HHS Public Access Author manuscript Author Manuscript
J Acquir Immune Defic Syndr. Author manuscript; available in PMC 2017 January 01. Published in final edited form as: J Acquir Immune Defic Syndr. 2016 January 1; 71(1): 65–69. doi:10.1097/QAI.0000000000000812.
Effects of tenofovir and amphotericin B deoxycholate coadministration on kidney function in patients treated for cryptococcal meningitis
Author Manuscript
Reuben Kiggundu, MBChB1,*, Bozena M Morawski, MPH2,*, Nathan C Bahr, MD2, Joshua Rhein, MD1,2, Abdu K Musubire, MMed1, Darlisha A Williams, MPH1,2, Mahsa Abassi, DO, MPH2, Henry W Nabeta, MBChB1, Kathy Huppler Hullsiek, PhD2, David B Meya, MMed1,2,3, and David R Boulware, MD, MPH2 on behalf of the ASTRO-CM Team 1Infectious
Disease Institute, Makerere University, Kampala, Uganda 2University of Minnesota, Minneapolis, MN, USA 3School of Medicine, College of Health Sciences, Makerere University
Abstract
Author Manuscript
The effect of tenofovir and amphotericin co-administration on kidney function is poorly characterized. We measured creatinine during induction therapy and at 4-weeks post-diagnosis in Ugandans undergoing cryptococcal meningitis therapy, and classified as not receiving antiretroviral therapy (ART), receiving non-tenofovir ART, or receiving tenofovir-based ART. Longitudinal creatinine changes and Grade 2-4 creatinine adverse events were evaluated across groups. Creatinine concentrations were similar across ART groups. At 4 weeks post-diagnosis, creatinine was 0.25mg/dL higher than at diagnosis, but similar across groups. Adverse event incidence was also similar across ART groups. Tenofovir and amphotericin co-administration did not increase the risk of kidney dysfunction.
Keywords cryptococcal meningitis; amphotericin B deoxycholate; tenofovir; renal toxicity
Introduction Author Manuscript
Cryptococcal meningitis accounts for >30% of adult meningitis in sub-Saharan Africa.1-3 Amphotericin B deoxycholate (amphotericin), in combination with other antifungal medications, remains the mainstay of cryptococcosis treatment despite its toxicity.4-6 Amphotericin-related nephrotoxicity occurs from direct damage to renal tubules and constriction of the renal vasculature.7 Acute kidney injury has been estimated to occur in
Corresponding Author: Reuben Kiggundu, MBChB, Infectious Disease Institute, Makerere University, Mulago Hospital Complex. P.O. Box 22418 Kampala, Uganda, [email protected]. *These authors equally contributed to this manuscript ASTRO-CM Team members: Lillian Tugume, Jonathan Dyal, Julie M Neborak, Alexa M King, Nathan Yueh, Jane Francis Ndyetukira, Cynthia Ahimbisibwe, Florence Kugonza, Alice Namudde, Alisat Sadiq, Tadeo Kiiza Kandole, Elissa K Butler, Julian Kaboggoza, Eva Laker, Andrew Akampuira, Tony Luggya, Paul R Bohjanen, Andrew Kambugu. Conflicts: There are no conflicts of interest.
Kiggundu et al.
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≥30% of patients receiving amphotericin.7-10 Furthermore, concurrent administration of amphotericin with other non-tenofovir nephrotoxic agents, e.g. aminoglycosides, foscarnet, ganciclovir, has been shown to increase the risk of kidney toxicity.10-12
Author Manuscript
Given increasing access to antiretroviral therapy (ART) in sub-Saharan Africa and the relatively high prevalence of cryptococcal antigenemia,13 an increasing number of patients are receiving ART at the time of cryptococcal meningitis diagnosis. Whether amphotericinrelated nephrotoxicity is exacerbated by ART is unknown. Tenofovir disoproxil fumarate (tenofovir) is of special concern, as tenofovir can induce kidney damage via proximal tubular cell dysfunction.14-18 Although tenofovir is part of first line ART worldwide,19,20 safety data guiding amphotericin and tenofovir co-administration are limited. The single in vitro and organ model study examining kidney interactions between amphotericin and tenofovir concluded that drug-drug interactions are unlikely at standard clinical doses of amphotericin and tenofovir.21 However, to guide clinical care, there is a need to characterize the effects of concurrent administration of amphotericin and tenofovir. We examined kidney function and the risk of kidney toxicity associated with amphotericin and tenofovir coadministration during cryptococcal meningitis therapy.
Materials and methods
Author Manuscript
From August 2013 through August 2014, 173 adults were enrolled in an open label pilot phase of the Adjunctive Sertraline for the Treatment of HIV-Associated Cryptococcal Meningitis trial (ClinicalTrials.gov: NCT01802385) at Mulago Hospital in Kampala, Uganda. Inclusion criteria were: HIV infection, ≥18 years of age, positive cerebrospinal fluid (CSF) cryptococcal antigen, and written informed consent. Exclusion criteria included pregnancy, breastfeeding, jaundice, cirrhosis, and receipt of >2 days amphotericin at enrollment. The University of Minnesota and Ugandan institutional review boards approved the protocol. All participants received high dose fluconazole (800-1200 mg/day), 7-14 days of amphotericin B deoxycholate (1.0 mg/kg/day, maximum 50 mg/day), 1.0L of intravenous saline before and 1.0L after amphotericin administration, trimethoprim-sulfamethoxazole prophylaxis, and universal electrolyte supplementation per World Health Organization guidelines.22,23 The duration of amphotericin-based induction therapy, while similar for most patients, was determined by the combination of 1) initial CSF fungal burden, 2) CSF fungal clearance, and 3) renal function (as evaluated by creatinine and potassium concentrations). Decisions to either administer
J Acquir Immune Defic Syndr. Author manuscript; available in PMC 2017 January 01. Published in final edited form as: J Acquir Immune Defic Syndr. 2016 January 1; 71(1): 65–69. doi:10.1097/QAI.0000000000000812.
