A possible case of bictegravir-associated severe unconjugated hyperbilirubinemia

BIC/FTC/TAF has been the first line treatment for PLWH and shown to be non-inferior to other STR containing dolutegravir in two clinical trials [7, 9]. GS-US-380-1490, a randomized clinical trial (RCT) tested BIC/FTC/TAF against dolutegravir, emtricitabine and tenofovir alafenamide and showed lower incidence of drug related events in the bictegravir group [7]. Another RCT GS-US-380–1489 compared BIC/FTC/TAF against dolutegravir, abacavir and lamivudine reported lower drug-related adverse events and two times lower in vitro resistance in the bictegravir group [9]. The adverse events in the dolutegravir group were primarily driven by nausea [9].

The contemporary ARV drugs have been associated with adverse events on liver by various mechanisms [4]. For example, the NNRTI have been shown in clinical trials to cause grade 3/ 4 elevations in alanine transaminase (ALT) / aspartate transaminase (AST) by causing direct cholestatic injury, hypersensitivity, or the immune reconstitution syndrome [10]. However, doravirine, an NNRTI has been shown to cause grade 2 bilirubin elevation in 2% patients enrolled in DRIVE-FORWARD trial without any other liver function test abnormalities [11].

The hepatotoxicity associated with NRTIs is thought to be mediated by mitochondrial toxicity [5]. PIs also carry warning for elevations in ALT/AST in preexisting liver disease and can cause acute hepatitis [4]. However, atazanavir (ATV), a PI is known to cause reversible increase in unconjugated bilrubin without liver injury due to UGT1A1 inhibition. In CASTLE study, ATV with ritonavir (ATV/r) was compared against lopinavir /ritonavir (LPV/r). It showed that 44% patients receiving ATV/r developed hyperbilirubinemia at any time through 96 weeks with 5% developing jaundice and < 1% discontinued treatment due to hyperbilirubinemia. It was not associated with abnormalities in liver transaminases or hepatic function [12].

Bilirubin is the product of heme catabolism. It is cleared by the liver by converting into a water-soluble metabolite for secretion into bile. This is done by conjugating bilirubin with glucuronic acid by bilirubin uridine diphosphate-glucuronosyltransferase (UGT), a microsomal enzyme [13].Unconjugated hyperbilirubinemia can be caused by either decreased uptake of bilirubin by liver cells or a defect in conjugation. Protease inhibitors (PIs) such as indinavir and ATV have an inhibitory effect on UGT enzyme and can cause hyperbilirubinemia, a mechanism similar to Gilbert syndrome [14]. Genetic polymorphisms of UGT1A1 gene have been known to impact UGT activity along with polymorphisms in multidrug resistance gene1(MDR1), a transporter for ATV inside cells. Haplotype UGT1A1, UGT1A3, UGT1A7 and MDR1 3435 have been associated with hyperbilirubinemia [14]. PIs also have been reported to inhibit the human organic anion transporting protein 1B1, which transports unconjugated bilirubin to the liver [15].

The hyperbilirubinemia by INSTIs is rarely reported and the mechanism remains unclear [4]. In a phase III trial with the new medication cabotegravir combined with rilpivirine, minor increase in bilirubin concentrations were noted and thought to be due to unconjugated bilirubin competing for UGT1A1 [16]. This may be a similar mechanism of unconjugated hyperbilirubinemia from BIC/FTC/TAF but it remains unknown.

The common adverse events reported in the Trial 1489 and 1490 for BIC/FTC/TAF were diarrhea, nausea, headache, fatigue, abnormal dreams, dizziness and insomnia in > 2% of HIV-1 infected patients [6]. More than 2% of the patients had grade 3 and 4 laboratory abnormalities such as elevation of hepatic enzymes, neutrophils, and cholesterol concentrations. Hyperbilirubinemia was seen in 12% of subjects in trials but was Grade 1 and Grade 2(6). Our case presented with grade 4 hyperbilirubinemia leading to discontinuation of the medication which has not been reported previously.

Among the medications in BIC/FTC/TAF, FTC and TAF are primarily excreted renally; the excretion of BIC is primarily hepatic. BIC is substrate for cytochrome P450-3A4 (CYP3A4) and uridine diphosphate glucuronosyltransferase 1 family, polypeptide A1 (UGT1A1), but the mechanism of hyperbilirubinemia, though looks similar to cabotegravir, remains to be defined [14]. In our case the laboratory value was significant for low haptoglobin level which might suggest a concomitant hemolytic process. There is scarce data on antiretroviral drugs effects on erythrocyte’s cell membrane in vivo and clinical data is limited to case reports [17, 18].

It might be possible that our patient had an underlying defect in bilirubin metabolism, for example Gilbert's syndrome and an additional inhibition of the enzyme by medication can presented with florid hyperbilirubinemia.

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