Correspondence
Mitochondrial DNA and Nucleoside Toxicity
N Engl J Med 2002; 347:216-218July 18, 2002
- Article
To the Editor:
Côté et al. (March 14 issue)1 propose that the mitochondrial DNA level in patients infected with the human immunodeficiency virus (HIV) be measured as a marker of nucleoside toxicity. The fact that nucleoside analogues can cause a depletion of mitochondrial DNA is well established.2 In HIV-infected patients, an association between drug toxicity and mitochondrial DNA depletion has been demonstrated in skeletal muscle and liver tissue.3 Côté et al. report that in eight HIV-positive patients toxic effects of nucleoside analogues were late events and suggest that the decline in the mitochondrial DNA level preceded symptomatic hyperlactatemia. The authors studied three groups — HIV-negative controls, untreated HIV-positive patients, and HIV-positive patients treated with nucleoside analogues who had symptomatic hyperlactatemia — and conclude that a quantitative mitochondrial DNA assay could be used to predict and to monitor toxic effects of nucleoside analogues. However, since it is not possible to predict such toxic effects clinically, the eight patients studied must be part of a large cohort of patients receiving the drugs. Before claiming that measurement of the mitochondrial DNA level is of interest, the authors should perform such measurements in treated patients with evidence of toxic effects and treated patients without such evidence. Since depletion of mitochondrial DNA has been reported in the muscle in asymptomatic patients treated with zidovudine,4 we believe that the clinical usefulness of the proposed marker remains unclear. The data that are available so far do not suggest that the value of the marker surpasses that which has already been demonstrated for the ratio of blood lactate to pyruvate — a more sensitive tool than the evaluation of lactate alone in the detection of zidovudine-induced myopathy.5
5 ReferencesPatrick Chariot, M.D.
Nacer Bourokba, M.D.
Hôpital Raymond Poincaré, 92380 Garches, France
patrick.chariot@rpc. ap-hop-paris. fr François Brivet, M.D.
Hôpital Antoine Béclère, 92141 Clamart, France1
Cote HCF ,Brumme ZL ,Craib KJP , et al. Changes in mitochondrial DNA as a marker of nucleoside toxicity in HIV-infected patients. N Engl J Med 2002;346:811-820
Full Text | Web of Science | Medline2
Chen C-H ,Vazquez-Padua M ,Cheng Y-C . Effects of anti-human immunodeficiency virus analogs on mitochondrial DNA and its implication for delayed toxicity. Mol Pharmacol 1991;39:625-628
Web of Science | Medline3
Chariot P ,Drogou I ,de Lacroix-Szmania I , et al. Zidovudine-induced mitochondrial disorder with massive liver steatosis, myopathy, lactic acidosis, and mitochondrial DNA depletion. J Hepatol 1999;30:156-160
CrossRef | Web of Science | Medline4
Casademont J ,Barrientos A ,Grau JM , et al. The effect of zidovudine on skeletal muscle mtDNA in HIV-1 infected patients with mild or no muscle dysfunction. Brain 1996;119:1357-1364
CrossRef | Web of Science | Medline5
Chariot P ,Monnet I ,Mouchet M , et al. Determination of the blood lactate:pyruvate ratio as a noninvasive test for the diagnosis of zidovudine myopathy. Arthritis Rheum 1994;37:583-586
CrossRef | Web of Science | Medline
To the Editor:
Côté and colleagues report that eight HIV-infected patients receiving antiretroviral therapy with symptomatic hyperlactatemia had significantly lower ratios of mitochondrial to nuclear DNA than did controls who were not receiving antiretroviral therapy. They suggest that this ratio may be useful “to monitor and evaluate mitochondrial toxicity among HIV-infected patients receiving antiretroviral therapy.” Although these findings are promising, they are limited by the choice of control group; a better comparison group would seem to be other HIV-infected patients receiving antiretroviral therapy who did not have hyperlactatemia. The question still remains whether a reduction in the ratio of mitochondrial to nuclear DNA is a marker of mitochondrial toxic effects and the development of hyperlactatemia or is simply associated with antiretroviral therapy, particularly stavudine (which all eight patients received).
