Depletion of mitochondrial DNA in liver under antiretroviral therapy with didanosine, stavudine, or zalcitabine

Abstract

A ntiretroviral therapy (ART) has significantly decreased the HIV-associated morbidity and mortality in industrialized countries. 1 ART usually consists of a combination of two nucleoside analogue reverse transcriptase inhibitors (NRTIs) with either protease inhibitors (PIs) or a nonnucleoside reverse transcriptase inhibitor (NNRTI), or of three NRTIs. 2 With prolonged exposure to antiretroviral drugs, clinicians became aware of long-term side effects of individual ART components. Many adverse effects of the NRTI class of anti-HIV drugs are now related to the fact that NRTIs undergo intracellular triphosphorylation, then inhibit the replication of mitochondrial DNA (mtDNA) by interacting with gamma-polymerase. 3 In vitro studies point toward differences between the potencies of the individual NRTIs in depleting mtDNA, with the socalled "D drugs" zalcitabine (ddC), didanosine (ddI), and stavudine (d4T) being relatively strong inhibitors of polymerase-gamma compared with the other currently licensed nucleoside analogues (so-called "non-D drugs"). 4,5 Studies performed in vitro and in animals suggest that depletion of mtDNA may represent an underlying mechanism of NRTI-related hepatic side effects in HIV patients. [5][6][7] Cell models and animal data, however, have limitations in predicting clinical toxicities, partly because Abbreviations: ART, antiretroviral therapy; NRTI, nucleoside analogue reverse transcriptase inhibitor; PI, protease inhibitor; NNRTI, nonnucleoside reverse transcriptase inhibitor; mtDNA, mitochondrial DNA; ddC, zalcitabine; ddI, didanosine; d4T, stavudine; HCV, hepatitis C virus; nDNA, nuclear DNA; ULN, upper limit of normal; ALT, alanine aminotranferase. From

Alteration of cytochrome oxidase subunit I labeling is associated with severe mitochondriopathy in NRTI-related hepatotoxicity in HIV patients

“…Thus, Vittecoq et al 29 have reported a dissociation between mitochondrial evaluation in muscular biopsies and in peripheral leukocytes. Interestingly, Walker et al 30 reported a profound liver mtDNA depletion in patients treated with ddC and ddI, both highly toxic NRTI in vitro. mtDNA was also decreased in patients with elevated lactates.…”

Hepatic steatosis in patients coinfected with human immunodeficiency virus/hepatitis C virus: A meta-analysis of the risk factors

“…Protease inhibitors (PI) and nucleoside reverse transcriptase inhibitors (NRTI) have been related to insulin resistance 14 and lipodystrophy 15 ; NRTI may cause mitochondrial dysfunction with subsequent direct hepatotoxic effects. 16 Moreover, HIV infection itself may facilitate DM by way of tumor necrosis factor-a stimulation and mitochondria damage. 13 Also, other coexistent morbidities such as alcohol consumption or HCV infection may enhance steatogenesis.…”

Quantitative and qualitative mtDNA-lesions with mitochondrial dysfunction in multiple organs after HAART-associated fatal lactacidosis

“…Lactic acidosis is a life-threatening complication of HAART with abrupt onset and uncharacteristic symptoms. ddI and d4T are strong inhibitors of polymerase-gamma which induces mtDNA depletion in adipose tissue and liver [1]. Respiratory chain dysfunction promotes liberation of reactive oxygen species at the respiratory chain, which can attack the respiratory chain itself or induce mitochondrial mutations, leading to mtDNA deletions.…”

“…MtDNA levels were profoundly depleted: liver 7%, kidney 20%, SM 28%, HM 72%. MtDNA of HM and SM were analysed for large scale deletions (8 HM/3 SM) [1]. Sequencing confirmed the DNA fragments to be mitochondrial.…”

“…Post-mortem, mtDNA copy numbers of the patient's liver, skeletal muscle (SM), heart (HM) and kidney were measured by PCR and compared with nine control autopsies [1]. MtDNA levels were profoundly depleted: liver 7%, kidney 20%, SM 28%, HM 72%.…”