SUN-563 - Delayed Onset of Diabetic Ketoacidosis After Bictegravir Antiretroviral Therapy With Complete Resolution Upon Discontinuation

Background:
Antiretroviral therapy (ART) containing integrase strand transfer inhibitors (INSTI) has been associated with metabolic effects such as hyperglycemia, weight gain, and dyslipidemia. Bictegravir (BIC) is a second-generation INSTI that is commonly used as part of ART for people living with HIV. Hyperglycemia was not reported in the initial clinical trials of BIC-based regimens; however, there are reports of new-onset hyperglycemia, with or without diabetic ketoacidosis (DKA), occurring within four months of starting BIC (1,2). Data on BIC-associated hyperglycemia remains limited, and optimal management strategies are not well defined. We present a case of a patient who developed severe hyperglycemia with DKA 18 months after transitioning to a BIC-based ART and subsequently achieved euglycemia following discontinuation of BIC.

Clinical

Case:
A 59-year-old female with virally suppressed HIV on lopinavir/ritonavir and tenofovir disoproxil fumarate/lamivudine was transitioned to bictegravir/tenofovir alafenamide/emtricitabine (BIC/TAF/FTC) in June 2024 to simplify her ART regimen. At the time of switch, she was euglycemic (A1c 5.4%, random BG 106 mg/dL). Eighteen months after the ART switch, she developed DKA (A1c 14.2%, random BG >500 mg/dL, fructosamine 569 umol/L), requiring initiation of basal-bolus insulin. Prior to this time, her random BG ranged from 91-123 mg/dL. Diabetes autoimmune antibodies were negative. Notably, she experienced significant weight gain (12 kg) from the time of ART switch to the time of DKA. Following BIC/TAF/FTC discontinuation and transition to a protease inhibitor-based ART regimen with darunavir/cobicistat/TAF/FTC, glycemia rapidly normalized (A1c 6.4%, random BG 101 mg/dL, estimated A1c by CGM 5.7%, time-in-range 100%) over approximately 7 weeks, allowing discontinuation of all antidiabetic medications. Naranjo score of 7 suggests a probable drug-induced adverse reaction.

Conclusion:
Compared to previous reports of BIC-induced hyperglycemia, this case is notable for its delayed onset, suggesting a broader timeline of risk. Consistent with prior reports, improvement in glycemia was observed following discontinuation of BIC. This case highlights the importance of ongoing metabolic monitoring with BIC-based ART, even beyond the early treatment period and suggests consideration of regimen modification in patients who develop worsening hyperglycemia after initiation or switching to BIC-based ART. Proposed mechanisms for BIC-induced hyperglycemia include insulin resistance, upregulation of gluconeogenic pathways, mitochondrial dysfunction, and oxidative stress. Further pharmacological research is warranted to determine the exact mechanism of this phenomenon.

References:
1. Nolan NS, et al. Open Forum Infect Dis. 2021;16;8(5):ofab077.
2. Aurora J Jr, et al. AACE Endocrinol Diabetes. 2025;13(1):60-62.

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