Challenger Joseph D, Gonçalves Bronner P, Bradley John, Bruxvoort Katia, Tiono Alfred B, Drakeley Chris, Bousema Teun, Ghani Azra C, Okell Lucy C
MRC Centre for Global Infectious Disease Analysis, Department of Infectious Disease Epidemiology, Imperial College London, London, United Kingdom.
Department of Immunology and Infection, London School of Hygiene and Tropical Medicine, London, United Kingdom.
BMJ Glob Health. 2019 Dec 10;4(6):e001856. doi: 10.1136/bmjgh-2019-001856. eCollection 2019.
Artemether-lumefantrine (AL) is the most widely-recommended treatment for uncomplicated malaria. Its efficacy has been extensively assessed in clinical trials. In routine healthcare settings, however, its effectiveness can be diminished by delayed access to treatment and poor adherence. As well as affecting clinical outcomes, these factors can lead to increased transmission, which is the focus of this study.
We extend a within-host model of to include gametocytes, the parasite forms responsible for onward transmission. The model includes a pharmacokinetic-pharmacodynamic model of AL, calibrated against both immature and mature gametocytes using individual-level patient data, to estimate the impact that delayed access and imperfect adherence to treatment can have on onward transmission of the parasite to mosquitoes.
Using survey data from seven African countries to determine the time taken to acquire antimalarials following fever increased our estimates of mean total infectivity of a malaria episode by up to 1.5-fold, compared with patients treated after 24 hours. Realistic adherence behaviour, based on data from a monitored cohort in Tanzania, increased the contribution to transmission by 2.2 to 2.4-fold, compared with a perfectly-adherent cohort. This was driven largely by increased rates of treatment failure leading to chronic infection, rather than prolonged gametocytaemia in patients who have slower, but still successful, clearance of parasites after imperfect adherence to treatment. Our model estimated that the mean infectivity of untreated infections was 29-51 times higher than that of treated infections (assuming perfect drug adherence), underlining the importance of improving treatment coverage.
Using mathematical modelling, we quantify how delayed treatment and non-adherent treatment can increase transmission compared with prompt effective treatment. We also highlight that transmission from the large proportion of infections which never receive treatment is substantially higher than those treated.
蒿甲醚-本芴醇（AL）是治疗非复杂性疟疾最广泛推荐的药物。其疗效已在临床试验中得到广泛评估。然而，在常规医疗环境中，治疗延迟和依从性差会降低其有效性。这些因素除了影响临床结果外，还会导致传播增加，这是本研究的重点。
我们扩展了一个宿主内模型，以纳入配子体，即负责进一步传播的寄生虫形式。该模型包括AL的药代动力学-药效学模型，使用个体水平的患者数据针对未成熟和成熟配子体进行校准，以估计治疗延迟和不完全依从对寄生虫向蚊子进一步传播的影响。
利用来自七个非洲国家的调查数据确定发热后获取抗疟药的时间，与24小时后接受治疗的患者相比，我们对疟疾发作平均总传染性的估计增加了高达1.5倍。基于坦桑尼亚一个监测队列的数据，与完全依从队列相比，实际的依从行为使传播贡献增加了2.2至2.4倍。这主要是由于治疗失败率增加导致慢性感染，而不是不完全依从治疗后寄生虫清除较慢但仍成功的患者中配子体血症延长。我们的模型估计，未经治疗的感染的平均传染性比经治疗的感染（假设药物完全依从）高29至51倍，强调了提高治疗覆盖率的重要性。
通过数学建模，我们量化了与及时有效的治疗相比，延迟治疗和不依从治疗如何增加传播。我们还强调，从未接受治疗的大部分感染的传播率大大高于接受治疗的感染。
