Artemether-Lumefantrine Combination Therapy for Treatment of Uncomplicated Malaria: The Potential for Complex Interactions with Antiretroviral Drugs in HIV-Infected Individuals
Treatment of malaria in HIV-infected individuals receiving antiretroviral therapy (ART) poses significant challenges. Artemether-lumefantrine (AL) is one of the artemisisnin-based combination therapies recommended for treatment of malaria. The drug combination is highly efficacious against sensitive and multidrug resistant falciparum malaria. Both artemether and lumefantrine are metabolized by hepatic cytochrome P450 (CYP450) enzymes which metabolize the protease inhibitors (PIs) and nonnucleoside reverse transcriptase inhibitors (NNRTIs) used for HIV treatment. Coadministration of NNRTIs and PIs with AL could potentially cause complex pharmacokinetic drug interactions. NNRTI by inducing CYP450 3A4 enzyme and PIs by inhibiting CYP450 3A4 enzymes could influence both artemether and lumefantrine concentrations and their active metabolites dihydroartemisinin and desbutyl-lumefantrine, predisposing patients to poor treatment response, toxicity, and risk for development of resistance. There are scanty data on these interactions and their consequences. Pharmacokinetic studies to evaluate these interactions in the target populations are urgently needed. 1. Introduction Human immunodeficiency virus (HIV) and malaria have overlapping geographical distribution. Together, the two diseases account for 4 million deaths a year worldwide [1]. Over 90% of the world malaria burden occurs in sub-Saharan Africa, the region with 67% of the global HIV burden. Given the extensive overlap in geographical distribution of the two diseases, any interaction between the two could have profound public health consequences. In areas with stable malaria transmission, HIV increases risk of malaria infection and clinical malaria especially in individuals with advanced immunosuppression and in areas with unstable malaria transmission; HIV-infected individuals are at increased risk for severe malaria and death [1, 2]. This vulnerable population requires prompt, safe and effective antimalarial treatment. Current guidelines for malaria treatment advocate use of artemisinin-based combination therapies (ACTs). Treatment of malaria in HIV-infected individuals receiving ART poses significant challenges with gaps in the knowledge of ART and ACT drug-drug interactions and their consequences. Antiretroviral drugs are among the most therapeutically risky drugs for drug-drug interactions due to the potent inhibition and induction of cytochrome (CYP) enzymes as well as transport proteins. The combination of at least three drugs for highly active ART increases the risk for drug-drug interactions. The
References
[1]
Malaria and HIV and Their Implications for Public Policy, World Health Organisation, Geneva, Switzerland, 2005.
[2]
V. Chalwe, J. P. Van Geertruyden, D. Mukwamataba et al., “Increased risk for severe malaria in HIV-1-infected adults, Zambia,” Emerging Infectious Diseases, vol. 15, no. 5, pp. 749–755, 2009.
[3]
S. C. Piscitelli and K. D. Gallicano, “Interactions among drugs for HIV and opportunistic infections,” The New England Journal of Medicine, vol. 344, no. 13, pp. 984–996, 2001.
[4]
S. Abdulla, I. Sagara, S. Borrmann et al., “Efficacy and safety of artemether-lumefantrine dispersible tablets compared with crushed commercial tablets in African infants and children with uncomplicated malaria: a randomised, single-blind, multicentre trial,” The Lancet, vol. 372, no. 9652, pp. 1819–1827, 2008.
[5]
S. Abdulla and I. Sagara, “Dispersible formulation of artemether/lumefantrine: specifically developed for infants and young children,” Malaria Journal, vol. 8, supplement 1, article S7, 2009.
[6]
A. A. Omari, C. Gamble, and P. Garner, “Artemether-lumefantrine (four-dose regimen) for treating uncomplicated falciparum malaria,” Cochrane Database of Systematic Reviews, no. 2, p. CD005965, 2006.
[7]
A. A. Omari, C. Gamble, and P. Garner, “Artemether-lumefantrine (six-dose regimen) for treating uncomplicated falciparum malaria,” Cochrane Database of Systematic Reviews, no. 4, p. CD005564, 2005.
[8]
N. J. White, M. Van Vugt, and F. Ezzet, “Clinical pharmacokinetics and pharmacodynamics of artemether-lumefantrine,” Clinical Pharmacokinetics, vol. 37, no. 2, pp. 105–125, 1999.
[9]
F. Ezzet, M. Van Vugt, F. Nosten, S. Looareesuwan, and N. J. White, “Pharmacokinetics and pharmacodynamics of lumefantrine (benflumetol) in acute falciparum malaria,” Antimicrobial Agents and Chemotherapy, vol. 44, no. 3, pp. 697–704, 2000.
[10]
N. J. White, M. Van Vugt, and F. Ezzet, “Clinical pharmacokinetics and pharmacodynamics of artemether-lumefantrine,” Clinical Pharmacokinetics, vol. 37, no. 2, pp. 105–125, 1999.
