IAS 2023: Bictegravir use in pregnancy: more data needed

Polly Clayden, HIV i-Base

Despite comparatively lower exposure to bictegravir, emtricitabine and tenofovir alafenamide during pregnancy, compared with postpartum, all participants remained undetectable in a small study presented at IAS 2023. [1]

Bictegravir (BIC), emtricitabine (FTC) and tenofovir alafenamide (TAF) is available as an adult fixed-dose combination (B/F/TAF) from the originator company and is widely used in high-income countries.

But there are limited data on B/F/TAF PK, safety and efficacy in pregnancy and although these data are reassuring and suggest B/F/TAF does not need a dose adjustment, information to guide its use is still lacking. 

BIC is highly protein bound and metabolised by UGT1A1 and CYP3A4. Increased activities of these enzymes, as well as alterations in protein binding and other physiological changes, have been reported in pregnancy.

Investigators from Gilead conducted a dedicated, open-label study in 33 pregnant women living with HIV. All participants had an undetectable viral load (less than 50 copies/mL) at the start of the study.

The primary objective was to evaluate steady state of BIC and confirm the dose of B/F/TAF (50/200/25 mg once-daily) in the second and third trimesters of pregnancy. The study also evaluated steady state PK of FTC and TAF and the maintenance of an undetectable viral load during the second and/or third trimesters.

Steady-state intensive plasma samples were collected over 24 hours post-dose of B/F/TAF during second and/or third trimesters of pregnancy and 6 and 12 weeks postpartum.

BIC and TAF, plasma protein binding was measured. As was tenofovir diphosphate in PBMCs. Cord blood was collected at delivery (BIC and TAF).

BIC concentrations were lower during pregnancy vs postpartum but similar within each period: second vs third trimester and 6 vs 12 weeks postpartum.

Individual Ctrough values were greater than IQ1 (0.162 ug/mL) across each of the four periods, apart from in one participant during the second trimester (who remained undetectable). Median Ctrough was 6.9- and 6 -fold of IQ1 during the second and third trimesters, respectively.

Total mean (%CV) AUCtau h*ug/mL was 62.8 (32.2), 60.2 (29.1), 135 (26.9) and 148 (28.5) in second and third trimester and week 6 and 12 postpartum, respectively. Exposure levels in pregnancy were closer to those in non-pregnant adults: mean (%CV) 102 (26.9). Mean total BIC AUCtau in the third trimester was approximately 41% lower than in non-pregnant adults.

Plasma FTC exposures were lower in pregnancy than postpartum: %GLSM ratio for total AUCtau ranged from 64.3% to 69.2%.

Plasma TAF exposures were also lower in pregnancy than postpartum: %GLSM ratio for total AUCtau ranged from 56.5% to 77.6%. When adjusted for changes in protein binding, %GLSM ratio for unbound AUCtau ranged from 83.6% to 89.3%. Trough tenofovir diphosphate levels in PBMCs were generally similar (but variable) during pregnancy and postpartum.

The investigators noted that US pregnancy guidelines state that no dose adjustment is require for TAF or FTC during pregnancy.

For BIC mean (%CV) cord blood to maternal blood plasma concentration ratio was 1.4 (35%). Median t1/2 in neonates was 43.1 hours, which is longer than that in adults (approximately 18 hours across postpartum). The investigators noted that other BIC PK parameters in neonates were not calculable or meaningful.

All adult participants (n=32) had undetectable viral load at delivery and through 18 weeks postpartum. CD4 and CD4% remained stable for adult participants throughout.

B/F/TAF was generally well-tolerated in adults and neonates (n=29). The majority of AEs were grade 1/2. There were no discontinuations due to AEs.

The investigators concluded: “Data from this study and available evidence suggest the suitability of once-daily B/F/TAF use throughout pregnancy, including the second and third trimesters, and indicate that no dose change is needed.”

comment

The “available evidence” to which this conclusion refers is one poster presentation at CROI earlier this year, from the BIC study arm of IMPAACT 2026.  This is an ongoing, open-label, parallel-group, multi-centre phase 4 prospective study of antiretroviral PK in pregnant women living with HIV.

Data from the 27 mother-infant pairs in this study similarly reported lower total BIC exposure in pregnancy but all C24 concentrations were above the estimated BIC protein-adjusted EC95 value of approximately 0.162 mcg/mL and 90% of participants were virally suppressed at delivery.

