Bictegravir/emtricitabine/tenofovir alafenamide-induced acute pancreatitis: a case report

Introduction

Bictegravir is a novel, unboosted, integrase inhibitor approved for the treatment of adults with human immunodeficiency virus (HIV) infection as a single tablet regimen co-formulated with emtricitabine and tenofovir alafenamide (BIC/FTC/TAF). ¹ In Phase 3 studies, more grades 3 and 4 laboratory abnormalities were found in the BIC/FTC/TAF arm, mainly driven by frequent, transient increase in serum amylase often associated with normal lipase. No episodes of pancreatitis were, however, reported.^2–6 This report describes a probable case of acute pancreatitis caused by BIC/FTC/TAF.

Clinical section

A 32-year-old male with recent diagnosis of HIV started BIC/FTC/TAF in December 2019. At baseline, HIV-RNA was 355,000 copies/mL, the CD4+ cell count was 583 cells/mm³ and the liver enzymes were within normal limits (aspartate aminotransferase (AST) 26 IU/L, alanine transaminase (ALT] 19 IU/L, γ-glutamyl transpeptidase (GGT) 15 IU/L, total bilirubin 0.6 mg/dL), as well as lipase (21 IU/L), amylase (16 IU/L) and triglycerides (93 mg/dL) Forty-five days after starting BIC/TAF/FTC, the patient returned to our outpatient clinic reporting severe epigastric pain radiating to the back, nausea, episodes of non-bloody non-bilious vomiting and anorexia. HIV-RNA was 56 copies/mL and CD4 cell count was 620 cells/mm³. Laboratory examination showed a rise in lipase (219 IU/L, normal range 13–42) with no alterations in serum transaminases (AST 23 IU/L, ALT 19 IU/L); amylase was not checked. Abdominal ultrasound revealed a non-homogeneous structure of the pancreatic parenchyma. No stones in the gallbladder and/or biliary tree were found. The patient had no history of hypertriglyceridemia, other diseases or family history of pancreatitis and denied recent/chronic alcohol abuse (indirectly confirmed by GGT of 12 IU/L), as well as taking other drugs, dietary supplements, or illegal substances (he had no history of recreational drug use). A diagnosis of mild drug-related acute pancreatitis was made and BIC/FTC/TAF was immediately stopped. His symptoms improved rapidly, and lipase normalized within 15 days (40 IU/L measured 2 weeks after BIC/FTC/TAF discontinuation). A novel antiretroviral regimen with rilpivirine plus dolutegravir was started. The association between the episode of acute pancreatitis and BIC/FTC/TAF was scored as probable according to the Naranjo causality scale ⁷ (score: 5).

Discussion

Our case met the criteria for acute pancreatitis, as the patient had characteristic symptoms and signs, lipase was elevated (more three times the upper limit of normal), and abdominal ultrasound showed evidence of pancreatic damage. The criteria for drug-induced pancreatitis were also met. ⁸ Indeed, the onset/offset of pancreatitis relative to the initiation/discontinuation of BIC/FTC/TAF, combined with the absence of any other medications or medical conditions known to be associated with pancreatitis, suggests that the likelihood of an association with BIC/FTC/TAF is ‘probable’ according to the Naranjo algorithm. The pathogenesis of BIC/FTC/TAF-induced pancreatitis is presently unknown. However, after having excluded predisposing anatomical causes (i.e. duct obstruction) or episodes of pancreatitis secondary to hypertriglyceridemia, as well as poor immune-virologic conditions (i.e. low CD4 cell count and/or high HIV viral load), a direct toxic effect of bictegravir on the pancreatic structures (i.e. through mitochondrial damage, induction of pro-oxidant and/or pro-inflammatory state) might be hypothesized, as recently described for other drugs. ⁹ This is indirectly supported also by cases of pancreatitis reported in patients treated with other integrase inhibitors. ¹⁰ The possibility that this event could have been worsened by FTC and/or TAF cannot be definitively ruled out as the three drugs are co-formulated.

Only mild alterations of pancreatic enzymes were reported during Phase 3 clinical trials involving 1215 patients treated with BIC/FTC/TAF.^2–6 The lack of any pancreatitis cases across these trials demonstrates the importance of post-market monitoring and reporting of rare but serious side effects that may go undetected during the drug development process. Indeed, we were able to identify seven cases of pancreatitis reported with BIC/FTC/TAF use during the post-marketing phase in the FDA Adverse Event Reporting System Database. ¹¹ Based on our findings, we recommend clinicians to monitor for the potential development of pancreatic damage (i.e. by assessing serum lipase and amylases during the first visits) following initiation of BIC/FTC/TAF.