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A possible case of bictegravir-associated severe unconjugated hyperbilirubinemia

A possible case of bictegravir-associated severe unconjugated hyperbilirubinemia Background Bictegravir (BIC) co-formulated with emtricitabine (FTC) and tenofovir alafenamide ( TAF) is approved by Federal Food and Drug Administration in 2018 for both treatment-naïve and experienced persons living with HIV (PLWH). Case presentation A young man with recently diagnosed human immunodeficiency virus (HIV ) infection presented with jaundice. Blood work was significant for mild anemia and grade 4 unconjugated hyperbilirubinemia. A compre - hensive evaluation for hemolytic anemia failed to reveal any etiology. Other causes of hyperbilirubinemia were nega- tive. Four months prior, patient was started on antiretroviral therapy with a single tablet regimen containing bictegra- vir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF), brand name Biktarvy , and the medication was suspected to be the cause. The medication was held, and the hyperbilirubinemia improved. Conclusion Severe hyperbilirubinemia can be found in the patient using BIC/FTC/TAF. The data for this adverse reac- tion is scarce, and more studies are needed on this possible side effect. The mechanism of unconjugated hyperbiliru- binemia by INSTI remains undefined. Keywords Hyperbilirubinemia, Biktarvy, Bictegravir Drug Administration in 2018 for both treatment-naïve Background and experienced persons living with HIV (PLWH) [1]. There are more than 30 antiretroviral medications (ARV) Subsequently, the Department of Health and Human currently available for the treatment of HIV. These pri - Services (DHHS) Panel on Antiretroviral Guidelines for marily belong to five major classes: nucleoside (and Adults and Adolescents in 2018 as well as the Interna- nucleotide) reverse transcriptase inhibitors (NRTIs), tional Antiviral Society (IAS) in 2020 has recommended non-nucleoside reverse transcriptase inhibitors (NNRTI), BIC/FTC/TAF as one of the first line medications in protease inhibitors (PIs), integrase strand transfer inhibi- treatment for PLWH [2, 3]. tors (INSTIs) and entry inhibitors. Bictegravir (BIC), is Antiretroviral medications are known to cause adverse co-formulated with emtricitabine (FTC) and tenofovir effects on liver including idiosyncratic reactions, direct alafenamide (TAF) and is approved by Federal Food and cholestatic injury, mitochondrial dysfunction, nonalco- holic steatohepatitis (NASH), or isolated hyperbiliru- *Correspondence: binemia [4, 5]. In the two clinical trials in adults with no Kanak Parmar kanak.parmar@ttuhsc.edu previous antiretroviral treatment, BIC/FTC/TAF caused Department of Internal Medicine, Texas Tech University Health Sciences hyperbilirubinemia in 12% of subjects [6]. The increase in Center, 3601 4th St, Lubbock, TX, USA bilirubin was primarily Grade 1, i.e., 1–1.5X ULN (upper Department of Pulmonary and Critical Care, Texas Tech University Health Sciences Center, Lubbock, TX, USA limit of normal) in 9% of subjects and Grade 2, i.e., 1.5 to Division of Infectious Disease, Texas Tech University Health Sciences 2.5 X ULN in 3% of subjects [7]. Here we report a case of Center, Lubbock, TX, USA © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Parmar et al. AIDS Research and Therapy (2023) 20:5 Page 2 of 5 a healthy man who presented with grade 4 hyperbiliru- Investigations binemia (> 5X ULN). The laboratory results revealed normochromic normo - cytic anemia, unconjugated hyperbilirubinemia with total and indirect bilirubin concentrations of 17.2 and Case presentation 16.2  mg/dL respectively (Table  1). Baseline laboratory An eighteen-year-old man with medical history of values showed mild elevation in bilirubin concentrations. recently diagnosed HIV infection presented with epigas- Liver enzymes were normal before as well as on presen- tric pain, nausea, and vomiting for 1 week. He denied any tation. Synthetic function of liver was normal. Evalua- history of recent travel, infection, or close contact with tion for hemolytic anemia showed elevated reticulocyte a sick person. Social history was negative for alcohol, count and decreased haptoglobin concentrations. Lac- tobacco, or illicit drug use. The patient denied any other tate dehydrogenase was normal. The peripheral blood herbal or over-the-counter medications. Surgical history smear showed minimal spherocytosis and macrocytosis. was negative. Family history was negative for any inher- However, the direct antiglobulin test (DAT) and glucose- ited disorders. He was started