CLINICALLY SIGNIFICANT DRUG-DRUG INTERACTION IN A LARGE ANTIRETROVIRAL TREATMENT CENTRE IN LAGOS, NIGERIA
Main Article Content
Keywords
potential drug interaction, antiretroviral therapy, co-prescribed non-antiretroviral
Abstract
Background
An important cause of treatment failure to antiretroviral therapy (ART) is the potential interaction between the antiretroviral (ARV) drugs and concomitant drugs (CD) used for the treatment of opportunistic infections and comorbid ailments in HIV-infected patients.
Objectives
The study evaluated potential Clinically Significant Drug Interactions (CSDIs) occurring between recommended ART regimens and their CD.
Method
This study was carried out in a large HIV treatment centre supported by AIDS Preventive initiative in Nigeria (APIN) clinic in a teaching hospital in Lagos, Nigeria, caring for over 20,000 registered patients. Electronic Medical Records (EMRs) of 500 patients, who received treatment between 2005 and 2015, were selected using systematic random sampling, reviewed retrospectively, and evaluated for potential CSDIs using Liverpool HIV Pharmacology Database and other databases for drug-drug interaction check.
Results
Majority of patients, 421 (84%) prescribed CDs were at risk of CSDIs, of which 410 (82%) were moderate and frequently involved co-trimoxazole + combinations of Nucleoside Reverse Transcriptase Inhibitors (NRTIs) such as zidovudine (or stavudine) /lamivudine 386 (77.2%) and Non-nucleoside Reverse Transcriptase Inhibitors (NNRTIs) or Protease Inhibitors (PIs) + artemisinin-based combination therapies (ACTs) 296 (59.2%). Age (p=0.13), sex (p=0.32) and baseline CD4+ cell counts (p=0.20) were not significantly associated with CSDIs. The interactions, however, were significantly associated with the development of antiretroviral treatment failure (p <0.001) which occurred in nearly a third 139 (27.8%) of the patients.
Conclusion
There is a high prevalence of CSDIs between ART and CDs, most of which were categorized as moderate. Further studies are required to evaluate the pharmacokinetic and clinical relevance of these interactions.
References
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4. Lorenzi P, Opravil M, Hirschel B, et al. Impact of drug resistance mutations on virologic response to salvage therapy. Swiss HIV Cohort Study AIDS 1999;13:17–21.
5. Kwobah C, Mwangi AW, Koech JK, Simiyu GN, Siika AM. Factors associated with first-line antiretroviral therapy failure amongst hiv-infected african patients: a case-control study. World J AIDS 2012;2:271–78.
6. Pirmohammed M. Drug-drug interactions and adverse drug reactions: separating the wheat from the chaff. Wien KlinWochenschr 2010;122:62–64.
7. Ingolf Cascorbi. Drug interactions—principles, examples and clinical consequences. Dtsch Arztebl Int 2012;109(33-34):546–56.
8. LaPorte C, Colbers E, Bertz R, et al. Pharmacokinetics of adjusted-dose lopinavir-ritonavir combined with rifampin in healthy volunteers. Antimicrob Agents Chemother 2004;48:1553–60.
9. Breen RA, Lipman MC, Johnson MA. Increased incidence of peripheral neuropathy with co-administration of stavudine and isoniazid in HIV-infected individuals. AIDS 2000;14:615.
10. Xu, C., and Desta Z. In vitro analysis and quantitative prediction of efavirenz inhibition of eight cytochrome P450 (CYP) enzymes (2013): major effects on CYPs 2B6, 2C8, 2C9 and 2C19. Drug Metab Pharmacokin 28(4):362–71.
11. Faucette SR, Zhang TC, Moore R, et al. Relative activation of human pregnane X receptor versus constitutive androstane receptor defines distinct classes of CYP2B6 and CYP3A4 inducers. J Pharmacol Experiment Ther 2007;320(1):72–80.
12. Dixit V, Hariparsad N, Li F, et al. Cytochrome P450 enzymes and transporters induced by anti-human immunodeficiency virus protease inhibitors in human hepatocytes: implications for predicting clinical drug interactions. Drug Metab Disp 2007;35(10)1853–59.
13. Sulaiman A, Akanmu, Usman SO, Oreagba IA, et al. Antiretrovirals and Co-prescribed drugs for people living with HIV/AIDS (PLWHA) in a University Teaching Hospital, South-West Nigeria. West African J Pharm 2015;26(2):103–115.
14. Oshikoya KA, Oreagba IA, Lawal S, Awodele O, et al. Potential drug-drug interactions in HIV-infected children on antiretroviral therapy in Lagos, Nigeria. HIV/AIDS Res Palliat Care 2014;6:49–59.