[11]
Z. G. Premji, S. Abdulla, B. Ogutu et al., “The content of African diets is adequate to achieve optimal efficacy with fixed-dose artemether-lumefantrine: a review of the evidence,” Malaria Journal, vol. 7, article 244, 2008.
[12]
F. Ezzet, R. Mull, and J. Karbwang, “Population pharmacokinetics and therapeutic response of CGP 56697 (artemether + benflumetol) in malaria patients,” British Journal of Clinical Pharmacology, vol. 46, no. 6, pp. 553–561, 1998.
[13]
M. Makanga and S. Krudsood, “The clinical efficacy of artemether/lumefantrine (Coartem？),” Malaria Journal, vol. 8, no. 1, article S5, 2009.
[14]
M. van Vugt, P. Wilairatana, B. Gemperli et al., “Efficacy of six doses of artemether-lumefantrine (benflumetol) in multidrug-resistant Plasmodium falciparum malaria,” American Journal of Tropical Medicine and Hygiene, vol. 60, no. 6, pp. 936–942, 1999.
[15]
M. Van Vugt, S. Looareesuwan, P. Wilairatana et al., “Artemether-lumefantrine for the treatment of multidrug-resistant falciparum malaria,” Transactions of the Royal Society of Tropical Medicine and Hygiene, vol. 94, no. 5, pp. 545–548, 2000.
[16]
G. Lefèvre, S. Looareesuwan, S. Treeprasertsuk et al., “A clinical and pharmacokinetic trial of six doses of artemether-lumefantrine for multidrug-resistant Plasmodium falciparum malaria in Thailand,” American Journal of Tropical Medicine and Hygiene, vol. 64, no. 5-6, pp. 247–256, 2001.
[17]
C. Hatz, J. Soto, H. D. Nothdurft et al., “Treatment of acute uncomplicated falciparum malaria with artemether-lumefantrine in non-immune populations: a safety, efficacy, and pharmacokinetic study,” American Journal of Tropical Medicine and Hygiene, vol. 78, no. 2, pp. 241–247, 2008.
[18]
A. Yeka, G. Dorsey, M. R. Kamya et al., “Artemether-lumefantrine versus dihydroartemisinin-piperaquine for treating uncomplicated malaria: a randomized trial to guide policy in Uganda,” PLoS ONE, vol. 3, no. 6, article e2390, 2008.
[19]
M. R. Kamya, A. Yeka, H. Bukirwa et al., “Artemether-lumefantrine versus dihydroartemisinin-piperaquine for treatment of malaria: a randomized trial,” PLoS Clinical Trials, vol. 2, no. 5, article e20, 2007.
[20]
A. M. Kabanywanyi, A. Mwita, D. Sumari, R. Mandike, K. Mugittu, and S. Abdulla, “Efficacy and safety of artemisinin-based antimalarial in the treatment of uncomplicated malaria in children in southern Tanzania,” Malaria Journal, vol. 6, Article ID 146, 2007.
[21]
H. Bukirwa, Y. Adoke, M. R. Kamya, et al., “Artemisinin combination therapies for treatment of uncomplicated malaria in Uganda,” Plos Clinical Trials, vol. 1, no. 1, article e7, 2006.
[22]
J. P. Van Geertruyden, M. Mulenga, L. Mwananyanda et al., “HIV-1 immune suppression and antimalarial treatment outcome in Zambian adults with uncomplicated malaria,” Journal of Infectious Diseases, vol. 194, no. 7, pp. 917–925, 2006.
[23]
C. Falade, M. Makanga, Z. Premji, C. E. Ortmann, M. Stockmeyer, and P. Ibarra de Palacios, “Efficacy and safety of artemether-lumefantrine (Coartem？) tablets (six-dose regimen) in African infants and children with acute, uncomplicated falciparum malaria,” Transactions of the Royal Society of Tropical Medicine and Hygiene, vol. 99, no. 6, pp. 459–467, 2005.
[24]
Advisory Committee Briefing Book, “Coartem？ (artemether/lumefantrine) tablets for the treatment of malaria in patients with acute, uncomplicated infections due to Plasmodium falciparum or mixed infections including P.falciparum,” http://www.fda.gov/ohrms/dockets/ac/08/briefing/2008-4398b1-02-Novartis.pdf, 2008.
[25]
C. Falade and C. Manyando, “Safety profile of Coartem？: the evidence base,” Malaria Journal, vol. 8, supplement 1, article S6, 2009.
[26]
J. Golenser, J. H. Waknine, M. Krugliak, N. H. Hunt, and G. E. Grau, “Current perspectives on the mechanism of action of artemisinins,” International Journal for Parasitology, vol. 36, no. 14, pp. 1427–1441, 2006.
[27]
F. T. Aweeka and P. I. German, “Clinical pharmacology of artemisinin-based combination therapies,” Clinical Pharmacokinetics, vol. 47, no. 2, pp. 91–102, 2008.
