Off-Label Dosing of Long-Acting Injectable Cabotegravir and Rilpivirine during Pregnancy: A Case Study with Therapeutic Drug Monitoring

We report off-label monthly use of high-dose of long-acting intramuscular cabotegravir/rilpivirine (CAB/RPV= 600mg/900mg) administered preconceptionally and throughout pregnancy to a young woman with perinatally-acquired HIV, hematologic and cardiovascular comorbidities and class III obesity. Therapeutic drug monitoring for CAB and RPV were performed throughout the pregnancy and postpartum. At 7 weeks gestation, the plasma CAB and RPV C trough were 16 (2.58 mg/L) and 9 (0.11 mg/L) times above the respective protein adjusted (PA)-IC 90 . From 7 to 32 weeks of gestation, plasma CAB and RPV C trough decreased to 1.28 mg/L and to 0.08 mg/L), respectively, but remained above PA-IC 90 and Q1 C trough for both drugs. After receiving two high-dose CAB/RPV injections 7 weeks postpartum, the plasma CAB and RPV C trough were 4.02 mg/L and 0.19 mg/L, 56% and 74% higher than at 7 weeks of gestation. Despite a transient decrease in cabotegravir (50%) and rilpivirine (27%) concentrations, plasma exposures remained above therapeutic thresholds. Undetectable viral load (<20 copies/mL) was maintained preconceptionally and throughout the pregnancy. Higher CAB and RPV exposures did not result in adverse maternal, pregnancy or infant safety outcomes. At seven weeks postpartum, CAB/RPV dosing was switched to standard bimonthly schedule. At 33 weeks postpartum, the patient remained undetectable on standard CAB/RPV bimonthly dose, though subsequent pregnancies might require long-acting CAB/RPV dosing adjustments. Our case of empiric use of high-dose CAB/RPV with monthly injections and therapeutic drug monitoring during pregnancy in a complex patient with class III obesity provides novel insights into pharmacokinetics of long-acting CAB/RPV.

Multiple physiological and psychosocial challenges contribute to suboptimal adherence to oral antiretroviral therapy (ART) during pregnancy (1). Co-administered long-acting injectable (LAI) cabotegravir/rilpivirine (CAB/RPV) has the potential to optimize adherence to ART in pregnant women, leading to improved maternal and neonatal health outcomes and prevention of vertical HIV transmission. Due to limited pharmacokinetic (PK) and clinical outcome data among pregnant women and neonates exposed in utero to CAB and RPV (2), guidelines on administration of LAI CAB/RPV during pregnancy or breastfeeding are limited and cautionary. Real-world data on the use of LAI CAB/RPV during conception, pregnancy and postpartum, and associated maternal and neonatal outcomes are needed (3,4). We report a case of a young woman with HIV treated with off-label monthly high-dose LAI CAB/RPV plus standard dosing of lenacapavir (LEN) throughout pregnancy and postpartum and describe the results of therapeutic drug monitoring (TDM) of CAB and RPV, and maternal and neonatal outcomes. Case Presentation A 23-year-old woman with perinatally-acquired HIV presented for her 11 th injection of monthly high-dose of LAI CAB/RPV (600mg/900mg, monthly) and reported a positive pregnancy self-test. Human chorionic gonadotropin blood test (1354 mIU/mL) and fetal ultrasound confirmed desired pregnancy at 7 weeks gestation. The patient was diagnosed with HIV at six years of age following recurrent bacterial infections including endocarditis, which subsequently required three tricuspid valve replacements. Other significant co-morbidities included Center for Disease Control and Prevention (CDC)-defined class III obesity, acquired von Willebrand disease, and depression. The patient experienced challenges with adherence to oral ART leading to multiple interruptions and sustained viremia with intermittent short periods of viral suppression. By thirteen years of