10th International Workshop on Adverse Drug Reactions and Lipodystrophy in HIV 6-8 November 2008, London, UK

MITOCHONDRIAL DAMAGE INDUCED BY THE HIGHLY ACTIVE ANTIRETROVIRAL TREATMENT IN NON-HIV-INFECTED PATIENTS

Antiviral Therapy 2008; 13(Suppl. 4):A69 (abstract no. P-63)

G Garrabou¹, E Pedrol², E Deig², C Morén¹, M Nicolàs¹, P Garcia², I Vidal², F Cardellach¹ and Ò Miró^1
1Mitochondrial Research Laboratory, IDIBAPS, University of Barcelona, Hospital Clinic of Barcelona and CIBER de Enfermedades Raras, Barcelona, Spain; ²Foundation Hospital, Asylum of Granollers, Granollers, Spain

INTRODUCTION: Antiretroviral (ARV) toxicity, especially of nucleoside analogues, together with HIV infection have both been demonstrated to induce mitochondrial DNA (mtDNA) depletion and mitochondrial dysfunction. The contribution of each mechanism (either HIV or ARV) to the observed mitochondrial damage present in HIV-infected patients on highly active ARV treatment (HAART) is difficult to elucidate. HIV-induced mitochondrial lesions have been studied in HIV-infected but not in non-HAARTtreated individuals; however, ARV-related mitochondrial damage has been poorly explored in non-infected patients. The aim of the present study is to assess in vivo mitochondrial toxicity of HAART without HIV infection effects.

METHODS: We included six healthy patients under 1 month of prophylactic ARV treatment consisting of FTC+TDF+SQVr to prevent HIV infection after risk exposition. All of them remained uninfected 6 months after HAART withdrawal. Mitochondrial studies were performed in mononuclear cells before and after the ARV treatment to assess mtDNA content using real-time PCR and mitochondrial function through the spectrophotometric measurement of the enzymatic activity of both mitochondrial respiratory chain (MRC) complex II (nonmitochondrial encoded) and complex IV (partially encoded in the mitochondrial genome). Statistic analyses compared mitochondrial results before and after ARV therapy using the t-test for repeated measures.

RESULTS: Mitochondrial DNA content was reduced by 20% in the studied patients undergoing ARV treatment (2.17 ±2.52 to 1.73 ±1.01, P=0.5). MRC complex IV enzymatic activity was reduced by 24% in these patients after HAART (55.2 ±15.9 to 42 ±6.3, P=0.1), although MRC complex II enzymatic activity remained unchanged after therapy discontinuation and with respect to baseline (26.5 ±10.5 to 27.8 ±9.4, P=0.98).

CONCLUSIONS: In non-HIV-infected patients, 1 month of ARV treatment induced mitochondrial damage, even when considering HAART consisting of FTC+TDF+SQV/r with a theoretical low mitochondrial toxic profile. Mitochondrial changes consisted of slight mtDNA depletion and moderated mtDNA-encoded MRC complex IV dysfunction, although none of these changes were statistically significant. These findings validate HAART-induced mitochondrial toxicity, even in the absence of HIV infection. Further studies should be performed to assess mitochondrial toxicity of different HAART schedules in non-infected individuals to elucidate toxic effects of ARVs without HIV or previous ARV interference.

This study was supported by: Fundació la Marató de TV3 020210 and 020631, FIPSE 36612/06, FIS 40381/04 and 41239/04, Suports a Grups de Recerca de la Generalitat de Catalunya 2005/SGR/0300 and CIBER de Enfermedades Raras (initiative of the ISCIII).

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2008-11-06
P-63

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