Antimalarials and antiretrovirals are antagonistic

At the 15th International Workshop on Clinical Pharmacology of HIV on May 19, 2014 at the University of Nebraska, it was shown that nevirapine co-prescribed with artemether-lumefantrine may reduce the artemether concentration in blood by 70%. Fehintola FA, Huanf L, Scarsi KK, Darin KM, Parikj S. Reduced artemether-lumefantrine exposure in HIV-infected Nigerian subjects on nevirapine-based antiretroviral therapy. 15th International Workshop on Clinical Pharmacology of HIV&Hepatitis Therapy Fehintola FA, Scarsi KK, Ma Q, Parikh S, Morse GD, Taiwo B, Akinola IT, Adewole IF, Lindegardh N, Phakderaj A, Ojengbede O, Murphy RL, Akinyinka OO, Aweeka FT. Nevirapine-Based Antiretroviral Therapy Impacts Artesunate and Dihydroartemisinin Disposition in HIV-Infected Nigerian Adults. AIDS Res Treat. 2012;2012:703604. doi: 10.1155/2012/703604. This is in line with similar results obtained in South Africa. Kredo T, Mauff K, Van der Walt JS, Wiesner L, Maartens G, Cohen K, Smith P, Barnes KI. Interaction between artemether-lumefantrine and nevirapine-based antiretroviral therapy in HIV-1-infected patients. Antimicrob Agents Chemother. 2011 Dec;55(12):5616-23. doi: 10.1128/AAC.05265-11. Artemether and nevirapine are metabolized by the cytochrome P450 3A4 enzyme system, which nevirapine induces. They conclude that studies investigating the interaction of nevirapine and artemether-lumefantrine in HIV-infected patients with malaria are urgently needed. Hoglund RM, Byakika-Kibwika P, Lamorde M, Merry C, Ashton M, Hanpithakpong W, Day NP, White NJ, Äbelö A, Tarning J. Artemether-lumefantrine co-administration with antiretrovirals: population pharmacokinetics and dosing implications. Br J Clin Pharmacol. 2015 Apr;79(4):636-49. doi: 10.1111/bcp.12529. Dihydroartemisinin (DHA)-piperaquine is promising for malaria chemoprevention in pregnancy. A recent study found that exposure to DHA and piperaquine were lower among pregnant women and particularly in women on efavirenz, up to 38%., Kajubi R, Huang L, Jagannathan P, Chamankhah N. Antiretroviral therapy with efavirenz accentuates pregnancy-associated reduction of dihydroartemisinin-piperaquine exposure during malaria chemoprevention. Clin Pharmacol Ther. 2017 Feb 10. doi: 10.1002/cpt.664. . At the Makerere University in Uganda it also was found that co-administration of coartem (AL) with efavirenz resulted in reduction in artemether, DHA, lumefantrine exposure. Pauline Byakika-Kibwika, Mohammed Lamorde, Jonathan Mayito, Lillian Nabukeera, Rhoda Namakula, Harriet Mayanja-Kizza, Elly Katabira, Muhammad Ntale, Nadine Pakker, Mairin Ryan, Warunee Hanpithakpong, Joel Tarning, Niklas Lindegardh, Peter J. de Vries, Saye Khoo, David Back and Concepta Merry. Significant pharmacokinetic interactions between artemether/lumefantrine and efavirenz or nevirapine in HIV-infected Ugandan adults. J Antimicrob Chemother 2012, 67, 2213-2221). Parikh S, Kajubi R, Huang L, Ssebuliba J, , Kakuru A, Achan J, Mwebaza N, Aweeka FT. Antiretroviral Choice for HIV Impacts Antimalarial Exposure and Treatment Outcomes in Ugandan Children. Clin Infect Dis. 2016 Aug 1;63(3):414-22. doi: 10.1093/cid/ciw291 Antagonism between antimalarial drugs and tuberculosis treatment also has been documented Intake of Rifampicin, a drug against tuberculosis, simultaneously with Coartem lowers the AUC of artemether by 83% and lumefantrine by 84%. Similar antagonisms have been noticed for Efavirenz and Neviparine which are often used indiscriminitaly agains HIV and tuberculosis. TheMakerere University found that co-administration of Coartem (AL) with Efavirenz resulted in reduction in artemether, DHA, lumefantrine exposure. Lamorde M, Byakika-Kibwika P, Mayito J, Nabukeera L, Ryan M, Hanpithakpong W, Lefèvre G, Back DJ, Khoo SH, Merry C. Lower artemether, dihydroartemisinin