age, the patient developed immunologically (CD4 count regimens included combinations of two nucleoside reverse-transcriptase inhibitors with either ritonavir-boosted protease inhibitors or integrase inhibitors, with her last ART including bictegravir, emtricitabine, and tenofovir alafenamide fumarate (BIC/FTC/TAF). Archived genotypes demonstrated wild type HIV with minor mutations. Motivated to switch to LAI ART, the patient achieved three consecutive months of undetectable viral loads (HIV RNA <20 copies/mL) on BIC/FTC/TAF. Standard monthly dosing of LAI CAB/RPV (400mg/600mg) without oral lead-in was administrated in ventrogluteal muscle triangle using extra-long 2-inch (5-cm) Terumo SurGuard ® 3 needles. The patient declined ultrasonographic injection guidance due to the associated time commitment. Due to patient’s body mass index (BMI) of 58.6 kg/m 2, the clinical team was concerned with depositing CAB and RPV in adipose tissue despite using extra-long needles. Therefore, at the 3 rd monthly injection, the LAI ART was empirically switched to monthly high-dose CAB/RPV (600mg/900mg) plus LEN (927mg subcutaneously [SQ] every 6 months) through shared decision making to leverage the risk of suboptimal CAB and RPV exposures, viremia, and potential emergence of viral resistance. In collaboration with the obstetrics and gynecology (OB/GYN) team and patient, the selected LAI ART regimen was continued throughout pregnancy with 100% adherence. Reported adherence to twice daily SQ enoxaparin (100 mg/mL) during pregnancy varied. Monitored monthly, the viral load was undetectable throughout pregnancy and 7 days prior to delivery. CD4 cell count remained <250 cells/mm 3 . Given complex hematologic and cardiac history and slow induced labor progression, cesarian delivery was obstetrically indicated. A healthy male infant without congenital anomalies was born at 38 weeks gestation. Birth weight was 3.37 kg and Apgar scores were 2/8 at 1 and 5 minutes, respectively. With a low HIV transmission risk and exclusive formula feeding, the infant received 2 weeks of oral zidovudine prophylaxis. Infant HIV DNA PCR tests at 4, 6, and 19 weeks of age were negative. TDM Methods and Results Pre-dose plasma CAB and RPV trough concentrations (C trough ) were measured during pregnancy and postpartum (Figure 1). A mid-dose blood sample was collected 19 days after the 11 th injection to measure interval concentrations (Figure 1). At delivery (17 days after the 18 th injection) cord blood was collected, but maternal blood was not obtained. TDM samples (1.5 mL each) were collected in a 5 mL K-EDTA tube protected from light and processed (centrifuged 1000 x g for 10 minutes at 4°C) within 1 hour of collection. Plasma samples were transferred to an amber 2 mL cryovial and frozen immediately at -80°C. CAB and RPV concentrations were measured using tandem mass spectrometry with quantitation limits of 25 and 1 ng/mL, respectively. LEN concentrations were not measured due to lack of validated laboratory method for clinical use. At the first TDM measurement, we assumed that steady-state plasma concentration was reached for CAB and had ~80% chance to be reached for RPV (5). At 7 weeks gestation (52 weeks on LAI CAB/RPV), the plasma CAB and RPV C trough were 16 (2.58 mg/L) and 9 (0.11 mg/L) times above the respective PA-IC 90 . From 7 to 32 weeks of gestation, plasma CAB and RPV C trough decreased by 50% (2.58 to 1.28 mg/L) and 27% (0.11 to 0.08 mg/L), respectively, but remained above PA-IC 90 and Q1 C trough for both drugs (6,7). Cord blood concentrations were 2.18 mg/L and 0.06 mg/L for CAB and RPV, respectively. After receiving two high-dose CAB/RPV injections 7 weeks postpartum (BMI=67.0 kg/m 2 ), the plasma CAB and RPV C trough were 4.02 mg/L and 0.19 mg/L, 56% and 74% higher than at 7 weeks of gestation.