Darius A. Rastegar, M.D.
Johns Hopkins Bayview Medical Center, Baltimore, MD 21224
drastega@jhmi.edu To the Editor:
Côté et al. provide an improved method for measuring mitochondrial DNA by the simultaneous quantification of nuclear and mitochondrial genes on lymphocytes and conclude that the mitochondrial DNA level was significantly decreased in HIV-infected patients who had hyperlactatemia. However, the depletion of mitochondrial DNA is an effect of nucleoside analogues that was recognized long ago in patients with toxic myopathy, neuropathy, or pancreatitis and even in asymptomatic persons1,2; the effect is reversed when nucleoside-analogue therapy is discontinued.3 Hyperlactatemia develops only rarely. Therefore, something more than mitochondrial DNA depletion must be involved in its development. Moreover, there was mitochondrial DNA depletion in the untreated HIV-infected patients in the study by Côté et al. Without a group of treated but asymptomatic HIV-infected patients, it is difficult to determine whether the severe mitochondrial DNA depletion in the patients with hyperlactatemia was present before the development of hyperlactatemia. Since lactate is the product of anaerobic glycosis, hyperlactatemia under normal aerobic conditions may indicate mitochondrial dysfunction. Functional studies of the mitochondrial respiratory chain could be the clue to a link between genetic and clinical findings.4
We assayed spontaneous oxygen consumption in lymphocytes from HIV-infected patients and uninfected persons and did not find significant differences (Figure 1Figure 1
Spontaneous Oxygen Consumption by Intact Lymphocytes.). Despite the mitochondrial DNA depletion demonstrated by Côté et al., our data suggest that the oxidative capacity of the mitochondrial respiratory chain is preserved in treated, asymptomatic HIV-infected patients. This does not exclude the possibility of decreased mitochondrial respiratory-chain function in tissues such as liver or skeletal muscle, which have higher metabolic rates than lymphocytes. More functional studies are warranted before we can conclude that lymphocyte mitochondrial DNA depletion is the cause of hyperlactatemia.4 ReferencesJordi Casademont, M.D.
Òscar Miró, M.D.
Francesc Cardellach, M.D.
University of Barcelona, 08036 Barcelona, Spain1
Helbert M ,Fletcher T ,Peddle B ,Harris JR ,Pinching AJ . Zidovudine-associated myopathy. Lancet 1988;2:689-690
CrossRef | Web of Science | Medline2
Casademont J ,Barrientos A ,Grau JM , et al. The effect of zidovudine on skeletal muscle mtDNA in HIV-1 infected patients with mild or no muscle dysfunction. Brain 1996;119:1357-1364
CrossRef | Web of Science | Medline3
Masanes F ,Barrientos A ,Cebrian M , et al. Clinical, histological and molecular reversibility of zidovudine myopathy. J Neurol Sci 1998;159:226-228
CrossRef | Web of Science | Medline4
Zaera MG ,Miro O ,Pedrol E , et al. Mitochondrial involvement in antiretroviral therapy-related lipodystrophy. AIDS 2001;15:1643-1651
CrossRef | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: We agree with Casademont et al. that depletion of mitochondrial DNA is a class effect of nucleoside analogues. However, our data show that there are substantial differences among these drugs in terms of their effect on the ratio of mitochondrial to nuclear DNA. As noted in Table 1 of our article, five of eight patients were able to resume successful antiretroviral therapy with nucleoside analogues, including lamivudine (in four patients), abacavir (in two patients), and zidovudine (in one patient), without significant changes in the ratio of mitochondrial to nuclear DNA, the lactate level, or most important, symptoms of mitochondrial toxic effects. There is also evidence that the assay we used shows differences in toxicity among nucleoside analogues.1 We also agree that functional mitochondrial studies would be of great interest. It is conceivable that a quantitative and a qualitative mitochondrial defect may, together or separately, contribute to the development of this nucleoside toxicity. Further work is necessary to clarify this issue.
