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HCV infected patients
Accepted Manuscript Letter to the Editor Hepatotoxicity and Potential Drug Interaction with Ledipasvir/Sofosbuvir In HIV/HCV Infected Patients Alice Tseng, David K. Wong PII: DOI: Reference:
S0168-8278(16)30201-X http://dx.doi.org/10.1016/j.jhep.2016.05.015 JHEPAT 6111
To appear in:
Journal of Hepatology
Received Date: Revised Date: Accepted Date:
9 March 2016 4 May 2016 9 May 2016
Please cite this article as: Tseng, A., Wong, D.K., Hepatotoxicity and Potential Drug Interaction with Ledipasvir/ Sofosbuvir In HIV/HCV Infected Patients, Journal of Hepatology (2016), doi: http://dx.doi.org/10.1016/j.jhep. 2016.05.015
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1 Hepatotoxicity and Potential Drug Interaction with Ledipasvir/Sofosbuvir In HIV/HCV Infected Patients (manuscript JHEPAT-D-16-00533)
Alice Tseng, Pharm.D. Immunodeficiency Clinic, University Health Network, Toronto, Canada; [email protected] David K. Wong, M.D. Immunodeficiency Clinic, University Health Network, Toronto, Canada; [email protected]
Corresponding author: Alice Tseng, 585 University Avenue, 13NU-1314, Toronto, Canada M5G 2N2. Phone: (416) 340-4800, ext. 8763. Fax: (416) 340-4890. Email: [email protected] Keywords: DILI (drug-induced liver injury); hepatitis C; ledipasvir; HIV; drug interaction Abbreviations: HIV: human immunodeficiency virus HCV: hepatitis C virus DILI: drug-induced liver injury Naranjo: Naranjo adverse drug reaction probability scale RUCAM: Roussel Uclaf Causality Assessment Method ART: antiretroviral therapy ALT: alanine transferase AST: aspartate aminotransferase ALP: alkaline phosphatase GGT: gamma-glutamyl transferase INR: international normalized ratio ULN: upper limit of normal
2 SVR12: sustained virological response 12 weeks following treatment completion MELD: Model for Endstage Liver Disease
Word count: 800 Figures/tables: 1 Figure
Conflict of interest: DKW: speaking honoraria (Abbvie, Gilead). AT: unrestricted educational grants (Abbvie, Gilead, Merck, ViiV, Janssen) and speaking honoraria (Abbvie, Gilead, Merck). Financial support statement: none of the authors received financial support in order to write the manuscript. Authors contributions: AT was involved in acquisition of data; analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript for important intellectual content. DKW was involved in acquisition of data; analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript for important intellectual content. Acknowledgements: We would like to thank Ms. Nancy Sheehan for providing antiretroviral concentration analysis and interpretation for case 3.
Lay summary: A rare side effect of ledipasvir/sofosbuvir is liver injury, which occurs within 2-6 weeks of starting treatment. Total and direct bilirubin values are greatly increased, and worsening of liver function may occur; symptoms are usually reversible when treatment is stopped. An interaction with lopinavir/ritonavir may contribute to this adverse effect.
3 To the Editor:
Hepatotoxicity in HIV-HCV infected patients receiving ledipasvir/sofosbuvir with or without ribavirin has been reported.1-3 We describe 3 additional cases of probably/highly probable drug-induced liver injury (DILI) with ledipasvir/sofosbuvir using established causality tools (Naranjo, RUCAM)4, 5. Our cases with those previously described confirm a consistent presentation for this rare but serious adverse effect. We also identify a potential interaction with lopinavir which may have contributed to this DILI; this has important clinical implications since early initiation of antiretroviral therapy (ART) is encouraged in coinfected patients.6 From 2014-2015, 67 HCV/HIV infected patients at our centre were treated with ledipasvir/sofosbuvir (4 with ribavirin). During treatment, none had elevations of ALT/AST, ALP/GGT, INR or fall in albumin from baseline. Three patients had isolated bilirubin increases with peak elevations 2-14 times the upper normal limit (ULN) within two weeks of initiating ledipasvir/sofosbuvir for HCV genotype 1a . Case 1 (Figure 1a): A 60-year old treatment-naïve woman with Childs B cirrhosis had bilirubin rise at week 2 and developed ascites at week 4 resulting in early treatment discontinuation. Bilirubin improved within 10 days of stopping ledipasvir/sofosbuvir and returned to baseline by 7 weeks. She achieved SVR12. Case 2 (Figure 1b): A 66 year old previously treated (ribavirin-pegylated interferon) male with Childs A cirrhosis and moderate renal dysfunction had bilirubin rise at week 2 with symptoms of persistent fatigue and malaise. At week 6, bilirubin peaked and ART was changed to stop lopinavir and tenofovir. Bilirubin improved one week later and returned to baseline after three weeks with symptom resolution. He has completed 21 of 24 planned weeks of ledipasvir/sofosbuvir therapy.
