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

项目概要： 整合酶链转移抑制剂（InSTI），如度鲁特韦（DTG）和比替拉韦（BIC），具有高的生物学活性。 抗HIV-1的抗病毒效力、优异的安全性和耐受性以及高耐药性屏障。是大 优先促进感染艾滋病毒的成人和儿童获得和合理使用InSTI，包括 肺结核（TB）。南非是世界上艾滋病和结核病合并感染率最高的国家， 在结核病患者中，50-80%携带艾滋病毒。利福平（RIF）是一种重要的一线抗结核药物， 代谢酶和转运蛋白的相互作用，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 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使用，前提是剂量增加一倍（至50毫克 每日两次）以减轻药物相互作用。虽然DTG剂量现已确定用于儿童， 体重为20 kg，没有数据可以指导结核病幼儿接受含RIF治疗的剂量。BIC，co- 与恩曲他滨和替诺福韦艾拉酚胺（BIC/FTC/TAF，Biktarvy®）一起配制的药物最近显示出 非劣效于基于DTG的治疗，在III期试验中未出现耐药性。然而，没有数据 HIV相关TB患者中存在BIC/FTC/TAF疗效、安全性或药代动力学（PK）， 每日两次与RIF一起给药。在HIV阴性的健康志愿者中，BIC谷浓度降低 RIF为80%（但仍高于蛋白质调整的有效浓度（paEC 95）3倍）。在另一 在一项研究中，TAF甚至与RIF一起产生更高浓度的细胞内替诺福韦二磷酸（TFV-DP）， 活性部分，比当替诺福韦二异丙酯富马酸盐（TDF）单独给予。研究的具体目标 因此，1）评估每日两次联合配制的BIC 50 mg/FTC的疗效、安全性和PK 200 mg/TAF 25 mg用于正在接受基于RIF的方案的HIV阳性、未经ART治疗的成年结核病患者。（二） 确定DTG 50 mg每日两次在服用含RIF的儿童（20- 35 kg）中的PK和安全性 治疗结核病的方案。拟议的研究是及时的，将产生所需的知识， 支持在正在服用RIF的HIV相关结核病成人和儿童中使用InSTI的循证使用- 基础治疗。这两项研究都具有很高的影响力。首先，南非，特别是夸祖鲁纳塔尔， 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携带艾滋病毒。其次是 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， RIF联合治疗的结核病患者，这种具有高遗传屏障的强效、安全药物不太可能 耐药性，可能提供有效的未来ART治疗选择，将在非洲提供，如果它不能， 用于结核病患者。第三，没有发表的数据支持DTG的剂量建议 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/结核病合并治疗方案 在儿童中极为有限，使这一领域的医疗需求严重得不到满足。

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.