15. Boyd MA, Zhang X, Dorr A, et al. Lack of enzyme inducing effect of rifampicin on the pharmacokinetics of enfuvirtide. J Clin Pharmacol 2003;43:1382–91.
16. Williamsona B, Dooleyb KE, Zhanga Y, et al. Induction of influx and efflux transporters and cytochrome P450 3A4 in primary human hepatocytes by rifampin, rifabutin, and rifapentine. Antimicrob. Agents Chemother 2013;57(12):6366–69.
17. Hughes CA, Foisy M, Tseng A. Interactions between antifungal and antiretroviral agents. Expert Opin Drug Saf 2010;9(5):723–42.
18. Marzolini C, Elzi L, Gibbons S, et al. Swiss HIV Cohort Study Prevalence of comedications and impact of potential drug-drug interactions in the Swiss HIV Cohort Study. Antivir Ther 2010;15:413–423.
19. Miller CD, El-Kholi R, Faragon JJ, Lodise TP. Prevalence and risk factors for clinically significant drug interactions with antiretroviral therapy. Pharmacotherapy 2007;27:1379–86.
20. Kigen G, Kimaiyo S, Nyandiko W, et al. USAID Academic Model for Prevention Treatment of HIV/AIDS Prevalence of potential drug-drug interactions involving antiretroviral drugs in a large Kenyan cohort. PLoS One 2010;6:e16800 f30.
21. Liverpool HIV Pharmacology Group (LHPG). Available at: http://www.hiv-druginteractions.org/main.aspx?PageId=7.
22. Drugs.com. Drug interactions. Available at: https://www.drugs.com/interactions-check.php?drug_listf28
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24. Armahizer M, Kane-Gill SL, Smithburger PL, Anthes AM, Seybert AL. Comparing drug-drug interaction severity for clinician opinion to proprietary databases. Adv Pharmacoepidemiol Drug Saf 2012;1:115. F29.
25. Chatton JY, Munafo A, Chave JP, et al. Trimethoprim, alone or in combination with sulphamethoxazole, decreases the renal excretion of zidovudine and its glucuronide. Br J Clin Pharmacol 1992;34:551–54.
26. Sahai J, Gallicano K, Pakuts A, Cameron DW Effect of fluconazole on zidovudine pharmacokinetics in patients infected with human immunodeficiency virus. J Infect Dis 169(1994):1103–1107.
27. Brockmeyer NH, et al. Pharmacokinetic interaction of fluconazole and zidovudine in HIV-positive patients. Eur J Med Res 1997;2:377–383.
28. Kredo T, Mauff K, Van der Walt JS, et al. The interaction between artemether-lumefantrine and NVP-based antiretroviral therapy in HIV-1 infected patients. Antimicrob Agents Chemother 2011;55(12):5616–23.
29. von Moltke LL, Greenblatt DJ, Granda BW, et al. Inhibition of human cytochrome P450 isoforms by nonnucleoside reverse transcriptase inhibitors. J Clin Pharmacol 2001;41(1):85–91.
30. Van Agtmael MA, Cheng-Qi S, Qing JX, Mull R, van Boxtel CJ. Multiple dose pharmacokinetics of artemether in Chinese patients with uncomplicated falciparum malaria. Int J Antimicrob Agents 1999;12:151–58.
31. Moore KHP, Yuen GJ, Raasch RH, Eron JJ, Martin D, Mydlow PK, Hussey EK. Pharmacokinetics of lamivudine administered alone and with trimethoprim-sulfamethoxazole. Clin Pharmacol Ther 1996;59:550–58
32. Fehintola AF,Scarsi KK,Ma Q,et al. NVP-based antiretroviral therapy impacts artesunate and dihydroartemisinin disposition in HIV-Infected Nigerian adults. Aids Res Treat 2012;Doi:10: 1155/2012/703604
33. Scarsi KK, Fehintola FA, Ma Q, et al. Disposition of amodiaquine and desethylamodiaquine in HIV-infected Nigerian subjects on nevirapine-containing antiretroviral therapy. J Antimicrob Chemother 2014;69(5):1370–76.
34. Akiyoshi Marie T, Murase S, Miyazaki M et al. Mechanism-based inhibition profiles of erythromycin and clarithromycin with cytochrome P450 3A4 genetic variants. Drug Metab Pharmacokin 2013;28(5):411–15.
35. Ribera E, Pou L, Lopez RM, et al. Pharmacokinetic interaction between nevirapine and rifampicin in HIV-infected patients with tuberculosis. J Acquir Immune Defic Syndr 2001;15;28(5):450–53.
