Walker Martin, Specht Sabine, Churcher Thomas S, Hoerauf Achim, Taylor Mark J, Basáñez María-Gloria
Department of Infectious Disease Epidemiology, Imperial College London, United Kingdom.
Institute for Medical Microbiology, Immunology and Parasitology, University Hospital Bonn, Germany.
Clin Infect Dis. 2015 Apr 15;60(8):1199-207. doi: 10.1093/cid/ciu1152. Epub 2014 Dec 23.
Onchocerca volvulus and lymphatic filariae, causing river blindness and elephantiasis, depend on endosymbiotic Wolbachia bacteria for growth, development, fertility, and survival. Clinical trials have shown that doxycycline treatment eliminates Wolbachia, causing long-term sterilization of adult female filariae and effecting potent macrofilaricidal activity. The continual reinfection by drug-naive worms that occurs in these trial settings dilutes observable anti-Wolbachia and antifilarial effects, making it difficult to estimate therapeutic efficacy and compare different doxycycline regimens, evaluated at different times after treatment.
A meta-analytical modeling framework is developed to link all usable data collected from clinical trials measuring the Wolbachia status and viability of individual female adult worms collected at various times after treatment with 4, 5, or 6 weeks of daily 100 or 200 mg oral doxycycline. The framework is used to estimate efficacy parameters that are not directly measurable as trial outcomes.
The estimated efficacy of doxycycline (the maximum proportional reduction in the percentage of adult female O. volvulus positive for Wolbachia) is 91%-94% on average, irrespective of the treatment regimen. Efficacy is >95% in the majority of trial participants. The life span of Wolbachia-depleted worms is reduced by 70%-80%, from approximately 10 years to 2-3 years.
The efficacy parameters are pertinent to the prospects of using doxycycline on a "test and treat" basis for onchocerciasis control and confirm doxycycline as a potent macrofilaricidal therapy. The modeling approach is more generally relevant to the design and evaluation of clinical trials for antifilarial drugs conducted in endemic settings.
盘尾丝虫和淋巴丝虫分别导致河盲症和象皮病，它们的生长、发育、繁殖及生存依赖于内共生沃尔巴克氏体细菌。临床试验表明，强力霉素治疗可清除沃尔巴克氏体，使成年雌性丝虫长期绝育，并具有强大的杀成虫活性。在这些试验环境中，未接触过药物的丝虫持续再感染会稀释可观察到的抗沃尔巴克氏体和抗丝虫效果，从而难以评估治疗效果以及比较不同强力霉素治疗方案（在治疗后不同时间进行评估）。
开发了一种荟萃分析建模框架，以关联从临床试验中收集的所有可用数据，这些试验测量了在每日口服100或200毫克强力霉素4周、5周或6周治疗后的不同时间收集的单个成年雌性虫体的沃尔巴克氏体状态和活力。该框架用于估计作为试验结果无法直接测量的疗效参数。
无论治疗方案如何，强力霉素的估计疗效（沃尔巴克氏体阳性的成年雌性盘尾丝虫百分比的最大比例降低）平均为91%-94%。大多数试验参与者的疗效>95%。缺乏沃尔巴克氏体的虫体寿命缩短了70%-80%，从约10年减至2-3年。
这些疗效参数与基于“检测和治疗”使用强力霉素控制盘尾丝虫病的前景相关，并证实强力霉素是一种有效的杀成虫疗法。该建模方法更广泛地适用于在流行地区进行的抗丝虫药物临床试验的设计和评估。
