Atazanavir Case Study

Atazanavir (ATV) boosted with low dose of ritonavir (rit) is a Protease Inhibitor used as part of alternative antiretroviral regimen in drug-naïve PLWHIV according to numerous national and regional guidelines, hence for almost a decade was used as part of first line / preferred / recommended regimen3. More than half of patients on atazanavir experience elevated bilirubin levels, which can reach grade 3-4 in approximately one third of all cases4. In ACTG 5237, 8% of the patients discontinued ATV due to jaundice5. The mechanism of this adverse event resembles Gilbert’s Syndrome, a form of mild unconjugated hyperbilirubinemia that affects ~3-9% of individuals in European ancestry6.
Atazanavir acts as an inhibitor of uridine diphosphate –glucuronsyltransferase (UGT), the enzyme responsible for hepatic conjugation of bilirubin. Three UGT subfamilies have been identified based on gene sequence similarity: UGT1A, UGT2A, UGT2B. The major UGT1A subfamily enzyme, UGT1A1, is expressed primarily in the liver and gastrointestinal track and is efficient for the effective elimination of bilirubin7. The most frequent genetic variant that affects UGT1A1 function is a dinucleotide TAn repeat polymorphism (rs8175347), which
Implications of UGT1A1 genetic testing for prescribing atazanavir, boosted with ritonavir or cobicistat may be influenced by several factors such as consequences of jaundice for the particular patient, receiving therapy with additional protease inhibitors (e.g. Darunavir) or integrase inhibitors. However in this population bilirubin could represent an adherence biomarker. For example PLWHIV on atazanavir with failure of plasma bilirubin to increase from baseline (regardless of UGT1A1 genotype) is a strong evidence that ATV/rit or ATV/cobicistat was not taken during the prior ~ 24