4 Case 3 (Figure 1c): A 50 year old treatment-naïve, non-cirrhotic male had bilirubin rise by week 2, with symptoms of dizziness, nausea, and constipation. Bilirubin peaked at week 4 and remained elevated throughout 12 weeks of treatment. Bilirubin returned to baseline and symptoms resolved one month after treatment completion. Stored sera for antiretroviral concentrations were available. Compared to baseline, lopinavir, raltegravir and maraviroc concentrations were increased 20%, 305% and 200%, respectively while on ledipasvir/sofosbuvir. He achieved SVR12. Our report doubles the number of published cases of hepatotoxicity with ledipasvir/sofosbuvir in HIVHCV patients.1-3 The pattern of toxicity described in all cases is strikingly similar. All patients had undetectable HIV viral load and were on stable antiretroviral therapy (1.5 to over 4 years duration for our cases) prior to starting ledipasvir/sofosbuvir. Onset of symptoms was rapid, within 2-6 weeks; clinical presentation was acute cholestasis with increased total and direct bilirubin in the context of improving/stable liver enzymes. All patients were symptomatic. Hepatic decompensation occurred in 3 subjects with decompensated cirrhosis and MELD scores of 13 and higher. In 5/6 cases, symptoms resolved and bilirubin improved after stopping ledipasvir/sofosbuvir or modification of ART. Causality assessments using the Naranjo and RUCAM scales suggest a probable or highly probable DILI associated with ledipasvir/sofosbuvir. Of note, all three of our cases as well as two of the 3 other cases in the literature were on lopinavir/ritonavir.1, 2 One patient described by Dyson et al.3 was not on lopinavir/ritonavir, but was the only case with prior hepatic decompensation and had the highest MELD score. This patient was on efavirenz, which can rarely be associated with hepatotoxicity.7 For our 3 cases, a possible/probable interaction between ledipasvir/sofosbuvir and ART was identified using DIPS causality assessment.8 The exact nature of potential interactions between ledipasvir/sofosbuvir and antiretrovirals is difficult to elucidate. Tenofovir exposures are increased 40-98% in the presence of ledipasvir/sofosbuvir,9 but
5 this would be expected to result in renal dysfunction. To date, hyperbilirubinemia with tenofovir has not been reported. Our third patient, as well as two other reported cases1, 2 were not on tenofovir. A probable interaction may exist between lopinavir and ledipasvir/sofosbuvir. In healthy volunteers, atazanavir trough concentrations were increased 63% with coadministration of ledipasvir/sofosbuvir,10 possibly due to P-gp inhibition by ledipasvir leading to decreased drug clearance. Lopinavir concentrations may similarly be increased by ledipasvir. This is supported by increased lopinavir exposures in our third patient during ledipasvir/sofosbuvir treatment compared to baseline. This patient also experienced a significant increase in maraviroc concentrations during ledipasvir/sofosbuvir treatment, which may have occurred due to the same mechanism. Of note, our second patient improved when lopinavir/ritonavir was switched to darunavir/ritonavir while continuing ledipasvir/sofosbuvir. In the previous study, coadministration of ledipasvir/sofosbuvir and darunavir/ritonavir did not alter darunavir exposures,10 perhaps because darunavir is associated with some enzyme inducing effects. Therefore, it is possible that his symptoms were secondary to increased lopinavir exposures which resolved with the switch to darunavir. In conclusion, DILI manifesting as significant bilirubin rise within 2 weeks of initiating ledipasvir/sofosbuvir while on ART may occur with symptoms and possibly hepatic decompensation. Cessation of treatment or alteration of potentially interacting antiretrovirals usually leads to rapid resolution. Coadministration of lopinavir/ritonavir with ledipasvir/sofosbuvir should be avoided until further data are available.
6 References: 1.
Marchan-Lopez A, Dominguez-Dominguez L, Kessler-Saiz P, et al. Liver failure in human immunodeficiency virus - Hepatitis C virus coinfection treated with sofosbuvir, ledipasvir and antiretroviral therapy. J Hepatol 2015 Dec 9.
2.
Dyson JK, McPherson S. Reply to "Liver failure in human immunodeficiency virus - Hepatitis C virus coinfection treated with sofosbuvir, ledipasvir and antiretroviral therapy". J Hepatol 2015 Dec 10.
