Impact of Once-Weekly Rifapentine and Isoniazid on the Steady State Pharmacokinetics of Dolutegravir and Darunavir Boosted with Cobicistat in Healthy Volunteers (R2D2)

结核病(TB)是一种由结核分枝杆菌引起的感染，据估计，世界上多达三分之一的人口感染了这种病原体。大多数感染者仍处于不活跃状态，称为潜伏性结核病感染(LTBI)，其特征是缺乏症状或感染他人的能力。然而，LTBI可以被重新激活并发展为活动性疾病。结核病在感染人类免疫缺陷病毒(HIV)的个人中问题尤其严重，因为个人患活动性结核病感染的可能性是HIV阴性个人的26倍，随着CD4T淋巴细胞数量下降和病毒载量增加，风险增加。结核病是全球艾滋病毒人群中最常见的机会性感染之一，2014年，艾滋病毒阳性个人占新发结核病病例的12%。此外，约25%的结核病死亡是由感染艾滋病毒的人造成的，33%的艾滋病毒/获得性免疫缺陷综合征(艾滋病)死亡是由结核病引起的。大多数结核病病例和死亡报告发生在非洲和亚洲的发展中国家。收入较高的国家，如美国，发病率要低得多。尽管如此，结核病仍然是一个重大的公共卫生问题。 为了减少HIV感染者的发病率和死亡率，活动性和LTBI的适当诊断和治疗是至关重要的。目前，对艾滋病毒阳性患者的一线治疗建议包括：(1)异烟肼(INH)300毫克/天+吡哆醇25毫克/天，持续9个月；或(2)异烟肼900毫克/周两次(作为直接观察疗法的一部分)+吡哆醇25毫克/天(DOT)，持续9个月。替代治疗方案包括(1)利福平(RIF)每日600毫克PO，持续4个月，或(2)利福平(RFB)(根据伴随的抗逆转录病毒(ARV)药物的剂量进行调整)4个月。基于异烟肼的疗法对LTBI的治疗非常有效。然而，由于疗程长和服药负担高，艾滋病毒感染者和非感染者的依从性和治疗完成率都很低。 利福喷丁(RPT)和异烟肼(INH)每周一次是艾滋病毒LTBI治疗的另一个最近增加的选择。在未接受抗逆转录病毒治疗(ART)的HIV感染者8个月和9个月中，该方案被发现与在6个月8和9个月内每天服用300 mg异烟肼的疗效相似，而在大部分HIV阴性的人群中，这两种方案的疗效都不逊于每天服用9个月的异烟肼。RPT+INH是治疗LTBI的一种有吸引力的治疗选择，因为它在12周内每周服用一次，可以作为直接观察疗法(DOT)治疗支持的一部分给予，并且接受这种疗法的患者耐受性很好。总而言之，这些优势转化为比异烟肼疗法更高的依从率，异烟肼疗法需要每天服药和6-9个月的治疗(分别为82-95%和48%-85%)。 尽管有这些潜在的好处，但在美国，由于关于这些药物之间相互作用的数据有限，目前不建议在接受抗逆转录病毒治疗的HIV感染成年人中使用每周一次的RPT和异烟肼。利福霉素每日给药可显著诱导细胞色素P3A的表达。RIF或RFB与ARV药物之间的前瞻性药物相互作用研究已经告知临床医生是否要避免某些组合或进行适当的剂量调整来缓解这些相互作用。然而，每周一次的RPT可能观察到的相互作用的程度是未知的。 达鲁那韦(DRV/c)是推荐用于艾滋病毒治疗的替代治疗方案的一部分。然而，这些抗逆转录病毒药物与RPT之间的药物相互作用值得关注。因此，本研究的目的是确定同时给予RPT和INH对DRV/c稳态PK的影响。 这是一项开放的、固定序列的受试者内药物相互作用研究，旨在评估DRV/c的稳定状态PK，并以治疗LTBI的剂量每周联合给予一次RPT和INH。ARM B将由两个阶段组成：(1)DRV/c单独每天一次(第1-4天)和(2)DRV/c每天一次+(RPT和INH)每周一次(第5-19天)。B组的参与者将在第4天、第14天和第19天进行定期连续ARV PK抽血。 DRV/c PK参数将使用非隔室方法确定。只有在DRV浓度显著降低的情况下，才会评估COBICISAT的水平。以下PK参数将在不同阶段进行比较：给药间隔的曲线下面积、最大血药浓度、达到最大血药浓度的时间、终末半衰期、表观口服清除量和最低血药浓度。不良事件将被分级和记录。

Tuberculosis (TB) is an infection caused by Mycobacterium tuberculosis, and up to one-third of the worlds population is estimated to be infected with this pathogen. The majority of infected individuals remain in an inactive state, referred to as latent TB infection (LTBI), which is characterized by a lack of symptoms or an ability to infect others. However, LTBI can be reactivated and develop into active disease. TB is particularly problematic in individuals infected with human immunodeficiency virus (HIV), as individuals are 26 times more likely to develop active TB infection than HIV-negative individuals, with increasing risk as CD4 T lymphocyte counts decline and viral loads increase. TB is one of the most common opportunistic infections in the HIV population worldwide, and in 2014, HIV-positive individuals accounted for 12% of newly developed TB cases. Furthermore, around 25% of all TB deaths were accounted for by those infected with HIV, and 33% of HIV/ acquired immunodeficiency syndrome (AIDS) deaths were attributed to TB. The majority of TB cases and deaths are reported in developing countries in Africa and Asia. Higher-income countries, such as the United States, are associated with much lower incidence rates. Nevertheless, TB still poses a significant public health problem. In order to reduce the morbidity and mortality observed in individuals with HIV, appropriate diagnosis and treatment of active and LTBI is essential. Currently, the first-line treatment