[28]
S. Khoo, D. Back, and P. Winstanley, “The potential for interactions between antimalarial and antiretroviral drugs,” AIDS, vol. 19, no. 10, pp. 995–1005, 2005.
[29]
N. J. White, “Preventing antimalarial drug resistance through combinations,” Drug Resistance Updates, vol. 1, no. 1, pp. 3–9, 1998.
[30]
A. Djimdé and G. Lefèvre, “Understanding the pharmacokinetics of Coartem？,” Malaria Journal, vol. 8, supplement 1, article S4, 2009.
[31]
G. Kokwaro, L. Mwai, and A. Nzila, “Artemether/lumefantrine in the treatment of uncomplicated falciparum malaria,” Expert Opinion on Pharmacotherapy, vol. 8, no. 1, pp. 75–94, 2007.
[32]
M. A. Travassos and M. K. Laufer, “Resistance to antimalarial drugs: molecular, pharmacologic, and clinical considerations,” Pediatric Research, vol. 65, no. 5, pp. 64R–70R, 2009.
[33]
C. Hoffmann, J. K. Rockstroh, and B. S. Kamps, HIV Medicine, Flying, Paris, Farnce, 2005.
[34]
A. Tseng and R. D. MacArthur, “Profile of etravirine for the treatment of HIV infection,” Therapeutics and Clinical Risk Management, vol. 6, no. 1, pp. 49–58, 2010.
[35]
D. Podzamczer and E. Fumero, “The role of nevirapine in the treatment of HIV-1 disease,” Expert Opinion on Pharmacotherapy, vol. 2, no. 12, pp. 2065–2078, 2001.
[36]
D. Back, S. Gibbons, and S. Khoo, “Pharmacokinetic drug interactions with nevirapine,” Journal of Acquired Immune Deficiency Syndromes, vol. 34, supplement 1, pp. S8–S14, 2003.
[37]
M. Colafigli, S. Di Giambenedetto, L. Bracciale et al., “Long-term follow-up of nevirapine-treated patients in a single-centre cohort,” HIV Medicine, vol. 10, no. 8, pp. 461–469, 2009.
[38]
A. Rivero, J. A. Mira, and J. A. Pineda, “Liver toxicity induced by non-nucleoside reverse transcriptase inhibitors,” Journal of Antimicrobial Chemotherapy, vol. 59, no. 3, pp. 342–346, 2007.
[39]
N. Y. Rakhmanina and J. N. van den Anker, “Efavirenz in the therapy of HIV infection,” Expert Opinion on Drug Metabolism and Toxicology, vol. 6, no. 1, pp. 95–103, 2010.
[40]
S. M. E. Vrouenraets, F. W. N. M. Wit, J. van Tongeren, and J. M. A. Lange, “Efavirenz: a review,” Expert Opinion on Pharmacotherapy, vol. 8, no. 6, pp. 851–871, 2007.
[41]
G. O. Adjei, K. Kristensen, B. Q. Goka et al., “Effect of concomitant artesunate administration and cytochrome P4502C8 polymorphisms on the pharmacokinetics of amodiaquine in Ghanaian children with uncomplicated malaria,” Antimicrobial Agents and Chemotherapy, vol. 52, no. 12, pp. 4400–4406, 2008.
[42]
C. Hoffmann, J. K. Rockstroh, and B. S. Kamps, HIV Medicine, Flying, Paris, France, 2006.
[43]
A. H. Corbett, M. L. Lim, and A. D. M. Kashuba, “Kaletra (lopinavir/ritonavir),” Annals of Pharmacotherapy, vol. 36, no. 7-8, pp. 1193–1203, 2002.
[44]
G. N. Kumar, V. K. Jayanti, M. K. Johnson et al., “Metabolism and disposition of the HIV-1 protease inhibitor lopinavir (ABT-378) given in combination with ritonavir in rats, dogs, and humans,” Pharmaceutical Research, vol. 21, no. 9, pp. 1622–1630, 2004.
[45]
P. German, S. Parikh, J. Lawrence et al., “Lopinavir/ritonavir affects pharmacokinetic exposure of artemether/lumefantrine in HIV-uninfected healthy volunteers,” Journal of Acquired Immune Deficiency Syndromes, vol. 51, no. 4, pp. 424–429, 2009.
[46]
K. Tamara, K. Mauff, P. Smith, et al., “Nevirapine increases lumefantrine exposure in HIV-infected patients,” in Proceedings of the Conference on Retroviruses and Opportunistic Infections, San Francisco, Calif, USA, 2010.
[47]
J. G. Kublin, P. Patnaik, C. S. Jere et al., “Effect of Plasmodium falciparum malaria on concentration of HIV-1-RNA in the blood of adults in rural Malawi: a prospective cohort study,” The Lancet, vol. 365, no. 9455, pp. 233–240, 2005.
