- Email: [email protected]
Itraconazole and antiretroviral therapy: strategies for empirical dosing
Correspondence
use of sitafloxacin could select strains with gyrA and parC mutations from those with parC mutations. At present, the most important action is to prevent M genitalium from evolving into strains that harbour gyrA and parC mutations and to preserve the effectiveness of the sitafloxacin regimen against M genitalium infections so that M genitalium infections do not become untreatable. Therefore, a treatment strategy for non-gonococcal urethritis that restricts the use of sitafloxacin is needed until new promising drugs become available. I declare no competing interests.
Takashi Deguchi [email protected] Department of Urology, Graduate School of Medicine, Gifu University, Gifu 501-1194, Japan 1 2
3
4
5
Jensen JS. Mycoplasma genitalium: yet another challenging STI. Lancet Infect Dis 2017; 17: 795–96. Horner PJ, Blee K, Falk L, van der Meijden W, Moi H. 2016 European guideline on the management of non-gonococcal urethritis. Int J STD AIDS 2016; 27: 928–37. Maeda S, Kubota Y, Tamaki M, et al. Association of mycoplasmas with persistent or recurrent non-gonococcal urethritis. Jpn J Sex Transm Dis 2004; 15: 139–43. Kikuchi M, Ito S, Yasuda M, et al. Remarkable increase in fluoroquinolone-resistant Mycoplasma genitalium in Japan. J Antimicrob Chemother 2014; 69: 2376–82. Deguchi T, Ito S, Yasuda M, et al. Emergence of Mycoplasma genitalium with clinically significant fluoroquinolone resistance conferred by amino acid changes both in GyrA and ParC in Japan. J Infect Chemother 2017; 23: 648–50.
Itraconazole and antiretroviral therapy: strategies for empirical dosing In their Review in, Andrew H Limper and colleagues1 highlight the importance of itraconazole for the management of HIV-associated endemic mycoses. Itraconazole is both a substrate and a potent inhibitor of cytochrome P450 3A4 (CYP3A4) and inhibits the membrane transporter P-glycoprotein, resulting in considerable drug–drug interactions with antiretrovirals.2 The reduction of itraconazole exposure 1122
when co-administered with the non-nucleotide reverse transcriptase inhibitors (NNRTIs) efavirenz and nevirapine, which are widely-used in developing countries, is particularly concerning. Limper and coworkers1 highlight this pharmacokinetic interaction, but they seem to suggest that because itraconazole and hydroxyitraconazole—its major metabolite—have similar antifungal activity, the clinical significance might be minimal.1 We caution against this interpretation and the authors’ implicit recommendation of standard itraconazole dosing with NNRTIs. First, efavirenz administration reduces both itraconazole and hydroxyitraconazole concentrations to a similar extent in healthy volunteers. 3 Second, two published case reports 4,5 have described favourable pharmacokinetic and clinical outcomes using higher itraconazole doses in patients treated with efavirenz. In one report, 5 therapeutic itraconazole concentrations and reduction of histoplasma urinary antigen were achieved only upon switching efavirenz to a protease inhibitor, even after doubling the daily dose of itraconazole. This response is most likely due to CYP3A4 inhibition by protease inhibitors resulting in increased plasma itraconazole exposures, which has led to the practice of reducing itraconazole doses for patients on protease inhibitorbased antiretrovirals.6,7 In addition to drug–drug interactions, bioavailability of itraconazole capsules—the only formulation available in most developing countries—is poor (and further diminished in advanced HIV) and is influenced by food and gastric acidity.2 This pharmacokinetic variability favours therapeutic drug monitoring to optimise itraconazole dosing. However, pharmacokinetic targets for itraconazole efficacy have not been defined in HIV-associated endemic mycoses, and therapeutic
drug monitoring for itraconazole is not widely available. Because of the inability to predict itraconazole exposures when coadministered with NNRTIs, and the potentially severe consequences of underdosing in HIV-associated endemic mycoses, we suggest that their combined use should be avoided without therapeutic drug monitoring for itraconazole. The integrase inhibitor dolutegravir, which does not affect CYP3A4, is now recommended as a component of first-line antiretrovirals; although co-administration has not been studied, this could represent an alternative for patients who require itraconazole. Otherwise, we recommend using protease inhibitorbased antiretrovirals with dose reduction of itraconazole to 200 mg daily. Our experiences of managing HIV-associated endemic mycoses in South Africa suggest acceptable outcomes can be safely attained with this approach,7 but pharmacokinetic and pharmacodynamic studies of itraconazole in people with HIV on antiretrovirals are needed to inform optimum dosing in this population. We declare no competing interests.