on BIC/FTC/TAF four 6-phosphate dehydrogenase (G-6-PD) screen were nega- months prior. Physical examination revealed jaundice tive. Vitamin B12 and folate levels were normal. His last and scleral icterus with anterior cervical lymphadenopa- CD4 count was 469 cells/mm and viral load was 93 thy. No abdominal tenderness or hepatosplenomegaly copies/ml three months prior to admission. Abdominal was noted. ultrasound did not reveal any abnormalities. Table 1 Laboratory values Three months On admission Day 3 3 weeks later 2 months later Reference values before admission WBC (K/uL) 5.20 7.41 6.46 6.82 6.5 4.5–5.2 Hemoglobin (g/dl) 15.5 16.1 12.1 11.7 16.3 13–16 Platelets (K/uL) 194 188 163 166 157 163–667 MCV (fl) 90.1 89.9 101.4 102 95.6 78–98 Reticulocyte % 4.83 0.5–1.8 Total bilirubin (mg/dL) 2.1 17.2 11.2 4.3 2.8 0–1 Direct bilirubin (mg/dL) 0.3 1 0.5 0.2 0–0.2 Indirect bilirubin (mg/dL) 16.2 10.7 4.1 0.1–1.1 ALP (IU/L) 81 55 45 63 70 35–129 ALT (IU/L) 16 16 18 13 39 5–41 AST (IU/L) 19 19 18 18 33 5–37 LDH (U/L) 205 135–225 Folate (ng/ml) 7.4 TSH (mcIU/ml) 0.64 0.27–4.2 Vitamin B12 (pg/ml) 303 232–1425 HIV RNA PCR copies/ml 93 426 CD4% 32 21 31–59 CD8% 44 53 13–37 ABO/Rh O positive Haptoglobin (mg/dL) < 8 43–212 Hepatitis A Virus, Ig G Reactive Hepatitis A Virus, IgM Non-Reactive Hepatitis B Surface Ag Non-Reactive Hepatitis B Surface Ab Positive Hepatitis B Core Ab IgG Non-Reactive Hepatitis C Ab IgG Non-Reactive MCV mean corpuscular volume, ALP alkaline phosphatase, ALT alanine transaminase, AST aspartate transaminase, LDH lactate dehydrogenase, TSH thyroid stimulating hormone, RNA ribonucleic acid, PCR polymerase chain reaction, Rh rhesus, CD cluster of differentiation, Ab antibody, Ig immunoglobulin P armar et al. AIDS Research and Therapy (2023) 20:5 Page 3 of 5 For example, the NNRTI have been shown in clinical tri- Differential diagnosis als to cause grade 3/ 4 elevations in alanine transaminase Based on history, physical examination, and initial labora- (ALT) / aspartate transaminase (AST) by causing direct tory results, the patient needed evaluation for this degree cholestatic injury, hypersensitivity, or the immune recon- of unconjugated hyperbilirubinemia. Medication side stitution syndrome [10]. However, doravirine, an NNRTI effect was the most likely cause of hyperbilirubinemia has been shown to cause grade 2 bilirubin elevation in 2% given recent history of taking new medication. Naranjo patients enrolled in DRIVE-FORWARD trial without any score calculated was 3 indicating possible adverse drug other liver function test abnormalities [11]. reaction [8]. He did not have elevation in hepatic enzymes The hepatotoxicity associated with NRTIs is thought to or abnormal findings on abdominal ultrasonography be mediated by mitochondrial toxicity [5]. PIs also carry which rule out cholestatic injury and obstructive jaun- warning for elevations in ALT/AST in preexisting liver dice. The differential diagnosis included overproduction disease and can cause acute hepatitis [4]. However, ataza- of bilirubin due to hemolytic anemia given undetectable navir (ATV), a PI is known to cause reversible increase haptoglobin concentration, reticulocytosis. However, the in unconjugated bilrubin without liver injury due to patient did not have any anemia on admission. Testing for UGT1A1 inhibition. In CASTLE study, ATV with rito- autoimmune hemolytic anemia and G-6-PD deficiency navir (ATV/r) was compared against lopinavir /ritonavir were also negative. Spherocytosis was also minimal in a (LPV/r). It showed that 44% patients receiving ATV/r blood smear. Congenital hemolytic evaluation was not developed hyperbilirubinemia at any time through obtained due to low likelihood. The differential diagnosis 96  weeks with 5% developing jaundice and < 1% discon- also included pathologies involving decreased uptake of tinued treatment due to hyperbilirubinemia. It was not bilirubin by liver, such as Gilbert’s syndrome, or defects associated with abnormalities in liver transaminases or with conjugation, example Criggler Najjar. Medication hepatic function [12]. side effect was also a possible etiology. Bilirubin is the product of heme catabolism. It is cleared by the liver by converting into a water-soluble Treatment metabolite for secretion into bile. This is done by conju - Due to concern for medication side effect as the cause of gating bilirubin with glucuronic acid by bilirubin uridine the hyperbilirubinemia, BIC/FTC/TAF was held on the diphosphate-glucuronosyltransferase (UGT), a microso- day of admission. The bilirubin started to trend down to mal enzyme [13].Unconjugated