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

项目总结： 整合酶链转移抑制剂(INSTI)，如多洛替格列韦(DTG)和比替格列韦(BIC)，具有较高的 针对HIV-1的抗病毒效力，出色的安全性和耐受性，以及高抗药性。这是一个很高的 优先促进艾滋病毒携带者成人和儿童获得和合理使用INSTI，包括 患有结核病(TB)的人。南非的艾滋病毒和结核病混合感染率是世界上最高的-- 在结核病患者中，50%-80%的人感染了艾滋病毒。利福平(RIF)是一种基本的一线结核病药物，是一种有效的诱导剂 影响代谢酶和转运蛋白，导致药物相互作用，限制了艾滋病毒-结核病联合治疗的选择。在……里面 成人，DTG，现在被世界卫生组织(WHO)推荐为首选的一线抗逆转录病毒药物 对于HIV-1的治疗，可以与结核病治疗一起服用，前提是剂量加倍(至50毫克 每天两次)，以减轻药物相互作用。虽然DTG剂量现在已经为儿童建立了低到 20公斤的体重，没有数据来指导幼儿结核病患者接受含RIF治疗的剂量。比克，共同- 由恩曲他滨和替诺福韦丙氨酰胺(BIC/FTC/TAF，Biktarvy®)配制的药物最近被证明是 不逊于基于DTG的治疗，在3期试验中没有出现耐药性。但是，没有数据 存在于HIV相关结核病患者的BIC/FTC/TAF的有效性、安全性或药代动力学(PK)时 每日两次，配合RIF使用。在HIV阴性的健康志愿者中，BIC谷浓度降低了 80%的RIF(但仍比蛋白质调节有效浓度(PaEC95)高3倍)。在另一个国家 研究表明，即使在有RIF的情况下，TAF也会产生更高浓度的替诺福韦-二磷酸(TFV-DP)， 活性部分，而不是单用富马酸替诺福韦(TDF)。这项研究的具体目的 因此，1)评估每日两次的联合配方BIC 50 mg/FTC的有效性、安全性和PK 200 mg/TAF 25 mg用于正在接受RIF方案的HIV阳性的未成年结核病患者。2) 对服用含RIF的儿童(20-35 kg)每日两次DTG 50 mg的PK和安全性进行测定 治疗结核病的治疗方案。拟议的研究是及时的，并将产生所需的知识 支持在正在服用RIF的成人和儿童中使用INSTI，这是基于证据的使用 以治疗为基础。这两项研究都具有很高的影响力。首先，南非和夸祖鲁·纳塔尔特别是 在结核病和艾滋病毒共同流行的震中，大多数结核病患者也感染了艾滋病毒。其次，有以下几种 没有数据支持Biktarvy®每天两次治疗艾滋病毒感染的安全性和有效性 结核病患者接受RIF联合治疗，这种具有高遗传屏障的有效、安全的药物不太可能 耐药性可能提供未来有效的抗逆转录病毒治疗选择，如果不能，将在非洲提供 可用于结核病患者。第三，没有已发表的数据支持DTG的剂量推荐 在接受结核病治疗的儿童中(特别是在拟议的体重范围内)。艾滋病毒-结核病联合治疗方案 儿童的死亡率极其有限，这使这一领域成为一个严重的未得到满足的医疗需求领域。

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.