3.
Dyson JK, Hutchinson J, Harrison L, et al. Liver toxicity associated with sofosbuvir, an NS5A inhibitor and ribavirin use. J Hepatol 2016 Jan;64(1):234-8.
4.
Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981 Aug;30(2):239-45.
5.
Chalasani NP, Hayashi PH, Bonkovsky HL, et al. ACG Clinical Guideline: the diagnosis and management of idiosyncratic drug-induced liver injury. The American journal of gastroenterology 2014 Jul;109(7):950-66; quiz 67.
6.
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. Department of Health and Human Services. Federal register January 28, 2016. p. 1-277 Available from: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.
7.
Sulkowski MS, Thomas DL, Mehta SH, et al. Hepatotoxicity associated with nevirapine or efavirenz-containing antiretroviral therapy: role of hepatitis C and B infections. Hepatology 2002 Jan;35(1):182-9.
8.
Horn JR, Hansten PD, Chan LN. Proposal for a new tool to evaluate drug interaction cases. Ann Pharmacother 2007;41(4):674-80.
9.
Gilead Sciences Canada Inc. Harvoni (ledipasvir/sofosbuvir) Product Monograph. Mississauga, ON October 14, 2014.
10.
German P, Garrison K, Pang P, et al. Drug-drug interactions between anti-HCV regimen ledipasvir/sofosbuvir and antiretrovirals [abstract 82]. Conference on Retroviruses and Opportunistic Infections (CROI), February 23-26, 2015, Seattle, WA.
7 Figure 1 Legend. Fig. 1. Pattern of liver function tests in relation to ledipasvir/sofosbuvir treatment in 3 cases of druginduced liver injury (DILI). (A) Case 1 with total bilirubin increase to 4 times ULN by week 2, peak of 7.36 times ULN at week 4 with symptomatic hepatic decompensation, and resolution 7 weeks after ledipasvir/sofosbuvir discontinuation. (B) Case 2 with total bilirubin increase to 3.13 times ULN by week 2, peak of 5.95 times ULN at week 6, resolution 3 weeks after changing antiretrovirals and continuing ledipasvir/sofosbuvir. (C) Case 3 with total bilirubin increase to 1.6 times ULN by week 2, peak of 2 times ULN at week 4 and resolution 4 weeks after completing ledipasvir/sofosbuvir treatment.
S0168-8278(16)30201-X http://dx.doi.org/10.1016/j.jhep.2016.05.015 JHEPAT 6111
To appear in:
Journal of Hepatology
Received Date: Revised Date: Accepted Date:
9 March 2016 4 May 2016 9 May 2016
Please cite this article as: Tseng, A., Wong, D.K., Hepatotoxicity and Potential Drug Interaction with Ledipasvir/ Sofosbuvir In HIV/HCV Infected Patients, Journal of Hepatology (2016), doi: http://dx.doi.org/10.1016/j.jhep. 2016.05.015
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1 Hepatotoxicity and Potential Drug Interaction with Ledipasvir/Sofosbuvir In HIV/HCV Infected Patients (manuscript JHEPAT-D-16-00533)
Alice Tseng, Pharm.D. Immunodeficiency Clinic, University Health Network, Toronto, Canada; [email protected] David K. Wong, M.D. Immunodeficiency Clinic, University Health Network, Toronto, Canada; [email protected]
Corresponding author: Alice Tseng, 585 University Avenue, 13NU-1314, Toronto, Canada M5G 2N2. Phone: (416) 340-4800, ext. 8763. Fax: (416) 340-4890. Email: [email protected] Keywords: DILI (drug-induced liver injury); hepatitis C; ledipasvir; HIV; drug interaction Abbreviations: HIV: human immunodeficiency virus HCV: hepatitis C virus DILI: drug-induced liver injury Naranjo: Naranjo adverse drug reaction probability scale RUCAM: Roussel Uclaf Causality Assessment Method ART: antiretroviral therapy ALT: alanine transferase AST: aspartate aminotransferase ALP: alkaline phosphatase GGT: gamma-glutamyl transferase INR: international normalized ratio ULN: upper limit of normal
2 SVR12: sustained virological response 12 weeks following treatment completion MELD: Model for Endstage Liver Disease
Word count: 800 Figures/tables: 1 Figure
Conflict of interest: DKW: speaking honoraria (Abbvie, Gilead). AT: unrestricted educational grants (Abbvie, Gilead, Merck, ViiV, Janssen) and speaking honoraria (Abbvie, Gilead, Merck). Financial support statement: none of the authors received financial support in order to write the manuscript. Authors contributions: AT was involved in acquisition of data; analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript for important intellectual content. DKW was involved in acquisition of data; analysis and interpretation of data; drafting of the manuscript; critical revision of the manuscript for important intellectual content. Acknowledgements: We would like to thank Ms. Nancy Sheehan for providing antiretroviral concentration analysis and interpretation for case 3.