We report the use of monthly high-dose LAI CAB/RPV plus LEN at conception, throughout pregnancy and postpartum in a young woman with perinatally-acquired HIV. Empiric selection of monthly high-dose LAI CAB/RPV at preconception was driven by AIDS diagnosis, class III obesity, and concerns for suboptimal drug concentrations despite using extra-long needles. Obesity and low initial drug concentrations have been identified as risk factors for virologic failure and developing resistance to CAB and/or RPV in a Phase 3 LAI CAB/RPV clinical trial (6). Furthermore, in a Phase 1 study where a >9-cm needle was used for LAI CAB/RPV, high variability in the location of the intramuscular CAB depot was observed, even with ultrasonographic injection guidance (8). A physiologically-based (PB) PK model for initiating LAI CAB/RPV at different trimesters of pregnancy predicted that bimonthly dosing of LAI CAB would maintain efficacy plasma concentrations (4xPA-IC 90 =664 ng/mL) for CAB throughout pregnancy, however, 0.5% of the pregnant population CAB concentrations would fall below therapeutic target in the third trimester with bimonthly dosing (9). Predicted week 12 C trough for monthly and bimonthly LAI RPV was below 4xPA-IC 90 (50 ng/mL) in ≥40% and pregnancy. A single published case report described similar CAB exposure and lower RPV (70-75%) plasma concentrations when the reported patient with a normal BMI was compared to non-pregnant adults (4). Our TDM data provides novel insights into the dynamics of the intramuscular depot affected by obesity plus pregnancy. High-dose CAB/RPV resulted in a smaller decrease in RPV concentrations than predicted in PBPK model and published case, and maintenance of RPV C trough above therapeutic targets throughout pregnancy (4,6,7,9). The dual effect of accumulated RPV depot (adipose and/or intramuscular) and high-dose is likely responsible for preserving therapeutic RPV concentration. The decrease in plasma CAB concentrations in our case was consistent with the PBPK modelling and the published case and remained above therapeutic targets (6,7,9). The cord blood CAB concentration was 4-fold higher in our case when compared to modelled transplacental LAI CAB transfer and a published case (4,10). Cord blood RPV concentration (0.0595 mg/L) was higher than the published case (0.032 mg/L) and was comparable to the study of oral RPV PK in pregnancy (median=0.05378 mg/L) (11). Unfortunately, no maternal/cord blood ratio is available. Despite higher CAB and RPV exposures, no congenital anomalies were observed, but high placental transfer of CAB and RPV requires further evaluation of the pregnancy and infant outcomes. At seven weeks postpartum, CAB/RPV dosing was switched to standard bimonthly scheduled as plasma CAB and RPV C troughs were maintained above target thresholds and to decrease the burden of monthly LAI visits. Despite even higher BMI (65.04 kg/m 2 ), we anticipated that the accumulated drug depot would play a role in continued therapeutic concentrations. A PBPK model comparing the effects of BMI on C trough predicted that a BMI of 50-60 kg/m 2 equated to over 50% of virtual individuals falling below the 4xPA-IC 90 threshold after 48 weeks (12). For bimonthly injections there were no predicted virtual individuals who fell below the CAB PA-IC 90 (166 ng/mL), however 8% were predicted to fall below the 25 th percentile for RPV PA-IC 90 (32 ng/mL) (12). At 33 weeks postpartum, the patient remained undetectable on standard LAI CAB/RPV bimonthly dose. Subsequent pregnancies will require LAI CAB/RPV dosing considerations.

Our case of empiric use of monthly high-dose LAI CAB/RPV with TDM during pregnancy in a complex patient with class III obesity provides novel insights into CAB/RPV PK. Despite a decrease in CAB and RPV concentrations during 2 nd and 3 rd trimesters, both C trough levels remained above therapeutic targets. Higher CAB/RPV exposures did not result in adverse maternal or infant safety outcomes. Further studies on the PK, efficacy and safety of LAI CAB/RPV during pregnancy are needed, including in patients with higher BMI.

The authorship team extends great appreciation for the patient and her infant. NR, EA, and RKS conceptualized the project and case report. NR, JU, and TW developed the initial draft of the case report with all co-authors equally revising. EA, KJR, and KW performed drug concentration analyses. The authors declare no conflicts of interest. RKS has received research funding from ViiV Healthcare, managed by MedStar Health. The HIV Prevention and Treatment Services (HPTS) program at Children’s National Hospital received funding support from Ryan White HRSA Part A, Part B and Minority AIDS Initiative (MAI) funding from DC Department of Health (DOH).

