Reduced exposure to elvitegravir in pregnancy: results from the PANNA Network
29 June 2018. Related: Conference reports, Pregnancy, PK and drug interactions, PK Workshop 19th 2018 Baltimore.
Polly Clayden, HIV i-Base
Preliminary data from a small pharmacokinetic (PK) study suggests exposure to elvitegravir is lower during the third trimester of pregnancy than postpartum. [1]
These results are in line with those from IMPAACT and support caution for its initial use in pregnancy. [2, 3, 4]
PANNA is an open-label, multi-centre, observational, phase 4 study in HIV positive pregnant women recruited in HIV treatment centres in Europe. The findings were presented at the 19th International Workshop on Clinical Pharmacology
Participants receiving elvitegravir/cobicistat 150/150mg + 2 NRTIs (86% TDF/FTC) once daily during pregnancy had intensive steady-state 24-hour PK-profiling in the third trimester and 5–7 weeks postpartum. Optional cord and matching maternal blood samples were taken at delivery. Seven participants with a median age of 32 years (range 25–40) years were included in the analysis.
Geometric mean ratios of PK parameters during the third trimester/postpartum were: 0.67 h*mg/L (90% CI: 0.47 to 0.96) for AUC0-24; 0.79 mg/L (90% CI: 0.61 to 1.02) for Cmax; 0.35 mg/L (90% CI: 0.0.16 to 0.76) for Ctrough.
Five out of seven participants had a sub-therapeutic Ctrough in the third trimester, one out of six postpartum. The median cord/maternal elvitegravir plasma concentration ratio (n=4) was 0.87 mg/L (range 0.3 to 1.2) – indicating substantial foetal exposure around delivery.
During pregnancy 71% of the participants had sub-therapeutic Ctrough versus 17% postpartum.
The investigators noted that cobicistat exposure was 56% lower during pregnancy, which might have led to less boosting, increased elvitegravir clearance and, in turn, lower exposure.
Approaching delivery 6/7 (86%) participants had viral load <50 copies/mL; one participant had a viral load of 6363 copies/mL six weeks before delivery.
There were no serious adverse events or birth defects in this small study and all infants were HIV negative.
comment
These PK results are similar to those presented previously by the IMPAACT Network, based on which, US DHHS perinatal guidelines do not recommend elvitegravir/cobicistat for initial use in pregnancy.
The upcoming BHIVA guidelines will recommend that elvitegravir/cobicistat may be continued with close monitoring if a woman receiving it with undetectable viral load becomes pregnant but not do recommend starting in pregnancy.
POSTSCRIPT: In March 2019 Gilead issue a Dear Doctor letter noting that elvitegravir/cobicistat should not be continued during pregnancy and that women should be changed to an alternative combination.
References
- Colbers A et al. Elvitegravir pharmacokinetics during pregnancy and postpartum.19th International Workshop on Clinical Pharmacology, 22–24 May 2018, Baltimore. Oral abstract 17.
http://regist2.virology-education.com/presentations/2018/Antiviralpk/19_colbers.pdf (PDF) - Best B et al.Elvitegravir/cobicistat pharmacokinetics in pregnancy and postpartum. CROI 2017. Seattle, Washington. February 13–16, 2017. Poster abstract 755.
http://www.croiconference.org/sessions/elvitegravircobicistat-pharmacokinetics-pregnancy-and-postpartum - US DHHS. Recommendations for the use of antiretroviral drugs in pregnant women with HIV infection and interventions to reduce perinatal HIV transmission in the United States. 30 May 2018.
https://aidsinfo.nih.gov/guidelines/html/3/perinatal/224/whats-new-in-the-guidelines - Clayden P. Key changes to upcoming UK HIV pregnancy guidelines (2018). HTB. 1 May 2018.
https://i-base.info/htb/34013