Two cases of neural tube defects with dolutegravir use at conception in south Brazil

Kreitchmann, Régis; Oliveira, Fernando Rocha de; Sprinz, Eduardo

doi:10.1016/j.bjid.2021.101572

Cited by 7 publications

(2 citation statements)

References 9 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Works outlined in this report provide unique insights into the underlying mechanisms linked to such adverse events. Recently, clinical and pre-clinical studies reported a potential association between DTG usage at the time of conception and NTDs ( Hill et al, 2018 ; Raesima et al, 2019 ; Zash et al, 2019 ; Kreitchmann et al, 2021 ) and postnatal neurological abnormalities( Crowell et al, 2020 ). Due to mass usage of DTG-based regimens worldwide, reports highlighted the need to find an underlying mechanism of potential DTG-related adverse neurodevelopmental outcomes.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of matrix metalloproteinases by HIV-1 integrase strand transfer inhibitors

et al. 2023

View full text Add to dashboard Cite

More than fifteen million women with the human immunodeficiency virus type-1 (HIV-1) infection are of childbearing age world-wide. Due to improved and affordable access to antiretroviral therapy (ART), the number of in utero antiretroviral drug (ARV)-exposed children has exceeded a million and continues to grow. While most recommended ART taken during pregnancy suppresses mother to child viral transmission, the knowledge of drug safety linked to fetal neurodevelopment remains an area of active investigation. For example, few studies have suggested that ARV use can be associated with neural tube defects (NTDs) and most notably with the integrase strand transfer inhibitor (INSTI) dolutegravir (DTG). After risk benefit assessments, the World Health Organization (WHO) made recommendations for DTG usage as a first and second-line preferred treatment for infected populations including pregnant women and those of childbearing age. Nonetheless, long-term safety concerns remain for fetal health. This has led to a number of recent studies underscoring the need for biomarkers to elucidate potential mechanisms underlying long-term neurodevelopmental adverse events. With this goal in mind, we now report the inhibition of matrix metalloproteinases (MMPs) activities by INSTIs as an ARV class effect. Balanced MMPs activities play a crucial role in fetal neurodevelopment. Inhibition of MMPs activities by INSTIs during neurodevelopment could be a potential mechanism for adverse events. Thus, comprehensive molecular docking testing of the INSTIs, DTG, bictegravir (BIC), and cabotegravir (CAB), against twenty-three human MMPs showed broad-spectrum inhibition. With a metal chelating chemical property, each of the INSTI were shown to bind Zn++ at the MMP’s catalytic domain leading to MMP inhibition but to variable binding energies. These results were validated in myeloid cell culture experiments demonstrating MMP-2 and 9 inhibitions by DTG, BIC and CAB and even at higher degree than doxycycline (DOX). Altogether, these data provide a potential mechanism for how INSTIs could affect fetal neurodevelopment.

show abstract

Section: Discussionmentioning

confidence: 99%

Inhibition of matrix metalloproteinases by HIV-1 integrase strand transfer inhibitors

et al. 2023

View full text Add to dashboard Cite

show abstract

“…Bone mineral density testing is recommended for at-risk populations such as postmenopausal women, older men, and individuals with a history of fractures or hypogonadism [ 55 ]. Dolutegravir- (DTG-) based regimens were initially not advised for pregnant women or those looking to conceive [ 55 , 71 ] because preliminary data indicated an increased risk of neural tube defects in infants born to those receiving DTG at the time of conception [ 72 , 73 ]. However, updated results from the same study [ 74 ] showed lower prevalence of neural tube defects following DTG exposure than initial estimates; neural tube defect prevalence in infants born to women on DTG at conception was nonsignificantly higher than any other non-DGT antiretrovirals (0.06% difference; 95% CI 0.03–0.20) [ 74 ].…”

Section: Considerations For the Use Of Art For Late Presentersmentioning

confidence: 99%

HIV Late Presenters in Asia: Management and Public Health Challenges

Wong

Wei

Kim

2023

AIDS Research and Treatment

View full text Add to dashboard Cite

Many individuals are diagnosed with human immunodeficiency virus (HIV) infection at an advanced stage of illness and are considered late presenters. We define late presentation as a CD4 cell count below 350 cells/mm3 at the time of HIV diagnosis, or presenting with an AIDS-defining illness regardless of CD4 count. Across Asia, an estimated 34–72% of people diagnosed with HIV are late presenters. HIV late presenters generally have a higher disease burden and higher comorbidity such as opportunistic infections than those who are diagnosed earlier. They also have a higher mortality rate and generally exhibit poorer immune recovery following combined antiretroviral therapy (cART). As such, late HIV presentation leads to increased resource burden and costs to healthcare systems. HIV late presentation also poses an increased risk of community transmission since the transmission rate from people unaware of their HIV status is approximately 3.5 times higher than that of early presenters. There are several factors which contribute to HIV late presentation. Fear of stigmatisation and discrimination are significant barriers to both testing and accessing treatment. A lack of perceived risk and a lack of knowledge by individuals also contribute to late presentation. Lack of referral for testing by healthcare providers is another identified barrier in China and may extend to other regions across Asia. Effective strategies are still needed to reduce the incidence of late presentation across Asia. Key areas of focus should be increasing community awareness of the risk of HIV, reducing stigma and discrimination in testing, and educating healthcare professionals on the need for early testing and on the most effective ways to engage with people living with HIV. Recent initiatives such as intensified patient adherence support programs and HIV self-testing also have the potential to improve access to testing and reduce late diagnosis.

show abstract