hyperbilirubinemia can bilirubin 11.2 mg/dL. Patient’s nausea and pain resolved. be caused by either decreased uptake of bilirubin by liver He was discharged dolutegravir and lamivudine, another cells or a defect in conjugation. Protease inhibitors (PIs) STR on day 3 with no increase in bilirubin on follow up such as indinavir and ATV have an inhibitory effect on labs. UGT enzyme and can cause hyperbilirubinemia, a mech- anism similar to Gilbert syndrome [14]. Genetic poly- Outcome and follow‑up morphisms of UGT1A1 gene have been known to impact Three weeks after discharge, the total bilirubin concen - UGT activity along with polymorphisms in multidrug trations were 4.3 mg/dL and further improved to 2.8 mg/ resistance gene1(MDR1), a transporter for ATV inside dL at two months. cells. Haplotype UGT1A1, UGT1A3, UGT1A7 and MDR1 3435 have been associated with hyperbilirubinemia [14]. Discussion PIs also have been reported to inhibit the human organic BIC/FTC/TAF has been the first line treatment for anion transporting protein 1B1, which transports uncon- PLWH and shown to be non-inferior to other STR con- jugated bilirubin to the liver [15]. taining dolutegravir in two clinical trials [7, 9]. GS-US- The hyperbilirubinemia by INSTIs is rarely reported 380-1490, a randomized clinical trial (RCT) tested BIC/ and the mechanism remains unclear [4]. In a phase III FTC/TAF against dolutegravir, emtricitabine and teno- trial with the new medication cabotegravir combined fovir alafenamide and showed lower incidence of drug with rilpivirine, minor increase in bilirubin concentra- related events in the bictegravir group [7]. Another RCT tions were noted and thought to be due to unconjugated GS-US-380–1489 compared BIC/FTC/TAF against bilirubin competing for UGT1A1 [16]. This may be a dolutegravir, abacavir and lamivudine reported lower similar mechanism of unconjugated hyperbilirubinemia drug-related adverse events and two times lower in vitro from BIC/FTC/TAF but it remains unknown. resistance in the bictegravir group [9]. The adverse events The common adverse events reported in the Trial 1489 in the dolutegravir group were primarily driven by nau- and 1490 for BIC/FTC/TAF were diarrhea, nausea, head- sea [9]. ache, fatigue, abnormal dreams, dizziness and insomnia The contemporary ARV drugs have been associated in > 2% of HIV-1 infected patients [6]. More than 2% of with adverse events on liver by various mechanisms [4]. Parmar et al. AIDS Research and Therapy (2023) 20:5 Page 4 of 5 Funding the patients had grade 3 and 4 laboratory abnormalities No funding is required for this manuscript. such as elevation of hepatic enzymes, neutrophils, and cholesterol concentrations. Hyperbilirubinemia was seen Data availability Not applicable. in 12% of subjects in trials but was Grade 1 and Grade 2(6). Our case presented with grade 4 hyperbilirubinemia Declarations leading to discontinuation of the medication which has not been reported previously. Ethics approval and consent to participate Among the medications in BIC/FTC/TAF, FTC and Not applicable. TAF are primarily excreted renally; the excretion of BIC Consent for publication is primarily hepatic. BIC is substrate for cytochrome Written consent has been acquired by the patient. P450-3A4 (CYP3A4) and uridine diphosphate glucu- Competing interests ronosyltransferase 1 family, polypeptide A1 (UGT1A1), The authors declare that they have no competing interests. but the mechanism of hyperbilirubinemia, though looks similar to cabotegravir, remains to be defined [14]. In our Received: 7 June 2022 Accepted: 3 January 2023 case the laboratory value was significant for low hapto - globin level which might suggest a concomitant hemo- lytic process. There is scarce data on antiretroviral drugs effects on erythrocyte’s cell membrane in vivo and clini - References cal data is limited to case reports [17, 18]. 1. https:// www. gilead. com/ news- and- press/ press- room/ press- relea ses/ It might be possible that our patient had an underly- 2018/2/ us- food- and- drug- admin istra tion- appro ves- gilea ds- bikta rvy- bicte gravir- emtri citab ine- tenof ovir- alafe namide- for- treat ment- of- hiv1- ing defect in bilirubin metabolism, for example Gilbert’s infec tion. Accessed 7 Feb 2018. syndrome and an additional inhibition of the enzyme by 2. https:// www. natap. org/ 2018/ HIV/ 032818_ 01. htm. medication can presented with florid hyperbilirubinemia. 