and lumefantrine concentrations during rifampicin-based tuberculosis treatment. AIDS. 2013 Mar 27;27(6):961-5. doi: 10.1097/QAD.0b013e32835cae3b. Synergy between amodiaquine and antiretrovirals enhances hepatotoxicity. P German, B Greenhouse, F Aweeka, Hepatotoxicity due to a drug interaction between amodiaquine plus artesunate and Efavirenz. Clinical Infectuous Diseases 2007, 44, 889-891. The antagonistic effect has not only been seen for artemisinin derivatives but also for quinine pharmacokinetics in pregnant women with Malaria-HIV Co-Infection A Uriel, P Lewthwaite. Malaria therapy in HIV: drug interactions between nevirapine and quinine. Int J STD AIDS 2011 Dec;22(12):768 Kayentao K, Guirou EA, Doumbo OK, Venkatesan M, Plowe CV, Parsons TL, Hendrix CW, Nyunt MM. Preliminary study of quinine pharmacokinetics in pregnant women with malaria-HIV co-infection. Am J Trop Med Hyg. 2014 Mar;90(3):530-4. doi: 10.4269/ajtmh.13-0655 Intermittent preventive treatment with mefloquine is associated with an increased risk of mother to child transmission of HIV. Kayentao K, Guirou EA, Doumbo OK, Venkatesan M, Plowe CV, Parsons TL, Hendrix CW, Nyunt MM. Preliminary study of quinine pharmacokinetics in pregnant women with malaria-HIV co-infection. Am J Trop Med Hyg. 2014 Mar;90(3):530-4. doi: 10.4269/ajtmh.13-0655. Epub 2014 Jan 13. Raquel González, Ghyslain Mombo-Ngoma , Smaïla Ouédraogo , Mwaka A. Kakolwa , Manfred Accrombessi,Salim Abdulla, Valérie Briand,Intermittent Preventive Treatment of Malaria in Pregnancy with Mefloquine in HIV-Negative Women: A Multicentre Randomized Controlled Trial. PLOS 2014 doi.org/10.1371/journal.pmed.1001733 Also for malarone frequently taken by European travellers, lower atovaquone/proguanil concentrations have been found in patients taking efavirenz, lopinavir/ritonavir or atazanavir/ritonavir. van Luin M, Van der Ende ME, Richter C, Visser M, Faraj D, Van der Ven A, Gelinck L, Kroon F, Wit FW, Van Schaik RH, Kuks PF, Burger DM. Lower atovaquone/proguanil concentrations in patients taking efavirenz, lopinavir/ritonavir or atazanavir/ritonavir. AIDS. 2010 May 15;24(8):1223-6. doi: 10.1097/QAD.0b013e3283389129. Natureeba P, Ades V, Luwedde F, Mwesigwa J, Plenty A, Okong P, Charlebois ED, Clark TD, Nzarubara B, Achan J, Kamya MR, Cohan D, Dorsey G. Lopinavir/ritonavir-based antiretroviral treatment (ART) versus efavirenz-based ART for the prevention of malaria among HIV-infected pregnant women. J Infect Dis. 2014 Dec 15;210(12):1938-45. doi: 10.1093/infdis/jiu346. A good summary of these recent studies is given in a review paper from 2014. Van Geertruyden JP. Interactions between malaria and human immunodeficiency virus anno 2014. Clin Microbiol Infect. 2014 Apr;20(4):278-85. doi: 10.1111/1469-0691.12597. Possible pathophysiological, clinical and epidemiological interactions between virus HIV and tropical pathogens, especially malaria parasites, constitute a concern in tropical areas. Two decades of research have shown that HIV-related immunosuppression is correlated with increased malaria infection, burden, and treatment failure, and with complicated malaria, irrespective of immune status. The recent role out of antiretroviral therapies and new antimalarials, such as artemisinin combination therapies, raise additional concerns regarding possible synergistic and antagonistic effects on efficacy and toxicity. Already in 2006 it was claimed that it was urgent to study drug interactions betweeen antimalarials and antiretrovirals, especially during pregnancy. But over the last decade millions of antimalarial and antiretroviral drugs for billions of dollars have been sold on the African market. Nosten F, McGready R, d'Alessandro U, Bonell A, Verhoeff F, Menendez C, Mutabingwa T, Brabin B. Antimalarial drugs in pregnancy: a review. Curr Drug Saf. 2006 Jan;1(1):1-15.