Infectious Diseases Research Collaboration, Kampala, Uganda.
Department of Medicine, University of California San Francisco, San Francisco, California, USA.
Antimicrob Agents Chemother. 2020 Nov 17;64(12). doi: 10.1128/AAC.01047-20.
Intermittent preventive treatment in pregnancy (IPTp) with monthly sulfadoxine-pyrimethamine (SP) is recommended for malaria-endemic parts of Africa, but efficacy is compromised by resistance, and, in recent trials, dihydroartemisinin-piperaquine (DP) has shown better antimalarial protective efficacy. We utilized blood samples from a recent trial to evaluate selection by IPTp with DP or SP of genetic polymorphisms that alter susceptibility to these drugs. The prevalence of known genetic polymorphisms associated with altered drug susceptibility was determined in parasitemic samples, including 375 collected before IPTp drugs were administered, 125 randomly selected from those receiving SP, and 80 from those receiving DP. For women receiving DP, the prevalence of mixed/mutant sequences was greater in samples collected during IPTp than that in samples collected prior to the intervention for PfMDR1 N86Y (20.3% versus 3.9%; < 0.001), PfMDR1 Y184F (73.0% versus 53.0%; < 0.001), and PfCRT K76T (46.4% versus 24.0%; < 0.001). Considering SP, prior to IPTp, the prevalence of all 5 common antifolate mutations was over 92%, and this prevalence increased following exposure to SP, although none of these changes were statistically significant. For two additional mutations associated with high-level SP resistance, the prevalence of PfDHFR 164L (13.7% versus 4.0%; = 0.004), but not PfDHPS 581G (1.9% versus 3.0%; = 0.74), was greater in samples collected during IPTp compared to those collected before the intervention. Use of IPTp in Uganda selected for parasites with mutations associated with decreased susceptibility to IPTp regimens. Thus, a potential drawback of IPTp is selection of parasites with decreased drug susceptibility.
在疟疾流行地区，建议采用每月一次的磺胺多辛-乙胺嘧啶（SP）间歇性预防治疗（IPTp），但由于耐药性的存在，该方法的疗效受到影响。最近的试验表明，双氢青蒿素-哌喹（DP）具有更好的抗疟保护效果。本研究利用最近一项试验中的血样，评估了 DP 或 SP 进行 IPTp 治疗对改变药物敏感性的遗传多态性的选择作用。在寄生虫血症样本中确定了与改变药物敏感性相关的已知遗传多态性的流行率，包括在给予 IPTp 药物之前采集的 375 个样本、从接受 SP 的 125 个随机样本和接受 DP 的 80 个样本。对于接受 DP 的女性，在 IPTp 期间采集的样本中 PfMDR1 N86Y（20.3%对 3.9%；<0.001）、PfMDR1 Y184F（73.0%对 53.0%；<0.001）和 PfCRT K76T（46.4%对 24.0%；<0.001）混合/突变序列的流行率高于干预前采集的样本。考虑到 SP，在 IPTp 之前，所有 5 种常见的抗叶酸突变的流行率均超过 92%，并且在接触 SP 后，这种流行率增加，尽管这些变化均无统计学意义。对于与高水平 SP 耐药相关的另外两种突变，PfDHFR 164L（13.7%对 4.0%；=0.004）的流行率高于干预前采集的样本，而 PfDHPS 581G（1.9%对 3.0%；=0.74）的流行率则没有差异。在乌干达使用 IPTp 选择了对 IPTp 方案敏感性降低的寄生虫突变体。因此，IPTp 的一个潜在缺点是选择了对药物敏感性降低的寄生虫。