1. Short WR, Lowenthal ED, Momplaisir F, Powis KM, Scott RK, Yee LM, et al. HIV and Pregnancy: Navigating Complex Decision Making and Preventing Perinatal Transmission. Vol. 22, Current HIV/AIDS Reports. Springer; 2025. 2. Patel P, Ford SL, Baker M, Meyer C, Garside L, D’Amico R, et al. Pregnancy outcomes and pharmacokinetics in pregnant women living with HIV exposed to long-acting cabotegravir and rilpivirine in clinical trials. HIV Med. 2023 May 1;24(5):568–79. 3. Short WR, Zimmerman M, Aziz M, Baron J, Bolduc P, Farmer E, et al. Long-Acting Cabotegravir/Rilpivirine in Pregnancy [CROI Abstract 1050]. Abstracts From the 2025 Conference on Retroviruses and Opportunistic Infections CROI 2025 Abstract eBook. 2025;601. 4. van der Wekken-Pas L, Weiss F, Simon-Zuber C, Sebisch R, Wiese C, van Leeuwen E, et al. Long-Acting Injectable Cabotegravir and Rilpivirine in a Pregnant Woman Living With Human Immunodeficiency Virus. Clinical Infectious Diseases. 2024 Dec 17; 5. Hodge D, Back DJ, Gibbons S, Khoo SH, Marzolini C. Pharmacokinetics and Drug–Drug Interactions of Long-Acting Intramuscular Cabotegravir and Rilpivirine. Vol. 60, Clinical Pharmacokinetics. Adis; 2021. p. 835–53. 6. Cutrell AG, Schapiro JM, Perno CF, Kuritzkes DR, Quercia R, Patel P, et al. Exploring predictors of HIV-1 virologic failure to long-acting cabotegravir and rilpivirine: a multivariable analysis. AIDS. 2021 Jul 15;35(9):1333–42. 7. Thoueille P, Saldanha SA, Schaller F, Choong E, Munting A, Cavassini M, et al. Real-world trough concentrations and effectiveness of long-acting cabotegravir and rilpivirine: a multicenter prospective observational study in Switzerland. The Lancet Regional Health - Europe. 2024 Jan 1;36. 8. Jucker BM, Fuchs EJ, Lee S, Damian V, Galette P, Janiczek R, et al. Multiparametric magnetic resonance imaging to characterize cabotegravir long-acting formulation depot kinetics in healthy adult volunteers. Br J Clin Pharmacol. 2022 Feb 1;88(4):1655–66. 9. Atoyebi S, Bunglawala F, Cottura N, Grañana-Castillo S, Montanha MC, Olagunju A, et al. Physiologically-based pharmacokinetic modelling of long-acting injectable cabotegravir and rilpivirine in pregnancy. Br J Clin Pharmacol. 2024; 10. Pencolé L, Lê MP, Bouchet-Crivat F, Duro D, Peytavin G, Mandelbrot L. Placental transfer of the integrase strand inhibitors cabotegravir and bictegravir in the ex-vivo human cotyledon perfusion model. AIDS. 2020 Nov 15;34(14):2145–9. 11. Tran AH, Best BM, Stek A, Wang J, Capparelli E V., Burchett SK, et al. Pharmacokinetics of Rilpivirine in HIV-Infected Pregnant Women. J Acquir Immune Defic Syndr (1988). 2016 Jul 1;72(3):289–96. 12. Bettonte S, Berton M, Stader F, Battegay M, Marzolini C. Effect of Obesity on the Exposure of Long-acting Cabotegravir and Rilpivirine: A Modeling Study. Clinical Infectious Diseases. 2024 Aug 15;79(2):477–86. Figure 1 . C trough for (A) cabotegravir and (B) rilpivirine at 7, 12, 22, 32 weeks of gestation and 7 weeks postpartum with BMI at each time point. The timing of LAI CAB/RPV injections are depicted on x-axis by an “x”. PA-IC 90 and Q1 plasma C trough for each drug are plotted for reference as proposed thresholds (7,8). Abbreviations: cabotegravir (CAB); rilpivirine (RPV); body mass index (BMI); trough concentration (C trough ); protein-adjusted 90% inhibitory concentration (PA-IC 90 ); 1 st quartile (Q1). Figure 1 . Information & Authors Information Version history Peer review timeline Published British Journal of Clinical Pharmacology Version of Record16 Dec 2025Published Copyright This work is licensed under a Non Exclusive No Reuse License. Collection Authors Metrics & Citations Metrics Article Usage 264views 163downloads Citations Download citation Natella Rakhmanina, Justin Unternaher, Tierra Williams, et al. Off-Label Dosing of Long-Acting Injectable Cabotegravir and Rilpivirine during Pregnancy: A Case Study with Therapeutic Drug Monitoring. Authorea. 08 October 2025. DOI: https://doi.org/10.22541/au.175993396.60448775/v1 DOI: https://doi.org/10.22541/au.175993396.60448775/v1 If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Simply select your manager software from the list below and click Download. For more information or tips please see 'Downloading to a citation manager' in the Help menu.