Mitochondria

“NRTI[nucleoside analog, such as AZT]-exposed (HIV+/NRTI+) subjectshad an increased frequency of COX-deficient muscle fibers, reaching or exceeding levels expected in healthy elderly individuals…The severity of the COX defect was strongly predicted by cumulative lifetime NRTI exposure, rather than therapy at the time of study, implicating a persistent and cumulative mitochondrial defect…The rapid clonal expansion of somatic mtDNA mutations we observed in NRTI-treated HIV-infected patients provides a plausible mechanism for accelerated aging in treated HIV infection.”

“Antiviral drugs of the category of nucleoside reverse transcriptase inhibitors (NRTIs), largely used for the treatment of HIV infection, can have toxic effects on mitochondria…[In this study] A total of 49 previously treatment-naive patients treated for a mean of 15 months with efavirenz plus didanosine plus lamivudine (group 1), or tenofovir disoproxil fumarate plus lamivudine (group 2), or didanosine plus abacavir (group 3)…No patient showed any clinical symptom; however, the amount of mtDNA [mitochondrial DNA] in CD4+ and CD8+ T-cells was significantly lower in groups 1 and 3; similarly, the expression of different mtRNAs in both CD4+ and CD8+ T-cells showed significant differences that were dependent upon the drug used.…An efficient didanosine-containing once-daily therapy can have more mitochondrial toxicity than regimens devoid of this drug.”

“We describe a 62-year-old male who was diagnosed with HIV-1 in 2001 and died with lactic acidosis under treatment with didanosine [ddI/Videx] and stavudine [d4T/Zerit]…Lactic acidosis is a life-threatening complication of HAART. The onset is often abrupt, with uncharacteristic muscular, cardiac or hepatic symptoms. The outcome can be fatal due to liver failure and cardiac arrhythmia. Didanosine and stavudine are strong inhibitors of polymerase-gamma, which are known to induce mtDNA [mitochondrial DNA] depletion in subcutaneous adipose tissue and in liver”

“Mitochondrial toxicity induced by nucleoside reverse transcriptase inhibitors (NRTIs) has been reported to be responsible for various adverse effects…Mitochondrial DNA (mtDNA) levels were quantified longitudinally from peripheral blood mononuclear cells (PBMCs) in 31 HIV-1-infected children from Pediatric AIDS Clinical Trial Group Study 382 who were receiving HAART, including nelfinavir, efavirenz, and different NRTIs, and who had had undetectable plasma HIV-1 RNA levels for >2 years…A multivariate analysis also demonstrated that didanosine, as part of HAART, was the only NRTI associated with the change in mtDNA levels. Children receiving didanosine-containing antiretroviral regimens have the lowest mtDNA levels in PBMCs and may be at greater risk for long-term adverse effects due to mitochondrial toxicity [however, not a single child was included who was not on AIDS drugs, making meaningful comparisons impossible]”

“[This study] included 1037 HIV-uninfected children born in 1991– 2002…Possible cases with unexplained signs of MD [mitochondrial dysfunction]…were identified through retrospective review. Associations between overall in utero NRTI [nucleoside reverse transcriptase inhibitor or 'nuke'] exposure, and trimester of first in utero NRTI exposure and possible MD were estimated…there were higher odds of first in utero exposure in the third trimester to lamivudine (3TC) and to zidovudine (ZDV [AZT]) and 3TC in combination (ZDV/3TC) among cases [of MD] than noncases. When adjusted for year of birth the odds of first exposure in the third trimester to 3TC [the risk was more than 10 times higher] and ZDV/3TC [was almost 10 times higher] were significantly higher among cases than non-cases…first exposure to 3TC or ZDV/3TC in the third trimester may be associated with the occurrence of possible MD”

“The measurement of extracellular lactate concentration revealed that fluoroquinolones, macrolides, clindamycin, rifampin, tetracycline, and especially chloramphenicol and linezolid impaired mitochondrial energetics in high concentrations [these are not AIDS drugs, but some are often given to AIDS patients]”

“Despite many unresolved physiopathological questions, there are coherent experimental and clinical arguments for the existence of mitochondrial toxicity following perinatal exposure to zidovudine [AZT], alone or in combination with lamivudine [3TC]. This effect may be transitory or persistent. Although, the clinical significance of the various biological and/or histopathological mitochondrial anomalies found at birth in NA-exposed animals or children has not been formally established, the high incidence of mitochondrial neurological diseases observed in the French cohort has not been contradicted to date in other cohorts.”