3. Saag MS, Gandhi RT, Hoy JF, Landovitz RJ, Thompson MA, Sax PE, et al. Antiretroviral drugs for treatment and prevention of HIV infection in adults: 2020 recommendations of the international antiviral society-USA Conclusion panel. JAMA. 2020;324(16):1651–69. This case presented with grade 4 hyperbilirubinemia 4. Otto AO, Rivera CG, Zeuli JD, Temesgen Z. Hepatotoxicity of contempo- rary antiretroviral drugs: a review and evaluation of published clinical while on BIC/FTC/TAF leading to discontinuation of the data. Cells. 2021;10(5):1263. https:// doi. org/ 10. 3390/ cells 10051 263. medication. The data for this adverse reaction is scarce, 5. Neff GW, Jayaweera D, Sherman KE. Drug-Induced liver injury in HIV and more studies are needed on this possible side effect. patients. Gastroenterol Hepatol. 2006;2(6):430–7. 6. Biktarvy (bictegravir, emtricitabine, tenofovir alafenamide) [prescribing information]. Foster City, CA: Gilead sciences March 2021. Learning points 7. Sax PE, Pozniak A, Montes ML, Koenig E, DeJesus E, Stellbrink HJ, et al. Coformulated bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir with emtricitabine and tenofovir alafenamide, for • Hyperbilirubinemia (Grade 1 and Grade2) has initial treatment of HIV-1 infection (GS-US-380-1490): a randomised, been found in 12% patients in trials with BIC/FTC/ double-blind, multicentre, phase 3, non-inferiority trial. Lancet. 2017;390(10107):2073–82. TAF. Severe hyperbilirubinemia can be found in the 8. Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A patient using BIC/FTC/TAF. method for estimating the probability of adverse drug reactions. Clin • The mechanism of unconjugated hyperbilirubinemia Pharmacol Ther. 1981;30(2):239–45. 9. Gallant J, Lazzarin A, Mills A, Orkin C, Podzamczer D, Tebas P, et al. in PIs is primarily through inhibition of UDP-glucu- Bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir, ronosyltransferases (UGT). However, the mechanism abacavir, and lamivudine for initial treatment of HIV-1 infection (GS-US- by INSTI remains undefined. 380-1489): a double-blind, multicentre, phase 3, randomised controlled non-inferiority trial. Lancet. 2017;390(10107):2063–72. • In cases where patients develop severe hyperbiliru- 10. Sulkowski MS, Thomas DL, Mehta SH, Chaisson RE, Moore RD. Hepa- binemia from HIV ARV therapy, an underlying Gil- totoxicity associated with nevirapine or efavirenz-containing antiret- bert syndrome should be investigated. roviral therapy: role of hepatitis C and B infections. Hepatology. 2002;35(1):182–9. 11. Molina JM, Squires K, Sax PE, Cahn P, Lombaard J, DeJesus E, et al. Dora- virine versus ritonavir-boosted darunavir in antiretroviral-naive adults Acknowledgements with HIV-1 (DRIVE-FORWARD): 96-week results of a randomised, double- None. blind, non-inferiority, phase 3 trial. Lancet HIV. 2020;7(1):e16–26. 12. McDonald C, Uy J, Hu W, Wirtz V, Juethner S, Butcher D, et al. Clinical Author contributions significance of hyperbilirubinemia among HIV-1-infected patients treated Drafting of the manuscript: KP. tables and formatting: KP. concept and design: with atazanavir/ritonavir through 96 weeks in the CASTLE study. AIDS KP. acquisition, analysis, or interpretation of data: KP. critical revision of the Patient Care STDs. 2012;26(5):259–64. manuscript for important intellectual content: PM, KN, JN. supervision: PM, KN, JN. All authors read and approved the final manuscript. P armar et al. AIDS Research and Therapy (2023) 20:5 Page 5 of 5 13. Erlinger S, Arias IM, Dhumeaux D. Inherited disorders of bilirubin trans- port and conjugation: new insights into molecular mechanisms and consequences. Gastroenterology. 2014;146(7):1625–38. 14. Tozzi V. Pharmacogenetics of antiretrovirals. Antiviral Res. 2010;85(1):190–200. 15. Campbell SD, de Morais SM, Xu JJ. Inhibition of human organic anion transporting polypeptide OATP 1B1 as a mechanism of drug-induced hyperbilirubinemia. Chem Biol Interact. 2004;150(2):179–87. 16. Rizzardini G, Overton ET, Orkin C, Swindells S, Arasteh K, Górgolas Hernán- dez-Mora M, et al. Long-acting injectable cabotegravir + rilpivirine for HIV maintenance therapy: week 48 pooled analysis of phase 3 ATLAS and FLAIR trials. J Acquir Immune Defic Syndr. 2020;85(4):498–506. 17. Bissinger R, Waibel S, Lang F. Induction of suicidal erythrocyte death by nelfinavir. Toxins. 2015;7(5):1616–28. 18. Watson A. Reversible acute haemolysis associated with indinavir. AIDS. 2000;14(4):465–6. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in pub- lished maps and institutional affiliations. Re Read ady y to to submit y submit your our re researc search h ? Choose BMC and benefit fr ? 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A possible case of bictegravir-associated severe unconjugated hyperbilirubinemia