*Ilan S Schwartz, Sean Wasserman [email protected] Division of Infectious Diseases, Departments of Medicine and Medical Microbiology, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R3E0J9, Canada (ISS); Global Health Institute, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium (ISS); and Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine, Department of Medicine, University of Cape Town, Cape Town, South Africa (SW) 1 2
3
Limper AH, Adenis A, Le T, Harrison TS. Fungal infections in HIV/AIDS. Lancet Infect Dis 2017; 17: e334–43. Lestner J, Hope WW. Itraconazole: an update on pharmacology and clinical use for treatment of invasive and allergic fungal infections. Expert Opin Drug Metab Toxicol 2013; 9: 911–26. Kaul S, Ji P, Dudley J, et al. Pharmacokinetic interaction between efavirenz and diltiazem or itraconazole after multiple-dose administration in adult healthy subjects. 14th Conference on Retroviruses and Opportunistic Infections; Los Angeles, CA; Feb 25–28, 2007. 561.
www.thelancet.com/infection Vol 17 November 2017
Correspondence
4
5
6
7
Huet E, Hadji C, Hulin A, Botterel F, Bretagne S, Lévy Y. Therapeutic monitoring is necessary for the association itraconazole and efavirenz in a patient with AIDS and disseminated histoplasmosis. AIDS 2008; 22: 1885–86. Koo HL, Hamill RJ, Andrade RA. Drug-drug interaction between itraconazole and efavirenz in a patient with AIDS and disseminated histoplasmosis. Clin Infect Dis 2007; 45: e77–79. Crommentuyn KML, Mulder JW, Sparidans RW, Huitema ADR, Schellens JHM, Beijnen JH. Drug-drug interaction between itraconazole and the antiretroviral drug lopinavir/ritonavir in an HIV-1-infected patient with disseminated histoplasmosis. Clin Infect Dis 2004; 38: e73–75. Schwartz IS, Kenyon C, Lehloenya R, et al. AIDS-related endemic mycoses in Western Cape, South Africa and clinical mimics: a cross-sectional study of adults with advanced HIV and recent-onset, widespread skin lesions. Open Forum Infect Dis 2017; published online Aug 25: DOI:10.1093/ofid/ofx186.
Author’s reply
We thank Ilan S Schwartz and Sean Wasserman for their interest in our paper on the management of HIV-associated endemic mycoses. 1 Schwartz and Wasserman rightly express concern regarding the known drug–drug interaction between itraconazole and nonnucleotide reverse transcriptase inhibitors (NNRTIs) efavirenz and nevirapine, which results in considerable reductions in plasma itraconazole concentrations following co-administration. NNRTIs are often included in standardised first-line antiretroviral therapy regimens in developing countries, and co-administration with itraconazole is commonly required during the consolidation and maintenance of therapy for histoplasmosis in Latin America and talaromycosis in Asia. Despite the pharmacokinetic interaction, treatment relapse is uncommon in patients who begin antiretroviral therapy with efavirenz or nevirapine. No disease relapse was observed in two talaromycosis cohorts in Taiwan (n=9)2 and Thailand (n=33)3 or in a histoplasmosis cohort in the USA (n=32). 4 NNRTI therapy was safely initiated in these cohorts, and itraconazole treatment was safely
terminated in patients who had a successful immune response to antiretroviral therapy.2–4 The pharmacokinetic interaction between itraconazole and NNRTIs has been documented in human volunteers and in histoplasmosis case reports. In the study by Huet and colleagues5—cited by Schwartz and Wasserman—efavirenz was associated with a 20–50% reduction in plasma itraconazole concentrations, but was also associated with substantial increases in the concentration of its active metabolite hydroxyitraconazole, which has similar antifungal activity. In the study by Koo and coworkers,6 itraconazole concentrations were inversely correlated with urine histoplasma