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Drug Interactions of Hepatitis C Direct-Acting Antivirals in the HIV-Infected Person

  • Co-infections and Comorbidity (S Naggie, Section Editor)
  • Published:
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Abstract

The development of direct-acting antivirals for hepatitis C has occurred at a rapid pace. Up to recently, HCV therapy has been limited to pegylated-interferon and ribavirin, but now physicians have several highly efficacious and well-tolerated interferon-free direct-acting antiviral agent (DAA) regimens available. In order to minimise patient harm and maximise the response to therapy, physicians must remain cognisant of the potential DAA drug-drug interactions in patients with HIV/HCV co-infection. HCV clearance needs to be achieved while maintaining HIV suppression and not compromising future antiretroviral options. CYP450 enzyme induction or inhibition accounts for many of the pharmacokinetic interactions between HCV DAA and HIV antiretrovirals, although an increasing number of transporter-mediated interactions are now recognised. DAA interactions in the HIV/HCV co-infected patient are largely extrapolated from drug-drug interaction studies with commonly used antiretrovirals. These studies then inform the selection of permitted antiretroviral regimens in phase II and III DAA clinical studies in HIV/HCV co-infection. We review the recently reported drug-drug interaction studies of HCV DAA therapy in the HIV-infected person and the HIV antiretroviral combinations in HCV DAA clinical trials.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Palella Jr FJ, Baker RK, Moorman AC, et al. Mortality in the highly active antiretroviral therapy era: changing causes of death and disease in the HIV outpatient study. J Acquir Immune Defic Syndr. 2006;43(1):27–34.

    Article  CAS  PubMed  Google Scholar 

  2. Hernando V, Perez-Cachafeiro S, Lewden C, et al. All-cause and liver-related mortality in HIV positive subjects compared to the general population: differences by HCV co-infection. J Hepatol. 2012;57(4):743–51.

    Article  PubMed  Google Scholar 

  3. Koziel MJ, Peters MG. Viral hepatitis in HIV infection. N Engl J Med. 2007;365:1445–54.

    Article  Google Scholar 

  4. Amin J, Kaye M, Skidmore S, et al. HIV and hepatitis C coinfection within the CAESAR study. HIV Med. 2004;5:174–9.

    Article  CAS  PubMed  Google Scholar 

  5. Chen J, Feeney E, Chung R. HCV and HIV co-infection: mechanisms and management. Nat Rev Gastroenterol Hepatol. 2014;11:363–71.

    Article  Google Scholar 

  6. EASL Recommendations on Treatment of Hepatitis C 2015. J Hepatol. 2015; doi:10.1016/j.jhep.2015.03.025 These recent recommendations provide guidance on treating patients with HIV/HCV co-infection, including a detailed section on clinical pharmacology and drug-drug interactions.

  7. American Association of the study of liver diseases (AASLD)-Infectious Diseases Society of America (IDSA) recommendations for testing, managing, and treating Hepatitis C. http://www.hcvguidelines.org. Clinical guidance in the USA for the use of HCV direct-acting antiviral as well as guidance on drug-drug interactions and their management in this with HIV/HCV co-infection.

  8. Van Der Meer AJ, Veldt BJ, Feld JJ, et al. Association between sustained virological response and all-cause mortality among patients with chronic hepatitis C and advanced hepatic fibrosis. JAMA. 2012;308(24):2584–93.

    Article  PubMed  Google Scholar 

  9. Berenguer J, Alvarez-Pellicer J, Martin PM, et al. Sustained virological response to interferon plus ribavirin reduces liver-related complication and mortality in patients co-infected with human immunodeficiency virus and hepatitis C virus. Hepatology. 2009;50(2):407–13.

    Article  CAS  PubMed  Google Scholar 

  10. Laguno M, Cifuentes C, Murillas J, et al. Randomised trial comparing pegylated interferon alpha-2b versus pegylated interferon alpha-2a, both plus ribavirin, to treat chronic hepatitis C in human immunodeficiency virus patients. Hepatology. 2009;49(1):22–31.

    Article  CAS  PubMed  Google Scholar 

  11. Sulkowski MS, Sherman KE, Dieterich DT, et al. Combination therapy with telaprevir for chronic hepatitis C virus genotype 1 infection in patients with HIV: a randomised trial. Ann Intern Med. 2013;159:86–96.

    PubMed  Google Scholar 

  12. Sulkowski M, Pol S, Mallolas J, et al. Boceprevir versus placebo with pegylated interferon alfa-2b and ribavirin for treatment of hepatitis C virus genotype 1 in patients with HIV: a randomised, double-blind, controlled phase 2 trial. Lancet Infect Dis. 2013;13:597–605.

    Article  CAS  PubMed  Google Scholar 

  13. Karageorgopoulos D, El-Sherif O, Bhagani S, et al. Drug interactions between antiretrovirals and new or emerging direct-acting antivirals in HIV/hepatitis C virus coninfection. Curr Opin Infect Dis. 2014;27:36–45.