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Abstract

Background Bictegravir (BIC) co-formulated with emtricitabine (FTC) and tenofovir alafenamide ( TAF) is approved by Federal Food and Drug Administration in 2018 for both treatment-naïve and experienced persons living with HIV (PLWH). Case presentation A young man with recently diagnosed human immunodeficiency virus (HIV ) infection presented with jaundice. Blood work was significant for mild anemia and grade 4 unconjugated hyperbilirubinemia. A compre - hensive evaluation for hemolytic anemia failed to reveal any etiology. Other causes of hyperbilirubinemia were nega- tive. Four months prior, patient was started on antiretroviral therapy with a single tablet regimen containing bictegra- vir/emtricitabine/tenofovir alafenamide (BIC/FTC/TAF), brand name Biktarvy , and the medication was suspected to be the cause. The medication was held, and the hyperbilirubinemia improved. Conclusion Severe hyperbilirubinemia can be found in the patient using BIC/FTC/TAF. The data for this adverse reac- tion is scarce, and more studies are needed on this possible side effect. The mechanism of unconjugated hyperbiliru- binemia by INSTI remains undefined. Keywords Hyperbilirubinemia, Biktarvy, Bictegravir Drug Administration in 2018 for both treatment-naïve Background and experienced persons living with HIV (PLWH) [1]. There are more than 30 antiretroviral medications (ARV) Subsequently, the Department of Health and Human currently available for the treatment of HIV. These pri - Services (DHHS) Panel on Antiretroviral Guidelines for marily belong to five major classes: nucleoside (and Adults and Adolescents in 2018 as well as the Interna- nucleotide) reverse transcriptase inhibitors (NRTIs), tional Antiviral Society (IAS) in 2020 has recommended non-nucleoside reverse transcriptase inhibitors (NNRTI), BIC/FTC/TAF as one of the first line medications in protease inhibitors (PIs), integrase strand transfer inhibi- treatment for PLWH [2, 3]. tors (INSTIs) and entry inhibitors. Bictegravir (BIC), is Antiretroviral medications are known to cause adverse co-formulated with emtricitabine (FTC) and tenofovir effects on liver including idiosyncratic reactions, direct alafenamide (TAF) and is approved by Federal Food and cholestatic injury, mitochondrial dysfunction, nonalco- holic steatohepatitis (NASH), or isolated hyperbiliru- *Correspondence: binemia [4, 5]. In the two clinical trials in adults with no Kanak Parmar kanak.parmar@ttuhsc.edu previous antiretroviral treatment, BIC/FTC/TAF caused Department of Internal Medicine, Texas Tech University Health Sciences hyperbilirubinemia in 12% of subjects [6]. The increase in Center, 3601 4th St, Lubbock, TX, USA bilirubin was primarily Grade 1, i.e., 1–1.5X ULN (upper Department of Pulmonary and Critical Care, Texas Tech University Health Sciences Center, Lubbock, TX, USA limit of normal) in 9% of subjects and Grade 2, i.e., 1.5 to Division of Infectious Disease, Texas Tech University Health Sciences 2.5 X ULN in 3% of subjects [7]. Here we report a case of Center, Lubbock, TX, USA © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Parmar et al. AIDS Research and Therapy (2023) 20:5 Page 2 of 5 a healthy man who presented with grade 4 hyperbiliru- Investigations binemia (> 5X ULN). The laboratory results revealed normochromic normo - cytic anemia, unconjugated hyperbilirubinemia with total and indirect bilirubin concentrations of 17.2 and Case presentation 16.2  mg/dL respectively (Table  1). Baseline laboratory An eighteen-year-old man with medical history of values showed mild elevation in bilirubin concentrations. recently diagnosed HIV infection presented with epigas- Liver enzymes were normal before as well as on presen- tric pain, nausea, and vomiting for 1 week. He denied any tation. Synthetic function of liver was normal. Evalua- history of recent travel, infection, or close contact with tion for hemolytic anemia showed elevated reticulocyte a sick person. Social history was negative for alcohol, count and decreased haptoglobin concentrations. Lac- tobacco, or illicit drug use. The patient denied any other tate dehydrogenase was normal. The peripheral blood herbal or over-the-counter medications. Surgical history smear showed minimal spherocytosis and macrocytosis. was negative. Family history was negative for any inher- However, the direct antiglobulin test (DAT) and glucose- ited disorders. He was started on BIC/FTC/TAF four 6-phosphate dehydrogenase (G-6-PD) screen were nega- months prior. Physical examination revealed jaundice tive. Vitamin B12 and folate levels