antigen levels in a patient who was clinically cured. None of the studies showed a correlation between low blood itraconazole concentrations and clinical response or relapse. Well designed pharmacokinetic and pharmacodynamics studies are required to evaluate the association between itraconazole exposure and response in the treatment of endemic mycoses to assess the therapeutic range of itraconazole, and to further investigate interactions between itraconazole and antiretrovirals. Of note, such analyses are in progress for a trial in Vietnam 7 comparing itraconazole and amphotericin B as an initial treatment for HIV-associated talaromycosis. All patients with HIV started treatment with efavirenz and received the standard maintenance dose of itraconazole of 200 mg daily. The overall relapse rate was low at 4·0%, and 1·5% in patients who received a course of amphotericin B before itraconazole.7 We do agree that therapeutic drug monitoring for itraconazole 8 and protease and integrase inhibitor-based antiretroviral therapy are appropriate strategies. However, at present we would maintain that the evidence is insufficient to change the current practice for consolidation and maintenance itraconazole dosing
www.thelancet.com/infection Vol 17 November 2017
for HIV-related endemic mycoses in resource-limited settings where protease inhibitors and intergrase inhibitors are not feasible options for first-line antiretroviral therapy and therapeutic drug monitoring is not available. Routinely increasing itraconazole dose results in a high pill burden, high costs, and potential harm in some cases. More clinical evidence must be generated to guide the management of endemic mycoses in HIV infection. AA delivered a talk for Janssen Pharmaceutical and received diagnostic tests for research from the Centers for Disease Control and Prevention Mycotic Diseases Branch and Immuno-Mycologics. TH reports grants from Gilead Sciences, personal fees from Pfizer and Viamet, and non-financial support from Immuno-Mycologics, outside the submitted work. TL and AL declare no competing interests.
Thuy Le, Antoine Adenis, Andrew Limper, *Thomas Harrison [email protected] Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, Ho Chi Minh City, Vietnam (TL); Centre d’Investigation Clinique Antilles Guyane, Inserm CIC1424, Centre Hospitalier de Cayenne, Cayenne, France (AA); Mayo Clinic College of Medicine, Rochester, MN, USA (AL); Institute of Infection and Immunity, St George’s, University of London, London SW17 ORE, UK (TH) 1 2
3
4
5
6
7
Limper AH, Adenis A, Le T, Harrison TS. Fungal infections in HIV/AIDS. Lancet Infect Dis 2017; 17: e334–43. Hung CC, Chen MY, Hsieh SM, Sheng WH, Hsiao CF, Chang SC. Discontinuation of secondary prophylaxis for penicilliosis marneffei in AIDS patients responding to highly active antiretroviral therapy. AIDS 2002; 16: 672–73. Chaiwarith R, Charoenyos N, Sirisanthana T, Supparatpinyo K. Discontinuation of secondary prophylaxis against penicilliosis marneffei in AIDS patients after HAART. AIDS 2007; 21: 365–67. Goldman M, Zackin R, Fichtenbaum CJ, et al. Safety of discontinuation of maintenance therapy for disseminated histoplasmosis after immunologic response to antiretroviral therapy. Clin Infect Dis 2004; 38: 1485–89. Huet E, Hadji C, Hulin A, Botterel F, Bretagne S, Lévy Y. Therapeutic monitoring is necessary for the association itraconazole and efavirenz in a patient with AIDS and disseminated histoplasmosis. AIDS 2008; 22: 1885–86. Koo HL, Hamill RJ, Andrade RA. Drug-drug interaction between itraconazole and efavirenz in a patient with AIDS and disseminated histoplasmosis. Clin Infect Dis 2007; 45: e77–79. Le T, Kinh NV, Cuc NTK, et al. A trial of itraconazole or amphotericin B for HIV-associated talaromycosis. N Engl J Med 2017; 376: 2329–40.
