Hyperbilirubinemia and Pharmacokinetics and Zinc Sulfate: Impact on Coadministration of Atazanavir-Ritonavir

tazanavir (ATV) is a commonly prescribed protease inhibitor(PI) approved for use in combination with other antiretrovi-ral (ARV) agents in naive and treatment-experienced adults withHIV infection (1). ATV is a substrate of cytochrome P450 3A4(CYP3A4) enzyme and coadministration with low doses of theCYP3A4 inhibitor ritonavir (r) increases ATV concentrations andensures optimal plasma exposures (2). Most individuals on ATV/r-based regimens receive ATV/r at 300/100 mg once daily.The most frequent symptomatic adverse events associated toATV/r intake are scleral icterus and jaundice, leading to discon-tinuation in 1% of recipients in clinical trials, and the mostfrequent laboratory abnormality is isolated hyperbilirubinemia(HBR) (3, 4). This is consequent to elevations of unconjugatedbilirubin due to inhibition of uridine 5=-diphospho-glucurono-syltransferase(UGT)1A1enzymebyATVandleadstoaGilbert’s-like syndrome (3, 4). ATV absorption is stomach acid dependent;plasma concentrations vary within and between patients andcorrelate with increases in unconjugated bilirubin (5). Withinthe hepatocytes, UGT 1A1 is responsible for the conjugation ofbilirubin to form the soluble glucuronide, which is then elim-inated (6).The increase in unconjugated HBR caused by ATV intake ap-pears within the first week of treatment and resolves promptlywhenthedrugisdiscontinued(4).However,althoughthereareanincreasing number of available ARVs, HIV-infected individualsmay need to continue ATV/r-based ARV treatment because of theneed of a PI/r-based therapy (i.e., second-line therapy in the pres-enceofaresistantvirus)(1)becauseofitsfavorabletoxicityprofilecompared to other agents of the same class (i.e., limited hyperlip-idemia) (7) or in case of local policies favoring less costly ARVcombinations (8). Therefore, strategies to limit unconjugated bil-irubin increases may benefit HIV-infected patients.Zinc sulfate (ZnSO