were normal. His last and scleral icterus with anterior cervical lymphadenopa- CD4 count was 469 cells/mm and viral load was 93 thy. No abdominal tenderness or hepatosplenomegaly copies/ml three months prior to admission. Abdominal was noted. ultrasound did not reveal any abnormalities. Table 1 Laboratory values Three months On admission Day 3 3 weeks later 2 months later Reference values before admission WBC (K/uL) 5.20 7.41 6.46 6.82 6.5 4.5–5.2 Hemoglobin (g/dl) 15.5 16.1 12.1 11.7 16.3 13–16 Platelets (K/uL) 194 188 163 166 157 163–667 MCV (fl) 90.1 89.9 101.4 102 95.6 78–98 Reticulocyte % 4.83 0.5–1.8 Total bilirubin (mg/dL) 2.1 17.2 11.2 4.3 2.8 0–1 Direct bilirubin (mg/dL) 0.3 1 0.5 0.2 0–0.2 Indirect bilirubin (mg/dL) 16.2 10.7 4.1 0.1–1.1 ALP (IU/L) 81 55 45 63 70 35–129 ALT (IU/L) 16 16 18 13 39 5–41 AST (IU/L) 19 19 18 18 33 5–37 LDH (U/L) 205 135–225 Folate (ng/ml) 7.4 TSH (mcIU/ml) 0.64 0.27–4.2 Vitamin B12 (pg/ml) 303 232–1425 HIV RNA PCR copies/ml 93 426 CD4% 32 21 31–59 CD8% 44 53 13–37 ABO/Rh O positive Haptoglobin (mg/dL) < 8 43–212 Hepatitis A Virus, Ig G Reactive Hepatitis A Virus, IgM Non-Reactive Hepatitis B Surface Ag Non-Reactive Hepatitis B Surface Ab Positive Hepatitis B Core Ab IgG Non-Reactive Hepatitis C Ab IgG Non-Reactive MCV mean corpuscular volume, ALP alkaline phosphatase, ALT alanine transaminase, AST aspartate transaminase, LDH lactate dehydrogenase, TSH thyroid stimulating hormone, RNA ribonucleic acid, PCR polymerase chain reaction, Rh rhesus, CD cluster of differentiation, Ab antibody, Ig immunoglobulin P armar et al. AIDS Research and Therapy (2023) 20:5 Page 3 of 5 For example, the NNRTI have been shown in clinical tri- Differential diagnosis als to cause grade 3/ 4 elevations in alanine transaminase Based on history, physical examination, and initial labora- (ALT) / aspartate transaminase (AST) by causing direct tory results, the patient needed evaluation for this degree cholestatic injury, hypersensitivity, or the immune recon- of unconjugated hyperbilirubinemia. Medication side stitution syndrome [10]. However, doravirine, an NNRTI effect was the most likely cause of hyperbilirubinemia has been shown to cause grade 2 bilirubin elevation in 2% given recent history of taking new medication. Naranjo patients enrolled in DRIVE-FORWARD trial without any score calculated was 3 indicating possible adverse drug other liver function test abnormalities [11]. reaction [8]. He did not have elevation in hepatic enzymes The hepatotoxicity associated with NRTIs is thought to or abnormal findings on abdominal ultrasonography be mediated by mitochondrial toxicity [5]. PIs also carry which rule out cholestatic injury and obstructive jaun- warning for elevations in ALT/AST in preexisting liver dice. The differential diagnosis included overproduction disease and can cause acute hepatitis [4]. However, ataza- of bilirubin due to hemolytic anemia given undetectable navir (ATV), a PI is known to cause reversible increase haptoglobin concentration, reticulocytosis. However, the in unconjugated bilrubin without liver injury due to patient did not have any anemia on admission. Testing for UGT1A1 inhibition. In CASTLE study, ATV with rito- autoimmune hemolytic anemia and G-6-PD deficiency navir (ATV/r) was compared against lopinavir /ritonavir were also negative. Spherocytosis was also minimal in a (LPV/r). It showed that 44% patients receiving ATV/r blood smear. Congenital hemolytic evaluation was not developed hyperbilirubinemia at any time through obtained due to low likelihood. The differential diagnosis 96  weeks with 5% developing jaundice and < 1% discon- also included pathologies involving decreased uptake of tinued treatment due to hyperbilirubinemia. It was not bilirubin by liver, such as Gilbert’s syndrome, or defects associated with abnormalities in liver transaminases or with conjugation, example Criggler Najjar. Medication hepatic function [12]. side effect was also a possible etiology. Bilirubin is the product of heme catabolism. It is cleared by the liver by converting into a water-soluble Treatment metabolite for secretion into bile. This is done by conju - Due to concern for medication side effect as the cause of gating bilirubin with glucuronic acid by bilirubin uridine the hyperbilirubinemia, BIC/FTC/TAF was held on the diphosphate-glucuronosyltransferase (UGT), a microso- day of admission. The bilirubin started to trend down to mal enzyme [13].Unconjugated hyperbilirubinemia can bilirubin 11.2 mg/dL. Patient’s nausea and pain resolved. be caused by either decreased uptake of bilirubin by liver He was discharged