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use of sitafloxacin could select strains with gyrA and parC mutations from those with parC mutations. At present, the most important action is to prevent M genitalium from evolving into strains that harbour gyrA and parC mutations and to preserve the effectiveness of the sitafloxacin regimen against M genitalium infections so that M genitalium infections do not become untreatable. Therefore, a treatment strategy for non-gonococcal urethritis that restricts the use of sitafloxacin is needed until new promising drugs become available. I declare no competing interests.
Takashi Deguchi [email protected] Department of Urology, Graduate School of Medicine, Gifu University, Gifu 501-1194, Japan 1 2
3
4
5
Jensen JS. Mycoplasma genitalium: yet another challenging STI. Lancet Infect Dis 2017; 17: 795–96. Horner PJ, Blee K, Falk L, van der Meijden W, Moi H. 2016 European guideline on the management of non-gonococcal urethritis. Int J STD AIDS 2016; 27: 928–37. Maeda S, Kubota Y, Tamaki M, et al. Association of mycoplasmas with persistent or recurrent non-gonococcal urethritis. Jpn J Sex Transm Dis 2004; 15: 139–43. Kikuchi M, Ito S, Yasuda M, et al. Remarkable increase in fluoroquinolone-resistant Mycoplasma genitalium in Japan. J Antimicrob Chemother 2014; 69: 2376–82. Deguchi T, Ito S, Yasuda M, et al. Emergence of Mycoplasma genitalium with clinically significant fluoroquinolone resistance conferred by amino acid changes both in GyrA and ParC in Japan. J Infect Chemother 2017; 23: 648–50.
Itraconazole and antiretroviral therapy: strategies for empirical dosing In their Review in, Andrew H Limper and colleagues1 highlight the importance of itraconazole for the management of HIV-associated endemic mycoses. Itraconazole is both a substrate and a potent inhibitor of cytochrome P450 3A4 (CYP3A4) and inhibits the membrane transporter P-glycoprotein, resulting in considerable drug–drug interactions with antiretrovirals.2 The reduction of itraconazole exposure 1122
when co-administered with the non-nucleotide reverse transcriptase inhibitors (NNRTIs) efavirenz and nevirapine, which are widely-used in developing countries, is particularly concerning. Limper and coworkers1 highlight this pharmacokinetic interaction, but they seem to suggest that because itraconazole and hydroxyitraconazole—its major metabolite—have similar antifungal activity, the clinical significance might be minimal.1 We caution against this interpretation and the authors’ implicit recommendation of standard itraconazole dosing with NNRTIs. First, efavirenz administration reduces both itraconazole and hydroxyitraconazole concentrations to a similar extent in healthy volunteers. 3 Second, two published case reports 4,5 have described favourable pharmacokinetic and clinical outcomes using higher itraconazole doses in patients treated with efavirenz. In one report, 5 therapeutic itraconazole concentrations and reduction of histoplasma urinary antigen were achieved only upon switching efavirenz to a protease inhibitor, even after doubling the daily dose of itraconazole. This response is most likely due to CYP3A4 inhibition by protease inhibitors resulting in increased plasma itraconazole exposures, which has led to the practice of reducing itraconazole doses for patients on protease inhibitorbased antiretrovirals.6,7 In addition to drug–drug interactions, bioavailability of itraconazole capsules—the only formulation available in most developing countries—is poor (and further diminished in advanced HIV) and is influenced by food and gastric acidity.2 This pharmacokinetic variability favours therapeutic drug monitoring to optimise itraconazole dosing. However, pharmacokinetic targets for itraconazole efficacy have not been defined in HIV-associated endemic mycoses, and therapeutic
drug monitoring for itraconazole is not widely available. Because of the inability to predict itraconazole exposures when coadministered with NNRTIs, and the potentially severe consequences of underdosing in HIV-associated endemic mycoses, we suggest that their combined use should be avoided without therapeutic drug monitoring for itraconazole. The integrase inhibitor dolutegravir, which does not affect CYP3A4, is now recommended as a component of first-line antiretrovirals; although co-administration has not been studied, this could represent an alternative for patients who require itraconazole. Otherwise, we recommend using protease inhibitorbased antiretrovirals with dose reduction of itraconazole to 200 mg daily. Our experiences of managing HIV-associated endemic mycoses in South Africa suggest acceptable outcomes can be safely attained with this approach,7 but pharmacokinetic and pharmacodynamic studies of itraconazole in people with HIV on antiretrovirals are needed to inform optimum dosing in this population. We declare no competing interests.
