Tan Kathrine R, Katalenich Bonnie L, Mace Kimberly E, Nambozi Michael, Taylor Steve M, Meshnick Steven R, Wiegand Ryan E, Chalwe Victor, Filler Scott J, Kamuliwo Mulakwa, Craig Allen S
Malaria Branch, US Centers for Disease Control and Prevention, Atlanta, GA, USA.
Malar J. 2014 Jun 9;13:227. doi: 10.1186/1475-2875-13-227.
Intermittent preventive treatment of malaria in pregnancy (IPTp) with sulphadoxine-pyrimethamine (SP) decreases adverse effects of malaria during pregnancy. Zambia implemented its IPTp-SP programme in 2003. Emergence of SP-resistant Plasmodium falciparum threatens this strategy. The quintuple mutant haplotype (substitutions in N51I, C59R, S108N in dhfr and A437G and K540E in dhps genes), is associated with SP treatment failure in non-pregnant patients with malaria. This study examined efficacy of IPTp-SP and presence of the quintuple mutant among pregnant women in Mansa, Zambia.
In Mansa, an area with high malaria transmission, HIV-negative pregnant women presenting to two antenatal clinics for the 1st dose of IPTp-SP with asymptomatic parasitaemia were enrolled and microscopy for parasitaemia was done weekly for five weeks. Outcomes were parasitological failure and adequate parasitological response (no parasitaemia during follow-up). Polymerase chain reaction assays were employed to distinguish recrudescence from reinfection, and identify molecular markers of SP resistance. Survival analysis included those who had reinfection and incomplete follow-up (missed at least one follow-up).
Of the 109 women included in the study, 58 (53%) completed all follow-up, 34 (31%) had incomplete follow-up, and 17 (16%) were lost to follow-up after day 0. Of those who had complete follow-up, 15 (26%, 95% confidence interval [CI] [16-38]) had parasitological failure. For the 92 women included in the survival analysis, median age was 20 years (interquartile range [IQR] 18-22), median gestational age was 22 weeks (IQR range 20-24), and 57% were primigravid. There was no difference in time to failure in primigravid versus multigravid women. Of the 84 women with complete haplotype data for the aforementioned loci of the dhfr and dhps genes, 53 (63%, 95% CI [50-70]) had quintuple mutants (two with an additional mutation in A581G of dhps). Among women with complete follow-up and quintuple mutants, 22% had parasitological failure versus 0% without (p = 0.44).
While underpowered, this study found 26% failure rates of SP given the moderate prevalence of the quintuple mutant haplotype. Despite the presence of resistance, SP retained some efficacy in clearing parasites in pregnant women, and may remain a viable option for IPTp in Zambia.
孕期使用磺胺多辛-乙胺嘧啶（SP）进行疟疾间歇性预防治疗（IPTp）可降低孕期疟疾的不良影响。赞比亚于2003年实施了其IPTp-SP项目。耐SP的恶性疟原虫的出现威胁到了这一策略。五重突变单倍型（二氢叶酸还原酶基因中的N51I、C59R、S108N以及二氢蝶酸合成酶基因中的A437G和K540E替换）与非孕期疟疾患者的SP治疗失败相关。本研究考察了赞比亚曼萨地区孕妇中IPTp-SP的疗效以及五重突变的存在情况。
在疟疾传播率高的曼萨地区，招募前往两家产前诊所接受首剂IPTp-SP且无症状寄生虫血症的HIV阴性孕妇，并在五周内每周进行一次寄生虫血症镜检。结局指标为寄生虫学治疗失败和充分的寄生虫学反应（随访期间无寄生虫血症）。采用聚合酶链反应检测来区分复发与再感染，并鉴定SP耐药的分子标志物。生存分析纳入了发生再感染和随访不完整（至少错过一次随访）的患者。
纳入研究的109名女性中，58名（53%）完成了所有随访，34名（31%）随访不完整，17名（16%）在第0天之后失访。在完成随访的患者中，15名（26%，95%置信区间[CI][16 - 38]）出现了寄生虫学治疗失败。在纳入生存分析的92名女性中，中位年龄为20岁（四分位间距[IQR]18 - 22），中位孕周为22周（IQR范围20 - 24），57%为初产妇。初产妇和经产妇的治疗失败时间无差异。在上述二氢叶酸还原酶和二氢蝶酸合成酶基因位点具有完整单倍型数据的84名女性中，53名（63%，95%CI[50 - 70]）有五重突变（两名在二氢蝶酸合成酶的A581G处有额外突变）。在完成随访且有五重突变的女性中，22%出现了寄生虫学治疗失败，而无五重突变的女性中这一比例为0%（p = 0.44）。
尽管本研究样本量不足，但鉴于五重突变单倍型的中等流行率，发现SP的失败率为26%。尽管存在耐药性，SP在清除孕妇体内寄生虫方面仍保留了一定疗效，可能仍是赞比亚IPTp的一个可行选择。
