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: 10226892
• 负责人: Kelly E. Dooley
• 金额: $ 33万
• 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/10226892
• 关键词: ABCB1 gene; Adult; Africa; Africa South of the Sahara; Anti-Retroviral Agents; Antiviral Agents; Area; CYP3A4 gene; Child; Clinical; Data; 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; Pharmaceutical Preparations; Plasma; Positioning Attribute; Price; Protease Inhibitor; Proteins; Publishing; Randomized; Recommendation; Regimen; Research; Resistance; Resistance development; Resources; Rifampin; Safety; Sampling; South Africa; Tablets; Tenofovir; Testing; Time; Treatment Protocols; Tuberculosis; UGT1A1 gene; Ursidae Family; Viral Load result; Weight; World Health Organization; antiretroviral therapy; base; clinically relevant; co-infection; efavirenz; effective therapy; emtricitabine; evidence base; genetic testing; healthy volunteer; inhibitor/antagonist; 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.

项目概要： 整合酶链转移抑制剂 (InSTI)，例如多替拉韦 (DTG) 和比克替拉韦 (BIC)，具有高 针对 HIV-1 的抗病毒效力、出色的安全性和耐受性以及高耐药屏障。这是一个高 优先促进 InSTI 在成人和儿童艾滋病毒感染者中的可用性和合理使用，包括 患有结核病 (TB) 的人。南非是世界上艾滋病毒和结核病双重感染率最高的国家—— 在结核病患者中，50-80% 患有艾滋病毒。利福平 (RIF) 是一种重要的一线结核病药物，是一种有效的诱导剂 代谢酶和转运蛋白的相互作用，导致限制 HIV-TB 联合治疗选择的药物相互作用。在 成人 DTG 现已被世界卫生组织 (WHO) 推荐为首选一线抗逆转录病毒药物 用于治疗 HIV-1，可与结核病治疗一起给予，前提是剂量加倍（至 50 毫克） 每日两次）以减轻药物相互作用。虽然 DTG 剂量现已确定为儿童低至 体重为 20 公斤，尚无数据指导患有结核病的幼儿接受含 RIF 治疗的剂量。 BIC，联合 最近显示，由恩曲他滨和替诺福韦艾拉酚胺（BIC/FTC/TAF，Biktarvy®）配制而成 不劣于基于 DTG 的治疗，在 3 期试验中未出现耐药性。然而，没有数据 HIV 相关结核病患者中存在 BIC/FTC/TAF 疗效、安全性或药代动力学 (PK) 时， 每天两次与 RIF 一起给药。在 HIV 阴性健康志愿者中，BIC 谷浓度降低了 RIF 为 80%（但仍比蛋白质调整有效浓度 (paEC95) 高 3 倍。在另一个例子中 研究表明，TAF 甚至与 RIF 一起产生了更高浓度的细胞内替诺福韦二磷酸盐 (TFV-DP)， 活性部分，比单独给予富马酸替诺福韦二吡呋酯 (TDF) 时更有效。研究的具体目的 因此 1) 评估每日两次联合配制的 BIC 50mg/FTC 的功效、安全性和 PK 200mg/TAF 25mg 用于接受基于 RIF 的治疗方案的 HIV 阳性未接受过 ART 的成人结核病患者。 2） 确定服用含 RIF 的儿童（20-35 公斤）每日两次 50 毫克 DTG 的 PK 和安全性 治疗结核病的方案。拟议的研究是及时的，并将产生所需的知识 支持在服用 RIF 的患有 HIV 相关结核病的成人和儿童中基于证据使用 InSTI 为基础的治疗。这两项研究都具有很高的影响力。首先，南非和夸祖鲁纳塔尔省尤其如此 在结核病和艾滋病毒共同流行的中心——大多数结核病患者也感染了艾滋病毒。其次，有 没有数据支持 Biktarvy® 每日两次治疗 HIV-1 感染的安全性和有效性 接受 RIF 联合治疗的结核病患者，这种具有高度遗传屏障的强效、安全药物不太可能 如果不能的话，非洲将提供耐药性，这可能会提供有效的未来 ART 治疗选择 用于结核病患者。第三，没有已发表的数据支持 DTG 的剂量建议 接受结核病治疗的儿童（特别是在建议的体重范围内）。 HIV-TB 联合治疗方案 对儿童的影响极其有限，这使得这一领域的医疗需求严重未得到满足。