    Article  CAS  PubMed  Google Scholar 

  14. Hodgson K. ADMET—turning chemicals into drugs. Nat Biotechnol. 2001;19(8):722–6.

    Article  CAS  PubMed  Google Scholar 

  15. The International Transporter consortium. Membrane transporters in drug development. Nat Rev Drug Discov. 2010;9(3):215–36.

    Article  PubMed Central  Google Scholar 

  16. Kiser J, Burton JR, Everson G. Drug-drug interactions during antiviral therapy for chronic hepatitis C. Nat Rev Gastroenterol Hepatol. 2013;10:596–606.

    Article  CAS  PubMed  Google Scholar 

  17. German P, Pang PS, West S et al. Drug interactions between direct-acting anti-HCV antivirals sofosbuvir and ledipasvir and HIV antiretrovirals. Abstract: 15th International Workshop on Clinical Pharmacology of HIV & Hepatitis Therapy; 2014; Washington, DC.

  18. Naggie S, Cooper C, Saag M et al. Ledipasvir and sofosbuvir for HCV in patients co-infected with HIV-1. N Engl J Med. 2015, in press. This large phase III study demonstrated the safety and efficacy of this DAA combination in the setting of HIV/HCV co-infection and provides valuable safety data and interaction data for several antiretroviral combinations when given with sofosbuvir and ledipasvir.

  19. Kirby B, Mathias A, Rossi S et al. No clinically significant interactions between GS-7977 and HIV antiretrovirals Atripla, rilpivirine, darunavir or raltegravir in healthy volunteers. Abstract No 1877: 63rd Annual Meeting of the American Association for the Study of Liver Disease; 2012; Boston, MA.

  20. German P, Garrison K, Pang PS et al. Drug interactions between the anti-HCV regimen ledipasvir/sofosbuvir and ritonavir boosted protease inhibitors plus FTC/TDF. Abstract: 22nd Conference on Retroviruses and Opportunistic Infections; 2015; Seattle, Washington.

  21. Garrison K, Custodio J, Pang P et al. Drug interactions between anti-HCV antivirals ledipasvir/sofosbuvir and integrase strand transfer inhibitor-based regimens. Abstract: 16th International Workshop on Clinical Pharmacology of HIV & Hepatitis Therapy; 2015; Washington, DC.

  22. Sekar V, Verloes R, Meyvisch P, et al. Evaluation of metabolic interactions for TMC435 via cytochrome P450 (CYP) enzymes in healthy volunteers. J Hepatol. 2010;52(S1):S416.

    Google Scholar 

  23. Ouwerkerk-Mahadevan S, Sekar V, Simion A et al. The pharmacokinetic interactions of the HCV protease inhibitor TMC-435 with HIV antiretroviral agents in healthy volunteers. Abstract: Infectious Disease Society Association Conference; 2012; San Diego, CA.

  24. Eley T, You X, Wang R, et al. Daclatasvir: overview of drug-drug interactions with antiretroviral agents and other common concomitant drugs. Abstract: HIV DART; 2014; Miami, FL.

  25. Bristol-Myers Squibb. Daklinza film-coated tablets. [Prescribing Information]. BMS Pharmaceutical Ltd, Middlesex, United Kingdom.

  26. Bow DAJ, Liu J, Kavetskaia O et al. A mechanistic non-clinical assessment of drug-drug interactions (metabolism and transporters) with the HCV regimen: ABT-450/r, ombitasvir, and dasabuvir. Poster Presentation: AASLD/EASL Special Conference on Hepatitis C, 2014.

  27. Menon R, Badri P, Khatri A et al. ABT-450/ritonavir + ombitasvir + dasabuvir: drug interactions mediated by transporters. Abstract: 15th International Workshop on Clinical Pharmacology of HIV & Hepatitis Therapy, 2014.

  28. AbbVie Corporation. Viekerax 12.5mg/75mg/50mg film-coated tablet. [Prescribing Information] AbbVie Ltd, Maidenhead, United Kingdom.

  29. AbbVie Corporation. Exviera 250mg film-coated tablet. [Prescribing Information] AbbVie Ltd, Maidenhead, United Kingdom.

  30. Menon R, Badri P, Wang T, et al. Drug-drug interaction profile of the All-oral hepatitis C virus regimen of paritaprevir/ritonavir, ombitasvir and dasabuvir. J Hepatol. 2015;63:20–9.

    Article  CAS  PubMed  Google Scholar 

  31. Khatri A, Wang T, Wang H et al. Drug-drug interactions of the direct acting antiviral regimen of ABT-450/r, ombitasvir, and dasabuvir with HIV protease inhibitors. Abstract: 54th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); 2014; Washington DC.

  32. Kharti A, Wang T, Wang H et al. Drug-drug interactions of the direct acting antiviral regimen of ABT-450/r, ombitasvir, and dasabuvir with emtricitabine + tenofovir, raltegravir, rilpivirine and efavirenz. Abstract: 54th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC); 2014; Washington DC.

  33. Yeh W, Marenco T, Feng H-P et al. Drug-drug interaction between HCV inhibitors grazoprevir/elbasvir with dolutegravir. Abstract: 22nd Conference on Retroviruses and Opportunistic Infections; 2015; Seattle, Washington.

