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First 2 Reports of Bictegravir in Pregnancy Suggest Efficacy
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International Workshop on Clinical Pharmacology of HIV, Hepatitis and Other Antiviral Drugs, September 20-22, 2021
By Mark Mascolini for NATAP and Virology Education
Although plasma levels of the integrase inhibitor bictegravir were moderately lower in the third trimester of pregnancy than after delivery, analysis of 2 mother-infant pairs suggests a bictegravir regimen can thwart perinatal transmission of HIV [1]. Cord blood/maternal blood ratios at delivery indicate that bictegravir crosses the placenta.
Guidelines do not recommend bictegravir for pregnant women because little is known about the safety and efficacy of this integrase inhibitor in preventing perinatal transmission of HIV. To begin a safety and efficacy database, European PANNA study researchers reported the first two cases of bictegravir taken by pregnant women.
PANNA is an ongoing, open-label, multicenter, observational study of antiretrovirals taken during pregnancy by women recruited in European clinics [2]. PANNA collaborators try to collect samples in the third trimester, at delivery, and several weeks after delivery. This study involved 2 women taking a regimen containing 50 mg of bictegravir once daily who had intensive steady-state sampling after an observed dose at gestation week 33, one of whom gave samples 6 weeks after delivery.
The first person, a 33-year-old black woman, had switched from another regimen to bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) 8 months before conception. The second woman was a 30-year-old white woman who had switched from darunavir//cobicistat/F/TAF to B/F/TAF 2 months after conception. In the second trimester the first woman weighed 106 kg and the second woman 53 kg.
At 33 weeks gestation bictegravir 24-hour area under the concentration-time curve (AUC0-24) in the first woman lay at 37.9 h*mg/L, trough concentration (Ctrough) at 0.63 mg/L, and maximum concentration (Cmax) at 3.82 mg/L. Compared with postpartum levels in this woman, these 33-week concentrations were 35%, 49%, and 19% lower-decreases the researchers characterized as "modest." But they noted that the exposure-response target for bictegravir has not been established, so it remains difficult to determine the clinical relevance of this lower bictegravir exposure in pregnancy.
At 33 weeks the second woman had a concentration of 1.63 mg/L just after unobserved drug intake and a Cmax of 4.84 mg/L. But concentrations 4 hours after the 33-week dose and postpartum levels were missing, so the researchers could not calculate other values.
The reported Ctrough in the first woman, 0.63 mg/L, corresponded to the Ctrough seen when people took twice-daily bictegravir with rifampin (0.61 mg/L) in another study [3], a trough considered undesirable. But the recorded 0.63 mg/L lay well above the protein-adjusted 95% inhibitory concentration of 0.16 mg/L [4].
Cord-to-plasma bictegravir concentration ratio was 1.49 in the first woman and 1.42 in the second woman about 20 and 7 hours after dosing. These ratios indicate that bictegravir crossed the placenta in these women.
Both women had a plasma viral load below 50 copies in the third trimester, and both babies were healthy and had a negative HIV DNA PCR. The first was a 2560-g girl naturally delivered at 38 weeks, the second a 2965-g boy naturally delivered at 40 weeks (considered small for gestational age).
References
1. Bukkems V, Hidalgo-Tenorio C, Garcia C, et al. First reported use of bictegravir in two pregnant women living with HIV. Clinical Pharmacology of HIV, Hepatitis and Other Antiviral Drugs 2021. September 20-22, 2021. Abstract 19.
2. PANNA. https://www.pannastudy.com/
3. Custodio JM, West SK, Collins S, et al. Pharmacokinetics of bictegravir administered twice daily in combination with rifampin. Conference on Retroviruses and Opportunistic Infections. 25th CROI. Boston, March 4-7, 2018. Abstract 34.
4. Tsiang M, Jones GS, Goldsmith J, et al. Antiviral activity of bictegravir (GS-9883), a novel potent HIV-1 integrase strand transfer inhibitor with an improved resistance profile. Antimicrob Agents Chemother. 2016;60:7086-7097. doi: 10.1128/AAC.01474-16. https://pubmed.ncbi.nlm.nih.gov/27645238/
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