dolutegravir and lamivudine, another cells or a defect in conjugation. Protease inhibitors (PIs) STR on day 3 with no increase in bilirubin on follow up such as indinavir and ATV have an inhibitory effect on labs. UGT enzyme and can cause hyperbilirubinemia, a mech- anism similar to Gilbert syndrome [14]. Genetic poly- Outcome and follow‑up morphisms of UGT1A1 gene have been known to impact Three weeks after discharge, the total bilirubin concen - UGT activity along with polymorphisms in multidrug trations were 4.3 mg/dL and further improved to 2.8 mg/ resistance gene1(MDR1), a transporter for ATV inside dL at two months. cells. Haplotype UGT1A1, UGT1A3, UGT1A7 and MDR1 3435 have been associated with hyperbilirubinemia [14]. Discussion PIs also have been reported to inhibit the human organic BIC/FTC/TAF has been the first line treatment for anion transporting protein 1B1, which transports uncon- PLWH and shown to be non-inferior to other STR con- jugated bilirubin to the liver [15]. taining dolutegravir in two clinical trials [7, 9]. GS-US- The hyperbilirubinemia by INSTIs is rarely reported 380-1490, a randomized clinical trial (RCT) tested BIC/ and the mechanism remains unclear [4]. In a phase III FTC/TAF against dolutegravir, emtricitabine and teno- trial with the new medication cabotegravir combined fovir alafenamide and showed lower incidence of drug with rilpivirine, minor increase in bilirubin concentra- related events in the bictegravir group [7]. Another RCT tions were noted and thought to be due to unconjugated GS-US-380–1489 compared BIC/FTC/TAF against bilirubin competing for UGT1A1 [16]. This may be a dolutegravir, abacavir and lamivudine reported lower similar mechanism of unconjugated hyperbilirubinemia drug-related adverse events and two times lower in vitro from BIC/FTC/TAF but it remains unknown. resistance in the bictegravir group [9]. The adverse events The common adverse events reported in the Trial 1489 in the dolutegravir group were primarily driven by nau- and 1490 for BIC/FTC/TAF were diarrhea, nausea, head- sea [9]. ache, fatigue, abnormal dreams, dizziness and insomnia The contemporary ARV drugs have been associated in > 2% of HIV-1 infected patients [6]. More than 2% of with adverse events on liver by various mechanisms [4]. Parmar et al. AIDS Research and Therapy (2023) 20:5 Page 4 of 5 Funding the patients had grade 3 and 4 laboratory abnormalities No funding is required for this manuscript. such as elevation of hepatic enzymes, neutrophils, and cholesterol concentrations. Hyperbilirubinemia was seen Data availability Not applicable. in 12% of subjects in trials but was Grade 1 and Grade 2(6). Our case presented with grade 4 hyperbilirubinemia Declarations leading to discontinuation of the medication which has not been reported previously. Ethics approval and consent to participate Among the medications in BIC/FTC/TAF, FTC and Not applicable. TAF are primarily excreted renally; the excretion of BIC Consent for publication is primarily hepatic. BIC is substrate for cytochrome Written consent has been acquired by the patient. P450-3A4 (CYP3A4) and uridine diphosphate glucu- Competing interests ronosyltransferase 1 family, polypeptide A1 (UGT1A1), The authors declare that they have no competing interests. but the mechanism of hyperbilirubinemia, though looks similar to cabotegravir, remains to be defined [14]. In our Received: 7 June 2022 Accepted: 3 January 2023 case the laboratory value was significant for low hapto - globin level which might suggest a concomitant hemo- lytic process. There is scarce data on antiretroviral drugs effects on erythrocyte’s cell membrane in vivo and clini - References cal data is limited to case reports [17, 18]. 1. https:// www. gilead. com/ news- and- press/ press- room/ press- relea ses/ It might be possible that our patient had an underly- 2018/2/ us- food- and- drug- admin istra tion- appro ves- gilea ds- bikta rvy- bicte gravir- emtri citab ine- tenof ovir- alafe namide- for- treat ment- of- hiv1- ing defect in bilirubin metabolism, for example Gilbert’s infec tion. Accessed 7 Feb 2018. syndrome and an additional inhibition of the enzyme by 2. https:// www. natap. org/ 2018/ HIV/ 032818_ 01. htm. medication can presented with florid hyperbilirubinemia. 3. Saag MS, Gandhi RT, Hoy JF, Landovitz RJ, Thompson MA, Sax PE, et al. Antiretroviral drugs for treatment and prevention of HIV infection in adults: 2020 recommendations of the international antiviral society-USA Conclusion panel. JAMA. 2020;324(16):1651–69. This case presented with grade 4 hyperbilirubinemia 4. Otto AO, Rivera CG, Zeuli JD, Temesgen Z. Hepatotoxicity of contempo- rary antiretroviral drugs: a review and evaluation of published clinical while on BIC/FTC/TAF leading to discontinuation of the data. Cells. 