*Ilan S Schwartz, Sean Wasserman [email protected] Division of Infectious Diseases, Departments of Medicine and Medical Microbiology, Max Rady College of Medicine, University of Manitoba, Winnipeg, MB R3E0J9, Canada (ISS); Global Health Institute, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium (ISS); and Clinical Infectious Diseases Research Initiative, Institute of Infectious Disease and Molecular Medicine, Department of Medicine, University of Cape Town, Cape Town, South Africa (SW) 1 2
3
Limper AH, Adenis A, Le T, Harrison TS. Fungal infections in HIV/AIDS. Lancet Infect Dis 2017; 17: e334–43. Lestner J, Hope WW. Itraconazole: an update on pharmacology and clinical use for treatment of invasive and allergic fungal infections. Expert Opin Drug Metab Toxicol 2013; 9: 911–26. Kaul S, Ji P, Dudley J, et al. Pharmacokinetic interaction between efavirenz and diltiazem or itraconazole after multiple-dose administration in adult healthy subjects. 14th Conference on Retroviruses and Opportunistic Infections; Los Angeles, CA; Feb 25–28, 2007. 561.
www.thelancet.com/infection Vol 17 November 2017
Correspondence
4
5
6
7
Huet E, Hadji C, Hulin A, Botterel F, Bretagne S, Lévy Y. Therapeutic monitoring is necessary for the association itraconazole and efavirenz in a patient with AIDS and disseminated histoplasmosis. AIDS 2008; 22: 1885–86. Koo HL, Hamill RJ, Andrade RA. Drug-drug interaction between itraconazole and efavirenz in a patient with AIDS and disseminated histoplasmosis. Clin Infect Dis 2007; 45: e77–79. Crommentuyn KML, Mulder JW, Sparidans RW, Huitema ADR, Schellens JHM, Beijnen JH. Drug-drug interaction between itraconazole and the antiretroviral drug lopinavir/ritonavir in an HIV-1-infected patient with disseminated histoplasmosis. Clin Infect Dis 2004; 38: e73–75. Schwartz IS, Kenyon C, Lehloenya R, et al. AIDS-related endemic mycoses in Western Cape, South Africa and clinical mimics: a cross-sectional study of adults with advanced HIV and recent-onset, widespread skin lesions. Open Forum Infect Dis 2017; published online Aug 25: DOI:10.1093/ofid/ofx186.
Author’s reply
We thank Ilan S Schwartz and Sean Wasserman for their interest in our paper on the management of HIV-associated endemic mycoses. 1 Schwartz and Wasserman rightly express concern regarding the known drug–drug interaction between itraconazole and nonnucleotide reverse transcriptase inhibitors (NNRTIs) efavirenz and nevirapine, which results in considerable reductions in plasma itraconazole concentrations following co-administration. NNRTIs are often included in standardised first-line antiretroviral therapy regimens in developing countries, and co-administration with itraconazole is commonly required during the consolidation and maintenance of therapy for histoplasmosis in Latin America and talaromycosis in Asia. Despite the pharmacokinetic interaction, treatment relapse is uncommon in patients who begin antiretroviral therapy with efavirenz or nevirapine. No disease relapse was observed in two talaromycosis cohorts in Taiwan (n=9)2 and Thailand (n=33)3 or in a histoplasmosis cohort in the USA (n=32). 4 NNRTI therapy was safely initiated in these cohorts, and itraconazole treatment was safely
terminated in patients who had a successful immune response to antiretroviral therapy.2–4 The pharmacokinetic interaction between itraconazole and NNRTIs has been documented in human volunteers and in histoplasmosis case reports. In the study by Huet and colleagues5—cited by Schwartz and Wasserman—efavirenz was associated with a 20–50% reduction in plasma itraconazole concentrations, but was also associated with substantial increases in the concentration of its active metabolite hydroxyitraconazole, which has similar antifungal activity. In the study by Koo and coworkers,6 itraconazole concentrations were inversely correlated with urine histoplasma antigen