Faculty of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, London, United Kingdom.
MRC Centre for Global Infectious Disease Analysis, Department of Infectious Disease Epidemiology, Imperial College London, London, United Kingdom.
PLoS Med. 2024 May 9;21(5):e1004376. doi: 10.1371/journal.pmed.1004376. eCollection 2024 May.
Recently revised WHO guidelines on malaria chemoprevention have opened the door to more tailored implementation. Countries face choices on whether to replace old drugs, target additional age groups, and adapt delivery schedules according to local drug resistance levels and malaria transmission patterns. Regular routine assessment of protective efficacy of chemoprevention is key. Here, we apply a novel modelling approach to aid the design and analysis of chemoprevention trials and generate measures of protection that can be applied across a range of transmission settings.
We developed a model of genotype-specific drug protection, which accounts for underlying risk of infection and circulating genotypes. Using a Bayesian framework, we fitted the model to multiple simulated scenarios to explore variations in study design, setting, and participant characteristics. We find that a placebo or control group with no drug protection is valuable but not always feasible. An alternative approach is a single-arm trial with an extended follow-up (>42 days), which allows measurement of the underlying infection risk after drug protection wanes, as long as transmission is relatively constant. We show that the currently recommended 28-day follow-up in a single-arm trial results in low precision of estimated 30-day chemoprevention efficacy and low power in determining genotype differences of 12 days in the duration of protection (power = 1.4%). Extending follow-up to 42 days increased precision and power (71.5%) in settings with constant transmission over this time period. However, in settings of unstable transmission, protective efficacy in a single-arm trial was overestimated by 24.3% if recruitment occurred during increasing transmission and underestimated by 15.8% when recruitment occurred during declining transmission. Protective efficacy was estimated with greater precision in high transmission settings, and power to detect differences by resistance genotype was lower in scenarios where the resistant genotype was either rare or too common.
These findings have important implications for the current guidelines on chemoprevention efficacy studies and will be valuable for informing where these studies should be optimally placed. The results underscore the need for a comparator group in seasonal settings and provide evidence that the extension of follow-up in single-arm trials improves the accuracy of measures of protective efficacy in settings with more stable transmission. Extension of follow-up may pose logistical challenges to trial feasibility and associated costs. However, these studies may not need to be repeated multiple times, as the estimates of drug protection against different genotypes can be applied to different settings by adjusting for transmission intensity and frequency of resistance.
世界卫生组织最近修订的疟疾化学预防指南为更有针对性的实施打开了大门。各国面临着是否要更换旧药物、针对更多年龄组、并根据当地药物耐药水平和疟疾传播模式调整给药时间表的选择。定期常规评估化学预防的保护效果是关键。在这里，我们应用一种新的建模方法来辅助化学预防试验的设计和分析，并生成可应用于多种传播环境的保护措施。
我们开发了一种针对特定基因型药物保护的模型，该模型考虑了感染的潜在风险和循环基因型。我们使用贝叶斯框架拟合模型，以探索不同的研究设计、环境和参与者特征。我们发现，没有药物保护的安慰剂或对照组虽然有价值但并不总是可行的。另一种方法是使用延长随访期（>42 天）的单臂试验，只要传播相对稳定，就可以在药物保护减弱后测量潜在的感染风险。我们表明，在单臂试验中目前推荐的 28 天随访导致估计 30 天化学预防效果的精度低，并且确定保护持续时间差异（12 天）的能力低（效能 = 1.4%）。在这段时间内传播稳定的情况下，将随访期延长至 42 天可以提高精度和效能（71.5%）。然而，在传播不稳定的环境中，如果招募发生在传播增加期间，单臂试验中的保护效果会高估 24.3%，如果招募发生在传播减少期间，则会低估 15.8%。在高传播环境中，保护效果的估计更为准确，而在耐药基因型罕见或过于常见的情况下，检测不同基因型之间差异的效能较低。
这些发现对当前的化学预防功效研究指南具有重要意义，并将有助于确定这些研究的最佳位置。结果强调了季节性环境中需要对照组，并提供了证据表明，在传播更稳定的环境中单臂试验中延长随访期可以提高保护效果测量的准确性。随访期的延长可能会对试验的可行性和相关成本造成后勤方面的挑战。然而，由于可以通过调整传播强度和耐药频率将针对不同基因型的药物保护估计应用于不同的环境，因此可能不需要多次重复这些研究。
