Ngan Nguyen Thi Thuy, Mai Nguyen Thi Hoang, Tung Nguyen Le Nhu, Lan Nguyen Phu Huong, Tai Luong Thi Hue, Phu Nguyen Hoan, Chau Nguyen Van Vinh, Binh Tran Quang, Hung Le Quoc, Beardsley Justin, White Nicholas, Lalloo David, Krysan Damian, Hope William, Geskus Ronald, Wolbers Marcel, Nhat Le Thanh Hoang, Thwaites Guy, Kestelyn Evelyne, Day Jeremy
Oxford University Clinical Research Unit, University of Oxford, Ho Chi Minh City, Vietnam.
Dept of Tropical Medicine, Cho Ray Hospital, Ho Chi Minh City, Vietnam.
Wellcome Open Res. 2019 Jan 22;4:8. doi: 10.12688/wellcomeopenres.15010.1. eCollection 2019.
: Cryptococcal meningitis is a leading cause of death in HIV-infected patients. International treatment guidelines recommend induction therapy with amphotericin B and flucytosine. This antifungal combination is most effective, but unfortunately flucytosine is expensive and unavailable where the burden of disease is greatest. Where unavailable, guidelines recommend treatment with amphotericin and fluconazole, but this is less effective, with mortality rates of 40-50%. Faster rates of clearance of yeast from cerebrospinal fluid (CSF) are associated with better outcomes - improving the potency of antifungal therapy is likely to be an effective strategy to improve survival. Tamoxifen, a selective estrogen receptor modulator used to treat breast cancer, has anti-cryptococcal activity, appearing synergistic when combined with amphotericin, and fungicidal when combined with fluconazole. It is concentrated in the brain and macrophages, off-patent, cheap and widely available. We designed a randomized trial to deliver initial efficacy and safety data for tamoxifen combined with amphotericin and fluconazole. : A phase II, open-label, randomized (1:1) controlled trial of tamoxifen (300mg/day) combined with amphotericin (1mg/kg/day) and fluconazole (800mg/day) for the first 2 weeks therapy for HIV infected or uninfected adults with cryptococcal meningitis. The study recruits at Cho Ray Hospital and the Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam. The primary end point is Early Fungicidal Activity (EFA-the rate of yeast clearance from CSF), over the first two weeks of treatment. 50 patients will be recruited providing ≈80% and 90% power to detect a difference in the EFA of -0.11 or -0.13 log10CFU/ml/day, respectively. The results of the study will inform the decision to proceed to a larger trial powered to mortality. The size of effect detectable has previously been associated with reduced mortality from this devastating disease. Particular side effects of interest include QT prolongation. : Clinicaltrials.gov NCT03112031 (11/04/2017).
隐球菌性脑膜炎是HIV感染患者死亡的主要原因。国际治疗指南推荐使用两性霉素B和氟胞嘧啶进行诱导治疗。这种抗真菌联合用药最为有效，但不幸的是，氟胞嘧啶价格昂贵，且在疾病负担最重的地区无法获得。在无法获得氟胞嘧啶的地区，指南推荐使用两性霉素和氟康唑进行治疗，但效果较差，死亡率为40%-50%。脑脊液（CSF）中酵母菌清除速度加快与更好的治疗结果相关——提高抗真菌治疗的效力可能是提高生存率的有效策略。他莫昔芬是一种用于治疗乳腺癌的选择性雌激素受体调节剂，具有抗隐球菌活性，与两性霉素联合使用时表现出协同作用，与氟康唑联合使用时具有杀菌作用。它在脑和巨噬细胞中富集，已过专利保护期，价格便宜且广泛可得。我们设计了一项随机试验，以提供他莫昔芬联合两性霉素和氟康唑的初步疗效和安全性数据。：一项II期、开放标签、随机（1:1）对照试验，研究他莫昔芬（300mg/天）联合两性霉素（1mg/kg/天）和氟康唑（800mg/天）用于治疗患有隐球菌性脑膜炎的HIV感染或未感染成年人的前2周治疗。该研究在越南胡志明市的Cho Ray医院和热带病医院招募患者。主要终点是治疗前两周的早期杀菌活性（EFA——CSF中酵母菌的清除率）。将招募50名患者，分别提供约80%和90%的检验效能，以检测EFA中-0.11或-0.13 log10CFU/ml/天的差异。研究结果将为是否进行更大规模的以死亡率为指标的试验提供决策依据。此前可检测到的效应大小与降低这种毁灭性疾病的死亡率相关。特别关注的副作用包括QT间期延长。：Clinicaltrials.gov NCT03112031（2017年4月11日）
