Depleted skeletal muscle mitochondrial DNA, hyperlactatemia, and decreased oxidative capacity in HIV‐infected patients on highly active antiretroviral therapy

Abstract

The nucleoside reverse transcriptase inhibitors (NRTIs), especially stavudine, may deplete mitochondrial (mt) DNA in human tissues by inhibiting the mitochondrial polymerase gamma, a setting, which is associated with hyperlactatemia. The aim of the present study was to examine whether hyperlactatemia is associated with depletion of skeletal muscle (sm)-mtDNA and decreased oxidative capacity in HIV-infected patients on NRTI based highly active antiretroviral therapy (HAART) and whether HIV infection itself is associated with sm-mtDNA depletion. Sm-mtDNA was determined in 42 HIV-infected patients (35 patients on HAART including at least one NRTI (HIV-NRTI) and 7 patients never treated with antiretroviral drugs (NAIVE)) and 14 healthy controls. Whole body oxidative capacity (DeltaGOX) was estimated in HIV-infected patients by indirect calorimetry. Hyperlactatemia (>or=2.0 mM) was detected in six HIV-NRTI, who all used Stavudine (P < 0.01), displayed depleted sm-mtDNA (P < 0.02) and decreased DeltaGOX (P < 0.01) compared with normolactatemic HIV-NRTI (n = 29). NAIVE displayed decreased sm-mtDNA (P < 0.05), increased HIV-RNA (P < 0.01) and increased plasma TNF-alpha (P < 0.05) compared to all HIV-NRTI (n = 35), in turn displaying decreased sm-mtDNA (P < 0.01) compared to healthy controls. Thus, hyperlactatemia in HIV-NRTI may be associated with pronounced depletion of sm-mtDNA, decreased oxidative capacity and current stavudine therapy. Further, HIV may deplete sm-mtDNA of NAIVE, which in part could be mediated through an enhanced pro-inflammatory response.

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

“…Although most of these studies focussed on fat distribution and adipocyte function, it is reasonable to assume that mitochondrial liver function would also be improved by switching to a less toxic NRTI backbone. One year after ddrug switching, 13 C-exhalation had recovered and almost…”

“…MeBT measurements were performed at the time of diagnosis and also 12, 24 and 48 weeks later. 13 C-exhalation was dramatically decreased at the diagnosis of acute HCV infection compared with baseline (cPDR 1.5h 1.572 and 1.146 compared with 4.813 and 6.985, respectively, at baseline). Both patients showed spontaneous viral elimination within 12 weeks without specific treatment.…”

“…Briefly, each patient received 2 mg/kg body weight [methyl- C isotope ratio of the breath samples were analysed by nondispersive isotope selective infrared spectroscopy (IRIS; Wagner Analysen Technik, Bremen, Germany). To measure the proportion of metabolized substrate, the results were expressed as cumulative percentage dose of 13 C recovered (cPDR 1.5h ) after a test time of 90 min. Additional biochemical evaluations included HIV viral load, CD4 cell count, alanine aminotransferase (ALT) levels and serological testing for HCV or hepatitis B virus (HBV) coinfection.…”

“…Mitochondrial toxicity plays a major role in the pathogenesis of fatty liver disease irrespective of the specific trigger, and subclinical changes in mitochondrial integrity may precede the common phenotype of steatosis/ steatohepatitis [6,7]. The 13 C-methionine breath test (MeBT) is a noninvasive diagnostic instrument for assessment of hepatic mitochondrial function in vivo [8]. Our previously published study examined metabolically well-characterized HIV-infected patients receiving different treatment modalities [9].…”

“…For the first time we have demonstrated a significant negative association between HIV viral load and breath test performance in naïve patients as well as a time-dependent decrease in 13 C-exhalation within a group of ARTexperienced patients with STI at baseline and follow-up. It is widely accepted that HIV itself can have toxic effects on mitochondrial function in lymphocytes and probably other tissues by creating a proinflammatory/proapoptotic environment, although the precise mechanisms underpinning this are not clear [11][12][13][14].Most of the patients with d4T-or ddI-containing regimens at baseline breath test measurement (MeBT1) later switched therapies for less toxic NRTIs (tenofovir or abacavir) for the purpose of preventing or reversing lipoatrophy. Several recent studies have confirmed the metabolically beneficial effects of d4T switching [15][16][17].…”