2021;10(5):1263. https:// doi. org/ 10. 3390/ cells 10051 263. medication. The data for this adverse reaction is scarce, 5. Neff GW, Jayaweera D, Sherman KE. Drug-Induced liver injury in HIV and more studies are needed on this possible side effect. patients. Gastroenterol Hepatol. 2006;2(6):430–7. 6. Biktarvy (bictegravir, emtricitabine, tenofovir alafenamide) [prescribing information]. Foster City, CA: Gilead sciences March 2021. Learning points 7. Sax PE, Pozniak A, Montes ML, Koenig E, DeJesus E, Stellbrink HJ, et al. Coformulated bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir with emtricitabine and tenofovir alafenamide, for • Hyperbilirubinemia (Grade 1 and Grade2) has initial treatment of HIV-1 infection (GS-US-380-1490): a randomised, been found in 12% patients in trials with BIC/FTC/ double-blind, multicentre, phase 3, non-inferiority trial. Lancet. 2017;390(10107):2073–82. TAF. Severe hyperbilirubinemia can be found in the 8. Naranjo CA, Busto U, Sellers EM, Sandor P, Ruiz I, Roberts EA, et al. A patient using BIC/FTC/TAF. method for estimating the probability of adverse drug reactions. Clin • The mechanism of unconjugated hyperbilirubinemia Pharmacol Ther. 1981;30(2):239–45. 9. Gallant J, Lazzarin A, Mills A, Orkin C, Podzamczer D, Tebas P, et al. in PIs is primarily through inhibition of UDP-glucu- Bictegravir, emtricitabine, and tenofovir alafenamide versus dolutegravir, ronosyltransferases (UGT). However, the mechanism abacavir, and lamivudine for initial treatment of HIV-1 infection (GS-US- by INSTI remains undefined. 380-1489): a double-blind, multicentre, phase 3, randomised controlled non-inferiority trial. Lancet. 2017;390(10107):2063–72. • In cases where patients develop severe hyperbiliru- 10. Sulkowski MS, Thomas DL, Mehta SH, Chaisson RE, Moore RD. Hepa- binemia from HIV ARV therapy, an underlying Gil- totoxicity associated with nevirapine or efavirenz-containing antiret- bert syndrome should be investigated. roviral therapy: role of hepatitis C and B infections. Hepatology. 2002;35(1):182–9. 11. Molina JM, Squires K, Sax PE, Cahn P, Lombaard J, DeJesus E, et al. Dora- virine versus ritonavir-boosted darunavir in antiretroviral-naive adults Acknowledgements with HIV-1 (DRIVE-FORWARD): 96-week results of a randomised, double- None. blind, non-inferiority, phase 3 trial. Lancet HIV. 2020;7(1):e16–26. 12. McDonald C, Uy J, Hu W, Wirtz V, Juethner S, Butcher D, et al. Clinical Author contributions significance of hyperbilirubinemia among HIV-1-infected patients treated Drafting of the manuscript: KP. tables and formatting: KP. concept and design: with atazanavir/ritonavir through 96 weeks in the CASTLE study. AIDS KP. acquisition, analysis, or interpretation of data: KP. critical revision of the Patient Care STDs. 2012;26(5):259–64. manuscript for important intellectual content: PM, KN, JN. supervision: PM, KN, JN. All authors read and approved the final manuscript. P armar et al. AIDS Research and Therapy (2023) 20:5 Page 5 of 5 13. Erlinger S, Arias IM, Dhumeaux D. Inherited disorders of bilirubin trans- port and conjugation: new insights into molecular mechanisms and consequences. Gastroenterology. 2014;146(7):1625–38. 14. Tozzi V. Pharmacogenetics of antiretrovirals. Antiviral Res. 2010;85(1):190–200. 15. Campbell SD, de Morais SM, Xu JJ. Inhibition of human organic anion transporting polypeptide OATP 1B1 as a mechanism of drug-induced hyperbilirubinemia. Chem Biol Interact. 2004;150(2):179–87. 16. Rizzardini G, Overton ET, Orkin C, Swindells S, Arasteh K, Górgolas Hernán- dez-Mora M, et al. Long-acting injectable cabotegravir + rilpivirine for HIV maintenance therapy: week 48 pooled analysis of phase 3 ATLAS and FLAIR trials. J Acquir Immune Defic Syndr. 2020;85(4):498–506. 17. Bissinger R, Waibel S, Lang F. Induction of suicidal erythrocyte death by nelfinavir. Toxins. 2015;7(5):1616–28. 18. Watson A. Reversible acute haemolysis associated with indinavir. AIDS. 2000;14(4):465–6. Publisher’s Note Springer Nature remains neutral with regard to jurisdictional claims in pub- lished maps and institutional affiliations. Re Read ady y to to submit y submit your our re researc search h ? Choose BMC and benefit fr ? 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Journal

AIDS Research and Therapy – Springer Journals

Published: Jan 23, 2023

Keywords: Hyperbilirubinemia; Biktarvy; Bictegravir

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