“Mitochondria are energy-producing parts (the scientific term is organelles) of human cells. They perform their functions separately from the rest of the cell. Mitochondria also have their own genetic machinery or DNA that is separate from the DNA that controls the rest of the cell's function…It has been known for a long time that nucleoside analog anti-HIV drugs (NRTIs [AZT and related drugs]) can sometimes be toxic to mitochondria…When the main DNA in human cells uses the fake DNA from NRTIs when making new cells, there are special repair mechanisms that prevent damage to the cell [a highly questionable statement]. But mitochondrial DNA is simpler and doesn't have these repair mechanisms. If fake DNA from nucleoside analogs gets used when mitochondria are copying themselves, the mitochondria can get damaged. Damaged mitochondria can't supply energy to a cell properly. The cell may become dysfunctional or even die…At the current time, the best way of dealing with mitochondrial toxicity isn't clear”

“NRTI [nucleoside reverse transcriptase inhibitor, such as AZT] mitochondrial toxicity limits treatment of HIV infection. NRTI-sparing regimens may obviate some mitochondrial manifestations, but also are limited. Studies here establish that ZDV [AZT] and d4T [Stavudine] (monotherapy, human therapeutic doses) cause mitochondrial structural and functional defects in vivo.”

“This study will examine abnormalities in mitochondria (energy-producing machinery of cells) and in genes related to mitochondria in the blood cells, muscle, and fat of HIV-positive patients who are taking nucleoside reverse transcriptase inhibitors (NRTIs) and in patients not currently taking HIV medications, and compare the results to healthy volunteers. Many patients with HIV infection take NRTIs to help control the infection. These medications may damage cell mitochondria, possibly causing side effects such as fatigue.”

“Mitochondrial toxicity…has been suggested as a possible causal mechanism for the development of a number of…treatment-related adverse events”

“Mitochondrial enzyme activity was assessed in adipocytes [fat cells] from 7 patients initiating nucleoside reverse transcriptase inhibitor (NRTI) regimens. After 6–12 months of therapy, adipocytes from six patients demonstrated cytochrome C oxidase (COX) activity reduced from baseline, correlating positively with mitochondrial DNA levels”

“Mitochondria are the key organelles in energy production in all human cells except erythrocytes. Energy, in the form of ATP, is produced through the highly efficient oxidative phosphorylation pathway. Additionally, mitochondria perform a range of other biological functions and carry a number of factors involved in cell apoptosis [cell death]…A wide range of adverse events occurring in persons with HIV infection receiving NRTI-based therapy have been suggested to be related to diminished mitochondrial function. The development programs of zidovudine, didanosine, zalcitabine, and stavudine all required dose de-escalations due to toxicities thought to be related to drug impact on mitochondria. Due to limitations in measurement technology, clinical studies of NRTI, while collecting adverse event data, have not specifically evaluated mitochondrial toxicity in a systematic way. Lactic acidosis is the event that establishes proof that clinically important mitochondria toxicity occurs in persons receiving NRTI although causation is not necessarily established by this observation…Other NRTI-associated adverse events where the weight of evidence favours mitochondrial injury include peripheral neuropathy, myopathy, and hepatic steatosis. However, multiple other etiologies for these adverse events exist and should be routinely sought in persons presenting with these effects. Other adverse effects observed during antiretroviral therapy that may represent manifestations of, or be contributed to, by mitochondrial toxicity include hypogonadism, pancreatitis, diabetes mellitus, dysphagia, nausea and vomiting, proximal renal tubular dysfunction, hair loss, dry skin, paronychia, encephalopathy and dementia, depression and psychosis, anemia, and neutropenia and peripheral fat atrophy”

“The side effects were substantial in the A/S/D [abacavir/stavudine/didanosine] arm. Nearly all of the adverse effects in the arm could be related to what is considered mitochondrial toxicity, with neuropathy and elevated lactate being most prominent.”

“An exhaustive study in a large prospective cohort with predetermined algorithm of the unexplained symptoms compatible with mitochondrial dysfunction. A total of 2644 of 4392 children were exposed to antiretrovirals…All the children with ‘established’ or ‘possible’ mitochondriopathy [mitochondrial damage] diagnosed in this study had been exposed to antiretroviral drugs. One of these children was treated with zidovudine [AZT] only during the prenatal period and received no treatment after birth…For the other children, the treatment was administered in the pre, per- and post-partum periods. It was zidovudine alone in five cases, a combination of zidovudine-lamivudine in 14 cases and another combination in one. 20 of the mothers received zidovudine by intravenous perfusion during labor.”

