Breakthrough HIV viraemia on bictegravir/emtricitabine/tenofovir alafenamide in the third trimester of pregnancy

Bictegravir is a second-generation HIV-1 integrase strand transfer inhibitor (INSTI) with potent antiviral activity. It is marketed as a single-tablet regimen in co-formulation with tenofovir alafenamide and emtricitabine.1 While a preferred therapy in many guidelines, and rarely associated with virologic breakthrough, data regarding efficacy and safety in pregnancy is limited.2,3 Here, we present the first known case of breakthrough HIV viraemia while on bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) during the third trimester of pregnancy. This gravida 3, para 2 (G3P2) 38-year-old female, originally from Burma, immigrated to Canada in 2011. She was diagnosed with HIV after screening blood work done for immigration purposes. She had no history of recreational/illicit drug use. Her pre-therapy viral load was >1 × 106 copies/mL. Genotyping and resistance testing revealed Clade C virus with a 179D NNRTI resistance mutation. She was on efavirenz/emtricitabine/tenofovir disoproxil fumarate (EFV/FTC/TDF) from 2011 until 2016 when she was switched to elvitegravir/cobicistat/emtricitabine/tenofovir (EVG/CBG/FTC/TAF) due to sleeping difficulties. In April 2022 she was switched to bimonthly cabotegravir/rilpivirine. Her viral load remained undetectable throughout this time, and her CD4 count ranged between 300 and 400 × 106 cells/L. She became pregnant in August 2022, and therapy was switched to bictegravir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF) daily at gestational age of 15 weeks due to lack of safety and efficacy data of cabotegravir/rilpivirine in pregnancy. Other medications included prenatal multivitamins taken 6 h apart from cabotegravir/rilpivirine. Her viral load and CD4 count timeline are summarized in Table 1. Viral load and CD4 count timeline GA, gestational age; PP, post-partum; TND, target not detected. Viral load and CD4 count timeline GA, gestational age; PP, post-partum; TND, target not detected. In January 2023, at 36 + 2 weeks’ gestation, her viral load had risen from undetectable to 547 copies/mL. At this time, the plasma drug level 18 h post-dose was measured, and bictegravir was reported low at 1.327 μg/mL. Cabotegravir was still detected at 98 ng/mL despite the last dose of cabotegravir being received 7 months prior. Resistance testing was done and reported no INSTI or NRTI resistance mutations. The 179D mutation was again detected. Her peak viral load was 1180 copies/mL at 27 + 2 weeks’ gestation. She was noted to be taking an iron supplement for iron deficiency anaemia, separated 12 h from BIC/FTC/TAF. Despite appropriate coadministration, iron was discontinued and BIC/FTC/TAF was instructed to be taken with food. Adherence assessed through patient self-report and pharmacy refill confirmed high-level adherence. At 38 + 2 weeks’ gestation, her regimen was changed to dolutegravir 50 mg twice daily, emtricitabine/tenofovir disoproxil fumarate 200/300 mg daily, darunavir/cobicistat 800/150 mg daily. At the time of delivery, the viral load was measured at 28.2 copies/mL. She delivered a 3400 g live male baby via Caesarean section without complications. There was no vertical transmission based on RNA/DNA PCR performed at birth, 2 weeks, and 1, 2 and 4 months of age. Two months after delivery, ART was simplified back to BIC/FTC/TAF with virological suppression confirmed 1 and 4 months following this change in antiretroviral regimen. Alterations in drug pharmacokinetics during pregnancy can be attributed to modifications in gastric motility and pH, increased volume of distribution, and variations in plasma proteins, such as albumin and alpha glycoproteins. The up-regulation of cytochrome p450 enzymes and uridine diphosphate-glucuronosyltransferase (UGT) enzymes during the second and third trimesters may also contribute to heightened drug clearance. The cumulative impact of these physiological changes during pregnancy is anticipated to lead to a decrease in drug levels4,5 There remains a paucity of safety, efficacy and pharmacokinetic data on the use of bictegravir in pregnancy. However, recent data from an open-label, multicentre, single-arm, Phase 1b study of 33 virologically suppressed pregnant women with HIV-1 on BIC/FTC/TAF showed that while areas under the concentration–time curve over the dosing interval for bictegravir, emtricitabine and tenofovir were lower during pregnancy versus post-partum, mean bictegravir trough concentrations remained over 6.5-fold greater than the protein-adjusted 95% effective concentration (EC95). Furthermore, host virological suppression was maintained.6 This is consistent with other published data on the pharmacokinetics of bictegravir in pregnancy.7,8 Based on this evidence, bictegravir is now recommended as an alternative antiretroviral for use in pregnancy, in addition to dolutegravir- and darunavir/ritonavir-based regimens.2,6 To date, this case is the first report of virological breakthrough associated with reduced exposure of bictegravir during pregnancy. Viral load increased steadily to 1180 copies/mL and prompted immediate changes to an antiretroviral regimen, which led to viral suppression (viral load of 28.2 copies/mL) at the time of birth. No bictegravir resistance-associated mutation was detected and BIC/FTC/TAF was resumed effectively post-partum. Thus, pharmacokinetic changes in pregnancy were felt to be the most likely contribution to this patient’s breakthrough viraemia, despite bictegravir exposure being eight times above the EC95 value of 0.162 μg/mL.9 Overall, this case illustrates that a greater understanding of bictegravir pharmacokinetics (and perhaps that of other antiretroviral agents) is needed to optimally guide management of HIV infection during pregnancy. We would like to thank Chanson Brumme at the BCCFE for performing the bictegravir level testing on this patient. This study was carried out as part of our routine work. None of the authors declared any conflict of interest for the submitted work. J.B.A. has received support for contract research and has served on advisory boards for Gilead Sciences and ViiV Healthcare. P.G. has served on advisory boards for Gilead Sciences and ViiV Healthcare. M.M. has served on advisory boards for Gilead Sciences.

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