Second Generation InSTIs for the Treatment of HIV-1 in patients with TB co-infection on Rifampicin-based Treatment in KwaZulu Natal, South Africa

在南非夸祖鲁纳塔尔省，第二代 InSTI 用于治疗接受利福平治疗的结核病合并感染患者的 HIV-1

• 批准号: 10829561
• 负责人: Kelly E. Dooley
• 金额: $ 12.98万
• 依托单位: CENTRE/AIDS PROGRAMME/RES/SOUTH AFRICA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-03 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10829561
• 关键词: ABCB1 gene; Adult; Africa; Africa South of the Sahara; Area; CYP3A4 gene; Child; Clinical; Data; Dedications; Diphosphates; Dose; Drug Exposure; Drug Interactions; Drug Kinetics; Drug usage; Enrollment; Ensure; Enzymes; Epidemic; Exposure to; Film; Formulation; Fumarates; Future; Generations; Genetic; Goals; HIV; HIV Infections; HIV Seronegativity; HIV Seropositivity; HIV-1; HIV/TB; Infection; Integrase; Investigation; Knowledge; Laboratories; Lamivudine; Measures; Medical; Patients; Persons; Pharmaceutical Preparations; Plasma; Positioning Attribute; Price; Protease Inhibitor; Proteins; Publishing; Qualifying; Randomized; Recommendation; Regimen; Research; Resistance; Resistance development; Resource-limited setting; Rifampin; Safety; Sampling; South Africa; Tablets; Tenofovir; Testing; Treatment Protocols; Tuberculosis; UGT1A1 gene; Viral; Viral Load result; Weight; World Health Organization; antiretroviral therapy; clinically relevant; co-infection; efavirenz; effective therapy; efficacy evaluation; emtricitabine; evidence base; genetic testing; healthy volunteer; inhibitor; mortality; pediatrician; phase III trial; pill; standard of care; treatment research; tuberculosis drugs; tuberculosis treatment

PROJECT SUMMARY: Integrase strand transfer inhibitors (InSTI), such as dolutegravir (DTG) and bictegravir (BIC), have high antiviral potency against HIV-1, excellent safety and tolerability, and a high barrier to resistance. It is a high priority to promote the availability and rational use of InSTI in adults and children with HIV, including those with tuberculosis (TB). South Africa has the highest rates of HIV and TB co-infection in the world-- among patients with TB, 50-80% have HIV. Rifampicin (RIF), an essential first-line TB drug, is a potent inducer of metabolizing enzymes and transporters, causing drug interactions that limit HIV-TB co-treatment options. In adults, DTG, now recommended by World Health Organisation (WHO) as the preferred first-line antiretroviral for the treatment of HIV-1, can be given together with TB treatment, provided the dose is doubled (to 50 mg twice daily) to mitigate the drug interaction. While DTG dosing has now been established for children down to a weight of 20kg, no data exist to guide dosing for young children with TB on RIF-containing treatment. BIC, co- formulated with emtricitabine and tenofovir alafenamide (BIC/FTC/TAF, Biktarvy®) was recently shown to be non-inferior to DTG-based treatment, with no emergence of resistance in Phase 3 trials. However, no data exist in patients with HIV-associated TB on BIC/FTC/TAF efficacy, safety, or pharmacokinetics (PK) when it is given twice daily with RIF. In HIV-negative healthy volunteers, BIC trough concentrations were reduced by 80% with RIF (but remained 3-fold higher that the protein adjusted effective concentration (paEC95). In another study, TAF even with RIF produced higher concentrations of intracellular tenofovir-diphosphate (TFV-DP), the active moiety, than when tenofovir disoproxil fumarate (TDF) was given alone. The specific aims of the study are therefore 1) To assess the efficacy, safety, and PK, of twice daily, co-formulated BIC 50mg/FTC 200mg/TAF 25mg in HIV positive ART-naïve adult patients with TB who are receiving a RIF-based regimen. 2) To determine the PK and safety of DTG 50mg twice daily in children (20-35kg) who are taking a RIF-containing regimen for the treatment of TB. The proposed studies are timely and will generate knowledge needed to support evidence-based use of InSTI in adults and children with HIV-associated TB who are taking RIF- based treatment. Both these studies are high impact. Firstly, South Africa and KwaZulu Natal in particular are in the epicenter of the TB-HIV co-epidemic- the majority of patients with TB also have HIV. Secondly, there are no data to support the safety and efficacy of Biktarvy® twice daily for the treatment of HIV-1 infection in patients with TB on RIF co-treatment and it is unlikely that this potent, safe drug with a high genetic barrier to resistance, that may provide effective future ART treatment options, will be made available in Africa if it cannot be used in patients with TB. Thirdly, there are no published data to support dose recommendations for DTG among children receiving TB treatment (particularly in the proposed weight-band). HIV-TB co-treatment options are extremely limited in children, making this an area of critical unmet medical need.