  34. Yeh W, Fraser IP, Caro L et al. No meaningful PK interaction between the HCV protease inhibitor MK-5172 and tenofovir or raltegravir. Abstract: Conference on retroviruses and opportunistic infections (CROI), 2014, Boston, MA.

  35. Caro L, Talaty JE, Guo Z et al. Pharmacokinetic interactions between the HCV protease inhibitor MK-5172 and ritonavir boosted protease inhibitors (atazanavir, lopinavir, darunavir) in healthy volunteers. Abstract 487: 64th Annual Meeting of the American Association for the Study of Liver diseases (AASLD), 2013, Washington DC.

  36. Yeh WY, Marshall W, Ma J et al. Ritonavir-boosted atazanavir, lopinavir, and darunavir increase HCV NS5A inhibitor MK-8742 levels. Abstract: Conference on retroviruses and opportunistic infections (CROI), 2014, Boston, MA.

  37. Talaty JE, Carol L, Yeh W et al. Pharmacokinetic interaction between the HCV protease inhibitor MK-5172 and efavirenz in normal healthy volunteers. Abstract 492: 64th Annual Meeting of the American Association for the Study of Liver diseases (AASLD), 2013, Washington DC.

  38. Yeh W, Marshall W, Mangin E et al. Pharmacokinetic interactions between the HCV NS5A inhibitor MK-8742 and efavirenz. Abstract: Conference on retroviruses and opportunistic infections (CROI), 2014, Boston, MA.

  39. Wyles DL, Ruane P, Sulkowski MS et al. Daclatasvir plus sofosbuvir for treatment of HCV genotypes 1-4 in HIV-HCV co-infection: the ALLY-2 study. Abstract: 50th annual meeting of the European association for the study of the liver, April 22–26, Vienna, Austria.

  40. Sulkowski MS, Eron JJ, Wyles D, et al. Ombitasvir, paritaprevir co-dosed with ritonavir, dasabuvir, and ribavirin for hepatitis C in patients co-infected with HIV-1: a randomised trial. JAMA. 2015;313(12):1223–31. A phase IIb study which provides a proof of concept of the efficacy of this augmented triple therapy regimen in patients with HIV-HCV co-infection as well as safety data of this combination with NNRTI-based regimens with atazanavir and raltegravir.

    Article  CAS  PubMed  Google Scholar 

  41. Rockstroch J, Nelson M, Katlama C et al. C-Edge coinfection: phase 3 study of grazoprevir and elbasvir in patients with HCV/HIV. Abstract: 50th annual meeting of the European association for the study of the liver, April 22–26, Vienna, Austria. High SVR rates were observed with the combination of grazoprevir and elbasvir in this phase III study of treatment naïve cirrhotics and non-cirrhotics with HIV infection and HCV genotypes 1 and 4.

  42. Herold C, Heinz R, Niedobitek G, et al. Quantitative testing of liver function in relation to fibrosis in patients with chronic hepatitis B and C. Liver. 2001;21:260–5.

    Article  CAS  PubMed  Google Scholar 

  43. Chalasani N, Gorski JC, Patel NH, et al. Hepatic and intestinal cytochrome P450 3A activity in cirrhosis: effects of transjugular intrahepatic portosystemic shunts. Hepatology. 2001;34:1103–8.

    Article  CAS  PubMed  Google Scholar 

  44. German P, Yang J, West S et al. Effect of food and acid reducing agents on the relative bioavailability and pharmacokinetics of ledipasvir/sofosbuvir fixed-dose combination tablet. Abstract: 15th International Workshop on Clinical Pharmacology of HIV & Hepatitis Therapy, 2014.

  45. FDA. FDA Drug Safety Communication: FDA warns of serious slowing of the heart rate when antiarrhythmic drug amiodarone is used with hepatitis C treatments containing sofosbuvir Harvoni or Sovaldi in combination with another direct acting antiviral drug. Available at http://www.fda.gov. Accessed 15 June 2015.

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Conflicts of Interest

Omar El-Sherif has received conference travel and accommodation support from AbbVie, Janssen and MSD.

D. Back reports grants and personal fees from Abbvie, Gilead, Merck and Janssen; and grants from BMS, outside the submitted work.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

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Authors and Affiliations

  1. St. James’s Hospital, Dublin, Ireland

    O. El-Sherif

  2. Department of Molecular and Clinical Pharmacology, Institute of Translational Medicine, University of Liverpool, Liverpool, UK

    D. Back

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  1. O. El-Sherif
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Correspondence to O. El-Sherif.

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This article is part of the Topical Collection on Co-infections and Comorbidity

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El-Sherif, O., Back, D. Drug Interactions of Hepatitis C Direct-Acting Antivirals in the HIV-Infected Person. Curr HIV/AIDS Rep 12, 336–343 (2015). https://doi.org/10.1007/s11904-015-0277-5

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  • DOI: https://doi.org/10.1007/s11904-015-0277-5

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