Rastegar asks the converse question of whether the ratio of mitochondrial to nuclear DNA represents a true marker of mitochondrial toxic effects or is rather a surrogate marker for the inclusion of stavudine in the regimen. We have now studied a large group of patients treated with stavudine-based regimens. Asymptomatic persons who are receiving stavudine therapy have a normal ratio of mitochondrial to nuclear DNA even after prolonged exposure.2
With regard to the comments by Chariot et al., we wish to clarify that our report demonstrates the in vivo changes in the ratio of mitochondrial to nuclear DNA in HIV-infected patients with symptomatic hyperlactatemia. The changes in this ratio occurred before the elevation of the lactate level, so it would seem reasonable to suggest that the ratio should be further evaluated as a potential prognostic or diagnostic tool in this setting. We do not claim, at this stage, that the ratio of mitochondrial to nuclear DNA can be incorporated into the clinical monitoring of nucleoside-based antiretroviral therapy. Further studies are under way to determine the optimal clinical use of the ratio of mitochondrial to nuclear DNA. Finally, we have made no claims regarding the value of this ratio as compared with the ratio of blood lactate to pyruvate first proposed by Chariot et al. in 1994.3
3 ReferencesJulio S.G. Montaner, M.D.
Hélène C.F. Coté, Ph.D.
P. Richard Harrigan, Ph.D.
British Columbia Centre for Excellence in HIV/AIDS, Vancouver, BC V6Z 1Y6, Canada
jmontaner@hivnet.ubc. ca 1
Coté HCF, Negredo E, Ruiz L, et al. Antiretroviral regimen-dependent mitochondrial DNA depletion in clinical samples from the SWATCH trial. Presented at the 9th Conference on Retroviruses and Opportunistic Infections, Seattle, February 24–28, 2002. abstract.
2
Coté HCF, Yip B, Chan JW, et al. Preserved mitochondrial/nuclear (mt/n) DNA ratios in peripheral blood cells from HIV-infected individuals on stavudine-sparing regimens. Presented at the XIV International AIDS Conference, Barcelona, Spain, July 7–12, 2002. abstract.
3
Chariot P ,Monnet I ,Mouchet M , et al. Determination of the blood lactate:pyruvate ratio as a noninvasive test for the diagnosis of zidovudine myopathy. Arthritis Rheum 1994;37:583-586
CrossRef | Web of Science | Medline
- Citing Articles (4)
Citing Articles
1
L. Gil del Valle. 2011. Pathophysiological Implications of Altered Redox Balance in HIV/AIDS Infection: Diagnosis and Counteract Interventions. , 39-70.
CrossRef2
James J. Kohler, William Lewis. (2007) A brief overview of mechanisms of mitochondrial toxicity from NRTIs. Environmental and Molecular Mutagenesis 48:3-4, 166-172
CrossRef3
Òscar Miró, Sònia López, Esteban Martínez, Benjamín Rodríguez-Santiago, José L. Blanco, Ana Milinkovic, Jose M. Miró, Virginia Nunes, Jordi Casademont, Josep M. Gatell, Francesc Cardellach. (2003) Short Communication: Reversible Mitochondrial Respiratory Chain Impairment During Symptomatic Hyperlactatemia Associated with Antiretroviral Therapy. AIDS Research and Human Retroviruses 19:11, 1027-1032
CrossRef4
T. D. Langford, S. L. Letendre, G. J. Larrea, E. Masliah. (2003) Changing Patterns in the Neuropathogenesis of HIV During the HAART Era. Brain Pathology 13:2, 195-210
CrossRef
