Impact of antiretroviral treatment on 13C-methionine metabolism as a marker of hepatic mitochondrial function: a longitudinal study

Abstract

ObjectivesUncontrolled viral replication and antiretroviral treatment (ART) may independently contribute to hepatic mitochondrial toxicity. The present study was designed to explore the longitudinal effects of treatment modifications on hepatic mitochondrial function by means of noninvasive 13 C-methionine breath test (MeBT) diagnostics. MethodsA total of 113 HIV-infected patients underwent two consecutive MeBTs over an interval of 11.8 AE 3.5 months. Forty-nine patients remained on stable ART or no therapy; 28 participants switched ART; 27 patients (re)initiated ART, and nine individuals underwent a structured treatment interruption (STI) of ART between MeBTs 1 and 2. Breath test results were expressed as cumulative percentage dose of 13 CO 2 recovered after 1.5 h test time (cPDR 1.5h ). ResultsInitiation of ART in treatment-naïve individuals and patients on STI was associated with a significant improvement of hepatic mitochondrial function (Po0.05). Cessation of ART or a prolonged delay in initiating therapy in treatment-naïve patients in turn led to a significant decline of 13 C-exhalation compared with baseline (Po0.05). A marked increase in 13 C-exhalation was observed in individuals who switched from stavudine or ddI to tenofovir or abacavir ( 1 170%; Po0.001), while no differences between MeBTs 1 and 2 were found in individuals on ART who had remained on stable regimens or in those who changed a protease inhibitor (PI) or nonnucleoside reverse transcriptase inhibitor (NNRTI) component. ConclusionThe present data suggest that hepatic mitochondrial function in HIV disease is a dynamic process with a high regenerative capacity and highlight the pathogenic relevance of HIV replication. Our findings suggest that modern ART per se does not negatively impact hepatic mitochondrial function. Keywords:13 C-methionine breath test, drug toxicity, HIV, mitochondrial toxicity IntroductionIncreasingly, deaths among HIV-infected persons are caused by hepatic complications [1,2]. Indeed, the majority of liver-related morbidity within the D:A:D cohort has been attributed to viral hepatitis coinfection. In the next few decades, a shift of morbidity to metabolic liver diseases is likely, analogous to the rising prevalence of the metabolic syndrome within the HIV-negative population [3]. The putative pathogenic role of antiretroviral therapy (ART) in this context is contested. Although the introduction of combination ART (cART) has reduced overall hepatic morbidity in both HIV-monoinfected and HIV/hepatitis C virus (HCV)-coinfected individuals, data on the long-term hepatotoxic effects of ART are absent. Two recently published cross-sectional trials showed a prevalence of DOI: 10.1111/j.1468-1293.2010.00847.x HIV Medicine (2011 r 2010 British HIV Association 40 nonalcoholic fatty liver disease in HIV-monoinfected patients of about 30%, which seems to be higher than calculated for the age-adjusted HIV-negative population [4,5]. Mitochondrial toxicity plays a major role in the pathogenesis of fatty liver disease irrespective...

Hepatic mitochondrial dysfunction in manifest and premanifest Huntington disease

“…Thus, MeBT might not only indicate HD progression but also an improved outcome after a potential disease-modifying therapy such as that shown for HIV. 5 …”

“…It is thought that MeBT exclusively measures hepatic mitochondrial function. 4,5 We can exclude an effect of medication on the liver.…”

“…2 Methyl-13 C-methionine breath test (MeBT) is established for noninvasive, easy to perform, and inexpensive quantification of the oxidative capacity of liver mitochondria. [3][4][5] METHODS Twenty-one patients with manifest HD, 30 premanifest HD (preHD) CAG repeat expansion mutation carriers, and 36 healthy controls were recruited. Participants with concurrent liver diseases were excluded.…”

“…6,7 MeBT was performed after an overnight fasting as established earlier. 5 Results were expressed as d 13 C/ 12 C isotope ratio over baseline, as percentage dose of 13 C recovery over time for each time interval and cumulative percentage dose of 13 C recovery (cPDR) every 10 minutes for 90 minutes (cPDR90).…”

Liver function assessment with three13C breath tests by two-point measurements

“…Several studies focusing on mitochondria indicated the usefulness of the α-ketoisocaproate breath test [32][33][34][35][36][37][38] and methionine breath test (MethioBT) [39][40][41][42][43][44][45][46][47][48][49][50]. In particular, one study found l-[1-13 C]methionine to be more useful than [methyl-13 C]-methionine for assessing the mitochondrial function [43].…”