Effects of tenofovir and amphotericin B deoxycholate coadministration on kidney function in patients treated for cryptococcal meningitis
Author Manuscript
Reuben Kiggundu, MBChB1,*, Bozena M Morawski, MPH2,*, Nathan C Bahr, MD2, Joshua Rhein, MD1,2, Abdu K Musubire, MMed1, Darlisha A Williams, MPH1,2, Mahsa Abassi, DO, MPH2, Henry W Nabeta, MBChB1, Kathy Huppler Hullsiek, PhD2, David B Meya, MMed1,2,3, and David R Boulware, MD, MPH2 on behalf of the ASTRO-CM Team 1Infectious
Disease Institute, Makerere University, Kampala, Uganda 2University of Minnesota, Minneapolis, MN, USA 3School of Medicine, College of Health Sciences, Makerere University
Abstract
Author Manuscript
The effect of tenofovir and amphotericin co-administration on kidney function is poorly characterized. We measured creatinine during induction therapy and at 4-weeks post-diagnosis in Ugandans undergoing cryptococcal meningitis therapy, and classified as not receiving antiretroviral therapy (ART), receiving non-tenofovir ART, or receiving tenofovir-based ART. Longitudinal creatinine changes and Grade 2-4 creatinine adverse events were evaluated across groups. Creatinine concentrations were similar across ART groups. At 4 weeks post-diagnosis, creatinine was 0.25mg/dL higher than at diagnosis, but similar across groups. Adverse event incidence was also similar across ART groups. Tenofovir and amphotericin co-administration did not increase the risk of kidney dysfunction.
Keywords cryptococcal meningitis; amphotericin B deoxycholate; tenofovir; renal toxicity
Introduction Author Manuscript
Cryptococcal meningitis accounts for >30% of adult meningitis in sub-Saharan Africa.1-3 Amphotericin B deoxycholate (amphotericin), in combination with other antifungal medications, remains the mainstay of cryptococcosis treatment despite its toxicity.4-6 Amphotericin-related nephrotoxicity occurs from direct damage to renal tubules and constriction of the renal vasculature.7 Acute kidney injury has been estimated to occur in
Corresponding Author: Reuben Kiggundu, MBChB, Infectious Disease Institute, Makerere University, Mulago Hospital Complex. P.O. Box 22418 Kampala, Uganda, [email protected]. *These authors equally contributed to this manuscript ASTRO-CM Team members: Lillian Tugume, Jonathan Dyal, Julie M Neborak, Alexa M King, Nathan Yueh, Jane Francis Ndyetukira, Cynthia Ahimbisibwe, Florence Kugonza, Alice Namudde, Alisat Sadiq, Tadeo Kiiza Kandole, Elissa K Butler, Julian Kaboggoza, Eva Laker, Andrew Akampuira, Tony Luggya, Paul R Bohjanen, Andrew Kambugu. Conflicts: There are no conflicts of interest.
Kiggundu et al.
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Author Manuscript
≥30% of patients receiving amphotericin.7-10 Furthermore, concurrent administration of amphotericin with other non-tenofovir nephrotoxic agents, e.g. aminoglycosides, foscarnet, ganciclovir, has been shown to increase the risk of kidney toxicity.10-12
Author Manuscript
Given increasing access to antiretroviral therapy (ART) in sub-Saharan Africa and the relatively high prevalence of cryptococcal antigenemia,13 an increasing number of patients are receiving ART at the time of cryptococcal meningitis diagnosis. Whether amphotericinrelated nephrotoxicity is exacerbated by ART is unknown. Tenofovir disoproxil fumarate (tenofovir) is of special concern, as tenofovir can induce kidney damage via proximal tubular cell dysfunction.14-18 Although tenofovir is part of first line ART worldwide,19,20 safety data guiding amphotericin and tenofovir co-administration are limited. The single in vitro and organ model study examining kidney interactions between amphotericin and tenofovir concluded that drug-drug interactions are unlikely at standard clinical doses of amphotericin and tenofovir.21 However, to guide clinical care, there is a need to characterize the effects of concurrent administration of amphotericin and tenofovir. We examined kidney function and the risk of kidney toxicity associated with amphotericin and tenofovir coadministration during cryptococcal meningitis therapy.
Materials and methods
Author Manuscript
From August 2013 through August 2014, 173 adults were enrolled in an open label pilot phase of the Adjunctive Sertraline for the Treatment of HIV-Associated Cryptococcal Meningitis trial (ClinicalTrials.gov: NCT01802385) at Mulago Hospital in Kampala, Uganda. Inclusion criteria were: HIV infection, ≥18 years of age, positive cerebrospinal fluid (CSF) cryptococcal antigen, and written informed consent. Exclusion criteria included pregnancy, breastfeeding, jaundice, cirrhosis, and receipt of >2 days amphotericin at enrollment. The University of Minnesota and Ugandan institutional review boards approved the protocol. All participants received high dose fluconazole (800-1200 mg/day), 7-14 days of amphotericin B deoxycholate (1.0 mg/kg/day, maximum 50 mg/day), 1.0L of intravenous saline before and 1.0L after amphotericin administration, trimethoprim-sulfamethoxazole prophylaxis, and universal electrolyte supplementation per World Health Organization guidelines.22,23 The duration of amphotericin-based induction therapy, while similar for most patients, was determined by the combination of 1) initial CSF fungal burden, 2) CSF fungal clearance, and 3) renal function (as evaluated by creatinine and potassium concentrations). Decisions to either administer