Lay summary: A rare side effect of ledipasvir/sofosbuvir is liver injury, which occurs within 2-6 weeks of starting treatment. Total and direct bilirubin values are greatly increased, and worsening of liver function may occur; symptoms are usually reversible when treatment is stopped. An interaction with lopinavir/ritonavir may contribute to this adverse effect.
3 To the Editor:
Hepatotoxicity in HIV-HCV infected patients receiving ledipasvir/sofosbuvir with or without ribavirin has been reported.1-3 We describe 3 additional cases of probably/highly probable drug-induced liver injury (DILI) with ledipasvir/sofosbuvir using established causality tools (Naranjo, RUCAM)4, 5. Our cases with those previously described confirm a consistent presentation for this rare but serious adverse effect. We also identify a potential interaction with lopinavir which may have contributed to this DILI; this has important clinical implications since early initiation of antiretroviral therapy (ART) is encouraged in coinfected patients.6 From 2014-2015, 67 HCV/HIV infected patients at our centre were treated with ledipasvir/sofosbuvir (4 with ribavirin). During treatment, none had elevations of ALT/AST, ALP/GGT, INR or fall in albumin from baseline. Three patients had isolated bilirubin increases with peak elevations 2-14 times the upper normal limit (ULN) within two weeks of initiating ledipasvir/sofosbuvir for HCV genotype 1a . Case 1 (Figure 1a): A 60-year old treatment-naïve woman with Childs B cirrhosis had bilirubin rise at week 2 and developed ascites at week 4 resulting in early treatment discontinuation. Bilirubin improved within 10 days of stopping ledipasvir/sofosbuvir and returned to baseline by 7 weeks. She achieved SVR12. Case 2 (Figure 1b): A 66 year old previously treated (ribavirin-pegylated interferon) male with Childs A cirrhosis and moderate renal dysfunction had bilirubin rise at week 2 with symptoms of persistent fatigue and malaise. At week 6, bilirubin peaked and ART was changed to stop lopinavir and tenofovir. Bilirubin improved one week later and returned to baseline after three weeks with symptom resolution. He has completed 21 of 24 planned weeks of ledipasvir/sofosbuvir therapy.
4 Case 3 (Figure 1c): A 50 year old treatment-naïve, non-cirrhotic male had bilirubin rise by week 2, with symptoms of dizziness, nausea, and constipation. Bilirubin peaked at week 4 and remained elevated throughout 12 weeks of treatment. Bilirubin returned to baseline and symptoms resolved one month after treatment completion. Stored sera for antiretroviral concentrations were available. Compared to baseline, lopinavir, raltegravir and maraviroc concentrations were increased 20%, 305% and 200%, respectively while on ledipasvir/sofosbuvir. He achieved SVR12. Our report doubles the number of published cases of hepatotoxicity with ledipasvir/sofosbuvir in HIVHCV patients.1-3 The pattern of toxicity described in all cases is strikingly similar. All patients had undetectable HIV viral load and were on stable antiretroviral therapy (1.5 to over 4 years duration for our cases) prior to starting ledipasvir/sofosbuvir. Onset of symptoms was rapid, within 2-6 weeks; clinical presentation was acute cholestasis with increased total and direct bilirubin in the context of improving/stable liver enzymes. All patients were symptomatic. Hepatic decompensation occurred in 3 subjects with decompensated cirrhosis and MELD scores of 13 and higher. In 5/6 cases, symptoms resolved and bilirubin improved after stopping ledipasvir/sofosbuvir or modification of ART. Causality assessments using the Naranjo and RUCAM scales suggest a probable or highly probable DILI associated with ledipasvir/sofosbuvir. Of note, all three of our cases as well as two of the 3 other cases in the literature were on lopinavir/ritonavir.1, 2 One patient described by Dyson et al.3 was not on lopinavir/ritonavir, but was the only case with prior hepatic decompensation and had the highest MELD score. This patient was on efavirenz, which can rarely be associated with hepatotoxicity.7 For our 3 cases, a possible/probable interaction between ledipasvir/sofosbuvir and ART was identified using DIPS causality assessment.8 The exact nature of potential interactions between ledipasvir/sofosbuvir and antiretrovirals is difficult to elucidate. Tenofovir exposures are increased 40-98% in the presence of ledipasvir/sofosbuvir,9 but
