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）是由结核分枝杆菌引起的感染，估计世界上多达三分之一的人口感染了这种病原体。大多数受感染的个体保持在非活动状态，称为潜伏性TB感染（LTBI），其特征在于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成活动性疾病。结核病在感染人类免疫缺陷病毒（HIV）的个体中尤其成问题，因为个体发生活动性结核病感染的可能性是HIV阴性个体的26倍，随着CD 4 T淋巴细胞计数下降和病毒载量增加，风险增加。结核病是全球艾滋病毒感染人群中最常见的机会性感染之一，2014年，艾滋病毒阳性个体占新发结核病病例的12%。 此外，所有结核病死亡中约25%是由艾滋病毒感染者造成的，33%的艾滋病毒/获得性免疫缺陷综合征（艾滋病）死亡归因于结核病。报告的大多数结核病例和死亡发生在非洲和亚洲的发展中国家。美国等高收入国家的发病率要低得多。然而，结核病仍然是一个严重的公共卫生问题。 为了降低艾滋病毒感染者的发病率和死亡率，对活动性和LTBI进行适当的诊断和治疗至关重要。目前，HIV阳性个体中LTBI的一线治疗建议包括（1）异烟肼（INH）300 mg每日+吡哆醇25 mg每日9个月或（2）INH 900 mg每周两次（作为直接观察治疗DOT的一部分）+吡哆醇25 mg每日9个月。替代治疗选择包括（1）利福平（RIF）600 mg PO每日一次，持续4个月，或（2）利福朋（RFB）（根据伴随抗逆转录病毒（ARV）药物调整剂量），持续4个月。基于INH的疗法对于LTBI治疗非常有效。然而，由于疗程长和药丸负担高，艾滋病毒感染者和未感染者的依从性和治疗完成率都很低。 每周一次利福喷丁（RPT）和INH是另一个最近增加的选择，以提供LTBI治疗艾滋病毒。在未接受抗逆转录病毒治疗（ART）的HIV感染LTBI患者中，发现该方案的疗效与INH 300 mg/d，持续6个月8和9个月9相似，并且在两个大部分HIV阴性人群中均不劣于INH每日给药，持续9个月。RPT + INH是LTBI的一种有吸引力的治疗选择，因为它每周给药一次，持续12周，可以作为直接观察治疗（DOT）治疗支持的一部分，并且接受这种治疗的患者耐受性良好。总的来说，这些优势转化为与INH治疗相比更高的依从性，INH治疗需要每日给药和6至9个月的治疗（分别为82-95%和48- 85%）。 尽管有这些潜在的益处，但由于这些药物之间药物相互作用的数据有限，目前不建议在美国接受ART的HIV感染成人中使用每周一次的RPT和INH。利福霉素每日给药可引起显著的CYP 3A诱导。RIF或RFB与ARV药物之间的前瞻性药物相互作用研究已告知临床医生是否应避免某些组合或进行适当的剂量调整以减轻这些相互作用。然而，每周一次RPT可能观察到的相互作用程度尚不清楚。 达芦那韦与cobicistat（DRV/c）联合使用是推荐用于治疗HIV的替代治疗方案的一部分。然而，这些抗逆转录病毒药物和RPT之间的药物相互作用是值得关注的。因此，本研究的目的是确定RPT和INH联合给药对DRV/c稳态PK的影响。 这是一项开放标签、固定序列、受试者内药物相互作用研究，旨在评价每周一次RPT和用于治疗LTBI的INH联合给药时DRV/c的稳态PK。B组将包括两个阶段：（1）DRV/c每日一次单独给药（第1-4天）和（2）DRV/c每日一次+（RPT和INH）每周一次给药（第5-19天）。B组受试者将在第4、14和19天接受定期系列ARV PK采血。 将使用非房室方法确定DRV/c PK参数。仅在DRV浓度显著降低时评估Cobicistat水平。将比较两个阶段的以下PK参数：给药间隔的曲线下面积、最大血浆浓度、至最大血浆浓度的时间、终末半衰期、表观口服清除率和最小血浆浓度。将对不良事件进行分级和记录。

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.