- Discussion
- 10.1002/bdr2.2057
Author reply to Copp et al. (2022) correspondence.
- Jun 13, 2022
- Birth Defects Research
- Lorraine Posobiec
This author reply is in reference to the recent correspondence entitled “Dolutegravir and rat whole embryo culture” (Copp et al., 2022) regarding the article entitled “No developmental toxicity observed with dolutegravir in rat whole embryo culture” (Posobiec et al., 2021). Copp et al. did not include updated data (Zash, 2019) from the clinical study in Botswana. These data, with more pregnancy exposures, did not confirm earlier preliminary results, and any differences between incidences of neural tube defects (NTDs) in children of mothers given Dolutegravir-based (DTG) anti-retrovirals (ART) and versus non-DTG ARTs are not statistically significant. WHO guidelines currently recommend DTG-based ARTs as first-line therapy for women of childbearing potential based on a benefit/risk assessment (WHO, 2019). Copp et al also did not mention the article entitled “Absence of Developmental and Reproductive Toxicity in Animals Exposed to Dolutegravir” (Stanislaus et al., 2019), which presents a comprehensive set of standard size preclinical studies conducted under GLP conditions in two species covering the entire life cycle. Concerns about the article in EBioMedicine that Copp et al. refers to (Mohan et al., 2021) have been published (Romach, Posobiec, Bloomer, Zamek-Gliszczynski, & Stanislaus, 2021), including small increases in NTDS only in the lower dose group but not in the higher dose group, using a combination of dolutegravir and other compounds which was formulated by crushing pills with no dose formulation analysis and no single agent controls. The conclusion made is contrary not only to the principles of teratology and establishing causality but also to the previous preclinical work (Stanislaus et al., 2019). To address the concerns that Copp et al. has presented in the recent correspondence, first, the number of embryos used in the whole embryo culture study is typical for these types of studies; the rationale is discussed further in the article (Posobiec et al., 2021) and enhances the Stanislaus et al. work. Second, as further discussed in Posobiec et al., the percentage of DTG in the embryo is approximately 6%, consistent with a DTG placental transfer study. Third, the metabolite profile in humans was similar to rodents and rabbits. As human-specific metabolites were not present, no DTG metabolite qualification studies were needed in the in vivo studies (Stanislaus et al., 2019).
Read more
61