What will it take to refute the possible safety signal for dolutegravir and neural tube defects?
What will it take to refute the possible safety signal for dolutegravir and neural tube defects?
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如何反驳多替拉韦和神经管缺陷可能存在的安全信号？
DOI：
10.1111/1471-0528.15864
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发表时间：
2019
期刊：
影响因子：
--
通讯作者：
Zash,RM
中科院分区：
文献类型：
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作者：
Zash,RM
2018年5月，监管当局发布了关于神经管缺陷(NTD)与受孕时暴露于基于多洛替格列韦(DTG)的抗逆转录病毒疗法(ART)之间可能联系的警示声明，其依据是博茨瓦纳TSepamo研究的数据，该研究报告了在受孕时接触DTG的426例孕妇中有4例NTD，而在受孕时暴露于不含DTG的ART的11 300例孕妇中有11例NTD(Zash等人)。《新英格兰医学杂志》2019；379：979-81)。鉴于单一研究的事件数量很少，需要更多的数据来证实或驳斥这种联系。很难找到这些额外的数据，这突显了现有药物警戒系统的局限性，以及结合不同的数据来源以了解罕见但重要的事件的挑战。Money等人(BJOG 2019；126：1338-45)关于2007年至2017年加拿大艾滋病毒感染妇女所生婴儿出生缺陷的报告。在这10年期间，在受孕时有69人暴露于DTG；没有发现NTD。在加拿大，一个强制谷物叶酸强化的国家，NTD的总体流行率为每10000名新生儿中有4名。鉴于这种较低的NTD患病率和受孕时只有69次接触DTG，Money研究有大约8%的能力检测到DTG受孕后NTD增加10倍。由于缺乏对死产或终止妊娠的出生缺陷的确认，电力进一步减少；在博茨瓦纳，终止妊娠是不合法的，25%的NTDS是在死产婴儿中发现的。这项研究是评估有DTG暴露的NTDS的最大研究之一，但出现假阴性结果(第二类错误)的可能性仍然是90%。鉴于NTD的总体患病率较低，小型研究的负面结果不足以反驳这一信号。未来的荟萃分析可能会提高疗效，但由于方法学的可变性、结果确定的不完全以及各国在未孕叶酸补充和基线NTD患病率方面的差异，不确定性仍将存在。在博茨瓦纳以外，积累足够的数据来证实或驳斥这一信号将需要时间。随着DTG的进一步推出和新药的推出，在艾滋病毒流行率高的低资源环境中扩大药物警戒是至关重要的，因为大多数胎儿ART暴露发生在那里。对NTD信号的持续不确定使ART治疗决定更具挑战性，但并不一定排除在具有生育潜力的女性中使用DTG。基于DTG的抗逆转录病毒治疗有许多优势(Vitoria等人)。艾滋病2018年；32：1551-61)，模型表明在低收入和中等收入国家使用DTG对公共健康有很大好处，当与可能的小的绝对NTD风险进行权衡时(Dugdale等人。安实习生医院
In May 2018, regulatory authorities released cautionary statements about the possible association between neural tube defects (NTDs) and dolutegravir (DTG)-based antiretroviral therapy (ART) exposure at conception, based on data from the Tsepamo study in Botswana which reported four NTDs among 426 pregnancies exposed to DTG at conception, compared with 11 among 11 300 who were exposed to ART at conception that did not contain DTG (Zash et al. NEJM 2019; 379: 979–81). Given the small number of events from a single study, more data are needed to confirm or refute this association. Difficulty finding these additional data highlights limitations of existing pharmacovigilance systems and challenges of combining disparate sources of data to understand rare but important events. Money et al.(BJOG 2019; 126: 1338–45) report on birth defects among infants born to HIV-infected women in Canada from 2007 to 2017. During this 10-year period, there were 69 exposures to DTG at conception; no NTDs were identified. In Canada, a country with mandated grain folate fortification, overall NTD prevalence is 4 per 10 000 births. Given this low NTD prevalence and only 69 exposures to DTG at conception, the Money study has approximately 8% power to detect a ten-fold NTD increase with DTG conception exposure. Power is further reduced because of lack of birth defect ascertainment among stillbirths or pregnancy terminations; in Botswana, where termination of pregnancy is not legal, 25% of NTDs were detected in stillborn infants.Since May 2018, the Money et al. study is among the largest to evaluate NTDs with DTG exposure, but the chance of a false-negative result (type 2 error) remains> 90%. Given low overall NTD prevalence, negative results from small studies provide insufficient evidence to refute the signal. Future meta-analyses may improve power, but uncertainty will remain because of methodological variability, incomplete outcome ascertainment, and differences between countries in preconception folate repletion and baseline NTD prevalence. Outside of Botswana, accrual of sufficient data to confirm or refute the signal will take time. Expanding pharmacovigilance in low-resource settings with high HIV prevalence, where the majority of fetal ART exposures occur, is essential as DTG is further rolledout and new drugs become available. Ongoing uncertainly about the NTD signal makes ART treatment decisions more challenging but does not necessarily preclude DTG use among women of reproductive potential. DTG-based ART has many advantages (Vitoria et al. AIDS 2018; 32: 1551–61), and modelling suggests large public health benefits of DTG use in low-and middle-income countries when weighed against small possible absolute NTD risks (Dugdale et al. Ann Intern Med