Probable hepatotoxicity with dolutegravir

Drug-induced liver injury (DILI) has been described with antiretrovirals including stavudine, nevirapine, and protease inhibitors [1]. Dolutegravir is a widely used integrase strand-transfer inhibitor (InSTI) with less than 1–2% discontinuation secondary to liver abnormalities in clinical trials [2]. We describe two cases of reversible grade 4 liver enzyme elevations (one with jaundice) in HLA-B*5701-negative men on dolutegravir with abacavir/lamivudine. Case 1 was a 57-year-old man, diagnosed with HIV in 2000. After 3 years on abacavir/lamivudine and lopinavir/ritonavir with viral suppression, he switched to dolutegravir/abacavir/lamivudine. Approximately 8 months later, his alanine transaminase (ALT) increased to 53 IU/l. Over the next 8 months, he became symptomatic with jaundice and his ALT, aspartate transaminase (AST), alkaline phosphatase (ALP), and total bilirubin (TBili) significantly increased to 699, 1404, 250 IU/l, and 242 μmol/l, respectively (Fig. 1). Viral and autoimmune hepatitis were ruled out. Liver biopsy showed extensive microvesicular steatosis, suggesting mitochondrial toxicity. His antiretrovirals were discontinued with decreases in his liver enzymes 1 month later, and he was restarted on abacavir/lamivudine and lopinavir/ritonavir. Three months later, liver enzymes returned to baseline and have remained stable for more than 11 months.Fig. 1: Liver enzymes on dolutegravir therapy and after switching to new regimens.3TC, lamivudine; ABC, abacavir; DTG, dolutegravir; FTC, emtricitabine; LFT, liver function test; LPV/r, lopinavir/ritonavir; RAL, raltegravir; RPV, rilpivirine; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate.Case 2 was a 42-year-old man who was found to have an ALT of 1416 IU/l 8 months after initiating dolutegravir/abacavir/lamivudine (Fig. 1). Abdominal ultrasound showed mildly enlarged liver, but was otherwise normal. Over the next 3 weeks, ALT, AST, and ALP remained elevated at 1399, 1046, 131 IU/l, respectively, whereas TBili rose to 85 μmol/l. After ruling out acute viral hepatitis, his antiretrovirals were discontinued. One month after stopping treatment, liver enzymes decreased and he was initiated on abacavir/lamivudine and raltegravir. His ALT and AST rebounded 1 week later, prompting treatment discontinuation. With subsequent reduction of ALT and AST, he was started on rilpivirine/emtricitabine/tenofovir disoproxil fumarate (TDF) and liver enzymes normalized after 2 months and remained stable with the only change being tenofovir alafenamide for TDF. In both cases, other medications including prescription, over-the-counter, and recreational drugs were ruled out as potential causes of DILI. Based on the Roussel Uclaf Causality Assessment Method causality scale [3], dolutegravir-associated DILI was considered probable for our first patient, and probable with either dolutegravir and raltegravir or abacavir for our second patient. We found two published reports of potential DILI with dolutegravir in HLA-B*5701-negative patients [4,5]. The first report described a 28-year-old woman who had previously tolerated an abacavir-containing regimen for over 6 months, but developed DILI requiring liver transplantation after receiving dolutegravir/abacavir/lamivudine for 4 weeks [4]. Her regimen was switched to raltegravir and emtricitabine/TDF, and her liver graft function remained normal 1-year posttransplantation. The second report was of a 47-year-old man who experienced serious DILI after being on dolutegravir/abacavir/lamivudine for 8 months [5]. Liver enzymes normalized after discontinuing therapy, and he was started on elvitegravir/cobicistat/emtricitabine/tenofovir alafenamide with no subsequent liver enzyme elevations. Our cases share some similarity to published reports. In our first case, liver biopsy suggested mitochondrial toxicity, which has been associated with older nucleoside reverse transcriptase inhibitors including stavudine and didanosine, but rarely with newer drugs such as abacavir, emtricitabine, lamivudine, and tenofovir [6]. The patient previously tolerated abacavir/lamivudine, and dolutegravir was the only new agent. In our second patient, DILI could have been associated with dolutegravir and raltegravir suggesting a potential class effect, or associated with abacavir. In the two published reports of dolutegravir-associated hepatotoxicity, patients were switched to raltegravir-containing and elvitegravir-containing regimens [4,5], suggesting that class sensitivity is rare. Raltegravir and elvitegravir have demonstrated well tolerated hepatic profiles with no reports of serious DILI requiring discontinuation of therapy [1]. Although uncommon, abacavir-associated DILI in HLA-B*5701-negative patients has been reported [7–9]. In these reports, DILI occurred 2–3 months after starting abacavir, with ALT elevations reaching 10–20 times the upper limit of the normal range (ULN) and AST elevations five to six times ULN. As blood work was only done at months 1 and 8 post antiretroviral initiation in our second patient, it is difficult to determine the true onset of liver enzyme elevation in this case and make any conclusions which drug was the more likely culprit. Our two cases highlight the potential for rare, idiosyncratic hepatotoxicity with dolutegravir. DILI was reversible upon discontinuation of dolutegravir. In some instances, patients may tolerate another InSTI although a class effect cannot be ruled out. Acknowledgements Conflicts of interest S.N., D.W., and K.G. declare no conflicts of interest. A.L.T. has received speaker and consultant honoraria from Abbvie, Gilead, Merck, and ViiV. D.Y. has received honoraria from Gilead and Merck.

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