项目摘要： 集成酶链转移抑制剂（Insti），例如Dolutegravir（DTG）和Victegravir（BIC） 针对HIV-1的抗病毒效力，出色的安全性和耐受性以及高阻力障碍。这是一个高 优先促进成人和艾滋病毒儿童的研究所的可用性和合理使用，包括 结核病（TB）的人。南非的艾滋病毒和结核病共同感染率最高 - 在结核病患者中，有50-80％的患者患有HIV。利福平（RIF）是一种必不可少的一线结核病药物，是一种潜在的诱导 代谢酶和转运蛋白，导致限制HIV-TB共同处理的药物相互作用。在 成人，DTG，现在由世界卫生组织（WHO）推荐为首选的一线抗逆转录病毒 对于HIV-1的治疗，可以将剂量加倍（至50 mg），可以与结核病治疗一起进行。 每天两次）减轻药物相互作用。虽然现在已经为儿童建立了DTG剂量 重量为20公斤，没有数据可指导含TB的幼儿对含RIF的治疗的剂量。 BIC，共同 最近证明，伪造的Emtritabine和Tenofovir alafenamide（BIC/FTC/TAF，Biktarvy®）是 在第3阶段试验中没有基于DTG的治疗，没有耐药性的出现。但是，没有数据 在BIC/FTC/TAF效率，安全性或药代动力学（PK）的患者中存在于HIV相关的TB患者中 每天与Rif一起两次。在HIV阴性健康志愿者中，BIC故障浓度降低了 RIF的80％（但保持蛋白质调整有效浓度的3倍（PAEC95）。在另一个 研究，TAF即使在RIF中也产生了较高浓度的细胞内替诺福韦 - 二磷酸（TFV-DP）， 主动部分，比单独给出替诺福韦毒素（TDF）时。研究的具体目的 因此，1）每天两次评估两次共同成型的BIC 50mg/ftc的效率，安全性和PK 200mg/taf 25mg的HIV阳性ART ART-ART-NETH成年患者接受了基于RIF的治疗方案。 2） 要确定每天两次DTG 50mg的PK和安全性的儿童（20-35kg） 治疗结核病方案。拟议的研究是及时的，将产生所需的知识 支持基于证据的研究所在成年人和与HIV相关的结核病儿童中使用，他们正在服用RIF- 基于治疗。这两项研究都是很大的影响。首先，尤其是南非和夸祖鲁·纳塔尔（Kwazulu Natal） 在TB-HIV共同流行的中心中，大多数结核病患者也患有HIV。其次，有 没有数据支持Biktarvy®的安全性和效率，每天两次用于治疗HIV-1感染 TB在RIF共同治疗上的患者，这种潜在的安全药物不太可能具有较高的遗传障碍 如果不能，抵抗可以提供有效的未来艺术治疗选择，如果不能 用于结核病患者。第三，没有公开的数据来支持DTG的剂量建议 在接受结核病治疗的儿童中（部分在拟议的体重带中）。 HIV-TB共同处理选项 儿童受到极大的限制，这使得这是至关重要的未满足医疗需求的领域。