recommendations for LTBI in HIV-positive individuals include (1) isoniazid (INH) 300 mg daily + pyridoxine 25 mg daily for 9 months or (2) INH 900 mg twice weekly (as part of directly observed therapy DOT) + pyridoxine 25 mg daily for 9 months. Alternative treatment options include (1) rifampin (RIF) 600 mg PO daily for 4 months, or (2) rifabutin (RFB) (dose-adjusted for concomitant antiretroviral (ARV) drugs) for 4 months. INH-based therapies are highly effective for LTBI treatment. However, adherence and treatment completion is low in both HIV-infected and -uninfected individuals due to long treatment courses and high pill burden. Once weekly rifapentine (RPT) and INH is another more recently added option to available LTBI treatments in HIV. This regimen was found to be similar in efficacy to INH 300 mg daily for 6 months8 and 9 months9 in HIV-infected individuals with LTBI not on antiretroviral therapy (ART), and noninferior to daily INH given for 9 months in both a largely HIV-negative population. RPT + INH is an attractive therapeutic option for LTBI as it is dosed once weekly over 12 weeks, can be given as part of directly observed therapy (DOT) treatment support, and is well tolerated by patients receiving this therapy. Collectively, these advantages translate into higher rates of adherence comparatively to INH therapy, which requires daily dosing and 6 to 9 months of therapy (82-95% vs. 48-85%, respectively). Despite these potential benefits, the use of once weekly RPT with INH is not currently recommended in HIV-infected adults on ART in the US due to limited data on drug interactions between these agents. Rifamycins can cause significant CYP3A induction with daily administration. Prospective drug interaction studies between RIF or RFB and ARV agents have informed clinicians of whether to avoid certain combinations or make appropriate dose adjustments to mitigate these interactions. However, the extent of interaction that may be observed with once weekly RPT is unknown. Darunavir boosted with cobicistat (DRV/c) comprises part of alternative treatment regimens recommended for the treatment of HIV. However, drug interactions between these ARV agents and RPT are of concern. Thus, the purpose of this study is to determine the effects of concomitant RPT and INH administration on the steady state PK of DRV/c. This is an open-label, fixed sequence, intrasubject drug-drug interaction study designed to evaluate the steady state PK of DRV/c with coadministration of once weekly RPT and INH given at doses used to treat LTBI. Arm B will be comprised of two phases: (1) DRV/c once daily alone (days 1-4) and (2) DRV/c once daily + (RPT and INH) once weekly (days 5-19). Participants in Arm B will undergo periodic serial ARV PK blood draws on days 4, 14, and 19. DRV/c PK parameters will be determined using non-compartmental methods. Cobicistat levels will only be assessed if DRV concentrations are significantly decreased. The following PK parameters will be compared between phases: area under the curve over the dosing interval, maximum plasma concentration, time to maximum plasma concentration, terminal half-life, apparent oral clearance, and minimum plasma concentration. Adverse events will be graded and recorded.