36. Brennan-Benson P, Lyus R, Harrison T, et al. Pharmacokinetic interactions between efavirenz and rifampicin in the treatment of HIV and tuberculosis: one size does not fit all. AIDS 2005;19:1541–43.
37. Byakika-Kibwika P, Lamorde M, Mayito J, et al. Significant Pharmacokinetic interactions between artemether/lumefantrine and efavirenz or nevirapine in HIV-infected Ugandan adults. J Antimicrob Chemother 2012;67(9):2213–21.
38. German P, Greenhouse B, Coates C, et al. Hepatotoxicity due to a drug interaction between amodiaquine plus artesunate and efavirenz. Clin Infect Dis 2007;44:889–91.
39. Cong Xu and Zeruesenay Desta. In vitro analysis and quantitative prediction of efavirenz inhibition of eight cytochrome P450 (CYP) enzymes: major effects on CYPs 2B6, 2C8, 2C9 and 2C19. Drug Metab Pharmacokinet 2013;28(4):362–71.
40. Elsharkawy AM, Schwab U, McCarron B, et al. Efavirenz induced acute liver failure requiring liver transplantation in a slow drug metaboliser. J Clin Virol 2013;58:331–3.
41. Wang P, Pradhan K, Zhong X and Ma X Isoniazid metabolism and hepatotoxicity. Acta Pharm Sin B 2016;6(5):384–92.
42. German P, Parikh S, Lawrence J, et al. Lopinavir/ritonavir affects pharmacokinetic exposure of artemether/lumefantrine in HIV-uninfected healthy volunteers. J Acquir Immune Defic Syndr 2009;51(4):424–29.
43. Yeh RF, Gaver VE, Patterson KB, et al Rezk. Lopinavir/ritonavir induces the hepatic activity of cytochrome P450 enzymes CYP2C9, CYP2C19, and CYP1A2 but inhibits the hepatic and intestinal activity of CYP3A as measured by a phenotyping drug cocktail in healthy volunteers. J Acquired Immune Def Synd 2006;42:52–60.
44. Gunness P, Aleksa K, Koren G. The effect of acyclovir on the tubular secretion of creatinine in vitro. J Transl Med 2010;8:139.
45. Wyen C, Fuhr U, Frank D, et al. Effect of an antiretroviral regimen containing ritonavir boosted lopinavir on intestinal and hepatic CYP3A, CYP2D6 and P-glycoprotein in HIV-infected patients. Clin Pharmacol Ther 2008;84(1):75–82.
46. Dixit A, Hariparsad N, Li F, et al. Cytochrome P450 enzymes and transporters induced by anti-human immunodeficiency virus protease inhibitors in human hepatocytes: implications for predicting clinical drug interactions. Drug Metab Disposit 2007;35(10)1853–59.
47. Khaliq Y, Gallicano K, Tisdale C, et al. Pharmacokinetic interaction between mefloquine and ritonavir in healthy volunteers. Br J Clin Pharmacol 2001;51:591–600
48. Krudsood S, Looareesuwan P, Wilairatama W, et al. Effect of artesunate and mefloquine in combination on the Fridericia corrected QT intervals in Plasmodium falciparum infected adults from Thailand. Trop Med Internat Health 2011;16(4):458–65.
49. Briasoulis A, Agarwal V and·Pierce WJ. QT prolongation and torsade de pointes induced by fluoroquinolones: infrequent side effects from commonly used medications. Cardiology 2011;120:103–110
50. Kharasch ED, Mitchell D, Coles R, and Blanco R. Rapid clinical induction of hepatic cytochrome P450 2B6 activity by ritonavir. Antimicrob Agents Chemother May 2008;52(5)1663–69.
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Jan 22, 2019
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Oreagba, I., Usman, S., Oshikoya, K., Akinyede, A. . ., Agbaje, E., Opanuga, O., & Akanmu, S. (2019). CLINICALLY SIGNIFICANT DRUG-DRUG INTERACTION IN A LARGE ANTIRETROVIRAL TREATMENT CENTRE IN LAGOS, NIGERIA. Journal of Population Therapeutics and Clinical Pharmacology, 26(1), e1-e19. https://doi.org/10.22374/1710-6222.26.1.1
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How to Cite
Oreagba, I., Usman, S., Oshikoya, K., Akinyede, A. . ., Agbaje, E., Opanuga, O., & Akanmu, S. (2019). CLINICALLY SIGNIFICANT DRUG-DRUG INTERACTION IN A LARGE ANTIRETROVIRAL TREATMENT CENTRE IN LAGOS, NIGERIA. Journal of Population Therapeutics and Clinical Pharmacology, 26(1), e1-e19. https://doi.org/10.22374/1710-6222.26.1.1