Identification of Novel UGT1A1 Variants Including UGT1A1 454C>A through the Genotyping of Healthy Participants of the HPTN 077 Study

Abstract

Cabotegravir (CAB) is an integrase strand-transfer inhibitor of HIV that has proven effective for HIV treatment and prevention in a long-acting injectable formulation, typically preceded by an oral formulation lead-in phase. Previous in vitro studies have demonstrated that CAB is primarily metabolized via glucuronidation by uridine diphosphate glucuronosyltransferase (UGT) 1A1 and 1A9. In this study, we performed next-generation sequencing of genomic DNA isolated from the HPTN 077 participants to explore the variants within UGT1A1 and UGT1A9 . Additionally, to enable correlation of UGT1A1 and UGT1A9 genotypes with plasma CAB-glucuronide levels, we quantified glucuronidated CAB following both oral administration of CAB and intramuscular injection of long-acting CAB. From these studies, 48 previously unreported variants of UGT1A1 and UGT1A9 were detected. Notably, 5/68 individuals carried a UGT1A1 454C>A variant that resulted in amino acid substitution P152T, and the use of in silico tools predicted a deleterious effect of the P152T substitution. Thus, the impact of this mutant on a range of UGT1A1 substrates was tested using a COS-7 cell-based assay. The glucuronide conjugates of CAB, dolutegravir, and raltegravir, were not formed in the COS-7 cells expressing the UGT1A1 P152T mutant. Further, formation of glucuronides of raloxifene and 7-ethyl-10-hydroxycamptothecin were reduced in the cells expressing the UGT1A1 P152T mutant. Using the same approach, we tested the activities of two UGT1A9 mutants, UGT1A9 H217Y and UGT1A9 R464G, and found that these mutations were tolerated and decreased function, respectively. These data provide insight into previously unreported genetic variants of UGT1A1 and UGT1A9 .

Safety and efficacy of long-acting injectable cabotegravir as preexposure prophylaxis to prevent HIV acquisition

“…HPTN 077 also found that CAB-LA had a longer terminal phase half-life among participants with an above median BMI, as compared to participants with a below median BMI [ 32 ]. An additional study from HPTN 077 found that genetic variants of enzymes that metabolize CAB-LA exist and could affect the rate at which CAB-LA is metabolized [ 47 ]. A better understanding of variability of CAB-LA's pharmacokinetics could improve optimization of dosing tailored to different populations.…”

Long‐acting injectable cabotegravir forPrEP: A game‐changer inHIVprevention?

“…The longer terminal half‐life was also associated with unsplit injection, higher body mass index, and shorter needles [36]. Polymorphism in enzymes metabolising CAB‐LA may also affect the pharmacokinetics of the drug [37]. Additional research will be needed to better understand the variability of the tail phase between different populations.…”