5 this would be expected to result in renal dysfunction. To date, hyperbilirubinemia with tenofovir has not been reported. Our third patient, as well as two other reported cases1, 2 were not on tenofovir. A probable interaction may exist between lopinavir and ledipasvir/sofosbuvir. In healthy volunteers, atazanavir trough concentrations were increased 63% with coadministration of ledipasvir/sofosbuvir,10 possibly due to P-gp inhibition by ledipasvir leading to decreased drug clearance. Lopinavir concentrations may similarly be increased by ledipasvir. This is supported by increased lopinavir exposures in our third patient during ledipasvir/sofosbuvir treatment compared to baseline. This patient also experienced a significant increase in maraviroc concentrations during ledipasvir/sofosbuvir treatment, which may have occurred due to the same mechanism. Of note, our second patient improved when lopinavir/ritonavir was switched to darunavir/ritonavir while continuing ledipasvir/sofosbuvir. In the previous study, coadministration of ledipasvir/sofosbuvir and darunavir/ritonavir did not alter darunavir exposures,10 perhaps because darunavir is associated with some enzyme inducing effects. Therefore, it is possible that his symptoms were secondary to increased lopinavir exposures which resolved with the switch to darunavir. In conclusion, DILI manifesting as significant bilirubin rise within 2 weeks of initiating ledipasvir/sofosbuvir while on ART may occur with symptoms and possibly hepatic decompensation. Cessation of treatment or alteration of potentially interacting antiretrovirals usually leads to rapid resolution. Coadministration of lopinavir/ritonavir with ledipasvir/sofosbuvir should be avoided until further data are available.
6 References: 1.
Marchan-Lopez A, Dominguez-Dominguez L, Kessler-Saiz P, et al. Liver failure in human immunodeficiency virus - Hepatitis C virus coinfection treated with sofosbuvir, ledipasvir and antiretroviral therapy. J Hepatol 2015 Dec 9.
2.
Dyson JK, McPherson S. Reply to "Liver failure in human immunodeficiency virus - Hepatitis C virus coinfection treated with sofosbuvir, ledipasvir and antiretroviral therapy". J Hepatol 2015 Dec 10.
3.
Dyson JK, Hutchinson J, Harrison L, et al. Liver toxicity associated with sofosbuvir, an NS5A inhibitor and ribavirin use. J Hepatol 2016 Jan;64(1):234-8.
4.
Naranjo CA, Busto U, Sellers EM, et al. A method for estimating the probability of adverse drug reactions. Clin Pharmacol Ther 1981 Aug;30(2):239-45.
5.
Chalasani NP, Hayashi PH, Bonkovsky HL, et al. ACG Clinical Guideline: the diagnosis and management of idiosyncratic drug-induced liver injury. The American journal of gastroenterology 2014 Jul;109(7):950-66; quiz 67.
6.
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. Department of Health and Human Services. Federal register January 28, 2016. p. 1-277 Available from: http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf.
7.
Sulkowski MS, Thomas DL, Mehta SH, et al. Hepatotoxicity associated with nevirapine or efavirenz-containing antiretroviral therapy: role of hepatitis C and B infections. Hepatology 2002 Jan;35(1):182-9.
8.
Horn JR, Hansten PD, Chan LN. Proposal for a new tool to evaluate drug interaction cases. Ann Pharmacother 2007;41(4):674-80.
9.
Gilead Sciences Canada Inc. Harvoni (ledipasvir/sofosbuvir) Product Monograph. Mississauga, ON October 14, 2014.
10.
German P, Garrison K, Pang P, et al. Drug-drug interactions between anti-HCV regimen ledipasvir/sofosbuvir and antiretrovirals [abstract 82]. Conference on Retroviruses and Opportunistic Infections (CROI), February 23-26, 2015, Seattle, WA.
7 Figure 1 Legend. Fig. 1. Pattern of liver function tests in relation to ledipasvir/sofosbuvir treatment in 3 cases of druginduced liver injury (DILI). (A) Case 1 with total bilirubin increase to 4 times ULN by week 2, peak of 7.36 times ULN at week 4 with symptomatic hepatic decompensation, and resolution 7 weeks after ledipasvir/sofosbuvir discontinuation. (B) Case 2 with total bilirubin increase to 3.13 times ULN by week 2, peak of 5.95 times ULN at week 6, resolution 3 weeks after changing antiretrovirals and continuing ledipasvir/sofosbuvir. (C) Case 3 with total bilirubin increase to 1.6 times ULN by week 2, peak of 2 times ULN at week 4 and resolution 4 weeks after completing ledipasvir/sofosbuvir treatment.