Atazanavir-Associated Choledocholithiasis Leading to Acute Hepatitis in an HIV-infected Adult

Abstract

OBJECTIVE To report a case of atazanavir-associated choledocholithiasis in an HIV-infected individual. CASE SUMMARY A 47-year-old treatment-naïve HIV-positive African female presented to the emergency department with a 3-day history of right epigastric pain. Six weeks prior to this episode, she began antiretroviral therapy with a regimen consisting of atazanavir 400 mg and abacavir/lamivudine 600/300 mg once daily. Alanine aminotransferase (766 U/L), aspartate aminotransferase (876 U/L), γ-glutamyltransferase (588 U/L), alkaline phosphatase (348 U/L), and total bilirubin (3.9 mg/dL) levels were elevated. Abdominal ultrasound revealed obstructive choledocholithiasis as well as intra- and extrahepatic biliary dilatation. She underwent a laparoscopic cholecystectomy, which revealed approximately 50 small calculi present in the gallbladder. Since previous ultrasounds had also shown gallstones, an analysis of the extracted calculi was performed to determine the possible association with atazanavir use; low amounts of atazanavir were detected. DISCUSSION Atazanavir is an inhibitor of the bilirubin-conjugating enzyme UGT1A1 and has been frequently linked to the occurrence of hyperbilirubinemia without complications. This individual experienced hyperbilirubinemia that peaked at hospital presentation after she developed choledocholithiasis and secondary acute hepatitis. Analysis of the extracted gallstones revealed that smaller stones contained a higher content of atazanavir than larger stones, which suggests that atazanavir precipitation may play a role in cholelithiasis, although the mechanism remains unknown. The low yield of atazanavir may be explained by the short, 6-week duration of drug exposure as well as the lack of assay for metabolites. The Naranjo probability scale implicated choledocholithiasis as a possible atazanavir-associated adverse event. This report provides the first published evidence that even short-term use of atazanavir may lead to hyperbilirubinemia with choledocholithiasis and secondary acute hepatitis in HIV-infected adults. CONCLUSIONS Atazanavir should be considered a possible contributor in the development of cholelithiasis or choledocholithiasis, and people with HIV should receive adequate counseling in the recognition of symptoms associated with gallstones. The exact incidence and mechanism still need to be elucidated.