降低病毒滴度方面最有效，以评估治疗期间和治疗后病毒DNA水平保持抑制多久，以及不同组合是否具有有利的体内PK特征（目的2）。然后将在稳定复制野生型HBV并发展CLD的HBV转基因SCID小鼠中评价最佳组合的长期抗病毒功效（目的3）。这项工作将开发联合疗法，证明对HBV、HIV合并感染患者、慢性感染酗酒者的HBV具有持续的抗病毒作用，以及对CLD的长期抑制。消除CLD将降低慢性HBV携带者发生HCC的风险。这将有助于未来临床试验的设计，这些临床试验将适用于慢性感染的长期治疗，而没有显著的副作用或频繁的耐药性发展，这些耐药性限制了目前针对HBV的治疗方法。公共卫生相关性全世界有超过3.5亿人慢性感染B型肝炎病毒（HBV），并有发生肝炎（肝脏炎症）、肝硬化和肝癌的风险。每年有数百万人死于肝硬化。肝癌是世界上五种最常见的肿瘤类型之一，估计每年有100万人死亡。目前慢性B型肝炎的治疗使用单一药物，这些药物昂贵，有副作用，并且选择耐药病毒。因此，迫切需要治疗长期病毒感染和相关疾病的新的治疗选择。拟议的工作将开发对HBV和相关慢性肝病、HIV合并感染患者中的HBV以及慢性酗酒者中的HBV具有持续抗病毒效果的联合疗法。预防和/或消除慢性肝病将降低HBV携带者发展为肝硬化和肝癌的风险，从而为改善公共卫生做出重要贡献。