Apart from this, the Antiretroviral Pregnancy Registry (APR) reports 14/324 birth defects with first trimester BIC exposure prospective cases with follow-up data through 31 January 2023: prevalence 4.3% (95% CI 2.4 to 7.1%). [3] This is slightly higher than most antiretrovirals (and the upper bound of the confidence interval is the same as ddI).

For the US perinatal guidelines, the panel uses a longstanding, systematic approach to evaluating birth defect risk for all antiretrovirals. [4]

In order to determine whether a drug has an increased risk of a rare birth defect, data from more than 2,000 periconception exposures are needed to rule out a threefold increase in risk. Data from more than 1,000 first-trimester exposures are needed to rule out a 1.5-fold increase in the risk of overall birth defects and a twofold increase in the risk of the most common classes (cardiovascular and genitourinary) of birth defects.

So the conclusion above that: “Data from this study and available evidence suggest the suitability of once-daily B/F/TAF use throughout pregnancy, including the second and third trimesters…” seems like over-interpretation of what is currently available on the safety of BIC in pregnancy.   

Surely the experience with dolutegravir (and before that efavirenz) emphasised the importance of obtaining sufficient data about antiretroviral drugs in pregnancy.

Although BIC is not a priority for low- and middle-income countries, where most pregnancies in women living with HIV occur, according to Fierce Pharma in 2022 (based on sales): “If it weren’t for COVID-19, Gilead Sciences’ HIV triplet Biktarvy would still be the world’s best-selling pharmaceutical product for an infectious disease”, and “ the highest level of market share any complete regimen has ever achieved in the US”. [5]

So it doesn’t seem unreasonable to ask why there is so little information to guide its use in pregnancy, considering B/F/TAF was approved over five years ago. [6]

And bictegravir is far from an isolated case.

NB: This study has now been published in the journal AIDS. [5]

1. Zhang H et al. Pharmacokinetics, safety, and efficacy of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) in virologically suppressed pregnant women with HIV. IAS 2023, 23–26 July 2023, Brisbane, Australia. Oral abstract 681.
   https://ias.reg.key4events.com/key4register/AbstractList.aspx?e=96&preview=1&aig=-1&ai=51111 (abstract)
   Prioritizing the clinical HIV care of women and children in 2023:
   https://conference.ias2023.org/media-1090-prioritizing-the-clinical-hiv-care-of-women-and-children-in-2023 (webcast)
2. Powis KM et al. Pharmacokinetics and virologic outcomes of bictegravir in pregnancy and postpartum. CROI 2023. 19–22 February 2023. Seattle, Washington. Poster abstract 783.
   https://www.croiconference.org/abstract/pharmacokinetics-and-virologic-outcomes-of-bictegravir-in-pregnancy-and-postpartum/ (abstract)
   https://www.croiconference.org/wp-content/uploads/sites/2/posters/2023/IMPAACT_PHARMACOKINETICS_AND_VIROLOGIC_15Feb23-133209845782009090.pdf
3. The Antiretroviral Pregnancy Registry interim report. 1 January 1989 through 31 January 2023.
   https://www.apregistry.com/forms/interim_report.pdf
4. Recommendations for the use of antiretroviral drugs during pregnancy and interventions to reduce perinatal HIV transmission in the United States. 31 January 2023.
   https://clinicalinfo.hiv.gov/en/guidelines/perinatal/whats-new
5. Fierce Pharma. The top 20 drugs by worldwide sales in 2021. (31 May 2022).
   https://www.fiercepharma.com/special-reports/top-20-drugs-worldwide-sales-2021
6. Gilead press release. US Food and Drug Administration approves Gilead’s Biktarvy (bictegravir, emtricitabine, tenofovir alafenamide) for treatment of HIV-1 infection. (7 February 2018).
   https://www.gilead.com/news-and-press/press-room/press-releases/2018/2/us-food-and-drug-administration-approves-gileads-biktarvy
7. Zhang H et al. A study of the pharmacokinetics, safety, and efficacy of bictegravir/emtricitabine/tenofovir alafenamide in virologically suppressed pregnant women with HIV. AIDS ():10.1097/QAD.0000000000003783, November 08, 2023. DOI: 10.1097/QAD.0000000000003783.

This report was first posted on 13 September 2023.