levels in a patient who was clinically cured. None of the studies showed a correlation between low blood itraconazole concentrations and clinical response or relapse. Well designed pharmacokinetic and pharmacodynamics studies are required to evaluate the association between itraconazole exposure and response in the treatment of endemic mycoses to assess the therapeutic range of itraconazole, and to further investigate interactions between itraconazole and antiretrovirals. Of note, such analyses are in progress for a trial in Vietnam 7 comparing itraconazole and amphotericin B as an initial treatment for HIV-associated talaromycosis. All patients with HIV started treatment with efavirenz and received the standard maintenance dose of itraconazole of 200 mg daily. The overall relapse rate was low at 4·0%, and 1·5% in patients who received a course of amphotericin B before itraconazole.7 We do agree that therapeutic drug monitoring for itraconazole 8 and protease and integrase inhibitor-based antiretroviral therapy are appropriate strategies. However, at present we would maintain that the evidence is insufficient to change the current practice for consolidation and maintenance itraconazole dosing
www.thelancet.com/infection Vol 17 November 2017
for HIV-related endemic mycoses in resource-limited settings where protease inhibitors and intergrase inhibitors are not feasible options for first-line antiretroviral therapy and therapeutic drug monitoring is not available. Routinely increasing itraconazole dose results in a high pill burden, high costs, and potential harm in some cases. More clinical evidence must be generated to guide the management of endemic mycoses in HIV infection. AA delivered a talk for Janssen Pharmaceutical and received diagnostic tests for research from the Centers for Disease Control and Prevention Mycotic Diseases Branch and Immuno-Mycologics. TH reports grants from Gilead Sciences, personal fees from Pfizer and Viamet, and non-financial support from Immuno-Mycologics, outside the submitted work. TL and AL declare no competing interests.
Thuy Le, Antoine Adenis, Andrew Limper, *Thomas Harrison [email protected] Oxford University Clinical Research Unit, Wellcome Trust Major Overseas Programme, Ho Chi Minh City, Vietnam (TL); Centre d’Investigation Clinique Antilles Guyane, Inserm CIC1424, Centre Hospitalier de Cayenne, Cayenne, France (AA); Mayo Clinic College of Medicine, Rochester, MN, USA (AL); Institute of Infection and Immunity, St George’s, University of London, London SW17 ORE, UK (TH) 1 2
3
4
5
6
7
Limper AH, Adenis A, Le T, Harrison TS. Fungal infections in HIV/AIDS. Lancet Infect Dis 2017; 17: e334–43. Hung CC, Chen MY, Hsieh SM, Sheng WH, Hsiao CF, Chang SC. Discontinuation of secondary prophylaxis for penicilliosis marneffei in AIDS patients responding to highly active antiretroviral therapy. AIDS 2002; 16: 672–73. Chaiwarith R, Charoenyos N, Sirisanthana T, Supparatpinyo K. Discontinuation of secondary prophylaxis against penicilliosis marneffei in AIDS patients after HAART. AIDS 2007; 21: 365–67. Goldman M, Zackin R, Fichtenbaum CJ, et al. Safety of discontinuation of maintenance therapy for disseminated histoplasmosis after immunologic response to antiretroviral therapy. Clin Infect Dis 2004; 38: 1485–89. Huet E, Hadji C, Hulin A, Botterel F, Bretagne S, Lévy Y. Therapeutic monitoring is necessary for the association itraconazole and efavirenz in a patient with AIDS and disseminated histoplasmosis. AIDS 2008; 22: 1885–86. Koo HL, Hamill RJ, Andrade RA. Drug-drug interaction between itraconazole and efavirenz in a patient with AIDS and disseminated histoplasmosis. Clin Infect Dis 2007; 45: e77–79. Le T, Kinh NV, Cuc NTK, et al. A trial of itraconazole or amphotericin B for HIV-associated talaromycosis. N Engl J Med 2017; 376: 2329–40.
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