Dolutegravir and neural tube defects: a new insight.

Dolutegravir is a highly effective antiretroviral therapy (ART) allowing a fast viral load decrease, which is promising in low-income and middle-income countries.1Dorward J Lessells R Drain PK et al.Dolutegravir for first-line antiretroviral therapy in low-income and middle-income countries: uncertainties and opportunities for implementation and research.Lancet HIV. 2018; 5: e400-e404Summary Full Text Full Text PDF PubMed Scopus (52) Google Scholar However, according to preliminary results from a nationwide birth surveillance programme in Botswana,2Zash R Makhema J Shapiro RL Neural-tube defects with dolutegravir treatment from the time of conception.N Engl J Med. 2018; 379: 979-981Crossref PubMed Scopus (218) Google Scholar it has been associated with the development of neural tube defects in newborn babies. Incidence of neural tube defects in the newborn babies of women who were taking dolutegravir at the time of conception was estimated to be 0·94% (95% CI 0·37–2·4). Updated results from this cohort3Zash R Holmes L Diseko M et al.Neural-tube defects and antiretroviral treatment regimens in Botswana.N Engl J Med. 2019; 381: 827-840Crossref PubMed Scopus (187) Google Scholar still showed a slightly increased incidence of neural tube defects of 0·3% (0·13–0·69) among newborn babies of women given dolutegravir at conception, compared with 0·10% (0·06–0·17) among those given any non-dolutegravir ART. These additional data were highly awaited since the communication in May, 2018, of the preliminary results led to a worldwide safety signal on dolutegravir.4WHOStatement on DTG—Geneva 18 May 2018. World Health Organization, Geneva2018https://www.who.int/medicines/publications/drugalerts/Statement_on_DTG_18May_2018final.pdfDate accessed: February 14, 2020Google Scholar Since then, studies done in several other cohorts have not confirmed this signal.5Chouchana L Beeker N Treluyer J-M Is there a safety signal for dolutegravir and integrase inhibitors during pregnancy?.J Acquir Immune Defic Syndr. 2019; 81: 481-486Crossref PubMed Scopus (10) Google Scholar Nonetheless, these studies, done in high-income countries (eg, Canada, Germany, France, and the UK) included few exposed pregnancies. A review of neural tube defect cases has also been done on pharmacovigilance databases; however, this review lacks data on dolutegravir exposure in pregnant women necessary to make any conclusion.6van De Ven NS Pozniak AL Levi JA et al.Analysis of pharmacovigilance databases for dolutegravir safety in pregnancy.Clin Infect Dis. 2019; (published online Oct 9.)DOI:10.1093/cid/ciz684Crossref PubMed Scopus (12) Google Scholar To provide additional information, we analysed the reporting of neural tube defects in the WHO pharmacovigilance database (VigiBase). This worldwide database includes more than 20 million individual case safety reports from over 130 countries,7Lindquist M VigiBase, the WHO Global ICSR database system: basic facts.Drug Inf J. 2008; 42: 409-419Crossref Scopus (365) Google Scholar which makes it a very powerful tool to do disproportionality analyses.8Montastruc J-L Sommet A Bagheri H Lapeyre-Mestre M Benefits and strengths of the disproportionality analysis for identification of adverse drug reactions in a pharmacovigilance database.Br J Clin Pharmacol. 2011; 72: 905-908Crossref PubMed Scopus (253) Google Scholar Our pharmacovigilance statistical approach, in which we used a case–non-case method, estimates whether an adverse event is differentially reported for a specific drug compared with other drugs. The association can be expressed using the odds ratio (OR) of reporting, which shows the advantages of this measure in the detection of safety signals.9Rothman KJ Lanes S Sacks ST The reporting odds ratio and its advantages over the proportional reporting ratio.Pharmacoepidemiol Drug Saf. 2004; 13: 519-523Crossref PubMed Scopus (355) Google Scholar To shorten possible indication bias, our analysis was restricted to individual case safety reports related to adult women—ie, aged 18–64 years according to VigiBase classes—and when patient sex was not reported, related to adverse events in the spectrum of congenital disorders. From 2012 (the year of the first individual case safety report for dolutegravir in VigiBase) to Sept 30, 2019, 17 cases of neural tube defects were reported for dolutegravir-containing regimens (anencephaly n=8, meningocele n=5, meningomyelocele n=1, spina bifida without details n=1, iniencephaly n=1, and encephalocele n=1). When comparing reporting for dolutegravir to that for all other ARTs, the OR of reporting for neural tube defects was 6·4 (95% CI 3·7–10·9), and was 10·4 (4·9–21·6) when using efavirenz-containing regimens as the reference (appendix). Interestingly, all the cases of dolutegravir-related neural tube defects were reported after the broadcast of the safety signal on neural tube defects in May, 2018. All except one case were recorded from the USA (three clusters of cases in August, 2018, and April and August, 2019); the other case originated from Botswana in February, 2019. Conversely, before May, 2018, five cases of neural tube defects were reported for efavirenz and 40 for other ARTs (appendix). OR of reporting for efavirenz-related neural tube defects using all other ARTs as reference was 0·3 (0·1–0·7) before May 2018, and 0·4 (0·2–0·7) for the overall period (appendix). Overall, the recent reporting waves could reflect a notoriety bias for dolutegravir after the safety communication, a well known phenomenon regarding spontaneous reporting that could have resulted in inflating the OR of reporting for dolutegravir-related cases of neural tube defects.10Pariente A Gregoire F Fourrier-Reglat A Haramburu F Moore N Impact of safety alerts on measures of disproportionality in spontaneous reporting databases: the notoriety bias.Drug Saf. 2007; 30: 891-898Crossref PubMed Scopus (170) Google Scholar Altogether, we believe that worldwide pharmacovigilance data do not provide strong support concerning the neural tube defects signal with dolutegravir. We declare no competing interests. The information from VigiBase comes from a variety of sources, and the probability that the suspected adverse effect is drug-related is not the same in all cases. The information does not represent the opinion of the Uppsala Monitoring Centre or WHO, and only reflects the authors’ opinion. For VigiBase website see https://www.who-umc.org/vigibase/vigibase/ For VigiBase website see https://www.who-umc.org/vigibase/vigibase/ Download .pdf (.23 MB) Help with pdf files Supplementary appendix Extended-spectrum β-lactamase-producing Escherichia coli in human-derived and foodchain-derived samples from England, Wales, and Scotland: an epidemiological surveillance and typing studyMost human bacteraemias with ESBL-E coli in the UK involve internationally prevalent human-associated STs, particularly ST131; non-human reservoirs made little contribution to invasive human disease. Any interventions that seek to target food or livestock can affect the numbers of human infections caused by ESBL-E coli; prevention of the spread of resistant lineages among humans is more vital. Full-Text PDF Open AccessEscherichia coli causing bloodstream and other extraintestinal infections: tracking the next pandemicIn The Lancet Infectious Diseases, Michaela J Day and colleagues1 present the results of a large genomic epidemiology study that asks whether a food source exists for extended-spectrum β-lactamase-producing Escherichia coli isolates (ESBL-E coli) that cause bloodstream infections in the UK. This question is controversial, with evidence both for and against the food-source hypothesis.2,3 Disagreements tend to revolve around the discriminatory power of genotyping approaches used to characterise E coli and on the scope and appropriateness of E coli sampling from human and non-human sources in past molecular epidemiology studies. Full-Text PDF Open Access