“NRTI [nucleoside reverse transcriptase inhibitor] treatment was associated with reduced adipocyte [fat cell] mtDNA [mitochondria] copies/cell, representing mean mtDNA depletion in NRTI treated individuals of 77.7% compared with the mean value for the HIV-infected control group…NRTI therapy is associated with mtDNA depletion and mitochondrial proliferation in adipocytes, consistent with the hypothesis that NRTI-induced mtDNA depletion contributes to the pathogenesis of subcutaneous fat wasting.”

“children of HIV+ mothers are at risk for mitochondrial damage [mitochondria are the energy regulating organelles essential to every living cell, and that have their own DNA] that is further increased in infants of mothers receiving AZT during pregnancy”

“Long-term alterations to body metabolism have become apparent with the prolonged use of antiretroviral nucleoside analogue reverse transcriptase inhibitors (NRTIs). The NRTIs differ in the mechanisms, potency and probably also tissue specificity of mitochondrial toxicity. One group of NRTIs, the so-called 'd-drugs' (zalcitabine> didanosine>stavudine) are relatively strong inhibitors of g-polymerase and thus cause a time- and dose-dependent decrease in the intracellular levels of mitochondrial DNA (mtDNA)…Drugs that contribute to mitochondrial toxicity should be avoided. Co-administration of didanosine and allopurinol is contradicated…Hydroxyurea and ribavirin also increase the active metabolite of didanosine…thus both drugs augment mitochondrial side effects…the most effective way of coping with mitochondrial toxicity is withdrawl of the NRTI that is responsible for it”

“A 2-year-old boy with AIDS, who presented with profound developmental regression despite long-standing undetectable HIV-RNA levels…was receiving zidovudine, didanosine, and nelfinavir…Extensive biochemical, histological and electron microscopic studies confirmed metabolic acidosis, organic aciduria, mitochondrial DNA depletion, and a reduction of mtDNA-encoded respiratory chain enzymes. T2-weighted magnetic resonance imaging of the brain revealed patchy foci of increased signal in the cerebral white matter Antiretroviral therapy was changed to a regimen excluding the nucleoside analogues-ritonavir, nelfinavir, and efavirenz…The patient’s motor abnormalities and global developmental status steadily improved. Repeat studies documented a normalization of mtDNA and resolution of metabolic and biochemical abnormalities. Six months after the initial magnetic resonance imaging, a repeat study demonstrated a marked improvement of the white matter lesions. Nucleoside analogue-induced mitochondrial dysfunction may be causally related to the leukoencephalopathy described by Langford et al. [1], and if so, appears to be a reversible condition if recognized early [and drugs stopped]”

“We tested the long-term mitochondrial toxicity of NRTI [Nucleoside Reverse Transcriptase Inhibitors] with respect to mtDNA [Mitochondrial DNA], mtDNA-encoded respiratory chain protein and cell function (lactate production, intracellular lipids and cell proliferation) and confirm previous findings that NRTI are able to mediate a rapid decline of mtDNA”

“Our study shows that significant mitochondrial damage [mitochondria are the energy regulating units in every living cell] is present in HIV-infected patients with severe adverse effects after long-term antiretroviral treatment…Several lines of evidence support the clinical relevance of the mitochondrial damage”

“Symptomatic hyperlactatemia [elevated lactic acid levels] was associated with marked reductions in the ratios of mitochondrial to nuclear DNA, which, during therapy, averaged 68% lower than those of non–HIV-infected controls and 43% lower than those of HIV-infected asymptomatic patients never treated with antiretroviral drugs. After the discontinuation of antiretroviral therapy, there was a statistically significant increase in the ratio of mitochondrial to nuclear DNA. In the patients followed longitudinally [for a period of time], the decline in mitochondrial DNA preceded the increase in venous lactate levels. Conclusions: Mitochondrial DNA levels are significantly decreased in patients with symptomatic, nucleoside- related hyperlactatemia, an effect that resolves on the discontinuation of therapy.”

“7 HIV patients presenting LD [Lipodystrophy, all taking antiretroviral therapy] and 5 HIV non-LD controls participated in the study…Structural muscle abnormalities, mitochondrial respiratory chain dysfunction or mtDNA deletions were detected in all HIV lipodystrophic patients. The mitochondrial abnormalities found suggest that mitochondrial dysfunction could play a role in the development of antiretroviral therapy-related lipodystrophy.”

“A decrease in mtDNA [DNA of the mitochondria; the autonomous energy regulating entities within every cell] content was found in HAART-treated HIV-infected patients with peripheral fat wasting in comparison with subjects in the control cohorts”

“Here, we postulate that the mitochondrial toxicity of the nucleoside-analogue reverse-transcriptase inhibitors plays an essential part in the development of this lipodystrophy [fat redistribution], similar to the role of mitochondrial defects in the development of multiple symmetrical lipomatosis.”